Copper-catalyzed vinylation of hydrazides. A regioselective entry to highly substituted pyrroles

Article abstract of DOI:10.1021/ol062978s

(Chemical Equation Presented) A modular route to highly substituted pyrroles has been developed. This transformation consists of two sequential copper-catalyzed vinylations of bis-Boc-hydrazine followed by thermal rearrangement/cyclization. A wide variety

Full text of DOI:10.1021/ol062978s

ORGANIC
LETTERS
2007
Vol. 9, No. 6
973-976
Copper-Catalyzed Vinylation of
Hydrazides. A Regioselective Entry to
Highly Substituted Pyrroles
Marta Rodr´ıguez Rivero and Stephen L. Buchwald*
Department of Chemistry, Massachusetts Institute of Technology,
Cambridge, Massachusetts 02139
sbuchwal@mit.edu
Received December 8, 2006
ABSTRACT
A modular route to highly substituted pyrroles has been developed. This transformation consists of two sequential copper-catalyzed vinylations
of bis-Boc-hydrazine followed by thermal rearrangement/cyclization. A wide variety of functionalized pyrroles can be prepared in a selective
manner from simple and easily accessible precursors.
The pyrrole ring is an important heteroaromatic system found
in many natural products and bioactive molecules.1 Further-
more, pyrroles are widely used in materials science and as
structural elements in molecular recognition studies.2 Clas-
sical methods for the synthesis of these nitrogen heterocycles
include the Knorr,3 Hantzsch,4 and Paal-Knorr5 reactions.6
However, these approaches usually present significant limita-
tions in terms of substituents that can be introduced, the
substitution pattern, or regioselectivity. Although several
novel synthetic strategies have been described in recent
years,7 a general, regioselective approach to generate pyrroles
with a wide functional group tolerance from readily available
precursors is still lacking.
(1) (a) Agarwal, S.; Ca¨mmerer, S.; Filali, S.; Fro¨hner, W.; Kno¨ll, J.;
Krahl, M. P.; Reddy, K. R.; Kno¨lker, H.-J. Curr. Org. Chem. 2005, 9, 1601.
(b) Fu¨rstner, A. Angew. Chem. Int. Ed. 2003, 42, 3528. (c) Hoffmann, H.;
Lindel, T. Synthesis 2003, 1753. (d) O’Hagan, D. Nat. Prod. Rep. 2000,
17, 435. (e) Joule, J. A.; Mills, K. Heterocyclic Chemistry; Blackwell
Science: Oxford, 2000.
More specifically, access to highly substituted electron-
rich pyrroles is particularly limited. The Piloty-Robinson
synthesis8 (Scheme 1), consisting of a [3,3]-rearrangement
(2) (a) Custelcean, R.; Delmau, L. H.; Moyer, B. A.; Sessler, J. L.; Cho,
W.-S.; Gross, D.; Bates, G. W.; Brooks, S. J.; Light, M. E.; Gale, P. A.
Angew. Chem., Int. Ed. 2005, 44, 2537. (b) Domingo, V. M.; Aleman, C.;
Brillas, E.; Julia, L. J. Org. Chem. 2001, 66, 4058.
Scheme 1. Piloty-Robinson Pyrrole Synthesis8a
(3) (a) Knorr, L. Ber. 1884, 17, 1635. For recent examples: (b) Shiner,
C. M.; Lash, T. D. Tetrahedron 2005, 61, 11628. (c) Bellingham, R. K.;
Carey, J. S.; Hussain, N.; Morgan, D. O.; Oxley, P.; Powling, L. C. Org.
Process Res. DeV. 2004, 8, 279. (d) Manley, J. M.; Kalman, M. J.; Conway,
B. G.; Ball, C. C.; Havens, J. L.; Vaidyanathan, R. J. Org. Chem. 2003,
68, 6447.
(4) (a) Hantzsch, A. Ber. 1890, 23, 1474. For recent examples: (b)
Matiychuk, V. S.; Martyak, R. L.; Obushak, N. D.; Ostapiuk, Y. V.;
Pidlypnyi, N. I. Chem. Heterocycl. Comp. 2004, 40, 1218. (c) Calvo, L.;
Gonza´lez-Ortega, A.; San˜udo, M. C. Synthesis 2002, 2450. (d) Trautwein,
A. W.; Su¨âmuth, R. D.; Jung, G. Bioorg. Med. Chem. Lett. 1998, 8, 2381.
(5) (a) Paal, C. Ber. 1885, 18, 367. (b) Knorr, L. Ber. 1885, 18, 299.
For recent examples: (c) Chen, J.; Wu, H.; Zheng, Z.; Jin, C.; Zhang, X.;
Su, W. Tetrahedron Lett. 2006, 47, 5383. (d) Minetto, G.; Raveglia, L. F.;
Sega, A.; Taddei, M. Eur. J. Org. Chem. 2005, 5277. (e) Banik, B. K.;
Banik, I.; Renteria, M.; Dasgupta, S. K. Tetrahedron Lett. 2005, 46, 2643.
of ketazines followed by ring formation, represents an
interesting approach to these kinds of systems. Despite the
potential utility of this transformation, it has only been rarely
(6) For some reviews on synthesis of pyrroles: (a) Balme, G. Angew.
Chem. Int. Ed. 2004, 43, 6238. (b) Ferreira, V. F.; de Souza, M. C. B. V.;
Cunha, A. C.; Pereira, L. O. R.; Ferreira, M. L. G. Org. Prep. Proced. Int.
2001, 33, 411.
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used due to the strongly acidic conditions (e.g., HCl gas or
ZnCl2, 180-220 °C) required for the reaction. Milder
variations based on the prior formation of the intermediate
bisene-hydrazides by acylation of the starting azines have
been reported.9 However, these approaches are still extremely
limited in scope and functional group compatibility. More
importantly, unsymmetrical ketazines are not practical
substrates in the transformation because the initial tautomer-
ization could occur at either of the R-positions, affording
mixtures of isomers. Therefore, the development of a new
method to obtain alkenyl hydrazides in a selective fashion
would dramatically increase the utility of the Piloty-
Robinson reaction.
Scheme 3. Ligand Screen
Recently, our research group disclosed the copper-
catalyzed coupling of bis-Boc-hydrazine with 1-iodo-1-en-
2-ynes and its application to the synthesis of pyrazoles.10
On the basis of these results, we envisioned taking advantage
of a metal-catalyzed C-N bond-forming reaction11 as a new
means to prepare bisene-hydrazides which would overcome
the lack of regio- and stereoselectivity of classical methods.
Herein, we describe a convenient and selective procedure
for the synthesis of highly substituted pyrroles by two
sequential Cu-catalyzed vinylations of bis-Boc-hydrazine12
followed by cyclization (Scheme 2).
octene as the coupling partner (Scheme 3). A ligand screen
was carried out using CuI as a precatalyst and Cs2CO3 as a
base in DMF at 80 °C. Among the ligands examined, a
catalyst based on 1,10-phenanthroline (L7) showed the
highest activity giving the desired hydrazide 1 in excellent
yield. It is important to note that double vinylation was not
observed in the formation of compound 1 under these
conditions. Reasonable results can also be achieved using a
ligandless catalytic system (L1).
Scheme 2. Synthesis of Pyrroles through a Sequential
Cu-Catalyzed Vinylation of the Bis-Boc-hydrazine/Cyclization
Strategy
As shown in Table 1, a variety of vinyl hydrazides can be
prepared employing these optimized conditions.13 We were
pleased to find that R-, â-, and disubstituted vinyl iodides
are all viable substrates. Different substituents on the alkene,
including alkyl, aryl, and heteroaryl moieties, as well as
several functional groups, are tolerated in the process.
Although the reaction of (Z)-4-iodo-4-octene did not proceed
under the optimized conditions, the use of a more activated
(Z)-alkenyl iodide afforded the desired hydrazide in moderate
yield (entry 5).14 As summarized below, the method shows
excellent selectivity; only a small amount of the double
vinylation product was obtained when activated vinyl iodides
were employed (entries 2 and 5).
Reaction conditions for the initial copper-catalyzed C-N
bond-forming reaction were explored using (E)-4-iodo-4-
With these alkenyl hydrazides in hand, we next studied
their further coupling reaction with vinyl halides (Scheme
4). Although the second vinylation proceeds slowly, the
(7) For recent syntheses of pyrroles: (a) Hiroya, K.; Matsumoto, S.;
Ashikawa, M.; Ogiwara, K.; Sakamoto, T. Org. Lett. 2006, 8, 5349. (b)
Fuchibe, K.; Ono, D.; Akiyama, T. Chem. Commun. 2006, 2271. (c) Dong,
C.; Deng, G.; Wang, J. J. Org. Chem. 2006, 71, 5560. (d) Binder, J. T.;
Kirsch, S. F. Org. Lett. 2006, 8, 2151. (e) Lu, L.; Chen, G.; Ma, S. Org.
Lett. 2006, 8, 835. (f) Harrison, T. J.; Kozak, J. A.; Corbella-Pane´, M.;
Dake, G. R. J. Org. Chem. 2006, 71, 4525. (g) Gorin, D. J.; Davis, N. R.;
Toste, F. D. J. Am. Chem. Soc. 2005, 127, 11260.
(8) (a) Piloty, O. Ber. 1910, 43, 489. (b) Robinson, G. M.; Robinson, R.
J. Chem. Soc. 1918, 43, 639.
(9) (a) Posvic, H.; Dombro, R.; Ito, H.; Telinski, T. J. Org. Chem. 1974,
39, 2575. (b) Baldwin, J. E.; Bottaro, J. C. J. Chem. Soc., Chem. Commun.
1982, 624.
(10) Mart´ın, R.; Rodr´ıguez Rivero, M.; Buchwald, S. L. Angew. Chem.
Int. Ed. 2006, 45, 7079.
(11) For recent reviews on palladium-catalyzed C-N bond-forming
reactions: (a) Hartwig, J. F. Synlett 2006, 1283. (b) Jiang, L.; Buchwald,
S. L. In Metal-Catalyzed Cross-Coupling Reactions, 2nd ed.; de Meijere,
A., Diederich, F., Eds.; Wiley-VCH: Weinheim, 2004; p 699.
(12) For recent reviews on Cu-catalyzed C-N bond-forming reactions:
(a) Beletskaya, I. P.; Cheprakov, A. V. Coord. Chem. ReV. 2004, 248, 2337.
(b) Ley, S. V.; Thomas, A. W. Angew. Chem. Int. Ed. 2003, 42, 5400. (c)
Kunz, K.; Scholz, U.; Ganzer, D. Synlett 2003, 2428.
(13) Two examples for the metal-catalyzed syntheses of monosubstituted
vinyl hydrazides from alkenyl boronic acids have been previously reported
in the literature: (a) Uemura, T.; Chatani, N. J. Org. Chem. 2005, 70, 8631.
(b) Kabalka, G. W.; Guchhait, S. K. Org. Lett. 2003, 5, 4129. During the
revision process of this manuscript, the Pd-catalyzed coupling between tert-
butyl carbazate and vinyl halides was reported: (c) Barluenga, J.; Moriel,
P.; Aznar, F.; Valde´s, C. Org. Lett. 2007, 9, 275.
(14) NOESY experiments for compounds in entries 3 and 5 (Table 1)
indicate that the double bond geometry of the starting vinyl iodides is
retained in the product.
974
Org. Lett., Vol. 9, No. 6, 2007

Table 1. Cu-Catalyzed Coupling of Vinyl Iodides with
Bis-Boc-hydrazinea
Table 2. Synthesis of Pyrroles through Sequential
Cu-Catalyzed Vinylation of Hydrazides/Cyclizationa
a
Reaction conditions: 5 mol % of CuI, 10 mol % of 1,10-phenanthro-
line, 1 equiv of vinyl iodide, 1.2 equiv of hydrazide, 1.2 equiv of Cs2CO3,
DMF (0.5 M in vinyl iodide), 80 °C. b Isolated yields (average of two runs)
of compounds estimated to be >95% pure as determined by 1H NMR and/
c
d
or combustion analysis. 2 equiv of bis-Boc-hydrazine were employed.
A 96:4 ratio of mono- and double-vinylation products was observed by 1H
e
NMR analysis of the crude reaction mixture. A 91:9 ratio of mono- and
double-vinylation products was observed by 1H NMR analysis of the crude
reaction mixture.
reaction between 1 and (E)-1-iodo-1-decene takes place in
good yield by utilizing 10 mol % of CuI and 20 mol % of
L7 and increasing the concentration of vinyl iodide to 1 M.
The resulting bisene-hydrazide 2 was then subjected to
thermal cyclization.15 After refluxing a solution of 2 in xylene
for 30 h, total consumption of the starting material was
observed. However, further acidic treatment at room tem-
perature was necessary to achieve complete aromatization
of intermediate I (Scheme 2) to the pyrrole.16
a
Reaction conditions: (i) 10 mol % of CuI, 20 mol % of 1,10-
phenanthroline, 1 equiv of vinyl iodide, 1 equiv of vinyl hydrazide, 1.2
equiv of Cs2CO3, DMF (1 M), 80 °C; (ii) m-xylene (0.25 M), 140 °C; (iii)
2 equiv of p-TsOH‚H2O, room temperature. b Isolated overall yields (average
of two runs) of compounds estimated to be >95% pure as determined by
1H NMR and/or combustion analysis. Addition of p-TsOH‚H2O was not
c
d
necessary. For details, see Supporting Information. Combined yield: R
Pyrrole 3 could also be obtained from 1 without purifica-
tion of the intermediate bisene-hydrazide. Once the vinyl
) Boc 38%, R ) H 16%. e Combined yield: R ) Boc 21%, R ) H 39%.
iodide was consumed, filtration of the crude product from
the copper-catalyzed reaction through Celite followed by a
solvent exchange and subjecting the solution to rearrange-
ment/cyclization conditions afforded the pyrrole in an overall
yield similar to that for the stepwise process.
Scheme 4. Cu-Catalyzed Synthesis of Bisene-hydrazides and
Further Cyclization Reaction
With these results, we examined the scope and generality
of this new protocol. As shown in Table 2, the standard
reaction conditions are applicable to the synthesis of a wide
variety of pyrroles. Both alkyl- and aryl-substituted vinyl
(15) The use of several Lewis acids to catalyze the [3,3] rearrangement
was tested. However, only decomposition products were obtained.
(16) For the isolation of similar intermediates in the Fischer indole
synthesis: (a) Tullberg, E.; Schacher, F.; Peters, D.; Frejd, T. Synthesis
2006, 1183. (b) Miyata, O.; Kimura, Y.; Naito, T. Synthesis 2001, 1635.
Org. Lett., Vol. 9, No. 6, 2007
975

iodides can be used to build the pyrrole framework.
Moreover, a wide range of functional groups, such as alkenes,
alkyl or benzyl ethers, ketones, esters, and nitriles, are
tolerated in the reaction. Another important feature of this
route is that it provides access not only to electron-rich
pyrroles but also to derivatives bearing electron-withdrawing
groups. The procedure allows easy and complete control over
the installation of substituents around the heterocyclic core,
by choosing the appropiate starting vinyl iodides.17
Although addition of p-TsOH is necessary to obtain
pyrrole 3 (Scheme 4), in some instances thermal treatment
gives rise directly to the aromatic heterocycle without further
addition of acid (entries 3, 4, 7, 9, and 11). In general, when
electron-withdrawing groups are attached to the pyrrole
framework, cleavage of the carbamate group takes place
under the reaction conditions, affording the deprotected
products (entries 3, 4, 6, 8, and 9), although in some cases
mixtures of free and Boc-protected pyrroles are obtained
(entries 5 and 12).
In summary, we have improved the utility of the Piloty-
Robinson reaction, allowing the flexible and regioselective
preparation of pyrroles through a sequential Cu-catalyzed
vinylation of bis-Boc-hydrazine/cyclization strategy. This
synthetic route accommodates a variety of substituents in
the heterocyclic ring, providing modular access from simple
and readily available precursors.
Acknowledgment. Generous financial support from the
National Institutes of Health (GM058160) is gratefully
acknowledged. M.R.R. thanks the Spanish Ministerio de
Educacio´n y Ciencia for a Postdoctoral Fellowship. Che-
metall is acknowledged for a gift of Cs2CO3. We are indebted
to Merck, Amgen, and Boehringer-Ingelheim for unrestricted
support.
Supporting Information Available: Experimental pro-
cedures and spectral data for all compounds. This material
is available free of charge via the Internet at http://pubs.acs.org.
(17) Starting vinyl iodides were readily prepared, generally in one or
two steps, from commercially available materials. For details, see the
Supporting Information.
OL062978S
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Org. Lett., Vol. 9, No. 6, 2007