Regioselective synthesis of halohydrin esters from epoxides: Reaction with acyl halides and rhodium-catalyzed three-component coupling reaction with alkyl halides and carbon monoxide

Article abstract of DOI:10.1039/b912907c

Regioselective synthesis of halohydrin esters was achieved by (1) the reaction of acyl halides with epoxides and (2) the rhodium-catalyzed three-component coupling reaction of alkyl halides, carbon monoxide, and epoxides. The Royal Society of Chemistry 20

Full text of DOI:10.1039/b912907c

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Regioselective synthesis of halohydrin esters from epoxides: reaction with
acyl halides and rhodium-catalyzed three-component coupling reaction
with alkyl halides and carbon monoxidewz
Koji Nakano, Shunsuke Kodama, Yessi Permana and Kyoko Nozaki*
Received (in Cambridge, UK) 1st July 2009, Accepted 6th October 2009
First published as an Advance Article on the web 16th October 2009
DOI: 10.1039/b912907c
Regioselective synthesis of halohydrin esters was achieved by (1)
the reaction of acyl halides with epoxides and (2) the rhodium-
catalyzed three-component coupling reaction of alkyl halides,
carbon monoxide, and epoxides.
Table 1 Halohydrin-ester synthesis by the reaction of acetyl halides
with propylene oxidea
Halohydrin esters can be used as building blocks for the
synthesis of lipids1 and biologically active compounds.2 One
of the common synthetic strategies for them is the conversion
of 1,2-diols.3 Another class of powerful synthetic strategies
includes using epoxides as a starting material. For example,
epoxides can be transformed into halohydrin esters via a
two-step procedure in one-pot: (i) the ring-opening by halogen
nucleophiles and (ii) the subsequent O-acylation of the resulting
halohydrin derivatives.4 An alternative pathway to halohydrin
esters from epoxides is the direct reaction with acyl halides.5 In
general, a mixture of regioisomers is obtained when using
unsymmetrical 1,2-diols or epoxides in each synthetic strategy
mentioned above. Accordingly, the achievement of high
regioselectivity would ensure a method gains prominence
as a useful synthetic transformation. Here we report the regio-
selective synthesis of halohydrin esters by using epoxides as
one of the starting materials.
Entry
X
Solvent Additive (mol%)
Yield of 1 (%)b 1/2c
1a, 35 53/47
1
2
3
4
Cl
Cl
Cl
I
—
—
—
—
3-MeO-pyridine (1.0) 1a, 80
Pyridine (1.0)
81/19
82/18
62/38
1a, 57
1b, 38
CH2Cl2 Pyridine (30)
a
Reaction conditions: acetyl chloride (5.6 mmol), propylene oxide
(14 mmol), additive, 75 1C, 12 h (entries 1–3); acetyl iodide (4.4 mmol),
propylene oxide (9.3 mmol), pyridine (1.24 mmol), CH2Cl2 (5.0 ml),
ꢀ78 1C, 3 h (entry 4). In entry 4, acetyl iodide in CH2Cl2 was slowly
added via syringe pump. NMR yield. Determined by 1H NMR
b
c
analysis of the reaction mixture.
in the presence of carbonylation catalysts. Accordingly, the
subsequent reaction of the resulting acid halides with epoxides
would give the corresponding halohydrin esters. This type
of catalytic transformation is attractive because three
easily-available substrates can be incorporated into one
molecule directly. Previously, Tanaka and co-workers
reported the three-component coupling reaction using a
palladium complex, while the proposed reaction mechanism
did not involve the formation of acid halides.9,10 This catalytic
reaction can be applied to a variety of substrates. Unfortunately,
however, a mixture of regio-isomers was formed when using
propylene oxide.
First, halohydrin-ester synthesis from acyl halides and
epoxides was investigated. Simple mixing of acetyl chloride
and propylene oxide provided regio-isomers 1a and 2a in
53/47 ratio in low yield (Table 1, entry 1). On the other hand,
the addition of pyridine derivatives was found to be
effective, giving higher yields and higher regioselectivities
(entries 2 and 3).6,7 The reaction of acetyl iodide also
proceeded, while the yield and the regioselectivity were lower
(entry 4).
Next, the transition-metal-catalyzed three-component coupling
reaction of organic halides, carbon monoxide, and epoxides
was investigated for halohydrin-ester synthesis.8 Based on the
well-known Monsanto process, we can expect that acid halides
are generated from organic halides and carbon monoxide
Regioselective synthesis of halohydrin esters was success-
fully achieved by using [PPN]+[Rh(CO)4]ꢀ as a catalyst
([PPN]+ = bis(triphenylphosphoranylidene)iminium). The
reaction of benzyl bromide, carbon monoxide (6 MPa), and
propylene oxide (2 equiv. to BnBr) in the presence of
[PPN]+[Rh(CO)4]ꢀ (0.5 mol%) and 3-methoxypyridine
(1 mol%) at 75 1C for 6 h gave 1-bromopropan-2-yl phenyl-
acetate (1c) in 77% yield, with high regioselectivity (Table 2,
entry 1). Only a small amount of the regio-isomer, 2-bromo-
propyl phenylacetate (2c) was observed (1c/2c = 97/3).
Addition of pyridine derivatives is necessary for high yield:
the reaction in the absence of 3-methoxypyridine for 12 h gave
a much lower yield of 12% (entry 2), while high regioselectivity
was maintained. Other pyridine derivatives such as pyridine
and 4-(N,N-dimethylamino)pyridine were also effective, although
Department of Chemistry and Biotechnology, Graduate School of
Engineering, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku,
Tokyo 113-8656, Japan. E-mail: nozaki@chembio.t.u-tokyo.ac.jp;
Fax: +81 3 5841 7263; Tel: +81 3 5841 7261
w This article is part of a ChemComm ‘Catalysis in Organic Synthesis’
web-theme issue showcasing high quality research in organic
chemistry. Please see our website (http://www.rsc.org/chemcomm/
organicwebtheme2009) to access the other papers in this issue
z Electronic supplementary information (ESI) available: Experimental
section, 1H and 13C NMR spectra and plausible reaction pathways.
See DOI: 10.1039/b912907c
ꢁc
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6970 | Chem. Commun., 2009, 6970–6972

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Table 2 Rhodium-catalyzed halohydrin-ester synthesis from benzyl
bromide, carbon monoxide, and propylene oxidea
Table 3 Scope of alkyl halides and epoxides in rhodium-catalyzed
halohydrin-ester synthesisa
Yield of
1c (%)b
Entry [PPN]+[M(CO)n]ꢀ Additive
1c/2cc
1
2
3
[PPN]+[Rh(CO)4]ꢀ 3-MeO-pyridine
[PPN]+[Rh(CO)4]ꢀ
[PPN]+[Rh(CO)4]ꢀ Pyridine
77
12
73
97/3
93/7
95/5
95/5
50/50
—
—
4
[PPN]+[Rh(CO)4]ꢀ 4-Me2N-pyridine 45
5d
6
[PPN]+[Co(CO)4]ꢀ 3-MeO-pyridine
[PPN]+[Mn(CO)5]ꢀ 3-MeO-pyridine
14
No reaction
Organic
Entry halide (R1–X)
Product,
yield (%)b
Epoxide (R2)
1/2c
a
Reaction conditions: benzyl bromide (1 equiv.), CO (6 MPa),
propylene oxide (2 equiv.), [PPN]+[M(CO)n]ꢀ (0.5 mol%), additive
(1 mol%), 75 1C, 6 h (entries 1, 3, and 4) or 12 h (entries 2, 5, and 6).
1
2
3
Bn–Br
Bn–Br
Bn–Br
–CH2OBn
–CH2Br
Cyclohexene
oxide
1d, 61 (70)
1e, 67 (68)
1f, 89 (84)
499/o1
499/o1
—
b
c
NMR yield. Determined by 1H NMR analysis of the reaction
d
mixture. Ether 3c (19%) and 4c (23%) were also produced.
4
Bn–Br
–CH3
(S)-1c,
94/6
(S, 499% ee) 73 (71)
5
6
7
8
Me–I
Allyl–Br
–CH3
–CH3
1b, 50 (40)
1g, 66 (41)
92/8
97/3
MeOC(O)CH2–Br –CH3
Bn–Cl –CH3
1h, 91 (70)d 92/8
1i, 22 (24)d 83/17
a
Reaction conditions: alkyl halide (1 equiv.), CO (6 MPa), epoxide
(2 equiv.), 75 1C. [PPN]+[Rh(CO)4]ꢀ (0.5 mol%), 3-methoxypyridine
(1 mol%), 24 h (entries 1 and 3); [PPN]+[Rh(CO)4]ꢀ (1 mol%),
3-methoxypyridine (2 mol%), 12 h (entries 2 and 5, 6, and 8);
[PPN]+[Rh(CO)4]ꢀ (0.5 mol%), 3-methoxypyridine (1 mol%), 12 h
(entry 4); [PPN]+[Rh(CO)4]ꢀ (1 mol%), 3-methoxypyridine (2 mol%),
the yields were slightly lower than that with 3-methoxypyridine
(entries 3 and 4).11 When using [PPN]+[Co(CO)4]ꢀ as a
catalyst, a significant amount of 2c and ethers 3c and 4c,
which were derived from benzyl bromide and propylene
oxide without carbonylation, were produced along with 1c
(entry 5). The use of [PPN]+[Mn(CO)5]ꢀ, which was
reported to be more nucleophilic toward methyl iodide than
[PPN]+[Co(CO)4]ꢀ,12 did not give any product (entry 6).
Accordingly, [PPN]+[Rh(CO)4]ꢀ was found to catalyze the
reaction efficiently with high regioselectivity.13
b
c
24 h (entry 7). NMR yield (isolated yield). Determined by 1H
d
NMR analysis of the reaction mixture. A small amount of regio-
isomer could not be separated by column chromatography.
present transformation. The reaction with tert-butyl bromide
gave a complex mixture without the desired halohydrin ester.14
Employment of bromobenzene also resulted in the recovery of
the starting materials.
With the optimized conditions, we examined the scope of
this transformation (Table 3). The reactions of benzyl glycidyl
ether and 3-bromopropylene oxide with benzyl bromide and
CO gave the corresponding halohydrin esters 1d and 1e,
respectively, with extremely high regioselectivity (entries 1
and 2). Cyclohexene oxide, a representative alicyclic epoxide,
was also applicable to this transformation (entry 3). The
obtained halohydrin ester 1f was found to be a trans isomer.
The reaction of (S)-propylene oxide (499% ee) gave (S)-1c
without a loss of enantiopurity (entry 4). The scope of alkyl
halides was also examined by using propylene oxide as a
coupling partner. Methyl iodide, allyl bromide, and methyl
bromoacetate were transformed into halohydrin esters 1b, 1g,
and 1h, respectively, in moderate yields (entries 5–7). Benzyl
chloride was also employable (entry 8), while the reaction was
slower than that with benzyl bromide (Table 2, entry 1). When
normal- and secondary-butyl bromides were used, the starting
materials were recovered. Such inertness of unactivated alkyl
halides is a key point for the successful formation of the
desired halohydrin esters since the produced halohydrin esters
1 themselves are alkyl halides, potential substrates for the
In conclusion, we have demonstrated that the addition of
pyridine derivatives is effective to attain higher yields and
higher regioselectivities in the halohydrin-ester synthesis from
acyl halides and epoxides. In addition, we also established a
three-component coupling reaction with alkyl halides, carbon
monoxide, and epoxides by using [PPN]+[Rh(CO)4]ꢀ as a
catalyst to produce halohydrin esters. The reaction can be
applied to a variety of epoxides and activated alkyl halides.
When using terminal epoxides, exclusively high regioselectivity
was accomplished.
This work was supported by a Grant-in-Aid for Scientific
Research on Priority Areas (No. 20037011, ‘‘Chemistry of
Concerto Catalysis’’) from the Ministry of Education, Culture,
Sports, Science and Technology, Japan.
Notes and references
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Chem. Commun., 2009, 6970–6972 | 6971

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13 Although the reaction mechanism is unclear, the possible reaction
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6 In order to improve regioselectivity, the reactions catalyzed
by CoCl2, ammonium salt, Pd(PPh3)4, or LiClO4 were also
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14 A similar reaction result was obtained without the rhodium
complex. Accordingly, the rhodium complex would not be
involved in the reaction.
ꢁc
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6972 | Chem. Commun., 2009, 6970–6972