Diastereoselective construction of highly functionalized tetrahydroquinolinoisoxazole scaffolds via intramolecular nitrone cycloaddition

Article abstract of DOI:10.1016/j.tetlet.2015.05.004

A novel strategy towards the construction of highly diversified tetrahydroquinolinoisoxazole frameworks with high diastereoselectivity via intramolecular 1,3-dipolar nitrone cycloaddition reaction is described for the first time. All the synthesized tetrahydroquinolinoisoxazoles are new and obtained in excellent yields under catalyst free condition.

Full text of DOI:10.1016/j.tetlet.2015.05.004

Tetrahedron Letters 56 (2015) 3954–3960
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Diastereoselective construction of highly functionalized
tetrahydroquinolinoisoxazole scaffolds via intramolecular nitrone
cycloaddition
b
Manickam Bakthadoss a,b, , Anthonisamy Devaraj
⇑
a Department of Chemistry, Pondicherry University, Pondicherry 605 014, India
b Department of Organic Chemistry, University of Madras, Guindy Campus, Chennai 600025, Tamil Nadu, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 24 February 2015
Revised 1 May 2015
Accepted 2 May 2015
Available online 8 May 2015
A novel strategy towards the construction of highly diversified tetrahydroquinolinoisoxazole frameworks
with high diastereoselectivity via intramolecular 1,3-dipolar nitrone cycloaddition reaction is described
for the first time. All the synthesized tetrahydroquinolinoisoxazoles are new and obtained in excellent
yields under catalyst free condition.
Ó 2015 Elsevier Ltd. All rights reserved.
Keywords:
Tetrahydroquinolinoisoxazole
Regio and diastereoselectivity
Intramolecular nitrone cycloaddition
Catalyst free condition
Introduction
can be conveniently transformed into amino alcohol derivatives
through reductive cleavage of the N–O bond.7 In literature we could
An efficient construction of highly functionalized poly hetero-
cyclic compounds with high diversity and substantial complexity
is an important endeavour in the field of organic synthesis. The
natural abundance as well as interesting chemical and biological
applications of heterocyclic compounds intrigued synthetic che-
mists to mimic those scaffolds in the chemical laboratory.1 In the
arena of nitrogen and oxygen containing heterocycles, quinoline2
and isoxazolidine3 are known to be the expedient classes of
compounds, which are prevalent in nature. It is well known in
the literature that, quinolines and their derivatives are prone to
exhibit interesting biological activities, such as anti-malarial,
bactericidal, anti-tumour, anti-inflammatory, anti-proliferative
and anti-viral.4
find an array of reports available6 for the formation of wide variety
of isoxazole fused heterocycles via 1,3-dipolar cycloaddition reac-
tion but they are limited with simple allylated systems with limited
substrate scope. Some of the representative examples of tetrahydro-
quinoline and isoxazole based compounds8 such as martinelline
core (1),
a2-adrenoceptor antagonists (2), anti-inflammatory agent
(3), and serotonin inhibitors (4) are shown in Figure 1.
The synthesis of isoxazolidine and its derivatives by 1,3-dipolar
cycloaddition reactions has been utilized towards the total synthe-
sis of alkaloids, diversified nitrogen containing natural products
and several bio-active compounds.9 In particular, the intramolecu-
lar fashion of nitrone cycloaddition has been utilized effectively to
obtain structurally more complex isoxazolidine derivatives of
either medicinal applications or as convenient precursors for
several synthetic transformations.
An array of highly functionalized five membered heterocycles5
can be easily achieved via 1,3-dipolar cycloaddition reaction as a
key step. 1,3-Dipolar cycloaddition6 reaction (1,3-DC) between
olefin and nitrone is found to be the most consistent protocol
towards the synthesis of important isoxazolidine moiety. This proto-
col involves in situ formation of a nitrone and later 1,3-dipolar
cycloaddition reaction sequence through inter as well as intramolec-
ular fashion and the isoxazolidine products obtained from 1,3-DC
The Baylis–Hillman reaction10 is an efficient carbon–carbon
bond-forming reaction which has seen exponential growth in sev-
eral synthetic aspects. The efficiency and practical applicability
with broad substrate scope are the important features of this
reaction. It is well known in the literature that the derivatives from
the reaction are widely employed as convenient source for the con-
struction of bio-active poly heterocyclic compounds and an array
of carbocyclic frameworks.
⇑
Owing to the proven biological applications of quinolines
and isoxazoles, we speculated that the bromo derivative of
Corresponding author. Tel.: +91 413 2654830; fax: +91 413 2656740.
E-mail address: bhakthadoss@yahoo.com (M. Bakthadoss).
http://dx.doi.org/10.1016/j.tetlet.2015.05.004
0040-4039/Ó 2015 Elsevier Ltd. All rights reserved.

M. Bakthadoss, A. Devaraj / Tetrahedron Letters 56 (2015) 3954–3960
R''
3955
X
N
O
HN
O
EtO2C
X = C, Y = O
X = C, Y = S
X = N, Y = O
X = C, Y = NH
R'''
Me
(1)
(2)
N
O
N
R''''
(3)
X
α2
Y
N
H
-Adrenoceptor antagonists
X = CH2, Martinelline core
Me
Anti-inflammatory agent
MeOC
X = O, Bio-active molecule
MeO
N
O
N
N
MeO
(4)
X
Serotonin inhibitors X = O, NH
Figure 1. Representative examples of tetrahydroquinoline and isoxazole containing frameworks
Baylis–Hillman adducts can be efficiently utilized for the synthesis
of quinolinoisoxazole hybrid molecules via nitrone cycloaddition
reaction. Recently, we reported a multicomponent domino proto-
col towards an array of quinolino pyranpyrazole frameworks using
Baylis–Hillman derivatives.1e In the literature we are unable to find
any precedents for the construction of tetrahydroquinolino
isoxazolidines via intramolecular nitrone cycloaddition using
Baylis–Hillman (B.H.) derivatives. Intrigued by this idea, we have
decided to utilize B.H. derivatives as a key precursor towards the
assembly of highly functionalized tetrahydroquinolinoisoxazole
frameworks via 1,3-dipolar nitrone cycloaddition in an
intramolecular fashion.
acrylate, bromo derivatives (4) of Baylis–Hillman adduct as shown
in retro synthetic analysis (Scheme 1).
In order to execute our idea, we subjected methyl (Z)-2-(bro-
momethyl)-3-phenylprop-2-enoate (4a), a bromo derivative of
the Baylis–Hillman adduct and N-tosylated amino benzaldehyde
(5) with an aid of K2CO3, mediated by acetonitrile which led to
the required precursor 6a. As mentioned in the retrosynthetic
analysis, the treatment of N-allylated aminobenzaldehyde (6a)
with N-methylhydroxylamine hydrochloride (7a) in ethanol
solvent medium under reflux temperature for a period of 10 h suc-
cessfully provided the desired tricyclic quinolinoisoxazolidine 9a
in excellent yield (90%) (Scheme 2). In order to check the efficacy
of the reaction, we have also carried out the reaction with molec-
ular sieves as an additive under similar reaction condition which
leads to the formation of anticipated product 9a in 85% yield over
a period of 8 h. We have also subjected the N-allylated aminoben-
zaldehyde (6a) with N-methylhydroxylamine hydrochloride (7a)
in benzene with Dean–Stark water separator system for a period
of 16 h leads to the target molecule 9a in 82% yield. Therefore, it
is well clear that the reaction carried out in ethanol under reflux
condition without any additive is found to be the best condition
for the formation of tricyclic quinolinoisoxazolidine. Prompted by
this result, we have treated various N-allylated aldehydes (6b–d,
f–h) with N-methylhydroxylamine hydrochloride (7a) using the
aforementioned condition which smoothly led to the formation
of a variety of tricyclic quinolinoisoxazolidines (9b–g) in 78–86%
yields as depicted in Scheme 2. The results are summarized in
Table 1.
Results and discussions
Since quinolinoisoxazole derivatives are well known for their
interesting biological properties,2–4,8 we envisaged that highly func-
tionalized quinolinoisoxazole hybrid molecules also may exhibit
similar type of activities which will be very interesting. In this
aspect, we are prompted to construct expedient classes of tetrahy-
droquinolino isoxazolidines via cycloaddition reaction using
Baylis–Hillman derivatives. In our continuous effort towards the
synthesis of highly functionalized poly heterocyclic compounds,1e,11
herein we report an efficient strategy for the construction of a wide
variety of tricyclic quinolinoisoxazole derivatives using Baylis–
Hillman derivatives via initial nitrone formation followed by an
intramolecular 1,3-dipolar cycloaddition reaction. The requisite
precursor (6) leads to the target molecule (9) through nitrone
formation followed by an intramolecular 1,3-dipolar cycloaddition
sequence. The precursor (6) can be synthesized from N-tosylated
amino aldehyde (5) using (Z)-methyl 2-(bromo methyl)-3-phenyl
By following a similar procedure described above, we have syn-
thesized a variety of quinolino isoxazolidines 9h–l in very good
yields using N-benzyl hydroxylamine (7b) via in situ formation of
nitrones followed by intramolecular [3+2] cycloaddition reaction
according to Scheme 3 (Table 1).
Further, we also extended this methodology with N-phenyl
hydroxylamine hydrochloride (7c) for the synthesis of quinoli-
noisoxazolidines 9m–n via an intramolecular 1,3-dipolar cycload-
dition reaction using N-allylated aminoaldehydes (6a–b). The
desired tricyclic quinolinoisoxazolidines 9m–n were formed in
81–83% yields (Scheme 4) and the results are summarized in
Table 1.
The highly regio- as well as diastereoselective nature of the
cycloaddition was clearly supported by 1H NMR spectroscopy
and single crystal X-ray diffraction analysis (Fig. 2). It is well clear
from the ORTEP diagram of compound 9n that the aryl group and
the adjacent ester moiety are in trans orientation, which is mainly
because of the initial trans geometry of the aryl and ester function-
alities present in the vicinal position of the double bond of Baylis–
Hillman derivative 6b.
N-alkylation
Ts
N
Ts NH
O
MeO2C
O
6
H
5
OHC
OMe
nitrone
MeNHOH
Br
formation
7
4
CO2Me
N
Ts
TsN
Me
O
[3+2] cycloaddition
N
O
O
OMe
N
H
H3C
9
8
To enhance the scope of the reaction further, we also used
bromo derivative (10) of the Baylis–Hillman adducts derived from
Scheme 1. Retrosynthetic analysis for Tetrahydroquinolinoisoxazole frameworks

3956
M. Bakthadoss, A. Devaraj / Tetrahedron Letters 56 (2015) 3954–3960
R1
O
O
Ts
N
K2CO3
H
R2O
OR2
R1
CH3CN
6 h , rt
NHTs
O
Br
OHC
6a-d, f-h
5
4a-d, f-h
R1 = H, 2-Me, 4-OMe, -OCH2O-,
3-Cl, 4-Cl, 2,4-diCl,
EtOH
reflux, 10 h
MeNHOH.HCl (7a)
R2 = Me, nBu
R1
R1
CO2R2
[3+2]
cycloaddition
Ts
Ts
N
R2O
N
O
N
O
H
O
H
Me
N
9 a-g
78-90%
8 a-g
Me
Scheme 2.
Table 1
Synthesis of tricyclic quinolinoisoxazolidine frameworks (9a–n) via intramolecular [3+2] dipolar cycloaddition reactiona,b,c
OMe
Cl
O
O
Me
Ts
CO2Me
N
CO2Me
N
CO2Me
CO2Me
N
CO2Me
N
Ts
Ts
Ts
Ts
N
O
O
O
O
O
N
N
N
N
N
H
H
Me
H
Me
H
H
Me
Me
Me
9b
9a
, 90%
, 79%
9c
, 78%
9e, 86%
9d, 78%
O
O
Cl
CO2nBu
N
Cl
Ts
CO2Me
N
CO2Me
CO2Me
Cl
Ts
Ts
CO2Me
Ts
N
N
Ts
O
O
N
O
O
O
N
N
N
N
H
N
H
Me
H
H
H
Me
Ph
Ph
Ph
9g
9f
, 80%
9h
9j, 80%
, 84%
Cl
, 90%
9i, 79%
CO2nBu
N
Me
CO2Me
N
CO2Me
N
CO2Me
N
Ts
Ts
Ts
Ts
O
O
O
O
N
N
N
N
H
H
H
H
Ph
Ph
Ph
9k
Ph
, 83%
, 81%
9nd, 83%
9l
, 86%
9m
d The structure of the molecules was further confirmed by single-crystal X-ray data.
a
All reactions were carried out on 2 mmol scale of N-alkylated aldehydes (6) with 2.1 mmol of N-methylhydroxylamine
hydrochloride/N-phenylhydroxylamine/N-benzylhydroxylamine hydro chloride in ethanol at reflux temperature for 10 h.
b
Isolated yield of the pure product.
All the compounds were fully characterized.
c
O
R1
OR2
NTs
CO2R2
O
R1
Ts
BnNHOH.HCl (7b)
N
R1
H
O
OCH3
NTs
N
R1
CO2Me
N
EtOH, reflux, 10 h
O
Ts
H
PhNHOH (7c)
H
O
Ph
EtOH, reflux, 10 h
N
O
6a, d-f, h
R1 = H, -OCH2O-, 2-Cl, 4-Cl
R2 = Me, nBu
H
9 h-l
79-90%
Ph
6a-b
9m-n
R1 = H, 2-Me
81-83%
Scheme 3.
Scheme 4.

M. Bakthadoss, A. Devaraj / Tetrahedron Letters 56 (2015) 3954–3960
3957
angularly substituted (cyano group) tricyclic quinolinoisoxazolidi-
nes (12a–f) in very good yields (74–83%) (Scheme 5 and Table 2).
To expand the applicability of the reaction, we subjected vari-
ous N-allylated amino aldehydes (11c–d, g) with N-benzylhydrox-
ylamine hydrochloride (7b) in ethanol under reflux condition
which successfully afforded the anticipated tricyclic quinolinoisox-
azolidines (12g–i) in 76–85% yields (Scheme 6).
The structure of the compound 12a was further confirmed
without any ambiguity by single crystal X-ray analysis and the
ORTEP diagram is shown in Figure 3 from which we can under-
stand the relative stereochemistry. From the ORTEP diagram of
compound 12a, we can understand that the aryl as well as adjacent
nitrile moieties adopt a cis orientation, which is mainly due to the
initial cis geometry of the aryl and nitrile moieties present in the
vicinal position of olefin 11. Therefore, it is well clear that all the
target molecules are obtained in a highly regio as well as diastere-
oselective fashion as evidenced by NMR spectroscopy and single
crystal X-ray analyses.
In order to study the substituent effect on the phenyl group
attached to the amino moiety, we have prepared a substrate 17
that contains a dimethoxy group prepared from 3,4-dimethoxy
benzaldehyde 13 through nitration, reduction, tosylation and sub-
stitution reaction. The treatment of N-allylated dimethoxyamino
aldehyde 17 with N-methylhydroxylamine hydrochloride (7a) in
ethanol under reflux condition for a period of 15 h successfully
provided the desired tricyclic quinolinoisoxazolidine 18 in 57%
yield (Scheme 7). It is important to note that the reaction gave only
57% yield even after 15 h of stirring under reflux condition which
may be attributed due to more electron density of aldehyde carbon
arising from dimethoxy substituents in the aryl moiety attached to
the amino group.
Among the hydroxylamines employed such as N-methylhy-
droxylamine hydrochloride/N-phenylhydroxylamine/N-benzylhy-
droxylamine hydrochloride for the nitrone formation, we found
that N-methyl derivative was more reactive, N-benzyl was moder-
ately reactive whereas N-Phenyl was relatively less reactive. In the
case of Baylis–Hillman derivatives we have utilized ester deriva-
tives [CO2Me, CO2nBu], nitrile derivatives [CN], and observed that
ester derivatives works well compared to nitrile derivatives.
Among ester derivatives [CO2Me, CO2nBu] we could not see any
Figure 2. ORTEP diagram12 of compound 9n.
R1
CHO
CN
H
CH3NHOH.HCl (7a)
Ts
N
N
R1
Ts
O
CN
EtOH, reflux,12h
N
Me
11a-f
R1 = H, 2-Me, 4-Me, 4-iPr, 2-OMe, 3,4-diOMe
74-83%
12a-f
Scheme 5.
acrylonitrile and utilized them for N-allylation reaction with N-to-
sylated aminobenzaldehyde (5). The treatment of the N-allylated
aminobenzaldehydes (11a–f) with N-methyl hydroxylamine (7a)
in ethanol under reflux temperature successfully led to the
Table 2
Synthesis of tricyclic quinolinoisoxazolidine frameworks (12a–i) containing nitrile functionality at ring junctiona,b,c
Me
Me
Ts
MeO
CN
CN
H
CN
H
CN
H
CN
H
Ts
Ts
Ts
Ts
N
N
N
N
N
O
O
O
O
O
N
N
N
N
N
H
Me
Me
Me
Me
Me
12ad,
, 83%
12e, 79%
12b
80%
12c
, 74%
12d, 76%
Me
O
OMe
O
MeO
CN
CN
CN
Ts
Ts
N
Ts
CN
H
N
N
Ts
O
O
O
N
O
N
N
N
H
H
N
H
Me
Ph
Ph
Ph
12h
, 85%
12i, 76%
12f
, 83%
12g
, 81%
d The structure of the molecules were further confirmed by single-crystal X-ray data.
a
All reactions were carried out on 2 mmol scale of N-alkylated aldehydes (11) with 2.1 mmol of N-methylhydroxylamine
hydrochloride/N-benzylhydroxylamine hydrochloride in ethanol as a solvent at reflux temperature for 12 h.
b
Isolated yield of the pure product.
All compounds were fully characterized.
c

3958
M. Bakthadoss, A. Devaraj / Tetrahedron Letters 56 (2015) 3954–3960
Me
N
Me
Hy
Hx
R1
Hy
Hx
N
CHO
O
O
CN
H
Ts
Ar
BnNHOH. HCl (7b)
CN
Ar
CO2Me
N
N
O
R1
Ts
N
N
CN
Ts
20
N
EtOH, reflux, 12h
Ts
19
11c-d, 11g
R1 = 4-Me, 4-iPr, -OCH2O-
Ph
12g-i
76-85%
Figure 4. Possible regioisomers in the cycloaddition reaction.
Scheme 6.
appreciable difference in the reactivity since the yields are in close
range. Similarly, both electron donating as well as electron with-
drawing substituents on the aryl ring of the Baylis–Hillman deriva-
tives does not have any influence in the cycloaddition reaction.
Even though there is a possibility for the formation of regio iso-
mers in the cycloaddition reaction, the negative charge on the oxy-
gen of nitrone 8 (see Scheme 2) attacks the b-position of the
a,b-
unsaturated ester moiety which is more electrophilic and the alter-
native pathway for the formation of bicyclic products (Fig. 4), that
is, attack of nitrone oxygen (8) at the a-position of the a,b-unsat-
urated ester was not observed. It is important to note that there
would be the appearance of two doublets with vicinal coupling
constants for Hx and Hy protons in the 1H NMR spectrum if the
regioisomers 19 and 20 had been formed in the cycloaddition reac-
tion. Absence of such spectral pattern evidences the regioselectiv-
ity of the reaction.
The plausible pathways for the formation of tricyclic quinoli-
noisoxazolidine frameworks can be elucidated based on the transi-
tion states shown in Scheme 8. There is a possibility of endo (path I
& III) as well exo (path II & IV) transition states for the formation of
quinolinoisoxazolidines. The p-effects or p-interactions in the 1,3-
dipolar cycloaddition reaction attributes the endo transition state
(path I & III) as the more favourable one which leads to cis-fused
ring systems in an effective manner.
In order to demonstrate the synthetic application of the newly
constructed tricyclic quinolinoisoxazolidine frameworks, we sub-
jected compound 9e to reductive cleavage using LAH which leads
to the amino alcohol 21 in 91% without column chromatography
purification (Scheme 9). It is interesting to note that the hindered
ester moiety also underwent reduction during the course of the
reaction.
Figure 3. ORTEP diagram12 of compound 12a.
MeO
MeO
CHO
MeO
MeO
CHO
NO2
MeO
MeO
CHO
NH2
Pd/C, H2 balloon
rt, 2h, 93%
Con. HNO3
0°C - rt, 2h, 95%
15
14
13
TsCl
CHCl3
N
rt, 10h, 97%
CO2Me
Br
Ts
N
OMe
OMe
MeO
MeO
MeO
CHO
4a
O
OHC
K2CO3, CH3CN, rt, 6h, 88%
NHTs
17
16
EtOH
reflux, 15 h
MeNHOH.HCl (7a)
CO2Me
Ts
N
O
N
H
Me
OMe
OMe
57%
18,
Scheme 7.

M. Bakthadoss, A. Devaraj / Tetrahedron Letters 56 (2015) 3954–3960
3959
TsN
TsN
TsN
TsN
Ar
NC
Ar
O
NC
Ar
O
N
R
N
R
MeO2C
MeO2C
O
O
N
R
N
R
Ar
path IV
path III
path II
path I
H
H
Ar
TsN
TsN
Ar
TsN
X
TsN
X
Ar
X
Ar
H
X
H
O
O
O
O
N
R
N
R
N
R
H
N
R
H
H
H
X = CN
X = CN
X = CO2Me
X = CO2Me
exo
exo
endo
endo
CN
CO2Me
H
CO2Me
N
H
Ts
CN
Ts
H
H
Ts
N
Ts
N
O
N
O
O
O
N
R
N
N
N
R
H
12''
not formed
H
9''
R
H
H
12
R
9
not formed
Scheme 8. Plausible pathway for the formation of tricyclic quinolinoisoxazolidines.
placed in a round bottom flask and kept under reflux condition
for 10–12 h. After completion of the reaction as indicated by TLC,
the reaction mixture was concentrated under reduced pressure.
The crude product was diluted with water and extracted with
ethylacetate (20 ml). The organic layer thus obtained was washed
with brine solution (10 ml) and concentrated. The crude product
was purified by column chromatography (10% EtAc and hexanes) to
provide the desired pure product 9/12 as colourless solid in excellent
yield.
Cl
N
Me
OH
OH
NH
CO2Me
N
LiAlH4, THF
-5 °C - rt, 2 h
Ts
O
Cl
N
Ts
H
Me
21, 91%
9e
Scheme 9.
Acknowledgements
Conclusions
We thank DST-SERB for the financial support. We also thank
DST-FIST for the NMR facility. A.D. thank CSIR – India for his SRF.
In conclusion, we achieved an efficient and general protocol
towards the regio-, diastereoselective construction of highly func-
tionalized tetrahydroquinolinoisoxazole frameworks with angular
substitution involving in situ formation of nitrone and later
intramolecular 1,3-dipolar nitrone cycloaddition using Baylis–
Hillman derivatives for the first time. It is worth to mention here
that all the quinolinoisoxazolidines are new and synthesized under
catalyst free condition. Other than N-methyl hydroxylamine
hydrochloride, we have also employed other hydroxylamines such
as N-phenyl hydroxylamine/N-benzyl hydroxylamine hydrochlo-
rides for the synthesis of library of quinolinoisoxazolidines. This
new protocol paved the pathway for the construction of cis-fused
tricyclic quinolinoisoxazolidines with the formation of two rings,
three contiguous stereocentres and one of them being a tetrasub-
stituted carbon centre in an efficient manner. Wide variety of tri-
cyclic quinolinoisoxazolidines were obtained in a highly regio as
well as diastereoselective manner with excellent yields. Hence, this
strategy also opens new avenues for the construction of libraries of
tetrahydroquinolinoisoxazole frameworks for further biological
studies.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2015.05.
004.
References and notes
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7259.
Experimental section
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N-alkyl/arylhydroxylamine (7) (2.1 mmol) in ethanol (15 ml) were

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ˇ
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12. Structures were confirmed by single-crystal X-ray data, CCDC number for the
compounds 9n and 12a have 1034631 & 1034632, respectively.