Indium(III) chloride catalyzed in situ generation of enamines and cyclization with imines: A novel route for synthesis of hexahydroxanthene-9-N- arylamines

Article abstract of DOI:10.1016/j.tet.2004.02.009

A simple, efficient, and novel method has been developed for the synthesis of hexahydroxanthene-9-N-arylamine derivatives through a one-pot reaction of cyclohexanone and morpholine with salicylaldehyde imines in the presence of indium(III) chloride as a catalyst. 1-(4-Morpholino)-cyclohexene enamine prepared in situ from cyclohexanone and morpholine in presence of 20mol% InCl₃ in acetonitrile under reflux condition was used without further purification, for the cyclization reaction with salicylaldehyde Schiff's bases.

Full text of DOI:10.1016/j.tet.2004.02.009

Tetrahedron 60 (2004) 2965–2969
Indium(III) chloride catalyzed in situ generation of enamines
and cyclization with imines: a novel route for synthesis
of hexahydroxanthene-9-N-arylamines
b
Marimuthu Anniyappan,a D. Muralidharan,a Paramasivan T. Perumala and Jagadese J. Vittal
,
*
aOrganic Chemistry Division, Central Leather Research Institute, Adyar, Chennai 600 020, India
bDepartment of Chemistry, National University of Singapore, Science Drive, Singapore 117543, Singapore
Received 27 September 2003; revised 16 January 2004; accepted 5 February 2004
Abstract—A simple, efficient, and novel method has been developed for the synthesis of hexahydroxanthene-9-N-arylamine derivatives
through a one-pot reaction of cyclohexanone and morpholine with salicylaldehyde imines in the presence of indium(III) chloride as a
catalyst. 1-(4-Morpholino)-cyclohexene enamine prepared in situ from cyclohexanone and morpholine in presence of 20 mol% InCl3 in
acetonitrile under reflux condition was used without further purification, for the cyclization reaction with salicylaldehyde Schiff’s bases.
q 2004 Elsevier Ltd. All rights reserved.
1. Introduction
fabianine9 and quaipyridines,10 including heteroaromatic
azadiene Diels–Alder reaction.
Xanthone derivatives are parent compounds of a large
number of naturally occurring, as well as synthetic
derivatives, and occupy a prominent position in medicinal
chemistry.1 Ishiguro et al. have reported the isolation of
clusone (1,3,4,5,6-pentamethoxy-9H-xanthen-9-one) from
the fresh flowers of Clusia insignis.2 4-Methoxyxanthen-9-
amine derivatives have been used for the synthesis of
pharmacologically important Clavizepine alkaloids.3 Boyd
et al. have reported that 9-aryl or alkylimino-xanthene
derivatives have been used for solid phase synthesis of (RS)-
1-aminophosphinic acid.4 Broggini et al. have reported the
synthesis of (2)-(1S,4aR,9R,9aS)-9-amino-1,2,3,4,4a,9a-
hexahydro-9H-xanthen-1-ol using intra-molecular nitrone
cycloadditions to the cyclohexene ring.5 Schemidt has
reported the synthesis of linear fused cyclohexyl benzo-
pyrans via 4þ2 cycloaddition reaction of o-hydroxybenzyl
carbocation with cyclohexene using SnCl4 as a catalyst.6
Indium trichloride has been effectively employed as a Lewis
acid catalyst for various transformations11 in organic
synthesis, such as aldol condensations, imino Diels–Alder
reactions, rearrangement of epoxides and prins-type cycli-
zation.12 InCl3 is readily available and found to retain its
activity even in the presence of water and other active
functional groups such as NO2, COOH, CN, NH2 in the
substrates.13 In continuation of our research interest on the
catalytic applications of InCl3,14 we herein describe another
remarkable catalytic activity of InCl3 in the synthesis of
novel xanthene-9-N-arylamine derivatives from salicyl-
aldehyde imines and 1-(4-morpholino)-cyclohexene
enamine in CH3CN at room temperature in excellent yields
within 40 min. 1-(4-Morpholino)-cyclohexene enamine is
moisture sensitive and undergoes hydrolysis easily.15 In
order to overcome this difficulty we have attempted the
generation of 1-(4-morpholino)-cyclohexene enamine in
situ using InCl3 (20 mol%) under reflux conditions.
Enamines have been intensively studied and used in organic
synthesis in a wide variety of ways following Stork’s report
on the application of enamines in the alkylation and
acylation of carbonyl compounds.7 Weidinger et al. have
reported that 1,3-diaza-1,3-butadiene have been shown to
participate in [4þ2] cycloaddition reactions with 1-[4-
morpholino]cyclohexene.8 Enamines have been used in
natural product synthesis, for example the total synthesis of
1-(4-Morpholino)-cyclohexene enamine 3 prepared in situ
from cyclohexanone 1 and morpholine 2 in the presence of
20 mol% InCl3 in acetonitrile under reflux conditions for
2–3 h was used without further purification, for the
cyclization with salicylaldehyde Schiff’s bases 4. A wide
range of salicylaldehyde Schiff’s bases 4 with various
substituent groups were subjected to this procedure and
converted to the corresponding linear fused hexahydrox-
anthene-9-N-arylamines 5 derivatives in high yields
(Scheme 1). In all these reactions, a single product 5 was
Keywords: Indium trichloride; Imines; Enamine; Xanthene.
*
Corresponding author. Tel.: þ910-442-491-3289; fax: þ910-442-491-
1589; e-mail address: ptperumal@hotmail.com
0040–4020/$ - see front matter q 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2004.02.009

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M. Anniyappan et al. / Tetrahedron 60 (2004) 2965–2969
obtained, which upon recrystallization with ethyl acetate
yielded pure crystalline products. The results are summar-
ized in Table 1.
The reaction is expected to proceed through the activation of
the imine nitrogen by co-ordination of the catalyst InCl3,
followed by nucleophilic addition at imine (CvN) bond and
subsequent cyclization of the iminium ion, resulting in the
formation of the linear fused hexahydroxanthene-9-N-
arylamines (Scheme 2).
The structures of 5a–l were confirmed by 1H and 13C NMR
spectroscopy. The structure assignment of 5e was supported
by an X-ray crystallography determination.16 The X-ray
crystal structure of 5e is shown in Figure 1.
The experimental procedure is simple and the products are
obtained in excellent yields. However, when the substituent
group R1 was benzyl, cyclohexyl, methyl and ethyl, the
cyclization under these reaction conditions was not
favoured. We have substituted different cyclic ketones,
such as cyclopentanone, cycloheptanone and cyclooctanone
instead of cyclohexanone in the reaction with morpholine
and salicylaldehydimine, under similar reaction conditions
and no reaction was observed, the starting materials, being
recovered as such. When the reaction was carried out at
ambient temperature using equimolar ratio of reagents and
20 mol% InCl3, the cyclization reaction was not observed
which led to the recovery of unchanged starting materials.
Scheme 1. Synthesis of hexahydroxanthene-9-N-arylamine.
Table 1. InCl3 catalyzed formation of hexahydroxanthene-9-N-arylaminea
Entry
R1
R2
Time (min) Yield (%) Mp (8C)
a
b
c
d
e
f
g
h
i
C6H5
H
H
H
H
H
20
30
20
40
30
30
35
25
20
30
40
20
96
89
93
90
87
95
82
87
90
92
86
91
156–158
140–143
160–162
164–166
166–168
174–178
187–189
132–134
148–149
180–182
152–154
128–130
2-CH3–C6H4
4-CH3O–C6H4
4-Br–C6H4
2-Pyridine
C6H5
4-NO2–C6H4
C6H5
4-CH3–C6H4
4-CH3–C6H4
2-Pyridine
2-Naphthyl
The influence of various solvents on the yield of the reaction
was investigated using o-hydroxy benzaldimine (entry a in
Table 1) as the substrate. The results indicate that
acetonitrile is the best solvent for the enamine formation
and cyclization reaction of 1-(4-morpholino)-cyclohexene
enamine with salicylaldehyde Schiff’s bases (Table 2). The
increased yield in the acetonitrile medium may be attributed
to the higher polarity of the solvent and miscibility with
water, formed during the enamine formation.
5-CH3O
H
7-Cl
7-Cl
j
k
l
5-CH3O
5-CH3O
5-CH3O
a
All the products were characterized by 1H NMR, 13C NMR, IR and MS.
All compounds gave satisfactory CHN values.
Scheme 2. Mechanism for the InCl3 catalysed synthesis of hexahydroxanthene-9-N-arylamines.

M. Anniyappan et al. / Tetrahedron 60 (2004) 2965–2969
2967
o-hydroxybenzaldehyde and aniline. Salicylaldehyde, sub-
stituted anilines, cyclohexanone and morpholine were
purchased from s. d. Fine Chem Ltd, India. Reagent grade
acetonitrile and other solvents were used as supplied. The
procedure does not require anhydrous solvent and inert
atmosphere. All the products obtained were purified by
recrystallization with ethyl acetate. IR measurements were
done as KBr pellets for solids using Perkin Elmer Spectrum
1
RXI FT-IR. The H and 13C NMR was recorded in CDCl3
with JEOL 400 MHz (model GSX 400) high resolution
NMR spectrometer. CDCl3 was used as the solvent for the
NMR spectral measurements and spectra were recorded in
ppm with TMS as internal standards. The products Mass
were analyzed by using a VG70-70H instrument. Melting
points were determined in capillary tubes and are
uncorrected. Analytical TLC was performed on precoated
plastic sheets of silica gel G/UV-254 of 0.2 mm thickness
(Macherey-Nagel, Germany).
2.1. Preparation of hexahydroxanthene-9-N-arylamines:
general procedure
To a mixture of cyclohexanone (0.3 g, 3.06 mmol) and
morpholine (0.27 g, 3.10 mmol), in acetonitrile (20 mL),
was added a catalytic amount of InCl3 (0.136 g, 20 mol%).
The reaction mixture was refluxed on a water bath under
nitrogen atmosphere for 3 h and then allowed to cool to
room temperature before the addition of o-hydroxy
benzaldimine 1a (0.6 g, 3.05 mmol). The stirring was
continued for 20 min. After completion of the reaction as
indicated by TLC, the reaction mixture was quenched by
addition of water (30 mL) and extracted with ethylacetate
(2£30 mL). The combined organic layer was dried over
anhydrous Na2SO4, filtered and the solvent evaporated in
vacuo, kept at 0 8C overnight in a fridge to obtain the crude
product. The crude solid was recrystallized from ethyl-
acetate to give the corresponding xanthene derivative 5a
(1.064 g, 96%).
Figure 1. A perspective view of one of the two independent molecules in
the asymmetric unit of 5e.
Table 2. Effect of the solvent medium on the reaction yield of o-hydroxy
benzaldimine with 20 mol% InCl3
2.1.1. Product 5a: N-phenyl-N-(4a-morpholin-4yl-
2,3,4,4a,9,9a-hexahydro-1H-xanthen-9-yl) amine. Yield
1.064 g (96%); colorless solid, mp 156–158 8C; IR (KBr)
3361 (NH), 3050, 3015, 2926, 2855, 2821, 1599, 1488,
1450, 1360, 1299, 1260, 1234, 1151, 1112, 1064, 1026, 973,
Entry
Solvent
Yield (%)
1
2
3
4
5
Benzene
Toluene
CH3CN
CHCl3
THF
94
89
97
65
37
1
973, 770, 745 cm21; H NMR (400 MHz, CDCl3) d 7.48–
6.57 (m, 9H), 4.12 (d, 1H, J¼9.8 Hz), 3.60–3.67 (m, 4H),
2.55–2.70 (m, 3H), 2.35–2.38 (m, 2H), 2.02 (t, 2H,
J¼13.2 Hz), 1.72–1.10 (m, 7H, including NH). 13C NMR
(100 MHz, CDCl3) d 150.6, 146.9, 129.6, 128.5, 123.3,
121.1, 116.9, 112.9, 112.2, 89.6, 67.4, 52.4, 45.3, 35.8, 29.0,
26.7, 25.1, 21.9; MS (m/z): 364 (Mþ). Anal. calcd for
C23H28N2O: C, 75.79; H, 7.74; N, 7.69. Found: C, 75.92; H,
7.69; N, 7.58%.
In summary, this paper describes a general method for the
synthesis of hexahydroxanthene-9-N-arylamines from
salicylaldimines and 1-(4-morpholino)-cyclohexene
enamine using sub-stoichiometric amounts of InCl3. The
catalyst is mild which has an advantage in that only
20 mol% is required for the reactions. In addition to its
efficiency, operational simplicity, mild reaction conditions
and easier work-up procedure make it a useful method for
the synthesis of fused hexahydroxanthene-9-N-arylamines
derivatives.
2.1.2. Product 5b: N-(2-methylphenyl)-N-(4a-morpholin-
4yl-2,3,4,4a,9,9a-hexahydro-1H-xanthen-9-yl)
amine.
Yield 0.797 g (89%); colorless solid, mp 140–143 8C; IR
(KBr) 3438 (NH), 3064, 3021, 2919, 2886, 2848, 2754,
1604, 1582, 1514, 1482, 1450, 1294, 1257, 1234, 1203,
1146, 1116, 1029, 975, 957, 750 cm21; 1H NMR (400 MHz,
CDCl3) d 7.49 (d, 1H, J¼7.82 Hz), 7.23 (m, 3H), 6.95 (t,
1H, J¼7.3 Hz), 6.83–6.81 (m, 1H), 6.69–6.62 (m, 2H),
5.26 (brs, 1H), 3.68–3.63 (m, 4H), 2.74–2.64 (m, 3H),
2. Experimental
o-Hydroxybenzaldimines prepared from appropriate

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M. Anniyappan et al. / Tetrahedron 60 (2004) 2965–2969
2.35–2.34 (m, 2H), 2.18 (s, 3H, CH3), 2.09–2.00 (m, 2H),
1.68–1.12 (m, 7H, including NH); 13C NMR (100 MHz,
CDCl3) d 151.9, 145.4, 130.6, 128.2, 127.3, 126.7, 124.5,
121.8, 120.8, 116.8, 116.4, 108.9, 90.9, 67.5, 47.4, 45.4,
34.1, 27.0, 24.6, 21.9, 21.8, 17.7; MS (m/z): 378 (Mþ). Anal.
calcd for C24H30N2O: C, 76.16; H, 7.79; N, 7.40. Found: C,
76.29; H, 7.67; N, 7.29%.
NMR (400 MHz, CDCl3) d 7.25–7.19 (m, 2H), 6.93–6.64
(m, 5H), 6.59 (d, 1H, J¼8.0 Hz), 4.66 (d, 1H, J¼10.3 Hz),
4.12 (d, 1H, J¼10.3 Hz), 3.86 (s, 3H), 3.72–3.61 (m, 2H),
2.56 (m, 2H), 2.39–2.12 (m, 3H), 1.80–1.61 (m, 6H), 1.52–
1.1 (m, 4H); 13C NMR (100 MHz, CDCl3) d 148.6, 147.0,
140.1, 129.8, 124.3, 122.5, 120.6, 117.2, 112.4, 123.0,
110.7, 89.8, 67.7, 56.2, 52.7, 45.5, 36.0, 29.2, 26.9, 25.2;
MS (m/z): 394 (Mþ). Anal. calcd for C24H30N2O: C, 73.07;
H, 7.66; N, 7.10. Found: C, 72.87; H, 7.57; N, 7.22.
2.1.3. Product 5c: N-(4-methoxyphenyl)-N-(4a-morpho-
lin-4yl-2,3,4,4a,9,9a-hexahydro 1H-xanthen-9-yl) amine.
Yield 0.807 g (93%); colorless solid, mp 160–162 8C; IR
(KBr) 3375 (NH), 3375, 3049, 3004, 2943, 2855, 2826,
1589, 1511, 1455, 1297, 1240, 1182, 1149, 1116, 1038, 975,
2.1.7. Product 5g: N-(4-nitrophenyl)-N-(4a-morpholin-
4yl-2,3,4,4a,9,9a-hexahydro-1H-xanthen-9-yl) amine.
Yield 0.693 g (82%); pale yellow colored solid, mp 187–
1
1
944, 819, 772 cm21; H NMR (400 MHz, CDCl3) d: H
NMR (400 MHz, CDCl3) d 6.89–7.29 (m, 4H), 6.81 (d, 2H,
J¼8.8 Hz), 6.55 (d, 2H, J¼8.8 Hz), 4.03 (d, 1H,
J¼10.3 Hz), 3.76 (s, 3H), 3.59 (m, 4H), 2.57 (m, 4H),
2.39–1.27 (m, 10H, including NH). 13C NMR (100 MHz,
CDCl3) d 151.8, 150.5, 141.3, 130.7, 128.5, 123.5, 121.0,
116.9, 115.2, 113.7, 89.6, 67.4, 55.7, 53.4, 45.5, 35.6, 29.1,
26.8, 25.1, 21.9; MS (m/z): 394 (Mþ) Anal. calcd for
C24H30N2O3: C, 73.07; H, 7.66; N, 7.10. Found: C, 73.31;
H, 7.77; N, 7.18%.
189 8C IR (KBr) 3392 (NH), 3053, 3015, 2928, 2849, 1596,
1
1493, 1459, 1321, 1234, 1119, 981, 773 cm21; H NMR
(400 MHz, CDCl3) d 8.12–8.10 (m, 2H), 7.30–7.18 (m,
3H), 6.96–6.83 (m, 2H), 6.61(d, 1H, J¼9.2 Hz), 5.26 (dd,
1H, J1¼5.8 Hz, J2¼9.8 Hz), 4.60 (d, 1H, J¼10.3 Hz),
3.67–3.61 (m, 2H), 2.78–2.02 (m, 6H), 1.84–1.14 (m,
9H); 13C NMR (100 MHz, CDCl3) d 153.1, 151.9, 138.4,
130.4, 129.5, 129.1, 126.9, 126.5, 122.5, 121.1, 116.9, 90.9,
67.5, 48.2, 45.5, 34.9, 27.0, 24.5, 22.1, 21.1; MS (m/z): 409
(Mþ). Anal. calcd for C23H27N3O: C, 67.46; H, 6.65; N,
10.26. Found: C, 67.23; H, 6.56; N, 10.38%.
2.1.4. Product 5d: N-(4-bromophenyl)-N-(4a-morpholin-
4yl-2,3,4,4a,9,9a-hexahydro-1H-xanthen-9-yl)
amine.
2.1.8. Product 5h: N-(phenyl)-N-(4a-morpholin-4yl-
2,3,4,4a,9,9a-hexahydro-1H-7-chloroxanthen-9-yl)
amine. Yield 0.749 g (87%); colorless solid, mp 132–
134 8C; IR (KBr) 3368 (NH), 3055, 3021, 2926, 2852, 2823,
Yield 0.722 g (90%); colorless solid, mp 164–166 8C; IR
(KBr) 3398 (NH), 3050, 3011, 2926, 2856, 1593, 1493,
1454, 1312, 1261, 1238, 1147, 1114, 1070, 976, 950, 811,
772 cm21
;
1H NMR (400 MHz, CDCl3) d 7.27 (d, 2H,
1591, 1482, 1457, 1298, 1235, 1117, 975, 775 cm21; H
1
J¼8.3 Hz), 7.25–7.17 (m, 2H), 6.95–6.80 (m, 2H), 6.46 (d,
2H, J¼8.8 Hz) 4.05 (d, 1H, J¼10.3 Hz), 3.57 (m, 4H),
2.63–2.54 (m, 3H), 2.34–2.30 (m, 2H), 2.06–2.02 (m, 2H),
1.70–1.24 (m, 7H, including NH); 13C NMR (100 MHz,
CDCl3) d 150.5, 145.9, 132.3, 130.6, 128.8, 122.8, 121.2,
117.1, 113.8, 108.5, 89.5, 67.5, 52.7, 48.1, 45.3, 35.7, 29.0,
26.7, 25.1, 21.9; MS (m/z):443 (Mþ). Anal. calcd for
C23H27N2O2Br: C, 62.31; H, 6.14; N, 7.10. Found: C, 62.18;
H, 6.01; N, 7.23%.
NMR (400 MHz, CDCl3) d 7.30 (d, 1H, J¼2.2 Hz), 7.25–
7.13 (m, 4H), 6.78–6.71 (m, 2H), 6.57–6.56 (d, 1H,
J¼7.4 Hz), 3.76–3.47 (m, 1H), 2.69–2.53 (m, 3H), 2.37–
2.02 (m, 2H), 1.72–1.24 (m, 11H); 13C NMR (100 MHz,
CDCl3) d 149.3, 146.6, 130.4, 129.8, 128.8, 125.9, 125.1,
118.4, 117.5, 112.3, 90.0, 67.5, 52.4, 46.1, 35.7, 29.1, 26.7,
25.1, 21.9; MS (m/z): 398 (Mþ). Anal. calcd for
C23H27N2O2Cl: C, 69.25; H, 6.82; N, 7.02. Found: C,
69.18; H, 6.89; N, 6.89%.
2.1.5. Product 5e: N-(4a-morpholin-4yl-2,3,4,4a,9,9a-
hexahydro-1H-xanthen-9-yl) pyridin-2-amine. Yield
0.802 g (87%); colorless solid, mp 164–166 8C; IR (KBr)
3348 (NH), 3062, 2936, 2854, 2817, 2744, 1607, 1513,
1487, 1450, 1344, 1283, 1241, 1198, 1139, 1108, 1033, 956,
2.1.9. Product 5i: N-(4-methylphenyl)-N-(4a-morpholin-
4yl-2,3,4,4a,9,9a-hexahydro-1H-7-chloroxanthen-9-yl)
amine. Yield 0.757 g (90%); colorless solid, mp 148–
149 8C; IR (KBr) 3445 (NH), 3067, 3018, 2915, 2879, 2843,
1603, 1578, 1518, 1469, 1451, 1298, 1238, 1156, 965,
1
1
850, 751 cm21; H NMR (400 MHz, CDCl3) d 8.08–8.06
748 cm21; H NMR (400 MHz, CDCl3) d 7.50–7.02 (m,
(m, 1H), 7.44–7.38 (m, 2H), 7.18–7.14 (m, 1H), 6.93–6.91
(m, 1H), 6.89–6.80 (m, 1H), 6.59–6.57 (m, 1H), 6.43 (d,
1H, J¼8.3 Hz), 4.53 (d, 1H, J¼9.8 Hz), 3.71–3.62 (m, 2H),
2.86–2.73 (m, 2H), 2.46–2.41 (m, 1H), 2.03–1.99 (m, 2H),
1.87 (brs, 1H, NH), 1.68–1.54 (m, 2H), 1.44–1.36 (m, 2H),
1.18–1.05 (m, 2H); 13C NMR (100 MHz, CDCl3) d 158.6,
152.4, 148.7, 137.6, 128.4, 126.6, 124.4, 120.9, 116.8,
113.3, 107.9, 91.3, 67.9, 46.7, 45.5, 34.8, 27.2, 24.9, 22.3,
22.2; MS (m/z): 365 (Mþ). Anal. calcd for C22H27N3O: C,
72.30; H, 7.45; N, 11.50. Found: C, 72.45; H, 7.53; N,
11.61%.
5H), 6.73 (d, 1H, J¼8.6 Hz), 6.58 (d, 1H, J¼8.6 Hz), 5.01
(brs, 1H, NH), 4.49 (d, 1H, J¼9.2 Hz), 4.05 (d, 1H,
J¼8.6 Hz), 4.49 (d, 1H, J¼9.2 Hz), 3.69–3.60 (m, 4H),
2.80–2.53 (m, 2H), 2.37–2.25 (m, 2H), 2.37–2.25 (m, 5H),
2.06–1.97 (m,1H), 1.71–1.02 (m, 9H); 13C NMR
(100 MHz, CDCl3) d 150.7, 144.9, 130.3, 128.7, 128.3,
126.9, 126.3, 125.7, 117.8, 113.4, 112.4, 91.4, 67.5, 52.6,
48.2, 45.3, 34.1, 24.5, 21.8, 21.7, 20.4; MS (m/z): 412 (Mþ).
Anal. calcd for C24H29N2O2Cl: C, 69.80; H, 7.08; N, 6.78.
Found: C, 69.92; H, 7.19; N, 6.86%.
2.1.10. Product 5j: N-(4-methylphenyl)-N-(4a-morpho-
lin-4yl-2,3,4,4a,9,9a-hexahydro-1H-5-methoxyxanthen-
9-yl) amine. Yield 0.779 g (92%); colorless solid, mp 180–
182 8C; IR (KBr) 3365 (NH), 3052, 3008, 2945, 2851, 2828,
2.1.6. Product 5f: N-(phenyl)-N-(4a-morpholin-4yl-
2,3,4,4a,9,9a-hexahydro-1H-5-methoxy xanthen-9-yl)
amine. Yield 0.825 g (95%); colorless solid, mp 174–
178 8C; IR (KBr) 3372 (NH), 3058, 3018, 2949, 2849, 2832,
1
1578, 1518, 1459, 1252, 1141, 1112, 972, 778 cm21; H
1
1582, 1516, 1443, 1245, 1147, 1118, 978, 767 cm21; H
NMR (400 MHz, CDCl3) d 7.32–6.70 (m, 6H), 6.60 (d,

M. Anniyappan et al. / Tetrahedron 60 (2004) 2965–2969
2969
J¼8.0 Hz), 6.50 (d, 1H, J¼8.0 Hz), 4.61 (d, 1H,
References and notes
J¼10.1 Hz), 4.09 (d, 1H, J¼9.7 Hz), 3.93 (s, 3H), 3.87–
3.38 (m, 3H), 2.97–2.96 (m, 2H), 2.72–2.41 (m, 4H), 2.37
(s, 3H), 2.32–1.03 (m, 8H); 13C NMR (100 MHz, CDCl3) d
161.7, 151.5, 148.5, 145.6, 137, 130.1, 129.8, 123.7, 121.1,
119.2, 118.5, 114.5, 90.2, 66.8, 56.2, 48.2, 45.4, 36.4, 29.5,
26.7, 21.9, 21.1; MS (m/z): 408 (Mþ). Anal. calcd for
C25H32N2O3: C, 73.50; H, 7.89; N, 6.86. Found; C, 73.35;
H, 7.97; N, 6.77%.
1. (a) Robak, J.; Gryglewski, R. J. Pol. J. Pharmacol. 1996, 48,
55. (b) Wang, H. K.; Morris-Natschke, S. L.; Lee, K. H. Med.
Res. Rev. 1997, 17, 367. (c) Rukavishnikov, A. V.; Smith,
M. P.; Birrell, G. B.; Keana, J. F. W.; Griffith, O. H.
Tetrahedron Lett. 1998, 39, 6637.
2. Ishiguro, K.; Chaudhuri, S. K.; Kubo, I. Phytochemistry 1998,
49, 2531.
3. Garcia, A.; Paz, S.; Dominguez, D. Tetrahedron Lett. 2001,
42, 665.
2.1.11. Product 5k: N-(4a-morpholin-4yl-2,3,4,4a,9,9a-
hexahydro-1H-5-methoxyxanthen-9-yl)pyridin-2-amine.
Yield 0.745 g (86%); colorless solid, mp 152–154 8C; IR
(KBr) 3355 (NH), 3068, 2938, 2855, 2812, 1605, 1521,
4. Boyd, E. A.; Chan, W. C.; Loh, V. M., Jr. Tetrahedron Lett.
1996, 37, 1647.
5. Broggini, G.; Folcin, F.; Sardone, N.; Zecchi, G. Tetrahedron
1996, 52, 11849.
1472, 1461, 1232, 1121, 951, 759 cm21
;
1H NMR
(400 MHz, CDCl3) d 7.89 (m, 1H), 7.32 (m, 1H), 6.88–
6.37 (m, 5H), 5.58 (d, 1H, J¼5.2 Hz), 3.98–3,49 (m, 2H),
3.35 (s, 3H), 2.64–1.88 (m, 6H), 1.70–1.06 (m, 10H); 13C
NMR (100 MHz, CDCl3) d 159.2, 148.4, 148.2, 141.5,
137.0, 125.4, 120.1, 118.9, 112.1, 117.0, 109.9, 91.4, 67.3,
56.1, 45.5, 34.2, 31.2, 26.7, 24.6, 22.7, 22.4; MS (m/z): 395
(Mþ). Anal. calcd for C24H29N3O3: C, 70.74; H, 7.17; N,
10.31. Found: C, 70.72; H, 7.18; N, 10.33%.
6. Schemidt, R. R. Tetrahedron Lett. 1969, 5279.
7. Stork, G.; Terrel, R.; Szmuszkovicz, J. J. Am. Chem. Soc.
1954, 76, 2029.
8. Weidinger, H.; Slurm, H. J. Justus Liebigs Ann. Chem. 1968,
716, 143.
9. (a) Sugita, T.; Koyama, J.; Tagahara, K.; Suzuta, Y.
Heterocycles 1986, 24, 29. (b) Sugita, T.; Koyama, J.;
Tagahara, K.; Suzuta, Y. Heterocycles 1985, 23, 2789.
10. Okatani, T.; Koyama, J.; Tagahara, K.; Suzuta, Y. Hetero-
cycles 1987, 26, 595.
2.1.12. Product 5l: N-(2-naphthyl)-N-(4a-morpholin-4yl-
2,3,4,4a,9,9a-hexahydro-1H-5-methoxyxanthen-9-yl)
amine. Yield 0.726 g (91%); brown colored solid, mp 128–
130 8C; IR (KBr) 3349 (NH), 3045, 2932, 2855, 2822, 1593,
11. (a) Babu, G.; Perumal, P. T. Aldrichemica Acta 2000, 33, 16.
(b) Loh, T. P.; Pei, J.; Cao, G.-Q. Chem. Commun. 1996, 1819.
(c) Babu, G.; Perumal, P. T. Tetrahedron Lett. 1997, 38, 5025.
(d) Loh, T.-P.; Wei, L.-L. Tetrahedron Lett. 1998, 39, 323.
(e) Ranu, B. C.; Jana, U. J. Org. Chem. 1998, 63, 8212.
(f) Miyai, T.; Onshi, Y.; Baba, A. Tetrahedron Lett. 1998, 39,
6291. (g) Hirashita, T.; Kamei, T.; Horie, T.; Yamamura, H.;
Kawai, M.; Araki, S. J. Org. Chem. 1999, 64, 172. (h) Loh,
T.-P.; Pei, J.; Lin, M. Chem. Commun. 1996, 2315.
12. Ranu, B. C.; Hajra, A.; Jana, U. J. Org. Chem. 2000, 65, 6270.
13. Ranu, B. C.; Hajra, A.; Jana, U. Org. Lett. 1999, 1, 1141.
14. (a) Babu, G.; Perumal, P. T. Tetrahedron Lett. 1997, 38, 5025.
(b) Babu, G.; Perumal, P. T. Tetrahedron 1998, 54, 1627.
(c) Babu, G.; Nagarajan, R.; Perumal, P. T. Synthesis 2000,
661. (d) Hadden, M.; Stevenson, P. J. Tetrahedron Lett. 1999,
40, 1215.
1492, 1453, 1281, 1260, 1237, 1122, 975, 772, 741 cm21
;
1H NMR (400 MHz, CDCl3) d 7.66–7.62 (m, 3H), 7.37–
6.79 (m, 7H), 4.83 (d, 1H, J¼9.7 Hz), 4.25 (d, 1H,
J¼8.6 Hz), 3.88 (s, 3H), 3.75–3.46 (m, 2H), 3.09 (m,
1H), 2.63–1.24 (m, 14H); 13C NMR (100 MHz, CDCl3) d
148.7, 144.6, 140.1, 135.4, 129.6, 127.8, 127.4, 126.6,
125.9, 124.1, 122.5, 122.1, 120.7, 117.8, 110.8, 103.0, 89.8,
68.1, 56.2, 52.7, 44.6, 35.4, 29.2, 26.9, 25.3, 22.2; MS (m/z):
442 (Mþ). Anal. calcd for C28H32N2O: C, 75.65; H, 7.26; N,
6.30. Found: C, 75.78; H, 7.14; N, 6.38%.
Acknowledgements
15. Hunig, S.; Lucke, E.; Brenninger, W. Org. Synth. Collect. Vol.
V 1973, 5, 808.
16. CCDC No: 226164.
One of the authors (M.A.) thanks the Council of Scientific
and Industrial Research, New Delhi, India for financial
support.