Sequential Ring-Closing Metathesis and Silicon-Assisted Cross-Coupling Reactions: Stereocontrolled Synthesis of Highly Substituted Unsaturated Alcohols

Article abstract of DOI:10.1021/ol015950j

(matrix presented) A sequential ring-closing metathesis/silicon-assisted cross-coupling sequence has been developed. Alkenyldimethylsilyl ethers of ω-unsaturated alcohols undergo facile ring closure with Schrock's catalyst to afford five-, six-, and seven

Full text of DOI:10.1021/ol015950j

ORGANIC
LETTERS
2001
Vol. 3, No. 11
1749-1752
Sequential Ring-Closing Metathesis and
Silicon-Assisted Cross-Coupling
Reactions: Stereocontrolled Synthesis
of Highly Substituted Unsaturated
Alcohols
Scott E. Denmark* and Shyh-Ming Yang
Roger Adams Laboratory, Department of Chemistry, UniVersity of Illinois,
600 South Mathews AVenue, Urbana, Illinois 61801
denmark@scs.uiuc.edu
Received April 5, 2001
ABSTRACT
A sequential ring-closing metathesis/silicon-assisted cross-coupling sequence has been developed. Alkenyldimethylsilyl ethers of ω-unsaturated
alcohols undergo facile ring closure with Schrock’s catalyst to afford five-, six-, and seven-membered cycloalkenylsiloxanes bearing substituents
on both alkenyl carbons. These siloxanes were highly effective coupling partners with various aryl and alkenyl halides and in the presence
of Pd(0) afforded styrenes and dienes in high yield and specificity and with good functional group compatibility.
The formation of carbon-carbon bonds by transition-metal-
catalyzed cross-coupling reactions, especially by palladium
catalysts, has emerged as a general and powerful method in
organic synthesis.1 Among the most notable and commonly
employed methods are the Suzuki coupling of organoboranes,
Stille coupling of organostannanes, and Negishi coupling of
organozinc compounds. In recent years, the coupling reac-
tions of organosilicon compound have provided a viable
alternative.2,3 Following the pioneering work of Hiyama2,3a
and Ito,3b,c the utility of this method has been expanded by,
inter alia, modulation of the silicon species, the use of
additives, and implementation of new catalysts.3 Recent
reports from these laboratories4 have demonstrated that
simple organosilicon components including silacyclo-
(2) For a recent review, see: Hiyama, T. In Metal-Catalyzed Cross-
Coupling Reactions; Diederich, F.; Stang, P. J., Eds.; Wiley-VCH: Wein-
heim, 1998; Chapter 10. (b) Hiyama, T.; Hatanaka, Y. Pure Appl. Chem.
1994, 66, 1471. (c) Hatanaka, Y.; Hiyama, T. Synlett 1991, 845.
(3) For recent examples of silicon-based cross-coupling, see: (a)
Hatanaka, Y.; Hiyama, T. J. Org. Chem. 1988, 53, 918 (b) Tamao, K.;
Kobayashi, K.; Ito, Y. Tetrahedron Lett. 1989, 30, 6051. (c) Suginome,
M.; Kinugasa, H.; Ito, Y. Tetrahedron Lett. 1994, 35, 8635. (d) Mowery,
M. E.; DeShong, P. J. J. Org. Chem. 1999, 64, 1684. (e) Mowery, M. E.;
DeShong, P. J. J. Org. Chem. 1999, 64, 3266. (f) Lam. P. Y. S.; Deudon,
S.; Averill, K. M.; Li, R.; He, M.; DeShong, P.; Lark, C. G. J. Am. Chem.
Soc. 2000, 122, 7600. (g) Hirabayashi, K.; Kawashima, J.; Nishihara, Y.;
Mori, A.; Hayama, T. Org. Lett. 1999, 1, 299. (h) Hirabayashi, K.; Kondo,
T.; Toriyama, F.; Nishihara, Y.; Mori, A. Bull. Chem. Soc. Jpn. 2000, 73,
749. (i) Lee, H. M.; Nolan, S. P. Org. Lett. 2000, 2, 2053. (j) Shibata, K.;
Miyazawa, K.; Goto, Y. Chem. Commun. 1997, 1309.
(1) (a) Metal-Catalyzed Cross-Coupling Reactions; Diederich, F., Stang,
P. J., Eds.; Wiley-VCH: Weinheim, 1998. (b) Tsuji, J. Palladium Reagents
and Catalysts, InnoVations in Organic Syntheses; Wiley: Chichester, U.K.,
1995. (c) Heck, R. F. Palladium Reagents in Organic Synthesis; Academic
Press: New York, 1985.
10.1021/ol015950j CCC: $20.00 © 2001 American Chemical Society
Published on Web 05/09/2001

butanes,4a-d silanols,4e silyl hydrides,4f cyclic silyl ethers,4g
and even oligosiloxanes4h can serve effectively as the donor
in Pd-catalyzed cross-coupling reactions. Among the practical
features of this process are (1) efficiency and mildness of
reaction conditions, (2) stereospecificity with respect to both
of addends, and (3) broad functional group compatibility.
One of the most important advantages of the silicon-based
cross-coupling is the diversity of methods available for the
introduction of the silafunctional unit into the organic
substrate. Moreover, the ability to introduce the silicon donor
in a regio- and stereocontrolled fashion is a prerequisite for
stereocontrolled construction of alkenes. We have recently
illustrated this aspect of the method by the use of intra-
molecular hydrosilylation/cross-coupling to efficiently and
stereoselectively prepare homopropargylic alcohols.4g In that
study, a temporary silicon tether was employed to set the
geometry of an alkylidenylsiloxane by hydrosilylation. We
now report a variant of the silicon-tether concept to the
generation of cycloalkenylsiloxanes by Mo-catalyzed ring-
closing metathesis (RCM) and their subsequent participation
as the nucleophilic partners in Pd-catalyzed cross-coupling.5
Ring-closing metathesis (RCM) catalyzed by Mo or Ru
complexes has revolutionized the way in which of carbo-
cycles and heterocycles are constructed.6 In view of the not
uncommon use of silyl ethers as tether anchor points, we
recognized the opportunity for the combination of RCM and
Pd-catalyzed cross-coupling chemistry by the use of alkenyl-
silyl ethers. The few reported examples of RCM of allylic
silyl ethers employ Grubbs ruthenium alkylidene complex
[Cl2(Cy3P)2RudCHPh] (1) as the catalyst.7 However, RCM
of the sterically more demanding vinylsilyl ether dienes
requires the less sterically sensitive molybdenum carbene
complex [(CF3)2MeCO]2Mo(dCHCMe2Ph)(dNC6H3-2,6-
i-Pr2) (2), developed by Schrock et al.8
To test the feasibility of the overall transformation, we
prepared vinylsilyl ether, 3, which was prepared by addition
of allylmagnesium bromide to benzaldehyde followed by
silylation with commercially available chlorodimethylvinyl-
silane, Scheme 1. Initial studies on the RCM reaction of 3
using the Grubbs alkylidene complex 1 failed; none of the
1
desired product, 4, was observed by H NMR analysis. All
variations in conditions, including change of solvent (CH2Cl2
or benzene) and/or temperature (room tempearture, 45 °C,
or 80 °C) were unsuccessful. Even the more reactive 1,3-
dimesityl-4,5-dihydroimidazol-2-ylidene-substituted ruthe-
nium complexes failed to promote the RCM reaction.9
Gratifyingly, substrate 3 did undergo the RCM process by
using the molybdenum complex 2 as the catalyst.10 After
careful optimization a near quantitative yield of 4 was
obtained with 5 mol % of 2 in benzene at ambient
temperature.
Scheme 1
Optimization of the Pd(0)-catalyzed coupling with siloxane
4 and 4-iodoacetophenone employed the conditions devel-
oped in our previous studies with alkenyl silanols4e (Table
1). Thus, siloxane 4 was combined with a 1.0 M THF
Table 1. Optimization of the Cross-Coupling of 4 with
4-Iodoacetophenonea
(4) (a) Denmark, S. E.; Choi, J. Y. J. Am. Chem. Soc. 1999, 121, 5821.
(b) Denmark, S. E.; Wehrli, D.; Choi, J. Y. Org. Lett. 2000, 2, 2491. (c)
Denmark, S. E.; Wang, Z. Synthesis 2000, 999. (d) Denmark, S. E.; Wu,
Z. Org. Lett. 1999, 1, 1495. (e) Denmark. S. E.; Wehrli, D. Org. Lett. 2000,
2, 565. (f) Denmark, S. E.; Neuville, L. Org. Lett. 2000, 2, 3221. (g)
Denmark, S. E.; Pan, W. Org. Lett. 2001, 3, 61. (h) Denmark, S. E.; Wang,
Z. J. Organomet. Chem. 2001, 624, 372. (h) Denmark, S. E.; Wang, Z.
Org. Lett. 2001, 3, 1073.
(5) To the best of our knowledge, the cross-coupling of cycloalkenyl-
siloxanes has not been reported.
(6) For recent reviews, see: (a) Fu¨rstner, A. Angew. Chem., Int. Ed. 2000,
39, 3012. (b) Grubbs, R. H.; Chang, S. Tetrahedron 1998, 54, 4413. (c)
Schuster, M.; Blechert, S. Angew. Chem., Int. Ed. Engl. 1997, 36, 2036.
(d) Alkene Metathesis in Organic Synthesis; Fu¨rstner, A., Ed.; Springer:
Berlin, 1998.
(7) (a) Taylor, R. E.; Engelhardt, F. C.; Yuan, H. Org. Lett. 1999, 1,
1257. (b) Taylor, R. E.; Schmitt, M. J.; Yuan, H. Org. Lett. 2000, 2, 601.
(c) Meyer, C.; Cossy, J. Tetrahedron Lett. 1997, 38, 7861. (d) Cassidy, J.
H.; Marsden, S. P.; Stemp, G. Synlett 1997, 1411. (e) Using [RuCl2(dCd
CdCPh2)(PCy3)2] or [RuCl4(dCdCdCPh2)(PCy3)(η6-MeC6H4-4-i-Pr)] as
the catalyst, see: Fu¨rstner, A.; Hill, A. F.; Liebl, M.; Wilton-Ely, J. D. E.
T. Chem. Commun. 1999, 601. (f) For asymmetric studies using chiral Mo
complex as the catalyst, see: Zhu, S. S.; Cefalo, D. R.; La, D. S.; Jamieson,
J. Y.; Davis, W. M.; Hoveyda, A. H.; Schrock, R. R. J. Am. Chem. Soc.
1999, 121, 8251.
Pd(dba)2,
mol %
TBAF,
equiv
time,
min
yield,b
%
entry
1
2
3
4
5.0
3.0
1.0
5.0
2.0
2.0
2.0
1.0
10
30
180
180
89
86
80c
65d
a All reactions employed 1.1 equiv of 4 and 1.0 equiv of 4-iodoaceto-
phenone at room temperature. b Yield of isolated 5a. c 5% of 4-iodoaceto-
phenone was recovered. d 19% of 4-iodoacetophenone was recovered.
(8) (a) Chang, S.; Grubbs, R. H. Tetrahedron Lett. 1997, 38, 4757. (b)
Ahmed, M.; Barrett, A. G. M.; Beall, J. C.; Braddock, D. C.; Flack, K.;
Gibson, V. C.; Procopiou, P. A.; Salter, M. M. Tetrahedron 1999, 55, 3219.
(c) Barrett, A. G. M.; Beall, J. C.; Braddock, D. C.; Flack, K.; Gibson, V.
C.; Salter, M. M. J. Org. Chem. 2000, 65, 6508. (d) The ruthenium carbene
complex 1 is more sensitive to the substitution pattern of alkenes than
molybdenum catalyst 2, see: Kirkland, T. A.; Grubbs, R. H. J. Org. Chem.
1997, 62, 7310.
solution of tetrabutylammonium fluoride (TBAF‚3H2O,
Fluka) at room temperature, followed by the addition of
4-iodoacetophenone and 5 mol % of Pd(dba)2 sequentially.
The reaction proceeded cleanly to completion in only 10 min
(Table 1, entry 1). Decreasing the loading of Pd(dba)2 (3
1750
Org. Lett., Vol. 3, No. 11, 2001

mol %, entry 2) only marginally affected the rate of the
coupling process. However, with a lower catalyst loading
(1.0 mol %, entry 3) or less TBAF (1.0 equiv, entry 4), the
reaction did not go to completion and a significant amount
of 4-iodoacetophenone was recovered.
h, 6 could be isolated in 78% yield with 2.5 mol % of
[allylPdCl]2 as the catalyst.
Scheme 2
With suitable conditions for both processes in hand, we
turned our attention to expanding the scope of this process
with various aryl iodides. Both the nature and position of
substituents on the aromatic ring were studied. The results
compiled in Table 2 reveal high compatibility with the com-
mon functional groups tested. For all aryl iodides examined,
the reaction gave uniformly high yields. Noteworthy features
of this process include the following: (1) electron-withdraw-
ing or -donating groups exhibit similar reactivity (entries 1
and 2), (2) the steric effect of ortho substituents is minimal
(entry 4) except in the cases where a possible chelation
between the substituent and the palladium may slow the
reductive elimination step (entries 5-7), (3) the reaction
tolerates diverse functional groups such as ester, ether, nitro,
and even free hydroxy group, and (4) the reactions of all
iodides were stereospecific.11
The next objective was to explore the influence of tether
length (i.e., ring size) and substituents on the RCM/cross-
coupling process. The allylic ether 7a (a five-membered ring
precursor) suffered RCM under the standard conditions (5
mol % of Mo complex in benzene, 1 h); however, only 75%
conversion could be obtained in 1 h. This problem was solved
by increasing the catalyst loading; using 7 mol % of catalyst,
the complete consumption of 7a was achieved within 3 h to
afford the product 8a in 89% yield (Table 3, entry 1).
However, for the preparation of seven-membered siloxane
8d, the reaction only went to 91% completion, giving an
81% yield under these conditions. With a monosubstituted
alkene or monosubstituted vinylsilane (entries 2 and 3), the
RCM process proceeded slowly compared to 4 albeit
ultimately to completion. Unfortunately, substitution on both
the alkene and vinylsilane (entry 4) did not lead to successful
closure (even under harsher conditions), presumably as a
result of the significant increase in steric demand.
Table 2. Palladium-Catalyzed Cross-Coupling of 4 with Aryl
Iodidesa
Pd(dba)2,
mol %
time,
min
yield,b
%
entry
R
product
Table 3. Molybdenum-Catalyzed Ring-Closing Metathesis of
7a
1c
2
3
4
5
4-COMe
4-OMe
3-CO2Et
2-Me
2-NO2
2-CH2OH
2-CO2Me
5.0
3.0
3.0
3.0
3.0
5.0
5.0
10
30
30
30
90
5a
5b
5c
5d
5e
5f
90
92
93
89
86
90
84
6
7
180
360
5g
a All reactions employed 4 (1.1 equiv), TBAF (2.0 equiv), aryl iodide
(1.0 equiv), and Pd(dba)2 (3.0-5.0 mol %) in THF at room temperature.
b Yields of analytically pure materials. c Yield of chromatographically
homogeneous material.
substrate,
catalyst, time,
yield,b
%
entry
n
R1
R2
mol %
h
product
1
2
3
4
7a , 0
7b, 1
7c, 1
7d , 1
7e, 2
H
H
C6H13
C6H13 Me
H
H
Me
H
7.0
8.0
7.0
3
15
12
8a
8b
8c
89
91
90
The cross-coupling of 4 was also successful with (E)-2-
bromostyrene (Scheme 2). The reaction rate and yield were
slightly lower than that obtained with aryl iodides. After 5
5c
H
7.0
12
8d
81
a Reactions were performed at 0.1 M concentration. b Yields of analyti-
cally pure materials. c 91% conversion was observed by 1H NMR analysis.
(9) Recently, the 1,3-dimesityl-4,5-dihydroimidazol-2-ylidene-substituted
ruthenium complex exhibited high reactivity in RCM, especially for di-,
tri-, or tetra-substituted cyclic alkenes; see: Scholl, M.; Ding, S.; Lee, C.
W.; Grubbs, R. H. Org. Lett. 1999, 1, 953.
(10) The molybdenum complex 2 is commercially available (Strem) and
can be prepared according to the reported procedure with consistent purity
and reactivity; see: (a) Fox, H. H.; Yap, K. B.; Robbins, J.; Cai, S.; Schrock,
R. R. Inorg. Chem. 1992, 31, 2287. (b) Schrock, R. R.; Murdzek, J. S.;
Bazan, G. C.; Robbins, J.; DiMare, M.; O’Regan, M. J. Am. Chem. Soc.
1990, 112, 3875. (c) Oskam, J. H.; Fox, H. H.; Yap, K. B.; McConville, D.
H.; O’Dell, R.; Lichtenstein, B. J.; Schrock, R. R. J. Organomet. Chem.
1993, 459, 185. (d) Fox, H. H.; Lee, J.-K.; Park, L. Y.; Schrock, R. R.
Organometallics 1993, 12, 759.
A variety of aryl iodides bearing various functional groups
was selected to expand the utility of this transformation. The
(11) The coupling products showed slight decomposition under distil-
lation; however, we were able to secure them in an analytically pure form
after silica gel chromatography. Although the stereospecificity could not
1
be determined by GC, no isomer was found by H NMR analysis.
Org. Lett., Vol. 3, No. 11, 2001
1751

Moreover, increasing the loading and portionwise addition
of the Pd(0) complex also provided complete conversion and
kept the palladium from precipitating in this slow coupling
reaction.
Table 4. Palladium-Catalyzed Cross-Coupling of 8 with Aryl
Iodidesa
A comparison between these results and those described
previously reveals that monosubstitution of alkenyl silanes
(silacyclobutanes4a-d and silanols4e) in either the R- or
â-position does not effect the rate of the cross-coupling
process significantly. The disubstituted alkenyl silanes
including cyclic siloxanes4g and silyl hydrides4f are also very
reactive in coupling process except in the case of the
substitution on both of the R- and â-cis-positions, for
example, 8c. The steric influence may slow the coupling
reaction and allow a competitive homocoupling of the aryl
iodides to intervene.
In conclusion, we have successfully demonstrated sequen-
tial RCM/cross-coupling reactions with readily available silyl
ethers. The cycloalkenylsiloxane serves as a competent donor
undergoing rapid and high-yielding cross-coupling with
various aryl and alkenyl halides. In addition, the ring size
and substitution on the olefin have similar behavior in the
coupling process as was seen in acyclic cases. Extension of
this method to double intramolecular RCM/cross-coupling
processes is in progress.
sub-
strate,
Pd(dba)2, time, prod- yield,b
entry
n
R1
R2
H
R3
mol %
h
uct
%
1
8a , 0
8b, 1
H
H
4-CO2Et
3.0
3.0
0.5
9a
85
83
81
85d
2
3c
Me 2-Me
0.75 9b
8c, 1 C6H13
8d , 2
H
H
3-CO2Et
4-OMe
10.0
3.0
24
0.5
9c
9d
4
H
a All reactions employed 8 (1.1 equiv), TBAF (2.0 equiv), aryl iodide
(1.0 equiv), and Pd(dba)2 (3.0 mol %) at room temperature unless otherwise
specified. b Yields of analytically pure materials. c Pd(dba)2 (2.5 mol %/3
h) and (0.25 mmol/3 h) were added portionwise. d Yield of chromatographi-
cally homogeneous material.
results collected in Table 4 reveal that (1) the different sizes
of cyclic alkenyl silanes exhibit similar reactivity in the
coupling reaction (entries 1 and 4) and (2) substitution on
the â-trans-position of the silyl group did not affect the
reactivity significantly (entry 2). The R-substituted alkenyl
silane 8c did undergo the coupling process; however, a
significantly reduced reaction rate compared to the related
silanes was observed. Moreover, the reaction mixture
contained a substantial amount of self-coupling product of
ethyl 3-iodobenzoate. The use of additives4c or slightly
elevated temperatures did not improve the results. Fortu-
nately, the addition of the iodide in portions satisfactorily
suppressed the formation of the self-coupling product.4g
Acknowledgment. We are grateful to the National
Science Foundation for generous financial support (NSF
CHE 9803124). We thank Professor Amir Hoveyda (Boston
College) for providing details for the preparation of catalyst
2.
Supporting Information Available: Full characterization
of all products and detailed procedures. This material is
available free of charge via the Internet at http://pubs.acs.org.
OL015950J
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Org. Lett., Vol. 3, No. 11, 2001