Nitrosocarbonyl-Henry and Denitration Cascade: Synthesis of α-Ketoamides and α-Keto Oximes

Article abstract of DOI:10.1021/acs.orglett.7b00482

An unprecedented Henry reaction of in situ generated nitrosocarbonyl intermediates and concomitant denitration cascade has been developed. The reaction is catalyzed by organic base at room temperature offering α-ketoamides, a demanding scaffold for drug discovery, in high yields. An alteration of substitution pattern also produced α-keto oximes, a high-value synthon. The protocol features operational simplicity and broad substrate scope.

Full text of DOI:10.1021/acs.orglett.7b00482

Letter
pubs.acs.org/OrgLett
Nitrosocarbonyl−Henry and Denitration Cascade: Synthesis of
α‑Ketoamides and α‑Keto Oximes
Mallu Kesava Reddy, Sumitava Mallik, Isai Ramakrishna, and Mahiuddin Baidya*
Department of Chemistry, Indian Institute of Technology Madras, Chennai 600 036, Tamil Nadu, India
S
* Supporting Information
ABSTRACT: An unprecedented Henry reaction of in situ generated
nitrosocarbonyl intermediates and concomitant denitration cascade
has been developed. The reaction is catalyzed by organic base at room
temperature offering α-ketoamides, a demanding scaffold for drug
discovery, in high yields. An alteration of substitution pattern also
produced α-keto oximes, a high-value synthon. The protocol features
operational simplicity and broad substrate scope.
itrosocarbonyl intermediates and the derivatives thereof
have occupied a prominent position in contemporary
Scheme 1. Bioactive α-Ketoamides and Reaction of
Nitroalkanes with Nitrosocarbonyl Intermediates
N
organic synthesis.1 They are very reactive and versatile
prototypes of ambident electrophiles allowing construction
both C−N and C−O bonds from a single source. In this
context, chemists have compiled a reaction compendium that
includes nitrosocarbonyl aldol, ene, Diels−Alder, and other
types of cycloaddition reactions.2−4 Despite these accomplish-
ments, heretofore, the reaction of nitroalkanes with nitro-
socarbonyl compounds, the so-called nitrosocarbonyl-Henry
reaction, remains elusive, which is the quintessence of this
report.5
α-Ketoamides represent an important structural motif found
in numerous natural products and bioactive molecules (Scheme
1a).6 They also serve as useful synthetic intermediates for
various transformations.6,7 Consequently, synthetic endeavors
toward this scaffold are in high demand and remain a focus of
general interest.6−9 We envisaged that Henry reaction of
substituted nitroalkane with in situ generated nitrosocarbonyl
intermediate could be a convenient transformative alternative
to access this scaffold (Scheme 1b, R2 = H). The product A
thus obtained through the Henry reaction may undergo a water
elimination−addition sequence to give densely substituted
hemiaminol C, which will trigger a denitration10 reaction to
produce the desired product α-ketoamide. However, formation
of the competing O-selective nitroso-Henry reaction and the
undesired hydrolysis as depicted in Scheme 1b poses significant
challenges to this strategy. Additionally, a mild oxidation cycle
for in situ generation of nitrosocarbonyl intermediate is crucial
to overcome the decomposition of substrate. Herein, we report
an unprecedented nitrosocarbonyl Henry reaction en route to
α-ketoamides (R2 = H) and α-keto oximes (R2 ≠ H) catalyzed
by cinchona alkaloid at room temperature (Scheme 1b). It is
worth noting that, similar to α-ketoamides, α-keto oximes are
also key building blocks for the synthesis of diverse heterocyclic
frameworks.11
(Table 1). A solution of 2a was slowly injected into a mixture of
1a and MnO2 oxidant in THF at room temperature under the
influence of various base catalysts (10 mol %). However, the
reaction was unfruitful for commonly employed tertiary amines
such as DBU, NEt3, and DABCO (entries 1−3). The
breakthrough came when cinchona alkaloid cinchonidine was
considered. To our satisfaction, the reaction proceeded with
complete N-selectivity, rendering the desired α-ketoamide 3a in
34% isolated yield. When the catalyst was changed to quinidine,
the yield increased to 78% (entry 5). Screening of other
solvents and oxidant gave inferior results (entries 6−9).
Control experiments revealed that the presence of both the
We commenced our investigation using keto-substituted
nitroalkane 1a as a model substrate and commercially available
hydroxamic acid 2a as a precursor of nitroso intermediate
Received: February 16, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b00482
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Table 1. Optimization of Reaction Conditions for the
Synthesis of α-Ketoamides
Scheme 2. Scope of α-Ketoamide Synthesis
a
b
entry
solvent
oxidant
MnO2
catalyst
DBU
yield (%)
1
2
3
4
5
6
7
8
THF
THF
THF
THF
THF
CH3CN
DCE
MeOH
THF
THF
THF
c
MnO2
NEt3
c
MnO2
DABCO
cinchonidine
quinidine
quinidine
quinidine
quinidine
quinidine
quinidine
c
MnO2
34
78
30
trace
trace
48
c, e
c
MnO2
MnO2
MnO2
MnO2
d
9
CuCl, Py, O2
10
11
MnO2
a
Reaction conditions: 1a (0.2 mmol), 2a (1.2 equiv), catalyst (0.1
b
c
equiv), MnO2 (5 equiv), solvent (3 mL), 48 h. Isolated yield. No
reaction with the recovery of 1a. CuCl (0.1 equiv), pyridine (Py, 0.2
equiv), O2 balloon. No reaction with recovery of 1a and 2a. DBU:
d
e
1,8-diazabicyclo[5.4.0]undec-7-ene. DABCO: 1,4-diazabicyclo[2.2.2]-
octane; DCE: 1,2-dichloroethane.
quinidine catalyst and the MnO2 oxidant is mandatory, and the
reaction was ineffective in the absence of either of them (entries
10 and 11).
With the optimized conditions in hand, the scope of the α-
ketoamide synthesis was then explored (Scheme 2). The
reaction is quite general. Various keto-substituted nitroalkanes
having electron-donating and -withdrawing substituents (1b−i)
uniformly delivered the desired products in good yields (55−
82%). Compound 3f was crystallized, and the structure was
unambiguously confirmed through X-ray analysis.12 Interest-
ingly, the reaction tolerates various functional groups; alkene
(3j) and alkyne (3k) groups were unaffected. Heterocyclic
systems are also compatible to the reaction conditions,
producing 3l,m in 63% and 57% yields, respectively.
Substitutions at the hydroxamic acid moiety were also explored
to furnish 3n−r in 62−74% isolated yields. Notably,
(−)-menthol-derived hydroxamic acid also efficiently partici-
pated in this reaction, and chiral α-ketoamides 3s−u were
obtained in good yields.
Interestingly, when a higher homologue of nitroalkane 4a (R2
= Me) was exposed to optimized reaction conditions in the
presence of Cbz-substituted hydroxamic acid 2a (R = Bn), α-
keto oxime 7a was obtained exclusively (Scheme 3). The
formation of oxime product can be rationalized on the basis of
the N-selective nitroso-Henry reaction en route to compound 5
followed by C−NO2 bond cleavage (Scheme 3). This
conjecture was corroborated by the fact that the reactions of
nitroalkane 4a with other hydroxamic acids, Troc-NHOH (2b)
and Boc-NHOH (2c), also produced the same product 7a but
in diminished yields (70% and 52%, respectively). This
fortuitous finding encouraged us to explore the reaction
further. To our delight, a series of nitroethanes and
nitropropanes reacted smoothly to produce substituted α-keto
oximes in high yields (52−80%, Scheme 3). The functional
group compatibility of this reaction is impressive. The reaction
can be performed in the presence of various halogens (7e−i,n),
nitrile (7j), acetal (7k), and double bond (7l) functionalities
without any difficulties. The mild reaction conditions are also
a
Reaction conditions: 1a (0.2 mmol), 2a (1.2 equiv), quinidine (0.1
equiv), MnO2 (5 equiv), THF (3 mL), 48 h. Isolated yield.
suitable for heterocyclic systems, furnishing furyl- (7o),
benzofuryl- (7p), and thienyl-substituted (7q) α-keto oximes
in good yields (60−66%). Furthermore, only E-oximes are
selectively formed in this reaction, and crystal structures of 7a
and 7q also support this observation.12 It is important to
emphasize that traditional α-keto oxime syntheses are usually
performed under acidic conditions.13 In contrast, our protocol
operates under catalytic basic conditions.
To highlight the synthetic utility of this protocol, we have
performed the reaction on a gram scale (Scheme 4). With only
10 mol % catalyst loading under the optimized conditions, the
gram-scale N-selective nitrosocarbonyl-Henry reaction of 1e
with 2a proceeded smoothly, and the corresponding product 3e
was isolated in comparable yield (76%). Additionally,
compound 3e was also exquisitely reduced with NaBH4,
rendering β-hydroxy-α-amino alcohol 8 in excellent yield
(Scheme 4).
In conclusion, we have described a Henry reaction of in situ
generated nitrosocarbonyl intermediates with keto-substituted
nitroalkanes and the subsequent denitration cascade. The
reaction is catalyzed by cinchona alkaloid quinidine and
proceeds at room temperature to deliver α-ketoamides in
high yields with nitromethane derivatives (up to 82%). When
B
DOI: 10.1021/acs.orglett.7b00482
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 3. Synthesis of Oximes via Nitrosocarbonyl-Henry
Reaction
AUTHOR INFORMATION
■
a
Corresponding Author
*E-mail: mbaidya@iitm.ac.in.
ORCID
Mahiuddin Baidya: 0000-0001-9415-7137
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We gratefully acknowledge DST (EMR/2014/000225) for
financial support. M. K. R thanks UGC New Delhi for a JRF,
and S. M. and I. R. thank IIT Madras for HTRA. We also thank
the Department of Chemistry, IIT-Madras for instrumental
facilities.
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ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.7b00482.
■
S
Complete experimental details and characterization data
for the prepared compounds (PDF)
Crystallographic data for 3f (CIF)
Crystallographic data for 7a (CIF)
Crystallographic data for 7q (CIF)
C
DOI: 10.1021/acs.orglett.7b00482
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
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D
DOI: 10.1021/acs.orglett.7b00482
Org. Lett. XXXX, XXX, XXX−XXX