Synthesis of functionalized triarylmethanes based on a 'FeCl3-catalyzed benzylation/[3+3] cyclocondensation' strategy

Article abstract of DOI:10.1016/j.tetlet.2009.01.079

Functionalized triarylmethanes are prepared in two steps by FeCl₃-catalyzed benzylation of acetylacetone to give 3-(diarylmethyl)pentane-2,4-diones and subsequent formal [3+3] cyclization of the latter with 1,3-bis(trimethylsilyloxy)-1,3-dienes

Full text of DOI:10.1016/j.tetlet.2009.01.079

Tetrahedron Letters 50 (2009) 1490–1492
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Synthesis of functionalized triarylmethanes based on a ‘FeCl3-catalyzed
benzylation/[3+3] cyclocondensation’ strategy
Rasheed Ahmad a, Abdolmajid Riahi a,b, Peter Langer a,b,
*
a Institut für Chemie, Universität Rostock, Albert-Einstein-Str. 3a, 18059 Rostock, Germany
b Leibniz-Institut für Katalyse e. V. an der Universität Rostock, Albert-Einstein-Str. 29a, 18059 Rostock, Germany
a r t i c l e i n f o
a b s t r a c t
Article history:
Functionalized triarylmethanes are prepared in two steps by FeCl3-catalyzed benzylation of acetylace-
tone to give 3-(diarylmethyl)pentane-2,4-diones and subsequent formal [3+3] cyclization of the latter
with 1,3-bis(trimethylsilyloxy)-1,3-dienes.
Received 27 November 2008
Revised 12 January 2009
Accepted 14 January 2009
Available online 20 January 2009
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Arenes
Catalysis
Cyclizations
Regioselectivity
Silyl enol ethers
Triarylmethanes are of considerable pharmacological relevance
and occur in a number of natural products. Pharmacological activi-
ties include estrogen receptor binding affinity,1a inhibition of hepa-
tic cholesterol,1b inhibition of aldose reductase 2,1c antiproliferative
activities,1d antiviral and cytotoxic activity,1e antifungal activity,1f
anti-HIV activity,1g,h and CNS activity.1i Naturally occurring triar-
ylmethanes, containing a (1,1-diphenylmethyl)phenol substruc-
ture, include mohsenone and a number of related molecules.2
(1,1-Diphenylmethyl)salicylates and related structures have been
reported to possess anti-HIV activity3a,1g and antibacterialactivity.3b
Well-known C–C coupling reactions, such as Friedel–Crafts
alkylations, are used for the functionalization of arenes. In spite
of the great synthetic utility of these methods, they have several
drawbacks, such as drastic reaction conditions and the formation
of regioisomeric mixtures or isomerization products. To address
these problems, Beller and coworkers developed novel
FeCl3ꢀ6H2O-catalyzed Friedel–Crafts type benzylations of arenes
using simple benzylic alcohols under mild conditions and with
high functional group tolerance.4 Christoffers et al. studied FeCl3-
catalyzed conjugate additions of 1,3-dicarbonyl compounds to
enones.5 Beller and co-workers have recently reported the FeCl3-
catalyzed condensation of 1,3-dicarbonyl compounds with simple
benzylic alcohols.6 A number of related transformations have been
studied in recent years.7
Despite the preparative utility of these reactions, the direct syn-
thesis of sterically encumbered triarylmethanes and diarylme-
thanes by Fe-catalyzed benzylation of 1,3-dicarbonyl compounds
is problematic. In addition, the synthesis of highly substituted
and functionalized products depends on the availability of the
starting materials, functionalized and highly substituted arenes.
Their regioselective synthesis by electrophilic aromatic substitu-
tion reactions can be a very difficult task. An alternative strategy
for the synthesis of sterically encumbered and highly functional-
ized arenes relies on the application of suitable dienes in cycliza-
tion reactions (building block approach). Some years ago, Chan
et al. developed8 a convenient approach to salicylates by formal
[3+3] cyclizations9 of 1,3-bis(trimethylsilyloxy)-1,3-dienes10 with
3-trimethylsilyloxy-2-en-1-ones. Herein, we report, for the first
time, the synthesis of sterically encumbered and functionalized tri-
arylmethanes by a combined FeCl3-catalyzed benzylation/[3+3]
cyclocondensation approach. The products reported herein are
not readily available by other methods and have, to the best of
our knowledge, not yet been prepared.
The FeCl3ꢀ6H2O-catalyzed benzylation of acetylacetone (1) with
benzylalcohols 1a–e, following conditions reported by Beller and
co-workers,6 afforded products 3a–e in very good yields (Scheme 1,
Table 1).11 The silylation of 3a–e afforded the 3-silyloxy-2-en-1-
ones 4a–e.
The TiCl4-mediated formal [3+3] cyclocondensation of 4a with
1,3-bis(silyloxy)-1,3-diene 5a, available from methyl acetoacetate
in two steps,8 afforded the triarylmethane 6a (Scheme 2). During
the optimization, it proved to be important to carry out the
* Corresponding author. Tel.: +49 381 4986410; fax: +49 381 4986412.
E-mail address: peter.langer@uni-rostock.de (P. Langer).
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.01.079

R. Ahmad et al. / Tetrahedron Letters 50 (2009) 1490–1492
1491
O
O
Me3SiO OSiMe3
R3
O
O
OH O
OR4
Me
Me
R3
Me
2
Me
ii
Me
5a-d
i
OR4
Me
i
OH
R1 R2
3a-e
Me3SiO
Me
O
+
R1 R2
1a-e
R1 R2
Me
R1 R2
4a-e
6a-m
Me3SiO
Me
O
Me
Scheme 3. Synthesis of 6a–m. Reagents and conditions: (i) TiCl4, CH2Cl2,
ꢁ78?20 °C, 20 h.
R1 R2
4a-e
Scheme 1. Synthesis of 4a–e. Reagents and conditions: (i) FeCl3ꢀ6H2O, NO2CH3,
50 oC, 4 h; (ii) Me3SiCl, NEt3, C6H6, 20 °C, 72 h.
Table 2
Synthesis of biaryls 6a–m
4
5
6
R1
R2
R3
R4
% (6)a
Table 1
Synthesis of 3a–e and 4a–e
a
a
a
a
b
b
c
a
b
c
a
b
c
d
e
f
g
h
i
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
H
H
Me
Et
H
H
H
H
H
Me
Et
Me
Me
Me
Et
Me
Et
Me
Et
42
45
31
42
32
37
33
37
50
53
40
42
55
3,4
R1
R2
% (3)a
% (4)a
d
a
b
a
b
a
b
c
a
b
c
d
e
Ph
Ph
91
88
87
85
94
90
91
89
92
81
4-(MeO)C6H4
4-(MeO)C6H4
4-FC6H4
4-FC6H4
4-ClC6H4
4-ClC6H4
4-ClC6H4
4-ClC6H4
Me
4-(MeO)C6H4
4-(MeO)C6H4
4-FC6H4
4-FC6H4
4-ClC6H4
4-ClC6H4
4-ClC6H4
4-ClC6H4
Ph
4-(MeO)C6H4
4-FC6H4
4-ClC6H4
Me
4-(MeO)C6H4
4-FC6H4
4-ClC6H4
Ph
c
d
d
d
d
e
j
k
l
H
a
Isolated yields.
Me
Et
H
Me
Me
Me
d
a
m
a
Isolated yields.
Me3SiO OSiMe3
O
OH
TiCl4
OMe
CH2Cl2
5a
OMe
Me
Ph
6a (42%)
and aromatization resulted in the formation of product 6a. Due
to the symmetrical structure of A, the attack of 1a on either termi-
nal allylic carbon atoms would result in the formation of the same
product (6a).
Me3SiO
O
_
Me
Ph
78 to 20 °C
14 h
+
Me
Me
Ph
Ph
The TiCl4-mediated [3+3] cyclocondensation of 4a-e with 1,3-
bis(silyloxy)-1,3-dienes 5a–d, available from the corresponding
1,3-dicarbonyl compounds in one or two steps,8 afforded the triar-
ylmethanes 6a–m (Scheme 3, Table 2). During the optimization, it
proved to be important to carry out the reactions in a highly con-
centrated solution.11 The yield of diarylmethane 6m was higher
than the yields of triarylmethanes 6a–l. The best yields of the tri-
arylmethanes were obtained for derivatives 6i,j, which are derived
from the chloro-substituted benzylalcohol 1d. The yields of triar-
ylmethanes 6a,b and 6i,j, derived from the unsubstituted dienes
5a,b, were higher than those of products 6c,d and 6k,l, which are
derived from dienes 5c,d (containing a substituent located at the
terminal carbon atom).
4a
TiCl4
_
H2O
O
O
TiCl4
Me3SiO
Me
O
OMe
OTiCl3
Me
+
Me
Ph
Me
Ph
Ph
Ph
D
A
1a
Me3SiCl
Me3SiCl
In conclusion,
a variety of functionalized and sterically
O
O
encumbered triarylmethanes were prepared by combination of
FeCl3-catalyzed benzylations of 1,3-diketones and formal [3+3]
cyclocondensation reactions. The products are not readily available
by other methods.
Me3SiO
OMe
TiCl3
Me3SiO
OMe
Me3SiCl
TiCl4
O
O
Me3SiO
Me
Ph
Me
Ph
Me
(Me3Si)2O
Me
Ph
Acknowledgement
Ph
B
C
Financial support from the State of Pakistan (HEC scholarship
for R.A.) is gratefully acknowledged.
Scheme 2. Possible mechanism of the formation of 6a.
References and notes
reactions in a highly concentrated solution.12 The formation of 6a
can be explained by reaction of 4a with TiCl4 to give intermediate
A. The attack of the terminal carbon atom of 5a onto A afforded
intermediate B. The elimination of TMS-siloxane (intermediate C)
and subsequent cyclization gave intermediate D. The elimination
of titanium hydroxide (before or during the aqueous work-up)
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1492
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11. In a pressure tube, FeCl3ꢀ6H2O (5 mol %), 1-phenylethanol (5.0 mmol), and
acetylacetone (20.0 mmol) were dissolved in 10 mL of nitromethane. After
stirring for 4 h at 50 °C, the reaction was quenched with water followed by
extraction with dichloromethane. The combined organic layers were dried over
MgSO4 and the solvents were distilled off. Then, the product was purified by
column chromatography (heptanes/ethyl acetate = 1:1).
12. Typical procedure for the synthesis of triarylmethanes 6a–m: To a CH2Cl2 solution
(5 mL) of 5a (236 mg, 1.0 mmol) and 4a (372 mg, 1.1 mmol) was dropwise
added TiCl4 (0.12 mL, 1.1 mmol) at ꢁ78 °C. The reaction mixture was allowed
to warm to 20 °C for 6–12 h. After stirring for additional 2–6 h at 20 °C,
hydrochloric acid (10%, 20 mL) was added. The organic, and the aqueous layers
were separated and the latter was extracted with dichloromethane
(3 ꢂ 25 mL). The combined organic layers were dried (Na2SO4), filtered and
the filtrate was concentrated in vacuo. The residue was purified by
chromatography (silica gel, heptanes/ethyl acetate) to give 6a as a colorless
solid (115 mg, 33%), mp = 153–155 °C. 1H NMR (250 MHz, CDCl3): d 1.98 (s, 3H,
CH3), 2.07 (s, 3H, CH3), 3.79 (s, 3H, OCH3), 5.92 (s, 1H, CH), 6.65 (s, 1H, ArH),
6.99–7.26 (m, 10H, Ph), 10.51 (s, 1H, OH). 13C NMR (250 MHz, CDCl3): d 20.3,
21.7 (CH3), 49.6 (CH), 50.9 (OCH3), 111.7 (C), 116.7, 124.9, 127.1, 128.0 (CHAr),
~
6. Kischel, J.; Mertins, K.; Michalik, D.; Zapf, A.; Beller, M. Adv. Synth. Catal. 2007,
349, 865.
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Angew. Chem. 2006, 118, 807. Angew. Chem., Int. Ed. 2006, 45, 793; (d) Rueping,
M.; Nachtsheim, B. J.; Ieawsuwan, W. Adv. Synth. Catal. 2006, 348, 1033; (e) Yao,
X.; Li, C. J. J. Am. Chem. Soc. 2004, 126, 6884; (f) Yao, X.; Li, C. J. J. Org. Chem.
2005, 70, 5752; (g) Motokura, K.; Fujita, N.; Mori, K.; Mizugaki, T.; Ebitani, K.;
Kaneda, K. Angew. Chem. 2006, 118, 2667. Angew. Chem., Int. Ed. 2006, 45, 2605.
132.1, 139.3, 141.0, 144.3, 158.8, 170.9 (C). IR (KBr):
m ¼ 2987 (w), 1663 (s),
1564 (m), 1435 (m), 1341 (m), 1210 (s), 1069 (s), 857 (m), 801 (s), 719 (s) 696
(s) cmꢁ1. MS (EI, 70 eV): m/z (%) = 346 (M+, 66), 314 (100), 299 (21), 237 (18),
165 (49). HRMS (EI): calcd for C23H22O3 [M]+: 346.156966; found: 346.15635.