On triazoles XLII [1,2]. A new convenient method for the N-alkylation of highly insoluble cyclic amides

Article abstract of DOI:10.1002/jhet.5570380136

A simple N-alkylation method of highly insoluble cyclic amides based on the high solubility of their easily isolable tetraalkylammonium and tetraalkylphosphonium salts was elaborated. The method has a rather wide scope, it is not influenced by the identity of the different rings attached to the 1,2,4-triazolo[1,5-a]-pyrimidinone moiety of isomers 1 and 2, nor the presence of the triazole substituents. It proceeds smoothly without any unwanted by-products, at relatively low temperatures, and is not sensitive to moisture. The method allows an easy isolation of all possible N-alkylated derivatives 3, 7, and 8. Spectral analysis of isomers 3, 7, and 8 showed that our previous results concerning the formation of 3 type N-alkylated derivatives as main products of the N-alkylations as well as the tautomeric structure of the non-alkylated isomers 1 and 2 is correct. However, it also showed that the isolation of a single N-alkylated isomer 3 and its comparison with the corresponding non-alkylated derivative to prove its tautomeric structure may lead to mistakes.

Full text of DOI:10.1002/jhet.5570380136

Jan-Feb 2001
On Triazoles XLII [1,2]. A New Convenient Method for
the N-Alkylation of Highly Insoluble Cyclic Amides
Gábor Berecz and József Reiter*
237
EGIS Pharmaceuticals Ltd., P. O. Box 100, H-1475 Budapest, Hungary
Received April 12, 2000
A simple N-alkylation method of highly insoluble cyclic amides based on the high solubility of their easily
isolable tetraalkylammonium and tetraalkylphosphonium salts was elaborated. The method has a rather wide
scope, it is not influenced by the identity of the different rings attached to the 1,2,4-triazolo[1,5-a]-
pyrimidinone moiety of isomers 1 and 2, nor the presence of the triazole substituents. It proceeds smoothly
without any unwanted by-products, at relatively low temperatures, and is not sensitive to moisture. The
method allows an easy isolation of all possible N-alkylated derivatives 3, 7, and 8. Spectral analysis of
isomers 3, 7, and 8 showed that our previous results concerning the formation of 3 type N-alkylated
derivatives as main products of the N-alkylations as well as the tautomeric structure of the non-alkylated
isomers 1 and 2 is correct. However, it also showed that the isolation of a single N-alkylated isomer 3 and its
comparison with the corresponding non-alkylated derivative to prove its tautomeric structure may lead to
mistakes.
J.Heterocyclic Chem., 38, 237 (2001).
Elucidation of the tautomeric structure of different 6-and
7-substituted [1,2,4]triazolo[1,5-a]pyrimidin-5-ones of
above alkylations strongly depended on the solubility of the
sodium salts in dimethylformamide, which can lead to dif-
ficulty during isolation of the products from the very
diluted dimethylformamide containing solutions. Moreover
the above methods enabled the isolation of the main N-
alkylated products only. Luckily the isolated N-alkylated
products of type 3 and 4 (Scheme 1) contain the same chro-
mophore systems as derivatives 1 and 2, respectively, mak-
ing their structure elucidation possible [2-10]. However, in
spite of their similarities, doubts still remained concerning
the validity of identifying the above structural pairs by
comparing the spectral data. To solve this problem
unambiguously we wanted to synthesize all possible
N-alkylated isomers of type 1 and that of their O-alkylated
analogues, i.e. derivatives 7-9 as well as compounds 3
(Scheme 3).
1
2
type 1 (1, R , R = alkyl) [3], their [1,2,4]triazolo[1,5-a]-
1
2
pyrimidin-7-one isomers of type 2 (2, R , R = alkyl) [3],
1
2
cycloalka[d]- (1, R + R = (CH )
)[4,5], and
2 3-10
1
2
cycloalka[e]- analogues (2, R + R = (CH ) )[4,5], and
the corresponding nitrogen (1 and 2, R + R = (CH ) -NR-
(CH ) )[6-8] and sulphur (1 and 2, R + R = (CH ) -S-
2 3-10
1
2
2 n
1
2
2 m
2 n
(CH ) )[9,10] containing hetero analogues required model
2 m
It was known [11] that the N-alkylation of different
cyclic amides can be performed in two-phase (liquid-
liquid or solid-liquid) systems using phase transfer
catalysts (quaternary ammonium or phosphonium salts).
Brändström [12] successfully isolated the stoichiometric
crystalline tetrabutylammonium salts (10) of weak
CH-acids like methyl 2,4-dioxovalerate (10z, X = COCH ,
3
Y = COOMe) and methyl cyanoacetate (10w, X = CN,
compounds of "fixed" tautomeric structures, like that of
derivatives 3 and 4 (Scheme 1). They were synthesized by
the N-alkylation of the corresponding sodium salts 5 and 6
(Scheme 2) prepared either in situ with sodium hydride in
dimethylformamide [2,4,6-9] or in advance in hot sodium
hydroxide solution [3,6,10]. However, the yields of the

238
G. Berecz and J. Reiter
Vol. 38
water thereby lowering their yields when extracted with
chloroform. However, in some cases [e.g. in case of
2-amino-1,2,4-triazolo[5,1-b]quinazolin-5-one (1j, Q =
Y = OMe) (Scheme 4) that were fairly soluble in chloro-
form and their chloroform solutions could be C-alkylated
at room temperature to yield monoalkylated derivatives
(11z and 11w, respectively) as well as a small amount of
the dialkylated products (12z and 12w, respectively).
The above results led us to the idea that derivatives 1
could also form crystalline stoichiometric tetraalkyl-
ammonium salts (13) (Scheme 5) that may be soluble in
simple low boiling organic solvents and thus could have
been N-alkylated to produce the mixture of derivatives 3, 7
and 8 (Schemes 1 and 3).
1
2
amino, R + R = (CH ) ] even the tetrabutylammonium
2 4
salt was fairly soluble in water thus it was necessary to
extract the reaction mixture several times with chloroform.
3
4
The tetrabutylammonium salts 13 (R = R = butyl,
Scheme 5) obtained were nicely soluble even at room
temperature in all common low boiling organic solvents
such as acetonitrile, 2-propanol, benzene, dichloro-
methane, etc., enabling their N-alkylation with alkyl
halides in homogeneous systems either at room
temperature or at the boiling points of the corresponding
solvents. The reactions were not sensitive to moisture,
proceeded smoothly without any unwanted by-products,
the N-alkylations reaction time was relatively short and the
main products usually crystallised in pure form from the
reaction mixtures. Because the only by-product of the
reaction was the corresponding tetrabutylammonium
halogenide, all N-alkylated isomers could be easily
isolated by evaporating the mother liquors to dryness and
chromatography of the residues (Tables V, VII and IX, for
their spectral data see Tables VI, VIII and X).
The tetraalkylammonium salts 13, which are derivatives of
1, were prepared by simple shaking of the corresponding
amides 1 in a mixture of 1 N sodium hydroxide solution and
the corresponding quaternary ammonium salt in chloroform
at room temperature for 5-10 minutes. After separating the
phases the chloroform layer was washed with water, dried and
evaporated in vacuo to dryness to yield the corresponding
tetraalkylammonium salts (13). Compounds 13 were usually
obtained in crystalline form that was pure enough for N-alkyl-
ation (Table I, for their spectral data see Table II). However, if
necessary, they could easily be recrystallised from an
appropriate solvent (ethyl acetate, diisopropyl ether, etc.).
Comparing the different tetralkylammonium salts (13)
the tetrabutylammonium ones proved to be the most
convenient. The corresponding benzyltriethylammonium
or tetraethylammonium salts were a bit more soluble in
As expected the most reactive alkyl halides, such as
methyl iodide reacted just at room temperature giving,
within a few minutes, high yields (up to 85%) of the main
alkylated products, while the reaction of alkyl chlorides
was a bit more sluggish requiring boiling of the reaction
mixtures.

Jan-Feb 2001
A New Convenient Method for the N-Alkylation of Highly Insoluble Cyclic Amides
239
To compare the productivity of our new N-alkylation
method with those N-alkylation methods known from the
literature we compared the yields of the N-benzylated
1
2
products of 1f [Q = methylthio, R + R = (CH ) ] obtained
2 4
with benzyl chloride using different type alkylations
(Table III).
As the data in Table III show, in addition to the simple
reaction conditions, our method gave, in some cases, better
yields of the main N-benzylated product 3f/6. Also,
isomers 7f/6 and 8f/6 could be isolated from the mother
liquors (see Note [13]).
To prove the rather wide scope of our N-alkylation reac-
tion, tetrabutylammonium salts of five different
2-methylthio-cycloalka[d][1,2,4]triazolo[1,5-a]pyrimidin-
1
2
5-ones (13e-i, Q = methylthio, R + R = (CH )
,
2 3,4,5,6, and 10
Table I
Mp (°C)
1
2
Compound
R
R
Q
Lit
mp
(°C)
Yield
(%)
Molecular
Formula
(MW)
Analysis
Calcd/Found
(cryst. from)
C
H
N
S
13a
13b
13c
13d
13e
13f
Me
Me
Me
H
H
H
SMe
87
94
94
99-101
(EtOAc)
C
C
C
H
N OS
63.12
63.32
64.47
64.36
65.09
64.89
69.56
69.67
64.75
64.66
65.37
65.44
65.94
66.05
66.49
66.66
68.40
68.26
67.22
67.37
67.40
67.32
69.96
70.12
60.56
60.51
67.56
67.44
9.90
10.11
10.17
10.42
10.29
10.44
10.51
10.76
9.78
16.00
15.88
15.04
14.99
14.60
14.68
16.22
16.08
15.10
15.01
14.66
14.75
14.24
14.08
13.85
13.72
12.46
12.32
18.81
18.95
16.26
16.22
13.98
14.06
14.13
14.02
14.77
14.68
7.33
7.26
6.88
6.77
6.68
6.57
23 43
5
437.70
N OS
i
S Pr
59-66
H
25 47
5
i
( Pr O)
465.75
N OS
2
SBu
57-60.5
H
26 49
5
(cyclohexane)
479.78
H N O
25 45 5
431.67
H N OS
25 45 5
463.73
H N OS
26 47 5
477.76
H N OS
27 49 5
491.79
H N OS
28 51 5
505.82
H N OS
32 59 5
-(CH ) -H
91126
12C3-
2 4
(EtOAc)
(EtOAc)
(EtOAc)
-(CH ) -SMe
85111.5 110.5C-
6.91
7.13
6.71
6.54
6.52
6.67
6.34
6.28
5.71
5.54
2 3
9.98
9.92
-(CH ) -SMe
95107
105C-
127C-
100C-
2 4
10.21
10.04
10.28
10.16
10.35
10.58
10.76
10.38
10.62
10.14
10.35
10.73
10.89
9.15
13g
13h
13i
-(CH ) -SMe
[5]
[5]
[5]
100138
127-138
98110
100-110
100
2 5
-(CH ) -SMe
2 6
-(CH ) -SMe
oily
crystals
oil
C
2 10
oily crystals
561.92
C H N O
25 46
13j
-(CH ) -NH
96
16C3-
96C-
98
99 95-
2 4
2
6
446.69
N O
13k
13l
-(CH ) -M
91866
9399
H
2 4
29 52
6
2
(EtOAc)
516.78
H N O
35 64 6
-(CH ) -M
2 10
2
(ether/EtOAc)
121-124
(EtOAc)
C
600.94
N OS
2
13m
13n
-(CH ) -S-
SMe
C
H
12.93
13.04
5.64
2 3
25 45
5
495.80
H N OS
32 52 6
568.88
9.44
9.21
9.33
-CH NBn(CH ) -SMe
91
2
2 2
(ether/EtOAc)
5.66
M: morpholin-4-yl.

240
G. Berecz and J. Reiter
Vol. 38

Jan-Feb 2001
A New Convenient Method for the N-Alkylation of Highly Insoluble Cyclic Amides
241
Table III
1
2
Comparison of Different type N-Benzylations of 1f [Q = methylthio, R +R = (CH ) ] with Benzyl Chloride
2 4
Method
Type of Salt
Deprot.
Agent
Solvent
DMF
Reaction
Conditions
room temp, 3 days
Isolated yield
of 3f/6
Isolated yield
Isolated yield
of 7f/6
of 8f/6
39%
+
o
Traditional
Na
NaH
70 , 10 hours
50 %
39 %
o
150 , 4 hours
Classical
PTC
NaOH/
+
+
-
o
Na
Bu N Br
CH Cl /H O
60 , 12 hours
60 %
4
2
2
2
(catalytic amount)
+
o
Our New
PrOMHethod
Bu N Salt
CH CN
80 , 1 hour
61 %
61 %
67 %
4.7 %
0.7 %
4
3
o
80
stoichio-2-
metric
, 1 hour
o
Benzene
80 , 1 hour
Derivatives 7 and 8 were isolated by column chromatography
Table IV
The Ratio of Isolated Isomeric N-Alkylated Proucts 3,7 and 8 Formed During the
Alkylation of Some Tetrabutyammonium Salts 13 with Benzyl Chloride in Acetonitrile
1
2
Compound
R
R
Q
Isolated Yield
(%)
3/6
7/6
8/6
i
13b [a]
13e
13f
13g
13h
13i
13k
13l
Me
H
S Pr
58
6
0.5
0.7
2.3
3
5.2
0.6
2
1.3
-(CH ) -SMe
77
61
56
54
32
3
2 3
-(CH ) -SMe
4.7
15
15
2 4
-(CH ) -SMe
2 5
-(CH ) -SMe
2 6
-(CH ) -SMe
24
2 10
-(CH ) -
M
M
SMe
76
41
52
10
19
0.2
2 4
-(CH )
-
2 10
13m
-(CH ) -S-
13
2 3
[a] Alkylated with 4-chlorobenzyl chloride. Derivatives 7 and 8 were isolated by column chromatography. M = morpholin-4-yl.
3
4
ω-N-alkylated derivatives 3k and 3l [Q = morpholin-4-yl,
respectively, R = R = n-butyl) (Scheme 5) were
N-benzylated in boiling acetonitrile, and in each case all
three N-benzylated isomers [3e-i/6, 7e-i/6 and 8e-i/6, Q =
1
2
R + R = (CH ) and (CH ) , respectively](Scheme 1,
2 4
2 10
Table IV). However, quite unexpectedly, in these cases the
1
2
corresponding 1-N-benzylated products 7k and 7l [Q =
methylthio, R = benzyl, R + R = (CH )
respectively] were isolated (Table IV).
Next the isomeric tetrabutyammonium salts 14e and 14i
(Q = methylthio, R + R = (CH ) and (CH )
respectively,) (Scheme 6) derived from derivatives of type
2 were in case of 14e N-benzylated with benzyl chloride in
boiling acetonitrile to yield the expected ω-N-benzylated
main product 4e/6 (Q = methylthio, R + R = (CH ) , R =
benzyl) with 70% yield and in case of 14i N-methylated in
,
2 3,4,5,6, and 10
1
2
morpholin-4-yl, R + R = (CH ) and (CH )
,
2 4
2 10
respectively] (Scheme 3) were not the most abundant
minor products of the reaction as observed in the previous
experiments, but just to the contrary in the mother liquors
1
2
,
2 3
2 10
1
2
of 3k and 3l [Q = morpholin-4-yl, R + R = (CH ) and
2 4
(CH ) , respectively] derivatives 8k and 8l [Q =
2 10
1
2
1
2
morpholin-4-yl, R + R = (CH ) and (CH )
,
2 4
2 10
2 3
respectively] were present in approximately 10-20% yield
and those of derivatives 7k and 7l [Q = morpholin-4-yl,
acetonitrile at room temperature with methyl iodide to
yield 4i/1 (Q = methylthio, R + R = (CH ) , R =
1
2
1
2
R + R = (CH ) and (CH ) , respectively] were present
2 4
2 10
2 10
in very low concentrations (Table IV). This fact is contrary
to previous literary observations [14], where the nitrogen
atom at position 3 of the 1,2,4-triazolo[1,5-a]pyrimidin-5-
ones can be only hardly alkylated.
A possible explanation for the results above can be
given by taking in account the coplanarity of the
2-S-methyl substituents with the 1,2,4-triazolo[1,5-a]-
pyrimidinone moiety of 13f (Scheme 7), which is
methyl) with 62% yield.
Our N-alkylation reaction proceeds independently of the
identity of the Q substituents in derivatives 1 as proved by
the N-alkylation of the corresponding 2-(morpholin-4-yl)-
cycloalka[d][1,2,4]triazolo[1,5-a]pyrimidin-5-one
tetrabutylammonium salts 13k and 13l [Q = morpholin-4-
1
2
3
4
yl, R + R = (CH ) and (CH ) , respectively, R = R =
2 4
2 10
n-butyl] (Scheme 5) to yield as main products again the

242
G. Berecz and J. Reiter
Vol. 38
Table V
1
2
Compund
R
R
R
Q
Lit
mp
(°C)
Reaction
time
(hours)
Yield
(%)
Mp (°C)
(cryst from)
Molecular
Formula
(MW)
Analysis
Calcd/Found
C
H
N
S
3a/1
3a/3
3a/6
3b/7
3c/1
3c/3
3d/6
3e/6
3f/1
Me
Me
Me
Me
Me
Me
H
H
H
H
H
H
Me
SMe
Lit [3]
213-215
12
(25 °C)
6
78
62
53
58
56
55
212-214
C H N OS
45.70
45.84
52.36
52.44
58.72
58.80
55.09
54.92
52.36
52.33
57.11
57.23
68.55
68.50
61.52
61.48
52.78
52.88
4.79 26.65
4.88 26.52
6.39 22.20
6.55 22.09
4.93 19.57
5.11 19.55
4.91 16.06
4.88 16.21
6.39 22.20
6.54 22.16
7.53 19.03
7.66 18.90
5.75 19.99
5.93 20.11
5.16 17.93
5.43 18.02
5.64 22.38
5.75 22.30
15.25
15.09
12.71
12.60
11.20
11.32
9.19
8
10 4
(CH CN)
210.26
N OS
3
n-Bu SMe
147-148
(EtOAc)
151.5-153
(EtOAc)
170-172
C
C
H
11 16
4
252.34
N OS
Bn
SMe
Lit [3]
145-147
6
7
5
6
H
14 14
4
286.36
C H ClN OS
16 17
i
Bn
(4-Cl)
Me
S Pr
4
(CH CN)
348.86
N OS
9.24
3
SBu
SBu
147-148
C
H
12.71
12.88
10.89
10.91
11 16
4
i
( Pr O/EtOAc)
252.34
N OS
2
n-Bu
H
77.5-78
(n-hexane)
C
C
H
14 22
4
294.42
H N O
16 16 4
280.33
H N OS
16 16 4
-(CH ) -Bn
3
38
77
191998-
2 4
(CH CN)
3
-(CH ) -Bn
SMe
Me
30
2221.5-
C
10.26
10.11
12.81
12.77
2 3
(CH CN)
312.40
H N OS
11 14 4
3
-(CH )
SMe
SMe
Bu N-salt
0.15
(25°C)
1
85
259-260
C
2 4-
4
(CH CN)
250.32
H N OS
13 18 4
3
Bu P-salt
65
16
4
i
3f/2
3f/4
3f/6
3g/6
3h/6
3i/6
3j/5
3k/6
3l/6
3m/6
-(CH ) -
Pr
34
206.5-207.5
(EtOAc)
C
56.09
56.13
56.50
56.42
62.55
62.48
63.50
63.55
64.38
64.40
67.28
67.33
62.26
62.36
65.74
65.66
69.46
69.62
55.79
55.84
66.16
66.02
6.52 20.13
6.67 20.23
5.84 20.27
5.90 20.21
5.56 17.16
5.60 17.25
5.92 16.46
6.11 16.40
6.26 15.81
6.52 15.99
7.36 13.65
7.56 13.58
8.01 24.20
7.95 24.30
6.34 19.16
6.35 19.02
7.85 15.58
7.88 15.51
4.68 16.27
4.78 16.33
5.55 16.77
5.67 16.68
11.52
11.47
11.60
11.64
9.82
10.01
9.42
9.38
9.05
8.94
7.81
7.88
2 4
278.38
H N OS
13 16 4
276.36
H N OS
17 18 4
-(CH ) -allyl
SMe
SMe
1.5
79
116689.5-
C
2 4
(CH CN)
3
-(CH ) -Bn
Lit
[4]
220-222
[5]
201-202
[5]
167.5-169
[5]
186-188
1
61
222422-
C
2 4
(CH CN)
326.42
H N OS
18 20 4
340.45
H N OS
19 22 4
354.48
H N OS
23 30 4
3
-(CH ) -Bn
SMe
Lit
Lit
1
56
202201-
(CH CN)
C
C
C
2 5
3
-(CH ) -Bn
SMe
1.5
1
54
1697.5-
2 6
(CH CN)
3
-(CH ) -Bn
SMe
Lit
32
11886-
2 10
(CH CN)
410.59
C H N O
15 23
3
-(CH ) -
n-Hex NH
M
4
4
2
8
6
27
76
41
52
46
227-229
2 4
2
5
(CH CN)
289.38
N O
3
-(CH ) -Bn
Lit
[4]
213-215
[5]
245.5-247.5
Lit [10]
236-238
Lit [7]
165-166
212109-
C
H
2 4
20 23
5
2
(CH CN)
365.44
H N O
26 35 5
3
-(CH ) -Bn
M
Lit
224457.5.5-
C
2 10
2
(CH CN)
449.60
N OS
2
3
-(CH ) -S-
Bn
SMe
SMe
239-241
C
H
18.62
18.58
7.68
2 3
16 16
4
(CH CN)
344.46
C H N OS
23 23 5
3
3n/6 -CH -NBn-(CH ) -Bn
1651-68(d)
2
2 2
(CH CN)
417.54
7.62
3
M = Morpholin-4-yl, Bn = benzyl, Bn(4-Cl) = 4-chlorobenzyl, n-Hex = n-hexyl
consistent with the X-ray diffraction spectra of some
analogous derivatives 15 and 16 (Scheme 8) [15-16], thus
enabling conjugation of the lone electron pair of the
sulphur atom with the 1,2,4-triazolo[1,5-a]pyrimidinone
ring system. This conjugation lowers the negative charge
(and consequently the nucleophilicity) of the nitrogen
atom at position 3. On the contrary, the 2-morpholin-4-yl
moiety of analogues 13k (Scheme 7) is strongly twisted
out of the plain compared to the 1,2,4-triazolo[1,5-a]-
pyrimidone ring system analogously to 17 (Scheme 9)
(for its X-ray diffraction spectra see [1]) thereby strongly
decreasing the conjugation of the lone electron pair of the
nitrogen atom with the conjugated double bonds of the
heterocyclic ring system. Consequently, it has little influ-
ence on the negative charge of the nitrogen atom at
position 3 which is now more negative (and thus more
nucleophilic) than the nitrogen atom at position 1.
The above facts are corroborated by the cmr spectra as
well. Thus while the coupling constant of the carbon atom
at position 2 of 13f coupled with the planar S-methyl
protons is 4.5 Hz (Scheme 7) the coupling constant of the
analogous carbon atom at position 2 of 13k coupled with
the strongly twisted morpholin-4-yl NCH protons is only
2
1.5 Hz (Scheme 7).

Jan-Feb 2001
A New Convenient Method for the N-Alkylation of Highly Insoluble Cyclic Amides
243

244
G. Berecz and J. Reiter
Vol. 38
Our N-alkylation reaction can be performed with the cor-
responding tetrabutylphosphonium salt 18 (Scheme 10) as
well. It was prepared analogously to the tetrabutylammo-
nium salts using tetrabutylphosphonium bromide instead of
the corresponding quaternary tetraalkylammonium salts.
This salt was also crystalline and soluble in common
organic solvents. Its N-alkylation in acetonitrile provided
again as the main product the ω-N-alkylated derivative 3f/1
(Scheme 10) that crystallised from the reaction mixtures.
However, the yield of this reaction was a bit lower than that
made with the corresponding tetrabutylammonium salt
(see the alkylations of 13f to yield 3f/1, Table V).
The O-alkylated derivatives 9 (Scheme 3) representing
the fourth possible isomer required for the structure
elucidation of the N-alkylated products were obtained by
analogy to the known methods [17-19] from the
corresponding 5-chloro derivative 19 (Scheme 11).
At last the methylation and benzylation of the tetrabutyl-
ammonium salt (21) of a thioamide, namely the
2-methylthio-6,7,8,9-tetrahydro-1,2,4-triazolo[5,1-b]-
quinazolin-5(10H)-thione (20) prepared by analogy to a
known method [20] was attempted. However, even though
the alkylation proceeded smoothly, in this case no N-alkyl-
ation occurred but instead the S-alkyl derivatives 22/1 and
22/6 (R = methyl and benzyl, respectively) were obtained
in high (86%) yield (Scheme 12).
The uv and cmr spectra of isomers 3, 7, 8 and 9 proved
the correctness of structures based on the analogy of the
uv and cmr spectral data of derivatives 3 and 1 reported
previously [3-10]. As expected they were very different
from each other. Thus the uv maxima of derivatives 3
recorded in ethanolic solution appeared as reported
previously [3-8] with two maxima at 229-237 and
272-285 nm (Table VI). The only exceptions observed
were from derivative 3d/6, the Q = H substituent did not
contain a lone electron pair, and consequently a
hypsochromic shift of the spectra was observed, and that
of compound 3m/6 where, just to contrary, the lone
electron pair of the sulphur atom of the thiacyclohexane
moiety is conjugated to the triazolo-pyrimidinone
chromophore thus causing a batochromic shift of the
spectra. The uv spectra of derivatives 7 recorded under
the same conditions were characterised also with two uv
maxima appearing at 221-227.5 and 284-291 nm
(Table VIII), derivatives 8 showed four uv maxima at
206-219, 240.5-246.5, 270.5-276.5 and 291.5-301 nm
(Table X) (the exceptions formed again derivatives 7d/6,
7m/6 and 8m/6 for the reasons discussed above), while
derivatives 9 showed three uv maxima at 210, 239-241
and 285-300 nm (see Experimental).
In the cmr spectra of derivatives 3 the carbon atoms 2, 5,
(ω-1)a and ωa (see Scheme 1, Table VI) appeared as
expected [3-8] at 163.0-164.8, 153.8-156.0, 144.5-153.5
and 150.2-152.8 ppm, respectively. Again the only
exceptions were compound 3d/6, where the carbon atom 2
of which appeared as a consequence of the CH group at

Jan-Feb 2001
A New Convenient Method for the N-Alkylation of Highly Insoluble Cyclic Amides
245
Table VII
1
2
Compound
R
R
R
Q
Lit. Reaction Yield Mp (°C)
Molecular
Formula
(MW)
Analysis
Calcd/Found
mp
time
(%) (cryst from)
(hours)
C
H
N
S
7a/3
7b/7
7c/1
Me
Me
Me
Me
H
n-Bu SMe
6
7
5
6
15
6
105-107
(c-hexane/
ether)
121-124
(c-hexane/
EtOAc)
123-125
(n-hexane/
ether)
C
H
252.34
N OS
52.36
52.44
6.39
6.56
22.20
22.09
12.71
12.65
11 16
4
i
H
H
H
Bn
(4-Cl)
S Pr
SBu
SBu
C
H
348.86
ClN OS
55.09
55.11
4.91
5.09
16.06
16.11
9.19
9.06
16 17
4
Me
3
C
H
N OS
52.36
52.28
6.39
6.44
22.20
22.25
12.71
12.77
11 16
4
252.34
7c/3
7d/6
7e/6
7f/1
7f/2
7f/4
7f/6
7g/6
7h/6
7i/6
n-Bu
H
10
77.5-79
(n-hexane)
C
C
C
H
N OS
57.11
57.08
68.55
68.46
61.52
61.65
52.78
52.86
56.09
55.98
56.50
56.44
62.55
62.60
63.50
63.47
64.38
64.44
67.28
67.39
62.26
62.36
65.74
65.77
69.46
69.38
55.79
55.84
7.53
7.65
5.75
5.83
5.16
5.32
5.64
5.78
6.52
6.59
5.84
5.96
5.56
5.79
5.92
6.07
6.26
6.52
7.36
7.54
8.01
8.35
6.34
6.45
7.85
7.89
4.68
4.85
19.03
19.11
19.99
19.78
17.93
17.88
22.38
22.28
20.13
20.32
20.27
20.18
17.16
17.08
16.46
16.55
15.81
15.88
13.65
13.70
24.20
24.32
10.89
10.94
14 22
4
294.42
H N O
16 16 4
-(CH ) -Bn
3
23 17117.50-
2 4
(EtOAc)
280.33
H N OS
16 16 4
-(CH ) -Bn
SMe
SMe
30
1
3
171068-
201097-
14
C
10.26
10.31
12.81
12.77
11.52
11.66
11.60
11.47
9.82
9.86
9.42
9.48
9.05
2 3
i
( Pr O)
312.40
H N OS
11 14 4
2
-(CH ) -Me
3
(25°C)
34
C
2 4
(EtOAc)
182-184
(EtOAc)
C
(ether)
C
(c-hexane)
C
(EtOAc)
C
250.32
H N OS
13 18 4
i
-(CH ) -
Pr
SMe
2 4
278.38
H N OS
13 16 4
276.36
H N OS
17 18 4
326.42
H N OS
18 20 4
340.45
H N OS
19 22 4
354.48
H N OS
23 30 4
410.59
C H N O
15 23
-(CH ) -allyl
SMe
SMe
SMe
SMe
SMe
1.5
1
4
5
13153.45-
2 4
-(CH ) -Bn
171371-
181784-
222423-
221131-
2 4
-(CH ) -Bn
1
15
15
2 5
-(CH ) -Bn
[5]
1.5
223-224
1
2 6
(benzene)
C
(benzene)
207-209
9.02
7.81
7.76
-(CH ) -Bn
[5]
24
2 10
211-213
7j/5
7k/6
7l/6
-(CH ) -
n-Hex NH
4
8
5
2 4
2
5
(CH CN)
289.38
N O
3
-(CH ) -Bn
M
M
4
2
0.6 191997-
C
(ether)
C
(ether)
192-194
(EtOAc/
H
2 4
20 23
5
2
365.44
H N O
26 35 5
-(CH ) -Bn
2
114453-
2 10
2
449.60
N OS
2
7m/6
-(CH ) -S-
Bn
SMe
13
C
H
16.27
16.23
18.62
18.66
2 3
16 16
4
344.46
C H N OS
23 23 5
CH CN)
3
7n/6
-CH -NBn-(CH ) -Bn
SMe
6
8
148-151(d)
66.16
66.24
5.55
5.68
16.77
16.85
7.68
7.62
2
2 2
(CH CN)
417.54
3
M = morpholin-4-yl, Bn = benzyl, Bn (4-Cl) = 4-chlorobenzyl, n-Hex = n-hexyl.
151.8 ppm, and derivative 3m/6, where as a consequence
of the thiacyclohexane sulphur atom attached to the
triazolo-pyrimidinone ring system carbon atoms 5 and
(ω-1)a appeared at 152.3 and 140.7 ppm, respectively.
In the cmr spectra of derivatives 7 the carbon atoms 2, 5,
(ω-1)a and ωa (see Scheme 3, Table VIII) appeared at
152.4-155.1, 154-157.1, 159.3-168.5 and 145.3-150.0
ppm, respectively, and in those of derivatives 8 appeared at
163.8-166.3, 154.0-157.6, 161.3-171.0 and 151.7-155.6
ppm, respectively (Table X) (the only exceptions formed
again derivatives 7d/6, 7m/6 and 8m/6 for the reasons
discussed above), while in those of derivatives 9 they
appeared at 167.6, 150.4-151.5, 165.6-165.7 and
156.1-156.2, respectively (see Experimental).
From the four chemical shifts corresponding to carbon
atoms 2, 5, (ω-1)a and ωa at least one always differed
significantly from all others, making possible a reliable basis
to differentiate between isomers 3, 7, 8 and 9. The present
results corroborated the structural decisions made earlier
[3-10]. However, they also showed that the chemical shifts of
the carbon atoms 2 and 5 of derivatives 3 and 8 are very
similar, thus a decision based on comparison of only these
two spectral data might lead to mistakes.
EXPERIMENTAL
Melting points were determined on a Koffler-Boëtius micro
apparatus and are not corrected. The infrared spectra were
obtained as potassium bromide pellets using a Perkin-Elmer 577

246
G. Berecz and J. Reiter
Vol. 38

Jan-Feb 2001
A New Convenient Method for the N-Alkylation of Highly Insoluble Cyclic Amides
247
spectrophotometer. The ultraviolet spectra were obtained by a
Varian Cary 1E UV-VIS spectrophotometer. The pmr and cmr
measurements were performed, if not stated otherwise, in
deuteriochloroform solutions using tetramethylsilane as internal
standard. Bruker WM-250 and Varian VXR-400 instruments,
standard Varian HSQC, HMBC and selective INEPT programs
were used. Ms spectra were acquired using a KRATOS MS 25
RFA double focusing instrument in EI and CI mode. The dry-
column flash chromatographies were performed according to
[21]. As adsorbents Aluminium oxide 60 G neutral (Merck 1090
for thin layer chromatography) and Silica gel 60 H (Merck 7736
for thin layer chromatography) were used. For preparative thin
layer chromatography pre-coated Merck plates were used under
the same conditions as for tlc measurements.
Typical Experiments for the Synthesis of Tetrabutylammonium
Salts (13).
2-Methylthio-6,7,8,9-tetrahydro-1,2,4-triazolo[5,1-b]quinazolin-
5(10H)-one tetrabutylammonium Salt (13f).
Using Tetrabutylammonium Hydrogen Sulphate.
A solution of 37.35 g (0.11 mole) of tetrabutylammonium
hydrogen sulphate (Fluka) in 100 ml of water was cooled to 5°
and at this temperature a solution of 8.80 g (0.22 mole) of
sodium hydroxide in 50 ml of water precooled to 5° was added
to it. To the solution obtained 23.63 g (0.1 mole) of
2-methylthio-6,7,8,9-tetrahydro-1,2,4-triazolo[5,1-b]quina-
1
2
zolin-5(10H)-one (1f, R + R = -(CH ) -, Q = methylthio) [4]
2 4
and 100 ml of chloroform was added in one portion and the
mixture was intensively stirred for 10 minutes. The lactame
dissolved within a short time during which the organic phase
turned yellow. The phases were separated, the water phase was
extracted with 50 ml of chloroform, the combined chloroform
phases were washed with 50 ml of water, dried over sodium
sulphate and evaporated in vacuo to dryness to yield 45.5 g
(95%) of crystalline tetrabutylammonium salt (mp 92-105°)
that after recrystallisation from 110 ml of ethyl acetate yielded
40.3 g (84%) of pure 2-methylthio-6,7,8,9-tetrahydro-1,2,4-
triazolo[5,1-b]quinazolin-5(10H)-one tetrabutylammonium salt
1
2
(13f, R + R = -(CH ) -, Q = methylthio) that melted at
2 4
105-107° (for the physical data of all 13 type tetrabutyl-
ammonium salts see Table I, for their spectral data see Table II).
Using Tetrabutylammonium Bromide.
To a solution of 3.23 g (0.01 mole) of tetrabutylammonium
bromide (Fluka) in 10 ml of water a solution of 0.44 g
(0.011 mole) of sodium hydroxide in 10 ml of water was added
at room temperature. To the solution obtained 2.36 g (0.01
mole) of 2-methylthio-6,7,8,9-tetrahydro-1,2,4-triazolo[5,1-b]-
1
2
quinazolin-5(10H)-one (1f, R + R = -(CH ) -, Q =
2 4
methylthio) [4] and 10 ml of chloroform was added in one
portion and the mixture was intensively shaken for 5 minutes.
The phases were separated, the aqueous phase was extracted
with 10 ml of chloroform, the combined chloroform phases
were washed with 5 ml of water, dried over sodium sulphate
and evaporated in vacuo to dryness to yield 4.38 g (92%) of
crystalline tetrabutylammonium salt that after recrystallisation
from 12 ml of ethyl acetate yielded 3.55 g (74%) of pure
2-methylthio-6,7,8,9-tetrahydro-1,2,4-triazolo[5,1-b]-
1
2
quinazolin-5(10H)-one tetrabutylammonium salt (13f, R + R
= -(CH ) -, Q = methylthio), mp 105-107° that was identical
2 4
with that of obtained in the previous experiment.

248
G. Berecz and J. Reiter
Vol. 38
Table IX
1
2
ο
Compound
R
R
R
Q
Lit. Reaction Yield
Mp ( C) Molecular Formula
Analysis
Mp
time
(%)
(cryst from)
(MW)
Calcd/Found
(°C) (hours)
C
H
N
S
i
8b/7
8e/6
8f/1
8f/6
8g/6
Me
H
Bn
(4-Cl)
SMe
S Pr
7
1.3
141-144
(ether)
C
(n-hexane)
C
(c-hexane)
C
(ether)
C
(c-hexane/
ether)
C
(ether)
C
C
H
ClN OS
55.09
55.17
61.52
61.48
52.78
52.66
62.55
62.63
63.50
63.38
4.91
5.08
5.16
5.22
5.64
5.73
5.56
5.65
5.92
5.99
16 17
4
348.86
H N OS
16 16 4
312.40
H N OS
11 14 4
250.32
H N OS
17 18 4
326.42
H N OS
18 20 4
340.45
H N OS
19 22 4
354.48
H N OS
23 30 4
-(CH ) -Bn
30
1
0.5
0.5
141845-
2 3
-(CH ) -Me
SMe
SMe
SMe
171774-
2 4
25°C
0.7 15125.51-
-(CH ) -Bn
1
2 4
-(CH ) -Bn
1
2.3
3
141543-
131936-
16.46
16.38
2 5
8h/6
8i/6
-(CH ) -Bn
SMe
SMe
M
1.5
64.38
64.45
67.28
67.12
65.74
65.79
6.26
6.44
7.36
7.51
6.34
6.45
15.81
15.74
13.65
13.60
19.16
19.11
9.05
8.98
7.81
7.69
2 6
-(CH ) -Bn
[5]
1
128-130
4
5.2
10
131028-
2 10
(ether)
410.58
N O
8k/6
-(CH ) -Bn
181886-
C
H
2 4
20 23
5
2
i
( Pr O/
365.44
H N O
26 35 5
2
EtOAc)
C
(ether)
166-169
(ether)
8l/6
-(CH ) -Bn
M
2
19
181280-
69.46
69.44
55.79
55.69
7.85
7.98
4.68
4.75
15.58
15.48
2 10
2
449.60
C H N OS
16 16
8m/6
-(CH ) -S-
Bn
SMe
8
0.2
2 3
4
2
344.46
Bn (4-Cl) = 4-chlorobenzyl, M: morpholin-4-yl.
A Typical Experiment for the N-Alkylation of Tetrabutyl-
ammonium Salts 13.
spectral data see Table VIII), and 14.5 mg (0.7%) of 3-benzyl-2-
methylthio-6,7,8,9-tetrahydro-1,2,4-triazolo[5,1-b]quinazolin-
1
2
5(3H)-one (8f/6, R + R = -(CH ) -, Q = methylthio, R =
2 4
o
benzyl), mp 151-152.5 (ether) (for the physical data of all 8 type
10-Benzyl-2-methylthio-6,7,8,9-tetrahydro-1,2,4-triazolo-
[5,1-b]quinazolin-5(10H)-one (3f/6), 1-Benzyl-2-methylthio-
6,7,8,9-tetrahydro-1,2,4-triazolo[5,1-b]quinazolin-5(1H)-one
(7f/6), and 3-Benzyl-2-methylthio-6,7,8,9-tetrahydro-1,2,4-
triazolo[5,1-b]quinazolin-5(3H)-one (8f/6).
derivatives see Table IX, for their spectral data see Table X).
Tetrabutylammonium Salts of the Isomeric Cyclopenta- and
Cyclododeca[e]-1,2,4-triazolo[1,5-a]pyrimidin-8- and -15-ones
(14e and 14i, Respectively).
To a solution of 3.07 g (0.0064 mole) of 2-methylthio-6,7,8,9-
Derivatives 14e and 14i were prepared analogously to the
tetrabutylammonium salts 13 starting from 2-methylthio-6,7-
dihydro-5H-cyclopenta[e]-1,2,4-triazolo[1,5-a]pyrimidin-
tetrahydro-1,2,4-triazolo[5,1-b]quinazolin-5(10H)-one
1
2
tetrabutylammonium salt (13f, R + R = -(CH ) -, Q =
2 4
methylthio) in 6.5 ml of acetonitrile 1.27 g (0.01 mole) of benzyl
chloride was added and the mixture refluxed for 1 hour. The crys-
tals that precipitated after cooling were filtered off and washed
with acetonitrile to yield 1.27 g (61%) of 10-benzyl-2-
methylthio-6,7,8,9-tetrahydro-1,2,4-triazolo[5,1-b]quinazolin-
1
2
8(9H)-one 2e (R + R = -(CH ) -, Q = methylthio) [9] and
2 3
2-methylthio-5,6,7,8,9,10,11,12,13,14-decahydro-cyclodo-
1
deca[e]-1,2,4-triazolo[1,5-a]pyrimidin-15(16H)-one 2i (R
+
2
R = -(CH ) -, Q = methylthio) [5], respectively. Derivative
2 10
14e was isolated in crystalline form, while the oily 14i was
methylated directly to 4i/1.
1
2
5(10H)-one (3f/6, R + R = -(CH ) -, Q = methylthio, R =
2 4
benzyl), mp 222-224° (acetonitrile) (for the physical data of all 3
type derivatives see Table V, for their spectral data see Table VI).
The mother liquor was evaporated to dryness and the residue
was partitioned between 20 ml of chloroform and 10 ml of water.
The phases were separated, the chloroform layer was washed
(in order to get rid of the water soluble tetrabutylammonium
chloride) with 2 x 10 ml of water, dried over sodium sulphate and
evaporated in vacuo to dryness. The residue was chroma-
tographed on a Silica gel 60 H column (eluents different mixtures
of benzene and chloroform of increasing polarities) to yield
98 mg (4.7%) of 1-benzyl-2-methylthio-6,7,8,9-tetrahydro-1,2,4-
2-Methylthio-6,7-dihydro-5H-cyclopenta[e]-1,2,4-triazolo-
[1,5-a]pyrimidin-8(9H)-one Tetrabutylammonium Salt (14e).
Compound 14e was obtained in 81% yield, mp 112-115° (ethyl
acetate/ether); pmr: δ, ppm 0.95 (t, 12H, 4 x CH ), 1.40 (m, 8H,
3
(CH ) ), 1.63 [m, 8H, (CH ) ], 2.11 (m, 2H, CH -6), 2.58 (s, 3H,
2 4
2 4
2
SCH ), 2.82 (t, 2H, CH -7), 3.08 (t, 2H, CH -5), 3.35 (m, 8H, 4 x
3
2
2
NCH ); cmr: δ, ppm 13.3 (4 x CH ), 13.9 (SCH ), 19.4
2
3
3
(4x CH CH ), 21.5 (C-6), 23.7 (4 x NCH CH ), 28.8 and 29.6
3
2
2
2
(C-5 and C-7), 58.5 (4 x NCH ), 117.6 (C-7a), 144.2 (C-4a),
2
1
2
triazolo[5,1-b]quinazolin-5(1H)-one (7f/6, R + R = -(CH ) -,
159.7 (C-9a), 161.6 (C-8), 169.8 (C-2).
2 4
Q = methylthio, R = benzyl) mp 171-173° (cyclohexane) (for the
Anal. Calcd. for C H N OS (MW 463.73): C, 64.75, H, 9.78,
25 45 5
physical data of all 7 type derivatives see Table VII, for their
N, 15.10, S, 6.91. Found: C, 64.70, H, 9.98, N, 14.97, S, 7.02.

Jan-Feb 2001
A New Convenient Method for the N-Alkylation of Highly Insoluble Cyclic Amides
249

250
G. Berecz and J. Reiter
Vol. 38
9-Benzyl-2-methylthio-6,7-dihydro-5H-cyclopenta[e]-1,2,4-
triazolo[1,5-a]pyrimidin-8(9H)-one (4e/6).
5-Benzyloxy-2-methylthio-6,7,8,9-tetrahydro-1,2,4-triazolo-
[5,1-b]quinazoline (9/6).
This compound was prepared analogously to derivatives 3
by benzylation of a solution of 250 mg (0.00054 mole) of
2-methylthio-6,7-dihydro-5H-cyclopenta[e]-1,2,4-triazolo-
[1,5-a]pyrimidin-8(9H)-one tetrabutylammonium salt 14e
To a mixture of 0.144 g (0.006 mole) of sodium hydride (240 mg
of 60% suspension Fluka washed with petroleum ether) and 15 ml
of absolute ether 0.65 g (0.006 mole) of freshly distilled benzyl-
alcohol was added. The mixture was stirred at room temperature
until the evolution of hydrogen ceased, at which time 1.27 g
(0.005 mole) of 5-chloro-2-methylthio-6,7,8,9-tetrahydro-1,2,4-
triazolo[5,1-b]quinazoline (19) [22] was added to the reaction
1
2
(R + R = -(CH ) -, Q = methylthio). Yield after dry column
2 3
flash chromatography (adsorbent Silica gel 60 H, eluent a 1:1
mixture of benzene and chloroform) 118 mg (70%), mp
o
-1
mixture which was stirred at 20 for an additional 3 hours. The
149-151° (cyclohexane/ethyl acetate). ir: ν C=O = 1668 cm ;
reaction mixture obtained was passed through a short silica gel
column and the column washed with 4 x 30 ml of ether. The
combined ether solutions were evaporated in vacuo to dryness, the
residue triturated with a mixture of cyclohexane and diisopropyl
ether and filtered to yield 0.98 g (60%) of the title product, mp
94-98° (dec); pmr (hexadeuteriobenzene): δ, ppm 1.21 (m, 2H,
CH -7), 1.27 (m, 2H, CH -8), 2.18 (t, 2H, CH -6), 2.53 (s, 3H,
pmr: δ, ppm 2.21 (m, 2H, CH -6), 2.63 (s, 3H, SCH ), 2.87
2
3
(t, 2H, CH -7), 3.16 (t, 2H, CH -5), 5.35 (s, 2H, PhCH ), 7.25
2
2
2
(m, 3H, PhH-3',4',5'), 7.6 (m, 2H, PhH-2',6'); cmr: δ, ppm 14.0
(SCH ), 21.3 (C-6), 28.2 (C-7), 30.1 (C-5), 46.5 (PhCH ),
3
2
116.6 (C-7a), 127.9 (PhC-4'), 128.3 (PhC-2',6'), 129.2
(PhC-3',5'), 135.5 (PhC-1'), 148.0 (C-4a), 152.0 (C-9a), 157.8
(C-8), 163.9 (C-2).
2
2
2
SCH ), 2.63 (t, 2H, CH -9), 5.50 (s, 2H, OCH ), 7.05 (m, 2H,
Anal. Calcd. for C H N OS (MW 312.40): C, 61.52, H,
3
2
2
16 16
4
PhH-2',6'), 7.20 (m, 3H, PhH-3',4',5'); pmr (deuteriochloroform):
5.16, N, 17.93, S, 10.26. Found: C, 61.32, H, 5.34, N, 18.03, S,
10.09.
δ, ppm 1.80 (m, 4H, CH -7,8), 2.60 (t, 2H, CH -6), 2.74 (s, 3H,
2
2
SCH ), 2.92 (t, 2H, CH -9), 5.88 (s, 2H, OCH ), 7.35 (m, 5H,
3
2
2
2-Methylthio-5,6,7,8,9,10,11,12,13,14-decahydrocyclododeca-
[e]-1,2,4-triazolo[1,5-a]pyrimidin-15(16H)-one tetrabutyl-
ammonium salt (14i) and its Methylation to 16-Methyl-2-
methylthio-5,6,7,8,9,10,11,12,13,14-decahydro-cyclododeca[e]-
1,2,4-triazolo[1,5-a]pyrimidin-15(16H)-one (4i/1).
PhH); cmr (deuteriochloroform): δ, ppm 13.8 (SCH ), 21.6 (C-7),
3
21.9 (C-6 and C-8), 33.0 (C-9), 74.9 (OCH ), 108.1 (C-5a), 128.46
2
and 128.50 (PhC-2',6' and 3',5'), 128.9 (PhC-4'), 134.8 (PhC-1'),
150.4qi (C-5), 156.1s (C-10a), 165.6m (C-9a), 167.6q (C-2); uv
-3
(EtOH): λ
[nm] (ε.10 ) 210 (24.4), 241 (30.2), 300 (8.6).
max
Anal. Calcd. for C H N OS (MW 326.42): C, 62.55, H, 5.56,
N, 17.16, S, 9.82. Found: C, 62.82, H, 5.67, N, 16.98, S, 10.02.
17 18
4
Compound 14i was prepared analogously to 14e starting
from 1.00
g
(0.0031 mole) of 2-methylthio-
5,6,7,8,9,10,11,12,13,14-decahydrocyclododeca[e]-1,2,4-tria-
2-Methylthio-6,7,8,9-tetrahydro-1,2,4-triazolo[5,1-b]quinazolin-
5(10H)-one Tetrabutylphosphonium Salt (18).
1
2
zolo[1,5-a]pyrimidin-15(16H)-one 2i (R + R = -(CH ) -, Q
2 10
= methylthio) [5]. The oily 14i was directly methylated
analogously to 14e to give an overall yield 62%, of 4i/1, mp
This compound was prepared analogously to the tetrabutyl-
1
2
ammonium salt 13f (R + R = -(CH ) -, Q = methylthio) using
o
-1
2 4
100-102 (acetonitrile). ir: ν C=O = 1663 cm ; pmr: δ, ppm
1.45 (m, 12H, CH -7,8,9,10,11,12), 1.73 (m, 2H, CH -13), 1.94
3.40 g (0.01 mole) of tetrabutylphosphonium bromide instead
of tetrabutylammonium bromide. Yield: 93%, mp 110-114°
2
2
(m, 2H, CH -6), 2.57 (t, 2H, CH -14), 2.62 (s, 3H, SCH ), 2.96
2
2
3
(ethyl acetate). pmr: δ, ppm 0.92 (t, 12H, 4 x CH ), 1.45
3
(t, 2H, CH -5), 3.64 (s, 3H, NCH ); cmr: δ, ppm 13.9 (SCH ),
2
3
3
(m, 16H, 8 x CH ), 1.75 (m, 4H, CH -7,8), 2.25 (m, 8H, 4 x
2
2
22.0, 22.1, 24.2, 24.7, 24.9, 25.2, 25.5, 25.8, 25.9 (two signals)
PCH ), 2.62 (m, 7H, SCH + CH -6,9); cmr: δ, ppm 13.0 [s, 4 x
2
3
2
(C-5 - C-14), 29.8 (NCH ), 116.0 (C-14a), 145.8 (C-4a), 150.2
3
4
1
CH , J(C,P) ≈ 0 Hz], 13.6 (SCH ), 18.2 [d, PCH , J(C,P) =
3
3
2
(C-16a), 160.4 (C-15), 162.6 (C-2).
47.4 Hz], 22.6 (C-7), 22.8 (C-8), 23.0 (C-6), 23.2 [d, PCH CH ,
2
2
Anal. Calcd. for C H N OS (MW 334.49): C, 61.05, H, 7.84,
2
3
17 26
4
J(C,P) = 4.4 Hz], 23.5 [d, PCH CH CH , J(C,P) = 15.4 Hz],
2
2
2
N, 16.75, S, 9.59. Found: C, 61.14, H, 7.95, N, 16.65, S, 9.72.
32.6 (C-9), 103.4 (C-5a), 157.4 (C-10a), 157.8 (C-9a), 158.3
(C-5), 161.6 (C-2).
2-Methylthio-5-methoxy-6,7,8,9-tetrahydro-1,2,4-triazolo-
[5,1-b]quinazoline (9/1).
10-Methyl-2-methylthio-6,7,8,9-tetrahydro-1,2,4-triazolo-
[5,1-b]quinazolin-5(10H)-one (3f/1).
To a solution of 0.115 g (0.005 mole) of sodium in 5 ml of
absolute methanol 1.27 g (0.005 mole) of 5-chloro-2-
methylthio-6,7,8,9-tetrahydro-1,2,4-triazolo[5,1-b]quinazoline
(19) [22] was added, and the mixture stirred at 20° for 90
minutes. The crystals that precipitated after addition of 10 ml
water to the reaction mixture were filtered off and washed with
water to yield 1.02 g (81%) of the title product, that
decomposed after recrystallisation from 2-propanol at
The alkylation was provided analogously to the alkylation of
the corresponding derivative 13f in acetonitrile using the
tetrabutylphosphonium salt 18 and methyl iodide as the alkyl-
ation agent. Yield: 65%, mp 258-260° (see also Table V). The
1
2
product is identical with 3f/1 (R + R = -(CH ) -, Q =
2 4
methylthio, R = methyl) obtained from the corresponding tetra-
1
2
butylammonium salt 13f (R + R = -(CH ) -, Q = methylthio).
2 4
106-109°; pmr: δ, ppm 1.85 (m, 4H, CH -7,8), 2.69 (s, 3H,
2
2-Methylthio-6,7,8,9-tetrahydro-1,2,4-triazolo[5,1-b]quinazolin-
5(10H)-thione (20).
SCH ), 2.72 (t, 2H, CH -6), 2.94 (t, 2H, CH -9), 4.48 (s, 3H,
3
2
2
OCH ); cmr: δ, ppm 13.5 (SCH ), 21.4 (C-7 and C-8), 21.7
3
3
(C-6), 32.8 (C-9), 60.9 (OCH ), 106.8 (C-5a), 151.5 (C-5),
To a suspension of 10.7 g (0.024 mole) of phosphorus
pentasulfide in 40 ml of bis(2-methoxyethyl)ether (diglyme) 4.73 g
(0.020 mole) of 2-methylthio-6,7,8,9-tetrahydro-1,2,4-triazolo-
3
156.2 (C-10a), 165.7 (C-9a), 167.6 (C-2); uv (EtOH): λ
[nm] (ε.10 ) 210 (28.0), 239 (33.6), 285 (9.0).
max
-3
1
2
Anal. Calcd. for C H N OS (MW 250.32): C, 52.78, H, 5.64,
[5,1-b]quinazolin-5(10H)-one (1f, R + R = -(CH ) -, Q =
11 14
4
2 4
methylthio) [4] was added followed by 8.07 g (0.096 mole) of
N, 22.38, S, 12.81. Found: C, 52.92, H, 5.87, N, 22.17, S, 12.78.

Jan-Feb 2001
A New Convenient Method for the N-Alkylation of Highly Insoluble Cyclic Amides
251
sodium hydrogen carbonate in little portions allowing the carbon
dioxide evolved to leave the mixture. The suspension was heated
with stirring at 110 for 40 hours. After cooling 150 ml of water was
ppm 13.8 (2-SCH ), 16.0 (5-SCH ), 21.9 (C-7), 22.2 (C-8),
3 3
26.1 (C-6), 33.4 (C-9), 120.5 (C-5a), 143.1 (C-5), 154.2
(C-10a), 162.7 (C-9a), 167.4 (C-2).
o
added to the reaction mixture by dropping it through a dropping
funnel (the hydrogen sulphide liberated was trapped in 10% sodium
hydroxide solution). The crystals separated were filtered off and
washed thoroughly with water and acetonitrile to yield after recrys-
tallisation from dimethylformamide 2.70 g (53%) of pure
2-methylthio-6,7,8,9-tetrahydro-1,2,4-triazolo[5,1-b]quinazolin-
Anal. Calcd. for C H N S (MW 266.39): C, 49.60, H, 5.30,
N, 21.03, S, 24.07. Found: C, 49.65, H, 5.46, N, 21.07, S, 23.96.
11 14
4 2
5-Benzylthio-2-methylthio-6,7,8,9-tetrahydro-1,2,4-triazolo-
[5,1-b]quinazoline (22/6).
To a solution of 493 mg (0.001 mole) of 2-methylthio-6,7,8,9-
tetrahydro-1,2,4-triazolo[5,1-b]quinazolin-5(10H)-thione
tetrabutylammonium salt (21) in 1.2 ml of acetonitrile 152 mg
(0.0012 mole) of benzyl chloride was added and the solution
stirred at room temperature for 1 hour. The mixture was
evaporated to dryness, the residue was dry column flash
chromatographed on a Silica gel 60 H layer (eluent benzene-
chloroform 1:1) to yield a crystalline product that was triturated
with diisopropyl ether and filtered off. By this method 294 mg
(86%) of pale yellow 5-benzylthio-2-methylthio-6,7,8,9-
tetrahydro-1,2,4-triazolo[5,1-b]quinazoline (22/6) was obtained,
+
5(10H)-thione (20), mp 277-283° (dec). MS (EI): M = 252; pmr
(DMSO-d ): δ, ppm 1.72 (m, 4H, CH -7,8), 2.58 (s, 3H, SCH ),
6
2
3
2.65 (m, 4H, CH -6,9); cmr (DMSO-d ): δ, ppm 13.5 (SCH ), 22.1
2
6
3
(C-7), 22.7 (C-8), 27.5 (C-6), 30.9 (C-9), 118.7 (C-5a), 151.3 and
151.5 (C-9a and C-10a), 163.6 (C-2), 171.8 (C-5); uv (EtOH):
-3
λ
[nm](ε.10 ) 254 (21.0), 294 (6.0), 336 (23.2).
max
Anal. Calcd. for C H N S (MW 252.30): C, 47.60, H, 4.79,
10 12
4 2
N, 22.21, S, 25.41. Found: C, 47.56, H, 4.88, N, 22.20, S, 25.32.
2-Methylthio-6,7,8,9-tetrahydro-1,2,4-triazolo[5,1-b]quinazolin-
5(10H)-thione Tetrabutylammonium Salt (21).
mp 98-99.5°; pmr: δ, ppm 1.75 (m, 4H, CH -7,8), 2.67 (m, 2H,
2
To a solution of 3.74 g (0.011 mole) of tetrabutylammoniun
hydrogen sulphate in 10 ml of water a pre-cooled solution of
0.88 g (0.022 mole) of sodium hydroxide in 8 ml of water was
added and the solution obtained cooled to 5°. After that 2.52 g
(0.01 mole) of 2-methylthio-6,7,8,9-tetrahydro-1,2,4-triazolo-
[5,1-b]quinazolin-5(10H)-thione (20) and 10 ml of chloroform
was added and the resulting yellow suspension was intensively
stirred until the thione dissolved (about 5 minutes). The phases
were separated, the aqueous layer was washed with 10 ml of
chloroform, the combined chloroform layers with 5 ml of water
and dried over sodium sulphate. After evaporating the solvent
in vacuo the residue was dissolved in 10 ml of ethyl acetate and
left to stand overnight. The crystals that precipitated were
filtered off and washed with cold ethyl acetate to yield 4.48 g
(90%) of the product, mp 106-109°. pmr: δ, ppm 0.91 (t, 12H, 4
CH -6), 2.76 (s, 3H, SCH ), 2.92 (m, 2H, CH -9), 4.64 (s, 2H,
2
3
2
SCH ), 7.05 (m, 2H, PhH-2',6'), 7.20 (m, 3H, PhH-3',4',5'); cmr:
2
δ, ppm 14.0 (SCH ), 21.8 (C-7), 22.2 (C-8), 26.4 (C-6), 33.5
3
(C-9), 36.8 (SCH ), 122.5 (C-5a), 127.6 (PhC-4'), 128.6 and
2
128.8 (PhC-2' and PhC-3'), 136.5 (PhC-1'), 141.2 (C-5), 154.3
(C-10a), 163.1 (C-9a) 167.8 (C-2).
Anal. Calcd. for C H N S (MW 342.49): C, 59.62, H, 5.30,
17 18
4 2
N, 16.36, S, 18.72. Found: C, 59.66, H, 5.42, N, 16.29, S, 18.70.
Acknowledgement.
The authors wish to express their thanks to Mrs. Sándorné
Sólyom and Mr. Antal Kovács for recording the ir spectra, to
Mr. Attila Fürjes, Mr. Vencel Bege and Mrs. Magdolna Nagy for
recording the nmr spectra, to Mr. Kálmán Újszászy,
Dr. Péter Slégel and Dr. Éva Szabó for recording the ms spectra,
to Miss Zsófia Kárpáti for recording the uv spectra, to
Mrs. Hirkóné Magdolna Csík for performing the elemental
analyses and to Mrs. Erika Korenné-Ausländer and
Mrs. Tamásné Czikolai for technical help.
x CH ), 1.29 (m, 8H, 4 x CH CH ), 1.51 (m, 8H, NCH CH ),
3
3
2
2
2
1.8 (m, 4H, CH -7,8), 2.65 (s, 3H, SCH ), 2.74 (m, 2H, CH -6),
2
3
2
2.86 (m, 2H, CH -9), 3.14 (m, 8H, 4 x NCH ); cmr: δ, ppm 13.6
2
2
(4x CH ), 14.1 (SCH ), 19.6 (CH CH ), 23.0 (C-7), 23.5 (C-8),
3
3
3
2
23.9 (4x NCH CH ), 28.3 (C-6), 33.5 (C-9), 58.7 (4 x NCH ),
2
2
2
119.7 (C-5a), 154.2 and 156.6 (C-9a and C-10a), 163.7 (C-2),
167.8 (C-5).
REFERENCES AND NOTES
Anal. Calcd. for C H N S (MW 493.83): C, 63.24, H, 9.59,
26 47
5 2
N, 14.18, S, 12.99. Found: C, 63.42, H, 9.66, N, 14.04, S, 13.09.
[1] For Part XLI see, J. Reiter, J. Barkóczy, Gy. Argay and A.
Kálmán, J. Heterocyclic Chem., 37, 261 (2000).
[2] Presented in part on the International Symposium on
Heterocyclic Chemistry, Hong-Kong, 1995, Congr. Abstr., p. 153
[3] J. Reiter, L. Pongó and P. Dvortsák, Tetrahedron, 43, 2497
(1987).
[4] J. Reiter and L. Pongó, Org. Prep. Proced. Int., 21, 163 (1989).
[5] J. Reiter, G. Berecz and I. Pallagi, J. Heterocyclic Chem., 28,
721 (1991).
[6] J. Reiter and E. Rivó, J. Heterocyclic Chem., 26, 971 (1989).
[7] J. Reiter and E. Rivó, J. Heterocyclic Chem., 25, 1497 (1988).
[8] E. Rivó and J. Reiter, J. Heterocyclic Chem., 29, 1189 (1992).
[9] K. Esses-Reiter and J. Reiter, J. Heterocyclic Chem., 24, 1503
(1987).
2,5-Bis(methylthio)-6,7,8,9-tetrahydro-1,2,4-triazolo-
[5,1-b]quinazoline (22/1).
To a solution of 493 mg (0.001 mole) of 2-methylthio-
6,7,8,9-tetrahydro-1,2,4-triazolo[5,1-b]quinazolin-5-(10H)-
thione tetrabutylammonium salt (21) in 1.2 ml of acetonitrile
170 mg (0.0012 mole) of methyl iodide was added and the
solution stirred at room temperature for 5 minutes. The
mixture was evaporated to dryness, the residue was dry
column flash chromatographed on a Silica gel 60 H layer
(eluent benzene-chloroform 1:1) to yield a crystalline product
that was triturated with ether and filtered off. By this method
229 mg (86%) of pale yellow 2,5-bis(methylthio)-6,7,8,9-
tetrahydro-1,2,4-triazolo[5,1-b]quinazoline (22/1) was
[10] J. Reiter and K. Esses-Reiter, J. Heterocyclic Chem., 28, 561
(1991) .
[11] Phase-Transfer Reactions, Fluka-Compendium (Ed. W. E.
Keller), Vol. 1-3, Thieme Verlag (1986/1987/1992)
o
+
obtained, mp 118-120 ; ms (EI): M = 266; pmr: δ, ppm 1.9
(m, 4H, CH -7,8), 2.71 (s, 3H, 2-SCH ), 2.85 (s, 3H,
2
3
5-SCH ), 2.87 (m, 2H, CH -6), 2.95 (m, 2H, CH -9); cmr: δ,
3
2
2

252
G. Berecz and J. Reiter
Vol. 38
[12a] A. Brändström, P. Berntsson, S. Carlsson, A. Djurhuus, K.
[15] A. Kálmán and Gy. Argay, J. Mol. Struct., 102, 391 (1983).
[16] A. Kálmán, L. Párkányi and J. Reiter, J. Mol. Struct., 118, 293
(1984).
[17] Y. Makisumi and H. Kano, Chem. Pharm. Bull., 11, 67
(1963).
Gustavii, U. Junggren, B. Lamm and B. Samuelsson, Acta Chem. Scand.,
23, 2202 (1969); [b] A. Brändström and U. Junggren, Acta Chem. Scand.,
23, 2203 (1969).
[13] The numbering of compounds used all through the paper is as
follows: The first number corresponds to the general Formula as seen on
the Schemes. It is followed by a vowel corresponding to the meaning of
[18] V. C. Chambers., J. Am. Chem. Soc., 82, 605 (1960).
[19] Y. Makisumi, Chem. Pharm. Bull., 11, 851 (1963).
[20] A. R. Lapucha, Synthesis, 256 (1987).
1
2
substituents R and R . This is followed by a dash and at last is a number
corresponding to the type of the N-alkyl group (if exists). Thus e.g. the
methylation of the tetrabutylammonium salt 13f led to 3f/1, 7f/1 and 8f/1,
while its benzylation yielded 3f/6, 7f/6 and 8f/6.
[21] L. M. Harwood, Aldrichimica Acta, 18, 25 (1985), see also
Vogel's Textbook of Practical Organic Chemistry, 5th Ed. (Longman,
1989), p. 220.
[14] G. Fischer, Advances in Heterocyclic Chemistry, Vol. 57,
81-138 (1993).
[22] J. Reiter Jr. and J. Reiter, J. Heterocyclic Chem., 34, 1519 (1997).