1,2,4-Triazine in organic synthesis. 16. Reactivity of 3-substituted 6-phenyl-1,2,4-triazines towards phenylacetonitrile anion in polar aprotic solvents

Article abstract of DOI:10.1023/A:1017959403370

The reactions of 3-X-6-phenyl-1,2,4-triazines (X = SMe, SPh, SO₂Ph) with phenylacetonitrile anion in DMF were studied. In these reactions the ring transformation product 3-amino-4,6-diphenylpyridazine, the covalent addition product 3-X-5-(α-cya

Full text of DOI:10.1023/A:1017959403370

Chemistry of Heterocyclic Compounds, Vol. 37, No. 11, 2001
1,2,4-TRIAZINE IN ORGANIC SYNTHESIS.
16.* REACTIVITY OF 3-SUBSTITUTED
6-PHENYL-1,2,4-TRIAZINES TOWARDS
PHENYLACETONITRILE ANION
IN POLAR APROTIC SOLVENTS*2
A. Rykowski1, E. Wolinska1, and H. C. van der Plas2
The reactions of 3-X-6-phenyl-1,2,4-triazines (X = SMe, SPh, SO2Ph) with phenylacetonitrile anion in
DMF were studied. In these reactions the ring transformation product 3-amino-4,6-diphenylpyridazine,
the covalent addition product 3-X-5-( -cyanobenzyl)-6-phenyl-2,5-dihydro-1,2,4-triazine, and the ipso-
α
substitution product 3-(1-cyano-1-phenylmethyl)-6-phenyl-1,2,4-triazine were obtained. Analogous
reactions carried out in DMA gave only the addition products in excellent yields as diastereomeric
mixtures of the corresponding 2,5-dihydro-1,2,4-triazines.
Keywords: 3-substitued 1,2,4-triazines, nucleophilic addition of phenylacetonitrile anion,
diastereomeric mixtures of 2,5-dihydrotriazines.
In a previous paper [2] of these series we reported on an ANRORC-type ring transformation of
3-chloro-6-phenyl-1,2,4-triazine (1a) with substituted acetonitriles (2a-d, R = Ph, CO2Et, CN, SO2Ph)
(Scheme 1) resulting in the formation of functionalized 3-amino-4-R-6-phenylpyridazines (5a-d, R = Ph, CO2Et,
CN, SO2Ph).
Scheme 1
_
Ph
H
N
Ph
N
Ph
N
CN
t-BuOK
N
Ph
N
– X
N
+
N
+
H3O
N
R
CN
DMA
N
X
N
X
CN
2
NH2
1
CH
R
a: X = Cl
R
R
CN
4
b: X = SMe
c: X = SPh
5
3
d: X = SO2Ph
2, 5 a: R = Ph, b: R = CO2Et c: R = CN, d: R = SO2Ph
_______
* For communication 15, see [1].
*2 Dedicated to Professor E. Lukevics on the occasion of his 65th birthday.
__________________________________________________________________________________________
1
Institute of Chemistry, University of Podlasie, ul. 3-go Maja 54, 08-110 Siedlce, Poland; e-mail:
rykowski@ap.siedlce.pl. 2 Laboratory of Organic Chemistry, University of Wageningen, Dreijenplein 8, 6703 HB
Wageningen, The Netherlands. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 11,
pp. 1549-1555, November, 2001. Original article submitted September 18, 2001.
1418
0009-3122/01/3711-1418$25.00©2001 Plenum Publishing Corporation

The reaction proceeded with high regioselectivity, involving addition of the nucleophile at C(5) in 1a,
ring opening with breaking of the N(4)–C(5) bond in 3 and an intramolecular ring closure of the resulting open-
15
chain intermediate 4. By a N study with labeled phenylacetonitrile (2a*) in DMF, it was proved that the ring
closure occurs by a nucleophilic attack of the hydrazone nitrogen to the carbon atom of the nitrile reagent. By
reacting 1a in dimethylacetamide (DMA) the reaction stops at the ring opening step and an open-chain
compound 4 (R = Ph) could be isolated after neutralization with acetic acid. Treatment of this open-chain
compound with aqueous ammonium hydroxide in acetone gives the final aminopyridazine 5a.
Continuing these investigations we became interested how the course of reaction would be influenced
by the presence of substituents at C(3) having a leaving group mobility but other than the chlorine atom. In the
present paper we report on the results of reaction of 3-(methylsulfanyl)- (1b), 3-(phenylsulfanyl)- (1c), and
3-(phenylsulfonyl)-6-phenyl-1,2,4-triazine (1d) with phenylacetonitrile (2a) in different polar aprotic solvents
under basic conditions.
Compound 1b was prepared by condensation of thiosemicarbazide with isonitrosoacetophenone
according to a reported method [3]. Reaction of 3-chloro-6-phenyl-1,2,4-triazine (1a) with potassium
thiophenolate proceeded smoothly and gave within 30 min at room temperature 6-phenyl-3-(phenylsulfanyl)-
1,2,4-triazine (1c) in good yield. Oxidation of sulfide 1c with potassium permanganate under phase-transfer
catalysis conditions provided sulfone 1d respectively (Scheme 1).
Treatment of 1b with 2a in DMF in the presence of an excess of potassium t-butoxide at 0°C led to a
mixture of three products: the ring transformation product, 3-amino-4,6-diphenylpyridazine (5a) (11%), the
covalent addition product, 5-( -cyanobenzyl)-2,5-dihydro-3-(methylsulfanyl)-6-phenyl-1,2,4-triazine (6b)
α
(20%), and the ipso substitution product, 3-( -cyanobenzyl)-6-phenyl-1,2,4-triazine (7) (23%) (Scheme 2).
α
Scheme 2
Ph
H
N
N
Ph
Ph
N
N
N
NH
N
N
t-BuOK
CN
CH
Ph
1b–d
2a
+
+
+
X
NH2
DMF
CH
Ph
Ph
CN
6b–d
5a
7
b X = SMe, c X = SPh, d X = SO2Ph
Products 5a and 6b are known compounds and were already described in a previous paper [2]. The
structure assignment of 7 is based on its micro analysis, its mass spectrum clearly showing the highly
delocalized phenylacetylene radical ion at 102 (100%) mass units, and on its IR spectrum featuring the presence
1
of the cyano group (2250 cm-1). In the H NMR spectrum a singlet for the methine hydrogen is observed at
= 5.10. Applying the same conditions, compound 1c gave with 2a a mixture of 5a (30%), 6c (22%), and
δ
7 (37%); compound 1d gave about a similar mixture of products, i.e., 5a (16%), 6d (51%), and 7 (16%).
The covalent addition products 6b-d are obtained as diastereomeric mixtures of the corresponding
1
2,5-dihydro-1,2,4-triazines [4]. The H NMR spectra of 6b-d are given in Table 1 together with those for
2,5-dihydro-1,2,4-triazine (8).
Compound 8 was prepared by the reaction of 1c with 2-phenylpropionitrile 2e in liquid ammonia
containing 2 equivalents of sodium amide at -75°C. These low-temperature conditions are necessary in order to
avoid oxidation of 2-phenylpropionitrile anion into acetophenone anion [5], since the latter compound easily
undergoes covalent addition at C(5) of 1c to yield compound 9 (Scheme 3).
1419

1
TABLE 1. H NMR Data of Compounds 1b-c, 6b-d and 8 for Two
Diastereomers
1H NMR, δ, ppm, J (Hz) [Δδ]*
Com-
Solvent
pound
Methine C–H
—
5-H
Ph
N–H
—
1b*2
6b*3
CDCl3
CDCl3
9.50 (s, 1H)
7.30-7.75
4.04 (d, 1H, J = 8.71) 5.24 (d, 1H, J = 5.72) 7.07-7.44 7.82 (s, 1H)
[4.26]
8.45 (s, 1H)
—
4.12 (d, 1H, J = 8.68) 5.49 (d, 1H, J = 5.72)
—
[4.01]
CDCl3
—
8.80 (s, 1H)
7.40-7.90
—
1c
6c
DMSO-d6 4.27 (d, 1H, J = 7.26) 5.32 (d, 1H, J = 7.3)
7.12-7.87 11.22 (s, 1H)
[3.48]
11.6 (s, 1H)
4.30 (d, 1H, J = 7.26) 5.51 (d, 1H, J = 7.3)
—
[3.29]
DMSO-d6
—
9.62 (s, 1H)
7.36-8.26
—
1d
6d
DMSO-d6 4.37 (d, 1H, J = 5.98) 5.56 (d, 1H, J = 6.03) 7.07-8.33 11.99 (s, 1H)
[4.05]
12.58 (s, 1H)
4.50 (d, 1H, J = 5.51) 5.78 (d, 1H, J = 5.29)
[3.84]
CDCl3
DMSO-d6
—
—
8.80 (s, 1H)
7.40-7.90
7.18-7.74 11.10 (s, 1H)
—
1c
8*4
5.34 (s, 1H) [3.46]
5.48 (s, 1H) [3.32]
11.28 (s, 1H)
_______
*
=
–
.
∆δ
δ
δ
6b-d 8
or
*2 Other1sbi-dgnal: 2.55 (s, 3H, Me).
*3 Other signals: 2.42 (s, 3H, Me), 2.61 (s, 3H, Me).
*4 Other signals: 1.54 (s, 3H, Me), 1.60 (s, 3H, Me).
Scheme 3
t-BuOK
Ph
H
N
N
Ph
H
Ph
NaNH2
NH3liq
NH
NH
DMA
1c
CN
+
H3C
SPh
SPh
N
CN
N
C
Ph
CH2
Ph
2e
CH3
9
O
8
Measurements of the 1H NMR spectra of 6b-d and 8 in CDCl3 or DMSO-d6 at room temperature showed
that diastereomeric H(5) protons in these compounds appeared at a much higer field than the resonance signals
observed in the solution of compounds 1b-d in CDCl3 (Table 1). The magnitudes of the upfield shifts
are
∆δ
1
very close to those found in -amino adducts [6]. The general view of the H NMR data of these 2,5-dihydro-
σ
1,2,4-triazines (6b-d) discloses that: (i) the replacement of the 3-methylsulfanyl by phenylsulfanyl group only
exerts a slight effect on H(5), but a significant effect on NH within each pair of diastereomers; (ii) the chemical
shifts of H(5) protons in 6b-d are nearly the same as that of the analogous proton in 8.
The structure assignments of 2,5-dihydro-1,2,4-triazines (6b-d) were confirmed by measuring their
13C NMR spectra under conditions as mentioned before. As expected, all carbon atoms are shifted upfield
compared with the shieldings of the corresponding carbon atoms of compounds 1b-d in CDCl3. The greater
upfield shift found for C(5) proves the formation of the covalent adduct 6 (Table 2).
1420

TABLE 2. 13C NMR Data of Compounds 1b-d and 6b-d
13C NMR, δ, ppm [Δδ]*
Com-
Solvent
pound
C(5)
C(6)
C(3)
CN
Methine C
Ph
1b*2
6b*3
CDCl3
CDCl3
152.98
145.97
172.00
—
—
126.19, 129.20
130.49, 132.95
125.83, 128.08
128.45, 128.60
128.81, 129.35
131.79, 133.63
57.58
143.37
[2.60]
157.36
[14.64]
118.74
38.52
[95.40]
DMSO-d6 153.46
147.85
171.28
—
—
126.42, 127.31
129.15, 129.59
129.80, 130.65
132.75, 135.22
125.56, 127.93
128.17, 128.32
128.65, 128.90
128.99, 129.06
132.58, 133.91
134.54, 134.61
1c
6c
DMSO-d6
56.23
141.17
[6.68]
154.87
[16.41]
119.47
38.33
[97.23]
DMSO-d6 157.87
149.97
165.55
—
—
127.85, 129.25
129.36, 129.74
131.90, 132.05
135.10, 136.77
126.03, 128.15
128.42, 128.48
128.62, 128.99
129.62, 129.92
131.80, 132.97
135.10, 136.64
1d
6d
DMSO-d6
55.84
140.68
[9.29]
154.57
[10.98]
118.75
40.58
[102.03]
_______
*
=
–
δ
∆δ
δ
6b-d
.
*2 Other1sbi-gd nal: 13.88, Me.
*3 Other signal: 14.02, Me.
The results of reaction 1b-d with 2a show a lower regioselectivity than reported earlier for 1a [2],
although from the yields of the products, 5a and 6b-d it is clear that the C(5) position in compounds 1b-d is still
the preferential site of nucleophilic attack. The low percentage of ring transformation product 5a and the
presence of an ipso substitution product 7 require some comments in terms of the leaving group mobility. As we
have seen before [2] the reaction of 2a with 1a proceeds via adduct 3, followed by ring opening; no traces of
product 7 were isolated, although the chlorine atom is considered to be a better leaving group than the sulfur-
containing groups when located at C(3) of the 1,2,4-triazine ring [7]. Since in this study we deal with
compounds 1b-d that do not contain a good leaving group at C(3), the driving force for bond breaking of the
intermediary 6b-d is diminished. The H-adducts 3b-d partly isomerize to the SR-, SPh-, and SO2Ph-adducts
σ
σ
σ
σ
3'b-d, respectively, via 1b-d. Departure of the leaving group from the latter adducts easily occurs, resulting in
the formation of product 7 (Scheme 4).
Scheme 4
Ph
N
N
CN
Ph
2a
N
2a
7
3b–d (R = Ph)
5a
1b–d
CH
X
3'b–d
1421

During preliminary exploration of the conditions for reaction of 1b with 2a we used DMA instead of
DMF as reaction medium. Under these conditions a stable 2,5-dihydro-1,2,4-triazine 6b was exclusively formed
after neutralization, as a mixture of two diastereomers [2]. Neither compound 5a nor 7 were obtained. Selective
preference of 6b over 5a and 7 in this solvent was also found with the compounds 1c and 1d. Reaction with 2a
in DMA gave, after neutralization, a mixture of diastereomeric 2,5-dihydro-1,2,4-triazines (6c) and 6d
respectively. The latter result indicates that even the highly reactive phenylsulfonyl group is drastically
deactivated towards nucleophilic substitution when the reaction is carried out in DMA. This unusual solvent
effect requires further studies.
EXPERIMENTAL
General Methods. Melting points were determined on a Boethius melting point aparatus and were
uncorrected. NMR spectra were recorded on Varian Gemini (200 MHz) with TMS as internal standard. Mass
spectra were obtained with AMD 604 Inectra spectrometer. Reactions were monitored by TLC using precoated
silica gel aluminium plates containing a fluorescent indicator. Detection was done by exposure to UV light
(254 nm).
Synthesis of 6-Phenyl-3-phenylsulfanyl-1,2,4-triazine (1c). To a stirred solution of KOH (0.233 g,
4 mmol) in anhydrous ethanol (5 ml) a solution of thiophenol (0.480 g, 4 mmol) in anhydrous ethanol (5 ml)
was added. The mixture was cooled in an ice-water bath to 0°C and 3-chloro-6-phenyl-1,2,4-triazine 1a
(0.764 g, 4 mmol) was added in one portion. After stirring at room temperature for 30 min, the precipitate was
filtered off and washed with chloroform. The combined extracts were evaporated under reduced presure and the
residue was recrystallized from ethanol to give 1c as a yellow needles. Yield 0.960 g (86 %); mp 95-97°C.
Found, %: C 68.12; H 4.13; N 15.78. C15H11O3S. Calculated, %: C 67.92; H 4.15; N 15.85.
Synthesis of 6-Phenyl-3-phenylsulfonyl-1,2,4-triazine (1d). To a solution of potassium permanganate
(1.050 g, 7 mmol) in water (25 ml) a solution of 1c (0.265 g, 1 mmol) in benzene (23 ml), tetrabutylammonium
bromide (45 mg), and acetic acid (3 ml) was added. The mixture was stirred at room temperature for 2 h. Then
the mixture was cooled in an ice-water bath and sodium pyrosulfite was added to remove manganese(IV) oxide.
The mixture was neutralized with potassium carbonate and the benzene layer was separated. The water phase
was extracted twice with benzene (30 ml). The benzene extracts were combined and dried with magnesium
sulfate. The solvent was evaporated under reduced pressure to give 1d. The product was purified by column
chromatography using chloroform–acetone (50:1) as eluent. Yield 0.155 g (69 %); mp 218-219°C. IR spectrum
(KBr), , cm-1: 1336, 1141 (SO2). Found, %: C 59.61; H 3.83; N 13.84. C15H11N3O2S·1/3H2O. Calculated, %:
ν
C 59.41; H 3.85; N 13.86.
Reactions of 1b-d with 2a in DMA. To a stirred solution of phenylacetonitrile 2a (0.190 g, 1 mmol)
and potassium t-butoxide (1 g) in dry DMA (4 ml) a solution of compounds 1b, 1c, or 1d (1 mmol) in DMA
(4 ml) was added dropwise at 0°C under argon. After stirring at 0°C for 4 h the reaction mixture was poured into
ice-water and neutralized with acetic acid. The precipitate was filtered off and washed with water. The product
was purified by column chromatography using chloroform as eluent, followed by recrystallization from ethanol.
5-(1-Cyano-1-phenylmethyl)-3-(methylsulfanyl)-6-phenyl-2,5-dihydro-1,2,4-triazine
(6b).
Yield 0.160 g (53 %); mp 163°C. IR spectrum (KBr), , cm-1: 3350 (NH), 2250 (CN). Found, %: C 67.38;
ν
H 5.04; N 17.41. C18H16N4S. Calculated, %: C 67.48; H 5.04; N 17.50.
5-(1-Cyano-1-phenylmethyl)-6-phenyl-3-(phenylsulfanyl)-2,5-dihydro-1,2,4-triazine
(6c).
Yield 0.186 g (85 %); mp 189-190°C. IR spectrum (KBr), , cm-1: 3480 (NH), 2260 (CN). Found, %: C 72.27;
ν
H 4.68; N 14.50. C23H18N4S. Calculated, %: C 72.25; H 4.71; N 14.65.
5-(1-Cyano-1-phenylmethyl)-6-phenyl-3-(phenylsulfonyl)-2,5-dihydro-1,2,4-triazine
(6d).
Yield 0.132 g (63 %); mp 194-196 C. IR spectrum (KBr), , cm-1: 3450 (NH), 1350, 1160 (SO2Ph). HRMS
°
ν
LSIMS found: 415.12269. C23H19N4O2S. Calculated 415.12287.
1422

Reactions of 1b-d with 2a in DMF. To a stirred solution of phenylacetonitrile 2a (0.190 g, 1 mmol)
and potassium t-butoxide (1 g) in dry DMF (4 ml) was added dropwise a solution of compounds 1b, 1c, or 1d
(1 mmol) in DMF (4 ml) at 0°C under argon. After stirring at 0°C for 4 h the reaction mixture was poured into
ice-water and neutralized with acetic acid. The precipitate was filtered off and washed with water. The products
were separated by preparative TLC using chloroform–acetone (50:1) as eluent. For yields of compounds 5a,
6b-d and 7 see the main text.
3-(1-Cyano-1-phenylmethyl)-6-phenyl-1,2,4-triazine (7). Mp 160-161°C. IR spectrum (KBr), , cm-1:
ν
1
2250 (CN). H NMR (CDCl3): 5.74 (s, 1H, CH); 7.31-7.64 (m, 9H, Ph and HHet); 8.02-8.11 (m, 2H, Ph).
Found, %: C 74.97; H 4.47; N 20.39. C17H12N4. Calculated, %: C 75.00; H 4.41; N 20.60.
Reaction of 1c with 2-Phenylpropionitrile (2e) and NaNH2 in NH3-liq. 2-Phenylpropionitrile (2e)
(0.269 g, 2 mmol) was added dropwise to a suspension of freshly prepared sodium amide (2 mmol) in liquid
ammonia (25 ml) at -75°C. After 1 min 1c (0.265 g, 1 mmol) dissolved in DMF (1 ml) was added dropwise at
such a rate that the temperature did not exceed -75°C. The reaction mixture was stirred for 2 min and quenched
with solid ammonium chloride (1.1 g, 20 mmol), and ammonia was evaporated. 5-(1-Cyano-1-phenylethyl)-6-
phenyl-3-phenylsulfanyl-2,5-dihydro-1,2,4-triazine (8) was isolated by extraction with chloroform and purified
by column chromatography (silica gel, hexane–ethyl acetate, 10:1) and recrystallized from ethanol.
Yield 0.174 g (44%); mp 89-90°C. IR spectrum (KBr), , cm-1: 2235 (CN), 3411 (NH), HRMS LSIMS found:
ν
397.14876. C24H21N4S. Calculated 397.14868.
Reaction of 1c with 2-Phenylpropionitrile in DMA. To a stirred solution of 2-phenylpropionitrile (2e)
(0.131 g, 1 mmol) and potassium t-butoxide (1 g) in dry DMA (4 ml) was added dropwise a solution of 1c
(265 mg, 1 mmol) in DMA (4 ml) at 0°C under argon. After stirring at 0°C for 1 h the reaction mixture was
poured into ice-water and neutralized with acetic acid. The precipitate was filtered off and washed with water.
5-Phenacyl-6-phenyl-3-phenylsulfanyl-2,5-dihydro-1,2,4-triazine (9) was purified by column chromatography
(silica gel, hexane–ethyl acetate 10:1) followed by recrystallization from ethanol. Yield 0.103 g (26%);
1
mp 153-154°C. IR spectrum (KBr), , cm-1: 1684 (CN), 3401 (NH). H NMR (CDCl3): 2.99 (dd, 1H, J = 15.6,
ν
4.6 Hz, HACHB); 3.41 (dd, 1H, J = 15.6, 8.5 Hz, HACHB); 5.57 (dd, 1H, J = 8.5, 4.6 Hz, 5-H); 7.35-7.58 (m,
11H, Ph); 7.71-7.75 (m, 2H, Ph); 7.86-7.89 (m, 2H, Ph). Found, %: C 71.77; H 4.72; N 10.98. C23H19N3OS.
Calculated, %: C 71.69; H 4.93; N 10.90.
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1423