Full Paper
1
1
37.81, 132.69, 131.46, 130.51, 129.47, 127.98, 127.55, 127.39,
128.29, 127.41, 126.55, 126.20, 122.75, 20.98, 20.00 ppm. HRMS (ESI-
+
26.85, 126.75, 125.41 ppm. HRMS (ESI-TOF) m/z calcd. for C H ClN TOF) m/z calcd. for C H N [M + H] : 248.1434, found 248.1445.
13
8
18 17
+
[
M + H] : 214.0418, found 214.0457.
Preparation of Compound 5: To a 35 mL sealed tube (with a Tef-
lon® cap) equipped with a magnetic stir bar was sequentially added
2
-Chlorobenzo[h]quinoline (2o): 1H NMR (400 MHz, CDCl ): δ =
3
9
.17–9.09 (m, 1 H), 8.00 (d, J = 8.3 Hz, 1 H), 7.91–7.77 (m, 1 H), 7.72 2-chloroquinoline (163.6 mg, 1.0 mmol, 1.0 equiv.), NaN (130.1 mg,
3
(
(
1
1
d, J = 8.8 Hz, 1 H), 7.69–7.58 (m, 2 H), 7.55 (d, J = 8.8 Hz, 1 H), 7.40
2.0 mmol, 2.0 equiv.) and DMF (2 mL). The tube was sealed and
submerged into a pre-heated 120 °C oil bath. The reaction was
stirred for 24 h and cooled down to room temperature. The reaction
1
3
d, J = 8.3 Hz, 1 H) ppm. C NMR (100 MHz, CDCl ): δ = 149.72,
3
46.48, 138.47, 133.78, 130.41, 128.69, 128.05, 127.70, 127.22,
24.91, 124.65, 124.43, 122.58 ppm. HRMS (ESI-TOF) m/z calcd. for mixture was diluted with EtOAc (10 mL). The organic layer was sepa-
+
C H ClN [M + H] : 214.0418, found 214.0431.
rated and the aqueous layer was extracted with EtOAc (3 × 10 mL).
The combined organic extracts were washed with water (3 ×
13 8
1
1
-Chloroisoquinoline (2p): H NMR (400 MHz, CDCl ): δ = 8.26 (d,
3
10 mL), followed by saturated brine (3 × 10 mL). The organic layer
J = 8.5 Hz, 1 H), 8.20 (d, J = 5.7 Hz, 1 H), 7.77 (d, J = 8.0 Hz, 1 H),
7
H), 7.53 (d, J = 5.6 Hz, 1 H) ppm. C NMR (100 MHz, CDCl ): δ =
1
HRMS (ESI-TOF) m/z calcd. for C H ClN [M + H] : 164.0262, found
1
was dried with anhydrous Na SO , filtered, and concentrated under
2
4
.68 (ddd, J = 8.2, 6.9, 1.3 Hz, 1 H), 7.61 (td, J = 7.6, 6.9, 1.3 Hz, 1
1
3
reduced pressure. The residue was purified by column chromatogra-
3
phy over silica gel to afford the desired product as a white solid in
51.53, 141.41, 137.70, 131.16, 128.52, 126.92, 126.37, 120.76 ppm.
1
+
84 % yield. H NMR (400 MHz, CDCl
8
3
): δ = 8.59 (d, J = 8.4 Hz, 1 H),
9
6
1
3
.01–7.85 (m, 2 H), 7.85–7.75 (m, 2 H), 7.71–7.57 (m, 1 H) ppm.
C
64.0260.
NMR (100 MHz, CDCl ): δ = 147.29, 133.27, 131.13, 130.66, 128.91,
3
1
-Chloro-3-methylisoquinoline (2q): 1H NMR (400 MHz, CDCl3):
1
27.93, 123.70, 116.68, 112.47 ppm. HRMS (ESI-TOF) m/z calcd. for
δ = 8.21 (d, J = 8.5 Hz, 1 H), 7.72–7.59 (m, 2 H), 7.53 (ddd, J = 8.2,
6
+
C H N [M + H] : 171.0655, found 171.0682.
9
6 4
1
3
.8, 1.3 Hz, 1 H), 7.35 (s, 1 H), 2.59 (s, 3 H) ppm. C NMR (100 MHz,
CDCl ): δ = 150.75, 150.54, 138.52, 131.20, 127.56, 126.33, 125.01,
3
1
18.82, 23.72 ppm. HRMS (ESI-TOF) m/z calcd. for C H ClN [M +
10 8
+
H] : 178.0418, found 178.0445.
-Chloro-6-methylisoquinoline (2r): 1H NMR (400 MHz, CDCl3):
δ = 8.11 (d, J = 5.7 Hz, 1 H), 8.08 (d, J = 8.7 Hz, 1 H), 7.48 (s, 1 H),
Acknowledgments
1
This work was supported by the National Natural Science Foun-
dation of China (NSFC) (grant number U1463201), the National
High Technology Research and Development Program of China
(grant number 2014AA021201), the National Basic Research Pro-
gram of China (grant number 2012CB721104).
1
3
7
1
2
1
.42–7.35 (m, 2 H) ppm. C NMR (100 MHz, CDCl ): δ = 151.23,
3
41.71, 141.42, 137.95, 130.66, 126.07, 125.81, 125.20, 120.22,
+
1.80 ppm. HRMS (ESI-TOF) m/z calcd. for C H ClN [M + H] :
1
0 8
78.0418, found 178.0432.
1
4
8
-Bromo-1-chloroisoquinoline (2s): H NMR (400 MHz, CDCl ): δ =
3
.37 (s, 1 H), 8.21 (d, J = 8.4 Hz, 1 H), 8.06 (d, J = 8.4 Hz, 1 H), 7.76 Keywords: Synthetic methods · Nitrogen heterocycles ·
(
ddd, J = 8.3, 7.0, 1.1 Hz, 1 H), 7.65 (ddd, J = 8.2, 7.0, 1.0 Hz, 1
Halogenation · Nitrogen oxides · Phosphanes · Regioselectivity
13
H) ppm. C NMR (100 MHz, CDCl ): δ = 150.89, 142.70, 136.13,
3
1
32.34, 129.39, 127.69, 126.82, 126.54, 118.96 ppm. HRMS (ESI-TOF)
+
[1] For reviews and selected examples, see: a) D. A. Horton, G. T. Bourne,
M. L. Smythe, Chem. Rev. 2003, 103, 893–930; b) M. Vieth, M. G. Siegel,
R. E. Higgs, I. A. Watson, D. H. Robertson, K. A. Savin, G. L. Durst, P. A.
Hipskind, J. Med. Chem. 2004, 47, 224–232; c) M. E. Welsch, S. A. Snyder,
B. R. Stockwell, Curr. Opin. Chem. Biol. 2010, 14, 347–361; d) J. S. Carey,
D. Laffan, C. Thomson, M. T. Williams, Org. Biomol. Chem. 2006, 4, 2337–
m/z calcd. for C H BrClN [M + H] : 241.9367, found 241.9395.
9
5
1
6
8
-Bromo-1-chloroisoquinoline (2t): H NMR (400 MHz, CDCl ): δ =
3
.23 (d, J = 5.7 Hz, 1 H), 8.13 (d, J = 9.0 Hz, 1 H), 7.95 (d, J = 1.8 Hz,
H), 7.69 (dd, J = 9.0, 1.9 Hz, 1 H), 7.45 (d, J = 5.7 Hz, 1 H) ppm.
1
13
C NMR (100 MHz, CDCl ): δ = 151.65, 142.49, 138.66, 132.17,
3
2
447; e) A. Gualandi, L. Mengozzi, E. Manoni, P. G. Cozzi, Catal. Lett. 2015,
1
29.12, 128.15, 126.36, 125.43, 119.72 ppm. HRMS (ESI-TOF) m/z
+
145, 398–419; f) S. Tao, L. Li, J. S. Yu, Y. D. Jiang, Y. C. Zhou, C. S. Lee, S. T.
Lee, X. H. Zhang, O. Kwon, Chem. Mater. 2009, 21, 1284–1287.
calcd. for C H BrClN [M + H] : 241.9367, found 241.9398.
9
5
Preparation of Compound 4: To a 50 mL sealed tube (with a Tef-
lon® cap) equipped with a magnetic stir bar was sequentially added
[2] For representative examples of pharmaceuticals, see: a) A. Markham, D.
Faulds, Drugs 1998, 56, 251–256; b) C. Fournier, M. Hamon, M. Hamon,
J. Wannebroucq, S. Petiprez, J. Pruvo, B. Hecquet, Int. J. Pharm. 1994, 106,
2
-chloroquinoline (163.6 mg, 1.0 mmol, 1.0 equiv.), 2,4,6-Trimethyl-
phenylboronic acid (246.1 mg, 1.5 mmol, 1.5 equiv.), Pd(OAc)2
22.5 mg, 0.1 mmol, 0.1 equiv.), PPh3 (131.2 mg, 0.5 mmol,
.5 equiv.), K CO (414.6 mg, 3.0 mmol, 3.0 equiv.), DME (7.5 mL),
4
1–49; c) R. Schmid, E. A. Broger, M. Cereghetti, Y. Crameri, J. Foricher,
M. Lalonde, R. K. Muller, M. Scalone, G. Schoettel, U. Zutter, Pure Appl.
Chem. 1996, 68, 131–138; d) J. K. Liu, W. T. Couldwell, Neurocrit. Care
(
0
2
3
2005, 2, 124–132; e) R. Naito, Y. Yonetoku, Y. Okamoto, A. Toyoshima, K.
and H O (1.9 mL). The tube was sealed and submerged into a pre-
2
Ikeda, M. Takeuchi, J. Med. Chem. 2005, 48, 6597–6606.
heated 95 °C oil bath. The reaction was stirred for 4 h and cooled
down to room temperature. Then the reaction mixture was diluted
with EtOAc (20 mL). The organic layer was separated and the aque-
ous layer was extracted with EtOAc (3 × 30 mL). The combined
organic extracts were washed with water (3 × 30 mL), followed by
saturated brine (3 × 30 mL). The organic layer was dried with anhy-
drous Na SO , filtered, and concentrated under reduced pressure.
[
3] For selected examples, see: a) F. Mongin, G. Quéguiner, Tetrahedron
2001, 57, 4059–4090; b) C. Zhu, R. Wang, J. R. Falck, Chem. Asian J. 2012,
7, 1502–1514; c) K. Sun, X.-L. Chen, X. Li, L.-B. Qu, W. Z. Bi, X. Chen, H.-L.
Ma, S.-T. Zhang, B.-W. Han, Y.-F. Zhao, C.-J. Li, Chem. Commun. 2015, 51,
12111–12114; d) D. E. Stephens, J. Lakey-Beitia, A. C. Atesin, T. A. Atesin,
G. Chavez, H. D. Arman, O. V. Larionov, ACS Catal. 2015, 5, 167–175; e)
L. Bering, A. P. Antonchick, Org. Lett. 2015, 17, 3134–3137; X.-P. Chen, X.-
L. Cui, F.-F. Yang, Y.-J. Wu, Org. Lett. 2015, 17, 1445–1448; R. Odani, K.
Hirano, T. Satoh, M. Miura, J. Org. Chem. 2015, 80, 2384–2391.
2
4
The residue was purified by column chromatography over silica gel
1
to afford the desired product as a white solid in 80 % yield. H NMR
[
4] For representative examples of C–H functionalization of N-heterocycles,
see: a) Y. Fujiwara, J. A. Dixon, F. O'Hara, E. D. Funder, D. D. Dixon, R. A.
Rodriguez, R. D. Baxter, B. Herle, N. Sach, M. R. Collins, Y. Ishihara, P. S.
Baran, Nature 2012, 492, 95–99; b) B. Liu, Y. M. Huang, J. B. Lan, F. J.
Songa, J. S. You, Chem. Sci. 2013, 4, 2163–2167; c) B. Yao, R. J. Song, Y.
(
400 MHz, CDCl ): δ = 8.10–8.03 (m, 2 H), 7.72 (d, J = 8.1 Hz, 1 H),
3
7
.63–7.56 (m, 1 H), 7.50–7.37 (m, 1 H), 7.22 (d, J = 8.4 Hz, 1 H), 6.84
1
3
(s, 2 H), 2.21 (s, 3 H), 1.93 (s, 6 H) ppm. C NMR (100 MHz, CDCl3):
δ = 160.46, 147.99, 137.72, 137.44, 136.06, 135.46, 129.35, 129.33,
Eur. J. Org. Chem. 2016, 1606–1611
www.eurjoc.org
1610
© 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim