New fatty acid derivatives based on barbiturates and other cyclic β-dicarbonyl compounds and an acyl migration

Article abstract of DOI:10.1007/s13738-014-0415-9

The use of DCC, triethylamine and 4-dimethylaminopyridine in dichloromethane provides a general and standard one-pot procedure for the O-acylation of cyclic β-dicarbonyl compound derivatives (1) with palmitic and stearic acids which have long hydrocarbon tails, to synthesis of new type of fatty acid derivative in good to excellent yields. Structure elucidation was carried out by FT-IR, ¹H NMR and ¹³C NMR spectroscopy techniques. The acyl migration was also found in results and the corresponding structure was characterized by X-ray crystallography. A proposed mechanism was discussed for the formation of products.

Full text of DOI:10.1007/s13738-014-0415-9

J IRAN CHEM SOC
DOI 10.1007/s13738-014-0415-9
ORIGINAL PAPER
New fatty acid derivatives based on barbiturates and other cyclic
b-dicarbonyl compounds and an acyl migration
•
Nader Noroozi Pesyan Marziyeh Bagheri
•
•
Ertan S¸ahin Tuncay Tunc¸
Received: 29 September 2013 / Accepted: 10 January 2014
Ó Iranian Chemical Society 2014
Abstract The use of DCC, triethylamine and
4-dimethylaminopyridine in dichloromethane provides a
general and standard one-pot procedure for the O-acyl-
ation of cyclic b-dicarbonyl compound derivatives (1)
with palmitic and stearic acids which have long hydro-
carbon tails, to synthesis of new type of fatty acid
derivative in good to excellent yields. Structure eluci-
dation was carried out by FT-IR, 1H NMR and 13C
NMR spectroscopy techniques. The acyl migration was
also found in results and the corresponding structure was
characterized by X-ray crystallography. A proposed
mechanism was discussed for the formation of products.
Most naturally fatty acids have a chain of an even
number of carbon atoms, from 4 to 28 [1–5]. These
compounds are usually derived from triglycerides or
phospholipids and are important sources of fuel because,
when metabolized, they yield large quantities of ATP.
Many cells can use either glucose or fatty acids in
particular, heart and skeletal muscles prefer fatty acids
instead brain cannot use fatty acids as a source of fuel
[6].
Molecular recognition of amphiphilic long chain
alkylated barbituric acid has been studied [7–11]. For
instance dodecyl barbituric acid (C18BA) with 2-amino-
4,6-dioctadecylamino-1,3,5-triazine (2C18TAZ) forms
Langmuir–Blodgett films [9]. The incorporation of
amphiphilic 5,5-di-n-dodecylbarbituric acid (DBA) and
its complementary molecule 9-hexadecyladenine (HA) in
phosphatidyl choline (PC) liposomes may be of signifi-
cant interest for inducing the interaction of liposomes.
These model liposomal systems are primarily prepared
for drug delivery applications [10]. Schiff base,
2-hydroxybenzaldehyde-octadecylamine (HBOA), has
been synthesized and its interfacial hydrogen bond for-
mation or molecular recognition with barbituric acid was
investigated [11] (Fig. 1).
Keywords Barbituric acid Á Fatty acid Á 4-
Dimethylaminopyridine Á Acyl migration Á O-acylation
Introduction
Fatty acid is an organic carboxylic acid with a long
aliphatic tail, which is either saturated or unsaturated.
Electronic supplementary material The online version of this
article (doi:10.1007/s13738-014-0415-9) contains supplementary
material, which is available to authorized users.
The synthesis of fatty acid derivative [12] such as
decyl barbituric acid with diethyl decyl-malonate ester
[13], alkylmalonic esters by oxalate condensations [14]
and some fatty acid derivatives based on D-glucosamine
[15] has been reported. Acyl halides then anhydrides are
commonly used as acylating agents, because these agents
form a strong electrophile when treated with some metal
catalysts [16].
N. Noroozi Pesyan (&) Á M. Bagheri
Faculty of Chemistry, Urmia University, 57159 Urmia, Iran
e-mail: n.noroozi@urmia.ac.ir; nnp403@gmail.com
E. S¸ahin
Department of Chemistry, Faculty of Science, Atatu
¨rk
University, 25240 Erzurum, Turkey
Micelles are molecules having both polar (hydrophile)
and non-polar (lipophilic) regions which form aggregates
in aqueous solution. In a micelle, hydrophile region form
T. Tunc¸
Department of Science Education, Aksaray University,
68000 Aksaray, Turkey
123

J IRAN CHEM SOC
Fig. 1 Schematic molecular
O
O
NH2
N
NH2
Me3N
structures of 2C18-TAZ, C18
BA, DBA, PC, HBOA and C16
A [9–11] and molecular
structures of 4–6 presented in
this work
-
H
O
H
O
H
O
H
O
N
N
N
N
N
N
-
N
HO
H
H
O
N
N
N
N
N
O
O
N
P
O
O
O
O
O
DBA
C16-A
C18-BA
2C18-TAZ
HBOA
PC
O
O
O
X-Y-X =
HN-CO-NH (a),
MeN-CO-NMe (b),
HN-CS-NH (c),
HN-CO-NMe (d),
EtN-CS-NEt (e),
NH-CS-NMe (f),
CH2-C(Me)2-CH2 (g),
(CH2)3 (h),
4
X
X
O
Y
O
X
5
X
O
Y
O-C(Me)2-O (i)
H
N
N
6
O
O
an outer shell in contact with water, while lipophilic tails
are sequestered in the interior. Hence, the long chain has
lipophilic (hydrophobic) property in the core of a
micelle. Micelles are widely used in biological and
industrial fields for their ability to dissolve and move
non-polar substances through an aqueous solution or for
delivery of drugs which are scarcely soluble in water
[17–24]. Several types of micelles of fatty acid tail
containing of various counter ion have already been
reported such as: sucrose monopalmitate (C16SE) [25],
dodecyl ammonium salts [26], anionic surfactants such
as sodium tridecylbenzenesulfonate [27, 28], anionic
surfactant like sodium lauryl ether sulfate (SLES) and
zwitterionic surfactant with a quaternary ammonium
cation as cocamidopropyl betaine (CAPB) [29].
antimicrobial agent [31], antifungal, antimalarial [31–33]
and micelle formation [17–29] (Fig. 1), we have devel-
oped a very simple one-pot synthetic procedure to obtain
palmitic and stearic acid derivatives based on barbitu-
rates and other cyclic b-dicarbonyl compounds in the
presence of triethylamine, 4-N,N-dimethylaminopyridine
(4-DMAP) and dicyclohexylcarbodiimide (DCC).
Experimental
General
The drawing and nomenclature of compounds were done
by ChemDraw Ultra 8.0 version software. Melting points
were measured with a digital melting point apparatus
Because of the importance of usual and unusual fatty
acids and their derivatives in medicine [30],
1
(Electrothermal) and were uncorrected. The H and 13C
123

J IRAN CHEM SOC
1,3-Diethyl-6-oxo-2-thioxo-1,2,3,6-tetrahydropyrimidin-4-
NMR spectra were recorded on Bruker 300 FT-NMR at
300 and 75 MHz, respectively (Urmia University, Urmia,
yl palmitate (4d)
1
Iran). H and 13C NMR spectra were obtained in CDCl3
Colorless solid, Yield: 78 % (341 mg), m.p.: 47 °C. 1H NMR
(300 MHz, CDCl3) d: 4.48–4.55 (m, 4H), 3.10 (t,
J = 7.2 Hz, 2H), 1.65–2.00 (m, 5H), 1.23–1.29 (m, 28H),
0.85 (t, J = 5.7 Hz, 3H); 13C NMR (75 MHz, CDCl3) d: 8.6,
12.0, 12.3, 14.1, 22.7, 24.7, 25.5, 26.4, 29.3, 29.5, 29.6, 29.7,
30.9, 31.9, 32.8, 37.6, 43.0, 43.3, 45.8, 96.7, 158.5, 168.0,
177.3, 201.9; IR (KBr, cm-1) mmax: 2,978, 2,921, 2,851, 1,649
(a shoulder appeared in the left side of this peak), 1,598,
1,562, 1,378, 1,265, 1,210, 1,102, 813.
as solvents using TMS as internal standard. The data are
reported as (s = singlet, d = doublet, t = triplet,
q = quartet, m = multiplet or unresolved, bs = broad
singlet, coupling constant(s) in Hz, integration). IR
spectra were determined in the region 4,000–400 cm-1
on a NEXUS 670 FT-IR spectrometer by preparing KBr
pellets (Urmia University, Urmia, Iran). Compounds 1a–
i, 2, 3, 13, dicyclohexylcarbodiimide (DCC), 4-dimeth-
ylaminopyridine (4-DMAP) and used solvents purchased
from Merck and Acros without further purification.
5,5-Dimethyl-3-oxocyclohex-1-enyl palmitate (4g)
General procedures for the preparation of 4a–i and 5a–i
Pale yellow solid, Yield: 81 % (490 mg), m.p.: 48–49 °C. 1H
NMR (300 MHz, CDCl3) d: 2.99 (s, 1H), 2.25–2.51 (m, 4H),
1.59–1.88 (m, 8H), 0.97–1.40 (m, 26H), 0.86 (t, J = 6.6 Hz,
3H); 13C NMR (75 MHz, CDCl3) d: 14.0, 22.7, 24.7, 25.3,
25.4, 25.5, 26.3, 28.1, 29.24, 29.33, 29.37, 29.40, 29.44,
29.49, 29.59, 29.63, 29.65, 30.6, 30.8, 31.9, 32.7, 34.4, 35.9,
40.3, 42.2, 46.9, 50.8, 52.6, 56.0, 111.9, 116.4, 154.1, 173.9,
195.0, 197.7, 199.4, 205.7 (an equilibrium mixture of enol–
keto forms); IR (KBr, cm-1) mmax: 3,349 (OH of enolic form),
2,924, 2,853, 1,755, 1,658, 1,555, 1,466, 1,414, 1,144, 1,111.
1,3-Dimethyl-2,6-dioxo-1,2,3,6-tetrahydropyrimidin-4-yl
palmitate (4b)
In a 25-mL round-bottom flask 1,3-dimethyl barbituric acid
(1b) (1.0 mmol, 0.20 g) and triethylamine (1.2 mmol,
0.16 g, 0.2 mL) were dissolved in 15 mL dichloromethane.
A mixture of palmitic acid (2) (1.0 mmol, 0.33 g), dicy-
clohexylcarbodiimide (1.2 mmol, 0.32 g) and 4-dimethyl-
aminopyridine (0.2 mmol, 0.03 g) was added into the
reaction mixture and stirred for 14–18 h. The reaction
progression was monitored by thin layer chromatography
(TLC, AcOEt:petroleum ether, 5:1). After the reaction
completion, the white solid precipitated (DCU), filtered off.
The mother liquified evaporated under reduced pressure,
white solid was remained (Yield: 83 %, 0.44 g). Colorless
solid, m.p.: 63–64 °C. 1H NMR (300 MHz, CDCl3) d: 3.38
(s, 3H), 3.34 (s, 3H), 3.32 (s, 1H), 3.13 (t, J = 7.5 Hz, 2H),
1.69 (sextet, J = 7.8 Hz, 2H), 1.26 (m, 24H), 0.88 (t,
J = 6.6 Hz, 3H); 13C NMR (75 MHz, CDCl3) d: 14.0,
23.3, 25.9, 27.8, 28.0, 28.6, 29.3, 29.4, 29.47, 29.50, 29.59,
29.65, 31.9, 36.5, 36.8, 95.2, 150.4, 160.9, 169.8, 200.0; IR
(KBr, cm-1) mmax: 2,919, 2,854, 1,724, 1,665, 1,584, 1,494,
1,474, 1,375, 1,044, 755, 421.
3-Oxocyclohex-1-enyl palmitate (4h)
1
Colorless solid, Yield: 70 % (350 mg), m.p.: 55–57 °C. H
NMR (300 MHz, CDCl3) d: 4.60 (bs, 1H, exchangeable with
D2O), 4.21 (m, 1H), 3.88 (s, 1H), 3.66 (m, 1H), 3.37 (s, 1H),
3.00 (t, J = 6.9 Hz, 1H), 2.65 (t, J = 6.6 Hz, 1H), 2.45, 2.39,
2.30 (t, J = 6.6, 7.8, 7.8 Hz, 2H), 1.62–1.96 (m, 7H), 1.24
(m, 20H), 0.86 (t, J = 6.6 Hz, 3H);13C NMR (75 MHz,
CDCl3) d: 14.0, 19.0, 22.7, 24.7, 24.9, 25.32, 25.50, 26.38,
29.27, 29.35, 29.39, 29.47, 29.52, 29.65, 29.68, 30.9, 31.9,
32.8, 33.3, 33.8, 36.0, 38.7, 38.8, 40.6, 49.3, 49.7, 56.2, 68.1,
128.8, 130.9, 154.1, 174.2, 195.3, 198.7, 206.4 (an equilib-
rium mixture of enol–keto forms); IR (KBr, cm-1) mmax
:
3,326 (OH of enolic form), 2,926, 2,855, 1,706, 1,641, 1,574,
1,457, 1,395, 893.
2,6-Dioxo-1,2,3,6-tetrahydropyrimidin-4-yl palmitate (4a)
Colorless solid, m.p.: 74.9 °C. 1H NMR (300 MHz,
CDCl3) d: 3.89 (s, 1H), 2.42 (t, J = 7.5 Hz, 2H), 1.09–1.98
(m, 26H), 0.89 (t, J = 6.6 Hz, 3H); 13C NMR (75 MHz,
CDCl3) d: 23.0, 25.0, 25.6, 26.4, 29.3, 29.50, 29.60, 29.65,
29.7, 30.9, 31.9, 32.8, 34.0, 36.0, 49.6, 93.0, 154.1, 167.0,
174.2, 199.0; IR (KBr, cm-1) mmax: 3,347, 3,278, 2,919,
2,849, 1,764, 1,704, 1,632, 1,543, 1,464, 1,246, 1,221, 771.
1,3-Dimethyl-2,6-dioxo-1,2,3,6-tetrahydropyrimidin-4-yl
stearate (5b)
Colorless solid, Yield: 85 % (486 mg), m.p.: 61–62 °C. 1H
NMR (300 MHz, CDCl3) d: 3.38 (s, 3H), 3.34 (s, 3H), 3.14
(t, J = 7.5 Hz, 2H), 1.68 (quin, 2H), 1.26–1.39 (m, 28H),
0.89 (t, J = 6.9 Hz, 3H); 13C NMR (75 MHz, CDCl3) d:
123

J IRAN CHEM SOC
14.0, 22.6, 24.6, 24.9, 25.3, 25.4, 25.8, 26.4, 27.8, 30.9,
31.9, 32.7, 33.8. 34.9, 35.9, 36.7, 55.7, 95.1, 150.3, 160.8,
169.7, 199.9; IR (KBr, cm-1) mmax: 2,919, 2,854, 1,724,
1,665, 1,575, 1,495, 1,372, 1,226, 879, 755.
shoulders appeared in the left side of this peak), 1,527, 1,459,
1,222, 1,189, 1,143, 1,083, 725, 651.
2,2-Dimethyl-6-oxo-6H-1,3-dioxin-4-yl stearate (5i)
1,3-Diethyl-6-oxo-2-thioxo-1,2,3,6-tetrahydropyrimidin-4-
Pale yellow solid, m.p.: 47 °C. 1H NMR (300 MHz, CDCl3)
d: 3.65 (q, J = 6.9 Hz, 2H), 3.15 (q, J = 7.5 Hz, 2H), 2.83,
(m, 2H), 1.58 (m, 6H), 1.15–1.28 (m, 26H), 0.83 (t,
J = 6.6 Hz, 3H); 13C NMR (75 MHz, CDCl3) d: 8.5, 14.1,
18.3, 22.6, 23.4, 23.7, 24.7, 24.9, 25.3, 25.4, 25.6, 25.9, 26.1,
26.3, 26.8, 29.0, 29.2, 29.3, 29.4, 29.6, 29.70, 29.72, 30.3,
30.8, 31.9, 32.1, 32.6, 33.8, 35.7, 38.7, 40.9, 41.9, 43.0, 46.1,
48.9, 49.2, 49.8, 55.7, 58.0, 89.5, 102.1, 154.1, 157.2, 166.4,
199.7 (an equilibrium mixture of enol-keto forms); IR (KBr,
cm-1) mmax: 2,925, 2,853, 1,744, 1,709, 1,650, 1,575, 1,403,
1,299, 1,270, 1,209, 1,029, 958, 646.
yl stearate (5d)
Pink solid, Yield: 87 % (405 mg), m.p.: 40–42 °C. 1H NMR
(300 MHz, CDCl3) d: 4.51 (m, 4H), 3.12 (t, 1H), 1.65–1.90
(m, 6H), 1.23 (m, 32H), 0.86 (t, J = 6.6 Hz, 3H); 13C NMR
(75 MHz, CDCl3) d: 12.0, 12.3, 14.1, 22.7, 23.0, 23.7, 24.1,
24.8, 25.5, 28.9, 29.4, 29.5, 29.60, 29.66, 29.69, 30.3, 31.9,
37.6, 38.7, 43.0, 43.3, 68.1, 128.8, 130.9, 168.0, 201.9; IR
(KBr, cm-1) mmax: 2,925, 2,854, 1,689 (a shoulder appeared in
the left side of this peak), 1,630, 1,561, 1,471, 1,385, 1,113,
876, 567.
Dicyclohexylurea (DCU, 10)
5,5-Dimethyl-3-oxocyclohex-1-enyl stearate (5g)
1
1
White solid, m.p.: 233–234 °C (lit. 231–235 °C [34]). H
Pale yellow solid, Yield: 78 % (513 mg), m.p.: 42 °C. H
NMR (300 MHz, CDCl3) d: 4.03 (bs, 2H), 3.49 (quin,
J = 9.9 Hz, 2H), 1.93 (d, J = 10.8 Hz, 4H), 1.65 (m, 6H),
1.33 (m, 4H), 1.14 (m, 6H); 13C NMR (75 MHz, CDCl3) d:
25.1, 25.5, 33.6, 49.5, 157.0; IR (KBr, cm-1) mmax: 3,327,
2,928, 2,851, 1,627, 1,575, 1,312, 1,243, 1,088, 892, 642.
NMR (300 MHz, CDCl3) d: 3.62 (s, 1H), 2.98 (t,
J = 7.2 Hz, 1H), 2.23–2.49 (m, 4H), 1.58–1.90 (m, 6H),
1.22 (m, 25H), 1.07 (s, 3H), 1.04 (s, 3H), 0.84 (t,
J = 6.6 Hz, 3H); 13C NMR (75 MHz, CDCl3) d: 22.6,
24.6, 24.7, 24.9, 25.3, 25.4, 25.6, 26.3, 27.1, 28.1, 28.9,
29.15, 29.2, 29.11, 29.3, 29.4, 29.5, 29.6, 30.6, 30.8, 31.9,
32.7, 33.1, 33.8, 34.0, 34.4, 34.9, 40.3, 42.2, 35.8, 46.9,
49.0, 49.7, 51.3, 50.8, 52.6, 55.7, 55.9, 60.0, 111.9, 116.4,
154.1, 168.2, 170.4, 173.8, 194.9, 197.7, 199.3, 205.6 (an
1,3-Dimethyl-2,6-dioxo-1,2,3,6-tetrahydropyrimidin-4-yl
ethyl carbonate (14b)
White solid, m.p.: 122–124 °C. 1H NMR (300 MHz, CDCl3)
d: 5.72 (s, 1H), 4.34 (q, J = 6.9 Hz, 2H), 3.31 (s, 3H), 3.28
(s, 3H), 1.36 (t, J = 6.9 Hz, 3H); 13C NMR (75 MHz,
CDCl3) d: 13.9, 28.1, 29.5, 66.8, 90.5, 149.5, 151.0, 153.5,
162.3; IR (KBr, cm-1) mmax: 3,579, 3,109, 2,985, 2,966,
1,787, 1,709, 1,655, 1,460, 1,371, 1,240, 1,177, 1,037, 969,
758, 539, 487, 409.
equilibrium mixture of enol-keto forms); IR (KBr, cm-1
)
mmax: 3,323 (OH of enolic form), 2,926, 2,854, 1,766,
1,741, 1,704, 1,670, 1,538, 1,465, 1,116, 722.
3-Oxocyclohex-1-enyl stearate (5h)
1
Colorless solid, Yield: 71 % (230 mg), m.p.: 50–52 °C. H
NMR (300 MHz, CDCl3) d: 4.19 (m, 1H), 3.87 (m, 1H), 3.64
(m, 1H), 3.44 (m, 1H), 2.98 (t, J = 7.2 Hz, 1H), 2.63 (t,
J = 5.7 Hz, 1H), 2.29–2.45 (m, 2H), 1.58–1.94 (m, 6H), 1.23
(m, 24H), 0.85 (t, J = 6.6 Hz, 3H); 13C NMR (75 MHz,
CDCl3) d: 14.1, 19.0, 22.6, 22.9, 23.7, 24.2, 24.6, 24.7, 24.9,
25.3, 25.5, 25.6, 26.3, 28.8, 28.9, 29.15, 29.24, 29.3, 29.36,
29.41, 29.5, 29.6, 29.7, 30.3, 30.8, 31.9, 32.7, 33.3, 33.8, 34.1,
35.2, 35.8, 38.7, 38.8, 40.6, 49.0, 49.7, 55.9, 68.1, 112.9,
128.7, 130.8, 154.1, 169.5, 173.8, 176.8, 195.2, 198.6, 206.3
1,3-Diethyl-2,6-dioxo-1,2,3,6-tetrahydropyrimidin-4-yl
ethyl carbonate (14d)
White solid, m.p.: 108–110 °C. 1H NMR (300 MHz, CDCl3)
d: 5.94 (s, 1H), 4.45–4.52 (m, 4H), 4.38 (q, J = 7.2 Hz, 2H),
1.40 (t, J = 7.2 Hz, 3H), 1.19–1.32 (m, 6H); 13C NMR
(75 MHz, CDCl3) d: 11.2, 12.7, 14.0, 43.7, 45.3, 67.0, 94.9,
149.5, 153.4, 160.2, 176.2; IR (KBr, cm-1) mmax: 2,982,
2,930, 2,865, 1,743, 1,645, 1,437, 1,403, 1,376, 1,238, 1,105,
1,035, 792, 492, 470.
(an equilibrium mixture of enol-keto forms); IR (KBr, cm-1
)
mmax: 3,344 (OH of enolic form), 2,924, 2,853, 1,662 (two
123

J IRAN CHEM SOC
Scheme 1 Reaction of fatty
acids (2 and 3) with cyclic b-
dicarbonyl compounds (1a–i)
X
O
Y
DCC, 4-DMAP
Y
X
X
X
+
CH3(CH2)nCOOH
+
+
DCU (10)
NH
N
Et3N, CH2Cl2
r.t.
O
O
O
O
n : 14 (2),
16 (3)
O
1
O
X-Y-X =
(CH2)nCH3
(CH2)nCH3
HN-CO-NH (a),
MeN-CO-NMe (b),
HN-CS-NH (c),
EtN-CS-NEt (d),
NH-CO-NMe (e),
NH-CS-NMe (f),
n : 14 (4),
16 (5)
n : 14 (6),
16 (7)
70-90%
CH2-C(Me)2-CH2 (g),
(CH2)3 (h),
O-C(Me)2-O (i)
5,5-Dimethyl-3-oxocyclohex-1-enyl ethyl carbonate (14g)
O
R = C15 (6)
C17 (7)
Acyl migration
1H NMR (300 MHz, CDCl3) d: 5.91 (s, 1H), 4.16 (q,
J = 7.2 Hz, 2H), 2.35 (s, 2H), 2.16 (s, 2H), 1.25 (t,
J = 7.2 Hz, 3H), 1.00 (s, 6H); 13C NMR (75 MHz, CDCl3)
d: 14.0, 28.0, 32.9, 41.6, 50.6, 65.2, 115.3, 151.0, 167.6,
199.3; IR (KBr, cm-1) mmax: 2,961, 2,879, 1,768, 1,674,
1,621, 1,469, 1,363, 1,234, 1,188, 1,144, 1,041,983, 875, 779,
609, 466.
N
N
H
path a
O
R
O
Me
N
Me
N
N
Me
Me
R
N
N
B
R
HN
O
O
R
Me
N
Me
N
O
- DCU
path b
A
Results and discussion
path c
path d
This article describes the one-pot reaction of fatty acids
such as palmitic (2) and stearic acid (3) with some cyclic
b-dicarbonyl compounds such as (thio)barbituric acids
(1a–f), dimedone (1g), 1,3-cyclohexanedione (1h) and
Meldrum’s acid (1i) in the presence of DCC, 4-DMAP
and triethylamine in dichloromethane at room tempera-
ture in good yield. In these reactions, new palmitic and
stearic acid esters based on cyclic b-dicarbonyl com-
pounds (4a–i through 5a–i), acyl migration products (6
and 7) and dicyclohexylurea (DCU, 10) were obtained
(Scheme 1).
DCC
O
O
H
O
N
N
N
O
R
path d
Me
Me
Me
O
Me
O
O
OH
N
- (4-DMAP)
R = C15 (2)
C17 (3)
path c
- (4-DMAP)
R
O
O
R = C15 (8b)
C17 (9b)
Me
O
Me
N
N
O
O
R
Representatively, according to Steglich esterification
[35], a suitable mechanism for the formation of new
fatty acid esters based on barbiturates and other cyclic b-
dicarbonyl compounds is proposed in Scheme 2. A
common explanation of the 4-N,N-dimethylaminopyridine
R = C15 (4b)
C17 (5b)
Scheme 2 Representatively, plausible mechanism for the formation
of 4b, 5b, 6 and 7
(4-DMAP) as
a catalyst acceleration suggests that
4-DMAP, as a stronger nucleophile than the DMBA
(1b), reacts with the O-acylisourea (A) leading to a
reactive amide (B). This intermediate reacts rapidly with
any nucleophile such as 1b. 4-DMAP acts as an acyl
transfer and subsequent reaction with the 1b (O-attack)
gives the fatty acid ester 4b and/or 5b (Scheme 2, path
c). No C-attack of 1b was occurred judging to no
observation of 8b and 9b (Scheme 2, path d).
In practice, dicyclohexylcarbodiimide (DCC) and
amines lead to amides without problems in the reaction
with carboxylic acids, while the addition of approximately
5 mol% 4-DMAP is crucial for the efficient formation of
esters. N-Acylureas (6 and/or 7), which may be quantita-
tively isolated in the absence of any nucleophile, are the
side products of an acyl migration that takes place slowly.
123

J IRAN CHEM SOC
Me
N
Me
O
O
O
O
O
N
O
O
Acyl migration
Slow
N
N
H
N
N
H3C(H2C)15
H3C(H2C)15
Me
Me
R
H
O
O
O
O
O
6 and/or 7
NH
N
H
H
R
9b[I]
9b[II]
R'NH2
Fast
10 + R'NHCOR (11)
H
A
ROH
Slow
O
O
O
O
O
N
O
N
10 + R'OCOR (12)
Me
Me
H3C(H2C)15
H3C(H2C)15
N
N
Scheme 3 Acyl migration and preparation of amides and esters from
O-acylisourea (A)
O
O
Me
Me
9b[III]
Scheme 5 Representatively, supposed tautomeric forms and
intramolecular H-bond of 1,3-dimethyl-5-stearoylpyrimidine-
2,4,6(1H,3H,5H)-trione (9b)
O
O
X
X
Y
X
Y
X
n : 14 (4),
16 (5)
O
O
:
O
O
R
O
[I]
O
R
O
Y
Y
(CH2)nCH3
(CH2)nCH3
O
O
O
Scheme 4 Resonance and mesomeric forms of 4a–i through 5a–i
O
O
[II] OH
Nucleophiles such as amines react readily with the O-
acylisourea (A) affords DCU (10) and amides (11). Simi-
larly, alcohols in the reaction with A slowly afford 10 and
esters (12) (Scheme 3). In the present research, the com-
pounds 6 and 7 were found in results of palmitoyl and
stearoyl migrations, respectively (An acyl migration).
Representatively, the structure of 6 was analyzed by X-ray
crystallography (See later).
Representatively, the 1H NMR spectra of 4b and 5b show
two distinct singlets at d 3.34 and 3.38 ppm for NMe groups
on barbituric acid ring moiety. 13C NMR spectrum of 4b
shows three carbonyl peaks at d 169.8, 160.9 and 150.4 ppm
for DMBA ring moiety. The esteric carbonyl peak unusually
appeared at down field in 4b (at d 200.0 ppm) because of the
resonance of oxygen lone pair with conjugated a,b-unsatu-
rated carbonyl group so has inductive effect on esteric car-
bonyl group (Scheme 4 and see experimental and
supplementary data). IR spectra of these compounds show no
hydroxyl (OH) frequency instead show the olefinic (C–H)
frequency up to 3,000 cm-1. Therefore, no C-acylation was
occurred with judging to these observations. One can unam-
biguously think that these compounds as a result of C-acyl-
ation and in this case, these compounds should have an
intramolecular H-bond as shown in Scheme 5. For instance in
the supposed structure of 9b, representatively, the two NMe
R
O
R
Y
Y
O
O
[III]
R = CH3(CH2)14 , Y = C(CH3)2 (4g)
R = CH3(CH2)14 , Y = CH2 (4h)
R = CH3(CH2)16 , Y = C(CH3)2 (5g)
R = CH3(CH2)16 , Y = CH2 (5h)
Scheme 6 Equilibrium mixture of tautomeric (keto ꢀ enol) and
mesomeric forms for 4g, 4h, 5g and 5h
Y
Y
O
Et3N, CH2Cl2
X
X
X
X
+
r.t.
O
Cl
O
O
O
O
1
13
-Et3NHCl
14
O
O
X-Y-X =
MeN-CO-NMe (b),
EtN-CS-NEt (d),
CH2-C(Me)2-CH2 (g)
Scheme 7 Reaction of 1b, 1d and 1g with ethylchloroformate (13) in
the presence of triethylamine
1
mixture of keto ([I]) ꢀ enol [II] forms (Scheme 6). For
instance, the 13C NMR spectrum of 4g shows at least six peaks
at the carbonyl region for down- to up-field at d 205.7, 197.7,
195.0 ppm for keto form and at d 173.9, 170.4 and 168.2 ppm
for enol form, respectively. IR spectra of these compounds (4g,
groups in H NMR and two carbonyl groups of DMBA ring
moiety in 13C NMR spectra should have equivalent chemical
shift so this is not the case.
IR spectra of 4g, 4h, 5g and 5h show a broad peak at the
frequency about 3,400 cm-1 and indicated the equilibrium
123

J IRAN CHEM SOC
˚
Table 1 Selected bond length (A) and torsion angles (°) for structure
of 6
O2–C29
1.221(6)
1.221(7)
1.373(7)
1.443(7)
1.488(7)
1.309(7)
1.471(7)
–5.7(8)
O1–C16
N1–C16
N1–C29
N1–C23
N2–C29
N2–C22
C22–N2–C29–O2
C22–N2–C29–N1
C16–N1–C29–O2
C23–N1–C29–O2
C23–N1–C16–O1
C16–N1–C29–N2
174.6(4)
107.1(6)
-60.4(6)
-4.7(8)
-73.2(6)
We performed the reaction of some cyclic b-dicarbonyls
(1b, 1d and 1g) with ethylchloroformate (13) in the presence
of triethylamine at room temperature (Scheme 7). The reac-
tion of 1 with 13 afforded 14 in good yield. For example, IR
spectrum of 14b shows both olefinic and aliphatic CH
stretching frequencies at 3,109 and 2,984 cm-1, respectively
and carbonyl bond frequencies at 1,787, 1,709 and
1
1,655 cm-1. H NMR spectrum of 14b shows a triplet at d
1.36 (J = 6.9 Hz, 3H), a quartet at d 4.34 (J = 6.9 Hz, 2H),
two singlets at d 3.28 and 3.31 ppm (29 NCH3, 6H) and a
singlet at 5.72 ppm (1H). 13C NMR spectrum shows nine
distinct peaks that confirm the assigned structure (see
‘‘Experimental’’).
X-Ray analysis of compound 6
For further study, an X-ray diffraction analysis of 6 was
undertaken (Fig. 2a). Single crystal of 6 was obtained as
colorless crystal by slow evaporation from methanol at room
temperature. Compound 6 crystallizes in the triclinic space
group P-1 with two molecules in the unit cell. In the mole-
cule, each cyclohexane ring has chair conformation. The
molecules in the unit cell are connected by N–HÁÁÁO H-bond
i
˚
interactions, N2–HÁÁÁO2 = 2.287 A, \(N2–HÁÁÁO2) = 1658
[Symmetry code (i) -1 ? x, y, z] (Fig. 2b). The crystal
packing diagram of 6 is shown in Fig. 2c.
Fig. 2 ORTEP view of 6 showing the atom-labeling scheme.
Displacement ellipsoids are drawn at the 50 % probability level (a),
H-bonding pattern (dashed lines) along the a-axis in the unit cell
(b) and the crystal packing of the molecules viewed down a-axis (c)
The selected bond lengths and torsion angles for 6 are
summarized in Table 1. The crystal structure of 6 demon-
strated that the bond length of N1–C16, N1–C29 and N2–C29
˚
was obtained 1.373(7), 1.443(7) and 1.309 (7) A, respectively.
4h, 5g and 5h) show a distinct hydroxyl broad peak at the
range of frequencies of 3,326–3,400 cm-1. Therefore, these
data support the equilibrium mixture of keto ꢀ enol forms of
these compounds (See also ‘‘Experimental’’ and supplementary
data).
The torsion angles of C16–N1–C29–N2, C23–N1–C29–O2
and C23–N1–C16–O1 were obtained -73.2 (6), -60.4 (6) and
-4.7 (8)°, respectively. These data support the simultaneous
resonance of N1 and N2 atom lone pairs with the C16=O1 and
C29=O2 groups, respectively. The resonance of N1 lone pair
123

J IRAN CHEM SOC
with the C29=O2 is invalid with judging to the N1–C16, N1–
˚
C29 bond lengths (1.373(7) versus 1.443(7) A, respectively)
H
N
H
N 2
(Scheme 8; Table 1).
1N
R
29
16
N
R
The single crystal of the compound 6 was used for data
collection on a Bruker SMART BREEZE CCD diffractometer.
The graphite-monochromatized MoKa radiation (k = 0.71073
O
O
O
O
˚
6[i]
[ii]
A) and oscillation scans technique with Dx = 5° for one
image were used for data collection. The lattice parameters
were determined by the least-squares methods on the basis of
all reflections with F2 [2r(F2). Integration of the intensities,
correction for Lorentz and polarization effects and cell refine-
ment were performed using Bruker SAINT (Bruker AXS Inc.,
2012) software [36]. The structure was solved by direct
methods using SHELXS-97 [37] and refined by a full-matrix
least-squares procedure using the program SHELXL-97 [37]. H
atoms were positioned geometrically and refined using a riding
model. The final difference Fourier maps showed no peaks of
chemical significance. The crystallographic data are summa-
rized in Table 2 and were deposited in CCDC registration
number 956201 and are available free of charge upon request
to CCDC, 12 Union Road, Cambridge, UK (fax: ?44-1223-
336033, e-mail: deposit@ccdc.cam.ac.uk).
R = C15
H
N
N
R
O
O
[iii]
Scheme 8 Favored resonance and mesomeric forms ([i] and [ii]) and
invalid mesomeric form ([iii]) for 6
Table 2 Crystal data and structure refinement for 6
Empirical formula
Formula weight
Temperature
C29H54N2O2
462.74
293(2) K
˚
Wavelength
0.71073 A
triclinic
P-1
Crystal system
Space group
Conclusion
˚
a = 5.2578(7) A
Unit cell
dimensions
a = 89.100(3)°
b = 87.303(3)°
c = 79.323(6)°
˚
b = 10.6655(15) A
New fatty acid ester derivatives of palmitic and stearic acids
based on barbiturates and other cyclic b-dicarbonyl compounds
were synthesized at room temperature. An acyl migration was
also occurred in parallel of the formation of fatty acid ester
derivatives. Some cyclic b-dicarbonyl compounds such as 1,3-
cyclohexanedione and dimedone showed an equilibrium mix-
ture of enol-keto forms. The crystal structure of 1,3-dicyclo-
hexyl-1-palmitoylurea as an acyl migration showed a weak
intermolecular hydrogen bond.
˚
c = 26.2315(16) A
3
˚
1,443.9(4) A
Volume
Z
2
Density
(calculated)
1.064 Mg/m3
Absorption
coefficient
0.065 mm21
F(000)
516
h range for data
collection
2.3°–28.3°
Index ranges
-5 B h B 5, -11 B k B 10,
-29 B l B 29
Acknowledgments We gratefully acknowledge financial support by
the Research Council of Urmia University.
Reflections
collected
16,249
Independent
reflections
4,168 [Rint = 0.074]
99.7 %
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