Three possible products from the reactions of Gewald's amide with aromatic aldehydes

Article abstract of DOI:10.1002/jhet.5570450243

(Chemical Equation Presented) Transformations of 2-amino-4,5,6,7- tetrahydrobenzo[b]thiophene-3-carboxamide (Gewald's amide) in the reactions with aromatic aldehydes were studied. Efficient methods for synthesis of three possible types of products: 2-aryl

Full text of DOI:10.1002/jhet.5570450243

Mar-Apr 2008
573
Three Possible Products from the Reactions of Gewald’s Amide
with Aromatic Aldehydes
Sergey G. Dzhavakhishvili1, Nikolay Yu. Gorobets*1, Boris V. Paponov2,
Vladimir I. Musatov1, Sergey M. Desenko1
1Department of Heterocyclic Compounds, STC “Institute for Single Crystals” of National Academy Science of
Ukraine, Lenin Ave 60, Kharkiv 61001, Ukraine, fax: +38(057)3409343; e-mail: gorobets@isc.kharkov.com
2Chemical Department, V.N. Karazin Kharkiv National University, Svobody sq. 4, Kharkiv, 61077, Ukraine
Received February 26, 2007
O
NH2
O
+
R
S
NH2
O
N
O
N
O
NH
NH2
NH
S
S
S
N
H
R
R
R
Transformations of 2-amino-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxamide (Gewald’s amide) in
the reactions with aromatic aldehydes were studied. Efficient methods for synthesis of three possible types
of products: 2-aryl-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-4(3H)-one, 2-(1-arylmethylidene-
amino)-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxamide and 2-aryl-2,3,5,6,7,8-hexahydro[1]benzo-
thieno[2,3-d]pyrimidin-4(1H)-one derivatives were developed. All the products were easily isolated by
filtration in very good overall yields. Mutual transformations of these compounds were also studied.
J. Heterocyclic Chem., 45, 573 (2008).
[10-19], whereas Schiff bases of type 1 was only isolated
as byproducts [22] and thieno[2,3-d]pyrimidines of type 2
were not described at all.
INTRODUCTION
Excellent synthetic methodology for a variety of
substituted 2-aminothiophenes [1-8] has been developed by
Gewald and co-workers [1-4]. Application of 2-cyano-
acetamide in three-component Gewald reaction [6-9] leads
to formation of 2-aminothiophene-3-carboxamides
(Gewald’s amide) which are 1,5-dinucleophiles applied for
synthesis of diverse thieno[2,3-d]pyrimidine derivatives
[10-19]. The last are known to possess anti-inflammatory,
antibacterial, antifungal and antiviral activity [12,14,15]. In
addition reactions of such vicinal amino-amides of various
structure with aromatic aldehydes are known to lead to
three types of products: Schiff bases 1 [20-22], dihydro-
4(1H)-pyrimidinones 2 [23-27], and 4(3H)-pyrimidinones 3
[10-19,27] (Figure 1).
RESULTS AND DISCUSSION
To clarify why not all types of possible products 1-3 are
known in the literature we aimed to investigate reactivity
of synthetically available 2-amino-4,5,6,7-tetrahydrobenzo-
[b]thiophene-3-carboxamide [7] 4 (Gewald’s amide,
Scheme 1) in reactions with aromatic aldehydes 5a-g.
Heating of Gewald’s amide 4 with aromatic aldehydes in
ethanol in the presence of HCl [14,15] in our hands leaded
to the desired products 6 in the mixture with byproducts
and their purification decreased significantly the isolated
yields. Variations of the reaction conditions showed that
heating of the reaction mixture in DMF in the presence of
piperidine leaded to the products 6a-g in good yields and
the purification stage was excluded (Scheme 1, Table 1).
During the variation of solvents it was found that
refluxing of amino-amide 4 with aldehydes 5a-g in
toluene resulted in formation of Schiff bases 7a-g in
excellent yields (Method A, Table 1). Alternatively, the
same compounds were formed in isopropyl alcohol in the
presence of catalytic amounts of piperidine under
controlled microwave irradiation [28] at 150°C for 5 min
O
O
O
R1
R2
R1
R2
R1
R2
NH2
R3
NH
R3
NH
R3
N
NH
N
1
2
3
Figure 1.
However, for the case of 2-aminothiophene-3-
carboxamides only one type of products 3 was described

574
S. G. Dzhavakhishvili, N. Yu. Gorobets, B. V. Paponov, V. I. Musatov, S. M. Desenko
Vol 45
Table 1
(Method B, Table 1). Fortunately, application of Method
B for the synthesis of azomethene 7b (R = 4-CH3) gave
the desired product in the mixture with minority of
Compound
R
Yieldsa, %
6a
6b
6c
6d
6e
6f
H
65
75
80
75
1
derivative 8b, which was observed in H NMR spectrum
4-CH3
4-OCH3
4-Br
of crude reaction product due to the presence of
characteristic singlet of C-H of dihydro-4(1H)-
pyrimidinone ring at 5.63 ppm. Thus, the compounds 8
unknown previously are stable enough and apparently can
be isolated.
4-N(CH3)2
2-OH
4-NO2
H
4-CH3
4-OCH3
4-Br
4-N(CH3)2
2-OH
4-NO2
H
69
72
6g
7a
7b
7c
7d
7e
7f
76
91 (95)b
98 (84)
95 (95)
92 (95)
89 (91)
92 (98)
98 (97)
79
Scheme 1
O
O
N
O
NH
NH2
DMF, !
7g
8a
8b
8c
8d
8e
+
R
S
S
base
NH2
R
4-CH3
4-OCH3
4-Br
83
86
75
84
6a-g
4
5a-g
!
,
t
n
e
v
l
DMF, !
o
S
e
4-N(CH3)2
s
a
b
5a-g
O
O
aThe isolated yields.
bThe yields are given for Method A (B).
NH2
NH
NH
DMF, rt
S
S
Methods
A or B
NaH
N
R
7a-g
8a-e
Thus, the transformations indicated above show that
azomethenes 7 and dihydro-4(1H)-pyrimidinone deriv-
atives 8 are intermediates in the reaction pathway from
Gewald’s amide 4 and aromatic aldehydes 5 to the
products of oxidative heterocyclization 6. However, these
intermediates are very unstable under reaction conditions
applied for the synthesis of the compounds 6. This fact,
probably, rationalizes the lack of literature data about
compounds 7 and 8.
R
Method A: toluene, !
Method B: MW 1500 C/5min, i-PrOH
Solvent: CH2Cl2; 1,4-dioxane; DMF; toluene.
R: a H; b 4-CH3; c 4-OCH3; d 4-Br; e 4-N(CH3)2; f 2-OH; g 4-NO2
To find proper conditions for the preparative synthesis
of compounds 8 we varied solvents and catalysts, time
and temperature under microwave irradiation. However,
high temperature, strong acidic or basic catalysts under
microwave irradiation resulted in the increase of amounts
of undesired products 6 in the final reaction mixtures even
under inert atmosphere. Consequently, the desired 2-aryl-
2,3,5,6,7,8-hexahydro[1]benzothieno[2,3-d]pyrimidin-
4(1H)-ones 8 were unstable under applied conditions and
transformed into 2-aryl-5,6,7,8-tetrahydro[1]benzothieno-
[2,3-d]pyrimidin-4(3H)-ones 6. Therefore, we switch over
to search after suitable conditions for transformation of
azomethenes 7 into dihydro-4(1H)-pyrimidinones 8.
The structure of the obtained compounds 6-8 was
1
identified by H and 13C NMR spectra. Signals of two NH
protons of dihydropyrimidone 8c (R = 4-OCH3) are
observed at 7.46 and 7.68 ppm, whereas amide protons of
azomethene 7c are significantly non-equivalent and
observed at 7.37 and 8.10 ppm. Chemical shifts of
azomethene CH proton and CH proton of dihydro-4(1H)-
pyrimidinone cycle also differ in values (8.43 ppm for 7c
and 5.63 ppm for 8c). In 13C NMR spectra carbon signals
of these methene groups are also distinguished well
(157.4 and 68.3 ppm for CH of 7c and 8c
correspondingly). In CDCl3 solution irradiation of this
methene proton of derivative 8c at 5.75 ppm gives a
significant Nuclear Overhauzer Effect (NOE) on both NH
protons at 4.68 and 5.32 ppm, whereas in the case of
Schiff base 7c such NOE is not observed.
The synthesis of derivatives 8a-e (Scheme 1) was
carried out successfully by dissolving of a mixture of
azomethenes 7a-e and sodium hydride in DMF at room
temperature followed by dilution with water. Such
heterocyclization into dihydro-4(1H)-pyrimidinone under
the found conditions leaded to isolation of products 8a-e
in very good yields (Table 1). It should be noted that even
mild heating of azomethenes 7a-e with sodium hydride in
the media of different solvents (DMF, 1,4-dioxane,
CH2Cl2, toluene) resulted in the formation of the
dehydration products 6. Furthermore, the same products 6
were also readily obtained from azomethenes 7 by
refluxing in DMF in the presence of piperidine.
In conclusion, in the present work we have studied the
transformations of Gewald’s amide in the reactions with
aromatic aldehydes leading to derivatives of 2-aryl-
5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-4(3H)-
one 6, 2-(1-arylmethylideneamino)-4,5,6,7-tetrahydro-
benzo[b]thiophene-3-carboxamide 7 and 2-aryl-2,3,5,6,
7,8-hexahydro[1]benzothieno[2,3-d]pyrimidin-4(1H)-

Mar-Apr 2008
Three Possible Products from the Reactions of Gewald’s Amide with Aromatic Aldehydes
575
1H), 12.11 (bs, 1H, NH); Anal. Calcd. for C16H16N2O2S: C,
63.98; H, 5.37; N, 9.33. Found: C, 63.95; H, 5.41; N, 9.35.
6g: mp >300 °C; ir (potassium bromide): 3401 (NH), 2930
one
8 in very good yields. It was found that
azomethenes 7 and dihydro-4(1H)-pyrimidinones 8
were unstable under the conditions which were used for
the reactions of Gewald’s amides with aromatic
aldehydes, however we succeeded in finding the
reaction conditions for preparation and identification of
these compounds. Thus, we proposed efficient protocols
for the synthesis of all three possible products of the
investigated reactions.
s
(Csp3-H), 1653 (C=O), 1519 (NO2as), 1343 (NO2 ), 848 (Car-N)
cm-1; 1H nmr (200 MHz, DMSO-d6): δ = 1.56-1.97 (m, 4H), 2.74
(s, 2H), 2.89 (s, 2H), 8.28 (d, J = 9.2 Hz, 2H), 8.35 (d, J = 9.2
Hz, 2H), 12.05 (bs, 1H, NH); Anal. Calcd. for C16H15N3O3S: C,
58.34; H, 4.59; N, 12.76. Found: C, 58.39; H, 4.50; N, 12.77.
General procedure for the synthesis of 2-(1-arylmethyl-
ideneamino)-4,5,6,7-tetrahydrobenzo[b]thiophene-3-car-
boxamide derivatives (7). Method A: The mixture of 2-amino-
4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxamide 4 (2 mmol)
and aromatic aldehyde 5 (2.2 mmol) in 5 mL of toluene was
refluxed for 15 minutes. After the mixture was cooled the
crystalline precipitate formed was filtered off and washed with
ethanol (2x1 mL). Method B: The mixture of 4 (2 mmol) and
aldehyde 5 (2.2 mmol), 0.15 mL of piperidine and 1.5 mL of
isopropyl alcohol in a sealed Emrys process vial (for 0.5-2.5 mL
of reaction mixture) was irradiated with microwaves at 150 °C
for 5 min (for the experiments EmrysTM Creator EXP from
Biotage, Uppsala was used, absorption was chosen as “Normal”,
the reaction time as “Fixed hold time”, the maximal pressure
inside the vial reached 8-10 bar). After the mixture was cooled a
yellow crystalline precipitate formed was filtered off and
washed with ethanol. Yields are listed in Table 1.
EXPERIMENTAL
General procedure for the synthesis of 2-aryl-5,6,7,8-
tetrahydro[1]benzothieno[2,3-d]pyrimidin-4(3H)-one deriv-
atives (6). A mixture of 2-amino-4,5,6,7-tetrahydrobenzo[b]-
thiophene-3-carboxamide 4 (2 mmol) and aromatic aldehyde 5
(2.2 mmol) was dissolved in 5 mL of DMF and 0.15 mL of
piperidine was added. The reaction mixture was refluxed for 20
– 30 minutes. A yellow crystalline precipitate formed was
collected by filtration and washed with ethanol. Yields are listed
in Table 1.
Compound 6a: mp 266-268 °C; ir (potassium bromide): 3401
(NH), 2932 (Csp3-H), 1657 (C=O) cm-1; 1H nmr (200 MHz,
DMSO-d6): δ = 1.51-1.99 (m, 4H), 2.73 (s, 2H), 2.89 (s, 2H),
7.38-7.70 (m, 3H), 7.99-8.21 (m, 2H), 12.48 (bs, 1H, NH); Anal.
Calcd. for C16H16N2OS: C, 67.58; H, 5.67; N, 9.85. Found: C,
67.55; H, 5.71; N, 9.95.
Compound 7a: mp 176-178 °C; ir (potassium bromide): 3376
(NH), 3178 (NH), 2929 (Csp3-H), 1655 (C=O), 1599 (C=N)
cm-1; 1H nmr (200 MHz, DMSO-d6): δ = 1.47-1.95 (m, 4H),
2.54-2.90 (m, 4H), 7.44 (s, 1H, NH2); 7.46-7.65 (m, 3H), 7.78-
7.96 (m, 2H), 8.01 (s, 1H, NH2), 8.52 (s, 1H); Anal. Calcd. for
C16H14N2OS: C, 68.06; H, 5.00; N, 9.92. Found: C, 68.01; H,
4.89; N, 9.92.
6b: mp 272-274 °C; ir (potassium bromide): 3401 (NH), 2931
(Csp3-H), 1651 (C=O) cm-1; H nmr (200 MHz, DMSO-d6): δ =
1.59-1.91 (m, 4H), 2.36 (s, 3H), 2.74 (s, 2H), 2.89 (m, 2H), 7.31
(d, J = 8.2 Hz, 2H), 8.01 (d, J = 8.2 Hz, 2H), 12.38 (bs, 1H, NH);
Anal. Calcd. for C17H18N2OS: C, 68.42; H, 6.08; N, 9.39. Found:
C, 68.40; H, 6.11; N, 9.37.
1
7b: mp 184-186 °C; ir (potassium bromide): 3400 (NH), 3171
1
(NH), 2929 (Csp3-H), 1648 (C=O), 1609 (C=N) cm-1; H nmr
(200 MHz, DMSO-d6): δ = 1.48-1.86 (m, 4H), 2.36 (s, 3H),
2.52-2.82 (m, 4H), 7.31 (d, J = 8.1 Hz, 2H), 7.39 (s, 1H, NH2),
7.78 (d, J = 8.1 Hz, 2H), 8.05 (s, 1H, NH2), 8.46 (s, 1H); Anal.
Calcd. for C17H16N2OS: C, 68.89; H, 5.44; N, 9.45. Found: C,
68.85; H, 5.52; N, 9.41.
6c: mp 265-267 °C; ir (potassium bromide): 3402 (NH), 2930
1
(Csp3-H), 1648 (C=O) cm-1; H nmr (200 MHz, DMSO-d6): δ =
1.58-1.95 (m, 4H), 2.72 (m, 2H), 2.87 (m, 2H), 3.81 (s, 3H),
7.03 (d, J = 9.0 Hz, 2H), 8.10 (d, J = 9.0 Hz, 2H), 12.35 (bs, 1H,
NH); 13C nmr (125 MHz, DMSO-d6): δ = 22.6 (CH2), 23.7
(CH2), 25.4 (CH2), 26.4 (CH2), 56.0 (OCH3), 114.6, 115.1 (CH),
129.8, 130.8, 131.4 (CH), 136.8, 151.5, 157.4, 163.0, 165.6
(APT); ms (EI, 70 eV): m/z (%) 284 (16), 285 (7), 297 (7), 311
(12), 312 (M+, 100), 313 (23), 314 (7); Anal. Calcd. for
C17H16N2O2S: C, 65.36; H, 5.16; N, 8.97. Found: C, 65.42; H,
5.21; N, 8.88.
6d: mp >300 °C; ir (potassium bromide): 3417 (NH), 2931
(Csp3-H), 1654 (C=O) cm-1; H nmr (200 MHz, DMSO-d6): δ =
1.66-1.91 (m, 4H), 2.75 (s, 2H), 2.90 (s, 2H), 7.71 (d, J = 8.8 Hz,
2H), 8.05 (d, J = 8.8 Hz, 2H), 12.52 (bs, 1H, NH); Anal. Calcd.
for C16H15BrN2OS: C, 52.90; H, 4.16; N, 7.71. Found: C, 53.02;
H, 4.14; N, 7.71.
7c: mp 160-162 °C; ir (potassium bromide): 3386 (NH), 3194
1
(NH), 2931 (Csp3-H), 1626 (C=O), 1600 (C=N) cm-1; H nmr
(200 MHz, DMSO-d6): δ = 1.57-1.87 (m, 4H), 2.55-2.82 (m,
4H), 3.82 (s, 3H), 7.06 (d, J = 8.7 Hz, 2H), 7.37 (s, 1H, NH2),
7.85 (d, J = 8.7 Hz, 2H), 8.10 (s, 1H, NH2), 8.43 (s, 1H); 1H nmr
(200 MHz, deuteriochloroform): δ = 1.56-2.02 (m, 4H), 2.53-
2.83 (m, 2H), 2.85-3.13 (m, 2H), 3.88 (s, 3H), 5.75 (bs, 1H,
NH), 6.97 (d, J = 8.9 Hz, 2H), 7.74 (d, J = 8.9 Hz), 8.33 (s, 1H),
8.82 (bs, 1H, NH); 13C nmr (125 MHz, DMSO-d6): δ = 22.6
(CH2), 23.1 (CH2), 25.4 (CH2), 26.4 (CH2), 56.0 (OCH3), 115.1
(CH), 128.4, 129.0, 130.8, 131.4 (CH), 136.3, 151.4, 157.4
(CH), 163.0, 165.5 (APT); ms (EI, 70 eV): m/z (%) 220 (9), 241
(11), 253 (6), 254 (6), 266 (12), 268 (13), 296 (28), 297 (72),
298 (12), 314 (M+, 100), 315 (20), 316 (8); Anal. Calcd. for
C17H18N2O2S: C, 64.94; H, 5.77; N, 8.91. Found: C, 65.01; H,
5.85; N, 8.79.
7d: mp 250-252 °C; ir (potassium bromide): 3386 (NH), 3194
(NH), 2931 (Csp3-H), 1630 (C=O), 1600 (C=N), 816 (C-Br) cm-1;
1H nmr (200 MHz, DMSO-d6): δ = 1.53-1.93 (m, 4H), 2.55-2.82
(m, 4H), 7.41 (s, 1H, NH2), 7.71 (d, J = 8.6 Hz, 2H), 7.83 (d, J =
8.6 Hz, 2H), 7.90 (s, 1H, NH2), 8.48 (s, 1H); 13C nmr (125 MHz,
DMSO-d6): δ = 22.5 (CH2), 23.0 (CH2), 25.4 (CH2), 26.0 (CH2),
125.9, 131.0, 131.4, 132.3, 132.4, 132.5, 132.7, 135.0, 156.3,
1
6e: mp 229-231 °C; ir (potassium bromide): 3405 (NH), 2938
1
(Csp3-H), 1650 (C=O) cm-1; H nmr (200 MHz, DMSO-d6): δ =
1.52-1.97 (m, 4H), 2.70 (s, 2H), 2.87 (s, 2H), 4.34 (s, 6H), 6.76
(d, J = 8.9 Hz, 2H), 8.02 (d, J = 8.9 Hz, 2H), 12.10 (bs, 1H, NH);
Anal. Calcd. for C18H21N3OS: C, 66.02; H, 6.46; N, 12.83.
Found: C, 66.11; H, 6.48; N, 12.85.
6f: mp >300 °C; ir (potassium bromide): 3416 (NH), 2940
(Csp3-H), 1655 (C=O), 1237 (C-O) cm-1; 1H nmr (200 MHz,
DMSO-d6): δ = 1.50-1.99 (m, 4H), 2.74 (s, 2H), 2.88 (s, 2H),
6.82-7.09 (m, 2H), 7.39 (tr, J = 7.9 Hz, 1H), 8.10 (d, J = 8.1 Hz,

576
S. G. Dzhavakhishvili, N. Yu. Gorobets, B. V. Paponov, V. I. Musatov, S. M. Desenko
Vol 45
165.5; Anal. Calcd. for C16H13BrN2OS: C, 53.20; H, 3.63; N,
7.75. Found: C, 53.24; H, 3.59; N, 7.73.
8d: mp 186-188 °C; ir (potassium bromide): 3328 (NH), 3182
1
(NH), 2931 (Csp3-H), 2834 (Csp3-H), 1645 (C=O) cm-1; H nmr
(200 MHz, DMSO-d6): δ = 1.45-1.85 (m, 4H), 2.45 (s, 2H), 2.63
(s, 2H), 5.68 (s, 1H), 7.40 (d, J = 8.6 Hz, 2H), 7.57 (d, J = 8.6
Hz, 2H), 7.66 (s, 1H, NH), 7.82 (s, 1H, NH); 13C nmr (125 MHz,
DMSO-d6): δ = 22.5 (CH2), 23.4 (CH2), 24.3 (CH2), 25.9 (CH2),
67.5 (CH), 110.9, 119.7, 121.9, 129.4, 131.6, 132.3, 141.2,
156.6, 162.6; Anal. Calcd. for C16H15BrN2OS: C, 52.90; H, 4.16;
N, 7.71. Found: C, 52.92; H, 4.11; N, 7.64.
7e: mp 122-124 °C; ir (potassium bromide): 3380 (NH), 3171
(NH), 2920 (Csp3-H), 1639 (C=O), 1611 (C=N), 813 (Car-N)
1
cm-1; H nmr (200 MHz, DMSO-d6): δ = 1.48-1.92 (m, 4H),
2.57-2.87 (m, 4H), 3.02 (s, 6H), 6.78 (d, J = 9.0 Hz, 2H), 7.28 (s,
1H, NH2), 7.70 (d, J = 8.7 Hz, 2H), 8.31 (s, 1H), 8.36 (s, 1H,
NH2); Anal. Calcd. for C18H19N3OS: C, 66.43; H, 5.88; N, 12.91.
Found: C, 66.39; H, 5.90; N, 12.91.
0
8e: mp 176-178 C; ir (potassium bromide): 3378 (NH), 3235
7f: mp 209-211 °C; ir (potassium bromide): 3404 (OH), 3311
(NH), 3245 (NH), 2934 (Csp3-H), 1640 (C=O), 1611 (C=N),
(NH), 2931 (Csp3-H), 2831 (Csp3-H), 1625 (C=O), 824 (Car-N)
cm-1; 1H nmr (200 MHz, DMSO-d6): δ = 1.51-1.84 (m, 4H); 2.44
(s, 2H); 2.64 (s, 2H); 2.87 (s, 6H); 5.56 (s, 1H); 6.69 (d, J = 9.0
Hz, 2H); 7.26 (d, J = 9.0 Hz, 2H); 7.32 (s, 1H, NH); 7.59 (s, 1H,
NH); Anal. Calcd. for C18H21N3OS: C, 66.02; H, 6.46; N, 12.83.
Found: C, 65.95; H, 6.40; N, 12.86.
1
1575 (NHdef), 1434 (NHdef) cm-1; H nmr (200 MHz, DMSO-d6):
δ = 1.30-2.03 (m, 4H), 2.49-3.01 (m, 4H), 6.68-7.04 (m, 2H),
7.22-7.44 (m, 1H), 7.50 (s, 1H, NH2), 7.66 (d, J = 7.9 Hz, 1H),
7.87 (s, 1H, NH2), 8.63 (s, 1H), 11.79 (s, 1H, OH); Anal. Calcd.
for C16H14N2O2S: C, 64.41; H, 4.73; N, 9.39. Found: C, 64.46;
H, 4.75; N, 9.35.
7i: mp 218-220 °C; ir (potassium bromide): 3380 (NH), 2928
s
REFERENCES
(Csp3-H), 1644 (C=O), 1572 (C=N), 1516 (NO2as), 1338 (NO2 )
1
cm-1; H nmr (200 MHz, DMSO-d6): δ = 1.49-1.88 (m, 4H),
[1] Gewald, K. Angew. Chem. 1961, 73, 114.
[2] Gewald, K. Chem. Ber. 1965, 98, 3571.
[3] Gewald, K.; Schinke, E.; Bottcher, H. Chem. Ber. 1966,
99, 94-98.
[4] Gewald, K.; Schinke E. Chem. Ber. 1966, 99, 2712.
[5] Peet, N. P.; Sunder, S.; Barbuch, R. J. J. Heterocycl.
Chem. 1986, 23, 129-134.
2.52-2.83 (m, 4H), 7.49 (s, 1H, NH2), 7.81 (s, 1H, NH2), 8.11 (d,
J = 8.9 Hz, 2H), 8.32 (d, J = 8.9 Hz, 2H), 8.60 (s, 1H); Anal.
Calcd. for C16H13N3O3S: C, 58.70; H, 4.00; N, 12.84; Found: C,
58.61; H, 3.96; N, 12.85.
General procedure for the synthesis of 2-aryl-2,3,5,
6,7,8-hexahydro[1]benzothieno[2,3-d]pyrimidin-4(1H)-one
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(8).
A mixture of 2-(1-arylmethylideneamino)-4,5,6,7-
tetrahydrobenzo-[b]thiophene-3-carboxamide 7 (2 mmol) and
sodium hydride (4 mmol) was dissolved in 2 mL of DMF at
room temperature. To the stirring reaction mixture 2 mL of
water was poured. A yellow crystalline precipitate formed was
filtered off and washed with ethanol (2x1 mL) and hexane (2x2
mL). Yields are listed in Table 1.
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Compound 8a: mp 148-150 °C; ir (potassium bromide): 3387
(NH), 3209 (NH), 2927 (Csp3-H), 2844 (Csp3-H), 1639 (C=O)
cm-1; 1H nmr (200 MHz, DMSO-d6): δ = 1.42-1.85 (m, 4H), 2.44
(s, 2H), 2.62 (s, 2H), 5.68 (s, 1H), 7.26-7.53 (m, 5H), 7.61 (s,
1H, NH), 7.81 (s, 1H, NH); Anal. Calcd. for C16H16N2OS: C,
67.58; H, 5.67; N, 9.85. Found: C, 67.51; H, 5.65; N, 9.87.
8b: mp 168-170 0C; ir (potassium bromide): 3375 (NH), 3213
1
(NH), 2929 (Csp3-H), 2838 (Csp3-H), 1634 (C=O) cm-1; H nmr
(200 MHz, DMSO-d6): δ = 1.51-1.86 (m, 4H); 2.44 (s, 2H); 2.64
(s, 2H); 2.28 (s, 3H); 5.63 (s, 3H); 7.16 (d, J = 8.3 Hz, 2H); 7.34
(d, J = 8.3 Hz, 2H); 7.52 (s, 1H, NH); 7.73 (s, 1H, NH); Anal.
Calcd. for C17H18N2OS: C, 68.42; H, 6.08; N, 9.39. Found: C,
68.37; H, 6.02; N, 9.39.
8c: mp 151-153 °C; ir (potassium bromide): 3344 (NH), 3249
1
(NH), 2930 (Csp3-H), 2834 (Csp3-H), 1629 (C=O) cm-1; H nmr
(200 MHz, DMSO-d6): δ = 1.49-1.83 (m, 4H), 2.45 (m, 2H),
2.64 (m, 2H), 3.73 (s, 3H), 5.63 (s, 1H), 6.92 (d, J = 8.8 Hz, 2H),
7.38 (d, J = 8.8 Hz, 2H), 7.46 (s, NH, 1H), 7.68 (s, NH, 1H); 1H
nmr (200 MHz, deuteriochloroform): δ = 1.47-2.03 (m, 4H),
2.56 (m, 2H), 2.62-3.12 (m, 2H), 3.81 (s, 3H), 4.68 (s, 1H, NH),
5.32 (s, 1H, NH), 5.75 (s, 1H), 6.90 (d, J = 8.5 Hz, 2H), 7.46 (d,
J = 8.5 Hz, 2H); 13C nmr (125 MHz, DMSO-d6): δ = 22.5 (CH2),
23.5 (CH2), 24.3 (CH2), 25.9 (CH2), 55.6 (OCH3) 68.3 (CH),
110.7, 114.0 (CH), 119.4, 128.6 (CH), 132.3, 133.2, 157.0,
159.8, 162.9 (APT); ms (EI, 70 eV): m/z (%) 179 (15), 284 (6),
297 (54), 298 (14), 312 (13), 314 (M+, 100), 315 (31), 316 (8);
Anal. Calcd. for C17H18N2O2S: C, 64.94; H, 5.77; N, 8.91.
Found: C, 65.03; H, 5.81; N, 8. 95.

Mar-Apr 2008
Three Possible Products from the Reactions of Gewald’s Amide with Aromatic Aldehydes
577
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