Tin-mediated organic reactions: A practical method for the synthesis of β-hydroxynitriles and β-hydroxyketones

Article abstract of DOI:10.1039/a809418g

In the presence of chlorotrimethylsilane, the tin mediated addition of bromoacetonitrile or α-bromacetophenone to aldehydes in THF gives β- hydroxynitriles or β-hydroxyketones in moderate to good yields.

Full text of DOI:10.1039/a809418g

View Article Online / Journal Homepage / Table of Contents for this issue
318 J. CHEM. RESEARCH (S), 1999
J. Chem. Research (S),
1999, 318^319y
Tin-mediated Organic Reactions: a Practical
Method for the Synthesis of b-Hydroxynitriles and
b-Hydroxyketonesy
Peipei Sun* and Baochuan Shi
Department of Chemistry, Nanjing Normal University, Nanjing, 210097, China
In the presence of chlorotrimethylsilane, the tin mediated addition of bromoacetonitrile or a-bromacetophenone to
aldehydes in THF gives b-hydroxynitriles or b-hydroxyketones in moderate to good yields.
Organic reactions promoted by metals have aroused much
interest in recent years.1 Among many types of applied
metals, tin plays an important role, not only for its low cost
but also for its availability. Most work has been directed
Ta b l e 1 Addition of bromoacetonitrile or a-bromoacetophenone to
aldehydes
Entry
R
t/h
T/8C
Product Yielda(%)
1
2
3
4
5
6
7
8
Ph
2
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
0
2a
2b
2c
2d
2e
2f
2g
2h
3a
3b
3c
3d
76
81
83
68
78
54
70
43
68
72
55
65
to the reaction of allylic halides which give, in general, good
5
yields and selectivity towards aldehydes and ketones.2
A
p-ClC6H4
p-BrC6H4
p-MeC6H4
p-CNC6H4
1.5
1.5
2
few other publications refer to reactions of a-bromoketones
and a-bromoesters.6 Such reactions proceed through an
allylic tin intermediate or a divalent tin enolate species.
Reports also indicated that many reactions could be accel-
erated by either sonication or the presence of water.7;8 These
signi¢cant studies provided a convenient method for the syn-
thesis of homoallyl alcohols and other important compounds.
It is anticipated that metallic tin will have a more widespread
use in organic synthesis.
2
p-MeOC6H4 2.5
PhCHˆCH
n-C7H15
Ph
p-ClC6H4
p-MeC6H4
n-C7H15
1.5
2.5
2
1.5
2
9
10
11
12
a
0
0
10
3
Isolated yields based on aldehydes
In view of the fact that the cyano group is becoming
increasingly valuable in many applications, and that many
very useful inversions can be derived from it, the production
of cyano group-containing compounds via e¡ective methods
is especially important. We have reported a tin-mediated
reaction for the synthesis of b-aminonitriles,9 and it was pro-
posed that the reaction proceeded through an organotin
intermediate. Now we report a simple and convenient pro-
cedure for the synthesis of b-hydroxynitriles mediated by
tin (Scheme 1).
During our continuous investigation on the exploration of
new synthetic reactions using metallic tin, we also found that
the reaction of a-bromoacetophenone with aldehydes gave
b-hydroxyketones (Scheme 2).
1. Sn, TMSCl, THF
RCHO + BrCH2COPh
RCH(OH)CH2COPh
2. H3O+
1
3
Scheme 2
1. Sn, TMSCl, THF
RCHO + BrCH2CN
RCH(OH)CH2CN
2. H3O+
The reaction took place under similar conditions as the
reaction of bromoacetonitrile above. Use of lower tempera-
tures led to higher yield and if TMSCl was not added,
the reaction was rather sluggish and also the reduction prod-
uct acetophenone would be generated. In the presence of
TMSCl, this side reaction was reduced and the correspond-
ing aldols were produced with moderate yields.
1
2
Scheme 1
The results are listed in Table 1. Commercial tin powder
was employed without any activation and reactions were
performed in THF. The addition of bromoacetonitrile to
aldehydes occurred slowly at room temperature, but required
5 h. Water did not promote reaction whereas when 1 equiv-
alent of chlorotrimethylsilane (TMSCl) was added most
reactions were accelerated and were complete within 2 h.
The action of TMSCl on the aldehyde may lead to an active
intermediate,10 and accelerate the reaction. The reaction
was found to be general and applicable to aromatic or ali-
phatic aldehydes and proceeded via an exclusive 1,2-addition
to a; b-unsaturated aldehydes; conjugate addition did not
occur (Table 1, entry 7). Addition to ketones did not occur
even at higher temperatures. Under the present reaction con-
ditions, no further reduction products were observed.
Although it is, as yet, not clear, we propose that an organotin
compound (BrSnCH2CN) is formed through the oxidative
addition of bromoacetonitrile to tin; and that nucleophilic
addition of this species to aldehydes gives the products.
Experimental
Melting points are uncorrected. IR spectra were recorded on a Per-
kin Elmer 683 spectrophotometer. 1H NMR spectra were obtained
for solutions in CDCl3 on a JEOL FX-90Q spectrometer with TMS
as an internal standard.
Typical Experimental Procedure.öAldehyde 1 (1mmol) was added
to
a
mixture of bromoacetonitrile or a-bromoacetophenone
(1.2 mmol) and metallic tin (1mmol) in THF (10 ml) under nitrogen
atmosphere. After stirring at 0 8C or room temperature for 10 min,
TMSCl (1 mmol) was added. The reaction mixture was stirred at
the appropriate temperature for the time listed in Table 1 before a
5% HCl solution was added. The product was extracted several
times with diethyl ether. After being dried over anhydrous
Na2SO4, the solvent was evaporated in vacuo and the residue
was column chromatographed on silica gel with diethyl ether^light
petroleum (bp 30^60 ꢀC) as eluent to yield the corresponding prod-
uct (2 or 3).
3-Hydroxy-3-phenylpropanenitrile (2a). Colorless oil. IR 3385, 3010,
1
2238, 1540 cm
.
1H NMR d 2.50 (br, 1H), 2.72 (d, J ˆ 5:8 Hz, 2 H),
* To receive any correspondence.
5.02 (t, J ˆ 5:8 Hz, 1H), 7.33 (s, 5 H).
y This is a Short Paper as de¢ned in the Instructions for Authors,
Section 5.0 [see J. Chem. Research (S), 1999, Issue 1]; there is
therefore no corresponding material in J. Chem. Research (M).
3-Hydroxy-3-(4-chlorophenyl)propanenitrile (2b). Colorless oil. IR
1
3384, 3022, 2241, 1540 cm
.
1H NMR d 2.42 (br, 1H), 2.70 (d,
J ˆ 6:0 Hz, 2 H), 5.10 (t, J ˆ 6:0 Hz, 1H), 7.20 (m, 4 H).

View Article Online
J. CHEM. RESEARCH (S), 1999 319
3-Hydroxy-3-(4-bromophenyl)propanenitrile (2c). Colorless oil. IR
Financial support of this research from the Education
Committee Nature Science Foundation of Jiangsu Province
is gratefully acknowledged.
1
3398, 3019, 2243, 1530 cm
.
1H NMR d 2.42 (br, 1H), 2.68 (d,
J ˆ 6:0 Hz, 2 H), 5.06 (t, J ˆ 6:0 Hz, 1H), 7.25 (m, 4 H).
3-Hydroxy-3-(4-methylphenyl)propanenitrile (2d). Colorless oil. IR
1
3370, 3025, 2235, 1545 cm
.
1H NMR d 2.28 (s, 3 H), 2.52 (br, 1H),
2.73 (d, J ˆ 5:4 Hz, 1H), 5.08 (t, J ˆ Hz, 1H), 7.35 (m, 4 H).
3-Hydroxy-3-(4-cyanophenyl)propanenitrile (2e). Mp 84 8C (lit,11
Received, 2nd December 1998; Accepted, 22nd January 1999
Paper E/8/09418G
1
84.5 8C). IR 3430, 3042, 2240, 2225 cm
.
1H NMR d 2.32 (br,
1 H), 2.72 (d, J ˆ 6:2 Hz, 1 H), 5.15 (t, J ˆ 6:2 Hz, 1 H), 7.23 (m,
4 H).
3-Hydroxy-3-(4-methylphenyl)propanenitrile (2f). Colorless oil. IR
1
3402, 3010, 2240, 1523 cm
.
1H NMR d 2.36 (br, 1H), 2.75 (d,
J ˆ 6:0 Hz, 2 H), 3.68 (s, 3 H), 5.01 (t, J ˆ 6:0 Hz, 1H), 7.22 (m, 4 H).
References
3-Hydroxy-5-phenylpent-4-enenitrile (2g). Colorless oil. IR 3390,
1
2
3
4
ꢁa† T. Yamamoto and N. Asao, Chem. Rev., 1993, 93, 2207; ꢁb†
C. J. Li, Chem. Rev., 1993, 93, 2023.
J. Y. Zhou, X. B. Yao, Z. G. Chen and S. H. Wu, Synth.
Commun., 1995, 25, 3081.
T. Mandai, J. Nokami and T. Yano, J. Org. Chem., 1984, 49,
172.
J. Y. Zhou, Z. G. Chen and S. H. Wu, J. Chem. Soc., Chem.
Commun., 1994, 278.
H. Walmann, Synlett, 1990, 627.
1
3021, 2235, 1528 cm
.
1H NMR d 2.28 (br, 1H), 2.70 (d, J ˆ 6:2Hz,
2 H), 4.52 (m, 1H), 6.38 (dd, J ˆ 6:0, 15.8 Hz, 1H), 6.85 (d,
J ˆ 15:8 Hz, 1H), 7.40 (m, 5 H).
3-Hydroxydecanenitrile (2h). Colorless oil. IR 3420, 2935, 2250,
1
1460 cm
.
1H NMR d 0.8^1.38 (m, 15 H), 2.48 (d, J ˆ 6:0 Hz, 2 H),
2.65 (br, 1H), 3.88 (m, 1H).
3-Hydroxy-1,3-diphenylpropan-1-one (3a). Mp 47 8C (lit.,12
1
44±46 8C). IR 3535, 1670, 1210, 750 cm
. d 3.35
1H NMR
5
6
7
(d, J ˆ 6:0 Hz, 2H), 3.43 (br, 1H), 5.10±5.43 (m, 1H), 7.10±8.00
T. Harada and T. Mukaiyama, Chem. Lett., 1982, 161; 467.
X. Gao, B. Z. Huang and S. H. Wu, Acta Chim. Sinica, 1991,
49, 827.
(m, 10H).
3-Hydroxy-3-(4-chlorophenyl)-1-phenylpropan-1-one (3b). Mp 96 8C
1
(lit,12 96±96.5 8C). IR 3465, 1668, 1210, 752, 685 cm
.
1H NMR d
8
9
W. Schmid and G. M. Whitesides, J. Am. Chem. Soc., 1991,
113, 6674.
P. Sun and Y. Zhang. Synth. Commun., 1997, 27, 3175.
3.32 (d, J ˆ 5:8 Hz, 2 H), 3.76 (br, 1 H), 5.12±5.38 (m, 1 H), 7.35
(m, 7 H), 7.86 (m, 2 H).
3-Hydroxy-3-(4-methylphenyl)-1-phenylpropan-1-one (3c). Mp 46 8C
10 X. L. Hou, X. L. Zheng and L. X. Dai, Tetrahedron Lett.,
1998, 39, 6949.
11 S. Inaba and R. D. Rieke, Tetrahedron Lett., 1985, 26, 155.
12 E. Hasegaya, K. Ishiyama, T. Horaguchi and T. Shimizu, J.
Org. Chem., 1991, 56, 1631.
13 S. Araki and Y. Butsugan, Bull. Chem. Soc. Jpn., 1991, 64,
727.
1
(lit,12 47±48 8C). IR 3470, 1685, 1210, 750 cm
.
1H NMR d 2.30 (s,
3 H), 3.31 (d, J ˆ 6:0 Hz, 2 H), 3.64 (br, 1 H), 5.10±5.40 (m, 1 H),
7.01±7.98 (m, 9 H).
3-Hydroxy-1-phenyldecanone (3d). Mp 47 8C (lit,13 48 8C). IR
3425, 1672, 1024, 745 cm
1
.
1H NMR d 0.80±1.38 (m, 15 H), 2.85
(br, 1 H), 3.10 (d, J ˆ 6:0 Hz, 2 H), 4.10±4.27 (m, 1 H), 7.20±8.02
(m, 5 H).