Trimethylsilyl chloride-accelerated reduction and pinacol coupling of carbonyl compounds by means of samarium diiodide

Article abstract of DOI:10.1039/a607774i

The combination of samarium diiodide (SmI₂) and trimethylsilyl chloride (Me₃SiCl) in THF-HMPA is found to accelerate the reduction of sterically hindered and enolisable ketones, and also to accelerate pinacolisation of the carbonyl compounds depending on the reaction conditions.

Full text of DOI:10.1039/a607774i

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Trimethylsilyl chloride-accelerated reduction and pinacol coupling of carbonyl
compounds by means of samarium diiodide
Toshio Honda* and Miho Katoh
Institute of Medicinal Chemistry, Hoshi University, Ebara 2-4-41, Shinagawa-ku, Tokyo 142, Japan
The combination of samarium diiodide (SmI2) and
trimethylsilyl chloride (Me3SiCl) in THF–HMPA is found to
accelerate the reduction of sterically hindered and enolisable
ketones, and also to accelerate pinacolisation of the carbonyl
compounds depending on the reaction conditions.
corresponding alcohol(s) with Birch-type reduction stereo-
chemistry in good yields.
Treatment of the 3-keto steroid 1 with 3 equiv. of SmI2 in the
presence of 3 equiv. of ButOH as a proton donor in THF–
HMPA at ambient temperature for 10 min afforded the
corresponding alcohols [2 (3a):3 (3b) = 28:57%].† When this
reduction was carried out in the presence of 3 equiv. of Me3SiCl
as an additive instead of ButOH under the same reaction
conditions, the yield improved to 90% [2 (3a):3 (3b)
= 30:60%].‡ Interestingly, reduction of the 20-keto steroid 4
with SmI2 and ButOH in THF–HMPA at room temperature
required 6 h to afford the corresponding alcohols [5 (20S):6
(20R) = 26:23%]. However, reduction of 4 under similar
reaction conditions in the presence of Me3SiCl proceeded
within 10 min to provide the alcohols (5 and 6)‡ in 93% yield,
in a ratio of 1:1. The reaction became significantly faster in the
presence of Me3SiCl. A dramatic change was observed in the
reduction of 6-keto steroid 7, which on treatment with SmI2 in
THF–HMPA gave none of the desired alcohol, although HMPA
was recognised to increase the rate of the reaction of SmI2.4
Samarium(ii) diiodide, originally introduced by Kagan and co-
workers1 into organic synthesis, has been established as a useful
synthetic reagent and a number of interesting reactions have
been developed by application of this reagent.2 SmI2 is a
powerful one-electron reducing agent and serves as an effective
reductant of carbonyl compounds. SmI2-promoted reduction of
carbonyl compounds usually proceeds quickly and completes
within a few minutes when the reaction is carried out in the
presence of a proton donor such as an alcohol or water in
tetrahydrofuran to prevent the formation of the pinacol coupling
product.1–3 During the course of our work on the synthesis of
physiologically active compounds employing SmI2, we ob-
served that the reduction of ketones with SmI2 in THF–HMPA
was accelerated in the presence of Me3SiCl to give the
i or ii
+
O
HO
HO
1
2
3
H
H
OH
O
OH
iii or ii
+
ButMe2SiO
ButMe2SiO
ButMe2SiO
4
5
6
H
H
H
OAc
OAc
OAc
iii or ii
+
AcO
AcO
AcO
OH
OH
O
8
9
7
i or ii
O
OH
10
11
Scheme 1 Reagents and conditions: i, SmI2, ButOH, THF–HMPA, room temp., 10 min; ii, SmI2, Me3SiCl, THF–HMPA, room temp., 1 min, then Bu4NF,
THF, room temp.; iii, SmI2, ButOH, THF–HMPA, room temp., 6 h
Chem. Commun., 1997
369

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treatment of the residue with Bu4NF (0.5 mmol) in THF (10
cm21) at room temperature afforded the desired alcohol.
The effectiveness of Me3SiCl for SmI2-mediated pinacol
coupling of the ketones in THF was also investigated. HMPA
was used as co-solvent to reduce the formation of reduction
products.5 The results are summarised in Table 1 and indicate
that the pinacol coupling of both aldehyde and ketone was also
accelerated by the presence of Me3SiCl. For example, it was
reported that the pinacol coupling of hexyl methyl ketone with
SmI2 in THF–HMPA required 24 h to give the corresponding
coupling product in 80% yield.5 However, the same reaction in
the presence of Me3SiCl proceeded within 3 min to give the
coupling product in 77% yield (entry 2). Similar results were
also obtained (see entires 5, 8 and 10), clearly indicating that
Me3SiCl as an additive accelerated the pinacol coupling
compared to the results previously reported.5 A typical
experimental procedure for the pinacol coupling is as follows—
to a stirred solution of SmI2 (5.1 mmol) in dry THF (50 cm3),
prepared from samarium metal and diiodoethane as above, were
added a solution of ketone (1.55 mmol) in THF (2 cm3) and
Me3SiCl (4.7 mmol). The resulting solution was stirred for the
appropriate time (see Table 1) under argon at room temperature.
The mixture was worked-up as described above to give the
coupling product.
However, reduction of 7 was carried out with SmI2 and ButOH
for 6 h to afford the alcohols [8 (6a):9 (6b) = 39:22%) in
moderate yields. Moreover treatment for 10 min of 7 with SmI2
in the presence of Me3SiCl afforded 8 as the sole product‡ in
91% yield. These varied reaction times and yields are reflected
by the steric hindrance of the carbonyl groups (6-keto >
20-keto > 3-keto) and the above results clearly suggest that
Me3SiCl accelerates the SmI2-mediated reduction of sterically
hindered ketones, although it is premature to present a detailed
mechanistic rationale at the present time. This type of reduction
was found to be effective to the enolisable ketones. Thus, the
reduction of indan-2-one 10 with SmI2 in THF–HMPA at
ambient temperature in the presence of Me3SiCl proceeded
within 1 min to give indan-2-ol 11 in 79% yield, whereas similar
reduction with SmI2 and ButOH after 10 min afforded 11 in
66% yield. The reduction was typically carried out as follows—
to a stirred solution of SmI2 in dry THF (7 cm3), prepared from
samarium metal (0.76 mmol) and diiodoethane (0.69 mmol),
under argon at room temperature, was added HMPA (0.9 cm3)
and the resulting mixture was stirred for a further 15 min. After
the successive addition of a solution of ketone (0.23 mmol) in
THF (1 cm3) and Me3SiCl (0.7 mmol), the mixture was stirred
for the appropriate time and then treated with saturated aqueous
sodium hydrogen carbonate. A stream of air was bubbled
through the solution and an excess of Celite and Et2O were
added. The solution was filtered and the filtrate was extracted
with ethyl acetate. Evaporation of the solvent followed by
In conclusion, we have found that Me3SiCl is an effective
additive for the SmI2-promoted reduction of ketones and also
for pinacol coupling. Recently, Kagan and co-workers6 reported
the improved reactivity of SmI2 by catalysis with transition
metal salts, in which Barbier-type reactions were found to be
accelerated in the presence of such metal salts. Me3SiCl in this
work may play a similar role as the metal salts.
Table 1 Pinacol coupling of the ketones
R2
C
R2
C
Footnotes
Sml2
R1
C
O
R2
R1
R1
THF, room temperature
additive
† The stereochemistry of the reduction products (2, 3, 5, 6, 8 and 9) were
determined by comparison with authentic samples prepared according to
literature procedures.
‡ The products from this reaction were trimethylsilyl ethers and the yields
were obtained after their conversion into the corresponding alcohols by
treatment with Bu4NF in THF.
OX
OX
Product
Starting material
Entry R1
Reaction conditions
Yield
(%)c
R2
Additive
Time
X
References
1
2
3
4
C6H13
Me
Me
Me
H
—
12 h
3 min
24 h
H
H
H
75
77
80d
81
37
45
C6H13
C6H13
C7H15
Me3SiCla
1 J. L. Namy, P. Girard and H. B. Kagan, Nouv. J. Chim., 1977, 1, 5;
P. Girard, J. L. Namy and H. B. Kagan, J. Am. Chem. Soc., 1980, 102,
2693.
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J. Synth. Org. Chem. Jpn., 1989, 47, 200; H. B. Kagan, New J. Chem.,
1990, 14, 453; J. A. Soderquist, Aldrichimica Acta, 1991, 24, 15;
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3 J. Souppe, J. L. Namy and H. B. Kagan, Tetrahedron Lett., 1982,
3497.
4 J. Inanaga, M. Ishikawa and M. Yamaguchi, Chem. Lett., 1987, 1485.
5 J. L. Namy, J. Souppe and H. B. Kagan, Tetrahedron Lett., 1983, 24,
765.
—
—
45 min
H
©Hb
®SiMe3
5
C7H15
H
Me3SiCla
1 min
6
7
8
9
C7H15
H
—
—
Me3SiCla
—
3 h
10 h
5 min
1 h
H
H
H
85d
78
78
65
53
30
PhCH2CH2
PhCH2CH2
PhCH2CH2
Me
Me
H
H
©Hb
®SiMe3
10
PhCH2CH2
H
Me3SiCla
1 min
a1.0 equiv. of starting material, 3.3 equiv. of SmI2 and 3.0 equiv. of Me3SiCl
were used. A mixture of the alcohol and its trimethylsilyl ether was
isolated. c Isolated yields. d This yield was based on the literature value (ref.
6).
6 F. Machrouhi, B. Hamann, J. L. Namy and H. B. Kagan, Synlett., 1996,
633.
b
Received, 18th November 1996; Com. 6/07774I
370
Chem. Commun., 1997