New ring-expansion reactions of hydroxy propenoyl cyclic compounds under palladium(0)/phosphine-catalyzed conditions

Article abstract of DOI:10.1021/ol049450c

Palladium(0)-catalyzed one-atom ring-expansion of 1-hydroxy-2,2-dialkyl-1- propenoylindan derivatives has been achieved in the presence of P(o-tolyl) ₃ giving 2-hydroxy-3,3-dialkyl-2-vinyl-1-tetralone derivatives in excellent yields. This ring-expansion reaction was applied to a 17-(1-oxo-2-propenyl)-β-estradiol derivative and furnished a similar ring-expanded product in an excellent yield.

Full text of DOI:10.1021/ol049450c

ORGANIC
LETTERS
2004
Vol. 6, No. 13
2133-2136
New Ring-Expansion Reactions of
Hydroxy Propenoyl Cyclic Compounds
under Palladium(0)/Phosphine-Catalyzed
Conditions
,†
Yoshimitsu Nagao,* Satoru Tanaka,† Akiharu Ueki,† Masunori Kumazawa,†
Satoru Goto,† Takashi Ooi,† Shigeki Sano,† and Motoo Shiro‡
Faculty of Pharmaceutical Sciences, The UniVersity of Tokushima,
Sho-machi, Tokushima 770-8505, Japan, and Rigaku Corporation,
3-9-12 Matsubara-cho, Akishima-shi, Tokyo 196-8666, Japan
ynagao@ph.tokushima-u.ac.jp
Received March 24, 2004
ABSTRACT
Palladium(0)-catalyzed one-atom ring-expansion of 1-hydroxy-2,2-dialkyl-1-propenoylindan derivatives has been achieved in the presence of
P(o-tolyl)3 giving 2-hydroxy-3,3-dialkyl-2-vinyl-1-tetralone derivatives in excellent yields. This ring-expansion reaction was applied to a 17-
(1-oxo-2-propenyl)-â-estradiol derivative and furnished a similar ring-expanded product in an excellent yield.
Ring-expansion reactions have provided chemists a consider-
ably useful tool for the construction of various biologically
active natural products and drugs.1 Recent efforts in our
laboratory have focused on base-mediated and Pd(0)-
catalyzed ring-expansion reactions (5 f 7 and 5 f 6) using
various hydroxy allenyl cyclic compounds.2 Liebeskind and
Stone3a and the Butenscho¨n group3b reported acid (CF3-
CO2H)-catalyzed ring-expansion reactions (4 f 5) of meth-
oxyallenylcyclobutenols via corresponding enone interme-
diates, thus releasing four-membered ring strain.3a However,
a similar acid-catalyzed ring-expansion reaction of the
1-hydroxy-2,2-dimethyl-1-propenoylindan 2a with CF3CO2H
resulted in a very low yield (6%) of a ring-expanded product
3a and 89% recovery of 2a. Conventional reaction conditions
using BF3‚OEt2 and KOH for the well-known R-ketol
rearrangement4 were also not available for the ring-expansion
reactions of 2a. We describe here the first successful
demonstration of the Pd(0)- and phosphine-catalyzed one-
atom ring-expansion reactions of 2a-d and 9 under neutral
conditions.
† The University of Tokushima.
‡ Rigaku Corporation.
(1) Hesse, M. Ring Enlargement in Organic Chemistry; VCH Publish-
ers: New York, 1991.
(2) (a) Jeong, I.-Y.; Nagao, Y. Tetrahedron Lett. 1998, 39, 8677. (b)
Jeong, I.-Y.; Lee, W. S.; Goto, S.; Sano, S.; Shiro, M.; Nagao, Y.
Tetrahedron 1998, 54, 14437. (c) Jeong, I.-Y.; Nagao, Y. Synlett 1999,
576. (d) Jeong, I.-Y.; Shiro, M.; Nagao, Y. Heterocycles 2000, 52, 85. (e)
Nagao, Y.; Tanaka, S.; Ueki, A.; Jeong, I.-Y.; Sano, S.; Shiro, M. Synlett
2002, 480. (f) Nagao, Y.; Ueki, A.; Asano, K.; Tanaka, S.; Sano, S.; Shiro,
M. Org. Lett. 2002, 4, 455. (g) Nagao, Y.; Sano, S. J. Synth. Org. Chem.,
Jpn. 2003, 61, 1088.
Scheme 1
(3) (a) Stone, G. B.; Liebeskind, L. S. J. Org. Chem. 1990, 55, 4614.
(b) Ziehe, H.; Wartchow, R.; Butenscho¨n, H. Eur. J. Org. Chem. 1999,
823.
10.1021/ol049450c CCC: $27.50 © 2004 American Chemical Society
Published on Web 05/27/2004

Table 1. One-Atom Ring-Expansion Reactions of 1-Hydroxy-2,2-dialkyl-1-propenoylindans 2a-d
entry
2
Pd (mol %)
additive (mol %)
time (h)
product
yield (%)a
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
2a
2b
2a
2b
2c
2d
2a
2a
2a
2a
2a
2a
2a
2a
2a
2b
2a
2a
2a
2a
Pd(PPh3)4 (5.0)
Pd(PPh3)4 (5.0)
Pd(PPh3)4 (5.0)
Pd(PPh3)4 (5.0)
Pd(PPh3)4 (5.0)
Pd(PPh3)4 (5.0)
7
15
7
15
18
22
7
24
7
7
3a
3b
3a
3b
3c
3d
3a
3a
3a
3a
3a
3a
3a
3a
3a
3b
3a
3a
3a
3a
52b (40b)c
68b (22b)c
92
99
90
P(o-tolyl)3 (10.0)
P(o-tolyl)3 (10.0)
P(o-tolyl)3 (10.0)
P(o-tolyl)3 (10.0)
P(o-tolyl)3 (10.0)
P(o-tolyl)3 (30.0)
PPh3 (10.0)
P(n-Bu)3 (10.0)
DPPE (10.0)
DABCO (10.0)
DBU (10.0)
80
43b (29b)c
71
55
12
13
7
7
7
7
23b (traceb)c
53
Et3N (10.0)
Me2S (10.0)
P(o-tolyl)3 (10.0)
25b (45b)c
13b (71b)c
62b (27b)c
26b (44b)c
28b (13b)c
5b (67b)c
83
7
15
24
24
24
7
PdCl2(MeCN)2 (5.0)
PdCl2(MeCN)2 (5.0)
Pd2(dba)3‚CHCl3 (2.5)
Pd2(dba)3‚CHCl3 (2.5)
P(o-tolyl)3 (10.0)
P(o-tolyl)3 (10.0)
a Isolation yield. b 1H NMR (400 MHz, CDCl3) analysis. c Recovery of starting material.
The precursor compounds 2a-d were prepared in 75-
88% yields by treatment of the corresponding dialkylin-
danones 1a-d5 with lithio methoxyallene, followed by
hydrolysis with 1 N HCl in MeOH-THF (Scheme 1).6,7
First, 2a was refluxed for 7 h in the presence of 5 mol %
Pd(PPh3)4 alone in THF. The desired one-atom ring-
expansion reaction proceeded to afford the 2-hydroxy-3,3-
dialkyl-2-vinyl-1-tetralone derivative 3a in 52% yield, but
2a (40%) was recovered (entry 1 in Table 1). Similar
treatment of 2b for 15 h gave 3b in 68% yield, together with
Scheme 2
22% recovery of 2b (entry 2 in Table 1). These results
suggested the decomposition of the Pd catalyst under the
reaction conditions used. Thus, 2a was refluxed for 7 h in
the presence of 5 mol % Pd(PPh3)4 and 10 mol % P(o-tolyl)3
as an additive,8 which is known to stabilize Pd catalysts and
improve turnover in THF. The desired ring-expansion
reaction proceeded smoothly to afford 3a in 92% yield (entry
3 in Table 1). Then, similar reactions of 2b-d using 5 mol
% Pd(PPh3)4 and 10 mol % P(o-tolyl)3 furnished 3b in 99%
yield, 3c in 90% yield, and 3d in 80% yield, respectively
(entries 4-6 in Table 1). All experimental results are
summarized in Scheme 2 and Table 1.
membered compounds 4a and 5a, respectively, with 5 mol
% Pd(PPh3)4 and 10 mol % P(o-tolyl)3 in THF under reflux
The structures of all ring-expanded products 3a-d were
explicitly determined by their characteristic spectroscopic
data and/or by X-ray crystallographic analysis of 3a, as
shown in Figure 1.7,9 Treatment of the six- and seven-
Figure 1. Computer-generated drawing from the X-ray coordinates
of compounds 3a and 10.
for 24 h led only to recovery of each corresponding starting
compound in either 79 or 90% yield.
To clarify the ring-expansion mechanism, several reactions
were carried out as follows. Compounds 2a,b were allowed
(4) Paquette, L. A.; Hofferberth, J. E. Org. React. 2003, 62, 477.
(5) Pletnev, A. A.; Larock, R. C. J. Org. Chem. 2002, 67, 9428.
(6) (a) Hoff, S.; Brandsma, L.; Arens, J. F. Recl. TraV. Chim. Pays-Bas
1968, 87, 916. (b) Hoff, S.; Brandsma, L.; Arens, J. F. Recl. TraV. Chim.
Pays-Bas 1968, 87, 1179. (c) Gange, D.; Magnus, P. J. Am. Chem. Soc.
1978, 100, 7746. (d) Weiberth, F. J.; Hall, S. S. J. Org. Chem. 1985, 50,
5308. (e) Zimmer, R. Synthesis 1993, 165. (f) Pulz, R. Synlett 2000, 1697.
(7) See also Supporting Information.
(9) X-ray data for 3a: C14H16O2, MW ) 216.28, colorless needle,
monoclinic, space group P21/c (#14), a ) 13.2235(4) Å, b ) 10.1349(5)
Å, c ) 18.0755(5) Å, V ) 2298.0(2) Å3, â ) 108.443(4)°, Z ) 8, R )
0.131, Rw ) 0.061. Structure factors are available from author upon request.
(8) For review, see: Crisp, G. T. Chem. Soc. ReV. 1998, 27, 427.
2134
Org. Lett., Vol. 6, No. 13, 2004

to react with several Lewis bases [e.g., P(o-tolyl)3, PPh3, 1,2-
bis(diphenylphosphino)ethane (DPPE), DABCO, DBU, Et3N,
Me2S], which are commonly employed in the traditional
Morita-Baylis-Hillman reaction,10 in THF under reflux
without the use of Pd(PPh3)4 to give 3a or 3b in 12-71%
yields, respectively (entries 7-16 in Table 1). On the basis
of recent reports11 that the propenoyl moiety can coordinate
to Pd(II), 2a was treated with PdCl2(MeCN)2 alone or a
mixture of PdCl2(MeCN)2 and P(o-tolyl)3. These reactions
gave 3a in 26 and 28% yields, respectively, together with
the recovery of 2a (entries 17 and 18 in Table 1). Upon
treatment with Pd2(dba)3‚CHCl3 alone as a Pd(0) catalyst,
the reaction of 2a scarcely proceeded (entry 19 in Table 1),
but in the presence of P(o-tolyl)3, the yield of 3a was
improved to 83% (entry 20 in Table 1). Thus, it was
demonstrated that the Pd(0) species were essential catalysts,
and the Pd(0)-catalyzed ring-expansion reaction required an
efficient additive such as P(o-tolyl)3. Subsequently, we
investigated the importance of the CdC bond in the
propenoyl moiety of 2a-c. 1-Hydroxy-1-propanoylindan
derivatives 6a-c, obtained by the catalytic hydrogenation
of 2a-c, were subjected to the same reaction conditions as
described above, but the corresponding R-tetralone deriva-
tives 7a-c were obtained in scant amounts, as shown in
Table 2. When 6a was refluxed in the presence of 50 mol
basis of the experimental results described above (Figure
2).2f,10-13 In the first step of the catalytic cycle, the oxidative
Figure 2. Plausible mechanisms for the Pd(0)- and phosphine-
catalyzed ring-expansion reactions of 2a-d.
addition of the hydroxy group of 2a-d to a Pd(0) catalyst
generates the complex A,2f,11-13 in which the reductive
elimination of the Pd(II) species, followed by migration of
the C1-C2 bond in a concerted manner (C), may give the
ring-expanded products 3a-d.
Conjugate addition of the phosphine species to the
propenoyl moiety of A may form complex D,10 in which
synchronous release of the Pd(II) species and the phospho-
nium moiety, followed by the migration of the C1-C2 bond,
would afford 3a-d. In another plausible first step of the
catalytic cycle, the coordination of the propenoyl moiety of
2a-d to the Pd(0) species may generate the weak complex
B, whereby the easy conjugate addition of the phosphine
species10 may generate the phosphonium intermediate E. In
E, hydrogen abstraction from the C1-OH group by the
resulting enolate, followed by ketonization and release of
the phosphonium moiety, would occur, together with syn-
chronous double-bond migration and C1-C2 bond migration
to give 3a-d.
The â-ketol rearrangement reaction of 17-hydroxy-20-
ketosteroids, referred to as the D-homo rearrangement, was
discovered in 1938 and has been the subject of investigation
ever since its discovery.14 Although all rearrangement
reactions of steroidal compounds are typically performed by
employing various bases and Lewis acids,14 such a neutral
Pd(0)- and phosphine-catalyzed rearrangement reaction has
never been reported. Hence, we attempted the ring-expansion
reaction of 17-(1-oxo-2-propenyl)-â-estradiol derivative 9
Table 2. Attempt at Ring-Expansion Reactions of
1-Hydroxy-1-propanoylindans 6a-c
Pd(PPh3)4 P(o-tolyl)3 time
yield
(%)a
entry
6
(mol %)
(mol %)
(h)
product
1
2
3
4
6a
6a
6b
6c
5
50
5
10
100
10
7
24
15
18
7a
7a
7b
7c
10 (87)b
88c
12 (78)b
8 (92)b
5
10
a 1H NMR (400 MHz, CDCl3) analysis. b Recovery of starting material.
c Isolation yield.
% Pd(PPh3)4 and 100 mol % P(o-tolyl)3 in THF, 7a could
be obtained in 88% yield. These results suggested that the
presence of the CdC bond in the conjugated propenoyl
moiety of 2a-c was very efficient in the Pd(0)- and
P(o-tolyl)3-catalyzed ring-expansion reactions.
(12) (a) Braga, D.; Sabatino, P.; Bugno, C. D.; Leoni, P.; Pasquali, M.
J. Organomet. Chem. 1987, 334, C46. (b) Bugno, D. C.; Pasquali, M.; Leoni,
P.; Sabatino, P.; Braga, D. Inorg. Chem. 1989, 28, 1390.
Speculative mechanisms for the Pd(0)- and phosphine-
catalyzed ring-expansion reactions can be suggested on the
(13) (a) Camacho, D. H.; Nakamura, I.; Saito, S.; Yamamoto, Y. Angew.
Chem., Int. Ed. 1999, 38, 3365. (b) Camacho, D. H.; Nakamura, I.; Saito,
S.; Yamamoto, Y. J. Org. Chem. 2001, 66, 270. (c) Kadota, I.; Lutete, L.
M.; Shibuya, A.; Yamamoto, Y. Tetrahedron Lett. 2001, 42, 6207.
(14) (a) Ruzicka, L.; Meldahl, H. F. HelV. Chim. Acta 1938, 21, 1760.
(b) Creary, X.; Inocencio, P. A.; Underiner, T. L.; Kostromin, R. J. Org.
Chem. 1985, 50, 1932. (c). Bischofberger, N.; Walker, K. A. M. J. Org.
Chem. 1985, 50, 3604. (d) Schor, L.; Seldes, A. M. S.; Gros, E. G. J. Chem.
Soc., Perkin Trans. 1 1990, 163. (e) Paryzek, Z.; Martynow, J. J. Chem.
Soc., Perkin Trans. 1 1994, 823.
(10) (a) Evans, D. A.; Hurst, K. M.; Takacs, J. M. J. Am. Chem. Soc.
1978, 100, 3467. (b) Basavaiah, D.; Rao, P. D.; Hyma, R. S. Tetrahedron
1996, 52, 8001. (c) Ciganek, E. Org. React. 1997, 51, 201.
(11) (a) Hosokawa, T.; Shinohara, T.; Ooka, Y.; Murahashi, S. I. Chem.
Lett. 1989, 2001. (b) Kawatsura, M.; Hartwig, J. F. Organometallics 2001,
20, 1960. (c) Miller, K. J.; Kitagawa, T. T.; Abu-Omar, M. M. Organo-
metallics 2001, 20, 4403.
Org. Lett., Vol. 6, No. 13, 2004
2135

(vide infra), which was prepared from 8, as shown in Scheme
3. Crude compound 9, without being purified on a silica gel
To confirm the importance of the conjugated propenoyl
system in the Pd(0)- and phosphine-catalyzed ring-expansion
of 9, compound 14, which was obtained by hydrogenation
of 9, was refluxed for 24 h under the same conditions as
those used in the case of 9. The ring-expansion reaction
proceeded to afford 15 in 39% yield, but 44% of 14 was
recovered (Scheme 4). This result suggested that the CdC
bond of the conjugated propenoyl moiety played an important
role; thus, the Morita-Baylis-Hillman reaction10 appeared
to be involved in the Pd(0)- and phosphine-catalyzed ring-
expansion reaction. The structure and stereochemistry of 15
were determined by its identification with the product, which
was prepared by catalytic hydrogenation of 10.7 Thus, the
Pd(0)- and phosphine-catalyzed ring-expansion reaction of
9 can be similarly explained in terms of the case of 2a-d,
as shown in Figure 2.
Scheme 3
In conclusion, we demonstrated new Pd(0)- and
P(o-tolyl)3-catalyzed one-atom ring-expansion reactions of
1-hydroxy-2,2-dialkyl-1-propenoylindan derivatives and a
steroidal compound. These new reactions are expected to
be useful for the construction of cyclohexanones bearing
vinyl and hydroxy groups and for further allylic rearrange-
ment.16
column, was refluxed in the presence of 5 mol % Pd(PPh3)4
and 10 mol % P(o-tolyl)3 in THF for 24 h. The desired ring-
expansion reaction proceeded in a stereospecific manner to
afford the sole product 10 in 86% yield from 8 among four
possible products, 10-13 (Scheme 3). The structure of 10
was clarified by X-ray crystallographic analysis, as shown
in Figure 1.7,15
On the basis of the stereochemistry (1H NOESY experi-
ment shown in Figure 3) of the precursor 9 and the product
Scheme 4
Acknowledgment. This work was supported by a Grant-
in-Aid for Scientific Research on Priority Areas (A)(2) (No.
13029085) from the Ministry of Education, Culture, Sports,
Science, and Technology, Japan.
Supporting Information Available: Typical experimen-
tal procedure for the synthesis of compounds 1b,c, 2a-d,
3a, 4a, 5a, 6a-c, 7a, 9, 10, 14, and 15 and their physical
and spectroscopic data, as well as X-ray structural data of
compounds 3a and 10 (CIF). This material is available free
of charge via the Internet at http://pubs.acs.org.
1
Figure 3. Selected H NMR NOE enhancement for 9.
10, it becomes evident that the ring-expansion reaction
proceeded by the stereospecific migration of the C13-C17
bond rather than by that of the C16-C17 bond.
OL049450C
(15) X-ray data for 10: C22H28O3, MW ) 340.46, colorless plate,
orthorhombic, space group P212121 (#19), a ) 7.4067(3) Å, b ) 7.8333(2)
Å, c ) 30.5900(9) Å, V ) 1774.80(10) Å3, Z ) 4, R ) 0.065, Rw ) 0.115.
Structure factors are available from author upon request.
(16) Hottop, T.; Gutke, H.-J.; Murahashi, S.-I. Tetrahedron Lett. 2001,
42, 3343.
2136
Org. Lett., Vol. 6, No. 13, 2004