Ring expansion of alkynyl cyclopropanes to highly substituted cyclobutenes via a N-sulfonyl-1,2,3-triazole intermediate

Article abstract of DOI:10.1039/c2cc34609e

Regioselective ring expansion of alkynyl cyclopropanes to highly substituted cyclobutenes was developed. The reaction involves a copper-catalyzed cycloaddition of an alkyne with an arylsulfonyl azide and a silver-catalyzed carbene formation followed by ring expansion of a cyclopropyl carbene intermediate.

Full text of DOI:10.1039/c2cc34609e

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Ring expansion of alkynyl cyclopropanes to highly substituted
cyclobutenes via a N-sulfonyl-1,2,3-triazole intermediatewz
Renhe Liu, Min Zhang, Gabrielle Winston-McPherson and Weiping Tang*
Received 27th June 2012, Accepted 23rd July 2012
DOI: 10.1039/c2cc34609e
Regioselective ring expansion of alkynyl cyclopropanes to highly
substituted cyclobutenes was developed. The reaction involves a
copper-catalyzed cycloaddition of an alkyne with an arylsulfonyl
azide and a silver-catalyzed carbene formation followed by ring
expansion of a cyclopropyl carbene intermediate.
structures of natural products pipercyclobutanamide A and
piperchabamide G.7 However, cyclopropyl diazo compound 1
is not very stable and its preparation is often lengthy.
To search for a more convenient and stable precursor for
cyclopropyl carbenes, we turned our attention to N-sulfonyl
1,2,3-triazoles,8 a diazo compound equivalent developed by
Fokin and Gevorgyan for annulation, cyclopropanation
and C–H insertion reactions.9–11 We found that cyclobutene
carboxylaldehyde 6 could be prepared directly from alkynyl
cyclopropane 4 through the triazole intermediate 5 (Scheme 1),
whose isolation was not necessary when two metal catalysts
were employed.
Four-membered rings are frequently presented in bioactive
natural products and employed as key intermediates for the
preparation of complex targets.1 Efficient synthesis of function-
alized four-membered rings still stimulates the development of
new selective methods that complement existing technologies.2
We previously developed a method for the synthesis of highly
substituted cyclobutenes from cyclopropyl metal carbenes
derived from Rh(II), Ag(I), or Cu(I)-catalyzed decomposition
of diazo compounds (Scheme 1).3,4 We took advantage of the
well-documented stereoselective cyclopropanation methods5
and transferred the substituents and stereochemistry of cyclo-
propanes to cyclobutenes.6 This method was recently applied
to the diastereo- and enantioselective synthesis of the proposed
Known aldehyde 8 was prepared by cyclopropanation of
styrene with tosyl triazole 7.10,11 Homologation of aldehyde 8
then afforded cyclopropyl acetylene 4a (Scheme 2).12 The acetylene
in 4a could be converted to tosyl triazole 9 following literature
procedures.13
Triazole 9 was then treated with three catalysts that we
previously used for the decomposition of cyclopropyl diazo
compounds (Scheme 3).3 Although Rh2(Oct)4 was a more
reactive catalyst than AgOTf and Cu(MeCN)4PF6, the latter
Scheme 2 Preparation of substituted cyclopropanes from alkenes.
Scheme 1 Ring expansion of cyclopropyl metal carbene.
School of Pharmacy, University of Wisconsin, Madison, WI 53705,
USA. E-mail: wtang@pharmacy.wisc.edu
w This article is part of the ChemComm ‘Emerging Investigators 2013’
themed issue.
z Electronic supplementary information (ESI) available: 1H NMR,
13C NMR, HRMS, and IR data and copies of NMR specta for all
starting materials and products. See DOI: 10.1039/c2cc34609e
Scheme 3 Effect of catalysts on the regioselectivity of ring expansion.
c
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Table 1 Synthesis of cyclobutene carboxylaldehyde 6 from alkynyl
cyclopropanesa
Entry
1
Substrate
Productb
Yield
85%
Scheme 4 Effect of azides on ring expansion.
two provided much higher regioselectivity for the formation of
cyclobutene 11 over isomer 12. Through the formation of tosyl
triazoles 7 and 9, carbons 1 and 2 in intermediate 10 were
converted to metal carbenes from alkynes conveniently.
We then examined the effect of arylsulfonyl azide on triazole
formation and ring expansion (Scheme 4). It has been reported
that the reactivity of N-sulfonyl 1,2,3-triazole increases and its
stability decreases when the tosyl group was replaced by a
triflate.11 We prepared triazoles 14a–14c from alkyne 4a and
azides 13a–13c, respectively. We found that the ring expansion
of triazole 14c could be completed in 4 h at room temperature
in the presence of a Ag(I) catalyst, while low conversions were
observed for triazoles 14a and 14b under the same conditions.
In the absence of any catalyst, no reaction was observed at
room temperature after 24 h. Triazole 14d derived from alkyne
4a and azide 13d was not stable enough to be isolated. Triazole
14c has balanced reactivity and stability.
2
80%
3
4
5
80%
73%
82%
86%
During the preparation of triazole 14c, we also observed
small amounts of the cyclobutene product 15c, suggesting that
CuTc was capable of catalyzing the decomposition of triazole.
However, even after we extended the reaction time from 4 h to
12 h, the ratio of 15c/14c was only about 1 : 2. Based on the
results shown in Scheme 3, the AgOTf catalyst has higher
reactivity than Cu(MeCN)4PF6 and higher selectivity than
Rh2(Oct)4. We then decided to treat cyclopropyl acetylene 4a with
azide 13c in the presence of both CuTc and AgOTf catalysts. We
were pleased to find that these two catalysts did not interfere with
each other and cyclobutene carboxylaldehyde 6a was isolated in
good yield and selectivity (entry 1, Table 1).
6
a
Conditions: (1) CuTc (10 mol%), AgOTf (10 mol%), 13c (1 equiva-
b
lent), rt, 4–8 h; (2) alumina oxide. Regioselectivity (>20 : 1) was
1
determined by H NMR of the crude product.
4g could be converted to sulfonamide 16g in 85% yield
(entry 2). The alkyl substituent on the 1-position of cyclo-
propane could also be tolerated (entry 3). We found that the
cyclobutenyl aldehyde derived from acetylene 4i was not very
stable at room temperature. Direct reduction of the imine
intermediate afforded stable sulfonamide 16i in good yield
and high regioselectivity (entry 4). Substrate 4j with an alkyl
group on the 1-position and aryl group on the 2-position of
cyclopropane also worked well (entry 5).
We then studied the scope of the ring expansion of different
cyclopropyl acetylenes facilitated by the dual catalyst in the
presence of azide 13c (Table 1). We first examined different
aryl groups on the 2- and 1-position of the cyclopropane ring
(entries 2–5). High regioselectivity (>20 : 1) was observed
in all cases. The selective formation of cyclobutenes with a
1,3-diaryl over 1,2-diaryl relationship may be due to steric
interactions between the two aryl groups during the ring
expansion. Alkyl groups could also be tolerated on the 2-position
of cyclopropanes (entry 6).
In summary, we have developed an efficient method for the
preparation of highly substituted cyclobutenes from alkynyl
cyclopropanes selectively. The tandem process was facilitated
by a dual catalyst system (CuTc and AgOTf). This new protocol
eliminated the need of isolating diazo or triazole intermediates.
Various cyclobutenes with aldehyde or sulfonamide function-
ality could be prepared. The synthesis of cyclobutenes is greatly
simplified by using N-sulfonyl-1,2,3-triazoles as the carbene
In addition to hydrolysis, the imine intermediate 15c could
also be reduced in situ to form sulfonamide 16a (Table 2). The
chirality in cyclopropane 4a was also successfully transferred
to the product (entry 1). This paved the way for enantio-
selective synthesis of four-membered rings from chiral alkynyl
cyclopropanes. Commercially available cyclopropyl acetylene
c
Chem. Commun.
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Table 2 Synthesis of cyclobutene sulfonamides 16 from alkynyl
cyclopropanes (Ar = 3,5-(CF3)2C6H3)a
Notes and references
1 (a) T. V. Hansen and Y. Stenstrom, in Organic Synthesis: Theory
and Applications, Elsevier Science Ltd., 2001, vol. 5, p. 1;
(b) V. M. Dembitsky, J. Nat. Med., 2008, 62, 1; (c) E. Lee-Ruff
and G. Mladenova, Chem. Rev., 2003, 103, 1449; (d) N. Gauvry,
C. Lescop and F. Huet, Eur. J. Org. Chem., 2006, 5207.
2 For selected examples of cyclobutene synthesis, see:
(a) K. Inanaga, K. Takasu and M. Ihara, J. Am. Chem. Soc.,
2005, 127, 3668; (b) Y. H. Liu, M. N. Liu and Z. Q. Song, J. Am.
Chem. Soc., 2005, 127, 3662; (c) E. Canales and E. J. Corey, J. Am.
Chem. Soc., 2007, 129, 12686; (d) V. Lopez-Carrillo and
A. M. Echavarren, J. Am. Chem. Soc., 2010, 132, 9292.
3 H. Xu, W. Zhang, D. Shu, J. B. Werness and W. Tang, Angew.
Chem., Int. Ed., 2008, 47, 8933.
4 (a) J. M. Um, H. Xu, K. N. Houk and W. Tang, J. Am. Chem.
Soc., 2009, 131, 6664; For related studies, see: (b) J. Barluenga,
L. Riesgo, L. A. Lopez, E. Rubio and M. Tomas, Angew. Chem.,
Int. Ed., 2009, 48, 7569; (c) C.-W. Li, K. Pati, G.-Y. Lin, S. M. Abu
Sohel, H.-H. Hung and R.-S. Liu, Angew. Chem., Int. Ed., 2010,
49, 9891.
Entry
Substrate
Productb
Yield
81%
1
2
3
85%
80%
5 For selected reviews on cyclopropanations, see: (a) M. P. Doyle,
Chem. Rev., 1986, 86, 919; (b) T. Ye and M. A. McKervey, Chem.
Rev., 1994, 94, 1091; (c) M. P. Doyle and D. C. Forbes, Chem.
Rev., 1998, 98, 911; (d) M. P. Doyle, M. A. McKervey and T. Ye,
Modern Catalytic Methods for Organic Synthesis with Diazo
Compounds, John Wiley & Sons, New York, 1998; (e) H. Lebel,
J.-F. Marcoux, C. Molinaro and A. B. Charette, Chem. Rev., 2003,
103, 977; (f) Z. Zhang and J. Wang, Tetrahedron, 2008, 64, 6577;
(g) H. Pellissier, Tetrahedron, 2008, 64, 7041; (h) H. M. L. Davies
and J. R. Denton, Chem. Soc. Rev., 2009, 38, 3061; (i) J. M.
Concellon, H. Rodriguez-Solla, C. Concellon and V. del Amo,
Chem. Soc. Rev., 2010, 39, 4103.
6 For a comprehensive review on transition metal mediated reactions
involving cyclopropanes, see: M. Rubin, M. Rubina and
V. Gevorgyan, Chem. Rev., 2007, 107, 3117.
4
78%
76%
7 (a) R. Liu, M. Zhang, T. P. Wyche, G. N. Winston-McPherson,
T. S. Bugni and W. Tang, Angew. Chem., Int. Ed., 2012, 51, 7503;
(b) For a contemporary synthesis of the proposed structure of
pipercyclobutanamide A, see: W. R. Gutekunst, R. Gianatassio
and P. S. Baran, Angew. Chem., Int. Ed., 2012, 51, 7507.
8 For a recent review on transition metal-catalyzed reactions of
1,2,3-trizoles, see: B. Chattopadhyay and V. Gevorgyan, Angew.
Chem., Int. Ed., 2012, 51, 862.
9 (a) T. Horneff, S. Chuprakov, N. Chernyak, V. Gevorgyan and
V. V. Fokin, J. Am. Chem. Soc., 2008, 130, 14972;
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J. Am. Chem. Soc., 2011, 133, 10352; (c) B. Chattopadhyay and
V. Gevorgyan, Org. Lett., 2011, 13, 3746.
5
a
Conditions: CuTc (10 mol%), AgOTf (10 mol%), 13c (1 equivalent),
b
rt, 1–8 h; (2) LiAlH4. Regioselectivity (>20 : 1) was determined by
1H NMR of the crude product. This is based on the ee of the
aldehyde precursor.
c
10 S. Chuprakov, S. W. Kwok, L. Zhang, L. Lercher and V. V. Fokin,
J. Am. Chem. Soc., 2009, 131, 18034.
precursor for cyclopropanation of alkene and ring expansion
of cyclopropanes.
11 N. Grimster, L. Zhang and V. V. Fokin, J. Am. Chem. Soc., 2010,
132, 2510.
12 (a) S. Muller, B. Liepold, G. J. Roth and H. J. Bestmann, Synlett,
1996, 521; (b) E. J. Corey and P. L. Fuchs, Tetrahedron Lett., 1972,
13, 3769.
We thank NIH (R01 GM088285) and the University of
Wisconsin for financial support and a Young Investigator
Award (to W.T.) from Amgen.
13 J. Raushel and V. V. Fokin, Org. Lett., 2010, 12, 4952.
c
This journal is The Royal Society of Chemistry 2012
Chem. Commun.