Rhodium-catalyzed carbonylative [3+3+1] cycloaddition of biscyclopropanes with a vinyl substituent to form seven-membered rings

Article abstract of DOI:10.1002/anie.200800432

(Chemical Equation Presented) Choose your catalyst wisely: Depending on the position of the cyclopropyl substituent on the bicyclo[4.1.0]hept-2-ene substrate, a different rhodium complex was used to catalyze the title reaction, which leads to bicyclic dienones in reasonable to excellent yields (see scheme). The products contain a highly substituted seven-membered ring with useful functionality for further manipulation. R¹ = H, Me; R² = H, Me, Ph; R³ = Me, Et; X = NR, O.

Full text of DOI:10.1002/anie.200800432

Communications
DOI: 10.1002/anie.200800432
Cycloaddition
Rhodium-Catalyzed Carbonylative [3+3+1] Cycloaddition of
Biscyclopropanes with a Vinyl Substituent To Form Seven-Membered
Rings**
Sun Young Kim, Sang Ick Lee, Soo Young Choi, and Young Keun Chung*
The synthesis of highly substituted carbocyclic seven-mem-
bered rings, which are found frequently in natural products, is
a significant challenge for the synthetic chemist.[1] Many
useful cycloaddition reactions for the synthesis of such rings
have been discovered; for example, [4+3],[2] [5+2],[3] [6+1],[4]
[4+2+1],[5] [3+2+2],[6] and [2+2+2+1] cycloaddition reac-
tions[7] have been studied in some detail. However, there has
been no report of a [3+3+1] cycloaddition reaction, which
can be regarded as the combination of two three-carbon-atom
donors and carbon monoxide.
clopropanes with a vinyl group under an atmosphere of
carbon monoxide (Scheme 1).
Cyclopropane derivatives[8] are particularly attractive
building blocks for organic chemistry.[9] Their unique struc-
tural and electronic properties give rise to an array of very
interesting, characteristic transformations. Various cyclopro-
pane derivatives have been used in the synthesis of carbocy-
clic ring systems, such as five- and six-membered ring
systems.[10] Among the transformations of cyclopropanes,
rhodium-catalyzed ring-opening cycloaddition reactions of
vinyl cyclopropanes with p systems to form seven-membered
rings are of particular interest.[3a,b,c,e] In these reactions, a
rhodium catalyst coordinates to the vinyl group of the vinyl
cyclopropane, and the cleavage of the cyclopropyl ring results
in the formation of a (p-allyl)(s-alkyl)RhIII intermediate that
can react with p systems.[11] Thus, the presence of a double
bond in the substrate is a prerequisite for the transition-metal-
catalyzed cycloaddition of cyclopropanes.
Scheme 1. RhI-catalyzed carbonylative [3+3+1] cycloaddition.
Biscyclopropane derivatives with a vinyl substituent were
obtained readily from cyclopropylenynes by transition-metal-
catalyzed cycloisomerization reactions.[12,13] The 1-cyclo-
propylbicyclo[4.1.0]hept-2-ene derivatives A and 7-cyclo-
propylbicyclo[4.1.0]hept-2-ene derivatives D used in this
study were obtained readily by PtCl2-catalyzed cycloisomeri-
zation of the corresponding enynes (Scheme 2).[13]
We envisioned that biscyclopropanes with a vinyl sub-
stituent would be useful substrates in a carbonylative [3+3+1]
cycloaddition reaction: Two cyclopropyl groups in a molecule
could act as two three-carbon-atom donors, and a carbon-
ylative cycloaddition of the two three-carbon-atom donors
would lead to the formation of a seven-membered-ring
compound. Herein, we show that certain catalytic systems
promote the carbonylative [3+3+1] cycloaddition of biscy-
Scheme 2. Synthesis of the substrates.
[*] S. Y. Kim, S. I. Lee, S. Y. Choi, Prof. Y. K. Chung
Intellectual Textile System Research Center
Department of Chemistry, College of National Sciences
Seoul National University
We studied the carbonylative [3+3+1] cycloaddition of
the biscyclopropane 1A (X = NTs, R1,R2 = H) as a model
substrate in the presence of a rhodium compound as a catalyst
under carbon monoxide at atmospheric pressure. When a
cationic rhodium catalyst system, such as [Rh(PPh3)2(CO)Cl]/
AgX, was used, no reaction was observed. However, when a
neutral rhodium compound was used as the catalyst, the
product 1B of carbonylative cycloaddition was obtained. We
therefore screened a number of neutral rhodium compounds,
such as [{RhCl(cod)}2], [RhCl(PPh3)3], and [RhCl(CO)-
(PPh3)2], as catalysts. [{RhCl(cod)}2] was found to be the
best catalyst with respect to the yield of 1B. Thus, the
Seoul 151-747 (Korea)
Fax: (+82)2-889-0310
E-mail: ykchung@snu.ac.kr
[**] This research was supported by a Korea Research Foundation grant
funded by the Korean Government (MOEHRD) (KRF-2008-341-
C00022 and KRF-2005-070-C00072) and the SRC/ERC program of
MOST/KOSEF (R11-2005-065). S.Y.K. and S.Y.C. are grateful for
Brain Korea 21 Fellowships and Seoul Science Fellowships.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.200800432.
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Chemie
treatment of 1A in the presence of a catalytic amount of
[{RhCl(cod)}2] (10 mol%) in toluene at 1008C for 18 h gave
the [3+3+1] cycloadduct 1B in 91% yield (Table 1).[13] The
bered rings. When the 4a-cyclopropylbenzo[1,3]cyclopropa-
[1,2-c]pyridine 12A was subjected to the standard reaction
conditions, the 6,6,7-tricyclic dienone 12B was obtained in
44% yield with the recovery of 12A in 42% yield [Eq. (2)].
1
formation of 1B was confirmed by H NMR and 13C NMR
Table 1: RhI-catalyzed carbonylation reaction.[a]
Entry
A
X
R1
R2
Yield [%]
Encouraged by these results, we next investigated the
rhodium-catalyzed [3+3+1] cycloaddition of 7-cyclo-
propylbicyclo[4.1.0]hept-2-ene derivatives D. We used 1D
(X = NTs, R3 = Me) as a model substrate and studied the
carbonylative [3+3+1] cycloaddition in the presence of a
rhodium catalyst under carbon monoxide at atmospheric
pressure. No reaction was observed when [{RhCl(cod)}2] was
used without an additive. However, the treatment of 1D with
a catalytic amount of [RhCl(CO)(PPh3)2] (5 mol%)/AgSbF6
(7 mol%) in dichloroethane at 808C for 4 h gave the [3+3+1]
cycloadduct 1E and the monocyclic triene 1F in 32 and 18%
yield, respectively.[13] The formation of 1E and 1F was
confirmed by 1H NMR spectroscopy, high-resolution mass
spectrometry, and X-ray diffraction (Figure 1). The structural
framework of E has not been described previously. Both
products result from ring opening of the two cyclopropane
rings.
1
2
3
4
5
6
7
8
9
1A
NTs
NTs
NTs
NMts
NSO2Ph
NNaph
O
O
O
NTs
H
Me
H
H
H
H
H
Me
H
Ph
H
H
Me
H
H
H
H
H
Ph
H
91
2A
3A
4A
5A
6A
7A
8A
9A
10A
46 (51)[b]
55 (38)[b]
61
83
83
98
61 (36)[b]
61 (19)[b]
n.r.
10
[a] Reaction conditions:
A (0.33 mmol), [{RhCl(cod)}2] (10 mol%),
toluene (6 mL), CO (1 atm), 1008C, 18 h. [b] The amount of A recovered
is given in parentheses. cod=1,5-cyclooctadiene, Mts=2,4,6-trimethyl-
benzenesulfonyl, Naph=2-naphthalenesulfonyl, n.r. =no reaction, Ts=
p-toluenesulfonyl.
spectroscopic investigations (COSY, HMQC, and HMBC)
and high-resolution mass spectrometry. Compound 1B
derives from the ring opening of the two cyclopropane rings
followed by carbonylation. We investigated the RhI-catalyzed
carbonylative cycloaddition of various 1-cyclopropylbicyclo-
[4.1.0]hept-2-ene compounds with the catalyst [{RhCl(cod)}2]
(Table 1). As expected, no reaction was observed in the
absence of CO.
Compounds with an O atom or substituted N atom
attached to the double bond of the vinyl substituent in the
tether to the substituted cyclopropane ring were useful
substrates. The corresponding products B of carbonylative
cycloaddition were obtained in high yields (up to 98%;
Table 1, entry 7). In cases in which the product was formed in
lower yield, some of the reactant was recovered intact
(Table 1, entries 2, 3, 8, and 9).
Figure 1. X-ray crystal structure of 1E.
We screened catalyst systems to find the optimum
conditions for the formation of 1E as the sole product (see
the Supporting Information). However, we always obtained a
mixture of 1E and 1F in varying ratios. The yield of the
product mixture varied greatly. Although our endeavor to
avoid the formation of 1F was unsuccessful, the two products
can be separated readily by column chromatography. The
most efficient catalytic system studied was a mixture of
[{RhCl(CO)2}2] (5 mol%), P(4-FC6H4)3 (20 mol%), and
AgSbF6 (12 mol%) under 1 atm of CO. We studied the RhI-
catalyzed carbonylative cycloaddition of various compounds
D under these reaction conditions (Table 2).[13] Substrates D
were transformed into E and F in high overall yields (78–
95%); however, the E/F ratio varied greatly depending on the
tether group. In contrast with the results in Table 1, our
catalytic system was ineffective when the substrate contained
an O atom in the tether. As expected, 1F was obtained as the
only product in the absence of CO.
Interestingly, substrate 10A, with a phenyl substituent R1
and an NTs tether, did not undergo the desired reaction
(Table 1, entry 10). In the case of the analogous O-tethered
substrate 11A, thermal opening of the fused cyclopropane in
the absence of a catalyst led to the dienyl aldehyde 11C as the
sole product [Eq. (1)].
This carbonylative [3+3+1] cycloaddition facilitates the
construction of polycyclic systems containing seven-mem-
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Communications
Table 2: RhI-catalyzed transformation of D into E and F.[a]
Entry
D
X
R3
Yield (E/F) [%][b]
1
2
3
4
5
6
1D
2D
3D
4D
5D
6D
NTs
NTs
Me
Et
Me
Me
Me
Me
95 (71/24)
90 (79/11)
85 (51/34)
92 (64/28)
90 (62/28)
78 (44/34)
À
N o-Ts
NSO2Ph
NMts
NNaph
[a] Reaction conditions: D (0.33 mmol), [{RhCl(CO)2}2] (5 mol%), P(4-
FC6H4)3 (20 mol%), AgSbF6 (12 mol%), acetone (2 mL), ClCH2CH2Cl
(4 mL), CO (1 atm), 808C, 4 h. [b] The yields of the isolated products E
and F are given in parentheses along with the combined yield. o-Ts=
o-toluenesulfonyl.
Although the double bond in D is in a different position to
that in A with respect to the two cyclopropane rings, and
although the carbonyl group is not in the same position in the
two product types, the two transformations are very similar.
In both cases, the carbonylative [3+3+1] cycloaddition
facilitates the construction of a seven-membered ring. Thus,
substantial structural variation can be accommodated. It
seems that this RhI-catalyzed intramolecular carbonylative
[3+3+1] cycloaddition of two cyclopropyl groups in biscyclo-
propanes may be a general process, although the reaction is
somewhat sensitive to the substrate.
All substrates used in this study have a common back-
bone. The following mechanism is proposed on the basis of
our results and previous studies (Scheme 3).[11,14] The pre-
coordination of the RhI center to the double bond (in I, I’)
leads to the formation of a (p-allyl)(s-alkyl)RhIII intermedi-
ate II, II’. The strain-driven cleavage of the cyclopropane in
the intermediate II would produce metallacycle II’’. A CO-
insertion step to give III, III’, followed by the elimination of
the metal fragment, provides the [3+3+1] cycloadduct B, E.
The formation of F appears to result from the facile ring
opening of the two cyclopropane rings before the insertion of
CO.
Scheme 3. Proposed mechanism.
added as a solution in toluene (2 mL), and the resulting mixture was
stirred at 1008C under a balloon of CO for 18 h. The product was
isolated by flash column chromatography on silica gel (eluent: n-
hexane/ethyl acetate 2:1).
General procedure for substrates D: [{RhCl(CO)2}2]
(0.0165 mmol), P(4-FC6H4)3 (0.066 mmol), and acetone (2 mL) were
placed in a Schlenk flask equipped with a stirring bar and capped with
a rubber septum, and the resulting mixture was stirred at room
temperature for 10 min. AgSbF6 (0.0396 mmol) and 1,2-dichloro-
ethane (2 mL) were then added, and the resulting suspension was
stirred for 30 min under a balloon of CO. The substrate (0.33 mmol)
was added as a solution in 1,2-dichloroethane (2 mL), and the
reaction mixture was stirred at 808C under a balloon of CO for 4 h.
The products were isolated by flash column chromatography on silica
gel (eluent: n-hexane/ethyl acetate 2:1).
In summary, we have demonstrated that judicious selec-
tion of the rhodium catalyst system enables the carbonylative
[3+3+1] cycloaddition of biscyclopropanes to give the
corresponding seven-membered-ring products in reasonable
to high yields. Recently, transition-metal-catalyzed cyclopro-
panation has been developed considerably. Thus, the unpre-
cedented RhI-catalyzed cycloisomerization of enynes bearing
a cyclopropyl group could become a highly versatile tool for
obtaining [3+3+1] cycloaddition products that can not be
attained readily by other methods. Further efforts to elucidate
the mechanism of the reaction are in progress.
Received: January 28, 2008
Published online: May 21, 2008
Keywords: carbonylation · cycloaddition · cyclopropanes ·
.
rhodium · seven-membered rings
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