Stereoselective Preparation of Dienyl Zirconocene Complexes via a Tandem Allylic C-H Bond Activation-Elimination Sequence

Article abstract of DOI:10.1021/ja036751t

Several dienyl zirconocene derivatives were easily prepared, as unique geometrical isomers, from simple non-conjugated unsaturated enol ethers with (1-butene)ZrCp₂ complexes. This new methodology is based on a tandem allylic C-H bond activation-elimination sequence and the mechanism has been mapped out by deuterium labeling experiments. The stereochemical outcome of this process was determined by addition of several electrophiles. Moreover, when the organometallic derivative is vinylic as well as allylic such as in 44-47Zr, an unexpected reversal of the stereochemistry has been found during the zirconium to copper transmetalation step.

Full text of DOI:10.1021/ja036751t

Published on Web 10/02/2003
Stereoselective Preparation of Dienyl Zirconocene Complexes
via a Tandem Allylic C-H Bond Activation-Elimination
Sequence
Nicka Chinkov, Swapan Majumdar, and Ilan Marek*
Contribution from the Department of Chemistry and Institute of Catalysis Science and
Technology, Technion-Israel Institute of Technology, Technion City, 32000 Haifa, Israel
Received June 18, 2003; E-mail: chilanm@tx.technion.ac.il
Abstract: Several dienyl zirconocene derivatives were easily prepared, as unique geometrical isomers,
from simple non-conjugated unsaturated enol ethers with (1-butene)ZrCp2 complexes. This new methodology
is based on a tandem allylic C-H bond activation-elimination sequence and the mechanism has been mapped
out by deuterium labeling experiments. The stereochemical outcome of this process was determined by
addition of several electrophiles. Moreover, when the organometallic derivative is vinylic as well as allylic
such as in 44-47Zr, an unexpected reversal of the stereochemistry has been found during the zirconium
to copper transmetalation step.
Scheme 1. General Scheme for Intermolecular Carbometalation
Reaction of Alkynes
Introduction
The intermolecular addition of organometallics 1 to alkynes
2 (carbometalation)1 constitutes an excellent method for the
preparation of alkenyl organometallics of type 3, which after a
reaction with electrophile reagents (E-X) provide polysubsti-
tuted olefins (Scheme 1).
In particular, carbocupration,1e zirconium-catalyzed carboalu-
mination,2 nickel-catalyzed carbozincation,3 allylmetalation of
metalated alkynes,3 allylzirconation,5 allylgallation,6 allylman-
ganation,7 and alkyllithiation8 have high synthetic potential due
to wide applicability. The addition of different substituted allyl-
and propargylsilanes to unactivated alkynes in the presence of
catalytic amounts of Lewis Acids was also recently reported.9
Although dienylmetals could be very useful synthetic precur-
sors for various targets, the vinylmetalation of alkynes has
remained comparatively unexplored.1,10 The principal reason for
this lack of development is that the vinylmetalation of unacti-
vated alkyne 2 with 1 (R ) alkenyl) affords a new vinylic
organometallic derivative 3, which has a similar reactivity to
that of 1 and therefore can participate also in a subsequent
carbometalation reaction. In this case, an oligomerization of the
unsaturated substrates results.
In the past decade, reactions based on dialkylzirconocene
complexes have found tremendous evolution.11 These achieve-
ments have triggered an avalanche of interest and many elegant
applications described in the literature corroborate the notion
that zirconocene-based synthesis of complex targets may clearly
outperform more conventional approaches.12 Particularly in the
field of metalated dienes, zirconocene derivatives were already
successfully used and some of the more important examples
will be briefly described.
(1) (a) Marek, I. J. Chem. Soc., Perkin Trans. 1, 1999, 535; (b) Marek, I. In
Modern C, C- and C, X.-Bond Formations by Metal-Catalyzed Cross-
Coupling Reactions; de Meijere, A., Diederich, F, Eds.; Wiley-VCH:
Weinheim, Germany, 2004, In press; (c) Marek, I. In Transition Metals
for Organic Synthesis, second Edition, Beller, M., Bolm, C., Eds.; Wiley-
VCH: Weinheim, Germany, 2003, In press; (d) Marek, I.; Normant, J. F.
In Metal-Catalyzed Cross Coupling Reactions; Diederich, F., Stang, P. J.,
Eds.; Wiley-VCH: Weinheim, Germany, 1998, 271; (e) Normant, J. F.;
Alexakis, A. Synthesis, 1981, 841; (f) Knochel, P. In ComprehensiVe
Organic Synthesis; Trost B. M., Fleming, I., Semmelhack, M. F., Eds.;
Pergamon Press: New York, 1991; Vol. 4, 865; (g) Negishi, E. Pure Appl.
Chem. 1981, 53, 2333 (h) Fallis, A. G.; Forgione, P. Tetrahedron 2001,
57, 5899.
(2) (a) Negishi, E.; Takahashi, T. Synthesis, 1988, 1; (b) Negishi, E.;
Montchamp, J.-L.; Anastasia, L.; Alizarov, A.; Choueiry, D. Tetrahedron
Lett. 1998, 39, 2503; (c) Ma, S.; Negishi, E. J. Org. Chem. 1997, 62, 784;
(d) Negishi, E.; Kondakov, D. Y.; Van Horn, D. E. Organometallics 1997,
16, 951.
(3) (a) Studemann, T.; Knochel, P. Angew. Chem., Int. Ed. Engl. 1997, 36,
93; (b) Studemann, T.; Ibrahim-Ouali, M.; Knochel, P. Tetrahedron 1998,
54, 1299.
Vinylmetalation of alkynes can be performed in a two-step
procedure (Scheme 2): stereoselective preparation of zircona-
cyclopentadiene derivative 4 followed by the stereoselective
reaction of 4 with an electrophile to give the carbometalated
dienyl product 5. The coupling of two alkynes, via low-valent
zirconocene species leads to the formation of zirconacyclopen-
(8) (a) Hojo, M.; Murakami, Y.; Aihara, H.; Sakuragi, R.; Baba, Y.; Hosomi,
A. Angew. Chem., Int. Ed. 2001, 40, 621.
(9) (a) Yoshikawa, E.; Kasahara, M.; Asao, N.; Yamamoto, Y. Tetrahedron
Lett. 2000, 41, 4499; (b) Yoshikawa, E.; Gevorgyan, V.; Asao, N.;
Yamamoto, Y. J. Am. Chem. Soc. 1997, 119, 6781.
(10) (a) Forgione, P.; Wilson, P. D.; Fallis, A. G. Tetrahedron Lett. 2000, 41,
17; (b) Forgione, P.; Wilson, P. D.; Yap, G. P. A.; Fallis, A. G. Synthesis,
2000, 921; (c) Alexakis, A.; Normant, J. F. Tetrahedron Lett. 1982, 23,
5151; (d) Furber, M.; Taylor, R. J. K.; Burford, S. C. J. Chem. Soc., Perkin
Trans 1 1986, 1809.
(4) Marek, I. Chem. ReV. 2000, 100, 2887.
(5) Yamanoi, S.; Imai, T.; Matsumoto, T.; Suzuki, K. Tetrahedron Lett. 1997,
38, 3031.
(6) Yamaguchi, M.; Sotokawa, T.; Hirama, M. Chem. Commun. 1997, 743.
(7) (a) Usugi, S.; Tang, J.; Shinokubo, H.; Oshima, K. Synlett 1999, 1417 (b)
Yorimitsu, H.; Tang, J.; Okada, K.; Shinokubo, H.; Oshima, K. Chem. Lett.
1998, 11.
9
13258
J. AM. CHEM. SOC. 2003, 125, 13258-13264
10.1021/ja036751t CCC: $25.00 © 2003 American Chemical Society

Dienyl Zirconocene Complexes
A R T I C L E S
Scheme 2. Preparation of Zirconadienyl Complexes
Scheme 3. Insertion of 1-chloro-1-lithioalkenes into Organozirconocenes
tadiene complexes.13 For the preparation of unsymmetrical
zirconacyclopentadienes, Cp2ZrEt2 as well as Cp2ZrBu2 (Negishi
reagent) under ethylene gas were found to be very useful
reagents but the regiochemistry for each alkyne is controlled
by the nature of the substituents. With a trimethylsilyl-substituted
acetylene (R1 or R3 ) SiMe3, R2 or R4 ) alkyl), the trimeth-
ylsilyl groups are placed in R-positions of zirconacyclopenta-
dienes with excellent selectivity.14 With a phenyl-substituted
alkyne (R1 or R3 ) C6H5, R2 or R4 ) alkyl), regioselective
reactions are usually observed, although in some cases a mixture
of two isomers may be formed. However, if two π-compounds
are similar in chemical properties such as in 2-pentyne (R1 or
R3 ) Me, R2 or R4 ) Et), nonselective cyclization should be
expected in the formation of the corresponding zirconacyclo-
pentadiene 4 and therefore nonselective formation of metalated
diene 5 will result (Scheme 2).
Indeed, even if 4 is obtained regiospecifically, the preparation
of stereodefined metalated dienyl zirconocenes requires a
stereospecific reaction of only one carbon-zirconium bond
(either C(R1)-Zr or C(R3)-Zr) of 4 with electrophiles (Scheme
2, path A). Consequently, only very few examples were reported
for the stereoselective reaction of unsymmetrical zirconacyclo-
pentadienes with electrophiles and they are all related to starting
materials in which the nature of R1 and R3 are very different
such as 2,3-diphenyl 4,5 dialkylzirconacyclopentadienes (R1 and
R2 ) alkyl, R3 and R4 ) phenyl).15 Ethenylzirconation reaction
has been also reported by combination of Cp2ZrEt2 with vinyl
ethers (Scheme 2, path B). In such a case, the elimination of
the alkoxy group in the zirconacyclopentene intermediate 6
generates the dienyl system 5.16 However, although with
symmetrical internal alkynes such as 5-decyne and diphenyl-
acetylene, vinylzirconation products were obtained with a good
isomeric purity, unsymmetrical alkynes such as 1-propynyl
benzene (R1 ) Ph, R2 ) Me) gave a mixture of isomers in an
81:19 ratio.
Scheme 4. Transformation of 2-Silyloxy-1,3-diene into
1-Methylene-2-propenylzirconium Derivatives
chloride 8 is performed at low temperature, the expected product
9 is obtained in moderate yield and isomeric ratio.18 However,
the deprotonations and insertion of (E,E)-4-alkyl-1-chloro-1,3-
butadiene 10 with alkylzirconocene chloride followed by
hydrolysis gave the nonterminal diene with high yield and
stereoselectivity (Scheme 3).
The same methodology was recently used for the geminal
dimetalation of alkylidene carbenoids with silylboranes and
diborons.19
Finally, Jan Szymoniak and co-workers have reported that
2-silyloxy-1,3-diene reacts with zirconocene Cp2Zr(1-butene)
to give 1-methylene-2-propenylzirconium compounds which
have been used as 2-dienylation reagents by addition of several
electrophiles (Scheme 4).20
The impressive results summarized above are perhaps the
most compelling examples of the power of zirconocene com-
pounds in organic synthesis but in a general sense, are also
illustrative for the serious limitations of the methodologies for
the stereoselective preparation of dienyl zirconocene derivatives:
(1) R1 and R2 as well as R3 and R4 in 4 have to be of different
electronic nature (Scheme 2, path A)
(2) Only unsubstituted terminal double bond can be prepared
by using the strategy described in Scheme 2, path B (6 to 5)
(11) (a) Negishi, E.; Takahashi, T. Bull. Chem. Soc. Jpn. 1998, 71, 755; (b)
Negishi, E.; Takahashi, T. Acc. Chem. Res. 1994, 27, 124.
(12) Titanium and Zirconium in Organic Synthesis; Marek, I., Ed; Wiley-
VCH: Weinheim, Germany 2002
(13) (a) Watt, G. W.; Drummond, F. O. Jr. J. Am. Chem. Soc. 1970, 92, 826;
(b) Negishi E.; Cederbaum, F. E.; Takahashi, T. Tetrahedron Lett. 1986,
27, 2829; (c) Takahashi, T.; Kageyama, M.; Denisov, V.; Hara, R.; Negishi,
E. Tetrahedron Lett. 1993, 34, 687; (d) Xi, Z.; Hara, R.; Takahashi, T. J.
Org. Chem. 1995, 60, 4444; (e) Buchwald, S. L.; Watson, B. T.; Huffman,
J. C. J. Am. Chem. Soc. 1987, 109, 2544; (f) Rosenthal, U.; Ohff, A.;
Michalik, M.; Gorls, H.; Burlakov, V. V.; Shur, V. B. Angew. Chem., Int.
Ed. Engl. 1993, 32, 1193; (g) Nitschke, J. R.; Zurcher, S.; Tilley, T. D. J.
Am. Chem. Soc. 2000, 122, 10 345.
(14) Buchwald, S. L.; Nielsen, R. B. J. Am. Chem. Soc. 1989, 111, 2870.
(15) Ubayama, H.; Xi, Z.; Takahashi, T. Chem. Lett. 1998, 517.
(16) Takahashi, T.; Kondakov, D. Y.; Xi, Z.; Suzuki, N. J. Am. Chem. Soc.
1995, 117, 5871.
(17) Kasatkin, A.; Whitby, R. J. Tetrahedron Lett. 1997, 38, 4857.
(18) Kasatkin, A.; Whitby, R. J. J. Am. Chem. Soc. 1999, 121, 7039.
Hydrozirconation of alkynes followed by insertion of 1-halo-
1-lithio-alkenes, generated in situ by lithium tetramethylpiperi-
dide deprotonations of vinyl halides, affords dienyl zirconocene
species, which may be further functionalized.17 When the
insertion of the carbenoid derived from the deprotonation of
(E)-1-chloro-2-methyl-1-octene 7 into (E)-1-hexenylzirconocene
9
J. AM. CHEM. SOC. VOL. 125, NO. 43, 2003 13259

A R T I C L E S
Chinkov et al.
Scheme 5. Isomerization Reaction of Dienes (path A) Combined
with the Preparation of Vinylic Organometallic Derivatives (path B)
as a New Source of Metalated Dienyl Zirconocenes Complexes
(path C)
Table 1. Preparation of Isomerically Pure Dienes and Trienes
1
2
3
entry
comp
R
R
R
n
conditiona
E−X
pdts yieldb(%)
1
2
3
4
5
6
7
8
9
20a-Z
20a-Z
20a-Z
20a-Z
20a-Z
20a-Z
20a-Z
20a-E
20b
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
0
0
0
0
0
0
0
0
1
2
5
0
5
A
B
C
A
B
A
A
A
A
A
A
A
A
H3O+
H3O+
H3O+
24
24
24
25
26
27
80
80
80
75
60
60
70
72
70
71
70
80
61
H
H
H
H
H
H
H
H
H
H
c
I2
NBSc
NCS
AllylCld 28
AllylCld 28
AllylCld 29
AllylCld 30
10 20c
11 20d
12 20e
13 20f
H3O+
31
AllylCld 29
H3O+
32
CH3
Hex
a Condition A: THF, 15 min, +50 °C; condition B: Et2O, 30 min, +35
°C; condition C: toluene, 15 min, +65 °C. bIsolated yield after purification
(3) Problems of stereoselectivity arise when unstable car-
benoids have to be used (except in the methodology leading to
11, Scheme 3)
(4) Stereoselectivity of the reaction could not be addressed
in the preparation of 1-methylene-2-propenylzirconium (Scheme
4).
c
by chromatography on silica gel. Iodo- and bromodiene are unstable at
d
room temperature and isomerized with time. Obtained after a transmeta-
lation step with 10 mol % of CuCl•2 LiCl.
with different unsaturated alkyl halides to give 20a-j as reported
by Normant and Alexakis (Scheme 6).28
On the other hand, the transition metal catalyzed isomerization
of terminal olefins into internal olefins has been extensively
studied and in general a mixture of 1-alkenes, (E)- and (Z)-2-
alkenes, reflecting the thermodynamic equilibrium, is obtained.21
Some low-valent titanocene derivatives are highly effective and
stereoselective in favor of the (E)-2-isomer.22 When noncon-
jugated dienes such as 12 containing one or two substituted vinyl
groups are treated with the zirconocene 13 (easily prepared from
commercially available Cp2ZrCl2 and 2 equivalents of n-BuLi
and called Negishi reagent),11 a regioisomerization of the less-
substituted double bond can occur and lead to the formation of
the conjugated diene-zirconocene complexes 14 (Scheme 5, path
A).23 As we have recently developed a new and straightforward
stereoselective preparation of vinylic organometallic derivatives
16 from heterosubstituted alkenes 15 such as vinyl enol ethers,24
silyl enol ether,24 vinyl (alkyl or aryl) sulfides, vinyl sulfoxides
and even vinyl sulfones,25 in a one-pot procedure (Scheme 5,
path B), we though that the combination of the isomerization
process with the elimination reaction would lead to an efficient
preparation of stereodefined metalated zirconocene complexes
18 from simple unsaturated enol ether 17 (Scheme 5, path C).
Indeed, all of these heterosubstituted alkenes 1526 smoothly react
with the same Negishi reagent (1-butene)ZrCp2 13 that was used
for the isomerization reaction of 12.
Originally, 20a was treated with (1-butene)ZrCp2 13 in THF
at room temperature and the evolution of the reaction was
followed by gas chromatography of hydrolyzed aliquots and
by 1H NMR of the reaction after hydrolysis. This examination
indicated that the starting material was consumed within 12 h
with concomitant formation of several products including the
expected diene 24 as the major product (with a maximum 60%
yield after hydrolysis, Scheme 7).
1
The H spectrum of 23a in C6D6/Et2O solution showed two
singlet peaks at 6.59 and 5.8 ppm assigned to the Zr-CH(sp2)
moiety and to the Cp protons respectively and a multiplet at
6.3 and 5.8 ppm for the hydrogens of the nonmetalated double
bond. Its 13C NMR spectrum revealed one singlet at 173.4 and
110 ppm which were assigned to the Zr-C(sp2) moiety and
Cp respectively and two more sp2 carbons at 138.2 and 120.3
ppm.
On the other hand, when 20a was treated with 13 either in
THF at +50 °C for 15 min (condition A, Table 1), in Et2O at
+35 °C for 30 min (condition B, Table 1) or in toluene at +65
°C for 15 min (condition C, Table 1), the corresponding diene
was constantly obtained with a yield of 80% (Scheme 7 and
Table 1, entries 1 to 3).
Interestingly, only in the experiments that have been done at
room temperature, the addition product 22 as well as dimers of
21 were detected and were attributed to the putative intermediate
21 (Scheme 7). Then, this zirconacycle intermediate disappears
in favor of the dienyl zirconocene complex, likely via the
formation of (alkene)zirconocene 23 through a skeletal rear-
Results and Discussion
All of our starting materials were very easily prepared in a
single-pot operation by treatment of the alkoxy-allene27 19 with
lithium organocuprate and trapping the resulting alkenyl copper
Scheme 6. Preparation of Nonconjugated Enol Ether 20a-j
9
13260 J. AM. CHEM. SOC. VOL. 125, NO. 43, 2003

Dienyl Zirconocene Complexes
A R T I C L E S
Scheme 7. Tandem Isomerization-Elimination Sequence for the Preparation of Dienyl Zirconocenes Derivatives
rangement29 and then isomerization to lead to 24. These results
support an associative mechanism involving the intermediary
formation of monocyclic zirconacyclopentane. When the reac-
tion is performed at higher temperature (reflux of solvent), the
equilibrium between 21 and 23 is very rapidly displaced in favor
of 23, which can cleanly undergo the isomerization process.
The last experimental condition will be further generally used
for the preparation of dienyl zirconocenes30 (see scope of the
reaction in Table 1).
of differential Nuclear Overhauser effect spectra. When the same
reaction was performed on the opposite isomer of the enol ether,
namely the E-isomer (easily obtained from the carbocupration
of alkoxy-allene but in THF as solvent instead of Et2O, Scheme
6),28 the same (E,Z)-dienylmetal was obtained as determined
by the stereochemistry of the resulting product after reaction
with allyl chloride (entry 8, Table 1). So, whatever the
stereochemistry of the starting enol ether, a unique isomer of
the dienyl zirconocene is obtained at the end of the process.
Further on, a mixture of E,Z-isomers will be used as starting
ω-ene-enol ether 20a-h. The formation of dienyl zirconocenes
is not limited to those dienes with a one-carbon tether (Table
1, entries 9 to11). Surprisingly, 20b-d (with 2, 3 and 6 carbons
tether respectively) also underwent this tandem reaction as fast
as 20a (only 15 min at +50 °C in THF) and in good overall
yields. When the migrating double bond is 1,2-disubstituted such
as in 20e (Table 1, entry 12), our tandem sequence of
isomerization-elimination still proceeds very efficiently and after
transmetalation of the resulting dienyl zirconocene with copper
salt, the allylation reaction gave the (E,Z)-triene 29 as unique
isomer in 80% isolated yield. By combination of a long tether
chain (6 carbons) with a 1,2-disubstituted olefin as in 20f, diene
32 was isolated in 61% yield.
However, when the double bond is 1,1-disubstituted or if an
alkyl group is located in the carbon tether such as in 20g and
20h respectively (Scheme 6), the reaction proceeds only in very
low yield (<10%). The limitation of this new methodology
could be attributed to an unfavorable initial ligand exchange
between (1-butene)ZrCp2 13 and the migrating olefin for steric
reason but also to the formation of a hypothetically less stable
trisubstituted zirconacyclopropane, 33 or 34 which should be
obtained after the first migration of the double bond (Figure
1). To overcome these limitations, the more bulky bis(trimeth-
ylsilyl)acetylene complex of zirconium 35 (Rosenthal’s com-
plex),32 which has recently offered a number of compelling
advantages in synthesis,33 was tested in our reaction with 20g
with the hope that the release of the bulky bis(trimethylsilyl)-
acetylene, after the ligand exchange, will be enough to drive
The presence of a discrete organometallic species as well as
the stereochemistry of the metalated diene were first checked
by iodinolysis and bromolysis (entries 4 and 5, Table 1) but
the corresponding iodo and bromo dienes 25 and 26 were found
to be unstable and rapidly isomerized to a mixture of (E) and
(Z)-isomers. Thus, to have a better picture of the stereochemical
outcome of the process, we treated the crude reaction mixture
with N-chlorosuccinimide (Table 1, entry 6) and the corre-
sponding chloro diene 27 was isolated in 60% yield with a
isomeric ratio >98/2. As alternative solution, we have also
determined the stereochemistry of the reaction by addition of
allyl chloride, in the presence of a catalytic amount of copper
salt, to the dienyl zirconocene derivative (Table 1, entry 7).31
28 was obtained in good overall yield with an isomeric ratio
greater than 98/2 in all cases. The (E,Z) stereochemistry of the
5-pentyl-octa-1, (4Z), (6E)-triene 28 was deduced on the basis
(19) Kurahashi, Hata, T.; Masai, H.; Kitagawa, H.; Shimizu, M.; Hiyama, T.
Tetrahedron 2002, 58, 6381.
(20) Ganchegui, B.; Bertus, P.; Szymoniak, J. Synlett 2001, 123.
(21) (a) Tolman, C. A. J. Am. Chem. Soc. 1972, 94, 2994 (b) Bingham, D.;
Hudson, B.; Webster, B. D. E.; Wells, P. B. J. Chem. Soc., Dalton Trans.,
1974, 1521 (c) Bingham, D.; Webster, D. E.; Wells, P. B. J. Chem. Soc.,
Dalton Trans. 1974, 1514.
(22) Akita, M.; Yasuda, H.; Nagasuna, K.; Nakamura A. Bull. Chem. Soc. Jpn.
1983, 56, 554.
(23) (a) Swanson, D. R.; Negishi, E. Organometallics 1991, 10, 825; (b) Maye,
J. P.; Negishi, E. Tetrahedron Lett. 1993, 34, 3359; (c) Negishi, E.; Maye,
J. P.; Choueiry, D. Tetrahedron 1995, 51, 4447.
(24) Liard, A.; Marek, I. J. Org. Chem. 2000, 65, 7218.
(25) Farhat, S.; Marek, I. Angew. Chem., Int. Ed. Engl. 2002, 41, 1410.
(26) (a) Liard, A.; Chechik, H.; Farhat, S.; Morlender-Vais, N.; Averbuj, C.;
Marek, I. J. Organomet. Chem. 2001, 624, 26; (b) Chinkov, N.; Chechik,
H.; Majumdar, S.; Marek, I. Synthesis 2002, 2473.
(27) Brandsma, L. Synthesis of Acetylenes, Allenes and Cumulenes; Elsevier:
Amsterdam, 1981.
(28) Alexakis, A.; Normant, J. F. Isr. J. Chem. 1984, 24, 113.
(29) Takahashi, T.; Fujimori, T.; Seki, T.; Saburi, M.; Uchida, Y.; Rousset, C.
J.; Negishi, E. J. Chem. Soc. Chem. Commun. 1990, 182.
(30) Chinkov, N.; Majumdar, S.; Marek, I. J. Am. Chem. Soc. 2002, 124, 10 282.
(31) (a) Wipf, P.; Jahn, H. Tetrahedron 1996, 52, 12 853; (b) Takahashi, T.;
Kotora, M.; Kasai, K.; Suzuki, N. Tetrahedron Lett. 1994, 35, 5685.
9
J. AM. CHEM. SOC. VOL. 125, NO. 43, 2003 13261

A R T I C L E S
Chinkov et al.
Scheme 8. Mechanistic Hypothesis for the Tandem C-H Bond Allylic Activation-Elimination Sequence
dideutero diene 39 was obtained in 62% isolated yield. The
examination of the 1H and 13C NMR indicates that, indeed, the
two deuterium atoms are now located at the vinylic and allylic
positions and led us to suggest the following mechanism for
the C-H bond allylic activation (isomerization)-elimination
reaction (Scheme 8).
(1-butene)ZrCp2 13 reacts first with the remote double bond
of 20j to give the corresponding zirconacyclopropane 39a and
free butene. Then, via a C-H bond allylic activation,34 the η3-
allyl intermediate 39b is generated as transient species and after
hydrogen insertion; the new zirconacyclopropane 39c is formed.
By the same sequence, namely C-D bond allylic activation with
deuterium migration (39c to η3-allyl 39d and then deuterium
insertion), the zirconacyclopropane 39e is produced. As soon
as 39e is formed, an irreversible step occurs transforming the
zirconacyclopropane 39e into zirconacyclopentene 39f, which
undergoes a â-elimination reaction to lead to 39g and then 39
after hydrolysis. On the basis of this mechanism, we can easily
understand that the stereochemistry of the starting enol ether
has no effect on the stereochemistry of the dienyl zirconocene;
the carbon-heteroatom bond of the metalated center in 39f can
freely epimerize to give the most stable isomer. Such an
isomerization could be caused by an interaction between the
ether moiety and the zirconium atom, which would weaken the
C1-Zr bond and facilitate the isomerization.35 In the particular
experiment described in Scheme 8, we did not see any
scrambling of deuterium atoms along the carbon skeleton and
this can be explained by the initial position of the two deuterium
atoms. Indeed, in this C-D bond allylic activation step, as soon
as the intermediate 39e is formed, an irreversible rearrangement-
elimination reaction (39e to 39g) occurs and therefore drives
the reaction toward the metalated diene 39g. However, when
the two-deuterium atoms are located in a different place in the
tether, a scrambling of deuterium is observed along this tether.
Figure 1. Limitation of the tandem isomerization-elimination sequence.
the reaction to completion. Unfortunately, no isomerization-
elimination was observed. Therefore, the precursor of a poten-
tially more stable trisubstituted zirconacyclopropane 20i was
prepared and submitted to the isomerization-elimination se-
quence. After hydrolysis, three products 36/Z-37/E-37 were
obtained in a 2.3/3/1 ratio respectively; Thus, when the migrating
1,1-disubstituted double bond is slightly activated toward the
formation of the zirconacyclopropane, the expected diene (beside
the direct transformation of the methoxy enol ether into 36 after
hydrolysis), could be formed but in this case, as a mixture of
two geometrical isomers.
To have more insight on the reaction mechanism and on the
stereochemical outcome of the reaction, we have performed the
following two experiments: First, we have checked that the
reaction of trisubstituted enol ether such as 38 did not lead to
the vinylic organometallic derivative24 (Figure 1) indicating that
this tandem reaction should occur first by the isomerization of
the remote double bond (only in the case of 20i, the direct
transformation of methoxy-enol ether into organometallic
derivative was detected, most probably due to a template effect
between the zirconocene 13 and the nonmigrating double bond);
then, we have studied this isomerization reaction with deuterium
labeling. Therefore, the dideutero enol ether 20j was easily
prepared by reaction of the alkoxy-allene 19 with dibutylcuprate
followed by addition of the electrophile CH3CH2CHdCHCH2-
CD2I, itself obtained by reduction of ethyl trans-3-hexenoate
with LiAlD4 and transformation of the primary alcohol into
iodide. When 20j was treated with 1.3 equivalent of (1-butene)-
ZrCp2 13 in THF for 15 min at +50 °C, the corresponding 3,5-
The unique stereochemistry of the diene is therefore resulting
from the elimination step and not from a further isomerization
of the dienyl zirconocene with zirconocene derivatives (i.e., Cp2-
(32) Rosenthal, U.; Burlakov, V. V. In Organometallic Chemistry of Titanocene
and Zirconocene Complexes with Bis(trimethylsilyl)acetylene as the basis
for Applications in Organic Synthesis in Titanium and Zirconium in Organic
Synthesis; Marek, I., Ed; Wiley-VCH: Weinheim, Germany 2002, 355.
(33) Nitschke, J. R.; Zurcher, S.; Tilley, D. T. J. Am. Chem. Soc. 2000, 122,
10 345.
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Dienyl Zirconocene Complexes
A R T I C L E S
Scheme 9. Stereoselective Preparation of (2E, 4Z)-Decadiene
Zr-catalyzed stilbene stereoisomerization)36 since the hydrozir-
conation reaction of several 1E-ene-3-yne and 1Z-ene-3-yne
derivatives with Cp2ZrH(Cl) lead only to the (E,E)- and (Z,E)-
isomers respectively in good yields.37
Scheme 10. Preparation of Acyclic 2-Arylsulfonyl 1,3-Dienes
In this new tandem allylic C-H bond activation followed
by an elimination reaction, substituted 1-zircono-1Z,3E-dienes
(zirconium moiety at the terminal position of the dienyl system)
were easily prepared. With the idea to extend this methodology
to the stereoselective synthesis of 3-zircono-1,3-diene (zirconium
moiety at the internal position of the dienyl system), we have
prepared and investigated the reactivity of 40 with (1-butene)-
ZrCp2 13 (40 was obtained by carbocupration of the R-allyl
alkoxy-allene).38 When 40 was submitted to the tandem reaction,
the diene 41 was isolated after hydrolysis as a unique (E,Z)-
isomer in 75% isolated yield (Scheme 9).
Treatment of 42b-c with 1.5 equiv of (1-butene)ZrCp2 at
room temperature leads only to the Z-isomers 45 and 46
whatever the stereochemistry of the starting dienyl sulfones (i.e.,
E-42d and Z-42d, Scheme 11). Even the unstable Z-isomer 44
was preferentially formed from 42b in this process with an
excellent Z/E ratio of 95/5. The low yield obtained for 45 is
attributed to the volatility of the resulting diene.
When the migrating group is geminated to the leaving group
such as in 40, the C-H bond allylic activation leads to 41a,
which subsequently undergoes now a â-elimination reaction to
lead to the â-metalated allenyl intermediate 41b. Then, 41b is
isomerized into its more stable dienyl form 41c39 in which the
alkyl and the organometallic groups are anti to each other for
steric reason. After hydrolysis, a unique isomer is observed
(determined by NOE effects). Although this tandem reaction
led also to the expected diene as unique isomer in good chemical
yield, this methodology had a serious drawback from a
preparative point of view because 40 could not be purified by
column chromatography. Indeed, each time that we have tried
to purify 40, the ketone resulting from the hydrolysis of the
enol ether moiety was obtained (enol ether from ketone is much
less stable toward purification than enol ether from aldehyde).
The isolated yield obtained for 41 is therefore based on the crude
starting material 40 used without purification. This very
promising route for the preparation of metalated diene such as
41c associated with the problem of stability of R-substituted
enol ether 40 led us to consider an alternative starting material.
We consequently turned our attention to the preparation of
sulfonyl 1,3-dienyls derivatives.40 As for the enol ether meth-
odology, the main advantage of this approach is the very easy
preparation of acyclic 2-arylsulfonyl 1,3-dienes 42a-d from
allylic sulfones and aldehydes in a single-pot operation as
described in Scheme 10.41
By analogy with the mechanistic pathway described for the
enol ether 40 (Scheme 9), we believe that the transformation
of 42a-c also occurs via the formation of the â-metalated
allenyl intermediate generated from the â-elimination of the
corresponding zirconacyclopropane and subsequent rearrange-
ment. However, the direct transformation of the vinyl sulfone
moieties into dienyl zirconocenes without intervention of the
terminal unsubstituted double bond cannot be ruled out at this
stage,25,26 particularly that when the more substituted dienyl
sulfone 42e (Scheme 11) was similarly treated with (1-butene)-
ZrCp2, a mixture of 3 isomers of undetermined geometry was
obtained after hydrolysis.
To further increase the scope of the reaction, transmetalation
of dienyl zirconium complexes such as 44Zr into the corre-
sponding dienyl organometallic derivatives was performed. To
our surprise, when 44Zr was transmetalated to copper deriva-
tives by addition of CuCl‚2LiCl for 1h at +45 °C, a complete
isomerization of the dienyl system was found; that is, trans-
44Zr is transmetalated into cis-44Cu, and then after hydrolysis,
only the E-isomer of 44 is formed in 70% yield (Table 2). When
heating the dienyl zirconocene 44Zr at +50 °C, with or without
added LiCl, no isomerization of the diene was detected.
As nothing is known on the exact nature of organocopper
coming from organozirconocene derivatives, we must await
further investigations to elucidate completely the mechanism
of this transmetalation, but this isomerization was found to be
general for all the examined cases (Table 2, 44-47Zr). It should
be noted that even when a secondary alkyl group is present on
the dienyl system as in 46Zr (Table 2, entry 3), the E-isomer
is the major isomer after the transmetalation step in a ratio of
86/14 (which implies that before hydrolysis, the copper is cis
(34) (a) Resconi, L. J. Mol. Cata. 1999, 146, 167; (b) Cohen, S. A.; Auburn, P.
R.; Bercaw, J. E. J. Am. Chem. Soc. 1983, 105, 1136.
(35) (a) Mintz, E. A.; Ward, A. S.; Tice, D. S. Organometallics 1985, 4, 1308
(b) Ward, A. S.; Mintz, E. A.; Kramer, M. P. Organometallics 1988, 7, 8.
(36) Takahashi, T.; Swanson, D. R.; Negishi, E. Chem. Lett. 1987, 623.
(37) Fryzuk, M. D.; Bates, G. S.; Stone, C. Tetrahedron Lett. 1986, 27, 1537.
(38) Clinet, J. C.; Linstrumelle, G. Tetrahedron Lett. 1978, 1137.
(39) Rozema, M. J.; Knochel, P. Tetrahedron Lett. 1991, 32, 1855.
9
J. AM. CHEM. SOC. VOL. 125, NO. 43, 2003 13263

A R T I C L E S
Chinkov et al.
Scheme 11. Preparation of Dienyl Zirconocenes from Conjugated Dienyl Sulfones
Table 2. Isomerization during the Transmetalation Reaction into
Scheme 12. Reactivity of the Dienyl Copper Derivatives
Dienyl Copper Derivatives
1
2
entry
compds
R
R
products
E,E/Z,E ratio
yielda(%)
1
2
3
4
trans-44Zr Ph
H
H
H
44
45
46
47
>99/1
80/20
86/14
92/8
73
48b
71
60
trans-45Zr C5H11
trans-46Zr c-C6H11
47Zrc
Ph
CH3
a
Yields of pure products after purification by chromatography on silica
gel blow yield attributed to the volatility of 45 c47Zr is a mixture of three
geometrical isomers.
to the secondary alkyl group). Moreover, from the three
geometrical isomers of 47Zr (Table 2, entry 4), this transmeta-
lation-isomerization led mainly to the E,E- isomer 47 after
hydrolysis (E,E/Z,E: 92/8).
(i) H3O+, (ii) allyl chloride, (iii) NBS, (iv)1-iodo-1-hexyne, 5% Pd-
(PPh3)4, (v) 4-iodotoluene, Pd(PPh3)4, (vi) methyl vinyl ketone, TMSCl,
(vii) cyclohexenone, TMSCl.
The synthetic use of this isomerization was also investigated
by reaction of the resulting dienyl copper derivatives with
several different electrophiles as described in Scheme 12.
44Cu reacts via an SN2′ process with allyl chloride to give a
unique E-isomer of the triene 48 and the geometrical mixture
of 45 and 46Cu gave, under the same experimental conditions,
the two allylated products with the E-isomer as major product
(it should be emphasized that although the transmetalation-
isomerization occurs at +50 °C, the reactivity of the organo-
copper remains intact in this process). The addition of methyl
vinyl ketone or cyclohexenone in the presence of TMSCl42 led
to the 1,4 adducts 52 and 53 in 75 and 59% yield respectively
as unique geometrical isomers. The palladium cross-coupling
reaction of 44Cu with alkynyl iodide and aryl iodide opens new
routes to further functionalization between two sp2 and sp2-sp
units as described for the preparation of 50 and 51.
In conclusion, we have reported a very easy and straightfor-
ward preparation of several metalated dienyl derivatives as
unique geometrical isomers in only two chemical steps from
commercially available or very accessible starting materials. This
new methodology is based on a tandem allylic C-H bond
activation-elimination sequence. Moreover, when the organo-
metallic derivative is vinylic as well as allylic such as in 44-
47Zr, an unexpected reversal of the stereochemistry has been
found during the zirconium to copper transmetalation step.
Acknowledgment. This work is dedicated to Yitzhak Apeloig
in honor of his 60th birthday. This research was supported by
the Israel Science Foundation administrated by the Israel
Academy of Science and Humanities (79/01-1) and by the Fund
for the promotion of Research at the Technion.
Supporting Information Available: Experimental procedures
and spectra data of all compounds are available (93 pages, print/
PDF). This material is available free of charge via the Internet
at http://pubs.acs.org
(40) Backvall, J.-E.; Chinchilla, R.; Najera, C.; Yus, M. Chem. ReV. 1998, 98,
2291.
(41) Cuvigny, T.; Herve du Penhoat, C.; Julia, M. Tetrahedron 1986, 42, 5329.
(42) (a) Nakamura, E.; Kuwajima, I. J. Am. Chem. Soc. 1984, 106, 3368; (b)
Corey, E. J.; Boaz, N. W. Tetrahedron Lett. 1985, 26, 6015; (c) Alexakis,
A.; Berlan, J. Besace, Y. Tetrahedron Lett. 1986, 27, 2143.
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13264 J. AM. CHEM. SOC. VOL. 125, NO. 43, 2003