Catalytic monoalkylation of 1,2-diols

Article abstract of DOI:10.1016/j.tetlet.2009.01.063

A catalytic monoalkylation of 1,2-diols by using a weak base has been developed. Copper(II) dichloride and boronic acids are effective catalysts for activating 1,2-diols in the presence of potassium carbonate as a base. Various 1,2-diols were selectively monoalkylated with allyl-, benzyl- and alkyl- halides in DMF by choosing a suitable catalyst for each 1,2-diols.

Full text of DOI:10.1016/j.tetlet.2009.01.063

Tetrahedron Letters 50 (2009) 1466–1468
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Tetrahedron Letters
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Catalytic monoalkylation of 1,2-diols
*
Toshihide Maki, Nobuto Ushijima, Yoshihiro Matsumura, Osamu Onomura
Graduate School of Biomedical Sciences, Nagasaki University, 1-14 Bunkyo-machi, Nagasaki 852-8521, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
A catalytic monoalkylation of 1,2-diols by using a weak base has been developed. Copper(II) dichloride
and boronic acids are effective catalysts for activating 1,2-diols in the presence of potassium carbonate
as a base. Various 1,2-diols were selectively monoalkylated with allyl-, benzyl- and alkyl- halides in
DMF by choosing a suitable catalyst for each 1,2-diols.
Received 13 December 2008
Revised 6 January 2009
Accepted 13 January 2009
Available online 19 January 2009
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Diol
Alkylation
Lewis acid
Allylation
Benzylation
Selective monoalkylation of 1,2-diols is an important transfor-
mation for organic synthesis. Various methods have been devel-
oped to achieve direct monoalkylation of one of two hydroxyl
groups in 1,2-diols. Usually an excess amount of 1,2-diols is used.1
Therefore, many stoichiometric methods have been developed,
such as reductive cleavage of acetals,2 use of polymer resins,3 thal-
lium salts,4 monosodium salts,5 silver oxide,6 dibutyltin oxide,7
arylboronic acid8 and direct allylation of 1,2-diols through intra-
molecular dehydrohalogenation.9 However, only a few catalytic
processes have been demonstrated for limited examples utilizing
tin dichloride,10 phase transfer catalysts,11 and crown ether.12
Thus, development of a general, highly selective, and convenient
catalytic protocol for monoalkylation of 1,2-diols remains to be
exploited.
character of forming complex Aa–c; (2) complex Aa–c is selec-
tively deprotonated by weak base, such as metal carbonate
affording alkoxide Ba–c because of its lowered pKa value than
1a–c through association with 4–8; (3) since Ba–c (or B0a–c)
has a higher reactivity than 1a–c, it is selectively monoalkylated
by R2–X. The resulting monoalkylated product 2a–c can not
coordinate with 4–8, therefore second alkylation of 2a–c does
not proceed.
Based on this concept, we employed allyl bromide as R2–X and
diethyl L-tartrate (1a) as a diol for initial test of various Lewis acids
as catalysts (Eq. 1). The results are summarized in Table 1.
Br
catalyst
EtO2C
EtO2C
OH
OH
EtO2C
EtO2C
O
EtO2C
EtO2C
O
O
+
OH
K2CO3, at rt,
38 h
We have developed the methods for catalytic monoacylation
of 1,2-diols in which 1,2-diols are selectively activated with Le-
wis acid such as dimethyltin dichloride13 or copper(II) salts14
in the presence of a weak base. We envisioned that this process
could be extended to catalytic monoalkylation of 1,2-diols. We
1a
2a
3a
ð1Þ
First, we examined dimethyltin dichloride (4) as a catalyst, which
has been used to effectively catalyze monobenzoylation of diol-
s,13a for monoallylation of 1a with allyl bromide.15 Use of THF
or CH2Cl2 led to monoallylated product 2a obtained in only 12%
or 21% yield (runs 1 and 2), while the yield of 2a was improved
in DMF (run 3). Change of catalyst to CuCl2 (5) instead of 4, led
to an improved yield for 2a (86% yield) (run 4). Phenylboronic
acids 6–8 were not effective for this reaction (runs 5–7). In all
cases, the formation of diallylated product 3a was negligible.
Encouraged by this impressive results, we examined the system
for dl-hydrobenzoin (1b) and cis-cyclohexane-1,2-diol (1c) (Eq. 2).
The results are summarized in Table 2.
present here
a general catalytic monoalkylation method for
1,2-diols catalyzed by copper(II) salt or boronic acids under mild
condition.
Our working hypothesis for selective monoalkylation of 1,2-
diols is depicted in Scheme 1. Here MXn 4–8 and R2–X repre-
sent Lewis acids and alkylating reagents, respectively. The
monoalkylation process is roughly divided into three steps: (1)
1,2-diol 1a–c is recognized by Mn+ because of its bidentate
* Corresponding author. Tel.: +81 95 819 2429; fax: +81 95 819 2476.
E-mail address: onomura@nagasaki-u.ac.jp (O. Onomura).
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.01.063

T. Maki et al. / Tetrahedron Letters 50 (2009) 1466–1468
1467
R1
R1
OH
OH
R1
R1
OH
MXn
4~8
MXn
4: Me2SnCl2
5: CuCl2
6: p-MeOPhB(OH)2
7: PhB(OH)2
8: p-FPhB(OH)2
OR2
2a-c
1a-c
first step
MXn
H
O
R1
R1
third step
O
H
R2-X
weak base
a: R1= -CO2Et
b: R1= -Ph
Aa-c
second step
c: R1= -(CH2)4-
H
O
H
O
R1
R1
R1
R1
- HX
2
+
: AllylBr,
BnBr, MeI,
EtI
R -X
MXn-1
(MXn-1)
O
O-
Ba-c
B'a-c
Scheme 1. Working hypothesis for 1,2-diols selective monoalkylation catalyzed by Lewis acid.
and 2c, respectively (runs 2 and 7). Replacement of 5 with catalyst
4 slightly improved the yields of 2b and 2c (runs 1 and 6), while
boronic acids 6–8 efficiently catalyzed monoallylation of 1b and
1c (runs 3–5, 8–10). More interestingly, substituents at para-posi-
tion on phenylboronic acids showed opposite effect on the catalytic
ability with respect to 1b and 1c. That is, for monoallylation of 1b, 6
substituted with electron donating methoxyl group improved the
yield of 2b, while 8 substituted with electron deficient fluoro group
gave lower yield (runs 3–5). On the contrary, for that of 1c, use of 8
afforded 2c in better yield than that of 6 (runs 7–9).
Table 1
Catalytic monoallylation of 1aa
Run
Catalyst
Solvent
Yieldb (%)
3a
2a
1
2
3
4
5
6
7
Me2SnCl2 (4)
4
4
CuCl2 (5)
p-MeOPhB(OH)2 (6)
PhB(OH)2 (7)
THF
12
21
50
86
23
21
27
ndc
Trace
2
Trace
Trace
2
CH2Cl2
DMF
DMF
DMF
DMF
DMF
This result indicates that there is a suitable combination be-
tween diols and catalysts to achieve an efficient catalytic cycle.
The best combination seems to be controlled by both acidity of
diols and Lewis acids. In the case of using relatively weak Le-
wis acid such as 5, the first and second steps could be slow,
while possibly higher reactivity of resulting intermediate Ba–c
would accelerate the third step (Scheme 1). On the other hand,
relatively strong Lewis acid such as 6–8 would be favor for
the first and second steps, while stabilized intermediate Ba–c
may make the third step sluggish. Thus, suitable catalyst,
which maximizes the overall reaction rate, would be deter-
mined depending on each diol’s acidity. Diol 1a has acidic hy-
droxyl groups that easily form a complex Ba with relatively
weak Lewis acid 5, which enhances the reaction rate for ally-
lation. On the other hand, less acidic diol 1c would be slow to
form a complex Bc, thus needs strong Lewis acid 8 to achieve
fast formation of Bc. Since the acidity of 1b is considered to
be located between 1a and 1c, the result that the best catalyst
for allylation of 1b is electron-rich boronic acid 6 seems to
meet this.
p-FPhB(OH)2 (8)
3
a
To a mixture of 1a, K2CO3 (1.5 equiv), and catalyst (0.1 equiv) in solvent was
added allyl bromide (2 equiv). The mixture was stirred for 38 h at rt.
b
Isolated yield.
Not detected.
c
Table 2
Catalytic monoallylation of 1b,ca
Run
1,2-Diol
Catalyst
Yield (%)
2
3
1
2
3
4
5
4
5
6
7
8
35b
15b
75b
70b
64b
ndc
ndc
ndc
ndc
ndc
Ph
Ph
OH
OH
1b
1c
6
7
8
9
10
4
5
6
7
8
12d
4d
ndc
ndc
ndc
ndc
ndc
OH
OH
61d
68d
78d
Next, we examined the catalytic process for diols 1a–d with
various alkylating reagents (Eq. 3). Table 3 shows the results.
a
To a mixture of diol, K2CO3 (1.5 equiv), and catalyst (0.1 equiv) in DMF was
R2-X
R1
R1
OH
OH
R1
R1
OR2
R1
R1
OR2
added allyl bromide (2 equiv). The mixture was stirred for 38 h at rt.
b
catalyst
Isolated yield.
Not detected.
Determined by GLC.
c
+
ð3Þ
OH
OR2
K2CO3, at rt
in DMF, 38 h
d
1
9
10
These alkylating reagents selectively afforded monoalkylated prod-
ucts 9a–d in good to moderate yields. Use of excess amount of
alkylating reagent was required because of its low reactivity. Even
in cases where large excess amount of alkylating reagents were
used, formation of corresponding dialkylated products 10a–d were
minute (runs 1, 3, 4, 8). It was found that MeCN and Et4NBr as a
phase transfer catalyst improved the yield of 9c(Bn) (run 5).
Although trans-cyclohexane-1,2-diol 1d afforded only poor yield
(25%) of 9e(Bn) under standard condition (run 9), the yield was
R1
R1
OH
OH
R1
R1
O
R1
R1
O
Br
catalyst
K2CO3, at rt
in DMF, 38 h
+
ð2Þ
OH
O
1b,c
2b,c
3b,c
In this case, however, 5 did not effectively catalyze monoallylation
of 1b and 1c, affording a disappointing yield of 15% and 4% for 2b

1468
T. Maki et al. / Tetrahedron Letters 50 (2009) 1466–1468
Table 3
Catalytic monoalkylation of 1,2-diolsa
Run
Diol
Catalyst
R2–X (equiv)
Productb (yield: %)
9
10
1
2
3
4
1a
1a
1a
1b
1b
1c
1c
1c
5
5
5
6
6
8
8
8
MeI
BnBr
EtI
MeI
BnBr
BnBr
BnBr
EtI
(10)
(1.2)
(5)
(10)
(1.5)
(1.5)
(1.5)
(5)
9a(Me)
9a(Bn)
9a(Et)
9b(Me)
9b(Bn)
9c(Bn)
9c(Bn)
9c(Et)
65b
10a(Me)
10a(Bn)
10a(Et)
10b(Me)
10b(Bn)
10c(Bn)
10c(Bn)
10c(Et)
<1
<1
<1
79b
45b
89b
64b
84b
99b
79f
ndc
ndc
ndc
ndc
ndc
5
6
7d
8e
9
8
BnBr
(1.5)
9d(Bn)
25b
10d(Bn)
ndc
OH
OH
10g
8
BnBr
(3)
9d(Bn)
91b
10d(Bn)
1
1d
To a mixture of diol, K2CO3 (1.5 equiv), and catalyst (0.1 equiv) in DMF was added R2–X. The mixture was stirred for 38 h at rt.
a
b
c
d
e
f
Isolated yield.
Not detected.
MeCN containing 0.2 equiv of Et4NBr was used instead of DMF.
46 h of reaction time was applied.
Determined by GLC.
g
A mixture of toluene and 50% KOH containing 1 equiv of Et4NBr was used instead of DMF–K2CO3.
significantly improved when a mixture of toluene and 50% KOH
containing 1 equiv of Et4NBr was used (run 10).
Moreover, the method was found to be applicable to monoben-
zylation of 1,3-diol 1d (Eq. 4).
References and notes
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OH
OH
OBn
OH
OBn
OBn
8 (0.1 equiv)
+
ð4Þ
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in DMF, at rt, 38 h
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10e(Bn)
not detected
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9e(Bn)
88% yield
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OH
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OH
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BnBr (1.5 equiv)
+
+
8 (0.1 equiv)
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15. Typical procedure for monoallylation of 1,2-diol: To a solution of 1a,b (1 mmol)
and catalyst (0.1 mmol) in DMF (2 mL) was added K2CO3 (1.5 mmol) and allyl
bromide (2 mmol) at room temperature. After stirring for 38 h, the mixture
was poured into water and extracted three portion of ethyl acetate. The organic
layer was combined and dried over MgSO4. After filtration, the organic portion
was concentrated under reduced pressure. The resulting residue was purified
by silica gel column chromatography.
OH
9c(Bn)
96% yield
K2CO3 (1.5 equiv)
in DMF, at rt, 38 h
1c
11 (1 equiv)
11
0% yield
ð5Þ
In conclusion, we have developed a new catalytic monoalkylation
method for 1,2-diols. This method is convenient and can be widely
applied, since it does not require a strong base such as NaH there-
fore tolerant to ester groups. Moreover, we have found that the
choice of catalysts for monoalkylation of 1,2-diols depended on
their acidity. The asymmetric version of monoalkylation is cur-
rently underway.
Acknowledgement
This work was supported by The Naito Foundation.