Acetonitrile-mediated synthesis of 2,4-dichloroquinoline from 2-ethynylaniline and 2,4-dichloroquinazoline from anthranilonitrile

Article abstract of DOI:10.1055/s-2005-922790

2,4-Dichloroquinolines and 2,4-dichloroquinazolines were synthesized from 2-ethynylanilines and anthranilonitriles, respectively, using diphosgene in acetonitrile and heating at 130 °C or 150 °C for 12 hours. This reaction was applied to the synthesis of 4,6-dichloropyrazolo[3,4-d]pyrimidine (dichloro-9H-isopurine). The postulated mechanism is also described. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2005-922790

LETTER
65
Acetonitrile-Mediated Synthesis of 2,4-Dichloroquinoline from 2-Ethynyl-
aniline and 2,4-Dichloroquinazoline from Anthranilonitrile
Synthesis
a
of 2,4-Dich
e
loroquinoline and
H
2,4-Dichloroquin
a
a
zoline k Lee,a Byoung Se Lee,a Hyunik Shin,b Do Hyun Nam,b Dae Yoon Chi*a
a
Department of Chemistry, Inha University, 253 Yonghyundong Namgu, Inchon 402-751, Korea
Fax +82(32)8675604; E-mail: dychi@inha.ac.kr
b
Chemical Development, LG Life Sciences, 104-1 Moonjidong, Yusunggu, Taejon 305-380, Korea
Received 24 September 2005
also be problematic from both an economic and environ-
mental point of view. Therefore, the preparation of 2,4-
dichloro compounds from 2,4-dihydroxy compounds is
significantly restricted from practical, economic, and
Abstract: 2,4-Dichloroquinolines and 2,4-dichloroquinazolines
were synthesized from 2-ethynylanilines and anthranilonitriles, re-
spectively, using diphosgene in acetonitrile and heating at 130 °C or
150 °C for 12 hours. This reaction was applied to the synthesis of
4,6-dichloropyrazolo[3,4-d]pyrimidine (dichloro-9H-isopurine). environmental aspects.
The postulated mechanism is also described.
While 2,4-dihydroxyquinolines can usually be synthe-
Key words: 2,4-dichloroquinoline, diphosgene, acetonitrile-medi-
ated reaction, 2,4-dichloroquinazoline
sized by the reaction of anilines and dialkyl malonates
with heating, 2,4-dihydroxyquinazolines can be prepared
by several synthetic routes; condensation of anthranilic
acid and urea,5,6 carbonylation of anthranilamide with
phosgene,7 reaction of phthaldiamide with sodium hy-
pochlorite via Hofmann reaction,8 and carbonylation of
anthranilonitrile using carbon dioxide (1 atm).9 Although
2,4-dihydroxy compounds can be prepared by several
methods10,11 in good yield, there have been no reports of
the direct synthesis of 2,4-dichloro compounds from
aniline analogues until now.
Many heterocyclic alkaloids isolated from natural sources
have been considered to have a wide spectrum of biologi-
cal activities, and are employed in numerous drug discov-
ery studies as lead compounds.1 Among these, quinoline
and quinazoline-based alkaloids having one or two nitro-
gen atoms have been ubiquitously found in plant, micro-
bial, and animal sources, and much attention has been
paid to their biological potential.2 Accordingly, a number
of research groups have tried to make libraries of ana-
logues via various synthetic routes such as introducing
functional groups into quinolines and quinazolines as well
as by ring formation of acyclic compounds. These efforts
have all been directed at finding more potent drug
candidates and have resulted in the development of many
efficient syntheses in the literature.3,4
Recently, our laboratory reported the novel acetonitrile-
mediated synthesis of 2-chloroquinolines from 2-vinyl-
anilines using diphosgene, showing a reasonable reaction
mechanism via acetonitrile-incorporated intermediate
(Scheme 1).12 By the same pathway, 2,4-dichloroquino-
lines and 2,4-dichloro quinazolines might be efficiently
prepared from anilines ortho-substituted with triple bonds
such as acetylene and nitrile, respectively. Herein, we
continue to report the efficient syntheses of 2,4-dichloro-
quinolines and 2,4-dichloroquinazolines from 2-ethynyl-
anilines and anthranilonitriles in the presence of
diphosgene in acetonitrile. In addition, another example is
also provided using a different starting compound under
the same reaction conditions to show the general applica-
bility of our method.
In terms of the diversity of quinolines and quinazolines,
2,4-dichloro compounds can play a role as key intermedi-
ates for the synthesis of 2,4-disubstituted quinoline and
quinazoline compounds, which could be synthesized by
stepwise substitution at the C4 and C2 positions. The pres-
ence of the chlorine atom permits not only direct substitu-
tion, with various nucleophiles, but transition metal-
catalyzed coupling reactions enable additional functional
groups to be incorporated. 2,4-Dichloroquinolines and
2,4-dichloroquinazolines have been prepared in a conven-
tional manner from the corresponding 2,4-dihydroxyquin-
olines and 2,4-dihydroxyquinazolines, respectively, using
excess phosphorous oxychloride under reflux conditions.
2,4-Dihydroxy compounds usually have poor solubility in
most organic solvents resulting in a very slow chlorination
reaction. In addition, removal of unreacted excess phos-
phorous oxychloride after completion of the reaction can
R2
R2
R1
R3
R1
R3
Cl
diphosgene
CH3CN
NH2
N
Scheme 1 Acetonitrile-mediated 2-chloroquinoline synthesis.
Based on our previous report, we thought that anilines, in
particular ortho-substituted anilines with a triple bond
such as acetylene or nitrile, would undergo the same
reaction to give the corresponding heterocyclic
compounds. It prompted us to extend this methodology to
anthranilonitrile, which should furnish 2,4-dichloro-
quinazoline under the same reaction conditions. Indeed,
SYNLETT 2006, No. 1, pp 0065–0068
0
5.
0
1.
2
0
0
6
Advanced online publication: 16.12.2005
DOI: 10.1055/s-2005-922790; Art ID: U27905ST
© Georg Thieme Verlag Stuttgart · New York

66
J. H. Lee et al.
LETTER
2,4-dichloroquinazoline was obtained in good yield with-
out any significant side products. This finding not only
supports our previously proposed mechanism, but also
encouraged us to synthesize a series of 2,4-dichloro
compounds.
X
X
C
R
R
diphosgene
H
N
CH3CN
NH2
N
O
C
130 °C, 12 h
CH3
2a–e, X = CH
3a–g, X = N
4
Various 2-ethynylanilines 2a–e13 and anthranilonitriles
3a–g were prepared from 2-iodoanilines 1a–g by the
Sonogashira reaction with trimethylsilylacetylene,14 and
nitrilation with copper(I) cyanide,15 respectively
(Scheme 2).21
Cl
Cl
Cl
HCl
R
R
X
NH2
X
NH
CH3
N
O
CH3
N
O
Cl
6
5
Cl
N
R
R
X
7a–e, X = CH
8a–g, X = N
b
R
R
I
- acetamide
a
O
NH2
Cl
2a–e
3a–g
NH2
N
H
CF3
c
R = H, Cl, Br, I, NO2, CH3, CF3
1a–g
R
CN
Scheme 3 Acetonitrile-mediated reaction mechanism.
R = H, Cl, Br, I, NO2, CH3, CF3
NH2
From this mechanism, a series of 6-substituted 2,4-dichlo-
ro compounds were synthesized from 4-substituted 2-
ethynylanilines 2a–e and 4-substituted anthranilonitriles
3a–g, respectively, in a tightly-capped pressure tube un-
der a nitrogen atmosphere by heating for 12 hours at 130
°C or 150 °C in moderate to good yield (Table 1).21
Scheme 2 Preparation of 2-ethynylanilines and anthranilonitriles.
Reagents and conditions: (a) ICl, DMF, r.t., 30 min, then trifluoro-
acetic anhydride, DMF, r.t., 30 min; (b) (i) aq K2CO3, MeOH, 50 °C,
24 h, (ii) TMSC≡CH, PdCl2(PPh3)2, CuI, THF–Et3N (4:1), r.t., 6 h. (iii)
TBAF, THF, 0 °C–r.t., 3 h; (c) (i) CuCN, DMF, 100 °C, 12 h, (ii) aq
K2CO3, MeOH, r.t., 12 h.
Table 1 Synthesis of 2,4-Dichloroquinazolines and 2,4-Dichloro-
As illustrated in Scheme 3, the reaction mechanism for the
synthesis of 2,4-dichloro compounds consists of the fol-
lowing four steps: (1) generation of phenylisocyanate, (2)
quinoline or quinazoline ring formation, (3) primary chlo-
rination of the C4 position, and (4) secondary chlorination
of the C2 position.
quinolinesa
Cl
X
R
R
diphosgene
X
CH3CN
12 h
NH2
N
Cl
2a–e, X = CH
3a–g, X = N
7a–e, X = CH
8a–g, X = N
In the first step, phenylisocyanates 4 are quickly formed
by the reaction of anilines and diphosgene, which is
known to decompose to two identical phosgenes at elevat-
ed temperatures. Secondly, quinoline and quinazoline
ring formation is achieved by the shift of one pair of p-
electrons of the triple bond to the partially activated car-
bon of the N=C=O functionality. This step is likely to be
catalyzed by an in situ generated proton, which binds to
the nitrogen of acetonitrile. The essential role of acetoni-
trile in this step was already proven: (1) no reaction oc-
curred when other solvents were used and (2) acetamide
was obtained as a by-product.12 As a result of incorpora-
Product
7a19a
7b19b
7c19c
R
X
Temperature (°C) Yieldb (%)
H
CH
CH
CH
CH
CH
N
150
150
150
150
150
130
130
130
130
130
130
130
61
40
55
74
25
86
72
46
47
62
80
41
Cl
NO2
CH3
CF3
H
7d19d
7e21
8a20a
tion of acetonitrile the reactive acetimidic ester intermedi- 8b20b
Cl
N
ate was generated. Although it remains unclear whether
chlorination of the C4 position follows the second step or
8c20b
Br
N
8d20c
8e20d
8f20d
8g21
I
N
occurs coincidently, we describe primary chlorination
separately as the third step to give a better understanding.
Finally, secondary chlorination of the C2 position is per-
formed by the replacement of the protonated acetimidic
ester leaving group with chloride, yielding the corre-
sponding 2,4-dichloro compounds (7a–e for 2,4-dichloro-
quinolines and 8a–g for 2,4-dichloroquinazolines) and
NO2
CH3
CF3
N
N
N
a All ring formations were carried out in a tightly capped pressure tube
acetamide as the by-product. In addition, similarly to the containing a MeCN solution of aniline (1–2 mmol, 1.0 equiv) and
synthesis of 2-chloroquinolines,12 a small amount of
diphosgene (1.5 equiv) under heating.
b Isolated yield.
2,4,6-trimethyl-1,3,5-triazine was obtained as another by-
product probably due to the Hoesch reaction.16
Synlett 2006, No. 1, 65–68 © Thieme Stuttgart · New York

LETTER
Synthesis of 2,4-Dichloroquinoline and 2,4-Dichloroquinazoline
67
It was observed that 2,4-dichloroquinoline synthesis re-
quired higher temperatures up to 150 °C compared with
2,4-dichloroquinazoline. Nonetheless, 2,4-dichloroquino-
lines were obtained in lower yield than 2,4-dichloro-
References and Notes
(1) (a) Palanki, M. S. S.; Suto, M. J. US Patent 5939421, 1999.
(b) Myers, M. R.; Spada, A. P.; Maguire, M. P.; Persons, P.
E.; Ziberstein, A.; Hus, C.-Y. J.; Johnson, S. E. US Patent
5714493, 1998. (c) Barker, A. J. US Patent 5942514, 1999.
(d) Barker, A. J. US Patent 5932574, 1999. (e) Goto, S.;
Tsuboi, H.; Kagara, K. Chem. Express 1993, 8, 761.
(f) Kagara, K.; Goto, S.; Tsuboi, H. Japanese Patent 25767,
1989. (g) Nauta, W. T. US Patent 3980650, 1976.
(h) Mizogami, S.; Miranuma, H.; Sekiya, T.; Hanazuka, M.
US Patent 4607034, 1986. (i) Rueeger, H.; Rigollier, P.;
Yamaguchi, Y.; Schmidlin, T.; Schilling, W.; Criscione, L.;
Whitebread, S.; Chiesi, M.; Walker, M. W.; Dhanoa, D.;
Islam, I.; Zhang, J.; Gluchowski, C. Bioorg. Med. Chem.
Lett. 2000, 10, 1175. (j) van Muijlwijk-Koezen, J. E.;
Timmerman, H.; van der Goot, H.; Menge, W. M. P. B.; von
Drabbe Künzel, J. F.; de Groote, M.; Ijzerman, A. P. J. Med.
Chem. 2000, 43, 2227. (k) Fry, D. W. Expert Opin. Invest.
Drugs 1994, 3, 577. (l) Gibson, K. H.; Grundy, W.;
Godfrey, A. A.; Woodbrun, J. R.; Ashton, S. E.; Curry, B. J.;
Scarlett, L.; Barker, A. J.; Brown, D. S. Bioorg. Med. Chem.
Lett. 1997, 7, 2723. (m) Myers, M. R.; Setzer, N. N.; Spada,
A. P.; Zulli, A. L.; Hsu, C.-Y. J.; Zilberstein, A.; Johnson, S.
E.; Hook, L. E.; Jacoski, M. V. Bioorg. Med. Chem. Lett.
1997, 7, 417. (n) Sielecki, T. M.; Johnson, T. L.; Liu, J.;
Muckelbauer, J. K.; Grafstrom, R. H.; Cox, S.; Boylan, J.;
Burton, C. R.; Chen, H.; Smallwood, A.; Chang, C.-H.;
Boisclair, M.; Benfield, P. A.; Trainor, G. L.; Seitz, S. P.
Bioorg. Med. Chem. Lett. 2001, 11, 1157.
(2) (a) Michael, J. P. Nat. Prod. Rep. 2000, 17, 603.
(b) Michael, J. P. Nat. Prod. Rep. 2001, 18, 543.
(3) Manske, R. H. F.; Kulka, M. Org. React. 1953, 7, 59.
(4) Cheng, C.-C.; Yan, S.-J. Org. React. 1982, 28, 37.
(5) Pastor, G.; Blanchard, C.; Montginoul, C.; Torrieilles, E.;
Giral, L.; Texier, A. Bull. Soc. Chim. Fr. 1975, 1331.
(6) Khalifa, M.; Osman, A. N.; Ibrahim, M. G.; Ossman, A.-R.;
Ismail, M. A. Pharmazie 1982, 37, 115.
(7) Michman, M.; Patai, S.; Wiesel, Y. Org. Prep. Proced. Int.
1978, 10, 13.
(8) Brown, D. J. Chem. Heterocycl. Compd. 1962, 16, 430.
(9) Mizuno, T.; Okamoto, N.; Ito, T.; Miyata, T. Tetrahedron
Lett. 2000, 41, 1051.
quinazolines
and
6-trifluoromethyl-2,4-dichloro
compounds 7e and 8g were obtained in the lowest yield,
while 2,4-dichloro compounds 7d and 8f having an elec-
tron-donating methyl group on the C6 position were ob-
tained in 74% and 80% yield, respectively.
Cl
CN
diphosgene
N
N
N
CH3CN
N
NH2
N
N
Cl
100 °C, 14 h
Bn
Bn
10
9
Scheme 4 Acetonitrile-mediated synthesis of 1-benzyl-4,6-dichlo-
ropyrazolo[3,4-d]pyrimidine.
On the basis of a successful synthesis of 2,4-dichloroqui-
nilines and 2,4-dichloroquinazolines, another example
was attempted to show that this reaction mechanism is
generally applicable to the synthesis of other heterocyclic
compounds. 5-Amino-1-benzyl-4-cyanopyrazole (9),17
which was prepared by the reaction of 5-amino-4-cyano-
1H-pyrazole and benzyl chloride in the presence of three
equivalents of potassium carbonate in DMF at 70 °C for
1.5 hours, as expected, furnished 1-benzyl-4,6-dichloro-
pyrazolo[3,4-d]pyrimidine (10)18 in 51% yield, showing
that this reaction is a very reliable method for the synthe-
sis of various heterocyclic compounds (Scheme 4).
In summary, five 2,4-dichloroquinolines and seven 2,4-
dichloroquinazolines were synthesized by this one-pot
reaction from 2-ethynylanilines and anthranilonitriles,
respectively, using diphosgene in acetonitrile via acetoni-
trile-mediated mechanism. It was found that 1-benzyl-
4,6-dichloropyrazolo[3,4-d]pyrimidine can also be pre-
pared under the same reaction conditions, suggesting that
our synthetic method has significant generality for the
synthesis of many heterocyclic compounds possessing
nucleophilic or transition-metal labile chlorine atoms.
(10) Kokel, B.; Menichi, G.; Huberthabart, M. Tetrahedron Lett.
1984, 25, 1557.
(11) Seijas, J. A.; Vázquez-Tato, M. P.; Martínez, M. M.
Tetrahedron Lett. 2000, 41, 2215.
(12) Lee, B. S.; Lee, J. H.; Chi, D. Y. J. Org. Chem. 2002, 67,
7884.
(13) (a) Gabriele, B.; Salerno, G.; Veltri, L.; Costa, M.; Massera,
C. Eur. J. Org. Chem. 2001, 4607. (b) Matsuda, H.; Okada,
S.; Nakanishi, H.; Kato, M.; Horai, S.; Horiishi, N. Japanese
Patent 07126223, 1995.
(14) Lindstrom, S.; Ripa, L.; Hallberg, A. Org. Lett. 2000, 2,
2291.
(15) Sargent, M. V. J. Chem. Soc., Perkin Trans. 1 1987, 231.
(16) Review: Spoerri, P. E.; DuBois, A. S. Org. React. 1949, 5,
387.
Acknowledgment
This work was supported by LG Life Sciences (2003) and National
Research and Development Program of MOST, Korea (2005-
03184). High resolution mass spectra were carried out at the Korea
Basic Science Institute (Daegu, Korea).
(17) Kelley, J. L.; Davis, R. G.; McLean, E. W.; Glen, R. C.;
Soroko, F. E.; Cooper, B. R. J. Med. Chem. 1995, 38, 2884.
(18) Schlager, L. H. Ger. Offen. Pat. 2310334, 1973.
(19) (a) Koller, G. Ber. Dtsch. Chem. Ges. 1927, 60, 8.
(b) Newman, M. S.; Powell, W. H. J. Org. Chem. 1961, 26,
812. (c) Lee, B. S.; Chu, S.; Lee, B.-S.; Chi, D. Y.; Song, Y.
S.; Jin, C. Bioorg. Med. Chem. Lett. 2002, 12, 811.
(d) Ashok, K.; Sridevi, G.; Umadevi, Y. Synthesis 1993, 623.
Synlett 2006, No. 1, 65–68 © Thieme Stuttgart · New York

68
J. H. Lee et al.
LETTER
(20) (a) Ram, V. J.; Farhanullah; Tripathi, B. K.; Srivastava, A.
K. Bioorg. Med. Chem. 2003, 11, 2439. (b) Weber, C.;
Demeter, A.; Szendrei, G. I.; Greiner, I. Tetrahedron Lett.
2003, 44, 7533. (c) Venuti, M. C.; Stephenson, R. A.;
Alvarez, R.; Bruno, J. J.; Strosberg, A. M. J. Med. Chem.
1988, 31, 2136. (d) Nakashima, Y.; Fujita, T.; Hizuka, M.;
Ikawa, H.; Hiruma, T. European Patent Application 899263,
1999.
(21) 2-Ethynylanilines 2a–e; General Procedure. The mixture
of N-trifluoro-2-iodoaniline (1.5 g, 4.76 mmol) and K2CO3
(1.97 g, 14.28 mmol) in 50 mL of MeOH–H2O (10:1) was
stirred at 50 °C for 24 h. H2O (200 mL) was added and the
product was extracted with EtOAc (3 × 50 mL), dried over
Na2SO4, and concentrated in vacuo. The resulting
cooling, the reaction mixture was poured into H2O (300 mL).
The product was extracted with EtOAc (3 × 100 mL), dried
over Na2SO4, and concentrated in vacuo. The crude was
added to a solution of K2CO3 (594 mg, 8.59 mmol) in
MeOH–H2O (10:1) and stirred at r.t. for 12 h. H2O (200 mL)
was added and the product was extracted with EtOAc (2 × 50
mL), dried over Na2SO4, and concentrated. The residue was
purified by flash column chromatography (10% EtOAc–
hexane). All 2-aminobenzonitriles gave satisfactory
analytical data; both 3a and 3c are commercially available.
2-Amino-5-chlorobenzonitrile (3b) Yield: 84%; gray
solid; mp 95.0–96.3 °C. 1H NMR (200 MHz, CDCl3): d =
7.35 (d, J = 2.6 Hz, 1 H), 7.28 (dd, J = 9.0, 2.0 Hz, 1 H), 4.42
(br s, 2 H). 13C NMR (50 MHz, CDCl3): d = 145.9, 131.9,
128.8, 119.9, 114.1, 113.9, 94.5. MS (EI): m/z (%) = 152.8
(M+). Anal. calcd for C7H5N2Cl: C, 55.10; H, 3.30; N, 18.36.
Found: C, 55.10; H, 3.44; N, 17.97.
2,4-Dichloroquinolines and 2,4-Dichloroquinazolines;
Typical Procedure. To a solution of 2a (500 mg, 4.27
mmol) in CH3CN (5 mL; dried over molecular sieves) was
added diphosgene (0.781 mL, 6.35 mmol) at r.t. (white
precipitate formed) under a N2 atmosphere. The reaction
mixture was placed in a tightly capped pressure tube, stirred
at 130 °C for 12 h, and then cooled to r.t. H2O was carefully
added to the mixture and then allowed to stand for 30 min at
r.t. The combined organic layers were washed with EtOAc
(3 × 100 mL), dried over Na2SO4, and concentrated in
vacuo. The residue was purified by flash column
iodoaniline (1.00 g, 4.56 mmol), TMSC≡CH (0.968 mL,
6.85 mmol), PdCl2(PPh3)2 (96.14 mg, 137 mmol), and CuI
(26.08 mg, 137 mmol) were dissolved in THF (200 mL) at r.t.
under a N2 atmosphere. After 5 min, Et3N (50 mL) was
added dropwise and the solution was stirred at r.t. for 1 h.
H2O was added, the reaction mixture was extracted with
EtOAc (3 × 50 mL), dried over Na2SO4, and concentrated in
vacuo. The crude material was dissolved directly in anhyd
THF (100 mL), and TBAF (1 M THF; 9.2 mL) was added
dropwise at 0 °C to r.t. The reaction mixture was extracted
with EtOAc (3 × 50 mL) and dried over Na2SO4. The residue
was purified by flash column chromatography (10%
EtOAc–hexane).
2-Ethynylaniline (2a) Yield: 90%; brown liquid. 1H NMR
(200 MHz, CDCl3): d = 7.32 (dd, J = 8.1, 1.5 Hz, 1 H), 7.15
(td, J = 7.7, 1.6 Hz, 1 H), 6.72–6.64 (m, 2 H), 4.24 (br s, 2
H), 3.39 (s, 1 H). 13C NMR (50 MHz, CDCl3): d = 148.4,
132.5, 130.0, 117.7, 114.2, 106.5, 82.4, 80.6. MS (ESI): m/z
(%) = 118.4 (M+ + H, 100), 91.5. HRMS (CI): m/z calcd for
C8H8N (MH+): 118.0657; found: 118.0661.
2-Ethynyl-4-trifluoromethylaniline (2e) Yield: 90%; dark
brown liquid. 1H NMR (200 MHz, CDCl3): d = 7.57 (d, J =
1.8 Hz, 1 H), 7.35 (dd, J = 8.8, 1.8 Hz, 1 H), 6.71 (d, J = 8.8
Hz, 1 H), 4.59 (br s, 2 H), 3.42 (s, 1 H). 13C NMR (50 MHz,
CDCl3): d = 148.6, 145.1, 127.7 (q, J = 3.7 Hz), 124.7 (q,
J = 3.6 Hz), 118.2 (q, J = 72.8 Hz), 111.4, 103.8, 81.2, 27.3.
MS (ESI): m/z (%) = 166.4 (MH+, 100), 117.4. HRMS (CI):
m/z calcd for C9H7F3N (MH+): 186.0531; found: 186.0533.
2-Aminobenzonitrile 3b, 3d, 3e; General Procedure.
Under a N2 atmosphere N-trifluoroacetyl-4-chloro-2-
iodoaniline (750 mg, 2.15 mmol) and CuCN (192.5 mg, 2.15
mmol) were dissolved in DMF (50 mL) at r.t., and then the
reaction mixture was heated at 100 °C for 30 min. After
chromatography (10% EtOAc–hexane).
2,4-Dichloro-6-trifluoromethylquinoline (7e) Yield: 25%;
white solid; mp 113.5–116.1 °C. 1H NMR (200 MHz,
CDCl3): d = 8.50 (d, J = 1.8 Hz, 1 H), 8.14 (d, J = 9.4 Hz, 1
H), 7.97 (dd, J = 8.8, 1.8 Hz, 1 H), 7.62 (s, 1 H). 13C NMR
(50 MHz, CDCl3): d = 152.3, 149.1, 145.1, 130.3, 129.5,
127.3 (q, J = 3.0 Hz), 123.4 (q, J = 84.9 Hz), 123.3, 122.2
(q, J = 4.5 Hz). MS (EI): m/z (%) = 269 (M+), 267 (M+), 265
(M+, 100), 230, 210, 194. HRMS (CI): m/z calcd for
C10H5Cl2F3N (MH+): 265.9751; found: 265.9753.
2,4-Dichloro-6-trifluoromethylquinazoline (8g) Yield:
41%; white solid; mp 100.4–102.5 °C. 1H NMR (200 MHz,
CDCl3): d = 8.57 (s, 1 H), 8.17–8.16 (m, 2 H). 13C NMR (50
MHz, CDCl3): d = 164.8, 157.2, 153.3, 131.7 (q, J = 3.1 Hz),
131.1 (q, J = 33.6 Hz), 129.4, 125.6, 123.9 (q, J = 4.4 Hz),
121.6. MS (ESI): m/z (%) = 271 (M+ + H), 269 (M+ + H), 267
(M+ + H), 249 (100), 229, 215, 195, 163, 123. HRMS (CI):
m/z calcd for C9H4Cl2F3N2 (MH+): 266.9704; found:
266.9700.
Synlett 2006, No. 1, 65–68 © Thieme Stuttgart · New York