Facile catalyst-free pseudo five-component domino reactions in the expedient synthesis of 5-aroyl-1,3-diarylhexahydropyrimidines

Article abstract of DOI:10.1016/j.tetlet.2011.12.097

The pseudo five-component domino reactions of (E)-3-(dimethylamino)-1- arylprop-2-en-1-one, formaldehyde and aniline afford 5-aroyl-1,3- diarylhexahydropyrimidines in good yields under catalyst-free conditions. This transformation involving 4 C-N and 1 C-

Full text of DOI:10.1016/j.tetlet.2011.12.097

Tetrahedron Letters 53 (2012) 1144–1148
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Facile catalyst-free pseudo five-component domino reactions in the
expedient synthesis of 5-aroyl-1,3-diarylhexahydropyrimidines
Sivasubramanian Muthusaravanan a, Subbu Perumal a, , Abdulrahman I. Almansour b
⇑
a Department of Organic Chemistry, School of Chemistry, Madurai Kamaraj University, Madurai 625 021, India
b Department of Chemistry, College of Science, King Saud University, PO Box 2455, Riyadh 11451, Saudi Arabia
a r t i c l e i n f o
a b s t r a c t
Article history:
The pseudo five-component domino reactions of (E)-3-(dimethylamino)-1-arylprop-2-en-1-one, formal-
dehyde and aniline afford 5-aroyl-1,3-diarylhexahydropyrimidines in good yields under catalyst-free
conditions. This transformation involving 4 C–N and 1 C–C bond formations in a one pot operation pre-
sumably proceeds via Michael addition–elimination–Mannich type reaction-condensative annulation–
reduction sequence.
Received 24 October 2011
Revised 21 December 2011
Accepted 23 December 2011
Available online 30 December 2011
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Domino reaction
(E)-3-(Dimethylamino)-1-arylprop-2-en-1-
one
Formaldehyde
Aniline
5-Aroyl-1,3-diarylhexahydropyrimidines
Hexahydropyrimidines constitute an important class of natural
and unnatural products, many of which exhibit useful biological
activity.1 The hexahydropyrimidine skeleton is present in a num-
ber of alkaloids, eudistomidins H and I (Fig. 1),2 tetraponerines,3
verbamethine4 and verbametrine.5 Hexetidine6 is a formalde-
hyde-releasing antimicrobial agent employed in mouthwashes
and numerous products of veterinary and human drugs. Besides,
hexahydropyrimidines also act as prodrugs of pharmacologically
active di-7 and polyamines.8 N-substituted hexahydropyrimidines
serve as synthetic intermediates for spermidine nitroimidazole
drugs useful in the treatment of A549 lung carcinoma.9 Polysubsti-
tuted hexahydropyrimidine scaffolds are one of the most com-
monly encountered heterocycles in medicinal chemistry with
diverse pharmacological properties such as antibacterials,10 and
parasiticides,11 antiviral, antitumor and antiinflammatory.12 Hexa-
hydropyrimidine nucleus also serves as a protecting group in selec-
tive acylations and additions of 1,3-diamines owing to its facile
cleavage in mild acidic media.13
by the microwave-assisted reaction of N-acyl-N0-aryl-1,3-propan-
ediamines with formaldehyde.16 It is pertinent to note that
1,3-diarylhexahydropyrimidines have been synthesized by the
FeCl3-catalyzed reaction of 1,3-dicarbonyl compounds, amines
and formaldehyde.17 1,3-Diaryl-5-spirohexahydropyrimidines
have also been synthesized by L-proline-catalyzed reaction of ani-
lines, formaldehyde and cyclohexanones.18 In this context, now we
report for the first time the synthesis of hitherto unreported 5-ar-
oyl-1,3-diarylhexahydropyrimidines from the reactions of (E)-3-
(dimethylamino)-1-arylprop-2-en-1-one, aniline and an excess of
formaldehyde by a pseudo five-component domino protocol under
catalyst-free conditions. A previous related study reports that the
reaction of (E)-1-aryl-3-(benzyl/arylamino)prop-2-en-1-one, pri-
mary amine and formaldehyde affords tetrahydropyrimidines,19
which would require an additional reduction step to obtain the
corresponding hexahydropyrimidines. The present study stems as
a continuation of our research programme embarked on the
construction of novel heterocycles employing domino multi-
component reactions occurring in one pot operation.20
Hexahydropyrimidines are classically prepared by the conden-
sation of substituted propane-1,3-diamines with aldehydes and
ketones.14,15 This method, however, limits the range of substitution
at 5-position of the hexahydropyrimidines, being restrained by the
availability of appropriately functionalized 1,3-diamines. Very re-
cently, N-acyl-N-arylhexahydropyrimidines have been obtained
Incidentally, multi-component reactions (MCRs)21,22 constitute
a highly valuable synthetic tool for the discovery of new com-
pounds required by pharmaceutical and agrochemical industries.
MCRs provide convergent, atom-economic and eco-friendly syn-
thetic protocols for molecules of high levels of complexity and
diversity, enabling the flexible assembly of three or more simple
building blocks in practical one-pot operations, besides being ame-
nable for combinatorial library generation.23 In particular, the
⇑
Corresponding author. Tel./fax: +91 452 2459845.
E-mail address: subbu.perum@gmail.com (S. Perumal).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.12.097

S. Muthusaravanan et al. / Tetrahedron Letters 53 (2012) 1144–1148
1145
CH3
O
N
CH3
H2N
HCHO
3
NMe2 + PhNH2
+
N
CH3
1
2
Me
CH3
H3C
1:2:2 or 1:2:3
molar ratio
1:2:4 molar
ratio
120 °C, 5-6 h
Hexetidine
DMF
NMe
Br
O
O
NMe
H
H
N
N
N
N
Br
N
Me
N
N
Me
N
Me
Me
eudistomidin l
eudistomidin H
8n (21 or 15%)
4n (69%)
Figure 1. Some naturally occurring hexahydropyrimidine alkaloids and drugs.
Scheme 1. Model reaction for optimization of molar equivalents of reactants.
molar ratio of 1:2:4 of 1, aniline and formaldehyde was employed
in all subsequent reactions (Scheme 2).
construction of heterocycles through MCR-based strategies is ac-
corded great importance,24 as about 60% of drugs currently in the
market or in the pipeline are heterocycles.
To identify the ideal solvent, the reaction furnishing 4n was
investigated in dioxane, dimethyl sulfoxide, toluene and triethyl-
amine (Table 1, entries 10–13). The results show that the reaction
when performed in DMF at 120 °C for 6 h afforded a maximum
yield of the product 4n (Table 1, entry 4). Under solvent-free con-
ditions, the reaction furnished a mixture of products, which in-
cluded only traces of 4n (Table 1, entry 14). Hence all the
subsequent reactions of a series of (E)-3-(dimethylamino)-1-aryl-
prop-2-en-1-ones with differently substituted anilines and
formaldehyde were performed in a 1:2:4 molar ratio in DMF at
120 °C, which were completed in 5–6 h25 (Table 2 and Scheme
2). After completion of the reaction, removal of the solvent and
flash column chromatographic purification of the residue furnished
Initially, the reaction of (E)-3-(dimethylamino)-1-(4-methyl-
phenyl)prop-2-en-1-one 1, aniline and formaldehyde in different
molar ratios was investigated in DMF at 120 °C with a view to opti-
mizing the reaction with respect to molar equivalents of the reac-
tants (Table 1; Scheme 1). These reactants in 1:2:2 and 1:2:3 molar
ratios led to the formation of tetrahydropyrimidine (8n) in 21% and
15% yields, respectively with traces of hexahydropyrimidine 4n. It
is found that the reactions of 1:2:4 and 1:2:6 molar ratios of the
reactants furnished almost similar yields, respectively, 69% and
71% yield of 4n. When 1 (Ar = p-MeC6H4), aniline and formalde-
hyde were used in 1:3:4 molar equivalents, the yield of 4n was
found to be almost halved to 35%. Consequently, the optimum
Table 1
Optimization of relative molar equivalents, solvent, temperature and reaction time for the synthesis of 4n
O
N
Me
N
4n
Entry
Solvent
Temp. (°C)
Mol ratio of 1, 2 and 3
Reaction time (h)
Yield of 4na (%)
1
2
3
4
5
6
7
8
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
120
120
120
120
120
60
1:2:2
1:2:3
1:2:4
1:2:6
1:3:4
1:2:4
1:2:4
1:2:4
1:2:4
1:2:4
1:2:4
1:2:4
1:2:4
1:2:4
6
6
5
6
5
5
6
6
6
8
10
10
10
5
21(8n)b
15(8n)b
69
71
35
28
35
48
60
80
100
110
105
110
140
90
9
DMF
10
11
12
13
14
Dioxane
Toluene
DMSO
Et3N
51
c
—
41
c
—
—
d
None
100
a
b
c
Isolated yield after purification by column chromatography.
Only tetrahydropyrimidine 8n (Ar = p-MeC6H4; Ar0 = C6H5) (Scheme 1) could be isolated from these reactions.
No reaction occurred.
Only traces of product formed.
d

1146
S. Muthusaravanan et al. / Tetrahedron Letters 53 (2012) 1144–1148
O
Ar'
Ar
N
O
120 °C, 5-6 h
DMF
+
2Ar'NH2
4HCHO
N
Ar'
+
Ar
NMe2
4
1
3
2
58-72%
Scheme 2. One-pot synthesis of 5-aroyl-1,3-diarylhexahydropyrimidines 4.
Table 2
a broad doublet at 3.86 ppm (J = 12.0 Hz), the vicinal coupling of
these protons with H-5 remaining unresolved. The H-4ax,6ax ap-
pear almost as a triplet at 3.31 ppm resulting from one large gem-
inal coupling with H-4eq,6eq (J = 12.0 Hz) and one large vicinal
diaxial coupling with H-5 (J = 11.1 Hz). The above results disclose
that both N-aryl rings prefer the same orientation, presumably
the equatorial orientation.
Interestingly, the structure determined from X-ray crystallo-
graphic studies26 (vide Supplementary data) shows one N-aryl ring
in equatorial and another in axial orientation. This difference in the
stereochemistry of 4 in solid state from that deduced in solution, is
presumably favoured by intermolecular interactions arising from
crystal packing. Presumably, atomic inversion at one of the nitro-
gens ushers in conformational equilibrium (Scheme 3), the posi-
tion of which critically depends on whether the compound exists
in solid state or in solution. Except the difference in the orientation
of one of the N-aryl rings, all other structural aspects of 4 in solu-
tion and solid state remain the same.
Synthesis of 5-aroyl-1,3-diarylhexahydropyrimidines 4a
Comp. Ar in 1 and 4 Ar0 in 2 and 4 Reaction time (h) Yield of 4b (%)
4a
4b
4c
4d
4e
4f
4g
4h
4i
C6H5
4-MeOC6H4
4-MeOC6H4
4-MeOC6H4
4-ClC6H4
4-BrC6H4
4-BrC6H4
4-BrC6H4
4-BrC6H4
4-ClC6H4
4-ClC6H4
4-FC6H4
5
5
5
6
6
5
6
5
5
5
5
6
6
5
6
5
6
6
62
68
60
58
60
63
68
71
63
66
61
58
72
69
59
68
58
—
4-H3CC6H4
4-ClC6H4
3-O2NC6H4
C6H5
4-H3CC6H4
4-ClC6H4
3-O2NC6H4
C6H5
4j
4k
4l
4-H3CC6H4
4-ClC6H4
3-O2NC6H4
C6H5
4-FC6H4
4-FC6H4
4m
4n
4o
4p
4q
4-H3CC6H4
4-ClC6H4
4-ClC6H4
4-MeOC6H4
4-MeOC6H4
C6H5
4-MeC6H4
C6H5
4-ClC6H4
4-O2NC6H4
c
—
A plausible mechanism for the formation of hexahydropyrimi-
dine 4 is depicted in Scheme 4. Probably, this transformation is
triggered by an initial Michael addition of aniline to 1 followed
by the elimination of dimethylamine leading to intermediate 5,
which could subsequently undergo Mannich type reaction with
imine 6, generated from formaldehyde and aniline, leading to
intermediate 7. This intermediate, 7 subsequently condenses with
a molecule of formaldehyde affording tetrahydropyrimidine 8,
which in its protonated form, is presumably reduced by the formic
acid, arising from the air oxidation of excess of formaldehyde
leading to 4. The air oxidation of formaldehyde to formic acid
a
Reactions were performed with 1:2:4 molar equivalents of reactants in DMF at
120 °C.
b
Isolated yield after purification by column chromatography.
Product not formed.
c
5-aroyl-1,3-diarylhexahydropyrimidines 4 in a pure form in 58–
72% yields (Table 2). It is pertinent to note that p-nitroaniline failed
to react, presumably due to its diminished nucleophilicity and
hence this method is applicable only to anilines, devoid of power-
ful electron-withdrawing groups.
and the latter reducing the C@C bond of
a,b-unsaturated ketone
has been reported previously.27 The proposed reduction of the
iminium ion 9 by formate finds credence from the analogous
mechanism of the Leuckart and Wallach reductive alkylation of
ammonium (or amine) salts of formic acid or formamides by alde-
hydes and ketones in the presence of excess formic acid.28 Thus the
entire transformation occurring in a one-pot operation proceeds
via Michael addition–elimination–Mannich type reaction-annula-
tion via condensation–reduction domino sequence, which is re-
ported now for the first time.
The structures of 5-aroyl-1,3-diarylhexahydropyrimidines 4 are
in accord with the 1H, 13C and 2D NMR spectroscopic data as illus-
trated for a representative example, 4m. In the 1H NMR spectrum
of 4m (Fig. 2), the H-5 appears as a triplet of triplets at 3.98 ppm
(J = 12.0 and 3.3 Hz), the J values arising respectively from vicinal
diaxial coupling of H-5 with H-4ax,6ax and vicinal axial-equatorial
coupling with H-4eq,6eq. This, in turn, discloses that the aroyl
group is in equatorial orientation. The doublets at 4.09 and
4.98 ppm (J = 12.0 Hz) are due to 2-CH2. The H-4eq,6eq appear as
3.31, 2H, t
(J = 12.0, 11.1 Hz)
H
H
H
H
199.6
53.2
H
COAr
6
53.2
H
4
40.8
5
H
3.86, 1H, bd
3.86, 1H, bd
H
(J =12.0 Hz)
(J=12.0 Hz)
H
2
H
Ar'
Ar'
70.5
N
N
H
53.2
3
53.2
O
1
H
H
H
H
F
1H, tt, 3.98
(J = 12.0, 3.3 Hz)
F
40.8
N
70.5
H
4.09, 4.98 d, 2H
N
H
H
(J=12.0 Hz)
H
Ar = C6H5; Ar’= 4-FC6H4
Figure 2. Selected HMBCs, 1H and 13C chemical shifts of 4m.

S. Muthusaravanan et al. / Tetrahedron Letters 53 (2012) 1144–1148
1147
H
H
H
H
H
H
COAr
COAr
COAr
H
H
H
H
H
N
H
H
H
N
H
N
.
.
..
.
.
Ar'
Ar'
Ar'
N
H
Ar'
H
N
H
N
Ar'
H
Ar'
H
H
..
Transition state for
inversion at one nitrogen
Scheme 3. Nitrogen inversion and conformational equilibrium of hexahydropyrimidines 4.
3. Renson, B.; Merlin, P.; Daloze, D.; Braekman, J. C.; Roisin, Y.; Pasteels, J. M. Can.
J. Chem. 1994, 72, 105–109.
4. Guggisberg, A.; Drandarov, K.; Hesse, M. Helv. Chim. Acta 2000, 83, 3035–3042.
5. (a) Braekman, J. C.; Daloze, D.; Flammang, R.; Maquestiau, A. Org. Mass
Spectrom. 1989, 24, 837–838; (b) Drandarov, K.; Guggisberg, A.; Hesse, M. Helv.
Chim. Acta 1999, 82, 229–234.
Condensation
HCHO
Ar'NH2
H2O
Ar'
O
H
H2C
N
Ar
HNMe2
6
NH
Ar'
6. Smith, P. A. S.; Loeppky, R. N. J. Am. Chem. Soc. 1967, 89, 1147–1157.
7. (a) Billman, J.; Khan, M. J. Med. Chem. 1968, 11, 312–314; (b) Chang, Y. H.;
Evanenga, G. R.; McLamore, W. M. U.S. Patent 3 729 564, 1973; Chem. Abstr.
1974, 79, 18762.
8. (a) Golding, B. T.; Nassereddin, I. K. J. Chem. Soc., Perkin Trans. 1 1985, 2011–
2015; (b) Bergeron, R. J.; Seligsohn, H. W. Bioorg. Chem. 1986, 14, 345–355.
9. Siddiqui, A. Q.; Merson-Davies, L.; Cullis, P. M. J. Chem. Soc., Perkin Trans. 1 1999,
3243–3252.
5
Ar'NH2
2
Mannich-type
reaction
Michael addition-
elimination
O
O
Ar
Ar'
N
H
NH
Ar'
Ar
1
NMe2
7
10. Bisceglia, J. A.; Garcia, M. B.; Massa, R.; Magri, M. L.; Zani, M.; Gutkind, G. O.;
Orelli, L. R. J. Heterocycl. Chem. 2004, 41, 85–90.
11. (a) Khan, M. S.; Gupta, M. Pharmazie 2002, 57, 377–383; (b) Kalyanam, N.;
Parthasarathy, P. C.; Ananthan, L.; Manyunatha, S. G.; Likhate, M. A. Indian J.
Chem., Sect B 1992, 31, 243–247; (c) Vanelle, P.; Maldonado, J.; Crozet, M. P.;
Senouki, K.; Delmas, F.; Gasquet, M.; Timon-David, P. Eur. J. Med. Chem. 1991,
26, 709–714.
12. (a) Tu, S.; Miao, C.; Fang, F.; Youjian, F.; Li, T.; Zhuang, Q.; Zhang, X.; Zhu, S.; Shi,
D. Bioorg. Med. Chem. Lett. 2004, 14, 1533–1536; (b) Kappe, C. O. Tetrahedron
1993, 49, 6937–6963; (c) Kappe, C. O. Eur. J. Med. Chem. 2000, 35, 1043–1052;
(d) Russowski, D.; Canto, R. F. S.; Sanches, S. A. A.; D’Oca, M. G. M.; Fatima, A. D.;
Carvalho, J. E. D. Bioorg. Chem. 2006, 34, 173–182.
Ar
Domino reactions
Ar'
O
N
HCHO
H2O
Condensative
annulation
N
Ar'
4
Reduction
Ar
H+
Ar
CO2
Ar'
H
O
N
Ar'
´
13. Rodryguez, B.; Bolm, C. J. Org. Chem 2006, 71, 2888–2891.
O
H
N
..
14. (a) Chantrapromma, K.; McManis, J. S.; Ganem, B. Tetrahedron Lett. 1980, 21,
2475–2476; (b) Chantrapromma, K.; Ganem, B. Tetrahedron Lett. 1981, 22, 23–
24; (c) Evans, R. F. Aust. J. Chem. 1967, 20, 1643–1661; (d) Finch, H.; Peterson, E.
A.; Ballard, S. A. J. Am. Chem. Soc. 1952, 74, 2016–2021; (e) Jutz, C.; Kirschner, A.
F.; Wagner, R. M. Chem. Ber. 1977, 110, 1259–1268; (f) Perillo, I. A.; Garcia, M.
B.; Bisceglia, J. A.; Orelli, L. R. J. Heterocycl. Chem. 2002, 39, 655–661; (g)
Katrizky, A. R.; Singh, S. K.; He, H. Y. J. Org. Chem. 2002, 67, 3115–3117.
15. (a) Mayr, M.; Buchmeiser, M. R. Macromol. Rapid Commun. 2004, 25, 231–236;
(b) Mayr, M.; Wurst, K.; Ongania, K. H.; Buchmeiser, M. R. Chem. Eur. J. 2004, 10,
1256–1266.
N
Protonation
O
8
N
Ar'
Ar'
9
O
O
O
H
H
H
H
O
3
Air oxidation
Scheme 4. Plausible mechanism for the formation of 5-aroyl-1,3-diarylhexahydro-
pyrimidines 4.
16. Díaz, J. E.; Bisceglia, J. Á.; Mollo, M. C.; Orelli, L. R. Tetrahedron Lett. 2011, 52,
1895–1897.
17. Mukhopadhyay, C.; Rana, S.; Butcher, R. J. Tetrahedron Lett. 2011, 52, 4153–
4157.
18. Wei, H. L.; Yan, Z. Y.; Niu, Y. N.; Li, G. Q.; Liang, Y. M. J. Org. Chem. 2007, 72,
8600–8603.
19. Chanda, K.; Dutta, M. C.; Karim, E.; Vishwakarma, J. N. J. Heterocycl. Chem. 2004,
41, 627–631.
In conclusion, we have described a facile pseudo five-compo-
nent synthesis of novel 5-aroyl-1,3-diarylhexahydropyrimidines
via the domino sequence of reactions from simple, readily available
starting materials in a one pot operation in good yields, consider-
ing the number of reactions involved, under catalyst-free condi-
tions by judicious optimization of the reaction conditions.
20. For our representative articles see: (a) Prasanna, P.; Balamurugan, K.; Perumal,
S.; Menéndez, J. C. Green Chem. 2011, 13, 2123–2129; (b) Michael Rajesh, S.;
Devi Bala, B.; Perumal, S.; Menéndez, J. C. Green Chem. 2011, 13, 3248–3254; (c)
Indumathi, S.; Perumal, S.; Menéndez, J. C. J. Org. Chem. 2010, 75, 472–475.
21. For general reviews on multicomponent reactions, see: (a) Dömling, A.; Ugi, I.
Angew. Chem., Int. Ed. 2000, 39, 3168–3210; (b) Ugi, A. Molecules 2003, 8, 53–
66; (c) Orru, R. V. A.; de Greef, M. Synthesis 2003, 10, 1471–1499; (d) Zhu, J. Eur.
J. Org. Chem. 2003, 1133–1144; (e) Tejedor, D.; González-Cruz, D.; Santos-
Expósito, A.; Marrero-Tellado, J. J.; de Armas, P.; García-Tellado, F. Chem. Eur. J.
2005, 11, 3502–3510; (f) Ramón, D. J.; Yus, M. Angew. Chem., Int. Ed. 2005, 44,
1602–1634; (g) Dömling, A. Chem. Rev. 2006, 106, 17–89; (h) Liéby-Muller, F.;
Simon, C.; Constantieux, T.; Rodriguez, J. QSAR Comb. Sci. 2006, 25, 432–438; (i)
Guo, H.; Ma, J. Angew. Chem., Int. Ed. 2006, 45, 354–366; (j) Tejedor, D.; García-
Tellado, F. Chem. Soc. Rev 2007, 36, 484–491; (k) Guillena, G.; Ramón, D. J.; Yus,
M. Tetrahedron: Asymmetry 2007, 18, 693–700; (l) Toure, B. B.; Hall, D. G. Chem.
Rev. 2009, 109, 4439–4486; (m) Ganem, B. Acc. Chem. Res. 2009, 42, 463–472.
22. (a) For a monograph on MCRs, see: Zhu, J.; Bienaymé, H. (Eds.), Multicomponent
Reactions. Wiley-VCH, 2005.; (b) For a symposium in print on MCRs, see:
Marek, I. (Ed.) Tetrahedron Symposia-in-Print 2005, 67, 11299.
Acknowledgement
S.M., S.P. and A.I.M. gratefully acknowledge the Deanship of Sci-
entific Research at King Saud University (KSU) for the research
grant, RGP-VPP-128.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2011.12.097.
References and notes
23. For reviews on the use of MCRs in drug discovery, see: (a) Tietze, L. F.; Modi, A.
Med. Res. Rev. 2000, 20, 304–322; (b) Weber, L. Curr. Med. Chem. 2002, 9, 2085–
2093; (c) Hulme, C.; Gore, V. Curr. Med. Chem. 2003, 10, 51–80.
24. For reviews, see: (a) Sapi, J.; Laronze, J. Y. Arkivoc 2004, 208–222; (b) Isambert,
N.; Lavilla, R. Chem. Eur. J. 2008, 14, 8444–8454; (c) Sunderhaus, J. D.; Martin, S.
F. Chem. Eur. J. 2009, 15, 1300–1308.
1. Jain, K. S.; Chitre, T. S.; Miniyar, P. B.; Kathiravan, M. K.; Bendre, V. S.; Veer, V. S.;
Shahane, S. R.; Shishoo, C. J. Curr. Sci. 2006, 90, 793–803.
2. Suzuki, T.; Kubota, T.; Kobayashi, J. Bioorg. Med. Chem. Lett. 2011, 21, 4220–
4223.

1148
S. Muthusaravanan et al. / Tetrahedron Letters 53 (2012) 1144–1148
25. General procedure for the synthesis of 5-aroyl-1,3-diarylhexahydropyrimi
dines 4: mixture of enaminone (1 mmol), aniline (2 mmol) and
40.5, 52.4, 68.5, 104.0, 113.2, 119.1, 128.4, 129.7, 132.3, 133.3, 148.2, 198.9.
Anal. Calcd for C24H22Br2N2O: C, 56.05; H, 4.31; N, 5.45%; Found C, 56.10; H,
4.35; N, 5.48%.
A
1
2
formaldehyde 3 (4 mmol) in DMF (5 ml) was heated at 120 °C for 5–6 h. The
reaction progress was monitored by thin layer chromatography. After
completion of the reaction, the solvent was removed and the product was
purified by flash column using petroleum ether–ethyl acetate mixture (4:1 v/v)
as eluent to afford 5-aroyl-1,3-diarylhexahydropyrimidines 4. Spectroscopic
data for representative 5-aroyl-1,3-diarylhexahydropyrimidines are given
below.
Procedure for (1,3-diphenyl-1,2,3,4-tetrahydropyrimidin-5-yl)(p-tolyl)metha
none 8n: When the reactants, (E)-3-(dimethylamino)-1-(4-methylphenyl)
prop-2-en-1-one 1, aniline and formaldehyde, were taken in 1:2:2 or 1:2:3
molar equivalents and the reaction performed as above for obtaining 4, the
tetrahydropyrimidine, (1,3-diphenyl-1,2,3,4-tetrahydropyrimidin-5-yl)(p-tolyl)
methanone 8n was obtained, in 21% and 15% yield respectively, as colourless
solid. mp = 144–146 °C; 1H NMR (300 MHz, CDCl3) dH 2.39 (s, 3H), 4.00 (s, 2H),
5.15 (s, 2H), 6.88–6.99 (m, 5H), 7.12–7.37 (m, 8H), 7.45–7.48 (m, 2H) 13C NMR
(75 MHz, CDCl3) dc 21.40, 47.12, 65.44, 110.96, 117.82, 121.12, 124.34, 128.57,
12.83, 129.30, 129.78, 136.73, 140.62, 144.01, 145.53, 148.50, 193.28. Anal.
Calcd for C24H22N2O: C, 81.33; H, 6.26; N, 7.90%; Found C, 81.40; H, 6.21; N,
7.95%.
(1,3-Bis(4-fluorophenyl)hexahydropyrimidin-5-yl)(phenyl)methanone
4m:
Isolated as white solid. Yield: 72%; mp = 124–126 °C; 1H NMR (300 MHz,
CDCl3) dH 3.31 (t, 2H, J = 12.0, 11.1 Hz), 3.86 (bd, 2H, J = 12.0 Hz), 3.98 (tt, 1H,
J = 12.0, 3.3 Hz), 4.09 (d, 1H, J = 12.0 Hz), 4.98 (d, 1H, J = 12.0 Hz), 6.98–7.03 (m,
8H), 7.43–7.48 (m, 2H), 7.56–7.62 (m, 1H), 7.90 (d, 2H, J = 8.1 Hz).13C NMR
2
(75 MHz, CDCl3) dc 40.8, 53.2, 70.5, 115.9, (d, JC,F = 22.1 Hz), 119.6, (d,
1
3JC,F = 7.6 Hz), 128.2, 128.9 133.6, 135.8, 145.7, 157.8, (d, JC,F = 238.6 Hz),
26. Crystallographic data (excluding structure factors) for (1,3-bis(4-
fluorophenyl)hexahydropyrimidin-5-yl)(4-chlorophenyl)methanone 4k in
this Letter have been deposited with Cambridge Crystallographic Data Centre
as supplementary publication number CCDC 845808. Copies of the data can be
obtained, free of charge, on application to CCDC, 12 Union Road, Cambridge
CB2 1EZ, UK [fax: +44 (0) 1223 336033 or e-mail: deposit@ccdc.cam.ac.uk].
27. Ferreira, S. B.; da Rocha, D. R.; Carneiro, J. W. M.; Santos, W. C.; Ferreira, V. F.
Synlett 2011, 11, 1551–1554.
28. (a) Musumarra, G.; Sergi, C. Heterocycles 1994, 37, 1033–1039; (b) Lee, S.-C.;
Park, S. B. Chem. Commun. 2007, 36, 3714–3716; (c) Leuckart, R. Ber. Dtsch.
Chem. Ges. 1885, 18, 2341–2344; (d) Wallach, O. Ber. Dtsch. Chem. Ges. 1891, 24,
3992–3993; (e) Moore, M. L. Org. React. 1949, 5, 301–330; (f) Wallach, O. Ann.
1892, 272, 99; (g) Muzalevskiy, V. M.; Valentine, G. N.; Shastin, A. V.;
Balenkova, E. S.; Haufe, G. J. Fluorine Chem. 2008, 129, 1052–1055; (h)
O’Connor, D.; Lauria, A.; Bondi, S. P.; Saba, S. Tetrahedron Lett. 2011, 52, 129–
132.
199.6. Anal. Calcd for C23H20 F2N2O: C, 73.00; H, 5.33; N, 7.40%;. Found C,
73.10; H, 5.42; N, 7.35%.
(1,3-Bis(4-fluorophenyl)hexahydropyrimidin-5-yl)(4-chlorophenyl)methanone
4k: Isolated as colourless solid. Yield: 61%; mp = 140–143 °C; 1H NMR
(300 MHz, CDCl3) dH 3.23 (t, 2H, J = 12.3 Hz), 3.74–3.89 (m, 3H), 4.02 (d, 1H,
J = 12.3 Hz), 4.89 (d, 1H, J = 12.3 Hz), 6.91–6.97 (m, 8H), 7.36 (d, 2H, J = 8.4 Hz),
7.75 (d, 2H, J = 8.4 Hz) 13C NMR (75 MHz, CDCl3) dc 40.8, 53.2, 70.5, 115.9, (d,
2JC,F = 22.1 Hz), 119.6, (d, 3JC,F = 7.7 Hz), 129.3, 129.6, 134.0, 140.2, 145.6, 157.8,
1
(d, JC,F = 239.1 Hz), 198.4. Anal. Calcd for C23H19ClF2N2O: C, 66.91; H, 4.64; N,
6.79%; Found C, 66.95; H, 4.69; N, 6.85%.
(1,3-Bis(4-bromophenyl)hexahydropyrimidin-5-yl)(p-tolyl)methanone
4f:
Isolated as colourless solid. Yield: 63%; mp = 161–165 °C; 1H NMR (300 MHz,
CDCl3) dH 2.44 (s, 3H), 3.36 (t, 2H, J = 12.3 Hz), 4.0–4.02 (m, 3H), 4.17 (d, 1H,
J = 12.3 Hz), 5.30 (d, 1H, J = 12.3 Hz), 6.96 (t, 2H, 7.5 Hz), 7.12 (d, 4H, J = 8.1 Hz),
7.26–7.37 (m, 4H), 7.86 (d, 2H, J = 8.1 Hz) 13C NMR (75 MHz, CDCl3) dc 21.6,