4-Hydroxy-4-methyl-5-tosylhexahydropyrimidin-2-imines: Synthesis and different dehydration pathways

Article abstract of DOI:10.1016/j.tet.2011.06.088

Synthesis of 4-hydroxy-4-methyl-5-tosylhexahydropyrimidin-2-imines by reaction of N-cyano-N′-(1-tosylalk-1-yl)guanidines with enolates of tosylacetone was developed. Base-catalyzed dehydration of the obtained pyrimidines gave the expected 6-methyl-5-tosyl

Full text of DOI:10.1016/j.tet.2011.06.088

Tetrahedron 67 (2011) 6883e6888
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4-Hydroxy-4-methyl-5-tosylhexahydropyrimidin-2-imines: synthesis
and different dehydration pathways
*
Anatoly D. Shutalev , Anastasia A. Fesenko
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
Synthesis of 4-hydroxy-4-methyl-5-tosylhexahydropyrimidin-2-imines by reaction of N-cyano-N0-(1-
tosylalk-1-yl)guanidines with enolates of tosylacetone was developed. Base-catalyzed dehydration of
the obtained pyrimidines gave the expected 6-methyl-5-tosyl-1,2,3,4-tetrahydropyrimidin-2-imines.
However, their acid-catalyzed dehydration led to mixtures of the latter compounds and the products of
tosyl group migration, 4-tosylmethyl derivatives. This reaction was strongly influenced by the nature of
the solvent. Plausible explanations of the obtained data were given.
Article history:
Received 22 March 2011
Received in revised form 14 June 2011
Accepted 24 June 2011
Available online 30 June 2011
Keywords:
Ó 2011 Elsevier Ltd. All rights reserved.
Hexahydropyrimidin-2-imines
1,2,3,4-Tetrahydropyrimidin-2-imines
Guanidinoalkylation
Tosyl migration
1. Introduction
interest because some of them are the constituents of the natural
guanidine alkaloids (e.g., tetrodotoxin, ptilocaulin, saxitoxin, bat-
Recently, we have developed
a
new general approach to
zelladine B, crambescin B, etc.), which possess a variety of biological
activities.2 In this communication, we describe a novel synthesis of
tosyl-substituted 2-cyanoiminohexahydropyrimidines and 2-
5-functionalized
4-hydroxyhexahydropyrimidine-2-thiones/ones
1a,b and 1,2,3,4-tetrahydropyrimidine-2-thiones/ones 2a,b (Fig. 1)
by the reaction of readily available N-(1-tosylalk-1-yl)thioureas and
cyanoimino-1,2,3,4-tetrahydropyrimidines using
lation as a key step.
a-guanidinoalky-
N-(1-tosylalk-1-yl)ureas with enolates of
a-substituted carbonyl
compounds.1
2. Results and discussion
2.1. Reaction of
cyanoguanidines with enolates of tosylacetone
a
-tosyl-substituted N-alkyl-N0-
Starting materials,
a
-tosyl-substituted N-alkyl-N0-cyanoguani-
dines 3a,b, were obtained by the three-component condensation of
equivalent amounts of cyanoguanidine, aliphatic aldehydes 4a,b
and p-toluenesulfinic acid (5) in water at rt (Scheme 1). Although
the reaction time was substantially longer (3e4 days) than in the
case of thioureas and ureas,1 3a,b were obtained in 85 and 83%
Fig. 1. Structures of 5-functionalized 4-hydroxyhexahydropyrimidine-2-thiones(ones,
imines) 1aec and 1,2,3,4-tetrahydropyrimidine-2-thiones(ones, imines) 2aec.
We hypothesized that the same synthetic approach might be
applicable to the preparation of 5-functionalized 4-hydroxyhe-
xahydropyrimidin-2-imines 1c and 1,2,3,4-tetrahydropyrimidin-
2-imines 2c (Fig. 1). These compounds are currently of great
Scheme 1. Synthesis of N-cyano -N0-(1-tosylalk-1-yl)guanidines 3a,b.
* Corresponding author. E-mail address: shutalev@orc.ru (A.D. Shutalev).
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.06.088

6884
A.D. Shutalev, A.A. Fesenko / Tetrahedron 67 (2011) 6883e6888
yields, respectively. The purity of the crude 3a,b was excellent
(>94% according to 1H NMR data), therefore, they were used in
further transformations without additional purification.
The obtained sulfones 3a,b reacted at rt with sodium or potassium
enolates of tosylacetone (6) generated by treatment of 6 with NaH or
KOH at rt to produce expected 4-hydroxyhexahydropyrimidin-
2-imines 7a,b (Scheme 2).
couplings observed. For compound 7a the position of the hydroxyl
group was determined using 1H,1H-NOESY experiments (Fig. 2).
NOEs were observed between the OH and 5-H protons and be-
tween one of the hydrogens of the exocyclic methylene group and
OH. These and other NOE relationships in the major diastereomer of
7a confirmed the axial orientation of OH, Ts and Et groups. Thus,
this isomer has the (4R*,5S*,6S*)-configuration. Comparison of 1H
and 13C NMR spectra of 7a and 7b allowed us to conclude that the
major diastereomer of 7b has the same (4R*,5S*,6S*)-configuration.
Scheme 2. Reaction of N-cyano-N0-(1-tosylalk-1-yl)guanidines 3a,b with enolates of
tosylacetone (6).
Fig. 2. Diagnostic NOE relationships in (4R*,5S*,6S*)-7a.
When
a
-tosyl-substituted N-alkyl(thio)ureas were used as
-functional-
starting compounds in the reaction with enolates of
a
Three-dimensional structures of minor isomers of 7a,b could
not be unambiguously determined by 1H NMR spectroscopy be-
cause of their small quantities in the obtained products (Table 1).
However, based on the presence of the long range coupling con-
stant 4JOH,5-H¼1.0 Hz in 1H NMR spectrum of the minor isomer of 7b
in DMSO-d6, we concluded that the hydroxyl and tosyl groups in
this isomer have axial and equatorial orientation, respectively.
Presumably, the minor diastereomer of 7b differs from the major
one only in the orientation of the tosyl group and therefore has
ized ketones under the similar conditions, hydroxypyrimidines
1a,b were the only products.1 In contrast, some amount of the re-
spective tetrahydropyrimidines 8a,b (Table 1) always formed in the
reaction of enolates of 6 with tosylguanidines 3a,b. The yield of 8a,b
increased when MeCN was used instead of THF (entry 2 vs entry 3;
entry 7 vs entry 8), with prolonged reaction time (entry 1 vs entry
2; entry 4 vs entry 5; entry 8 vs entry 9 vs entry 10), and at higher
reaction temperature (entry 4 vs entry 6). Under more forcing
conditions, spectroscopically pure 8a,b were obtained in good
yields (entries 5, 6 and 11). On the other hand, under the optimal
conditions (NaH, THF, rt, 2.6e3.5 h) the hydroxypyrimidines 7a,b
formed contained only the small amount (6e7 mol %) of 8a,b
(entries 1 and 7).
(4R*,5R*,6S*)-configuration. The same configuration has one of the
4
minor diastereomers of 7a (
d
OH¼6.38 ppm, doublet, JOH,5-
¼1.2 Hz).
H
Thus, high tendency of compounds 7a,b to dehydration is
caused by 1,3-diaxial repulsion between the alkyl group at C6 and
Table 1
Reaction of guanidines 3a,b with tosylacetone (6) in the presence of bases
Entry
Guanidine 3
Base
Solvent
Reaction conditions
Product(s)
7/8 molar ratioa
Yield 7þ8, %b
Diastereomer ratio of 7c
1
2
3
4
5
6
7
8
3a
3a
3a
3a
3a
3a
3b
3b
3b
3b
3b
NaH
NaH
NaH
KOH
KOH
KOH
NaH
NaH
NaH
NaH
KOH
THF
THF
rt, 2.6 h
rt, 7.4 h
rt, 7.5 h
rt, 24.3 h
rt, 47.5 h
rt, 7.5 h, then reflux, 1.5 h
rt, 3.5 h
rt, 4 h
rt, 6.1 h
7a, 8a
7a, 8a
7a, 8a
7a, 8a
7a, 8a
8a
7b, 8b
7b, 8b
7b, 8b
7b, 8b
7b, 8b
93:7
83
90
81
90
78
64
79
82
81
80
82
96:3:1
95:2:3
89:11
74:26
66:34
d
83:17
78:22
26:74
4:96
0:100
94:6
75:25
69:31
46:54
2:98
MeCN
EtOH
EtOH
EtOH
THF
MeCN
MeCN
MeCN
EtOH
79:21
74:26
72:28
82:18
67:33
9
10
11
rt, 10 h
rt, 47.3 h
a
According to 1H NMR data of the crude products.
b
c
Calculated using 7/8 molar ratios.
Determined by integration of the signals of OH protons (6.08e6.38 ppm range) in 1H NMR spectra of the crude products in DMSO-d6.
We supposed that a pronounced tendency of hydroxypyrimidin-
the hydroxyl group at C4. We suppose that, because of the basicity
of the reaction media, this dehydration proceeds via E1cB mecha-
nism (Scheme 3).
2-imines 7a,b to dehydration could be explained by the three-
dimensional structure of these compounds. According to 1H NMR
data, they formed as a mixture of two or three diastereomers with
a great predominance of one of them (Table 1).3 The major isomer
of 7a,b has axial orientation of the alkyl group at C6, which follows
from the value of the coupling constant 3JN(1)H,6-H¼4.4e4.5 Hz.4 The
3
value of the characteristic coupling constant J5-H,6-H was close to
zero thus confirming that the respective dihedral angle was almost
90ꢀ. Calculations of geometry of the hydroxypyrimidines 7a,b with
various orientations of substituents at C5 and C4 using semi-
empirical methods AM1 and PM65 showed that only the axial
orientation of the tosyl group could be in agreement with the
Scheme 3. Mechanism of base-catalyzed dehydration of 7a,b.

A.D. Shutalev, A.A. Fesenko / Tetrahedron 67 (2011) 6883e6888
6885
According to this mechanism, deprotonation of N(3)H with
a base followed by OH-anion elimination from the obtained anions
9a,b, which is favoured by stereoelectronic factors6 leads to for-
mation of tetrahydropyrimidines 10a,b. The latter undergo an
imineeenamine tautomeric shift to give 8a,b.
2.2. Acid-catalyzed dehydration of 4-hydroxy-5-
tosylhexahydropyrimidin-2-imines. Tosyl group migration
We found that acid-catalyzed dehydration of hydroxypyr-
imidines 7a,b using 25 mol % TsOH in refluxing EtOH gave pre-
dominantly products of the tosyl group migration, pyrimidines
11a,b, along with small amounts (6e11%) of the expected 8a,b
(Scheme 4) (Table 2, entries 2 and 6). In contrast, the migration of
tosyl group under the similar conditions was not observed in case of
dehydration of 4-hydroxy-4-methyl-5-tosylhexahydropyrimidine-
2-thiones/ones.1c,7
Scheme 5. A plausible pathway for transformation of 7a,b into 8a,b and 11a,b under
acidic conditions.
Transformation of 7a,b into 11a,b via 4-methylenpyrimidines
13a,b is confirmed by the direct observation of 13a,b in some
cases during crystallization of 7a,b from MeCN. Thus, a mixture of
13a,8 11a and 7a in a ratio of 86:11:3 was obtained from 7a, and
a mixture of 13b,9 11b, 8b and 7b in a ratio of 46:23:14:17 was
prepared from 7b.
The hypothetic reaction pathway described above is consistent
with a higher stability of allylsulfones in comparison with vinyl-
sulfones10 and migration ability of arylsulfonyl groups in
allylsulfones.11
Scheme 4. Acid-catalyzed dehydration of 7a,b.
Table 2
3. Conclusion
The influence of the solvent and catalyst on the ratio of 8/11 in the acid-catalyzed
dehydration of 7
In summary, a convenient method for the synthesis of pre-
viously unknown 2-cyanoimino-4-hydroxy-4-methyl-5-tosylh-
exahydropyrimidines by reaction of N-cyano-N0-(1-tosylalk-1-yl)
guanidines with tosylacetone in the presence of bases was de-
veloped. The obtained compounds readily dehydrated under basic
conditions to give the expected 2-cyanoimino-5-tosyl-1,2,3,4-
tetrahydropyrimidines. In contrast, the dehydration under acidic
conditions afforded also the products of the tosyl group migration,
2-cyanoimino-4-tosylmethyl-1,2,3,4-tetrahydropyrimidines. Protic
solvents strongly favoured this migration. The mechanisms of these
reactions were discussed.
Entry Pyrimidine 7 Solvent
Catalyst
Products Yield 8þ11, % 8/11
molar
ratioa
1
2
3
4
5
6
7
7a
7a
7a
7a
7b
7b
7b
MeCN
EtOH
EtOH/H2O TsOH
EtOH
MeCN
EtOH
TsOH
TsOH
8a, 11a
8a, 11a
8a, 11a
95
79
77
77
50:50
11:89
26:74
35:65
63:37
6:94
4-MeC6H4SOOH 8a, 11a
TsOH
TsOH
8b, 11b 100
8b, 11b
8b, 11b
93
81
EtOH/H2O TsOH
16:84
a
According to 1H NMR data of the crude products.
The unexpected formation of 11a,b led us to study the acid-
catalyzed dehydration of hydroxypyrimidines 7a,b in more detail
(Table 2). The ratios of 11 to 8 were strongly affected by the solvent
used. Thus, the percentage of 11a increased from 50 to 89% when
protic EtOH was applied instead of aprotic MeCN (entry 1 vs entry
2). The further increase in the solvation strength of the reaction
media decreased the amount of 11a to 74% (entry 2 vs entry 3). An
analogous solvent effect was observed for 7b (entries 5, 6 and 7).
Increase in acidity of the catalyst favoured formation of compound
11a (entry 2 vs entry 4).
Transformation of 7a,b into 8a,b and 11a,b is kinetically con-
trolled. Indeed, after treatment of 8a or 11b with 30 mol % of TsOH
(EtOH, reflux, 5 h and MeCN, reflux, 40 min, respectively) only the
starting compounds were recovered.
Scheme 5 shows a plausible pathway for the transformation of
7a,b into 8a,b and 11a,b under acidic conditions. The first step of
the reaction involves formation of intermediate acyliminium cat-
ions 12a,b. The following proton loss from 12a,b gives either tet-
rahydropyrimidines 8a,b or 4-methylenpyrimidines 13a,b. The
allylic rearrangement of 13a,b with tosyl group migration proceeds
via carbocations 14a,b and results in the formation of 11a,b.
According to our experimental data (Table 2), the increase of the
solvation ability of the reaction media favours formation of cations
14a,b and facilitates the rearrangement.
4. Experimental section
4.1. General
Acetonitrile was dried by distillation from P2O5 and then from
CaH2. p-Toluenesulfinic acid (5) was synthesized by treatment of
a saturated aqueous solution of sodium p-toluenesulfinate12 with
hydrochloric acid at 0 ꢀC, dried over P2O5 and stored at 0 ꢀC. Sodium
hydride (60% suspension in mineral oil) was washed with dry
hexane, dried in vacuum desiccator prior to use. All other reagents
and solvents were purchased from commercial sources and used
without further treatment.
IR spectra (in Nujol or KBr pellet) were recorded using a Bruker
Equinox 55/S and PerkineElmer Spectrum BX spectrophotometers.
Peak intensities in the IR spectra are defined as strong (s), medium
(m) or weak (w). NMR spectra were recorded on a Bruker DPX-300
spectrometer at 300.13 (1H) and 75.48 (13C) MHz and a Bruker
Avance 600 spectrometer at 600.13 MHz (1H) as solutions in DMSO-
d6. 1H NMR chemical shifts are referenced to the residual proton
signal for DMSO-d6 (2.50 ppm). 13C NMR chemical shifts are
reported to the carbon signal for DMSO-d6 (39.50 ppm). Multi-
plicities are reported as singlet (s), doublet (d), triplet (t), quartet
(q), some combination of these, multiplet (m). Thin layer

6886
A.D. Shutalev, A.A. Fesenko / Tetrahedron 67 (2011) 6883e6888
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. Plates were visualised with iodine vapour or UV light. All
yields refer to isolated, spectroscopically and TLC pure compounds.
(1.065 g, 3.80 mmol) and anhydrous THF (2.6 mL). The formed sus-
pension was stirred at rt for 2.6 h, and the solvent was removed in
vacuum. The white solid residue was triturated with hexane (5 mL),
a saturated aqueous solution of NaHCO3 (2 mL) was added and the
obtained dense suspension was left in a water bath (bath tempera-
ture 32 ꢀC) for 3.5 h. Upon cooling to 0 ꢀC, the white precipitate was
filtered, washed with ice-cold water, hexane, dried, washed with
cold (0 ꢀC) ether (2ꢂ5 mL), and dried to give 1.058 g of product as
a 93:7 mixture of hydroxypyrimidine 7a (three diastereomers,
96:3:1) and tetrahydropyrimidine 8a (Table 1, entry 1).13 The yield
calculated for pure 7a is 83%. An analytically pure sample of 7a (two
diastereomers, 98:2) was obtained by rapid crystallization from
4.1.1. N-Cyano-N0-(1-tosylpropyl)guanidine (3a). To a mixture of
propanal (3.041 g, 52.36 mmol) and H2O (60 mL) was added p-
toluenesulfinic acid (8.182 g, 52.38 mmol) under stirring followed
by the addition of H2O (15 mL). After 10 min to the obtained white
suspension were added finely powdered cyanoguanidine (4.402 g,
52.35 mmol) and H2O (15 mL). The reaction mixture was left at rt
for 70 h, occasionally stirring it. Upon cooling to 0 ꢀC, the white
precipitate was filtered, washed with ice-cold water, hexane, and
dried to give 12.536 g (85%) of 3a, which was used without further
purification. An analytically pure sample was obtained by re-
crystallization from MeCN. Mp 154.5e155 ꢀC (MeCN). 1H NMR
MeCN.14 Mp 150e151 ꢀC (decomp., MeCN). 1H NMR of the major
4
isomer (600.13 MHz, DMSO-d6)
d
: 8.08 (1H, d, JN(3)H,N(1)H¼2.0 Hz,
N(3)H), 7.76e7.79 (2H, m, AA0 part of AA0XX0 spin system, C(2)H and
C(6)H in 4-MeC6H4), 7.72 (1H, dd, 3JN(1)H,6-H¼4.4, 4JN(1)H,N(3)H¼2.0 Hz,
N(1)H), 7.44e7.47 (2H, m, XX0 part of AA0XX0 spin system, C(3)H and
C(5)H in 4-MeC6H4), 6.08 (1H, s, OH), 3.67 (1H, d, 3J5-H,6-H¼0.7 Hz, 5-
H), 3.62 (1H, dddd, 3J6-H,CH(A)¼8.8, 3J6-H,CH(B)¼6.4, 3J6-H,N(1)H¼4.4, 3J6-
(300.13 MHz, DMSO-d6)
d
: 7.67e7.72 (2H, m, AA0 part of AA0XX0 spin
3
system, C(2)H and C(6)H in 4-MeC6H4), 7.61 (1H, d, JNH,CH¼9.7 Hz,
NH), 7.42e7.47 (2H, m, XX0 part of AA0XX0 spin system, C(3)H and
¼0.7 Hz, 6-H), 2.42 (3H, s, CH3 in Ts), 1.86 (1H, ddq,
H,5-H
C(5)
H
in 4-MeC6H4), 6.79 (2H, br s, NH2), 4.94 (1H, ddd,
2JCH(A),CH(B)¼13.3, 3JCH(A),6-H¼8.8, 3JCH(A),CH3¼7.4 Hz, CH(A) in 6-CH2),
3JCH,CH(B)¼10.7, 3JCH,NH¼9.7, 3JCH,CH(A)¼3.1 Hz, CHeSO2), 2.41 (3H, s,
CH3 in Ts), 1.91e2.10 (1H, unresolved m, CH(A) in CH2), 1.60 (1H,
1.70 (1H, ddq, JCH(B),CH(A)¼13.3, JCH(B),6-H¼6.4, JCH(B),CH3¼7.4 Hz,
2
3
3
3
CH(B) in 6-CH2), 1.68 (3H, s, 4-CH3), 0.61 (3H, t, JCH3,CH(A)
2
3
3
ddq, JCH(B),CH(A)¼13.8, JCH(B),CH¼10.7, JCH(B),CH3¼7.3 Hz, CH(B) in
¼3JCH3,CH(B)¼7.4 Hz, CH3 in Et). 1H NMR of the minor isomer
CH2), 0.91 (3H, t, 3JCH3,CH(A)¼3JCH3,CH(B)¼7.3 Hz, CH3 in Et). 13C NMR
(300.13 MHz, DMSO-d6)
d
: 7.98 (1H, br s, N(3)H), 6.38 (1H, d, JOH,5-
4
(75.48 MHz, DMSO-d6)
d
: 160.9 (NeC]N), 144.8 (C(4) in 4-MeC6H4),
¼1.2 Hz, OH), 1.74 (3H, s, 4-CH3), 0.75 (3H, t, 3JCH3,CH2¼7.3 Hz, CH3
H
133.7 (C(1) in 4-MeC6H4), 129.7 (C(3) and C(5) in 4-MeC6H4), 128.9
in Et). Signals of other protons overlap with proton signals of the
(C(2) and C(6) in 4-MeC6H4), 116.6 (C^N), 71.7 (CHeN), 21.2 (CH3 in
major isomer. 13C NMR of the major isomer (75.48 MHz, DMSO-d6)
d:
Ts), 20.1 (CH2 in Et), 9.7 (CH3 in Et). IR (Nujol)
3335 (s), 3274 (m), 3218 (w), 3173 (m), 3125 (w) (
3048 (w) ( CHarom), 2180 (s), 2166 (s) ( C^N), 1635 (s) [NHeC(]
N)eNH], 1599 (m) ( CC in Ts), 1538 (s) [NHeC(]N)eNH], 1495 (w)
CC in Ts), 1313 (s) (nas SO2), 1143 (s) (ns SO2), 815 (s) ( CHarom).
n
, cmꢁ1: 3423 (s),
155.8 (C(2)), 144.8 (C(4) in 4-MeC6H4), 135.4 (C(1) in 4-MeC6H4), 129.8
(C(3) and C(5) in 4-MeC6H4), 128.5 (C(2) and C(6) in 4-MeC6H4), 117.7
(C^N), 78.1 (C(4)), 64.1 (C(5)), 51.3 (C(6)), 28.5 (CH2 in Et), 28.1 (4-CH3),
n
NH), 3070 (w),
n
n
n
21.1 (CH3 in Ts), 10.0 (CH3 in Et). IR (Nujol)
(sh), 3191 (s), w3130 (sh) ( NH, OH), 2179 (s) (
[NHeC(]N)eNH], 1596 (m) ( CC in Ts), 1564 (s) [NHeC(]N)eNH],
1303 (s) (nas SO2), 1142 (s) (ns SO2), 814 (s) ( CHarom). Anal. Calcd for
n
, cmꢁ1: 3435 (m), 3264
C^N), 1653 (s)
(n
d
n
n
n
Anal. Calcd for C12H16N4O2S: C, 51.41; H, 5.75; N 19.99. Found: C,
51.49; H, 6.04; N, 19.70.
n
d
C15H20N4O3S: C, 53.56; H, 5.99; N, 16.65. Found: C, 53.53; H, 6.00; N,
16.48.
4.1.2. N-Cyano-N0-(1-tosylbutyl)guanidine (3b). Compound 3b
(6.842 g, 83%) was synthesized as a white solid in the same way as
3a by reaction of butanal (2.019 g, 28.01 mmol) with p-toluene-
sulfinic acid (4.372 g, 27.99 mmol) and cyanoguanidine (2.356 g,
52.35 mmol) in water (50 mL) at rt for 90 h. Mp 161.5e162 ꢀC
4.1.4. 2-(Cyanimino)-4-hydroxy-4-methyl-6-propyl-5-tosylhexahyd-
ropyrimidine (7b). Compound 7b was synthesized as a white solid
in the same way as 7a from tosylacetone (6) (1.069 g, 5.04 mmol),
NaH (0.122 g, 5.08 mmol) and guanidine 3b (1.482 g, 5.03 mmol) in
anhydrous THF (15 mL) at rt for 3.5 h. The obtained product
(1.384 g) was a 94:6 mixture of hydroxypyrimidine 7b (two di-
astereomers, 79:21) and tetrahydropyrimidine 8b (Table 1, entry
7).15 The yield calculated for pure 7b is 79%. An analytically pure
sample of 7b (two diastereomers, 98:2) was obtained by rapid
crystallization from MeCN.14 Mp 148.5e150 ꢀC (decomp., MeCN). 1H
(decomp., MeCN). 1H NMR (300.13 MHz, DMSO-d6)
d: 7.67e7.72
(2H, m, AA0 part of AA0XX0 spin system, C(2)H and C(6)H in 4-
3
MeC6H4), 7.62 (1H, br d, JNH,CH¼9.8 Hz, NH), 7.42e7.47 (2H, m,
XX0 part of AA0XX0 spin system, C(3)H and C(5)H in 4-MeC6H4), 6.77
3
3
(2H, br s, NH2), 4.99 (1H, ddd, JCH,CH(B)¼11.1, JCH,NH¼9.8,
3JCH,CH(A)¼3.1 Hz, CHeSO2), 2.41 (3H, s, CH3 in Ts), 1.82e2.00 (1H,
2
unresolved m, CH(A) in CH2), 1.60 (1H, dddd, JCH(B),CH(A)¼13.6,
JCH(B),CH¼11,1, 3JCH(B),CH(A )¼8.7, 3JCH(B),CH(B )¼4.8 Hz, CH(B) in CH2),
NMR of the major isomer (600.13 MHz, DMSO-d6) d: 8.06 (1H, d,
3
0
0
1.18e1.48 (2H, m, CH(A0) and CH(B0) in CH2), 0.86 (3H, t,
4JN(3)H,N(1)H¼1.6 Hz, N(3)H), 7.76e7.79 (2H, m, AA0 part of AA0XX0
3
3JCH3,CH2¼7.3 Hz, CH3 in Pr). 13C NMR (75.48 MHz, DMSO-d6)
d:
spin system, C(2)H and C(6)H in 4-MeC6H4), 7.74 (1H, dd, JN(1)H,6-
4
160.8 (NeC]N), 144.8 (C(4) in 4-MeC6H4), 133.6 (C(1) in 4-MeC6H4),
129.7 (C(3) and C(5) in 4-MeC6H4), 128.9 (C(2) and C(6) in 4-MeC6H4),
116.6 (C^N), 70.1 (CHeN), 28.1 (CH2 in Pr), 21.1 (CH3 in Ts), 18.0
¼4.5, JN(1)H,N(3)H¼1.6 Hz, N(1)H), 7.44e7.47 (2H, m, XX0 part of
H
AA0XX0 spin system, C(3)H and C(5)H in 4-MeC6H4), 6.08 (1H, s, OH),
3
3
3
3.74 (1H, ddd, J6-H,CH(B)¼8.4, J6-H,CH(A)¼6.3, J6-H,N(1)H¼4.5 Hz, 6-
H), 3.66 (1H, s, 5-H), 2.42 (3H, s, CH3 in Ts), 1.80e1.87 and
1.63e1.69 (1H each, two m, CH2CH2CH3), 1.67 (3H, s, 4-CH3),
1.13e1.22 and 0.92e1.01 (1H each, two m, CH2CH2CH3), 0.68 (3H, t,
(CH2 in Pr), 13.2 (CH3 in Pr). IR (KBr)
3265 (m), 3172 (m), 3123 (w) ( NH), 3068 (w), 3003 (w) (
2181 (s), 2164 (s) ( C^N), 1637 (s) [NHeC(]N)eNH], 1597 (m) (
CC in Ts), 1541 (s) [NHeC(]N)eNH], 1312 (s) (nas SO2), 1142 (s) (ns
SO2), 813 (m) ( CHarom). Anal. Calcd for C13H18N4O2S: C, 53.04; H,
n
, cmꢁ1: 3429 (s), 3340 (s),
CHarom),
n
n
n
n
3JCH3,CH2¼7.4 Hz, CH3 in Pr). 1H NMR of the minor isomer
4
d
(300.13 MHz, DMSO-d6)
d
: 7.94 (1H, d, JN(3)H,N(1)H¼1.9 Hz, N(3)H),
6.16; N, 19.03. Found: C, 53.01; H, 6.35; N, 18.92.
6.36 (1H, d, 4JOH,5-H¼1.0 Hz, OH), 2.41 (3H, s, CH3 in Ts), 1.73 (3H, s,
3
4-CH3), 0.79 (3H, t, JCH3,CH2¼7.2 Hz, CH3 in Pr). Signals of other
4.1.3. 2-(Cyanimino)-6-ethyl-4-hydroxy-4-methyl-5-tosylhexahydr-
protons overlap with proton signals of the major isomer. 13C NMR of
opyrimidine (7a). To
a
mixture of tosylacetone (6) (0.805 g,
the major isomer (75.48 MHz, DMSO-d6) d: 155.8 (C(2)), 144.7 (C(4)
3.79 mmol) and NaH (0.092 g, 3.83 mmol) was added anhydrous THF
(5 mL), and the obtained mixture was stirred for 7 min upon cooling
on ice-bath. Then to the resulting solution were added guanidine 3a
in 4-MeC6H4), 135.4 (C(1) in 4-MeC6H4), 129.8 (C(3) and C(5) in 4-
MeC6H4), 128.4 (C(2) and C(6) in 4-MeC6H4), 117.7 (C^N), 78.1
(C(4)), 64.7 (C(5)), 49.2 (C(6)), 37.8 (CH2 in Pr), 28.1 (4-CH3), 21.1 (CH3

A.D. Shutalev, A.A. Fesenko / Tetrahedron 67 (2011) 6883e6888
6887
in Ts), 18.2 (CH2 in Pr), 13.2 (CH3 in Pr). IR (KBr)
3255 (s) ( NH, OH), 2174 (s) ( C^N), 1631 (s) [NHeC(]N)eNH],
1597 (w) ( CC in Ts), 1562 (s) [NHeC(]N)eNH], 1492 (w) ( CC in
Ts), 1303 (s) (nas SO2), 1141 (s) (ns SO2), 815 (s) ( CHarom). Anal. Calcd
for C16H22N4O3S: C, 54.84; H, 6.33; N, 15.99. Found: C, 54.62; H,
6.60; N, 15.84.
n
, cmꢁ1: 3434 (s),
CH3 in Ts), 2.19 (3H, s, 6-CH3), 1.12e1.56 (4H, m, CH2CH2 in Pr), 0.83
n
n
n
(3H, t, 3JCH3,CH2¼7.2 Hz, CH3 in Pr). 13C NMR (75.48 MHz, DMSO-d6)
d:
n
n
155.6 (C(2)), 145.5 (C(6)), 143.9 (C(4) in 4-MeC6H4), 139.5 (C(1) in 4-
MeC6H4), 130.1 (C(3) and C(5) in 4-MeC6H4), 126.4 (C(2) and C(6) in
4-MeC6H4),116.3 (C^N), 110.2 (C(5)), 49.9 (C(4)), 38.4 (CH2 in Pr), 21.0
d
(CH3 in Ts),16.6 (CH2 in Pr), 16.2 (6-CH3),13.5 (CH3 in Pr). IR (Nujol)
cmꢁ1: 3193 (s), 3049 (s) (
NH), 2204 (sh), 2192 (s) ( C^N), 1658
(sh), 1648 (s) [NHeC(]N)eNH], 1602 (w) ( CC in Ts), 1520 (s)
[NHeC(]N)eNH],1495 (w) ( CC in Ts), 1311 (s) (nas SO2), 1156 (s) (ns
SO2), 808 (s) ( CHarom). Anal. Calcd for C16H20N4O2S: C, 57.81; H,
n,
n
n
4.1.5. 2-Cyanimino-4-ethyl-6-methyl-5-tosyl-1,2,3,4-tetrahydropyr-
imidine (8a). Method A. To a stirred solution of KOH (0.117 g,
2.09 mmol) in EtOH (3 mL) at rt was added tosylacetone (6) (0.423 g,
1.99 mmol) at once. After 5 min to the obtained solution were added
guanidine 3a (0.588 g, 2.00 mmol) and EtOH (2 mL). The resulting
solution was stirred at rt for 47.5 h, the solvent was removed under
vacuum and the oily residue was triturated with light petrol (3 mL)
and saturated aqueous solution of NaHCO3 (1.5 mL) until crystalli-
zation. The obtained suspension was left overnight at rt, the white
precipitate was filtered, washed with water, light petrol, dried,
washed with ether (2ꢂ3 mL), and dried to give 0.499 g of product as
a 96:4 mixture of 8a and hydroxypyrimidine 7a (two diastereomers,
66:34) (Table 1, entry 5). The yield calculated for pure 8a is 78%. An
analytically pure sample of 8a was obtained by crystallization from
n
n
d
6.06; N, 16.85. Found: C, 57.77; H, 6.21; N, 16.82.
4.1.7. 2-Cyanimino-4-ethyl-6-(tosylmethyl)-1,2,3,4-tetrahydropyrim-
idine (11a). To a 91:9 mixture of hydroxypyrimidine 7a and tetra-
hydropyrimidine 8a (0.427 g) containing 0.390 g (1.16 mmol) of 7a
were added TsOH$H2O (0.065 g, 0.34 mmol) and EtOH (5 mL). The
obtained suspension was refluxed for 1 h 20 min under stirring. At
the start solid substance dissolved and after 3 min new white
precipitate formed. After the reaction was complete, the solvent
was removed in vacuum. To the solid residue was added a saturated
aqueous solution of NaHCO3 (1 mL) and the resulting substance was
triturated under cooling until complete crystallization. The
obtained suspension was cooled to 0 ꢀC, the white precipitate was
filtered, washed with ice-cold water, light petrol, ether, and dried to
give 0.327 g of product as a mixture of 11a and 8a in a ratio of 79:21.
The calculated overall yield of 11a and 8a, and 11a/8a ratio based on
the quantity of starting 7a were 79% and 89:11, respectively (Table
2, entry 2). Crystallization of the mixture from EtOH afforded pure
MeCN. Mp 226e226.5 ꢀC (decomp., MeCN). 1H NMR (300.13 MHz,
3
DMSO-d6)
d
: 10.23 (1H, s, N(1)H), 8.83 (1H, d, JN(3)H,4-H¼3.8 Hz,
N(3)H), 7.70e7.76 (2H, m, AA0 part of AA0XX0 spin system, C(2)H and
C(6)H in 4-MeC6H4), 7.40e7.46 (2H, m, XX0 part of AA0XX0 spin sys-
3
3
tem, C(3)H and C(5)H in 4-MeC6H4), 4.10 (1H, dt, J4-H,CH2¼5.6, J4-
¼3.8 Hz, 4-H), 2.40 (3H, s, CH3 in Ts), 2.20 (3H, s, 6-CH3),
H,N(3)H
3
3
1.54 (2H, dq, JCH2,CH3¼7.4, JCH2,4-H¼5.6 Hz, CH2 in Et), 0.80 (3H, t,
3JCH3,CH2¼7.4 Hz, CH3 in Et). 13C NMR (75.48 MHz, DMSO-d6)
d: 155.7
11a. Mp 238e238.5 ꢀC (decomp., EtOH). 1H NMR (300.13 MHz,
3
(C(2)), 145.6 (C(6)), 143.9 (C(4) in 4-MeC6H4), 139.5 (C(1) in 4-MeC6H4),
130.0 (C(3) and C(5) in 4-MeC6H4), 126.4 (C(2) and C(6) in 4-MeC6H4),
116.2 (C^N), 109.7 (C(5)), 51.3 (C(4)), 29.5 (CH2 in Et), 21.0 (CH3 in Ts),
DMSO-d6)
d
: 8.86 (1H, s, N(1)H), 7.89 (1H, d, JN(3)H,4-H¼2.3 Hz,
N(3)H), 7.72e7.78 (2H, m, AA0 part of AA0XX0 spin system, C(2)H and
C(6)H in 4-MeC6H4), 7.43e7.49 (2H, m, XX0 part of AA0XX0 spin
3
16.2 (CH3), 8.0 (CH3 in Et). IR (Nujol)
NH), 2205 (s), 2179 (s) ( C^N), 1660 (sh), 1655 (s) [NHeC(]N)e
NH], 1599 (w) ( CC in Ts), 1523 (s) [NHeC(]N)eNH], 1492 (w) ( CC
in Ts), 1309 (s) (nas SO2), 1155 (s) (ns SO2), 810 (s) ( CHarom). Anal.
n
, cmꢁ1: 3193 (s), 3057 (s) (
n
system, C(3)H and C(5)H in 4-MeC6H4), 4.57 (1H, br d, J5-H,4-
n
¼3.7 Hz, 5-H), 4.21 (1H, d,
A part of AC spin system,
H
n
n
2JAC¼14.1 Hz, CH(A)eSO2), 4.16 (1H, d, B part of AC spin system,
3
3
d
2JAC¼14.1 Hz, CH(B)eSO2), 3.86 (1H, ddt, J4-H,CH2¼5.6, J4-H,5-
3
Calcd for C15H18N4O2S: C, 56.59; H, 5.70; N, 17.60. Found: C, 56.41; H,
5.81; N, 17.61.
¼3.7, J4-H,N(3)H¼2.3 Hz, 4-H), 2.41 (3H, s, CH3 in Ts), 1.54 (2H,
H
3
3
dq, JCH2,CH3¼7.4, J4-H,CH2¼5.6 Hz, CH2 in Et), 0.67 (3H, t,
Method B. To a stirred solution of KOH (0.214 g, 3.81 mmol) in
EtOH (6 mL) at rt was added tosylacetone (6) (0.810 g, 3.82 mmol)
at once. After 4 min to the obtained solution were added guanidine
3a (1.075 g, 3.83 mmol) and EtOH (6.8 mL). The resulting solution
was stirred at rt for 7 h, then at reflux for 1.5 h. The reaction mixture
was neutralized with 18% aqueous solution of HCl to pH 5, the
solvent was removed under vacuum and the oily residue was trit-
urated with light petrol (2ꢂ3 mL) followed by decantation. To the
obtained residue was added saturated aqueous solution of NaHCO3
(4 mL) and the mixture was allowed to stand overnight at rt. Upon
cooling to 0 ꢀC, the precipitate was filtered, washed with ice-cold
water, hexane, and dried to give 0.777 g (64%) of 8a (Table 1, en-
try 6) as a white solid.
3JCH3,CH2¼7.4 Hz, CH3 in Et). 13C NMR (75.48 MHz, DMSO-d6)
d:
155.6 (C(2)), 144.6 (C(4) in 4-MeC6H4), 135.1 (C(1) in 4-MeC6H4), 129.7
(C(3) and C(5) in 4-MeC6H4), 128.1 (C(2) and C(6) in 4-MeC6H4), 124.8
(C(6)), 116.8 (C^N), 105.8 (C(5)), 56.7 (CH2eS), 51.4 (C(4)), 29.8 (CH2
in Et), 21.1 (CH3 in Ts), 7.7 (CH3 in Et). IR (Nujol)
3080 (m) ( NH), 2185 (s) ( C^N), 1697 (m) ( C]C), 1643 (s), 1632
(s), 1622 (sh) [NHeC(]N)eNH], 1537 (s) [NHeC(]N)eNH], 1495
(w) ( CC in Ts),1323 (s) (nas SO2),1163 (s) (ns SO2), 812 (s) ( CHarom).
n
, cmꢁ1: 3202 (s),
n
n
n
n
d
Anal. Calcd for C15H18N4O2S: C, 56.59; H, 5.70; N, 17.60. Found: C,
56.41; H, 5.71; N, 17.93.
4.1.8. 2-Cyanimino-4-propyl-6-(tosylmethyl)-1,2,3,4-tetrahydropyri-
midine (11b). Compound 11b was synthesized as a white solid in
the same way as 11a by refluxing hydroxypyrimidine 7b (0.257 g,
0.73 mmol) and TsOH$H2O (0.042 g, 0.22 mmol) in EtOH (3 mL) for
2 min. The obtained product (0.224 g, 93%) was a mixture of 11b
and 8b in a ratio of 94:6 (Table 2, entry 6). An analytically pure
sample of 11b was obtained by crystallization from EtOH. Mp
4.1.6. 2-(Cyanimino)-6-methyl-4-propyl-5-tosyl-1,2,3,4-tetrahydro-
pyrimidine (8b). Compound 8b was synthesized as a white solid in
the same way as 8a according to Method A from tosylacetone (6)
(0.681 g, 3.21 mmol), KPH (0.188 g, 3.36 mmol) and guanidine 3b
(0.944 g, 3.21 mmol) in EtOH (8 mL) at rt for 47.3 h. The obtained
product (0.874 g) was a 98:2 mixture of 8b and hydroxypyrimidine
7b (two diastereomers, 67:33) (Table 1, entry 11). The yield calcu-
lated for pure 8b is 82%. An analytically pure sample of 8b was
obtained by crystallization from MeCN. Mp 225e226 ꢀC (decomp.,
236.5e237 ꢀC (decomp., EtOH). 1H NMR (300.13 MHz, DMSO-d6)
d:
8.83 (1H, unresolved dd, 4JN(1)H,N(3)H¼1.9, 4JN(1)H,5-H¼1.6 Hz, N(1)H),
4
7.88 (1H, unresolved ddd, 3JN(3)H,4-H¼2.4, JN(3)H,N(1)H¼1.9, 4JN(3)H,5-
¼1.6 Hz, N(3)H), 7.72e7.77 (2H, m, AA0 part of AA0XX0 spin sys-
H
tem, C(2)H and C(6)H in 4-MeC6H4), 7.43e7.49 (2H, m, XX0 part of
MeCN). 1H NMR (300.13 MHz, DMSO-d6)
d: 10.24 (1H, s, N(1)H), 8.86
AA0XX0 spin system, C(3)H and C(5)H in 4-MeC6H4), 4.56 (1H, dt, 3J5-
(1H, d, 3JN(3)H,4-H¼3.9 Hz, N(3)H), 7.69e7.75 (2H, m, AA0 part of AA0XX0
spin system, C(2)H and C(6)H in 4-MeC6H4), 7.41e7.46 (2H, m, XX0 part
of AA0XX0 spin system, C(3)H and C(5)H in 4-MeC6H4), 4.12 (1H, ddd,
¼4.1, 4J5-H,N(1)H¼4J5-H,N(3)H¼1.6 Hz, 5-H), 4.22 (1H, d, A part of
H,4-H
2
AC spin system, JAC¼14.2 Hz, CH(A)eSO2), 4.16 (1H, d, B part of
2
3
AC spin system, JAC¼14.2 Hz, CH(B)eSO2), 3.87 (1H, ddt, J4-
3
3
3
3
3J4-H,CH(A)¼7.5, J4-H,N(3)H¼3.9, J4-H,CH(B)¼3.8 Hz, 4-H), 2.39 (3H, s,
¼5.7, J4-H,5-H¼4.1, J4-H,N(3)H¼2.4 Hz, 4-H), 2.41 (3H, s, CH3 in
H,CH2

6888
A.D. Shutalev, A.A. Fesenko / Tetrahedron 67 (2011) 6883e6888
3. Crystallization of the diastereomeric mixtures of 7a,b from MeCN gave the
practically pure major isomers of these compounds (98 mol % according to 1H
NMR data).
Ts), 1.23e1.37 and 0.95e1.17 (2H each, two m, CH2CH2 in Pr), 0.81
(3H, t, 3JCH3,CH2¼7.2 Hz, CH3 in Pr). 13C NMR (75.48 MHz, DMSO-d6)
4. Previously16 we proposed a convenient criterion for the determination of the
substituent orientation at C4 and C6 in hexahydropyrimidine-2-thiones/ones,
which was based on the values of vicinal coupling constants JN(1)H,6-H and JN(3)
d: 155.6 (C(2)), 144.6 (C(4) in 4-MeC6H4), 135.0 (C(1) in 4-MeC6H4),
129.7 (C(3) and C(5) in 4-MeC6H4), 128.2 (C(2) and C(6) in 4-MeC6H4),
124.6 (C(6)), 116.8 (C^N), 106.2 (C(5)), 56.7 (CH2eS), 50.3 (C(4)), 39.3
(CH2 in Pr), 21.1 (CH3 in Ts), 16.5 (CH2 in Pr),13.7 (CH3 in Pr). IR (KBr)
.
H,4-H
5. The PM6 and AM1 calculations were carried out using the Mopac 2009 (James J.
P. Stewart, Stewart Computational Chemistry, Version 9.211W, http://open-
mopac.net/index.html).
6. Deslongchamps, P. Stereoelectronic Effects in Organic Chemistry; Pergamon:
Oxford, 1983.
n
, cmꢁ1: 3430 (s), 3207 (s), 3080 (s) (
n
NH), 2183 (s) (
C]C), 1637 (s), 1627 (s) [NHeC(]N)eNH], 1598 (w) (H CC in
Ts), 1539 (s) [NHeC(]N)eNH], 1497 (w) (H CC in Ts), 1320 (s) (Has
SO2), 1162 (s) ns SO2), 811 (s) CHarom). Anal. Calcd for
n C^N), 1700
(m) (
n
(
(d
7. (a) Shutalev, A. D.; Fesenko, A. A.; Lonina, N. N. Proceedings of ECSOC-8, the
Eight International Electronic Conference on Synthetic Organic Chemistry, Pa-
C16H20N4O2S: C, 57.81; H, 6.06; N, 16.85. Found: C, 58.05; H, 6.26; N,
16.75.
ꢀ
per A009 CD-ROM edition In. Seijas, J. A., Vazquez Tato, M. P., Eds.; November
1e30, 2004; ISBN 3-906980-15-4;; http://www.mdpi.org/ecsoc-8.htm Published in
2004 by MDPI, Basel, Switzerland; (b) Fesenko, A. A.; Tullberg, M. L.; Shutalev, A. D.
Tetrahedron 2009, 65, 2344e2350; (c) Fesenko, A. A.; Shutalev, A. D. Tetrahedron
2010, 66, 7219e7226.
Acknowledgements
8. Spectral characteristics of 13a: 1H NMR (300.13 MHz, DMSO-d6)
d: 9.90 (1H, d,
3
4
4JN(3)H,N(1)H¼1.8 Hz, N(3)H), 8.38 (1H, dd, JN(1)H,6-H¼5.0, JN(1)H,N(3)H¼1.8 Hz,
N(1)H), 7.70e7.75 (2H, m, AA0 part of AA0XX0 spin system, C(2)H and C(6)H in 4-
MeC6H4), 7.41e7.47 (2H, m, XX0 part of AA0XX0 spin system, C(3)H and C(5)H in 4-
MeC6H4), 4.71 (1H, s, CH in H2C¼), 4.38 (1H, br s, 5-H), 4.08 (1H, s, CH in
H2C]), 3.78e3.86 (1H, m, 6-H), 2.42 (3H, s, CH3 in Ts), 1.25e1.50 (2H, m, CH2 in
We thank Dr. Andrei Guzaev (AM Chemicals LLC, Oceanside, CA,
U.S.A.) for helpful discussions. A.A.F is grateful for financial support
from the President of the Russian Federation (programme for the
support of young scientists, grant no. MK-4400.2011.3).
Et), 0.83 (3H, t, 3JCH3,CH2¼7.4 Hz, CH3 in Et). 13C NMR (75.48 MHz, DMSO-d6)
d:
154.01 (C(2)), 144.93 (C(4) in 4-MeC6H4), 133.64 (C(1) in 4-MeC6H4), 130.50 (C(4))
,
129.57 (C(3) and C(5) in 4-MeC6H4), 129.00 (C(2) and C(6) in 4-MeC6H4), 117.07
(C^N), 100.17 (]CH2), 63.47 (C(5)), 48.51 (C(6)), 28.06 (CH2 in Et), 21.18 (CH3 in
Ts), 9.59 (CH3 in Et).
Supplementary data
9. Spectral characteristics of 13b: 1H NMR (300.13 MHz, DMSO-d6)
d: 9.89 (1H, d,
Supplementary data associated with this article can be found in
the online version, at doi:10.1016/j.tet.2011.06.088. These data in-
clude MOL files and InChIKeys of the most important compounds
described in this article.
3
4
4JN(3)H,N(1)H¼1.8 Hz, N(3)H), 8.38 (1H, dd, JN(1)H,6-H¼5.0, JN(1)H,N(3)H¼1.8 Hz,
N(1)H), 4.72 (1H, s, CH in H2C]), 4.35 (1H, br s, 5-H), 4.08 (1H, s, CH in H2C]),
3.88e3.96 (1H, m, 6-H), 2.42 (3H, s, CH3 in Ts). Signals of other protons overlap
with proton signals of compounds 7b, 8b and 11b.
10. (a) O’Connor, D. E.; Lyness, W. I. J. Am. Chem. Soc. 1964, 86, 3840e3846; (b)
Broaddus, C. D. Acc. Chem. Res. 1968, 1, 231e238; (c) Hirata, T.; Sasada, Y.; Oh-
tani, T.; Asada, T.; Kinoshita, H.; Senda, H.; Inomata, K. Bull. Chem. Soc. Jpn. 1992,
65, 75e96.
References and notes
11. (a) Lin, P.; Whitham, G. H. J. Chem. Soc., Chem. Commun. 1983, 1102e1103; (b)
Shimizu, I.; Ohashi, Y.; Tsuji, J. Tetrahedron Lett. 1984, 25, 5183e5186; (c) Padwa,
A.; Bullock, W. H.; Dyszlewski, A. D. Tetrahedron Lett. 1987, 28, 3193e3196; (d)
Barre, V.; Uguen, D. Tetrahedron Lett. 1987, 28, 6045e6048; (e) Padwa, A.;
Bullock, W. H.; Dyszlewski, A. D. J. Org. Chem. 1990, 55, 955e964.
12. Field, L.; Clark, R. D. Org. Synth. 1958, 38, 62e63.
1. (a) Shutalev, A. D.; Kuksa, V. A. Chem. Heterocycl. Compd. 1995, 31, 86e91; (b)
Shutalev, A. D.; Kuksa, V. A. Chem. Heterocycl. Compd. 1997, 33, 91e95; (c)
Shutalev, A. D. Chem. Heterocycl. Compd. 1997, 33, 1469e1470; (d) Shutalev, A.
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13. Similarly, compound 7a was obtained by using MeCN as a solvent at rt for 7.7 h
(Table 1, entry 3).
14. Crystallization of compounds 7 was performed as quickly as possible using
previously heated solvent to prevent the formation of dehydration products 8,
11 and 13.
15. Similarly, compound 7b was obtained by using MeCN as a solvent at rt (Table 1,
entries 8e10).
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