Synthesis of functionalized tetrahydro-1,3-diazepin-2-ones and 1-carbamoyl-1H-pyrroles via ring expansion and ring expansion/ring contraction of tetrahydropyrimidines

Article abstract of DOI:10.1039/c1ob06284k

A general approach to 6-phenylthio-substituted 2,3,4,5-tetrahydro-1H-1,3- diazepin-2-ones based on the ring expansion reaction of 1,2,3,4- tetrahydropyrimidin-2-ones under the action of nucleophiles has been developed. The first step of the synthesis was preparation of N-[(2-benzoyloxy-1-tosyl) ethyl]urea by three-component condensation of 2-benzoyloxyethanal, urea and p-toluenesulfinic acid. Nucleophilic substitution of the tosyl group in the obtained sulfone with sodium enolates of α-phenylthioketones followed by cyclization-dehydration, and debenzoylation gave 4-hydroxymethyl-5-phenylthio-1, 2,3,4-tetrahydropyrimidin-2-ones which were transformed into the 4-mesyloxymethyl-derivatives. Treatment of the latter with nucleophilic reagents, such as NaCN, sodium diethyl malonate, PhSNa, MeONa, NaBH₄, sodium succinimide, or potassium phthalimide, afforded the target multi-functionalized diazepinones. The obtained 6-phenylthio-diazepinones and their 6-tosyl-substituted analogues were converted into 3-substituted 1-carbamoyl-1H-pyrroles under acidic conditions as a result of ring contraction. Effective one-pot synthesis of the latter from 4-mesyloxymethyl-pyrimidines was realized using a ring expansion/ring contraction sequence.

Full text of DOI:10.1039/c1ob06284k

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PAPER
Synthesis of functionalized tetrahydro-1,3-diazepin-2-ones and
1-carbamoyl-1H-pyrroles via ring expansion and ring expansion/ring
contraction of tetrahydropyrimidines†
Anastasia A. Fesenko, Ludmila A. Trafimova and Anatoly D. Shutalev*
Received 28th July 2011, Accepted 26th September 2011
DOI: 10.1039/c1ob06284k
A general approach to 6-phenylthio-substituted 2,3,4,5-tetrahydro-1H-1,3-diazepin-2-ones based on
the ring expansion reaction of 1,2,3,4-tetrahydropyrimidin-2-ones under the action of nucleophiles has
been developed. The first step of the synthesis was preparation of N-[(2-benzoyloxy-1-tosyl)ethyl]urea
by three-component condensation of 2-benzoyloxyethanal, urea and p-toluenesulfinic acid.
Nucleophilic substitution of the tosyl group in the obtained sulfone with sodium enolates of
a-phenylthioketones followed by cyclization–dehydration, and debenzoylation gave
4-hydroxymethyl-5-phenylthio-1,2,3,4-tetrahydropyrimidin-2-ones which were transformed into the
4-mesyloxymethyl-derivatives. Treatment of the latter with nucleophilic reagents, such as NaCN,
sodium diethyl malonate, PhSNa, MeONa, NaBH4, sodium succinimide, or potassium phthalimide,
afforded the target multi-functionalized diazepinones. The obtained 6-phenylthio-diazepinones and
their 6-tosyl-substituted analogues were converted into 3-substituted 1-carbamoyl-1H-pyrroles under
acidic conditions as a result of ring contraction. Effective one-pot synthesis of the latter from
4-mesyloxymethyl-pyrimidines was realized using a ring expansion/ring contraction sequence.
Introduction
Development of general approaches to rare heterocyclic scaffolds
is important from the viewpoint of both synthetic and medicinal
chemistry. We have been interested in straightforward synthesis
of monocyclic tetrahydro-1H-1,3-diazepin-2-ones, particularly
2,3,4,5-tetrahydro-1H-1,3-diazepin-2-ones, which remain practi-
cally unexplored.1,2 The representatives of this class of heterocycles
possess various biological activities. For example, 2-oxo-2,3,6,7-
tetrahydro-1H-1,3-diazepine-5-carboxylates were demonstrated
to be useful in the treatment of cardiovascular disorders.3 The
Scheme 1 Conversion of pyrimidines 2 to 6-functionalized 2,3,4,5-
tetrahydro-1H-1,3-diazepin-2-ones 1.
derivatives of 2,3,4,5-tetrahydro- and 2,3,4,7-tetrahydro-1H-1,3-
diazepin-2-ones were shown to be powerful inhibitors of cytidine
deaminase2c,4 and potent inhibitors of metalloenzymes.5
EWG = COOMe, R = Me and EWG = COOEt, R = Me, Ph) have
been prepared in extremely low to moderate yields (2–65%).6b,6c
Although the preparation of 5-functionalized 1,2,3,4-
tetrahydropyrimidin-2-ones is well documented,7,8 there are only
rare examples of the synthesis of pyrimidines 2 or their possible
precursors.6b,6c,9 Obviously, the development of a general approach
to tetrahydropyrimidinones of type 2 will give an access to various
tetrahydrodiazepinones 1.
The reported approaches to tetrahydro-1H-1,3-diazepin-2-ones
are rather specific. The promising synthesis of 2-oxo-2,3,6,7-
tetrahydro-1H-1,3-diazepine-5-carboxylates (1 FG = COOR¢) by
ring expansion of 4-chloromethyl-substituted tetrahydropyrim-
idines 2 (FG = COOR¢, LG = Cl) under the action of nucleophiles3,6
(Scheme 1) is dramatically limited by the poor availability of
starting materials. Only three tetrahydropyrimidines 2 (LG = Cl;
Previously, we described
a general three-step synthesis
Department of Organic Chemistry, Moscow State Academy of Fine Chemical
Technology, 86 Vernadsky Avenue, 119571, Moscow, Russian Federation.
E-mail: shutalev@orc.ru; Fax: +7-495-9368909; Tel: +7-495-9368910
of 5-functionalized 1,2,3,4-tetrahydropyrimidin-2-ones/thiones
3 based on the reaction of a-tosyl-substituted N-alkylureas
and N-alkylthioureas 4 with enolates of a-substituted ke-
tones followed by acid-catalyzed dehydration of the obtained
4-hydroxyhexahydropyrimidin-2-ones/thiones 5 (Scheme 2).10
† Electronic supplementary information (ESI) available: IR and NMR (1H
and 13C) spectra of all obtained compounds, detailed procedure for multi-
gram scale syntheses of 2-benzoyloxyethanal (8) and N-[(2-benzoyloxy-1-
tosyl)ethyl]urea (9). See DOI: 10.1039/c1ob06284k
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diazepines into 3-functionalized 1-carbamoyl-1H-pyrroles and the
synthesis of the latter from tetrahydropyrimidines using a one-pot
ring expansion/ring contraction sequence.
Results and discussion
Synthesis of diazepine precursors
Key intermediates for the diazepinone synthesis, 4-mesyloxy-
methyl-5-phenylthio-substituted 1,2,3,4-tetrahydropyrimidin-2-
ones 6a,b were prepared as outlined in Scheme 3.
The assembly of tetrahydropyrimidine ring comprised three
steps. The first step was a three-component condensation of 2-
benzoyloxyethanal (8), p-toluenesulfinic acid (7) and urea in water
at room temperature that provided access to sulfone 9 in 97% yield
on a multi-gram scale.13
Scheme 2 General synthesis of 5-functionalized 1,2,3,4-tetrahydropyrim-
idin-2-ones/thiones 3.
Starting sulfones 4 were prepared by three-component conden-
sation of aldehyde, p-toluenesulfinic acid and (thio)urea in water
at room temperature followed by filtration of the precipitate.
This synthesis is flexible and gives easy access to 1,2,3,4-
tetrahydropyrimidin-2-ones/thiones bearing various functional
groups at C5 and substituents at C4 and C6 including func-
tionalized ones. Using this method, we have prepared 4-
mesyloxymethyl-, 4-tosyloxymethyl- and 4-chloromethyl-5-tosyl-
1,2,3,4-tetrahydropyrimidin-2-ones (2 LG = OMs, OTs, Cl; FG =
Ts) and demonstrated that they can serve as precursors for
tetrahydrodiazepinones (1 FG = Ts).11
In continuation of our research in this area, we describe here the
synthesis of 4-mesyloxymethyl-5-phenylthio-substituted 1,2,3,4-
tetrahydropyrimidin-2-ones and their reaction with various nu-
cleophiles affording novel 2,3,4,5-tetrahydro-1H-1,3-diazepin-2-
ones as a result of ring expansion. Before our studies this
transformation was demonstrated only for substrates bearing
electron-withdrawing groups at C5, such as an alkoxycarbonyl
group (2 FG = COOR¢)3,6 or a tosyl group (2 FG = Ts).11 We
envisage that the introduction of the electron-donating PhS group
at C5 of the starting pyrimidinones can clarify some peculiarities
of the mechanism of this transformation and can be of value for
other similar reactions of one-carbon atom ring expansion.3,4b,6,12
We also describe acid-catalyzed ring contraction of some obtained
The second step involved nucleophilic substitution of the tosyl
group in urea 9 by the enolates of a-phenylthio-substituted
ketones 10a,b generated by reacting corresponding CH-acids with
NaH in dry MeCN. With phenylthioacetone 10a this substitution
proceeded smoothly in MeCN at rt over 8 h, and the obtained
product (b-oxoalkylurea 11a or hydroxypyrimidine 12a) was
dehydrated without isolation after the addition of TsOH (1.33
equiv.) to the reaction mixture followed by refluxing for 2 h to
give 4-benzoyloxymethyl-pyrimidine 13a in 88% yield. This one-
pot methodology of tetrahydropyrimidine synthesis failed when
phenylthioacetophenone 10b was used as a starting material. The
addition of TsOH (1.5 equiv.) and refluxing of the reaction mixture
formed after completion of the reaction of urea 9 with sodium
enolate of 10b for 4 h led to formation of considerable amounts of
side products, which significantly decreased the yield and purity
of tetrahydropyrimidine 13b. This compound was successfully
prepared in two steps in 83% overall yield. The reaction of 9 with
the sodium enolate of 10b (MeCN, rt, 8 h) gave b-oxoalkylurea 11b
as a mixture of two diastereomers (78 : 22) which was dehydrated
by refluxing for 4 h in MeCN in the presence of TsOH (0.5 equiv.).
The benzoyl protection in 13a,b was removed using an EtOH–
H2O solution of KOH (1.8 equiv.) (rt, 3 h) to give hydroxymethyl-
tetrahydropyrimidines 14a and 14b in 70 and 85% yields, re-
spectively. Previously we have shown11b that the mesyloxy group
Scheme 3 Synthesis of 5-phenylthio-substituted 4-mesyloxymethyl-1,2,3,4-tetrahydropyrimidin-2-ones 6a,b.
448 | Org. Biomol. Chem., 2012, 10, 447–462 This journal is The Royal Society of Chemistry 2012
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Table 1 Reaction of mesyloxymethyl-pyrimidines 6a,b with NaCN (1.49–1.69 equiv.)
Starting
material
Conc. of 6
Reaction
conditions
Conversion
Purity of
Yieldd
(%)
Entry
Catalysta
Solvent
(mol L-1)
of 6b (%)
Product
15c (%)
1
2
3
4
5
6
7
8
6a
6a
6a
6a
6a
6a
6b
6b
6b
6b
6b
18-crown-6
18-crown-6
18-crown-6
18-crown-6
—
MeCN
MeCN
MeCN
MeCN
DMF
0.033
0.050
0.067
0.250
1.429
2.500
0.033
0.067
0.200
1.000
2.500
reflux, 5 h
reflux, 5 h
reflux, 3 h
reflux, 3.25 h
rt, 3 h
73
15a
15a
15a
15a
15a
15a
15b
15b
15b
15b
15b
—
59
52
32
—
39
70
38
22
—
35
—
55
—
—
—
(30)
63
—
15
100
100
100
49
100
100
100
100
87
—
DMF
rt, 6.7 h
18-crown-6
18-crown-6
18-crown-6
—
MeCN
MeCN
MeCN
DMF
reflux, 4 h
reflux, 3.2 h
reflux, 3 h
rt, 2.5 h
9
10
11
—
(33)
—
DMF
rt, 7 h
100
a 0.1–0.2 equiv. b According to 1H NMR spectroscopy of the crude isolated material. c Purity was estimated as ratio of the expected integral intensity of
the aromatic protons region (5 H for 15a, 10 H for 15b) to the observed integral intensity in this region in the 1H NMR spectrum of the crude product
multiplied by 100. d Isolated yields after column chromatography. The yields in parenthesis were determined by 1H NMR spectroscopy with 1,4-dioxane
as an internal standard.
is the best good-leaving group into which the hydroxy group
can be transformed. Under optimized reaction conditions, 4-
mesyloxymethyl-tetrahydropyrimidines 6a,b were prepared by the
reaction of 14a,b with MsCl in the presence of DMAP in CH2Cl2
at room temperature. The ratio of pyrimidine/MsCl/DMAP was
1 : 1.2 : 1.4 for 14a and 1 : 1.5 : 2 for 14b.14 A slightly greater excess
of reagents was used with 14b to reduce the reaction time (2 h
20 min instead of 5 h 40 min at a 14b/MsCl/DMAP ratio of
1 : 1.2 : 1.4).15 The yields of 6a and 6b after crystallization were 68
and 78%, respectively. Thus, the 4-mesyloxymethyl-5-phenylthio-
substituted pyrimidines 6a,b were obtained from urea 9 in 42–56%
overall yields.
5-tosyl-substituted analogues.11 Selected experimental data for
the reaction of 6a,b and NaCN giving 4-cyano-6-phenylthio-
2,3,4,5-tetrahydro-1H-1,3-diazepin-2-ones 15a,b (Scheme 4) are
summarized in Table 1.
The noticeable spectral characteristic of 6-methyl-
pyrimidinones 6a, 13a, and 14a is the long-range coupling
between protons 4-H and 6-CH3 (5J4-H,6-CH3 = 0.8–1.0 Hz) which,
together with the value of vicinal coupling between 4-H and
N(3)H (3JN(3)H,4-H = 2.7 Hz), demonstrates that the orientation of
the substituent at the C4-position of the pyrimidine ring is pseudo
equatorial (in DMSO-d6 solution). Close values of couplings
3JN(3)H,4-H = 2.4–2.8 Hz for 6-phenyl-substituted pyrimidinones
6b, 13b, and 14b show that the orientation of the substituent at
C4 is the same. Thus, the conformation of pyrimidinones 6, 13,
and 14 significantly differs from that previously described for
other 5-functionalized tetrahydropyrimidinones.11,16 Generally,
1H NMR spectra of the latter show values of vicinal coupling
3JN(3)H,4-H in the range of 3.4–3.9 Hz and no long-range coupling
5J4-H,6-CH3 (for 6-methyl-pyrimidinones).
Scheme 4 Synthesis of 4-cyano-6-phenylthio-2,3,4,5-tetrahydro-1H-1,3-
diazepin-2-ones 15a,b by the reaction of mesyloxymethyl-pyrimidines 6a,b
with NaCN.
The ring expansion reaction of 6a,b under the action of NaCN
(1.49–2.01 equiv.) was carried out in refluxing MeCN,17 THF or
1,4-dioxane for 3–9 h in the presence of 18-crown-6 (0.10–0.22
equiv.). Under all studied conditions an amount of unidentified
side products always formed along with diazepinones 15a,b as
detected by 1H NMR spectra of the isolated crude materials. The
characteristic feature of these spectra was an increase in the relative
integral intensity of the aromatic protons region (6.70–7.70 ppm).
Purity of the isolated diazepinones 15a,b strongly depended on
the starting concentration of 6a,b. At higher concentrations the
amount of side products increased (entries 2–4 for 6a; entries 7–
9 for 6b). Polarity of solvent, reaction temperature, amounts of
NaCN and 18-crown-6 caused only insignificant changes in the
purity of diazepinones 15a,b. In dry DMF the reaction of 6a,b with
NaCN was complete in about 7 h at room temperature (entries 6
and 11). However, under these conditions side reactions similar to
those proceeding in MeCN, THF or 1,4-dioxane were observed.
Under optimal conditions 4-cyano-substituted diazepinones 15a
(entry 2) and 15b (entry 7) were isolated in 55 and 63% yields,
respectively, after column chromatography.
Synthesis of diazepinones via ring expansion
We studied the reaction of one-carbon atom ring expansion of
4-mesyloxymethyl-pyrimidines 6a,b under the action of various
C-, N-, S-, H- and O-nucleophiles. Since the phenyl-group at
the C6-position of the pyrimidine ring significantly complicates
the reaction with all nucleophiles,11 we focused on the reactivity
of 6-phenylpyrimidine 6b, and optimal conditions found for this
starting material were used for 6-methylpyrimidine 6a.
Sodium diethyl malonate and sodium cyanide were used as
C-nucleophiles. With both nucleophiles the reactions proceeded
under more forcing conditions compared with the corresponding
The reaction of 6b with sodium diethyl malonate (1.25 equiv.)
affording diazepinone 16b (Scheme 5) proceeded very slowly in dry
MeCN at room temperature, and according to TLC a considerable
amount of starting material remained in the reaction mixture after
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was refluxed in dry MeCN in the presence of sodium succinimide
(1.5 equiv.) generated by treatment of succinimide with NaH, the
formation of some side products was observed. The reaction of
6a,b with sodium succinimide proceeded smoothly in THF at
reflux (3.75–4 h) to give products 18a,b in 93 and 92% yields,
respectively.
Sodium borohydride acted as a nucleophile, mediating the ring
expansion of pyrimidines 6a,b in THF at reflux for 1.8–4.2 h to
obtain 4-unsubstituted diazepinones 19a and 19b, which were
isolated using column chromatography in 66 and 72% yields,
respectively.
It is noteworthy that the reactions of 6a,b with nucleophiles as
described above gave only products of ring expansion, the corre-
sponding tetrahydro-1H-1,3-diazepin-2-ones 15–19. The products
of direct nucleophilic substitution of the leaving group (1,2,3,4-
tetrahydropyrimidin-2-ones) were not observed. However, the
reaction of 6a,b with PhSNa generated by treatment of PhSH
with NaH gave three different products: tetrahydrodiazepinones
20a,b, dihydrodiazepinones 21a,b, and tetrahydropyrimidinones
22a,b (Scheme 6). Under optimal conditions the total amount of
side products (compounds 21a,b and 22a,b) did not exceed 5%
Scheme
5
Synthesis of 6-phenylthio-2,3,4,5-tetrahydro-1H-1,3-
diazepin-2-ones 16–19a,b by the reaction of mesyloxymethyl-pyrimidines
6a,b with sodium malonate, potassium phthalimide, sodium succinimide,
and NaBH4. Reagents and conditions: a) CH2(COOEt)2, NaH, THF, rt,
5 h; b) potassium phthalimide, MeCN, reflux, 0.5–1.7 h; c) succinimide,
NaH, THF, reflux, 3.75–4 h; d) NaBH4, THF, reflux, 1.8–4.2 h.
1
according to H NMR data of isolated crude materials (Table
2). Under these conditions the yields of 4-phenylthio-substituted
diazepinones 20a and 20b were 93 and 95%, respectively.
In contrast to the previously studied reaction of ethyl
4-chloromethyl-6-methyl-2-oxo-1,2,3,4-tetrahydropyrimidine-5-
carboxylate and 6-methyl-4-mesyloxymethyl-5-tosyl-1,2,3,4-
tetrahydropyrimidin-2-one with PhSNa with or without
PhSH,11,18 with 6a,b formation of the products of direct
nucleophilic substitution (compounds 22a,b) proceeded even
without large excesses of PhSH. In a polar solvent (MeCN), a
temperature increase (Table 2, entry 14 vs. entries 13 and 3) and
a greater excess of nucleophile (entry 12 vs. entry 13) favored
this process. No product of direct substitution was detected even
in the presence of small amounts of PhSH without excess of
nucleophile in a less polar solvent (THF) at reflux (entry 5);
however, some amount of starting material was recovered. At
8 h. Some unreacted 6b was observed (TLC) after 6 h 40 min
even after the amount of nucleophile was increased to 1.80 equiv.
No starting material was detected (TLC) in the reaction mixture
(6b/sodium diethyl malonate at the ratio of 1.00 : 1.25) in refluxing
dry MeCN for 40 min, however some side products were formed. In
order to avoid this we increased the basicity of the reaction media
using a less polar solvent such as dry THF. In THF the reaction of
4-mesyloxymethyl-pyrimidines 6a,b with sodium diethyl malonate
(1.26–1.29 equiv.) proceeded smoothly at room temperature in 5 h
to give diazepinones 16a and 16b in 90 and 92% yields, respectively.
Pyrimidinones 6a,b readily reacted with N-nucleophiles. With
potassium phthalimide (1.5 equiv.) the expected products 17a,b
formed in refluxing MeCN for 0.5–1.7 h in 96% yield. When 6b
Table 2 Reaction of mesyloxymethyl-pyrimidines 6a,b with PhSH in the presence of NaH
Product distributiona (%)
Starting
material
Molar ratio of
6/PhSH/NaH
Reaction
conditions
Yield of
Entry
Solvent
6
20
21
22
20b (%)
1
2
3
4
5
6
7
8
6a
6a
6a
6a
6b
6b
6b
6b
6b
6b
6b
6b
6b
6b
6b
6b
1 : 1.20 : 1.20
1 : 1.19 : 1.19
1 : 1.13 : 1.10
1 : 1.29 : 1.25
1 : 1.12 : 1.03
1 : 1.28 : 1.28
1 : 1.20 : 1.20
1 : 2.09 : 2.07
1 : 1.39 : 1.24
1 : 3.12 : 3.09
1 : 3.13 : 3.11
1 : 1.10 : 1.03
1 : 1.12 : 1.10
1 : 1.09 : 1.07
1 : 1.22 : 1.21
1 : 1.20 : 1.20
THF
THF
MeCN
THF
THF
THF
THF
THF
THF
THF
THF
MeCN
MeCN
MeCN
1,4-dioxane
THF
reflux, 2 min
reflux, 1 h
reflux, 40 min
rt, 4 h
reflux, 1 h
rt, 8 h
reflux, 1 h
reflux, 1 h
rt, 1 h 40 min
reflux, 3 min
reflux, 1 h
reflux, 50 min
reflux, 30 min
rt, 3 h
—
—
—
—
8
—
—
—
—
—
—
—
—
23
—
—
95
89
53
90
92
89
77
44
82
77
51
95
66
77
49
95
1
5
6
4
—
4
21
56
—
23
49
5
10
—
38
2
4
6
41
6
—
7
93
—
—
—
—
—
—
—
—
—
—
—
—
—
—
95
2
—
18
—
—
—
24
—
13
3
9
10
11
12
13
14
15
16
reflux, 1 h
reflux, 1 min
a Determined by 1H NMR spectroscopy. b Isolated yield.
450 | Org. Biomol. Chem., 2012, 10, 447–462
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Scheme 6 Synthesis of 4,6-diphenylthio-2,3,4,5-tetrahydro-1H-1,3-diazepin-2-ones 20a,b by the reaction of mesyloxymethyl-pyrimidines 6a,b with
PhSNa.
room temperature in THF a greater excess of PhSH caused an
increase in the amount of 22b (entry 4 vs. entry 9).
The structure of compounds 22a,b was determined by
comparison of their 1H NMR spectra with those re-
ported previously for ethyl 4-phenylthiomethyl-6-methyl-2-
oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate and 6-methyl-4-
phenylthiomethyl-5-tosyl-1,2,3,4-tetrahydropyrimidin-2-one.18
Unexpectedly, other side products were detected in the reac-
tion of 6a,b with PhSNa. We suppose that these products (5-
phenylthio-2,3-dihydro-1H-1,3-diazepin-2-ones 21a,b)19 formed
as a result of elimination of PhSH from 20a,b under the reaction
Scheme 7 Synthesis of 4-methoxy-2,3,4,5-tetrahydro-1H-1,3-diazepin-2-
conditions. The amount of 21a,b increased with prolongation of
ones 24a–d by the reaction of mesyloxymethyl-pyrimidines 6a,b, 23a,b with
the reaction time both at room temperature (entry 9 vs. entry
MeONa in MeOH.
6) and reflux (entry 16 vs. entry 7; entry 10 vs. entry 11; entry
1 vs. entry 2), an increase in the amount of nucleophile (entry
donating (PhS) to electron-withdrawing (Ts). In contrast to 6a,
12 vs. entry 13; entry 7 vs. entries 8 and 11) and with a rise in
the reaction of 5-tosyl-substituted pyrimidine 23a was complete
temperature (entry 7 vs. entry 15). The tendency for elimination of
in 50 min to give diazepinone 24c in 95% yield. Changing the
PhSH affording the corresponding dihydrodiazepinone is stronger
leaving group from Cl to MsO also increased the reaction rate.
for 7-phenyl-substituted tetrahydrodiazepinone 20b than for its 7-
Indeed, at room temperature chloromethyl-substituted pyrimidine
23b reacted with MeONa in MeOH very slowly: after 4 h of
reaction a significant amount of starting material remained in
the reaction mixture (according to TLC). However, at reflux this
reaction proceeded in 2 min affording 4-methoxy-diazepinone 24d
in 93% yield.
methyl-substituted analogue 20a.
The dihydrodiazepinone structure of 21b was determined on
the basis of its 1H and 13C NMR spectra. The 1H NMR spectrum
exhibited a doublet of doublets at 5.16 ppm assigned to 6-H
(3J6-H,7-H = 8.2 Hz, 4J6-H,N(1)H = 1.2 Hz), a doublet of doublets at 5.85
ppm due to 7-H (3J7-H,6-H = 8.2 Hz, 3J7-H,N(1)H = 5.8 Hz), a doublet
The structure of the obtained diazepinones 15–20a,b and
at 8.12 ppm due to N(3)H (4JN(3)H,N(1)H = 2.2 Hz), and a doublet of
24a–d was confirmed by NMR spectroscopic data as described
doublets of doublets at 8.18 ppm corresponding to N(1)H. In the 13C
NMR spectrum the signals of the dihydrodiazepinone ring were
observed at 164.5 (C-2), 143.7 (C-4), 129.2 (C-7), 114.6 (C-6), and
elsewhere.11 For example, characteristic features of 1H NMR
spectra of 15–16a,b, 20a,b and 24a–d included a high geminal
coupling constant between 5-H(A) and 5-H(B) (14.8–16.7 Hz),
a rather high vicinal coupling constant between N(3)H and 4-H
(4.6–7.0 Hz), and long-range coupling between 5-H(A) and 7-CH3
for 7-methyl-diazepinones (1.5–1.7 Hz). Additional spectroscopic
1
112.6 (C-5) ppm. The H and 13C NMR spectral characteristics
for 21a were similar.
4-Methoxy-6-phenylthio- and 4-methoxy-6-tosyl-substituted
diazepinones 24a–d were obtained in the reaction of pyrimidines
6a,b and 23a,b with MeONa (2.5 equiv.) in MeOH (Scheme 7).
5-Tosyl-substituted pyrimidinones 23a,b were prepared as de-
scribed previously.11 Experimental data obtained with MeONa
as a nucleophile clearly demonstrated that the reaction rate
strongly depends on the functional group at C5, the substituent
at C6 and the leaving group LG. The rate of ring expansion
increased with 6-methyl-substituted substrates compared with
their 6-phenyl-substituted counterparts. 6-Methyl-pyrimidine 6a
reacted with MeONa in MeOH for 2 h at room temperature to
give diazepinone 24a in 97% yield, while under these conditions
the reaction of 6-phenyl-pyrimidine 6b was complete after only 4 h
to provide diazepinone 24b in the same yield. The reaction rate
increased with the change of functional group at C5 from electron-
data, such as a doublet in the range of 3.63–3.76 ppm (3JCH,4-H
=
8.8–9.9 Hz) for the methine proton in CH(COOEt)2 observed for
compounds 16a,b, and two multiplets (each 2H) in the ranges
of 3.14–3.33 and 2.38–2.56 ppm for 4-H and 5-H observed for
19a,b, also confirmed the diazepine structure of the products
obtained. Formation of the diazepine ring for compounds 17–
1
18a,b is unambiguously confirmed by their H NMR spectra in
which long-range couplings between 5-H(B) and N(3)H (1.2–1.5
Hz) and between 5-H(A) and 7-CH3 (1.2–1.3 Hz for 17a and 18a)
were observed.
The values of coupling constants between N(3)H, 4-H, 5-H(A),
and 5-H(B) (3J4-H,5-H(A) = 1.4–3.3, 3J4-H,5-H(B) = 4.8–7.4, and 3J4-H,N(3)H
=
4.6–7.0 Hz) have proved that tetrahydrodiazepinones 15–16a,b,
20a,b, 24a–d exist predominantly in a puckered conformation with
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a pseudo axial orientation of the substituent at C4 (in DMSO-d6).
The conformation of diazepinones 17a,b and 18a,b formed in the
reaction of 6a,b with N-nucleophiles differs in the orientation
of the substituent at C4 which is pseudo equatorial. This is in
agreement with the lower values of the geminal coupling constant
between 5-H(A) and 5-H(B) (2J5-H(A),5-H(B) = 13.7–14.3 Hz), the
high values of the vicinal coupling constant between 4-H and
5-H(A) (3J5-H(A),4-H = 10.5–11.1 Hz), and the low vicinal coupling
constant between N(3)H and 4-H (3JN(3)H,4-H = 0.8–1.3 Hz), which
were observed in their 1H NMR spectra in DMSO-d6.
Plausible mechanism of the ring expansion reaction
Previously it was demonstrated that nitrogen-containing heterocy-
cles (1,4-dihydropyridines,12d,k,m–o 1,2,3,4-tetrahydropyrimidines,6
9,10-dihydroacridines12a,b
) with HN–C C–C–C–LG moiety
(LG = good leaving group, e.g. Cl, OTs, OMs) underwent one-
carbon atom ring expansion reactions under the action of nucle-
ophiles. It was shown that the basic properties of the nucleophiles
played a significant role for these transformations which started
via proton abstraction from the NH group. The formed anion
was supposed to undergo intramolecular nucleophilic substitution
of the leaving group to give corresponding bicyclic cyclopropane
intermediates followed by the formation of the final products.
Recently, we studied the ring expansion reaction of pyrim-
idinones 2 (Scheme 1, R = Me; FG = Ts, COOEt; LG = Cl,
OMs) under the action of strong non-nucleophilic bases (NaH,
DBU)11a,20 or PhSNa in the presence of PhSH.18 The data obtained
was in good agreement with the above route of the reaction.
The detailed mechanism of formation of tetrahydrodi-
azepinones 15–20 and 24 is shown in Scheme 8. Proton ab-
straction from the more acidic N(1)H group21 under the action
of a nucleophile initiates the reaction. The obtained anions A
give bicyclic cyclopropane intermediates B. We suppose that
further transformation of B into diazepinones under basic nu-
cleophilic conditions may proceed via three different pathways:
NH deprotonation followed by ring expansion, electrocyclic
opening of the cyclopropane ring or nucleophilic attack on
the bridge-head carbon atom bound with nitrogen. Ab initio
calculations (B3LYP/6-31+G(d,p))22 performed for the reaction
of 2,4-diazabicyclo[4.1.0]hept-4-en-3-one with hydride anion as
a model reaction showed that the first pathway is preferable.23
Thus, deprotonation of B results in formation of extremely
unstable anions C, followed by spontaneous ring expansion to give
diazepine anions D. Protonation of anions D and addition of the
nucleophile to the obtained acylimines E give the final products.
The proposed mechanism is in good agreement with the
experimental data described above. Indeed, an increase in the
reaction rate with the change from an electron-donating group
(SPh) to an electron-withdrawing group (Ts) at C5 of the starting
pyrimidines 6, 23 can be explained by better stabilization of anions
A and D with Ts compared with the SPh substituent.
Scheme 8 A plausible pathway for transformation of 6a,b, 23a,b into
diazepinones 15–20a,b, 24a–d.
To confirm the proposed mechanism, we attempted to detect the
intermediates in the reactions of 4-mesyloxymethyl-pyrimidines
1
6a,b and 23a with NaCN and potassium phthalimide using H
NMR spectroscopy. A solution of 6a,b or 23a in DMSO-d6 was
treated with the nucleophiles (1.3–1.4 equiv.) in an NMR tube and
the progress of the reactions was monitored by 1H NMR at 25 ◦C.
The reactions of 5-tosylpyrimidine 23a with both nucleophiles
proceeded very quickly and completed in 20–25 min to give the
corresponding diazepinones.11b After 7–9 min of reaction, only
small amounts of starting material (6–8%) were observed. 5-
Phenylthiopyrimidines 6a,b reacted with the nucleophiles much
more slowly and all the reactions completed in 24 h to give
diazepinones 15a,b and 17a,b. After 30 min, the 1H NMR spectra
showed 16–24% and 64–67% conversions for the reactions of 6a
and 6b, respectively. No intermediates were detected in all NMR
experiments described above, because of their short lifetimes under
experimental conditions.
According to the proposed mechanism (Scheme 8), conversion
of pyrimidinones 6a,b, 23a,b into diazepinones 15–20a,b, 24a–d
can be divided into two consecutive sets of reactions: the first
set is the pyrimidine ring expansion determined by the basicity
of the nucleophile resulting in acylimines E, and the second
one is the nucleophilic addition to acylimines E determined by
the nucleophilicity of the nucleophile to give the final products.
Clearly, the first set of reactions can proceed without addition
of nucleophile in the presence of an appropriate non-nucleophilic
base (e.g., DBU). To confirm this hypothesis, a solution of 6a,b
in DMSO-d6 was treated with DBU (2.5–4 equiv.) in an NMR
tube and the progress of the reactions was monitored by 1H NMR
spectroscopy at 25 ◦C. The reaction of 6b proceeded very quickly
An alternative pathway of tetrahydropyrimidine ring expansion
could include proton abstraction from N(3)H to give anions F
followed by formation of aziridine intermediates G. However, ring
opening of aziridines G under the action of nucleophiles would
lead to attachment of the nucleophile to C5 to give compounds H
rather than to C4 as was observed. Thus, reaction pathway via the
formation of aziridine intermediates can be excluded.
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and after 9 min only 8% of starting material was observed. The 1H
NMR spectrum of the reaction mixture showed signals from three
new compounds: dihydrodiazepinone 21b (65%), the conjugated
base of 21b (13%),24 and bicyclic intermediate B (Scheme 8, FG =
SPh, R = Ph) (14%).25 After 2 days, the 1H NMR spectrum showed
only compound 21b. Evidently, the formation of the latter can be
explained by DBU-promoted ring expansion reaction of 6b to
give the corresponding acylimine E (Scheme 8). In the absence
of nucleophiles, the latter affords 21b as a result of acylimine–
enamide tautomerization. The reaction of 6a with DBU proceeded
similarly to that of 6b, however, more slowly. The final product
dihydrodiazepinone 21b in a ratio of 14 : 61 : 25, respectively, was
obtained (according to the 1H NMR spectrum) (entry 3). Use of
EtOH (95%) instead of MeOH in the ring contraction reaction was
more effective. Thus, 1-carbamoylpyrroles 25b–d were prepared
from 24b–d in 78, 88 and 96% yields respectively in refluxing EtOH
in the presence of TsOH (entries 4, 6 and 7). Pyrrole 25a was also
obtained from 4-phenylthio-substituted diazepinone 20a in 84%
yield using EtOH as a solvent (entry 2). We suppose that the better
result achieved with EtOH compared to that with MeOH can be
explained by the presence of water in EtOH. It was confirmed by
the smooth transformation of 24b into pyrrole 25b in refluxing
95% aqueous MeOH (entry 5).
The data obtained were used for efficient preparation of
pyrroles 25a–d directly from pyrimidines 6a,b, 23a,b without
isolation of intermediate methoxydiazepines 24a–d via the ring
expansion/ring contraction sequence (Scheme 10). In the case
of 6a, TsOH was added to the reaction mixture formed after
the reaction of 6a with MeONa in MeOH followed by refluxing
for 25 min to give pyrrole 25a in 89% yield. In all other cases,
after completion of the reaction between 6b, 23a,b and MeONa
in MeOH the solvent was evaporated, and the ring contraction
reaction in the presence in TsOH was carried out in refluxing
EtOH to produce pyrroles 25b–d. The use of a one-pot procedure
for 6a,b increased the overall yield of the corresponding pyrroles.27
1
detected by H NMR was dihydrodiazepinone 21a only. After
14 min and 1.5 h from the beginning of the reaction, the 1H
NMR spectra showed the presence of starting material, 21a, the
conjugated base of 21a, and bicyclic intermediate B (FG = SPh,
R = Me)26 in the ratios of 89 : 7 : 2 : 2 and 54 : 29 : 7 : 10, respectively.
Synthesis of 1-carbamoylpyrroles via ring contraction
Due to the low availability of 2,3,4,5-tetrahydro-1,3-1H-diazepin-
2-ones their chemistry has remained poorly explored. Only two
tetrahydrodiazepine-5-carboxylates were reported to undergo an
acid-catalyzed transformation into 1-carbamoyl-1H-pyrrole-3-
carboxylates via ring contraction.6c In order to develop the synthe-
sis of 1-carbamoyl-3-phenylthio-1H-pyrroles and 1-carbamoyl-
3-tosyl-1H-pyrroles we studied the reactivity of 4-phenylthio-
and 4-methoxy-diazepinones 20a, 24a–d under acidic conditions
(Scheme 9, Table 3).
Scheme 10 Synthesis of 1-carbamoyl-1H-pyrroles 25a–d from pyrim-
idines 6a,b, 23a,b using the ring expansion/ring contraction sequence.
A plausible mechanism of transformation of diazepinones 20,
24 into 1-carbamoylpyrroles 25 is outlined in Scheme 11.
The mechanism includes formation of acyliminium ions A as
a result of acid-catalyzed elimination of MeOH followed by the
addition of water, which affords 4-hydroxydiazepinones B. Ring
opening of the latter with subsequent recyclization of the obtained
ureas C leads to pyrrolines D, dehydration of which under the
action of TsOH gives the final products. The participation of water
in this process is in good agreement with experimental data (Table
3, entry 3 vs. entry 5).
Scheme 9 Acid-catalyzed ring contraction of diazepinones 20a, 24a–d to
1-carbamoyl-1H-pyrroles 25a–d.
Firstly, we studied the ring contraction reactions of 24a–d in
refluxing MeOH in the presence of TsOH. 7-Methyl-6-phenylthio-
diazepinone 24a was smoothly converted into pyrrole 25a in 0.5 h
in 89% yield (entry 1). Under similar conditions, reactions of 24b–
d proceeded more slowly and gave side products. For example, in
the case of 24b, a mixture of starting material, pyrrole 25b and
Table 3 Acid-catalyzed ring contraction reaction of diazepinones 20a, 24a–d into 1-carbamoyl-1H-pyrroles 25a–da
Entry
Starting material
Solventb
Equiv. of TsOH
Reaction time, min
Product(s)
Yield of 25d (%)
1
2
3
4
5
6
7
24a
20a
24b
24b
24b
24c
24d
MeOH
EtOH
MeOH
EtOH
MeOH–H2O, 95 : 5
EtOH
EtOH
0.10
0.21
0.10
0.05
0.1
0.1
0.1
30
25a
89
84
—
78
78
88
96
240
180
10
50
15
25a
21b+24b+25bc
25b
25b
25c
25d
60
a Reflux in alcohols in the presence of TsOH. b 99.5% MeOH and 95% EtOH were used. c In a ratio of 25 : 14 : 61, respectively. d Isolated yield.
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In 13C NMR spectra, the DMSO-d6 signal (39.50 ppm) was used
as a reference. Multiplicities are reported as singlet (s), doublet (d),
triplet (t), quartet (q), and some combinations of these, multiplet
(m). Selective 1H–1H decoupling and DEPT-135 experiments were
used to aid in the assignment of 1H- and 13C-NMR signals. Thin-
layer chromatography (TLC) was carried out on Merck silica gel
60 F254 aluminum backed plates in chloroform–methanol (9 : 1,
v/v) and chloroform–methanol (5 : 1, v/v) as solvent systems.
Spots were visualized with iodine vapors or UV light. Column
chromatography was performed with Merck silica gel 60 (0.04–
0.063 mm). All yields refer to isolated, spectroscopically and TLC
pure compounds. The color of analytically pure samples of all the
obtained compounds is white except for compound 6b (slightly
yellow).
4-(Mesyloxymethyl)-6-phenyl-5-phenylthio-1,2,3,4-tetrahydro-
pyrimidin-2-one (6b). To a cooled in an ice bath, stirred sus-
pension of pyrimidine 14b (3.500 g, 11.20 mmol) and DMAP
(2.759 g, 22.58 mmol) in dry CH2Cl2 (25 mL) was added a
solution of MsCl (1.933 g, 16.87 mmol) in dry CH2Cl2 (25 mL)
over 5 min. The obtained suspension was stirred for 5 min, the
ice bath was removed, stirring continued at room temperature
for 2 h 20 min, and the solvent was removed in vacuum. The
solid residue was triturated with ice-cold water (20 mL) and PE
(15 mL), the suspension was cooled (0 ◦C), the precipitate was
filtered, washed with ice-cold water, PE, cold ether, and dried to
give crude 6b (4.092 g) which was crystallized from 182 mL of
MeCN (decolorizing with silica gel) to obtain 6b (3.417 g, 78%)
as a slightly yellow solid◦which was used in the ring expansion
reactions; mp 170–170.5 C (decomp., MeCN); found: C, 54.97;
H, 4.86; N, 7.37. Calc. for C18H18N2O4S2: C, 55.37; H, 4.65; N,
7.17; nmax(Nujol)/cm-1 3331br s, 3235br s, 3124sh, 3103br m (NH),
3052w, 3028w, 3012 w (CHarom), 1711vs (amide I), 1632 m (C C),
1580 m, 1497 m (CCarom), 1338 s, 1170 s (SO2), 741 s, 702 m (CHarom);
Scheme 11 Transformation of 20a, 24a–d into 1-carbamoylpyrroles
25a–d.
Conclusions
A
six-step approach to 6-phenylthio-substituted 2,3,4,5-
tetrahydro-1,3-1H-diazepin-2-ones based on the ring expansion
reaction of 4-mesyloxymethyl-1,2,3,4-tetrahydropyrimidin-2-ones
under the action of various nucleophiles was developed. Synthe-
sis of pyrimidinones included the reaction of ureidoalkylation
of sodium enolates of a-phenylthio-substituted ketones with
readily available N-[(2-benzoyloxy-1-tosyl)ethyl]urea followed by
heterocyclization–dehydration, debenzoylation and mesylation.
A plausible mechanism of pyrimidine ring expansion involved
formation of cyclopropane intermediates followed by spontaneous
ring expansion and addition of a nucleophile to the formed
acylimine. 3-Functionally substituted 1-carbamoyl-1H-pyrroles
were synthesized from 4-methoxy- and 4-phenylthio-diazepinones
under acidic conditions via ring contraction. A pathway for this
transformation includes formation of acyliminium ions followed
by addition of water, ring opening and closure to give the
corresponding pyrroles. Effective one-pot synthesis of the latter
from 4-mesyloxymethyl-pyrimidines was realized using the ring
expansion/ring contraction sequence.
4
dH (300.13 MHz, DMSO-d6) 9.21 (1 H, d, JN(1)H,N(3)H = 2.0 Hz,
N(1)H), 7.29–7.41 (8 H, m, ArH and N(3)H), 7.12–7.23 (3 H, m,
ArH), 4.39 (1 H, dd, 2JCH(A),CH(B) = 10.5, 3JCH(A),4-H = 4.5 Hz, H(A) in
OCH2), 4.16 (1 H, dd, 2JCH(B),CH(A) = 10.5, 3JCH(B),4-H = 2.6 Hz, H(B) in
OCH2), 3.94 (1 H, ddd, 3J4-H,CH(A) = 4.5, 3J4-H,N(3)H = 2.8, 3J4-H,CH(B)
=
2.6 Hz, 4-H), 3.20 (3 H, s, CH3SO2); dC (75.48 MHz, DMSO-d6)
152.8 (C-2), 148.5 (C-6), 136.3 (C), 134.0 (C), 129.4 (2CH), 129.2
(CH), 128.8 (2CH), 127.9 (2CH), 125.9 (2CH), 125.6 (CH), 92.6
(C-5), 71.4 (OCH2), 54.6 (C-4), 36.9 (CH3SO2).
Experimental section
General
4-(Mesyloxymethyl)-6-methyl-5-phenylthio-1,2,3,4-tetrahydro-
pyrimidin-2-one (6a). This compound was prepared according
to the same procedure as described for 6b from pyrimidine 14a
(2.803 g, 11.20 mmol), DMAP (1.936 g, 15.85 mmol) and MsCl
(1.551 g, 13.54 mmol) in dry CH2Cl2 (50 mL) (rt, 2 h). The
crude product (3.506 g) was crystallized from 12 mL of MeCN
(decolorizing with silica gel) to give 6a (2.501 g, 68%) as a white
solid; mp 136.5–137 ◦C (decomp., MeCN); found: C, 47.57; H,
4.98; N, 8.67. Calc. for C13H16N2O4S2: C, 47.55; H, 4.91; N, 8.53;
All used solvents were distilled before use. 95% EtOH was used
unless otherwise indicated. The petroleum ether (PE) had a
distillation range of 40–60 ◦C. Dry solvents (MeCN, THF, CH2Cl2,
MeOH, EtOH, DMF) were obtained according to the standard
procedures. Sodium hydride (NaH) (60% suspension in mineral
oil) was thoroughly washed with dry pentane and dried in vacuum
prior to use. All other reagents were purchased from commercial
sources and used without additional purification. IR spectra (in
Nujol) were recorded using a Bruker Vector 22 spectrophotometer.
Band characteristics in the IR spectra are defined as very strong
n
max(Nujol)/cm-1 3413 m, 3377w, 3238br s, 3141br m (NH), 3077w,
3060w, 3020w, 3002 w (CHarom), 1701 s, 1680 m (amide I), 1657
1
(vs), strong (s), medium (m), weak (w), and shoulder (sh). H
and proton-decoupled 13C NMR spectra (solutions in DMSO-d6)
were acquired using a Bruker DPX 300 spectrometer at 300.13
MHz (1H) and 75.48 MHz (13C). H NMR chemical shifts are
s (C C), 1581 m (CCarom), 1350 s, 1171 s (SO2), 744 s, 692 m
4
(CHarom); dH (300.13 MHz, DMSO-d6) 8.97 (1 H, d, JN(1)H,N(3)H
2.1 Hz, N(1)H), 7.30–7.37 (2 H, m, ArH), 7.24 (1 H, dd, 3JN(3)H,4-H
=
=
2.7, 4JN(3)H,N(1)H = 2.1 Hz, N(3)H), 7.14–7.23 (3 H, m, ArH), 4.18 (1
H, dd, 2JCH(A),CH(B) = 10.4, 3JCH(A),4-H = 4.6 Hz, H(A) in OCH2), 4.06
1
referenced to the residual proton signal in DMSO-d6 (2.50 ppm).
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2
3
(1 H, dd, JCH(B),CH(A) = 10.4, JCH(B),4-H = 2.7 Hz, H(B) in OCH2),
reaction mixture becomes dark red. The solvent was removed in
vacuum. The oily dark red residue was triturated with PE (3 ¥
15 mL), then satd. aqueous NaHCO3 (8 mL) and PE (15 mL)
were added, the mixture was warmed in a water bath (40 ◦C) for 3
h and left overnight at room temperature, then cooled to 0 ◦C, the
oily substance was filtered using a glass filter, washed with ice-cold
water and divided into small portions (for better drying). The filter
with crude product was dried in a vacuum desiccator (over P2O5),
3
3
3
3.91 (1 H, dddq, J4-H,CH(A) = 4.6, J4-H,N(3)H = 2.7, J4-H,CH(B) = 2.7,
5J4-H,6-CH3 = 0.9 Hz, 4-H), 3.11 (3 H, s, CH3SO2), 1.97 (3 H, d,
5J6-CH3,4-H = 0.9 Hz, 6-CH3); dC (75.48 MHz, DMSO-d6) 152.6 (C-
2), 146.1 (C-6), 136.3 (C), 129.3 (2CH), 125.7 (2CH), 125.5 (CH),
90.5 (C-5), 71.2 (OCH2), 54.8 (C-4), 36.7 (CH3SO2), 16.9 (6-CH3).
N-[(1-Benzoyloxy-4-oxo-4-phenyl-3-phenylthio)but-2-yl]urea
(11b). To a mixture of phenylthioacetophenone 10b (2.328 g,
10.20 mmol) and NaH (0.244 g, 10.16 mmol) was added dry
MeCN (14 mL), the mixture was stirred in an ice-cold bath for
11 min and to the resulting solution were added sulfone 9 (3.674 g,
10.14 mmol) and MeCN (5 mL). The suspension was stirred at
room temperature for 8 h, and solvent was removed in vacuum.
The oily residue was triturated with PE (3 ¥ 15 mL), to the formed
yellow solid was added satd. aqueous NaHCO3 (8 mL) and PE
(15 mL) and the obtained suspension was warmed on a water bath
(40 ◦C) for 3 h, left overnight at room temperature, and cooled to
0 ◦C. The precipitate was filtered, washed with ice-cold water and
PE. The solid obtained was dried in a vacuum desiccator (over
P2O5) on the filter, cooled (-10 ◦C), washed with cold (-10 ◦C)
ether (3 ¥ 10 mL), and dried to give 11b (3.600 g, 85%) as a
slightly yellow solid with the ratio of diastereomers 78 : 22. After
crystallization from ethyl acetate–hexane (4 : 1) compound 11b was
obtained as a white solid with a 88 : 12 diastereomeric ratio; mp
143.5–144.5 ◦C (EtOAc/hexane, 4 : 1, v/v); found: C, 66.31; H,
5.33; N, 6.69. Calc. for C24H22N2O4S: C, 66.34; H, 5.10; N, 6.45;
◦
cooled (-10 C), the oily matter was triturated and washed with
cold (-10 ◦C) ether until crystallization was complete, then ether
was removed from powder by passing air through the filter and
the product was washed with ice-cold water, and dried to give 13a
(2.382 g, 88%) as a pale brown solid. Recrystallization from EtOH
◦
afforded 13a as a white solid; mp 200–201 C (decomp., EtOH);
found: C, 64.43; H, 5.26; N, 7.71. Calc. for C19H18N2O3S: C, 64.39;
H, 5.12; N, 7.90; nmax(Nujol)/cm-1 3245br s, 3094br s (NH), 1725 s
(C O in PhCOO), 1699vs (amide I), 1663 m (C C), 1603w, 1583
w (CCarom), 1267 s, 1114 s (C–O), 744 m, 714 s, 690 m (CHarom); dH
(300.13 MHz, DMSO-d6) 9.08 (1 H, d, 4JN(1)H,N(3)H = 2.0 Hz, N(1)H),
7.95–8.00 (2 H, m, ArH), 7.63–7.71 (1 H, m, ArH), 7.49–7.57 (2
3
4
H, m, ArH), 7.31 (1 H, dd, JN(3)H,4-H = 2.7, JN(3)H,N(1)H = 2.0 Hz,
N(3)H), 7.10–7.31 (5 H, m, ArH), 4.25 (1 H, dd, 2JCH(A),CH(B) = 11.2,
3JCH(A),4-H = 4.4 Hz, H(A) in OCH2), 4.17 (1 H, dd, 2JCH(B),CH(A) = 11.2,
3
3JCH(B),4-H = 2.9 Hz, H(B) in OCH2), 3.96 (1 H, dddq, J4-H,CH(A)
=
4.4, 3J4-H,CH(B) = 2.9, 3J4-H,N(3)H = 2.7, 5J4-H,6-CH3 = 0.8 Hz, 4-H), 1.96 (3
H, d, 5J6-CH3,4-H = 0.8 Hz, 6-CH3); dC (75.48 MHz, DMSO-d6) 165.7
(C O in PhCOO), 153.2 (C-2), 145.8 (C-6), 136.7 (C), 133.4 (CH),
129.5 (C), 129.4 (2CH), 129.3 (2CH), 128.7 (2CH), 125.6 (2CH),
125.4 (CH), 91.5 (C-5), 66.6 (OCH2), 54.9 (C-4), 16.9 (6-CH3).
n
max(Nujol)/cm-1 3448 s, 3326sh, 3300br s, 3195 m (NH), 3056 w
(CHarom), 1719 s (C O in PhCOO), 1672 s (C O in COPh), 1653
s (amide I), 1596w, 1582 m (CCarom), 1551 s, 1533 s (amide II),
1274 s, 1119 s (C–O), 736 m, 717 s, 684 m (CHarom); dH for the
diastereomeric mixture (88 : 12) (300.13 MHz, DMSO-d6) 7.84–
7.98 (4 H, m, ArH), 7.58–7.69 (2 H, m, ArH), 7.35–7.55 (6 H,
m, ArH), 7.23–7.55 (3 H, m, ArH), 6.40–6.47 (1 H, m, NH), 5.75
(0.24 H, s, NH2 for the major isomer), 5.62 (1.76 H, s, NH2 for the
minor isomer), 5.20–5.28 (1 H, m, CH–S), 4.46–4.67 (2.64 H, m,
OCH2CH for the major isomer), 4.17–4.41 (0.36 H, m, OCH2CH
for the minor isomer); dC for the major diastereomer (75.48 MHz,
DMSO-d6) 194.8 (C O in COPh), 165.5 (C O in PhCOO), 157.9
(NHCONH2), 135.8 (C), 133.5 (CH), 133.3 (CH), 132.6 (2CH),
132.3 (C), 129.5 (C), 129.3 (2CH), 129.2 (2CH), 128.7 (2CH), 128.5
(2CH), 128.4 (2CH), 128.3 (CH), 65.1 (OCH2), 51.4 (CH–S), 49.6
(CH–N).
4-(Benzoyloxymethyl)-6-phenyl-5-phenylthio-1,2,3,4-tetrahy-
dropyrimidin-2-one (13b). A solution of compound 11b (5.115 g,
11.77 mmol) and TsOH·H2O (1.147 g, 6.03 mmol) in dry MeCN
(35 mL) was refluxed for 4 h under stirring and then the solvent
was removed in vacuum. The solid residue was triturated with
satd. aqueous NaHCO3 (20 mL), PE (15 mL) was added, and
the mixture was stirred at room temperature for 1 h for better
grinding of the obtained precipitate, cooled to 0 ◦C, the precipitate
was filtered, washed with ice-cold water, PE, and dried to give 13b
(4.803 g, 98%) as a pale yellow solid. Recrystallization from MeCN
afforded 13b as a white solid; mp 192–195 ◦C (MeCN); found: C,
69.24; H, 4.85; N, 6.61. Calc. for C24H20N2O3S: C, 69.21; H, 4.84;
N, 6.73; nmax(Nujol)/cm-1 3365 s, 3195br s, 3088br s, 3066 s (NH),
1703 s (C O in PhCOO), 1688vs (amide I), 1649 m (C C),
1600w, 1580w, 1492 w (CCarom), 1281 s, 1108 m (C–O), 742 m,
713 s, 699 s (CHarom); dH (300.13 MHz, DMSO-d6) 9.22 (1 H, d,
4-(Benzoyloxymethyl)-6-methyl-5-phenylthio-1,2,3,4-tetrahy-
dropyrimidin-2-one (13a). To a mixture of phenylthioacetone 10a
(1.295 g, 7.79 mmol) and NaH (0.185 g, 7.71 mmol) was added
dry MeCN (16 mL), the mixture was stirred in an ice-cold bath for
12 min and to the resulting solution were added sulfone 9 (2.771 g,
7.65 mmol) and MeCN (2 mL). The suspension was stirred at
room temperature for 8 h, then TsOH·H2O (1.948 g, 10.24 mmol)
was added and the reaction mixture was refluxed under stirring for
2 h. At the beginning of the reflux the reaction mixture becomes
very dense, which complicates stirring, thus the flask was shaken
to keep the internal temperature of the mixture roughly the same
throughout the entire volume. Without this procedure thermal
decomposition of the mixture occurs at the bottom of the flask,
which significantly reduces the purity and yield of the product.
20 min after the beginning of the reflux the suspension becomes
fluid enough to be stirred normally. At the end of the reflux the
4JN(1)H,N(3)H = 2.0 Hz, N(1)H), 8.01–8.07 (2 H, m, ArH), 7.63–7.71 (1
3
H, m, ArH), 7.49–7.57 (2 H, m, ArH), 7.38 (1 H, dd, JN(3)H,4-H
=
2.7, 4JN(3)H,N(1)H = 2.0 Hz, N(3)H), 7.11–7.37 (10 H, m, ArH), 4.58 (1
H, dd, 2JCH(A),CH(B) = 11.2, 3JCH(A),4-H = 4.0 Hz, H(A) in OCH2), 4.24
2
3
(1 H, dd, JCH(B),CH(A) = 11.2, JCH(B),4-H = 2.8 Hz, H(B) in OCH2),
3
3
3
4.03 (1 H, ddd, J4-H,CH(A) = 4.0, J4-H,CH(B) = 2.8, J4-H,N(3)H = 2.7
Hz, 4-H); dC (75.48 MHz, DMSO-d6) 165.7 (C O in PhCOO),
153.2 (C-2), 147.9 (C-6), 136.5 (C), 134.0 (C), 133.4 (CH), 129.5
(C), 129.4 (2CH), 129.3 (2CH), 129.0 (CH), 128.7 (2CH), 128.6
(2CH), 127.8 (2CH), 125.9 (2CH), 125.5 (CH), 93.8 (C-5), 66.6
(OCH2), 54.8 (C-4).
4-Hydroxymethyl-6-phenyl-5-phenylthio-1,2,3,4-tetrahydropyri-
midin-2-one (14b). To a solution of KOH (1.158 g, 20.64 mmol)
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3
4
in H2O (10 mL) were added pyrimidine 13b (4.803 g, 11.53 mmol)
and EtOH (36 mL). The obtained suspension was stirred at room
temperature for 2 h 50 min, cooled in an ice bath, neutralized
with 15% aqueous HCl to pH 6, and the solvent was removed in
vacuum. To the solid residue was added s◦atd. aqueous NaHCO3
(15 mL), the suspension was cooled to 0 C, the precipitate was
filtered, washed with ice-cold water, PE, cold (-10 ◦C) ether, and
dried to give 14b (3.078 g, 85%) as a yellow solid. Recrystallization
from nBuOH afforded 14b as a white solid; mp 241 ◦C (decomp.,
nBuOH); found: C, 65.42; H, 5.27; N, 8.95. Calc. C17H16N2O2S
(312.39): C, 65.36, H, 5.16; N, 8.97; nmax(Nujol)/cm-1 3378 m,
3340w, 3328w, 3288 m, 3213br s, 3086br s, 3075sh (NH, OH),
3031 w (CHarom), 1670vs (amide I), 1658vs (C C), 1601w, 1580w,
1495 w (CCarom), 768 m, 742 s, 699 s (CHarom); dH (300.13 MHz,
2.2 Hz, N(1)H), 7.87 (1 H, ddd, JN(3)H,4-H = 6.6, JN(3)H,N(1)H = 2.2,
4JN(3)H,5-H(B) = 0.8 Hz, N(3)H), 7.15–7.38 (10 H, m, ArH), 4.73 (1
H, ddd, J4-H,N(3)H = 6.6, J4-H,5-H(B) = 5.0, J4-H,5-H(A) = 3.3 Hz, 4-H),
3
3
3
2
3
3.02 (1 H, dd, J5-H(A),5-H(B) = 16.3, J5-H(A),4-H = 3.3 Hz, 5-H(A)),
2.71 (1 H, ddd, 2J5-H(B),5-H(A) = 16.3, 3J5-H(B),4-H = 5.0, 4J5-H(B),N(3)H = 0.8
Hz, 5-H(B)); dC (75.48 MHz, DMSO-d6) 154.9 (C-2), 144.1 (C-7),
138.0 (C), 136.4 (C), 129.3 (2CH), 128.5 (CH), 128.3 (2CH), 128.0
(2CH), 126.5 (2CH), 125.5 (CH), 118.5 (CN), 104.6 (C-6), 43.0
(C-4), 37.7 (C-5).
4-Cyano-7-methyl-6-phenylthio-2,3,4,5-tetrahydro-1H -1,3-
diazepin-2-one (15a). This compound was prepared according
to the same procedure as described for 15b from pyrimidine 6a
(0.643 g, 1.96 mmol), NaCN (0.144 g, 2.94 mmol) and 18-crown-
6 (0.050 g, 0.19 mmol) in dry MeCN (41 mL) (5 h, reflux). The
crude product was purified by column chromatography on silica
gel 60 (16 g) eluting with PE/CHCl3 (from 33 : 67 to 0 : 100) to
afford pure 15a (0.281 g, 55%) as a white solid; mp 204.5–205.5 ◦C
(EtOH); found: C, 60.17; H, 5.19; N, 16.32. Calc. for C13H13N3OS:
C, 60.21; H, 5.05; N, 16.20; nmax(Nujol)/cm-1 3376 s, 3245 s, 3144br
s (NH), 3073 w (CHarom), 2243 w (C N), 1690vs (amide I), 1634 s
(C C), 1580 m, 1508 w (CCarom), 737 s, 692 m (CHarom); dH (300.13
DMSO-d6) 8.91 (1 H, d, 4JN(1)H,N(3)H = 2.0 Hz, N(1)H), 7.26–7.39 (7
3
H, m, ArH), 7.10–7.22 (3 H, m, ArH), 6.96 (1 H, dd, JN(3)H,4-H
=
4
3
2.4, JN(3)H,N(1)H = 2.0, Hz, N(3)H), 4.89 (1 H, t, JOH,CH2 = 5.7 Hz,
3
3
3
OH), 3.64 (1 H, ddd, J4-H,CH(A) = 5.7, J4-H,CH(B) = 2.9, J4-H,N(3)H
=
2
3
2.4 Hz, 4-H), 3.58 (1 H, ddd, JCH(A),CH(B) = 11.0, JCH(A),4-H = 5.7,
3JCH(A),OH = 5.7 Hz, H(A) in OCH2), 3.47 (1 H, ddd, JCH(B),CH(A)
=
2
11.0, 3JCH(B),OH = 5.7, 3JCH(B),4-H = 2.9 Hz, H(B) in OCH2); dC (75.48
MHz, DMSO-d6) 153.3 (C-2), 147.1 (C-6), 136.9 (C), 134.3 (C),
129.2 (2CH), 128.9 (CH), 128.8 (2CH), 127.7 (2CH), 125.7 (2CH),
125.2 (CH), 94.7 (C-5), 63.6 (OCH2), 57.6 (C-4).
4
MHz, DMSO-d6) 8.68 (1 H, d, JN(1)H,N(3)H = 2.2 Hz, N(1)H), 7.83
3
4
4
(1 H, ddd, JN(3)H,4-H = 7.0, JN(3)H,N(1)H = 2.2, JN(3)H,5-H(B) = 0.8 Hz,
N(3)H), 7.27–7.35 (2H, m, ArH), 7.13–7.23 (3 H, m, ArH), 4.63 (1
H, ddd, J4-H,N(3)H = 7.0, J4-H,5-H(A) = 3.3, J4-H,5-H(B) = 4.8 Hz, 4-H),
2.90 (1 H, ddq, J5-H(A),5-H(B) = 16.7, J5-H(A),4-H = 3.3, J5-H(A),7-CH3
3
3
3
4-Hydroxymethyl-6-methyl-5-phenylthio-1,2,3,4-tetrahydropyri-
midin-2-one (14a). Compound 14a (1.978 g, 70%) as a pale brown
solid was prepared from pyrimidine 13a (4.018 g, 11.34 mmol) and
KOH (1.139 g, 20.30 mmol) in H2O (10 mL) and EtOH (35 mL)
(2 h 45 min, rt) as described for 14b. Recrystallization from EtOH
(decoloration of boiling solution with charcoal) afforded 14a as a
white solid; mp 212–214 ◦C (decomp., EtOH); found: C, 57.71; H,
5.70; N, 11.12. Calc. for C12H14N2O2S: C, 57.58, H; 5.64; N, 11.19;
2
3
5
=
=
2
3
1.7 Hz, 5-H(A)), 2.58 (1 H, dddq, J5-H(B),5-H(A) = 16.7, J5-H(B),4-H
4.8, 4J5-H(B),N(3)H = 0.8 Hz, 5J5-H(B),7-CH3 = 0.7 Hz, 5-H(B)), 2.14 (3 H,
dd, 5J7-CH3,5-H(A) = 1.7, 5J7-CH3,5-H(B) = 0.7 Hz, 7-CH3); dC (75.48 MHz,
DMSO-d6) 155.6 (C-2), 141.1 (C-7), 136.1 (C), 129.2 (2CH), 126.3
(2CH), 125.5 (CH), 118.6 (CN), 101.0 (C-6), 41.9 (C-4), 38.9 (C-5),
21.3 (7-CH3).
n
max(Nujol)/cm-1 3296br s, 3261 s, 3141 m, 3108 m (NH, OH),
4-[Di(ethoxycarbonyl)methyl]-7-phenyl-6-phenylthio-2,3,4,5-
tetrahydro-1H-1,3-diazepin-2-one (16b). To a cooled in an ice
bath, stirred suspension of NaH (0.016 g, 0.67 mmol) in dry
THF (1 mL) was added a solution of diethyl malonate (0.117 g,
0.73 mmol) in THF (1.5 mL) over 2 min, and the solution was
stirred for 8 min, then pyrimidine 6b (0.207 g, 0.53 mmol) and
THF (2.5 mL) were added. The resulting suspension was stirred at
room temperature for 5 h, the solvent was removed in vacuum, and
the solid residue was triturated with PE (2 mL) and H2O (2 mL)
until crystallization was complete. The obtained suspension was
cooled (0 ◦C), the precipitate was filtered, washed with ice-cold
water, PE, and dried to give 16b (0.222 g, 92%) as a white solid;
mp 116.5–118 ◦C (EtOH); found: C, 63.42; H, 5.93; N, 6.18. Calc.
for C24H26N2O5S: C, 63.42; H, 5.77; N, 6.16; nmax(Nujol)/cm-1 3413
s, 3340w, 3211 s, 3095sh, 3080 s (NH), 3032w, 3013 w (CHarom),
1728vs (C O), 1679vs (amide I), 1620 s (C C), 1579 m, 1494
m (CCarom), 1255 s, 1159 s, 1038 s (C–O), 744 s, 695 s (CHarom);
1703vs, 1695vs, 1674 m (amide I), 1651 s (C C), 1578 m (CCarom),
748 s, 698 m (CHarom); dH (300.13 MHz, DMSO-d6) 8.72 (1 H,
4
d, JN(1)H,N(3)H = 2.1 Hz, N(1)H), 7.27–7.35 (2 H, m, ArH), 7.10–
3
4
7.22 (3 H, m, ArH), 6.82 (1 H, dd, JN(3)H,4-H = 2.7, JN(3)H,N(1)H
=
3
2.1 Hz, N(3)H), 4.75 (1 H, t, JOH,CH2 = 5.6 Hz, OH), 3.57 (1 H,
m, 4-H), 3.31–3.49 (2 H, m, OCH2), 1.93 (3 H, d, 5J6-CH3,4-H = 1.0
Hz, 6-CH3); dC (75.48 MHz, DMSO-d6) 153.1 (C-2), 144.6 (C-6),
137.1 (C), 129.2 (2CH), 125.4 (2CH), 125.1 (CH), 92.4 (C-5), 63.7
(OCH2), 57.9 (C-4), 16.8 (6-CH3).
4-Cyano-7-phenyl-6-phenylthio-2,3,4,5-tetrahydro-1H-1,3-dia-
zepin-2-one (15b). A suspension of pyrimidine 6b (0.571 g,
1.46 mmol), finely powdered NaCN (0.107 g, 2.18 mmol) and 18-
crown-6 (0.051 g, 0.19 mmol) in dry MeCN (45 mL) was refluxed
under stirring for 4 h. The solvent was removed in vacuum, the
obtained oily residue was triturated upon cooling with H2O (5 mL)
and PE (5 mL) until crystallization was complete. The resulting
suspension was cooled to 0 ◦C, the precipitate was filtered, washed
with ice-cold water, PE, dried, and the product was purified
by column chromatography on silica gel 60 (15 g) eluting with
PE/CHCl3 (from 50 : 50 to 0 : 100) to give 15b (0.296 g, 63%) as a
white solid; mp 228–229 ◦C (decomp., MeCN); found: C, 66.92; H,
4.98; N, 13.22. Calc. for C18H15N3OS: C, 67.27; H, 4.70; N, 13.07;
4
dH (300.13 MHz, DMSO-d6) 8.24 (1 H, d, JN(1)H,N(3)H = 2.2 Hz,
N(1)H), 7.28–7.39 (7 H, m, ArH), 7.14–7.22 (3 H, m, ArH), 7.09
(1 H, dd, 3JN(3)H,4-H = 4.6, 4JN(3)H,N(1)H = 2.2 Hz, N(3)H), 4.04–4.19 (2
H, m, OCH2), 4.07 (2 H, q, 3JCH2,CH3 = 7.1 Hz, OCH2), 4.01 (1 H,
dddd, 3J4-H,CH = 8.8, 3J4-H,5-H(B) = 7.4, 3J4-H,N(3)H = 4.6, 3J4-H,5-H(A) = 2.7
3
Hz, 4-H), 3.76 (1 H, d, JCH,4-H = 8.8 Hz, CH in CH(COOEt)2),
2
3
n
max(Nujol)/cm-1 3235 s, 3220sh, 3081 s (NH), 3056 w (CHarom),
2.77 (1 H, dd, J5-H(B),5-H(A) = 15.3, J5-H(B),4-H = 7.4 Hz, 5-H(B)),
2 3
2242 w (CN), 1688vs (amide I), 1626 m (C C), 769 s, 749 s, 701
2.66 (1 H, dd, J5-H(A),5-H(B) = 15.3, J5-H(A),4-H = 2.7 Hz, 5-H(A)),
1.16 (3 H, t, JCH3,CH2 = 7.1 Hz, CH3 in COOEt), 1.12 (3 H, t,
3
s (CHarom); dH (300.13 MHz, DMSO-d6) 8.61 (1 H, d, 4JN(1)H,N(3)H
456 | Org. Biomol. Chem., 2012, 10, 447–462
=
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©

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3JCH3,CH2 = 7.1 Hz, CH3 in COOEt); dC (75.48 MHz, DMSO-d6)
166.8 (C O in COOEt), 166.7 (C O in COOEt), 155.5 (C-2),
143.8 (C-7), 137.7 (C), 136.3 (C), 129.2 (2CH), 128.5 (3CH), 127.9
(2CH), 126.7 (2CH), 125.5 (CH), 105.8 (C-6), 61.4 (OCH2), 61.2
(OCH2), 55.5 (CH in CH(COOEt)2), 52.0 (C-4), 37.0 (C-5), 13.7
(CH3 in COOEt).
7-Methyl-6-phenylthio-4-phthalimido-2,3,4,5-tetrahydro-1H-1,
3-diazepin-2-one (17a). Diazepinone 17a (0.570 g, 96%) as a
slightly yellow solid was prepared from pyrimidine 6a (0.515 g,
1.57 mmol) and potassium phthalimide (0.430 g, 2.32 mmol)
in MeCN (14 mL) (1 h 40 min, reflux) as described for 17b.
Recrystallization from MeCN afforded 17a as a white solid; mp
195.5–196.5 ◦C (decomp., MeCN); found: C, 63.10; H, 4.70;
N, 11.00. Calc. for C20H17N3O3S: C, 63.31; H, 4.52; N, 11.07;
4-[Di(ethoxycarbonyl)methyl]-7-methyl-6-phenylthio-2,3,4,5-
tetrahydro-1H-1,3-diazepin-2-one
(16a). Diazepinone
16a
n
max(Nujol)/cm-1 3230br s, 3099br s, 3071sh (NH), 1778 m, 1719vs
(0.177 g, 90%) as a white solid was prepared from pyrimidine
6a (0.165 g, 0.50 mmol), diethyl malonate (0.108 g, 0.67 mmol)
and NaH (0.015 g, 0.63 mmol) in dry THF (6.5 mL) (rt, 5 h) as
described for 16b; mp 124–129.5 ◦C (EtOH); found: C, 58.33; H,
6.29; N, 7.25. Calc. for C19H24N2O5S: C, 58.15; H, 6.16; N, 7.14;
(amide I, phthalimide fragment), 1678 s (amide I), 1638 s (C C),
1580 m (CCarom), 745 m, 718 s, 691 m (CHarom); dH (300.13 MHz,
DMSO-d6) 8.49 (1 H, d, 4JN(1)H,N(3)H = 2.0 Hz, N(1)H), 7.79–7.87 (4
H, m, ArH of phthalimide fragment), 7.25–7.32 (2 H, m, ArH),
7.24 (1 H, br ddd, 4JN(3)H,N(1)H = 2.0, 3JN(3)H,4-H = 1.3, 4JN(3)H,5-H(B) ~ 1.2
n
max(Nujol)/cm-1 3346w, 3304 s, 3212br s, 3104sh, 3072 m (NH),
Hz, N(3)H), 7.11–7.19 (3 H, m, ArH), 5.40 (1 H, ddd, 3J4-H,5-H(A)
=
3
3
1725vs (C O), 1682 s (amide I), 1649 s (C C), 1579w, 1499 w
10.5, J4-H,5-H(B) = 2.7, J4-H,N(3)H = 1.3 Hz, 4-H), 3.57 (1 H, ddq,
2J5-H(A),5-H(B) = 14.3, 3J5-H(A),4-H = 10.5, 5J5-H(A),7-CH3 = 1.2 Hz, 5-H(A)),
2.47–2.55 (1 H, m, 5-H(B)), 2.08 (3 H, br d, 5J7-CH3,5-H(A) = 1.2 Hz,
7-CH3); dC (75.48 MHz, DMSO-d6) 166.9 (2C O of phthalimide
fragment), 154.5 (C-2), 142.8 (C-7), 135.8 (C), 134.4 (2CH of
phthalimide fragment), 131.5 (2 C of phthalimide fragment), 129.2
(2CH), 126.9 (2CH), 125.7 (CH), 123.0 (2CH of phthalimide
fragment), 104.8 (C-6), 61.0 (C-4), 36.8 (C-5), 19.7 (7-CH3).
(CCarom), 1258vs, 1156 s, 1027 s (C–O), 751 s, 689 m (CHarom);
4
dH (300.13 MHz, DMSO-d6) 8.32 (1 H, d, JN(1)H,N(3)H = 2.1 Hz,
3
N(1)H), 7.25–7.34 (2 H, m, ArH), 7.21 (1 H, dd, JN(3)H,4-H = 5.7,
4JN(3)H,N(1)H = 2.1, Hz, N(3)H), 7.08–7.19 (3 H, m, ArH), 3.94–4.19
3
3
(4 H, m, two OCH2), 3.86 (1 H, dddd, J4-H,CH = 9.9, J4-H,5-H(B)
6.1, 3J4-H,N(3)H = 5.7, 3J4-H,5-H(A) = 2.7 Hz, 4-H), 3.63 (1 H, d, 3JCH,4-H
=
=
9.9 Hz, CH in CH(COOEt)2), 2.64 (1 H, ddq, 2J5-H(A),5-H(B) = 16.1,
3J5-H(A),4-H = 2.7, J5-H(A),7-CH3 = 1.5 Hz, 5-H(A)), 2.55 (1 H, br dd,
5
7-Phenyl-6-phenylthio-4-succinimido-2,3,4,5-tetrahydro-1H-1,
2J5-H(B),5-H(A) = 16.1, J5-H(B),4-H = 6.1 Hz, 5-H(B)), 2.10 (3 H, br s,
3
3-diazepin-2-one (18b).
A suspension of NaH (0.029 g,
3
7-CH3), 1.17 (3 H, t, JCH3,CH2 = 7.1 Hz, CH3 in COOEt), 1.11
(3 H, t, JCH3,CH2 = 7.1 Hz, CH3 in COOEt); dC (75.48 MHz,
1.21 mmol) and succinimide (0.120 g, 1.21 mmol) in dry THF
(5.5 mL) was stirred at room temperature for 1 h, then pyrimidine
6b (0.317 g, 0.81 mmol) and THF (4.5 mL) were added and the
resulted suspension was refluxed under stirring for 4 h, the solvent
was removed in vacuum, the solid residue was triturated with
H2O (3 mL) until crystallization was complete, the suspension
3
DMSO-d6): d = 166.8 (C O in COOEt), 166.5 (C O in COOEt),
155.9 (C-2), 140.7 (C-7), 136.4 (C), 129.1 (2CH), 126.5 (2CH),
125.4 (CH), 101.1 (C-6), 61.3 (OCH2), 61.2 (OCH2), 55.0 (CH in
CH(COOEt)2), 50.2 (C-4), 38.6 (C-5), 20.9 (7-CH3), 13.72 (CH3
in COOEt), 13.69 (CH3 in COOEt).
◦
was cooled (0 C), the precipitate was filtered, washed with ice-
cold water, PE, and dried to give 18b (0.294 g, 92%) as a white
solid; mp 231 ◦C (decomp., DMF/EtOH, 1 : 1, v/v); found: C,
63.93; H, 4.94; N, 10.54. Calc. for C21H19N3O3S: C, 64.11; H,
4.87; N, 10.68; nmax(Nujol)/cm-1 3248 s, 3144 m, 3124 m (NH),
3066w, 3053 w (CHarom), 1772 m, 1705vs (amide I, succinimide
fragment), 1694sh (amide I), 1645 m (C C), 1580 m, 1494 m
(CCarom), 769 m, 741 m, 705 m (CHarom); dH (300.13 MHz, DMSO-
7-Phenyl-6-phenylthio-4-phthalimido-2,3,4,5-tetrahydro-1H-1,
3-diazepin-2-one (17b). A suspension of pyrimidine 6b (0.520 g,
1.33 mmol) and potassium phthalimide (0.370 g, 2.00 mmol) in
dry MeCN (12 mL) was refluxed under stirring for 35 min, the
solvent was removed in vacuum, to the solid residue was added
◦
H2O (5 mL), the suspension was cooled to 0 C, the precipitate
was filtered, washed with ice-cold water, PE, and dried to give
17b (0.566 g, 96%) as a slightly yellow solid. Recrystallization
from DMF/EtOH (1 : 2) afforded 17b as a white solid; mp
229.5 ◦C (decomp., DMF/EtOH, 1 : 2, v/v); found: C, 67.89; H,
4.73; N, 9.64. Calc. for C25H19N3O3S: C, 68.01; H, 4.34; N 9.52;
4
d6) 8.50 (1 H, d, JN(1)H,N(3)H = 2.0 Hz, N(1)H), 7.31–7.43 (7 H, m,
ArH), 7.17–7.29 (3 H, m, ArH), 7.03 (1 H, br s, N(3)H), 5.28 (1 H,
ddd, 3J4-H,5-H(A) = 11.1, 3J4-H,5-H(B) = 3.0, 3J4-H,N(3)H = 0.8 Hz, 4-H), 3.74
(1 H, dd, 2J5-H(A),5-H(B) = 13.7, 3J5-H(A),4-H = 11.1 Hz, 5-H(A)), 2.51 (4 H,
s, CH2CH2 of succinimide fragment), 2.33 (1 H, ddd, 2J5-H(B),5-H(A)
=
n
max(Nujol)/cm-1 3228br s, 3180w, 3127w, 3096sh, 3082 m, 3055
13.7, 3J5-H(B),4-H = 3.0, 4J5-H(B),N(3)H = 1.5 Hz, 5-H(B)); dC (75.48 MHz,
DMSO-d6) 176.8 (2C O of succinimide fragment), 154.9 (C-2),
144.8 (C-7), 136.3 (C), 136.0 (C), 129.5 (2CH), 129.0 (CH), 128.8
(2CH), 127.9 (2CH), 126.6 (2CH), 125.7 (CH), 107.7 (C-6), 61.5
(C-4), 35.0 (C-5), 27.9 (CH2CH2 of succinimide fragment).
m (NH), 3024 w (CHarom), 1776 m, 1724vs (amide I, phthalimide
fragment), 1686vs (amide I), 1628 m (C C), 1581 m, 1493 m
(CCarom), 738 s, 718 s, 694 s (CHarom); dH (300.13 MHz, DMSO-
4
d6) 8.58 (1 H, d, JN(1)H,N(3)H = 2.0 Hz, N(1)H), 7.79–7.89 (4 H,
m, ArH of phthalimide fragment), 7.16–7.46 (11 H, m, ArH and
N(3)H), 5.47 (1 H, ddd, 3J4-H,5-H(A) = 10.9, 3J4-H,5-H(B) = 3.1, 3J4-H,N(3)H
=
7-Methyl-6-phenylthio-4-succinimido-2,3,4,5-tetrahydro-1H-1,
3-diazepin-2-one (18a). Diazepinone 18a (0.248 g, 93%) as a
white solid was prepared from pyrimidine 6a (0.264 g, 0.80 mmol),
succinimide (0.119 g, 1.20 mmol) and NaH (0.029 g, 1.21 mmol)
in dry THF (4◦.8 mL) (3 h 45 min, reflux) as described for 18b;
mp 221.5–222 C (decomp., EtOH/DMF, 18 : 5, v/v); found: C,
57.71; H, 5.16; N, 12.63. Calc. for C16H17N3O3S: C, 57.99; H, 5.17;
N, 12.68; nmax(Nujol)/cm-1 3244 s, 3148w, 3101 m (NH), 3071 w
(CHarom), 1773 m, 1708vs (amide I, succinimide fragment), 1694 s
2
3
1.0 Hz, 4-H), 3.77 (1 H, dd, J5-H(A),5-H(B) = 13.7, J5-H(A),4-H = 10.9
2
3
Hz, 5-H(A)), 2.60 (1 H, ddd, J5-H(B),5-H(A) = 13.7, J5-H(B),4-H = 3.1,
4J5-H(B),N(3)H = 1.5 Hz, 5-H(B)); dC (75.48 MHz, DMSO-d6) 167.0
(2C O of phthalimide fragment), 154.8 (C-2), 145.0 (C-7), 136.3
(C), 135.9 (C), 134.4 (2CH of phthalimide fragment), 131.5 (2 C
of phthalimide fragment), 129.4 (2CH), 129.0 (CH), 128.9 (2CH),
127.9 (2CH), 126.9 (2CH), 125.8 (CH), 123.0 (2CH of phthalimide
fragment), 107.9 (C-6), 61.6 (C-4), 35.9 (C-5).
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(amide I), 1651 s (C C), 1582 m, 1499 m (CCarom), 741 s, 700 m
(0.530 g, 1.36 mmol) and THF (2 mL) were added. The suspension
was refluxed under stirring for 1 min, the solvent was removed
in vacuum, the oily residue was triturated with PE (3 ¥ 5 mL),
then H2O (3 mL) and PE (2 mL) were added and the product
was triturated under cooling until complete crystallization. The
suspension was cooled (0 ◦C), the precipitate was filtered, washed
with ice-cold water, PE, and dried to give 20b (0.521 g, 95%) as a
slightly yellow solid. Recrystallization from MeCN afforded 20b
4
(CHarom); dH (300.13 MHz, DMSO-d6) 8.42 (1 H, d, JN(1)H,N(3)H
=
2.0 Hz, N(1)H), 7.28–7.36 (2 H, m, ArH), 7.13–7.21 (3 H, m, ArH),
7.01 (1 H, ddd, 4JN(3)H,N(1)H = 2.0, 4JN(3)H,5-H(B) = 1.6, 3JN(3)H,4-H = 1.0 Hz,
N(3)H), 5.20 (1 H, ddd, 3J4-H,5-H(A) = 10.7, 3J4-H,5-H(B) = 2.6, 3J4-H,N(3)H
=
1.0 Hz, 4-H), 3.57 (1 H, ddq, 2J5-H(A),5-H(B) = 14.3, 3J5-H(A),4-H = 10.7,
5J5-H(A),7-CH3 = 1.3 Hz, 5-H(A)), 2.48 (4 H, s, CH2CH2 of succinimide
2
3
fragment), 2.24 (1 H, ddd, J5-H(B),5-H(A) = 14.3, J5-H(B),4-H = 2.6,
◦
4J5-H(B),N(3)H = 1.6 Hz, 5-H(B)), 2.05 (3 H, d, J7-CH3,5-H(A) = 1.3 Hz,
as a white solid; mp 173.5–175 C (decomp., MeCN); found: C,
5
7-CH3); dC (75.48 MHz, DMSO-d6) 176.7 (2C O of succinimide
fragment), 154.5 (C-2), 142.4 (C-7), 135.8 (C), 129.3 (2CH), 126.7
(2CH), 125.6 (CH), 104.6 (C-6), 60.8 (C-4), 36.0 (C-5), 27.9
(CH2CH2 of succinimide fragment), 19.7 (7-CH3).
68.12, H, 5.05, N, 6.94. Calc. for C23H20N2OS2: C, 68.29; H, 4.98;
N, 6.92; nmax(Nujol)/cm-1 3213br s, 3074 s, 3056 m (NH), 3018
w (CHarom), 1675vs (amide I), 1612 m (C C), 1579 m, 1492 m
(CCarom), 742 s, 699 s (CHarom); dH (300.13 MHz, DMSO-d6) 8.40
4
3
(1H, d, JN(1)H,N(3)H = 2.2 Hz, N(1)H), 7.80 (1 H, dd, JN(3)H,4-H
5.3, JN(3)H,N(1)H = 2.2 Hz, N(3)H), 7.44–7.51 (2 H, m, ArH), 7.13–
=
7-Phenyl-6-phenylthio-2,3,4,5-tetrahydro-1H-1,3-diazepin-2-
one (19b). A suspension of pyrimidine 6b (0.589 g, 1.51 mmol)
and finely powdered NaBH4 (0.062 g, 1.64 mmol) in dry THF
(11 mL) was refluxed under stirring for 4 h 10 min. The solvent was
removed in vacuum, the oily residue was triturated upon cooling
with satd. aqueous NaHCO3 (2 mL) and PE (3 mL) until complete
4
3
3
7.39 (13 H, m, ArH), 4.99 (1 H, ddd, J4-H,5-H(B) = 6.4, J4-H,N(3)H
=
3
2
5.3, J4-H,5-H(A) = 3.0 Hz, 4-H), 3.04 (1 H, dd, J5-H(A),5-H(B) = 15.4,
3J5-H(A),4-H = 3.0 Hz, 5-H(A)), 2.83 (1 H, dd, J5-H(B),5-H(A) = 15.4,
2
3J5-H(B),4-H = 6.4 Hz, 5-H(B)); dC (75.48 MHz, DMSO-d6) 154.9
(C-2), 143.8 (C-7), 138.0 (C), 136.7 (C), 133.6 (C), 131.9 (2CH),
129.2 (2CH), 129.0 (2CH), 128.5 (CH), 128.4 (2CH), 127.9 (2CH),
127.3 (CH), 126.8 (2CH), 125.5 (CH), 105.4 (C-6), 61.0 (C-4), 41.1
(C-5).
◦
crystallization. The resulting suspension was cooled to 0 C, the
precipitate was filtered, washed with ice-cold water, PE, dried, and
the product was purified by column chromatography on silica gel
60 (13 g) eluting with PE/CHCl3 (from 67 : 33 to 0 : 100) to give
19b (0.322 g, 72%) as a white solid; mp 163–164.5 ◦C (MeCN);
found: C, 68.95; H, 5.66; N, 9.56. Calc. for C17H16N2OS: C, 68.89;
H, 5.44; N 9.45; nmax(Nujol)/cm-1 3212sh, 3204 s, 3088sh, 3069 s
(NH), 3021 w (CHarom), 1689vs (amide I), 1627 s (C C), 1597w,
1580 m (CCarom), 748 m, 736 m, 698 s (CHarom); dH (300.13 MHz,
7-Methyl-4,6-di(phenylthio)-2,3,4,5-tetrahydro-1H-1,3-diaze-
pin-2-one (20a). Diazepinone 20a (0.333 g, 93%) as a white solid
was prepared from pyrimidine 6a (0.345 g, 1.05 mmol), thiophenol
(0.139 g, 1.26 mmol) and NaH (0.030 g, 1.25 mmol) in dry
THF (9 mL) (2 min, reflux) as described for 20b; mp 133.5–
135 ◦C (decomp.); found: C, 63.20; H, 5.45; N, 7.93. Calc. for
C18H18N2OS2: C, 63.13; H, 5.30; N, 8.18; nmax(Nujol)/cm-1 3215br
s, 3056br s (NH), 1684 s (amide I), 1638 s (C C), 1580 m (CCarom),
738 s, 690 m (CHarom); dH (300.13 MHz, DMSO-d6) 8.55 (1 H,
4
DMSO-d6) 7.78 (1 H, d, JN(1)H,N(3)H = 2.3 Hz, N(1)H), 7.23–7.37
(8 H, m, ArH and N(3)H), 7.10–7.19 (3 H, m, ArH), 3.25–3.33 (2
H, m, 4-H), 2.50–2.56 (2 H, m, 5-H); dC (75.48 MHz, DMSO-d6)
157.5 (C-2), 143.6 (C-7), 139.1 (C), 136.9 (C), 129.2 (2CH), 128.3
(2CH), 128.1 (CH), 127.8 (2CH), 126.4 (2CH), 125.1 (CH), 106.4
(C-6), 40.9 (C-4), 36.3 (C-5).
4
3
d, JN(1)H,N(3)H = 2.2 Hz, N(1)H), 7.89 (1 H, dd, JN(3)H,4-H = 6.5,
4JN(3)H,N(1)H = 2.2 Hz, N(3)H), 7.41–7.47 (2 H, m, ArH), 7.23–7.36 (5
H, m, ArH), 7.11–7.22 (3 H, m, ArH), 4.93 (1 H, ddd, 3J4-H,N(3)H
=
3
3
7-Methyl-6-phenylthio-2,3,4,5-tetrahydro-1H-1,3-diazepin-2-
one (19a). This compound was prepared according to the same
procedure as described for 19b from pyrimidine 6a (0.664 g,
2.02 mmol) and NaBH4 (0.084 g, 2.22 mmol) in dry THF (10 mL)
(1 h 50 min, reflux). The crude product was purified by column
chromatography on silica gel 60 (12 g) eluting with CHCl3 to
afford pure 19a (0.315 g, 66%) as a white solid; mp 142–143.5 ◦C
(MeCN); found: C, 61.52; H, 5.94; N, 12.02. Calc. for C12H14N2OS:
C, 61.51; H, 6.02; N, 11.96; nmax(Nujol)/cm-1 3360w, 3270 s, 3144
m, 3115sh (NH), 3078w, 3069w, 3059w, 3024w, 3016 w (CHarom),
1699vs (amide I), 1647 s (C C), 1583 m, 1507 m (CCarom), 728
s, 686 s (CHarom); dH (300.13 MHz, DMSO-d6) 8.05 (1 H, d,
4JN(1)H,N(3)H = 2.3 Hz, N(1)H), 7.26–7.34 (2 H, m, ArH), 7.22 (1
H, dt, 3JN(3)H,4-H = 4.9, 4JN(3)H,N(1)H = 2.3 Hz, N(3)H), 7.08–7.16 (3 H,
m, ArH), 3.14–3.20 (2 H, m, 4-H), 2.38–2.44 (2 H, m, 5-H), 2.08
6.5, J4-H,5-H(B) = 5.1, J4-H,5-H(A) = 2.9 Hz, 4-H), 3.04 (1 H, ddq,
2J5-H(A),5-H(B) = 15.9 Hz, 3J5-H(A),4-H = 2.9, 5J5-H(A),7-CH3 = 1.7 Hz, 5-H(A)),
2.71 (1 H, dd, 2J5-H(B),5-H(A) = 15.9, 3J5-H(B),4-H = 5.1 Hz, 5-H(B)), 2.11
(3 H, d, 5J7-CH3,5-H(A) = 1.7 Hz, 7-CH3); dC (75.48 MHz, DMSO-d6)
155.4 (C-2), 141.0 (C-7), 136.7 (C), 134.2 (C), 131.5 (2CH), 129.1
(2CH), 129.0 (2CH), 127.0 (CH), 126.3 (2CH), 125.3 (CH), 100.9
(C-6), 59.7 (C-4), 42.4 (C-5), 21.1 (7-CH3).
4-Methoxy-7-methyl-6-phenylthio-2,3,4,5-tetrahydro-1H-1,3-
diazepin-2-one (24a). To a solution of MeONa in MeOH formed
after dissolution of Na (0.063 g, 2.74 mmol) in dry MeOH (10 mL)
was added pyrimidine 6a (0.365 g, 1.11 mmol) and the resulting
reaction mixture was stirred at room temperature for 2 h. 25 min
after the beginning of the reaction the solution formed and after
an additional 25 min new solid precipitated. The suspension was
cooled in an ice bath, neutralized by AcOH (0.100 mL, 1.75 mmol),
the excess of AcOH was removed by addition of solid NaHCO3
(0.050 g),28 and the mixture was stirred in an ice bath for 5 min.
Then the solvent was removed in vacuum (with the temperature
of the bath not higher than 30 ◦C), the oily residue was triturated
with H2O (2 mL), satd. aqueous NaHCO3 (1 mL) and PE (3 mL)
until crystallization was complete, the obtained suspension was
cooled (0 ◦C), the precipitate was filtered, washed with ice-cold
water, PE, and dried to give 24a (0.285 g, 97%) as an almost white
5
(3 H, t, J7-CH3,5-H = 1.3 Hz, 7-CH3); dC (75.48 MHz, DMSO-d6)
158.1 (C-2), 140.5 (C-7), 136.9 (C), 129.2 (2CH), 125.9 (2CH),
125.0 (CH), 102.7 (C-6), 40.2 (C-4), 37.5 (C-5), 21.6 (7-CH3).
7-Phenyl-4,6-di(phenylthio)-2,3,4,5-tetrahydro-1H-1,3-diaze-
pin-2-one (20b). To a cooled in an ice bath, stirred suspension
of NaH (0.039 g, 1.63 mmol) in dry THF (1.5 mL) was added a
solution of thiophenol (0.180 g, 1.63 mmol) in THF (2.5 mL), the
resulting white suspension was stirred for 12 min and pyrimidine 6b
458 | Org. Biomol. Chem., 2012, 10, 447–462
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solid.29 Recrystallization from MeOH/H2O (2 : 1) afforded 24a
as a white solid; mp 54–56 ◦C (MeOH/H2O, 2 : 1, v/v); found:
C, 59.15; H, 6.18; N, 10.50. Calc. for C13H16N2O2S: C, 59.07; H,
6.10; N, 10.60; nmax(Nujol)/cm-1 3218br s, 3072br s (NH), 1688
s, 1678sh (amide I), 1639vs (C C), 1580 m (CCarom), 1079 s (C–
O), 739 s, 691 m (CHarom); dH (300.13 MHz, DMSO-d6) 8.41 (1
4-Methoxy-7-phenyl-6-tosyl-2,3,4,5-tetrahydro-1H-1,3-diaze-
pin-2-one (24d). To a solution of MeONa in MeOH formed
after dissolution of Na (0.155 g, 6.74 mmol) in dry MeOH
(20 mL) was added pyrimidine 23b (1.016 g, 2.70 mmol) and the
resulted suspension was refluxed under stirring for 2 min. The
obtained solution was cooled in an ice bath, neutralized by AcOH
(0.236 mL, 4.12 mmol), to the formed suspension was added solid
NaHCO3 (0.080 g) to remove the access of AcOH, the mixture was
stirred in an ice bath for 5 min. Then the solvent was removed in
vacuum (the temperature of bath not higher than 30 ◦C), the oily
residue was triturated with H2O (5 mL), satd. aqueous NaHCO3
(3 mL) and PE (10 mL) until complete crystallization, the obtained
suspension was cooled (0 ◦C), the precipitate was filtered, washed
with ice-cold water, PE, and dried to give 24d (0.938 g, 93%) as a
slightly yellow solid. Recrystallization from MeCN afforded 24d
as a white solid; mp 175 ◦C (decomp., MeCN); found: C, 61.23; H,
5.61; N, 7.56. Calc. for C19H20N2O4S: C, 61.27; H, 5.41; N, 7.52;
4
3
H, d, JN(1)H,N(3)H = 2.1 Hz, N(1)H), 7.83 (1 H, dd, JN(3)H,4-H = 5.6,
4JN(3)H,N(1)H = 2.1 Hz, N(3)H), 7.25–7.32 (2 H, m, ArH), 7.09–7.20
3
3
(3 H, m, ArH), 4.32 (1 H, ddd, J4-H,N(3)H = 5.6, J4-H,5-H(B) = 5.2,
3J4-H,5-H(A) = 2.0 Hz, 4-H), 3.21 (3 H, s, 4-OCH3), 2.69 (1 H, ddq,
3
5
2J5-H(A),5-H(B) = 15.5, J5-H(A),4-H = 2.0, J5-H(A),7-CH3 = 1.6 Hz, 5-H(A)),
2.58 (1 H, dd, 2J5-H(B),5-H(A) = 15.5, 3J5-H(B),4-H = 5.2 Hz, 5-H(B)), 2.03
(3 H, d, J7-CH3,5-Ha = 1.6 Hz, 7-CH3); dC (75.48 MHz, DMSO-d6)
5
155.3 (C-2), 140.2 (C-7), 137.0 (C), 129.0 (2CH), 126.0 (2CH),
125.0 (CH), 100.8 (C-6), 81.8 (C-4), 54.2 (OCH3), 40.2 (C-5), 20.6
(7-CH3).
n
max(Nujol)/cm-1 3225br s, 3088br s (NH), 1684vs (amide I), 1627
4-Methoxy-7-phenyl-6-phenylthio-2,3,4,5-tetrahydro-1H-1,3-
diazepin-2-one (24b). Diazepinone 24b (0.648 g, 97%) as a white
solid was prepared from pyrimidine 6b (0.797 g, 2.04 mmol), Na
(0.117 g, 5.09 mmol) and dry MeOH (17 mL) (4 h, rt) as described
for 24a; mp 162–163.5 ◦C (decomp., EtOH); found: C, 66.21; H,
5.68; N, 8.66. Calc. for C18H18N2O2S: C, 66.23; H, 5.56; N, 8.58;
s (C C), 1596 m, 1490 m (CCarom), 1316vs, 1148 s (SO2), 1084
s, 1069 s (C–O), 812 s, 768 m, 699 s (CHarom); dH (300.13 MHz,
4
DMSO-d6) 8.57 (1 H, d, JN(1)H,N(3)H = 2.0 Hz, N(1)H), 8.04 (1 H,
dd, 3JN(3)H,4-H = 4.8, 4JN(3)H,N(1)H = 2.0 Hz, N(3)H), 7.12–7.37 (7 H, m,
3
ArH), 6.94–7.04 (2 H, m, ArH), 4.42 (1 H, ddd, J4-H,5-H(B) = 6.7,
3J4-H,N(3)H = 4.8, 3J4-H,5-H(A) = 2.0 Hz, 4-H), 3.28 (1 H, dd, 2J5-H(B),5-H(A)
=
n
max(Nujol)/cm-1 3319 br w, 3231 s, 3095 s, 3080sh (NH), 3055
3
15.0, J5-H(B),4-H = 6.7 Hz, 5-H(B)), 3.25 (3 H, s, 4-OCH3), 2.69 (1
H, dd, 2J5-H(A),5-H(B) = 15.0, 3J5-H(A),4-H = 2.0 Hz, 5-H(A)), 2.32 (3 H, s,
CH3 in Ts); dC (75.48 MHz, DMSO-d6) 153.6 (C-2), 147.1 (C-7),
142.6 (C), 139.4 (C), 134.7 (C), 129.8 (2CH), 129.1 (CH), 128.9
(2CH), 127.2 (2CH), 127.0 (2CH), 116.6 (C-6), 82.7 (C-4), 54.2
(OCH3), 32.1 (C-5), 20.9 (CH3 in Ts).
w (CHarom), 1677vs (amide I), 1619 m (C C), 1579 m, 1493 m
(CCarom), 1070vs (C–O), 769 m, 747 s, 699 s (CHarom); dH (300.13
MHz, DMSO-d6) 8.33 (1 H, d, 4JN(1)H,N(3)H = 2.2 Hz, N(1)H), 7.72 (1
H, dd, 3JN(3)H,4-H = 4.7, 4JN(3)H,N(1)H = 2.2 Hz, N(3)H), 7.26–7.37 (7 H,
m, ArH), 7.14–7.25 (3 H, m, ArH), 4.43 (1 H, ddd, 3J4-H,5-H(B) = 5.7,
3
3J4-H,N(3)H = 4.7, J4-H,5-H(A) = 3.0 Hz, 4-H), 3.24 (3 H, s, 4-OCH3),
2.75 (1 H, dd, 2J5-H(A),5-H(B) = 14.8, 3J5-H(A),4-H = 3.0 Hz, 5-H(A)), 2.71
(1 H, dd, 2J5-H(B),5-H(A) = 14.8, 3J5-H(B),4-H = 5.7 Hz, 5-H(B)); dC (75.48
MHz, DMSO-d6) 155.1 (C-2), 143.3 (C-7), 137.5 (C), 137.1 (C),
129.2 (2CH), 128.6 (2CH), 128.5 (CH), 127.8 (2CH), 126.5 (2CH),
125.3 (CH), 105.3 (C-6), 83.8 (C-4), 54.2 (OCH3), 38.8 (C-5).
1-Carbamoyl-2-methyl-3-phenylthio-1H-pyrrole (25a).
Method A. A solution of diazepinone 24a (0.213 g, 0.81 mmol)
and TsOH·H2O (0.015 g, 0.08 mmol) in MeOH (7 mL) was refluxed
under stirring for 30 min, then the solvent was removed in vacuum,
the oily residue was triturated with satd. aqueous NaHCO3 (2 mL)
and PE (2 mL) until crystallization was complete, the obtained
suspension was cooled (0 ◦C), the precipitate was filtered, washed
with ice-cold water, PE, and dried to give 25a (0.166 g, 89%) as an
almost white solid.
4-Methoxy-7-methyl-6-tosyl-2,3,4,5-tetrahydro-1H-1,3-diaze-
pin-2-one (24c). Diazepinone 24c (0.499 g, 95%) as a white solid
was prepared from pyrimidine 23a (0.636 g, 1.70 mmol), Na
(0.097 g, 4.22 mmol) and dry MeOH (15.5 mL) (50 min, rt) as
described for 24a; mp 173 ◦C (decomp., EtOH) when the rate
of heating was about 1 ◦C in 15 s (fast heating), mp 180.5 ◦C
with decomposition without melting at 170–171 ◦C when the
rate of heating was more than 1 ◦C in 15 s; found C, 54.22; H,
6.02; N, 9.05. Calc. for C14H18N2O4S: C, 54.18; H, 5.85; N, 9.03;
Method B. To a solution of MeONa in MeOH formed after
dissolution of Na (0.049 g, 2.13 mmol) in dry MeOH (7 mL)
was added pyrimidine 6a (0.283 g, 0.86 mmol) and the reaction
mixture was stirred at room temperature for 2.5 h, to a formed
suspension was added TsOH·H2O (0.292 g, 1.54 mmol) and the
reaction mixture was refluxed under stirring for 25 min, the
solvent was removed in vacuum, the oily residue was triturated
with satd. aqueous NaHCO3 (1 mL), H2O (1 mL) and PE
(5 mL) until complete crystallization, the suspension was cooled
(0 ◦C), the precipitate was filtered, washed with ice-cold water,
PE, and dried to give 25a (0.177 g, 89%) as a slightly yellow
solid. The analytically pure sample (white crystals) was obtained
using column chromatography on silica gel 60 (5 g) eluting with
PE/CHCl3 (from 3 : 1 to 1 : 1) followed by crystallization from
PE/CHCl3 (~1 : 1, v/v); mp 109–110 ◦C; found: C, 61.93; H,
5.24; N, 11.91. Calc. for C12H12N2OS: C, 62.04; H, 5.21; N, 12.06;
n
max(Nujol)/cm-1 3297 s, 3228 s, 3093br s (NH), 1685vs (amide
I), 1632vs (C C), 1518 m (CCarom), 1299 s, 1147 s (SO2), 1076
s (C–O), 812 s (CHarom); dH (300.13 MHz, DMSO-d6) 8.70 (1 H,
4
3
d, JN(1)H,N(3)H = 2.0 Hz, N(1)H), 8.13 (1 H, dd, JN(3)H,4-H = 5.6,
4JN(3)H,N(1)H = 2.0, Hz, N(3)H), 7.69–7.74 (2 H, m, ArH), 7.35–
7.41 (2 H, m, ArH), 4.40 (1 H, ddd, J4-H,5-H(B) = 6.1, J4-H,N(3)H
3
3
=
3
2
5.6, J4-H,5-H(A) = 1.4 Hz, 4-H), 3.26 (1 H, dd, J5-H(B),5-H(A) = 15.4,
3J5-H(B),4-H = 6.1 Hz, 5-H(B)), 3.17 (3 H, s, 4-OCH3), 2.48 (1 H, ddq,
2J5-H(A),5-H(B) = 15.4, J5-H(A),4-H = 1.4, J5-H(A),7-CH3 = 1.5 Hz, 5-H(A)),
2.38 (3 H, s, CH3 in Ts), 2.04 (3 H, d, 5J7-CH3,5-H(A) = 1.5 Hz, 7-CH3);
dC (75.48 MHz, DMSO-d6) 154.0 (C-2), 145.1 (C-7), 142.9 (C),
140.3 (C), 129.4 (2CH), 126.6 (2CH), 113.2 (C-6), 81.2 (C-4), 54.1
(OCH3), 32.6 (C-5), 21.0 (CH3 in Ts), 19.4 (7-CH3).
3
5
n
max(Nujol)/cm-1 3360 s, 3325sh, 3238 m, 3196 s (NH), 3074w,
3057 w (CHarom), 1739 m, 1688vs (amide I), 1634 m, 1617 m,
1580 m, 1498 m (CCarom), 736 s, 688 m (CHarom); dH (300.13 MHz,
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DMSO-d6) 7.65 (2 H, br s, NH2), 7.35 (1 H, d, 3J5-H,4-H = 3.4 Hz, 5-
NaHCO3 (5 mL) and PE (5 mL) until crystallization was complete,
the suspension was cooled (0 ◦C), the precipitate was filtered,
washed with ice-cold water, PE, and dried to give 25d (0.444 g,
96%) as a slightly yellow solid.
H), 7.21–7.28 (2 H, m, ArH), 7.06–7.13 (1 H, m, ArH), 6.98–7.03
3
(2 H, m, ArH), 6.24 (1 H, d, J4-H,5-H = 3.4 Hz, 4-H), 2.42 (3 H,
s, 2-CH3); dC (75.48 MHz, DMSO-d6) 152.1 (C O), 138.5 (C-2),
135.6 (C), 129.0 (2CH), 125.4 (2CH), 124.9 (CH), 120.0 (C-5),
114.6 (C-4), 109.1 (C-3), 12.6 (2-CH3).
Method C. Pyrrole 25a (0.116 g, 84%) as an almost white solid
was prepared by refluxing a solution of diazepinone 20a (0.205 g,
0.60 mmol) in EtOH (3.2 mL) in the presence of TsOH·H2O
(0.024 g, 0.12 mmol) for 4 h as described in Method A.
Method B. To a solution of MeONa in MeOH formed after
dissolution of Na (0.050 g, 2.17 mmol) in dry MeOH (8 mL) was
added pyrimidine 23b (0.330 g, 0.88 mmol) and the resulted sus-
pension was refluxed under stirring for 2 min, the formed solution
was cooled, TsOH·H2O (0.296 g, 1.56 mmol) was added and the
solvent was removed in vacuum. To the resulting solid residue
EtOH (10 mL) was added, the reaction mixture was refluxed
under stirring for 30 min, the solvent was removed in vacuum, the
obtained oily residue was triturated with satd. aqueous NaHCO3
(3 mL) and PE (5 mL) until crystallization was complete, the
obtained suspension was cooled (0 ◦C), the precipitate was filtered,
washed with ice-cold water, PE, and dried to give 25d (0.249 g,
83%) as a slightly yellow solid. Recrystallization from MeCN
afforded 25d as a white solid; mp 201–202 ◦C (decomp., MeCN);
found C, 63.45; H, 4.87; N, 8.26. Calc. for C18H16N2O3S: C, 63.51;
H, 4.74; N, 8.23; nmax(Nujol)/cm-1 3409 s, 3365 m, 3306 s, 3218 s,
3168w, 3137 w (NH), 3060 w (CHarom), 1737 s, 1713vs (amide I),
1631 s, 1597 m, 1506 w (CCarom), 1299 s, 1146vs (SO2), 815 m, 775
1-Carbamoyl-2-phenyl-3-phenylthio-1H-pyrrole (25b).
Method A. A solution of diazepinone 24b (0.108 g, 0.33 mmol)
and TsOH·H2O (0.003 g, 0.02 mmol) in EtOH (2 mL) was refluxed
under stirring for 8 min, then the solvent was removed under
vacuum, the oily residue was dissolved in CHCl3 (5 mL), and the
solution was washed with H2O (3 ¥ 2 mL) and brine (2 ¥ 1 mL). The
solvent was removed in vacuum and the residue was co-evaporated
with absolute EtOH (2 mL), the residual oil was kept under high
vacuum for 3 h to remove traces of solvent to give 25b (0.076 g,
78%) as a slightly yellow oil.
Method B. To a solution of MeONa in MeOH formed after
dissolution of Na (0.035 g, 1.52 mmol) in dry MeOH (7 mL) was
added pyrimidine 6b (0.238 g, 0.61 mmol) and the suspension
was stirred at room temperature for 4 h, to a formed suspension
was added TsOH·H2O (0.206 g, 1.08 mmol), and the solvent was
removed in vacuum. To the resulting solid residue was added
EtOH (6 mL), the reaction mixture was refluxed under stirring for
5 min, the solvent was removed in vacuum, the oily residue was
dissolved in CHCl3 (15 mL), and the solution was washed with
H2O (3 ¥ 5 mL) and brine (2 ¥ 3 mL). The solvent was removed
in vacuum, the residue was co-evaporated with absolute EtOH
(3 ¥ 3 mL), and the residual oil was kept under high vacuum
for 3 h to give 25b (0.134 g, 75%) as a slightly yellow oil. The
white crystals of pyrrole 25b were obtained after addition of ether
(2 mL) to the oil, which first dissolved in ether and then the crystals
precipitated. The suspension was cooled (-10 ◦C), the crystals
were filtered as fast as possible through a previously cooled glass
filter (the crystals are highly soluble in ether), washed with cold
ether (1 mL), and dried to give 0.061 g of 25b (from 0.134 g of
the oil). The analytically pure sample was obtained using column
chromatography on silica gel 60 eluting with CHCl3/PE (1 : 3)
followed by ether work-up as described above; mp 116.5–118 ◦C;
found: C, 69.33, H, 4.67, N, 9.53. Calc. for C17H14N2OS: C, 69.36;
H, 4.79; N, 9.52; nmax(Nujol)/cm-1 3451 s, 3408 s, 3311br s, 3235
s, 3168br s, 3150w, 3117 w (NH), 3067w, 3040w, 3019 w (CHarom),
1724 s, 1692vs (amide I), 1614w, 1591 m, 1581 m, 1500 w (CCarom),
77 s, 737 s, 700 s (CHarom); dH (300.13 MHz, DMSO-d6) 7.65 (2
s, 741 m, 713 m, 692 s (CHarom); dH (300 MHz, DMSO-d6) 7.75 (2
3
H, br s, NH2), 7.28–7.44 (5 H, m, ArH), 7.31 (1 H, d, J5-H,4-H
=
3.3 Hz, 5-H), 7.13–7.25 (4 H, m, ArH), 6.68 (1 H, d, 3J4-H,5-H = 3.3
Hz, 4-H), 2.31 (3 H, s, CH3); dC (75.48 MHz, DMSO-d6) 150.7
(C O), 143.3 (C), 139.7 (C), 134.4 (C-2), 130.2 (2CH), 129.6 (C),
129.4 (2CH), 128.5 (CH), 127.4 (2CH), 126.4 (2CH), 124.9 (C-3),
121.2 (C-5), 109.5 (C-4), 20.9 (CH3).
1-Carbamoyl-2-methyl-3-tosyl-1H-pyrrole (25c).
Method A. Pyrrole 25c (0.265 g, 88%) as an almost white solid
was prepared by refluxing a solution of diazepinone 24c (0.336 g,
1.08 mmol) in EtOH (6 mL) in the presence of TsOH·H2O (0.021 g,
0.11 mmol) for 15 min as described for 25d according to Method
A.
Method B. To a solution of MeONa in MeOH formed after
dissolution of Na (0.049 g, 2.13 mmol) in dry MeOH (8 mL)
was added pyrimidine 23a (0.322 g, 0.86 mmol) and the resulted
suspension was stirred at room temperature for 46 min, to a
formed suspension was added TsOH·H2O (0.293 g, 1.54 mmol)
and the solvent was removed in vacuum. To the resulting solid
residue was added EtOH (7 mL), the reaction mixture was refluxed
under stirring for 15 min, the solvent was removed in vacuum, the
obtained oily residue was triturated with satd. aqueous NaHCO3
(3 mL) and PE (5 mL) until crystallization was complete, the
obtained suspension was cooled (0 ◦C), the precipitate was filtered,
washed with ice-cold water, PE, and dried to give 25c (0.149 g, 63%)
as a slightly yellow solid. Recrystallization from EtOH afforded
3
H, br s, NH2), 7.40 (1 H, d, J5-H,4-H = 3.2 Hz, 5-H), 7.21–7.37 (7
H, m, ArH), 7.01–7.13 (3 H, m, ArH), 6.34 (1 H, d, 3J4-H,5-H = 3.2
Hz, 4-H); dC (75.48 MHz, DMSO-d6) 151.5 (C O), 138.8 (C-
2), 136.9 (C), 131.3 (C), 129.5 (2CH), 129.0 (2CH), 127.5 (2CH),
127.4 (CH), 125.7 (2CH), 125.1 (CH), 122.4 (C-5), 114.8 (C-4),
110.8 (C-3).
◦
25c as a white solid; mp 198.5–200 C (decomp., EtOH); found
C, 55.85; H, 5.32; N, 9.78. Calc. for C13H14N2O3S: C, 56.10; H,
5.07; N 10.07; nmax(Nujol)/cm-1 3447 s, 3352w, 3259 s, 3201br s,
3145 m, 3125 w (NH), 1739vs (amide I), 1627 s, 1595w, 1509 w
(CCarom), 1312 s, 1144 s (SO2), 809 m, 729 s, 709 s, 697 s (CHarom);
dH (300 MHz, DMSO-d6) 7.85 (2 H, br s, NH2), 7.71–7.77 (2 H,
m, ArH), 7.36–7.42 (2 H, m, ArH), 7.20 (1 H, d, 3J5-H,4-H = 3.5 Hz,
1-Carbamoyl-2-phenyl-3-tosyl-1H-pyrrole (25d).
Method A. A solution of diazepinone 24d (0.506 g, 1.36 mmol)
and TsOH·H2O (0.026 g, 0.14 mmol) in EtOH (10 mL) was
refluxed under stirring for 1 h, then the solvent was removed
in vacuum, the oily residue was triturated with satd. aqueous
3
5-H), 6.49 (1 H, d, J4-H,5-H = 3.5 Hz, 4-H), 2.56 (3 H, s, 2-CH3),
2.36 (3 H, s, CH3 in Ts); dC (75.48 MHz, DMSO-d6) 151.5 (C O),
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143.4 (C), 140.3 (C), 133.6 (C-2), 129.9 (2CH), 126.3 (2CH), 123.3
(C-3), 120.2 (C-5), 109.0 (C-4), 21.0 (CH3 in Ts), 12.0 (2-CH3).
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Acknowledgements
This research was supported by the Presidential grant for young
scientists no. MK-4400.2011.3.
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15 Decrease in the mesylation rate for 14b compared with 14a can be
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607–608; (b) J. Ashby and D. J. Griffiths, J. Chem. Soc., Perkin Trans. 1,
1975, 657–662; (c) E. Bullock, R. A. Garter, R. Cochrane, B. Gregory
and D. C. Shields, Can. J. Chem., 1977, 55, 895–905; (d) D. A. Claremon
and S. A. Rosenthal, Synthesis, 1986, 664–665.
7 For reviews, see: (a) C. O. Kappe, Tetrahedron, 1993, 49, 6937–6963;
(b) C. O. Kappe, Acc. Chem. Res., 2000, 33, 879–888; (c) M. A. Kolosov,
V. D. Orlov, D. A. Beloborodov and V. V. Dotsenko, Mol. Diversity,
2009, 13, 5–25.
8 For some recent examples, see: (a) P. M. Kumar, K. S. Kumar, S. R.
Poreddy, P. K. Mohakhud, K. Mukkanti and M. Pal, Tetrahedron
Lett., 2011, 52, 1187–1191; (b) G. B. D. Rao, B. N. Acharya, S.
K. Verma and M. P. Kaushik, Tetrahedron Lett., 2011, 52, 809–812;
17 In contrast to 5-tosyl-substituted analogues11 reaction of 6a,b with
NaCN in MeCN in the presence of 18-crown-6 did not proceed at
room temperature (according to TLC).
18 A. A. Fesenko, L. A. Trafimova, D. A. Cheshkov and A. D. Shutalev,
Tetrahedron Lett., 2010, 51, 5056–5059.
19 Compounds 21a,b are representatives of monocyclic 2,3-dihydro-1H-
1,3-diazepin-2-ones which remain practically unknown with only rare
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examples described in the literature.2f,30 Preparative synthesis of these
heterocycles will be the subject of our forthcoming communications.
20 A. D. Shutalev, A. A. Fesenko, D. A. Cheshkov and D. V. Goliguzov,
Tetrahedron Lett., 2008, 49, 4099–4101.
24 Structure of N-anion of dihydrodiazepinone 21b was confirmed by
its 1H NMR spectrum showing two doublets at 6.13 and 5.60 ppm
due to the 7-H and 6-H protons with vicinal coupling constant 7.9
Hz. In addition, proton signals of 4-Ph group were considerably up-
field shifted (6.72–6.99 ppm) compared with aromatic proton signals
of dihydrodiazepinone 21b (7.08–7.42 ppm).
21 According to ab initio calculations (B3LYP/6-31+G(d,p))22 performed
for 4-mesyloxymethyl-1,2,3,4-tetrahydropyrimidin-2-one as a model
compound, the anion resulted from N(1)H deprotonation in the gas
phase is significantly more stable (10.3 kcal mol-1) than the anion
obtained after N(3)H deprotonation.
25 The noticeable 1H NMR characteristic of the bicyclic intermediate, 5-
phenyl-6-(phenylthio)-2,4-diazabicyclo[4.1.0]hept-4-en-3-one, is a dou-
blet of doublets at 5.53 ppm (J = 11.2 and 2.8 Hz) due to the 1-H proton.
26 The noticeable 1H NMR characteristic of the bicyclic intermediate, 5-
methyl-6-(phenylthio)-2,4-diazabicyclo[4.1.0]hept-4-en-3-one, is a dou-
blet of doublets at 5.34 ppm (J = 10.5 and 2.5 Hz) due to the 1-H proton.
27 Decrease in the yield of both tosyl-substituted pyrroles (especially 25c)
is explained by partial loss of 25c,d during work-up due to their
moderate solubility in the solutions formed after addition of satd.
NaHCO3. Addition of water to these solutions did not cause additional
precipitation of the products.
22 The ab initio calculations were carried out using the Gaussian 09
program: M. J. Frisch, G. W. Trucks, H. B. Schlegel, G. E. Scuseria,
M. A. Robb, J. R. Cheeseman, G. Scalmani, V. Barone, B. Mennucci,
G. A. Petersson, H. Nakatsuji, M. Caricato, X. Li, H. P. Hratchian,
A. F. Izmaylov, J. Bloino, G. Zheng, J. L. Sonnenberg, M. Hada, M.
Ehara, K. Toyota, R. Fukuda, J. Hasegawa, M. Ishida, T. Nakajima,
Y. Honda, O. Kitao, H. Nakai, T. Vreven, J. A. Montgomery, Jr., J.
E. Peralta, F. Ogliaro, M. Bearpark, J. J. Heyd, E. Brothers, K. N.
Kudin, V. N. Staroverov, R. Kobayashi, J. Normand, K. Raghavachari,
A. Rendell, J. C. Burant, S. S. Iyengar, J. Tomasi, M. Cossi, N. Rega, J.
M. Millam, M. Klene, J. E. Knox, J. B. Cross, V. Bakken, C. Adamo, J.
Jaramillo, R. Gomperts, R. E. Stratmann, O. Yazyev, A. J. Austin, R.
Cammi, C. Pomelli, J. W. Ochterski, R. L. Martin, K. Morokuma, V.
G. Zakrzewski, G. A. Voth, P. Salvador, J. J. Dannenberg, S. Dapprich,
A. D. Daniels, O. Farkas, J. B. Foresman, J. V. Ortiz, J. Cioslowski and
D. J. Fox, Gaussian 09, Revision A.02, Gaussian, Inc., Wallingford CT,
2009.
28 The removal of traces of AcOH by NaHCO3 is especially important for
preparation of diazepinone 24a because it has a very strong tendency to
ring contraction in the presence of acids. Neutralization of the reaction
mixture with conc. HCl (with small excess towards the calculated
amount) immediately led to formation of pyrrole 25a.
29 Any contact of methoxy-diazepinone 24a with EtOH (during work-up
of the reaction mixture or when we attempted to crystallize it from
EtOH/H2O) led to formation of some amount of the corresponding
4-ethoxy analogue (according to 1H NMR data).
23 According to ab initio calculations, the anion resulted from NH
deprotonation of 2,4-diazabicyclo[4.1.0]hept-4-en-3-one is extremely
unstable. This anion undergoes ring expansion to give N-anion of
1,5-dihydro-2H-1,3-diazepin-2-one without energy barrier in the gas
phase or with very low activation barrier (0.12 kcal mol-1) in MeCN.
For, comparison, calculated activation barrier of electrocyclic opening
of cyclopropane ring in 2,4-diazabicyclo[4.1.0]hept-4-en-3-one is 11.25
kcal mol-1 in the gas phase and 8.85 kcal mol-1 in MeCN.
30 (a) C. Addicott and C. Wentrup, Aust. J. Chem., 2008, 61, 592–599;
(b) A. Reisinger, R. Koch and C. Wentrup, J. Chem. Soc., Perkin Trans.
1, 1998, 2247–2249; (c) M. Dias, P. Richomme and R. Mornet, J.
Heterocycl. Chem., 1996, 33, 1035–1039; (d) V. G. Kartsev and E. M.
Gizatullina, Chem. Heterocycl. Compd., 1991, 27, 672; (e) C.-H. Kim
and V. E. Marquez, J. Org. Chem., 1987, 52, 1979–1983; (f) H. Balli, M.
Huys-Francotte and F. Schmidlin, Helv. Chim. Acta, 1987, 70, 2045–
2057.
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