Rh(I)-catalyzed [5 + 1] cycloaddition of vinylcyclopropanes and CO for the synthesis of α,β- and β,γ-cyclohexenones

Article abstract of DOI:10.1021/ol2031526

A cationic Rh(I)-catalyzed [5 + 1] cycloaddition of vinylcyclopropanes and CO has been developed, affording either β,γ-cyclohexenones as major products or α,β-cyclohexenones exclusively, under different reaction conditions.

Full text of DOI:10.1021/ol2031526

ORGANIC
LETTERS
2012
Vol. 14, No. 3
692–695
Rh(I)-Catalyzed [5 þ 1] Cycloaddition
of Vinylcyclopropanes and CO for the
Synthesis of r,β- and β,γ-Cyclohexenones
Guo-Jie Jiang, Xu-Fei Fu, Qian Li, and Zhi-Xiang Yu*
Beijing National Laboratory of Molecular Sciences (BNLMS), Key Laboratory of
Bioorganic Chemistry and Molecular Engineering, College of Chemistry, Peking
University, Beijing 100871, China
*E-mail: yuzx@pku.edu.cn
Received November 24, 2011
ABSTRACT
A cationic Rh(I)-catalyzed [5 þ 1] cycloaddition of vinylcyclopropanes and CO has been developed, affording either β,γ-cyclohexenones as major
products or R,β-cyclohexenones exclusively, under different reaction conditions.
Transition-metal-catalyzed cycloadditions (annulations)
via coordination, oxidative addition, insertion, and re-
ductive elimination processes1 provide powerful ap-
proaches to synthesize various sized ring compounds,
which range from three- to nine-membered carbocycles.
Despite this, developing new transition-metal-catalyzed
cycloadditions that can expand, complement, or even
surpass the reported ones is still highly demanded, con-
sidering the possible different skeletons, substitutions,
and stereochemistry of the target molecules. Among them,
developing metal-catalyzed cycloadditions to synthesize
six-membered nonbenzenoid carbocycles is one of the most
actively pursued research fields, because six-membered
nonbenzenoid carbocycles are the most ubiquitous
ring compounds in organic chemistry. Until now, some
(1) Selected reviews of transition-metal-catalyzed cycloaddition re-
actions: (a) Lautens, M.; Klute, W.; Tam, W. Chem. Rev. 1996, 96,
49. (b) Reissig, H.-U.; Zimmer, R. Chem. Rev. 2003, 103, 1151.
(c) Rubin, M.; Rubina, M.; Gevorgyan, V. Chem. Rev. 2007, 107,
3117. (d) Inglesby, P. A.; Evans, P. A. Chem. Soc. Rev. 2010, 39, 2791.
(e) Yu, Z.-X.; Wang, Y.; Wang, Y. Chem.;Asian J. 2010, 5, 1072.
(2) (a) Huang, Y.; Lu, X. Tetrahedron Lett. 1988, 29, 5663. (b) He,
X.-C.; Wang, B.; Bai, D. Tetrahedron Lett. 1998, 39, 411.
(5) [5 þ 1] cycloadditions of allenylcyclopropanes: (a) Iwasawa, N.;
Owada, Y.; Matsuo, T. Chem. Lett. 1995, 115. (b) Owada, Y.; Matsuo,
T.; Iwasawa, N. Tetrahedron 1997, 53, 11069. (c) Murakami, M.; Itami,
K.; Ubukata, M.; Tsuji, I.; Ito, Y. J. Org. Chem. 1998, 63, 4. (d) Shu, D.;
Li, X.; Zhang, M.; Robichaux, P. J.; Tang, W. Angew. Chem., Int. Ed.
2011, 50, 1346.
(6) Rh-catalyzed [5 þ 1] steps are also involved in the following
reactions of dienylcyclopropanes and 1-yneꢀvinylcyclopropanes: (a)
Yao, Z.-K.; Li, J.; Yu, Z.-X. Org. Lett. 2011, 13, 134. (b) Lin, M.; Li, F.;
Jiao, L.; Yu, Z.-X. J. Am. Chem. Soc. 2011, 133, 1690.
(7) [5 þ 1] cycloadditions of vinylcyclopropenes: (a) Grabowski,
N. A.; Hughes, R. P.; Jaynes, B. S.; Rheingold, A. L. J. Chem. Soc.,
Chem. Commun. 1986, 1694. (b) Cho, S. H.; Liebeskind, L. S. J. Org.
Chem. 1987, 52, 2631. (c) Semmelhack, M. F.; Ho, S.; Steigerwald, M.;
Lee, M. C. J. Am. Chem. Soc. 1987, 109, 4397.
(8) [5 þ 1] cycloaddition of 3-acyloxy-1,4-enynes: Brancour, C.;
Fukuyama, T.; Ohta, Y.; Ryu, I.; Dhimane, A.-L.; Fensterbank, L.;
Malacria, M. Chem. Commun. 2010, 46, 5470.
(3) (a) See refs in 1a and 3bꢀ3g. For selected examples, see: (b) Wender,
P. A.; Jenkins, T. E.; Suzuki, S. J. Am. Chem. Soc. 1995, 117, 1843.
(c) O’Mahony, D. J. R.; Belanger, D. B.; Livinghouse, T. Org. Biomol.
Chem. 2003, 1, 2038. (d) Aikawa, K.; Akutagawa, S.; Mikami, K. J. Am.
€
Chem. Soc. 2006, 128, 12648. (e) Furstner, A.; Stimson, C. C. Angew.
Chem., Int. Ed. 2007, 46, 8845. (f) Kusama, H.; Karibe, Y.; Onizawa, Y.;
Iwasawa, N. Angew. Chem., Int. Ed. 2010, 49, 4269. (g) Kim, S. M.; Park,
J. H.; Chung, Y. K. Chem. Commun. 2011, 47, 6719.
(4) [5 þ 1] cycloadditions of vinylcyclopropanes: (a) Ben-Shoshan,
R.; Sarel, S. J. Chem. Soc., Chem. Commun. 1969, 883. (b) Victor, R.;
Ben-Shoshan, R.; Sarel, S. Tetrahedron Lett. 1970, 4253. (c) Sarel, S.
Acc. Chem. Res. 1978, 11, 204. (d) Aumann, R. J. Am. Chem. Soc. 1974,
96, 2631. (e) Taber, D. F.; Kanai, K.; Jiang, Q.; Bui, G. J. Am. Chem. Soc.
2000, 122, 6807. (f) Taber, D. F.; Joshi, P. V.; Kanai, K. J. Org. Chem. 2004,
69, 2268. (g) Kurahashi, T.; de Meijere, A. Synlett 2005, 2619.
(9) For reports of hetero-[5 þ 1] reactions, see: (a) Kamitani, A.;
Chatani, N.; Morimoto, T.; Murai, S. J. Org. Chem. 2000, 65, 9230.
(b) ref 4g.
r
10.1021/ol2031526
Published on Web 01/18/2012
2012 American Chemical Society

elegant transition-metal-catalyzed cycloadditions, for
example, the metal-catalyzed [3 þ 3],2 [4 þ 2],3 [5 þ 1],4ꢀ9
[2 þ 2 þ 2],10 [3 þ 2 þ 1],11 and [4 þ 1 þ 1]12 reactions,
have been developed for the synthesis of six-membered
carbocycles. In particular, the metal-mediated or -catalyzed
[5 þ 1] reactions of vinylcyclopropanes (VCPs)4 or
allenylcyclopropanes5 with CO are of synthetic signifi-
cance, due to the easy preparation of the substrates and
generation of various functionalized cyclohexenones. The
[5 þ 1] reactions of vinylcyclopropanes and CO can be
mediated by Fe(CO)5 under photoirradiation (developed
by Sarel,4aꢀc Aumann,4d and Taber4e,f) or catalyzed by
Co2(CO)8 or [Rh(CO)2Cl]2 (developed by de Meijere4g).
The [5 þ 1] cycloadditions of allenylcyclopropanes and
CO can be catalyzed by either Co catalyst (developed
by Iwasawa5a,b) or Ir complex (developed by Murakami
and Ito5c). Very recently, Tang and co-workers developed
a Rh-catalyzed tandem 1,3-acyloxy migration/[5 þ 1]
cycloaddition reaction to produce highly functionalized
cyclohexenones.5d In Tang’s reaction, the key step is the
Rh-catalyzed 1,3-acyloxy migration of propargyl esters
to give allenylcyclopropanes, which then produce the
[5 þ 1] cycloadducts under the same catalytic condition.
The importance of the [5 þ 1] reaction of vinylcyclopro-
panes and CO has been demonstrated by its application
in total synthesis by Taber’s group.13 Even though the
Rh-catalyzed [5 þ 1] reaction of in situ generated allenyl-
cyclopropanes and CO by Tang and co-workers has broad
scope, the [5 þ 1] reaction of VCPs and CO catalyzed by Rh
has not been developed into a general one. In the reported
[5 þ 1] reaction of VCPs and CO catalyzed by [Rh(CO)2Cl]2
from de Meijere’s group, only very special VCP substrates can
give good results. Here we report our development of a gen-
eral cationic Rh(I) complex-catalyzed [5 þ 1] reaction of VCPs
and CO to synthesize both R,β- and β,γ-cyclohexenones.
We discovered the [5 þ 1] reaction of VCP and CO
serendipitously during our study of the [3 þ 2] reaction of
R-eneꢀVCPs and R-yneꢀVCPs.14 Previously we found
that, under the Rh catalysis, R-eneꢀVCPs underwent
intramolecular [3 þ 2] cycloadditions15 to give 5/6- and
5/7-bicyclic compounds (Scheme 1a). When an R-yne-
VCP was used, a cycloisomerization happened instead.
Inspired by many [m þ n þ o] cycloadditions,1 we
wondered whether a [(3 þ 2) þ 1] reaction could also be
developed if CO was introduced to the reaction system.
Scheme 1. (a) Our Previous Report of R-Ene/Yne-VCP and
(b) Observed [5 þ 1] Cycloadditiona
a DCE = 1,2-dichloroethane.
We first used an R-yneꢀVCP substrate to test this pro-
posal. However, cycloisomerization still took place
instead of the designed [(3 þ 2) þ 1] cycloaddition
(Scheme 1a). To our surprise, when the standard R-ene-
VCP substrate 1a was tested in the presence of CO, [5 þ 1]
cycloaddition occurred, affording both β,γ- and R,β-
cyclohexenones (2a and 3a, Scheme 1b) in 51% and 30%
yields, respectively. The tethered alkene part in the
R-eneꢀVCP substrate was not involved in the cycloaddi-
tion. Considering the [5 þ 1] cycloaddition reaction is
very useful in the six-membered ring synthesis, we began
to investigate whether the Rh-catalyzed [5 þ 1] reaction
of more general VCP substrates and CO is possible.
To improve the [5 þ 1] reaction yield and the selectivity
between R,β- and β,γ-cyclohexenones, we further screened
the reaction conditions, using the more easily accessible
substrate 1b (Table 1). To our delight, under the catalysis
of [Rh(dppp)]SbF6, the total yield was high, even though
the selectivity was not very good. In this case, 41% of the
β,γ-cyclohexenone 2b and 34% of the R,β-unsaturated
product 3b were generated (entry 1). Both neutral
[Rh(CO)2Cl]2 (this is effective in some special substrates
shown by de Meijere and Kurahashi4g) and cationic
[Rh(CO)2]SbF6 failed to promote the desired cycloaddi-
tion (entries 2 and 3). We then tested a few other bidentate
phosphine ligands and found that the yields became lower
(entries 4ꢀ6). In particular, the standard reaction condi-
tion of the [3 þ 2] cycloaddition was not suitable for the
[5 þ 1] reaction at all, giving no product (entry 4). We
(10) For recent reviews on transition-metal-catalyzed [2 þ 2 þ 2]
cycloadditions, see: (a) Kotha, S.; Brahmachary, E.; Lahiri, K. Eur. J.
Org. Chem. 2005, 4741. (b) Gandon, V.; Aubert, C.; Malacria, M. Chem.
Commun. 2006, 2209. (c) Chopade, P. R.; Louie, J. Adv. Synth. Catal.
2006, 348, 2307.
(11) (a) Koga, Y.; Narasaka, K. Chem. Lett. 1999, 705. (b) Lee, S. I.;
Park, J. H.; Chung, Y. K.; Lee, S.-G. J. Am. Chem. Soc. 2004, 126, 2714.
(c) Jiao, L.; Lin, M.; Zhuo, L.-G.; Yu, Z.-X. Org. Lett. 2010, 12, 2528.
(d) Li, C.; Zhang, H.; Feng, J.; Zhang, Y.; Wang, J. Org. Lett. 2010, 12,
3082.
(12) Taber, D. F.;Guo, P.; Guo, N. J. Am. Chem. Soc. 2010, 132, 11179.
(13) Taber, D. F.; Sheth, R. B.; Tian, W. J. Org. Chem. 2009, 74, 2433.
(14) Li, Q.; Jiang, G.-J.; Jiao, L.; Yu, Z.-X. Org. Lett. 2010, 12, 1332.
(15) For other intramolecular [3 þ 2] cycloadditions employing VCP
as a three-carbon unit, see: (a) Jiao, L.; Ye, S.; Yu, Z.-X. J. Am. Chem.
Soc. 2008, 130, 7178. (b) Jiao, L.; Lin, M.; Yu, Z.-X. Chem. Commun.
2010, 46, 1059.
˚
found that the presence of 4 A molecular sieves (MS) was
essential to this reaction because the yield was much lower
Org. Lett., Vol. 14, No. 3, 2012
693

Table 1. Screening of the Reaction Conditionsa
Table 2. Scope of the [5 þ 1] Reaction
t
CO
yields
entry
catalystb
solventc (°C) (atm) additive (2b, 3b)d (%)
˚
1
2
3
4
5
6
7
8
9
[Rh(dppp)]SbF6 DCE
[Rh(CO)2Cl]2 DCE
85 0.2 4 A MS
41, 34
NRe
˚
85 0.2 4 A MS
[Rh(CO)2]SbF6 DCE
[Rh(dppm)]SbF6 DCE
[Rh(dppe)]SbF6 DCE
[Rh(dppb)]SbF6 DCE
[Rh(dppp)]SbF6 DCE
[Rh(dppp)]SbF6 DCE
[Rh(dppp)]SbF6 DCE
85 0.2 4 A MS
decf
˚
85 0.2 4 A MS
NRe
˚
˚
85 0.2 4 A MS
20, 15
19, 24
0, 44
decf
NRe
decf
˚
85 0.2 4 A MS
85 0.2 no
˚
95 0.2 4 A MS
˚
75 0.2 4 A MS
˚
10 [Rh(dppp)]SbF6 DCE
11 [Rh(dppp)]SbF6 DCE
12 [Rh(dppp)]OTf DCE
13 [Rh(dppp)]OTf DME
85
1
4 A MS
˚
85 0.1 4 A MS
27, 39
66, 12
16, 0
decf
˚
85 0.2 4 A MS
˚
85 0.2 4 A MS
˚
14 [Rh(dppp)]OTf dioxane 85 0.2 4 A MS
˚
15g [Rh(dppp)]SbF6 DCE
16h [Rh(dppp)]OTf DCE
85 0.2 4 A MS
0, 73
22, 2
˚
85 0.2 4 A MS
a Conditions: 10 mol % of Rh(I) catalyst, substrate concentration
0.05 M, 24 h. b dppp =1,3-bis(diphenylphosphino)propane, dppm =
bis(diphenylphosphino)methane, dppe =1,2-bis(diphenylphosphino)-
ethane, dppb =1,4-bis(diphenylphosphino)butane. c DCE = 1,2-di-
chloroethane, DME = 1,2-dimethoxyethane. d Isolated yield after column
chromatography. e No reaction occurred. f The substrate decomposed.
g After the reaction was finished, 1 equiv of DBU was added and the
mixture was stirred at room temperature for 1 h. h 5 mol % of Rh(I)
catalyst was used.
without this additive (entry 7). Screening of the reaction
temperature and the pressure of CO gave no better results
(entries 8ꢀ11). Notably, 1 atm of CO is not beneficial
to the [5 þ 1] reaction (entry 10). To our delight, using
AgOTf instead of AgSbF6 can improve the selectivity of
the β,γ-unsaturated product 2b (66% yield), together
with 12% of the R,β-unsaturated product 3b (entry 12).
When the solvent was changed to DME or dioxane, the
result became worse (entries 13 and 14). To obtain the
R,β-cyclohexenone exclusively, DBU (1,8-diazabicyclo-
[5.4.0]undec-7-ene) was added to the reaction system at
room temperature after the accomplishment of the [5 þ 1]
cycloaddition. After 1 h, only a single product 3b was
obtained in 73% yield through the isomerization proce-
dure (entry 15). If the catalyst loading was reduced to
5 mol %, the reaction yield decreased sharply (entry 16).
We selected two conditions as the optimal conditions to
explore the substrate scope of the [5 þ 1] reaction:
conditions A (using [Rh(dppp)]OTf as the catalyst to
obtain the β,γ-unsaturated product 2 as the major
product) and conditions B (using [Rh(dppp)]SbF6 (for
VCPs without substituents on the cyclopropyl rings) or
[Rh(dppp)]OTf (for VCPs with substituents on the cyclo-
propyl rings) as the catalyst, and then treating the [5 þ 1]
system with DBU to obtain the R,β-unsaturated product
3 exclusively. See the Supporting Information for a
a
˚
Conditions A: 10 mol % of [Rh(dppp)]OTf, 4 A MS (100 mg),
0.2 atm of CO, DCE as solvent (0.05 M), 85 °C, 24 h. Conditions B:
10 mol % of [Rh(dppp)]SbF6 (for VCPs without substituents on the
˚
cyclopropyl rings), 4 A MS (100 mg), 0.2 atm of CO, DCE as solvent
(0.05 M), 85 °C, 24 h; then DBU (1 equiv), rt, 1 h. DCE = 1,2-dichlo-
roethane. b Isolated yield after column chromatography. c Because of the
˚
instability of the product to DBU and the presence of 4 A MS, 5 equiv of
TsOH H2O was used instead of DBU, and the mixture reacted at rt for 2 h.
3
detailed discussion) (Tables 2 and 3). Besides the neutral
phenyl group, both electron-donating and electron-with-
drawing substituents can be tolerated in the cycloaddition
(entries 2, 3 and 5, Table 2). The more hindered substrates
1d and 1g also afforded the desired products in good
yields (entries 4 and 7). In addition, a heterocyclic aryl-
substituted substrate can also give a moderate yield (entry
6). Moreover, the R group could be alkyl substituents
(entries 1 and 8ꢀ10). The [5 þ 1] cycloaddition was not
affected even if there was an alkene substituent or an
acidic hydrogen in the substrates (entries 1 and 10). The
addition of DBU made the [5 þ 1] product of substrate 1j
decompose; therefore, TsOH H2O was used instead to
give a good yield of the isomerized product (entry 10).
3
694
Org. Lett., Vol. 14, No. 3, 2012

Table 3. Scope of the [5 þ 1] Reaction
Figure 1. Unsuccessful substrates for the [5 þ 1] reaction.
exclusively under conditions A, in moderate to good yields
(entries 1 and 2). At the same time, cis-2-benzyloxy-
methyl-VCP (1m) can also be subjected to the [5 þ 1]
reaction (entry 3). The benzyl protecting group in 1m can
be changed to a TBS (tert-butyldimethylsilyl) group, and
even unprotected alcohols can be tolerated in the cycload-
dition (entries 4ꢀ6). In the reactions of substrates 1mꢀo,
the cyclopropanes were cleaved on the less hindered
monosubstituted CꢀC bonds; therefore, only one kind
of [5 þ 1] cycloaddition product was observed. Compared
with substrate 1o, the [5 þ 1] reaction of its trans-isomer
1o0 gave two cyclopropane cleavage products 2o and 2o0
with a total yield higher than that in the reaction of 1o.
The reaction of the substrate 1p, which has a six-membered
ring fused with the VCP and has the vinyl group at the
bridgehead position, can also take place, affording
a functionalized nonconjugated 6/6-bicyclic compound
(entry 7). However, if the vinyl group is not at the bridge-
head position (1r and 1s, Figure 1), the formation of the
6/6-cycloadducts was not observed and the reasons for this
are not clear at this stage. We were pleased to find that for
substrates 1q and 1q0, which have a five-membered ring fused
with the VCP and have the vinyl group at the nonbridgehead
position, the expected [5 þ 1] reaction can happen via two
cyclopropane cleavage modes, giving two [5 þ 1] cycload-
ducts 2q and 2q0 (the skeleton of the natural products of
Taiwaniaquinoids16) in moderate yields (entries 8 and 9,
Table 3). Most β,γ-unsaturated products could isomerize to
the R,β-unsaturated ones quantitatively under reaction con-
ditions B, except for 2k and 2p (Table 3). To our disappoint-
ment, the β-substituted VCPs (for example, 1t,Figure1) were
not suitable substrates for this [5 þ 1] cycloaddition reaction.
In conclusion, we have developed a useful Rh(I)-
catalyzed [5 þ 1] cycloaddition of vinylcyclopropanes
(VCPs) and CO. This reaction provides a new strategy
forthe assemblyofsix-memberedcarbocycles. Application
of this reaction in synthesis is ongoing in our laboratory.
a
˚
Conditions A: 10 mol % of [Rh(dppp)]OTf, 4 A MS (100 mg),
0.2 atm of CO, DCE as solvent (0.05 M), 85 °C, 24 h. Conditions B:
10 mol % of [Rh(dppp)]OTf (for VCPs with substituents on the cyclo-
Acknowledgment. We thank the Natural Science Foun-
dation of China (20825205-National Science Fund for Dis-
tinguished Young Scholars) and the National Basic Research
Program of China-973 Program (2010CB833203) for finan-
cial support. Dr. Yuanyuan Zhu of Peking University is
appreciated for his preliminary exploration of this subject.
˚
propyl rings), 4 A MS (100 mg), 0.2 atm of CO, DCE as solvent (0.05 M),
85 °C, 24 h; then DBU (1 equiv), rt, 1 h. DCE = 1,2-dichloroethane.
b Isolated yield after column chromatography. c The β,γ-cyclohexenone 2
could not isomerize to R,β-cyclohexenone 3 after some attempts. d The
reaction time was 36 h. e 3% of 2l was also isolated. f 75 °C was used, and
the reaction time was 48 h. g The reaction time was 48 h. h 6% of 3q was
also isolated. i Because of the instability of the product to DBU, and the
˚
presence of 4 A MS, 5 equiv of TsOH H2O was used instead of DBU, and
3
the mixture reacted at 50 °C for 4 h.
Supporting Information Available. Experimental details.
This material is available free of charge via the Internet
at http://pubs.acs.org.
The substrates could have other different substitution
patterns (Table 3). Both 1-phenyl- and benzyloxymethyl-
VCP (1k, 1l) could afford the β,γ-unsaturated products
(16) Majetich, G.; Shimkus, J. M. J. Nat. Prod. 2010, 73, 284.
Org. Lett., Vol. 14, No. 3, 2012
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