Copper-catalyzed C-N bond formation using dialkyl azodicarboxylate as the amination reagent

Article abstract of DOI:10.1016/j.tetlet.2015.12.036

An efficient copper-catalyzed reaction for C-N bond formation using aryl halides, dialkyl azodicarboxylate, and a hydride source is reported. Using this procedure, aryl iodides reacted at ambient conditions, while aryl bromides required heating to 60 °C to accomplish the transformation. Various functional groups were tolerated under the optimum conditions.

Full text of DOI:10.1016/j.tetlet.2015.12.036

Accepted Manuscript
Copper-Catalyzed C-N Bond Formation Using Dialkyl Azodicarboxylate as the
Amination Reagent
Alireza Samzadeh-Kermani
PII:
S0040-4039(15)30451-2
DOI:
http://dx.doi.org/10.1016/j.tetlet.2015.12.036
TETL 47083
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
5 April 2015
26 November 2015
8 December 2015
Please cite this article as: Samzadeh-Kermani, A., Copper-Catalyzed C-N Bond Formation Using Dialkyl
Azodicarboxylate as the Amination Reagent, Tetrahedron Letters (2015), doi: http://dx.doi.org/10.1016/j.tetlet.
2015.12.036
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers
we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and
review of the resulting proof before it is published in its final form. Please note that during the production process
errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Copper-Catalyzed
C-N Bond Formation
Using
Dialkyl
Azodicarboxylate as the Amination Reagent
Alireza Samzadeh-Kermani
Department of Chemistry, Faculty of Science, University of Zabol, Zabol, Iran
Fax +98-61-335856; E-mail: drsamzadeh@gmail.com; arsamzadeh@uoz.ac.ir
ABSTRACT
An efficient copper-catalyzed reaction for C-N bond formation using aryl halides, dialkyl
azodicarboxylate, and a hydride source is reported. Using this procedure, aryl iodides reacted at
ambient conditions, while aryl bromides required heating to 60 ˚C to accomplish the
transformation. Various functional groups were tolerated under the optimum conditions.
Keywords:
Aryl hydrazide
C-N Cross–coupling
Copper salts
Dialkyl azodicarboxylate
Carbon-nitrogen bonds are prevalent in a wide range of pharmaceuticals and bioactive
agents1-2 and many publications for the synthesis of the C-N bond have been reported,3a-c with
cross-coupling reactions based on transition metals catalysts being among the most studied
procedures.4-6 In recent years, copper-catalyzed coupling reactions have received much attention

due to their efficiency and low cost.7-8 However, most copper(I) salts are insoluble in common
organic solvents and to improve the catalyst efficiency the reactions are often performed at high
temperatures or with ligands.9-10 Dialkyl azodicarboxylates (DAAD) have been utilized as
coupling partners in reactions with aryl Grignard reagents,11a aryllithium reagents,11b and aryl
zinc halides11c for the synthesis of N-aryl hydrazides. However, these reactions are typically
limited to electron-rich aryl sources. Yavari and co-workers have disclosed a concise procedure
for the construction of this type of C-N bond in the reaction between various aryl halides and
Mitsunobu reagents.12 While the importance of such reaction cannot be overstated, the
transformation suffered from the limitations such as formation of the phosphine oxide by-product
and low atom economy. Recently, they also reported a complementary route for the synthesis of
N-aryl hydrazides using aryl triflates, dialkyl azodicarboxylates, and sodium hydride.13 These
results encouraged us to examine alternative conditions for the synthesis of N-aryl hydrazides in
the presence of copper salts.
The coupling reaction was initially examined using diisopropyl azodicarboxylate (1a) and
iodobenzene (2a) in the presence of CuI (0.05 mmol) using NaBH4 as the hydride source.
Stirring in DMF at ambient conditions for 12 h under N2 gave phenylhydrazide 3a in 31% yield,
together with diisopropyl hydrazodicarboxylate 4 in 64% yield (Table 1, entry 9).15
To develop the reaction conditions a variety of copper salts, hydride sources, and solvents
were examined (Table 1). No C-N bond formation occurred without the copper salt even at
higher temperature (80 ˚C) and instead diisopropyl hydrazodicarboxylate was obtained in 95%
yield (Table 1, entry 1). Additionally, no reaction took place in the absence of a hydride source
(Table 1, entry 13). Among the hydride sources examined, NaH gave the best result (Table 1,
entry 8), most likely due to the increased ionic character of the Na-H bond over the other hydride

sources examined. Other copper salts also promoted the reaction, however the yields were lower
(Table 1, entries 2-4). Finally, a solvent screen showed that DMF gave superior yields in
comparison to other solvents (Table 1, entries 5-8).
Table 1. Optimization of the reaction conditionsa
Entry
1
2
3
4
5
6
7
8
Catalyst
-
Cu2O
CuCl
Cu(OAc)2
CuI
Solvent Hydride source Yield of 3a (%)
b
DMF
DMF
DMF
DMF
THF
NaH
NaH
NaH
NaH
NaH
-
81
38
trace
27
46
73
87
31c
18
26
35
-
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
dioxane
DMSO
DMF
DMF
DMF
DMF
DMF
DMF
NaH
NaH
NaH
9
NaBH4
Et3SiH
Ph3SiH
PhMe2SiH
-
10
11
12
13
a Reaction conditions: 1a (1.1 mmol), 2a (1.0 mmol), hydride source (1.1 mmol), CuX (0.05 mmol), solvent (3 mL),
25 °C, 12 h, N2 atmosphere.
b 4 was obtained in 95% yield.
c Other common hydride sources (entries 9-12) afforded 4 in 29-65% yields.
We next sought to explore the scope of the reaction (Table 2).15 Cross-coupling of
electron-neutral aryl iodides (2a-b) proceeded in good yields (Table 2, entries 1 and 2). Electron-
poor substrates (2i-l) gave higher yields than those of electron-neutral substrates which was
likely due to the increased electrophilicity of the aromatic ring (Table 2, entries 9-12), while the
electron-rich substrate 2f gave a comparatively poorer yield (Table 2, entry 6). ortho-Substitution

was also tolerated and 2e was cross-coupled cleanly (Table 2, entry 5), however the more bulky
substrate 2g only afforded the product in moderate yield (Table 2, entry 7). Aryl bromides 5a-j
required higher temperatures and longer reaction times to accomplish the transformation. The
difference in reactivity was reflected in the reaction of 1-bromo-4-iodobenzene (2h), where
amination exclusively occurred at the iodide substituent (Table 2, entry 8). Heteroaromatic
substrates 2m, 5h, and 5j also afforded the desired products in good yields (Table 2, entries 13,
21, and 23).
Table 2. Reaction scope for aryl iodidesa and bromidesb
Entry
1
2
3
4
5
6
7
8
X = I, Ar
Ph
1-Naphthyl
4-Tol
3-Tol
2-Tol
Yield of 3 (%) Entry
X = Br, Ar
Ph
1-Naphthyl
2-Tol
4-MeO-C6H4
2-F3C-C6H4
3-F3C-C6H4
4-NO2-C6H4
2-Thienyl
Yield of 3 (%)
3a, 88
3b, 86
3e, 84
3f, 70
3g, 67
3i, 89
3k, 94
3m, 81
3n, 76
2
a
b
c
d
e
f
g
h
i
5
a
b
c
d
e
f
g
h
i
3a, 93
3b, 89
3c, 86
3d, 88
3e, 85
14
15
16
17
18
19
20
21
22
23
4-MeO-C6H4 3f, 72
2-F3C-C6H4
4-Br-C6H4
3-F3C-C6H4
4-NC-C6H4
4-NO2-C6H4
2-NO2-C6H4
2-Thienyl
3g, 58
3h, 89
3i, 95
3j, 85
3k, 98
3l, 87
3m, 84
9
2-Br-C6H4
2-N-methyl-pyrrole
10
11
12
13
3o, 85
j
k
l
j
m
a Reaction conditions: 1a (1.1 mmol), 2 or 5 (1.0 mmol), NaH (1.1 mmol), CuI (0.05 mmol), DMF (3 mL), 12 h, 25
°C, N2 atmosphere.
b Reaction mixture was stirred for 20 h at 60 °C.
Diethyl azodicarboxylate (1b, DEAD) was also examined as an amination reagent and in
all cases, the corresponding N-aryl hydrazide was obtained in acceptable yield (Table 3).

Table 3. Examination of DEAD as an amination reagenta
Entry
X = I, Ar
1-Naphthyl
4-Tol
3-Tol
3-F3C-C6H4
Yield of 3 (%)
3p, 84
3q, 87
3r, 86
3s, 91
2
b
c
d
i
1
2
3
4
5
4-NO2-C6H4 3t, 93
k
a Reaction conditions: 1b (1.1 mmol), 2 (1.0 mmol), NaH (1.1 mmol), CuI (0.05 mmol), DMF (3 mL), 12 h, 25 °C,
N2 atmosphere.
Note that when 1a was reacted with 2.0 equivalents of phenyl iodide 2a and NaH,
diisopropyl 1,2-(diphenyl)-1,2-hydrazinedicarboxylate (6) was obtained in 71% yield (Scheme
1).
Scheme 1. 1,2-Diarylation of DIAD
Although at this time we cannot provide a definitive mechanism for the formation of N-
aryl hydrazides, previous work proposed that hydride transfer to the diisopropyl
azodicarboxylate generating a hydrazide anion followed by cross-coupling of this anionic adduct
with active aryl sources using copper salts affords the desired product.13 To probe the action of
the hydride source, diisopropyl azodicarboxylate was treated with iodobenzene and sodium
deuteride in extra dry DMF. While no coupling reaction occurred in the absence of catalyst,

addition of 5% CuI resulted in the formation of the desired coupling product 7 in 90% yield
(Scheme 2).16 Note that no reaction occurred when a mixture of diisopropyl
hydrazodicarboxylate (4) and iodobenzene was treated with NaH using CuI in DMF. These
results indicate that the reaction does not proceed through a hydrazide intermediate and a radical
pathway may well be operative.
Scheme 2. Examination of NaD as a hydride source
In conclusion, we have reported an efficient C-N bond formation reaction for the
synthesis of N-aryl hydrazide derivatives. This reaction proceeds under mild conditions and
tolerates a range of functional groups. 1-Bromo-4-iodobenzene could be chemoselectively cross-
coupled with DIAD at the 4-position in high yield. This procedure did not suffer from the
limitations of the previously reported reactions such as low atom economy, harsh reaction
conditions, costly catalysts, and electron rich substrates.
References and notes
1. Ridley, R. G. Nature 2002, 415, 686.
2. Olliaro, P. L.; Taylor, R. G. J. Exp. Biol. 2003, 206, 3753.

3. (a) Li, X.; Chen, N.; Xu, J. Synthesis 2010, 3423. (b) Miriyala, B.; Bhattacharyya, S.;
Williamson, J. S. Tetrahedron 2004, 60, 1463. (c) Bredihhin, A.; Mäeorg, U. Org. Lett. 2007,
9, 4975.
4. Mann, G.; Hartwig, J. F. Tetrahedron Lett. 1997, 38, 8005.
5. Klapars, A.; Buchwald, S. L. Org. Lett. 2001, 3, 23.
6. Larsson, P.; Bolm, C.; Norrby, P. Chem. Eur. J. 2010, 16, 13613.
7. Kiyomori, A.; Marcoux, J.-F.; Buchwald, S. L. Tetrahedron Lett. 1999, 40, 2657.
8. Wolfe, J. P.; Wagaw, S.; Marcoux, J.-F.; Buchwald, S. L. Acc. Chem. Res. 1998, 31, 805.
9. Gujadhur, R.; Venkataraman, D.; Kintigh, J. T. Tetrahedron Lett. 2001, 42, 4791.
10. Kalinin, A. V.; Bower, J. F.; Riebel, P.; Snieckus, V. J. Org. Chem. 1999, 64, 2986.
11. (a) Demers, J. P.; Klaubert, D. H. Tetrahedron Lett. 1987, 28, 4933. (b) Metallinos, C.;
Nerdinger, S.; Snieckus, V. Org. Lett. 1999, 1, 1183. (c) Velarde-Ortiz, R.; Guijarro, A.;
Rieke, R. D. Tetrahedron Lett. 1998, 39, 9157.
12. Yavari, I.; Ghazanfarpour-Darjani, M.; Ahmadian, S.; Solgi, Y. Synlett 2011, 1745.
13. Yavari, I.; Ghazanfarpour-Darjani, M.; Bayat, M.; Malekafzali, A. Synlett 2015, 924.
14. Uemura, T.; Chatani, N. J. Org. Chem. 2005, 70, 8631.
15. Typical procedure for preparation of aryl hydrazides 3. A mixture of aryl halide (1.0
mmol), DAAD (1.1 mmol), and CuI (9 mg, 0.05 mmol) in DMF (2 mL) was stirred for 30
min at 0 °C. A suspension of NaH (0.050 g, 1.1 mmol) in DMF (1 mL) was slowly added to
the reaction mixture over 20 min. The mixture was then evacuated and back-filled with N2 (3
times) and stirred for 12-20 h at the appropriate temperature. The crude reaction mixture was
diluted with CH2Cl2 (5 mL) and a saturated NH4Cl solution (3 mL). The mixture was stirred
for an additional 30 min and two layers were separated. The aqueous layer was extracted

with CH2Cl2 (3 × 2 mL). The combined organic layers were dried over MgSO4, filtered, and
concentrated in vacuo. The residue was purified by flash column chromatography (silica gel,
hexane:EtOAc 3:1) to give the desired product.
16. A mixture of iodobenzene (0.2 mmol), DAAD (0.2 mmol), and CuI (2 mg, 0.02 mmol) in dry
DMF (0.5 mL) was stirred for 30 min at 0 °C. A suspension of NaD (0.2 mmol) in extra dry
DMF (0.5 mL) was slowly added to the reaction mixture over 10 min. The mixture was then
evacuated and back-filled with N2 (3 times) and stirred for 12 h at 25 °C. The crude reaction
mixture was diluted with CDCl3 (3 mL) and D2O (3 mL). The organic layer was concentrated
in vacuo. The crude reaction mixture was then analyzed by NMR spectroscopy.
17. All known compounds (3a-3d, 3f-3m, 4) gave satisfactory spectroscopic data and were
consistent with that reported in the literature (see ESI for characterization data of all
products).

Graphical Abstract
Copper-Catalyzed
C-N Bond Formation
Using Dialkyl
Azodicarboxylate as the Amination Reagent
Alireza Samzadeh-Kermani