TMSCL as a rate-accelerating additive in acylations of amines with 5-(α-AMINO-α′-Hydroxy)methylene meldrum acids

Article abstract of DOI:10.1080/00397911.2010.533805

Aspects are presented of the acylation of amines, alcohols, and thiols with 5-(α-amino-α′-hydroxy)methylene Meldrum acids. We placed special emphasis on the acylation reaction of secondary amines with 5-(α-amino-α′-hydroxy)methylene Meldrum acids, which, because of their basicity, caused problems concerning salt formation with a Meldrum acid derivative. We found that secondary amines, which react at the slowest rate and give a poor yield with 5-(α-amino-α′-hydroxy)methylene Meldrum's acid, react quickly and with high yields with the same reagent in the presence 1 to 3 equivalents of TMSCl. Acylation with this derivative of Meldrum acid was optimized for such factors as reaction temperature, solvent polarity, and acidity of the environment. We have prepared a wide range of nonsymmetrical malononic acid diamids, esters, and thioesters of malonamic acid. Taylor & Francis Group, LLC.

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TMSCl as a Rate-Accelerating Additive
in Acylations of Amines with 5-(α-
Amino-α′-hydroxy)methylene Meldrum
Acids
Karolina Janikowska a & Sławomir Makowiec a
a Department of Organic Chemistry, Faculty of Chemistry, Gdansk
University of Technology, Gdańsk, Poland
Accepted author version posted online: 06 Sep 2011.Version of
record first published: 16 Dec 2011.
To cite this article: Karolina Janikowska & Sławomir Makowiec (2012): TMSCl as a Rate-Accelerating
Additive in Acylations of Amines with 5-(α-Amino-α′-hydroxy)methylene Meldrum Acids, Synthetic
Communications: An International Journal for Rapid Communication of Synthetic Organic Chemistry,
42:7, 975-988
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Synthetic Communications1, 42: 975–988, 2012
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2010.533805
TMSCL AS A RATE-ACCELERATING ADDITIVE IN
ACYLATIONS OF AMINES WITH 5-(a-AMINO-
a’-HYDROXY)METHYLENE MELDRUM ACIDS
Karolina Janikowska and Sławomir Makowiec
Department of Organic Chemistry, Faculty of Chemistry, Gdansk University
´
of Technology, Gdansk, Poland
GRAPHICAL ABSTRACT
Abstract Aspects are presented of the acylation of amines, alcohols, and thiols with 5-(a-
amino-a0-hydroxy)methylene Meldrum acids. We placed special emphasis on the acylation
reaction of secondary amines with 5-(a-amino-a0-hydroxy)methylene Meldrum acids,
which, because of their basicity, caused problems concerning salt formation with a Meldrum
acid derivative. We found that secondary amines, which react at the slowest rate and give a
poor yield with 5-(a-amino-a0-hydroxy)methylene Meldrum’s acid, react quickly and with
high yields with the same reagent in the presence 1 to 3 equivalents of TMSCl. Acylation
with this derivative of Meldrum acid was optimized for such factors as reaction tempera-
ture, solvent polarity, and acidity of the environment. We have prepared a wide range of
nonsymmetrical malononic acid diamids, esters, and thioesters of malonamic acid.
Keywords Acylation; amides; decarboxylation; enols; ketens
INTRODUCTION
Derivatives of malonic acid find broad scope of application in various fields.
Among other malonic acid diamids, the structural fragment might be find in
retro-inverso-modified pseudopeptides,[1] small molecules of gene regulation,[2]
low molecular organogelators,[3] or neuromediator prodrugs[4] and macrocyclic
Received August 24, 2010.
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@chem.pg.gda.pl
975

976
K. JANIKOWSKA AND S. MAKOWIEC
compounds,[5] whereas esters of malonamic acid have anti-inflammatory and anal-
gesic effects,[6] anti-ischemic properties,[7] and even ligands for thyroid receptors.[8]
Whereas synthesis of symmetrical malonic acid derivatives is a trivial labora-
tory procedure[9] synthesis of nonsymmetrical malonamids or esters of malonamic
acid require several steps to obtain the final product. The selective classical
procedure[10] for preparation of nonsymmetrical malondiamids starting from diethyl
malonate require half-hydrolysis, activation of the free carboxyl group, coupling
with amine, hydrolysis of ester, another activation, and coupling with a second
amine. Even using commercially available alkyl malonyl chloride, it still takes at
least four steps to prepare a simple compound. Of course, such a synthetic problem
with malonic acid is related to the impossibility of using anhydride in this case.
In the chemical literature over the past few years, several methods have been
described that bypass this long procedure. Lopez-Avendano et al.[11] proposed the
synthesis of malonamic derivatives based on the reaction of a b-amidothioester with
various nucleophiles. They obtain good results, and the b-amidothioester could be
prepared quickly as a single-step reaction from isocyanates and commercially avail-
able tert-butyl acetothiocetate; however, the problem is the cost of tert-butyl
acetothiocetate.
Another selective procedure[12,13] is based on the use of Meldrum acid as an
equivalent of malonic anhydride for the rapid preparation of malonamic acid deri-
vatives, coupled in the next step with another amine under typical conditions. How-
ever, while this procedure works well with amino acid esters, with other amines the
reaction time is as long as 50 to 70 h,[13] and in some cases it fails to work. We were
not able to obtain N,N-dietylmalonamic acid by this procedure.
Apart from these methods, sometimes unselective coupling of malonic acid
with amine or amino acid is used, followed by separation of malonamic acid deriva-
tive from unreacted malonic acid and diamid.[14]
5-(a-Amino-a0-hydroxy)methylene Meldrum acid, similar to classical
acyl-Meldrum[15] acids, are able to generate ketenes upon thermal decomposition.
This property underlies the method developed by Lee et al.[16] in which 5-(a-
amino-a0-hydroxy)methylene Meldrum acid reacts in boiling solvent with amine in
a one-step process, giving the desired unsymmetrical malonamid.
RESULTS AND DISCUSSION
In our laboratory, we needed unsymmetrical malonoamides of secondary
amines. Taking into consideration of all the known methods, we decided to adopt
the method of Lee et al.[16] as the most promising. However, when we tried to pre-
pare N-phenyl-3-oxo-3-piperidin-1-yl-propionamide (3aa) in the reaction of 5-(a-
phenylamino-a0-hydroxy)methylene Meldrum acid (1a) with piperidine (2a) in boling
ethylbenzene, we obtained the desired amide with only 34% yield after 20 h of reac-
tion (entry 1, Table 1). Similarly, reaction of 1a with diethyl amine (2b) gave amide
(3ab) with poor yield (entry 4, Table 1). We repeated these reaction scrupulously
again to eliminate any possible experimental errors; however, we still obtained these
amides with poor yields. To check if we committed an unknown error, we decided to
perform experiments on models very close to these presented by Lee et al. We carried
out four of experiments in which 1a was heated in boiling ethylbenzene respectively

ACYLATIONS WITH CARBAMOYL MELDRUM ACIDS
977
Table 1. Acylation of amines with 5-(a-amino-a0-hydroxy)methylene Meldrum acid (1)
Entry
Malonamide 3
TMSCl eq
Solvent
Time (h)
Yield of 3 (%)
1
2b
3c
3aa
3aa
3aa
3ab
3ab
3ac
3ad
3ae
3ae
3ae
3af
0
0
E
E
E
E
E
E
E
D
C
E
E
E
E
E
A
D
A
B
B
B
B
B
B
B
B
E
E
E
B
D
D
20
2
34
26
42
50
43
80
80
70
75
74
77
78
82
85
96
90
n.r
n.r
n.r
93
90
34
73
86
68
91
75
71
85
70
75
0
1,5
1
4
5c
0
0
1
6
0
1
7
0
1
8
0
23
23
1
9
0
10
11
12
13
14
15
16
17
18
19d
20
21
22
23
24
25
26
27
28
29
30
31
0
0
1
3ag
3aa
3aa
3aa
3aa
3aa
3aa
3aa
3ab
3ac
3ae
3ae
3af
0
2,5
1,5
1
1
3
1,5
1,5
0
2,5
2,5
2,5
2,5
2,5
3
0
0
1,5
1,5
8
4
3
3
7
3
2
3ag
3bc
3be
3bg
3bc
3be
3bg
3
21
1
0
0
1,5
1
0
1,5
3
24
23
5
3
aEquimolar amount of reagent.
b2,5 eq of TFA was added.
cReaction mixture was saturated with HCl.
dExcess of 1a was used.
Solvents A ¼ DCM; B ¼ benzene; C ¼ dioxane, D ¼ toluene, E ¼ ethylbenzene.
with 4-methylaniline, benzyl amine, tert-butylamine, and isobutylamine. Surpris-
ingly, in these experiments we obtain amides 3ad, 3ae, 3af, and 3ag with good yields
(entries 7, 10, 11, and 12, Table 1). We paid more attention to the reaction of benzyl
amine with 1a because Lee et al. reported that 4-metylbenzyl amine was required for
the reaction with 5-(a-amino-a0-hydroxy)methylene Meldrum acid and harsh con-
ditions (refluxing for an hour in boiling o-dichlorobenzene); otherwise they observed
only formation of salt of amine with 1.
When we reacted 2 eq of benzyl amine with 1 eq of 1a in toluene, the prolonged
time of reaction was required and also we observed formation of undissolved salt,
which we suspected was a cause of the slow reaction (entry 8, Table 1). Therefore,
the next experiment we performed in boiling dioxane; however, the better ability
of dioxane to dissolve this salt did not affect the reaction time (entry 9, Table 1).

978
K. JANIKOWSKA AND S. MAKOWIEC
As one can see, there is a rather obvious correlation between the basicity of
amines and the yield of malonamides (entries 1, 4 versus 7, 10, 11, 12, Table 1).
On the other hand, in experiments performed by Lee et al. the yields were high
and the reaction times short, but only weakly basic aromatic amines with electron
withdrawing group (EWG) were used. When we attempted to use stronger bases
as secondary aliphatic amines, the equilibrium in the formation of salt with 1a
shifted in favor of salt product, resulting in much lower yield of nonsymetrical mal-
onamids and very long reaction time. This result should not be surprising, and taking
into account the work of Xu et al.[15a] a correlation between concentration of free
acid form of Meldrum derivative and rate of decomposition has been demonstrated.
We tried to improve the yield of reactions of secondary amines with 1a by cre-
ating a more acidic condition for the reaction in accordance with the observations
described by Xu et al.[15a] for acyl Meldrum acids.
The addition of 2.5 eq of trifluoroacetic acid (TFA) to the reaction mixture pre-
pared from 1 eq 1a and 2 eq of piperidine (2e) in ethylbenzene accelerated the rate of
decomposition of 1a, although the yield of amide (3aa) remained unacceptable (entry
2, Table 1). The application of gaseous HCl to the reaction of piperidine with 1a or
to the reaction of diethylamine with 1a resulted in a yield that was still comparable to
the reaction without any additives (entries 3 and 5, Table 1).
Finally, we checked whether the addition of TMSCl influenced the reaction time
or yields, because TMSCl may be at least a convenient source of HCl (Scheme 1). Sur-
prisingly, we obtained significantly better yields when reaction of piperidine with 1a in
boiling ethylbenzene was in the presence of 1 or 3 eq of TMSCl (entries 13 and 14,
Table 1). As the next step, we repeated this reaction in lower boiling solvents: toluene
and DCM in the presence of 1.5 eq of TMSCl and gave almost quantative yield within
2.5 h. It should be noted that for reaction in DCM the temperature was almost 60 ꢀC
lower than for the reaction without TMSCl (entries 15 and 16, Table 1).
Similarly, the reactions of diethylamine and morpholine with 1a were strongly
accelerated in the presence of TMSCl (entries 20 and 21, Table 1). Reactions of
Scheme 1. Acylation of amines with 5-(a-amino-a0-hydroxy)methylene Meldrum acid (1).

ACYLATIONS WITH CARBAMOYL MELDRUM ACIDS
979
primary amines with 1a were also accelerated; however, the use of only 1.5 eq of
TMSCl gave a reaction of insufficient acceleration, so 3 eq of TMSCl and longer
reaction times are required than for secondary amines. When the larger amounts
of TMSCl were used, the yield dropped (entries 22–25, Table 1).
To confirm our assumption about the accelerating influence of TMSCl, we car-
ried out two experiments in which 1a was heated with 2 eq of piperidine in low-boiling
solvents, DCM or benzene without TMSCl, and in neither reactions did we observe
the formation of malonamide in the specified time (entries 17 and 18, Table 1). We also
checked to see whether the use of excess of 1a to ensure an acidic condition could
improve the yield of this reaction, but when we used 1.2 eq of 1a per 1 eq of piperidine
after 2.5 h in boiling benzene, no reaction was observed (entry 19, Table 1).
The influence of TMSCl was less significant when 1b was used, and for the
reactions of 1b with benzyl amine or with morpholine we did not observe any accel-
eration of the reaction by TMSCl (entries 29 and 30, Table 1).
Generally, it can be stated that TMSCl significantly accelerates the reaction
when a more acidic Meldrum derivative (1a) and a more basic secondary amine were
used. At this time, we cannot explain the mechanism of reaction in which TMSCl
participates with any certainty, but the influence of liberated HCl as a reason for
the acceleration could be excluded if saturation with HCl does not change the yield
(entries 3 and 5, Table 1).
In subsequent studies, we checked whether 1 can acylate alcohols and thiols
(Scheme 2). In the first experiment, we use boiling ethylbenzene to heat 1a with 2
eq of benzyl alcohol for 3.5 h, obtaining N-phenyl malonamic acid benzyl ester with
only 50% yield and N,N0-diphenyl malonamid with 50% yield. The formation of
N,N0-diphenyl malonamid was also observed when 1a was heated alone in ethylben-
zene. It appears that, in this case, to ensure a clean reaction it is necessary to use a
large excess of alcohol. Use of 20-fold excess of ethyl or allyl alcohol gave malonamic
acid esters with good to excellent yields. More importantly, weakly nucleophilic tert-
butyl alcohol gave malonamic acid tert-butyl esters with good yields (entries 3 and 6,
Table 2). In a similar way, we examined the reaction of 2 eq of thiols with 1a and
obtained malonamic acid thioesters (entries 7 and 8, Table 2).
Scheme 2. Acylation of alcohols and thiols with 5-(a-amino-a0-hydroxy)methylene Meldrum acid (1).

980
K. JANIKOWSKA AND S. MAKOWIEC
Table 2. Acylation of alcohols and thiols with 5-(a-amino-a0-hydroxy)methylene Meldrum acid (1)
Entry
Malonamic ester 5
TMSCl (eq)
Solvent
Time (h)
Yield of 5 (%)
1
2
5aa
5ab
5ac
5ba
5bb
5cc
5ad
5ae
5ae
5aa
5ac
0
0
0
0
0
0
0
0
0
2
2
E
E
E
E
E
E
E
D
F
E
E
20
2,5
24
24
4
81
82
68
96
90
94
31
45
63
79
63
3
4
5
6
24
2
7
8
2,5
4
9
10
11
23
23
Note. Solvents D, toluene; E, ethylbenzene; F, acetonitrile.
In the case of ethyl and tert-butyl alcohols, the boiling point of a mixture of
solvents was approximately 80 ꢀC, which extends the reaction time (entries 1, 3, 4,
and 6, Table 2). Based on our experience in reactions between amines and 1, we
checked whether the addition of TMSCl accelerates the process. However, two
experiments with the addition of 2 eq of TMSCl (entries 10 and 11, Table 2) showed
that reaction of alcohols with 1a is not accelerated by TMSCl.
CONCLUSION
A method of preparing malonamids was developed to circumvent the problem
of the formation of unreactive salt between secondary amines and Meldrum acid
derivative (1a). The addition of TMSCl allows the process to produce yields in sig-
nificantly milder condition than was possible before.[16] In addition, we have
expanded the scope of use of 5-(a-amino-a0-hydroxy)methylene Meldrum acid to
include preparation of malonamic acid esters and thioesters.
EXPERIMENTAL
Reagents were purchased from Sigma-Aldrich. Benzene, toluene, ethylbenzene,
and dioxane was distilled from potassium under argon. Dichloromethane (DCM)
was distilled from P2O5. Acetonitrile was distilled from CaH2 under argon. Analyti-
cal thin-layer chromatography (TLC) was performed on aluminum sheets of silica
gel UV-254 Merck. Flash chromatography was carried out using silica gel (40–63
microns) Zeochem. 1H and 13C NMR were recorded on Varian Gemini 200 and Var-
ian Unity Plus 500 instruments.
5-(a-Phenylamino-a’-hydroxy)methylene Meldrum Acid (1a)
Compound 1a was prepared according to literature procedure[17] and crystal-
lized twice from AcOEt. Yield 89%, mp 105–107 ꢀC (lit.[17] mp 109–110 ꢀC). Spectral
data are in agreement with literature data.

ACYLATIONS WITH CARBAMOYL MELDRUM ACIDS
981
5-(a-Cyclohexylamino-a’-hydroxy)methylene Meldrum Acid (1b)
Et3N (1.4 ml, 10 mmol) was added to a solution of Meldrum’s acid (0.72 g,
5 mmol) in dry DMF (5 ml) in a glass ampoule. Cyclohexylisocyanate (0.751 g,
6 mmol) was added, and the ampoule was sealed. The ampoule was placed in the
bath for 20 h at 40 ꢀC. The solution was poured into a 2 M HCl (30 ml) mixture of
ice and water. The solid precipitate was filtered and washed with cold water. The pre-
cipitate was dissolved in ethyl acetate (30 ml) and dried with MgSO4, and after cool-
ing the solution the precipitate of DCU was removed by filtration. The solvent was
removed under reduced pressure. Crystallization from AcOEt=hexane gave 0.795 g
1
(60% yield), mp 103–104.5 ꢀC. H NMR (500 MHz, CDCl3): d 1.28 (m, 1H), 1.40
(m, 4H), 1.64 (m, 1H), 1.73 (m, 6H), 1.78 (m, 2H), 1.98 (m, 2H), 3.81 (m, 1H),
9.22 (s, 1H), 14.91 (s, 1H). 13C NMR (125 MHz, CDCl3): d 24.59, 25.42, 26.51,
32.73, 50.09, 73.02, 104.77, 164.60, 169.42, 170.65. HRMS (ESI): m=z [M þ Na]þ
calcd. for C13H19NO5: 269.1262; found: 269.1266.
5-(a-Ethylamino-a’-hydroxy)methylene Meldrum Acid (1c)
Et3N (1.4 ml, 10 mmol) was added to a solution of Meldrum’s acid (0.72 g,
5 mmol) in dry DMF (5 ml) in a glass ampoule. Ethylisocyanate (0.426 g, 6 mmol)
was added, and the ampoule was sealed. The ampoule was placed in the bath for
10 h at 40 ꢀC. The solution was poured into a 2 M HCl (30 ml) mixture of ice and
water. The solid precipitate was filtered and washed with cold water. The precipitate
was dissolved in ethyl acetate (30 ml) and dried with MgSO4. The solvent was
removed under reduced pressure. Crystallization from AcOEt=hexane gave 0.706 g
1
(65% yield), mp 72–74 ꢀC. H NMR (500 MHz, CDCl3): d 1.30 (t, 3H, J ¼ 7.3 Hz),
1.74 (s, 6H), 3.49 (m, 2H), 9.25 (brs, 1H), 14.98 (s, 1H). 13C NMR (125 MHz,
CDCl3): d 14.7, 26.4, 35.8, 104.2, 164.1. HRMS (ESI): m=z [M þ Na]þ calcd. for
C9H13NO5: 215.0794; found: 215.0792.
General Procedure for Acylation of Amines with 1
A solution of 1 (2 mmol), the corresponding amine (2) (4 mmol), and trimethyl-
chlorosilane (0–8 eq) in anhydrous solvent (10 ml) was stirred under reflux. Amounts
of TMSCl, solvent, and reaction time are specified in Table 1. After completion of
the reaction, the solvent was removed under vacuum, and the residue was purified.
N-Phenyl-3-oxo-3-piperidin-1-yl-propionamide (3aa)
Purification by flash column chromatography (AcOEt=hex, 5:2), mp
1
115–117 ꢀC; H NMR (500 MHz, CDCl3): d 1.61–1.70 (m, 6 H, CH2), 3.49 (s, 2H,
CH2), 3.52–3.65 (m, 4H, CH2), 7.12 (t, J ¼ 7.32 Hz, 1Harom), 7.34 (t, J ¼ 7.81 Hz,
2Harom), 7.60 (d, J ¼ 7.81 Hz, 2Harom), 10.18 (s, 1H, NH). 13C NMR (125 MHz,
CDCl3): d 24.5, 25.8, 26.7, 40.1, 43.6, 47.5, 120.3, 124.5, 129.2, 138.1, 164.6, 167.0.
HRMS (ESI): m=z [M þ Na]þ calcd. for C14H18N2O2: 246.1368; found: 246.1381.

982
K. JANIKOWSKA AND S. MAKOWIEC
N,N-Diethyl-N’-phenyl-malonamide (3ab)
Purification by flash column chromatography (AcOEt=hex, 3:2), oil; 1H NMR
(500 MHz, CDCl3): d 1.05–1.11 (m, 6H, CH3), 3.25–3.34 (m, 4H, CH2), 3.39 (s, 2H,
CH2), 6.97–7.0 (m, 1Harom), 7.18–7.21 (m, 2Harom), 7.50 (d, J ¼ 7.8 Hz, 2Harom),
10.25 (s, 1H, NH). 13C NMR (125 MHz, CDCl3): d 12.8, 14.1, 39.9, 40.9, 42.6,
119.8, 124.0, 128.7, 137.7, 164.3, 167.8. HRMS (ESI): m=z [M þ Na]þ calcd. for
C13H18N2O2: 234.1368; found: 234.1346.
N-Phenyl-3-morpholin-4-yl-3-oxo-propionamide (3ac)
Crystallization from AcOEt=hex, mp 126–130 ꢀC; 1H NMR (500 MHz,
CDCl3): d 3.50 (s, 2H, CH2), 3.61–3.63 (m, 2H, CH2), 3.71–3.74 (m, 6H, CH2),
7.13 (t, J ¼ 7.32 Hz, 1Harom), 7.34 (dd, J ¼ 7.32 Hz, J ¼ 7.81 Hz, 2Harom), 7.58 (d,
J ¼ 7.81 Hz, 2Harom), 9.85 (s, 1H, NH). 13C NMR (125 MHz, CDCl3): d ¼ 40.5,
42.6, 46.8, 66.8, 66.9, 120.3, 124.7, 129.2, 137.9, 164.2, 167.3. HRMS (ESI): m=z
[M þ Na]þ calcd. for C13H16N2O3: 248.1160; found: 248.1145.
N-Phenyl-N’-p-tolyl-malonamide (3ad)
1
Crystallization from AcOEt=hex, mp 223–225 ꢀC; H NMR (500 MHz, acet-
one): d ¼ 2.08 (s, 3H, CH3), 3.55 (s, 2H, CH2), 7.11 (t, J ¼ 7.32 Hz, 1Harom), 7.15
(d, J ¼ 8.3 Hz, 2Harom), 7.35 (t, J ¼ 7.82 Hz, 2Harom), 7.58 (d, J ¼ 8.3 Hz, 2Harom),
7.70 (d, J ¼ 8.3 Hz, 2Harom), 9.61 (s, 1H, NH), 9.70 (s, 1H, NH). 13C NMR
(125 MHz, acetone): d 20.2, 45.0, 119.6, 119.7, 123.9, 129.0, 129.4, 133.3, 136.6,
139.1, 165.4, 165.6. HRMS (ESI): m=z [M þ Na]þ calcd. for C16H16N2O2:
268.1212; found: 268.1191.
N-Benzyl-N’-phenyl-malonamide (3ae)
Crystallization from AcOEt=hex, mp 146–149 ꢀC; alternatively in the cases of
entries 22 and 23 in Table 1 the residue was purified by flash column chromato-
1
graphy (AcOEt=hex, 1:1). H NMR (500 MHz, CDCl3): d 3.44 (s, 2H, CH2), 4.48
(d, J ¼ 5.38 Hz, 2H, CH2), 7.15 (t, J ¼ 7.32, 1Harom), 7.29–7.59 (m, 8H, Harom
NH), 7.56–7.58 (m, 2Harom), 9.55 (s, 1H, NH). 13C NMR (125 MHz, CDCl3): d
43.9, 44.1, 120.4, 124.9, 128.0, 129.0, 129.1, 129.2, 137.6, 137.8, 165.4, 167.9. HRMS
(ESI): m=z [M þ Na]þ calcd. for C16H16N2O2: 268.1211; found: 268.1212.
N-tert-Butyl-N’-phenyl-malonamide (3af)
Crystallization from AcOEt=hex, mp 168–171 ꢀC; 1H NMR (500 MHz,
CDCl3): d 1.41 (s, 9H, CH3 (t-Bu)), 3.37 (s, 2H, CH2), 6.95 (s, 1H, NH), 7.13 (t,
J ¼ 7.32 Hz, 1 Harom), 7.24 (dd, J ¼ 7.32 Hz, J ¼ 8.3 Hz, 2Harom), 7.62 (d, J ¼ 8.3 Hz,
2Harom), 9.81 (s, 1H, NH). 13C NMR (125 MHz, CDCl3): d 28.8, 44.9, 52.1, 120.5,
124.7, 129.2, 138.0, 166.2, 167.3. HRMS (ESI): m=z [M þ Na]þ calcd. for
C13H18N2O2: 234.1368; found: 234.1340.

ACYLATIONS WITH CARBAMOYL MELDRUM ACIDS
983
N-iso-Butyl-N’-phenyl-malonamide (3ag)
Crystallization from AcOEt=hex, mp 147–148 ꢀC; alternatively, in the case of
entry 25 in Table 1 the residue was purified by flash column chromatography
1
(AcOEt=hex, 1:1). H NMR (500 MHz, CDCl3): d 0.95 (d, J ¼ 6.35 Hz, 6H, CH3),
1.84 (n, J ¼ 6.35 Hz, J ¼ 6.84 Hz, 1H, CH), 3.15 (dd, J ¼ 6.84 Hz, J ¼ 6.35 Hz, 2H,
CH2) 3.46 (s, 2H, CH2), 7.14 (t, J ¼ 7.32 Hz, 1Harom), 7.27 (s, 1H, NH), 7.34 (t,
J ¼ 7.81 Hz, 2Harom), 7.60 (d, J ¼ 7.81 Hz, 2Harom), 9.72 (s, 1H, NH). 13C NMR
(125 MHz, CDCl3): d 20.4, 28.6, 44.1, 47.4, 47.5, 120.4, 124.8, 129.2, 137.9, 166.0,
168.1. HRMS (ESI): m=z [M þ Na]þ calcd. for C13H18N2O2: 234.1368; found:
234.1392.
N-Cyclohexyl-3-morpholin-4-yl-3-oxo-propionamide (3bc)
Crystallization from AcOEt=hex, mp 101–103 ꢀC; 1H NMR (500 MHz,
CDCl3): d 1.17–1.23 (m, 3H), 1.33–1.40 (m, 2H), 1.59–1.62 (m, 1H), 1.69–1.72 (m,
2H), 1.88–1.90 (m, 2H), 3.31 (s, 2H, CH2), 3.57–3.59 (m, 2H), 3.64–3.65 (m, 2H),
3.67–3.70 (m, 4H), 3.75–3.80 (m, 1H), 7.25 (s, 1H, NH). 13C NMR (125 MHz,
CDCl3): d 24.9, 25.7, 33.0, 41.0, 42.5, 46.8, 48.5, 66.9, 164.5, 167.8. HRMS (ESI):
m=z [M þ Na]þ calcd. for C13H22N2O3: 254.1630; found: 254.1594.
N-Cyclohexyl-N’-benzyl-malonamide (3be)
Crystallization from AcOEt=hex, mp 136–138 ꢀC; alternatively, in the case of
entry 30 in Table 1 the residue was purified by flash column chromatography
1
(AcOEt). H NMR (500 MHz, CDCl3): d 1.18–1.24 (m, 3H), 1.32–1.39 (m, 2H),
1.60–1.63 (m, 1H), 1.71–1.74 (m, 2H), 1.87–1.90 (m, 2H), 3.22 (s, 2H, CH2), 4.43
(d, J ¼ 5.37 Hz, 2H, CH2), 7.12 (s, 1H, NH), 7.27–7.35 (m, 5Harom), 7.77 (s, 1H,
NH). 13C NMR (125 MHz, CDCl3): d 25.2, 25.9, 33.1, 43.6, 43.9, 48.9. 127.8,
128.0, 129.0, 138.4, 167.0, 168.1. HRMS (ESI): m=z [M þ Na]þ calcd. for
C16H22N2O2: 274.1680; found: 274.1657.
N-Cyclohexyl-N’-isobutyl-malonamide (3bg)
Crystallization from AcOEt=hex, mp 115–116 ꢀC; alternatively in the case of
entry 31 in Table 1 the residue was purified by flash column chromatography
(AcOEt). 1H NMR (200 MHz, CDCl3): d 0.91 (d, J ¼ 6.84 Hz, 6H, CH3),
1.09–1.38 (m, 5H, CH2), 1.55–1.90 (m, 6H, CH2, CH), 3.08 (dd, J ¼ 6.31 Hz,
J ¼ 6.51 Hz, 2H, CH2), 3.16 (s, 2H, CH2), 3.71–3.76 (m, 1H, CH), 6.93 (s, 1H,
NH), 7.26 (s, 1H, NH). 13C NMR (50 MHz, CDCl3): d ¼ 20.6, 25.2, 25.9, 28.9,
33.2, 43.7, 47.4, 49.0, 163.5, 164.1. HRMS (ESI): m=z [M þ Na]þ calcd. for
C13H24N2O2: 240.1837; found: 240.1796.
General Procedure for Acylation of Alcohols with 1
A solution of 1 (1 mmol), with corresponding alcohol 4 (20 mmol) and tri-
methylchlorosilane (0–2 eq) in anhydrous solvent (10 ml), was stirred under reflux.

984
K. JANIKOWSKA AND S. MAKOWIEC
Amount of TMSCl, solvent, and reaction time are specified in Table 2. After
completion of reaction, the solvent was removed under vacuum, and the residue
was purified.
N-Phenyl-malonamic Acid Ethyl Ester (5aa)
Purification by flash column chromatography (AcOEt=hex, 1:2), oil; 1H NMR
(200 MHz, CDCl3): d 1.32 (t, J ¼ 7.20 Hz, 3H, CH3), 3.47 (s, 2H, CH2), 4.27 (q,
J ¼ 7.20 Hz, 2H, CH2), 7.10–7.17 (m, 1Harom), 7.26–7.37 (m, 2Harom), 7.54–7.58
(m, 2Harom), 9.24 (s, 1H, NH). 13C NMR (50 MHz, CDCl3): d 14.1, 41.5, 61.9,
120.1, 124.6, 129.0, 137.5, 162.9, 170.1. HRMS (ESI): m=z [M þ Na]þ calcd. for
C11H13NO3: 207.0894; found: 207.0882.
N-Phenyl-malonamic Acid Allyl Ester (5ab)
Purification by flash column chromatography (AcOEt=hex, 2:5), oil; 1H NMR
(500 MHz, CDCl3): d 3.51 (s, 2H, CH2), 4.66 (d, J ¼ 5.86 Hz, 2H), 5.27 (dd,
J2 ¼ 9.77 Hz, J4 ¼ 1.0 Hz, 1Hvin), 5.35 (dd, J2 ¼ 15.63 Hz, J4 ¼ 1.46 Hz, 1Hvin),
5.87–5.95 (m, J ¼ 5.86 Hz, J ¼ 1.0 Hz, J ¼ 9.77 Hz, J ¼ 15.63 Hz, 1Hvin), 7.12 (t,
J ¼ 7.32 Hz, 1Harom), 7.31 (t, J ¼ 7.32 Hz, 2Harom), 7.56 (d, J ¼ 7.33 Hz, 2Harom),
9.29 (s, 1H, NH). 13C NMR (125 MHz, CDCl3): d 42.5, 66.5, 119.4, 120.5, 124.9,
129.2, 131.5, 137.8, 163.9, 169.1. HRMS (ESI): m=z [M þNa]þ calcd. for
C12H13NO3: 219.0894; found: 219.0915.
N-Phenyl-malonamic Acid tert-Butyl Ester (5ac)
Purification by flash column chromatography (AcOEt=hex, 1:4), mp 75–78 ꢀC;
1H NMR (500 MHz, CDCl3): d 1.54 (s, 9H), 3.41 (s, 2H, CH2), 7.15 (t, J ¼ 7.32 Hz,
1Harom), 7.29 (s, 1Harom), 7.36 (t, J ¼ 7.81 Hz, 2Harom), 7.60 (d, J ¼ 8.3 Hz, 2Harom),
9.36 (s, 1H, NH). 13C NMR (50 MHz, CDCl3): d 28.5, 43.2, 83.5, 120.6, 124.9, 129.4,
138.1, 164.3, 169.5. HRMS (ESI): m=z [M þ Na]þ calcd. for C13H17NO3: 235.1207;
found: 235.1204.
N-Cyclohexyl-malonamic Acid Ethyl Ester (5ba)
Crystallization from AcOEt=hex, mp 69–70 ꢀC; 1H NMR (500 MHz, CDCl3): d
1.21–1.44 (m, 8H), 1.61–1.73 (m, 3H), 1.91–1.94 (m, 2H), 3.30 (s, 2H, CH2),
3.80–3.85 (m, 1H), 4.22 (q, J ¼ 7.30 Hz, 2H, CH2), 7.05 (s, 1H, NH). 13C NMR
(125 MHz, CDCl3): d 14.0, 24.7, 25.5, 32.8, 41.3, 48.2, 61.4, 163.9, 169.7. HRMS
(ESI): m=z [M þ Na]þ calcd. for C11H19NO3: 213.1365; found: 213.1331.
N-Cyclohexyl-malonamic Acid Allyl Ester (5bb)
Crystallization from AcOEt=hex, mp 45–48 ꢀC, 1H NMR (500 MHz, CDCl3): d
1.20–1.29 (m, 3H), 1.34–1.43 (m, 2H), 1.60–1.64 (m, 1H), 1.70–1.74 (m, 2H),
1.90–1.93 (m, 2H), 3.34 (s, 2H, CH2), 3.79–3.86 (m, 1H), 4.65 (d, J ¼ 5.86 Hz, 2H),
5.30 (dd, J2 ¼ 9.28 Hz, J4 ¼ 1.0 Hz, 1Hvin), 5.36 (dd, J2 ¼ 16.11 Hz, J4 ¼ 1.46 Hz,

ACYLATIONS WITH CARBAMOYL MELDRUM ACIDS
985
1Hvin), 5.89–5.97 (m, J ¼ 5.86 Hz, J ¼ 1.0 Hz, J ¼ 9.28 Hz, J ¼ 16.1 Hz, 1Hvin), 6.98
(s, 1H, NH). 13C NMR (50 MHz, CDCl3): d 24.9, 25.8, 33.1, 48.4, 66.3, 119.4,
131.6, 163.9, 169.7. HRMS (ESI): m=z [M þ Na]þ calcd. for C12H19NO3:
225.1365; found: 225.1367.
N-Ethyl-malonamic Acid tert-Butyl Ester (5cc)
Purification by flash column chromatography (AcOEt=hex, 1:2), oil; 1H NMR
(500 MHz, CDCl3): d 1.19 (t, J ¼ 7.32 Hz, 3H, CH3), 1.49 (s, 9H), 3.23 (s, 2H, CH2),
3.33–3.36 (m, 2H, CH2), 7.29 (s, 1H, NH). 13C NMR (50 MHz, CDCl3): d 15.1, 28.5,
34.8, 42.5, 82.9, 165.8, 169.5. HRMS (ESI): m=z [M þ Na]þ calcd. for C9H17NO3:
187.1207; found: 187.1170.
General Procedure for Acylation of Thiols with 1
A solution of 1 (1 mmol), with corresponding thiol (4) (2 mmol) and solvent
(5 ml), was stirred under reflux. Solvent and reaction time are specified in Table 2.
After completion of the reaction, the solvent was removed under vacuum and the
residue was purified.
N-Phenyl-thiomalonamic Acid S-Phenyl Ester (5ad)
Purification by flash column chromatography (AcOEt=hex, 1:3), yellow solid,
1
mp 81–83 ꢀC; H NMR (200 MHz, CDCl3): d 3.81 (s, 2H, CH2), 7.08–7.53 (m,
10Harom), 8.70 (s, 1H, NH). 13C NMR (50 MHz, CDCl3): d 50.1, 120.1, 124.7,
129.0, 129.6, 130.3, 134.6, 137.3, 161.8, 195.1. HRMS (ESI): m=z [M þ Na]þ calcd.
for C15H13NO2S: 271.0667; found: 271.0637.
N-Phenyl-thiomalonamic Acid S-p-Tolyl Ester (5ae)
Purification by flash column chromatography (AcOEt=hex, 1:3), mp
1
118–120 ꢀC; H NMR (500 MHz, CDCl3): d 2.43 (s, 3H, CH3), 3.82 (s, 2H, CH2),
7.13–7.16 (m, 1Harom), 7.29–7.37 (m, 6Harom), 7.53–7.55 (m, 2Harom), 8.79 (s, 1H,
NH). 13C NMR (50 MHz, CDCl3): d 21.9, 50.4, 120.6, 123.3, 125.2, 129.5, 130.9,
135.0, 137.9, 141.2, 162.5, 196.1. HRMS (ESI): m=z [M þ Na]þ calcd. for
C16H15NO2S: 285.0822; found: 285.0332.
ACKNOWLEDGMENT
This scientific work was financed from Funds for Science in 2010–2011 as
Research Project NN204 088338.
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