Preparation of 3-haloquinolines from 3-amino-2-halo-2-alkenimines

Full text of DOI:10.1021/jo9600215

J . Org. Chem. 1996, 61, 7195-7197
7195
Sch em e 1
Sch em e 2
Sch em e 3
P r ep a r a tion of 3-Ha loqu in olin es fr om
3-Am in o-2-h a lo-2-a lk en im in es
Pedro J . Campos,* Cheng-Quan Tan,†
Miguel A. Rodr´ıguez, and Elena An˜o´n
Departamento de Qu´ımica, Universidad de La Rioja, 26071
Logron˜o, Spain
Received J anuary 2, 1996
The quinoline ring system occurs in natural products,
especially alkaloids.1 The quinoline skeleton is often used
for the design of many synthetic compounds with phar-
macological properties such as nitroxaline, chloroquine,
which is one example of an antimalarial compound, the
tetrahydroquinoline derivative oxamniquine, which is
used to eradicate blood flukes, a major cause of disease
in tropical regions, and quinolone derivatives, which show
a high antibacterial activity.2 In particular, halogen-
containing quinolines are of significant interest because
halogen atoms sometimes play a pivotal role in bioactive
compounds and they provide a further avenue for struc-
tural elaboration.3
We have previously reported the synthesis of substi-
tuted quinolines by irradiation of 3-amino-2-alkenimines
(Scheme 1).4 Considering the significance of the halo-
quinoline substrates, we undertook a study of the pho-
tochemical behavior of halo-functionalized alkenimines.
Taking into account our experience in iodination reac-
tions with bis(pyridine)iodonium(I) tetrafluoroborate5 and
the simplicity of functionalization of 3-amino-2-alken-
imines at the 2-position,6,7 we carried out the preparation
of 3-amino-2-iodo-2-alkenimines (Scheme 2).8 We report
here the results obtained for the irradiation of 3-amino-
2-halo-2-alkenimines.
of the iodofunctionalized alkenimine 1a in methanol
using a medium-pressure mercury lamp through quartz.
The complete consumption of starting product (3 h) was
monitored by 1H NMR spectroscopy. This reaction gives
the quinoline 2a together with the alkenimine resulting
from the iodine atom photocleavage 3a (Scheme 3),
instead of the expected iodoquinoline, as it is elucidated
from the spectroscopic data (1H and 13C NMR) and mass
spectrometry. We have verified that direct irradiation
of alkenimine 3 (prepared according to ref 9) did not
suffer any appreciable change for 3 h. Therefore, the
quinoline 2a should be produced by iodine loss after
cyclization. In fact, the irradiation of aryl halides is a
well-documented process that usually results in an initial
homolysis of the C-halogen bond,10 and the photodebro-
mination of quinolines and isoquinolines has already
been described.11
Ir r a d ia tion of 3-Am in o-2-iod o-2-a lk en im in es. The
ultraviolet absorption spectrum of 3-(p-tolylamino)-2-
iodo-1,3-diphenyl-2-alkenimine 1a in methanol shows
bands at 212, 222, and 366 nm (ꢀ ≈ 17 500, 14 800, and
3100, respectively). These data are related to that
described for the photocyclization of alkenimines.4 There-
fore, we carried out the irradiation of a 10-2 M solution
The photodebromination of quinolines should occur
through a mechanism involving an electron transfer from
a nucleophile followed by hydrogen transfer from the
solvent.11 The electron transfer process is favored upon
increasing the solvent polarity.12 Thus, the irradiation
was assayed in a less polar solvent, benzene. In this case,
the formation of iodoquinoline 4a as well as the quinoline
2a and traces of 3a was observed. The most advanta-
geous rate, in relation to 4a , was found at 8 h of reaction
time (Scheme 4 and Table 1). The increase in the
reaction time can be explained by the energy loss because
of benzene absorption. Similar results were obtained
with several iodoalkenimines. The larger photodeiodi-
nation after 24 h of irradiation should be noted. Quino-
lines 2 and 4 were isolated and purified by column
chromatography (silica gel, hexane-ether, 3:1) and ana-
† Present address: University of Dalian, Dalian, China.
(1) (a) Kametani, T.; Kasai, H. In Studies in Natural Products
Chemistry; Atta-ur-Rahman, Ed.; Elsevier Scientific Publishing Co.:
Amsterdam, 1989; Vol. 3, p 385. (b) Yates, F. S. In Comprehensive
Heterocyclic Chemistry; Katritzky, A. R., Rees, C. W., Eds.; Perga-
mon: Oxford, U.K., 1984; Vol. 2, p 511. (c) Sainsbury, M. In Rodd’s
Chemistry of Carbon Compounds; Coffey, S., Ed.; Elsevier Scientific
Publishing Co.: Amsterdam, 1978; Part G, p 171.
(2) For reviews of methods for the synthesis of quinoline derivatives
see: (a) J ones, G. In ref 1a; p 395. (b) Campbell, N. In ref 1c; 1976;
Part F, p 235. (c) Newkome, G. R.; Paudler, W. W. Contemporary
Heterocyclic Chemistry. Syntheses, Reactions, and Applications;
Wiley: New York, 1982; p 200. (d) Gilchrist, T. L. Heterocyclic
Chemistry, 2nd ed.; Longman Scientific & Technical: Essex, U.K.,
1992; p 152. (e) J oule, J . A.; Mills, K.; Smith, G. F. Heterocyclic
Chemistry, 3rd ed.; Chapman & Hall: London, 1995; p 120.
(3) Newhouse, B. J .; Bordner, J .; Augeri, D. J .; Litts, C. S.; Kleinman,
E. F. J . Org. Chem. 1992, 57, 6991. Torii, S.; Xu, L. H.; Sadakane, M.;
Okumoto, H. Synlett 1992, 513.
lyzed by H and 13C NMR spectroscopy and mass spec-
trometry. All reported quinolines show spectral data
1
(4) Campos, P. J .; Tan, C.-Q.; Gonza´lez, J . M.; Rodr´ıguez, M. A.
Tetrahedron Lett. 1993, 34, 5321.
(5) Barluenga, J .; Gonza´lez, J . M.; Campos, P. J .; Asensio, G. Angew.
Chem., Int. Ed. Engl. 1985, 24, 319. Barluenga, J .; Rodr´ıguez, M. A.;
Campos, P. J .; Asensio, G. J . Am. Chem. Soc. 1988, 110, 5567.
Barluenga, J .; Gonza´lez, J . M.; Garc´ıa-Martin, M. A.; Campos, P. J .;
Asensio, G. J . Org. Chem. 1993, 58, 2058.
(6) Barluenga, J .; Toma´s, M.; Lo´pez-Ortiz, J . F.; Gotor, V. J . Chem.
Soc., Perkin Trans. 1 1983, 2273.
(7) Barluenga, J .; J ardo´n, J .; Gotor, V. J . Org. Chem. 1985, 50, 802.
(8) Campos, P. J .; Tan, C.-Q.; Rodr´ıguez, M. A. Tetrahedron Lett.
1995, 36, 5257.
(9) Hoberg, H.; Barluenga, J . Synthesis 1970, 82. For a review of
alkenimine chemistry see: Barluenga, J . Bull. Soc. Chim. Belg. 1988,
97, 545. Barluenga, J .; Aznar, F.; Fustero, S.; Toma´s, M. Pure Appl.
Chem. 1990, 62, 1957.
(10) Horspool, W.; Armesto, D. Organic Photochemistry: A Com-
prehensive Treatment; Ellis Horwood: London, 1992; p 457 and
references cited therein.
(11) Pa´rka´nyi, C.; Lee, Y. J . Tetrahedron Lett. 1974, 1115.
(12) Santamaria, J . In Photoinduced Electron Transfer; Fox, M. A.,
Chanon, M., Eds.; Elsevier Scientific Publishing Co.: Amsterdam,
1992; Part B, p 483.
S0022-3263(96)00021-7 CCC: $12.00 © 1996 American Chemical Society

7196 J . Org. Chem., Vol. 61, No. 20, 1996
Notes
Sch em e 4
Sch em e 5
Ta ble 1. Ir r a d ia tion of 3-Am in o-2-iod o-2-a lk en im in es 1a
1b
R1
R4
R5
4c (%) 2c (%) 4/2 ratiod
a
b
c
d
e
e
p-MeC6H4 Ph
6-Me
32
28
31
26
36
5
23
23
18
19
22
79
1/0.8
1/0.9
1/0.7
1/0.8
1/0.7
1/14e
p-MeC6H4 p-MeC6H4 6-Me
Ph Ph
o-MeC6H4 p-MeC6H4 8-Me
a
Prepared according to ref 6. bIrradiation time through quartz
H
c
for 1 mmol of alkenimine 5 with a 125 W mercury lamp. Yields
of isolated quinolines, relative to starting 5, purified by column
chromatography (silica, hexane-ether 3:1). dQuinoline 6/2 ratios,
determined by 1H NMR spectra of the crude reaction.
Ph
Ph
p-MeC6H4
p-MeC6H4
H
H
a
Irradiation in benzene, through quartz, during 8 h for 1 mmol
of alkenimine 1 with a 125 W mercury lamp (starting 1 was
Sch em e 6
b
completely consumed). Prepared according to ref 8. c Yields of
isolated quinolines, relative to starting 1, purified by column
d
chromatography (silica, hexane-ether 3:1). Quinoline 4/2 ratios,
determined by 1H NMR spectra of the crude reaction. e After 24 h
of irradiation.
and elemental analyses in accordance with the given
structures.
Ir r a d ia tion of 3-Am in o-2-br om o-2-a lk en im in es.
To compare the photochemical behavior of the iodinated
compounds with their analogous bromine and chlorine,
we have synthesized the compounds from halogenation
of 3-amino-2-alkenimines with both N-bromosuccinimide
and N-chlorosuccinimide, respectively.6
a
Prepared according to ref 6. bYields of isolated chloroquinolines
8, relative to starting alkenimine 7 with a 125 W mercury lamp.
The ultraviolet absorption spectrum of 3-(p-tolylamino)-
2-bromo-1,3-diphenyl-2-alkenimine 5a in methanol shows
bands at 210, 258, and 348 nm (ꢀ ≈ 28 200, 16 700, and
4400, respectively). The previous approach was extended
to the irradiation of bromoalkenimines 5. Under these
conditions, compounds 5 led to the formation of bromo-
quinolines 6 and debrominated quinolines 2 (Scheme 5).
The obtained rates depend on the solvent polarity and
reaction time. Bromoquinolines are obtained when tet-
rahydrofuran is used as solvent. This can be easily
explained considering the larger C-Br bond photochemi-
cal stability.13 After 1.5 h of irradiation in tetrahydro-
furan, the bromoquinoline is the major product while at
4 h it has been converted into the debrominated quino-
line. As expected, the debromination process is slowed
in benzene. Toluene exhibits similar absorption to
benzene but a higher polarity, and consistently, after 12
h of irradiation the bromoquinoline 6a /quinoline 2a rate
(1/0.61) is smaller than in benzene (1/0.54) at the same
reaction time.
2-chloro-1,3-diphenyl-2-alkenimine 7a in methanol shows
bands at 208, 254, and 354 nm (ꢀ ≈ 31 400, 19 300, and
7100, respectively). In this case, the irradiation of
choloroalkenimines 7 leads to the formation of 3-chloro-
quinolines 8 in quantitative yields after 2.5 h of irradia-
tion in tetrahydrofuran (Scheme 6). Dechlorination was
not observed.
In conclusion, the irradiation of haloalkenimines leads
to the formation of 3-haloquinolines. Moreover, the
reaction with chloro derivatives is quantitative, and
bromo- and iodoquinolines can be easily isolated in good
yields from the reaction crudes. Due to its mildness,
simplicity, cleanness, and quickness, we anticipate this
procedure should prove widely applicable. In addition,
its interest is enhanced since 3-haloquinolines often
exhibit pharmacological properties and can be further
functionalized. The experimental and theoretical study
of the reaction mechanisms for the cyclization and
photodehalogenation processes are in progress.
Ir r a d ia tion of 3-Am in o-2-ch lor o-2-a lk en im in es.
The ultraviolet absorption spectrum of 3-(p-tolylamino)-
Exp er im en ta l Section
Gen er a l Asp ects. 1H and 13C spectra were recorded on a
Bruker ARX-300 spectrometer in CDCl3 with TMS as internal
standard. Mass spectra were run on a HP 5987 A apparatus.
(13) See, for example: Kropp, P. J .; McNeely, S. A.; Davis, R. D. J .
Am. Chem. Soc. 1983, 105, 6907. Davidson, R. S.; Goodin, J . W.; Kemp,
G. Adv. Phys. Org. Chem. 1984, 20, 191.

Notes
J . Org. Chem., Vol. 61, No. 20, 1996 7197
Elemental analyses were performed on a Perkin-Elmer 240
elemental analyzer. All solvents were purified by standard
procedures and freshly destilled prior to use. Reagents were of
commercial grade (Aldrich). 3-Amino-2-iodo-2-alkenimines were
prepared in accordance with the described method in ref 4 and
bromo- and chloroalkenimines according to ref 6.
Gen er a l P r oced u r e: Ir r a d ia tion of 3-Am in o-2-h a lo-2-
a lk en im in es. A solution of 3-amino-2-halo-2-alkenimine (1
mmol) in the corresponding anhydrous solvent (50 mL) was
irradiated, at room temperature under argon atmosphere, using
a medium-pressure mercury lamp (125 W) until the consumption
of starting product was complete (monitored by 1H NMR, see
Table 1 and Schemes 5 and 6). The solution was evaporated
under reduced pressure, and the resulting quinoline was purified
by column chromatography (silica, hexane-ether 3:1).
3-Br om o-6-m eth yl-2,4-d ip h en ylqu in olin e (6a ): 1H NMR
δ 2.42 (s, 3 H), 7.15 (s, 1 H), 7.33-7.36 (m, 2 H), 7.45-7.58 (m,
7 H), 7.71-7.74 (m, 2 H), 8.06 (d, J ) 8.6 Hz, 1 H); 13C NMR δ
158.2, 148.8, 144.9, 141.0, 138.2, 137.3, 132.0, 129.3, 129.2, 128.8,
128.6, 128.4, 128.2, 127.8, 127.6, 125.0, 118.5, 21.7. Anal. Calcd
for C22H16NBr: C, 70.60; H, 4.31; N, 3.74. Found: C, 70.57; H,
4.18; N, 3.85.
3-Br om o-6-m eth yl-2-p h en yl-4-p-tolylqu in olin e (6b): 1H
NMR δ 2.42 (s, 3 H), 2.49 (s, 3 H), 7.16-7.18 (m, 3 H), 7.36-
7.65 (m, 8 H), 8.05 (d, J ) 8.6 Hz, 1 H); 13C NMR δ 157.9, 149.0,
144.9, 141.0, 137.2, 135.2, 132.0, 131.0, 129.3, 129.2, 129.1, 128.4,
128.3, 128.1, 127.8, 125.1, 118.6, 21.7, 21.4. Anal. Calcd for
C
23H18NBr: C, 71.14; H, 4.67; N, 3.61. Found: C, 71.16; H, 4.70;
N, 3.57.
1
3-Ch lor o-6-m eth yl-2,4-d ip h en ylqu in olin e (8a ): H NMR
δ 2.39 (s, 3 H), 7.17 (s, 1 H), 7.34-7.37 (m, 2 H), 7.44-7.56 (m,
7 H), 7.76-7.79 (m, 2 H), 8.07 (d, J ) 8.6 Hz, 1 H); 13C NMR δ
156.5, 146.2, 144.9, 139.4, 137.3, 135.9, 131.8, 129.5, 129.4, 129.3,
128.6, 128.5, 128.3, 127.9, 127.6, 126.3, 124.7, 21.7. Anal. Calcd
for C22H16NCl: C, 80.11; H, 4.89; N, 4.25. Found: C, 80.09; H,
4.79; N, 4.33.
3-Iod o-6-m eth yl-2,4-d ip h en ylqu in olin e (4a ): 1H NMR δ
2.41 (s, 3 H), 7.14 (s, 1 H), 7.24-7.34 (m, 3 H), 7.41-7.68 (m, 8
H), 8.05 (d, J ) 8.6 Hz, 1 H); 13C NMR δ 160.8, 153.8, 145.4,
143.7, 142.2, 137.3, 132.3, 129.2, 129.0, 129.0, 128.5, 128.4, 128.3,
127.9, 127.2, 125.4, 98.6, 21.7. Anal. Calcd for C22H16NI: C,
62.72; H, 3.83; N, 3.32. Found: C, 62.70; H, 3.75; N, 3.41.
3-Ch lor o-6-m eth yl-2-p h en yl-4-p-tolylqu in olin e (8b): 1H
NMR δ 2.41 (s, 3 H), 2.49 (s, 3 H), 7.19-7.27 (m, 3 H), 7.33 (d,
J ) 8.1 Hz, 2 H), 7.42-7.51 (m, 4 H), 7.74 (d, J ) 8.1 Hz, 2 H),
8.07 (d, J ) 8.2 Hz, 1 H); 13C NMR δ 156.4, 146.2, 144.6, 139.4,
138.0, 137.1, 132.8, 131.6, 129.4, 129.2, 129.1, 129.1, 128.5, 127.9,
127.7, 126.3, 124.7, 21.6, 21.3. Anal. Calcd for C23H18NCl: C,
80.34; H, 5.28; N, 4.07. Found: C, 80.40; H, 5.39; N, 4.01.
3-Ch lor o-2,4-d ip h en ylqu in olin e (8c): 1H NMR δ 7.33-7.82
(m, 13 H), 8.2 (d, J ) 8.6 Hz, 1 H); 13C NMR δ 157.4, 146.8,
145.9, 139.2, 135.6, 129.4, 129.4, 129.3, 129.3, 128.7, 128.4, 128.3,
127.9, 127.5, 127.1, 126.2, 125.9. Anal. Calcd for C21H14NCl:
C, 79.87; H, 4.47; N, 4.44. Found: C, 79.86; H, 4.40; N, 4.49.
3-Ch lor o-8-m eth yl-2-p h en yl-4-p-tolylqu in olin e (8d ): 1H
NMR δ 2.47 (s, 3 H), 2.83 (s, 3 H), 7.22-7.50 (m, 10 H), 7.86-
7.92 (m, 2 H); 13C NMR δ 155.5, 147.0, 145.1, 139.7, 138.0, 137.6,
133.3, 129.9, 129.4, 129.3, 129.1, 128.6, 127.7, 127.3, 126.8, 126.1,
124.1, 21.4, 18.1. Anal. Calcd for C23H18NCl: C, 80.34; H, 5.28;
N, 4.07. Found: C, 80.33; H, 5.25; N, 4.11.
3-Iodo-6-m eth yl-2-ph en yl-4-p-tolylqu in olin e (4b): 1H NMR
δ 2.41 (s, 3 H), 2.49 (s, 3 H), 7.16-7.18 (m, 3 H), 7.36-7.65 (m,
8 H), 8.05 (d, J ) 8.6 Hz, 1 H); 13C NMR δ 160.8, 153.9, 145.4,
143.8, 139.3, 138.1, 137.2, 133.3, 129.2, 129.0, 129.0, 128.9, 128.4,
127.9, 127.4, 125.5, 98.9, 21.7, 21.5. Anal. Calcd for C23H18NI:
C, 63.46; H, 4.17; N, 3.22. Found: C, 63.47; H, 4.22; N, 3.19.
3-Iod o-2,4-d ip h en ylqu in olin e (4c): 1H NMR δ 7.21-7.76
(m, 13 H), 8.17 (d, J ) 8.6 Hz, 1 H); 13C NMR δ 154.6, 147.2,
146.8, 143.6, 142.0, 130.0, 129.3, 129.2, 129.2, 129.0, 128.5, 128.5,
128.4, 127.9, 127.2, 126.8, 98.4. Anal. Calcd for C21H14NI: C,
61.93; H, 3.46; N, 3.44. Found: C, 61.93; H, 3.55; N, 3.37.
3-Iodo-8-m eth yl-2-ph en yl-4-p-tolylqu in olin e (4d): 1H NMR
δ 2.49 (s, 3 H), 2.81 (s, 3 H), 7.17 (d, J ) 8.2 Hz, 2 H), 7.26-7.31
(m, 2 H), 7.37 (d, J ) 8.2 Hz, 2 H), 7.45-7.57 (m, 4 H), 7.71-
7.75 (m, 2 H); 13C NMR δ 160.0, 154.7, 145.9, 143.9, 139.8, 138.1,
137.5, 129.9, 129.7, 129.1, 129.1, 129.0, 128.3, 127.6, 126.8, 124.9,
98.4, 21.4, 18.0. Anal. Calcd for C23H18NI: C, 63.46; H, 4.17;
N, 3.22. Found: C, 63.43; H, 4.05; N, 3.29.
3-Iod o-2-p h en yl-4-p-tolylqu in olin e (4e): 1H NMR δ 2.49
(s, 3 H), 7.19 (d, J ) 8.1 Hz, 2 H), 7.37 (d, J ) 8.1 Hz, 2 H),
7.43-7.77 (m, 8 H), 8.15 (d, J ) 8.2 Hz, 1 H); 13C NMR δ 161.8,
154.8, 146.8, 143.7, 139.1, 138.3, 130.0, 129.2, 129.2, 129.1, 128.9,
128.5, 127.9, 127.9, 127.1, 126.9, 98.8, 21.4. Anal. Calcd for
Ack n ow led gm en t. This work was supported by
Spanish DGICYT (PB91-0668) and Universidad de La
Rioja (94PYC06PCG). Two of us (C.-Q.T. and E.A.)
thank the Ministerio de Educacio´n y Ciencia (Spain) for
a fellowship.
C
22H16NI: C, 62.72; H, 3.83; N, 3.32. Found: C, 62.70; H, 3.79;
N, 3.39.
J O9600215