Iridium complex-catalyzed reaction of 1,6-enynes: Cycloaddition and cycloisomerization

Article abstract of DOI:10.1021/ol050085e

(Chemical Equation Presented) 1,6-Enynes reacted with monoynes to give cyclohexadiene derivatives in the presence of a catalytic amount of [lr(cod)Cl]₂/ligand. DPPE was most suitable for cycloaddition. Diastereoselective cycloaddition was also possible. In the absence of monoynes, 1,6-enynes cycloisomerized to (Z)-1-alkylidene-2-methylenecyclopentane derivatives. DPPF was most suitable for cycloisomerization. These results are the first examples of highly Z-selective cycloisomerization.

Full text of DOI:10.1021/ol050085e

ORGANIC
LETTERS
2005
Vol. 7, No. 9
1711-1714
Iridium Complex-Catalyzed Reaction of
1,6-Enynes: Cycloaddition and
Cycloisomerization
Satoko Kezuka, Toshiaki Okado, Eri Niou, and Ryo Takeuchi*
Department of Chemistry and Biological Science, Aoyama Gakuin UniVersity,
Fuchinobe, Sagamihara 229-8558, Japan
takeuchi@chem.aoyama.ac.jp
Received January 14, 2005
ABSTRACT
1,6-Enynes reacted with monoynes to give cyclohexadiene derivatives in the presence of a catalytic amount of [Ir(cod)Cl]2/ligand. DPPE was
most suitable for cycloaddition. Diastereoselective cycloaddition was also possible. In the absence of monoynes, 1,6-enynes cycloisomerized
to (Z)-1-alkylidene-2-methylenecyclopentane derivatives. DPPF was most suitable for cycloisomerization. These results are the first examples
of highly Z-selective cycloisomerization.
The cycloaddition of R,ω-enynes catalyzed by transition-
metal complexes1 is efficient, because it can be used to
construct polycyclic compounds in a single step without any
wasteful byproducts. For example, the Pauson-Khand reac-
tion is useful for producing bicyclic cyclopentenones, which
are a common structural component of naturally occurring
and biologically active molecules.2 The application of the
Pauson-Khand reaction in the synthesis of natural products
has been extensively studied.2a On the other hand, there is
limited information available on the intermolecular cycload-
dition of enynes with unsaturated molecules such as
monoynes.3 The cycloaddition of R,ω-enyne with monoynes
gives cyclohexadiene derivatives. These compounds are used
in the Diels-Alder reaction, which provides a rich and
diverse chemistry.4 This cycloaddition is the simplest route
to a bicyclic cyclohexadiene framework. We previously
reported that the [Ir(cod)Cl]2/dppe-catalyzed cycloaddition
of 1,6-heptadiynes with monoynes gave the corresponding
indane derivatives in high yields.5 In this study, we extended
this chemistry to the reaction of 1,6-enynes. We found that
[Ir(cod)Cl]2 with a phosphine ligand was an efficient catalyst
for the intermolecular cycloaddition of 1,6-enynes with
monoynes and also that this catalyst is effective in the
cycloisomerization of 1,6-enynes to (Z)-1-alkylidene-2-
methylenecyclopentane derivatives.
(3) Intermolecular cycloaddition of enynes with alkynes, see: (a)
Yamamoto, Y.; Kuwabara, S.; Ando, Y.; Nagata, H.; Nishiyama, H.; Itoh,
K. J. Org. Chem. 2004, 69, 6697. (b) Oh, C. H.; Sung, H. R.; Jung, S. H.;
Lim, Y. M. Tetrahedron Lett. 2001, 42, 5493. (c) Rhyoo, H.-Y.; Lee, B.
Y.; Yu, H. K. B.; Chung, Y. K. J. Mol. Catal. 1994, 92, 41. (d) Trost, B.
M.; Tanoury, G. J. J. Am. Chem. Soc. 1987, 109, 4753. (e) Grigg, R.; Scott,
R.; Stevenson, P. J. Chem. Soc., Perkin Trans. 1 1988, 1365. (f) Chang,
C.-A.; King, J. A. Jr.; Vollhardt, K. P. C. J. Chem. Soc., Chem. Commun.
1981, 53. Intermolecular cycloaddition of enynes with dienes, see: (g)
Evans, P. A.; Robinson, J. E.; Baum, E. W.; Fazal, A. N. J. Am. Chem.
Soc. 2002, 124, 8782. Intermolecular cycloaddition of dienynes with
monoyne, see: (h) Gilbertson, S. R.; DeBoef, B. J. Am. Chem. Soc. 2002,
124, 8784.
(1) (a) Saito, S.; Yamamoto, Y. Chem. ReV. 2000, 100, 2901. (b) Lautens,
M.; Klute, W.; Tam, W. Chem. ReV. 1996, 96, 49. (c) Ojima, I.;
Tzamarioudaki, M.; Li, Z.; Donovan, R. J. Chem. ReV. 1996, 96, 635. (d)
Schore, N. E. Chem. ReV. 1988, 88, 1081.
(2) (a) Blanco-Urgoiti, J.; Ao`orbe, L.; Pe´rez-Serrano, L.; Dom´ınguez,
G.; Pe´rez-Castells, J. Chem. Soc. ReV. 2004, 33, 32. (b) Gibson, S. E.;
Stevenazzi, A. Angew. Chem., Int. Ed. 2003, 42, 1800.
(4) Fringuelli, F.; Taticchi, A. Dienes in Diels-Alder Reaction; John
Wiley: New York, 1990.
(5) (a) Takeuchi, R. Synlett 2002, 1954. (b) Takeuchi, R.; Tanaka, S.;
Nakaya, Y. Tetrahedron Lett. 2001, 42, 2991. (c) Takeuchi, R.; Nakaya,
Y. Org. Lett. 2003, 5, 3659.
10.1021/ol050085e CCC: $30.25
© 2005 American Chemical Society
Published on Web 04/07/2005

Enyne 1a (R1 ) Me) reacted with 3-hexyne (2a) to give
a cyclohexadiene derivative 3a and a cycloisomerization
product 4a (eq 1).
Table 2. Cycloaddition of 1 with 2a
time
yield of 3
(%)b
yield of 4
(%)b
entry
enyne
alkyne
(h)
1
2
3
4
5
6
1a
1a
1a
1a
1b
1c
2a
2b
2c
2d
2a
2a
3
6
14
24
3
75 (3a)
53 (3b)
39 (3c)
71 (3d)
15 (3e)
12 (3f)
10 (4a)
20 (4a)
25 (4a)
2 (4a)
75 (4b)c
73 (4c)d
3
a Mixture of 1 (1 mmol), 2 (3 mmol), Ir complex (0.02 mmol), ligand
(P/Ir)2), and toluene (5 mL) was stirred in refluxing toluene. b Yields are
isolated yields based on 1. c (Z)-4b/(E)-4b/5b ) 74/2/24. d (Z)-4c/(E)-4c/
5c ) 66/11/23.′
decreased with the use of 4-octyne (2b) and 5-decyne (2c)
(entries 2 and 3 vs entry 1), but the reaction with 1,4-
dimethoxy-2-butyne (2d) gave 3d in 71% yield, which was
comparable to that with 3-hexyne (2a) (entry 4). The reaction
of 1a with 1-alkynes such as 1-hexyne or propargylic alcohol
did not give any cyclohexadiene derivatives. The starting
material was recovered in quantitative yield. The substituent
on the alkyne part of the enyne strongly affected the reaction.
The reaction of an enyne substituted with other than a methyl
group on the alkyne part with 2a gave a cycloisomerization
product as a major product (entries 5 and 6). These reactions
gave cycloaddition products in low yields.
Cycloaddition competed with cycloisomerization to give 4a.
Phosphine ligands affected the yields of the products. The
results are shown in Table 1. Dppe gave the best results
Table 1. Effect of Ligands on Cycloaddition of 1a with 2aa
time yield of 3a yield of 4a
entry
ligandb
(h)
(%)c
(%)c
1
2
3
4
5
dppm
dppe
dppp
dppb
1,2-bis(diphenyl-
phosphino)benzene
(Z)-1,2-bis(diphenyl-
phosphino)ethylene
dppf
5
3
19
2
69
75
12
2
3
10d
51
The cycloisomerization of enynes has been extensively
studied as a unique tool for the synthesis of various types of
cyclic compounds.6 Several transition metal complexes such
as Pd,7 Rh,8 Ru,9 Co,10 and Ti11 have been reported to be
catalysts for this reaction. However, new catalysts are still
needed to expand the scope and selectivity of this reaction.
90e
23
8
51
6
10
65
3
7
8
9
1
25
24
0
0
7
90f
74g
63h
PPh3
PMePh2
(6) (a) Fairlamb, I. J. S. Angew. Chem., Int. Ed. 2004, 43, 1048. (b)
Lloyd-Jones, G. C. Org. Biomol. Chem. 2003, 1, 215. (c) Aubert, C.; Buisine,
O.; Malacria, M. Chem. ReV. 2002, 102, 813. (d) Trost, B. M.; Krische, M.
J. Synlett 1998, 1.
a Mixture of 1a (1 mmol), 2a (3 mmol), Ir complex (0.02 mmol), ligand
(P/Ir ) 2), and toluene (5 mL) was stirred in refluxing toluene. b Abbre-
viations: dppm, 1,2-bis(diphenylphosphino)methane; dppe, 1,2-bis(diphenyl-
phosphino)ethane; dppp, 1,2-bis(diphenylphosphino)propane; dppb, 1,2-
bis(diphenylphosphino)butane; dppf, 1,1′-bis(diphenylphosphino)ferocene
c Yields are isolated yields based on 1a. d (Z)-4a/(E)-4a/5a ) 89/7/4. e (Z)-
4a/(E)-4a/5a ) 94/3/3. f (Z)-4a/(E)-4a/5a ) 95/4/1. g (Z)-4a/(E)-4a/5a )
50/45/5. h (Z)-4a/(E)-4a/5a ) 56/39/5.
(7) (a) Mikami, K.; Hatano, M. Proc. Natl. Acad. Sci. U.S.A. 2004, 101,
5767. (b) Hatano, M.; Mikami, K. J. Am. Chem. Soc. 2003, 125, 4704. (c)
Hatano, M.; Terada, M.; Mikami, K. Angew. Chem., Int. Ed. 2001, 40, 249.
(d) van Boxtel, L. J.; Ko¨rbe, S.; Noltemeyer, M.; De Meijere, A. Eur. J.
Org. Chem. 2001, 12, 2283. (e) Galland, J.-C.; Dias, S.; Savignac, M.; Geneˆt,
J.-P. Tetrahedron 2001, 57, 5137. (f) Goeke, A.; Sawamura, M.; Kuwano,
R.; Ito, Y. Angew. Chem., Int. Ed. 1996, 35, 662. (g) Trost, B. M.; Tanoury,
G. J.; Lautens, M.; Chan, C.; MacPherson, D. T. J. Am. Chem. Soc. 1994,
116, 4255. (h) Trost, B. M., Romero, D. L.; Rise, F. J. Am. Chem. Soc.
1994, 116, 4268. (i) Trost, B. M.; Lautens, M.; Chan, C.; Jebaratnam, D.
J.; Mueller, T. J. Am. Chem. Soc. 1991, 113, 636. (j) Trost, B. M. Acc.
Chem. Res. 1990, 23, 34.
(8) (a) Tong, X.; Li, D.; Zhang, Z.; Zhang, X. J. Am. Chem. Soc. 2004,
126, 7601. (b) Mikami, K.; Yusa, Y.; Hatano, M.; Wakabayashi, K.; Aikawa,
K. J. Chem. Soc., Chem. Commun. 2004, 98. (c) Mikami, K.; Yusa, Y.;
Hatano, M.; Wakabayashi, K.; Aikawa, K. Tetrahedron 2004, 60, 4475.
(d) Tong, X.; Zhang, Z.; Zhang, X. J. Am. Chem. Soc. 2003, 125, 6370. (e)
Lei, A.; Waldkirch, J. P.; He, M.; Zhang, X. Angew. Chem., Int. Ed. 2002,
41, 4526. (f) Cao. P.; Zhang, X. Angew. Chem., Int. Ed. 2000, 39, 4104.
(g) Cao, P.; Wang B.; Zhang, X. J. Am. Chem. Soc. 2000, 122, 6490.
(9) (a) Trost, B. M.; Toste, F. D. J. Am. Chem. Soc. 2002, 124, 5025.
(b) Paih, J. L.; Rodr´ıguez, D. C.; De´rien, S.; Dixneuf, P. H. Synlett 2000,
95. (c) Nishida, M.; Adachi, N.; Onozuka, K.; Matsumura, H.; Mori, M. J.
Org. Chem. 1998, 63, 9158.
(entry 2). The reaction in refluxing toluene for 3 h gave 3a
in 75% yield. The reaction using dppm gave 3a in 69% yield
(entry 1). Dppp and dppb were less effective than dppe
(entries 3 and 4). Reactions using 1,2-bis(diphenylphosphi-
no)benzene and (Z)-1,2-bis(diphenylphosphino)ethylene gave
3a in a yield comparable to that with dppm (entries 5 and
6). When the ligand was dppf, PPh3, or PMePh2, cyclo-
isomerization was preferred to cycloaddition (entries 7-9).
The reaction using dppf gave cycloisomerization product 4a
in 90% yield (vide infra) (entry 7).
On the basis of these results, several internal monoynes
were examined for [Ir(cod)Cl]2/dppe-catalyzed cycloaddition
(Table 2). Enyne 1a reacted with 2b-d under the same
conditions as with 2a. The yields of 1,3-cyclohexadienes (3)
(10) (a) Ajamian, A.; Gleason, J. L. Org. Lett. 2003, 5, 2409. (b) Buisine,
O.; Aubert, C.; Malacria, M. Chem. Eur. J. 2001, 7, 3517. (c) Llerena, D.;
Aubert, C.; Malacria, M. Tetrahedron Lett. 1996, 37, 7353.
(11) Sturla, S. J.; Kablaoui, N. M.; Buchwald, S. L. J. Am. Chem. Soc.
1999, 121, 1976.
1712
Org. Lett., Vol. 7, No. 9, 2005

Scheme 1
A single example of iridium complex-catalyzed cycloisomer-
for 3 h gave an 85:6:9 mixture of (Z)-4a, (E)-4a, and 5a in
45% yield (entry 2). Dppp and dppb improved the yield and
selectivity of (Z)-4a (entries 3 and 4). On the other hand,
dpph and PMePh2 decreased the yield of the products (entries
5 and 6). By using dppf and lowering the reaction temper-
ature, we increased the selectivity of (Z)-4a up to 99% (entry
10). A previous example of iridium complex-catalyzed
cycloisomerization of 1,6-enynes required acetic acid as an
additive to give a product in high yield.12a In contrast, our
cycloisomerization gave the product in high yield without
acetic acid.
ization of 1,6-enynes was reported in 2001.12a As described
above, cycloisomerization product 4a was obtained as a
byproduct of the cycloaddition of 1a. We next focused on
the cycloisomerization of 1,6-enynes. The results described
below represent the first examples of the highly Z-selectiVe
cycloisomerization of 1,6-enynes. The stereochemistry of an
alkylidene group in similar cycloisomerizations has been
reported to be E.7b,c,f-j,8,9,10b,c,11,12a The presence of phosphine
ligands affected the yield and selectivity of cycloisomeriza-
tion (Table 3). The cycloisomerization of 1a gave (Z)-4a,
(E)-4a, and 5a.
The cycloisomerization of various 1,6-enynes catalyzed
by [Ir(cod)Cl]2/dppf was examined (eq 2).
Table 3. Effect of Ligands on Cycloisomerization of 1aa
time yield
(h) (%)c (Z)-4a:(E)-4a:5a
entry
ligandb
1
2
3
4
5
6
7
dppm
dppe
dppp
dppb
dpph
3
3
3
18d
45d
83
82
49e
53
14:85:1
85:6:9
89:9:2
94:4:2
48:46:4
45:47:8
91:4:5
1
45
21
1
PMePh2
2,2′-bis(diphenyl-
phosphino)-1,1′-biphenyl
1,2-bis(dipentafluoro-
phenylphosphino)ethane
dppf
88
The reactions of 1b,c were also highly Z-selective. The
reaction of 1,6-enynes 1d containing a phenyl group on the
alkyne part gave a 77:23 mixture of (Z)-4d and (E)-4d.
Unlike the reaction of 1a-d, the reaction of 1e containing
a trimethylsilyl group on the alkyne part exclusively gave
(E)-4e. These results suggest that the steric bulkiness of the
substituent on the alkyne part was important for the stereo-
control of the alkylidene group (vide infra).
A proposed mechanism is given in Scheme 1. Oxidative
cyclization of 1 gives iridacyclopentene 6. Monoyne coor-
dinates to a vacant site on the iridium. Insertion of a monoyne
into the Ir-C bond followed by reductive elimination gives
3. There are two possibilities for the insertion into 7; one is
insertion into a Csp2-Ir bond, and the other is insertion into
a Csp3-Ir bond. The former insertion involves steric
repulsion between a substituent on an incoming monoyne
and a substituent on the carbon adjacent to iridium. Actually,
the yield of the cycloaddition products was decreased with
the use of enyne 1b and 1c (Table 2). These observations
8
9
1
87
91:2:7
0.5 92
2
2
96:3:1
98:2:0
99:1:0
10f dppf
11g dppf
88
92
a Mixture of 1a (1 mmol), Ir complex (0.02 mmol), ligand (P/Ir ) 2),
and toluene or benzene (5 mL) was stirred in refluxing solvent. b Abbre-
viation: dpph, 1,2-bis(diphenylphosphino)hexane c Yields are isolated
yields based on 1a. d Conversion was 100%. Other products were not
identified. e 1a was recovered. f Reaction temperature: 80 °C. g Benzene
was used.
Product 5a resulted from the further double-bond isomer-
ization of 4a. The reaction using dppe in refluxing toluene
(12) (a) Chatani, N.; Inoue, H.; Morimoto, T.; Muto, T.; Murai, S. J.
Org. Chem. 2001, 66, 4433. Cycloisomerization of dieneynes, see: (b)
Shibata, T.; Takasaku, K.; Takesue, Y.; Hirata, N.; Takagi, K. Synlett 2002,
1681.
Org. Lett., Vol. 7, No. 9, 2005
1713

suggest that an incoming monoyne is inserted into a Csp2-
Ir bond in 7. The regioselectivity of the insertion can be
explained by the fact that the insertion product 8 is more
stable than 9 due to the presence of a conjugated dienyl unit.
both isomerization to give (Z)-4d and reductive elimination
to give (E)-4d. Thus, a mixture of (E)- and (Z)-4d is obtained.
Diastereoselective cycloaddition of enynes with monoynes
was possible. The [Ir(cod)Cl]2/dppe-catalyzed reaction of
enyne 13, bearing a phenyl group at the allylic position, with
3-hexyne (2a) in refluxing toluene for 7 h gave 15b in 62%
yield (>99% de). The diastereoselectivity of this cycload-
dition reaction could be explained in Scheme 2. The oxidative
Ligands affected whether intermediate 6 undergoes inser-
tion leading to cycloaddition or â-hydride elimination leading
to cycloisomerization. Dppm, dppe, 1,2-bis-(diphenylphos-
phino)benzene, and (Z)-1,2-bis(diphenylphosphino)ethylene
favor insertion, whereas dppp, dppb, and dppf favor â-hy-
dride elimination, even in the presence of an alkyne. Since
a ligand with a smaller bite angle occupies less space around
the iridium center, it stabilizes six-coordinated intermediate
7 compared to a ligand with a large bite angle. The stabili-
zation of 7 promotes insertion to increase the yield of the
cycloaddition product.
Scheme 2
In the absence of monoyne, intermediate 6 undergoes
â-hydride elimination to give 10, which suffers from steric
repulsion between the iridium moiety and the cis substituent
on the alkene. Isomerization of 10 to 11 via the zwitterionic
carbene intermediate 12 releases steric repulsion.13 Reductive
elimination from 11 gives (Z)-4. Dppb and dppf were good
ligands for Z-selective cycloisomerization. Their large bite
angles14 increase the steric bulkiness of the iridium moiety
to promote the isomerization of 10 to 11. Compound 1e gives
unique results. The reaction of 1e exclusively gave (E)-4e.
The steric bulkiness of a trimethylsilyl group plays a crucial
role. The steric repulsion between a trimethylsilyl group and
the cis substituent on the alkene in 11 is stronger than that
between the iridium moiety and the cis substituent on the
alkene in 10. Therefore, 11 (R ) SiMe3) is sterically more
congested than 10 (R ) SiMe3). Isomerization of 10 to 11
leading to (Z)-4e does not occur. A phenyl group is more
bulky than a primary alkyl group and less bulky than a
trimethylsilyl group. Intermediate 10 (R ) Ph) undergoes
cyclization of enyne 13 preferentially gives 14b, because
intermediate 14a suffers from serious steric hindrance
between phenyl group and hydrogen.
In conclusion, we have demonstrated that [Ir(cod)Cl]2/
diphosphine is an effective catalyst for both cycloaddition
with a monoyne and cycloisomerization. Our catalyst system
shows unique reactivity and selectivity compared to related
reactions catalyzed by other late transition metal complexes.
Further synthetic applications and mechanistic studies of
these reactions are under investigation in our laboratory.
Acknowledgment. This research was supported in part
by Grants-in-Aid for Scientific Research (C) and for
Scientific Research on Priority Areas (A) “Exploitation of
Multi-Element Cyclic Molecules” from the Japan Society
for the Promotion of Science and the Ministry of Education,
Culture, Sports, Science and Technology of Japan.
(13) Similar isomerization of alkenylmetal complexes has been proposed
in catalytic reactions. The driving force of the isomerization is to release
steric repulsion; see: (a) Ojima, I.; Clos, N.; Donovan, R. J.; Ingallina, P.
Organometallics 1990, 9, 3127. (b) Tanke, R. S.; Crabtree, R. H. J. Am.
Chem. Soc. 1990, 112, 7984. Isomerization of alkenylmetal complexes was
observed; see: (c) Huggins, J. M.; Bergman, R. G. J. Am. Chem. Soc. 1981,
103, 3002.
(14) (a) Freixa, Z.; van Leeuwen, P. W. N. M. J. Chem. Soc., Dalton
Trans. 2003, 1890. (b) Kamer, P. C. J.; van Leeuwen, P. W. N. M.; Reek,
J. N. H. Acc. Chem. Res. 2001, 34, 895. (c) van Leeuwen, P. W. N. M.;
Kamer, P. C. J.; Reek, J. N. H.; Dierkes, P. Chem. ReV. 2000, 100, 2741.
(d) Dierkes, P.; van Leeuwen, P. W. N. M. J. Chem. Soc., Dalton Trans.
1999, 1519.
Supporting Information Available: Experimental pro-
cedures and compound characterization data. This material
is available free of charge via the Internet at http://pubs.acs.org.
OL050085E
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Org. Lett., Vol. 7, No. 9, 2005