Synthesis of 6-chloroquinolines using benzyltrimethylammonium tetrachloroiodate as a selective chlorinating agent and an efficient generator of HCl

Article abstract of DOI:10.1007/s00706-009-0170-2

A simple and efficient one-pot synthesis of 6-chloroquinolines was achieved in good yields via the three-component reaction of 2-aminoaryl ketones, α-methylene carbonyl compounds, and BTMA ICl₄ in AcOH.

Full text of DOI:10.1007/s00706-009-0170-2

Monatsh Chem (2009) 140:1195–1198
DOI 10.1007/s00706-009-0170-2
ORIGINAL PAPER
Synthesis of 6-chloroquinolines using benzyltrimethylammonium
tetrachloroiodate as a selective chlorinating agent and an efficient
generator of HCl
Liqiang Wu Æ Chunguang Yang Æ Binxuan Niu Æ
Fulin Yan
Received: 31 December 2008 / Accepted: 29 July 2009 / Published online: 21 August 2009
Ó Springer-Verlag 2009
Abstract A simple and efficient one-pot synthesis of
6-chloroquinolines was achieved in good yields via the
three-component reaction of 2-aminoaryl ketones, a-meth-
ylene carbonyl compounds, and BTMA ICl4 in AcOH.
microwave [20], urea [21], poly(N-bromo-N-ethylbenzene-
1,3-disulfonamide) [22], and KOtBu [23] have been shown
to be effective for the synthesis of quinolines.
In this work, we report a modification of the Friedlander
reaction for the synthesis of 6-chloroquinolines, which
involves the formation in situ of the chloroaminoaryl
ketone using benzyltrimethylammonium tetrachloroiodate
(BTMA ICl4) as chlorinating agent. This latter reagent also
serves as an in situ generator of HCl, which acts as a cat-
alyst for the subsequent Friedlander condensation.
Keywords Benzyltrimethylammonium
tetrachloroiodate Á 6-Chloroquinolines Á Catalysts Á
Chlorination Á Aldol reactions
Introduction
The synthesis of 6-chloroquinoline derivatives has been
considered of great interest to organic chemists owing to
their wide range of biological and pharmaceutical properties
[1–7], such as antiparasitic, antitubercular, antibacterial,
antifilarial, HIV inhibiting, HMG-CoA reductase inhibiting,
cell adhesion inhibiting, cytokine formation inhibiting
agents, and allosteric enhancers of the GABAB receptors.
Friedlander quinoline synthesis is one of the most straight-
forward approaches for the synthesis of 6-chloroquinolines.
This method involves the acid or base catalyzed or thermal
condensation between a 2-aminoaryl ketone and another
carbonyl compound possessing an a-reactive methylene
group followed by cyclodehydration. Recently, Lewis acids
[8–15], such as Ag3PW12O40, SnCl2, FeCl3, Mg(ClO4)2,
Nd(NO3)3, Y(OTf)3, NiCl2, I2/CAN, and heterogeneous
solid acid catalysts [16–18], including NaHSO4–SiO2, Am-
berlyst 15, dodecyl phosphoric acid, ionic liquids [19],
Results and discussion
A range of 6-chloroquinolines was synthesized from a
combination of 2-aminoaryl ketones (1), a-methylene car-
bonyl compounds (2) and BTMA ICl4 (3) in a 1:1:1 ratio in
AcOH, and the reaction was completed in 10–14 h at room
temperature (Table 1).
Previously, BTMA ICl4 was used as a chlorinating agent
[24]. This solid reagent is considerably safe and conve-
nient, and has a fine selectivity. It is well known that the
chlorination of amines having electron withdrawing groups
in the aromatic ring with a calculated amount of BTMA
ICl4 can give the desired p-chloro-substituted products
[25]. Thus, it is conceivable that the reaction involves the
following two steps: (1) the chloroaminoaryl ketone is
initially formed in situ using BTMA ICl4 as chlorinating
agent; (2) BTMA ICl4 serves as an in situ generator of HCl,
which acts as a catalyst for the subsequent Friedlander
condensation in the second step (see Scheme 1).
It is well known that the reaction of acetophenone with 2
equiv of BTMA ICl4 in AcOH at 70 °C can give a,a-di-
chloroacetyl derivatives [26], which can result in the
formation of the product 5. However, as shown in entries
L. Wu (&) Á C. Yang Á B. Niu Á F. Yan
School of Pharmacy, Xinxiang Medical University,
453003 Xinxiang, Henan, People’s Republic of China
e-mail: wliq1974@sohu.com
123

1196
L. Wu et al.
Table 1 Synthesis of
6-chloroquinolines
R1
N
O
O
Cl
R3
R2
R1
AcOH, r.t.
10-14h
+
R3
+ BnMe3N ICl4
R2
NH2
2
3
1
4
Mp/oC
found
Yield/%
Entry Substrate 1 Substrate 2 Product 4
(Time/h)
(Reported)
O
O
Cl
OEt
a
oil
oil
92 (10)
87 (12)
O
O
N
NH2
O
OEt
O
Cl
b
NH2
N
105–106
O
O
O
c
76 (10)
93 (10)
Cl
Cl
O
O
OEt
([19] 108)
NH2
OEt
O
N
N
107–108
O
O
d
ClH2C
OEt
OEt ([1] 106–108)
NH2
CH2Cl
147–148
([l9] 151)
161–162
([19] 163)
O
O
e
f
86 (12)
84 (12)
O
O
Cl
NH2
O
N
O
Cl
NH2
N
103–104
O
g
86 (12)
82 (14)
O
Cl
([19] 105)
NH2
N
206–207
O
O
O
O
h
Cl
([13] 208–209)
NH2
N
113–114
([8] 110)
Cl
O
Cl
O
i
90 (10)
Cl
O
O
OEt
OEt
NH2
N
137–138
([11] 138–140)
150–151
Cl
O
Cl
O
j
k
l
92 (10)
86 (12)
87 (12)
O
O
Cl
NH2
N
Cl
O
O
O
Cl
Cl
Cl
Cl
([8] 153)
NH2
N
N
141–142
Cl
O
([8] 141)
NH2
2-Aminoaryl ketones:a-
methylene carbonyl
compounds:BTMA
ICl4 = 1:1:1; reactions
executed in a sealed vessel at
room temperature
Cl
O
Cl
O
O
O
m
213
86 (14)
Cl
NH2
N
123

Synthesis of 6-chloroquinolines using benzyltrimethylammonium tetrachloroiodate
1197
R1
N
Scheme 1
O
O
O
R3
R2
R3
Cl
Cl
R2
R1
R1
BTMA ICl4
+
HCl
AcOH
NH2
NH2
Scheme 2
CHCl2
R3
O
O
R3
CHCl2
R2
O
O
+
HCl
N
R2
NH2
BTMA ICl4
AcOH
5
NH2
O
R3
Cl
Cl
R3
R2
R2
+
HCl
NH2
N
4
a–b, only product 4 was formed under the reaction con-
ditions. This means that chlorination of the aromatic ring is
faster than side-chain chlorination (Scheme 2).
solvent was evaporated under reduced pressure. The resi-
due was subjected to column chromatography over silica
gel using EtOAc (8%) in hexane to obtain pure quinoline 4.
In summary, we have developed a simple and efficient
methodology to synthesize 6-chloroquinolines using BTMA
ICl4 as a selective chlorinating agent and an efficient
generator of HCl in Friedlander reaction. We believe that this
methodology will be a valuable addition to the existing
methods in the field of 6-chloroquinolines [27, 28].
Ethyl 6-chloro-2,4-dimethylquinoline-3-carboxylate
(4a, C14H14Cl2NO2)
1
Viscous oil. H NMR (300 MHz, CDCl3): d = 8.02 (d,
J = 8.9 Hz, 1H), 7.68 (d, J = 2.5 Hz, 1H), 7.55 (dd,
J = 8.9, 2.5 Hz, 1H), 4.82 (q, J = 7.0 Hz, 2H), 2.92 (s,
3H), 2.76 (s, 3H), 1.74 (t, J = 7.0 Hz, 3H) ppm; 13C NMR
(75 MHz, CDCl3): d = 167.4, 153.6, 146.5, 140.8, 128.9,
128.7, 127.2, 125.8, 124.9, 123.1, 60.5, 23.0, 15.9,
Experimental
ꢀ
14.9 ppm; IR (KBr): m = 3,072, 2,942, 2,863, 1,730,
1,615, 1,582, 1,200, 1,080, 620 cm-1
.
NMR spectra were taken on a Bruker AV-300 spectrometer
with TMS as internal standard. Coupling constants (J) were
measured in Hz. Elemental analyses were recorded on a
PEA-1110 elemental analyzer and agreed favorably with
calculated values. Melting points were determined on a
Mel-Temp capillary tube apparatus. BTMA ICl4 was pre-
pared according to the literature [26]. Commercially
available reagents were used without further purification
unless otherwise stated.
7-Chloro-9-methyl-2,3-dihydro-1H-cyclopenta[b]quinoline
(4b, C13H12ClNO)
1
Viscous oil. H NMR (300 MHz, CDCl3): d = 8.04 (d,
J = 8.7 Hz, 1H), 7.65 (d, J = 2.3 Hz, 1H), 7.52 (dd,
J = 8.7, 2.3 Hz, 1H), 3.22 (t, J = 7.0 Hz, 2H), 3.22 (t,
J = 7.2 Hz, 2H), 2.42 (s, 3H), 2.08–2.01 (m, 2H) ppm; 13
C
NMR (75 MHz, CDCl3): d = 164.2, 145.3, 136.2, 132.2,
127.5, 127.1, 126.3, 124.8, 122.3, 33.6, 28.9, 21.9,
ꢀ
15.8 ppm; IR (KBr): m = 3,068, 2,954, 1,609, 921,
756 cm-1
.
General procedure for the preparation of 4
7-Chloro-3,3-dimethyl-9-phenyl-3,4-dihydroacridin-
1(2H)-one (4m, C21H18ClNO)
To a stirred solution of the 2-aminoaryl ketone (1 mmol)
and the a-methylene carbonyl compound (1 mmol) in
4 cm3 AcOH at room temperature in a 20 cm3 vessel,
BTMA ICl4 (1 mmol) was added in a single portion. The
vessel was sealed immediately and stirred at room tem-
perature for 10–14 h. After completion of the reaction
(TLC), the mixture was filtered and then poured into
50 cm3 saturated NaHCO3 solution, extracted with 50 cm3
diethyl ether, and dried over sodium sulfate, and the
1
Yellow solid. M.p.: 212 °C; H NMR (300 MHz, CDCl3):
d = 8.01 (d, J = 8.79 Hz, 1H), 7.67–7.45 (m, 5H), 7.35–
7.30 (m, 2H), 2.96 (s, 2H), 2.42 (s, 2H), 1.10 (s, 6H) ppm;
13C NMR (75 MHz, CDCl3): d = 198.4, 156.2, 146.3,
142.8, 136.7, 135.6, 133.1, 130.2, 129.3, 129.2, 129.0,
128.2, 127.9, 126.3, 125.0, 123.3, 55.3, 49.2, 32.0, 28.3
ꢀ
(2C) ppm; IR (KBr) m = 3,043, 2,980, 1,710, 1,605, 1,540,
1,220, 745 cm-1
.
123

1198
L. Wu et al.
Acknowledgments We are pleased to acknowledge the financial
support from Xinxiang Medical University (no. 04GXLP05).
13. Dabiri M, Baghbanzadeh M, Arzroomchilar E (2008) Heterocy-
cles 75:397
14. Wu J, Xia HG, Gao K (2006) Org Biomol Chem 4:26
15. Likhar PR, Subhas MS, Roy S, Kantam ML, Sridhar B, Seth RK,
Biswas S (2009) Org Biomol Chem 7:85
16. Dabiri M, Azimi SC, Bazgir A (2007) Monatsh Chem 138:659
17. Das B, Damodar K, Chowdhury N, Kumar RA (2007) J Mol
Catal A Chem 274:148
18. Ghassamipour S, Sardarian AR (2009) Tetrahedron Lett 50:514
19. Palimkar SS, Siddiqui SA, Daniel T, Lahoti RJ, Srinivasan KV
(2003) J Org Chem 68:9371
20. Szatmari I, Fulop F (2009) Synthesis 5:775
21. Qi C, Zheng Q, Hua R (2009) Tetrahedron 65:1316
22. Ghorbani-Vaghei R, Akbari-Dadamahaleh S (2009) Tetrahedron
Lett 50:1055
References
1. Muscia GC, Bollini M, Carnevale JP, Bruno AM, Asis SE (2006)
Tetrahedron Lett 47:8811
2. Desai PK, Desai P, Machhi D, Desai CM, Patel D (1996) Indian
J Chem Sect B 35B:871
3. Srivastava SK, Chauhan PMS, Bhaduri AP, Fatima N, Chatterjee
R (2000) J Med Chem 43:2275
4. Kirsch R, Kleim JP, Ries G, Rosenstock B, Roesner M, Winkler I
(1997) DE Patent: 19613591
5. Suzuki M, Iwasaki H, Fujikawa Y, Kitahara M, Sakashita M,
Sakoda R (2001) Bioorg Med Chem 9:2727
23. Mierde HV, Voort PVD, Verpoort F (2009) Tetrahedron Lett
50:201
6. Sato S, Aitani K, Kumakura S (2002) JP Patent: 2002371078
7. Malherbe P, Masciadri R, Norcross RD, Ratni H, Thomas AW
(2006) US Patent: 2006094754
8. Yadav JS, Reddy BVS, Sreedhar P, Rao RS, Nagaiah K (2004)
Synthesis 14:2381
9. Arumugam P, Karthikeyan G, Atchudan R, Murlidharan D,
Perumal PT (2005) Chem Lett 34:314
10. Wu J, Zhang L, Diao TN (2005) Synlett 17:2653
11. Varala R, Enugala R, Adapa SR (2006) Synthesis 22:3825
12. De SK, Gibbs RA (2005) Tetrahedron Lett 46:1647
24. Kajigaeshi S, Kakinami T (1995) Encyclopedia of reagents for
organic synthesis. Wiley, Sussex, p 384
25. Kakinami T, Nozu T, Yonemaru S, Okamoto T, Shinmasu Y,
Kajigaeshi S (1991) Nippon Kagaku Kaishi 112:44
26. Kajigaeshi S, Kakinami T, Ikeda H, Okamoto T (1988) Chem
Express 3:659
27. Gabriele B, Mancuso R, Salerno G, Ruffolo G, Plastina P (2007)
J Org Chem 72:6873
28. Bartolo G, Mancuso R, Salerno G, Lupinacci E, Ruffolo G, Costa
M (2008) J Org Chem 73:4971
123