CDCl3) δ 169.9 (d, 3 *J*PC = 7.3 Hz, Cquat), 162.2 (dd, 1 *J*FC = 246.1 Hz, 4 *J*PC = 2.9 Hz, Cquat), 143.6 (Cquat), 139.0 (d, 4 *J*PC = 1.4 Hz, Cquat), 137.1 (t, 2 *J*PC = 3 *J*FC = 7.1 Hz, Cquat), 129.4 (dd, 3 *J*FC = 8.1 Hz, 4 *J*PC = 2.8 Hz, CH), 129.2 (CH), 127.5 (CH), 123.7 (dd, 3 *J*PC = 5.2 Hz, 4 *J*FC = 2.9 Hz, CH), 116.0 (dd, 2 *J*FC = 24.1 Hz, 3 *J*PC = 4.9 Hz, CH), 115.3 (dd, 2 *J*FC = 21.0 Hz, 5 *J*PC = 3.0 Hz, CH), 61.9 (dd, 1 *J*PC = 153.6 Hz, 4 *J*FC = 1.9 Hz, Cquat), 61.1 (CH2), 54.6 (d, 2 *J*PC = 7.4 Hz, CH3), 54.3 (d, 2 *J*PC = 7.6 Hz, CH3), 38.1 (CH2), 21.6 (CH3), 14.2 (CH3). 31P NMR (120 MHz, CDCl3): δ 21.7. 19F NMR (282 MHz, CDCl3) δ −113.0. FTIR (neat) νmax 3281 (N-H), 1732 (C=O), 1333 (O=S=O), 1244 (P=O), 1157 (O=S=O). HRMS (ESI-TOF) *m/z*: calcd for C20H26FNO7PS [M + H]+ 474.1146, found 474.1155.

*Ethyl 3-(dimethoxyphosphoryl)-3-(2-fluorophenyl)-3-((4-methylphenyl)sulfonamido)propanoate***(7l)**. The general procedure was followed, starting form imine **3l** (417 mg, 1 mmol) to afford 440 mg (93%) of **7l** as a pale yellow solid. M.p. (CH2Cl2-hexanes). 140–141 ◦C. 1H NMR (400 MHz, CDCl3) δ 7.58 (d, 3 *J*HH = 8.3 Hz, 2H), 7.48–7.40 (m, 1H), 7.23–7.19 (m, 1H), 7.16 (d, 3 *J*HH = 8.3 Hz, 2H), 6.99 (m, 1H), 6.80 (dd, 3 *J*FH = 12.8 Hz, 3 *J*HH = 8.1 Hz, 1H), 6.21 (d, 3 *J*PH = 13.1 Hz, 1H), 4.17–4.01 (m, 2H), 3.63 (d, 3 *J*PH = 10.8 Hz, 3H), 3.60 (m, 2H), 3.54 (d, 3 *J*PH = 10.7 Hz, 3H),2.38 (s, 3H), 1.23 (t, 3 *J*HH = 7.1 Hz, 3H). 13C{1H} NMR (101 MHz, CDCl3) δ 170.2 (d, 3 *J*PC = 10.8 Hz, Cquat), 160.6 (dd, 1 *J*FC = 249.9 Hz, 3 *J*PC = 5.8 Hz, Cquat), 143.3 (Cquat), 138.8 (d, 4 *J*PC = 1.3 Hz, Cquat), 130.4 (dd, 3 *J*FC = 9.4, 3 *J*PC = 2.8 Hz, CH), 130.3 (dd, 3 *J*FC = 4.8 Hz, 5 *J*PC = 2.9 Hz, CH), 129.2 (CH), 127.6 (CH), 123.9 (dd, 4 *J*FC = 3.3 Hz, 4 *J*PC = 2.5 Hz, CH), 123.2 (m, Cquat), 116.4 (dd, 2 *J*FC = 24.6 Hz, 4 *J*PC = 2.5 Hz, CH), 61.4 (dd, 1 *J*PC = 154.0, 3 *J*FC = 3.4 Hz, Cquat), 60.9 (CH2), 54.7 (d, 2 *J*PC = 7.6 Hz, CH3), 54.5 (d, 2 *J*PC = 7.4 Hz, CH3), 38.6 (d, 4 *J*FC = 6.8 Hz, CH2), 21.6 (CH3), 14.2 (CH3). 31P NMR (120 MHz, CDCl3): δ 22.1. 19F NMR (282 MHz, CDCl3) δ −107.6. FTIR (neat) νmax 3236 (N-H), 1755 (C=O), 1328 (O=S=O), 1239 (P=O), 1160 (O=S=O). HRMS (ESI-TOF) *m/z*: calcd for C20H26FNO7PS [M + H]+ 474.1146, found 474.1126. The spectroscopic data match the data reported in the literature [51].

*Ethyl 3-(2,4-difluorophenyl)-3-(dimethoxyphosphoryl)-3-((4-methylphenyl)sulfonamido) propanoate* **(7m)**. The general procedure was followed, starting form imine **3m** (403 mg, 1 mmol) to afford 457 mg (93%) of **7m** as a white solid. M.p. (CH2Cl2-hexanes). 135–136 ◦C. 1H NMR (400 MHz, CDCl3) δ 7.55 (d, 3 *J*HH = 8.3 Hz, 2H), 7.39 (m, 1H), 7.15 (d, 3 *J*HH = 8.3 Hz, 2H), 6.68 (m, 1H), 6.52 (m, 1H), 6.25 (br d, 3 *J*PH = 8.9 Hz, 1H), 4.09 (m, 2H), 3.65 (d, 3 *J*PH = 10.8 Hz, 3H), 3.57 (d, 3 *J*PH = 10.7 Hz, 3H), 3.57–3.47 (m, 2H), 2.37 (s, 3H), 1.22 (t, 3 *J*HH = 7.1 Hz, 3H). 13C{1H} NMR (101 MHz, CDCl3) δ 170.0 (d, 3 *J*PC = 10.9 Hz, Cquat), 162.9 (ddd, 1 *J*FC = 251.3 Hz, 3 *J*FC = 12.7 Hz, 5 *J*PC = 2.9 Hz, Cquat), 160.7 (ddd, 1 *J*FC = 252.9 Hz, 3 *J*FC = 11.7 Hz, 3 *J*PC = 5.7 Hz, Cquat), 143.5 (Cquat), 138.6 (Cquat), 131.4 (m, CH), 129.2 (CH), 127.5 (CH), 119.4 (m, Cquat), 110.8 (br d, 2 *J*FC = 21 Hz, CH), 104.5 (ddd, 2 *J*FC = 27.9 Hz, 2 *J*FC = 25.3 Hz, 4 *J*PC = 2.5 Hz, CH), 60.9 (CH2), 60.9 (dd, 1 *J*PC = 154.6 Hz, 3 *J*FC = 3.7 Hz, Cquat), 54.6 (br d, 2 *J*PC = 7.6 Hz, CH3), 54.6 (br d, 2 *J*PC = 7.3 Hz, CH3), 38.5 (d, 4 *J*FC = 6.9 Hz, CH2), 21.6 (CH3), 14.1 (CH3). 31P NMR (120 MHz, CDCl3): δ 22.0. 19F NMR (282 MHz, CDCl3) δ −103.0, −110.3 ppm. FTIR (neat) νmax 3248 (N-H), 1741 (C=O), 1335 (O=S=O), 1247 (P=O), 1155 (O=S=O). HRMS (ESI-TOF) *m/z*: calcd for C20H25F2NO7PS [M + H]+ 492.1052, found 492.1058.

*Ethyl 3-(3,4-difluorophenyl)-3-(dimethoxyphosphoryl)-3-((4-methylphenyl)sulfonamido) propanoate* **(7n)**. The general procedure was followed, starting form imine **3n** (403 mg, 1 mmol) to afford 447 mg (91%) of **7n** as a white solid. M.p. (CH2Cl2-hexanes). 98–99 ◦C. 1H NMR (400 MHz, CDCl3) δ 7.48 (d, 3 *J*HH = 8.0 Hz, 2H), 7.19 (d, 3 *J*HH = 8.0 Hz, 2H), 7.17–7.07 (m, 2H), 6.95 (q, 3 *J*HH = 9.2 Hz, 1H), 6.21 (d, 3 *J*PH = 9.6 Hz, 1H), 4.19 (q, 3 *J*HH = 7.1 Hz, 2H), 3.61 (m, 1H), 3.59 (d, 3 *J*PH = 11.1 Hz, 3H), 3.53 (d, 3 *J*PH = 10.6 Hz, 3H), 3.36 (dd, 2 *J*HH = 16.1 Hz, 3 *J*PH = 7.9 Hz, 1H), 2.41 (s, 3H), 1.29 (t, 3 *J*HH = 7.2 Hz, 3H). 13C{1H} NMR (101 MHz, CDCl3) δ 169.8 (d, 3 *J*PC = 6.8 Hz, Cquat), 150.2 (ddd, 1 *J*FC = 250.6 Hz, 2 *J*FC = 11.8 Hz, 5 *J*PC = 3.1 Hz, Cquat), 149.5 (ddd, 1 *J*FC = 246.0 Hz, 2 *J*FC = 10.6 Hz, 4 *J*PC = 3.0 Hz, Cquat), 143.9 (Cquat), 139.0 (d, 4 *J*PC = 1.3 Hz, Cquat), 131.6 (m, Cquat), 129.3 (CH), 127.5 (CH), 124.4 (m, CH), 118.4 (dd, 2 *J*FC = 19.6 Hz, 3 *J*PC = 4.8 Hz, CH), 116.5 (dd, 2 *J*FC = 17.4 Hz, 4 *J*PC = 2.7 Hz, CH), 61.5 (d, 1 *J*PC = 154.6 Hz, Cquat), 61.3 (CH2), 54.7 (d, 2 *J*PC

= 7.3 Hz, CH3), 54.4 (d, 2 *J*PC = 7.6 Hz, CH3), 38.2 (CH2), 21.6 (CH3), 14.2 (CH3). 31P NMR (120 MHz, CDCl3): δ 21.7. 19F NMR (282 MHz, CDCl3) δ −137.6, −138.0. FTIR (neat) νmax 3262 (N-H), 1738 (C=O), 1338 (O=S=O), 1249 (P=O), 1163 (O=S=O). HRMS (ESI-TOF) *m/z*: calcd for C20H25F2NO7PS [M + H]+ 492.1052, found 492.1060.

*Ethyl 3-(dimethoxyphosphoryl)-3-((4-methylphenyl)sulfonamido)-3-(perfluorophenyl) propanoate* **(7o)**. The general procedure was followed, starting form imine **3o** (457 mg, 1 mmol) to afford 501 mg (92%) of **7o** as a colorless oil. 1H NMR (400 MHz, CDCl3) δ 7.52 (d, 3 *J*HH = 8.3 Hz, 2H), 7.16 (d, 3 *J*HH = 8.3 Hz, 2H), 6.23 (d, 3 *J*PH = 10.5 Hz, 1H), 4.18–4.07 (m, 2H), 3.98 (m, 1H), 3.80 (d, 3 *J*PH = 10.9 Hz, 3H), 3.75 (d, 3 *J*PH = 10.9 Hz, 3H), 3.45 (m, 1H), 2.36 (s, 3H), 1.24 (t, 3 *J*HH = 7.1 Hz, 3H). 13C{1H} NMR (101 MHz, CDCl3) δ 170.1 (d, 3 *J*PC = 8.4 Hz, Cquat), 145.9 (m, Cquat), 144.1 (Cquat), 140.8 (m, Cquat), 137.7 (d, 4 *J*PC = 1.9 Hz, Cquat), 137.5 (m, Cquat), 129.2 (CH), 127.1 (CH), 111.2 (m, Cquat), 61.0 (CH2), 60.0 (d, 1 *J*PC = 153.3 Hz, Cquat), 55.7 (d, 2 *J*PC = 7.2 Hz, CH3), 54.9 (d, 2 *J*PC = 7.8 Hz, CH3), 40.3 (d, 4 *J*FC = 5.3 Hz, CH2), 21.4 (CH3), 14.1 (CH3). 31P NMR (120 MHz, CDCl3): δ 21.7. 19F NMR (282 MHz, CDCl3) δ −135.0, −154.3, −162.8. FTIR (neat) νmax 3284 (N-H), 1741 (C=O), 1333 (O=S=O), 1254 (P=O), 1166 (O=S=O). HRMS (ESI-TOF) *m/z*: calcd for C20H22F5NO7PS [M + H]+ 546.0769, found 546.0781.

*Ethyl 3-(dimethoxyphosphoryl)-3-((4-methylphenyl)sulfonamido)-3-(4-(trifluoromethyl) phenyl)propanoate* **(7p)**. The general procedure was followed, starting form imine **3p** (435 mg, 1 mmol) to afford 455 mg (87%) of **7p** as a white solid. M.p. (CH2Cl2-hexanes). 114–115 ◦C. 1H NMR (400 MHz, CDCl3) δ 7.47 (3 *J*HH = 8.8 Hz, 3 *J*FH = 2.3 Hz, 2H), 7.42 (d, 3 *J*HH = 8.4 Hz, 2H), 7.34 (d, 3 *J*HH = 8.4 Hz, 2H), 7.12 (d, 3 *J*HH = 8.2 Hz, 2H), 6.24 (d, 3 *J*PH = 10.1 Hz, 1H), 4.18 (qd, 3 *J*HH = 7.2 Hz, 3 *J*FH = 1.7 Hz, 2H), 3.68 (dd, 3 *J*PH = 23.8 Hz, 2 *J*HH = 16.2 Hz, 1H), 3.58 (d, 3 *J*PH = 10.8 Hz, 3H), 3.49 (d, 3 *J*PH = 10.8 Hz, 3H), 3.44 (dd, 3 *J*PH = 8.2 Hz, 2 *J*HH = 16.2 Hz, 1H), 2.39 (s, 3H), 1.28 (t, 3 *J*HH = 7.1 Hz, 3H). 13C{1H} NMR (75 MHz, CDCl3) δ 170.0 (d, 3 *J*PC = 6.8 Hz, Cquat), 143.7 (Cquat), 138.9 (Cquat), 138.6 (d, 2 *J*PC = 6.6 Hz, Cquat), 130.4 (dq, 2 *J*FC = 32.8 Hz, 5 *J*PC = 3.0 Hz, Cquat), 129.3 (CH), 128.8 (d, 3 *J*PC = 5.0 Hz, CH), 127.5 (CH), 124.7 (m, CH), 123.9 (q, 1 *J*FC = 272.4 Hz, Cquat), 62.0 (d, 1 *J*PC = 152.8 Hz, Cquat), 61.3 (CH2), 54.8 (d, 2 *J*PC = 7.4 Hz, CH3), 54.4 (d, 2 *J*PC = 7.6 Hz, CH3), 38.1 (CH2), 21.6 (CH3), 14.3 (CH3). 31P NMR (120 MHz, CDCl3): δ 21.9. 19F NMR (282 MHz, CDCl3) δ −63.4. FTIR (neat) νmax 3261 (N-H), 1735 (C=O), 1327 (O=S=O), 1263 (P=O), 1163 (O=S=O). HRMS (ESI-TOF) *m/z*: calcd for C21H26F3NO7PS [M + H]+ 524.1114, found 524.1121.

*Ethyl 3-(dimethoxyphosphoryl)-3-((4-methylphenyl)sulfonamido)-3-(4-nitrophenyl)propanoate* **(7q)**. The general procedure was followed, starting form imine **3q** (412 mg, 1 mmol) to afford 425 mg (85%) of **7q** as a white solid. M.p. (CH2Cl2-hexanes). 129–130 ◦C. 1H NMR (400 MHz, CDCl3) δ 7.96 (d, 3 *J*HH = 9.0 Hz, 2H), 7.56 (dd, 3 *J*HH = 9.0 Hz, 3 *J*PH = 2.3 Hz, 2H), 7.50 (d, 3 *J*HH = 8.2 Hz, 2H), 7.17 (d, 3 *J*HH = 8.2 Hz, 2H), 6.30 (d, 3 *J*PH = 10.3 Hz, 1H), 4.16 (m, 2H), 3.62 (dd, 2 *J*HH = 16.5 Hz, 3 *J*PH = 6.2 Hz, 1H), 3.58 (d, 3 *J*PH = 10.8 Hz, 3H), 3.55 (d, 3 *J*PH = 10.7 Hz, 3H), 3.48 (dd, 2 *J*HH = 16.5 Hz, 3 *J*PH = 8.2 Hz, 1H), 2.41 (s, 3H), 1.27 (t, 3 *J*HH = 7.2 Hz, 3H). 13C{1H} NMR (101 MHz, CDCl3) δ 169.7 (d, 3 *J*PC = 7.6 Hz, Cquat), 147.4 (d, 5 *J*PC = 3.4 Hz, Cquat), 144.1 (Cquat), 142.5 (d, 2 *J*PC = 6.6 Hz, Cquat), 138.8 (d, 4 *J*PC = 1.4 Hz, Cquat), 129.4 (CH), 129.3 (d, 3 *J*PC = 5.0 Hz, CH), 127.5 (CH), 122.8 (d, 4 *J*PC = 2.6 Hz, CH), 62.3 (d, 1 *J*PC = 152.2 Hz, Cquat), 61.4 (CH2), 54.9 (d, 2 *J*PC = 7.3 Hz, CH3), 54.6 (d, 2 *J*PC = 7.5 Hz, CH3), 38.3 (CH2), 21.7 (CH3), 14.2 (CH3). 31P NMR (120 MHz, CDCl3): δ 21.2. FTIR (neat) νmax 3272 (N-H), 1743 (C=O), 1349 (O=S=O), 1244 (P=O), 1163 (O=S=O). HRMS (ESI-TOF) *m/z*: calcd for C20H26N2O9PS [M + H]+ 501.1091, found 501.1098.

*Ethyl 3-(5-chlorothiophen-2-yl)-3-(dimethoxyphosphoryl)-3-((4-methylphenyl)sulfonamido) propanoate* **(7r)**. The general procedure was followed, starting form imine **3r** (407 mg, 1 mmol) to afford 378 mg (76%) of **7r** as a pale brown solid. M.p. (CH2Cl2-hexanes). 93–94 ◦C. 1H NMR (400 MHz, CDCl3) δ 7.48 (d, 3 *J*HH = 8.3 Hz, 2H), 7.17 (d, 3 *J*HH = 8.3 Hz, 2H), 6.79 (dd, 3 *J*HH = 4.0 Hz, 4 *J*PH = 3.4 Hz, 1H), 6.61 (d, 3 *J*HH = 4.0 Hz, 1H), 6.23 (d, 3 *J*PH = 7.2 Hz, 1H), 4.20 (q, 3 *J*HH = 7.2 Hz, 2H), 3.68 (d, 3 *J*PH = 10.7 Hz, 3H), 3.66 (d, 3 *J*PH = 10.5 Hz, 3H), 3.61 (m, 1H), 3.21 (dd, 2 *J*HH = 15.5 Hz, 3 *J*PH = 7.1 Hz, 1H), 2.40 (s, 3H), 1.30 (t, 3 *J*HH = 7.2 Hz, 3H). 13C{1H} NMR (101 MHz, CDCl3) δ 169.5 (d, 3 *J*PC = 5.6 Hz, Cquat), 143.6 (Cquat),

138.7 (d, 4 *J*PC = 1.4 Hz, Cquat), 135.9 (d, 2 *J*PC = 7.7 Hz, Cquat), 132.3 (d, 5 *J*PC = 3.6 Hz, Cquat), 129.3 (CH), 128.6 (d, 3 *J*PC = 7.3 Hz, CH), 127.5 (CH), 125.3 (d, 4 *J*PC = 2.8 Hz, CH), 61.4 (CH2), 60.0 (d, 1 *J*PC = 161.5 Hz, Cquat), 55.2 (d, 3 *J*PC = 7.3 Hz, CH3), 54.5 (d, 3 *J*PC = 7.6 Hz, CH3), 39.0 (CH2), 21.7 (CH3), 14.2 (CH3). 31P NMR (120 MHz, CDCl3): δ 20.3. FTIR (neat) νmax 3270 (N-H), 1735 (C=O), 1341 (O=S=O), 1243 (P=O), 1163 (O=S=O). HRMS (ESI-TOF) *m/z*: calcd for C18H24ClNO7PS2 [M + H]+ 496.0415, found 496.0444..

*Ethyl 3-([1,1'-biphenyl]-4-yl)-3-(dimethoxyphosphoryl)-3-((4-methylphenyl)sulfonamido) propanoate* **(7s)**. The general procedure was followed, starting form imine **3s** (443 mg, 1 mmol) to afford 478 mg (90%) of **7s** as a white solid. M.p. (CH2Cl2-hexanes). 112–113 ◦C. 1H NMR (400 MHz, CDCl3) δ 7.56–7.46 (m, 4H), 7.45–7.40 (m, 5H), 7.39–7.33 (m, 2H), 7.13 (d, 3 *J*HH = 8.3 Hz, 2H), 6.21 (d, 3 *J*PH = 10.5 Hz, 1H), 4.20 (q, 3 *J*HH = 7.2 Hz, 2H), 3.69 (dd, 3 *J*PH = 23.4 Hz, 2 *J*HH = 16.4 Hz, 1H), 3.56 (d, 3 *J*PH = 10.7 Hz, 3H), 3.49 (m, 1H), 3.46 (d, 3 *J*PH = 10.6 Hz, 3H), 2.38 (s, 3H), 1.29 (t, 3 *J*HH = 7.2 Hz, 3H). 13C{1H} NMR (101 MHz, CDCl3) δ 170.3 (d, 3 *J*PC = 7.3 Hz, Cquat), 143.3 (Cquat), 141.0 (d, 5 *J*PC = 3.1 Hz, Cquat), 140.1 (d, 4 *J*PC = 1.4 Hz, Cquat), 139.2 (Cquat), 129.2 (CH), 129.0 (CH), 128.8 (d, 3 *J*PC = 5.1 Hz, CH), 128.3 (Cquat), 127.8 (CH), 127.7 (CH), 127.1 (CH), 126.5 (d, 4 *J*PC = 2.8 Hz, CH), 62.1 (d, 1 *J*PC = 153.9 Hz, Cquat), 61.1 (CH2), 54.7 (d, 2 *J*PC = 7.4 Hz, CH3), 54.2 (d, 2 *J*PC = 7.6 Hz, CH3), 38.2 (CH2), 21.7 (CH3), 14.3 (CH3). 31P NMR (120 MHz, CDCl3): δ 22.2. FTIR (neat) νmax 3308 (N-H), 1729 (C=O), 1332 (O=S=O), 1241 (P=O), 1161 (O=S=O). HRMS (ESI-TOF) *m/z*: calcd for C26H31NO7PS [M + H]+ 532.1553, found 532.1555.

*Methyl 3-(dimethoxyphosphoryl)-3-(3-fluorophenyl)-3-((4-methylphenyl)sulfonamido) propanoate* **(12)**. The general procedure was followed, starting form imine **3k** (417 mg, 1 mmol) to afford 372 mg (81%) of **12** as a white solid. M.p. (CH2Cl2-hexanes). 115–116 ◦C. 1H NMR (400 MHz, CDCl3) δ 7.48 (d, 3 *J*HH = 8.3 Hz, 2H), 7.20–7.09 (m, 4H), 7.00 (m, 1H), 6.91 (m, 1H), 6.21 (br d, 3 *J*HH = 7.8 Hz, 1H), 3.73 (s, 3H), 3.64 (dd, 3 *J*PH = 24.4 Hz, 2 *J*HH = 16.2 Hz, 1H), 3.56–3.50 (m, 6H), 3.46 (dd, 2 *J*HH = 16.2 Hz, 3 *J*PH = 7.6 Hz, 1H), 2.39 (s, 3H). 13C{1H} NMR (101 MHz, CDCl3) δ 170.6 (d, 3 *J*PC = 6.8 Hz, Cquat), 162.3 (dd, 1 *J*FC = 246.0 Hz, 4 *J*PC = 3.0 Hz, Cquat), 143.7 (Cquat), 139.0 (Cquat), 137.1 (m, Cquat), 129.5 (dd, 3 *J*FC = 8.1 Hz, 4 *J*PC 2.8 Hz, CH), 129.3 (CH), 127.5 (CH), 123.7 (dd, 3 *J*PC = 5.1 Hz, 4 *J*FC = 3.0 Hz, CH), 116.1 (dd, 2 *J*FC = 24.1 Hz, 3 *J*PC = 4.8 Hz, CH), 115.5 (dd, 2 *J*FC = 21.1 Hz, 5 *J*PC = 2.9 Hz, CH), 62.0 (dd, 1 *J*PC = 153.7 Hz, 4 *J*FC = 1.4 Hz, Cquat), 54.9 (d, 2 *J*PC = 7.7 Hz, CH3), 54.4 (d, 2 *J*PC = 7.6 Hz, CH3), 52.3 (CH3), 38.2 (CH2), 21.6 (CH3). 31P NMR (120 MHz, CDCl3): δ 21.7. 19F NMR (282 MHz, CDCl3) δ −112.9. FTIR (neat) νmax 3281 (N-H), 1729 (C=O), 1330 (O=S=O), 1243 (P=O), 1159 (O=S=O). HRMS (ESI-TOF) *m/z*: calcd for C19H24FNO7PS [M + H]+ 460.0990, found 460.1004.

*Benzyl 3-(dimethoxyphosphoryl)-3-(3-fluorophenyl)-3-((4-methylphenyl)sulfonamido) propanoate* **(13a)**. The general procedure was followed, starting form imine **3k** (417 mg, 1 mmol) to afford 449 mg (84%) of **13a** as a white solid. M.p. (CH2Cl2-hexanes). 78–79 ◦C. 1H NMR (400 MHz, CDCl3) δ 7.47 (d, 3 *J*HH = 8.2 Hz, 2H), 7.41–7.31 (m, 5H), 7.17–7.08 (m, 4H), 7.03–6.98 (m, 1H), 6.94–6.87 (m, 1H), 6.24 (d, 3 *J*PH = 10.2 Hz, 1H), 5.19 (d, 2 *J*HH = 12.3 Hz. 1H), 5.13 (d, 2 *J*HH = 12.3 Hz, 1H), 3.73–3.63 (m, 1H), 3.57–3.34 (m, 7H), 2.38 (s, 3H). 13C{1H} NMR (101 MHz, CDCl3) δ 169.9 (d, 3 *J*PC = 6.9 Hz, Cquat), 162.3 (dd, 1 *J*FC = 246.0 Hz, 4 *J*PC = 3.0 Hz, Cquat), 143.6 (Cquat), 139.0 (d, 4 *J*PC = 1.3 Hz, Cquat), 137.1 (Cquat), 135.6 (Cquat), 129.4 (dd, 3 *J*FC = 8.2 Hz, 4 *J*PC = 2.5 Hz, CH), 129.3 (CH), 128.7 (CH), 128.7 (CH), 128.5 (CH), 127.5 (CH), 123.7 (dd, 3 *J*PC = 5.0, 4 *J*FC = 2.9 Hz, CH), 116.0 (dd, 2 *J*FC = 24.0 Hz, 3 *J*PC = 4.7 Hz, CH), 115.4 (dd, 2 *J*FC = 21.1 Hz, 5 *J*PC = 3.1 Hz, CH), 67.0 (CH2), 61.9 (dd, 1 *J*PC = 153.6 Hz, 4 *J*FC = 1.6 Hz, Cquat), 54.8 (d, 2 *J*PC = 7.5 Hz, CH3), 54.3 (d, 2 *J*PC = 7.7 Hz, CH3), 38.2 (CH2), 21.6 (CH3). 31P NMR (120 MHz, CDCl3): δ 21.6. 19F NMR (282 MHz, CDCl3) δ −112.9. FTIR (neat) νmax 3281 (N-H), 1735 (C=O), 1331 (O=S=O), 1247 (P=O), 1154 (O=S=O). HRMS (ESI-TOF) *m/z*: calcd for C25H28FNO7PS [M + H]+ 536.1303, found 536.1322.

*Benzyl 3-(dimethoxyphosphoryl)-3-((4-methylphenyl)sulfonamido)-3-phenylpropanoate* **(13b)**. The general procedure was followed, starting form imine **3a** (367 mg, 1 mmol) to afford 476 mg (92%) of **13b** as a white solid. M.p. (CH2Cl2-hexanes). 84–85 ◦C. 1H NMR (400 MHz, CDCl3) δ 7.46 (d, *J* = 8.3 Hz, 2H), 7.37–7.29 (m, 7H), 7.20–7.15 (m, 1H), 7.12–7.06 (m, 4H),

6.22 (d, 3 *J*PH = 11.1 Hz, 1H), 5.14 (d, 2 *J*HH = 12.2 Hz, 1H), 5.09 (d, 2 *J*HH = 12.2 Hz, 1H), 3.65 (dd, 3 *J*PH = 22.3 Hz, 2 *J*HH = 16.6 Hz, 1H), 3.49 (dd, 2 *J*HH = 16.6 Hz, 3 *J*PH = 7.5 Hz, 1H), 3.37 (d, 3 *J*PH = 10.7 Hz, 3H), 3.31 (d, 3 *J*PH = 10.7 Hz, 3H), 2.34 (s, 3H). 13C{1H} NMR (101 MHz, CDCl3) δ 169.8 (d, 3 *J*PC = 8.1 Hz, Cquat), 143.1 (Cquat), 139.0 (d, 4 *J*PC = 1.4 Hz, Cquat), 135.5 (Cquat), 134.1 (d, 2 *J*PC = 7.3 Hz, Cquat), 129.0 (CH), 128.4 (CH), 128.4 (CH), 128.2 (CH), 128.2 (CH), 128.0 (d, 3 *J*PC = 5.0 Hz, CH), 127.8 (d, 4 *J*PC = 2.6 Hz, CH), 127.4 (CH), 66.5 (CH2), 61.9 (d, 1 *J*PC = 154.1 Hz, Cquat), 54.4 (d, 2 *J*PC = 7.4 Hz, CH3), 53.8 (d, 2 *J*PC = 7.7 Hz, CH3), 37.7 (CH2), 21.4 (CH3). 31P NMR (120 MHz, CDCl3): δ 22.0. FTIR (neat) νmax 3322 (N-H), 1739 (C=O), 1337 (O=S=O), 1248 (P=O), 1163 (O=S=O). HRMS (ESI-TOF) *m/z*: calcd for C25H29NO7PS [M + H]+ 518.1397, found 518.1372.

Procedure for the Obtention of 3-(Dimethoxyphosphoryl)-3-((4-methylphenyl)sulfonamido)- 3-phenylpropanoic acid **14**

A mixture of aminophosphonate **13b** (518 mg, 1 mmol) and Pd-C 10% (106 mg, 0.1 mmol) in MeOH (50 mL) were stirred for 12 h under H2 atmosphere (75 psi). The mixture was then filtered on celite and concentrated under reduced pressure to yield product **14** as a white solid (402 mg, 94%), after crystallization in MeOH. M.p. (MeOH). 145–146 ◦C. 1H NMR (400 MHz, CDCl3) δ 9.91 (br s, 1H), 7.48 (d, 3 JHH = 8.2 Hz, 2H), 7.33 (d, *3 JHH* = 7.6 Hz, 2H), 7.20 (m, 1H), 7.17–7.09 (m, 4H), 6.60 (d, *3 JPH* = 10.6 Hz, 1H), 3.67 (dd, *3 JPH* = 23.9 Hz, *2 JHH* = 16.0 Hz, 1H), 3.52 (d, *3 JPH* = 10.8 Hz, 3H), 3.49 (m, 1H), 3.47 (d, *3 JPH* = 10.6 Hz, 3H), 2.38 (s, 3H). 13C{1H} NMR (101 MHz, CDCl3) δ 173.5 (d, *3 JPC* = 7.7 Hz, Cquat), 143.3 (Cquat), 139.2 (d, *4 JPC* = 1.4 Hz, Cquat), 134.1 (d, *2 JPC* = 7.6 Hz, Cquat), 129.2 (CH), 128.4 (d, *5 JPC* = 3.0 Hz, CH), 128.3 (d, *3 JPC* = 5.1 Hz, CH), 128.0 (d, *4 JPC* = 2.6 Hz, CH), 127.6 (CH), 62.1 (d, *1 JPC* = 155.6 Hz, Cquat), 55.1 (d, *2 JPC* = 7.3 Hz, CH3), 54.5 (d, *2 JPC* = 7.9 Hz, CH3), 38.0 (CH2), 21.6 (CH3). 31P NMR (120 MHz, CDCl3): δ 21.8. FTIR (neat) νmax 3500–2500 (O-H st), 3271 (N-H st), 1714 (C=O st), 1337 (O=S=O st as), 1235 (P=O st), 1163 (O=S=O st sim) cm–1. HRMS (ESI-TOF) *m/z*: calcd for C18H23NO7PS [M + H]+ 428.0927, found 428.0901.

Procedure for the Obtention of Dimethyl (1-((4-methylphenyl)sulfonamido)-1-phenylethyl) phosphonate **18**

A solution of **3a** (367 mg, 1 mmol) in dry CH3CN (3 mL) was stirred at room temperature under N2 atmosphere. To this mixture, Me2Zn (1.7 mL, 1.2 M in toluene, 2 mmol) was added and the mixture was stirred for 2h at room temperature. The reaction was quenched by a slow addition of a saturated aqueous solution of NH4Cl (1 mL) and dried over anhydrous MgSO4. The solid was removed by filtration and washed with AcOEt, and the filtrate was concentrated at reduced pressure to yield the crude product, which was purified by column chromatography in silica gel (AcOEt/Hexanes) to give 326 mg (85%) of **18** as a white solid [60]. M.p. (Et2O/pentane). 163–164 ◦C. Lit. 161–162 (Et2O). 1H NMR (400 MHz, CDCl3) δ 7.53 (d, *3 JHH* = 8.3 Hz, 2H), 7.40 (m, 2H), 7.22–7.18 (m, 3H), 7.11 (d, *3 JHH* = 8.2 Hz, 2H), 5.78 (d, *3 JPH* = 8.1 Hz, 1H), 3.70 (d, *3 JPH* = 10.4 Hz, 3H), 3.35 (d, *3 JPH* = 10.4 Hz, 3H), 2.36 (s, 3H), 1.97 (d, 3 JPH = 16.8 Hz, 3H). 13C {1H} NMR (75 MHz, CDCl3) δ 142.3 (Cquat), 141.8 (d, *4 JPC* = 1.7 Hz, Cquat), 133.4 (Cquat), 128.6 (CH), 128.4 (d, *3 JPC* = 6.0 Hz, CH), 128.1 (d, *4 JPC* = 2.2 Hz, CH), 128.0 (d, *5 JPC* = 2.9 Hz, CH), 126.7 (CH), 61.1 (d, *1 JPC* = 152.2 Hz, Cquat), 54.5 (d, *2 JPC* = 7.1 Hz, CH3), 53.9 (d, *2 JPC* = 7.0 Hz, CH3), 21.3 (CH3), 20.4 (d, *2 JPC* = 5.2 Hz CH3). 31P NMR (120 MHz, CDCl3) δ 26.1. FTIR (neat) νmax 3315 (N-H), 1327 (O=S=O), 1242 (P=O), 1166 (O=S=O). HRMS (ESI-TOF) *m/z*: calcd. for C17H22NO5PS [M + Na]+ 406.0848, found 406.0856.

### *3.2. Biology*

### 3.2.1. Materials

Reagents and solvents were used as purchased without further purification. All stock solutions of the investigated compounds were prepared by dissolving the powered materials in appropriate amounts of dimethylsulfoxide (DMSO). The final concentration of DMSO never exceeded 5% (*v*/*v*) in the reactions. The stock solution was stored at 5 ◦C until it was used.

### 3.2.2. Cell Culture

Human epithelial lung carcinoma cells (A549) (ATCC® CCL-185™, ATCC, Manassas, VA, USA) were grown in Kaighn's Modification of Ham's F-12 Medium (ATCC® 30-2004™, ATCC, Manassas, VA, USA) and lung fibroblast cells (MRC5) (ATCC® CCL-171™, ATCC, Manassas, VA, USA) were grown in Eagle's Minimum Essential Medium (EMEM, ATCC® 30-2003™, ATCC, Manassas, VA, USA). Epithelial ovary adenocarcinoma cells (SKOV3) (ATCC® HTB-77™, ATCC, Manassas, VA, USA) were grown in McCoy's 5A medium (ATCC® 30-2007™, ATCC, Manassas, VA, USA). All of them were supplemented with 10% of fetal bovine serum (FBS) (Sigma-Aldrich, Madrid, Spain) and with 1% of NORMOCIN solution (Thermo Fisher, Waltham, MA, USA). Cells were incubated at 37 ◦C and 5% CO2 atmosphere, and were split every 3–4 days to maintain monolayer coverage. For the cytotoxicity experiments, the A549 and SKOV3 cells were seeded in 96-well plates at a density of 2.5–3 × 103 cells per well and incubated overnight to achieve 70% of confluence at the time of exposition to the cytotoxic compound.

### 3.2.3. Cytotoxicity Assays

Cells were exposed to different concentrations of the cytotoxic compounds and were incubated for 48 h. Then, 10 µL of cell counting kit-8 was added into each well for an additional two hours' incubation at 37 ◦C. The absorbance of each well was determined by an Automatic Elisa Reader System (Thermo Scientific Multiskan FC Automatic Elisa Reader System, Thermo Scientific, Shanghai, China) at 450 nm wavelength.

### **4. Conclusions**

In conclusion, we report an efficient methodology for the preparation of phosphonate analogs of aspartic acid, holding a variety of substituents at their α-aromatic ring. α-Ketiminophosphonates are generated by the oxidation of their parent tertiary α-aminophosphonates and a subsequent aza-Reformatsky reaction with alkyl iodoacetate derivatives. Moreover, this methodology has been successfully extended to aldimines and activated ketimines, affording the Reformatsky products in high yields. This strategy allows the possibility of assorted structural diversity in the resultant scaffold depending on the starting imine or alkyl iodoacetate. Moreover, the phosphorated analogues of aspartic acid **6** showed in vitro cytotoxicity inhibiting the growth of human tumor cell lines SKOV3 (human ovarian carcinoma) and A549 (carcinomic human alveolar basal epithelial cell), and a high selectivity toward the MRC5 non-malignant lung fibroblasts. The most active substrates were proved to be ethyl ester derivatives. Although *p*-tolyl derivatives showed the best result against A549, the introduction of a trifluoromethylphenyl moiety in the para position exhibited the most remarkable IC50 value against the SKOV3 cell line. Moreover, the majority of the compounds were selective toward the non-malignant cells. The best IC50 values obtained are 9.80 µM in the SKOV3 cell line for α-aminophosphonate **7p**, with a *p*-trifluorophenyl substituent, and 0.34 µM in the A549 cell line for substrate **7k**, holding a *p*-methylphenyl moiety. Most of the compounds presented in this study show low micromolar activity and a high selectivity toward the non-malignant cells. It has also been proved that the absolute configuration of the tetrasubstituted stereocenter does not have any influence on the biological activity of the phosphorated aspartic acid derivatives, since both enantiomers of substrate **7k** showed similar IC50 values.

**Supplementary Materials:** The following supporting information can be downloaded at: https:// www.mdpi.com/article/10.3390/molecules27228024/s1, 1H, 13C, 31P and 19F copies of compounds **5**, **6**, **7**, **12**, **13**, **14** and **18**. 2D-NMR of compound **7a**.

**Author Contributions:** Conceptualization, X.d.C., A.M., F.P. and J.V.; methodology: evaluation of the in vitro antiproliferative activity, X.d.C.; methodology: organic synthesis, A.M. and A.L.-F.; software, X.d.C. and A.M.; validation, J.V.; formal analysis, X.d.C. and A.M.; investigation, X.d.C., A.M. and A.L.-F.; resources, F.P. and J.V.; data curation, X.d.C., A.M. and A.L.-F.; writing—original draft preparation, J.V.; writing—review and editing, X.d.C., A.M., A.L.-F., F.P. and J.V.; visualization, F.P. and J.V.; supervision, J.V.; project administration, F.P. and J.V.; funding acquisition, F.P. and J.V. All authors have read and agreed to the published version of the manuscript.

**Funding:** Financial support by Ministerio de Economía, Industria y Competividad (PID2021-122558OB-I00) and Gobierno Vasco (GV-IT1701-22) is gratefully acknowledged. X.d.C. and A.L.-F. thank the Basque Country Government for a predoctoral grant.

**Institutional Review Board Statement:** Not applicable.

**Informed Consent Statement:** Not applicable.

**Data Availability Statement:** The data presented in this study are available in the supplementary materials file or on request from the corresponding author (1H, 13C, 19F and 31P-NMR and HRMS spectra and cytotoxicity essays).

**Acknowledgments:** The authors thank for the technical and human support provided by SGIker (UPV/EHU/ERDF, EU).

**Conflicts of Interest:** The authors declare no conflict of interest.

**Sample Availability:** Samples of the compounds are not available.

### **References**

## *Article* **One-Pot Phosphonylation of Heteroaromatic Lithium Reagents: The Scope and Limitations of Its Use for the Synthesis of Heteroaromatic Phosphonates**

**Ewa Chmielewska 1,\* , Natalia Miodowska 1 , Błazej Dziuk ˙ 2 , Mateusz Psurski 3 and Paweł Kafarski 4**

**Abstract:** A one-pot lithiation–phosphonylation procedure was elaborated as a method to prepare heteroaromatic phosphonic acids. It relied on the direct lithiation of heteroaromatics followed by phosphonylation with diethyl chlorophosphite and then oxidation with hydrogen peroxide. This protocol provided the desired phosphonates with satisfactory yields. This procedure also had some limitations in its dependence on the accessibility and stability of the lithiated heterocyclic compounds. The same procedure could be applied to phosphonylation of aromatic compounds, which do not undergo direct lithiation and thus require the use of their bromides as substrates. The obtained compounds showed weak antiproliferative activity when tested on three cancer cell lines.

**Keywords:** aminophosphonates; heteroaromatic; lithiation; phosphonylation; phosphonic acids; organophosphorus chemistry; P-containing drugs

### **1. Introduction**

Useful biological and practical applications of heteroaromatic phosphonates, as well as their utility as intermediates in organic synthesis, have stimulated intensive studies directed toward methods of their preparation [1]. As indicated, this is a challenging research endeavor, and quite frequently, the yields of the applied procedures are moderate or even low [2–5]. Therefore, it is not surprising that the number of papers devoted to the elaboration of methods to prepare these compounds has increased in recent years [6–12]. The most commonly used method for the introduction of a phosphonate moiety to an sp2 hybridized aromatic carbon atom is a palladium-catalyzed reaction [5–11]. Due to continual improvements in its conditions, catalysts, and procedures, this method provides high yields of products of variable structures. An alternative strategy is to use aryl bromides and the application of copper (I), nickel (II), or manganese (II) catalysts [2,6,13]. Finally, the formation of lithium derivatives or Grignard reagents using aryl halides as substrates may be also employed [2,6,7]. In the past decade, interesting methods of nontypical specific procedures for the synthesis of heteroaromatic phosphonates have been studied and elaborated [12,14–25].

It is well known that electron-rich heterocycles easily undergo direct lithiation at Position 2 when alkyllithium is used. The formed salts are important intermediates in the syntheses of many groups of organic compounds [26–29]. Thus, the objective of this paper is to evaluate the scope and limitations of the direct lithiation of heterocyclic compounds,

**Citation:** Chmielewska, E.; Miodowska, N.; Dziuk, B.; Psurski, M.; Kafarski, P. One-Pot Phosphonylation of Heteroaromatic Lithium Reagents: The Scope and Limitations of Its Use for the Synthesis of Heteroaromatic Phosphonates. *Molecules* **2023**, *28*, 3135. https://doi.org/10.3390/ molecules28073135

Academic Editor: Gabriele Micheletti

Received: 7 March 2023 Revised: 24 March 2023 Accepted: 29 March 2023 Published: 31 March 2023

**Copyright:** © 2023 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/).

followed by a one-pot reaction with chlorophosphates or chlorophosphites, applied as a method to synthesize heteroaromatic phosphonic acids. Additionally, the antiproliferative activity of the obtained phosphonic acids was evaluated using three cell lines, RAW 264.7 (used to screen for possible antiosteoporotic and anti-inflammatory activities), PC-3, and MCF-7 (human prostate cancer and breast cancer cell lines, respectively), showing a practical lack of activity of the obtained compounds.

### **2. Results**

### *2.1. Chemistry*

The usefulness of the direct lithiation of indole followed by phosphonylation of the formed lithium salt has been chosen as a model reaction. As shown previously, lithiation of indole with *n*-buthyllithium had to be preceded by the suitable protection of the reactive amino group [28]. The use of *t*-butoxycarbonyl-(*Boc*) protection followed by reaction with trivalent phosphoryl chloride, namely, with 1-chloro-*N*,*N*-diisopropyl-1 methoxyphosphinamine, followed by an aqueous work-up, was described as a method for the synthesis of methyl 2-indolyl phosphinate [30]. Unfortunately, lithiated *Boc*-indole, when reacted with both diethyl chlorophosphate and chlorophosphite, failed to produce the desired product. Thus, the one-pot synthesis of Kartitzky and Akutagawa was adopted [31], which relied on the conversion of indole into 1*H*-indolyl-1-carboxylic acid prior to phosphonylation (Scheme 1). Initially, the utility of diethyl chlorophosphate as an electrophile was planned; however, the literature reports [32] suggested that better results were obtained with the use of diethyl chlorophosphite. Hydrolysis of the resulting diethyl 1*H*-indol-2 ylphosphonate (compound **1a**) in concentrated hydrochloric caused the decomposition of the obtained esters with the simultaneous formation of phosphorous acid (H3PO3). Moreover, the application of mild conditions for the removal of ester groups from the phosphonate moiety, by conversion of **1** into its di(trimethylsilyl) ester with trimethylchlorosilane, followed by its cleavage with methanol, also failed to deliver the desired acid **2** [33] and yielded similar products of decomposition.

**Scheme 1.** Phosphonylation of indole.

The reduction of diethyl 1*H*-indol-2-ylphosphonate **1** provided diethyl indoline-2 phosphonate (compound **3**), which was readily converted into the corresponding acid **4**, albeit with moderate yield. Quite unexpectedly, the hydrolysis of diethyl 1*H*-indol-2 ylphosphinate also failed, and the decomposition of the molecule with production of indole was observed.

The elaborated procedure was then used for the phosphonylation of benzothiophene and benzothiazole (Scheme 2). There was no need to apply the Kartitzky and Akutagawa procedure in this case. The only disadvantage of this method was the extreme instability of the lithium derivative of benzothiazole. This problem was solved by slight modifications of the synthetic procedure and reversal of the order of addition of reagents; the heterocyclic compound was added to the solution of *n*-butyllithium. Because the resulting phosphonates esters, diethyl benzo[*d*]thiazol-2-ylphosphonate **5** and diethyl benzo[*b*]thiophen-2-ylphosphonate **6,** could be unstable under harsh acidic conditions, we applied transesterification with bromotrimethylsilane for the preparation of the corresponding acids benzo[*d*]thiazol-2-ylphosphonic acid **7** and benzo[*b*]thiophen-2-ylphosphonic acid **8**.

**Scheme 2.** Phosphonylation of benzothiazole, benzothiophene and benzoxazole.

The phosphonylation of the lithiated benzoxazole failed, resulting in a complex mixture of products despite the modifications to the synthetic procedure. This may derive from the possible opening of the pentacyclic ring of this compound upon the action of lithium [34]. According to the published data, the opened product is in equilibrium with lithiated benzoxazole (Scheme 2); however, it did not react with diethyl chlorophosphite in the desired manner, and the compound **9** was not obtained.

In turn, the reaction of benzofuran yielded the inseparable mixture of phosphonate **10** and phosphinate **11** in moderate yield accompanied with the equimolar mixture of tri-2 benzofuryl phosphine **12** and its oxide **13**. This mixture was the major reaction product (Scheme 3). The mixture of compounds **12** and **13** readily crystallized out over time from the reaction mixture. The pure compound **13** was obtained in a small quantity only in a single case by crystallization from the spent solvent after the crystallization of the mixture of compounds **12** and **13**. The transesterification of the ester groups of the mixture of **10** and **11** with bromotrimethylsilane followed by methanolysis afforded benzofuran-2-ylphosphonic acid **14**.

**Scheme 3.** Phosphonylation of benzofurane.

The crystallographic data are given in Table 1.

**Table 1.** X-ray crystallography experimental details.

The solid-state structure of the crystals was determined by the X-ray diffraction

method. The structure was solved in the trigonal crystal system and the R − 3 space group, respectively. In the unit cell, there was tri-2-benzofuryl phosphine oxide (Figure 1) cocrystallized with a water molecule, which occurred on threefold axes. In the crystal structure, there were channels formed by phosphine along the c axis. The partial occupancy oxygen atoms O5 from the water molecules were located in the channels by O-H . . . O

hydrogen bonds, arranging the molecules in crystal packing in quite a rare and specific network (Figure 2).

**Figure 1.** Compound **13** in the asymmetric part of the unit cell. The displacement ellipsoids are drawn at the 50% probability level. Hydrogen atoms are omitted for clarity.

**Figure 2.** Crystal packing of the complex of tri-2-benzofuryl phosphine oxide **13.** The displacement ellipsoids are drawn at the 50% probability level. Hydrogen atoms are omitted for clarity.

The reaction of furan afforded a complex mixture of products from which only tri-2-furylphosphinoxide **15** was isolated in low yield (Scheme 4). Its structure was also confirmed by X-ray analysis (Figure 3).

**Scheme 4.** Phosphonylation of furane.

**Figure 3.** The crystal structure of tri-2-furylphosphinoxide **15**.

The structure of tri-2-furylphosphinoxide **15** was solved in the orthorhombic crystal system and *P*212121 space group, respectively (Figure 3). This structure was measured at room temperature and compared with the one described earlier by Jenkis and coworkers [35]. In our investigation, for the measurement series, the structure was confirmed at 100 K. In the molecular structure, the bond lengths and angles were within normal ranges [36]. The crystal structure involved intermolecular C-H . . . O hydrogen bonds.

It is well known that *N*-methylbenzimidazole and *N*-methylindoles undergo lithiation quite readily at C2 [27]. However, these compounds*,* similar to the unprotected benzimidazole, did not provide the desired phosphonates (reaction of butyllithium with trivalent phosphorus compound), and instead the predominant formations of tributyl phosphine or salts of ethyl butyl phosphinous acid were observed. Moreover, the application of the Kartitzky and Akutagawa procedure failed to provide the desired phosphinates in these cases.

To enlarge the scope of the studied reaction, lithiation–phosphonylation of 2-methylthiophene and *N*-methylpyrrole was carried out. As expected, the 2-methylthiophene reacted readily, providing the desired diethyl 2-methyltihophen-5-yl-phosphonate **16**, which upon sequence of transesterification with trimethylbromosilane and methanolysis readily afforded 2-methylthiophene-5-yl-phosphonic acid **17** in good yield (Scheme 5A). Since *N*-methylpyrrole is not susceptible to direct lithiathion [37], addition of a known lithium chelator, tetramethylethylenediamine (TMEDA), and an elevated temperature of the reaction (boiling diethyl ether instead of −70 ◦C) were required to promote the reaction. In the reaction carried out in this way, an equimolar amount of chlorophosphite was added dropwise to the solution of the lithiated *N*-methylpyrrole. After oxidation with hydrogen peroxide provided the mixture of two esters, diethyl (1*H*-pyrrol-2-yl)phosphonate **18** and ethyl di(1*H*-pyrrol-2-yl)phosphinate **19** (Scheme 5B) were obtained, with compound **19** being the major. Diethyl phosphite **20** was the third product of this reaction. The reversal of the addition of the reagents (lithium reagent added to chlorophosphite solution) also provided the mixture of esters **18** and **19**, still with the predominance of compound **19**.

The utility of the elaborated procedure of direct phosphonylation was additionally proven using bromobenzene, 1-bromo-3-methoxybenzene, and 1-bromonaphthalene as substrates, since the direct lithiation of benzene, anisole, and naphtalene is impossible. As

seen from Scheme 6, in this case also, the proposed one-pot procedure had satisfactory results providing the desired diethyl phosphonates (diethyl phenylphosphonate **21**, diethyl 3-methoxylphenylphosphonate **22**, and diethyl naphthalen-1-ylphosphonate **23**), which were converted into the corresponding phosphonic acids (compounds **24**, **25**, and **26**) by hydrolysis with 6N concentrated hydrochloric acid.

**Scheme 5.** Phosphonylation of 2-methylthiophene (**A**) and N-methylpyrrole (**B**).

**Scheme 6.** Phosphonylation of bromobenzene, 1-bromo-3-methoxybenzene, and 1-bromonaphthalene.

### *2.2. In Vitro Antiproliferative Evaluation*

The antiproliferative activities of the obtained phosphonic acids were evaluated towards three cell cultures, namely, RAW 264.7, PC-3, and MCF-7.

The choice of these lines was governed by the fact that the murine macrophage cell line, RAW 264.7, is often used to initially screen the immunomodulating activity of natural compounds [38] and is used as an osteoclast surrogate in preliminary screening for compounds inhibiting osteoclastogenesis [39], thus being promising antiosteoporotic agents. On the other hand, the PC-3 cell is considered as a classic prostate cancer cell line used as a model of androgen-independent prostate cancer [40], while MCF-7 is popular largely due to its exquisite hormone sensitivity through expression of the estrogen receptor, making it an ideal model to study the hormone response [41]. All the studied compounds appeared to be weakly active or lacked activity and could be considered as practically inactive towards these cell lines. The most active compounds are collected in Table 2.

**Table 2.** Structures and in vitro antiproliferative activities of the phosphonic acids against RAW 264.7 mouse macrophages, PC-3 human prostate cancer cells, and MCF-7 human breast cancer cells.

a IC50 values were determined at concentrations in the range of 1–1000 µg/mL. Values are the mean ± standard deviation from at least three experiments, performed in triplicate.

As seen in Table 2, all the studied phosphonic acids more effectively inhibited the proliferation of the RAW 264.7 cells than the effective antiosteoporotic drug, zolendronate, simultaneously being significantly less active than the popular anticancer agent cisplatin. This suggests that they could rather be considered as antiosteoporotic than anti-inflammatory agents. However, in order to determine their potential as antiosteoporotics, more detailed studies are required.

All the studied compounds exerted quite substantial antiproliferative activity towards PC-3 and MCF-7 cells, being nearly equipotent or even more active than cisplatin. In this respect, compounds **4**, **7**, **24**, and **26** were found to be the most effective. Thus, they might be considered lead substances for further studies.

### **3. Conclusions**

A one-pot lithiation–phosphonylation procedure starting from the lithiation of a heteroaromatic compound with butyllithium, with the further reaction of an intermediate lithium salt with diethylchlorophospite, followed by the oxidation of the product with hydrogen peroxide, appeared to be an interesting alternative for the synthesis of heteroaromatic phosphonates. This simple reaction, however, had significant limitations, which were dependent on the ease of the lithiation procedure, as well as on the stability and reactivity of the lithium intermediate. The elaborated procedure was also successfully used for the preparation of aromatic phosphonates when starting from simple bromoarenes.

### **4. Materials and Methods**

### *4.1. General Information*

All solvents and reagents, purchased from commercial suppliers were of analytical grade and were used without further purification. Unless otherwise specified, the solvents were removed with a rotary evaporator. The 1H-, 31P-, and 13C-NMR spectroscopic experiments were performed on a Bruker Avance II Ultrashield Plus (Bruker, Rheinstetten, Germany) operating at 600.58 MHz (1H), 243.12 MHz (31P{1H}), and 151.016 MHz (13C), a Bruker Avance III 500 MHz (Bruker, Rheinstetten, Germany) operating at 500.14 MHz ( 1H), 202.46 MHz (31P{1H}), and 125.77 MHz (13C), and a JEOL JNM-ECZ 400S Research FT NMR Spectrometer (JEOL Ltd., Tokyo, Japan) operating at 399.78 MHz (1H), 161.83 MHz ( 31P{1H}), and 100.53 (13C). Measurements were made in CDCl3, D2O, and solutions of D2O + NaOD at 300 K, and all solvents were supplied by Merck Life Science (Darmstadt, Germany). The chemical shifts are reported in ppm relative to TMS and 85% H3PO4, used as external standards, and the coupling constants are reported in Hz. The melting points were determined on an SRS Melting Point Apparatus OptiMelt MPA 100 (Stanford Research Systems, Sunnyvale, CA, USA) and are reported uncorrected. The purity of all test compounds was higher than 95% by 1H NMR and LC-MS. The mass spectra were recorded at the Faculty of Chemistry, Wroclaw University of Science and Technology, using a Waters LCT Premier XE mass spectrometer (method of electrospray ionization, ESI) (Waters, Milford, MA, USA).

### *4.2. Crystallography*

The relevant crystallographic data for the molecules and the full geometrical information are summarized in Table 2 and Supplementary Materials Table S2. The crystals were mounted on a CCD Xcalibur diffractometer (Rigaku Oxford Diffraction, Sevenoaks, Kent, UK), equipped with a CCD detector and a graphite monochromator (Rigaku Oxford Diffraction), with MoKα radiation, λ = 0.71073 Å at 100.0 (1) K. The reciprocal space was explored by ω scans with detector positions at 60 mm distance from the crystal. The diffraction data processing of the studied compounds (Lorentz and polarization corrections were applied) was performed using the CrysAlis CCD software package version <IP_ADDRESS>c; Oxford Diffraction Ltd: Abingdon, Oxfordshire, UK, 2005 [42]. Both crystal structures were solved by direct methods using the SHELXS-2013/1 and SHELXL-2014/7 programs [43,44]. All non-hydrogen atoms were located from difference Fourier synthesis and refined by the least squares method in the full-matrix anisotropic approximation using SHELXL14 software [42,43]. In both structures, the H atoms were located from difference Fourier synthesis. The structure drawings were prepared using the Mercury 2022.3.0 program [45].

The crystallographic data for **13** and **15** have been deposited at the Cambridge Crystallographic Data Centre as supplementary publication nos. CCDC 1904705 for 13 and CCDC 1960286 for 15. These data can be obtained free of charge via http://www.ccdc.cam. ac.uk/conts/retrieving.html (accessed on 5 March 2023) or from the Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: 144-1223-336-033; email<EMAIL_ADDRESS>
### *4.3. General Procedure for the Synthesis*

### 4.3.1. Preparation of Diethyl 1*H*-indol-2-ylphosphonate (**1**)

First, 10 mmol of indole (1.17 g) was dissolved in 20 mL dry THF. The solution was cooled to −70 ◦C while a slow stream of N2 was passed through. Subsequently, 10.5 mmol of BuLi (6.6 mL, 1.6 M in hexane) was added to the solution resulting in the appearance of the suspension of the lithium salt. The mixture was left for 30 min at −70 ◦C. Then, dry CO2 was bubbled through the mixture until the solution became completely clear (ca. 10 min), and it was left for 10 min at −70 ◦C. In the next step, the solvent and excess of CO2 were evaporated under reduced pressure at the lowest possible temperature. The resulting solid residue was dissolved in 20 mL of dry THF and cooled to −70 ◦C under a nitrogen atmosphere. Then, 10.5 mmol of BuLi (6.6 mL, 1.6 M in hexane) was added, and the precipitation of the yellow intermediate was observed. The temperature was maintained at −70 ◦C for 1 h. Afterwards, 10 mmol (1.56 g, 1.42 mL) of ClP(OEt)2 dissolved in 5 mL dry THF was added dropwise, and the resulting mixture was allowed to warm to −40 ◦C. Subsequently 3 mL of a 30% solution of H2O2 was added dropwise, and the solution was left to reach room temperature. The resulting mixture was poured out into 30 mL of saturated solution of NH4Cl, acidified with sulfuric acid, and slightly warmed. The product was extracted with diethyl ether and purified by column chromatography (silica gel/ethyl acetate). Compound **1** was obtained as a cream-colored solid (2.10 g, 83%); m.p. 66–67 ◦C (lit.[46] m.p. 81–82 ◦C); 31P-NMR (243.12 MHz, CDCl3,): δ = 10.54 ppm; 1H-NMR (600.58 MHz, CDCl3): δ = 1.36 (t, 6H, *J =* 7.1 Hz, POCH2C*H*3), 4.12–4.25 (m, 4H, POC*H2*CH3), 7.09 (s, 1H, C*H* = CP), 7.19 (t, 1H, *J =* 7.4 Hz, Ar*H*), 7.33 (t, 1H, *J =* 8.3 Hz, Ar*H*), 7.51 (d, 1H, *J =* 7.9 Hz, Ar*H*), 9.67 (s, 1H, N*H*) ppm; 13C-NMR (151.02 MHz, CDCl3): δ = 16.14 (d, *J* = 7.55 Hz, POCH2*C*H3), 62.98 (d, *J =* 4.53 Hz, PO*C*H2), 112.15 (d, *J =* 9.06 Hz, P-C=*C*), 112.26 (d, *J =* 9.06 Hz), 120.48, 121.75, 123.01 (d, *J =* 220.49 Hz, P-*C*=C), 124.60, 127.23 (d, *J =* 15.10 Hz, P-C=C-*C*), 138.43 (d, *J =* 12.08 Hz, P-C=C-N-*C*) ppm; HRMS (ESI + TOF) *m*/*z*: [M + H]+ . Calcd for C12H16NO3P: 254.0946; found: 254.0954.

### 4.3.2. Preparation of 1*H*-indolin-2-ylphosphonic Acid (**4**)

To 1 mmol (0.25 g) of ester **1** dissolved in TFA (10 mL) and cooled in an ice bath, 6.3 mmol (0.40 g) of NaBH3CN was added carefully over a period of 30 min, and the mixture was left stirring for 24 h at room temperature. Then, the flask contents were poured into a solution prepared by dissolving 5 g of NaOH in a 20 mL water/ice mixture. The crude product was extracted with CHCl3 (4 × 20 mL) and purified by column chromatography (silica/ethyl acetate). Then, 0.10 g of the resulting diethyl ester of 1*H*indolin-2-ylphosphonic acid (compound **3**, yield 50%) was refluxed for 4 h with 8 mL of a 1:1 mixture of concentrated HCl and H2O. Then, the volatile residues were removed by a rotary evaporator, and the solid material was heated with 3 mL of anhydrous EtOH. After cooling, the 1*H*-indolin-2-ylphosphonic acid crystalized from the dry ethanol. The solids were filtered, washed with cooled dry ethanol, and dried.

1*H*-indolin-2-ylphosphonic acid (**4**) was obtained as a white solid (60 mg, 78% of yield; m.p. 217–218 ◦C; 31P-NMR (202.46 MHz, D2O + NaOD) δ = 18.47 ppm; 1H-NMR (500.14 MHz, D2O + NaOD) δ = 3.17–3.31 (m, 2H, C*H*2CHP), 3.69–3.74 (m, 1H, CH2C*H*P), 6.85 (t, 1H, *J* = 9.35 Hz, Ar*H*), 6.86 (t, 1H, *J* = 7.35 Hz, Ar*H*), 7.14 (t, 1H, *J* = 7.60 Hz, Ar*H*), 7.24 (d, 1H, *J* = 7.25 Hz, Ar*H*) ppm; 13C-NMR (125.76 MHz, D2O + NaOD) δ = 32.11, 56.87 (d, *J* = 137.07 Hz, *C*P), 111.15, 119.63, 124.91, 127.23, 131.09, 150.84; HRMS (ESI + TOF) *m*/*z*: [M − H]+ . Calcd. for C8H10NO3P: 198.0320; found: 198.0318.

4.3.3. General Procedure for the Preparation of Benzo[*b*]tiophen-2-ylphosphonic Acid (**8**), Tri-2-benzofuryl Phosphine Oxide (**13**), Benzofuran-2-ylphosphonic Acid (**14**), Tri-2-furyl oxide (**15**), 5-Methyltiophen-2-ylphosphonic Acid (**17**), Phenylphosphonic Acid (**24**), 3-Methoxyphenylphosphonic Acid (**25**), and Aphtha-1-ylphosphonic Acid (**26**)

To the mixture of an appropriate substrate (20 mmol of benzotiophene, benzofuran, furan, 2-methyltiophene, 1-bromo-naphthalene, bromobenzene, or 3-bromoanisole) dissolved in 30 mL anhydrous THF and cooled to −70 ◦C, BuLi (16.2 mL, 26.0 mmol, 1.6 M in hexane) was added dropwise for 30 min under a stream of N2. Then, the resulting solution or suspension was stirred for 30 min at −70 ◦C followed by the dropwise addition of a solution of 20 mmol of ClP(OEt)2 (3.13 g, 2.85 mL) in 30 mL of dry THF, maintaining the temperature below −65 ◦C. After the addition was complete, the reaction was continued for 60 min, and then the cooling bath was removed. When the temperature of the mixture reached −30 ◦C, 5 mL of 30% aqueous solution of hydrogen peroxide was added very cautiously drop by drop, and the mixture was allowed to warm to room temperature. The resulting solution was poured into 200 mL of water. The crude phosphonic ester was extracted with dichloromethane (3 × 20 mL). The organic layers were combined, dried over anhydrous MgSO4, filtered, and evaporated under reduced pressure. The products were purified by column chromatography (silica/diethyl ether or ethyl acetate) or used directly in the next step. The aryl derivatives were hydrolyzed by refluxing in diluted hydrochloric acid (20%), and the crude products were recrystallized from water. Phosphonate esters of heterocyclic derivatives were deprotected by application of TMSBr. Thus, 10.0 mmol of the ester was mixed with dry CH2Cl2 and 40 mmol (6.12 g) of TMSBr and stirred for 72 h. The volatile components were evaporated under reduced pressure to give a solid residue to which 15 mL of MeOH was added, and the mixture was stirred for 1 h at room temperature. The precipitated product was filtered off, washed with MeOH and Et2O, and recrystallized from anhydrous ethanol.

Benzo[*b*]tiophen-2-ylphosphonic acid (**8**) was obtained as creamy prisms (36% of yield); m.p. 198–199 ◦C; 31P-NMR (202.46 MHz, D2O + NaOD) δ = 4.33 ppm; 1H-NMR (500.14 MHz, D2O + NaOD) δ = 7.22–7.28 (m, 2H, Ar*H*), 7.44 (d, 1H, *J* = 7.95 Hz, Ar*H*), 7.76 (d, 1H, *J* = 7.45 Hz, Ar*H*), 7.81 (d, 1H, *J* = 7.70 Hz, Ar*H*) ppm; 13C-NMR (125.76 MHz, D2O + NaOD) δ = 122.45 (d, *J* = 1.79 Hz), 123.99, 124.30, 124.60, 126.78 (d, *J* = 9.39 Hz), 140.15 (d, *J* = 14.91Hz, *C*S), 141.43 (d, *J* = 6.36 Hz, *C*HCP), 144.17 (d, *J* = 170.89 Hz, *C*P); HRMS (ESI + TOF) *m*/*z*: [M − H]+ . Calcd. for C8H7O3P: 212.9775; found: 212.9774.

4.3.4. Mixture of Diethyl Benzofuran-2-ylphosphonate (**10**) and Diethyl Benzofuran-2-ylphosphinate (**11**)

After work-up with water, the mixture of products was extracted to dichloromethane (3 × 20 mL), dried over anhydrous MgSO4, filtered, and evaporated under reduced pressure. This resulted in a mixture of an oily and crystalline product. The first fraction of crystalline product (mixture of compound **12** and **13**) was isolated by treatment of the mixture with methanol and filtration. The remaining oil was purified by column chromatography (silica/diethyl ether), which resulted in the separation of the desired compound **10** from the mixture of **11** and **12**.

The mixture of products **10** (major one) and **11** (minor one) was obtained as a yellow oil (0.90 g, 18%); 31P-NMR (151.02 MHz, CDCl3) δ = 4.57 and −0.79 ppm (respectively); 1H-NMR (600.58 MHz, CDCl3) δ = 1.368 and 1.369 (t each, *J*1 = 7.07 Hz, minor, OCH2C*H*3), 1.40 (t, *J* = 7.07 Hz, major, OCH2C*H*3), 4.05–4.31 (m, both compounds, OC*H*2CH3), 7.330 (t, *J* = 7.51 Hz, minor, Ar*H*), 7.334 (t, *J* = 7.50 Hz, major, Ar*H*), 7.44 (t, *J* = 7.75 Hz, minor, Ar*H*), 7.46 (t, *J* = 7.75 Hz, major, Ar*H),* 7.53 (dd, *J*1 = 2.67 Hz, *J*2 = 0.73 Hz, major, Ar*H*), 7.57 (dd, *J*1 = 3.42 Hz, *J*2 = 0.72 Hz, minor, Ar*H*), 7.59 (bd, *J* = 8.38 Hz, minor, Ar*H*), 7.60 (bd, *J* = 8.38 Hz, major, Ar*H*), 7.71 (bd, *J* = 7.8 Hz, both compounds, Ar*H*); 13C-NMR (151.02 MHz, CDCl3) δ = 16.16 (d, *J* = 6.63 Hz, minor, POCH2*C*H3), 16.29 (d, *J* = 6.40 Hz, major, POCH2*C*H3), 63.22 (d, *J* = 5.36 Hz, major, PO*C*H2CH3), 63.64 (d, *J* = 5.66 Hz, minor, PO*C*H2CH3), 112.14 (minor), 112.18 (major), 118.53 (d, *J* = 17.54 Hz, minor); 119.05 (d, *J* = 24.12 Hz, major), 122.48 (major), 122.50 (minor), 123.61 (major), 123.67 (minor), 126.92 (minor), 127.00 (major), 145.97 (d, *J* = 236.47 Hz, major, *C*P), 148.00 (d, *J* = 214.03 Hz, minor, *C*P) ppm; HRMS (ESI + TOF) *m*/*z*: [M + H]+ . Calcd. for C12H15O4P (**10**): 255.0786; found: 255.0778; 277.0663 (M + Na); 531.1357 (2M + Na).

The mixture of tri-2-benzofuryl phosphine and its oxide (**12** and **13**) was obtained as white crystals (1.75 g, 62%); m.p. 210–211 ◦C; 31P-NMR (243.12 MHz, CDCl3) δ = −67.73 and −8.26 ppm; 1H-NMR (600.58 MHz, CDCl3) δ = 7.27 (td, 1H, *J*1 = 7.15 Hz, *J*2 = 0.70 Hz, Ar*H*), 7.30 (dd, 1H, *J*1 = 1.83 Hz, *J*2 = 0.89 Hz, Ar*H*), 7.36 (m, 2H, Ar*H*), 7.48 (t, 1H, *J* = 7.52 Hz, Ar*H*), 7.57 (dd, 1H, *J*1 = 8.37 Hz, *J*2 = 0.62 Hz, Ar*H*), 7.61 (dd, 1H, *J*1 = 1.57 Hz, *J*2 = 0.61 Hz, Ar*H*), 7.63 (m, 1H, Ar*H*), 7.72 (dd, 1H, *J*1 = 2.78 Hz, *J*2 = 0.76 Hz, Ar*H*) 7.74 (d, 1H, *J* = 7.84 Hz, Ar*H*) ppm; 13C-NMR (151.02 MHz, CDCl3) δ = 111.76, 112.43, 118.39 (d, *J* = 22.39 Hz), 120.53 (d, *J* = 20.92 Hz), 121.47, 122.75, 123.04, 123.88, 125.60, 126.50 (d, *J* = 10.02Hz), 127.53, 127.84 (d, *J* = 6.42 Hz), 147.09 (d, *J* = 152.99 Hz, *C*P(O)), 150.88 (d, *J* = 4.98 Hz, *C*P), 158.14 (d, *J* = 5.48 Hz, *C*OCP), 158.09 (d, *J* = 11.61 Hz, *C*OCP(O)) ppm; HRMS (ESI + TOF) *m*/*z*: [M + H]+ . Calcd. for C24H15O4P: 399.0786; found: 399.0792.

Tri-2-benzofuryl phosphine oxide (**13**) was obtained as a white solid (24%) 31P-NMR (161.83 MHz, CDCl3) δ = −7.63 ppm; 1H-NMR (399.78 MHz, CDCl3) δ = 7.32 (ddd, 1H, *J*1 = 0.95 Hz, *J*2 = 7.20 Hz, *J*3 = 8.03 Hz, Ar*H*), 7.42–7.46 (m, 1H, Ar*H*), 7.568 (ddd, 1H, *J*1 = 0.88 Hz, *J*2 = 1.73 Hz, *J*3 = 8.44 Hz, Ar*H*), 7.67 (dd, 1H, *J*1 = 0.98 Hz, *J*2 = 2.86 Hz, Ar*H*), 7.67–7.71 (m, 1H, Ar*H*) ppm; 13C-NMR (100.53 MHz, CDCl3) δ = 112.50 (d, *J* = 1.16 Hz), 120.62 (d, *J* = 21.01 Hz), 122.84, 123.96 (d, *J* = 1.15 Hz), 126.56 (d, *J* = 10.07 Hz), 127.61, 147.13 (d, *J* = 153.07 Hz, *C*P), 158.16 (d, *J* = 9.29 Hz) ppm; HRMS (ESI + TOF) *m*/*z*: [M + H]+ . Calcd. for C24H15O4P: 399.0786; found: 399.0854; [M + Na]+ 421.0623.

Benzofuran-2-ylphosphonic acid (**14**) was obtained as orange crystals (0.90 g, 46%); decomposed around 400oC; 31P-NMR (161.83 MHz, D2O) δ = 0.62 ppm; 1H-NMR (399.78 MHz, D2O) δ = 7.17 (dd, *J*1 = 0.95 Hz, *J*2 = 2.66 Hz, 1H, Ar*H*), 7.23 (td, *J*1 = 0.97 Hz, *J*2 = 7.62 Hz, 1H, Ar*H*), 7.32–7.36 (m, 1H, Ar*H*), 7.52 (dd, *J*1 = 0.84 Hz, *J*2 = 8.36 Hz, 1H, Ar*H*), 7.64 (d, *J* = 7.72 Hz, 1H, Ar*H*), ppm; 13C-NMR (100.53 MHz, D2O) δ = 111.82 (d, *J* = 1.27 Hz), 113.70, 113.92, 122.39, 123.38, 126.13, 127.02 (d, *J* = 11.08 Hz), 152.72 (d, *J* = 217.97 Hz, *C*P), 156.41 (d, *J* = 10.56 Hz, *C*OCP) ppm; HRMS (ESI + TOF) *m*/*z*: [M − H]−. Calcd. for C8H7O4P: 197.0004; found: 197.0001; [2M − H] 395.0263.

Tri-2-furyl oxide (**15**) was obtained as a white solid (0.6 g, 12%); 31P-NMR (161.83 MHz, CDCl3) δ = −11.04 ppm; 1H-NMR (399.78 MHz, CDCl3) δ = 6.54 (dt, 1H, *J*1 = 1.66 Hz, *J*2 = 3.40 Hz, Ar*H*), 7.15 (ddd, 1H, *J*1 = 0.72 Hz, *J*2 = 2.05 Hz, *J*3 = 3.49 Hz, Ar*H),* 7.72 (ddd, 1H, *J*1 = 0.72. Hz, *J*2 = 1.70 Hz, *J*3 = 2.53 Hz, Ar*H)* ppm; 13C-NMR (100.53 MHz, CDCl3) δ = 111.15, (d, *J* = 9.41 Hz), 123.60 (d, *J* = 21.05 Hz), 146.02 (d, *J* = 158.84 HZ, *C*P), 148.98 (d, J = 8.81 Hz) ppm; HRMS (ESI + TOF) *m*/*z*: [M + H]+ . Calcd. for C12H9O4P: 249.0317; found: 249.0354; [M + Na]+ 271.0129.

Diethyl 2-Methylthiophen-5-yl-phosphonate *(***16***)* was obtained as a yellow oil (2.22 g, 48%); 31P-NMR (243.12 MHz, CDCl3) δ = 12.10 ppm; 1H-NMR (600.58 MHz, CDCl3) δ = 1.35 (t, 6H, *J* = 7.11 Hz, 6H, OCH2C*H*3), 2.56 (s, 3H, CC*H*3), 4.08–4.19 (m, 4H, OC*H*2CH3), 6.85 (q, *J*1 = 2.65 Hz, 1H Ar*H*), 7.49 (dd, *J*1 = 8.52 Hz, *J*2 = 3.51 Hz, 1H Ar*H*) ppm; 13C-NMR (151.03 MHz, CDCl3) δ = 15.26 (d, *J* = 1.38 Hz, C*C*H3), 16.21 (d, *J* = 6.87 Hz, POCH2*C*H3), 62.44 (d, *J* = 5.32 Hz, PO*C*H2CH3), 124.91(d, *J* = 211.78 Hz, *C*P), 126.59 (d, *J* = 17.07 Hz), 137.28 (d, *J* = 11.53 Hz), 148.90 (d, *J* = 7.15 Hz) ppm; HRMS (ESI + TOF) *m*/*z*: [M + H]+ . Calcd. for C9H15O3PS: 235.0558; found: 235.0567; [M + Na]+ 257.0345; [2M + H]+ 469.0922; [2M + Na]+ 491.0674.

5-Methylthiophen-2-ylphosphonic acid (**17**) was obtained as an amorphous solid (65% yield), m.p. 50 ◦C; 31P-NMR (161.98 Hz, CDCl3) δ = 15.26 ppm; 1H-NMR (400.13 MHz, CDCl3) δ = 2.52 (s, 3H, CC*H*3), 6.78–6.80 (m, 1H, Ar*H*), 7.43 (dd, *J*1 = 3.40 Hz, *J*2 = 9.26 Hz, 1H, Ar*H*), 7.96–8.21 (m, 2H, PO3*H*2) ppm; 13C-NMR (151.02 MHz, CDCl3) δ = 15.26 (d, *J* = 1.38 Hz, C*C*H3), 124.91 (d, *J* = 211.78 Hz, C*C*P), 126.59 (d, *J* = 17.07 Hz), 137.28 (d, *J* = 11.63 Hz), 148.90 (d, *J* = 7.15 Hz) ppm; HRMS (ESI + TOF) *m*/*z*: [M − H]−. Calcd. for C5H7SO3P: 176.9775; found: 176.9773; [2M + Na]- 375.5813.

Diethyl phenylphosphonate (**21**) was obtained as a dense oil (66% yield); 31P-NMR (202.46 MHz, CDCl3) δ = 19.08 ppm; 1H-NMR (500.14 MHz, CDCl3) δ = 1.23 (t, 6H, *J* = 7.05 Hz, OCH2C*H*3), 3.93–4.08 (m, 4H, OC*H*2), 7.36–7.41 (m, 2H, Ar*H*), 7.45–7.49 (m, 1H, Ar*H*), 7.67–7.72 (m, 2H, Ar*H*) ppm; 13C-NMR (125.76 MHz, CDCl3) δ = 16.05 (d, *J* = 6.45 Hz, POCH2*C*H3), 62.25 (d, *J* = 5.57 Hz, PO*C*H2), 127.69 (d, *J* = 198.520 Hz, P*C*), 128.46 (d, *J* = 15.08 Hz), 131.53 (d, *J* = 9.96 Hz), 132.51 (d, *J* = 3.04 Hz) ppm; HRMS (ESI + TOF) *m*/*z*: [M + H]+ . Calcd. for C6H7O3P: 159.0211; found: 159.0209.

Phenylphosphonic acid (**24**) was obtained as a white solid (51% yield from bromobenzene); m.p. 161–163 ◦C (lit.[47] m.p. 166); 31P-NMR (202.46 MHz, D2O + NaOD) δ = 11.31 ppm; 1H-NMR (500.14 MHz, D2O + NaOD) δ = 7.10–7.24 (m, 3H, Ar*H*), 7.42–7.55 (m, 2H, Ar*H*) ppm; 13C-NMR (125.76 MHz, D2O + NaOD) δ = 127.70 (d, *J* = 12.56 Hz), 128.71 (d, *J* = 2.15 Hz), 130.07 (d, *J* = 8.75 Hz) ppm; HRMS (ESI + TOF) *m*/*z*: [M − H]+ . Calcd. for C6H7O3P: 157.0055; found: 157.0048.

Diethyl 3-methoxyphenylphosphonate (**22**) was obtained as a dense oil (63%, yield); 31P-NMR (202.46 MHz, CDCl3) δ = 18.64 ppm; 1H-NMR (500.14 MHz, CDCl3) δ = 1.32 and 1.36 (t, 6H, *J*1 = 7.05 Hz, *J*2 = 7.10 Hz, OCH2C*H*3), 3.84 (s, 3H, OC*H*3), 4.04–4.18 (m, 4H, OC*H*2), 7.07–7.09 (m, 1H, Ar*H*), 7.31–7.35 (m, 1H, Ar*H*), 7.36–7.39 (m, 2H, Ar*H*) ppm; 13C-NMR (125.76 MHz, CDCl3) δ = 16.30 (d, *J* = 6.49 Hz, POCH2*C*H3), 55.40 (O*C*H3), 62.16 (d, *J* = 5.39 Hz, PO*C*H2), 116.37 (d, *J* = 11.36 Hz), 118.72 (d, *J* = 3.18 Hz), 118.72 (d, *J* = 3.18 Hz), 123.93 (d, *J* = 9.28 Hz), 129.55 (d, *J* = 186.89 Hz, *C*P), 129.73 (d, *J* = 17.58 Hz), 159.43 (d, *J* = 18.89 Hz) ppm; HRMS (ESI + TOF) *m*/*z*: [M + H]+ . Calcd. for C11H17O4P: 245.0943; found: 245.0940. These data are in good agreement with the literature [48].

3-Methoxyphenylphosphonic *acid* (**25**) was obtained as a brownish solid (50% yield from bromoanisole) m.p. 124–126 ◦C (lit.[49] m.p. 139–142 ◦C); 31P-NMR (202.46 MHz, D2O + NaOD) δ = 10.82 ppm; 1H-NMR (500.14 MHz, D2O + NaOD) δ = 3.75 (s, 3H, OC*H*3), 6.88 (d, 1H, *J* = 7.05 Hz, Ar*H*), 7.19–7.27 (m, 3H, Ar*H*) ppm; 13C-NMR (125.76 MHz, D2O + NaOD) δ = 55.38 (O*C*H3), 114.33 (d, *J* = 2.64 Hz), 115.59 (d, *J* = 9.85 Hz), 123.14 (d, *J* = 8.23 Hz), 129.10 (d, *J* = 14.46 Hz), 142.72 (d, *J* = 165.84 Hz, *C*P), 158.04 (d, *J* = 15.82 Hz) ppm; HRMS (ESI + TOF) *m*/*z*: [M − H]+ . Calcd. for C7H9O4P: 187.0160; found: 187.0169.

Naphth-1-ylphosphonic acid (**26**) was obtained as a white solid (56% yield from 1 bromonaphtalene) m.p. 203–204 ◦C (lit. [50] m.p. 204–206 ◦C); 31P-NMR (202.46 MHz, D2O + NaOD) δ = 9.09 ppm; 1H-NMR (500.14 MHz, D2O + NaOD) δ = 7.34 (t, 2H, *J* = 7.40 Hz, Ar*H*), 7.42 (t, 1H, *J* = 7.40 Hz, Ar*H*), 7.75 (d, *J* = 8.10 Hz, Ar*H*), 7.83 (dd, *J* = 6.90 Hz, *J* = 13.85 Hz, PC = C*H*), 8.59 (d, 1H, *J* = 8.45 Hz, Ar*H*) ppm; 13C-NMR (125.76 MHz, D2O + NaOD) δ = 125.09 (d, *J* = 13.69 Hz), 125.65 (d, *J* = 19.86 Hz), 128.24, 128.62 (d, *J* = 4.55 Hz), 129.41 (d, *J* = 2.64 Hz), 129.99 (d, *J* = 7.58 Hz), 132.97 (d, *J* = 8.79 Hz), 133.28 (d, *J* = 10.16 Hz), 137.70 (d, *J* = 163.22 Hz, *C*P) ppm; HRMS (ESI + TOF) *m*/*z*: [M − H]+ . Calcd. for C10H9O3P: 207.0211; found 207.0212.

### 4.3.5. Preparation of Benzo[*b*]thiazol-2-ylphosphonic Acid (**7**)

The mixture of 30 mL anhydrous THF containing 16 mmol of BuLi (16.2 mL, 1.6 M in hexane) was placed in a round-bottom flask and cooled to −70 ◦C, while 20 mmol of benzothiazole (2.70 g) was added dropwise under a stream of N2. The resulting yellow suspension of lithium salt was stirred for an additional 30 min at −70 ◦C. In the meantime, in a separate flask, 20 mmol of ClP(OEt)2 (3.13 g) in 30 mL dry THF was prepared and cooled in an ice bath, and the suspension of the lithium salt to the solution of ClP(OEt)2 in one batch was added to this solution. The resulting orange solution was stirred for the next 30 min, while the temperature was maintained at 0 ◦C followed by the dropwise addition of 3 mL of 30% aqueous solution of H2O2, which resulted in the appearance of a yellow precipitate. The reaction was continued for an additional 1 h. After that, the flask contents were poured into 200 mL of cold water, and the crude phosphonic ester was extracted with diethyl ether (3 × 20 mL). The organic phases were combined, dried over anhydrous MgSO4, filtered, and evaporated under reduced pressure. The product was purified by column chromatography (SiO2/Et2O) to yield 3.24 g (60%) of diethyl benzo[*b*]thiazol-2-ylphosphonate, which was used immediately in the next reaction. Thus, 10.0 mmol (2.71 g) of the resulting ester was mixed with dry CH2Cl2 and 40 mmol (6.12 g) of TMSBr and stirred for 72 h. The volatile components were evaporated under reduced pressure to give a solid residue to which 15 mL of MeOH was added, and the mixture was stirred for 1 h at room temperature. The precipitated product was filtered off, washed with MeOH and Et2O, and dried.

Compound **7** was obtained as a yellowish solid (84% yield (total yield 50%) m.p. 231–232 ◦C (lit.[51] m.p. 161–163 ◦C); 31P-NMR (202.46 MHz, D2O + NaOD) δ = 0.14 ppm; 1H-NMR (500.14 MHz, D2O + NaOD) δ = 7.34 (t, 1H, *J* = 7.40 Hz, Ar*H*), 7.42 (t, 1H, *J* = 7.10 Hz, Ar*H*), 7.93 (t, 2H, *J* = 7.50 Hz, Ar*H*) ppm; 13C-NMR (125.76 MHz, D2O + NaOD) δ = 122.26, 122.43, 125.57, 126.23, 135.45, 153.76 (d, *J* = 20.00 Hz), 176.30 (d, *J* = 187.65 Hz, *C*P) ppm; HRMS (ESI + TOF) *m*/*z*: [M − H]+ . Calcd. for C7H6SNO3P: 213.9728; found: 213.9728.

### 4.3.6. Preparation of Ethyl Bis(*N*-methylpyrrol-2-yl)phosphinate (**19**)

To the mixture of *N-*methylpyrrole (0.81 g, 10 mmol) and TMEDA (1.42 g, 15 mmol) in 15 mL of dry diethyl ether, a solution of *n*-butyllithium (10.6 mL, 17 mmol, 1.6 M in hexane) was added dropwise, while a slow stream of N2 was passed through. Then, the resulting solution was refluxed for 1 h, and ClP(OEt)2 (1.56 g, 10 mmol) in 5 mL of Et2O was added dropwise with cooling in an ice bath. The reaction was then continued for 8 h at room temperature, and the solution was once again cooled in an ice bath followed by the slow addition of 3 mL of a 30% aqueous solution of H2O2. When the addition

was complete, the flask contents were poured onto 30 mL of water. The crude product containing mostly compound **19** was extracted with CH2Cl2 (3 × 20 mL) and purified by column chromatography (silica/AcOEt) to yield 0.66 g (52%) of ethyl bis(1-methylpyrrol-2 yl)phosphinate as a colorless oil. 31P-NMR (202.46 MHz, CDCl3): δ = 14.92 ppm. 1H-NMR (500.14 MHz, CDCl3): δ = 1.30 (t, 3H, *J* = 7.05 Hz, POCH2CH3), 3.68 (s, 6H, NC*H*3), 4.08–4.13 (m, 2H, POC*H*2), 6.03–6.06 (m, 2H, Ar*H*); 6.53 (td, 2H, *J* = 3.62 Hz, *J* = 1.70 Hz, Ar*H*), 6.73–6.74 (m, 2H, Ar*H*) ppm; 13C-NMR (125.76 MHz, CDCl3): 16.47 (d, *J* = 6.99 Hz), 36.09, 61.36 (d, *J* = 5.51 Hz), 108.20 (d, *J* = 13.42 Hz), 121.32 (d, *J* = 17.79 Hz), 122.48 (d, *J* = 179.35 Hz, *C*P), 129.38 (d, *J* = 6.95 Hz) ppm; HRMS (ESI + TOF) *m*/*z*: [M + H]+ . Calcd. For C12H17N2O2P: 253.1106; found: 253.1112.

For all the spectral data, see the Supplementary Information.

### *4.4. Antiproliferative Activity*

### 4.4.1. Cell Culture

Mycoplasma-free MCF-7, PC-3, and RAW 264.7 cell lines were purchased from the European Collection of Authenticated Cell Cultures (ECACC) and maintained at the Institute of Immunology and Experimental Therapy (IIET), Wroclaw, Poland. The MCF-7 cell line was cultured in an Eagle medium (Life Technologies, Warszawa, Poland), supplemented with 10% (*v/v*) FBS, 2 mM L-glutamine, 1% NEAA, and 0.01 mg/mL insulin (all Sigma-Aldrich, Pozna´n, Poland). The PC-3 cell line was cultured in RPMI-1640 medium (Life Technologies, Scotland), supplemented with 10% (*v/v*) FBS and 2 mM L-glutamine. The RAW 264.7 cell line was cultured in DMEM (Life Technologies, Scotland), supplemented with 10% (*v/v*) FBS and 2 mM L-glutamine. All culture media were additionally supplemented with 100 µg/mL streptomycin and 100 U/mL penicillin. All cell lines were cultured during all experiments in a humid atmosphere at 37 ◦C and 5% CO2 and passaged twice a week using EDTA-Trypsin (pH 8; IIET, Wroclaw, Poland) solution as a detachment agent.

### 4.4.2. SRB Antiproliferative Assay

Twenty-four hours before adding the tested compounds, the cells were seeded on 96-well plates (Sarstedt, Germany) in an appropriate culture medium with 0.75 × 105 cells/mL for MCF-7, 105 cells/mL for PC-3, and 0.1 × 105 cells/mL for RAW 264.7. The cells were treated with each compound in at least four concentrations in the range of 1000 µM–1 µM for 72 h. The 0.2 M NaOH, used as a stock solution solvent, was tested for antiproliferative activity, and it did not affect the cell proliferation at 1 mM, the highest concentration used in the compound solutions.

This was used as previously described [52], with minor modifications for all adherent cells. Briefly, the cells were fixed with 50 µL/well of 50% (*w/v*) trichloroacetic acid (Avantor Performance Materials, Gliwice, Poland). After 1 h incubation, the plates were washed several times with tap water, and 50 µL of a 0.1% (*w/v*) solution of sulforhodamine B (Sigma-Aldrich, Schnelldorf, Germany) in 1% (*v/v*) acetic acid (Avantor Performance Materials, Gliwice, Poland) was added to each well. After 30 min incubation at room temperature, the unbound dye was washed out with 1% (*v/v*) acetic acid, whereas the bound dye was solubilized with 10 mM of unbuffered TRIS (Avantor Performance Materials, Gliwice, Poland) solution. The entire procedure was performed using a Biotek EL-406 washing station (BioTek Instruments, Winooski, VT, USA). The absorbance was then read using a Biotek Hybrid H4 reader (BioTek Instruments, USA) at a 540 nm wavelength.

The compounds at each concentration were tested in triplicate in a single experiment, and each experiment was repeated at least three times independently. The results are presented as the mean IC50 ± standard deviation (SD) calculated using the Prolab-3 system based on Cheburator 0.4 software [53].

**Supplementary Materials:** The following supporting information can be downloaded at: https:// www.mdpi.com/article/10.3390/molecules28073135/s1, Figures S1–S77: The 31P-NMR, 1H-NMR, 13C- NMRand HRMS spectra of the representative compounds; Table S1: Relevant crystallographic data for the molecule and the full geometrical information (Å, ◦ ); Table S2: Selected hydrogen-bond parameters.

**Author Contributions:** E.C. performed the synthetic studies, conceived and designed the experiments, wrote the paper and interpreted the NMR spectra; N.M. synthesized compounds; B.D. obtained and analyzed the crystal structure of compounds **13** and **15**; M.P. performed biological studies; P.K. interpreted the obtained results. All authors have read and agreed to the published version of the manuscript.

**Funding:** Support by subsidy of Ministry of Science and Higher Education No<PHONE_NUMBER>.

**Institutional Review Board Statement:** Not applicable.

**Informed Consent Statement:** Not applicable.

**Data Availability Statement:** The data presented in this study and associated additional data are available upon request.

**Acknowledgments:** We thank K. Ejsmont for the crystallographic analysis.

**Conflicts of Interest:** The authors declare no conflict of interest. The funding sponsors had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript; or in the decision to publish the results.

### **References**

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## *Article* **Highly** *Z***-Selective Horner–Wadsworth–Emmons Olefination Using Modified Still–Gennari-Type Reagents**

**Ignacy Janicki \* and Piotr Kiełbasi ´nski \***

Division of Organic Chemistry, Centre of Molecular and Macromolecular Studies, Polish Academy of Sciences, Sienkiewicza 112, 90-363 Łód´z, Poland

**\*** Correspondence<EMAIL_ADDRESS>(I.J<EMAIL_ADDRESS>(P.K.)

**Abstract:** In this report, new, easily accessible reagents for highly *Z*-selective HWE reactions are presented. Alkyl di-(1,1,1,3,3,3-hexafluoroisopropyl)phosphonoacetates, structurally similar to Still– Gennari type reagents, were tested in HWE reactions with a series of various aldehydes. Very good *Z*-selectivity (up to a 98:2 *Z*:*E* ratio) was achieved in most cases along with high yields. Application of the new reagents may be a valuable, practical alternative to the well-established Still–Gennari or Ando *Z*-selective carbonyl group olefination protocols.

**Keywords:** HWE reaction; Still-Gennari olefination; Ando olefination; stereoselective synthesis; *Z*-selectivity; Wittig reaction; phosphonates; alkenes; hexafluoroisopropanol; C=C bond formation

### **1. Introduction**

Stereoselective alkene synthesis is one of the major challenges in organic synthesis [1]. The configuration of carbon–carbon double bonds affects all properties of molecules, therefore, highly selective methods for the synthesis of *E* or *Z* olefins are of great value. However, *Z*-selective reactions are considerably more difficult and less developed, mainly because of thermodynamic factors, which usually favor formation of the more stable *E*-products [2]. One of the well-established, typically highly *E*-selective alkene formation methods is the Horner–Wadsworth–Emmons (HWE) reaction, which is based on the olefination of carbonyl groups using dialkyl phosphonate reagents (Scheme 1) [3–7]. Its high *E*-selectivity results from the thermodynamic stabilization of *E*-products and intermediates leading to its formation. The selectivity of the HWE reaction is one of its important advantages, but in its classical form, it is restricted to the synthesis of *E*-alkenes. Nevertheless, the selectivity of the HWE reaction is highly dependent on the structure of the phosphonate reagents and it can be modified [8,9]. Attempts to develop *Z*-selective HWE reagents were made already in the late 1970s [10–12], but the first reliable and highly *Z*-selective modification of HWE reaction was reported in 1983 by Still and Gennari (Figure 1) [13]. In the standard HWE reaction, diethyl or dimethyl phosphonate reagents are usually applied. The Still–Gennari modification of the HWE reaction, fairly called "Still–Gennari olefination" due to its broad applicability and inverted selectivity, is based on the application of bis(2,2,2-trifluoroethyl) phosphonate reagents for the olefination of carbonyl compounds, usually in the presence of a strong base system—potassium bis(trimethylsilyl)amide (KHMDS) with 18-crown-6 crown ether. Along with the modification developed in the mid-1990s by Ando [14–18], the Still–Gennari olefination is one of the most widely applied *Z*-selective modifications of the HWE reaction. Its scope of applications was recently discussed in our review article [19]. *Molecules* **2022**, *27*, x FOR PEER REVIEW 2 of 10

.

**Scheme 1.** General scheme of the Horner–Wadsworth–Emmons reaction. phonate reagents bearing 1,1,1,3,3,3-hexafluoroisopropyl R groups. These compounds are **Scheme 1.** General scheme of the Horner–Wadsworth–Emmons reaction.

**Figure 1.** Comparison of *Z*-selective reagents for the HWE reaction [11–14].

thetic toolbox.

aryl substituents.

Still–Gennari and Ando-type reagents constitute important tools for the *Z*-selective alkene formation. However, examples from a total synthesis of biologically active, complex molecules show that achieving high *Z*-selectivity using these reagents is not always easy and the outcome of the olefination reactions is highly dependent on the reaction conditions and the type of reagent used [19]. Therefore, it would be desirable to broaden the scope of reliable *Z*-selective carbonyl olefination reagents in order to improve our syn-

The *Z*-selectivity of Still–Gennari olefination is a result of the kinetic control of the reaction. An electron-withdrawing effect of R groups (Scheme 1), such as 2,2,2-trifluoroethyl or phenyl, favors the *Z*-selective course of the reaction in contrast to standard *E*selective HWE reaction where R is usually the ethyl group (pKa of 2,2,2-trifluoroethanol is 12.4 and pKa of phenol is 10, while pKa of ethanol is 16). The correlation between the electron-withdrawing effect of the R group and the stereoselectivity of the reaction was investigated in more detail by Motoyoshiya and coworkers [9]. Moreover, steric hindrance of R groups may further affect *Z*-selectivity as in the case of Ando-type reagents bearing

In our previous study, we reported a very simple protocol for the synthesis of Still– Gennari and Ando-type phosphonates [20]. We also reported the synthesis of new phos-

**Citation:** Janicki, I.; Kiełbasi ´nski, P. Highly *Z*-Selective Horner– Wadsworth–Emmons Olefination Using Modified Still–Gennari-Type Reagents. *Molecules* **2022**, *27*, 7138. https://doi.org/10.3390/ molecules27207138

Academic Editor: Jakub Adamek

Received: 16 September 2022 Accepted: 18 October 2022 Published: 21 October 2022

**Publisher's Note:** MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

**Copyright:** © 2022 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/).

$$\begin{array}{c} \text{CF}\_3\text{CH}\_2\text{O} \\ \text{CF}\_3\text{CH}\_2\text{O} \end{array} \bigvee \text{COOR}$$

**Scheme 1.** General scheme of the Horner–Wadsworth–Emmons reaction.

.

**Figure 1.** Comparison of *Z*-selective reagents for the HWE reaction [11–14]. **Figure 1.** Comparison of *Z*-selective reagents for the HWE reaction [11–14].

Still–Gennari and Ando-type reagents constitute important tools for the *Z*-selective alkene formation. However, examples from a total synthesis of biologically active, complex molecules show that achieving high *Z*-selectivity using these reagents is not always easy and the outcome of the olefination reactions is highly dependent on the reaction conditions and the type of reagent used [19]. Therefore, it would be desirable to broaden the Still–Gennari and Ando-type reagents constitute important tools for the *Z*-selective alkene formation. However, examples from a total synthesis of biologically active, complex molecules show that achieving high *Z*-selectivity using these reagents is not always easy and the outcome of the olefination reactions is highly dependent on the reaction conditions and the type of reagent used [19]. Therefore, it would be desirable to broaden the scope of reliable *Z*-selective carbonyl olefination reagents in order to improve our synthetic toolbox.

scope of reliable *Z*-selective carbonyl olefination reagents in order to improve our synthetic toolbox. The *Z*-selectivity of Still–Gennari olefination is a result of the kinetic control of the reaction. An electron-withdrawing effect of R groups (Scheme 1), such as 2,2,2-trifluoroethyl or phenyl, favors the *Z*-selective course of the reaction in contrast to standard *E*selective HWE reaction where R is usually the ethyl group (pKa of 2,2,2-trifluoroethanol is 12.4 and pKa of phenol is 10, while pKa of ethanol is 16). The correlation between the The *Z*-selectivity of Still–Gennari olefination is a result of the kinetic control of the reaction. An electron-withdrawing effect of R groups (Scheme 1), such as 2,2,2-trifluoroethyl or phenyl, favors the *Z*-selective course of the reaction in contrast to standard *E*-selective HWE reaction where R is usually the ethyl group (pKa of 2,2,2-trifluoroethanol is 12.4 and pKa of phenol is 10, while pKa of ethanol is 16). The correlation between the electron-withdrawing effect of the R group and the stereoselectivity of the reaction was investigated in more detail by Motoyoshiya and coworkers [9]. Moreover, steric hindrance of R groups may further affect *Z*-selectivity as in the case of Ando-type reagents bearing aryl substituents.

electron-withdrawing effect of the R group and the stereoselectivity of the reaction was investigated in more detail by Motoyoshiya and coworkers [9]. Moreover, steric hindrance of R groups may further affect *Z*-selectivity as in the case of Ando-type reagents bearing aryl substituents. In our previous study, we reported a very simple protocol for the synthesis of Still– Gennari and Ando-type phosphonates [20]. We also reported the synthesis of new phosphonate reagents bearing 1,1,1,3,3,3-hexafluoroisopropyl R groups. These compounds are In our previous study, we reported a very simple protocol for the synthesis of Still– Gennari and Ando-type phosphonates [20]. We also reported the synthesis of new phosphonate reagents bearing 1,1,1,3,3,3-hexafluoroisopropyl R groups. These compounds are expected to be highly *Z*-selective olefination reagents because of a stronger electron-withdrawing effect of 1,1,1,3,3,3-hexafluoroisopropyl R groups (pKa of 1,1,1,3,3,3- hexafluoroisopropanol is 9.4). In the present research, we decided to test the performance of our new reagents and evaluate their applicability on the basis of a series of model reactions with various aldehydes.

### **2. Results and Discussion**

The reagents being subjects of this study, methyl, and ethyl bis(1,1,1,3,3,3-hexafluoroi sopropyl) phosphonates **1a** and **1b**, were synthesized according to our previously reported procedure [20]. Because of a structural resemblance and similar reactivity we may consider **1a** and **1b** as "Still–Gennari-type" reagents. We decided to test these reagents for the synthesis of disubstituted alkenes by *Z*-selective HWE reaction. In order to maximize the yield and the stereoselectivity of the reaction, optimization of the reaction conditions was necessary (Table 1, Scheme 2).

**Table 1.** Reaction of **1b** with benzaldehyde **2a**—optimization [a] .

[a] All the reactions were conducted in 10 mL of THF for 1 h by analogy with the general procedure (see Section 3.2); [b] yield was determined by 1H-NMR with dimethyl terephthalate as internal standard; [c] determined by 1H-NMR; [d] 0.15 equivalent excess of NaH was used; [e] 1 equivalent of NaI was used; [f] 5 equivalents of 18-crown-6 were used. gents for the synthesis of disubstituted alkenes by *Z*-selective HWE reaction. In order to maximize the yield and the stereoselectivity of the reaction, optimization of the reaction conditions was necessary (Table 1, Scheme 2).

**Scheme 2.** Optimization of conditions based on the reaction of **1b** with benzaldehyde **2a**. **Scheme 2.** Optimization of conditions based on the reaction of **1b** with benzaldehyde **2a**.

**Table 1.** Reaction of **1b** with benzaldehyde **2a**—optimization [a] . **Entry Base Temperature Yield [b]** *Z***:***E* **Ratio [c]** 1 NaH −78 °C traces --- 2 NaH −40 °C 82% 97:3 3 NaH −20 °C 94% 97:3 4 NaH 0 °C 85% 95:5 5 NaH (excess) [d] 0 °C 55% 95:5 6 NaH + NaI[e] −20 °C 95% 97:3 7 KHMDS −78 °C 37% 91:9 8 KHMDS + 18-crown-6 [f] −78 °C 34% 84:16 During the optimization study, several base systems were evaluated in the reaction of **1b** with benzaldehyde at various temperatures (Scheme 2). All the reactions were run in THF for 1 h. When using NaH as a base at −78 ◦C, the reaction was very slow, only traces of *Z*-product could be detected after 1 h (Table 1, entry 1). This is most probably due to the slow deprotonation of the phosphonate reagent at this low temperature because when the reaction was heated from −78 ◦C to room temperature, hydrogen gas evolved, and the reaction proceeded. Based on this observation, higher temperatures were evaluated (Table 1, entries 2–4). Quite unexpectedly, the best results regarding yield (94%) and selectivity (97:3 *Z*:*E*) were obtained using NaH at −20 ◦C (Table 1, entry 3), while Still–Gennari olefination is usually conducted at lower temperatures (typically −78 ◦C). This result is very promising because it shows that by using our new reagents high stereoselectivity may be achieved

9 KHMDS −40 °C 52% 90:10 10 KHMDS + 18-crown-6 [f] −40 °C 61% 86:14

12 K2CO3 r.t. traces traces of *Z* 13 Triton-B −20 °C 23% 14:86 14 (CF3)2CHONa −20 °C 93% 96:4 [a] All the reactions were conducted in 10 mL of THF for 1 h by analogy with the general procedure (see experimental section); [b] yield was determined by 1H-NMR with dimethyl terephthalate as internal standard; [c] determined by 1H-NMR; [d] 0.15 equivalent excess of NaH was used; [e] 1

During the optimization study, several base systems were evaluated in the reaction of **1b** with benzaldehyde at various temperatures (Scheme 2). All the reactions were run in THF for 1 h. When using NaH as a base at −78 °C, the reaction was very slow, only traces of *Z*-product could be detected after 1 h (Table 1, entry 1). This is most probably due to the slow deprotonation of the phosphonate reagent at this low temperature because when the reaction was heated from −78 °C to room temperature, hydrogen gas evolved, and the reaction proceeded. Based on this observation, higher temperatures were

equivalent of NaI was used; [f] 5 equivalents of 18-crown-6 were used.

at higher temperatures. Only a slight decrease in stereoselectivity was observed at 0 ◦C (Table 1, entry 4). It is noteworthy that using an excess of a base resulted in a significant decrease in the yield (Table 1, entry 5). The possibility of increasing the stereoselectivity of the reaction by providing additional sodium ions to the reaction mixture according to Pihko et al. was also investigated. However, no influence of the additive on the reaction course was observed (Table 1, entry 6) [21].

In contrast to the classic Still–Gennari olefination protocol, application of KHMDS or KHMDS with 18-crown-6 additive appears to be an inferior option (we made a similar observation in our previous work concerning the synthesis of *Z*-α,β-unsaturated phosphonates) [22]. The yields of the reactions were moderate (34–61%) and the selectivity was lower in comparison to the results obtained with NaH (up to a 91:9 *Z*:*E* ratio—Table 1, entries 7–10). Running the reaction at a lower temperature somewhat favored *Z*-selectivity, however, it decreased the yield (Table 1, entries 8 and 10). The addition of crown ether surprisingly decreased the selectivity of the reaction. Moreover, in our hands, the reaction with KHMDS tends to be a little capricious, sensitive to the reaction conditions, and difficult to reproduce, since we have previously reported better results which we were unable to repeat now.

Other bases which were tested include *t*-BuOK, K2CO3, triton-B (benzyltrimethylammonium hydroxide), and (CF3)2CHONa. Reaction with *t*-BuOK at −20 ◦C gave 62% yield of the product in only an 81:19 *Z*:*E* ratio (Table 1, entry 11), however, conducting the reaction at a lower temperature may improve the yield and *Z*-selectivity to 80% and 92:8 *Z*:*E*, as presented earlier [20]. Unfortunately, the reaction with a mild base K2CO3 was unsuccessful, and only traces of *Z*-product were detected (Table 1, entry 12). Interestingly, the application of triton-B (according to Ando) [14] inverted the stereoselectivity of the reaction (14:86 *Z*:*E* ratio) proving the high influence of the reaction conditions on the observed results (Table 1, entry 13). Unexpectedly, very good results were obtained using (CF3)2CHONa—93% yield and 96:4 *Z*:*E* product ratio. Based on this observation we decided to investigate the possibility of using this base with other HWE reagents (Table 2, Scheme 3). *Molecules* **2022**, *27*, x FOR PEER REVIEW 5 of 10 *Molecules* **2022**, *27*, x FOR PEER REVIEW 5 of 10 *Molecules* **2022**, *27*, x FOR PEER REVIEW 5 of 10 *Molecules* **2022**, *27*, x FOR PEER REVIEW 5 of 10

**Table 2.** HWE reaction of phosphonate reagents **1** and benzaldehyde **2a** with (CF3 )2CHONa as a base [a] . **Table 2.** HWE reaction of phosphonate reagents **1** and benzaldehyde **2a** with (CF3)2CHONa as a base [a] . **Table 2.** HWE reaction of phosphonate reagents **1** and benzaldehyde **2a** with (CF3)2CHONa as a **Table 2.** HWE reaction of phosphonate reagents **1** and benzaldehyde **2a** with (CF3)2CHONa as a

(see experimental section). [b] Yield was determined by 1H-NMR with dimethyl terephthalate as an internal standard. [c] Determined by 1H-NMR. (see experimental section). [b] Yield was determined by 1H-NMR with dimethyl terephthalate as an internal standard. [c] Determined by 1H-NMR. [a] All the reactions were conducted in 10 mL of THF for 1 h according to the general procedure (see experimental section). [b] Yield was determined by 1H-NMR with dimethyl terephthalate as an internal standard. [c] Determined by 1H-NMR. [a] All the reactions were conducted in 10 mL of THF for 1 h according to the general procedure (see experimental section). [b] Yield was determined by 1H-NMR with dimethyl terephthalate as an internal standard. [c] Determined by 1H-NMR. [a] All the reactions were conducted in 10 mL of THF for 1 h according to the general procedure (see Section 3.2). [b] Yield was determined by 1H-NMR with dimethyl terephthalate as an internal standard.

The application of (CF3)2CHONa as a base in the standard HWE reaction of methyl dimethylphosphonoacetate **1c** or ethyl diethylphosphonoacetate **1d** with benzaldehyde resulted in excellent *E*-selectivity and very good yields (Table 2, entries 1 and 2). This observation indicates that (CF3)2CHONa may be successfully used in HWE reactions. Despite excellent results with **1b** and standard HWE reagents **1c** and **1d**, the reaction using

The application of (CF3)2CHONa as a base in the standard HWE reaction of methyl dimethylphosphonoacetate **1c** or ethyl diethylphosphonoacetate **1d** with benzaldehyde resulted in excellent *E*-selectivity and very good yields (Table 2, entries 1 and 2). This observation indicates that (CF3)2CHONa may be successfully used in HWE reactions. De-

The application of (CF3)2CHONa as a base in the standard HWE reaction of methyl dimethylphosphonoacetate **1c** or ethyl diethylphosphonoacetate **1d** with benzaldehyde resulted in excellent *E*-selectivity and very good yields (Table 2, entries 1 and 2). This observation indicates that (CF3)2CHONa may be successfully used in HWE reactions. De-

The application of (CF3)2CHONa as a base in the standard HWE reaction of methyl dimethylphosphonoacetate **1c** or ethyl diethylphosphonoacetate **1d** with benzaldehyde resulted in excellent *E*-selectivity and very good yields (Table 2, entries 1 and 2). This ob-

was only moderately stereoselective, although very high yielding (Table 2, entries 3–6). It is noteworthy that lowering the temperature to −78 °C resulted in little increased *Z*-selec-

(CF3)2CHONa with Still–Gennari and Ando-type phosphonates (**1e** and **1f,** respectively) was only moderately stereoselective, although very high yielding (Table 2, entries 3–6). It is noteworthy that lowering the temperature to −78 °C resulted in little increased *Z*-selec-

(CF3)2CHONa with Still–Gennari and Ando-type phosphonates (**1e** and **1f,** respectively) was only moderately stereoselective, although very high yielding (Table 2, entries 3–6). It is noteworthy that lowering the temperature to −78 °C resulted in little increased *Z*-selec-

was only moderately stereoselective, although very high yielding (Table 2, entries 3–6). It is noteworthy that lowering the temperature to −78 °C resulted in little increased *Z*-selec-

The time course of the reaction of **1b** with benzaldehyde in the presence of NaH at −20 °C was also investigated (Figure 2). Measurements were taken after 5, 10, 15, 30, 60, and 120 min. The reaction proceeded very fast, after 5 min the yield reached 72% and the

The time course of the reaction of **1b** with benzaldehyde in the presence of NaH at −20 °C was also investigated (Figure 2). Measurements were taken after 5, 10, 15, 30, 60, and 120 min. The reaction proceeded very fast, after 5 min the yield reached 72% and the

The time course of the reaction of **1b** with benzaldehyde in the presence of NaH at −20 °C was also investigated (Figure 2). Measurements were taken after 5, 10, 15, 30, 60, and 120 min. The reaction proceeded very fast, after 5 min the yield reached 72% and the

The time course of the reaction of **1b** with benzaldehyde in the presence of NaH at −20 °C was also investigated (Figure 2). Measurements were taken after 5, 10, 15, 30, 60, and 120 min. The reaction proceeded very fast, after 5 min the yield reached 72% and the

tivity compared to the reaction at −20 °C, without significant loss of yield.

tivity compared to the reaction at −20 °C, without significant loss of yield.

tivity compared to the reaction at −20 °C, without significant loss of yield.

tivity compared to the reaction at −20 °C, without significant loss of yield.

**Figure 2.** Time course of the reaction of **1b** and benzaldehyde with NaH at −20 °C.

**Figure 2.** Time course of the reaction of **1b** and benzaldehyde with NaH at −20 °C.

**Figure 2.** Time course of the reaction of **1b** and benzaldehyde with NaH at −20 °C.

**Figure 2.** Time course of the reaction of **1b** and benzaldehyde with NaH at −20 °C.

Time [min]

Time [min]

Time [min]

Time [min]

0 20 40 60 80 100 120

0 20 40 60 80 100 120

0 20 40 60 80 100 120

0 20 40 60 80 100 120

Yield [%]

Yield [%]

Yield [%]

Yield [%]

1

2

5

$$\begin{array}{ccccc} \circ & \circ & \circ \\ \circ & \circ & \circ \\ \circ & \circ & \circ \end{array} \begin{array}{ccccc} \circ & \circ & \circ \\ \circ & \circ & \circ \\ \circ & \circ & \circ \end{array} \begin{array}{ccccc} \circ & \circ & \circ \\ \circ & \circ & \circ \\ \circ & \circ & \circ \end{array} \begin{array}{ccccc} \circ & \circ \\ \circ & \circ & \circ \\ \circ & \circ & \circ \end{array}$$

**Table 2.** HWE reaction of phosphonate reagents **1** and benzaldehyde **2a** with (CF3)2CHONa as a

−20 °C 87% 2:98

−20 °C 79% >99% *E*

−20 °C 99% 68:32

**Scheme 3.** Reaction of reagents **1** with various aldehydes **2** under optimized conditions. **Scheme 3.** Reaction of reagents **1** with various aldehydes **2** under optimized conditions. internal standard. [c] Determined by 1H-NMR.

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**Entry Reagent Temperature Yield [b]** *Z***:***E* **Ratio [c]**

4 −78 °C 96% 75:25

base [a] .

**1c**

**1d**

**Table 3.** Reactions of **1a** and **1b** with aldehydes **2a–2m** [a] . **Entry Substrate Aldehyde Reagent 1a Reagent 1b Product Yield [b]** *Z***:***E* **[c] Product Yield [b]** *Z***:***E* **[c]** 1 **2a 3aa** 91% 97:3 **3ba** 95% (99%) [d] 97:3 (74:26) [d] The application of (CF3)2CHONa as a base in the standard HWE reaction of methyl dimethylphosphonoacetate **1c** or ethyl diethylphosphonoacetate **1d** with benzaldehyde resulted in excellent *E*-selectivity and very good yields (Table 2, entries 1 and 2). This observation indicates that (CF3)2CHONa may be successfully used in HWE reactions. Despite excellent results with **1b** and standard HWE reagents **1c** and **1d**, the reaction using (CF3)2CHONa with Still–Gennari and Ando-type phosphonates (**1e** and **1f,** respectively) was only moderately stereoselective, although very high yielding (Table 2, entries 3–6). It is noteworthy that lowering the temperature to −78 ◦C resulted in little increased *Z*-selectivity compared to the reaction at −20 ◦C, without significant loss of yield. The application of (CF3)2CHONa as a base in the standard HWE reaction of methyl dimethylphosphonoacetate **1c** or ethyl diethylphosphonoacetate **1d** with benzaldehyde resulted in excellent *E*-selectivity and very good yields (Table 2, entries 1 and 2). This observation indicates that (CF3)2CHONa may be successfully used in HWE reactions. Despite excellent results with **1b** and standard HWE reagents **1c** and **1d**, the reaction using (CF3)2CHONa with Still–Gennari and Ando-type phosphonates (**1e** and **1f,** respectively) was only moderately stereoselective, although very high yielding (Table 2, entries 3–6). It is noteworthy that lowering the temperature to −78 °C resulted in little increased *Z*-selectivity compared to the reaction at −20 °C, without significant loss of yield.

2 **2b 3ab** 84% 96:4 **3bb** 81% 96:4 The time course of the reaction of **1b** with benzaldehyde in the presence of NaH at −20 ◦C was also investigated (Figure 2). Measurements were taken after 5, 10, 15, 30, 60, and 120 min. The reaction proceeded very fast, after 5 min the yield reached 72% and the reaction was complete within 1 h (94%). The time course of the reaction of **1b** with benzaldehyde in the presence of NaH at −20 °C was also investigated (Figure 2). Measurements were taken after 5, 10, 15, 30, 60, and 120 min. The reaction proceeded very fast, after 5 min the yield reached 72% and the reaction was complete within 1 h (94%).

8 **2h 3ah** 88% 92:8 **3bh** 79% 95:5 **Figure 2.** Time course of the reaction of **1b** and benzaldehyde with NaH at −20 °C. **Figure 2.** Time course of the reaction of **1b** and benzaldehyde with NaH at −20 ◦C.

9 **2i 3ai** 79% 94:6 **3bi** 89% 95:5 10 **2j 3aj** 78% 89:11 **3bj** 82% 91:9 Based on the above observations, all further reactions of **1a** and **1b** with a series of various aldehydes **2a**–**2m** were carried out in THF at −20 ◦C for 1 h, using NaH as a base (Scheme 3, Table 3). Generally, similar reaction yields were observed for both reagents **1a** and **1b**; however, slightly better stereoselectivities were observed for ethyl bis-(1,1,1,3,3,3-hexafluoroisopropyl)phosphonoacetate **1b** than for methyl bis-(1,1,1,3,3,3 hexafluoroisopropyl)phosphonoacetate **1a**.

11 **2k 3ak** 69% 86:14 **3bk** 70% 87:13 12 **2l 3al** 88% 88:12 **3bl** 90% (92%) [d] 88:12 (78:22) [d] 13 **2m 3am** 77% 88:12 **3bm** 90% 88:12 [a] All the reactions were conducted according to the general procedure (see experimental section). [b] Yield was determined by 1H-NMR with dimethyl terephthalate as the internal standard. [c] Determined by 1H-NMR. [d] Reaction with Still–Gennari reagent **1e**. Very good results were obtained with most of the aromatic aldehydes tested (Table 3, entries 1–9). The standard reaction of **1a** or **1b** with benzaldehyde **2a** gave very high yields of products **3aa** and **3ba** respectively along with excellent *Z*-selectivity with a 97:3 *Z*:*E* ratio. Similarly, reactions with *para*, *meta*, and *ortho* tolualdehydes **2b**–**2d** resulted in high yields of products **3ab**–**3ad** and **3bb**–**3bd** (81–87%) and a very high *Z*-selectivity. Besides minimally better stereoselectivity with *o*-tolualdehyde **2d**, no significant differences in reactivity of **2b**–**2d** with **1a** or **1b** were observed. Olefination of *para* chloro, bromo, and nitro benzaldehydes **2e**, **2f**, and **2g**, respectively, proceeds in a nearly quantitative manner (93–99% yield) with very high *Z*-selectivity as well (94:6–96:4 *Z*:*E* ratio). Olefination of

heterocyclic furfural **2h** and 2-thiophenecarboxaldehyde **2i** resulted in slightly lower yields, however, the reactions were still highly stereoselective. **Scheme 3.** Reaction of reagents **1** with various aldehydes **2** under optimized conditions. **Scheme 3.** Reaction of reagents **1** with various aldehydes **2** under optimized conditions.

**Scheme 3.** Reaction of reagents **1** with various aldehydes **2** under optimized conditions.

**Table 3.** Reactions of **1a** and **1b** with aldehydes **2a–2m** [a] . **Table 3.** Reactions of **1a** and **1b** with aldehydes **2a–2m** [a] . **Table 3.** Reactions of **1a** and **1b** with aldehydes **2a–2m** [a] . **Scheme 3.** Reaction of reagents **1** with various aldehydes **2** under optimized conditions. **Scheme 3.** Reaction of reagents **1** with various aldehydes **2** under optimized conditions. **Scheme 3.** Reaction of reagents **1** with various aldehydes **2** under optimized conditions.

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termined by 1H-NMR. [d] Reaction with Still–Gennari reagent **1e**. termined by 1H-NMR. [d] Reaction with Still–Gennari reagent **1e**. termined by 1H-NMR. [d] Reaction with Still–Gennari reagent **1e**. [b] Yield was determined by 1H-NMR with dimethyl terephthalate as the internal standard. [c] Determined by 1H-NMR. [d] Reaction with Still–Gennari reagent **1e**. [b] Yield was determined by 1H-NMR with dimethyl terephthalate as the internal standard. [c] Determined by 1H-NMR. [d] Reaction with Still–Gennari reagent **1e**. [b] Yield was determined by 1H-NMR with dimethyl terephthalate as the internal standard. [c] Determined by 1H-NMR. [d] Reaction with Still–Gennari reagent **1e**. [a] All the reactions were conducted according to the general procedure (see experimental section). [b] Yield was determined by 1H-NMR with dimethyl terephthalate as the internal standard. [c] Determined by 1H-NMR. [d] Reaction with Still–Gennari reagent **1e**. [a] All the reactions were conducted according to the general procedure (see Section 3.2). [b] Yield was determined by 1H-NMR with dimethyl terephthalate as the internal standard. [c] Determined by 1H-NMR. [d] Reaction with Still–Gennari reagent **1e**.

Olefination of α,β-unsaturated cinnamaldehyde **2j** and aliphatic aldehydes **2k**–**2m** using reagents **1a** and **1b** gave the corresponding products **3aj**–**3am** and **3bj**–**3bm** in good yields (69–90%) with high *Z*-selectivity (86:14–91:9 *Z*:*E* ratio, Table 3, entries 10–13). Similar to that reported for Ando and Still–Gennari *Z*-selective HWE reaction, olefination of aliphatic aldehydes resulted in a bit inferior selectivity compared to reactions with aromatic aldehydes. Nevertheless, the results obtained with our new reagents **1a** and **1b** are comparable with those previously reported [13–18].

In order to compare the performance of the newly developed reagent **1b** under the reported conditions (using NaH in dry THF at −20 ◦C) with standard Still–Gennari reagent **1e**, two model reactions with benzaldehyde and octanal were performed (Table 3, entries 1 and 12 in brackets). The *Z:E* selectivity using Still–Gennari reagent **1e** with NaH at −20 ◦C was found to be inferior both in the olefination of aromatic and aliphatic aldehydes. The reaction of **1e** with benzaldehyde resulted in a quantitative yield but only moderate *Z*:*E* selectivity 74:26, while the application of **1b** resulted in an excellent 97:3 *Z*:*E* ratio. Similarly, the reaction of **1e** with octanal resulted in poorer *Z*:*E* selectivity (78:22) than the reaction using reagent **1b** (88:12 *Z*:*E* ratio). These observations (along with data from Table 1—entries 2–4) suggest that a very good stereochemical outcome of the reactions with **1b** may be achieved using an easily accessible base, at higher temperatures than in the case of Still–Gennari reagent **1e**, as typically −78 ◦C and KHMDS with 18-crown-6 additive is required in order to achieve high *Z*-selectivity in standard Still–Gennari olefination.

### **3. Materials and Methods**

### *3.1. General Information*

The NMR spectra were recorded using a Bruker Avance Neo 400 spectrometer. Dimethyl terephthalate was used as an internal standard in all NMR experiments [23]. All solvents were dried and distilled prior to use. All the starting materials were purchased from Merck, Sigma-Aldrich, TCI Chemicals, or Fluorochem. Reagents **1a** and **1b** were prepared according to the procedure reported earlier [20]. All the reactions were run in duplicate. The spectra of all the products obtained were in agreement with the data reported in the literature (see Supplementary Materials) [24–38].

### *3.2. General Procedure for the Reaction of* **1a** *or* **1b** *with Aldehydes* **2a***–***2m**

In a round bottom flask with a magnetic stirrer, under an argon atmosphere, 1.2 mmol of base (typically sodium hydride—48 mg of 60% dispersion in mineral oil) was placed and 3 mL of THF was added. The solution was cooled to −20 ◦C and 1.3 mmol of reagent **1a** (590 mg) or **1b** (608 mg) in 2 mL of dry THF was added. The reaction mixture was stirred for 15 min and 1 mmol of appropriate aldehyde in 5 mL of THF was added. After 1 h, 0.5 mL samples were collected by a syringe and quenched with saturated NH4Cl solution. The aqueous layer was extracted two times with 0.5 mL of CH2Cl2. Combined organic fractions were dried using anhydrous Na2SO4, filtered, and next condensed under reduced pressure. To a thus obtained crude product, a specific amount of dimethyl terephthalate was added (as an internal standard for the 1H-NMR measurements), and the mixture was dissolved in CDCl3 to take 1H-NMR spectra. Yields and *Z*:*E* product ratios of the reactions were calculated based on 1H-NMR with an internal standard [12].

### **4. Conclusions**

In conclusion, we have developed a successful application of new reagents, methyl, and ethyl bis(1,1,1,3,3,3-hexafluoroisopropyl)phosphonates, **1a** and **1b** in a highly *Z*-selective HWE reaction. The reagents are easily accessible via previously reported synthetic protocol [20]. In contrast to previous *Z*-selective HWE reagents, the application of **1a** or **1b** does not require very low temperatures (−78 ◦C) to achieve high stereoselectivity. Moreover, readily accessible sodium hydride was found to be a very good base for the presented reaction.

Olefination of aromatic aldehydes using reagents **1a** and **1b** gives excellent results—up to a 98:2 *Z*:*E* product ratio, and up to quantitative yield. Slightly lower, however, very high *Z*-selectivity can also be achieved in the olefination of aliphatic aldehydes. The presented reagents may constitute a valuable alternative to well-established Ando and Still–Gennaritype reagents for highly *Z*-selective olefination of carbonyl compounds, especially in the total synthesis of complex biologically active products.

**Supplementary Materials:** The following supporting information can be downloaded at: https: //www.mdpi.com/article/10.3390/molecules27207138/s1, Section S1: Time study; Section S2: NMR spectra.

**Author Contributions:** Conceptualization, I.J.; methodology, I.J.; software, I.J.; validation, I.J. and P.K.; formal analysis, I.J.; investigation, I.J.; resources, I.J. and P.K.; data curation, I.J.; writing—original draft preparation, I.J.; writing—review and editing, I.J. and P.K.; visualization, I.J.; supervision, I.J. and P.K.; project administration, I.J.; funding acquisition, P.K. All authors have read and agreed to the published version of the manuscript.

**Funding:** The research was financed by the Centre of Molecular and Macromolecular Studies, Polish Academy of Sciences (500-02).

**Data Availability Statement:** Not applicable.

**Conflicts of Interest:** The authors declare no conflict of interest.

### **References**

## *Review* **Comprehensive Review on Synthesis, Properties, and Applications of Phosphorus (PIII, PIV, PV) Substituted Acenes with More Than Two Fused Benzene Rings**

**Marek Koprowski 1,\* , Krzysztof Owsianik 1 , Łucja Knopik 1 , Vivek Vivek 1 , Adrian Romaniuk 1 , Ewa Rózycka-Sokołowska ˙ 2 and Piotr Bałczewski 1,2,\***

**Abstract:** This comprehensive review, covering the years 1968–2022, is not only a retrospective investigation of a certain group of linearly fused aromatics, called acenes, but also a presentation of the current state of the knowledge on the synthesis, reactions, and applications of these compounds. Their characteristic feature is substitution of the aromatic system by one, two, or three organophosphorus groups, which determine their properties and applications. The (PIII, PIV, PV) phosphorus atom in organophosphorus groups is linked to the acene directly by a P-Csp2 bond or indirectly through an oxygen atom by a P-O-Csp2 bond.

**Keywords:** acene; anthracene; phosphine; phosphonate; phosphonium salt; phosphorane; phosphate; diphosphene; tri-, tetra-, pentacoordinated phosphorus; properties

### **1. Introduction**

Organophosphorus-substituted acenes are an increasingly important group of aromatic hydrocarbons due to the unique properties of the phosphorus atom, which can form tri-, tetra-, and pentacoordinated compounds. This creates the possibility of tuning the electronic properties of the aromatic system of acenes by substituting with organophosphorus groups with different electron characters, from electron-donating phosphine groups to strongly electron-accepting phosphonium groups. The acenes of this type, especially anthracenes, have usually been synthesized with the intention of applying them to organic light-emitting diodes (OLEDs) [1,2]. Other uses of these acenes include the synthesis of ligands for metal catalysts in the hydroformylation reaction [3] or in the Diels–Alder reaction as dienes [4]. Anthrylphosphonic acids and their derivatives have also been employed in the synthesis of self-assembled monolayers [5,6] and anthrylbisphosphonates were used to synthesize fluorescent organic nanoparticles as apoptosis inducers of cancer cells [7].

*Scope*: Acenes, as defined, are a group of aromatic compounds containing linearly fused benzene rings. In the literature, compounds with angularly fused benzene rings, such as phenanthrene, and compounds with fused heteroaromatic five- and six-membered rings are sometimes included in this group, and they are specifically called angularly fused acenes and heteroacenes, respectively. Both groups, due to the large number of combinations of ring types and the ring positioning in the fused acene, in addition to derivatives of the simplest linearly fused acene, naphthalene, are not the subject of this review. By virtue of their chemical structure, organophosphorus groups have not been restricted and include all groups containing three-, four-, and five-coordinate phosphorus atoms. In the compounds reviewed, organophosphorus groups contain a phosphorus atom,

**Citation:** Koprowski, M.; Owsianik, K.; Knopik, Ł.; Vivek, V.; Romaniuk, A.; Rózycka-Sokołowska, E.; ˙ Bałczewski, P. Comprehensive Review on Synthesis, Properties, and Applications of Phosphorus (PIII, PIV, P V) Substituted Acenes with More Than Two Fused Benzene Rings. *Molecules* **2022**, *27*, 6611. https:// doi.org/10.3390/molecules27196611

Academic Editor: Jakub Adamek

Received: 9 September 2022 Accepted: 27 September 2022 Published: 5 October 2022

**Publisher's Note:** MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

**Copyright:** © 2022 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/).

which is linked to the acene directly by a P-Csp2 bond or indirectly through an oxygen atom by a P-O-Csp2 bond, such as in phosphates.

This review of the literature covers the period of 1968–2021 and reveals a lack of aromatics that contain more than three fused benzene rings (tetracenes, pentacenes, etc.). Therefore, the subject of this review is anthracenes substituted with any organophosphorus groups.

In addition to the synthesis, this review discusses the reactions that these compounds undergo, and therefore, due to the difficulty of separating the two categories, "synthesis and reactions" are combined together in sections and subsections. Moreover, this review discusses the properties and applications of the synthesized derivatives as well.

This manuscript is divided into five main sections covering phosphines, PIII acids derivatives, diphosphenes, phosphonates and phosphonic acids, phosphates, and the hetero analogs of the mentioned compounds. In the subsections, groups of compounds that can be obtained directly from the precursor included in the main section are identified, e.g., phosphine oxides, phosphonium salts, and phosphoranes can be obtained from phosphines by oxidation, alkylation, and halogenation, respectively, and therefore they are included in the section devoted to the synthesis and reactions of phosphines and derivatives.

Finally, a comment on Section 3 is necessary. Phosphines (λ 3 -phosphanes), by definition, are PIII compounds containing a combination of three P-Z bonds (Z = C,H). Halophosphines AnthPX2 and Anthr2PX (X = F, Cl), which contain at least one P-C bond and one or two halogen atoms, are here classified as halides of the corresponding lower PIII acids [8]. Additionally included in this group are other representatives of the lower PIII acids, i.e., phosphonous acid diamides AnthP(NR2)2 (diaminophosphines) and phosphorous acid esters (phosphites).

As a consequence of this division, phosphonous acid PIV tautomers (*H*-phosphinic acids) and phosphinous acid PIV tautomers (*H*-phosphine oxides) are also reviewed in this section.

Diphosphenes, as the only compounds with a functional group containing more than one phosphorus atom, are discussed separately in Section 6.

### **2. Synthesis and Reactions of Phosphines (AnthPR2) (Anth = Anthryl) and Derivatives**

This section discusses phosphines, which contain a three-coordinated phosphorus atom linked to three carbon atoms. The subsections of this chapter include groups of compounds that can easily be obtained from phosphine precursors by direct transformation to give compounds with tetra- and pentacoordinated phosphorus atoms. Phosphine oxides, sulfides, and selenides are placed together in one subsection because most papers simultaneously describe the synthesis and reactions of two or three groups of these derivatives. Secondary phosphine oxides (*H*-phosphine oxides) are discussed in Section 3.5 as phosphinous acid PIV tautomers.

9-Bromoanthracene **1** is the most frequently used starting material for the syntheses of anthryl phosphines and other derivatives (cf. other subsections throughout this review).

A number of sterically shielded phosphorus ligands for metal catalysts were synthesized by Straub and co-workers via a selective stepwise nucleophilic substitution reaction at the phosphorus atom in triphenyl phosphite (Scheme 1). Thus, first, diphenyl 9 anthrylphosphonite **2** was obtained in a 70% yield by substitution of one phenoxy group by anthryllithium, generated from 9-bromoanthracene **1** and *n*-butyllithium. Next, the second phenoxy group in triphenyl phosphite was replaced by 1-naphthyllithium to afford phenyl 9-anthryl(1-naphthyl)phosphinite **3** in an overall yield of 46%. Finally, the third least reactive phenoxy group was replaced by phenyllithium to give (anthryl)(naphthyl)(phenyl)phosphine **4** in a 66% isolated yield over three steps. In another synthetic sequence, [di(9-anthryl)](2 methoxyphenyl)phosphine **5** was obtained from triphenyl phosphite via phenyl phosphinite **6** by reacting triphenyl phosphite first with 9-anthryllitium, followed by 2-methoxyphenyllitium at −85 ◦C. Since phosphorus ligands, employed in homogeneous catalysis, often contain at least one sterically demanding substituent, this method delivers a strategy for the rapid and cost-efficient synthesis of such ligands [9].

ands [9].

sequence, [di(9-anthryl)](2-methoxyphenyl)phosphine **5** was obtained from triphenyl phosphite via phenyl phosphinite **6** by reacting triphenyl phosphite first with 9-anthryllitium, followed by 2-methoxyphenyllitium at −85 °C. Since phosphorus ligands, employed in homogeneous catalysis, often contain at least one sterically demanding substituent, this method delivers a strategy for the rapid and cost-efficient synthesis of such lig-

**Scheme 1.** The synthesis of sterically hindered phosphine ligands **4** and **5**. **Scheme 1.** The synthesis of sterically hindered phosphine ligands **4** and **5**.

Schmutzler et al. reported the synthesis of (anthryl)(diphenyl)phosphine **7** and trianthrylphosphine **8** starting from 9-bromoanthracene **1,** which was lithiated to give the intermediate 9-lithioanthracene **9**. The latter was reacted with 1 equiv. of chlorodiphenylphosphine or 1/3 equiv. of PCl3 in diethyl ether at reflux to give **7** or **8** in 71% and 7% yields, respectively. The irradiation of **7** in the presence of W(CO)6 with a mercury lamp for 34 h formed the pentacarbonyltungsten complex **10** in an 18% yield (Scheme 2) [10]. Schmutzler et al. reported the synthesis of (anthryl)(diphenyl)phosphine **7** and trianthrylphosphine **8** starting from 9-bromoanthracene **1**, which was lithiated to give the intermediate 9-lithioanthracene **9**. The latter was reacted with 1 equiv. of chlorodiphenylphosphine or 1/3 equiv. of PCl3 in diethyl ether at reflux to give **7** or **8** in 71% and 7% yields, respectively. The irradiation of **7** in the presence of W(CO)6 with a mercury lamp for 34 h formed the pentacarbonyltungsten complex **10** in an 18% yield (Scheme 2) [10]. *Molecules* **2022**, *27*, x FOR PEER REVIEW 4 of 53

**Scheme 2**. The synthesis of (anthryl)(diphenyl)phosphine **7** and trianthrylphosphine **8** and the pentacarbonyltungsten complex **10**. **Scheme 2.** The synthesis of (anthryl)(diphenyl)phosphine **7** and trianthrylphosphine **8** and the pentacarbonyltungsten complex **10**.

Chan and co-workers reported a simple monophosphinylation reaction of 1,8-dichloro-anthracene **11**, leading to 8-chloro-1-(diphenylphosphino)anthracenes **12** in a 33% yield (Scheme 3) [11]. This reaction was carried out in DMF at 160 °C for 60 h and catalyzed by 10 mol% of palladium supported on charcoal in the presence of 5 equiv. of tri-

and only the mono-derivative **12** was observed, despite the presence of an excess of triphenylphosphine. The authors claimed that steric hindrance of the diphenylphosphino group in position 1 of anthracene protected against the reaction of the second chlorine

**11 12** (33%)

Misochko and co-workers [12] obtained 9-(1-phosphirano)anthracene **13** from 9 phosphinoanthracene **14** and ethylene glycol ditosylate as substrates by adapting the procedure of Robinson et al. [13] (Scheme 4). In the next step, 9-(1-phosphirano)anthracene **13** was subjected to UV photolysis to receive a stable triplet anthrylphosphinidene **15**,

Cl Cl Cl PPh Cl PPh2 3 I

oC, 60 h

which could be characterized by electron paramagnetic resonance (EPR).

**Scheme 3**. The synthesis of 8-chloro-1-(diphenylphosphino)anthracenes **12**.

DMF, 160

5 equiv. Ph3P

10 mol% Pd/C

5 equiv. NaI

atom.

Chan and co-workers reported a simple monophosphinylation reaction of 1,8-dichloroanthracene **11**, leading to 8-chloro-1-(diphenylphosphino)anthracenes **12** in a 33% yield (Scheme 3) [11]. This reaction was carried out in DMF at 160 ◦C for 60 h and catalyzed by 10 mol% of palladium supported on charcoal in the presence of 5 equiv. of triphenylphosphine. The addition of 5 equiv. of sodium iodide improved both the rate and yield of the reaction. The second chlorine atom in **11** was not substituted in this reaction and only the mono-derivative **12** was observed, despite the presence of an excess of triphenylphosphine. The authors claimed that steric hindrance of the diphenylphosphino group in position 1 of anthracene protected against the reaction of the second chlorine atom. Chan and co-workers reported a simple monophosphinylation reaction of 1,8-dichloro-anthracene **11**, leading to 8-chloro-1-(diphenylphosphino)anthracenes **12** in a 33% yield (Scheme 3) [11]. This reaction was carried out in DMF at 160 °C for 60 h and catalyzed by 10 mol% of palladium supported on charcoal in the presence of 5 equiv. of triphenylphosphine. The addition of 5 equiv. of sodium iodide improved both the rate and yield of the reaction. The second chlorine atom in **11** was not substituted in this reaction and only the mono-derivative **12** was observed, despite the presence of an excess of triphenylphosphine. The authors claimed that steric hindrance of the diphenylphosphino group in position 1 of anthracene protected against the reaction of the second chlorine atom.

Ph2PCl

3.5 h reflux

hexane Et2O

Li

P Anth Anth

**8** (7%)

1.5 h, 0

1.5 h, reflux

**Scheme 2**. The synthesis of (anthryl)(diphenyl)phosphine **7** and trianthrylphosphine **8** and the pen-

oC then

PPh2

P Ph Ph W(CO)5

(18%)

**10**

Hg lamp h

> then rt toluene

**7** (71%)

1.1 equiv. W(CO)6 34 h

0.5 equiv. W(CO)6 4 days

**Scheme 3**. The synthesis of 8-chloro-1-(diphenylphosphino)anthracenes **12**. **Scheme 3.** The synthesis of 8-chloro-1-(diphenylphosphino)anthracenes **12**.

*Molecules* **2022**, *27*, x FOR PEER REVIEW 4 of 53

*n*-BuLi

1/3 equiv. PCl3 Et2O

Br

**1**

tacarbonyltungsten complex **10**.

**9**

Misochko and co-workers [12] obtained 9-(1-phosphirano)anthracene **13** from 9 phosphinoanthracene **14** and ethylene glycol ditosylate as substrates by adapting the procedure of Robinson et al. [13] (Scheme 4). In the next step, 9-(1-phosphirano)anthracene **13** was subjected to UV photolysis to receive a stable triplet anthrylphosphinidene **15**, which could be characterized by electron paramagnetic resonance (EPR). Misochko and co-workers [12] obtained 9-(1-phosphirano)anthracene **13** from 9 phosphinoanthracene **14** and ethylene glycol ditosylate as substrates by adapting the procedure of Robinson et al. [13] (Scheme 4). In the next step, 9-(1-phosphirano)anthracene **13** was subjected to UV photolysis to receive a stable triplet anthrylphosphinidene **15**, which could be characterized by electron paramagnetic resonance (EPR). *Molecules* **2022**, *27*, x FOR PEER REVIEW 5 of 53 *Molecules* **2022**, *27*, x FOR PEER REVIEW 5 of 53

**Scheme 4.** Synthesis of 9-(1-phosphirano)anthracene **13**, a precursor of the phosphinidene **15**. **Scheme 4.** Synthesis of 9-(1-phosphirano)anthracene **13**, a precursor of the phosphinidene **15**. **Scheme 4.** Synthesis of 9-(1-phosphirano)anthracene **13**, a precursor of the phosphinidene **15**.