Pd-assisted cross-coupling reactions with 4-chlorocinnoline

Article abstract of DOI:10.1002/jhet.1050

A series of 4-ethynylcinnolines 3a-e was prepared by Sonogashira reaction of 4-chlorocinnoline (1) with appropriate alkynes. Moreover, Suzuki coupling of with boronic esters gave the corresponding 4-arylcinnolines 5a-c. Detailed NMR spectroscopic data including unambiguous chemical shift assignments of all ¹H, ¹³C, and ¹⁵N resonances of the obtained cinnoline derivatives are reported.

Full text of DOI:10.1002/jhet.1050

January 2013
Pd‐Assisted Cross‐Coupling Reactions with 4‐Chlorocinnoline
141
*
Helmut Julian Heiter, Gyte Vilkauskaite, and Wolfgang Holzer
Department of Drug and Natural Product Synthesis, Faculty of Life Sciences,
University of Vienna, A‐1090 Vienna, Austria
*
E-mail: wolfgang.holzer@univie.ac.at
Received May 6, 2011
DOI 10.1002/jhet.1050
View this article online at wileyonlinelibrary.com.
A series of 4‐ethynylcinnolines 3a–e was prepared by Sonogashira reaction of 4‐chlorocinnoline (1)
with appropriate alkynes. Moreover, Suzuki coupling of 1 with boronic esters gave the corresponding
4‐arylcinnolines 5a–c. Detailed NMR spectroscopic data including unambiguous chemical shift assign-
1
ments of all H, 13C, and 15N resonances of the obtained cinnoline derivatives are reported.
J. Heterocyclic Chem., 50, 141 (2013).
INTRODUCTION
attempts to react 1 with phenylacetylene in triethylamine
in the presence of bis(triphenylphosphine)palladium(II)
chloride showed a high degree of conversion. This hints
to a sufficient reactivity of the chloro atom in compound
1 regarding Sonogashira‐type reactions, for which a
general reactivity I > OTf ∼ Br > Cl is specified in the
literature [15]—with a considerable number of cases known
where chloroarenes do not react. In the following, 1 was
reacted with a series of terminal alkynes 2a–e to obtain the
corresponding 4‐alkynylcinnolines 3a–e in moderate to
good yields (Scheme 1). Of this series, only 3a is a known
compound that has been formerly prepared by reaction of
4‐methylsulfonylcinnoline and phenylacetylene in the
presence of a base [16].
In contrast, Suzuki couplings of 4‐chlorcinnoline (1) with
substituted phenyboronic acids have been already reported
by Quéguiner and coworkers [13]. In addition, we reacted
1 with phenylboronic acid (4a), (2‐formylphenyl)boronic
acid (4b) and 3‐thienylboronic acid (4c) to reach the
corresponding 4‐arylcinnolines 5a–c (Scheme 1).
The obtained 4‐substituted cinnolines of types 3 and
5 were subjected to detailed NMR spectroscopic investi-
gations (concentrations of the used solutions ∼ 0.15 M).
Full and unambiguous assignment for all proton, carbon,
and nitrogen resonances was achieved by combined
application of standard NMR spectral techniques [17]
such as fully 1H‐coupled 13C‐NMR spectra, APT,
COSY, HMQC, HSQC, and HMBC. In special cases,
for the unambiguous determination of long‐range 13C,1H
coupling constants 2D(d,J) INEPT spectra with selective
excitation were applied [18]. The 15N‐NMR spectra were
mainly recorded using the gradient selected, sensitivity
In contrast to the pyridazine system that is the core
structure of a considerable number of drug molecules [1],
benzo[a]pyridazine, i.e., cinnoline, is a rather rarely
concerned system which has fallen somewhat into obliv-
ion for medicinal chemists [2]. Thus, the antibacterial
agent Cinoxacin (Fig. 1) is yet the only example of a drug
molecule on the market incorporating a cinnoline nucleus [3].
In continuation of our studies on 4‐substituted cinno-
lines [4, 5], we here report on investigations regarding
functionalization of 4‐chlorocinnoline (1) via Pd‐assisted
cross‐coupling reactions. Such types of reactions have
emerged to be one of the most powerful tools in modern
synthetic organic chemistry, enabling not only carbon–
carbon but as well carbon–nitrogen bond formation
[6–9]. Also for the cinnoline system, commensurate cou-
plings of 3‐ and 4‐halocinnolines have been reported [10–14].
However, to the best of our knowledge, a systematic
study concerning Sonogashira‐type couplings with 4‐
chlorocinnoline (1) has not been published. The latter
compound represents an ideal starting material due to its
stability and its facile accessibility. Hence, we here
report on the Sonogashira couplings with 4‐chlorocinnoline
(1) and on some arylations of the former using the Suzuki
protocol. In addition, a substantiated NMR study with the
obtained 4‐substituted cinnolines including also 15N‐NMR
chemical shifts is presented.
RESULTS AND DISCUSSION
The starting material 1 was obtained on treatment of
cinnolin‐4(1H)‐one with phosphoryl chloride [4]. Initial
© 2013 HeteroCorporation

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H. J. Heiter, G. Vilkauskaite, and W. Holzer
Vol 50
Shimadzu QP 1000 instrument (EI, 70 eV) and on a Finnigan
MAT 8230 instrument (ESI, HRMS). IR spectra were recorded
on a Perkin‐Elmer FTIR spectrum 1000 spectrophotometer.
Elemental analyses were performed at the Microanalytical
Laboratory, University of Vienna, using a Perkin‐Elmer 2400
1
CHN Elemental Analyzer. H‐NMR and 13C‐NMR spectra were
recorded on a Varian UnityPlus 300 spectrometer at 25°C
(299.95 MHz for 1H, 75.43 MHz for 13C) or on a Bruker Avance
500 spectrometer at 298 K (500.13 MHz for 1H, 125.77 MHz for
13C) from deuterichloroform solutions. The centre of the solvent
signal was used as an internal standard which was related to
tetramethylsilane with d 7.26 ppm (1H) and d 77.0 ppm (13C). The
15N‐NMR spectra were obtained on a Bruker Avance 500 instrument
with a “directly” detecting broadband observe probe and were
referenced against external nitromethane. Column chromatographic
separations were carried out using Silicagel60 (mesh) as stationary
phase. 4‐Chlorocinnoline (1) was prepared according to a procedure
described in the literature [4]. Product yields were not optimized.
General procedure for the reaction of 4‐chlorocinnoline (1)
with terminal acetylenes 2 (Sonogashira reaction). Triethylamine
(2.08 mL, 15 mmol), the appropriate acetylene 2 (4.5 mmol), Pd
(PPh3)2Cl2 (211 mg, 0.3 mmol), and CuI (114 mg, 0.6 mmol) were
added to a solution of 4‐chlorocinnoline (1) (494 mg, 3 mmol) in dry
dimethylformamide (10 mL) under an argon atmosphere. The
reaction mixture was stirred at 55°C under an argon atmosphere for 2
h, then it was poured into water (30 mL).The mixture was extracted
with ethyl acetate (3 × 20 mL), the combined organic layers were
washed with brine and dried over sodium sulfate. The solvent was
evaporated, and the residue was treated as described below.
4‐(Phenylethynyl)cinnoline (3a). Column chromatography
(SiO2, eluent ethyl acetate/light petroleum, 1:3 v/v) afforded
387 mg (56%) of brownish crystals, mp 106–107°C (EtOH)
(lit. [16] mp 107.5–108°C); IR (KBr): 2203 (C C) cm−1; ms:
m/z 231 (M+ + 1, 18), 230 (M+, 61), 202 (30), 201 (30), 200
(48), 149 (24), 75 (21), 74 (29), 73 (29), 71 (43), 70 (25), 69
(80), 67 (27), 57 (100), 56 (35), 55 (85), 51 (21), 50 (26), 43 (94).
4‐(3‐Thienylethynyl)cinnoline (3b). Column chromatography
(SiO2, eluent ethyl acetate/light petroleum, 1:3 v/v) afforded 545 mg
(77%) of brownish crystals, mp 87.5–89°C (EtOH); IR (KBr): 2198
(C C) cm−1; ms: m/z 236 (M+, 30), 163 (22), 85 (33), 83 (24), 73
(30), 71 (41), 69 (37), 57 (100), 56 (60), 55 (90), 43 (94). Anal.
Calcd. for C14H8N2S•0.1 H2O: C, 70.62; H, 3.47; N, 11.77.
Found: C, 70.65; H, 3.26; N, 11.56.
Figure 1. Cinoxazin, an antibacterial agent containing a cinnoline nucleus.
enhanced HMBC sequence [19]. The obtained data show a
high degree of consistency and are summarized for com-
pound 3 in Table 1 (1H‐NMR, 13C‐NMR, and 15N‐NMR).
The data of 5a–c are given in the Experimental section.
In Figure 2, the chemical shifts (1H, 13C, and 15N) for
compound 3b—as a representative example—are displayed.
1
Moreover, selected H,13C correlations extracted from the
HMBC spectra, being important for the unequivocal assign-
ment of resonances, are marked by round arrows.
It should be mentioned that the 1H‐NMR chemical shifts
of the cinnoline H‐atoms frequently exhibit a notable
dependence on the concentration. Thus, for instance, the
1H‐NMR spectrum of 3d taken from a less concentrated
solution (0.05M) shows 0.11–0.16 ppm larger chemical
shifts for all cinnoline ring protons compared to those
found with the 0.15M solution specified in Table 1. In
contrast, the corresponding 13C‐NMR spectra do not
manifest such explicit differences.
In conclusion, we have shown that 4‐alkynylcinnolines
are smoothly obtained by the Sonogashira coupling of 4‐
chlorocinnoline (1) with appropriate acetylenes. Com-
pound 1 is an ideal starting material for Suzuki couplings
as well, the latter leading to different 4‐arylcinnolines.
EXPERIMENTAL
Melting points were determined on a Reichert–Kofler hot‐stage
microscope and are uncorrected. Mass spectra were obtained on a
Scheme 1
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Pd‐Assisted Cross‐Coupling Reactions with 4‐Chlorocinnoline
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Table 1
1H‐NMR, 13C‐NMR, and 15N‐NMR data of compounds 3a–e in deuteriochloroform.
Nuclei
3a
3b
3c
3d
3e
9.29
8.17
7.79
7.85
8.51
H‐3a
H‐5
H‐6
H‐7
H‐8
9.36
8.26
7.8
7.86
8.52
9.31
8.2
7.76
7.82
8.49
9.27
8.16
7.77
7.84
8.53
9.13
8.02
7.65
7.75
8.41
H of R
7.67 (H2′,6′)
7.42 (H3′,5′)
7.43 (H4′)
7.73 (H2′)b
7.29 (H4′)b
7.36 (H5′)b
2.60 (≡CCH2)
1.69 (CH2)
1.54 (CH2Me)
0.98 (CH3)
–
2.88 (CH2)
3.99 (CH2OH)
3.91 (OH)
0.34 (Si(CH3)3)
N‐1
N‐2
C‐3
36.1
29.6
35.6
29.4
30.9
25.6
37.8
29.8
–
146
145.9
146.6
146.3
146.3
1J = 186.3
119.2
1J = 186.3
118.9
1J = 186.1
119.9
1J = 186.2
119.6
1J = 186.4
118.5
C‐4
2J(H3) = 5.5
3J(H5) = 4.9
125.4
C‐4a
125.7
126.3
126
125.7
3J(H3) = 5.2
124.8
C‐5
C‐6
C‐7
C‐8
C‐8a
124.8
131.5
131
130.1
149.7
124.9
131.3
130.9
130
124.8
131.4
131
129.6
149.5
124.9
131.7
131
131.5
130.9
130
130.1
149.7
149.7
149.7
4J(H3) = 1.0
82.2
Cinn‐C≡
82.5
74.2
75.1
3J(H3) = 4.3
3J(CH2) = 4.3
101.8
97.3
3J(H3) = 4.1
3J(H3) = 4.1
3J(H3) = 4.3
3J(CH2) = 4.3
104.6
3J(H3) = 4.0
Cinn‐C≡C
102.2
97
3J(H2′) = 3.8, 3J(H4′) = 2.2
131.1 (C2′)
109.2
C of R
121.6 (C1′)
19.6 (≡CCH2)
30.4 (≡CCH2CH2)
22.1
24.4
(≡CCH2)
–0.4 (SiCH3)
1J = 120.4
3J = 2.0
132.0 (C2′,6′)
128.6 (C3′,5′)
129.8 (C4′)
1J = 188.4, 3J(H4′) = 8.4, 3J(H5′) = 4.7
120.6 (C3′)
1J = 132.1
60.6 (CH2OH)
1J = 144.1
2J(H2′) = 3.2
(CH2CH3)
13.6 (CH3)
2J(H4′) = 4.9
3J(H5′) = 11.1
129.7 (C4′)
1J = 174.6
2J(H5′) = 4.6
3J(H2′) =8.3
126.1 (C5′)
1J = 187.9
2J(H4′) = 7.1
3J(H2′) = 5.8
d in ppm, J in Hz.
aH‐3 always gives a singlet signal, signals of H‐5 to H‐8, and most H of R are multiplets.
bThiophene system: 4J(H2′,H4′) = 1.1 Hz, 4J(H2′,H5′) = 3.0 Hz, 3J(H4′,H5′) = 5.0 Hz.
4‐(1‐Hexyn‐1‐yl)cinnoline (3c). Flash chromatography (SiO2,
eluent ethyl acetate) and further purification by column
chromatography (SiO2, eluent dichloromethane) gave 353 mg
(56%) of a tan oil; IR (KBr): 2223 (C C) cm−1; ms: m/z 210
(M+, 71), 167 (28), 166 (23), 165 (41), 154 (30), 153 (27), 152
(58), 140 (27), 139 (100), 126 (21), 75 (25), 74 (25), 63 (60),
51 (31), 50 (30), 43 (36). Anal. Calcd. for C14H14N2•0.2 H2O:
C, 78.62; H, 6.79; N, 13.10. Found: C, 78.33; H, 6.39; N, 12.81.
62 (28), 57 (44), 51 (39), 50 (25), 43 (42). Anal. Calcd. for C12H10N2O:
C, 72.71; H, 5.08; N, 14.13. Found: C, 72.47; H, 4.91; N, 14.00.
4‐[(Trimethylsilyl)ethynyl]cinnoline (3e). The raw product was
digested with light petroleum. Subsequent column chromatography
(SiO2, eluent ethyl acetate/light petroleum, 1:2 v/v) afforded 386
mg (57%) of a brownish oil which slowly solidified on standing;
IR (KBr): 2155 (C C) cm−1, ms: m/z 226 (M+, 10), 211 (26), 154
(100), 126 (71), 87 (25), 76 (56), 75 (52), 74 (84), 73 (24), 69
(32), 63 (58), 62 (36), 61 (34), 51 (26), 50 (84), 43 (23). HRMS
(ESI): Calcd. for C13H14N2NaSi: 249.0824. Found: 249.0819.
4‐(4‐Cinnolinyl)‐3‐butyn‐1‐ol (3d).
Column chromatography
(SiO2, eluent ethyl acetate/light petroleum, 1:1 v/v → ethyl acetate)
afforded 297 mg (50%) of bright yellow crystals, mp 92.5–93.5°C
(toluene); IR (KBr): 3353 (OH), 2225 (C C) cm−1; ms: m/z 198 (M+,
62), 140 (25), 139 (100), 77 (21), 74 (21), 69 (79), 67 (21), 63 (56),
General procedure for the reaction of 4‐chlorocinnoline (1)
with boronic acids 4 (Suzuki coupling).
Anhydrous K3PO4
(1.27 g, 6 mmol), the appropriate arylboronic acid 4 (3.15 mmol),
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H. J. Heiter, G. Vilkauskaite, and W. Holzer
Vol 50
(21), 71 (47), 67 (22), 63 (26), 57 (100), 51 (29), 43 (87). Anal.
Calcd. for C15H10N2O•0.1 H2O: C, 76.32; H, 4.36; N, 11.87.
Found: C, 76.30; H, 4.06; N, 11.63.
4‐(3‐Thienyl)cinnoline (5c).
Column chromatography
(SiO2, eluent ethyl acetate/light petroleum, 1:2 v/v) afforded
413 mg (65%) of brownish crystals, mp 109–110.5°C (EtOH);
1H‐NMR: d 7.40 (dd, 1H, J = 1.3, 5.0 Hz, Th H‐4), 7.58 (dd,
1H, J = 3.0, 5.0 Hz, Th H‐5), 7.65 (dd, 1H, J = 1.3, 3.0 Hz, Th
H‐2), 7.76 (m, 1H, H‐6), 7.86 (m, 1H, H‐7), 8.14 (m, 1H, H‐5),
8.56 (m, 1H, H‐8), 9.30 (s, 1H, H‐3); 13C‐NMR: d 124.5 (C‐5
1
3
and C‐4a), 126.6 (Th C‐2, J = 185.6 Hz, J(C2,H4) = 8.7 Hz,
3J(C2,H5) = 4.8 Hz), 127.3 (Th C‐5, J = 185.5 Hz, J(C5,H4)
1
2
3
1
= 5.3 Hz, J(C5,H2) = 8.7 Hz), 128.4 (Th C‐4, J = 168.4 Hz,
2J(C4,H5) = 5.3 Hz, 3J(C4,H2) = 8.7 Hz), 130.1 (C‐8), 130.7
1
(C‐7), 130.9 (C‐4), 131.6 (C‐6), 134.4 (Th C‐3), 143.7 (C‐3, J
= 182.8 Hz), 150.3 (C‐8a); 15N‐NMR: d 22.0 (N‐2), 27.7 (N‐1);
ms: m/z 213 (M+ + 1, 17), 212 (M+, 93), 184 (59), 183 (27),
152 (59), 140 (20), 139 (100), 79 (24), 75 (30), 74 (39), 69
(46), 63 (53), 62 (31), 58 (30), 57 (36), 51 (31), 50 (43), 45
(65). Anal. Calcd. for C12H8N2S•0.2 H2O: C, 66.77; H, 3.92; N,
12.98. Found: C, 66.79; H, 3.70; N, 12.62.
Figure 2. 1H (in italics), 13C, and 15N (in bold) NMR chemical shifts and
HMBC correlations (round arrows) for 3b (in deuteriochloroform).
Pd(PPh3)4 (277 mg, 0.24 mmol), and KBr (393 mg, 3.3 mmol)
were added to a solution of 4‐chlorocinnoline (1) (494 mg,
3 mmol) in 1,4‐dioxane (20 mL) under an argon atmosphere.
After refluxing under an argon atmosphere for 4 h, the mixture
was diluted with water (20 mL) and exhaustively extracted with
ethyl acetate. The combined organic layers were washed with
brine and dried over sodium sulfate. The residue obtained after
evaporation of the solvent (reduced pressure) was further treated
as described below.
Acknowledgments. The authors are grateful to L. Jirovetz for
recording the mass spectra.
REFERENCES AND NOTES
4‐Phenylcinnoline (5a). To remove a by‐product, the residue
was dissolved in 6N HCl (20 mL), the HCl‐phase was extracted
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with 2N NaOH and exhaustively extracted with dichloromethane.
The combined organic layers were dried over sodium sulfate, and
the solvent was evaporated. Column chromatography (SiO2,
eluent ethyl acetate/light petroleum, 1:2 v/v) afforded (248 mg,
40 %) of yellowish oil (lit. [20] mp 65.5–66°C).
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1H‐NMR: d 7.52–7.62 (m, 5H, Ph‐H), 7.74 (m, 1H, H‐6), 7.88
(m, 1H, H‐7), 8.01 (m, 1H, H‐5), 8.61 (m, 1H, H‐8), 9.28 (s, 1H,
H‐3); 13C‐NMR: d 124.5 (C‐4a), 124.6 (C‐5), 129.0 (Ph C‐3,5),
129.2 (Ph C‐4), 129.8 (Ph C‐2,6), 130.2 (C‐8), 130.4 (C‐7),
131.2 (C‐6), 134.2 (Ph C‐1), 135.2 (C‐4), 144.5 (C‐3, 1J =
183.4 Hz), 150.6 (C‐8a); 15N‐NMR: d 16.8 (N‐2), 25.1 (N‐1);
ms: m/z 206 (M+, 100), 178 (62), 177 (42), 176 (22), 152 (65),
151 (42), 150 (22), 78 (24), 77 (25), 76 (54), 75 (40), 74 (35),
63 (56), 62 (27), 57 (22), 52 (23), 51 (72), 50 (65). HRMS
(ESI): Calcd. for C14H10N2Na: 229.0742. Found: 229.0747.
2‐(4‐Cinnolinyl)benzaldehyde (5b). Column chromatography
(SiO2, eluent ethyl acetate/light petroleum, 1:2 v/v) afforded 344
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1
(KBr): 1688 (C O); H‐NMR: d 7.44 (m, 1H, Ph H‐3), 7.53 (m,
1H, H‐5), 7.71 (m, 2H, H‐6 and Ph H‐5), 7.78 (m, 1H, Ph H‐4),
7.88 (m, 1H, H‐7), 8.13 (m, 1H, Ph H‐6), 8.62 (m, 1H, H‐8),
9.24 (s, 1H, H‐3), 9.66 (s, 1H, CHO); 13C‐NMR: d 124.2 (C‐5),
125.5 (C‐4a), 129.4 (Ph C‐6), 129.9 (Ph C‐5), 130.2 (C‐8), 130.9
(C‐7), 131.3 (Ph C‐3), 132.1 (C‐6), 132.5 (C‐4), 134.1 (Ph C‐4),
134.5 (Ph C‐1), 136.3 (Ph C‐2), 144.4 (C‐3, 1J = 183.4 Hz),
149.9 (C‐8a), 190.1 (CHO, 1J = 177.5 Hz); 15N‐NMR: d 29.8
(N‐2), 37.0 (N‐1); ms: m/z 234 (M+, 3), 206 (21), 205 (71), 176
(33), 152 (23), 151 (22), 149 (27), 77 (21), 76 (29), 75 (22), 74
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet