The development of new efficient processes to construct *N*-heterocycles continues to motivate synthetic groups because of the ubiquitous nature of these structural motifs in bioactive and electronic molecules.^[@ref1],[@ref2]^ Our group believes that these important compounds could be efficiently synthesized through transition-metal-catalyzed C--H bond amination, which would create the ArN--C bond from aryl azides. While we have successfully developed a series of C--H bond amination processes,^[@ref3]−[@ref5]^ the number of steps often required to access the aryl azide substrates diminished the overall efficiency of our *N*-heterocycle synthesis. In our intramolecular sp^2^-C--H bond amination studies,^[@cit5b]^ seven linear steps were required to introduce the fully substituted *o*-alkyl substituent present in the aryl azide (e.g., **1**) (Scheme [1](#sch1){ref-type="scheme"}). This study underscored the need to streamline our substrate construction,^[@ref6]^ and we anticipated that a modular synthesis could be achieved if the aryl azide moiety was installed through an α-arylation of a carbonyl compound.^[@ref7]−[@ref12]^ We were surprised, however, to find that no examples of this reaction existed with aryl azides.^[@ref13]^ Herein, we report the first α-arylation of β-ketoesters and γ-lactams with aryl azides and leverage this reaction to efficiently synthesize 3*H*-indoles.

![Current Challenges To Synthesizing 2-Substituted Aryl Azides](ol-2014-010615_0002){#sch1}

While there are many catalyzed and noncatalyzed α-arylation reactions of carbonyl compounds,^[@ref7]−[@ref13]^ our survey of popular methods and environmentally benign arylating reagents found them to be incompatible with the *o*-azide moiety.^[@ref14]^ The failure of these methods prompted us to examine the α-arylation of β-ketoesters using an aryllead as the electrophilic reagent. Although the use of these complexes is well-established,^[@ref11]^ there are no examples of using an aryl azide substituent (much less an *o*-azide) in the α- arylation processes. The requisite 2-azidoaryllead acetate was readily prepared from either the 2-azidoarylboronic acid pinacolate ester (**8**)^[@ref15]^ or analogous stannane using the conditions reported by Pinhey and co-workers without any decomposition of the azido group.^[@cit11b],[@cit11c]^ With **4a** in hand, a variety of conditions were screened to find the optimal conditions for the α-arylation of β-ketoester **9a** (Table [1](#tbl1){ref-type="other"}). For the initial screen, an excess of **9a** was used (entries 1--3). We found that the equivalents of **9a** could be reduced to three without attenuating the yield of **6a**. A significant reduction in conversion was observed, however, when a slight excess of the β-ketoester was used (entry 3). To improve the conversion, several amine bases were screened (entries 4--6).^[@cit11d]^ While the addition of dabco, phenanthroline, or pyridine did improve the yield, it plateaued at 78%. Using pyridine, a further improvement was realized by increasing the temperature of the reaction to 50 °C (entry 7). Next, we examined if the stoichiometry of our α-arylation could be reversed in order to enable the use of the 2-azidoaryllead acetate as a reagent for the α-arylation of more valuable β-ketoesters (entries 8 and 9). To our delight, we found that yield diminished only slightly, and if 3 equiv of **4a** was used, the yield recovered to 88%. Finally, we attempted the α-arylation in one-flask directly from 2-azidophenylboronic pinacolate ester **8a** without isolation the 2-azidoaryllead acetate to afford **6a** in 45% (entry 10).

###### Determination of the Optimal Conditions for α-Arylation

![](ol-2014-010615_0003){#fx1}

  entry   base (equiv)         **4a** (equiv)   **9a** (equiv)   yield[a](#t1fn1){ref-type="table-fn"} (%)
  ------- -------------------- ---------------- ---------------- -------------------------------------------
  1       none                 1                5                90
  2       none                 1                3                89
  3       none                 1                1.05             59
  4       dabco (3)            1                1.05             44
  5       phenanthraline (3)   1                1.05             62
  6       pyridine (3)         1                1.05             78
  7       pyridine (3)         1                1.05             87[b](#t1fn2){ref-type="table-fn"}
  8       pyridine (3)         1.05             1                83[b](#t1fn2){ref-type="table-fn"}
  9       pyridine (3)         3                1                88[b](#t1fn2){ref-type="table-fn"}
  10      pyridine (3)         1                1.05             45[c](#t1fn3){ref-type="table-fn"}

As determined using ^1^H NMR spectroscopy using CH~2~Br~2~ as an internal standard.

Reaction performed at 50 °C.

Two-step yield from **8a**.

###### Effect of Changing the Identity of the β-Ketoester

![](ol-2014-010615_0004){#fx2}

![](ol-2014-010615_0005){#fx3}

Reaction performed using 1 equiv of **4a**, 1.05 equiv of **9**, and 3 equiv of pyridine in CHCl~3~ at 50 °C.

Isolated yield of **6** after silica gel chromatography; only product obtained.

Using these optimal conditions, a series of β-ketoesters were examined to determine the scope and limitations of our α-arylation reaction (Table [2](#tbl2){ref-type="other"}). We found that the ring size of the β-ketoester could be modified without affecting the yield of our α-arylation reaction to provide functionalized aryl azides **6b**--**d** (entries 1--3). Acyclic β-ketoesters, such as **4e**, could even be smoothly converted to product without much attenuation of the yield (entry 4). Next, the effect of the composition of the β-ketoester on the yield of the arylation was examined (entries 5--7): indanone **9f**, 4-tetrahydropyranone **9g**, and 4-aminocyclohexanone **9h** produced aryl azides **6f**--**h** in good yields. To our surprise, while the α-arylation of amides has generated considerable excitement,^[@ref16],[@ref17]^ γ-lactams have never been used in these processes despite the synthetic utility of these molecules. We found that they could be efficiently arylated to produce **6i** in good yield (entry 8). Next, the stereoselectivity of our α-arylation reaction was investigated. Exposure of 4-*tert*-butyl-substituted β-ketoester **9j** to our reaction conditions furnished **6j** with 10:1 diastereoselectivity (entry 9). To our delight, the selectivity was not affected by the size of the 4-substituent: the diastereoselectivity remained 10:1 when the 4-*tert*-butyl group was replaced with a smaller 4-phenyl group (entry 10). Finally, we examined the effect of changing the nature of the carboxylate group (entries 11--13). We found that an ester was necessary for the α-arylation reaction. While the methyl ester could replaced with either an allyl or menthol (albeit with no diastereoselectivity observed), β-ketoamides proved to be unreactive in our process.

###### Determination of the Optimal Conditions for α-Arylation

![](ol-2014-010615_0006){#fx4}

![](ol-2014-010615_0007){#fx5}

Reaction performed using 1 equiv of **4**, 1.05 equiv of **9**, 3 equiv of pyridine in CHCl~3~ at 50 °C.

Isolated yield of **6** after silica gel chromatography; only product obtained.

3 equiv of **4** used.

The effect of adding substituents to the 2-azidoaryllead acetate on the α-arylation of β-ketoester **9a** or γ-lactam **9i** was examined next (Table [3](#tbl3){ref-type="other"}). For β-ketoester **9a**, we found that the arylation reaction tolerated halide, alkyl, or ether substituents (entries 1--6). The yield, however, did depend on the electronic nature of **4** with the highest yields observed for the electron-rich or electron-neutral arylleads bearing methoxy- or methyl groups (entries 4 and 5). Further, the azide group could be placed at the 4-position without much diminishment of the yield of the arylation reaction (entry 7). To determine the generality of our reaction, we next examined the α-arylation of γ-lactam **9i**, a substrate never reported as nucleophile in this process (entries 8--12).^[@ref17]^ To our delight, we found that a range of different 2-azidoaryllead acetates reacted with γ-lactam **9i**. Its reactivity, however, was diminished in comparison to β-ketoester **9a**. To obtain comparable yields, it was often necessary to increase the amount of the 2-azidoaryllead to 3 equiv (entries 10--12).

###### Conversion of Aryl Azides to 3*H*-Indoles

![](ol-2014-010615_0008){#fx6}

![](ol-2014-010615_0009){#fx7}

Isolated yield of **7** after silica gel chromatography.

As determined using ^1^H NMR spectroscopy; 3*H*-indole **7b** rapidly decomposed upon exposure to air.

The synthetic utility of our α-arylation reaction was demonstrated next by exposing aryl azides **6** to a Staudinger reduction (Table [4](#tbl4){ref-type="other"}).^[@ref18]^ We found that exposure of aryl azides **6** to triphenylphospine produced 3*H*-indoles **7** in nearly quantitative yield. Although the ring size of the β-ketoester could be modified in between the 5- and 7-carbons without affecting the Staudinger reaction, 3*H*-indole **7b** readily decomposed when exposed to air (entries 1--3). The reduction tolerated heteroatoms in the β-ketoester to enable access to important *N*-heterocyclic structural motifs,^[@ref19]^ such as γ-carboline **7h** (entries 4 and 5). The Staudinger reaction could even be extended to γ-lactams to efficiently access 3*H*-pyrroloindole **7i** in nearly quantitative yield (entry 6), whose structure is ubiquitous in bioactive alkaloids.^[@ref20]^ Finally, submission of aryl azide **6k** to the reduction conditions furnished 3*H*-indole **7k** in good yield without loss of any diastereoselectivity (entry 7). Together these results illustrate that when paired with a Staudinger reduction our α-arylation reaction to diastereoselectively access a range of 3*H*-indoles.

In conclusion, we developed an α-arylation reaction of β-ketoesters using 2-azidoaryllead acetates to afford a range complex, functionalized aryl azides with fully substituted *o*-alkyl substituents. The synthetic utility of our process was showcased using γ-lactam substrates to enable efficient construction of functionalized 3*H*-indoles after Staudinger reduction.

Complete experimental procedures and spectroscopic and analytical data for the products. This material is available free of charge via the Internet at <http://pubs.acs.org>.

Supplementary Material
======================

###### 

ol5010615_si_001.pdf

The authors declare no competing financial interest.

We are grateful to the National Science Foundation (CHE-126563), National Institutes of Health NIGMS (R01GM084945), and the University of Illinois at Chicago for their generous support. We also thank Mr. Furong Sun for mass spectrometry data.
