Pd-catalyzed and CsF-promoted reaction of bromoalkynes with isocyanides: Regioselective synthesis of substituted 5-iminopyrrolones

Article abstract of DOI:10.1039/c2cc17717j

The palladium-catalyzed and CsF-promoted annulation reaction of bromoalkynes and isocyanides regioselectively affords a diverse set of 5-iminopyrrolone derivatives. This chemistry presumably proceeds through the bromoacrylamide intermediates, which can be readily prepared from the nucleophilic addition reaction of isocyanides to bromoalkynes in the presence of CsF.

Full text of DOI:10.1039/c2cc17717j

View Article Online / Journal Homepage / Table of Contents for this issue
Dynamic Article Links
ChemComm
Cite this: Chem. Commun., 2012, 48, 3545–3547
www.rsc.org/chemcomm
COMMUNICATION
Pd-catalyzed and CsF-promoted reaction of bromoalkynes with
isocyanides: regioselective synthesis of substituted 5-iminopyrrolonesw
Yibiao Li, Jian Zhao, Huoji Chen, Bifu Liu and Huanfeng Jiang*
Received 9th December 2011, Accepted 20th February 2012
DOI: 10.1039/c2cc17717j
The palladium-catalyzed and CsF-promoted annulation reaction
of bromoalkynes and isocyanides regioselectively affords a diverse
set of 5-iminopyrrolone derivatives. This chemistry presumably
proceeds through the bromoacrylamide intermediates, which can
be readily prepared from the nucleophilic addition reaction of
isocyanides to bromoalkynes in the presence of CsF.
The development of general and efficient methodologies for
the synthesis of complex molecular skeletons is the central
focus of modern organic chemistry. Haloalkynes are attractive
starting materials in palladium-catalyzed transformations
because they are highly reactive and readily available from
the inexpensive acetylides. Plus, they can tolerate various
Scheme 1 New reaction hypothesis.
reaction conditions and generally do not require additional
oxidant or base.1 Previously, we have demonstrated that the
independently reported the copper-catalyzed reaction of alkynes
conjugated cis-bromo-alkenynes and 7-alkynyl norbornanes
with isocyanides for the synthesis of 2,4-di-EWG-substituted
of internal alkynes and norbornene derivatives.2 Herein, we wish
pyrroles, whereas the phosphine-catalyzed reaction of isocyanides
could be prepared from the stereo-selective bromoalkynylation
with alkynes affords the 2,3-di-EWG-substituted pyrroles.
to report the first synthesis of 5-iminopyrrolones via palladium-
Recently, our group reported the first synthesis of amides
catalyzed annulation reaction of bromoalkynes and isocyanides.
via the palladium-catalyzed coupling reaction of aryl halides and
isocyanides.9 Interestingly, highly functionalized cis-haloalkenes
This chemistry presumably proceeds through the intermediacy of
haloacrylamides, which could be readily prepared from the
can also be prepared by the acetification and iodation reaction of
nucleophilic addition reaction of isocyanides to bromoalkynes.
haloalkynes in a regio- and stereo-selective fashion.10 Encour-
Polysubstituted iminopyrrolinone derivatives are the core
aged by these results, we decided to investigate the reaction of
structures of numerous natural products, pharmaceuticals and
organic materials.3 Consequently, the synthesis of imino-
isocyanides and haloalkynes in the presence of appropriate bases
and transition metals, which not only provides an efficient
pyrrolinone heterocycles has attracted great attention, and a
strategy for the synthesis of haloacrylamide skeletons, but also
number of methodologies have been reported, yet an efficient
and general approach is still in demand.4 Isocyanides are versatile
allows us to study the migratory insertion reaction of isocyanides
into palladium species (Scheme 1). To the best of our knowledge,
synthons in synthetic organic chemistry, and a few transition-
no example of palladium-catalyzed cyclization of haloalkynes
metal-catalyzed reactions involving isocyanides have been
with isocyanides has been described in the literature. The major
disclosed. It appears that the coordination between isocyanides
challenge in this hypothesis is the control of chemo- and regio-
and transition metals may enhance the reactivity of isocyanides,
selectivity, since the examples of regioselective reactions involving
providing more opportunities for novel methodologies develop-
haloalkynes are still limited.11
ment.5,6 For instance, Yamamoto et al.7 and de Meijere et al.8
To our delight, the CsF-promoted nucleophilic addition reaction
of isocyanides to bromoalkynes afforded good to excellent
yields of functionalized cis-bromoacrylamides (Scheme 2).12
For instance, phenylethynyl bromide was allowed to react with
tert-butyl isocyanide in the presence of 1.2 equiv. of CsF in
DMSO at 90 1C for 12 h. This reaction afforded 87% yield of
the desired N-tert-butyl-3-bromo-2-phenylacrylamide product
(Scheme 2, 3a).13 With this result in hand, various aryl halides
and alkyl ethynyl bromides were employed in this transformation
School of Chemistry and Chemical Engineering,
South China University of Technology, Guangzhou, 510640, China.
E-mail: jianghf@scut.edu.cn; Fax: +86 20-87112906;
Tel: +86 20-87112906
w Electronic supplementary information (ESI) available: Experimental
section, characterization of all compounds, copies of 1H and 13C
NMR spectra for isolated compounds. CCDC 847837. For ESI and
crystallographic data in CIF or other electronic format see DOI:
10.1039/c2cc17717j
c
This journal is The Royal Society of Chemistry 2012
Chem. Commun., 2012, 48, 3545–3547 3545

View Article Online
Scheme 2 CsF-promoted reaction of haloalkynes with isocyanidesa.
to investigate the reaction scope and limitations. In all of the
examples investigated, good yields and high selectivities were
obtained, which indicates the exceptional generality of this novel
methodology. As a matter of fact, bromoalkynes in which the
phenyl ring bears various functional groups like Me, OMe, F and
Cl were very well tolerated in this reaction (Scheme 2, 3b to 3f).
Alkyl-substituted alkynylbromides such as 1-pentyl bromide
and (2-bromoethynyl)-cyclopropane also afforded the desired
product in excellent yields. Interestingly, sterically-hindered iso-
cyanides like 2-isocyano-2,4,4-trimethylpentane and isocyano-
cyclohexane could also be employed in this transformation and
these reactions afforded the acrylamide products in 86% and
88% yields, respectively (Scheme 2, 3k and 3l).
Bromoacrylamides are an important class of Br-containing
amides in organic chemistry, and also potential precursors
for the synthesis of numerous natural products and potent
pharmaceuticals.14 With a viable route to the functionalized
bromoacrylamides, we are then working on exploring their
potential applications as building blocks for the synthesis of
highly substituted heterocycles. During the course of these
studies, we discovered that the Pd-catalyzed one-pot annulation
of phenylethynyl bromide with tert-butyl isocyanide gave
5-iminopyrrolinone 4a and other regioisomers (Scheme 3).
With these results in hand, we envisioned that the in situ
bromo-substituted acrylamides could react with palladium(0)
species and generate the highly reactive vinylpalladium inter-
mediates, which subsequently should react with another iso-
cyanide to afford the biologically-interesting 5-iminopyrrolone
derivatives in a one pot process. The reaction scope and
limitation are summarized in Scheme 4. Generally, this reaction
proceeds smoothly under the optimal conditions to afford
various polysubstituted 5-iminopyrrolones in a regioselective
manner in good to excellent yields. With regard to phenyl-
ethynyl bromides, both electron-rich and electron-poor func-
tional groups can be tolerated and the reaction efficiency and
selectivity are exceptional (Scheme 4, 4b–4l). In particular, the
reactivity of the cyclization reaction of alkyl-substituted
Scheme 4 Palladium-catalyzed synthesis of iminopyrrolinones from
haloalkynes and isocyanidesa.
ethynyl bromide appears to be higher than that of the aryl-
substituted ethynyl bromide, presumably due to the fact that a
less hindered group is in favour of nucleophilic addition
reaction and migratory insertion of isocyanides (Scheme 4,
4n, 4p and 4q). It is worth noting that the ethynyl bromide
substrates containing reactive groups such as C–C double/
triple bonds can also be employed in this transformation and
the desired products (4o–4q) were obtained in reasonable to
good yields. In order to confirm the structure of the products
obtained, the molecular structure of compound 4d was estab-
lished by X-ray crystallography (see ESIw).
With the use of various isocyanides as substrates, this
transformation can also be performed in one pot to afford
the corresponding iminopyrrolinone products in good yields
(Scheme 4, 4r–4v). However, the isocyanides with less hindered
substituents such as 1-isocyanobenzene or 2-isocyanoacetate
gave a very low yield (Scheme 4, 4w). We guess that when the
reaction took place over a long reaction time at higher tempera-
tures, decomposition or hydroxylation of 1-isocyanobenzene
occurred prior to completion of the annulation reaction.
The postulated reaction mechanism is depicted in
Scheme 5.9,15,16 The catalytic cycle was initiated by the nucleo-
philic addition of isocyanides to bromoalkynes, which gave the
bromoacrylamides A in the presence of CsF. Subsequently,
bromoacrylamide A underwent oxidative addition reaction
to afford vinylpalladium complex B. Subsequently, another
isocyanide could undergo 1,1-insertion reaction to afford
Scheme 3 One-pot synthesis of 5-iminopyrrolinone from bromoalkyne
and isocyanide.
c
3546 Chem. Commun., 2012, 48, 3545–3547
This journal is The Royal Society of Chemistry 2012

View Article Online
3 (a) S. Tekkam, M. A. Alam, S. C. Jonnalagadda and
V. R. Mereddy, Chem. Commun., 2011, 47, 3219; (b) E. Awuah
and A. Capretta, J. Org. Chem., 2011, 76, 3122;
(c) U. A. Kshirsagar and N. P. Argade, Tetrahedron, 2009,
65, 5244; (d) J. Bessho, Y. Shimotsu, S. Mizumoto, N. Mase,
H. Yoda and K. Takabe, Heterocycles, 2004, 63, 1013; (e) L. Li,
D. Du, J. Ren and Z. Wang, Eur. J. Org. Chem., 2011, 3, 614.
4 For selected examples, see: (a) Y. Xie, Y. Zhao, B. Qian, L. Yang,
C. Xia and H. Huang, Angew. Chem., Int. Ed., 2011, 50, 5682;
(b) E. A. Sidorova, E. S. Kostenko, I. S. Arustamova,
E. A. Kaigorodova and L. D. Konyushkin, Chem. Heterocycl.
Compd., 2011, 47, 294; (c) H. Ueda, H. Satoh, K. Matsumoto,
K. Sugimoto, T. Fukuyama and H. Tokuyama, Angew. Chem., Int.
Ed., 2009, 48, 7600.
5 Transition-metal-free-catalyzed reactions of isocyanides, see:
(a) F. Sha and X. Huang, Angew. Chem., Int. Ed., 2009,
48, 3458; (b) B. O. Okandeji and J. K. Sello, J. Org. Chem.,
2009, 74, 5067; (c) J. Wang, Z. He, X. Chen, W. Song, P. Lu
and Y. Wang, Tetrahedron, 2010, 66, 1208; (d) J. Gao, R. F. Henry,
T. G. Pagano, R. W. Duerst and A. J. Souers, Tetrahedron Lett.,
2007, 48, 7395; (e) A. Fayol and J. Zhu, Org. Lett., 2004, 6, 115;
(f) D. Kadzimirsz, D. Hildebrandt, K. Merz and G. Dyker, Chem.
Commun., 2006, 661; (g) Y. Li, X. Xu, J. Tan, C. Xia, D. Zhang
and Q. Liu, J. Am. Chem. Soc., 2011, 133, 1775.
6 Transition-metal-catalyzed reactions of isocyanides, see:
(a) I. Nakamura and Y. Yamamoto, Chem. Rev., 2004,
104, 2127; (b) N. T. Patil and Y. Yamamoto, Chem. Rev., 2008,
108, 3395; (c) N. Chatani, M. Oshita, M. Tobisu, Y. Ishii and
S. Murai, J. Am. Chem. Soc., 2003, 125, 7812; (d) Y. Fukumoto,
M. Hagihara, F. Kinashi and N. Chatani, J. Am. Chem. Soc., 2011,
133, 10014; (e) T. Saito, N. Furukawa and T. Otani, Org. Biomol.
Chem., 2010, 8, 1126; (f) S. Majumder, K. R. Gipson and
A. L. Odom, Org. Lett., 2009, 11, 4720; (g) E. Barnea,
S. Majumder, R. J. Staples and A. L. Odom, Organometallics,
2009, 28, 3876; (h) J. Brioche, G. Masson and J. Zhu, Org. Lett.,
2010, 12, 1432; (i) H. Takaya, S. Kojima and S. I. Murahashi, Org.
Lett., 2001, 3, 421.
7 (a) S. Kamijo, C. Kanazawa and Y. Yamamoto, J. Am. Chem.
Soc., 2005, 127, 9260; (b) C. Kanazawa, S. Kamijo and
Y. Yamamoto, J. Am. Chem. Soc., 2006, 128, 10662.
8 A. V. Lygin, O. V. Larionov, V. S. Korotkov and A. de Meijere,
Chem.–Eur. J., 2009, 15, 227.
9 H. Jiang, B. Liu, Y. Li, A. Wang and H. Huang, Org. Lett., 2011,
13, 1028.
10 (a) Z. Chen, J. Li, H. Jiang, S. Zhu, Y. Li and C. Qi, Org. Lett.,
2010, 12, 3262; (b) Z. Chen, H. Jiang, Y. Li and C. Qi, Chem.
Commun., 2010, 46, 8049.
11 (a) A. Trofimov, N. Chernyak and V. Gevorgyan, J. Am. Chem.
Soc., 2008, 130, 13538; (b) A. Allen, K. Villeneuve, N. Cockburn,
E. Fatila, N. Riddell and W. Tam, Eur. J. Org. Chem., 2008, 4178.
12 For selected reviews on cis-nucleophilic addition to haloalkynes,
see: (a) M. Yamagishi, J. Okazaki, K. Nishigai, T. Hata and
H. Urabe, Org. Lett., 2012, 14, 34; (b) M. Yamagishi,
K. Nishigai, T. Hata and H. Urabe, Org. Lett., 2011, 13, 4873.
13 See ESIw for optimization of reaction conditions.
14 (a) J. M. Humphrey and A. R. Chamberlin, Chem. Rev., 1997,
97, 2243; (b) T. Cupido, J. Tulla-Puche, J. Spengler and
F. Albericio, Curr. Opin. Drug Discovery Dev., 2007, 10, 768;
(c) G. Wang, Z. Huang and E. Negishi, Org. Lett., 2008, 10, 3223.
15 For selected examples of isocyanide insertion into palladium–
carbon bonds, see: (a) P. J. Boissarie, Z. E. Hamilton, S. Lang,
J. A. Murphy and C. J. Suckling, Org. Lett., 2011, 13, 6256;
Scheme 5 Proposed mechanism for annulation reaction.
intermediate C. Possibly, the amine group of intermediate C
could coordinate to the palladium metal and a subsequent
proton abstraction should afford the palladium metallacycle
intermediate D. The reductive elimination of metallacycle
intermediate D would afford the annulated product E.
In conclusion, we have developed a new strategy for the
synthesis of bromoacrylamides and polysubstituted imino-
pyrrolinones in good to excellent yields from readily available
starting materials. This chemistry proceeds smoothly under
the optimal reaction conditions and various functional groups
can be tolerated with exceptional selectivity. The methodology
is highly practical and it provides a straightforward approach
to a series of 5-iminopyrrolones and haloacrylamides in a
regioselective manner. Current efforts aiming at broadening
the scope of the catalytic system and exploring synthetic
applications are still ongoing.
We thank the National Natural Science Foundation of
China (20932002 and 21172076), National Basic Research
Program of China (973 Program) (2011CB808600), Doctoral
Fund of Ministry of Education of China (20090172110014),
Guangdong Natural Science Foundation (10351064101000000)
and the Fundamental Research Funds for the Central Universities
(2010ZP0003) for financial support.
Notes and references
1 For selected examples, see: (a) T. Morishita, H. Yoshida and
J. Ohshita, Chem. Commun., 2010, 46, 640; (b) T. Wada,
M. Iwasaki, A. Kondoh, H. Yorimitsu and K. Oshima,
Chem.–Eur. J., 2010, 16, 10671; (c) X. Chem, W. Kong, H. Cai,
L. Kong and G. Zhu, Chem. Commun., 2011, 47, 2164;
(d) C. Spiteri and J. E. Moses, Angew. Chem., Int. Ed., 2009,
49, 31; (e) Y. Ano, M. Tobisu and N. Chatani, J. Am. Chem. Soc.,
2011, 133, 12984; (f) M. O. Frederick, J. A. Mulder, M. R. Tracey,
R. P. Hsung, J. Huang, K. C. M. Kurtz, L. Shen and C. J. Douglas,
J. Am. Chem. Soc., 2003, 125, 2368; (g) I. V. Seregin, V. Ryabova
and V. Gevorgyan, J. Am. Chem. Soc., 2007, 129, 7742;
(h) D. L. Usanov and H. Yamamoto, J. Am. Chem. Soc., 2011,
133, 1286; (i) W. Shi, Y. Luo, X. Luo, L. Chao, H. Zhang, J. Wang
and A. Lei, J. Am. Chem. Soc., 2008, 130, 14713; (j) K. Villeneuve,
N. Riddell, R. W. Jordan, G. C. Tsui and W. Tam, Org. Lett.,
2004, 6, 4543; (k) Y. Liu and H. Gao, Org. Lett., 2006, 8, 309;
(l) S. Wang, P. Li, L. Yu and L. Wang, Org. Lett., 2011, 13, 5968.
2 (a) Y. Li, X. Liu, H. Jiang and Z. Feng, Angew. Chem., Int. Ed.,
2010, 49, 3338; (b) Y. Li, X. Liu, H. Jiang, B. Liu, Z. Chen and
P. Zhou, Angew. Chem., Int. Ed., 2011, 50, 6341.
(b) G. V. Baelen, S. Kuijer, L. Ry´ cek, S. Sergeyev, E. Janssen, F.
J. J. de Kanter, B. U. W. Maes, E. Ruijter and R. V. A. Orru,
Chem.–Eur. J., 2011, 17, 15039; (c) J. Vicente, M. T. Chicote,
A. J. Martı
2010, 29, 5693; (d) J. Vicente, I. Saura-Llamas and J. A. Garcı
Lopez, Organometallics, 2009, 28, 448.
´
nez-Martı
´
nez and A. Abella
´
n-Lo
´
pez, Organometallics,
´
a-
´
16 For selected examples of isocyanide insertion into rhodium–carbon
bonds, see: (a) C. Zhu, W. Xie and J. R. Falck, Chem.–Eur. J.,
2011, 17, 12591; (b) D. D. Wick, T. O. Northcutt, R. J. Lachicotte
and W. D. Jones, Organometallics, 1998, 17, 4484.
c
This journal is The Royal Society of Chemistry 2012
Chem. Commun., 2012, 48, 3545–3547 3547