A new synthetic approach towards 7-substituted 2-alkyl-2,3,4,9-tetrahydro- 1H-fluorenes

Article abstract of DOI:10.1007/s11172-011-0325-2

Cyclization of 2-(4-bromophenyl)-5-pentylcyclohex-1-ene-1-carboxylic acid followed by reduction of the carbonyl group resulted in the corresponding 7-substituted derivative of 2-alkyl-2,3,4,9-tetrahydro-1H-fluorene.

Full text of DOI:10.1007/s11172-011-0325-2

Russian Chemical Bulletin, International Edition, Vol. 60, No. 10, pp. 2114—2116, October, 2011
2114
A new synthetic approach towards 7ꢀsubstituted
2ꢀalkylꢀ2,3,4,9ꢀtetrahydroꢀ1Hꢀfluorenes
V. V. Mezhnev and R. Ch. Geivandov
Fine Organic Synthesis and Organic Functional materials, INCORFIN, Ltd,
27 ul. Burakova, 105118 Moscow, Russian Federation.
Eꢀmail: r.ch.geivandov@gmail.com
Cyclization of 2ꢀ(4ꢀbromophenyl)ꢀ5ꢀpentylcyclohexꢀ1ꢀeneꢀ1ꢀcarboxylic acid followed by
reduction of the carbonyl group resulted in the corresponding 7ꢀsubstituted derivative of 2ꢀalkylꢀ
2,3,4,9ꢀtetrahydroꢀ1Hꢀfluorene.
Key words: βꢀchloroenal, fluorenes, crossꢀcoupling
In continuation of our study1—3 in the field of liquid
crystal structures bearing monoꢀ, biꢀ, and tricyclic fragꢀ
ments, we developed a synthetic route towards key interꢀ
mediates for preparing the novel class of liquid crystals,
7ꢀsubstituted derivatives of 2ꢀalkylꢀ2,3,4,9ꢀtetrahydroꢀ1Hꢀ
fluorene.4
In the present work, we report synthetic approach toꢀ
wards hitherto unknown 7ꢀbromoꢀ2ꢀpentylꢀ2,3,4,9ꢀtetraꢀ
hydroꢀ1Hꢀfluorene (1) (Scheme 1).
Formylation of 4ꢀpentylcyclohexanone (2) with a mixꢀ
ture of phosphorus oxychloride and DMF in chloroform
according to the Vilsmeier—Haack—Arnold procedure5
Scheme 1
i. 1) POCl3, HC(O)NMe2, CHCl3, 5–10 °C, 10 min, 2) 1, 50—60 °C, 3 h; ii. 4ꢀBrC6H4B(OH)2, BuNBr, 10% Pd/C, K2CO3, H2O,
85 °C, 6 h; iii. NaClO2, H2O, 10—20 °C, 12 h; iv. 1) SOCl2, DMF, CH2Cl2, 20 °C, 1 h, 2) reflux, 15 min, 3) AlCl3, CH2Cl2, 20 °C,
30 min or (CF3CO)2O, CHCl3, molecular sieves 4 Å, 20 °C, 18 h; v. DIBALꢀH, CH2Cl2, –78 °C, 15 min; vi. PBr3, PhMe, 0 °C, 24 h;
vii. NaBH3CN, HMPA, 70 °C, 1 h.
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 10, pp. 2077—2079, October, 2011.
1066ꢀ5285/11/6010ꢀ2114 © 2011 Springer Science+Business Media, Inc.

Derivatives of 2,3,4,9ꢀtetrahydroꢀ1Hꢀfluorene
Russ.Chem.Bull., Int.Ed., Vol. 60, No. 10, October, 2011
2115
ic layers were washed with water, dried with Na2SO4, and the
furnished βꢀchloroenal 3 in 80% yield. Compound 3 was
crossꢀcoupled with 4ꢀbromophenylboronic acid employꢀ
ing the modified published procedure6. Mild oxidation of
the resulted aldehyde 4 by sodium chlorite7 afforded acid 5
in 85% yield. It is of note that the use of the other oxidants
including silver oxide and the Jones reagent resulted in
recovering of the starting aldehyde, low yield of acid 5 or
complex mixture of products of oxidizing of tetrahydroꢀ
fluorene system. For the intramolecular cyclization of acid
5, two methods were applied. The first method involved
transformation of acid 5 into the corresponding acid chloꢀ
ride and subsequent intramolecular acylation of the latter
by treatment with AlCl3 to give tetrahydrofluorenone 6 in
72% yield. The second method is the cyclization of acid 5
using trifluoroacetic anhydride in the presence of molecuꢀ
lar sieves 4 Å in chloroform; in this case the yield of 6 was
84%. Reduction of ketone 6 by diisobutylalumohydride
(DIBALꢀH) under mild conditions afforded alcohol 7 in
96% yield. Subsequent replacement of hydroxy group by
bromine atom using phosphorus tribromide furnished diꢀ
bromide 8 in 72% yield. Chemoselective reduction of the
bromine atom at the position 9 of the fluorene system of 8
by sodium cyanoborohydride in HMPA8 gave the target
product 1 in 75% yield.
solvent was removed in vacuo. Yield 80%, b.p. 92—94 °C
(0.240 Torr), nD 1.4925. MS, m/z: 214 [M]+. NMR 1H
20
(CDCl3)), δ: 10.17 (s, 1 H, CHO); 2.65—2.49 (m, 3 H, CH2,
CH, cycl.); 1.91—1.67 (m, 2 H, CH2, cycl.); 1.59—1.42 (m, 2 H,
CH2, cycl.); 1.33—1.2 (m, 8 H, CH2, alkyl); 0.87 (t, 3 H, CH3,
J = 6.6 Hz). Found (%): C, 67.05; H, 8.94. C12H19ClO. Calcuꢀ
lated (%): C, 67.12; H, 8.92.
2ꢀ(4ꢀBromophenyl)ꢀ5ꢀpentylcyclohexꢀ1ꢀeneꢀ1ꢀcarboxaldeꢀ
hyde (4). A mixture of compound 3 (0.56 g, 2.59 mmol),
4ꢀbromophenylboronic acid (0.57 g, 2.83 mmol), tetrabutylamꢀ
monium bromide (0.84 g, 2.60 mmol), 10% Pd/C, K2CO3 (0.89 g,
6.45 mmol) and deionized water (5 mL) was stirred at 85 °C for
6 h. The reaction mixture was diluted with water (15 mL) and
the products were extracted with AcOEt (3×30 mL), organic
layer was separated and stirred with charcoal for 30 min, dried
with Na2SO4, and the solvent was removed in vacuo. The prodꢀ
uct was distilled under reduced pressure. Yield 68%, b.p.
20
183—190 °C (0.120 Torr), nD 1.5660, m.p. 28—30 °C. MS,
1
m/z: 334 [M]+. H NMR (CDCl3), δ: 9.48 (s, 1 H, CHO); 7.52
(d, 2 H, CH, Ar, J = 8.4 Hz); 7.07 (d, 2 H, CH, Ar, J = 8.1 Hz);
2.68—2.49 (m, 3 H, CH2, CH, cycl.); 1.94—1.50 (m, 4 H, CH2,
cycl.); 1.42—1.21 (m, 8 H, CH2, alkyl); 0.90 (t, 3 H, CH3,
J = 6.8 Hz). Found (%): C, 64.59; H, 6.94. C18H23BrO. Calcuꢀ
lated (%): C, 64.48; H, 6.91.
2ꢀ(4ꢀBromophenyl)ꢀ5ꢀpentylcyclohexꢀ1ꢀeneꢀ1ꢀcarboxylic
acid (5). A solution of NaClO2 (1.22 g, 11.2 mmol) in water
(10 mL) was added dropwise to a stirred mixture of solutions of
aldehyde 4 (2.45 g, 7.32 mmol) in MeCN (30 mL), NaH2PO4
(0.350 g, 2.26 mmol) in water (3 mL), and 30% aqueous H2O2
(3.8 mL) cooled to 10 °C. The reaction mixture was stirred for
12 h at ambient temperature. Then Na2SO3 (0.5 g) was added
and the mixture was acidified with 10% aqueous HCl. The preꢀ
cipitate that formed was filtered off and the product was purified
by chromatography (SiO2, elution with EtOAc). Yield 85%, m.p.
119—120 °C (hexane). MS, m/z: 350 [M]+. 1H NMR (CDCl3),
δ: 10.87 (s, 1 H, OH); 7.42 (d, 2 H, CH, Ar, J = 8.4 Hz); 7.00
(d, 2 H, CH, Ar, J = 8.1 Hz); 2.60 (dd, 1 H, CH, cycl., J = 17.4 Hz,
J = 4.2 Hz); 2.42—2.34 (m, 2 H, CH2, cycl.); 2.01—1.80 (m, 2 H,
CH2, cycl.); 1.66—1.54 (m, 1 H, CH2, cycl.); 1.41—1.25 (m, 9 H,
1 H CH2, cycl., and 8 H CH2, alkyl); 0.90 (t, 3 H, CH3, J = 6.8 Hz).
Found (%): C, 61.42; H, 6.62. C18H23BrO2. Calculated (%):
C, 61.54; H, 6.60.
The suggested synthetic approach can be used for preꢀ
paring the similar tetrahydrofluorene derivatives.
Experimental
The progress of the reactions was monitored by TLC on
Merck Kieselgel 60 F254 plates with visualization by the UV light
(λ = 254 nm). Melting points of starting and synthesized comꢀ
pounds were determined on a MettlerꢀFPꢀ90 apparatus equipped
with polarizing microscope Olympus BHꢀ2. The purity of startꢀ
ing compounds and products were monitored by gasꢀliquid chroꢀ
matography on a Crystall 2000M chromatograph equipped with
flame ionizing detector, column length was 1—3 m, (d = 4 mm),
stationary phase was 5% XEꢀ60 on Chromaton NꢀAWꢀDMCS
(0.2—0.25 mm), carrier gas was helium (flow rate is 30 mL min–1),
flow rate of hydrogen was 25 mL min–1, flow rate of air was
250 mL min–1, temperature of injector was 200—280 °C, temꢀ
perature of detector was 300 °C, temperature of the columns was
50—250 °C. 1H NMR spectra were recorded with Bruker AMꢀ300
and Bruker Avance II 300 instruments in CDCl3. Chemical shifts
are given in the δ scale relative to Me4Si. Mass spectra (EI,
70 eV) were recorded on a Kratos MSꢀ30 instrument.
7ꢀBromoꢀ2ꢀpentylꢀ1,2,3,4ꢀtetrahydroꢀ9Hꢀfluorenꢀ9ꢀone (6).
A. To a solution of acid 5 (0.351 g, 1.0 mmol) in CH2C12 (2 mL),
a solution of SOC12 (2 mL) and DMF (2 drops) in CH2C12
(3 mL) was added dropwise over a period of 30 min at ambient
temperature. The reaction mixture was stirred for 30 min at
room temperature and refluxed for 15 min, then the solvent was
removed in vacuo. The resulting acid chloride was dissolved in
CH2C12 (2 mL) and added dropwise to a solution of AlC13 (0.152 g,
1.14 mmol) in CH2C12 (2 mL) at ambient temperature. The
mixture was stirred for 30 min, poured into cold water (10 mL),
extracted with CH2C12 (3×30 mL), the combined organic layꢀ
ers were washed with water, aqueous NaHCO3, and dried
with Na2SO4. The solvent was removed in vacuo, the resiꢀ
due was purified by chromatography (silica gel, elution with
EtOAc—hexane, 1 : 9). Yield 72%, m.p. 77—79 °C (EtOH). MS,
4ꢀPentylcyclohexanone (2) was synthesized according the
known procedure.9 B.p. 95—98 °C (1.0 Torr) (cf. Ref. 9: b.p.
98—100 °C (0.1 Torr)), nD20 1.4550.
2ꢀChloroꢀ5ꢀpentylcyclohexꢀ1ꢀeneꢀ1ꢀcarboxaldehyde (3). To
a solution of DMF (10.3 mL) in chloroform (25 mL), POCl3
(10.1 mL) was added at 5—10 °C and the mixture was stirred for
10 min. Then a solution of 4ꢀpentylcyclohexanone (2) (16.8 mL,
0.1 mol) in chloroform (25 mL) was added dropwise at 20 °C.
The reaction mixture was heated at 55—60 °C for 3 h and poured
into solution of AcONa (35 g) in water (120 ml). The product
was extracted with chloroform (3×30 mL), the combined organꢀ
1
m/z: 332 [M]+. H NMR (CDCl3), δ: 7.46—7.41 (m, 2 H, CH,
Ar); 6.81 (d, 1 H, CH, Ar, J = 7.3 Hz); 2.59—2.32 (m, 3 H, CH2,
CH, cycl.); 2.01—1.92 (m, 1 H, CH2, cycl.); 1.81—1.55 (m, 2 H,

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Russ.Chem.Bull., Int.Ed., Vol. 60, No. 10, October, 2011
Mezhnev and Geivandov
CH2, cycl.); 1.43—1.25 (m, 9 H, 1 H CH2, cycl., and 8 H CH2,
alkyl); 0.90 (t, 3 H, CH3, J = 6.8 Hz). Found (%): C, 64.71;
H, 6.37. C18H21BrO. Calculated (%): C, 64.87; H, 6.35.
B. To a solution of acid 5 (100 mg, 0.29 mmol) in anhydrous
CHCl3 (2 mL) trifluoroacetic anhydride (0.04 mL, 0.3 mmol)
and molecular sieves 4 Å (150 mg) were added. The reaction
mixture was stirred at ambient temperature for 18 h, filtered, and
the solvent was removed in vacuo. The viscous residue was trituꢀ
rated with MeOH (10 mL), the precipitate that formed was reꢀ
crystallized from EtOH. Yield 84%, m.p. 76—78 °C.
7ꢀBromoꢀ2ꢀpentylꢀ1,2,3,4ꢀtetrahydroꢀ9Hꢀfluorenꢀ9ꢀol (7).
To a solution of ketone 6 (0.29 g, 0.877 mmol) in CH2Cl2 (9 mL),
DIBALꢀH (1 mL, 1.0 M solution in hexane) was added dropwise
at –78 °C. After 15 min, MeOH (0.1 mL) was added dropwise at
the same temperature, and the reaction mixture was warmed to
ambient temperature, then water (2 mL) was added and the
mixture was acidified with 1 M HCl (20 mL), and the product
was extracted with CH2Cl2 (3×15 mL). The combined organic
layers were dried with MgSO4 and the solvent was removed
in vacuo. Yield 96%, m.p. 122—124 °C (hexane). MS, m/z: 334
[M+]. 1H NMR (CDCl3), δ: 7.57 (s, 1 H, CH, Ar); 7.38 (d, 1 H,
CH, Ar, J = 8.8 Hz); 6.93 (d, 1 H, CH, Ar, J = 7.7 Hz); 4.86
(s, 1 H, OH); 2.65—2.21 (m, 3 H, CH2, CH, cycl.); 2.11—1.63
(m, 4 H, 3 H CH2, cycl., and 1 H CHOH); 1.43—1.24 (m, 9 H,
1 H, CH2, cycl., and 8 H CH2, alkyl); 0.91 (t, 3 H, CH3,
J = 6.5 Hz). Found (%): C, 64.34; H, 6.93. C18H23BrO. Calcuꢀ
lated (%): C, 64.48; H, 6.91.
heated at 70 °C for 1 h. Then water (10 mL) was added and the
mixture was extracted with diethyl ether (3×15 mL). The comꢀ
bined organics were dried with MgSO4, the solvent was removed
in vacuo, and the product was purified by chromatography (silica
gel, elution with hexane). Yield 75%, m.p. 78—80 °C. MS, m/z:
1
318 [M]+. H NMR (CDCl3), δ: 7.49 (s, 1 H, CH, Ar); 7.37
(d, 1 H, CH, Ar, J = 8.1 Hz); 7.03 (d, 1 H, CH, Ar, J = 8.1 Hz);
3.20 (s, 2 H, CH2, cycl.); 2.57—2.28 (m, 3 H, CH2, CH, cycl.);
2.09—1.90 (m, 2 H, CH2, cycl.); 1.79—1.66 (m, 1 H, CH2,
cycl.); 1.45—1.26 (m, 9 H, 1 H CH2, cycl., and 8 H CH2, alkyl);
0.93 (t, 3 H, CH3, J = 6.6 Hz). 13C NMR (DMSOꢀd6), δ: 145.06
(C, C=C), 145.01 (C, C=C), 141.91 (C, Ar), 135.49 (C, Ar),
129.04 (C, Ar), 126.61 (C, Ar), 118.73 (C—Br), 117.49 (C, Ar),
40.53 (CH2), 36.41 (Ctert), 34.44, 32.54, 32.23, 29.03, 26.87,
22.80, 22.00 (CH2), 14.21 (CH3). Found (%): C, 67.63; H, 7.24.
C18H23Br. Calculated (%): C, 67.71; H, 7.26.
References
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7,9ꢀDibromoꢀ2ꢀpentylꢀ1,2,3,4ꢀtetrahydroꢀ9Hꢀfluorene (8).
To a solution of alcohol 7 (0.837 g, 2.5 mmol) in toluene (10 mL),
PBr3 (0.1 mL, 1.2 mmol) was added dropwise at 0 °C. After 24 h,
the mixture was cooled to –10 °C, 10% aqueous NaHCO3
(10 mL) was added, and the product was extracted with CH2Cl2
(3×15 mL). The combined organics were dried with MgSO4, the
solvent was removed in vacuo, and the residue was recrystallized
from hexane. Yield 72%, m.p. 98—100 °C. MS, m/z: 398 [M+].
1H NMR (CDCl3), δ: 7.59 (s, 1 H, CH, Ar); 7.36 (d, 1 H, CH,
Ar, J = 8.7 Hz); 6.90 (d, 1 H, CH, Ar, J = 7.7 Hz); 2.60—2.23
(m, 3 H, CH2, CH, cycl.); 2.00—1.67 (m, 4 H, 3 H CH2, cycl.,
and 1 H CHBr); 1.43—1.26 (m, 9 H, 1 H CH2, cycl., and 8 H
CH2, alkyl); 0.90 (t, 3 H, CH3, J = 6.7 Hz). Found (%): C, 54.46;
H, 5.58. C18H22Br2. Calculated (%): C, 54.30; H, 5.57.
6. S. Hesse, G. Kirsch, Synthesis, 2001, 5, 755.
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mani, B. E. Maryanoff, J. Org. Chem., 1977, 42, 82.
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H. Murawski, C. Kruger, Chem. Ber., 1985, 118, 3332.
7ꢀBromoꢀ2ꢀpentylꢀ2,3,4,9ꢀtetrahydroꢀ1Hꢀfluorene (1). To
a solution of dibromide 8 (0.398 g, 1.0 mmol) in HMPA (5 mL),
NaBH3CN (0.256 g, 4 mmol) was added and the mixture was
Received January 28, 2011;
in revised form June 2, 2011