Ring contraction of N-acetyl-2-aryl-1,2,3,4-tetrahydro-4-quinolones with [hydroxy(tosyloxy)iodo]benzene to trans methyl N-acetyl-2-aryl-2,3-dihydroindol- 3-carboxylates

Article abstract of DOI:10.3184/030823407X270329

The ring contraction of N-acetyl-2-aryl-1,2,3,4-tetrahydro-4-quinolones with [hydroxy(tosyloxy)iodo]benzene to trans methyl N-acetyl-2-aryl-2,3- dihydroindol-3-carboxylates in trimethylorthoformate in good yield is described.

Full text of DOI:10.3184/030823407X270329

680 RESEARCH PAPER
DECEMBER, 680–682
JOURNAL OF CHEMICAL RESEARCH 2007
Ring contraction of N-acetyl-2-aryl-1,2,3,4-tetrahydro-4-quinolones
with [hydroxy(tosyloxy)iodo]benzene to trans methyl
N-acetyl-2-aryl-2,3-dihydroindol-3-carboxylates
Ashok Kumar, Sunil Kumar, Rakesh K. Gupta and Devinder Kumar*
Department of Chemistry, Guru Jambheshwar University of Science and Technology, Hisar-125001, Haryana, India
The ring contraction of N-acetyl-2-aryl-1,2,3,4-tetrahydro-4-quinolones with [hydroxy(tosyloxy)iodo]benzene to
trans methyl N-acetyl-2-aryl-2,3-dihydroindol-3-carboxylates in trimethylorthoformate in good yield is described.
Keywords: [hydroxy(tosyloxy)iodo]benzene, 4-quinolones, 2,3-dihydroindoles
Hypervalent iodine reagents have been widely used in organic
synthesis over the past few years.1 These reagents have
been found to be excellent substitutes for metal-containing
oxidising agents, such as lead(IV), thallium(III) and
mercury(II) salts. Oxidation of quinolones with hypervalent
iodine reagents, particularly iodobenzene diacetate (IBD) and
[(hydroxytosyloxy)iodo] benzene (HTIB) have been shown
to afford different products depending upon the reaction
conditions2,3 (Scheme 1).
The 2,3-dihydroindole ring is present in many naturally
occurring compounds including biologically active
alkaloids.6,7 2,3-Dihydroindoles have also been found to
behave as selective monoamine oxidase inhibitors8 and
as non-peptide angiotensin II receptor antagonists.9 2,3-
Dihydroindoles are also potential intermediates for the
synthesis of other indoles.10
Results and discussion
Oxidation of 2-aryl-1,2,3,4-tetrahydro-4-quinolones (1)
with IBD under basic conditions in methanol gave 2-aryl-
4-quinolones (2) via dehydrogenation2 whilst treatment of
compound 1 with HTIB under acidic conditions in trialkyl
orthoformate resulted in the naturally occurring 4-alkoxy-
2-arylquinoline (3) alkaloids.3 These compounds have also
been obtained by oxidation with iodine-methanol.4 Further,
oxidation of 2-methyl-4-quinolones using HTIB afforded 2-
methyl-3-iodo-4-phenoxyquinolines with the intermediacy of
isolable α-phenyliodonio tosylates and novel monocarbonyl
iodonium ylides.5 In continuation of our earlier work on
oxidation of quinolones by hypervalent iodine,2,5 the oxidative
ring contraction of N-acetyl-2-aryl-1,2,3,4-tetrahydro-4-
quinolones to trans methyl N-acetyl-2-aryl-2,3-dihydroindol-
3-carboxylates in trimethylorthoformate (TMOF) using HTIB
is described.
The reaction of N-acetyl-2-aryl-1,2,3,4-tetrahydro-4-
quinolones (4) with HTIB was examined in trimethyl
orthoformate (TMOF) in the presence of a few drops of either
HClO4 or H2SO4 at room temperature. The stereoselective
ring-contracted products which were formed were identified as
trans methyl N-acetyl-2-aryl-2,3-dihydroindol-3-carboxylates
(5). A side product, methyl p-toluenesulfonate (6), was also
isolated (Scheme 2) in small quantity. The structures of
5a–e and 611 were established by physical and spectroscopic
1
techniques (IR, H and 13C NMR). The characteristic feature
in the 1H NMR spectrum of compounds 5a–e was the doublet
(or broad singlet) of C3–H at d 3.79–3.97 (J = 1.8 Hz,
broad singlet of C2–H at d 5.73–5.99 and downfield signal
of C7–H at d 8.24–8.43 (probably due to its deshieding by
N-acetyl group). The trans stereochemistry of dihydroindole
ring in 5a–e was established by comparing the coupling
H
H
N
Ar
N
N
Ar
Ar
HTIB
IBD, KOH
MeOH
CH(OR)3, HClO4
OR
O
O
3
2
1
Scheme 1
CH3
COCH3
COCH3
N
N
H
Ar
HTIB
+
Ar
TMOF, HClO4
or H2SO4
stir, r.t.
H
H3COOC
O
S
O
O
OCH3
4
5
4, 5; a, Ar =C6H5
6
b, Ar =C6H5Br (p)
c, Ar =C6H5OMe (p)
d, Ar =C6H5NO2 (p)
e, Ar =C6H5Cl (p)
Scheme 2
* Correspondent. E-mail: dk_ic@yahoo.com
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JOURNAL OF CHEMICAL RESEARCH 2007 681
COCH3
COCH3
N
COCH3
N
N
Ar
I
Ar
Ar
HTIB, TMOF
-OTs
TMOF
Ph
HClO4 or H2SO4
stir, r.t.
OH
H3CO
OCH3
OCH3
O
8
7
4
-PhI
-OH
CH3
COCH3
COCH3
N
H
N
Ar
+
Ar
H
H3COOC
O
S
O
OCH3
H3CO
OCH3
6
5
9
Scheme 3
15–30 min. at room temperature (30°C). HTIB (753 mg, 2.2 mmol)
was added in small amounts and the resulting solution was further
stirred for 1 h. After completion of the reaction, as monitored by
TLC, the reaction mixture was extracted with dichloromethane
(3 x 15 ml), washed with saturated aq. sodium bicarbonate solution
followed by water. The combined extract was dried over anhydrous
Na2SO4. Removal of excess of solvent afforded gummy mass which
was chromatographed over a neutral alumina column using hexane:
ethyl acetate (9:1) as eluent to afford 5a–e and 6.
constant between C2–H and C3–H with that of reported cis and
trans 2,3-dihydroindoles.12 The coupling constant between
C2–H and C3–H of cis 2,3-dihydroindoles where nitrogen is
protected with nitrosyl or arylsulfonyl is 8–9 Hz, whereas that
of trans isomer is < 4 Hz. The less coupling constant (1.8 Hz)
in 5a–e is perhaps due to p–p interaction between N-acetyl
and C2-aryl groups, thus significantly altering the C2–H/C3–H
dihedral angle.13
Compound 5a (Ar = Ph): Oil,14 yield 68%. IR: 2953 (C–H), 1738
(C=O), 1652 (C=O), 1494, 1385, 1280, 1265, 1029, 756 cm-1. NMR:
dH 2.05(s, 3H, COCH3), 3.76(s, 3H, COOCH3), 3.97(d, 1H, J=1.8Hz,
C3–H), 5.85 (brs, 1H, C2–H), 7.06–7.10 (m, 1H, C5–H), 7.17–7.19
(m, 2H, C4–H and C6–H), 7.25–7.37 (m, 5H, C6H5), 8.34 (1H, d,
J = 7.88 Hz, C7–H); dC 24.1, 52.8, 55.7, 65.6, 117.2, 124.1, 125.0,
125.8, 126.0, 128.2, 129.3, 129.4, 141.3, 142.9, 169.5, 171.1.
Compound 5b (Ar =C6H5Br-p): Oil, yield 73%. IR: 2923 (C–H),
1736 (C=O), 1661 (C=O), 1504, 1392, 1277, 1026, 759 cm-1. NMR:
dH 2.03 (s, 3H, COCH3), 3.70 (s, 3H, COOCH3), 3.85 (brs, 1H, C3–
H), 5.74 (brs, 1H, C2–H), 7.00–7.04 (m, 3H, C4–H, C5–H and C6–H),
7.28 (d, 2H, J = 7.70 Hz, C2'–H and C6'–H), 7.37 (d, 2H, J = 7.70 Hz,
C3'–H and C5'–H), 8.24 (d, 1H, J = 7.60 Hz, C7–H); dC 24.2, 53.0,
55.6, 65.0, 117.3, 122.2, 124.4, 125.7, 125.9, 126.9, 129.5, 132.5,
140.4, 142.8, 169.3, 171.0. Anal. Calcd. for C18H16BrNO3: C, 57.8;
H, 4.3; N, 3.7. Found: C, 57.9; H, 4.21; N, 3.6.
The probable mechanism involves the ketalisation of 4
with TMOF in presence of either HClO4 or H2SO4 to afford
intermediate enol ether 7. The electrophilic attack of HTIB
on the double bond of enol ether 7 furnished the iodine (III)
complex, 8. Reductive elimination of iodobenzene from 8
with simultaneous migration of aryl residue from C4 to
C3 position gave intermediate carbocation 9 which on
hydrolysis afforded the ring contracted product 5 alongwith
6. The migration of aryl residue is preferred over C2 aryl
ring probably because of greater stability of the carbocation
formed. Compound 5 was formed by ring contraction of
compound 4 under the reaction conditions while side product
6 was formed probably due to condensation of methanol and
p-toluenesulfonic acid formed in situ.
The present approach for the synthesis of trans methyl
N-acetyl-2-aryl-2,3-dihydroindol-3-carboxylates is simple. This
method avoids the use of toxic thallium salts for a similar type
of reaction of N-acetyl-2-aryl-1,2,3,4-tetrahydro-4-quinolones
(4) that results in a mixture of trans methyl N-acetyl-2-
aryl-2,3-dihydroindol-3-carboxylates (5) and 4-methoxy-2-
arylquinolines.14 It should be noted that compound 4a has also
been reported to produce 3-phenylquinoline using HTIB under
microwave irradiation instead of a ring contracted product.15
Compound 5c (Ar =C6H5OMe-p): Oil,14 yield 65%. IR: 2970
(C–H), 1735 (C=O), 1650 (C=O), 1501, 1369, 1095, 1122, 1033,
753 cm-1. NMR: dH 2.37 (s, 3H, COCH3), 3.66 (s, 6H, COOCH3
and OCH3), 3.79 (brs, 1H, C3–H), 5.73 (brs, 1H, C2–H), 6.88 (d, 2H,
J = 7.80 Hz, C3'–H and C5'–H) 7.01–7.10 (m, 3H, C4–H, C5–H, and
C6–H), 7.49 (d, 2H, J = 7.80 Hz, C2' –H and C6'–H), 8.29 (1H, d,
J = 8.28 Hz, C7–H).
Compound 5d (Ar =C6H5NO2-p): Oil, yield 71%. IR: 2950 (C–H),
1739 (C=O), 1660 (C=O), 1597, 1538, 1480, 1390, 1210, 867, 760
cm-1. NMR: dH (CDCl3) 2.04 (s, 3H, COCH3), 3.82 (s, 3H, COOCH3),
3.95 (brs, 1H, C3–H), 5.99 (brs, 1H, C2–H), 7.11 (m, 1H, C5–H),
7.36–7.41 (m, 4H, C4–H, C6–H, C3'–H and C5'–H), 8.19 (d, 2H,
J = 7.84 Hz, C2'–H and C6'–H), 8.32 (d, 1H, J = 7.16 Hz, C7–H);
dC 24.1, 53.1, 55.3, 64.9, 117.3, 124.6, 125.2, 126.0, 126.2, 129.7,
132.5, 142.5, 147.7, 148.3, 168.9, 170.0.Anal. Calcd. for C18H16N2O5:
C, 63.52; H, 4.7; N, 8.2. Found: C, 63.7; H, 4.65; N, 8.1.
Experimental
FTIR spectra were obtained in KBr/neat film on Perkin Elmer
Spectrum RX1 instruments and are reported in cm-1. 1H and 13C
NMR spectra were recorded on Bruker Avance II 400 MHz and
100 MHz NMR Spectrometer, respectively in CDCl3; shifts are
expressed as ppm with respect to TMS. Elemental analysis was
carried out on Perkin Elmer 2400 instrument. 2-Aminochalcone,
Compound 5e (Ar =C6H5Cl-p): White solid, m.p. 52–53°C (lit.,14
m.p. 52–53°C), yield 72%. IR: 2950 (C–H), 1735 (C=O), 1651
(C=O), 1492, 1387, 1280, 1260, 1032, 760, 557 cm-1. NMR: dH 2.05
(s, 3H, COCH3), 3.76 (s, 3H, COOCH3), 3.97 (d, 1H, J = 1.8 Hz,
C3–H), 5.81 (brs, 1H, C2–H), 7.05–7.11 (m, 3H, C2'–H, C6'–H and
C5–H), 7.26–7.41 (m, 4H, C3'–H, C5'–H, C4–H and C6–H), 8.43 (1H,
d, J = 8.10 Hz, C7–H).
2-aryl-1,2,3,4-tetrahydro-4-quinolones,
N-acetyl-2-aryl-1,2,3,4-
tetrahydro-4-quinolones were synthesised using known methods.14,16
General procedure
Compound 6: Oil (lit.,11 m.p. 25–28°C), IR:2921 (C–H), 1529,
1369, 1195, 1038, 771, 680, 563 cm-1. NMR: dH 2.45 (s, 3H, CH3),
3.72 (s, 3H, OCH3), 7.35 (dd, 2H, J = 8.44 and 0.40 Hz, C3–H and
C5–H), 7.77 (dd, 2H, J = 8.44 and 1.70 Hz, C2–H and C6–H); dC 21.6,
To a solution of N-acetyl-2-aryl-1,2,3,4-tetrahydro-4-quinolones (4,
2 mmol) in freshly distilled trimethylorthoformate (15 ml), was added
1–2 drops of either HClO4 (70%) or conc. H2SO4 and stirred for
PAPER: 07/4940

682 JOURNAL OF CHEMICAL RESEARCH 2007
6
7
8
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H, 5.41. Found: C, 51.7; H, 5.3.
The authors are grateful to UGC and CSIR, New Delhi for
providing financial assistance and Mr. Avtar Singh, SAIF,
Chandigarh for recording the NMR spectra.
9
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(b) W.H. Cheung, S.L. Zheng, W.Y. Yu, G.C. Zhou and C.M. Che,
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Received 15 November 2007; accepted 13 December 2007
Paper 07/4940
doi: 10.3184/030823407X270329
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