Synthesis of cyclobutenes by highly selective transition-metal-catalyzed ring expansion of cyclopropanes

Article abstract of DOI:10.1002/anie.200803910

(Chemical Equation Presented) A highly chemoselective, regioselective, and stereospecific synthesis of polysubstituted cyclobutenes, by catalyst-controlled ring expansion of cyclopropanes via metal carbene intermediates, is reported. Transition-metal cata

Full text of DOI:10.1002/anie.200803910

Angewandte
Chemie
DOI: 10.1002/anie.200803910
Ring Expansion
Synthesis of Cyclobutenes by Highly Selective Transition-Metal-
Catalyzed Ring Expansion of Cyclopropanes**
Huadong Xu, Wen Zhang, Dongxu Shu, Jenny B. Werness, and Weiping Tang*
The four-membered ring is an important structural motif,
present in many bioactive natural products[1] and key
intermediates in the synthesis of structurally complex targets
by facile ring-opening reactions.[2] Several selective methods
have been developed for the synthesis of cyclobutanes and
cyclobutenes.[3] However, highly substituted four-membered-
ring natural products, such as sceptrin, welwitindolinone A,
and their diverse derivatives still represent a demanding
synthetic challenge, and stimulate the development of new
selective methods.[4] We wish to explore the use of cyclo-
propanes, for which stereoselective preparations have been
well documented,[5] as precursors for the synthesis of complex
Scheme 1. Ring expansion of cyclopropyl metal carbenes to cyclobu-
tenes by the migration of bond x or y.
four-membered rings.
Cyclopropyl carbenes, generated from thermal decompo-
sition of diazo compounds, can undergo a rearrangement to
give cyclobutenes but the thermal process requires harsh
conditions, and affords low yields and poor selectivities.[6] The
profound effect of transition-metal catalysts, such as com-
plexes of rhodium and copper, on the reactivity of metal
selectivity. Herein, we report a synthesis of poly-substituted
cyclobutenes by transition-metal-catalyzed highly selective
ring expansion of readily available cyclopropanes (Scheme 1).
The unique chemo-, regio-, and stereoselectivity for the ring
expansion of novel cyclopropyl dirhodium(II), copper(I), and
silver(I) carbenes are described.
We first screened a variety of transition-metal catalysts for
the ring expansion of simple monosubstituted cyclopropane
1a, and observed complete conversion of diazo compound 1a
into cyclobutenoate 1b in less than five minutes at ambient
temperature with a range of catalysts (Table 1, entries 1–3).[11]
Notably, some of the metal catalysts known to promote the
formation of the proposed cyclopropyl metal carbene inter-
mediates from enynes or MCPs were inactive in this reaction.
Electrophilic metal carbenes were presumably generated
from diazo compound 1a following dissociation of dinitrogen
in the presence of dirhodium(II), copper(I), or silver(I)
catalysts.[7] Ring expansion of cyclopropyl metal carbenes by a
carbenes has been widely recognized in cyclopropanations,
[7]
À
C H insertions, and dipolar cycloadditions. We envision
that transition-metal catalysts may offer unusual selectivity
for the ring expansion of cyclopropyl metal carbenes to
cyclobutenes. Cyclopropyl metal carbenes have been pro-
posed as intermediates in the formation of various isomeric
bicyclic cyclobutenes by cycloisomerization of tethered
enynes, by the groups of Trost, Echavarren, and Fürstner
with palladium, platinum, or gold catalysts (Scheme 1).[8]
Alternatively, cyclopropyl metal carbenes may derive from
methylenecyclopropanes (MCPs). Monosubstituted cyclobu-
tenes have been prepared from MCP by Shi and co-workers,
using palladium(II) catalysts (Scheme 1).[9] A mechanism
involving no cyclopropyl metal carbenes was proposed by
Fürstner and Aissa for the conversion of MCPs into mono-
substituted cyclobutenes, catalyzed by platinum(II).[10]
Despite these elegant studies, selective synthesis of highly
desirable polysubstituted cyclobutenes[1–3] remains an elusive
target, as many issues have arisen regarding reactivity and
Table 1: Screening of metal catalysts.[a]
[*] Dr. H. Xu, Dr. W. Zhang, Prof. Dr. W. Tang
The School of Pharmacy, University of Wisconsin
Madison, WI 53705-2222 (USA)
Entry
Catalyst
Yield
1
2
[Rh2(OAc)4]
[Cu(CH3CN)4]PF6
AgOTf
88%[b]
80%[b]
Fax: (+1)608-262-5345
E-mail: wtang@pharmacy.wisc.edu
3
90%[b] (87%[c])
91%[b]
4[d]
[Cu(acac)2]
D. Shu, J. B. Werness
Department of Chemistry, University of Wisconsin
[a] No product was detected by thin-layer chromatograpy after 5 h for the
following catalysts: Pd(OAc)2, [Ni(cod)2], [AuClPPh3], and [RuCl2-
(PPh3)3]. [b] Yield determined by 1H NMR spectroscopy in CDCl3, using
CH2Br2 as the internal standard. [c] Yield of isolated product. [d] 5 h,
room temperature. cod=cycoocta-1,5-diene.
[**] We thank the University of Wisconsin for startup funding and the
Analytical Instrument Center (AIC) for NMR support.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.200803910.
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Table 3: Scope of the AgOTf-catalyzed ring expansion.[a]
Cyclopropane Cyclobutene
À
1,2-migration of one of the cyclopropane C C s bonds then
led to cyclobutenoate 1b.
Yield
Ratio[b]
–
We then set out to investigate the reactivity and selectivity
of cyclopropyl dirhodium(II), copper(I), and silver(I) car-
benes, which are not easily accessible from other methods.
Metal carbenes are well known to cyclopropanate olefins.[5,7]
Indeed, a mixture of ring-expansion product 2b and intra-
molecular cyclopropanation product 2c was detected after
diazo compound 2a was treated with a [Rh2(OAc)4] catalyst
(Table 2, entry 1). Surprisingly, both [Cu(CH3CN)4]PF6 and
91%
77%
–
72%
90%
–
–
Table 2: Chemoselectivity of metal catalysts.
single
isomer
71%
Entry
Catalyst
2b/2c[a]
Yield
single
isomer
92%
73%
70%
1
2
3
[Rh2(OAc)4]
[Cu(CH3CN)4]PF6
AgOTf
3:1
1:0
1:0
91%[a]
89%[b]
87%[b]
10:1
[a] The isomeric ratio was determined by 1H NMR spectroscopy. [b] Yield
of isolated product.
10:1[c]
AgOTf catalysts exhibited excellent chemoselectivity for the
selective formation of cyclobutenoate 2b (Table 2, entries 2
and 3) even though the copper(I)- and silver(I)-catalyzed
cyclopropanation of alkenes is well-documented.[12]
The scope of the silver(I)-catalyzed ring expansion was
explored for various substituted 2-cyclopropyl-2-diazoace-
tates (Table 3), which are generally chromatographically
stable and prepared in three steps by a sequence of alkene-
cyclopropanation, tosylhydrazone formation, and base-medi-
ated a elimination. Ring expansion occurred smoothly for
substrate 3a despite the presence of two relatively reactive
single
isomer
87%
77%
single
isomer
[a] Conditions: CH2Cl2,room temperature, 5 min, 5 mol% AgOTf, unless
noted otherwise. Yields given are yields of isolated product. [b] The
isomeric ratio was determined by 1H NMR spectroscopy. [c] À208C,
30 min.
À
benzylic C H bonds towards 1,5-insertion. The 1,2-disubsti-
tuted cyclobutene 4b and bicyclic cyclobutenes 5b and 6b
were synthesized efficiently under the standard conditions
(Table 3). Ring expansion took place stereospecifically using
the AgOTf catalyst, as demonstrated by the conversion of cis-
cyclopropane 7a into cis-cyclobutene 7b, and trans-cyclo-
propane 8a into trans-cyclobutene 8b, respectively. These
results indicate that the migrating carbon atom retains its
configuration during the AgOTf-catalyzed ring expansion.
When substrate 9a was treated with AgOTf, a regioiso-
meric ratio of 10:1 favoring cyclobutene 9b was obtained by
migration of the carbon atom next to the double bond, which
may stabilize the partial positive charge developed on the
migrating allylic carbon atom during ring expansion. From
ester-substituted cyclopropane 10a, a mixture of regioiso-
meric cyclobutenes was obtained in a 6:1 ratio at ambient
temperature, and a 10:1 ratio at À208C, favoring the less
sterically congested 1,3-disubstituted cyclobutene 10b. The
formation of 10b is also electronically favored, because the
migrating carbon atom with a partial positive charge is further
removed from the electron-withdrawing ester group in 10a.
The mutual reinforcement of steric and electronic effects may
contribute to the exclusive formation of 1,3,3-trisubstituted
cyclobutene 11b and 1,3,3,4-tetrasubstituted cyclobutene
12b, from 11a and 12a, respectively. Notably, this reaction,
which involves metal carbene intermediates, is compatible
with a variety of functional groups, such as relatively reactive
À
benzylic C H bonds, aromatic rings, ethers, olefins, and esters.
The resulting cyclobutenoates can be further functionalized
by hydrogenation or conjugated addition, to afford saturated
cyclobutanes.[13]
When cyclopropane 13 or 14 (Ar= Ph) was treated with
AgOTf, a mixture of cyclobutenes 15 and 16 was obtained
with low regioselectivity (Table 4, entries 2 and 10). After
some tailoring of reaction conditions, both cyclobutenes were
prepared with good selectivity, by judicious selection of
cyclopropanes and metal catalysts (Table 4, entries 4 and 9).
The formation of the less-congested 1,3-disubstituted cyclo-
butene 16 is favored sterically, but the formation of cyclo-
butene 15 is favored electronically, as the phenyl group can
stabilize the partial positive charge on the migrating benzylic
carbon atom, induced by metal catalysts during ring expan-
sion. From either trans-13 or cis-14, the ratio of products 15/16
is dependent on the metal catalyst, decreasing in the order
copper(I), silver(I), dirhodium(II). These results may reflect
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Table 4: Catalyst-dependent regioselectivity.
In summary, we have developed a highly chemoselective,
regioselective, and stereospecific synthesis of polysubstituted
cyclobutenoates and demonstrated the crucial effect of
transition-metal catalysts on the reactivity and selectivity of
metal carbenes. The intriguing catalyst-dependent divergence
in the chemo- and regioselectivity of metal carbenes may
create myriad opportunities for mechanistic investigations,
design of new reactions, and target-oriented synthesis. The
stereospecificity of this metal-catalyzed ring expansion paves
the way for asymmetric synthesis of cyclobutenes from readily
available, optically pure cyclopropanes. The electronic and
steric effects for the regioselective cleavage of cyclopropane
Cyclopropane
Entry
Catalyst
x/y[b]
Yield
1
2
3
[Cu(CH3CN)4]PF6
AgOTf
5:1
1:2
1:7
1:9
1:4
1:5
1:7
2:1
17:1
3:1
1:4
1:3
13:1
100% 18
100% 18
1:2
–
–
–
[Rh2(OAc)4]
[Rh2(octanoate)4]
[Rh2(O2CCPh3)4]
[Rh2(O2CCF3)4]
[Rh2(caprolactam)4]
heat[f]
4[c,d]
5
89%[e]
–
–
–
À
C C s bonds illustrated here may find applications in many
6
7
8
other metal-catalyzed reactions involving cyclopropanes as
building blocks.
48%[g]
93%[e]
–
9[d]
10
11
12
13
14
15
16
[Cu(CH3CN)4]PF6
AgOTf
[Rh2(OAc)4]
–
Experimental Section
heat[f]
35%[g]
–
General procedure: Silver triflate (5 mol%) was added to a solution
of the diazo compound (0.3–0.5 mmol) in CH2Cl2 (3–5 mL, 0.1m)
under argon. The reaction mixture was stirred at room temperature
for 5 min. The solvent was removed under reduced pressure and the
residue was purified by column chromatography on silica gel using
ethyl acetate and hexane as the eluent.
Ag(O2CCF3)
[Cu(CH3CN)4]PF6
AgOTf
90%[g]
90%[g]
–
[Rh2(OAc)4]
[a] CH2Cl2, room temperature, 5 min, 10 mol% catalyst, isomeric ratio
was determined by 1H NMR spectroscopy, unless noted otherwise.
[b] Isomeric ratio of products resulting from the migration of bond x or y.
[c] À208C, 30 min. [d] 5 mol% catalyst. [e] Yield of isolated product.
Received: August 7, 2008
Published online: October 10, 2008
1
[f] 708C for 24 h in toluene. [g] Yield determined by H NMR spectros-
Keywords: carbenes · cyclobutenes · homogeneous catalysis ·
copy in CDCl3, using CH2Br2 as the internal standard.
.
rearrangement · ring expansion
the net results of the opposing electronic and steric effects in
different cyclopropyl metal carbenes (for example, electronic
effects dominate in the case of copper(I) carbene and steric
effects dominate in the case of dirhodium(II) carbene). In
addition, steric repulsion between the two cis substituents in
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À
14 may significantly weaken the C C bond x (see Table 4) so
that a higher proportion of product 15 was obtained from cis-
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entries 1 versus 9, 2 versus 10, or 3versus 11). In sharp
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To further understand this unprecedented catalyst-depen-
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we prepared compound 17 (Ar= 4-MeOC6H4), incorporating
an electron-rich para-methoxyphenyl substituent. If our
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from the ring expansion of 17) should be greater than the ratio
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compound 17 was treated with copper(I) or silver(I) catalysts
(Table 4, entries 14 and 15). The dirhodium(II) catalyst
provides a 1:2 ratio for compounds 18/19 (Table 4, entry 16),
which is more in favor of the electronically favored product
than the 1:7 ratio for compounds 15/16 (Table 4, entry 3).
Angew. Chem. Int. Ed. 2008, 47, 8933 –8936
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Communications
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