Synthesis of novel 3-bromo-1,2-dihydroquinolines via palladium mediated intramolecular cyclization of N-tosyl-N-propargyl anilines

Article abstract of DOI:10.1016/j.tetlet.2011.02.004

Facile synthesis of novel 3-bromo-1,2-dihydroquinolines by the intramolecular cyclization of N-tosyl-N-propargyl anilines catalyzed by Pd(OAc)₂ in conjunction with CuBr₂ and LiBr.

Full text of DOI:10.1016/j.tetlet.2011.02.004

Tetrahedron Letters 52 (2011) 1783–1787
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Tetrahedron Letters
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Synthesis of novel 3-bromo-1,2-dihydroquinolines via palladium mediated
intramolecular cyclization of N-tosyl-N-propargyl anilines
⇑
Savitha Gurunathan, Paramasivam Thirumalai Perumal
Organic Chemistry Division, Central Leather Research Institute, Adyar, Chennai 600 020, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Facile synthesis of novel 3-bromo-1,2-dihydroquinolines by the intramolecular cyclization of N-tosyl-N-
propargyl anilines catalyzed by Pd(OAc)2 in conjunction with CuBr2 and LiBr.
Ó 2011 Elsevier Ltd. All rights reserved.
Received 12 October 2010
Revised 31 January 2011
Accepted 2 February 2011
Available online 25 February 2011
Keywords:
Quinolines
LiBr
Pd(OAc)2
CuBr2
Propargyl aniline
Quinolines and their derivatives occur in numerous natural
products, and many of them display interesting biological activi-
ties.1 In particular, one of the partially hydrogenated quinoline
moieties namely dihydroquinoline is an important building block
in various natural products and exhibits a broad range of biological
activities and potential pharmaceutical applications.2 Typical
biological activities of such compounds include psychotropic,3
anti-allergenic,4 anti-inflammatory,5 and estrogenic activities.6
Compounds possessing this motif have also been shown to act as
lipid peroxidation inhibitors,7 HMG-CoA reductase inhibitors,8 ileal
bile acid transporter inhibitors9 and progesterone agonists10 and
antagonists.11 Owing to the biological and pharmaceutical impor-
tance of this class of heterocycles, there has been a constant
research in the development of new methodologies for their syn-
thesis .12
Among various quinoline systems, halogen containing quino-
lines are of significant interest because the halogen atom some-
times plays a pivotal role in the compound’s bioactivity, and
such compounds provide further avenue for structural elabora-
tion.13 Although simple 3-bromoquinolines can be obtained by
the bromination of quinoline hydrochlorides,14 the site selective
aromatic halogenation of substituted quinolines remains a syn-
thetic challenge.15 3-Haloquinolines have also been synthesized
by a photochemical method,16 a modified Skraup quinoline synthe-
sis employing halo-substituted acroleins and anilines,17 and the
Friedlander quinoline synthesis.13c Some of these methods suffer
from relatively low yields, poor regioselectivity, and/or rather
lengthy synthetic sequences. Hence, efficient and general synthetic
routes to these heterocyclic frameworks are of strong interest.
Taking these factors into consideration we were interested in
developing a methodology that provides facile access to halogen
substituted quinoline derivatives in good yields.
Recently, we described an efficient synthesis of 3-bromo-2H-
chromene derivatives from the corresponding aryl propargyl
ethers via an intramolecular cyclization catalyzed by Pd(OAc)2 in
the presence of LiBr and CuBr2.18
Herein we wish to report the results of our investigations on the
palladium mediated cyclization of N-tosyl-N-propargyl amines to
novel 3-bromo-1,2-dihydroquinoline derivatives.
Our initial efforts focused on the cyclization of N-tosyl-N-prop-
argyl aniline 1a to the corresponding 3-bromo-1,2-dihydroquino-
line derivative 2a in the presence of Pd(OAc)2 and CuBr2. While
screening a number of solvents to effect the cyclization it was
found that solvents such as CH3CN, CH2Cl2, DMSO, DMF, 1,4-diox-
ane were totally inefficient to effect the cyclization both at ambient
and at reflux conditions. Whereas, acetic acid effected the cyliza-
tion of 1a in the presence of 5 mol % of Pd(OAc)2 and CuBr2
(2.5 equiv) at 80 °C in 3 h to the corresponding 3-bromo-1,2-dihy-
droquinoline derivative 2a in 45% yield (Scheme 1., Condition a).
Further attempts to improve the yield by prolonging the reac-
tion time and by increasing the mole ratio of Pd(OAc)2 and CuBr2
were futile.
Then we supposed that by increasing the bromide ion concen-
tration in the reaction mixture we could arrive at the desired
product. LiBr was our choice of bromide ion source.
⇑
Corresponding author. Tel.: +91 44 24911386; fax: +91 44 24911589.
E-mail address: ptperumal@gmail.com (P.T. Perumal).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.02.004

1784
S. Gurunathan, P. T. Perumal / Tetrahedron Letters 52 (2011) 1783–1787
CH3
a
Br
N
2a
45 %
CH3
Ts
CH3
b
Br
N
N
Ts
80 %
Ts
1a
CH3
CH3
Br
Br
c
Br
N
+
N
Ts
Ts
2a'
2a
Scheme 1. Reagents and conditions: (a) 5 mol % Pd(OAc)2, 2.5 equiv CuBr2, AcOH, 80 °C; (b) 5 mol % Pd(OAc)2, 2.5 equiv CuBr2, 1 equiv LiBr, AcOH, 80 °C; (c) 5 mol % Pd(OAc)2,
2.5 equiv CuBr2, >1 equiv LiBr, AcOH, 80 °C.
R2
Table 1
R2
Optimization of the palladium catalyzed cyclization of N-tosyl, N-propargyl aniline 1a
to 3-bromo-1,2-dihydroquinoline derivative 2a using LiBr
R
Br
R
5 mol% Pd(OAc)2
Entry
LiBr (equiv)
Time in mins
Yield (%)aof 2a
1equiv. LiBr
2.5 equiv. CuBr2
AcOH, 80 °C
N
N
1
2
3
4
5
0
180
120
90
60
50
45
52
64
73
80
0.2
0.5
0.8
1
R1
R1
Ts
Ts
1b-l
2b-l
R2 = -CH3, -C2H5, -C3H7
R = H, Me, OMe, Cl
R1= H, Me
a
Isolated yield after column chromatography.
Scheme 2.
To our expectation, when 0.2 equiv of LiBr was used in addition
to 5 mol % of Pd(OAc)2 and 2.5 equiv CuBr2 in the reaction, the
yield of the cyclized product 2a improved to 52%. Further we found
that the time required for the completion of the reaction and the
yield of the product 2a was affected by increasing the quantity of
LiBr (Table 1)
After a series of trials best result was obtained using 5 mol %
Pd(OAc)2 in conjunction with 2.5 equiv CuBr2 and 1 equiv of LiBr
in acetic acid at 80 °C. The reaction proceeded smoothly and the
cyclization took place effectively furnishing the corresponding
3-bromo-1,2-dihydroquinoline 2a in 50 min in 80% yield
after purification through column chromatography (Scheme 1,
Condition b).
It was found that the reaction does not proceed in the absence
of either Pd(OAc)2 or CuBr2 illustrating their significant roles in the
reaction.
Having established the optimum condition for the reaction, a
variety of N-tosyl-N-propargyl aniline derivatives (1b–1l) were
cyclized following the optimized reaction conditions (Scheme 2).20
It was found that in all the cases the reaction proceeded
smoothly furnishing the corresponding 3-bromo-1,2-dihydroquin-
oline derivatives in good yields. The results are summarized in
Table 2.
The structure of the compounds (2b–2l) was confirmed through
1H NMR, 13C NMR and mass spectroscopic techniques. X-ray dif-
fraction studies were also performed to confirm the structure.21
The ORTEP diagram of compound 2f is given in Figure 1.
A plausible mechanism for the formation of 3-bromo-1,2-dihy-
droquinoline derivatives from the corresponding N-tosyl-N-prop-
argyl aniline is given in Scheme 3.
The mechanism may involve co-ordination of palladium to the
alkyne (step 1) which may lead to an intramolecular cyclization
(step 2) to form the organointermediate (i). This intermediate
may be converted to the palladium(IV) species (ii), which may
decompose through reductive elimination to give the product 2.22
An alternate mechanism can also be explained for the formation
of the product 2 from the intermediate (i) via intermediate (iii) in
which copper(II) assists in ligand transfer while retaining palla-
dium in its +2 oxidation state.23
It was found that, further increasing the amount of LiBr beyond
1 equiv resulted in the formation of a dibrominated product 2a0 in
addition to the expected cyclized product 2a (Scheme 1, Condition
c). It is to be noted that when the amount of the LiBr was increased
to 1.2 and 1.5 equiv the ratio of the product 2a0 to that of product
2a increased and when the amount of LiBr was further increased to
2 equiv only the dibrominated product 2a0 was obtained as the
product of the reaction.
The structure of the product 2a was confirmed through spectro-
scopic studies. In the 1H NMR spectrum of compound 2a, the pres-
ence of only eight protons in the aromatic region confirmed the
cyclization of 1a to the corresponding 3-bromo-4-methyl-1,2-
dihydroquinoline 2a. Further the absence of the alkynyl carbon
signals in the 13C NMR spectrum confirmed the formation of the
product 2a. Finally mass spectral studies also supported the forma-
tion of 2a.19

S. Gurunathan, P. T. Perumal / Tetrahedron Letters 52 (2011) 1783–1787
1785
Table 2
Synthesis of 3-bromo-1,2-dihydroquinoline derivatives
Entry
Aryl propargyl aniline (1)
3-Bromo-1,2-dihydroquinoline (2)
Time in mins
Yieldm (%)
CH3
CH3
Br
a
50
80
81
79
83
78
85
82
75
72
N
N
Ts
Ts
C2H5
C2H5
Br
b
c
d
e
f
50
45
30
35
40
45
40
80
75
N
N
Ts
Ts
C3H7
C3H7
Br
N
N
Ts
Ts
CH3
CH3
MeO
MeO
Me
Me
Me
Cl
Br
Br
MeO
MeO
Me
Me
Me
Cl
N
N
Ts
Ts
C2H5
C2H5
N
N
Ts
Ts
CH3
CH3
Br
N
N
Ts
Ts
C2H5
C2H5
Br
Br
g
h
i
N
N
Ts
Ts
C2H5
C2H5
N
N
Me
Ts
Me
Ts
C2H5
C2H5
Br
N
N
Ts
Ts
C3H7
C3H7
Cl
Br
Cl
j
70
N
N
Ts
Ts
(continued on next page)

1786
S. Gurunathan, P. T. Perumal / Tetrahedron Letters 52 (2011) 1783–1787
Table 2 (continued)
Entry
Aryl propargyl aniline (1)
CH3
3-Bromo-1,2-dihydroquinoline (2)
Time in mins
Yieldm (%)
CH3
Br
Cl
Cl
k
70
69
N
N
Ts
Ts
CH3
CH3
Me
Br
Me
l
65
73
N
N
Me
Ts
Me
Ts
m
Isolated yield after column chromatography.
L
Pd
X
L
IV
R
L
L
R
R
R
2 CuX2
2 CuX
L
Step 2
PdII
X
X
L
PdII
X
Cat. PdII
N
L
(ii)
CuX2
N
N
(i)
N
Ts
-PdII
Ts
Step 1
Ts
Ts
1
reductive
elimination
X = Br
L = Br, OAc
L
R
R
N
PdII
X
Br
-PdII
L
CuII
N
(iii)
Ts
Ts
assisted reductive elimination
CuII
2
Scheme 3.
CH3
CH3
MeO
Br
MeO
Br
10 equiv. NaOH
EtOH, 50 oC
1.5 h
N
N
Ts
96%
2d
3
Scheme 4.
Acknowledgment
One of the authors G.S. expresses her gratitude to the Council of
Scientific and Industrial Research, New Delhi, for a research
fellowship.
Figure 1. ORTEP diagram of compound 2f.
References and notes
The 3-bromo-1,2-dihydroquinolines synthesized can be easily
converted to the corresponding 3-bromoquinolines by treating
with NaOH in EtOH at 50 °C as shown in Scheme 4.24
In conclusion we have described a new approach for the facile
synthesis of 3-bromo-1,2-dihydroquinolines in good yields from
the easily accessible starting materials under mild reaction
conditions.
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7.07–7.12 (m, 2H), 7.23–7.28 (m, 4H), 7.32–7.35 (m, 1H), 7.68 (d, 1H,
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24. 3-Bromo-6-methoxy-4-methylquinoline (3): White crystalline solid. mp: 82–
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2.73 (s, 3H), 3.94 (s, 3H), 7.17 (d, 1H, J = 2.3 Hz), 7.34 (dd, 1H, J1 = 9.2 Hz,
J2 = 3.1 Hz), 7.95 (d, 1H, J = 9.2 Hz), 8.74 (s, 1H). 13C NMR: (125 MHz, CDCl3) d
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