Generation of reactive low-valent titanium species using metal-arenes as efficient organic reductants for TiCl3: Applications to organic synthesis

Article abstract of DOI:10.1021/jo001586a

A comprehensive study on the use of metal-arene systems as organic reductants for TiCl₃ has resulted in an efficient method for the generation of highly reactive low-valent titanium (LVT) reagents. The activated titanium species could be prepared by refluxing a mixture of substoichiometric amounts of arenes, TiCl₃, and Li/Mg in THF or DME. Among the LVT reagents screened, TiCl₃ - Li-naphthalene - THF (reagent I) was the best for coupling of carbonyls to olefins. The reagent could carry out the McMurry olefination of both aromatic and aliphatic substrates at a lower temperature and in a much reduced time as compared to the conventional procedures. Subtle changes in the method of preparation of the LVT reagents influenced the stereoisomeric ratio of the olefins. The reagent was also useful for the synthesis of O- and N- heterocycles and vicinal diamines via intramolecular carbonyl coupling and reductive duplication of imines, respectively.

Full text of DOI:10.1021/jo001586a

2990
J . Org. Chem. 2001, 66, 2990-2994
Gen er a tion of Rea ctive Low -Va len t Tita n iu m Sp ecies Usin g
Μeta l-Αr en es a s Efficien t Or ga n ic Red u cta n ts for TiCl3:
Ap p lica tion s to Or ga n ic Syn th esis
Shyam Rele, Sanjay Talukdar, Asoke Banerji, and Subrata Chattopadhyay*
Bio-Organic Division, Bhabha Atomic Research Centre, Mumbai 400 085, India
schatt@apsara.barc.ernet.in
Received November 8, 2000
A comprehensive study on the use of metal-arene systems as organic reductants for TiCl3 has
resulted in an efficient method for the generation of highly reactive low-valent titanium (LVT)
reagents. The activated titanium species could be prepared by refluxing a mixture of substoichio-
metric amounts of arenes, TiCl3, and Li/Mg in THF or DME. Among the LVT reagents screened,
TiCl3-Li-naphthalene-THF (reagent I) was the best for coupling of carbonyls to olefins. The
reagent could carry out the McMurry olefination of both aromatic and aliphatic substrates at a
lower temperature and in a much reduced time as compared to the conventional procedures. Subtle
changes in the method of preparation of the LVT reagents influenced the stereoisomeric ratio of
the olefins. The reagent was also useful for the synthesis of O- and N- heterocycles and vicinal
diamines via intramolecular carbonyl coupling and reductive duplication of imines, respectively.
In tr od u ction
nations as potential organic reductants in organometallic
electron transfer processes prompted us to explore their
utility as efficient organic reductants for the generation
of the activated LVT reagents.
Due to the unique features of high oxophilicity and
reducing power, low valent titanium (LVT) reagents have
gained widespread acceptance in organic synthesis.1 In
particular, the remarkable scope of LVT reagents to effect
reductive coupling of carbonyls (McMurry reaction) has
resulted in a variety of applications such as synthesis of
strained olefins,1 heterocyclic compounds,1c,2 and macro-
cyclic ring systems1,3 to complex natural products includ-
ing paclitaxel.4
For this purpose, a lexicon of reactive LVT reagents
have been developed by reducing titanium salts with a
variety of inorganic reducing agents5 such as Zn, Mg, Li,
C8K, Zn-Cu, LAH, etc. In contrast, the soluble organic
reductants have received scarce attention6 for this pur-
pose. Recent reports7 on the use of metal-arene combi-
Earlier, it has been shown by us8-10 and others11 that
the reducing ability of LVT-based reagents can be
rationally tuned by the simple addition of cosolvents,8
external ligands,9 and chemical redox agents.10 We envis-
aged that the use of metal-arenes for reducing Ti salts
might produce the LVT species which would be coordi-
nated with the arenes. The coordination, in turn, might
activate the LVT reagents by augmenting the electron
density on the LVT species and also possibly by increas-
ing their solubility in an organic medium. In this context,
it is worth noting that another SET agent, the low-valent
Sm species, scores over the LVT species in terms of their
reactivity. This may be partly attributed12 to the solubil-
ity of the Sm species in a variety of polar solvents. The
LVT-based reagents, on the other hand, are insoluble in
organic solvents, which affects their reactivity neces-
sitating prolonged heating in most of the LVT-mediated
reactions including McMurry olefination. In addition,
* To whom correspondence should be addressed. Fax: 91-22-550-
5151.
(1) (a) McMurry, J . E. Chem. Rev. 1989, 89, 1513. (b) Lenoir, D.
Synthesis 1989, 883. (c) Furstner, A.; Bogdanovic, B. Angew. Chem.,
Int. Ed. Engl. 1996, 35, 2442. (d) Dushin, R. G. In Comprehensive
Organometallic Chemistry II; Hegedus, L. S., Ed.; Pergamon: Oxford,
1995; Vol. 12, p 1071.
(2) (a) Nayak, S. K.; Banerji, A. J . Chem. Soc., Chem. Comm. 1990,
150. (b) Furstner, A.; J umbam, D. N. Tetrahedron 1992, 48, 5991. (c)
Furstner, A.; Ernst, A.; Krause, H.; Ptock, A. Tetrahedron, 1996, 52,
7328. (d) Furstner, A.; Hupperts, A. J . Am. Chem. Soc. 1995, 117, 4468.
(e) Furstner, A.; Hupperts, A.; Ptock, A.; J anssen, E. J . Org. Chem.
1994, 59, 5215.
(3) (a) Furstner, A.; Seidel, G. Synthesis 1995, 63. (b) Furstner, A.;
Seidel, G.; Kopiske, C.; Kruger, C.; Mynott, R. Liebigs Ann. 1996, 655.
(4) (a) Nicolaou, K. C.; Yang, Z.; Liu, J . J .; Ueno, H.; Nantermet, P.
G.; Guy, R. K.; Claiborne, C. F.; Renaud, J .; Couladouros, E. A.;
Paulvannnan, K.; Sorensen, E. J . Nature 1994, 367, 630. (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, 634. (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.
(6) There is only one report on the use of Na-naphthalenide in the
preparation of LVT reagent for annulation reactions. However, no
systematic study has been done, see: Clive, D. L. J .; Zhang, C.;
Keshava Murthy, K. S.; Hayward, W. D.; Diagneault, S. J . Org. Chem.
1991, 56, 6447.
(7) (a) Connelly, N. G.; Geiger, W. E. Chem. Rev. 1996, 96, 877 and
references therein. (b) Lai, Y.-H. Synthesis 1981, 585 and references
therein. (c) Rieke, R.; Kim, S.-H. J . Org. Chem. 1998, 63, 5235. (d)
Kahn, B. E.; Rieke, R. D. Organometallics 1988, 7, 463.
(8) (a) Nayak, S. K.; Banerji, A. J . Org. Chem. 1991, 56, 1940. (b)
Banerji, A.; Nayak, S. K. J . Chem. Soc., Chem Commun. 1991, 1432.
(9) (a) Balu, N.; Nayak, S. K.; Banerji, A. J . Am. Chem. Soc. 1996,
118, 5932. (b) Talukdar, S.; Nayak, S. K.; Banerji, A. Full. Sci. Technol.
1995, 3, 327. (c) Nayak, S. K.; Kadam, S.; Talukdar, S.; Banerji, A. J .
Indian Inst. Sci. 1994, 74, 401.
(10) Talukdar, S.; Nayak, S. K.; Banerji, A. J . Org. Chem. 1998, 63,
4925.
(11) (a) Lipski, T. A.; Hilfiker, M. A.; Nelson, S. G. J . Org. Chem.
1997, 62, 4566. (b) Mukaiyama, T.; Kagayama, A.; Shiina, I. Chem.
Lett. 1998, 1107. (c) Ganauser, A.; Pierobon, M.; Bluhm, H. Angew.
Chem., Int. Ed. Engl. 1998, 37, 101.
(5) For different recipes for the generation of activated LVT re-
agents, see: (a) Cintas, P. Activated Metals in Organic Synthesis; CRC
Press: Boca Raton, 1996. (b) Fu¨rstner, A. Active Metals - Preparation,
Characterization, Applications. VCH: Weinheim, 1996. (c) Rieke, R.;
Bales, S. F. J . Am. Chem. Soc. 1974, 96, 1775.
10.1021/jo001586a CCC: $20.00 © 2001 American Chemical Society
Published on Web 04/12/2001

Metal-Arenes as Efficient Organic Reductants
J . Org. Chem., Vol. 66, No. 9, 2001 2991
Sch em e 1
Changing the metal to sodium in the above reagent
protocol, i.e., Na-naphthalene, however, was found to
be less efficient for the olefination reaction. Reaction of
1a with the LVT reagent (reagent E) generated by Na-
naphthalene and TiCl3 afforded mainly the pinacol 2a
(65%) along with only 25% of the stilbene 3a (run 5).
Because of the smaller size of Li metal, Li-arenes are
known7a to be superior reducing agents for metal salts.
Hence, we used Li in conjunction with different arenes
for the preparation of the LVT species. The LVT reagents
(reagents F and G) produced with Li-phenanthrene and
Li-biphenyl both appeared less effective for the desig-
nated transformation, wherein the pinacol 2a was ob-
tained as the major product in 48% and 58% yields,
respectively (runs 6 and 7). On the other hand, the Li-
anthracene combination generated another new LVT
species (reagent H) which smoothly furnished the desired
stilbene 3a in 70% yield at 25 °C within 3 h (run 8).
However, best result was obtained with the LVT reagent
prepared by refluxing a mixture of Li, naphthalene, and
TiCl3 in THF for 3 h (reagent I). Reaction of 1a with it,
under refluxing temperature, produced the stilbene 3a
(89%) within 1.5 h (run 9). However, reduction of 1a with
Li-naphthalene alone (in the absence of TiCl3), led to a
complex mixture of products along with the recovery of
the substrate. This clearly demonstrated that the acti-
vated LVT species was only responsible for the McMurry
reaction. Interestingly, the reagent I was also effective
in producing the stilbene even at lower temperatures and
in a shorter time. For example, 3a was obtained in 77%
and 65% yields, respectively, at 25 °C and -15 °C (runs
10 and 11). In contrast, although the conventional
McMurry reagent (TiCl3-Li-THF)13a (reagent D) pro-
vided 3a with the same yield, it required refluxing for
16 h (run 14).
The reactivity of the reagent I showed striking depen-
dence on the nature of the reaction medium and the
stoichiometry of the electron carrier used. The LVT
species (reagent J ) prepared with lesser amount of
naphthalene (0.12 equiv with respect to TiCl3) i. e., Li-
naphthalene-TiCl3 also produced the stilbene albeit less
efficiently. Thus, with reagent J , although compound 1a
gave the stilbene 3a and the pinacol 2a in 68% and 18%
yields respectively (run 12), it required more time (6 h).
The effect of the reaction medium was, however, more
drastic. For this study, an LVT reagent (reagent K) was
prepared by refluxing a mixture of TiCl3 and Li-
naphthalene in dimethoxyethane (DME) instead of THF.
Reaction of 1a with reagent K at 25 °C proceeded only
up to the stage of pinacol formation that too with modest
yield (34%) (run 13). Similar pinacol formation was
reported with a reactive Mn reagent generated by reduc-
tion of Mn-salts with Li-naphthalenide.7c
although a catalytic process2d in LVT is in hand, most of
the LVT-mediated synthetic ventures require the use of
superstoichiometric amounts of the reagents due to the
heterogeneity of the reaction conditions.
Resu lts a n d Discu ssion
P r ep a r a tion of th e Activa ted LVT Rea gen ts w ith
Meta l-Ar en es: In flu en ce on McMu r r y Olefin a tion .
For this study, a set of reactive LVT reagents was
generated in situ by reducing TiCl3 with different com-
binations of metals and arenes. The potential of these
LVT reagents in McMurry olefination was then investi-
gated using coupling of acetophenone (R1 ) Ph, R2) CH3;
1a ) to 2,3-diphenyl-2-butene (3a ) as the model reaction
(Scheme 1, Table 1). In most of the experiments, 0.25
equiv of the arenes with respect to TiCl3 was used. In
the initial trials, a combination of Mg and different
arenes was evaluated as the reductants. Thus, when a
mixture of TiCl3, Mg, and phenanthrene in THF was
refluxed for 3 h, a viscous but homogeneous LVT species
(reagent A) was formed. In comparison, the inorganic
reducing agents produce a suspension of the LVT
reagent. Addition of 1a to the reagent A at 25 °C and
subsequent stirring furnished the intermediate pinacol
2a (51% yield) as the major product along with 33% of
the stilbene 3a (run 1) within 3 h. The yield of the
stilbene 3a could be augmented to 66%, even at 25 °C,
using anthracene (reagent B) as the electron carrier (run
2) and increased further to 73% with reagent C, prepared
by using Mg-naphthalene as the reductant (run 3). In
contrast, when the reaction was carried out at 25 °C
using the conventional McMurry reagent (TiCl3-Li-
THF)13a (reagent D), the pinacol 2a was isolated as the
sole product (87%) even after prolonged (16 h) stirring
(run 4). This clearly indicated the efficacy of Mg-
naphthalene as an organic reductant for the generation
of the LVT reagent.
Ster ic Cou r se of Stilben e F or m a tion . The study of
the stereochemical outcome (E/Z) of the olefination with
the above LVT reagents (reagents A-K) was revealing.
In general, the reagents derived by using Mg-arenes,
i.e., Mg-phenanthrene, Mg-anthracene and Mg-naph-
thalene as reductants led to the preferential formation
of the Z-stilbene (Table 1, runs 1-3). A complete reversal
in stereoselectivity was observed by switching over to
alkali metal-based reductants. Thus, the E-isomer of 3a
was found to be the major product (Table 1, runs 5, 6,
8-10) when the reactions were carried out using the LVT
reagents generated from TiCl3 and Li-phenanthrene/Li-
anthracene/Li-naphthalene and even Na-naphthalene.
(12) For reviews on organic synthesis using SmI2, see: (a) Nomura,
R.; Endo, T. Chem. Eur. J . 1998, 4, 1605. (b) Molander, G. A.; Harris,
C. R. Chem. Rev. 1996, 96, 307. (c) Imamoto, T. Lanthanides in Organic
Synthesis; Academic Press: London, 1994. (d) Kagan, H. B.; Namy, J .
L. Tetrahedron 1986, 42, 6573. (e) Gu, X.; Curran, D. P. In Transition
Metals for Organic Synthesis - Building Blocks and Fine Chemicals;
Beller, M., Bolm, C., Eds; Wiley-VCH: Weinheim, 1998; Vol. 1, p 425.
(13) (a) McMurry, J . E.; Fleming, M. P.; Kees, K. L.; Krepski, L. R.
J . Org. Chem. 1978, 43, 3255. (b) McMurry, J . E.; Rico, J . G.
Tetrahedron Lett. 1989, 30, 1169. (c) McMurry, J . E.; Dushin, R. G. J .
Am. Chem.Soc. 1990, 112, 6942.

2992 J . Org. Chem., Vol. 66, No. 9, 2001
Ta ble 1. McMu r r y Olefin a tion of Acetop h en on e (1a ) w ith TiCl3-Meta l-Ar en e System s
Rele et al.
time (h),
temp (°C)
% yieldc (dl/meso)d
% yieldc
unreacted
run
metal
arenea (equiv)b
of 2a
(E/Z)d of 3a
1a (%)c
1
2
3
4
5
6
7
8
9
10
11
12
13
14
Mg
Mg
Mg
Li
Na
Li
Li
Li
Li
Li
phenanthrene (0.25) [reagent A]
anthracene (0.25) [reagent B]
naphthalene (0.25) [reagent C]
nil [reagent D]
3.0, 25
2.0, 25
2.0, 25
16, 25
51 (68:32)
22 (70:30)
18 (60:40)
87 (75:25)
65 (80:20)
48 (77:23)
58 (72:28)
trace
nil
trace
15 (80:20)
18 (75:25)
34 (90:10)
33 (30:70)
66 (25:75)
73 (40:60)
trace
25 (60:40)
35 (65:35)
9
70 (70:30)
89 (56:44)
77 (68:32)
65 (80:20)
68 (30:70)
5
9
naphthalene (0.25) [reagent E]
phenanthrene (0.25) [reagent F ]
biphenyl (0.25) [reagent G]
anthracene (0.25) [reagent H]
naphthalene (0.25) [reagent I]
naphthalene (0.25) [reagent I]
naphthalene (0.25) [reagent I]
naphthalene (0.12) [reagent J ]
naphthalene (0.25) [reagent K]e
nil [reagent D]
2.0, 25
2.5, 25
3.0, 25
3.0, 25
1.5, reflux
2.0, 25
6, -15
6.0, 25
5.0, 25
16, reflux
7
14
6
Li
Li
Li
Li
32
89 (75:25)
a
LVT species were generated in each case by refluxing a mixture of TiCl3 and respective metal-arenes in THF for 3 h under Ar.
Figure denotes the stoichiometry of arenes with respect to TiCl3 used. c Isolated yields. Products were fully characterized by 1H NMR,
b
IR, mp and mass spectra. The dl/meso and E/Z ratios were estimated14 from 1H NMR analyses of crude product mixtures. e Instead of
d
THF, DME was used as the solvent in this case.
Ta ble 2. Low Tem p er a tu r e McMu r r y Olefin a tion of
Ar om a tic Ca r bon yls w ith Rea gen t I
Ta ble 3. Low Tem p er a tu r e McMu r r y Olefin a tion of
Alip h a tic Ca r bon yls w ith Rea gen t I
run substrate time (h)/temp (°C) product (% yield)a E/Zb
run
substrate
time (h)/temp (°C)
product (% yield)a
1
2
3
4
5
6
7
8
9
1b
1b
1c
1d
1e
1f
1g
1h
1i
4.5/reflux
5.5/25
2.5/25
3.0/25
2.0/25
2.0/25
3.0/25
5.5/0 to -10
7.0/25
3b (68)
3b (61)
3c (72)
3d (64)c
3e (72)
3f (70)
3g (68)
3h (65)c
3i (78)
60:40
70:30
78:22
76:24
100
100
60:40
100
1
2
3
4
5
1j
1k
1l
1m
1n
6.5/reflux
8.0/25
4.0/25
5.5/25
8.0/25
3j (78)
3k (72)
3l (75)
3m (47)
3n (59)
a
Isolated yields of pure products, fully characterized by IR and
1H NMR spectra
also ensured excellent chemoselectivity in the McMurry
olefination.
a
Isolated yields of pure products, fully characterized by IR and
1H NMR spectra. Stereoisomeric ratios of olefins were deter-
The general stereochemical features discussed earlier
were also applicable with all these substrates. In these
cases also, lowering of reaction temperature improved the
E-selectivity. This was clearly evident with 2-naphthyl-
methyl ketone (1b) which produced more of the E-stilbene
3b at 25 °C as compared to that under refluxing condition
(Table 2, runs 1,2). Similarly, reactions of 4′-methyl-
acetophenone (1c) and 4′-tert-butylacetophenone (1d )
with reagent I at ambient temperature resulted in the
predominant formation of the respective E-stilbenes as
the major products (Table 2, runs 4, 5). The stereoselec-
tivities of the stilbene formation were determined as
b
mined by comparing lit. data.10,14 c 2% of 2d was isolated. 2%
d
of 2h was isolated.
The preponderance of E-olefination was augmented by
carrying out the reaction at lower temperatures. Thus,
lowering the reaction temperature from reflux to 25 °C
to -15 °C resulted in progressively increased E-selectivity
in the formation of 3a from 1a with reagent I (Table 1,
runs 9-11). Surprisingly, the isomeric composition (E/
Z) of the olefin 3a was reversed (compare runs 10 and
12, Table 1) while changing the stoichiometry of naph-
thalene (0.25 equiv to 0.12 equiv). This observation was,
however, inexplicable.
carried out earlier10 by H NMR spectroscopy.
1
One of the striking limitations16 of the McMurry
reaction is its inability to effectively couple aliphatic
carbonyls to olefins. The relatively strong alkyl-oxygen
bonds in the intermediate pinacolates17 necessitates
prolonged refluxing for the required deoxygenation. Even
then, the yields of the product olefins are often unsatis-
factory. However, using the present soluble LVT reagent
(reagent I), reductive couplings of alicyclic ketones 1j and
1k , aliphatic aldehydes 1l and 1m including the sterically
hindered ketone 1n to their respective olefins were
achieved at ambient temperature and in yields almost
comparable to those with aromatic carbonyls (Scheme 1,
Table 3).
Gen er a lity a n d Selectivity. Based on the reactivity
profile of different LVT reagents described in Table 1,
the combination of TiCl3-Li-naphthalene (0.25 equiv)-
THF (reagent I) was found to be best suited for McMurry
olefination and hence all the subsequent studies were
carried out with this reagent only.
To explore the generality and scope of the reagent I,
experiments were carried out using a variety of substi-
tuted aryl carbonyls, such as, aryl alkyl ketones (Table
2, runs 1-5), aryl aldehydes (Table 2, runs 6-9) and a
diaryl ketone (Table 2, run 10) (Scheme 1). In all the
cases, the respective olefins were obtained in good yields
(65-78%) as the exclusive products. Interestingly, since
the reagent I was effective for McMurry olefination even
at lower temperatures, functional groups such as halo-
gen, aryl-OMe, and methylenedioxy (Table 2, runs 7-9),
which are otherwise incompatible under refluxing
conditions,8b,15 remained unaffected. Thus, the reagent
Syn th esis of Heter ocyclic Com p ou n d s. The scope
of the reagent I was further extended for the synthesis
(15) (a) Talukdar, S.; Banerji, A. Synth. Commun. 1996, 26, 1051.
(b) Talukdar, S.; Banerji, A. Synth. Commun. 1995, 25, 813. (c) Tyrlik,
S.; Wolochowicz, I. J . Chem. Soc., Chem. Commun. 1975, 781.
(16) Dams, R.; Malinowski, M.; Westdrop, I.; Geise, H. Y. J . Org.
Chem. 1982, 47, 248.
(17) McMurry, J . E.; Silvestri, M. G.; Fleming, M. P.; Hoz, T.;
Grayston, M. W. J . Org. Chem. 1978, 43, 3249.
(14) Andersson, P. G. Tetrahedron Lett. 1994, 35, 2609.

Metal-Arenes as Efficient Organic Reductants
J . Org. Chem., Vol. 66, No. 9, 2001 2993
Ta ble 4. Syn th esis of Heter ocyclic Com p ou n d s via
McMu r r y Olefin a tion w ith Rea gen t I
run
substrate
product
yield (%)
rep yielda (ref)
1
2
3
4a
4b
4c
5a
5b
5c
55
52
60
55 (2a)
56 (2a)
75 (2b)
a
The reactions were carried out at reflux temperature.
Ta ble 5. Im in o-P in a col Cou p lin g w ith Rea gen t I
run
substrate
products (% yields)
rep yields (%)
ref
1
2
6a
6b
7a (45a) 8a (30)
7b (52a) 8b (28)
7a (78) 8a (0)
7b (80) 8b (0)
19a
19b
a
The dl/meso ratios were 65:35 and 3:7 for 7a and 7b,
respectively.
F igu r e 1. Possible route to activated LVT species using
soluble organic reductants.
Sch em e 2
yield in only 0.5 h. However, competitive unimolecular
reduction also produced N-benzyl aniline (8a ) in an
appreciable amount (30%). Similar reaction on N-(2-
hydroxybenzylidene)aniline (7a ) with reagent I produced
the corresponding dimeric product 7b in 52% yield after
1.5 h, along with 28% of the monoamine 8b. Thus, the
reagent I was capable of carrying out the imino-pinacol
coupling, albeit less efficiently than the LVT reagent
(TiCl3-Li/THF) used earlier.19a,b The poorer result might
be due to the formation of the mono-amines, formed by
unimolecular reductions.
Sch em e 3
Mech a n istic Asp ects. The high reactivity of the LVT
reagent prepared by reducing TiCl3 with Li-naphthalene
could be rationalized on the basis of a soluble model. The
redox properties of both Li+/Li and naphthalene/lithium-
naphthalenide should be similar as their standard redox
potential values are same (∼ -3.0 eV).7a However, based
on the previous report7a on metal-arene mediated gen-
eration of reactive metals, it appears that the soluble
naphthalenide anion is the actual reducing species for
TiCl3 in this case. During this process, the free arene is
liberated to take part in continuing the redox cycle
(Figure 1). It is, thus, imperative that unlike the report6
by Clive et al., the arene need not be present in stoichio-
metric amounts. At the same time, the study revealed
that rather than a catalytic quantity, a minimum of 0.25
equiv of the arene was required for optimum activity.
This possibly might be accounted by considering a
coordination of the arene with LVT species.
Earlier, the nature of the active Ti species has been
put to considerable debate.1c,16,20 The mechanism of action
and active sites are known to differ in homogeneous and
heterogeneous cases.21 In analogy to Dams et al.,16 it is
proposed that LVT species generated in the present case
mostly exist in the zero valent state. We also envisage
that the new homogeneous LVT reagents were possibly
organometallic Ti(0) complexes generated by coordination
of the LVT species with the arenes used. This would then
result in their higher activity. It is important to note that
while the McMurry reagent (TiCl3-Li-THF) is obtained
as a colloidal suspension,1 reagent I was homogeneous
of heterocycles via intramolecular keto-ester2a and keto-
amide2b cyclization reaction developed earlier by us and
other laboratories. Thus, reaction of 2-(benzoyloxy)-
acetophenone (4a ) and 2-(benzoyloxy)-5-(methoxy)aceto-
phenone (4b) with reagent I afforded the corresponding
benzofurans 5a and 5b, respectively, in moderate yields
(Scheme 2). Similarly, reaction of 2-(N-benzoylamino)-
acetophenone (4c) furnished 2-phenyl-3-methyl indole
(5c) in only 2 h at 25 °C (Scheme 2). These results were
comparable with those previously reported.2a,2b Thus, the
LVT reagent I appeared to be better for the synthesis of
heterocycles via McMurry coupling as the reaction could
be carried out at room temperature.
Syn th esis of Vicin a l Dia m in es. Vicinal diamines
find extensive applications in radiopharmaceuticals and
as complexing agents and chiral auxiliaries.18 In view of
their frequent occurrence in natural products and me-
dicinal compounds, we have earlier developed an LVT
mediated synthesis of them via an imino-pinacol coupling
reaction.19a In this study, the utility of the activated
reagent I for the coupling of imino substrates was also
explored (Scheme 3). Thus, addition of N-benzylidene-
aniline (6a ) to the reagent I at 25 °C furnished N1,N2-
di(phenyl)-1,2-diphenyl-1,2-ethanediamine (7a ) in 45%
(20) For discussions on the nature of active species of LVT, see: (a)
Aleandri, L. E.; Bogdanovic, B.; Gaidies, A.; J ones, D. J .; Liao, S.;
Michalowicz, A.; Roziere, J .; Schott, A. J . Organomet. Chem. 1993, 459,
87. (a) Aleandri, L. E.; Becke, S.; Bogdanovic, B.; J ones, D. J .; Roziere,
J . J . Organomet. Chem. 1994, 472, 97. (b) Bogdanovic, B.; Bolte, A. J .
Organomet. Chem. 1995, 502, 109.
(18) Lucet, D.; Gall, T. L.; Mioskowski, C. Angew. Chem., Int. Ed.
Eng. 1998, 37, 2580.
(19) (a) Talukdar, S.; Banerji, A.; J . Org. Chem. 1998, 63, 3468 and
references therein. (b) Talukdar, S. Ph.D. Thesis, University of
Mumbai, 1997.
(21) Idriss, H.; Pierce, K. G.; Barteau, M. A. J . Am. Chem. Soc. 1994,
116, 3063.

2994 J . Org. Chem., Vol. 66, No. 9, 2001
Rele et al.
as mentioned in our previous publication.10 Lithium rods cut
into small pieces were used for the reduction of TiCl3.
in nature. Thus, the redox-active arenes play a dual role
of acting both as the electron carrier and also as ligand,
thereby augmenting the reactivity.
Gen er a l Meth od for th e P r ep a r a tion of Activa ted LVT
r ea gen ts. To a stirred suspension of Li (33 mmol, 0.23 g) in
dry THF (20 mL) under argon was successively added TiCl3
(10 mmol, 1.55 g) in THF (20 mL) and arene (2.5 mmol) at
room temperature. After refluxing for 3 h, a thick dense
homogeneous black mass of activated Ti species was obtained
in each case. The modified LVT reagent was then allowed to
cool to ambient temperature and used for the subsequent
reactions.
Mechanistically, the McMurry olefination is widely
regarded1 to proceed via the initial formation of the
titanium pinacolates followed by their deoxygenation
under forcing experimental conditions to give the olefins.
More recently, Ephritikhine has proposed22a,b another
interesting mechanism involving metallocarbenoid spe-
cies which also accounted for the generation of alkanes/
alkenes in the above reaction via direct deoxygenation
of the carbonyl substrates. In addition, the mechanism
could also explain the dimerization of aliphatic ketones
to olefins even at room temperature with the LVT reagent
prepared from TiCl4/Li(Hg). However, as suggested by
them, the carbenoid mechanism is primarily operative
for McMurry olefination of especially hindered aliphatic
substrates and may well be the case with one of the
chosen substrates, 1n . In contrast, the other substrates
of the present study do not have any significant steric
hindrance and thus would follow the classical pinacolate
route. Hence, their smooth dimerization to the respective
olefins at lower temperatures could only possibly be
explained by considering activation of the LVT species
through ligation with the arene as proposed above. This
argument was also substantiated by the fact that the
conventional McMurry reagent (Reagent D) produced the
pinacol only at room temperature.
Gen er a l P r oced u r e of Red u ctive Cou p lin g of Ca r bo-
n yl/Im in o Su bstr a tes w ith Rea gen t I. To the activated LVT
reagent, prepared as above, was added the substrate 1a -n
(2.5 mmol) or 6a and 7a (4 mmol) in THF (5 mL) and the
reaction mixture was stirred at temperatures indicated in the
Tables 1-3 and 5. After disappearance of the substrate (cf.
TLC), the reaction mixture was diluted with hexane, quenched
with aqueous saturated NH4Cl solution, and the supernatant
was passed through a bed of Celite. The eluent was extracted
with a mixture of ethyl acetate-hexane (1:4) and the organic
extract was washed with brine and dried (Na2SO4). Removal
of solvent in vacuo yielded the crude product from which
naphthalene was removed by vacuum sublimation (50 °C/10
mm) and the residue subjected to preparative TLC to afford
the respective products (yields and the ratio of E/Z mixtures
are presented in respective Tables). The products were char-
acterized on the basis of their spectral (1H NMR, MS, and IR)
and physical data which were found to be in agreement with
those of authentic samples and literature data.9,10,14,19
Typ ica l P r oced u r e of R ed u ct ive Cou p lin g of Ac-
etop h en on e (1a ) u sin g Rea gen t I. To a stirred solution of
the reagent I was added 1a (0.3 g, 2.5 mmol) in THF (5 mL)
and the reaction mixture was stirred at temperatures indicated
in Table 1. After disappearance of the substrate (cf. TLC), the
reaction mixture was diluted with hexane and quenched with
aqueous saturated NH4Cl solution and the supernatant was
passed through a bed of Celite. The eluent was worked-up as
above and the crude product was subjected to preparative TLC
(silica gel, EtOAc/hexane (5/95)) to afford the known com-
pound10,14 3a (the yield and stereoisomeric ratio is given in
Table 1).
Con clu sion
The present investigation describes an efficient strat-
egy for the generation of reactive LVT species by reducing
TiCl3 with in situ formed metal-arenide systems acting
as the soluble organic reductants. Thus, the addition of
a substoichiometric amount of an electron carrier, e. g.,
naphthalene to a mixture of Li-TiCl3, provided an easy
access to a reactive homogeneous LVT species. The
applicability of the LVT reagent for carrying out SET-
induced coupling processes such as inter- and intramo-
lecular carbonyl coupling reactions as well as imino-
pinacol couplings under milder conditions are reported.
A facile entry to biologically important benzofurans,
indoles, and vicinal diamines under milder conditions
further augments the utility of the reagent system. The
present study unfolds a potentially important variation
in the preparation of activated LVT reagent using soluble
organic reductants instead of conventional inorganic
species (under a complete heterogeneous condition). The
present finding is likely to enhance the utility of LVT
reagents in a multitude of synthetic endeavors and will
open up new avenues in preparative chemistry.
Syn th esis of F u r a n s, 5a ,b, a n d In d ole, 5c, u sin g Rea -
gen t I. Similar reactions of reagent I with keto-esters 4a and
4b and keto-amide 4c (2.5 mmol, 10 mL THF) according to
the above-mentioned procedure afforded the intramolecularly
coupled O-/N- heterocycles 5a -c. Spectroscopic data (NMR,
IR, MS) and physical constants of the isolated products were
in full agreement with the authentic samples.2a,b
Ack n ow led gm en t. One of the authors, S. R., is
grateful to the Department of Atomic Energy, Govern-
ment of India, for a Senior Research Fellowship.
Exp er im en ta l Section
Su p p or tin g In for m a tion Ava ila ble: The physical and
spectral (IR, 1H NMR, and mass) data for 3a -3n , 5a -5c, and
7a , 7b (3 pages). This material is available free of charge via
the Internet at http://pubs.acs.org.
Gen er a l Meth od s. General information regarding instru-
ments, techniques, and source of chemicals used were the same
(22) (a) Villiers, C.; Ephritikhine, M. Angew. Chem., Int. Ed. Engl.
1997, 36, 2380. (b) Ephritikhine, M. Chem. Commun. 1998, 2549.
J O001586A