Three-component condensations of aldehydes with N-methoxycarboxamides

Article abstract of DOI:10.1016/j.tetlet.2004.10.058

The first condensations of N-methoxycarboxamides (component A) with aliphatic acetals (component B) are described. Depending upon the conditions, the hemiaminal type products (AB) can usually be isolated. Conducting the condensations with 2 equiv of acetal affords β-(N-methoxy)amido aldehydes (type ABB products). A condensation using anisole (component C) afforded a product of type ABC.

Full text of DOI:10.1016/j.tetlet.2004.10.058

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 9007–9010
Three-component condensations of aldehydes with
N-methoxycarboxamides
Charles M. Marson* and Sabrina Pucci
Department of Chemistry, University College London, Christopher Ingold Laboratories, 20 Gordon Street, London WC1H 0AJ, UK
Received 9 August 2004; revised 29 September 2004; accepted 8October 2004
Abstract—The first condensations of N-methoxycarboxamides (component A) with aliphatic acetals (component B) are described.
Depending upon the conditions, the hemiaminal type products (AB) can usually be isolated. Conducting the condensations with
2equiv of acetal affords b-(N-methoxy)amido aldehydes (type ABB products). A condensation using anisole (component C) afforded
a product of type ABC.
Ó 2004 Elsevier Ltd. All rights reserved.
Condensations of amides with carbonyl compounds can
provide access to a wide variety of compounds, many
highly functionalised and difficult to prepare by other
means.1,2 In the typical case, an amidoalkylating species
is generated which then reacts with a third molecule act-
ing as a nucleophile, leading necessarily to a multicom-
ponent product.3,4 Much less general than the
corresponding aminoalkylations (e.g., Mannich proc-
esses),5,6 amidoalkylation at carbon frequently involves
the condensation of an active methylene compound
other than an aldehyde with an imine (Schiffꢀs base)
derived from an aromatic aldehyde. In 1988, our group
described the preparation of b-amido aldehydes by
means of a three-component condensation involving
an amide and two molecules of an aliphatic aldehyde.7
Those reactions extend the scope of C-amidoalkylations
and do not involve isolation of the amidoalkylating
species prior to reaction with the C-nucleophile, as is
otherwise often the case.
In view of the importance of hydroxamic acids in medi-
cinal chemistry, especially as inhibitors of matrix metallo-
proteinases8 and of histone deacetylase,9 it seemed very
desirable to develop a reaction that involved a multi-
component condensation of a hydroxamic acid, or a
derivative, with carbonyl compounds and especially
aldehydes or their equivalents, thereby forming a func-
tionalised compound with likely enzyme inhibitory
potency and also capable of being readily diversified.
However, condensations of hydroxamic acids or their
derivatives with aliphatic carbonyl compounds have
been little described; reactions with aliphatic aldehydes
are very scarce,10 and to our knowledge no such multi-
component process involving carbon–carbon bond for-
mation has been described previously. Herein we
report novel condensations of N-methoxycarboxamides
with acetals to give, via hemiaminal type intermediates
3, the multicomponent products, b-(N-methoxy)amido
aldehydes 4 (Scheme 1).
O
O
O
OR3
OR
OR
OR
BF3.OEt2 or
CF3SO3H
R2
R1
N
H
R1
R2
N
R1
R2
N
OR3
BF3.OEt2 or
CF3SO3H
1
CHO
OR3
OR3
+
R2
R2
4
3
OR3
2
Scheme 1.
Keywords: Hydroxamic acid derivatives; Acetals; Condensation; Multicomponent reaction.
*
Corresponding author. Tel.: +44 20 76794712; fax: +44 20 7679 7463; e-mail: c.m.marson@ucl.ac.uk
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.10.058

9008
C. M. Marson, S. Pucci / Tetrahedron Letters 45 (2004) 9007–9010
The starting point for this investigation was the conden-
sation of hydroxamic acid 5b with n-butyraldehyde. In
propan-2-ol at reflux, condensation with ring-closure
occurred to give 6, analogous to other imidazolidine-4-
ones.11 By introducing an electron-withdrawing group
at the amine nitrogen atom, electrophilic attack was
hoped to be induced exclusively on the hydroxamic acid
nitrogen atom. Gratifyingly, the Boc-protected hydroxa-
mic acid 5a afforded the hemiaminal 3a at 20°C, which
exhibited a signal at 80.8ppm in the 13C NMR spectrum
for the hemiaminal carbon atom (in contrast to the cor-
responding signal at 72.1ppm for the cyclised product 7)
(Scheme 2).
nent condensation, it was realised from previous work7
that careful selection of reactants and conditions was
likely to be important. In three-component condensa-
tions of amides with aldehydes7 it was found in some
instances that the use of the symmetrical trioxane
was preferable to the corresponding aldehyde, in part
because of the tendency of the latter to form aldol
side-products derived from self-condensation. Encour-
agingly, an exploratory reaction using 3d showed that
replacement of acetaldehyde dimethyl acetal with a
1,3,5-trioxane enabled the reaction to proceed further,
giving the b-(N-methoxy)amido aldehyde 4d (Table 1).
Further studies showed that in some cases the ABB
product was better obtained from the symmetrical tri-
oxane, in others from the corresponding dimethyl acetal;
in the present study no clear trend was discerned,
although the use of the dimethyl acetal appears to be
more general. Investigation of the condensing agent
showed that, in many cases, BF3ÆOEt2 (in acetonitrile)
was found to be more satisfactory than trifluorometh-
anesulfonic acid for the preparation of the b-(N-meth-
oxy)amido aldehydes 4.13 The mildness of the
procedure is consistent with other functionality includ-
ing isolated double bonds (Table 1, entry 1), imides
(entries 4 and 6) and ethers (entry 3). The sequential
nature of the reaction, as well as proceeding via an elec-
trophilic species derived from the intermediate N-(a-
methoxyalkyl)-N-methoxycarboxamides 3 was further
demonstrated by treatment of 3d with anisole in the
presence of excess BF3ÆOEt2 (Scheme 4) whereupon
the multicomponent product 8 was obtained. Manipula-
tion of the functionality in the multicomponent adducts
4 was examined by protection of the aldehyde group of
4d as the acetal 9 (ethylene glycol, toluene, p-TsOH,
80°C, 90%) followed by deprotection with hydrazine
to give the highly functionalised amine 10. Although a
reductive cyclisation using palladium on carbon did
not afford 11 in satisfactory yield, it should be possible
to synthesise N-heterocycles containing pharmacophore
regions through the use of products 4 of this novel
multicomponent process involving the condensation of
O-alkylated hydroxamic acids with acetals. Addition-
ally, the aldehyde group of the b-(N-methoxy)amido
aldehydes 4 could participate in another multicompo-
nent reaction such as a reductive amination, thereby
enabling the rapid assembly of diversely functionalised
compounds.
O
O
O
OH
OH
CHCl3
N
N
H
+
H
H
RN
RNH
20 °C, 3 h
(R=Boc 35%)
HO
5a R=Boc
5b R=H
3a R=Boc
propan-2-ol,
reflux, 4 h
(R=H 71%)
O
O
OH
N
OH
N
Boc2O, Et3N
HN
N
CHCl3
20 °C, 12 h
Boc
7
6
Scheme 2.
However, several attempted condensations using other
hydroxamic acids and aldehydes, with or without acid
catalysts, did not lead to satisfactory yields, either of
hemiaminals or related products. The use of acetals as
the aldehyde equivalents was then explored, and after
considerable investigation it was found that trifluoro-
methanesulfonic acid (2% in dichloromethane) in a rig-
orously dry medium effected the condensation of N-
methoxycarboxamides with acetals to give N-(a-meth-
oxyalkyl)-N-methoxycarboxamides such as 3d and 3f
(Scheme 3).12 To our knowledge, a-oxy-substituted car-
boxamides bearing an N-alkoxy (or N-hydroxy) group
such as 3 have not been described previously, and in
related condensations involving amides the correspond-
ing N-(a-hydroxyalkyl)carboxamides were not detected.
In order to achieve the required goal of a three-compo-
2% CF3SO3H
O
O
P2O5, Na2SO4
O
OMe
OMe
O
+
N
OMe
OMe
N
OMe
OMe
CH2Cl2, -50 °C,
4 h 82%
N
H
N
N
O
O
3d
2% CF3SO3H
P2O5, Na2SO4
O
O
OMe
OMe
+
OMe
OMe
CH2Cl2, -50 °C,
4 h 53%
N
H
3f
Scheme 3.

C. M. Marson, S. Pucci / Tetrahedron Letters 45 (2004) 9007–9010
9009
Table 1. Condensation of N-methoxycarboxamides with acetals using BF3ÆOEt2 in MeCN at À40°C or 2% CF3SO3H v/v in CH2Cl2 with P2O5
(5equiv) and Na2SO4 (5equiv) at À50°C
Entry
N-Methoxycarboxamide
Acetal
Reagent
Product (%)
O
O
MeO
1
BF3ÆOEt2
OMe
N
OMe
4a (78)
4b (48)
N
OMe
H
CHO
1a
2a
O
N
O
MeO
OMe
CHO
OMe
N
2
3
BF3ÆOEt2
BF3ÆOEt2
OMe
OMe
H
2a
1b
O
O
MeO
MeO
OMe
CHO
MeO
4c (68)
OMe
N
N
H
1c
2a
O
O
O
O
O
4
5
CF3SO3H,
P2O5, Na2SO4
4d (53)
4e (52)
N
O
OMe
N
OMe
O
O
N
N
H
O
CHO
1d
1e
2b
O
O
O
OMe
BF3ÆOEt2
OMe
O
O
N
N
H
CHO
2b
O
O
O
O
OMe
N
O
OMe
N
6
7
BF3ÆOEt2
4f (33)
N
OMe
N
H
OMe
CHO
O
1d
1e
2c
2c
O
OMe
O
OMe
OMe
N
BF3ÆOEt2
4g (35)
OMe
N
H
CHO
BF3.OEt2
(7 equiv.)
MeCN, -50 °C,
3 h, 54%
O
O
O
O
+
N
OMe
OMe
N
OMe
N
N
OMe
O
O
4 equiv.
3d
8
OMe
O
O
O
O
OMe
H2N
OMe
N
N
OMe
N
N
NH2NH2
HN
O
ethanol,
reflux
10
11
9
O
O
O
O
88%
Scheme 4.
Acknowledgements
References and notes
1. (a) Marson, C. M.; Grabowska, U.; Walsgrove, T.;
Eggleston, D. S.; Baures, P. W. J. Org. Chem. 1991, 56,
2603; (b) Marson, C. M.; Grabowska, U.; Walsgrove, T.;
A studentship (to S.P.) from the Engineering and Physi-
cal Sciences Research Council is gratefully acknowl-
edged.

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Eggleston, D. S.; Baures, P. W. J. Org. Chem. 1994, 59,
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J. Org. Chem. 1994, 59, 291.
prepared by adding O-methylhydroxylamine hydrochlo-
ride (1.5equiv) in methanol to a stirred solution of
potassium hydroxide (1.5equiv) in methanol at 0°C,
stirring for 15min and filtration.
13. Preparation of N-methoxy-N-(1-methyl-3-oxopropyl)acet-
amide (4a). To
a solution of (E)-hex-3-enoic acid
3. (a) Zaugg, H. E. Synthesis 1984, 85; (b) Zaugg, H. E.
Synthesis 1984, 181.
4. Zaugg, H. E.; Martin, W. B. Org. React. 1965, 14, 52.
5. Blicke, F. F. Org. React. 1942, 1, 303.
6. Brewster, J. H.; Eliel, E. L. Org. React. 1953, 7, 99.
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9. Marks, P. A.; Rifkind, R. A.; Richon, V. M.; Breslow, R.;
Miller, T.; Kelly, W. K. Nat. Rev. Cancer 2001, 1, 194.
10. (a) Motorina, I. A.; Sviridova, L. A.; Golubeva, G. A.;
Bundel, Yu. G. Tetrahedron Lett. 1989, 30, 117; (b)
Reisner, D. B.; Ludwig, B. J.; Stiefel, F. J.; Gister, S.;
Meyer, M.; Powell, L. S.; Sofia, R. D. Arzneim.-Forsch.
1977, 27, 760.
hydroxyamide (0.10g, 0.78mmol) in dry acetonitrile
(3.5mL) cooled to À35°C was added borontrifluoride
diethyl etherate (0.55mL, 4.5mmol). Acetaldehyde
dimethyl acetal (0.28mL, 2.3mmol) was then added
dropwise and the mixture stirred for 24h at À35°C. The
solution was allowed to warm to 0°C and neutralised with
saturated aqueous sodium hydrogen carbonate solution.
The organic layer was washed first with water then with
brine, dried, filtered and concentrated under reduced
pressure. The residue was purified by column chromato-
graphy (1:9 ethyl acetate:toluene) to give 4a (0.13g, 78%;
6:1 aldehyde:diol hydrate form) as a colourless oil. For 4a:
IR mmax (cmÀ1) (KBr disc) 1700 (CO), 1670 (NCO), 1635
(C@C); 1H NMR (300MHz) d 9.60 (1H, t, J = 2Hz), 5.56
(2H, m), 4.80 (1H, m), 3.72 (3H, s), 3.33 (1H, d,
J = 10.5Hz), 3.28(1H, d, J = 10.5Hz), 2.81 (1H, ddd,
J = 12.5, 8.5, 2Hz), 2.63 (1H, ddd, J = 12.5, 6, 1.5Hz),
2.03 (2H, m), 1.30 (3H, d, J = 7Hz), 0.96 (3H, t,
J = 7.5Hz); 13C NMR (75MHz) d 200.1, 173.2, 136.2,
121.0, 64.7, 55.8, 47.8, 36.9, 25.6, 18.1, 13.5. LRMS m/z
(EI) 214 (M+1; 10), 117 (35), 69 (87), 59 (100). HRMS:
calcd for C11H19NO3+H 214.1143, found 214.1141. For
the hydrate of 4a: 1H NMR (300MHz) d 5.66 (2H, m),
4.80 (1H, m), 3.82 (3H, s), 3.33 (1H, d, J = 10.5 Hz), 3.21
(1H, m), 3.28(1H, d, J = 10.5Hz), 2.03 (2H, m), 2.81 (1H,
m), 2.63 (1H, m), 1.11 (3H, d, J = 6.3Hz), 0.96 (3H, t,
J = 7.5Hz); 13C NMR (75MHz) d 173.2, 136.3, 121.1,
102.5, 65.3, 56.1, 49.5, 38.6, 25.6, 18.7, 13.5.
11. Harmon, R. E.; Rizzo, V. L.; Gupta, S. K. J. Heterocycl.
Chem. 1970, 7, 439.
12. N-Methoxycarboxamides were prepared by stirring a
mixture of a carboxylic acid (1equiv), ethyl chloroformate
(1.2equiv) and N-methylmorpholine (1.3equiv) in diethyl
ether at 0°C for 15min. Filtration gave a solution that was
added to a solution of O-methylhydroxylamine in meth-
anol and the mixture stirred at 20°C, the reaction being
usually complete within 1h. After work-up the material
was purified by chromatography on silica using ethyl
acetate 60–80°C petroleum ether or ethyl acetate–toluene
as eluent. The solution of hydroxylamine in methanol was