One-pot synthesis of azaindoles via palladium-catalyzed α-heteroarylation of ketone enolates

Article abstract of DOI:10.1021/jo100623d

(Figure presented) A convenient, one-pot method for the construction of a variety of azaindoles using simple ketones and haloaminopyridines is described.

Full text of DOI:10.1021/jo100623d

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precursor. Despite the initial success of this route for 2-phenyl-
One-Pot Synthesis of Azaindoles via Palladium-
Catalyzed r-Heteroarylation of Ketone Enolates
substituted 7-azaindoles, SAR generation was slowed due to
the stepwise nature of the coupling-cyclization protocol,
which failed to translate into an efficient one-pot process.4
Reaction of acetylene 3 (or its TMS-protected version) with
aryl bromides was not practical since complex mixtures were
obtained, with 1 (R = H) being the major product observed
under all conditions.5 In this paper, we report a simple one-
step method for the construction of a variety of azaindoles
using simple ketones and haloaminopyridines.
Steven H. Spergel,* Danielle R. Okoro,† and William Pitts
Bristol-Myers Squibb, Princeton, New Jersey 08543-4000,
and †Hunter College, New York, New York 10065
steven.spergel@bms.com
Received April 1, 2010
The difficulty encountered in the Sonagashira approach
(Scheme 1) led us to explore the reaction of ketones with com-
mon intermediate 2 (Scheme 2). The palladium-catalyzed
ꢀ7a
enamine-Heck indole synthesis,6,8 extended by Nazare
and others to the preparation of azaindoles, was only
productive, in this instance, with ethyl pyruvate.8 We also
investigated the Pd-catalyzed tandem coupling of gem-
dichloroolefins7b described by Lautens. This method affords
good yields in the case of simple azaindoles but was un-
successful in our complex system. Since these methods were
not able to generate the diversity to sustain our discovery
program, the palladium-catalyzed R-arylation of enolates
was explored. Such an approach would provide the azain-
dole 5 through a Reissert-type intermediate. To our know-
ledge, this methodology had been applied to indoles11 but
has not been extended to the preparation of azaindoles.
Buchwald and Hartwig have pioneered the palladium-
catalyzed R-arylation of enolates.12 We conducted scouting
reactions with 2 (I and Br) and a substituted acetophenone
under Buchwald conditions13 (Pd2(dba)3, xantphos, with K3PO4,
Cs2CO3, NaOtBu, or NaN(SiMe3)2, in THF at 70 °C) but did
not detect any desired product 5.14 After exploration of
A convenient, one-pot method for the construction of a
variety of azaindoles using simple ketones and haloamino-
pyridines is described.
Azaindoles represent one of the most important hetero-
cyclic scaffolds in medicine, and as a result, several methodo-
logies have been invented for their construction.1 However,
these methods were not amenable to late-stage diversifica-
tion while executing our medicinal chemistry SAR plan. As
part of our effort to identify inhibitors of IκB Kinaseβ, IKK-2,
we sought to prepare derivatives of tricycle 1 with diversity at
the 7-position (2-azaindole position, Scheme 1).2 Our origi-
nal SAR diversification plan was based on direct arylation
chemistry utilizing 1 (R = H) as a key intermediate; how-
ever, we were unsuccessful.3 After some experimentation, the
synthetic pathway which was adopted relied upon a 5-endo-
dig cyclization from an appropriately substituted acetylene
(4) (a) Larock, R. C.; Yum, E. K. J. Am. Chem. Soc. 1991, 113, 6689.
(b) Park, S. S.; Choi, H.-K.; Yum, E. K.; Ha, D.-C. Tetrahedron. Lett. 1998,
48, 221. (c) Rodriguez, A. L.; Koradin, C.; Dohle, W.; Knochel, P. Angew.
Chem., Int. Ed. Engl. 2000, 39, 2488.
(5) This result was consistent with previous literature reports; see:
Kumar, V.; Dority, J. A.; Bacon, E. R.; Singh, B.; Lesher, G. Y. J. Org.
Chem. 1992, 57, 6995.
(6) Chen, C.-Y.; Lieberman, D. R.; Larsen, R. D.; Verhoeven, T. R.;
Reider, P. J. J. Org. Chem. 1997, 62, 2676.
ꢀ
(7) (a) Nazare, M.; Schneider, C.; Lindenschmidt, A.; Will, D. W. Angew.
Chem., Int. Ed. 2004, 43, 4526. (b) Fang, Y.-Q.; Yuen, J.; Lautens, M. J. Org.
Chem. 2007, 72, 5152.
(8) This reaction proceeded in approximately 30% yield for ethyl pyru-
vate. We subjected a mixture of 2 (I or Br) and a substituted acetophenone to
the Nazare conditions; however, none of the desired product formed. No
improvements were seen when microwave conditions were employed.9
Control experiments with 2 and a substituted acetophenone in the presence
of dehydrating reagents such as p-TsOH,10 magnesium sulfate, or 4A
molecular sieves at elevated temperature failed to demonstrate the formation
of the anticipated enamine, although removal of the Boc protecting group
was evident under forcing conditions.
(9) Lachance, N.; April, M.; Joly, M.-A. Synthesis 2005, 15, 2571.
(10) Blanche, Y.; Sinibaldi-Troin, M.-E.; Hichour, M.; Benezech, V.;
Chavignon, O.; Gramain, J.-C.; Teulade, J.-C.; Chapat, J.-P. Tetrahedron
1999, 55, 1959.
(11) After this research was conducted, a thorough search of the literature
identified that this methodology had been applied to indoles. See: Cho, C. S.;
Kim, J. H.; Kim, T.-J.; Shim, S. C. J. Chem. Res. 2004, 9, 630.
(12) For reviews, see: (a) Lloyd-Jones, G. C. Angew. Chem., Int. Ed. 2002,
41, 953. (b) Culkin, D. A.; Hartwig, J. F. Acc. Chem. Res. 2003, 36, 234.
(13) Fox, J. M.; Huang, X.; Chieffi, A. J. Am. Chem. Soc. 2000, 122, 1360.
(14) We cannot disclose the exact structure of 5; however, the aryl ring
contains no functionality which might interfere with the reaction.
(1) (a) Popowycz, F.; Routier, S.; Joseph, B.; Merour, J.-Y. Tetrahedron
2007, 63, 1031. (b) Song, J. J.; Reeves, J., T.; Gallou, F.; Tan, Z.; Yee, N., K.;
Senanayake, C., H. Chem. Soc. Rev. 2007, 36, 1120 (further review).
(c) Popowycz, F.; Merour, J.-Y.; Joseph, B. Tetrahedron 2007, 63, 8689.
(2) Kempson, J.; Guo, J.; Das, J.; Moquin, R. V.; Spergel, S. H.;
Watterson, S. H.; Langevine, C. M.; Dyckman, A., J.; Burke, J., R.; Taylor,
T.; McIntyre, K.; Barrish, J. C.; Pitts, W. J. Bioorg. Med. Chem. Lett. 2009,
19, 2646–2649.
(3) (a) Sezen, B.; Sames, D. J. Am. Chem. Soc. 2003, 125, 5274. Attempts
at the direct arylation of the H-compound were conducted in 2005, prior to
the retraction of this paper in: J. Am. Chem. Soc. 2006, 128, 8364. We did not
explore direct C-2 arylation of N-substituted azaindoles for which there is
precedence. For example, see: (b) Lane, B. S.; Sames, D. Org. Lett. 2004, 6,
2897. (c) Huestis, M. P.; Fagnou, K. Org. Lett. 2009, 11, 1357.
5316 J. Org. Chem. 2010, 75, 5316–5319
Published on Web 07/01/2010
DOI: 10.1021/jo100623d
r
2010 American Chemical Society

Spergel et al.
JOCNote
SCHEME 1. Initial Disconnections Explored
TABLE 1. Catalyst Scan
SCHEME 2. Ketone Routes Explored
aisolated yield. bDetermined by NMR integration. cPd(dba)2. dPd(OAc)2.
These conditions produced a more complete reaction (43%
isolated yield); however, a significant amount of ketone self-
condensation product was evident.
Substitution of sodium or lithium (in the case of aryl
iodides) hexamethylsilylamide for sodium tert-butoxide and
extending the reaction time to 4 h resulted in essentially
complete conversion of starting material, and following
workup and TFA deprotection, analogues 5 were isolated
in moderate yields.
We returned to examine several catalyst systems (under
optimized conditions, as for 5) in a model system (Table 1).
Consistent with the results we had obtained previously, use
of (SIPr)Pd(allyl)Cl, 6 (entry 1), proceeded to completion,
and 2-phenylazaindole (9) was isolated in 74% yield. Low-
ering the catalyst loading to 10 mol % resulted in incomplete
reaction at 4 h (43% conversion); thus, a 20 mol % catalyst
loading was used to screen the other catalyst systems. Use of
xantphos or rac-2-(di-tert-butylphosphino)-1,10-binaphthyl,
which have recently been shown tobeeffectiveinthereactionof
orthobromophenols and ketones to produce benzofurans,16
did not proceed to any appreciable extent (entries 2 and 3).
Use of P(tBu)3 (entry 4), which has been shown to be
effective for R-arylation in a number of systems,17 and bis-
(diisopropyl)phosphinoferrocene (entry 5), which was the
several alternative catalyst systems, we found the N-heterocyclic
carbene catalyst, (SIPr)Pd(allyl)Cl, 6, described by Nolan15
when used under standard conditions (NaOtBu, THF at 70
°C) resulted in partial conversion to 5 by LCMS analysis.
In an effort to drive the reaction to completion, the
temperature was increased from 70 to 100 °C (sealed vessel).
(15) (a) Viciu, M. S.; Germaneau, R. F.; Nolan, S. P. Org. Lett. 2002, 4,
4053 (commercially available from Strem Chemical Co. catalog no. 46-0039).
(b) For a review of N-heterocyclic carbene catalysis, see: Marion, N.; Nolan,
S. P. Acc. Chem. Res. 2008, 41, 1440.
(16) Eidamshaus, C.; Burch, J. D. Org. Lett. 2008, 10, 4211.
(17) Hama, T.; Hartwig, J. F. Org. Lett. 2008, 10, 1549.
J. Org. Chem. Vol. 75, No. 15, 2010 5317

Spergel et al.
JOCNote
TABLE 2. Ketone Substrate Scope
TABLE 3. Heterocycle Substrate Scope
aNo optimization was attempted.
ranged from low (entries 1-3) to moderate (entries 4 and 5).
Other than the enamine-Heck route,9 there are few methods
reported to provide access to all of the azaindole regio-
isomers.18
We have demonstrated the application of N-heterocyclic
carbene palladium catalysts to the construction of azaindoles
and related heterocycles via ketone R-arylation chemistry.
We have demonstrated the utility of this method as an alter-
native to the stepwise approach, relying upon a 5-endo-dig
cyclization of acetylenes as part of our medicinal chemistry
effort. The recent report of the synthesis of azaindole 15,
from 2-aminopicoline in three steps (one protection step) in
57% overall yield,19 underscores the need for alternative
methodologies to provide rapid and convenient access to
azaindoles. Our one-pot approach does not require the use
of an amine protecting group, can be applied to nonsym-
metrical ketones with excellent regioselectivity, and allows
for late-stage diversification, making it a useful addition to
current methodologies.
a>95% single isomer by NMR.
most effective catalyst reported for indole formation,11
produced 9 in yields approaching that of (SIPr)Pd(allyl)Cl, 6.
Since the yield using (SIPr)Pd(allyl)Cl, 6, appeared to be
slightly better, we chose it to conduct a substrate scan.
Acetophenones (entries 1-5), alkyl ketones (entries 6 and
7), and cyclohexanone (entry 8) afforded azaindoles in yields
ranging from good to excellent (Table 2). Examination of the
crude NMR of 23 showed the 2-propylazaindole as the
Experimental Section
1
predominant isomer (>20:1 by HNMR). This ability to
General Procedure. Sodium bis(trimethylsilyl)amide, 1.0 M in
THF (1.5 mL, 1.5 mmol), was added to a solution of allyl(1,3-
bis(2,6-diisopropylphenyl)imidazolidin-2-ylidene)palladium(IV)
chloride (6) (28.7 mg, 0.05 mmol) and ketone (1.0 mmol) in THF
(1 mL) at rt. After the mixture was stirred for 5 min at rt,
o-bromoaminoheterocycle (0.25 mmol) was added as a solution in
employ unsymmetrical ketones represents an improvement
over the enamine-Heck methodology, although we did not
extend this observation further. The formation of a predo-
minant regioisomer has also been observed in the related
indole and benzofuran syntheses.11,16
With these results in hand, we turned our attention to the
preparation of other fused azaheterocycles (Table 3). We
found that the method appears to be general for other
electron-deficient heterocyclic systems, although the yields
(18) For a successful multistep strategy to provide all 2-aryl-substituted
azaindole isomers, see: Kuzmich, D.; Mulrooney, C. Synthesis 2003, 11,
1671.
(19) Parcerisa, J.; Romero, M.; Pujol, M. D. Tetrahedron 2008, 64, 500.
5318 J. Org. Chem. Vol. 75, No. 15, 2010

Spergel et al.
JOCNote
THF (0.2 mL), and the reaction was heated to 100-105 °C in a
pressure tube for 4 h. After being cooled to rt, the reaction mixture
was partitioned between EtOAc (30 mL) and saturated NH4Cl
solution (30 mL). The organic layer was washed with saturated
NH4Cl solution (30 mL), and the combined aqueous layers were
back-extracted with EtOAc (15 mL). After drying (MgSO4) and
filtration, the combined organic layer was concentrated to afford a
residue that was chromatographed on a silica gel, eluting with an
EtOAc/Hex gradient. Concentration of the pure fractions afforded
the product.
116.13, 122.42, 125.97 (2 C), 128.24, 128.77, 129.08 (2 C), 132.51,
139.66, 142.12, 150.06; HRMS calcd for C13H11N2 [M þ H]þ
195.09168, found 195.09173.
Acknowledgment. We would like to thank Bethanne Warrack
and Sarah Traeger from Discovery Analytical Sciences for
their analytical support and Dr. James Kempson and Dr. Scott
Watterson for helpful suggestions regarding the preparation of
this paper.
1
Characterization data for 9: H NMR (400 MHz, CDCl3) δ
6.79 (d, J = 1.5 Hz, 1 H), 7.10 (dd, J = 7.8, 4.8 Hz, 1 H), 7.40
(t, J = 7.4 Hz, 1 H), 7.52 (t, J = 7.6 Hz, 2 H), 7.88 (d, J = 7.1 Hz,
2 H), 7.96 (dd, J = 7.8, 1.3 Hz,1 H), 8.30 (dd, J = 4.8, 1.3 Hz,
1 H), 12.31 (s, 1 H); 13C NMR (101 MHz, CDCl3) δ 97.40,
Supporting Information Available: Experimental proce-
dures and full characterization data for all compounds. This
material is available free of charge via the Internet at http://
pubs.acs.org.
J. Org. Chem. Vol. 75, No. 15, 2010 5319