Zr-Catalyzed Electrophilic Carbomagnesation of Aryl Olefins. Mechanism-Based Control of Zr-Mg Ligand Exchange

Article abstract of DOI:10.1021/ol0160607

(Formula Presented) The first examples of efficient electrophilic Zr-catalyzed carbomagnesations are disclosed, where in contrast to previous catalytic carbomagnesations the alkyl moiety of the electrophile is transferred (vs that of the Grignard reagent)

Full text of DOI:10.1021/ol0160607

ORGANIC
LETTERS
2001
Vol. 3, No. 13
2097-2100
Zr-Catalyzed Electrophilic
Carbomagnesation of Aryl Olefins.
Mechanism-Based Control of Zr−Mg
Ligand Exchange
Judith de Armas and Amir H. Hoveyda*
Department of Chemistry, Merkert Chemistry Center, Boston College,
Chestnut Hill, Massachusetts 02467
amir.hoVeyda@bc.edu
Received May 2, 2001
ABSTRACT
The first examples of efficient electrophilic Zr-catalyzed carbomagnesations are disclosed, where in contrast to previous catalytic
carbomagnesations the alkyl moiety of the electrophile is transferred (vs that of the Grignard reagent). The identity of the Grignard reagent
is manipulated so that Zr−Mg exchange is facilitated, leading to the formation of alkylmagnesium halide products.
Design and study of efficient and selective catalytic alky-
lation of unactivated olefins is an important objective in
organic synthesis.1 Past research in these laboratories has
led to the development of Zr-catalyzed carbomagnesation
of terminal and cyclic disubstituted allylic alcohols and
ethers.2 Despite the demonstrated utility of catalytic carbo-
magnesation in stereoselective synthesis,1e a number of
limitations still remain.3 A notable shortcoming is that alkyl
Grignard reagents other than ethylmagnesium halides are less
efficient or fail to participate in catalytic carbomagnesation.4
To address this problem, we recently initiated an investiga-
tion regarding Zr-catalyzed olefin alkylations, where various
electrophiles (e.g., alkyl tosylates and bromides) are used in
the presence of a Grignard reagent and 5-10 mol % of Cp2-
ZrCl2 (see i f ix, Scheme 1).5
There are two significant factors that distinguish the two
alkylation pathways: (i) In catalytic ethylmagnesation (i f
W, Scheme 1), the Et group of the Grignard reagent is
transferred,6 whereas in the more recent variant (i f ix),
the alkyl moiety of the electrophile is incorporated within
the product structure. (ii) Whereas the earlier transformations
(1) For representative examples, see: (a) Dzhemilev, U. M.; Vostrikova,
O. S. J. Organomet. Chem. 1985, 285, 43-51. (b) Yanagisawa, A.; Habaue,
S.; Yamamoto, H. J. Am. Chem. Soc. 1989, 111, 366-368. (c) Tsukada,
N.; Sato, T.; Inoue, Y. Chem. Commun. 2001, 237-238. (d) Liepins, V.;
Backvall, J. E. Chem. Commun. 2001, 265-266. For reviews on metal-
catalyzed enantioselective alkylation of olefins and applications to total
synthesis, see: (e) Hoveyda, A. H.; Heron, N. M. In ComprehensiVe
Asymmetric Catalysis; Jacobsen, E. N., Pfaltz, A., Yamamoto, H., Eds.;
Springer-Verlag: Berlin, 1999; pp 431-454. (f) Marek, I. J. Chem. Soc.,
Perkin Trans 1 1999, 535-544.
(2) Zr-catalyzed diastereoselective alkylations: (a) Hoveyda, A. H.; Xu,
Z. J. Am. Chem. Soc. 1991, 113, 5079-5080. (b) Morken, J. P.; Hoveyda,
A. H. J. Org. Chem. 1993, 58, 4237-4244. (c) Hoveyda, A. H.; Morken,
J. P.; Houri, A. F.; Xu, Z. J. Am. Chem. Soc. 1992, 114, 6692-6697. (d)
Houri, A. F.; Didiuk, M. T.; Xu, Z.; Horan, N. R.; Hoveyda, A. H. J. Am.
Chem. Soc. 1993, 115, 6614-6624.
(3) For previous studies from these laboratories that address this issue,
see: (a) Didiuk, M. T.; Morken, J. P.; Hoveyda, A. H. J. Am. Chem. Soc.
1995, 117, 7273-7274. (b) Heron, N. M.; Adams, J. A.; Hoveyda, A. H.
J. Am. Chem. Soc. 1997, 119, 6205-6206. (c) Gomez-Bengoa, E.; Heron,
N. M.; Didiuk, M. T.; Luchaco, C. A.; Hoveyda, A. H. J. Am. Chem. Soc.
1998, 120, 7649-7650. (d) Adams, J. A.; Heron, N. M.; Koss, A. M.;
Hoveyda, A. H. J. Org. Chem. 1999, 64, 854-860.
(4) Didiuk, M. T.; Johannes, C. W.; Morken, J. P.; Hoveyda, A. H. J.
Am. Chem. Soc. 1995, 117, 7097-7104.
(5) (a) de Armas, J.; Kolis, S. P.; Hoveyda, A. H. J. Am. Chem. Soc.
2000, 122, 5977-5983. For related studies, see: (b) Terao, J.; Watanabe,
T.; Saito, K.; Kambe, N.; Sonoda, N. Tetrahedron Lett. 1998, 39, 9201-
9204.
10.1021/ol0160607 CCC: $20.00 © 2001 American Chemical Society
Published on Web 06/06/2001

Scheme 1. Two Different Methods for Zr-Catalyzed
Scheme 2. â-H Abstraction of Dialkylzirconiums versus
Zr-Mg Ligand Exchange through Zirconates
Alkylation of Olefins
reasons: (1) In contrast to dialkylZr Wiii, zirconate xi does
not possess a vacant d orbital required for â-H abstraction.
(2) Previous studies2c,d suggest that the formation of carbo-
magnesation product xiii likely involves Zr-Mg ligand
exchange through zirconate xi. Accordingly, we surmised
that formation of carbomagnesation product xiii can be
facilitated through increasing the amount of available zir-
conate. This objective may be accomplished in the following
ways: (1) A more nucleophilic alkylmagnesium reagent may
shift the dialkylZr/zirconate equilibrium toward the latter.
(2) Solvents of higher polarity (e.g., THF vs Et2O) may favor
the formation of the more polar zirconate xi. (3) The
alkylmagnesium halide reagent may be selected so that â-H
abstraction is sterically less favored (discourage pathway
involving x, Scheme 2). This proposal is based on mecha-
nistic studies regarding the rates of â-H abstraction of
dialkylzirconocenes, where the following relative reactivity
of alkyl groups as â-H donors has been established: â-CH3
≈ â-CH2Ar > â-CH2 > â-CH.7
proceed through zirconacyclopentanes (ii and iii, Scheme 1),6
the more recent processes likely involve regioselective
alkylation of the electron-rich zirconate Wii by the electro-
phile. In catalytic ethylmagnesation, metallacycle intermedi-
ate iii undergoes site-selective Zr-Mg exchange followed
by â-H abstraction to afford an alkylmagnesium halide
product (W). Dialkylzirconocene Wiii from alkylation of
zirconate Wii undergoes a â-H abstraction as well; however,
in this case, hydrocarbon ix is generated.
The above mechanistic rationales led us to carry out the
Zr-catalyzed alkylations shown in Table 1, where styrene
(1a) and n-C8H17OTs are used as substrate and electrophile,
respectively. As illustrated in entry 1, under previously
reported conditions5a (n-BuMgCl, 55 °C, THF), 2a is formed
only as the minor constituent of the product mixture (10%);
the major product (90%) is 3a, derived from the â-H
abstraction pathway shown in Scheme 2 (Wiii f ix). With
the less polar Et2O as solvent, <2% 2a is observed (entry
2). As predicted above, the amount of the desired product
(2a) is increased significantly when the more nucleophilic
n-Bu2Mg is employed in THF (entry 3; 62% 2a in the
product mixture vs 10% with n-BuMgCl). As depicted in
entry 4, a less favorable ratio of 2a:3a is obtained at 22 °C.
The data in entries 5-6 show that the use of Et2O as the
reaction medium delivers <2% of 2a.
More recently, we set out to develop a new class of Zr-
catalyzed electrophilic alkylations that deliver alkylmagne-
sium halide products. Such a transformation could carry the
advantages of both forms of catalytic alkylation: a wide
range of alkyl moieties (not just Et) could be added to
alkenes, affording readily functionalizable alkylmagnesium
products. Herein, we report the first examples of Zr-catalyzed
electrophilic olefin carbomagnesations. Various aryl olefins
undergo facile carbometalation in the presence of 5-10 mol
% of Cp2ZrCl2, an alkyl electrophile and a Grignard reagent.
As illustrated in Scheme 2, to favor the formation of a
carbomagnesation (vs hydrocarbon) product (xiii), reaction
conditions must be chosen so that the formation of dialkyl-
zirconate xi is preferred (vs dialkylZr Wiii). This is for two
(6) (a) References 1a-d. (b) Takahashi, T.; Seki, T.; Nitto, Y.; Saburi,
M.; Rousset, C. J.; Negishi, E. J. Am. Chem. Soc. 1991, 113, 6266-6268.
(c) Knight, K. S.; Waymouth, R. M. J. Am. Chem. Soc. 1991, 113, 6268-
6270. (d) Lewis, D. P.; Muller, P. M.; Whitby, R. J.; Jones, R. V. H.
Tetrahedron Lett. 1991, 32, 6797-6800.
(7) (a) Buchwald, S. L.; Nielsen, R. B. J. Am. Chem. Soc. 1988, 110,
3171-3175. (b) Negishi, E.; Nguyen, T.; Maye, J. P.; Choueiri, D.; Suzuki,
N.; Takahashi, T. Chem. Lett. 1992, 2367-2370.
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Org. Lett., Vol. 3, No. 13, 2001

Scheme 3
Table 1. Zr-Catalyzed Electrophilic Carbomagnesation of
Styrenea
tion involving the benzylic H2 does not appear to be a
competitive pathway when n-BuMgCl or n-Bu2Mg is used
(entries 1-6), with the sterically demanding Grignard
reagents in entries 8-10, 14-28% of 4a is generated via
zirconacyclopropane 8 (see below for further discussion
regarding formation of styrenyl alkylation products).
As illustrated in Table 2, electron-rich styrenes 1b-c
undergo catalytic electrophilic carbomagnesation with levels
Table 2. Effect of Aryl Substituents on the Efficiency of
Zr-Catalyzed Electrophilic Carbomagnesationa
To improve the efficiency of the electrophilic carbomag-
nesation, we began to modify the structure of the Grignard
reagent so as to discourage the competitive â-H process. We
reasoned that if â-H abstraction were to involve a sterically
more hindered CH bond (vs the CH2 group in n-BuMg
reagents), lower amounts of 3a would be generated. As
shown in entry 7, when i-BuMgBr is used, <2% reaction
takes place. This is presumably because the sterically
hindered alkylmetal inhibits formation of the reactive zir-
conate intermediate (see Wii, Scheme 1). However, with
i-amylMgBr as the alkylating agent (entry 8), 2a becomes
the major component of the product mixture (67%) and only
5% 3a is generated. Nonetheless, another minor product in
the reaction of entry 8 is alkene 4a (28%). Use of (i-
amyl)2Mg improves selectivity in favor of 2a (72% vs 67%;
compare entries 9 and 8). Finally, the most efficient
conditions for the formation of carbomagnesation adduct 2a
are shown in entry 10; in the presence of 2 equiv of
2-cyclohexylethylmagnesium bromide the product mixture
contains 81% 2a, 5% 3a, and 14% 4a.
of selectivity similar to that of styrene (1a). The slightly
higher selectivity in the reaction of 1c is likely due to the
steric inhibition imposed in the course of benzylic â-H
abstraction that would lead to 4c (<2% formed, see entry
2). The exclusive formation of 4d in the reaction of electron-
deficient 1d is consistent with the mechanistic work of
Buchwald;7a accumulation of electron density at the benzylic
carbon during â-H abstraction (to afford 4d) is favored by
the para electron-withdrawing group.
Several additional issues regarding the data in entries 8-10
merit mention. (1) As shown in Scheme 3, with i-amylMgBr
as the Grignard reagent (entry 8), even though â-H abstrac-
tion involves a methylene CH2 (see H1 in 5, Scheme 3), the
steric influence of the terminal dimethyl unit significantly
diminishes formation of 3a (5%). (2) Although â-H abstrac-
As shown in Table 3, Zr-catalyzed electrophilic carbo-
magnesation may be carried out with a variety of alkyl
tosylates (electrophile 1) and the resulting alkylmagnesium
Org. Lett., Vol. 3, No. 13, 2001
2099

amounts of the styrenyl adduct 4. With secondary alkyl
tosylates, however, the carbomagnesation product (13 or 14)
is formed exclusively (<2% hydrocarbon or styrene byprod-
Table 3. Sequential Zr-Catalyzed Reaction of Styrene with
Two Different Electrophilesa
1
uct observed by 400 MHz H NMR analysis). Such high
product selectivity is probably due to the steric repulsion
involved in â-H abstraction at the benzylic site caused by
the larger alkyl substituent (isopropyl or cyclohexyl vs
n-alkyl). With the sterically more demanding alkyl tosylates,
10 mol % of catalyst loading is required for appreciable
yields; when the reaction in entry 5 is effected with 5 mol
% of Cp2ZrCl2, 13 is formed in 48% isolated yield (vs 73%).9
In summary, we disclose a potentially useful Zr-catalyzed
electrophilic olefin alkylation that delivers functionalized
alkylmagnesium halide products. Since the resulting carbo-
magnesation product can be treated with a range of electro-
philes, the present protocol provides a new catalytic method
for regioselective bisfunctionalization of aryl olefins. The
products obtained in this study can be accessed by alternative
methods; the mechanistic principles established herein may
however be employed in the development of a catalytic
alternative for C-C bond formation by a fundamentally new
disconnection which also has the potential to be enantio-
selective. Future studies are directed at catalytic carbo-
magnesation of nonaryl olefins, utilization of other classes
of electrophiles, and the development of the corresponding
enantioselective variants.
Acknowledgment. This research was supported by the
NIH (GM-47480).
Supporting Information Available: Experimental pro-
cedures and spectral and analytical data for all reaction
products. This material is available free of charge via the
Internet at http//:www.acs.pubs.org.
OL0160607
(8) In situ oxidation of the addition product to afford ketone 12 finds
precedence in previous reports regarding the catalytic activity of Zr alkoxides
(with secondary alcohols). See: Krohn, K. Synthesis 1997, 1115-1127 and
references therein.
(9) The rate of transmetalation is sensitive to the zirconocene/Grignard
reagent ratio. When the amount of zirconocene is increased without using
an additional amount of the alkylmetal, lower yields of carbomagnesation
product are obtained.
halide product can be treated with a subsequent electrophile
(electrophile 2).8 In cases where a primary alkyl tosylate is
used (entries 1-4), the reaction mixture contains varying
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Org. Lett., Vol. 3, No. 13, 2001