Iron-catalyzed reductive dehydroxylation of benzylic alcohols using polymethylhydrosiloxane (PMHS)

Article abstract of DOI:10.1055/s-0031-1289857

The combination of FeCl₃ and PMHS is an efficient reducing system for the selective dehydroxylation of secondary benzylic alcohols, even in the presence of carbonyls, under very mild conditions. Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0031-1289857

2862
LETTER
Iron-Catalyzed Reductive Dehydroxylation of Benzylic Alcohols Using
Polymethylhydrosiloxane (PMHS)
R
eductive Dehy
i
droxylation o
Y
f
B
enzylic Alcoho
a
ls n Chan, Jazreel Seh Kai Lim, Sunggak Kim*
Division of Chemistry and Biological Chemistry, School of Physical and Mathematical Sciences, Nanyang Technological University,
Singapore 637371, Singapore
Fax +65(6791)1961; E-mail: sgkim@ntu.edu.sg
Received 12 August 2011
utilized in the chemo- and enantioselective reduction of
Abstract: The combination of FeCl3 and PMHS is an efficient re-
carbonyl compounds to the corresponding alcohols using
ducing system for the selective dehydroxylation of secondary ben-
zylic alcohols, even in the presence of carbonyls, under very mild
chiral phosphine and nitrogen derived ligands.9 In addi-
tion, it is noteworthy that PMHS in the presence of
FeCl3·6H2O catalyst reduced aldehydes and ketones to
their corresponding hydrocarbons at high temperature
(120 °C) under microwave irradiation, as demonstrated
by Campagne in 2009.14
conditions.
Key words: reductive dehydroxylation, benzylic alcohol, silox-
anes, FeCl3
Nonetheless, the direct dehydroxylation of alcohols is
rarely explored.15 The application of chlorodiphenylsilane
as a hydride source, together with InCl3 catalysis, was
found to reduce secondary and tertiary benzylic alcohols
chemoselectively to produce the desired alkanes.15b,c Re-
cently, a new approach to dehydroxylation via the benzyl-
ic alkoxides using chloroboranes15d has been reported
along with its application to the direct substitution of ben-
zylic hydroxyl groups by vinyl and alkynyl groups.16
Reduction reactions play an important role in functional
group interconversions and the continual development of
safer, simpler and more environmentally friendly chemi-
cal methods is therefore beneficial, especially in the area
of organic synthesis.1 Sauer’s group first synthesized
polymethylhydrosiloxane (PMHS) in 1946.2 PMHS is an
effective polymeric hydride source for reduction, and is
well known for its inertness to air and moisture. It is also
readily available and non-toxic,3 making it a better option
than commonly used hydride transfer agents such as
LiAlH4, NaBH4, and H2, which are known for their haz-
ardous properties.4 The most commonly used catalysts in
combination with PMHS to carry out reduction reactions,
comprise of tin,5 titanium,6 palladium,7 and recently dis-
covered, zinc8 and iron complexes.9 Several examples
have been described for the reduction of aldehydes and
ketones using PMHS. Lipowitz and Bowman5 reported
such reductions using the PMHS–DBATO [bis(dibutyl-
acetoxytin)oxide] system in 1973. Titanium-catalyzed hy-
drosilylation using titanocene derivatives was also
effective for the asymmetric reduction of ketones.6 Simi-
larly, along with new procedures for the chemo- and enan-
tioselective reduction of carbonyl compounds using Zn
salts and PMHS under milder conditions,8 PMHS together
with the strong Lewis acid B(C6F5)3 was further used for
deoxygenation of carbonyls to the corresponding alkanes
under mild conditions,10 as compared to the well-known
Clemmensen11 and Wolff–Kishner reduction systems.12
Table 1 Optimizing Reaction Conditions with Various Iron Cata-
lystsa
OH
Ph
Ph
[Fe] (5 mol%), PMHS
CH2Cl2, r.t.
+
Ph
Ph
Ph
Ph
Ph
O
Ph
1
2
3
Entry
[Fe]
Time (h)
Isolated yield (%)
2
3
1
2
3
4
5
6
Fe(acac)3
FeF3
5
–
–
5
–
–
FeCl2
5
–
–
FeCl3
1
87
–
–
Fe(ClO4)3
Fe(OTf)3
1
>99
35
0.5
–
a Reaction conditions: diphenyl methanol 1 (0.3 mmol), PMHS (0.05
mL; 1 mmol Si–H = 0.06 mL19), [Fe] (5 mol%), CH2Cl2, r.t.
An increasing trend of using iron catalysts in various
organic reactions such as cross-coupling reactions, the
Friedel–Crafts reactions, and other functional group trans-
formations has developed over the years, largely due to
the abundance, low toxicity, and inexpensive characteris-
tics of Fe salts.13 Iron catalyst–PMHS systems have been
In connection with our interest in environmentally friend-
ly iron-catalyzed systems,17 we have studied the possi-
bility of using PMHS as a hydride source in the
chemoselective reductive dehydroxylation of benzylic al-
cohols. To explore the efficiency of various iron salts in
the reductive dehydroxylation of benzylic alcohols, we
began our studies with diphenylmethanol (1), as shown in
Table 1. Fe(acac)3, FeF3 or FeCl2 displayed no catalytic
SYNLETT 2011, No. 19, pp 2862–2866
x
x
.x
x
.2
0
1
1
Advanced online publication: 09.11.2011
DOI: 10.1055/s-0031-1289857; Art ID: U05811ST
© Georg Thieme Verlag Stuttgart · New York

LETTER
Reductive Dehydroxylation of Benzylic Alcohols
2863
Fe(ClO4)3 as the catalyst, the reaction did not afford the
desired product but, instead, resulted in almost quantita-
tive formation of an ether 3 side product (Table 1, entry
5). Similarly, the Fe(OTf)3-catalyzed reaction, as illustrat-
ed in entry 6, also afforded ether 3, but in lower yield.
Thus, FeCl3 was chosen to be the iron catalyst employed
in the dehydroxylation reaction.
Table 2 Exploring the Solvent Effects in Reductive Dehydroxyla-
tiona
Ph
Ph
OH
[Fe] (5 mol%), PMHS
+
Ph
Ph
Ph
O
3
Ph
Ph
Ph
2
1
Entry
Solvent
Temp (°C) Time (h) Isolated yield (%)
The FeCl3-catalyzed reduction of 1 using PMHS in vari-
ous solvents was then carried out. As shown in Table 2,
the reaction was very sensitive to the solvent used, and re-
sults obtained here confirmed that reductive dehydroxyla-
tion performed well in dichloromethane and 1,2-
dichloroethane, affording the desired product 2 in excel-
lent yields of 87 and 99%, respectively. When toluene was
employed, rather surprisingly, ether 3 was formed exclu-
sively in 37% yield (Table 2, entry 3) at 60 °C after one
hour. The reaction did not proceed at all in THF (entry 4),
even after prolonged heating at 60 °C for seven hours.
With the optimized conditions in hand, the PMHS–FeCl3
catalyzed reductive dehydroxylation in 1,2-dichloro-
ethane was then further explored to determine the scope
and limitations of the present method using various ben-
zylic alcohols.
2
3
1
2
3
4
CH2Cl2
ClCH2CH2Cl
toluene
r.t.
r.t.
60
60
1
1
1
7
87
99
–
–
–
37
–
THF
–
a Reaction conditions: diphenyl methanol 1 (0.3 mmol), PMHS (0.05
mL), FeCl3 (5 mol%), solvent (2 mL) r.t. or 60 °C.
activities when 1 was treated with PMHS in the presence
of 5 mol% Fe catalyst in dichloromethane at room temper-
ature for five hours (entries 1–3). The formation of ether
3 depended very much on the iron catalyst used, and this
was exemplified in the results.18
The use of FeCl3 afforded the desired reductive dehydrox-
ylation product 2, which was isolated exclusively in 89%
yield (Table 1, entry 4). Interestingly, by employing
Table 3 Reductive Dehydroxylation of Benzylic Alcohols 4a
OH
FeCl3 (5 mol%), PMHS
ClCH2CH2Cl, r.t.
Ar
R
Ar
R
5
4
R = alkyl, aryl
Entry
1
Substrate
Time (h)
Product
Isolated yield (%)
92
OH
1
5a
4a
OH
2
1
96
5b
5c
4b
OH
3
4
2
1
75
91
4c
OH
C6H13
C6H13
MeO
MeO
OMe
OMe
5d
4d
Synlett 2011, No. 19, 2862–2866 © Thieme Stuttgart · New York

2864
L. Y. Chan et al.
LETTER
Table 3 Reductive Dehydroxylation of Benzylic Alcohols 4a (continued)
OH
FeCl3 (5 mol%), PMHS
ClCH2CH2Cl, r.t.
Ar
R
Ar
R
5
4
R = alkyl, aryl
Entry
5
Substrate
Time (h)
Product
Isolated yield (%)
84
OH
OH
1
Ph
Ph
Et
Ph
Ph
5e
4e
6
7
0.5
1
80
0
Ph
Ph
Et
5f
4f
Ph
OH
Ph
5g
4g
OH
8
1
83
5h
4h
OH OH
OH
9b
3
2
2
72
65
81
5i
4i
OH
OH
C6H13
C6H13
10
HO
HO
5j
4j
C6H13
11b
C6H13
Br
Br
5k
4k
OH
12b
13
2
1
1
0
Br
Br
4l
5l
OH
Ph
OH
Ph
OH
92
5m
4m
H
OH
+
76
(1:1)
14
Ph
Ph
Ph
Ph
Ph
Ph
5n'
5n
4n
Ph
Ph
Ph
OH
84
(1.7:1)
15
1
+
4o
5o
5o'
a Reaction conditions: benzylic alcohol 4 (0.3 mmol), PMHS (0.05 mL), FeCl3 (5 mol%), 1,2-dichloroethane (2 mL), r.t.
b Reaction was carried out at 60 °C.
Synlett 2011, No. 19, 2862–2866 © Thieme Stuttgart · New York

LETTER
Reductive Dehydroxylation of Benzylic Alcohols
2865
Table 3 summarizes the reductive dehydroxylation of a neighboring methyl group can possibly undergo deproto-
range of benzylic alcohols under the optimized condi- nation, increasing the competition for forming the elimi-
tions. 1-(naphthalen-2-yl)ethanol (4a) was effectively re- nated product.
duced at room temperature within one hour to give 2-
ethylnaphthalene (5a) in 92% yield (entry 1), and 4b was
also reduced to 5b in 96% yield. Similarly, the dehydrox-
Carbonyl compounds including aldehydes and ketones
were found to be inert under the standard PMHS–FeCl3
catalyzed conditions, as exemplified in Table 4. The pres-
ylation system also worked well for 4c, giving 5c in 75%
ence of aldehyde 6a–c, ketone 6d, or ester 6e did not in-
yield, notably with the olefin still intact and stable (entry
fluence the efficiency of the reductive dehydroxylation of
3). Compound 4d was reduced to give 5d in 91% yield.
1. In fact, the reaction proceeded smoothly with almost
Electron-donating methoxy groups that are meta and para
quantitative recovery of carbonyl 6 in all cases (Table 4).
to the benzylic alcohol can substantially enhance the rate
Table 4 Selective Dehydroxylation of 1 in the Presence of 6a
of the SN1-like dehydroxylation reaction with PMHS by
stabilizing the cationic intermediate through resonance
(entry 4).
OH
O
O
FeCl3 (5 mol%), PMHS
R2
ClCH2CH2Cl, r.t., 1 h
+
Ph
+
Ph
R1
R1
R2
Ph
Ph
The dehydroxylation of secondary benzylic allylic alco-
hol 4e and secondary allylic alcohol 4f was also possible;
these reactions occurred smoothly at room temperature to
yield the corresponding alkanes in good yields of 84 and
80%, respectively (Table 3, entries 5, 6). Apparently, the
presence of a double bond stabilized the cationic interme-
diate through resonance, thus promoting the hydride dis-
placement reaction. However, it is noteworthy that the
primary alcohol 4g was unreactive under the present re-
ducing system (entry 7) due to its low reactivity. Indenol
4h was reduced effectively at room temperature to give its
corresponding indene 5h in 83% yield after one hour (en-
try 8). While 4i required a longer reaction time of three
hours at 60 °C, it also furnished the desired product, 2-eth-
ylphenol (5i), without affecting the o-phenolic alcohol
(entry 9). A similar observation was seen with 4j, where-
by the dehydroxylation was successful without disturbing
the p-phenolic alcohol obtained in 5j (entry 10). In con-
trast, introduction of the electron-withdrawing group Br
(entry 11) at the para position of 4k reduced the reaction
rate drastically; under these conditions, the reaction re-
quired heating at 60 °C to proceed. Primary benzylic alco-
hol 4l was also inert to the conditions (entry 12). Thus,
selective reductive dehydroxylation of a secondary ben-
zylic alcohol was further illustrated in Table 3, entry 13.
With compound 4m, which contains both primary and
secondary benzylic alcohols, however, only the secondary
alcohol reacted, to yield 5m exclusively, with the primary
alcohol still in place.
1
6
2
6
Entry
6
Isolated yield (%)
2
6
MeO
O
O
1
97
>99
MeO
6a
2
3
93
96
95
97
6b
O
O
6c
6d
6e
O
4
5
95
97
82
89
O
O
a Reaction conditions: 1 (0.3 mmol), carbonyl 6 (0.3 mmol), PMHS
(0.05 mL), FeCl3 (5 mol%), 1,2-dichloroethane (2 mL), r.t., 1 h.
In the dehydroxylation of tertiary alcohols 4n and 4o, the
eliminated products, vinyl 5n and 5o, together with the
desired product 5n¢ and 5o¢ were obtained in a 1:1
(Table 3, entry 14) and 1:1.7 ratio (Table 3, entry 15), re-
spectively. Such a phenomenon was observed because the
Furthermore, reductive dehydroxylation of 7 occurred se-
lectively on the benzylic alcohol, keeping the ketone in-
tact, providing 8 in 82% yield at 80 °C after three hours
(Scheme 1).
O
O
OH
FeCl3 (5 mol%), PMHS
ClCH2CH2Cl, 80 °C, 3 h
OMe
OMe
8
7
OMe
OMe
82% yield
Scheme 1
Synlett 2011, No. 19, 2862–2866 © Thieme Stuttgart · New York

2866
L. Y. Chan et al.
LETTER
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In summary, we have developed a highly efficient and
mild FeCl3–PMHS system for the reductive dehydroxyla-
tion of benzylic alcohols.20 The present method is inert
toward carbonyl groups, enabling the selective dehydroxy-
lation of benzylic alcohols in the presence of carbonyl
groups.
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We gratefully acknowledge financial support from Nanyang Tech-
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(20) General procedure for the reductive dehydroxylation of
benzylic alcohols 4: Anhydrous FeCl3 (2.4 mg, 0.015 mmol,
5 mol% equiv) was carefully weighed and stirred in 1,2-
dichloroethane (2 mL) for 5 min. PMHS (0.05 mL, 0.9
mmol, 3.0 equiv) was then added to the prepared catalyst
solution, followed by benzylic alcohol 4 (0.3 mmol, 1.0
equiv) and stirred at either r.t. or heated to the respective
temperature. The residual crude product was concentrated in
vacuo and purified by flash chromatography to afford the
desired product 5. 1H NMR and 13C NMR data of previously
unknown compounds: 4-heptyl-1,2-dimethoxybenzene (5d).
1H NMR (400 MHz, CDCl3): d = 7.26–6.70 (m, 3 H), 3.87
(s, 3 H), 3.85 (s, 3 H), 2.54 (t, J = 7.8 Hz, 2 H), 1.60–0.86
(m, 13 H); 13C NMR (100 MHz, CDCl3): d = 148.7, 147.0,
135.6, 120.1, 111.8, 111.2, 55.9, 55.8 35.6, 31.8, 31.7, 29.3,
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J = 8.3 Hz, 2 H), 7.03 (d, J = 8.3 Hz, 2 H), 2.54 (t, J = 7.8
Hz, 2 H), 1.63–1.53 (m, 2 H), 1.36–1.19 (m, 8 H), 0.88 (t,
J = 6.8 Hz, 3 H); 13C NMR (100 MHz, CDCl3): d = 141.8,
131.2, 130.1, 119.2, 35.3, 31.8, 31.3, 29.1, 29.1, 22.6, 14.1;
HRMS (ESI): m/z [M + 1] calcd for C13H20Br: 255.0748;
found: 255.0757.
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