One-step formation of N-alkenyl-malonamides and N-alkenyl-thiomalonamides from carbamoyl meldrum's acids

Article abstract of DOI:10.1080/00397911.2011.634082

A one-pot synthesis for the preparation of N-alkenyl-malonamides and N-alkenyl-thiomalonamides was developed. 5-[Hydroxy/mercapto(aryl/alkylamino) methylene]-2,2-dimethyl-1,3-dioxane-4,6-dione act as a source of ketenes that react with the tautomeric form of alkyl-(2-phenyl-propylidene)-amines. A possible [2 + 2] or [4 + 2] cycloaddition product of ketene to imines was not observed.

Full text of DOI:10.1080/00397911.2011.634082

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One-Step Formation of N-Alkenyl-
malonamides and N-Alkenyl-
thiomalonamides from Carbamoyl
Meldrum's Acids
Paweł Punda a & Sławomir Makowiec a
a Department of Organic Chemistry, Faculty of Chemistry, Gdansk
University of Technology, Gdańsk, Poland
Accepted author version posted online: 08 May 2012.Version of
record first published: 05 Mar 2013.
To cite this article: Paweł Punda & Sławomir Makowiec (2013): One-Step Formation of N-
Alkenyl-malonamides and N-Alkenyl-thiomalonamides from Carbamoyl Meldrum's Acids, Synthetic
Communications: An International Journal for Rapid Communication of Synthetic Organic Chemistry,
43:10, 1362-1367
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Synthetic Communications1, 43: 1362–1367, 2013
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2011.634082
ONE-STEP FORMATION OF N-ALKENYL-
MALONAMIDES AND N-ALKENYL-
THIOMALONAMIDES FROM CARBAMOYL
MELDRUM’S ACIDS
Paweł Punda and Sławomir Makowiec
Department of Organic Chemistry, Faculty of Chemistry, Gdansk University
´
of Technology, Gdansk, Poland
GRAPHICAL ABSTRACT
Abstract A one-pot synthesis for the preparation of N-alkenyl-malonamides and N-alkenyl-
thiomalonamides was developed. 5-[Hydroxy/mercapto(aryl/alkylamino)methylene]-2,2-
dimethyl-1,3-dioxane-4,6-dione act as a source of ketenes that react with the tautomeric
form of alkyl-(2-phenyl-propylidene)-amines. A possible [2 þ 2] or [4 þ 2] cycloaddition
product of ketene to imines was not observed.
Keywords Acylations; amides; ketenes; Meldrum’s acid; tautomerism
INTRODUCTION
Meldrum acid derivatives are widely used in organic synthesis,[1] usually
because 3-substituted-1,3-dioxadiones are a potential source of ketenes in the course
of thermolysis.[2] Among them, acyl Meldrum acids play the most significant role as
a starting material for structurally diverse compounds such as 3-substituted-b-
lactams,[3] isooxazolols,[4] pilicides,[5] 1,3-oxazinones,[6] pyrones,[7] and derivatives
of tetramic acid.[8]
Recently we have focused our efforts on the application of particular deriva-
tives, 5-[hydroxy(aryl=alkylamino)methylene]-2,2-dimethyl-1,3-dioxane-4,6-diones
1a, in organic synthesis. During thermal decomposition 1a is a source of carba-
moylketenes, which, as demostrated by Lee et al.[9] and our own research, may
Received September 12, 2011.
Address correspondence to Sławomir Makowiec, Department of Organic Chemistry, Faculty of
´
Chemistry, Gdansk University of Technology, Narutowicza 11=12, Gdansk 80-952, Poland. E-mail:
mak@pg.gda.pl
1362

FORMATION OF N-ALKENYL-MALONAMIDES
1363
acylate amines, alcohols, and thiols.[10] Moreover, carbamoylketenes generated from
1a as with other ketenes could undergo [2 þ 2] cycloaddition with aldimines, leading
to the formation of 1,4-disubstituted-2-oxoazetidine-3-carboxylic acid amides.[11]
Our previous research on the reactivity of 1a was limited to nonenolizable aldi-
mines. However, experiments performed by Emtenas et al.[5] with ketenes genereated
from acyl Meldrum acids and thiazolines with acidic protons in a-position showed
the formation of unexpected 2-pyridinones as a product, whereas the same acyl
ketenes generated in the same way by Yamamoto react with nonenolizable aldimines
giving [2 þ 2] or [4 þ 2] cycloaddition product.[12]
In addition, Trogolo and coworkers have explored the reaction of ketenes
generated from 2,2,6-trimethyl-4H-1,3-dioxin-4-one with enolizable aldimines and
observed exclusively the formation of N-alkenyl-3-ketoamides but no products of
Scheme 1. Possible routes of reaction of carbamoyl ketenes or thiocarbamoylketenes with alkyl-(2-
phenyl-propylidene)-amines.

1364
P. PUNDA AND S. MAKOWIEC
[4 þ 2] or [2 þ 2] cycloadition.[13] The results obtained by Trogolo and Almquist
inspired us to check which product will be formed in the reaction of carba-
moylketenes or thicarbamoylketenes obtained from 5-[hydroxy=mercapto(aryl=
alkylamino)methylene]-2,2-dimethyl-1,3-dioxane-4,6-diones 1a–d during thermal
decomposition in the presence of enolizable aldimines. The analysis of literature data
as well as our own experience with carbamoylketenes suggests the possibility of
creating four different products, among which the formation of N-alkenyl-(thio)-
malonamides or 4-amino-2-pyridinones seems the most likely (Scheme 1).
RESULTS AND DISCUSSION
For a model of enolizable aldimines with well-known equilibrum between
imine and enamine we chose alkyl-(2-phenyl-propylidene)-amines 2, described by
Ahlbrecht et al.,[14] which was also used in experiments performed by Trogolo.
In the first experiment we heat in boiling toluene 1 eq. of 1a with 1 eq.
iso-propyl-(2-phenyl-propylidene)-amine 2a until disappearance of 1a, which takes
approximately 3 h. We choose toluene as a solvent because of the optimal rate of
decomposition of 1a. When using lower boiling solvents, decomposition of 1a takes
up to 28 h, while the higher boiling solvents may result in the formation of by-
products.[11] From the reaction mixture after chromatographic purification we iso-
lated N-isopropyl-N’-phenyl-N-[(1E)-2-phenyl-prop-1-enyl]-malonamide 3aa as the
only product in 37% yield (Scheme 2, Table 1, entry 1). Our previous experience with
trapping carbamoylketenes[10,11] suggested that using an excess of nucleophile may
help increase the yield of reaction. For this purpose we next made two experiments
with the same combination of reagent and in the same conditions but using a greater
ratio of enolizable aldimine, 2 and 4 eq., respectively. In both cases, after purification
we obtained the same 60% yield of 3aa, which indicates that the maximum is
achieved at 2 eq. of aldimine. It should be noted that in all these experiments we
observed the formation in significant amounts of yellow-brown tar, which remained
on the silica gel during flash chromatography. To check the scope and limitation of
the reaction under investigation we decided to perform a series of experiments with
other derivatives of alkyl-(2-phenyl-propylidene)-amines as well as with Meldrum
acid derivatives containing nitrogen 3-chlorophenyl or ethyl group, using 2 eq. of
aldimine per 1 eq. of 1. In all these experiments we obtained N-alkenyl-malonamides
with good to moderate yields (entries 5 and 7–14) with the exception of the reaction
of 1b with 2c, where the product required chromatographic purification three times,
which caused a poor yield (entry 11).
On the other hand, our experience with the reaction of secondary amine with
carbamoylketenes showed that the use of TMS-Cl as an additive to the reaction
Scheme 2. Synthesis of N-alkenyl-malonamides and N-alkenyl-thiomalonamides.

FORMATION OF N-ALKENYL-MALONAMIDES
1365
Table 1. Synthesis of N-alkenyl-malonamides and N-alkenyl-thiomalonamides
Entry
1
R1
X
2
R2
Product 3
Yield (%)
1a
2
a
a
a
a
a
a
a
a
b
b
b
b
c
Ph
Ph
O
O
O
O
O
O
O
O
O
O
O
O
O
O
S
a
a
a
a
b
b
c
i-Pr
i-Pr
3aa
3aa
3aa
3aa
3ab
3ab
3ac
3ad
3ba
3bb
3bc
3bd
3ca
3cb
3da
3db
3dc
3dd
37
60
60
21
47
40
41
48
56
60
22
40
63
57
49
47
55
32
3b
4c
5
Ph
Ph
i-Pr
i-Pr
Ph
Ph
t-Bu
t-Bu
6d
7
Ph
Ph
Et
8
d
a
b
c
PhCH2CH2
i-Pr
t-Bu
9
3-ClC6H4
3-ClC6H4
3-ClC6H4
3-ClC6H4
Et
10
11
12
13
14
15
16
17
18
Et
d
a
b
a
b
c
PhCH2CH2
i-Pr
t-Bu
c
Et
d
d
d
d
CH3
CH3
CH3
CH3
i-Pr
t-Bu
S
S
Et
PhCH2CH2
S
d
a1 eq of 2a was used.
b4 eq of 2a was used.
c1 eq of 2a was used and the reaction mixture was saturated with HCl.
d1.5 eq of TMS-Cl was added.
mixture could strongly increase yield of amide.[10] We refluxed in boiling
toluene 1 eq. of 1a with 2 eq. of 2b in the presence of 1.5 eq. of TMS-Cl, obtaining
malonylamide 3ab with a worse yield than in the experiment without TMS-Cl
(entry 6).
In the further course of research we checked whether the thicarbamoyloketenes
generated from 5-[mercapto(methylamino)methylene]-2,2-dimethyl-1,3-dioxane-4,6-
dione 1d can also acylate aldimines in the same manner. Also, in this case, we noticed
that appropriate N-alkyl-N-[(1E)-2-phenyl-prop-1-enyl]-2-methylthiocarbamoyl-
acetamide 3da–dd are formed with good yield when 1 eq. of 1d is heated to reflux
in toluene in the presence of 2 eq. of 2 (entries 15–18).
As we pointed out at the beginning, one possible route of the reaction of aldi-
mines with carbamoylketenes colud be [2 þ 2] cycloaddition, leading to the forma-
tion of b-lactams. Therefore, we carried out an experiment in conditions most
conducive to the formation of b-lactams, meaning a reaction in boiling toluene
saturated with HCl. However, we again obtain only N-alkenyl-malonamide 3aa
acompanied by lots of tar (entry 4).
The developed one-pot method of synthesis of N-alkenyl-malonamides and
N-alkenyl-thiomalonamides eliminates the need for tedious preparation of 3-arylo=
alkiloamino-3-oxopropanoic acids, 3-arylo=alkiloamino-3-thioxopropanoic acids, or
their chlorides to obtain suitable N-alkenyl-malonamides and N-alkenyl-thiomalo-
namides. The obtained N-alkenyl-malonamides, as with other known N-alkenyl-
amides, should be a valuable substrate for various chemical transformation.[15] Their
application in synthesis is under investigation in our laboratory.

1366
P. PUNDA AND S. MAKOWIEC
EXPERIMENTAL
Isopropyl-(2-phenyl-propylidene)-amine (2a) (701 mg, 4 mmol) was added to a
solution of 5-[hydroxy(phenylamino)methylene]-2,2-dimethyl-1,3-dioxane-4,6-dione
(1a) (526 mg, 2 mmol) in anhydrous toluene (10 ml), which was stirred under reflux
for 3 h. After completion of the reaction, the solvent was removed under vacuum,
and the residue was purified by flash column chromatography (EtOAc–hexanes,
1
1:2) to give 3aa (400 mg, 60%);. H NMR (200 MHz, CDCl3): d ¼ 1.20 (d, J ¼ 6.7 Hz,
6 H,), 2.00 (d, J ¼ 1.25 Hz, 3 H), 3.45 (s, 2 H), 4.96 (hept, J ¼ 6.7 Hz, 1 H), 6.28 (d,
J ¼ 1.25 Hz, 1 H), 7.1 (t, J ¼ 7.3 Hz, 1 H), 7.26–7.49 (m, 7 H), 7.6 (d, J ¼ 1.25 Hz,
2 H), 10.23 (s, 1 H); 13C NMR (50 MHz, CDCl3): d ¼ 16.6, 20.3, 41.7, 47.6, 120.5,
121.3, 124.6, 126.7, 129.1, 129.2, 129.4, 138.4, 139.7, 142.8, 164.9, 168.8; HRMS
(ESI): m=z [M þ Na]þ calcd. for C21H24N2NaO2: 359.1735; found: 359.1745.
ACKNOWLEDGMENT
Scientific work was financed from Funds for Science in 2010–2011 as research
project NN204 088338.
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