Rh(II)-catalyzed skeletal reorganization of 1,6- and 1,7-enynes through electrophilic activation of alkynes

Article abstract of DOI:10.1021/ja9047637

The skeletal reorganization of 1,6- and 1,7-enynes leading to 1-vinylcycloalkenes using Rh(II) as a catalyst is reported. Two possible isomers of 1-vinylcycloalkenes, type I and type II, can be obtained, the ratio of which are highly dependent on the subs

Full text of DOI:10.1021/ja9047637

Published on Web 10/06/2009
Rh(II)-Catalyzed Skeletal Reorganization of 1,6- and
1,7-Enynes through Electrophilic Activation of Alkynes
Kazusa Ota, Sang Ick Lee, Jhih-Meng Tang, Manabu Takachi, Hiromi Nakai,
Tsumoru Morimoto,† Hitoshi Sakurai, Ken Kataoka, and Naoto Chatani*
Department of Applied Chemistry, Faculty of Engineering, Osaka UniVersity, Suita,
Osaka 565-0871, Japan
Received June 10, 2009; E-mail: chatani@chem.eng.osaka-u.ac.jp
Abstract: The skeletal reorganization of 1,6- and 1,7-enynes leading to 1-vinylcycloalkenes using Rh(II)
as a catalyst is reported. Two possible isomers of 1-vinylcycloalkenes, type I and type II, can be obtained,
the ratio of which are highly dependent on the substitution pattern of the enynes used. Formation of type
I compounds involves a single cleavage of a C-C double bond, the product of which is identical to that of
enyne metathesis. In contrast, the formation of type II compounds involves the double cleavage of both
the C-C double and triple bonds, which has an anomalous bond connection. The presence of both a
phenyl group at the alkyne carbon and a methyl group at the internal alkene carbon facilitates the formation
of type II compounds. The electronic and steric nature of the substituents on the aromatic ring also affects
the ratio of type I and type II. The nature of a tether also has a significant effect on the course of the
reaction. Experimental evidence for the intermediacy of a cyclopropyl rhodium carbenoid, a key intermediate
in the skeletal reorganization of enynes, is also reported. In addition to the skeletal reorganization of enynes,
Rh(II) complexes were found to have a high catalytic activity for some cycloisomerization reactions of alkyne
derivatives, including the bicyclization of enynes to bicyclo[4.1.0]heptene derivatives and the cyclization of
alkynylfurans to phenol derivatives.
Introduction
posed as a key intermediate in most of the cycloisomerization
reactions of enynes reported thus far. The electrophilic activation
The development of new, efficient methods for the construc-
tion of ring systems from simple acyclic building blocks
represents an important ongoing challenge for synthetic organic
chemists. One of the most recently studied methods involve
transition metal catalyzed cycloisomerization reactions of enynes
and their related processes.1 From a mechanistic perspective,
metallacycles or metal vinylidene complexes have been pro-
of alkynes by transition metal halides or their cation complexes,
such as Ru(II), Pt(II), Pt(IV), Ir(I), Au(I), Au(III), and even
typical elemental halides, such as Ga(III) and In(III), has recently
(3) For papers on the Pd-catalyzed skeletal reorganization of enynes, see:
(a) Trost, B. M.; Tanoury, G. J. J. Am. Chem. Soc. 1988, 110, 1636–
1638. (b) Trost, B. M.; Trost, M. K. J. Am. Chem. Soc. 1991, 113,
1850–1852.
(4) For papers on the Pt-catalyzed skeletal reorganization of enynes, see:
(a) Trost, B. M.; Chang, V. K. Synthesis 1993, 824–832. (b) Fu¨rstner,
A.; Szillat, H.; Gabor, B.; Mynott, R. J. Am. Chem. Soc. 1998, 120,
8305–8314. (c) Trost, B. M.; Doherty, G. A. J. Am. Chem. Soc. 2000,
122, 3801–3810. (d) Fu¨rstner, A.; Szillat, H.; Stelzer, F. J. Am. Chem.
Soc. 2000, 122, 6785–6786. (e) Fu¨rstner, A.; Stelzer, F.; Szillat, H.
J. Am. Chem. Soc. 2001, 123, 11863–11869. (f) Oi, S.; Tsukamoto,
I.; Miyano, S.; Inoue, Y. Organometallics 2001, 20, 3704–3709. (g)
Oh, C. H.; Bang, S. Y.; Rhim, C. Y. Bull. Korean Chem. Soc. 2003,
24, 887–888. (h) Bajracharya, G. B.; Nakamura, I.; Yamamoto, Y. J.
Org. Chem. 2005, 70, 892–897. (i) Ferrer, A.; Raducan, M.; Nevado,
C.; Claverie, C. K.; Echavarren, A. M. Tetrahedron 2007, 63, 6306–
6316.
† Present address: Graduate School of Materials Science, Nara Institute
of Science and Technology (NAIST), 8916-5 Takayama, Ikoma, Nara 630-
0192, Japan.
(1) For reviews, see: (a) Aubert, C.; Buisine, O.; Malacria, M. Chem.
ReV. 2002, 102, 813–834. (b) Lloyd-Jones, G. C. Org. Biomol. Chem.
2003, 1, 215–236. (c) Echavarren, A. M.; Nevado, C. Chem. Soc. ReV.
2004, 33, 453–436. (d) Diver, S. T.; Giessert, A. J. Chem. ReV. 2004,
104, 1317–1382. (e) An˜orbe, L.; Dom´ınguez, G.; Pe´rez-Castells, J.
Chem.sEur. J. 2004, 10, 4938–4943. (f) Bruneau, C. Angew. Chem.,
Int. Ed. 2005, 44, 2328–2334. (g) Zhang, L.; Sun, J.; Kozmin, S. A.
AdV. Synth. Catal. 2006, 348, 2271–2296. (h) Marco-Contelles, J.;
Soriano, E. Chem.sEur. J. 2007, 13, 1350–1357. (i) Jime´nez-Nu´n˜ez,
E.; Echavarren, A. M. Chem. ReV. 2008, 108, 3326–3350. (j) Michelet,
V.; Toullec, P. Y.; Geneˆt, J.-P. Angew. Chem., Int. Ed. 2008, 47, 4268–
4315. (k) Lee, S. I.; Chatani, N. Chem. Commun. 2009, 371–384.
(2) For papers on skeletal reorganization of enynes from our laboratory,
see: (a) [RuCl2(CO)3]2: Chatani, N.; Morimoto, T.; Muto, T.; Murai,
S. J. Am. Chem. Soc. 1994, 116, 6049–60590. (b) PtCl2: Chatani, N.;
Furukawa, N.; Sakurai, H.; Murai, S. Organometallics 1996, 15, 901–
903. Miyanohana, Y.; Inoue, H.; Chatani, N. J. Org. Chem. 2004, 69,
8541–8543. (c) [IrCl(CO)2]n: Chatani, N.; Inoue, H.; Morimoto, T.;
Muto, T.; Murai, S. J. Org. Chem. 2001, 66, 4433–4436. (d) GaCl3:
Chatani, N.; Inoue, H.; Kotsuma, T.; Murai, S. J. Am. Chem. Soc.
2002, 124, 10294–10295. (e) InCl3: Miyanohana, Y.; Chatani, N. Org.
Lett. 2006, 8, 2155–2158. (f) Rh2(O2CF3)4: Ota, K.; Chatani, N. Chem.
Commun. 2008, 2906–2907.
(5) For papers on the Au-catalyzed skeletal reorganization of enynes, see:
(a) Nieto-Oberhuber, C.; Mun˜oz, M. P.; Bun˜uel, E.; Nevado, C.;
Ca´rdenas, D. J.; Echavarren, A. M. Angew. Chem., Int. Ed. 2004, 43,
2402–2406. (b) Nieto-Oberhuber, C.; Lo´pez, S.; Mun˜oz, M. P.;
Ca´rdenas, D. J.; Bun˜uel, E.; Nevado, C.; Echavarren, A. M. Angew.
Chem., Int. Ed. 2005, 44, 6146–6148. (c) Me´zailles, N.; Ricard, L.;
Gagosz, F. Org. Lett. 2005, 7, 4133–4136. (d) Nieto-Oberhuber, C.;
Mun˜oz, M. P.; Lo´pez, S.; Jimenez-Nunez, E.; Nevado, C.; Herrero-
Gomez, E.; Raducan, M.; Echavarren, A. M. Chem.sEur. J. 2006,
12, 1677–1693.
(6) For a paper on the Ru-catalyzed skeletal reorganization of enynes,
see: Madhushaw, R.; Lo, C.-Y.; Hwang, C.-W.; Su, M.-D.; Shen, H.-
C.; Pal, S.; Shaikh, I. R.; Liu, R.-S. J. Am. Chem. Soc. 2004, 126,
15560–15565.
9
10.1021/ja9047637 CCC: $40.75  2009 American Chemical Society
J. AM. CHEM. SOC. 2009, 131, 15203–15211 15203

A R T I C L E S
Ota et al.
Scheme 1. Skeletal Reorganization of Enynes
involves a double cleavage of both the C-C double and C-C
triple bonds. The terminal alkene carbon migrates between the
two alkyne carbons. The course of the reaction is highly
dependent on the catalyst used and substitution patterns of the
substrates. In the skeletal reorganization of enynes,2-6 electro-
philic interactions between metal complexes, MXn, and an
alkyne, as in A, are proposed to trigger the catalysis, and a
cyclopropyl metal carbene B is proposed as a key intermediate
in the case of late transition metal halide complexes based on
experiments involving the trapping of the metal carbenoid
intermediate9 and on DFT studies (Scheme 1).12 In fact, we
and other groups succeeded in trapping metal carbenoid B by
cyclopropanation with intra-9 and intermolecular alkenes10 and
by addition of carbon nucleophiles.13 Cyclopropyl metal car-
benoid B was also oxidatively trapped by the treatment with
diphenylsulfoxide.14 A zwitter ionic resonance form C of a
cyclopropyl gold carbenoid was trapped by intramolecular
alkenes.15
The possible intermediacy of metal carbenoid complex B in
the skeletal reorganization of enynes prompted us to use Rh(II)
complexes as a catalyst for the skeletal reorganization of enynes.
It is well-known that Rh(II) complexes have the ability to
stabilize carbenes and to function as catalysts in various
reactions involving carbenes as intermediates,16 and rhodium(II)
complexes were recently found to serve as an activator of an
alkyne.17 In addition, we have already reported that a Rh(II)
complex was active in polycyclization of dienes-ynes.9a We wish
to report in full detail how a Rh(II) complex shows high catalytic
activity for various types of cycloisomerization reactions of
alkyne derivatives, including the skeletal reorganization of
been recognized as a key step in various cycloisomerization
reactions of alkyne derivatives, such as enynes,2-7 yne-
benzenes,8 and other alkyne derivatives.9-11 Cycloisomerization
reactions of enynes catalyzed by such electrophilic metal
complexes have recently attracted considerable attention because
of the great diversity of products that can be produced from
them. Among the various cycloisomerization reactions of
enynes, skeletal reorganization is most interesting because of
the potential synthetic utility as well as the anomalous bond
connection provided by this process as shown in Scheme 1.
Two possible isomers, type I and type II, can be produced in
the skeletal reorganization of enynes. The formation of type I
isomers involves the cleavage of the original alkene C-C bonds
and the migration of the terminal alkene carbon on the terminus
of the alkyne. In contrast, the formation of type II isomers
(7) For a recent review on cycloisomerization of enynes using Pt(II) or
Au(I), see:Zhang, L.; Sun, J.; Kozmin, S. A. AdV. Synth. Catal. 2006,
348, 2271–2296. For recent selected papers, see: Mamane, V.; Gress,
T.; Krause, H.; Fu¨rstner, A. J. Am. Chem. Soc. 2004, 126, 8654–8655.
Harrak, Y.; Blaszykowski, C.; Bernard, M.; Cariou, K.; Mainetti, E.;
Mourie`s, V.; Dhimane, A.-L.; Fensterbank, L.; Malacria, M. J. Am.
Chem. Soc. 2004, 126, 8656–8657. Fu¨rstner, A.; Hannen, P. Chem.
Commun. 2004, 2546–2547. Luzung, M. R.; Markham, J. P.; Toste,
F. D. J. Am. Chem. Soc. 2004, 126, 10858–10859. Shi, X.; Gorin,
D. J.; Toste, F. D. J. Am. Chem. Soc. 2005, 127, 5802–5803. Zhang,
L.; Kozmin, S. A. J. Am. Chem. Soc. 2005, 127, 6962–6963. Fu¨rstner,
A.; Davies, P. W.; Gress, T. J. Am. Chem. Soc. 2005, 127, 8244–
8245. Couty, S.; Meyer, C.; Cossy, J. Angew. Chem., Int. Ed. 2006,
45, 6726–6730. Toullec, P. Y.; Genin, E.; Leseurre, L.; Genet, J.-P.;
Michelet, V. Angew. Chem., Int. Ed. 2006, 45, 7427–7430. Sun, J.;
Conley, M. P.; Zhang, L.; Kozmin, S. A. J. Am. Chem. Soc. 2006,
128, 9705–9710. Buzas, A.; Gagosz, F. J. Am. Chem. Soc. 2006, 128,
12614–12615. Buzas, A. K.; Istrate, F. M.; Gagosz, F. Angew. Chem.,
Int. Ed. 2007, 46, 1141–1144. Odabachian, Y.; Gagosz, F. AdV. Synth.
Catal. 2009, 351, 379–386.
(10) For a paper on trapping of cyclopropyl metal carbenoid by intermo-
lecular alkenes, see: Lo´pez, S.; Herrero-Go´mez, E.; Pe´rez-Galan, P.;
Nieto-Oberhuber, C.; Echavarren, A. M. Angew. Chem., Int. Ed. 2006,
45, 6029–6032.
(11) For a recent review on Pt(II)- or Au(I)-catalyzed reactions via
electrophilic activation of alkynes, see: Fu¨rstner, A.; Davies, P. W.
Angew. Chem., Int. Ed. 2007, 46, 3410–3449. For selected recent
papers, see: Kirsch, S. F.; Binder, J. T.; Lie´bert, C.; Menz, H. Angew.
Chem., Int. Ed. 2005, 45, 5878–5880. Taduri, B. P.; Ran, Y.-F.; Huang,
C.-W.; Liu, R.-S. Org. Lett. 2006, 8, 883–886. Hotha, S.; Kashyap,
S. J. Am. Chem. Soc. 2006, 128, 9620–9621. Park, S.; Lee, D. J. Am.
Chem. Soc. 2006, 128, 10664–10665. Horino, Y.; Luzung, M.; Toste,
F. D. J. Am. Chem. Soc. 2006, 128, 11364–11365. Seregin, I. V. J. Am.
Chem. Soc. 2006, 128, 12050–12051. Dube´, P.; Toste, F. D. J. Am.
Chem. Soc. 2006, 128, 12062–12063. Gorin, D. J.; Dube, P.; Toste,
F. D. J. Am. Chem. Soc. 2006, 128, 14480–14481.
(12) For papers on DFT calculation of skeletal reorganization of enynes,
see: Soriano, E.; Ballesteros, P.; Marco-Contelles, J. Organometallics
2005, 24, 3172–3181. Nieto-Oberhuber, Lo´pez, S.; Mun˜oz, M. P.;
Cardenas, D. J.; Bun˜uel, E.; Nevado, C.; Echavarren, A. M. Angew.
Chem., Int. Ed. 2005, 44, 6146–6148. Soriano, E.; Marco-Contelles,
J. J. Org. Chem. 2005, 70, 9345.
(8) For a recent review, see: Nevado, C.; Echavarren, A. M. Synthesis
2005, 167–182. Kitamura, T. Eur. J. Org. Chem. 2009, 1111–1125.
For selected papers, see: Chatani, N.; Inoue, H.; Ikeda, T.; Murai, S.
J. Org. Chem. 2000, 65, 4913–4918. Inoue, H.; Chatani, N.; Murai,
S. J. Org. Chem. 2002, 67, 1414–1417. Pastine, S. J.; Youn, S. W.;
Sames, D. Org. Lett. 2003, 5, 1055–1058. Mamane, V.; Hannen, P.;
Fu¨rstner, A. Chem.sEur. J. 2004, 10, 4556–4575. Ferrer, C. F.; Amijs,
C. H. M.; Echavarren, A. M. Chem.sEur. J. 2007, 13, 1358–1373.
(9) For papers on trapping of cyclopropyl metal carbenoid by intramo-
lecular alkenes or aromatic compounds, see: (a) Chatani, N.; Kataoka,
K.; Murai, S.; Furukawa, N.; Seki, Y. J. Am. Chem. Soc. 1998, 120,
9104–9105. (b) Mainetti, E.; Mouries, V.; Fensterbank, L.; Malacria,
M.; Marco-Contelles, J. Angew. Chem., Int. Ed. 2002, 41, 2132–2135.
(c) Nieto-Oberhuber, C.; Lo´pez, S.; Echavarren, A. M. J. Am. Chem.
Soc. 2005, 127, 6178–6179. (d) Marco-Contelles, J.; Arroyo, N.;
Anjum, S.; Mainetti, E.; Marion, N.; Cariou, K.; Lemie`re, G.; Mourie`s,
V.; Fensterbank, L.; Malacria, M. Eur. J. Org. Chem. 2006, 4618–
4633. (e) Witham, C. A.; Mauleo´n, P.; Shapiro, N. D.; Sherry, B. D.;
Toste, F. D. J. Am. Chem. Soc. 2007, 129, 5838–5839. (f) Nieto-
Oberhuber, C.; Pe´rez-Gala´n, P.; Herrero-Go´mez, E.; Lauterbach, T.;
Rodr´ıguez, C.; Lo´pez, S.; Bour, C.; Rosello´n, A.; Ca´rdenas, D. J.;
Echavarren, A. M. J. Am. Chem. Soc. 2008, 130, 269–279. (g) Trost,
B. M.; Hashmi, A. S. K. Angew. Chem., Int. Ed. Engl. 1993, 32, 1085–
1087. (h) Trost, B. M.; Hashmi, A. S. K. J. Am. Chem. Soc. 1994,
116, 2183–2184.
(13) For papers on trapping of cyclopropyl metal carbenoid by carbon
nucleophiles, see: Toullec, P. Y.; Genin, E.; Leseurre, L.; Geneˆt, J.-
P.; Michelet, V. Angew. Chem., Int. Ed. 2006, 45, 7427–7430. Amijs,
C. H. M.; Lo´pez-Carrillo, V.; Raducan, M.; Pe´rez-Gala´n, P.; Ferrer,
C.; Echavarren, A. M. J. Org. Chem. 2008, 73, 7721–7730. Toullec,
P. Y.; Chao, C.-M.; Chen, Q.; Gladiali, S.; Geneˆt, J.-P.; Michelet, V.
AdV. Synth. Catal. 2008, 350, 2401–2408. Chao, C.-M.; Vitale, M. R.;
Toullec, P. Y.; Geneˆt, J.-P.; Michelet, V. Chem.sEur. J. 2009, 15,
1319–1323.
(14) Witham, C. A.; Mauleon, P.; Shapiro, N. D.; Sherry, B. D.; Toste,
F. D. J. Am. Chem. Soc. 2007, 129, 5838–5839.
(15) Fu¨rstner, A.; Morency, L. Angew. Chem., Int. Ed. 2008, 47, 5030–
5033. Seidel, G.; Mynott, R.; Fu¨rstner, A. Angew. Chem., Int. Ed.
2009, 48, 2510–2513.
(16) For recent reviews, see: Merlic, C. A.; Zechman, A. L. Synthesis 2003,
113, 7–1156. Doyle, M. P Top. Organomet. Chem. 2004, 13, 203–
222. Davies, H. M. L. Angew. Chem., Int. Ed. 2006, 45, 6422–6425.
(17) Miki, K.; Washitake, Y.; Ohe, K.; Uemura, S. Angew. Chem., Int.
Ed. 2004, 43, 1857–1860. Shikanai, D.; Murase, H.; Hata, T.; Urabe,
H. J. Am. Chem. Soc. 2009, 131, 3166–3167.
9
15204 J. AM. CHEM. SOC. VOL. 131, NO. 42, 2009

Rh(II)-Catalyzed Reorganization of 1,6- and 1,7-Enynes
A R T I C L E S
Table 1. Rh2(O2CCF3)4-Catalyzed Skeletal Reorganization of
Enynesa
enynes leading to the production of 1-vinylcycloalkenes, the
bicyclization of enynes to bicyclo[4.1.0]heptene derivatives, and
the cyclization of yne-furans to phenol derivatives. All of these
reactions are initiated by the electrophilic activation of alkynes
by Rh(II). In addition, experimental evidence for the interme-
diacy of a cyclopropyl rhodium carbenoid in the skeletal
reorganization of enynes is also described.
Scheme 2. Rh(II)-Catalyzed Skeletal Reorganization of Enynes
Results and Discussion
The treatment of a simple enyne 1 (0.5 mmol) with a catalytic
amount of Rh2(OAc)4 (0.01 mmol) in toluene (2.5 mL) at 80
°C for 20 h resulted in no reaction (Scheme 2). Changing the
solvent to CH2Cl2 failed to improve the reaction. However, the
use of Rh2(O2CCF3)4 as a catalyst gave the expected 1-vinyl-
cyclopentene 2 in 80% yield after only a reaction time of 1.5 h.
This result indicates that a highly electrophilic catalyst is
required to activate an alkyne. Although Rh2(O2CC3F7)4 is more
electrophilic than Rh2(O2CCF3)4, its reactivity was lower than
that of Rh2(O2CCF3)4. This is probably due to a steric hindrance
of a perfluorocarboxylate moiety.
Results for reactions of various enynes in the presence of
Rh2(O2CCF3)4 as the catalyst are shown in Table 1. Irrespective
of the geometries of the starting enynes with respect to the
alkene moiety, only the trans isomer was obtained, as in 4. This
trend is similar to previously reported Ru(I)- and Pt(II)-catalyzed
reactions2a,b but in sharp contrast to the Ga(III)- and In(III)-
catalyzed reaction of enynes, in which the reaction proceeds in
a stereospecific manner.2d,e The reaction was also applicable to
1,7-enynes leading to the production of 1-vinylcyclohexene 6.
However, the reaction of a 1,8-enyne gave no reaction. It is
noteworthy that the substitution of an oxy group at the
propargylic position facilitated the reaction. Enynes having a
siloxy group at the propargylic position gave the corresponding
1-vinylcyclopentenes 7-11 in high yields, irrespective of the
nature of the substituent on the alkyne carbon. Thus, enynes
with a substituent on the alkyne carbon served as good
substrates, in contrast to previously reported examples in which
they were not appropriate in most cases, except for a PtCl2-
catalyzed reaction.2b Although the use of a benzyloxy group at
the propargylic position gave the corresponding product 12 in
high yield, the acetoxy isomer gave complex mixtures (result
not shown in Table 1). It is noteworthy that a hydroxyl group,
if present on the starting material, need not be protected as in
13. The selectivity proved to be general for a number of
additional substrates, rendering the present reaction a unique
method for preparing substituted 1-vinylcyclopentenes. In all
examples of enynes that contain substituents at the alkyne carbon
or terminal alkene carbon shown in Table 1, type I compounds
were selectively obtained.
a Reaction conditions: enyne (0.5 mmol), Rh2(O2CCF3)4 (0.01 mmol),
toluene (2.5 mL) at 80 °C for 20 h. b Isolated yield. c Rh2(OAc)4 was
used as the catalyst.
cant difference between the two reactions is the operative
mechanism. Enyne metathesis is initiated by a [2 + 2]
cycloaddition of a carbene complex and an alkyne (or alkene).
In contrast, the electrophilic interaction between the alkyne and
the catalyst initiates the skeletal reorganization of enynes, as
shown in Scheme 1. Most importantly, the possible formation
The present skeletal reorganization at first glance appears to
be the same transformation as enyne metathesis1,18 since both
lead to formation of 1-vinylcycloalkenes. However, the signifi-
9
J. AM. CHEM. SOC. VOL. 131, NO. 42, 2009 15205

A R T I C L E S
Ota et al.
Scheme 3. Type I vs Type II
Table 2. Rh2(O2CCF3)4-Catalyzed Skeletal Reorganization of
1,6-Enynesa
of type II compounds is the characteristic feature of this type
of skeletal reorganization (Scheme 3). The formation of type
II compounds involves an unusual bond reconstitution, in which
the double cleavage of both C-C double and triple bonds.
However, only a limited number of studies have reported the
occurrence of type II compounds, among which their selective
formation is rare.19 In most cases, type I products were
selectively obtained. In fact, type I products were clearly formed
in the Rh(II)-catalyzed skeletal reorganization of enynes, as
shown in Table 1.
Because of this, we were prompted to examine various effects,
such as the electronic and steric nature of substituents, chain
length, and the nature of tether atoms on the ratio of type I and
type II compounds. It was found that the structure of the enynes
used has a significant effect on the distribution of type I and
type II products, as shown in Table 2. The reaction of enyne
14, which contains a phenyl group at the alkyne carbon, gave
15-I (type I) selectively. On the other hand, the substitution of
a methyl group at the internal alkene carbon, as in 16a, led to
the formation of a mixture of 17a-I (type I) and 17a-II (type
II) in nearly a 1:1 ratio. Surprisingly, the product 17a-II had a
cis configuration. We next examined the electronic effects of
substituents on the phenyl ring on product distribution. The
presence of an electron-withdrawing group, as in 16d and 16e,
dramatically increased the ratio of type II products. Based on
these results, it is expected that a type I product will be a major
isomer in the reaction of an enyne with a 4-methoxypheny group
on the phenyl ring, as in 16b, because of its strong electron-
donating nature. However, this was not the case. The reaction
of 16b gave the bicyclo[3.2.0]heptene derivative 18 as a major
isomer, along with 17b-II (Scheme 4), with no type I compound
being formed. Use of a sterically hindered aryl group, as in 16f,
also selectively gave a type II product (Table 2). These results
suggest that a malonate tether would favor the formation of type
I products, as in 14, but this effect is overcome by the effect of
a methyl group at the internal alkene carbon (14 vs 16a) and a
substituent having an electron-withdrawing effect (16a and 16c
vs 16d and 16e).
a Reaction conditions: enyne (0.5 mmol), Rh2(O2CCF3)4 (0.01 mmol),
toluene (2.5 mL) at 80 °C for 20 h. b Isolated yield. c The reaction was
carried out at 60 °C. d Np ) naphthyl.
Scheme 4. Formation of Four-Membered Product
Of more interest is the dramatic effect of a substituent in the
tether. Replacement of a malonate tether by a ketal tether
facilitated the formation of a type II compound (compare 14
with 19). Analogous to the case of malonates, the presence of
a methyl group at an internal alkene carbon, as in 21, led to the
selective formation of type II products 22-II. The presence of
a gem-dimethyl group, as in 25, also gave a type II product
selectively.
The reaction was also applicable to 1,7-eynes, as shown in
Table 3. In most cases, type II products were exclusively
obtained. The trend for the preferential formation of a (Z)-isomer
(18) For recent reviews on the enyne metathesis, see: Poulsen, C. S.;
Madsen, R. Synthesis 2003, 1–18. Villar, H.; Frings, M.; Bolm, C.
Chem. Soc. ReV. 2007, 36, 55–66.
(19) To the best of knowledge, there are four papers in which selective
formation of type II is described. But, only one specific example was
shown in each paper. See refs 2b, 4f, 4g, and 5b.
9
15206 J. AM. CHEM. SOC. VOL. 131, NO. 42, 2009

Rh(II)-Catalyzed Reorganization of 1,6- and 1,7-Enynes
A R T I C L E S
Table 3. Rh2(O2CCF3)4-Catalyzed Skeletal Reorganization of
Scheme 6. Rh(II)-Catalyzed Bicyclization of Enyne with a Nitrogen
Tether
Phenyl-Substituted 1,7-Enynesa
of all carbons, as shown in Table 2. It was found that the
presence of a nitrogen tether had more significant effects on
the course of the reaction. The reaction of enynes with a
p-tosylamide functionality in the tether, such as 38, gave the
bicyclization product 39 as the major isomer, along with a small
amount of the skeletal reorganization product (Scheme 6).
This type of transformation was first reported by Blum, who
reported that 1,6-enynes containing an oxygen atom in the tether
underwent bicyclization in the presence of PtCl4, to give
oxabicyclo[4.1.0]heptenes.20 Later, Fru¨stner4d,e and Echavarren21
found that PtCl2 is a good catalyst for the bicyclization of 1,6-
enynes having an oxygen or nitrogen atom in the tether. Ir(I),22
Au(I),23 and an (NHC)-Pt complex24 were also recently
reported to catalyze the cycloisomerization of 1,6-enynes that
contain a nitrogen functionality in the tether to azabicyclo[4.1.0]-
heptenes. Rh(II) is also found to be active in the bicyclization
of various enynes with a nitrogen or oxygen atom in the tether,
as shown in Table 4. However, use of 1,7-enyne 45 led to the
selective formation of type II product 46, although the PtCl2-
catalyzed reaction gave a bicyclization product 47. Similar to
the case of a malonate tether, as in 27 and 29, shown in Table
3, the position of an NTs group also has a significant effect on
the reactivity of substrates. Thus, in sharp contrast to 45, 48
was completely unreactive.
Scheme 7. Cycloisomerization of Pentafluorophenyl-Substituted
Enyne
a Reaction conditions: enyne (0.5 mmol), Rh2(O2CCF3)4 (0.01 mmol),
toluene (2.5 mL) at 80 °C for 20 h. b Isolated yield. The number in
parentheses is selectivity for type II.
Scheme 5. Ester-Substituted 1,6-Enyne
appears to be quite general, similar to the case of 1,6-enynes.
The reaction of 27 gave type II product 28 exclusively, even
though 27 contained a malonate tether and no electron-
withdrawing group on the phenyl ring, showing that chain length
has a stronger effect than both tether and electronic effects (16a
vs 27). Curiously, the reaction of enyne 29 resulted in no
conversion, indicating that the position of a malonate in the
tether also has a significant effect on the efficiency of the
reaction. In all cases shown in Table 3, type II products were
formed exclusively.
An interesting result was observed when pentafluorophenyl-
substituted enyne 49 was used a substrate (Scheme 7). The
reaction of 49 gave all three possible products, the bicyclization
product 50, 51 (type I), and 52 (type II). When PtCl2 was used
as a catalyst in place of Rh2(O2CCF3)4, the bicyclization product
The reaction of an enyne 36 containing an ester group at the
alkyne carbon was examined (Scheme 5). In sharp contrast to
enynes containing an aryl group at the alkyne carbon, the type
I product was the major isomer. This result is in contrast with
the case of the PtCl2-catalyzed reaction, in which a mixture of
type I and type II products is obtained with type II being
favored.2b
(20) Blum, J.; Beer-Kraft, H.; Badrieh, Y. J. Org. Chem. 1995, 60, 5567–
5569.
(21) Nevado, C.; Ferrer, C.; Echavarren, A. M. Org. Lett. 2004, 6, 3191–
000.
(22) Shibata, T.; Kobayashi, Y.; Maekawa, S.; Toshida, N.; Takagi, K.
Tetrahedron 2005, 61, 9018–9024.
(23) Lee, S. I.; Kim, S. M.; Choi, M. R.; Kim, S. Y.; Chung, Y. K. J. Org.
Chem. 2006, 71, 9366–9372.
The nature of the tether in enynes has a marked effect on the
course of the reaction, even for cases where the chain consists
(24) Brissy, D.; Skander, M.; Jullien, H.; Retailleau, P.; Marinett, A. Org.
Lett. 2009, 11, 2137–2139.
9
J. AM. CHEM. SOC. VOL. 131, NO. 42, 2009 15207

A R T I C L E S
Ota et al.
Table 4. Rh(II)-Catalyzed Bicyclization of Enynes with a
Scheme 8. 13C-Labeling Experiment
Heteroatom in the Tethera
Scheme 9. Rh2(O2CCF3)4-Catalyzed Polycyclization of Diene-ynes
A detailed reaction mechanism will be proposed later, but
the intermediacy of a cyclopropyl metal carbenoid is proposed
in the skeletal reorganization of enynes. To collect experimental
evidence for the intermediacy of a cyclopropyl metal carbenoid
in the Rh(II)-catalyzed skeletal reorganization of enynes, an
attempt to trap the cyclopropyl metal carbenoid by an intramo-
lecular alkene using 53 was made (Scheme 9).9a We were
pleased to succeed in trapping the cyclopropyl metal carbenoid
by an intramolecular alkene to stereoselectively give the
tetracyclic compound 54 in good yield. However, the cis-isomer
56 did not give the corresponding tetracyclic compound, but a
complex mixture was obtained. These contrasting results can
be rationalized by considering the stereochemistry of the
proposed cyclopropyl metal carbenoid intermediates 55 and 57.
The carbenoid moiety in 55 is sufficiently close to react with
the intramolecular alkene, since the carbenoid and the alkene,
which may react, are located in the cis form in the cyclopropane
ring in 55. On the other hand, the carbenoid moiety in 57 is
located too far from the alkene to undergo cyclopropanation
since the carbenoid and alkene have a trans relationship.
The results for the reaction of diene-ynes are shown in Table
5. The presence of a methyl, phenyl, and chloro substituent at
the internal alkene carbon, as in 58, 60, and 62, has little effect
on the efficiency of polycyclization. Diene-ynes 64 and 66, with
a heteroatom in the tether, also underwent polycyclization to
give 65 and 67. The reaction of 6-methylene-undec-1-en-10-
yne derivatives 68, in which a second alkene moiety is attached
a Reaction conditions: enyne (0.5 mmol), Rh2(O2CCF3)4 (0.01 mmol),
toluene (2.5 mL) at 80 °C for 20 h. b Isolated yield. c The reaction was
carried out by using Rh2(O2CCF3)4 (0.15 mmol) at 100 °C. d PtCl2 (0.01
mmol) was used as a catalyst.
50 was formed in 78% yield as a single product. This serves to
demonstrate the complexity of enyne reactions.
A 13C-labeling experiment using the simple enyne 1-C13 was
performed to determine which type of product is formed in the
case of a simple enyne.4f It would be helpful to have precise
information on the ratio of type I to type II compounds
produced, to better understand the reaction mechanism for the
skeletal reorganization of enynes. The reaction of 1-C13 in the
presence of Rh2(O2CCF3)4 in toluene at 80 °C gave a mixture
of type I and II isomers with type II being slightly favored,
showing that the anomalous bond connection is a slightly
favored route, even in the case of a simple enyne (Scheme 8).25
(25) Nakai, H.; Chatani, N. Chem. Lett. 2007, 36, 1494–1495.
9
15208 J. AM. CHEM. SOC. VOL. 131, NO. 42, 2009

Rh(II)-Catalyzed Reorganization of 1,6- and 1,7-Enynes
A R T I C L E S
Table 5. Rh2(O2CCF3)4-Catalyzed Polycyclization of Diene-ynesa
Scheme 11. Additional Evidences for the Intermediacy of
Cyclopropyl Carbenoid
We also found that Rh2(O2CCF3)4 shows high catalytic activity
for a similar transformation, as shown in Scheme 11. The
reaction of 73 gave 74 in high yield, similar to the case of Lee’s
system. This involves the 5-exo cyclization of an enyne moiety
leading to the production of a cyclopropyl carbenoid 75 followed
by a metalotropic [1,3]-shift27 leading to a second cyclopropyl
carbenoid 76, which undergoes cyclopropanation to give 74.
In sharp contrast to Lee’s work, in which 6-endo cyclization
occurred selectively when a substrate with nitrogen function-
alities in the tether was used as a substrate, even 77 selectively
underwent 5-exo cyclization in the presence of a rhodium
catalyst to give 78, and only trace amounts of 6-endo cyclization
product 79 was formed.28
A proposed reaction mechanism is shown in Scheme 12. The
mechanism is essentially the same as that previously proposed
for the Pt(II)- and Au(I)-catalyzed reactions.4f,12 type I products
are formed via the mechanism depicted by blue arrows. Type
II products are formed via the mechanism depicted by red solid
arrows. The electrophilic interaction of the alkyne in 80 with
Rh(II) generates a cyclopropyl rhodium carbenoid 81, the
intermediacy of which has already been proposed, based on the
trapping experiments of the corresponding cyclopropyl metal
carbenoids by intramolecular and intermolecular alkenes9,10 and
on DFT caluculations.12 The carbenoid 81 undergoes rearrange-
ment to give the cyclobutene intermediate 82 or a spiro
intermediate 83. Depending on the substitution pattern, the spiro
intermediate 83 undergoes fragmentation to give either the
a Reaction conditions: enyne (0.5 mmol), Rh2(O2CCF3)4 (0.01 mmol),
toluene (2.5 mL) at 80 °C for 1 h. b Isolated yield. c For 2 h. d For 1 day.
Scheme 10. Usual Skeletal Reorganization Occurs
at the internal alkene carbon, also underwent polycyclization
to give the tetracyclic compounds 69.
Compounds such as 70, 71, and 72 did not give the correspond-
ing polycyclic compound, but the usual skeletal reorganization
products were formed (Scheme 10). The distance between the
carbenoid and alkene moiety in the proposed cyclopropyl carbenoid
is an important aspect of the reaction (53 vs 71 and 68 vs 72).
Lee recently reported on the PtCl2-catalyzed double ring-
closing reaction of tetradeca-1,13-diene-6,8-diyne derivatives.26
(26) Cho, E. J.; Kim, M.; Lee, D. Org. Lett. 2006, 8, 5413–5416.
(27) For a review on metalotropic [1,3]-shift, see: Lee, D.; Kim, M. Org.
Biomol. Chem. 2007, 5, 3418–3427.
(28) The reaction of 77 under the same reaction conditions reported by
Lee (PtCl2 under 1 atm of CO) gave a 13:87 ratio of 78 and 79 in
total 91% yield, in favor of the 6-endo product 79.
9
J. AM. CHEM. SOC. VOL. 131, NO. 42, 2009 15209

A R T I C L E S
Ota et al.
Scheme 12. Proposed Reaction Mechanism of Skeletal Reorganization
carbocation 84 or another carbenoid 85. The elimination of
Rh(II) from 84 and 85 gives two alternative products, type I
and type II, respectively. Hence, a type I product is formed
from 82 or 84, and a type II product from 85. When R3 ) H,
the type I product is formed from 82 by ring-opening, because
the primary carbocation 84 is too unstable to generate. When
substrates have a substitution of R3 on the alkene carbon, 84
becomes a secondary carbocation, which is stabilized by the
presence of the R3 group, resulting in the exclusive formation
of a trans-isomer, as in 4, irrespective of the stereochemistry of
the starting enynes, as shown in Table 1.
Complex 85 undergoes a 1,2-H shift to give cis-configured
type II products.29 Depending on the nature of R2, the ratio of
type I and II changed when R1 ) Ph. Thus, in the case whre
R1 ) Ph, R2 ) H, and R3 ) H, a type I product is exclusively
formed through 82. In sharp contrast, the selective formation
of a type II product is observed when R2 ) Me. This can be
rationalized by the fact that the methyl group (R2) stabilizes
the tertiary cation in 83, leading to the selective generation of
85.30
When X ) NTs, bicyclization occurred, to give the 2-aza-
bicyclo[4.1.0]heptene derivative, as shown in Scheme 6 and
Table 4. The involvement of a carbenoid complex 86, generated
from 80 via the 6-endo pathway, is inferred based on the
formation of a 2-aza-bicyclo[4.1.0]heptene derivative. Another
alternative route to type I products involves the ring opening
of the cyclobutyl cation intermediate 87, which is formed from
86. The formation of 18 suggests the generation of 87, which
is stabilized by an electron-donating group, such as 4-MeOC6H4.
It should be noted that, even with nitrogen or oxygen tethered
enyne derivatives (66 in Table 5 and 77 in Scheme 11), the
reaction can proceed favorably by the 5-exo pathway as an initial
step.
The carbenoids 81 and 86 are limited structural representa-
tions of the rapid equilibrium between 81 and 86. The course
of the reaction is determined by the relative rate of conversion
from 81 or 86 or the stability of intermediates generated from
81 or 86. This would explain the observation that enynes with
a nitrogen or oxygen atom in the tether react via either the 5-exo
and 6-endo pathways, depending on the structure of substrates.
As shown in Table 2, the nature of substituents in the tether
has a significant effect on the course of the reaction. The
substrates having a ketal functionality in the tether, as in 19
and 21a, has a tendency to form type II products in comparison
with the substrates with a malonate tether, as in 14 and 15a.
The presence of an oxy group at the proparglyic position also
favors the exclusive formation of type I products irrespective
of the nature of the substituent at the alkyne carbon, as shown
in Table 1. These effects of substituent groups in the tether on
the product distribution are not currently clear. Irrespective of
the nature of the tether or the substituents on the aromatic ring,
1,7-enynes selectively gave type II products, because of the
unfavorable 7-endo pathway.
To examine the utility of Rh(II) for use in diverse transforma-
tions, some other cycloisomerization reactions, which would
involve the electrophilic activation of alkynes as the key step,
were also investigated. We were pleased to find that the reaction
of alkynylfurans 91 proceeds via cyclization to give a regioi-
someric mixture of phenol derivatives 92 and 93 in good yields
(Scheme 13). Hashmi has extensively studied this type of
reaction using Au(III) as the catalyst,31 and Echavarren discov-
ered that PtCl2 can also be used to catalyze the same transfor-
mation and reveal mechanistic details of the reaction by
observation of side products that are produced and by theoretical
calculations.32 Similar to the above cases, the presence of a
methyl group at the 5-position, as in 94, resulted in the selective
(29) Taber, D. F.; Joshi, P. V. J. Org. Chem. 2004, 69, 4276.
(30) When R3 ) H, the path to 83 from 84 does not occur because 84 is
a primary cation.
9
15210 J. AM. CHEM. SOC. VOL. 131, NO. 42, 2009

Rh(II)-Catalyzed Reorganization of 1,6- and 1,7-Enynes
A R T I C L E S
Scheme 13. Cycloisomerization of Alkynylfurans
importantly, two possible isomers of 1-vinylcycloalkenes, type
I and type II products, can be obtained, the ratio of which are
highly dependent on the substitution pattern of the enynes. The
use of enynes having an aryl group at the alkyne carbon and a
methyl group at the alkene internal carbon resulted in the
exclusive formation of type II. The presence of an electron-
withdrawing group on the phenyl ring facilitates the formation
of type II products. The nature of the tether also has a significant
effect on the course of the reaction. In addition, Rh(II) is also
active in some cycloisomerization reactions of alkyne deriva-
tives, which are known to proceed in the presence of Pt(II),
Au(I), or Au(III) as catalysts.
Experimental Section
formation of phenol derivative 95. In addition, the reaction of
94 was completed within 2 h, even at a temperature of 25 °C.
A few representative examples are listed here. Experimental
procedures and spectroscopic data for new compounds can be found
in the Supporting Information.
Conclusions
Typical Procedure for Rh(II)-Catalyzed Skeletal Reor-
ganization. A 10-mL two-necked flask equipped with a reflux
condenser connected to a N2 line was flame-dried under a flow of
N2 and cooled to room temperature. Enyne (0.5 mmol) and Rh(II)
(0.01 mmol) were added, and toluene (2.5 mL) was added via a
syringe. The vessel was heated in an oil bath at 80 °C. The reaction
was monitored by GC, and after it was completed, the vessel was
cooled. The volatile components were removed in Vacuo, and the
residue was subjected to column chromatography on silica gel to
give a product.
The findings reported herein demonstrate that Rh(II) com-
plexes are also active in the skeletal reorganization of 1,6- and
1,7-enynes to 1-vinylcycloalkenes. A characteristic feature of
the Rh(II)-catalyzed skeletal reorganization of enynes is the wide
applicability of enynes having a substituent, such as an alkyl,
aryl, chloro, and ester substituent at the alkyne carbon. Most
(31) For selected papers, see: Hashmi, A. S. K.; Frost, T.; Bats, J. W. J. Am.
Chem. Soc. 2000, 122, 11553–11554. Hashmi, A. S. K.; Frost, T. M.;
Bats, J. W. Org. Lett. 2001, 3, 3769–3771. Hashmi, A. S. K.;
Weyrauche, J. P.; Rudolph, M.; Kurpejovic´, E. Angew. Chem., Int.
Ed. 2004, 43, 6545–6547. Hashmi, A. S. K.; Grundl, L. Tetrahedron
2005, 61, 6231–6236. Hashmi, A. S. K.; Rudolph, M.; Weyrauch,
J. P.; Wo¨lfe, M.; Frey, W.; Btas, J. W. Angew. Chem., Int. Ed. 2005,
44, 2798–2801. Hashmi, A. S. K.; Blanco, M. C.; Kurpejovic´, E.;
Frey, W.; Bats, J. W. AdV. Synth. Catal. 2006, 348, 709–713. Carrettin,
S.; Blanco, M. C.; Corma, A.; Hashmi, A. S. K. AdV. Synth. Catal.
2006, 348, 1283–1288. Hashmi, A. S. K.; Weyrauch, J. P.; Kurpejovic,
E.; Frost, T. M.; Miehlich, B.; Frey, W.; Bats, J. W. Chem.sEur. J.
2006, 12, 5806–5814. Hashmi, A. S. K.; Salathe´, R.; Frey, W.
Chem.sEur. J. 2006, 12, 6991–6996. Hashmi, A. S. K.; Rudolph,
M.; Siehl, H.-U.; Tanaka, M.; Bats, J. W.; Frey, W. Chem.sEur. J.
2008, 14, 3703–3708. Hashmi, A. S. K.; Scha¨fer, S.; Bats, J, W.; Frey,
W.; Rominger, F. Eur. J. Org. Chem. 2008, 489, 1–4899. Hashmi,
A. S.; Rudolph, M.; Huck, J.; Frey, W.; Bats, F. J. W.; Hamzic´, M.
Angew. Chem., Int. Ed. 2009, 48, 5848–5852.
Acknowledgment. This work was partially supported by The
Ministry of Education, Science, Sport, and Culture, Japan. NC
acknowledges the Merck Research Laboratories for financial
support. Dr. S. I. Lee wishes to acknowledge financial support from
KRF (2007-357-C0057) (Korea Research Foundation) and JSPS
(Japan Society for the Promotion of Science) for a postdoctoral
fellowship.
Supporting Information Available: Experimental procedures
and spectroscopic data for new compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
JA9047637
(32) Mart´ın-Matute, B.; Ca´rdenas, D. J.; Echavarren, A. M. Angew. Chem.,
Int. Ed. 2001, 40, 4754–4757. Mart´ın-Matute, B.; Nevado, C.;
Ca´rdenas, D. J.; Echavarren, A. M. J. Am. Chem. Soc. 2003, 125,
5757–5766. Nevado, C.; Ferrer, C.; Echavarren, A. M. Org. Lett. 2004,
6, 3191–3194.
9
J. AM. CHEM. SOC. VOL. 131, NO. 42, 2009 15211