Ruthenium-catalyzed pyrrole synthesis via oxidative annulation of enamides and alkynes

Article abstract of DOI:10.1021/ol303159h

An efficient and regioselective ruthenium-catalyzed oxidative annulation of enamides with alkynes via the cleavage of C(sp²)-H/N-H bonds is reported. The reactions can afford N-acetyl substituted or N-unsubstituted pyrroles by altering the reaction conditions slightly.

Full text of DOI:10.1021/ol303159h

ORGANIC
LETTERS
2013
Vol. 15, No. 1
136–139
Ruthenium-Catalyzed Pyrrole Synthesis
via Oxidative Annulation of Enamides
and Alkynes
Bin Li,*,† Nuancheng Wang,† Yujie Liang,† Shansheng Xu,† and Baiquan Wang*,†,‡
State Key Laboratory of Element-Organic Chemistry, College of Chemistry,
Nankai University, Tianjin 300071, P. R. China, and State Key Laboratory of
Organometallic Chemistry, Chinese Academy of Sciences, Shanghai 200032, P. R. China
nklibin@nankai.edu.cn; bqwang@nankai.edu.cn
Received November 16, 2012
ABSTRACT
An efficient and regioselective ruthenium-catalyzed oxidative annulation of enamides with alkynes via the cleavage of C(sp2)ÀH/NÀH bonds is
reported. The reactions can afford N-acetyl substituted or N-unsubstituted pyrroles by altering the reaction conditions slightly.
Pyrroles represent one of the most important classes of
five-membered heterocycle compounds that constitute the
core motif of many natural products.1 Furthermore, they
are useful building blocks in the synthesis of compounds
with interesting biological and pharmaceutical activities2
and are widely used in the field of materials chemistry.3 As
a result, many new synthetic methods have been developed
for the construction of pyrroles and their derivatives over
the years.4 Among these methods, the transition-
metal-catalyzed reactions play a prominent role.5 However,
(4) For reviews, see: (a) Gossauer, A. In Methoden der Organischen
Chemie (Houben-Weyl); Kreher, R. P., Ed.; Georg Thieme Verlag: Stuttgart,
1994; E6a, pp 556À798. (b) Gilchrist, T. L. J. Chem. Soc., Perkin Trans. 1
1999, 2849. (c) Tarasova, O. A.; Nedolya, N. A.; Vvedensky, V. Yu.;
Brandsma, L.; Trofimov, B. A. Tetrahedron Lett. 1997, 38, 7241.
(d) 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.
(5) For reviews, see: (a) Balme, G. Angew. Chem., Int. Ed. 2004, 43,
6238. (b) Nakamura, I.; Yamamoto, Y. Chem. Rev. 2004, 104, 2127. For
recent selected reports, see: (c) Maiti, S.; Biswas, S.; Jana, U. J. Org.
Chem. 2010, 75, 1674. (d) Liu, W.; Jiang, H.; Huang, L. Org. Lett. 2010,
12, 312. (e) Aponick, A.; Li, C.-Y.; Malinge, J.; Marques, E. F. Org. Lett.
2009, 11, 4624. (f) Lu, Y.; Arndtsen, B. A. Angew. Chem., Int. Ed. 2008,
47, 5430. (g) Cyr, D. J. S.; Arndtsen, B. A. J. Am. Chem. Soc. 2007, 129,
† Nankai University.
‡ Chinese Academy of Sciences.
(1) (a) Pyrroles, Part II; Jones, R. A., Ed.; Wiley: New York, 1992.
(b) Walsh, C. T.; Garneau-Tsodikova, S.; Howard-Jones, A. R. Nat. Prod. Rep.
€
2006, 23, 517. (c) Furstner, A. Angew. Chem., Int. Ed. 2003, 42, 3582.
(2) (a) Lipkus, A. H.; Yuan, Q.; Lucas, K. A.; Funk, S. A.; Bartelt,
W. F., III; Schenck, R. J.; Trippe, A. J. J. Org. Chem. 2008, 73, 4443.
(b) Sundberg, R. J. In Comprehensive Heterocyclic Chemistry II;
Katritzky, A. R.; Rees, C. W.; Scriven, E. F. V., Eds.; Pergamon Press:
New York, Oxford, 1996; Vol. 2, pp 119À206. (c) Fan, H.; Peng, J.;
Hamann, M. T.; Hu, J.-F. Chem. Rev. 2008, 108, 264. (d) Huffman, J. W.
Curr. Med. Chem. 1999, 6, 705.
(3) (a) Domingo, V. M.; Aleman, C.; Brillas, E.; Julia, L. J. Org.
Chem. 2001, 66, 4058. (b) Electronic Materials: The Oligomer Approach;
M€ullen, K., Wegner, G., Eds.; Wiley-VCH: Weinheim, Germany, 1998.
(c) Novak, P.; M€uller, K.; Santhanam, K. S. V.; Haas, O. Chem. Rev. 1997,
97, 207. (d) Sessler, J. L.; Camiolo, S.; Gale, P. A. Coord. Chem. Rev.
2003, 240, 17. (e) Gale, P. A. Acc. Chem. Res. 2006, 39, 465.
12366. (h) Martın, R.; Rivero, M. R.; Buchwald, S. L. Angew. Chem.,
´
Int. Ed. 2006, 45, 7079. (i) Crawley, M. L.; Goljer, I.; Jenkins, D. J.;
Mehlmann, J. F.; Nogle, L.; Dooley, R.; Mahaney, P. E. Org. Lett. 2006,
8, 5837. (j) Lu, L.; Chen, G.; Ma, S. Org. Lett. 2006, 8, 835. (k) Binder,
J. T.; Kirsch, S. F. Org. Lett. 2006, 8, 2151. (l) Gorin, D. J.; Davis, N. R.;
Toste, F. D. J. Am. Chem. Soc. 2005, 127, 11260. (m) Kamijo, S.;
Kanazawa, C.; Yamamoto, Y. J. Am. Chem. Soc. 2005, 127, 9260. (n)
Dhawan, R.; Arndtsen, B. A. J. Am. Chem. Soc. 2004, 126, 468. (o)
Nazare, M.; Schneider, C.; Lindenschmidt, A.; Will, D. W. Angew.
Chem., Int. Ed. 2004, 43, 4526. (p) Gabriele, B.; Salerno, G.; Fazio, A.
J. Org. Chem. 2003, 68, 7853. (q) Kel’in, A. V.; Sromek, A. W.;
Gevorgyan, V. J. Am. Chem. Soc. 2001, 123, 2074. (r) Chen, F.; Shen,
T.; Cui, Y.; Jiao, N. Org. Lett. 2012, 14, 4926.
r
10.1021/ol303159h
Published on Web 12/12/2012
2012 American Chemical Society

the catalytic CÀH bond functionalization6 strategy has not
been introduced into the field of pyrrole synthesis until 2010,
which provides a more atom-economical and environ-
mentally friendly approach. In this respect, to the best of
our knowledge, only two reports on rhodium-catalyzed
reactions were described. The seminal work by the research
groups of Glorius7 as well as Stuart and Fagnou8 have
revealed two novel polysubstituted pyrrole synthesis meth-
ods through Cp*RhIIILn (Cp* = C5Me5) catalyzed allylic
C(sp3)ÀH activation of enamines or C(sp2)ÀH activation
of enamides followed by the cyclization with an internal
alkyne. But in these transformations, an expensive catalyst
was required.
above reaction system, our ruthenium-catalyzed process
also offers an interesting route of a direct synthesis to the
synthetically more attractive N-unsubstituted pyrroles.
We began our study with the annulation reaction of
methyl 2-acetamidoacrylate (1a) and diphenylacetylene
(2a). Treatment of 1a (1.0 equiv) with 2a (1.1 equiv) in
the presence of 5.0 mol % of [{RuCl2(p-cymene)}2] and
2.2 equiv of Cu(OAc)2 H2O in 1,2-dichloroethane (DCE)
at 100 °C for 12 h gave the desired N-acetyl substituted
pyrrole 3aa in 89% yield. The structure of 3aa was con-
3
1
firmed by H and 13C NMR analysis and mass spectro-
metry, which are consistent with those reported
previously.8 Other solvents, such as t-AmOH (t-Am =
tert-amyl) and dioxane, were also effective solvents for
the reaction, giving 3aa in 84% and 83% isolated yield,
respectively. But a change of solvent to CH3CN and H2O
led to a low yield. It was interesting to find that reducing
Very recently, the less-expensive and readily available
ruthenium complex [{RuCl2(p-cymene)}2] has been used
as a catalyst in the chelation-assisted oxidative cycloa-
ddition reactions between aromatic or alkenyl CÀH bond
and alkynes.9 In this regard, methods to synthesize iso-
quinolones,9a,b pyridines,9c indenols,9e indoles,9f iso-
coumarins,9g,h pyrans,9i and isoquinolines9j through
catalytic CÀH bond activation have been developed by
Ackermann et al., Jeganmohan et al., Cheng et al., and us.
In contrast, as far as we know, [{RuCl2(p-cymene)}2]-
catalyzed pyrrole synthesis via CÀH transformation was
not available in the literature. As a continuation of our
interest in [{RuCl2(p-cymene)}2]-catalyzed CÀH func-
tionalization,9b,k,10 we here disclose our development of
oxidative annulation of enamides with alkynes via the
cleavage of C(sp2)ÀH/NÀH bonds in the presence of
the amount of Cu(OAc)2 H2O to 0.5 equiv resulted in no
3
loss in yield of 3aa (90%).11 Notably, no silver salt (such as
AgSbF6) was needed in our reaction system as compared
to the previously reported rhodium-catalyzed transforma-
tion. In Stuart and Fagnou’s catalytic system, the preacti-
vation of the Rh(III) precursor with AgSbF6 resulted in
a great enhancement in catalyst efficiency to allow low
temperature reactions.8 However, we found that the addi-
tion of AgSbF6 resulted in the deacetylation of 3aa in our
reaction (see below).
We then explored the internal alkyne scope of our
ruthenium-catalyzed oxidative annulation transformation
of 1a under the optimized reaction conditions (Scheme 1).
With both the electron-poor and -rich tolanes, the reaction
proceeded smoothly and provided the corresponding ad-
ducts 3abÀ3ag in good to excellent yields. Gratifyingly,
functional groups such as fluoro, chloro, bromo, car-
boxylic ester, and methoxy substituents were very compa-
tible in the present catalytic reaction. These functional
groups offer the opportunity for further functionalization
to construct more complex molecules. The symmetrically
aliphatic or heteroaryl-substituted alkynes, such as 3-hex-
yne (2h) and 4-octyne (2i) or di(2-thiophenyl)ethylene (2j),
were successfully coupled with 1a to yield 3ahÀ3aj but
generally exhibited lower reactivity (62À72%). When un-
symmetrical aryl alkyl-disubstituted alkynes (2kÀ2m)
were employed, the reactions exhibit high regioselectivity:
3akÀ3am were isolated as single regioisomers with an aryl-
substituted carbon center connected to nitrogen. Good
results were also obtained from using ethyl (1b) and benzyl
(1c) ester-substituted enamides together with various inter-
nal alkynes, providing the products 3ba, 3bi, 3bk, 3bl, 3ca,
3ci, 3ck, 3cl, and 3cj in up to85% yield. Replacement of the
ester with a phenyl group led to the formation of 3da in low
yield.
[{RuCl2(p-cymene)}2] as the catalyst and Cu(OAc)2 H2O
3
as the oxidant to synthesize a N-acetyl substituted pyrrole.
In addition, with the addition of AgSbF6 and MeOH tothe
(6) For recent selected general reviews about CÀH bond activation,
see: (a) Arockiam, P. B.; Bruneau, C.; Dixneuf, P. H. Chem. Rev. 2012,
112, 5879. (b) Engle, K. M.; Mei, T.-S.; Wasa, M.; Yu, J.-Q. Acc. Chem.
Res. 2012, 45, 788. (c) Colby, D. A.; Tsai, A. S.; Bergman, R. G.; Ellman,
J. A. Acc. Chem. Res. 2012, 45, 814. (d) Song, G.; Wang, F.; Li, X. Chem.
Soc. Rev. 2012, 41, 3651. (e) Ackermann, L. Chem. Rev. 2011, 111, 1315.
€
(f) Wencel-Delord, J.; Droge, T.; Liu, F.; Glorius, F. Chem. Soc. Rev.
2011, 40, 4740. (g) Wendlandt, A. E.; Suess, A. M.; Stahl, S. S. Angew.
Chem., Int. Ed. 2011, 50, 11062. (h) Sun, C.-L.; Li, B.-J.; Shi,
Z.-J. Chem. Rev. 2011, 111, 1293. (i) Herrmann, P.; Bach, T. Chem. Soc.
Rev. 2011, 40, 2022. (j) Yeung, C. S.; Dong, V. M. Chem. Rev. 2011, 111,
1215. (k) Cho, S. H.; Kim, J. Y.; Kwak, J.; Chang, S. Chem. Soc. Rev. 2011,
40, 5068. (l) Topics in Current Chemistry, CÀH Activation; Yu, J.-Q., Shi, Z.-
J., Eds.; Springer: Berlin, 2010; Vol. 292. (m) Sun, C.-L.; Li, B.-J.; Shi, Z.-J.
Chem. Commun. 2010, 46, 677. (n) Jazzar, R.; Hitce, J.; Renaudat, A.;
Sofack-Kreutzer, J.; Baudoin, O. Chem.;Eur. J. 2010, 16, 2654. (o)
Dudnik, A. S.; Gevorgyan, V. Angew. Chem., Int. Ed. 2010, 49, 2096.
(7) Rakshit, S.; Patureau, F. W.; Glorius, F. J. Am. Chem. Soc. 2010,
132, 9585.
(8) Stuart, D. R.; Alsabeh, P.; Kuhn, M.; Fagnou, K. J. Am. Chem.
Soc. 2010, 132, 18326.
(9) (a) Ackermann, L.; Lygin, A. V.; Hofmann, N. Angew. Chem.,
Int. Ed. 2011, 50, 6379. (b) Li, B.; Feng, H.; Xu, S.; Wang, B. Chem.;
Eur. J. 2011, 17, 12573. (c) Ackermann, L.; Lygin, A. V.; Hofmann, N.
Org. Lett. 2011, 13, 3278. (d) Ackermann, L.; Wang, L.; Lygin, A. V.
Chem. Sci. 2012, 3, 177. (e) Chinnagolla, R. K.; Jeganmohan, M. Eur. J.
Org. Chem. 2012, 417. (f) Ackermann, L.; Lygin, A. V. Org. Lett. 2012,
14, 764. (g) Ackermann, L.; Pospech, J.; Graczyk, K.; Rauch, K. Org.
Lett. 2012, 14, 930. (h) Chinnagolla, R. K.; Jeganmohan, M. Chem.
Commun. 2012, 48, 2030. (i) Thirunavukkarasu, V. S.; Donati, M.;
Ackermann, L. Org. Lett. 2012, 14, 3416. (j) Parthasarathy, K.; Senthilkumar,
N.; Jayakumar, J.; Cheng, C.-H. Org. Lett. 2012, 14, 3478. (k) Li, B.;
Feng, H.; Wang, N.; Ma, J.; Song, H.; Xu, S.; Wang, B. Chem.;Eur. J.
2012, 18, 12873.
In addition, by using (E)-1-cyanopropenyl-2-acetamide
(4) as the substrate, the formation of pentasubstituted
pyrroles (5) was achieved in moderate yield (55À61%)
and high regioselectivity (eq 1).
(10) Li, B.; Ma, J.; Wang, N.; Feng, H.; Xu, S.; Wang, B. Org. Lett.
2012, 14, 736.
(11) For detailed optimization studies, see Table S1 in the Supporting
Information.
Org. Lett., Vol. 15, No. 1, 2013
137

Scheme 1. Results of Ruthenium-Catalyzed N-Acetyl Substi-
tuted Pyrrole (3) Synthesisa
Scheme 2. Results of Ruthenium-Catalyzed N-Unsubstituted
Pyrrole (6) Synthesis
converted. As shown in Scheme 2, the internal alkynes
2aÀ2f, 2j, 2k, and 2l were all successfully reacted with 1a
as well as 1b and 1c, providing the corresponding trisub-
stituted pyrroles 6 in moderate to excellent yield and high
regioselectivity.
a 20.0 mol % of AgSbF6 and 2.0 equiv of Cu(OAc)2 H2O in CH3CN
3
were used.
We then conducted a series of experiments to unveil
the nature of the reaction mechanism.13 First, reactions
with isotopically labeled solvents were studied. Only NÀH
deuteration was observed in the absence of the Ru cata-
lyst, and an additional 12% deuterium incorporation at
the CHolefin was found in the presence of Ru (eq 3). This
result suggests that, under the reaction conditions, the
CÀH bond metalation step is probably irreversible. Then,
It was demonstrated that a separate deprotection step
is necessary for the synthesis of N-unsubstituted pyrroles
in previously reported Rh-catalyzed reactions.7,8 Intrigu-
ingly, the combination of pyrrole formation and subse-
quent deacetylation in one process was realized in our
ruthenium-catalyzed process. When the above-mentioned
reaction conditions were altered slightly;5.0 mol % of
[{RuCl2(p-cymene)}2], 20 mol % of AgSbF6, and 2.0 equiv
in the absence of Cu(OAc)2 H2O, two reactions between
3
1a and 2a were conducted using 5.0 mol % [{RuCl2-
(p-cymene)}2] and 20.0 mol % [{RuCl2(p-cymene)}2], re-
pectively. After 12 h at 100 °C, 3aa was formed in 8% and
38% NMR yield, respectively. Afterwards, the addition of
of Cu(OAc)2 H2O in a mixed solvent system of MeOH/
3
0.5 equiv of Cu(OAc)2 H2O to these mixtures and pro-
3
DCE (2:1, 0.2 M) at 100 °C for 12 h;the synthetically
more attractive N-unsubstituted pyrroles 6 were isolated
as single products in high yield.12 Control experiments
reveal that deacetylation of 3 results in the generation
of 6 and both AgSbF6 and MeOH are essential for this
transformation (eq 2): 6ak was isolated in 98% yield from
3ak under the standard reaction conditions, whereas in
the absence of AgSbF6 or MeOH, only part of 3ak was
longed heating for 4 h at 100 °C led to a quantitative NMR
yield of 3aa for both reactions (eq 4). These results indicate
that Cu(II) is not essential for product formation. Finally,
competition experiments between tolane and its derivative
2c or 2g reveal that the reaction slightly favors the electron-
rich alkyne (electron-poor 2c < 2a < electron-rich 2g,
eq 5). This finding is in contrast with the reported Rh-
catalyzed pyrrole synthesis by Glorius et al.
(12) For detailed optimization studies, see Table S2 in the Supporting
Information.
(13) See Supporting Information for details.
138
Org. Lett., Vol. 15, No. 1, 2013

After removal of the acetyl group of 3ak in the presence of
AgSbF6 and MeOH, 6ak is formed in situ.
Inconclusion, we havedevelopeda ruthenium-catalyzed
oxidative annulation of enamides with alkynes to syn-
thesize N-acetyl substituted pyrroles via the cleavage of
C(sp2)ÀH/NÀH bonds. The catalytic reaction exhibits
excellent regioselectivity. With the addition of AgSbF6
and MeOH, our ruthenium-catalyzed process can afford
N-unsubstituted pyrroles directly. Further studies to ex-
plore ruthenium-catalyzed oxidative CÀH bond transfor-
mations are ongoing in our laboratory and will be reported
in due course.
Scheme 3. Proposed Mechanism (L = p-Cymene)
Based on the above information and the known metal-
catalyzed oxidative annulation reactions,7À9 a potential
mechanism is proposed. As shown in Scheme 3, [{RuCl2-
(p-cymene)}2] reacts with Cu(OAc)2 H2O to form an
3
acetate-ligated species. It may also be coordinated by 1a
via the amide oxygen. Then an irreversible CÀH bond
cleavage process occurs to afford a six-membered ruthena-
cycle B with concomitant formation of acetic acid via an
acetate-assisted mechanism.6e,14 Alkyne 2k may then co-
ordinate B, followed by insertion into the RuÀC bond and
cleavage of NÀH to form a six-membered ruthenacycle
intermediate C. Subsequently, the oxidative coupling of the
CÀN bond takes place to form the pyrrole product 3ak with
the reduction of the ruthenium center from Ru(II) to Ru(0).
The Ru(0) undergoes oxidation to regenerate the catalyti-
cally active Ru(II) complex with the aid of a copper oxidant.
Acknowledgment. Support of this work by NSFC
(21072097, 21072101) and SRFDP (20110031110009) is
gratefully acknowledged.
Supporting Information Available. Detailed experimen-
tal procedures and full spectroscopic data for all new
compounds. This material is available free of charge via
the Internet at http://pubs.acs.org.
(14) (a) Flegeau, E. F.; Bruneau, C.; Dixneuf, P. H.; Jutand, A. J. Am.
Chem. Soc. 2011, 133, 10161. (b) Li, L.; Brennessel, W. W.; Jones, W. D.
Organometallics 2009, 28, 3492.
The authors declare no competing financial interest.
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