Mannich bases as synthetic intermediates: Alkylation of amines and diamines with bis-ketonic Mannich bases

Article abstract of DOI:10.1515/znb-2008-0516

The bis-ketonic Mannich base, N,N-bis(β-benzoylethyl)methylamine hydrochloride (1) reacts with primary arylamines and diamines to give ketonic sec-arylamines 3a-e and 4. The piperidines 7a-c were obtained from 1 and primary alkylamines, whereas the 1,4-diazepine derivative 10 was obtained from 1 and ethylenediamine. Treatment of the bis-base l,4-di[β-(N-morpholino) propionyl]benzene bis(hydrochloride) (11) with primary arylamines gave the corresponding bis-(sec-arylamines) 12a - b, whereas its reaction with o-phenylenediamine afforded the bis[1,5-benzodiazepine] ring system 14. The synthesis of the diazacyclophane ring system 15 has been achieved by treating 11 with piperazine. Attempted synthesis of 4-aza-[7]-paracyclophane (16) from 11 and benzylamine led to 17. The reaction of 1 or 11 with phenylhydrazine gave the 2-pyrazolines 18 and 19. Treatment of 3 or 4 with phenylhydrazine and formaldehyde afforded the 2H-1,2,4-triazepines 20a-c and the bis[2H-1,2,4-triazepine] ring system 21.

Full text of DOI:10.1515/znb-2008-0516

Mannich Bases as Synthetic Intermediates: Alkylation of Amines
and Diamines with Bis-ketonic Mannich Bases
Elsayed M. Afsah, Metwally Hammouda, Mona M. Khalifa, and Essam H. Al-shahaby
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. 2008, 63b, 577 – 584; received December 12, 2007
The bis-ketonic Mannich base, N,N-bis(β-benzoylethyl)methylamine hydrochloride (1) reacts with
primary arylamines and diamines to give ketonic sec-arylamines 3a – e and 4. The piperidines 7a – c
were obtained from 1 and primary alkylamines, whereas the 1,4-diazepine derivative 10 was obtained
from 1 and ethylenediamine.
Treatment of the bis-base 1,4-di[β-(N-morpholino)propionyl]benzene bis(hydrochloride) (11) with
primary arylamines gave the corresponding bis-(sec-arylamines) 12a – b, whereas its reaction with o-
phenylenediamine afforded the bis[1,5-benzodiazepine] ring system 14. The synthesis of the diazacy-
clophane ring system 15 has been achieved by treating 11 with piperazine. Attempted synthesis of 4-
aza-[7]-paracyclophane (16) from 11 and benzylamine led to 17. The reaction of 1 or 11 with phenyl-
hydrazine gave the 2-pyrazolines 18 and 19. Treatment of 3 or 4 with phenylhydrazine and formalde-
hyde afforded the 2H-1,2,4-triazepines 20a – c and the bis[2H-1,2,4-triazepine] ring system 21.
Key words: Bis-(Mannich Bases), Transamination, 1,2,4-Triazepines, Diazacyclophanes
Introduction
appropriate primary aromatic amine afforded a se-
ries of β-(arylamino)propiophenones 3a – e in excel-
lent yields.
Mannich bases and their quaternary salts have been
employed frequently as potential synthetic interme-
diates, particularly in alkylation reactions. The alky-
lation of various substrates such as amines [1 – 7],
enamines [8 – 10], NH-heterocycles [11 – 13] and thi-
ols [1, 7, 14, 15] with ketonic Mannich bases has been
the subject of extensive studies. Although the synthetic
utility of mono-(Mannich bases) in alkylation reactions
was well established [1 – 16], the use of bis-(Mannich
bases) in such reactions was less widely recognized
and has been limited [17 – 21].
The analogous reaction of 1 with p-phenylenedi-
amine gave N,Nꢀ-bis(β-benzoylethyl)-p-phenylenedi-
amine (4). Compounds 3c – e and 4 are identical (m. p.,
1
IR and H NMR spectra) to authentic samples previ-
ously prepared from the mono-(Mannich base) 2 and
the appropriate amine [3]. The IR spectra of 3a – e
and 4 showed sharp bands around 3392– 3355 (NH),
1363 – 1317 (C–N stretch of sec-arylamine) and 1677 –
1
1665 cm−1 (CO). The H NMR spectra revealed the
presence of an amine proton at δ = 4.20– 4.45 and
the methylene protons as two triplets at δ = 2.35 – 2.42
(COCH2) and 3.15 – 3.31 (CH2NHAr) with J = 7 Hz in
both cases. The formation of 3 and 4 from 1 may be ra-
tionalized on the basis of a mechanism which involves
the elimination-addition sequence that is operative
with ketonic Mannich bases [1 – 4] via the intermedi-
acy of the enone 5, which is formed in situ through two
successive deamination reactions of the bis-(Mannich
base) 1. Nucleophilic addition of the primary aromatic
amine to 5 provided 3a – e and 4 (Scheme 1).
In connection with our studies in this area [7, 21 –
24], and in view of the wide range of biological activ-
ities of ketonic Mannich bases such as antimicrobial
[25, 26], cytotoxic [27– 29] and anticancer [28] activ-
ities, the present work is concerned with attempts to
extend the scope of the N-alkylation of amines and di-
amines with bis-(ketonic Mannich bases) to include the
synthesis of some new Mannich bases and related het-
erocycles of pharmaceutical interest.
Results and Discussion
On the other hand, the reaction of 1 with primary
The bis-(Mannich base) N,N-bis(β-benzoylethyl)- aliphatic amines such as cyclohexylamine, benzyl-
methylamine hydrochloride (1) was prepared accord- amine and 2-(3,4-dimethoxyphenyl)ethylamine takes
ing to an earlier report [30]. Treatment of 1 with the a different course. The products were identified as
c
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578
E. M. Afsah et al. · Alkylation of Amines and Diamines with Bis-ketonic Mannich Bases
Scheme 1.
the N-substituted 3-benzoyl-4-hydroxy-4-phenylpiper-
idines 7a – c. Compounds 7a, b are identical (m. p.,
mixed m. p. and spectral data) with authentic samples
obtained from the mono-(Mannich base) 2 and the
appropriate amine as previously reported [4, 31]. The
structure of 7a – c was confirmed on the basis of analyt-
ical and spectral data. In each case, the identity of the
product as the N-substituted piperidinol 7 and not the
isomeric diketo base 6, was shown by the IR spectra
which possessed a strong OH band around 3400 cm−1
as well as the (CO) absorption band (1675 cm−1).
Obviously, compounds 7a – c were formed via the
non-isolable diketo bases 6a – c, which were read-
ily converted into 7 by intramolecular aldolization.
The double N-alkylation of primary aliphatic amines
with Mannich bases, leading to 6a – c, can be rational-
ized by consideration of their strong basicity and nu-
cleophilicity as compared with aromatic amines. At-
tempts to isolate the intermediates 6a – c were unsuc-
cessful due to the ease with which such bases undergo
intramolecular aldolization even at r. t.
Scheme 2.
iperidine derivative 8, as could have been expected in
analogy to the formation of 7a–c. Actually, the prod-
uct of such a reaction was identified on the basis of
its analytical and spectral data as 2,3,6,7-tetrahydro-1-
(β-benzoylethyl)-5-phenyl-1H-1,4-diazepine (10). Its
mass spectrum showed the molecular ion at m/z = 306.
The base peak at m/z = 105 (100%) is due to the
(PhCO) ion. Two peaks at m/z = 174 and 173 identify
the 1,4-diazepine unit (Scheme 2).
1
The H NMR spectrum of 10 supported the struc-
ture, as it revealed the 1,4-diazepine ring protons as
It is interesting in this connection that the reaction two triplets at δ = 2.96 and 3.32 (6-H2 and 7-H2), and
of 1 with ethylenediamine does not afford the dip- a multiplet at 3.38 – 3.42 (2-H2 and 3-H2), and the side
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E. M. Afsah et al. · Alkylation of Amines and Diamines with Bis-ketonic Mannich Bases
579
R
O
R2N
O
NR2
2 HCl
2 ArNH2
NH
O
O
11
EtOH-H2O
NR2 = N-morpholino
HN
12a
: R = Me
o-phenylenediamine
EtOH - AcONa
12b
: R = OMe
R
O
O
2
3
N
HN
HN
HN
4
Scheme 4.
5b
NH
N
5
5a
In order to extend the scope of the reaction
of 11 with diamines, the synthetic possibilities af-
forded by replacing o-phenylenediamine with pip-
erazine have been investigated as a possible route
to the new diazacyclophane ring system 15. The
synthesis of 15 has been achieved by treating
11 with an equimolar amount of piperazine to
afford 1,12-diaza-tricyclo[10.2.2.25,8]octadeca-5(18),
8(17)-triene-4,9-dione (15) (Scheme 4).
13
14
Scheme 3.
chain protons as two triplets at 2.61 (COCH2) and 3.14
(CH2N). The formation of 10 rather than 8 or 7 (R =
CH2CH2NH2) may be attributed to the intermediacy of
the non-isolable 1H-1,4-diazepine9, resulting from the
cyclocondensation reaction of ethylenediamine with 5,
which readily reacts further with a second molecule of
5 to afford the new Mannich base 10.
In connection with the present study, the N-
alkylation of amines with bis-(Mannich bases) was fur-
ther extended to the use of 1,4-di[β-(N-morpholino)
propionyl]benzene bis(hydrochloride) (11), and some
interesting results were obtained. Treatment of 11 with
p-toluidine or p-anisidine gave the expected 1,4-di[β-
(arylamino)propionyl]benzenes (12a,b) respectively,
via a double transamination reaction (Scheme 3). The
bis-base 12a was again the sole product when the reac-
tion conditions were modified in the hope of isolating
a mixed bis-base, in which one N-morpholino group is
replaced by a sec-arylamino group.
The mass spectrum of 15 indicated the molecular
ion peak at m/z = 272 (M+). The base peak at m/z =
159 (100%) is due to the [CH2=CH-CO-C6H4-CO]+
fragment. The 1H NMR spectrum supported the struc-
ture as it revealed a broad singlet at δ = 2.61 assignable
to [N(CH2CH2)2N] of the piperazine ring, and a mul-
tiplet at 3.12– 3.56 (2 × COCH2CH2N).
The tendency of primary aliphatic amines to
undergo double N-alkylation with Mannich bases
prompted us to investigate the reaction of 11 with benz-
ylamine as a possible route to the 4-aza-[7]-paracycl-
ophane ring system 16, but this has not been realized.
Actually, the reaction product was identified on the ba-
sis of its analytical and spectral data as 4-[β-(benzyl-
amino)propionyl]acrylophenone (17).
On the other hand, the reaction of 11 with o-
phenylenediamine afforded 4,4ꢀ-[p-phenylene-bis(2,3-
In an extension of this study, the reaction of the
dihydro-1H-1,5-benzodiazepine)] (14) rather than the di-keto base 1 with phenylhydrazine in boiling acetic
macrocyclic compound 13, which would be the ex- acid containing sodium acetate afforded 1,3-diphen-
pected product. The IR spectrum of 14 revealed the yl-2-pyrazoline (18), which is identical (m. p., mixed
absence of a carbonyl group and showed strong bands m.p˙. and spectral data) with an authentic sample
at 3394 (NH) and 1612 cm−1 (C=N). The mass spec-
obtained from 2 and phenylhydrazine as previously
trum exhibited a molecular ion peak at m/z = 366 (M+) reported [33]. A similar reaction takes place with
(100 %). The benzodiazepine moiety could be identi- 11 yielding 3,3ꢀ-[p-phenylene-bis(1-phenyl-2-pyrazol-
fied by two peaks at m/z = 145 and 143. The forma- ine)] (19) (Scheme 5).
tion of 14 is in line with the work of Roman et al.
It is believed that the initially formed phenylhydr-
[32], who obtained 4-aryl-2,3-dihydro-1H-1,5-benzo- azones of 1 or 11 cyclized readily via an intramolec-
diazepine via cyclocondensation of the mono-base 2 ular amine exchange reaction, leading to 18 and 19, as
with o-phenylenediamine.
confirmed by analytical and spectral data.
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580
E. M. Afsah et al. · Alkylation of Amines and Diamines with Bis-ketonic Mannich Bases
the 1,2,4-triazepine series. The simplicity of the proce-
dure is an attractive feature.
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 solution on a Var-
ian XL 200 MHz instrument using TMS as internal standard.
Chemical shifts are reported in ppm (δ) downfield from inter-
nal 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 1 [30]
and 2 [34] were prepared as previously described.
Scheme 5.
β-Arylaminopropiophenones 3a–e
A mixture of 1 (1.66 g, 5 mmol) and the appropriate amine
(10 mmol) in 50 % aqueous ethanol (60 mL) was refluxed
for 90 min. The product obtained on cooling was filtered and
crystallized from ethanol to give 3a – e.
β-(p-Bromophenylamino)propiophenone (3a)
◦
M. p. 141 C. – Yield 85 % (white crystals). – IR (KBr):
Scheme 6.
ν = 3392 (NH), 1668 (CO), 1594, 1388, 1317, 1068 cm−1. –
1H NMR (200 MHz, CDCl3, 25 ◦C, TMS): δ = 2.42
In addition, it has been found that a convenient
(t, J = 6.7 Hz, 2H, COCH2CH2N), 3.29 (t, J = 6.7 Hz,
2H, COCH2CH2N), 4.38 (s, 1H, ArNH), 7.21 – 7.83 (m,
9H, aromatic). – MS (EI, 70 eV): m/z (%) = 304 (6)
[M]+, 303 (30) [M–1]+, 199 (5) [M–PhCO]+, 185 (96)
[Br-C6H4-NHCH2]+, 184 (100) [Br-C6H4-N=CH2]+, 133
(4) [PhCOCH2CH2]+, 119 (7) [PhCOCH2]+, 105 (46)
[PhCO]+, 77 (54) [Ph]+. – C15H14BrNO (304.18): calcd.
C 59.23, H 4.64, N 4.60; found C 59.13, H 4.52, N 4.47.
new route to the 2H-1,2,4-triazepine ring system
starts with the ketonic sec-amine bases of the type 3,
which were treated with phenylhydrazine and subse-
quently with formaldehyde under mild conditions to
give 3,4,5,6-tetrahydro-4-aryl-2,7-diphenyl-2H-1,2,4-
triazepines 20a – c. A similar reaction takes place on
treating the diphenylhydrazone of the bis-(sec-amine
base) 4 with formaldehyde yielding 4,4ꢀ-[p-phenylene-
bis(3,4,5,6-tetrahydro-2,7- diphenyl-2H-1,2,4-triazep-
ine)] (21) (Scheme 6).
β-(p-Hydroxyphenylamino)propiophenone (3b)
◦
M. p. 144 C. – Yield 91 % (pale brown crystals). – IR
1
The mass and H NMR spectra of compounds 20
(KBr): ν = 3405 (OH), 3274 (NH), 1677 (CO), 1517, 1427,
and 21 are consistent with the proposed structures. The
1363, 1222 cm−1. – 1H NMR (200 MHz, CDCl3, 25 C,
◦
1
main characteristic features of the H NMR spectrum
TMS): δ = 2.40 (t, J = 7 Hz, 2H, COCH2CH2N), 3.30 (t, J =
7 Hz, 2H, COCH2CH2N), 4.45 (s, 1H, ArNH), 7.15 – 7.88
(m, 9H, aromatic), 11.85 (s, 1H, OH). – MS (EI, 70 eV): m/z
(%) = 241 (25) [M]+, 242 (4) [M+1]+, 136 (3) [HO-C6H4-
NHCH2CH2]+, 132 (13) [PhCOCH=CH2]+, 122 (100)
[HO-C6H4-NHCH2]+, 105 (42) [PhCO]+, 77 (47) [Ph]+. –
C15H15NO2 (241.29): calcd. C 74.67, H 6.27, N 5.81; found
of 20a are a singlet at δ = 4.96 assignable to 3-H2 and
two triplets at δ = 3.51 (5-H2) and 3.13 (6-H2). Simi-
lar signals appeared in the spectrum of 20b, c and 21.
A practical advantage of the reactions leading to com-
pounds 20 and 21 is that it is often unnecessary to iso-
late the phenylhydrazone intermediates. The reactions
described in Scheme 6 provide an important entry into C 74.60, H 6.11, N 5.45.
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E. M. Afsah et al. · Alkylation of Amines and Diamines with Bis-ketonic Mannich Bases
β-(p-Anisylamino)propiophenone (3c) N-Benzyl-3-benzoyl-4-hydroxy-4-phenylpiperidine (7b)
581
◦
◦
◦
◦
M. p. 118 C (ethanol) (119 C [31]). Yield 87 % (color-
M. p. 112 C (112 C [3]). Yield 94 % (white crystals). –
IR (KBr): ν = 3355 (NH), 1662 (CO), 1568, 1370, 1322,
1109 cm−1. – 1H NMR (200 MHz, CDCl3, 25 ◦C, TMS): δ =
2.38 (t, J = 6.8 Hz, 2H, COCH2CH2N), 3.22 (t, J = 6.8 Hz,
2H, COCH2CH2N), 3.81 (s, 3H, OMe), 4.31 (s, 1H, ArNH),
7.30 – 7.91 (m, 9H, aromatic).
less crystals). – IR (KBr): ν = 3421 (OH), 1670 (CO), 1492,
1377, 1231, 1115 cm−1
.
N-[2-(3,4-Dimethoxyphenyl)ethyl]-3-benzoyl-4-hydroxy-4-
phenylpiperidine (7c)
M. p. 142 ◦C (ethanol). Yield 77 % (white crystals). –
β-(p-Chlorophenylamino)propiophenone (3d)
IR (KBr): ν = 3410 (OH), 1673 (CO), 1447, 1365, 1217,
1119 cm−1. – 1H NMR (200 MHz, CDCl3, 25 C, TMS):
◦
◦
◦
M. p. 135 C (134 C [3]). Yield 91 % (white crystals). –
δ = 1.96 (m, 1H, 5-H ax), 2.51 – 2.70 (m, 4H, ArCH2CH2N),
2.78 (m, 1H, 5-H eq), 3.48 (m, 4H, 2-H2 and 6-H2), 3.80
(s, 3H, OMe), 3.83 (s, 3H, OMe), 5.17 (d, J = 2.9 Hz, 1H,
OH), 5.43 (dd, J = 4 Hz, J = 10.8 Hz, 1H, 3-H), 7.05 – 8.20
(m, 13H, aromatic). – C28H31NO4 (445.55): calcd. C 75.48,
H 7.01, N 3.14; found C 75.35, H 6.88, N 3.01.
IR (KBr): ν = 3368 (NH), 1668 (CO), 1605, 1375, 1319,
◦
1110 cm−1. – 1H NMR (200 MHz, CDCl3, 25 C, TMS):
δ = 2.41 (t, J = 7 Hz, 2H, COCH2CH2N), 3.30 (t, J = 7 Hz,
2H, COCH2CH2N), 4.42 (s, 1H, ArNH), 7.18 – 7.88 (m, 9H,
aromatic).
β-(Phenylamino)propiophenone (3e)
2,3,6,7-Tetrahydro-1-(β-benzoylethyl)-5-phenyl-1H-1,4-
diazepine (10)
◦
◦
M. p. 114 C (113 C [3]). Yield 81 % (white crystals). –
IR (KBr): ν = 3359 (NH), 1665 (CO), 1665, 1385, 1318,
1207 cm−1. – 1H NMR (200 MHz, CDCl3, 25 ◦C, TMS): δ =
2.35 (t, J = 7 Hz, 2H, COCH2CH2N), 3.15 (t, J = 7 Hz, 2H,
COCH2CH2N), 4.20 (s, 1H, PhNH), 7.11 – 7.73 (m, 10H,
aromatic).
A solution of 1 (1.66 g, 5 mmol) and ethylenediamine
(0.15 g, 2.5 mmol) in 50 % aqueous ethanol (60 mL) was
refluxed for 2 h, and allowed to stand at r. t. for 24 h. The
product obtained was filtered and purified by preparative
chromatography on Al2O3 using pet. ether 40 – 60 ◦C / ethyl
acetate (2 : 1) as eluent. The product was crystallized from
N,Nꢀ-Bis(β-benzoylethyl)-p-phenylenediamine (4)
◦
ethanol to give 10. M. p. 192 C. Yield 25 % (white crys-
This compound was prepared from equimolar amounts of
1 and p-phenylenediamine (5 mmol) in ethanol (60 mL),
following the same procedure as described above. Crys-
tallization of◦ the product from chloroform gave 4. M. p.
tals). – IR (KBr): ν = 3430 (NH), 1670 (CO), 1625 (C=N),
1445, 1273, 1122 cm−1. – 1H NMR (200 MHz, CDCl3,
◦
25 C, TMS): δ = 2.61 (t, J = 6.4 Hz, 2H, COCH2CH2N),
2.96 (t, J = 5.6 Hz, 2H, 6-H2), 3.14 (t, J = 6.4 Hz, 2H,
COCH2CH2N), 3.32 (t, J = 5.6 Hz, 2H, 7-H2), 3.38 –
3.42 (m, 4H, 2-H2 and 3-H2), 6.92 – 7.75 (m, 10H, aro-
matic). – MS (EI, 70 eV): m/z (%) = 306 (2) [M]+, 173
(13) [M–PhCOCH2CH2]+, 133 (7) [PhCOCH2CH2]+, 132
(33) [PhCOCH=CH2]+, 131 (14) [PhCOCH2CH2–2H]+,
105 (100) [PhCO]+, 77 (83) [Ph]+. – C20H22N2O (306.40):
calcd. C 78.40, H 7.24, N 9.14; found C 78.25, H 7.08,
N 8.91.
◦
178 C (179 C [3]). Yield 54 % (buff leaflets). – IR (KBr):
ν = 3351 (NH), 1667 (CO), 1331, 1222, 1120 cm−1. –
1H NMR (200 MHz, CDCl3, 25 ◦C, TMS): δ = 2.41 [t, J =
6.8 Hz, 4H, 2 × (COCH2CH2N)], 3.24 [t, J = 6.8 Hz, 4H,
2 × (COCH2CH2N)], 4.22 (s, 1H, NH), 4.36 (s, 1H, NH),
7.31 – 7.94 (m, 14H, aromatic).
N-Substituted 3-benzoyl-4-hydroxy-4-phenylpiperidines
7a – c
1,4-Bis[β-(N-morpholino)propionyl]benzene bis(hydro-
chloride) (11)
A mixture of 1 (1.66 g, 5 mmol) and the appropriate amine
(10 mmol) in 50 % aqueous ethanol (60 mL) was refluxed for
90 min, and allowed to stand at r. t. for 24 h. The reaction
mixture was diluted with water (20 mL), and the product ob-
tained was filtered and crystallized from ethanol or aqueous
ethanol to give 7a – c. Compounds 7a, b are identical (m. p.,
mixed m. p., IR and TLC ) with authentic samples obtained
from the mono-(Mannich base) 2 and the appropriate amine
as previously reported [4, 31].
To a solution of 1,4-diacetylbenzene (4 g, 25 mmol)
and morpholine hydrochloride (6.2 g, 50 mmol) in absolute
ethanol (80 mL), paraformaldehyde (1.65 g, 55 mmol) was
added, followed by hydrochloric acid (37 % w/v, 0.2 mL),
and the mixture was refluxed for 6 h. The product obtained
on cooling was filtered and crystallized from ethanol to
◦
give 11. M. p. 220 C (dec). Yield 61 % (pale brown crys-
tals). – IR (KBr): ν = 1670 (CO), 1605, 1458, 1330, 1239,
N-Cyclohexyl-3-benzoyl-4-hydroxy-4-phenylpiperidine (7a)
1143 cm−1. – 1H NMR (200 MHz, D2O, 25 ◦C, TMS):
◦
◦
M. p. 136 C (aqueous ethanol) (137 C [4]). Yield 81 % δ = 2.91 – 3.33 [m, 8H, 2 × (CH2-N-CH2) of morpholine],
(colorless needles). – IR (KBr): ν = 3400 (OH), 1675 (CO), 4.01 – 4.20 [m, 8H, 2 × (CH2-O-CH2) of morpholine], 3.42
1515, 1380, 1211 cm−1
.
[t, J = 6.9 Hz, 4H, 2 × (COCH2CH2N)], 3.76 [t, J = 6.9 Hz,
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E. M. Afsah et al. · Alkylation of Amines and Diamines with Bis-ketonic Mannich Bases
24H22N4 (366.46): calcd. C 78.66, H 6.05, N 15.29; found
4H, 2 × (COCH2CH2N)], 6.69 – 7.66 (m, 4H, aromatic). –
C
C20H30N2O4Cl2 (433.37): calcd. C 55.43, H 6.97, N 6.46; C 78.48, H 6.00, N 15.05.
found C 55.25, H 6.88, N 6.29.
1,12-Diaza-tricyclo[10.2.2.25,8]octadeca-5(18),8(17)-
triene-4,9-dione (15)
1,4-Bis[β-(arylamino)propionyl]benzenes 12a, b
A solution of 11 (1.08 g, 2.5 mmol) and piperazine
(0.22 g, 2.5 mmol) in 50 % aqueous ethanol (50 mL)
was refluxed for 4 h, and allowed to stand at r. t. for
24 h. The product obtained was filtered and crystallized
from ethanol-chloroform (1 : 1) to give 15. M. p. 230 ◦C
(dec.). Yield 73 % (beige powder). – IR (KBr): ν = 1677
(CO), 1404, 1314, 1266, 1211, 853 cm−1. – 1H NMR
(200 MHz, CDCl3, 25 ◦C, TMS): δ = 2.61 [br s, 8H,
N(CH2CH2)2N)], 3.12 – 3.56 [m, 8H, 2 × (COCH2CH2N)],
7.96 – 8.08 (m, 4H, aromatic). – 13C NMR (200 MHz,
CDCl3): δ = 39.11 (all COCH2), 46.98 (all CH2N),
56.35 (all piperazine-C), 129.62, 144.26 (all Ar-C), 203.26
(CO). – MS (EI, 70 eV): m/z (%) = 273 (1) [M–1]+,
272 (3) [M]+, 230 (52) [CO-C6H4-CO(CH2)2N(CH2)4]+,
186 (22) [C6H4-(COCH=CH2)2]+, 159 (100) [CO-C6H4-
COCH=CH2]+, 131 (9) [C6H4-COCH=CH2]+, 104 (10)
[C6H4-CO]+, 86 (7) [piperazine]+, 76 (11) [C6H4]+,
55 (20) [COCH=CH2]+. – C16H20N2O2 (272.34): calcd.
C 70.56, H 7.40, N 10.29; found C 70.49, H 7.22, N 10.16.
A mixture of 11 (1.08 g, 2.5 mmol) and the appropriate
amine (5 mmol) in 50 % aqueous ethanol (60 mL) was re-
fluxed for 3 h. The product obtained on cooling was filtered
and crystallized from DMF to give 12a, b.
1,4-Bis[β-(p-tolylamino)propionyl]benzene (12a)
◦
M. p. 205 C (dec). – Yield 70 % (reddish crystals). – IR
(KBr): ν = 3392 (NH), 1678 (CO), 1617, 1517, 1402, 1301,
◦
1207, 1123 cm−1. – 1H NMR (200 MHz, CDCl3, 25 C,
TMS): δ = 2.27 (s, 3H, ArMe), 2.92 (s, 3H, ArMe), 3.58 –
3.73 [m, 8H, 2 × (COCH2CH2N)], 4.22 (s, 1H, ArNH),
4.24 (s, 1H, ArNH), 7.11 – 7.89 (m, 12H, aromatic). –
C26H28N2O2 (400.51): calcd. C 77.97, H 7.05, N 6.99; found
C 77.88, H 6.98, N 6.79.
1,4-Bis[β-(p-anisylamino)propionyl]benzene (12b)
M. p. 195 ◦C. – Yield 73 % (dark red crystals). – IR
(KBr): ν = 3388 (NH), 1677 (CO), 1513, 1402, 1376, 1240,
1035 cm−1. – 1H NMR (200 MHz, CDCl3, 25 ◦C, TMS): δ =
3.55 – 3.76 [m, 8H, 2 × (COCH2CH2N)], 3.79 (s, 3H, OMe),
3.82 (s, 3H, OMe), 4.18 (s, 1H, ArNH), 4.21 (s, 1H, ArNH),
6.91 – 7.86 (m, 12H, aromatic). – MS (EI, 70 eV): m/z
(%) = 432 (0.4) [M]+, 309 (17) [M–MeO-C6H4-NH2]+, 159
(18) [CO-C6H4-COCH=CH2]+, 136 (100) [MeO-C6H4-
NHCH2]+, 123 (25) [MeO-C6H4-NH2]+. – C26H28N2O4
(432.51): calcd. C 72.20, H 6.53, N 6.48; found C 72.08,
H 6.48, N 6.35.
4-[β-(Benzylamino)propionyl]acrylophenone (17)
This compound was obtained from equimolar amounts
of 11 and benzylamine (2 mmol) in 50 % aqueous ethanol
(40 mL), following the same procedure as described above.
Crys◦tallization of the product from ethanol gave 17. M. p.
148 C. Yield 49 % (pale yellow crystals). – IR (KBr): ν =
3435 (NH), 1673 (CO), 1603 (α,β-unsaturated CO), 1452,
1360, 1208, 1071 cm−1. – 1H NMR (200 MHz, CDCl3,
25 ◦C, TMS): δ = 2.62 – 2.94 [m, 4H, (COCH2CH2N)],
3.66 (s, 2H, PhCH2N), 1.44 (s, 1H, NH), 5.78 (dd, J =
10.5, 1.8 Hz, 1H, H2), 6.48 (dd, J = 16.8, 1.8 Hz, 1H, H3),
7.16 (dd, J = 16.8, 10.5 Hz, 1H, H1), 7.21 – 8.05 (m, 9H,
aromatic). – MS (EI, 70 eV): m/z (%) = 293 (3) [M]+,
186 (20) [C6H4(COCH=CH2)2]+, 159 (99) [CO-C6H4-
COCH=CH2]+, 131 (12) [C6H4-COCH=CH2]+, 107 (22)
[PhCH2NH2]+, 106 (73) [PhCH2NH]+, 91 (34) [PhCH2]+,
55 (100) [COCH=CH2]+. – C19H19NO2 (293.36): calcd.
C 77.79, H 6.53, N 4.77; found C 77.73, H 6.11, N 4.34.
4,4ꢀ-[p-Phenylene-bis(2,3-dihydro-1H-1,5-benzodiazepine)]
(14)
A mixture of 11 (1.08 g, 2.5 mmol), o-phenylenediamine
(0.54 g, 5 mmol) and fused sodium acetate (1.5 g) in ab-
solute ethanol (80 mL) was refluxed for 10 h. The crys-
talline product was filtered and washed◦with boiling ethanol-
acetone (1 : 1) to give 14. M. p. 272 C. Yield 65 % (yel-
low crystals). – IR (KBr): ν = 3394 (NH), 1612 (C=N),
1490, 1373, 1328, 1261, 1106 cm−1. – 1H NMR (200 MHz,
CDCl3, 25 ◦C, TMS): δ = 2.95 (t, J = 5.7 Hz, 4H, 2 × 3-H2),
3.71 (t, J = 5.7 Hz, 4H, 2 × 2-H2), 3.83 (s, 1H, NH), 3.84
(s, 1H, NH), 6.94 – 7.83 (m, 12H, aromatic). – 13C NMR
1,3-Diphenyl-2-pyrazoline (18)
A solution of 1 (1.66 g, 5 mmol), phenylhydrazine (1.08 g,
(200 MHz, CDCl3): δ = 32.66 (C-3), 49.12 (C-2), 113.84, 10 mmol) and sodium acetate (2 g) in 50 % acetic acid
119.22, 123.84, 127.88, 130.15, 134.55 (all Ar-C), 138.01 (50 mL) was refluxed for 3 h, then poured onto water
(C-5a), 138.83 (C-5b), 167.61 (C-4). – MS (EI, 70 eV): m/z (100 mL). The product was filtered off and recrystallized
◦
◦
(%) = 366 (100) [M]+, 367 (25) [M+1]+, 365 (34), 337 (15), from ethanol to give 18. M. p. 150 C (151 C [33]). Yield
310 (21), 248 (7), 182 (13), 145 (14), 128 (7), 119 (34). – 54 % (white crystals). The structure was confirmed by a com-
Unauthenticated
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E. M. Afsah et al. · Alkylation of Amines and Diamines with Bis-ketonic Mannich Bases
583
parison of IR data, m. p. and TLC with an authentic sam- 3,4,5,6-Tetrahydro-4-(p-hydroxyphenyl)-2,7-diphenyl-2H-
ple obtained from 2 and phenylhydrazine as previously re- 1,2,4-triazepine (20b)
ported [33].
◦
M. p. 197 C. Yield 75 % (yellow crystals). – IR (KBr):
ν = 3332 (OH), 1610 (C=N), 1554, 1457, 1334, 1234,
3,3ꢀ-[p-Phenylene-bis(1-phenyl-2-pyrazoline)] (19)
◦
1068 cm−1. – 1H NMR (200 MHz, CDCl3, 25 C, TMS):
δ = 3.15 (t, 2H, 6-H2), 3.47 (t, 2H, 5-H2), 4.98 (s, 2H, 3-H2),
7.05 – 8.31 (m, 14H, aromatic), 14.86 (s, 1H, OH). – MS (EI,
70 eV): m/z (%) = 344 (2) [M+1]+, 343 (8) [M]+, 238 (100)
[M–PhN2]+, 237 (60) [M–PhN=NH]+, 222 (33) [M–(HO-
C6H4-N=CH2)]+, 121 (10) [HO-C6H4-N=CH2]+, 93 (9)
[C6H4-OH]+, 77 (27) [Ph]+. – C22H21N3O (343.42): calcd.
C 76.94, H 6.16, N 12.24; found C 76.81, H 6.03, N 11.94.
This compound was obtained from 11 (1.08 g, 2.5 mmol)
and phenylhydrazine (0.54 g, 5 mmol), following the
same procedure as described above. The product precipi-
tated from the reaction mixture was filtered and crystal-
lized from methanol-chloroform (1 : 1) to give 19. M. p.
272 ◦C. Yield 82 % (orange crystals). – IR (KBr): ν =
1622 (C=N), 1552, 1382, 1301, 1122 cm−1. – 1H NMR
◦
(200 MHz, CDCl3, 25 C, TMS): δ = 3.12 [m, 4H, 2 × (5-
3,4,5,6-Tetrahydro-4-(p-anisyl)-2,7-diphenyl-2H-1,2,4-
triazepine (20c)
H2)], 3.68 [m, 4H, 2 × (4-H2)], 7.12 – 8.20 (m, 14H, aro-
matic). – MS (EI, 70 eV): m/z (%) = 367 (27) [M+1]+,
366 (100) [M]+, 365 (10) [M–1]+, 364 (23) [M–2]+, 260
(4) [M–PhN=NH]+, 221 (5) [M–(1-phenylpyrazoline)]+, 77
(23) [Ph]+. – C24H22N4 (366.46): calcd. C 78.66, H 6.05,
N 15.29; found C 78.59, H 5.90, N 15.04.
M. p. 183 ◦C. Yield 81 % (yellow crystals). – IR
(KBr): ν = 1613 (C=N), 1557, 1461, 1326, 1240, 1118,
◦
1029 cm−1. – 1H NMR (200 MHz, CDCl3, 25 C, TMS):
δ = 3.17 (t, 2H, 6-H2), 3.54 (t, 2H, 5-H2), 3.83 (s, 3H, OMe),
5.10 (s, 2H, 3-H2), 7.01 – 8.40 (m, 14H, aromatic). – MS
(EI, 70 eV): m/z (%) = 358 (2) [M+1]+, 357 (9) [M]+, 252
(100) [M–PhN2]+, 222 (28) [M–(MeO-C6H4-N=CH2)]+,
135 (24) [MeO-C6H4-N=CH2]+, 105 (12) [PhN2]+, 91
(45) [PhN]+, 77 (90) [Ph]+. – C23H23N3O (357.45): calcd.
C 77.28, H 6.49, N 11.76; found C 77.32, H 6.33, N 11.55.
3,4,5,6-Tetrahydro-4-aryl-2,7-diphenyl-2H-1,2,4-triazepines
20a – c
A solution of the β-(arylamino)propiophenone (3a – c)
(5 mmol) and 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 prod-
uct obtained on cooling was filtered and crystallized from
ethanol-chloroform (1 : 1) to give 20a – c.
4,4ꢀ-[p-Phenylene-bis(3,4,5,6-tetrahydro-2,7-diphenyl-2H-
1,2,4-triazepine)] (21)
A solution of 4 (0.93 g, 2.5 mmol) and phenylhydrazine
(0.54 g, 5 mmol) in ethanol (25 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 mix-
ture was heated for 1 h, and the product obtained on cool-
ing was filtered and crystallized from dioxane to give 21.
3,4,5,6-Tetrahydro-4-(p-bromophenyl)-2,7-diphenyl-2H-
1,2,4-triazepine (20a)
M. p. 174 ◦C. Yield 78 % (gray crystals). – IR (KBr): ν =
1612 (C=N), 1595, 1332, 1201, 1072 cm−1. – 1H NMR
◦
◦
M. p. 228 C. Yield 66 % (white powder). – IR (KBr): ν =
(200 MHz, CDCl3, 25 C, TMS): δ = 3.13 (t, 2H, 6-H2),
1617 (C=N), 1559, 1455, 1328, 1203, 1115, 1068 cm−1. –
3.51 (t, 2H, 5-H2), 4.96 (s, 2H, 3-H2), 7.03 – 8.22 (m, 14H,
aromatic). – 13C NMR (200 MHz, CDCl3): δ = 29.66 (C-6),
53.12 (C-5), 82.22 (C-3), 112.48, 113.77, 115.65, 117.52,
128.86, 129.14, 130.33, 132.47, 144.63, 145.52 (all Ar-C),
164.67 (C-7). – MS (EI, 70 eV): m/z (%) = 407 (3) [M+1]+,
405 (2) [M–1]+, 301 (21) [M–(PhN2)]+, 222 (30) [M–(Br-
C6H4-N=CH2)]+, 184 (16) [Br-C6H4-N=CH2]+, 105 (21)
[PhN2]+, 91 (49) [PhN]+, 77 (100) [Ph]+. – C22H20BrN3
(406.32): calcd. C 65.03, H 4.96, N 10.34; found C 65.21,
H 4.81, N 10.08.
◦
1H NMR (200 MHz, CDCl3, 25 C, TMS): δ = 3.15 (t,
4H, 6-H2, 6ꢀ-H2), 3.59 (t, 4H, 5-H2, 5ꢀ-H2), 5.12 (s, 4H,
3-H2, 3ꢀ-H2), 7.02 – 7.98 (m, 24H, aromatic). – MS (EI,
70 eV): m/z (%) = 576 (2) [M]+, 366 (16) [M–2PhN2]+,
250 (13) [diphenyltriazepine–H]+, 249 (50) [C16H15N3]+,
132 (11) [H2C=N-C6H4-N=CH2]+, 105 (13) [PhN2]+,
91 (41) [PhN]+, 77 (100) [Ph]+. – C38H36N6 (576.73):
calcd. C 79.14, H 6.29, N 14.57; found C 79.01, H 6.13,
N 14.25.
[1] M. Tramontini, Synthesis 1973, 703.
[2] M. Tramontini, L. Angiolini, Tetrahedron 1990, 46,
1791.
[3] J. C. Craig, M. Moyle, L. F. Johnson, J. Org. Chem.
1964, 29, 410.
[4] J. C. Craig, S. R. Johns, M. Moyle, J. Org. Chem. 1963,
28, 2779.
[5] M. Hammouda, W. S. Hamama, E. M. Kandeel, E. M.
Afsah, Pharmazie 1988, 43, 529.
Unauthenticated
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584
E. M. Afsah et al. · Alkylation of Amines and Diamines with Bis-ketonic Mannich Bases
[6] E. M. Afsah, H. M. Hassan, S. A. Elagizy, M. T. Zi-
maity, J. Prakt. Chem. 1984, 326, 841.
[7] E. M. Afsah, E. M. Kandeel, M. M. Khalifa, W. M.
Hammouda, Z. Naturforsch. 2007, 62b, 540.
[8] M. Von Strandtmann, M. P. Cohen, J. Shavel, J. Org.
Chem. 1965, 30, 3240.
[21] E. M. Afsah, M. Hammouda, W. S. Hamama, Monatsh.
Chem. 1985, 116, 851.
[22] M. Hammouda, E. M. Kandeel, W. S. Hamama, E. M.
Afsah, Arch. Pharm. Res. 1993, 16, 68.
[23] E. M. Afsah, M. Hammouda, M. M. Abou-Elzahab,
Monatsh. Chem. 1984, 115, 581.
[9] M. Von Strandtmann, M. P. Cohen, J. Shavel, Tetrahe-
dron Lett. 1965, 3103.
[10] I. Fleming, M. H. Karger, J. Chem. Soc. C 1967, 226.
[11] D. F. Rane, A. G. Fishman, R. E. Pike, Synthesis 1984,
694.
[12] F. Andreani, R. Andrisano, C. Della Casa, M. Tramon-
tini, Tetrahedron Lett. 1968,1059.
[13] G. Roman, E. Comanita, B. Comanita, Chem. Hetero-
cycl. Comp. 2002, 38, 1072.
[24] E. M. Afsah, M. A. Metwally, M. M. Khalifa, Monatsh.
Chem. 1984, 115, 303.
[25] H. I. Gul, T. Ojanen, O. Hanninen, Biol. Pharm. Bull.
2002, 25, 1307.
[26] H. I. Gul, A. A. Denizci, E. Erciyas, Arzneimittel-
forschung 2002, 52, 773.
[27] O. Hanninen, Biol. Pharm. Bull. 2003, 26, 613.
[28] J. R. Dimmock, P. Kumar, Curr. Med. Chem. 1997, 4,
1.
[14] R. Andrisano, A. S. Angeloni, M. Tramontini, Ann.
Chim. (Rome) 1965, 55, 1093; Chem. Abstr. 1966, 64,
11117h.
[15] A. S. Angeloni, L. Angeloni, P. De Maria, A. Fini,
J. Chem. Soc. C 1968, 2295.
[29] H. I. Gul, J. Vepsalainen, M. Gul, E. Erciyas, O. Han-
ninen, Pharm. Acta Helv. 2000, 74, 393.
[30] J. H. Plati, W. Wenner, J. Org. Chem. 1949, 14, 543.
[31] J. H. Plati, R. A. Schmidt, W. Wenner, J. Org. Chem.
1949, 14, 873.
[16] J. H. Brewster, E. L. Eliel, Org. React. 1953, 7, 99.
[17] M. M. Hassan, A. F. Casy, Tetrahedron 1970, 26, 4517.
[18] G. Gottarelli, Tetrahedron Lett. 1965, 2813.
[19] V. Prelog, P. Barman, M. Zimmermann, Helv. Chim.
Acta 1950, 33, 356.
[32] G. Roman, E. Comanita, B. Comanita, Acta. Chim.
Solv. 2002, 49, 575.
[33] A. Jacob, J. Madinaveitia, J. Chem. Soc. 1937, 1929.
[34] A. Vogel, Practical Organic Chemistry, Longman,
London 1978, pp. 815.
[20] V. Prelog, M. M. Wirth, L. Ruzicka, Helv. Chim. Acta
1946, 29, 1425.
Unauthenticated
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