Indium-catalyzed direct chlorination of alcohols using chlorodimethylsilane-benzil as a selective and mild system

Article abstract of DOI:10.1021/ja048688t

The InCl₃-catalyzed reaction of alcohols with chlorodimethylsilane (HSiMe₂Cl) in the presence of benzil gave the corresponding organic chlorides under mild conditions. Benzil significantly changes the reaction course because the reducing product through dehydroxyhydration was obtained in the absence of benzil. The secondary or tertiary alcohols were effectively chlorinated. The substrates bearing acid-sensitive functional groups were also applied to this system. The highly selective chlorination of the tertiary site was observed in the competitive reaction between tertiary and primary alcohols. The highly coordinated hydrosilane generated from benzil and HSiMe₂Cl is an important intermediate. Copyright

Full text of DOI:10.1021/ja048688t

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Indium-Catalyzed Direct Chlorination of Alcohols Using
Chlorodimethylsilane-Benzil as a Selective and Mild System
Makoto Yasuda, Satoshi Yamasaki, Yoshiyuki Onishi, and Akio Baba*
Department of Molecular Chemistry and Handai Frontier Research Center, Graduate School of Engineering, Osaka
UniVersity, 2-1 Yamadaoka, Suita, Osaka 565-0871, Japan
Received March 8, 2004; E-mail: baba@chem.eng.osaka-u.ac.jp
Table 1. Effect of Benzil on Selective Formation of Chloride
Alcohols are one of the most common and versatile compounds
for transformation into other classes of chemicals. However, due
to the lower leaving ability, the hydroxyl moieties are hardly
substituted under mild conditions.1 Chlorodehydroxylation of
alcohols into organic chlorides has been accepted as a general and
basic transformation pathway in organic synthesis by using HCl
gas, PCl3, SOCl2, Vilsmeier-Haack reagent, Viehe salt.2 However,
the co-generation of HCl often causes undesired side reactions. The
system using Ph3P-CCl4 serves as a useful reagent for converting
primary alcohols into the corresponding chlorides under neutral
conditions in which triphenylphosphine oxide and CHCl3 are
byproducts. In this context, further development of a direct
chlorination method under neutral conditions would be greatly
desired. This communication describes a novel methodology for
chlorination of alcohols with HSiMe2Cl in the presence of benzil
under mild and neutral conditions.
yield %
entry
additive
H−Si−Cl
conditions
2a
3a
1
2
3
-
benzil
benzil
HSiPh2Cl
HSiPh2Cl
HSiMe2Cl
80 °C, 1.7 h
80 °C, 1.7 h
rt, 15 h
40
0
0
0
47
68
Chart 1. Additive Effects on Yields in the Reaction of 1a with
HSiMe2Cl
We have previously reported that 1-phenyl-2-propanol (1a) was
reduced to 1-phenylpropane (2a) in the presence of 1.1 equiv of
HSiPh2Cl with an InCl3 catalyst (Table 1, entry 1).1a The reaction
course includes the step of removal of HCl, giving the correspond-
ing silyl ether, which then transforms to 2a. Surprisingly, the
addition of benzil (PhCOCOPh) significantly changed the reaction
course to give 47% of 2-chloro-1-phenylpropane (3a) exclusively
without formation of 2a (entry 2).3 The yield was improved to 68%
by using HSiMe2Cl at room temperature (entry 3). Apparently, this
yield suggests that an equimolar amount of HSiMe2Cl is stoichio-
metric in this chlorination and no elimination of HCl is involved.
When InCl3 was not loaded, almost no formation of 3a was
observed. This result prompted us to investigate a HSiMe2Cl/InCl3/
benzil system that would contribute to a useful chlorination reaction
of alcohols under neutral conditions.
Scheme 1. NMR Study
Scheme 2. Plausible Reaction Course
generation of H2 was also confirmed during this reaction step.6 After
stirring for 18 h, transformation from 5 to the chloride 3a was
completed.
The choice of additive is very important (Chart 1). The
R-ketoester and R-alkoxyketone in place of benzil gave the product
in lower yields. The reaction using R-diester afforded no product
at all. The use of phenanthraquinone or anthraquinone also gave
no product. It was surprising that most of the benzil was recovered
unchanged after the reaction although we have reported that usual
carbonyl compounds suffered reductive chlorination by HSiMe2Cl
with an InCl3 catalyst.4 The choice of the catalyst (InCl3) is also
crucial for this chlorination. Other typical Lewis acids such as AlCl3
and Sc(OTf)3 hardly catalyzed the reaction.5
A plausible reaction course is proposed as shown in Scheme 2.
The chlorosilylation of benzil by HSiMe2Cl takes place at the first
step and gives the intermediate 6, whose Si-H bond must be
activated by the intramolecular carbonyl coordination. This path is
faster than the reduction (hydrosilylation) of benzil with HSiMe2-
Cl. The formed species 6 is kinetically unstable and reacts with
the indium-activated alcohol 7 to generate H2 and 8. The formed
alkoxysilyl ether 8 transforms to 9 that corresponds to 5 in Scheme
1. The silyl ether 9 gives the product mediated by InCl3.1,7 The
following points in Scheme 2 can explain the results in Chart 1:
the additive requires (i) a ketone moiety to be added by chlorosilane
at the first step, (ii) chelation ability in the intermediate, and (iii)
a flexible carbon framework to generate the highly coordinated
hydrosilane. Therefore, benzil gave the best results among the
additives examined.
1
The chlorination was monitored by H NMR to examine the
reaction mechanism (Scheme 1). When the mixture of 1a and
HSiMe2Cl in dichloromethane was stirred at room temperature for
1 h and the solvent removed under reduced pressure, the signal of
hydrosilyl ether 4 was observed.1a On the other hand, the loading
of benzil and InCl3 catalyst caused the appearance of the signal of
chlorosilyl ether 5, whereas no signal of 4 was detected. The
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J. AM. CHEM. SOC. 2004, 126, 7186-7187
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C O M M U N I C A T I O N S
Table 2. Chlorination of Various Alcoholsa
Scheme 3. Competitive Reaction between Tertiary and Primary
Alcohols
tion only at the tertiary site proceeded in the reaction of diol 10 to
give 11. It is noted that one equivalent of hydrosilane is enough
for the selective reaction for diol, while our previous systems
involving reduction1a or alkylation1b require an excess amount of
reagents. Even if the primary OH site reacts with hydrosilane faster
than the tertiary site, silyl transfer finally affords the silyl tertiary
alkoxide, which leads to the tertiary chloride. On the contrary,
conventional chlorination systems such as PPh3/CCl4 or PCl5 gave
the primary chloride 12. Similar selectivity in an intermolecular
version was also observed between 1f and 13. These results show
the unique and interesting selectivity of this chlorination system.
In conclusion, we have demonstrated a novel method for
chlorination of alcohols using HSiMe2Cl/benzil/InCl3 system under
neutral conditions. This system can be used for acid-sensitive
substrates. High selectivity for tertiary alcohols over primary alcohol
was observed. Further utility of this novel system is currently under
investigation.
a All entries were carried out at room temperature in CH2Cl2 with 5 mol
% of InCl3. 1.1 equiv of HSiMe2Cl and 1.0 equiv of benzil. b Rearrangement
products (regio isomers) were observed in 23% yield. c dr ) 1:1. d <2%
ee. e 2-Phenylpropane was obtained in 49% yield. f Premixing of HSiMe2Cl
and MeOH (1.0 equiv) followed by the addition of 1r.
The generality of this chlorination methodology is summarized
in Table 2.8 Various secondary and tertiary alcohols were converted
into chlorides in high yields (entries 1-7). The rearranged product
3i was obtained in the reaction with 1i (entry 8). This result supports
the carbocation mechanism in the chlorination. The primary alcohol
1j did not give the desired product (entry 9). However, effective
transformation was observed in the reaction with benzyl alcohols
1k-m which bear electron-withdrawing or -donating substituents
(entries 10-12). Nitro and ester moieties tolerated these reaction
conditions to furnish the corresponding chlorides 3n and 3o in 97%
and 77% yields, respectively (entries 13 and 14). When the optically
pure alcohol 1p was used (entry 15), racemization was observed.
This result also suggests the carbocation mechanism. The reaction
with hydroxyester 1q gave the desired product 3q in high yield
(entry 16). Those good results using acid-sensitive substrates clearly
confirm the advantage of this reaction system. In fact, the reaction
of 1q with PCl3 gave a complicated mixture. The chlorination with
PCl5 gave 3q in lower yield (66%) along with ethyl 3-phenyl-2-
propenoate (5%) through HCl elimination.9 The alcohol 1r did not
give the desired chloride 3s but a reduced product (2-phenylpropane)
in 49% (entry 17). We found that premixing of methanol (1 equiv)
and HSiMe2Cl/benzil/cat. InCl3 followed by the loading of 1r
successfully gave a high yield of 3r (entry 18). It is assumed that
methanol readily reacts with HSiMe2Cl with the generating H2, that
was actually confirmed, and affords the methoxysilane like 8. The
silyl transfer between methoxysilane and the added alcohol gener-
ates the desired alkoxysilane 8. The premixing with methanol avoids
the undesired process releasing HCl.
Acknowledgment. This work was supported by a Grant-in-Aid
for Scientific Research from the Ministry of Education, Culture,
Sports, Science and Technology of the Japanese Government.
Supporting Information Available: Reaction procedure and
spectroscopic details of new compounds. This material is available free
of charge via the Internet at http://pubs.acs.org.
References
(1) (a) Yasuda, M.; Onishi, Y.; Ueba, M.; Miyai, T.; Baba, A. J. Org. Chem.
2001, 66, 7741-7744. (b) Yasuda, M.; Saito, T.; Ueba, M.; Baba, A.
Angew. Chem., Int. Ed. 2004, 43, 1414-1416.
(2) (a) ComprehensiVe Organic Transformations, 2nd ed.; Larock, R. C., Ed.;
Wiley-VCH: New York, 1999; pp 689-702. (b) Copenhaver, J. E.;
Whaley, A. M. In Organic Syntheses; Wiley and Sons: New York, 1941;
Vol. 1, pp 144-145. (c) Lewis, E. S.; Boozer, C. E. J. Am. Chem. Soc.
1952, 74, 308-311. (d) Hepburn, D. R.; Hudson, H. R. J. Chem. Soc.,
Perkin Trans. 1 1976, 754-757. (e) Gomez, L.; Gellibert, F.; Wagner,
A.; Mioskowski, C. Tetrahedron Lett. 2000, 41, 6049-6052 and references
therein.
(3) During our trial for competitive reaction between alcohols and carbonyls,
we unexpectedly found this interesting outcome.
(4) (a) Onishi, Y.; Ogawa, D.; Yasuda, M.; Baba, A. J. Am. Chem. Soc. 2002,
124, 13690-13691. (b) Onishi, Y.; Ito, T.; Yasuda, M.; Baba, A.
Tetrahedron 2002, 58, 8227-8235.
(5) Although BiCl3-catalyzed chlorination by chlorosilanes was reported, the
system generates HCl in situ and requires an excess amount of chlorosi-
lanes. Labrouillere, M.; Le Roux, C.; Gaspard-Iloughmane, H.; Dubac, J.
Synlett 1994, 723-724.
(6) Detected by GC (packed with porapak-Q).
(7) The chlorosilyl ether 5 transformed to the chloride 3a (82% yield) in the
presence of InCl3 and benzil (See Supporting Information).
(8) Although Scheme 2 shows that a catalytic amount of benzil could work,
lower yields were, in fact, obtained in the catalytic reactions using alcohols
in Table 2. Much less generation of 6 in catalytic conditions does not
give a practical reaction rate to chlorides.
The methanol method (Table 2, entry 18) including silyl transfer
prompted us to examine the diol which bears both primary and
tertiary hydroxyl sites (Scheme 3). Gratifyingly, selective chlorina-
(9) Even the PPh3/CCl4 system that is considered as a neutral reagent also
gave the lower yield of the product 3r (62%) and the enoate (8%).
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