General approach to 6-tosyl-2,3,4,5-tetrahydro-1H-1,3-diazepin-2-ones via nucleophile-mediated ring expansion of tetrahydropyrimidines

Article abstract of DOI:10.1016/j.tet.2009.01.015

A general six-step approach to 6-tosyl-2,3,4,5-tetrahydro-1H-1,3-diazepin-2-ones has been developed. The key step involves a ring expansion reaction of 4-mesyloxymethyl- or 4-tosyloxymethyl-5-tosyl-1,2,3,4-tetrahydropyrimidin-2-one mediated by nucleophili

Full text of DOI:10.1016/j.tet.2009.01.015

Tetrahedron 65 (2009) 2344–2350
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General approach to 6-tosyl-2,3,4,5-tetrahydro-1H-1,3-diazepin-2-ones via
nucleophile-mediated ring expansion of tetrahydropyrimidines
*
Anastasia A. Fesenko, Marcus L. Tullberg, Anatoly D. Shutalev
Department of Organic Chemistry, Moscow State Academy of Fine Chemical Technology, 86 Vernadsky Avenue, 119571 Moscow, Russian Federation
a r t i c l e i n f o
a b s t r a c t
Article history:
A general six-step approach to 6-tosyl-2,3,4,5-tetrahydro-1H-1,3-diazepin-2-ones has been developed.
The key step involves a ring expansion reaction of 4-mesyloxymethyl- or 4-tosyloxymethyl-5-tosyl-
1,2,3,4-tetrahydropyrimidin-2-one mediated by nucleophilic reagents.
Received 28 October 2008
Received in revised form 8 December 2008
Accepted 5 January 2009
Ó 2009 Elsevier Ltd. All rights reserved.
Available online 10 January 2009
Keywords:
1,2,3,4-Tetrahydropyrimidin-2-ones
2,3,4,5-Tetrahydro-1H-1,3-diazepin-2-ones
Ring expansion
1. Introduction
Previously, we have developed a general synthesis of 5-func-
tionalized 1,2,3,4-tetrahydropyrimidin-2-ones(thiones) based on
Monocyclic 2,3,4,5-tetrahydro-1H-1,3-diazepin-2-ones (e.g., 1,
Fig. 1) are poorly accessible heterocyclic compounds. As for func-
tionalized diazepinones 1, some of which are useful in the treatment
of cardiovascular disorders,1 hitherto they remain practically
the reaction of readily available a-tosyl-substituted N-alkylureas or
N-alkylthioureas with enolates of carbonyl compounds followed by
dehydration of obtained 4-hydroxyhexahydropyrimidin-2-ones
(thiones).5 We attempted to synthesize pyrimidines 2 using this
approach. However, reaction of urea 3 with the sodium enolate of
ethyl acetoacetate led to unexpected formation of 5-ureido-4,5-
dihydrofuran 5 (Scheme 1)6 instead of hydroxypyrimidine 4. Ob-
viously, formation of compound 5 can be explained by the presence
of an additional electrophilic center at b
-position to nitrogen in 3.7
Figure 1. Structures of 2,3,4,5-tetrahydro-1H-1,3-diazepin-2-ones
omethyl-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylates 2.
1 and 4-chlor-
unknown with only rare examples being described in the litera-
ture.1–3 A promising method of their preparation is based on the ring
expansion of chloromethyl-substituted tetrahydropyrimidinones 2
(Fig. 1) under the action of external nucleophilic agents to provide
esters of 2-oxo-2,3,6,7-tetrahydro-1H-1,3-diazepine-5-carboxylic
acids.1,3 The major disadvantage of this approach is the low avail-
abilityof the starting compounds 2.4 This confines application of this
approach to synthesis of various diazepines.
Scheme 1. Synthesis of 5-ureido-4,5-dihydrofuran 5 by reaction of urea 3 with the
sodium enolate of ethyl acetoacetate.
We hypothesized that
a functional group at -position (e.g., acyloxy group), which can be
transformed into a good leaving group (e.g., Cl, Br, OMs, OTs, etc.) at
a-tosyl-substituted N-alkylureas bearing
b
* Corresponding author. Tel.: þ7 495 936 8908; fax: þ7 495 936 8909.
E-mail address: shutalev@orc.ru (A.D. Shutalev).
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.01.015

A.A. Fesenko et al. / Tetrahedron 65 (2009) 2344–2350
2345
the final stages of synthesis, can serve as starting compounds for
the synthesis of diazepines 1. Our retrosynthetic plan is shown in
Scheme 2 and includes preparation of 4-hydroxymethyl-1,2,3,4-
tetrahydropyrimidin-2-ones as key compounds.
oxoalkylurea 10 formed as a mixture of diastereomers (62:38),
while the formation of an isomeric cyclic compound 11 did not
occur in this instance.
Reflux of compound 10 in EtOH in the presence of TsOH
(32 mol %) for 3.6 h led to cyclization of 10 into hydroxypyrimidine
11 followed by its dehydration to give tetrahydropyrimidine 12 in
75% yield. The yield of 12 was further improved (up to 93%) by using
a greater amount of TsOH (0.5 equiv) in MeCN as a solvent under
the reflux conditions (2 h). The benzoyl protection in 12 was readily
removed by treatment with KOH (3 equiv) in EtOH/H2O to give
compound 13 in 91% yield (Scheme 3). Thus, overall yield of 13 from
6 equals 60%.
In order to convert the hydroxyl group in 13 into a good leaving
group we first attempted the synthesis of 14 by treatment of 13
with SOCl2 under reflux conditions or with SOCl2 in pyridine at
100 ꢀC (Scheme 4). In both cases we obtained complex reaction
mixtures where 14 was contaminated with a variety of by-products.
Scheme 2. Retrosynthesis of 2,3,4,5-tetrahydro-1H-1,3-diazepin-2-ones 1.
In this communication we describe the application of this
strategy to the synthesis of previously unknown 6-tosyl-2,3,4,5-
tetrahydro-1H-1,3-diazepin-2-ones.
2. Results and discussion
Scheme 4. Synthesis of 4-chloromethyl- (14), 4-mesyloxymethyl- (15), and 4-tosy-
loxymethyl-5-tosyl-1,2,3,4-tetrahydropyrimidin-2-ones (16). Reagents and conditions:
(a) SOCl2, reflux or SOCl2, Py, 100 ꢀC; (b) MsCl or TsCl, DMAP, CHCl3, rt, 96% (for 15) and
84% (for 16).
2.1. Synthesis of 4-mesyloxymethyl- and 4-tosyloxymethyl-5-
tosyl-1,2,3,4-tetrahydropyrimidin-2-ones
The key precursor for the synthesis of diazepinones, compound
13, was prepared as shown in Scheme 3. First, readily available 6 was
reacted with p-toluenesulfinic acid 7 and urea (5 equiv) in water (rt,
7.7 h) to give 8 in 85% yield. A fivefold excess of urea was used to
prevent the formation of N,N’-disubstituted side product (see
Ref. 5c). As evidenced by 1H NMR data, the crude 8 was 94% pure and
was used in further transformations without additional purification.
In contrast, treatment of 13 with MsCl or TsCl (DMAP/CHCl3) led
to a smooth formation of respective O-mesyl- and O-tosyl-de-
rivatives 15 and 16 (Scheme 4). Under optimized conditions (13/
MsCl/DMAP or 13/TsCl/DMAP in a ratio of 1:2:3) excellent yields of
15 and 16 (96 and 84%, respectively) were obtained, while pyridine
and NEt3 appeared to be ineffective in this instance. For example,
the yield of 16 in reaction of 13 with TsCl in pyridine (rt, 5 days) was
only 21%.
2.2. Ring expansion of 15 and 16 under nucleophilic
conditions to form 1,3-diazepin-2-ones
Ring expansion of 4-chloromethyltetrahydropyrimidin-2-ones 2
under the action of strong nucleophilic agents to form 1,3-diazepin-
2-ones has been described in the literature.3 Similarly, 4-chloro-
methyl-1,4-dihydropyridines and related compounds have been
reported to transform into dihydro- and tetrahydroazepines.8
It was reasonable to expect that compounds 15 and 16 would
undergo a similar conversion to provide a relatively simple access
to novel 4-substituted 6-tosyl-2,3,4,5-tetrahydro-1H-1,3-diazepin-
2-ones. Indeed, when treated with NaCN in DMF for 5 h at room
temperature, 15 gave 4-cyanodiazepinone 17 in 95% yield (Scheme
5). The latter was also obtained by the reaction of 15 and 16 with
NaCN in MeCN plus a catalytic amount of 18-crown-6 (17–30 mol %)
for 5.6 and 22.5 h, respectively, at room temperature in excellent
yields (Scheme 5). In the absence of 18-crown-6, the progress of the
reaction of 15 with NaCN in MeCN as a solvent was dramatically
retarded. Under these conditions, after 3 days the reaction mixture
consisted of pyrimidine 15 and diazepine 17 (23:77) as evidenced
by 1H NMR. The reaction of tosyloxymethylpyrimidine 16 with
NaCN in DMSO-d6 as a solvent was studied by 1H and 13C NMR to
reveal no long-lived intermediates. This experiment has shown that
the only product of the reaction was diazepinone 17.
Scheme 3. Synthesis of 4-hydroxymethyl-6-methyl-5-tosyl-1,2,3,4-tetrahydropyr-
imidin-2-one (13). Reagents and conditions: (a) H2O, rt, 7.7 h, 85%; (b) TsCH2C(O)Me
(9), NaH, MeCN, rt, 7.7 h, 84%; (c) 32 mol % TsOH, EtOH, reflux, 3.6 h, 75% or 51 mol %
TsOH, MeCN, reflux, 2 h, 93%; (d) KOH, H2O/EtOH, rt, 1.5 h, 91%.
Tosylacetone 9 was treated with NaH in MeCN to generate the
respective Na-enolate, which was reacted with sulfone 8 (MeCN, rt,
7.7 h) to result in the substitution of the tosyl group in 8 and give
a product in 84% yield. According to IR in solid phase and NMR in
DMSO-d6, the product structure was assigned to an open-chain
In a similar fashion, compound 15 was reacted with sodium
thiophenolate and the sodium salt of diethyl malonate (rt, MeCN) to
give diazepinones 18 and 19 in 97% and 95% yields, respectively
(Scheme 5).

2346
A.A. Fesenko et al. / Tetrahedron 65 (2009) 2344–2350
Previously we described a stereoselective conversion of ethyl
6-methyl-2-oxo-4-chloromethyl-1,2,3,4-tetrahydropyrimidine-5-
carboxylate into diethyl 9-methyl-5-methylene-3,11-dioxo-2,3,4,-
5,6a,7,10,11-octahydro-1,6-methano[1,3]diazepino[1,7-e][1,3,5]tri-
azocine-6,8(1H)-dicarboxylate9 in the presence of strong non-
nucleophilic bases (NaH, DBU) as a result of cascade reactions.
We have found that this reaction is quite general. Being treated
with NaH in MeCN (rt, 3 h) compound 15 afforded tricyclic bis-
diaz-epinone 23 in 92% yield (Scheme 7). We suppose that this
compound forms by the scheme analogous to that suggested in
our previous communication.9
Scheme 5. Synthesis of 4-substituted 6-tosyl-2,3,4,5-tetrahydro-1H-1,3-diazepin-2-
ones 17–19. Reagents and conditions: (a) NaCN, DMF, rt, 5.1 h, 95% (from 15); (b) NaCN,
MeCN, 18-crown-6, rt, 5.6 h, 94% (from 15) or NaCN, MeCN, 18-crown-6, rt, 22.5 h, 89%
(from 16); (c) PhSH, NaH, rt, 5 h, 97% (from 15); (d) CH2(COOEt)2, NaH, rt, 1.5 h, 95%
(from 15).
Scheme 7. Transformation of 4-mesyloxymethyl-5-tosyl-1,2,3,4-tetrahydropyrimidin-
2-one 15 into tricyclic bis-diazepinone 23.
The structures of diazepinones 17–19 were unambiguously
confirmed by 1H NMR data. The values ofcouplingconstants ofN(3)H,
4-H, 5-H(A), and 5-H(B) allowed us to conclude that 17–19 exist
predominantly in puckered conformation with pseudo axial orien-
tation of substituent at C4. The spectra of 17–19 distinctly differ from
pyrimidinones 20–22 (Scheme 6) whose formation cannot be ruled
out a priori. Indeed, a high value of geminal coupling constant be-
tween 5-H(A) and 5-H(B) (16.0–16.6 Hz), a rather high value of vicinal
coupling constant between N(3)H and 4-H (5.9–6.9 Hz), the long
range coupling between 7-CH3 and one of 5-H (1.2–1.4 Hz) are char-
acteristic of 17–19 rather than of their counterparts 20–22. The
presence of diazepine ring in 19 was also confirmed by the splitting of
methyne proton in CH(COOEt)2 fragment at 3.46 ppm (doublet) un-
characteristic of the respective pyrimidine 22.
Bis-diazepinone 23 formed as a single diastereomer with
(1R
*
,6S
*
,6aS
)-configuration according to 1H–1H ROESY data. NOEs
*
were observed between 7-Ha and 13-Ha and between 6a-H and
]CHa.
3. Conclusion
In summary, a six-step general approach to novel 6-tosyl-
2,3,4,5-tetrahydro-1H-1,3-diazepin-2-ones 17–19 was developed. It
is based on preparation of 4-mesyloxymethyl- 15 or 4-tosyloxy-
methyl-5-tosyl-1,2,3,4-tetrahydropyrimidin-2-ones 16 followed by
reaction with nucleophilic reagents (sodium thiophenolate, NaCN,
sodium salt of diethyl malonate), which proceeds with ring ex-
pansion. In the presence of NaH compound 15 undergoes a cascade
reaction resulting in the tricyclic diazepinone 23.
The starting heterocyclic compound 4-(benzoyloxymethyl)-6-
methyl-5-tosyl-1,2,3,4-tetrahydropyrimidin-2-one (12) was obtained
by the reaction of readily available N-[(2-benzoyloxy-1-tosyl)-
ethyl]urea (8) with tosylacetone in the presence of NaH
followed by heterocyclization and dehydration of formed N-[(1-ben-
zoyloxy-4-oxo-3-tosyl)but-2-yl]urea (10). Hydrolysis of 12 in EtOH/
H2O in the presence of KOH gave 4-hydroxymethyltetrahydropyr-
imidine 13, which was converted into the 15 or 16 by reaction with
MsCl or TsCl in the presence of DMAP.
An advantage of the developed method is that it can be utilized
for synthesis of not only 6-tosyl-substituted but also of other 6-
fuctionalyzed tetrahydro-1,3-diazepin-2-ones 1 (see Scheme 2),
which will be the subject of forthcoming communications.
4. Experimental section
4.1. General
Scheme 6. A plausible pathway for transformation of 15 or 16 into 17–19.
A reasonable mechanism for a transformation of pyrimidines 2
into ethyl 2-oxo-2,3,6,7-tetrahydro-1H-1,3-diazepine-5-carboxyl-
ates has been reported in the literature.3b,c We have hypothesized
that the conversion of 15 and 16 into diazepines 17–19 under
treatment with nucleophilic reagents proceeds in a similar manner
(Scheme 6). Upon the proton abstraction from N(1)H, anion A un-
dergoes intramolecular nucleophilic substitution to give cyclopro-
pane intermediate B. An external strong nucleophile then attacks
the most electrophilic bridgehead carbon in B to result in the
opening of cyclopropane ring and in the formation of diazepinone
anion C. The latter abstracts proton from the conjugated acid of
nucleophilic reagent to give diazepinones 17–19.
Acetonitrile was dried by distillation from P2O5 and then from
CaH2. Chloroform was purified by distillation over P2O5 prior to use.
2-Benzoyloxyethanal (6) was synthesized according to modified
literature procedure10 in 40% overall yield by reaction of commer-
cially available dimethyl acetal of 2-chloroethanal with PhCOONa in
dry DMF (reflux, 61 h) followed by hydrolysis of the obtained di-
methyl acetal of 2-benzoyloxyethanal with 80% aqueous HCOOH
(rt, 4 h). p-Toluenesulfinic acid (7) was synthesized by treatment of
a saturated aqueous solution of sodium p-toluenesulfinate11 with
hydrochloric acid at 0 ꢀC, dried over P2O5, and stored at 0 ꢀC. So-
dium hydride (60% suspension in mineral oil) was washed with

A.A. Fesenko et al. / Tetrahedron 65 (2009) 2344–2350
2347
anhydrous hexane and dried in vacuo prior to use. All other re-
agents and solvents were purchased from commercial sources and
used without additional purification.
removed in vacuum. To the white solid residue was added a satu-
rated aqueous solution of NaHCO3 (6 mL). The obtained mixture
was left overnight at room temperature. Upon cooling to 0 ꢀC, the
precipitate was filtered off, washed with ice-cold water, light petrol,
cold (ꢁ10 ꢀC) ether, and dried to give 1.043 g (83.9%) of 10 as
a mixture of diastereomers, 62:38. Mp 145–145.5 ꢀC (EtOH/hexane,
IR spectra (in Nujol or KBr) were recorded on a FTIR Bruker
‘Equinox 55/S’ spectrophotometer. Peak intensities in the IR spectra
are defined as strong (s), medium (m) or weak (w). NMR spectra of
synthesized compounds (solutions in DMSO-d6 and pyridine-d5)
were recorded on a Bruker Avance 600 spectrometer at 600.13 MHz
(1H) and 150.90 MHz (13C) and a Bruker DPX 300 spectrometer at
300.13 MHz (1H) and 75.48 MHz (13C). 1H NMR chemical shifts are
referenced to the residual proton signal in DMSO-d6 (2.50 ppm) or
pyridine-d5 (Ha 8.74 ppm). In 13C NMR spectra, signals of DMSO-d6
(39.50 ppm) or Cg in pyridine-d5 (135.91 ppm) were used as a ref-
erence. Protons OCH2, 4-H, and N(3)H for 12, 15, and 16 in DMSO-d6
gave ABCX spin systems, which were analyzed using full-lineshape
iteration in gNMR software (v.4.1.0). Multiplicities are reported as
singlet (s), doublet (d), triplet (t), quartet (q), and some combina-
tions of these, multiplet (m).
3:1 v/v). 1H NMR of major diastereomer (300.13 MHz, DMSO-d6)
d:
7.87–7.93 (2H, m, C(2)H and C(6)H in Ph), 7.73–7.79 (2H, m, C(2)H and
C(6)H in 4-MeC6H4), 7.63–7.70 (1H, m, C(4)H in Ph), 7.48–7.56 (2H, m,
C(3)H and C(5)H in Ph), 7.38–7.43 (2H, m, C(3)H and C(5)H in 4-
3
MeC6H4), 6.30 (1H, d, JNH,CH¼9.5 Hz, N–H), 5.76 (2H, s, NH2), 4.97
3
3
(1H, d, JCH,CH¼7.9 Hz, CH–SO2), 4.74 (1H, dddd, JCH,NH¼9.5 Hz,
3JCH,CH¼7.9 Hz, 3JCH,CH(B)¼5.6 Hz, 3JCH,CH(A)¼3.6 Hz, CH–N), 4.37 (1H,
dd, 2JCH(A),CH(B)¼11.4 Hz, 3JCH(A),CH¼3.6 Hz, CH(A) in OCH2), 4.25 (1H,
dd, 2JCH(B),CH(A)¼11.4 Hz, 3JCH(B),CH¼5.6 Hz, CH(B) in OCH2), 2.35 (3H,
s, CH3 in Ts), 2.26 ppm (3H, s, CH3 in Ac). 1H NMR of minor di-
astereomer (300.13 MHz, DMSO-d6) d: 7.93–7.99 (2H, m, C(2)H and
C(6)H in Ph), 7.72–7.76 (2H, m, C(2)H and C(6)H in 4-MeC6H4), 7.63–
7.70 (1H, m, C(4)H in Ph), 7.48–7.56 (2H, m, C(3)H and C(5)H in Ph),
7.42–7.47 (2H, m, C(3)H and C(5)H in 4-MeC6H4), 6.26 (1H, d,
3JNH,CH¼8.8 Hz, N–H), 5.69 (2H, s, NH2), 5.08 (1H, d, 3JCH,CH¼7.9 Hz,
CH–SO2), 4.50 (1H, dddd, 3JCH,NH¼8.8 Hz, 3JCH,CH¼7.9 Hz,
3JCH,CH(B)¼6.5 Hz, 3JCH,CH(A)¼4.2 Hz, CH–N), 4.33 (1H, dd,
2JCH(A),CH(B)¼11.4 Hz, 3JCH(A),CH¼4.2 Hz, CH(A) in OCH2), 4.23 (1H, dd,
Thin layer chromatography (TLC) was performed on silica gel
plates Silufol UV 254 (Czech Republic) or Kieselgel 60 F254 (Merck)
in chloroform/methanol (20:1, v/v) and chloroform/methanol (9:1,
v/v) as solvent systems. Spots were visualized with iodine vapors or
UV light.
All yields refer to isolated, spectroscopically and TLC pure
material.
3
2JCH(B),CH(A)¼11.4 Hz, JCH(B),CH¼6.5 Hz, CH(B) in OCH2), 2.41 (3H, s,
CH3 in Ts), 2.28 ppm (3H, s, CH3 in Ac). 13C NMR of major di-
4.2. N-[(2-Benzoyloxy-1-tosyl)ethyl]urea (8)
astereomer (75.48 MHz, DMSO-d6) d: 199.59 (C]O in Ac), 165.31
(C]O in PhCOO), 157.53 (N–C]O), 145.33 (C(4) in 4-MeC6H4),
134.95 (C(1) in 4-MeC6H4), 133.49 (C(4) in Ph), 129.92 (C(2) and C(6) in
Ph), 129.37 (C(3) and C(5) in 4-MeC6H4), 129.23 (C(1) in Ph), 128.65
(C(3) and C(5) in Ph), 128.63 (C(2) and C(6) in 4-MeC6H4), 73.87 (CH–
SO2), 65.65 (O–CH2), 47.23 (CH–N), 31.57 (CH3 in Ac), 21.12 ppm
(CH3 in Ts). 13C NMR of minor diastereomer (75.48 MHz, DMSO-d6)
To
a fine emulsion of 2-benzoyloxyethanal (6) (3.191 g,
19.44 mmol) in H2O (25 mL) was added p-toluenesulfinic acid (7)
(3.041 g, 19.47 mmol) under vigorous stirring for 1 min followed by
the addition of H2O (15 mL). After 23 min to the obtained suspen-
sion was added urea (5.857 g, 97.53 mmol). The reaction mixture
was stirred at room temperature for 7 h 42 min, cooled to 0 ꢀC, the
precipitate was filtered off, washed with ice-cold water, light petrol,
and dried to give 5.981 g (84.9%) of 8, which was used without
further purification. An analytically pure sample was obtained by
recrystallization from MeCN. Mp 127–131 ꢀC (decomp., MeCN). 1H
d: 199.74 (C]O in Ac), 165.36 (C]O in PhCOO), 157.56 (N–C]O),
145.05 (C(4) in 4-MeC6H4), 135.33 (C(1) in 4-MeC6H4), 133.53 (C(4) in
Ph), 129.71 (C(2) and C(6) in Ph), 129.39 (C(3) and C(5) in 4-MeC6H4),
129.30 (C(1) in Ph), 128.90 (C(3) and C(5) in Ph), 128.72 (C(2) and C(6)
in 4-MeC6H4), 74.15 (CH–SO2), 64.92 (O–CH2), 47.72 (CH–N), 32.68
NMR (300.13 MHz, DMSO-d6)
Ph), 7.71–7.76 (2H, m, C(2)H and C(6)H in 4-MeC6H4), 7.64–7.71 (1H,
m, C(4)H in Ph), 7.49–7.55 (2H, m, C(3)H and C(5)H in Ph), 7.38–7.44
d
: 7.86–7.91 (2H, m, C(2)H and C(6)H in
(CH3 in Ac), 21.18 ppm (CH3 in Ts). IR (Nujol)
3295 s, 3206 m ( NH), 3061 w ( CHarom), 1716 s (
w1712 sh ( C]O in Ac), 1657 s (amide-I), 1596 m (
(amide-II), 1496 w ( CCarom), 1320 s (nas SO2), 1277 s (
ns SO2), 1116 s ( C–O), 817 m ( CHarom in Ts), 764 m, 714 s (d
n
, cmꢁ1: 3462 s, 3382 s,
C]O in PhCOO),
CCarom), 1549 s
C–O), 1154 s
CHarom
n
n
n
n
n
3
(2H, m, C(3)H and C(5)H in 4-MeC6H4), 7.13 (1H, d, JNH,CH¼10.4 Hz,
n
n
3
N–H), 5.91 (2H, s, NH2), 5.47 (1H, ddd, JCH,NH¼10.4 Hz,
(
n
d
3JCH,CH(A)¼4.9 Hz, 3JCH,CH(B)¼4.7 Hz, CH–N), 4.69 (1H, dd,
in Ph). Anal. Calcd for C20H22N2O6S: C, 57.40; H, 5.30; N, 6.69.
Found: C, 57.20; H, 5.47; N, 6.92.
3
2JCH(A),CH(B)¼12.1 Hz, JCH(A),CH¼4.9 Hz, CH(A) in OCH2), 4.61 (1H,
2
3
dd, JCH(B),CH(A)¼12.1 Hz, JCH(B),CH¼4.7 Hz, CH(B) in OCH2),
2.37 ppm (3H, s, CH3). 13C NMR (75.48 MHz, DMSO-d6)
d
: 165.15
4.4. 4-(Benzoyloxymethyl)-6-methyl-5-tosyl-1,2,3,4-
tetrahydropyrimidin-2-one (12)
(C]O in PhCOO), 156.50 (N–C]O), 144.72 (C(4) in 4-MeC6H4),
134.69 (C(1) in 4-MeC6H4), 133.70 (C(4) in Ph), 129.80 (C(2) and C(6) in
Ph), 129.46 (C(3) and C(5) in 4-MeC6H4), 128.94 (C(1) in Ph), 128.77
(C(3) and C(5) in Ph), 128.69 (C(2) and C(6) in 4-MeC6H4), 68.60 (N–
A solution of compound 8 (3.356 g, 8.02 mmol) and TsOH$H2O
(0.772 g, 4.06 mmol) in MeCN (53 mL) was refluxed for 2 h under
stirring and then solvent was removed in vacuum. To the white
solid residue was added saturated aqueous solution of NaHCO3
(8 mL). The obtained suspension was left at room temperature for
2 h. Upon cooling to 0 ꢀC, the precipitate was filtered off, washed
with ice-cold water, light petrol, cold (ꢁ10 ꢀC) ether, and dried to
CH), 61.37 (O–CH2), 21.15 ppm (CH3). IR (Nujol)
3444 s, 3346 s, 3324 s, 3250 m, 3202 m ( NH), 3060 w (
1727 s ( C]O in PhCOO), 1670 s (amide-I),1597 m ( CCarom),1525 s
(amide-II),1492 w ( CCarom), 1304 m (nas SO2), 1271 s ( C–O), 1128 s
ns SO2), 1115 s ( C–O), 810 m ( CHarom in Ts), 749 m, 712 s ( CHarom
n
, cmꢁ1: 3511 s,
CHarom),
n
n
n
n
n
n
(
n
d
d
in Ph). Anal. Calcd for C17H18N2O5S: C, 56.34; H, 5.01; N, 7.73. Found:
C, 56.61; H, 4.87; N, 7.56.
give 3.000 g (93.4%) of 12. Mp 223.5–224 ꢀC (decomp., MeCN). 1H
4
NMR (300.13 MHz, DMSO-d6)
d
: 9.60 (1H, d, JN(1)H,N(3)H¼1.9 Hz,
N(1)H), 7.95–8.00 (2H, m, C(2)H and C(6)H in Ph), 7.74–7.79 (2H, m,
3
4.3. N-[(1-Benzoyloxy-4-oxo-3-tosyl)but-2-yl]urea (10)
C(2)H and C(6)H in 4-MeC6H4), 7.74 (1H, dd, JN(3)H,4-H¼3.7 Hz,
4JN(3)H,N(1)H¼1.9 Hz, N(3)H), 7.64–7.71 (1H, m, C(4)H in Ph), 7.49–7.57
To a mixture of tosylacetone (9) (0.633 g, 2.98 mmol) and NaH
(0.071 g, 2.96 mmol) was added dry MeCN (7 mL) and the obtained
mixture was stirred for 3 min. Then to the resulting solution was
added tosylurea 8 (1.077 g, 2.97 mmol). The formed suspension
was stirred at room temperature for 7 h 43 min and the solvent was
(2H, m, C(3)H and C(5)H in Ph), 7.38–7.43 (2H, m, C(3)H and C(5)H
in 4-MeC6H4), 4.34 (1H, ddd, C part of ABCX spin system,
3
3
3J4-H,CH(B)¼5.4 Hz, J4-H,N(3)H¼3.7 Hz, J4-H,CH(A)¼3.1 Hz, 4-H), 4.27
2
(1H, dd,
B
part of ABCX spin system, JCH(B),CH(A)¼10.9 Hz,
3JCH(B),4-H¼5.4 Hz, CH(B) in OCH2), 4.22 (1H, dd, A part of ABCX spin

2348
A.A. Fesenko et al. / Tetrahedron 65 (2009) 2344–2350
2
3
system, JCH(A),CH(B)¼10.9 Hz, JCH(A),4-H¼3.1 Hz, CH(A) in OCH2),
DMSO-d6)
d
: 9.54 (1H, d, 4JN(1)H,N(3)H¼1.9 Hz, N(1)H), 7.74–7.79 (2H,
2.38 (3H, s, CH3 in Ts), 2.20 ppm (3H, s, 6-CH3). 1H NMR
(300.13 MHz, pyridine-d5)
m, C(2)H and C(6)H in 4-MeC6H4), 7.75 (1H, dd, JN(3)H,4-H¼3.7 Hz,
3
4
d
: 11.17 (1H, d, JN(1)H,N(3)H¼1.9 Hz,
4JN(3)H,N(1)H¼1.9 Hz, N(3)H), 7.40–7.45 (2H, m, C(3)H and C(5)H in 4-
3
4
3
N(1)H), 9.29 (1H, dd, JN(3)H,4-H¼3.7 Hz, JN(3)H,N(1)H¼1.9 Hz, N(3)H),
MeC6H43), 4.24 (1H, ddd, C part of ABCX spin system, J4-H,CH(B)
¼
3
8.10–8.16 (4H, m, C(2)H and C(6)H in Ph, C(2)H and C(6)H in
6.0 Hz, J4-H,N(3)H¼3.7 Hz, J4-H,CH(A)¼2.8 Hz, 4-H), 4.17 (1H, dd, B
2 3
4-MeC6H4), 7.39–7.46 (1H, m, C(4)H in Ph), 7.20–7.31 (4H, m, C(3)
H
part of ABCX spin system, JCH(B),CH(A)¼10.2 Hz, JCH(B),4-H¼6.0 Hz,
CH(B) in OCH2), 4.13 (1H, dd, A part of ABCX spin system,
2JCH(A),CH(B)¼10.2 Hz, 3JCH(A),4-H¼2.8 Hz, CH(A) in OCH2), 3.17 (3H, s,
and C(5)H in Ph, C(3)H and C(5)H in 4-MeC6H4), 5.28 (1H, ddd,
3J4-H,CH(B)¼6.4 Hz, J4-H,N(3)H¼3.7 Hz, J4-H,CH(A)¼3.4 Hz, 4-H), 4.94
3
3
2
3
(1H, dd, JCH(B),CH(A)¼11.1 Hz, JCH(B),4-H¼6.4 Hz, CH(B) in OCH2),
CH3SO2), 2.39 (3H, s, CH3 in Ts), 2.18 ppm (3H, s, 6-CH3). 1H NMR
2
3
4
4.87 (1H, dd, JCH(A),CH(B)¼11.1 Hz, JCH(A),4-H¼3.4 Hz, CH(A) in
OCH2), 2.62 and 2.22 ppm (3H and 3H, two s, 6-CH3, CH3 in Ts). 13
NMR (75.48 MHz, pyridine-d5) : 166.84 (C]O in PhCOO), 154.39
(300.13 MHz, pyridine-d5)
d
: 11.11 (1H, d, JN(1)H,N(3)H¼1.9 Hz,
3
4
C
N(1)H), 9.58 (1H, dd, JN(3)H,4-H¼3.7 Hz, JN(3)H,N(1)H¼1.9 Hz, N(3)H),
d
8.05–8.11 (2H, m, C(2)H and C(6)H in 4-MeC6H4), 7.24–7.30 (2H, m,
3
(C(2)), 150.99 (C(6)), 144.30 (C(4) in 4-MeC6H4), 141.79 (C(1) in
4-MeC6H4), 133.60 (C(4) in Ph), 130.82 (C(1) in Ph), 130.63 (C(2) and
C(6) in Ph),130.37 (C(3) and C(5) in 4-MeC6H4), 128.98 (C(3) and C(5) in
Ph), 127.42 (C(2) and C(6) in 4-MeC6H4), 105.61 (C(5)), 68.84 (O–CH2),
52.30 (C(4)), 21.57 (CH3 in Ts), 17.72 ppm (6-CH3). IR (Nujol)
3362 s, 3202 m, 3114 m ( NH), 1721 s ( C]O in PhCOO), 1702 s
(amide-I), 1644 s ( C]C), 1596 w, 1490 w ( CCarom), 1293 s (nas
SO2), 1265 s ( C–O), 1151 s (ns SO2), 1132 s ( C–O), 813 s ( CHarom in
Ts), 718 s, 702 s ( CHarom in Ph). Anal. Calcd for C20H20N2O5S: C,
C(3)H and C(5)H in 4-MeC6H4), 5.16 (1H, ddd, J4-H,CH(A)¼8.0 Hz,
3J4-H,N(3)H¼3.7 Hz, 3J4-H,CH(B)¼2.9 Hz, 4-H), 4.89 (1H, dd,
2JCH(B),CH(A)¼10.1 Hz, JCH(B),4-H¼2.9 Hz, CH(B) in OCH2), 4.75 (1H,
3
2
3
dd, JCH(A),CH(B)¼10.1 Hz, JCH(A),4-H¼8.0 Hz, CH(A) in OCH2), 3.28
n
, cmꢁ1
:
(3H, s, CH3SO2), 2.58 and 2.21 ppm (3H and 3H, two s, 6-CH3, CH3 in
n
n
Ts). 13C NMR (75.48 MHz, DMSO-d6)
d: 151.93 (C(2)), 150.36 (C(6)),
n
n
143.79 (C(4) in 4-MeC6H4), 139.70 (C(1) in 4-MeC6H4), 130.09 (C(3)
and C(5) in 4-MeC6H4), 126.33 (C(2) and C(6) in 4-MeC6H4), 101.98
(C(5)), 72.38 (O–CH2), 50.39 (C(4)), 36.75 (CH3 in Ms), 21.06 (CH3 in
n
n
d
d
59.99; H, 5.03; N, 7.00. Found: C, 59.71; H, 5.29; N, 6.97.
Ts), 16.66 ppm (6-CH3). IR (Nujol)
NH), 3025 w ( CHarom), 1727 s (amide-I), 1652 s (
1492 w ( CCarom), 1354 s (nas SO2 in MsO), 1314 s (nas SO2 in Ts), 1178
s (ns SO2 in MsO), 1152 s (ns SO2 in Ts), 817 m ( CHarom). Anal. Calcd
n
, cmꢁ1: 3234 br s, 3107 br s (
C]C), 1593 m,
n
n
n
4.5. 4-Hydroxymethyl-6-methyl-5-tosyl-1,2,3,4-
tetrahydropyrimidin-2-one (13)
n
d
for C14H18N2O6S2: C, 44.91; H, 4.85; N, 7.48. Found: C, 44.69; H, 5.12;
N, 7.34.
To a mixture of KOH (1.231 g, 21.94 mmol) and pyrimidinone 10
(2.900 g, 7.24 mmol) were added EtOH (42 mL) and H2O (8 mL). The
obtained mixture was stirred at room temperature for 1.5 h. Solid
substance dissolved in 20 min after mixing. After the reaction was
complete, to the formed solution was added AcOH (1 mL) and the
solvent was removed in vacuum. To the solid residue was added
saturated aqueous solution of NaHCO3 (10 mL). The obtained sus-
pension was left at room temperature for 1 h. Upon cooling to 0 ꢀC,
the precipitate was filtered off, washed with ice-cold water, light
petrol, and dried to give 1.951 g (90.9%) of 13. Mp 236–237 ꢀC
4.7. 6-Methyl-5-tosyl-4-tosyloxymethyl-1,2,3,4-
tetrahydropyrimidin-2-one (16)
Compound 16 was synthesized in the same way as 15 from
hydroxymethylpyrimidinone 13 and TsCl in 84.2% yield. Mp 95–
96 ꢀC (toluene/ethyl acetate, 4:1 v/v). 1H NMR (300.13 MHz, DMSO-
d6)
and C(6)
d
: 9.47 (1H, d, 4JN(1)H,N(3)H¼1.9 Hz, N(1)H), 7.73–7.79 (2H, m, C(2)
H
3
H
in 5-Ts or OTs), 7.70 (1H, dd, JN(3)H,4-H¼3.8 Hz,
(decomp., EtOH). 1H NMR (300.13 MHz, DMSO-d6)
d: 9.23 (1H, d,
4JN(3)H,N(1)H¼1.9 Hz, N(3)H), 7.62–7.67 (2H, m, C(2)H and C(6)H in OTs
or 5-Ts), 7.46–7.52 (2H, m, C(3)H and C(5)H in 5-Ts or OTs), 7.35–7.41
(2H, m, C(3)H and C(5)H in OTs or 5-Ts), 4.09 (1H, ddd, C part of ABCX
spin system, 3J4-H,CH(B)¼6.1 Hz, 3J4-H,N(3)H¼3.8 Hz, 3J4-H,CH(A)¼2.9 Hz,
4-H), 3.96 (1H, dd, B part of ABCX spin system, 2JCH(B),CH(A)¼10.0 Hz,
3JCH(B),4-H¼6.1 Hz, CH(B) in OCH2), 3.91 (1H, dd, A part of ABCX spin
4JN(1)H,N(3)H¼1.9 Hz, N(1)H), 7.69–7.74 (2H, m, C(2)H and C(6)H in 4-
MeC6H4), 7.39–7.43 (2H, m, C(3)H and C(5)H in 4-MeC6H4), 7.37 (1H,
3
4
dd, JN(3)H,4-H¼3.7 Hz, JN(3)H,N(1)H¼1.9 Hz, N(3)H), 4.99 (1H, t,
3JOH,CH2¼5.5 Hz, OH), 3.88 (1H, dt, J4-H,CH2¼4.7 Hz, J4-H,N(3)H
¼
3
3
3.7 Hz, 4-H), 3.35 (2H, dd, 3JCH2,OH¼5.5 Hz, 3JCH2,4-H¼4.7 Hz, OCH2),
2
3
2.38 (3H, s, CH3 in Ts), 2.12 ppm (3H, s, 6-CH3). 13C NMR (75.48 MHz,
system, JCH(A),CH(B)¼10.0 Hz, JCH(A),4-H¼2.9 Hz, CH(A) in OCH2),
DMSO-d6)
d: 152.62 (C(2)), 148.95 (C(6)), 143.37 (C(4) in 4-MeC6H4),
2.44 (3H, s, CH3 in OTs), 2.38 (3H, s, CH3 in 5-Ts), 2.15 ppm (3H, s, 6-
140.39 (C(1) in 4-MeC6H4),129.95 (C(3) and C(5) in 4-MeC6H4),126.14
(C(2) and C(6) in 4-MeC6H4), 104.04 (C(5)), 64.59 (CH2–OH), 53.32
CH3). 13C NMR (75.48 MHz, DMSO-d6)
d: 151.75 (C(2)), 150.35 (C(6)),
145.03 (C(4) in OTs), 143.68 (C(4) in 5-Ts), 139.54 (C(1) in 5-Ts), 132.00
(C(1) in OTs), 130.20 (C(3) and C(5) in OTs), 129.96 (C(3) and C(5) in 5-
Ts), 127.59 (C(2) and C(6) in OTs), 126.17 (C(2) and C(6) in 5-Ts), 101.61
(C(5)), 72.35 (O–CH2), 50.05 (C(4)), 21.13 (CH3 in Ts), 20.99 (CH3 in Ts),
(C(4)), 21.04 (CH3 in Ts), 16.65 ppm (6-CH3). IR (Nujol)
s ( OH), 3282 m, 3216 m, 3138 sh, 3090 m ( NH), 1709 s (amide-I),
1634 s ( C]C), 1595 w, 1490 w ( CCarom), 1300 s (nas SO2), 1147 s (ns
SO2), 1064 s ( C–O), 815 m ( CHarom). Anal. Calcd for C13H16N2O4S:
n
, cmꢁ1: 3479
n
n
n
n
n
d
16.57 ppm (6-CH3). IR (Nujol)
NH), 1714 s (amide-I), 1645 s (
n
, cmꢁ1: 3214 s, 3084 s, 3067 sh (
C]C), 1597 m, 1494 w ( CCarom),
n
C, 52.69; H, 5.44; N, 9.45. Found: C, 52.82; H, 5.55; N, 9.54.
n
n
1366 s (nas SO2 in TsO), 1317 s (nas SO2 in 5-Ts), 1176 s (ns SO2 in TsO),
1155 ns SO2 in 5-Ts), 813 CHarom). Anal. Calcd for
C20H22N2O6S2: C, 53.32; H, 4.92; N, 6.22. Found: C, 53.44; H, 5.02; N,
6.30.
4.6. 4-Mesyloxymethyl-6-methyl-5-tosyl-1,2,3,4-
tetrahydropyrimidin-2-one (15)
s
(
s (d
To a stirred suspension of hydroxymethylpyrimidine 13 (1.924 g,
6.49 mmol) and DMAP (2.316 g, 18.96 mmol) in dry CHCl3 (10 mL)
at 0 ꢀC was added a solution of MsCl (1.485 g, 12.96 mmol) in dry
CHCl3 (16 mL) over 4 min. The obtained suspension was stirred for
16 min, the ice bath was removed and stirring continued at room
temperature for 45 min. The formed solution was concentrated
under vacuum to give a stable foam. Ice-cold water (20 mL) was
added to the foam and the oily matter was triturated under cooling
until complete crystallization. The precipitate was filtered off,
washed with ice-cold water, hexane, and dried to give 2.326 g
(95.6%) of 15. Mp 148.5 ꢀC (decomp., MeCN). 1H NMR (300.13 MHz,
4.8. 4-Cyano-7-methyl-6-tosyl-2,3,4,5-tetrahydro-1H-1,3-
diazepin-2-one (17)
Method A: to mesyloxymethylpyrimidine 15 (0.574 g,
1.53 mmol) and finely powdered NaCN (0.083 g, 1.69 mmol) was
added dry DMF (5 mL). The obtained suspension was stirred at
room temperature for 5.1 h, the solvent was removed under high
vacuum (temperature of bath not higher then 40 ꢀC), the oily res-
idue was triturated with dry ether until crystallization and the
precipitate was filtered off and washed with dry ether. To the

A.A. Fesenko et al. / Tetrahedron 65 (2009) 2344–2350
2349
obtained solid substance was added H2O (3 mL), the obtained
4.10. 4-[Di(ethoxycarbonyl)methyl]-7-methyl-6-tosyl-2,3,4,5-
suspension was cooled, the precipitate was filtered off, washed
with ice-cold water, light petrol, and dried to give 0.444 g (94.8%) of
tetrahydro-1H-1,3-diazepin-2-one (19)
17. Mp 213.5–214 ꢀC (decomp., MeOH). 1H NMR (300.13 MHz,
To a stirred suspension of NaH (0.047 g, 1.96 mmol) in dry MeCN
(2 mL) at 0 ꢀC was added a solution of diethyl malonate (0.323 g,
2.02 mmol) in dry MeCN (5 mL) over 2 min. The obtained white
suspension was stirred for 10 min, then mesyloxymethylpyr-
imidine 15 (0.646 g, 1.73 mmol) and MeCN (3 mL) were added. The
reaction mixture was stirred at room temperature for 1 h 27 min,
the solvent was removed under vacuum and the oily residue was
triturated with light petrol until crystallization. A saturated aque-
ous solution of NaHCO3 (2 mL) was added, the obtained suspension
was cooled, the precipitate was filtered off, washed with ice-cold
water, light petrol, and dried to give 0.720 g (95.4%) of 19. Mp 150–
4
DMSO-d6)
d
: 8.99 (1H, d, JN(1)H,N(3)H¼2.0 Hz, N(1)H), 8.20 (1H, dd,
3JN(3)H,4-H¼6.9 Hz, JN(3)H,N(1)H¼2.0 Hz, N(3)H), 7.68–7.74 (2H, m,
4
C(2)H and C(6)H in 4-MeC6H4), 7.37–7.43 (2H, m, C(3)H and C(5)
H
3
3
in 4-MeC6H4), 4.78 (1H, ddd, J4-H,N(3)H¼6.9 Hz, J4-H,5-H(B)¼5.7 Hz,
3J4-H,5-H(A)¼2.5 Hz, 4-H), 3.35 (1H, dd, J5-H(B),5-H(A)¼16.6 Hz,
2
3J5-H(B),4-H¼5.7 Hz, 5-H(B)), 2.76 (1H, ddq, J5-H(A),5-H(B)¼16.6 Hz,
2
3J5-H(A),4-H¼2.5 Hz, 5J5-H(A),7-CH3¼1.4 Hz, 5-H(A)), 2.38 (3H, s, CH3 in
5
Ts), 2.16 ppm (3H, d, J7-CH3,5-H(A)¼1.4 Hz, 7-CH3). 13C NMR
(75.48 MHz, DMSO-d6) d: 154.02 (C(2)), 146.26 (C(7)), 143.43 (C(4) in
4-MeC6H4), 139.73 (C(1) in 4-MeC6H4), 129.81 (C(3) and C(5) in 4-
MeC6H4), 126.43 (C(2) and C(6) in 4-MeC6H4), 118.03 (CN), 112.74
(C(6)), 42.11 (C(4)), 32.53 (C(5)), 21.02 (CH3 in Ts), 19.91 ppm (7-CH3).
151 ꢀC (ethyl acetate). 1H NMR (300.13 MHz, DMSO-d6)
d: 8.74 (1H,
d, 4JN(1)H,N(3)H¼1.7 Hz, N(1)H), 7.60–7.66 (2H, m, C(2)H and C(6)H in 4-
3
4
IR (KBr)
CHarom), 2244 w (
1494 m ( CCarom), 1295 s (nas SO2), 1142 s (ns SO2), 815 m (
n
, cmꢁ1: 3372 m, 3280 s, 3122 m (
n
NH), 3063 w, 3011 w (
CN), 1705 s (amide-I), 1642 s ( C]C), 1600 w,
CHarom).
n
MeC6H4), 7.62 (1H, dd, JN(3)H,4-H¼5.9 Hz, JN(3)H,N(1)H¼1.7 Hz,
n
n
N(3)H), 7.37–7.43 (2H, m, C(3)H and C(5)H in 4-MeC6H4), 3.98–4.20
3
3
n
d
(4H, m, two OCH2), 3.86 (1H, dddd, J4-H,CH¼9.8 Hz, J4-H,5-H(B)¼
3 3
Anal. Calcd for C14H15N3O3S: C, 55.07; H, 4.95; N, 13.76. Found: C,
54.93; H, 4.82; N, 13.54.
6.4 Hz, J4-H,N(3)H¼5.9 Hz, J4-H,5-H(A)¼2.2 Hz, 4-H), 3.46 (1H, d,
3JCH,4-H¼9.8 Hz, CH in CH(COOEt)2), 2.95 (1H, dd, J5-H(B),5-H(A)
¼
¼
2
3
2
Method B: a mixture of 15 (0.173 g, 0.46 mmol), finely powdered
NaCN (0.026 g, 0.53 mmol),18-crown-6 (0.021 g, 0.08 mmol) and dry
MeCN (3 mL) was stirred at room temperature for 5.6 h. The solvent
was removed under vacuum and tothe solid residuewas added water
(1 mL). The obtained suspension was cooled to 0 ꢀC, the precipitate
was filtered off, washed with ice-cold water, light petrol, dried, and
then washed with ether (2ꢂ2 mL) to give 0.132 g (93.6%) of 17.
Similarly, compound 17 was obtained by reaction of 16 with
NaCN in MeCN (rt, 22.5 h) in the presence of 18-crown-6 (30 mol %)
in 88.7% yield.
16.0 Hz, J5-H(B),4-H¼6.4 Hz, 5-H(B)), 2.60 (1H, ddq, J5-H(A),5-H(B)
3 5
16.0 Hz, J5-H(A),4-H¼2.2 Hz, J5-H(A),7-CH3¼1.4 Hz, 5-H(A)), 2.38 (3H,
s, CH3 in Ts), 2.20 (3H, br s, 7-CH3), 1.17 (3H, t, 3JCH3,CH2¼7.1 Hz, CH3
3
in OEt), 1.16 ppm (3H, t, JCH3,CH2¼7.1 Hz, CH3 in OEt). 13C NMR
(75.48 MHz, DMSO-d6) d: 166.75 (C]O in COOEt), 166.34 (C]O in
COOEt), 154.47 (C(2)), 146.27 (C(7)), 143.33 (C(4) in 4-MeC6H4), 139.67
(C(1) in 4-MeC6H4), 129.88 (C(3) and C(5) in 4-MeC6H4), 126.28 (C(2)
and C(6) in 4-MeC6H4), 111.98 (C(6)), 61.48 (O–CH2), 61.34 (O–CH2),
55.21 (CH in CH(COOEt)2), 50.11 (C(4)), 31.73 (C(5)), 21.01 (CH3 in Ts),
19.67 (7-CH3), 13.79 ppm (CH3 in COOEt). IR (Nujol)
m, 3298 s, 3274 s, 3223 s, 3143 m, 3109 s ( NH), 1742 m, 1721 s (
C]O in COOEt), 1690 s (amide-I), 1639 s ( C]C), 1599 w, 1494 w (
CCarom), 1312 s (nas SO2), 1264 s, 1185 s (
CHarom). Anal. Calcd for C20H26N2O7S: C, 54.78; H, 5.98; N, 6.39.
Found: C, 54.53; H, 6.21; N, 6.42.
n
, cmꢁ1: 3361
n
n
4.9. 7-Methyl-4-phenylthio-6-tosyl-2,3,4,5-tetrahydro-1H-
1,3-diazepin-2-one (18)
n
n
n C–O), 1150 s (ns SO2), 813 m
(d
To a stirred suspension of NaH (0.028 g, 1.17 mmol) in MeCN
(1 mL) was added a solution of thiophenol (0.137 g, 1.24 mmol) in
MeCN (3 mL) and the resulting white suspension was stirred at
room temperature for 17 min. Mesyloxymethylpyrimidine 15
(0.409 g, 1.09 mmol) and MeCN (1 mL) were added and the
obtained suspension was stirred at room temperature for 5 h. After
the reaction was complete the solvent was removed under vacuum,
the oily residue was triturated with light petrol (3ꢂ5 mL), H2O
(2 mL) was added and the residue was triturated under cooling
until complete crystallization. The formed suspension was cooled,
the precipitate was filtered off, washed with ice-cold water, light
petrol, and dried to give 0.407 g (97.1%) of 18. Mp 160–160.5 ꢀC
4.11. 9-Methyl-5-methylene-6,8-ditosyl-1,2,4,5,6,6a,7,10-
octahydro-1,6-methano[1,3]diazepino[1,7-e][1,3,5]triazocine-
3,11-dione (23)
To a mixture of NaH (0.084 g, 3.50 mmol) and mesyloxy-
methylpyrimidine 15 (1.170 g, 3.12 mmol) was added dry MeCN
(9.6 mL). The obtained suspension was stirred in an ice bath for
15 min and then at room temperature for 3 h and the solvent was
removed under vacuum. To the solid residue was added water
(3 mL) and to the formed suspension was added 2% HCl to pH 6. A
saturated aqueous solution of NaHCO3 (3 mL) was added, the sus-
pension was cooled, the precipitate was filtered off, washed with
ice-cold water, light petrol, and dried to give 0.799 g (91.9%) of 23.
(EtOH). 1H NMR (300.13 MHz, DMSO-d6)
d: 8.84 (1H, d,
3
4JN(1)H,N(3)H¼1.9 Hz, N(1)H), 8.27 (1H, dd, JN(3)H,4-H¼6.1 Hz,
4JN(3)H,N(1)H¼1.9 Hz, N(3)H), 7.67–7.73 (2H, m, C(2)H and C(6)H in 4-
MeC6H4), 7.25–7.44 (5H, m, Ph), 7.37–7.42 (2H, m, C(3)H and C(5)
H
Mp >300 ꢀC (decomp., DMF). 1H NMR (600.13 MHz, DMSO-d6)
d
:
3
3
4
in 4-MeC6H4), 4.97 (1H, ddd, J4-H,N(3)H¼6.1 Hz, J4-H,5-H(B)¼6.1 Hz,
8.79 (1H, s, N(10)H), 7.84 (1H, d, JN(4)H,N(2)H¼2.0 Hz, N(4)H), 7.74–
7.77 (2H, m, C(2)H and C(6)H in 6-Ts), 7.66–7.69 (2H, m, C(2)H and
C(6)H in 8-Ts), 7.42–7.46 (4H, m, C(3)H and C(5)H in 6-Ts and 8-Ts),
2
3J4-H,5-H(A)¼2.4 Hz, 4-H), 3.35 (1H, dd, J5-H(B),5-H(A)¼16.0 Hz,
2
3J5-H(B),4-H¼6.1 Hz, 5-H(B)), 2.87 (1H, ddq, J5-H(A),5-H(B)¼16.0 Hz,
3J5-H(A),4-H¼2.4 Hz, 5J5-H(A),7-CH3¼1.2 Hz, 5-H(A)), 2.38 (3H, s, CH3 in
7.26 (1H, dd, JN(2)H,1-H¼6.5 Hz, JN(2)H,N(4)H¼2.0 Hz, N(2)H), 5.37
3
4
5
Ts), 2.15 ppm (3H, d, J7-CH3,5-H(A)¼1.2 Hz, 7-CH3). 13C NMR
(1H, s, CH(a) in ]CH2), 5.12 (1H, dd, 3J1-H,13-H(a)¼7.9 Hz, 3J1-H, N(2)H
¼
¼
3
(75.48 MHz, DMSO-d6)
d: 154.11 (C(2)), 145.99 (C(7)), 143.21 (C(4) in
6.5 Hz, 1-H), 5.11 (1H, s, CH(b) in ]CH2), 4.03 (1H, d, J6a-H,7-H(a)
2
4-MeC6H4), 139.97 (C(1) in 4-MeC6H4), 133.56 (C(1) in SPh), 131.63
(C(2) and C(6) in SPh), 129.70 (C(3) and C(5) in 4-MeC6H4), 129.06 (C(3)
and C(5) in SPh), 127.24 (C(4) in SPh), 126.54 (C(2) and C(6) in 4-
MeC6H4), 112.51 (C(6)), 58.72 (C(4)), 35.63 (C(5)), 21.02 (CH3 in Ts),
9.7 Hz, 6a-H), 3.91 (1H, d, J7-H(b),7-H(a)¼16.5 Hz, 7-H(b)), 2.93 (1H,
2
3
dd, J13-H(a),13-H(b)¼12.7 Hz, J13-H(a),1-H¼7.9 Hz, 13-H(a)), 2.77 (1H,
2
3
5
ddq, J7-H(a),7-H(b)¼16.5 Hz, J7-H(a),6a-H¼9.7 Hz, J7-H(a),9-CH3¼1.7 Hz,
7-H(a)), 2.43 and 2.41 (3H and 3H, two s, CH3 in 6-Ts and 8-Ts),
2
19.89 ppm (7-CH3). IR (Nujol)
NH), 1681 s (amide-I), 1629 s (
SO2), 814 m ( CHarom in Ts), 751 s, 691 s (
n
, cmꢁ1: 3217 s, 3142 m, 3062 s (
C]C), 1296 s (nas SO2), 1146 s (ns
CHarom in Ph). Anal.
n
2.37 (1H, d, J13-H(b),13-H(a)¼12.7 Hz, 13-H(b)), 2.15 ppm (3H, d,
n
5J9-CH3,7-H(a)¼1.7 Hz, 9-CH3). 13C NMR (150.90 MHz, DMSO-d6)
d:
d
d
156.13 (C(3)), 152.66 (C(11)), 144.98, 144.91, 143.16 and 142.18 (C(5),
Calcd for C19H20N2O3S2: C, 58.74; H, 5.19; N, 7.21. Found: C, 58.52; H,
5.29; N, 7.02.
C(9), C(4) in 6-Ts, C(4) in 8-Ts), 140.23 (C(1) in 8-Ts), 133.42 (C(1) in
6-Ts), 130.18 (C(3) and C(5) in 6-Ts), 129.74 (C(3) and C(5) in 8-Ts),

2350
A.A. Fesenko et al. / Tetrahedron 65 (2009) 2344–2350
3. (a) Ashby, J.; Griffiths, D. J. Chem. Soc., Chem. Commun. 1974, 607–608; (b) Ashby,
J.; Griffiths, D. J. Chem. Soc., Perkin Trans. 1 1975, 657–662; (c) Bullock, E.; Garter,
R. A.; Cochrane, R.; Gregory, B.; Shields, D. C. Can. J. Chem. 1977, 55, 895–905; (d)
Claremon, D. A.; Rosenthal, S. A. Synthesis 1986, 664–665.
129.64 (C(2) and C(6) in 6-Ts), 126.06 (C(2) and C(6) in 8-Ts), 113.66
(C(8)), 109.85 (]CH2), 74.84 (C(6)), 67.82 (C(1)), 64.03 (C(6a)), 32.76
and 32.37 (C(7), C(13)), 21.12 and 20.95 (CH3 in 6-Ts and 8-Ts),
4. At present timeonly two pyrimidinones 2 (R¼Me, Et; R1¼Me) are readilyavailable.
5. (a) Shutalev, A. D.; Kuksa, V. A. Khim. Geterotsikl. Soedin. 1997, 33, 105–109;
[ Chem. Heterocycl. Compd. (Engl. Transl.) 1997, 33, 91–95 ]; (b) Shutalev, A. D.
Khim. Geterotsikl. Soedin. 1997, 33, 1696–1697; [ Chem. Heterocycl. Compd. (Engl.
Transl.) 1997, 33, 1469–1470 ]; (c) Shutalev, A. D.; Kishko, E. A.; Sivova, N. V.;
Kuznetsov, A. Yu. Molecules 1998, 3, 100–106; (d) Fesenko, A. A.; Shutalev, A. D.
Tetrahedron Lett. 2007, 48, 8420–8423; (e) Fesenko, A. A.; Cheshkov, D. A.;
Shutalev, A. D. Mendeleev Commun. 2008, 18, 51–53.
20.28 ppm (9-CH3). IR (Nujol)
NH), 1698 s, 1669 s (amide-I), 1631 s (
1302 s (nas SO2), 1139 s (ns SO2), 914 m (
n
, cmꢁ1: 3353 s, 3211 s, 3115 s, 3093 s
(n
n
C]C), 1599 w (
n
CCarom),
d
]CH2), 821 m (
d CHarom).
Anal. Calcd for C26H28N4O6S2: C, 56.10; H, 5.07; N, 10.07. Found: C,
55.85; H, 5.35; N, 9.78.
Acknowledgements
6. Kurochkin, N. N.; Goliguzov, D. V.; Cheshkov, D. A.; Shutalev, A. D. In Proceedings
of the Tenth International Electronic Conference on Synthetic Organic Chemistry;
Paper A038, (ECSOC-10), Seijas, Julio A., Pilar Va´zquez Tato, M., Eds.; MDPI:
Basel, Switzerland, 2006; ISBN 3-906980-18-9, November 1–30, 2006; CD-ROM
edition; http://www.usc.es/congresos/ecsoc/.
We thank Dr. Andrei Guzaev (AM Chemicals LLC, Oceanside, CA,
USA) for helpful discussions. M.L.T is grateful to the Hans Werthen
Foundation at the Royal Swedish Academy of Engineering Science
for postdoctoral grant.
7. Formation of ureido-substituted 4,5-dihydrofurans also occurred in the re-
action of enolates of other
(our unpublished data).
a-substituted carbonyl compounds with tosylurea 3
8. (a) Ashby, J.; Cort, L. A.; Elvidge, J. A.; Eisner, U. J. Chem. Soc. C 1968, 2311–2317;
(b) Claremon, D. A.; McClure, D. E.; Springer, J. P.; Baldwin, J. J. J. Org. Chem.
1984, 49, 3871–3874; (c) Gregory, B.; Bullock, E.; Chen, T.-S. Can. J. Chem. 1985,
63, 843–848; (d) Cid, M. M. Tetrahedron Lett. 1996, 37, 6033–6036.
9. Shutalev, A. D.; Fesenko, A. A.; Cheshkov, D. A.; Goliguzov, D. V. Tetrahedron Lett.
2008, 49, 4099–4101.
References and notes
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Marquez, V. E.; Rao, K. V. B.; Silverton, J. V.; Kelley, J. A. J. Org. Chem. 1984, 49,
912–919.
10. Du, J.; Watanabe, K. A. Synth. Commun. 2004, 34, 1925–1930.
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