Sequential silylcarbocyclization/silicon-based cross-coupling reactions

Article abstract of DOI:10.1021/ja067854p

A sequential rhodium-catalyzed silylcarbocyclization of enynes parlayed with a palladium-catalyzed, silicon-based cross-coupling reaction has been developed for the synthesis of highly substituted cyclopentanes. 1,6-Enynes reacted with benzyldimethylsilan

Full text of DOI:10.1021/ja067854p

Published on Web 03/03/2007
Sequential Silylcarbocyclization/Silicon-Based
Cross-Coupling Reactions
Scott E. Denmark* and Jack Hung-Chang Liu
Contribution from the Roger Adams Laboratory, Department of Chemistry, UniVersity of Illinois,
Urbana, Illinois 61801
Received November 2, 2006; E-mail: denmark@scs.uiuc.edu
Abstract: A sequential rhodium-catalyzed silylcarbocyclization of enynes parlayed with a palladium-
catalyzed, silicon-based cross-coupling reaction has been developed for the synthesis of highly substituted
cyclopentanes. 1,6-Enynes reacted with benzyldimethylsilane in the presence of rhodium catalysts to afford
five-membered rings bearing a (Z)-alkylidenylbenzylsilyl group. A variety of substitution patterns and
heteroatom substituents were compatible. The silylcarbocyclization in which an unsaturated ester participated
was also achieved. The resulting alkylidenylsilanes underwent palladium-catalyzed cross-coupling using
tetra-n-butylammonium fluoride. This cross-coupling reaction displayed a broad substrate scope. A wide
variety of substitution patterns, electronic properties, and heteroatoms were compatible. All of the cross-
coupling reactions proceeded in high yields under very mild conditions and with complete retention of double
bond configuration, resulting in densely functionalized 3-(Z)-benzylidenecyclopentanes and heterocycles.
Introduction
extensively studied. Ojima and co-workers have developed a
Silylcarbocyclization1 is a ring-forming reaction of a poly-
unsaturated acyclic substrate initiated by silylmetalation of a
double bond or a triple bond. As first described by Tamao and
Ito in 1989, 1,7-diynes and hydrosilanes react in the presence
of a low-valent nickel catalyst to afford exocyclic 1-(Z)-
silylmethylene-2-methylenecyclohexanes.2a Substrates suitable
for silylcarbocyclization are not limited to diynes2 but also
include enynes,3 dienes,4 allenynes,5 alkynals,6 allenals,7 tet-
raenes,8 and endiynes,9 of which enynes have been most
highly efficient silylcarbocyclization of 1,6-enynes with hy-
drosilanes, catalyzed by Rh4(CO)12 under very mild conditions,
with a very broad range of substrates (Scheme 1).3a,c Closely
related to silylcarbocyclization is carbonylative silylcarbocy-
clization,1 which affords a formylated homologue of the
silylcarbocyclization product. Notably, asymmetric variants of
both silylcarbocyclization3d,g and carbonylative silylcarbo-
cyclization10 have been reported recently. The products obtained
from the silylcarbocyclization reaction of enynes feature a silyl-
alkylidenyl functionality with a defined double bond geometry,
which we envisioned as an opportunity for further synthetic
elaboration.
(1) For reviews on silylcarbocyclization, see: (a) Tamao, K.; Kobayashi, K.;
Ito, Y. Synlett 1991, 539-546. (b) Ojima, I.; Moralee, A. C.; Vassar,
V. C. Top. Catal. 2002, 19, 89-99. (c) Widenhoefer, R. A. Acc. Chem.
Res. 2003, 35, 905. (d) Varchi, G.; Ojima, I. Curr. Org. Chem. 2006, 10,
1341-1362. (e) Fujiwara, M.; Ojima, I. In Modern Rhodium-Catalyzed
Organic Reactions; Evans, P. A., Ed.; Wiley-VCH: Weinheim, 2005;
Chapter 7.
Scheme 1
(2) (a) Tamao, K.; Kobayashi, K.; Ito, Y. J. Am. Chem. Soc. 1989, 111, 6478-
6480. (b) Ojima, I.; Zhu, J.; Vidal, E. S.; Kass, D. F. J. Am. Chem. Soc.
1998, 120, 6690-6697. (c) Muraoka, T.; Matsuda, I.; Itoh, K. Tetrahedron
Lett. 1998, 39, 7325-7328. (d) Muraoka, T.; Matsuda, I.; Itoh, K.
Organometallics 2002, 21, 3650-3660. (e) Liu, C.; Widenhoefer, R. A.
Organometallics 2002, 21, 5666-5673. (f) Wang, X.; Charkrapani, H.;
Madine, J. W.; Keyerleber, M. A.; Widenhoefer, R. A. J. Org. Chem. 2002,
67, 2778-2788. (g) Uno, T.; Wakayanagi, S.; Sonoda, Y.; Yamamoto, K.
Synlett 2003, 1997-2000.
(3) (a) Ojima, I.; Donovan, R. J.; Shay, W. R. J. Am. Chem. Soc. 1992, 114,
6580-6582. (b) Molander, G. A.; Retsch, W. H. J. Am. Chem. Soc. 1997,
119, 8817-8825. (c) Ojima, I.; Vu, A. T.; Lee, S.-Y.; McCullagh, J. V.;
Moralee, A. C.; Fujiwara, M.; Hoang, T. M. J. Am. Chem. Soc. 2002, 124,
9164-9174. (d) Chakrapani, H.; Liu, C.; Widenhoefer, R. A. Org. Lett.
2003, 5, 157-159. (e) Park, K. H.; Kim, S. Y.; Son, S. U.; Chung, Y. K.
Eur. J. Org. Chem. 2003, 4341-4345. (f) Park, K. H.; Jung, I. G.; Kim,
S. Y.; Chung, Y. K. Org. Lett. 2003, 5, 4967-4970. (g) Fan, B.-M.; Xie,
J.-H.; Li, S.; Wang, L.-X.; Zhou, Q.-L. Angew. Chem., Int. Ed. 2007, 46,
1275-1277.
(4) (a) Widenhoefer, R. A.; DeCarli, M. A. J. Am. Chem. Soc. 1998, 120, 3805-
3806. (b) Widenhoefer, R. A. Acc. Chem. Res. 2002, 35, 905-913. (c)
Perch, N. S.; Widenhoefer, R. A. J. Am. Chem. Soc. 2004, 126, 6332-
6346.
Palladium-catalyzed, silicon-based cross-coupling has emerged
as a useful alternative to the classical Stille and Suzuki cross-
coupling reactions.11 One of the main advantages of the silicon-
based cross-coupling process is that the silicon-containing
functionality can be easily introduced into substrates by a wide
variety of methods with a high degree of functional group
tolerance. To better harness of the power of silicon-based cross-
coupling, we have developed a number of sequential processes
(7) (a) Kang, S.-K.; Ha, Y.-H.; Ko, B.-S.; Lim, Y.; Jung, J. Angew. Chem.,
Int. Ed. 2002, 41, 343-345. (b) Kang, S.-K.; Hong, Y.-T.; Lee, J.-H.; Kim,
W.-Y.; Lee, I.; Yu, C.-M. Org. Lett. 2003, 5, 2813-2816.
(8) Takacs, J. M.; Chandramouli, S. Organometallics 1990, 9, 2877-2880.
(9) Ojima, I.; McCullagh, J. V.; Shay, W. R. J. Organomet. Chem. 1996, 521,
421.
(5) Shibata, T.; Kadowaki, S.; Takagi, K. J. Organomet. Chem. 2004, 23,
4116-4120.
(6) Ojima, I.; Tzamarioudaki, M.; Tsai, C.-Y. J. Am. Chem. Soc. 1994, 116,
3643-3644.
(10) Maerten, E.; Delerue, H.; Queste, M.; Nowicki, A.; Suisse, I.; Agbossou-
Niedercorn, F. Tetrahedron: Asymmetry 2004, 15, 3019-3022.
9
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J. AM. CHEM. SOC. 2007, 129, 3737-3744
3737

A R T I C L E S
Denmark and Liu
Results
that begin with introduction of the silyl moiety by intramolecular
hydrosilylation,12 intermolecular hydrosilylation,13 ring-closing
metathesis,14 or silylformylation15 and are followed by silicon-
based cross-coupling. These methods allow for the expedient
introduction of silicon-containing functionality in a regioselec-
tive and stereocontrolled fashion, which is a prerequisite for
the construction of alkenes with a defined geometry. To this
end, we have also developed the cross-coupling of highly
substituted vinylsilanols to afford highly substituted olefins with
defined geometry.16
1. Silylcarbocyclization of Enynes with Benzyldimethyl-
silane. The optimized protocol3c developed by Ojima for
silylcarbocyclization was employed because of its efficiency
and generality. Benzyldimethylsilane was chosen as the source
of the silyl group because the benzyl-silicon linkage can be
readily cleaved in the presence of fluoride to afford silanols.21
In addition, benzylsilanes are stable under acidic and basic
conditions. As such, vinylbenzylsilanes can serve as silanol
surrogates for cross-coupling.
As a part of an ongoing effort to expand the scope of methods
for introducing silicon-containing functionalities for cross-
coupling, we envisioned that the silylcarbocyclization of 1,6-
enynes would allow access to tri- or tetrasubstituted vinylsilanes
with exclusively Z-geometry. When subjected to the conditions
of the cross-coupling reaction with aryl iodides, this intermediate
will be transformed into a highly substituted alkene, which
would be difficult to synthesize using conventional carbonyl
olefination methods17 in a stereocontrolled manner (Scheme 2).
Thus, in the presence of 1.5 equiv of benzyldimethylsilane
and 0.5 mol % of Rh4(CO)12 in hexane at room temperature
under a CO atmosphere (1 atm), the silylcarbocyclizations of
4,4-bis(carbethoxy)-6-hepten-1-yne (1) and N-benzylallylpro-
pargylamine (2) proceeded rapidly to afford cyclization products
6 and 7 in 84% and 91% yields, respectively (Table 1, entries
1 and 2). The tertiary amine moiety in 2 did not attenuate the
activity of the rhodium catalyst. Pyrrolidine 7 was found to be
very sensitive, as a trace amount of adventitious acid, such as
in deuterated chloroform, can cause the exocyclic double bond
to isomerize to an endocyclic double bond. Accordingly, neutral
alumina (Activity I) and reverse-phase silica gel chromatography
were used for the purification of 7. In addition, either chloro-
form-d that was passed through a plug of basic alumina (Activity
I) or deuterated benzene-d6 was used for the 1H NMR analysis.
In contrast to the high reactivity of 2, N-tert-butoxycarbonyl-
allylpropargylamine did not undergo silylcarbocyclization reac-
tion under identical conditions. Only the decomposition of
the starting material was observed, and this is presumably due
to the very rapid C-N bond cleavage caused by rhodium-
Scheme 2
Similar sequential carbocyclization/cross-coupling reactions
have been reported in the literature. For example, in their original
work, Tamao and Ito combined the nickel-catalyzed silylcar-
bocyclization of 1,7-diynes with a cross-coupling reaction.2a,18
More recently, Zhou and co-workers described an enantiose-
lective, rhodium-catalyzed silylcarbocyclization with a cross-
coupling.3g In addition, Widenhoefer and co-workers described
a sequential rhodium-catalyzed asymmetric borylcarbocycliza-
tion of 1,6-enynes followed by a Suzuki coupling.19 Herein we
describe the sequential rhodium-catalyzed silylcarbocyclization
followed by palladium-catalyzed cross-coupling reactions, to
provide access to functionalized cyclopentanes with a highly
substituted exocyclic double bond with a defined geometry.20
1
containing species, as judged by H NMR analysis. For the
silylcarbocyclization of allyl propargyl ether (3) with ben-
zyldimethylsilane, elevated temperature (70 °C) was required,
and a more thermally stable rhodium catalyst, Rh(acac)(CO)2,
was employed.3c Disappointingly, only 53% of 8 was isolated
(entry 3). The modest yield is most likely due to competing
unconstructive pathways that produced silylated, uncyclized
products (observed by 1H NMR spectroscopy) under the reaction
conditions.22
(11) For reviews on silicon-based cross-coupling, see: (a) Hatanaka, Y.; Hiyama,
T. Synlett 1991, 845-853. (b) Hiyama, T.; Hatanaka, Y. Pure Appl. Chem.
1994, 66, 1471-1478. (c) Hiyama, T. In Metal Catalyzed Cross-Coupling
Reactions; Diederich, F., Stang, P. J., Eds.; Wiley-VCH: Weinheim, 1998;
Chapter 10. (d) Hiyama, T.; Shirakawa, E. Top. Curr. Chem. 2002, 219,
62-85. (e) Denmark, S. E.; Sweis, R. F. Chem. Pharm. Bull. 2002, 50,
1531-1541. (f) Denmark, S. E.; Sweis, R. F. Acc. Chem. Res. 2002, 35,
835-846. (g) Denmark, S. E.; Ober, M. H. Aldrichimica Acta 2003, 36,
57-85. (h) Denmark, S. E.; Sweis, R. F. In Metal Catalyzed Cross-Coupling
Reactions, 2nd ed.; de Meijere, A., Diederich, F., Eds.; Wiley-VCH:
Weinheim, 2004; Chapter 4. (i) Denmark, S. E.; Baird, J. D. Chem. Eur.
J. 2006, 12, 4954-4963.
The effects of substitution were examined by studying the
silylcarbocyclization of substituted enynes with benzyldimeth-
ylsilane. The procedure described by Ojima and co-workers for
the silylcarbocyclization of 4 with dimethylphenylsilane3c was
followed. Thus, a solution of 4 and benzyldimethylsilane in
hexane was stirred in the presence of 0.5 mol % of Rh4(CO)12
at room temperature under 1 atm of CO for 3 h. Surprisingly,
the results diverged significantly from those in the literature
(Ojima reported that the phenyl analogue of 9 was obtained in
89% yield).3c In addition to approximately 25% of 9, silyl-
formylation product 12 and both constitutional isomers of
(12) (a) Denmark, S. E.; Pan, W. Org. Lett. 2001, 3, 61-64. (b) Denmark,
S. E.; Pan, W. Org. Lett. 2002, 4, 4163-4166. (c) Denmark, S. E.; Pan,
W. Org. Lett. 2003, 5, 1119-1122.
(13) Denmark, S. E.; Wang, Z. Org. Lett. 2001, 3, 1073-1076.
(14) (a) Denmark, S. E.; Yang, S.-M. Org. Lett. 2001, 3, 1749-1752. (b)
Denmark, S. E.; Yang, S.-M. J. Am. Chem. Soc. 2002, 124, 2102-2103.
(c) Denmark, S. E.; Yang, S.-M. Tetrahedron 2004, 60, 9695-9708.
(15) Denmark, S. E.; Kobayashi, T. J. Org. Chem. 2003, 68, 5153-5159.
(16) Denmark, S. E.; Pan, W. J. Organomet. Chem. 2002, 633, 98-104.
(17) For recent reviews on carbonyl olefination, see: (a) Kulkarni, Y. S.
Aldrichimica Acta 1990, 23, 39-42. (b) Johnson, A. W. Ylides and Imines
of Phosphorus; Wiley-Interscience: New York, 1993. (c) Vedejs, E.;
Peterson, M. J. Top. Stereochem. 1994, 21, 1-157.
(18) Tamao, K.; Kobayashi, K.; Ito, Y. Tetrahedron Lett. 1989, 30, 6051-6054.
(19) Kinder, R. E.; Widenhoefer, R. A. Org. Lett. 2006, 8, 1967-1969.
(20) Similar structures have recently been accessed via an alternative method:
the rhodium-catalyzed sequential carborhodation/cyclization of enynes.
See: (a) Shintani, R.; Okamoto, K.; Otomaru, Y.; Ueyama, K.; Hayashi,
T. J. Am. Chem. Soc. 2005, 127, 54-55. (b) Shintani, R.; Tsurusaki, A.;
Okamoto, K.; Hayashi, T. Angew. Chem., Int. Ed. 2005, 44, 3909-3912.
(21) (a) Trost, B. M.; Machacek, M. R.; Ball, Z. T. Org. Lett. 2003, 5, 1895-
1898. (b) Denmark, S. E.; Tymonko, S. A. J. Am. Chem. Soc. 2005, 127,
8004-2005. (c) Trost, B. M.; Machacke, M. R.; Faulk, B. D. J. Am. Chem.
Soc. 2006, 128, 6745-6754.
(22) In response to a comment from one of the reviewers, we investigated the
silylcarbocyclization of 1-heptyn-6-ene, a substrate similar in structure to
3, but without the geminal diester moiety. The silylcarbocyclization of this
substrate had not been reported previously.1 We studied the reaction of
this enyne with benzyldimethylsilane in the presence of Rh4(CO)12 (1.0-
2.5 mol %) under a variety of conditions (0.05-0.2 M in hexane or pentane
with temperature control to modulate the exotherm). Unfortunately, the
desired product could not be isolated in a synthetically useful yield (39-
43% at best), and the reaction was plagued by the appearance of many of
byproducts.
9
3738 J. AM. CHEM. SOC. VOL. 129, NO. 12, 2007

Sequential Silylcarbocyclization/Si-Based Cross-Coupling
A R T I C L E S
Table 1. Results of Silylcarbocyclization of Enynes with Benzyldimethylsilanea
a All reactions run in hexane unless otherwise specified. b Rh4(CO)12 used unless otherwise specified. c Yields of analytically pure products. d Reaction
run in toluene; catalyst, Rh(acac)(CO)2. e Reaction run in dioxane; 20 mol % of P(OEt)3 was used in addition to Rh4(CO)12.
Table 2. Optimization of Silylcarbocyclization of 4a
hydrosilylation products 13 and 14 were obtained in 17%, 25%,
and 15% yields, respectively (Table 2, entry 1). To determine
the source of this disparity, the silylcarbocyclization of 4 with
dimethylphenylsilane was repeated using the same batch of Rh4-
(CO)12 as in entry 1; however, the literature findings were not
successfully reproduced. Approximately 55% of silylcarbocy-
clization product, 11% of silylformylation product, and 10%
of carbonylative silylcarbocyclization product along with ap-
proximately 18% of unreacted 4 were obtained. Therefore, at
this time we can only conclude that the difference rests in the
difference in purity of the commercially available Rh4(CO)12.23
yield,b
%
Fortunately, the silylcarbocyclization of 4 with benzyldimeth-
ylsilane could be optimized using the available batch of rhodium
catalyst. The hydrosilylation of 4 could be completely sup-
pressed if the solvent used was presaturated with CO. With
this modification, the rate of formation of the desired product
9 was significantly lower (Table 2, entry 2). However, rate of
formation of 9 could be accelerated by heating 4 with 2 equiv
of benzyldimethylsilane and 2 mol % of Rh4(CO)12 dissolved
in CO-saturated hexane under a CO atmosphere (1 atm) at 50
°C. The complete conversion of 4 was observed in 20 min, and
an 85% yield of 9 was obtained (Table 2, entry 3). Gratifyingly,
the silylformylation pathway was suppressed, as 12 was not
Rh4(CO)12
loading,
mol %
HSiMe2Bn
loading,
equiv
temp,
entry
°
C
time
9
12
13
14
1
1
1
2
1.5
1.5
2.0
rt
rt
50
3 h
24 h
20 min 85
25c 17 25c 15
2d
3d
20e 23
0
0
0
0
0
a All reactions performed in hexane at 1.0 mmol scale under a CO
atmosphere. b Yield of chromatographically homogeneous product unless
otherwise noted. c Yield estimated from NMR integration of a mixture of
9 and 13. d Hexane used was saturated with CO by bubbling for 30 min.
e Yield estimated from NMR integration of a mixture of 4 and 9.
Approximately 61% of unreacted 4 remained.
1
observed by H NMR analysis. After distillation, analytically
silylation was completely regioselective, as C(3)-silylated
product was not observed.
pure 9 was obtained in 81% yield (Table 1, entry 4). This
9
J. AM. CHEM. SOC. VOL. 129, NO. 12, 2007 3739

A R T I C L E S
Denmark and Liu
Table 3. Optimization of Silylcarbocyclization of 5a
ratio of 10/15 cannot be estimated accurately). When the loading
of CO was reduced to 8 mol % (3.9 mL, equimolar to the
rhodium in Rh4(CO)12 employed), under otherwise identical
conditions, the yield of 10 improved to 90%, and the ratio 10/
15 also increased to 33/1 (entry 3). When the reaction was
carried out at 5.00 mmol scale, after 3 h of stirring under
conditions identical to those of entry 3, the desired product 10
was isolated in 91% yield (entry 4), and after distillation,
analytically pure 10 was obtained in an 87% yield (Table 1,
entry 5).
An alternative method to prepare a C(4)-functionalized
cyclopentane is the carbonylative silylcarbocyclization of
enynes. Following the procedure of carbonylative silylcarbocy-
clization described by Ojima and co-workers,3c a solution of
enyne 1, 1.05 equiv of benzyldimethylsilane, 1 mol % of Rh4-
(CO)12, and 20 mol % of P(OEt)3 in dioxane was stirred under
20 atm of CO at 105 °C for 48 h in an autoclave. The resulting
aldehyde 11 was obtained in 72% yield (Table 1, entry 6). The
silylcarbocyclization of 1-5 was found to be completely
Z-selective, as verified by nuclear Overhauser effect (NOE)
experiments. In no case was the E-isomer ever observed.
scale,
mmol
time,
h
yield,b
%
entry
atmosphere
remarkc
1
2
3
4
5
0.50
1.75
2.00
2.00
5.00
dynamic CO
static Ar
24 mol % CO/Ar
8 mol % CO/Ar
8 mol % CO/Ar
2
12
2.5
3.5
3.0
nd
76
72
90
91
10/15 ≈ 3/1
10/15 ≈ 17/1
10/15 ≈ 33/1
10/15 ≈ 14/1
a All reactions performed with 1.0 equiv of 5, 1.5 equiv of benzyldim-
ethylsilane, and 2 mol % of Rh4(CO)12 in hexane at 1.0 mmol scale under
the specified atmosphere. b Yield of chromatographically homogeneous
product unless otherwise noted. c The amount of 15 was estimated by NMR
integration.
2. Cross-Coupling. 2.1. Identification of Catalyst. With the
objective of identifying the most active catalyst for the cross-
coupling, a number of palladium complexes were surveyed.
Thus, 6 was subjected to the conditions previously developed
in these laboratories for alkenyl-aryl cross-coupling with tetra-
n-butylammonium fluoride (TBAF) and ethyl 4-iodobenzoate
as the coupling partner.24 Thus, 1.1 equiv of 6 was treated with
2.0 equiv of TBAF (1.0 M in tetrahydrofuran (THF)), and the
resulting light-yellow solution was stirred at room temperature
for 3 min before the palladium catalyst (5 mol % of Pd) and
1.0 equiv of aryl iodide were added sequentially. This reaction
mixture was stirred at room temperature, and the progress of
the reaction was monitored by HPLC analysis.
Silylcarbocyclization products 6-9 bear a methyl group at
C(4) resulting from the terminal alkene in the starting materials.
To increase the degree of functionalization at this position, the
silylcarbocyclization of an enyne bearing an R,â-unsaturated
ester group 5 was examined. The presence of an electron-
deficient double bond in 5 led to different behavior compared
to that of other enynes under these conditions. If the reaction
was carried out under a CO atmosphere, a significant amount
of acyclic silylformylation product was observed (10/15 ≈ 3/1)
(Table 3, entry 1). The formation of the undesired byproduct
could be completely suppressed by carrying out the reaction in
a sealed Schlenk flask under an atmosphere of argon. The
desired product 10 was obtained in 76% yield (entry 2).
However, the consumption of 5 was significantly slower than
that in an atmosphere of CO. The solution to this problem was
to blend a substoichiometric amount of CO with the argon. Thus,
enyne 5, 1.5 equiv of benzyldimethylsilane, and 2 mol % of
Rh4(CO)12 were combined in a Schlenk flask purged with argon.
Subsequently, 24 mol % of CO (11.6 mL, equimolar to the CO
ligand of Rh4(CO)12 employed) was added via gastight syringe,
and the Schlenk flask remained sealed throughout the reaction
period. The conversion to 10 was complete within 2.5 h. A
similar amount (72% yield) of 10 was isolated, and the ratio
10/15 was 17/1 (due to the small amount of 15 produced, the
Gratifyingly, the conversion of 6 to 16a was essentially
complete within 2 h at room temperature using 2.5 mol % of
Pd2(dba)3‚CHCl3 (Table 4, entry 3). By comparison, Pd(dba)2,
Pd2(dba)3, and [allylPdCl]2 displayed somewhat attenuated
catalytic activity (entries 1, 2, and 4). Thus, the optimal
palladium catalyst was identified to be Pd2(dba)3‚CHCl3, and
the optimal conditions were 2 equiv of TBAF, 1.1 equiv of 6,
and 1.0 equiv of aryl iodide in THF at room temperature. In
general, the production of homo-coupling product 17 was
insignificant.
2.2. Coupling Partner Studies. To explore the scope of the
coupling partner with silane 6, a variety of aryl iodides were
examined using the optimized conditions described above. The
reaction proceeded smoothly with a broad range of aryl iodides.
For example, electron-deficient arenes such as ethyl 4-iodo-
benzoate, 4-iodoacetophenone, and 4-iodobenzonitrile were
viable coupling partners, as the yields of 16a-c ranged from
76% to 90% (Table 5, entries 1-3). Notably, 4-iodoacetophe-
none, bearing an enolizable ketone, was well tolerated (entry
2). Likewise, 4-iodoanisole, an aryl iodide with an electron-
donating substituent, smoothly cross-coupled with 6 under
identical conditions to afford an 82% yield of 16d (entry 4).
Both 2-iodotoluene (entry 5) and methoxymethyl 3-iodobenzyl
ether (18) (entry 6) cross-coupled with 6 to give 16e and 16f in
(23) For the preparation of Rh4(CO)12, see: (a) Chini, P.; Martinengo, S. Chem.
Commun. 1968, 251-252. (b) Booth, B. L.; Else, M. J.; Fields, R.;
Goldwhite, H.; Haszeldine, R. N. J. Organomet. Chem. 1968, 14, 417-
422. (c) Chini, P.; Martinengo, S. Inorg. Chim. Acta 1969, 3, 21-24. (d)
Chini, P.; Martinengo, S. Inorg. Chim. Acta 1969, 3, 315-318. (e)
Martinengo, S.; Chini, P.; Giordano, G. J. Organomet. Chem. 1971, 27,
389-391. (f) James, B. R.; Rempel, G. L. Chem. Ind. 1971, 1036-1037.
(g) Cattermole, P. E.; Osborne, A. G. J. Organomet. Chem. 1972, 37, C17-
C18. (h) Giordano, G.; Martinengo, S.; Donatella, S.; Chini, P. Gazz. Chim.
Ital. 1975, 105, 613-615. (i) Uson, R.; Oro, L. A.; Cuchi, J. A. Quim.
Nat. Zaragoza 1975, 20, 173-177. (j) Cattermole, P. E.; Osborne, A. G.
Inorg. Synth. 1977, 17, 115-117. (k) Hunter, D. L. U.S. Patent 4514380,
1985. (l) Martinengo, S.; Giordano, G.; Chini, P. Inorg. Synth. 1990, 28,
242-245. (m) Hoshi, H. Japanese Patent 03097628, 1991. (n) Moszner,
M.; Ziolkowski, J. J. Organomet. Chem. 1991, 411, 281-283. (o) Serp,
P.; Kalck, P.; Feurer, R.; Morancho, R. Rhodium Express 1995, 9, 5-7.
(p) Serp, P.; Kalck, P.; Feurer, R.; Morancho, R. Inorg. Synth. 1998, 32,
284-287. (q) Cariati, E.; Dragonetti, C.; Roverto, D.; Ugo, R.; Lucenti, E.
Inorg. Chim. Acta 1969, 349, 189-194.
(24) Denmark, S. E.; Wehrli, D. Org. Lett. 2000, 2, 565-568.
9
3740 J. AM. CHEM. SOC. VOL. 129, NO. 12, 2007

Sequential Silylcarbocyclization/Si-Based Cross-Coupling
A R T I C L E S
Table 4. Survey of Palladium Catalysts for Cross-Couplinga
to identify the optimal combination of solvents for column
chromatography. In the cases where normal-phase chromatog-
raphy did not remove the polysiloxanes completely, reverse-
phase (C-18) chromatography was performed to obtain the
products free from polysiloxanes.
Figure 1. Possible structures of polysiloxanes.
HPLC yield,b
16a
%
17c
time,
h
2.3. Substrate Studies. The generality of the cross-coupling
of functionalized alkylidenylsilane substrates was next exam-
ined. Each of the silanes 7-10 was subjected to TBAF-promoted
cross-coupling reactions with an electron-poor aryl iodide (ethyl
4-iodobenzoate), an electron-rich aryl iodide (4-iodoanisole),
and an ortho-substituted aryl iodide (2-iodotoluene) to establish
the utility of each substrate.
The nitrogen-containing alkylidenylsilane 7 was an excellent
substrate for cross-coupling. The tertiary amine moiety did not
interfere with the catalytic activity of Pd2(dba)3‚CHCl3, as
evidenced by the good to excellent yields of cross-coupling
products 19a-c (Table 6, entries 1-3).
entry
Pd catalyst
1
Pd(dba)2
2
4
2
4
2
4
2
4
92
104
83
90
99
100
80
78
1
2
1
2
2
2
1
3
2
3
4
Pd2(dba)3
Pd2(dba)3‚CHCl3
[allylPdCl]2
a All reactions performed in 1.0 M TBAF solution in THF with 1.1 equiv
of 6, 1.0 equiv of aryl iodide, and 5 mol % of Pd catalyst at 0.20 mmol
scale under an Ar atmosphere at room temperature. b Yield determined by
HPLC analysis using naphthalene as the internal standard. c Yield of 17
calculated on the basis of 0.10 mmol theoretical yield.
Table 6. Cross-Coupling Reactions of Substrates 7-10a
81% and 85% yields, respectively. Finally, 1-iodonaphthalene
proved to be an excellent coupling partner, and the correspond-
ing cross-coupling product was obtained in 93% yield (entry
7). In all of the cross-coupling reactions, the product was
obtained with exclusively Z-geometry, which was unambigu-
ously verified by NOE experiments.
Table 5. Cross-Coupling Reaction with Aryl Iodidesa
temp,
yield,b
%
entry substrate
X
R1
R2
R3
°C
product
1
2
3
4
5
6
7
8
9
7
7
7
8
8
8
9
9
9
N-Bn
H
H
H
H
H
H
H
H
H
H
4-CO2Et rt
19a
19b
19c
20a
20b
20c
21a
21b
21c
22a
22b
22c
72c
90c
85c
88c
89c
77
72
74
64
74
N-Bn
N-Bn
O
O
O
C(CO2Et)2 Me
C(CO2Et)2 Me
C(CO2Et)2 Me
C(CO2Et)2
C(CO2Et)2
C(CO2Et)2
H
H
H
H
H
4-OMe
2-Me
rt
rt
4-CO2Et rt
entry
Aryl-I
product
yield,b
%
4-OMe
2-Me
rt
rt
1
2
3
4
5
6
7
4-(EtO2C)C6H4I
4-(MeCO)C6H4I
4-NCC6H4I
16a
16b
16c
16d
16e
16f
90
86
76
82
81
85
93
4-CO2Et 35
4-OMe
2-Me
35
35
4-MeOC6H4I
2-MeC6H4I
3-(MOMOCH2)C6H4I (18)
1-iodonaphthalene
10
11
12
10
10
10
H
H
H
CO2Me 4-CO2Et rt
CO2Me 4-OMe
CO2Me 2-Me
rt
rt
77
73
16g
a All reactions performed in 1.0 M TBAF solution in THF with 1.1 equiv
of 6, 1.0 equiv of aryl iodide, and 2.5 mol % of Pd2(dba)3‚CHCl3 at 1.00
mmol scale under an Ar atmosphere at room temperature. b Yields of
analytically pure products.
a All reactions performed in 1.0 M TBAF solution in THF with 1.1 equiv
of substrate, 1.0 equiv of aryl iodide, and 2.5 mol % of Pd2(dba)3‚CHCl3
at 1.0 mmol scale under an Ar atmosphere at the specified temperature.
b Yields of analytically pure products unless otherwise specified. c Yields
of chromatographically homogeneous materials.
The purification of cross-coupling products 16a-g was
complicated by the contamination with polysiloxanes shown in
Figure 1 (the structure of the polysiloxanes was obtained by
1H NMR analysis). In general, one-column chromatography was
not sufficient to remove all the polysiloxanes. Depending on
the polarity of the cross-coupling product different polysiloxanes
co-eluted. In addition, although the H2SO4 stain was found to
be most general for the visualization of polysiloxanes on thin-
layer chromatographic plates, not all of them were readily
visualized. As such, a survey of a variety of eluents was needed
In addition, the furan-containing substrate 8 underwent cross-
coupling readily under the standard conditions. However, the
cross-coupling of this substrate was sensitive to scale. The yield
of product 20c decreased from 75% to 61% when the reaction
of 8 with 2-iodotoluene was scaled from 0.2 to 1.0 mmol (Table
7, entries 1 and 2). On a 1.0 mmol scale, an exotherm was
clearly evident when 2-iodotoluene was added in one portion
into the reaction mixture. However, this exotherm could be
moderated by adding 2-iodotoluene (neat) to the dark purple
9
J. AM. CHEM. SOC. VOL. 129, NO. 12, 2007 3741

A R T I C L E S
Denmark and Liu
Table 8. Optimization of the Cross-Coupling of 9a
solution of 8, TBAF solution, and Pd2(dba)3‚CHCl3 such that
the internal temperature was not allowed to rise more than
3 °C above the initial temperature. With this simple modifica-
tion, the yield of 20c improved to 84%. After distillation,
analytically pure 20c was obtained in 77% yield (Table 6, entry
6). The beneficial effect of slow addition of 2-iodotoluene was
found to be general for the other aryl iodides as well. In the
cross-coupling of 8 with 4-iodoanisole, if the iodide was added
in one portion, only 78% of the product 20b was isolated.
However, the yield of 20b was improved to 89% if a solution
of 4-iodoanilsole in THF was added slowly to the reaction
mixture with close monitoring of the internal temperature (Table
7, entry 3). A similar slow addition of aryl iodide was also
employed for the cross-coupling of 8 with ethyl 4-iodobenzoate,
which resulted in an 88% yield of 20a (Table 6, entry 4).
Products 19 and 20 were sensitive to silica gel, such that
repeated purification by column chromatography led to an
unacceptable loss in material.
entry
scale, mmol
temp,
°
C
yield,b
%
1
2
3
4
0.2
0.2
0.2
1.0
rt
35
50
35
76
83
82
83
a All reactions performed in 1.0 M TBAF solution in THF with 1.1 equiv
of 9, 1.0 equiv of ethyl 4-iodobenzoate, and 2.5 mol % of Pd2(dba)3‚CHCl3
at under an Ar atmosphere at the specified temperature for 24 h. b Yields
of chromatographically homogeneous materials.
that 21c existed as a 1:1 mixture of two atropisomers, which
was confirmed by variable-temperature NMR experiments.
Coalescence of the NMR signals attributed to the C(6) methyl
group and the C(8) methyl group was observed when 21c was
heated to approximately 60 °C in toluene-d8. However, coales-
cence of the C(4) methyl and C(4) proton signals did not occur
even at 100 °C, but instead, peak broadening was observed
above 80 °C. On the basis of these experiments, the intercon-
version barrier was estimated to be 17 kcal/mol, and the rate of
conversion was approximately 32 s-1 (Figure 2).
Table 7. Optimization of Cross-Coupling Reaction of 8a
entry
R
scale, mmol
product
yield,b
%
1
2-Me
2-Me
2-Me
4-OMe
4-OMe
0.2
1.0
1.0
1.0
1.0
20c
20c
20c
20b
20b
75
61
84
78
89
2
3c
4
Figure 2. Atropisomers of 21c.
5d
Not surprisingly, cross-coupling of substrate 10 proceeded
cleanly and with rates comparable to those obtained with 6.
Little interference from the additional carbomethoxy group was
expected. At room temperature, in the presence of 2.5 mol %
of Pd2(dba)3‚CHCl3, 10 underwent cross-coupling with ethyl
4-iodobenzoate, 4-iodoanisole, and 2-iodotoluene smoothly to
afford 22a-c with good yields, ranging from 73% to 77%
(Table 6, entries 10-12). The double bond geometry of all the
cross-coupling products (19-22) has been verified unambigu-
ously by NOE experiments, and the Z-geometry was observed
exclusively. The same difficulty as noted in the purification of
16 was encountered during the purification of compounds 20
and 21. Therefore, the survey of eluents and reverse-phase
chromatography were utilized to completely remove polysilox-
anes derived from starting materials 9 and 10 and to obtain
analytically pure materials.
a All reactions performed in 1.0 M TBAF solution in THF with 1.1 equiv
of 8, 1.0 equiv of aryl iodide, and 2.5 mol % of Pd2(dba)3‚CHCl3 at under
an Ar atmosphere without any external heating. b Yields of chromatographi-
cally homogeneous materials. c 2-Iodotoluene (neat) added dropwise in the
course of 5 min. Internal temperature during addition, 19-21 °C. d A
solution of 4-iodoanisole (1 mmol) in THF (0.2 mL) added dropwise in
the course of 12 min. Internal temperature during addition, 25-28 °C.
To examine the effects of substitution geminal to the silicon
group, 9 was subjected to the cross-coupling conditions with
aryl iodides. The reaction of 9 with ethyl 4-iodobenzoate
afforded only a 76% yield of 21a when conducted at room
temperature (Table 8, entry 1). However, the yield could be
improved to 83% by mild heating at 35 °C (entry 2), though
elevated temperature (50 °C) did not improve the yield of 21a
(entry 3). At a 1.0 mmol scale, the yield of 21a was reproduced
(entry 4). This material was further purified to afford 72% of
analytically pure product (Table 6, entry 7). When conducted
at 35 °C, the cross-coupling of 9 with 4-iodoanisole proceeded
smoothly to afford 21b in a comparable yield (74%) (Table 6,
entry 8). However, under identical conditions, the yield of the
cross-coupling of 9 with 2-iodotoluene was somewhat lower
(64%), presumably due to the steric hindrance of both the
substrate and the aryl iodide (entry 9).
Discussion
1. Silylcarbocyclization. Although the silylcarbocyclization
of 1,6-enynes has been well studied, the cyclization of a
substrate bearing an electron-deficient double bond such as 5
was unprecedented. Substrates 1 and 2 cyclized without dif-
ficulty following the literature procedure, in which an atmo-
sphere of CO was used to prevent catalyst decomposition.
However, when 5 was subjected to identical conditions, the
result was unsatisfactory due to the formation of a significant
amount of silylformylation product. This suggests that the ability
of the double bond to bind to the rhodium center to facilitate
cyclization is important. Accordingly, an electron-rich double
1
Very interestingly, the H NMR spectrum of 21c exhibited
two sets of similar signals with identical splitting patterns and
with equal intensities. The 1H/1H COSY spectrum showed that
these two sets of signals did not have cross-peaks with each
other. In addition, NOE experiments indicated that both
components bore a Z-double bond. Thus, it was hypothesized
9
3742 J. AM. CHEM. SOC. VOL. 129, NO. 12, 2007

Sequential Silylcarbocyclization/Si-Based Cross-Coupling
A R T I C L E S
Scheme 3 25
Scheme 4
bond favors cyclization more than an electron-poor double bond.
This can be rationalized in light of the mechanistic insights from
a very recent computational study on the Rh2Co2(CO)12-
catalyzed alkyne silylformylation reported by Nakamura, Ojima,
and co-workers.25 These authors found that when an alkyne, a
hydrosilane, and Rh2Co2(CO)12 are mixed, intermediate A, a
silylrhodium η2-alkyne π-complex, is produced. The silylrho-
dation reaction, the process in which the silylrhodium intermedi-
ate adds across the triple bond, then proceeds on to produce a
16-electron vinylrhodium intermediate B. This intermediate
accepts a CO ligand, resulting in an 18-electron intermediate
C, before undergoing carbonyl insertion to produce D. Direct
carbonyl insertion is disfavored because this would lead to an
unstable, coordinatively unsaturated 14-electron complex
(Scheme 3).
analogy, if the vinylrhodium species E accepts a CO molecule,
the carbonyl insertion will follow via the intermediacy of F
(pathway a, Scheme 4). However, the binding of an electron-
rich double bond (R ) H, 1) is favored compared to CO binding,
since the formation the π-complex G is an intramolecular
process. Thus, the cyclization takes place (pathway b, Scheme
4). In contrast, with an electron-poor double bond (R )
CO2Me, 5), CO binding may become competitive (pathway a,
Scheme 4). This implies that silylformylation can be suppressed
by decreasing the amount of CO available. Indeed, this hypo-
thesis is supported by the observation that the amount of
silylformylation product was reduced as the amount of CO in
the reaction mixture was decreased.
2. Cross-Coupling. Substrates 6-10, obtained by silylcar-
bocyclization reactions, were all competent substrates for the
TBAF-promoted cross-coupling, thus displaying a good func-
tional group compatibility. In addition, aryl iodides with broad
This mechanistic sequence can also explain the appearance
of a silylformylation product derived from 5 (Scheme 4). By
(25) Yoshikai, N.; Yamanaka, M.; Ojima, I.; Morokuma, K.; Nakamura, E.
(26) Denmark, S. E.; Sweis, R. F.; Wehrli, D. J. Am. Chem. Soc. 2004, 126,
4865-4875.
Organometallics 2006, 25, 3867-3875.
9
J. AM. CHEM. SOC. VOL. 129, NO. 12, 2007 3743

A R T I C L E S
Denmark and Liu
ranges of electronic properties and steric demands were all good
coupling partners. No clear trend of reactivity has been observed.
This is not surprising, considering that an earlier mechanistic
study indicates that, under the TBAF-promoted conditions, the
oxidative addition of the C-I bond of the aryl iodide is a fast
process, and the Si-to-Pd transmetalation of the alkenyl group
is rate limiting.26 Therefore, the substituent on the aryl iodide
will only moderately affect the rate of the cross-coupling
reaction. Given that the same alkylidenylsilane is used, the
reactivity should be consistent among various aryl iodides.
Unlike the cross-coupling of all other substrates, the reaction
of 8 was noticeably exothermic, indicating a high rate. This
outcome presumably arises because 8 lacks functional groups
that can reversibly bind to the palladium catalyst, such as the
gem-diester (6, 9, and 10) or the tertiary amine (7). Thus, at a
given time, the concentration of the catalytically active pal-
ladium-containing species is higher when using 8 than in the
presence of other substrates. The sensitivity of the cross-coupling
of 8 to scale is likely found in the inefficiency of heat dissipation
at a larger scale, which causes a higher internal temperature.
This outcome is detrimental to the yield of the cross-coupling
reaction because the undesired homo-coupling reaction is
accelerated at a higher reaction temperature. Thus, the slow
addition of the aryl iodide ensures that the reaction temperature
does not rise significantly.
rotation along the C(6)-C(7) bond caused by the three methyl
groups that are in close proximity.
Conclusion
The sequential rhodium-catalyzed silylcarbocyclization/pal-
ladium-catalyzed, silicon-based cross-coupling has been suc-
cessfully developed. 1,6-Enynes underwent silylcarbocyclization
with benzyldimethylsilane to afford densely functionalized
cyclopentanes and heterocycles bearing a (Z)-benzyldimethyl-
silylmethylidene group with complete stereoselectivity. The
substitutions on C(1) and C(7) of the enyne as well as the
presence of heteroatoms were well tolerated. It was found that
if the enyne bears an electron-deficient double bond (5), then
the major side reaction, silylformylation, can be suppressed by
carrying out the reaction under a substoichiometric amount of
CO. In addition to the silylcarbocyclization of 5, the carbon-
ylative silylcarbocyclization was also feasible, thus gaining
access to C(4)-functionalized cyclopentanes. The cross-coupling
of the silylcarbocyclization products with aryl iodides also
proceeded smoothly under very mild conditions in good to
excellent yields with a variety of coupling partners and
substrates. Aryl iodides with a broad range of electronic
properties as well as with para, meta, and ortho substituents
all led to cross-coupling products in good to excellent yields.
In general, heating was not required, except for the most
sterically demanding substrate 9. The application of this
sequential process in the total synthesis of biologically active
natural products will be reported in due course.
The slowest cross-coupling reaction was observed with 9.
This outcome is expected because 9 bears a substituent on the
double bond, which very likely slows down the rate-determining
silicon-to-palladium transmetalation.26 Therefore, the rate of
cross-coupling can be accelerated simply by mild heating. The
ability to prepare 21c, a tetrasubstituted double bond with an
ortho-substituted aromatic moiety, under mild reaction condi-
tions is noteworthy. The steric congestion near C(6) is evident
from the fact that 21c was isolated as a pair of slowly
interconverting atropisomers, and this is due to the restricted
Acknowledgment. We are grateful to the National Institutes
of Health for generous financial support (R01 GM63167).
Supporting Information Available: Detailed experimental
procedures and full characterization of all products. This material
is available free of charge via the Internet at http://pubs.acs.org.
JA067854P
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3744 J. AM. CHEM. SOC. VOL. 129, NO. 12, 2007