Organocatalytic Mitsunobu reactions

Article abstract of DOI:10.1021/ja063141v

A catalytic Mitsunobu reaction system is described in which the azo reagent is used as an organocatalyst and iodosobenzene diacetate is used as the stoichiometric oxidant. In this system, iodosobenzene diacetate oxidizes the formed hydrazine byproduct to regenerate the azo reagent. Yields obtained in the catalytic reactions using a variety of carboxylic acids and alcohols were slightly lower than those obtained from corresponding stoichiometric reactions. Both primary and secondary alcohols can be used as substrates in this reaction system, with the secondary alcohols affording products with inverted stereochemistry at the carbinol center. Copyright

Full text of DOI:10.1021/ja063141v

Published on Web 07/06/2006
Organocatalytic Mitsunobu Reactions
Tracy Yuen Sze But and Patrick H. Toy*
Department of Chemistry, The UniVersity of Hong Kong, Pokfulam Road, Hong Kong, People’s Republic of China
Received May 5, 2006; E-mail: phtoy@hku.hk
Scheme 1. Proposed Catalytic Mitsunobu Reaction Cycle
The Mitsunobu reaction is a powerful and widely used procedure
for the synthesis of a range of acid derivatives.1 This reaction
involves the dehydrative coupling of an alcohol with an acidic
component to form esters, ethers, imides, and so on, using a
combination of a reducing (phosphine) and an oxidizing (azo)
reagent. One of the major attractions of this reaction is that it inverts
the stereochemistry of the alcohol starting material.2 However, a
significant drawback is that these reactions require four reagents
and starting materials (an alcohol, an acid/pro-nucleophile, a
phosphine, and an azo reagent) and, thus, the desired product can
be difficult to separate from the excess starting materials and
reagents and the reaction byproducts (a phosphine oxide and a
hydrazine derivative). Thus, numerous modified reagents and
separation techniques have been developed with the aim of
facilitating isolation of the desired product from these reactions.3
In this area, we have had an interest in the development of
polymeric phosphine reagents for use in Mitsunobu reactions4 and
have recently reported a reaction system in which both the required
phosphine and azo reagents are attached to individual polymers.5
We have also described an organocatalytic dual polymer system
for selective nitroxyl radical mediated alcohol oxidation in which
the stoichiometric oxidant is a polystyrene-supported analogue of
iodosobenzene diacetate (1).6 In the course of investigating the latter
reaction system, it occurred to us that since 1 is known to oxidize
1,2-dicarbethoxyhydrazine (2) to diethyl azodicarboxylate (3),7 it
might be possible to use 1 as the stoichiometric oxidant in
Mitsunobu reactions and, thus, allow 3 to be used as a catalyst
(Scheme 1). Despite the large volume of research dedicated to
improving the Mitsunobu reaction, to our knowledge no system
has yet been reported in which product recovery is facilitated by
using one of the reagents that produces a difficult to remove
byproduct as a catalyst rather than as a stoichiometric reagent.
Herein we report the development of such an organocatalytic
Mitsunobu reaction system that uses 3 as a catalyst and 1 as the
stoichiometric oxidant.8,9
To test the feasibility of the concept outlined in Scheme 1, we
first examined the reaction of 4-nitrobenzoic acid (5)10 with
2-phenylethanol (6) under various conditions. Gratifyingly, the
desired ester 7 was formed in good yield using the initial conditions
of 0.2 equiv of catalyst 3 in conjunction with 1.5 equiv of oxidant
1 and 1.2 equiv of 4. Eventually, optimal conditions were
determined to be the use of 0.1 equiv of 3 and 2.0 equiv of both 1
and 4 (Table 1, entry 1). This combination of reagents allowed for
excellent yield of product to be formed that could be separated
from the reaction byproducts in an efficient manner. However, it
should be noted that a control reaction in which 3, but not 4, was
omitted afforded 18% yield of the 7 (Table 1, entry 2), and omission
of both 3 and 4 resulted in no formation of 7 (Table 1, entry 3).
Regardless of this background reaction and the details of its
mechanism, our isolated yields clearly indicate that a process
catalytic in 3 is occurring because the isolated yield of 7 (90%) is
greater than the sum of the background yield (18%) and the amount
Table 1. Catalytic Mitsunobu Esterification of 4-Nitrobenzoic Acid
entry
reaction conditions
yielda (%)
1
5 (1.1 eq.), 6 (1.0 eq.), 4 (2.0 eq.), 3 (0.1 eq.),
and 1 (2.0 eq.), THF, rt, 16 h
90
2
3
4
5
5 (1.1 eq.), 6 (1.0 eq.), 4 (2.0 eq.), and 1 (2.0 eq.),
THF, rt, 16 h
5 (1.1 eq.), 6 (1.0 eq.), and 1 (2.0 eq.),
THF, rt, 16 h
5 (1.1 eq.), 6 (1.0 eq.), 4 (2.0 eq.), 8 (0.1 eq.),
and 1 (2.0 eq.), THF, rt, 16 h
5 (1.1 eq.), 6 (1.0 eq.), 4 (2.0 eq.), 9 (0.1 eq.),
and 1 (2.0 eq.), THF, rt, 16 h
18
0
69
41
a Average isolated yield of at least two 1.8 mmol scale experiments.
of 3 (10%) used. Importantly, when primary alcohols are used as
the electrophile, the background reaction provides the same product
as the organocatalytic reaction and, thus, it actually increases the
overall yield of the desired product.
Encouraged by these initial results, we also examined the catalytic
use of other azo reagents, such as 8, which is less expensive and
reportedly easier to handle than 3,3a and 9, which allows for the
use of a wider range of nucleophiles than does 3.11 With both
reagents, the desired product 7 was isolated in slightly lower yield
than was obtained with 3 (Table 1, entries 4 and 5).
We next examined the range of alcohols that could be used in
the reaction system. In addition to primary aliphatic alcohol 6, other
benzylic and aliphatic alcohols all afford the desired product in
slightly lower yield in the catalytic reaction than the corresponding
reaction that was stoichiometric in 3 (Table 2, entries 1-4). The
success with benzylic alcohol substrates is noteworthy because 1
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10.1021/ja063141v CCC: $33.50 © 2006 American Chemical Society

C O M M U N I C A T I O N S
Table 2. Catalytic Mitsunobu Reaction Productsa
to the reaction mixture of 1, 3, the alcohol, and the acid. By adding
4 at a rate of 0.25 equiv per hour, the yield of the desired product
was increased to 59%.13 Importantly, in two of the three examples
studied, when chiral secondary alcohols were used (Table 2, entries
8 and 9), the products isolated from the catalytic reactions had
essentially identical optical rotation and similar enantiomer ratios
as did products from stoichiometric reactions (see SI for details).
Only the catalytic reaction with chiral 1-phenylethanol afforded a
lower enantiomer product ratio than did the corresponding stoi-
chiometric reaction (68% ee vs 86% ee). Furthermore, this slow
addition procedure greatly reduced the amount of the azo-free
background reaction.
In conclusion, we have developed a Mitsunobu reaction system
that is catalytic in the oxidizing azo reagent (3, 8, or 9) and that
uses a hypervalent iodine species as the stoichiometric oxidant. The
benefit of using 1 is that its byproducts (iodobenzene and acetic
acid) are relatively simple to remove, while at the same time the
amount of formed hydrazine byproduct (e.g., 2) is dramatically
reduced. Experiments to further optimize this reaction and to
elucidate the mechanism of the background reaction are currently
being performed.
Acknowledgment. This research was supported financially by
the University of Hong Kong and the Research Grants Council of
the Hong Kong Special Administrative Region, P. R. of China
(Project No. HKU 7027/03P). We thank Prof. Paul R. Hanson (U.
of Kansas) and Prof. Hideo Togo (Chiba U.) for their prior research
collaborations that inspired this project.
Supporting Information Available: Experimental details and
characterization data for all compounds. This material is available free
of charge via the Internet at http://pubs.acs.org.
References
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is reported to slowly oxidize such primary benzylic alcohols to the
corresponding carboxylic acids under certain conditions.12
The aliphatic carboxylic acids phenyl acetic acid and Boc-
protected glycine were also examined as pronucleophiles. Again,
in these cases, the catalytic reaction afforded similar or slightly
lower yield than did the corresponding stoichiometric reaction
(Table 2, entries 5 and 6). It should also be noted that reactions
using these acids exhibited more of the azo-free background reaction
than did reactions with 5 and that the corresponding acetate was a
significant byproduct.
The use of secondary alcohols as the electrophile in this catalytic
system, when all of the reagents are added at once, affords poor
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oxidized by 1 so that it cannot participate in subsequent reaction
cycles. For example, the use of 1-phenylethanol afforded only 17%
yield in the catalytic system (Table 2, entry 7). Therefore, we
modified the experimental procedure so that 4 was added slowly
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from an 18 mmol scale reaction.
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