One-Carbon Homologation of Primary Alcohols to Carboxylic Acids, Esters, and Amides via Mitsunobu Reactions with MAC Reagents

Article abstract of DOI:10.1021/acs.orglett.6b00790

A method is reported for the one-carbon homologation of an alcohol to the extended carboxylic acid, ester, or amide. The process involves the Mitsunobu reaction with an alkoxymalononitrile, followed by unmasking in the presence of a suitable nucleophile. The homologation and unmasking can even be performed in a one-pot process in high yield.

Full text of DOI:10.1021/acs.orglett.6b00790

Letter
pubs.acs.org/OrgLett
One-Carbon Homologation of Primary Alcohols to Carboxylic Acids,
Esters, and Amides via Mitsunobu Reactions with MAC Reagents
,
†,‡
§
,§
Natsuko Kagawa,* Antoinette E. Nibbs, and Viresh H. Rawal*
†
Graduate School of Pharmaceutical Sciences, Chiba University, 1-8-1 Inohana, Chiba 260-8675, Japan
‡
Center for Environment, Health and Field Sciences, Chiba University, 6-2-1 Kashiwa-no-ha, Kashiwa 277-0882, Japan
§Department of Chemistry, University of Chicago, 5735 South Ellis Avenue, Chicago, Illinois 60637, United States
*
S Supporting Information
ABSTRACT: A method is reported for the one-carbon
homologation of an alcohol to the extended carboxylic acid,
ester, or amide. The process involves the Mitsunobu reaction
with an alkoxymalononitrile followed by unmasking in the
presence of a suitable nucleophile. The homologation and
unmasking can even be performed in a one-pot process in high
yield.
xtending the framework of a molecule by a single carbon is
Mitsunobu reaction using a MAC reagent could provide a
10,11
E
a commonly encountered task in chemical synthesis. This
seemingly simple process can require anywhere from two to
four steps, depending on the oxidation state of the starting
functional group and that desired of the product. Given the
importance of such elongations, numerous solutions have been
developed for this task, most taking advantage of the rich
solution.
The mild reaction conditions, wide substrate
scope, and high stereospecificity make the Mitsunobu one of
the most commonly used reactions for C−O, C−S, and C−N
bond formations. While the nucleophile substrate scope is
broad with respect to oxygen, sulfur, and nitrogen species, that
for carbon-based nucleophiles is rather limited, due in large part
1
chemistry of the carbonyl group. For example, the trans-
to the requirement for a relatively acidic pronucleophile (pK ≤
a
10,12
formation of a carboxylic acid to the corresponding one-carbon
homologated derivative can be accomplished through the
venerable Arndt−Eistert method, typically requiring a three-
15, preferably <11).
Given the high acidity of malononi-
13
trile, MAC reagents were expected to be effective as
nucleophiles in the Mitsunobu reaction. A noteworthy
advantage of the MAC reagent is their versatility, in that the
intermediate can be unmasked to give either a carboxylic acid,
2
,3
step reaction sequence. The extension of an aldehyde or
ketone carbonyl by one carbon can be achieved using the
4
,5
7,8
Wittig olefination or one of its many variants. However, in
contrast to the countless methods developed for the
homologation of carbonyl groups, relatively few options are
an ester, or an amide (Scheme 1).
Scheme 1. Plan for MAC−Mitsunobu Homologation
6
available to extend a primary alcohol by one carbon. In the
course of exploring the umpolung capability of alkoxymalono-
nitrile reagents, termed masked acyl cyanide (MAC) reagents,
for hydrogen-bonding-mediated enantioselective processes, we
became interested in their potential for other useful trans-
7
,8
formations. We report here that MAC reagents can serve as
nucleophiles in Mitsunobu reactions, thereby allowing a net
oxidative, one-carbon homologation of alcohols to their
corresponding carboxylic acids, esters, and amides.
The initial studies to assess the feasibility of the above
concept were carried out with phenethyl alcohol (1a) and
revealed the importance of the order of addition of the
reagents. When the MAC reagent was added before the alcohol,
amination with the azodicarboxylate occurred to give the MAC-
The standard protocol for extending an alcohol by one
carbon calls for a three-step sequence: (1) conversion to a
halide or sulfonate, (2) displacement by cyanide, and (3)
hydrolysis to a primary amide or acid. The current state of this
homologation methodology is illustrated in the endgame to the
14
hydrazine dicarboxylate adduct. On the other hand, the
desired product was obtained cleanly when the MAC reagent
was added last. Thus, treatment of a chilled solution (0 °C) of
9
elegant total synthesis of kingianin A by Lim and Parker. Faced
Ph P and phenethyl alcohol in THF with diisopropyl
with the challenge of transforming two primary alcohols to their
respective homologated secondary amides, the authors utilized
a four-step sequence that proceeded in 31% overall yield.
In considering a direct and more general route for the
homologation of primary alcohols, we recognized that the
3
azodicarboxylate (DIAD) followed after 15 min by addition
Received: March 18, 2016
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b00790
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
of MOM-protected hydroxymalononitrile (MOM-MAC, 2a)
afforded the desired product of C−C bond formation (3a) in
effective, Ac-MAC generally provided adducts in lower yields
16
than did MOM-MAC (cf., entries 2−5). Furfuryl alcohol gave
the expected homologation product in good yield. Three allylic
alcohols were examined as substrates, and all afforded MAC-
addition products in good yields, with none of the products of
15
7
8% isolated yield (Scheme 2). Comparable results were
obtained in CH Cl . Further optimization improved the yield of
2
2
3a to 82%.
S 2′ displacement (entries 7−9). The Mitsunobu conditions
N
were similarly effective for the two propargylic alcohols studied
Scheme 2. Initial Result for MOM−Mitsunobu Reaction
(
entries 10−12). A small amount of the allenyl-MAC
byproduct was observed with propargyl alcohol itself. Several
unactivated primary alcohols were also subjected to the
Mitsunobu conditions, and all performed well, although they
required longer reaction times than cinnamyl or propargylic
alcohols (entries 13−21). The indolic primary alcohol,
tryptophol, produced the expected homologation product, 3n,
in 66% isolated yield (entry17). Of note is the double-
Mitsunobu reaction with diol substrates, shown in entries 19
and 20. The lower yield with the first one, butanediol, may well
be due to the competing intramolecular cyclization to form
tetrahydrofuran. The homologation of cyclopropyl carbinol
The optimized reaction conditions were then applied to a
broad selection of primary alcohols, and the MAC adducts were
generally obtained in good to high yields (Table 1). Benzyl
alcohol and 2-methyl benzyl alcohol performed well in the
reaction. A few of these reactions were also carried out using
17
15
the acetyl-protected MAC reagent (Ac-MAC, 2b). While
Table 1. Substrate Scope of Mitsunobu Reactions Using MAC Reagents
a
b
Reaction conditions: PPh , (1.1 equiv), DIAD (1.1 equiv), ROH (1.1 equiv), MAC (0.4 mmol), THF (2.0 mL), 0−23 °C. PPh , (1.5 equiv),
3
3
c
DIAD (1.5 equiv), ROH (1.5 equiv), MAC (0.4 mmol), THF (2.0 mL), 0−23 °C. PPh , (1.3 equiv), DIAD (1.3 equiv), ROH (1.3 equiv), MAC
3
d
(
0.4 mmol), THF (2.0 mL), 0−23 °C. Calculated based on MAC reagent used as the limiting reagent.
B
DOI: 10.1021/acs.orglett.6b00790
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
proceeded uneventfully, without complications from conceiv-
able rearrangements (entry 21). Secondary alcohols were
generally not willing partners in the homologation, although 3-
butyn-2-ol yielded the desired MAC-adduct 3s in 68% yield
secondary amide 6b was formed in quantitative yield (Scheme
3). Unfortunately, the product had an R close to that of the
f
Scheme 3. One-Pot Conversion of an Alcohol to the
Homologated Secondary Amide
1
8
(
entry 22).
To demonstrate fully the usefulness of the homologation
methodology, we developed protocols for unmasking the MAC
unit to reveal the one-carbon extended carboxylic ester, amide,
8
or acid. Treatment of an alcohol adduct with camphorsulfonic
acid in a solution of acetic acid and DME produced a
dicyanohydrin intermediate (4), which upon addition of
methanol and triethylamine was converted to the methyl
ester (5). Alternatively, addition of a primary or secondary
amine to intermediate 4 gave the corresponding amide, 6.
Addition of water to intermediate 4 afforded the carboxylic
acid, 7. A selection of MAC adducts were subjected to the
unmasking protocol, and the results are summarized in Table 2.
hydrazine dicarboxylate byproduct of DIAD, necessitating
tedious chromatographic separations. To circumvent the
isolation difficulty, the Mitsunobu step was carried out using
DMEAD, the hydrazine dicarboxylate byproduct of which is
water soluble. Subsequent subjection to unmasking conditions
with EtNH2 as the nucleophile gave the corresponding
19
ethylamide (6b′) in 85% isolated yield. As hoped, the
hydrazine byproduct of DMEAD was easily separated from 6b′.
The results described above demonstrate that the Mitsunobu
reaction of MAC reagents followed by unmasking provides an
efficient solution for the one-carbon homologation of primary
alcohols. The versatility of the described methodology has a
distinct advantage: the intermediate MAC adduct can be
uncloaked to reveal either the extended carboxylic ester, the
amide, or the acid. Although the two processes were generally
carried out as separate steps, with isolation and purification of
the intermediate MAC adduct, we have also demonstrated the
feasibility of performing them sequentially in a one-pot process.
We expect this methodology to provide effective solutions for
homologation problems in complex molecule synthesis.
Table 2. Unmasking of Homologation Products
ASSOCIATED CONTENT
Supporting Information
■
*
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.6b00790.
Experiments and analytical data for new compounds are
included (PDF)
AUTHOR INFORMATION
Corresponding Authors
■
*
*
E-mail: knatsuko@faculty.chiba-u.jp.
E-mail: vrawal@uchicago.edu.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
a
■
Reaction conditions: 3 (0.1−0.2 mmol), (R)-CSA (1.1 equiv),
Partial support of this work by the National Institutes of Health
(R01GM069990) and JSPS KAKENHI (26870101) is grate-
fully acknowledged. We thank Dr. Michael J. Hillier (AbbVie)
for encouraging us to examine the Mitsunobu reaction of a
MAC reagent.
AcOH/DME (1:1, 0.5 M), 60 °C; then MeOH, Et N (20 equiv), −40
to 0 °C. Same unmasking conditions, then CH Cl , amine (20 equiv),
Et N (20 equiv), −40 to 0 °C. (R)-CSA (0.5−5.0 equiv), AcOH/
H O (1:1, 0.2 M), 60 °C. Based on recovered starting material
3
b
2
2
c
3
d
2
(
21%).
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