Remarkably fast acylation of alcohols with benzoyl chloride promoted by TMEDA

Article abstract of DOI:10.1055/s-1999-3521

Reaction of alcohols with benzoyl chloride in the presence of TMEDA at - 78°C resulted in very fast acylation to afford the corresponding benzoates in excellent yields.

Full text of DOI:10.1055/s-1999-3521

PAPER
1141
Remarkably Fast Acylation of Alcohols with Benzoyl Chloride Promoted by
TMEDA
Tomohumi Sano, Kousaburo Ohashi, Takeshi Oriyama*
Faculty of Science, Ibaraki University, 2-1-1 Bunkyo, Mito 310-8512, Japan
Fax +81(29)2288406; E-mail: tor@mito.ipc.ibaraki.ac.jp
Received 13 January 1999
OH
OBz
TMEDA
Abstract: Reaction of alcohols with benzoyl chloride in the pres-
ence of TMEDA at –78°C resulted in very fast acylation to afford
the corresponding benzoates in excellent yields.
+
BzCl
o
MS 4A, CH2Cl2, –78 °C
Ph
Ph
2a
1a
Key Words: TMEDA, benzoyl chloride, benzoylation of alcohols,
chemoselectivity
Scheme 1
Acylation of alcohols is a very important functional group
transformation in synthetic organic chemistry. Acylations
in general take place by the treatment of alcohols with
Table 1 Acylation of 4-Phenylbutan-2-ol (1a) with Benzoyl Chlo-
ride (BzCl) in the Presence of TMEDA
acid anhydride or acid halide under the influence of a base Entry
such as triethylamine, pyridine etc.1,2 For example, the
benzoylation of alcohols with benzoyl chloride usually
BzCl
(equiv)
TMEDA Time
Yield
of 2a
(%)a
Recovery
of 1a
(equiv)
(min)
(%)a
proceeds in the presence of pyridine at above 0°C. Several
other procedures for the benzoylation of alcohols at –40°C
or upper have been reported.3 However, to the best of our
knowledge, only Koreeda et al.4 have reported that benz-
oylation with benzoyl triflate in the presence of pyridine
can be carried out smoothly even at –78°C.
1
2
3
4
5
1.2
1.2
1.1
1.1
1.1
1.0
1.0b
0.6
0.6
0.6c
5
5
5
20
20
96
72
96
97
87
0
21
trace
0
7
a Isolated yield of purified product.
b Carried out without MS 4Å.
Our previous reports have documented the utility of chiral
1,2-diamines derived from (S)-proline as efficient cata-
lysts capable of catalyzing an asymmetric acylation of ra-
cemic secondary alcohols5 and meso-1,2-diols6 with
achiral benzoyl chloride. The use of only 0.5 mol% of
chiral 1,2-diamine to the substrate combined with a stoi-
chiometric amount of achiral triethylamine at –78°C gave
the corresponding benzoate with good to excellent ee in
good yields.
c Performed in EtCN instead of CH2Cl2.
Amine
OH
OBz
+
BzCl
o
MS 4A, CH2Cl2, –78 °C
Ph
Ph
1a
2a
Scheme 2
Now we wish to report an expedient method for the re-
markably fast acylation of alcohols at –78°C with benzoyl
chloride promoted by the 1,2-diamine, TMEDA
(N,N,N’,N’-tetramethylethylenediamine)7. In the first
place, we undertook to examine the acylation of 4-phen-
ylbutan-2-ol (1a) as a model substrate with benzoyl chlo-
ride in the presence of TMEDA and molecular sieves 4Å
(MS) at –78°C in dichloromethane (Scheme 1, Table 1).
When the reaction was performed with 1.2 equivalents of
benzoyl chloride in the presence of 1.0 equivalent of
TMEDA for 5 minutes, the corresponding benzoate 2a
was obtained in 96% yield (Entry 1). On the other hand,
the reaction proceeded in the absence of MS 4Å some-
what slower than in its presence (Entry 2). When the
amount of TMEDA was decreased to 0.6 equivalent, a
similar fast acylation was completed in 20 minutes to give
the benzoate 2a in 97% yield (Entry 4). In EtCN the start-
ing alcohol 1a still remained after 20 minutes (Entry 5).
Table 2 The Effect of Various Amines on the Acylation of 4-Phen-
ylbutan-2-ol (1a) with Benzoyl Chloride (BzCl)
Entry Amine (equiv)
BzCl
(equiv)
Time
Yield of
2a (%)a
1
2
3
4
5
6
7
8
9
TMEDA (0.6)
none
Et3N (1.1)
1.1
1.5
1.5
1.5
1.1
1.5
1.6
1.1
1.1
20 min 97
3 h
3 h
5 h
3 h
3 h
3 h
3 h
3 h
0
2
Py (1.0)
48
Me2NCH2NMe2 (0.6)
DMPRAc (1.1)
DABCOd (1.1)
Me2N(CH2)3NMe2 (0.6)
Me2N(CH2)4NMe2 (0.6)
2b
26
88
22
16
a Isolated yield of purified product.
b N,N-Dimethylbenzamide was obtained in 85% from BzCl.
c DMPRA = 1,4-dimethylpiperazine.
d DABCO = 1,4-diazabicyclo[2.2.2]octane.
Synthesis 1999, No. 7, 1141–1144 ISSN 0039-7881 © Thieme Stuttgart · New York

1142
T. Sano et al.
PAPER
gave rise to acylation of 1 at –78°C to afford the benzoy-
lated product 2 even after 3–5 hours in only 2 and 48%
yield, respectively (Entries 3 and 4). The 1,1-diamine,
N,N,N’,N’-tetramethylmethanediamine also hardly gave
the benzoate 2a because it reacted with benzoyl chloride
to afford N,N-dimethylbenzamide (Entry 5). 1,2-Di-
amines such as DMPRA (1,4-dimethylpiperazine) and
DABCO (1,4-diazabicyclo[2.2.2]octane), 1,3-diamine
such as N,N,N’,N’-tetramethylpropane-1,3-diamine, and
1,4-diamine such as N,N,N’,N’-tetramethylbutane-1,4-di-
amine were not effective compared with TMEDA (Entries
6–9). These results showed that TMEDA was the most ef-
fective amine for the acylation with benzoyl chloride at
–78°C. Acylation of 1a occurred very smoothly at –78°C
for 20 minutes to give the benzoate 2a in 97% yield (Entry
1).
TMEDA
O
O
R2CCl
R1OCR2
R1OH
+
o
MS 4A, CH2Cl2
–78 °C, 20 min
1
2
Scheme 3
Table 3 Acylation of Various Alcohols with Acyl Chlorides in the
Presence of TMEDAa
Entry R1OH
R2
Ph
Prod- Yield
uct
(%)b
1
2a
97
OH
(1a)
Ph
The acylation was conducted with a variety of alcohols
and the results are represented in Table 3 (Scheme 3).
Similar fast acylations with substituted benzoyl chloride
having nitro, methoxyl, and methyl groups were also suc-
cessful as shown in Entries 2–5. On the other hand, acyla-
tion with acetyl chloride proceeded slowly under the same
reaction conditions to give the acetate even after 6 hours
in only 33% yield (Entry 6). Various alcohols including
primary and secondary alcohols and, acyclic and cyclic al-
cohols were benzoylated facilely to the corresponding
benzoates in excellent yields (Entries 7–10). Diols also
gave the corresponding dibenzoates in excellent yields
(Entries 11 and 12). Phenolic hydroxyl groups were also
acylated readily with benzoyl chloride in the presence of
TMEDA (Entries 13 and 14). However, tertiary alcohol
did not react with benzoyl chloride under similar reaction
conditions (Entry 15). This prompted us to examine the
chemoselective acylation between secondary and tertiary
alcohols.
2
4-NO2C6H4
4-MeOC6H4
4-MeC6H4
2-MeC6H4
Me
2b
2c
2d
2e
2f
99
95
96
95
33
97
3
4
5c
6d
7
Ph
2g
(1g)
OH
Ph
OH
8
Ph
2h
97
(1h)
(1i)
Ph
OH
Ph
9d
10
Ph
Ph
2i
2j
94
96
OH
(1j)
(1k)
(1l)
Ph
OH
11e
12e
Ph
Ph
2k
2l
96f
95f
OH
OH
2-Methylpentane-2,4-diol (3) having both secondary and
tertiary hydroxyl groups was reacted with benzoyl chlo-
ride in the presence of TMEDA at –78°C to give specifi-
cally the monobenzoate 4 of the secondary hydroxyl
group in 99% yield (Scheme 4).
OH
Br
OH (1m)
13
14
Ph
Ph
2m
2n
95
96
OH (1n)
OH
15g
Ph
2o
0
(1o)
Ph
1.0 equiv.
1.5 equiv.
TMEDA
HO
OH
BzO
OH
+
BzCl
o
MS 4A, CH2Cl2
–78 °C, 2 h
a R2COCl (1.1 equiv), TMEDA (0.6 equiv).
b Isolated yield of purified product.
c Reaction was carried out for 2 h.
d Reaction was carried out for 6 h.
3
4 99%
Scheme 4
e 1.2 equivalents of TMEDA and 2.2 equivalents of BzCl were used.
f Corresponding dibenzoate.
The details of the reaction mechanism are not clear at
present; however, we suppose that a benzoyl chloride–
TMEDA complex 5 (Figure) plays a significant role for
the very fast benzoylation. 1H NMR spectra of the benzoyl
chloride–TMEDA complex 5 showed that both signals of
methyl and methylene of TMEDA displayed evident
downfield shift (2.37 from 2.24, 2.60 from 2.38 ppm, re-
spectively) compared with TMEDA alone, which sug-
g Reaction was carried out for 3 h.
The effect of various amines was then examined (Scheme
2, Table 2). No acylation of 1a with benzoyl chloride in
the presence of only MS 4Å took place at –78°C (Entry 2).
A stoichiometric amount of triethylamine and pyridine
Synthesis 1999, No. 7, 1141–1144 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Remarkably Fast Acylation of Alcohols with Benzoyl Chloride Promoted by TMEDA
1143
IR (neat): n = 1257, 1510, 1606, 1708 cm–1.
gested steady complexation of benzoyl chloride and
TMEDA.8
2-(4-Methylbenzoyl)-4-phenylbutane (2d)
1H NMR: d = 1.36 (d, 3 H, J = 6.2 Hz), 1.93 (m, 1 H), 2.06 (m, 1 H),
2.39 (s, 3 H), 2.70 (m, 2 H), 5.16 (m, 1 H), 7.14–7.27 (m, 7 H), 7.93
(d, 2 H, J = 7.1 Hz).
Me
Me
13C NMR: d = 20.06, 21.53, 31.76, 37.71, 70.80, 125.83, 127.99,
N
N
O
Me
Cl
Me
128.26, 128.34, 128.94, 129.48, 141.50, 143.30, 166.15.
IR (neat): n = 754, 1109, 1276, 1612, 1712, 2976 cm–1.
Ph
5
2-(2-Methylbenzoyl)-4-phenylbutane (2e)
1H NMR: d = 1.37 (m, 3 H), 1.93 (m, 1 H), 2.07 (m, 1 H), 2.61 (s, 3
H), 2.73 (m, 2 H), 5.18 (m, 1 H), 7.16–7.36 (m, 7 H), 7.39 (m, 1 H),
7.89 (m, 1 H).
Figure. Structure of benzoyl chloride-TMEDA complex
13C NMR: d = 20.13, 21.74, 31.89, 37.80, 70.91, 125.65, 125.91,
128.31, 128.42, 130.27, 130.36, 131.61, 131.71, 139.85, 141.51,
167.25 cm–1.
IR (neat): n = 739, 1078, 1257, 1715, 2976 cm–1.
In summary, the present fast acylation of hydroxyl groups
has the following synthetic advantages: 1) excellent
chemical yield, 2) high efficiency (1.1 equivalents of ben-
zoyl chloride and 0.6 equivalent of TMEDA), and 3) sim-
ple operation. Further studies towards synthetic
applications and to clarify the detailed reaction mecha-
nism are under way in our laboratory.
2-Acetoxy-4-phenylbutane (2f)
1H NMR: d = 1.25 (d, 3 H, J = 6.2 Hz), 1.81 (m, 1 H), 1.92 (m, 1 H),
2.02 (s, 3 H), 2.63 (m, 2 H), 4.94 (m, 1 H), 7.18 (m, 3 H), 7.27 (m,
2 H).
All reactions were carried out under argon atmosphere. 1H and 13
C
13C NMR: d = 19.98, 21.28, 31.79, 37.53, 70.52, 125.87, 128.28,
NMR spectra were recorded at 400 and 100 MHz on a JEOL GSX-
400 spectrometer, respectively. The chemical shifts are reported in
ppm (d) relative to TMS in CDCl3. IR spectra were recorded in
cm–1 on a JASCO FT/IR-300E spectrometer. CH2Cl2 was distilled
from CaH2. TLC were performed on Wakogel B-5F silica gel with
EtOAc and hexane as eluent.
128.37, 141.51, 170.70.
IR (neat): n = 700, 1244, 1373, 1736 cm–1.
1-Benzoyloxy-3-phenylpropane (2g)
1H NMR: d = 2.10 (m, 2 H), 2.79 (t, 2 H, J = 7.3 Hz), 4.34 (t, 2 H,
J = 6.6 Hz), 7.21–7.31 (m, 5 H), 7.43 (m, 2 H), 7.55 (t, 1 H, J = 7.3
Hz), 8.03 (m, 2 H).
13C NMR: d = 30.28, 32.29, 64.24, 126.00, 128.31, 128.40, 128.43,
129.51, 130.36, 132.83, 141.15, 166.56.
IR (neat): n = 720, 1120, 1278, 1527, 1720 cm–1.
2-Benzoyloxy-4-phenylbutane (2a); Typical Procedure
To molecular sieves 4Å (40 mg) was added a solution of TMEDA
(21.4 mg, 0.184 mmol) in CH2Cl2 (1 mL) and a solution of 1a (45.7
mg, 0.304 mmol) in CH2Cl2 (1 mL) at r.t. under argon atmosphere.
Benzoyl chloride (47.0 mg, 0.334 mmol) dissolved in CH2Cl2 (0.5
mL) was then added at –78°C. After stirring for 20 min at –78°C the
mixture was quenched with a phosphate buffer (pH 7) and the or-
ganic materials were extracted with CH2Cl2. The combined extracts
were washed with brine, dried (Na2SO4), and concentrated in vacuo.
The crude product was purified by TLC on silica gel to give 2a;
yield: 74.9 mg (97%).
1-Benzoyloxy-1-phenylethane (2h):
1H NMR: d = 1.68 (d, 3 H, J = 6.6 Hz), 6.13 (q, 1 H, J = 6.6 Hz),
7.26–7.46 (m, 7 H), 7.55 (m, 1 H), 8.08 (m, 2 H).
13C NMR: d = 22.39, 72.90, 126.03, 127.88, 128.32, 128.54, 129.63,
130.55, 132.89, 141.78, 165.81.
IR (neat): n = 712, 1068, 1109, 1271, 1450, 1716 cm–1.
1-Benzoyloxy-2-methyl-1-phenylpropane (2i)
1H NMR: d = 0.89 (d, 3 H, J = 6.6 Hz), 1.05 (d, 3 H, J = 6.6 Hz),
2.25 (m, 1 H), 5.73 (d, 1 H, J = 7.33 Hz), 7.22–7.55 (m, 8 H), 8.09
(d, 2 H, J = 7.0 Hz).
13C NMR: d = 18.39, 18.81, 33.82, 81.40, 126.87, 127.66, 128.17,
128.32, 129.56, 130.54, 132.83, 139.71, 165.75.
2-Benzoyloxy-4-phenylbutane (2a)
1H NMR: d = 1.38 (d, 3 H, J = 6.2 Hz), 1.96 (m, 1 H), 2.09 (m, 1 H),
2.74 (m, 2 H), 5.20 (m, 1 H), 7.19 (m, 2 H), 7.28 (m, 3 H), 7.44 (m,
2 H), 7.56 (m, 1 H), 8.04 (m, 2 H).
13C NMR: d = 20.11, 31.83, 37.74, 71.15, 125.91, 128.29, 128.32,
128.42, 129.51, 130.76, 132.75, 141.51, 166.16.
IR (neat): n = 712, 1107, 1271, 1719, 2964 cm–1.
trans-1-Benzoyloxy-2-phenylcyclohexane (2j)
1H NMR: d = 1.38–2.01 (m, 7 H), 2.30 (m, 1 H), 2.84 (m, 1 H), 5.18
(m, 1 H), 7.10 (m, 1 H), 7.21–7.29 (m, 6 H), 7.42 (m, 1 H), 7.80 (d,
2 H, J = 7.0 Hz).
13C NMR: d = 24.73, 25.83, 32.33, 33.83, 49.82, 76.81, 126.35,
127.39, 128.02, 128.23, 129.29, 130.62, 132.42, 143.08, 165.80.
IR (neat): n = 713, 1116, 1277, 1451, 1717 cm–1.
2-(4-Nitrobenzoyl)-4-phenylbutane (2b)
1H NMR: d = 1.41 (d, 3 H, J = 6.6 Hz), 2.00 (m, 1 H), 2.12 (m, 1 H),
2.74 (m, 2 H), 5.24 (m, 1 H), 7.18 (m, 3 H), 7.27 (m, 2 H), 8.15 (d,
2 H, J = 8.8 Hz), 8.27 (d, 2 H, J = 8.8 Hz).
13C NMR: d = 20.00, 31.81, 37.41, 72.57, 123.42, 126.02, 128.26,
128.47, 130.59, 136.06, 141.16, 150.44, 164.20.
IR (KBr): n = 712, 1111, 1273, 1714, 2935 cm–1.
trans-1,2-Dibenzoyloxycyclohexane (2k)
IR (neat): n = 712, 1117, 1275, 1452, 1718 cm–1.
1H NMR: d = 1.49 (m, 2 H), 1.63 (m, 2 H), 1.82 (m, 2 H), 2.23 (m,
2 H), 5.24 (m, 2 H), 7.36 (m, 4 H), 7.48 (m, 2 H), 7.97 (m, 4 H).
2-(4-Methoxybenzoyl)-4-phenylbutane (2c)
1H NMR: d = 1.36 (d, 3 H, J = 6.3 Hz), 1.93 (m, 1 H), 2.06 (m, 1 H),
2.73 (m, 2 H), 3.84 (s, 3 H), 5.17 (m, 1 H), 6.91 (d, 2 H, J = 9.2 Hz),
7.17–7.28 (m, 5 H), 7.99 (d, 2 H, J = 9.2 Hz).
13C NMR: d = 23.45, 30.17, 74.23, 128.25, 129.56, 130.17, 132.81,
165.99.
IR (KBr): n = 715, 1117, 1282, 1713, 2946 cm–1.
13C NMR: d = 20.11, 20.14, 31.81, 37.77, 55.34, 55.37, 70.69,
113.49, 123.15, 125.84, 128.29, 128.36, 131.47, 141.56, 163.19,
165.88.
Synthesis 1999, No. 7, 1141–1144 ISSN 0039-7881 © Thieme Stuttgart · New York

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T. Sano et al.
PAPER
cis-1,2-Dibenzoyloxycyclohexane (2l)
References
1H NMR: d = 1.58 (m, 2 H), 1.88 (m, 4 H), 2.12 (m, 2 H), 5.40 (m,
2 H), 7.41 (m, 4 H), 7.54 (m, 2 H), 8.01 (m, 4 H).
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13C NMR: d = 21.86, 28.01, 71.88, 128.33, 129.63, 130.47, 132.89,
165.77.
IR (KBr): n = 711, 1118, 1282, 1451, 1722, 2942 cm–1.
1-Benzoyloxy-4-bromobenzene (2m)
1H NMR: d = 7.11 (d, 2 H, J = 8.8 Hz), 7.49–7.55 (m, 4 H), 7.64 (t,
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13C NMR: d = 118.95, 123.52, 128.61, 129.16, 130.17, 132.50,
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(t, 1 H, J = 8.8 Hz), 8.22 (d, 2 H, J = 8.4 Hz).
13C NMR: d = 16.19, 16.22, 121.97, 126.06, 126.95, 128.56, 128.61,
129.46, 130.11, 130.16, 130.27, 131.14, 133.53, 133.57, 149.51,
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(7) A few acylations of hydroxyl functions catalyzed by 1,2-
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4-Benzoyloxy-2-methyl-2-pentanol (4)
1H NMR: d = 1.25 (s, 3 H), 1.27 (s, 3 H), 1.39 (d, 3 H, J = 6.2 Hz),
1.76 (dd, 1 H, J = 15.0, 3.3 Hz), 2.06 (dd, 1 H, J = 15.0, 8.8 Hz),
2.12 (br, 1 H), 5.42 (m, 1 H), 7.43 (m, 2 H), 7.55 (t, 1 H J = 8.8 Hz),
8.03 (m, 2 H).
13C NMR: d = 21.75, 29.63, 29.93, 49.06, 69.33, 69.98, 128.34,
129.45, 130.47, 132.91, 166.16.
IR (neat): n = 714, 1117, 1281, 1715, 2974, 3448 cm–1.
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Acknowledgement
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5432.
This work was partially supported by the Inamori Foundation, the
Itoh Science Foundation, the Sasakawa Foundation (to T. S.), and a
Grant-in-Aid for Scientific Research from the Ministry of Educa-
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5136.
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Article Identifier:
1437-210X,E;1999,0,07,1141,1144,ftx,en;F10498SS.pdf
Synthesis 1999, No. 7, 1141–1144 ISSN 0039-7881 © Thieme Stuttgart · New York