Rh-catalyzed [7 + 1] cycloaddition of buta-1,3-dienylcyclopropanes and CO for the synthesis of cyclooctadienones

Article abstract of DOI:10.1021/ol102700m

Discovering new carbon building blocks is very significant to advance transition-metal-catalyzed cycloadditions for the synthesis of various-sized ring compounds. A new seven-carbon building block from buta-1,3- dienylcyclopropanes (BDCPs) has been developed, showing that, under the catalysis of [Rh(CO)₂Cl]₂, BDCPs react with CO to give [7 + 1] cycloaddition products, cyclooctadienones. The present [7 + 1] reaction provides an efficient entry to the synthetically challenging eight-membered carbocyclic skeleton, which is present in many natural products of medicinal and biological significance.

Full text of DOI:10.1021/ol102700m

ORGANIC
LETTERS
2011
Vol. 13, No. 1
134-137
Rh-Catalyzed [7 + 1] Cycloaddition of
Buta-1,3-dienylcyclopropanes and CO
for the Synthesis of Cyclooctadienones
Zhong-Ke Yao, Jianjun Li, and Zhi-Xiang Yu*
Beijing National Laboratory of Molecular Sciences (BNLMS) and Key Laboratory of
Bioorganic Chemistry and Molecular Engineering of Ministry of Education, College of
Chemistry and Molecular Engineering, Peking UniVersity, Beijing 100871, China
yuzx@pku.edu.cn
Received November 8, 2010
ABSTRACT
Discovering new carbon building blocks is very significant to advance transition-metal-catalyzed cycloadditions for the synthesis of various-
sized ring compounds. A new seven-carbon building block from buta-1,3-dienylcyclopropanes (BDCPs) has been developed, showing that,
under the catalysis of [Rh(CO)2Cl]2, BDCPs react with CO to give [7 + 1] cycloaddition products, cyclooctadienones. The present [7 + 1]
reaction provides an efficient entry to the synthetically challenging eight-membered carbocyclic skeleton, which is present in many natural
products of medicinal and biological significance.
Discovering and developing transition-metal-catalyzed [m +
n], [m + n + o], and [m + n + o + x] cycloadditions, where
the m, n, o, and x refer to various atom building blocks
ultimately incorporated in the final cycloadducts, is very
important in today’s science of synthesis.1 This is because
the newly discovered cycloadditions are expected to provide
new and efficient approaches and strategies to synthesize ring
compounds of various sizes, which are building blocks and/
or skeletons of natural products, drugs, materials, etc.2 Today
many scientists are endeavoring to discover and develop new
transition-metal-catalyzed cycloadditions by designing and
screening various combinations of transition metals and the
existing atom building blocks. To further advance this
research field, it is very significant to discover new building
blocks that can be used in cycloadditions. If a new building
block is found, it could have various combinations with the
known building blocks and transition metals to reach ring
compounds of various sizes and substitutions.
Today many carbon building blocks from one to six
(referred to as the Cx building blocks, x ) 1, 2, 3, 4, 5, 6)
have been discovered and used in transition-metal-catalyzed
cycloadditions. However, discovering a seven-carbon build-
ing block (C7) and larger carbon building blocks is still a
formidable challenge.3 We regard the discovery and develop-
ment of such large building blocks as significant toward the
synthesis of medium- and large-sized ring compounds, which
can be only reached by a limited number of reactions today.
Here we report for the first time a rhodium-catalyzed [7 +
(1) (a) Lautens, M.; Klute, W.; Tam, W. Chem. ReV. 1996, 96, 49. (b)
Yet, L. Chem. ReV. 2000, 100, 2963. (c) Murakami, M. Angew. Chem., Int.
Ed. 2003, 42, 718. (d) Nakamura, I.; Yamamoto, Y. Chem. ReV. 2004, 104,
2127. (e) Butenscho¨n, H. Angew. Chem., Int. Ed. 2008, 47, 5287. (f) Yu,
Z.-X.; Wang, Y.; Wang, Y. Chem.sAsia J. 2010, 5, 1072. (g) Inglesby,
P. A.; Evans, P. A. Chem. Soc. ReV. 2010, 39, 2791.
(3) The only known building block larger than a C6 building block, to
the best of our knowledge, is a C7 building block of divinyl cyclopropane,
which undergoes a [7 + 1] cycloaddition with CO of Fe(CO)5 and a [7 +
2] cycloaddition with tetracyanoethene. However, this [7 + 1] cycloaddition
requires excess Fe(CO)5 (3 equiv) and light irradiation. See: (a) Sarel, S.;
Langbeheim, M. J. Chem. Soc., Chem. Commun. 1977, 593. (b) Sarel, S.;
Langbeheim, M. J. Chem. Soc., Chem. Commun. 1977, 827.
(2) (a) Nicolaou, K. C.; Vourloumis, D.; Wissinger, N.; Baran, P. S.
Angew. Chem., Int. Ed. 2000, 39, 44. (b) Maimone, T. J.; Baran, P. S. Nat.
Chem. Biol. 2007, 3, 396. (c) Wender, P. A.; Miller, B. L. Nature 2009,
460, 197.
10.1021/ol102700m  2011 American Chemical Society
Published on Web 11/24/2010

1] cycloaddition of buta-1,3-dienylcyclopropanes (BDCPs)
and CO for the synthesis of cyclooctadienones, where BDCPs
act as a C7 building block. This new [7 + 1] reaction
complements the known transition-metal-catalyzed cycload-
ditions4,5 to the synthetically challenging eight-membered
carbocyclic skeleton, which is present in many natural
products of medicinal and biological significance.6 Of the
same importance, the discovery of this new C7 building block
expands the existing set of building blocks and would create
opportunities to develop other transition-metal-catalyzed [7
+ x], [7 + x + y] cycloadditions.
Scheme 1. Previous [1,3]-Shift and Our Proposed [7 + 1]
Reaction of Buta-1,3-dienylcyclopropanes
BDCPs usually undergo [1,3]-shift reactions to give
3-vinyl-cyclopentene derivatives, either by the catalysis of
transition metals7a,b or flash vacuum pyrolysis, as the vinyl
cyclopropanes do (Scheme 1a).7c We reasoned that, under
the catalysis of Rh complex, BDCP could become a C7
building block and take part in [7 + 1] cycloaddition with
CO (Scheme 1b). In the presence of a Rh complex, BDCP
could form an η4-complex A with Rh. Then cyclopropane
cleavage gives intermediate B or C. Reductive elimination
from B to give a seven-membered carbocyclic product is
expected to be difficult since this step involves the formation
of a C(sp3)-C(sp3) bond.8 However, once CO is present,
through coordination and insertion processes, complex D or
E will be generated. Finally a migratory reductive elimination
from D or E to generate a C(sp2)-C(sp3) bond is much easier
than the reductive elimination step from B, leading to the [7
+ 1] cycloadduct F.9
and Ar (CO/Ar ) 1:9 V/V)) to 10 mol % catalyst of
[Rh(CO)2Cl]2 in dioxane.10 To our delight, this reaction really
gave the [7 + 1] cycloadduct 2a with a reaction yield of
22% (Table 1, entry 1). 2a is a conjugated cyclooctadienone11
and is probably generated from a nonconjugated cycloocta-
dienone, 3a, which is the expected [7 + 1] cycloadduct
according to the proposed mechanism shown in Scheme 1b.
This hypothesis was proved to be true by the following
experiments. First, when the partial pressure of CO was
increased to 0.5 atm, both 2a and 3a were obtained with 3a
as the minor product (Table 1, entry 2). Second, 3a can be
isomerized to 2a under the catalysis of [Rh(CO)2Cl]2 in
dioxane (Scheme 2).
To improve the [7 + 1] reaction yield, we further screened
the reaction conditions. When the CO pressure was 1.0 atm,
the [7 + 1] reaction yield was 74% with a conversion of
81% (entry 3). Further increasing the CO pressure did not
improve the reaction yield. For example, the [7 + 1] reaction
yield decreased to 57% and 45% when CO pressure was
2.0 and 4.0 atm, respectively (entries 4 and 5, Table 1).
Reducing the load of catalyst resulted in low yield (entry
6). The best solvent for the present [7 + 1] reaction is
dioxane since reactions carried out in DCE and toluene gave
lower yields (entries 7 and 8). In all cases, conjugated
cycloocta-2,4-dienone 2a is the main product, accompanied
by the minor product 3a.
We started our test of the proposed [7 + 1] reaction by
subjecting 1a and CO (balloon pressured mixed gas of CO
(4) For Rh-catalyzed cycloadditions to eight-membered rings, see: (a)
Wender, P. A.; Correa, A. G.; Sato, Y.; Sun, R. J. Am. Chem. Soc. 2000,
122, 7815. (b) Wender, P. A.; Gamber, G. G.; Hubbard, R. D.; Zhang, L.
J. Am. Chem. Soc. 2002, 124, 2876. (c) Evans, P. A.; Robinson, J. E.; Baum,
E. W.; Fazal, A. N. J. Am. Chem. Soc. 2002, 124, 8782. (d) Gilbertson,
S. R.; DeBoef, B. J. Am. Chem. Soc. 2002, 124, 8784. (e) Evans, P. A.;
Baum, E. W. N. J. Am. Chem. Soc. 2004, 126, 11150. (f) Hermann, A. W.;
de Merjere, A.; Wender, P. A. J. Am. Chem. Soc. 2005, 127, 6530. (g)
Evans, P. A.; Baum, E. W.; Fazal, A. N.; Pink, M. Chem. Commun. 2005,
63. (h) Wender, P. A.; Christy, J. P. J. Am. Chem. Soc. 2006, 128, 5354.
(i) Wang, Y.; Wang, J.; Su, J.; Huang, F.; Jiao, L.; Liang, Y.; Yang, D.;
Zhang, S.; Wender, P. A.; Yu, Z.-X. J. Am. Chem. Soc. 2007, 129, 10060.
(j) DeBoef, B.; Counts, W. R.; Gilbertson, S. R. J. Org. Chem. 2007, 72,
799. (k) Huang, F.; Yao, Z.-K.; Wang, Y.; Wang, Y.; Zhang, J.; Yu, Z.-X.
Chem.sAsian J. 2010, 5, 1555
.
(5) For recent other transition metal-catalyzed cycloadditions to eight-
membered rings, see: (a) Wender, P. A.; Ihle, N. J. Am. Chem. Soc. 1986,
108, 4678. (b) Wender, P. A.; Snapper, M. L. Tetrahedron Lett. 1987, 28,
2221. (c) Rigby, J. H.; Kirova-Snover, M. Tetrahedron Lett. 1997, 38, 8153.
(d) Varela, J. A.; Castedo, L.; Saa, C. Org. Lett. 2003, 5, 2841. (e) Achard,
M.; Tenaglia, A.; Buono, G. Org. Lett. 2005, 7, 2353. (f) Murakami, M.;
Ashida, S.; Matsuda, T. J. Am. Chem. Soc. 2006, 128, 2166. (g) Wender,
P. A.; Christy, J. P. J. Am. Chem. Soc. 2007, 129, 13402. (h) Tenaglia, A.;
Gaillard, S. Angew. Chem., Int. Ed. 2008, 47, 2454. (i) Hilt, G.; Paul, A.;
Hengst, C. Synthesis 2009, 3305. (j) For other reactions, see citations in
ref 1f.
Substrate 1a, which is a mixture of the Z (1a-Z) and E
(1a-E) isomers, could not be consumed in all of the
(6) (a) Faulkner, D. J. Nat. Prod. Rep. 1988, 5, 613. (b) Daum, R. S.;
Kar, S.; Kirkpatrick, P. Nat. ReV. Drug DiscoVery 2007, 6, 865. (c) Kingston,
D. G. I. J. Org. Chem. 2008, 73, 3975.
(7) (a) Murakami, M.; Nishida, S. Chem. Lett. 1979, 927. (b) Morizawa,
Y.; Oshima, K.; Nozaki, H. Tetrahedron Lett. 1982, 23, 2871. (c) See a
recent review about the chemistry of vinylcyclopropane to cyclopentene
chemistry :Hudlicky, T.; Reed, J. W. Angew. Chem., Int. Ed. 2010, 49,
4864.
(10) Low pressure of CO was found to be beneficial for some
[Rh(CO)2Cl]2-catalyzed cycloadditions such as [(5 + 2) + 1], [(3 + 2) +
1], and [(2 + 2) + 1] cycloadditions. See: (a) Kobayashi, T.; Koga, Y.;
Narasaka, K. J. Organomet. Chem. 2001, 624, 73. (b) Jiao, L.; Lin, M.;
Zhuo, L.-G.; Yu, Z.-X. Org. Lett. 2010, 12, 2528. (c) See refs 4i
and 4k.
(8) (a) Yu, Z.-X.; Wender, P. A.; Houk, K. N. J. Am. Chem. Soc. 2004,
126, 9154. (b) Yu, Z.-X.; Cheong, P. H.-Y.; Liu, P.; Legault, C. Y.; Wender,
P. A.; Houk, K. N. J. Am. Chem. Soc. 2008, 130, 2378.
1
(11) The structure of 2a was identified by H and 13C NMR of 2a and
(9) Similar intermediates were involved in [6 + 2], [5 + 2 + 1] reactions;
see refs 4a,i, and k.
confirmed by the crystallographic data of the hydrazone derivative of 2a
(see the Supporting Information).
Org. Lett., Vol. 13, No. 1, 2011
135

Table 1. Screening of the [7 + 1] Reaction Conditionsa
Table 3. Scope of the [7 + 1] Reactiona
entry CO(atm) solvent time(h) convn(%)b yield (%)c(2a:3a)
1
2
3
4
0.1d
0.5f
1.0
2.0
4.0
1.0
1.0
1.0
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
DCE
48
48
48
48
48
60
56
48
80
80
81
83
78
81
64
80
22 (-)e
35 (13:1)
74 (6:1)
57 (10:1)
45 (2:1)
32 (-)e
5
6g
7h
8
33 (3:1)
60 (6:1)
Toluene
a General conditions: 1a (0.2 mmol), [Rh(CO)2Cl]2 (10 mol %), solvent
(4 mL), 90 °C. b Based on recovered starting material. c Combined isolated
yield. d Balloon pressured mixed gas of CO and Ar (1:9, V/V). e Only 2a
was isolated. f Balloon pressured mixed gas of CO and Ar (1:1, V/V).
g Reaction run with 5 mol % [Rh(CO)2Cl]2. h Reaction run at 80 °C.
Scheme 2. Rhodium-Catalyzed Isomerizations of
Cycloocta-3,5-dienones to Cycloocta-2,4-dienones
described reaction conditions shown in Table 1. To
understand the reasons behind this, we studied the
Table 2. Reactivity Comparison of Z and E Isomers of BDCPa
a General conditions: 1 (0.2 mmol), [Rh(CO)2Cl]2 (10 mol %), solvent
(4 mL). b Based on recovered starting material. c Combined isolated yield.
d Isomerization was shown in Scheme 2. e Only 2j was isolated.
yield
entry substrate time(h) temp(°C) convn(%)b (%)c(2a:3a)
1
2
3
4
1a-Z
1a-Z
1a-Z
1a-E
70
70
58
58
60
80
95
95
32
20 (1:2)
58 (3:1)
62 (11:1)
38 (7:1)
66d
individual reactions of the pure Z (1a-Z) and E (1a-E)
isomers of 1a (Table 2). It was found that both isomers
could undergo [7 + 1] cycloaddition, but with different
reactivities. The Z isomer gave products in yield of 20%
at 60 °C, with a conversion of 32% (68% of the starting
1a-Z was recovered) (entry 1). By increasing the reaction
100
41
a General conditions: 1a-Z or 1a-E (0.2 mmol), [Rh(CO)2Cl]2 (10 mol
%), dioxane (4 mL). b Based on recovered starting material. c Combined
isolated yield. d 30% of E isomer (1a-E) was isolated.
136
Org. Lett., Vol. 13, No. 1, 2011

temperature to 80 °C, the Z isomer gave a reaction yield
of 58% with a conversion of 66% (entry 2). Notably, the
E isomer, 1a-E, was obtained in 30% in this case,
indicating that the Z isomer can isomerize to its E isomer
at this relatively high temperature (e.g., 80 °C). By a
further increase in the reaction temperature to 95 °C, the
Z isomer could be consumed in 58 h, with a yield of 62%
(entry 3). Unlike the Z isomer, the E isomer behaved more
sluggishly in the [7 + 1] cycloaddition: even at 95 °C, it
gave cycloadducts in yield of 38%, with a conversion of
only 41% (entry 4). About 59% of 1a-E was recovered in
this reaction, suggesting that 1a-E is much more stable
than 1a-Z in the present reaction system. To summarize,
data in Table 2 demonstrate that both E and Z isomers of
BDCPs can take part in the [7 + 1] reaction, but BDCP
with the cyclopropyl and terminal alkene in a trans
configuration (1a-Z) is more reactive than BDCP with the
cyclopropyl and terminal alkene in a cis configuration (1a-
E) in the [7 + 1] cycloaddition. The reasons behind these
differences are the subject of future mechanistic investiga-
tion.
Scheme 3. Unexpected Reactions of BDCPs and CO
Scheme 4. Unsuccessful Substrates for the [7 + 1] Reaction
With the new discovered reaction in hand, we further
studied the scope of this [7 + 1] reaction. It was found that
BDCPs with various substituents could undergo the [7 + 1]
cycloaddition to give eight-membered carbocycles in moder-
ate to good yields (Table 3, entries 1-9). The substituents
could be electron-neutral aryl (entries 2, 4, and 7), electron-
rich aryl (entries 1 and 5), electron-poor aryl (entry 3),
heterocyclic aryl (entry 6), and alkyl (entries 8 and 9) groups.
Electron-rich and -neutral substituents gave good reaction
yields (entries 1, 2, 4, and 7-9). Electron-poor and hetero-
cyclic aryl substituents gave moderate reaction yields (entries
3 and 6). BDCP with a trisubstituted diene moiety could also
undergo [7 + 1] cycloaddition smoothly and gave a moderate
yield (entry 5). A methyl substituent gave a low yield of
12% (entry 10). When R2 ) H in 1, no [7 + 1] cycloadducts
but cyclohex-3-enone derivatives 4k and 4l were obtained
in yields of 66% and 69%, respectively (Scheme 3). The
proposed mechanism of the formation of 4k and 4l was given
in the Supporting Information.
Unfortunately, an aryl substitution (Scheme 4, 1m) or a
fused six-membered ring (1p and 1q) on the cyclopropane
totally retarded the target [7 + 1] reactions. Alkynyl substrate
1n or enolate 1o could not undergo the [7 + 1] reactions
either. In all these unsuccessful cases, only starting materials
were recovered under the standard reaction conditions.
In summary, we have shown, for the first time, a
Rh-catalyzed [7 + 1] cycloaddition of BDCPs and CO. This
reaction provides a new strategy for the assembly of eight-
membered carbocycles. This is the first report of BDCPs
acting as a C7 building block and is expected to bring
opportunities to develop other transition-metal-catalyzed
cycloadditions. Further work to study the scope and detailed
reaction mechanism of this [7 + 1] reaction and explore this
C7 building block in transition-metal-catalyzed cycloadditions
is underway.
Acknowledgment. We are indebted to the generous
financial support from the National Natural Science Founda-
tion of China (20825205-National Science Fund for Distin-
guished Young Scholars, 20772007, 20672005) and the
Ministry of Science and Technology (2011CB808603 and
2010CB833203-National Basic Research Programs of China,
973 Programs). We also thank Mr. Meng Dou of Peking
University for experimental assistance.
Supporting Information Available: Detailed experimen-
tal procedures and characterization data of compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL102700M
Org. Lett., Vol. 13, No. 1, 2011
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