Atropisomerization in N-aryl-2(1H)-pyrimidin-(thi)ones: A ring-opening/rotation/ring-closure process in place of a classical rotation around the pivot bond

Article abstract of DOI:10.1021/jo402149f

Uncatalyzed racemization processes in atropisomeric diphenyl-like frameworks are classically described as the result of the rotation around the pivotal single bond linking two planar frameworks. Severe constraints leading to more or less distorted transit

Full text of DOI:10.1021/jo402149f

Article
pubs.acs.org/joc
Atropisomerization in N‑aryl-2(1H)‑pyrimidin-(thi)ones: A Ring-
Opening/Rotation/Ring-Closure Process in Place of a Classical
Rotation around the Pivot Bond
Ennaji Najahi,‡,§ Nicolas Vanthuyne,† Francoise Nepveu,‡,§ Marion Jean,† Ibon Alkorta,∥ Jose Elguero,∥
̧
́
and Christian Roussel*,†
†Aix Marseille Universite,
́
Centrale Marseille, CNRS, iSm2 UMR 7313, 13397, Marseille, France
‡Universite
́
de Toulouse, UPS, PHARMA-DEV, UMR 152, 118 Route de Narbonne, 31062 Toulouse cedex 9, France
§IRD, UMR 152, 31062 Toulouse cedex 9, France
∥Instituto de Quimica Medica (IQM-CSIC), Juan de la Cierva, 3, 28006 Madrid, Spain
S
* Supporting Information
ABSTRACT: Uncatalyzed racemization processes in atropisomeric diphenyl-like frameworks are classically described as the
result of the rotation around the pivotal single bond linking two planar frameworks. Severe constraints leading to more or less
distorted transition states account for the experimental barrier to atropenantiomerization. In 1988, one of us hypothesized that, in
N-aryl-2(1H)-pyrimidin-(thi)ones, a ring-opening/ring-closure process was contributing to the observed racemization process
accounting for the lower barriers in the sulfur analogues than in oxygen analogues. Now, a series of six novel 6-amino-5-cyano-
1,4-disubstituted-2(1H)-pyrimidinones 5a−5f and two 6-amino-5-cyano-4-p-tolyl-1-substituted-2(1H)-pyrimidinethiones 6a and
6b were synthesized and characterized through spectroscopic and X-ray diffraction studies. Semipreparative HPLC chiral
separation was achieved, and enantiomerization barriers were obtained by thermal racemization. The rotational barriers of 6-
amino-5-cyano-1-o-tolyl-4-p-tolyl-2(1H)-pyrimidinone (5b) and 6-amino-5-cyano-1-(naphthalen-1-yl)-4-p-tolyl-2(1H)-pyrimidi-
none (5e) were found to be 120.4 and 125.1 kJ·mol−1 (n-BuOH, 117 °C), respectively, and those of the corresponding thiones
were 116.8 and 109.6 kJ·mol−1 (EtOH, 78 °C), respectively. DFT calculations of the rotational barriers clearly ruled out the
classical rotation around the pivotal bond with distorted transition states in the case of the sulfur derivatives. Instead, the ranking
of the experimental barriers (sulfur versus oxygen, and o-tolyl versus 1-naphthyl in both series) was nicely reproduced by
calculations when the rotation occurred via a ring-opened form in N-aryl-2(1H)-pyrimidinethiones.
dimethyl-2(1H)-pyrimidinones. 2′-Methyl derivative 1 was
resolved using D-camphor sulfonic acid, and the barrier to
rotation was 125.8 kJ·mol−1 in MeOH,6 and 126.1 kJ·mol−1
(solvent not specified) (Figure 1).7 The barriers for 1-aryl-4,6-
dimethylpyrimidin-2(1H)-ones were compared to those
obtained for the 2(1H)-thione analogues.7 The authors stated
that “the rotational barrier was expected to increase when
sulphur replaced oxygen”; however, the barrier was found to be
smaller for the sulfur analogue (2: 115.8 kJ·mol−1) and a
“pronounced single bond character of the thiocarbonyl group”
was advocated to account for these unexpected results. Roussel
INTRODUCTION
■
Atropisomerism in N-aryl heterocyclic frameworks attracts a lot
of interest in the design of new chiral ligands, in a drug’s
activity, in symmetry breaking, and in the stereochemical
outcome of natural products.1 Since the pioneering work of
Bock and Adams, the barriers to rotation in many N-aryl axially
chiral five- or six-membered heterocycles have been meas-
ured,1−4 and they match with a classical model of rotation
around the pivotal bond, which takes into account the steric
substitution pattern along the axis to rotation like in substituted
biphenyl.5 Few papers concerning restricted rotation about the
carbon−nitrogen single bond in 1-aryl-2(1H)-pyrimidin-(thi)-
ones have been reported.6−10 Kashima et al. were the first to
isolate enantiomers resulting from atropisomerism in 1-aryl-4,6-
Received: October 8, 2013
Published: December 4, 2013
© 2013 American Chemical Society
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and an amino group in the 6-aryl-1,1,5-trimethylindane
model,13a whereas an amino group is found slightly larger
than a methyl group in the more recent 1-aryl-3-isopropyldi-
methylsilylbenzene model.13b,c The experimental barriers will
be compared to the calculated ones for a classical rotation
around the pivotal bond or for a ring-opening process.
RESULTS AND DISCUSSION
■
The 2(1H)-pyrimidinones 5a−5f were synthesized in good
yields by the condensation of ethyl 2,2-dicyanovinylcarbamate
derivatives 7 with primary aromatic amines (o-tolylamine or
naphthalen-1-ylamine).12 Starting from the methyl N-(amino-
thiocarbonyl)imidates 814 and malononitrile, the 2(1H)-
pyrimidinethiones 6a and 6b were obtained in acceptable
yield (Scheme 1).
Figure 1. Structure of N-aryl-2(1H)-pyrimidin-(thi)ones 1−6.
et al. revisited the barriers to atropisomerization for 1-(2-
methylphenyl)-4,6-dimethylpyrimidin-2(1H)-one 1 and the
corresponding thione 2 in diglyme, after separation of the
enantiomers on microcrystalline cellulose triacetate (MCTA).8
The experimental values of the barriers were 118.2 and 107.7
kJ·mol−1, for 1 and 2, respectively, confirming a lower barrier
for the sulfur derivative. These values are lower than those
reported by Kashima et al. for the same compounds, and they
are consistent with the solvent effect reported more recently by
Sakamoto et al.9
Scheme 1. Synthesis of N-aryl-2(1H)-pyrimidin-(thi)ones
5 and 6
a
To account for the lower barrier in the sulfur derivative and
the weak sensitivity to the buttressing effect, Roussel et al.
hypothesized a ring-opening and a ring closure that would be
easier in the thio derivative 2 than in the oxygen analogue 1.8
The experimental barriers would thus refer to the energy of the
electrocyclic ring-opening process and not to the classical
rotation around the pivotal bond.
a
Reagents and conditions: (i) primary aromatic amines, chloroben-
zene, 110 °C, (2−4) h (80−96% yields); (ii): malononitrile, Na/
MeOH, reflux, 4 h (63−66% yields).
Sakamoto et al. have recently reported the barrier to
racemization for the 1-(2-methylphenyl)-4,6-dimethyl-
pyrimidin-2(1H)-one 19 and for the 1-(1-naphthyl) analogue
3 in different solvents after separation of the enantiomers on
“Chiralcel OD”.10 The barriers (vide infra) were strongly
solvent-dependent, but noteworthy in the same solvent, the
barriers were almost identical for the 2-methylphenyl and 1-
naphthyl analogues. These new data bring additional evidence
that the racemization barrier is surprisingly insensitive to the
steric contribution of the ortho substituent in the methyl and 1-
naphthyl series. Such a behavior is hardly accounted for on the
basis of a racemization process involving a simple rotation
around the pivot bond. The barriers for 1-(1-naphthyl)-4,6-
dimethylpyrimidin-2(1H)-one 3 and the corresponding thione
4 have been reported in 2010 after separation of the
enantiomers on “Chiralcel OD”.10 Here again, the barrier was
lower in the thione analogue in three different solvents.
Referring to AM1 calculations on the barrier of N-aryl-pyridone
analogue,11 Sakamoto et al. concluded that “a mechanism
involving non-planar conformation may contribute to the
racemization of 3 and 4, because the alcohol adduct from the
open form could not be obtained. However, a mechanism
involving open form could not be perfectly excluded”.10
Clearly, further experimental data and appropriate calcu-
lations were mandatory in this domain. In the course of our
studies on a series of N-aryl-2(1H)-pyrimidin-(thi)ones,12 we
report herein the barriers of racemization in 6-amino-5-cyano-
1,4-disubstituted-pyrimidinones 5a−5f and the 6-amino-5-
cyano-4-p-tolyl-1-substituted-pyrimidinethiones 6a and 6b. If
one considers the substitution pattern around the pivotal N-aryl
bond, compounds 5a−5f to 6a−6b differ from the previous
studies in the field of atropisomeric 2(1H)-pyrimidin-(thi)ones
by the introduction of a NH2 substituent at the place of a Me
group in compounds 1−4. The effective steric requirements
derived from rotational barriers are very similar for a methyl
X-ray crystallographic analyses of N-(1-naphthyl)-2(1H)-
pyrimidinone 5d revealed that the pyrimidinone crystallized in
the monoclinic and centrosymmetric space group P21/c.12
Each single crystal of pyrimidinone 5d is composed of both
enantiomers (Figure 2). The two arene planes are almost
perpendicular to each other (inter-ring dihedral C11−N2−
C12−C21: 73.22°) in each molecule.
Figure 2. Packing diagram of 5d in the P21/c crystal system.
Each compound 5 and 6 exists as a pair of enantiomers that
were nicely separated on several chiral stationary phases. The
enantiomers were obtained in high optical purity by semi-
preparative chromatography without noticeable racemization
during the collection and evaporation of the solvent. The
details of chromatographic data are given in the Supporting
Information. Having in hand pure enantiomers, they were
submitted to thermal racemization in an alcoholic medium. The
solvents, butan-1-ol or ethanol, were chosen according to the
barrier range of the individual samples, butan-1-ol for the
compounds 5a−5f and ethanol for compounds 6a and 6b. The
rotation barriers (enantiomerization barriers) are reported in
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Table 1. Barriers to Rotation of the C−N Bond in 6-Amino-5-cyano-1,4-disubstituted-2(1H)-pyrimidin-(thi)ones
a
b
compd
X
R1
Ar
solvent
T (°C)
105 k (s−1
)
ΔG⧧ (kJ·mol−1
)
5a
O
O
O
O
O
O
S
phenyl
p-tolyl
benzyl
phenyl
p-tolyl
benzyl
p-tolyl
o-tolyl
butan-1-ol
butan-1-ol
butan-1-ol
butan-1-ol
butan-1-ol
butan-1-ol
ethanol
117
117
117
117
117
117
78
59.4
62.0
25.2
12.6
14.5
16.9
3.1
120.5
120.4
123.3
125.6
125.1
124.6
116.8
109.6
5b
o-tolyl
5c
o-tolyl
5d12
5e12
5f12
6a
1-naphthyl
1-naphthyl
1-naphthyl
o-tolyl
6b
S
p-tolyl
1-naphthyl
ethanol
78
36.4
a
b
Rate constant of enantiomerization. Enantiomerization barrier.
Table 1; in all cases, first-order kinetic data were obtained (see
the Supporting Information).
Going from pyrimidinones (X = O) 5a,5b to pyrimidine-
thione (X = S) 6a, the barriers are significantly smaller in the
latter case. As mentioned before, such a behavior is already
exemplified in the literature for this type of frameworks.7−10
Quite unexpectingly, the barrier was found to be smaller in the
pyrimidinethione 6b than in pyrimidinethione 6a, the differ-
ence being 7.5 kJ·mol−1. In these pyrimidinethiones, the 1-
naphthyl group has thus an apparent smaller steric requirement
than the o-tolyl group during the rotation process, whereas the
opposite holds true in the pyrimidinone series!
One of us proposed many years ago that the lower barrier in
the case of pyrimidinethiones was an indication of the
contribution of a ring-opening process leading to an
isothiocyanate intermediate 10 in which the rotation of the
N-aryl group will be quite fast and insensitive to the buttressing
effect. In other words, the experimental barrier would result
from the ring-opening process and the higher stability of the
isothiocyanate than that of the isocyanate would account for
the lower barrier to rotation in the pyrimidinethione.
The barriers to rotation in compounds 5 and 6 are
particularly unexpected and deserve a careful analysis. In the
series of the pyrimidinones (X = O, 5a,5b/5d,5e), the barriers
are significantly higher (ca. 5 kJ·mol−1) for the 1-naphthyl
substituent than for the o-tolyl analogues. This is what is
expected from the steric requirement of a 1-naphthyl group
compared to that of an o-tolyl group. In the 1-naphthyl group,
the C8-H mimics the steric requirement of a locked methyl
group as it was shown in comparing the kinetics of N-
methylation of quinoline and 2-methylpyridine.15 Sakamoto et
al. reported the barriers to rotation about the N-aryl axis in
pyrimidinones 1 and 3 in propan-1-ol, xylene, and DMF. The
barriers were quite sensitive to the solvent. The barriers in
propan-1-ol were 126.2 and 127.5 kJ·mol−1 for 19 and 3,10
respectively; thus, the barrier was slightly higher for the 1-
naphthyl derivative than for the o-tolyl group without the
marked difference we observed in comparing 5a with 5d and 5b
with 5e. It is worth mentioning that the barrier in 5a or 5b is
smaller than the barrier in 1 (ca. 6 kJ·mol−1) in alcohols while
the ranking of the sizes of an amino and a methyl group is NH2
≥ CH3 in biaryls depending on the model.13a−c
Shirok et al. reported the synthesis of a series of 6-amino-1-
aryl-2-pyridones.11a Three compounds bearing a methyl,
isopropyl, or methoxy group in the ortho-position were
particularly relevant for our study since they provide a similar
environment around the pivotal bond than the one that consists
of an amino group and a carbonyl in compounds 5.
Unfortunately, the experimental rotation barrier was not
reported for the methyl analogue but for the sole methoxy
one. The experimental barrier in compound 9 (139 kJ·mol−1 in
boiling water) is ca. 20 kJ·mol−1 higher than that in 5a,5b
(Scheme 2).11b
Compounds 5 and 6 were particularly attractive since we
expected that intermediate 11 might tautomerize into
intermediate 12, which, after rotation and cyclization, would
lead to pyrimidinethione 13 (Scheme 3). The rearranged
Scheme 3. Structures of Isothiocyanate Generated from
2(1H)-Pyrimidin-(thi)ones
pyrimidinethiones 13 were not detected during the racemiza-
tion process, probably pointing out a large preference for the
tautomer 11 in which conjugation with the aryl group is
favorable. Another explanation would be that the easy rotation
of the N-aryl group occurred on the reaction pathway leading
to the formation of intermediate 11 during a considerably
elongated N···C state before a complete dissociation is attained,
such as in 14 (Scheme 4).
Scheme 2. Structure of Compound 9
Such an elongated state that maintains a weak bonding
character between the nitrogen atom and the sp carbon atom
being formed would as well prevent the formation of the
rearranged product. It would also prevent a possible
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same substituent on the nitrogen, the barriers are higher for the
pyrimidinethiones.
Scheme 4
The racemization of the oxo derivatives is possible through
rotation of the aromatic ring. The most favorable TSs for the
racemization correspond to those cases where the more bulky
group of the aromatic ring is in syn to the oxo group (Figure 3).
This process reproduces the experimental data showing a
higher steric demand for the rotation of the naphthyl group in
comparison to the o-tolyl group.
intermolecular reaction of the formed isothiocyanate with the
alcoholic solvent. Sakamoto et al. pointed out that the
formation of carbamate was not observed when the
racemization of compound 4 was performed in alcoholic
solvent.10 The formation of (thio)carbamates was also not
observed during our racemization studies in butan-1-ol or
ethanol.
DFT CALCULATIONS
■
The geometry of the systems has been optimized at the
B3LYP/6-31G(d) computational method. Frequency calcula-
tion has been carried out at the same computational level to
confirm that the obtained structures correspond to energetic
minima or true transition states (number of imaginary
frequencies zero and one, respectively).16 In addition, in
some selected cases, the effect of the solvent has been
considered using the polarizable continuum model (PCM)
with the parameters of the butan-1-ol and ethanol.17 The
calculations were performed on compounds 5a, 5d, 6′a, and
6′b. Compounds 6′a and 6′b are the analogues of 6a and 6b in
which the R1 p-tolyl group was replaced by a phenyl group. The
similarity of the experimental barriers in the couples 5a−5b,
and 5d−5e, respectively, justifies this simplification for the
calculations.
Figure 3. The most favorable transition states for the rotation of o-
tolyl and 1-naphthyl groups in compounds 5a and 5d.
In a second step, the barriers were calculated through a ring-
opening + rotation process. All the attempts to obtain the open
structure with X = O have been unsuccessful. In all cases, the
system reverts toward the original pyrimidinone. For the
pyrimidinethiones, a very easy ring-opening occurs through TS
with 69.8 and 66.8 kJ·mol−1 for 6′a and 6′b, respectively (Table
3). The ring-opening energy + the low rotation energy of the
aryl groups in the open form is the determining step for the
−1
racemization: 91.1 and 83.3 kJ·mol
for 6′a and 6′b,
respectively, for the low-energy TSs. Interestingly, the increased
conjugation of the naphthyl group accounts for the lower
barrier in 6′b in comparison to 6′a. The results for the opening
reaction and the racemization process through rotation are
gathered in Table 3. The gas-phase calculations reproduce the
ranking of the experimental barriers.
In a first series of calculations, the racemizations were
calculated through a pure classical rotational process for the
pyrimidone and for the pyrimidinethione series according to
the two possible transition states (Table 2).
Table 2. Calculated Barriers for Racemization through Pure
Rotational Processes
The racemization of the thioxo derivatives may proceed
through an opening of the pyrimidine, followed by the rotation
of the aromatic ring and ring-closure back to the
pyrimidinethione. The ranking of the barriers in 6′a and 6′b
results from the difference in conjugation of the o-tolyl group
and naphthyl group in the rotation TS. The stability of the
open structure for the CNH tautomer (12, R1 = phenyl) as
well as the cyclization process has been calculated. Both the
open structure and the TS for the cyclization are less favorable
by ca. 18 kJ·mol−1 than in tautomer 11 (R1 = phenyl).
In addition to the calculation in vacuum, the effect of the
solvent (butan-1-ol for X = O and ethanol for X = S) has been
considered using the polarizable continuum model (PCM) with
the parameters of the butan-1-ol and ethanol for the structures
corresponding to minima and the most favorable TSs. The
PCM model that does not localize hydrogen bonds is for sure a
rough estimation in the present case. Nevertheless, the resulting
barriers are worth mentioning (Table 4) and shall be handled
with high care. We shall limit our discussion in saying that the
inclusion of solvent provides values astonishingly close to those
obtained experimentally. In a more realistic way, the trends
revealed by the experimental data are correctly reproduced by
the calculations when a pure rotation process is operating in the
pyrimidinone series, and a ring-opening−rotation−ring-closure
process is operating in the pyrimidinethione series.
compds
X
R1
N-aryl
o-tolyl
G (Hartree)
ΔG⧧ (kJ·mol−1
)
5a
O
Ph
−988.353051
−988.310552
−988.301026
−1102.65948
−1102.61341
−1102.60503
−1311.30680
−1311.25799
−1311.25297
−1425.61262
−1425.56184
−1425.55765
a
5a-ts1
111.6
5a-ts2
5d
136.6
O
Ph
Ph
Ph
1-naphthyl
o-tolyl
5d-ts1
5d-ts2
6′a
6′a-ts1
6′a-ts2
6′b
120.9
142.9
S
S
S
S
S
S
128.1
141.3
1-naphthyl
6′b-ts1
6′b-ts2
133.3
144.3
a
ts1 and ts2 are the two possible transition states for the pure rotation
processes.
If we consider the lower of the two possible transition states
(in bold in Table 2), the barriers in the gas phase are following
the expected order of steric requirements: in the series
pyrimidone and pyrimidinethione, the barriers are higher for
the 1-naphthyl group than for the o-tolyl group, and for the
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Table 3. Calculated Enantiomerization Barriers* for a Stepwise Ring-Opening + Rotation Process in Pyrimidinethiones 6′a
(o‑Tolyl) and 6′b (1-Naphthyl)
compds
G (Hartree)
ΔG⧧ (kJ·mol−1
)
6′a (ground state)
6′a (TS for the open form)
6′a (open form 11 like)
6′a (TS1 for o-tolyl rotation in open form)
6′a (TS2 for o-tolyl rotation in open form)
6′b (ground state)
6′b (TS for the open form)
6′b (open form 11 like)
−1311.30680
−1311.28019
−1311.28268
−1311.25923
−1311.27208
−1425.61262
−1425.58716
−1425.59072
−1425.58089
−1425.56328
69.8
63.3
124.9
91.1*
66.8
57.5
6′b (TS1 for 1-naphthyl rotation in open form)
6′b (TS2 for 1-naphthyl rotation in open form)
83.3*
129.5
Table 4. Summary of the Experimental and Calculated Barriers with and without PCM Model
X
R1
N-aryl
o-tolyl
solvent
ΔG⧧ exptl (kJ·mol−1
)
ΔG⧧ vac calcd (kJ·mol−1
)
ΔG⧧ PCM calcd (kJ·mol−1
)
O
O
S
phenyl
phenyl
phenyl
phenyl
butan-1-ol
butan-1-ol
ethanol
120.5
125.6
111.6
120.9
121.9
129.6
1-naphthyl
a
b
b
o-tolyl
116.8
91.1
114.6
a
b
b
S
1-naphthyl
ethanol
109.6
83.3
105.5
a
b
Experimental data for 6a and 6b. Calculated data for 6′a and 6′b.
The comparison of the pure rotation process and the ring-
opening−rotation process is cartooned in Figure 4. This figure
rotation of the aryl group in an open or nearly open form. The
calculations were performed for a stepwise process; a smoother
process that combines ring-opening and concomitant rotation
of the aryl groups is probably quite realistic. It accounts for the
low barrier in pyrimidinethiones in comparison to pyrimidi-
nones. A better conjugation of the naphthyl group with the
imino group in the TS accounts for the lower barrier in the 1-
naphthyl than in the o-tolyl derivative. The open form is not
populated enough to react significantly with the alcoholic
solvent to yield thiocarbamate during racemization experi-
ments. Because the tautomeric form 12 is less stable than 11 by
ca. 18 kJ·mol−1, the rearranged product 13 is not formed during
the racemization experiment time scale.
The traditional picture of atropisomerization about a pivotal
N-aryl axis shall take into account ring-opening when it is
possible.18
EXPERIMENTAL SECTION
■
Chemicals. Commercial reagent grade chemicals were used as
received without additional purification. All reactions were followed by
TLC (Kieselgel 60 F-254). Column chromatography was performed
on silica gel (60−200 mesh). Solvents used for enantioselective
chromatography and determination of the rotation barrier were HPLC
grade.
Figure 4. Comparison of a pure rotation versus a ring-opening−
rotation process for 6′a. All the reported calculated values (in kJ·
mol−1) are those obtained using the PCM model for butan-1-ol.
1
1
General. H, 13C, and H−1H COSY NMR spectra were recorded
at 300, 400, or 600 MHz (1H), 75 or 125 MHz (13C), and 300 MHz
(1H−1H COSY) using (CD3)2SO as solvent with (CD3)2SO (δH 2.5)
or (CD3)2SO (δC 39.5). Chemical shifts (δ) are reported in parts per
million (ppm) relative to tetramethylsilane (0 ppm) as the internal
reference, and the following multiplicity abbreviations were used: s,
singlet; d, doublet; t, triplet; q, quadruplet; m, multiplet; J in hertz.
The mass spectra were recorded on an ion trap mass spectrometer
using electrospray as an ionization source. Melting points are
uncorrected. For chromatography on chiral stationary phases, the
analytical analyses were monitored by a DAD-detector and a circular
dichroism detector.
is, of course, providing quite a rigid and stepwise description of
what might be occurring. The rotation around the N-aryl axis
may occur at any point during the ring-opening process without
the requirement to reach a full open form in which the rotation
is quite easy. The rotation may occur in 14.
CONCLUSION
■
The atropisomerization of N-aryl pyrimidinones mostly
proceeds by a classical rotation process around the pivotal
bond. The ranking of the barriers for o-tolyl and 1-naphthyl fits
this model, and the trend is supported by DFT calculations.
The atropisomerization of N-aryl pyrimidinethiones mostly
proceeds through a ring-opening process, followed by the
Synthesis. Preparation of 6-amino-5-cyano-1-o-tolyl-4-substituted-
2(1H)-pyrimidinones (5a−5c). The 2(1H)-pyrimidinones 5a−5c
were prepared according to the reported procedure.12 The 2(1H)-
pyrimidinones 5d−5f have been already described.12
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6-Amino-5-cyano-4-phenyl-1-o-tolyl-2(1H)-pyrimidinone (5a).
Yield: 82% (248 mg). White solid, mp 227−229 °C. IR (KBr,
cm−1): 3514, 3462, 2217, 1666, 1599, 1581, 1555. 1H NMR: (DMSO-
d6, 300 MHz): δ 2.08 (s, 3H, CH3), 7.30−7.45 (m, 6H), 7.52−7.62
(m, 3H), 7.85 (dd, J = 9 Hz, J = 3 Hz, 2H), the NH2 are located under
the aromatic area according to the total integration. 13C NMR
(DMSO-d6, 75 MHz): δ 17.1 (CH3), 72.7 (C-CN), 117.0 (CN); 9C-
Harom:128.4, 128.7, 128.76 (×2), 128.83 (×2), 130.2, 131.5, 132.0;
5Cq: 133.8, 136.1, 137.3, 153.4, 160.1; 172.2 (CO). MS-(+)ESI, m/z
(%): 303 ([M + H]+, 100), 325 ([M + Na]+, 4), 627 ([2 M + Na]+,
38). HRMS-ESI (m/z): cald for C18H15N4O [M + H]+ 303.1246,
found 303.1257.
(br, 1H, NH). 13C NMR (DMSO-d6, 75 MHz): δ 21.5, 55.3, 123.1,
124.4, 125.7, 126.0, 126.6, 127.6, 128.1, 128.5, 128.8, 129.5, 129.8,
134.2, 135.2, 142.1, 157.0, 191.7.
General Procedure for Preparation of 2(1H)-pyrimidine-
thiones (6a and 6b). To a solution of Na (0.14 g, 6 mmol) in dry
MeOH (15 mL) were added malononitrile (0.33 g, 5 mmol) and the
imidate 8 (5 mmol). The solution was stirred under reflux for 4 h and
cooled to room temperature. Glacial HOAc (0.4 g, 7 mmol) and water
(50 mL) were added. The precipitate was collected by filtration and
recrystallized from MeOH to yield the 2(1H)-pyrimidinethione 6.
6-Amino-5-cyano-1-o-tolyl-4-p-tolyl-2(1H)-pyrimidinethione
(6a). Yield: 63% (1.04 g). Yellow solid, mp 251−253 °C. IR (KBr,
cm−1): 3533, 3429, 2214, 1699, 1610, 1545, 1516, 1318, 1243, 1172,
6-Amino-5-cyano-1-o-tolyl-4-p-tolyl-2(1H)-pyrimidinone (5b).
1
1149, 1007. H NMR (CD3OD, 600 MHz): δ 2.19 (s, 3H, o-CH3),
Yield: 96% (303 mg). White solid, mp 221−223 °C. IR (KBr,
1
cm−1): 3510, 3462, 2210, 1671, 1645, 1609, 1578, 1548. H NMR
2.44 (s, 3H, p-CH3), 7.24 (d, J = 7.2 Hz, 1H), 7.36 (dd, J = 0.6 Hz, J =
8.4 Hz, 2H), 7.43−7.50 (m, 3H), 7.88 (d, J = 8.4 Hz, 2H). (DMSO-d6,
400 MHz): δ 2.08 (s, 3H, o-CH3), 2.41 (s, 3H, p-CH3), 7.26 (dd, J =
6.4 Hz, J = 2 Hz, 1H), 7.37−7.42 (m, 5H), 7.82 (d, J = 8 Hz, 2H). 13C
NMR (DMSO-d6, 125 MHz): δ 16.7 (o-CH3), 21.0 (p-CH3), 77.5 (C-
CN), 116.0 (CN); 8C-Harom: 127.84, 128.27, 128.68 (×2), 128.91
(×2), 129.77, 131.84; 6Cq: 132.98, 134.97, 136.5, 141.56, 157.78,
164.03; 180.73 (CS). MS-(+)ESI, m/z (%): 333 ([M + H]+, 100),
355 ([M + Na]+, 12). HRMS-ESI (m/z): cald for C19H17N4S [M +
H]+ 333.1174, found 333.1181.
(DMSO-d6, 300 MHz): δ 2.07 (s, 3H, o-CH3), 2.40 (s, 3H, p-CH3),
7.29−7.44 (m, 6H), 7.77 (d, J = 9 Hz, 2H), the NH2 are located under
the aromatic area according to the total integration. 13C NMR
(DMSO-d6, 75 MHz): δ 17.2 (o-CH3), 21.5 (p-CH3), 72.4 (C-CN),
117.1 (CN); 8C-Harom:128.3, 128.8, 128.9 (×2), 129.3 (×2), 130.2,
132.0; 6Cq: 133.9, 134.5, 136.1, 141.6, 153.4, 160.1; 171.9 (CO).
MS-(+)ESI, m/z (%): 317 ([M + H]+, 100), 339 ([M + Na]+, 3), 655
([2 M + Na]+, 38). HRMS-ESI (m/z): cald for C19H17N4O [M + H]+
317.1402, found 317.1416.
6-Amino-5-cyano-1-(naphthalen-1-yl)-4-p-tolyl-2(1H)-pyrimidi-
nethione (6b). Yield: 65% (1.2 g). Yellow solid, mp 263−265 °C. IR
(KBr, cm−1): 3527, 3386, 2215, 1698, 1610, 1551, 1518, 1445, 1330,
1242, 1173, 1007. 1H NMR: (DMSO-d6, 300 MHz): δ 2.44 (s, 3H, p-
CH3), 7.41 (d, J = 9 Hz, 2H), 7.54−7.69 (m, 6H), 7.88 (d, J = 9 Hz,
2H), 8.08−8.10 (m, 2H). (CD3OD, 600 MHz): δ 2.47 (s, 3H, p-CH3),
7.39 (d, J = 8.1 Hz, 2H), 7.56−7.62 (m, 4H), 7.68 (t, J = 7.8 Hz, 1H),
7.93 (d, J = 8.1 Hz, 2H), 8.05 (d, J = 7.8 Hz, 1H), 8.12 (d, J = 7.8 Hz,
1H). 13C NMR (DMSO-d6, 75 MHz): δ 21.6 (p-CH3), 77.7 (C-CN),
116.2 (CN); 11C-Harom:121.5, 126.3, 126.6, 127.17(×2?), 128.55,
128.66 (×2), 128.84 (×2), 129.93; 7Cq: 128.24, 133.2, 134.0, 134.7,
141.4, 158.48, 164.24; 182.3 (CS). MS-(+)ESI, m/z (%): 369 ([M +
H]+, 100), 391 ([M + Na]+, 10). HRMS-ESI (m/z): cald for
C22H17N4S [M + H]+ 369.1174, found 369.1165.
Chromatographic Screening. The resolution of the enantiomers
of compounds 5a−5f and 6a and 6b was performed on several chiral
stationary phases using various eluents to select the best conditions for
future semipreparative separation. Immobilized Daicel columns
Chiralpak IA, IB, IC, and ID were used in all cases, and (S,S)-Ulmo
was also screened in some cases. The temperature was regulated at 25
°C, and the flow rate was set at 1 mL/min. For each compound,
excellent separations with α > 1.65 were achieved on one or several
columns. For all the samples, Chiralpak IB gave very poor or no
separation, whereas IA, IC, or ID columns produced baseline
separation. For solubility reasons, the racemates were dissolved in a
mixture of ethanol and chloroform, which prevented the use of coated
polysaccharide phases. The separations were monitored using a DAD
detector and a circular dichroism detector set at 254 nm. All the
chromatographic data including mobile phase composition, retention
times and retention factors, enantioseparation and resolution obtained
from screening experiments are reported for each compound in the
Supporting Information. When the sensitivity was sufficient, the CD
signs at 254 nm in the mobile phase of the first and second eluted
enantiomers are also given.
6-Amino-4-benzyl-5-cyano-1-o-tolyl-2(1H)-pyrimidinone (5c).
Yield: 92% (290 mg). White solid, mp 256−258 °C. IR (KBr,
cm−1): 3517, 3464, 2212, 1682, 1611, 1567, 1529. 1H NMR (DMSO-
d6, 300 MHz): 1H NMR (DMSO-d6, 300 MHz): δ 2.00 (s, 3H, CH3),
3.89 (d, J = 15 Hz, 1H, CH2), 3.95 (d, J = 15 Hz, 1H, CH2), 7.22−7.41
(m, 9H), 7.80 (br, 2H−NH2). 13C NMR (DMSO-d6, 75 MHz): δ
17.1(o-CH3), 43.4 (CH2), 73.6 (C-CN), 116.4 (CN); 9C-Harom: 127.3,
128.3, 128.8, 129.0 (×2), 129.5 (×2), 130.2, 131.9; 5Cq: 133.8, 136.0,
137.0, 153.5, 159.3; 175.7 (CO). MS-(+)ESI, m/z (%): 317 ([M +
H]+, 100), 339 ([M + Na]+, 4), 655 ([2 M + Na]+, 29). HRMS-ESI
(m/z): cald for C19H17N4O [M + H]+ 317.1402, found 317.1416.
Synthesis of Imidate (8). To a solution of iminoester (10 mmol),
prepared according to the method described by Pinner,19 in methanol
and 4-methylbenzonitrile (15/15 mL) was bubbled with dry HCl.
Then, the iminoester was free of its salt, in 50 mL of ether, by a
solution of sodium carbonate. (o-Tolyl or 1-naphthyl)isothiocyanate
(10 mmol) was added dropwise at 0 °C in the iminoester solution.
The mixture was stirred for 2 h, and the ether was evaporated. The
imidate was recrystallized from petroleum ether.
(Z/E)-1-(Methoxy-p-tolyl-methylene)-3-o-tolyl-thiourea (8a).
Yield: 78% (2.32 g). White solid, mp 139−141 °C. IR (KBr, cm−1):
3138, 2943, 1659, 1524, 1436, 1289, 1242, 1208, 1183, 1151, 1099.
MS-(+)ESI, m/z (%): 299 ([M + H]+, 100), 321 ([M + Na]+, 9).
HRMS-ESI (m/z): cald for C17H19N2OS [M + H]+ 299.1218, found
1
299.1208. Z-isomer: H NMR (DMSO-d6, 300 MHz): δ 2.06 (s, 3H,
CH3), 2.35 (s, 3H, CH3), 3.63 (s, 3H, CH3), 7.07−7.24 (m, 4H), 7.27
(d, J = 9 Hz, 2H), 7.57 (d, J = 9 Hz, 2H), 10.82 (br, 1H, NH). 13C
NMR (DMSO-d6, 75 MHz): δ 17.7, 21.5, 55.0, 126.5, 127.1, 127.3,
127.5, 128.7, 129.5, 130.8, 134.1, 137.4, 142.5, 154.9, 189.3. E-isomer:
1H NMR (DMSO-d6, 300 MHz): δ 2.07 (s, 3H, CH3), 2.36 (s, 3H,
CH3), 3.90 (s, 3H, CH3), 7.07−7.24 (m, 4H), 7.32 (d, J = 9 Hz, 2H),
7.79 (d, J = 9 Hz, 2H), 10.67 (br, 1H, NH). 13C NMR (DMSO-d6, 75
MHz): δ 17.9, 21.5, 55.1, 126.5, 127.4, 127.9, 128.1, 128.8, 129.4,
130.8, 134.8, 137.9, 142.0, 156.9, 190.6.
Enantiomer Enrichment and Isolation. 5a. Chiralpak IA (10 ×
250 mm; mobile phase: hexane/ethanol/chloroform 70/10/20; flow: 5
mL/min; UV at 290 nm. Sample preparation: 98 mg in 20 mL of
chloroform and 20 mL of the mobile phase. 100 injections (400 μL).
(Z/E)-1-(Methoxy-p-tolyl-methylene)-3-naphthalen-1-yl-thiourea
(8b). Yield 86% (2.87 g). White solid, mp 134−136 °C. IR (KBr,
cm−1): 3134, 2946, 1675, 1515, 1497, 1280, 1241, 1210, 1158, 1099.
MS-(+)ESI, m/z (%): 335 ([M + H]+, 100). HRMS-ESI (m/z): cald
for C40H36N4NaO2S2 [2M + Na]+ 691.2177, found 691.2177. Z-
isomer: 1H NMR (DMSO-d6, 300 MHz): δ 2.31 (s, 3H, CH3), 3.78 (s,
3H, CH3), 7.26 (d, J = 9 Hz, 2H), 7.35−7.55 (m, 7H), 7.95 (d, J = 9
Hz, 2H), 11.40 (br, 1H, NH). 13C NMR (DMSO-d6, 75 MHz): δ 21.5,
54.8, 123.6, 124.6, 125.7, 126.0, 126.7, 127.0, 127.8, 128.4, 128.7,
Recovery: 40 mg of each enantiomer was obtained (98% ee). αD25
+98 (c 0.24, CHCl3) for the first eluted enantiomer.
=
5b. (S,S)-Ulmo (10 × 250 mm); mobile phase: hexane/ethanol/
chloroform 60/20/20; flow: 5 mL/min; UV at 300 nm. Sample
preparation: 142 mg in 10 mL of chloroform, 10 mL of ethanol and 5
mL of hexane. 36 injections (700 μL). Recovery: 65 mg of each
enantiomer (99% ee). α2D5 = −87 (c 0.26, CHCl3) for the first eluted
enantiomer.
1
129.0, 129.4, 134.0, 134.7, 142.5, 154.9, 190.0. E-isomer: H NMR
(DMSO-d6, 300 MHz): δ 2.40 (s, 3H, CH3), 3.96 (s, 3H, CH3), 7.19
(d, J = 9 Hz, 2H), 7.35−7.55 (m, 7H), 7.87 (d, J = 9 Hz, 2H), 11.12
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5c. Chiralpak IC (10 × 250 mm); mobile phase: hexane/ethanol/
chloroform 50/30/20; flow: 5 mL/min; UV at 300 nm. Sample
preparation: 150 mg in 30 mL of chloroform, 30 mL of ethanol and 15
mL of hexane. 75 injections (1000 μL). Recovery: 72 mg of each
enantiomer (99% ee). α2D5 = +94 (c 0.36, CHCl3) for the first eluted
enantiomer.
5d. Chiralpak IA (10 × 250 mm); mobile phase: hexane/ethanol/
chloroform 70/10/20; flow: 5 mL/min; UV at 300 nm. Sample
preparation: 95 mg in 15 mL of chloroform, 15 mL of ethanol and 5
mL of hexane. 70 injections (500 μL). Recovery: 39 mg of each
enantiomer (98% ee). α2D5 = +67 (c 0.29, CHCl3) for the first eluted
enantiomer.
5e. Chiralpak IA (10 × 250 mm); mobile phase: hexane/ethanol/
chloroform 70/10/20; flow: 5 mL/min; UV at 330 nm. Sample
preparation: 75 mg in 15 mL of chloroform, 15 mL of ethanol and 20
mL of hexane. 100 injections (450 μL). Recovery: 32 mg of each
enantiomer (97% ee). α2D5 = +68 (c 0.26, CHCl3) for the first eluted
enantiomer.
5f. Chiralpak IA (10 × 250 mm); mobile phase: hexane/ethanol/
chloroform 70/10/20; flow: 5 mL/min; UV at 260 nm. Sample
preparation: 63 mg in 30 mL of chloroform, 30 mL of ethanol and 10
mL of hexane due to the poor solubility of the sample. 140 injections
(500 μL). Recovery: 29 mg of each enantiomer (98% ee). α2D5 = +62 (c
0.036, CHCl3) for the first eluted enantiomer.
6a. Chiralpak IA (10 × 250 mm); mobile phase: hexane/ethanol/
chloroform 70/10/20; flow: 5 mL/min; UV at 400 nm. Sample
preparation: 97 mg in 6 mL of chloroform/ethanol (8:2). 45 injections
(130 μL). Recovery: 36 mg of each enantiomer (98% ee). α2D5 = +150
(c 0.11, CHCl3) for the first eluted enantiomer.
6b. Chiralpak IA (10 × 250 mm); mobile phase: hexane/ethanol
70/30; flow: 5 mL/min; UV at 400 nm. Sample preparation: 55 mg in
10 mL of chloroform/ethanol (1:1). 50 injections (200 μL). Recovery:
5 mg of each enantiomer (97% ee). α2D5 = +157 (c 0.059, CHCl3) for
the first eluted enantiomer.
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ASSOCIATED CONTENT
■
S
* Supporting Information
Chromatographic analysis; kinetics of enantiomerization;
crystallographic data (CIFs); 1H NMR, 13C NMR, and
1H−1H COSY NMR spectra for compounds 5a−5f, 6a, 6b,
8a, and 8b; analysis LC-DAD-LIF-MS for 5a-5f; and tables of
atom coordinates and absolute energies from theoretical
calculations. This material is available free of charge via the
Internet at http://pubs.acs.org.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: christian.roussel@univ-amu.fr.
Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS
■
The authors wish to thank Dr. Carine Duhayon for providing
the X-ray crystal analysis and Pierre Perio, Roseline Rosas, and
Dr. Daniel Farran for their help in the physicochemical
characterization of our compounds.
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