Synthesis and reactions of (1E, 2Z)-2-N,N-dialkylhydrazono-2-phenylethanal N,N-dimethylhydrazones

Article abstract of DOI:10.1055/s-2003-40528

(1E,2Z)-2-N,N-Dialkylhydrazono-2-phenylethanal N,N-dimethylhydrazones 3a-e were synthesised by the reaction of 1,4,5-triazapentadienium salts 2 with N,N-dimethylhydrazine. The compounds 3a and 3d did not react with tosyl isocyanate in an electrophilic substitution reaction at the azomethine C-1 as aza-enamines, but they reacted at room temperature in benzene in a 1,4-dipolar cycloaddition to yield 1,3,5-triazinan-2,4-diones 5a and 5d, whereas at 70°C octahydroimidazoimidazol-2,5-dione 6a was formed via criss-cross addition reaction. With dimethyl sulfate in DMF, 3a was transformed into the trimethylhydrazonium salts 7a and 8a, isolated as co-crystallised perchlorates (molar ratio 1:1).

Full text of DOI:10.1055/s-2003-40528

1620
PAPER
Synthesis and Reactions of (1E,2Z)-2-N,N-Dialkylhydrazono-2-phenylethanal
N,N-Dimethylhydrazones
(
1
E
,2
Z)-2-N,
N
-
D
a
i
zono-2-
n
phenylethan
e
al
N
,
N
-Dim
r
e
thylhydrazon
B
es rehme,*a Günter Reck,b Burkhard Schulz,b Reiner Radegliab
a
Max-Planck-Institut für Kolloid- und Grenzflächenforschung, Abt. Grenzflächen, 14424 Potsdam, Germany
b
Bundesanstalt für Materialforschung und –prüfung, Richard-Willstätter-Straße 11, 12489 Berlin, Germany
Fax +49(30)81045927; E-mail: guenter.reck@bam.de
Received 19 December 2002; revised 2 April 2003
We found that compounds 3 bearing only alkyl groups at
the terminal N-atom have not been described in the litera-
ture so far. Here we report on the synthesis of bishydra-
zones 3 and their reactions with electrophilic reagents like
Abstract: (1E,2Z)-2-N,N-Dialkylhydrazono-2-phenylethanal N,N-
dimethylhydrazones 3a–e were synthesised by the reaction of 1,4,5-
triazapentadienium salts 2 with N,N-dimethylhydrazine. The com-
pounds 3a and 3d did not react with tosyl isocyanate in an electro-
philic substitution reaction at the azomethine C-1 as aza-enamines, tosyl isocyanate and dimethyl sulfate.
but they reacted at room temperature in benzene in a 1,4-dipolar cy-
cloaddition to yield 1,3,5-triazinan-2,4-diones 5a and 5d, whereas
at 70 °C octahydroimidazoimidazol-2,5-dione 6a was formed via
criss-cross addition reaction. With dimethyl sulfate in DMF, 3a was
transformed into the trimethylhydrazonium salts 7a and 8a, isolated
as co-crystallised perchlorates (molar ratio 1:1).
Key words: aza-enamines, heterocycles, hydrazonium salts, 1,4-
dipolar cycloaddition, criss-cross addition reaction
Aldehyde hydrazones can be considered as aza-ena-
mines.1a,d,f Like enamines2 they are attacked from electro-
philic reagents at their nucleophilic center, i.e. the
azomethine C-atom (*) (Scheme 1).
E
_
NR2
+ E+
NR2
Scheme 2
*
R
- H+
R
N
N
As starting material for the synthesis of compounds 3,
1,4,5-triaza-pentadienium salts 2 were used which were
prepared by reacting benzaldehyde N,N-dialkylhydra-
zones 1 with the Vilsmeier–Haack reagent (Scheme 2).
These 1,4,5-triazapentadienium salts 2 easily reacted at
room temperature with N,N-dimethylhydrazine (DMH) to
yield compounds 3. The starting materials 2a,b and d
were reacted as perchlorates (X = ClO4)1b,c in an apolar
solvent. Isolation of 2c and 2e as perchlorates failed.1c In
these cases dimethylhydrazine was added in excess to the
crude reaction mixture of 2c and 2e [X = Cl2P(O)O] and
the formed 3c and 3e were isolated as hydroperchlorates.
Thus, we not only synthesised hydrazones with the same
alkyl groups at the terminal amino groups 3a,c,d but also
those with different alkyl groups 3b and e. Characteristic
for the compounds 3 are the chemical shifts of their
R: alkyl, aryl
* : Azomethine-C-atom
NR2: dimethylamino
pyrrolidino
Scheme 1
For example, they react with the Vilsmeier–Haack reagent
to yield hydrazones of 2-oxoethanals (E = CHO),1a–c,1h
with the Mannich reagent to give hydrazones of aminom-
ethyl ketones (E = CH2NR 2),1d with tosyl isocyanate to
form tosyl amides (E = CONHTs)1b,1d–g etc.3–5 As a pre-
requisite for a successful reaction the aldehyde hydra-
zones need–in analogy to enamines– a terminal amino
group which is a good electron donor, like the dimethyl-
amino or the pyrrolidino group.2
1
azomethine protons (position 1) in the H NMR spectra
being in the range of 7.14–7.47 ppm.
In our study presented here, it was our initial question
whether 2-N,N-dialkylhydrazono-2-phenylethanal N,N-
dimethylhydrazones 3 (Scheme 2) would also behave as
aza-enamines being liable to electrophilic reaction at C-1.
The reaction of 3a with tosyl isocyanate proceeded in a
two-step mechanism (Scheme 3). First step was the elec-
trophilic attack at the azomethine N-atom in the 1a-posi-
tion of 3 forming the intermediate 1,4-dipole 4 which
subsequently reacted with a second equivalent of tosyl
isocyanate in a 1,4-dipolar cycloaddition6 to give the
Synthesis 2003, No. 10, Print: 21 07 2003.
Art Id.1437-210X,E;2003,0,10,1620,1625,ftx,en;T13002SS.pdf.
© Georg Thieme Verlag Stuttgart · New York

PAPER
(1E,2Z)-2-N,N-Dialkylhydrazono-2-phenylethanal N,N-Dimethylhydrazones
1621
1,3,5-triazinan-2,4-diones 5a. The 1H NMR signal at
=
NMe2
3
R'
NR2
λmax (nm,
n-hexanes)
-
6.25 for the proton in position 6 proved the attack of the
isocyanate at position 1a of the compound 3a. An addi-
tional argument for this structure was provided by the sig-
nal at = 76.6 in the 13C NMR spectrum assigned to C-6
of 5a. These signals are characteristic for such 1,3,5-triaz-
inan-2,4-diones 5.1e
N
1a
______________________________
R'
a
c
H
NMe2
NMe2
NMe2
353
345
383
OCH3
NO2
d
N
+
NR2
A
α
β
e
NO2
388
N
-
_
NMe2
NMe2
N
N
-
O2N
O2N
1
1
2
2
N
N
+
+
NR2
C
B
NR2
Figure 1 Dipolar resonance structures of compounds 3 and their
UV absorptions
Scheme 3
As a result, the bishydrazone 3a did not react – as expect-
ed – like an aza-enamine in a electrophilic substitution re-
action at azomethine C-1 but in an addition reaction at the
N-atom 1a.
By introducing a nitro group in position 4′ of the aromatic
core we tried to diminish the electron density at N-atom 1a
(Figure 1, structure A) by decoupling the twin aza-enam-
ine (diene) system according to Figure 1, resonance struc-
tures B and C. The influence of the nitro group can be
Figure 2 Crystal structure of the compound (1E,2Z)-3d. Selected
bond distances (Å): N(6)–N(5) = 1.334, N(5)–C(4) = 1.285, C(4)–
C(3) = 1.453, C(3)–N(2) = 1.292, N(2)–N(1) = 1.426. Selected bond
angels: C(7)–N(6)–C(8) = 122.0°, C(9)–N(1)–C(10) = 110.6°. The
compounds 3e and 3b·HClO4 show similar values for the distances
N(6)–N(5) and N(5)–C(4) and the angle C(7)–N(6)–C(8).
deduced from the
values shown in Figure 1. A red
max
shift of 30–40 nm was observed on comparing 3a and 3c
with 3d and 3e (see also Ref.7).
Corresponding with this fact, the angle C(7)–N(6)–C(8)
of the dimethylamino group 1b in the crystal of 3d
(Figure 2) amounts to 122.0° and the bond distances of
N(6)–N(5) and N(5)–C(4) amount to 1.334 and 1.285 Å
indicating a -electron delocalisation favouring the reso-
nance structure C in Figure 1.
pound 5d. Thus, the decoupling of the twin aza-enamine
was not sufficient.
The structure of 5d was proved by the signal at 6.28 ppm
in the 1H NMR spectrum for the proton in position 6 and
its 13C NMR signal at 76.5 ppm for C-6. Compound 5d is
sensitive towards hydrolysis. It gradually decomposed at
room temperature and faster at 70 °C in aqueous MeCN
forming back the red coloured 3d and tosyl amide
(Scheme 3). In refluxing benzene, however, 3a reacted
with tosyl isocyanate in a [2+3] criss-cross addition reac-
tion to yield the imidazoimidazol-2,5-dione 6a8
(Scheme 4).
Because of these results, an electrophilic substitution re-
action at the azomethine C-1 according to the aza-ena-
mine concept could be expected. Nevertheless, the nitro
compound 3d reacted with the tosyl isocyanate in the
same manner as 3a and did not behave as shown in
Figure 1, structure C; i.e. 3d was not attacked at the
azomethine C-1 under substitution of the proton but an ad-
dition reaction occurred at the N-atom 1a forming com-
Synthesis 2003, No. 10, 1620–1625 © Thieme Stuttgart · New York

1622
R. Brehme et al.
PAPER
ture 8a came from the fact that the methyl group at N-2a
caused a rotational hindrance to the neighbouring dimeth-
ylamino group indicated by splitting in two signals at 3.33
and 3.25 ppm. The decisive proof of the positions of the
introduced methyl groups resulted from the X-ray crystal-
lographic analysis, confirming the methylation of N-at-
oms 2a or 2b. The 1:1 composition of the co-crystallisate
was verified by X-ray analysis, showing 7a and 8a as two
independent molecules of the same configuration; the
substituents at the double bonds C-1/N-1a are E-config-
ured, those at the double bonds C-2/N-2a are Z-config-
ured. The same configurations were established for
compound 7d as well as 3b HClO4 and 3d (Table 1).
Alkylation of 3d exclusively resulted in quaternisation at
the terminal amino group 2b to 7d. Pure 7a could be iso-
lated from the methanolic mother liquor of the recrystalli-
sation. As a result, also with the reagent (MeO)2SO2/DMF
a formylation reaction at the C-1 did not happen.
Scheme 4
1
The H NMR spectrum shows signals at 77.2 and 82.5
ppm for C-6a and -3a and a singlet at 5.27 ppm for the pro-
ton at C-6a. Furthermore, the structure of 6a was deter-
mined by an X-ray crystallographic analysis. In contrast
to the reaction at room temperature, discussed above, at
70 °C 3a was attacked by tosyl isocyanate on both sides of
the molecule at the azomethine N-atoms in 1a and in 2a
position. A formation of the corresponding compound 6d
from 3d under the same reaction conditions could not be
detected.
The preference for the electrophilic attack at N-2a and N-
2b in comparison to N-1a and N-1b in compound 8a and
at N-2b in 7a,d (Scheme 5) may be caused by the thermo-
dynamic control of the alkylation reaction. The alkylation
at position 2b could be attributed to the lone pair of the
amino group 2b in 3d [Figure 2, angle C(9)–N(1)–C(10):
110.6°] in contrast to the sp2-hybridisation of the amino
group 1b [Figure 2, angle C(7)–N(6)–C(8): 122.0°]. Also
in the compound 3b·HClO4 the nitrogen atom of the pyr-
rolidino group in position 2b is protonated.
Finally, we treated the bishydrazones 3a and 3d with dim-
ethyl sulfate in DMF at room temperature, aiming to
formylate these compounds at the azomethine C-1 by us-
ing this soft formylation reagent.9 Instead of being formy-
lated, compound 3a was methylated at room temperature
at two positions, either at N-2a or at N-2b resulting after
addition of NaClO4 in a mixture of compounds 7a10 and
8a (Scheme 5).
The question why tosyl isocyanate attacked the azome-
thine nitrogen in 1a position can not be answered distinct-
ly. Presumably, steric reasons favour the attack of tosyl
isocyanate at the N-1a being in the -position with respect
to the aromatic core.
1b
NMe2
1a
N
E
The attack of the isocyanate at the N-atoms 1a and 2a and
of the dimethyl sulfate/DMF at the atoms 2a and 2b led to
the stable final products 5, 6a as well as 7 and 8, respec-
tively (Schemes 3– 5). The attack of electrophilic agents
such as trifluoroacetophenone , trifluoroacetic anhydride,
the Vilsmeier or the Mannich reagent etc. to the N-atoms
of the compounds 3 can not lead to stable products. The
question is not answered up to now, whether the attack in
this cases alternatively would take place at the azomethine
C-1 forming stable final products in an electrophilic sub-
stitution reaction corresponding the aza-enamine concept.
R
1
2
-
ClO4
Z
7d:R'=NO2
53%
NMe2
N
2a
+
N
NMe3
2b
E
7a,d
1
R
(CH3O)2SO2/
DMF
r.t.
2
1b
Z
7a + 8a:R'=H
NMe2
69%
N
1a
N
NMe2
E
3a,d
R
1
2
-
ClO4
Z
R'
The NMR spectra (instrument DMX 400 (Bruker)) were recorded
at 300, 400, 500 MHz and 75, 100, 125, respectively. For calibration
the solvent signals: CDCl3 7.23 ppm (1H) and 77.0 ppm (13C),
CD3CN 1.93 ppm (1H) and 1.3 ppm (13C) were used. Microcombus-
tion analyses were performed by Elemental Analyzer 1110 CHNS,
CE Instruments. Mass spectra were recorded in ‘Liquid secondary
Ion Mass Spectrometry-mode’, spectrometer AUTOSPEC, firm
Micromass. The yields were not optimised.
+
R =
N
2a
Me
NMe2
2b
8a
Scheme 5
Recrystallisation from MeOH led to a co-crystallised
product which contained 7a and 8a in a molar ratio 1:1.
This fact was confirmed by the 1H NMR spectrum which
indicated all signals of compounds 7a and 8a well separat-
ed and in a molar ratio of 1:1. A further evidence for struc-
(1E,2Z)-2-N,N-Dimethylhydrazono-2-phenylethanal N,N-Dim-
ethylhydrazone (3a)
Benzaldehyde N,N-dimethylhydrazone (1a;1c,11 7.0 g, 47 mmol)
[prepared from benzaldehyde (10.6 g, 100 mmol), N,N-dimethylhy-
drazine (DMH, 6.6 g, 110 mmol) and AcOH (3 drops) in refluxing
Synthesis 2003, No. 10, 1620–1625 © Thieme Stuttgart · New York

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(1E,2Z)-2-N,N-Dialkylhydrazono-2-phenylethanal N,N-Dimethylhydrazones
1623
Table 1 1H NMR Spectra of Compounds 3, 5–8 and References to X-Ray Analyses Data
Product
1H NMR (MeCN)
, J (Hz)
3a
300 MHz: 7.54 (2 H, C-2 a), 7.46 (s, 1 H,C-1), 7.32 (2 H,C-3 ), 7.35 (1 H,C-4 ), 2.97 [s, 6 H, N(CH3)2, brb] 2.55 [s, 6 H,
N(CH3)2, sharp)
c
3b·HClO4
3c
7.32 (m, 5 H,C-2 ,3 ,4 ), 7.14 (s, 1 H, C-1), 2.85 [m,d 4 H ( )], 2.77 [s, 6 H, N(CH3)2, br], 1.64 [m,d 4 H ( )]
400 MHz: 7.53 (2 H, C-2 e), 7.47 (s, 1 H, C-1), 6.87 (2 H, C-3 ), 3.79 (s, 3 H, OCH3), 2.97 [s, 6 H, N(CH3)2, brb), 2.55
[s, 6 H, N(CH3)2, sharp]
3dc
3ec
5a
300 MHz (CDCl3): 8.20 (2 H, C-3 e), 7.80 (2 H, C-2 ), 7.43 (s, 1 H, C-1), 3.08 [s, 6 H, N(CH3)2, brb], 2.71 [s, 6 H, N(CH3)2,
sharp]
400 MHz: 8.13 (2 H, C-3 e), 7.83 (2 H, C-2 ), 7.18 (s, 1 H, C-1), 3.28 [m,d 4 H ( )], 2.96 [s, 6 H, N(CH3)2, brb), 1.85
[m d,4 H ( )]
400 MHz: 6.25 (s, 1 H, C-6), 7.50–7.34 (m, 9 H, C-2 ,3 ,4 ,C-3 ), 8.06 (2 H,C-2 e), 7.83 (2 H, C-2 ), 2.46 (CH3, C-4 ),
2.45 (CH3, C-4 ), 2.33 [very br, 6 H, N(CH3)2], 2.23 [s, 6 H, N(CH3)2 at N-1]
5d
6a
400 MHz (CDCl3): 6.28 (s, 1 H, C-6), 8.18 (2 H, C-3 e), 7.52 (2 H, C-2 ), 8.13 (2 H, C-2 ), 7.80 (2 H, C-2 ), 7.25
(2 H, C-3 ), 7.34 (2 H, C-3 ), 2.37 [s, 6 H, N(CH3)2 at N-1], 2.48 [6 H, N(CH3)2, br], 2.42 (CH3, C-4 ), 2.40 (CH3, C-4 )
500 MHz: 5.27 (s, 1 H, C-6a), 7.45 (2 H, C-2 a), 7.52 (2 H, C-3 ), 7.52 (1 H, C-4 ), 7.86 (2 H, C-2 e), 7.78 (2 H, C-2 ),
7.41 (2 H, C-3 ), 7.35 (2 H, C-3 ), 2.93 (s, 3 H, NCH3 at N-3), 2.50 (s, 3 H, NCH3 at N-3), 2.52 [6 H, very br, (CH3)2 at
N-6], 2.44 (CH3, C-4 ), 2.43 (CH3, C-4 )
7dc
400 MHz: 6.92 (s, 1 H, C-1), 8.23 (2 H, C-3 e), 7.66 (2 H, C-2 ), 3.56 [s, N(CH3)3, 9 H), 3.22 [s, 6 H, N(CH3)2, brb]
7ac,f
400 MHz: 6.91 (s, 1 H, C-1), 7.48 (2 H, C-2 a), 7.40 (2 H, C-3 ), 7.47 (1 H, C-4 ), 3.35 [s, N(CH3)3, 9 H], 3.21 [6 H,
N(CH3)2, brb, N-1b]
8ac,f
400 MHz: 7.79 (s, 1 H, C-1), 7.33 (2 H, C-2 a), 7.44 (2 H, C-3 ), 7.58 (1 H, C-4 ), 3.33g (s, 3 H, CH3 at N-2b), 3.25g
(s, 3 H, CH3 at N-2b), 3.07 (s, 3 H, CH3 at N-2a), 2.73 [s, 6 H, N(CH3)2 at N-1b]
a The assignment of the phenyl groups in the 1H NMR spectra of 3a, 6a and of the crystals consisting of 7a and 8a resulted from computer
simulation.
b The hindrance of the rotation of the dimethylamino groups of compounds 3a,b HClO4,c,d,e,7a and 7d in the segment Me2NN=CH(C-1)
causes strong broadening of the signals in the 1H NMR-spectra.
c Structure was confirmed by a X-ray crystallographic analysis; complete data were deposited at the Cambridge Crystallographic Data Center
under the following registered CCDC-numbers. 3b HClO4 CCDC 171743; 3d: CCDC 171743; 3e: CCDC 210614; 6a: CCDC 171740; 7a:
CCDC 171741 and 171742; 7d: CCDC 171744; 8a: CCDC 171741. Copies can be obtained from CCDC, 12 Union Road, Cambridge CB2
1EZ, UK [e-mail: deposit@ccdc.cam.ac.uk].
d The signals of the pyrrolidino groups of 3b and 3e have the design of AA A A BB B B -spectra.
e The signals of the 1H NMR spectra of the 4 -substituted phenyl groups (4 -nitrophenyl-, 4 -methoxyphenyl- and the tosyl groups, respec-
tively) have the known feature of an AA BB -spin system.
f Compounds 7a and 8a were formed as co-crystallisate, the 1H NMR spectrum showed all signals of both compounds well separated, well
assignable and in a molar ratio 1:1.
g The existence of both signals at = 3.33 and 3.25 assigned to the methyl groups in position 2b of 8a indicated the inhibition of their rotation.
anhyd EtOH (10 mL) for 2.5 h, yield: 14.33 g (97%)] was dissolved
in anhyd DMF (5 mL) and Vilsmeier–Haack reagent (Vilsm. rg.)
(28.2 g, 94 mmol) was added slowly under ice cooling [1 mol
Vilsm. rg. = 300 g from POCl3 (150 g, 1 mol) + DMF (150 g, 2
mol)]. After 2 h, the mixture was poured onto ice (50 g) and a solu-
tion of NaClO4 (20 g, 143 mmol) in H2O (15 mL) was added. The
precipitate 2a (X = ClO4, mp 118–127 °C)1b,c was separated and
washed with EtOH (10 mL). To a stirred suspension of 2a in EtOH
(40 mL) was added N,N-dimethylhydrazine (DMH) (3.18 g, 53
mmol) at r.t. After 1 h, EtOH was evaporated, the residue was dis-
solved in Et2O and the solution was washed with H2O until neutral;
yield: 7.59 g (74%); yellow oil; crude product pure enough for fur-
ther reactions. Additional purification was carried out as follows: A
sample of crude 3a was dissolved in a small amount of DMF and dil.
aq HClO4 was added. The precipitate [mp 137–140 °C (MeOH)
beige coloured crystals] was suspended in Et2O and transformed
into the free base by shaking with dil. aq NaOH solution; pure 3a:
mp 33–36 °C; yellow crystals.
13C NMR (75.9 MHz, MeCN): = 162.0 (C-2), 139.0 (C-1 ), 130.3
(C-2 ), 129.3 (C-4 ), 128.2 (C-3 ), 125.1 (C-1), 48.0 (CH3), 42.4
(CH3).
MS: m/z = 219 (M + 1).
Anal. Calcd for C12H18N4 (218.30): C, 66.02; H, 8.31; N, 25.67:
Found: C, 66.25; H, 8.36; N, 25.48.
(1E,2Z)-2-N,N-Tetramethylenehydrazono-2-phenylethanal
N,N-Dimethylhydrazone Perchlorate 3b HClO4
Compound 2b [X = ClO4, mp 143–148 °C;1c 2.2 g, 6.67 mmol, syn-
thesised in analogy to 2a (X = ClO4)] was suspended in benzene
and DMH (0.627 g, 10.5 mmol) was added at r.t. After 1 h, the so-
lution was washed with H2O until neutral and dried (CaCl2). The
crude 3b was purified by filtration of its benzene solution through a
layer of silica gel (2 cm high, 1 cm); yield: 1.4 g (86%); mp 76–
78.5 °C; yellow solid. A sample in Et2O was treated with HClO4
Synthesis 2003, No. 10, 1620–1625 © Thieme Stuttgart · New York

1624
R. Brehme et al.
PAPER
giving 3b·HClO4; mp 108.5–112 °C (MeOH); yellow crystals, de-
composed slowly at r.t.
13C NMR (400 MHz, CDCl3): = 76.6 (C-6), 147.1, 145.9 (C-2,4),
134.0 (C- ), 125.5 (C-1 ), 128.8 (C-2 ), 128.8 (C-3 ), 129.1 (C-4 ),
135.5, 134.1 (C-1 ), 129.7, 129.5 (C-2 ), 129.4, 129.3 (C-3 ),
145.4, 145.4 (C-4 ), 46.3 (NCH3 at N-1), 43.4 (NCH3), 21.7, 21.6
(CH3 at C-4 ).
(1E,2Z)-2-N,N-Dimethylhydrazono 2-(4-methoxyphenyl)etha-
nal N,N-Dimethylhydrazone (3c)
Vilsm. rg. (3 g, 10 mmol) was added to an ice-cooled solution of
1c1c [(0.89 g, 5 mmol), prepared from 4-methoxybenzaldehyde (4 g,
30 mmol), DMH (2.16 g, 36 mmol), AcOH (2 drops) in anhyd re-
fluxing EtOH for 2 h; yield: 4.88 g (91%)] in DMF (1 mL). After 20
h, DMH was added dropwise to this cooled reaction mixture until
pH 9 was reached, the solution was mixed with Et2O, washed with
H2O till neutral and dried (CaCl2). The crude 3c was an yellow sirup
and was purified by treatment with HClO4 in Et2O to form a bishy-
drazonium perchlorate that was recrystallised by dissolving in a
small amount of MeOH followed by addition of hot EtOAc up to the
beginning of the crystallisation; mp 173–175 °C; yellow crystals
(1.49 g). The free base 3c was obtained by shaking the hydroper-
chlorate in Et2O with aq 25% NaOH solution and the organic layer
was afterwards washed with H2O until neutral; yield: 0.855 g
(69%); oil.
MS: m/z = 613 (M + 1).
Anal. Calcd for C28H32N6O6S2 (612.70): C, 54.88; H, 5.26; N,
13.72. Found: C, 54.87; H, 5.22; N, 13.70.
1-Dimethylamino-6-[ -(N,N-dimethylhydrazono)-4-nitroben-
zyl]-3,5-ditosyl-1,3,5-triazinan-2,4-dione (5d)
Tosyl isocyanate (0.13 g, 0.66 mmol) was added to 3d (0.079 g, 0.3
mmol) in benzene (1 mL) and the mixture was kept for 5 d at r.t.
Thereafter the solvent was evaporated and MeOH was added to the
residue, the crystals obtained were washed with MeOH and filtered;
yield (crude): 0.135 g (67%); mp 130–136 °C (EtOAc); yellow nee-
dles.
13C NMR (400 MHz, CDCl3): 76.5 (C-6), 146.9, 147.7 (C-2,4),
141.3 (C- ), 131.2 (C-1 ),130.1 (C-2 ), 123.7 (C-3 ), 145.8 (C-4 ),
135.3, 134.1 (C-1 ), 129.6, 129.4 (C-2 ), 129.3, 129.3 (C-3 ),
145.7, 145.6 (C-4 ), 46.7 (NCH3 at N-1), 43.6 (NCH3), 21.8, 21.6
(CH3 at C-4 ). The NMR spectra had to be recorded at once after
dissolving 5d in CDCl3 because of its decomposition.
Anal. Calcd for C13H20N4O (248.32): C, 62.87; H, 8.12; N, 22.56:
Found: C, 62.79; H, 7.95; N, 21.43.
(1E,2Z)-2-N,N-Dimethylhydrazono-2-(4-nitrophenyl)ethanal
N,N-Dimethylhydrazone (3d)
Anlal. Calcd for C28H31N7O8S2 (657.70): C, 51.13; H, 4.75; N,
14.91. Found: C, 51.49; H, 4.62; N, 14.56.
DMH (0.3 g, 5 mmol) was slowly added to a suspension of 2d
[X = ClO4, mp 130–132 °C;1b,c 1.462 g, 4.19 mmol, synthesised in
analogy to 2a (X = ClO4)] in benzene (7 mL). After 1 h, the black
coloured solution was washed with H2O, the organic solution was
dried (CaCl2) and the solvent was evaporated. Compound 3d was a
dark-red to black coloured sirup and did not crystallise. It was treat-
ed in DMF (3 mL) with HClO4 (15 mmol in 5 mL H2O). The yellow
bishydrazonium perchlorate [mp 167–170 °C (MeOH)] was
washed with H2O, stirred with aq 25% NaOH solution and Et2O.
The organic layer was washed with H2O, dried and the solvent was
removed; yield (crude): 1.016 g (92%); mp 74.0–75.5 °C (hexanes);
red coloured prisms.
Hydrolysis of 5d to 3d
A solution of 5d (6.57 g, 10 mmol) in MeCN (20 mL) and H2O (1
mL) was warmed to 70 °C. The compound dissolved under gas for-
mation. The red coloured solution was stirred further for 20 min and
the solvent was evaporated. Compound 3d was separated from tosyl
amide (mp 135–137 °C) by repeated extraction with cyclohexane
(total amount 120 mL). The crude 3d, after removal of the solvent,
was dissolved in a few drops of warm EtOAc. Addition of warm
heptanes (40 mL) to this solution allowed 3d to crystallise slowly;
yield: 2 g (76%); mp 73–74 °C.
Anal. Calcd for C12H17N5O2 (263.30): C, 54.74; H, 6.51; N, 26.60:
Found: C, 54.79; H, 6.43; N, 26.43.
3,6-Bis(dimethylamino)-3a-phenyl-1,4-ditosyloctahydroimida-
zo[4,5d]imidazol-2,5-dione (6a)
A solution of 3a (0.218 g, 1 mmol) and tosyl isocyanate (0.434 g,
2.2 mmol) in benzene (1.5 mL) was kept at 70 °C for 2 h and the res-
idue obtained after removal of benzene was allowed to crystallise
from MeOH; yield (crude): 0.214 g (35%); mp 252–253.5 °C
(MeOH). The compounds 5a and 6a could be observed well sepa-
rated by TLC in EtOAc–hexanes (1:2) (Merck, Kieselgel 60 plates).
13C NMR (75.9 MHz): = 82.5 (C-3a), 77.2 (C-6a), 151.3, 150.8
(C-2,5), 136.7 (C-1 ), 127.0 (C-2 ), 129.1 (C-3 ), 130.5 (C-4 ),
137.9, 137.3 (C-1 ), 130.3, 130.5 (C-2 ), 130.1, 129.9 (C-3 ),
146.6, 146.5 (C-4 ), 45.1, 44.7 (NCH3 at N-3, N-6), 41.5 (very
broad), 21.60, 21.62 (CH3 at C-4 ).
(1E,2Z)-2-N,N-Tetramethylenhydrazone-2-(4-nitrophenyl)-
ethanal N,N-Dimethylhydrazone (3e)
Vilsm. rg. (0.45 g, 1.5 mmol) was added to an ice-cooled solution
of 1e1d (0.274 g, 1.25 mmol) in DMF (1 mL). After 1 h, DMH was
added to this cooled reaction mixture until pH 9 was reached. The
mixture was then stirred for 1 h, Et2O was added and the Et2O layer
was washed with H2O until neutral. Removal of Et2O gave crude 3e
as a black resinous mass, which did not crystallise. It was treated in
DMF with dil. aq HClO4 to give a bishydrazonium perchlorate as a
sirup, that crystallised overnight to a brown product. The free base
3e was obtained by shaking the hydroperchlorate in Et2O with aq
25% NaOH solution and isolated in the usual manner; yield (crude):
0.114 g (32%); mp 100.0–101.5 °C (heptanes); red coloured prisms.
MS: m/z = 613 (M + 1).
Anal. Calcd for C28H32N6O6S2 (612.70): C 54.88; H, 5.26; N, 13.72:
Found: C, 55.27; H, 5.00; N, 13.53.
Anal. Calcd for C14H19N5O2 (289.33): C, 58.11; H, 6.62; N, 24.21.
Found: C, 58.31; H, 6.56; N, 23.82.
(1E,2Z)-2-N,N,N-Trimethylhydrazonium-2-(4-nitrophenyl)-
ethanal N,N-Dimethylhydrazone Perchlorate (7d)
1-Dimethylamino-6-( -N,N-dimethylhydrazonobenzyl)-3,5-di-
tosyl-1,3,5-triazinan-2,4-dione (5a)
Dimethyl sulfate (0.39 g, 3.1 mmol) in DMF (1 mL) was added to
3d (0.263 g, 1 mmol) dissolved in DMF (0.5 mL). After 15 h, the
solution was poured into H2O (3 mL). The amorphous precipitate
was extracted with Et2O and aq 50% NaClO4 (1 mL) was added;
yield: 0.20 g (53%); mp 192–195 °C (dec.) (MeOH); small yellow-
brown staffs.
Tosyl isocyanate (0.434 g, 2.2 mmol) was added to a solution of 3a
(0.218 g, 1 mmol) in benzene (2 mL) cooled to 5 °C. The mixture
was kept at r.t. for 2 h and thereafter the solvent was removed in a
rotary evaporator. To the residue MeOH was added to crystallise
5a, which was analytically pure; yield: 0.459 g (75%); mp 132–
134 °C. The melted product became solid again above 134 °C and
was transformed into 6a. A sample of 5a recrystallised from AcOH
also gave 6a; mp 251–253 °C.
Anal. Calcd for C13H20ClN5O6 (377.79): C, 41.33; H, 5.34; N,
18.54. Found: C, 41.14; H, 5.25; N, 18.27.
Synthesis 2003, No. 10, 1620–1625 © Thieme Stuttgart · New York

PAPER
(1E,2Z)-2-N,N-Dialkylhydrazono-2-phenylethanal N,N-Dimethylhydrazones
1625
Mixture of (1E,2Z)-2-N,N,N-Trimethylhydrazonium-2-phen-
ylethanal N,N-Dimethylhydrazone Perchlorate (7a) and
(1E,2Z)-2-N,N,N -Trimethylhydrazonium-2-phenylethanal
N,N-Dimethylhydrazone Perchlorate (8a)
Acknowledgement
R.B. thanks Prof. Dr. Günter Scherowsky for helpful references.
Dimethyl sulfate (1.26 g, 10 mmol) in DMF (3 mL) was added to 3a
(0.8 g, 3.66 mmol) dissolved in DMF (1.5 mL). After 2 h at r.t., the
solution was added to H2O (10 mL). The amorphous precipitate was
extracted with Et2O and the solution was added to NaClO4 (1.11 g,
7.9 mmol in 2 mL H2O). A thick sirup was formed that became solid
overnight. It was washed twice with EtOAc by stirring and filtered;
yield (crude mixture): 0.843 g (69%); mp 150–153 °C (MeOH);
yellowish coloured prisms.
References
(1) (a) Brehme, R.; Nikolajewski, H. E. Z. Chem. 1968, 8, 226.
(b) Brehme, R.; Nikolajewski, H. E. Tetrahedron Lett. 1982,
23, 1131. (c) Brehme, R. Chem. Ber. 1990, 123, 2039.
(d) Brehme, R.; Nikolajewski, H. E. Tetrahedron 1976, 32,
731. (e) Brehme, R.; Stroede, B. J. Prakt. Chem. 1987, 329,
246. (f) Brehme, R.; Nikolajewski, H. E. Tetrahedron 1969,
25, 1159. (g) Brehme, R.; Klemann, A. Tetrahedron 1987,
43, 4113. (h) Brehme, R.; Gründemann, E.; Schneider, M.;
Radeglia R.; Reck, G.; Schulz, B. Synthesis 2003, in print.
(2) (a) Stork, G.; Brizzolara, A.; Landesman, H.; Szmuszkovicz,
J.; Terell, R. J. Am. Chem. Soc. 1963, 85, 207. (b) Otto, P.;
Feiler, L. A.; Huisgen, R. Angew. Chem. 1968, 80, 759.
(3) Kamitori, Y.; Hojo, M.; Masuda, R.; Fujitani, T.; Ohara, S.;
Yokoyama, T. J. J. Org. Chem. 1988, 53, 129.
(4) Fernandez, R.; Lasaletta, J. M. Synlett 2000, 1228.
(5) Enders, D.; Vazquez, J.; Raabe, G. Eur. J. Org. Chem. 2000,
893.
(6) Huisgen, R. Z. Chem. 1968, 8, 290.
(7) Brehme, R.; Radeglia, R.; Gründemann, E. J. Prakt. Chem.
1990, 332, 911.
Anal. Calcd for C13H21ClN4O4 (332.79): C, 46.92; H, 6.36; N,
16.84. Found: C, 46.82; H, 6.28; N, 16.68.
7a
Additionally a small amount of pure 7a crystallised out. After sep-
aration of the co-crystallisate 7a and 8a, from the mother liquor of
the recrystallisation, 7a forms at first fine needles which changed
after dilution of this solution with a small amount of H2O to star like
spears; mp 133–136 °C (MeOH).
X-Ray Crystal Analysis of 3d
Crystal Data: C12H17N5O2, triclinic, space group P-1, a =
9.5312(12) Å, b = 9.7709(12) Å, c = 9.9516(13) Å,
=
105.444(3)o, = 103.348(2)o, = 117.754(3)o, V = 718.9(2) Å3,
Z = 2, Dc = 1.216 Mgm–3, F(000) = 280, = 0.087 mm–1, T = 293°
K. Data Collection: A crystal of 0.905 × 0.55 × 0.35 mm was used
(8) Takahashi, M.; Miyadai, S. Heterocycles 1990, 31, 883.
(9) Meindl, H.; Ackermann, H. Helv. Chim. Acta 1972, 106,
1039.
(10) Remers, W.; Gibs, G. J.; Weiss, M. J. J. Med. Chem. 1967,
10, 274.
to register 2495 independent intensities (Mo-K radiation, 2
max
50°) on a Bruker AXS SMART diffractometer. Structure Refine-
ment: The structure was refined anisotropically to R1 = 0.054. Hy-
drogen atoms were included using a riding model. X-ray data of the
structures 7a, 8a, 3b, 3d, 3e, 6a, and 7d were deposited at the Cam-
bridge Crystallographic Data Center (CCDC) (see Table 1).
(11) Newkome, G. R.; Fishel, D. L. J. Org. Chem. 1966, 31, 677.
Synthesis 2003, No. 10, 1620–1625 © Thieme Stuttgart · New York