γ-oxo carboxylic acids in heterocyclic synthesis IV. Synthesis of some pyridazines containing phthalyl and tosyl amino acids using DCC as the condensing agent

Article abstract of DOI:10.1080/10426500390221096

The 3(2H)-oxo-, 3(2H)-thioxo- or 3-amino-pyridazine derivatives 4, 6 and 7 were coupled with N-phthalyl- or N-tosyl-amino acids in one-step using N,N′-dicyclohexyl-carbodiimide as the condensing agent to furnish the corresponding 3-(N-phthalyl- or N-tosyl-aminoacyl)pyridazine derivatives 8-10 respectively. Hydrazinolysis of the N-phthalyl derivatives in methanol yielded the corresponding unprotected derivatives 11-13. The antibacterial activities of the prepared compounds were tested.

Full text of DOI:10.1080/10426500390221096

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γ-Oxo Carboxylic Acids in Heterocyclic Synthesis IV.
Synthesis of Some Pyridazines Containing Phthalyl and
Tosyl Amino Acids Using Dcc as the Condensing Agent
A. A. Aly a & A. A. F. Wasfy a
a Benha University , Benha, Egypt
Published online: 23 Aug 2006.
To cite this article: A. A. Aly & A. A. F. Wasfy (2003) γ-Oxo Carboxylic Acids in Heterocyclic Synthesis IV. Synthesis of Some
Pyridazines Containing Phthalyl and Tosyl Amino Acids Using Dcc as the Condensing Agent, Phosphorus, Sulfur, and Silicon and
the Related Elements, 178:9, 1911-1921, DOI: 10.1080/10426500390221096
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Phosphorus, Sulfur, and Silicon, 178:1911–1921, 2003
ꢀC
Copyright Taylor & Francis Inc.
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426500390221096
γ-OXO CARBOXYLIC ACIDS IN HETEROCYCLIC
SYNTHESIS IV. SYNTHESIS OF SOME PYRIDAZINES
CONTAINING PHTHALYL AND TOSYL AMINO
ACIDS USING DCC AS THE CONDENSING AGENT
A. A. Aly and A. A. F. Wasfy
Benha University, Benha, Egypt
(Received September 24, 2002; accepted February 18, 2003)
The 3(2H)-oxo-, 3(2H)-thioxo- or 3-amino-pyridazine derivatives 4, 6
and 7 were coupled with N-phthalyl- or N-tosyl-amino acids in one-step
using N,Nꢁ-dicyclohexyl-carbodiimide as the condensing agent to fur-
nish the corresponding 3-(N-phthalyl- or N-tosyl-aminoacyl)pyridazine
derivatives 8–10 respectively. Hydrazinolysis of the N-phthalyl deriva-
tives in methanol yielded the corresponding unprotected derivatives
11–13. The antibacterial activities of the prepared compounds were
tested.
Keywords: Antibacterial activities; 3(2H)-oxo-, 3(2H)-thioxo- or 3-
amino-pyridazine derivatives; pyridazine congeners
The pyridazine ring plays an essential role in several biological
processes.1,2 Likewise, phenoxathiines are found to be associated with
significant industrial uses,3 potential bioresponses, and physiological
activities.4,5 Moreover, the presence of D-amino acid residues in antibi-
otics such as the gramicidins,6 tyrocidine,7 penicillins,8 and aerosporin9
has aroused interest in the inhibitory potentialities of various nitro-
gen heterocycles containing amino acids. In an earlier report,10 we de-
scribed the preparation of 2-(N-phthalyl- or tosyl-aminoacyl)mercapto-
or amino-pyrimidine derivatives. Accordingly, a massive research effort
has been expended to synthesize novel congeners bearing these biologi-
cally active structural moieties within a molecular framework likely to
constitute potent antimicrobial agents. An attempt also has been made
to take an insight into the structure-activity relationship.
The authors are grateful to Dr. M. Amer, Botany Department, Faculty of Science,
Benha University, for biological screening.
Address correspondence to A. A. F. Wasfy, Chemistry Department, Faculty of Science,
Benha University, Benha, Egypt.
1911

1912
A. A. Aly and A. A. F. Wasfy
SCHEME 1 (1): N2H4; (2): PhCHO/EtONa; (3): POCl3/PCl5; (4): H2NCSNH2;
(5): AcONH4.
The various steps involved in the synthesis of the key intermediate
compounds 6 and 7 and their reaction with amino acid residues are
shown in Schemes 1 and 2.
The required 6-(phenoxathiin-2-yl)-2,3,4,5-tetrahydro-pyridazin-3-
one11 (2) was synthesized by the condensation of 4-(phenoxathiin-2-
yl)-4-oxobutanoic acid12 (1) with hydrazine hydrate in boiling ethanol.
Claisen condensation of 2 with benzaldehyde in ethanolic sodium
ethoxide gave 4-benzyl-6-(phenoxathiin-2-yl)pyridazin-3(2H)-one (4)
through a prototropic rearrangement of the originally formed product 3
(Scheme 1). The IR data showed an absorption band around 1665 cm−1
characteristic of the carbonyl group of a cyclic amide thereby indicating
the lactam form. It reacted when heated with POCl3/PCl5 on a steam
bath to yield the corresponding 4-benzyl-3-chloro-6-(phenoxathiin-
2-yl)pyridazine (5) with a fairly good yield. Subsequent reaction
with thiourea in refluxing ethanol and/or ammonium acetate by fusion

γ -Oxo Carboxylic Acids in Heterocyclic Synthesis IV
1913
SCHEME 2 Ar: cf. Scheme 1; (1): Phthalyl- or tosyl aminoacid; (2): N2H4.
furnished the target compounds 3(2H)-thioxo- or 3-amino-4-benzyl-6-
(phen-oxathiin-2-yl)pyridazines (6) and (7) respectively. Compounds 4,
6, and 7 were coupled with phthalyl and tosyl derivatives of the amino
acids glycine, DL-alanine, DL-phenylalanine, and L-valine in a one-
step, room temperature reaction using N,Nꢁ-dicyclohex-ylcarbodiimide
as the condensing agent to furnish the 4-benzyl-6-(phenoxathiin-2-
yl)-3-(N-phthalyl- or N-tosyl-glycyl, -DL-alanyl, -DL-phenylalanyl, or
-L-valyl)oxy-, mercapto- or amino-pyridazines 8–10 respectively. Hy-
drazinolysis of the N-phthalyl derivatives with hydrazine hydrate in

1914
A. A. Aly and A. A. F. Wasfy
methanol under mild conditions yielded the corresponding 4-benzyl-
6-(phenoxathiin-2-yl)-3-(glycyl, DL-alanyl-, DL-phenylalanyl-, or L-
valyl)oxy-, mercapto-, or amino-pyridazines 11–13 respectively. The
structures of all prepared compounds were confirmed from their phys-
ical and spectral data. The analytical data, 1H NMR and mass spectra
are compiled in Tables II and III.
SCREENING FOR AN ANTIMICROBIAL ACTIVITY
The antimicrobial activity of the synthesised derivatives was exam-
ined in vitro by the hole plate and filter-paper disc methods.13 All com-
pounds were tested for activity against several strains of Gram-positive
and Gram-negative bacteria using sulfadiazine and streptomycin sul-
fate as a reference standard. The culture medium was normal nutrient
agar supplemented with 1 g of yeast per ml. According to the solubility
of the tested compounds, different polar and nonpolar solvents were
used; good solubility was found in 10% (V/V) acetone for all the tested
compounds. Based on the previous preliminary test, closely spaced test
concentrations were selected; they are 500, 250, 125 µg/L. Sulfadiazine
and streptomycin sulfate were dissolved in filter sterilized 10 ml of 10%
actone (V/V) and employed in similar concentration as control. A qual-
itative screen was performed on all compounds while quantitative as-
says were done on active compounds only. The results are summarized
in Table I.
Structure-activity relationship (SAR) studied showed that the pres-
ence of the tosyl group in the amino acid moiety of our compounds
enhances their activities compared with the phthalyl group. Also, it
was found that the removal of the phthalyl group from the compounds
decreases the activities. Compounds 8e, 9e, and 10e exhibit activities
which are nearly comparable to commercial antibacterial agents, such
as sulfadiazine and streptomycin sulfate.
EXPERIMENTAL
Melting points were taken in open capillary tubes and are uncorrected.
IR spectra in KBr were recorded on a Shimadzu 470 spectrophotome-
1
ter and H NMR spectra were recorded on a Varian Gemini, 200 MHz
instrument using TMS as internal reference (chemical shifts are ex-
pressed as δ, ppm). Mass spectra were determined on a Shimadzu,
GCMS QP 1000 EX mass spectrometer (70 eV EI mode).
The starting compounds phthalyl- or tosyl-amino acids were pre-
pared according to the published procedures.

γ -Oxo Carboxylic Acids in Heterocyclic Synthesis IV
1915
TABLE I Antimicrobial Activity (A) and Minimum Inhibitory Concentration
(MIC, mmol/L) for Compounds (8a–13a)∗,†
Bacillus
subtilis
Rhadococcus Escherichia
equii coli
Salmonella
typhimurium
Pseudomonas
aeruginosa
Compounds
A
MIC
A
MIC
A
MIC
A
MIC
A
MIC
8a
8e
9a
9e
++
++
++
0.44
0.21
0.21
++
++
++
0.44
0.21
0.85
++
++
++
0.44
0.21
0.21
++
++
++
1.13
0.21
0.21
++
++
++
1.13
0.21
0.21
0.20
1.14
0.21
1.13
1.10
1.14
0.50
0.09
+++ 0.20 +++ 0.20 +++ 0.20 +++ 0.20 +++
10a
10e
11a
12a
13a
Sa
+
++
+
0.44
0.21
1.13
1.10
1.14
+
++
+
0.44
0.21
0.44
0.85
1.14
++
++
+
0.44
0.21
1.13
1.10
1.14
++
++
+
1.14
0.21
1.13
1.10
1.14
0.50
0.09
+
++
+
++
+
++
+
++
+
++
+
++
+
—
NTc +++ 0.50 +++ 0.50
++
++
Sb
—
NTc +++ 0.09 +++ 0.09
++
++
∗The width of the inhibition zone indicates the potency of activity (diameter of the
zone, mm): + mild (1–7); ++ moderate (8–13); +++ marked (14–17).
The results of control samples (showing negative response) are not included.
†Origin of cultures: Botany Department, Faculty of Science, Benha University, Benha
(Egypt).
aSulfadiazine.
bStreptomycin sulfate.
cNot tested.
Phthalylglycine (92%), m.p. 192–194◦C (from methanolether), lit.,14
m.p. 193–195◦C; phthalyl-DL-alanine (90%), m.p. 160–162◦C (from
ethanol-water), lit.,15 m.p. 160–161◦C; phthalyl-DL-phenylalanine
(78%), m.p. 173–175◦C (from methanol-water), lit.,16 m.p. 174–175◦C;
phthalyl-L-valine (69%), 113–115◦C (from cyclohexane), lit.,16 m.p.
114–115◦C, [α]2D7 −68.5
1.0◦ in abs. EtOH; tosylglycine (68%), m.p.
148–149◦C (from methanol-ether), lit.,17 m.p. 148◦C; tosyl-DL-alanine
(70%), m.p. 137–139◦C (from methanol-ether), lit.,17 m.p. 139◦C; tosyl-
DL-phenylalanine (65%), m.p. 124–126◦C from (methanol-water), lit.,18
m.p. 125–127◦C; tosyl-L-valine (66%), m.p. 147–149◦C (from methanol-
water), lit.,18 m.p. 148◦C.
6-(Phenoxathiin-2-yl)-2,3,4,5-tetrahydropyridazin-3-one
(2)
A solution of 112 (27 g, 0.09 mmol) in ethanol (200 ml) was treated
with hydrazine hydrate (6.8 ml, 99%, 0.14 mmol) and the mixture was
refluxed for 6 h. The solid that separated after concentration and cooling
was crystallised from ethanol to furnish the desired compound 2, 21 g

1916
A. A. Aly and A. A. F. Wasfy
(79%), m.p. 230–232◦C; IR (cm−1): 3280–2950 broad (NH), 1665 (amidic
CO), 1600 (C N); 1H NMR (DMSO-d6) δH: 2.51 (t, 2H, CH2, H-4), 3.04 (t,
2H, CH2 H-5), 6.88–8.24 (m, 7H, Ar-H), 8.94 (br s, 1H, NH, exchange-
able). Found: C, 64.72; H, 4.17; N, 9.33%. Calcd for C16H12N2O2S: C,
64.85; H, 4.08; N, 9.45%.
4-Benzyl-6-(phenoxathiin-2-yl)pyridazin-3(2H)-one (4)
To a mixture of 2 (20.7 g, 0.07 mmol) and benzaldehyde (7.3 ml,
0.072 mmol) in ethanol (150 ml) was added an ethanolic sodium ethox-
ide solution prepared from sodium (1.66 g, 0.072 mmol) and dry ethanol
(∼80 ml). The reaction mixture was left overnight at room temperature,
diluted with water, and rendered just acidic with conc. HCl. The solid
thus obtained was filtered and crystallized from methanol to give 4,
23.4 g (87%), m.p. 203–205◦C; IR (cm−1): 3270–2980 broad (NH), 1665
(amidic CO), 1605 (C N); 1H NMR (DMSO-d6) δH: 3.64 (s, 2H, CH2Ph),
6.85–8.33 (m, 13H, Ar-H), 8.99 (br s, 1H, NH, exchangeable). Found: C,
71.72; H, 4.26; N, 7.36%. Calcd for C23H16N2O2S: C, 71.85; H, 4.19; N,
7.29%.
4-Benzyl-3-chloro-6-(phenoxathiin-2-yl)pyridazine (5)
A mixture of pyridazinone 4 (34 g, 0.088 mmol), POCl3 (137 ml,
1.5 mmol) and PCl5 (31 g, 0.15 mmol) was refluxed on a steam bath
for 5 h. The reaction mixture was poured gradually on crushed ice and
the solid that separated was filtered off and crystallized from ethanol
to afford 5, 27.3 g (77%), m.p. 191–193◦C; IR (cm−1): 2920–2840 (alkyl-
H), 1619 (C C), 1588 (C N); 1H NMR (CDCl3) δH: 3.68 (s, 2H, CH2Ph),
6.92–8.44 (m, 13H, Ar-H). Found: C, 68.66; H, 3.68; N, 6.82%. Calcd for
C23H15ClN2OS: C, 68.56; H, 3.75; N, 6.95%.
4-Benzyl-6-(phenoxathiin-2-yl)pyridazin-3(2H)-thione (6)
A solution of 5 (12.5 g, 0.031 mmol) and thiourea (5.3 g, 0.07 mmol)
in anhydrous ethanol (100 ml) was refluxed for 5 h. After cooling, the
precipitate was filtered, and recrystallized from methanol to obtain 6,
10.5 g (85%), m.p. 208–210◦C; IR (cm−1): 3260–3100 broad (NH), 2285
(SH), 1628 (C N), 1255 (C S), such IR data explain that the thione 6
ꢀ
really exists in the thioamide ( NH C S)
iminothiol ( N C SH)
ꢁ
dynamic equilibrium; 1H NMR (DMSO-d6) δH: 3.62 (s, 2H, CH2Ph),
6.88–8.32 (m, 13H, Ar-H), 9.18 (br s, 1H, NHC S ratio 55.8), 11.57
(br s, 1H, SH ratio 44.2). Found: C, 68.85, H, 4.12; N, 6.83%. Calcd for
C23H16N2OS2: C, 68.97; H, 4.03; N, 6.99%.

γ -Oxo Carboxylic Acids in Heterocyclic Synthesis IV
1917
3-Amino-4-benzyl-6-(phenoxathiin-2-yl)pyridazine (7)
A mixture of 5 (14.5 g, 0.036 mmol) and ammonium acetate (12.3 g,
0.16 mmol) was heated in an oil bath at 180◦C for 4 h. Then the reaction
mixture was poured into water and the solid separated was filtered and
crystallized from ethanol to give the target compound 7, 10 g (73%),
m.p. 216–218◦C; IR (cm−1): 3360–3175 (multiple bands, NH2), 2940–
2830 (alkyl-H), 1620 (C C), 1592 (C N); 1H NMR (CDCl3) δH: 3.74 (s,
2H, CH2Ph), 5.46 (br s, 2H, NH2, exchangeable), 6.94–8.31 (m, 13H,
Ar-H). Found: C, 72.12; H, 4.58; N, 10.85%. Calcd for C23H17N3OS: C,
72.04; H, 4.47; N, 10.96%.
4-Benzyl-6-(phenoxathiin-2-yl)-3-(N-phthalyl- or
N-tosyl-glycyl, -DL-alanyl, -DL-phenylalanyl or
-L-valyl)oxy-, mercapto- or amino-pyrimidines 8–10
An N-phthalyl- or N-tosyl-amino acids (0.0031 mmol), namely,
glycine, DL-alanine, DL-phenylalanine, or L-valine and the pyridazine
derivatives 4, 6, and/or 7 (0.0031 mmol) were dissolved in tetrahy-
drofuran (30 ml). The reaction mixture was cooled to 0◦C, then N,Nꢁ-
dicyclohexylcarbodiimide, DCC (0.68 g, 0.0033 mmol) was added and
the mixture was stirred for 2 h at 0◦C, and for another 15 h at room
temperature. The precipitated dicyclohexylurea was filtered off and the
filtrate was washed successively with 1 N HCl, 1N NaHCO3, and a
saturated solution of 1 N NaCl and dried on anhydrous sodium sul-
fate and left overnight. It was then filtered and the excess of solvent
was removed. The residue thus obtained was dissolved in benzene and
kept aside for 2 h. The dicyclohexylurea which again precipitated out
was filtered off. The solvent was removed at reduced pressure and the
residue was crystallized from a proper solvent to furnish compounds
8–10 (Tables II and III). IR (cm−1) of (8–10)a–d: 2975–2820 (alkyl-H),
1785–1750 (imidic CO). In addition to the above bands (8, 9)a–d ex-
hibited bands at 1740–1730 ( O C O, S C O) and 10a–d exhibited
bands at 3340–3180 (NH, CONH), 1680–1645 (amidic CO). IR (cm−1) of
(8–10)e–h: 3220–3080 (NH, SO2NH), 2970–2840 (alkyl-H), 1458, 1370,
and 1090 (SO2NH). In addition to the above bands (8, 9)e–h exhibited
bands at 1750–1735 ( O C O, S C O) and 10e–h exhibited bands
at 3332–3140 (NH, CONH), 1670–1655 (amidic CO).
4-Benzyl-6-(phenoxathiin-2-yl)-3-(glycyl-, DL-alanyl-,
DL-phenyl-alanyl-, or L-valyl)oxy-, mercapto-, or
amino-pyridazines 11–13
The N-phthalyl derivatives (8–10)a–d (0.0014 mmol) were sus-
pended in (30 ml) of methanol. The suspension was brought to reflux.

1918
A. A. Aly and A. A. F. Wasfy
TABLE II Analytical Data of Compounds 8–13
Calcd (found) (%)
Compd.
No.
m.p. [b]
Yield
(%)
Mol. Formula
(mol. wt.)
R[a]
θ m/◦C
C
H
N
8a
b
c
Pht. Gly
185–187e
176–178a
71
64
62
58
62
65
63
70
61
59
70
66
61
68
73
62
70
73
68
71
65
67
73
C33H21N3O5S
(571.61)
C34H23N3O5S
(585.63)
C40H27N3O5S
(661.73)
C36H27N3O5S
(613.69)
C32H25N3O5S2
(595.69)
C33H27N3O5S2
(609.72)
C39H31N3O5S2
(685.82)
C35H31N3O5S2
(637.77)
C33H21N3O4S2
(587.67)
C34H23N3O4S2
(601.70)
C40H27N3O4S2
(677.80)
C36H27N3O4S2
(629.75)
C32H25N3O4S3
(611.76)
C33H27N3O4S3
(625.78)
C39H31N3O4S3
(701.88)
C35H31N3O4S3
(653.84)
C33H22N4O4S
(570.62)
C34H24N4O4S
(584.65)
C40H28N4O4S
(660.75)
C36H28N4O4S
(612.70)
C32H26N4O4S2
(594.71)
C33H28N4O4S2
(608.73)
C39H32N4O4S2
(684.83)
69.34
3.70
7.35
(69.46) (3.79) (7.42)
69.73 3.96 7.18
(69.84) (3.84) (7.26)
72.60 4.11 6.35
(72.71) (4.19) (6.42)
70.46 4.43 6.85
(70.56) (4.35) (6.72)
64.52 4.23 7.05
(64.63) (4.11) (7.13)
65.01 4.46 6.89
(65.13) (4.35) (6.76)
68.30 4.56 6.13
(68.39) (4.47) (6.19)
65.91 4.90 6.59
(65.80) (4.81) (6.44)
67.45 3.60 7.15
(67.57) (3.69) (7.05)
67.87 3.85 6.98
(67.73) (3.96) (6.86)
70.88 4.02 6.20
(70.76) (4.12) (6.29)
68.66 4.32 6.67
(68.78) (4.41) (6.56)
62.83 4.12 6.87
(62.92) (4.21) (6.72)
63.34 4.35 6.71
(63.42) (4.22) (6.83)
66.74 4.45 5.99
(66.83) (4.53) (5.87)
64.29 4.78 6.43
(64.39) (4.67) (6.52)
69.46 3.89 9.82
(69.54) (3.97) (9.71)
69.85 4.14 9.58
(69.72) (4.22) (9.46)
72.71 4.27 8.48
(72.63) (4.38) (8.59)
70.57 4.61 9.14
(70.42) (4.72) (9.26)
64.63 4.41 9.42
(64.51) (4.54) (9.53)
65.11 4.64 9.20
(65.21) (4.76) (9.29)
68.40 4.71 8.18
Pht.DL-Ala
Pht.DL-Phe 190–192a
d
e
Pht.L-Val
Tos. Gly
222–224e
237–239a
251–253b
197–199b
165–167e
163–165b
183–185b
f
Tos.DL-Ala
Tos.DL-Phe
Tos.DL-Val
Pht. Gly
g
h
9a
b
c
Pht.DL-Ala
Pht.DL-Phe 200–202e
d
e
Pht.L-Val
Tos. Gly
225–227e
151–153b
f
Tos. DL-Ala 170–172a
g
Tos.DL-Phe
Tos.L-Val
Pht. Gly
190–192a
201–203b
162–164a
153–155b
h
10a
b
c
Pht.DL-Ala
Pht.DL-Phe 193–195c
d
e
Pht.L-Val
Tos. Gly
180–182e
207–209b
f
Tos. DL-Ala 211–213b
Tos. DL-Phe 170–172a
g
(68.52) (4.83) (8.30)
(Continued on next page)

γ -Oxo Carboxylic Acids in Heterocyclic Synthesis IV
1919
TABLE II Analytical Data of Compounds 8–13 (Continued)
Calcd (found) (%)
Compd.
No.
m.p. [b]
Yield
(%)
Mol. Formula
(mol. wt.)
R[a]
θ m/◦C
C
H
N
h
Tos. DL-Val 190–192a
68
72
65
62
73
81
71
82
69
70
65
67
59
C35H32N4O4S2
(636.79)
C25H19N3O3S
(441.50)
C26H21N3O3S
(455.53)
C32H25N3O3S
(531.63)
C28H25N3O3S
(483.59)
C25H19N3O2S2
(457.57)
C26H21N3O2S2
(471.60)
C32H25N3O2S2
(547.69)
C28H25N3O2S2
(499.65)
C25H20N4O2S
(440.52)
C26H22N4O2S
(454.55)
C32H26N4O2S
(530.65)
66.02
5.07
8.80
(8.91)
9.52
(9.43)
9.22
(9.31)
7.90
(7.79)
8.69
(8.78)
9.18
(9.09)
8.91
(8.80)
7.67
(7.55)
8.41
(66.19) (5.13)
68.01 4.34
(68.13) (4.41)
68.55 4.65
(68.68) (4.77)
72.30 4.74
(72.42) (4.85)
69.54 5.21
(69.66) (5.10)
65.62 4.19
(65.74) (4.28)
66.22 4.49
(66.31) (4.58)
70.18 4.60
(70.26) (4.73)
67.31 5.04
(67.44) (5.15)
68.16 4.58
11a
b
Gly
242–244a
248–250b
221–223b
261–263e
210–212e
230–232e
236–238b
240–242b
250–252a
271–273a
231–233e
217–219a
DL-Ala
DL-Phe
L-Val
c
d
12a
b
Gly
DL-Ala
DL-Phe
L-Val
c
d
(8.54)
12.72
13a
b
Gly
(68.26) (4.70) (12.61)
68.70 4.88 12.33
(68.61) (4.97) (12.42)
72.43 4.94 10.56
(72.31) (4.81) (10.69)
69.69 5.43 11.61
(69.54) (5.56) (11.73)
DL-Ala
DL-Phe
L-Val
c
d
C28H26N4O2S
(482.60)
[a] Pht = phthalyl, Tos = tosyl, Gly = glycine, Ala = alanine, Phe = phenylalanine,
Val = valine.
[b] solvent for crystallization.
aEthanol.
bMethanol.
cBenzene.
dCyclohexane.
eEthyl acetate.
A clear solution resulted, hydrazine hydrate (0.15 ml, 0.003 mmol) was
added, and the solution was stored for 20 h at 30◦C. The solvent was
removed in vacuo. To the dry residue there was added (10 ml) of 0.5 N
hydrochloric acid, the suspension was kept in an ice-bath for 2 h, and
the insoluble phthalylhydrazide was removed by filtration. The filtrate
was evaporated to dryness in vacuo. To the oily residue was added ace-
tone (10 ml), followed by ether (30 ml), and the solution was stored for
8 h at 0◦C. The product was collected by filtration. Crystallization from

1920
A. A. Aly and A. A. F. Wasfy
TABLE III Spectral Data of Compounds 8–13
Compd.
No.
MS (70 eV)
m/z (%)
1H NMR (DMSO-d6) δ/ppma
8a
8b
3.74 (s, 2H, CH2Ph), 4.88 (s, 2H, COCH2), 6.89–8.24 (m, 17H, Ar-H) 571 (M+, 58)
b1.18 (d, 3H, J = 6.8 Hz, CHCH3), 3.67 (s, 2H, CH2Ph), 5.58 (q, 1H, 585 (M+, 67)
J = 6.8 Hz, COCH), 6.98–8.32 (m, 17H, Ar-H)
8c
8d
8e
8f
b2.88 (d, 2H, J = 6.2 Hz, CHCH2), 3.84 (s, 2H, CH2Ph), 5.48 (t, 1H,
J = 6.2 Hz, COCH), 6.88–8.34 (m, 22H, Ar-H)
661 (M+, 34)
613 (M+, 70)
595 (M+, 76)
609 (M+, 83)
1.15 (d, 6H, J = 6.5, 2xCH3), 2.37 (m, 1H, CH(CH3)2), 3.81 (s, 2H,
CH2Ph), 5.61 (d, 1H, J = 6.1, COCH), 6.81–8.27 (m, 17H, Ar-H)
2.34 (s, 1H, ArCH3), 3.78 (s, 2H, CH2Ph), 4.76 (s, 2H, COCH2),
6.83–8.21 (m, 17H, Ar-H), 10.18 (br s, 1H, NH)
b1.21 (d, 3H, J = 6.8 Hz, CHCH3), 2.28 (s, 3H, ArCH3), 3.68 (s, 2H,
CH2Ph), 5.44 (q, 1H, J = 6.8 Hz, COCH), 6.85–8.26 (m, 17H,
Ar-H), 10.09 (br s, 1H, NH)
8h
b1.10 (d, 6H, J = 6.5, 2xCH3), 2.34 (s, 3H, ArCH3), 2.32 (m, 1H,
CH(CH3)2), 3.78 (s, 2H, CH2Ph), 5.53 (d, 1H, J = 6.1 Hz, COCH),
6.90–8.31 (m, 17H, Ar-H), 10.30 (br s, 1H, NH)
637 (M+, 66)
9a
9c
3.68 (s, 2H, CH2Ph), 4.91 (s, 1H, COCH2), 6.80–8.14 (m, 17H, Ar-H) 587 (M+, 67)
b2.79 (d, 2H, J = 6.1 Hz, CHCH2), 3.75 (s, 2H, CH2Ph), 5.36 (t, 1H,
J = 6.1 Hz, COCH), 6.90–8.20 (m, 22H, Ar-H)
1.08 (d, 3H, J = 6.7 Hz, CHCH3), 2.37 (s, 3H, ArCH3), 3.70 (s, 2H,
CH2Ph), 5.38 (q, 1H, J = 6.7 Hz, COCH), 6.92–8.24 (m, 17H,
Ar-H), 10.32 (br s, 1H, NH)
677 (M+, 48)
9f
625 (M+, 55)
10a
10b
10g
b3.65 (s, 2H, CH2Ph), 4.92 (s, 2H, COCH2), 6.88–8.25 (m, 17H,
Ar-H), 9.99 (br s, 1H, NH)
0.98 (d, 3H, J = 6.8 Hz, CHCH3), 3.75 (s, 2H, CH2Ph), 5.52 (q, 1H,
J = 6.8 Hz, COCH), 6.98–8.41 (m, 17H, Ar-H), 9.95 (br s, 1H, NH)
2.77 (d, 2H, J = 6.2 Hz, CHCH2), 2.31 (s, 3H, ArCH3), 3.74 (s, 2H,
CH2Ph), 5.46 (t, 1H, J = 6.2 Hz, COCH), 6.88–8.27 (m, 22H,
Ar-H), 9.88–10.60 (br s, 2H, 2x NH)
570 (M+, 70)
584 (M+, 86)
684 (M+, 66)
11a
11b
b3.64 (s, 2H, CH2Ph), 4.82 (s, 2H, COCH2), 6.02 (br s, 2H, NH2),
6.90–8.28 (m, 13H, Ar-H)
1.09 (d, 3H, J = 6.4 Hz, CHCH3), 3.84 (s, 2H, CH2Ph), 5.42 (q, 1H,
J = 6.4 Hz, COCH), 5.99 (br s, 2H, NH2), 6.88–8.31 (m, 13H,
Ar-H)
2.81 (d, 2H, J = 6.0 Hz, CHCH2), 3.71 (s, 2H, CH2Ph), 5.38 (t, 1H,
J = 6.0 Hz, COCH), 5.92 (br s, 2H, NH2), 6.80–8.22 (m, 18H,
Ar-H)
441 (M+, 80)
455 (M+, 62)
11c
531 (M+, 52)
12a
12b
3.74 (s, 2H, CH2Ph), 4.86 (s, 2H, COCH2), 5.88 (br s, 2H, NH2),
6.85–8.30 (m, 13H, Ar-H)
457 (M+, 51)
b1.18 (d, 3H, J = 6.8 Hz, CHCH3), 3.77 (s, 2H, CH2Ph), 5.40 (q, 1H, 471 (M+, 60)
J = 6.8 Hz, COCH), 5.95 (br s, 2H, NH2), 6.89–8.33 (m, 13H,
Ar-H)
12c
13a
2.88 (d, 2H, J = 6.2 Hz, CHCH2) 3.68 (s, 2H, CH2Ph), 5.41 (t, 1H,
J = 6.2 Hz, COCH), 6.02 (br s, 2H, NH2), 6.78–8.20 (m, 18H,
Ar-H)
3.82 (s, 2H, CH2Ph), 4.80 (s, 2H, COCH2), 6.12 (br s, 2H, NH2),
6.91–8.35 (m, 13H, Ar-H), 10.22 (br s, 1H, NH)
547 (M+, 71)
440 (M+, 48)
aAll NH2 and NH signals were exchangeable with deuterium oxide.
bIn CDCl3.

γ -Oxo Carboxylic Acids in Heterocyclic Synthesis IV
1921
a proper solvent yielded the unprotected compounds 11–13 (Tables II
and III). IR (cm−1) of 11 and 12: 3480–3290 (multiple bands, NH2),
2974–2860 (alkyl-H), 1755–1740 ( O C O, S C O), IR (cm−1) of 13
showed bands at 3472–3188 (multiple bands, NH2 and NH), 2950–2840
(alkyl-H), 1670–1655 (amidic CO).
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