Organozinc generation via the titanium-catalyzed activation of alkyl halides

Article abstract of DOI:10.1021/ol902374v

[Chemical Equation Presented] A protocol for the generation of organozinc reagents via catalytic activation of alkyl halides is described herein. Subsequent nucleophilic addition to carbonyl derivatives provided the desired products in good to excellent y

Full text of DOI:10.1021/ol902374v

ORGANIC
LETTERS
2009
Vol. 11, No. 24
5670-5673
Organozinc Generation via the
Titanium-Catalyzed Activation of Alkyl
Halides
Lauren M. Fleury and Brandon L. Ashfeld*
Department of Chemistry and Biochemistry, UniVersity of Notre Dame,
Notre Dame, Indiana 46556
bashfeld@nd.edu
Received October 14, 2009
ABSTRACT
A protocol for the generation of organozinc reagents via catalytic activation of alkyl halides is described herein. Subsequent nucleophilic
addition to carbonyl derivatives provided the desired products in good to excellent yields (76-99%). Evidence suggests that titanocene
dichloride catalyzes the formation of an organozinc species. This discovery will have wide ranging applicability in the generation of highly
reactive organometallic reagents.
The formation of reactive organometallic reagents often
requires vigorous conditions or the preactivation of low
valent metals, as in the Rieke metals of zinc1 and magne-
sium.2 In general, there are few mild, catalytic methods to
generate stoichiometric quantities of highly reactive orga-
nometallics from alkyl halides.3 Recently, Krische has
introduced a powerful iridium-catalyzed hydrogenative car-
bonyl allylation employing 1,3-dienes,4 allenes,5 and allyl
acetates6 as allylmetal precursors. Alternatively, we consid-
ered the possibility of catalytically activating alkyl halides
for the stoichiometric in situ generation of highly reactive
organometallics. Rather than focus on activating the metal
to facilitate the reduction of alkyl halides, our approach was
to develop a protocol in which the alkyl halide is catalytically
activated by an early transition metal complex. Transmeta-
lation will then provide an organometallic reagent with a
broader reactivity profile. We identified titanium as well
suited for our purpose due to its excellent chemoselectivity,
low electronegativity, inexpensiveness, and minimal toxicity.7
Our procedural design involves formation of a R-TiIVLn
from R-X followed by zinc-mediated reduction of titanium
to provide a transient R-TiIIILn intermediate (Scheme 1).8
Transmetalation to Zn(II) yields a stoichiometric amount of
RZnIIX and regenerates the catalytically active TiIIILn. This
method can provide stoichiometric quantities of highly
reactive organometallics under mild conditions without the
need for an activated metal and can even be performed in
the presence of the desired electrophile. The metalation
occurs at or below room temperature to circumvent chemose-
(1) Rieke, R. D.; Uhm, S. J.; Hudnall, P. M. J. Chem. Soc., Chem.
Commun. 1973, 269.
(2) Rieke, R. D.; Hudnall, P. M. J. Am. Chem. Soc. 1972, 94, 7178.
(3) (a) Takai, K.; Ueda, T.; Hayashi, T.; Moriwake, T. Tetrahedron Lett.
1996, 37, 7049. (b) Bogdanoviæ, B.; Schwickardi, M. Angew. Chem., Int.
Ed. 2000, 39, 4610.
(4) Bower, J. F.; Patman, R. L.; Krische, M. J. Org. Lett. 2008, 10,
1033.
(7) (a) Ding, Y.; Zhao, Z.; Zhou, C. Tetrahedron 1997, 53, 2899. (b)
Parrish, J. D.; Shelton, D. R.; Little, R. D. Org. Lett. 2003, 5, 3615. (c)
Duthaler, R. O.; Bienewald, F.; Hafner, A. Transition Met. Org. Synth. (2nd
Ed.) 2004, 1, 491. (d) Odom, A. L. Dalton Trans. 2005, 225. (e) Ramon,
D. J.; Yus, M. Chem. ReV. 2006, 106, 2126.
(5) (a) Bower, J. F.; Skucas, E.; Patman, R. L.; Krische, M. J. J. Am.
Chem. Soc. 2007, 129, 15134. (b) Skucas, E.; Bower, J. F.; Krische, M. J.
J. Am. Chem. Soc. 2007, 129, 12678.
(6) (a) Kim, I. S.; Ngai, M.-Y.; Krische, M. J. J. Am. Chem. Soc. 2008,
130, 6340. (b) Kim, I. S.; Ngai, M.-Y.; Krische, M. J. J. Am. Chem. Soc.
2008, 130, 14891.
(8) (a) Brintzinger, H. J. Am. Chem. Soc. 1967, 89, 6871. (b) Martin,
H. A.; Jellinek, F. J. Organomet. Chem. 1967, 8, 115.
10.1021/ol902374v  2009 American Chemical Society
Published on Web 11/19/2009

presence of the carbonyl substrate has yet to be developed.1,18
This method would ultimately allow for the formation of
highly reactive allylmetal reagents in the presence of sensitive
functionality often encountered complex total synthesis.
Although allyltitanium(IV) complexes are known to undergo
addition to aldehydes smoothly, ketones often require longer
reaction times and elevated temperatures.9,19 Therefore, this
transformation would be an ideal testing ground for the
metalation procedure illustrated in Scheme 1. Thus, addition
of enone 1a and allyl bromide (2a) to a mixture of zinc dust
and 1 mol % of Cp2TiCl2 yielded alcohol 3a in 79% yield
at -20 °C and 99% in a mere 5 min at room temperature
(eq 1). Titanium plays a clear role in the reaction, as is
evidenced by the quantitative recovery of enone 1a in the
absence of Cp2TiCl2 at -20 °C. With this observation in
hand, we sought to gain insight into the scope and
mechanism of this titanium-catalyzed metalation protocol.
Scheme 1. Titanium-Catalyzed Organozinc Formation
lectivity issues that may arise from conventional methods
of alkylmetal formation. Inspired by the previous work of
Ding,9 and more recently Gansauer,10 on titanocene-catalyzed
carbon-carbon bond formations, we began by exploring in
detail the reactivity observed by the combination of Cp2TiCl2
and zinc dust.
To evaluate our hypothesis, we chose to examine the
formation of allylzinc intermediates and their use in carbonyl
addition reactions.11 The allylation of carbonyl derivatives
is of fundamental importance to the field of organic synthesis,
as it constitutes one of the principal methods for constructing
polyketides.12 Although remarkable advances in the stereo-
and chemoselectivity of allylation protocols have occurred
over the past four decades,13 the pregeneration of stoichio-
metric organometallic species can be problematic.14 Begin-
ning with the seminal publications of Umani-Ronchi,15
Keck,16 and Denmark17 on chiral Lewis acid-catalyzed
allylations, whose methods require the stoichiometric pre-
generation of organometallic reagents, and arriving at the
work of Krische on the catalytic generation of allyliridium
intermediates from 1,3-dienes,2 the field of allylation has
experienced a number of truly groundbreaking advances.
However, a mild method by which an allyl halide can be
activated catalytically for stoichiometric metalation in the
During our optimization studies with benzaldehyde (1b),
we observed that the temperature of the reaction had a
profound effect on the overall efficiency (Table 1). Excellent
Table 1. Temperature and Additive Effects20
entry
additive (5 mol %)
temperature
yield (%)
(9) (a) Ding, Y.; Zhao, G. J. Chem. Soc., Chem. Commun. 1992, 941.
(b) Ding, Y.; Zhao, G. Tetrahedron Lett. 1992, 33, 8117. (c) Ding, Y.;
Zhao, Z.; Zhou, C. Tetrahedron 1997, 53, 2899.
1
2
3
4
5
6
7
8
-
-
-
0 °C
-20 °C
-40 °C
-40 °C
-40 °C
-40 °C
-40 °C
-78 °C
95
91
NRa
96
(10) (a) Gansauer, A. Synlett 1998, 801. (b) Gansa¨uer, A. Synlett 1998,
801. (c) Rosales, A.; Oller-Lo´pez Juan, L.; Justicia, J.; Gansa¨uer, A.; Oltra,
J. E.; Cuerva, J. M. Chem. Commun. 2004, 2628. (d) Este´vez, R. E.; Justicia,
J.; Bazdi, B.; Fuentes, N.; Paradas, M.; Choquesillo-Lazarte, D.; Garc´ıa-
Ruiz, J. M.; Robles, R.; Gansa¨uer, A.; Cuerva, J. M.; Oltra, J. E.
Chem.sEur. J. 2009, 15, 2774.
PPh3
PCy3
dppp
(()-BINAP
PCy3
95
99
98
(11) (a) Yamamoto, Y.; Asao, N. Chem. ReV. 1993, 93, 2207. (b) Gao,
Y.; Urabe, H.; Sato, F. J. Org. Chem. 1994, 59, 5521. (c) Knochel, P.;
Perea, J. J. A.; Jones, P. Tetrahedron 1998, 54, 8275.
NRa
a Reaction was run for g48 h.
(12) For recent reviews on allyl metal carbonyl additions, see: (a)
Kennedy, J. W. J.; Hall, D. G. Angew. Chem., Int. Ed. 2003, 42, 4732. (b)
Roush, W. R. Actual. Chim. 2004, 21. (c) Hall, D. G. Synlett 2007, 1644.
(13) For recent reviews on allylations, see: (a) Yamamoto, Y.; Asao,
N. Chem. ReV. 1993, 93, 2207. (b) Denmark, S. E.; Fu, J. Chem. ReV. 2003,
103, 2763. (c) Bower, J. F.; Kim, I. S.; Patman, R. L.; Krische, M. J. Angew.
Chem., Int. Ed. 2009, 48, 34. (d) Tietze, L. F.; Kinzel, T.; Brazel, C. C.
Acc. Chem. Res. 2009, 42, 367.
yields were obtained in 5-10 min at temperatures as low as
-20 °C (entries 1 and 2), but at -40 °C the reaction failed
completely, leading to recovered starting material (entry 3).
However, we discovered that upon addition of 5 mol % PPh3
catalytic activity was restored and alcohol 3b was obtained
in 96% yield (entry 4). A similar effect was witnessed with
the trialkyl phosphine PCy3 and bisphosphines dppp and (()-
(14) For selected references where purification issues arose utilizing
Brown’s asymmetric allylation, see: (a) Brown, H. C.; Jadhav, P. K. J. Am.
Chem. Soc. 1983, 105, 2092. (b) Ireland, R. E.; Armstrong, J. D.; Lebreton,
J.; Meissner, R. S.; Rizzacasa, M. A. J. Am. Chem. Soc. 1993, 115, 7152.
(c) Burova, S. A.; McDonald, F. E. J. Am. Chem. Soc. 2004, 126, 2495.
(d) Gao, D.; O’Doherty, G. A. Org. Lett. 2005, 7, 1069. (e) White, J. D.;
Hansen, J. D. J. Org. Chem. 2005, 70, 1963.
(18) For catalytic generation, see: Tanaka, H.; Inoue, K.; Pokorski, U.;
(15) Costa, A. L.; Piazza, M. G.; Tagliavini, E.; Trombini, C.; Umani-
Ronchi, A. J. Am. Chem. Soc. 1993, 115, 7001.
Taniguchi, M.; Torii, S. Tetrahedron Lett. 1990, 31, 3023.
(19) (a) Szymoniak, J.; Moise, C. Titanium Zirconium Org. Synth. 2002,
451. (b) Este´vez, R. E.; Justicia, J.; Bazdi, B.; Fuentes, N.; Paradas, M.;
Choquesillo-Lazarte, D.; Garc´ıa-Ruiz, J. M.; Robles, R.; Gansa¨uer, A.;
(16) Keck, G. E.; Tarbet, K. H.; Geraci, L. S. J. Am. Chem. Soc. 1993,
115, 8467.
(17) Denmark, S. E.; Fu, J. J. Am. Chem. Soc. 2001, 123, 9488.
Cuerva, J. M.; Oltra, J. E. Chem.sEur. J. 2009, 15, 2774.
Org. Lett., Vol. 11, No. 24, 2009
5671

BINAP. Further cooling of the reaction to -78 °C resulted
in no reaction. At this time, the role of the phosphine additive,
and the effect it has on the metalation step, is unclear but
appears to be quite general and a useful modification for
performing the desired metalation at lower temperatures.
Scheme 2. Cyclopropyl Allyl Bromide Metalation
Given the extremely facile allylation depicted in eq 1, we
initially set out to determine the role of titanium and zinc
and the nature of the reactive organometallic reagent in the
carbon-carbon bond-forming event. The pregeneration of
Cp2TiIIICl from Cp2TiIVCl2 and Zn(0) is required, as no
reaction is observed without this initial reduction event.
Allylation of enone 1a with allyl bromide and zinc dust in
the absence of Cp2TiIVCl2 took substantially longer (>6 h)
to reach full conversion, but the use of more reactive allyl
iodide resulted in alcohol 3a in 68% yield after 60 min.
On the basis of our findings, it appears unlikely that the
Lewis acidic properties of zinc or titanium alone are
responsible for the overall efficiency of the allylation and
that Cp2TiIIICl must be participating in the formation of a
more reactive allylzinc species. Thus, a proposed mechanism
is illustrated in Scheme 3.26 Initial reduction of Cp2TiIVCl2
Additionally, we observed no reaction with stoichiometric
Cp2TiIIICl in the absence of zinc dust after prolonged reaction
times (>24 h). These results indicate that both titanium and
zinc participate in the allylation to achieve the levels of
reactivity observed. We next considered the possibility that
ZnCl2, the byproduct of Cp2TiIVCl2 reduction with Zn(0),
could be acting as a Lewis acid in the addition of an
allyltitanium(III) intermediate.1 However, the addition of
ZnCl2 to allyl bromide, enone 1a, and stoichiometric
Cp2TiIIICl failed to provide alcohol 3a.21 These results
support our hypothesis that although an allyltitanium(IV)
reagent is formed a transmetalation event from an allyltita-
nium(III) species must occur.22 The involvement of an
allylzinc species is corroborated by the observation that the
addition of allylzinc chloride23 to enone 1a yields alcohol
3a in 98% yield, and allylation of 4-t-butylcyclohexanone
provides the corresponding homoallyl alcohol in a syn/anti
ratio of 6:1. These results are consistent with addition of an
allylzinc reagent24 and not an allyltitanium complex (dr )
2:1).14b Additionally, the use of manganese as the reducing
metal gave quantitative recovery of enone 1a, lending more
weight to the intermediacy of an allylzinc species.
Scheme 3. Proposed Catalytic Cycle
Although these results provide compelling support for the
general mechanism depicted in Scheme 1, further evidence
for two rapid single electron reductions of allyl bromide by
Cp2TiIIICl was obtained by the examination of vinylcyclo-
propane 2b as the allylmetal precursor (Scheme 2).25 If the
substrate were to demonstrate radical character en route to
metalation, we would expect to see strain-driven ring
expansion of the cyclopropane. However, if titanium induces
an inner sphere reduction of the allyl bromide followed by
rapid radical-radical annihilation, the cyclopropane ring
should remain intact throughout the metalation process.
Treatment of 2b and either enone 1a or benzaldehyde (1b)
to Cp2TiCl2 (1 mol %) and Zn(0) cleanly provided alcohols
3c and 3d, respectively, absent any evidence of cyclopropane
ring opening.
is followed by metalation of bromide (2) to yield allyl-TiIV
4.27 Reduction to allyl-TiIII 56,28 facilitates transmetalation
to zinc, thereby providing allylzinc 6, which reacts rapidly
with substrate 1 and regenerates titanocene(III). It should
be noted that although titanium is not depicted as involved
in the carbon-carbon bond-forming event, it may serve a
secondary role as a Lewis acid.
We next sought to explore the scope of this method by
examining a series of carbonyl derivatives (Table 2).
Electron-rich, electron-poor, and aliphatic aldehydes, even
(23) Generated by treatment of allyl magnesium bromide with ZnCl2.
(24) Shono, T.; Ishifune, M.; Kashimura, S. Chem. Lett. 1990, 19, 449.
(25) Wipf, P.; Walczak, M. A. A. Angew. Chem., Int. Ed. 2006, 45,
4172.
(26) (a) Waltz, K. M.; Gavenonis, J.; Walsh, P. J. Angew. Chem., Int.
Ed. 2002, 41, 3697. (b) Kim, J. G.; Camp, E. H.; Walsh, P. J. Org. Lett.
2006, 8, 4413. (c) Wooten, A. J.; Kim, J. G.; Walsh, P. J. Org. Lett. 2007,
9, 381.
(20) A representative procedure can be found in the Supporting
Information.
(21) Motoyama, Y.; Nishiyama, H. Lewis Acids Org. Synth. 2000, 1,
(27) (a) Riediker, M.; Duthaler, R. O. Angew. Chem., Int. Ed. 1989, 28,
494. (b) Jana, S.; Guin, C.; Roy, S. C. Tetrahedron Lett. 2004, 45, 6575.
(28) Eisch, J. J.; Boleslawski, M. P. J. Organomet. Chem. 1987, 334,
59.
(22) Rele, S.; Chattopadhyay, S.; Nayak, S. K. Tetrahedron Lett. 2001,
42, 9093.
C1.
5672
Org. Lett., Vol. 11, No. 24, 2009

the amount of titanocene resulted in substantial pinacol
coupling production.
Table 2. Titanium-Catalyzed Allylation of Ketones and Esters19
Our observation that phosphine additives facilitate low-
temperature metalation led us to hypothesize that an enan-
tioselective allylation with a highly reactive allylmetal
reagent could be performed with a catalytic amount of chiral
ligand. We reasoned that this could be achieved by control-
ling the reaction temperature such that only the ligand-bound
reagent would undergo carbonyl addition.
By controlling the reaction temperature, the unselective
background reaction can be minimized. Thus, the addition
of benzaldehyde and allyl bromide to a mixture of lithiated
diamine 8 (50 mol %), Cp2TiCl2 (2 mol %), dppe (15 mol
%), and Zn(0) at -40 °C for 8 h provided alcohol (+)-3o in
68% ee.30 Interestingly, the direct use of a chiral phosphine
or chiral titanocene proceeded with no selectivity. This result
demonstrates that a substoichiometric amount of chiral ligand
can be successfully used for the enantioselective addition of
a highly reactive organometallic reagent, even when gener-
ated in the presence of a carbonyl substrate.
yield
(%)
entry
R1
R2
2
R3 R4
3
1
2
3
4
5
6
7
8
p-Me2N-C6H4 (1d)
p-MeO2C-C6H4 (1e)
n-hexyl (1f)
o-HO-C6H4 (1g)
p-MeO-C6H4CHdCH (1h) Me 2a
p-CF3-C6H4CHdCH (1i) Me 2a
H
2a
2a
H
H
H
H
3e 91
3f 90
H
H
H
2b Me Me 3g 82
2a
H
H
H
H
H
H
3h 97
3i
3j
91
92
c-C3H5CHdCH (1j)
p-MeO-C6H4CHdCH (1k) OEt 2a
a Reaction time ) 3 h. R2 ) CH2CHdCH2 for product 3l.
Me 2b Me Me 3k 97
H
H
3l
87a
those containing free phenols, underwent allylation in <5
min (entries 1-4). Ketone allylation mediated by transition
metal complexes, such as in chromium-catalyzed Nozaki-
Hiyama-Kishi reactions, can be problematic.29 However,
in the presence of Cp2TiCl2 (1 mol %) and Zn(0), ketones
and esters underwent rapid allylation in excellent yields
(entries 5-8).
Not surprisingly, the metalation of benzyl and aliphatic
bromides proved more difficult. Zincation of benzyl bromide
(2c) in the presence of aldehyde 1l, Cp2TiCl2, zinc dust, and
1,2-bis(diphenylphosphino)ethane (dppe) (5 mol %) provided
alcohol 3m in 44% yield (Scheme 4). To achieve an alkylzinc
In conclusion, an efficient titanium-catalyzed metalation
procedure is described. This method allows for the mild,
stoichiometric production of highly reactive organometallic
reagents utilizing a titanocene-catalyzed approach toward
substrate activation. The procedure described herein repre-
sents a unique opportunity to confront the challenges of
generating organometallic reagents with broad reactivity
profiles in the company of sensitive functional groups. These
studies, their applications in new carbon-carbon bond-
forming transformations, expanding the scope to new orga-
nometallic reagents, and the development of an improved
enantioselective protocol are ongoing and will be reported
in due course.
Scheme 4. Benzyl and Aliphatic Organozinc Formation
Acknowledgment. The authors would like to thank Profs.
Seth N. Brown and Kenneth W. Henderson of the University
of Notre Dame and Professor Peter Wipf of the University
of Pittsburgh for helpful discussions and the University of
Notre Dame for financial support of this research.
formation, it was necessary to increase the titanocene catalyst
loading to 50 mol %. Addition of dppe appears to increase
the rate of metalation in a similar fashion to that illustrated
by Table 1. Substituting 1-bromobutane (2d) for benzyl
bromide gave alcohol 3n but in diminished yield. Increasing
Supporting Information Available: Experimental pro-
cedures and spectral data for all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(29) (a) Fu¨rstner, A.; Shi, N. J. Am. Chem. Soc. 1996, 118, 12349. (b)
Bandini, M.; Cozzi, P. G.; Umani-Ronchi, A. Polyhedron 2000, 19, 537.
(c) McManus, H. A.; Cozzi, P. G.; Guiry, P. J. AdV. Synth. Catal. 2006,
348, 551. (d) Hargaden, G. C.; Mu¨ller-Bunz, H.; Guiry, P. J. Eur. J. Org.
Chem. 2007, 4235.
OL902374V
(30) Mimoun, H.; de Saint Laumer, J. Y.; Giannini, L.; Scopelliti, R.;
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Org. Lett., Vol. 11, No. 24, 2009
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