Pyridine activation via copper(I)-catalyzed annulation toward indolizines

Article abstract of DOI:10.1021/ja106751t

The copper(I)-catalyzed regioselective [3 + 2] cyclization of pyridines toward alkenyldiazoacetates leading to functionalized indolizine derivatives is reported. A broad range of pyridine derivatives (including quinoline and isoquinoline) is compatible with this cyclization reaction. The process represents the first successful example of metal-catalyzed cyclization of a π-deficient heterocyclic system with alkenyldiazo compounds.

Full text of DOI:10.1021/ja106751t

Published on Web 09/08/2010
Pyridine Activation via Copper(I)-Catalyzed Annulation toward Indolizines
Jose´ Barluenga,* Giacomo Lonzi, Lorena Riesgo, Luis A. Lo´pez, and Miguel Toma´s*
Instituto UniVersitario de Qu´ımica Organometa´lica “Enrique Moles”, Unidad Asociada al CSIC, UniVersidad de
OViedo, Julia´n ClaVer´ıa 8, 33006 OViedo, Spain
Received July 29, 2010; E-mail: barluenga@uniovi.es; mtl@uniovi.es
Moreover, the annulation of diazoacetates 2a and 2b to 1a occurred
with complete regioselectivity.
Abstract: The copper(I)-catalyzed regioselective [3 + 2] cycliza-
tion of pyridines toward alkenyldiazoacetates leading to function-
alized indolizine derivatives is reported. A broad range of pyridine
derivatives (including quinoline and isoquinoline) is compatible
with this cyclization reaction. The process represents the first
successful example of metal-catalyzed cyclization of a π-deficient
heterocyclic system with alkenyldiazo compounds.
Next, we examined the scope of this new catalytic transformation
of the pyridine ring. We were pleased to find that the copper(I)-
catalyzed reaction of pyridines 1 and vinyldiazoacetates 2 allowed
the preparation of indolizines with a variety of substitution patterns
(Table 1).
Pyridine derivatives play a pivotal role in coordination chemistry
and catalysis. A number of complexes involving coordination of
different metals to a great variety of pyridine-containing ligands
have been reported in the literature.1 In apparent contradiction with
Table 1. Cu(I)-Catalyzed Synthesis of Indolizine Derivatives 3 from
Pyridines 1 and Ethyl Alkenyldiazoacetates 2a
the easy formation of this sort of complex, transformations of the
pyridine skeleton catalyzed by transition-metal complexes are very
scarce and often suffer from harsh reaction conditions and/or limited
substrate scope (for instance, pyridine itself proved to be particularly
reluctant to partake in most of the reported catalytic processes).2
For these reasons, the ability to efficiently functionalize pyridines
and their derivatives (e.g., quinoline, isoquinoline, etc.) remains
an important issue in synthetic chemistry.
On the other hand, the pyridine core is present in a huge number
of relevant heteropolycycles. Among them, the indolizine frame-
work is a common substructure in a number of biologically
important natural products and pharmaceuticals3 and is used to
provide a high level of fluorescence.4 Most synthetic strategies
require starting from pyridinium N-methylides5 or pyridines with
specific C2 functionalization.6 In contrast, only two annulation
reactions of the pyridine ring that involve N-alkylation/nucleophilic
cyclization have recently been reported.7
Continuing our interest in the design of new metal-catalyzed
processes using copper as an eco-friendly, cheap transition metal,
we found that pyridine itself and substituted pyridines do behave
as noninnocent ligands. Specifically, herein we report the Cu(I)-
catalyzed [3 + 2] cyclization of the pyridine ring toward alkenyl-
diazoacetates leading to substituted indolizines.8
Thus, we found that stirring a mixture of pyridine (1a) (1 equiv),
ethyl vinyldiazoacetate 2a (1 equiv), and CuBr (5 mol %) in CH2Cl2
at room temperature led to complete disappearance of the starting
diazo compound after 4 h (TLC, 5:1 hexane/ethyl acetate).
Purification by column chromatography (SiO2, 5:1 hexane/ethyl
acetate) afforded indolizine 3aa in 34% isolated yield (eq 1). This
result seemed promising, as indolizines are highly sensitive to
chromatographic media.9,10 Encouraged by this initial result, we
next addressed this heterocyclization using substituted vinyldiaz-
oacetates. We found that the presence of a methyl substituent at
C3 of the diazo ester had a large and favorable effect on the yield
of the reaction. Thus, running the reaction of ethyl isopropenyl-
diazoacetate (2b) and 1a under the same reaction conditions resulted
in the isolation of pure indolizine 3ab in 90% yield (eq 1).
a Yields of isolated products after column chromatography are
reported.
First, pyridine reacts with alkenyldiazoacetates with various
substitution patterns, though with varying efficiency. Thus, the
reaction yield increased in going from unsubstituted (R5 ) R6 )
H) to substituted (R5 * H or R5, R6 * H) diazo compounds (3aa
vs 3ab and 3ac) and from ꢀ-substituted (R4 ) Et) to R-substituted
(R3 ) Me) diazo compounds (3ad vs 3ab).
The reaction tolerated substitution of various kinds at C4 of
pyridine. Besides methyl and phenyl groups, which afforded
indolizines 3bb and 3cb in 94 and 76% yield, respectively, a great
variety of functionalization (vinyl, methoxycarbonyl, acyl, formyl,
cyano) was compatible with the protocol, providing indolizines
3db-hb in moderate to good yields (37-85%). Moreover, 4-chlo-
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10.1021/ja106751t  2010 American Chemical Society

C O M M U N I C A T I O N S
ropyridine (1i) furnished chloroindolizidine 3ib, which is amenable
to further elaboration by standard cross-coupling methods.11 On
the contrary, the reaction was rather ineffective in the case of
electron-donor-substituted pyridines. In fact, 4-methoxy- and 4-dim-
ethylaminopyridine led to complex mixtures of products, while
4-tosylpyridine (1j) afforded 3jb in 28% yield. Substitution at C2
also makes the reaction sluggish, as illustrated for the annulation
of 2-picoline (1k), which gave 3kb in 40% yield. The [3 + 2]
cyclization also proved to be amenable for disubstituted pyridines.
Thus, treatment of 3,5-dimethylpyridine (1l) and 3,5-dichloropy-
ridine (1m) with diazo compound 2b under the above condition
reactions afforded in moderate yields the indolizine derivatives 3lb
(66%) and 3mb (60%).
The issue of the regioselectivity of the annulation of 3-sub-
stituted pyridines toward diazo compound 2b was then addressed
(Table 2). It was found that the ratio of isomers resulting from
the cyclizations toward C6 (indolizines 4) and C2 (indolizines
5) is highly dependent on the nature of the substituent.
Interestingly, the strong-acceptor nitro group not only was
compatible but also directed the cyclization exclusively toward
the regioisomer 4nb in acceptable yield (64%). Standard
electron-withdrawing groups also favored the cyclization through
C6 of the pyridine ring, providing adducts 4 in preference over
5 (R ) CN, 4ob/5ob ) 10; R ) CO2Et, 4pb/5pb ) 3) in
54-73% yield. On the contrary, this regioselective trend was
reversed for 3-picoline and 3-X-pyridines (X ) F, Cl), which
yielded indolizines 5 as the major isomers in 45-60% yield.
A tentative rationale for this cyclization is illustrated in Scheme
1 for the cyclization of 1a with diazo compound 2b. Initially,
decomposition of 2b would form the copper(I) alkenylcarbene
species I,12 which then would evolve to the cuprate II by Michael-
type addition of the pyridine nitrogen,13 probably directed by
pyridine-copper coordination. The cyclization of the latter would
generate the copper(III) metallacycle III, which would undergo
reductive elimination assisted by the proximal ring C-C double
bond, giving rise to the Cu(I) complex IV.14 Further metal
decoordination would afford the dihydroindolizine V, thus conclud-
ing the catalytic cycle. Finally, oxidative aromatization would result
in the formation of the corresponding indolizidine.15
Scheme 1. Proposed Mechanism for the Cu(I)-Catalyzed Synthesis
of Indolizine Derivatives from Pyridines 1 and Diazo Compounds 2
Table 2. Cu(I)-Catalyzed Synthesis of Indolizine Derivatives 4 and
5 from 3-Substituted Pyridines 1n-s and Ethyl
Isopropenyldiazoacetate 2b
entry
1
R
4
5
4/5a
yield (%)b
1
2
3
4
5
6
1n
1o
1p
1q
1r
1s
NO2
CN
CO2Me
Cl
F
Me
4nb
4ob
4pb
4qb
4rb
4sb
5nb
5ob
5pb
5qb
5rb
5sb
4nb only
10:1
3:1
1:1.5
1:3
64
73
54
45
60
54c
1:7
The selectivity of the cyclization observed in the case of
3-substituted pyridines is in accordance with this mechanistic model
in the sense that the major regioisomer observed results from the
more stable complex intermediate IV. In the case of 3-methylpy-
ridine, the coordination involving the more electron-rich C3dC4
bond is preferred, whereas the coordination of copper through the
less electron-poor, nonconjugated C4dC5 bond occurs for 3-ni-
tropyridine (Figure 1). Theoretical calculations at the B3LYP/6-
31G* level (see the Supporting Information) support this mecha-
nistic model and predict that (i) the formation of II is the rate-
determining step and (ii) the major complex IV observed is
kinetically and thermodynamically favored over the other one.16
a
1
Estimated by H NMR spectroscopy (400 MHz) of the crude reaction
mixture. b Yield of isolated products after column chromatography. c Iso-
lated as a nonseparable mixture of regioisomers.
Interestingly, simple benzo-fused pyridines 1t-v were found to
work well, leading to more complex cycloadducts in variable yields.
Thus, quinoline (1t) and isoquinoline (1u) afforded substituted
pyrrolo[1,2-a]quinoline 6 and pyrrolo[2,1-a]isoquinoline 7 in yields
of 65 and 80%, respectively, upon reaction with 2b (eqs 2 and 3):
Figure 1. Preferred intermediates IV for 3-X-pyridines (X ) Me,
NO2).
In contrast, the reaction with phenanthridine (1v) proved to be more
challenging and provided the pyrrolo[1,2-f]phenanthridine structure
8 in only 30% yield (eq 4):
In conclusion, direct annulation of pyridine derivatives to form
indolizine derivatives has been accomplished in a regioselective
manner. All of the heterocyclic substrates used were commercially
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C O M M U N I C A T I O N S
available and did not require additional purification.17 A broad range
of pyridine substrates is compatible with this operationally simple
and mild copper-catalyzed cyclization, allowing heterocyclic nuclei
as important as indolizidines and benzoindolines (pyrroloquinolines
and -isoquinolines) to be readily obtained with a broad array of
substitution and functionalization patterns. It is noteworthy that this
is the first successful example of metal-catalyzed cyclization of a
π-deficient heterocyclic system with alkenyldiazo compounds, in
contrast to the extensive chemistry performed on π-excessive
heterocycles.18 From these results, it can be envisioned that copper
will prove to be a suitable eco-friendly candidate for catalyzing
transformations onto other nitrogen heterocycles rather than simply
undergoing metal-ligand coordination.
Rhodes, A. J.; Sarpong, R. Org. Lett. 2007, 9, 1169. (g) Schwier, T.;
Sromek, A. W.; Yap, D. M. L.; Chernyak, D.; Gevorgyan, V. J. Am. Chem.
Soc. 2007, 129, 9868. (h) Seregin, I. V.; Gevorgyan, V. J. Am. Chem. Soc.
2006, 128, 12050. (i) Kaloko, J., Jr.; Hayford, A. Org. Lett. 2005, 7, 4305.
(7) From donor-acceptor-substituted cyclopropanes: (a) Morra, N. A.; Morales,
C. L.; Bajitos, B.; Wang, X.; Jang, H.; Wang, J.; Yu, M.; Pagenkopf, B. L.
AdV. Synth. Catal. 2006, 348, 2385. Using Baylis-Hillman bromides: (b)
Basavaiah, D.; Devendar, B.; Lenin, D. V.; Satyanarayana, T. Synlett 2009,
411. (c) Viswambharan, B.; Selvakumar, K.; Madhavan, S.; Shanmugam,
S. Org. Lett. 2010, 12, 2108.
(8) Rh(II)- and Cu(I)-catalyzed [3 + 2] cyclizations of vinyldiazoacetates and
p-nitroaniline-derived imines have been reported. See: Doyle, M. P.; Yan,
M.; Hu, W.; Gronenberg, L. J. Am. Chem. Soc. 2003, 125, 4692.
(9) The easy decomposition of some indolizine derivatives is well-known (for
example, see: Kel’in, A. V.; Sromek, A. W.; Gevorgyan, V. J. Am. Chem.
Soc. 2001, 123, 2074). In fact, we found that pure indolizine 3aa undergoes
partial decomposition during column chromatography (SiO2, 5:1 hexane/
ethyl acetate).
(10) The use of other solvents (THF, toluene, acetonitrile) and copper complexes
([(MeCN)4Cu][BF4], CuCl, CuCN, Cu(OTf)2) did not improve the yield
of the process. On the other hand, no reaction at all occurred using
Rh2(OAc)4.
(11) For the synthesis of 3-arylindolizines from 3-chloroindolizines under
Suzuki-Miyaura conditions, see: Xia, J.-B.; You, S.-L. Org. Lett. 2009,
11, 1187.
Acknowledgment. This work is respectfully dedicated to the
memory of Prof. Jose´ M. Concello´n. We are grateful to the
MICINN/FEDER (Grant CTQ2007-61048) and the Principado de
Asturias (Grant IB 08-088). G.L. and L.R. thank the MICINN and
European Union (Fondo Social Europeo) for predoctoral fellow-
ships. We are also grateful to Dr. J. Gonza´lez for his assistance in
the computational study.
(12) The generation of copper(I) carbenes by the decomposition of diazoacetates
is a well-documented process. For example, see: Doyle, M. P.; McKervey,
M. A.; Ye, T. Modern Catalytic Methods for Organic Synthesis with Diazo
Compounds: From Cyclopropanes to Ylides; Wiley: New York, 1998.
(13) The electrophilic reactivity at the vinylogous and carbenoid positions of
vinylcarbenoids has been reported previously. For example, see: (a) Davies,
H. M. L.; Saikali, E.; Young, W. B. J. Org. Chem. 1991, 56, 5696. (b)
Davies, H. M. L.; Hu, B.; Saikali, E.; Bruzinski, P. R. J. Org. Chem. 1994,
59, 4535. (c) Davies, H. M. L.; Yokota, Y. Tetrahedron Lett. 2000, 41,
4851. (d) Sevryugina, Y.; Weaver, B.; Hansen, J.; Thompson, J.; Davies,
H. M. L.; Petrukhina, M. A. Organometallics 2008, 27, 1750. For significant
enhancement of vinylogous vs carbenoid reactivity in copper vinylcar-
benoids, see: Yue, Y.; Wang, Y.; Hu, W. Tetrahedron Lett. 2007, 48, 3975.
For a related intramolecular Michael-type addition of the pyridine nitrogen,
see ref 6d.
(14) Reductive elimination involving copper(III) complexes has been proposed
for C-C bond-forming reactions leading to either acyclic and cyclic adducts.
For example, see: (a) Ito, H.; Toyoda, T.; Sawamura, M. J. Am. Chem.
Soc. 2010, 132, 5990. (b) Phipps, R. J.; Gaunt, M. J. Science 2009, 323,
1593. The generation of intermediate IV by direct attack of the vinyl anion
on the iminium function of II, as found in related rhodium-catalyzed [3 +
2] cyclization reactions (ref 13b), cannot be ruled out.
Supporting Information Available: Experimental procedures and
spectral and analytical data for compounds 3-8. This material is
available free of charge via the Internet at http://pubs.acs.org.
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