Rhodium(I)-catalyzed cycloisomerization of 1,6-enynes to bicyclo[4.1.0]heptenes

Article abstract of DOI:10.1021/jo902273x

(Chemical Equation Presented) Efficient rhodium(I)-catalyzed cyclopropanation reactions of nitrogen-tethered 1,6-enynes to azabicyclo[4.1.0]heptenes are reported. Moreover, rhodium(I)-catalyzed tandem cycloisomerization and carbonylative [3+3+1] cycloaddition reactions of a cyclopropylenyne have been observed. 2010 American Chemical Society.

Full text of DOI:10.1021/jo902273x

pubs.acs.org/joc
used as catalysts.2 Also recently, main group Lewis acids
Rhodium(I)-Catalyzed Cycloisomerization of
1,6-Enynes to Bicyclo[4.1.0]heptenes
have been used as catalysts.3 Through the cycloisomerization
reaction of enynes, various skeletal frames can be formed. In
particular, the selective synthesis of cyclopropane deriva-
tives4 is attracting a lot of attention, presumably due to their
widespread occurrence as a subunit in natural products.5 In
other respects, they can be considered as three-carbon do-
nors in the synthesis of larger rings.6 Especially, we recently
reported7 on a carbonylative [3þ3þ1] cycloaddition reaction
that uses two cyclopropyl groups in a molecule as two three-
carbon donors in the formation of large rings.
Sun Young Kim and Young Keun Chung*
Intelligent Textile System Research Center, and Department
of Chemistry, College of Natural Sciences, Seoul National
University, Seoul 151-747, Korea
ykchung@snu.ac.kr
Received October 26, 2009
Until now, several rhodium-catalyzed cycloisomerization
reactions have been disclosed.7,8 Dechy-Cabaret et al. repor-
ted8e on the Rh(I)-catalyzed cyclosiomerization of two oxygen-
tethered enynes derived from terpenoids. Recently, Chatani
reported8c,9 the Rh2(O2CCF3)4-catalyzed cycloisomerization of
enynes to cyclopropanated products. However, reports on the
Rh(I)-catalyzed cycloisomerization of enynes to cyclopropa-
nated products, namely bicyclo[4.1.0]heptenes, are still scarce.
And the substrate scope is limited and the data are fragmentary.
To complement the previous studies, we focused our efforts to
find a Rh(I)-catalyzed cycloisomerization of nitrogen-tethered
enynes leading to cyclopropanated products. In particular, in
relation to the previous research,7 we also had interest in the
Rh(I)-catalyzed tandem cycloisomerization and carbonyla-
tive [3þ3þ1] cycloaddition reactions of cyclopropylenyne
(Scheme 1). We herein report on the Rh(I)-catalyzed transfor-
mationof N-tetheredenynesto3-azabicyclo[4.1.0]hept-4-enes.
Our initial study used enyne 1a as a model substrate and
[RhCl(CO)(PPh3)2]/AgSbF6 as a catalyst. The catalytic sys-
tem [RhCl(CO)(PPh3)2]/AgSbF6 was previously used10 in
Efficient rhodium(I)-catalyzed cyclopropanation reactions
of nitrogen-tethered 1,6-enynes to azabicyclo[4.1.0]heptenes
are reported. Moreover, rhodium(I)-catalyzed tandem cy-
cloisomerization and carbonylative [3þ3þ1] cycloaddition
reactions of a cyclopropylenyne have been observed.
(4) (a) Bruneau, C. Angew. Chem., Int. Ed. 2005, 44, 2328. (b) Nieto-
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from acyclic precursors of substantially less molecular com-
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DOI: 10.1021/jo902273x
r
Published on Web 01/22/2010
J. Org. Chem. 2010, 75, 1281–1284 1281
2010 American Chemical Society

Kim and Chung
JOCNote
SCHEME 1. Rh(I)-Catalyzed Cycloisomerization and [3þ3þ1]
TABLE 2. Rhodium(I)-Catalyzed Cyclopropanation of Enynesa
Cycloaddition Reactions from Cyclopropylenyne
the carbonylative cycloaddition of dienynes. The reaction of
1a (0.330 mmol) in the presence of a catalytic amount of
[RhCl(CO)(PPh3)2] (10 mol %)/AgSbF6 (12 mol %) in 1,2-
dichloroethane at room temperature for 1.5 h gave the
cyclopropanated product 1b in 77% with a recovery of 1a
in 16% yield (Table 1).
TABLE 1. Optimum Conditions for Cycloisomerization
solvent
temp (°C)
time (h)
yield (1a/1b)a (%)
1,2-dichloroethane
1,2-dichloroethane
toluene
1,4-dioxane
1,2-dichloroethane
1,2-dichloroethane
rt
60
60
60
60
110
1.5
1.5
4
2
18
18
16/77b
0/95
63/37
65/5
45/48c
0/80c
aReaction conditions: 0.33 mmol of a substrate, [RhCl(CO)(PPh3)2]
(5 mol %), AgSbF6 (6 mol %), 1,2-dichloroethane (6 mL), 60 °C, 1-2 h.
bIsolated yields. c15 h. 3c was obtained in 23% yield.
aIsolated yields. b10 mol % of [RhCl(CO)(PPh3)2] and 12 mol % of
AgSbF6 were used. c[RhCl(CO)2]2 was used under 13 atm of CO.
The formation of 1b was confirmed by 1H NMR and HR-
mass. When the amount of catalyst decreased to 5 mol % and
the reaction temperature was increased to 60 °C, the yield of
1b dramatically improved to 95%. When the reaction med-
ium was changed to toluene or 1,4-dioxane, the yield was
quite poor and a considerable amount of 1a was recovered.
We also screened neutral rhodium complexes such as
[RhCl(CO)2]2 and trans-[RhCl(CO)(dppp)]2. Both Rh com-
plexes were inactive under most reaction conditions, but they
were quite active under 13 atm of CO. Interestingly, the
reaction was highly dependent upon the pressure of carbon
monoxide. It has been reported11 that in some transition
metal-catalyzed reactions, the presence of carbon monoxide
was helpful to the reaction even though the reaction was not
related to the carbonylation.
Using [RhCl(CO)(PPh3)2]/AgSbF6 as a catalyst, the cycloi-
somerization was studied. The results are summarized in Table 2.
Changing a substituent at the alkyne terminus (entries 1, 2, and
3) and at the olefinic carbon (entries 4 and 5) exerted a great
influence on the yield. In the case of entry 3, 3b and methyle-
necyclohexene 3c were isolated in 28% and 23% yields,
respectively. The formation of 3c was previously observed12
in cationic (PPh3)Au(I)-catalyzed cycloisomerization reac-
tions. Enyne with a terminal alkyne 3a gave relatively poor
d5-6 h. eThe parentheses represents the reactant recovered. fReaction
conditions: 0.330 mmol of a substrate, [RhCl(CO)(PPh3)2] (10 mol %),
AgSbF6 (12 mol %), 1,2-dichloroethane (6 mL), 70 °C, 1.5 h.
yields, but enyne with a phenyl-substituted alkyne 2a produced
relatively higher yields (86%). When an enyne with a cyclo-
propyl-substituted alkyne 6a was used as a substrate, a rela-
tively poor yield (37%) was observed. Interestingly, an
electronic effect was observed when an aryl group was intro-
duced to the 6-position (entries 8-10): the methoxy group
enhanced the yield to 85%, but the CF3 group diminished the
yield to 20% with a recovery of the reactant in 62%. When two
methyl groups were introduced to the 3 and 6 positions of 1,6-
enyne, 11b was isolated in 74%.
When a 1,7-enyne 12a was used as a substrate under the
same reaction conditions, compound 12d was obtained as the
sole product in 56% yield (eq 1). The formation of 12d could
be deduced by a Rh-catalyzed double-bond migration fol-
lowed by a Rh-catalyzed Alder-ene reaction13 and its molec-
ular structure was confirmed by an X-ray diffraction study
(Supporting Information).14 Thus, the chain length has a
significant effect on the reactivity of a substrate. Interestingly,
12a in the presence of [Rh2(O2CCF3)4] afforded a skeletal
€
(11) (a) Furstner, A.; Davies, P. W.; Gress, T. J. Am. Chem. Soc. 2005,
127, 8244. (b) Chatani, N.; Morimoto, T.; Murai, S. J. Am. Chem. Soc. 1994,
116, 6049. (c) Chatani, N.; Inoue, H.; Morimoto, T.; Muto, T.; Murai, S. J.
Org. Chem. 2001, 66, 4433.
(13) Cao, P.; Wang, B.; Zhang J. Am. Chem. Soc. 2000, 122, 6490.
(14) The spectroscopic data of the new compound is summarized in the
Supporting Information. CCDC-751911 (12d) contains the supplementary
crystallographic data for this paper. These data can be obtained free of
charge from The Cambridge Crystallographic Data Centre via www.ccdc.
cam.ac.uk/data_request/cif.
~
(12) (a) Nieto-Oberhuber, C.; Munoz, M. P.; Bunuel, E.; Nevado, C.;
Cardenas, D. J.; Echavarren, A. M. Angew. Chem., Int. Ed. 2004, 43, 2402. (b)
~
ꢀ
~
Nieto-Oberhuber, C.; Munoz, M. P.; Lopez, S.; Jimenez-Nunez, E.; Nevado,
C.; Herrero-Gomez, E.; Rducan, M.; Echavarren, A. M. Chem.;Eur. J.
2006, 12, 1677.
1282 J. Org. Chem. Vol. 75, No. 4, 2010

Kim and Chung
JOCNote
reorganized compound 12e in 53% yield and in PtCl2 12b in
21% yield.9b
TABLE 3. Rhodium(I)-Catalyzed Cyclopropanation of Cyclopropyle-
nynesa
substrate
entry
R1
R2
yield (%)a
1
2
3
4
5
Me
H
Et
Ph
Me
H
H
H
H
Me
13a
14a
15a
16a
17a
78 (13b)
39 (14b)
68 (15b)
80 (16b)
78 (17b)
When an 1,6-enyne with a cyclopropyl-substituted olefin
13a was used as a substrate, a [5þ2] cycloadduct 13f was
quantitatively obtained, as we expected. But when the same
reaction was carried out under 1 atm of CO at 80 °C, a
mixture of three compounds, a [5þ2] cycloadduct 13f, a
carbonylative [3þ3þ1] cycloadduct 13g, and a cycloisome-
rized triene 13h, was obtained, respectively (eq 2). The
carbonylative [3þ3þ1] cycloadduct and the cycloisomerized
triene are derived from a bicyclopropyls 13b.7 The yield from
cyclopropanation might be 52%.
aIsolated yields.
SCHEME 2. Proposed Mechanism
the above results and previous studies15 (Scheme 2). The first
step is a metal-based alkyne activation, which is followed by
intramolecular cyclopropanation. A metal carbene I can be
produced, which is expected to undergo a facile [1,2] hydride
shift to generate a zwitterion species II, followed by elimina-
tion of the metal fragment to produce bicyclo[4.1.0]heptene
and regeneration of the metal catalyst, which enters the next
catalytic cycle.
In summary, we have demonstrated that the judicious
choice of a rhodium catalyst system allows the cyclopropa-
nation of nitrogen-tethered enynes. The reaction yield was
highly sensitive to the substrate and to the a substituent(s) at
the alkyne and alkene moieties. Further synthetic applica-
tions of these reactions are under investigation.
We had to find a catalytic system that would be effective for
the cyclopropanation of the enynes with a cyclopropyl-sub-
stituted alkene. Gratifyingly, the catalyst trans-[RhCl(CO)-
(dppp)]2 was quite effective under 13 atm of CO (Table 3).
Changing a substituent on the alkyne terminus (entries 1-4)
led to the isolation of b in reasonable yields (39-80%). As
above, an enyne with a terminal alkyne (entry 2) gave the lowest
yield (39%). In other cases, a reasonable to high yield was
obtained (68-80%).
An enyne with a cyclopropyl-substituted alkyne 6a was
subjected to the same reaction conditions except for a catalyst
[RhCl(CO)2]2 instead of [RhCl(CO)(dppp)]2. The expected [3þ
3þ1] cycloaddition product was not observed, but a Pauson-
Khand-type product was obtained as the sole product in 29%
yield (eq 3).
Experimental Section
General Procedure for Rh(I)-Catalyzed Cycloisomerization of
Enynes (Table 2). Synthesis of 1-Methyl-6-phenyl-3-tosyl-3-
azabicyclo[4.1.0]hept-4-ene (2b). [RhCl(CO)(PPh3)2] (12 mg,
0.017 mmol), AgSbF6 (6.9 mg, 0.020 mmol), and 1,2-dichlor-
oethane (2 mL) were added to a Schlenk flask equipped with a
stirring bar and capped with a rubber septum. The reaction
mixture was stirred at room temperature for 5 min. Then a
substrate 2a (110 mg, 0.33 mmol) and 1,2-dichloroethane (4 mL)
were added to the Schlenk flask. The resulting mixture was
stirred until the substrate completely disappeared (as checked by
TLC) at 60 °C. The reaction mixture was purified by flash
chromatography on a silica gel column eluting with n-hexane/
ethyl acetate (v/v, 10:1). SiO2 flash chromatography afforded
the 1-methyl-6-phenyl-3-tosyl-3-azabicyclo[4.1.0]hept-4-ene 2b
as a solid (96 mg, 86%). 1H NMR (300 MHz, CDCl3) δ 0.78 (s,
3 H), 1.03 (d, J = 4.7 Hz, 1 H), 1.21 (d, J = 4.7 Hz, 1 H), 2.45
Although little mechanistic information has been ob-
tained, a plausible mechanism is proposed on the basis of
(15) For review, see: Zhnag, L.; Sun, J.; Kozman, S. A. Adv. Synth. Catal.
2006, 348, 2271.
J. Org. Chem. Vol. 75, No. 4, 2010 1283

Kim and Chung
JOCNote
(s, 3 H), 2.78 (d, J = 11.5 Hz, 1 H), 3.94 (d, J = 11.5 Hz, 1 H),
5.34 (d, J = 8.0 Hz, 1 H), 6.40 (d, J = 8.0 Hz, 1 H), 7.13 (d, J =
7.6 Hz, 2 H), 7.19-7.28 (m, 3 H), 7.35 (d, J = 7.9 Hz, 2 H), 7.70
(d, J = 8.0 Hz, 2 H) ppm. 13C NMR (75 MHz, CDCl3) δ 18.7,
21.5, 23.3, 28.1, 32.5, 46.3, 117.2, 120.4, 126.3, 127.0, 128.0,
128.9, 129.7, 134.9, 141.1, 143.7 ppm. HRMS (EI) calcd for
[C20H21NO2S]þ 339.1293, found 339.1291.
General Procedure for Rh(I)-Catalyzed Cycloisomerization of
Cyclopropylenynes to Bicyclopropyls (Table 3). Synthesis of
7-Cyclopropyl-3-tosyl-3-azabicyclo[4.1.0]hept-4-ene (14b). Re-
actions were carried out in a 100 mL stainless steel autoclave
equipped with a stirring bar. [RhCl(CO)(dppp)]2 (38 mg, 0.0330
mmol), 1,2-dichloroethane (20 mL), and cyclopropylenynes
14a (95 mg, 0.33 mmol) were added to an autoclave. The reactor
was charged with 13 atm of CO and heated at 110 °C for 18 h.
After the reactor was cooled to room temperature, the solution
was concentrated and a product was isolated by chromatogra-
phy on a silica gel column, eluting with n-hexane/ethyl acetate
(v/v, 10:1). SiO2 flash chromatography afforded the 7-cyclopro-
pyl-3-tosyl-3-azabicyclo[4.1.0]hept-4-ene 14b as a solid (37 mg,
39%). 1H NMR (300 MHz, CDCl3) δ -0.11 to 0.06 (m, 2 H),
0.30-0.33 (m, 2 H), 0.48-0.60 (m, 2 H), 0.90-0.96 (m, 1 H),
1.29-1.32 (m, 1 H), 2.42 (s, 3 H), 2.97 (dd, J = 11.7, 2.9 Hz,
1 H), 3.85 (d, J = 11.7 Hz, 1 H), 5.40 (dd, J = 7.9, 5.5 Hz, 1 H),
6.28 (d, J = 8.0 Hz, 1 H), 7.30 (d, J = 8.0 Hz, 2 H), 7.62 (d, J =
8.2 Hz, 2 H) ppm. 13C NMR (75 MHz, CDCl3) δ 3.1, 3.3, 11.4,
13.1, 21.4, 24.1, 29.5, 40.3, 112.2, 120.6, 126.9, 129.6, 134.6,
143.5 ppm. HRMS (EI) calcd for [C16H19NO2S]þ 289.1137,
found 289.1140.
Acknowledgment. S.Y.K. thanks the Brain Korea 21
fellowships and the Seoul Science Fellowships.
Note Added after ASAP Publication. Equation 1 contained
an error in the version published ASAP on January 22, 2010; the
correct version posted to the web on January 26, 2010.
Supporting Information Available: NMR spectra and HR-
mass data for all compounds. This material is available free of
charge via the Internet at http://pubs.acs.org.
1284 J. Org. Chem. Vol. 75, No. 4, 2010