One-pot, three-component synthesis of linearly substituted homoallylic alcohols via allyl(isopropoxy)dimethylsilane

Article abstract of DOI:10.1021/ol048892l

(Chemical Equation Presented) A two-step approach that involves the synthesis of vinylsilane from allyl(isopropoxy)dimethylsilane (6) and the subsequent Pd-catalyzed cross-coupling of the resulting vinylsilane is applied in developing a novel diversity-oriented, three-component synthesis to homoallylic alcohols of common structure 1. Upon treatment of 6 with s-BuLi, the silylallylmetal 5 is generated and reacted with carbonyl compounds to produce functionalized vinylsilanes, which can couple with aryl/vinyl halides in the presence of palladium catalyst to afford 1.

Full text of DOI:10.1021/ol048892l

ORGANIC
LETTERS
2004
Vol. 6, No. 18
3091-3094
One-Pot, Three-Component Synthesis of
Linearly Substituted Homoallylic
Alcohols via
Allyl(isopropoxy)dimethylsilane
Lianhai Li* and Neenah Navasero
Department of Medicinal Chemistry, Merck Frosst Centre for Therapeutic Research,
PO Box 1005, Pointe-Claire-DorVal, Quebec, Canada H9R 4P8
lianhai_li@merck.com
Received June 13, 2004
ABSTRACT
A two-step approach that involves the synthesis of vinylsilane from allyl(isopropoxy)dimethylsilane (6) and the subsequent Pd-catalyzed
cross-coupling of the resulting vinylsilane is applied in developing a novel diversity-oriented, three-component synthesis to homoallylic alcohols
of common structure 1. Upon treatment of 6 with s-BuLi, the silylallylmetal 5 is generated and reacted with carbonyl compounds to produce
functionalized vinylsilanes, which can couple with aryl/vinyl halides in the presence of palladium catalyst to afford 1.
Interest in using vinylsilanes to replace other vinylmetals1
in Pd-catalyzed cross-coupling with aryl or vinyl halides/
triflates was initiated by Hiyama2 and Ito,3 who reported that
vinyltrimethylsilane undergoes palladium-catalyzed cross-
coupling under harsh conditions. It was later found that
silafunctional vinylsilane undergoes the Pd-catalyzed cross-
coupling under very mild conditions,4 drawing much atten-
tion as a new coupling partner owing to low cost, low
toxicity, ease of handling, high functional group compat-
ibilities, mild reaction conditions, and simplicity of byproduct
removal.
novel multicomponent diversity-oriented synthesis by ex-
ecuting this cross-coupling at the end. This would require a
way of introducing a silafunctional vinylsilane moiety into
a complex molecule along with the formation of at least one
additional carbon-carbon (C-C) or carbon-heteroatom
(C-X) bond. Many reported methods for the synthesis of
silafunctional vinylsilanes based on the direct introduction
of silyl substituents to a vinyl functional via reactions such
as selective inter-5 or intramolecular6 hydrosilylation of a
triple bond and the silafunctional silylation of a vinylmetal
reagent7 would not meet the demand. However, it is possible
to fulfill the purpose by synthesizing the desired vinylsilane
from an organosilicon reagent; during the process the
Attracted by these advantages and the high stability of the
silicon-carbon bond, we were interested in developing a
(1) For a review, see: Metal-Catalyzed, Cross-coupling Reactions;
Diederich, F., Stang, P. J., Eds.; Wiley-VCH: Weinheim, 1998.
(2) (a) Hatanaka, Y.; Hiyama, T. J. Org. Chem. 1988, 53, 918. (b) For
a review, see: Hatanaka, Y.; Hiyama, T. Synlett 1991, 845.
(3) Tamao, K.; Kobayashi, K.; Ito, Y. Tetrahedron Lett. 1989, 30, 6051.
(4) For reviews, see: (a) Denmark, S. E.; Sweis, R. F. Chem. Pharm.
Bull. 2002, 50, 1531. (b) Denmark, S. E.; Sweis, R. F. Acc. Chem. Res.
2002, 35, 835. (c) Denmark, S. E.; Ober, M. E. Aldrichimica Acta 2003,
35, 75.
(5) See recent examples and references in: (a) Trost, B. M.; Ball, Z. T.
J. Am. Chem. Soc. 2001, 123, 12726. (b) Trost, B. M.; Ball, Z. T.; Joege,
T. Angew. Chem., Int. Ed. 2003, 42, 3415. (c) Trost, B. M.; Machacek, M.
R.; Ball, Z. T. Org. Lett. 2003, 5, 1895. (d) Denmark, S. E.; Wang, Z. Org.
Lett. 2001, 3, 1073.
(6) (a) Denmark, S. E.; Pan, W. Org. Lett. 2001, 3, 61. (b) Denmark, S.
E.; Pan, W. Org. Lett. 2003, 5, 1119. (c) Trost, B. M.; Ball, Z. T. J. Am.
Chem. Soc. 2003, 125, 30.
(7) Denmark, S. E.; Neuville, L. Org. Lett. 2000, 2, 3221.
10.1021/ol048892l CCC: $27.50 © 2004 American Chemical Society
Published on Web 08/06/2004

Scheme 1
Table 1. Generation of Allyl Anion and Addition to
Benzaldehyde
entry
solvent
base
eq
1H NMR yield (%)
1
2
3
4
5
6
7
THF
THF
THF
THF
THF
THF
Ether
s-BuLi/TMEDA
s-BuLi
n-BuLi
t-BuLi
s-BuLi
1.1
1.1
1.1
1.1
1.0
1.2
1.1
59
70 (65)c
a
b
65
67
20
organosilicon reagent acts as one component to react with
at least one other component through new C-C or C-X
bond formation. By carrying out the Pd-catalyzed cross-
coupling in the final step to introduce one more component,
the organosilicon reagent would provide at least two reaction
sites for new bond formation, thus securing a multicomponent
synthesis.
s-BuLi
s-BuLi
a Multiple products: n-BuCH(OH)Ph and n-BuSi(Me)2CH2CHdCH2.
b Main product was t-BuCH(OH)Ph. c Isolated yield by flash chromatog-
raphy over Florisil.
Homoallylic alcohols of the common structure 1 (Scheme
1) are important intermediates in organic synthesis8 and
frequently appear in natural products and bioactive com-
pounds.9 Most literature preparations are based upon two-
component approaches10 and have certain drawbacks to serve
as a general and diversity-oriented synthesis. A three-
component synthesis of 1 by using allyldiindium 4 (Scheme
1; M1, M2 ) In)11 is attractive because of easy access to
various carbonyl compounds and aryl/vinyl halides. Its
drawback is the poor stereochemical control of the resulting
double bond and the lack of flexibility due to the instability
of the carbon-indium bond. Later, Hiyama and co-workers
reported that the synthesis of the corresponding alkyl ether
of 1 could be achieved by a two-step sequence that involves
the allylation of acetals with 1-silyl-1-boryl-2-alkenes and
the subsequent Pd-catalyzed cross-coupling of the resulting
vinylborate.12 Denmark’s recent synthesis of (Z)-isomers of
1 by a RCM and Pd-catalyzed cross-coupling sequence
represents another interesting example.13 Inspired by these
works and the synthetic potential of the synthesis of
vinylsilane from organosilicon reagents, we thought that if
a highly regio- and stereoselective γ-addition14 of silylal-
lylmetal 5 to carbonyl compounds could be achieved, a three-
component diversity-oriented synthesis of homoallylic al-
cohols 1 could be realized (Scheme 1). Treatment of 6 with
a base to generate 5 as an equivalent to allyldimetal 4
provides the first reaction site to carry out the synthesis of
vinylsilane. By taking advantage of the high stability of the
Si-C bond, we expected the sequence could be performed
stepwise as well as in a one-pot fashion.
(8) (a) Tiecco, M.; Testaferri, l.; Santi, C.; Tomassini, C.; Marini, F.;
Bagnoli, L.; Temperini, A. Chem.- Eur. J. 2002, 8, 1118. (b) Merlic, C.
A.; Aldrich, C. C.; Albaneze-Walker, J.; Saghatelian, A. J. Am. Chem. Soc.
2000, 122, 3224. (c) Bennett, F.; Bedford, S. B.; Bell, K. E.; Fenton, G.;
Knight, D. W.; Shaw, D. Tetrahedron Lett. 1992, 33, 6507. (d) Kang, S.
H.; Hwang, T. S.; Kim, W. J.; Lim, J. K. Tetrahedron Lett. 1991, 32, 4015.
(e) Kang, S. H.; Hwang, T. S.; Kim, W. J.; Lim, J. K. Tetrahedron Lett.
1990, 31, 5917. (f) Mori, K.; Takaishi, H. Tetrahedron 1989, 45, 1639.
(9) (a) Tatsuta, K.; Takano, S.; Sato, T.; Nakano, S. Chem. Lett. 2001,
172. (b) Materal-Saadi, M. S. Phosphorus, Sulfur Silicon Relat. Elem. 2000,
164, 269. (c) Schmidt, E. W.; Faulkner, D. J. Tetrahedron 1998, 54, 3043.
(10) (I) Wittig: (a) Boesen, T.; Feeder, N.; Eastgate, M. D.; Fox, D. J.;
Medlock, J. A.; Tyzack, C. R.; Warren, S. J. Chem. Soc., Perkin Trans. 1
2001, 118. (b) Enholm, E. J.; Satici, H.; Prasad, G. J. Org. Chem. 1990,
55, 324. (c) Le Bigot, Y.; El Gharbi, R.; Delmas, M.; Gaset, A.; Cheik-
Rouhou, F. Synth. Commun. 1986, 16, 1617. (d) Maryanoff, B. E.; Reitz,
A. B.; Duhl-Emswiler, B. A. J. Am. Chem. Soc. 1985, 107, 217. (e) Meyers,
A. I.; Durandetta, J. L.; Munavu, R. J. Org. Chem. 1975, 40, 2025. (f)
Hands, A. R.; Mercer, A. J. H. J. Chem. Soc. C 1968, 2448. (II) Addition
to carbonyls: see examples and references in (a) Lautens, M.; Maddess,
M. L.; Sauer, E. L.; Ouellet, S. G. Org. Lett. 2002, 4, 83. (b) Lautens, M.;
Ouellet, S. G.; Raeppel, S. Angew. Chem., Int. Ed. 2000, 39, 4079. (c)
Tabuchi, T.; Inanaga, J.; Yamaguchi, M. Tetrahedron Lett. 1986, 27, 1195.
(d) Imamoto, T.; Kusumoto, T.; Tawarayama, Y.; Sugiura, Y.; Mita, T.;
Hatanaka, Y.; Yokoyama, M. J. Org. Chem. 1984, 49, 3904. (e) Hayashi,
T.; Kumada, M. J. Org. Chem. 1983, 48, 281. (f) Parnes, Z. N.; Bolestova,
G. I. Synthesis 1984, 991. (g) Loh, T.-P.; Tan, K.-T.; Yang, J.-Y.; Xiang,
C.-L. Tetrahedron Lett. 2001, 42, 8701. (III) Ene-reaction: (a) Salomon,
M. F.; Pardo, S. M.; Salomon, R. G. J. Am. Chem. Soc. 1984, 106, 3797.
(b) Gill, G. B.; Hj Idris, M. S. Tetrahedron 1993, 49, 219. (c) Beak, P.;
Song, Z.; Resek, J. E. J. Org. Chem. 1992, 57, 944. (IV) Allyl transfer: (a)
Loh, T. P.; Tan, K. T.; Hu, Q. Y. Angew. Chem., Int. Ed. 2001, 40, 2921.
(b) Nokami, J.; Yoshizane, K.; Matsuura, H.; Sumida, S. J. Am. Chem.
Soc. 1998, 120, 6609. (V) Cross-metathesis: Barrett, A. G. M.; Beall, J.
C.; Gibson, V. C.; Giles, M. R.; Walker, G. L. P. Chem. Commun. 1996,
2229. (VI) Cross-coupling: Nicolaou, K. C.; Winssinger, N.; Pastor, J.;
Murphy, F. Angew. Chem., Int. Ed. 1998, 37, 2534. (VII) Heck reaction:
Dyker, G.; Markwitz, H. Synthesis 1998, 1750. (VIII) Miscellaneous
synthesis: (a) Trost, B. M.; Quayle, P. J. Am. Chem. Soc. 1984, 106, 2469.
Gupta, A.; Vankar, Y. D. Tetrahedron Lett. 1999, 40, 1369. (b) Ihara, M.;
Suzuki, S.; Taniguchi, T.; Tokunaga, Y.; Fukumoto, K. Tetrahedron 1995,
51, 9873. (c) Maleczka, R. E.; Geng, F. Org. Lett. 1999, 1, 1111.
(11) Hirashita, T.; Yamamura, H.; Kawai, M.; Araki, S. Chem. Commun.
2001, 387.
Allylsilane 6 was prepared by silylation of 2-propanol with
commercially available allylchlorodimethylsilane. We first
tested the generation of 5 from 6 with LDA15 or Schlosser’s
base13d,16 by following literature procedure in ether or THF.
Unfortunately, its addition to PhCHO only afforded 7 in less
1
than 50% yield when determined by using H NMR of the
crude with toluene as an internal standard. This prompted
us to test other bases. We were pleased to find that when 6
was treated with 1.1 equiv of s-BuLi/TMEDA complex in
THF for 1 h at - 78 °C, followed by reaction with PhCHO
for 1 h at - 78 °C, 7 was obtained in 59% yield (entry 1,
Table 1). The yield was further improved to 70% when
s-BuLi was used alone (entry 2, Table 1). With n-BuLi as
base, nucleophilic replacement of the isopropoxy group on
(12) Shimizu, M.; Kitagawa, H.; Kurahashi, T.; Hiyama, T. Angew.
Chem., Int. Ed. 2001, 40, 4283.
(13) Denmark, S. E.; Yang, S. M. Org. Lett. 2001, 3, 1749.
3092
Org. Lett., Vol. 6, No. 18, 2004

Table 2. Pd-Catalyzed Cross-Coupling of 7 with RX
Table 3. One-Pot Synthesis: Variation of ArI
Pd equiv of
cat.a TBAF
isolated
yield (%)b
entry
Ar-I
product Ar
Ph
Ph
Ph
4-EtO2CC6H4
4-AcC6H4
4-MeOC6H4
2-MeC6H4
2-MeOC6H4
1
2
3
4
5
6
7
8
9
Ph-I
Ph-I
Ph-I
4-EtO2CC6H4I
4-AcC6H4I
4-MeOC6H4I
2-MeC6H4I
2-MeOC6H4I
2-MeO2CC6H4I
A
A
A
A
A
A
B
B
B
2
2.4
3
2.4
2.4
2.4
2.4
2.4
2.4
1a (85)
1a (90)
1a (89)
1b (89)
1c (91)
1d (86)
1e (63)
1f (65)
2-MeO2CC6H4 1i (56)
a Catalyst: A ) 5% Pd2(dba)3; B ) 5% (AllylPdCl)2. b The product
yields were calculated on the basis of the limiting reagents aryl iodides
used.
which effected the coupling to give 1f in 93% yield (entry
7, Table 2). Using (allylPdCl)2 instead of Pd2(dba)3 also
improved the coupling yield between 7 and 2-iodotoluene
from 80% to 99% (entries 5 and 8, Table 2).
a Catalyst: A ) Pd2(dba)3; B ) (AllylPdCl)2. b Reaction done at 50 °C
instead of room temperature. c Same yield obtained when equal molar of
crude 7 was used.
By running the reaction at 50 °C for 24 h and with
(allylPdCl)2 as catalyst, PhBr coupled with 7 to produce 1a
in 82% yield (entry 9, Table 2). Under similar conditions,
2-bromopropene also coupled with 7 to give 1g in 38% yield
(entry 10, Table 2).20 The coupling between 7 and 2-bro-
mostyrene21 went smoothly, and 1h was obtained in 66%
yield in 2 h (entry 11, Table 2).
Our findings above demonstrate that the sequence can be
carried out stepwise and also set a stage for further
investigation of performing the sequence in a one-pot fashion.
We first prepared vinylsilane 7 as described in entry 2 of
Table 1. Without workup, the resulting mixture was neutral-
ized with 1.1 equiv of AcOH, and 0.7 equiv22 of iodobenzene
and 5 mol % of Pd2(dba)3 were added. The reaction was
stirred at room temperature for 24 h23 after the addition of
TBAF. We found that by using 2 equiv of TBAF, 1a was
obtained in 85% yield (entry 1, Table 3). The yield was
slightly improved to 90% with 2.4 equiv of TBAF (entry 2,
Table 3), and no further improvement was observed with
3.0 equiv of TBAF (entry 3, Table 3).
silicon by n-Bu dominated (entry 3, Table 1).14 To avoid
this, t-BuLi was tested, but no formation of 7 was observed
(entry 4, Table 1). The predominant formation of t-BuCH-
(OH)Ph suggested that no metalation of 6 had occurred.
Slight alteration of the amount of s-BuLi to 1.0 or 1.2 equiv
did not affect the yield (entries 5 and 6, Table 1). Using
Et2O instead of THF as solvent had a negative impact (entry
7, Table 1).17 Thus, the conditions described in entry 2 of
Table 1 were selected as standard conditions for vinylsilane
preparation.16 It is worth noting that in all cases only the
trans substituted γ-adduct was observed.
With 7 prepared, we started to investigate its cross-
coupling with aryl halides and vinyl bromides (Table 2). We
found that the coupling between 7 and PhI proceeded
smoothly at room temperature in THF to afford 1a in 97%
yield with 5 mol % of Pd2(dba)3 and 2 equiv of TBAF (entry
1, Table 2).18 para-Substituted aryl iodides were also good
coupling partners with 7 to produce alcohols 1b-d in
excellent yields (entries 2-4, Table 2). Pd2(dba)3 is efficient
in catalyzing the coupling of 7 with 2-iodotoluene to afford
1e in 80% yield (entry 5, Table 2) but failed to catalyze the
cross-coupling of 7 with 2-iodoanisole to form 1f; instead,
the homo-coupling of 2-iodoanisole dominated (entry 6,
Table 2).19 We solved the problem by using (allylPdCl)2,
Being satisfied with the results obtained in entry 2 of Table
3, we moved on to test the variation of aryl iodide in this
one-pot synthesis under similar conditions by using benzal-
dehyde as a representative carbonyl compound. We found
that the para-substituted aryl iodides worked well and
afforded 1b-d in excellent yields (86-91%, entries 4-6,
Table 3). The ortho-substituted aryl iodides were less
(14) Examples of γ-addition of various silylallylmetals to carbonyl
compounds: (a) Corriu, R. J. P.; Guerin, C.; M’Boula, J. Tetrahedron Lett.
1981, 22, 2985. (b) Ehlinger, E.; Magnus, P. J. Am. Chem. Soc. 1980, 102,
5004. (c) Chan, T. H.; Labrecque, D. Tetrahedron Lett. 1992, 33, 7997. (d)
Liu, L.; Wang, D. J. Chem. Res., Synop. 1998, 612.
(19) Literature example of Pd-catalyzed homocoupling in the presence
Bu4NBr: Dyker, G. J. Org. Chem. 1993, 58, 234.
(15) Tamao, K.; Nakajo, E.; Ito, Y. Synth. Commun. 1987, 17, 1637.
(16) Schlosser, M.; Franzini, L. Synthesis 1998, 707.
(17) Various reaction temperatures and reaction times were tested; no
better yield of 7 was obtained.
(18) By using 3% and 4% of the catalyst, 1a was obtained in 89% and
95% yield, respectively.
(20) Low yield seemed caused by instability of 1g under the conditions.
(21) E and Z ratio about 6:1 of 2-bromostyrene was reflected in 1h
accordingly.
(22) This amount was used to match the yield of vinylsilane 7; the product
yields were calculated on the basis of the limiting reagent aryl iodides used.
(23) No attempt was done to optimize the reaction time.
Org. Lett., Vol. 6, No. 18, 2004
3093

benzaldehyde in the preparation of vinylsilanes24 and then
performed the cross-coupling with aryl iodides. When
iodobenzene was used with Pd2(dba)3 as catalyst, alcohols
1j-l were afforded in 71%, 62%, and 87% yield, respec-
tively. With 2-iodoanisole as a representative ortho-
substituted aryl iodide and with (allylPdCl)2 as catalyst,
alcohols 1m-o were obtained in 45%, 41%, and 71% yield,
respectively.
Table 4. One-Pot Synthesis: Variation of ArI and Carbonyls
In summary, we have developed a two-step sequence,
including the synthesis of silafunctional vinylsilane from
allyl(isopropoxy)dimethylsilane (6) and the subsequent Pd-
catalyzed cross-coupling of the resulting vinylsilane, to
achieve a diversity-oriented, three-component synthesis to
linearly substituted homoallylic alcohols of common structure
1 (Scheme 1). Upon treatment of 6 with s-BuLi, the
corresponding silylallylmetal 5, which serves as an equivalent
to allyldimetal 4, was generated and further reacted with
carbonyl compounds to produce functionalized vinylsilanes.
In the presence of (allylPdCl)2 or Pd2(dba)3 as catalyst, the
vinylsilanes thus formed can couple with aryl/vinyl halides
to afford 1. The whole sequence can be performed stepwise
as well as in a one-pot fashion.
a The product yields were calculated on the basis of the limiting reagents
aryl iodides used.
Acknowledgment. We would like to extend our great
thanks to Dr. Zhaoyin Wang, Dr. Claudio Sturino, and Mr.
Carl Berthelette for proof-reading the manuscript.
efficient coupling partners than the para-substituted ones,
and 1e-f and 1i were obtained in 56-65% yields (entries
7-9, Table 3).
This one-pot process was also extended to synthesize
homoallylic alcohols from other carbonyl compounds (Table
4). Here we chose acetone, cyclohexanone, and 3-phenyl-
propanal as representative aliphatic ketone, aliphatic cyclic
ketone, and aliphatic aldehyde, respectively, to replace
Supporting Information Available: Experimental pro-
cedure and characterization data. This material is available
free of charge via the Internet at http://pubs.acs.org.
OL048892L
(24) Conditions were not modified for different carbonyl compounds.
3094
Org. Lett., Vol. 6, No. 18, 2004