Development of a highly α-regioselective indium-mediated allylation reaction in water

Article abstract of DOI:10.1016/S0040-4039(01)01883-4

Linear α homoallylic alcohol adducts were obtained with high regioselectivities in moderate to good yields using allylic indium reagents in the presence of 10 M water. The exceptionally high regioselectivities observed were neither steric nor electronic i

Full text of DOI:10.1016/S0040-4039(01)01883-4

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 8701–8703
Development of a highly a-regioselective indium-mediated
allylation reaction in water
Teck-Peng Loh,* Kui-Thong Tan, Jian-Ying Yang and Chao-Li Xiang
Department of Chemistry, National University of Singapore, 3 Science Drive 3, Singapore 117543
Received 28 August 2001; revised 21 September 2001; accepted 5 October 2001
Abstract—Linear a homoallylic alcohol adducts were obtained with high regioselectivities in moderate to good yields using allylic
indium reagents in the presence of 10 M water. The exceptionally high regioselectivities observed were neither steric nor electronic
in origin from the results presented in this paper. © 2001 Elsevier Science Ltd. All rights reserved.
The addition of allylic metals to carbonyl compounds
has become one of the most important reactions in
organic synthesis. This is because the homoallylic alco-
hols generated are versatile building blocks for the
synthesis of many biologically active molecules such as
macrolides, polyhydroxylated natural products and
polyether antibiotics.1,2 Among the many metal-medi-
ated allylation reactions, indium-mediated allylation
has gained popularity in view of the possibility of
carrying out the reaction in water.3,4 The use of water
as a solvent to carry out organic reactions offers practi-
cal convenience as it alleviates the need to handle
flammable and anhydrous organic solvents. It also sim-
plifies the tedious protection–deprotection sequences
for certain functional groups containing acidic protons,
which leads to an increase in overall synthetic
efficiency.5
mediated allylation of aldehydes with g-substituted
allylic indiums occurs regioselectively at the g-position
of the allylic metal reagent.6,7 For example, the allyla-
tion of crotyl bromide with benzaldehyde produces
solely the g-adduct. This severely limits access to the
corresponding a-homoallylic alcohol adducts. In this
paper, we report a general method for indium-mediated
allylation reactions that affords the a-adducts with high
selectivities.
In view of our interest in the application of indium-
mediated allylation for the synthesis of complex
molecules, efforts were directed toward exploring the
effect of solvents on the reactivity, as well as the
diastereoselectivity of the indium-mediated allylation
reaction. In our initial study, the reaction of cyclohex-
ane carboxaldehyde with crotyl bromide in water was
investigated. To our surprise, when the amount of
water added was decreased while stirring was pro-
longed, we consistently detected a significant amount of
the a-adduct.
Although these reactions have been found to be highly
regio- and stereoselective, one severe limitation inherent
to this strategy is the difficulty in obtaining the a-
adduct when g-substituted allylic metals are employed
(Scheme 1). Except for some special cases, the indium-
This interesting result prompted us to study further the
effect of solvents on the regioselectivity (a-adduct ver-
sus g-adduct). The results are summarized in Table 1.
OH
R1
Br
O
OH
+
R1
R
Among the various solvents examined, the reactions
carried out in DMF, THF, ethanol and water (0.5 M)
afforded only the g-homoallylic alcohols (entries 1, 2, 5
and 10). The addition of equal amounts of water to
THF or DMF does not improve the regioselectivity.
However, water (10 M) and water/dichloromethane (10
M/10 M) distinguished themselves by exhibiting excel-
lent a-selectivity (entries 3, 4 and 8).8
R
H
R
In, H2O
R1
γ-adduct
α-adduct
Scheme 1.
* Corresponding author. Tel.: +65-874-1781; fax: +65-779-1691;
e-mail: chmlohtp@nus.edu.sg
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)01883-4

8702
T.-P. Loh et al. / Tetrahedron Letters 42 (2001) 8701–8703
Table 1. The effect of solvent on the indium-mediated allylation of cyclohexanecarboxaldehyde with crotyl bromidea
O
OH
OH
Br
In, Solvent
+
H
γ-adduct
α-adduct
Entry
Solvent
Amount (M)
Time (h)
Yield %d (a:g)c
1b
2
DMF
H2O
H2O
H2O
THF
CH2Cl2
THF/H2O
CH2Cl2/H2O
DMF/H2O
10
0.5
10
10
10
10
10:10
10:10
10:10
10
72
72
24
72
72
24
72
24
72
72
65 (0:100)
90 (0:100)
85 (99:1)
3b
4
87 (86:14)
20 (0:100)
5
6
7
e
–
95 (0:100)
68 (\99:1)
80 (0:100)
97 (0:100)
8
9b
10
CH3CH2OH
a All reactions were performed with aldehyde (1 mmol), crotyl bromide (1.2 mmol) and indium (1.5 mmol) at room temperature unless otherwise
noted.
b The reactions were carried out at 40°C for 12 h.
c Determined by 1H NMR.
d Combined yield.
e Neither the g- nor a-adduct was observed.
It is important to note that the amount of water added
is crucial for the a-selectivity. Higher a-regioselectivity
was observed when the amount of water was 10 M.
When the reaction was carried out in the presence of
0.5 M of water, no a-adduct was observed even after
the reaction was stirred for 72 h. Furthermore, the
regioselectivity increased when a higher temperature
was applied (entry 3).
It was found that the reaction of benzaldehyde with
crotyl bromide gave the a-regioisomer almost exclu-
sively (entry 1). Using 10 M of water as the solvent, a
totally different regioisomer was obtained as compared
to previously published results using water or other
solvents. Furthermore, the reaction of hydrocin-
namaldehyde and hexanal with crotyl bromide also
gave very good a-regioselectivity (entries 3 and 4). The
results shown in Table 2 suggest that indium-mediated
allylation can give the a-homoallylic alcohol adducts
regardless of the substituents. Accordingly, an increase
in the steric bulkiness of the aldehyde and bromide
To our best knowledge, this is the first example where
the a-homoallylic alcohol adduct was synthesized via
an indium-mediated allylation without the use of a
sterically hindered substituent at the bromide and alde-
hyde. A previous publication by Chan et al.9 revealed
that a steric effect operates in determining the regio-
selectivity. In general, the reaction gives the g-adduct,
exclusively, if no sterically bulky carbonyl or allyl bro-
mide substituent is presented. For example, Chan et al.
found that the reaction of isopropyl aldehyde with
bromide 1 gives the a-adduct in an 87% yield (Scheme
2).
Table 2. Indium-mediated allylation of aldehydes with
crotyl bromide and cinnamyl bromidea
OH
R1
Br
O
OH
R1
R
+
In
R
H
R
R1
γ-adduct
10 M H2O
α-adduct
Entry
R
R1
Time (h)
Yield %c (a:g)b
(E/Z)b
With the unveiling of water (10 M solution) as an
important criterion for obtaining the a-homoallylic
alcohol adduct, we extended the reaction to a variety of
substrates and the results are shown in Table 2. In all
cases, the a-adducts were obtained with high selectivi-
ties in moderate to good yields.
1
2
3
4
5
6
7
8
Ph
Me
Me
Me
Me
Ph
Ph
Ph
Ph
36
24
36
18
72
72
85
160
60 (99:1) (55/45)
85 (99:1) (70/30)
75 (98:2) (65/35)
67 (97:3) (55/45)
66 (98:2) (E)
73 (96:4) (98/2)
71 (99:1) (90/10)
50 (99:1) (95/5)
c-C6H11
n-C5H11
PhCH2CH2
Ph
c-C6H11
n-C5H11
PhCH2CH2
O
OH
a All reactions were performed with aldehyde (1 mmol), bromide (1.2
mmol) and indium (1.5 mmol) with water (0.10 mL) at room
temperature for 12 h, followed by heating to 40°C, unless otherwise
noted.
In
Br
+
H
H2O
87%
(1)
b Determined by 1H and 13C NMR.
c Total yield.
Scheme 2.

T.-P. Loh et al. / Tetrahedron Letters 42 (2001) 8701–8703
8703
gave no significant improvement in the a-regioselectiv-
Acknowledgements
ity. This type of reaction seems to be quite general
irrespective of the allylic bromides used. Even when
cinnamyl bromide was used, the a-adducts were
obtained with excellent selectivities and good yields.
This work was supported by grants from the National
University of Singapore.
In conclusion, a general and new method for obtain-
ing a-adducts by the indium-mediated allylation has
been developed. By using 10 or 0.5 M water, the
regioselectivity of the allylation can be completely
inverted. Further mechanistic studies of this a-regio-
selective indium-mediated allylation are reported in the
following paper.
References
1. Roush, W. R. In Comprehensive Organic Synthesis; Trost,
B. M.; Fleming, I.; Heathcock, C. H., Eds.; Pergamon Press:
Oxford, 1991; Vol. 2, p. 1.
2. Yamamoto, Y.; Asao, N. Chem. Rev. 1993, 93, 2207.
3. For reviews, see: (a) Li, C. J.; Chan, T. H. Tetrahedron 1999,
55, 11149; (b) Li, C. J.; Chan, T. H. Organic Reactions in
Aqueous Media; John Wiley & Sons: New York, 1997.
4. For some pioneer studies, see: (a) Li, C. J.; Chan, T. H.
Tetrahedron Lett. 1991, 32, 7017; (b) Wang, R. B.; Lim, C.
M.; Tan, C. H.; Lim, B. K.; Sim, K. Y.; Loh, T. P.
Tetrahedron: Asymmetry 1995, 6, 1825; (c) Paquette, L. A.;
Mittzel, T. M. Tetrahedron Lett. 1995, 36, 6863.
5. For some examples, see: (a) Chan, T. H.; Li, C. J. Chem.
Commun. 1992, 747; (b) Kim, E.; Gordon, D. M.; Schmid,
W.; Whitesides, G. M. J. Org. Chem. 1993, 58, 5500; (c) Loh,
T. P.; Cao, G. Q.; Pei, J. Tetrahedron Lett. 1998, 39, 1457;
(d) Loh, T.-P.; Hu, Q.-Y.; Vittal, J. J. Synlett 2000, 523; (e)
Loh, T. P.; Lye, P. L. Tetrahedron Lett. 2001, 42, 3511.
6. For some examples of obtaining a-adducts from indium
regents, see: (a) Araki, S.; Ito, H.; Katsumura, N.; Butsugan,
Y. J. Organomet. Chem. 1989, 369, 291; (b) Araki, S.;
Katsumura, N.; Butsugan, Y. J. Organomet. Chem. 1991,
415, 7.
7. Recently, Araki used the allylic di-indium reagent to prepare
linear homoallylic alcohols (a-adducts), see: Hirashita, T.;
Yamamura, H.; Kawai, M.; Araki, S. Chem. Commun. 2001,
387.
8. We also performed the reaction of cyclohexane carboxyalde-
hyde with crotyl bromide under neat conditions, however,
neither the g- nor the a-adduct was obtained. For indium-
mediated reactions under neat conditions, see: Yi, X. H.;
Haberman, J. X.; Li, C. J. Synth. Commun. 1998, 28, 2999.
9. Isaac, M. B.; Chan, T. H. Tetrahedron Lett. 1995, 36, 8957.
A representative procedure for the preparation of a-
homoallylic alcohol adducts: To a mixture of cyclo-
hexane carboxaldehyde (0.11 g, 1 mmol) and indium
powder (0.17 g, 100 mesh, 1.5 mmol) in H2O (0.10
mL) was added crotyl bromide (0.16 g, 1.2 mmol)
slowly at room temperature. The reaction mixture was
stirred for 12 h followed by heating at 40°C for a
further 12 h. Diethyl ether was added to dilute the
reaction mixture followed by 1 M HCl to quench the
reaction. The mixture was extracted with diethyl ether.
The combined organic layer was washed with brine
and dried over anhydrous magnesium sulfate, filtered
and the solvent was removed in vacuo. The crude
product was purified by column chromatography to
afford the linear a-homoallylic alcohol adduct as a
colorless oil.
Rf 0.45 (4:1, hexane:ethyl acetate). 1H NMR (300
MHz, CDCl3) mixture of E and Z isomer: l 5.61–5.38
(m, 2H), 3.39–3.29 (m, 1H), 2.24 (t, J=8.4 Hz, 1H),
2.05 (t, J=8.4 Hz, 1H), 1.69 (d, J=5.6 Hz, 3H),
1.87–0.94 (m, 11H). 13C NMR (75.4 MHz, CDCl3) E
isomer: l 128.7, 127.6, 74.9, 42.9, 37.4, 29.0, 28.1,
26.5, 26.2, 26.1, 18.0; Z isomer: l 127.0, 126.6, 75.5,
42.59, 37.46, 31.7, 29.0, 28.1, 26.5, 26.2, 26.1. FTIR
(film) 3591, 3422, 3020, 2925, 2854, 1625, 1448, 1261,
1086, 1065, 1030, 968, 892 cm−1. HRMS calcd for
C11H20O [M+]: 168.1514. Found: 168.1520.