Influence of external ligands and auxiliaries on the reactivity of low-valent titanium in McMurry reaction: Selectivity and mechanistic profile

Article abstract of DOI:10.1021/ja9535221

Influence of various external ligands/auxiliaries on the reductive carbonyl coupling reactions mediated by low-valent titanium (LVT) reagents (McMurry coupling) has been explored. The LVT species generated from Tyrlik's TiCl₃-Mg-THF system has been selected for the reactivity-tuning trials. Our studies show that incorporation of about 10 equiv of pyridine (a π-acceptor ligand) with respect to TiCl₃ to the THF solvated LVT reagent could arrest the reductive dimerization of acetophenone at the intermediate pinacol stage. Modulation of the LVT-species by covalently-binding monohydroxy, 1,2- and 1,3-dihydroxy auxiliaries also resisted deoxygenation completely to give the pinacols in higher yields and better diastereoselectivity, as compared to pyridine-modified LVT system. Amongst these modified reagents, the LVT-catechol (1:1) system was found to be the most efficient combination for total pinacolization of aromatic carbonyl compounds, even under refluxing conditions. The actual titanium reagent responsible for this transformation is proposed to be a Ti(II) complex formed in situ. Further enhancement of stereoselectivity (threo-selectivity) of the pinacols has been achieved by carrying out the reactions with LVT-complexes modified by a variety of covalently-linking auxiliaries at low temperatures. The results demonstrate that by the judicious incorporation of various ligands/auxiliaries into LVT reagents it is possible to widen the scope and applicability of the classical McMurry reaction.

Full text of DOI:10.1021/ja9535221

5
932
J. Am. Chem. Soc. 1996, 118, 5932-5937
Influence of External Ligands and Auxiliaries on the Reactivity
of Low-Valent Titanium in McMurry Reaction: Selectivity and
Mechanistic Profile
N. Balu, S. K. Nayak, and A. Banerji*
Contribution from the Bio-Organic DiVision, Bhabha Atomic Research Centre, Trombay,
Bombay 400 085, India
X
ReceiVed October 20, 1995
Abstract: Influence of various external ligands/auxiliaries on the reductive carbonyl coupling reactions mediated by
low-valent titanium (LVT) reagents (McMurry coupling) has been explored. The LVT species generated from Tyrlik’s
TiCl3-Mg-THF system has been selected for the reactivity-tuning trials. Our studies show that incorporation of
about 10 equiv of pyridine (a π-acceptor ligand) with respect to TiCl3 to the THF solvated LVT reagent could arrest
the reductive dimerization of acetophenone at the intermediate pinacol stage. Modulation of the LVT-species by
covalently-binding monohydroxy, 1,2- and 1,3-dihydroxy auxiliaries also resisted deoxygenation completely to give
the pinacols in higher yields and better diastereoselectivity, as compared to pyridine-modified LVT system. Amongst
these modified reagents, the LVT-catechol (1:1) system was found to be the most efficient combination for total
pinacolization of aromatic carbonyl compounds, even under refluxing conditions. The actual titanium reagent
responsible for this transformation is proposed to be a Ti(II) complex formed in situ. Further enhancement of
stereoselectivity (threo-selectivity) of the pinacols has been achieved by carrying out the reactions with LVT-complexes
modified by a variety of covalently-linking auxiliaries at low temperatures. The results demonstrate that by the
judicious incorporation of various ligands/auxiliaries into LVT reagents it is possible to widen the scope and
applicability of the classical McMurry reaction.
1
. Introduction
The immense synthetic potential of reductive coupling of
carbonyl compounds by low-valent titanium (LVT) reagents
McMurry reaction) has been exemplified by a variety of
(
applications ranging from the preparation of simple symmetrical
Scheme 1. Classical Mechanism of LVT Mediated
Reductive Deoxygenation of Aldehyde/Ketone
alkenes1-4 to the strategic construction of an eight-membered
ring during the synthesis of the anticancer drug taxol by
Nicolaou and co-workers.5 Furthermore, recent reports on the
6
syntheses of various heterocyclic compounds, the first acylsi-
7
lane couplings, and the synthesis of macrocyclic compounds
like archaebacterial membrane lipids8 etc. serve as ample
evidences for the wide applicability of the classical McMurry
X
Abstract published in AdVance ACS Abstracts, May 15, 1996.
(
(
(
(
1) McMurry, J. E. Acc. Chem. Res. 1983, 16, 405-411.
2) Lai, Y.-H. Org. Prep. Proced. Int. 1980, 12, 363-391.
3) Welzel, P. Nachr. Chem. Tech. Lab. 1983, 31, 814-816.
4) (a) Auderset, P. C.; Gartenmann, T. C. C.; Gesing, E. R. F. Kontakte
(
Darmstadt) 1985, 3, 14-21. (b) Dang, Y.; Geise, H. J. Janssen Chim.
Acta 1988, 6, 3-10. (c) Gleiter, R.; Borzyk, O. Angew. Chem., Int. Ed.
Engl. 1995, 34, 1001-1002. (d) Columbus, I.; Biali, S. E. J. Org. Chem.
reaction. The reaction, in general, is operationally simple and
provides an easy, one-flask synthetic strategy to difficultly
1
994, 59, 3402-3407.
9-13
accessible olefins (eq 1).
(5) (a) Nicolaou, K. C.; Yang, Z.; Liu, J. J.; Ueno, H.; Nantermet, P. G.;
The LVT-induced reductive deoxygenation of carbonyls to
olefins takes place in two successive steps (Scheme 1): (i)
reductive dimerization of the starting ketone or aldehyde to form
a carbon-carbon bond and (ii) deoxygenation of the 1,2-diolate
intermediate to give the alkene, which is the rate determining
step of the reaction. The first step in this reaction involves
transfer of an electron to the carbonyl group yielding an anion
Guy, R. K.; Claiborne, C. F.; Renaud, J.; Couladouros, E. A.; Paulvannan,
K.; Sorensen, E. J. Nature 1994, 367, 630-634. (b) Nicolaou, K. C.; Liu,
J. J.; Yang, Z.; Ueno, H.; Sorensen, E. J.; Claiborne, C. F.; Guy, R. K.;
Hwang, C.-K.; Nakada, M.; Nantermet, P. G. J. Am. Chem. Soc. 1995, 117,
6
34-644. (c) Nicolaou, K. C.; Yang, Z.; Liu, J. J.; Nantermet, P. G.;
Claiborne, C. F.; Renaud, J.; Guy, R. K.; Shibayama, K. J. Am. Chem.
Soc. 1995, 117, 645-652.
(6) (a) F u¨ rstner, A.; Hupperts, A. J. Am. Chem. Soc. 1995, 117, 4468-
4
3
7
6
475. (b) McMurry, J. E.; Rico, J. G.; Shih, Y-n. Tetrahedron Lett. 1989,
0, 1173-1176. (c) F u¨ rstner, A.; Ernst, A. Tetrahedron, 1995, 51, 773-
86. (d) F u¨ rstner, A.; Weintritt, H.; Hupperts, A. J. Org. Chem. 1995, 60,
637-6640. (e) F u¨ rstner, A.; Hupperts, A.; Ptock, A.; Janssen, E. J. Org.
1
1
radical (ketyl) which dimerizes to 1,2-diolates. The deoxy-
genation of the pinacolate involving cleavage of the carbon-
Chem. 1994, 59, 5215-5229. (f) Banerji, A.; Nayak, S. K. J. Chem. Soc.,
Chem. Commun. 1990, 150-151.
(9) Kahn, B. E.; Rieke, R. D. Chem. ReV. 1988, 88, 733-745.
(10) (a) Lenoir, D. Synthesis 1989, 883-897 and references cited therein.
(b) Betschart, C.; Seebach, D. Chimia 1989, 43, 39-49.
(7) F u¨ rstner, A.; Seidel, G.; Gabor, B.; Kopiske, C.; Kruger, C.; Mynott,
R. Tetrahedron 1995, 51, 8875-8888.
8) Eguchi, T.; Terachi, T.; Kakinuma, K. J. Chem. Soc., Chem. Commun.
994, 137-138.
(11) McMurry, J. E. Chem. ReV. 1989, 89, 1513-1524.
(
(12) Olah, G. A.; Prakash, G. K. S. J. Org. Chem. 1977, 42, 580-582.
(13) Mukaiyama, T.; Sato, T.; Hanna, J. Chem. Lett. 1973, 1041-1044.
1
S0002-7863(95)03522-0 CCC: $12.00 © 1996 American Chemical Society

ReactiVity of Low-Valent Titanium in McMurry Reaction
J. Am. Chem. Soc., Vol. 118, No. 25, 1996 5933
Table 1. Modulation of the Reactivity of LVT by Pyridine
oxygen bonds resulted in the formation of olefin and oxide
coated titanium.
a
Incorporation in the Reductive Coupling of Acetophenone (1a)
The carbon-oxygen bond cleavage (step 2, Scheme 1) has
been found to be more facile in aromatic carbonyls as compared
to aliphatic ones. This can be attributed to the relatively weak
rxn tempb conversion of
product balance
run TiCl
3
:pyridine
°C
1a (%)
2a (%) 3a (%)
1
2
3
4
5
6
7
8
9
1:0
1:1
1:2
1:4
1:6
1:6
1:10
1:10
1:50
25
25
25
25
25
reflux
25
reflux
25
85
82
91
92
96
75
98
53
83
50
23
13
11
9
10
35
47
48
54
47
76
77
63
14
benzyl-oxygen bond in comparison to the alkyl-oxygen bond
of the intermediate 1,2-diolates. This is evidenced by the pre-
dominant formation of alkenes with aromatic systems and 1,2-
diols with aliphatic systems, during the reactions at room
temperature. Besides the native state of the metal, the activity
of LVT reagents is also dependent on the coordinating solvents
and the stability of the complexes formed in situ. For example,
diethyl ether-solvated LVT is less reactive compared to that
prepared in THF, while the use of stronger coordinating solvents
like pyridine or cyclopentadiene causes the complete arrest of
the reaction.1 However, no systematic study on the effects
of ligands on the reactivity of LVT species has been reported
so far.
7
c
trace
14
trace
a
3
Low-valent titanium reagent was generated from TiCl /Mg (1.5
b
equiv)/THF. TiCl -1a ratio was kept at 1:1 in all the cases. The
3
reaction mixture was stirred at room temperature and/or refluxed for
16 h after the addition of 1a in all the trials. c dl/meso ratio was found
to be 2.03.
5a
plexes of LVT are expected to be less reactive. In view of the
greater ability of nitrogen heterocycles to form stronger
coordination complexes with 3d-block metals, the effect of an
organic base pyridine on the activity of LVT has been explored.
The 3d-block transition metals in their reduced states are rich
in electrons (soft acids). Thus the coordination of pyridine to
LVT, i.e., donation of electrons by nitrogen-lone-pair to the
vacant 3d-orbitals of the metal, is expected to increase the
electron density at the metal center. However, the back donation
of the electrons from the filled d-orbitals of the metal to the
The present studies on reactivity modulation stems from our
previous observations on LVT mediated reactions. We have
demonstrated that by the choice of appropriate solvents it is
possible to control the stereochemistry of the products formed
during the carbonyl coupling reactions.16 It was also noticed
that the dealkoxylation of aryl alkyl ethers took place with the
unique reagent, i.e., TiCl3/Li/THF, while similar reagent system
1
7a
like TiCl3/Li/DME was ineffective for this reaction.
How-
ever, addition of catalytic amounts of pyridine1 or fullerenes
7b
17c
to THF-solvated LVT resulted in increased yields of the reaction
products. The dramatic effect exerted by pyridine prompted
us to undertake a detailed investigation on the influence of
various external ligands/auxiliaries on the reactivity of LVT
reagents. We envisaged that, by incorporating appropriate
additives/ligands, it should be possible to enhance the synthetic
scope of LVT reagents.
vacant orbitals of pyridine will contribute to the stability of the
metal complex (Chatt-Dewar-Duncunson model).2
0,21
In
effect, the reactivity, i.e., electron donating capacity of the metal
can be controlled by the judicious incorporation of such an
2
2
external ligand into the metal complex.
Based on these
considerations, covalent complexes with auxiliaries having
mono- and dihydroxy functionalities (where the metal undergoes
change in oxidation states) are also expected to show reduced
activity.
This paper presents the results of our studies on the effects
of (i) π-acceptor ligands and (ii) mono- and dihydroxy
auxiliaries and a 1,3-diketone on the reactivity of LVT reagent
during the reductive duplication of aromatic carbonyl com-
pounds. Reductive coupling of acetophenone was chosen as
the model reaction. A plausible mechanistic model has been
formulated based on the results obtained from a series of
stoichiometric experiments.
In the present studies, Tyrlik’s reagent (TiCl3/Mg/THF) was
selected as the LVT- source on the grounds of its unique
reactivity toward carbonyl coupling reactions.15 It has been
18
suggested that an inorganic Grignard reagent [Ti(MgCl2)‚nTHF]
is the actual reducing species present in the above LVT-system,
and therefore it was the reagent of choice for a series of
stoichiometric studies.
Even though, the use of tertiary amines as additives to LVT
systems has precedence in the literature,19 systematic study on
the influence of external agents on the LVT-reactivity has not
been attempted. Our approach in the selection of the ligands
(
additives) for the reactivity modulation, however, has been
2
. Results and Discussion
made on the lines of classical complexation theory. It is well-
known that the reactivity and stability of transition metal
complexes are mutually exclusive, and hence the stable com-
Reductive Coupling of Acetophenone by Pyridine-Modi-
fied Low-Valent Titanium Reagent. Based on our earlier
work on the effect of various nitrogenous bases on the reactivity
of LVT reagent for dealkoxylation of aryl alkyl ethers,1
pyridine was selected for the present studies on account of its
high efficacy and easy availability. The LVT generated from
TiCl3 and 1.5 equiv of Mg metal in THF was treated with
increasing amounts of pyridine, keeping a constant THF-volume.
The reductive dimerization of acetophenone (1a) was carried
out mainly at room temperature (25 °C). The results of the
experiments with pyridine are summarized in Table 1. A control
reaction (Scheme 2) performed without any external additives
afforded a mixture of R,R′-dimethyl stilbene (2a) and 2,3-
diphenylbutan-2,3-diol (3a) in a product balance of 50 and 10%,
respectively (Table 1, run 1). Addition of 1 equiv of pyridine
to LVT system brought down the yield of 2a to almost half
(
14) McMurry, J. E.; Silvestri, M. G.; Fleming, M. P.; Hoz, T.; Grayston,
M. W. J. Org. Chem. 1978, 43, 3249-3255.
15) (a) Dams, R.; Malinowsky, M.; Westdorp, I.; Geise, H. J. J. Org.
Chem. 1982, 47, 248-259. (b) Tyrlik, S.; Wolochowicz, I. Bull. Soc. Chim.
Fr. 1973, 2147-2148.
7b
(
(
(
16) Nayak, S. K.; Banerji, A. J. Org. Chem. 1991, 56, 1940-1942.
17) (a) Nayak, S. K.; Banerji, A. J. Chem. Soc., Chem. Commun. 1991,
1
432-1434. (b) Kadam, S. M.; Nayak, S. K.; Banerji, A. Synth. Commun.
995, 25, 135-142. (c) Talukdar, S.; Nayak, S. K.; Banerji, A. Full. Sci.
1
Tech. 1995, 3, 327-332.
(18) (a) Aleandri, L. E.; Bogdanovic, B. In ActiVe Metals, Preparation,
Chracterization, Applications; F u¨ rstner, A., Ed.; VCH: Weinheim, 1995;
pp 299-338. (b) Aleandri, L. E.; Bogdanovic, B.; Gaidies, A.; Jones, D.
J.; Liao, S.; Michalowicz, A.; Roziere, J.; Schott, A. J. Organomet. Chem.
1
993, 459, 87-93. Related references: (c) Bogdanovic, B.; Bolte, A. J.
Organomet. Chem. 1995, 502, 109-121. (d) Aleandri, L.; Becke, S.;
Bogdanovic, B.; Jones, D. J.; Roziere, J. J. Organomet. Chem. 1994, 472,
9
1
7-112.
(19) (a) McMurry, J. E.; Miller, D. D. J. Am. Chem. Soc. 1983, 105,
(20) Chatt, J.; Duncanson, L. A. J. Chem. Soc. 1953, 2939-2947.
(21) Dewar, M. J. S. Bull. Soc. Chim. Fr. 1951, C 71-79.
660-1661. (b) F u¨ rstner, A.; Weidmann, H. Synthesis 1987, 1071-1075.
(
c) Ishida, A.; Mukaiyama, T. Chem. Lett. 1976, 1127-1130. (d) Lenoir,
(22) Hegedus, L. S. In ComprehensiVe Organometallic Chemistry II;
Hegedus, L. S., Ed.; Pergamon; Oxford, 1995; Vol. 12, pp 1-7.
D. Synthesis 1977, 553-554.

5
934 J. Am. Chem. Soc., Vol. 118, No. 25, 1996
Balu et al.
Scheme 2
Table 2. Effect of Hydroxy Auxiliaries on the Reactivity of LVT
toward the Reductive Coupling of Acetophenone (1a)
product balance
rxn temp
(°C)
% conversion
3a (%)
2a (%) (dl/meso)
runa auxiliary
of 1a
1
2
3
4
5
6
7
8
9
0
1
4
4
5
5
6
7
8
8
8
9
25
25
97
50
30
22
97
84
62
59
60
50
85
25
trace
67 (4.33)
88 (4.19)
87 (4.20)
85 (1.87)
94 (3.33)
71 (4.28)
97 (4.27)
43 (4.97)
69 (5.98)
60 (3.08)
10 (1.66)
b
25
(
2
i.e., 23%), while 3a was obtained in 35% yield (Table 1, run
). The ligand effect became more pronounced as the amounts
reflux, 25c
25
25
25
25
0-25
25
25
of pyridine were increased stoichiometrically (runs 3 and 4). A
six-fold excess of pyridine led to a preferential formation of 3a
b
(
2a:3a ) 9:54) at room temperature (run 5). With further
increase in the amount of pyridine (ten-fold excess), the olefin
a was obtained only in traces, while the yield of diol 3a
d
1
1
2
Nil
50
increased to 76% (run 7). Thus, progressive increase in the
amounts of pyridine resulted in concomitant increase in the yield
of 3a. There was marginal change in the yields of the reaction
products up to the addition of 50 equiv of pyridine (run 9).
Earlier, it has been reported that when pyridine alone was used
as solvent, the reaction did not occur at all,1 and 2a was the
sole product when THF was used instead. Thus, it has been
established that by judicious addition of pyridine to the THF-
solvated LVT, the activity of the latter can be modulated to
furnish preferentially the diol 3a.
a
3
TiCl :1a ratio was kept 1:1 in all experiments, and the reaction
mixture was stirred at room temperature and/or refluxed for 16 h after
the addition of 1a in all the trials. Two equiv of auxiliaries were used.
The reaction mixture was refluxed for 1 h after the addition of the
auxiliary. 1a was added at 0 °C, stirred for 3 h, and slowly allowed
b
c
d
5a
to reach 25 °C; and then stirred for 16 h.
observed when 5 was used as the auxiliary molecule (run 3).
This could be due to deoxygenation of 5 by LVT to ethylene
gas, evolution of which was observed during the reaction.
Heating of the reaction mixture resulted in further decrease in
the conversion of acetophenone (run 4). This conjecture gained
credence when it was observed that the use of 2,2-dimethyl-
1,3-propanediol (7), where the deoxygenation is rather difficult,
afforded 71% of the pinacol 3a, and the auxiliary was recovered
unchanged (run 6). These observations led us to explore
aromatic 1,2-diol, catechol (8), as the auxiliary unit. Indeed,
use of LVT-catechol reagent resulted in 62% conversion of 1a
at room temperature (25 °C), and 3a was isolated in 97% yield
(dl/meso ) 4.27) (run 7). When the same reaction was carried
out at lower temperature (0-25 °C), yield of 3a was less, but
better selectivity (dl/meso ) 5.98) was observed (run 9). Use
of acetyl acetone (9) as an auxiliary unit did not show much
conversion possibly due to the stability of the resulting complex
through pronounced chelation (run 10). Heating of the reaction
mixture also did not improve the yields. Thus, amongst the
above auxiliaries, 6, 7, and 8 were found to be efficient in
controlling the reactivity of the low-valent titanium species.
Besides affording 3a as the sole product, the use of 8 offered
operational advantages due to the ease of separation (by base)
and recovery of auxiliary from the reaction mixture.
The effect of another π-acceptor, PPh3, on the reactivity of
LVT has also been studied. Thus, addition of 2 equiv of PPh3
(with respect to TiCl3) to the THF solvated LVT reagent yielded
3
a in 48% yield (dl/meso ) 2.94) as the sole product under the
same reaction conditions. Compared to pyridine, use of PPh3
suffered from operational shortcomings due to its high molecular
weight and difficulty in separation from the reaction mixture.
From the foregoing experiments, it is clear that the activity
of LVT species with the same oxidation states is highly
dependent on the coordinating ligands.
Reductive Coupling Mediated by LVT Modified by
Covalently Binding Auxiliaries. The stability, tendency for
aggregation, and the reactivity of LVT reagents are highly
influenced by the steric and electronic factors. Titanium when
covalently bonded to auxiliaries undergoes change in oxidation
states with a considerable difference in the electronic environ-
ment around the metal. Therefore, a number of experiments
were carried out using mono- and dihydroxy auxiliaries for the
reactivity modulation studies.
Menthol (4), ethylene glycol (5), and 1,2:5,6-di-O-cyclo-
hexylidine-D-mannitol (6) were used as external auxiliaries for
the preliminary trials. Carefully controlled stoichiometric
procedures have been adopted for all the trials (Table 2). When
the reaction was carried out with the addition of a molar equiv
of 4 to the LVT reagent system, followed by the addition of 1
equiv of 1a at room temperature, a mixture of 3a (67%) along
with 25% of 2a was isolated (Table 2, run 1). However, use
of two equiv of 4 furnished 3a as the sole product (run 2). The
To optimize the efficacy of LVT-catechol complex, a Ti-
auxiliary-ketone ratio of 2:2:1 was used for the reductive
dimerization of various carbonyl compounds at 25 °C (Table
3
). Using this reagent system, acetophenone (1a) and benzal-
dehyde (1b) underwent 100% conversion with 95% and 82%
yields of pinacols, respectively (Table 3, runs 1 and 2). At the
same time, sterically bulky aromatic ketones such as benzophe-
none (1c), o-methoxyacetophenone (1d), and valerophenone (1e)
furnished the corresponding 1,2-diols in poor yield (10-39%)
(runs 3, 4, and 5). This can be attributed to the influence of
the steric bulk of the substrate during the dimerization process.
Total Pinacolization of Aromatic Carbonyl Compounds
with TiCl3-Mg-THF-Catechol Reagent at Higher Tem-
perature. The efficient construction of pinacols as strategic
synthetic intermediates is of great importance as exemplified
by the preparation of various biologically active compounds such
substantial reduction in the yield of 2a, compared to the control
reaction where no auxiliary was used (run 11), represents the
pronounced influence exerted by 4 on the reactivity of LVT.
Use of diol 6, derived from mannitol, as the auxiliary afforded
excellent (97%) conversion of 1a and 3a was isolated in 94%
yield (run 5). However, much reduced product turnover (30%
conversion), even lower than the control reaction (run 11), was

ReactiVity of Low-Valent Titanium in McMurry Reaction
Table 3. Reductive Dimerization of Various Ketone/Aldehyde by
J. Am. Chem. Soc., Vol. 118, No. 25, 1996 5935
(86%) without even a trace of stilbene 2a (Table 4, run 1). While
improving the yield and reaction time, no significant reduction
in the diastereoselectivity was observed as compared to the trial
carried out at room temperature (Table 2, run, 7). Similarly,
reaction of benzaldehyde (1b) with LVT at room temperature
(0.5 h) without incorporating catechol yielded a mixture of 1,2-
diphenyl-1,2-ethanediol (3b) and stilbene (2b) (Table 4, run 2).
However, when the same reaction was carried out under reflux
(80 °C, 0.5 h) in the absence of catechol, 2b was obtained as
the sole product (run 3). Expectedly, the use of catechol-LVT
reagent afforded 3b as the sole product in 76% yield under
refluxing conditions (0.5 h) (run 4). Incidentally, this is the
first report of LVT-mediated total pinacolization of aromatic
carbonyl compounds at higher temperatures.
a
Using Catechol-LVT-Complex at 25 °C (Scheme 3)
run substrate ketone converted (%) yield of the pinacol (%)
b
1
2
3
4
5
1a
1b
1c
1d
1e
100
100
66
25
29
95
82
39
b
b
c
10
d
20
a
TiCl -catechol-substrate ratio was maintained at 2:2:1, and the
3
reaction mixture was stirred at room temperature (25 °C) for 16 h after
the addition of respective carbonyl compounds in all the trials.
b
c
d
Reference 32. Reference 38. Reference 39.
Table 4. Reductive Dimerization of Carbonyl Compounds with
LVT-Catechol Reagent at Higher Temperature (Scheme 3)
To explore the synthetic scope of LVT-catechol reagent,
various aromatic carbonyl compounds such as 4′-methoxyace-
tophenone (1f), 3,4-(methylenedioxy)benzaldehyde (1g), 2-acetyl-
naphthalene (1h), 2-chlorobenzaldehyde (1i), 3′-methoxyace-
tophenone (1j), and 4-chlorobenzaldehyde (1k) (Scheme 3) were
used as substrates, and in all the cases corresponding pinacols
were obtained in good to excellent yields (62-87%) under the
above reaction conditions (Table 4). In general, the aldehydes
gave lesser diastereoselectivity as compared to ketones.
Enhancement of threo-Selectivity by Modification of LVT
with Various Auxiliaries and Temperature Control. Ste-
reoselectivity in pinacolization is highly desirable phenomenon
as threo-1,2-diols have, after resolution, frequently been used
%
yield
b
rxn temp °C of pinacol
% yieldb
of alkene
run substrate auxiliarya
(time, h)
(dl/meso)
c
1
2
3
4
5
6
7
8
9
0
1
1a
1b
1b
1b
1f
8
80 (1)
25 (0.5)
80 (0.5)
80 (0.5)
80 (1)
80 (1)
80 (1)
80 (1)
80 (1)
80 (1)
80 (1)
86 (3.35)
29 (0.73)
43
62
8
76 (1.16)
27 (3.50)
82 (4.60)
71 (4.35)
87 (2.27)
77 (0.54)
72 (2.51)
42
1f
8
8
8
8
8
8
1g
1h
1i
1j
1k
1
1
d
62 (0.74)
a
31
TiCl
3
-substrate-auxiliary ratio was kept at 1:1:1 in all the trials.
Products were characterized by spectral data (IR, HNMR). dl:meso
assignments were made according to ref 32. 26% of 1k was recovered.
as auxiliaries in asymmetric syntheses. Although, a number
b
1
c
of methods have been developed for the reductive duplication
d
2
8,32
of carbonyl compounds,
threo-selective pinacolization has
3
3
34
been found only with stannylene precursors, NbCl3(DME),
Scheme 3
“active-titanium(III) reagent” prepared from TiCl4 and n-BuLi,35
or with cyclopentadienyl-bound titanium(III) reagent derived
3
6
from Cp2TiCl2 and sec-BuMgCl. Highly pH-controlled pi-
TiCl
3
- Mg -THF -Catechol
nacolizations mediated by aqueous-TiCl3 gave only moderate
threo-selectivity (dl/meso ) 2 to 3.2).
2
9
Our results, sum-
marized in Table 2 (runs 7 and 9), reveal that as the temperature
is lowered, though the extent of conversion goes down, the
threo-selectivity of the 1,2-diols increased. To optimize the
selectivity, low-temperature reactions were carried out with 4,
6
, and 8 along with some additional auxiliaries such as (+)-
diisopropyl tartrate (10), L-proline (11), and L-prolinol (12)
(Table 5).
as sarcophytol6b and taxol.5 Among the wide range of reagents,
2
3
24
25
26
27
Viz., Mg-MgI2, Al-Hg, Al-KOH, Ce/I2, SmI2, TiCl4-
Mg(Hg), aqueous TiCl3, n-Bu3SnH,30 which have been
employed for pinacolizations, titanium based reagents are of
special importance. In the light of the observations with TiCl3-
Mg-THF-catechol, the possibility of total and rapid pina-
colization of various aromatic carbonyl compounds at higher
temperatures were undertaken (Table 4, Scheme 3). Interest-
ingly, when a mixture of acetophenone (1a) and catechol-
modified LVT reagent (in 1:1 ratio) was refluxed (80 °C, 1 h),
the conversion was better than the room temperature reaction,
and pinacol 3a was obtained as the sole product in high yield
2
8
29
Stereoselectivity (dl/meso ratio) of the pinacols was analyzed
by NMR spectroscopy of chromatographically homogeneous
diastereomeric mixtures. Though the conversion was not high,
excellent stereoselection could be obtained by using 4 and 12
(
31) (a) McNamara, J. M.; Kishi, Y. J. Am. Chem. Soc. 1982, 104, 7371-
(
23) Gomberg, M.; Bachmann, W. E. J. Am. Chem. Soc. 1927, 49, 236-
7372. (b) Ghribi, A.; Alexakis, A.; Normant, J. F. Tetrahedron Lett. 1984,
25, 3083-3086. (c) Konradi, A. W.; Pedersen, S. F. J. Org. Chem. 1990,
55, 4506-4508.
2
5
57.
(24) Schreibmann, A. A. P. Tetrahedron Lett. 1970, 4271-4272.
25) Khurana, J. M.; Sehgal, A. J. Chem. Soc., Chem. Commun. 1994,
(
(32) F u¨ rstner, A.; Czuk, R.; Rohrer, C.; Weidmann, H. J. Chem. Soc.,
Perkin Trans. I 1988, 1729-1734.
71.
26) Imamoto, T.; Kusumoto, T.; Hatanaka, Y.; Yokoyama, M. Tetra-
hedron Lett. 1982, 23, 1353-1356.
27) Namy, J. L.; Souppe, J.; Kagan, H. B. Tetrahedron Lett. 1983, 24,
(
(33) Grugel, C.; Neumann, W. P.; Sauer, J.; Seifert, P. Tetrahedron Lett.
1978, 19, 2847-2850.
(
(34) Szymoniak, J.; Besancon, J.; Moise, C. Tetrahedron 1992, 48,
3867-3876.
7
65-766.
(
976, 41, 260-265.
(
28) Corey, E. J.; Danheiser, R. L.; Chandrasekaran, S. J. Org. Chem.
(35) (a) Seebach, D.; Weidmann, B.; Widler, L. Modern Synthetic
Methods; Scheffold, R., Ed.; Sauerlander, AG, Aarau, Switzerland, 1983;
Vol. 3, pp 217-353. (b) Seebach, D. Chimia 1986, 40, 12.
(36) Handa, Y.; Inanaga, J. Tetrahedron Lett. 1987, 28, 5717-5718.
1
29) Clerici, A.; Porta, O. J. Org. Chem. 1985, 50, 76-81.
30) Hays, D. S.; Fu, G. C. J. Am. Chem. Soc. 1995, 117, 7283-7284.
(

5
936 J. Am. Chem. Soc., Vol. 118, No. 25, 1996
Balu et al.
Table 5. Reductive Duplication of Acetophenone (1a) Using
Auxiliary-Modified LVT at Low Temperatures
complexes of type [B] (eq 3) with different Ti/pyridine/THF
ratios are expected to exhibit varying reducing activities as
exemplified by the results in Table 1. Thus, addition of pyridine
up to 10 equiv with respect to TiCl3 suppresses the deoxygen-
ation of the pinacolate intermediate (step 2, Scheme 1). Though
weak, the ligand-exchange effects operating here can influence
the reactivity of LVT species to a reasonable extent.
a
run auxiliary conversion of 1a (%) yield of 3a (%)b ratio dl/meso
c
1
2
3
4
5
6
4
6
8
10
11
12
38
45
98
92
56
57
78
100
91
90
81
8.43
5.68
6.10
4.45
2.40
7.72
60
[
A] + yPy h TiMgCl ‚(THF) (Py) + yTHF (3)
2 x-y y
a
All reactions were carried out at the temperature range of -70 to
5 °C, and TiCl :auxiliary:1a ratio was kept 1:1:0.5 in all the trials
[B]
2
3
b
except in run 1 where 1:2:0.5 ratio was used. Yields were calculated
The highly electron rich and oxophilic nature of Ti in the
complex [A] is likely to undergo oxidation to Ti(II) alkoxide
c
on the basis of reacted 1a. Diastereoselectivity was determined by
2
00 MHz NMR spectroscopy.
[C] in the presence of alcohol Via a hydride intermediate as
as auxiliaries at low temperatures (Table 5, runs 1 and 6) (see
Experimental Section). The pinacols with dl/meso ratios, as
high as 8.43 and 7.72 respectively, were obtained using these
auxiliaries. More interestingly, use of catechol (8) resulted in
the conversion of the ketone to pinacol in high yield (91%)
with significant improvement in threo-selectivity (dl/meso )
shown in eq 4. In other words, 2 equiv of monohydroxy alcohol
or 1 equiv of a diol are required for complete conversion of
[A] to [C]. The reactivity or electron donating ability of
titanium in [C] is definitely lower than that in complex [A].
This is evidenced by the fact that the reductive dimerization of
acetophenone (1a) by [A] furnished the olefin 2a as the major
product (eq 5), while addition of 2 equiv of menthol (4) or 1
equiv of catechol to [A] yielded 3a as the only product (eqs 7
and 8). Expectedly, use of 1 equiv of 4 provided a mixture of
2a (25%) and 3a (67%) (eq 6). The uncomplexed [A] (almost
50%) is believed to be responsible for the deoxygenation of 3a
to 2a (Table 2, run 1) in this case.
6
.10) (run 3). Even though, 10 had given better conversion
under the present temperature range, it exhibited a lower dl/
meso ratio (4.45) (run 4).
Mechanistic Considerations. Preparation and use of several
low-valent titanium reagents by the reduction of titanium halides
(
TiCl3 and TiCl4) with strong reducing agents such as K, Li,
3
7
Mg, Zn, LiAlH4, etc. have been reported in the literature.
[
A] + 2ROH f [H Ti(OR) MgCl ‚(THF) ] f
However, the reactivities of these reagents were found to be
dependent on their methods of preparation as discussed earlier.
Identification of the “active species” responsible for chemical
transformations in these LVT reagents are still under debate.
The ambiguity which surrounds the mechanistic interpretation
is mainly due to the heterogeneous and oxophilic nature of these
reagents. Our interpretation described herein are mainly based
on the results obtained by the stoichiometric incorporation of
various ligands/auxiliaries into the LVT reagent prepared from
TiCl3/1.5 Mg/THF (Tyrlik’s reagent), during a series of carbonyl
coupling reactions.
2 2 2 y
Ti(OR) ‚MgCl ‚(THF) + H v (4)
2
2
z
2
[C]
[A] + 1a f 2a (major) + 3a (minor)
(5)
[
A] + 1 menthol + 1a f
II
0
.5 Ti (O-menthyl) + 0.5 [A] f
2
2a (minor) + 3a (major) (6)
II
Based on ESR studies, Geise et al. have proposed that the
reduction of TiCl3 with 1.5 equiv of Mg in THF under reflux
[A] + 2 menthol + 1a f Ti (O-menthyl) f 3a (only)
2
(7)
(8)
(
3 h) (Rieke type activation process) leads to the formation of
II
15a
a suspension of titanium species in zero-valent state.
A recent
[A] + 1 catechol + 1a f Ti (catechol) f 3a (only)
study by Bogdanovic et al. suggests that in the McMurry
reaction with Tyrlik’s reagent, a bimetallic “inorganic Grignard”
reagent [TiMgCl2(THF)x] is involved as the active species (eq
The pronounced threo-selectivity during the pinacolizations
could be ascribed to the bulkiness of the resultant Ti-complex
formed as a result of the combined effect of the auxiliary,
1
8
2
).
3
6
MgCl2, and the solvent coordinated to the metal. A very
probable situation involving the formation of complex [D] is
diagramatically shown in Scheme 4. Most likely, the transition
state tends to orient the bulkier substituents away from one
another so as to keep the steric forces a minimum. The use of
chiral auxiliaries, however, imparted no significant asymmetric
induction in the purified dl-isomers obtained by crystallization
from the dl-meso mixture.
TiCl + 1.5Mg + THF f
3
[
TiMgCl (THF) ] + 0.5MgCl (THF) (2)
2
x p
2
2
[A]
Because of the existence of a definite Ti-Mg bond in [A],
Ti is likely to assume higher electron density (compared to
metallic Ti) when one considers the more electropositive
character of Mg. This might also explain our earlier observation
of higher reactivity of TiCl3/Li/THF in the reductive dealkoxyl-
ation of aryl alkyl ethers,1 because of the higher electroposi-
tivity of Li as compared to that of Mg in TiCl3/Mg/THF system.
The incorporation of pyridine, by the displacement of THF
from the coordination site on Ti in [A], is expected to reduce
the net electron density around Ti due to back donation of metal
electrons to the vacant orbitals of pyridine. Consequently,
3. Conclusions
The reactivity of low-valent titanium (LVT) reagents in
carbonyl coupling reactions largely depends on the choice of
reducing metals, solvents, and the oxidation state of the resulting
metallic species. Reductive coupling of aromatic carbonyl
compounds mediated by LVT reagents usually lead to the
preferential formation of stilbenes at room temperature. In the
present study, we have demonstrated that by the addition of
various external agents, it is possible to design LVT reagents
of variable reactivities. Reductive coupling of acteophenone
with Tyrlik’s LVT-system (TiCl3/Mg/THF) has been selected
as the model reaction for a series of reactivity-control experi-
7a
(
37) Cintas, P. ActiVated Metals in Organic Synthesis; CRC Press:
London, 1993, pp 130-153.
(
(
38) Banerji, A.; Nayak, S. K. J. Chem. Res (S) 1989, 314-315.
39) Crawford, H. M.; Saeger, M. E.; Warneke, F. E. J. Am. Chem. Soc.
1
942, 64, 2862-2864.

ReactiVity of Low-Valent Titanium in McMurry Reaction
J. Am. Chem. Soc., Vol. 118, No. 25, 1996 5937
Scheme 4
(362 mg, 15 mmol). The mixture was refluxed for 3 h with stirring
during which the color of the reaction mixture changed from violet to
black. The black slurry thus obtained was cooled to ambient temper-
ature and required amount of dry pyridine was added in a single lot.
Stirring continued for 1 h and then a solution of acetophenone (10
mmol) in THF (5 mL) was added. After stirring at room temperature
(25 °C) for 16 h, the reaction mixture was diluted with diethyl ether,
quenched with cold saturated solution of NH
4
Cl, and then passed
through a small bed of Celite on a sintered glass filter to remove
inorganic salts. The filtrate was extracted with ether, washed with 2
N HCl and water, and then dried (Na SO ). Removal of the solvent
2 4
and subsequent column chromatography over silica gel (100-200 mesh)
yielded the products (Table 1).
Typical Procedure for Reductive Coupling of Acetophenone by
Modified LVT Reagent by Mono-, Dihydroxy, and 1,3-Diketone
Auxiliaries. A solution of required amount of the ligand was added
Via a syringe to the black suspension of the LVT reagent prepared as
described earlier. A rapid evolution of H
2
gas was observed on addition
of the auxiliary. The mixture was stirred at 25 °C for 1 h, and then a
solution of 1a (1 equiv) in THF was added to it. Stirring was continued
at 25 °C for an additional 16 h under a gentle stream of argon. The
reaction mixture was worked up in the usual way to isolate the products
(Table 2).
Typical Experiment with Catechol-Titanium Complex for the
Pinacolization Reactions at Room Temperature (25 °C). In these
experiments, the LVT species generated from TiCl
treated with equimolar amount of catechol and stirred for 0.5 h at 25
C. Appropriate aldehyde/ketone (0.5 equiv) was then added to the
reagent and then stirred at 25 °C for 16 h. Usual workup (by alkali
3
/Mg/THF was
°
wash) followed by column chromatography (SiO
as reported in Table 3.
Typical Experiment with Catechol-Titanium Complex for the
Pinacolization at Higher Temperature (80 °C). In these experiments,
2
) afforded the products
ments. Modulation of LVT has been effected in two different
ways: (i) by reducing the electron density of Ti center by
displacing THF by pyridine or triphenylphosphine, both having
σ-donating and π-accepting properties, and (ii) by changing the
oxidation state of the metal atom by the incorporation of various
covalent-bond-forming auxiliaries like mono- and diols, 1,3-
diketone, amino acid, amino alcohol, etc.
LVT species generated from TiCl
amount of catechol and stirred for 0.5 h at 25 °C. One equiv of ketone/
aldehyde (TiCl : substrate ) 1:1) was then added, and the reaction
3
/Mg/THF, was treated with equimolar
3
mixture was refluxed (80 °C) for specified time. The usual workup
afforded the products as reported in Table 4.
Incorporation of about 10 equiv of pyridine to the THF-
solvated complex could arrest the reductive dimerization of
acetophenone at the intermediate 1,2-diol stage. Stoichiometric
incorporation of covalently-linking hydroxylated auxiliaries also
afforded 1,2-diols as the sole products with appreciable dias-
tereoselectivity (threo-selectivity)). Further enhancement of
threo-selectivity in 1,2-diol formation has been achieved by
carrying out the reactions at low temperatures. The stereocontrol
of the reaction is governed by the nature of the ligands used.
Amongst the modified LVT reagents, the LVT-catechol system
was found to be efficient for total pinacolizations eVen under
refluxing conditions.
Our observations on the behavior of modified LVT reagents
further elaborate the scope, limitations, and applicability of the
classical McMurry reaction. More significantly, the present
study provides important guidelines for the reactivity-modulation
of various low valent metal-based reagents and thereby widening
their synthetic scope.
Typical Procedure for Reductive Coupling of Acetophenone with
Modified LVT at Low Temperatures. LVT reagent was prepared
as described above. A solution of the auxiliary (1 equiv) in THF was
introduced into the LVT system (except that of 11 which was added
directly because of its insolubility in THF and 2 equiv of 4 was used)
and stirred at room temperature for 1 h. The reaction mixture was
then cooled to -70 °C, and THF solution of 1a (0.5 equiv) was added
dropwise. The reaction mixture was stirred for 3 h at -70 °C and
then allowed to reach room temperature (25 °C) over a period of 3 h.
The stirring was continued for 16 h and the usual workup followed by
column chromatography on silica gel (100-200 mesh) afforded the
products as mentioned in Table 5.
1
NMR Measurements. 200 MHz H NMR spectra assignments were
used for the determination of dl/meso ratio of the pinacols obtained.
Chromatographically purified homogeneous diastereomeric mixture was
used for the analysis. Assignments were made by comparing the
relative heights of methyl signals at δ 1.5 and 1.6, respectively, for dl
and meso isomers, as reported by F u¨ rstner et al.32
Product Balances. The product balances were calculated based on
the percentage of conversion of ketone/aldehyde to corresponding
stilbene/pinacol. All the reactions were carried out at least twice for
4. Experimental Section
1
concordant values. Products were characterized by IR, H NMR, and
Infrared spectra were run on a Perkin-Elmer spectrophotometer
mass spectral data.
1
(
Model 783). H NMR spectra were recorded on a Varian EM 360
(
60 MHz) or Bruker AC-200 (200 MHz) spectrometer using CDCl
3
Acknowledgment. The authors thank Mr. R. G. Bhandari
and Dr. P. Pradhan for H NMR analyses. N.B. is grateful to
with TMS as an internal standard. Mass spectra were obtained on a
Shimadzu QP 1000A mass spectrometer.
1
TiCl
3
and Mg turnings were purchased from Aldrich Chemical Co.,
the Department of Atomic Energy, Government of India, for a
Senior Research Fellowship.
U.S.A. Rigorous anhydrous conditions were maintained during the
reactions. THF was distilled freshly from benzophenone-sodium ketyl.
All operations were carried out under an atmosphere of dry argon.
Typical Procedure for the Reductive Coupling of Acetophenone
with LVT-Pyridine System. In a typical experiment, a dry argon-
filled, three-necked, round-bottom flask was charged with dry THF
Supporting Information Available: Experimental data for
3
f-k (1 page). See any current masthead page for ordering
and Internet access instructions.
(40 mL), titanium(III) chloride (1.54 g, 10 mmol), and Mg-turnings
JA9535221