Regioselective synthesis of annulated quinoline and pyridine derivatives by silver-catalyzed 6-endo-dig cycloisomerization

Article abstract of DOI:10.1055/s-0030-1259097

3H-pyrano[3,2-f]quinoline-3-one, 4-methyl-4,7-phen-anthrolin-3(4H)-one, and 1,3-dimethylpyrido[3,2-d]pyrimidine-2,4(1H,3H)-dione derivatives have been synthesized by hitherto unreported silver-catalyzed 6-endo-dig mode of cycloisomerization from various N-propargylated heterocyclic compounds. The silver-catalyzed reaction provides the synthesis of potential bioactive compounds in excellent yields. Georg Thieme Verlag Stuttgart - New York.

Full text of DOI:10.1055/s-0030-1259097

1
16
LETTER
Regioselective Synthesis of Annulated Quinoline and Pyridine Derivatives by
Silver-Catalyzed 6-endo-dig Cycloisomerization
S
K
ynthesis of
A
nnu
.
lated Quinoli
C
ne and Pyridine
.
D
erivative
s
Majumdar,* Raj Kumar Nandi, Sintu Ganai, Abu Taher
Department of Chemistry, University of Kalyani, Kalyani 741235, West Bengal, India
E-mail: kcm_ku@yahoo.co.in
Received 29 September 2010
lyzed reaction.13 Nevertheless, these are improvements
over traditional methods. However, these methods also
Abstract: 3H-pyrano[3,2-f]quinoline-3-one, 4-methyl-4,7-phen-
anthrolin-3(4H)-one, and 1,3-dimethylpyrido[3,2-d]pyrimidine-
have some limitations. Some methods are not environ-
2
,4(1H,3H)-dione derivatives have been synthesized by hitherto un-
reported silver-catalyzed 6-endo-dig mode of cycloisomerization mentally benign in terms of toxicity,1
1,12
some are time
13
from various N-propargylated heterocyclic compounds. The silver- consuming processes or having different byproducts. A
catalyzed reaction provides the synthesis of potential bioactive
compounds in excellent yields.
thorough search of literature reveals that there are a few
examples of activated gold- and copper-catalyzed cycloi-
Key words: 3H-pyrano[3,2-f]quinoline-3-one, 4-methyl-4,7-phen- somerization reactions to afford substituted pyridine and
quinoline derivatives.14 To our knowledge, there is no
such report for the synthesis of bioactive pyridocoumarin
or pyridoquinolone or pyridopyrimidine solely by silver-
catalyzed reaction. This prompted us to undertake a study
anthrolin-3(4H)-one,
1,3-dimethylpyrido[3,2-d]pyrimidine-
2
,4(1H,3H)-dione, AgSbF , cycloisomerization, 6-endo-dig
6
There is flurry of activities on the synthesis of quinoline to develop a methodology for the synthesis of these het-
and its annulated derivatives due to their broad spectrum erocycles. We report here the results of our investigation.
of biological profiles, which includes antialergic, antidia-
The required precursors 3a–f were prepared in high yields
betic, antimicrobial, analgesic, insecticidal, antifungal,
by the reaction of 1a–c with propargyl bromides 2a,b in
antipyretic, tyrosine kinase inhibition, and also cytotoxic
the presence of anhydrous potassium carbonate in reflux-
1
properties. Due to these bioactivities quinoline deriva-
ing acetone for five hours and the precursors 3g,h were
tives are widely used in pharmaceutical and agrochemical
prepared by the reaction of 5-amino-1,3-dimethyl uracil
sectors, besides these derivatives are also used as func-
tional materials. The quinoline derivatives have gained
considerable attention due to their central role as building
blocks in the synthesis of natural products. On the other
hand natural products possessing coumarin, quinolone,
and uracil subunits show wide range of bioactivity. There
are many alkaloids which contain pyrido-coumarin, pyri-
do-quinolone skeleton, due to the presence of these cores
the alkaloids are also bioactive. Some examples of natu-
1
d and 2a,b in dry acetonitrile at room temperature for
2
seven hours (Scheme 1).
3
H
NH2
+
Br
N
(i)
4
O
X
O
X
R
R
5
1a–c
2a,b
3a X = O, R = H
b X = O, R= Me
3c X = NMe, R = H
3
ral products are dutadrupine, helietidine, geibalansine,
and amphimedine. Moreover bioactivity of pyrido-pyri-
midines are well known, besides their antibacterial and
3
d X = NMe, R = Me
6
3e X = NEt, R = H
3f X = NEt, R = Me
7
antiallergic properties they also inhibit enzyme adenosine
kinase (AK) and dihydrofolate reductase (DHFR). Re-
O
O
N
8
Br
H
N
Me
O
NH2
Me
O
N
(ii)
N
cently, it has been found that substituted pyridines effi-
ciently inhibit HMG-CoA reductase and cholesterol
+
N
R
9
transport proteins.
Me
Me
R
1
0
Traditional approaches have frequently been employed
for the synthesis of quinoline ring system in the total syn-
1d
2a,b
3g R = H
3
h R = Me
thesis of quinoline based alkaloids. However, all these re- Scheme 1 Reagents and conditions: (i) anhyd K CO , dry acetone,
2
3
actions usually require harsh conditions, tedious reaction reflux for 5 h; (ii) anhyd K CO (1 equiv), dry MeCN, r.t., stirred for
2 3
7
h.
procedure, or give poor yield. Over the last two decades,
there has been growing interest for the development of
syntheses of quinoline derivatives, which include radical The substrate 3a, when subjected to cycloisomerization in
1
1
12
15
reaction, iodine-mediated cyclization, and metal-cata- the presence of AgSbF (0.1 equiv) in DMSO at 110 °C
6
1
6
for 45 minutes, gave the product 4a in 98% yield. The
optimized conditions for this cycloisomerization were
established through a series of experiments, in which
sequential changes were made in catalyst, amount of cat-
SYNLETT 2011, No. 1, pp 0116–0120
Advanced online publication: 10.12.2010
DOI: 10.1055/s-0030-1259097; Art ID: G28010ST
Georg Thieme Verlag Stuttgart · New York
x
x.
x
x.
2
0
1
0
©

LETTER
Synthesis of Annulated Quinoline and Pyridine Derivatives
117
alyst, and also solvent used for the reaction of the sub- Table 1 Optimization of Cycloisomerization of Compound 3a
strate 3a (Table 1).
H
To optimize the reaction conditions we have used various
N
N
metal catalysts. Among the catalysts used, the AuCl in
3
DMSO (entry 4) gave very poor yield of the product.
However, when the reaction was carried out with equal
mol% of AuCl and AgSbF (10 mol% of each catalyst)
O
O
O
O
3
a
4a
3
6
Entry
Catalysta
Solvent Temp
(°C)
Time Yield
gave excellent yield (96%) both in DMSO and acetic acid
b
1
4a,b,d
(h)
0.75
5
(%)
98
60
75
5
as a solvent (entries 5 and 6). There are reports
where
this high yield has been explained by the activation of
gold catalyst in the presence of the silver salt, but when-
ever the reaction was carried out solely in the presence of
1
2
3
4
5
6
7
8
9
AgSbF6
AgSbF6
AgSbF6
AuCl3
DMSO 110
DMSO r.t.
AgSbF in DMSO, we observed a reasonably good yield
6
DMSO 80
1
1
7
(
entry 1) compared to the mixed catalyst.
DMSO 110
DMSO 110
AcOH 100
AcOH 100
AcOH 100
MeCN reflux
MeOH reflux
toluene 110
CH Cl reflux
4
Among different solvents used DMSO and acetic acid
both gave better results but we have chosen DMSO as an
optimized solvent as it is milder than acetic acid. We have
also carried out this reaction with another coinage metal-
based (copper) catalyst (entries 13–15). In the case of
Cu(I) we obtained very poor yield, but Cu(II) gave a com-
paratively good result. A series of Lewis acid catalysts
were investigated (entries 17–20) but none of them pro-
vided a good result. It is also noticeable that another silver
c
c
AuCl ·AgSbF
1
96
96
96
–
3
6
AuCl ·AgSbF
1
3
6
AgSbF6
AuCl3
1
5
AgSbF6
AgSbF6
AgSbF6
4
98
72
68
45
15
82
68
64
21
18
7
10
11
12
13
14
15
4
species AgNO (entry 16) gave a better result under the
3
1
8
same conditions. Toste reported that over 80 °C coinage
metal catalyst are not that stable and produce related
Brønsted acid. We have carried out the reaction at room
temperature for five hours to give 60% yield of the prod-
uct (entry 2). The same reaction has also been conducted
at 80 °C for one hour to give 75% yield (entry 3). More-
over, the reaction in DMSO at 110 °C for four hours with
catalytic amount of HCl, H SO , and TfOH (entries 21–
7
AgSbF6
2
2
6
CuI
DMSO 110
DMSO 110
DMSO 110
DMSO 110
DMSO 110
DMSO 110
DMSO 110
DMSO 110
DMSO 110
DMSO 110
DMSO 110
6
Cu(OAc)2
3.5
4
CuSO ·5H O
4
2
2
4
2
3) failed to give any product, only the starting material 16
AgNO
ZnCl2
3
5
was recovered. Variation of the catalyst and solvent
1
7
12
14
12
12
4
showed that in DMSO solvent 10 mol% AgSbF at 110 °C
6
provides best result. The optimized reaction conditions 18
were used to examine the cycloisomerization of the other
N-propargyl amines (3b–h). The results are summarized
in Table 2.
NiCl ·2H O
2
2
1
9
FeCl3
20
21
AlCl3
HCl
15
–
Treatment of 3b with 10 mol% AgSbF in DMSO at
6
1
10 °C for 45 minutes afforded the product 4b in 97%
2
2
3
H SO
4
–
yield. Similarly, compound 3c furnished product 4c in
2
4
9
3
9
8% yield. When the same reactions were carried out with
d and 3e products 4d and 4e were obtained in 96% and
3% yields, respectively, after 45 minutes. Similarly, the
2
TfOH
4
–
1
9
a
Reactions (enries 1–20) were carried out with 3a (1 equiv) and cat-
alyst (0.1 equiv). Reactions (entries 21–23) were carried out in the
product 4f was obtained in 96% yield when the reaction
was carried out with 3f for 45 minutes. Under the similar
reaction conditions substrates 3g and 3h afforded prod-
ucts 4g and 4h in 89% and 94% yields, respectively, after
one hour. The products were characterized from their
spectroscopic data.
presence of a catalytic amount of the Brønsted acid.
b
Isolated yield,
Conditions: 0.1 equiv each of both catalyst were used.
c
of anhydrous potassium carbonate and dry acetonitrile at
room temperature for seven hours. When the substrate 6a
was subjected to cycloisomerization in the presence of 10
Using the optimized conditions, we next explored the
scope and generality of the silver-catalyzed cycloisomer-
ization reaction by carrying out this reaction with N-pro-
pargylated aniline (Scheme 2).
mol% AgSbF in DMSO at 110 °C for one hour the prod-
6
uct 7a2 was obtained in 84% yield. Similarly, substrate
0a
b afforded the product 7b2 in 88% yield.
0b
6
The precursors 6a,b were prepared by the reaction of
aniline (5) with propargyl bromides 2a,b in the presence
Synlett 2011, No. 1, 116–120 © Thieme Stuttgart · New York

1
18
K. C. Majumdar et al.
Table 2 Cycloisomerization of 3a–h
Entry Starting material 3 Products 4
LETTER
R
Br
(
i)
Time Yield
min) (%)a
+
(
NH2
R
N
R
H
H
5
2a,b
6a R = H
N
6
b R = Me
N
N
N
1
2
45
45
98
97
R
O
O
O
O
O
O
(
ii)
3a
a16
4
H
N
N
H
N
6
a,b
7a R = H20a
7b R = Me2
0b
O
Scheme 2 Reagents and conditions: (i) K CO , dry MeCN, r.t. (ii)
O
2
3
AgSbF (10 mol%), DMSO, 110 °C.
6
4
b
3b
H
N
sence of any co-catalyst like CuCl or AuCl and the
reaction time is also shorter. There are also reports of met-
al-catalyzed synthesis of quinoline and pyridine deriva-
3
4
5
6
45
45
45
45
98
96
93
96
O
N
14
Me
O
N
tives where costly gold catalyst is used as catalyst. It is
Me
16
3c
pertinent to mention that Hon et al. have recently report-
ed the synthesis of 3H-pyrano[3,2-f]quinoline-3-one (4a)
in low yield through a multistep process.
4
c
H
N
N
N
N
From the results shown in Table 2 and Scheme 2 it is ob-
served that the reaction shows high regioselectivity, only
six-membered quinoline derivatives are obtained
O
N
Me
O
N
Me
3d
4d19
(
Scheme 3). Therefore, the reaction proceeds via 6-endo-
H
N
dig mode of cyclization (i.e., path a) and not via 5-exo-dig
cyclization (i.e., path b). On the basis of the above results,
the formation of the products can be rationalized (path a).
Initially a p-complex A may be formed between the
alkyne moiety and silver cation. The lone pair of the nitro-
gen atom assists the conjugated double bond to attack
regioselectively at the complex segment via 6-endo-dig
mode of cyclization leading to the intermediate B. The cy-
O
N
Et
O
N
Et
3e
4
e
H
N
+
O
N
clized intermediate B then may lose H and silver ion to
Et
O
N
give the intermediate C, which on aromatization may af-
ford the pyridine (quinoline) skeleton D. We have also
carried out the reaction by protecting the NH of the sub-
strate 3a with tosyl/methyl group, but in these cases the
reactions did not occur. Regioselective formation of the
angular pyridocoumarins and pyridoquinolones 4a–f in-
stead of the linear pyridocoumarins and pyridoquinolones
may be rationalized by the greater reactivity of the 5-po-
sition than that of the 7-position of the respective hetero-
cyclic system.
Et
3f
4f
O
O
H
N
Me
O
Me
N
N
N
7
60
60
89
94
N
O
N
Me
Me
g13c
4g13c
3
O
O
H
N
Me
O
Me
N
N
N
Here we have developed a new straightforward methodol-
ogy for the regioselective synthesis of bioactive mole-
cules exclusively by 6-endo-dig cyclization followed by
aromatization with the use of a silver catalyst. Silver cat-
alyst is usually applied to activate the gold catalyst for this
type of cycloisomerization,1 To our knowledge the ef-
8
N
O
N
Me
Me
4
h
3h
a
Isolated yields.
4a,b
ficacy of the AgSbF individually as a catalyst for this
type of cycloisomerization has not been examined.
Recently, Kuninobu et al.14b have reported the synthesis of
quinoline derivatives from various N-propynyl anilines
by the treatment of catalytic amount of silver triflate and
copper(I) chloride or gold (I) chloride in dichloroethane at
6
14a,b,d
Moreover, the silver-catalyzed reaction has received less
17,21
attention.
In conclusion, we have developed a novel and efficient
method for the regioselective synthesis of 3H-pyrano[3,2-
8
0 °C for 24 hours. In this respect, our reaction is interest-
ing as we have achieved quinoline derivatives in the ab-
Synlett 2011, No. 1, 116–120 © Thieme Stuttgart · New York

LETTER
Synthesis of Annulated Quinoline and Pyridine Derivatives
119
H
H
N
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2
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1
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lated heterocyclic substrates by solely silver-catalyzed 6-
endo-dig mode of cycloisomerization followed by aroma-
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Acknowledgment
(
b) Stoltefuss, J.; Lögers, M.; Schmidt, G.; Brandes, A.;
We thank the CSIR (New Delhi) and DST (New Delhi) for financial
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CSIR (New Delhi) for their Research Fellowships. We also thank
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Synlett 2011, No. 1, 116–120 © Thieme Stuttgart · New York

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K. C. Majumdar et al.
LETTER
(
(
(
(
(
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–
1 1
2009, 5618.
mp 172 °C. IR (KBr): 1646, 1561 cm . H NMR (400 MHz,
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3
3
3
1 H, J = 10.0 Hz, C H of quinolone), 7.34 (d, 1 H, J = 4.4
3
Hz, ArH), 7.77 (d, 1 H, J = 9.6 Hz, ArH), 8.22 (d, 1 H,
108, 3351.
J = 9.2 Hz, ArH), 8.72 (d, 2 H, J = 10.0 Hz, C H of
4
1
3
19) Synthesis of 4,10-Dimethyl-4,7-phenanthrolin-3 (4H)-
quinolone and ArH). C NMR (100 MHz, CDCl ): d = 26.4,
30.6, 115.6, 117.9, 119.7, 125.8, 126.5, 134.2, 136.9, 140.4,
3
one (4d)
To a stirred solution of AgSbF (7.6 mg, 0.022 mmol) in
143.3, 145.4, 148.6, 161.5. HRMS: m/z calcd for C H N O
6
14 12
2
DMSO (5 mL), 6-(but-2-ynylamino)-1-methylquinolin-2
[M + H]: 225.1016; found: 225.1022.
(
1H)-one (3d, 50 mg, 0.22 mmol) was added at r.t. and
(20) (a) Balk, W.; Kim, D. I.; Lee, H. J.; Chung, W.-J.; Kim,
stirred at 110 °C for 45 min to complete the reaction (as
monitored by TLC). The light green colored reaction
mixture was cooled and neutralized with sat. NaHCO3
solution. This was extracted with CH Cl (3 × 15 mL). The
B. H.; Lee, S. W. Tetrahedron Lett. 1997, 38, 4579.
(b) Ranu, B. C.; Hajra, A.; Dey, S. S.; Jana, U. Tetrahedron
2003, 59, 813.
(21) Gelin, E.; Toullec, P. Y.; Antoniotti, S.; Brancour, C.; Genet,
J.-P.; Michelet, V. J. Am. Chem. Soc. 2006, 128, 3122.
2
2
combined organic extract was washed with brine and dried
over (Na SO ). The solvent was distilled off. The resulting
2
4
Synlett 2011, No. 1, 116–120 © Thieme Stuttgart · New York

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