Gold(l)-catalyzed ring expansions of unactivated alkynylcyclopropanes to (E)-2-alkylidenecyclobutanamines in the presence of sulfonamides

Article abstract of DOI:10.1021/ol9028786

(Chemical Equation Presented) The ring expansion of cyclopropane derivatives provides a powerful method to construct synthetically useful four-membered carbocycles. Herein, a new type of gold(l)-catalyzed ring expansion of an unactivated alkynylcyclopropane/sulfonamide trapping strategy to (E)-2-alkylidenecyclobutanamines was described. The reaction tolerates a range of aryl and alkyl substituents with moderate to good yields.

Full text of DOI:10.1021/ol9028786

ORGANIC
LETTERS
2010
Vol. 12, No. 4
804-807
Gold(I)-Catalyzed Ring Expansions of
Unactivated Alkynylcyclopropanes to
(E)-2-Alkylidenecyclobutanamines in the
Presence of Sulfonamides
Siyu Ye and Zhi-Xiang Yu*
Beijing National Laboratory for Molecular Sciences (BNLMS), Key Laboratory of
Bioorganic Chemistry and Molecular Engineering of Ministry of Education,
College of Chemistry, Peking UniVersity, Beijing 100871, China
yuzx@pku.edu.cn
Received December 14, 2009
ABSTRACT
The ring expansion of cyclopropane derivatives provides a powerful method to construct synthetically useful four-membered carbocycles.
Herein, a new type of gold(I)-catalyzed ring expansion of an unactivated alkynylcyclopropane/sulfonamide trapping strategy to (E)-2-
alkylidenecyclobutanamines was described. The reaction tolerates a range of aryl and alkyl substituents with moderate to good yields.
Four-membered carbocycles are found in many natural products
of significant biological activities.1 Also, four-membered car-
bocycles are very useful building blocks that can be further
transformed to various ring skeletons in organic synthesis.2
However, methods for synthesis of four-membered carbocycles
are limited compared to the synthesis of five- and six-membered
carbocycles. This is mainly due to the following reasons.
Thermal [2 + 2] cycloaddition3 of two π components with or
without catalysts is limited to special substrates. Photochemical
[2 + 2] cycloaddition4 is another approach to achieve four-
membered carbocycles, in which the intramolecular type is
usually efficient, but the intermolecular type has not been well
developed.5 Due to this, synthesis of four-membered car-
bocycles has to be accomplished via either a ring expansion or
a ring contraction strategy. Ring expansion6 is a powerful method
to realize this dream because cyclopropanes can be easily pre-
pared by many known methods, such as Simmons-Smith,7
Kulinkovich,8 de Meijere-Kulinkovich,9 and others. Asymmetric
(3) (a) Kimura, M.; Horino, Y.; Wakamiya, Y.; Okajima, T.; Tamaru,
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Angew. Chem., Int. Ed. 2004, 43, 610. (d) Takasu, K.; Ueno, M.; Inanaga,
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Kawachi, A. Org. Lett. 2006, 8, 1343. (f) Hiroaki Ohno, H.; Mizutani, T.;
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Chem. 2007, 72, 4378. (g) Canales, E.; Corey, E. J. J. Am. Chem. Soc.
2007, 129, 12686. (h) Ogasawara, M.; Okada, A.; Nakajima, K.; Takahashi,
T. Org. Lett. 2009, 11, 177. (i) Feltenberger, J. B.; Hayashi, R.; Tang, Y.;
Babiash, E. S. C.; Hsung, R. P. Org. Lett. 2009, 11, 3666.
(1) (a) Hansen, T. V.; Stenstrom, Y. Organic Synthesis: Theory and
Applications; Hudlicky, T., Ed.; Elsevier Science Ltd.: New York, NY, 2001;
Vol. 5, pp 1-38. (b) Dembitsky, V. M. J. Nat. Med. 2008, 62, 1.
(2) (a) Fu, N.-Y.; Chan, S.-H.; Wong, H. N. C. Chemistry of Cyclobu-
tanes; Rappoport, Z., Liebman, J. F., Eds.; John Wiley & Sons Ltd.:
Chichester, UK, 2005; Vol. 1, pp 357-440. (b) Kabalka, G. W.; Yao, M.-
L. Tetrahedron Lett. 2003, 44, 7885. (c) Anderson, E. A.; Alexanian, E. J.;
Sorensen, E. J. Angew. Chem., Int. Ed. 2004, 43, 1998. (d) Jung, M. E.;
Nishimura, N.; Novack, A. R. J. Am. Chem. Soc. 2005, 127, 11206. (e)
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Z.-X. Org. Lett. 2006, 8, 5877. (f) Jiang, M.; Shi, M. Org. Lett. 2008, 10,
2239. (g) Jiang, M.; Shi, M. Tetrahedron 2009, 65, 798.
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10.1021/ol9028786  2010 American Chemical Society
Published on Web 01/15/2010

synthesis of cyclopropanes10 has also been well developed, and
therefore ring expansion from chiral cyclopropanes to chiral
cyclobutane skeletons can be fulfilled potentially.
Inspired by these seminal studies, we envisioned that
alkynylcyclopropanes without activating groups in the cy-
clopropane ring could also undergo cation-triggered expan-
sion to give four-membered carbocycles if an appropriate
nucleophile could trap the in situ generated cation (Scheme
1).15 If this can be realized, multifunctional four-membered
carbocycles can be readily synthesized from simple alky-
nylcyclopropanes.
One such ring expansion strategy is to use alkynylcyclo-
propanes as substrates. For example, Toste’s group11 and
Trost’s group12 reported intramolecular ring expansions of
alkynylcyclopropanols13 to alkylidenecyclobutanones under
Au and Ru catalysts, respectively. In Au catalysis, it was
proposed that cationic species were generated by coordination
of transition metals to the carbon-carbon triple bonds of
the alkynylcyclopropanes. Then a cation-triggered ring
expansion gave the four-membered carbocyclic cations,
which underwent further reactions to furnish the final
alkylidenecyclobutanones. It must be pointed out that the
hydroxyl group in the cyclopropane rings is required for the
success of Toste’s and Trost’s reactions. Recently, Jiao’s
group14 also reported Fe-catalyzed ring expansions of
alkynylcyclopropyl alkanols to cyclobutanols (eq 2, Scheme
1). Here, a cation was generated from the secondary alcohol
We quickly synthesized alkynylcyclopropane 1a by So-
nogashira cross-coupling from commercially available 1-chlo-
ro-4-iodobenzene and cyclopropylacetylene. Treatment of
substrate 1a with various nucleophiles (water, phenol, indole,
aniline, BocNH2, and TsNH2, in a stoichiometric amount)16
under 10 mol % (PPh3)AuOTf suggested that only TsNH2
was efficient. The reaction produced alkylidenecyclobutan-
amine 3a in 65% yield as a single olefin isomer (entry 1,
Table 1).17 We then concentrated on screening the optimal
conditions for this reaction. When only AgOTf was employed
as the catalyst, a trace amount of 3a was observed, indicating
that the effective component should be the cationic gold(I)
(entry 2, Table 1). N-Heterocyclic carbene ligand (N,N′-
bis(2,6-diisopropylphenyl)imidazol-2-ylidene) turned out to
be less efficient in this ring expansion (entry 3, Table 1).
Other common Lewis acids, which may have good affinity
toward the alkynes, such as AuCl3, PtCl2, and Sc(OTf)3, were
also tested, but the yields were far from ideal (entries 4-7,
Table 1). Strong Bro¨nsted acid TfOH could accelerate the
consumption of substrate 1a but did not improve the yield.
In contrast, weaker Bro¨nsted acid, such as CF3COOH, was
not effective to catalyze this transformation (entries 8 and
9, Table 1). The solvent effect was quite strong because the
ring expansion deteriorated in dioxane and toluene (entries
10 and 11, Table 1). When the catalyst loading was reduced
from 10 mol % to 5 mol %, the reaction became slower
(entry 12, Table 1). By raising the temperature to 80 °C, the
reaction gave the highest efficiency with a 76% yield and a
complete conversion of the substrate (entry 13, Table 1).
Scheme 1
of the substrate. Then, a similar ring expansion occurred to
give a cationic four-membered carbocycle, which was then
trapped by the hydroxyl group to give the final product.
Table 1. Optimization Studies on the Ring Expansiona
entry
catalyst
solvent
temp (°C)
time (h)
yield (%)b
conversion (%)
1
2
3
4
5
6
7
8
10 mol % AuPPh3Cl, 10 mol % AgOTf
10 mol % AgOTf
10 mol % AuIPrCl, 10 mol % AgOTf
10 mol % AuCl3, 10 mol % AgOTf
10 mol % AuCl3
10 mol % PtCl2
10 mol % Sc(OTf)3
10 mol % TfOH
10 mol % CF3COOH
10 mol % AuPPh3Cl, 10 mol % AgOTf
10 mol % AuPPh3Cl, 10 mol % AgOTf
5 mol % AuPPh3Cl, 5 mol % AgOTf
5 mol % AuPPh3Cl, 5 mol % AgOTf
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
dioxane
toluene
DCE
DCE
60
60
60
60
60
60
60
60
60
60
60
60
80
24
24
24
24
24
24
24
7
24
24
24
24
14
65
>99
tracec
21
85
>99
15
tracec
NRd
20
44
>99
28
9
NRd
NDe
20
10
11
12
13
88
52
90
74
76
>99
a Reaction condition: 1a (0.5 mmol), TsNH2 (0.6 mmol), catalyst (0.05 or 0.025 mmol), solvent (5 mL). b Isolated yields without considering the recovered
1a.c Mostof1aremainedunchanged.d NR)noreaction.e ND)productnotdetected.DCE)1,2-dichloroethane.IPr)N,N′-bis(2,6-diisopropylphenyl)imidazol-2-ylidene.
Org. Lett., Vol. 12, No. 4, 2010
805

electron-donating the aryl group in the substrate was, the
worse the result was. For example, the phenyl-substituted
substrate 1b afforded a slightly diminished yield (entry 2,
Table 2), while the yield dropped to 46% when the p-tolyl
group was introduced (entry 3, Table 2). The electron-rich
1-napthyl group turned out to be less suitable. When substrate
1d was heated at higher temperature (100 °C) to reach full
conversion, the yield became poorer (entries 4 and 5, Table
2). Unfortunately, the strong electron-donating p-methoxy
group did not fit this reaction, as demonstrated by the fact
that substrate 1e failed to furnish the desired product (entries
6 and 7, Table 2).
Table 2. Ring Expansions of Alkylnylcyclopropanesa
However, electron-withdrawing groups were well compatible
with this ring expansion. From the weak electron-withdrawing
bromo group to the strong ones, such as ester, trifluoromethyl,
cyano, and nitro groups, all of them afforded the expected
alkylidenecyclobutanamines in moderate to good yields (entries
8-12, Table 2). We found that electron-withdrawing groups
made the target reaction very slow. Consequently, the reaction
temperatures for these substrates needed to be elevated (solvent
changed from DCE to TCE) for the reaction completion in a
reasonably short time. Besides para-substitution, ortho-, meta-,
and even disubstituted phenyl alkynyl substrates could be well
transformed into the expected products (entries 13-17, Table
2), suggesting that the steric effect on the benzene ring did not
affect the reactivity significantly.
It is noteworthy that alkyl-substituted substrate 1p underwent
the ring expansion smoothly to give product 3p in 45% yield
(entry 18, Table 2). However, when the substituent was
hydrogen, an imine product 418 with the cyclopropyl moiety
unchanged was obtained, indicating that cyclopropylacetylene
1q underwent a hydroamination19 instead of a ring expansion
(Scheme 2). Furthermore, other sulfonamides, like TsNHMe
Scheme 2
a Condition A: DCE as solvent, heated at 80 °C. Condition B: TCE as
solvent, heated at 100 °C. Condition C: DCE as solvent, heated at 50 °C.
b Isolated yields without considering the recovered substrates. c 33% of 1d
was recovered. d ND ) product not detected. e A considerable amount of
1e remained. f 1e was totally consumed. DCE ) 1,2-dichloroethane. TCE
) 1,1,2,2-tetrachloroethane.
(5) and NsNH2 (6), were proved to be effective trapping reagents
in the ring expansion (Scheme 2). In addition, the framework
and the E olefin configuration of the products 3a-3s were
further confirmed by X-ray crystallographic analysis of 3h
(Figure 1). Finally, we examined the effect of certain substit-
uents on the cyclopropane ring. Unfortunately, these reactions
gave mixtures of unidentified products, and no target products
were obtained (for details, see Supporting Information).
In summary, we have developed a new type of gold(I)-
catalyzed ring expansion of unactivated alkynylcyclopro-
panes, which can be easily synthesized from simple and
We then studied the scope and limitation of this reaction.
Because the p-chloro phenyl group was demonstrated as a
suitable substituent in the substrate, we speculated that
electron-rich aryl groups in substrates would increase the
nucleophilicity of the carbon-carbon triple bond through
conjugation toward cationic gold catalyst, making these
substrates more reactive. However, we found that the more
806
Org. Lett., Vol. 12, No. 4, 2010

The reaction tolerates a range of aryl and alkyl substituents,
especially the electron-withdrawing ones. We believe this
ring expansion/trapping reaction provides a general, easy,
and quick approach to synthesize multifunctional cyclobu-
tanes and will find application in organic synthesis.
Acknowledgment. We are indebted to the generous
financial support from the Natural Science Foundation of
China (20825205-National Science Fund for Distinguished
Young Scholars, 20772007, and 20672005) and the National
Basic Research Program of China-973 Program
(2010CB833203).
Figure 1. X-ray structure of product 3h.
commercially available starting materials. The in situ gener-
ated cation from the ring expansion can be efficiently trapped
by sulfonamides. This reaction provides an easy and efficient
way to synthesize (E)-2-alkylidenecyclobutanamines that are
architecturally interesting and useful in organic synthesis.
Supporting Information Available: Experimental pro-
cedures, spectral data of all new compounds, and crystal
structure data of 3h in CIF format. This material is available
free of charge via the Internet at http://pubs.acs.org.
OL9028786
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