Angewandte
Chemie
DOI: 10.1002/anie.201408335
Heterocycle Synthesis
Rhodium-Catalyzed NH Insertion of Pyridyl Carbenes Derived from
Pyridotriazoles: A General and Efficient Approach to 2-Picolylamines
and Imidazo[1,5-a]pyridines**
Yi Shi, Anton V. Gulevich, and Vladimir Gevorgyan*
Abstract: A general and efficient NH insertion reaction of
rhodium pyridyl carbenes derived from pyridotriazoles was
developed. Various NH-containing compounds, including
amides, anilines, enamines, and aliphatic amines, smoothly
underwent the NH insertion reaction to afford 2-picolylamine
derivatives. The developed transformation was further utilized
in a facile one-pot synthesis of imidazo[1,5-a]pyridines.
annulation reaction of pyridotriazoles based on the reaction
of B with nitriles. It was shown that Cl, Br, or OMe
substituents at C7 (AG = activating group), as well as
electron-withdrawing (EWG) groups at C3, were requisite
for efficient formation of the imidazo[1,5-a]pyridines (Sche-
me 1a).[1a] Naturally, we were interested in expanding the
scope of imidazo[1,5-a]pyridines which can be accessed by
transannulation reaction of pyridotriazoles. Herein, we report
a general rhodium-catalyzed NH insertion reaction of B,
derived from 1, to afford the valuable picolylamine deriva-
tives 3 (Scheme 1b),[5] and their application in a one-pot
synthesis of the imidazo[1,5-a]pyridines 4.[6] This new method
toward imidazo[1,5-a]pyridines features a much broader
scope, in that the presence of an AG and EWG in starting
1 is no longer required.
T
ransition-metal-catalyzed denitrogenative transannulation
of pyridotriazoles[1] is a powerful method for the synthesis of
nitrogen-containing heterocycles.[2–4] As a convenient progen-
itor of metal carbene species, the pyridotriazole 1 exists in
equilibrium with the diazo form A, which can be trapped with
rhodium(II) to form the reactive pyridyl carbene intermedi-
ate B (Scheme 1a). In 2007, our group reported the trans-
In continuation of our studies on application of diazo-
compounds for the synthesis of nitrogen-containing hetero-
cycles,[7] we investigated the reaction of pyridotriazoles with
primary amides as a potential route to imidazo[1,5-a]pyri-
dines. The 7-Cl-substituted triazole 1a, which proved to be an
effective carbene precursor,[1] was tested in the rhodium-
catalyzed NH insertion reaction first (Table 1).[8] Indeed, the
reaction of 1a with BocNH2 in the presence of a [Rh2(esp)2]
catalyst at room temperature produced the corresponding
piclolyl amine 3aa in 74% yield (entry 1).[9] Attempts to
employ the 7-unsubstituted pyridotriazole 1b under these
reaction conditions failed. However, we were pleased to find
that at 1208C it underwent the insertion reaction to furnish
the picolylamine 3ab in 90% yield (entry 2).[10]
Next, we examined the scope of this NH insertion
reaction. Thus, alkyl carbamates, such as tBuOCONH2,
EtOCONH2, and BnOCONH2 produced the picolyl amines
3ab–ad in high yields (Table 1, entries 2–4). The reaction also
worked efficiently with alkyl and aryl amides (entries 5–7), as
well as with alkenyl amide (entry 8). Notably, a cyano group
and alkenyl moiety, which normally react with metal car-
benes, stayed intact under these reaction conditions (entries 6
and 8). Moreover, we found that phenyl urea and sulfonamide
could also participate in this transformation to produce the
insertion products 3ai and 3aj (entries 9 and 10). Secondary
amides, such as oxazolidin-2-one (entry 11) and 3(2-H)-
pyridazinone (entry 12), were also competent reaction part-
ners. Notably, the reaction also efficiently proceeded with
pyridotriazoles containing different substituents at the C3
poisition. Thus, 3-aryl pyridotriazoles (entries 13–16) and
even 3-methyl pyridotriazole (entry 17) reacted smoothly to
produce the desired NH insertion products. In addition, 4-
methyl pyridotriazole (entry 18), N-fused quinolinotriazole
(entry 19), and benzoxazolotriazole (entry 20) also under-
Scheme 1. Transannulation reactions of pyridotriazoles. DCE=1,2-
dichloroethane, esp=a,a,a’,a’-tetramethyl-1,3-benzenedipropionic
acid, Ts=4-toluenesulfonyl.
[*] Y. Shi, Dr. A. V. Gulevich, Prof. Dr. V. Gevorgyan
Department of Chemistry, University of Illinois at Chicago
845 W Taylor St., Room 4500, Chicago, IL 60607 (USA)
E-mail: vlad@uic.edu
[**] The support of the National Institutes of Health (GM 64444) is
gratefully acknowledged.
Supporting information for this article is available on the WWW
Angew. Chem. Int. Ed. 2014, 53, 1 – 6
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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