An efficient synthesis of 6H,7H-chromeno[4,3-b]chromenes and 6,7-dihydrothio chromeno[3,2-c]chromenes as 9-substituted xanthene like analogs

Article abstract of DOI:10.1016/j.tetlet.2011.08.127

An efficient synthetic route with good overall yields to access 7-aryl/heteroaryl/alkyl substituted 6H,7H-chromeno[4,3-b]chromene, and 6,7-dihydrothiochromeno[3,2-c]chromene scaffolds has been developed. The route to these xanthene-like analogs involves a

Full text of DOI:10.1016/j.tetlet.2011.08.127

Tetrahedron Letters 52 (2011) 5951–5955
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Tetrahedron Letters
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An efficient synthesis of 6H,7H-chromeno[4,3-b]chromenes and 6,7-dihydrothio
chromeno[3,2-c]chromenes as 9-substituted xanthene like analogs q
⇑
Sudipta Kumar Manna, Maloy Kumar Parai, Gautam Panda
Medicinal and Process Chemistry Division, CSIR, Central Drug Research Institute, Lucknow 226001, UP, India
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient synthetic route with good overall yields to access 7-aryl/heteroaryl/alkyl substituted 6H,7H-
chromeno[4,3-b]chromene, and 6,7-dihydrothiochromeno[3,2-c]chromene scaffolds has been developed.
The route to these xanthene-like analogs involves a three-step reaction sequence: (1) Michael addition of
readily available phenol and thiophenol to 4-chloro-2,2-dimethyl-2H-chromene-3-carbaldehyde, (2)
Grignard reaction of different aryl, heteroaryl and alkyl magnesium bromides on the resulting carbalde-
hydes followed by (3) FeCl3 catalyzed spontaneous intramolecular Friedel–Craft’s reaction on the dia-
rylmethyl carbinols.
Received 22 June 2011
Revised 20 August 2011
Accepted 23 August 2011
Available online 5 September 2011
Ó 2011 Elsevier Ltd. All rights reserved.
Xanthenes and related compounds have been of significant
interest because of their broad spectrum of pharmaceutical impor-
tance, such as analgesic,1 anti-bacterial,2 anti-inflammatory,3 and
anti-viral activities.4 These compounds are being used as antago-
nists for the paralyzing action of zoxazolamine5 and in photody-
namic therapy (PDT).6 Many benzoxanthene derivatives are
potent nonpeptidic inhibitors of recombinant human calpain I,7
and novel CCR1 receptor antagonists.8 It is also worth mentioning
that xanthenes and the related condensed ring systems are being
used as dyes and fluorescent materials because of their useful
spectroscopic properties.9 Examples include fluorescein, rosamine,
and fluorone (Fig. 1). Fluorone derivatives have wide applications,
such as in the detection of a variety of metal ions,10 sugars,11 phos-
phorylated molecules,12 HIV-1 nucleocapsid protein,13 reactive
oxygen species,14 in screening assays for mitochondrial permeabil-
ity,15 telomerase inhibition,16 and acetylcholinesterase inhibi-
tion.17 Furthermore, these heterocycles have also been utilized in
laser technologies,18 as pH sensitive fluorescent materials for the
visualization of biomolecules,19 cosmetics, potential agrochemi-
cals, pigments.20 Moreover, this prototype is also common in sev-
eral bioactive natural products.21
ular O-arylation of o-halobenzophenones and applied SNAr reac-
tions with KOH as base under aqueous condition to synthesize
xanthone scaffolds.
Careful analysis of reaction conditions suggests that the above
methods have several drawbacks, such as the use of unfavorable
reaction conditions (strong acidic media with high temperature),
stoichiometric amounts of reaction promoters, and the moisture
sensitiveness of the reported catalysts. This warrants new, ample
scope for the development of new synthetic protocols toward
xanthene scaffolds. We are currently engaged in the design and
synthesis of symmetrical and unsymmetrical trisubstituted meth-
anes (TRSMs) for the development of new anti-tubercular and anti-
cancer agents by intermolecular diarylmethylation of electron-rich
HO
O
O
R2N
O
NR2X
The importance and utility of this family of compounds have led
to the development of several synthetic strategies for accessing
xanthene scaffolds.22 Very recently, some elegant synthetic proto-
cols for xanthones have been reported. Larock and co-workers23 re-
ported an aryl to imidoyl palladium migration involving
Fluorone 1
Rosamine 2
X
O
X
X
R1
O
intramolecular C–H activation to access xanthone skeletons.
O
O
24
´
Domınguez and co-workers employed Cu-mediated intramolec-
R2
X =
, Fluorescein 3
OH
q
CDRI communication number 8119.
5
X = NR2, Rhodamine 4
⇑
Corresponding author. Tel.: +91 522 2612411 18x4385, 4469, 4474; fax: +91
522 2623405.
E-mail address: gautam.panda@gmail.com (G. Panda).
X = O, S
Figure 1. Structures of some common xanthene dyes (1–4) and target molecule (5).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.08.127

5952
S. K. Manna et al. / Tetrahedron Letters 52 (2011) 5951–5955
Table 1
Optimization studies for the synthesis of 11i.
S
S
O
Lewis acid or Protic acid
Dry CH 2Cl2 or Benzene
Cl
O
HO
H3CO
Cl
H3CO
10i
11i
Entry
Catalyst
Conditions
Yielda (%)
1
2
3
4
5
6
7
Conc. H2SO4 (Catalytic)
Anhyd. AlCl3 (1.2 equiv)
TfOH (10 mol %)
Anhyd. FeCl3 (1.2 equiv)
Sc(OTf)3 (10 mol %)
Dry benzene, reflux, 20 min
Dry CH2Cl2, 0 °C to rt, 12 min
Dry CH2Cl2, 0 °C to rt, 10 min
Dry CH2Cl2, 0 °C to rt, 2–5 min
Dry CH2Cl2, 0 °C to rt, 12 min
Dry CH2Cl2, 0 °C to rt, 2–5 min
Dry CH2Cl2, 0 °C to rt, 8 min
32
51
45
68
52
77
48
Anhyd. FeCl3 (10 mol %)
BF3–OEt2 (10 mol %)
a
Isolated yield of 11i after silica gel column chromatography.
arenes using diaryl carbinols as alkylating agents.25,26 In continua-
tion, we became interested in synthesizing 9-substituted xanth-
enes as conformationally constrained triarylmethanes (TRAMs)
for which not many methods are available.27,28 In this context,
we envision a versatile and efficient method of synthesizing xan-
thene motifs like 5 with distinct skeletal frameworks involving
Grignard reaction and Lewis acid catalyzed intramolecular Fri-
edel–Craft’s arylation as the key synthetic steps (Scheme 1).
The requisite aryl, heteroaryl, and alkyl substituted methanols
10a–l were synthesized by the reaction between Grignard reagents,
generated from commercially available aryl, heteroaryl and alkyl
bromo derivatives, and carbaldehydes 9a–d, which in turn were
easily generated from the intermolecular Michael addition29 of
phenols or thiophenols 8a–c on 4-chloro-2,2-dimethyl-2H-chro-
mene-3-carbaldehydes 7 with 65–71% yields. The carbaldehyde 7
was readily synthesized from corresponding 4-chromanone 6 via
the Vilsmeier–Haack–Arnold reaction30 (Scheme 1).
In our initial endeavor, we examined the cyclization reaction of
carbinol 10i to the corresponding xanthene derivative 11i in the
presence of conc. H2SO4 (Table 1, Entry 1). Thus, a solution of 10i
in dry benzene along with a catalytic amount of conc. H2SO4 was
heated at reflux temperature, leading to partial decomposition of
the starting material and hence the yield of the expected product
was only 32%. To further improve the yield and optimize the
standard reaction conditions, the same reaction was carried out
in the presence of several protic and Lewis acid catalysts, such as
TfOH, anhydrous AlCl3, BF3–OEt2, and Sc(OTf)3. Finally, it was found
that 10i could be transformed into 11i in high yield by treating a
solution of 10i in dry CH2Cl2 at 0 °C to rt using a catalytic amount
of anhydrous FeCl3 (10 mol %) (Entry 6).32
On the basis of these facts and the above optimization proto-
cols, we treated all the resulting diarylmethyl carbinols 10a–l with
FeCl3 (10 mol %) in anhydrous dichloromethane (CH2Cl2) at 0 °C to
rt to furnish the corresponding desired substituted xanthene scaf-
folds 11a–l (Table 2).31
After optimizing the reaction conditions and with final products
at hand, we explored the conversion of carboxaldehydes 9a and 9b
directly to indole containing xanthene like scaffolds (compounds
11m and 11n) through a one-pot scalable synthetic step. Toward
this objective, the carbaldehydes 9a–b on reaction with POCl3
and indole in dry CH2Cl2 furnished 11m and 11n33 in 55% and
64% yield, respectively (Scheme 2). However, this reaction was per-
formed two times on gram scale (9a: 3.544 mmol, 54% and
3.705 mmol, yield: 52%; 9b: 3.676 mmol, yield: 53%, and
3.060 mmol, yield: 56%) and the yield varies from 52–56%. In this
reaction, a small amount of the unsubstituted side products 12m
and 12n were also formed through FeCl3 catalyzed carbon–carbon
bond cleavage27,28 (9 and 17% respectively).
HX
Cl
O
CHO
ii
R1
i
R
R
O
8a
8b
O
; R 1
; R1
=
=
=
p
-OMe, X = O
7
6
m
-OMe, X = S
R =
7 -OMe, H
8c ; R 1
p-Cl, X = S
R
R1
X
X
CHO
iii
R1
R
O
O
HO
10a-l
R2 = Aryl, Heteroaryl, Alkyl
9a ; R= H, R
=
=
=
p
-OMe, X = O
-OMe, X = S
-Cl, X = S
-OMe, X = S
R2
9b; R= H, R 1
m
1
1
9c
; R= H, R
p
9d; R=
7
-OMe,R 1
=
m
Scheme 1. Reagents and conditions: (i) POCl3, dry DMF, 0 °C to rt, 72–75% (ii) NaH, dry THF, 0 °C to rt, 2–3 h, 65–71%; (iii) R2-Br, Mg/I2, dry THF, rt, 1 h, 62–71%.

S. K. Manna et al. / Tetrahedron Letters 52 (2011) 5951–5955
5953
Table 2
Synthesis of unsymmetrical 9-substituted xanthene like scaffolds 11a–l
R
R
Anhyd. FeCl
,
3
X
X
Dry CH 2 Cl 2
R1
R1
0
oC - r.t , 2 - 5 min
O
O
HO
R2
R2
10a-l
11a-l
Entry
Aldehydes
Alcohols, Yield (%)
Products
Yield (%)
H3CO
S
H3CO
S
O
O
1
10a, 68
73
OHC
S
11a
O
O
O
O
H3CO
H3CO
OHC
2
10b, 63
58
SCH 3
11b
O
O
O
O
H3CO
H3CO
OHC
3
4
5
10c, 65
10d, 62
10e, 64
71
OCH3
11c
H 3CO
S
H3CO
S
O
O
66
OHC
H 3CO
11d
H3CO
S
H3CO
S
O
O
OHC
67
OCH 3
11e
(continued on next page)

5954
S. K. Manna et al. / Tetrahedron Letters 52 (2011) 5951–5955
Table 2 (continued)
Entry
Aldehydes
Alcohols, Yield (%)
Products
Yield (%)
O
O
O
O
H3CO
6
OHC
10f, 66
H3CO
63
S
11f
O
O
O
O
H3CO
H3CO
OHC
7
10g, 63
59
CF 3
11g
S
S
O
O
8
10h, 68
55
Cl
Cl
OHC
S
11h
S
S
O
Cl
O
9
10i, 70
77
Cl
OHC
H 3CO
11i
S
S
O
O
Cl
Cl
OHC
10
10j, 71
61
OCH
3
11j
H3CO
S
H3 CO
S
11
12
10k, 65
63
56
O
O
OHC
CH3
11k
OCH
OCH 3
3
H3CO
S
H3CO
S
10l, 67
O
O
OHC
CH 3
11l
In conclusion, we have demonstrated a convenient and efficient
synthetic procedure for the synthesis of structurally diverse 6H,7H-
chromeno[4,3-b]chromenes and 6,7-dihydrothiochromeno[3,2-
c]chromene in good overall yields. Synthesis of these 9-substituted
xanthene like heteroatoms containing scaffolds employed a Grig-
nard reaction followed by a Lewis acid catalyzed intramolecular
Friedel–Craft’s reaction. These diverse xanthene like skeletons
may have new interesting biological properties.

S. K. Manna et al. / Tetrahedron Letters 52 (2011) 5951–5955
5955
X
POCl3, Indole ,
Dry CH2Cl2
0 °C - r.t, 6 h
X
X
R1
O
R1
R1
O
O
OHC
12m; R1 = p-OMe, X = O, 9%
12n; R1 = m-OMe, X = S, 17%
9a; R1 = p-OMe, X = O
9b; R1 = m-OMe, X = S
HN
11m; R1 = p-OMe, X = O, 55%
11n; R1 = m-OMe, X = S, 64%
Scheme 2. Reagents and conditions: (a) POCl3 (1.5 mol %), dry CH2Cl2, 0 °C to rt, 6 h, 55–64%.
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Acknowledgments
This research project was partly supported by ICMR and DST,
New Delhi, India. Sudipta and Maloy thank the Council of Scientific
and Industrial Research (CSIR), India for research fellowships.
Instrumental facilities from SAIF, CDRI is acknowledged.
23. Zhao, J.; Yue, D.; Campo, M. A.; Larock, R. C. J. Am. Chem. Soc. 2007, 129, 5288.
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24. (a) Barbero, N.; SanMartin, R.; Domınguez, E. Green Chem. 2009, 11, 830; (b)
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Supplementary data
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Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2011.08.127.
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31. Selected spectral data with experimental procedures.
Typical procedure for Friedel–Craft’s reaction to access 6H,7H-chromeno[4,3-
b]chromenes and 6,7-dihydrothiochromeno[3,2-c]chromenes:
To a 0.025 molar solution of diarylmethyl carbinol in anhydrous CH2Cl2, a
catalytic amount (10 mol %) of anhydrous FeCl3 was added at 0 °C and was
stirred for 2–5 min. After completion of the reaction water was added and the
resulting mixture was extracted with CH2Cl2. The crude reaction mixture was
purified by silica gel column chromatography (AcOEt/hexane, 4:96) to generate
the desired products.
32. 9-chloro-7-(2-methoxyphenyl)-6,6-dimethyl-6,7-dihydro thiochromeno[3,2-
c]chromene 11i:
A
mixture of carbinol 10i (115 mg, 0.261 mmol) and FeCl3 (4.233 mg,
0.026 mmol) furnished the product 11i as a viscous pink oil (yield: 77%,
85 mg). Rf = 0.5 (10% AcOEt/hexane); IR (Neat): 3449, 3070, 2928, 2365, 1597,
1482, 1243, 1031, 764, 672 cmÀ1 1H NMR (300 MHz, CDCl3): dH 7.62–7.48 (m,
;
3H), 7.23–7.12 (m, 4H), 7.09–6.94 (m, 1H), 6.87–6.77 (m, 3H), 5.39 (s, 1H), 3.96
(s, 3H), 1.42 (s, 3H), 1.25 (s, 3H); 13C NMR (75 MHz, CDCl3): dC 155.2, 151.8,
138.0, 132.0, 131.9, 130.6, 129.6, 129.2, 128.8, 128.5, 128.4, 127.8, 126.5, 124.2
123.6, 121.1, 121.0, 116.7, 110.8; 79.6, 55.4, 40.2, 26.0, 25.7. MS (ESI): m/z
421.2 [M+1]+; Anal. Calcd. for C25H21ClO2S: C, 71.33; H, 5.03. Found C, 71.46; H,
5.15.
33. 3-(10-methoxy-6,6-dimethyl-6,7-dihydrothiochromeno [3,2-c] chromen-7-yl)-1H-
indole 11n:
To a stirred solution of 9b (116 mg, 0.355 mmol) in dry CH2Cl2 (8 mL) were
added indole (63 mg, 0.532 mmol) in dry CH2Cl2 (8 mL) and POCl3
(0.005 mmol, 0.481 mL) at 0 °C and the mixture was stirred at room
temperature until completion of the reaction (as observed on TLC). After
completion of the reaction, the mixture was poured into ice-water and
extracted with CH2Cl2, washed with brine and dried over Na2SO4. The reaction
mixture was concentrated in vauco and purified by silica gel column
chromatography (AcOEt/hexane, 10:90), furnished 11n as a viscous brownish
oil (64%, 97 mg). Rf = 0.4 (15% AcOEt/hexane); IR (Neat): 3483, 2924, 2854,
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1638, 1487, 1458, 1218, 1035, 767 cmÀ1 1H NMR (300 MHz, CDCl3): dH 7.87
;
(br s, 1H), 7.82–7.79 (m, 1H), 7.56–7.52 (m, 1H), 7.46 (d, 1H, J = 8.51 Hz), 7.26–
7.18 (m, 3H), 7.15–7.09 (m, 2H), 6.99–6.94 (m, 1H), 6.89–6.85 (m, 2H), 6.77–
6.74 (m,1H), 5.09 (s, 1H), 3.71 (s, 3H), 1.42 (s, 6H); 13C NMR (75 MHz, CDCl3): dC
157.9, 151.6, 136.5, 133.7, 132.0, 129.4, 129.3, 129.0, 125.8, 123.8, 122.8, 122.4,
121.8, 121.1, 120.9, 119.5, 118.6, 116.6, 115.4, 113.2, 111.9, 111.3, 79.5, 55.4,
39.7, 26.2, 25.9. MS (ESI): m/z 426.5 [M+1]+; Anal. Calcd. for C27H23NO2S: C,
76.21; H, 5.45; N, 3.29. Found: C, 76.36; H, 5.56; N, 3.45.