TBHP/R4N+X– promoted hydroaroylation of dialkyl azodicarboxylates with methyl arenes, aldehydes, aryl methanols and arylmethyl chlorides

Article abstract of DOI:10.1016/j.tet.2018.05.038

Efficient TBHP/R₄N⁺X^– promoted hydroaroylations of dialkyl azo-1,2-dicarboxylates with methyl arenes, aldehydes, aryl methanols and arylmethyl chlorides are described. These oxidation/oxygenation and hydroaroylation processes were carried out by tert-butyl hydroperoxide as terminal oxidant/oxygen source, and were catalyzed by tetrabutylammonium bromide and tricaprylmethylammonium chloride as the driving force. During this investigation, all these hydroaroylating sources were found to be highly efficient reagents without the need of any transition-metal.

Full text of DOI:10.1016/j.tet.2018.05.038

Accepted Manuscript
+ –
TBHP/R N X promoted hydroaroylation of dialkyl azodicarboxylates with methyl
4
arenes, aldehydes, aryl methanols and arylmethyl chlorides
Mehdi Adib, Rahim Pashazadeh, Saideh Rajai-Daryasarei, Fatemeh Moradkhani,
Mehdi Jahani, Seyed Jamal Addin Gohari
PII:
S0040-4020(18)30571-4
10.1016/j.tet.2018.05.038
TET 29545
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 23 November 2017
Revised Date: 10 May 2018
Accepted Date: 15 May 2018
Please cite this article as: Adib M, Pashazadeh R, Rajai-Daryasarei S, Moradkhani F, Jahani M,
+ –
Gohari SJA, TBHP/R N X promoted hydroaroylation of dialkyl azodicarboxylates with methyl arenes,
4
aldehydes, aryl methanols and arylmethyl chlorides, Tetrahedron (2018), doi: 10.1016/j.tet.2018.05.038.
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ACCEPTED MANUSCRIPT
TBHP/R4N+X– promoted hydroaroylation of
dialkyl azodicarboxylates with methyl arenes, aldehydes,
aryl methanols and arylmethyl chlorides
Mehdi Adib, Rahim Pashazadeh, Saideh Rajai-Daryasarei, Fatemeh Moradkhani, Mehdi Jahani, Seyed
Jamal Addin Gohari
ArCH3
TBHP (8 equiv.)
TBAB (50 mol%), 80 ºC, 1 h
ArCH2OH
TBHP
Aliquat 336 (30 mol%), PhCl, 60 ºC, 3 h
O
(3 equiv.)
CO2R'
CO2R'
Ar
N
N
R'O2C
N
N
CO2R'
ArCHO
H
TBHP
(30 mol%)
Aliquat 336 (30 mol%), PhCl, 40 ºC, 2 h
ArCH2Cl
(10 equiv.)
TBHP
Aliquat 336 (20 mol%),
K2CO3 (0.5 equiv.), PhCl, 120 ºC, 1 h
1

ACCEPTED MANUSCRIPT
TBHP/R4N+X– promoted hydroaroylation of dialkyl
azodicarboxylates with methyl arenes, aldehydes, aryl methanols and
arylmethyl chlorides
Mehdi Adib,a,* Rahim Pashazadeh,a Saideh Rajai-Daryasarei,a Fatemeh Moradkhani,b
Mehdi Jahani,a Seyed Jamal Addin Goharic
a School of Chemistry, College of Science, University of Tehran, PO Box 14155-6455,
Tehran, Iran
b Department of Medicinal Chemistry, Drug Design and Development Research
Center, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran
c Department of Chemistry, Imam Hossein University, Tehran, Iran
Abstract: Efficient TBHP/R4N+X– promoted hydroaroylations of dialkyl azo-1,2-
dicarboxylates with methyl arenes, aldehydes, aryl methanols and arylmethyl
chlorides are described. These oxidation/oxygenation and hydroaroylation processes
were carried out by tert-butyl hydroperoxide as terminal oxidant/oxygen source, and
were catalyzed by tetrabutylammonium bromide and tricaprylmethylammonium
chloride as the driving force. During this investigation, all these hydroaroylating
sources were found to be highly efficient reagents without the need of any transition-
metal.
Keywords:
tert-butyl
hydroperoxide,
tetrabutylammonium
bromide,
tricaprylmethylammonium chloride, methyl arenes, aldehydes, aryl methanols,
arylmethyl chlorides, dialkyl azo-1,2-dicarboxylates, hydrazine imides.
*Corresponding author. Tel./fax: +98(21)66495291; E-mail: madib@khayam.ut.ac.ir
1

ACCEPTED MANUSCRIPT
1. Introduction
C−H functionalization protocol is a rapidly expanding area in organic synthesis as it
offers high impetus for developing novel, short and attractive methodologies for
synthesizing a variety of complex organic molecules.1 Moreover, due to their
relatively inert nature, the functionalization and activation of C−H bonds plays a vital
role in the development of more efficient and sustainable bond forming reactions.
From an atom-economical and environmental point of view, the use of un-
functionalized starting materials in the construction of C−C and C−heteroatom bonds
is one of the major concerns for synthetic chemists.2
Methyl arenes,3 alcohols4 and arylmethyl halides4c,5 have been recognized as cheap,
simple, stable and easily available starting materials, which made them attractive
substrates from both academic and industrial perspective in the synthesis of complex
molecules.
Remarkably, construction of various bonds and complex compounds using
oxidant/R4N+X– system has emerged as an efficient and unique catalytic methodology
which obviates the foregoing impediments of metal-catalyzed reactions.6
Dialkyl azodicarboxylates (DAADs) are excellent electrophiles due to the presence of
two carboalkoxy groups and electrophilic π bond on the nitrogen atoms of the azo
skeleton.7 Thus, DAADs have been employed as nucleophile acceptors and coupling
partners in various reactions such as N-arylation,8 C−H derivatization at the α-
position to heteroatoms,9 electrophilic α-amination of carbonyl compounds,10 ene-
type reactions with olefins11 and also reactions with zwitterionic intermediates.12
On the other hand, acylation of DAADs has also received considerable attention from
the synthetic community.13 In recent years, hydrazine imides have been prepared
from aliphatic and aromatic aldehydes as hydroacylating agents. While the reaction
can be performed under various conditions using metal catalyst such as Rh(II),14
Cu(II),15 and Zn(II),16 aqueous media,17 ionic liquid,18 Lewis- and Brønsted-acid
catalysis,19 pyridine-catalysis under microwave irradiation,20 photocatalytic
method,21a decatungstate anion photocatalysis,21b graphite flakes as the
carbocatalyst,21c and CoO-Fe3O4 as magnetic catalysis.22
As part of our continuing effort to develop efficient methods for the preparation of
biologically active organic compounds from readily available precursors,23 recently,
we have been particularly interested in oxidant/R4N+X– catalytic systems and have
focused our attention on the development of acylation-based novel transformations.24
2

ACCEPTED MANUSCRIPT
Herein, we present highly efficient and transition metal-free hydroaroylations of
DAADs with readily accessible hydroaroylating reagents via C(sp3)−H and C(sp2)−H
oxidation functionalization strategies promoted by oxidant/R4N+X– leading to the
corresponding hydrazine imides (Scheme 1).
O
H
O
O
N
OR
H
Ar
O
H
Ar
H
H
RO
N
N
TBHP
N
O
or
_
+
Ar
+
OR
R4N X (cat.)
H
H
H H
RO
O
Ar
OH
Ar
Cl
Scheme 1 Synthesis of hydrazine imides through hydroaroylation of dialkyl
azodicarboxylate promoted by the TBHP/R4N+X– system.
2. Result and discussion
Initially, we selected toluene 1a and DAAD 2a as the model substrates to evaluate the
most suitable conditions. In this optimization, various parameters such as the type as
well as the quantity of oxidant and additive, solvents, and reaction temperature were
examined (Table 1). The reaction between 1a and 2a was first started in the presence
of tert-butyl hydroperoxide (TBHP, 6 equiv.) as oxidant and tetrabutylammonium
bromide (TBAB, 30 mol%) as additive at ambient temperature for 1 h, however, no
reaction was observed (entry 1). Carrying out the reaction at 50 and 80 °C, gave
dialkyl hydrazine-1,2-dicarboxylate (DAHD, 3a) in 28 and 55% yields, respectively
(entries 2 and 3). In order to improve the reaction efficiency, reaction time increased
to 2 h, but the yield of 3a decreased to 35% (entry 4). By increasing the reaction time,
the NH group of the formed hydrobenzoylated product may undergo further oxidation
and functionalizion.25 By increasing the amount of TBHP and TBAB the efficiency of
the reaction improved (entries 5–7) and the best result was observed with 50 mol% of
TBAB and 8.0 equiv of TBHP at 80 °C with which 3a was obtained in 93% yield
(entry 6). However, higher TBHP loading did not improve the formation of 3a (entry
7). An excess amount of TBHP led to the formation of benzoic acid in the reaction
mixture. Also, in several reports, increasing the amount of the oxidant has a negative
effect on the yield of the product.5,26 Other additives were also examined (entries 8–
13). NBS, TBPB and Aliquat 336 gave 3a in 10%, 75%, and 48% yields, respectively
(entries 8–10) and KI as well as elemental iodine (I2) were ineffective (entries 11 and
12). Notably, no product was detected by use of BPO, K2S2O8, and H2O2 as oxidant
3

ACCEPTED MANUSCRIPT
(entries 13–15). Moreover, the solvent screening studies indicated that no product
was formed in solvents such as PhCl, CH3CN, 1,4-dioxane and DMSO (entries 16–
19). Furthermore, the reaction was carried out in the presence of different amounts of
toluene (4, 6 and 10 mmol), which led to the formation of 3a in 40%, 62%, and 79%
yields, respectively (entries 20–22). In the absence of TBHP and TBAB, 3a was not
detected (entries 23 and 24), which suggested that both TBHP and TBAB played a
crucial role in this reaction. Carrying out the reaction at 100 °C and 120 °C, 3a was
obtained in 93% and 90% yields, respectively, after 30 minutes (entries 25 and 26).
According to the above results, the optimal conditions for synthesis of DAHD 3a
were determined as: DAAD 2a (0.4 mmol), toluene (8 mmol,), TBHP (8 equiv.), 50
mol% of TBAB, at 80 °C for 1 h (entry 6).
4

ACCEPTED MANUSCRIPT
Table 1. Optimization of the reaction conditions for the hydrobenzoylation of 2a with toluene
1aa
CO2i-Pr
CH3
O
i-PrO2C
N
Oxidant, additive
solvent
H
N
N
N
+
i-PrO2C
CO2i-Pr
1a
3a
2a
Entry
1
2
Oxidant (equiv.)b Additive (mol%)b
Solvent
PhCH3
PhCH3
PhCH3
PhCH3
PhCH3
PhCH3
PhCH3
PhCH3
PhCH3
PhCH3
PhCH3
PhCH3
PhCH3
PhCH3
PhCH3
PhCl
Temp. (°C)
r.t.
50
Yield (%)c
NRf
28
TBHPd (6)
TBHP (6)
TBHP (6)
TBHP (6)
TBHP (8)
TBHP (8)
TBHP (10)
TBHP (8)
TBHP (8)
TBHP (8)
TBHP (8)
TBHP (8)
BPOk (8)
K2S2O8 (8)
TBABe (30)
TBAB (30)
TBAB (30)
TBAB (30)
TBAB (30)
TBAB (50)
TBAB (50)
NBSh (50)
TBPBi (50)
Aliquat 336j (50)
KI (50)
3
4g
80
80
55
35
5
80
52
6
7
8
80
80
80
93
82
10
9
80
80
75
48
10
11
12
13
14
15
16m
17
18
19
20n
21o
22p
23
24
25q
26q
80
80
NR
NR
NR
NR
NR
NR
NR
NR
NR
40
I2 (50)
TBAB (50)
TBAB (50)
TBAB (50)
TBAB (50)
TBAB (50)
TBAB (50)
TBAB (50)
TBAB (50)
TBAB (50)
TBAB (50)
TBAB (50)
80
80
l
H2O2 (8)
80
80
TBHP (8)
TBHP (8)
TBHP (8)
TBHP (8)
TBHP (8)
TBHP (8)
TBHP (8)
−
CH3CN
Dioxane
DMSO
PhCH3
PhCH3
PhCH3
PhCH3
PhCH3
PhCH3
PhCH3
80
80
80
80
80
80
62
79
80
NR
NR
93
TBHP (8)
TBHP (8)
TBHP (8)
80
−
TBAB (50)
TBAB (50)
100
120
90
aReaction conditions: 1a (8 mmol), 2a (0.4 mmol) for 1 h. bIn respect to 2a. cIsolated yields. d70
e
f
g
wt% t-BuOOH in H2O. Tetrabutylammonium bromide. NR = no reaction. Reaction time of 2
h
i
j
h. N-Bromosuccinimide. Tetrabutylphosphonium bromide. Methyltrioctylammonium chloride.
l
kBenzoyl peroxide. 30wt% H2O2 in H2O. mEntries 17–20: 0.5 mL solvent. n1a (4 mmol). o1a (6
mmol). p1a (10 mmol). qReaction time of 30 min.
With the optimal conditions in hand, various methyl arenes 1 and DAADs 2a,b were
used and the corresponding DAHDs 3a–q were obtained in 75–93% yields. The
results are summarized in Table 2. The reaction of methyl arenes with neutral and
electron-donating substituents such as (one or more) Me and OMe at the meta-, ortho-
and para-positions of the aryl ring with DAADs 2a,b afforded the corresponding
DAHDs 3a–d and 3j–l in 80–93% yields. Also, strong electron-withdrawing nitro
group on meta-position of the methyl arene decreased the yield of the corresponding
5

ACCEPTED MANUSCRIPT
products 3f and 3o, whereas chloro substituent gave 3e, 3m and 3n in 75–85% yields.
The reaction was also carried out by use of methyl heteroarenes with furan and
thiophene rings and methyl naphthalene, which afforded the corresponding products
3g–i, 3p and 3q in 75–92% yields.
Table 2. Substrate scope for the synthesis of DAHDs 3a-r by use of methyl arenes 1a,b
O
CO2R
TBHP (8 equiv.)
TBAB (50 mol%)
RO2C
N
N
N
N H
Ar CH3
+
Ar
80 °C, 1 h
CO2R
CO2R
1
3a-q
2a,b
CO2i-Pr
CO2i-Pr
CO2i-Pr
CO2i-Pr
O
O
O
OMe
O
N
H
N
H
N
H
N
N H
N
N
N
CO2i-Pr
CO2i-Pr
CO2i-Pr
3d, 80%
CO2i-Pr
H3C
MeO
3b, 85%
3a, 93%
Cl
3c, 88%
OMe
O
CO2i-Pr
CO2i-Pr
CO2i-Pr
CO2i-Pr
O
O
N
O
O
N
N
N
N
N
H
N
H
H
N
H
CO2i-Pr
CO2i-Pr
CO2i-Pr
CO2i-Pr
3h, 77%
3e, 85%
3g, 92%
NO2
OMe
3f, 78%
O
CO2Et
O
CO2Et
OMe
O
CO2Et
CO2i-Pr
O
N
N
H
N
N
N
H
N
N
H
N
H
CO2Et
CO2Et
CO2Et
S
MeO
CO2i-Pr
3j, 83%
3k, 90%
CO2Et
OMe
O
3l, 82%
3i, 82%
Cl
O
CO2Et
O
N
CO2Et
O
O
CO2Et
Cl
N
H
N
N
N
H
N
H
N
H
N
CO2Et
3o, 75%
CO2Et
CO2Et
3n, 85%
CO2Et
3m, 81%
3p, 75%
NO2
O
CO2Et
N
H
N
S
CO2Et
3q, 78%
aReaction conditions: DAADs (2, 0.4 mmol), methyl arenes (1, 8 mmol), TBHP (3.2 mmol), TBAB (50
mol%) for 1 h. bIsolated yields.
Encouraged by the above results, we extended the scope of this reaction with
aldehydes as aroylating sources. Thus, the optimal conditions for the reaction
between DAADs 2 and aldehydes 4 leading to 3 were determined: aldehyde 2 equiv.
(in respect to 2), Aliquat 336 (30 mol%) and TBHP (30 mol%.) in chlorobenzene at
40 °C for 2 h (entry 5, Table 3).
6

ACCEPTED MANUSCRIPT
Table 3. Condition screening for the conversion of DAAD 2a to DAHD 3a by use of benzaldehyde 4aa
CO2i-Pr
O
O
CO2i-Pr
Oxidant, additive
solvent
N
N
N
+
Ph
N
H
Ph
H
i-PrO2C
i-PrO2C
4a
3a
2a
Entry
1
2
3
4
Oxidant (mol%)b
TBHPd (0.2)
TBHP (0.2)
TBHP (0.2)
TBHP (0.3)
TBHP (0.3)
TBHP (0.5)
TBHP (1.0)
TBHP (0.3)
TBHP (0.3)
TBHP (0.3)
TBHP (0.3)
TBHP (0.3)
TBHP (0.3)
TBHP (0.3)
TBHP (0.3)
K2S2O8 (0.3)
BPOi (0.3)
Additive (mol%)b
Solvent
PhCl
PhCl
PhCl
PhCl
PhCl
PhCl
PhCl
PhCl
PhCl
PhCl
PhCl
PhCl
PhCl
PhCl
PhCl
PhCl
PhCl
PhCl
PhCl
DCE
PhCH3
DMSO
Temp (ºC) Yield (%)c
18
18
40
40
40
40
40
40
50
70
40
40
40
40
40
40
40
40
40
40
40
40
NRe
NR
40
−
Aliquat 336 (15)
Aliquat 336 (15)
Aliquat 336 (15)
65
5
6
7
8
Aliquat 336 (30)
Aliquat 336 (30)
Aliquat 336 (30)
Aliquat 336 (40)
Aliquat 336 (30)
Aliquat 336 (30)
TBPBf (30)
90
82
80
90
88
78
65
65
NR
NR
NR
25
50
20
10
60
30
NR
9
10
11
12
13
14
15
16
17
18
19
20
21
22
TBABg (30)
TBAIh
KI (30)
I2 (30)
Aliquat 336 (30)
Aliquat 336 (30)
Aliquat 336 (30)
Aliquat 336 (30)
Aliquat 336 (30)
Aliquat 336 (30)
Aliquat 336 (30)
Aliquat 336 (30)
Aliquat 336 (30)
Aliquat 336 (30)
Aliquat 336 (30)
Aliquat 336 (30)
Aliquat 336 (30)
Aliquat 336 (30)
(NH4)2S2O8 (0.3)
j
H2O2 (0.3)
TBHP (0.3)
TBHP (0.3)
TBHP (0.3)
TBHP (0.3)
TBHP (0.3)
TBHP (0.3)
TBHP (0.3)
TBHP (0.3)
TBHP (0.3)
23
24
25
26
27
28
29
30
31k
32l
H2O
THF
40
40
40
40
40
40
40
40
40
40
10
trace
10
60
Trace
20
NR
35
75
DMSO:H2O (1:1)
CH2Cl2
CH3CN
EtOAc
PhCl
PhCl
PhCl
PhCl
−
TBHP (0.3)
TBHP (0.3)
TBHP (0.3)
−
Aliquat 336 (30)
Aliquat 336 (30)
70
aReaction conditions: 1a (1.0 mmol), 2a (0.5 mmol), solvent (1 mL) for 2 h. bIn respect to 2a. cIsolated yields. d70
wt% t-BuOOH in H2O. eNR = no reaction. fTetrabutylphosphonium bromide. gTetrabutylammonium bromide.
hTetrabutyla mmonium iodide. iBenzoyl peroxide. j30 wt% H2O2 in H2O. kRatio 1a:2a (1:1). lRatio 1a:2a (3:1).
To our delight, aldehydes with neutral and electron-donating groups such as 3-Me, 4-
Me, 4-iPr and 3,4-(OMe)2 or electron-withdrawing groups including 2-Cl and 3-Cl
were converted to the desired DAHDs in excellent yields (Table 4).
7

ACCEPTED MANUSCRIPT
Table 4. Hydroaroylation of DAADs 2 with aldehydes 4 promoted by the TBHP/Aliquat 336 systema,b
CO2R
O
O
CO2R
TBHP (30 mol%)
N
N
N
N H
+
Ar
Aliquat 336 (30 mol%)
PhCl, 40 ºC, 2 h
Ar
H
RO2C
CO2R
4
2a,b
3
OMe
O
CO2Et
CO2i-Pr
CO2i-Pr
CO2i-Pr
O
O
N
Cl
O
N
H
N
H
N
N
N
H
N
N
H
CO2Et
CO2i-Pr
CO2i-Pr
CO2i-Pr
H3C
3j, 85%
3e, 87%
3a, 90%
3b, 97%
O
CO2Et
O
CO2Et
CO2i-Pr
CO2i-Pr
O
O
N
H
N
N
N
H
N
N
H
N
H
N
CO2Et
CO2Et
3n, 86%
CO2i-Pr
3r, 94%
MeO
CO2i-Pr
3k, 87%
Cl
3s, 90%
CH3
CO2i-Pr
O
MeO
MeO
N
N
H
CO2i-Pr
3t, 84%
aReaction conditions: DAADs (2, 0.5 mmol), aldehyde (4, 1.0 mmol), TBHP (30 mol%), Aliquat 336 (30 mol%), in
PhCl (1 mL). bIsolated yields.
Next, we were stimulated to examine other approaches for the construction of
DAHDs. The high efficiency of the hydroaroylation reaction with the
azodicarboxylate component prompted us to explore the possibility of employing
simple aryl methanols as hydroaroylating agents. A slightly different optimum
reaction conditions relative to the aldehydes were obtained. The optimal conditions
for the conversion of DAADs 2 to DAHDs 3 by use of aryl methanols 5 as
hydroaroylating agents include: aryl methanol (2 equiv. in respect to 2), TBHP (3
equiv.), 30 mol% of Aliquat 336, in chlrorobenzene at 60 °C for 3 h (entry 6, Table 5)
which afforded the corresponding DAHDs 3 in 77–90% yields (Table 6).
8

ACCEPTED MANUSCRIPT
Table 5. Condition screening for the hydrobenzoylation of 2a with benzyl alcohol 5aa
CO2i-Pr
O
CO2i-Pr
OH
Oxidant, additive
solvent
N
N H
N
N
Ph
i-PrO2C
+
Ph
i-PrO2C
3a
Temp. (ºC)
25
25
60
60
60
60
60
60
80
100
60
60
60
60
60
60
60
60
60
60
60
60
60
60
5a
2a
Entry
1
2
3
4
5
6
7
8
Oxidant (equiv.)b Additive (mol%)b
Solvent
PhCl
PhCl
PhCl
PhCl
PhCl
PhCl
PhCl
PhCl
PhCl
PhCl
PhCl
PhCl
PhCl
PhCl
PhCl
PhCl
PhCl
PhCl
PhCl
DCE
PhCH3
DMSO
H2O
Yield (%)c
NRe
NR
35
68
80
88
78
88
81
TBHPd (1)
−
TBHP (1)
TBHP (1)
TBHP (2)
TBHP (3)
TBHP (3)
TBHP (4)
TBHP (3)
TBHP (3)
TBHP (3)
TBHP (3)
TBHP (3)
TBHP (3)
TBHP (3)
TBHP (3)
K2S2O8 (3)
BPOi (3)
Aliquat 336 (15)
Aliquat 336 (15)
Aliquat 336 (15)
Aliquat 336 (15)
Aliquat 336 (30)
Aliquat 336 (30)
Aliquat 336 (40)
Aliquat 336 (30)
Aliquat 336 (30)
TBPBf (30)
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31k
32l
74
60
60
TBABg (30)
TBAIh
KI (30)
I2 (30)
NR
NR
NR
NR
40
NR
NR
72
Aliquat 336 (30)
Aliquat 336 (30)
Aliquat 336 (30)
Aliquat 336 (30)
Aliquat 336 (30)
Aliquat 336 (30)
Aliquat 336 (30)
Aliquat 336 (30)
Aliquat 336 (30)
Aliquat 336 (30)
Aliquat 336 (30)
Aliquat 336 (30)
Aliquat 336 (30)
Aliquat 336 (30)
(NH4j)2S2O8 (3)
H2O2 (3)
TBHP (3)
TBHP (3)
TBHP (3)
TBHP (3)
TBHP (3)
TBHP (3)
TBHP (3)
TBHP (3)
TBHP (3)
−
25
NR
NR
NR
NR
NR
55
NR
NR
NR
53
THF
DMSO:H2O (1:1) 60
CH2Cl2
CH3CN
EtOAc
PhCl
PhCl
PhCl
60
60
60
60
60
60
60
TBHP (3)
TBHP (3)
TBHP (3)
−
Aliquat 336 (30)
Aliquat 336 (30)
PhCl
66
aReaction conditions: 1a (1.0 mmol), 2a (0.5 mmol), solvent (1 mL) for 3 h. bIn respect to 2a. cIsolated yields. d70
wt% t-BuOOH in H2O. eNR = no reaction. fTetrabutylphosphonium bromide. gTetrabutylammonium bromide.
hTetrabutylammonium iodide. iBenzoyl peroxide. j30 wt% H2O2 in H2O. kRatio 1a:2a (1:1). lRatio 1a:2a (3:1).
9

ACCEPTED MANUSCRIPT
Table 6. Hydroaroylation of DAADs 2 with aryl methanols 5 promoted by the TBHP/Aliquat 336
systema,b
CO2R
O
CO2R
OH
TBHP (3 equiv.)
N
N
N
+
Ar
N
H
Aliquat 336 (30 mol%)
PhCl, 60 ºC, 3 h
Ar
RO2C
CO2R
3
5
2a,b
CO2i-Pr
CO2i-Pr
CO2i-Pr
CO2i-Pr
O
O
Cl
O
O
N
H
N
N
N
H
N
N
N
H
N
H
CO2i-Pr
CO2i-Pr
CO2i-Pr
CO2i-Pr
MeO
MeO
H3C
3c, 82%
3e, 81%
OMe
3a, 88%
3b, 90%
CO2Et
OMe
O
O
CO2Et
O
CO2Et
CO2i-Pr
O
N
N
N
N
N
H
N
H
N
H
N
H
CO2Et
CO2Et
CO2Et
OMe 3l, 79%
S
CO2i-Pr
3j, 81%
3k, 80%
3i, 83%
O
CO2Et
CO2i-Pr
CO2i-Pr
CO2i-Pr
O
O
O
N
N
N
MeO
N
H
N
N
H
H
N
N
H
O
CO2Et
CO2
i
-Pr
CO2i-Pr
CO2i-Pr
MeO
3p, 77%
3t, 86%
3s, 82%
CH3
3r, 86%
O
CO2Et
O
CO2Et
O
N
CO2Et
N
H
N
H
N
N
N
H
CO2Et
CO2Et
Cl
CO2Et
3v, 77%
CH3
3u, 84%
3w, 86%
aReaction conditions: DAADs (2, 0.5 mmol), aryl methanol (5, 1.0 mmol), TBHP (1.5 mmol), Aliquat 336 (30
mol%), in PhCl (1 mL).
bIsolated yields.
To develop a more general and useful method, we subsequently turned our attention
to investigate the hydroaroylation reaction between arylmethyl chlorides 6 and
DAADs 2 under the TBHP/Aliquat 336 optimized conditions (entry 4, Table 7). This
hydroaroylation methodology is correspondingly compatible with various substituted
arylmethyl chlorides providing DAHDs 3 in 67–83% yields (Table 8).
10

ACCEPTED MANUSCRIPT
Table 7. Optimization of the reaction conditions for the formation of DAHD 3a by use of benzyl chloride
6aa
CO2i-Pr
O
CO2i-Pr
Cl
Oxidant, additive
solvent, base
N
N
N
Ph
N
H
+
i-PrO2C
i-PrO2C
3a
6a
Oxidant (equiv)b
TBHPd (10)
TBHP (10)
TBHP (10)
TBHP (10)
TBHP (10)
TBHP (10)
TBHP(10)
2a
Entry
1
2
3
4
5
6
7
8
Additive (mol%)b Base (eq.)b
Solvent
T (°C)
120
120
120
120
120
120
120
120
120
120
120
120
120
120
120
120
120
120
80
Yieldc %
NRf
NR
NR
83
79
63
55
30
NR
NR
NR
NR
11
trace
NR
68
TBABe(20)
K2CO3 (0.5)
K2CO3(0.5)
K2CO3 (0.5)
K2CO3 (0.5)
KHCO3 (0.5)
Na2CO3 (0.5)
Cs2CO3 (0.5)
K2CO3 (0.5)
K2CO3 (0.5)
K2CO3 (0.5)
K2CO3 (0.5)
K2CO3 (0.5)
K2CO3 (0.5)
K2CO3 (0.5)
K2CO3 (0.5)
K2CO3 (0.5)
K2CO3 (0.5)
PhCl
PhCl
PhCl
PhCl
PhCl
PhCl
PhCl
DCE
DMF
CH3CN
EtOH
DMSO
PhCl
PhCl
PhCl
PhCl
PhCl
PhCl
PhCl
PhCl
TBPBg(20)
TBAIh (20)
Aliquat 336i (20)
Aliquat 336 (20)
Aliquat 336 (20)
Aliquat 336 (20)
Aliquat 336 (20)
Aliquat 336 (20)
Aliquat 336 (20)
Aliquat 336 (20)
Aliquat 336 (20)
Aliquat 336 (20)
Aliquat 336 (20)
Aliquat 336 (20)
Aliquat 336 (20)
−
TBHP (10)
TBHP (10)
TBHP (10)
TBHP (10)
TBHP (10)
TBHP (5)
9
10
11
12
13
14
15
16k
17
18
19l
20m
j
H2O2 (10)
K2S2O8 (10)
TBHP (10)
TBHP (10)
TBHP (10)
TBHP (10)
TBHP (10)
20
11
53
Aliquat 336 (20)
Aliquat 336 (20)
Aliquat 336 (20)
−
K2CO3 (0.5)
K2CO3 (0.5)
100
76
b
c
d
aReaction conditions: 6a (1.5 mmol), 2a (0.3 mmol) for 3 h. In respect to 2a. Isolated yields. 70 wt% t-
e
f
g
BuOOH in H2O. Tetrabutylammonium bromide. NR = No reaction. Tetrabutylphosphonium bromide.
hTetrabutylammonium iodide. iTricaprylmethylammonium chloride. j30wt% H2O2 in H2O. 6a (0.9 mmol).
k
lReaction temperature of 80 °C. mReaction temperature of 100 °C.
11

ACCEPTED MANUSCRIPT
Table 8. Hydroaroylation of DAADs 2 with arylmethyl chlorides 6 promoted by the TBHP/Aliquat
336 systema,b
CO2R
O
CO2R
Cl
N
N
TBHP (10 equiv.)
N
Ar
N
H
+
Ar
Aliquat 336 (20 mol%)
K2CO3 (0.5 equiv.)
RO2C
CO2R
PhCl, 120 ºC, 3 h
3
6
2a,b
CO2i-Pr
CO2i-Pr
CO2i-Pr
CO2i-Pr
O
O
O
O
N
N
N
N
H
N
H
H
N
H
N
N
CO2i-Pr
CO2i-Pr
CO2i-Pr
CO2i-Pr
MeO
3c, 78%
3a, 83%
3g, 81%
NO2
Cl
3f, 67%
OMe
O
CO2Et
O
CO2Et
O
CO2Et
CO2i-Pr
O
Cl
N
N
N
H
N
N
N
H
N
H
N
H
CO2Et
3m, 74%
CO2Et
CO2Et
O
CO2i-Pr
3n, 76%
OMe 3l, 75%
3h, 70%
O
CO2Et
O
CO2Et
O
CO2Et
O
CO2Et
N
H
N
N
H
N
N
N
H
N
N
H
CO2Et
CO2Et
CO2Et
CO2Et
Cl
H3C
3v, 75%
3x, 82%
CH3 3u, 76%
3w, 81%
aReaction conditions: DAADs (2, 0.3 mmol), arylmethyl chloride (6, 1.5 mmol), TBHP (3.0 mmol), Aliquat
336 (20 mol%), K2CO3 (0.15 mmol) in PhCl (1 mL).
bIsolated yields.
Under the optimized conditions (Tables 2, 4, 6 and 8), addition of the radical
scavenger 2,2,6,6-tetramethylpiperidinyloxy (TEMPO) to the reaction mixtures of the
hydrobenzoylating reagents 1a, 4a, 5a or 6a with DAAD 2a, hydrobenzoylated
product 3a was not detected (Eq. I). Torii and Anelli have reported that some TEMPO
derivatives were converted to their N-oxoammonium salts in the presence of an
oxidizing reagent (NaBrO2 or NaOCl/KBr co-catalyst) in a pH 8.6 buffer (using aq.
NaHCO3 solution), which oxidized alcohols to the corresponding carbonyl
compounds.27 However, when benzyl alcohol 5a was subjected to TEMPO and
Aliquat 336 under the standard reaction conditions (Table 6) in the absence of TBHP,
benzaldehyde 4a was not observed. (Eq. II). Thus, to sum up, according to these
results and the reported articles, the reactions probably occur via radical mechanisms
(Scheme 2).28
12

ACCEPTED MANUSCRIPT
TBHP (8 equiv.)
TBAB (50 mol%)
PhCH3
TEMPO (2 equiv.)
80 ºC, 1 h
1a
TBHP (30 mol%)
Aliquat 336 (30 mol%)
CO2i-Pr
O
PhCHO
TEMPO (2 equiv.)
PhCl, 40 ºC, 2 h
4a
N
H
i-PrO2C
N
N
N
(I)
+
TBHP (3 equiv.)
Aliquat 336 (30 mol%)
CO2i-Pr
3a, was not detected
CO2i-Pr
2a
PhCH2OH
TEMPO (2 equiv.)
5a
PhCl, 60 ºC, 3 h
TBHP (10 equiv.)
Aliquat 336 (20 mol%)
K2CO3 (0.5 equiv.)
PhCH2Cl
TEMPO (2 equiv.)
PhCl, 120 ºC, 3 h
6a
O
TEMPO (2 equiv.)
H
OH
(II)
Aliquat 336 (30 mol%)
PhCl, 60 ºC, 3 h
5a
4a, was not detected
Scheme 2 Control experiments
GC-Mass analyses of the reaction mixtures of toluene 1a, benzyl alcohol 5a and
benzyl chloride 6a under the related optimum conditions confirmed the presence of
benzaldehyde in the mixtures. As another control experiment, the reactions of 1a, 5a
and 6a with TBHP/TBAB or -/Aliquat 336 in the absence of DAAD 2 were
examined, all of which gave benzaldehyde confirming the formation of benzoyl
radical through all these reactions.
On the bases of these experimental results, a tentative reaction mechanism is proposed
in Scheme 3. Initially, tetrabutylammonium hypobromite (n-Bu4N+[BrO]–) A or
tetrabutylammonium bromite (n-Bu4N+[BrO2]–) A′ species could be generated
through the reaction between TBHP and TBAB.6e,6h,6m,29 Then, toluene 1a may be
oxidized by A or A′ to benzoyl radical B via benzaldehyde 4a. Benzoyl radical B may
be coupled with DAAD 2 to give hydrazine imide radical C. Finally, hydrogen
abstraction of C from benzaldehyde 4a produces DAHD 3 by returning benzoyl
radical B to the reaction cycle.
13

ACCEPTED MANUSCRIPT
RO2C
N
N
t-BuOH
t-BuOOH
t-BuOH
2
CO2R
O
_
_
O
.
CO2R
+
+
_
Bu4N [BrO]
Bu4N [BrO]
A
A
Ph
N
N
+
Bu4N Br
or
+
or
Ph
C
_
_
.
+
B
RO2C
Bu4N [BrO2]
Bu4N [BrO2]
A'
A'
O
O
O
.
Ph
CH3
Ph
O
Ph
H
Ph
H
4a
CO2R
1a
4a
B
Ph
RO2C
N
N
3
H
Scheme 3 Proposed mechanism for the formation of DAHD 3 promoted by the
TBHP/TBAB system
We also proposed a mechanism for the formation of benzaldehyde 4a from benzyl
chloride 6a (Scheme 4). The reaction may be initiated by deprotonation of TBHP by
K2CO3 followed by an SN2 attack of the peroxide anion to the benzylic position of
benzyl chloride 6a to produce benzyl (tert-butyl) peroxide D. Peroxide D may be
collapsed under the thermal reaction conditions to form benzaldehyde 4a and tert-
butanol.30 The in situ generated benzaldehyde will form benzoyl radical B, which
could hydroaroylate DAADs according to the outlined mechanism in Scheme 3.
H
t-BuOOH
K2CO3
O
Cl
O
O
HO
+
_
HCl
D
4a
6a
Scheme 4 Suggested mechanism for the conversion of benzyl chloride 6a to
benzaldehyde 4a promoted by the TBHP/K2CO3 system
A plausible reaction mechanism has been provided with regard to aryl methanols,
which may undergo a different process according to the literature (Scheme 5).
Intermediate E may be generated via hydrogen abstraction from benzyl alcohol 5a in
the presence of R4N+[ClO]– A′′ or R4N+[ClO2]– A′′′ species generated under the
reaction conditions.31 Next, radical addition of E to DAAD 2, gives radical species F
(Path i) followed by further oxidation under the reaction conditions which leads to the
14

ACCEPTED MANUSCRIPT
formation of 3. It is also possible that intermediate E undergo hydrogen abstraction
under the reaction condition to produce benzaldehyde 4a32 (Path ii) which in turn can
hydroaroylate DAADs according to the suggested mechanism in Scheme 3.
t-BuOOH
t-BuOH
t-BuOOH
t-BuOH
_
_
+
+
_
_
R4N [ClO]
R4N [ClO]
A''
A''
+
+
R4N Cl
R4N Cl
or
+
or
+
_
_
R4N [ClO2]
R4N [ClO2]
A'''
A'''
Path i
RO2C
OH
O
N
N
CO2R
CO2R
2
.
CO2R
Ph
RO2C
N
N
Ph
RO2C
N
N
OH
OH
Ph
Ph
.
5a
E
3
H
F
Path ii
A'' or A'''
O
H
Ph
4a
Scheme 5 Possible reaction mechanisms for the hydroaroylation of DAADs 2 with
benzyl alcohol 5a promoted by the TBHP/Aliquat 336 system
Providing the utility of the reaction products, hydrazine imide 3a treated with 2-
bromo-4-methyl aniline 7, benzyl alcohol 5a and thiophenol 10, which afforded
amide 8 (80%), benzyl benzoate 9 (76%) and thioester 11 (64%), respectively
(Scheme 6, eqs. I, II and III).
CO2i-Pr
NH2
O
CH3
Br
N
N H
O
Cs2CO3 (1 equiv.)
DMF, r.t., 12 h
Ph
+
(I)
Ph
N
H
CO2i-Pr
Br
CH3
3a (1 mmol)
CO2i-Pr
8, 80%
7 (1 mmol)
HO
O
O
O
N
Cs2CO3 (1 equiv.)
DMF, r.t., 12 h
Ph
N
H
+
(II)
Ph
O
CO2i-Pr
3a (1 mmol)
5a (1 mmol)
9, 76%
CO2i-Pr
SH
O
N
Cs2CO3 (1 equiv.)
DMF, r.t., 16 h
Ph
N
H
(III)
+
Ph
S
CO2i-Pr
3a (1 mmol)
10 (1 mmol)
11, 64%
Scheme 6 Using hydrazine imide 3a for the preparation of amide 8, ester 9 and
thioester 11
15

ACCEPTED MANUSCRIPT
3. Conclusion
In conclusion, efficient methods leading to dialkyl hydrazine-1,2-dicarboxylates have
been developed via TBHP/R4N+X– promoted C(sp3)−H and C(sp2)−H bond
functionalization of ArX (X = CH3, CH2OH, CH2Cl, CHO) with dialkyl
azodicarboxylates. Stable and easily accessible methyl arenes, aryl methanols,
arylmethyl chlorides and aldehydes were used as ideal hydroaroylation reagents, and
TBHP was utilized as an effective oxidant and oxygen source to form the
corresponding hydrazine imides. These methodologies showed high efficiency, short
time, metal-free and mild reaction conditions, operational simplicity, and good to
excellent yields.
4. Experimental
4.1. General
All chemicals were purchased from Merck (Germany) and were used without further
purification. Melting points were measured on an Electrothermal 9100 apparatus and
1
are uncorrected. H and 13C NMR spectra were measured (CDCl3 solution) with
Bruker DPX-250 (at 250.1 and 62.8 MHz, resp.) instrument. Chromatography
columns were prepared from Merck silica gel 230–240 meshes.
4.2. General procedure for synthesis of diisopropyl 1-benzoylhydrazine-1,2-
dicarboxylate (3a): To the mixture of diisopropyl azodicarboxylate 2a (0.4 mmol,
0.08 g) in toluene 1a (8 mmol, 0.74 g), tert-butylhydroperoxide (3.2 mmol, 0.42 g)
and TBAB (0.2 mmol, 0.064 g) was added. The reaction mixture was stirred at 80 °C
under air atmosphere in a sealed tube and the process of the reaction was monitored
by TLC. Upon completion, the reaction mixture was transferred to a round-bottom
flask. The solvent was then removed under vacuum and the residue was purified by
silica gel chromatography, using a mixture of n-hexane/EtOAc (4:1) to afford the
desired product 3a.
4.2.1. Diisopropyl 1-benzoylhydrazine-1,2-dicarboxylate (3a)
1
Yield: 0.114 g (93%); colorless crystal; m.p. 119–121 °C, [lit.21a 115–117 °C]. H
NMR (250.1 MHz, CDCl3): δ 1.07 (d, J = 6.0 Hz, 6H, 2CH3), 1.28 (d, J = 6.1 Hz, 6H,
2CH3), 4.9 (sept, J = 6.2 Hz, 1H, OCH), 5.0 (sept, J = 6.2 Hz, 1H, OCH), 7.15 (br s,
1H, NH), 7.40 (t, J = 7.3 Hz, 2H, 2CH), 7.51 (t, J = 7.2 Hz, 1H, CH), 7.68 (d, J = 6.3
13
Hz, 2H, 2CH). C NMR (62.8 MHz, CDCl3): δ 21.1, 21.8, 70.5, 72.3, 128.0, 128.2,
131.7, 135.1, 152.8, 155.2, 171.1.
16

ACCEPTED MANUSCRIPT
4.2.2. Diisopropyl 1-(4-methylbenzoyl)hydrazine-1,2-dicarboxylate (3b)
1
Yield: 0.109 g (85%); white solid; m.p. 106–108 °C [lit.20 105–107 °C]. H NMR
(250.1 MHz, CDCl3): δ 1.10 (d, J = 5.7 Hz, 6H, 2CH3), 1.27 (d, J = 6.1 Hz, 6H,
2CH3), 2.38 (s, 3H, CH3), 4.90 (sept, J = 6.2 Hz, 1H, OCH), 5.00 (sept, J = 6.2 Hz,
13
1H, OCH), 7.18 (s, 1H, NH), 7.22 (s, 2H, 2CH), 7.59 (d, J = 6.6 Hz, 2H, 2CH). C
NMR (62.8 MHz, CDCl3): δ 21.2, 21.5, 21.8, 70.4, 72.2, 128.3, 128.6, 132.0, 142.6,
153.0, 155.2, 171.1.
4.2.3. Diisopropyl 1-(4-methoxybenzoyl)hydrazine-1,2-dicarboxylate (3c)
1
Yield: 0.119 g (88%); white solid; m.p. 85–86 °C [lit.21a colorless oil]. H NMR
(250.1 MHz, CDCl3): δ 1.11 (d, J = 5.6 Hz, 6H, 2CH3), 1.26 (d, J = 5.8 Hz, 6H,
2CH3), 3.83 (s, 3H, OCH3), 4.85–5.03 (m, 2H, 2OCH), 6.89 (d, J = 8.5 Hz, 2H, 2CH),
13
7.27 (s, 1H, NH), 7.70 (d, J = 5.6 Hz, 2H, 2CH). C NMR (62.8 MHz, CDCl3): δ
21.3, 21.8, 55.3, 70.4, 72.1, 113.3, 130.9, 132.1, 153.1, 155.4, 162.8, 170.4.
4.2.4. Diisopropyl 1-(2,5-dimethoxybenzoyl)hydrazine-1,2-dicarboxylate (3d)
Yield: 0.118 g (80%); colorless oil. 1H NMR (250.1 MHz, CDCl3): δ 1.07 (d, J = 5.3
Hz, 6H, 2CH3), 1.21 (d, J = 6.2 Hz, 6H, 2CH3), 3.70 (s, 3H, OCH3), 3.71 (s, 3H,
OCH3), 4.80–4.98 (m, 2H, 2OCH), 6.76 (d, J = 9.0 Hz, 1H, CH), 6.91 (dd, J = 7.5, 2.9
13
Hz, 1H, CH), 6.96 (s, 1H, NH), 7.28 (d, J = 2.0 Hz, 1H, CH). C NMR (62.8 MHz,
CDCl3): δ 21.2, 21.7, 55.6, 56.0, 70.1, 72.0, 111.9, 113.6, 117.4, 125.7, 150.0, 152.1,
153.2, 155.0, 167.8. Anal. Calcd for C17H24N2O7 (368.39): C, 55.43; H, 6.57; N, 7.60.
Found: C, 55.28; H, 6.45; N, 7.49%.
4.2.5. Diisopropyl 1-(2-chlorobenzoyl)hydrazine-1,2-dicarboxylate (3e)
Yield: 0.116 g (85%); white crystal; m.p. 119–120 °C. 1H NMR (250.1 MHz, CDCl3):
δ 1.09 (s, 6H, 2CH3), 1.29 (d, J = 6.2 Hz, 6H, 2CH3), 4.86–5.07 (m, 2H, 2OCH), 7.02
(br s, 1H, NH), 7.33–7.48 (m, 4H, 4CH). 13C NMR (62.8 MHz, CDCl3): δ 21.1, 21.7,
70.6, 72.6, 126.5, 127.8, 129.2, 130.8, 131.2, 136.0, 151.5, 154.9, 168.4. Anal. Calcd
for C15H19ClN2O5 (342.78): C, 52.56; H, 5.59; N, 8.17. Found: C, 52.43; H, 5.64; N,
8.04%.
4.2.6. Diisopropyl 1-(3-nitrobenzoyl)hydrazine-1,2-dicarboxylate (3f)
1
Yield: 0.110 g (78%); white crystsal; m.p. 116–118 °C [lit.33 114–116 °C]. H NMR
(250.1 MHz, CDCl3): δ 1.15 (d, J = 5.9 Hz, 6H, 2CH3), 1.30 (d, J = 6.2 Hz, 6H,
2CH3), 4.88–5.06 (m, 2H, 2OCH), 7.21 (s, 1H, NH), 7.63 (t, J = 7.8 Hz, 1H, CH),
8.01 (d, J = 6.1, 1H, CH), 8.36 (d, J = 8.1, 1H, CH), 8.48 (s, 1H, CH). 13C NMR (62.8
17

ACCEPTED MANUSCRIPT
MHz, CDCl3): δ 21.3, 21.8, 70.9, 73.0, 122.9, 126.0, 129.3, 133.6, 136.6, 147.6,
152.3, 155.0, 168.8.
4.2.7. Diisopropyl 1-(1-naphthoyl)hydrazine-1,2-dicarboxylate (3g)
Yield: 0.132 g (92%); white solid; m.p. 122–124 °C.34 1H NMR (250.1 MHz, CDCl3):
δ 0.68 (d, J = 5.2 Hz, 6H, 2CH3), 1.35 (d, J = 6.2 Hz, 6H, 2CH3), 4.69 (sept, J = 6.1
Hz, 1H, OCH), 5.09 (sept, J = 6.1 Hz, 1H, OCH), 7.21 (s, 1H, NH), 7.44–7.54 (m,
4H, 4CH), 7.66 (d, J = 5.8 Hz, 1H, CH), 7.86–7.95 (m, 2H, 2CH), 8.20 (d, J = 6.7 Hz,
1H, CH). 13C NMR (62.8 MHz, CDCl3): δ 20.7, 21.9, 70.6, 72.2, 124.5, 124.6, 126.3,
127.2, 128.1, 129.8, 130.4, 133.0, 134.0, 152.0, 155.3, 170.4. Anal. Calcd for
C19H22N2O5 (358.39): C, 63.68; H, 6.19; N, 7.82. Found: C, 63.74; H, 6.01; N, 7.58%.
4.2.8. Diisopropyl 1-(furan-2-carbonyl)hydrazine-1,2-dicarboxylate (3h)
1
Yield: 0.092 g (77%); white solid; m.p. 94–95 °C. H NMR (250.1 MHz, CDCl3): δ
1.23 (d, J = 6.1 Hz, 12H, 4CH3), 4.93–5.06 (m, 2H, 2OCH), 6.51 (dd, J = 3.5, 1.6 Hz,
1H, CH), 7.12 (s, 1H, NH), 7.20 (d, J = 3.3 Hz, 1H, CH), 7.56 (s, 1H, CH). 13C NMR
(62.8 MHz, CDCl3): δ 21.4, 21.7, 70.5, 72.4, 112.0, 119.2, 145.9, 152.5, 155.2, 159.2.
Anal. Calcd for C13H18N2O6 (298.30): C, 52.35; H, 6.08; N, 9.39. Found: C, 52.33; H,
5.91; N, 9.12%.
4.2.9. Diisopropyl 1-(thiophene-2-carbonyl)hydrazine-1,2-dicarboxylate (3i)
1
Yield: 0.103 g (82%); pale yellow oil, [lit.21a orange oil]. H NMR (250.1 MHz,
CDCl3): δ 1.01–1.11 (m, 12H, 4CH3), 4.74–4.88 (m, 2H, 2OCH), 6.90 (s, 1H, NH),
13
7.44 (d, J = 4.3 Hz, 1H, CH), 7.72 (d, J = 3.6 Hz, 1H, CH), 8.17 (s, 1H, CH). C
NMR (62.8 MHz, CDCl3): δ 21.2, 21.6, 70.3, 72.2, 126.9, 133.6, 134.3, 135.4, 152.3,
155.6, 162.5.
4.2.10. Diethyl 1-(2-methoxybenzoyl)hydrazine-1,2-dicarboxylate (3j)
Yield: 0.103 g (83%); cream oil. 1H NMR (250.1 MHz, CDCl3): δ 1.01–1.20 (m, 6H,
2CH3), 3.74 (s, 3H, OCH3), 4.06–4.14 (m, 4H, 2OCH2), 6.83 (d, J = 8.3 Hz, 1H, CH),
6.92 (d, J = 7.5 Hz, 1H, CH), 7.36 (m, 2H, 2CH), 7.55 (br s, 1H, NH). 13C NMR (62.8
MHz, CDCl3): δ 13.5, 14.2, 55.5, 62.2, 63.6, 110.5, 120.4, 128.7, 131.9, 134.4, 155.5,
155.9, 162.9, 168.1. Anal. Calcd for C14H18N2O6 (310.31): C, 54.19; H, 5.85; N, 9.03.
Found: C, 54.00; H, 5.86; N, 8.86%.
4.2.11. Diethyl 1-(4-methoxybenzoyl)hydrazine-1,2-dicarboxylate (3k)
1
Yield: 0.111 g (90%); colorless oil, [lit.19 colorless oil]. H NMR (250.1 MHz,
CDCl3): δ 1.07 (t, J = 6.8 Hz, 3H, CH3), 1.21 (t, J = 6.7 Hz, 3H, CH3), 3.77 (s, 3H,
OCH3), 4.07–4.20 (m, 4H, 2OCH2), 6.84 (d, J = 8.7 Hz, 2H, 2CH), 7.65 (d, J = 8.0
18

ACCEPTED MANUSCRIPT
13
Hz, 2H, 2CH), 7.80 (s, 1H, NH). C NMR (62.8 MHz, CDCl3): δ 13.7, 14.2, 55.3,
62.3, 63.7, 113.3, 130.9, 131.9, 153.7, 155.8, 162.8, 170.4.
4.2.12. Diethyl 1-(2,5-dimethoxybenzoyl)hydrazine-1,2-dicarboxylate (3l)
Yield: 0.112 g (82%); cream oil. 1H NMR (250.1 MHz, CDCl3): δ 0.94 (t, J = 6.2 Hz,
3H, CH3), 1.09 (t, J = 7.1 Hz, 3H, CH3), 3.58 and 3.60 (s, 6H, 2OCH3), 3.95–4.10 (m,
4H, 2CH2), 6.68 (d, J = 9 Hz, 1H, CH), 6.78 (d, J = 2.8 Hz, 1H, CH), 6.85 (d, J =
11.5 Hz, 1H, CH), 7.88 (s, 1H, NH). 13C NMR (62.5 MHz, CDCl3): δ 13.4, 14.0,
55.4, 56.0, 62.0, 63.5, 111.9, 113.7, 117.2, 125.4, 150.0, 152.7, 153.1, 155.5, 167.7.
Anal. Calcd for C15H20N2O7 (340.33): C, 52.94; H, 5.92; N, 8.23. Found: C, 52.82; H,
5.85; N, 8.05%.
4.2.13. Diethyl 1-(2-chlorobenzoyl)hydrazine-1,2-dicarboxylate (3m)
1
Yield: 0.102 g (81%); colorless oil, [lit.19 colorless oil]. H NMR (250.1 MHz,
CDCl3): δ 1.07 (t, J = 6.6 Hz, 3H, CH3), 1.27 (t, J = 7.1 Hz, 3H, CH3), 4.15 (q, J =
7.07 Hz, 2H, CH2), 4.23 (q, J = 7.1 Hz, 2H, CH2), 7.26–7.40 (m, 5H, 4CH and NH).
13C NMR (62.5 MHz, CDCl3): δ 13.5, 14.2, 62.6, 64.1, 126.6, 127.8, 129.2, 130.9,
131.7, 135.6, 152.2, 155.3, 170.1.
4.2.14. Diethyl 1-(3-chlorobenzoyl)hydrazine-1,2-dicarboxylate (3n)
1
Yield: 0.107 g (85%); white solid; m.p. 83–85 °C. H NMR (250.1 MHz, CDCl3): δ
1.12 (t, J = 6.9 Hz, 3H, CH3), 1.30 (t, J = 7.1 Hz, 3H, CH3), 4.14–4.29 (m, 4H,
2OCH2), 7.28–7.65 (m, 5H, 4CH and NH). 13C NMR (62.8 MHz, CDCl3): δ 13.6,
14.2, 62.7, 64.1, 126.0, 127.9, 129.4, 131.8, 133.4, 134.1, 153.0, 155.5, 169.7. Anal.
Calcd for C13H15ClN2O5 (314.73): C, 49.61; H, 4.80; N, 8.90. Found: C, 49.44; H,
4.63; N, 8.75%.
4.2.15. Diethyl 1-(3-nitrobenzoyl)hydrazine-1,2-dicarboxylate (3o)
1
Yield: 0.098 g (75%); white solid; m.p. 83–85 °C. H NMR (250.1 MHz, CDCl3): δ
1.17 (t, J = 7.0 Hz, 3H, CH3), 1.31 (t, J = 7.0 Hz, 3H, CH3), 4.20–4.32 (m, 4H,
2OCH2), 7.36 (s, 1H, NH), 7.64 (t, J = 7.9 Hz, 1H, CH), 7.99 (d, J = 6.7 Hz, 1H, CH),
8.37 (d, J = 8.1 Hz, 1H, CH) 8.49 (s, 1H, CH). 13C NMR (62.8 MHz, CDCl3): δ 13.7,
14.2, 62.9, 64.4, 122.9, 126.1, 129.3, 133.6, 136.3, 147.7, 152.9, 155.4, 170.8. Anal.
Calcd for C13H15N3O7 (325.28): C, 48.00; H, 4.65; N, 12.92. Found: C, 47.88; H,
4.39; N, 12.84%.
4.2.16. Diethyl 1-(furan-2-carbonyl)hydrazine-1,2-dicarboxylate (3p)
Yield: 0.081 g (75%); pale yellow oil.35 1H NMR (250.1 MHz, CDCl3): δ 1.10–1.26
(m, 6H, 2CH3), 4.07–4.24 (m, 4H, 2CH2), 6.46 (s, 1H, CH), 7.16 (d, J = 2.9 Hz, 1H,
19

ACCEPTED MANUSCRIPT
CH), 7.51 (s, 1H, NH), 7.73 (s, 1H, CH). 13C NMR (62.5 MHz, CDCl3): δ 13.8, 14.1,
62.4, 63.9, 112.0, 119.4, 146.0, 146.2, 153.1, 155.7, 158.9. Anal. Calcd for
C11H14N2O6 (270.24): C, 48.89; H, 5.22; N, 10.37. Found: C, 48.73; H, 5.05; N,
10.08%.
4.2.17. Diethyl 1-(thiophene-2-carbonyl)hydrazine-1,2-dicarboxylate (3q)
1
Yield: 0.089 g (78%); colorless oil, [lit.19 colorless oil]. H NMR (250.1 MHz,
CDCl3): δ 1.24–1.29 (m, 6H, 2CH3), 4.21–4.33 (m, 4H, 2OCH2), 7.07 (d, J = 4.4 Hz,
1H, CH), 7.54 (s, 1H, NH), 7.59 (d, J = 4.9 Hz, 1H, CH), 7.87 (d, J = 3.7 Hz, 1H,
CH). 13C NMR (62.8 MHz, CDCl3): δ 13.9, 14.2, 62.8, 64.2, 127.1, 133.6, 133.8,
135.6, 153.8, 155.8, 162.5.
4.2.18. Diisopropyl 1-(3-methylbenzoyl)hydrazine-1,2-dicarboxylate (3r)
Yield: 0.138 g (86%); colorless crystal; m.p. 101–103 °C [lit.2 102–104 °C]. 1H NMR
(250.1 MHz, CDCl3): δ 1.07 (d, J = 5.8 Hz, 6H, 2CH3), 1.29 (d, J = 6.1 Hz, 6H,
2CH3), 2.37 (s, 3H, CH3), 4.90 (sept, J = 6.2 Hz, 1H, OCH), 5.01 (sept, J = 6.2 Hz,
13
1H, OCH), 7.09 (s, 1H, NH), 7.30 (d, J = 6.2 Hz, 2H, 2CH), 7.49 (s, 2H, 2CH). C
NMR (62.8 MHz, CDCl3): δ 21.1, 21.2, 21.8, 70.5, 72.2, 125.2, 127.9, 128.5, 132.5,
135.0, 137.8, 152.8, 155.2, 171.0.
4.2.19. Diisopropyl 1-(4-isopropylbenzoyl)hydrazine-1,2-dicarboxylate (3s)
1
Yield: 0.144 g (82%); white solid; m.p. 104–106 °C [lit.20 105–107 °C]. H NMR
(250.1 MHz, CDCl3): δ 0.89 (d, J = 5.8 Hz, 6H, 2CH3), 1.07 (d, J = 6.8 Hz, 12H,
4CH3), 2.76 (sept, J = 6.8 Hz, 1H, CH), 4.73 (sept, J = 6.0 Hz, 1H, OCH), 4.84 (sept,
J = 6.2 Hz, 1H, OCH), 7.08 (t, J = 8.1 Hz, 2H, 2CH), 7.47 (d, J = 7.6 Hz, 2H, 2CH),
13
8.23 (s, 1H, NH). C NMR (62.8 MHz, CDCl3): δ 20.9, 21.5, 23.4, 33.9, 69.8, 71.8,
125.8, 126.1, 128.3, 132.5, 152.9, 155.5, 171.0.
4.2.20. Diisopropyl 1-(3,4-dimethoxybenzoyl)hydrazine-1,2-dicarboxylate (3t)
Yield: 0.158 g (86%); white crystal; m.p. 110–112 °C. 1H NMR (250.1 MHz, CDCl3):
δ 1.13 (d, J = 6.1 Hz, 6H, 2CH3), 1.26 (d, J = 6.1 Hz, 6H, 2CH3), 3.88 (s, 3H, OCH3),
3.90 (s, 3H, OCH3), 4.83–5.06 (m, 2H, 2OCH), 6.85 (d, J = 8.3 Hz, 1H, CH), 7.18 (s,
1H, CH), 7.28 (s, 1H, NH), 7.37 (d, J = 6.4 Hz, 1H, CH). 13C NMR (62.8 MHz,
CDCl3): δ 21.3, 21.8, 55.8, 55.9, 70.3, 72.1, 109.9, 111.4, 122.9, 126.8, 148.4, 152.5,
153.2, 155.3, 170.6. Anal. Calcd for C17H24N2O7 (368.39): C, 55.43; H, 6.57; N, 7.60.
Found: C, 55.14; H, 6.36; N, 7.45%.
4.2.21. Diethyl 1-(3-methylbenzoyl)hydrazine-1,2-dicarboxylate (3u)
20

ACCEPTED MANUSCRIPT
1
Yield: 0.124 g (84%); white solid; m.p. 71–73 °C, [lit.19 colorless oil]. H NMR
(250.1 MHz, CDCl3): δ 1.08 (t, J = 7.0 Hz, 3H, CH3), 1.30 (t, J = 7.1 Hz, 3H, CH3),
2.38 (s, 3H, CH3), 4.11–4.29 (m, 4H, 2OCH2), 7.21 (br s, 1H, NH), 7.31 (d, J = 7.2
13
Hz, 2H, 2CH), 7.50 (s, 2H, 2CH). C NMR (62.8 MHz, CDCl3): δ 13.6, 14.2, 21.1,
62.5, 63.8, 125.2, 127.9, 128.5, 132.7, 134.6, 137.9, 153.4, 155.5, 170.0.
4.2.22. Diethyl 1-(4-chlorobenzoyl)hydrazine-1,2-dicarboxylate (3v)
1
Yield: 0.121 g (77%); white solid; m.p. 83–85 °C. H NMR (250.1 MHz, CDCl3): δ
1.12 (t, J = 6.9 Hz, 3H, CH3), 1.28 (t, J = 7.0 Hz, 3H, CH3), 4.16 (q, J = 7.0 Hz, 2H,
CH2), 4.23 (q, J = 7.1 Hz, 2H, CH2), 7.37 (s, 1H, NH), 7.40 (s, 2H, 2CH), 7.62 (d, J =
7.7 Hz, 2H, 2CH). 13C NMR (62.5 MHz, CDCl3): δ 13.7, 14.2, 62.6, 64.0, 128.3,
129.5, 132.9, 138.2, 153.2, 155.6, 170.1. Anal. Calcd for C13H15ClN2O5 (314.73): C,
49.61; H, 4.80; N, 8.90. Found: C, 49.53; H, 4.66; N, 8.68%.
4.2.23. Diethyl 1-(1-naphthoyl)hydrazine-1,2-dicarboxylate (3w)
Yield: 0.142 g (86%); white solid; m.p. 88–90 °C.34 1H NMR (250.1 MHz, CDCl3): δ
0.73 (t, J = 6.2 Hz, 3H, CH3), 1.34 (t, J = 7.0 Hz, 3H, CH3), 3.93 (q, J = 6.5 Hz, 2H,
OCH2), 4.32 (q, J = 7.0 Hz, 2H, OCH2), 7.35 (s, 1H, NH), 7.44–7.65 (m, 4H, 4CH),
7.86–7.96 (m, 2H, 2CH), 8.20 (d, J = 6.4 Hz, 1H, CH). 13C NMR (62.8 MHz, CDCl3):
δ 13.2, 14.3, 62.7, 63.8, 124.5, 124.8, 126.3, 127.3, 128.2, 129.7, 130.6, 133.0, 133.5,
152.6, 155.6, 170.3. Anal. Calcd for C17H18N2O5 (330.34): C, 61.81; H, 5.49; N, 8.48.
Found: C, 61.67; H, 5.26; N, 8.37%.
4.2.24. Diethyl 1-(4-methylbenzoyl)hydrazine-1,2-dicarboxylate (3x)
1
Yield: 0.072 g (82%); white solid; m.p. 67–69 °C. H NMR (250.1 MHz, CDCl3): δ
1.11 (t, J = 7.0 Hz, 3H, CH3), 1.29 (t, J = 7.0 Hz, 3H, CH3), 2.40 (s, 3H, CH3), 4.17
(q, J = 7.1 Hz, 2H, OCH2), 4.24 (q, J = 7.1 Hz, 2H, OCH2), 7.22 (d, J = 7.9 Hz, 2H,
2CH), 7.28 (s, 1H, NH), 7.61 (d, J = 7.4 Hz, 2H, 2CH). 13C NMR (62.8 MHz,
CDCl3): δ 13.7, 14.2, 21.5, 62.5, 63.8, 128.4, 128.7, 131.6, 142.8, 153.5, 155.6, 170.9.
Anal. Calcd for C14H18N2O5 (294.31): C, 57.14; H, 6.16; N, 9.52. Found: C, 56.91; H,
6.89; N, 9.35%.
Acknowledgement
This research was supported by the Research Council of University of Tehran.
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