Extended scope of in situ iodotrimethylsilane mediated selective
reduction of benzylic alcohols
Gary A. Cain* and Edward R. Holler
Chemical and Physical Sciences, DuPont Pharmaceuticals Company, P.O. Box 80336, Experimental
Station E336/109, Wilmington, DE 19880-0336, USA. E-mail: gary.a.cain@dupontpharma.com
Received (in Corvallis, OR, USA) 14th March 2001, Accepted 7th May 2001
First published as an Advance Article on the web 25th May 2001
Iodotrimethylsilane, generated in situ from chlorotrime-
thylsilane and sodium iodide in acetonitrile, selectively
reduces moderately electron deficient benzylic alcohols to
the analogous toluenes; other reduction sensitive functional
groups such as ketone, aldehyde, nitrile, and nitro are
unaffected.
°C, readily provided the benzylic alcohol 3 in 74% yield after
flash chromatography. At this stage of our work we followed the
in situ TMSI benzylic alcohol reduction conditions from the
first pertinent literature paper we could locate.3 This reference
used 6 eq. each of TMSCl and NaI with acetonitrile as solvent
at 0 °C for 5 min. Under these conditions, however, we did not
observe any reduction product. Eventually we found that upon
heating the reaction to 55 °C (the boiling point of TMSCl)
overnight we obtained a near quantitative yield of the desired
reduction product 4 after standard workup (see Table 1, Ex.
1).
Upon subsequently conducting a more thorough literature
search, we were surprised to find that the defluoro analog of our
above example was reported4 to provide a 0% yield under
attempted TMSI reduction. Because this particular paper was
mainly concerned with electron rich systems, which proceeded
quickly at low temperature, these workers may not have
attempted the higher temperature and longer time that we had
found necessary. Indeed, when we attempted the reduction of
1-(3-pyridyl)phenylmethanol at 55 °C (Ex. 2), we found that the
reduction did proceed, although quite slowly. After 5 days the
reduction was observed to be 67% complete by proton NMR.
Having thus established that electron poor 3-pyridyl benzylic
alcohols were successful substrates for the in situ TMSI
reduction, we then explored several other electron deficient
examples to begin to understand the scope of the reaction. These
results are summarized in the Table 1, Examples 1–8.
The use of iodotrimethylsilane (TMSI), generated in situ from
ClSiMe3 (TMSCl) and NaI in dry CH3CN, is known to be a
useful reagent for the reduction of secondary benzylic alco-
hols.1–3 Although infrequently utilized, this reagent provides
high yields of the deoxygenated toluene products, particularly
for electron rich aromatic systems. The near exclusive use of
these conditions for electron rich substrates may be associated
with the proposed intermediacy of a benzylic stabilized
carbocation at the reduction site. We now report that in situ
TMSI reductions can be extended to moderately electron
deficient benzylic alcohols, and that these conditions are
selective in the presence of other reduction sensitive functional
groups.
Our interest in the area began when we required a preparation
of 3-(4-fluorobenzyl)pyridine. Being a previously unknown
compound, we envisaged that it should be accessible via a
Grignard reaction to form the benzylic alcohol, followed by
selective benzylic –OH reduction in the presence of the
potentially reduced pyridine ring (Scheme 1). In practice, the
Grignard reaction, using commercially available 4-fluorophe-
nylmagnesium bromide 1 and 3-formylpyridine 2 in Et2O at 0
It is apparent from these results that moderately electron
deficient diarylmethanols are good substrates for this reduction.
Comparison of Ex. 3–5 illustrates that increasingly electron
deficient systems, as by the sequential introduction of more
fluorines onto the rings, led to much slower reactions and poorer
yields. The reaction of the 2-pyridyl analog (Ex. 6), with the
electron deficient node directly adjacent to the reaction center,
failed completely. Strongly electron deficient 4-nitrophenyl
Scheme 1
Table 1 In situ TMSI reduction of electron deficient benzylic alcohols
Ex. #
Ar
R
Time
Temp/°C
Yield (%)a
1
2
3
4
5
6
7
8
3-Pyridyl
3-Pyridyl
4-F-Ph
3,4,5-Tri-F-Ph
F5-Ph
2-Pyridyl
4-NO2-Ph
4-NO2-Ph
4-F-Ph
4-Ac-Ph
4-F-Ph
4-F-Ph
Ph
4-F-Ph
3,4,5-Tri-F-Ph
F5-Ph
Ph
Me
Ph
4-CN-Ph
4-Ac-Ph
4-CHO-Ph
Me
18 h
5 d
4 h
6 d
7 d
55
55
rt
55
55
55
55
55
rt
99
26b (67)
98
12b (74)
0
0
5 d
6 d
0
24 h
3 h
15 min
18 h
18 h
38
96
100
58
99
1
9
10
11
12
rt
rt
rt
4-Ac-Ph
a Yields are for isolated and fully characterized pure products. Yields in parentheses are estimated amounts in the crude product H NMR. b Additional
product was present in mixed chromatography fractions.
1168
Chem. Commun., 2001, 1168–1169
This journal is © The Royal Society of Chemistry 2001
DOI: 10.1039/b102495g
Cain
