boronic acids and their 
 derivatives are versatile reagents in modern 
 organic synthesis , and the hydroboration reaction is a well - established 
 method for generating these building blocks through the addition of 
 b 
first described by hurd in 
 1948 and later developed in detail by brown , this reaction has inspired many catalyzed variants .
recently , several compelling examples of related b  x bond 
 addition reactivity have been reported for x = c , si , sn , s , b , cl , br , and i ( figure 1a ) .
many of these transformations 
 proceed through the oxidative addition of a catalytic transition metal 
 such ni(0 ) , pd(0 ) , or pt(0 ) into the b  x  bond .
( a ) previous 
 work developing addition of b  x bonds across 
 alkynes .
o 
 bonds across alkynes . despite this progress , the corresponding activation of b 
o 
 bonds and addition to c  c multiple bonds  alkoxyboration  has 
 remained elusive for 65 years .
this striking dearth 
 of b  o bond activation reactivity may be due to the extremely 
 high strength of the b  o bond , 136 kcal / mol , compared 
 to less than 105 kcal / mol for all others entries in the series .
this high stability may render the b  o 
 bond unreactive toward oxidative addition , thus preventing the successful 
 application of ni , pd , or pt catalysis in an alkoxyboration reaction .
organoboron reagents are the building 
 blocks of choice for medicinal chemistry and drug discovery . given that ethers are found in many diverse 
 classes of natural products and in nearly 
 25% of the top - grossing pharmaceuticals in the united states for 2012 , the development of such a transformation allows 
 for the preparation of oxygen - containing building blocks useful in 
 drug discovery and materials science .
herein we report the realization of an alkoxyboration reaction 
 of alkynes ( figure 1b ) , through which new o- heterocyclic organoboronate coupling partners are available 
 for downstream functionalization .
the high functional group tolerance 
 of this reaction enables downstream divergent synthesis of functionalized 
 benzofurans  the ability to access multiple benzofurans from 
 one bench stable precursor .
in contrast , current methods for synthesizing 
 benzofurans often rely on harsh conditions that limit compatibility 
 with functional groups desirable for divergent synthesis .
we envisioned that the desired alkoxyboration 
 reactivity could 
 be promoted through an activation pathway employing a bifunctional 
 lewis acidic / lewis basic catalyst , which could simultaneously activate 
 both the alkyne and the b  o  bond partners .
we anticipated 
 that this unique strategy could allow for the anti addition of b 
o bonds across alkynes by circumventing the 
 previous problematic strategy of oxidative cleavage of the b  o 
 bond .
our optimized one - pot procedure begins with 2-alkynyl 
 phenols ( 1 ) , which are converted into the requisite boric 
 ester intermediate 2 using the readily available reagent b - chlorocatecholborane 
 ( figure 2 ) .
treatment of this intermediate 
 with the commercially available lewis acidic gold(i ) precatalyst ipraucl 
 and natfa affords alkoxyboration product 3 in good to 
 excellent conversion as determined by the eretic method .
interestingly , our examination of alternative 
 -lewis acidic transition metal catalysts revealed no other 
 active catalysts aside from au(i ) .
for 
 synthetic ease , the catechol boronic ester alkoxyboration product 3 was converted into either the organotrifluoroborate or n - methyliminodiacetic acid 
 ( mida ) boronate derivative , 4 , both of which are air stable indefinitely .
values in parentheses represent h nmr yields of the corresponding catechol boronic ester 3 versus an external mesitylene standard using the eretic 
 method .
organotrifluoroborate 4a is readily isolated in high 
 yield using a chromatography - free purification , making this derivatization 
 method particularly amenable to applying the alkoxyboration reaction 
 on preparative scale .
the corresponding mida derivative ( 4b ) provides an option for purification by silica gel chromatography , 
 but this comes at the cost of slightly diminished yield .
single - crystal 
 x - ray diffraction analysis of 4b allowed for the unambiguous 
 identification of the alkoxyboration product ( figure 3 ) .
x - ray structure of 4b with the thermal ellipsoids 
 set at the 50% probability level ( b , yellow ; c , gray ; h , white ; o , 
 red ; n , blue ) .
the alkoxyboration reaction 
 is tolerant of a variety of functional 
 groups suitable for downstream reactivity .
aryl bromide 4c , silyl - protected alcohol 4d , terminal alkyne 4f , amide 4 g , esters 4h and 4i , and the functionally dense iodonitrile 4j are compatible with the reaction conditions . many of these alkoxyboration 
 reactions proceed smoothly at 50 c , although the reactions generating 4d , 4 g , 4h , and 4j required 
 heating to 90 c in order to affect full conversion .
we attribute 
 the relatively slow formation of 4d to the high steric 
 encumbrance from the silyl ether at the 2-position of the benzofuran . 

the cyclization of substrates containing lewis basic nitrogen atoms 
 ( forming 4 g , 4h , and 4j ) was 
 likely retarded by reversible n 
b coordination that was observed 
 by b nuclear magnetic resonance ( nmr ) spectroscopy . for 
 all substrates , the mass balance was largely attributable to protonolysis 
 of the product c  b bond .
notably , many of these products 
 contain functional groups incompatible 
 with commonly employed methods of benzofuran synthesis , including 
 via other borylation techniques ( figure 4 ) . 
 in one frequently used borylation technique , an aryl lithium intermediate 

is trapped by a boron electrophile ( method 1 ) ; thus , electrophiles 
 such as carbonyl or nitrile groups and enolizable protons are not 
 generally tolerated due to the highly nucleophilic and basic nature 
 of the requisite organolithium intermediate .
the miyaura borylation is a more mild alternative that is compatible 
 with electrophilic functional groups ( method 2 ) , but aryl halides 
 are borylated through this pd(0)-catalyzed reaction and are therefore not spectator functional groups under 
 these conditions . finally , the ir - catalyzed c 
h activation / borylation 
 reaction is an effective means of accessing 
 aryl boronic acid derivatives ( method 3 ) , but this reaction is regioselective 
 for either 2- or 7-borylation ; 3-borylated benzofurans such as those 
 available through the alkoxyboration reaction can not be synthesized 
 regioselectively through c  h activation / borylation .
benzofuran boronic acid derivatives inaccessible using 
 conventional 
 borylation methods but newly accessible using the alkoxyboration reaction .
we set out to demonstrate the 
 utility in divergent synthesis of 
 the alkoxyboration products enabled through this synthesis in subsequent 
 divergent functionalization steps ( scheme 1 ) .
rh - catalyzed conjugate addition of 4i into methyl 
 vinyl ketone using the method developed by batey provides -benzofuranyl ketone 6 in 
 moderate yield .
subjection of the same benzofuran trifluoroborate 
 to suzuki - miyaura coupling conditions described by molander and biolatto afforded afford 3-arylated benzofuran 8 with concomitant methanolysis of the ethyl ester . finally , 
 addition of 4i to an iminium ion was used to prepare 
 aminated benzofuran 10 .
thus , a single bench - stable alkoxyboration 
 product can be functionalized in a variety of ways , which is important 
 in diversity - oriented syntheses to develop compound catalogs for drug 
 discovery .
ester - containing phenol 1i was successfully converted 
 to more than 1 g of organotrifluoroborate 4i on a 5 mmol 
 scale with 2.5% gold catalyst ( eq 1 ) .
full conversion 
 of starting material was affected even with this lower au catalyst 
 loading .
this convenient scalability demonstrates that quantities 
 of o - heterocyclic boronic acid derivatives sufficient 
 for multistep synthesis may be prepared using the alkoxyboration method.1 having demonstrated the utility of this transformation in 
 generating 
 members of the benzofuran class of o - heteroaryl boronic 
 acid derivatives , we explored its application to the synthesis of 
 a nonaromatic oxygen - containing heterocycle ( eq 2 ) .
simple and commercially available homopropargyl alcohol 11 was subjected to standard alkoxyboration reaction conditions 
 to prepare dihydrofuran product 12 .
a large number of 
 unidentifiable trace coproducts were detected in this reaction , possibly 
 consistent with intermolecular reactivity .
this substrate demonstrates 
 the potential for generality in the alkoxyboration reaction : the reaction 
 features low labor  setup cost  by employing simple , 
 commercially available starting materials to generate highly value - added o - heterocyclic organoboronate compounds in one synthetic 
 step , and the cyclization proceeds without requiring the gain of 
 product aromaticity or the need for a fused ring system that enforces 
 a conformational bias toward cyclization.2 a number of lewis - acidic metal catalysts have been developed 
 for 
 the addition of oxygen - electrophile bonds across alkynes , albeit not 
 with boron and thus not generating these building blocks for downstream 
 functionaliztion .
we propose the catalytic 
 cycle shown in scheme 2 featuring bifunctional 
 lewis acidic / lewis basic substrate activation .
the bifunctional catalyst 
 iprautfa can be generated in situ from ipraucl and 
 natfa .
reaction of the lewis basic trifluoroacetate moiety with electrophilic 
 boric ester 2a gives nucleophilic borate 14 .
the resulting lewis acidic au(i ) cation may then bind to the alkyne 
 ( 15 ) , increasing its electrophilicity .
 au  complex by the phenol b  o bond 
 would provide two neutral intermediates : boron electrophile 16 and organogold nucleophile 17 , which could 
 recombine to regenerate 13 with concomitant formation 
 of the observed alkoxyboration product 3a .
thus , the 
 iprau moiety of the catalyst activates the alkyne for 
 nucleophilic attack , and the tfa counterion allows for reversible 
 tuning from a boron electrophile to a nucleophilic borate adduct . 

this reaction manifold is fundamentally unique from the metal - catalyzed 
 addition of b  c , b 
s  
 bonds , which often proceed through oxidative addition of a low - valent 
 metal catalyst into the b  x bond .
we believe that the new activation 
 strategy employed in the alkoxyboration reaction could be extended 
 to other types of b 
notably , this approach 
 also suggests a new generalizable mechanism for au catalyst turnover 
 by trapping with electrophilic boron to generate other previously 
 inaccessible organoboron building blocks .
this fundamentally 
 new activation is showcased in a mild , scalable technique for the 
 preparation of o - heterocyclic boronic acid derivatives 
 and downstream - functionalized benzofurans .
the reaction provides a 
 simple new bond disconnection for constructing these motifs with different 
 regioselectivity and broader functional group compatibility than existing 
 methods . this compatibility yields highly functionalized bench - stable 
 building blocks for divergent synthesis that are not directly accessible 
 using alternative methods . the carbophilic lewis acid activation mechanism 
 for b 
x addition reactions and the ability to synthesize previously 
 inaccessible organoboron building blocks via this new strategy for 
 turning over gold and other carbophilic metal catalysts .
sodium trifluoroacetate 
 was dried at 130 c at 10 mtorr for 18 h before use .
toluene 
 and dichloromethane were purified by passage through an alumina column 
 under argon pressure on a push - still solvent system .
anhydrous dimethylsulfoxide 
 was obtained by stirring over activity i alumina 18 h under n2 atmosphere , decanting the liquid , and distilling the liquid 
 at 10 torr over cah2 .
toluene - d8 was dried over cah2 , degassed using 
 three freeze  pump  thaw cycles , and vacuum transferred 
 prior to use .
all manipulations were conducted in a glovebox under 
 nitrogen atmosphere or using standard schlenk techniques unless otherwise 
 specified .
plates were visualized under uv 
 irradiation ( 254 nm ) and/or using a basic aqueous solution of potassium 
 permanganate .
flash chromatography was conducted using a teledyne 
 isco combiflash rf 200 automated flash chromatography system , and 
 teledyne isco redisep 3570 m silica gel .
all proton 
 and carbon nuclear magnetic resonance ( h and c nmr ) spectra were recorded on a bruker drx-400 spectrometer , bruker 
 drx-500 spectrometer outfitted with a cryoprobe , or a bruker avance-600 
 spectrometer . all boron nuclear magnetic resonance ( b 
 nmr )
all 
 fluorine nuclear magnetic resonance ( f nmr ) spectra were 
 recorded on a bruker drx-400 .
all chemical shifts (  ) are reported 
 in parts per million ( ppm ) downfield of tetramethylsilane , and referenced 
 to the residual protiated solvent peak (  = 7.26 ppm for cdcl3 ,  = 2.50 ppm for dmso - d6 , or  = 1.94 ppm for cd3cn in h nmr 
 spectroscopy experiments ;  = 77.16 ppm for cdcl3 ,  = 39.52 ppm for dmso - d6 , or 
  = 1.34 ppm for cd3cn in c nmr spectroscopy 
 experiments ) .
b and f nmr spectroscopy experiments 
 are referenced to the absolute frequency of 0 ppm in the h dimension according to the xi scale .
low- and high - resolution mass 
 spectrometry data were obtained at the university of california , irvine .
all 
 alkoxyboration reactions were conducted in a n2-filled 
 glovebox due to the high moisture sensitivity of the boric ester intermediate 2 .
the reaction progress was monitored by removing a small aliquot 
 of the reaction mixture from the glovebox and diluting it in 1:1 etoac : water . 

this results in rapid hydrolysis of boric ester intermediate 2 back to the phenol starting material 1 .
thus , 
 co - spotting the reaction mixture versus phenol 1 provides 
 a convenient method for determining whether or not intermediate 2 has been fully consumed .
the addition of pph3 to quench the au catalyst between the 
 alkoxyboration step and the formation of the organotrifluoroborate 
 or mida boronate was essential .
a solution 
 of phenol 1a ( 97.0 mg , 0.500 mmol , 1.00 equiv ) in 1.0 
 ml of toluene was added to a flame - dried 10-ml schlenk tube . to this 
 stirring solution was added dropwise at 25 c a suspension of 
 nah ( 69 wt % purity , 17.4 mg , 0.500 mmol , 1.00 equiv ) in 0.5 ml of 
 toluene over 2 min .
a suspension of natfa ( 20 mg , 0.15 mmol , 30 mol 
 % ) in 0.5 ml of toluene was added next , and the resulting suspension 
 was stirred for 15 min to affect full deprotonation . to the resulting 
 stirring sodium phenoxide suspension
was added at 25 c a solution 
 of b - chlorocatecholborane ( 77.0 mg , 0.500 mmol , 1.00 
 equiv ) in toluene ( 1.0 ml ) , using additional toluene as a rinse to 
 ensure full transfer ( 2  0.5 ml portions ) .
the resulting suspension 
 was stirred vigorously for 30 min to allow for full conversion to 
 boric ester intermediate 2a .
next , a suspension of ipraucl 
 ( 16 mg , 0.025 mmol , 5.0 mol % ) in toluene ( 0.5 ml ) was added to the 
 reaction mixture at 25 c , using additional toluene as a rinse 
 to aid in full transfer ( 1  0.5 ml portion ) .
the reaction mixture 
 was then sealed with a ground glass stopper and a ptfe sealing ring 
 and placed in a preheated 50 c copper shot heating bath .
after 24 h , analysis by tlc ( 20% etoac / hexanes ) indicated full 
 consumption of boric ester intermediate 2a .
the reaction 
 mixture was cooled to 25 c , and a solution of pph3 ( 13 mg , 0.050 mmol , 10 mol % ) in toluene ( 0.5 ml ) was added .
the 
 resulting suspension was stirred for 22 h at 25 c in order to 
 quench iprautfa before proceeding .
the quenched reaction mixture was 
 removed from the glovebox and filtered through a fiberglass filter 
 to remove the suspended solids .
the filter was then rinsed with toluene 
 ( 3  3 ml ) , and the combined filtrates were concentrated in vacuo 
 to a pale yellow powder , which was suspended in acetone ( 4.5 ml ) and 
 added to a stirring solution of khf2 ( 140 mg , 1.8 mmol , 
 3.5 equiv ) in water ( 1.5 ml ) .
the resulting mixture was stirred at 
 25 c for 30 min , and then concentrated in vacuo to remove the 
 solvents . to this residue
was added 2 ml of et2o and the 
 solution was subsequently concentrated at ca .
the resulting pale yellow solid 
 residue was washed with et2o ( 4  2 ml ) and extracted 
 with acetone ( 4  2 ml ) .
the combined acetone extracts were concentrated 
 in vacuo , and the resulting residue was subjected to an additional 
 washing / extraction cycle to yield 4a as a white powder 
 ( 113 mg , 75% yield ) after removing volatiles at 25 c and ca . 

10 mtorr for 18 h. h nmr ( dmso - d6 , 600 mhz ) :  8.10 ( d , j = 7.4 hz , 
 2h ) , 7.88 ( d , j = 7.7 hz , 1h ) , 7.42 ( d , j = 8.0 hz , 1h ) , 7.38 ( t , j = 7.6 hz , 2h ) , 7.26 ( t , j = 7.3 hz , 1h ) , 7.13 ( td , j = 6.5 hz , 
 1.2 hz , 1h ) , 7.08 ( td , j = 7.4 , 0.9 hz , 1h ) .
c nmr ( dmso - d6 , 125 mhz ) :  
 154.7 ( q , jc 
f = 4.6 hz ) , 153.8 , 
 135.4 , 133.3 , 127.9 , 126.8 , 126.7 ( q , jc  f = 2.3 hz ) , 124.1 ( q , jc 
[ note : as with many organotrifluoroborates , the ipso carbon was not detected , presumably due to broadening 
 through coupling to the 11b nucleus .
b nmr ( dmso - d6 , 193 mhz ) :  3.2 ( br s ) .
f nmr ( dmso - d6 , 376 mhz ) :  131.9 
 ( br s ) . hrms ( esi- ) : calculated for c14h9bf3o ( [ m  k ] ) , 261.0701 ; found , 261.0706 .
a solution of phenol 1a ( 97.0 mg , 0.500 mmol , 1.00 equiv ) in 1.0 ml of toluene 
 was added to a flame - dried 10-ml schlenk tube . to this stirring solution 

was added dropwise at 25 c a suspension of nah ( 92 wt % purity , 
 13.0 mg , 0.500 mmol , 1.00 equiv ) in 0.5 ml of toluene over 2 min . 
 a suspension of natfa ( 20 mg
, 0.15 mmol , 30 mol % ) in 0.5 ml of toluene 
 was added next , and the resulting suspension was stirred for 15 min 
 to affect full deprotonation . to the resulting stirring sodium phenoxide 
 suspension was added at 25 c a solution of b - chlorocatecholborane ( 77.0 mg , 0.500 mmol , 1.00 equiv ) in toluene 
 ( 1.0 ml ) , using additional toluene as a rinse to ensure full transfer 
 ( 2  0.5 ml portions ) .
the resulting suspension was stirred vigorously 
 for 30 min to allow for full conversion to boric ester intermediate 2a .
next , a suspension of ipraucl ( 16 mg , 0.025 mmol , 5.0 
 mol % ) in toluene ( 0.5 ml ) was added to the reaction mixture at 25 
 c , using additional toluene as a rinse to aid in full transfer 
 ( 1  0.5 ml portion ) . the reaction mixture was then sealed with 
 a ground glass stopper and a ptfe sealing ring and placed in a preheated 
 50 c copper shot heating bath .
after 24 h , analysis 
 by tlc ( 20% etoac / hexanes ) indicated full consumption of boric ester 
 intermediate 2a .
the reaction mixture was cooled to 25 
 c , and a solution of pph3 ( 13 mg , 0.050 mmol , 10 
 mol % ) in toluene ( 0.5 ml ) was added .
the resulting suspension was 
 stirred for 16 h at 25 c in order to quench iprautfa before 
 proceeding .
anhydrous dmso ( 2.0 ml ) and h2mida ( 81 mg , 
 0.55 mmol , 1.1 equiv ) were added to the quenched alkoxyboration reaction 
 mixture , and the resulting suspension was stirred at 90 c for 
 2 h. the reaction mixture was then cooled to 25 c and removed 
 from the glovebox .
the resulting semisolid residue was adsorbed onto celite 
 from a mecn suspension and purified by silica gel chromatography using 
 an elution gradient from 100% et2o to 100% mecn .
10 mtorr for 18 h afforded mida 
 boronate 4b as a white powder ( 101 mg , 58% yield ) .
crystals 
 suitable for x - ray diffraction analysis were prepared by slow diffusion 
 of et2o into a saturated solution of 4b in 
 et2o / acetone at 25 c over 3 days .
h nmr 
 ( cd3cn , 600 mhz ) :  7.72 ( dd , j = 
 7.8 hz , 0.8 hz , 1h ) , 7.677.65 ( m , 2h ) , 7.55 ( d , j = 9.7 hz , 1h ) , 7.477.44 ( m , 3h ) , 7.357.31 ( m , 1h ) , 
 7.297.26 ( m , 1h ) , 3.97 ( d , j = 17.1 hz , 2h ) , 
 3.65 ( d , j = 17.1 hz , 2h ) , 2.56 ( s , 3h ) .
c nmr ( cd3cn , 125 mhz ) :  169.0 , 156.0 , 133.6 , 133.0 , 
 130.6 , 130.2 , 129.3 , 125.2 , 123.9 , 123.5 , 111.8 , 63.0 , 48.2 .
[ note : 
 no signals were observed for the quaternary c  b ipso carbon or the quaternary carbon at the benzofuran 2 position . ] b nmr ( cd3cn , 193 mhz ) :  11.3 ( br s ) .
hrms 
 ( esi+ ) : calculated for c17h19bbrno5 ( [ m + na ] ) , 372.1023 ; found , 372.1016 .
 for nearly 70 years , the addition 
 of boron  x  bonds 
 to carbon  
 carbon multiple bonds has been employed in the preparation 
 of organoboron reagents . however , the significantly higher strength 
 of boron  
 oxygen bonds has thus far precluded their activation 
 for addition , preventing a direct route to access a potentially valuable 
 class of oxygen - containing organoboron reagents for divergent synthesis . 
 
 we herein report the realization of an alkoxyboration reaction , the 
 addition of boron  oxygen  bonds to alkynes . functionalized o - heterocyclic boronic acid derivatives are produced using 
 this transformation , which is mild and exhibits broad functional group 
 compatibility . 
 our results demonstrate activation of this boron  
 o 
  bond using a gold catalysis strategy that is fundamentally 
 different from that used previously for other boron addition reactions . 
Introduction
Results and Discussion
Conclusions
Experimental Section