Rhodium-catalyzed intermolecular [2 + 2] cycloaddition of terminal alkynes with electron-deficient alkenes

Article abstract of DOI:10.1021/ol303510k

The first catalytic intermolecular [2 + 2] cycloaddition of terminal alkynes with electron-deficient alkenes is reported. The reaction proceeds with an 8-quinolinolato rhodium/phosphine catalyst system to give cyclobutenes from various substrates having polar functional groups in high yields with complete regioselectivity.

Full text of DOI:10.1021/ol303510k

ORGANIC
LETTERS
2013
Vol. 15, No. 5
1024–1027
Rhodium-Catalyzed Intermolecular [2 þ 2]
Cycloaddition of Terminal Alkynes with
Electron-Deficient Alkenes
Kazunori Sakai, Takuya Kochi, and Fumitoshi Kakiuchi*
Department of Chemistry, Faculty of Science and Technology, Keio University,
3-14-1 Hiyoshi, Kohoku-ku, Yokohama, Kanagawa 223-8522, Japan
kakiuchi@chem.keio.ac.jp
Received December 21, 2012
ABSTRACT
The first catalytic intermolecular [2 þ 2] cycloaddition of terminal alkynes with electron-deficient alkenes is reported. The reaction proceeds with
an 8-quinolinolato rhodium/phosphine catalyst system to give cyclobutenes from various substrates having polar functional groups in high yields
with complete regioselectivity.
Cyclobutenes are versatile building blocks in organic
synthesis and have been used as key intermediates for the
synthesis of natural products and bioactive compounds.1
The [2 þ 2] cycloaddition of alkynes with alkenes can be
regarded as one of the most straightforward methods to
access cyclobutene structures. Concerted [2 þ 2] cycloaddi-
tion of alkynes with alkenes needs photoirradiation condi-
tions based on the WoodwardꢀHoffmann rules, but these
reactions often suffer from low yields of cyclobutene prod-
ucts and formation of a mixture of regioisomers.2,3
The use of transition-metal catalysts has been investi-
gated by many researchers to develop more practical inter-
molecular [2 þ 2] cycloadditions of alkynes with alkenes,
(5) (a) Snider, B. B.; Brown, L. A.; Conn, R. S. E.; Killinger, T. A.
Tetrahedron Lett. 1977, 18, 2831. (b) Clark, R. D.; Untch, K. G. J. Org.
Chem. 1979, 44, 248. (c) Clark, R. D.; Untch, K. G. J. Org. Chem. 1979,
44, 253. (d) Fienemann, H.; Hoffmann, H. M. R. J. Org. Chem. 1979, 44,
2802. (e) Snider, B. B.; Rodini, D. J.; Conn, R. S. E.; Sealfon, S. J. Am.
Chem. Soc. 1979, 101, 5283. (f) Snider, B. B.; Roush, D. M.; Rodini,
D. J.; Gonzalez, D.; Spindell, D. J. Org. Chem. 1980, 45, 2773. (g)
Rosenblum, M.; Scheck, D. Organometallics 1982, 1, 397. (h) Quendo,
A.; Rousseau, G. Tetrahedron Lett. 1988, 29, 6443. (i) Faron, K. L.;
(1) (a) Lee-Ruff, E.; Mladenova, G. Chem. Rev. 2003, 103, 1449. (b)
Namyslo, J. C.; Kaufmann, D. E. Chem. Rev. 2003, 103, 1485. (c)
Dembitsky, V. M. J. Nat. Med. 2008, 62, 1.
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Transformations; Katritzky, A. R., Meth-Cohn, O., Rees, C. W., Eds.;
Elsevier: Oxford, U.K., 1995; Vol. 1, pp 516ꢀ519. (b) Coyle, J. D. In
The Chemistry of the CarbonꢀCarbon Triple Bond; Patai, S., Ed.; John
Wiley & Sons: Chichester, UK, 1978; pp 523ꢀ551.
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Coulson, D. R. J. Org. Chem. 1972, 37, 1253. (c) Mitsudo, T.; Kokuryo,
K.; Takegami, Y. J. Chem. Soc., Chem. Commun. 1976, 722. (d)
Mitsudo, T.; Naruse, H.; Kondo, T.; Ozaki, Y.; Watanabe, Y. Angew.
Chem., Int. Ed. Engl. 1994, 33, 580. (e) Yi, C. S.; Lee, D. W.; Chen, Y.
Organometallics 1999, 18, 2043. (f) Huang, D.-J.; Rayabarapu, D. K.; Li,
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B.-M.; Li, X.-J.; Peng, F.-Z.; Zhang, H.-B.; Chan, A. S. C.; Shao, Z.-H.
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(3) For limited sets of substrates, thermal [2 þ 2] cycloaddition of
alkynes with alkenes can proceed. See ref 2a.
(4) (a) Ficini, J. Tetrahedron 1976, 32, 1449. (b) Narasaka, K.;
Hayashi, Y.; Shimadzu, H.; Niihata, S. J. Am. Chem. Soc. 1992, 114,
8869. (c) Ito, H.; Hasegawa, M.; Takenaka, Y.; Kobayashi, T.; Iguchi,
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Mizutani, K.; Ogawa, T.; Takahashi, A.; Ishihara, H. J. Org. Chem.
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r
10.1021/ol303510k
Published on Web 02/11/2013
2013 American Chemical Society

but the scope of such reactions is still limited. Most of the
reported examples require activated substrates such as
alkynes directly attached to heteroatoms4 or ester groups,5
or ring-strained alkenes such as norbornene derivatives.6
In contrast, there have been much fewer examples reported
for the [2 þ 2] cycloadditions between nonactivated alkynes
and unstrained alkenes.7 Concerning the [2 þ 2] cycloaddi-
tion of internal alkynes, Hilt et al. developed a cycloaddition
of internal alkynes with monocyclic alkenes,7a while Baba
et al. reported a Rh-catalyzed cycloaddition of diphenyl
acetylene with electron-deficient alkenes.7b Very recently,
Ogoshi et al. also reported the cyclobutene formation from
internal conjugate enynes and electron-deficient alkenes.7c
The use of terminal alkynes in the metal-catalyzed [2 þ 2]
cycloaddition with alkenes has met with less success. Echa-
varren et al. reported the [2 þ 2] cycloaddition of terminal
alkynes with styrene and aliphatic alkenes using sterically
hindered cationic gold catalysts.8a Recently, Hashmi et al.
also reported gold-catalyzed reaction of 1,2-diethynylben-
zenes with aliphatic alkenes.8b However, there has been no
metal-catalyzed [2 þ 2] cycloaddition between simple term-
inal alkynes with electron-deficient alkenes.
PPh2(C6F5) and P(OMe)3 were not successful (entries 7 and
8). Further optimization of the reaction conditions revealed
that an increase of the amount of DMA to 1.5 mL improved
the yield to 97% (entry 9). The use of an appropriate base was
important for obtaining high yields.11 While CsHCO3 and
Cs2CO3 gave 4aa in lower yields (entries 10 and 11), the
reactions did not proceed when CsCl or KF was used as a
base (entries 12 and 13). DBU was also found to promote the
reaction to afford 4aa in 36% yield (entry 14). It should be
noted that 3, P(4-F3CC6H4)3, and CsF are all necessary for
the formation of 4aa, and if any one of them was not added,
the cycloaddition did not proceed (entries 15ꢀ17).
Various aliphatic terminal alkynes were applicable for
the [2 þ 2] cycloaddition, and in all cases the reaction
proceeded with complete regioselectivity (Table 2). When
1-octyne (1a), 3-cyclohexyl-1-propyne (1b), and cyclohexyl-
acetylene (1c) were reacted with 2a, cyclobutenes 4aaꢀ4ca
were isolated in nearly quantitative yields (entries 1ꢀ3). The
reaction can also be performed with a substrate having
various functional groups. The reactions of alkynes bearing
ester and nitrile groups (1d and 1e) gave the corresponding
cyclobutenes 4da and 4ea in 73% and 94% yields, respec-
tively (entries 4 and 5). The THP-protected alcohol moiety
of alkyne 1f also tolerated the reaction to give product 4fa
in 71% yield (entry 6). Methylpropargyl ether (1g) can also
be employed as a substrate for the cycloaddition, and a
50% yield of cyclobutene 4ga was obtained (entry 7).
Internal alkynes, 4-octyne and 1-phenyl-1-butyne, were also
Herein we describe the first catalytic intermolecular [2 þ 2]
cycloaddition of simple terminal alkynes with electron-
deficient alkenes (eq 1). The reaction was catalyzed by a
combination of Rh(Q)(cod) (Q = 8-quinolinolato) with a
phosphine. The cycloaddition proceeds with complete
regioselectivity to form a bond between the internal carbon
of the terminal alkyne and the β-carbon of the acrylates.
Table 1. Optimization of [2 þ 2] Cycloaddition of 1a with 2aa
Our research group has been studying the catalytic activity
of 8-quinolinolato rhodium complexes and developed cata-
lytic anti-Markovnikov additions of alcohols9a and secondary
amines9b to terminal alkynes. In the course of our re-
search on the reactivity of the 8-quinolinolato rhodium comple-
xes, it was found that the reaction between 1-octyne (1a) and
n-butyl acrylate (2a) in DMA using 10 mol % Rh(Q)(cod)
(3), 20 mol % PPh3, and 3 equiv of CsF gave cyclobutene
product 4aa, albeit in low yield (Table 1, entry 1).10 Catalytic
activities of other Rh and Ru complexes were examined but
resulted in <5% yield of 4aa.11 Various phosphines were then
screened for the cycloaddition. While electron-rich triarylpho-
sphines were ineffective (entries 2 and 3), higher yields were
obtained with triarylphosphines bearing electron-withdraw-
ing groups (entries 4ꢀ6). Particularly, the use of P(4-
F3CC6H4)3 provided the product in 71% yield. Attempts to
use other less electron-donating phosphorus ligands such as
DMA
(mL)
yield of
entry
phosphine
PPh3
base
CsF
4aab
1
0.6
0.6
0.6
0.6
0.6
0.6
0.6
0.6
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
14%
13%
15%
51%
71%
43%
ndc
2
P(4-MeOC6H4)3
P(4-MeC6H4)3
P(4-FC6H4)3
P(4-F3CC6H4)3
P(3-FC6H4)3
PPh2(C6F5)
CsF
3
CsF
4
CsF
5
CsF
6
CsF
7
CsF
8
P(OMe)3
CsF
ndc
9
P(4-F3CC6H4)3
P(4-F3CC6H4)3
P(4-F3CC6H4)3
P(4-F3CC6H4)3
P(4-F3CC6H4)3
P(4-F3CC6H4)3
P(4-F3CC6H4)3
none
CsF
97%
69%
34%
ndc
10
11
12
13
14
15
16
17d
Cs2CO3
CsHCO3
CsCl
KF
ndc
(7) (a) Hilt, G.; Paul, A.; Treutwein, J. Org. Lett. 2010, 12, 1536. (b)
Motokura, K.; Nakayama, K.; Miyaji, A.; Baba, T. ChemCatChem
2011, 3, 1419. (c) Nishimura, A.; Ohashi, M.; Ogoshi, S. J. Am. Chem.
Soc. 2012, 134, 15692. See also ref 6k.
DBU
none
CsF
36%
ndc
ndc
ꢀ
(8) (a) Lopez-Carrillo, V.; Echavarren, A. M. J. Am. Chem. Soc.
P(4-F3CC6H4)3
CsF
ndc
2010, 132, 9292. (b) Hashmi, A. S. K.; Wieteck, M.; Braum, I.; Rudolph,
M.; Rominger, F. Angew. Chem., Int. Ed. 2012, 51, 10633.
(9) (a) Kondo, M.; Kochi, T.; Kakiuchi, F. J. Am. Chem. Soc. 2011,
133, 32. (b) Sakai, K.; Kochi, T.; Kakiuchi, F. Org. Lett. 2011, 13, 3928.
(10) Dimers and trimers of 1a were formed as byproducts.
(11) See the Supporting Information.
a Reaction conditions: 1a (0.6 mmol), 2a (0.2 mmol), 3 (0.02 mmol),
phosphine (0.04 mmol), base (0.6 mmol) in DMA, 80 °C, 24 h. b 1H
NMR yield. c Not detected. d Performed without catalyst 3.
Org. Lett., Vol. 15, No. 5, 2013
1025

reaction of 1a with phenyl acrylate (2g) did not give the
[2 þ 2] cycloadduct probably due to the high leaving ability
of the phenoxide ion (entry 6). Methyl methacrylate (2h)
and acrylonitrile (2i) were also examined as substrates
under the standard conditions, and the corresponding
cycloaddition products, 4ah and 4ai, were produced in
26% and 28% yields, respectively (entries 7 and 8). The
reaction with methylenemalonate 4aj did not provide any
cyclobutene product (entry 9).
Table 2. [2 þ 2] Cycloaddition of Various Aliphatic Terminal
Alkynes with 2aa
entry
1
R
4
yieldb
1
2
3
4
5
6
7
1a
1b
1c
1d
1e
1f
C6H13
4aa
4ba
4ca
4da
4ea
4fa
99%
99%
99%
73%
94%
71%
50%
CyCH2
Table 3. [2 þ 2] Cycloaddition of 1a with Electron-Deficient
Cy
Alkenesa
MeO2C(CH2)3
NC(CH2)3
THPO(CH2)3
MeOCH2
1g
4ga
a Reaction conditions: 1 (1.8 mmol), 2a (0.6 mmol), 3 (0.06 mmol),
P(4-F3CC6H4)3 (0.12 mmol), CsF (1.8 mmol) in DMA (4.5 mL), 80 °C,
24 h. b Isolated yield.
entry
2
EWG
R1
4
yieldb
1
2
3
4
5
6
7
8
9
2b
2c
2d
2e
2f
CO2Me
CO2Et
CO2Bn
H
H
H
H
H
H
4ab
4ac
4ad
4ae
4af
4ag
4ah
4ai
84%
96%
90%
99%
81%
nd
investigated as substrates, but the corresponding cyclobu-
tene products were not detected.
The reaction of arylacetylenes was found to be more
complicated, and in addition to cyclobutenes, 1:2 addition
products of alkynes and acrylates were observed. For
example, when 4-ethynylanisole (1h) was reacted with an
excess of 2a in the presence of 3, P(3-FC6H4)3, and CsF for
24 h, 2:1 addition product 5ha was formed in 28% yield
along with a 24% yield of 4ha (eq 2).12 When the reaction
was conducted for 48 h, 4ha and 5ha were obtained in 3%
and 42% yields, respectively, and this result suggests that
5ha was formed by Michael addition of the enolate of 4ha
with another equivalent of 2a.13
i
CO2 Pr
t
CO2 Bu
2g
2h
2i
CO2Ph
CO2Me
CN
Me
H
26%
28%
nd
t
t
2j
CO2 Bu
CO2 Bu
4aj
a Reaction conditions: 1a (1.8 mmol), 2 (0.6 mmol), 3 (0.06 mmol),
P(4-F3CC6H4)3 (0.12 mmol), CsF (1.8 mmol) in DMA (4.5 mL), 80 °C,
24 h. b Isolated yield.
We also examined whether alkenes having a substituent
at the β-position can be used for the cycloaddition. While
the reaction of 1a with (E)-ethyl crotonate gave no [2 þ 2]
cycloaddition product, the reaction with fumarate (E)-2k
gave6 in 44% NMR yield (eq 3). Whenmaleate (Z)-2kwas
used, cyclobutene 6 was also obtained in 16% NMR yield.
Product 6 cannot be formed by concerted [2 þ 2] addition
of 1a with (Z)-2k, but it is not clear whether the cycloaddi-
tion product was formed via the reaction of 1a with (Z)-2k
or (E)-2k, because E/Z isomerization of 2k can take place
in the presence of 3, P(4-F3CC6H4)3, and CsF.11
The [2 þ 2] cycloaddition was also examined with
various acrylates (Table 3). While the reaction of methyl
acrylate (2b) with 1a proceeded in 84% yield, when ethyl
acrylate (2c) was used, product 4ac was obtained in 96%
yield. The reaction of 1a with benzyl acrylate (2d) also gave
cyclobutene 4ad in 90% yield. Acrylates derived from
secondary and tertiary alcohols were also applicable, and
the cycloaddition with isopropyl and tert-butyl acrylates
(2e and 2f) provided cyclobutenes 4ae and 4af in 99% and
81% yields, respectively (entries 4 and 5). However, the
Cyclobutene product 4aa can be transformed into cy-
clobutane7 by simple hydrogenation usinga Pd/C-catalyst
(eq 4). Hydrolysis of the ester functional group can also be
(12) When 2a was reacted with excess 1h in the presence of 3, P(4-
F3CC6H4)3, and CsF for 24 h, only a trace of 4ha was detected.
(13) The reaction of 4ha with 2a in the presence of P(3-FC6H4)3 and
CsF in DMA at 80 °C for 24 h gave 5ha in ca. 30% NMR yield.
(14) The NMR study using DMF-d7 suggests that the incomplete
deuterium incorporation is mainly due to an H/D exchange between the
alkyne and adventitious water; see: Kim, H.; Lee, C. J. Am. Chem. Soc.
2005, 127, 10180.
1026
Org. Lett., Vol. 15, No. 5, 2013

performed under basic conditions to give carboxylic acid 8
while maintaining the cyclobutene core.
To gain an understanding of the reaction mechanism, a
deuterium-labeling experiment was carried out (eq 5).
When the reaction of 1a-d1 with n-butyl acrylate (2a) was
performed, cyclobutene product 4aa-d1 was obtained in
78% isolated yield withthe deuterium only incorporated at
the vinylic position. The moderate incorporation of deu-
terium (64%) may be attributed to the presence of a trace
amount of H2O in the reaction system.14
Figure 1. Proposed mechanisms of the [2 þ 2] cycloaddition.
The mechanism of the [2 þ 2] cycloaddition of terminal
alkynes with electron-deficient alkenes is unclear at this
point. However, based on the results that deuterium was
selectively incorporated on the vinylic carbon and no
[2þ 2] cycloaddition product from internal alkynes was
observed, we propose two possible mechanisms depicted in
Figure 1. Oxidative addition of an sp CꢀH bond in a
terminal alkyne to rhodium complex Igives alkynyl(hydrido)-
rhodium species II. The base is considered to promote the
reaction by coordination (IIIa) or deprotonation of the
hydride ligand (IIIb) to make the alkynyl metal species
more nucleophilic. Subsequent nucleophilic attack of the
β-carbon of rhodium acetylide on the electron-deficient
alkene occurs to form rhodium vinylidene IVa or IVb.15,16
The newly generated carbanion then attacks the R-carbon
of the vinylidene ligand to form the four-membered ring.
Finally, the cyclobutene product is released by reductive
elimination from Va or protonation of Vb. The electron-rich
nature of the 8-quinolinolato rhodium complex may facil-
itate the oxidative addition of terminal alkynes and the
nucleophilic addition of alkynylrhodium species and stabi-
lize the rhodium vinylidene species.
In summary, we developed the first catalytic intermole-
cular [2 þ 2] cycloaddition of terminal alkynes with
electron-deficient alkenes. The 8-quinolinolato rhodium/
phosphine catalystpromotes the reaction inthe presenceof
bases to give cyclobutenes in high yields. This reaction
provides a convenient, straightforward route to synthesize
cyclobutenes, which are not easily accessible by other
methods. The cycloaddition is completely regioselective,
and various combinations of terminal alkynes and acryl-
ates can be used for the cycloaddition. Extension of the
scope of the electrophiles and elucidation of the reaction
mechanism are now underway.
(15) For reviews including the addition of alkynyl β-carbon to
electrophiles to form vinylidene complexes, see: (a) Bruce, M. I. Chem.
Rev. 1991, 91, 197. (b) Cadierno, V.; Gamasa, M. P.; Gimeno, J. Coord.
Chem. Rev. 2004, 248, 1627. For recent examples, see: (c) Chen, K.-H.;
Feng, Y. J.; Ma, H.-W.; Lin, Y.-C.; Liu, Y.-H.; Kuo, T.-S. Organome-
tallics 2010, 29, 6829. (d) Nakaya, R.; Yasuda, S.; Yorimitsu, H.;
Ohshima, K. Chem.;Eur. J. 2011, 17, 8559. (e) Boone, M. P.; Stephan,
D. W. Organometallics 2011, 30, 5537.
Acknowledgment. This work was supported, in part, by
a Grant-in-Aid for Scientific Research and Technology
(MEXT), Japan, and by The Science Research Promotion
Fund.
(16) For catalytic reactions involving the nucleophilic attack of an
alkynyl β-carbon in alkynylmetal species, see: (a) Joo, J. M.; Yuan, Y.;
Lee, C. J. Am. Chem. Soc. 2006, 128, 14818. (b) Hashmi, A. S. K.; Braun,
I.; Rudolph, M.; Rominger, F. Organometallics 2012, 31, 644. (c) Ye, L.;
Wang, Y.; Aue, D. H.; Zhang, L. J. Am. Chem. Soc. 2012, 134, 31. (d)
Supporting Information Available. Experimental pro-
cedures and full spectroscopic data for all new com-
pounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
€
Hashmi, A. S. K.; Wieteck, M.; Braun, I.; Nosel, P.; Jongbloed, L.;
Rudolph, M.; Rominger, F. Adv. Synth. Catal. 2012, 354, 555. (e)
€
€
Hashmi, A. S. K.; Braun, I.; Nosel, P.; Schadlich, J.; Wieteck, M.;
Rudolph, M.; Rominger, F. Angew. Chem., Int. Ed. 2012, 51, 4456. (f)
Fukumoto, Y.; Daijo, M.; Chatani, N. J. Am. Chem. Soc. 2012, 134,
8762. See ref 8b.
The authors declare no competing financial interest.
Org. Lett., Vol. 15, No. 5, 2013
1027