First Friedel-Crafts reaction of the Baylis-Hillman adducts derived from nitroolefins: Application towards synthesis of pyrrolidines and spiropyrrolidines

Article abstract of DOI:10.1055/s-0030-1260557

A general and simple protocol for the arylation of Baylis-Hillman adducts derived from nitroolefins leading to novel classes of (E)-2-nitro-1,3- diarylprop-1-enes and 1-[(E)-2-nitro-3-arylallyl]naphthalenes via an intermolecular Friedel-Crafts reaction ha

Full text of DOI:10.1055/s-0030-1260557

1296
LETTER
First Friedel–Crafts Reaction of the Baylis–Hillman Adducts Derived from
Nitroolefins: Application towards Synthesis of Pyrrolidines and
Spiropyrrolidines
F
riedel–Crafts Reactio
a
n of
B
aylis
n
i
ducts
D
c
erived from
k
Nitroolefin
a
s
m Bakthadoss,* Nagappan Sivakumar
Department of Organic Chemistry, University of Madras, Guindy Campus, Chennai 600 025, India
Fax +91(44)22352494; E-mail: bhakthadoss@yahoo.com
Received 17 December 2010
in the field of organic chemistry.21 The 1,3-dipolar cy-
cloaddition reaction is an important method for the prepa-
ration of five-membered heterocycles. The reaction of an
azomethine ylide with an alkene provides the pyrrolidine
Abstract: A general and simple protocol for the arylation of
Baylis–Hillman adducts derived from nitroolefins leading to novel
classes of (E)-2-nitro-1,3-diarylprop-1-enes and 1-[(E)-2-nitro-3-
arylallyl]naphthalenes via an intermolecular Friedel–Crafts reac-
tion have been achieved. Further application of these compounds moiety which is present in numerous natural products and
biologically active molecules.22 It is well documented in
has been demonstrated for the synthesis of pyrrolidines and 3-spiro-
pyrrolidines which are integral components of many natural prod-
the literature that the Baylis–Hillman adducts have been
ucts and bioactive molecules.
utilized for the synthesis of various heterocycles.23 How-
ever, the synthesis of heterocyclic spiro compounds via
azomethine ylide based [3+2] cycloaddition using
Key words: Baylis–Hillman reaction, Friedel–Crafts reaction, in-
termolecular [3+2] cycloaddition, arylation, spiro compounds
Friedel–Crafts products of Baylis–Hillman adducts de-
rived from nitrostyrene has not been reported to date.
The Baylis–Hillman reaction is a well-known coupling re-
In continuation of our interest in the Baylis–Hillman
action of aldehydes and activated alkenes catalyzed by
chemistry,14,15,24 herein we report the first protocol for the
tertiary amines or tertiary phosphines1 and has emerged as
syntheses of (E)-2-nitro-1,3-diarylprop-1-enes and 1-
a carbon–carbon bond-forming reaction producing dense-
[(E)-2-nitro-3-arylallyl]napthalenes via an intermolecular
ly functionalized molecules that have been utilized for
Friedel–Crafts reaction. Furthermore we also disclose a
various organic transformations.2–7 The Friedel–Crafts
simple and convenient route for the synthesis of pyrroli-
reaction is a widely used reaction in academic as well as
dine and 3-spiropyrrolidine frameworks using the
industrial fields.8–13 The Friedel–Crafts reaction with
Friedel–Crafts products of Baylis–Hillman adducts de-
Baylis–Hillman adducts was initially reported by Basavaiah
rived from nitroolefins with sarcosine-based dipoles (gen-
et al. and, following this pionioring work, various reports
erated via in situ imine formation and decarboxylation) by
have appeared in connection with Friedel–Crafts chemis-
an intermolecular [3+2] cycloaddition reaction sequence.
try on Baylis–Hillman adducts. For example, Basavaiah et
To execute our idea, first we chose the Baylis–Hillman
adduct (E)-2-nitro-3-phenylprop-2-en-1-ol (1a)25 derived
from nitrostyrene and formaldehyde as starting material
for the Friedel–Crafts reaction. The best results were ob-
tained with addition of a catalytic amount of concentrated
H2SO4 to the solution of a compound 1a in benzene (2) at
room temperature, successfully leading to the desired (E)-
(2-nitroprop-1-ene-1,3-diyl)dibenzene (3a) in 75% yield
al. have described the synthesis of functionalized indene
and indane derivatives via intramolecular Friedel–Crafts
reaction of Baylis–Hillman adducts in the presence of
P2O5.14 They have also synthesized the antifungal natural
product, bonducellin methyl ether, involving an intramo-
lecular Friedel–Crafts reaction as the key step.15 There are
also reports describing the Friedel–Crafts reaction of
Baylis–Hillman adducts in the synthesis of 2-benzox-
epines, 2-benzazepines, 7H-benzocycloheptane, inde-
no[1,2-b]quinolin-10-ones, 1-hydroxynaphthalenes, and
methylenedinaphthyl-bis-chromanones.16–20
1
after column chromatography (Scheme 1). The H NMR
spectrum of compound 3a showed a singlet for CH2 pro-
tons at d = 4.25 ppm. The aromatic protons appeared as
However, there is no report available in the literature for
the Friedel–Crafts reaction of the Baylis–Hillman adducts
derived from nitroolefins. We envisaged that such adducts
would undergo Friedel–Crafts reaction to produce a new
class of diaryl compounds.
NO2
R
OH
1a–h
NO2
CH2Cl2
+
R
concd H2SO4
(cat.)
The synthesis of nitrogen- and oxygen-containing hetero-
cycles continues to be an important and challenging area
3a–h
2
SYNLETT 2011, No. 9, pp 1296–1302
Advanced online publication: 16.05.2011
x
x.
x
x.
2
0
1
1
R = H, 2-Me, 4-Me, 4-Et, 4-i-Pr, 2-OMe, 4-OMe, 3,4-di-OMe
DOI: 10.1055/s-0030-1260557; Art ID: D32910ST
Scheme 1
© Georg Thieme Verlag Stuttgart · New York

LETTER
Friedel–Crafts Reaction of Baylis–Hillman Adducts Derived from Nitroolefins
1297
multiplet in the region of d = 7.19–7.43 ppm, and the ole- To explore the generality of the reaction we treated Baylis–
finic proton appeared as singlet at d = 8.29 ppm.
Hillman adduct 1a with p-xylene (4) in the presence of a
catalytic amount of concentrated H2SO4 which resulted in
the desired Friedel–Crafts product, that is, 1,4-dimethyl-
2-[(E)-2-nitro-3-phenylallyl]benzene (5a) in 77% yield
after column chromatography purification (Scheme 2).
The 1H NMR spectrum of compound 5a showed two sin-
glets for two methyl protons at d = 2.25 and 2.30 ppm. The
benzylic protons showed a singlet at d = 4.13 ppm, and the
Encouraged by this result, we prepared a variety of (E)-2-
nitro-3-arylprop-2-en-1-ols 1b–h as starting materials for
the syntheses of (E)-2-nitro-1,3-diarylprop-1-enes. Treat-
ment of the compounds 1b–h with catalytic amount of
concentrated H2SO4 successfully led to the desired com-
pounds 3b–h in 65–70% yields (Scheme 1). The results
are summarized in Table 1.
Table 1 Friedel–Crafts Reaction on Baylis–Hillman Adducts Derived from Nitroolefins with Benzene
Entry
1
Substrate
Producta
Yield (%)b,c
NO2
NO2
OH
75
1a
3a
NO2
NO2
OH
2
65
1b
1c
3b
3c
3d
NO2
NO2
3
4
5
70
67
70
OH
NO2
NO2
OH
1d
NO2
NO2
OH
1e
3e
OMe
OMe
NO2
NO2
OH
6
68
1f
3f
NO2
NO2
OH
7
8
65
70
MeO
MeO
1g
3g
MeO
NO2
MeO
NO2
OH
MeO
MeO
1h
3h
a All reactions were carried out using 2 mmol of Baylis–Hillman alcohol 1a–h with benzene (0.5 mL) in 5 mL of CH2Cl2 and a catalytic amount
of concd H2SO4 at r.t. for 0.5 h.
b All products gave satisfactory IR, 1H NMR, 13C NMR, MS spectral data and elemental analyses.
c Yields of the pure products 3a–h obtained after column chromatography (silica gel, 2% EtOAc in hexanes).
Synlett 2011, No. 9, 1296–1302 © Thieme Stuttgart · New York

1298
M. Bakthadoss, N. Sivakumar
LETTER
aromatic protons appeared in the region of d = 6.83–7.41 A variety of Baylis–Hillman adducts 1b–h with p-xylene
ppm. The olefinic proton appeared as a singlet at d = 8.37 smoothly led to the desired Friedel–Crafts products 5b–h
ppm.
in 65–72% yields (Scheme 2, Table 2).
To extend the generality of the procedure further we em-
ployed naphthalene (6) as the arene. Treatment of Baylis–
Table 2 Friedel–Crafts Reaction on Baylis–Hillman Adducts Derived from Nitroolefins with p-Xylene
Entry
Substrate
Producta
Yield (%)b,c
NO2
NO2
OH
1
77
1a
5a
NO2
NO2
OH
2
72
5b
1b
1c
5b
NO2
NO2
3
4
5
70
67
68
OH
5c
5d
5e
NO2
NO2
OH
1d
NO2
NO2
OH
1e
OMe
OMe
NO2
NO2
OH
6
65
1f
5f
NO2
NO2
OH
7
8
65
67
MeO
MeO
1g
5g
MeO
NO2
MeO
NO2
OH
MeO
MeO
1h
5h
a All reactions were carried out using 2 mmol of Baylis–Hillman alcohol 1a–h with p-xylene (0.5 mL) in 5 mL of CH2Cl2 and catalytic amount
of concd H2SO4 at r.t. for 0.5 h.
b All products gave satisfactory IR, 1H NMR, 13C NMR, MS spectral data and elemental analyses.
c Yields of the pure products 5a–h obtained after column chromatography (silica gel, 2% EtOAc in hexanes).
Synlett 2011, No. 9, 1296–1302 © Thieme Stuttgart · New York

LETTER
Friedel–Crafts Reaction of Baylis–Hillman Adducts Derived from Nitroolefins
1299
1
NO2
OH
77% yields (Scheme 3, Table 3). The H NMR spectrum
of compound 7a showed a singlet for CH2 protons at d =
4.68 ppm. The aromatic protons appeared as multiplet in
the region of d = 7.23–7.99 ppm, and the olefinic proton
R
1a–h
NO2
CH2Cl2
+
R
appeared as singlet at d = 8.00 ppm.
concd H2SO4
(cat.)
NO2
R
OH
5a–h
4
1a–e
NO2
CH2Cl2
R = H, 2-Me, 4-Me, 4-Et, 4-i-pr, 2-OMe, 4-OMe, 3, 4-di-OMe
R
+
concd H2SO4
(cat.)
Scheme 2
7a–e
Hillman adducts 1a–e with naphthalene in the presence of
catalytic amount of concentrated H2SO4 led to the antici-
pated 1-[(E)-2-nitro-3-arylallyl]naphthalenes 7a–e in 67–
R = H, 2-Me, 4-Me, 4-Et, 4-i-Pr
6
Scheme 3
Table 3 Friedel–Crafts Reaction on Baylis–Hillman Adducts Derived from Nitroolefins with Naphthalene
Entry
Substrate
Producta
Yield (%)b,c
NO2
NO2
OH
1
77
1a
7a
NO2
NO2
OH
2
3
72
1b
1c
7b
NO2
NO2
70
OH
7c
7d
7e
NO2
NO2
OH
4
5
67
68
1d
1e
NO2
NO2
OH
a All reactions were carried out using 2 mmol of Baylis–Hillman alcohol 1a–e with naphthalene (2 mmol) in 5 mL of CH2Cl2 and catalytic
amount of concd H2SO4, at r.t. for 0.5 h.
b All products gave satisfactory IR, 1H NMR, 13C NMR, MS spectral data and elemental analyses.
c Yields of the pure products 7a–e obtained after column chromatography (silica gel, 2% EtOAc in hexanes).
Synlett 2011, No. 9, 1296–1302 © Thieme Stuttgart · New York

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M. Bakthadoss, N. Sivakumar
LETTER
Table 4 Synthesis of Pyrrolidine Compounds from Friedel–Crafts Products
Entry
Substrate
Producta
Yield (%)b,c
Me
N
NO2
1
77
NO2
3a
8
9
Me
N
NO2
2
72
NO2
5a
Me
N
NO2
NO2
3
70
7a
10
a All reactions were carried out using 1 mmol of Friedel–Crafts products 3a, 5a, and 7a) with N-methyl glycine (3 mmol), and formaldehyde
(6 mmol) in 8 mL MeCN under reflux conditions for 10 h.
b All products gave satisfactory IR, 1H NMR, 13C NMR, MS spectral data and elemental analyses.
c Yields of the pure products 8–10 obtained after column chromatography (silica gel, 10% EtOAc in hexanes).
To demonstrate the application of the 1,3-diaryl com-
NO2
pounds thus obtained, we have utilized them for [3+2]-
cycloaddition reaction for the construction of pyrrolidines
Hc Me
Hc
O
Ar
N
Hb
Hb
Ha
Ha
H
and spiro pyrrolidines. We first selected (E)-(2-nitroprop-
1-ene-1,3-diyl)dibenzene (3a) derived from Baylis–
Hillman adduct 1a as a starting material for cycloaddition
with the dipole generated from N-methyl glycine and
HCHO. Best results were obtained when 3a was treated
with HCHO and N-methyl glycine without catalyst in ac-
etonitrile for 10 hours at reflux, successfully providing 3-
benzyl-1-methyl-3-nitro-4-phenylpyrrolidine (8) in good
yield (77%) after column chromatography purification
Hd
3a, 5a, 7a
N
HO
Me
+
MeCN
reflux, 10 h
HCHO
O2N
Ar
Ar = Ph, p-xylene, naphthalene
8, 9, 10
Scheme 4
72% and 70% yields, respectively (Scheme 4). The results
are summarized in Table 4.
1
(Scheme 4). The H NMR spectrum of compound 8
To probe further the application of the Friedel–Crafts
products, we subjected 3a, 5a, and 7a with the dipole gen-
erated from isatin and N-methylglycine to construct spiro-
pyrrolidines. Best results were obtained when 3a, 5a, and
7a were treated with isatin and N-methylglycine without
catalyst in acetonitrile solvent for 10 hours at reflux, suc-
cessfully providing the desired spiropyrrolidine oxindole
compounds 11, 12, and 13, respectively, in 76–84% yields
showed a singlet for NCH3 protons at d = 2.44 ppm. The
benzylic two Ha protons appeared as two doublets at d =
2.53 and 2.62 ppm. One of the Hb proton and one of the Hc
proton appeared as multiplet in the region of d = 2.75–
2.86 ppm. One of the Hb proton appeared as doublet at
d = 3.60 ppm, and one of the Hc proton showed a triplet at
d = 3.26 ppm. The Hd proton appeared as a triplet at d =
4.07 ppm. The aromatic protons appeared as a multiplet in
the region of d = 6.91–7.52 ppm.
1
(Scheme 5, Table 5). The H NMR spectrum of com-
pound 11 showed a singlet for NCH3 protons at d = 2.19
ppm. The benzylic two Ha protons appeared as two dou-
blets at d = 3.47 and 3.61 ppm. Two triplets were observed
at d = 3.69 and 3.93 ppm for two Hb protons. The Hc pro-
ton showed a triplet at d = 5.05 ppm. The aromatic protons
Encouraged by this result, we successfully converted 1,4-
dimethyl-2-[(E)-2-nitro-3-phenylallyl]benzene (5a) and
1-[(E)-2-nitro-3-phenylallyl]naphthalene (7a) into pyrro-
lidines 9 and 10 using HCHO and N-methyl glycine in
Synlett 2011, No. 9, 1296–1302 © Thieme Stuttgart · New York

LETTER
Friedel–Crafts Reaction of Baylis–Hillman Adducts Derived from Nitroolefins
1301
Table 5 Synthesis of 3-Spiropyrrolidine Compounds from Baylis–Hillman Adducts
Entry
Substrate
Producta
Yield (%)b,c
Me
N
O
O
O
NO2
H
NH
NH
NH
1
80
O2N
3a
11
Me
N
NO2
H
2
84
O2N
5a
12
Me
N
NO2
H
3
76
O2N
7a
13
a All reactions were carried out using 1 mmol of Friedel–Crafts products 3a, 5a, and 7a with N-methylglycine (1 mmol) and isatin (1 mmol) in
8 mL MeCN under reflux conditions for 10 h.
b All products gave satisfactory IR, 1H NMR, 13C NMR, and MS spectral data.
c Yields of the pure products 11–13 obtained after column chromatography (silica gel, 20% EtOAc in hexanes).
NO2
Ar
O
General Procedure for the Synthesis of (E)-(2-Nitroprop-1-ene-
1,3-diyl)dibenzene (3a)
Me
Hb
Hb
NH
O
N
H
3a, 5a, 7a
To a stirred solution of (E)-2-nitro-3-phenylprop-2-en-1-ol (1a,
0.36 g, 2 mmol) in CH2Cl2 (5 mL), benzene (0.5 mL) was added at
r.t. The reaction mixture was cooled to 0 °C and then a catalytic
amount of concd H2SO4 was added dropwise and the mixture stirred
at r.t. (ca. 0.5 h). After completion of reaction (TLC), the mixture
was poured into H2O, and the aqueous layer was extracted with
EtOAc (3 × 10 mL). The combined organic layers were washed
with brine (20 mL), dried (Na2SO4) and concentrated. The crude
product thus obtained was purified by column chromatography on
silica gel (Acme 100–200 mesh), using (2%, EtOAc–hexanes) to
provide the pure compound 3a in 75% (0.36 gm) yield as a yellow
oil.
N
HO
Me
+
MeCN
reflux, 10 h
Hc
Ha
NO2
Ar
H
N
Ha
O
11, 12, 13
Ar = Ph, p-xylene, naphthalene
O
Scheme 5
appeared as a multiplet in the region of d = 6.37–7.56
ppm.
In conclusion this methodology represents the first
Friedel–Crafts reaction of the Baylis–Hillman adducts de-
rived from nitroolefins with a variety of arenes, mediated
by concentrated H2SO4, providing a simple route for the
synthesis of (E)-2-nitro-1,3-diarylprop-1-enes and 1-[(E)-
2-nitro-3-arylallyl]naphthalenes. Further application of
these compounds has been demonstrated for the synthesis
of pyrrolidines and 3-spiropyrrolidines.
Experimental Procedure for the Synthesis of 3-Benzyl-1-meth-
yl-3-nitro-4-phenylpyrrolidine (8)
A mixture of (E)-(2-nitroprop-1-ene-1,3-diyl)dibenzene (3a, 1
mmol, 0.26 g), HCHO (6 mmol, 0.20 g), and N-methyl glycine (3
mmol, 0.2 g) in MeCN (8 mL) was heated to reflux for 10 h. After
the completion of the reaction (TLC), the reaction mixture was con-
centrated, and the resulting crude material was diluted with H2O (10
mL) and extracted with EtOAc (3 × 10 mL). The combined organic
layers were washed with brine (2 × 10 mL), dried (Na2SO4), fil-
tered, and the organic layer was concentrated and the residue puri-
fied by column chromatography on silica gel (Acme 100–200
mesh), using EtOAc–hexanes (1:9) to afford the title compound 8
as a colorless solid in 77% (0.23 g) yield.
Synlett 2011, No. 9, 1296–1302 © Thieme Stuttgart · New York

1302
M. Bakthadoss, N. Sivakumar
LETTER
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A mixture of (E)-(2-nitroprop-1-ene-1,3-diyl)dibenzene (3a, 1
mmol, 0.26 g), isatin (1 mmol, 0.2 g), and N-methyl glycine (1
mmol, 0.13 g) in MeCN (8 mL) was heated to reflux for 10 h. After
completion of reaction (TLC), the reaction mixture was concentrat-
ed, and the resulting crude material was diluted with H2O (20 mL)
and extracted with EtOAc (3 × 10 mL). The combined organic lay-
ers were washed with brine (3 × 10 mL), dried (Na2SO4), filtered,
concentrated and purified by column chromatography on silica gel
(Acme 100–200 mesh), using EtOAc–hexanes (2:8) to provide 11
as a colorless solid in 80% (0.33 g) yield.
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(E)-(2-Nitroprop-1-ene-1,3-diyl)dibenzene (3a)
Yield 75%. IR (KBr): 1645, 1575, 1505, 1318 cm–1. 1H NMR (300
MHz, CDCl3): d = 4.25 (s, 2 H), 7.19–7.43 (m, 10 H), 8.29 (s, 1 H).
13C NMR (75 MHz, CDCl3): d = 32.99, 127.03, 127.69, 128.98,
129.17, 129.72, 130.47, 132.05, 135.51, 136.28, 149.70. MS:
m/z = 239 [M+]. Anal. Calcd for C15H13NO2: C, 75.30; H, 5.48; N,
5.85. Found: C, 75.25; H, 5.41; N, 5.91.
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3-Benzyl-1-methyl-3-nitro-4-phenylpyrrolidine (8)
Mp 82–84 °C. Yield 77%. IR (KBr): 1623, 1537, 1312 cm–1. H
1
NMR (300 MHz, CDCl3): d = 2.44 (s, 3 H), 2.53 (d, J = 14.4 Hz, 1
H), 2.62 (d, J = 11 Hz, 1 H), 2.75–2.86 (m, 2 H), 3.26 (t, J = 9.7 Hz,
1 H), 3.60 (d, J = 11.7 Hz, 1 H), 4.07 (t, J = 8.1 Hz, 1 H), 6.91–7.52
(m, 10 H). 13C NMR (75 MHz, CDCl3): d = 41.98, 42.73, 54.60,
61.35, 62.99, 100.49, 127.49, 127.93, 128.56, 128.66, 129.14,
129.71, 134.73, 136.93. MS: m/z = 296 [M+]. Anal. Calcd for
C18H20N2O2: C, 72.95; H, 6.80; N, 9.45. Found: C, 72.97; H, 6.85;
N, 9.49.
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Synlett 2009, 1014. (d) Bakthadoss, M.; Sivakumar, N.;
Sivakumar, G.; Murugan, G. Tetrahedron Lett. 2008, 49,
820. (e) Bakthadoss, M.; Murugan, G. Synth. Commun.
2008, 38, 3406. (f) Bakthadoss, M.; Murugan, G. Synth.
Commun. 2009, 39, 1290.
Mp 180–182 °C. Yield 80%. IR (KBr): 3268, 1648, 1525, 1342 cm–
1. 1H NMR (300 MHz, CDCl3): d = 2.19 (s, 3 H), 3.47 (d, J = 15.9
Hz, 1 H), 3.61 (d, J = 15.9 Hz, 1 H), 3.69 (t, J = 9.0 Hz, 1 H), 3.93
(t, J = 9.0 Hz, 1 H), 5.05 (t, J = 8.7 Hz, 1 H), 6.37–7.56 (m, 15 H).
13C NMR (75 MHz, CDCl3): d = 35.23, 37.43, 50.27, 59.52, 79.59,
107.11, 109.70, 123.50, 125.22, 125.63, 125.91, 127.46, 127.52,
128.30, 129.49, 130.41, 131.01, 134.23, 137.47, 140.94, 175.77.
MS: m/z = 413 [M+]. Anal. Calcd for C25H23N3O3: C, 72.62; H,
5.61; N, 10.16. Found: C, 72.58; H, 5.67; N, 10.10.
Acknowledgment
We thank CSIR and UGC (New Delhi) for the financial support. We
also thank DST-FIST for the NMR facility. N.S. thanks CSIR for
his SRF fellowship.
References and Notes
(1) (a) Drewes, S. E.; Roos, G. H. P. Tetrahedron 1988, 44,
4653. (b) Basavaiah, D.; Rao, P. D.; Hyma, R. S.
Tetrahedron 1996, 52, 8001.
(25) Rastogi, N.; Namboothiri, I. N. N.; Cojocaru, M.
(2) (a) Basavaiah, D.; Reddy, B. S.; Badsara, B. S. Chem. Rev.
2010, 110, 5447. (b) Basavaiah, D.; Venkateswara Rao, K.;
Reddy, R. J. Chem. Soc. Rev. 2007, 36, 1581.
(c) Basavaiah, D.; Rao, A. J.; Satyanarayana, T. Chem. Rev.
2003, 103, 811.
Tetrahedron Lett. 2004, 45, 4745.
Synlett 2011, No. 9, 1296–1302 © Thieme Stuttgart · New York