Heterocycle-bridged and conformationally constrained retinoids: Synthesis of 4-(7,8,9,10-Tetrahydro-7,7,10,10-tetramethyl-4H-benzo[6,7]chromeno-[4,3-d]thiazole-2-yl)benzoic acid

Article abstract of DOI:10.1002/cjoc.201090325

Retinoids are a class of synthetic and natural compounds structurally related to retinoic acid. In a search for discovery of a new class of heterocycle-bridged and conformationally constrained retinoids, here we report the synthesis of 4-(7,8,9,10-tetrahydro-7,7,10,10-tetramethyl-4H-benzo[6,7]chromeno[4,3-d]thiazole-2-yl)benzoic acid (10) starting from 5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphthalen-2-ol (13). Several approaches was attempted to obtain target compound 10. Structure elucidation of synthesized compounds has been made on the basis of elemental analysis and spectral data (¹H NMR, IR and MS).

Full text of DOI:10.1002/cjoc.201090325

FULL PAPER
Heterocycle-bridged and Conformationally Constrained
Retinoids: Synthesis of 4-(7,8,9,10-Tetrahydro-
7,7,10,10-tetramethyl-4H-benzo[6,7]chromeno-
[4,3-d]thiazole-2-yl)benzoic Acid
Lamei, Navida
Foroumadi, Alirezaa,b
Emami, Saeedc
Amini, Mohsena,b
Shafiee, Abbas*,a,b
a Drug Design & Development Research Center, Tehran University of Medical Sciences, Tehran 14174, Iran
b Department of Medicinal Chemistry, Faculty of Pharmacy & Pharmaceutical Sciences Research Center,
Tehran University of Medical Sciences, Tehran 14174, Iran
c Department of Medicinal Chemistry and Pharmaceutical Sciences Research Center, Faculty of Pharmacy,
Mazandaran University of Medical Sciences, Sari, Iran
Retinoids are a class of synthetic and natural compounds structurally related to retinoic acid. In a search for
discovery of a new class of heterocycle-bridged and conformationally constrained retinoids, here we report the syn-
thesis of 4-(7,8,9,10-tetrahydro-7,7,10,10-tetramethyl-4H-benzo[6,7]chromeno[4,3-d]thiazole-2-yl)benzoic acid (10)
starting from 5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphthalen-2-ol (13). Several approaches was attempted to ob-
tain target compound 10. Structure elucidation of synthesized compounds has been made on the basis of elemental
analysis and spectral data (1H NMR, IR and MS).
Keywords retinoids, conformationally constrained analog, thiazole
Introduction
ceptor-selective retinoids, not only to characterize the
functions of specific receptors but also to develop new
therapeutic agents.8,9
Retinoids belong to the steroid-thyroid-retinoid su-
perfamily of hormones that regulate gene transcription
by binding to and activating nuclear receptors.1 Retinoic
acid (1) plays a crucial role in many aspects of cell pro-
liferation and differentiation, and has proved useful for
the treatment of dermatologic diseases, photoaging and
several cancers.1 As a consequence, synthetic and natu-
ral retinoid analogs have a broad and different range of
activities including regulation of cell differentiation and
proliferation, embryonic development, bone formation,
carbohydrates and lipids metabolism, carcinogenesis
and immune system function.2-4
Retinoids bind to the six known retinoid receptors,
the retinoic acid receptors— RARα, RARβ and RARγ-
and retinoid X receptors— RXRα, RXRβ and RXRγ. It
is believed that RARs and RXRs act mainly as
RAR-RXR heterodimers, the functional units that also
affect other cell signaling pathways, albeit RXR can also
function autonomously.5 trans-Retinoic acid (1) is the
natural ligand for RARs, and its isomer 9-cis-retinoic
acid (2) has almost the same binding affinity toward
both RXRs and RARs.6,7
Several potent retinoids, such as AM580 (3), TTNPB
(4), and LGD1069 (5) have an aromatic carboxylic acid
moiety instead of the polyenecarboxylic acid of retinoic
acid (Figure 1). The presence of aryl rings as substitutes
of terminal dienes imparts greater stability in some of
the most active analogues, thus increasing the chances
for therapeutic application. In this type of compounds,
the hydrophobic part and the spacer between aromatic
carboxylic acid and hydrophobic section can be varied
with retention of high activity. Generally the 2,6,6-
trimethyl-1-cyclohexenyl ring (hydrophobic part) is re-
placed by the lipophilic bioisostere 5,6,7,8-tetrahydro-
5,5,8,8-tetramethylnaphthalene.10,11
The development of new active retinoids and the
identification of two distinct retinoid receptors have led
to an increased understanding of the cellular effects of
activation of these receptors and of mechanisms in-
volved in the retinoid-induced apoptosis. The stereo-
chemistry of the C-9 alkenyl portion of natural 9-cis-
retinoic acid seemed of particular importance for the
apoptotic activity, thus novel retinoid analogs bearing a
sterically restricted flexibility in this region were pre-
Extensive efforts have been made to synthesize re-
*
E-mail: ashafiee@ams.ac.ir; Tel.: 0098-21-66406757; Fax: 0098-21-66461178
Received October 20, 2009; revised March 22, 2010; accepted April 2, 2010.
Project supported by grants from Drug Design & Development Research Center, Tehran University of Medical Sciences and INSF (Iran National
Sciences Foundation).
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Lamei et al.
FULL PAPER
pared previously. The alkenyl basic motif of (E)-4-[2-
(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)-
propen-1-yl]benzoic acid (TTNPB) (4) was replaced by
an isoxazoline moiety (compounds 6 and 7) or an
isoxazole (compounds 8 and 9, Figure 2), which may
enable the system to better fit the receptor and also re-
duced toxicity.12
In the search for the new heterocyclic retinoids, we
considered that the conformational features of retinoid
could be changed by the incorporation of thiazole ring
and an additional oxymetylene spacer as a linker of tet-
rahydrotetramethylnaphthalenyl ring and aromatic car-
boxylic acid motifs. Thus we report here, synthesis of
compound 10 as a new class of heterocycle-bridged and
conformationally constrained retinoid (Figure 2).
Results and discussion
In the course of the investigation of the synthetic
pathway to target compound 10, we found that thiazole
ring closure of appropriate thiobenzamide with
3-bromochromanone was key reaction.13,14 As precursor
2,3,6,7,8,9-hexahydro-6,6,9,9-tetramethylbenzo[g]-
chromen-4-one (17) were a synthesized as outlined in
Scheme 1. At the first, the related diol (11) was con-
verted to di-chloro-analog (12) by using concentrated
hydrochloric acid saturated with hydrogen chloride gas
in room temperature. Friedel-crafts dialkylation of phe-
nol with compound 12 in the presence of AlCl3 was
used for preparing compound 13 in good yield. For
chromanone ring construction from phenolic compound
(13), three different routes were attempted: (i) nucleo-
philic substitution of 3-bromopropionic acid in the
presence of NaH and DMF followed by cyclization with
PPA; (ii) addition to acrylonitrile using NaOMe as a
base and subsequent cyclization with H2SO4 under
heating; (iii) acylation reaction with 3-chloropropionic
acid in the presence of trifluoromethane sulfonic acid
(TFMSA), followed by interamolecular nucleophilic
substitution using aqueous NaOH as a base. Best result
was achieved using the latter method with 41% overall
yield. However, in this method, overheating (more than
80 ℃) of β-chloropropiophenone (16) resulted in HCl
elimination and formation of α,β-unsaturated ketone (18)
as a by-product. As illustrated in Scheme 2, chromanone
(17) was brominated with copper(II) bromide in reflux-
ing CHCl3-EtOAc to give corresponding 3-bromo-
chromanone (19) (in contamination with dibromo-
compound) which was purified by column chromatog-
raphy.15
Figure 1 Structures of some natural and synthetic retinoids.
Several approaches were attempted to obtain target
compound 10 from 3-bromochromanone (19). The
Hantzsch reaction of 3-bromochromanone (19) with
4-bromobenzothioamide in refluxing EtOH afforded the
corresponding 4-bromophenylthiazole (20). As the next
step, we had planned to exchange the bromo-group of
compound 20 to a carboxylic acid substituent. However
the effort to introduce the carboxylic acid substituent by
butyl lithium hydride and CO2 failed due to the decom-
position. A further approach to final compound 10 was
intended to proceed via 4-methylphenylthiazole inter-
mediate (21) and subsequent oxidation of methyl group
to the carboxylic acid substituent. Thus, 3-bromochro-
manone (19) was refluxed in EtOH with 4-methylben-
Figure 2 Structures of some heterocycle-bridged retinoids 6— 9,
and heterocycle-bridged and conformationally constrained reti-
noid 10.
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Heterocycle-bridged and Conformationally Constrained Retinoids
Scheme 1 Synthesis of key intermediate 17
Reagents and conditions: (a) Concentrated HCl, HCl gas, r.t., 98%; (b) AlCl3, CH2Cl2, reflux, 88%; (c) bromopropionic acid, NaH, DMF, 70
—80 ℃, r.t., 16 h, 37%; (d) PPA, 80 ℃, 4 h, 46%; (e) acrylonitrile, NaOMe, 70—80 ℃, 7 h, 35%; (f) aq. H2SO4, 95—100 ℃, 3 h, 29%; (g) tri-
fluoromethane sulfonic acid (TFMSA), 3-chloropropionic acid, reflux, 40 min, 65—70 ℃, 68%; (h) aq. NaOH, r.t., 4 h, 63%
Scheme 2 Synthetic approaches to target compound 10
Reagents and conditions: (a) CuBr2, EtOAc-CHCl3 (V∶V, 50∶50), reflux, 3 h, 57%; (b) 4-bromobenzothioamide, EtOH, reflux, 3 h, 62%;
(c) buthyl lithium hydride, CO2, －10 ℃, 2 h; (d) 4-methyl benzothioamide, EtOH, reflux, 2 h, 58%; (e) aq. H2SO4, reflux, 2 h; (f) EtOH, reflux,
2 h, 42%; (g) K4[Fe(CN)6]•3H2O, Pd(OAc)2, sodium carbonate, dimethylacetamide (DMAC), 120 ℃, 43%; (h) aq. H2SO4, reflux, 1 h, 51%
zothioamide to afford corresponding 4-methylphenyl-
thiazole analog (21). Attempts to oxidation of the
methyl group of 4-methylphenylthiazole intermediate
(21) using different oxidant, such as potassium dichro-
mate was unsuccessful because of decomposition. Fi-
nally, the alternative approach was direct incorporation
of carboxylic acid in the course of thiazole formation.
Therefore, 4-bromobenzothioamide (22) was converted
to cyanobenzothioamide (23) using K4[Fe(CN)6]•3H2O
in the presence of Pd(OAc)2. Hydrolysis of cyanoben-
zothioamide (23) with aqueous solution of H2SO4 gave
thiocarbamoylbenzoic acid (24). Compound 24 was re-
acted with 3-bromochromanone (19) to afford thiazole
compound (10) in 37% yield.
Experimental
Chemicals and all solvents used in this study were
purchased from Merck AG and Aldrich Chemical
(Darmstadt and Steinheinresp, Germany). Melting
points were determined on a Kofler hot stage apparatus
(C. Reihert, Vienna, Austria) and uncorrected. The IR
spectra were obtained on a Shimadzu 470 spectropho-
tometer (potassium bromide disk; Shimadzu, Tokyo,
Chin. J. Chem. 2010, 28, 1951— 1956
© 2010 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.cjc.wiley-vch.de
1953

Lamei et al.
FULL PAPER
Japan). H NMR spectra were measured using a Bruker
1
chromatographed over silica gel column using petro-
leum ether-ethyl acetate (V∶V, 75∶25) as eluent to
give the title product as a yellow powder (4.09 g). Yield
80 or 500 spectrometers (Bruker, Rheinstetten, Ger-
many), and chemical shifts are expressed as δ with
tetramethylsilane (TMS) as internal standard. Merck
silica gel 60 F254 plates were used for analytical TLC.
Yields are based on the purified products and were not
optimized. Column chromatography was performed on
Merck silica gel (70—230 mesh).
1
37%; m.p. 77—79 ℃; H NMR (CDCl3) δ: 10.25 (s,
1H, COOH), 7.60 (d, J＝4.5 Hz, 1H, aromatic), 6.60—
6.81 (m, 2H, aromatic), 4.21—4.25 (m, 2H, OCH2),
3.91—3.95 (m, 2H, CH2COOH), 1.70 (s, 4H, CH2CH2),
1.31 (s, 12H, 4CH3); IR (KBr) ν: 3220 (OH), 1715 (C＝
＋
－1
O) cm ; MS m/z (%): 276 (M , 22), 259 (55), 190
2,5-Dichloro-2,5-dimethylhexane (12)
(100), 137 (40), 118 (25), 90 (25), 50 (15).
A solution of 2,5-dimethylhexane-2,5-diol (11) (30 g,
0.20 mol) in concentrated HCl was stirred for 30 min.
The mixture was saturated with HCl by HCl gas for 3 h.
After 2 h of stirring, the solutions change into a biphasic
mixture. The mixture was cooled and the light pink solid
was filtered and washed with water and crystallized in
hot methanol to give compound 12 as a white solid
(35.89 g). Yield 98%; m.p. 59—60 ℃; 1H NMR
(CDCl3) δ: 1.95 (s, 4H, CH2CH2), 1.60 (s, 12H, 4CH3);
3-(1,2,3,4-Tetrahydro-1,1,4,4-tetramethylnaphthalen-
6-yloxy) propanenitrile (15)
A
mixture of 5,6,7,8-tetrahydro-5,5,8,8-tetrame-
thylnaphthalen-2-ol (13, 10.2 g, 0.05 mol), acrylonitrile
(5.3 g, 0.1 mol) and sodium methoxide (1.0 g) was re-
fluxed for 5 h. After this period, the excess acrylontrile
was distilled off under vacuum and the residue was
treated with ethyl acetate and stirred for 5 min. The pre-
cipitated solids were filtered and the filtrate was washed
with water, brine solution and dried (Na2SO4). After
evaporation of the solvent, the residue was chroma-
tographed over silica gel using CH2Cl2-EtOAc (V∶V,
90∶10) as eluent to give the desired product 15 as a
－1
IR (KBr＋) ν: 2950 and 1387 (C—H) cm ; MS m/z (%):
184 (M , 63), 182 (100), 186 (11). Anal. calcd for
C8H16Cl2: C 52.47, H 8.81; found C 52.21, H 8.95.
5,6,7,8-Tetrahydro-5,5,8,8-tetramethylnaphthalen-2-
ol (13)
1
white powder (4.50 g). Yield 35%; m.p. 77—78 ℃; H
To a stirring solution of compound 12 (36.6 g, 0.20
mol) and phenol (18.8 g, 0.20 mol) in dried dichloro-
methane (100 mL), aluminum chloride (10.5 g, 0.08 mol)
was added over 15 min. After stirring for an additional
30 min at room temperature, the reaction mixure was
refluxed for 45 min. After cooling, 25 mL of hydrochlo-
ric acid (25%) was added at room temperature. The pre-
cipitated solid was filtered and the aqueous layer was
extracted with CHCl3 (50 mL) and dried over Na2SO4.
After concentration, the residue was crystallized from
petroleum ether-chloroform to afford 13 as a white solid
NMR (CDCl3) δ: 7.58 (s, 1H, aromatic), 6.24—6.31 (m,
2H, aromatic), 3.40—3.44 (m, 2H, OCH2), 3.13—3.17
(m, 2H, CH2CN), 1.75 (s, 4H, CH2CH2), 1.38 (s, 12H,
－1
4CH3); IR (KBr) ν: 2304 (CN) cm ; MS m/z (%): 257
(M＋, 40), 188 (100), 112 (35), 98 (15), (20), 60 (25).
3-Chloro-1-(1,2,3,4-tetrahydro-6-hydroxy-1,1,4,4-
tetramethylnaphthalen-7-yl)propan-1-one (16)
To a stirring mixture of 3-chloropropionic acid (8.7 g,
0.08 mol) and 13 (16.3 g, 0.08 mol), was added
trifluoromethanesulfonic acid (54 mL, 0.35 mol) over a
30 min period while keeping the temperature less than 5
℃. The solution was allowed to stir at 5 ℃ for 30 min.
After stirring, the mixture was refluxed for 40 min at 65
℃ (Attention: in this stage, if the temperature is ex-
ceeded more than 80 ℃ and the reaction is continued
for more than 40 min, the elimination reaction occurred
to give a by-product 18), cooled to room temperature
and poured into water. The aqueous mixture was ex-
tracted with CHCl3 (20 mL×3). The combined organic
layers were dried over Na2SO4 and filtered. The solvent
was removed in reduced pressure to give 16 as red oil.
This product was purified by column chromatography
eluting with n-hexane-dichloromethane (V∶V, 1∶9) to
give a yellow powder (16.04 g). Yield 68%; m.p. 78—
1
(35.96 g). Yield 88%; m.p. 164—166 ℃; H NMR
(CDCl3) δ: 7.23 (d, J＝2.3 Hz, 1H, aromatic), 7.11 (s,
1H, OH), 6.55—6.77 (m, 2H, aromatic), 1.65 (s, 4H,
CH2CH2), 1.24 (s, 12H, 4CH3); IR (KBr) ν: 3200 (OH)
＋
－1
cm ; MS m/z (%): 204 (M , 18), 190 (100), 147 (45),
118 (15), 91 (20), 57 (17). Anal. calcd for C14H20O: C
82.30, H 9.87; found C 82.44, H 9.69.
3-(1,2,3,4-Tetrahydro-1,1,4,4-tetramethylnaphthalen-
6-yloxy)propanoic acid (14)
To a mixture of sodium hydride (8.15 g, 50%, 0.16
mol) in DMF (45 mL) was added 5,5,8,8-tetrahy-
dronaphtalen-2-ol (13, 8.15 g, 0.04 mol) in DMF (15
mL) at 10—15 ℃ and the mixture was stirred at room
temperature for 0.5 h. Then a solution of 3-bromo-
propionic acid (72 g, 0.07 mol) in DMF (15 mL) was
added and the mixture was stirred at room temperature
for 14 h. The reaction mixture was diluted with HCl,
and extracted with ethyl acetate (100 mL×2). The com-
bined ethyl acetate layer was washed with water (50
mL), brine (30 mL), and dried over sodium sulfate. The
residue obtained after evaporation of the solvent was
1
79 ℃; H NMR (CDCl3) δ: 11.20 (s, 1H, OH), 7.74 (s,
1H, aromatic), 6.87 (s, 1H, aromatic), 3.91 (t, J＝5.7 Hz,
2H, CH2Cl), 3.59 (t, J＝5.3 Hz, 2H, COCH2), 1.62 (s,
4H, CH2CH2), 1.24 (s, 12H, 4CH3); IR (KBr) ν: 3414
＋
－1
(OH), 1642 (C＝O) cm ; MS m/z (%): 294 (M , 100),
296 (32), 295 (17). Anal. calcd for C17H23ClO2: C 69.26,
H 7.86; found C 69.30, H 8.01.
1954
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Heterocycle-bridged and Conformationally Constrained Retinoids
2,3,6,7,8,9-Hexahydro-6,6,9,9-tetramethylbenzo[g]-
chromen-4-one (17)
(16),128 (15). Anal. calcd for C17H21BrO2: C 60.54, H
6.28; found C 60.32, H 6.11.
Preparation from compound 14: A mixture of
3-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphtalen-2-yl-
oxy) propionic acid (14, 2.76 g, 0.01 mol) and poly-
phosphoric acid (8.0 g) was stirred at 80 ℃ for 2 h and
then at room temperature for 2 h. The mixture was di-
luted with ice-cold water and extracted with ether (100
mL×2). The combined ethereal solution was washed
with aqueous sodium carbonate (10%, 40 mL), water
(100 mL), brine (60 mL), and dried (Na2SO4). After
evaporation, the residue was chromatographed over sil-
ica gel column using petroleum ether-ethyl acetate (V∶
V, 85∶15) as eluent to give acid compound 17, as a
white solid (1.19 g). Yield 46%.
4-Cyanobenzothioamide (23)
A mixture of 4-bromobenzothioamide (22) (12.9 g,
0.06 mol), K4[Fe(CN)6]•3H2O (5.57 g, 0.013 mol), so-
dium carbonate (6.36 g, 0.06 mol) and Pd(OAc)2 (5
mol%) in dimethylacetamide (100 mL) was heated to
120 ℃ under N2 atmosphere. After completion of the
reaction, the mixture was cooled to room temperature
and diluted with EtOAc (20 mL). The resulting slurry
was filtered and the filtrate was washed with water (25
mL×2). The organic layer was dried (Na2SO4) and the
volatiles were removed under reduced pressure to give
compound 23 as a yellow solid (4.18 g). Yield 43%; m.p.
1
189—190 ℃; H NMR (CDCl3) δ: 7.93—7.46 (m, 4H,
Preparation from compound 15: A mixture of
2-(1,2,3,4-tetrahydro-1,1,4,4-tetramethyl naphthalen-6-
yloxy) propanenitrile (15, 2.57 g, 0.01 mol) and aqueous
sulfuric acid (50%, 50 mL) was refluxed for 3 h. After
cooling, the mixure was extracted with ethyl acetate.
The combined ethyl acetate layer was concentrated and
the residue was chromatographed over silica gel column
using hexane-ethyl acetate (V∶V, 60∶40) as eluent to
give compound 17 (0.75 g). Yield 29%.
－1
ArH); IR (KBr) ν: 3498, 3380 (NH2), 2249 (CN) cm ;
MS m/z (%): 162 (M＋, 65), 136 (100), 110 (45), 87 (30),
70 (25), 63 (20), 46 (15). Anal. calcd for C8H6N2S: C
59.23, H 3.73, N 17.27; found C 59.45, H 3.70, N 17.39.
4-Thiocarbamoylbenzoic acid (24)
A mixture of 4-cyanobenzothioamide (23) (4.8 g,
0.04 mol), sulfuric acid (98%, 30 mL) and water (50 mL)
was stirred for 30 min at room temperature. The solution
was slowly refluxed for 1 h. After cooling in an ice bath,
water (50 mL) was added. The precipitated solid was
filtered and washed with water. The product was puri-
fied by flash column chromatography eluting with
CH2Cl2-ethyl acetate (V∶V, 70∶30) and crystallized
from methanol to give compound 24 as a yellow solid
Preparation from compound 16: Compound 16 (8.8 g,
0.03 mol) was added to a solution of sodium hydroxide
(1 mol/L, 50 mL) and the resulting suspension was
stirred for 4 h at room temperature. Then, the reaction
mixture was acidified with diluted HCl (10%). The
aqueous mixture was extracted with ethyl acetate (25
mL×3), dried (Na2SO4) and concentrated to give com-
1
1
(3.69 g). Yield 51%; m.p. 238—240 ℃; H NMR
pound 17 (4.88 g). Yield 63%; m.p. 101—103 ℃; H
(CDCl3) δ: 10.82 (s, 1H, COOH), 7.83 (d, J＝7.6 Hz,
2H, aromatic), 7.13 (d, J＝7.6 Hz, 2H, aromatic); IR
(KBr) ν: 3497, 3365 (NH2), 3200 (OH), 1705 (C＝O)
NMR (DMSO-d6) δ: 7.85 (s, 1H, aromatic), 6.89 (s, 1H,
aromatic), 4.49 (t, J＝6.6 Hz, 2H, OCH2), 2.76 (t, J＝
6.6 Hz, 2H, COCH2), 1.67 (s, 4H, CH2CH2), 1.27 (s,
＋
－1
－1
cm ; MS m/z (%): 182 (M , 78), 180 (27), 136 (54), 88
(100), 77 (19). Anal. calcd for C8H7NO2S: C 53.02, H
3.89, N 7.73; found C 52.89, H 3.89, N 7.66.
12H, 4CH3); IR (KBr) ν: 1691 (C＝O) cm ; MS m/z
(%): 258 (M＋, 30), 244 (60), 242 (100), 200 (30), 127
(21), 115 (18). Anal. calcd for C17H22O2: C 79.03, H
8.58; found C 78.88, H 8.61.
4-(7,8,9,10-Tetrahydro-7,7,10,10-tetramethyl-4H-
benzo[6,7]chromeno[4,3-d]thiazole-2-yl)benzoic acid
(10)
3-Bromo-2,3,6,7,8,9-hexahydro-6,6,9,9-tetramethyl-
benzo[g]chromen-4-one (19)
To a solution of compound 19 (3.36 g, 0.01 mol) in
EtOH (25 mL) under argon, was added 24 (3.6 g, 0.02
mol). The solution was stirred and reflux for 2 h. After
cooling, solvent was evaporated under reduce pressure
to give a red solid. The residue was purified by flash
column chromatography on silica gel eluting with
n-hexane-ethyl acetate (V∶V, 4∶1) to afford target
compound 10 as a yellow powder (1.76 g). Yield 42%;
A vigorously stirring mixture of pulverized copper(II)
bromide (4.6 g, 0.02 mol) and compound 17 (5.16 g,
0.02 mol) in chloroform-ethyl acetate (V∶V, 1∶1, 40
mL) was refluxed until the reaction was completed as
judged by a disappearance of all black solid, and cessa-
tion of HBr evolution (3 h). After removal of the copper(I)
bromide (white solid) by filtration, the solvents were
evaporated from the filtrate under reduced pressure to
give an oil. The residue was purified by flash column
chromatography on silica gel eluting with n-hexane-
CH2Cl2 (V∶V, 1∶9) to give 19 as a white solid (3.84
g). Yield 57%; m.p. 139—141 ℃; 1H NMR (DMSO-d6)
δ: 7.89 (s, 1H, aromatic), 6.91 (s, 1H, aromatic), 4.67—
4.50 (m, 3H, OCH2CHBr), 1.67 (s, 4H, CH2CH2), 1.28
1
m.p. 285—289 ℃; H NMR (DMSO-d6, 500 MHz) δ:
9.89 (s, 1H, COOH), 7.89 (d, J＝8.25 Hz, 2H, aromatic),
7.68 (s, 1H, aromatic), 7.34 (d, J＝8.25 Hz, 2H, aromatic),
6.90 (s, 1H, aromatic), 5.48 (s, 2H, OCH2), 1.65 (s, 4H,
CH2CH2), 1.28 (s, 6H, 2CH3), 1.25 (s, 6H, 2CH3); IR
－1
(KBr) ν＋: 3220 (OH), 1715 (C＝O) cm ; MS m/z (%):
－1
419 (M , 20), 403 (100), 376 (20), 374 (42), 334 (15),
216 (21), 114 (22). Anal. calcd for C25H25NO3S: C
71.57, H 6.01, N 3.34; found C 71.70, H 5.95, N 3.33.
(s, 12H, 4CH3); IR (KBr) ν: 1690 (C＝O) cm ; MS m/z
(%): 339 (10), 338 (18), 336 (M＋, 20), 321 (100), 200
Chin. J. Chem. 2010, 28, 1951— 1956
© 2010 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
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1955

Lamei et al.
FULL PAPER
2-(4-Bromophenyl)-7,8,9,10-tetrahydro-7,7,10,10-
tetramethyl-4H-benzo[6,7]chromeno[4,3-d]thiazole
(20)
Eds.: Sporn, M. B.; Roberts, A. B.; Goodman, D. S., Raven
Press, New York, 1994, pp. 319— 350.
de Lera, A. R.; Bourguet, W.; Altucci, L.; Gronemeyer, H.
Nat. Rev. Drug Discov. 2007, 6, 811.
Thacher, S. M.; Vasudevan, J.; Chandraratna, R. A. Curr.
Pharm. Des. 2000, 6, 25.
Altucci, L.; Gronemeyer, H. Nat. Rev. Cancer 2001, 1, 181.
Germain, P.; Iyer, J.; Zechel, C.; Gronemeyer, H. Nature
2002, 415, 187.
Levin, A. A.; Sturzenbecker, L. J.; Kazmer, S.; Bosakowski,
T.; Huselton, C.; Allenby, G.; Speck, J.; Kratzeisen, C. I.;
Rosenberger, M.; Lovey, A.; Grippo, J. F. Nature 1992, 355,
359.
Ikegami, S.; Iimori, T.; Sudo, M.; Kitsukawa, M.; Forou-
madi, A.; Yonemura, T.; Takahashi, H.; Kizaki, K.; Ishii, H.
Bioorg. Med. Chem. 2006, 14, 5099.
Viligonda, V.; Garst, M. E.; Chandraratna, R. A. S. Bioorg.
Med. Chem. Lett. 1999, 9, 589.
Wong, M. F.; Repa, J. J.; Clagett-Dame, M.; Curley, R. W.,
Jr. Bioorg. Med. Chem. Lett. 1997, 7, 2313.
2
3
Compound 20 was prepared starting from compound
19 and 4-bromobenzothioamide as method described for
compound 10. Yield 62% (2.82 g, brown powder); m.p.
1
4
5
192—193 ℃; H NMR (DMSO-d6) δ: 7.90—7.38 (m,
4H, aromatic), 7.24 (s, 1H, aromatic), 6.89 (s, 1H, aro-
matic), 5.40 (s, 2H, OCH2), 1.69 (s, 4H, CH2CH2), 1.31
(s, 12H, 4CH3); MS m/z (%): 455 (M＋, 38), 453 (40),
440 (36), 360 (18), 183 (16), 84 (100). Anal. calcd for
C24H24BrNOS: C 63.43, H 5.32, N 3.08; found C 63.79,
H 5.38, N 3.00.
6
7
2-(4-Methylphenyl)-7,8,9,10-tetrahydro-7,7,10,10-
tetramethyl-4H-benzo[6,7]chromeno[4,3-d]thiazole
(21)
8
9
Compound 21 was prepared starting from compound
19 and 4-methylbenzothioamide as method described
for compound 10. Yield 58% (2.26 g, white solid); m.p.
1
152—154 ℃; H NMR (DMSO-d6) δ: 7.89 (d, J＝8.8
10 Kagechika, H. Curr. Med. Chem. 2002, 9, 591.
11 Zusi, F. C.; Vivat-Hannah, V.; Lorenzi, M. V. Drug Dis-
covery Today 2002, 7, 1165.
12 Simoni, D.; Tolomeo, M. Curr. Pharm. Des. 2001, 7, 1823.
13 Mushfiq, M.; Mahboob, A. J. Chin. Chem. Soc. 2007, 54,
219.
Hz, 2H, aromatic), 7.35—7.20 (m, 3H, aromatic), 6.69
(s, 1H, aromatic), 5.44 (s, 2H, OCH2), 2.40 (s, 3H, CH3),
1.69 (s, 4H, CH2CH2), 1.34—1.25 (m, 12H, 4CH3); MS
m/z (%): 389 (M＋, 100), 373 (89), 330 (25), 148 (20),
87 (65), 84 (60), 54 (93). Anal. calcd for C25H27NOS: C
77.08, H 6.99, N 3.60; found C 76.93, H 7.12, N 3.68.
14 Qiao, Q.; So, S.-S.; Goodnow, Jr. R. A. Org. Lett. 2001, 3,
3655.
References
15 Emami, S.; Foroumadi, A.; Samadi, N.; Faramarzi, M. A.;
Rajabalian, S. Arch. Pharm. Chem. Life Sci. 2009, 342, 405.
1
The Retinoids: Biology, Chemistry and Medicine, 2nd ed.,
(E0910206 Cheng, B.; Zheng, G.)
1956
www.cjc.wiley-vch.de
© 2010 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2010, 28, 1951— 1956