Cu-catalyzed ring opening reaction of 2H-azirines with terminal alkynes: An easy access to 3-alkynylated pyrroles

Article abstract of DOI:10.1021/ol502282j

A highly efficient Cu-catalyzed ring expansion reaction of 2H-azirines with terminal alkynes has been developed. This transformation provides a powerful method for the synthesis of 3-alkynyl polysubstituted pyrroles under mild conditions in good yields. The direct transformation process, specific selectivity, and good tolerance to a variety of substituents make it an alternative approach to the reported protocols.

Full text of DOI:10.1021/ol502282j

Letter
pubs.acs.org/OrgLett
Cu-Catalyzed Ring Opening Reaction of 2H‑Azirines with Terminal
Alkynes: An Easy Access to 3‑Alkynylated Pyrroles
Tengfei Li, Xiaoyi Xin, Chunxiang Wang, Dongping Wang, Fan Wu, Xincheng Li, and Boshun Wan*
Dalian Institute of Chemical Physics, Chinese Academy of Sciences, 457 Zhongshan Road, Dalian 116023, China
S
* Supporting Information
ABSTRACT: A highly efficient Cu-catalyzed ring expansion reaction of 2H-
azirines with terminal alkynes has been developed. This transformation provides a
powerful method for the synthesis of 3-alkynyl polysubstituted pyrroles under mild
conditions in good yields. The direct transformation process, specific selectivity, and
good tolerance to a variety of substituents make it an alternative approach to the
reported protocols.
yrroles are not only key structures in numerous natural
products and pharmaceuticals but also important building
Scheme 1. Synthesis of Alkynylated Pyrroles
P
blocks in material sciences.1 Consequently, the synthesis and
functionalization of pyrroles have attracted much attention.2
Owing to the rigidity property and convenient transformation of
the triple bond, the introduction of an alkynyl group into pyrroles
for constructing alkynylated pyrroles will bring about different
physical, chemical, and pharmacological properties.3 To date,
many elegant catalytic methods have been developed for the
synthesis of alkynylated pyrroles. However, most of these
methods focused on the construction of a 2-alkynylated product
due to the higher reactivity at the C2-position of pyrroles.4 In
constrast, only limited examples on the synthesis of 3-alkynylated
pyrroles have been described. The cross-coupling reaction
between pyrrole halides and terminal alkynes is one of the
most widely used methods for constructing 3-alkynylated
pyrroles, but it requires the premodification of the starting
materials (Scheme 1, eq 1).5 Recently, the direct alkynylation of
pyrroles has emerged as a more efficient tool for the introduction
of alkynyl groups. Waser reported a gold(I)-catalyzed
alkynylation of pyrroles with a hypervalent iodine reagent via a
formal inverse Sonogashira reaction,6 and the regioselectivity
largely depends on the N-substitution of pyrroles (Scheme 1, eq
2). Subsequently, Nevado documented a gold(I)-catalyzed
oxidative cross-coupling of N-benzyl pyrrole and electron-
deficient terminal alkynes, with mixtures of 2- and 3-alkynylated
pyrroles as the products (Scheme 1, eq 3).7 Despite these
advances, most of these methods have some limitations with
respect to the regioselectivity and substrate scope. Therefore, the
development of an efficient strategy for the regioselective
synthesis of 3-alkynylated pyrroles is still highly desirable yet a
great challenge.
transformations, the C−N single bond of 2H-azirine is easily
cleaved in the presence of heat, metal catalysts, nucleophilic
reagents, or light irradiation. In this context, and following our
ongoing interest in the synthesis of pyrroles,15 we envisioned the
possibility of transferring the alkynyl group to 2H-azirine
through cleavage of the C−N single bond (Scheme 1, eq 4). In
such a process, the nucleophilic addition of in situ generated
metal acetylide species to 2H-azirine would produce an α-
alkynylated imine species, which would be further captured by
alkynes, alkenes, or azirines to construct 3-alkynylated pyrroles.
Herein, we report a Cu-catalyzed ring expansion reaction of 2H-
Strain-driven ring expansion is regarded as an effective method
for the construction of carbo- and heterocyclic structures.8 2H-
Azirines are highly strained three-membered heterocyclic
compounds and have been exploited as useful precursors for
reactive intermediates such as vinyl nitrenes and nitrile ylides.9
Therefore, 2H-azirines have been employed in the synthesis of
various N-containing heterocycles, such as pyrroles,10 indoles,11
pyridines,12 isoquinolines,13 and piperidines.14 Among these
Received: July 31, 2014
Published: September 3, 2014
© 2014 American Chemical Society
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Letter
a
,b
azirines to construct 3-alkynylated pyrroles in which the N-atom
is unprotected.
Table 2. Substrate Scope
Initially, we attempted to synthesize the target compound via a
three-component reaction of 2H-azirine, terminal alkyne, and
another molecule of alkyne or alkene but failed. Fortunately,
without adding any additional trapping reagent, the reaction
between 2H-azirine and terminal alkyne could provide the
desired product. Therefore, 4-ethynyltoluene 1a and 2H-azirine
2a were selected as substrates for the optimization of reaction
conditions (Table 1). To our delight, the desired 3-alkynylated
a
Table 1. Optimization of the Reaction Conditions
b
entry
Cu(I)
solvent
THF
temp
1a/2a
yield (%)
1
CuI
50 °C
50 °C
50 °C
50 °C
50 °C
50 °C
50 °C
rt
1:2.5
1:2.5
1:2.5
1:2.5
1:2.5
1:2.5
1:2.5
1:2.5
1:2
14
21
15
52
36
52
77
83
56
2
CuCN
CuOTf
CuOAc
CuOAc
CuOAc
CuOAc
CuOAc
CuOAc
CuOAc
CuOAc
THF
3
THF
4
THF
5
toluene
6
DCE
7
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
8
9
rt
c
10
11
rt
1:3
89 (86)
78
rt
1:4
a
Reaction conditions: alkyne 1a (0.2 mmol), 2H-azirine 2a, Cu(I) (10
b
mol %), solvent (2 mL), 20 h. Determined by HPLC using biphenyl
as an internal standard. Isolated yield.
c
pyrrole 3aa was obtained in 14% yield (Table 1, entry 1) when
using CuI as a catalyst. A screening of Cu(I) catalysts showed that
CuOAc was the most effective catalyst (Table 1, entries 1−4).
Subsequently, examination of different solvents revealed that the
reaction proceeded well in 1,4-dioxane and afforded the best
result (Table 1, entries 4−7). Intriguingly, when decreasing the
temperature to rt, the catalyst system was somewhat more
effective (Table 1, entry 8). Increasing the ratio of 2a to 1a
resulted in a slight improvement in the yield and afforded the
desired product in 89% yield (Table 1, entry 10). However,
decreasing or further increasing the ratio all jeopardized the yield
(Table 1, entries 9 and 11). Therefore, the optimal conditions
were established as follows: 10 mol % of CuOAc as the catalyst,
with 3 equiv of 2a in 1,4-dioxane at rt.
With the optimal conditions in hand, we examined the
substrate scope of the reaction (Table 2). First, various aryl
substituted terminal alkynes were investigated in this reaction
with 2H-azirine 2a. Both electron-withdrawing (3ca−3ha) and
electron-donating (3aa, 3ia) groups were compatible on the aryl
alkynes, generating the functionalized products in good yields.
Aryl alkynes with the CF3 group at the ortho-, meta-, and para-
positions were all well tolerated (3fa−3ha). Notably, the
trimethylsilylacetylene afforded 3-alkynylated pyrrole 3ja16 in
excellent yield, which could be easily converted into a free
acetylene product or used as a precursor for further
functionalization. Fortunately, not only aryl alkynes but also
aliphatic alkynes could be transformed into corresponding
a
Alkyne 1 (0.4 mmol) and 2H-azirine 2 (1.2 mmol) with CuOAc (10
b
mol %) in 1,4-dioxane (4 mL) at rt. Isolated yields.
pyrroles (3ka−3ma). Both cyclohexylacetylene 1l and cyclo-
propylacetylene 1m reacted well with 2a to afford the
corresponding pyrroles 3la (78%) and 3ma (81%), respectively.
The heterocyclic alkynes also reacted but with a lower yield,
which may be attributed to the decreased activity of the catalyst
caused by heteroatoms (3na, 3oa). In addition, the reaction of
sterically hindered 1-naphthylacetylene (1p) afforded the
product with a slightly lower yield (3pa).
Subsequently, we turned our attention to evaluate various 2H-
azirines with alkyne 1a. Generally, most reactions proceeded
smoothly to give 3-alkynylated pyrroles in moderate yields
(3ab−3af). Reactions with both electron-rich and -deficient aryl
groups gave the corresponding products in moderate to good
yields (3ab−3ae). 2H-Azirines with a meta- and ortho-methyl
group on the phenyl ring afforded the corresponding 3-
alkynylated pyrroles 3af and 3ag in 64% and 47% yield,
respectively. The steric effect may be the main reason for the low
yield of 3ag. A similar result was also observed in the reaction of
1a with 2h which bears a sterically demanding naphthyl group,
leading to the formation of 3ah in 49% yield.
To clarify the reaction mechanism, a series of control
experiments were conducted under standard conditions. In the
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presence of a radical scavenger 2,2,6,6-tetramethyl-1-piperidiny-
loxy (TEMPO), the reaction provided pyrrole 3aa in 64% yield
(Scheme 2, eq 5, versus 86% yield in Table 1, entry 10). This
sized18 to test the reaction. The reaction of 5′ and 2H-azirine 2a
provided pyrrole 6 in 40% yield (Scheme 3, eq 10), which was
analogous to 3aa. This discovery indicated that the reaction
maybe go through the yne-enamine intermediate.
On the basis of these experimental data, a plausible mechanism
was proposed (Scheme 4). Initially, copper acetylide A is formed
Scheme 2. Control Experiments
Scheme 4. Possible Reaction Pathway
observation indicated that the reaction could not be triggered
through a radical pathway. It is noteworthy that copper acetylide
A was precipitated during the reaction process when terminal
alkyne 1a was added into the solution of CuOAc in 1,4-dioxane.
Therefore, copper acetylide A was isolated and then subjected
into the reaction system. Without the addition of alkyne 1a, the
reaction of 2H-azirine 2a and a stoichiometric amount of A
generated pyrrole 3aa in 95% yield (Scheme 2, eq 6). Moreover,
the reaction of alkyne 1a and 2H-azirine 2a in the presence of 10
mol % of A afforded the desired product in 51% yield. These
experiments suggested that copper acetylide A attacked 2H-
azirine at the beginning and acted as a real catalyst (Scheme 2, eq
7). Notably, the reaction of 2a with deuterated terminal alkyne
1a-D afforded 3aa in 83% yield without accompanying any
deuterated product (Scheme 2, eq 8). The production of
ammonia (NH3) was expectedly detected by a gas mass
spectrometer after reaction completion,17 demonstrating that
ammonia was removed as a byproduct in the reaction.
from terminal alkyne in the presence of Cu(I) salt. The reaction
of copper acetylide A with 2H-azirine leads to cleavage of the C−
N single bond of 2H-azirine and generates copper-imine species
B, which readily isomerizes to afford copper-enamine species C.
Intermediate C then attacks another molecule of 2H-azirine on
the imine carbon to generate species D. Subsequently, an
intramolecular cyclization reaction occurs to give intermediate E,
which is quickly transformed into the pyrroline intermediate F
driven by ring strain.19 Further protonation of F regenerates
Cu(I) into the catalytic cycle and provides intermediate G.
Finally, elimination of one molecule of ammonia from G affords
3-alkynylated pyrrole product 3. It is noteworthy that the CC
triple bond of alkyne remains unchanged in this pathway.
In conclusion, we have developed a powerful strategy for the
synthesis of 3-alkynylated pyrroles from 2H-azirines and terminal
alkynes at rt. In the presence of the CuOAc catalyst, this
approach provides a straightforward access to the 3-alkynyl
polysubstituted pyrroles with complete regiocontrol. A possible
mechanism involving the yne-enamine intermediate is proposed
to satisfactorily elucidate the generation of 3-alkynylated
pyrroles. In view of the direct transformation process, specific
selectivity, mild reaction conditions, and good functional group
tolerance, we believe that this protocol would be potentially
utilized in synthetic chemistry. Further exploration of a detailed
mechanism and other reactions involving 2H-azirines is currently
underway.
Furthermore, the exposure of the C3-unsubstituted pyrrole 4
and alkyne 1a to the standard reaction conditions failed to deliver
any 3-alkynylated pyrrole 3aa (Scheme 3, eq 9), revealing that
Scheme 3. Intermediate Simulation Experiment
the alkynyl moiety was not introduced into the pyrrole ring via
the Cu-catalyzed cross-coupling between 4 and 1a. In contrast,
the alkynyl moiety might be performed in the C3-position of the
pyrrole ring before its formation. Accordingly, we envisioned that
an α-alkynylated imine species (Scheme 1, eq 4) might be
involved. However, attempts to synthesize yne-enamine
intermediate 5 did not succeed. Fortunately, a structure similar
to that of (Z)-3-amino-3-phenylacrylonitrile 5′ was synthe-
ASSOCIATED CONTENT
■
S
* Supporting Information
Experimental procedures, characterization data, X-ray structure,
and NMR spectra. This material is available free of charge via the
Internet at http://pubs.acs.org.
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2014, 53, 5653. (g) Farney, E. P.; Yoon, T. P. Angew. Chem., Ed. Int.
2014, 53, 793.
AUTHOR INFORMATION
■
Corresponding Author
(11) (a) Taber, D. F.; Tian, W. W. J. Am. Chem. Soc. 2006, 128, 1058.
(b) Chiba, S.; Hattori, G.; Narasaka, K. Chem. Lett. 2007, 36, 52.
(c) Jana, S.; Clements, M. D.; Sharp, B. K.; Zheng, N. Org. Lett. 2010, 12,
3736. (d) Candito, D. A.; Lautens, M. Org. Lett. 2010, 12, 3312.
(12) (a) Loy, N. S. Y.; Singh, A.; Xu, X. X.; Park, C. M. Angew. Chem.,
Int. Ed. 2013, 52, 2212. (b) Park, C. M.; Jiang, Y. Chem. Sci. 2014, 5,
2347. (c) Prechter, A.; Henrion, G.; Faudot dit Bel, P.; Gagosz, F. Angew.
Chem., Int. Ed. 2014, 53, 4959.
*E-mail: bswan@dicp.ac.cn.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We are grateful for the financial support from the National
Natural Science Foundation of China (21372219, 21172218).
(13) Wang, Y. F.; Toh, K. K.; Lee, J. Y.; Chiba, S. Angew. Chem., Int. Ed.
2011, 50, 5927.
(14) Palacios, F.; Ochoa de Retana, A. M.; Gil, J. I.; Lopez de Munain,
R. Org. Lett. 2002, 4, 2405.
REFERENCES
■
(15) (a) Xin, X. Y.; Wang, D. P.; Li, X. C.; Wan, B. S. Angew. Chem., Int.
Ed. 2012, 51, 1693. (b) Pan, B.; Wang, C. X.; Wang, D. P.; Wu, F.; Wan,
B. S. Chem. Commun. 2013, 49, 5073. (c) Hu, Y. C.; Wang, C. X.; Wang,
D. P.; Wu, F.; Wan, B. S. Org. Lett. 2013, 15, 3146. (d) Pan, B.; Lu, X. D.;
Wang, C. X.; Hu, Y. C.; Wu, F.; Wan, B. S. Org. Lett. 2014, 16, 2244.
(16) CCDC 993260 contains the supplementary crystallographic data
for 3ja in this paper. These data can be obtained free of charge from The
Cambridge Crystallographic Data Centre via www.ddcd.cam.ac.uk/
data_request/cif.
(1) (a) Garrido-Hernandez, H.; Nakadai, M.; Vimolratana, M.; Li, Q.;
Doundoulakis, T.; Harran, P. G. Angew. Chem., Int. Ed. 2005, 44, 765.
(b) Fan, H.; Peng, J.; Hamann, M. T.; Hu, J. F. Chem. Rev. 2008, 108,
264. (c) Estevez, V.; Villacampa, M.; Menendez, J. C. Chem. Soc. Rev.
2010, 39, 4402. (d) Young, I. S.; Thornton, P. D.; Thompson, A. Nat.
Prod. Rep. 2010, 27, 1801.
(2) For reviews on the synthesis of pyrroles, see: (a) Nakamura, I.;
Yamamoto, Y. Chem. Rev. 2004, 104, 2127. (b) Estev
́
ez, V.; Villacampa,
M.; Menendez, J. C. Chem. Soc. Rev. 2010, 39, 4402. (c) Gulevich, A. V.;
́
(17) See Figure 1 in the Supporting Information.
Dudnik, A. S.; Chernyak, N.; Gevorgyan, V. Chem. Rev. 2013, 113, 3084.
For selected recent examples, see: (d) Zhang, M.; Neumann, H.; Beller,
M. Angew. Chem., Int. Ed. 2013, 52, 597. (e) Srimani, D.; Ben-David, Y.;
Milstein, D. Angew. Chem., Int. Ed. 2013, 52, 4012. (f) Shi, Z. Z.; Suri, M.;
Glouris, F. Angew. Chem., Int. Ed. 2013, 52, 4892. (g) Liu, J.; Fang, Z.;
Zhang, Q.; Liu, Q.; Bi, X. Angew. Chem., Int. Ed. 2013, 52, 6953. (h) Gao,
M.; He, C.; Chen, H.; Bai, R.; Cheng, B.; Lei, A. Angew. Chem., Int. Ed.
2013, 52, 6958. (i) Parr, B. T.; Green, S. A.; Davies, H. M. J. Am. Chem.
Soc. 2013, 135, 4716. (j) Zhang, M.; Fang, X.; Neumann, H.; Beller, M. J.
Am. Chem. Soc. 2013, 135, 11384. (k) Michlik, S.; Kempe, R. Nat. Chem.
2013, 5, 140. (l) Zhao, M. N.; Ren, Z. H.; Wang, Y. Y.; Guan, Z. H. Org.
Lett. 2014, 16, 608.
(18) (a) de Paulis, T.; Hemstapat, K.; Chen, Y.; Zhang, Y.; Saleh, S.;
Alagille, D.; Baldwin, R. M.; Tamagnan, G. D.; Conn, P. J. J. Med. Chem.
2006, 49, 3332. (b) Jagtap, S. R.; Bhanushali, M. J.; Nandurkar, N. S.;
Bhanage, B. M. Synth. Commun. 2007, 37, 2253.
(19) (a) Law, K. W.; Lai, T. F.; Sammes, M. P.; Katritzky, A. R.; Mak, T.
C. J. Chem. Soc., Perkin Trans. 1 1984, 111. (b) Nitta, M.; Kobayashi, T.
Chem. Lett. 1983, 1715.
(3) (a) Eisler, S.; Tykwinski, R.; Diederich, F.; Stang, P.; Tykwinski, R.
Acetylene Chemistry: Chemistry, Biology, and Material Science; Wiley-
VCH: Weinheim, 2005. (b) Brand, J. P.; Waser, J. Chem. Soc. Rev. 2012,
41, 4165.
(4) (a) Seregin, I. V.; Ryabova, V.; Gevorgyan, V. J. Am. Chem. Soc.
2007, 129, 7742. (b) Trofimov, B. A.; Sobenina, L. N.; Stepanova, Z. V.;
Vakul’-skaya, T. I.; Kazheva, O. N.; Aleksandrov, G. G.; Dyachenko, O.
A.; Mikhaleva, A. I. Tetrahedron 2008, 64, 5541. (c) Dudnik, A. S.;
Gevorgyan, V. Angew. Chem., Int. Ed. 2010, 49, 2096. (d) Jie, X. M.;
Shang, Y. P.; Hu, P.; Su, W. P. Angew. Chem., Int. Ed. 2013, 52, 3630.
(5) (a) Sonogashira, K.; Tohda, Y.; Hagihara, N. Tetrahedron Lett.
1975, 16, 4467. (b) Alvarez, A.; Guzman, A.; Ruiz, A.; Velarde, E.;
Muchowski, J. M. J. Org. Chem. 1992, 57, 1653. (c) Liu, J. H.; Yang, Q.
C.; Mak, T. C. W.; Wong, H. N. C. J. Org. Chem. 2000, 65, 3587.
(6) (a) Brand, J. P.; Charpentier, J.; Waser, J. Angew. Chem., Int. Ed.
2009, 48, 9346. (b) Brand, J. P.; Chevalley, C.; Scopelliti, R.; Waser, J.
Chem.Eur. J. 2012, 18, 5655.
(7) de Haro, T.; Nevado, C. J. Am. Chem. Soc. 2010, 132, 1512.
(8) (a) Carson, C. A.; Kerr, M. A. Chem. Soc. Rev. 2009, 38, 3051.
(b) Cavitt, M. A.; Phun, L. H.; France, S. Chem. Soc. Rev. 2014, 43, 804.
(c) Seiser, T.; Saget, T.; Tran, D. N.; Cramer, N. Angew. Chem., Int. Ed.
2011, 50, 7740. (d) Schneider, T. F.; Kaschel, J.; Werz, D. B. Angew.
Chem., Int. Ed. 2014, 53, 5504.
(9) (a) Gilchrist, T. L. Aldrichimica Acta 2001, 34, 51. (b) Palacios, F.;
de Retana, A. M. O.; de Marigorta, E. M.; de los Santos, J. M. Eur. J. Org.
Chem. 2001, 2401. (c) Okamoto, K.; Mashida, A.; Watanabe, M.; Ohe,
K. Chem. Commun. 2012, 48, 3554.
(10) (a) Padwa, A.; Gasdaska, J. R.; Haffmanns, G.; Rebello, H. J. Org.
Chem. 1987, 52, 1027. (b) Muller, F.; Mattay, J. Angew. Chem., Int. Ed.
̈
Engl. 1992, 31, 209. (c) Qi, X. X.; Xu, X. X.; Park, C. M. Chem. Commun.
2012, 48, 3996. (d) Khlebnikov, A. F.; Golovkina, M. V.; Novikov, M. S.;
Yufit, D. S. Org. Lett. 2012, 14, 3768. (e) Jiang, Y. J.; Chan, W. C.; Park,
C. M. J. Am. Chem. Soc. 2012, 134, 4104. (f) Xuan, J.; Xia, X. D.; Zeng, T.
T.; Feng, Z. J.; Chen, J. R.; Lu, L. Q.; Xiao, W. J. Angew. Chem., Ed. Int.
4809
dx.doi.org/10.1021/ol502282j | Org. Lett. 2014, 16, 4806−4809