Intramolecular cyclization of 2′-aminochalcones by halomethyleniminium salts derived from btc/dmf

Full text of DOI:10.1080/00304940902802156

This article was downloaded by: [University of New Hampshire]
On: 27 February 2013, At: 11:09
Publisher: Taylor & Francis
Informa Ltd Registered in England and Wales Registered Number: 1072954 Registered
office: Mortimer House, 37-41 Mortimer Street, London W1T 3JH, UK
Organic Preparations and Procedures
International: The New Journal for
Organic Synthesis
Publication details, including instructions for authors and
subscription information:
http://www.tandfonline.com/loi/uopp20
Intramolecular Cyclization
of 2′-Aminochalcones by
Halomethyleniminium Salts Derived from
BTC/DMF
Zhen-Hua Li a , Cun Zheng a , Ren-Er Chen a & Weike Su a
a Key Laboratory of Pharmaceutical Engineering of Ministry of
Education, College of Pharmaceutical Sciences, Zhejiang University
of Technology, Hangzhou, PR, China
Version of record first published: 22 Apr 2009.
To cite this article: Zhen-Hua Li , Cun Zheng , Ren-Er Chen & Weike Su (2009): Intramolecular
Cyclization of 2′-Aminochalcones by Halomethyleniminium Salts Derived from BTC/DMF, Organic
Preparations and Procedures International: The New Journal for Organic Synthesis, 41:2, 156-161
To link to this article: http://dx.doi.org/10.1080/00304940902802156
PLEASE SCROLL DOWN FOR ARTICLE
Full terms and conditions of use: http://www.tandfonline.com/page/terms-and-conditions
This article may be used for research, teaching, and private study purposes. Any
substantial or systematic reproduction, redistribution, reselling, loan, sub-licensing,
systematic supply, or distribution in any form to anyone is expressly forbidden.
The publisher does not give any warranty express or implied or make any representation
that the contents will be complete or accurate or up to date. The accuracy of any
instructions, formulae, and drug doses should be independently verified with primary
sources. The publisher shall not be liable for any loss, actions, claims, proceedings,
demand, or costs or damages whatsoever or howsoever caused arising directly or
indirectly in connection with or arising out of the use of this material.

156
Li et al.
Organic Preparations and Procedures International, 41:156–161, 2009
Copyright © Taylor & Francis Group, LLC
ISSN: 0030-4948 print
DOI: 10.1080/00304940902802156
Intramolecular Cyclization of 2ꢀ-Aminochalcones
by Halomethyleniminium Salts Derived
from BTC/DMF
Zhen-Hua Li, Cun Zheng, Ren-Er Chen, and Weike Su
Key Laboratory of Pharmaceutical Engineering of Ministry of Education,
College of Pharmaceutical Sciences, Zhejiang University of Technology,
Hangzhou, P. R. China
Quinolines and their derivatives occur in numerous natural products. Many quinolines
exhibit a broad spectrum of biological activities such as anti-malarials,1 anti-fungal,2 anti-
depressants,3 etc. There are many publications concerning the methods for the synthesis of
various 2-substituted-4-chloroquinolines,4–6 but to the best of our knowledge, the synthe-
sis of 2-substituted-4-chloro-N-formyl-1,2-dihydroquinolines has rarely been reported so
far. Comparatively, the Vilsmeier cyclization of 2ꢀ-aminochalcones is a convenient method
for the synthesis of 2-substituted-4-chloro-N-formyl-1,2-dihydroquinolines.7 However, the
traditional Vilsmeier reagent employs the use of phosphorus oxychloride, which forms inor-
ganic phosphorus salts as by-products.8 Due to the great importance of quinolines, the devel-
opment of novel synthetic methods remains an active research area. bis-(Trichloromethyl)
carbonate (BTC) in combination with DMF, has emerged as a versatile synthetic auxiliary
for the synthesis of some important organic compounds.9–12 Herein, we report a practi-
cal route for one-pot synthesis of 2-substituted-4-chloro-N-formyl-1,2-dihydroquinolines
from the reaction of 2ꢀ-aminochalcones with halomethyleniminium salts derived from
BTC/DMF (Scheme 1).
Scheme 1
Submitted October 12, 2008.
Address correspondence to W.K. Su, Zhejiang University of Technology, College of Pharmaceu-
tical Sciences, Hangzhou, 310014, P. R. China. E-mail: suweike@zjut.edu.cn

Intramolecular Cyclization of 2ꢀ-Aminochalcones
157
Table 1
Synthesis of 2-Substituted-4-chloro-N-formyl-1,2-dihydroquinolines using BTC and DMF
Yield
(%)
mp (◦C)
(lit. m.p.)
IR
(cm−1
Cmpda
)
1H NMR (δ)
2a
86
Oil Dense
oil7
1682 6.38 (d, 1 H, J = 6.5 Hz, 2-H), 6.71
952
759
(d, 1 H, J = 6.5 Hz, 3-H), 7.23–7.32
(m, 3 H, ArH), 7.39–7.43 (m, 3 H,
ArH), 7.54 (d, 1 H, J = 7.5 Hz, ArH),
7.60–7.62 (m, 2 H, ArH), 8.83 (s, 1
H, CHO)
2b
2c
2d
92
93
82
118–120
1675 6.31 (d, 1 H, J = 6.5 Hz, 2-H), 6.40
(110–1197)
839
756
(d, 1 H, J = 6.0 Hz, 3-H), 7.04–7.06
(m, 1 H, ArH), 7.21 (s, 4 H, ArH),
7.26–7.33 (m, 2 H, ArH), 7.71
(m, 1 H, ArH), 8.66 (s, 1 H, CHO)
75–77
(77–787)
1675 6.33 (d, 1 H, J = 6.5 Hz, 2-H), 6.40
831
761
(d, 1 H, J = 6.0 Hz, 3-H), 7.08–7.16
(m, 1 H, ArH), 7.14–7.36 (m, 5 H,
ArH), 7.71–7.74 (m, 2 H, ArH), 8.68
(s, 1 H, CHO)
69–71
(68–697)
1687 3.74 (s, 3 H, MeO), 6.33 (d, 1 H, J =
838
759
6.0 Hz, 2-H), 6.40 (d, 1 H, J = 6.0
Hz, 3-H), 6.78–6.80 (m, 2 H, ArH),
7.04–7.06 (m, 1 H, ArH), 7.22–7.23
(m, 2 H, ArH), 7.26–7.32 (m, 2 H,
ArH), 7.72–7.74 (m, 1 H, ArH), 8.67
(s, 1 H, CHO)
2e
2f
81
87
85
151–153
1674 6.37 (d, 1 H, J = 6.5 Hz, 2-H), 6.51
841
757
(d, 1 H, J = 6 Hz, 3-H), 7.08–7.10
(m, 1 H, ArH), 7.30–7.38 (m, 2 H,
ArH), 7.45–7.47 (m, 2 H, ArH),
7.74–7.75 (m, 1 H, ArH), 8.11–8.14
(m, 2 H, ArH), 8.70 (s, 1 H, CHO)
Oil
1682 6.34 (d, 1 H, J = 6.5 Hz, 2-H), 6.42
844
759
(d, 1 H, J = 6.5 Hz, 3-H), 6.92–7.09
(m, 2 H, ArH), 7.08–7.09 (m, 2 H,
ArH), 7.22–7.24 (m, 1 H, ArH),
7.25–7.72 (m, 2 H, ArH), 7.73 (d, 1
H, J = 1.5, ArH), 8.69 (s, 1 H, CHO)
2g
73–75
1685 6.34 (d, 1 H, J = 6.5 Hz, 2-H), 6.41
833
758
(d, 1 H, J = 6.5 Hz, 3-H), 7.01–7.16
(m, 2 H, ArH), 7.22 (d, 1 H, J = 7.0
Hz, ArH), 7.28–7.35 (m, 3 H, ArH),
7.38–7.44 (m, 1 H, ArH), 7.73–7.75
(m, 1 H, ArH), 8.69 (s, 1 H, CHO)
(Continued on next page)

158
Li et al.
Table 1
Synthesis of 2-Substituted-4-chloro-N-formyl-1,2-dihydroquinolines using BTC and DMF
(Continued)
Yield
(%)
mp (◦C)
(lit. m.p.)
IR
(cm−1
Cmpda
)
1H NMR (δ)
2hb
94
Oil
1687 6.09 (d, 1 H, J = 5.5 Hz, 2-H), 6.86
759
(d, 1 H, J = 1 Hz, 3-H), 6.87–6.93 (m,
1 H, ArH), 7.13–7.22 (m, 3 H, ArH),
7.25–7.28 (m, 1 H, ArH), 7.36–7.39
(m, 1 H, ArH), 7.70–7.72 (m, 1 H,
ArH), 8.80 (s, 1 H, CHO)
2i
2j
84
120–122
130–132
1677 6.38 (d, 1 H, J = 6.5 Hz, 2-H), 6.63
849
764
(d, 1 H, J = 6 Hz, 3-H), 6.87–6.89 (m,
1 H, 5ꢀ-H), 6.97–6.98 (m, 1 H, 4ꢀ-H),
7.07–7.09 (m, 1 H, ArH), 7.17–7.18
(d, 1 H, J = 1.5 Hz, ArH), 7.26–7.34
(m, 2 H, 3ꢀ-H and ArH), 7.72–7.74
(m, 1 H, ArH), 8.68 (s, 1 H, CHO)
86
1687 6.37 (d, 1 H, J = 6.5 Hz, 2-H), 6.63
785
(d, 1 H, J = 6.0 Hz, 3-H), 6.86- 6.88
(m, 1 H, 5ꢀ-H), 6.97 (d, 1 H, J = 3.0
Hz, 4ꢀ-H), 7.07 (d, 1 H, J = 7.5 Hz,
ArH), 7.17 (d, 1 H, J = 5 Hz, ArH),
7.26–7.33 (m, 2 H, 3ꢀ-H and ArH),
7.30 (d, 1 H, J = 7.5 Hz, ArH), 8.67
(s, 1 H, CHO)
2k
83
81–83
1672 2.18 (s, 6 H, CH3), 6.32 (d, 1 H, J = 6.5
765
Hz, 2-H), 6.37 (d, 1 H, J = 6.5 Hz,
3-H), 6.97–7.01 (m, 2 H, ArH),
7.05–7.07 (m, 2 H, ArH), 7.25–7.30
(m, 2 H, ArH), 7.70–7.72 (m, 1 H,
ArH), 8.67 (s, 1 H, CHO)
a) Yellow solids unless otherwise stated.
It was determined that the best ratio of 2ꢀ-aminochalcone/BTC/DMF in toluene should
be 1:2:6. A temperature of 90◦C was found to be best to carry out the conversion and a wide
range of substituted 2ꢀ-aminochalcones were subjected to these conditions to afford a va-
riety of 2-substituted-4-chloro-N-formyl-1,2-dihydroquinolines in good to excellent yields
(Table 1). 2ꢀ-Aminochalcones with electron-withdrawing group (e.g. 2-F-6-ClC6H3 and
p-ClC6H4) were obtained in high yields, while with 2ꢀ-aminochalcones bearing electron-
donating groups (e.g. p-MeOC6H4 and 3,4-diMeC6H3), the reaction proceeded in relatively
low yields. The structures of the compounds were confirmed by 1H-NMR, IR and MS (Table
2). New compounds were further comfirmed by 13C NMR and elemental analysis (Table 3).

Intramolecular Cyclization of 2ꢀ-Aminochalcones
159
Table 2
MS, 13C NMR and Elemental Analysis for Unknown Compounds
Elemental
Analysis Found
(Calcd)
Cmpd 2
MS(EI) m/z (%)
13C NMR (δ)
2e
314 (M+, 9), 316 ([M + 2]+, 3), 51.8, 118.1, 123.2,
C, 60.78 (61.06);
H, 3.51 (3.52);
N, 8.91 (8.90)
192 (33), 164 (100)
124.1, 126.1, 126.2,
128.3, 130.0, 130.7,
144.1, 161.4
2f
287 (M+, 39), 289 ([M + 2]+,
52.1, 114.2, 114.4,
115.3, 115.5, 118.1,
123.0, 124.2, 124.3,
125.9, 129.2, 130.3,
130.4, 134.5, 161.5
52.0, 118.1, 122.9,
124.0, 124.3, 125.9,
126.0, 129.3, 130.3,
131.6, 134.4, 140.2,
161.6
C, 66.48 (66.79);
H, 3.83 (3.85);
N, 4.86 (4.87)
13), 192 (55), 164 (100)
2g
2h
346 (M+, 28), 348 ([M + 2]+,
34), 350 ([M + 4]+, 9), 192
(70), 164 (100)
C, 54.82 (55.12);
H, 3.17 (3.18);
N, 4.01 (4.02)
320 (M+, 6), 321 ([M + 2]+, 8), 50.7, 115.0, 115.2,
C, 59.45 (59.65);
H, 3.12 (3.13);
N, 4.37 (4.35)
324 ([M + 4]+, 2), 192 (45),
116.0, 121.0, 124.9,
125.7, 125.8, 125.8,
128.5, 129.7, 129.8,
130.3, 162.1
164 (100)
2i
2j
259 (M+, 27), 261 ([M + 2]+, 9), 48.1, 118.0, 124.2,
C, 64.54 (64.75);
H, 3.86 (3.88);
N, 5.40 (5.39)
230 (70), 164 (100)
125.9, 126.2, 126.9,
129.3, 130.3, 134.1,
140.7, 160.8
275 (M+, 15), 277 ([M + 2]+, 5), 48.1, 118.3, 124.2,
C, 60.76 (60.98);
H, 3.64 (3.66);
N, 5.09 (5.08)
246 (73), 164 (100)
124.2, 125.8, 125.9,
126.2, 126.4, 126.9,
129.3, 130.3, 134.1,
140.7, 160.8
2k
297 (M+, 15), 299 ([M + 2]+, 4), 19.5, 19.8, 52.6, 118.1, C, 72.30 (72.60);
192 (35), 164 (100)
124.6, 125.3, 125.7,
128.3, 128.6, 130.0,
130.0, 134.8, 135.4,
136.9, 137.1, 161.5
H, 5.39 (5.42);
N, 4.71 (4.70)
In summary, we have developed an efficient intramolecular cyclization
of 2ꢀ-aminochalcones to 2-substituted-4-chloro-N-formyl-1,2-dihydroquinolines by
halomethyleniminium salts derived from BTC/DMF. This method provides excellent
chemoselectivity, higher yields, and avoids the formation of inorganic phosphorus salts.

160
Li et al.
Table 3
1H NMR, 13C NMR, MS, and Elemental Analysis for Unknown Compounds 1
Cmpd 1
1f
1h
1k
99.8–101.1
mp(◦C)
1H NMR
105.2–106.5
107.5–108.7
6.35 (br s, 2 H, NH2), 6.43 (br s, 2 H, NH2), 2.30 (s, 3 H, CH3),
6.69–6.72 (m, 2 H, 6.68–6.72 (m, 2 H, 2.31 (s, 3 H, CH3),
ArH), 7.06–7.11 (m, ArH), 7.05–7.10 (m, 6.33 (br s, 2 H,
1H, ArH),
7.26–7.39 (m, 4 H,
2 H, ArH),
7.22–7.32 (m, 3 H,
NH2), 6.69–6.72
(m, 2 H, ArH), 7.17
(d, 1 H, J = 7.6 Hz,
ArH), 7.25–7.30 (m,
2 H, ArH), 7.57 (d,
1 H, J = 15.6 Hz,
CH = CH), 7.71 (d,
1 H, J = 15.6 Hz,
CH = CH),
ArH), 7.58–7.70 (m, CH = CH, ArH),
2 H, CH = CH),
7.83–7.86 (m, 1 H,
ArH)
7.83 (m, 1 H, ArH),
7.90–7.95 (m, 2 H,
ArH)
7.86–7.88 (m, 1 H,
ArH)
13C NMR (δ)
114.3 (d, J = 22 Hz), 114.7 (d, J = 23.5
115.9, 116.9 (d, J = Hz), 115.9, 117.3.,
19.7, 19.8, 115.9,
117.3, 119.4, 122.0,
126.0, 129.4, 123.2,
131.0, 133.0, 134.1,
137.1, 139.3, 143.3,
150.8, 191.9
21.2 Hz) 117.3,
118.9, 120.2, 124.3
(d, J = 13.7 Hz),
130.4
120.1 (d, J = 10.7
Hz), 126.0, 129.9,
130.0, 130.2, 130.3,
131.2, 132.6, 134.5,
151.2, 163.2, 191.6
(d, J = 8.3 Hz),
131.0, 134.5, 137.6,
141.4, 151.1, 161.9
(d, J = 245 Hz)
191.3
MS(EI) m/z (%) 241 (M+, 68), 146
275 (M+, 51), 277
([M+2], 17), 146
(100)
251 (M+, 100) 146
(100)
(100)
Elemental
Analysis Found
(Calcd)
C, 74.66 (74.67), N,
5.85 (5.81), H, 4.98
(5.01)
C, 65.31 (65.35), N,
5.06 (5.08), H, 4.01
(4.02)
C, 81.21 (81.24), N,
5.54 (5.57), H, 6.69
(6.82)
Experimental Section
Melting points (mp) were determined on a digital melting point apparatus WRS-1B and are
uncorrected. 1H NMR and 13C NMR spectra were obtained on a Bruker ANANCE III-500
spectrometer in CDCl3 using TMS as an internal standard. Infrared spectra were recorded
neat or as KBr pellets on a Thermo Nicolet Avatar 370 spectrophotometer. MS (EI) spectra
were acquired on a Finnigan Trace DSQ spectrometer. Elemental analysis was determined

Intramolecular Cyclization of 2ꢀ-Aminochalcones
161
on a Carlo-Erba 1108 instrument. The progress of the reaction was monitored by TLC. The
prerequisite 2ꢀ-aminochalcones were prepared as previously described.13
General Procedure for the Preparation of 2-Substituted-4-chloro-N-formyl-1,2-dihydro-
quinolines.
A solution of BTC (0.3 g, 1 mmol) in toluene (8 mL) was added dropwise to a solution of
DMF (0.3 mL, 3 mmol) in toluene (5 mL) immersed in an ice-water cooled bath. The mixture
was stirred for 20 minutes. The temperature was then raised to 20◦C and was stirred for an
additional 0.5–1 hour. Then substituted 2ꢀ-aminochalcones 1 (0.5 mmol) in toluene (10 mL)
was added dropwise to the mixture below 5◦C, and when the addition was complete, the
mixture was heated to 90◦C and maintained for 1–3 hours. After completion of the reaction
[monitored by TCL (petroleum ether/ethyl acetate = 5:1)], the mixture was poured into
ice water and stirred for 1–1.5 hour. The organic layer was separated and the aqueous
layer was extracted with ethyl acetate (20 mL × 2). The combined organic layers was
washed successively with 10% NaOH (20 mL × 2) and then with brine (20 mL × 3). After
evaporation of the organic solvent, the residue was subjected to column chromatography.
Elution with petroleum ether/ethyl acetate 20:1) afforded the pure products.
Acknowledgement
We are grateful to the National Natural Science Foundation of China (Nos. 20876147 and
20676123) for financial support.
References
1. R. W. Winter, J. X. Kelly, M. J. Smilkstein, R. Dodean, D. Hinrichs and M. K. Riscoe, Exp
Parasitol., 118, 487 (2008).
2. R. Musiol, J. Jampilek, K. Kralova, D. R. Richardson, D. Kalinowski, B. Podeszwa, J. Finster,
H. Niedbala, A. Palkaa and J. Polanskia, Bioorg. Med. Chem., 15, 1280 (2007).
3. A. A. Alhaider, M. A Abdelkader and J. L. Eric, J. Med. Chem., 28, 1394 (1985).
4. M. C. Kimber, J. P. Geue, S. F. Lincoln, A. D. Ward and E. R. T. Tiekink, Australian J. Chem.,
56, 39 (2003).
5. C. Wolf and R. Lerebours, J. Org. Chem., 68, 7077 (2003).
6. B. K. Chan and M. A. Ciufolini, J. Org. Chem., 72, 8489 (2007).
7. S. Akila, S. Selvi and K. Balasubramanian, Tetrahedron, 57, 3465 (2001).
8. W. Ziegenbein and W. Franke, Angew. Chem. Int. Ed., 71, 573 (1959).
ˇ
9. L. Cotarca, P. Delogu, A. Nardelli and V. Sunjic´, Synthesis, 553 (1996).
10. W. K. Su, W. H. Zhong, G. F. Bian, X. J. Shi and J. P. Zhang, Org. Prep. Proced. Int., 36, 499
(2004).
11. I. A. Rivero, K. A. Espinoza and A. Ochoa, J. Comb. Chem., 6, 270 (2004).
12. W. K. Su, and C. Jin, Org. Lett., 9, 993 (2007).
13. J. A. Donnelly and D. F. Farrell, J. Org. Chem., 55, 1757 (1990).