Gold-catalyzed direct amination of arenes with azodicarboxylates

Article abstract of DOI:10.1021/ol200373q

Gold(III) chloride catalyzed direct amination of arenes with azodicarboxylates was developed. The new catalytic system was active to a broad range of substrates, and the reaction was carried out under mild conditions. It represents the first catalytic sys

Full text of DOI:10.1021/ol200373q

ORGANIC
LETTERS
2011
Vol. 13, No. 7
1872–1874
Gold-Catalyzed Direct Amination of
Arenes with Azodicarboxylates
Liuqun Gu, Boon Siong Neo, and Yugen Zhang*
Institute of Bioengineering and Nanotechnology, 31 Biopolis Way, the Nanos,
Singapore 138669
ygzhang@ibn.a-star.edu.sg
Received February 10, 2011
ABSTRACT
Gold(III) chloride catalyzed direct amination of arenes with azodicarboxylates was developed. The new catalytic system was active to a broad
range of substrates, and the reaction was carried out under mild conditions. It represents the first catalytic system for the direct amination of
electron-deficient arenes with azodicarboxylates to the best of our knowledge. This reaction provides an important approach for the synthesis of
heterocyclic compounds in pharmaceutical and chemical industries.
Aryl hydrazides are highly valuable synthetic intermedi-
ates for the preparation of heterocycles such as indoles,
pyrazoles, etc.1 In addition, they could also be deprotected
into aromatic amines and aryl hydrazines, which are well
utilized in the pharmaceutical industry and other indu-
stries.2 Traditionally, aryl hydrazides could be obtained by
the reaction of aryllithium or aryl magnesium bromide
reagentswithazodicarboxylates.3 Y. Leblancetal. recently
described the catalytic amination of electron-rich arenes
with bis(2,2,2-trichloroethyl)azodicarboxylate.4 In Le-
blanc’s systems, Lewis acids or Brønsted acids were used as
catalysts based on pioneering works in the 1960s.5 Later,
diethyl azodicarboxylate (DEAD) was also proven to be a
suitable reagent for catalytic amination of electron-rich
arenes with strong Lewis acid Sc(OTf)2.6 Great improve-
ments were obtained in these procedures compared to the
stoichiometric reactions. However, only electron-rich are-
nes are active in Leblanc’s4 and follower’s methods.6,7
T. H. Kim and J. N. Kim et al. modified Leblanc’s method,
and the resulting method could be applied tothe amination
of a broader range of arene substrates including arenes
with certain electron-withdrawing groups.8 However the
modified method used stoichiometric super acid (TfOH)
and a large amount trifluoroacetic acid (as solvent) that
limited its application. In view of these facts, it is still highly
desirable to develop efficient ways for the direct amination
of a broad range of arenes, especially for electron-deficient
arenes. Inthe pursuitof moreefficient catalyticsystems, we
found that gold(III) chloride showed an extremely high
efficiency in the amination of arenes with azodicarboxy-
lates. Not only electron-rich arenes but also electron-
deficient ones could be aminated under mild conditions.
(1) Paquette, L. A. Encyclopedia of Reagents for Organic Synthesis:
Wiley: 1995.
(2) Schmidt, E. W. Hydrazine and its Derivatives: Preparation, Prop-
erties, Applications, 2nd ed.; Wiley-Interscience: 2001.
(3) Demers, P.; Klaubert, D. H. Tetrahedron Lett. 1987, 28, 4933.
(4) (a) Leblanc, Y.; Boudreault, N. J. Org. Chem. 1995, 60, 4268.
(b) Mitchell, H.; Leblanc, Y. J. Org. Chem. 1994, 59, 682. (c) Zaltsgendler,
I.; Leblanc, Y.; Bernstein, M. A. Tetrahedron Lett. 1993, 34, 2441.
(d) Boudreault, N.; Leblanc, Y. Org. Synth. 1997, 74, 241. (e) Bombek,
S.; Lenarsic, R.; Kocevar, M.; Saint-Jalmes, L.; Desmurs, J.-R.; Polanc,
S. Chem. Commun. 2002, 1494. (f) Bombek, S.; Pozgan, F.; Kocevar, M.;
Polanc, S. J. Org. Chem. 2004, 69, 2224. (g) Yadav, J. S.; Reddy, B. V. S.;
Kumar, G. M.; Madan, C. Synlett 2001, 1781.
(7) (a) Lenarsic, R.; Kocevar, M.; Polanc, S. J. Org. Chem. 1999, 64,
2558. (b) Kinart, W. J.; Kinart, C. M.; Tran, Q. T.; Oszczeda, R.;
Nazarski, R. B. Appl. Organomet. Chem. 2004, 18, 398.
(8) Lee, K. Y.; Im, Y. J.; Kim, T. H.; Kim, J. N. Bull. Korean Chem.
Soc. 2001, 22, 127.
(9) (a) For another method to prepare aryl hydrazides from aromatic
boronic acids and azodicarboxylates with Pd complexes, see: Muniz, K.;
Iglesias, A. Angew. Chem., Int. Ed. 2007, 46, 6350. (b) During the
preparation of this manuscript, Pd-catalyzed cross-coupling of aryl
chlorides and tosylates with hydrazine affording aryl hydrazine was
reported: Lundgren, R. J.; Stradiotto, M. Angew. Chem., Int. Ed. 2010,
49, 8686.
(5) (a) Carlin, R. B.; Moores, M. S. J. Am. Chem. Soc. 1962, 84, 4107.
(b) Schroeter, S. H. J. Org. Chem. 1969, 34, 4012.
(6) Yadav, J. S.; Reddy, B. V. S.; Veerendhar, G.; Rao, R. S.;
Nagaiah, K. Chem. Lett. 2002, 318.
r
10.1021/ol200373q
Published on Web 03/02/2011
2011 American Chemical Society

To the best of our knowledge, it is the first example of the
catalytic direct amination of electron-deficient arenes with
azodicarboxylates.9
Scheme 1. Amination of Various Arenes with Azodicarboxylates
In previous amination research, most of the efforts have
focused on the activation of azodicarboxylates with Lewis
acids or Brønsted acids.4 In order to enhance the reaction
activity, we conceived a dual activation proposal with gold(III)
chloride as a catalyst. Gold(III) chloride is well-known for
the activation of a CAr-H bond. Aryl gold(III) complexes
could be generated at room temperature under anhydrous
conditions.10,11 On the other hand, it is also known that
gold(III) chloride (or the aryl gold(III) complex) could
activate the azodicarboxylates. Therefore, the catalytic
activity of gold(III) chloride in the direct amination of arenes
with azodicarboxylates was investigated.
Table 1. Amination of Mesitylene with Diisopropyl Azodicar-
boxylate in Dichloromethane (DCM)a
entry
catalyst
time (h)
yield (%)b
1
2
3
4
5
6
AuCl3
2
24
24
24
2
57 (34)c
26
Cu(OTf)2
AgOTf
10
Sc(OTf)2
6
AuCl3 1 mol %
HCl in dioxane 20 mol %
80 (16)c
trace
24
a Conditions: mestylene (2 mmol, 2 equiv), 2 (1 mmol), catalyst
(2 mol %), DCM (1 mL), all except 2 are added in the glovebox before
the mixture was moved out. Rt for 2 to 24 h. b Isolated yield. c Isolated
yield of bisaminated product.
aIsolated yield of bisaminated product is 16%. b2 mol % catalyst was
used. c1 equiv phenol was used. dThe yields of mono- and bisaminated
mixtures could be improved to 43% and 42%, respectively by perform-
ing the reaction in 1,2-dichloroethane (DCE) (0.7 mL) at 80 °C for 1 d.
eBoth mono- and bisaminated products are unseparated mixtures of
isomers. fDCE was the solvent, and the reaction temperature was 60 °C.
Initially, gold(III) chloride together with other typical
Lewis acids and Brønsted acid catalysts were tested in a
model reaction of mesitylene and diisopropyl azodicarbox-
ylate (Table 1). With 2 mol % gold(III) chloride as the
catalyst, the reaction was completed within 2 h affording
an aminated product in 57% yield (34% for a bisaminated
product, based on azodicarboxylate). When 2 mol %
Cu(OTf)2, AgOTf, andSc(OTf)2 wereusedascatalysts, the
yields of desired product were as low as 26%, 10%, and
6%, respectively even after the reaction times were pro-
longed to 24 h (Table 1, entries 2-4). Only a trace amount
of product was observed in the reaction with HCl
(in dioxane, 20 mol %) as the catalyst. This result excluded
the possibility that the reaction was catalyzed by in situ
generated HCl from gold(III) chloride metalation of arenes
(Table 1, entry 6). These amination results indicated the
superb catalytic activity of gold(III) chloride. The yield of the
monosubstituted product was further improved to 80%
when the loading of gold(III) chloride was decreased to
1 mol % (Table 1, entry 5).
phenol and 1,3,5-trimethoxylbenzene could be achieved in
excellent yields within 10 min in the presence of 1 mol %
gold catalyst (Scheme 1, 3a and 3d). For the reaction of
durene, the yield of amination product (3b) was moderate
(66%) even after a longer reaction time (5 h) and double
the amount of catalyst (2 mol %). This low yield probably
is due to the bulkiness of durene. Naphthalenes with
different functional groups were also suitable substrates
for the amination reactions (3e, 3f). To our disappoint-
ment, the reactions gave low yields with inactive arenes
toluene and benzene as substrates.
(10) For selected reviews, see: (a) Ma, S.; Yu, S.; Gu, Z. Angew.
Chem., Int. Ed. 2006, 45, 200. (b) Hashmi, A. S. K.; Hutchings, C. J.
€
Angew. Chem., Int. Ed. 2006, 45, 7896. (c) Furstner, A.; Davies, P. W.
Angew. Chem., Int. Ed. 2007, 46, 3410. (d) Hashmi, A. S. K. Chem. Rev.
2007, 107, 3180. (e) Li, Z.; Brouwer, C.; He, C. Chem. Rev. 2008, 108,
3239. (f) Arcadi, A. Chem. Rev. 2008, 108, 3266. (g) Gorin, D. J.; Sherry,
B. B. D.; Toste, F. D. Chem. Rev. 2008, 108, 3351.
Encouraged by these promising results, we investigated
the substrate scope of arenes. The amination products of
Org. Lett., Vol. 13, No. 7, 2011
1873

To further expand the scope of the methodology, dif-
ferent commercially available azodicarboxylates were
tested in the amination of inactive arenes. Gratifyingly,
with bis(2,2,2-trichloroethyl)azodicarboxylate 4and 5 mol %
AuCl3, the inactive arenes including halo benzenes could
be converted to hydrazides in moderate to good yields.12
For benzene, a 1,4-bisaminated product (3h) was obtained
as a single regioisomer. The reaction of toluene with 4 was
very complex giving a mixture of monoaminated products
(p/m = 7/3) and bisaminated products (m,m/m,p = 1/1).
The amination of halo benzenes afforded para-directed
products (3i, 3j, 3k). Herein, for monosubstituted benzene
substrates, only para-aminated products (3d, 3e, 3f, 3i, 3j,
3k) wereobtained, indicating excellent regioselectivitywith
gold(III) chloride as catalyst.
A series of control experiments were conducted to gain
insight into the mechanism. Since AuCl and HAuCl4 could
be generated as a byproduct in the process of AuCl3
metalation of arenes, control reactions of fluorobenzene
and azodicarboxylate with 5 mol % AuCl or HAuCl4 were
performed. Under the same conditions, the yields of the
desired product with the AuCl catalyst (8%) and HAuCl4
catalyst (21%) were much lower than that with AuCl3
(72%). The results suggested the amination reaction was
mainly catalyzed by AuCl3. In order to probe the interac-
tion of the AuCl3 catalyst and azodicarboxylates, reactions
of azodicarboxylates and stoichometric amounts of AuCl3
were performed. In the absence of arene, the NMR (1Hand13C)
shifts of azodicarboxylates remained unchanged upon
Figure 1. Proposed reaction pathway of the AuCl3-catalyzed
amination of arenes.
not involved in the rate-determining step in the overall
catalytic processes.13
Based on the above mechanistic clues and data, a
proposed major pathway of the AuCl3-catalyzed amina-
tion of arenes via C-H bond activation is shown in Figure
1. In the first step, aryl gold(III) complexes were generated
quickly and then coordinated with azodicarboxylate af-
fording complex 5. A reduction coupling reaction occurred
slowly in complex 5 resulting in the formation of inter-
mediate 6, which could be protonated quickly to form aryl
hydrazide and regenerate the AuCl3 catalyst.
In summary, we have developed a new catalytic system
for the direct amination of arenes with azodicarboxylates
by using AuCl3 as a catalyst. The reactions are highly
efficient so that electron-poor arenes could also be cataly-
tically aminated. The present work is expected to be a
useful method for the synthesis of heterocyclic compounds
with biological activity in the pharmaceutical industry.
1
addition of AuCl3. However, an obvious H shift was
observed when azodicarboxylate was added to the system
inthe presenceofbothgold(III) chlorideand arenes.11 This
evidence suggested auration may indeed occur and it was
aryl gold(III) complexes, not AuCl3, which activated the
azodicarboxylate. To identify any kinetic isotope effects, a
competition experiment between bromobenzene and its
deuterated derivative was also performed. The amination
reaction did not exhibit a kinetic isotope effect (kH/kD =1.0),
which indicated that the C-H bond cleavage of arene was
(11) For original study on AuCl3 metalation of arenes, see: (a)
Kharasch, M. S.; Isbell, H. S. J. Am. Chem. Soc. 1931, 53, 3053. (b) de
Graaf, P. W. J.; Boersma, J.; van der Kerk, G. J. M. J. Organomet. Chem.
1976, 105, 399. (c) Fuchita, Y.; Utsunomiya, Y.; Yasutake, M. J. Chem.
Soc., Dalton Trans. 2001, 2330.
Acknowledgment. This work was supported by the In-
stitute of Bioengineering and Nanotechnology (Biomedical
Research Council, Agency for Science, Technology and
Research, Singapore).
(12) No product was detected in the reactions with 5 mol% Cu(OTf)2
catalyst or without catalyst.
(13) This result is consistent with the reported fact in ref 10. The
metalation reaction between AuCl3 and arene happened very quickly to
generate aryl gold(III) complexes. For KIE experiments, see the Sup-
porting Information.
Supporting Information Available. Experimental pro-
cedures and NMR of products. This material is available
free of charge via Internet at http://pubs.acs.org.
1874
Org. Lett., Vol. 13, No. 7, 2011