Synthesis of sterically hindered ortho-substituted tetraphenylethenes. Electronic effects in the McMurry olefination reaction

Article abstract of DOI:10.1021/ol060318h

Contrary to literature consensus, the McMurry olefination reaction can be extended to the direct synthesis of sterically encumbered tetrakis(2- substituted) tetraphenylethenes from the corresponding 2,2′-disubstituted benzophenones. The reaction exploits

Full text of DOI:10.1021/ol060318h

ORGANIC
LETTERS
2006
Vol. 8, No. 7
1491-1494
Synthesis of Sterically Hindered
Ortho-Substituted Tetraphenylethenes.
Electronic Effects in the McMurry
Olefination Reaction
Mee-Kyung Chung, Guizhong Qi, and Jeffrey M. Stryker*
Department of Chemistry, UniVersity of Alberta, Edmonton, Alberta, Canada T6G 2G2
jeff.stryker@ualberta.ca
Received February 6, 2006
ABSTRACT
Contrary to literature consensus, the McMurry olefination reaction can be extended to the direct synthesis of sterically encumbered tetrakis-
(2-substituted) tetraphenylethenes from the corresponding 2,2 -disubstituted benzophenones. The reaction exploits previously unrecognized
′
substrate-based electronic effects that dominate over otherwise controlling steric considerations and provides highly efficient access to derivatives
of tetrakis(2-hydroxyphenyl)ethene, a novel preorganized ligand system for polymetallic coordination chemistry and catalysis.
The reductive coupling of carbonyl compounds, a range of
low-valent titanium reactions commonly referred to as the
McMurry reaction, constitutes an important method for the
synthesis of highly substituted alkenes.1,2 McMurry reactions,
however, are generally unsuitable for the preparation of
sterically hindered tetraaryl olefins; the reaction leads instead
to competitive reduction of the starting ketone and/or
formation of coupled but overreduced 1,1,2,2,-tetrasubstituted
ethanes. Ortho-substituted diaryl ketones in particular mani-
fest this apparent steric limitation: neither bis(ortho-tolyl)-
methanone nor bis(2-methoxyphenyl)methanone affords the
corresponding olefin in acceptable yield under McMurry
conditions.3 The latter is converted exclusively to tetrakis-
(2-methoxyphenyl)ethane (85% yield) upon reaction with
TiCl4/Zn/pyridine/THF.4
We recently introduced a novel preorganized tetradentate
ligand system based on the tetrakis(2-hydroxyphenyl)ethene
structural class I,5 a differentially constrained analogue of
the ubiquitous calix[4]arenes II. The rather inefficient three-
step protocol developed for the olefination of bis(2-meth-
oxyphenyl)methanone and the corresponding bis(5-tert-butyl)
derivative5a prompted us to reinvestigate the McMurry
reaction for the reductive coupling of ortho-substituted ben-
zophenones. Here, we report that, contrary to literature con-
sensus, the McMurry reaction of substituted benzophenones
(3) Using TiCl3/LiAlH4, bis(ortho-tolyl)methanone gives a very low yield
of tetrakis(2-methylphenyl)ethene (15%) along with tetrakis(2-methylphen-
yl)ethane (40%): (a) Willem, R.; Pepermans, H.; Hallenga, K.; Gielen, M.;
Dams, R.; Giese, H. J. J. Org. Chem. 1983, 48, 1890-1898. (b) Bottine, F.
A.; Finocchiaro, P.; Libertini, E.; Reale, A.; Recca, A. J. Chem. Soc., Perkin
Trans. 2 1982, 77-81.
(1) (a) Mukaiyama, T.; Sato, T.; Hanna, J. J. Chem. Lett. 1973, 1041-
1044. (b) Tyrlik, S.; Wolochowicz, I. Bull. Soc. Chem. Fr. 1973, 2147-
2148. (c) McMurry, J. E.; Fleming, M. P. J. Am. Chem. Soc. 1974, 96,
4708-4709.
(2) Reviews: (a) McMurry, J. E. Chem. ReV. 1989, 89, 1513-1524. (b)
Kahn, B. E.; Rieke, R. D. Chem. ReV. 1988, 88, 733-745. (c) Lectka, T.
In ActiVe Metals: Preparation, Characterization, Applications; Fu¨rstner,
A., Ed.; VCH: New York, 1996; Chapter 3. (d) Ephritikhine, M. J. Chem.
Soc., Chem. Commun. 1988, 2549-2554.
(4) von Itter, F.-A.; Vo¨gtle, F. Chem. Ber. 1985, 118, 2300-2313.
(5) (a) Verkerk, U. H.; Fujita, M.; Dzwiniel, T. L.; McDonald, R.; Stryker,
J. M. J. Am. Chem. Soc. 2002, 124, 9988-9989. (b) Fujita, M.; Qi, G.;
Verkerk, U. H.; Dzwiniel, T. L.; McDonald, R.; Stryker, J. M. Org. Lett.
2004, 6, 2653-2656.
10.1021/ol060318h CCC: $33.50
© 2006 American Chemical Society
Published on Web 03/03/2006

is dominated not by steric effects but by substrate-based
electronic effects. On the basis of this newly recognized con-
trol element, the extension of the McMurry reaction to the
preparation of a range of tetrakis(ortho-substituted) tetraphen-
ylethylenes and related compounds has been realized.
reduction products. Replacement of DME with THF as sol-
vent promotes simple reduction over coupling (entry 3), a
predictable consequence of the increased propensity for hy-
drogen atom donation from tetrahydrofuran over an acyclic
ether.
To suppress the formation of reactive surface hydrides,7
LiAlH4 was replaced by Zn(Cu), another standard McMurry
reductant.2 The use of Zn(Cu) proved transforming, dramati-
cally shifting the product distribution to provide, for the first
time, reasonable selectivity for the formation of the desired
tetraarylethylene product (entry 4).
Using bis(5-tert-butyl-2-methoxyphenyl)methanone 1a as
the test substrate, we initially undertook an empirical
optimization of the relevant reaction parameters (Table 1).6
Among the operational parameters, the impact of reagent
preparation time is highly significant, despite previous reports
that no reduction of TiCl3 by Zn(Cu) occurs in the absence
of substrate.8 Omitting the reagent preparation step entirely
produces several unidentified minor compounds at the
expense of the desired alkene (entry 5), but intermediate
reagent preparation times inexplicably produce less selective
reactions (entries 6 and 7). Neither the reductant stoichiom-
etry (entries 8 and 9) nor the reaction temperature (entries
10 and 11) exerts more than an incremental effect on yields
and product distributions.9
The reaction is reasonably tolerant of the titanium source;
both bulk unsolvated TiCl3 and first quality TiCl3‚1.5DME
function very similarly.10 The latter reagent, however, is
relatively insensitive to the reagent preparation time, provid-
ing nearly identical results under both standard conditions
and the operationally advantageous “instant” method8b
(entries 12 and 13). Finally, the reaction provides greater
selectivity at larger scale (entry 14): this substrate, clearly,
suffers no inhibitory steric effect.
Table 1. Reagents, Conditions,a and Product Distribution in
the McMurry Olefination Reaction of Benzophenone 1a6
yield (%)d
time (h)b (°C)c 2a 3a 4a
reductant
(equiv)
activation Treact
entry
Ti source
TiCl3
1
2
LiAlH4 (0.5)
LiAlH4 (0.25)
LiAlH4 (0.25)
Zn(Cu) (0.5)
Zn(Cu) (0.5)
Zn(Cu) (0.5)
Zn(Cu) (0.5)
Zn(Cu) (4.0)
Zn(Cu) (1.0)
Zn(Cu) (0.5)
Zn(Cu) (0.5)
14
14
14
14
0
rt
rt
rt
rt
rt
rt
rt
rt
rt
14
9 61
TiCl3
38 27 16
3e TiCl3
30
9
30
5
4
5
TiCl3
TiCl3
TiCl3
TiCl3
TiCl3
TiCl3
TiCl3
TiCl3
74 20
60 21
51 24
48 26
The dramatic shift in product distribution observed by
using the TiCl3/Zn(Cu) reagent rather than TiCl3/LiAlH4
suggests the incorporation of strongly Lewis acidic [Zn(II)?]
coordination sites into the reagent, promoting substrate
binding and reduction on the reagent surface, strongly
favoring the bimolecular olefination. Substrate binding may
arise via chelation of the proximal ether and carbonyl
functionality or via unidentate coordination of the electron-
rich carbonyl. To address this question and distinguish steric
from electronic effects, a series of differentially substituted
benzophenones have been investigated (Table 2).
1
6
2
4
2
7
6
8
14
14
14
14
0
63 13 22
74 13 14
9
10
11
reflux 65 19
0
3
37
rt
rt
rt
68 20
12f TiCl3‚1.5DME Zn(Cu) (0.5)
79 4i 7i
78 7i 4i
84 5i 7i
13g TiCl3‚1.5DME Zn(Cu) (0.5)
14
14
14h TiCl3
Zn(Cu) (0.5)
a In DME solvent, unless otherwise noted. b Reaction time to generate
the low-valent titanium reagent (LiAlH4, rt; Zn(Cu), 89 °C). c Temperature
of the reductive coupling reaction. d Isolated yields after careful purification
by flash column chromatography. e THF used as solvent. f Large-scale
experiment using 6.0 g of 1a. g Large-scale experiment using 13.7 g of 1a.
h Large-scale experiment using 9.6 g of 1a. i For these experiments, the
1
yields of the minor products were obtained by H NMR integration of the
(6) Complete experimental procedures and characterization data are
provided as Supporting Information.
crude product mixture, normalized to the isolated yield of 2a.
(7) The TiCl3/LiAlH4/THF reagent consists principally of the hydride-
rich cluster [HTiCl(thf)0.5]x, a potential source of H•, H2, and reactive
hydride: Aleandri, L. E.; Becke, S.; Bogdanivic, B.; Jones, D. J.; Rozie`re,
J. J. Organomet. Chem. 1994, 472, 97-112.
(8) (a) Fu¨rstner, A.; Jumbam, D. N. Tetrahedron 1992, 48, 5991-6010.
(b) Fu¨rstner, A.; Hupperts, A.; Ptock, A.; Janssen, E. J. Org. Chem. 1994,
59, 5215-5229. (c) Bogdanivic, B.; Bolte, A. J. Organomet. Chem. 1995,
501, 109-121. (d) Stahl, M.; Pidun, U.; Frenking, G. Angew. Chem., Int.
Ed. Engl. 1997, 36, 2234-2237.
(9) Control experiments conducted by adding tetrakis(5-tert-butyl-2-
methoxyphenyl)ethene 2a to an active McMurry reduction of 2,2′-
dimethoxybenzophenone 1b clearly indicate that overreduction product 3a
does not arise from direct reduction of 2a.
(10) The unsolvated TiCl3 powder has recently become difficult to obtain
commerically. TiCl3‚1.5DME is conveniently prepared from TiCl4 and Ti
powder in DME: Sullivan, J. M. U.S. Patent 6307063, 2001.
In nearly all cases, the McMurry reaction proceeds to give
three principal reduction products, accompanied by traces
of other, unidentified, byproducts (eq 1). The low-valent ti-
tanium species generated from titanium trichloride and Li-
AlH4 is a generally inferior reagent, with the highest percen-
tage of undesired reduction products 3a and 4a obtained from
using the literature-optimized3a 1:0.5 molar ratio of TiCl3/
LiAlH4 (entry 1). Lowering the ratio of TiCl3/LiAlH4 to
1:0.25 dramatically improves the isolated yield of olefination
product 2a (entry 2), but the reaction remains dominated by
1492
Org. Lett., Vol. 8, No. 7, 2006

Table 2. McMurry Reaction of bis(ortho-Substituted)
Diarylmethanones 1b-ea
Table 3. McMurry Reaction of Unsymmetrically Substituted
Diarylmethanones 1f-ia
a Conditions: TiCl3, 0.5 equiv of Zn(Cu), DME, 14 h reagent preparation
time (reflux). A, reaction at room temperature; B, reaction at reflux. b CdO
stretching absorption frequency (cm-1) of substrates in anhydrous DME.
c Product identification provided as Supporting Information. d Ethane
obtained as a ∼1:1 diastereomeric mixture. e Stereochemistry assignment
tentative, based on spectroscopic comparisons to the rigorously assigned
isomers Z-2h and E-2h. f Major product is the Z-isomer, as determined by
X-ray crystallography.6 g Yield not determined; the ethane(s) could not be
isolated free from minor byproducts.
a Conditions: TiCl3, 0.5 equiv of Zn(Cu), DME. Reagent preparation:
14 h at reflux. A, reaction at room temperature; B, reaction at reflux.
b Carbonyl infrared absorption (cm-1) in anhydrous DME. c Complete
characterization provided as Supporting Information. d Tetraphenylethane
product obtained as a ∼1:1 diastereomeric mixture. e Yields derived from
NMR integration of the purified but inseparable product mixture. f Two
additional byproducts 5 (rt, 26%; reflux, 0%) and 6 (rt, 17%; reflux, 16%)
are also isolated. g Recovered benzophenone 1d (39%) and bis(ortho-
tolyl)methanol (28%) were also obtained. h Benzophenone 1e (15%) was
also recovered.
The reaction of bis(2-methoxyphenyl)methanone 1b pro-
ceeds in comparable yield and selectivity to the closely ana-
logous 1a (entry 1). Replacement of one methoxy substituent
with the less-electron-donating but roughly isosteric methyl
group (1c, entries 2 and 3) substantially undermines the
McMurry process. Two additional compounds are isolated
from this reaction, ipso-substitution product 5 and anthracene
6, with the latter presumably being derived from the former
by a second ipso-substitution reaction.
and substantial formation of the simple diarylmethanol
product (entry 4). Surprisingly, however, conducting the
reaction at reflux temperature leads to the isolation of
tetrakis(1-methylphenyl)ethene 2d in very good yield (entry
5), providing for the first time3 reaction conditions for
successful olefination of this sterically challenging and
electronically unactivated substrate.
The electronic influence of conjugating methoxy substit-
uents can be isolated from interacting steric effects by
appending para-methoxy substituents to bis(2-methylphenyl)-
methanone 1d (entries 6 and 7). At room temperature, bis-
(4-methoxy-2-methylphenyl)methanone 1e undergoes mark-
edly higher conversion (viz., nearly 3-fold), albeit with little
change in product distribution. At reflux, however, this
substrate undergoes the McMurry olefination with remark-
ably high selectivity and yield. Although multidentate
substrate coordination to the heterogeneous surface might
well be invoked to rationalize the reaction of bis(ortho-
Replacement of the remaining methoxy substituent with
a methyl group leads to poor conversion at room temperature
Org. Lett., Vol. 8, No. 7, 2006
1493

substituted) 1b, such a chelation effect is not possible in the
para-substituted benzophenone 1e.
With the exception of 2-methoxy-2′-methylbenzophenone
1c, which is diverted into a unique reactivity manifold, the
qualitative correlation of carbonyl infrared absorption energy
with observed reactivity in the McMurry reaction extends
to both series of benzophenone subtrates. The general
preference for the formation of the Z-olefin from the
unsymmetrically substituted series of substrates (Table 3) is
a significant bonus, albeit very difficult to rationalize.
To complement this assessment of substrate-based elec-
tronic perturbations in the McMurry reaction, a series of
substrates incorporating a substantial reduction in steric
demands at the carbonyl functionality were also investigated
(Table 3). Relocation of one ortho-methoxy substituent to
the para-position in either ring maintains the high efficiency
of the McMurry reaction (1f/1g, entries 1 and 2), delivering
a yield and product distribution almost identical to that
obtained from bis(2-methoxyphenyl)methanone 1b. Contrary
to expectations, however, deletion of one ortho-methoxy
substituent leads to a dramatic decrease in both selectivity
and yield (1h, entry 3), despite mitigating the steric effect:
this McMurry reaction is dominated by electronic rather than
steric effects. Increasing the reaction temperature at least
partially compensates for the electronic deactivation, restor-
ing both yield and selectivity (entry 4).
The development of a McMurry protocol for the direct
synthesis of tetrakis(2-methoxyphenyl)ethene derivatives
(e.g., 2a and 2b) from the corresponding 2,2′-dimethoxy-
benzophenone renders obsolete our prior synthetic route5a
to these potentially important ligand systems.
Further extensions in scope and continued investigation
and exploitation of electronic effects in the McMurry
olefination of sterically hindered bis(ortho-substituted) diaryl
ketones remain under investigation.
As inferred from the results obtained from bis(ortho-
substituted) benzophenones 1d and 1e, the relative reactivities
of substrates 1f-h are inconsistent with a substrate chelation
effect. The results, instead, track the basicity of the carbonyl
functionality, as measured by the carbonyl absorption
frequencies in the infrared spectra (Table 3).
Acknowledgment. We thank NSERC-CRO for financial
support and R. McDonald and M. Ferguson for X-ray
structures. M.-K.C. thanks Alberta Ingenuity/Killam Trusts
for a postdoctoral fellowship. We also thank Paul D. Fancy
for preparing substrate 1g.
The impact of the electrophilic para-trifluoromethyl sub-
stituent in substrate 1i (entries 5 and 6) is considerably more
ambiguous, returning yields and product distributions nearly
identical to those of 2-methoxybenzophenone 1h, both at
room temperature and at reflux. The near fidelity in infrared
absorption frequencies for the carbonyl functionality in the
two substrates (see Table 3) suggests that conjugation to the
carbonyl functionality11 is dominated by the arene bearing
the electron-donating methoxy substituent, with the triflu-
oromethyl group exerting surprisingly little influence on the
electron density at the carbonyl.
Supporting Information Available: Experimental pro-
cedures and complete characterization data for all new
compounds; details of the X-ray crystallography for com-
pounds Z-2h, 3e, and 6. This material is available free of
charge via the Internet at http://pubs.acs.org.
OL060318H
(11) The two benzophenone arene rings cannot simultaneously maintain
planarity with the carbonyl functionality, a consequence of ortho-substituent
peri-interactions and, presumably, four-electron repulsion of methoxy and
carbonyl lone electron pairs.
1494
Org. Lett., Vol. 8, No. 7, 2006