Synthesis of α-ketoamides by a molecular-sieves-promoted formal oxidative coupling of aliphatic aldehydes with isocyanides

Article abstract of DOI:10.1002/anie.200704840

(Chemical Equation Presented) A twist in the Ugi four-component reaction: The reaction of an aldehyde, an isocyanide, N-methylhydroxylamine, and acetic acid in the presence of 4-A molecular sieves afforded α-ketoamides in moderate to good yields (see scheme). In contrast, 3-A molecular sieves did not promote the desired multicomponent reaction. R¹ = alkyl; R² = alkyl, aryl.

Full text of DOI:10.1002/anie.200704840

Angewandte
Chemie
DOI: 10.1002/anie.200704840
Multicomponent Reactions
Synthesis of a-Ketoamides by a Molecular-Sieves-Promoted Formal
Oxidative Coupling of Aliphatic Aldehydes with Isocyanides**
Jean-Marie Grassot, GØraldine Masson,* and Jieping Zhu*
The a-ketoamide functionality has been found in a number of
biologically important natural products, such as FK 506[1] and
cyclotheonamide.[2] The facile formation of stable tetrahedral
adducts between the highly electrophilic a-oxo group and
nucleophilic residues (OH, SH) at the active site of enzymes
make a-ketoamides an excellent basis for the development of
enzyme inhibitors.Indeed, this structural motif has often been
incorporated strategically at the P1 position of designed
protease inhibitors.[3] a-Ketoamides[4] have been prepared
Scheme 1. Use of N-alkyl hydroxylamines 1 in the Ugi 4CR. Bn =
mainly by the following strategies: 1) amidation of a-keto
acids;[5] 2) oxidation of a-hydroxyamides,[6] a-cyanoamides,[7]
and a-aminoamides (transamination);[8] 3) oxidation of acyl
cyanophosphoranes followed by amidation of the resulting
a,b-diketone nitrile;[9] 4) transition-metal-catalyzed double
carbonylative amination of aryl halides;[10] 5) reaction of
isocyanides with aromatic acyl chlorides or anhydrides
followed by hydrolysis of the resulting a-ketoimidoyl chlo-
ride.[11] In spite of the availability of these synthetic method-
ologies, a general and efficient synthesis of a-ketoamides is
still in high demand.
In connection with our ongoing project on the develop-
ment of novel multicomponent reactions,[12] we had occasion
to examine the Ugi four-component reaction (4CR)[13,12k] of
N-methylhydroxylamine (1a), heptanal (2a), benzyl isocya-
nide (3a), and acetic acid (4a).[14,15] Under the conditions of
Guanti and co-workers (MeOH, room temperature), we
obtained the expected Ugi 4CR adduct 5a and the non-
acylated adduct 6 (R = Me) in 45 and 18% yield, respectively
(Scheme 1).However, the unexpected product N-benzyl-2-
oxooctanamide (7a) was also isolated in 10% yield (Table 1,
entry 1).The formation of 7a corresponds to a formal
oxidative coupling of an aldehyde with an isocyanide.[16] The
simple reaction conditions and the lack of a one-pot synthesis
of a-ketoamides prompted us to examine in detail this
benzyl.
Table 1: Optimization of the reaction conditions for the synthesis of
a-ketoamides.[a]
Entry
c[b]
R
Additive
Yield [%][c]
[molLÀ1
]
5
6
7
1
2
3
4
5
6
7
8
9
0.4
0.4
0.4
0.4
0.4
1.0
1.0
1.0
1.0
Me (1a)
Me (1a)
Me (1a)
Me (1a)
Me (1a)
Me (1a)
Me (1a)
tBu (1b)
Bn (1c)
none
45
25
38
13
18
0
18
5
5
0
0
0
0
0
10
20
10
58
47[d]
65
60[e]
0
MgSO4
3-Š MS
4-Š MS
4-Š MS
4-Š MS
4-Š MS
4-Š MS
4-Š MS
0
57
0
0
55
[a] General conditions: 1/2a/3a/AcOH 1.1:1.0:1.0:9 (molar ratio),
NaHCO3 (2 equiv). [b] Concentration of 2a. [c] Yield of the product
after purification by chromatography. [d] Just 3 equivalents of AcOH were
used. [e] PhCOOH was used instead of AcOH.
unprecedented transformation.We report herein our pre-
liminary results.
Initial experiments indicated that the reaction is sensitive
to a number of parameters.It is crucial to use an excess of
acetic acid (9 equiv) in methanol to obtain the a-ketoamide
7a.Only the corresponding nitrone (65%) was isolated when
the reaction was performed in CH2Cl2, whereas a complex
mixture of products was produced in THF.The addition of
MgSO4 to the reaction mixture led to a slight increase in the
yield of 7a (Table 1, entry 2).No beneficial effect was
observed when the reaction was performed in the presence
of 3-Š molecular sieves (MS, Table 1, entry 3).However,
when the 3-Š MS were simply exchanged for 4-Š MS under
otherwise identical conditions, the yield of 7a increased
significantly (Table 1, entry 4).The contrast between the
effects of 3-Š and 4-Š MS is intriguing.However, examples of
the different behavior of these two zeolites in a given
transformation have been reported previously.[17] The reac-
tion was improved further by increasing the substrate
concentration (Table 1, entry 6).Benzoic acid can also
[*] J.-M. Grassot, Dr. G. Masson, Dr. J. Zhu
Institut de Chimie des Substances Naturelles, CNRS
91198 Gif-sur-Yvette Cedex (France)
Fax: (+33)1-6907-7247
E-mail: masson@icsn.cnrs-gif.fr
zhu@icsn.cnrs-gif.fr
Homepage: http://www.icsn.cnrs-gif.fr/article.
php3?id_article=122
[**] Financial support from the CNRS and this institute is gratefully
acknowledged. J.M.G. thanks this institute for a doctoral fellowship.
We thank Professor G. Guanti for helpful discussions.
Supporting information for this article, including experimental
1
procedures, product characterization, and copies of the H and
13CNMR spectra of compounds 5a, 6a, and 7a–7n, is available on
the WWW under http://www.angewandte.org or from the author.
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Table 2: Synthesis of a-ketoamides by the coupling of an aldehyde with
mediate this coupling reaction to afford 7a in 60% yield
an isocyanide.[a]
(Table 1, entry 7).The nature of the substituent on the
N atom of the hydroxylamine influenced the efficiency of the
reaction.The use of N-tert-butylhydroxylamine hydrochloride
(1b) led to only the a-acyloxyamino amide 5b (Table 1,
entry 8), whereas the reaction of N-benzylhydroxylamine
hydrochloride (1c) afforded the a-ketoamide 7a, albeit in
slightly reduced yield (55%; Table 1, entry 9).
Entry
Aldehyde
Isocyanide
Product
(yield [%][b])
1
2
3
The generality of this formal oxidative coupling of
aldehydes with isocyanides was next examined with
N-methylhydroxylamine hydrochloride (1a) and acetic acid
(4) as mediators.Both aromatic and aliphatic isocyanides,
including a-isocyanoacetates, underwent the desired reaction
to provide a-ketoamides in moderate to good yields (Table 2).
However, the coupling product was obtained in low yield with
sterically hindered tert-butyl isocyanide (Table 2, entry 2).
The amide 7e, which can serve as a precursor to a-keto-
octanoic acid, was also obtained in low yield, certainly
because of the low nucleophilicity of the convertible isocy-
anide 3e (Table 2, entry 4).[18] Aliphatic aldehydes, including
functionalized aldehydes, are effective substrates (Table 2,
entries 1–9).The coupling reaction proceeded well with 6-( N-
benzyloxycarbamoyl)hexanal (2c).With a-aminoaldehydes,
double protection of the a-amino group was crucial for the
reaction to occur smoothly (Table 2, entry 10).However, the
reaction of aromatic aldehydes with isocyanides afforded the
corresponding a-ketoamides in only low yield.The chiral
aldehydes (S)-citronellal (2e) and 2 f were transformed
efficiently into the corresponding a-ketoamides 7l, 7m, and
7n without racemization (Table 2, entries 11–13).
A plausible reaction sequence that accounts for the
formation of a-ketoamides is shown in Scheme 2.The
condensation of an N-substituted hydroxylamine 1 and an
aldehyde 2 gives a nitrone 8, which reacts with an isocyanide 3
to afford the nitrilium intermediate 9.The species 9 can
conceivably be transformed into an a-ketoamide 7 through
two different mechanistic pathways: Intramolecular trapping
of the nitrilium moiety by the tethered oxygen nucleophile
would lead to the 4-imino-1,2-oxazetidine intermediate 10.
The fragmentation of 10 via its enamine form 11 would
provide the a-iminoamide 12, the hydrolysis of which would
2a
2a
4
5
2a
2a
6
7
2b
2b
3b
8
9
3a
3a
3a
3b
10
11
12
2e
13
3a
[a] All reactions were carried out in methanol at room temperature in the
presence of the hydrochloride salt of N-methylhydroxylamine and acetic
acid. [b] Yield of the product after chromatography on silica gel. Cbz =
carbobenzyloxy, TBDPS = tert-butyldiphenylsilyl.
afford the observed product 7.Alternatively, the classic Ugi
reaction pathway would lead to the formation of a-acyloxy-
amino amides 5 via an imidate intermediate 13.The
b elimination of acetic acid would then afford an a-imino-
amide 12, which would be hydrolyzed to 7.
To probe the reaction mechanism, the authentic 4-imino-
1,2-oxazetidine 15 was prepared by treating the nitrone 14
with the isocyanide 3g in the presence of BF3·OEt2
(Scheme 3).[19] When 15 was submitted to our reaction
conditions, the a-aminocarboxamide 17 was isolated exclu-
sively in 33% yield.This mode of fragmentation, that is,
preferential deprotonation of the N-methyl group followed by
À
N O bond cleavage, is in accord with results reported
Scheme 2. Reaction pathway leading to a-ketoamides 7.
previously.[19]
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These findings, and the fact that the a-acyloxyamino
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In summary, we have developed a novel synthesis of
a-ketoamides by a formal oxidative coupling of an aldehyde
with an isocyanide.[22] The reaction is carried out under mild
conditions in the presence of both N-methylhydroxylamine
and acetic acid as mediators.We also demonstrated the
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Experimental Section
Typical procedure: Heptanal (2a; 112 mL, 0.80 mmol) was added to a
solution of 1a (74 mg, 0.88 mmol, 1.1 equiv), NaHCO3 (132 mg,
1.57 mmol, 2 equiv), and 4-Š molecular sieves (600 mg) in methanol
(0.80 mL), and the resulting mixture was stirred for 30 min at room
temperature.Benzyl isocyanide ( 3a; 100 mL, 0.84 mmol, 1.05 equiv)
and acetic acid (400 mL, 9 equiv) were then added, and stirring was
continued for 24 h at room temperature.The reaction mixture was
then filtered, and the solvent was removed in vacuo.The crude
product was purified by flash chromatography (SiO2, 10% ethyl
acetate in heptane) to afford 7a (128 mg, 65%) as a white solid.
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Received: October 18, 2007
Published online: December 18, 2007
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Keywords: isocyanides · ketoamides ·
multicomponent reactions · nitrones · Ugi reaction
.
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Communications
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À
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=
PhCH2CH2, R3 = cyclohexyl) in ethanol (which can not be
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