Unexpected and divergent reactions of N -formyl-1,2-dihydroquinolines with sodium azide: Highly chemoselective formation of 2-substituted quinolines and isoxazolo[4,3- c ]quinolines

Article abstract of DOI:10.1055/s-0029-1219800

Efficient and divergent synthesis of 2-substituted quinolines and isoxazolo[4,3-c]quinolines was achieved from N-formyl-1,2-dihydroquinolines with the aid of sodium azide. The synthesis is substituent-dependent. Thus N-formyl-1,2-dihydroquinolines with a hydrogen atom at the 3-position afforded 2-substituted quinolines in good to excellent yields, while with a 3-formyl group, N-formyl-1,2-dihydroquinolines unexpectedly gave isoxazolo[4,3-c] quinolines in high yields. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-0029-1219800

LETTER
1281
Unexpected and Divergent Reactions of N-Formyl-1,2-dihydroquinolines with
Sodium Azide: Highly Chemoselective Formation of 2-Substituted Quinolines
and Isoxazolo[4,3-c]quinolines
Highly Chemoselective
eFormation
i
of 2-Su
k
bstituted
Q
u
e
Key Laboratory of Pharmaceutical Engineering of Ministry of Education, College of Pharmaceutical Sciences,
Zhejiang University of Technology, Hangzhou 310014, P. R. of China
Fax +86(571)88320752; E-mail: pharmlab@zjut.edu.cn
Received 22 January 2010
nylquinoline and sodium azide as previously reported.8
Instead, 2-phenylquinoline (2a), resulting from the one-
pot N-deformylation and aromatization, was obtained in
excellent yield (95%) (Scheme 2).
Abstract: Efficient and divergent synthesis of 2-substituted quino-
lines and isoxazolo[4,3-c]quinolines was achieved from N-formyl-
1,2-dihydroquinolines with the aid of sodium azide. The synthesis
is substituent-dependent. Thus N-formyl-1,2-dihydroquinolines
with a hydrogen atom at the 3-position afforded 2-substituted quin-
olines in good to excellent yields, while with a 3-formyl group, N-
formyl-1,2-dihydroquinolines unexpectedly gave isoxazolo[4,3-
c]quinolines in high yields.
CHO
NH2
N
R
BTC, DMF
R
NaOH, H2O
Key words: azides, quinolines, chemoselectivity, deformylation
heterocycles
O
Cl
Scheme 1
Quinolines and their derivatives represent an important
class of organic molecules that attract continuing interest
of both synthetic and medicinal chemists. Functionalized
quinolines are integral to a large number of biologically
active synthetic drug substances.1 In particular, 2-substi-
tuted quinolines are naturally occurring in antiplatelet
agents,2 5-lipoxygenase inhibitors,3 LTD4 receptor anta-
gonists,4 and other biologically active molecules. Despite
currently available methodologies for the construction of
quinoline derivatives, the development of new synthetic
methods is still of considerable ongoing interest.5
CHO
N
Ph
NaN3, DMSO
X
CHO
N
90 °C
Ph
N3
2a'
N
Ph
Cl
NaN3, DMSO
90 °C
1a
2a
In our constant medicinal chemistry effort in searching for
the compounds with pharmacological importance, we un-
dertook the program of synthesis of a variety of 4-substi-
tuted quinolines as key building blocks. Recently, we
have reported an efficient method to form 4-chloro 2-sub-
stituted N-formyl-1,2-dihydroquinolines from 2¢-ami-
nochalcones by a new Vilsmeier-type regent, bis-
(trichloromethyl) carbonate (BTC)–DMF, as shown in
Scheme 1.6 Since the chlorine atom at the 4-position could
be replaced by various groups in producing physiological-
ly activated compounds,7 we attempted the preparation of
4-azido quinolines from 4-chloro 2-substituted N-formyl-
1,2-dihydroquinolines.
Scheme 2 Reaction of 1a with sodium azide
According to our knowledge, N-deformylation of form-
amides is generally achieved by heating of the substrates
in strongly acidic or basic solutions.9 Recently, Perumal et
al. developed a novel method for the oxydic deformyla-
tion of N-formyldihydroquinolines employing ferric chlo-
ride hexahydrate.10 Taking into account the simple and
efficient method employed here, we further optimized this
unexpected reaction so as to develop a new and conve-
nient metal-free synthesis of quinolines via consecutive
N-deformylation and aromatization.
To set up the standard reaction conditions, the ratio of 1a
to NaN3, solvent and reaction temperature were then in-
vestigated. A series of experiments revealed that using
one equivalent of NaN3 could afford the corresponding
product with a preferable yield while reducing the amount
of NaN3 would lead to incomplete conversion. The reac-
tion did not afford 2a in better yield with higher molar
ratio of NaN3:1a. Besides DMSO, a number of other sol-
vents such as DMF and H2O,11 DMF,12 and MeCN were
further surveyed under similar conditions. However, no
4-Chloro-2-phenyl-N-formyl-1,2-dihydroquinoline (1a)
was selected as a model substrate to test the reaction.
However, the reaction between 1a and sodium azide did
not afford the expected 4-azido products 2a¢, which was in
contrast with the reaction between 4-chloro-2-phe-
SYNLETT 2010, No. 8, pp 1281–1284
x
x.
x
x.
2
0
1
0
Advanced online publication: 25.03.2010
DOI: 10.1055/s-0029-1219800; Art ID: W01110ST
© Georg Thieme Verlag Stuttgart · New York

1282
W. Su et al.
LETTER
Table 1 Synthesis of 2-Substituted Quinolines 2 (continued)
obvious improvement was observed in comparison with
DMSO. The optimal results were obtained when the reac-
tion was performed with one equivalent of NaN3 at 90 °C
for 0.5 hour, whereby the yield of 2a reached 95%.
CHO
N
R1
N
R1
NaN3, DMSO
Table 1 Synthesis of 2-Substituted Quinolines 2
Cl
CHO
2a–n
1a–n
N
R1
N
R1
R1
Producta Time Yieldb
NaN3, DMSO
Entry
13
1
(h)
(%)
Cl
Tol
2a–n
1a–n
1m
2md
2nd
3.5
85
N
N
Entry
1
R1
Producta Time Yieldb
(h)
(%)
Ph
1
2
3
4
5
1a
1b
1c
1d
1e
2a
2b
2c
2d
2e
0.5
95
14
1n
3.5
88
N
Et
0.5
0.5
0.5
0.5
99
99
99
99
a Reactions were carried out with 1 (1.0 mmol) and sodium azide (1.0
mmol) at 90 °C.
Cl
Cl
b Isolated yield based upon 1a–n.
c Reaction temperature: 150 °C.
d Reaction temperature: 120 °C.
With the best reaction conditions in hand, the scope of this
novel cascade reaction with different N-formyl-1,2-dihy-
droquinolines 1 was examined. Gratifyingly, under the
optimized conditions, all the substrates listed in Table 1
afforded the desired N-deformylated products 2 in good
yields.
NO2
NO2
Cl
As shown in Table 1, compounds 1 with an electron-with-
drawing group at the 2-aryl of quinoline produced the cor-
responding N-deformylated products in excellent yields
(Table 1, entries 2–8). On the other hand, compounds 1i
and 1j with electron-donating aryl groups afforded 2i and
2j in relatively lower yields (Table 1, entries 9 and 10).
When this protocol was applied to more substrates, espe-
cially various 2-heteroaryl-4-chlorodihydroquinolines,
good yields of the desired quinoline products were also
isolated (Table 1, entries 11–14). At this stage, it could be
concluded that this N-deformylation and aromatization
reaction tolerates a wide variety of N-formyl-1,2-dihydro-
quinolines.
6
1f
2f
0.5
99
F
7
8
1g
1h
2g
2h
0.5
0.5
97
97
Br
F
9
1i
2i
1.0
94
To further extend the scope and generality of the reaction,
3-formyl-substituted
N-formyl-1,2-dihydroquinolines
10
11
1j
2jc
3.5
3
84
86
such as 4-chloro-2-phenylquinoline-1,3(2H)-dicarbalde-
hyde (1o) was introduced.13 However, instead of obtain-
ing the desired N-deformylation product 3o¢, 4-
phenylisoxazolo[4,3-c]quinoline-5(4H)-carbaldehyde (3o)
was isolated as the single product and no azirine was de-
tected.14a,b A plausible pathway is therefore suggested in
Scheme 3 to rationalize the formation of this unexpected
product.
OMe
1k
2kc
S
Ph
12
1l
2ld
2
86
N
N
Encouraged by the results that 1o could undergo a hetero-
cyclization to form 3o in the presence of sodium azide, we
subsequently applied the method for synthesizing more
isoxazolo[4,3-c]quinolines. It was found that isoxazo-
Ph
Synlett 2010, No. 8, 1281–1284 © Thieme Stuttgart · New York

LETTER
Highly Chemoselective Formation of 2-Substituted Quinolines
1283
Table 2 Synthesis of Isoxazolo[4,3-c]quinolines 3
CHO
N
CHO
CHO
N
CHO
N
N
NaN3
R1
R1
NaN3, DMSO
DMSO, r.t.
CHO
CHO
CHO
N3
Cl
1o
B
N
Cl
O
1o–r
3o–r
CHO
N
Entry
1
R1
Ph
Producta Time (h) Yieldb (%)
N
1
2
3
4
1o
1p
1q
1r
3o
3p
3q
3r
0.5
0.5
0.5
0.5
88
90
89
89
4-ClC6H4
CHO
N
3o
O
3o'
3,4-Me2C6H3
4-MeOC6H4
Scheme 3 Reaction pathway for the formation of 3
a Reactions were carried out with 1o–r (1.0 mmol) and sodium azide
(1.5 mmol) at r.t.
lo[4,3-c]quinolines 3o–r were obtained in satisfactory
yields (Table 2).
b Isolated yield based upon 1o–r.
On the basis of the above results, a possible mechanism
for these two divergent reactions is presented in
Scheme 4. Although it is premature to propose a detailed
mechanism at this stage, based on the above results a
probable sequence of reactions may be proposed. The
overall transformation of route 1 arises from the [1,3]-pro-
ton transfer, which is followed by azide nucleophilic at-
tack of 1a–n to provide an N-formyl azide intermediate A.
Elimination of formyl azide accompanied by elimination
of chlorine ion finally produces 2-substituted quinolines
2. Formation of isoxazolo[4,3-c]quinolines 3 (route 2) is
not mechanistically consistent with the quinolines pro-
duced in route 1. In this case, the above [1,3]-H shift to
generate intermediate C is disfavored. The formyl at the
3-position of quinoline conjugates with the C=C bond and
chlorine, thus forming an electron-deficient a,b-unsatur-
ated carbonyl system.
The azide anion attacks in a way of conjugate addition and
subsequent elimination of the chlorine would lead to inter-
mediate B.14 The azido-aldehyde intermediate B then un-
dergoes spontaneous denitrogenation and ring closure to
isoxazolo[4,3-c]quinolines 3. The details of the reaction
mechanism and the role of sodium azide are currently un-
der investigation.
In summary, we have developed a new and convenient ap-
proach to the construction of quinoline derivatives from
the readily accessible N-formyldihydroquinolines by
treatment with sodium azide. Depending upon the 3-sub-
stituent on the substrates, the protocol could give either 2-
substituted quinolines15 or 4-substituted isoxazolo[4,3-
c]quinolines-5(4H)-carbaldehydes16 in good to excellent
yields.
CHO
N
R1
R2
route 1
route 2
Cl
1
H
O
N3
CHO
CHO
N
CHO
N
R1
N
R1
H
R1
H
R1
N
NaN3, DMSO
R2 = H
NaN3, DMSO
R2 = CHO
[1,3]-H shift
heat
CHO
CHO
N3
N3 Cl
Cl
Cl
B
N2
N3
O
CHO
N
CHO
N
R1
R1
O
R1
H
N
R1
N
N
O
N
+
HCON3 Cl
Cl
2
3
A
Scheme 4 Plausible mechanism
Synlett 2010, No. 8, 1281–1284 © Thieme Stuttgart · New York

1284
W. Su et al.
LETTER
(12) Ismail, M. M.; Abass, M.; Hassan, M. M. Molecules 2000, 5,
1224.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
(13) Experimental Procedure for the Synthesis of 4-Chloro-2-
substituted Quinolines; 1,3-(2H)-dicarbaldehyde 1o–r:
To an ice-cold magnetically stirred solution of DMF (10 mL)
and 2-arylquinoline (5.0 mmol), POCl3 (30 mmol, 2.8 mL)
was added dropwise. The reaction mixture was heated to
50 °C for 3 h. After which it was poured into the crush ice,
neutralized with sat. K2CO3 solution and extracted with
EtOAc. After drying and condensation of the organic layer ,
the crude reaction product was purified by column
chromatography using 5% EtOAc in PE as eluent to afford
pure 1o–r.
Acknowledgment
We are grateful to the National Key Technology R&D Program
[2007BAI34B00], the National Natural Science Foundation of Chi-
na [No. 20876147] and the Opening Foundation of Zhejing Provin-
cial Top Key Pharmaceutical Discipline for financial support.
References and Notes
(14) (a) Brahma, S.; Ray, J. K. J. Heterocycl. Chem. 2008, 45,
311. (b) Brahma, S.; Ray, J. K. Tetrahedron Lett. 2005, 46,
6575. (c) Becher, J.; Jorgensen, P. L.; Pluta, K.; Krake, N. J.;
Falt-Hansen, B. J. Org. Chem. 1991, 57, 2127.
(1) (a) Kleeman, A.; Engel, J.; Kutscher, B.; Reichert, D.
Pharmaceutical Substances, Synthesis, Patents,
Applications; Thieme: Stuttgart, New York, 2001.
(b) Michael, J. P. Nat. Prod. Rep. 2001, 18, 543.
(c) Funayama, S.; Murata, K.; Noshita, T. Heterocycles
2001, 54, 1139.
(15) General Procedure for the Synthesis of 2-Substituted
Quinolines 2a–n: To a solution of DMSO (5 mL) and 4-
chloro-N-formyl-1,2-dihydroquinolines 1a–n (1.0 mmol),
NaN3 (1 mmol, 0.065 g) was added at r.t. The solution was
then heated at the indicated temperature (90 °C or 120 °C or
150 °C) for the indicated time. After completion of the
reaction (monitored by TLC) the mixture was treated with
ice-water and extracted with EtOAc. The organic layer was
washed with H2O, and then with brine. After condensation of
the organic layer, the products 2a–n were obtained by
column chromatography (PE–EtOAc).
(2) Huang, L. J.; Hsieh, M. C.; Teng, C. M.; Lee, K. H.; Kuo,
S. C. Bioorg. Med. Chem. 1998, 6, 1657.
(3) Musser, J. H.; Chakraborty, U. R.; Sciortino, S.; Gordon, R.
J.; Khandwala, A.; Neiss, E. S.; Pruss, T. P.; Van Inwegen,
R.; Weinryb, I.; Coutts, S. M. J. Med. Chem. 1987, 30, 96.
(4) Gauthier, J. Y.; Jones, T.; Champion, E.; Charette, L.;
Dehaven, R.; Ford-Hutchinson, A. W.; Hoogsteen, K.; Lord,
A.; Masson, P.; Piechuta, H.; Pong, S. S.; Springer, J. P.;
Therien, M.; Zamboni, R.; Young, R. N. J. Med. Chem.
1990, 33, 2841.
2-(2-Chloro-6-fluorophenyl)quinoline (2f)
New compound. Yield: 99%; light yellow oil; Rf 0.53 (PE–
EtOAc, 5:1). 1H NMR (400 MHz, CDCl3): d = 8.27 (1 H, d,
J = 8.0 Hz), 8.20 (1 H, d, J = 8.4 Hz), 7.89 (1 H, d, J = 8.0
Hz), 7.74–7.79 (1 H, m), 7.60 (1 H, t, J = 8.0 Hz), 7.50 (1 H,
(5) For example: (a) Majumder, S.; Gipson, K. R.; Odom, A. L.
Org. Lett. 2009, 11, 4720. (b) Martinez, R.; Ramon, D. J.;
Yus, M. J. Org. Chem. 2008, 73, 9778. (c) Schramm, O. G.;
Oeser, T.; Kaiser, M.; Brun, R.; Müller, T. J. J. Synlett 2008,
359. (d) Zhang, Z. H.; Tan, J. J.; Wang, Z. Y. Org. Lett.
2008, 10, 173. (e) Horn, J.; Marsden, S. P.; Nelson, A.;
House, D.; Weingarten, G. G. Org. Lett. 2008, 10, 4117.
(f) Li, L.; Jones, W. D. J. Am. Chem. Soc. 2007, 129, 10707.
(g) Sandelier, M. J.; DeShong, P. Org. Lett. 2007, 9, 3209.
(6) Li, H.; Zheng, C.; Chen, R. E.; Su, W. K. Org. Prep. Proced.
Int. 2009, 41, 156.
(7) (a) Wolf, C.; Lerebours, R. J. Org. Chem. 2003, 68, 7077.
(b) Pierce, A. C.; ter Haar, E.; Binch, H. M.; Kay, D. P.;
Patel, S. R.; Li, P. J. Med. Chem. 2005, 48, 1278.
(c) Andersen, K. E.; Lundt, B. F.; Jorgensen, A. S.;
Braestrup, C. Eur. J. Med. Chem. 1996, 31, 417. (d) Holla,
B. S.; Mahalinga, M.; Karthikeyan, M. S.; Poojary, B.;
Akberali, P. M.; Kumari, N. S. Eur. J. Med. Chem. 2005, 40,
1173. (e) Zhong, B. Y.; Al-Awar, R. S.; Shih, C.; Grimes,
J. H. Jr.; Vieth, M.; Hamdouchi, C. Tetrahedron Lett. 2006,
47, 2161. (f) Lim, J.; Stock, N.; Pracitto, R.; Boueres, J. K.;
Munoz, B.; Chaudhary, A.; Santini, A. M.; Orr, K.;
Schaffhauser, H.; Bezverkov, R. E.; Aiyar, J.; Venkatraman,
S. Bioorg. Med. Chem. Lett. 2004, 14, 1913.
d, J = 8.0 Hz), 7.32–7.38 (2 H, m), 7.11–7.16 (1 H, m). 13
C
NMR (100 MHz, CDCl3): d = 160.7 (d, 1JC–F = 248.7 Hz),
152.5, 147.9, 136.4, 134.3, 130.2 (d, 3JC–F = 9.9 Hz), 129.8,
129.6, 127.6, 127.3, 127.1, 125.6 (d, 4JC–F = 3.1 Hz), 123.0,
114.6 (d, 2JC–F = 22.0 Hz). HRMS (ESI): m/z [M + H]+ calcd
for C15H10ClFN: 258.0408; found: 258.0477.
(16) General Procedure for the Synthesis of 4-Substituted
Isoxazolo[4,3-c]quinolines-5-(4H)-carbaldehyde 3o–r:
To a solution of DMSO (5 mL) and 4-chloro-2-substituted
quinolines-1,3 (2H)-dicarbaldehyde 1o–r (1.0 mmol), NaN3
(1.5 mmol, 0.098 g) was added at r.t. and the reaction
mixture was kept at this temperature for 0.5 h. After
completion of the reaction (monitored by TLC) the mixture
was treated with ice-water and extracted with EtOAc. The
organic layer was washed with H2O, and then with brine.
After condensation of the organic layer, the products 3o–r
were obtained by column chromatography (PE–EtOAc).
4-Phenylisoxazolo[4,3-c]quinoline-5-(4H)-carbaldehyde (3o)
New compound. Yield: 88%; white crystals; mp 176–178
°C; Rf 0.46 (PE–EtOAc, 3:1). IR (KBr): 3121, 3057, 2851,
1677, 1609, 1574, 1475 cm–1. 1H NMR (400 MHz, DMSO):
d = 9.21 (1 H, s), 8.86 (1 H, s), 7.94 (1 H, d, J = 8.0 Hz), 7.73
(1 H, d, J = 8.0 Hz), 7.54–7.59 (1 H, m), 7.37–7.41 (1 H, m),
7.22–7.30 (3 H, m), 7.16 (2 H, d, J = 8.0 Hz), 7.10 (1 H, s).
13C NMR (100 MHz, DMSO): d = 162.4, 156.0, 153.8,
138.8, 136.1, 132.2, 128.7, 127.8, 126.3, 126.1, 124.6,
121.2, 117.1, 114.7, 46.9. HRMS (EI): m/z [M+] calcd for
C17H12N2O2: 276.0899; found: 276.0899.
(8) Sashida, H.; Fujii, A.; Tsuchiya, T. Chem. Pharm. Bull.
1987, 35, 3182.
(9) Smith, K. M.; Miura, M.; Tabba, H. D. J. Org. Chem. 1983,
48, 4779.
(10) Kumar, K. H.; Peruma, P. T. J. Heterocycl. Chem. 2008, 45,
597.
(11) Delfourne, E.; Darro, F.; Bontemps-Subielos, N.;
Decaestecker, C.; Bastide, J.; Frydman, A.; Kiss, R. J. Med.
Chem. 2001, 44, 3275.
Synlett 2010, No. 8, 1281–1284 © Thieme Stuttgart · New York

Copyright of Synlett is the property of Georg Thieme Verlag Stuttgart and its content may not
be copied or emailed to multiple sites or posted to a listserv without the copyright holder's
express written permission. However, users may print, download, or email articles for
individual use.