Synthesis of 3,4-disubstituted cinnolines by the Pd-catalyzed annulation of 2-iodophenyltriazenes with an internal alkyne

Article abstract of DOI:10.1016/j.tet.2011.04.079

A simple and efficient synthesis of cinnolines was achieved by a palladium-catalyzed annulation methodology. 3,4-Disubstituted cinnolines are prepared via palladium-catalyzed annulation of 2-iodophenyltriazenes with an internal alkyne in moderate to good yields. Several internal alkynes are applicable to this reaction and it is compatible with a number of functional groups.

Full text of DOI:10.1016/j.tet.2011.04.079

Tetrahedron 67 (2011) 4933e4938
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Synthesis of 3,4-disubstituted cinnolines by the Pd-catalyzed annulation of
2-iodophenyltriazenes with an internal alkyne
*
Chuan Zhu, Motoki Yamane
Division of Chemistry and Biological Chemistry, School of Physical and Mathematical Sciences, Nanyang Technological University, 21 Nanyang Link, Singapore 637371, Singapore
a r t i c l e i n f o
a b s t r a c t
Article history:
A simple and efficient synthesis of cinnolines was achieved by a palladium-catalyzed annulation
methodology. 3,4-Disubstituted cinnolines are prepared via palladium-catalyzed annulation of 2-iodo-
phenyltriazenes with an internal alkyne in moderate to good yields. Several internal alkynes are appli-
cable to this reaction and it is compatible with a number of functional groups.
Ó 2011 Published by Elsevier Ltd.
Received 4 November 2010
Received in revised form 6 April 2011
Accepted 21 April 2011
Available online 28 April 2011
Keywords:
Palladium-catalyzed reaction
Heterocycles
Cinnoline
Annulation
2-Iodotriazene
1. Introduction
2. Results and discussion
Cinnolines and their derivatives exhibit a broad range of bi-
ological activity, such as: anticancer, fungicidal, bactericidal, and
anti-inflammatory properties.1 Additionally, compounds contain-
ing a cinnoline fragment demonstrate a series of interesting phys-
ical characteristics, such as luminescent and nonlinear optical
properties.2 Hence, the synthesis of cinnoline has been studied for
many years.3 Most syntheses of cinnolines involve arenediazonium
salts,4 arylhydrazones,5 arylhydrazines,6 and nitriles7 as their
starting materials. These procedures often suffer from certain
drawbacks, such as multi-step reactions and harsh reaction con-
ditions. Recently, alkynyl-substituted aryltriazene was used as the
precursor to prepare cinnoline,8 however high temperatures or
strong acidic conditions were still required. These reported annu-
lation reactions prompted us to investigate a single catalytic
reaction to prepare cinnolines and their derivatives. Palladium-
catalyzed annulation of alkynes by functionally substituted aryl
halides has been demonstrated to be a versatile methodology to
construct a wide variety of complicated hetero- and carbocycles.9
Herein, we would like to report a novel and efficient protocol to
synthesize various 3,4-disubstituted cinnolines by the reaction of
2-iodotriazenes with internal alkyne with a palladium catalyst.
The palladium-catalyzed reactions of 2-iodophenyltriazene
with diphenylacetylene are summarized in Table 1. 2-Iodophenyl-
triazene 1a was treated with diphenylacetylene (3 equiv) and Et3N
(2 equiv) in the presence of 10 mol % Pd(dba)2 in DMF and the re-
action mixture was heated at 100 ꢀC for 24 h. As we expected, 3,4-
diphenylcinnoline 3a was obtained in 40% yield (entry 1). Polar
solvents gave better yields and DMF was found as the best solvent
amongst the four solvents examined (entries 1e4). PdCl2/PPh3 gave
a similar result with 42% yield of 3a (entry 5). Various phosphine
ligands were tested and P(o-Tolyl)3 gave higher yield than the
others (entries 6e9). Furthermore, different bases, such as Et3N,
iPr2NEt, nBu3N, and K2CO3 were tested in the reaction, it was
revealed that nBu3N is superior to the others (entries 10e13). When
lower catalyst loadings were tested with 7.5 mol % and 5 mol %
PdCl2, cinnoline 3a was still obtained in 71% and 69% yields, al-
though they required longer reaction times, 15 h and 36 h, re-
spectively (entries 13 and 14). We therefore conclude that the
optimal reaction conditions for this annulation reaction is as fol-
lows: a mixture of 2-iodophenyltriazene and 3 equiv of alkyne in
DMF in the presence of 7.5 mol % of PdCl2, 15 mol % P(o-Tolyl)3 and
n
2 equiv of Bu3N are stirred at 90 ꢀC.
We proceeded to examine the scope and generality of this re-
action. A series of 4-substituted phenyltriazenes were employed in
this reaction (Table 2). We found that the reaction can tolerate a lot
of functional groups, such as alkyl, methoxy, cyano, nitro, tri-
fluoromethyl, acetyl, and methoxycarbonyl groups. The triazenes
* Corresponding author. Tel.: þ65 6515 8014; fax: þ65 67911961; e-mail address:
yamane@net.edu.sg (M. Yamane).
0040-4020/$ e see front matter Ó 2011 Published by Elsevier Ltd.
doi:10.1016/j.tet.2011.04.079

4934
C. Zhu, M. Yamane / Tetrahedron 67 (2011) 4933e4938
Table 1
Palladium-catalyzed reaction of 2-iodophenyltriazene 1a with Diphenylacetylene 2aa
N
[Pd], Ligand
Base
N
NEt2
N
N
+
Ph
Ph
Ph
Solvent
I
Ph
1a
2a
3a
Entry
Catalyst
Solvent
Base
Ligand
Temp (ꢀC)
Time (h)
Yield (%)
1
2
3
4
5
6
7
8
Pd(dba)2
Pd(dba)2
Pd(dba)2
Pd(dba)2
PdCl2
PdCl2
PdCl2
PdCl2
PdCl2
PdCl2
PdCl2
PdCl2
PdCl2
DMF
CH3CN
Toluene
1,4-Dioxane
DMF
DMF
DMF
DMF
DMF
DMF
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
None
None
None
None
PPh3
P(o-Tolyl)3
dppe
100
Reflux
100
100
90
90
90
90
90
90
90
100
90
90
24
24
24
24
24
12
24
24
24
24
12
12
15
24
40
30
7
8
42
62
Trace
45
30
65
67
65
71b
69c
dppf
9
Et3N
P(2-Furyl)3
P(o-Tolyl)3
P(o-Tolyl)3
P(o-Tolyl)3
P(o-Tolyl)3
P(o-Tolyl)3
10
11
12
13
14
iPr2NEt
nBu3N
K2CO3
nBu3N
nBu3N
DMF
DMF
DMF
DMF
PdCl2
a
Compound 1a (0.25 mmol), 2a (0.75 mmol), [Pd] (10 mol %), ligand (20 mol %), base (0.5 mmol), and solvent (5 mL) were heated under N2.
PdCl2 (7.5 mol %) and 15 mol % P(o-Tolyl)3 were employed.
PdCl2 (5 mol %) and 10 mol % P(o-Tolyl)3 were employed.
b
c
Table 2
iodophenyltriazene 1a was faster in the reaction with electron
deficient alkyne such as ethyl phenylpropiolate, the reaction gave
cinnoline and unidentified byproducts. (3,3-Diethoxyprop-1-ynyl)
benzene (2f) gave a mixture of regioselective products, 3-phenyl-
cinnolines having an acetal or aldehyde moiety. Coordination of the
ethoxy group of the alkyne may facilitate the regioselective addi-
tion of organopalladium intermediate although we are not sure
because the yield of the regioselective product is not high enough
to discuss the regioselectivity.
Palladium-Catalyzed Reaction of 2-Iodophenyltriazene 1 with diphenylacetylene
2aa
cat. PdCl2, P(o-Tolyl)3
N
N
I
NEt2
N
n
Bu3N
N
+
Ph
Ph
R1
Ph
R1
DMF, 90 °C
Ph
1a-i
2a
3a-i
Entry
R1
Time (h)
Yield (%)
1
2
3
4
5
6
7
8
9
H (1a)
15
15
12
15
24
36
24
18
24
3a
71
73
84
50b
42
46c
52
64
60
Plausible mechanisms for the annulation reaction of 1 with in-
ternal alkyne 2 are illustrated in Scheme 1. Oxidative addition of the
2-iodoaryltriazene to the in situ generated palladium(0) species
leads to arylpalladium intermediate A, which is followed by the
formation of vinylpalladium iodide complex B via addition to the
alkyne. One pathway is intermediate B undergoes a 6-endo addi-
tion10 of the vinylpalladium intermediate to the nitrogenenitrogen
Me (1b)
3b
3c
3d
3e
3f
3g
3h
3i
tBu (1c)
OMe (1d)
CN (1e)
NO2 (1f)
CF3 (1g)
COMe (1h)
COOMe (1i)
double bond to form an aminopalladium intermediate F11 or a 6
electron cyclization8cee occurs to give another aminopalladium
intermediate E. And then -amino elimination from E or F forms
the desired cinnoline as well as a diethylaminopalladium species,
which undergoes a -hydride elimination and subsequent elimi-
p
a
Conditions:
1 (0.25 mmol), 2a (0.75 mmol), PdCl2 (7.5 mol %), P(o-Tolyl)3
(15 mol %), and nBu3N (0.5 mmol) in 5 mL DMF under N2 atm, 90 ꢀC.
b
b
K2CO3 (2 equiv) was used as base and stirred at 100 ꢀC for 24 h.
c
nBu3N (5 equiv) was employed.
b
nation of HI by base to regenerate the Pd(0) catalyst. An alternative
pathway is that coordination of the pendent triazene to vinylic
palladium to form a seven-membered palladacyle C, which sub-
sequently generates a diethyliminoimmonium salt D as well as
Pd(0) via reductive elimination.12 As previously suggested by Haley
the diethyliminommounium salt D would afford cinnoline 3 in
presence of base.8d
gave the corresponding annulation products in moderate to good
yields. Amongst these substrates triazenes bearing alkyl sub-
stitutions lead to higher yields (entries 2 and 3).
Next, we examined the applicability of internal alkynes for this
reaction (Table 3). Symmetrical alkynes were tested first to check
the functional group tolerance. When 4,40-substituted diphenyla-
cetylenes 2bee were used in the reaction with 3,3-diethyl-(2-
iodophenyl)triazene (1a), the corresponding 3,4-disubstituted
cinnolines 3jem were obtained in good yields (entries 1e4). Thus,
carbonyl and chloro groups on the phenyl ring of the internal al-
kyne were found to be tolerated. When we used unsymmetrical
alkynes, such as ethyl phenylpropiolate (2g),1-phenylpropyne (2h),
and 1-phenylhexyne (2i), two regioisomers of cinnolines were
obtained in moderate yields in 56:44, 59:41, and 33:67 ratios, re-
spectively (entries 6e8). Although the consumption of the
3. Conclusion
In summary, we have demonstrated a simple and efficient
strategy for the synthesis of potentially important 3,4-disubstituted
cinnoline derivatives by palladium-catalyzed annulation of o-
iodophenyltriazene and internal alkyne. A wide range of function-
alized o-iodophenyltriazene as well as symmetric and asymmetric
internal alkyne can be utilized.

C. Zhu, M. Yamane / Tetrahedron 67 (2011) 4933e4938
4935
Table 3
Synthesis of 3,4-disubstituted cinnoline of 1a with 2a
7.5 mol% PdCl2
15 mol% P(o-Tolyl)3
N
N
I
NEt2
N
n
2.0 eq. Bu3N
N
R2
R3
+
R3
DMF, 90 °C
R2
3j-q
1a
2b-i
Entry
1
Alkyne
Time (h)
18
Product
Yield %
3j
75
Cl
Cl
N
N
R
2
3
18
18
3k
3l
82
73
MeOC
Me
COMe
Me
R
R = Cl, COMe, Me, OMe
4
5
15
15
3m
78
50
MeO
OMe
N
N
+
CH(OEt)2
Ph
3nþ3n0 (92:8)
CHO
Ph
CH(OEt)2
COOEt
Ph
6
7
15
3oþ3o0 (56:44)
35
Ph
N
N
+
Ph
81b
80
R
15
15
3pþ3p0 (59:41)
3qþ3q0 (33:67)
Ph
Ph
Me
R
Ph
R = COOEt, Me, Bu
n
8
Bu
a
n
Conditions: 1a (0.25 mmol), 2 (0.75 mmol), PdCl2 (7.5 mol %), P(o-Tolyl)3 (15 mol %), and Bu3N (0.5 mmol) in 5 mL DMF under N2, 90 ꢀC.
b
The two regioisomers were obtained as an inseparable mixture and their regiostructures were not assigned.
4. Experimental
4.1.1. 1-[4-(3,3-Diethyltriaz-1-en-1-yl)-3-iodophenyl]ethan-1-one
(1i). Yellow oil; IR (neat) 2974, 2934, 2872, 1674, 1581,
4.1. General
1542 cmꢁ1
;
1H NMR (400 MHz, CDCl3)
d
¼1.35 (dt, J¼19.6, 7.0 Hz,
6H), 3.84 (q, J¼7.0 Hz, 4H), 7.40 (d, 1H, J¼8.4 Hz), 7.87 (dd, J¼8.4,
1H NMR spectra were recorded at Bruker 400 MHz in CDCl3
1.6 Hz, 1H), 8.42 (d, J¼1.6 Hz, 1H); 13C NMR (100 MHz, CDCl3)
[using (CH3)4Si (for 1H,
d
¼0.00) as internal standard]. 13C NMR
d
¼10.9, 14.4, 26.5, 42.7, 49.7, 96.2, 116.8, 128.9, 134.8, 139.8,
spectra were recorded at Bruker 100 MHz in CDCl3 [using CDCl3 (for
153.9, 196.1. ESI-HRMS calcd for C12H17N3OI 346.0416, found
346.0416.
13C,
d
¼77.00) as internal standard]. IR spectra were recorded on
a Shimazu IR Prestige-21 FT-IR Spectrometer. High-resolution mass
spectra were obtained with a Finnigan MAT 95 XP mass spec-
trometer (Thermo Electron Corporation). Melting points were un-
corrected and were recorded on a Buchi B-54 melting point
apparatus.
4.2. General procedure for annulation of 2-iodoaryltriazene
with internal alkyne
A solution of compound 1 (0.25 mmol), alkyne (0.75 mmol),
PdCl2 (3.3 mg, 0.02 mmol), P(o-Tolyl)3 (11.4 mg, 0.04 mmol), and
Compounds 1aei were prepared according to known procedures.8e

4936
C. Zhu, M. Yamane / Tetrahedron 67 (2011) 4933e4938
n
u
3N
B
H
n
u
3N
B
Pd0
N
H
N
N
R
+
I
H
N
I-
Pd
D
N
I
NEt2
N
R
N
N
H
NEt2
+
N
N
G
R
N
NEt2
I
N
I-
Pd
N
Pd
R
A
I
R
3
Pd
N
R
R
N
C
I
R
Pd
N
NEt2
R
R
N
3
R
or
F
R
N
NEt2
N
N
NEt2
Pd
R
N
I
Pd
R
I
R
R
E
B
Scheme 1. Possible reaction mechanisms.
nBu3N (119
m
L, 0.50 mmol) in DMF (5 mL) was stirred at 90 ꢀC until
154.4. ESI-HRMS: found: m/z 339.1861. Calcd for C24H23N2: (MþH)þ
1 was consumed as monitored by TLC. The reaction mixture was
allowed to cool to room temperature. The solvent was evaporated
and the residue was purified by column chromatography on silica
gel (hexane/ethyl acetate/dichloromethane 10e5:1:1) to afford
corresponding cinnoline.
339.1869.
4.2.4. 6-Methoxy-3,4-diphenylcinnoline (3d). Rf¼0.22 (ethyl acetate/
hexane 1:3); yield: 50% (39.1 mg, 0.13 mmol); pale brown solid; mp
161e162 ꢀC (ethyl acetate); IR (neat) 3084, 3055, 2980, 2964, 2253,
1620 cmꢁ1
;
1H NMR (400 MHz, CDCl3)
d
¼3.77 (s, 3H), 6.87 (d,
J¼2.8 Hz,1H), 7.23e7.26 (m, 5H), 7.39e7.46 (m, 5H), 8.48 (d, J¼9.2 Hz,
1H); 13CNMR(100 MHz, CDCl3)
4.2.1. 3,4-Diphenylcinnoline (3a)13. Rf¼0.29 (ethyl acetate/hexane
1:3); yield: 71% (50.1 mg, 0.18 mmol); pale yellow solid; mp
150e151 ꢀC (ethyl acetate); IR (neat) 3105, 3061, 2980, 2930,
d¼55.6,101.3,123.6,127.6,127.8,128.2,
128.6, 130.2, 130.5, 131.7, 131.9, 134.6, 137.8, 146.8, 153.0, 161.2. ESI-
2245, 1636 cmꢁ1; 1H NMR (400 MHz, CDCl3)
d
¼7.24e7.28 (m, 5H),
HRMS: found: m/z 313.1347. Calcd for C21H17N2O: (MþH)þ 313.1341.
7.40e7.42 (m, 3H), 7.47e7.49 (m, 2H), 7.64e7.68 (m, 1H),
7.72e7.75 (m, 1H), 7.80e7.84 (m, 1H), 8.61e8.64 (m, 1H); 13C NMR
4.2.5. 3,4-Diphenylcinnoline-6-carbonitrile (3e). Rf¼0.30 (ethyl ac-
etate/hexane 1:3); yield: 42% (32.3 mg, 01.0 mmol); yellow solid;
mp 171e172 ꢀC (ethyl acetate); IR (neat) 3103, 3055, 2984, 2253,
(100 MHz, CDCl3)
d
¼125.3, 125.5, 127.87, 127.9, 128.3, 128.5, 129.8,
129.9, 130.4, 130.5, 131.2, 132.9, 134.1, 137.6, 149.4, 153.0. ESI-
HRMS: found: m/z 283.1236. Calcd for C20H15N2: (MþH)þ
283.1235.
2231, 1645, 1616 cmꢁ1; 1H NMR (400 MHz, CDCl3)
d¼7.24e7.26 (m,
2H), 7.31e7.32 (m, 3H), 7.48e7.49 (m, 5H), 7.95 (dd, J¼8.8, 1.6 Hz,
1H), 8.16 (d, J¼1.6 Hz, 1H), 8.75 (d, J¼8.8 Hz, 1H); 13C NMR
4.2.2. 6-Methyl-3,4-diphenylcinnoline (3b). Rf¼0.27 (ethyl acetate/
hexane 1:3); yield: 73% (54.0 mg, 0.18 mmol); pale yellow solid; mp
211e212 ꢀC (ethyl acetate); IR (neat) 3055, 2982, 2951, 2305,
(100 MHz, CDCl3)
d
¼114.9, 117.8, 125.0, 128.1, 128.6, 129.0, 129.2,
130.0, 130.2, 130.5, 131.6, 132.7, 132.8, 136.7, 148.4, 154.5. ESI-HRMS:
found: m/z 308.1198. Calcd for C21H14N3: (MþH)þ 308.1188.
1622 cmꢁ1; 1H NMR (400 MHz, CDCl3)
d¼2.47 (s, 3H), 7.22e7.26 (m,
5H), 7.39e7.41 (m, 3H), 7.45e7.47 (m, 3H), 7.63 (dd, J¼8.4, 1.2 Hz,
4.2.6. 6-Nitro-3,4-diphenylcinnoline (3f). Rf¼0.36 (ethyl acetate/
hexane 1:3); yield: 46% (37.6 mg, 0.12 mmol); yellow solid; mp
192e193 ꢀC (ethyl acetate); IR (neat) 3090, 3049, 2986, 2305,
1H), 8.49 (d, J¼8.4 Hz, 1H); 13C NMR (100 MHz, CDCl3)
¼22.2,
d
123.5, 125.6, 127.8, 128.2, 128.5, 129.6, 130.4, 130.5, 132.3, 134.3,
137.8, 141.9, 148.4, 153.0. ESI-HRMS: found: m/z 297.1398. Calcd for
C21H17N2: (MþH)þ 297.1392.
1624 cmꢁ1
;
1H NMR (400 MHz, CDCl3)
d
¼7.27e7.33 (m, 5H),
7.48e7.50 (m, 5H), 8.53e8.56 (m, 1H), 8.69 (d, J¼2.0 Hz, 1H), 8.81
(d, J¼9.2 Hz, 1H); 13C NMR (100 MHz, CDCl3)
¼123.0, 123.2, 125.0,
d
4.2.3. 6-tert-Butyl-3,4-diphenylcinnoline (3c). Rf¼0.37 (ethyl ace-
tate/hexane 1:3); yield: 84% (71.2 mg, 0.21 mmol); pale yellow
solid; mp 147e148 ꢀC; IR (neat) 3051, 2966, 2909, 2870, 1620,
128.1, 128.6, 129.1, 129.3, 130.3, 130.5, 132.4, 132.6, 134.2, 136.5,
148.4, 149.1, 154.5; ESI-HRMS: found: m/z 328.1092. Calcd for
C20H14N3O2: (MþH)þ 328.1086.
1554 cmꢁ1; 1H NMR (400 MHz, CDCl3)
d¼1.32 (s, 9H), 7.25e7.27 (m,
5H), 7.40e7.41 (m, 3H), 7.46e7.48 (m, 2H), 7.65 (d, J¼2.0 Hz, 1H),
4.2.7. 3,4-Diphenyl-6-(trifluoromethyl)cinnoline
(3g). Rf¼0.52
7.92 (dd, J¼8.8, 2.0 Hz, 1H), 8.55 (d, J¼8.8 Hz, 1H); 13C NMR
(ethyl acetate/hexane 1:3); yield: 52% (45.4 mg, 0.13 mmol); yel-
(100 MHz, CDCl3)
d
¼30.7, 35.5, 119.6, 125.3, 127.7, 127.8, 128.2,
low solid; mp 164e165 ꢀC (ethyl acetate); IR (neat) 3084, 3053,
128.4, 129.1, 129.4, 130.4, 130.5, 133.0, 134.3, 137.9, 148.4, 153.1,
2984, 2253, 1634 cmꢁ1
;
1H NMR (400 MHz, CDCl3)
d
¼7.26e7.31

C. Zhu, M. Yamane / Tetrahedron 67 (2011) 4933e4938
4937
(m, 5H), 7.45e7.49 (m, 5H), 7.97e8.00 (m, 1H), 8.07 (s, 1H), 8.77 (d,
7.61e7.65 (m, 1H), 7.75e7.79 (m, 2H), 8.56e8.58 (m, 1H); 13C NMR
(100 MHz, CDCl3)
129.8, 130.2, 130.9, 131.6, 131.8, 132.1, 149.2, 152.8, 159.3, 159.5. ESI-
HRMS: found: m/z 343.1454. Calcd for C22H19N2O2: (MþH)þ
343.1447.
J¼8.8 Hz, 1H); 13C NMR (100 MHz, CDCl3)
d
¼122.0, 123.3 (q,
d
¼55.1, 55.2,113.4,114.1,125.3,125.9,126.3,129.5,
J¼272.0 Hz), 123.7 (q, J¼5.0 Hz), 124.8, 125.5 (q, J¼3.0 Hz), 128.0,
128.4, 128.89, 128.94, 130.3,130.5, 131.6, 132.5 (q, J¼22.0 Hz), 133.1,
133.6, 137.0, 149.2, 154.2. ESI-HRMS: found: m/z 351.1119. Calcd for
C21H14F3N2: (MþH)þ 351.1109.
4.2.14. 4-(Diethoxymethyl)-3-phenylcinnoline (3n). Rf¼0.35 (ethyl
acetate/hexane 1:3); yield: 46% (35.4 mg, 0.11 mmol); pale brown
oil. The regiostructure of 3n was confirmed by NOESY analysis,
which shows no correlation between the hydrogen next to ethoxy
groups and the hydrogen on 5-cabon of cinnoline; IR (neat) 3061,
4.2.8. 1-(3,4-Diphenylcinnolin-6-yl)ethan-1-one
(3h). Rf¼0.19
(ethyl acetate/hexane 1:3); yield: 64% (51.8 mg, 0.16 mmol); yellow
solid; mp 170e171 ꢀC (ethyl acetate); IR (neat) 3053, 2984, 2304,
2252, 1687 cmꢁ1
;
1H NMR (400 MHz, CDCl3)
d
¼2.60 (s, 3H),
7.27e7.31 (m, 5H), 7.44e7.49 (m, 5H), 8.32e8.34 (m, 2H), 8.69 (d,
2957, 2930, 2870, 1738, 1657 cmꢁ1 1H NMR (400 MHz, CDCl3)
;
J¼9.2 Hz,1H); 13C NMR (100 MHz, CDCl3)
d
¼26.7,125.0,127.5,127.8,
d
¼1.15 (t, J¼7.2 Hz, 6H), 3.36 (m, 2H), 3.68 (m, 2H), 5.60 (s, 1H),
128.0, 128.2, 128.79, 128.85, 130.4, 130.5, 130.6, 133.4, 134.0, 137.1,
138.3, 149.7, 154.0, 197.0. ESI-HRMS: found: m/z 325.1335. Calcd for
C22H17N2O: (MþH)þ 325.1341.
7.52e7.58 (m, 3H), 7.69e7.71 (m, 2H), 7.77 (dd, J¼8.4, 8.4 Hz, 1H),
7.83 (dd, J¼8.4, 8.4 Hz, 1H), 8.58 (d, J¼8.4 Hz, 1H), 8.81 (d, J¼8.4 Hz,
1H); 13C NMR (100 MHz, CDCl3)
d¼15.2, 64.0, 102.3, 123.5, 126.8,
128.0, 128.4, 128.8, 129.9, 130.0, 130.2, 130.7, 137.2, 150.6, 153.5. ESI-
HRMS: found: m/z 309.1599. Calcd for C19H21N2O2: (MþH)þ
309.1603.
4.2.9. Methyl 3,4-diphenylcinnoline-6-carboxylate (3i). Rf¼0.30
(ethyl acetate/hexane 1:3); yield: 60% (51.0 mg, 0.15 mmol); yellow
solid; mp 199e200 ꢀC (ethyl acetate); IR (neat) 3053, 2986, 2955,
2305, 1724 cmꢁ1
;
1H NMR (400 MHz, CDCl3)
d
¼3.94 (s, 3H),
7.26e7.30 (m, 5H), 7.44e7.49 (m, 5H), 8.37e8.40 (m, 1H), 8.49e8.50
(m, 1H), 8.66e8.69 (m, 1H); 13C NMR (100 MHz, CDCl3)
4.2.15. 4-Phenylcinnoline-3-carbaldehyde (3n0). Rf¼0.25 (ethyl ac-
etate/hexane 1:3); yield: 5% (3.2 mg, 0.01 mmol); pale yellow solid.
The regiostructure of 3n0 was confirmed by NOESY analysis, which
shows no correlation between the hydrogen on the formyl group
and the hydrogen on 5-cabon of cinnoline; mp 245e246 ꢀC; IR
(neat) 3163, 3001, 2943, 2291, 2253, 1634 cmꢁ1; 1H NMR (400 MHz,
d¼52.7,
124.8, 128.0, 128.2, 128.8, 129.2, 130.4, 130.5, 132.1, 133.4, 133.9,
137.2, 149.7, 153.9, 165.8. ESI-HRMS: found: m/z 341.1294. Calcd for
C22H17N2O2: (MþH)þ 341.1290.
DMSO-d6, using residual DMSO as the internal standard;
d
¼2.50)
4.2.10. 3,4-Bis(4-chlorophenyl)cinnoline (3j). Rf¼0.31 (ethyl acetate/
hexane 1:3); yield: 75% (65.6 mg, 0.19 mmol); pale yellow solid; mp
164e165 ꢀC (ethyl acetate); IR (neat) 3053, 2984, 2305, 1645, 1636,
d
¼7.23e7.31 (m, 2H), 7.51 (d, J¼7.6 Hz, 1H), 7.56e7.63 (m, 3H),
7.77e7.79 (m, 2H), 8.21 (d, J¼7.6 Hz, 1H); 13C NMR (100 MHz,
DMSO-d6, using DMSO-d6 as the internal standard;
d
¼39.5)
1597 cmꢁ1; 1H NMR (400 MHz, CDCl3)
d
¼7.20 (d, J¼8.4 Hz, 2H), 7.28
d
¼112.0, 113.5, 121.0, 122.4, 123.7, 125.8, 129.0, 129.77, 129.84, 129.9,
(d, J¼8.4 Hz, 2H), 7.40 (d, J¼8.4 Hz, 2H), 7.43 (d, J¼8.4 Hz, 2H), 7.70
135.9, 149.1, 185.5. ESI-HRMS: found: m/z 257.0700. Calcd for
C15H10NaN2O: (MþNa)þ 257.0691.
(m, 2H), 7.84 (m, 1H), 8.61 (d, J¼8.4 Hz, 1H); 13C NMR (100 MHz,
CDCl3)
d
¼124.8, 125.1, 128.3, 129.1, 130.0, 130.2, 131.61, 131.65, 131.7,
131.8, 132.3, 134.4, 134.8, 135.8, 149.3, 151.7. ESI-HRMS: found: m/z
4.2.16. Ethyl 4-phenylcinnoline-3-carboxylate (3o). Rf¼0.28 (ethyl
acetate/hexane 1:3); yield: 19% (13.2 mg, 0.05 mmol); pale yellow
viscous oil. The regiostructure of 3o was assumed according to the
assignment of the regiostructure of 3o0; IR (neat) 3055, 2984, 2936,
351.0453. Calcd for C20H13Cl2N2: (MþH)þ 351.0456.
4.2.11. 1-{4-[3-(4-Acetylphenyl)cinnolin-4-yl]phenyl}ethan-1-one
(3k). Rf¼0.22 (ethyl acetate/hexane 1:1); yield: 82% (75.0 mg,
0.20 mmol); pale yellow solid; mp 182e183 ꢀC (ethyl acetate); IR
1722, 1626 cmꢁ1
;
1H NMR (400 MHz, CDCl3)
d
¼1.11 (t, J¼7.2 Hz,
3H), 4.27 (q, J¼7.2 Hz, 2H), 7.38e7.40 (m, 2H), 7.52e7.55 (m, 3H),
(neat) 3053, 3003, 2984, 1684, 1606 cmꢁ1 1H NMR (400 MHz,
;
7.75 (d, J¼3.6 Hz, 1H), 7.91e7.95 (m, 1H), 8.68 (d, J¼8.4 Hz, 1H), 8.65
CDCl3)
d
¼2.60 (s, 3H), 2.66 (s, 3H), 7.40 (d, J¼8.4 Hz, 2H), 7.58 (d,
(dd, J¼8.4 Hz, 1H); 13C NMR (100 MHz, CDCl3)
¼13.8, 62.0, 125.1,
d
J¼8.4 Hz, 2H), 7.68 (d, J¼8.4 Hz, 1H), 7.75 (dd, J¼8.4, 6.8 Hz, 1H),
125.8, 128.5, 129.0, 129.2, 130.2, 131.5, 131.8, 133.1, 135.6, 145.9,
150.5, 165.9. ESI-HRMS: found: m/z 279.1129. Calcd for C17H15N2O2:
(MþH)þ 279.1134.
7.88e7.93 (m, 3H), 8.03 (d, J¼8.4 Hz, 2H), 8.68 (d, J¼8.4 Hz, 1H); 13C
NMR (100 MHz, CDCl3)
d¼26.6, 124.8, 124.9, 128.0, 130.2, 130.6,
130.71, 130.74, 131.9, 132.3, 136.4, 137.0, 138.7, 141.9, 149.4, 151.6,
197.3, 197.7. ESI-HRMS: found: m/z 367.1448. Calcd for C24H19N2O2:
(MþH)þ 367.1447.
4.2.17. Ethyl 3-phenylcinnoline-4-carboxylate (3o0). Rf¼0.32 (ethyl
acetate/hexane 1:3); yield: 16% (11.2 mg, 0.04 mmol); pale yellow
solid. The structure of 3o0 was confirmed by comparing the spectral
data of the authentic compound, which was synthesized according
4.2.12. 3,4-Bis(4-methylphenyl)cinnoline (3l). Rf¼0.38 (ethyl ace-
tate/hexane 1:3); yield: 73% (56.6 mg, 0.18 mmol); pale yellow
solid; mp 136e137 ꢀC (ethyl acetate); IR (neat) 3049, 3030, 2982,
to the reference;14 1H NMR (400 MHz, CDCl3)
d
¼1.10 (t, J¼7.2 Hz,
3H), 4.32 (q, J¼7.2 Hz, 2H), 7.51e7.56 (m, 3H), 7.82e7.92 (m, 4H),
2922, 2243, 1612 cmꢁ1
2.40 (s, 3H), 7.08 (d, J¼8.0 Hz, 2H), 7.13 (d, J¼8.0 Hz, 2H), 7.21 (d,
J¼8.0 Hz, 2H), 7.39 (d, J¼8.0 Hz, 2H), 7.60e7.7.64 (m, 1H), 7.71e7.74
(m, 1H), 7.75e7.79 (m, 1H), 8.57e8.60 (m, 1H); 13C NMR (100 MHz,
;
1H NMR (400 MHz, CDCl3)
d
¼2.32 (s, 3H),
8.03 (d, J¼8.0 Hz, 1H), 8.65 (d, J¼8.4 Hz, 1H); 13C NMR (100 MHz,
CDCl3)
d
¼13.7, 62.4, 122.3, 124.0, 124.6, 128.6, 129.27, 129.29, 130.4,
132.5, 137.2, 149.3, 151.1, 166.6.
CDCl3)
d
¼21.2, 21.3, 125.4, 125.7, 128.6, 129.2, 129.6, 129.8, 130.2,
4.2.18. 3-Methyl-4-phenylcinnoline (3p) and 4-methyl-3-phenyl-
cinnoline (3p0). Rf¼0.18 (ethyl acetate/hexane 1:3); an inseparable
59:41 mixture of two isomers 3p and 3p0 were obtained in 81%
yield (44.6 mg, 20.2 mmol) as a pale yellow solid. Their regios-
tructures were not assigned. IR (neat) 3051, 2980, 2930, 2304,
130.4, 130.9, 131.2, 132.7, 134.8, 137.6, 138.0, 149.2, 153.0. ESI-HRMS:
found: m/z 311.1542. Calcd for C22H19N2: (MþH)þ 311.1548.
4.2.13. 3,4-Bis(4-methoxyphenyl)cinnoline (3m). Rf¼0.12 (ethyl ac-
etate/hexane 1:3); yield: 78% (66.8 mg, 0.20 mmol); pale yellow
solid; mp 137e138 ꢀC (ethyl acetate); IR (neat) 3051, 3005, 2960,
1616 cmꢁ1; 1H NMR (400 MHz, CDCl3) for minor isomer:
d
¼2.76 (s,
3H), 7.30e7.32 (m, 2H), 7.47e7.62 (m, 5H), 7.73e7.77 (m, 1H), 8.53
(d, J¼8.4 Hz, 1H). 1H NMR (400 MHz, CDCl3) for major isomer:
2936, 2837, 2250, 1609 cmꢁ1; 1H NMR (400 MHz, CDCl3)
d¼3.79 (d,
J¼1.2 Hz, 3H), 3.85 (d, J¼0.8 Hz, 3H), 6.82 (d, J¼8.4 Hz, 2H), 6.96 (d,
J¼8.4 Hz, 2H), 7.17 (d, J¼8.4 Hz, 2H), 7.44 (d, J¼8.4 Hz, 2H),
d
¼2.71 (s, 3H), 7.47e7.62 (m, 3H), 7.67e7.70 (m, 2H), 7.78e7.86 (m,
2H), 8.07e8.09 (m, 1H), 8.56e8.58 (m, 1H). 13C NMR (100 MHz,

4938
C. Zhu, M. Yamane / Tetrahedron 67 (2011) 4933e4938
Indian J. Chem. 2006, 45B, 1704e1709; (j) Choudhari, B. P.; Mulwad, V. V. Indian J.
CDCl3) for mixture:
d
¼14.6, 20.9, 123.3, 124.7, 125.4, 126.4, 128.3,
Chem. 2006, 45B, 309e313; (k) Vikas, S.; Darbhamulla, S. Afr. Health Sci. 2009, 9,
275e278; (l) Shaban, M. A.; Al Badry, O. M.; Kamala, A. M.; el Wahap Abd El-
Gawad, M. A. J. Chem. Res. 2008, 715e718; (m) Vargas, F.; Zoltan, T.; Rivas, C.;
128.46, 128.52, 128.8, 129.1, 129.2, 129.6, 129.7, 130.2, 130.4, 130.8,
130.9, 133.5, 134.3, 138.0, 148.5, 149.3, 151.5, 155.3. ESI-HRMS:
found: m/z 221.1081. Calcd for C15H13N2: (MþH)þ 221.1079.
ꢀ
ꢀ
ꢀ
Ramirez, A.; Cordero, T.; Díaz, Y.; Izzo, C.; Cardenas, Y. M.; Lopez, V.; Gomez, L.;
Ortega, J.; Fuentes, A. J. Photochem. Photobiol., B 2008, 92, 83e90; (n) Ryu, C.-K.;
Lee, J. Y. Bioorg. Med. Chem. Lett. 2006, 16, 1850e1853; (o) Ramalingam, P.;
Ganapaty, S.; Babu Rao, C.; Ravi, T. K. Indian J. Heterocycl. Chem. 2006, 15,
359e362 Cinnoline used as anti-inflammatory reagents: Lunniss, C.; Eldred, C.;
Aston, N.; Craven, A.; Gohil, K.; Judkins, B.; Keeling, S.; Ranshaw, L.; Robinson,
E.; Shipley, T.; Trivedi, N. Bioorg. Med. Chem. Lett. 2010, 20, 137e140.
4.2.19. 3-Butyl-4-phenylcinnoline (3q). Rf¼0.24 (ethyl acetate/hex-
ane 1:3); yield: 27% (17.7 mg, 0.07 mmol); pale yellow viscous oil.
The regiostructure of 3q was confirmed by NOESY analysis, which
showed no correlation between butyl hydrogen and the hydrogen
on 5-carbon of the cinnoline ring. IR (neat) 3061, 2959, 2930, 2870,
2. Cinnoline and derivertives exhibit luminescent and nonlinear optical proper-
ties: (a) Mitsumori, T.; Bendikov, M.; Sedo, J.; Wudl, F. Chem. Mater. 2003, 15,
1634, 1614 cmꢁ1
;
1H NMR (400 MHz, CDCl3)
d
¼0.82 (t, J¼7.4 Hz,
ꢀ
3759e3768; (b) Chapoulaud, V. G.; Ple, N.; Turck, A.; Queguiner, G. Tetrahedron
2000, 56, 5499e5507; (c) Busch, A.; Turck, A.; Nowicka, K.; Barasella, A.; An-
draud, C.; Ple, N. Heterocycles 2007, 71, 1723e1741.
3H), 1.24e1.32 (m, 2H), 1.70e1.76 (m, 2H), 3.00e3.04 (m, 2H),
7.29e7.31 (m, 2H), 7.44 (d, J¼8.4 Hz, 1H), 7.51e7.60 (m, 4H),
7.72e7.76 (m,1H), 8.54 (d, J¼8.4 Hz,1H); 13C NMR (100 MHz, CDCl3)
ꢀ
3. For the review about cinnoline synthesis, see: (a) Haider, N.; Holzer, W. Sci.
Synth. 2004, 16, 251e313; (b) Vinogradova, O. V.; Balova, I. A. Chem. Heterocycl.
Compd. 2008, 44, 501e522 For some recent examples, see: (c) Alajarin, M.;
Bonillo, B.; Marin-Luna, M.; Vidal, A.; Orenes, R.-A. J. Org. Chem. 2009, 74,
3558e3561; (d) Jiang, B.; Hao, W.-J.; Zhang, J.-P.; Tu, S.-J.; Shi, F. Org. Biomol.
Chem. 2009, 7, 1
d
¼13.8, 22.5, 32.5, 33.4, 125.0, 125.7, 128.4, 128.6, 129.1, 129.4, 129.8,
130.7, 133.2, 134.3, 149.0, 155.3. ESI-HRMS: found: m/z 263.1541.
Calcd for C18H19N2: (MþH)þ 263.1548.
171e1175; (e) Hasegawa, K.; Kimura, N.; Arai, S.; Nishida, A. J.
Org. Chem. 2008, 73, 6363e6368; (f) Vinogradova, O. V.; Sorokoumov, V. N.;
Vasilevskii, S. F.; Balovaa, I. A. Russ. Chem. Bull. 2008, 57, 1725e1733; (g) Ichi-
kawa, J.; Wada, Y.; Kuroki, H.; Miharab, J.; Nadanob, R. Org. Biomol. Chem. 2007,
5, 3956e3962; (h) Vinogradova, O. V.; Sorokoumov, V. N.; Vasilevsky, S. F.;
Balova, I. A. Tetrahedron Lett. 2007, 48, 4907e4909.
4.2.20. 4-Butyl-3-phenylcinnoline (3q0). Rf¼0.33 (ethyl acetate/hex-
ane 1:3); yield: 53% (34.8 mg, 0.13 mmol); pale yellow solid. The
regiostructure of 3q0 was confirmed by NOESY analysis, which
showed a correlation between butyl hydrogen and the hydrogen on
5-carbon of the cinnoline ring. Mp 68e69 ꢀC (ethyl acetate); IR
(neat) 3061, 2959, 2930, 2870, 1638, 1614 cmꢁ1; 1H NMR (400 MHz,
4. Cinnoline synthesis from arenediazonium salts: (a) Vasilevsky, S. F.; Tretyakov,
E. V.; Verkruijsse, H. D. Synth. Commun. 1994, 24, 1733e1736; (b) Vasilevsky, S.
F.; Tretyakov, E. V. Liebigs Ann. Chem. 1995, 775e779; (c) Alford, E. J.; Irving, H.;
Marsh, H. S.; Schofield, K. J. Chem. Soc. 1952, 2991e2993; (d) Nunn, A. J.;
Schofield, K. J. Chem. Soc. 1953, 3700e3706.
CDCl3)
d
¼0.85 (t, J¼7.4 Hz, 3H), 1.32e1.38 (m, 2H), 1.60e1.66 (m,
5. Cinnoline synthesis from arylhydrazones: (a) Pfannstiel, K.; Janecke, J. Ber.
Dtsch. Chem. Ges. 1942, 75, 1096e1107; (b) Baumgarten, H. E.; Anderson, C. H. J.
Am. Chem. Soc. 1958, 80, 1981e1984; (c) Kanner, C. B.; Pandit, U. K. Tetrahedron
1981, 37, 3513e3518; (d) Kiselyov, A. S. Tetrahedron Lett. 1995, 36, 1383e1386;
(e) Domingues, C. Tetrahedron Lett. 1999, 40, 5111e5114; (h) Shvartsberg, M. S.;
Ivanchikova, I. D. Tetrahedron Lett. 2000, 41, 771e773; (i) Al-Awadi, N. A.; El-
nagdi, M. H.; Ibrahim, Y. A.; Kaul, K.; Kumar, A. Tetrahedron 2001, 57,
1609e1614; (j) Gomaa, M. A.-M. Tetrahedron Lett. 2003, 44, 3493e3496.
2H), 3.05e3.09 (m, 2H), 7.49e7.56 (m, 3H), 7.60e7.63 (m, 2H),
7.77e7.84 (m, 2H), 8.09 (dd, J¼7.8,1.8 Hz,1H), 8.58 (dd, J¼7.8,1.8 Hz,
1H); 13C NMR (100 MHz, CDCl3)
d
¼13.6, 22.9, 27.5, 33.0,123.4,125.7,
128.3,129.6,129.8,130.7,130.8,133.2,138.4,149.2,155.5. ESI-HRMS:
found: m/z 263.1539. Calcd for C18H19N2: (MþH)þ 263.1548.
}
6. Cinnoline synthesis from arylhydrazines: (a) Neber, P. W.; Knoller, G.; Herbst,
Acknowledgements
K.; Trissler, H. A. Liebigs Ann. Chem. 1929, 471, 113e145; (b) Alford, E. J.; Scho-
field, K. J. Chem. Soc. 1952, 2081e2088.
7. Cinnoline synthesis from nitrile: Chen, D.; Yang, C.; Xie, Y.; Ding, J. Heterocycles
2009, 77, 273e277.
8. For review about triazene, see: Kimball, D. B.; Haley, M. M. Angew. Chem., Int. Ed.
We thank Nanyang Technological University for the generous
financial support.
2002, 41, 3338e3351 For cinnoline synthesis from triazenes, see: (a) Brase, S.;
€
Dahmen, S.; Heuts, J. Tetrahedron Lett. 1999, 40, 6201e6203; (b) Brase, S.; Gil, C.;
Supplementary data
Knepper, K. Bioorg. Med. Chem. 2002, 10, 2415e2437; (c) Kimball, D. B.; Hayes,
A. G.; Haley, M. M. Org. Lett. 2000, 2, 3825e3827; (d) Kimball, D. B.; Weakley, T.
J. R.; Herges, R.; Haley, M. M. J. Am. Chem. Soc. 2002, 124, 13463e13473; (e)
Kimball, D. B.; Weakley, T. J. R.; Haley, M. M. J. Org. Chem. 2002, 67, 6395e6405;
(f) Kimball, D. B.; Weakley, T. J. R.; Herges, R.; Haley, M. M. J. Am. Chem. Soc.
2002, 124, 1572e1573; (g) Vinogradovaa, O. V.; Sorokoumova, V. N.; Balova, I. A.
Tetrahedron Lett. 2009, 50, 6358e6360.
9. For review about palladium-catalyzed annulation with alkynes, see: (a) Zeni,
G.; Larock, R. C. Chem. Rev. 2006, 106, 4644e4680; (b) Zeni, G.; Larock, R. C.
Chem. Rev. 2004, 104, 2285e2309 For some recent examples, see: (c) Tsuka-
moto, H.; Kondo, Y. Org. Lett. 2007, 9, 4227e4230; (d) Heller, S. T.; Natarajan, S.
R. Org. Lett. 2007, 9, 4947e4950; (e) Yang, M.; Zhang, X.; Lu, X. Org. Lett. 2007, 9,
5131e5133; (f) Chernyak, N.; Tilly, D.; Li, Z.; Gevorgyan, V. Chem. Commun. 2010,
150e152.
Supplementary data associated with this article include 1H
and 13C NMR of 1i and 3aeq. Supplementary data associated
with this article can be found in online version at doi:10.1016/
j.tet.2011.04.079. These data include MOL files and InChIKeys of
the most important compounds described in this article.
References and notes
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~
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~
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