Domino Prins/pinacol reaction for the stereoselective synthesis of spiro[pyran-4,4′-quinoline]-2′,3′-dione derivatives

Article abstract of DOI:10.1039/c5ob01077b

A wide array of aldehydes undergo smooth cross-coupling with 3-hydroxy-3-(4-hydroxybut-1-en-2-yl)-1-methylindolin-2-one in the presence of 10 mol% BF₃·OEt₂ at 0 °C in dichloromethane to afford the corresponding 2,3,5,6-tetrahydro-1′H-spiro[pyran-4,4′-quinoline]-2′,3′-dione derivatives in good yields with excellent diastereoselectivity. This is the first report on the synthesis of tetrahydro-1′H-spiro[pyran-4,4′-quinoline]-2′,3′-dione scaffolds through a cascade of Prins/pinacol reactions.

Full text of DOI:10.1039/c5ob01077b

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Domino Prins/pinacol reaction for the
stereoselective synthesis of spiro-
Cite this: DOI: 10.1039/c5ob01077b
[pyran-4,4’-quinoline]-2’,3’-dione derivatives†
B. V. Subba Reddy,*a S. Gopal Reddy,a,b M. Durgaprasad,a Manika Pal Bhadrab and
B. Sridharc
A wide array of aldehydes undergo smooth cross-coupling with 3-hydroxy-3-(4-hydroxybut-1-en-2-yl)-
1-methylindolin-2-one in the presence of 10 mol% BF3·OEt2 at 0 °C in dichloromethane to afford the
corresponding 2,3,5,6-tetrahydro-1’H-spiro[pyran-4,4’-quinoline]-2’,3’-dione derivatives in good yields
with excellent diastereoselectivity. This is the first report on the synthesis of tetrahydro-1’H-spiro[pyran-
4,4’-quinoline]-2’,3’-dione scaffolds through a cascade of Prins/pinacol reactions.
Received 28th May 2015,
Accepted 8th July 2015
DOI: 10.1039/c5ob01077b
www.rsc.org/obc
Introduction
Nitrogen containing heterocycles are considered as privileged
scaffolds because of their occurrence in natural products and
designed pharmaceuticals.1 Among them, quinolones rep-
resent an important class of biologically active nitrogen hetero-
cycles.2 On the other hand, the tetrahydropyran ring
comprises a core structure of many bioactive natural pro-
ducts.3 In order to generate combinatorial libraries for drug
discovery, a large number of hybrid molecules can be gener-
ated if these two interesting frameworks are integrated into a
complex structure. Indeed, there are some reports on the amal-
gamation of these two bioactive scaffolds to make another
complex structure so as to improve or generate new biological
activity.4 Furthermore, spirocycles are important structural
scaffolds in medicinal chemistry, which are key components of
many bioactive molecules displaying potent pharmacological
activity.5 They are often found in drug molecules.6 Moreover,
the rigidity of these structures has been explored for the con-
struction of chiral ligands.7 In addition, spiroquinoline/isoqui-
noline derivatives are known to exhibit a broad spectrum of
biological activities such as antiarrhythmic, anti-depressant,
and stimulant effects on respiration, analgesic and cardiotonic
Fig. 1 Biologically active molecules.
behaviour (Fig. 1).8 As a result, numerous synthetic strategies
have been developed for the synthesis of spirocycles.5–7 Among
them, pinacol terminated Prins cyclization is an elegant
process for the stereoselective construction of spirocarbocycles
and oxacycles.9,10
Due to the fascinating molecular architecture and proven
biological activity of spirocycles,11 we also reported a few
cascade reactions for their synthesis.12
aNatural Product Chemistry, CSIR-Indian Institute of Chemical Technology,
Hyderabad, India. E-mail: basireddy@iict.res.in; Fax: +91-40-27160512;
Tel: +91-40-27193535
Results and discussion
bCentre for Chemical Biology, CSIR-Indian Institute of Chemical Technology,
Hyderabad, India
Inspired by the versatility of cascade reactions in organic syn-
thesis,13 we herein report a novel synthesis of spiropyranoqui-
nolinone scaffolds through a Prins/pinacol reaction. The
reaction proceeds in two steps but in one-pot through a
sequential Prins/pinacol cascade. The required enediol (3) was
cLaboratory of X-ray Crystallography, CSIR-Indian Institute of Chemical Technology,
Hyderabad, India
†Electronic supplementary information (ESI) available: Copies of 1H and 13C
NMR spectra of products. CCDC 1061396. For ESI and crystallographic data in
CIF or other electronic format see DOI: 10.1039/c5ob01077b
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prepared from homopropargyl alcohol (1). Hydrobromination this reaction further with various aldehydes bearing a diverse
of 1 using PBr3/H2O gave the vinyl bromide (2a), which was substitution pattern.
then protected as its TBS ether (2). Lithiation of 2 using n-BuLi
followed by treatment with N-methylisatin afforded the desired excellent yields with high selectivity. It is worth mentioning
enediol (3) (Scheme 1). that a wide range of functional groups are well tolerated under
In most of the cases, the products were obtained in good to
As the outset, we attempted the coupling of 3 with pival- these reaction conditions (Table 2). The substituent present on
dehyde using several Lewis and Brønsted acids in different the aromatic ring had shown a modest effect on the conver-
solvents at various temperatures (Table 1). Lewis acids such as sion. It was observed that both electron rich and electron
In(OTf)3, Sc(OTf)3, Cu(OTf)2, InCl3, and InBr3 gave the product deficient aldehydes gave the products in comparatively lower
in low yields (Table 1, entries a–f). No significant improvement yields than the corresponding halogenated or alkyl substituted
in yield was observed even by increasing the catalyst loading aromatic aldehydes. Furthermore, the reaction was also quite
(Table 1, entry b). However, the use of 10 mol% BF3·OEt2 at successful with aliphatic aldehydes such as pivaldehyde and
0 °C gave the expected product in 80% yield as a single diaster- propanaldehyde (Table 2, entries a and n), but relatively in
1
eomer (entry i, Table 1), which was confirmed by the H NMR lower yields than aromatic counterparts. The relative stereo-
spectrum. In addition, TMSOTf was also found to be equally chemistry of 5a was established by X-ray crystallography
effective. Alternatively, Brønsted acids such as p-TSA and CSA (Fig. 2).14
were unsuccessful even at elevated temperature after a long
The scope of the reaction was further extended to ketones.
reaction time (Table 1, entries g and h). After several experi- However, the sterically hindered isatin failed to undergo Prins
ments, BF3·OEt2 gave the best results in terms of conversion. cyclization under the present reaction conditions. Interest-
Among different solvents, DCM was found to be the best for ingly, cyclohexanone gave the desired product in good yield
this cascade reaction. These results prompted us to investigate with high selectivity (entry r, Table 2). Furthermore, substi-
tuted enediols such as 5-chloro-, and 5-methoxy- derivatives
participated effectively in this cyclization (entries p and q,
Table 2). In addition to N-methyl derivative, the reaction also
proceeded with N-allyl enediol (entry o, Table 2). The stereo-
chemistry of different compounds that are reported in Table 2
was confirmed by the analogy of NMR chemical shifts/coup-
ling constants with 5a. Based on our earlier observation, we
propose a plausible reaction pathway in Scheme 2. The reac-
tion is assumed to proceed through the formation of an oxo-
Scheme 1 Preparation of the starting material (3). Reagents: (a) PBr3/
H2O, DCM, 40 °C, TEAB; (b) TBSCl, imidazole; (c) n-BuLi, THF, N-methyl-
isatin, −78 °C; and (d) TBAF, THF.
carbenium ion (A) from an aldehyde and alkenol under acidic
conditions. A subsequent attack of the olefin on the oxo-carbe-
nium ion leads to the formation of a tertiary carbocation (B),
which is terminated by a pinacol 1,2-shift to give the desired
spirocycle (5). The expected diastereoselectivity can be
explained by a favourable trapping of the carbocation from a
less hindered equatorial side in order to avoid unfavourable
1,3-diaxial interactions.15
Table 1 Optimization of reaction conditionsa
It is known that all substituents on cyclohexane in the chair
conformation occupy an equatorial position to relieve the
molecule from torsional strain.3 In the above cyclization, there
is a possibility of acyl migration over the aryl group.16
However, in the present case, the aryl migration was observed
exclusively due to electronic factors.17
Temp
(°C)
Time
(h)
Yieldb
(%)
Entry
Lewis acid
mol%
a
b
c
d
e
f
g
h
i
In(OTf)3
In(OTf)3
Sc(OTf)3
Cu(OTf)2
InBr3
InCl3
p-TSA
CSA
BF3·OEt2
TMSOTf
0.3
1.0
0.5
0.5
0.5
1.0
1.0
1.0
0.1
0.1
25
25
25
25
25
25
80
80
0
12
12
12
12
12
12
12
12
0.5
0.5
20
40
30
10
30
20
—
—
80
75
Conclusion
In summary, we have developed a novel one-pot strategy for
the synthesis of spiropyranoquinolone scaffolds from
3-hydroxy-3-(4-hydroxybut-1-en-2-yl)-1-methylindolin-2-one and
aldehydes through a Prins/pinacol cascade reaction. Note-
worthy features of this protocol include mild reaction con-
ditions, a wide substrate scope, good yields and excellent
diastereoselectivity, which make it an attractive process for the
synthesis of biologically relevant spirocycles in a single-step.
j
0
a Reaction was performed at the 0.5 mmol scale. b Yield refers to pure
products.
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Table 2 Synthesis of spirotetrahydropyranoquinolones
Table 2 (Contd.)
Yielda,b (%)
80
Entry
i
Aldehyde (4)
Product (5)
Yielda,b (%)
85
Entry
a
Aldehyde (4)
Product (5)
b
c
83
82
80
j
88
90
k
d
l
92
80
e
f
92
93
m
n
o
75
82
g
90
87
p
90
h
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Table 2 (Contd.)
Entry
q
Aldehyde (4)
Product (5)
Yielda,b (%)
85
r
75
Scheme 2 A plausible reaction pathway.
a Yield refers to pure products after column chromatography.
b Reaction was carried out on the 0.5 mmol scale.
(60–120 mesh) using ethyl acetate/hexane as the eluent to
afford the pure spirocycle.
Acknowledgements
SGR and MD thank CSIR, New Delhi, for the award of
fellowships.
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Typical procedure
To a stirred solution of 3 (0.5 mmol) and an aldehyde
(0.6 mmol) in dry dichloromethane (5 mL) was added 10 mol%
BF3·OEt2 at 0 °C. The resulting mixture was stirred at the
same temperature under a nitrogen atmosphere for the speci-
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