Organocatalytic mitsunobu reactions with 3,5-dinitrobenzoic acid

Article abstract of DOI:10.1055/s-0029-1219795

A second generation procedure for organocatalytic Mitsunobu reactions using 3,5-dinitrobenzoic acid as the pro-nucleophile has been developed. The increased acidity of this acid compared to 4-nitrobenzoic acid, which was used in the original procedure, allowed for higher isolated yields of the desired products and eliminated formation of undesired acetate byproducts. Georg Thieme Verlag Stuttgart - New York.

Full text of DOI:10.1055/s-0029-1219795

LETTER
1115
Organocatalytic Mitsunobu Reactions with 3,5-Dinitrobenzoic Acid
O
rganocatalytic
r
Mitsuno
a
buReactio
c
ns with 3,5
y
-Dinitrobenzoic
A
c
Y
id uen Sze But, Jinni Lu, Patrick H. Toy*
Department of Chemistry, The University of Hong Kong, Pokfulam Road, Hong Kong, P. R. of China
Fax +852 28571586; E-mail: phtoy@hku.hk
Received 4 February 2010
1 and 2 that facilitate removal of their corresponding oxi-
dized and reduced byproducts (analogous to 3 and 4, re-
spectively).6 In this area, we have developed polymeric
reagents for use in Mitsunobu reactions so that their
Abstract: A second generation procedure for organocatalytic
Mitsunobu reactions using 3,5-dinitrobenzoic acid as the pro-
nucleophile has been developed. The increased acidity of this acid
compared to 4-nitrobenzoic acid, which was used in the original
procedure, allowed for higher isolated yields of the desired products byproducts can be removed simply by filtration,7 and re-
and eliminated formation of undesired acetate byproducts.
ported a reaction system in which both the required phos-
phine reductant and azo oxidant are attached separately to
individual polymers that are used together.8 Additionally,
many other research groups have reported the design and
use of alternative azo oxidizing reagents in place of 2 that,
due to the nature of their structure, allow for easier remov-
al of the reduced byproduct compared to 4. For example,
polystyrene-supported,9 polymerizable,10 acid-labile,11
fluorous-tagged,12 cyclodextrin-binding,13 and phospho-
nium ion functionalized14 analogues of 2 have been
reported to simplify Mitsunobu reaction product purifica-
tion. More recently, the use of di(4-chlorobenzyl) ester
5,15 di(2-methoxyethyl) ester 6,16 and azopyridine 717
have also been described in this context (Figure 1).
Key words: 3,5-dinitrobenzoic acid, (diacetoxyiodo)benzene, cata-
lytic oxidation, organocatalysis, Mitsunobu reaction
The Mitsunobu reaction is a versatile and widely used
method in organic synthesis for the dehydrative coupling
of a pro-nucleophile/acid with an alcohol using the com-
bination of a reducing phosphine reagent, usually triphe-
nylphosphine (1), and an oxidizing azo reagent, typically
diethyl azodicarboxylate (2; Scheme 1).1–4 The great util-
ity of this reaction stems, in part, from the fact that it oc-
curs with inversion of the stereochemistry at the carbinol
center, that a broad range of substrates can be used, and
that a diverse range of products can be obtained. For ex-
ample, carboxylic acids, phenols, diols, activated carbon
acids, and imides, etc. can all serve as the acid/pro-nucleo-
phile reaction component and, thus, this reaction can be
used to prepare esters, aryl ethers, cyclic ethers, carbon–
carbon and carbon–nitrogen bonds, and other valuable
moieties. However, one of the major drawbacks of the
Mitsunobu reaction is that stoichiometric quantities of
phosphine oxide (3) and reduced hydrazide (4) are formed
as byproducts, often making isolation of the desired prod-
uct difficult, expensive, and time consuming.5
O
O
O
N
N
O
Cl
Cl
5
O
O
MeO
OMe
O
N
N
O
6
N
N
N
N
7
Figure 1
Nu
+
Ph3P=O
R1
R2
NuH
+
3
Rather than introducing another new azo oxidizing re-
agent, a new strategy we recently introduced for address-
ing the issue of product purification was to change the role
of 2 from being a stoichiometric oxidant to that of a cata-
lyst, and to use it in conjunction with a terminal oxidant
whose byproducts are relatively simple to separate from
the desired product. In this regard, we have reported our
initial findings using the combination of 2 and PhI(OAc)2
(8; Scheme 2),18 and demonstrated the validity of our con-
cept using 4-nitrobenzoic acid (9) as the pro-nucleophile/
acid reaction component.19
Ph3P (1)
O
O
O
O
OH
EtOC
N N COEt
EtOC
N
H
N
H
COEt
+
R1
R2
DEAD (2)
DEAD-H2 (4)
Scheme 1
In response to this issue, much research has been directed
towards improving the efficiency of product isolation and
purification in the Mitsunobu reaction. One such strategy
has focused on the development of alternative reagents to
Unfortunately, a problem we encountered in this previous
study was the formation of acetate byproducts, which
were presumably formed by reaction of the substrate alco-
hol with the acetic acid byproduct derived from 8
(Scheme 2). In some cases, 5–10% of this undesired ester
SYNLETT 2010, No. 7, pp 1115–1117
Advanced online publication: 23.03.2010
x
x.
x
x.
2
0
1
0
DOI: 10.1055/s-0029-1219795; Art ID: W02010ST
© Georg Thieme Verlag Stuttgart · New York

1116
T. Y. S. But et al.
LETTER
Table 1 Catalytic Mitsunobu Reactions using Acids 9 or 1021
R1COOH + R2OH
O
O
O
O
Ph3P
PhI + 2 AcOH
O2N
EtO
N
N
OEt
OR
OR
conditions
O2N
1
9 or 10
+
ROH
2
or
catalytic oxidant
11a–j
NO2
12a–j
13a–j
O
O
O=PPh3
PhI(OAc)2
EtO
N
H
N
H
OEt
Entry
Alcohol
Ester Product, Yield (%)a
3
8
Acid 9b
Acid 10b
stoichiometric oxidant
R1COOR2
4
HO
Scheme 2 Catalytic Mitsunobu reaction cycle
1
2
3
4
12a (95)c
13a (99)c
was formed and it was often rather difficult to separate it
from the desired ester formed from 9. Therefore, in order
to minimize acetate formation in our organocatalytic
Mitsunobu reactions, we sought to investigate the use of a
pro-nucleophile/acid reaction component with a lower
pKa compared to that of 9 in order to reduce the competi-
tive reaction of acetic acid, thereby increasing the isolated
yield of the desired product and further simplifying its pu-
rification. Herein, we report the findings of a study in
which 3,5-dinitrobenzoic acid (10) was used in place of
9.20
11a
12b (86)
12c (78)
12d (73)
13b (100)
13c (92)
13d (85)
HO
11b
HO
11c
HO
Me
11d
Gratifyingly, the use of 10 in our organocatalytic
Mitsunobu reaction system, in place of 9, increased the
isolated yield of the desired ester product (12a–j vs. 13a–
j) by ca. 5–15% in most of the cases examined (Table 1).21
An exception to this trend was when 3-methoxybenzyl al-
cohol (11h) was used as the alcohol substrate (entry 8),
however, the reason for this result is not clear. When ben-
zyl alcohol (11a) was used as the substrate, better yield of
the desired ester 13a was obtained when a slightly larger
excess of acid 10 (1.3 equiv) was used (entry 1). When
only 1.1 equivalents were used in reactions with 11a, it
appeared (according to TLC analysis) that some oxidation
to the corresponding aldehyde occurred. Importantly, no
acetate products were observed in any reactions and, thus,
it was very easy to purify all of the desired products since
none of the byproducts had similar polarity to the desired
esters. In addition to primary alcohols 11a–h (entries 1–
8), chiral secondary alcohols 11i and 11j were also ame-
nable to this new procedure, and excellent isolated yields
of products 13i–j, with high enantiomeric excesses, were
obtained from these reactions (entries 9 and 10). Consid-
ering that the yields reported in Table 1 are the average of
two experiments that afforded nearly identical product
yields, we are confident that the experimental evidence
confirms our hypothesis that acetate formation can be sup-
pressed and isolated product yield can be increased by us-
ing more highly acidic 10 in place of originally used 9.
NO2
HO
5
12e (95)
12f (87)
12g (85)
12h (85)
13e (99)
13f (88)
13g (86)
11e
HO
6
7
8
9
NO2
11f
HO
Br
11g
OMe
HO
13h (79)
13i (99)
11h
12i (90)
(ee = 96%)
HO
(ee = 94%)
11i
12j (65)d
(ee = 100%)
13j (69)
(ee = 100%)
O
10
HO
OEt
11j
a Reported yields are the average of two experiments.
b Reagents and conditions: 11 (1.0 equiv, 1.8 mmol), 9 or 10 (1.1
equiv), 2 (0.1 equiv), 8 (2.0 equiv) and 1 (2.0 equiv) added at a rate of
0.25 equiv/h, at r.t. in THF for 16 h.
c Reagents and conditions: 11 (1.0 equiv, 1.8 mmol), 9 or 10 (1.3
equiv), 2 (0.1 equiv), 8 (2.0 equiv) and 1 (2.0 equiv) added at a rate of
0.25 equiv/h, at r.t. in THF for 16 h.
In conclusion, we have developed a second generation or-
ganocatalytic Mitsunobu reaction procedure using 10 as
the pro-nucleophile/acid reaction component and applied
it to a range of alcohol substrates. The reaction afforded
both high yield and excellent stereoselectivity of the de-
sired ester, without the formation of any undesired acetate
d Results from Ref. 18.
Synlett 2010, No. 7, 1115–1117 © Thieme Stuttgart · New York

LETTER
Organocatalytic Mitsunobu Reactions with 3,5-Dinitrobenzoic Acid
1117
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http://www.thieme-connect.com/ejournals/toc/synlett.
Acknowledgment
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(21) General Procedure for Catalytic Mitsunobu Reactions:
To a solution of 10 (1.98 mmol) and the alcohol substrate
(1.8 mmol) in anhydrous THF (11 mL) under a N2
atmosphere, was added 2 (0.028 mL, 0.18 mmol) and 8 (1.16
g, 3.6 mmol). This was followed by the addition of a solution
of 1 (0.94 g, 3.6 mmol) in anhydrous THF (4 mL) slowly by
syringe pump (0.25 equiv/h). The reaction mixture was
stirred for a total of 16 h and then was diluted with Et2O (30
mL). The organic phase was separated and then washed
sequentially with sat. aq NaHCO3 (2 × 20 mL), and brine (20
mL), dried with Na2SO4, filtered and concentrated in vacuo.
The crude product was purified by column chromatography.
All ester products were characterized by 1H and 13C NMR
spectroscopy. Enantiomeric excesses were determined by
HPLC. See Supporting Information for details
(22) Shang, Y.; But, T. Y. S.; Togo, H.; Toy, P. H. Synlett 2007,
67.
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