Indium-Mediated Reaction of Trialkylsilyl Propargyl Bromide with Aldehydes: Highly Regioselective Synthesis of Allenic and Homopropargylic Alcohols

Article abstract of DOI:10.1021/ja037410i

High regioselective preparation of either the allenic alcohols or homopropargylic alcohols using the indium-mediated reaction of trialkylsilyl propargyl bromides with various aldehydes has been accomplished. By just changing the silyl groups and the react

Full text of DOI:10.1021/ja037410i

Published on Web 10/03/2003
Indium-Mediated Reaction of Trialkylsilyl Propargyl Bromide with Aldehydes:
Highly Regioselective Synthesis of Allenic and Homopropargylic Alcohols
Man-Jing Lin and Teck-Peng Loh*
Department of Chemistry, National UniVersity of Singapore, 3 Science DriVe 3, Singapore 117543
Received July 20, 2003; E-mail: chmlohtp@nus.edu.sg
Table 1. Indium-Mediated Reactions of Nonyl Aldehyde with
Tuning the regioselectivity of the reaction of propargylmetals
with carbonyl compounds toward the synthesis of either allenic
alcohols or homopropargylic alcohols remains an important chal-
lenge in organic synthesis.1,2 Recently, Chan and Li reported the
first indium-mediated reaction of aldehydes with trimethylsilyl
propargyl bromides in aqueous media, with the allenic alcohol as
the major product in low to moderate selectivities.3,4 Herein, we
report a general strategy using the indium-mediated reaction of
trialkylsilyl propargyl bromides with various aldehydes to obtain
either the allenic alcohols or homopropargylic alcohols in high
regioselectivities (Scheme 1).
Propargyl Bromide in Organic Solventsa
entry
R
solvent
yieldb %(3:4)
1
2
3
4
5
6
7
8
9
10
TMS
TMS
TMS
TMS
Ph
TMS
TMS
TMS
TIPS
TBDPS
THF, rt, 20 h
THF/reflux, 20 h
86 (57:43)
89 (72:28)
90 (63:37)
95 (99:1)
65 (12:88)
88 (99:1)
75 (87:13)c
93 (99:1)
58 (99:1)
35 (99:1)
THF/rt, (10 mol % InBr3), 20 h
THF /reflux, (10 mol % InBr3), 20 h
THF /reflux, (10 mol % InBr3), 20 h
CH2Cl2/reflux, (10 mol % InBr3), 19 h
THF /reflux, (10 mol % InF3), 9 h
THF /reflux, (10 mol % InF3), 9 h
THF /reflux, (10 mol % InF3), 9 h
THF /reflux, (10 mol % InF3), 9 h
Scheme 1
a Except where indicated, all reactions were carried out on 0.5 mmol
scale with aldehyde:bromide:indium ) 1:2:2. b Isolated yield. c Reaction
was carried out with aldehyde:bromide:indium ) 1:1:1.
On the basis of our observation that indium complexes may
chelate with silicon group5 and observation by others that indium
complexes in organic and aqueous media are likely different
species,6 and the dramatic solvent effects on the propargylation and
allenylation with metallic tin,7 we hypothesized that the judicious
choice of solvent and steric and chelation effects may provide
us with the designed conditions to select a product of choice
(Scheme 2).
Table 2. Indium-Mediated Propargylation of Aldehydes with
Trimethylsilypropargyl Bromidea
Scheme 2
I (5:6)
yieldb %
II (5:6)
yieldb %
entry
aldehyde
5
1
2
3
4
5
hydrocinnamaldehyde
cinnamaldehyde
cyclohexanecarbaldehyde
benzaldehyde
a
b
c
d
e
85 (99:1)
89 (99:1)
90 (99:1)
92 (99:1)
95 (99:1)
89 (99:1)
92 (99:1)
94 (99:1)
92 (99:1)
93 (99:1)
To prove our hypothesis, we first focused on the indium-mediated
reaction of propargyl bromide under anhydrous conditions. The
results are shown in Table 1.
nonyl aldehyde
a All reactions were carried out in THF on 0.5 mmol scale with aldehyde:
trimethylsilylpropargyl bromide:indium ) 1:2:2. b Isolated yield.
Contrary to the reported results obtained in water,3,4 excellent
regioselectivities can be obtained when the reactions were carried
out in THF in the presence of catalytic amount of indium tribromide
or indium trifluoride. The reaction was found to proceed faster in
the presence of InF3 as compared to InBr3 (entries 4 and 8). This
type of reaction is limited to silicon-containing propargyl bromides
as shown in Table 1 that phenyl propargyl bromide afforded the
homopropargylic alcohols in low selectivities (entry 5). Furthermore,
the reactions of triisopropyl silyl propargyl bromide and diphenyl-
tert-butyl silyl propargyl bromide also furnished the homopropagylic
alcohols, albeit in lower yields (entries 9 and 10). It is also important
to note that two equivalents of the indium reagent are essential to
obtain high regioselectivity (entry 7). With the unveiling of 0.1
equiv InBr3 or 0.1 equiv InF3 and 2 equiv of trialkylsilyl propargyl
bromide in THF as important criteria to obtain the trialkylsilyl
homopropargylic alcohol adduct, we extended the reaction to
various aldehydes. The results are shown in Table 2.
In all cases, the homopropargylic alcohols were obtained with
excellent selectivities in high yields. No allenic alcohols were
observed in all these cases.
Next, to suppress the possible chelation of the silicon with the
halide of indium and inspired by the results of T. H. Chan,3 C. J.
Li,4 and Hammond,8 we decided to explore the reaction with more
bulky trialkylsilyl propargyl bromides in aqueous media. The results
are summarized in Table 3.
In all these cases, the allenic alcohols were obtained in moderate
to good yields with high selectivities. It is also important to note
that addition of the aldehyde first followed by bromide afforded
the product in higher yield.
The following observations are of mechanistic interest: (1) The
reaction with InF3 is faster than with InBr3. (2) A mixture of
homopropargylic and allenic alcohols is formed initially with the
homopropargylic alcohol observed as the major product. Refluxing
9
13042
J. AM. CHEM. SOC. 2003, 125, 13042-13043
10.1021/ja037410i CCC: $25.00 © 2003 American Chemical Society

C O M M U N I C A T I O N S
Table 3. Indium-Mediated Reactions of Aldehydes with
Scheme 4
Trialkylsilyl Propargyl Bromidesa
R ) TIPS
yield % (8:9)
R ) TBDPS
yield % (8:9)
entry
aldehyde
1
2
3
4
5
nonyl aldehyde
hydrocinnamaldehyde
cinnamaldehyde
cyclohexanecarbaldehyde
benzaldehyde
52 (95:5)
71 (93:7)
46 (92:8)
61 (95:5)
59 (96:4)
a
b
c
d
e
45 (95:5)
50 (90:10)
52 (97:3)
56 (95:5)
55 (96:4)
f
g
h
i
j
to the steric repulsion of indium complex (which complexes to water
molecules) with the bulky silicon group.
a All reactions were carried out on 0.25 mmol scale with aldehyde:
trialkylsilylpropargyl bromide:indium ) 1:2:2. b Isolated yield.
In conclusion, we have developed a general strategy to obtain
either the allenic alcohols or homopropargylic alcohols in high
regioselectivities via the indium-mediated reaction of trialkylsilyl
propargyl bromides with various aldehydes. This method is
extremely easy. By just changing the silyl group and the reaction
conditions, both the allenic and homopropargylic alcohols can be
obtained in high regioselectivities. Furthermore, mechanistic studies
have revealed that silicon plays an important role in the high
regioselectivities. These studies pave the way for the design of an
enantioselective version for the synthesis of allenic alcohols and
homopropargylic alcohols. Further application of this concept to
the control stereochemistry in other systems is in progress.
the reaction longer afforded only the homopropargylic alcohols.
(3) It is important to note that two equivalent of propargyl bromide
was necessary to obtain high selectivity. (4) A cross-over experiment
was carried out as shown in Scheme 3. After the reaction, column
chromatography provided the crossover product 5c in 35% yield
in addition to the indium-coupling product. (5) Stereochemical
studies using steroidal aldehyde with trimethylsilyl propargyl
bromide and indium/indium trifluoride in THF resulted in the
formation of the Cram’s product.9 (6) No allenic product was
obtained with the reaction of homopropargyl alcohol and aldehydes.
Scheme 3
Acknowledgment. We are grateful to National University of
Singapore for their generous financial support. We thank Professor
E. J. Corey for helpful discussion and Professor Milan Stojanovic
for proof reading the manuscript.
Supporting Information Available: Spectroscopic and analytical
data for all compounds and the representative procedure (PDF). This
material is available free of charge via the Internet at http://pubs.acs.org.
References
(1) For reviews, see: (a) Yamamoto, H. In ComprehensiVe Organic Synthesis;
Heathcock, C. H., Ed.; Pergamon Press: Oxford, 1991; Vol. 2, Chapter
1.3, pp 81-98. (b) Panek, J. S. In ComprehensiVe Organic Synthesis;
Schreiber, S. L., Ed.; Pergamon: Oxford, 1991, Vol. 1, p 595 and
references therein.
(2) (a) Miao, W.; Chan, T. H. Synthesis 2003, 5, 785. (b) Reddy, L. R.; Gais,
H. J.; Woo, C. W.; Raabe, G. J. Am. Chem. Soc. 2002, 124, 10427. (c)
Evans, D. A.; Sweeney, Z. K.; Rovis, T.; Tedrow, J. S. J. Am. Chem.
Soc. 2001, 123, 12095. (d) Denmark, S. E.; Wynn, T. J. Am. Chem. Soc.
2001, 123, 6199. (e) Marshall, J. A.; Adams, N. D. J. Org. Chem. 1999,
64, 5201. (f) Ogoshi, S.; Fukunishi, Y.; Tsutsumi, K.; Kurosawa, H. Chem.
Commun. 1995, 2485. (g) Doherty, S.; Corrigan, J. F.; Carty, A. J.; Sappa,
E. AdV. Organoment. Chem. 1995, 37, 39. (h) Tsuji, J.; Mandai, T. Angew.
Chem., Int. Ed. Engl. 1995, 34, 2589. (i) Hoffmann, R. W.; Lanz, J.;
Metternich, R.; Tarava, G.; Hoppe, D. Angew. Chem., Int. Ed. Engl. 1987,
26, 1145. (j) Daniels, R. G.; Paquette, L. A. Tetrahedron Lett. 1981, 22,
1579.
(3) (a) Isaac, M. B.; Chan, T. H. Chem. Commun. 1995, 1003. (b) Ishiguro,
M.; Ikeda, N.; Yamamoto, H. J. Org. Chem. 1982, 47, 2225.
(4) Yi, X. H.; Meng, Y.; Hua, X. G.; Li, C. J. J. Org. Chem. 1998, 63, 7472.
(5) Loh, T. P.; Xu, K. C.; Ho, D. S. C.; Sim, K. Y. Synlett 1998, 4, 369.
(6) Chan, T. H.; Yang, Y. J. Am. Chem. Soc. 1999, 121, 3229.
(7) Nokami, J.; Tamaoka, T.; Koguchi, T.; Okawara, R. Chem. Lett. 1984,
1939.
All these suggest that silicon may be playing a key role in this
reaction, most probably facilitating the retro cleavage of allenic
alcohol or/and shifting the equilibrium of the indium species toward
the formation of species 12 due to the coordination with the halogen
of the indium (Scheme 4). The preferential formation of species
12 coupled with the retro cleavage of the allenic alcohol to form
the aldehyde10 which further reacts with the excess organoindium
reagent resulted in the selective formation of the thermodynamically
more stable homopropargylic alcohols.
On the other hand, the indium species generated in aqueous
media using more bulky silicon will preferentially form species 13
which reacts with aldehydes to form the kinetically favored allenic
alcohols. The preferential formation of species 13 is probably due
(8) Hammond, G. B.; Wang, Z. G. J. Org. Chem. 2000, 65, 6547.
(9) (a) Hershberg, E. B.; Oliveto, E. P.; Gerold, C.; Johnson, L. J. Am. Chem.
Soc. 1951, 73, 5073. (b) Loh T. P.; Hu, Q. Y.; Chok, Y. K.; Tan, K. T.
Tetrahedron Lett. 2001, 42, 9277.
(10) Kondo, T.; Kodoi, K.; Nishinaga, E.; Okada, T.; Morisaki, Y.; Watanabe,
Y.; Mitsudo, T. J. Am. Chem. Soc. 1998, 120, 5587.
JA037410I
9
J. AM. CHEM. SOC. VOL. 125, NO. 43, 2003 13043