N-arylhexahydropyrimidines. Part 1. Synthesis and 1H NMR characterization of 1,3-Di and 1,2,3-trisubstituted derivatives

Article abstract of DOI:10.1002/jhet.5570390409

A series of N-arylhexahydropyrimidines 1a-I were synthesized by condensation of N-aryl-N′-alkyl- (or aryl)-1,3-propanediamines 2a-h with aldehydes. Reactions with formaldehyde proceeded in hydroalcoholic solution, while condensation with aromatic aldehyde

Full text of DOI:10.1002/jhet.5570390409

1
Jul-Aug 2002
655
N-Arylhexahydropyrimidines. Part 1. Synthesis and H NMR
Characterization of 1,3-Di and 1,2,3-Trisubstituted Derivatives
*
Isabel A. Perillo, María B. García, Juan Á. Bisceglia and Liliana R. Orelli
Departamento de Química Orgánica, Facultad de Farmacia y Bioquímica,
Universidad de Buenos Aires, Junín 956 (1113), Buenos Aires, Argentina
Received November 2, 2001
A series of N-arylhexahydropyrimidines 1a-l were synthesized by condensation of N-aryl-N'-alkyl- (or
aryl)-1,3-propanediamines 2a-h with aldehydes. Reactions with formaldehyde proceeded in hydroalcoholic
solution, while condensation with aromatic aldehydes required in general the use of activated molecular
1
sieves. H NMR spectra of compounds 1a-l were analyzed and the results correlated with their conforma-
tional features. Derivatives devoid of a 2-substituent 1a-g show fast ring reversal and N-inversion. The pres-
ence of a 2-aryl group shifts the ring reversal equilibrium towards conformations where the 2-aryl substituent
is equatorial. Differential assignment of axial and equatorial hydrogens in these compounds was made on the
basis of coupling constants and chemical shift values. In compound 1k spectral data suggest the axial orien-
tation of the N-methyl group. Such findings were confirmed in the corresponding NOESY spectrum.
J. Heterocyclic Chem., 39, 655 (2002).
Introduction.
salts with metal hydride complexes led, in all cases, to
acyclic overreduction products, through selective cleavage
of the hexahydropyrimidine nucleus.
Hexahydropyrimidines are a subject of interest due to
their pharmacological activity, as some members behave
as prodrugs of biologically active di [1] and polyamines
[2]. Besides, some suitably substituted derivatives form
stable complexes with metal ions, acting as antiamoebic
[3] or decontaminating agents [4]. In organic synthesis,
the hexahydropyrimidine system has been widely
employed as protecting group in selective acylations [5]
and additions [6] of 1,3-diamines, due to its easy cleavage
in mild acid medium. Other applications include the syn-
thesis of selectively N-substituted trimethylenediamines
and tetrahydropyrimidinium salts through reduction [7]
and dehydrogenation [8] reactions respectively.
In the present work hexahydropyrimidines 1a-l were syn-
thesized by the classical method (Scheme I). One limita-
tion of this procedure was the preparation of the corre-
sponding unsymmetrically N,N'-disubstituted 1,3-propane-
diamines 2. According to their substitution patterns, such
compounds were synthesized employing two alternative
procedures developed in previous work [15,16].
1
The assignment of H NMR spectra of compounds 1 is
discussed and some spectral parameters are correlated with
their stereochemical and conformational features.
Synthesis.
The hexahydropyrimidine ring is also interesting from
the perspective of conformational analysis. The stereo-
Unsymmetrically substituted diamines 2a-e,h were syn-
thesized by the sequences depicted in Scheme I, in which
one of the amino groups is generated by aminolysis of a
bromo derivative and the other by reduction of an amide.
Route a, involves reduction of N-acyl-N'-aryltrimethylene-
diamines 3 [15]. This route led to good yields of the
desired diamines 2b,e-h in the case of benzamides and
alkanamides (3, R= aryl or alkyl). Instead, reduction of
formamides 3 (R=H) with borane led to low yields of the
corresponding N-methyl derivatives, due to incomplete
decomposition of boron derivatives in the reaction work-
up. A second limitation of Route a, is that it cannot be
employed for the synthesis of derivatives in which the
amino moiety generated by reduction of the amide con-
tains a secondary or tertiary alkyl or an aryl substituent.
Thus, diamines 2a,d were synthesized with high yields by
reduction of the corresponding 3-arylaminopropanamides
4 (Scheme I, Route b) [16].
1
chemistry of such systems was extensively studied by H
13
and C NMR between 1970 and 1980 [9] and more
recently by computational methods [10]. It was observed
that certain chemical shifts and coupling constants in the
1
H NMR spectra of hexahydropyrimidines are quite sensi-
tive to the conformation. Such parameters have been
employed for the elucidation of the stereochemistry of
more complex diazabicycloalkanes [11]. Data in the liter-
ature, however, are restricted to N,N'-dialkylhexahydropy-
rimidines, while N-aryl-N'-alkyl and N,N'-diaryl deriva-
tives have not been studied yet.
The classic synthesis of 1,3-disubstituted hexahydropy-
rimidines involves the condensation of adequately substi-
tuted 1,3-propanediamine derivatives with carbonyl com-
pounds. Alternative synthetic methods involve reduction
of cyclic urea derivatives [12] or dihydropyrimidines [13],
leading to 2 or 3-unsubstituted hexahydropyrimidines
respectively. In previous work we attempted the synthesis
of 1,2-diaryl-3-methylhexahydropyrimidines by reduction
of the corresponding cyclic amidinium salts [14].
However, treatment of 1,4,5,6-tetrahydropyrimidinium
Condensation of precursors 2a-h with aldehydes led to
the corresponding hexahydropyrimidines 1a-l (Scheme I).
It was observed that optimum reaction conditions
depended strongly on the type of carbonyl compound
employed and also on the stability towards hydrolysis of

656
I. A. Perillo, M. B. García, J. Á. Bisceglia and L. R. Orelli
Vol. 39
Route a
Route b
Compd.
Ar
p-ClC H
R
R
2
1
1a, 2a
1b, 2b
1c, 2c
1d, 2d
1e, 2e
1f, 2f
1g, 2g
1h, 2h
1i
H
H
H
H
H
H
H
CH
3
6
4
4
4
4
4
p-ClC H
C H
6
2
5
7
p-ClC H
C H
3
iso-C H
iso-C H CH
3 7 2
6
p-ClC H
6
3 7
p-ClC H
6
C H
C H
6
5
6 5
p-ClC H
p-ClC H
6
6
4
4
4
2
p-ClC H
p-NO C H
p-NO C H
p-NO C H
p-NO C H
C H CH
6
2
6
4
4
4
4
4
6
5
C H
C H
6
5
2
6
6
5
1j
1k
1l
p-ClC H
p-ClC H
6
CH
C H
2 5
6
4
4
4
2
6
4
p-ClC H
6
2
6
3
p-ClC H
p-NO C H
6
2
6
o
[a] BH /tetrahydrofurane, reflux, 3 hs.; [b] 2 ArNH , 100-120 C, 1 hour.
3
2
the resulting cyclic aminals. It is widely accepted that
compounds of this type undergo hydrolysis through carbo-
cation-iminium ions (Scheme II) [17]. The stability of
such intermediates is enhanced by electron donor sub-
stituents on the carbocationic carbon and by N-alkyl
groups, whereas N-aryl substituents do not provide stabi-
lization. Thus, N,N'-diaryl and 2-unsubstituted cyclic ami-
nals are more resistant towards hydrolysis [18].
vated molecular sieves [19]. The reaction was monitored in
cellulose tlc plates until disappearance of the starting mate-
rials (48 hours) and the products were purified chromato-
graphically employing the same stationary phase. Instead,
purification on neutral alumina or silica gel led to complete
hydrolysis of the aminals. Attempts to extend this method-
ology to the condensation of N-(p-chlorophenyl)-N'-
methyl-1,3-propanediamine with aliphatic aldehydes were
unsuccessful. Reaction of 2a with acetaldehyde led to
intensely coloured materials resulting from autocondensa-
tion of the carbonyl compound, while condensation with
pivaldehyde, devoid of α-hydrogens, did not take place due
perhaps to its low reactivity.
Reaction of N-aryl-N'-alkyl- (or aryl)-1,3-propanedi-
amines with formaldehyde was performed in hydroalco-
holic solution at room temperature and led to high yields of
2-unsubstituted hexahydropyrimidines 1a-g. These com-
pounds were easily purified by column chromatography
using neutral alumina as stationary phase, while attempts of
chromatographic purification employing silica gel led to
partial hydrolysis. Condensation of N,N'-diaryl-1,3-
propanediamines 2f,g with p-nitrobenzaldehyde took place
without difficulties in anhydrous ethanol, where the result-
ing hexahydropyrimidines 1i,j were insoluble. In contrast,
reaction of N-(p-chlorophenyl)-N'-methyl-1,3-propanedi-
amine 2a with p-nitrobenzaldehyde under the same condi-
tions did not lead to the desired products and unreacted
starting materials were recovered. The condensation also
failed when carried out in anhydrous benzene solution, with
azeotropic distillation of water, or in the presence of p-
toluenesulphonic acid. The synthesis of 2-aryl derivatives
1h,k,l was accomplished by employing a physical dehy-
drating agent in an aprotic low boiling point anhydrous sol-
vent. The condensation was carried out by stirring at room
temperature equimolar amounts of the reagents in anhy-
drous dichloromethane solution, in the presence of acti-
Spectral Properties and Conformational Features.
The stereochemistry of the hexahydropyrimidine
nucleus involves two different processes, namely ring
reversal and N-inversion (Scheme III). Variable tempera-
ture NMR experiments [9h,i] on hexahydropyrimidines
indicate that both ring reversal and N-inversion are fast
processes at room temperature, although their coalescence
temperatures are substantially different. In 1,2,3-trialkyl
derivatives, ring inversion becomes slow in the NMR
timescale below –40 ºC, while slowing of N-inversion
requires temperatures below –100 ºC [9i]. In N,N'-dialkyl-
hexahydropyrimidines the absence of a 2-substituent low-
ers the energy barrier for ring reversal and N-inversion
[9h]. Although N-arylhexahydropyrimidines have not been
studied, literature indicates that in acyclic [20] and six
membered cyclic [21,22] tertiary arylamines, the nitrogen
3
atom has substantial sp character. Thus, in N-arylhexa-

N-Arylhexahydropyrimidines. Part 1
Jul-Aug 2002
657
hydropyrimidines 1 the aryl substituent could in principle
be axial or equatorial, as depicted in Scheme III. Due to
partial conjugation, N-inversion is much faster for aryl
than for alkylamines [23].
rium towards a preferred conformation in which the 2-sub-
stituent is equatorial (Scheme II, set A) [9a-e,h,i,n]. Due to
this conformational bias, in 1,2,3-trisubstituted derivatives
1h-l the geminal protons on the trimethylene portion
appear anisochronous (Table II). According to the nature
of both N-substituents, these compounds show spectral
patterns of different complexity, which will be analyzed
separately.
1
H NMR spectra of hexahydropyrimidines 1a-l under
study show differences according to their conformational
behavior, which is in turn related to the presence or
absence of a 2-substituent.
Like N,N'-dialkylhexahydropyrimidines [9h], deriva-
tives 1a-g (Table I) show isochronicity of the geminal pro-
tons on the trimethylene portion and on C2 due to fast ring
reversal and N-inversion at room temperature. The assign-
1,3-Diaryl-2-(p-nitrophenyl)hexahydropyrimidines 1i,j
show two separate signals corresponding to axial and
equatorial hydrogens on C4,C6 and two higher field reso-
nances corresponding to C5 protons (Table II).
Differential assignment of axial and equatorial hydrogens
in the trimethylene portion was made on the basis of their
coupling constants and chemical shift values, listed in
1
ment of the H NMR spectra of compounds 1a-e was made
on the basis of the 1,3-diaryl derivative 1g, taken as model
compound. Thus, in all cases, the lower frequency triplet
was assigned to methylene H4 and the higher frequency
triplet to methylene H6. For compound 1a, such assign-
ment was confirmed by means of the corresponding
HMBC spectrum. When hexahydropyrimidines 1a,b,d are
compared inter se, an increasing deshielding of methyl-
enes H2 and H4 is observed. This trend would be related
to a decreasing hyperconjugative effect along the series N-
methyl-ethyl-isopropyl, which was previously observed
for N-alkylpiperidines [24].
2
Table II. For hydrogens on C4, C6, J (H,H) correspond to
the geminal coupling constants. Both multiplets show two
further vicinal splittings, J and J . The difference between
2
3
such coupling constants is greater for the lowest frequency
signals, which were thus assigned to the axial protons
(H4 , H6 ). Differential assignment of C5 hydrogens was
a
a
performed on the basis of their chemical shift values.
Unlike cyclohexane, where axial hydrogens resonate at
higher fields than their equatorial partners, in azahetero-
cycles β-axial hydrogens show the highest resonance fre-
quencies [26,9n]. Thus, in our case, the multiplets
The introduction of a substituent in position 2 of the
hexahydropyrimidine ring shifts the ring inversion equilib-
Table I
H NMR Spectra of 1,3-Disubstituted Hexahydropyrimidines 1a-g
1
Compd.
Ar
R
H4
H6
H5
H2
Ar
R
1a
CH
2.60 (t) 3.26 (t) 1.75 (p) 3.79 (s)
2': 6.87 (dd)
3': 7.19 (dd)
2.30 (s)
3
1b
1c
CH CH
2.66 (t) 3.26 (t) 1.75 (p) 3.86 (s)
2.67 (t) 3.26 (t) 1.74 (p) 3.86 (s)
2': 6.87 (dd) a: 2.49 (q)
3': 7.19 (dd) b: 1.15 (t)
2
3
a
b
CH CH CH
2': 6.87 (dd) a: 2.36-2.41 (m)
3': 7.18 (dd) b: 1.57 (m)
c: 0.93 (t)
2
2
3
a
b c
1d
1e
CH(CH )
2.73 (t) 3.24 (t) 1.73 (p) 3.94 (s)
2.63 (t) 3.25 (t) 1.71 (p) 3.83 (s)
2': 6.86 (dd) a: 2.84 (m)
3': 7.18 (dd) b: 1.11 (d)
3 2
a b
CH CH(CH )
2': 6.87 (dd) a: 2.18 (d)
3': 7.17 (dd) b: 1.80 (m)
c: 0.93 (d)
2
a
3 2
b
c
1f
3.37 (t)
3.39 (t)
1.80 (p) 4.59 (s)
1.83 (p) 4.56 (s)
2': 7.01 (dd)
3': 7.27 (dt)
4': 6.83 (dt)
1g
2': 6.93 (dd)
3': 7.23 (dd)

658
I. A. Perillo, M. B. García, J. Á. Bisceglia and L. R. Orelli
Vol. 39
Table II
1
H NMR Spectra of 1,2,3-Trisubstituted Hexahydropyrimidines 1h-l
1
R
2
1
Compd. H2
H4
H6
H4
H6
H5
H5
e
Ar
R
R
a
a
e
e
a
1i
6.42
(s)
6.32
(s)
3.35 (ddd) [a]
3.37 (ddd) [c]
3.60 (ddd) [b]
3.54 (ddd) [d]
1.80-2.21 (m) 1.42-1.61 (m)
1.99-2.09 (m) 1.51-1.58 (m)
2', 4': 6.75-6.82 (m),
3': 7.21 (dt)
3": 8.13 (dd)
2": 7.54 (dd)
3”: 8.21 (dd)
2”: 7.55 (dd)
3": 8.16 (dd)
2": 7.64 (dd)
3": 8.18 (dd)
2": 7.67 (dd)
1j
1k
1l
2’: 6.75 (dd)
3’: 7.27 (dd)
5.25 3.03 (ddd) 3.26 (ddd)
2.62 (ddd)
[g]
3.60 (ddd) 2.12-2.22 (m) 1.36-1.44 (m) 2': 6.82 (dd)
2.54 (s)
(s)
5.58 2.86-2.97
(s) (m) [i]
[e]
[f]
3.26
(ddd) [j]
[h]
3.65-3.76
(m)
3': 7.17 (dd)
2': 6.77 (dd) CH : 2.70-2.82
2.70-2.82
(m) [i]
2.07-2.22
(m)
1.17-1.25
(m)
2
3': 7.18 (dd)
(m) [i] and
2.86-2.97 (m) [i]
CH : 1.13 (t)
3
1h
5.45 3.07 (ddd) 3.29 (ddd) 2.89 (d, b. s.) 3.78 (d, b.s) 2.22-2.37 (m) 1.25-1.29 (m) 2’: 6.69 (dd)
(s) [k] [l] 3’: 7.17 (dd)
2”: 7.66 (dd) CH : 3.87 (d) [m]
3”: 8.17 (dd) and 4.08 (d) [m]
2
C H : 7.29-7.33 (m)
6
5
[a] J : 12.4 Hz, J : 7.8 Hz, J : 4.5 Hz; [b] J : 12.4 Hz, J : 6.9 Hz, J : 5.4 Hz; [c] J : 12.7 Hz, J : 7.9 Hz, J : 4.4 Hz; [d] J : 12.7 Hz, J : 6.7 Hz; J : 5.4 Hz; [e]
1
2
3
1
2
3
1
2
3
1
2
3
J : 13.5 Hz, J : 10.2 Hz, J : 3.7 Hz; [f] J : 13.1 Hz, J : 10.0 Hz, J : 3.5 Hz; [g] J : 13.5 Hz, J = J : 4.1 Hz; [h] J : 13.1 Hz, J = J : 4.4 Hz; [i] overlapping
1
2
3
1
2
3
1
2
3
1
2
3
signals; [j] J : 13.2 Hz, J : 11.8 Hz, J : 3.4 Hz; [k] J : 14.1 Hz, J : 12.4 Hz, J : 3.3 Hz; [l] J : 14.1 Hz, J : 11.5 Hz, J : 3.3 Hz; [m] J :13.2 Hz.
1
2
3
1
2
3
1
2
3
1
cent
ered at ca. 2.00 ppm were assigned to H5 , while the
3.26 and 3.03 ppm were assigned respectively as H6 and
a
a
remaining signals were attributed to H5 .
H4 , while the remaining signals, centered at 3.60 and 2.62
e
a
The trimethylene portion of the unsymmetrically substi-
tuted hexahydropyrimidine 1k displays four separate sig-
nals corresponding to axial and equatorial hydrogens on
C4 and C6, and two higher field resonances corresponding
to C5 protons. Differential assignment of axial and equato-
rial hydrogens was made on the basis of their coupling
constants and chemical shift values (Table II). For both
ppm, were respectively attributed to H6 and H4 .
e e
Following the same criterion as for compound 1i the mul-
tiplet centered at 2.20 ppm was assigned to H5 , and the
a
signal centered at 1.40 ppm to H5 .
e
On the basis of the spectral parameters discussed before
and some literature data, we attempted to disclose some
stereochemical and conformational features of compound
1k. Previously reported spectral data indicate that in 1,3-
dialkyl-2-phenylhexahydropyrimidines the ring inversion
equilibrium is highly biased towards conformations with
the 2-phenyl equatorial (Scheme II, set A) [9n]. Taking
into account these data, we assume the same preference for
the 2-p-nitrophenyl group. The preferential orientation of
the N-methyl substituent was tentatively established on the
basis of the geminal coupling constant of C4 methylene and
of H2 chemical shift. The influence of heteroatom lone
2
hydrogens on C4 and C6, J (H,H) correspond to the gem-
inal coupling constants, and were used to pair the corre-
sponding geminal protons. By comparison with the same
signals in the symmetrical derivative 1i, the pair with
higher chemical shift was assigned as H6 -H6 and the
a
e
remaining pair as H4 -H4 . Two additional splittings were
a
e
present in all four signals, J and J . For one of the signals
2
3
within each pair, J shows values which are characteristic
2
of trans-diaxial coupling. Thus, the multiplets centered at

N-Arylhexahydropyrimidines. Part 1
Jul-Aug 2002
659
formed the corresponding NOESY spectrum. Relevant
correlations are shown in Scheme IV. Correlations of the N-
methyl group with H5 and H4 indicate the axial disposi-
pairs on the magnitude of geminal H-H coupling constants
of adjacent methylene groups has been well established in a
variety of nitrogen and oxygen heterocycles [27], including
hexahydropyrimidines. In such systems, the presence of
one or more axially oriented lone pairs causes a decrement
a
e
tion of the former, while its correlation with H2'' confirms
the relative cis orientation of both groups. Besides, correla-
tion of H2 and the ortho hydrogens of the N-aryl (H2') sug-
gest a cis relationship between them.
in the absolute value of geminal coupling constants, as a
*
consequence of lone pair-σ
electron delocalization.
C-H
1
The trimethylene portion of the H NMR spectra of 1,2-
This hyperconjugative interaction leads also to differential
shielding of the adjacent axial hydrogen antiperiplanar to
the lone pair (H2). In our case, the value of the geminal
coupling constant of C4 methylene (13.6 Hz) suggests the
absence of an antiperiplanar lone pair and therefore the
axial orientation of the N-methyl substituent. In fact, in
N-alkylpiperidines this constant is 11.5 Hz in the equator-
ial conformer and 13.6 Hz in the axial conformer [27a].
To confirm the proposed orientation of the N-methyl, the
chemical shift of H2 in 1k (δ=5.25 ppm) was compared
with the corresponding signal in the homologous
1,2-diaryl-3-methylimidazolidine (δ=4.25 ppm) [18], in
which this hydrogen is cis with respect to the N-methyl
[28]. The observed chemical shift difference (1 ppm)
would indicate a shielding effect of the trans lone pair in
the imidazolidine, which does not operate in the hexahy-
dropyrimidine as a consequence of the trans orientation of
H2 and N-methyl. In order to confirm the proposed orienta-
tion of the substituents in hexahydropyrimidine 1k we per-
diaryl-3-alkylhexahydropyrimidines 1h,l has approxi-
mately the same pattern as that of the 3-methyl derivative
1k. Thus, assignment of the corresponding resonances
was made by comparison with the latter (Table II). When
the N-methyl group is replaced by a CH X type sub-
2
stituent, both methylene hydrogens are anisochronous.
Diasterotopicity of N-methylene hydrogens in these com-
pounds is attributed to the presence of a stereogenic centre
(C2) in the molecule.
EXPERIMENTAL
Melting points were taken on a Büchi capillary apparatus and
1
are uncorrected. H NMR spectra were recorded on a Bruker
MSL 300 MHz spectrometer. HMBC spectrum of compound 1a
and NOESY spectrum of compound 1k were performed in a
Bruker AVANCE DRX300 spectrometer (mixing time for the
NOESY spectrum=0.5 seconds). Deuteriochloroform was used
as the solvent, and the standard concentration of the samples was
20mg/mL. Chemical shifts are reported in ppm (δ) relative to
TMS as an internal standard. Coupling constants (J values) are
given in Hz. Splitting multiplicities are reported as singlet (s),
broad signal (bs), doublet (d), double doublet (dd), double double
doublet (ddd), triplet (t), double triplet (dt), quartet (q), pentet (p)
and multiplet (m). Mass spectra (electron impact) were recorded
with a GC-MS Shimadzu QP-1000 spectrometer operating at 20
eV. Tlc analyses were carried out either on aluminium sheets
Alumina 60 F
using chloroform as the solvent or on alu-
254
minium Cellulose F sheets using n-pentane. Column chromatog-
raphy was performed either on Aluminium Oxide (neutral, grade

660
I. A. Perillo, M. B. García, J. Á. Bisceglia and L. R. Orelli
Vol. 39
I, 70-230 mesh) or on Cellulose microcrystalline, with typically
30-50 g of stationary phase per gram substance. Reagents, sol-
vents and starting materials were purchased from standard
sources and purified according to literature procedures.
N,N'-Diaryl-1,3-propanediamines 2f,g were obtained accord-
ing to the literature procedure (mp 2f 39-41 °C, lit. [29] 40-41 °C
and 2g 79-80 °C, lit. [29] 78-79 °C). N-Aryl-N'-alkyl (or aralkyl)-
1,3-propanediamines 2b,c,e,h were obtained by reduction of the
corresponding N-aryl-N'-acyl-1,3-propanediamines [15]. N-Aryl-
N'-alkyl-1,3-propanediamines 2a,d were obtained by reduction
of the corresponding 3-arylaminopropanamides [16].
1,3-Diaryl-2-(p-nitrophenyl)hexahydropyrimidines (1i,j).
General Procedure.
A stirred solution of N,N'-diaryl-1,3-propanediamine 2i,j (5
mmol) in anhydrous ethanol (50 mL) was treated with p-
nitrobenzaldehyde (5 mmol). After 2 hours a solid precipitated,
which was filtered and washed with anhydrous ethanol to yield
1
compounds 1i,j. H NMR data of these compounds are given in
Table II. Yields, mass spectra and elemental analyses of new
compounds are as follows:
1,3-Diphenyl-2-(p-nitrophenyl)hexahydropyrimidine (1i).
This compound was obtained in 81% yield, yellow crystals;
mp 89-90 ºC (anhydrous ethanol); ms: m/z 359 (M ).
1,3-Disubstituted Hexahydropyrimidines 1a-g. General
Procedure.
+.
Anal. Calcd for C H N O : C, 73.52; H, 5.89; N, 11.69.
22 21
3 2
A solution of 1,3-propanediamine 2a-f (5 mmol) in methanol
(50 mL) was treated with 37% aqueous formaldehyde (5 mmol).
The solution was stirred at room temperature for 2 hours, after
which it was treated with 20% aqueous sodium carbonate (10
mL). The mixture was extracted with methylene chloride (3 x 30
mL) and the organic layers were washed with water (5 mL) and
dried over anhydrous sodium sulphate. The solvent was evapo-
rated and the crude products were purified by column chromatog-
raphy on neutral alumina (grade I) using chloroform as mobile
Found: C, 73.65; H, 5.80; N, 11.60.
1,3-Di(p-chlorophenyl-2-(p-nitrophenyl)hexahydropyrimidine
(1j).
This compound was obtained in 83% yield, yellow crystals;
+.
mp 160-162 ºC (anhydrous ethanol); ms: m/z 427 (M ).
Anal. Calcd for C H Cl N O : C, 61.69; H, 4.47; N, 9.81.
22 19
2 3 2
Found: C, 61.78; H, 4.41; N, 9.73.
1,2-Diaryl-3-alkylhexahydropyrimidines (1h,k,l). General
Procedure.
1
phase, to yield compounds 1a-g. H NMR data of compounds
1a-g are given in Table I. Yields, mass spectra and elemental
analyses of new compounds are as follows:
The aldehyde (5 mmol) was added to a solution of diamine
2a,b,h (5 mmol) in anhydrous dichlorometane (50 mL).
Previously activated 3 Å molecular sieves [19] (4 g) were added
to the solution, which was stirred at room temperature protected
from moisture. The reaction was monitored by tlc (cellulose
microcrystalline, n-pentane) until disappearance of the starting
materials (approximately 48 hours), after which molecular sieves
were separated by filtration. The solvent was removed in vacuo
and the crude products purified by column chromatography,
1-(p-Chlorophenyl)-3-methylhexahydropyrimidine (1a).
+.
This compound was obtained as an oil (84%); ms: m/z 210 (M ).
Anal. Calcd for C H N Cl: C, 62.70; H, 7.18; N, 13.29.
11 15
2
Found: C, 62.59; H, 7.22; N, 13.25.
1-(p-Chlorophenyl)-3-ethylhexahydropyrimidine (1b).
+.
This compound was obtained as an oil (85%); ms: m/z 224 (M ).
Anal. Calcd for C H N Cl: C, 64.13; H, 7.62; N, 12.47.
1
using cellulose microcrystalline (n-pentane). H NMR data of
compounds 1h,k,l are given in Table II. Yields, mass spectra and
elemental analyses are as follows:
12 17
2
Found: C, 64.05; H, 7.70; N, 12.42.
1-(p-Chlorophenyl)-3-propylhexahydropyrimidine (1c).
1-(p-Chlorophenyl)-2-(p-nitrophenyl)-3-methylhexahydropyrim-
idine (1k).
+.
This compound was obtained as an oil (87%); ms: m/z 238 (M ).
Anal. Calcd for C H N Cl: C, 65.40; H, 8.02; N, 11.73.
13 19
2
+.
This compound was obtained as an oil (74%); ms: m/z 331 (M ).
Found: C, 65.33; H, 8.10; N, 11.75.
Anal. Calcd for C H N O Cl: C, 61.54; H, 5.47; N, 12.66.
17 18
3 2
1-(p-Chlorophenyl)-3-isopropylhexahydropyrimidine (1d).
Found: C, 61.65; H, 5.40; N, 12.69.
+.
This compound was obtained as an oil (86%); ms: m/z 238 (M ).
Anal. Calcd for C H N Cl: C; 65.40, H; 8.02, N; 11.73.
1-(p-Chlorophenyl)-3-ethyl-2-(p-nitrophenyl)hexahydropyrimi-
dine (1l).
13 19
2
Found: C, 65.35; H, 8.07; N, 11.67.
+.
This compound was obtained as an oil (76%); ms: m/z 345 (M ).
Anal. Calcd for C H N O Cl: C, 62.52; H, 5.83; N, 12.15.
Found: C, 62.40; H, 5.79; N, 12.24.
18 20
3 2
1-(p-Chlorophenyl)-3-(2-methylpropyl)hexahydropyrimidine (1e).
+.
This compound was obtained as an oil (85%); ms: m/z 252 (M ).
1-(p-Chlorophenyl)-3-benzyl-2-(p-nitrophenyl)-hexahydropy-
rimidine (1h).
Anal. Calcd for C H N Cl: C, 66.52; H, 8.37; N, 11.08.
14 21
2
Found: C, 66.45; H, 8.35; N, 11.01.
+.
1,3-Diphenylhexahydropyrimidine (1f) (89%) was synthesized
employing the same procedure, mp 86-87 °C (from ethanol) (lit.,
[29] 87 °C).
This compound was obtained as an oil (78%); ms: m/z 407 (M ).
Anal. Calcd for C H ClN O C, 67.73; H, 5.44; N, 10.30.
23 22
3 2
Found: C, 67.60; H, 5.47; N, 10.41.
1,3-Di-(p-chlorophenyl)hexahydropyrimidine (1g).
Acknowledgements.
This compound was obtained in 91% yield, mp 84-86 ºC
(methanol/water); ms: m/z 306 (M ).
This work was supported by the Universidad de Buenos Aires
and by CONICET (Consejo Nacional de Investigaciones
Científicas y Técnicas). We are grateful to Farm. María Laura
Magri for the preparation of some synthetic intermediates.
+.
Anal. Calcd for C H N Cl : C, 62.55; H, 5.25; N, 9.12.
16 16
2
2
Found: C, 62.61; H, 5.12; N, 9.08.

N-Arylhexahydropyrimidines. Part 1
Jul-Aug 2002
661
REFERENCES AND NOTES
Young, J. Am. Chem. Soc., 123, 4451 (2001).
[10a] L. Carballeira, B. Fernández, R. A. Mosquera, M. A. Ríos,
J. Rodríguez Otero and S. Vázquez, J. Mol. Struct. (Theochem), 205,
223 (1990); [b] M. Ladika and N. Rondan, J. Mol. Struct.
(Theochem), 365, 21 (1996).
[11a] G. V. Shustov, S. N. Denisenko, I. I. Chervin, N. L.
Asfandiarov and R. G. Kostyanovsky, Tetrahedron, 41, 5719 (1985);
[b] R. W. Alder, E. Heibronner, E. Honneger, A. B. McEven, R. E.
Moss, E. Olefirowicz, P. A. Petillo, R. B. Sessions, G. R. Weisman, J.
M. White and Z.-Z. Yang, J. Am. Chem. Soc., 115, 6580 (1993).
[12] H. A. Bates, N. Condulis and N. L. Stein, J. Org. Chem.,
51, 2228 (1986).
[13] C. Kashima, M. Shimazu, A. Katoh and Y. Omote, J.
Heterocyclic Chem., 21, 441 (1984).
[14] M. R. Dal Maso, L. R. Orelli and I. A. Perillo, J.
Heterocyclic Chem., 31, 25 (1994).
[15] L. R. Orelli, A. Salerno, M. E. Hedrera and I. A. Perillo,
Synth. Commun., 28, 1625 (1998).
[*] Author to whom correspondence should be addressed. E-
mail: lorelli@ffyb.uba.ar.
[1a] J. Nieper, Arzneim.-Forsch., 20, 18 (1960); [b] J. Billman
and M. Khan, J. Med. Chem., 11, 312 (1968); [c] G. Rank, D.
Harding and S. Szina, J. Med. Chem., 13, 1242 (1970); [d] Y. H.
Chang, G. R. Evanenga and W. M. McLamore, US Patent, 3,729,564;
Chem. Abstr., 79, 18762 (1974).
[2a] B. T. Golding and I. K. Nassereddin, J. Chem. Soc., 2011
(1985); [b] R. J. Bergeron and H. W. Seligsohn, Bioorg. Chem., 14,
345 (1986).
[3] N. Kalyanam, P. C. Parthasarathy, L. Ananthan, S. G.
Manyunatha and M. A. Likhate, Indian J. Chem., Sect. B, 31, 243
(1992).
[4] H. W. Seligsohn, Diss. Abstr. Int. B, 49, 1189 (1988).
[5] K. Chantrapromma and B. Ganem, Tetrahedron Lett, 22,
23 (1981).
[16] L. R. Orelli, M. M. Blanco, M. B. García, M. E. Hedrera
and I. A. Perillo, Synth. Commun., 31, 41 (2001).
[17] T. H. Fife, J. E. C. Hutchins and A. M. Pellino, J. Am.
Chem. Soc., 100, 6455 (1978).
[18] A. Salerno, V. Ceriani and I. A. Perillo, J. Heterocyclic
Chem., 29, 1725 (1992).
[6] K. Chantrapromma, J. S. McManis and B. Ganem,
Tetrahedron Lett., 21, 2475 (1980).
[7a] K. Chantrapromma, J. S. McManis and B. Ganem,
Tetrahedron Lett., 21, 2605 (1980); [b] H. Yamamoto and K.
Maruoka, J. Am. Chem. Soc., 103, 4186 (1981).
[8a] J. E. Douglass and R. Dial, Synthesis, 654 (1975); H.
Piotrowska and H. Prejzner, Rocz. Chem., 51, 1775 (1977); [b] H.
Piotrowska and H. Prejzner, Pol. J. Chem., 54, 2341 (1980); [c] L. R.
Orelli, M. B. García and I. A. Perillo, Heterocycles, 53, 2437 (2000).
[9a] H. Booth and R. U. Lemieux, Can. J. Chem., 49, 777
(1971); [b] F. G. Riddell and D. A. R. Williams, Tetrahedron Lett.,
23, 2073 (1971); [c] E. L. Eliel, L. D. Kopp and J. E. Dennis,
Tetrahedron Lett., 37, 3412 (1971); [d] R. A. Y. Jones, A. R.
Katritzky, K. A. F. Record and R. Scattergood, J. Chem. Soc., Perkin
Trans. 2, 406 (1974); [e] V. J. Baker, A. R. Katritzky, J.-P. Majoral, S.
F. Nelsen and P. J. Hintz, Chem. Commun., 823 (1974); [f] I. J.
Ferguson, A. R. Katritzky and D. M. Read, Chem. Commun., 255
(1975); [g] I. J. Ferguson, A. R. Katritzky and D. M. Read, J. Chem.
Soc., Perkin Trans. 2, 1861 (1976); [h] I. J. Ferguson, A. Katritzky
and D. M. Read, J. Chem. Soc., Perkin Trans. 2, 818 (1977); [i] A. R.
Katritzky, V. J. Baker, I. J. Ferguson and R. C. Patel, J. Chem. Soc.,
Perkin Trans. 2, 143 (1979); [j] A. Katritzky, V. Baker, F. Brito-
Palma and I. Ferguson, J. Chem. Soc., Perkin Trans. 2, 1746 (1980);
[k] W. L. F. Armarego, Stereochemistry of Heterocyclic Compounds.
Part 1, Wiley-Interscience, New York, pp 180-183 (1977); [l] F. G.
Riddell, The conformational Analysis of Heterocyclic Compounds,
Academic Press, New York (1980); [m] T. A. Crabb and A. R.
Katritzky, Adv. Het. Chem., 36, 1 (1984); [n] C. L. Perrin and D. B.
[19] Molecular sieves (pellets, 3 Å) were heated at 200 °C
under vacuum for 24 hours and allowed to cool in a desiccator before
use.
[20] S. Davalli and L. Lunazzi, J. Org. Chem., 56, 1739 (1991).
[21] A. T. Bottini and C. P. Nash, J. Am. Chem. Soc., 84, 734
(1962).
[22] M. D. Rozeboom, K. N. Houk, S. Searles and S. Ebrahim
Seyedrezai, J. Am. Chem. Soc., 104, 3448 (1982).
[23] J. B. Lambert, Top. Stereochem., 6, 19 (1971).
[24] H. Booth and J. H. Little, Tetrahedron, 22, 615 (1967).
[25a] J. B. Lambert, J. Am. Chem. Soc., 89, 1346 (1967); [b] J.
B. Lambert, Am. Chem. Res., 4, 87 (1971).
[26] J. B. Lambert and J. E. Goldstein, J. Am. Chem. Soc., 99,
5689 (1977).
[27a] R. C. Cookson and T. A. Crabb, Tetrahedron, 24, 2385
(1968); [b] R. Cahill, R. C. Cookson and T. A. Crabb, Tetrahedron,
25, 4681 (1969); [c] P. J. Chivers and T. A. Crabb, Tetrahedron, 26,
3389 (1970); [d] V. M. S. Gil and W. von Philisborn, Magn. Reson.
Chem., 27, 409 (1989).
[28] A. Salerno, G. Y. Buldain and I. A. Perillo, J. Heterocyclic
Chem., 38, 849 (2001).
[29] W. L. C. Veer, Recl. Trav. Chim. Pays-Bas, 57, 989 (1938).