Low temperature organocopper-mediated two-component cross coupling/cycloisomerization approach toward N-fused heterocycles

Article abstract of DOI:10.1021/ol8008705

(Chemical Equation Presented) Organocopper reagents smoothly react with heterocyclic propargyl mesylates at low temperature to produce N-fused heterocycles. The copper reagent plays a "double duty" in this novel cascade transformation, which proceeds via an S_N2′ substitution followed by a subsequent cycloisomerization step.

Full text of DOI:10.1021/ol8008705

ORGANIC
LETTERS
2008
Vol. 10, No. 11
2307-2310
Low Temperature
Organocopper-Mediated Two-Component
Cross Coupling/Cycloisomerization
Approach Toward N-Fused Heterocycles
Dmitri Chernyak, Surendra Babu Gadamsetty, and Vladimir Gevorgyan*
Department of Chemistry, UniVersity of Illinois at Chicago, 845 West Taylor Street,
Chicago, Illinois 60607-7061
Vlad@uic.edu
Received April 15, 2008
ABSTRACT
Organocopper reagents smoothly react with heterocyclic propargyl mesylates at low temperature to produce N-fused heterocycles. The copper
reagent plays a “double duty” in this novel cascade transformation, which proceeds via an SN2′ substitution followed by a subsequent
cycloisomerization step.
The transition metal-catalyzed cycloisomerization approach
is a powerful tool for the assembly of diverse heterocyclic
frameworks.1 We have developed the base-assisted Cu-
catalyzed cycloisomerization of conjugated alkynylpyridines
1 into monosubstituted N-fused heterocycles 22 (eq 1). Later,
our group and others reported alternative methods for
cycloisomerization of skipped propargyl imines 3 into 1,2-
or 1,3-disubstituted N-fused heterocycles 43 (eq 2). Although
both approaches are quite general with respect to the
heterocyclic cores, they still have certain boundaries. Thus,
the former method is restricted to the synthesis of hetero-
cycles which do not possess substituents at the C-1 and C-2
positions, whereas the latter approach is limited to the
oxygen-based substituents at C-1 (OR2), as these propargylic
precursors 3 are normally prepared from the corresponding
heterocyclic aldehydes. Accordingly, development of more
general methodologies toward multisubstituted N-fused
heterocyclic scaffolds is desirable. Herein, we wish to report
the copper-mediated coupling/cyclization cascade reaction
of propargyl mesylates 5 toward N-fused heterocyclic
frameworks 6 (eq 3). Not only does this method give access
to C-1 alkyl- or aryl-substituted heterocycles, unavailable
by existing cycloisomerization techniques, but it also holds
a promise for a quick assembly of libraries of heterocyclic
compounds via the two-component coupling/cycloisomer-
ization strategy.
It was suggested that the copper-catalyzed cycloisomer-
ization of 1 into the monosubstituted heterocycles 2 proceeds
10.1021/ol8008705 CCC: $40.75
Published on Web 05/08/2008
2008 American Chemical Society

via a 1,3-disubstituted allenyl intermediate i (eq 1).2 Ac-
cordingly, we aimed at the analogous 1,1,3-trisubstituted
allenyl intermediates en route to 1,3-disubstituted N-fused
heterocyclic cores. Likely, these reactive allenyl intermediates
8 can be generated in situ via the SN2′-substitution4 of the
corresponding propargyl esters 5 (eq 4).
Table 1. Optimization of Reaction Conditions
run
[CuR]a
LG
OMs
OMs
OMs
OMs
OMs
OAc
solvent
Et2O
Et2O
THF
Et2O
THF
THF
THF
yield %b
1
2
3
4
5
6
7
8
9
s-Bu(Me)Cu(CN)Li2
n-Bu2Cu(CN)Li2
Me2Cu(CN)Li2
MeCu(CN)Li
MeCu(CN)Li
MeCu(CN)Li
MeCu(CN)Li
MeCu(CN)Li
MeCu(CN)Li
11
traces
0
8
90
21
16
0
We chose to employ the organocopper nucleophiles,5
based on the reasoning that, potentially, the copper reagent
(or the copper byproduct) can also mediate the subsequent
cycloisomerization step of V into the heterocycle 6, thus
playing a “double duty” in this transformation.6
OTFA
OC(O)OEt THF
OP(O)OEt2 THF
27
10 MeCu(CN)Li
11 MeCu(CN)Li
12 MeCu(CN)Li
13 Ph2Cu(CN)Li2
OTf
THF
THF
THF
Et2O
Et2O-THF
Et2O
THF
5
OBs
ONs
OMs
traces
traces
traces
9
0
71
To this end, a possible substitution/cycloisomerization
cascade of pyridyl-containing propargyl alcohol derivatives
5 with various copper reagents7 has been examined (Table
1). It was found that the higher order alkyl cuprate reagents
were not efficient in this transformation (entries 1-3). In
contrast, the lower order cyanocuprate (MeCu(CN)Li) reacted
with mesylate 5 very smoothly, affording the C-1 alkylated
indolizine derivative 6a in 90% yield (entry 5)! Attempts to
14 Ph2Cu(CN)Li2/BF3·Et2O OMs
15 PhCu(CN)Li
OMs
OMs
16 PhCuc
a Reactions were carried out with 1.0 mmol of 5 and 1.2 mmol of copper
reagent at -78 °C for 1 h, then at rt for 1 h. b Isolated yield. c Prepared by
mixing PhMgBr with CuBr•SMe2 complex.
substitute mesylate with another leaving group8 were not
successful (entries 6-12).
(1) For recent reviews, see: (a) Fu¨rstner, A.; Davies, P. W. Angew.
Chem., Int. Ed. 2007, 46, 3410. (b) Alonso, F.; Beletskaya, I. P.; Yus, M.
Chem. ReV. 2004, 104, 3079. (c) Nakamura, I.; Yamamoto, Y. Chem. ReV.
2004, 104, 2127.
Short optimization indicated that employment of a phenyl
copper reagent was resonably efficient for the construction
of C-1 phenyl-substituted indolizine 6 (entry 16). Importantly,
in all cases, the corresponding allenes 8 were detected at
early stages of the reaction, thus confirming for the first time
that the cycloisomerizations of propargyl imines, indeed,
proceed via allenic intermediates i2,3 (eq 1) and 8 (eq 4).
Next, the generality of the substitution/cycloisomerization
cascade of differently substituted propargyl mesylates 5 was
examined (Table 2). Thus, secondary alkyl-susbtituted me-
sylates 5a and 5b underwent smooth cyclization upon
treatment with primary (7a-c), secondary (7d), and tertiary
(7e) lower order cyanocuprates to produce the corresponding
indolizines 6 in good to excellent yields (Table 2, entries
1-7). Noteworthy, primary mesylate 5d can also be em-
ployed in this reaction, giving access to monosubstituted
indolizine 6ga, a heterocycle, which can be further elaborated
at C-3 via a direct C-H functionalization protocol.9 The
secondary aryl-substituted mesylates 5e-i were also efficient
in this cyclization, producing C-3 arylated indolizines in good
yields. Notably, ester (entry 10), chloro (entry 11), cyano
(entry 12), and nitro (entry 13) functionalities were perfectly
(2) (a) Kel’in, A. V.; Sromek, A. W.; Gevorgyan, V. J. Am. Chem. Soc.
2001, 123, 2074. (b) Kim, J. T.; Butt, J.; Gevorgyan, V. J. Org. Chem.
2004, 69, 5638. (c) Kim, J. T.; Gevorgyan, V J. Org. Chem. 2005, 70,
2054. (d) Schwier, T.; Sromek, A. W.; Yap, D. M. L.; Chernyak, D.;
Gevorgyan, V. J. Am. Chem. Soc. 2007, 129, 9868.
(3) (a) Seregin, I. V.; Gevorgyan, V. J. Am. Chem. Soc. 2006, 128,
12050. (b) Seregin, I. V.; Schammel, A. W.; Gevorgyan, V. Org. Lett. 2007,
9, 3433. (c) Smith, C. R.; Bunnelle, E. M.; Rhodes, A. J.; Sarpong, R. Org.
Lett. 2007, 9, 1169. (d) Hardin, A. R.; Sarpong, R. Org. Lett. 2007, 9, 4547.
(e) Yan, B.; Zhou, Y.; Zhang, H.; Chen, J.; Liu, Y. J. Org. Chem. 2007,
72, 7783. (f) Kim, J.; Choi, H. K.; Won, G.; Lee, H. Tetrahedron Lett.
2007, 48, 6863.
(4) For a general review, see: (a) Krause, N.; Hashmi, S. K. Modern
Allene Chemistry; Wiley-VCH: Weinheim, Germany, 2004; p 1143. See
also: (b) Krause, N.; Hoffmann-Roeder, A. Tetrahedron 2004, 60, 11671.
(c) Krause, N.; Hoffmann-Roeder, A. Angew. Chem., Int. Ed. 2002, 41,
2933.
(5) For recent examples on synthesis of allenes using copper reagents
via SN2′ substitution approach, see: (a) Saito, A.; Kanno, A.; Hanzawa, Y.
Angew. Chem., Int. Ed. 2007, 46, 3931. (b) Ghosh, P.; Lotesta, S. D.;
Williams, L. J. J. Am. Chem. Soc. 2007, 129, 2438. (c) Dieter, R. K.; Chen,
N.; Gore, V. K. J. Org. Chem. 2006, 71, 8755. (d) Pacheco, M. C.;
Gouverneur, V. Org. Lett. 2005, 7, 1267. (e) Dieter, R. K.; Chen, N.; Yu,
H.; Nice, L. E.; Gore, V. K. J. Org. Chem. 2005, 70, 2109. (f) Rega´s, D.;
Afonso, M. M.; Rodr´ıguez, M. L.; Palenzuela, J. A. J. Org. Chem. 2003,
68, 7845. (g) Dieter, R. K.; Yu, H. Org. Lett. 2001, 3, 3855.
(6) For copper-mediated cascade transformations, see for example: (a)
Sherman, E. S.; Chemler, S. R.; Tan, T. B.; Gerlits, O. Org. Lett. 2004, 6,
1573. (b) Sherman, E. S.; Fuller, P. H.; Kasi, D.; Chemler, S. R. J. Org.
Chem. 2007, 72, 3896.
(7) For general reviews on copper reagents, see: (a) Lipshutz, B. H. In
Organometallics in Synthesis: A Manual; Schlosser, M., Ed.; Wiley-VCH:
Weinheim, Germany, 1994; pp 283-376. (b) Krause, N. Modern Orga-
nocopperChemistry; Wiley-VCH: Weinheim, Germany, 2002. (c) Caprio,
V. Lett. Org. Chem. 2006, 3, 339. (d) Nakamura, E.; Seiji, M. Angew. Chem.,
Int. Ed. 2000, 39, 3750. (e) Woodward, S. Chem. Soc. ReV. 2000, 29, 393.
(f) Krause, N.; Gerold, A. Angew. Chem., Int. Ed. Engl. 1997, 36, 186. (g)
Taylor, R. J. K.; Casy, G. In Organocopper Reagents-A Practical
Approach; Taylor, R. J. K., Ed.; Oxford University Press: New York, 1994.
(8) It was also recently reported by Krause that the lower order
cyanocuprates provide high selectivity in SN2′-substitution reaction employ-
ing propargyl acetates. See: (a) Jansen, A.; Krause, N. Inorg. Chem. Acta
2006, 359, 1761. (b) Jansen, A.; Krause, N. Synthesis 2002, 1987.
(9) For a review, see: (a) Seregin, I. V.; Gevorgyan, V. Chem. Soc. ReV.
2007, 36, 1173. For a direct arylation of indolizines, see: (b) Park, C.-H.;
Ryabova, V.; Seregin, I. V.; Sromek, A. W.; Gevorgyan, V. Org. Lett. 2004,
6, 1159. For a direct alkynylation of indolizines, see: (c) JSeregin, I. V.;
Gevorgyan, V. J. Am. Chem. Soc. 2007, 129, 7742.
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Org. Lett., Vol. 10, No. 11, 2008

Table 2. Organocopper-Mediated Synthesis of N-Fused Heterocyclesa
tolerated under these reaction conditions. It was also shown
that pyrroloquinoline (entries 15 and 16) and pyrroloiso-
quinoline (entry 17) cores can efficiently be assembled via
this protocol. As discussed above, phenyl copper-mediated
cyclization of 5a produced C-1 aryl-substituted indolizine
6af in 71% yield. Likewise, application of the same reagent
to cyclization of 5j led to formation of arylated pyrrolo-
quinoline 6jf, albeit in 51% yield (entry 16, Table 2).
We also investigated the efficacy of a possible stepwise
approach toward N-fused heterocycles 6 (Table 3). It was
found that addition of cuprate reagents to the mesylates 5 at
-78 °C in 1 h led to formation of the allenes 8 in varying
yields (27-89%).10 The next step, cycloisomerization of
allenes 8 under the standard conditions,2a was even less
efficient, producing trace to low yields of indolizines 6 (Table
3). Evidently, due to low stability of the pyridyl allenes 8
and low yields of their cyclization under the catalytic
cyclization conditions,2a the two-step process is much less
(10) See Supporting Information for complete experimental data.
Org. Lett., Vol. 10, No. 11, 2008
2309

nitrogen at the Cu-activated double bond of allene, produces
cyclic intermediate 9. The latter can transform into product
6 either via the deprotonation-protonation sequence (Path
A) or through the 1,2-hydride shift in the carbenoid
intermediate 9 (Path B). To verify which mechanism
operates, we performed a deuterium-labeling experiment.
Indeed, if the reaction proceeds via Path A, then cyclization
of 5b-d should produce 6ba, a product with significant or
total deuterium loss.11
Table 3. Attempts at the Stepwise Synthesis of N-Fused
Heterocycles
overall
yieldb
%
yielda
%
yielda
%
In contrast, the end-game via Path B would give 6ba-d
with complete preservation of the deuterium label.12 It was
found that, under the standard cyclization conditions, the
reaction of isotopically pure 5b-d produced indolizine 6ba
with total deuterium loss, thus strongly supporting Path A.
run
R1
R2
8
6
6
1
2
3
H
Me
Me
s-Bu
27c
89
34
0
42
27
trace (61)
37 (82)
9 (62)
C6H4-p-CO2Me Me
a Isolated yield. b Overall isolated yield for a stepwise process. Yield
for cascade transformation from Table 2 is given in parentheses. c Trace
amounts of 6 were also isolated.
In summary, we have developed a novel organocopper-
mediated two-component coupling/cycloisomerization cas-
cade transformation. This mild and efficient method allows
for easy synthesis of C-1 alkyl- and aryl-substituted N-fused
heterocycles, such as indolizines, pyrroloquinolines, and
pyrroloisoquinolines, from easily available starting materials.
It deserves mentioning that these important heterocyclic
scaffolds13 with an alkyl or aryl substituent at C-1 are not
available via the existing cycloisomerization methods.
efficient compared to the cascade substitution/cycloisomer-
ization process (Table 2).
We propose the following mechanism for the substitution/
cycloisomerization cascade of propargyl mesylates 5 with
copper reagents into N-fused heterocycles 6 (Scheme 1).
First, SN2′-substitution of mesylate in 5 leads to allene 8,
which, upon intramolecular nucleophilic attack of pyridyl
Acknowledgment. Financial support from the National
Institutes of Health (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.
Scheme 1. Proposed Mechanism for Cascade Cyclization
OL8008705
(11) For substantial deuterium loss in the Cu-mediated cycloisomeriza-
tion, see ref 2a.
(12) For complete preservation of the deuterium label in the cycloi-
somerization proceeding via a 1,2-deuterium shift in carbenoid intermediate,
see: (a) Sromek, A. W.; Rubina, M.; Gevorgyan, V. J. Am. Chem. Soc.
2005, 127, 10500. (b) Dudnik, A. S.; Sromek, A. W.; Rubina, M.; Kim,
J. T.; Kel’in, A. V.; Gevorgyan, V. J. Am. Chem. Soc. 2008, 130, 1440.
(13) For biological activity of N-fused pyrroloheterocycles, see for
example: (a) Fujita, T.; Matsumoto, Y.; Kimura, T.; Yokota, S.; Sawada,
M.; Majima, M.; Ohtani, Y.; Kumagai, Y. Br. J. Clin. Pharmacol 2002,
54, 283. (b) Facompre´, M.; Tardy, C.; Bal-Mahieu, C.; Colson, P.; Perez,
C.; Manzanares, I.; Cuevas, C.; Bailly, C. Cancer Res. 2003, 63, 7392. (c)
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. (d) Østby, O. B.; Dalhus, B.; Gundersen, L.-L.; Rise, F.; Bast,
A.; Haenen, G. R. M. M. Eur. J. Org. Chem. 2000, 3763. (e) 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.
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