Reaction of Huisgen zwitterion with diaryl ketones leading to the facile synthesis of mono- and bis(alkoxycarbonyl)hydrazones

Article abstract of DOI:10.1055/s-2008-1032125

The Huisgen zwitterion, generated from triphenylphosphine and dialkyl azodicarboxylates, afforded upon reaction with diaryl ketones both mono- and bis(alkoxycarbonyl)hydrazones, depending on the reaction conditions. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2008-1032125

1078
PAPER
Reaction of Huisgen Zwitterion with Diaryl Ketones Leading to the Facile
Synthesis of Mono- and Bis(alkoxycarbonyl)hydrazones
S
ynthesis of Mono
i
-
a
nd B
j
is(alko
a
xycarbonyl
y
)hydrazones Nair,* Smitha C. Mathew, Akkattu T. Biju, Eringathodi Suresh
Organic Chemistry Section, National Institute for Interdisciplinary Science and Technology (Formerly Regional Research Laboratory),
CSIR, Trivandrum 695 019, India
Fax +91(471)2491712; E-mail: vijaynair_2001@yahoo.com
Received 16 August 2007; revised 18 December 2007
intercept the zwitterion 3 with non-enolizable ketones. In
Abstract: The Huisgen zwitterion, generated from triphenylphos-
this context and as part of our general interest in the chem-
phine and dialkyl azodicarboxylates, afforded upon reaction with
diaryl ketones both mono- and bis(alkoxycarbonyl)hydrazones, de-
pending on the reaction conditions.
istry of zwitterions,1c,8 we undertook a detailed study of
the reactivity of Huisgen zwitterion towards diaryl ke-
tones and the results are presented in this paper.
Key words: Huisgen zwitterion, diaryl ketones, azo compounds,
esters, hydrazones
In the initial experiment, a toluene solution of benzophe-
none (4a; 1 equiv) was refluxed with diisopropyl azodi-
carboxylate (2c; 1 equiv) and triphenylphosphine (1; 1
equiv) for 12 hours. The reaction afforded the bis(isoprop-
oxycarbonyl)hydrazone derivative 5a in 39% yield as the
sole product (Scheme 2; Table 1, entry 1).
The reaction of electrophiles with zwitterions generated
from phosphines and activated carbon–carbon multiple
bonds has emerged as an efficient synthetic strategy for
the construction of carbon–carbon and carbon–heteroat-
om bonds.1 Although the zwitterion formed by the addi-
tion of triphenylphosphine to dialkyl azodicarboxylate,
commonly known as the Huisgen zwitterion (Scheme 1),2
has found extensive use as the pivotal intermediate in the
well-known Mitsunobu reaction,3 its general application
in organic synthesis was unexplored.
CO2i-Pr
N
O
i-PrO2C
+
i-PrO2C
N
N
N
toluene, 110 °C
12 h, 39%
PPh3
+
Ph
Ph
Ph
Ph
CO2i-Pr
1
2c
4a
5a
Scheme 2 Reaction of the triphenylphosphine–diisopropyl azodi-
carboxylate zwitterion with benzophenone, with use of equimolar
quantities of starting materials
RO2C
Ph3P
CO2R
N
N
Ph3P
N
N
RO2C
CO2R
Since more than half of the starting material remained un-
changed, the reaction was repeated, and 1.5 equivalents of
the phosphine–azodicarboxylate zwitterion was used
(Table 1, entry 2). Complete consumption of the starting
material occurred, and the bis(isopropoxycarbonyl)hydra-
zone derivative 5a was obtained in 75% yield. In addition
to the bis(isopropoxycarbonyl)hydrazone derivative 5a, a
minor amount of the mono(isopropoxycarbonyl)hydra-
zone 6a also formed (Table 1). Interestingly, when the
stoichiometry of the phosphine–azodicarboxylate zwitter-
ion was increased (from 1.5 equiv to 4 equiv), the
mono(isopropoxycarbonyl)hydrazone derivative 6a be-
came the major product and the bis(isopropoxycarbon-
yl)hydrazone derivative 5a formed in a minor amount
only (Table 1, entries 2–6).
1
2
3
R = Me (2a), Et (2b), i-Pr (2c)
Scheme 1 Huisgen zwitterion
In 2005, Lee and co-workers reported the reaction of
Huisgen zwitterion with aliphatic aldehydes and a-keto
esters4 leading to the synthesis of bisadducts and oxadi-
azolines; synthesis of hydrazones from salicylaldehydes5
and using Huisgen zwitterion was reported elsewhere.
Contemporaneous studies from our laboratory have dem-
onstrated that this zwitterionic species can be used effi-
ciently for the synthesis of a variety of novel heterocycles,
e.g. dihydrobenzoxadiazole derivatives from o-benzo-
quinones,6a functionalized pyrazoles from allenic esters,6b
pyrazolopyridazines from dienones,6c and acyclic mono-
hydrazones from diaryl-1,2-diones.6d Reaction of Huisgen
zwitterion with carbonyl compounds possessing an a-hy-
drogen atom resulted in the formation of vinylhydrazine
derivatives.4,7 However, there has not been any attempt to
Even at the higher stoichiometry of the triphenylphos-
phine–diisopropyl azodicarboxylate zwitterion, a minor
amount of bis(isopropoxycarbonyl)hydrazone 5a formed
along with mono(isopropoxycarbonyl)hydrazone 6a. In
the case of unsymmetrically substituted diaryl ketones 4,
the mono(isopropoxycarbonyl)hydrazone 6 formed as an
inseparable mixture of regioisomers in an approximately
1:1 ratio. The reaction was found to be general with re-
spect to various substituted diaryl ketones. The results are
SYNTHESIS 2008, No. 7, pp 1078–1084
Advanced online publication: 06.03.2008
DOI: 10.1055/s-2008-1032125; Art ID: Z20307SS
x
x
.x
x
.2
0
0
8
© Georg Thieme Verlag Stuttgart · New York

PAPER
Synthesis of Mono- and Bis(alkoxycarbonyl)hydrazones
1079
Table 1 Effect of the Stoichiometry of the Starting Materials on the Reaction of the Triphenylphosphine–Diisopropyl Azodicarboxylate Zwit-
terion with Benzophenone
CO2i-Pr
CO2i-Pr
N
N
HN
O
i-PrO2C
+
N
i-PrO2C
N
N
toluene, 110 °C
12 h
+
PPh3
+
Ph
Ph
4a
Ph
Ph
Ph
Ph
CO2i-Pr
1
2c
5a
6a
Entry
Equiv of 1a
Equiv of 2ca
Yield of 5a (%)
Yield of 6a (%)
1
2
3
4
5
6
1
1
39
75
50
16
14
14
–
1.5
2
1.5
2
15
35
82
84
84
2.5
3
2.5
3
4
4
a The number of equivalents of 1 and 2c are relative to that of 4a (1 equiv).
Table 2 Reaction of 1.5 Equivalents Triphenylphosphine–Diisopropyl Azodicarboxylate Zwitterion with Various Diaryl Ketonesa
CO2i-Pr
H
O
N
N
i-PrO2C
+
N
CO2i-Pr
N
CO2i-Pr
N
N
PPh3
+
+
R1
R2
R2
R1
R1
R2
CO2i-Pr
1
2
4a–i
5b–i
6b–i
Entry
R1
R2
Product 5
Yield (%)
Product 6
Yield (%)
1
2
3
4
5
6
7
8
4-PhC6H4
4-ClC6H4
4-Tol
4-PhC6H4
4-ClC6H4
4-Tol
5b
5c
5d
5e
5f
88
96
39
40
44
56
35
39
6b
6c
6d
6e
6f
–
–
39
26
43
28
28
38
4-t-BuC6H4
4-Tol
4-t-BuC6H4
Ph
Ph
Ph
Ph
3-Tol
5g
5h
5i
6g
6h
6i
3,4-Me2C6H3
PMP
a Reagents and conditions: DIAD (2c; 1.5 equiv), PPh3 (1; 1.5 equiv), 4 (1 equiv), toluene, 110 °C, 12 h.
summarized in Table 2 (use of 1.5 equiv PPh3–DIAD
zwitterion) and Table 3 (use of 2.5 equiv PPh3–DIAD
zwitterion).
The products were structurally characterized by spectro-
scopic analysis. The IR spectrum of compound 5b showed
the ester carbonyl absorptions at 1744 and 1726 cm–1; the
structure was further confirmed by the 13C NMR spec-
trum, in which the carbonyl carbon was discernible at d =
175.8. The methine and methyl protons of the isopropyl
group resonated as multiplets at d = 5.01–4.97 and 1.33–
1.24 ppm, respectively. Finally, the structure of 5b was
established unequivocally by single-crystal X-ray analy-
Figure 1 Single-crystal X-ray crystallographic structure of com-
pound 5b
sis (Figure 1).9
Synthesis 2008, No. 7, 1078–1084 © Thieme Stuttgart · New York

1080
V. Nair et al.
PAPER
Table 3 Reaction of 2.5 Equivalents Triphenylphosphine–Diisopropyl Azodicarboxylate Zwitterion with Various Diaryl Ketonesa
CO2i-Pr
H
O
N
N
i-PrO2C
+
N
CO2i-Pr
N
CO2i-Pr
N
N
PPh3
+
+
R1
R2
R2
R1
R1
R2
CO2i-Pr
1
2
4a–i
5b–i
6b–i
Entry
R1
R2
Product 5
Yield (%)
Product 6
Yield (%)
1
2
3
4
5
6
7
4-PhC6H4
4-Tol
4-PhC6H4
4-Tol
5b
5d
5e
5f
82
24
22
18
24
18
32
6b
6d
6e
6f
16
65
40
80
56
80
63
4-t-BuC6H4
4-Tol
4-t-BuC6H4
Ph
Ph
Ph
Ph
3-Tol
5g
5h
5i
6g
6h
6i
3,4-Me2C6H3
PMP
a Reagents and conditions: DIAD (2c; 2.5 equiv), PPh3 (1; 2.5 equiv), 4 (1 equiv), toluene, 110 °C, 12 h.
The structure of mono(isopropoxycarbonyl)hydrazone 6d
was assigned on the basis of spectroscopic data. The IR
spectrum of the compound showed an absorption at 3352
cm–1 indicating the presence of the NH functionality. The
ester carbonyl absorption was visible at 1747 cm–1. In the
1H NMR spectrum, the NH proton resonated as a singlet
at d = 7.71 ppm (exchangeable by D2O). The methyl pro-
tons resonated as singlets at d = 2.45 and 2.34 ppm, re-
spectively. The methine proton of the isopropyl group
appeared as a multiplet at d = 5.08–4.99 ppm. The ester
carbonyl carbon was discernible at d = 151.2 ppm in the
13C NMR spectrum. The structure was established unam-
Figure 2 Single-crystal X-ray crystallographic structure of com-
pound 6d
biguously by single-crystal X-ray analysis (Figure 2).10
Analogous results were obtained when diethyl- and di-
tert-butyl-substituted azodicarboxylates were used in
place of diisopropyl azodicarboxylate. The results are
summarized in Table 4. It may be noted that hydrazones
make up a versatile class of chemical intermediates capa-
ble of acting as both electrophiles and nucleophiles.11
These are useful precursors for the synthesis of heterocy-
cles such as pyrazoles and oxadiazoles.12
Table 4 Reactions of the Triphenylphosphine–Diethyl or Di-tert-Butyl Azodicarboxylate Zwitterion with Various Diaryl Ketonesa
CO2R
H
N
N
O
RO2C
+
N
CO2R
N
CO2R
N
N
+
PPh3
+
R1
R2
R1
R2
R1
R2
CO2R
1
2
4
7
8
Entry
R
R1
R2
Ph
Product 7
Yield (%)
Product 8
Yield (%)
1
2
3
4
5
Et
Et
Et
Et
Ph
7a
7b
7c
7d
7e
40
18
–
8a
8b
8c
8d
8e
57
81
85
60
55
4-PhC6H4
4-ClC6H4
4-t-BuC6H4
4-t-BuC6H4
4-PhC6H4
4-ClC6H4
4-t-BuC6H4
4-t-BuC6H4
20
30
t-Bu
a Reagents and conditions: 2 (2.5 equiv), PPh3 (1; 2.5 equiv), 4 (1 equiv), toluene, 110 °C, 12 h.
Synthesis 2008, No. 7, 1078–1084 © Thieme Stuttgart · New York

PAPER
Synthesis of Mono- and Bis(alkoxycarbonyl)hydrazones
1081
All reactions were carried out in oven-dried glassware under argon
atmosphere. Progress of the reactions was monitored by TLC (visu-
alization by exposure to UV light or I2), while purification was ef-
A mechanistic rationalization for the formation of the
products can be outlined as follows (Scheme 3). The zwit-
terion 3 generated from triphenylphosphine and the di-
alkyl azodicarboxylate initially adds to the carbonyl group
to form the tetrahedral intermediate 9, which cyclizes to
form 10 (Scheme 3). The latter can undergo two types of
rearrangement. Elimination of one molecule of phosphine
oxide followed by a nitrogen-to-nitrogen migration of the
alkoxycarbonyl group will afford the bis(alkoxycarbon-
yl)hydrazone product 12 (Scheme 3). When excess zwit-
terion is present in the reaction medium, it can attack the
relatively less hindered ester group on the nitrogen atom,
thereby making the phosphine oxide elimination more
1
fected by silica gel column chromatography (100–200 mesh). H
(300 MHz) and 13C (75 MHz) NMR data of samples in CDCl3 were
collected at r.t. on a Bruker Avance DPX-300 MHz NMR spectrom-
eter. IR spectra were recorded on a Bomem MB Series FT-IR spec-
trophotometer. Melting points were recorded on a Büchi melting
point apparatus and are uncorrected. HRMS (EI, at 5000 resolution)
was carried out on a JEOL JMS 600H mass spectrometer.
Bis(alkoxycarbonyl)hydrazones 5 and 7 and Mono(alkoxycar-
bonyl)hydrazones 6 and 8; General Procedure
The appropriate dialkyl azodicarboxylate 2 (0.76 mmol) was added
to a stirred soln of the appropriate diaryl ketone 4 (0.51 mmol) in
facile and thus leading to the formation of the toluene (5 mL), and the mixture was stirred under reflux. Ph3P (199
mg, 0.76 mmol) in toluene (2 mL) was added dropwise to the reflux-
ing soln, and the reaction mixture was kept stirring under reflux for
mono(alkoxycarbonyl)hydrazone 14. The attack of the
excess zwitterion occurs at the intermediate stage, i.e. be-
12 h. It was then cooled and the solvent was removed under reduced
fore the elimination of triphenylphosphine oxide, not after
pressure on a rotary evaporator. The residue was subjected to col-
the formation of bis(alkoxycarbonyl)hydrazone. This
umn chromatography (silica gel, hexanes–EtOAc, 85:15); this
afforded the bis(alkoxycarbonyl)- and mono(alkoxycarbonyl)hy-
drazone derivatives 5–8.
conclusion is drawn from the fact that the bis(alkoxycar-
bonyl)hydrazone derivative remains unchanged when it is
subjected to toluene reflux in the presence of triphe-
nylphosphine and dialkyl azodicarboxylate for 12 hours.
Diisopropyl 2-(Diphenylmethylene)hydrazine-1,1-dicarboxy-
late (5a)
Colorless viscous liquid; yield: 141 mg (75%).
RO2C
Ph
Ph
RO2C
N –
N
IR (film): 3014, 2987, 1778, 1737, 1610, 1517, 1473, 1377, 1263,
1211, 1095, 927, 786 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.65 (d, J = 7.2 Hz, 2 H), 7.48–
7.47 (m, 2 H), 7.39–7.36 (m, 4 H), 7.27–7.21 (m, 2 H), 4.97–4.89
(m, 2 H), 1.28–1.20 (m, 12 H).
Ph
Ph
N
RO2C
O
RO2C
+
N
N
N
Ph3P
+
Ph3P
O
–
PPh3
+
CO2R
CO2R
CO2R
9
1
3
2
13C NMR (75 MHz, CDCl3): d = 176.4, 150.9, 144.8, 136.7, 134.5,
132.2, 129.9, 129.7, 129.5, 128.0, 127.9, 124.2, 115.4, 112.4, 70.9,
29.6, 21.7.
CO2R
–
O
R
O
RO2C
N
N
N
O
N
RO2C
Ph
Ph
+
N
RO
Ph3P
N
HRMS (EI): m/z calcd for C21H24N2O4 [M+]: 368.1503; found:
O
Ph
Ph
368.1518.
10
Ph
Ph
12
11
+
Isopropyl 2-(Diphenylmethylene)hydrazinecarboxylate (6a)
White solid; yield: 120 mg (82%); mp 91–93 °C.
PPh3
RO2C
OR
N
3
N
IR (KBr): 3334, 3018, 2937, 1805, 1734, 1485, 1448, 1377, 1321,
1276, 1207, 1114, 1103, 1026, 920, 844, 788 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.71 (s, 1 H), 7.59–7.55 (m, 5 H),
7.32–7.26 (m, 5 H), 5.07–5.01 (m, 1 H), 1.36–1.21 (m, 6 H).
13C NMR (75 MHz, CDCl3): d = 157.9, 149.2, 148.6, 137.1, 132.0,
129.8, 129.6, 128.4, 128.2, 127.5, 71.8, 21.6.
HRMS (EI): m/z calcd for C17H18N2O2 [M+]: 282.1736; found:
CO2R
–
RO
O–
RO
O
N
Ph
Ph
– CO2R NHN(CO2R)2
N
HN
Ph
O
O
N
N
14
N
O
– Ph3P=O
PPh3
Ph
Ph
Ph
OR
13
15
16
282.1739.
Scheme 3 Proposed reaction mechanism
Diisopropyl 2-[Bis(1,1¢-biphenyl-4-yl)methylene]hydrazine-1,1-
dicarboxylate (5b)
Colorless crystalline solid; yield: 233 mg (88%); mp 175–178 °C.
In summary, we have examined the general reaction of
various symmetrically and unsymmetrically substituted
diaryl ketones with the nitrogen nucleophile derived from
triphenylphosphine and an azodicarboxylate. By variation
of the concentration of the phosphine–azodicarboxylate
zwitterion, the reactivity could be tuned, and thereby se-
lective synthesis of mono(alkoxycarbonyl)hydrazone and
bis(alkoxycarbonyl)hydrazone derivatives could be
achieved.
IR (KBr): 2976, 1744, 1726, 1699, 1593, 1487, 1376, 1286, 1235,
1180, 1113, 1095, 1044, 1006, 909, 842, 769, 731, 693, 613 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.80 (d, J = 8.1 Hz, 2 H), 7.66–
7.61 (m, 8 H), 7.49–7.35 (m, 8 H), 5.01–4.97 (m, 2 H), 1.33–1.24
(m, 12 H).
13C NMR (75 MHz, CDCl3): d = 175.8, 150.9, 144.3, 142.4, 140.2,
135.6, 133.4, 130.6, 130.1, 128.9, 128.6, 128.4, 127.9, 127.1, 127.0,
126.9, 126.8, 72.0, 71.1, 22.1, 21.8, 21.7, 21.6.
HRMS (EI): m/z calcd for C33H32N2O4 [M+]: 520.2362; found:
520.2361.
Synthesis 2008, No. 7, 1078–1084 © Thieme Stuttgart · New York

1082
V. Nair et al.
PAPER
Isopropyl 2-[Bis(1,1¢-biphenyl-4-yl)methylene]hydrazinecar-
boxylate (6b)
Colorless crystalline solid; yield: 181 mg (82%); mp 157–159 °C.
13C NMR (75 MHz, CDCl3): d = 176.3, 154.6, 152.4, 150.8, 134.3,
131.7, 129.4, 127.9, 125.1, 71.1, 70.8, 34.9, 34.8, 31.3, 21.8, 21.6,
20.9.
IR (KBr): 3346, 3030, 2974, 1749, 1712, 1606, 1489, 1394, 1323,
1301, 1207, 1111, 1064, 1014, 933, 854, 763, 736, 700, 495 cm–1.
HRMS (EI): m/z calcd for C29H40N2O4 [M+]: 480.2988; found:
480.2870.
1H NMR (300 MHz, CDCl3): d = 7.80 (m, 3 H), 7.71–7.65 (m, 4 H),
Isopropyl 2-[Bis(4-tert-butylphenyl)methylene]hydrazinecar-
boxylate (6e)
White solid; yield: 72 mg (40%); mp 176–178 °C.
7.59–7.31 (m, 12 H), 5.09–5.06 (m, 1 H), 1.36–1.27 (m, 6 H).
13C NMR (75 MHz, CDCl3): d = 150.0, 142.7, 142.1, 140.4, 139.9,
136.0, 130.7, 128.9, 128.8, 128.4, 128.0, 127.5, 127.1, 127.0, 126.8,
72.1, 22.1, 21.7.
HRMS (EI): m/z calcd for C29H26N2O2 [M+]: 434.1994; found:
434.1941.
IR (KBr): 3261, 2958, 1747, 1720, 1492, 1367, 1226, 1109, 1056,
1020, 939, 829, 769 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.77 (s, 1 H), 7.55 (d, J = 8.3 Hz,
2 H), 7.49 (d, J = 8.5 Hz, 2 H), 7.31 (d, J = 8.5 Hz, 2 H), 7.18 (d,
J = 8.3 Hz, 2 H), 5.10–5.02 (m, 1 H), 1.39 (s, 9 H), 1.30 (s, 15 H).
13C NMR (75 MHz, CDCl3): d = 152.6, 134.7, 129.2, 128.2, 127.4,
126.5, 125.0, 69.4, 34.9, 31.4, 31.3, 29.7, 22.1.
Diisopropyl 2-[Bis(4-chlorophenyl)methylene]hydrazine-1,1-
dicarboxylate (5c)
Colorless crystalline solid; yield: 205 mg (96%); mp 91–93 °C.
IR (KBr): 2983, 1745, 1726, 1691, 1585, 1487, 1462, 1382, 1342,
1282, 1253, 1176, 1093, 833, 761 cm–1.
HRMS (EI): m/z calcd for C25H34N2O2 [M+]: 394.2620; found:
394.2635.
1H NMR (300 MHz, CDCl3): d = 7.59 (d, J = 8.6 Hz, 2 H), 7.41–
7.33 (m, 4 H), 7.18 (d, J = 8.4 Hz, 2 H), 4.96–4.88 (m, 2 H), 1.23–
1.21 (m, 12 H).
13C NMR (75 MHz, CDCl3): d = 173.6, 150.5, 137.8, 135.7, 134.5,
132.2, 130.5, 130.0, 129.7, 129.3, 128.4, 128.2, 71.1, 21.8, 21.5.
HRMS (EI): m/z calcd for C21H22Cl2N2O4 [M+]: 436.0957; found:
436.0956.
Diisopropyl (2Z)-2-[Phenyl(4-tolyl)methylene]hydrazine-1,1-
dicarboxylate (5f)
Colorless viscous liquid; yield: 86 mg (44%).
IR (film): 3018, 2985, 1765, 1517, 1471, 1423, 1379, 1276, 1220,
1209, 1093, 927, 788, 727, 669, 624 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.65 (d, J = 8.1 Hz, 1 H), 7.56 (d,
J = 7.8 Hz, 2 H), 7.4–7.36 (m, 2 H), 7.24–7.18 (m, 3 H), 7.12 (d,
J = 8.1 Hz, 1 H), 5.01–4.91 (m, 2 H), 2.39 (s, 3 H), 1.22 (d, J = 6.3
Hz, 12 H).
13C NMR (75 MHz, CDCl3): d = 176.4, 150.7, 139.7, 134.5, 132.2,
130.4, 129.6, 128.9, 128.4, 128.3, 128.2, 128.0, 127.6, 127.5, 72.1,
70.9, 22.1, 21.8, 21.6, 21.5.
Diisopropyl 2-[Bis(4-tolyl)methylene]hydrazine-1,1-dicarboxy-
late (5d)
Colorless viscous liquid; yield: 77 mg (39%).
IR (film): 2983, 2929, 1743, 1714, 1593, 1506, 1454, 1377, 1344,
1282, 1255, 1180, 1138, 1093, 910, 827, 767 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.54 (d, J = 8.1 Hz, 2 H), 7.18–
7.08 (m, 6 H), 4.97–4.89 (m, 2 H), 2.38 (s, 6 H), 1.25–1.21 (m, 12
H).
13C NMR (75 MHz, CDCl3): d = 176.6, 150.7, 141.6, 139.3, 134.2,
131.7, 129.5, 128.8, 128.6, 127.9, 71.9, 70.7, 21.7, 21.5, 21.4, 21.3,
20.9.
HRMS (EI): m/z calcd for C23H28N2O4 [M+]: 396.2049; found:
396.2023.
HRMS (EI): m/z calcd for C22H26N2O4 [M+]: 382.1893; found:
382.1893.
Isopropyl (2Z)- and (2E)-2-[Phenyl(4-tolyl)methylene]hydra-
zinecarboxylate (6f)
Colorless viscous liquid; yield: 120 mg (80%).
IR (film): 3352, 2981, 1745, 1608, 1487, 1379, 1323, 1217, 1107,
1064, 920, 825, 771, 698 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.76 (s, 2 H), 7.58–7.53 (m, 6 H),
7.45 (d, J = 8.1 Hz, 2 H), 7.35 (d, J = 7.8 Hz, 2 H), 7.30–7.24 (m, 4
H), 7.16–7.08 (m, 4 H), 5.08–5.00 (m, 2 H), 2.45 (s, 3 H), 2.38 (s, 3
H), 1.29–1.23 (m, 12 H).
13C NMR (75 MHz, CDCl3): d = 152.1, 151.9, 139.6, 139.4, 137.2,
134.3, 132.2, 132.0, 130.4, 129.7, 129.6, 129.3, 128.9, 128.8, 128.4,
128.3, 128.1, 127.5, 127.4, 71.7, 69.4, 22.0, 21.7, 21.6, 20.9.
Isopropyl 2-[Bis(4-tolyl)methylene]hydrazinecarboxylate (6d)
White solid; yield: 100 mg (65%); mp 122–124 °C.
IR (KBr): 3352, 2980, 1747, 1610, 1485, 1406, 1379, 1323, 1222,
1178, 1105, 1064, 970, 824, 768, 497 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.71 (s, 1 H), 7.45 (d, J = 8.1 Hz,
2 H), 7.35 (d, J = 7.8 Hz, 2 H), 7.15–7.07 (m, 4 H), 5.08–4.99 (m, 1
H), 2.45 (s, 3 H), 2.34 (s, 3 H), 1.36–1.19 (m, 6 H).
13C NMR (75 MHz, CDCl3): d = 151.2, 139.5, 134.5, 131.4, 128.8,
128.3, 127.5, 69.3, 22.7, 21.7, 21.6, 21.4.
HRMS (EI): m/z calcd for C18H20N2O2 [M+]: 296.1525; found:
296.1522.
Diisopropyl (2Z)-2-[Phenyl(3-tolyl)methylene]hydrazine-1,1¢-
dicarboxylate (5g)
Colorless viscous liquid; yield: 109 mg (56%).
HRMS (EI): m/z calcd for C19H22N2O2 [M+]: 310.1681; found:
310.1675.
IR (film): 3020, 2983, 1768, 1739, 1517, 1473, 1423, 1379, 1274,
1209, 1093, 1045, 927, 844, 748, 669 cm–1
1H NMR (300 MHz, CDCl3): d = 7.66 (d, J = 7.2 Hz, 2 H), 7.57 (s,
1 H), 7.49–7.46 (m, 1 H), 7.41–7.36 (m, 3 H), 7.30–7.21 (m, 2 H),
5.13–5.01 (m, 2 H), 2.36 (s, 3 H), 1.31–1.29 (m, 12 H).
13C NMR (75 MHz, CDCl3): d = 176.9, 149.9, 137.8, 137.5, 136.7,
134.5, 131.3, 129.7, 128.2, 127.9, 127.8, 126.9, 124.8, 72.2, 70.9,
21.9, 21.8, 21.7, 21.3.
Diisopropyl 2-[Bis(4-tert-butylphenyl)methylene]hydrazine-
1,1-dicarboxylate (5e)
White solid; yield: 98 mg (40%); mp 76–78 °C.
IR (KBr): 2976, 2960, 1745, 1465, 1355, 1259, 1182, 1143, 1097,
910, 840 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.58 (d, J = 8.4 Hz, 2 H), 7.40–
7.36 (m, 4 H), 7.15 (d, J = 8.3 Hz, 2 H), 4.96–4.92 (m, 2 H), 1.34 (s,
18 H), 1.22–1.19 (m, 12 H).
Synthesis 2008, No. 7, 1078–1084 © Thieme Stuttgart · New York

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Synthesis of Mono- and Bis(alkoxycarbonyl)hydrazones
1083
HRMS (EI): m/z calcd for C22H26N2O4 [M+]: 382.1893; found:
382.1924.
Diisopropyl (2Z)- and (2E)-2-[(4-Methoxyphenyl)(phe-
nyl)methylene]hydrazinecarboxylate (6i)
White crystalline solid; yield: 100 mg (63%); mp 60–62 °C.
Isopropyl (2Z)- and (2E)-2-[Phenyl(3-tolyl)methylene]hydra-
zinecarboxylate (6g)
Colorless viscous liquid; yield: 84 mg (56%).
IR (KBr): 3354, 3290, 2981, 2935, 1739, 1606, 1487, 1377, 1261,
1219, 1176, 1106, 1055, 1029, 918, 837, 781, 766, 702, 580 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.84 (s, 1 H), 7.65 (s, 1 H), 7.60–
7.50 (m, 6 H), 7.32–7.18 (m, 8 H), 7.07 (d, J = 8.7 Hz, 2 H), 6.83
(d, J = 8.9 Hz, 2 H), 5.11–5.02 (m, 2 H), 3.89 (s, 3 H), 3.80 (s, 3 H),
1.30–1.26 (m, 12 H).
13C NMR (75 MHz, CDCl3): d = 160.7, 160.4, 149.9, 137.4, 129.8,
129.6, 129.2, 128.9, 128.4, 128.0, 127.6, 72.0, 69.3, 55.2, 55.1,
22.0, 21.9, 21.7, 21.6.
IR (film): 3321, 3018, 1737, 1600, 1521, 1423, 1222, 927, 771, 667
cm–1.
1H NMR (300 MHz, CDCl3): d = 7.70 (br s, 2 H), 7.58–7.44 (m, 7
H), 7.32–7.24 (m, 7 H), 7.16–7.13 (m, 2 H), 7.06–7.04 (m, 2 H),
5.12–5.00 (m, 2 H), 2.42 (s, 3 H), 2.32 (s, 3 H), 1.36–1.25 (m, 12 H).
13C NMR (75 MHz, CDCl3): d = 152.8, 148.5, 139.5, 137.6, 137.1,
136.9, 132.2, 131.9, 130.4, 130.2, 129.7, 129.6, 129.2, 128.7, 128.4,
128.1, 127.9, 127.8, 127.5, 125.3, 124.9, 71.6, 69.4, 22.0, 21.7,
21.4.
HRMS (EI): m/z calcd for C18H20N2O3 [M+]: 312.1474; found:
312.1440.
HRMS (EI): m/z calcd for C18H20N2O2 [M+]: 296.1525; found:
296.1539.
Diethyl 2-(Diphenylmethylene)hydrazine-1,1¢-dicarboxylate
(7a)
White solid; yield: 69 mg (40%); mp 67–69 °C.
Diisopropyl (2Z)-2-[(3,4-Dimethylphenyl)(phenyl)methyl-
ene]hydrazine-1,1-dicarboxylate (5h)
Colorless viscous liquid; yield: 70 mg (35%).
IR (KBr): 3018, 2980, 1774, 1741, 1521, 1475, 1423, 1371, 1265,
1209, 1105, 1045, 927, 848, 740, 667 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.67–7.64 (m, 2 H), 7.42–7.38 (m,
6 H), 7.23–7.19 (m, 2 H), 4.39–4.26 (m, 4 H), 1.39–1.29 (m, 6 H).
13C NMR (75 MHz, CDCl3): d = 176.6, 150.8, 136.5, 134.3, 131.4,
129.9, 129.5, 128.2, 127.7, 127.4, 66.3, 63.9, 62.9, 14.4, 14.1, 13.8.
HRMS (EI): m/z calcd for C19H20N2O4 [M+]: 340.1423; found:
340.1434.
IR (film): 3014, 2987, 1778, 1737, 1610, 1517, 1473, 1377, 1263,
1211, 1095, 928, 786 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.66–7.64 (m, 1 H), 7.53–7.45 (m,
2 H), 7.39–7.34 (m, 2 H), 7.22–7.19 (m, 1 H), 7.14–7.09 (m, 1 H),
6.95–6.93 (m, 1 H), 4.99–4.91 (m, 2 H), 2.28 (s, 3 H), 2.23 (s, 3 H),
1.24–1.21 (m, 12 H).
13C NMR (75 MHz, CDCl3): d = 177.3, 150.7, 140.6, 138.1, 136.2,
134.7, 131.3, 130.3, 129.9, 129.6, 129.5, 129.3, 128.8, 128.1, 128.0,
127.9, 127.4, 125.4, 125.3, 72.1, 70.9, 21.9, 21.8, 21.6, 20.0.
HRMS (EI): m/z calcd for C23H28N2O4 [M+]: 396.2049; found:
396.2061.
Ethyl 2-(Diphenylmethylene)hydrazinecarboxylate (8a)
White solid; yield: 76 mg (57%); mp 93–95 °C.
IR (KBr): 3350, 2981, 1747, 1506, 1492, 1444, 1325, 1219, 1068,
1028, 765, 698 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.76 (s, 1 H), 7.59–7.56 (m, 5 H),
7.36–7.26 (m, 5 H), 4.28–4.26 (m, 2 H), 1.32 (br s, 3 H).
13C NMR (75 MHz, CDCl3): d = 152.1, 136.9, 131.9, 129.7, 128.4,
128.1, 127.5, 118.2, 61.8, 14.5.
Isopropyl (2Z)- and (2E)-2-[(3,4-Dimethylphenyl)(phe-
nyl)methylene]hydrazinecarboxylate (6h)
White solid; yield: 125 mg (80%); mp 96–98 °C.
HRMS (EI): m/z calcd for C16H16N2O2 [M+]: 268.1212; found:
268.1187.
IR (KBr): 3358, 2980, 1747, 1489, 1448, 1379, 1321, 1273, 1219,
1180, 1141, 1107, 1068, 924, 823, 771, 704, 501 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.82 (s, 1 H), 7.70 (s, 1 H), 7.61–
7.46 (m, 6 H), 7.31–7.18 (m, 7 H), 7.06–6.97 (m, 3 H), 5.13–5.00
(m, 2 H), 2.33 (d, J = 10.4 Hz, 6 H), 2.23 (d, J = 4.7 Hz, 6 H), 1.42–
1.21 (m, 12 H).
Diethyl 2-[Bis(1,1¢-biphenyl-4-yl)methylene]hydrazine-1,1¢-di-
carboxylate (7b)
Colorless viscous liquid; yield: 44 mg (18%).
13C NMR (75 MHz, CDCl3): d = 152.9, 151.1, 138.2, 138.1, 137.2,
136.2, 134.6, 132.2, 130.7, 129.6, 129.5, 129.3, 129.1, 128.3, 127.9,
127.4, 125.6, 125.3, 71.6, 69.2, 21.6, 21.5, 19.8, 19.6, 19.5.
IR (film): 3018, 2983, 1770, 1517, 1473, 1419, 1373, 1276, 1209,
1103, 1043, 927, 848, 752, 669 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.78–7.74 (m, 2 H), 7.63–7.54 (m,
8 H), 7.45–7.27 (m, 8 H), 4.19–4.16 (m, 4 H), 1.24–1.20 (m, 6 H).
HRMS (EI): m/z calcd for C19H22N2O2 [M+]: 310.1681; found:
13C NMR (75 MHz, CDCl3): d = 176.0, 150.4, 144.4, 142.4, 140.0,
135.3, 133.1, 129.9, 128.9, 128.7, 128.3, 127.8, 127.7, 126.9, 126.7,
63.9, 62.9, 14.3, 13.9.
HRMS (EI): m/z calcd for C31H28N2O4 [M+]: 492.2049; found:
492.2046.
310.1645.
Diisopropyl (2Z)-2-[(4-Methoxyphenyl)(phenyl)methylene]hy-
drazine-1,1-dicarboxylate (5i)
Colorless viscous liquid; yield: 79 mg (39%).
IR (KBr): 3018, 1737, 1606, 1510, 1489, 1467, 1375, 1263, 1226,
1095, 1033, 927, 779, 667 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.65–7.59 (m, 2 H), 7.39–7.35 (m,
2 H), 7.23–7.16 (m, 2 H), 6.91–6.79 (m, 3 H), 5.07–4.99 (m, 2 H),
3.82 (s, 3 H), 1.37–1.30 (m, 12 H).
13C NMR (75 MHz, CDCl3): d = 176.1, 150.7, 144.8, 137.2, 134.7,
131.2, 129.8, 129.6, 129.2, 128.1, 127.9, 127.8, 113.5, 70.8, 69.9,
55.2, 21.8, 21.7, 21.6.
Ethyl 2-[Bis(1,1¢-biphenyl-4-yl)methylene]hydrazinecarboxy-
late (8b)
Colorless viscous liquid; yield: 173 mg (81%).
IR (KBr): 3346, 3030, 2974, 1749, 1712, 1606, 1489, 1394, 1323,
1301, 1207, 1111, 1064, 1014, 933, 854, 763, 736, 700, 495 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.87 (s, 1 H), 7.81–7.78 (m, 2 H),
7.71–7.64 (m, 4 H), 7.60–7.31 (m, 12 H), 4.34–4.29 (m, 2 H), 1.35–
1.30 (m, 3 H).
HRMS (EI): m/z calcd for C22H26N2O5 [M+]: 398.1842; found:
398.1833.
Synthesis 2008, No. 7, 1078–1084 © Thieme Stuttgart · New York

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V. Nair et al.
PAPER
tert-Butyl 2-[Bis(4-tert-butylphenyl)methylene]hydrazinecar-
13C NMR (75 MHz, CDCl3): d = 150.4, 142.5, 142.0, 140.2, 139.7,
135.8, 130.4, 128.9, 128.8, 127.9, 126.9, 126.7, 63.9, 14.1.
boxylate (8e)
White solid; yield: 118 mg (55%); mp 189–191 °C.
HRMS (EI): m/z calcd for C28H24N2O2 [M+]: 420.1838; found:
420.1847.
IR (film): 3261, 2960, 1745, 1714, 1487, 1363, 1240, 1163, 1114,
1060, 877, 850, 831, 567 cm–1.
Ethyl 2-[Bis(4-chlorophenyl)methylene]hydrazinecarboxylate
(8c)
White crystalline solid; yield: 144 mg (85%); mp 157–159 °C.
1H NMR (300 MHz, CDCl3): d = 7.68 (s, 1 H), 7.54 (d, J = 8.3 Hz,
2 H), 7.49 (d, J = 8.5 Hz, 2 H), 7.29 (d, J = 8.5 Hz, 2 H), 7.18 (d,
J = 8.2 Hz, 2 H), 1.42–1.39 (m, 9 H), 1.29–1.28 (m, 18 H).
IR (KBr): 3230, 2987, 1749, 1693, 1602, 1485, 1452, 1377, 1334,
1298, 1170, 1122, 1014, 831, 771, 690 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.69 (s, 1 H), 7.57 (d, J = 8.3 Hz,
2 H), 7.49 (d, J = 8.5 Hz, 2 H), 7.28 (d, J = 11.3 Hz, 2 H), 7.21 (d,
J = 11.3 Hz, 2 H), 4.28–4.25 (m, 2 H), 1.32–1.25 (m, 3 H).
13C NMR (75 MHz, CDCl3): d = 152.5, 134.7, 129.3, 128.2, 127.3,
126.5, 124.9, 81.1, 34.9, 31.4, 31.3, 28.4.
HRMS (EI): m/z calcd for C26H36N2O2 [M+]: 408.2777; found:
408.2768.
13C NMR (75 MHz, CDCl3): d = 153.1, 148.5, 136.2, 135.6, 135.1,
130.6, 130.2, 129.8, 128.5, 128.4, 61.9, 14.4.
Acknowledgment
HRMS (EI): m/z calcd for C16H14Cl2N2O2 [M+]: 336.0432; found:
336.0435.
Financial assistance from the Council of Scientific and Industrial
Research (CSIR), Government of India, is acknowledged. The au-
thors also thank Mrs. Saumini Mathew for recording NMR spectra
and Mrs. S. Viji for mass spectral data.
Diethyl 2-[Bis(4-tert-butylphenyl)methylene]hydrazine-1,1¢-di-
carboxylate (7d)
White solid; yield: 46 mg (20%); mp 147–149 °C.
References
IR (KBr): 3018, 2968, 1780, 1735, 1614, 1502, 1473, 1371, 1267,
1207, 1105, 1047, 927, 842, 766, 669 cm–1.
(1) For reviews, see: (a) Methot, J. L.; Roush, W. R. Adv. Synth.
Catal. 2004, 346, 1035. (b) Lu, X.; Zhang, C.; Xu, Z. Acc.
Chem. Res. 2001, 34, 535. (c) Nair, V.; Menon, R. S.;
Sreekanth, A. R.; Abhilash, N.; Biju, A. T. Acc. Chem. Res.
2006, 39, 520.
(2) (a) Brunn, E.; Huisgen, R. Angew. Chem., Int. Ed. Engl.
1969, 8, 513. (b) Huisgen, R. In The Adventure Playground
of Mechanisms and Novel Reactions: Profiles, Pathways
and Dreams; Seeman, J. I., Ed.; American Chemical
Society: Washington DC, 1994, 62; and references cited
therein.
(3) (a) Mitsunobu, O. Synthesis 1981, 1. (b) Hughes, D. L. Org.
Prep. Proced. Int. 1996, 28, 127. (c) Watanabe, T.;
Gridnave, I. D.; Imamoto, T. Chirality 2000, 12, 346.
(4) Otte, R. D.; Sakata, T.; Guzei, I. A.; Lee, D. Org. Lett. 2005,
7, 495.
1H NMR (300 MHz, CDCl3): d = 7.59 (d, J = 8.5 Hz, 2 H), 7.39 (d,
J = 8.5 Hz, 4 H), 7.13 (d, J = 8.4 Hz, 2 H), 4.22–4.13 (m, 4 H),
1.33–1.31 (m, 18 H), 1.26–1.20 (m, 6 H).
13C NMR (75 MHz, CDCl3): d = 176.6, 154.8, 152.4, 151.0, 133.9,
131.5, 129.4, 125.1, 63.7, 62.8, 34.7, 31.2, 31.1, 14.2, 14.1.
HRMS (EI): m/z calcd for C27H36N2O4 [M+]: 452.2519; found:
452.2517.
Ethyl 2-[Bis(4-tert-butylphenyl)methylene]hydrazinecarboxy-
late (8d)
White solid; yield: 116 mg (60%); mp 144–146 °C.
IR (KBr): 3290, 2960, 2902, 1751, 1724, 1496, 1400, 1363, 1321,
1267, 1230, 1064, 835 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.79 (s, 1 H), 7.56–7.48 (m, 4 H),
7.31 (d, J = 8.6 Hz, 2 H), 7.17 (d, J = 8.4 Hz, 2 H), 4.28–4.25 (m, 2
H), 1.42–1.37 (m, 9 H), 1.30 (s, 12 H).
13C NMR (75 MHz, CDCl3): d = 152.6, 151.2, 134.5, 130.0, 129.1,
128.1, 127.4, 126.5, 125.8, 124.9, 61.7, 34.9, 31.3, 31.2, 14.6.
(5) Girard, M.; Murphy, P.; Tsou, N. N. Tetrahedron Lett. 2005,
46, 2449.
(6) (a) Nair, V.; Biju, A. T.; Vinod, A. U.; Suresh, E. Org. Lett.
2005, 7, 5139. (b) Nair, V.; Biju, A. T.; Mohanan, K.;
Suresh, E. Org. Lett. 2006, 8, 2213. (c) Nair, V.; Mathew, S.
C.; Biju, A. T.; Suresh, E. Angew. Chem. Int. Ed. 2007, 46,
2070. (d) Nair, V.; Biju, A. T.; Abhilash, K. G.; Menon, R.
S.; Suresh, E. Org. Lett. 2005, 7, 2121.
HRMS (EI): m/z calcd for C24H32N2O2 [M+]: 380.2464; found:
380.2396.
(7) (a) Nair, V.; Biju, A. T.; Mathew, S. C. Synthesis 2007, 697.
(b) Liu, Y.; Xu, C.; Liu, L. Synthesis 2003, 1335.
(8) Nair, V.; Rajesh, C.; Vinod, A. U.; Bindu, S.; Sreekanth, A.
R.; Mathen, J. S.; Balagopal, L. Acc. Chem. Res. 2003, 36,
899.
(9) The crystal structure data of compound 5b have been
deposited at the Cambridge Crystallographic Data Centre
and allocated the reference no. CCDC 650903.
(10) The crystal structure data of compound 6d have been
deposited at the Cambridge Crystallographic Data Centre
and allocated the reference no. CCDC 650904.
(11) Keith, J. M.; Gomez, L. J. Org. Chem. 2006, 71, 7113.
(12) (a) Haddad, N.; Baron, J. Tetrahedron Lett. 2002, 43, 2171.
(b) Dabiri, M.; Salehi, P.; Bagbanzadeh, M.; Bahramnejad,
M. Tetrahedron Lett. 2006, 47, 6983.
Di-tert-butyl 2-[Bis(4-tert-butylphenyl)methylene]hydrazine-
1,1¢-dicarboxylate (7e)
White solid; yield: 78 mg (30%); mp 117–119 °C.
IR (KBr): 2960, 2868, 1747, 1724, 1606, 1504, 1456, 1396, 1365,
1328, 1274, 1251, 1159, 1118, 854, 771, 686 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.55 (d, J = 8.4 Hz, 2 H), 7.39–
7.35 (m, 4 H), 7.19 (d, J = 8.3 Hz, 2 H), 1.39 (br s, 18 H), 1.34–1.33
(m, 18 H).
13C NMR (75 MHz, CDCl3): d = 174.5, 152.2, 149.7, 134.3, 131.6,
129.8, 129.1, 127.9, 124.9, 124.8, 82.3, 34.8, 34.6, 34.5, 31.1, 31.0,
28.1, 27.9, 27.8.
HRMS (EI): m/z calcd for C31H44N2O4 [M+]: 508.3301; found:
508.3300.
Synthesis 2008, No. 7, 1078–1084 © Thieme Stuttgart · New York