Highly regio- and stereoselective synthesis of tetracyclic indolenoisoxazolidines via intramolecular 1,3-dipolar nitrone cycloadditions

Article abstract of DOI:10.1055/s-0032-1317928

A facile method for the simple synthesis of tetracyclic indoloisoxazolidine frameworks from Baylis-Hillman derivatives through formation of nitrones in situ followed by an intramolecular [3+2]-dipolar cycloaddition reaction sequence is described. High regio- and stereoselectivity, excellent yields, together with the creation of two rings and three contiguous stereogenic centers including one all carbon quaternary center, are the salient features of the present method. Georg Thieme Verlag Stuttgart New York.

Full text of DOI:10.1055/s-0032-1317928

PAPER
▌237
pHapiegr hly Regio- and Stereoselective Synthesis of Tetracyclic Indoleno-
isoxazolidines via Intramolecular 1,3-Dipolar Nitrone Cycloadditions
Synthesis of Tetracyclic Indolenoisoxazolidines
Manickam Bakthadoss,*a,b Govindan Sivakumar,a Duddu S. Sharadac
a
Department of Organic Chemistry, University of Madras, Guindy Campus, Chennai, 600 025, India
Fax +91(44)22352494; E-mail: bhakthadoss@yahoo.com
b
Department of Chemistry, Pondicherry University, Pondicherry 605 014, India
c
Department of Chemistry, Indian Institute of Technology, Hyderabad 502 205, India
Received: 17.10.2012; Accepted after revision: 27.11.2012
NMe2
Abstract: A facile method for the simple synthesis of tetracyclic
OH
indoloisoxazolidine frameworks from Baylis–Hillman derivatives
NMe2
through formation of nitrones in situ followed by an intramolecular
[3+2]-dipolar cycloaddition reaction sequence is described. High
N
N
regio- and stereoselectivity, excellent yields, together with the cre-
ation of two rings and three contiguous stereogenic centers includ-
ing one all carbon quaternary center, are the salient features of the
present method.
OH
H
N
OH
NMe2
HO
Key words: fused-ring systems, indoles, 1,3-dipolar cycloaddition,
stereoselectivity, regioselectivity
OH
yuremamine
HO
flindrole C
NHMe
H
N
The 1,3-dipolar cycloaddition (1,3-DC) reaction has
emerged as a powerful tool in organic synthesis.1a–c The
isoxazolidines formed through 1,3-DC reactions are im-
portant intermediates in the preparation of natural prod-
ucts, such as alkaloids and α-amino acids.1d Up to three
contiguous stereocenters can be formed through 1,3-DC
reactions and the challenge of controlling the absolute and
relative stereochemistry has attracted much attention in
recent years.1e,f,2
O
HN
O
N
H
N
OH
H
OH
OH
NHMe
O
isoborreverine
(–)-isatisine A
O
O
CO2NH2
OMe
Due to the labile nature of the N–O bond under mild re-
ducing conditions, isoxazolidines provide easy access to a
variety of fascinating 1,3-difunctional amino alcohols.3
The intramolecular nitrone-olefin cycloaddition reaction
is one of the most powerful synthetic methods for the con-
struction of fused bi-, tri- or tetra-cyclic isoxazolidines of
either biological significance or as useful synthetic inter-
mediates for target molecules.4 In fact, certain fused isox-
azolines/isoxazoles with indoleno moieties are already
known for their antidepressant, antipsychotic, and anti-
anxiolytic activities.
N
H
H2N
N
NH
OAc
H
polyavolensin
mitomycin C
Figure 1 Representative examples of indolizidine-containing natu-
ral products
many natural products and biologically active mole-
cules.10
Representative examples of indolizidine-containing natu-
ral products4 such as yuremamine,5 mitomycin C,6
isatisine A,7 flindrole C and isoborreverine8 are shown in
Figure 1.
Since indole-fused isoxazoline/isoxazoles are well known
for their biological applications, we envisaged that the
bromo-derivative of Baylis–Hillman adducts could be ex-
ploited to access the skeletons mentioned above. To the
best of our knowledge, the Baylis–Hillman derivatives
have not been utilized for the synthesis of angularly sub-
stituted indole-fused isoxazoline derivatives through ni-
trone formation followed by intramolecular nitrone
cycloaddition. Therefore, we envisaged that Baylis–
Hillman derivatives would be suitable substrates for the
synthesis of complex angularly substituted tetracyclic in-
doloisoxazolidines by intramolecular 1,3-dipolar nitrone
cycloaddition.
The Baylis–Hillman reaction is one of the most important
carbon–carbon bond-forming reactions in the field of or-
ganic chemistry.9 The Baylis–Hillman adducts and their
derivatives are useful building blocks for the synthesis of
SYNTHESIS 2013, 45, 0237–0245
Advanced online publication: 13.12.2012
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
DOI: 10.1055/s-0032-1317928; Art ID: SS-2012-N0823-OP
© Georg Thieme Verlag Stuttgart · New York

238
M. Bakthadoss et al.
PAPER
Me
Me
Me
Me
N+
O–
H
Me
[3+2]
cycloaddition
nitrone
formation
CHO
N
N
N
N
CO2Me
O
CO2Me
MeO2C
6
H
4
5
formylation
Me
Me
N
H
O
N
2
CO2Me
N-alkylation
OMe
1
Br
3
Scheme 1 Retrosynthetic strategy for the synthesis of tetracyclic frameworks
In a continuation of our interest in the field of heterocyclic molecular 1,3-dipolar cycloaddition reaction according to
chemistry,11 herein we describe a novel protocol for the the retrosynthetic strategy shown in Scheme 1.
synthesis of angularly substituted fused tetracyclic indo-
loisoxazolidines frameworks by using Baylis–Hillman
derivatives through formation of nitrone in situ followed
by an intramolecular [3+2]-dipolar cycloaddition reac-
To execute our idea, we first treated (Z)-methyl 2-(bromo-
methyl)-3-phenylacrylate (1a) with 3-methylindole (2) to
obtain N-allylated12 indole intermediate (3a). Further
formylation12 of 3a led to the corresponding aldehyde 4a
tion. Initially we planned to utilize (Z)-methyl 2-(bromo-
in excellent yield (94%). The catalyst-free reaction of 4a
methyl)-3-phenylacrylate11b (2) with 3-methyl indole (1)
with N-methylhydroxylamine hydrochloride in ethanol at
reflux temperature successfully provided the desired tet-
to generate the require N-allylated precursor (4) with a
view to obtaining the desired tetracyclic frame works 6
racyclic indoloisoxazolidine 6a in excellent yield (95%;
through tandem nitrone formation followed by an intra-
Scheme 2).
Me
Me
O
Me
CHO
TBAB
OMe
N
N
R1
POCl3, DMF
r.t., 4 h
+
CO2Me
CO2Me
N
50% NaOH
PhMe, r.t., 4 h
Br
H
2
1a–f
R1
R1
3a–f
4a–f
hydroxylamines
MeNHOH⋅HCl
PhNHOH
EtOH
reflux, 6 h
hydroxylamines
BnNHOH·HCl
Me
Me
R2
N+
R2
O–
H
[3+2]
cycloaddition
N
N
N
R1 = H, 4-Me, 4-i-Pr, 3-Cl, 4-Cl, 2,4-diCl
2 = Me, Ph, Bn
O
CO2Me
MeO2C
R1
H
R
R1
5a–j
91–98%
6a–j
Scheme 2
Synthesis 2013, 45, 237–245
© Georg Thieme Verlag Stuttgart · New York

PAPER
Synthesis of Tetracyclic Indolenoisoxazolidines
239
Table 1 Synthesis of Tetracyclic Frameworks 6a–j (continued)
Encouraged by this result, we synthesized a variety of in-
doloisoxazolidines 6b–j through application of the intra-
molecular 1,3-dipolar cycloaddition reaction. Treatment
of N-substituted 3-methylindole-2-carboxylaldehydes
4a–f with N-methylhydroxyl amine hydrochloride, N-
phenylhydroxylamine, or N-benzylhydroxylamine hydro-
chloride in ethanol at reflux temperature successfully pro-
vided the desired tetracyclic indoloisoxazolidines 6b–j in
excellent yields (91–98%; Scheme 2, Table 1).
Entry Substrate
Producta,b
Yield
(%)c
Me
Me
Me
H
CHO
N
N
N
CO2Me
O
5
94
MeO2C
H
Table 1 Synthesis of Tetracyclic Frameworks 6a–j
Entry Substrate
Producta,b
Yield
(%)c
Cl
Cl
6e
4d
Me
Me
Me
Me
Me
H
Bn
H
CHO
N
N
N
CHO
N
N
N
O
CO2Me
O
CO2Me
1
95
MeO2C
H
6
96
MeO2C
H
4a
6ad
4a
6f
Me
Me
Me
Me
Me
H
Bn
H
N
N
CHO
N
N
N
CHO
O
N
O
CO2Me
MeO2C
CO2Me
2
H
91
MeO2C
H
7
98
Me
Me
Me
Me
4b
4b
6b
6g
6h
6i
Me
Me
Me
Me
Me
H
Bn
H
N
N
CHO
N
N
N
CHO
O
N
O
CO2Me
MeO2C
CO2Me
H
3
93
MeO2C
H
8
97
i-Pr
Cl
i-Pr
Cl
4c
6c
4e
Me
Me
Me
Me
Ph
H
Bn
H
CHO
CO2Me
N
N
N
N
N
CHO
O
N
O
4
97
MeO2C
H
CO2Me
MeO2C
H
9
96
i-Pr
4a
6d
i-Pr
4c
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 237–245

240
M. Bakthadoss et al.
PAPER
Table 1 Synthesis of Tetracyclic Frameworks 6a–j (continued)
described above successfully provided the anticipated tet-
racyclic indoloisoxazolidines 11a–j in excellent yields
(92–97%; Scheme 3, Table 2).
Entry Substrate
Producta,b
Yield
(%)c
Table 2 Synthesis of Tetracyclic Frameworks 11a–j
Me
Me
Entry Substrate
Producta,b
Yield
(%)c
Bn
H
N
N
CHO
N
O
Me
CO2Me
MeO2C
Me
CN
10
94
H
Cl
H
Me
N
N
CHO
N
O
Cl
Cl
1
95
Cl
NC
H
4f
6j
a Reaction conditions: 4 (1 mmol), N-methylhydroxylamine hydro-
chloride/N-phenylhydroxylamine/N-benzylhydroxylamine hydro-
chloride (1.1 mmol), EtOH, reflux, 6 h.
9a
11ad
Me
b All compounds were fully characterized.
c Isolated yield of the pure product.
Me
H
Me
d The structure of the molecule was further confirmed by single-
crystal X-ray data.13
N
N
O
CHO
N
NC
H
2
96
It is worth mentioning that the highly stereoselective na-
ture of the reaction was clearly shown by 1H NMR spec-
troscopy and X-ray crystal analyses (Figure 2). The
crystal structure of 6a shows that the phenyl group and the
adjacent ester moiety adopt an anti orientation, which is
presumably due to the initial trans geometry of the phenyl
group and ester moiety present in the double bond at the
vicinal positions of compound 4a.
CN
OMe
OMe
9c
11b
Me
Me
H
Me
N
N
CHO
N
OMe
O
3
97
NC
H
OMe
CN
9d
11c
Me
Me
H
Ph
N
N
CHO
N
O
4
95
NC
H
CN
Me
9a
11d
Me
H
Ph
Figure 2 X-ray crystal structure of 6a
N
N
CHO
O
N
NC
After the successful synthesis of tetracyclic indoloisoxa-
zolidines possessing an ester moiety at the angular posi-
tion, we planned to synthesize indoloisoxazolidines
bearing a nitrile moiety at the angular position. Thus,
treatment of N-substituted 3-methylindole-2-carboxylal-
dehydes 8a–f with N-methylhydroxylamine hydrochlo-
ride/N-phenylhydroxylamine/N-benzylhydroxylamine
hydrochloride under similar reaction conditions to those
H
5
93
CN
Me
Me
9b
11e
Synthesis 2013, 45, 237–245
© Georg Thieme Verlag Stuttgart · New York

PAPER
Synthesis of Tetracyclic Indolenoisoxazolidines
241
Table 2 Synthesis of Tetracyclic Frameworks 11a–j (continued)
The relative stereochemistry of compound 11a was fur-
ther confirmed by X-ray crystallographic analysis (Figure
3). The X-ray crystal structure of compound 11a shows
that the phenyl group and adjacent nitrile moiety adopt a
syn orientation, which was presumably due to the initial
cis geometry of the phenyl group and nitrile moiety pres-
ent in the double bond at the vicinal positions of com-
pound 8a.
Entry Substrate
Producta,b
Yield
(%)c
Me
Me
H
Ph
N
N
CHO
N
OMe
O
6
97
NC
H
OMe
CN
9d
11f
Me
Me
H
Bn
N
N
CHO
N
O
7
92
NC
H
CN
9a
Figure 3 X-ray crystal structure of 11a
11g
Me
Me
H
Bn
It is important to mention here that the reaction is highly
regio- and diastereoselective, as evidenced by NMR spec-
tral data and X-ray crystal data analyses. The negative
charge generated on the oxygen atom in intermediates 5
and 10 (see Scheme 2 and Scheme 3) forms an intramo-
lecular bond with the electrophilic carbon at the β-position
of the α,β-unsaturated ester/cyano moiety in the same
molecule rather than forming a bond at the α-position.
Furthermore, if regioisomers 12 and 13 had been formed
(Figure 4), two doublets (vicinal coupling constants) cor-
responding to the Hx and Hy protons would be anticipated
N
N
O
CHO
N
NC
8
94
H
CN
Me
OMe
OMe
9c
11h
Me
H
Bn
1
in the H NMR spectrum. However, we did not observe
such patterns in the spectra of our compounds.
N
N
CHO
N
OMe
O
9
96
NC
H
OMe
Hy
Hx
Me
Hy
Hx
CN
Me
Me
Me
N
Ar
N
Ar
9d
O
O
N
11i
N
Me
CO2Me
CN
13
12
Me
H
Bn
N
N
Figure 4 Possible alternative regioisomers
O
CHO
N
NC
H
10
94
O
O
In conclusion, we have successfully developed a simple
protocol for the facile synthesis of complex angularly sub-
stituted tetracyclic frameworks containing an indoloisox-
azolidine ring system involving formation of a nitrone in
situ followed by an intramolecular 1,3-dipolar nitrone cy-
cloaddition reaction using Baylis–Hillman derivatives. It
is important to mention here that all the indoloisoxazoli-
dines were synthesized under catalyst-free conditions.
The new [3+2]-cycloaddition reaction leads to a novel
class of angularly substituted fused tetracyclic indoloisox-
azolidines, creating two rings, three contiguous stereocen-
ters, one being an all-carbon quaternary center, in a
CN
O
O
9f
11j
a Reaction conditions: 9 (1 mmol), N-methylhydroxylamine hydro-
chloride/N-phenylhydroxylamine/N-benzylhydroxylamine hydro-
chloride (1.1 mmol), EtOH, reflux, 6 h
b All compounds were fully characterized.
c Isolated yield of the pure product.
d The structure of the molecule was further confirmed by single-
crystal X-ray data.13
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 237–245

242
M. Bakthadoss et al.
PAPER
Me
CN
Me
Me
POCl3
DMF
CHO
TBAB
N
Br
R
+
r.t., 4 h
CN
50% NaOH
PhMe, r.t., 4 h
N
N
H
R
7a–f
2
R
9a–f
CN
8a–f
EtOH
reflux, 6 h
hydroxylamines
hydroxylamines
MeNHOH⋅HCl
PhNHOH
BnNHOH⋅HCl
R1
Me
Me
N
O
[3+2]
cycloaddition
R1
H
N
R = H, 4-Me, 4-Et, 4-i-Pr, 3-Cl, 2,4-diCl
N
N
O
R1 = Me, Ph, Bn
R
CN
10a–j
NC
H
R
11a–j
Scheme 3
MS: m/z = 363 [M + 1]+.
unique fashion. Angularly substituted tricyclic com-
pounds were obtained in a highly regio- and stereoselec-
tive fashion with excellent yields.
Anal. Calcd for C22H22N2O3: C, 72.91; H, 6.12; N, 7.73. Found: C,
73.19; H, 6.47; N, 7.98.
Methyl 8,11-Dimethyl-13-(4-methylphenyl)-12-oxa-1,11-diaza-
tetracyclo[7.6.0.02,7.010,14]pentadeca-2(7),3,5,8-tetraene-14-car-
boxylate (6b)
All reagents were purchased from commercial sources and used
without further purification. Solvents were distilled prior to use.
Column chromatography was performed on silica gel. IR spectra
were recorded with an FTIR-8300 Shimadzu spectrometer. 1H (300
MHz) and 13C (75 MHz) NMR spectra were recorded with a Bruker
spectrometer using CDCl3 as solvent and TMS as internal standard.
MS were recorded with a Jeol-JMS-DX 303 HF mass spectrometer.
Elemental analyses were recorded with a Perkin–Elmer 240C-CHN
analyzer. Melting points are uncorrected. Thin-layer chromatogra-
phy (TLC) was performed using glass plates coated with silica gel
(ACME, 254F). Spots were visualized using iodine vapor and a UV
lamp.
Yield: 0.342 g (91%); white solid; mp 201–203 °C.
IR (KBr): 1728, 1625, 1516, 1221 cm–1.
1H NMR (300 MHz): δ = 2.35 (s, 3 H), 2.36 (s, 3 H), 3.03 (s, 3 H),
3.82 (d, J = 11.1 Hz, 1 H), 3.87 (s, 3 H), 4.07 (d, J = 11.1 Hz, 1 H),
5.16 (s, 1 H), 5.83 (s, 1 H), 7.03–7.56 (m, 8 H).
13C NMR (75 MHz): δ = 9.25, 21.22, 43.99, 47.47, 53.24, 72.59,
72.65, 83.57, 109.62, 119.03, 119.15, 119.24, 121.30, 126.18,
126.61, 129.27, 129.57, 132.30, 133.30, 138.27, 173.16.
MS: m/z = 377 [M + 1]+.
Anal. Calcd for C23H24N2O3: C, 73.38; H, 6.43; N, 7.44. Found: C,
73.59; H, 6.55; N, 7.86.
Methyl 8,11-Dimethyl-13-phenyl-12-oxa-1,11-diazatetracyc-
lo[7.6.0.02,7.010,14]pentadeca-2(7),3,5,8-tetraene-14-carboxylate
(6a); Typical Procedure
Methyl 8,11-Dimethyl-13-[4-(propan-2-yl)phenyl]-12-oxa-1,11-
diazatetracyclo[7.6.0.02,7.010,14]pentadeca-2(7),3,5,8-tetraene-
14-carboxylate (6c)
A mixture of 4a (1 mmol) and N-methylhydroxylamine hydrochlo-
ride (1.1 mmol) and EtOH (5 mL) were placed in a round-bottom
flask and heated at reflux for 6 h. After completion of the reaction,
as indicated by TLC, the reaction mixture was concentrated under
reduced pressure, H2O (10 mL) was added and the mixture was ex-
tracted with EtOAc (20 mL). The organic layer washed with brine
(10 mL) and concentrated. The crude product was purified by col-
umn chromatography (EtOAc–hexane, 10%) to provide the desired
pure product 6a.
Yield: 0.375 g (93%); white solid; mp 209–211 °C.
IR (KBr): 1727, 1621, 1523, 1220 cm–1.
1H NMR (300 MHz): δ = 1.24 (d, J = 6.9 Hz, 6 H), 2.36 (s, 3 H),
2.83–3.04 (m, 4 H), 3.88–4.16 (m, 5 H), 5.16 (s, 1 H), 5.84 (s, 1 H),
7.04–7.56 (m, 8 H).
13C NMR (75 MHz): δ = 9.02, 23.90, 23.96, 33.87, 38.76, 47.47,
53.22, 72.63, 77.24, 109.62, 119.01, 119.24, 119.85, 121.26,
124.10, 126.64, 126.69, 127.73, 132.59, 133.31, 149.24, 173.12.
Yield: 0.344 g (95%); white solid; mp 195–197 °C.
IR (KBr): 1729, 1625, 1519, 1217 cm–1.
1H NMR (300 MHz): δ = 2.37 (s, 3 H), 3.03 (s, 3 H), 3.78 (d,
J = 10.5 Hz, 1 H), 3.88 (s, 3 H), 4.07 (d, J = 10.8 Hz, 1 H), 5.16 (s,
1 H), 5.88 (s, 1 H), 7.01–7.56 (m, 9 H).
13C NMR (75 MHz): δ = 9.69, 42.02, 56.73, 52.34, 71.30, 72.21,
83.39, 109.43, 110.56, 118.72, 118.89, 121.38, 121.63, 124.54,
127.09, 128.90, 129.34, 134.42, 136.45, 173.26.
MS: m/z 405 [M + 1]+.
Anal. Calcd for C25H28N2O3: C, 74.23; H, 6.98; N, 6.93. Found: C,
73.95; H, 6.91; N, 7.01.
Synthesis 2013, 45, 237–245
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Synthesis of Tetracyclic Indolenoisoxazolidines
243
Methyl 8-Methyl-11,13-diphenyl-12-oxa-1,11-diazatetracyc-
lo[7.6.0.02,7.010,14]pentadeca-2(7),3,5,8-tetraene-14-carboxylate
(6d)
Methyl 11-Benzyl-13-(4-chlorophenyl)-8-methyl-12-oxa-1,11-
diazatetracyclo[7.6.0.02,7.010,14]pentadeca-2(7),3,5,8-tetraene-
14-carboxylate (6h)
Yield: 0.411 g (97%); white solid; mp 199–201 °C.
Yield: 0.459 g (97%); white solid; mp 202–204 °C.
IR (KBr): 1727, 1628, 1514, 1216 cm–1.
IR (KBr): 1725, 1628, 1516, 1219 cm–1.
1H NMR (300 MHz): δ = 2.39 (s, 3 H), 3.71 (s, 3 H), 3.91 (d, J =
10.8 Hz, 1 H), 4.17 (d, J = 11.1 Hz, 1 H), 5.73 (s, 1 H), 5.99 (s,
1 H), 7.02–7.59 (m, 14 H).
1H NMR (300 MHz): δ = 2.08 (s, 3 H), 3.72 (d, J = 11.1 Hz, 1 H),
3.93 (s, 3 H), 4.06 (d, J = 11.1 Hz, 1 H), 4.36 (dd, J = 12, 26.4 Hz,
2 H), 5.32 (s, 1 H), 5.94 (s, 1 H), 6.95–7.56 (m, 13 H).
13C NMR (75 MHz): δ = 8.57, 47.30, 53.17, 72.72, 73.13, 84.61,
109.56, 114.56, 119.15, 119.39, 121.36, 122.50, 126.80, 128.68,
128.79, 129.34, 132.36, 133.49, 134.36, 136.98, 149.65, 172.27.
13C NMR (75 MHz): δ = 8.30, 47.59, 53.42, 60.22, 71.34, 72.15,
83.84, 104.36, 109.41, 119.07, 119.26, 121.27, 127.92, 127.98,
128.27, 128.64, 128.82, 129.79, 132.25, 133.50, 133.77, 134.52,
136.30, 173.16.
MS: m/z = 425 [M + 1]+.
MS: m/z = 474 [M + 1]+.
Anal. Calcd for C27H24N2O3: C, 76.39; H, 5.70; N, 6.60. Found: C,
76.47; H, 5.82; N, 6.52.
Anal. Calcd for C28H25ClN2O3: C, 71.10; H, 5.33; N, 5.92. Found:
C, 71.03; H, 5.44; N, 5.86.
Methyl 13-(3-Chlorophenyl)-8-methyl-11-phenyl-12-oxa-1,11-
diazatetracyclo[7.6.0.02,7.010,14]pentadeca-2(7),3,5,8-tetraene-
14-carboxylate (6e)
Yield: 0.373 g (94%); white solid; mp 117–119 °C.
IR (KBr): 1724, 1629, 1523, 1216 cm–1.
1H NMR (300 MHz): δ = 2.37 (s, 3 H), 3.03 (s, 3 H), 3.78 (d,
J = 10.8 Hz, 1 H), 3.88 (s, 3 H), 4.07 (d, J = 11.1 Hz, 1 H), 5.16 (s,
1 H), 5.87 (s, 1 H), 7.01–7.56 (m, 8 H).
13C NMR (75 MHz): δ = 8.34, 41.82, 47.17, 52.30, 71.32, 72.21,
82.27, 120.33, 121.06, 126.22, 126.94, 127.14, 127.28, 128.80,
130.49, 130.83, 131.40, 131.76, 133.70, 134.65, 137.20, 173.26.
Methyl 11-Benzyl-13-[4-(propane-2-yl)phenyl]-8-methyl-12-
oxa-1,11-diazatetracyclo[7.6.0.02,7.010,14]pentadeca-2(7),3,5,8-
tetraene-14-carboxylate (6i)
Yield: 0.461 g (96%); white solid; mp 212–214 °C.
IR (KBr): 1731, 1629, 1516, 1220 cm–1.
1H NMR (300 MHz): δ = 1.17 (d, J = 6.9 Hz, 6 H), 1.97 (s, 3 H),
2.81 (sept, J = 6.9 Hz, 1 H), 3.77 (d, J = 10.8 Hz, 1 H), 3.86 (s,
3 H), 4.02 (d, J = 10.8 Hz, 1 H), 4.32 (dd, J = 11.4, 16.2 Hz, 2 H),
5.23 (s, 1 H), 5.89 (s, 1 H), 6.89–7.48 (m, 13 H).
13C NMR (75 MHz): δ = 6.69, 22.33, 22.38, 22.31, 45.81, 51.74,
69.90, 70.82, 83.04, 102.44, 107.86, 117.29, 117.64, 119.45,
125.09, 125.26, 126.32, 127.04, 127.25, 128.37, 130.69, 131.91,
134.89, 136.00, 147.82, 171.82.
MS: m/z = 398 [M + 2]+.
Anal. Calcd for C22H21ClN2O3: C, 66.58; H, 5.33; N, 7.06. Found:
C, 66.69; H, 5.27; N, 7.15.
MS: m/z = 481 [M + 1]+.
Methyl 11-Benzyl-13-phenyl-8-methyl-12-oxa-1,11-diazatetra-
cyclo[7.6.0.02,7.010,14]pentadeca-2(7),3,5,8-tetraene-14-carboxyl-
ate (6f)
Anal. Calcd for C31H32N2O3: C, 77.47; H, 6.71; N, 5.83. Found: C,
77.59; H, 6.62; N, 5.95.
Yield: 0.420 g (96%); white solid; mp 202–204 °C.
Methyl 11-Benzyl-13-(2,4-dichlorophenyl)-8-methyl-12-oxa-
1,11-diazatetracyclo[7.6.0.02,7.010,14]pentadeca-2(7),3,5,8-tet-
raene-14-carboxylate (6j)
Yield: 0.477 g (94%); white solid; mp 195–197 °C.
IR (KBr): 1729, 1625, 1519, 1217 cm–1.
1H NMR (300 MHz): δ = 2.17 (s, 3 H), 3.66 (d, J = 11.1 Hz, 1 H),
3.90 (s, 3 H), 4.22–4.58 (m, 3 H), 5.16 (s, 1 H), 6.20 (s, 1 H), 6.99–
7.56 (m, 12 H).
13C NMR (75 MHz): δ = 8.45, 46.68, 53.39, 60.06, 72.32, 73.10,
82.52, 104.43, 109.45, 119.04, 119.30, 121.40, 127.47, 127.94,
128.58, 128.81, 129.27, 129.87, 132.37, 132.49, 132.93, 133.25,
134.91, 136.12, 136.44, 172.80.
IR (KBr): 1727, 1622, 1512, 1223 cm–1.
1H NMR (300 MHz): δ = 2.06 (s, 3 H), 3.78 (d, J = 11.1 Hz, 1 H),
3.94 (s, 3 H), 4.07 (d, J = 10.8 Hz, 1 H), 4.39 (dd, J = 12.3, 19.5 Hz,
2 H), 5.31 (s, 1 H), 5.99 (s, 1 H), 6.94–7.58 (m, 14 H).
13C NMR (75 MHz): δ = 8.30, 47.43, 53.35, 60.29, 71.45, 72.36,
84.55, 104.10, 109.40, 118.91, 119.22, 121.09, 126.82, 127.92,
128.61, 129.90, 132.24, 133.48, 135.15, 136.38, 136.43, 137.43,
173.33.
MS: m/z = 439 [M + 1]+.
Anal. Calcd for C28H26N2O3: C, 76.69; H, 5.98; N, 6.39. Found: C,
76.58; H, 5.83; N, 6.76.
MS: m/z = 508 [M + 1]+.
Methyl 11-Benzyl-13-(4-methylphenyl)-8-methyl-12-oxa-1,11-
diazatetracyclo[7.6.0.02,7.010,14]pentadeca-2(7),3,5,8-tetraene-
14-carboxylate (6g)
Anal. Calcd for C28H24Cl2N2O3: C, 66.28; H, 4.77; N, 5.52. Found:
C, 66.19; H, 4.47; N, 5.98.
Yield: 0.443 g (98%); white solid; mp 198–200 °C.
8,11-Dimethyl-13-phenyl-12-oxa-1,11-diazatetracyc-
lo[7.6.0.02,7.010,14]pentadeca-2(7),3,5,8-tetraene-14-carbonitrile
(11a)
Yield: 0.313 g (95%); white solid; mp 185–187 °C.
IR (KBr): 2214, 1629, 1514, 1217 cm–1.
1H NMR (300 MHz): δ = 2.36 (s, 3 H), 3.09 (s, 3 H), 4.44 (d,
J = 10.8 Hz, 1 H), 4.62 (d, J = 10.5 Hz, 1 H), 4.73 (s, 1 H), 5.23 (s,
1 H), 7.13–7.58 (m, 9 H).
13C NMR (75 MHz): δ = 9.17, 44.44, 51.74, 63.48, 87.23, 106.26,
109.63, 119.14, 119.79, 119.84, 122.65, 126.80, 128.89, 129.76,
132.79, 133.20, 133.55, 134.11.
IR (KBr): 1732, 1627, 1518, 1219 cm–1.
1H NMR (300 MHz): δ = 2.04 (s, 3 H), 2.34 (s, 3 H), 3.82 (d,
J = 11.1 Hz, 1 H), 3.92 (s, 3 H), 4.07 (d, J = 11.1 Hz, 1 H), 4.39 (dd,
J = 12, 17.1 Hz, 2 H), 5.30 (s, 1 H), 5.95 (s, 1 H), 6.96–7.58 (m,
13 H).
13C NMR (75 MHz): δ = 8.24, 21.24, 47.40, 53.32, 60.25, 71.37,
72.33, 84.65, 103.96, 109.43, 118.88, 119.21, 121.04, 126.78,
127.91, 128.62, 129.29, 129.94, 131.97, 132.26, 133.49, 136.46,
137.58, 138.45, 173.40.
MS: m/z = 454 [M + 1]+.
MS: m/z = 330 [M + 1]+.
Anal. Calcd for C29H28N2O3: C, 76.97; H, 6.24; N, 6.19. Found: C,
76.77; H, 6.18; N, 6.59.
Anal. Calcd for C21H19N3O: C, 76.57; H, 5.81; N, 12.76. Found: C,
76.92; H, 5.66; N, 12.45.
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 237–245

244
M. Bakthadoss et al.
PAPER
13-(4-Methoxyphenyl)-8,11-dimethyl-12-oxa-1,11-diazatetra-
cyclo[7.6.0.02,7.010,14]pentadeca-2(7),3,5,8-tetraene-14-carboni-
trile (11b)
13-(2-Methoxyphenyl)-8-methyl-11-phenyl-12-oxa-1,11-diaza-
tetracyclo[7.6.0.02,7.010,14]pentadeca-2(7),3,5,8-tetraene-14-car-
bonitrile (11f)
Yield: 0.345 g (96%); white solid; mp 213–215 °C.
Yield: 0.408 g (97%); white solid; mp 201–203 °C.
IR (KBr): 2217, 1626, 1514, 1221 cm–1.
IR (KBr): 2215, 1625, 1518, 1217 cm–1.
1H NMR (300 MHz): δ = 2.37 (s, 3 H), 3.03 (s, 3 H), 3.97 (s, 3 H),
4.50 (s, 1 H), 4.58 (d, J = 10.8 Hz, 2 H), 5.48 (s, 1 H), 6.97–7.58 (m,
8 H).
1H NMR (300 MHz): δ = 2.18 (s, 3 H), 3.97 (d, J = 10.8 Hz, 1 H),
4.06 (s, 3 H), 4.21 (d, J = 11.1 Hz, 1 H), 5.43 (s, 1 H), 6.09 (s, 1 H),
7.12–7.71 (m, 13 H).
13C NMR (75 MHz): δ = 8.20, 42.42, 52.82, 54.43, 63.23, 76.19,
82.45, 105.14, 108.51, 109.22, 118.49, 118.69, 120.04, 121.48,
122.76, 124.81, 128.81, 131.73, 132.22, 154.63.
13C NMR (75 MHz): δ = 9.67, 52.27, 59.49, 73.33, 83.61, 105.30,
109.45, 118.68, 118.82, 118.87, 119.10, 121.34, 121.86, 124.42,
126.73, 127.21, 128.43, 128.77, 129.60, 136.60, 144.08, 146.21.
MS: m/z = 360 [M + 1]+.
MS: m/z = 422 [M + 1]+.
Anal. Calcd for C22H21N3O2: C, 73.52; H, 5.89; N, 11.69. Found: C,
73.61; H, 5.79; N, 11.75.
Anal. Calcd for C27H23N3O2: C, 76.94; H, 5.50; N, 9.97. Found: C,
76.79; H, 5.88; N, 9.69.
13-(2-Methoxyphenyl)-8,11-dimethyl-12-oxa-1,11-diazatetra-
cyclo[7.6.0.02,7.010,14]pentadeca-2(7),3,5,8-tetraene-14-carboni-
trile (11c)
11-Benzyl-8-methyl-13-phenyl-12-oxa-1,11-diazatetracyc-
lo[7.6.0.02,7.010,14]pentadeca-2(7),3,5,8-tetraene-14-carbonitrile
(11g)
Yield: 0.348 g (97%); white solid; mp 179–181 °C.
Yield: 0.373 g (92%); white solid; mp 166–168 °C.
IR (KBr): 2218, 1631, 1522, 1215 cm–1.
IR (KBr): 2218, 1627, 1521, 1218 cm–1.
1H NMR (300 MHz): δ = 2.37 (s, 3 H), 3.03 (s, 3 H), 3.97 (s, 3 H),
4.50 (s, 1 H), 4.58 (d, J = 10.8 Hz, 1 H), 4.80 (d, J = 10.8 Hz, 1 H),
5.48 (s, 1 H), 6.97–7.58 (m, 8 H).
13C NMR (75 MHz): δ = 9.23, 53.85, 55.13, 55.46, 57.61, 64.26,
83.47, 109.55, 109.89, 110.25, 119.52, 119.71, 121.07, 121.87,
122.51, 123.79, 125.84, 129.83, 132.76, 132.87, 133.24, 155.66.
1H NMR (300 MHz): δ = 2.33 (s, 3 H), 4.33–4.65 (m, 4 H), 5.08 (s,
1 H), 5.17 (s, 1 H), 7.17–7.59 (m, 14 H).
13C NMR (75 MHz): δ = 9.07, 51.09, 61.77, 62.17, 74.20, 86.97,
106.32, 109.57, 118.96, 119.75, 119.83, 122.58, 126.88, 127.87,
128.50, 128.81, 129.24, 129.72, 132.74, 133.27, 133.54, 134.48,
136.09.
MS: m/z = 360 [M + 1]+.
MS: m/z = 406 [M + 1]+.
Anal. Calcd for C22H21N3O2: C, 73.52; H, 5.89; N, 11.69. Found: C,
73.41; H, 5.97; N, 11.58.
Anal. Calcd for C27H23N3O: C, 79.97; H, 5.72; N, 10.36. Found: C,
80.17; H, 5.82; N, 10.52.
8-Methyl-11,13-diphenyl-12-oxa-1,11-diazatetracyc-
lo[7.6.0.02,7.010,14]pentadeca-2(7),3,5,8-tetraene-14-carbonitrile
(11d)
11-Benzyl-13-(4-methoxyphenyl)-8-methyl-12-oxa-1,11-diaza-
tetracyclo[7.6.0.02,7.010,14]pentadeca-2(7),3,5,8-tetraene-14-car-
bonitrile (11h)
Yield: 0.371 g (95%); white solid; mp 185–187 °C.
Yield: 0.409 g (94%); white solid; mp 171–173 °C.
IR (KBr): 2218, 1627, 1521, 1219 cm–1.
IR (KBr): 2218, 1617, 1518, 1215 cm–1.
1H NMR (300 MHz): δ = 2.05 (s, 3 H), 3.83 (d, J = 10.8 Hz, 1 H),
4.08 (d, J = 11.1 Hz, 1 H), 5.30 (s, 1 H), 5.96 (s, 1 H), 6.96–7.58 (m,
14 H).
1H NMR (300 MHz): δ = 1.99 (s, 3 H), 3.60 (d, J = 14.1 Hz, 1 H),
3.77–3.83 (m, 6 H), 4.39 (d, J = 11.7 Hz, 2 H), 7.59–8.64 (m,
13 H).
13C NMR (75 MHz): δ = 9.57, 42.30, 52.31, 58.59, 72.44, 85.40,
105.30, 109.48, 110.46, 118.49, 118.69, 121.15, 124.64, 125.25,
125.32, 126.52, 126.72, 126.84, 128.70, 129.61, 130.62, 131.42,
131.70, 133.55, 136.32, 141.76.
13C NMR (75 MHz): δ = 7.24, 28.68, 53.76, 54.29, 57.35, 57.48,
60.02, 83.17, 107.83, 108.38, 113.07, 118.37, 119.01, 121.92,
126.39, 126.83, 127.26, 127.37, 127.53, 128.29, 129.31, 129.53,
134.69, 135.42, 158.80.
MS: m/z = 392 [M + 1]+.
MS: m/z = 436 [M + 1]+.
Anal. Calcd for C26H21N3O: C, 79.77; H, 5.41; N, 10.73. Found: C,
79.85; H, 5.30; N, 10.82.
Anal. Calcd for C28H25N3O2: C, 77.22; H, 5.79; N, 9.65. Found: C,
77.66; H, 5.89; N, 9.87.
8,11-Dimethyl-13-(4-methylphenyl)-12-oxa-1,11-diazatetracyc-
lo[7.6.0.02,7.010,14]pentadeca-2(7),3,5,8-tetraene-14-carbonitrile
(11e)
11-Benzyl-13-(2-methoxyphenyl)-8-methyl-12-oxa-1,11-diaza-
tetracyclo[7.6.0.02,7.010,14]pentadeca-2(7),3,5,8-tetraene-14-car-
bonitrile (11i)
Yield: 0.377 g (93%); white solid; mp 206–208 °C.
Yield: 0.418 g (96%); white solid; mp 167–169 °C.
IR (KBr): 2215, 1625, 1518, 1217 cm–1.
IR (KBr): 2223, 1625, 1517, 1221 cm–1.
1H NMR (300 MHz): δ = 2.36 (s, 3 H), 2.39 (s, 3 H), 4.01 (d, J =
11.1 Hz, 1 H), 4.10 (d, J = 10.8 Hz, 1 H), 5.62 (s, 1 H), 6.05 (s, 1 H),
7.02–7.59 (m, 13 H).
1H NMR (300 MHz): δ = 2.07 (s, 3 H), 3.68 (d, J = 14.1 Hz, 1 H),
3.82–3.87 (m, 4 H), 4.51 (d, J = 11.7 Hz, 1 H), 4.56 (s, 1 H), 4.67–
4.71 (m, 2 H), 6.94–8.20 (m, 13 H).
13C NMR (75 MHz): δ = 8.49, 21.29, 48.73, 58.41, 73.89, 85.78,
105.54, 109.60, 114.87, 119.72, 120.17, 122.07, 123.56, 126.44,
129.13, 129.71, 129.79, 132.42, 133.63, 135.20, 139.67, 148.36.
13C NMR (75 MHz): δ = 8.29, 50.58, 54.98, 55.42, 58.48, 60.12,
84.45, 108.86, 109.15, 115.63, 119.37, 119.96, 120.95, 122.83,
123.89, 127.37, 128.30, 128.38, 129.64, 130.84, 135.76, 136.55,
156.80.
MS: m/z = 406 [M + 1]+.
MS: m/z = 436 [M + 1]+.
Anal. Calcd for C27H23N3O: C, 79.97; H, 5.72; N, 10.36. Found: C,
79.85; H, 5.63; N, 10.22.
Anal. Calcd for C28H25N3O2: C, 77.22; H, 5.79; N, 9.65. Found: C,
77.45; H, 5.87; N, 9.78.
Synthesis 2013, 45, 237–245
© Georg Thieme Verlag Stuttgart · New York

PAPER
Synthesis of Tetracyclic Indolenoisoxazolidines
245
13-(2H-1,3-Benzodioxol-4-yl)-11-benzyl-8-methyl-12-oxa-1,11-
diazatetracyclo[7.6.0.02,7.010,14]pentadeca-2(7),3,5,8-tetraene-
14-carbonitrile (11j)
(4) (a) Nair, V.; Suja, T. D. Tetrahedron 2007, 63, 12247.
(b) Jeong, J. H.; Weinreb, S. M. Org. Lett. 2006, 8, 2309.
(c) Tamura, O.; Iyama, N.; Ishibashi, H. J. Org. Chem. 2004,
69, 1475. (d) Dhavale, D. D.; Jachak, S. M.; Karche, N. P.;
Trombini, C. Tetrahedron 2004, 60, 3009. (e) White, J. D.;
Hansen, J. D. J. Am. Chem. Soc. 2002, 124, 4950.
(f) Gribble, G. W.; Barden, T. C. J. Org. Chem. 1985, 50,
5900. (g) Enders, D.; Wang, C.; Yang, X.; Raabe, G. Synlett
2011, 469.
Yield: 0.422 g (94%); white solid; mp 179–181 °C.
IR (KBr): 2220, 1619, 1515, 1218 cm–1.
1H NMR (300 MHz): δ = 2.32 (s, 3 H), 4.32 (d, J = 13.8 Hz, 1 H),
4.46 (dd, J = 10.8, 13.2 Hz, 2 H), 4.59 (d, J = 10.8 Hz, 1 H), 5.05 (s,
1 H), 5.08 (s, 1 H), 6.01 (s, 2 H), 6.83–7.58 (m, 12 H).
13C NMR (75 MHz): δ = 9.04, 51.15, 58.41, 61.78, 62.13, 74.08,
86.81, 101.45, 106.32, 107.32, 108.46, 109.56, 118.99, 119.74,
120.78, 122.58, 127.87, 128.49, 129.23, 132.75, 133.25, 134.45,
136.05, 148.08, 148.72.
(5) Johansen, M. B.; Kerr, M. A. Org. Lett. 2008, 10, 3497.
(6) Pearson, W. H.; Fang, W.-K. J. Org. Chem. 2000, 65, 7158.
(7) Zhang, X.; Mu, T.; Zhan, F.; Ma, L.; Liang, G. Angew.
Chem. Int. Ed. 2011, 50, 6164.
MS: m/z = 450 [M + 1]+.
(8) Vallakati, R.; May, J. A. J. Am. Chem. Soc. 2012, 134, 6936.
(9) (a) Basavaiah, D.; Rao, A. J.; Satyanarayana, T. Chem. Rev.
2003, 103, 811. (b) Declerck, V.; Martinez, J.; Lamaty, F.
Chem. Rev. 2009, 109, 1. (c) Basavaiah, D.; Rao, K. V.;
Reddy, R. J. Chem. Soc. Rev. 2007, 36, 1581. (d) Singh, V.;
Batra, S. Tetrahedron 2008, 64, 4511. (e) Basavaiah, D.;
Rao, P. D.; Hyma, S. R. Tetrahedron 1996, 52, 8001.
(f) Prasad, B. A. S.; Knochel, P. Tetrahedron 1997, 53,
16711. (g) Ciganek, E. Organic Reactions; Vol. 51;
Paquette, L. A., Ed.; Wiley: New York, 1997, 201.
(10) (a) Basavaiah, D.; Rao, J. S.; Reddy, R. J. J. Org. Chem.
2004, 69, 7379. (b) Basavaiah, D.; Krishnamacharyula, M.;
Hyma, R. S.; Sarma, P. K. S.; Kumaragurubaran, N. J. Org.
Chem. 1999, 64, 1197. (c) Basavaiah, D.; Reddy, R. M.;
Kumaragurubaran, N.; Sharada, D. S. Tetrahedron 2002, 58,
3693. (d) Basavaiah, D.; Sarma, P. K. S. J. Chem. Soc.,
Chem. Commun. 1992, 955. (e) Weichert, A.; Hoffmann, H.
M. R. J. Org. Chem. 1991, 56, 4098.
Anal. Calcd for C28H23N3O3: C, 74.82; H, 5.16; N, 9.35. Found: C,
74.99; H, 5.58; N, 9.10.
Acknowledgment
We thank CSIR, Nanoscience and Nanotechnology (NSNT), Uni-
versity of Madras for the financial support. We thank DST-FIST for
the NMR facility. G.S. thanks CSIR, New Delhi for the award of
SRF. D.S.S. thanks DST, New Delhi for her research grant.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis.SnuIomprifgtooatrinSugpIoi
n
nfomartit
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© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 237–245