Mannich bases as synthetic intermediates: Convenient synthesis of functionalized 1,2,4-triazepines, 1,4-diazepines and 1,5-diazocines

Article abstract of DOI:10.1515/znb-2011-0605

Transamination between the ketonic Mannich bases 1a, b and primary arylamines gave a series of ketonic sec-Mannich bases 2a - h. A variety of tetrahydro-1,2,4-triazepines 3a - f have been synthesized by treating the arylhydrazones of 2 with formaldehyde. A similar reaction with the benzenesulfonylhydrazone of 2b afforded 4. The 3-styryl-2H-1,2,4-triazepine 5 was obtained from the phenylhydrazone of 2a and cinnamaldehyde. Treatment of arylhydrazones of the 4-methoxystyryl keto base 7 with formaldehyde and cinnamaldehyde afforded the 3,4,5,6-tetrahydro-2H-1,2,4-triazepines 8a, b. Mannich reaction with 4-(p-hydroxyphenyl)-tetrahydro-1,2,4-triazepine 3d afforded the Mannich bases 9, 10 and 11. The reaction of 1b with o-phenylenediamine leads to the 1,5-benzodiazepine 13. The new tetrahydro- 1,4-diazepine and tetrahydro-1,5-diazocine Mannich bases 15 and 17 were obtained from 1b and ethylenediamine or 1,3-diaminopropane, respectively. The bi(piperidine) derivative 19 was obtained from 1a and 1,3-diaminopropane.

Full text of DOI:10.1515/znb-2011-0605

Mannich Bases as Synthetic Intermediates: Convenient Synthesis of
Functionalized 1,2,4-Triazepines, 1,4-Diazepines and 1,5-Diazocines
Elsayed M. Afsah, Eman M. Keshk, Abdel-Rahman H. Abdel-Rahman, and Najla F. Jomah
Chemistry Department, Faculty of Science, Mansoura University, ET-35516, Mansoura, Egypt
Reprint requests to Prof. Dr. E. M. Afsah. E-mail: emafsah@yahoo.com
Z. Naturforsch. 2011, 66b, 577 – 584; received March 25, 2011
Transamination between the ketonic Mannich bases 1a, b and primary arylamines gave a series
of ketonic sec-Mannich bases 2a – h. A variety of tetrahydro-1,2,4-triazepines 3a – f have been syn-
thesized by treating the arylhydrazones of 2 with formaldehyde. A similar reaction with the ben-
zenesulfonylhydrazone of 2b afforded 4. The 3-styryl-2H-1,2,4-triazepine 5 was obtained from the
phenylhydrazone of 2a and cinnamaldehyde. Treatment of arylhydrazones of the 4-methoxystyryl
keto base 7 with formaldehyde and cinnamaldehyde afforded the 3,4,5,6-tetrahydro-2H-1,2,4-tri-
azepines 8a, b. Mannich reaction with 4-(p-hydroxyphenyl)-tetrahydro-1,2,4-triazepine 3d afforded
the Mannich bases 9, 10 and 11.
The reaction of 1b with o-phenylenediamine leads to the 1,5-benzodiazepine 13. The new tetra-
hydro-1,4-diazepine and tetrahydro-1,5-diazocine Mannich bases 15 and 17 were obtained from 1b
and ethylenediamine or 1,3-diaminopropane, respectively. The bi(piperidine) derivative 19 was ob-
tained from 1a and 1,3-diaminopropane.
Key words: Mannich Bases, 1,2,4-Triazepines, 1,4-Diazepines, 1,5-Diazocines
Introduction
azepines, tetrahydro-1,4-diazepines, tetrahydro-1,5-di-
azocines, and bi(piperidines), which possess consider-
able synthetic and pharmaceutical interest.
Mannich bases have been used extensively in the
synthesis of heterocyclic systems [1 – 6] and of hetero-
cycles having a potential basic side chain of alkaloidal
nature [7 – 13]. In particular, ketonic tert-Mannich
bases and their quaternary salts have been employed
Results and Discussion
A series of ketonic sec-Mannich bases 2a – h was
frequently as potential intermediates in the synthe- prepared by transamination reaction between the ke-
sis of a multitude of heterocycles of pharmaceutical tonic tert-Mannich base hydrochloride 1a or 1b and
interest, such as pyrazolines [9 – 11], pyridines [3], the appropriate primary aromatic amine, according to
piperidines [14 – 16], 1,5-benzo- or 1,5-hetero-diazep- an earlier report [27]. Compounds 2f – h have been re-
ines [16 – 19], and quinolines [20]. The use of sec- ported for the first time by this study. It was found
Mannich bases as synthetic intermediates has been re- that treatment of the ketonic sec-amines of the type 2
ported in a limited number of cases for the synthesis with p-nitrophenylhydrazine or phenylhydrazine, and
of pyrimidines [21], quinolines [22, 23] and isoquino- subsequently with formaldehyde under mild condi-
lines [24, 25], and recently we reported [16] the syn- tions, afforded a series of 3,4,5,6-tetrahydro-2,4,7-tri-
thesis of the 2H-1,2,4-triazepine ring system starting aryl-2H-1,2,4-triazepines (3a – f) with different sub-
with ketonic sec-amine bases.
stituents on the 1,2,4-triazepine ring (Scheme 1).
In line with this, the 2-benzenesulfonyl-tetrahydro-
In connection with our studies in the area of Man-
nich bases [4, 11 – 13, 16, 26] and in view of the 1,2,4-triazepine derivative 4 was obtained by treat-
widespread and increasing interest in the chemistry ing 2b with benzenesulfonyl hydrazide and formalde-
and biological activities of Mannich bases and related hyde. The synthesis of the 3-styryl-tetrahydro-1,2,4-
compounds, the synthetic potential of ketonic sec- triazepine 5 was achieved by treating the phenylhy-
Mannich bases as intermediates in heterocyclic synthe- drazone of 2a with cinnamaldehyde. A practical ad-
sis was further investigated. We report here on the syn- vantage of the reactions leading to the 3,4,5,6-tetra-
thesis of some new functionalized tetrahydro-1,2,4-tri- hydro-2H-1,2,4-triazepine derivatives 3 – 5 is that it is
c
0932–0776 / 11 / 0600–0577 $ 06.00 ꢀ 2011 Verlag der Zeitschrift fu¨r Naturforschung, Tu¨bingen · http://znaturforsch.com
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E. M. Afsah et al. · Mannich Bases as Synthetic Intermediates
3c: m/z = 406 M+ (14)
m/z = 407 (3)
m/z = 408 (4)
NO2
m/ z = 122 (8)
m/ z = 111 (14)
+2H+
Cl
(a)
H
N
N
N
N
(b)
N
Cl
N
Ph
m/ z = 77
(c)
(18)
m/ z = 98 (5)
m/z = 207 (100%)
+H+ m/z = 208 (19)
+2H+ m/ z = 209 (4)
(c)
Ar
N
N
H2C=N
Cl
Ph
+
m/ z = 267 (26)
Ar = C6H4-4-NO2
m/z = 139 (10)
+H+ m/ z = 140 (20)
Scheme 2.
spectively (Scheme 3). The analytical and spectral data
of 8a and 8b are consistent with their structures.
The Mannich reaction of the 4-(p-hydroxyphenyl)-
tetrahydro-2H-1,2,4-triazepine (3d) is of particular in-
terest, because it provides access to tetrahydro-2H-
1,2,4-triazepines having a phenolic Mannich base as
a structural unit. This has been achieved by treating 3d
with dimethylamine or piperidine and formaldehyde to
Scheme 1.
often unnecessary to isolate the arylhydrazone inter-
mediates of the ketonic sec-Mannich bases. The mass
1
and H NMR spectra of compounds 3 – 5 are consis-
tent with their structures. The main characteristic fea-
1
tures of the H NMR spectrum of 3a are a singlet at
δ = 5.35 assignable to 3-H2 and two triplets at δ =
3.65 (5-H2) and 3.38 (6-H2), and a singlet at δ = 2.33
(Ar-CH3). The mass spectra of 3a – f, 4 and 5 contain
peaks of the respective molecular ions, and fragmen-
tation patterns which supported their structures. As an
example the fragmentation pattern of 3c is depicted in
Scheme 2.
The scope of the above reaction has been
broadened by treatment of the arylhydrazones de-
rived from 1-(p-anisyl)-5-(p-tolylamino)-1-penten-3-
one (7) with formaldehyde or cinnamaldehyde to
afford 7-(4-methoxystyryl)-tetrahydro-2-phenyl-4-(p-
tolyl)-2H-1,2,4-tiazepine (8a) and 7-(4-methoxystyr-
yl)-3-styryl-tetrahydro-2H-1,2,4-triazepine (8b), re- Scheme 3.
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E. M. Afsah et al. · Mannich Bases as Synthetic Intermediates
579
new Mannich base 15. The reaction of 1b with 1,3-
diaminopropane proceeded quite analogously to af-
ford 3,4,7,8-tetrahydro-1-(β-4-hydroxybenzoylethyl)-
6-(4-hydroxyphenyl)-2H-1,5-diazocine (17). The re-
action of 1b with ethylenediamine and 1,3-diamino-
propane is of particular interest, because it offers
access with good yields to the new tetrahydro-
1,4-diazepine and tetrahydro-1,5-diazocine Mannich
bases 15 and 17, respectively.
The mass spectrum of 17 exhibited a molecular ion
peak at m/z = 352 [M]+ and a peak at m/z = 110
due to the tetrahydro-1,5-diazocineunit. The side chain
can be identified by two peaks at m/z = 121 and 149
(Scheme 6). The formation of 15 and 17 is in line with
our recent report [16] on the reaction of bis-ketonic
Mannich bases with ethylenediamine.
On the other hand, the reaction of 1a with 1,3-di-
aminopropane in a molar ratio of 4 : 1 takes a dif-
ferent course. The reaction proceeded smoothly to
Scheme 4.
give the mono-(Mannich base) 9 or the bis-(Mannich
bases) 10 and 11 depending on the molar ratio of the
reactants (Scheme 4).
The structures of compounds 9 – 11 are supported
by analytical and spectral data. The 1H NMR specrum
of 9 displays four singlets at δ = 2.38 (NMe2), 3.67
(Ar-CH2N), 5.17 (3-H2), and 6.71 (ArOH), and two
triplets at δ = 3.62 (5-H2) and 3.34 (6-H2). The mass
spectra of 9, 10 and 11 revealed molecular ion peaks
at m/z = 400, 458 [M+1]+ and 537, respectively, and
fragmentation patterns which supported their struc-
tures.
In connection with the present study, the transam-
ination reaction between 1b and o-phenylenedi-
amine afforded the 2,3-dihydro-4-(p-hydroxyphenyl)-
1H-1,5-benzodiazepine 13. It is believed that the ini-
tially formed intermediate 12 readily undergoes cy-
clodehydration to give 13, as confirmed by analytical
and spectral data (Scheme 5).
On the other hand, the reaction of 1b with ethylene-
diamine led to the formation of 2,3,6,7-tetrahydro-1-
(β-4-hydroxybenzoylethyl)-5-(4-hydroxyphenyl)-1H-
1,4-diazepine (15) rather than the tetrahydro-1,4-di-
azepine 14, which would be the expected product.
Obviously, 15 was formed via the intermediacy of
the non-isolable tetrahydro-1,4-diazepine 14, result-
ing from the cyclocondensation reaction of ethylene-
diamine with 1b, which readily reacts further with a
second molecule of 1b via transamination to afford the Scheme 5.
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E. M. Afsah et al. · Mannich Bases as Synthetic Intermediates
50 % aqueous ethanol (80 mL) was refluxed for 90 min.
The product obtained on cooling was filtered and crystallized
from ethanol to give 2f – h.
4-(3-Oxo-3-phenylpropylamino)benzamide (2f)
M. p. 198 ◦C. Yield 75 % (colorless crystals). – IR (KBr):
ν = 3399 (NH), 3360 (CONH), 1666 (CO), 1592, 1388,
1326, 1060 cm−1. – 1H NMR (CDCl3): δ = 2.46 (t, 2H,
COCH2CH2N), 3.31 (t, 2H, COCH2CH2N), 4.40 (s, 1H,
ArNH), 7.19 – 7.73 (m, 9H, aromatic), 8.11 (br. s, 2H,
CONH2). – MS (EI, 70 eV): m/z (%) = 268 (18) [M]+, 267
(2) [M–1]+, 149 (100) [CH2NH-C6H4-CONH2]+, 136 (7),
133 (3), 132 (12), 120 (11), 105 (37), 77 (32). – C16H16N2O2
(268.31): calcd. C 71.62, H 6.01, N 10.44; found C 71.59,
H 5.58, N 10.21.
Scheme 6.
give 1,3-bis(3-benzoyl-4-hydroxy-4-phenylpiperidin-
1-yl)propane (19), via the intermediacy of N,N,Nꢀ,Nꢀ-
tetra(β-benzoylethyl)-1,3-diaminopropane(18), which
undergoes intramolecular aldolization to give 19 as the
end product. The identity of the product as the bi-
(piperidinol) 19, and not the isomeric tetraketo base 18,
was shown by the IR spectrum which displayed a
strong OH band at 3421 cm−1 as well as the absorption
band at 1629 cm−1 for C=O. The tendency of primary
alkyl amines to undergo double N-alkylation with ke-
tonic Mannich bases, and subsequent aldolization of
the resulting bis-(ketonic Mannich bases) to N-alkyl
piperidinols, has been previously reported [14– 16].
Attempts to isolate the intermediate tetraketo base 18
were unsuccessful due to the ease with which such
bases undergo aldolization even at r. t.
4-(3-Oxo-3-phenylpropylamino)benzenesulfonamide (2g)
M. p. 220 ◦C. Yield 60 % (colorless crystals). – IR (KBr):
ν = 3410 (NH), 3380 (SO2NH), 1671 (CO), 1469, 1330,
1226, 1145 cm−1. – MS (EI, 70 eV): m/z (%) = 304 (14)
[M]+, 305 (3) [M+1]+, 303 (2) [M–1]+, 185 (100) [CH2NH-
C6H4-SO2NH2]+, 172 (10), 156 (6), 133 (4), 119 (10)
[PhCOCH2]+, 105 (56) [PhCO]+, 77 (39). – C15H16N2O3S
(304.36): calcd. C 59.19, H 5.30, N 9.20; found C 59.09,
H 5.21, N 9.11.
3-(4-Hydroxyphenylamino)-1-(4-hydroxyphenyl)propan-1-
one (2h)
◦
M. p. 185 C. Yield 57 % (yellow crystals). – IR (KBr):
ν = 3439 (OH), 3366 (NH), 1664 (CO), 1492, 1338,
1226, 1120 cm−1. – 1H NMR (CDCl3): δ = 2.34 (t, 2H,
COCH2CH2N), 3.42 (t, 2H, COCH2CH2N), 4.46 (s, 1H,
ArNH), 7.11 – 7.82 (m, 8H, aromatic), 11.77 (s, 2H, 2×
OH). – MS (EI, 70 eV): m/z (%) = 257 (10) [M]+,
148 (37) [HO-C6H4-COCH=CH2]+, 121 (100) [HO-C6H4-
CO]+, 109 (43), 93 (25). – C15H15NO3 (257.28): calcd.
C 70.02, H 5.88, N 5.44; found C 69.95, H 5.82, N 5.31.
Experimental Section
All melting points (uncorrected) were determined on a
Gallenkamp electric melting point apparatus. Elemental mi-
croanalyses were carried out at the Microanalytical Unit,
Faculty of Science, Cairo University. Infrared spectra were
measured on a Mattson 5000 FTIR spectrometer. 1H and
13C NMR data were obtained in CDCl3 or [D6]DMSO so-
lution on a Varian XL 200 MHz instrument using TMS as
internal standard. Chemical shifts are reported in ppm (δ)
downfield from internal TMS. Mass spectra were recorded
on a GC-MS QP-1000 EX Shimadzu instrument. The course
of the reaction and the purity of the synthesized compounds
were monitored by TLC using EM science silica gel-coated
plates with visualization by irradiation with an ultraviolet
lamp. Compounds 3f, 8b, 17, and 19 are of limited solu-
bility in common 1H NMR solvents. Compounds 1b [28],
2a – d [27], 2c and e [16], 3d [16], and 6 [9] were prepared
as previously described.
3,4,5,6-Tetrahydro-2,4,7-triaryl-2H-1,2,4-triazepines 3a – f
A solution of the appropriate β-(arylamino)propiophen-
one (2a – h) (5 mmol) and p-nitrophenylhydrazine (0.77 g,
5 mmol) or phenylhydrazine (0.54 g, 5 mmol) in ethanol
(30 mL) was heated on a steam bath for 20 min, then formalin
(37 %, 0.6 mL, 8 mmol) and acetic acid (0.1 mL) were added.
The reaction mixture was heated for 5 min, and the product
obtained on cooling was filtered and crystallized from the
appropriate solvent to give 3a – f.
3,4,5,6-Tetrahydro-2-(p-nitrophenyl)-7-phenyl-4-p-tolyl-2H-
1,2,4-triazepine (3a)
β-Arylaminopropiophenones 2f – h
◦
A mixture of 1a (2.13 g, 10 mmol) or 1b (2.29 g,
M. p. 196 C (ethanol). Yield 71 % (yellow crystals). –
10 mmol) and the appropriate amine (10 mmol) in IR (KBr): ν = 1610 (C=N), 1520, 1365, 1238, 1210,
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E. M. Afsah et al. · Mannich Bases as Synthetic Intermediates
581
870 cm−1. – 1H NMR (CDCl3): δ = 2.33 (s, 3H, ArMe), 3,4,5,6-Tetrahydro-4,7-di(p-hydroxyphenyl)-2-phenyl-2H-
3.38 (t, 2H, 6-H2), 3.65 (t, 2H, 5-H2), 5.35 (s, 2H, 3-H2), 1,2,4-triazepine (3f)
6.88 – 8.08 (m, 13H, aromatic). – 13C NMR (CDCl3): δ =
◦
M. p. 199 C (washed with boiling ethanol). Yield 50 %
20.51 (CH3), 30.98 (C-6), 45.64 (C-5), 71.62 (C-3), 112.88,
116.60, 126.40, 128.54, 129.14, 130.12, 132.47, 138.10,
140.03, 146.01, 152.31 (all Ar-C), 154.94 (C-7). – MS (EI,
(dark-brown powder). – IR (KBr): ν = 3410–3329 (OH),
1610 (C=N), 1523, 1456, 1215, 1112, 956 cm−1. – MS (EI,
70 eV): m/z (%) = 360 (51) [M+1]+, 238 (62) [M–(HO-
C6H4-N=CH2)]+, 173 (58), 121 (33) [HO-C6H4-N=CH2]+,
97 (100), 96 (67), 95 (56), 93 (83), 77 (15). – C22H21N3O2
(359.42): calcd. C 73.52, H 5.89, N 11.69; found C 73.49,
H 5.80, N 11.62.
70 eV): m/z (%) = 386 (3) [M]+, 387 (1) [M+1]+, 268 (17),
309 (5), 236 (100) [M–(NO2-C6H4-N=CH2)]+, 218 (11),
173 (3), 150 (4), 122 (12), 119 (62) [Me-C6H4-N=CH2]+,
120 (31), 105 (54), 91 (79), 77 (36). – C23H22N4O2 (386.45):
calcd. C 71.48, H 5.74, N 14.50; found C 71.40, H 5.68,
N 14.44.
3,4,5,6-Tetrahydro-4-(p-methoxyphenyl)-2-benzenesulfonyl-
7-phenyl-2H-1,2,4-triazepine (4)
3,4,5,6-Tetrahydro-4-(p-bromophenyl)-2-(p-nitrophenyl)-7-
phenyl-2H-1,2,4-triazepine (3b)
A solution of 2b (0.64 g, 2.5 mmol) and benzenesulfonyl
hydrazide (0.43 g, 2.5 mmol) in ethanol (30 mL) was heated
on a steam bath for 20 min. After standing at r. t. for 2 h,
formalin (37 %, 0.3 mL, 4 mmol) and acetic acid (0.1 mL)
were added. The reaction mixture was heated for 5 min, and
the product obtained on cooling was filtered and crystallized
from ethanol to give 4. M. p. 134 ◦C. Yield 60 % (pale-yellow
crystals). – IR (KBr): ν = 1614 (C=N), 1515, 1478, 1362,
1165, 849 cm−1. – 1H NMR (CDCl3): δ = 3.22 (t, 2H, 6-H2),
3.52 (t, 2H, 5-H2), 3.83 (s, 3H, OMe), 5.51 (s, 2H, 3-H2),
7.12 – 7.77 (m, 14H, aromatic). – 13C NMR (CDCl3): δ =
54.67 (OMe), 29.97 (C-6), 46.76(C-5), 72.78 (C-3), 111.98,
116.10, 126.34, 128.14, 129.10, 130.11, 132.17, 138.11,
146.22, 152.41 (all Ar-C), 156.44 (C-7). – MS (EI, 70 eV):
m/z (%) = 421 (2) [M]+, 422 (1) [M+1]+, 252 (40), 251
(100), 173 (48), 174 (18), 142 (30), 107 (16) [C6H4-OMe)]+,
97 (8), 77 (59). – C23H23N3O3S (421.51): calcd. C 65.54,
H 5.50, N 9.97; found C 65.48, H 5.47, N 9.88.
◦
M. p. 188 C (ethanol). Yield 60 % (reddish crystals). –
IR (KBr): ν = 1615 (C=N), 1529, 1355, 1218, 1110,
875 cm−1. – 1H NMR (CDCl3): δ = 3.32 (t, 2H, 6-H2), 3.57
(t, 2H, 5-H2), 5.15 (s, 2H, 3-H2), 7.17 – 8.24 (m, 13H, aro-
matic). – MS (EI, 70 eV): m/z (%) = 451 (14) [M]+, 452 (9)
[M+1]+, 301 (100), 300 (93) [M–(NO2-C6H4-N=CH2)]+,
267 (38) [M–(Br-C6H4-N=CH2)]+, 220 (27), 207 (73),
184 (25), 156 (12), 77 (43). – C22H19BrN4O2 (451.32):
calcd. C 58.55, H 4.24, N 12.41; found C 58.48, H 4.18,
N 12.21.
3,4,5,6-Tetrahydro-4-(p-chlorophenyl)-2-(p-nitrophenyl)-7-
phenyl-2H-1,2,4-triazepine (3c)
◦
M. p. 190 C (ethanol). Yield 65 % (reddish crystals). –
IR (KBr): ν = 1617 (C=N), 1537, 1326, 1209, 1100,
855 cm−1. – 1H NMR (CDCl3): δ = 3.28 (t, 2H, 6-
H2), 3.51 (t, 2H, 5-H2), 4.86 (s, 2H, 3-H2), 7.21 – 8.12
(m, 13H, aromatic). – MS (EI, 70 eV): m/z (%) = 406
(14) [M]+, 407 (3) [M+1]+, 408 (4) [M+2]+, 267 (26),
208 (19), 207 (100) [M–(Ph+C6H4-NO2)]+, 139 (10),
122 (8), 111 (14), 77 (16). – C22H19ClN4O2 (406.86):
calcd. C 64.94, H 4.71, N 13.77; found C 64.88, H 4.60,
N 13.65.
3,4,5,6-Tetrahydro-2,7-diphenyl-3-styryl-4-p-tolyl-2H-1,2,4-
triazepine (5)
This compound was obtained from 2a (0.60 g, 2.5 mmol)
and phenylhydrazine (0.27 g, 2.5 mmol) in the manner
described for the synthesis of 3a – f, except for the use
of cinnamaldehyde (0.40 g, 3 mmol) instead of formalde-
hyde. The product was crystallized from ethanol to give 5.
M. p. 180 ◦C. Yield 65 % (pale-yellow crystals). – IR (KBr):
ν = 1610 (C=N), 1577, 1458, 1322, 1222, 1145, 870 cm−1. –
4-(2,3,5,6-Tetrahydro-2,7-diphenyl-1,2,4-triazepin-4-yl)-
benzamide (3e)
M. p. 215 ◦C (DMF). Yield 53 % (pale-yellow crys- 1H NMR (CDCl3): δ = 2.31 (s, 3H, ArMe), 3.36 (t, 2H, 6-
tals). – IR (KBr): ν = 3359 (CONH2), 1645 (CO), 1610 H2), 3.58 (t, 2H, 5-H2), 4.87 (d, 2H, 3-H2), 6.22 (d, 1H, -
(C=N), 1517, 1436, 1225, 1142, 879 cm−1. – 1H NMR CH=CH-Ph), 6.61 (d, 1H, -CH=CH-Ph), 6.83–7.68 (m, 19H,
([D6]DMSO): δ = 3.26 (t, 2H, 6-H2), 3.87 (t, 2H, 5-H2), 5.43 aromatic). – 13C NMR (CDCl3): δ = 21.81 (Me), 31.10
(s, 2H, 3-H2), 6.66 (br. s, 2H, CONH2), 7.25 – 7.84 (m, 14H, (C-6), 47.56 (C-5), 72.18 (C-3), 113.44, 114.36, 117.18,
aromatic). – MS (EI, 70 eV): m/z (%) = 370 (4) [M]+, 371 124.44 (Ph-CH=CH), 127.12, 128.11, 129.12, 131.22 (Ph-
(2) [M+1]+, 369 (1) [M–1]+, 265 (100) [M–PhN=N]+, 222 CH=CH), 134.44, 138.33, 142.63, 147.41 (all Ar-C), 157.27
(65), 221 (93), 149 (53), 105 (35), 77 (81). – C23H22N4O (C-7). – MS (EI, 70 eV): m/z (%) = 443 (58) [M]+, 442 (50)
(370.45): calcd. C 74.57, H 5.99, N 15.12; found C 74.50, [M–1]+, 350 (59) [M–(p-tolyl)]+, 264 (55), 131 (29), 119
H 6.01, N 15.04.
(100) [PhC(=NH)Me]+, 117 (88), 103 (47), 91 (45) [C6H4-
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582
E. M. Afsah et al. · Mannich Bases as Synthetic Intermediates
Me]+. – C31H29N3 (443.58): calcd. C 83.94, H 6.59, N 9.47; 2-(Dimethylaminomethyl)-4-(2,3,5,6-tetrahydro-2,7-
found C 83.88, H 6.56, N 9.39.
diphenyl-1,2,4-triazepin-4-yl)phenol (9)
A solution of 3d [16] (1.37 g, 4 mmol), formalin (37 %,
0.4 mL, 5 mmol) and dimethylamine (40 %, 0.56 mL,
5 mmol) in ethanol (50 mL) was refluxed for 6 h. After
standing at r. t. for 24 h, the product obtained was filtered
and crystallized from ethanol to give 9. M. p. 145 ◦C. –
Yield 72 % (colorless crystals). – IR (KBr): ν = 3373 (OH),
1605 (C=N), 1588, 1454, 1371, 1271, 1113, 1073 cm−1. –
1H NMR (CDCl3): δ = 2.38 (s, 6H, N(Me)2), 3.33 (t, 2H,
6-H2), 3.60 (t, 2H, 5-H2), 3.67 (s, 2H, CH2N), 5.17 (s, 2H, 3-
H2), 12.01 (s, 1H, OH), 6.88 – 7.85 (m, 13H, aromatic). –
13C NMR (CDCl3): δ = 30.98 (C-6), 44.21 (C-5), 46.61
(NMe), 62.44 (CH2N), 74.89 (C-3), 115.32, 117.12, 118.89,
119.42, 120.54, 126.11, 126.29, 128.29, 128.56, 128.84,
139.42, 141.74, 148.33, (all Ar-C), 152.09 (C-7). – MS (EI,
70 eV): m/z (%) = 400 (4) [M]+, 401 (1) [M+1]+, 250 (59)
[M–(C6H3-OH+CH2Me2)]+, 251 (13), 93 (7), 77 (100), 58
(15) [CH2NMe2]+. – C25H28N4O (400.52): calcd. C 74.97,
H 7.05, N 13.99; found C 74.91, H 6.97, N 13.90.
1-(p-Anisyl)-5-(p-tolylamino)-1-penten-3-one (7)
A mixture of 6 (2.15 g, 8 mmol) and p-toluidine (0.85 g,
8 mmol) in 50 % aqueous ethanol (80 mL) was refluxed
for 90 min. The product obtained on cooling was filtered and
crystallized from ethanol to give 6. M. p. 110 ◦C. Yield 85 %
(yellow crystals). – IR (KBr): ν = 3382 (NH), 1653
(CO), 1605, 1557, 1460, 1319, 1209, 1105, 868 cm−1. –
1H NMR (CDCl3): δ = 2.24 (s, 3H, ArMe), 2.96 (t, 2H,
COCH2CH2N), 3.52 (t, 2H, COCH2CH2N), 3.52 (s, 3H
OMe), 6.64 (s, 1H, ArNH), 6.59 (d, 2H, Ar-CH=CH-CO),
6.93 (d, 2H, Ar-CH=CH-CO), 7.12 – 7.58 (m, 8H, aro-
matic). – C19H21NO2 (295.38): calcd. C 77.26, H 7.17,
N 4.74; found C 77.18, H 7.10, N 4.69.
7-(4-Methoxystyryl)-3,4,5,6-tetrahydro-2-phenyl-4-p-tolyl-
2H-1,2,4-triazepine (8a)
This compound was obtained from equimolar amounts
of 6, phenylhydrazine and formaldehyde (5 mmol) in
ethanol (40 mL), following the procedure described for
the synthesis of 3a – f. The product was crystallized from
2,6-Bis-(dimethylaminomethyl)-4-(2,3,5,6-tetrahydro-2,7-
diphenyl-1,2,4-triazepin-4-yl)phenol (10)
◦
Procedure A: This compound was obtained from equimo-
lar amounts of 9, formalin and dimethylamine (5 mmol) in
ethanol (50 mL), following the procedure described for the
synthesis of 9. The◦product was crystallized from ethanol to
give 10. M. p. 190 C. Yield 55 % (colorless crystals). – IR
(KBr): ν = 3370 (OH), 1612 (C=N), 1577, 1446, 1335, 1221,
1108, 1079 cm−1. – 1H NMR (CDCl3): δ = 2.30 (s, 12H, 2×
NMe2), 3.34 (t, 2H, 6-H2), 3.96 (t, 2H, 5-H2), 4.17 (s, 4H,
2× CH2N), 5.31 (s, 2H, 3-H2), 12.11 (s, 1H, OH), 6.94 –
7.75 (m, 12H, aromatic). – MS (EI, 70 eV): m/z (%) = 457
(6) [M]+, 456 (18) [M–1]+, 370 (6), 222 (40), 233 (27), 248
(10), 263 (100) [M–(Ph=N-NPh)]+, 264 (75), 104 (23), 77
(19), 57 (34). – C28H35N5O (457.61): calcd. C 73.49, H 7.71,
N 15.30; found C 73.41, H 7.69, N 15.22.
ethanol to give 8a. M. p. 184 C. Yield 55 % (yellow crys-
tals). – IR (KBr): ν = 1617 (C=N), 1597, 1489, 1308,
1229, 1114, 1082, 847 cm−1. – 1H NMR (CDCl3): δ =
2.28 (s, 3H, ArMe), 3.42 (t, 2H, 6-H2), 3.60 (s, 3H,
OMe), 3.94 (t, 2H, 5-H2), 4.58 (s, 2H, 3-H2), 6.89 (d,
2H, Ar-CH=CH-), 6.96 (d, 2H, Ar-CH=CH-), 7.02–7.33
(m, 8H, aromatic). – 13C NMR (CDCl3): δ = 22.11
(Me), 32.18 (C-6), 48.44 (C-5), 54.23 (OMe), 79.89 (C-3),
113.33, 114.28, 116.88, 127.14, 129.44, 130.10, 136.47 (Ar-
CH=CH), 138.33 (Ar-CH=CH), 142.63, 146.41, 156.10,
158.31 (all Ar-C), 154.77 (C-7). – C26H27N3O (397.51):
calcd. C 78.56, H 6.85, N 10.57; found C 78.50, H 6.77,
N 10.49.
Procedure B: A solution of 3d (1.37 g, 4 mmol), for-
malin (37 %, 0.8 mL, 10 mmol) and dimethylamine (40 %,
1.12 mL, 10 mmol) in ethanol (50 mL) was refluxed for 8 h.
After standing at r. t. for 24 h, the product obtained was fil-
tered and crystallized from ethanol to give 10. M. p. 190 –
192 ◦C. Yield 60 %. The structure was confirmed by a com-
parison of 1H NMR data, m. p. and TLC with that from Pro-
cedure A.
7-(4-Methoxystyryl)-3,4,5,6-tetrahydro-2-(4-nitrophenyl)3-
styryl-4-p-tolyl-2H-1,2,4-triazepine (8b)
This compound was obtained from equimolar amounts
of 6, p-nitrophenylhydrazine and cinnamaldehyde (5 mmol)
in ethanol (80 mL), in the manner described for the synthe-
sis of 3a – f. The product obtained was filtered and washed
◦
with boiling ethanol (3 × 15 mL) to give 8b. M. p. 265 C.
Yield 33 % (yellow powder). – IR (KBr): ν = 1622 (C=N),
1588, 1459, 1326, 1232, 1119, 1066, 865 cm−1. – MS
(EI, 70 eV): m/z (%) = 530 (46) [M–Me]+, 213 (67),
134 (52), 107 (6), 103 (61), 98 (70) [triazepine unit]+, 84
(100) [triazepine unit–(CH2)]+. – C34H32N4O3 (544.64):
2,6-[Bis-(piperidin-1-ylmethyl)]-4-(2,3,5,6-tetrahydro-2,7-
diphenyl-1,2,4-triazepin-4-yl)phenol (11)
This compound was obtained from 3d (1.37 g, 4 mmol),
calcd. C 74.98, H 5.92, N 10.29; found C 74.91, H 5.89, formalin (37 %, 1 mL, 12 mmol) and piperidine (1 g,
N 10.21.
12 mmol), following the procedure described for the syn-
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E. M. Afsah et al. · Mannich Bases as Synthetic Intermediates
583
thesis of 9. The product was crystallized from ethanol to fluxed for 3 h. After standing at r. t. for 24 h, the product
give 11. M. p. 142 ◦C. Yield 49 % (colorless crystals). – obtained was filtered and washed with boiling DMF-ethanol
IR (KBr): ν = 3377 (OH), 1618 (C=N), 1557, 1426, 1355, (1 : 1) to give 15. M. p. 255 ◦C. Yield 52 % (pale-yellow
1216, 1100, 1050 cm−1. – 1H NMR (CDCl3): δ = 1.52 – powder). – IR (KBr): ν = 3422 (OH), 1610 (C=N), 1510,
1.67 [m, 12H, 2× (3-H2, 4-H2, 5-H2) of piperidine], 2.55 1349, 1036, 1008, 814 cm−1. – 1H NMR ([D6] DMSO):
(m, 4H, 2-H2, 6-H2 of piperidine), 3.35 (t, 2H, 6-H2), 3.60 δ = 2.48 (m, 2H, 7-H2), 2.52 (m, 2H, COCH2CH2N),
(t, 2H, 5-H2), 3.68 (s, 4H, 2× CH2N), 5.16 (s, 2H, 3- 2.64 (m, 2H, 2-H2), 2.96 (m, 2H, COCH2CH2N), 3.28 (m,
H2), 11.11 (s, 1H, OH), 6.85 – 7.86 (m, 12H, aromatic). – 2H, 6-H2), 3.56 (m, 2H, 3-H2), 6.78 – 7.77 (m, 8H, aro-
13C NMR (CDCl3): δ = 23.92 (C-3, C-4, C-5 of piperidine), matic), 10.11 (br. s, 1H, OH). – C20H22N2O3 (338.40):
25.72 (C-6), 31.21 (C-5), 46.65 (C-2, C-6 of piperidine), calcd. C 70.99, H 6.55, N 8.28; found C 70.91, H 6.49,
53.85 (CH2N), 75.10 (C-3), 115.33, 118.82, 120.54, 126.12, N 8.20.
126.29, 128.28, 128.54, 128.82, 139.45, 142.45, 148.98 (all
3,4,7,8-Tetrahydro-1-(β-4-hydroxybenzoylethyl)-6-(4-hydr-
oxyphenyl)-2H-1,5-diazocine (17)
Ar-C), 150.54 (C-7). – MS (EI, 70 eV): m/z (%) = 537
(1) [M]+, 440 (61) [M–(CH2NC5H10)+H]+, 250 (100) [M–
(C6H2OH(CH2NC5H10)2]+, 251 (22), 222 (16), 204 (10),
84 (4) [NC5H10]+. – C34H43N5O (537.74): calcd. C 75.94,
H 8.06, N 13.02; found C 75.91, H 7.98, N 12.97.
This compound was obtained from equimolar amounts
of 1b and 1,3-diaminopropane (5 mmol), following the pro-
cedure described for the synthesis of 15. The product ob-
tained was filtered and washed with boiling DMF-ethanol
2,3-Dihydro-4-(p-hydroxyphenyl)-1H-1,5-benzodiazepine
(13)
◦
(1 : 1) to give 17. M. p. 260 C. Yield 33 % (yellow pow-
der). – IR (KBr): ν = 3940 (OH), 1619 (C=N), 1479, 1407,
1336, 1217, 1102 cm−1. – MS (EI, 70 eV): m/z (%) =
352 (1) [M]+, 149 (12) [HO-C6H4-COCH2CH2]+, 121 (6),
119, 110 (7), 109 (10), 111(11), 93 (11), 85 (28), 71 (43),
69 (100) [(C4H7)N]+, 55 (69). – C21H24N2O3 (352.43):
calcd. C 71.57, H 6.86, N 7.95; found C 71.50, H 6.79,
N 7.87.
A mixture of 1b (1.14 g, 5 mmol), o-phenylenediamine
(0.54 g, 5 mmol) and fused sodium acetate (1.5 g) in ab-
solute ethanol (80 mL) was refluxed for 6 h. The crystalline
product was filtered and washe◦d with boiling ethanol-acetone
(1 : 1) to give 13. M. p. 134 C. Yield 60 % (yellow crys-
tals). – IR (KBr): ν = 3394 (OH), 3360 (NH), 1611 (C=N),
1513, 1493, 1344, 1144, 810 cm−1. – 1H NMR (CDCl3):
δ = 3.11 (m, 2H, 3-H2), 3.54 (m, 2H, 2-H2), 6.16 (br. s, 1H,
NH), 6.84 – 7.83 (m, 8H, aromatic), 8.22 (br. s, 1H, OH). –
13C NMR (CDCl3): δ = 32.16 (C-3), 47.11 (C-2), 113.44,
119.20, 123.24, 127.81, 130.35, 134.45 (all Ar-C), 138.11
1,3-Bis(3-benzoyl-4-hydroxy-4-phenylpiperidin-1-yl)prop-
ane (19)
This compound was obtained from 1a (3.83 g, 18 mmol)
(C-5a), 138.55 (C-5b), 168.11 (C-4). – MS (EI, 70 eV): m/z and 1,3-diaminopropane (0.33 g, 4.5 mmol), following the
(%) = 238 (1) [M]+, 222 (2), 210 (4), 121 (9), 120 (100),
119 (12), 107 (31), 106 (27), 92 (19), 77 (35). – C15H14N2O
procedure described for the synthesis of 15. The product ob-
tained was filtered and washed with boiling DMF-ethanol
◦
(238.28): calcd. C 75.61, H 5.92, N 11.76; found C 75.55, (1 : 1) to give 19. M. p. 256 C. Yield 71 % (colorless pow-
der). – IR (KBr): ν = 3421 (OH), 1629 (CO), 1600, 1483,
1407, 1216, 1102, 941 cm−1. – MS (EI, 70 eV): m/z (%) =
601 (58) [M–1]+, 416 (47), 275 (57), 228 (48), 206 (63),
207 (39), 185 (83), 158 (58), 110 (100), 105 (27), 98 (87),
96 (60), 77 (35). – C39H42N2O4 (602.76): calcd. C 77.71,
H 5.88, N 11.69.
2,3,6,7-Tetrahydro-1-(β-4-hydroxybenzoylethyl)-5-(4-hydr-
oxyphenyl)-1H-1,4-diazepine (15)
A mixture of 1b (1.14 g, 5 mmol) and ethylenediamine
(0.3 g, 5 mmol) in 50 % aqueous ethanol (50 mL) was re- H 7.02, N 4.65; found C 77.70, H 6.98, N 4.58.
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