Synthesis of N,N -diethylbenzamides via a nonclassical mitsunobu reaction

Article abstract of DOI:10.1080/00397911.2013.839796

The use of the Mitsunobu reaction for the synthesis of N,N- diethylbenzamides affords ortho-, meta-, and para-substituted benzamides containing both electron-donating and electron-withdrawing groups. While the preparation of numerous functional groups has

Full text of DOI:10.1080/00397911.2013.839796

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Synthesis of N,N-Diethylbenzamides via
a Nonclassical Mitsunobu Reaction
J. Mason Hoffman a , Justin N. Miller a , Margaret E. Gardner a
Danielle R. LePar b & Rongson Pongdee a
,
a Department of Chemistry , Sewanee: The University of the South ,
Sewanee , Tennessee , USA
b Department of Chemistry and Biochemistry , Colorado College ,
Colorado Springs , Colorado , USA
Accepted author version posted online: 08 Nov 2013.Published
online: 24 Feb 2014.
To cite this article: J. Mason Hoffman , Justin N. Miller , Margaret E. Gardner , Danielle R. LePar &
Rongson Pongdee (2014) Synthesis of N,N-Diethylbenzamides via a Nonclassical Mitsunobu Reaction,
Synthetic Communications: An International Journal for Rapid Communication of Synthetic Organic
Chemistry, 44:7, 976-980, DOI: 10.1080/00397911.2013.839796
To link to this article: http://dx.doi.org/10.1080/00397911.2013.839796
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Synthetic Communications1, 44: 976–980, 2014
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2013.839796
SYNTHESIS OF N,N-DIETHYLBENZAMIDES VIA A
NONCLASSICAL MITSUNOBU REACTION
J. Mason Hoffman,1 Justin N. Miller,1 Margaret E. Gardner,1
Danielle R. LePar,2 and Rongson Pongdee1
1Department of Chemistry, Sewanee: The University of the South, Sewanee,
Tennessee, USA
2Department of Chemistry and Biochemistry, Colorado College, Colorado
Springs, Colorado, USA
GRAPHICAL ABSTRACT
Abstract The use of the Mitsunobu reaction for the synthesis of N,N-diethylbenzamides
affords ortho-, meta-, and para-substituted benzamides containing both electron-donating
and electron-withdrawing groups. While the preparation of numerous functional groups
has been efficiently demonstrated employing the Mitsunobu reaction, our methodology
represents the first application of the Mitsunobu reaction for the construction of benzamides
using benzoic acid and amine starting materials. Moreover, this synthetic transformation is
believed to proceed via a nonclassical mechanism involving the existence of an acyloxypho-
sphonium ion.
[Supplementary materials are available for this article. Go to the publisher’s online
edition of Synthetic Communications1 for the following free supplemental resource(s):
Full experimental and spectral details.]
Keywords Acylation; amides; Mitsunobu reaction
INTRODUCTION
The regioselective preparation of functionalized aromatic and heteroaromatic
compounds remains an area of fundamental importance within the synthetic com-
munity. The presence of these architectural motifs in biologically active secondary
metabolites and synthetic compounds of pharmaceutical value has continued to fuel
the development of methodology for their efficient construction. One of the most
Received August 21, 2013.
Address correspondence to Rongson Pongdee, Department of Chemistry, Sewanee: The University
of the South, 735 University Avenue, Sewanee, TN 37383-1000, USA. E-mail: rpongdee@sewanee.edu
976

N,N-DIETHYLBENZAMIDES VIA MITSUNOBU REACTION
977
powerful synthetic transformations available for the regiocontrolled introduction of
various functional groups onto aromatic scaffolds is the directed ortho-metalation
(DoM) reaction, extensively studied by Snieckus and coworkers over the past 30
years.[1,2] Within this context, one of the most widely employed directing groups is
the N,N-diethylamide functional group owing to its strong Lewis basicity, which
allows for tight coordination with the Lewis acidic lithium cation of the alkyllithium
base to direct deprotonation of an ortho-position on the aromatic ring.
During the course of our work toward the synthesis of members of the angucy-
cline family of antitumor antibiotics, we envisioned employing a DoM strategy, uti-
lizing a N,N-diethylamide directing group, for the preparation of a target fragment.
Previously, our group disclosed the application of the Mitsunobu reaction for the
efficient construction of arylbenzoates involving benzoic acids and phenols.[3] Within
that context, we also postulated that our methodology proceeded through a nonclas-
sical mechanism, involving an acyloxyphosphonium ion rather than the more
traditional alkoxyphosphonium ion, that would allow for the introduction of various
nucleophiles other than substituted phenols within a similar framework.[4] As such,
we elected to explore the feasibility of preparing N,N-diethylbenzamides as an
extension of our Mitsunobu methodology.
RESULTS AND DISCUSSION
Initially, we began investigating the conversion of 4-methoxybenzoic acid (1) to
N,N-diethyl-4-methoxybenzamide (2), as depicted in Fig. 1. We explored various
solvents, temperatures, and stoichiometric ratios in attempts to identify the optimal
reaction conditions. We found that increasing the stoichiometry of DIAD, Ph3P,
and Et2NH to more than 1.2 equivalents led to greater difficulty in obtaining pure
products after column chromatography. In each case, we were pleased to obtain
1
the desired benzamide product 2 following analysis of the H NMR spectra. How-
ever, each sample was contaminated, presumably by the reduced azodicarboxylate
and=or unreacted starting materials, from the Mitsunobu reaction. Over the years,
numerous reports in the chemical literature have appeared, describing methods for
the removal of by-products associated with the Mitsunobu reaction.[5] Unfortunately,
our attempts to employ alternative azodicarboxylates, such as di-2-methoxyethyl azo-
dicarboxylate (DMEAD), di-p-chlorobenzyl azodicarboxylate (DCAD), di-tert-butyl
azodicarboxylate (DTBD), or structurally modified phosphines proved unsuccessful
in alleviating our purification difficulties.[5d,5i,5k] After several attempts at varying
the reaction conditions, we were pleased to discover that the inclusion of an acid–base
extraction, involving 1 M sodium hydroxide, as part of the reaction workup afforded
chromatographically pure benzamide 2 in good yield.
Figure 1.

978
J. M. HOFFMAN ET AL.
Table 1. Synthesis of N,N-diethylbenzamides using the Mitsunobu reaction
Entry
Benzoic Acid
Producta
Yield (%)
1
3a, R ¼ 2-OCH3
64
2
3
4
5
3b, R ¼ 3-OCH3
1, R ¼ 4-OCH3
52
67
64
57
3c, R ¼ 4-N(Me)2
3d, R ¼ 2-OH, 4-CH3
6
3e, R ¼ 3-NO2
35
7
8
3f, R ¼ 4-NO2
3g, R ¼ 4-CN
33
26
aProducts obtained were >95% pure by 1H and 13C NMR.

N,N-DIETHYLBENZAMIDES VIA MITSUNOBU REACTION
979
Next, we turned our attention to an examination of the substrate scope for our
newfound methodology. As illustrated in Table 1, the reaction works reasonably well
with electron-rich benzoic acids in the ortho-, meta-, or para-positions (entries 1–5).
Additionally, free phenols (entry 5) can be employed with little detriment to the over-
all reaction outcome. It is worth mentioning that the preparation of benzamide 4d
via the acid chloride resulted in dramatically lower yields (41% compared to 57%
employing our Mitsunobu methodology). To a lesser extent, the reaction is also
tolerant of electron-poor benzoic acid substrates (entries 6–8). We believe that a par-
tial reason for lower yields associated with electron-poor benzoic acids is incomplete
consumption of the starting material employing our typical reaction conditions.
In summary, we have demonstrated a new application for the Mitsunobu
reaction involving the preparation of N,N-diethylbenzamides. We believe that our
methodology will benefit researchers employing directed ortho-metalation (DoM)
strategies for a variety of synthetic applications. Additionally, our methodology
may also be advantageous when traditional carboxylic acid derivative chemistry
proves ineffective. Mechanistic studies of our nonclassical Mitsunobu reaction are
currently under way and will be reported in due course.
EXPERIMENTAL
Triphenylphosphine (1.20 eq), diethylamine (1.20 eq), and the benzoic acid
(1.00 eq) were dissolved in toluene (0.2 M solution) at room temperature and allowed
to stir for 10 min. Diisopropylazodicarboxylate (1.20 eq) was then added dropwise
and the reaction was heated to reflux overnight (18 h), at which time the reaction
was diluted with EtOAc and washed with 1 M NaOH brine. The combined organic
layers were dried over anhydrous Na2SO4, filtered, concentrated in vacuo, and the
resulting residue was purified by flash column chromatography (EtOAc=hexanes
2:1) to afford the desired benzamides.
ACKNOWLEDGMENTS
We gratefully acknowledge financial support from the National Institute of
Allergy and Infectious Diseases (R15, AI084075-02) and the donors of the American
Chemical Society Petroleum Research Fund (PRF 52168-UR1). Additionally, we
thank the National Science Foundation, as part of its Major Research Instrumen-
tation (MRI) Program (CHE-1126231), for the acquisition of a JEOL ECS-400
nuclear magnetic resonance spectrometer. Accurate mass measurements were per-
formed by Dr. William Boggess of the Mass Spectrometry and Proteomics Facility
at the University of Notre Dame.
SUPPORTING INFORMATION
Full experimental details, along with full characterization data for compounds
2 and 4a–g, can be found via the Supplementary Content section of this article’s
Web page.

980
J. M. HOFFMAN ET AL.
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