The redox-Mannich reaction

Article abstract of DOI:10.1021/ol501365j

A complement to the classic three-component Mannich reaction, the redox-Mannich reaction, utilizes the same starting materials but incorporates an isomerization step that enables the facile preparation of ring-substituted β-amino ketones. Reactions occur

Full text of DOI:10.1021/ol501365j

Letter
pubs.acs.org/OrgLett
The Redox-Mannich Reaction
Weijie Chen and Daniel Seidel*
Department of Chemistry and Chemical Biology, Rutgers, The State University of New Jersey, Piscataway, New Jersey 08854,
United States
S
* Supporting Information
ABSTRACT: A complement to the classic three-component
Mannich reaction, the redox-Mannich reaction, utilizes the same
starting materials but incorporates an isomerization step that
enables the facile preparation of ring-substituted β-amino ketones.
Reactions occur under relatively mild conditions and are facili-
tated by benzoic acid.
he classic three-component Mannich reaction of a primary
offered a unique set of challenges (vide infra) and would provide
Tor a secondary amine with a nonenolizable aldehyde products of synthetic utility, we were intrigued by the possibility
of developing an unprecedented redox version of the Mannich
reaction.
For the purpose of exploring the feasibility of a redox-Mannich
reaction, we selected a substrate combination of pyrrolidine, 2,6-
dichlorobenzaldehyde, and acetophenone (Table 1). Following
and a C−H acidic carbonyl compound remains an extremely
valuable method for C−C bond construction.1,2 Among the most
extensively studied variants are oxidative two-component
approaches with tertiary amines that provide access to ring-
substituted β-amino ketones, products not available by the classic
Mannich approach (eq 1).3 Here we report a redox-neutral
alternative that utilizes the same starting materials as the regular
Mannich reaction but leads to amine α-C−H bond functional-
ization (eq 2).
a
Table 1. Reaction Development
entry
deviation from optimized conditions
none
yield (%)
1
56
trace
45
48
45
45
43
51
39
28
42
2
no PhCOOH
3
100 mol % of PhCOOH
4
20 mol % of PhCOOH
5
direct mixing of all reagents, reflux, 1 h
2 equiv of pyrrolidine
6
7
with 4 Å MS
8
slow addition of aldehyde only
2-EHA instead of PhCOOH
4-Me2N-C6H4-COOH instead of PhCOOH
4-MeO-C6H4-COOH instead of PhCOOH
9
The oxidative functionalization of amine α-C−H bonds via
cross-dehydrogenative coupling reactions (CDC reactions) is an
attractive avenue for the generation of more complex amines
from simpler starting materials.4 Different oxidants and strategies
including photoredox approaches have been utilized, often in the
context of functionalizing N-aryl tetrahydroisoquinolines.4,5
Recently, our group has advanced an alternate and redox-neutral
concept for amine α-C−H bond functionalization that obviates
the need for an oxidant by effectively linking a reductive N-
alkylation event to an oxidative α-functionalization.6−8 Unstabi-
lized azomethine ylides9 have been identified as intermediates in
these processes. In some instances, in particular for relatively
acidic substrates such as phenols, amine α-functionalization can
be achieved in the absence of any additives.6k,m Other redox-
transformations with concurrent amine α-C−H bond function-
alization are facilitated by carboxylic acids6d,f,j,k,n or simply by the
solvent (e.g., ethanol).6h Because the realization of such a process
10
11
a
Reactions were performed on a 0.5 mmol scale. A mixture of
aldehyde and ketone in 0.5 mL of toluene was added over 5 h to a
solution of pyrrolidine and benzoic acid in 2 mL of toluene. All yields
correspond to isolated yields. 2-EHA: 2-ethylhexanoic acid.
extensive experimentation, the most successful conditions that
were identified call for the slow addition (5 h) of a toluene
solution of a 1:1.5 mixture of 2,6-dichlorobenzaldehyde and
acetophenone to excess pyrrolidine (5 equiv), heated under
reflux in toluene in the presence of benzoic acid (50 mol %).
The reaction was completed (as judged by the disappearance of
Received: May 13, 2014
© XXXX American Chemical Society
A
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Letter
2,6-dichlorobenzaldehyde) within <5 min after the slow addition
had ended. Under these conditions, β-amino ketone 1a was
isolated in 56% yield. The redox-Mannich reaction proved
remarkably tolerant to deviation from the optimized conditions.
While the presence of a carboxylic acid catalyst was a strict
requirement, the nature or the amount of acid was found to be
less important. Also, slow addition of ketone and aldehyde or
aldehyde alone was not absolutely necessary and the amount of
pyrrolidine could be reduced to 2 equiv without a major
reduction in yield. Interestingly, the addition of molecular sieves
led to a decrease in yield. This is in contrast to other redox
processes in which molecular sieves greatly increase substrate
conversion and product yields.
Scheme 2. Scope of the Redox-Mannich Reaction with
Tetrahydroisoquinoline
a
Under the optimized conditions, the pyrrolidine/2,6-dichloro-
benzaldehyde pair was found to readily undergo redox-Mannich
reactions with a range of aromatic and heteroaromatic meth-
ylketones (Scheme 1). Electron-donating and -withdrawing
Scheme 1. Scope of the Redox-Mannich Reaction with
a
Pyrrolidine
a
Reactions were performed on a 0.5 mmol scale. The substrates were
b
mixed directly. All yields correspond to isolated yields. 3 equiv of
acetone were used.
and acetophenone. Acetone was also shown to act as a competent
nucleophile in this process.
In an effort to further extend the scope of the redox-Mannich
reaction, nitroalkanes were evaluated as nucleophiles (Scheme 3).
a
Scheme 3. Redox-Mannich Reactions with Nitroalkanes
a
Reactions were performed on a 0.5 mmol scale. A mixture of aldehyde and
ketone in 0.5 mL of toluene was added over 5 h to a solution of pyrrolidine
and benzoic acid in 2 mL of toluene. All yields correspond to isolated yields.
substituents in the m- and p-position of the ring were well
tolerated. Interestingly, o-substituted acetophenones failed to
undergo the title reaction, possibly due to less favorable keto/
enol equilibration.
a
Reactions were performed on a 0.5 mmol scale. Yields were
Tetrahydroisoquinoline (THIQ) was found to be an excellent
substrate for redox-Mannich reactions (Scheme 2). Consistent
with the enhanced reactivity of the benzylic α-C−H bond of
THIQ over the α-C−H bond of pyrrolidine, reactions could be
performed at a reduced temperature of 50 °C. A 20 mol %
loading of benzoic acid was optimal, and slow addition of
substrate was unnecessary. Unlike in the case of pyrrolidine, the
addition of molecular sieves had a beneficial effect on the reaction
outcome. The scope of this transformation was shown to be
broad with regard to the aldehyde. Electronically diverse
aromatic and heteroaromatic aldehydes with various substitution
patterns readily engaged in redox-Mannich reactions with THIQ
determined by 1H NMR using an internal standard. Yields in
parentheses correspond to isolated yields.
Gratifyingly, the conditions optimized for ketones were directly
applicable to this class of nucleophiles and reactions of pyrrolidine
and THIQ proceeded in good to excellent yields. It should be
noted, however, that products 3 (in particular 3b and 3c) and 4
were found to be relatively unstable to column chromatographic
purification.
A remarkable feature of the redox-Mannich reactions
described herein is that regular Mannich products were never
B
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Letter
observed as byproducts in any of the reactions. There is probably
a rather simple explanation for this observation which, on cursory
inspection, might appear rather surprising. While reactions of
secondary aliphatic amines with formaldehyde and various
ketones readily provide isolable β-amino ketones, as established
by Carl Mannich himself,10 the corresponding products from
other nonenolizable aldehydes, in particular aromatic aldehydes,
are known to be relatively unstable by way of amine elimination
under thetypically acidic reaction conditions.11 On theother hand,
secondary aliphatic amines are known to add to the thus formed
α,β-unsaturated ketones under neutral conditions. For instance,
THIQ was reported to add to chalcone (5) to give 6 (eq 3).12,13
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: seidel@rutchem.rutgers.edu.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
Financial support from the NIH−NIGMS (Grant
R01GM101389-01) is gratefully acknowledged.
■
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ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental procedures and characterization data. This material
is available free of charge via the Internet at http://pubs.acs.org.
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