α-Halogenohydrazides: Useful starting material for the synthesis of hydrazinoazapeptides and azauracils

Article abstract of DOI:10.1139/v99-013

An efficient method for the synthesis of pseudodipeptides, which combines an aza glycine residue with various hydrazinoacid moieties by simple substitution of the halogen of α-halohydrazides, is described. Some of these hydrazinoazapeptides lead to hydrazones by oxidation or to azaaminouracils by cyclization.

Full text of DOI:10.1139/v99-013

263
␣-Halogenohydrazides: useful starting material
for the synthesis of hydrazinoazapeptides and
azauracils
Catherine Barré, Sophie Carret, Michel Guerro, Philippe Le Grel,
and Michèle Baudy-Floc’h
Abstract: An efficient method for the synthesis of pseudodipeptides, which combines an aza glycine residue with
various hydrazinoacid moieties by simple substitution of the halogen of α-halohydrazides, is described. Some of these
hydrazinoazapeptides lead to hydrazones by oxidation or to azaaminouracils by cyclization.
Key words: hydrazinohydrazides, hydrazones, hydrazinoazapeptides, azaaminouracils, pseudopeptides.
Résumé : Une méthode de synthèse efficace de pseudopeptides, combinant une unité azaglycine avec divers
hydrazinoacides, est décrite. Celle-ci consiste en une simple réaction de substitution de l’halogène de divers α-
halohydrazides. Nous montrons également que certains de ces hydrazinoazapeptides peuvent conduire à des hydrazones
par oxydation et par cyclisation intramoléculaire à des hétérocyles très peu représentés, les azaaminouracils.
Mots clés : hydrazinohydrazides, hydrazones, hydrazinoazapeptides, azaaminouracils, pseudopeptides. Barré et al.
270
case of the lowest basic hydrazides or carbazates must some
additional base (NEt3) be added to promote the reaction.
Following our studies on the high lability of the chloro or
bromo atom of α-halogenohydrazides 1 (1, 2), which occurs
under basic conditions with rapid substitution of the halogen
by nucleophiles, we focussed our attention on the reaction of
various substituted hydrazines. Here is a full report of the re-
action of hydrazines, hydrazides, or carbazates 2 with α-
halogenohydrazides 1, which affords hydrazinoazapeptides
3, 4, or azauracils 9. Such pseudopeptides are interesting
since hydrazinopeptides (3), as well as azapeptides (4), are
analogues of peptides in which the modification of the am-
ide bond decreases the enzymatic biodegradability (5).
Moreover, though azauracils are well known compounds (6),
only a few of them are N-amino substituted and they have
been shown to act as herbicidal agents (7).
Most of the cases we have examined give moderate to
good yields (Tables 1 and 2). It is interesting to note that
monoalkylated hydrazines 2 react either exclusively (R3 =
1
Me, CH2Ph; R4 = H; only one isomer 4 is observed by H
NMR spectra of the crude reaction mixture) or predomi-
nantly (R3 = CH2CF3; R4 = H) through the substituted nitro-
gen, the most nucleophilic one being due to the electron
donor substituent (Table 2). In the former case, both isomers
3 and 4, which can be separated by column chromatography,
are formed in the proportion 3:7. The structure 4 was proved
by NMR spectroscopy as well as by condensation with an
aldehyde or a ketone to give 5 (Scheme 1).
Some exceptions to the general reaction must be noted.
(i) The use of N-aminotriazole 6 affords the triazolium salt 7
instead of the expected α-hydrazino compound (Scheme 2).
1
This structure was confirmed by H NMR spectroscopy; in
particular, the CH at 6.75 ppm is in accord with a proton in
the α position of a pyridinium salt (8). (ii) The reaction with
phenylhydrazine 2 (R3 = Ph, R4 = H) leads to the corre-
sponding hydrazone 8 (syn and anti) probably via the oxida-
tion of an α-hydrazino intermediate 3 (Scheme 3). (iii) In
some cases (Table 3), if the reaction is run in refluxing tolu-
ene, the formation of N-aminoazauracil 9 was observed even
under a nitrogen or argon atmosphere. This reaction proba-
bly takes place through the oxidation of the primary α-
hydrazinohydrazide 3. It was possible to isolate 3 at room
temperature and to show that the α-hydrazinohydrazide can
be oxidized by DDQ to yield the hydrazone 8, which affords
N-aminoazauracil 9 by cyclization in the presence of NEt3
(Scheme 4).
α-Hydrazinohydrazides 3 or 4 are readily obtained via a
simple procedure that involves stirring the starting α-halo-
genohydrazides 1 with an excess of nucleophiles 2 (typically
3- to 6-fold excess) at room temperature. The basicity of
most of the hydrazine derivatives 2 means that only in the
Received October 6, 1998.
C. Barré, S. Carret, M. Guerro, P. Le Grel, and M.
Baudy-Floc’h.1 Groupe de synthèse et électrosynthèse
organique, UMR 6510 au Centre national de la recherche
scientifique, Université de Rennes I, Campus de Beaulieu,
F-35042 Rennes Cédex, France.
1Author to whom correspondence may be addressed.
Fax: +(33)0299286738.
e-mail: Michele.Baudy-Floch@univ-rennes1.fr
Regarding the peptidomimic properties of the resulting
compounds 3 and 4, it appears that a lot of them are interest-
ing pseudopeptidic building blocks that combine an
Can. J. Chem. 77: 263–270 (1999)
© 1999 NRC Canada

264
Can. J. Chem. Vol. 77, 1999
Table 1. Yields for compounds 3a–3q.
Compound
R1
R2
R3
R4
Yield, %
3a
3b
3c
3d
3e
3f
3g
3h
3i
3j
3k
3l
3m
3n
3o
3p
3q
pClC6H4
pMeC6H4
pMeC6H4
pMeC6H4
pClC6H4
pClC6H4
pMeC6H4
pClC6H4
pClC6H4
pMeC6H4
pMeC6H4
pClC6H4
pMeC6H4
pClC6H4
2,4-Cl2C6H3
pMeC6H4
pMeC6H4
Ph
Ph
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
COPh
COPh
COPh
CO2Et
CO2Et
H
H
H
H
H
H
H
H
H
H
H
H
Me
Me
70
72
55
60
82
65
70
78
69
71
60
88
48
44
40
74
27
OMe
OtBu
OtBu
Ph
OMe
OMe
Ph
Ph
OMe
OMe
OMe
OMe
OMe
Ph
CO2tBu
CO2tBu
Me
Me
(CH2)2O(CH2)2
(CH2)5
CF3CH2
OMe
H
Table 2. Yields for compounds 4a–4n.
Compound
R1
R2
R3
Yield
General procedures
1H NMR spectra were recorded at 80 MHz on a Bruker
WP 80 or at 300 MHz on a Bruker AM 300 spectrometer
and 13C NMR spectra at 75 MHz on a Bruker AM 300 spec-
trometer with tetramethylsilane as internal reference. Mass
spectra were determined with a Varian Mat 311 spectrometer
from the Centre Régional de Mesures Physiques de l’Ouest.
IR spectra were determined with a Perkin–Elmer 225 or
1420 spectrometer. Elemental analyses were performed by
the analytical laboratory, CNRS (Lyon). Melting points were
taken with a Kofler hot stage apparatus. α-Halohydrazides 1
(X = Cl or Br) were prepared as previously described (14).
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
4m
4n
pClC6H4
pMeC6H4
pClC6H4
Et
pClC6H4
pClC6H4
pMeC6H4
Et
OMe
OMe
Ph
Ph
Me
OtBu
OtBu
OtBu
OtBu
OCH2Ph
OCH2Ph
OMe
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
PhCH2
PhCH2
CF3CH2
73
70
68
68
47
93
70
70
76
78
60
55
41
63
H
pClC6H4
pMeC6H4
pClC6H4
pMeC6H4
pMeC6H4
OMe
OMe
Preparation of hydrazinoazapeptides 3a–3e
A mixture of α-halohydrazide 1 (8 mmol), methylhydra-
zinocarboxylate 2 (R3 = CO2Me, R4 = H) (32 mmol), and
NEt3 (32 mmol) was stirred for 16 h in CH3CN (50 mL). Af-
ter removal of the solvent under reduced pressure, the resi-
due was diluted in CH2Cl2 (100 mL), and the organic layer
was washed with an aqueous solution of HCl (100 mL) and
water (100 mL) and then dried (Na2SO4). Evaporation af-
forded the α-hydrazinohydrazide 3.
azaglycine residue (ester form) with various hydrazinoaryl-
glycine moieties in racemic form (Scheme 5). Such associa-
tion of aza aminoacids and hydrazino acids has not been
previously reported; moreover, substituted phenylglycine de-
rivatives have been described as potent agonists or antago-
nists of the glutamate receptors of the central nervous
system (9).
3a (R1 = pClC6H4, R2 = Ph, R3 = CO2Me, R4 = H):
Yield 70%, mp 144°C (CHCl3–Et2O). IR (Nujol), ν: 3270,
1
3200, 3100, 1695, 1655 cm–1. H NMR (80 MHz, DMSO-
It is important to note that although the presence of an ad-
ditional nitrogen makes their incorporation into peptidic
backbones (10) difficult, such pseudodipeptides (3 and 4)
could be linked to aminoacids (3b). For example the N ex-
tremity could be coupled with the free carboxylic acid func-
tion of protected aminoacids or peptides. Alternatively, the
Boc-hydrazino (11) or Bz-hydrazino (12) moiety could be
deprotected, leading to an hydrazido extremity that could re-
act with isocyano aminoester (13). Of course these two as-
pects could be combined to integrate the pseudodipeptides
into elaborated peptidic analogues. This last promising as-
pect is under investigation in our laboratory.
d6), δ: 3.57 (s, 3 H), 4.72 (s, 1 H), 5.27 (br, 1 H), 7.45–7.95
(m, 9 H), 8.45 (br, 1 H), 10.12 (s, 1 H), 10.40 (s, 1 H). Anal.
calcd. for C17H17N4O4Cl: C 54.18, H 4.52, N 14.87, Cl
9.43%; found: C 54.41, H 4.82, N 15.08, Cl 9.36%.
3b (R1 = pMeC6H4, R2 = Ph, R3 = CO2Me, R4 = H):
Yield 72%, mp 105°C (CHCl3–Et2O). IR (Nujol), ν: 3220,
1
1720, 1685, 1645 cm–1. H NMR (80 MHz, DMSO-d6), δ:
2.30 (s, 3 H), 3.57 (s, 3 H), 4.65 (s, 1 H), 5.12 (br, 1 H),
7.10–7.92 (m, 9 H), 8.42 (br, 1 H), 10.02 (br, 1 H), 10.40
(br, 1 H). Anal. calcd for C18H20N4O4: C 60.66, H 5.65,
N 15.72%; found: C 60.31, H 5.73, N 15.14%.
© 1999 NRC Canada

Barré et al.
265
Scheme 1.
H
N
H
N
O
H
N
O
2
R4
2
1
R
R
R
3
4
N
N
H
N
H
R = COR, R =H
R3
O
O
1
3
4
R
O
X
R = CH CF , R =H
2
3
3 a-q
CH CN
3
1 (X=Cl or Br)
+
R3
N
O
H
N
40-93%
H2NNR3R4
2
R
3
4
R = CH CF , R =H
2
3
N
H2N
2
3
1
R = Me, CH Ph,
2
R
H
4 a-n
4
R =H
R5R6CO
5
6
64-100%
R =R =Me
5
6
R =H, R =pMeC H
6
4
R3
N
O
H
R5
2
N
R
N
H
N
R6
1
R
O
5 (a, l, n)
Scheme 2.
H2N
Br _
+
H
O
CH CN
3
N
N
pClC H
N
+
O
H
∆, 30 min
6
4
N
OMe
N NH2
N
H
56%
N
OMe
N
N
N
H
O
2
Br
pClC H
O
6
4
1
1, R =pClC H , R =OMe,
7
6
4
6
X=Br
Scheme 3.
H
N
O
H NNHPh
2
H
N
O
2, R3 = Ph, R4= H
OMe
N
pMeC H
6
OMe
4
N
4 H
8
N
H
PhHN
CH CN, rt, 1h
3
pMeC H
O
6
O
X
63%
1
2
1, R =pMeC H , R =OMe
6
4
syn and anti
(s, 9 H), 2.32 (s, 3 H), 3.67 (s, 3 H), 4.67 (s, 1 H), 6.80 (br,
1 H), 7.07–7.40 (m, 6 H), 8.30 (br, 1 H). Anal. calcd. for
C16H24N4O5: C 54.56, H 6.82, N 15.91%; found: C 54.86, H
6.83, N 16.12%.
Table 3. Yields for compounds 9a–9d.
Compound
R1
R2
R3
Yield, %
9a
9b
9c
9d
pClC6H4
pMeC6H4
mClC6H4
pClC6H4
Ph
Ph
Me
Me
OMe
OMe
OMe
OMe
61
40
42
40
3e (R1 = pClC6H4, R2 = OtBu, R3 = CO2Me, R4 = H):
Yield 82%, mp 113°C (CHCl3–Et2O). IR (CCl4), ν: 3410,
1
3280, 1735, 1715 cm–1. H NMR (80 MHz, CDCl3), δ: 1.40
(s, 9 H), 3.65 (s, 3 H), 4.67 (s, 1 H), 6.85 (br, 1 H), 7.15–
3c (R1 = pMeC6H4, R2 = OMe, R3 = CO2Me, R4 = H):
Yield 55%, mp 99°C (CHCl3–Et2O). IR (Nujol), ν: 3340,
3305, 3270, 1760, 1740, 1710, 1650 cm–1. 1H NMR
(80 MHz, CDCl3 + CF3CO2H), δ: 2.37 (s, 3 H), 3.80 (s, 6
H), 5.30 (s, 1 H), 7.30 (s, 4 H). Anal. calcd. for C13H18N4O5:
C 49.36, H 5.70, N 17.72%; found: C 50.35, H 5.63, N
18.24%.
7.47 (m,
6 H), 8.95 (br, 1 H). Anal. calcd. for
C15H21N4O5Cl: C 48.32, H 5.64, N 15.03, Cl 9.53%; found:
C 48.42, H 5.83, N 15.12, Cl 9.64%.
Preparation of hydrazinoazapeptides 3f–3h
The α-halohydrazide 1 (6 mmol) was added to a solution
of benzoylhydrazine 2 (R3 = COPh, R4 = H) (18 mmol) and
NEt3 (18 mmol) in toluene (30 mL). The mixture was then
heated for 24 h. Cooling afforded a precipitate of α-
hydrazinohydrazide 3, which was filtered and dried.
3d (R1 = pMeC6H4, R2 = OtBu, R3 = CO2Me, R4 = H):
Yield 60%, mp 100°C (CHCl3–Et2O). IR (CCl4), ν: 3405,
1
3310, 1720, 1700 cm–1. H NMR (80 MHz, CDCl3), δ: 1.45
© 1999 NRC Canada

266
Can. J. Chem. Vol. 77, 1999
Scheme 4.
Scheme 5.
H2NNR3R4
R3
N
O
1
H
OH
N
H
R
H
N
O
3
2
H
N
2
R4
O
N
2, R =CO R
N
2
R
R
2
4
N
H
1
N
R3
N
H
R
R =H
NHCOR2
R
H2N
N
1
N
H
1
R
O
R
O
NEt3
toluene, ∆
O
X
N
hydrazinoacide azaglycine(ester)
hydrazinoacide azaglycine(ester)
1
O
9
3
4
H2NNR3R4
3
MeCN
rt
2, R =CO R
2
NEt3
4
R =H
3i (R1 = pClC6H4, R2 = Ph, R3 = CO2 Et, R4 = H): Yield
69%, mp 152°C (EtOH). IR (Nujol), ν: 3280, 3240, 3210,
toluene, ∆
NEt3
1700, 1675, 1655 cm–1. H NMR (80 MHz, DMSO-d6), ν:
1
H
O
3
3
H
H
1.22 (t, 3 H, J = 8 Hz), 4.07 (q, 2 H, J = 8 Hz), 4.72 (s, 1
H), 5.12 (br s, 1 H), 7.30–7.97 (m, 9 H), 8.35 (br s, 1 H),
10.10 (br s, 1 H), 10.40 (br s, 1 H). Anal. calcd. for
C18H19N4O4Cl: C 55.31, H 4.86, N 14.34, Cl 9.10%; found:
C 55.00, H 4.97, N 14.01, Cl 8.99%.
O
2
R3
N
2
R3
R
N
DDQ
N
N
R
N
N
H
N
H
N
MeCN
rt
1
1
R
H
O
R
O
H
3
3
3, R = CO R
8, R = CO R
2
2
3j (R1 = pMeC6H4, R2 = Ph, R3 = CO2Et, R4 = H): Yield
71%, mp 136°C (CH2Cl2). IR (Nujol), ν: 3310, 3280, 3210,
1
1660, 1655 cm–1. H NMR (80 MHz, DMSO-d6), δ: 1.20
3f (R1 = pClC6H4, R2 = Ph, R3 = COPh, R4 = H): Yield 65%,
mp 247°C. IR (CCl4), ν: 3280, 3262, 3240, 1678, 1630,
3
3
(t, 3 H, J = 8 Hz), 2.30 (s, 3 H), 4.05 (q, 2 H, J = 8 Hz),
4.65 (s, 1 H), 5.10 (br s, 1 H), 7.07–7.95 (m, 9 H), 8.37
(br s, 1 H), 10.00 (br s, 1 H), 10.35 (br s, 1 H). Anal. calcd.
for C19H22N4O4: C 61.62, H 5.95, N 15.14%; found: C
61.50, H 5.89, N 15.25%.
1
1605 cm–1. H NMR (80 MHz, DMSO-d6), δ: 4.85 (s, 1 H),
5.25–4.62 (br, 1 H), 7.25–8.00 (m, 14 H), 10.00 (s, 1 H),
10.25 (s, 1 H), 10.40 (s, 1 H). Anal. calcd. for C23H22N4O3:
C 62.48, H 4.50, N 13.25, Cl 8.40%; found: C 62.52, H
4.33, N 13.43, Cl 8.54%.
Preparation of hydrazinoazapeptides 3k–3l
To a mixture of tertiobutylhydrazino carboxylate 2 (R3 =
CO2tBu, R4 = H) (30 mmol) and NEt3 (30 mmol) in CH3CN
(10 mL) was added the α-halohydrazide 1 (10 mmol). After
24 h stirring at room temperature the solvent was removed
under reduced pressure, and the residue was diluted in
CH2Cl2 (50 mL). The organic layer was washed with an
aqueous solution of HCl (50 mL) and with water (50 mL)
and finally dried (Na2SO4). Evaporation afforded the α-
hydrazinohydrazide 3, pure enough for analysis.
3g (R1 = pMeC6H4, R2 = OMe, R3 = COPh, R4 = H):
Yield 70%, mp 154°C. IR (Nujol), ν: 3310, 3260, 3190,
1
1678, 1630, 1605 cm–1. H NMR (80 MHz, DMSO-d6), δ:
2.30 (s, 3 H), 3.55 (s, 3 H), 4.70 (s, 1 H),5.60 (br, 1 H),
7.07–7.85 (m, 9 H), 9.02 (s, 1 H), 9.95 (s, 2 H). 13C NMR
2
(75 MHz, DMSO-d6), δ: 170 (d, J = 9 Hz), 165, 156, 137
2
2
1
(q, J = 6 Hz), 134, 133 (t, J = 8 Hz), 131 (dt, J = 205 Hz,
2J = 8 Hz), 128 (dd, J = 161 Hz, J = 7 Hz), 65 (d, J =
1
2
1
1
1
142 Hz), 52 (q, J = 157 Hz), 20 (q, J = 117 Hz). HRMS,
M+• calcd. for C18H20N4O4: 356.1484; found: 356.1489.
Anal. calcd.: C 60.67, H 5.62, N 15.73%; found: C 60.29, H
5.62, N 14.95%.
3k (R1 = pMeC6H4, R2 = OMe, R3 = CO2tBu, R4 = H):
Yield 60%, mp 112°C. IR (CCl4), ν: 3410, 3300, 1745,
1
1720 cm–1. H NMR (80 MHz, CDCl3), δ: 1.42 (s, 9 H),
2.27 (s, 3 H), 3.40 (br s, 1 H), 3.67 (s, 3 H), 4.62 (s, 1 H),
6.82 (s, 1 H), 7.00–7.45 (m, 5 H), 9.07 (br s, 1 H). Anal.
calcd. for C16H24N4O5: C 54.54, H 6.82, N 15.91%; found:
C 54.35, H 6.79, N 15.97%.
3h (R1 = pClC6H4, R2 = OMe, R3 = COPh, R4 = H):
Yield 78%, mp 199°C. IR (Nujol), ν: 3310, 3240, 3180,
1
1725, 1680, 1645 cm–1. H NMR (80 MHz, DMSO-d63), δ:
3
3.55 (s, 3 H), 4.75 (d, 1 H, J = 6 Hz), 5.72 (t, 1 H, J =
3l (R1 = pClC6H4, R2 = CO2Me, R3 = CO2tBu, R4 = H):
Yield 88%, mp 128°C. IR (CCl4), ν: 3410, 3300, 1750,
6 Hz,), 7.32–7.85 (m, 9 H), 9.05 (br s, 1 H), 10.02 (br s, 2
H). Anal. calcd. for C17H17N4O4Cl: C 54.18, H 4.51, N
14.87, Cl 9.43%; found: C 54.25, H 4.62, N 15.11, Cl
9.60%.
1
1715 cm–1. H NMR (80 MHz, CDCl3), δ: 1.42 (s, 9 H),
3.60 (s, 3 H), 4.60 (s, 1 H), 4.90 (br s, 1 H), 7.40 (m, 4 H),
7.97 (br s, 1 H), 8.97 (br s, 2 H), 9.82 (br s, 1 H). Anal.
calcd. for C15H21N4O5Cl: C 48.32, H 5.64, N 15.03, Cl
9.53%; found: C 48.35, H 5.78, N 15.12, Cl 9.78%.
Preparation of hydrazinoazapeptides 3i–3j
To a mixture of ethylhydrazinocarboxylate 2 (R3 = CO2Et,
R4 = H) (30 mmol) and NEt3 (30 mmol) in CH3CN (30 mL)
was added the α-halohydrazide 1 (10 mmol). After 24 h stir-
ring at room temperature the solvent was removed under re-
duced pressure. The residue was diluted in CH2Cl2 (50 mL).
The organic layer was washed with an aqueous solution of
HCl (50 mL) and with water (50 mL) and then dried
(Na2SO4). Evaporation of the solvent afforded the α-hydra-
zinohydrazide 3.
Preparation of hydrazinoazapeptides 3m and 3n
To a solution of N,N-dimethylhydrazine 2 (R3 = R4 = Me)
(30 mmol) in CH3CN (10 mL) was added the α-halohy-
drazide 1 (5 mmol). The α-hydrazinohydrazide 3 precipi-
tated after 16 h (R1 = pClC6H4) or 60 h (R1 = pMeC6H4) of
stirring at room temperature and was then filtered and dried
(pure enough for analysis).
© 1999 NRC Canada

Barré et al.
267
3m (R1 = pMeC6H4, R2 = OMe, R3 = R4 = Me): Yield 48%,
mp 171°C. IR (Nujol), ν: 3260, 3180, 1740, 1696 cm–1.
1H NMR (80 MHz, CDCl3 + CF3CO2H), δ: 2.40 (s, 3 H),
3.27 (s, 3 H), 3.47 (s, 3 H), 3.72 (s, 3 H), 5.62 (s, 1 H),
7.40–7.60 (m, 4 H). Anal. calcd. for C13H20N4O3: C 55.71,
H 7.14, N 17.14%; found: C 55.72, H 7.32, N 17.29%.
solved in CH2Cl2 (50 mL) and washed with water (50 mL).
The organic layer was dried (Na2SO4) and concentrated by
evaporation of the solvent. Addition of ether afforded 4.
4a (R1 = pClC6H4, R2 = OMe, R3 = Me): Yield 73%, mp
178°C (EtOH). IR (Nujol), ν: 3310, 3250, 3150, 1730,
1670 cm –1. 1H NMR (80 MHz, CDCl3 + DMSO-d6), δ: 2.31
(s, 3 H), 3.25 (br, 1 H),3.60 (s, 3 H), 3.96 (s, 1 H),
4.15–5.47 (br, 1 H), 8.50–9.50 (br, 1 H), 7.41 (m, 4 H).
13C NMR (75 MHz, DMSO-d6–D2O), δ: 45 (q, 1J =
135 Hz), 52 (q, 1J = 148 Hz), 75 (d, 1J = 136 Hz), 128 (d, 1J
= 168 Hz), 130 (d, 1J = 138 Hz), 133, 134, 157, 171.
HRMS, M+• calcd. for C11H15N4O3Cl: 286.0832; found:
286.0823. Anal. calcd.: C 46.07, H 5.24, N 19.55, Cl
12.39%; found: C 46.16, H 5.30, N 19.44, Cl 12.56%.
3n (R1 = pClC6H4, R2 = OMe): Yield 44%, mp 180°C. IR
1
(Nujol), ν: 3280, 3240, 3180, 3140, 1700 cm–1. H NMR
(CDCl3 + DMSO-d6), δ: 2.97 (s, 3 H), 3.37 (s, 3 H), 3.52
(s, 3 H), 4.98 (s, 1 H), 6.61 (br s, 2 H), 7.61 (A2B2, 4 H, 3J =
4 Hz), 8.45 (br s, 1 H). Anal. calcd. for C12H17N4O3Cl: C
47.92, H 5.69, N 18.63, Cl 11.78%; found: C 47.72, H 5.70,
N 18.46, Cl 11.87%.
Preparation of α-hydrazinohydrazide 3o
4b (R1 = pMeC6H4, R2 = OMe): Yield 70%, mp 158°C
(EtOH). IR (Nujol), ν: 3318, 3180, 3150, 1732, 1670 cm–1.
1H NMR (80 MHz, CDCl3 + DMSO-d6), δ: 2.30 (s, 3 H),
2.32 (s, 3 H), 3.57 (s, 3 H), 3.95 (s, 1 H), 4.25–5.25 (br, 1
H), 9.00 (br, 1 H), 7.25 (A2B2, 4 H, J = 8 Hz). Anal. calcd.
for C12H18N4O3: C 54.13, H 6.76, N 21.05%; found: C
53.73, H 6.55, N 20.81%.
To a solution of N-aminomorpholine 2 (R3, R4 = -(CH2)2O
(CH2)2-) (25 mmol) in CH3CN (10 mL) was added the α-
halohydrazide 1 (5 mmol). After 16 h stirring at room tem-
perature the solvent was removed under reduced pressure,
the residue was partially dissolved in CH2Cl2 (10 mL), the
halohydrate of N-aminomorpholine was filtered, and the fil-
trate saturated by addition of petroleum ether. Cooling af-
forded a precipitate of α-hydrazinohydrazide 3o.
3
4c (R1 = pClC6H6, R2 = Ph): Yield 68%, mp 132°C (EtOH).
IR (Nujol), ν: 3275, 3210, 1695, 1645 cm–1. 1H NMR
(80 MHz, CDCl3 + DMSO-d6), δ: 2.32 (s, 3H), 3.30 (br,
2H), 4.07 (s, 1H), 7.32–8.10 (m, 9H), 10.50 (br, 1H). Anal.
calcd. for C16H17N4O2Cl + H2O: C 54.77, H 5.46, N 15.97,
Cl 10.10%; found: C 54.68, H 5.36, N 15.99, Cl 10.09%.
3o (R1 = 2,4-Cl2C6H3, R2 = OMe, R3, R4 = -(CH2)2O(CH2)2-):
Yield 40%, mp 149°C (CH2Cl2 – petroleum ether). IR (Nujol),
1
ν: 3362, 3270, 3227, 1728, 1700 cm–1. H NMR (80 MHz,
CDCl3 + CF3CO2H), δ: 2.72 (m, 4 H), 3.57 (m, 4 H), 3.60
(s, 3 H), 4.87 (s, 1 H), 7.28–7.77 (m, 3 H), 9.00 (br s, 1 H),
9.85 (br s, 1 H). HRMS, M+• calcd for C14H18N4O4Cl2:
376.0705; found: 376.0721. Anal. calcd.: C 44.57, H 4.80, N
14.85, Cl 18.80%; found: C 44.32, H 4.84, N 14.62, Cl
19.26%.
4d (R1 = Et, R2 = Ph): Yield 68%, mp 132°C (EtOH). IR
(Nujol), ν: 3290, 3160, 1685, 1645 cm–1. 1H NMR (80 MHz,
3
CDCl3 + DMSO-d6), δ: 0.92 (t, 3 H, J = 6 Hz), 1.65 (m, 2
3
H), 2.50 (s, 3 H), 3.00 (t, 1 H, J = 7 Hz), 5.55–7.05 (br, 3
H), 7.70 (m, 5 H). Anal. calcd. for C12H18N4O2: C 57.60, H
7.20, N 22.40%; found: C 57.34, H 7.46, N 22.32%.
Preparation of α-hydrazinohydrazide 3p
To a solution of N-aminopiperidine 2 (R3, R4 = -(CH2)5)
(25 mmol) in CH3CN (10 mL) was added the α-halohy-
drazide 1 (5 mmol). After 16 h stirring at room temperature
a first precipitate of α-hydrazinohydrazide 3p was filtered,
the solvent was then evaporated, the residue dissolved in
CH2Cl2 (50 mL) and thenwashed by water (50 mL). The or-
ganic layer was dried (Na2SO4) and concentrated by evapo-
ration of the solvent. Addition of acetone and cooling
afforded a new fraction of 3p.
4e (R1 = pClC6H4, R2 = Me): Yield 47%, mp 188°C
(EtOH). IR (Nujol): ν: 3280, 3210, 3180, 1690, 1650 cm–1.
1H NMR (80 MHz, CDCl3 + CF3CO2H), δ: 2.17 (s, 3 H),
2.87 (s, 3 H), 5.00 (s, 1 H), 7.45 (m, 4 H). Anal. calcd. for
C11H15N4O2Cl: C 48.80, H 5.54, N 20.70, Cl 13.12%; found:
C 48.70, H 5.83, N 20.54, Cl 13.41%.
4f (R1 = pClC6H4, R2 = OtBu): Yield 93%, mp 166°C
(toluene). IR (Nujol), ν: 3300, 3170, 1720, 1675 cm–1.
1H NMR (80 MHz, CDCl3 + CD3COCD3), δ: 1.42(s, 9 H),
2.22 (s, 3 H), 4.05 (s, 1 H), 7.35 (m, 4 H), 7.67 (s, 1 H).
3p (R1 = pMeC6H4, R2 = Ph, R3, R4 = -(CH2)5): Yield 74%,
mp 201°C (acetone). IR (Nujol), ν: 3321, 3255, 3200, 3155,
1695, 1670 cm–1. 1H NMR (80 MHz, CDCl3 + CF3CO2H), δ:
2.00 (m, 6H), 2.42 (s, 3H), 3.47–4.00 (m, 4H), 5.96 (s, 1H),
7.27–7.90 (m, 9H). HRMS, M+• calcd. for C21H26N4O2:
1
13C NMR (75 MHz, CD3COCD3), δ: 28 (q, J = 125 Hz),
1
1
3
44(q, J = 140 Hz), 75 (d, J = 130 Hz), 80 (q, J = 4 Hz),
1
1
129 (d, J = 159 Hz), 129.5 (d, J = 166 Hz), 132, 134, 156,
167. HRMS, M+• calcd. for C14H21N4O3Cl: 328.1302; found:
328.1301. Anal. calcd.: C 51.14, H 6.44, N 17.04, Cl
10.78%; found: C 51.24, H 6.52, N 16.70, Cl 10.97%.
366.2055;
found:
366.2065.
Anal.
calcd.
for
C21H26N4O2·HBr: C 56.37, H 6.08, N 12.52, Br 17.86%;
found: C 56.09, H 6.06, N 12.59, Br 17.41%.
4g (R1 = pMeC6H4, R2 = OtBu): Yield 70%, mp 135°C
(toluene). IR (Nujol), ν: 3370, 3300, 1720, 1705, 1685 cm–1.
1H NMR (80 MHz, CDCl3), δ: 1.40 (s, 9 H), 2.29 (s, 3 H),
2.35 (s, 3 H), 3.76 (s, 1 H), 7.17 (m, 4 H). 13C NMR
(75 MHz, CDCl3), δ: 21 (q, 1J = 126 Hz), 28 (q, 1J =
Preparation of hydrazinoazapeptides 4a–4k
To a solution of methylhydrazine 2 (R3 = Me, R4 = H)
(30 mmol) in CH3CN (10 mL) was added the α-halohy-
drazide 1 (5 mmol). When R2 = OMe, Me, Ph, or CH2Ph,
after 2 h stirring at room temperature, the α-hydrazinohy-
drazide 4 precipitated and was filtered. When R2 = OtBu or
R1 = H the solution was evaporated and the residue was dis-
1
1
3
127 Hz), 46 (q, J = 136 Hz), 76 (d, J = 136 Hz), 81 (q, J
1
1
= 4 Hz), 128 (d, J = 156 Hz), 129 (d, J = 153 Hz), 131,
© 1999 NRC Canada

268
Can. J. Chem. Vol. 77, 1999
1
138 (q, 3J = 7 Hz), 155, 171. HRMS, M+• calcd. for
C15H24N4O3: 308.1848; found: 308.1835. Anal. calcd.: C
58.42, H 7.84, N 18.17%; found: C 58.54, H 7.88, N 18.02%.
1665 cm–1. H NMR (80 MHz, CDCl3 + CF3CO2H), δ: 2.37
(s, 3H), 3.80 (s, 3H), 4.15 (s, 2H), 7.05–7.47 (m, 9H). Anal.
calcd. for C18H22N4O3: C 63.14, H 6.47, N 16.36%; found:
C 62.89, H 6.42, N 16.18%.
4h (R1 = Et, R2 = OtBu): Yield 70%, mp 121°C (toluene).
1
IR (Nujol), ν: 3310, 3160, 1720, 1715, 1680 cm–1. H NMR
Preparation of hydrazinoazapeptides 3q and 4n
3
To a solution of 2 (R3 = CF3CH2, R4 = H) (36 mmol, in
solution in water 60%) in CH3CN (10 mL) was added the
α-halohydrazide 1 (6 mmol). After 12 h stirring at room
temperature the solvent was evaporated and the residue dis-
solved in CH2Cl2 (100 mL) and washed with water (2 ×
50 mL). The organic layer was dried (Na2SO4) and then con-
centrated by evaporation of the solvent. The oil was sepa-
rated by silica gel chromatography, and eluted by 80:20
Et2O:petroleum ether to afford 4n (Rf 0.18) and 3q (Rf 0.12).
(80 MHz, CDCl3), δ: 1.00 (t, 3 H, J = 3 Hz),1.51 (s, 9 H),
3
2.65 (s, 3 H), 2.78 (m, 2 H), 3.00 (t, 1 H, J = 7 Hz), 6.9 (s,
1 H). 13C NMR (75 MHz, CDCl3), δ: 10 (q, 1J = 126 Hz), 22
(t, 1J = 128 Hz), 28 (q, 1J = 125 Hz), 45 (q, 1J = 135 Hz), 72
1
(d, J = 137 Hz), 81, 155, 172. Anal. calcd. for C10H22N4O3:
C 48.78, H 8.94, N 22.76%; found: C 48.29, H 9.00, N
22.65%.
4i (R1 = H, R2 = OtBu): Yield 76%, mp 103°C (toluene).
IR (Nujol), ν: 3340, 3310, 1730, 1705, 1680, 1650 cm–1.
1H NMR (80 MHz, CDCl3), δ: 1.45 (s, 9 H), 2.57 (s, 3 H),
4n (R1 = pMeC6H4, R2 = OMe): Yield 63%, mp 122°C. IR
1
3.25 (s, 2 H). 13C NMR (75 MHz, CDCl3), δ: 10 (q, J =
1
(Nujol), ν: 3410, 3330, 3250, 1745, 1697 cm–1. H NMR
126 Hz), 22 (t, 1J = 128 Hz), 28 (q, 1J = 125 Hz), 45 (q, 1J =
3
(80 MHz, CDCl3), δ: 2.33 (s, 3 H), 3.21 (q, 2 H, J HF = 18),
1
135 Hz), 72 (d, J = 137 Hz), 81, 155, 172. Anal. calcd. for
3.70 (br, 2 H), 3.71 (s, 3 H), 4.50 (s, 1 H), 7.15–7.29 (m, 5
C8H18N4O3: C 44.03, H 8.26, N 25.69%; found: C 43.92, H
8.03, N 25.53%.
1
H), 8.60 (br, 1 H). 13C NMR (75 MHz, CDCl3): δ: 21 (q, J
1
1
2
= 128 Hz), 53.1 (q, J = 148 Hz), 57 (tq, J = 138 Hz, J CF
1
1
= 30 Hz), 74 (d, J = 139 Hz), 125 (q, JCF = 279 Hz), 129
(d), 129.6 (d), 130, 138.9, 157.1, 171. HRMS M+• calcd. for
C13H17N4O3F3: 334.1252; found: 334.1249. Anal. calcd.: C
46.70, H 5.13, N 16.76, F 17.05%; found: C 46.78, H 5.04,
N 16.70, F 16.99%.
4j (R1 = pClC6H4, R2 = OCH2Ph): Yield 78%, mp 169°C
(EtOH). IR (Nujol), ν: 3295, 3115, 1715, 1660 cm–1.
1H NMR (80 MHz, CDCl3 + CF3CO2H), δ: 2.66 (s, 3 H),
4.98 (s, 1 H), 5.03 (s, 2 H) 7.29 (m, 9 H). 13C NMR
1
(75 MHz, CDCl3 + CF3CO2H), δ: 42 (q, J = 138 Hz), 68 (t,
1J = 151 Hz), 70 (d, 1J = 139 Hz), 127 (d, 1J = 164 Hz), 128
3q (R1 = pMeC6H4, R2 = OMe): Yield 27%, oil. IR (Nujol),
ν: 3410, 3220, 1745, 1697 cm–1. 1H NMR (80 MHz,
CDCl3), δ: 2.30 (s, 3 H), 3.30 (q, 2 H, J HF = 18 Hz), 3.69
1
1
1
(d, J = 165 Hz), 129.2 (d, J = 160 Hz), 129.6 (d, J =
1
159 Hz), 130 (d, J = 160 Hz), 134.2, 134.8, 136, 156, 169.
3
Anal. calcd. for C17H19N4O3Cl: C 56.27, H 5.28, N 15.44,
Cl 9.77%; found: C 56.05, H 5.07, N 15.45, Cl 9.72%.
(s, 3 H), 4.47 (s, 1 H), 7.10–7.47 (m, 7 H), 8.75 (br, 1 H).
13C NMR (75 MHz, CDCl3), δ: 21 (q, J = 126 Hz), 53 (q,
1
1J = 147 Hz), 52 (tq, 1J = 122 Hz, 2J CF = 26 Hz), 67 (d, 1J =
4k (R1 = pMeC6H4, R2 = OCH2Ph): Yield 60%, mp 148°C
(EtOH). IR (Nujol), ν: 3290, 3140, 1725, 1660, 1685 cm–1.
1H NMR (80 MHz, CDCl3 + CF3CO2H), δ: 2.36 (s, 3 H),
2.81 (s, 3 H), 5.04 (s, 1 H), 5.14 (s, 2 H), 7.26 (m, 9 H).
Anal. calcd. for C18H22N4O3: C 58.42, H 7.84, N 18.17%;
found: C 58.54, H 7.88, N 18.02%.
1
141 Hz), 125.2 (q, J CF = 278 Hz), 129 (d), 129.6 (d), 132,
138.6, 157, 172. HRMS, M+• calcd. for C13H17N4O3F3:
334.1252; found: 334.1249. Anal. calcd.: C 46.70, H 5.13, N
16.76; F 17.05%; found: C 46.27, H 5.45, N 16.32, F 16.44%.
Preparation of hydrazone 5a
A mixture of α-hydrazinohydrazide 4a (2 mmol) and
p-tolualdehyde (2.5 mmol) in MeCN was stirred for 15 h at
room temperature. After evaporation of the solvent, the
crude product afforded the hydrazone 5a, by trituration with
ether.
Preparation of hydrazinoazapeptides 4l–4m
To a suspension of benzylhydrazine dihydrochloride
2·2HCl (R3 = PhCH2, R4 = H) (9 mmol) in CH3CN (15 mL)
was added NEt3 (27 mmol) and water (1 mL) to afford a ho-
mogeneous solution, after which the α-halohydrazide 1
(3 mmol) was added in small portions. After 6 h stirring at
room temperature the solution was evaporated and the resi-
due dissolved in CH2Cl2 (30 mL) and then washed with wa-
ter (2 × 30 mL). The organic layer was dried (Na2SO4) and
concentrated by evaporation of the solvent. Addition of ether
afforded 4.
5a (R1 = pClC6H4, R2 = OMe, R3 = Me, R5 = pMeC6H4, R6
= H): Yield 64%, mp 100°C (CH2Cl2). IR (Nujol), ν: 3400,
3260, 1750, 1670 cm–1. 1H NMR (80 MHz, DMSO-d6
–
CDCl3), δ: 2.25 (s, 3 H), 2.75 (s, 3 H), 3.62 (s, 3 H), 5.22 (s,
1 H), 7.02–7.47 (m, 9 H), 8.84 (br, 1 H), 9.65 (s, 1 H).
1
13C NMR (75 MHz, CDCl3), δ: 21 (q, J = 126 Hz), 36 (q,
1
1J = 136 Hz), 73 (d, J = 136 Hz), 126 (d), 128 (d), 129 (d),
4l (R1 = pClC6H4, R2 = OMe): Yield 55%, mp 179°C
(EtOH). IR (Nujol), ν: 3335, 3310, 3280, 3200, 1735, 1705,
1
130, 132 (d), 133, 134, 137 (d, J = 160 Hz), 138, 156, 170.
1
HRMS, M+• calcd. for C19H21N4O3Cl: 388.1302; found:
388.1283.
1665 cm–1. H NMR (80 MHz, CDCl3 + CF3CO2H), δ: 3.69
(s, 3 H), 4.03 (br, 2 H), 5.00 (s, 1 H), 7.29–7.42 (m, 9 H).
HRMS, M+• calcd. for C17H19N4O3Cl: 362.1145; found:
362.1135. Anal. calcd.: C 56.27, H 5.24, N 15.48, Cl 9.80%;
found: C 56.29, H 5.17, N 15.42, Cl 9.51%.
Preparation of hydrazones 5l, 5n
α-Hydrazinohydrazide 4 (2 mmol) was refluxed in ace-
tone (25 mL) for 30 min. After evaporation of the solvent
the crude product, by trituration with ether, afforded the
hydrazone 5 (R5 = R6 = Me).
4m (R1 = pMeC6H4, R2 = OMe): Yield 41%, mp 158°C
(EtOH). IR (Nujol), ν: 3340, 3300, 3200, 1730, 1700,
© 1999 NRC Canada

Barré et al.
269
5l (R1 = pClC6H4, R2 = OMe, R3 = PhCH2, R5 = Me, R6 =
Me): Yield 100%, mp 108°C. IR (Nujol), ν: 3410, 3360,
8 (R1 = pMeC6H4, R2 = OMe, R3 = Ph): Rf 0.10, yield 25%.
1
IR (Nujol), ν: 3420, 3260, 1735, 1665, 1610 cm–1. H NMR
1
3230, 1770, 1670 cm–1. H NMR (CDCl3), δ: 1.35 (s, 3 H),
(80 MHz, CDCl3), δ: 2.37 (s, 3 H), 3.72 (s, 3 H), 6.87–
7.35 (m, 10 H), 8.15 (s, 1 H), 8.62 (s, 1 H). 13C NMR
(75 MHz, DMSO), δ: 20 (q, 1J = 126 Hz), 51 (q, 1J =
1.52 (s, 3 H), 3.27–3.77 (m, 2 H), 3.67 (s, 3 H), 4.22 (s, 1
1
H), 6.97–7.40 (m, 11 H). 13C NMR (CDCl3), δ: 24 (q, J =
125 Hz), 53 (q, 1J = 147 Hz), 58 (t, 1J = 135 Hz), 77 (d, 1J =
136 Hz), 127, 128.2, 128.6, 128.9, 129, 129.2, 130, 134,
136, 157, 168. HRMS, M+• calcd. for C20H23N4O3Cl:
402.1458; found: 402.1442.
146 Hz), 114 (d, J = 162 Hz), 120 (d, J = 161 Hz), 127 (d,
1J = 156 Hz), 127, 129(d), 135, 138, 144, 157, 164. HRMS,M+•
calcd. for C17H18N4O3: 326.1378; found: 326.1375.
1
1
Preparation of hydrazones 8 by oxydation of 3
5n (R1 = pMeC6H4, R2 = OMe, R3 = CF3CH2, R4 = H, R5 =
Me, R6 = Me): Yield 100%, mp 195°C. IR (Nujol), ν: 3480,
To a solution of DDQ (dichloro-2,3-dicyano-5,6-paraben-
zoquinone) (12 mmol) in CH3CN (150 mL) was added the
α-halohydrazide 1 (12 mmol). After 1 h stirring the solvent
was removed under reduced pressure and the residue dis-
solved in CH2Cl2 (60 mL), and washed by NaHCO3 (2 ×
50 mL). The organic layer was dried (Na2SO4), and concen-
trated by evaporation of the solvent to afford 8 as a mixture
of two isomers, syn and anti, in the ratio 6:4. NMR data of
only the major isomer are reported.
1
3220, 3170, 1715, 1650 cm–1. H NMR (80 MHz, CDCl3),
3
δ: 1.42 (s, 3 H), 1.57 (s, 3 H), 2.32 (s, 3 H), 3.02 (q, 2 H, J
= 10 Hz), 3.72 (s, 3 H), 4.45 (s, 1 H), 6.77 (s, 1 H), 7.25 (m,
1
5 H). 13C NMR (75 MHz, CDCl3), δ: 20 (q, J = 126 Hz),
1
1
1
24.1 (q, J = 129 Hz), 24.3 (q, J = 129 Hz), 53 (q, J =
1
1
1
147 Hz), 58 (t, J = 132 Hz), 71 (d, J = 135 Hz), 124 (q, J
= 281 Hz), 128.2 (d, 1J = 157 Hz), 128.7 (d, 1J =
CF
158 Hz), 137, 138, 156, 167. HRMS, calcd. for C13H16N2F3:
8a (R1 = pMeC6H4, R2 = Ph, R3 = OMe): Yield 60%, mp
130°C. IR (Nujol), ν: 3420, 3260, 1735, 1665, 1610 cm–1.
1H NMR (80 MHz, DMSO-d6), δ: 2.37 (s, 3 H), 3.72 (s, 3
H), 7.32–7.47 (m, 9 H), 10.22 (s, 1 H), 10.54 (s, 1 H) ;
257.1265; found, M+ – CONHNHCO2Me: 257.1263.
Preparation of triazolium salt 7
To a solution of 4-amino-4H-1,2,4-triazole 6 (28 mmol) in
CH3CN (20 mL) was added α-halohydrazide 1 (9 mmol)
under stirring, and the solution was then heated (water bath)
for 30 min. After 16 h stirring at room temperature the pre-
cipitate of salt 7 was filtered, and washed with hot CH3CN.
1
10.75 (s, 1 H). 13C NMR (75 MHz, DMSO-d6), δ: 21 (q, J
1
= 129 Hz), 52 (q, J = 146 Hz), 127.5, 127.6, 128.7, 131,
131.5, 132.5, 135, 143, 154, 163, 167, 169. Anal. calcd. for
C18H18N4O4: C 61.02, H 5.08, N 15.82%; found: C 60.86, H
4.95, N 15.96%.
8b (R1 = pClC6H4, R2 = Ph, R3 = OMe): Yield 60%, mp
100°C. IR (Nujol), ν: 3420, 3260, 1735, 1665, 1610 cm–1.
1H NMR (80 MHz, DMSO-d6), δ: 3.80 (s, 3 H), 7.18–7.79
(m, 9 H), 8.31 (s, 1 H), 9.09 (s, 1 H), 9.85 (s, 1 H).
7 (R1 = pClC6H4, R2 = OMe): Yield 56%, mp 234°C
(EtOH). IR (Nujol), ν: 3260, 3110, 3020, 1690, 1612 cm–1.
1H NMR (DMSO–CDCl3), δ: 3.57 (s, 3 H), 6.75 (s, 1 H),
3
7.10 (br, 2 H), 7.57 (A2B2, 4 H, J = 8 Hz), 9.20 (br, 2 H),
1
13C NMR (75 MHz, DMSO), δ: 54 (q, J = 146 Hz), 125.5,
10.25 (s, 1 H), 10.52 (s, 1 H). 13C NMR (DMSO-d6), δ: 52
1
1
1
127.5, 128.7, 129.8, 130, 131.5, 132.5, 137, 141.7, 153, 161,
166. Anal. calcd. for C17H15N4O4Cl: C 54.47, H 4.01,
N 14.95, Cl 9.48%; found: C 54.68, H 3.94, N 15.03, Cl
9.03%.
(q, J = 147 Hz), 65 (d, J = 146 Hz), 129 (d, J = 169 Hz),
131 (d, 1J = 160 Hz), 130, 134, 143 (d, 1J = 229 Hz), 145 (d,
1J = 228 Hz), 156, 164. Anal. calcd. for C12H14N6O3BrCl: C
35.5, H 3.45, N 20.70, Cl 18.75, Br 19.73%; found: C 35.68,
H 3.59, N 20.38, Cl 8.81, Br 19.25%.
Preparation of azaaminouracils 9
Preparation of hydrazone 8
General procedure
NEt3 (20 mmol) was added to a solution of α-halohy-
drazide 1 (7 mmol) and phenylhydrazine 2 (R3 = Ph, R4 =
H) (20 mmol) in toluene (20 mL) and refluxed for 65 h. The
solvent was then removed and the residue was dissolved in
Et2O (60 mL) and washed with water (2 × 50 mL). The or-
ganic layer was dried (Na2SO4), and concentrated by evapo-
ration of the solvent. The oil was resolved by silica gel
chromatography, eluted by 50:50 Et2O:petroleum ether to af-
ford syn and anti 8. It was not possible to determine which
was the syn or the anti isomer.
NEt3 (12 mmol) was added to a mixture of α-halohy-
drazide 1 (4 mmol) and hydrazine 2 (R3 = OMe, R4 = H)
(12 mmol) in toluene (25 mL) and refluxed for 20 h. After
cooling, the solvent was removed and the residue dissolved
in CH2Cl2 (60 mL). Addition of acidified water (4 N HCl)
afforded a precipitate of 9.
Via the hydrazone 8
NEt3 (14 mmol) was added to hydrazone 8 (7 mmol) in
toluene (80 mL) and refluxed for 24 h. After cooling, the
azaaminouracil 9 was filtered.
8 (R1 = pMeC6H4, R2 = OMe, R3 = Ph): Rf 0.38, yield 38%.
1
IR (Nujol), ν: 3420, 3270, 1740, 1710, 1640 cm–1. H NMR
9a (R1 = pClC6H4, R2 = Ph): Yield 61%, mp > 260°C (ethyl
acetate). IR (Nujol) ν: 3378, 3300, 3120, 1752, 1730,
(80 MHz, CDCl3), δ: 2.37 (s, 3 H), 3.77 (s, 3 H),
6.80–7.62 (m, 11 H), 12.30 (s, 1 H). 13C NMR (75 MHz,
1675 cm–1. H NMR (80 MHz, DMSO–CDCl3), δ: 7.40–8.00
1
1
1
DMSO), δ: 20 (q, J = 126 Hz), 51 (q, J = 146 Hz), 112 (d,
(m, 9 H), 11.28 (s, 1 H), 13.06 (s, 1 H). 13C NMR (75 MHz,
DMSO-d6), δ: 127.8, 128.3, 128.6, 129, 130.8 (t, J = 7 Hz),
131 (t, J = 8 Hz), 132, 134 (t, J = 11 Hz), 140 (d, J = 7 Hz),
148 (d, J = 7 Hz), 154.2, 165 (d, J = 7 Hz), 156, 164.
1J = 161 Hz), 120 (d, J = 159 Hz), 125 (d, J = 159 Hz),
129(d), 131, 137, 138, 144, 156, 164. HRMS, M+• calcd. for
C17H18N4O3: 326.1378; found: 326.1375.
1
1
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Can. J. Chem. Vol. 77, 1999
HRMS, M+• calcd. for C16H11N4O3Cl: 342.0519; found:
342.0509. Anal. calcd.: C 56.06, H 3.23, N 16.35, Cl
10.34%; found: C 56.11, H 3.22, N 16.47, Cl 10.23%.
2. C. Barré, P. Le Grel, A. Robert, and M. Baudy-Floc’h. J.
Chem. Soc. Chem. Commun. 607 (1994).
3. (a) M. Sletzinger, R.A. Firestone, D.F. Reinhold, and C.S.
Rooney. J. Med. Chem. 11, 261 (1968); (b) A. Amour, A. Col-
let, C. Dubar, and M. Reboud-Ravaux. Int. J. Pept. Protein
Res. 43, 297 (1994); L. Guy, J. Vidal, A. Collet, A. Amour,
and M. Reboud-Ravaux. J. Med. Chem. 41, 4833 (1998).
4. (a) J. Gante, M. Krug, G. Lauterbach, and R. Weitzel. Liebigs
Ann. Chem. 1231 (1994); (b) M. Quibell, W.G. Turnell, and T.
Johnson. J. Chem. Soc. Perkin Trans. 1, 2843 (1993).
5. M. Marraud, V. Dupont, V. Grand, S. Zerkout, A. Lecoq, G.
Boussard, J. Vidal, A. Collet, and A. Aubry. Biopolymers, 33,
1135 (1993).
6. (a) A.K. Mansour, M.M. Eid, R.A. Hassan, A. Haemers, S.R.
Pattyn, D.A. Vanden Berghe, and L. Van Hoff. J. Heterocycl.
Chem. 25, 279 (1988); (b) Y.A. Ibrahim, M.M. Eid, M.A.
Badawi, and S.A.L. Abdel-Hady. J. Heterocycl. Chem. 18, 953
(1981).
9b (R1 = pMeC6H4, R2 = Ph): Yield 40%, mp 240°C (ethyl
acetate). IR (Nujol), ν: 3185, 3120, 1720, 1670, 1650 cm–1.
1H NMR (80 MHz, DMSO-d6 – CDCl3), δ: 2.35 (s, 3 H),
7.28–7.58 (m, 4 H), 7.81–8.02 (m, 4 H), 11.47 (s, 1 H),
1
13.13 (s, 1 H). 13C NMR (75 MHz, DMSO), δ: 20.8 (q, J =
1
1
127 Hz), 127.7 (d, J = 161 Hz), 127.8 (d, J = 162 Hz),
1
1
128.6 (d, J = 162 Hz), 128.8 (d, J = 160 Hz), 129.2, 131,
1
132.6 (d, J = 162 Hz), 139.6, 141, 148.2, 154.3, 164.9.
HRMS, M+• calcd. for C17H14N4O3: 322.1066; found:
322.1052. Anal. calcd.: C 63.35, H 4.35, N 17.39%; found:
C 63.52, H 4.36, N 17.28%.
9c (R1 = mClC6H4, R2 = Me): Yield 42%, mp 209°C (ethyl
acetate). IR (Nujol): ν = 3290, 3200, 3110, 1732, 1660,
1
1675 cm–1. H NMR (80 MHz, DMSO – CDCl3), δ: 2.05 (s,
7. (a) Bayer. US Patent 3 966 715 (1976); (b) Y. Nakayama, Y.
Sanemitsu, H. Yoshioka, and A. Nishinaga. Tetrahedron Lett.
23, 2499 (1982).
8. C. Florac, P. Le Grel, M. Baudy-Floc’h, and A. Robert. J.
Chem. Soc. Perkin Trans. 1, 1143 (1991).
3 H), 7.30–7.97 (m, 4 H), 12.77 (s, 1 H), 13.05 (br,1 H).
HRMS, M+• calcd. for C11H9N4O3Cl: 280.0363; found:
280.0411. Anal. calcd.: C 47.14, H 3.21, N 20.00, Cl
12.70%; found: 280.0411. C 47.23, H 3.43, N 19.58, Cl
12.68%.
9. M.J. Garcia and R. Azerad. Tetrahedron Asymmetry, 8, 85
(1997).
9d (R1 = pClC6H4, R2 = Me): Yield 40%, mp > 209°C (ethyl
acetate). IR (Nujol), ν: 3230, 3130, 1730, 1680 cm–1.
1H NMR (80 MHz, DMSO-d6 – CDCl3), δ: 2.02 (s, 3 H),
7.67 (m, 4 H), 10.67 (s, 1 H), 12.97 (s, 1 H). HRMS, M+•
calcd. for C11H9N4O3Cl: 280.0363; found: 280.0379. Anal.
calcd.: C 47.14, H 3.21, N 20.00, Cl 12.70%; found: C
47.07, H 3.23, N 19.96, Cl 12.63%.
10. (a) H. Niedrich. Chem. Ber. 100, 3273 (1967); (b) H. Niedrich
and G. Koller. J. Prakt. Chem. 316, 729 (1974).
11. (a) K.D. Kopple, T.J. Scamper, and A. Go. J. Am. Chem. Soc.
96, 2597 (1974); (b) S.F. Brady, S.L. Varga, R.M. Friedinger,
D.A. Schwenk, M. Mendlowski, F.W. Holly, and D.F. Veber. J.
Org. Chem. 44, 3101 (1979).
12. B. El Amin, G.M. Anatharamaiah, G.P. Royer, and G.E. Means.
J. Org. Chem. 44, 3442 (1979).
13. J. Gante. Synthesis, 405 (1989)
14. P. Le Grel, M. Baudy-Floc’h, and A. Robert. Synthesis, 306
(1987).
1. P. Le Grel, M. Baudy-Floc’h, and A. Robert. Tetrahedron, 15,
4805 (1988).
© 1999 NRC Canada