ORIGINAL PAPER

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

Nader Noroozi Pesyan • Marziyeh Bagheri •

Ertan Sahin • Tuncay Tunc

Received: 29 September 2013 / Accepted: 10 January 2014

� 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.

Keywords Barbituric acid � Fatty acid � 4-

Dimethylaminopyridine � Acyl migration � O-acylation

Introduction

Fatty acid is an organic carboxylic acid with a long

aliphatic tail, which is either saturated or unsaturated.

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).

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].

Micelles are molecules having both polar (hydrophile)

and non-polar (lipophilic) regions which form aggregates

in aqueous solution. In a micelle, hydrophile region form

Electronic supplementary material The online version of thisarticle (doi:10.1007/s13738-014-0415-9) contains supplementarymaterial, which is available to authorized users.

N. Noroozi Pesyan (&) � M. Bagheri

Faculty of Chemistry, Urmia University, 57159 Urmia, Iran

e-mail: n.noroozi@urmia.ac.ir; nnp403@gmail.com

E. Sahin

Department of Chemistry, Faculty of Science, Ataturk

University, 25240 Erzurum, Turkey

T. Tunc

Department of Science Education, Aksaray University,

68000 Aksaray, Turkey

123

J IRAN CHEM SOC

DOI 10.1007/s13738-014-0415-9

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].

Because of the importance of usual and unusual fatty

acids and their derivatives in medicine [30],

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

(Electrothermal) and were uncorrected. The 1H and 13C

N N

O

O O

HH

OP

OO O

Me3N

HO

N

HBOA

PC

DBA

N

N N

N

NH2

C16-A

N N

O

O O

H H

C18-BA

N

N

N

NH2

N NH H

2C18-TAZ

XXY

OO

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),O-C(Me)2-O (i)

XXY

OO

4

5

O

O

N

6 O

HN

O

OO

O

O

Fig. 1 Schematic molecular

structures of 2C18-TAZ, C18-

BA, DBA, PC, HBOA and C16-

A [9–11] and molecular

structures of 4–6 presented in

this work

J IRAN CHEM SOC

123

NMR spectra were recorded on Bruker 300 FT-NMR at

300 and 75 MHz, respectively (Urmia University, Urmia,

Iran). 1H and 13C NMR spectra were obtained in CDCl3as 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.

General procedures for the preparation of 4a–i and 5a–i

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.

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-Diethyl-6-oxo-2-thioxo-1,2,3,6-tetrahydropyrimidin-4-

yl palmitate (4d)

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.

5,5-Dimethyl-3-oxocyclohex-1-enyl palmitate (4g)

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.

3-Oxocyclohex-1-enyl palmitate (4h)

Colorless solid, Yield: 70 % (350 mg), m.p.: 55–57 �C. 1H

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.

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:

J IRAN CHEM SOC

123

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.

1,3-Diethyl-6-oxo-2-thioxo-1,2,3,6-tetrahydropyrimidin-4-

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.

5,5-Dimethyl-3-oxocyclohex-1-enyl stearate (5g)

Pale yellow solid, Yield: 78 % (513 mg), m.p.: 42 �C. 1H

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

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)

Colorless solid, Yield: 71 % (230 mg), m.p.: 50–52 �C. 1H

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

(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

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)

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.

Dicyclohexylurea (DCU, 10)

White solid, m.p.: 233–234 �C (lit. 231–235 �C [34]). 1H

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.

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.

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.

J IRAN CHEM SOC

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5,5-Dimethyl-3-oxocyclohex-1-enyl ethyl carbonate (14g)

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.

Results and discussion

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).

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

(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.

X XY

O OX

XY

O

O

1

X-Y-X =HN-CO-NH (a),MeN-CO-NMe (b),HN-CS-NH (c),EtN-CS-NEt (d),NH-CO-NMe (e),NH-CS-NMe (f),CH2-C(Me)2-CH2 (g),(CH2)3 (h),O-C(Me)2-O (i)

+ CH3(CH2)nCOOHDCC, 4-DMAP

Et3N, CH2Cl2r.t.n : 14 (2),

16 (3)

DCU (10)

70-90%

+

n : 14 (4),16 (5)

O

(CH2)nCH3

NH

NO

(CH2)nCH3

O

+

n : 14 (6),16 (7)

Scheme 1 Reaction of fatty

acids (2 and 3) with cyclic b-

dicarbonyl compounds (1a–i)

R OH

O

DCC

RO

O

HN

N

N NMe

Me

NR

ON

Me

Me

NR

ON

Me

Me

N N

O

O O

MeMe

H

NN

O

MeMe

OO

OR

- (4-DMAP)R = C15 (2)

C17 (3)

R = C15 (4b)C17 (5b)

A

B

path cpath d

NN

O

MeMe

OO

- (4-DMAP)

path c

path d

O

R

R = C15 (8b)C17 (9b)

- DCU

Acyl migrationNH

N

O

ROpath a

path b

R = C15 (6)C17 (7)

Scheme 2 Representatively, plausible mechanism for the formation

of 4b, 5b, 6 and 7

J IRAN CHEM SOC

123

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

groups in 1H 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

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,

X

XY

O

O

n : 14 (4),16 (5)

O

(CH2)nCH3

:

X

XY

O

O

O

(CH2)nCH3

Scheme 4 Resonance and mesomeric forms of 4a–i through 5a–i

N

N

O

O

O

Me

Me

H3C(H2C)15

O H

N

N

O

O

O

Me

Me

H3C(H2C)15

OH

N

N

O

O

O

Me

Me

H3C(H2C)15

OH

9b[I] 9b[II]

N

N

O

O

O

Me

Me

H3C(H2C)15

OH

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)

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)

YO

O

[II]

R

O

YO

O

R

O

YO

OH

[III]

R

O

YO

O[I]

R

O

Scheme 6 Equilibrium mixture of tautomeric (keto � enol) and

mesomeric forms for 4g, 4h, 5g and 5h

NH

NO

OR

NH

N

O

Acyl migration

Slow

R'NH2

Fast

ROH

Slow

10 + R'NHCOR (11)

10 + R'OCOR (12)

6 and/or 7

A

RO

Scheme 3 Acyl migration and preparation of amides and esters from

O-acylisourea (A)

X XY

O O1

X-Y-X =MeN-CO-NMe (b),EtN-CS-NEt (d),CH2-C(Me)2-CH2 (g)

+Et3N, CH2Cl2

r.t.O Cl

O X XY

O O-Et3NHCl13 14OO

Scheme 7 Reaction of 1b, 1d and 1g with ethylchloroformate (13) in

the presence of triethylamine

J IRAN CHEM SOC

123

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).

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

1,655 cm-1. 1H NMR spectrum of 14b shows a triplet at d1.36 (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–H���O H-bond

interactions, N2–H���O2i = 2.287 A,\ (N2–H���O2) = 1658[Symmetry code (i) -1 ? x, y, z] (Fig. 2b). The crystal

packing diagram of 6 is shown in Fig. 2c.

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.

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

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)

Table 1 Selected bond length (A) and torsion angles (�) for structure

of 6

O2–C29 1.221(6)

O1–C16 1.221(7)

N1–C16 1.373(7)

N1–C29 1.443(7)

N1–C23 1.488(7)

N2–C29 1.309(7)

N2–C22 1.471(7)

C22–N2–C29–O2 –5.7(8)

C22–N2–C29–N1 174.6(4)

C16–N1–C29–O2 107.1(6)

C23–N1–C29–O2 -60.4(6)

C23–N1–C16–O1 -4.7(8)

C16–N1–C29–N2 -73.2(6)

J IRAN CHEM SOC

123

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)

(Scheme 8; Table 1).

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

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).

Conclusion

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.

Acknowledgments We gratefully acknowledge financial support by

the Research Council of Urmia University.

References

1. A. Poulos, D.W. Johnson, K. Beckman, I.G. White, C. Easton,

Biochem. J. 248, 961 (1987)

2. A. Laufenberg, A. Behr, US Patent, 5,481,025; Jan., 2, (1996)

3. A. Poulos, B.S. Robinson, A. Ferrante, D.P. Harvey, S.J. Hardy,

A.W. Murray, Immunology 73, 102 (1991)

4. T. Rezanka, M. Podojil, Lipids 19, 472 (1984)

5. A. Poulos, K. Beckman, D.W. Johnson, B.C. Paton, B.S. Rob-

inson, P. Sharp, S. Usher, H. Singh, Adv. Exp. Med. Biol. 318,

331 (1992)

6. M.K. Campbell, S.O. Farrell, Biochemistry, 5th edn. (Cengage

Learning, 2006), p. 579

7. T.M. Bohanon, P.-L. Caruso, S. Denzinger, R. Fink, D. Mobius,

W. Paulus, J.A. Preece, H. Ringsdorf, D. Schollmeyer, Langmuir

15, 174 (1999)

NR

O

N

O

1 2H

2916 NR

O

N

O

H

NR

O

N

O

HR = C15

6[i] [ii]

[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 C29H54N2O2

Formula weight 462.74

Temperature 293(2) K

Wavelength 0.71073 A

Crystal system triclinic

Space group P-1

Unit celldimensions

a = 5.2578(7) A a = 89.100(3)�b = 10.6655(15) A b = 87.303(3)�c = 26.2315(16) A c = 79.323(6)�

Volume 1,443.9(4) A3

Z 2

Density(calculated)

1.064 Mg/m3

Absorptioncoefficient

0.065 mm21

F(000) 516

h range for datacollection

2.3�–28.3�

Index ranges -5 B h B 5, -11 B k B 10,-29 B l B 29

Reflectionscollected

16,249

Independentreflections

4,168 [Rint = 0.074]

Completeness toh = 27.50�

99.7 %

Max. and min.transmission

0.9982 and 0.9822

Refinement method Full-matrix least-squares onF2

Data/parameters 2,218/298

Goodness-of-fiton F2

1.305

Final R indices[F2 [ 2r(F2)]

R1 = 0.085, wR2 = 0.205

Largest diff. peakand hole

0.795 and -0.295 e A23

J IRAN CHEM SOC

123

8. T. Hasegawa, Y. Hatada, J. Nishijo, J. Umemura, Q. Huo, R.M.

Leblanc, J. Phys. Chem. B 103, 7505 (1999)

9. D. Tsiourvas, Z. Sideratou, A.A. Haralabakopoulos, G. Pistolis,

C.M. Paleos, J. Phys. Chem. 100, 14087 (1996)

10. S. Sideratou, D. Tsiourvas, C.M. Paleos, A. Tsortos, S. Pyrpas-

sopoulos, G. Nounesis, Langmuir 18, 829 (2002)

11. T. Jiao, M. Liu, J. Phys. Chem. B 109, 2532 (2005)

12. H.J. Harwood, Prog. Chem. Fat. Lipids 1, 127 (1952)

13. R. Oda, K. Teramura, H. Itagaki, Bull. Inst. Chem. Res., Kyoto

University 31, 61 (1953)

14. D.E. Floyd, S.E. Miller, J. Am. Chem. Soc. 69, 2354 (1947)

15. Y. Inouye, K. Onodera, S. Kitaoka, S. Hirano, J. Am. Chem. Soc.

78, 4722 (1956)

16. G.A. Olah, Friedel-Crafts Chemistry (Wiley-Interscience, New

York, 1973)

17. M.J. Rosen, J.T. Kunjappu, Surfactants and Interfacial Phe-

nomena, 4th edn. (New Jersey, 2012), p. 1

18. T.L. Metcalfe, P.J. Dillon, C.D. Metcalfe, Environ. Toxicol.

Chem. 27, 811 (2008)

19. W. Abdelwahed, G. Degobert, A. Dubes, H. Fessi, Int. J. Pharm.

351, 289 (2008)

20. S. Garoff, Proc. Natl. Acad. Sci. USA 84, 4729 (1987)

21. E. Fahy, S. Subramaniam, R.C. Murphy, M. Nishijima, C.R.H.

Raetz, T. Shimizu, F. Spener, G. van Meer, M.J.O. Wakelam,

E.A. Dennis, J. Lipid Res. 50, 9 (2009)

22. S. Subramaniam, E. Fahy, S. Gupta, M. Sud, R.W. Byrnes, D.

Cotter, A.R. Dinasarapu, M.R. Maurya, Chem. Rev. 111, 6452

(2011)

23. A.R. Zarei, F. Gholamian, Anal. Biochem. 412, 224 (2011)

24. A. Patist, T. Axelberd, D.O. Shah, J. Colloid Interface Sci. 208,

259 (1998)

25. K. Aramakia, S. Hoshida, S. Arima, Colloids and surfaces: a

physicochem. Eng. Aspects 396, 278 (2012)

26. A. Kitahara, J. Colloid Sci. 12, 342 (1957)

27. K. Morigaki, P. Walde, M. Misran, B.H. Robinson, Colloids and

surfaces a: physicochem. Eng. Aspects 213, 37 (2003)

28. K.D. Farquhar, M. Misran, B.H. Robinson, D.C. Steytler, P.

Morini, P.R. Garrett, J.F. Holzwarth, J. Phys. Condens. Matter 8,

9397 (1996)

29. S.S. Tzocheva, P.A. Kralchevsky, K.D. Danov, G.S. Georgieva,

A.J. Post, K.P. Ananthapadmanabhan, J. Colloid Interface Sci.

369, 274 (2012)

30. P.H. Chan, R.A. Fishman, S. Longar, S. Chen, A. Yu, Prog. Brain

Res. 63, 227 (1985)

31. J. Kabara, D.M. Swieczkowski, A.J. Conley, J.P. Truant, Agents

Chemother. 2, 23 (1972)

32. T.J. Avis, R.R. Belanger, Appl. Environ. Microbiol. 67, 956

(2001)

33. N.M. Carballeira, Progr. Lipid Res. 47, 50 (2008)

34. M.-K. Leung, J.-L. Lai, K.-H. Lau, H.-H. Yu, H.-J. Hsiao, J. Org.

Chem. 61, 4175 (1996)

35. B. Neises, W. Steglich, Angew. Chem. Int. Ed. 17, 522 (1978)

36. Bruker, APEX2, SAINT and SADABS. Bruker AXS Inc.

(Madison, Wisconsin, USA, 2012)

37. G.M. Sheldrick, SHELXS97 and SHELXL97, University of Got-

tingen, (Germany, 1997)

J IRAN CHEM SOC

123