Efficient organocatalytic synthesis of 1,8-dioxo-octahydroxanthenes

Article abstract of DOI:10.1080/00397911.2011.571804

(Chemical Equation Presented) L-Proline has been used as an organocatalyst for an efficient synthesis of 1,8-dioxo-octahydroxanthenes by treatment of aldehydes (aromatic, heteroaromatic, and aliphatic) with 5,5-dimethyl-1,3- cyclohexanedione. Three new co

Full text of DOI:10.1080/00397911.2011.571804

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Efficient Organocatalytic Synthesis of
1
,8-Dioxo-octahydroxanthenes
a a
a
Biswanath Das , J. Kashanna , Rathod Aravind Kumar
&
a
Paramesh Jangili
a
Organic Chemistry Division I, Indian Institute of Chemical
Technology, Hyderabad, India
Accepted author version posted online: 02 Jan 2012.Published
online: 29 May 2012.
To cite this article: Biswanath Das , J. Kashanna , Rathod Aravind Kumar & Paramesh Jangili (2012)
Efficient Organocatalytic Synthesis of 1,8-Dioxo-octahydroxanthenes, Synthetic Communications: An
International Journal for Rapid Communication of Synthetic Organic Chemistry, 42:19, 2876-2884,
DOI: 10.1080/00397911.2011.571804
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1
Synthetic Communications , 42: 2876–2884, 2012
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2011.571804
EFFICIENT ORGANOCATALYTIC SYNTHESIS
OF 1,8-DIOXO-OCTAHYDROXANTHENES
Biswanath Das, J. Kashanna, Rathod Aravind Kumar, and
Paramesh Jangili
Organic Chemistry Division I, Indian Institute of Chemical Technology,
Hyderabad, India
GRAPHICAL ABSTRACT
Abstract L-Proline has been used as an organocatalyst for an efficient synthesis of
1
,8-dioxo-octahydroxanthenes by treatment of aldehydes (aromatic, heteroaromatic, and
aliphatic) with 5,5-dimethyl-1,3-cyclohexanedione. Three new compounds have been
prepared.
Keywords Aldehydes; 5,5-dimethyl-1,3-cyclohexanedione; 1,8-dioxo-octahydroxanthenes;
L-proline
INTRODUCTION
Organocatalytic reactions have attracted much attention in recent years
[
1,2]
because they do not require harmful metal-based catalysts.
contribute significantly to green chemistry. In the continuation of our work
These reactions thus
[
3–5]
on
the development of useful synthetic methodologies, we have discovered an efficient
method for organocatalytic synthesis of 1,8-dioxo-octahydroxanthenes. These com-
pounds possess important biological properties and are valuable synthetic intermedi-
[
6]
ates. Earlier different Lewis acids, heterogeneous catalysts, and ionic liquids were
used for preparation of these compounds.
[7–23]
However, the immediate preparation
of the catalysts, long reaction times, unsatisfactory yields, harsh reaction conditions,
and limited applicability are problems in various methods of synthesis of the com-
pounds. Here, we report the organocatalytic synthesis of these compounds that we
developed.
Received December 7, 2010.
Part 215 in the series ‘‘Studies on novel synthetic methodologies.’’
Address correspondence to Biswanath Das, Organic Chemistry Division I, Indian Institute of
Chemical Technology, Hyderabad 500007, India. E-mail: biswanathdas@yahoo.com
2
876

1
,8-DIOXO-OCTAHYDROXANTHENES
2877
RESULTS AND DISCUSSION
The synthesis of 1,8-dioxo-octahydroxanthenes was carried out by treatment of
aldehydes with 5,5-dimethyl-1,3-cyclohexanedione in the presence of L-proline as a
ꢀ
catalyst at 60 C (Scheme 1).
Initially, the reaction of benzaldehyde with 5,5-dimethyl-1,3-cyclohexanedione
was conducted in different solvents such as MeOH, tetrahydrofuran (THF), CHCl3,
dichloroethane (DCE), dichloromethane (DCM) and 1,4-dioxane (Table 1) at differ-
ꢀ
ent temperatures. Considering the yield, DCE was found to be most effective at 60 C.
However, at low temperature and room temperature the reaction did not afford any
isolable product (Table 2). The reaction in DCE was complete within 6 h, and the
Scheme 1. Synthesis of 1,8-dioxo-octahydroxanthenes.
Table 1. Synthesis of 1,8-dioxo-octahydroxanthenes using 5-dimethyl-1,
3-cyclohexanedione (2.0 mmol) and benzaldehyde (1.0 mmol) for 6 h using
different solvents (4 ml) in the presence of L-proline (0.4 mmol) under reflux
Entry
Solvent
MeOH
Isolated yield (%)
1
2
3
4
5
6
7
8
9
76
69
71
66
62
53
49
83
0
Isopropanol
THF
1,4-Dioxane
DMF
CHCl
DCM
DCE
3
Toluene
Table 2. Optimization of the reaction temperature as the condensation of
,5-dimethyl-1,3-cyclohexanedione (2.0 mmol) and benzaldehyde (1.0 mmol)
using DCE (4 ml) in the presence of L-proline (0.4 mmol)
5
ꢀ
Entry
Time (h)
Temperature ( C)
Isolated yield (%)
1
2
3
4
5
6
12
12
12
12
6
ꢁ20
Rt
40
0
Trace
31
50
60
76
83
6
80
83

2878
B. DAS ET AL.
Table 3. Effect of catalysts in the condensation of 5,5-dimethyl-1,3-cyclohexanedione and benzaldehyde
ꢀ
Entry
Catalyst
Time (h)
Temperature ( C)
Isolated yield (%)
Reference
1
2
3
4
5
[bmim]PF
DBSA
L-Proline
6
7
6
6
6
6
80
80
60
80
80
55
81
22
12
—
9
83
60
PPA ꢂ SiO
2
HClO
4
ꢂ SiO
2
Trace
9
yield was 83%. Using other solvents, the reaction time was longer and the yield
was less. The catalytic activity of L-proline has also been compared with that of
other catalysts used earlier for the preparation of xanthene derivatives (Table 3),
and the present catalyst was most effective. Thus, subsequently DCE was used
ꢀ
at 60 C to prepare a series of 1,8-dioxo-octahydroxanthenes from various alde-
hydes and 5,5-dimethyl-1,3-cyclohexanedione in the presence of L-proline (Table 4).
Both aromatic and aliphatic aldehydes were employed to prepare the xanthene
[
7–23]
derivatives. Earlier in several methods only the aromatic aldehydes were used.
In the present synthesis, aromatic aldehydes contained both electron-donating and
a
Table 4. Synthesis of 1,8-dioxo-octahydroxanthenes
Entry
Aldehyde
Product
Isolated yield (%)
Reference
a
83
12
b
73
12
c
79
—
(
Continued )

1
,8-DIOXO-OCTAHYDROXANTHENES
2879
Table 4. Continued
Entry
Aldehyde
Product
Isolated yield (%)
Reference
d
79
75
80
81
12
13
16
12
e
f
g
h
78
12
i
79
18
(
Continued )

2880
B. DAS ET AL.
Table 4. Continued
Entry
Aldehyde
Product
Isolated yield (%)
Reference
j
82
14
k
79
12
l
90
12
m
69
—
n
65
17
23
o
p
60
59
—
(
Continued )

1
,8-DIOXO-OCTAHYDROXANTHENES
2881
Table 4. Continued
Entry
Aldehyde
Product
Isolated yield (%)
Reference
a
1
13
The structures of the products were established from their spectral (IR, H and C NMR, and MS)
and elemental analysis data.
electron-withdrawing groups. Heteroaromatics such as furan and thiofuran also
underwent conversion smoothly. Various functional groups including hydroxyl,
ether, halogen, nitro, and nitrile groups remained intact. The structures of the pro-
1
13
ducts were established from their spectral [infrared (IR), H and C NMR, and mass
MS)] and analytical data. The hydrogen and carbon atoms of each compound were
(
assigned with the aid of 2D NMR [correlation spectroscopy (COSY) and heteronuc-
lear multiple-bond correlation (HMBC)] spectra and distortionless enhancement by
polarization transper (DEPT) experiment.
L-Proline is a less expensive and readily available amino acid. It has been used
successfully to catalyze the synthesis of the title compounds. The yields of the
Scheme 2. Mechanism of the synthesis of 1,8-dioxo-octahydroxanthenes.

2882
B. DAS ET AL.
products were greater than those obtained earlier by using different catalysts
Table 3). The reaction temperature was also less in the present conversion. How-
(
ever, the products were yielded in nonchiral form, possibly because of their easy
racemization. The reaction occurs spontaneously, and no intermediate has been iso-
[24]
lated. However, following the literature,
the mechanism of the conversion has
been proposed (Scheme 2). When N-Boc-protected L-proline was used instead of
L-proline, the reaction afforded only a trace amount of products, supporting the
presented mechanism.
CONCLUSION
In conclusion, we have developed an efficient organocatalytic synthesis of
,8-dioxo-octahydroxanthene by treatment of aldehydes (aromatic, heteroaromatic,
1
and aliphatic) with 5,5-dimethyl-1,3-cyclohexanedione using L-Proline as a catalyst.
The mild reaction conditions, utilization of a metal-free catalyst, good yields, and
wide applicability are the advantages of the present method.
EXPERIMENTAL
Synthesis of 1,8-Dioxo-octahydroxanthenes
To a mixture of 5,5-dimethyl-1,3-cyclohexanedione (2.0 mmol) and L-proline
0.4 mmol) in DCE (4.0 ml), aldehyde (1.0 mmol) was added. The reaction mixture
was heated at 60 C for 6 h. The solvent was removed under reduced pressure, and
water (10 ml) was added to the residue. The mixture was extracted with ethyl acetate
(
ꢀ
(
3 ꢃ 10 ml). The extract was dried (anhydrous Na SO ), concentrated, and subjected
2
4
to column chromatography [silica gel (100–200 mesh), EtOAc-n hexane] to obtain a
pure product.
Compound 3c
ꢁ1
1
IR (KBr): 2961, 2871, 1664, 1463, 1362, 1339, 1198, 667 cm . H NMR
0
0
(
200 MHz, CDCl ): d 7.12 (2H, d, J ¼ 8.0 Hz, H-3 , H-5 ), 7.01 (2H, d, J ¼ 8.0 Hz,
3
0
0
H-2 , H-6 ), 4.64 (1H, s, H-9), 2.80 (1H, m, -CHMe ), 2.42 (4H, s, H -2, H -7),
2
2
2
2
.19 (4H, s, H -4, H -5), 1.20 (6H, d, J ¼ 7.0 Hz, -CHMe ), 1.11 and 0.99 (6H each,
2
2
2
1
3
s, Me -3, Me -6). C NMR (50 MHz, CDCl ); d 195.1 (C-1, C-8), 161.3 (C-4a,
C-5a), 146.0 (C-4 , 141.2 (C-1 ), 128.8 (C-2 , C-6 ), 125.4 (C-3 , C-5 ), 115.7 (C-1a,
C-8a), 50.2 (C-2, C-7), 40.1 (C-4,6 C-5), 34.6 (-CHMe ), 32.4 (C-9), 30.8 (C-3,
2 2 3
0
0
0
0
0
0
2
þ
C-6), 29.8, 27.5 (Me -3, Me -6), 24.6 (CHMe ). ESIMS; m=z 393 [M þ H] , 273
2
2
2
þ
M-Ar] . Anal. calcd. for C H O : C, 79.59; H, 8.16%. Found: C, 79.52; H, 8.21%.
26 32 3
[
Compound 3m
IR (KBr): 2926, 2854, 1670, 1446, 1359, 1196, 761 cm . H NMR (200 MHz,
ꢁ
1 1
0
0
0
CDCl ): d 7.11 (1H, m, H-4 ), 6.21 (1H, m, H-2 ), 6.18 (1H, m, H-3 ), 4.90 (1H, s,
3
H-9), 2.42 (4H, s, H -2, H -7), 2.21 (4H, s, H -4, H -5), 1.11 (6H, s), 1.02 (6H, s,
3
2
2
2
2
1
Me -3, Me -6). C NMR (50 MHz, CDCl ): d 195.3 (C-1, C-8), 163.2 (C-4a,
2
2
3

1
,8-DIOXO-OCTAHYDROXANTHENES
2883
0
0
0
0
C-5a, C-1 ), 140.2 (C-4 ), 110.3 (C-3 ), 106.0 (C-2 ), 50.2 (C2, C-7), 40.1 (C-4, C-5),
þ
3
0.3, 29.9 (C-3, C-9), 26.5 (Me -3, Me -6). ESIMS: m=z 341 [M þ H] , 273
2
2
þ
M-Ar] . Anal. calcd. for C H O : C, 74.12; H, 7.06%. Found: C, 74.22; H, 7.12%.
21 24 4
[
Compound 3p
ꢁ
1
1
IR (KBr): 2960, 2224, 1672, 1608, 1463, 1361, 1123, 654 cm . H NMR
(
4
200 MHz, CDCl ): d 3.72 (1H, m, H-9), 2.28 (4H, s, H -2, H -7), 2.16 (4H, s, H -
3
2
2
2
0
, H -5), 1.56–1.33 (4H, m, H -1, H -2 ), 1.12 (6H, s), 1.10 (6H each, s, Me -3,
2 2 2 2
0
13
Me -6), 0.73 (3H, t, J ¼ 7.0 Hz, Me-3 ). C NMR (50 MHz, CDCl ): d 195.8 (C-1,
2
3
C-8), 163.2 (C-4a, C-5a) 96.2 (C-2a, C-8a) 51.3 (C-2, C-7), 41.4 (C-4, C-5), 30.2
0 0
C-3, C6), 29.6 (C-9), 27.5, 26.8 (Me -3, Me -6), 25.7 (C-1 ), 20.9 (C-2 ), 10.6
2 2
(
0
þ
(
8
Me-3 ). ESIMS: m=z 317 [M þ H] . Anal. calcd. for C H O : C, 75.95; H,
2
0
28
3
.86%. Found: C, 75.83; H, 8.92%.
ACKNOWLEDGMENTS
The authors thank the Council of Scientific and Industrial Research and the
University Grants Commission, New Delhi, for financial assistance.
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