Regioselective alkylation of catechols via Mitsunobu reactions

Article abstract of DOI:10.1055/s-0030-1259031

A mild and efficient Mitsunobu protocol for the regioselective alkylation of catechols such as 3,4-dihydroxybenzaldehyde and methyl 3,4-dihydroxybenzoate is described. The para-alkylation products could be easily prepared via the Mitsunobu reaction with high selectivity in moderate to good yields. Georg Thieme Verlag Stuttgart - New York.

Full text of DOI:10.1055/s-0030-1259031

LETTER
2947
Regioselective Alkylation of Catechols via Mitsunobu Reactions
R
egioselective
Alk
i
ylation
a
of Catecho
o
ls via Mitsu
l
nobu R
o
eactions ng Wang,*a Tingting Ju,a Xiaodong Li,a Xiaoping Caob
a
School of Chemical and Biological Engineering, Lanzhou Jiaotong University, Lanzhou 730070, P. R. of China
Fax +86(931)4956512; E-mail: wangxl@mail.lzjtu.cn
Department of Chemistry, State Key Laboratory of Applied Organic Chemistry, Lanzhou University, Lanzhou 730000, P. R. of China
b
Received 1 September 2010
tion of a highly reactive alkoxyphosphonium intermediate
that undergoes nucleophilic displacement under mild and
nearly neutral conditions with virtually complete inver-
sion of configuration at the electrophilic center.3 Since its
discovery in 1967, the Mitsunobu reaction has become a
powerful method for the introduction of novel functional
groups such as C–O, C–S, C–N, C–C and S–O bonds.4
The clean stereochemical inversion, the compatibility of
the reaction conditions with a wide range of functional
groups and the simplicity of the experimental protocol
render the reaction widely applicable in the synthesis and
transformation of natural products.5
Abstract: A mild and efficient Mitsunobu protocol for the regiose-
lective alkylation of catechols such as 3,4-dihydroxybenzaldehyde
and methyl 3,4-dihydroxybenzoate is described. The para-alkyla-
tion products could be easily prepared via the Mitsunobu reaction
with high selectivity in moderate to good yields.
Key words: regioselective alkylation, Mitsunobu reaction, cate-
chol, 3,4-dihydroxybenzaldehyde, different acidity
The regioselective alkylation derivatives of catechols
such as 3,4-dihydroxybenzaldehyde have been extensive-
ly used as valuable synthetic intermediates in organic syn-
thesis and the preparation of many biologically active
natural products.1 For examples, 4-benzyloxy-3-hydroxy-
benzaldehyde has widely served as an important building
block for the enantioselective synthesis of chiral 1,4-ben-
zodioxane lignans.1a,b 4-Allyloxy-3-hydroxybenzalde-
hyde was elegantly applied to the preparation of
isoproterenol derivatives.1c The para-butylated product of
methyl 3,4-dihydroxybenzoate was used as a precursor in
the synthesis of unsymmetrical dialkoxy quinazolines.1d
Methyl 4-benzyloxy-3-hydroxybenzoate has been utilized
for the regiospecific construction of a crown ether diester,
which was finally converted to a pyridyl cryptand.1e In ad-
dition, methyl 3,5-dihydroxy-4-methoxybenzoate, the
monomethylated product of methyl gallate, has also been
employed in the total synthesis of morphine.1f In spite of
the great importance of these regioselectively alkylated
derivatives, only few methods have been reported for their
synthesis. The conventional and typical method for the
preparation of these derivatives is the selective alkylation
of the corresponding catechols with alkyl halides promot-
ed by a base, such as K2CO3, NaHCO3, NaH or NaOEt, in
an appropriate solvent. However, the reported methodol-
ogies for these regioselective alkylation are usually asso-
ciated with several disadvantages such as harsh reaction
conditions, low yields, difficult workup, long reaction
time as well as low selectivity.1,2 Consequently, the devel-
opment of practical and efficient methods for the selective
alkylation of this type of catechols is desirable.
Apart from its well-documented stereospecificity, the
Mitsunobu reaction also exhibits excellent regioselectivi-
ty in cases where substrates carrying different multi-hy-
droxy groups are involved.3 Unsymmetrical 1,2-diols
underwent a chemoselective monobenzoylation under
Mitsunobu conditions to afford the more sterically en-
cumbered C-2 benzoate as the major product, in which a
cyclic intermediate has been proposed wherein steric ef-
fect was proposed to determine the regiochemical out-
comes.6 The benzoylation of vicinal diols derived from
monosaccharides via Mitsunobu reaction afforded
monobenzoates only, where the regioselectivity was also
reported to depend on the stereochemistry of the sugar
starting material.7 L-Ascorbic acid, although bearing four
different hydroxy groups, was selectively 3-O-alkylated
when reacted with various alcohols under Mitsunobu con-
ditions presumably due to the highest acidity of the 3-hy-
droxy group.8 Mitsunobu reactions of syn-2,3-dihydroxy
esters exhibited complete regioselection for the b-hy-
droxy group, which was postulated to take advantage of
the electron-withdrawing inductive effect of the ester
group that would make the b-hydroxy group more nucleo-
philic.9 In light of these cases and considering the differ-
ent acidity of the hydroxy groups of 3,4-di-
hydroxybenzaldehyde and methyl 3,4-dihydroxybenzoate
etc.,10 we envisioned that it seemed feasible to apply the
Mitsunobu reaction as an attractive route to pursue for the
regioselective alkylation of such catechols by reacting
with an alcohol.
The Mitsunobu reaction is popularly known to be a proto-
col for condensation of an alcohol with an acidic com-
pound in the presence of dialkyl azodicarboxylate and
triphenylphosphine. The reaction involves in situ forma-
In our previous work, we have successfully utilized
Mitsunobu reaction as a vital protocol in the synthesis of
natural products.11 As a part of our continuing efforts on
the exploitation of novel utilizations for the conventional
and classical reactions,12 herein we report the successful
application of Mitsunobu reaction for the regioselective
alkylation of catechols such as 3,4-dihydroxybenzalde-
SYNLETT 2010, No. 19, pp 2947–2949
x
x
.x
x
.2
0
1
0
Advanced online publication: 10.11.2010
DOI: 10.1055/s-0030-1259031; Art ID: W13410ST
© Georg Thieme Verlag Stuttgart · New York

2948
X. Wang et al.
LETTER
hyde. In this novel methodology, we speculate that the ethyl alcohol and 4-methoxybenzyl alcohol, yielding the
different acidity of the hydroxy groups should be the con- corresponding para-alkylated products in moderate to
tributory factor for the regioselectivity. To the best of our good yields (Table 1, entries 2–6). Undoubtedly, methyl
knowledge, there have been no previous reports on the 3,4-dihydroxybenzoate reacted with benzyl, allyl and me-
same applications in the literature. A few examples deal- thyl alcohols, etc. equally well to provide the correspond-
ing with the selective alkylation of polyphenols such as ing para-alkylated derivatives in good yields (Table 1,
2,4-dihydroxydeoxybenzoins under Mitsunobu condi- entries 7–12). As compared to the conventional methods
tions have been reported,13 but the selectivity in these for the preparation of these derivatives,1,2 the yields and
cases was undoubtedly attributed to the intramolecular H- the selectivity in these cases described above (Table 1, en-
bonding that exists between the ortho-hydroxy and the tries 1–12) were extremely improved. Besides these cases,
electron-withdrawing group (EWG). It should be noted we also examined the reaction between methyl gallate and
that our protocol for the selective alkylation of catechols methyl alcohol. To our delight, although containing three
such as 3,4-dihydroxybenzaldehyde offered two obvious hydroxy groups on the benzene ring, methyl gallate was
advantages over the existing methods.1,2 First, the proce- smoothly monomethylated under the same Mitsunobu
dure employed readily available alcohols as alkylating condition to furnish methyl 3,5-dihydroxy-4-methoxy-
agents, as opposed to alkyl halides that may not be com- benzoate in 79% yield (Table 1, entry 13). Compared to
mercially available. Second, the reaction proceeded under the reported methodology which requires a series of te-
mild, essentially neutral conditions.
dious steps for such transformation,1f our Mitsunobu pro-
tocol has proven to be more convenient and efficient. In
all the cases listed in Table 1, high regioselectivity was
observed and the products were easily characterized on
the basis of physical and spectral data and also by compar-
ison with authentic samples.1,2,14
Initially, according to the reported procedures,8,9 the reac-
tion between benzyl alcohol and 3,4-dihydroxybenzalde-
hyde under Mitsunobu conditions, viz. with a reaction
stoichiometry of one equivalent of catechol, one equiva-
lent of alcohol, 1.5 equivalent of diisopropyl azodicarbox-
ylate (DIAD), and 1.5 equivalent of triphenylphosphine
(Ph3P), was chosen to attempt the feasibility of regioselec-
tive alkylation. In light of the fact that para-hydroxy of
3,4-dihydroxybenzaldehyde is more acidic than meta-
hydroxy due to the presence of the EWG,10 and inspired
by the reported observations,8 we reasoned that the 4-hy-
droxy would be preferentially deprotonated to form the
nucleophilic center which should finally result in the
para-alkylated product. Gratifyingly, this turned out to be
the case. The desired 4-benzylated product, subsequently
confirmed by comparing its melting point and NMR spec-
tral data with the literature values,2c–e was obtained as a
colorless solid within five hours in 84% yield with a small
amount of separable dibenzylation product. No trace of
the 3-benzylated isomer could be detected according to
NMR spectroscopy (Scheme 1). Our subsequent attempts
to optimize the reaction conditions, however, did not re-
sult in a significant enhancement of the reaction rate or
yield.
Table 1 Regioselective Alkylation of Catechols such as 3,4-Dihy-
droxybenzaldehyde under Mitsunobu Conditions
HO
HO
ROH
HO
EWG
RO
EWG
DIAD, Ph3P
THF, 0 °C to r.t.
X
X
Entry
1
X
H
H
H
H
H
H
H
H
H
H
H
H
OH
EWG
R
Yield (%)a
CHO
Bn
84
81
76
75
76
63
81
82
80
66
73
70
79
2
CHO
CH2=CH2CH2
Me
3
CHO
4
CHO
n-Bu
5
CHO
PhCH2CH2
4-MeOBn
Bn
6
CHO
7
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
HO
HO
8
CH2=CH2CH2
Me
BnOH
DIAD, Ph3P
9
HO
CHO
BnO
CHO
THF, 0 °C to r.t.
84%
10
11
12
13
n-Bu
Scheme 1 Regioselective alkylation of 3,4-dihydroxybenzaldehyde
PhCH2CH2
4-MeOBn
Me
In order to explore the scope of this new methodology for
regioselective alkylation of the aforementioned catechols,
other combinations of commercially available alcohols
and catechols were subjected to the protocol under the
same reaction conditions as noted above. The results are
summarized in Table 1. As expected, 3,4-dihydroxybenz-
aldehyde similarly showed high regioselectivity for the
para-hydroxy group when reacted with different alcohols
such as allyl alcohol, methyl alcohol, butyl alcohol, phen-
a Isolated yield.
In conclusion, an extremely efficient and practical
Mitsunobu protocol for the regioselective alkylation of
catechols such as 3,4-dihydroxybenzaldehyde has been
developed. This method is bestowed with several unique
Synlett 2010, No. 19, 2947–2949 © Thieme Stuttgart · New York

LETTER
Regioselective Alkylation of Catechols via Mitsunobu Reactions
2949
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Acknowledgment
We are grateful for the generous financial support by the ‘Qing Lan’
talent engineering funds (QL-06-01A) by the Lanzhou Jiaotong
University.
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(14) General Procedure for the Regioselective Alkylation
under Mitsunobu Conditions: DIAD (4.5 mmol) and Ph3P
(4.5 mmol) were dissolved in anhyd THF (20 mL), and the
solution was cooled in an ice bath. Alcohol (3 mmol) was
added. After the mixture was stirred for 10 min, a solution of
catechol (3 mmol) in anhyd THF (5 mL) was added
immediately. After stirring for 30 min, the reaction mixture
was warmed to r.t. and stirred. When the reaction was judged
to be complete (TLC), the mixture was evaporated under
vacuum and the residue was purified by column chroma-
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Spectral Data for Methyl 4-Butyloxy-3-hydroxybenzoate
(Table 1, Entry 10): colorless crystals; mp 114–115 °C.
1H NMR (400 MHz, CDCl3): d = 0.99 (t, J = 7.2 Hz, 3 H),
1.50 (m, 2 H), 1.82 (m, 2 H), 3.87 (s, 3 H), 4.10 (t, J = 6.4
Hz, 2 H), 5.71 (s, 1 H), 6.85 (d, J = 9.2 Hz, 1 H), 7.59 (m, 2 H).
13C NMR (100 MHz, CDCl3): d = 13.7, 19.1, 31.0, 51.9,
68.8, 110.6, 115.5, 122.7, 123.1, 145.3, 149.8, 166.8.
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Synlett 2010, No. 19, 2947–2949 © Thieme Stuttgart · New York