New Trimethylaluminum-Induced Mannich-Type Reaction of Hydrazones

Article abstract of DOI:10.1021/jo0352272

Trimethylaluminum addition to N-monoalkyl or N-monoaryl hydrazones followed by aldehyde addition leads to the formation of N-alkylated hydrazones in a new formal Mannich-type process. Addition compounds were also obtained in moderate yields with ketones.

Full text of DOI:10.1021/jo0352272

TABLE 1. Tr im eth yla lu m in u m -In d u ced Rea ction of
Hyd r a zon es 1 w ith Ca r bon yl Der iva tives 2a
New Tr im eth yla lu m in u m -In d u ced
Ma n n ich -Typ e Rea ction of Hyd r a zon es
Laurent El Kaim,* Laurence Grimaud,
Yannick Perroux, and Cornelia Tirla
Laboratoire Chimie et proce´de´s, Ecole Nationale Supe´rieure
de Techniques Avance´es, 32 Bd Victor,
time, h
(temp, °C)
75739 Paris Cedex 15, France
entry
1
2
product
yield, %
1
2
3
4
5
6
7
8
9
1a
1a
1a
1b
1b
1b
1b
1b
1c
1d
2a
2b
2c
2a
2b
2d
2e
2f
3a
3b
3c
3d
3e
3f
3g
3h
3i
24 (rt)
4 (83)
4 (83)
13 (rt)
3 (83)
7 (rt)
6 (rt)
6 (rt)
48 (rt)
72 (rt)
91
92
94
82
73
58
39
32
43
59
elkaim@ensta.fr
Received August 21, 2003
Abstr a ct: Trimethylaluminum addition to N-monoalkyl or
N-monoaryl hydrazones followed by aldehyde addition leads
to the formation of N-alkylated hydrazones in a new formal
Mannich-type process. Addition compounds were also ob-
tained in moderate yields with ketones. The mechanism as
well as possible intermediates involved in the reaction are
discussed.
2b
2a
10
3j
a
Structures 1a -d and 2a -f.
Following our studies on the C-alkylation of hydra-
zones through Mannich coupling with aldehydes and
N-benzylpiperazine,1 we were interested in testing vari-
ous conditions to promote the direct coupling of hydra-
zones with aldehydes. In this sense, trialkylaluminum
species were selected for their high oxygen affinity and
their ability to form N-aluminated compounds with
relatively acidic NH compounds.2
When trimethylaluminum (2 equiv) was added to a
solution of hydrazone 1a in 1,2-dichloroethane at -20 °C,
fast gas evolution was observed; propionaldehyde 2a was
then added to this solution and the mixture left at room
temperature for 24 h to give instead of the C-alkylated
expected hydrazone, the new N-alkylated hydrazone 3a
in 91% isolated yield (Scheme 1).
reactivity of alkyl-substituted ones. Most examples have
been performed on aromatic aldehydes derived from
hydrazones as hydrazones amenable to easy enamine
formation (1c) gave the expected coupling compounds
with much lower yields. The same is true for hydrazones
derived from ketones; cyclohexanone N-phenylhydrazone
failed to react with aldehyde 2a whereas benzophenone
hydrazone 1d gave an addition product in moderate yield.
The high efficiency of this new reaction was demon-
strated by the surprisingly successful coupling of hydra-
zone 1b with ketones 2e and 2f leading to highly
sterically hindered hydrazones.
SCHEME 1
Though the N-alkylation of hydrazones with electro-
philes (allyl chloride under basic conditions) is well-
known, this coupling of hydrazones with aldehydes was
rather surprising. The hydrazones 3 obtained can be
viewed as formal addition compounds of trimethylalu-
minum onto iminium derived from hydrazones; to our
knowledge, Mannich-type additions of trimethylalumi-
num to aldehydes in the presence of amines is not
described in the literature and indeed the addition of
benzaldehyde to a solution of trimethylaluminum and
morpholine or N-benzylpiperazine failed to give any
aminoalkylated compound. Trimethylaluminum-induced
nucleophilic methyl addition onto iminium has however
already been reported in the ring opening of cyclic N,O
acetals, the methyl group being there probably delivered
intramolecularly from the intermediate alkoxytrimeth-
ylaluminum.3 In our reaction, the interaction of both
nucleophilic nitrogen atoms with Lewis acid aluminum
species probably plays a significant role in the product
Several hydrazones and aldehydes behaved similarly
as shown in Table 1. The reaction is usually much faster
with aliphatic aldehydes than with aromatic ones. For
the latter aldehydes, the coupling is best obtained by
refluxing the mixture for a few hours. The R-â unsatur-
ated aldehyde 2c gave exclusively a 1,2 addition product
in excellent yield. N-Alkyl and N-aryl hydrazones equally
gave addition products in good yield with a higher
(1) Atlan, V.; Bienayme´, H.; El Ka¨ım, L.; Majee, A. Chem Commun.
2000, 1585-1586.
(2) Brillaud, P.; Maire, Y.; Maire, J . C.; Ramiaramanana, J . New J .
Chem. 1995, 19, 1009-1013.
10.1021/jo0352272 CCC: $25.00 © 2003 American Chemical Society
Published on Web 10/08/2003
J . Org. Chem. 2003, 68, 8733-8735
8733

SCHEME 2. P ossible In ter m ed ia tes In volved in
th e Rea ction
Exp er im en ta l Section
Proton and carbon nuclear magnetic resonance (1H, 13C NMR)
were recorded on a 400-MHz magnetic resonance spectrometer
with chloroform-d as a solvent. Chemical shifts are reported as
d in units of parts per million downfield from tetramethylsilane
(d 0.0), used as an internal standard for 1H NMR spectra. 13C
NMR spectra were calibrated to the 77-ppm signal of CDCl3. IR
spectra were recorded as neat samples or in CCl4 solution.
Melting points were obtained by using a metal block and are
uncorrected. The starting hydrazones were prepared from the
corresponding ketones and arylhydrazines in ethanol as solvent.
1,2-Dichloroethane was dried by distilling over calcium hydride.
Gen er a l P r oced u r e for th e Cou p lin g of Hyd r a zon es
w ith Ald eh yd es a n d Keton es. To a solution of hydrazone 1
(1.0 mmol) in dichloroethane (5 mL) at -30 °C was added Al-
(CH3)3 (1.0 mL of a 2 M solution in hexane, 2.0 mmol, 2.0 equiv).
The cold bath was removed and the resulting solution was
stirred 5 min at room temperature under inert atmosphere. The
reaction mixture was cooled at -30 °C and the carbonyl
compound (1.1 mmol, 1.1 equiv) was added. The resulting
solution was stirred at room temperature or at reflux while TLC
monitoring. The reaction mixture was quenched with a saturated
aqueous solution of dipotassium L(+)-tartrate. After usual
workup, the residue was purified by flash chromatography on
silica gel with diethyl ether in petroleum ether as eluent.
N-sec-Bu t yl-N′-(4-ch lor ob en zylid en e)-N-p h en ylh yd r a -
zin e (3a ). Reagents: 1a (230 mg, 1.0 mmol) and propionaldehyde
(80 µL, 58 mg, 1.1 mmol, 1.1equiv). The reaction mixture was
stirred at room temperature for 24 h. After usual workup the
residue was purified by flash column chromatography with
diethyl ether (5%) in petroleum ether to afford 260 mg (91%) of
formation; this is consistent with the lower yields ob-
tained when hydrazones prone to enamine formation
under Lewis acid activation are involved in the reaction.
Addition products between trimethylaluminum and
hydrazones already have been studied and several X-ray
structures are available. These studies suggest that the
addition product exists as a dimeric complex II in
nonchelating solvent.4 From this dimer one can easily
imagine different monomeric complexes in equlibrium,
the obvious N-aluminated I but also the zwitterionic
complex III (Scheme 2). Interaction of III with an
aldehyde would form a transient aluminacycle IV that
could easily break into iminium species followed by
methyl transfer. Alternatively, the dinuclear aluminum
complex V could also be proposed as the active structure
reacting with aldehyde; a similar dinuclear complex has
been isolated from the reaction of 2-pyridinecarboxalde-
hyde phenylhydrazone with trimethylaluminum.4 The
faster reaction, increased yields, and the absence of
alcohol formation when the reaction is conducted with 2
equiv of trimethylaluminum are in agreement with such
intermediates V as the active species in our reaction.
1
3a as a yellow oil. H NMR δ 7.48-7.44 (m, 4H), 7.29-7.22 (m,
6H), 3.71 (sext, J ) 7.13 Hz, 1H), 2.00-1.94 (m, 1H), 1.62-1.59
(m, 1H), 1.34 (d, J ) 6.6 Hz, 3H), 1.04 (t, J ) 7.4 Hz, 2H). 13C
NMR δ 145.0, 136.2, 132.7, 131.5, 129.9, 128.9, 127.7, 127.0,
126.5, 63.8, 31.4, 19.3, 11.9. IR (cm-1) 2930, 1654, 1610, 1560,
1507, 1495, 1490, 1453, 1154, 1092, 1011, 845, 752, 698. MS (CI,
NH3) m/z 287 (M+), 257. Anal. Calcd for C17H19ClN2: C, 71.19;
H, 6.68. Found: C, 71.11; H, 6.55.
N′-(4-Ch lor ob en zylid en e)-N-[1-(4-ch lor op h en yl)et h yl]-
N-p h en ylh yd r a zin e (3b). Reagents: 1a (230 mg, 1.0 mmol)
and p-chlorobenzaldehyde (154 mg, 1.1 mmol, 1.1 equiv). The
reaction mixture was stirred at reflux for 4 h. After usual workup
the residue was purified by flash column chromatography with
diethyl ether (5%) in petroleum ether as eluent to afford 339
mg (92%) of 3b as a red oil. 1H NMR δ 7.51-7.05 (m, 14H), 4.99
(q, J ) 7.0 Hz, 1H), 1.77 (d, J ) 7.0 Hz, 3H). 13C NMR δ 145.1,
141.5, 135.7, 136.4, 129.9, 129.0, 128.9, 127.2, 126.6, 63.8, 20.2.
IR (cm-1) 2900, 1557, 1497, 1147, 1088, 1011, 822, 752, 725, 699,
576, 530. MS (CI, NH3) m/z 370 (M+), 317. Anal. Calcd for C21H18
Cl2N2: C, 68.30; H, 4.91. Found: C, 68.61; H, 5.11.
-
N′-(4-Ch lor oben zylid en e)-N-(1-m eth yl-3-p h en yla llyl)-N-
p h en ylh yd r a zin e (3c). Reagents: 1a (230 mg, 1.0 mmol) and
cinnamaldehyde (138 µL, 145 mg, 1.1 mmol, 1.1 equiv). The
reaction mixture was stirred at reflux for 4 h. After usual workup
the residue was purified by flash column chromatography with
diethyl ether (5%) in petroleum ether as eluent to afford 339
mg (94%) of 3c as a yellow oil. 1H NMR δ 7.55-7.29 (m, 15H,
CH), 6.54 (s, 2H, CH), 4.72-4.66 (m, 1H, CH), 1.77 (d, J ) 6.8
Hz, 3H). 13C NMR δ 145.3, 137.5, 135.9, 133.3, 131.7, 130.8,
129.9, 129.0, 127.9, 127.3, 126.9, 126.6, 126.3, 62.4, 19.4. IR
(cm-1) 2923, 1652, 1558, 1506, 1490, 1453, 1090, 1012, 965, 745,
692, 668, 547, 529. MS (CI, NH3) m/z 360 (M+), 346, 231. Anal.
Calcd for C23H21ClN2: C, 76.55; H, 5.87. Found: C, 76.38; H,
5.87.
An alternative mechanism involving well-documented
methyl addition to aldehyde followed by ionic fragmenta-
tion and alkylation was easily discarded by a control
experiment: the intermediate alkoxy compounds were
formed by letting 2 equiv of trimethylaluminum react
with aldehyde 2a or 2b; after completion hydrazone 1a
was added and the mixture was refluxed for several hours
without further reaction being observed.
This reaction gives new insight on the wealth of
trialkylaluminum chemistry and is of high interest for
the formation of substituted hydrazine derivatives. Its
mechanism and synthetic potential will be further stud-
ied in our research group.
N-sec-Bu t yl-N′-(4-ch lor ob en zylid en e)-N-m et h ylh yd r a -
zin e (3d ). Reagents: 1b (169 mg, 1.0 mmol) and propionalde-
hyde (80 µL, 58 mg, 1.1 mmol, 1.1 equiv). The reaction mixture
was stirred at room temperature for 13 h. After usual workup
the residue was purified by flash column chromatography with
diethyl ether (5%) in petroleum ether to afford 184 mg (82%) of
(3) Yamazaki, N.; Suzuki, H.; Kibayashi, C. J . Org. Chem. 1997,
62, 8280.
(4) Kim, S. J .; Yang, N.; Kim, D. H.; Kang, S. O.; Ko, J . Organome-
tallics 2000, 19, 4036-4042.
1
3d as a yellow oil. H NMR δ 7.49 (d, J ) 8.5 Hz, 2H), 7.27 (d,
J ) 8.5 Hz, 2H), 7.11 (s, 1H), 3.44 (sext, J ) 4.5 Hz, 1H), 2.84
8734 J . Org. Chem., Vol. 68, No. 22, 2003

(s, 3H), 1.77-1.74 (m, 1H), 1.54-1.50 (m, 1H), 1.17 (d, J ) 6.6
Hz, 3H), 0.94 (t, J ) 6.5 Hz, 3H). 13C NMR δ 136.9, 132.2, 128.9,
127.9, 127.0, 64.7, 34.5, 28.1, 18.0, 11.8. IR (cm-1) 1653, 1558,
1539, 1506, 1456, 667. MS (IC, NH3) m/z 225 (M+), 195. Anal.
Calcd for C12H17ClN2: C, 64.13; H, 7.62. Found: C, 64.35; H,
7.51
2.14 (m, 2H), 1.63-1.47 (m, 6H), 1.05 (s, 3H). 13C NMR δ 137.4,
132.0, 129.0, 127.5, 127.0, 61.7, 36.8, 31.0, 26.4, 24.2, 22.6. IR
(cm-1) 2927, 2854, 1699, 1652, 1581, 1553, 1396, 1360, 1284,
1260, 1160, 993, 867, 817, 708, 668, 813, 528. MS (CI, NH3) m/z
265 (M+). Anal. Calcd for C19H25ClN2: C, 68.04; H, 7.99. Found:
C, 68.07; H, 7.92.
N′-(4-Ch lor ob en zylid en e)-N-[1-(4-ch lor op h en yl)et h yl]-
N-m eth ylh yd r a zin e (3e). Reagents: 1b (169 mg, 1.0 mmol)
and p-chlorobenzaldehyde (154 mg, 1.1 mmol, 1.1 equiv). The
reaction mixture was stirred at reflux for 3 h. After usual workup
the residue was purified by flash column chromatography with
diethyl ether (5%) in petroleum ether to afford 225 mg (73%) of
an inseparable mixture of two diastereomers as a yellow oil.
Major isomer: 1H NMR δ 7.55 (d, J ) 8.5 Hz, 2H), 7.36-7.25
(m, 6H), 7.17 (s, 1H), 4.62 (q, J ) 10.9 Hz, 1H), 2.69 (s, 3H),
1.67 (d, J ) 6.9 Hz, 3H). 13C NMR δ 140.9, 136.4, 133.3, 132.8,
129.1, 129.0, 127.2, 127.0, 65.7, 35.7, 19.2. Minor isomer: 1H
NMR δ 7.55 (d, J ) 8.5 Hz, 2H), 7.36-7.25 (m, 6H), 7.17 (s,
1H), 4.89 (q, J ) 10.9 Hz, 1H), 2.69 (s, 3H), 1.50 (d, J ) 6.9 Hz,
3H). 13C NMR δ 140.9, 136.4, 133.3, 132.8, 129.1, 129.0, 127.2,
127.0, 70.1, 35.7, 25.7. IR (cm-1) 2975, 1652, 1558, 1506, 1489,
1471, 1098, 1012, 828, 668, 551. MS (CI, NH3) m/z 307 (M+).
Anal. Calcd for C23H21ClN2: C, 62.55; H, 5.25. Found: C, 62.78;
H, 5.67.
N-[1,1-Bis-(4-flu or op h en yl)et h yl]-N′-(4-ch lor ob en zyli-
d en e)-N-m eth ylh yd r a zin e (3h ). Reagents: 1b (169 mg, 1.0
mmol) and 4,4′-difluorobenzophenone (240 mg, 1.1 mmol, 1.1
equiv). The reaction mixture was stirred at room temperature
for 6 h. After usual workup the residue was purified by flash
column chromatography with diethyl ether (5%) in petroleum
ether to afford 123 mg (32%) of 3h as a yellow oil. 1H NMR δ
7.39-7.22 (m, 10H), 7.03 (t, J ) 8.7 Hz, 5H), 2.71 (s, 3H), 1.69
(s, 3H). 13C NMR δ 163.1, 160.7, 141.1, 141.0, 136.5, 132.9, 129.9,
129.8, 129.0, 128.9, 115.2, 115.0, 71.9, 35.2, 23.1. IR (cm-1) 2988,
1600, 1554, 1506, 1230, 1161, 1087, 832, 604. MS (CI, NH3) m/z
386 (MH+), 384, 306, 217, 170. Anal. Calcd for C22H19ClF2N2:
C, 68.66; H, 4.98. Found: C, 69.25; H, 5.26.
N-[1-(4-Ch lor op h en yl)eth yl]-N-m eth yl-N′-(3-p h en ylp r o-
p ylid en e)h yd r a zin e (3i). Reagents: 1c (162 mg, 1.0 mmol) and
p-chlorobenzaldehyde (154 mg, 1.1 mmol, 1.1 equiv). The reac-
tion mixture was stirred at room temperature for 48 h. After
usual workup the residue was purified by flash column chro-
matography with diethyl ether (5%) in petroleum ether to afford
143 mg (43%) of 3i as a yellow oil. 1H NMR δ 7.36-7.23 (m,
9H), 6.64 (t, J ) 5.0 Hz, 1H), 4.49 (q, J ) 6.9 Hz, 1H), 2.90 (t,
J ) 7.7 Hz, 2H), 2.71-2.60 (m, 2H), 2.43 (s, 3H), 1.54 (d, J )
6.9 Hz, 3H). 13C NMR δ 142.1, 140.8, 136.3, 133.1, 129.3, 128.9,
128.8, 128.6, 126.3, 64.8, 35.3, 34.3, 33.5, 17.8. IR (cm-1) 2904,
N′-(4-Ch lor oben zylid en e)-N-[1-fu r a n -2-yleth yl)-N-m eth -
ylh yd r a zin e (3f). Reagents: 1b (169 mg, 1.0 mmol) and furfural
(91 µL, 106 mg, 1.1 mmol, 1.1 equiv). The reaction mixture was
stirred at room temperature for 7 h. After usual workup the
residue was purified by flash column chromatography with
diethyl ether (5%) in petroleum ether to afford 152 mg (58%) of
an inseparable mixture of two diastereomers as a yellow oil.
Major isomer: 1H NMR δ 7.53 (d, J ) 8.5 Hz, 2H), 7.38 (s, 1H),
7.30 (d, J ) 8.5 Hz, 2H), 7.22 (s, 1H), 6.35-6.34 (m, 1H), 6.22-
6.21 (m, 1H), 4.85 (q, J ) 7.0 Hz, 1H), 2.75 (s, 3H), 1.58 (d, J )
7.0 Hz, 3H). 13C NMR 155.9, 142.2, 136.2, 132.9, 129.0, 127.1,
110.4, 107.1, 60.3, 34.0, 16.3. Minor isomer: 1H NMR δ 7.53 (d,
J ) 8.5 Hz, 2H), 7.38 (s, 1H), 7.30 (d, J ) 8.5 Hz, 2H), 7.22 (s,
1H), 6.35-6.34 (m, 1H), 6.22-6.21 (m, 1H), 4.62 (q, J ) 7.0 Hz,
1H), 2.69 (s, 3H), 1.67 (d, J ) 7.0 Hz, 3H). 13C NMR 155.9, 142.2,
1601, 1490, 1453, 1089, 1013, 831, 746, 698, 635, 620, 607 cm-1
.
MS (CI, NH3) m/z 302 (MH+), 301 (M+), 300, 295. Anal. Calcd
for C18H21ClN2: C, 71.87; H, 7.04. Found: C, 71.55; H, 7.12
N′-Ben zh ydr yliden e-N-sec-bu tyl-N-ph en ylh ydr azin e (3j).
Reagents: 1d (272 mg, 1.0 mmol) and propionaldehyde (80 µL,
58 mg, 1.1 mmol, 1.1 equiv). The reaction mixture was stirred
at room temperature for 72 h. After usual workup the residue
was purified by flash column chromatography with diethyl ether
(5%) in petroleum ether to afford 194 mg (59%) of 3j as a yellow
oil. 1H NMR δ 7.65-7.60 (m, 4H), 7.38-7.28 (m, 6H), 7.13-7.07
(m, 3H), 6.96 (t, J ) 7.3 Hz, 1H), 6.88-6.74 (m, 1H), 3.50 (sext,
J ) 7.6 Hz, 1H), 2.02 (sept, J ) 7.4 Hz, 1H), 1.72 (sept, J ) 7.0
Hz, 1H), 1.31 (d, J ) 6.5 Hz, 3H), 1.05 (t, J ) 7.4 Hz, 3H). 13C
NMR δ 158.1, 151.2, 145.0, 140.0, 130.2, 129.7, 129.6, 129.5,
129.3, 128.1, 128.7, 128.5, 128.3, 127.8, 127.0, 124.0, 122.9, 120.6,
113.4, 66.6 (CH), 28.9, 17.0, 12.3. IR (cm-1) 3001, 2945, 2866,
1518, 1473, 1406, 1342, 1199. MS (CI, NH3) m/z 328 (M+), 298,
273, 180. Anal. Calcd for C23H24N2: C, 84.11; H, 7.37. Found:
C, 83.99; H, 7.05
136.2, 132.9, 129.0, 127.1, 110.4, 105.5, 64.0, 34.0, 19.5. IR (cm-1
)
2980, 1588, 1554, 1399, 1147, 1087, 1058, 1011, 918, 883, 822,
602. MS (CI, NH3) m/z 263 (M+). Anal. Calcd for C14H55ClN2O:
C, 64.00; H, 5.75. Found: C, 64.12; H, 5.85.
N′-(4-Ch lor ob en zylid en e)-N-m et h yl-N-(1-m et h ylcyclo-
h exyl)h yd r a zin e (3g). Reagents: 1b (169 mg, 1.0 mmol) and
cyclohexanone (114 µL, 108 mg, 1.1 mmol, 1.1 equiv). The
reaction mixture was stirred at room temperature for 6 h. After
usual workup, the residue was purified by flash column chro-
matography with diethyl ether (5%) in petroleum ether to afford
103 mg (39%) of 3b as a yellow oil. 1H NMR δ 7.50 (d, J ) 8.5
Hz, 2H), 7.30 (d, J ) 8.5 Hz, 2H), 7.19 (s, 1H), 2.80 (s, 3H), 2.18-
J O0352272
J . Org. Chem, Vol. 68, No. 22, 2003 8735