Synthesis of 1,3-Disubstituted Hexahydropyrimidine Derivatives from Dibenzoylmethane, Acetylacetone, Ethyl Acetoacetate: One-Pot FeCl 3-Catalyzed Mannich Reaction

Article abstract of DOI:10.1080/00397911.2014.916302

1,3-Disubstituted hexahydropyrimidin-5-yl(phenyl)methanone (products 1-5) were prepared from the reaction of dibenzoylmethane with primary amines and formaldehyde in the presence of Lewis acid catalyst at ambient temperature. Replication of the reaction w

Full text of DOI:10.1080/00397911.2014.916302

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Synthesis of 1,3-Disubstituted
Hexahydropyrimidine Derivatives from
Dibenzoylmethane, Acetylacetone, Ethyl
Acetoacetate: One-Pot FeCl3-Catalyzed
Mannich Reaction
Abdullah Saleh a , Martha Morton b & John D'Angelo c
a Department of Chemistry , Hashemite University , Zarqa , Jordan
b Department of Chemistry , University of Nebraska , Lincoln ,
Nebraska , USA
c Division of Chemistry , Alfred University , Alfred , New York , USA
Accepted author version posted online: 20 May 2014.Published
online: 02 Jul 2014.
To cite this article: Abdullah Saleh , Martha Morton & John D'Angelo (2014) Synthesis of 1,3-
Disubstituted Hexahydropyrimidine Derivatives from Dibenzoylmethane, Acetylacetone, Ethyl
Acetoacetate: One-Pot FeCl3-Catalyzed Mannich Reaction, Synthetic Communications: An
International Journal for Rapid Communication of Synthetic Organic Chemistry, 44:18, 2715-2723,
DOI: 10.1080/00397911.2014.916302
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Synthetic Communications1, 44: 2715–2723, 2014
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2014.916302
SYNTHESIS OF 1,3-DISUBSTITUTED
HEXAHYDROPYRIMIDINE DERIVATIVES FROM
DIBENZOYLMETHANE, ACETYLACETONE, ETHYL
ACETOACETATE: ONE-POT FeCl3-CATALYZED
MANNICH REACTION
Abdullah Saleh,1 Martha Morton,2 and John D’Angelo3
1Department of Chemistry, Hashemite University, Zarqa, Jordan
2Department of Chemistry, University of Nebraska, Lincoln, Nebraska, USA
3Division of Chemistry, Alfred University, Alfred, New York, USA
GRAPHICAL ABSTRACT
Abstract 1,3-Disubstituted hexahydropyrimidin-5-yl(phenyl)methanone (products 1–5)
were prepared from the reaction of dibenzoylmethane with primary amines and formalde-
hyde in the presence of Lewis acid catalyst at ambient temperature. Replication of the
Received January 7, 2014.
Address correspondence to Abdullah Saleh, Department of Chemistry, Hashemite University,
Zarqa 13115, Jordan. E-mail: a-saleh@hu.edu.jo
2715

2716
A. SALEH, M. MORTON, AND J. D’ANGELO
reaction with acetylacetone and ethyl aetoacetate yielded 1,10-(1,3-disubstituted
hexahydropyrimidine-5,5-diyl)diethanone (products 6–10) and ethyl 5-acetylhexa-
hydropyrimidine-5-carboxylate (products 11–13), respectively. Yields obtained ranged
from 69 to 89%.
Keywords Debenzoylation; hexahydropyrimidines; Mannich reaction
INTRODUCTION
Hexahydropyrimidines are compounds with broad biological activities and
have been found in many natural products.[1–5] A number of these compounds are
suspected to have important biological activities.[6–16] Recent in vitro testing of some
hexahydropyrimidine derivatives showed promising new leads with pharmaceutical
interest. Biological activities include, for example, leishmanicidal,[17] antimicrobial,[7]
and cytotoxic activities.[18] Several hexahydropyrimidine derivatives also have been
evaluated for their anti-HIV-1 activity.[19,20] Anti-inflammatory and analgesic activi-
ties of some hexahydropyrimidines were evaluated with comparable results to diclo-
fenac sodium gel (Relaxyl gel) and aspirin.[21,22] Additionally, hexahydropyrimidines
were important as transport molecules for tumor inhibition and antineoplastic
Scheme 1. Synthesis of hexahydropyrimidines using dibenzoylmethane, primary amine, and
formaldehyde.

2717

2718
A. SALEH, M. MORTON, AND J. D’ANGELO
activity.[15,23–27] Antiviral activity of hexahydropyrimidines were also tested with
interesting results.[28]
Acid-mediated aminomethylation with formaldehyde and primary amines at
the a-position of 1,3-dicarbonyl compounds is a well-established procedure for the
synthesis of hexahydropyrimidines.[29–34] Indeed several 1,3-dicarbonyl compounds
have been reported to undergo this reaction under mild conditions at room tempera-
ture in the presence of catalytic amounts of FeCl3.[35] However, reports of this reac-
tion with dibenzoylmethane (DBM) are lacking. In an effort to prepare
hexahydropyrimidine derivatives of DBM, the known one-pot procedure for related
systems using FeCl3 was initially pursued.[35] Unexpectedly, when the products were
isolated and identified, the monocarbonyl derivatives were obtained (Scheme 1, 1–5).
The expected dicarbonyl derivatives were not detected. It was evident that one of the
benzoyl groups had been cleaved off in the course of the reaction. The presence of
benzoic acid, a logical by-product of the debenzoylation, was confirmed by NMR,
further supporting that conclusion. When DBM was replaced by either acetylacetone
(ACAC) or ethyl acetoacetate (EAA), the expected dicarbonyl products were suc-
cessfully isolated and characterized (Scheme 1, Table 1), suggesting that this obser-
vation is unique to the dibenzoyl system.
RESULTS AND DISCUSSION
Primary amine (Table 1) was reacted with DBM in the presence of aqueous for-
maldehyde and a catalytic amount of FeCl3 (5 mol%) in dichloromethane at room
temperature (Scheme 1). The reaction was monitored by thin-layer chromatography
(TLC). The product obtained was thoroughly purified and characterized by standard
spectroscopic and analytical methods to show that one of the benzoyl groups had
been cleaved off from the starting material dibenzoylmethane. Products obtained
(1–5) are listed in Table 1.
To explore this observation further, the reaction was replicated with the same
set of primary amines using acetylacetone and ethyl acetoacetate. In both cases,
analogous deacylation was not detected. Furthermore, because literature procedure
calls for only 6 h of stirring time, herein the elongated stirring time did not change
the course of the reaction and the expected products (6–13) were obtained in
comparable yields.[35]
The reaction of ACAC, according to Scheme 1, was repeated at elevated tem-
perature (refluxing temperature of chloroform). It was found that higher tempera-
ture did not affect the outcome of this reaction. In conclusion, all of the evidence,
taken together, makes it apparent that the observed carbonyl group fission can be
associated to the DBM system.
It turns out that the observed carbonyl group cleavage is not entirely unusual.
There are several literature precedents in which deacylation and debenzoylation have
been observed for 1,3-dicarbonyl compounds.[37,38] An interesting debenzoylation
have been observed for a,a-dialkylated dibenzoylmethane derivative when treated
with alkali.[39] However, the mechanism is still largely speculative.
The generally accepted mechanism for the reaction shown in Scheme 1 has
been recently discussed by Mukhopadhyay et al.[35] With this mechanism in mind,
currently it is not clear at which step the benzoyl group is lost. In an effort to

SYNTHESIS OF HEXAHYDROPYRIMIDINE DERIVATIVES
2719
Scheme 2. Debenzoylation of DBM-derived hexahydropyrimidines in the presence of FeCl3 and water.
determine when the debenzoylation was occurring, DBM was mixed with FeCl3
alone under the reaction conditions. When the product mixture was analyzed by
TLC, the formation of acetophenone, a putative by-product of the debenzoylation
should DBM denbzoylate in this case, was not detected. Similarly, benzoic acid
did not form either. It is highly likely that both water (from the aqueous formalde-
hyde) and the Lewis acid catalyst, FeCl3, are playing a role. The formation of stoi-
chiometric quantities of benzoic acid equivalent to that of the main product suggests
that water is essential. The presence of Lewis acid catalyst ought to facilitate the
nucleophilic addition of water to the carbonyl group. However, why this appears
to only occur in the DBM case remains unclear. Additionally, the Lewis acid iro-
n(III) chloride catalyst form is not known at this stage. A hydrated form
(FeCl3 ꢀ 6H2O) of the catalyst in the presence of water cannot be ruled out.
It is possible that the electron-withdrawing nature of the benzene ring just suf-
ficiently activate the carbonyl carbon. If this were the case, systems with an
electron-donating group attached to the benzene ring, or a mixed system containing
only one benzoyl group may result in different reactions. Unfortunately, the former,
to our knowledge, is not commercially available.
The observed debezoylation with DBM-hexahydropyrimidines is probably due
to the FeCl3-assisted water nucleophilic addition to one of the carbonyl carbons of the
initial hexahydropyrimidine product (Scheme 2). A transient intermediate I will be a
logical product of this addition. The adjacent phenyl group will also play an assistive
role in this nucleophilic addition. When DBM is compared to EAA and ACAC, the
absence of this additional assistance might explain the survival of the dicarbonyl
hexahydropyrimidine products of EAA and ACAC. Subsequently, the decompo-
sition of intermediate I will ultimately lead to the observed cleavage of the carbon–
carbon bond. The isolation of benzoic acid by-product supports that conclusion.
Literature procedures of DBM hexahydropyrimidine synthesis[36] require heat-
ing at much greater temperatures and less commercially available starting materials.
The present methodology has the advantages of taking place at room temperature
using simpler starting material and with comparable yields although with lower
overall atom economy.
EXPERIMENTAL
Column chromatography was performed on 230- to 400-mesh silica gel
(Merck) and TLC plates with silica gel 60 F254(Merck) were used. A mixture of

2720
A. SALEH, M. MORTON, AND J. D’ANGELO
AcOEt=hexane (30%) was used as eluent for all chromatographic separations.
Infrared (IR) spectra were recorded as either thin films or KBr discs on Magna-IR
560 Nicolet FT-IR spectrometer and are reported in wave numbers (cmꢁ1). NMR
spectra were recorded at room temperature on Brucker-Avance (III) spectrometer
at 400 MHz using CDCl3 as solvent. Chemical shifts are expressed in d values
1
(ppm) relative to tetramethylsilane (TMS) as internal standard for H and relative
to TMS (0.00 ppm) or to CDCl3 (77.05 ppm) for 13C NMR spectra. Coupling con-
stants J values are reported in hertz (Hz). Elemental analyses were performed on
a EuroEA 3000, EuroVector CHN analyzer. Structural assignments of the derived
compounds were established by analysis of their combined spectroscopic data.
General Procedure
A typical experimental procedure followed for the preparation of hexahydro-
pyrimidines using either dibenzoyl methane, acetylacetone, or ethyl acetoacetate
using FeCl3 catalyst is as follows: A mixture of 1,3-dicarbonyl compound (1 equiva-
lent), primary amine (2 equivalents), formaldehyde (3 equivalents, 37–41% aqueous
solution), and a catalytic amount of FeCl3 (5 mol%) was stirred for 24 h at room tem-
perature in dichloromethane. The solvent was removed by a rotary evaporator.
Crude products were purified by column chromatography with 30% ethyl acetate
in hexane. Spectral and analytical data of all the compounds in Table 1 are given
in the supplementary material. The spectral and analytical data of representative
compounds are as follows.
Compound 1, [1,3-Bis(4-chlorophenyl)hexahydropyrimidin-
5-yl](phenyl)methanone
1
White solid, FT-IR: nmax (thin film)=cmꢁ1 3052, 2827, 1674, and 1594; H
NMR (400 MHz,) dH: 7.93 (2H, d, J ¼ 7.4 Hz, PhH), 7.63 (1H, t, J ¼ 7.4 Hz,
PhH), 7.51 (2H, t, J ¼ 7.4 Hz, PhH), 7.29 (4H, d, J ¼ 8.7 Hz, ArH), 7.01 (4H, d,
J ¼ 8.7 Hz, ArH), 5.13 (1H, d, J ¼ 11.3 Hz, N-CH-N), 4.17 (1H, d, J ¼ 11.3 Hz,
N-CH-N), 3.93–4.03 (3H, m, CH, CH), 3.34 (2H, t, J ¼ 10.8 Hz, CH); 13C NMR
(CDCl3) dC: 199.4 (C, CO), 147.7 (C, Caromat), 135.7 (C, Caromat), 133.8
(CH, Caromat), 129.4 (CH, Caromat), 129.0 (CH, Caromat), 128.2 (CH, Caromat), 125.9
(C, Caromat), 118.8 (CH, Caromat), 68.7 (CH2, N-CH2-N), 52.4 (CH2, N-CH2), 40.6
(CH, CO-CH). Anal. calcd. for C23H20Cl2N2O: C, 67.16; H, 4.90; N, 6.81. Found:
C, 67.41; H, 4.92; N, 6.79.
Compound 6, 1,1’-[1,3-Bis(4-chlorophenyl)hexahydropyrimidine-5,
5-diyl]diethanone
1
White solid, FT-IR: nmax (thin film)=cmꢁ1 3088, 2992, 1691, and 1583; H
NMR (400 MHz,) dH: 7.27 (4H, d, J ¼ 8.8 Hz, ArH), 7.01 (4H, d, J ¼ 8.8 Hz,
ArH), 4.33 (2H, s, N-CH2-N), 3.81 (4H, s, CH2-N), 2.17 (6H, s CH3); 13C NMR
(CDCl3) dC: 203.2 (C, CO), 147.7 (C, Caromat), 129.3 (CH, Caromat), 126.6 (C, Caromat),
119.2 (CH, Caromat), 69.2 (CH2, N-CH2-N), 67.1 (C, C-CO), 53.3 (CH2, N-CH2),

SYNTHESIS OF HEXAHYDROPYRIMIDINE DERIVATIVES
2721
26.6 (CH3). Anal. calcd. for C20H20Cl2N2O2: C, 61.39; H, 5.15; N, 7.16. Found: C,
61.67; H, 5.17; N, 7.13.
Compound 11, Ethyl 5-Acetyl-1,3-bis(4-chlorophenyl)
hexahydropyrimidine-5-carboxylate
White solid, FT-IR: nmax (thin film)=cmꢁ1 3065, 2983, 1771, 1593, and 1496;
1H NMR (400 MHz,) dH: 7.19 (4H, d, J ¼ 8.9 Hz, ArH), 6.94 (4H, d, J ¼ 8.9 Hz,
ArH), 4.40 (1H, d, J ¼ 11.5 Hz, N-CH-N), 4.32 (1H, d, J ¼ 11.5 Hz, N-CH-N),
3.98 (2H, q, J ¼ 7.1, CH2-O), 3.90 (2H, d, J ¼ 12.7 Hz, CH2-N), 3.71 (2H, d,
J ¼ 12.7 Hz, CH2-N), 2.18 (3H, s, CH3-CO), 1.11 (3H, s, CH3); 13C NMR (CDCl3)
dC: 202.0 (C, CO), 168.0 (C, COO), 147.8 (C, Caromat), 129.1 (CH, Caromat), 125.8
(C, Caromat), 119.0 (CH, Caromat), 67.4 (CH2, N-CH2-N), 61.9 (CH2, CH2-CO), 59.9
(C, CH2-C-CH2), 53.5 (CH2, CH2-N), 26.5 (CH3, CH3-CO), 13.8 (CH3). Anal. calcd.
for C21H22Cl2N2O3:C, 59.87; H, 5.26; N, 6.65. Found: C, 60.03; H, 5.28; N, 6.68.
ACKNOWLEDGMENTS
The authors thank Fatmeh Soubani, Adnan Abu-Surrah, Bader Salameh, and
Kayed Abu-Safieh at the Hashemite University.
SUPPLEMENTAL MATERIAL
Supplemental data for this article can be accessed on the publisher’s website.
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