Alternative products in one-pot reaction of benzylidenemalononitrile, N-methyl-2-thiocarbamoylacetamide, and ω-bromoacetophenone

Article abstract of DOI:10.1007/s10593-007-0102-1

N-Methyl-2-benzoylmethylsulfanyl-4-phenylnicotinamide and N-methyl-2-(4-phenyl-1,3-thiazol-2-yl)-acetamide have been obtained as alternative products to the desired N-methyl-2,3-dihydro-7H-thiazolo[3,2-a] pyridine-8-carboxamide by a one-pot cyclocondensation of benzylidenemalononitrile, N-methyl-2-thiocarbamoylacetamide, piperidine, and ω-bromoacetophenone. 2-Amino-1-methyl-6-oxo-4-phenyl-5-(4-phenyl-1,3- thiazol-2-yl)-1,6-dihydropyridine-3-carbonitrile has been obtained as main product by treatment of benzylidenemalononitrile with N-methyl-2-(1,3-thiazol-2- yl)acetamide.

Full text of DOI:10.1007/s10593-007-0102-1

Chemistry of Heterocyclic Compounds, Vol. 43, No. 5, 2007
ALTERNATIVE PRODUCTS IN ONE-POT REACTION OF BENZYLIDENE-
MALONONITRILE, N-METHYL-2-THIOCARBAMOYLACETAMIDE,
AND ω-BROMOACETOPHENONE
A. Krauze, M. Viļums, L. Sīle, G. Duburs
N-Methyl-2-benzoylmethylsulfanyl-4-phenylnicotinamide and N-methyl-2-(4-phenyl-1,3-thiazol-2-yl)-
acetamide have been obtained as alternative products to the desired N-methyl-2,3-dihydro-7H-
thiazolo[3,2-a]pyridine-8-carboxamide by a one-pot cyclocondensation of benzylidenemalononitrile,
N-methyl-2-thiocarbamoylacetamide, piperidine, and ω-bromoacetophenone. 2-Amino-1-methyl-
6-oxo-4-phenyl-5-(4-phenyl-1,3-thiazol-2-yl)-1,6-dihydropyridine-3-carbonitrile has been obtained as
main product by treatment of benzylidenemalononitrile with N-methyl-2-(1,3-thiazol-2-yl)acetamide.
Keywords: 2-(benzoylmethylsulfanyl)nicotinamide, 2,3-dihydro-7H-thiazolo[3,2-a]pyridine-8-carbox-
amide, N-methyl-2-(1,3-thiazol-2-yl)acetamide, 6-oxo-5-(thiazol-2-yl)-1,6-dihydropyridine-3-carbo-
nitrile.
Previously it was established that the one-pot condensation of benzylidenemalononitrile (1), N-methyl-
2-thiocarbamoylacetamide (2b), piperidine 3a, and chloroacetone 4a resulted in N-methyl-3-hydroxy-3-methyl-
2,3-dihydro-7H-thiazolo[3,2-a]pyridine-8-carboxamide (5) obtained in 82% yield (Scheme 1) [1].
It was also proved that N-unsubstituted 3-hydroxy-3-phenyl-2,3-dihydro-7H-thiazolo[3,2-a]pyridine-8-
carboxamide (6a) can be prepared both by the above mentioned one-pot multicomponent synthesis (yield 84%)
[1] or by treatment of 1,4-dihydropyridine-6-thiolate 8a [2] with ω-bromoacetophenone 4b (yield 83%) [1].
Scheme 1
Ph
Ph
NC
CONHMe
Cl
O
NC
CONHMe
+
+
+
CN
CSNH2
2b
N
H
H2N
N
Me
S
3a
4a
1
HO
Me
5
_______
* Dedicated to Professor I. Kalvinsh on his 60th birthday
__________________________________________________________________________________________
Latvian Institute of Organic Synthesis, Riga LV-1006, Latvia; e-mail: krauze@osi.lv, e-mail:
gduburs@osi.lv. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 5, pp. 777-781, May, 2007.
Original article submitted March 27, 2007.
0009-3122/07/4305-0653©2007 Springer Science+Business Media, Inc.
653

The mechanism for the formation of the thiazolo[3,2-a]pyridine-8-carboxamides 5 and 6a is as follows:
in the first stage the Michael addition of 2-thiocarbamoylacetamide 2 to benzylidenemalononitrile 1 affords
4,4-dicyanothiobutyramides of type 7, which easily undergo intramolecular cyclization producing thiolates 8 [2].
Then alkylation of 8 and another intramolecular cyclization occur to give thiazolo[3,2-a]pyridine-8-
carboxamides 5 and 6. It should be noted, firstly, that the intramolecular cyclizations of Michael adducts like 7,
which produce 2-oxo-3-thiocarbamoyl-1,2,3,4-tetrahydropyridines [3, 4] or 3-carbamoyl-2-thioxo-1,2,3,4-
tetrahydropyridines [1, 5, 6] are competing reactions, and, secondly, that the substituents and the reaction
conditions significantly influence the structure of the products formed.
Our efforts to obtain the analog of 5, N-methyl-5-amino-6-cyano-3-hydroxy-3,7-diphenyl-2,3-dihydro-7H-
thiazolo[3,2-a]pyridine-8-carboxamide (6b) by condensation of benzylidenemalononitrile 1, N-methyl-2-
thiocarbamoylacetamide 2b, piperidine 3a, and bromoacetophenone 4b (in a similar manner as for 6a) were
unsuccessful. The isolated products (Scheme 2) were N-methyl-6-amino-2-benzoylmethylsulfanyl-5-cyano-4-
phenylnicotinamide (10) and N-methyl-2-(4-phenyl-1,3-thiazol-2-yl)acetamide (11).
Scheme 2
Ph
Ph
NC
CONHR
S
NC
Br
O
CONHR
+
+
+
CN
CSNH2
2a,b
Ph
H2N
N
N
H
3a
HO
1
4b
Ph
4b
6a,b
+
Ph
Ph
Ph
NC
CONHR
_
NC
CONHMe
S
NC
CONHR
4b
+
+ 3a
CN CSNH2
H2N
N
H
S
H2N
N
+
NH2
Ph
7a,b
8a,b
9
O
Ph
Ph
CONHMe
NC
Ph
NC
CONHMe
CONHMe
NC
4b
+
4b
+
3b +
_
H2N
N
S
H2N
N
S
H2N
N
H
S
Ph
+
NH2
13
10
O
12
Ph
HO
Ph
Ph
O
H2N
N
N
R = Me
S
S
S
1 + 2b + 3a + 4b
HN
O
HN
Me
O
14
HN
Me
O
Me
11
15
2b + 3a + 4b
a R = H, b R = Me
654

The formation of alternative products 10 and 11 can be explained as follows. Under mild reaction
conditions two competing reactions take place. First, the Michael addition of N-methyl-2-
thiocarbamoylacetamide (2b) to compound 1 affords 4,4-dicyanothiobutyramide 7b, which further through
thiolate 8b and 2-benzoylmethylsulfanyl-3,4-dihydronicotinamide
9
produces 2-(benzoylmethyl-
sulfanyl)nicotinamide 10. The alternative path, i. e. oxidation of 1,4-dihydropyridine-2-thiolate 8b to pyridine-
2-thiolate 13 and its alkylation with bromoacetophenone 4b yielding pyridine 10, also cannot be excluded. In both
cases, benzylidenemalononitrile 1 could act as oxidizing agent, which in turn could diminish yields of the
products. Secondly, due to alkylation of N-methyl-2-thiocarbamoylacetamide 2b (soft nucleophile) with
bromoacetophenone 4b, 3-amino-3-alkylthioacrylamide 14 forms, which by intramolecular acylation yields
N-methyl-2-(4-hydroxy-4-phenyl-4,5-dihydro-1,3-thiazol-2-yl)acetamide 15, which, in turn, after dehydration
produces N-methyl-2-(4-phenyl-1,3-thiazol- 2-yl)acetamide (11).
As the sterically smaller 7H-thiazolo[3,2-a]pyridines 5 and 6a were obtained in high yields, an
explanation for the difference in the case of the desired 6b could be the following: due to steric reasons the
intramolecular acylation of N-methyl-2-benzoylmethylsulfanyl-3,4-dihydronicotinamide (9), obviously,
proceeds slower and competing oxidation takes place to form pyridine 10. Compound 10 was prepared also by
alkylation of thione 12 [2] with 4b in the presence of triethylamine (3b).
N-Methyl-2-(4-phenyl-1,3-thiazol-2-yl)acetamide (11) was obtained also by treatment of compound 2b
with bromoacetophenone 4b in the presence of piperidine 3a.
Treatment of compound 11 with nitrile 1 at room temperature yielded 2-amino-1-methyl-6-oxo-4-phenyl-
5-(4-phenyl-1,3-thiazol-2-yl)-1,6-dihydropyridine-3-carbonitrile (16) as the main product applying either
piperidine 3a or NaOMe (3c) as a base (Scheme 3). Refluxing of the above-mentioned reagents (1 and 11 plus 3a
or 3c) leads to complicated inseparable reaction mixtures. The formation of 16 can be explained as follows. First,
the Michael addition of 11 to 1 takes place to form adduct 17, which further intramolecularly cyclizes and
oxidizes.
Scheme 3
Ph
Ph
Ph
N
N
Ph
+
NC
NC
NC
S
S
3a or 3c
CN
HN
Me
O
HN
Me
O
11
1
17
Ph
Ph
N
N
Ph
Ph
NC
NC
S
S
H2N
N
O
H2N
N
O
Me
Me
16
18
The structures of compounds 10, 11, and 16 have been proved by spectroscopic methods. In the case of
1
10 the characteristic bands for νC=O and νC≡N are observed in the IR spectrum. In the H NMR spectra of
compounds 10 and 11, contrary to 16, the characteristic doublets (J = 4.5–4.6 Hz) of NHCH3 protons are
observed.
To conclude, the investigation of a one-pot cyclocondensation of benzylidenemalononitrile 1, N-methyl-
2-thiocarbamoylacetamide 2b, piperidine 3a, and bromoacetophenone 4b showed that instead of the desired
N-methyl-2,3-dihydro-7H-thiazolo[3,2-a]pyridine-8-carboxamide
(6b),
N-methyl-2-benzoylmethylsulfanyl-4-
phenylnicotin-amide (10), and N-methyl-2-(4-phenyl-1,3-thiazol-2-yl)acet- amide (11) were formed.
655

The formation of alternative products 10 and 11 was determined by competitive Michael reaction of 1
and compound 2b and alkylation of 2b with compound 4b, which proceeded under similar reaction conditions.
Formation of 10 instead of 6b is explained by steric reasons. Due to them, the intramolecular acylation
of N-methyl-2-benzoylmethylsulfanyl-3,4-dihydronicotinamide 9, obviously, proceeded slower and a competing
oxidation took place to form 10.
Easily proceeding cascade reactions by alkylation of 2b with compound 4b led to stable compound 11.
By treatment of 11 with compound 1 under mild reaction conditions, another cascade reaction took place,
yielding 1-methyl-6-oxo-5-(1,3-thiazol-2-yl)-1,6-dihydropyridine-3-carbonitrile 16.
EXPERIMENTAL
Melting points were determined on a Boetius apparatus and are uncorrected. The IR spectra of
suspensions of the compounds in mineral oil were recorded (ν, cm-1) with a Perkin–Elmer 580 B spectrometer.
1
The H NMR spectra were obtained with a Bruker WH 90/DC (90 MHz) spectrometer. Chemical shifts were
expressed downfield from TMS. The course of the reactions and the purity of the substances were monitored by
TLC on Kieselgel 60 F Merck plates with dichloromethane–hexane–methanol (5:5:1) as eluent. Compounds
were recrystallized from EtOH.
N-Methyl-6-amino-2-benzoylmethylsulfanyl-5-cyano-4-phenylnicotinamide (10). A mixture of thione
12 [2] (0.57 g, 1 mmol), triethylamine 3b (0.28 ml, 2 mmol), and bromoacetophenone 4b (0.4 g, 2 mmol) in
ethanol (10 ml) was refluxed for 5 min and stirred at room temperature for 1 h. Then the precipitate was filtered
off and washed with ethanol (2 ml) and water (5 ml) to give nicotinamide 10 (0.66 g, 82%) as yellow crystals,
1
mp 218-220°C. IR spectrum, ν, cm-1: 3460, 3300, 3204 (NH, NH2); 2205 (C≡N); 1698, 1640 (C=O). H NMR
spectrum (DMSO-d6), δ, ppm (J, Hz): 2.42 (3H, d, J = 4.5, NHCH3); 4.86 (2H, s, SCH2); 6.96 (2H, s, NH2); 7.2-
8.2 (11H, m, NHCH3, 2C6H5). Found, %: C 64.69; H 4.33; N 13.61; S 7.87. C22H18N4O2S. Calculated, %: C
65.65; H 4.51; N 13.92; S 7.97.
N-Methyl-2-(4-phenyl-1,3-thiazol-2-yl)acetamide (11).
A
mixture of N-methylthiocarba-
moylacetamide (2b) (2.64 g, 20 mmol), ω-bromoacetophenone 4b (4.4 g, 21 mmol), and piperidine 3a (1 ml,
10 mmol) in ethanol (25 ml) was heated till dissolution and filtered, and gradually of water (10 ml) was added.
After 2 h the precipitate was removed by filtration to give 11 (4.40 g, 94%) as colorless crystals, mp 118-120°C.
1
IR spectrum, ν, cm-1: 3280 (N–H); 1640 (C=O). H NMR spectrum (CDCl3), δ, ppm (J, Hz): 2.86 (3H, d,
J = 4.6, NHCH3); 3.92 (2H, s, CH2); 7.18 (1H, q, J = 4.6, NHCH3); 7.42 (1H, s, H-5); 7.3–7.9 (5H, m, 4-C6H5).
Found, %: C 61.86; H 5.17; N 11.83; S 13.62. C12H12N2OS. Calculated, %: C 62.04; H 5.21; N 12.06; S 13.80.
Cyclocondensation of [1 + 2b + 3a + 4b]. A. A mixture of compounds 1 (0.77 g, 5 mmol), 2b (0.66 g,
5 mmol), and piperidine 3a (0.55 ml, 5.5 mmol) in methanol (10 ml) was stirred at 50°C till dissolution of
reagents; then 4b (1.0 g, 5 mmol) was added and the resulting mixture was stirred at room temperature for 1 h.
Then acetic acid (0.5 ml) was added and after 30-min stirring the reaction mixture was poured into of (100 ml)
water. The precipitate was separated and after recrystallization from ethanol nicotinamide 10 (0.40 g, 20%) as
yellow crystals was obtained, mp 218-220°C. From the remaining filtrate after 5 days, N-methyl-2-(4-phenyl-
1,3-thiazol-2-yl)acetamide (11) (0.14 g, 12%) as colorless crystals was separated by filtration, mp 100–102°C.
B. A mixture of compounds 1 (0.31 g, 2 mmol), 2b (0.27 g, 2 mmol), and piperidine 3a (0.3 ml, 3 mmol)
in 5 ml of ethanol was stirred at 50°C till dissolution of reagents, then 4b (1.0 g, 5 mmol) was added and the
resulting mixture was refluxed for 1 h. Then acetic acid (0.3 ml) was added and after 30-min stirring the reaction
mixture was poured into water (50 ml). The precipitate was separated and after recrystallization from ethanol
nicotinamide 10 (0.39 g, 48%) as yellow crystals was obtained, mp 218–220°C. From the remaining filtrate after
5 h, N-methyl-2-(4-phenyl-1,3-thiazol-2-yl)acetamide (11) (0.11 g, 24%) as colorless crystals was separated
by filtration, mp 100-102°C.
656

Cyclocondensation of [11 + 1 + 3a]. A mixture of compounds 11 (0.70 g, 3 mmol), 1 (0.46 g, 3 mmol),
and piperidine 3a (0.3 ml, 3 mmol) in 10 ml of ethanol was stirred at room temperature for 1 h. Then acetic acid
(0.35 ml) was added and after 30-min stirring the reaction mixture was poured into water (50 ml). The
precipitate was separated and after recrystallization from ethanol 2-amino-1-methyl-6-oxo-4-phenyl-5-(4-
phenyl-1,3-thiazol-2-yl)-1,6-dihydropyridine-3-carbonitrile (16) (0.27 g, 23%) as yellow crystals was
1
obtained, mp 258-259°C. IR spectrum, ν, cm-1: 3430, 3320, 3225 (NH2); 2215 (C≡N); 1652 (C=O). H NMR
spectrum (DMSO-d6), δ, ppm: 3.53 (3H, s, NCH3); 7.1-7.6 (10H, m, 2C6H5); 7.78 (1H, s, thiazolyl H-5); 7.97 (2H,
br. s, 6-NH2). Found, %: C 68.49; H 4.12; N 14.29; S 8.36. C22H16N4OS. Calculated, %: C 68.73; H 4.19;
N 14.57; S 8.34.
Cyclocondensation of [11 + 1 + 3c]. A mixture of compounds 11 (1.16 g, 5 mmol) and 1 (0.77 g, 5 mmol)
in methanol (10 ml) shortly heated till dissolution. Then 2N NaOMe 3c (2.6 ml) was added, the reaction mixture
was stirred for 1 h at the ambient temperature, acetic acid (0.5 ml) was added and the resulted reaction mixture
poured into 100 ml of water. The precipitated crude product was dissolved in ethanol (15 ml) and during 5 days
the precipitated crystals were separated by filtration to give compound 16 (0.61 g, 32%) as yellow crystals, mp
258-259°C.
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