Efficient synthesis of 3 H-indoles enabled by the lead-mediated α-arylation of β-ketoesters or γ-lactams using aryl azides

Article abstract of DOI:10.1021/ol5010615

The development of a lead-mediated α-arylation reaction between aryl azides and β-ketoesters or γ-lactams that facilitates the formation of 3H-indoles is disclosed. Twenty-five examples are included which demonstrate the generality of this reaction to access aryl azides bearing tetrasubstituted o-alkyl substituents. When paired with a Staudinger reduction, this reaction streamlines the synthesis of functionalized 3H-indoles.

Full text of DOI:10.1021/ol5010615

Letter
pubs.acs.org/OrgLett
Efficient Synthesis of 3H‑Indoles Enabled by the Lead-Mediated
α‑Arylation of β‑Ketoesters or γ‑Lactams Using Aryl Azides
Fei Zhou and Tom G. Driver*
Department of Chemistry, University of Illinois at Chicago, 845 West Taylor Street, Chicago, Illinois 60607-7061, United States
S
* Supporting Information
ABSTRACT: The development of a lead-mediated α-
arylation reaction between aryl azides and β-ketoesters or γ-
lactams that facilitates the formation of 3H-indoles is disclosed.
Twenty-five examples are included which demonstrate the
generality of this reaction to access aryl azides bearing
tetrasubstituted o-alkyl substituents. When paired with a Staudinger reduction, this reaction streamlines the synthesis of
functionalized 3H-indoles.
Table 1. Determination of the Optimal Conditions for α-
Arylation
he development of new efficient processes to construct N-
Theterocycles continues to motivate synthetic groups
because of the ubiquitous nature of these structural motifs in
bioactive and electronic molecules.1,2 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,3−5 the number of steps often required
to access the aryl azide substrates diminished the overall
efficiency of our N-heterocycle synthesis. In our intramolecular
sp2-C−H bond amination studies,5b seven linear steps were
required to introduce the fully substituted o-alkyl substituent
present in the aryl azide (e.g., 1) (Scheme 1). This study
underscored the need to streamline our substrate construction,6
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.7−12 We were surprised, however, to find
that no examples of this reaction existed with aryl azides.13
Herein, we report the first α-arylation of β-ketoesters and γ-
lactams with aryl azides and leverage this reaction to efficiently
synthesize 3H-indoles.
a
entry
base (equiv)
none
4a (equiv)
9a (equiv)
yield (%)
1
2
1
5
90
89
59
44
62
78
none
1
3
3
none
1
1.05
1.05
1.05
1.05
1.05
1
4
dabco (3)
1
5
phenanthraline (3)
pyridine (3)
pyridine (3)
pyridine (3)
pyridine (3)
pyridine (3)
1
6
1
b
7
1
87
b
8
1.05
3
83
b
9
1
88
c
10
1
1.05
45
a
As determined using 1H NMR spectroscopy using CH2Br2 as an
b
c
internal standard. Reaction performed at 50 °C. Two-step yield from
8a.
While there are many catalyzed and noncatalyzed α-arylation
reactions of carbonyl compounds,7−13 our survey of popular
methods and environmentally benign arylating reagents found
them to be incompatible with the o-azide moiety.14 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,11
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)15 or analogous
stannane using the conditions reported by Pinhey and co-
workers without any decomposition of the azido group.11b,c
With 4a in hand, a variety of conditions were screened to find
the optimal conditions for the α-arylation of β-ketoester 9a
Scheme 1. Current Challenges To Synthesizing 2-
Substituted Aryl Azides
Received: April 11, 2014
© XXXX American Chemical Society
A
dx.doi.org/10.1021/ol5010615 | Org. Lett. XXXX, XXX, XXX−XXX

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Letter
Table 2. Effect of Changing the Identity of the β-Ketoester
Table 3. Determination of the Optimal Conditions for α-
Arylation
a
Reaction performed using 1 equiv of 4, 1.05 equiv of 9, 3 equiv of
b
pyridine in CHCl3 at 50 °C. Isolated yield of 6 after silica gel
chromatography; only product obtained. 3 equiv of 4 used.
c
(entries 4−6).11d 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).
Using these optimal conditions, a series of β-ketoesters were
examined to determine the scope and limitations of our α-
arylation reaction (Table 2). 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-amino-
cyclohexanone 9h produced aryl azides 6f−h in good yields. To
our surprise, while the α-arylation of amides has generated
considerable excitement,16,17 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
a
Reaction performed using 1 equiv of 4a, 1.05 equiv of 9, and 3 equiv
b
of pyridine in CHCl3 at 50 °C. Isolated yield of 6 after silica gel
chromatography; only product obtained.
(Table 1). 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
B
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Letter
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).
Table 4. Conversion of Aryl Azides to 3H-Indoles
The synthetic utility of our α-arylation reaction was
demonstrated next by exposing aryl azides 6 to a Staudinger
reduction (Table 4).18 We found that exposure of aryl azides 6
to triphenylphospine produced 3H-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, 3H-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,19 such as γ-carbo-
line 7h (entries 4 and 5). The Staudinger reaction could even
be extended to γ-lactams to efficiently access 3H-pyrroloindole
7i in nearly quantitative yield (entry 6), whose structure is
ubiquitous in bioactive alkaloids.20 Finally, submission of aryl
azide 6k to the reduction conditions furnished 3H-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 diastereose-
lectively access a range of 3H-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 3H-indoles after Staudinger reduction.
ASSOCIATED CONTENT
* Supporting Information
■
S
a
b
Isolated yield of 7 after silica gel chromatography. As determined
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.
using 1H NMR spectroscopy; 3H-indole 7b rapidly decomposed upon
exposure to air.
AUTHOR INFORMATION
Corresponding Author
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.
■
*E-mail: tgd@uic.edu.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
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.
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). 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).17 To our delight, we found that a range
of different 2-azidoaryllead acetates reacted with γ-lactam 9i. Its
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