Synthesis of heterosubstituted hexaarylbenzenes via asymmetric carbonylative couplings of benzyl halides

Article abstract of DOI:10.1021/ol0629770

Asymmetric carbonylative couplings of benzyl halldes have been shown to give heterosubstituted 1,3-diarylacetones In moderate to high yields. These asymmetric ketones were converted via Knoevenagel condensations to tetraarylcyclopentadienones, and further

Full text of DOI:10.1021/ol0629770

ORGANIC
LETTERS
2007
Vol. 9, No. 7
1187-1190
Synthesis of Heterosubstituted
Hexaarylbenzenes via Asymmetric
Carbonylative Couplings of Benzyl
Halides
Robert G. Potter and Thomas S. Hughes*
Department of Chemistry, Cook Physical Sciences Building, 82 UniVersity Place,
UniVersity of Vermont, Burlington, Vermont 05401
thomas.s.hughes@uVm.edu
Received December 8, 2006
ABSTRACT
Asymmetric carbonylative couplings of benzyl halides have been shown to give heterosubstituted 1,3-diarylacetones in moderate to high
yields. These asymmetric ketones were converted via Knoevenagel condensations to tetraarylcyclopentadienones, and further conversion via
dehydro-Diels−Alder cycloadditions gave highly heterofunctionalized hexaarylbenzenes with uniquely functionalized aryl groups at the para
positions of the central benzene. This method allows control of the substituents on each of four unique pendent aryl group positions, giving
rise to substitution patterns not available using symmetrical 1,3-diarylacetones.
The synthesis of phenylene oligomers and dendrimers has
received much attention in recent years. These compounds
have been synthesized as conductive polymers1 and as
precursors for conductive discotic liquid crystals2 and
graphitic materials.3 Polymers containing cyclopentadienone
moieties in the main chain have also been synthesized as
low-band gap materials.4 Further development of these
materials depends on the ability to synthesize specific
arrangements of phenylene units, as well as to substitute
certain phenyl groups in a controllable fashion. Early
syntheses of tetraarylcyclopentadienones (tetracyclones) and
hexaarylbenzenes (HABs) have employed the route shown
in Scheme 1, which involves the initial Knoevenagel
condensation of a 1,3-diarylacetone 1 with a derivative of
benzil, followed by the Diels-Alder cycloaddition of the
resulting tetraarylcyclopentadienone 2 with a diarylethyne
3 to give 4.5
While the substituents on the various synthons can easily
be altered to give the substitution pattern shown in Scheme
1,6 the lack of regiocontrol in both the Knoevenagel
condensation and the Diels-Alder cycloaddition prevent the
formation of a HAB with certain sets of distinctly and
differently substituted aryl rings. However, a single regio-
(1) Wu, J.; Gherghel, L.; Watson, M.; Li, J.; Wang, Z.; Simpson, C. D.;
Kolb, U.; Mu¨llen, K. Macromolecules 2003, 36, 7082.
(2) Schmidtke, J. P.; Friend, R. H.; Kastler, M.; Mu¨llen, K. J. Chem.
Phys. 2006, 124, 174704. Warman, J. M.; Piris, J.; Pisula, W.; Kastler, M.;
Wasserfallen, D.; Mu¨llen, K. J. Am. Chem. Soc. 2005, 127, 14257.
Fechtenkotter, A.; Saalwachter, K.; Harbison, M. A.; Mu¨llen, K.; Speiss,
H. W. Angew. Chem., Int. Ed. 1999, 38, 3039.
(3) Mu¨llen, K.; Grimsdale, A. C. Angew. Chem., Int. Ed. 2005, 44, 5592
and references therein. Gherghel, L.; Ku¨bel, C.; Lieser, G.; Ra¨der, H.-J.;
Mu¨llen, K. J. Am. Chem. Soc. 2002, 124, 13130.
(4) Tamao, K.; Yamaguchi, S.; Ito, Y. J. Chem. Soc., Chem. Commun.
1994, 229.
(5) Dilthey, W.; Hurtig, G. Ber. 1934, 67, 2007. Ried, W.; Boen-
nighausen, K. H.; Chem. Ber. 1960, 93, 1769. Bergmann, P.; Paul, H. Chem.
Ber. 1967, 100, 828. Broser, W.; Siegle, P.; Kurreck, H. Chem. Ber. 1968,
101, 69. Broser, W.; Reusch, J.; Kurreck, H.; Siegle, P. Chem. Ber. 1969,
102, 1715.
(6) Thomas, K. R. J.; Velusamy, M.; Lin, J. T.; Chuen, C. H.; Tao, Y.-
T. J. Mater. Chem. 2005, 15, 4453. Wu, J.; Watson, M. D.; Tchebotareva,
N.; Wang, Z.; Mu¨llen, K. J. Org. Chem. 2004, 69, 8194.
10.1021/ol0629770 CCC: $37.00
© 2007 American Chemical Society
Published on Web 02/27/2007

Scheme 1. Established Synthesis of Hexaarylbenzenes
Scheme 2. Desymmetrization of a Tetraarylcyclopentadienone
faster than the second. The presumed mechanism of this
reaction is depicted in Scheme 3.8,9 It predicts the addition
isomer would result if exactly one of the synthons was
asymmetric. Asymmetrically substituted benzils and diaryl-
ethynes would give HABs with distinguishable ortho-related
A and B or D and E rings, while rings C and F, which are
para to each other on the central aromatic ring, could be
distinguished by using an asymmetric 1,3-diarylacetone. Such
regiospecificity is especially desirable if the resulting tetra-
cyclones or HABs are to be linked further into oligomers or
polymers, and the chemistry employed should allow the
installation of substituents that can be readily converted into
functional groups that can be used to attach additional
tetracyclone and/or HAB moieties.
One approach to the synthesis of such asymmetric tet-
raarylcyclopentadienones is the desymmetrization of sym-
metrical 2a by radical bromination (Scheme 2). Controlling
the stoichiometry of this reaction favors the monobrominated
product, but a statistical mixture is still obtained that is quite
difficult to resolve by column chromatography or any other
method. This non-regiospecific chemistry resulted in a 32%
yield of purified asymmetric tetraarylcyclopentadienone,
which is much less than desired if this methodology is to be
applied to the construction of larger oligomers of cyclopen-
tadienones. Since the 1,3-diarylacetones are convenient
synthetic precursors of the cyclopentadienones, a route to
asymmetric 1,3-diarylacetones was sought.
Scheme 3. Presumed Mechanism of Carbonylative Coupling
of Benzyl Bromides
of 1 equiv of halide to give the intermediate 5, which then
undergoes oxidative addition to the potentially different
second alkyl halide, followed by rearrangement to an acyl
intermediate that reductively eliminates the asymmetric
ketone 1. This reaction was shown to be functional group
tolerant but has previously only been applied in an inter-
molecular sense to aliphatic primary halides,9,10 and to
intramolecular cyclizations.7,11 This paper describes the
application of this carbonylative coupling to the synthesis
of asymmetric 1,3-diarylacetones from benzyl halides.
The synthesis of an asymmetric ketone via the Collman
reagent requires that the first oxidative addition is complete
before the second halide is added to the reaction mixture.
However, since kinetic data for the oxidative additions in
homogeneous solution has previously only been measured
for aliphatic alkyl halides,12 it was necessary to determine
the rate of the first oxidative addition of iron tetracarbonyl
to a benzyl bromide. The reaction of 4-methylbenzyl bromide
with iron tetracarbonyl disodium in N-methyl-2-pyrrolidone
(NMP) was monitored by in situ IR. Principal component
analysis showed two dominant species in solution, as can
be seen in Figure 1. The disappearance of the absorption at
1876 cm-1, and its shoulder at 1907 cm-1, characteristic of
Symmetrical 1,3-diarylacetones can be conveniently syn-
thesized in a phase-transfer carbonylative coupling of 2 equiv
of benzyl halide.7 However, if an asymmetric ketone is
desired, a reaction that allows more control over the addition
of the halides is required. Collman et al. demonstrated the
synthetic utility of iron tetracarbonyl disodium as a carbo-
nylative coupling agent to transform 2 equiv of alkyl halide
to a dialkyl ketone (Scheme 3).8
The two oxidative additions that must occur during this
reaction occur at different rates, with the first being much
(9) Collman, J. P. Acc. Chem. Res. 1975, 8, 342.
(10) Winter, S. R. Ph.D. Thesis, Stanford University, Stanford, CA, 1973
(11) Johnson, B. F. G.; Lewis, J.; Thompson, D. J. Tetrahedron Lett.
1974, 3789
(12) Collman, J. P.; Finke, R. G.; Cawse, J. N.; Brauman, J. I. J. Am.
Chem. Soc. 1977, 99, 2515.
(7) Tanguy, G.; Weinberger, B.; des Abbayes, H. Tetrahedron Lett. 1984,
25, 5529. des Abbayes, H.; Cle´ment, J.-C.; Laurent, P.; Tanguy, G.;
Thilmont, N. Organometallics 1988, 7, 2293.
(8) Collman, J. P.; Winter, S. R.; Clark, D. R. J. Am. Chem. Soc. 1972,
94, 1788.
1188
Org. Lett., Vol. 9, No. 7, 2007

Table 1. Asymmetric 1,3-Diarylacetones Synthesized via
Carbonylative Coupling with Collman’s Reagenta
R
R′
yield (%)
1a
1b
1c
1d
1e
1f
1g
1h
1i
CH2OCH3
CH2OTIPS
CH2OBn
CH2OTBS
CH3
OCH3
Br
NO2
CO2CH3
CH2OCH3
CH2OTBS
OCH3
CH2OCH3
CH2OTIPS
CH2OBn
CH2OTBS
CH3
OCH3
Br
NO2
CO2CH3
CH2OTIPS
CH2OBn
NO2
64
90
60
64
94
83
77
0
37
74
66
>10b
63
Figure 1. In situ solution IR of the reaction of 4-methyl benzyl
bromide and iron tetracarbonyl disodium in NMP. See the text for
details. Absorbance units (z-axis) are arbitrary. Addition of the
benzyl bromide occurred at 222 s.
1j
1k
1l
iron tetracarbonyl and the appearance of an absorption at
1916 cm-1, characteristic of the intermediate 5,13 indicated
the first oxidative addition was complete within minutes. In
a solution of 0.095 M bromide and 0.033 M iron tetracar-
bonyl disodium in NMP, the second-order rate constants were
determined to be 0.1 M-1 s-1 for the disappearance of Na2-
Fe(CO)4 and 0.07 M-1s-1 for the formation of 5. A rate
constant of 0.12 M-1s-1 was measured for the oxidative
addition of Na2Fe(CO)4 to 1-bromo-2,2-dimethylpropane,12
so there does not appear to be a large rate increase arising
from the benzylic nature of the sites of nucleophilic attack
in the present study. For the synthesis of each of the asym-
metric ketones described below, the second benzyl bromide
was added to the reaction mixture within 1 h after the first.
The diarylacetones synthesized by this method are shown
in Table 1. Moderate to high yields were obtained for most
of the functional groups employed. The protected benzyl
alcohols were of particular interest because they can be
conveniently converted into benzyl halides, which can then
in turn be subjected to the same reaction conditions to build
oligoHABs. While Collman’s reagent has been shown to be
fairly functional-group tolerant, this study represents the first
application of this reaction to a variety of benzyl halides.
While most functional groups allowed good coupling
yields, if a strong enough electron withdrawing group is
attached to the aromatic ring of the benzyl bromide the yield
of the corresponding ketone decreases to zero (Table 1). This
dramatic decrease in yield is proposed to result from
competing redox reactions between iron tetracarbonyl diso-
dium and the benzyl bromide since electron-poor aryls have
sufficiently low reduction potentials.14 The benzyl protons
of a dihydrostilbene product consistent with a dissociative
1m
OCH3
Br
a The first halide was stirred with the Na2Fe(CO)4 for 1 h at 0 °C under
an inert N2 atmosphere. The second halide was then added, and the reaction
mixture was warmed to room temperature. Yields of homocouplings are
reported based on recovered starting material. Yields of heterocouplings
are based on the recovered first halide reagent, and in most cases recovery
of the second halide added was nearly quantitative. b Yield based on ES-
LCMS.
Both dilute homogeneous and phase-transfer carbonylative
couplings were attempted on 2g and 2h to prepare ketone
macrocycles and elongated diarylacetones, but the negligible
yields were obtained of the desired macrocycles and oligo-
mers, respectively. These results were consistent with the
bimolecular rate-determining step of the coupling being
disfavored under the dilute conditions of the attempted
macrocyclization, as well as the competitive redox chemistry
of the easily reduced cyclopentadienones.16
Protected benzyl alcohols were employed in this study
because they can serve as masked benzyl bromides that can
be coupled in similar reactions to synthesize larger phenylene
dendrimers with widely varied substituents. The regiocontrol
made possible by the use of asymmetric 1,3-diarylacetones
now allows the syntheses of specific oligophenylenes and
oligotetracyclones that were not previously possible. Such
syntheses, including those of cyclic oligotetracyclones and
oligo-p-phenylenes, are currently being pursued in our
laboratories.
Various tetraarylcyclopentadienones were synthesized by
Knoevenagel condensation with benzil or 4,4′-dibromobenzil.
In the reactions reported in Table 2, the lower yields are
most likely the result of the reaction of the strong hydroxide
base with the moderately labile silyl ether protected benzyl
alcohols.
1
electron-transfer reaction15 are present in the H NMR of
the 4-nitrobenzyl bromide homocoupling product mixture.
(13) The IR of (CO)4FeCH2PPh3 has peaks at 1905(vs) and 1880(s): des
Abbayes, H.; Clement, J. C.; Laurent, P.; Yaouanc, J. J.; Tanguy, G.;
Weinberger, B. J. Organomet. Chem. 1989, 359, 205.
(14) Redox potential E is -0.49 V for PhNO2 (Meisel, D.; Neta, P. J.
Am. Chem. Soc. 1975, 97, 5198) and -1.95 V for Na2Fe(CO)4 (Amatore,
C.; Verpeaux, J.-N.; Krusic, P. J. Organometallics 1988, 7, 2426).
(15) Save´ant, J.-M. AdVances in Electron Transfer Chemistry; JAI
Press: Greenwich, CT, 1994; Vol. 4, p 53.
(16) Redox potential E1/2 of 2(R ) R′ ) H, Ar ) Ph) was measured to
be -0.87 V (van Willigen, H.; Gieger, W. E.; Rausch, M. D. Inorg. Chem.
1977, 16, 581) and E, -0.83 V (Kawase, T.; Ohsawa, T.; Enomoto, T.;
Oda, M. Chem. Lett. 1994, 7, 1333).
Org. Lett., Vol. 9, No. 7, 2007
1189

Table 2. Cyclopentadienones Synthesized from Asymmetric
Table 3. Hexaarylbenzenes with Specific, Unique Groups at
1,3-Diarylacetones
the 1,4 Positions
R
R′
Ar
C6H5
C6H5
C6H5
C6H5
C6H5
p-BrC6H4
yield (%)
2a
2b
2c
2d
2e
2f
CH3
CH3
88
83
85
64
78
75
CH2OTIPS
CH2OBn
CH2OTBS
CH2OTIPS
CH2OTIPS
CH2OTIPS
CH2OBn
CH2OBn
CH2OCH3
CH2OCH3
Ar
C6H5
C6H5
p-C6H4Br
p-C6H4Br
Ar′
C6H5
p-C6H4OCH3
p-C6H4OCH3
p-C6H4Br
yield (%)
4a
4b
4c
4d
86
80
72
62
Several hexaarylbenzenes were prepared via a Diels-
Alder cyclization with 1,2-diarylethynes as shown in Table
3. The yields obtained were moderate to high, and most likely
reflect the relative difficulty in the purification of substituted
hexaarylbenzenes. Unsubstituted hexaphenylbenzene usually
crystallizes from the reaction mixture in the protocol used,17
but column chromatography was required to purify the
compounds shown which contained side chains that frustrated
spontaneous crystallization. Melting point determinations for
all compounds 4 showed decomposition before melting near
the boiling point of phenyl ether; lower temperatures and
longer reaction times may increase cycloaddition yields.
In conclusion, a variety of uniquely and asymmetrically
substituted tetracyclones and HABs suitable for further
elongation into oligomers and polymers have been synthe-
sized in good yields. The key to their synthesis is an
asymmetric carbonylative coupling reaction with Collman’s
reagent that converts two different benzyl halides into a 1,3-
diarylacetone by the addition of each halide at appropriate
reaction times. The tetracyclones and HABs obtained herein
are currently being coupled to form longer oligophenylenes,
as well as being oxidized to form fused polycyclic aromatic
hydrocarbons with novel substitution patterns.
Acknowledgment. This work was supported by the
University of Vermont, and the in situ IR experiments were
supported by the NSF (CHE 0342861). We thank Prof.
William Geiger at the University of Vermont for helpful
discussions concerning iron carbonyl species.
Supporting Information Available: Experimental pro-
cedures and spectroscopic data for all new compounds and
details of the determination of rate constant for the carbo-
nylative coupling reaction. This material is available free of
charge via the Internet at http://pubs.acs.org.
(17) Fieser, L. F.; Fieser, M. Reagents for Organic Synthesis; Wiley:
New York, 1968; Vol. 1, p 241.
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