Copper(I) iodide catalyzed formation of aryl hydrazides from a mitsunobo reagent and aryl halides

Article abstract of DOI:10.1055/s-0030-1260802

The Mitsonubo reagent (triphenylphosphine and dialkyl azodicarboxylates) was employed as a potential anionic nucleophile in a reaction involving aryl halides to produce aryl hydrazides. Aryl iodides and bromides, with electron-withdrawing as well as electron-releasing groups on the aromatic ring, undergo coupling reactions in good yields. The optimized conditions are developed for aryl iodides at room temperature and for aryl bromides at 60-75C. Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0030-1260802

LETTER
1745
Copper(I) Iodide Catalyzed Formation of Aryl Hydrazides from a Mitsunobo
Reagent and Aryl Halides
C
opper(
I
s
)
Iodide
C
s
atalyzed F
a
ormation of
Aryl
Y
H
ydrazides avari,* Majid Ghazanfarpour-Darjani, Yazdan Solgi, Salome Ahmadian
Chemistry Department, Tarbiat Modares University, PO Box 14115-175, Tehran, Iran
Fax +98(21)82883455; E-mail: yavarisa@modares.ac.ir
Received 10 February 2011
Table 1 Optimization Reaction Conditions for the Formation of
Aryl Hydrazides from Aryl Iodides, Ph3P, and DAAD
Abstract: The Mitsonubo reagent (triphenylphosphine and dialkyl
azodicarboxylates) was employed as a potential anionic nucleophile
in a reaction involving aryl halides to produce aryl hydrazides. Aryl
iodides and bromides, with electron-withdrawing as well as elec-
tron-releasing groups on the aromatic ring, undergo coupling reac-
tions in good yields. The optimized conditions are developed for
aryl iodides at room temperature and for aryl bromides at 60–75 °C.
Catalyst Solvent
Yield (%) Catalysta Solvent Yield (%)b
CuI
CuI
CuI
CuI
CuI
CuI
DMSO
DMF
65
55
15
92
78
46
Cu
THF
THF
THF
THF
THF
n.r.
72
CuCl
toluene
THF
CuBr
Cu2O
Cu(OAc)2
20
Key words: aryl iodide, aryl bromide, Mitsonubo reagent, aryl
hydrazide, copper(I) iodide
35
MeCN
dioxane
trace
Aryl hydrazides are important subunits in a wide range of
pharmaceuticals and bioactive agents.1,2 Dialkyl azodicar-
boxylates (DAAD) have been used in the preparation of
hydrazides,3 which are useful precursors in the synthesis
of amines.4 New methods such as amination of aryl Grig-
nard reagents,5 aryllithium reagents,6 and aryl zinc
halides7 with DAAD have been developed for the synthe-
CuCl2
CuIc
THF
THF
trace
80
a 10 mol% catalyst unless stated otherwise.
b Reaction time16 h.
c 5 mol% catalyst, reaction time was 24 h.
sis of hydrazides. However, these reactions are limited to Subsequently, a variety of substituted aryl iodides was
electron-rich arenes because they proceed via an electro- tested under the optimized reaction conditions, and the re-
philic substitution.8 Recently, Buchwald reported the syn- sults are summarized in Scheme 1. Aryl iodides having
thesis of N-aryl hydrazides by amination of aryl iodides
with hydrazides.9 In addition, Chatani has reported the
synthesis of N-aryl hydrazides from the reaction of aryl-
boronic acids and DAAD in the presence of copper salts.10
electron-rich, electron-deficient, or bulky groups on the
aromatic ring afforded good to excellent yields.
Ar
CO2R
CuI
N
CO2R
N
In this Letter, we report a mild procedure for the synthesis
of aryl hydrazides from the reaction of the Mitsunobu re-
agent system [triphenylphosphine (Ph3P) and DAAD]
with aryl halides in good yields (Scheme 1).11 Investiga-
tions started with the coupling reaction of Ph3P with diiso-
propyl azodicarboxylate (1b) and iodobenzene (2a) in the
presence of copper(I) iodide as catalyst. When the reac-
tion of equimolar amounts of Ph3P with 1b and 2a was
performed in the presence of CuI (0.025 mmol) in toluene
at room temperature for 20 hours under nitrogen, phenyl
hydazide 3b was obtained in 10% yield together with di-
isopropyl hydrazodicarboxylate in 65% yield (Table 1).
After screening a variety of solvents and catalysts, the best
results were obtained in THF at room temperature for 16
hours in the presence of 10 mol% of CuI. Decreasing the
amount of CuI to 5 mol%, resulted in incomplete con-
sumption of iodobenzene (Table 1). Under these opti-
mized conditions, the diisopropyl hydrazodicarboxylate
was not detected in the reaction mixture.
+ ArI
N
+
RO2C
N
Ph3P
RO2C
THF, r.t.
H
Ar
3a Ph
3b Ph
3c 4-Tol
3d 4-Tol
R
Et
i-Pr
Et
i-Pr
R
Ar
2a Ph
2b 4-Tol
2c 4-O2NC6H4
2d 4-MeOC6H4
2e 2-CF3C6H4
2f 4-BrC6H4
Et
1a
1b
i-Pr
3e 4-O2NC6H4 Et
3f 4-O2NC6H4 i-Pr
3g 4-MeOC6H4 i-Pr
3h 2-CF3C6H4 i-Pr
3i 4-BrC6H4
i-Pr
Scheme 1
When aryl bromides were subjected to the reaction condi-
tions developed for the aryl iodides (Table 1), no aryl hy-
drazides were detected in the reaction mixture. After
screening a variety of solvents and catalysts, the best re-
sults were obtained in MeCN at 60–75 °C for 16 hours in
the presence of 10 mol% of CuI and 20 mol% of Phen
(1,10-phenanthroline) as a ligand12 (Table 2). Subse-
quently, a variety of substituted aryl bromides was tested
under the optimized reaction conditions, and the results
are summarized in Scheme 2.13
SYNLETT 2011, No. 12, pp 1745–1747
x
x
.x
x
.2
0
1
1
Advanced online publication: 21.06.2011
DOI: 10.1055/s-0030-1260802; Art ID: D04211ST
© Georg Thieme Verlag Stuttgart · New York

1746
I. Yavari et al.
LETTER
(2) (a) Gribble, G. W. J. Chem. Soc., Perkin Trans. 1 2000,
Table 2 Optimization Reaction Conditions for Aryl Bromides
1045. (b) Oliva, A.; Ellis, M.; Fiocchi, L.; Menta, E.;
Krapcho, A. P. J. Heterocycl. Chem. 2000, 37, 47.
(c) Hughes, D. L. Org. Prep. Proced. Int. 1993, 25, 607.
(d) Yavari, I.; Khalili, G.; Mirzaei, A. Helv. Chim. Acta
2010, 93, 277.
Catalyst Solvent
Yield (%)Catalysta
Solvent
MeCN
MeCN
MeCN
MeCN
Yield (%)b
CuI
CuI
CuI
CuI
CuI
CuI
DMSO
DMF
73
61
15
70
90
78
Cu
n.r
CuCl
CuBr
Cu2O
78
(3) (a) Duthale, R. O. Angew. Chem. Int. Ed. 2003, 42, 975.
(b) Waser, J.; Carreira, E. M. J. Am. Chem. Soc. 2004, 126,
5676. (c) Saaby, S.; Bella, M.; Jorgensen, K. A. J. Am.
Chem. Soc. 2004, 126, 8120.
(4) Ragnarsson, U. Chem. Soc. Rev. 2001, 30, 205.
(5) Demers, J. P.; Klaubert, D. H. Tetrahedron Lett. 1987, 28,
4933.
(6) Metallinos, C.; Nerdinger, S.; Snieckus, V. Org. Lett. 1999,
1, 1183.
(7) Velarde-Ortiz, R.; Guijarro, A.; Rieke, R. D. Tetrahedron
Lett. 1998, 39, 9157.
(8) (a) Bombek, S.; Lenarsic, R.; Kocevar, M.; Saint-Jalmes, L.;
Desmurs, J.-R.; Polanc, S. Chem. Commun. 2002, 1494.
(b) Kinart, W. J.; Kinart, C. M. J. Organomet. Chem. 2003,
665, 233.
(9) Wolter, M.; Klapars, A.; Buchwald, S. L. Org. Lett. 2001, 3,
3803.
(10) Uemura, T.; Chatani, N. J. Org. Chem. 2005, 70, 8631.
(11) Typical Procedure for the Preparation of Aryl
Hydrazides 3a–i
toluene
THF
32
28
MeCN
dioxane
Cu(OAc)2 MeCN
trace
CuCl2
CuIc
MeCN
MeCN
trace
80
a 10 mol% catalyst unless stated otherwise; Phen 20 mol%.
b Reaction time 20 h.
c 5 mol% catalyst, reaction time was 26 h.
Ar
CO2R
CuI, Phen
N
CO2R
R
N
+
ArBr
Ar
N
+
RO2C
Ar
3j 3-Tol
3k 3-Tol
3l 1-naphthyl
3m 1-naphthyl
3n 4-NCC6H4
3o 2-O2NC6H4
3p 2-O2NC6H4
3q 3-F3CC6H4
3r 3-F3CC6H4
3s 2-thienyl
N
Ph3P
RO2C
MeCN, reflux
H
R
1a
Et
1b i-Pr
2g 3-Tol
Et
i-Pr
Et
i-Pr
i-Pr
Et
i-Pr
Et
i-Pr
i-Pr
2h 1-naphthyl
2i 4-NCC6H4
2j 2-O2NC6H4
2k 3-F3CC6H4
2l 2-thienyl
To a stirred solution of aryl iodide (1 mmol) and Ph3P (0.263
g, 1 mmol) in THF (2 mL), was added CuI (9 mg, 0.05
mmol) in one portion. The mixture was stirred at r.t. for 30
min under N2. Then, the DAAD (1.2 mmol) was added to the
reaction mixture, which was stirred at r.t. for 18 h under
nitrogen. After removal of the solvent, the residue was
purified by chromatography (silica gel, hexane–EtOAc =
5:1) to give hydrazides 3a–i.
Scheme 2
Representative Analytical Data
Diethyl 1-Phenyl-hydrazine-1,2-dicarboxylate (3a)
Colorless solid, mp 81–83 °C; yield 0.23 g (91%). IR (KBr):
n
The optimized reaction conditions given above were com-
patible with the presence of functional groups, such as
CN, NO2, CF3, OMe, and halogen, on the aromatic ring of
the aryl halide. Various aryl bromides afforded the corre-
sponding aryl hydrazides in good to excellent yields.
max = 3280, 1599, 1518, 1340, 1100 cm–1. 1H NMR (500.1
MHz, CDCl3): d = 1.27 (3 H, t, 3J = 7.0 Hz, Me), 1.28 (3 H,
t, 3J = 7.0 Hz, Me), 4.22 (4 H, m, 2 CH2O), 7.09 and 7.19 (1
H, br s, NH), 7.20 (1 H, t, 3J = 7.1 Hz), 7.33 (2 H, t, 3J = 7.6
Hz), 7.42 (2 H, d, 3J = 7.4 Hz). 13C NMR (125.7 MHz,
CDCl3): d = 14.4 (Me), 14.5 (Me), 62.3 (CH2O), 63.0
(CH2O), 124.3 (2 CH, br), 126.3 (2 CH), 128.6 (CH), 141.7
(C), 155.0 (C=O), 156.4 (C=O). MS: m/z (%) = 252 (1)
[M+], 180 (10), 152 (100), 134 (16), 108 (22), 107 (69), 106
(14), 91 (17), 77 (32). Anal. Calcd (%) for C12H16N2O4
(252.27): C, 57.13; H, 6.39; N, 11.10. Found: C, 57.59; H,
6.44; N, 11.23.
In summary, the Mitsonubo reagent system has been em-
ployed as a potential anionic nucleophile in a reaction in-
volving aryl halides to produce aryl hydrazides. Aryl
bromides and iodides with electron-withdrawing as well
as electron-releasing groups undergo these coupling reac-
tions in good yields. In this methodology, the optimized
conditions have been developed for aryl iodides at room
temperature and for aryl bromides at 60–75 °C. The ad-
vantages of this methodology are the use of the air-stable,
inexpensive CuI catalyst under mild reaction conditions.
Diisopropyl 1-Phenyl-hydrazine-1,2-dicarboxylate (3b)
Colorless solid, mp 90–92 °C; yield 0.25 g (92%). IR (KBr);
n
max = 3241, 1569, 1500, 1325, 1110 cm–1. 1H NMR (500.1
MHz, CDCl3): d = 1.26 (6 H, t, 3J = 6.6 Hz, 2 Me), 1.29 (6
H, t, 3J = 6.8 Hz, 2 Me), 5.08–5.10 (2 H, m, CHO), 6.96 and
7.12 (1 H, br s, NH), 7.20 (1 H, t, 3J = 7.1 Hz), 7.36 (2 H, t,
3J = 7.1 Hz), 7.46 (2 H, d, 3J = 7.4 Hz). 13C NMR (125.7
MHz, CDCl3): d = 21.0 (2 Me), 21.7 (2 Me), 70.0 (CHO),
70.7 (CHO), 121.2 (2 CH, br), 125.9 (2 CH), 128.9 (CH),
139.3 (C), 154.7 (C=O), 156.0 (C=O). MS: m/z (%) = 280
(1) [M+], 194 (16), 152 (100), 134 (11), 108 (19), 107 (65),
106 (12), 91 (14), 77 (25). Anal. Calcd (%) for C14H20N2O4
(280.32): C, 59.99; H, 7.19; N, 9.99. Found: C, 59.69; H,
7.24; N, 9.93..
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
References and Notes
(1) (a) Enders, E. In Methoden der Organischen Chemie, Vol.
10/2; Stroh, R., Ed.; Thieme: Stuttgart, 1967, 546.
(b) Dekeyser, M.; McDonald, P. T.; Angle, G. W. Jr.
J. Agric. Food Chem. 1994, 42, 1358. (c) Reich, M. F.;
Fabio, P. F.; Lee, V. J.; Kuck, N. A.; Testa, R. T. J. Med.
Chem. 1989, 32, 2474.
(12) Typical Procedure for the Preparation of Aryl
Hydrazides 3j–s
To a stirred solution of aryl bromide (1 mmol), Ph3P (0.263
g, 1 mmol), and Phen (0.036 g, 20 mol%) in MeCN (2 mL)
Synlett 2011, No. 12, 1745–1747 © Thieme Stuttgart · New York

LETTER
was added CuI (9 mg, 0.05 mmol) in one portion. The
Copper(I) Iodide Catalyzed Formation of Aryl Hydrazides
1747
(17), 91 (8). Anal. Calcd (%) for C13H18N2O4 (266.29): C,
58.63; H, 6.81; N, 10.52. Found: C, 58.83; H, 6.88; N, 10.69.
Diisopropyl 1-(3-Methylphenyl)-hydrazine-1,2-
dicarboxylate (3k)
mixture was stirred at r.t. for 30 min under N2. Then, the
DAAD (1 mmol) was added to the reaction mixture, which
was stirred at 60–75 °C for 16 h under N2. After removal of
the solvent, the residue was purified by chromatography
(silica gel, hexane–EtOAc = 5:1) to give hydrazides 3j–s.
Representative Analytical Data
Yellow oil; yield 0.24 g (81%). IR (KBr): nmax = 3291, 1527,
1524, 1314, 1112 cm–1. 1H NMR (500.1 MHz, CDCl3):
d = 1.17 (6 H, d, 3J = 7.2 Hz, Me), 1.28 (6 H, t, 3J = 7.1 Hz,
Me), 2.32 (3 H, s, Me), 4.97–4.99 (2 H, m, 2 CHO), 6.67 and
6.71 (1 H, br s, NH), 6.90 (1 H, d, 3J = 7.2 Hz, CH), 6.97
(1 H, d, 3J = 7.3 Hz, CH), 7.20 (1 H, s, CH), 7.28 (1 H, t,
3J = 7.2 Hz, CH). 13C NMR (125.7 MHz, CDCl3): d = 21.6
(2 Me), 21.9 (2 Me), 29.6 (Me), 70.6 (CHO), 70.8 (CHO),
121.4 (CH, br), 124.3 (CH, br), 126.6 (CH), 128.3 (CH),
138.2 (C), 141.8 (C), 154.5 (C=O), 156.5 (C=O). MS: m/z
(%) = 294 (1) [M+], 208 (13), 166 (100), 148 (16), 122 (14),
120 (68), 105 (17). Anal. Calcd (%) for C15H22N2O4
(294.35): C, 61.21; H, 7.53; N, 9.52. Found: C, 61.42; H,
7.62; N, 9.60.
Diethyl1-(3-Methylphenyl)-hydrazine-1,2-dicarboxylate
(3j)
Yellow oil; yield 0.22 g (83%). IR (KBr): nmax = 3310, 1539,
1510, 1321, 1132 cm–1. 1H NMR (500.1 MHz, CDCl3):
d = 1.27 (3 H, t, 3J = 7.2 Hz, Me), 1.30 (3 H, t, 3J = 7.1 Hz,
Me), 2.32 (3 H, s, Me), 4.20 (4 H, m, 2 CH2O), 6.96 and 7.07
(1 H, br s, NH), 7.12 (1 H, d, 3J = 7.2 Hz, CH), 7.20 (1 H, d,
3J = 7.3 Hz, CH), 7.26 (1 H, s, CH), 7.45 (1 H, t, 3J = 7.2 Hz,
CH). 13C NMR (125.7 MHz, CDCl3): d = 19.6 (Me), 19.9
(Me), 26.6 (Me), 67.6 (CH2O), 68.2 (CH2O), 125.4 (CH, br),
130.3 (CH, br), 133.6 (CH), 136.3 (CH), 141.2 (C), 143.8
(C), 156.5 (C=O), 161.5 (C=O). MS: m/z (%) = 266 (1)
[M+], 194 (13), 166 (100), 148 (16), 122 (14), 120 (68), 105
(13) The reaction of aryl bromides was improved in the presence
of Phen.
Synlett 2011, No. 12, 1745–1747 © Thieme Stuttgart · New York

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