Oxidative conversion of imines into 2-azadienes

Article abstract of DOI:10.1055/s-0029-1219172

Several 2-azadienes were prepared by treatment of imines derived from diphenylmethanamine and ketones with sodium hydride in DMF under an air atmosphere. Georg Thieme Verlag Stuttgart New York.

Full text of DOI:10.1055/s-0029-1219172

LETTER
441
Oxidative Conversion of Imines into 2-Azadienes
C
onversio
u
nof
I
mines
i
l
nto 2-A
i
zadien
e
es n Capra, Thierry Le Gall*
CEA Saclay, iBiTecS, Service de Chimie Bioorganique et de Marquage, Bât. 547, 91191 Gif-sur-Yvette Cedex, France
Fax +33(1)69087991; E-mail: thierry.legall@cea.fr
Received 8 October 2009
by two singlets at d = 4.70 and 4.94 ppm corresponding to
Abstract: Several 2-azadienes were prepared by treatment of im-
ines derived from diphenylmethanamine and ketones with sodium
hydride in DMF under an air atmosphere.
the ethylenic protons.
To the best of our knowledge, this kind of transformation
from an imine to an azadiene has not been previously re-
ported, so we embarked in preliminary investigations, us-
ing imines derived from acetophenones as starting
materials. Imine 4a, derived from acetophenone and
diphenylmethanamine, was treated at first under the con-
ditions described above (KOt-Bu, r.t.), which also led to a
mixture of isomerized imine 5a (Figure 1) and azadiene
6a. By using sodium hydride in DMF, imine 4a was also
partially converted into the azadiene, while no isomerized
imine 5a was formed.
Key words: imines, oxygen, azadienes, oxidations, heterocycles
2-Azadienes are useful precursors for the synthesis of
nitrogen-containing heterocyclic compounds.1 They can
be prepared using various methods, including the aza-
Wittig reaction of N-vinylic phosphoranes,2 the base-
induced dehydrochlorination of chloroaldimines,3 the si-
lylation of N-acylimidates,4 the nucleophile-induced rear-
rangement of azine-3-methacrylates.5 In this letter, we
disclose a new preparation of 2-azadienes from imines,
based on the oxygen-mediated oxidation of the corre-
sponding anions.
Ph
Me
Ph
N
Ph
5a
The 1,3-proton-shift isomerization of imines is a process
that occurs in the metabolic pathway of a-keto acids and
amino acids. Pyridoxal-dependent enzymes, aminotrans-
ferases, are involved in these transformations.6 Several
groups have studied the 1,3-isomerization of imines under
various conditions, with the aim to develop catalytic as
well as enantioselective processes.7,8
Figure 1
On the basis of prior reports on the oxygen-mediated oxi-
dation of anions,10 oxygen was suspected to be involved
in the formation of the azadiene. The reaction was then
performed under different atmospheres containing oxy-
gen at room temperature (Table 1). Sodium hydride was
employed as the base, and the reaction was continued for
two days in each case. After this period of time, no evolu-
tion was observed in the reactions.
In the course of a study on the 1,3-isomerization of imines
of a-keto esters and a-keto amides, imine 1, prepared
from 1-pyruvylpyrrolidine and diphenylmethanamine,
was treated with KOt-Bu at room temperature
(Scheme 1). Aside from the expected isomerization prod-
uct 2, the presence of a large amount of azadiene 3, corre-
sponding to the dehydrogenation product of 1, was also
observed in the crude product. After chromatography on
silica gel treated with triethylamine, it was isolated in 27%
yield. Azadiene 39 was notably characterized in 1H NMR
Azadiene 6a was obtained even under an argon atmo-
sphere (entry 1). Using a pure oxygen atmosphere led to a
similar proportion of imine 4a and azadiene 6a (entry 2).
However, when the reaction was performed under a
Table 1 Effect of the Atmosphere on the Formation of 6a
Ph
Ph
Me
Ph
Me
Ph
Me
NaH
KOt-Bu
THF
Ph
N
Ph
N
N
Ph
N
Ph
DMF, 48 h
Ph
N
Ph
N
4a
6a
O
O
1
2
Entry Base (equiv) Atmosphere Ratio of 4a/6aa Yield of 6a (%)
+
Ph
1
2.2
2.2
2.2
3.3
Ar
45:55
47:53
35:65
30:70
42
41
50
65
N
Ph
N
2b
3b
4
O2
O
3
1:1 O2/Ar
dry air
Scheme 1 Conversion of imine 1 into imine 2 and azadiene 3
a Ratio determined from the integrations in the 1H NMR spectrum.
SYNLETT 2010, No. 3, pp 0441–0444
Advanced online publication: 07.01.2010
DOI: 10.1055/s-0029-1219172; Art ID: D28609ST
© Georg Thieme Verlag Stuttgart · New York
1
2.
0
2.
2
0
1
0
b A small amount of oxazoline 7 was also observed in the crude prod-
uct.

442
J. Capra, T. Le Gall
LETTER
mixed argon–oxygen atmosphere an increase of azadiene The imines were then treated under the previously opti-
formation was observed (entry 3). Eventually, a larger mized conditions, employing sodium hydride in DMF at
amount of azadiene was produced using dry air (entry 4). room temperature (Table 3).15 The time needed for the
consumption of the starting material was found to depend
to a great extent on the nature of the aryl group. After
In several cases (entries 2, 3), 3-oxazoline 711 (Figure 2)
was also obtained as side product and identified after
about two days, compounds 4a and 4d had completely
reacted, and the corresponding 2-azadienes 6a and 6d
were isolated, after chromatographic purification on silica
gel impregnated with triethylamine, in 80% and 65%
yield, respectively (entries 1 and 4). Imines 4c, 4e, and 4f
had reacted after four to five days (entries 3, 5, 6). The
azadienes products 6c and 6e were then isolated in good
yields. However, the purification of compound 6f was dif-
ficult and led to a low 8% yield; in this case, an isomerized
imine was also isolated in 15% yield. Compound 4b, hav-
ing a 2-methoxyphenyl group, reacted very sluggishly,
and was still present in the reaction mixture after 15 days,
at which time the reaction was stopped; the purification
afforded 6b in 23% yield (entry 2).
chromatographic purification.12 The identification of this
cyclic compound follows from the spectroscopic data (IR,
1
NMR, mass spectrum). Thus, in the H NMR spectrum,
the methylene protons appear as a singlet at d = 5.19 ppm;
in 13C NMR, the imine carbon appears at d = 166.9 ppm.
O
Ph
Ph
N
Ph
7
Figure 2
The scope of the reaction leading to 2-azadienes was then
evaluated starting from several imines 4a–f (Table 2).
These imines were prepared from the corresponding
ketones 8a–f and diphenylmethanamine, either at reflux in
toluene using a Dean–Stark trap filled with MgSO4 (meth-
od A) or by treatment with titanium chloride (method
B).13
Table 3 Preparation of 2-Azadienes 6a–f
Ph
Ph
Me
NaH (3.3 equiv)
air
Ph
N
Ph
N
R
R
DMF, r.t.
6a–f
4a–f
Table 2 Preparation of Imines 4a–f
Entry
6
R
Time (h)
45
Yield (%)
Ph2CHNH2
toluene, reflux
Dean–Stark trap, MgSO4
(method A)
Me
Ph
Me
1
2
3
4
5
6
6a
6b
6c
6d
6e
6f
H
76
23
80
65
55
8
O
Ph
N
2-MeO
3-MeO
4-MeO
4-Cl
360
96
R
R
or TiCl4, reflux, MgSO4
Dean–Stark trap
(method B)
4
8
48
Entry
4
R
Method Time (d) Z/Ea
Yield (%)b
120
96
1
2
3
4
5
6
4a
4b
4c
4d
4e
4f
H
A
A
A
A
A
B
5
18
18
10
18
0:100
90:10
0:100
0:100
0:100
0:100
97
43
43
60
59
59
4-CN
2-MeO
3-MeO
4-MeO
4-Cl
We did not undertake a systematic mechanistic study to
explain the conversion of imines 4 into azadienes 6. Nev-
ertheless, a tentative hypothesis, depicted in Scheme 2, is
proposed for the formation of both azadiene 6a and 3-
oxazoline 7 from imine 4a.
4-CN
2.5
The anion 9 generated by the reaction of 4a with sodium
hydride could undergo, in the presence of oxygen, a single
electron transfer leading to radical 10 and superoxide an-
ion. This would then result in the formation of hydroper-
oxide anion 11. This species could be in equilibrium with
the less favored carbanion 12, which could evolve along
two different routes. Firstly, a 1,4-elimination of hydro-
peroxide would afford azadiene 6a (route a, red arrows);
this step is related to the 1,4-elimination of chloride re-
ported by De Kimpe.3 On the other hand, an intramolecu-
lar attack of the carbanion, resulting in the ejection of
hydroxide, would afford oxazoline 7 (route b, blue ar-
rows).
a Ratio determined from the integrations in the 1H NMR spectrum of
the recrystallized imine.
b Yield of recrystallized compound.
The reactions usually led to mixtures of stereoisomers, in
which the E-isomer was predominant in most cases. Iden-
tification of the stereoisomers was based on the chemical
shifts observed in 1H NMR. In accordance with studies by
several authors,14 the protons belonging to the MeC=N
groups are shifted to lower field in the E-isomer, and the
a-N methine proton is shifted to higher field in the E-iso-
mer. Pure E-isomers were isolated after recrystallization,
except in the case of compound 4b, which was obtained as
a mixture, the major isomer being Z-configurated.
Unactivated 2-azadienes have been shown to react in
[4+2] cycloadditions with various heterodienophiles.1
Synlett 2010, No. 3, 441–444 © Thieme Stuttgart · New York

LETTER
Conversion of Imines into 2-Azadienes
443
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Ph
Ph
–
Me
Me
NaH
Ph
N
Ph
Ph
N
Ph
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4a
9
Ph
Me
O2
–
•
•
O2
Ph
N
Ph
10
–O
–
HO
O
O
Me
CH2
Ph
Ph
Ph
Ph
N
12
Ph
N
Ph
(7) For selected references, see: (a) Zimmerman, S. C.;
Czarnik, A. W.; Breslow, R. J. Am. Chem. Soc. 1983, 105,
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11
Ph
CH2
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Lett. 2007, 9, 1009.
– OOH–
(a)
(b)
Ph
N
Ph
6a
12
O
N
Ph
Ph
– OH–
Ph
7
Scheme 2 Postulated mechanism for the conversion of imine 4a
into azadiene 6a and 3-oxazoline 7
(8) For the use of transaminases for the biocatalytic production
of chiral amines, see: (a) Stewart, J. D. Curr. Opin. Chem.
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Int. Ed. 2008, 47, 9337. (c) Truppo, M. D.; Turner, N. J.;
Rozzell, J. D. Chem. Commun. 2009, 2127.
The treatment of azadiene 6a with diethyl ketomalonate16
for 15 hours in THF at reflux was found to produce the ex-
pected Diels–Alder cycloadduct 13 (Figure 3) in 37%
yield.
(9) Analytical Data for N-(Diphenylmethylene)-1-
(pyrrolidin-1-yl)ethenamine (3)
Ph Ph
IR (KBr pellet): 3450, 3059, 2972, 2877, 1715, 1628 (s),
1490, 1445, 1341, 1317, 1278, 1239, 1183, 1157, 1074,
1030, 969, 919, 872, 783, 765, 699, 639 cm–1. 1H NMR (400
MHz, CDCl3): d = 7.68 (d, 2 H, ArH), 7.50–7.30 (m, 8 H,
ArH), 4.94 (s, 1 H, =CHH), 4.70 (s, 1 H, =CHH), 3.51 (m,
2 H, NCH2), 3.29 (m, 2 H, NCH2), 1.81–1.76 (m, 4 H,
NCH2CH2). 13C NMR (100 MHz, CDCl3): d = 169.1, 166.1,
151.5, 139.2, 136.2, 132.6, 131.0, 130.2, 129.5, 129.2,
129.0, 128.4, 128.3, 128.1, 126.1, 105.8 (C=CHH), 48.9
(NCH2), 46.0 (NCH2), 26.4 (NCH2CH2), 24.2 (NCH2CH2).
MS (ESI-TOF): m/z = 305.2 [M + H]+.
N
O
CO2Et
CO2Et
Ph
13
Figure 3
In conclusion, we report a method for the conversion of
imines derived from diphenylmethanamine into 2-aza-
dienes, by treatment with sodium hydride under an air
atmosphere. Overall, the process corresponds to an oxida-
tive dehydrogenation of imines, and the mechanism is be-
lieved to involve the oxygenation of a carbanion. Further
developments of this method starting from other imines
are currently under way.
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Lipshutz, B. H.; Tremper, A. W.; Wu, J. S. J. Org. Chem.
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(11) Analytical Data for 2,2,4-Triphenyl-2,5-dihydro-
oxazole (7)
References and Notes
(1) (a) Jayakumar, S.; Ishar, M. P. S.; Mahajan, M. P.
Tetrahedron 2002, 58, 379. (b) Boger, D. L. In
Comprehensive Organic Synthesis, Vol. 5; Trost, B. M.;
Paquette, L. A., Eds.; Pergamon Press: Oxford, 1991, 451.
(2) For reviews on the aza-Wittig reaction, see: (a) Barluenga,
J.; Palacios, F. Org. Prep. Proced. Int. 1991, 23, 1.
(b) Eguchi, S.; Matsushita, Y.; Yamashita, K. Org. Prep.
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IR (KBr pellet): 3058, 3027, 2925, 2850,, 2603, 2359, 1817,
1726, 1662, 1631 (C=N), 1578, 1550, 1531, 1490, 1446,
1363, 1313, 1285, 1230, 1209, 1065, 1028, 963, 941, 919,
(3) (a) De Kimpe, N.; Stanoeva, E.; Verhé, R.; Schamp, N.
Synlett 2010, No. 3, 441–444 © Thieme Stuttgart · New York

444
J. Capra, T. Le Gall
LETTER
869, 799, 758, 692, 643, 561, 535 cm–1. 1H NMR (400 MHz,
CDCl3): d = 7.87–7.84 (m, 2 H, ArH), 7.61–7.57 (m, 4 H,
ArH), 7.49–7.42 (m, 3 H, ArH), 7.36–7.31 (m, 4 H, ArH),
7.29–7.24 (m, 2 H, ArH), 5.19 (s, 2 H, CH2). 13C NMR (100
MHz, CDCl3): d = 166.9 (C=N), 144.2, 131.7, 131.1, 128.9,
128.3, 128.2, 127.8, 126.4, 113.9 (CPh2), 74.2 (CH2). MS
(ESI-TOF): m/z = 300.2 [M + H]+.
(15) Typical Experimental Procedure for the Synthesis of 2-
Azadienes: Benzhydrylidene-[1-(4-methoxyphenyl)-
vinyl]amine (6d)
A solution of imine 4d (200 mg, 0.634 mmol, 1 equiv) in
anhyd DMF (6.3 mL) was placed under a dry air atmosphere.
A suspension of NaH (84 mg of a 60% dispersion in mineral
oil, 2.1 mmol, 3.3 equiv) in anhyd DMF (2.1 mL) was added,
and the reaction mixture was stirred at r.t. for 2 d. Cold H2O
was then added, the aqueous layer was extracted three times
with CH2Cl2 and the combined organic layers dried over
MgSO4. After filtration and concentration under vacuum, the
residue obtained was purified by column chromatography
(silica gel, 96:4 cyclohexane–EtOAc containing 4% Et3N),
to give 2-azadiene 6d as an off-white solid (129 mg, 65%);
mp 137–139 °C. IR (KBr pellet): 3052, 3021, 2965, 2929,
2837, 2046, 1960, 1901, 1820, 1660, 1622, 1604, 1569,
1509, 1443, 1414, 1312, 1291, 1249, 1178, 1150, 1121,
1094, 1073, 1028, 998, 966, 938, 834, 812, 788, 770, 746,
700, 670, 647, 615, 579, 553 cm–1. 1H NMR (400 MHz,
CDCl3): d = 7.79–7.75 (m, 2 H, ArH), 7.46–7.44 (m, 3 H,
ArH), 7.42–7.38 (m, 2 H, ArH), 7.34–7.27 (m, 3 H, ArH),
7.13–7.09 (m, 2 H, ArH), 6.86–6.82 (m, 2 H, ArH), 4.70 (s,
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Sergeeva, E.; Vorontsov, E.; Starikova, Z.; Lysenko, K.;
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H. A. Justus Liebigs Ann. Chem. 1967, 708, 36.
(b) Meléndez, E.; Pérez Ossorio, R.; Sànchez del Olmo, V.
An. Quim. 1970, 66, 87. (c) Abramovitch, R. A.; Kyba, E. P.
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1 H, CHH), 4.03 (s, 1 H, CHH), 3.80 (s, 3 H, OCH3). 13
C
NMR (100 MHz, CDCl3): d = 167.5 (C=N), 159.6, 154.4,
139.4, 136.2, 130.9, 130.8, 130.2, 129.4, 128.8, 128.6,
128.5, 128.4, 128.3, 128.3, 127.9, 126.9, 113.7, 94.0 (CH2),
55.4 (OCH3). HRMS (ESI-TOF): m/z calcd for C22H20NO
[M + H]+: 314.1545; found: 314.1547.
(16) Barluenga, J.; González, F. J.; Fustero, S. Tetrahedron Lett.
1989, 30, 2685.
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