Organocatalytic Modified Guareschi-Thorpe Type Regioselective Synthesis: A Unified Direct Access to 5,6,7,8-Tetrahydroquinolines and Other Alicyclic[ b]-Fused Pyridines

Article abstract of DOI:10.1021/acs.orglett.8b02132

An unprecedented organocatalytic, regioselective, modified Guareschi-Thorpe type protocol toward the modular synthesis of 5,6,7,8-tetrahydroquinolines 22a-g and other alicyclic[b]-fused pyridines 23-28 via the identification of Chitosan as a heterogeneous

Full text of DOI:10.1021/acs.orglett.8b02132

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Organocatalytic Modified Guareschi−Thorpe Type Regioselective
Synthesis: A Unified Direct Access to 5,6,7,8-Tetrahydroquinolines
and Other Alicyclic[b]‑Fused Pyridines
Pradeep K. Jaiswal,† Vashundhra Sharma,† Manas Mathur,‡ and Sandeep Chaudhary*,†
†Laboratory of Organic and Medicinal Chemistry, Department of Chemistry, Malaviya National Institute of Technology, Jawaharlal
Nehru Marg, Jaipur-302017, India
‡Department of Botany, University of Rajasthan, Jawaharlal Nehru Marg, Jaipur-302004, India
S
* Supporting Information
ABSTRACT: An unprecedented organocatalytic, regioselective, modified Guareschi−Thorpe type protocol toward the
modular synthesis of 5,6,7,8-tetrahydroquinolines 22a−g and other alicyclic[b]-fused pyridines 23−28 via the identification of
Chitosan as a heterogeneous catalyst is reported. This novel strategy is operationally simple and showed a wide range of
functional group tolerance and substrate compatibility. The proposed mechanistic pathway involves an imine-enamine cascade
approach for the synthesis of structurally diverse alicyclic[b]-fused pyridine heterocycles. The gram scale synthesis and
identification of a new class of antifungal molecules 29−31 emphasize the practicality of this method.
pyridine ring. While the latter route involves routine chemistry,
the former route is quite challenging, as the construction of
highly substituted pyridine is required to be built on the
alicyclic ring. Almost a century ago, the Guareschi−Thorpe
method was the landmark reaction for pyridine synthesis,
which involves the condensation of the cyanoacetic ester with
an acetoacetic ester in the presence of ammonia [Scheme 1A].5
Since then, several methodologies have been reported in the
literature to construct the alicyclic[b]-fused pyridines using
cyclic ketones or its analogues.6 Earlier, the synthesis of
alicyclic[b]-fused pyridine was carried out via Pd-catalyzed
oxidation of hydroxyenaminones followed by subsequent
cyclization/aromatization [Scheme 1B(i)].7a Functionalized
5,6,7,8-tetrahydroquinoline i.e, a cyclohexane[b]-fused pyr-
idine, was obtained in a lower yield when 2-methylcyclo-
hexanone oxime was treated with diphenylacetylene in the
presence of an iridium catalyst [Scheme 1B(ii)].7b The desired
skeleton could also be constructed when cyclic/acyclic 1,3-
dicarbonyl compounds react with activated α, β-unsaturated
ketone in the presence of NH4OAc using K5CoW12O40·3H2O
as the catalyst [Scheme 1B(iii)].7c A metal-free, MW-assisted
four-component strategy using arylaldehydes, cyclohexanone,
rganocatalysis has received tremendous attention from
Osynthetic chemists to catalyze transition-metal-free
reactions to construct various natural products, pharmaceut-
icals, and organic materials during the past two decades
because of its several advantages such as selectivity, safety, ease
of handling, and economic perspectives.1 Pyridine-nucleus-
including substituted alicyclic[b]-fused pyridines, as a part or
as a whole, constitute the core of a large family of natural
products, bioactive pharmaceuticals, vitamins, alkaloids, chiral
ligands, and functional materials2,3 and are endowed with a
wide range of biological activities4 as shown by a few
pharmaceutically privileged molecules 1a−e (Figure 1).
Few methodologies for the synthesis of functionalized
alicyclic[b]-fused pyridines have been reported via the
construction of the pyridine ring either on alicyclic ring
systems or via the construction of the alicyclic ring on the
Figure 1. Few selected examples of pharmaceutically privileged
molecules 1a−e having functionalized alicyclic[b]-fused pyridines.
Received: August 1, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b02132
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Scheme 1. Some Previous and Present Reports for the
Table 1. Optimization Study: Identification of Catalyst
Synthesis of Alicyclic[b]-fused Pyridines
yield of yield of
c
c
mol temp time
22a
19aa
s. no. solvent
catalyst
(%)
(°C)
(h)
(%)
(%)
b
1
2
3
4
5
6
7
8
9
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
−
DBU
−
80
80
80
80
80
80
80
80
80
80
4
4
4
4
4
4
4
4
4
4
trace
46
37
32
34
28
41
21
48
65
92
48
52
53
57
60
54
68
44
32
30
30
30
30
30
30
30
30
DABCO
Et2NH
L-proline
piperidine
DMAP
Et3N
pyrolidine
chitosan
d
10
30
a
Reaction conditions: 19a (0.20 mmol), 20 (0.30 mmol), 21b (0.30
mmol), and catalysts (mol %) were dissolved in EtOH and heated at
b
80 °C temperature under a N2 atmosphere for 4 h. Not isolated.
c
d
Isolated yield. Performed with chitosan catalyst 60 mg (30 wt %,
w.r.t. substrate 19a).
As NH3 was used as a nitrogen source as well as a base in
Guareschi−Thorpe pyridine synthesis, we also planned to
perform our reaction using NH4OAc, which will provide a
basic medium and also act as a nitrogen source. Unfortunately,
it did not furnish the desired product 22a (entry 1). Product
19a exists in equilibrium with either 19aa or 19ab under the
reaction medium. While 19aa, the unreacted form of 19a, was
isolated in our reaction conditions, 19ab was not detected at
all. It prompted us to investigate this reaction using other
various primary, sec- and tert-amines (Table 1; entries 2−9). A
number of bases such as DBU, DABCO, Et2NH, L-proline,
Piperidine, DMAP, Et3N, pyrrolidine, etc. were used in
catalytic amounts (30 mol %) under reflux conditions in
EtOH which furnished 22a in 21−52% yields (Table 1, entries
2−9). Its other regioisomer, 22b, was not detected at all.
However, 19aa, the unreacted form of 19a, was isolated in 44−
68% yields. The structures of 22a and 19aa were fully
ammonium acetate, and N-phenacylpyridinium bromide as an
activated ketone has also been utilized to construct alicyclic[b]-
fused pyridines [Scheme 1B(iv)].7d However, all the previously
reported protocols suffer from serious drawbacks, such as the
use of expensive and toxic transition metal catalysts, harsh
reaction conditions, multistep synthesis, activated carbonyl
substrates, lower yields, and a limited substrate scope. Hence,
the development of a more general, operationally simple, and
environmentally benign method for the synthesis of alicyclic-
[b]-fused pyridine motifs is highly desirable.
Herein, we report the identification of a commercially
available chitosan as heterogeneous organocatalyst, which
catalyzes an unprecedented, regioselective, three-component
condensation reaction of an unactivated ketone, a diketo-ester
and NH4OAc in 1,4-dioxane as solvent at 80 °C which
furnished alicyclic[b]-fused pyridines 22−31, with a broad
range of functional group tolerance and substrate compatibility
[Scheme 1B(v)]. To the best of our knowledge, this is the first
report of an organocatalyzed modified Guareschi−Thorpe type
regioselective synthesis of 5,6,7,8-tetrahydroquinolines and
other novel alicyclic[b]-fused pyridines.
1
characterized by ESI-MS, H NMR, 13C NMR, FT-IR, and
HRMS data. Furthermore, biopolymer chitosan has been well
reported in literature which has been utilized as a
heterogeneous catalyst in organic synthesis.8 Therefore, we
also carried out our model reaction using chitosan as a
heterogeneous organocatalyst. Surprisingly, 22a was obtained
in 65% yield (Table 1, entry 10).
We further optimized the reaction efficacy by using chitosan
in different solvents (Table 2, entries 1−8); consequently, 1,4-
dioxane was found to be the best solvent which afforded 22a in
70% yield (Table 2, entry 6). In contrast, the reaction did not
furnish 22a in H2O (Table 2, entry 8).
To develop a modified Guareschi−Thorpe type condensa-
tion for the synthesis of alicyclic[b]-fused pyridines, we started
our initial investigation on the model reaction using methyl
2,4-dioxo-4-phenylbutanoate 19a, NH4OAc 20, and cyclo-
hexanone 21b as an unactivated ketone dissolved in EtOH, for
the synthesis of methyl 2-phenyl-5,6,7,8-tetrahydroquinoline-4-
carboxylate 22a via screening of various catalysts (Table 1).
Then, the effect of catalyst loading was studied on the model
reaction (Table 2, entries 9−12). It was found that an increase
in chitosan loading (80 mg) decreases the yield of 22a (Table
2, entry 9). Contrary to this, a decrease in chitosan loading (40
B
DOI: 10.1021/acs.orglett.8b02132
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a b
,
Table 2. Optimization Study: Screening of Reaction
Parameters for the Synthesis of 22a
Scheme 2. Substrate Scope
a
b
s. no.
solvent
EtOH
CHCl3
MeOH
DMF
DMSO
1,4-dioxane
toluene
amount (mg) temp (°C) time (h) yield (%)
1
2
3
4
5
6
7
8
60
60
60
60
60
60
60
60
80
40
30
20
30
30
30
30
80
80
80
80
80
80
80
80
80
80
80
80
80
80
100
80
4
4
4
4
4
4
4
4
4
4
4
8
8
10
12
24
65
28
63
52
47
70
20
00
56
68
77
61
80
87
81
79
H2O
9
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
10
11
12
13
14
15
16
a
Reaction conditions: 19a (0.20 mmol), 20 (0.30 mmol), 21b (0.30
mmol), and chitosan (as given amounts in table) were dissolved in
solvents (as given in table) and heated at the given temperature under
b
a N2 atmosphere at given time. Isolated yields after two steps. In the
second step, the recovered intermediate 19aa was again subjected to
the same reaction conditions along with 20 and 21b.
mg) increases the product yield to 68% (Table 2, entry 10).
On further decreasing the chitosan loading to 30 mg, it was
observed that a 30% catalyst loading was found to be the
optimum condition for obtaining the product in 77% yield
(Table 2, entry 11). A further decrease in chitosan loading
does not have beneficial effects (Table 2, entry 12). Then, we
studied the optimization of temperature and time (Table 2;
entries 13−16); it was found that an 80 °C temperature and a
10 h time are optimal. Thus, overall, a catalyst loading of 30
mg of chitosan in a 1,4-dioxane solvent at 80 °C for 10 h was
found to be the best reaction conditions for the synthesis of
22a (Table 2, entry 14). The chitosan can be reused up to the
fourth cycle with a minor decrease in yield indicating its
catalytic efficiency (see Table 1 in the Supporting Information
(SI)).
To explore the substrate scope and generality of the present
method, various substituted aromatic/heteroaromatic/aliphatic
diketo-esters 19a−n, different cyclic (4/5/6/7/8-membered)/
acyclic/aromatic carbonyl compounds 21a−f, and 20 were
subjected to the optimized reaction conditions which furnished
the alicyclic[b]-fused pyridines 22−31 in up to 89% yields
(Scheme 2). The present method proceeds smoothly for the
synthesis of a variety of functionalized alicyclic[b]-fused
pyridines. Initial observation showed that the different
diketo-esters 19a−j react with various cyclic ketones 21a−d
in the presence of NH4OAc 20 under the optimized conditions
to afford 22−28 in excellent yields. The seven- and eight-
membered cyclic ketones, i.e. 21c−d, furnished the corre-
sponding alicyclic[b]-fused pyridine 24−25 in 71−76% yields.
Similarly, reaction of heteroaromatic/alicyclic diketoesters
19k−m with cyclic ketones 21a−c along with 20 under
a
Reaction conditions: (a) 19a−n (0.20 mmol), 20 (0.30 mmol),
21a−e or 21fa−fb (0.30 mmol), chitosan (30 mg, 15 wt % w.r.t.
b
19a−n, respectively), 1,4-dioxane, 80 °C, N2 atmosphere. Isolated
yields. Not isolated. Inseparable complex mixture. For preparation
of 36, see section 1.2.5 in the SI.
c
d
e
optimized conditions furnished 29−31 in 41−72% yields. The
generality of the reaction was also attempted using highly
constrained cyclobutanone 21e along with 19a and 20;
unfortunately, 32 was formed in traces (<5%) but could not
be isolated. It infers that the reaction proceeds smoothly with
aromatic and alicyclic diketo esters 19a−j and 19m, with
nonconstrained cyclic ketones 21a−d. However, it proceeded
slightly in low yields with heteroaromatic diketoesters 19k−m.
In contrast, the reaction did not furnished 33 with aliphatic
diketoester 19n. Also, 34 was not isolated when 21fa, 19g, and
20 were treated under the optimized reaction conditions, but
1
the crude H NMR spectra showed an inseparable complex
mixture. Moreover, the reaction of 19g with 21fb and 20 did
not furnish 35 due to the lower reactivity of 21fb in
comparison with cyclic ketones 21a−d. Overall, the reaction
proceeds smoothly with nonconstrained cyclic ketones as
compared to constrained/acyclic ones. Aromatic diketoesters
19a−j were found to be the most suitable substrate to generate
a variety of 2-aryl substituted alicyclic [b]-fused pyridines
(Scheme 2).
To illustrate the type of mechanism involved, control
experiments were carried out under optimized reaction
conditions in the presence of free-radical scavengers such as
C
DOI: 10.1021/acs.orglett.8b02132
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Organic Letters
Letter
Figure 2. Plausible mechanism.
Tempo and BHT, which furnished 22a in up to 84% and 79%
yields, respectively. This indicates the involvement of an ionic
mechanism rather than a free-radical mechanism (see SI;
section 1.2.4).
Moreover, isonicotinic acid (regioisomer of vitamin B3) and
its analogues are present in a large number of natural products
and drug candidates;4a,9 the alicyclic[b]-fused isonicotinic acid
derivative 36 was synthesized by the hydrolysis of compound
22a using LiOH·H2O (see SI; section 1.2.5). The versatility of
the method was demonstrated by performing a gram scale
synthesis of 22a, which was obtained in 79% yield (see SI;
section 4).
pyridines 23−31. With the operational simplicity, functional
group compatibility, low catalyst loading, and reusability of the
catalyst, the present methodology has substantially expanded
the scope of fused pyridine derivatives accessible from readily
available cyclic ketones and diketoesters as starting substrates.
Also, the gram-scale synthesis and identification of new
antifungal molecules (29−31) emphasize the practicality of
this methodology. These findings disclosed a new synthetic
route for the green synthesis of structurally diverse alicyclic[b]-
fused pyridine heterocycles.
ASSOCIATED CONTENT
■
S
* Supporting Information
A plausible mechanism for the synthesis of 22a involves
imine-enamine cascade reactions (Figure 2). It is to be noted
that 19a exists in equilibrium with either more stable 19aa
(isolated) or less stable 19ab (not detected) under an acidic
medium of acetic acid generated from ammonium acetate. The
reaction starts with the activation of compound 19aa and 19ab
with chitosan via either path A or path B to generate iminium
ion intermediate I or IA, respectively. Then, the leftover
carbonyl group will be immediately attacked by enamine 21ba
(which is formed in situ from 21b and NH4OAc 20) and forms
more favorable intermediates II (less steric hindrance)
preferentially over less favored IIA (due to steric hindrance
between the cyclohexyl and phenyl moiety). Then, the
sequence of reactions, i.e., removal of water, deprotonation
of amines, abstraction of enolizable proton, and cyclization,
furnished the desired product 22a with the release of the
catalyst (path A). On the other hand, 22b was not isolated in
our reaction. It is anticipated that steric hindrance between the
cyclohexyl group and phenyl group destabilizes the formation
of transition state IIA (path B). Therefore, this reaction occurs
in a regioselective manner exclusively via path A (Figure 2).
Compounds 29−31 were assessed for their antifungal
activity in vitro against Aspergillus niger and Candida albicans
fungal strains.10 The indole-based analogue 29 showed
promising antifungal activity (MIC = 6.25 μg/mL) in vitro
against the Aspergillus niger strain compared to Ketoconazole
(MIC = 12.5 μg/mL; for details, see SI).
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.8b02132.
Experimental details and characterization data, 1H NMR
and 13C NMR spectra of all compounds 19aa, 22−31,
and 36 (PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: schaudhary.chy@mnit.ac.in.
ORCID
Sandeep Chaudhary: 0000-0002-1444-3895
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
S.C. acknowledges CSIR, New Delhi for CSIR-EMR Grant
[02(0189)/14/EMR-II]; DST, New Delhi for DST-RFBR
Indo-Russian Joint Research Project (INT/RUS/RFBR/P-
169); and SERB, New Delhi for a Start-up Research Grant
(Grant No. CS-037/2013). V.S. and P.K.J. thank MNIT, Jaipur
and CSIR, New Delhi, respectively for fellowships. Materials
Research Centre (MRC), MNIT, Jaipur is gratefully acknowl-
edged for providing analytical facilities.
In conclusion, our study uncovered an unprecedented
organocatalyst, regioselective, modified Guareschi−Thorpe
type protocol for the modular synthesis of structurally diverse
5,6,7,8-tetrahydroquinolines 22a−g and alicyclic[b]-fused
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