Base- and ligand-free room-temperature synthesis of N-fused heteroaromatic compounds via the transition metal-catalyzed cycloisomerization protocol

Article abstract of DOI:10.1021/ol701464j

A new practical method for the synthesis of N-fused heterocycles via the transition metal-catalyzed cycloisomerization of heterocyles possessing a propagyl group has been developed. This very mild, base- and ligand-free method allows for the synthesis of diverse fused heterocyclic cores in good to excellent yields.

Full text of DOI:10.1021/ol701464j

ORGANIC
LETTERS
2007
Vol. 9, No. 17
3433-3436
Base- and Ligand-free
Room-Temperature Synthesis of
N-Fused Heteroaromatic Compounds via
the Transition Metal-Catalyzed
Cycloisomerization Protocol
Ilya V. Seregin, Alex W. Schammel, and Vladimir Gevorgyan*
Department of Chemistry, UniVersity of Illinois at Chicago, 845 West Taylor Street,
Chicago, Illinois 60607-7061
Vlad@uic.edu
Received June 20, 2007
ABSTRACT
A new practical method for the synthesis of N-fused heterocycles via the transition metal-catalyzed cycloisomerization of heterocyles possessing
a propagyl group has been developed. This very mild, base- and ligand-free method allows for the synthesis of diverse fused heterocyclic
cores in good to excellent yields.
Heteroaromatic molecules containing N-fused bicyclic frag-
ments and their partially or completely reduced analogues
are pharmaceutically important scaffolds, widely found in
naturally occurring, as well as synthetic biologically active,
molecules.1 For instance, it was shown that molecules
containing indolizine and other closely related cores exhibit
strong anti-inflammatory,2 anti-HIV,3 and anti-leukemia
activities.4 Although few routes toward substituted fused
pyrrolo-heterocycles exist,5 new methods allowing for the
efficient construction of these heterocycles with different
substitution patterns are of high demand.
We have recently developed two complementary protocols
for the synthesis of C-3 substituted6 and C-1-C-2 disubsti-
tuted7 fused and nonfused pyrrole-containing heterocycles
(Scheme 1). The first approach which operates via a copper-
assisted cycloisomerization of conjugated alkynyl imines into
pyrrole ring (eq 1) was demonstrated to be very general and
efficient, though requires excess base and elevated temper-
atures, and is limited to C-3 monosubstituted products.6
Another protocol is based on a gold-catalyzed cascade
alkyne-vinylidene isomerization/1,2-metalloid migration in
(1) For review, see: Michael, J. P. Nat. Prod. Rep. 1999, 16, 675.
(2) For studies on sPLA2 inhibition activity, see: Hagishita, S.; Yamada,
M.; Shirahase, K.; Okada, T.; Murakami, Y.; Ito, Y.; Matsuura, T.; Wada,
M.; Kato, T.; Ueno, M.; Chikazawa, Y.; Yamada, K.; Ono, T.; Teshirogi,
I.; Ohtani, M. J. Med. Chem. 1996, 39, 3636.
(3) For studies on biological activity of Lamellarin family, see: (a)
Facompre, M.; Tardy, C.; Bal-Mahieu, C.; Colson, P.; Perez, C.; Manza-
nares, I.; Cuevas, C.; Bailly, C. Cancer Res. 2003, 63, 7392. (b) Reddy,
M. V.; Rao, M. R.; Rhodes, D.; Hansen, M. S.; Rubins, K.; Bushman, F.
D.; Venkateswarlu, Y.; Faulkner, D. J. J. Med. Chem. 1999, 42, 1901. (c)
Østby, O. B.; Dalhus, B.; Gundersen, L.-L.; Rise, F.; Bast, A.; Haenen, G.
R. M. M. Eur. J. Org. Chem. 2000, 3763.
(5) For a general review, see: (a) Behnisch, A.; Behnisch, P.; Eggen-
weiler, M.; Wallenhorst, T. Indolizine. In Houben-Weyl; Thieme: Stuttgart,
Germany, 1994; Vol. E6b/1, 2a, pp 323-450. See also: (b) Marchalin, S.;
Baumlova, B.; Baran, P.; Oulyadi, H.; Daich, A. J. Org. Chem. 2006, 71,
9114. (c) Kaloko, J., Jr.; Hayford, A. Org. Lett. 2005, 7, 4305.
(6) Kel’in, A. V.; Sromek, A. W.; Gevorgyan, V. J. Am. Chem. Soc.
2001, 123, 2074.
(4) (a) Anderson, W. K.; Heider, A. R.; Raju, N.; Yucht, J. A. J. Med.
Chem. 1988, 31, 2097. (b) Anderson, W. K.; DeRuiter, J.; Heider, A. R. J.
Org. Chem. 1985, 50, 722.
(7) Seregin, I. V.; Gevorgyan, V. J. Am. Chem. Soc. 2006, 128, 12050.
10.1021/ol701464j CCC: $37.00
© 2007 American Chemical Society
Published on Web 07/17/2007

Scheme 1. Formation of Differently Substituted Pyrrole Ring
Table 1. Catalyst Optimization
by Transition Metal-Catalyzed Cycloisomerizations
no.
catalyst
CuI
CuCl
AuCl3
AuI
AlCl3
Sn(OTf)2
Mg(OTf)2
In(OTf)2
PtCl2
PdCl2(PPh3)2
Pd(OAc)2
AgBF4
AgPF6
AgSbF6
HOTf
reaction time
yield, %b
1
2
3
4
5
6
7
8
3 h
77%
83%
71%
95%
64%c
31%
52%
33%
41%
61%
74%
>99%
>99%
52%
9%
30 min
30 min
3 h
48 h
48 h
48 h
48 h
48 h
30 min
30 min
30 min
30 min
30 min
30 min
9
10
11
12
13
14
15
nonconjugated propargyic systems (eq 2).7 This method does
not require base and can be efficiently used at 60 °C to
construct C-1-C-2 bifunctional scaffolds. Herein, we wish
to report a room temperature, base- and additive-free
transition metal-catalyzed cycloisomerization of propagyl
heterocycles leading to the formation of C-1-C-3 disubsti-
tuted N-fused heterocycles in good to excellent yields (eq
3).8
a Reactions were run in the presence of 3 mol % of catalyst in DCM
(0.25 M) at room temperature. Most reactions work equally well in toluene.
b GC-MS yields. c Reaction run using 10 mol % of catalyst.
We hypothesized that a π-philic metal would coordinate
to the propargylic moiety of the heterocycle rendering its
triple bond electrophilic, thus provoking cyclization via an
intramolecular nucleophilic attack of heterocyclic nitrogen
(Scheme 1, eq 3). To test this hypothesis, we first subjected
easily available9 propargyl-containing pyridine 1a to the
copper-catalyzed cycloisomerization conditions.6,10 It was
found that 1a, indeed, underwent the desired cycloizomer-
ization, affording indolizine 2a in good yield. After brief
optimization, we were pleased to find that this reaction can
be performed equally well at room temperature, the base can
be omitted, and DMA can be substituted with easier to handle
dichloromethane.
we tested this reaction in the presence of triflic acid.
However, it was found that only small amounts of 2a were
produced under Brønsted catalysis (entry 15).
Next, the scope of this cycloisomerization was examined
under the optimized conditions (Table 2). To our delight,
acetyloxy, diethylphosphatyloxy, and O-TBS-protected pro-
pargylic substrates 1a-k bearing alkyl (entries 2, 8, 10), aryl
(entries 1, 5, 9), heteroaryl (entry 11), and alkenyl (entries
3, 7) substituents at the triple bond, as well as those
possessing terminal alkyne moiety (entries 4, 6), underwent
very smooth cycloizomerization to give corresponding
heterocycles 2a-k in good to excellent yields. In contrast,
the reaction of diyne-containing substrate 1l gave a very low
yield of pyrrolo-thiazole 2l (entry 12).12 It deserves mention-
ing that this cycloisomerization protocol appeared to be
general with regard to the heterocyclic core: C-1-C-3
disubstituted indolizines (entries 1-6), pyrrolo-quinoxalines
(entries 7, 8), and pyrrolothiazoles (entries 9-11) can
efficiently be synthesized via this method from readily
available precursors.9
Next, catalyst optimization for this transformation was
performed. Thus, it was found that dramatic decrease of the
catalyst load to 3 mol % of CuI or CuCl had virtually no
effect on the reaction course, producing indolizine 2a in 77%
and 83% yields respectively (Table 1). Similarly, gold
catalysts were found to be efficient in this transformation:
AuCl3 afforded 71% yield, while AuI gave 95%, though the
reaction was slower. In contrast, employment of Al, Sn, In,
Mg, Pt, and Pd catalysts under these conditions resulted in
moderate yields only, and the reactions were generally much
more sluggish. Gratifyingly, switching to AgBF4 and AgPF6
led to nearly quantitative yields of 2a (entries 12, 13). To
verify whether an eventual proton can serve as a catalyst,11
We propose the following mechanistic rationale for the
transition metal-catalyzed cycloizomerization of propargyl-
heterocycles 1 (Scheme 2). π-Philic metal activates the
(11) For recent discussions on the role of Brønsted acids in transition
metal-catalyzed transformations, see: (a) Hashmi, A. S. K. Catal. Today
2007, 122, 211. (b) Li, Z.; Zhang, J.; Brouwer, C.; Yang, C.-G.; Reich, N.
W.; He, C. Org. Lett. 2006, 8, 4175. (c) Rosenfeld, D. C.; Shekhar, S.;
Takemiya, A.; Utsunomiya, M.; Hartwig, J. F. Org. Lett. 2006, 8, 4179.
(d) Rhee, J. U.; Krische, M. J. Org. Lett. 2005, 7, 2493.
(12) Alkynyl N-fused heterocycles can be alternatively accessed via our
recently developed direct C-H alkynylation approach: Seregin, I. V.;
Ryabova, V.; Gevorgyan, V. J. Am. Chem. Soc. 2007, 129, 7742.
(8) When this project was underway, a report on a related Pt-catalyzed
1,2-migration/cyclization toward indolizine core appeared, see: Smith, C.
R.; Bunnelle, E. M.; Rhodes, A. J.; Sarpong, R. Org. Lett. 2007, 9, 1169.
(9) See Supporting Information for detailed preparative procedures.
(10) The reactions were performed in N,N-dimethylacetamide (DMA)
at 130 °C in the presence of 30 mol % CuI.
3434
Org. Lett., Vol. 9, No. 17, 2007

Scheme 2. Proposed Mechanisms for Cycloisomerization
Table 2. Scope of Cycloisomerization
reaction mixture. Thus, we hypothesized that if deprotona-
tion-protonation event indeed takes place (Path A), a
substantial deuterium scrambling would be observed.14 On
the other hand, if the rearomatization proceeds via a hydride
shift (Path B), deuterium would cleanly end up at the C-2
position of the cyclized product 2.15 To test the above idea,
we performed a deuterium-labeling experiment employing
isotopically pure propargyl pyridine 5 (Scheme 3). It was
Scheme 3. Deuterium-Labeling Experiment
found that a severe proton-deuterium exchange took place
upon cycloizomerization, thus, strongly supporting the
deprotonation-protonation pathway A, and ruling out the
possibility of a clean hydride shift (Path B).
(13) For selected examples on nucleophilic attack of heteroatom at alkyne
activated by Au and Ag complexes, see: (a) Gorin, D. J.; Davis, N. R.;
Toste, F. D. J. Am. Chem. Soc. 2005, 127, 11260. (b) Dube´, P.; Toste, F.
D. J. Am. Chem. Soc. 2006, 128, 12062. (c) Shapiro, N. D.; Toste, N. D.
J. Am. Chem. Soc. 2007, 129, 4160. (d) Hashmi, A. S. K.; Rudolph, M.;
Schymura, S.; Visus, J.; Frey, W. Eur. J. Org. Chem. 2006, 4905. (e)
Hashmi, A. S. K.; Weyrauch, J. P.; Frey, W.; Bats, J. W. Org. Lett. 2004,
6, 4391. (f) Belting, V.; Krause, N. Org. Lett. 2006, 8, 4489. (g) Sun, J.;
Kozmin, S. A. Angew. Chem., Int. Ed. 2006, 45, 4991. (h) Wang, S.; Zhang,
L. J. Am. Chem. Soc. 2006, 128, 14274. (i) McDonald, F. E.; Gleason, M.
M. J. Am. Chem. Soc. 1996, 118, 6648. (j) McDonald, F. E.; Burova, S.
A.; Huffman, L. G. Synthesis 2000, 970.
(14) For an example of a base-assisted substantial deuterium scrambling
upon cycloisomerization in conjugated propargylic systems, see ref 6.
(15) For an example of a clean 1,2-deuterium shift upon cycloisomer-
ization, see: Sromek, A. W.; Rubina, M.; Gevorgyan, V. J. Am. Chem.
Soc. 2005, 127, 10500.
a Isolated yields. b Reaction run using 10 mol % of catalyst. c Reaction
was performed at 40 °C. d NMR yield.
triple bond toward an intramolecular nucleophilic attack of
the heterocyclic nitrogen,13 leading to the formation of a
bicyclic zwitterionic adduct 3. The latter can rearomatize into
product 2 via two different ways: through a deprotonation-
protonation sequence (Path A), or via 1,2- or 1,5-hydride
shift (Path B). In the former scenario, heterocyclic nitrogen
of 1 serves as a base, as there is no other base present in the
Org. Lett., Vol. 9, No. 17, 2007
3435

In summary, we have developed an exceptionally mild,
practical, and efficient method en route to C-1-C-3 disub-
stituted N-fused heterocycles, including indolizines, pyrrolo-
quinoxalines, and pyrrolothiazoles. This approach is comple-
mentary to our previously developed methods6,7 as it allows
for the synthesis of heterocycles with different substitution
patterns.
Acknowledgment. The support of the National Institutes
of Health (Grant GM-64444) is gratefully acknowledged.
Supporting Information Available: Preparative proce-
dures, analytical and spectral data. This material is available
free of charge via the Internet at http://pubs.acs.org.
OL701464J
3436
Org. Lett., Vol. 9, No. 17, 2007