Csp3-Csp3 and C sp3-H bond activation of 1,1-disubstituted cyclopentane

Article abstract of DOI:10.1021/ja309830p

The unprecedented C_sp³-C_sp³ bond cleavage of unactivated cyclopentane has been achieved. Rh ^I-catalyzed cycloaddition of allenylcyclopentane-alkynes produced in situ the 9-cyclopentyl-8-rhodabicyclo[4.3.0]nona-1,6-diene intermediates, which subsequently underwent [7+2] cycloaddition via β-C elimination, affording bicyclo[7.4.0]tridecatriene derivatives in good yields. Changing the Rh ^I catalyst effected the Cγ-H bond activation of the common 9-cyclopentyl-8-rhodabicyclo[4.3.0]nona-1,6-diene intermediate to produce the novel spiro[2.4]heptane skeleton in a site-selective manner.

Full text of DOI:10.1021/ja309830p

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Communication
Csp3-Csp3 and Csp3-H Bond Activation of 1,1-Disubstituted Cyclopentane
Chisato Mukai, Yuu Ohta, Yuki Oura, Yasuaki Kawaguchi, and Fuyuhiko Inagaki
J. Am. Chem. Soc., Just Accepted Manuscript • Publication Date (Web): 12 Nov 2012
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Journal of the American Chemical Society
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Csp3-Csp3 and Csp3-H Bond Activation of 1,1-Disubstituted
Cyclopentane
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Chisato Mukai,* Yuu Ohta, Yuki Oura, Yasuaki Kawaguchi and Fuyuhiko Inagaki
Division of Pharmaceutical Sciences, Graduate School of Medical Sciences, Kanazawa University, Kakuma-machi,
Kanazawa 920-1192 (Japan)
clobutanes as it does with vinylcyclobutanones. The
smaller strain energy of cyclobutane (26.3 kcal/mol)11
might reflect the lower reactivity of the cyclobutanes
compared to the cyclopropanes. We have recently dis-
closed that the RhI-catalyzed cycloaddition of the allenyl-
ABSTRACT: The unprecedented Csp3-Csp3 bond cleavage
of the unactivated cyclopentane has been achieved. The
RhI-catalyzed cycloaddition of allenylcyclopentane-
alkynes produced in situ the 9-cyclopentyl-8-
rhodabicyclo[4.3.0]nona-1,6-diene intermediates, which
were subsequently susceptible to the [7+2] cycloaddition
cyclopropane-alkynes
1
(n=1) afforded the bicy-
clo[5.4.0]undecatrienes 2 (n=1)12a in the [5+2] ring-closing
manner. A similar conversion was realized when the al-
lenylcyclobutane-alkynes 1 (n=2) were exposed to the RhI
catalyst producing the corresponding eight-membered
bicyclic compounds 2 (n=2)12b in high yields (Scheme 1). It
is noteworthy that the simplest unactivated cyclobutanes
were unexpectedly and smoothly incorporated into the
eight-membered carbocycles. The production of 2 (n=2)
would tentatively be rationalized by the initial formation
of the rhodabicyclo[4.3.0] intermediate 3, followed by the
β-carbon elimination,6 which should release the strain
energy (26.3 kcal/mol) of the cyclobutane11 giving rise to
the nine-membered rhodabicyclic species 4. The reduc-
tive elimination of 4 would then provide the final prod-
ucts. Since the strain energies of the normal-sized cyclo-
alkanes, namely cyclopentane and cyclohexane, are too
low (6.3 kcal/mol and approximately 0 kcal/mol, respec-
tively)11 compared to those of the small-sized ones, utiliza-
tion of the former as acyclic C5- and C6-building blocks
have never been recorded to date. This study describes
the preliminary results about the unprecedented incorpo-
ration of cyclopentane into nine-membered carbocycles
via carbon-carbon bond activation by the β-carbon elimi-
nation6 of the rhodabicyclo[4.3.0]nonadiene intermedi-
ates during the RhI-catalyzed cycloaddition of allenylcy-
clopentane-alkyne substrates.
via
β-carbon
elimination
affording
the
bicy-
clo[7.4.0]tridecatriene derivatives in good yields. Chang-
ing the RhI catalyst effected the Cγ-H bond activation of
the common 9-cyclopentyl-8-rhodabicyclo[4.3.0]nona-
1,6-diene intermediate to produce the novel spi-
ro[2.4]heptane skeleton in a site-selective manner.
Small-sized cycloalkanes are often of significant use
from synthetic points of view.1 In particular, highly-
strained cyclopropane derivatives have been well recog-
nized as useful and powerful acyclic C3-buliding blocks for
the transition metal catalyzed ring-forming reaction lead-
ing to various ring systems. The relief of the high strain
energy (27.5 kcal/mol) of cyclopropanes2 is thought to
facilitate the Csp3-Csp3 bond cleavage and make them a
significantly important C3-unit. The intramolecular RhI-
catalyzed [5+2] cycloaddtion of vinylcyclopropanes3,4 with
carbon-carbon π components, for example, efficiently
produced the corresponding bicyclo[5.3.0] frameworks in
which the terminal unactivated cyclopropane was incor-
porated into the seven-membered carbocycles. In sharp
contrast to the ring opening of cyclopropanes, the one-
carbon homologated cyclobutanes5 require an activating
functional group directly attached to the four-membered
ring for their ring opening.6 Thus, the functionalized cy-
clobutanes, for instance, such as cyclobutanone,5,7 hy-
droxycyclobutane,8 an alkylidenecyclobutane unit,9 or
spiro[3.3]heptenone10a and heptanone10b units have been
used, whereas the simplest cyclobutane without any other
functional groups on its ring has been hardly employed as
an acyclic C4-building block for the transition metal cata-
lyzed ring-forming reaction.6 In fact, Wender7a reported
the efficient transformation of vinylcyclobutanone-alkene
or -allene substrates into the corresponding bicyclo[6.3.0]
compounds via the RhI-catalyzed [6+2] cycloaddtion and
pointed out that this reaction does not work with vinylcy-
Our initial attempt was performed using the allenylcy-
clopentane 5a possessing a phenysulfonyl group on the
allenyl moiety for screening the reaction conditions.
Treatment of 5a with 10 mol% [RhCl(CO)2]2, which was
effective for the ring opening of the allenylcyclopropane 1
(n=1),12a in refluxing xylene for 0.2 h surprisingly produced
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Page 2 of 9
the desired bicyclo[7.4.0]tridecatriene 6a in 30% yield. In transformation. Thus, the ring-closing reaction of the
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addition, the novel spiro[2.4]heptane derivative 7a was
isolated in 38% yield (Table 1, entry 1). [RhCl(CO)dppp]2,
another effective catalyst for 1 (n=1),12a afforded a similar
result [6a (29%) and 7a (45%)](entry 2). RhCl(dppp)2 was
the most suitable catalyst for the ring opening of the al-
lenylcyclobutane 1 (n=2).12b Thus, exposure of 5a to 10
mol% RhCl(dppp)2 resulted in the increased production
of 7a in 52% yield along with 6a in 39% yield (entry 3).
Several other catalysts, such as RhCl(PPh3)3, [RhCl(cod)]2,
phosphonate derivative 5i proceeded well to produce 6i in
69% yield (entry 8). Furthermore, the ring-closing reac-
tion of allenylcyclopentanes having alkyl substituent such
as butyl (5j), isopropyl (5k), tert-butyl (5l) and benzyl
group (5m) on the allenyl moiety also produced the cor-
responding bicyclo[7.4.0] products 6j (71%), 6k (73%), 6l
(75%) and 6m (58%), respectively (entries 9~12). In addi-
tion, the phenyl derivative 5n was found to furnish the
desired product 6n in 62% yield (entry 13). The allenylcy-
clopentane derivative 5o possessing a butyl substituent
(R2=nBu) at the allenic position instead of a methyl group
required a longer reaction time (3 h) and the yield of 6o
decreased (47%)(entry 14). In addition, the benzyloxyme-
thyl congener 5p (R2=CH2OBn) required more drastic
conditions (heated at reflux in xylene for 20 h) to com-
plete consumption of the starting material and the bicy-
clic compound 6p was obtained in a rather low yield
(40%)(entry 15).
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[RhCl(cod)]2/P(C6F5)3,
[RhCl(cod)]2/P(Cy)3,
and
[RhCl(cod)]2/rac-BINAP with or without a silver salt were
examined, but most of them furnished poor results except
for RhCl(PPh3)3. Indeed 5a was treated with 10 mol%
RhCl(PPh3)3 in xylene for 0.2 h to produce 6a in an im-
proved yield (73%) together with 7a in 16% yield (entry 4).
A milder condition (heating at 80 °C in toluene for 0.5 h)
furnished the similar result (6a: 72%)(entry 5). 1,2-
Dichloroethane (DCE) and 1,4-dioxane, both of which
were frequently employed in the rhodium-catalyzed reac-
tion, were examined instead of toluene, but no significant
improvement could be observed.
The best condition [10 mol% RhCl(PPh3)3 in toluene at
80 °C] was applied to several allenylcyclopentanes (Table
2). We first examined the ring-closing reaction of sub-
strates 5b-f having a gem-disubstituent effect.13 Treatment
of the bis(phenylsulfonyl) derivative 5b with RhCl(PPh3)3
afforded the desired bicyclo[7.4.0] product 6b in 85%
yield as the only isolated product (entry 1). The bis(MOM)
compound 5c also produced the corresponding bicyclic
compound 6c in 85% yield (entry 2). A similar result (6d:
78%) was obtained when the cyclic acetal derivative 5d
was exposed to the standard conditions (entry 3). The free
dihydroxyl compound 5e could be converted into the bi-
cyclic nine-membered one 6e in 51% yield (entry 4). Alt-
hough a higher reaction temperature (xylene reflux) was
needed, the bis(p-nitrobenzoyloxymethyl) compound 5f
gave 6f in 53% (entry 5). An X-ray analysis of 6f unambig-
We have isolated the novel spiro[2.4]heptane derivative
7a from the RhI-catalyzed cycloaddition of 5a (Table 1). In
particular, 7a was obtained in 52% yield as a major prod-
uct when treated with RhCl(dppp)2. In order to improve
the chemical yield of 7a, we reinvestigated this reaction
and found that a higher reaction temperature (heated at
reflux in toluene) is enough to obtain 7a in a satisfactory
yield. Indeed, 7a was obtained in 81% yield along with 6a
in 5% yield (Table 3, entry 1). Several other allenylcyclo-
uously established its structure having
a
bicy-
clo[7.4.0]tridecatriene skeleton (see SI for details). The
simple carbon tether analogue 5g without the gem-
disubstituent effect also provided the bicyclic derivative
6g in 53% yield (entry 6). The nitrogen congener 5h pro-
duced the corresponding aza-compound 6h in 60% yield
(entry 7). It was shown that having a phenylsulfonyl sub-
stituent on the allenyl moiety was not essential for this
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Journal of the American Chemical Society
tives 7 from the common rhodabicyclo[4.3.0] intermedi-
pentane-alkynes were examined to ascertain the generali-
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ty of the formation of the spiro[2.4]heptane skeleton. Up-
on exposure to the standard conditions, 5e having two
free hydroxyl groups smoothly underwent the ring-
closing reaction to produce 7e14 in 78% (entry 2). The
bis(p-nitrobenzoyloxymethyl) derivative 5f was heated at
reflux in toluene in the presence of RhCl(dppp)2 for 1 h to
afford the spiro[2.4]heptane 7f in 76% yield along with 6f
in 5% yield (entry 3). The bis(p-chlorobenzoyloxymethyl)
compound 5q provided 7q in 60% yield as the sole isolat-
ed product (entry 4). The nitrogen containing substrate
5h under similar conditions produced 7h in a lower yield
(50%)(entry 5). The site-selective Cγ-H bond activation of
the methyl group rather than the methylene moiety of the
cyclopentane framework led to the exclusive formation of
7 instead of 7’, although the reasonable explanation is still
uncertain. Thus, it may be concluded that transformation
ate B could be tentatively considered as follows. The Cγ-
H17 bond of B would be activated with the aid of RhIII
when the C-H bond of methyl group is placed on the
same plane as that of the C-RhIII bond (B’) (Scheme 2). A
type of σ-bond metathesis17,18 would then occur between
the activated C-H bond and C-RhIII bonds ending up with
the formation of the three-membered intermediate D,
which should collapse to the final product 7. Finally, the
experiment with the deuterated substrate 10 was per-
formed in order to obtain some information on the mech-
anism for the formation of 7 (Scheme 4). A solution of 10
in toluene in the presence of a catalytic amount of
RhCl(dppp)2 was heated at reflux for 1 h to afford the spi-
ro[2.4]heptane derivative 11 and the nine-membered
compound 12 in 63% and 11% yields, respectively. It be-
came apparent that deuterium was exclusively incorpo-
rated at the allylic position (on the cyclopropane ring) of
11. This result might support the mechanism depicted in
Scheme 2.
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of the allenylcyclopentane-alkynes
5 into the spi-
ro[2.4]heptane derivatives 7 consistently occurred when
treated with RhCl(dppp)2.
The production of the [7+2] product 6 is tentatively ra-
tionalized based on the proposed mechanism for the ring
cleavage of the allenylcyclobutane.12b The initial coordina-
tion of 5 with RhI would occur between an allenic distal
double bond and an alkyne to form the intermediate A,
which should immediately collapse to the rhodabicy-
clo[4.3.0] intermediate B via the oxidative ring-closing
reaction (Scheme 2). This intermediate B would undergo
a β-carbon elimination6 presumably assisted by release of
the ring strain of the cyclopentane (6.3 kcal/mol)11 result-
ing in the formation of the ten-membered bicyclic
rhodacycle C. The subsequent reductive elimination pro-
cess of C would give the final product 6. The intermediacy
of rhodabicyclo[4.3.0] intermediate B would be strongly
supported by the following experimental result. Upon
exposure to the standard conditions, the substrate 8 hav-
ing a hydrogen at the allenic position afforded the mono-
cyclic product 9 in 86% yield (Scheme 3). The formation
of 9 could be well rationalized in terms of the β-hydride
elimination15 of the intermediate E, which has possessed
the common rhodabicyclo[4.3.0] intermediate of B. Dur-
ing our program ongoing, Oonishi and Sato16 have very
recently reported the similar cyclopropanation of al-
lenynes having tert-butyl group at the allenic terminus.
Based on their proposed mechanism, the plausible mech-
anism for the production of the spiro[2.4]heptane deriva-
In summary, we have succeeded in the unprecedented
carbon-carbon bond cleavage of the simple unactivated
cyclopentane ring. The in situ generated 8-
rhodabicyclo[4.3.0]nona-1,6-diene intermediate having a
cyclopentane at the C9-position underwent the [7+2] cy-
cloaddition through Cβ-Cγ bond cleavage (β-carbon elim-
ination) to produce the bicyclo[7.4.0]tridecatiene deriva-
tives in good yields. In addition, by changing the rhodium
catalyst, the same 8-rhodabicyclo[4.3.0]nona-1,6-diene
intermediate produced the novel spiro[2.4]heptane skele-
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Matsuda, T. J. Am. Chem. Soc. 2005, 127, 6932-6933. (g) Matsuda,
ton via a Cγ-H bond activation process in a site-selective
manner. These results should provide new insights into
the chemistry of Csp3-Csp3 as well as Csp3-H bond19 activa-
tion. Further studies regarding these two novel aspects,
the carbon-carbon and carbon-hydrogen bond activa-
tions, are currently in progress.
1
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5
6
7
T.; Makino, M.; Murakami, M. Angew. Chem. Int. Ed. 2005, 44,
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ASSOCIATED CONTENT
8
9
(7) (a) Wender, P. A.; Correa, A. G.; Sato, Y.; Sun, R. J. Am.
Chem. Soc. 2000, 122, 7815-7816. (b) Murakami, M.; Ashida, S.;
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Ishida, N.; Murakami, M. Angew. Chem. Int. Ed. 2012, 51, 2485-
2488, and references cited therein.
(8) (a) Wender, P. A.; Deschamps, N. M.; Sun, R. Angew.
Chem. Int. Ed. 2006, 45, 3957-3960. (b) Trost, B. M.; Xie, J. J. Am.
Chem. Soc. 2008, 130, 6231-6242. (c) Seiser, T.; Cramer, N. Angew.
Chem. Int. Ed. 2008, 47, 9294-9297. (d) Ishida, N.; Sawano, S.;
Murakami, M. Chem. Commun. 2012, 48, 1973-1975. and refer-
ences cited therein.
(9) Crépin, D.; Dawick, J.; Aïssa, C. Angew. Chem. Int. Ed.
2010, 49, 620-623.
(10) (a) Huffman, M. A.; Liebeskind, L. S. J. Am. Chem. Soc.
1993, 115, 4895-4896. (b) Murakami, M.; Takahashi, K.; Amii, H.;
Ito, Y. J. Am. Chem. Soc. 1997, 119, 9307-9308.
Experimental procedures and compound characteriza-
tion data (PDF) and X-ray data (CIF). This material is
available free of charge via the Internet at
http://pubs.acs.org.
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AUTHOR INFORMATION
Corresponding Author
mukai@p.kanazawa-u.ac.jp
ACKNOWLEDGMENT
This work was supported in part by a Grant-in Aid for
Scientific Research from the Ministry of Education,
Culture, Sports, Science and Technology, Japan, for
which we are thankful.
(11) Kaarsemaker, S.; Coops, J. Recl. Trav. Chim. Pays-Bas, 1952,
71, 261-276.
(12) (a) Inagaki, F.; Sugikubo, K.; Miyashita, Y.; Mukai, C. An-
gew. Chem. Int. Ed. 2010, 49, 2206-2210. (b) Inagaki, F.; Sugikubo,
K.; Oura, Y.; Mukai, C. Chem. Eur. J. 2011, 17, 9062-9065.
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(14) The spiro structure of 7 was unambiguously established
by an X-ray analysis of the bis(indol-2-ylcarbonyloxymethyl)
derivative 7r, which was derived from 7e under the standard
esterification conditions (details were described in SI).
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Chem. Soc. 2002, 124, 13976-13977. (f) Murakami, M.; Ashida, S.;
(17) Cγ-H abstraction by metal atom, for example, see: Itazaki,
M.; Yoda, C.; Nishihara, Y.; Osakada, K. Organometallics 2004,
23, 5402-5409.
(18) Cγ-H activation, followed by the formation of cyclopro-
pane, for example, see: Mallien, M.; Haupt, E. T. K.; tom Dieck,
H. Angew. Chem. Int. Ed. 1988, 27, 1062-1064.
(19) (a) Ye, L.; Wang, Y.; Aue, D. H.; Zhang, L. J. Am. Chem.
Soc. 2012, 134, 31-34. (b) Hashmi, A. S. K.; Braun, I.; Nösel, P.;
Schädlich, J.; Wieteck, M.; Rudolph, M.; Rominger, F. Angew.
Chem. Int. Ed. 2012, 51, 4456-4460.
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Table of Contents
5
6
7
Me
R'
H
C-C bond
activation
C-H bond
activation
R'
8
9
RhCl(PPh3)3
RhCl(dppp)2
X
R
10
11
12
13
14
15
16
17
18
19
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22
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X
H
Rh
up to 85% yield
R =
up to 81% yield
Strain Energy
6.3 kcal/mol
R'
X
R
R
Y
Y
Y
R
Y
R
n
•
β
Rh
R=H, Me
RhIII
X
X
X
X
n
Rh
III
1
3
4
2
Scheme 1. Rh(I)-Catalyzed Cycloaddition of Allenylcycloalkane-Alkynes (n=1,2)
Table 1. Rh(I)-Catalyzed Cycloaddition of Allenylcyclopentane-Alkyne 5a
Me
Me
PhO2S
PhO2S
PhO2S
•
10 mol%
RhI catalyst
MeO2C
MeO2C
+
Z
Z
xylene, reflux
Z=CO2Me
Z
Z
5a
7a
6a
entry
catalyst
product and yield (%)
time (h)
1
2
3
4
0.2
0.2
[RhCl(CO)2]2
6a (30%), 7a (38%)
6a (29%), 7a (45%)
[RhCl(CO)dppp]2
0.2
0.2
0.5
RhCl(dppp)2
RhCl(PPh3)3
RhCl(PPh3)3
6a (39%), 7a (52%)
6a (73%), 7a (16%)
5a
b
6a (72%)
aReaction was carried out in toluene at 80 °C.
bA mixture of 7a and unknown compounds was obtained in small amounts.
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Table 2. Formation of Bicyclo[7.4.0]tridecatrienes 6 from Allenylcyclopentane-Alkynes 5
R2
7
8
R1
R2
R1
9
•
10 mol% RhCl(PPh3)3
toluene, 80 °C
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
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X
X
5
6
R2
time (h) producta and yieldb
X
entry
1
R1
substrate
C(SO2Ph)2
Me
0.2
SO2Ph
5b
6b (85%)
C(MOM)2
Me
Me
2
2
3
SO2Ph
SO2Ph
5c
5d
6c (85%)
C(CH2O)2CMe2
2
6d (78%)
C(CH2OH)2
Me
Me
Me
Me
Me
Me
Me
0.75
4
5
SO2Ph
SO2Ph
SO2Ph
SO2Ph
P(O)(OEt)2
nBu
5e
5f
6e (51%)
0.2c,d
C(CH2O2CC6H4-NO2-p)2
CH2
6f (53%)
6
4e
5g
5h
5i
6g (53%)
0.2e
NTs
7
6h (60%)
C(CO2Me)2
C(CO2Me)2
C(CO2Me)2
8
4
6i (69%)
9
1
5j
6j (71%)
10
iPr
1.5
5k
6k (73%)
1f
tBu
C(CO2Me)2
C(CO2Me)2
C(CO2Me)2
C(CO2Me)2
C(CO2Me)2
11
12
13
14
15
Me
5l
6l (75%)
Me
1.5
Bn
5m
5n
5o
5p
6m (58%)
Me
1
Ph
6n (62%)
nBu
3
SO2Ph
SO2Ph
6o (47%)
CH2OBn
20c
6p (40%)
aCompound 6 was isolated as a pure form and a mixture of spiro derivative 7 and unknown
compounds was detected in small amounts. bIsolated yield. cRefluxed in xylene. d0.05M of
solvent was used. eRefluxed in toluene (0.025 M). fRefluxed in toluene (0.1 M).
ORTEP drawing of 6f
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Table 3. Formation of Spiro[2.4]heptane Derivatives 7 from Allenylcyclopentane-Alkynes 5
4
5
6
7
8
Me
Me
PhO2S
PhO2S
X
PhO2S
X
•
10 mol % RhCl(dppp)2
toluene, reflux
+
6
X
9
10
11
12
13
14
15
16
17
18
19
20
21
22
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7'
not observed
5
7
time (h)
product and yielda
X
entry substrate
1
2
1.5
0.5
1
5a
5e
5f
C(CO2Me)2
C(CH2OH)
7a (81%), 6a (5%)
7e (78%)
C(CH2O2CC6H4-NO2-p)2
C(CH2O2CC6H4-Cl-p)2
NTs
7f (76%), 6f (5%)
7q (60%)
3
4
3.5
1
5q
5h
5
7h (50%), 6h (trace)
aIsolated yield.
Me
R
Me
R
R
•
X
X
X
H
5
7
6
RhI
reductive
elimination
reductive
elimination
Me
Me
R
R
R
•
I
Rh
X
III
X
III
A
X
RhH
Rh
C
oxidative
ring-closing
reaction
D
σ-bond
metathesis
β-carbon
elimination
R
Me
R
γ
β
RhIII
H
Rh
X
X
III
B
B'
Scheme 2. Plausible Mechanisms
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H
PhO2S
PhO2S
PhO2S
10
11
12
13
14
15
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•
10 mol% RhCl(PPh3)3
H
RhIII
MeO2C
MeO2C
Z
Z
toluene, 80 °C, 86%
Z=CO2Me
Z
Z
9
E
8
Scheme 3. Rh(I)-Catalyzed Cycloisomerization of 8.
Me
D
PhO2S
Me
PhO2S
PhO2S
10 mol % RhCl(dppp)2
•
D
+
D
Z
toluene, reflux, 1 h
Z=CO2Me
Z
MeO2C
MeO2C
Z
Z
11 (63%)
12 (11%)
10
Scheme 4. Deuterium-Labeling Experiment of Allenylcyclopentane-Alkynes 10.
Reference 14
PhO2S
O
N
H
O
O
7r
O
NH
ORTEP drawing of
7r and CH3CN
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