Ligand-Modified Catalysts for the McMurry Pinacol Reaction

Full text of DOI:10.1021/jo970792o

4566
J . Org. Chem. 1997, 62, 4566-4567
Ta ble 1. Ca ta lyzed P in a col Cou p lin g of Ald eh yd es a n d
Keton esa
Liga n d -Mod ified Ca ta lysts for th e McMu r r y
P in a col Rea ction
entry
substrate
C6H5CHO
% yieldb
dl:mesoc,d
Timothy A. Lipski, Mark A. Hilfiker, and
Scott G. Nelson*
a
b
c
d
e
f
90
95
85
79
76
81
84
69:31
55:45
83:17
74:26
67:33
67:33
62:38
p-BrC6H4CHO
C6H11CHO
Department of Chemistry, University of Pittsburgh,
Pittsburgh, Pennsylvania 15260
PhCH2CH2CHO
Me2CHCH2CHO
C6H5COCH3
Received May 7, 1997
g
2-C10-H7COCH3
a
The McMurry pinacol reaction is an exceptionally
versatile bond construction in organic synthesis and is,
in many instances, the singular method for the prepara-
tion of highly strained alkenes and macrocyclic or poly-
cyclic ring systems.1 Despite the level of sophistication
achieved in the McMurry reaction, intermolecular pinacol
reactions continue to suffer from the requirement of
stoichiometric quantities of expensive or difficult to
prepare reducing agents and the notorious lack of ste-
reoselection typically observed in these reactions.2,3 Cata-
lyzed reducing systems offer a potential solution to the
operational and economic difficulties associated with
these reactions, a fact that has undoubtedly contributed
to recent reports of pinacol reactions catalyzed by Ti(III),4
V(I),5 Sn(IV),3b and Sm(II) complexes.6 Intermolecular
pinacol couplings promoted by Ti(III)4b,7 and V(II) re-
agents8 are among the rare examples of highly diaste-
reoselective reductive carbonyl-coupling reactions. In the
context of developing catalyzed reductive C-C bond
constructions, we were interested in simultaneously
addressing the issues of cost, operational simplicity, and
stereochemical control by developing catalyzed pinacol
reactions with the intent of modulating reaction stereo-
selection via the catalyst complex and its attendant
ligands. We report herein the use of organic-soluble Ti-
(III) complexes as highly efficient catalysts for pinacol
homocoupling reactions and the development of ligand-
modified catalysts for controlling diastereoselectivity in
the reductive coupling of aryl aldehydes (eq 1).
Reactions were carried out using the conditions given in ref
b
14. Values reported are those for chromatographically purified
materials after silyl ether hydrolysis. c Ratios determined by 1H
d
NMR analysis of crude reaction mixture. Stereochemical assign-
ments made by comparison of spectroscopic data to that reported
in the literature.
While investigating the pinacol coupling of enolization-
prone aldehydes, we discovered that the organic-soluble
trichlorortris(tetrahydrofuran)titanium(III) complex9 was
the optimal reducing agent for effecting these bond
constructions. In the course of this investigation, sub-
stoichiometric quantities of TiCl3(THF)3 were found to
dramatically accelerate pinacol coupling reactions em-
ploying the Zn/TMSCl reducing system originally re-
ported by Boudjouk.10 Catalyst loadings of TiCl3(THF)3
as low as 1 mol % effect the pinacol homocoupling of
benzaldehyde at -78 °C, in the presence of Zn (0.6-1.2
equiv) and TMSCl (1.2 equiv), to afford hydrobenzoin in
quantitative yield (1.2:1 dl:meso).11,12 Analogous reaction
conditions provided no pinacol product in the absence of
the titanium catalyst. While the TiCl3(THF)3-catalyzed
reducing system proved effective for coupling benzalde-
hyde, reaction diastereoselection was unacceptably low,
and coupling reactions of less electrophilic aromatic or
aliphatic aldehydes proceeded only slowly or not at all
under these reaction conditions. These limitations
prompted us to pursue the development of modified
catalyst complexes that would provide greater substrate
generality and improved levels of diastereoselection.
Efforts to extend the TiCl3(THF)3-catalyzed pinacol
couplings to less reactive substrates were advanced
considerably by the observation that certain reaction
additives dramatically enhance pinacol reaction rates.
Substoichiometric quantities (5-30 mol %) of protic (t-
BuOH, catechol, 2,2′-biphenol) or Lewis basic (DMPU,
DMF, N,N-dimethylacetamide) additives afford ∼5-10-
fold rate accelerations relative to the parent TiCl3(THF)3
catalyst.13 The catalyst system derived from TiCl3-
(THF)3-t-BuOH emerged from this investigation as the
optimal pinacol catalyst on the basis of turnover rates
and operational simplicity. Thus, in the presence of Zn
(1.2 equiv) and TMSCl (1.2 equiv), TiCl3(THF)3-t-BuOH
(5 mol %) catalyzes the reductive homocoupling of a
variety of carbonyl compounds (Table 1), with diastereo-
selection ranging from dl:meso ) 1.5-3:1 for aryl alde-
hydes (entries a and b), aliphatic aldehydes (entries d
(1) (a) McMurry, J . E. Chem. Rev. 1989, 89, 1513-1524 and
references cited therein.
(2) Robertson, G. M. In Comprehensive Organic Synthesis: Carbon-
Carbon σ-Bond Formation; Trost, B. M., Fleming, I., Heathcock, C.
H., Eds.; Pergamon Press: New York, 1991; Vol. 3, Chapter 2.6, pp
563-611.
(3) A number of highly diastereoselective intramolecular pinacol
couplings have been reported; see: (a) Reference 1. (b) Raw, A. S.;
Pedersen, S. F. J . Org. Chem. 1991, 56, 830-833. (c) Guidot, J . P.; Le
Gall, T.; Mioskowski, C. Tetrahedron Lett. 1994, 35, 6671-6672. (d)
Hays, D. S.; Fu, G. C. J . Am. Chem. Soc. 1995, 117, 7283-7284. (e)
Kang, M.; Park, J .; Konradi, A. W.; Pedersen, S. F. J . Org. Chem. 1996,
61, 5528-5531.
(4) (a) Fu¨rstner, A.; Hupperts, A. J . Am. Chem. Soc. 1995, 117,
4468-4475. (b) Gansa¨uer, A. J . Chem. Soc., Chem. Commun. 1997,
457-458.
(9) Manzer, L. E. Inorg. Synth. 1982, 21, 135-140.
(10) So, J .-H.; Park, M.-K.; Boudjouk, P. J . Org. Chem. 1988, 53,
5871-5875.
(11) The structure of the Ti(III) catalyst proved to be a determining
factor in the success of the catalyzed pinacol reactions. Titanium(III)
chloride that had not been precomplexed with THF was inactive as a
catalyst under the indicated reaction conditions.
(12) For a discussion of possible mechanisms of low-valent metal-
catalyzed pinacol reactions in the presence of TMSCl, see refs 4, 5,
and 6b.
(13) The magnitude of the rate acceleration is substrate dependent;
less reactive substrates (e.g., aliphatic aldehydes) exhibit the largest
rate accelerations relative to the parent catalyst system.
(5) Hirao, T.; Hasegawa, T.; Muguruma, Y.; Ikeda, I. J . Org. Chem.
1996, 61, 366-367.
(6) (a) Le´onard, E.; Dun˜ach, E.; Pe´richon, J . J . Chem. Soc., Chem.
Commun. 1989, 276-277. (b) Nomura, R.; Matsuno, T.; Endo, T. J .
Am. Chem. Soc. 1996, 118, 11666-11667.
(7) (a) Raubenheimer, H. G.; Seebach, D. Chimia 1986, 40, 12-13.
(b) Handa, Y; Inanaga, J . Tetrahedron Lett. 1987, 28, 5717-5718. (c)
Barden, M. C.; Schwartz, J . J . Am. Chem. Soc. 1996, 118, 5484-5485.
(8) Konradi, A. W.; Kemp, S. J .; Pedersen, S. F. J . Am. Chem. Soc.
1994, 116, 1316-1323 and references cited therein.
S0022-3263(97)00792-5 CCC: $14.00 © 1997 American Chemical Society

Communications
J . Org. Chem., Vol. 62, No. 14, 1997 4567
Ta ble 2. Dia ster eoselective Hom ocou p lin g of Ar yl
Ald eh yd esa
and e), and aryl methyl ketones (entries f and g) to dl:
meso ) 4.8:1 for an R-branched aliphatic aldehyde (entry
c).14 The sensitive 1,5- and 1,6-dialdehydes 1 and 2 also
undergo annulative pinacol coupling under these catalytic
reaction conditions (eqs 2 and 3).15
entry
substrate
C6H5CHO
% yieldb
dl:mesoc,d
a
b
c
d
e
f
89
83
90
90
94
95
88:12 (69:31)
90:10 (70:30)
87:13
p-CH3OC6H4CHO
o-CH3C6H4CHO
p-(i-Pr)C6H4CHO
p-(C6H5)C6H4CHO
PhCH2CH2CHO
87:13
91:9
67:33
a
Reactions were carried out using the conditions given in ref
14 with 30 mol % 1,3-diethyl-1,3-diphenylurea (DEPU). b Reported
yields are for chromatographically purified materials after silyl
ether hydrolysis. c Ratios determined by 1H NMR analysis of crude
d
reaction mixture. Values in parentheses are for reaction in the
absence of DEPU.
chiral pinacol diastereomers with substantially enhanced
levels of stereoselectivity relative to reactions employing
the parent TiCl3(THF)3-t-BuOH catalyst (Table 2).18
Thus, aromatic aldehydes undergo catalyzed diastereo-
selective homocoupling to afford the chiral pinacol prod-
ucts with diastereomeric ratios of dl:meso ) 87:13 to 91:
9. The insensitivity of diastereoselection in the coupling
of aliphatic aldehydes to the DEPU-modified catalyst
suggests that π-stacking interactions between substrate
and ligand may contribute to defining the stereochemical
course of these reactions.19
The present study establishes ligand-modified Ti(III)
complexes as effective catalysts for executing the reduc-
tive homocoupling of various carbonyl compounds. The
capacity of catalyst architecture to influence reaction
diastereoselection in the catalyzed pinacol reactions has
been demonstrated for the first time. The insights
enumerated herein are expected to prove valuable in
devising catalyzed asymmetric variants of these impor-
tant C-C bond constructions.
Our success in influencing pinacol reaction rates
through modifying the catalyst complex led us to explore
catalyst architecture as a vehicle for establishing stere-
ochemical control in the pinacol bond constructions.
Modified catalyst structures could readily be accessed
from the parent TiCl3(THF)3 complex by exploiting the
lability of coordinated THF toward ligand exchange.16
This analysis and the Lewis base-induced rate accelera-
tion exhibited by the Ti-catalyzed pinacol reactions
prompted us to assay the sensitivity of reaction diaste-
reoselection to the steric and electronic characteristics
of various amide and urea ligands.17 The catalyst
complex derived from 5 mol % TiCl3(THF)3-t-BuOH and
30 mol % 1,3-diethyl-1,3-diphenylurea (DEPU) proved to
be the most successful catalyst system, delivering the
(14) General experimental procedure for coupling 1.1 mmol of
substrate: under
a nitrogen atmosphere, 20 mg of trichlorotris-
(tetrahydrofuran)titanium (III) (54 µmol), 87 mg of 1,3-diethyl-1,3-
diphenylurea (0.32 mmol), and 85 mg of Zn powder (1.3 mmol) were
suspended in 22 mL of THF. The resulting gray suspension was cooled
to 0 °C, and 10 µL of 2-methyl-2-propanol (0.11 mmol), 164 µL of TMSCl
(1.30 mmol), and 1.1 mmol of the aldehyde were added to the catalyst
mixture via syringe. Once TLC analysis indicated that all the aldehyde
had been consumed (∼6 h), the excess Zn powder was removed by
filtration. Methanol (4 mL) and 1 N aqueous HCl (2 mL) were added
to the filtrate, and the reaction was stirred at room temperature for 2
h. The volatiles were evaporated in vacuo, the resulting aqueous
residue was diluted with ethyl acetate, and the layers were separated.
The aqueous portion was extracted with ethyl acetate (2 × 5 mL), and
the combined organic layers were washed successively with a saturated
aqueous solution of NaHCO3 and brine. The organic portion was dried
over MgSO4 and concentrated in vacuo. Flash chromatography (hex-
anes/ethyl acetate) afforded the desired diol in the indicated yield and
diastereoselectivity (Table 2). Results reported in Table 1 were for
reactions employing this same experimental procedure but excluding
the 1,3-diethyl-1,3-diphenylurea.
Ack n ow led gm en t. The donors of the Petroleum
Research Fund, administered by the American Chemi-
cal Society, the American Cancer Society, and the
University of Pittsburgh are gratefully acknowledged
for support of this work. The authors wish to thank
Dennis Curran and Peter Wipf for helpful suggestions
in the preparation of this manuscript.
Su p p or tin g In for m a tion Ava ila ble: Experimental pro-
cedures and details of compound characterization are provided
(3 pages).
J O970792O
(15) Use of magnesium as the stoichiometric reductant, in place of
zinc, provided substantially improved chemical yields in the annulative
pinacol coupling of glutaraldehyde (1) and adipaldehyde (2).
(16) Girolami, G. S.; Wilkinson, G.; Galas, A. M. R.; Thorton-Pett,
M.; Hursthouse, M. B. J . Chem. Soc., Dalton Trans. 1985, 1339-1348.
(17) Ligand effects in stoichiometric McMurry pinacol reactions have
been examined, see: Balu, N.; Nayak, S. K.; Banerji, A. J . Am. Chem.
Soc. 1996, 118, 5932-5937.
(18) The structure of the added ligand and TiCl3:ligand stoichiom-
etry proved to influence reaction diastereoselectivity. The reported
TiCl3-DEPU catalyst system was deduced by optimizing both of these
reaction variables.
(19) Stoichiometric quantities of other urea additives (e.g., DMPU)
do not afford improved stereoselectivity, suggesting that enhanced
diastereoselection due to the DEPU ligand is not simply an artifact of
a modified catalyst aggregation state.