Formation of cinnoline derivatives by a gold(I)-catalyzed hydroarylation of N-propargyl-N′-arylhydrazines

Article abstract of DOI:10.1016/j.jorganchem.2010.06.017

A study concerning the gold(I)-catalyzed hydroarylation of N-propargyl-N′-arylhydrazinecarboxylic acid methyl esters is described. The use of the gold complex [XPhosAu(NCCH₃)SbF₆] as the catalyst in refluxing nitromethane allows the

Full text of DOI:10.1016/j.jorganchem.2010.06.017

Journal of Organometallic Chemistry 696 (2011) 37e41
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Journal of Organometallic Chemistry
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Formation of cinnoline derivatives by a gold(I)-catalyzed hydroarylation of
N-propargyl-N0-arylhydrazines
*
Igor Dias Jurberg, Fabien Gagosz
Laboratoire de Synthèse Organique, UMR 7652 CNRS/Ecole Polytechnique, Ecole Polytechnique, 91128 Palaiseau, France
a r t i c l e i n f o
a b s t r a c t
A study concerning the gold(I)-catalyzed hydroarylation of N-propargyl-N0-arylhydrazinecarboxylic acid
methyl esters is described. The use of the gold complex [XPhosAu(NCCH3)SbF6] as the catalyst in
refluxing nitromethane allows the generally rapid and efficient synthesis of a range of functionalized
4-exo-methylene-1,2-dihydrocinnolines.
Article history:
Received 25 May 2010
Received in revised form
15 June 2010
Accepted 16 June 2010
Available online 25 June 2010
Ó 2010 Elsevier B.V. All rights reserved.
Keywords:
Homogeneous catalysis
Gold complexes
Hydroarylation
Cinnoline derivatives
1. Introduction
N-propargyl-N0-arylhydrazine derivatives 6 might be transformed
into the corresponding tetrahydrocinnolines 7 by a nucleophilic
While being less frequently used than the quinoline heterocycle,
the isosteric cinnoline moiety remains a structural unit of choice in
medicinal chemistry for the discovery of new biologically active
substances (Fig. 1) [1]. The continuous attention which has been paid
over the past 50 years to the development of new strategies allowing
the efficient synthesis of heterocyclic compounds possessing a cin-
noline moiety is mainly due to the exceptional spectrum of phar-
maceutical activities exerted by such molecules [1]. The use of
cinnoline derivatives in drug design has also been investigated and
several tetrahydrocinnolines [2] and 1,2-dihydrocinnolines [3], such
as compound 1 or the marketed drugs cinnopentazone 2 and cin-
nofuradione 3, have been reported as bioactive molecules.
Given the general interest in the cinnoline motif and followingour
continuousinterestinthe fieldofgold-catalyzedsynthesis ofnitrogen
containing heterocycles [4], we envisaged developing a new access to
molecules possessing either a tetrahydro- or a dihydrocinnoline unit
in their structure. Our synthetic approach is depicted in Scheme 1. It is
based on our recent finding that a wide range of N-aminophenyl
propargyl malonates 4 can be easily converted into tetrahy-
droquinolines 5 following a gold(I)-catalyzed hydroarylation process
[5,6]. By analogy with this transformation, we surmised that the
addition of the aromatic nucleus onto the gold(I)-activated alkyne [7].
The hydroarylation product 7 would be subsequently converted into
1,2-dihydrocinnolines 8 by treatment with an acid.
It is important to note that the gold(I) formation of tetrahy-
droquinolines 5 we recently reported could only be performed with
substrates 4 possessing a basic nitrogen atom (i.e. R2 ¼ alkyl or aryl)
[8]. Moreover, the efficiency of this transformation was directly
associated with the presence of the malonate moiety that was
supposed to prevent or limit the coordination of the gold(I)
complex with the nitrogen atom probably through steric and
electronic effects [9]. These results caused us to initially question
the possibility of performing an analogous gold(I)-catalyzed
hydroarylation on hydrazine derivatives 6 as it was supposed in this
case that the nitrogen atom attached to the aromatic nucleus would
be more accessible and therefore more prone to coordination than
that in substrates 4. We report herein our investigations in this
domain which have led to the development of a new synthetic
approach to functionalized cinnoline derivatives.
2. Results and discussion
N-Propargyl-N0-phenylhydrazine derivative 9, easilyand efficiently
obtained in a two steps sequence from diethyl azadicarboxylate
(DEAD), was first chosen as a model substrate to validate our synthetic
approach to tetrahydrocinnolines (Scheme 2).
* Corresponding author.
E-mail address: gagosz@dcso.polytechnique.fr (F. Gagosz).
0022-328X/$ e see front matter Ó 2010 Elsevier B.V. All rights reserved.
doi:10.1016/j.jorganchem.2010.06.017

38
I.D. Jurberg, F. Gagosz / Journal of Organometallic Chemistry 696 (2011) 37e41
Bioactive 1,2-dihydrocinnolines
Bioactive tetrahydrocinnolines
O
Ph
O
N
N
O
N
N
H
R
N
N
O
R
cinnoline core
1
R=
C5H11 cinnopentazone
R= NHC3H7, piperidino
pyrrolidino
2
(antiinflammatory)
(sedative, neuroleptic)
O
cinnofuradione
3
(analgesic)
Fig. 1. Example of bioactive 1,2-dihydro- and tetrahydrocinnolines.
Synthesis of quinoline derivatives (Ref [5])
H
hydroarylation
Au(I)
R1
R1
CO2Et
CO2Et
CO2Et
CO2Et
N
N
6-exo
R2
R2
4
5
Synthesis of cinnoline derivatives (this work)
H
AuL
hydroarylation
Me
N
Au(I)
H+
R1
R1
R1
N
N
N
CO2Me
N
CO2Me
N
CO2Me
6-exo
R2
R2
6
R2
7
8
Scheme 1. Synthetic approach to cinnoline derivatives.
However, under the optimal catalytic conditions previously
moieties. The reduced nucleophilicity of the phenyl nucleus, due to
the presence of the carboxymethyl group on the nitrogen atom
attached to the aromatic, might also be invoked to explain the
inertness of 9 [5]. To circumvent this problem and in order to
increase the nucleophilicity of the aryl group, one of the carbamate
moiety was therefore replaced by another phenyl group
(Scheme 3).
The treatment of compound 14 with 1 mol% of gold complex 10
in refluxing nitromethane did not allow the formation of the
desired cinnoline derivative 15. However, the use of a higher
used for the hydroarylation of N-aminophenyl propargyl malonates
4 (1 mol% of gold complex [XPhosAu(NCCH3)SbF6] 10 in refluxing
nitromethane) [5], no formation of the exo-methylene tetrahy-
drocinnoline 13 could be observed. Using a higher catalyst loading
or changing the nature of the solvent and the reaction temperature
was not beneficial. Such a negative result might be attributed to the
presence of two possible conformers 11 and 12 among which the
cyclizing one (12) should be less favoured due to a steric interaction
and/or
a
dipole repulsion between the two carboxymethyl
CO2Me
N
N
AuL
Cy
Cy
P Au NCMe
SbF
CO2Me
11
10
6
i-Pr
i-Pr
1- PhMgBr, THF
CO2Me
i-Pr
-78°C
N
N
N
2- NaH,
Br
N
CO2Me
solvent, temp.
CO2Me
CO2Me
TBAI, DMF, RT
80%
9
DEAD
AuL
N
N
CO2Me
CO2Me
N
N
CO2Me
12
CO2Me
13
10
SolventT emp. Time
Yield 13
1 mol%
4 mol%
4 mol%
100°C
100°C
110°C
3h
24h
24h
0%
0%
0%
CH3NO2
CH3NO2
toluene
Scheme 2. Hydroarylation attempt with arylhydrazine 9.

I.D. Jurberg, F. Gagosz / Journal of Organometallic Chemistry 696 (2011) 37e41
39
Cy
Cy
P Au NCMe
10
SbF
Me
6
i-Pr
pTsOH
i-Pr
(5 mol%)
i-Pr
N
N
N
N
Ph
CO2Me
N
CO2Me
N
Ph
CO2Me
CHCl3
1.5h, 60°C
76%
CH3NO2, 100°C
Ph
14
15
16
10
Time
Yield 15
1 mol%
4 mol%
5h
1h
0%
99%
Scheme 3. Hydroarylation attempt with arylhydrazine 14.
1- MeOC(O)Cl, DCM
0°C to RT
3- RMgX
THF, -78°C
NH2
N
N
N
H
N
CO2Me
N
R
CO2Me
17a-d
4- NaH,
Br
TBAI, DMF, RT
2- MnO2, DCM, RT
R= C5H11
Bn
64%
20%
17a
17b
17c
17d
i-Pr
t-Bu
47%
66%
Scheme 4. Four steps/1 purification procedure for the synthesis of phenylhydrazine derivatives 17aed.
loading of the catalyst (4 mol%) had a remarkable effect since the
exo-methylene tetrahydrocinnoline 15 was obtained in 99% yield
after only 1 h of reaction [10]. Notably, no formation of 1,2-dihy-
drocinnoline 16 that could be formed by a gold-catalyzed isomer-
ization of the exo-methylene functionality was observed under
these conditions [11]. Isomeric compound 16 could however be
obtained in a good yield (76%) by a simple subsequent treatment of
15 with a catalytic amount of pTsOH (5 mol%) in refluxing
chloroform.
Having in hand an efficient catalytic system for the conversion
of substrate 15 into tetrahydrocinnoline 16, we next decided to
study its applicability to other substrates. We first focused our
attention on the variation of the substituent at the nitrogen atom
attached to the phenyl ring. For this purpose, a series of N-alkylated
substrates 17aed were synthesized from phenylhydrazine in
a practical 4 steps/1 purification procedure (Scheme 4). With the
exception of benzyl derivative 17b, this synthetic route proved to be
efficient and the desired substrates for the hydroarylation reaction
17aed were obtained in yields ranging from 47e66%.
The transformation tolerated either a primary (pentyl or benzyl)
or a secondary (isopropyl) alkyl group on the nitrogen atom. A low
yield (25%) was however obtained in the case of the N-tert-butyl
substituted substrate 17d. A possible competitive 5-endo nucleo-
philic addition of the tert-butylamino group onto the activated
alkyne, which would lead to the formation of a probably unstable
dihydropyrazole 190 after fragmentation of the t-Bu-N bond, might
be responsible for this loss of efficiency (Scheme 5) [12].
Compounds 18aec could also be easily isomerized into 1,2-dihy-
drocinnolines 19aec under acidic conditions.
We next turned our attention to the possibility of performing
the hydroarylation on substrates possessing variously substituted
aromatic nuclei. para-Substituted phenylhydrazine derivatives
20aeg were then synthesized following the same practical route
than that used for the formation of compounds 17aed (see Scheme
4) and subsequently reacted with gold catalyst 10.
As seen from the results compiled in Table 2, the nature of the
para substituent had no noticeable influence on the efficiency of the
reaction. Substrates 20aef bearing either an electron-donating
group (OMe), an electron-withdrawing group (CO2Et, CN, CF3) or an
halogen atom (F, Cl) on the aryl nucleus reacted equally to give the
corresponding exo-methylene tetrahydrocinnolines 21aef in good
to excellent yields (63-99%). The reaction times were however
increased to 5e18 h. Compounds 21aef could be subsequently
isomerized into the corresponding 1,2-dihydrocinnolines 22aef by
treatment with a catalytic amount of pTsOH. A limit in reactivity
was however reached with the electron poor para-nitrophenyl
derivative 20g which did not furnish the desired tetrahydrocinno-
line 21g even after a prolonged reaction time.
We were pleased to see that the treatment of substrates 17aed
with 4 mol% of 10 in refluxing nitromethane also led to the rapid
formation (1e3 h) of the corresponding exo-methylene tetrahy-
drocinnoline 18aed in generally high yields (25e99%) (Table 1).
Table 1
Hydroarylation of N-substituted phenylhydrazine derivatives 17aed.
The formation of cinnoline derivatives from ortho- and meta-
substituted aryl substrates was next investigated (Scheme 6). For
AuL
R
Time (h)
Yielda (%)
Time (h)
Yielda (%)
LAu
5-endo
- AuL
C5H11
Bn
i-Pr
18a
18b
18c
18d
2.5
1.5
1
99
87
96
25
19a
19b
19c
1
0.5
0.5
91
80
75
N
N
CO2Me
t-Bu
CO2Me
N
N
Ph
N
N
CO2Me
Ph
-
Ph
19'
t-Bu
17d
t-Bu
3
a
Isolated yields.
Scheme 5. Possible competitive reaction in the case of substrate 17d.

40
I.D. Jurberg, F. Gagosz / Journal of Organometallic Chemistry 696 (2011) 37e41
Table 2
difficult in these cases due to a probable unfavorable steric inter-
action in the cyclization transition state between the methyl group
on the nitrogen atom and the substituent at the ortho position of
the aryl group. This possible steric interaction might also be
invoked to explain the unexpected formation of compounds 28a,b
(minimizing the interactions between the methyl group and the
ortho sustituent in the cyclization transition state might allow the
direct competitive formation of a new 7-membered cycle).
Hydroarylation of para-substituted phenylhydrazine derivatives 20aeg.
We finally focused our attention on the hydroarylation of
hydrazine derivatives possessing a phenyl group and a substituted
aryl groups attached to the same nitrogen atom (Scheme 7).
The reactions of substrates 29aec were rapid and extremely effi-
cientwhateverthenatureofthesubstituentattheparapositionofthe
second aromatic nucleus. Surprisingly, little selectivity was observed
in the case of substrates 29a and 29b bearing respectively an electron
donating alkoxy group and an electron-withdrawing ester group. In
these cases, tetrahydrocinnolines 31a and 31b, resulting from the
attack of the unsubstituted aromatic ring onto the gold-activated
R
Yielda (%)
Time (h) Yieldb (%)
Time (h) Yieldb (%)
MeO 20a 60
Cl
F
CO2Et 20d 71
CN
21a
9
83
99
79
86
63
76
0
22a
22b
22c
22d
1
1
1
1
88
95
75
81
73
67
20b 71
20c 99
21b 18
21c 13
21d 14
20e 87
20f 77
20g 71
21e
5
22e 4.5
22f 1.5
CF3
NO2
21f 17
21g 24
a
Global yield for the formation of 20 from the corresponding arylhydrazine.
Isolated yields.
b
R
10 (4 mol%)
N
N
N
R
N
CO2Me
R
N
CO2Me
N
CO2Me
CH3NO2, 100°C
Me
24a-b
Me
23a-b
Me
25a-b
(24a:25a = 1:1)
(24b:25b = 1:1)
R= Me 23a 73%
(24a+25a) 3.5h 96%
(24b+25b) 14h 96%
23b 70%
Cl
10 (4 mol%)
N
N
N
N
N
CO2Me
N
CO2Me
CH3NO2, 100°C
CO2Me
R
R
Me
26a-b
R
Me
27a-b
Me
28a-b
(27a:28a = 6.5:1)
R= Me 26a
(27a+28a)
72%
32h 81%
(27b:28b = 3:1) (50-60% SM)
26b 70%
(27b+28b) 72h 32%
Cl
Scheme 6. Hydroarylation of ortho- and meta-substituted phenylhydrazine derivatives 23a,b and 26a,b.
meta-substituted substrates 23a,b, the hydroarylation step could be
efficiently performed but mixtures of tetrahydrocinnolines 24a,b
and 25a,b were obtained as the result of an unselective nucleophilic
addition of the aryl nucleus onto the gold-activated alkyne. In the
case of ortho-substituted substrates 26a,b, the hydroarylation
proved to be more difficult and longer reaction times were
required. Moreover, mixtures of products were isolated in these
cases. While the tetrahydrocinnolines 27a,b remained the major
products, they were isolated in mixture with variable amounts of
compounds 28a,b which were formed following a competitive 7-
endo hydroarylation process. The hydroarylation might be more
alkyne, were found to be the major compounds. This poor selectivity
is unexpected as one would have supposed that the more electron
rich aromatic moiety would have been the more probable nucleo-
philic partner in the hydroarylation process. The result obtained with
substrate 29c was even more surprising. The presence of a simple
fluorine atom atthepara positionofone of thearomaticsdramatically
increased the selectivity. In this case, the nucleophilic addition of the
unsubstituted phenyl ring on the alkyne was predominant. While
only little effect of the fluorine atom onto the selectivity of the reac-
tion might have been expected, tetrahydrocinnoline 31c was formed
as the major compound. The rationalization of the observed
R
CO2Me
R
R
N
10 (4 mol%)
N
N
N
N
Ph
CO2Me
N
CO2Me
82%
CH3NO2, 100°C
Ph
29a-c
31a-c
30a-c
(30a:31a = 1:2)
(30b:31b = 1:1.5)
(30c:31c = 1:6)
R=
29a
(30a+31a)
OMe
CO2Et
F
1h 81%
29b 72%
29c 77%
(30b+31b) 0.5h 97%
(30c+31c) 0.5h 99%
Scheme 7. Competitive hydroarylation experiments with diarylhydrazine derivatives 29aec.

I.D. Jurberg, F. Gagosz / Journal of Organometallic Chemistry 696 (2011) 37e41
41
(b) F. Istrate, A. Buzas, I. Dias Jurberg, Y. Odabachian, F. Gagosz, Org. Lett. 10
(2008) 925e928;
(c) F. Istrate, F. Gagosz, Org. Lett. 9 (2007) 3181e3184;
selectivity is difficult as it cannot be easily explained by simply
considering the involvement of electronic and/or steric effects. These
results will lead us to look into the exact nature of the hydroarylation
mechanism since the one initially presented in Scheme 1 appears to
be too simplistic in the light of these final observations.
(d) A. Buzas, F. Gagosz, Synlett 17 (2006) 2727e2730.
[5] C. Gronnier, Y. Odabachian, F. Gagosz, Chem. Commun. (2010). doi:10.1039/
C0CC00033G.
[6] For examples of gold(I)-catalyzed formation of quinoline derivatives following
a hydroarylation process, see: (a) R.S. Menon, A.D. Findlay, A.C. Bissember,
M.G. Banwell, J. Org. Chem. 74 (2009) 8901e8903;
3. Summary
(b) X. Zeng, G.D. Frey, R. Kinjo, B. Donnadieu, G. Bertrand, J. Am. Chem. Soc.
131 (2009) 8690e8696;
In summary, we have shown that a series of N-propargyl-N0-
arylhydrazines can be efficiently converted into functionalized exo-
methylene tetrahydrocinnolines following a hydroarylation process
catalyzed by a gold(I) complex. This new synthetic procedure is
extremely practical since the hydroarylation substrates can be easily
obtained in a 4 steps/1 purification procedure from commercially
available arylhydrazines. The transformation was found to be
compatible with the presence of different aryl or alkyl groups on the
nitrogen atom attached to the aromatic nucleus and tolerates various
aromatic substituents [13]. Notably, the reaction was performed on
substrates possessing a basic nitrogen atom. The possible coordina-
tion of the electrophilic gold (I) complex [XPhosAu(NCCH3)SbF6] 10
with this nitrogen atom should therefore be ineffective or at least not
strongly competitive with the coordination to the alkyne moiety and
its subsequent activation. The hydroarylated compound could also be
subsequently isomerized into the corresponding 1,2-dihydrocinno-
lines under catalytic acidic conditions. Further studies related to the
synthesis of other polycyclic heteroaromatics by a gold-catalyzed
hydroarylation reaction as well as studies concerning the elucidation
of the exact mechanism of the process are underway.
(c) F. Xiao, Y. Chen, Y. Liu, J. Wang, Tetrahedron 64 (2008) 2755e2761;
(d) X.-Y. Liu, P. Ding, J.-S. Huan, C.-M. Che, Org. Lett. 9 (2007) 2645e2648;
(e) C. Nevado, A.M. Echavarren, Chem.dEur. J. 11 (2005) 3155e3164.
[7] For a recent review on hydroarylation reactions catalyzed by electrophilic
metal complexes, see: P. de Mendoza, A.M. Echavarren Pure Appl. Chem. 82
(2010) 801e820 For selected reviews on gold catalysis, see:;
(a) A. Fürstner, Chem. Soc. Rev. 38 (2009) 3208e3221;
(b) P. Belmont, E. Parker, Eur. J. Org. Chem. (2009) 6075e6089;
(c) V. Michelet, P.Y. Toullec, J.P. Genêt, Angew. Chem., Int. Ed. 47 (2008)
4268e4315;
(d) A.S.K. Hashmi, M. Rudolph, Chem. Soc. Rev. 37 (2008) 1766e1775;
(e) E. Jiménez-Núñez, A.M. Echavarren, Chem. Rev. 108 (2008) 3326e3350;
(f) Z. Li, C. Brower, C. He, Chem. Rev. 108 (2008) 3239e3265;
(g) A. Arcadi, Chem. Rev. 108 (2008) 3266e3325;
(h) D.J. Gorin, F.D. Toste, Chem. Rev. 108 (2008) 3351e3378;
(i) R. Skouta, C.-J. Li, Tetrahedron 64 (2008) 4917e4938.
[8] A carbamate or a tosylamide group was not compatible with this trans-
formation, see Ref. [5].
[9] A very low yield of the desired quinoline derivative was obtained when the
malonate group was omitted, see Ref. [5].
[10] A more favourable coordination of the nitrogen atom with the gold complex
in hydrazine derivative 14 might be responsible for the higher loading of gold
catalyst required (by comparison with the formation of quinoline derivatives
5, see Ref. [5]).
[11] This contrasts with our previously reported synthesis of quinoline derivatives
5 for which a partial gold-catalyzed isomerization of the exo-methylene
function was generally observed, see Ref. [5].
[12] The formation of numerous unidentified by-products lacking the tert-butyl
moiety was observed. For selected examples of intermolecular hydro-
aminations of alkynes, see: (a) S. Kramer, J.L.H. Madsen, M. Rottländer,
T. Skrydstrup, Org. Lett. 12 (2010) 2758e2761;
Acknowledgement
The authors wish to thank Prof. S. Z. Zard for helpful discussions
and G. Henrion for preliminary results.
(b) H. Duan, S. Sengupta, J.L. Petersen, N.G. Akhmedov, X. Shi, J. Am. Chem. Soc.
131 (2009) 12100e12102;
(c) X. Zeng, G.D. Frey, S. Kouzar, G. Bertrand, Chem.dEur. J. 15 (2009)
3056e3060;
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unsuccessful.
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