Olefins turned alkylating agents: Diastereoselective intramolecular Zr-catalyzed olefin alkylations

Article abstract of DOI:10.1021/ol017090c

(Equation Presented) 62% yield; 12 : 1 syn : anti The first examples of intramolecular Zr-catalyzed electrophilic alkylation of aryl olefins are disclosed. Substituted carbo-and heterocycles are prepared efficiently and diastereoselectively.

Full text of DOI:10.1021/ol017090c

ORGANIC
LETTERS
2002
Vol. 4, No. 3
395-398
Olefins Turned Alkylating Agents:
Diastereoselective Intramolecular
Zr-Catalyzed Olefin Alkylations
Richard R. Cesati III, Judith de Armas, and Amir H. Hoveyda*
Department of Chemistry, Merkert Chemistry Center, Boston College,
Chestnut Hill, Massachusetts 02467
amir.hoVeyda@bc.edu
Received November 21, 2001
ABSTRACT
The first examples of intramolecular Zr-catalyzed electrophilic alkylation of aryl olefins are disclosed. Substituted carbo- and heterocycles are
prepared efficiently and diastereoselectively.
During the past several years, research in these laboratories
has involved the design and development of various catalytic
regio- and stereoselective protocols for alkylations of ole-
fins.1,2 Investigations in connection to reactions of activated
alkenes, such as R,â-unsaturated enones,3 allylic acetals,4 or
phosphates,5 have benefited from precedence regarding
fundamental reactivity. In contrast, studies on transformations
of unactivated olefins1 typically require identification of less
appreciated reactivity profiles. We have thus been able to
develop efficient and highly selective Zr-catalyzed intermo-
lecular alkylations of allylic and homoallylic alcohols and
ethers, where reactions proceed via metalacyclopentane
intermediates. However, various limitations, such as the
inability of Grignard reagents other than ethylmagnesium
halides to undergo efficient addition,6 have led us to seek
alternative and more general strategies for catalytic alkyla-
tions of unactivated alkenes.7 We have accordingly been
involved in the development of Zr-catalyzed electrophilic
olefin alkylations. These processes effect net coupling of an
olefin and common electrophiles such as alkyl halides and
tosylates (Scheme 1).8,9 In these catalytic electrophilic
(1) For selected examples of diastereoselective Zr-catalyzed olefin
alkylations, see: (a) Hoveyda, A. H.; Xu, Z. J. Am. Chem. Soc. 1991, 113,
5079-5080. (b) Hoveyda, A. H.; Morken, J. P.; Houri, A. F.; Xu, Z. J.
Am. Chem. Soc. 1992, 114, 6692-6697. (c) Houri, A. F.; Didiuk, M. T.;
Xu, Z.; Horan, N. R.; Hoveyda, A. H. J. Am. Chem. Soc. 1993, 115, 6614-
6624. For selected examples of Zr-catalyzed enantioselective olefin alky-
lations, see: (d) Morken, J. P.; Didiuk, M. T.; Hoveyda, A. H. J. Am. Chem.
Soc. 1993, 115, 6697-6698. (e) Morken, J. P.; Didiuk, M. T.; Visser, M.
S.; Hoveyda, A. H. J. Am. Chem. Soc. 1994, 116, 3123-3124. (f) Visser,
M. S.; Heron, N. M.; Didiuk, M. T.; Sagal, J. F.; Hoveyda, A. H. J. Am.
Chem. Soc. 1996, 118, 4291-4298. (g) Harrity, J. P. A.; La, D. S.; Cefalo,
D. R.; Visser, M. S.; Hoveyda, A. H. J. Am. Chem. Soc. 1998, 120, 2343-
2351. (h) Adams, J. A.; Heron, N. M.; Koss, A. M.; Hoveyda, A. H. J.
Org. Chem. 1999, 64, 854-860.
(2) For reviews on stereoselective alkylations of olefins, see: (a)
Hoveyda, A. H.; Heron, N. M. In ComprehensiVe Asymmetric Catalysis;
Jacobsen, E. N., Pfaltz, A., Yamamoto, H., Eds.; Springer: Berlin, 1999;
pp 431-454. (b) Marek, I. J. Chem. Soc., Perkin Trans. 1 1999, 535-544.
(3) Degrado, S. J.; Mizutani, H.; Hoveyda, A. H. J. Am. Chem. Soc.
2001, 123, 755-756. (b) Mizutani, H.; Degrado, S. J.; Hoveyda, A. H. J.
Am. Chem. Soc. In press.
(5) Luchaco-Cullis, C. A.; Mizutani, H.; Murphy, K. E.; Hoveyda, A.
H. Angew. Chem., Int. Ed. 2001, 40, 1456-1460.
(6) Didiuk, M. T.; Johannes, C. W.; Morken, J. P.; Hoveyda, A. H. J.
Am. Chem. Soc. 1995, 117, 7097-7104.
(7) For efficient and enantioselective Zr-catalyzed additions of various
alkylaluminum reagents to unactivated alkenes, see: (a) Kondakov, D. Y.;
Negishi, E. J. Am. Chem. Soc. 1995, 117, 10771-10772. (b) Kondakov,
D. Y.; Negishi, E. J. Am. Chem. Soc. 1996, 118, 1577-1578. (c) Kondakov,
D. Y.; Wang, S.; Negishi, E. Tetrahedron Lett. 1996, 37, 3803-3806. (d)
Wipf, P.; Ribe, S. Org. Lett. 2000, 2, 1713-1716. (e) Wipf, P.; Ribe, S.
Org. Lett. 2001, 3, 1503-1505.
(4) Gomez-Bengoa, E.; Heron, N. M.; Didiuk, M. T.; Luchaco, C. A.;
Hoveyda, A. H. J. Am. Chem. Soc. 1998, 120, 7649-7650.
10.1021/ol017090c CCC: $22.00 © 2002 American Chemical Society
Published on Web 01/08/2002

disclosed. These catalytic C-C bond-forming reactions are
efficient and provide a new route for the stereoselective
synthesis of a range of polycyclic structures.
Scheme 1
As illustrated in entry 1 of Table 1, treatment of unsatur-
ated tosylate 2 with 5 mol % of Cp2ZrCl2 (1) and 5 equiv of
EtMgCl (55 °C, THF) leads to the formation of carbocycle
3 in 70% isolated yield. The catalytic C-C bond formation
can be used to synthesize six-membered carbo- and hetero-
cycles as well. Zr-catalyzed conversion of unsaturated
tosylates 4 and 6 (entries 2-3, Table 1) under identical
conditions affords bicycle 5 and chromane 7 in 87% and
60% isolated yields, respectively. Unsaturated chromene 8
is readily converted to 9 by the Zr-catalyzed process, a
transformation that may be viewed as an intramolecular
electrophilic allylic substitution.10
Table 1. Zr-Catalyzed Intramolecular Electrophilic Alkylation
of Aromatic Olefinsa
alkylations, the C-C π system is rendered highly nucleo-
philic through association with the transition metal catalyst
(cf. i, Scheme 1). It is thus the alkyl group of the electrophile
that becomes incorporated within the product structure (vs
the alkyl group of the Grignard reagent); the role of the
Grignard reagent is only to generate a potent nucleophile in
the form of a reactive zirconate (cf. i, Scheme 1). To enhance
the synthetic utility of the catalytic electrophilic alkylations,
we recently introduced protocols that afford the more
versatile alkylmagnesium products (R1 ) MgCl in iii,
Scheme 1) instead of the corresponding branched alkanes
(R1 ) H in iii, Scheme 1);8b these studies were guided by
various key mechanistic data.
a Conditions: 5 mol % of Cp2ZrCl2 (1), 5 equiv of EtMgCl, THF, 55
°C, 3.5 h (entries 1-3); 5 mol % of 1, 2 equiv of n-BuMgCl, THF, 55 °C,
14 h (entry 4). b g95% conv in all cases, determined by analysis of 1H
NMR spectra of unpurified product mixtures. Isolated yields after silica
gel chromatography.
A potential advantage of the Zr-catalyzed electrophilic
alkylation is that it may be carried out in an intramolecular
manner (formation of W via iW, Scheme 1). This strategy
would provide a unique catalytic pathway for the synthesis
of carbo- and heterocyclic structures. Moreover, the enhanced
structural organization inherent in intramolecular reactions
may allow for effective relay of asymmetry. We now report
the first examples of Zr-catalyzed intramolecular electrophilic
alkylations of aryl olefins; the first diastereoselective ex-
amples of this new catalytic alkylation process are also
Several issues regarding the data shown in Table 1 merit
mention: (1) In the absence of catalyst, none of the tosylates
undergo any form of alkylation (<2% by 1H NMR analysis).
(2) Reactions with the corresponding bromides can lead
to the formation of uncatalyzed alkylation products. Thus,
subjection of 10, the corresponding bromide of 2, to the
above conditions but in the absence of 1, leads to the
formation of 3 (60% conversion); with bromide 11 (cf. 6,
entry 3, Table 1), only ∼15% conversion to 7 is observed.11
(8) (a) de Armas, J.; Kolis, S. P.; Hoveyda, A. H. J. Am. Chem.
Soc. 2000, 122, 5977-5983. (b) de Armas, J.; Hoveyda, A. H. Org. Lett.
2001, 3, 2097-2100. For a related report, see: (c) Terao, J.; Watanabe,
T.; Saito, K.; Kambe, N.; Sonoda, N. Tetrahedron Lett. 1998, 39,
9201-9204.
(9) For a recent report on Rh-catalyzed allylation of styrenes, see:
Tsukada, N.; Sato, T.; Inoue, Y. Chem. Commun. 2001, 237-238.
(3) Although alkyl bromides undergo uncatalyzed ring
closures, these reactions are noticeably faster in the presence
396
Org. Lett., Vol. 4, No. 3, 2002

of 5 mol % of 1. For example, whereas reaction of bromide
11 proceeds to 50% conversion within 3.5 h without catalyst,
with 5 mol % of 1, >95% conversion is observed within
the same period of time.
Table 2. Diastereoselective Intramolecular Electrophilic
Alkylation of Aromatic Olefinsa
(4) Depending on the substrate, varying amounts of minor
1
byproducts are generated (400 MHz H NMR analysis).
These byproducts are represented by 1212 and 1313 for the
catalytic reaction of 2 (entry 1, Table 1). Thus, 20% of 12
and 10% of 13 are also formed in the catalytic alkylation of
2. In the intramolecular alkylation of 6, <2% of the
derived exocyclic olefin is observed, but the unpurified
reaction mixture contains 8% of the product correspond-
ing to 13 (entry 3, Table 1). No detectable levels of by-
products are formed in reactions of 4 and 8 (entries 2 and 4,
Table 1).
Next, we began our examination of diastereoselective Zr-
catalyzed intramolecular alkylations. As illustrated in entry
1 of Table 2, treatment of secondary tosylate 15 with 5 mol
% of 1 in the presence of 5 equiV of n-BuMgCl leads to the
formation of 16 in 68% isolated yield with excellent
diastereoselectiVity (>25:1).14 Although catalytic closure of
17 (entry 3) is facile, indane 18 is obtained with lower
stereocontrol (7:1). To improve stereochemical induction, we
utilized the sterically more demanding rac-(ebthi)ZrCl2 (14)
as the catalyst.15,16 As depicted in entry 4, this modification
led to the formation of 18 in 68% yield and >25:1
diastereoselectivity. Although the use of 14 as the catalyst
leads to high yield and stereoselectivity with 15 as well (entry
2), this strategy does not provide a solution to the lack of
stereoselection observed in the otherwise efficient formation
of tetrahydronaphthalene 20 (entries 5-6). As illustrated in
entries 7-8, similar results are obtained with tosylate 21,
a Conditions: indicated mol % of Cp2ZrCl2 (1) or rac-(ebthi)ZrCl2 (14),
5 equiv of n-BuMgCl, THF, 55 °C, 3.5 h for 1, 14 h for 14. b Determined
1
by GLC (CD-GTA column) and H NMR analysis. c Isolated yields after
silica gel chromatography. For entries 1-4, the yield also includes 20-
25% of the corresponding olefinic product (cf. 12); <10% of related products
observed in entries 5-14. d Reaction performed with EtMgCl.
(10) Reaction of 8 is carried out in the presence of n-BuMgCl, since
use of EtMgCl leads to the formation of substantial amounts of unidentified
products. In other cases, either of the two Grignard reagents may be used
with similar efficiency.
(11) The major product (∼50%) is phenol i, formed presumably by
generation of the magnesium halide of 11 followed by a â-alkoxide
elimination.
regardless of the catalyst used. It should however be noted
that reaction of tosylate 21 (entry 7) can be carried out in
the presence of EtMgCl (vs n-BuMgCl) without generating
any detectable amount of the intermolecular ethylmagnesa-
tion product (<2%).1a
(12) Exocyclic alkenes such as 12 are formed through â-hydride
abstraction involving the benzylic H through the dialkylzirconocene
intermediate. See refs 8a,b for details.
(13) The mechanism for the formation of compounds represented by 13
is not clear at the present time. This may involve catalytic ethylmagnesation
of the styrene olefin followed by intramolecular reaction of the resulting
benzylic magnesium halide with the neighboring tosylate or bromide.
(14) The stereochemical identity of 16 and 18 was established through
comparison with previously reported data. See: Troutman, M. V.; Apella,
D. H.; Buchwald, S. L. J. Am. Chem. Soc. 1999, 121, 4916-4917.
(15) Reactions are less efficient with lower catalyst loadings. As an
example, when 15 is treated with 5 mol % of 14 (THF, 55 °C, 14 h), 16 is
isolated in 52% yield.
The Zr-catalyzed alkylations shown in entries 9-14 of
Table 2 are synthetically significant, as they allow for
effective control of 1,4 relative stereochemistry. Reactions
proceed to completion in all cases, and levels of diastereo-
(16) For a review of the utility of chiral metallocenes in stereoselective
synthesis, see: Hoveyda, A. H.; Morken, J. P. Angew. Chem., Int. Ed. Engl.
1996, 35, 1263-1284.
Org. Lett., Vol. 4, No. 3, 2002
397

In conclusion, we have developed a unique method for
efficient formation of a range of aromatic carbo- and
heterocycles by stereoselective Zr-catalyzed electrophilic
alkylation of olefins. Reactions proceed effectively with Cp2-
ZrCl2 and (ebthi)ZrCl2 and provide excellent levels of
diastereoselectivity. Many of the products obtained by the
present method would be otherwise significantly more
difficult to accesssparticularly in a diastereoselective fash-
ion. Moreover, it is important to note that, as illustrated by
the example shown in eq 1, selection of an appropriate
Scheme 2a
a For clarity and ease of depiction, models corresponding to
different enantiomers are shown.
Grignard reagent (to favor Zr-Mg exchange vs â-hydride
abstraction)8b can lead to the formation of carbomagnesation
products in intramolecular alkylations, thus extending the
synthetic potential of these catalytic processes.19,20 The utility
of this class of C-C bond-forming reactions has not yet been
extended beyond non-aryl olefins. However, in terms of
application to the synthesis of biologically significant
molecules, it appears that it is the efficient and selective
alkylation of aryl alkenes that will be of notable signifi-
cance.21 Applications to total synthesis of medicinally
important agents and development of additional catalytic
olefin alkylations are in progress.
selectivity are improved when (ebthi)ZrCl2 (14) is utilized.17
The stereochemical identity of the major isomer (syn) has
been established through determination of the X-ray structure
of 28 (see Supporting Information).
Although detailed mechanistic studies regarding the in-
tramolecular Zr-catalyzed alkylations have not yet been
performed, models illustrated in Scheme 2 offer a plausible
rationale for the stereochemical outcomes in Table 2. It may
be suggested that, for the formation of five-membered ring
products shown in entries 1-4 of Table 2, mode of addition
I should be favored on steric grounds (vs II). A similar
argument can be made for the preference of III (vs IV) in
connection to transformations depicted in entries 9-14 of
Table 2. These models offer an explanation for the higher
degree of stereoselectivity in transformations promoted by
14; steric interactions with the chiral ligand are more severe
in II and IV. It is however difficult to explain why the
formation of six-membered rings in entries 5-8 of Table 2
is nonselective. It should also be noted that these models
assume that the intermediate zirconate is alkylated with
retention of stereochemistry. Although alkylmetals are typi-
cally shown to react with retention,18 there is as yet no
definitive experimental evidence to support this hypothesis
in regard to Zr-catalyzed electrophilic alkylations.
Acknowledgment. This research was supported by the
NIH (GM-47480-10); R.R.C. is grateful to the NIH for a
postdoctoral fellowship (GM-64151-01). We thank Steven
B. Garber and Jarred T. Blank for determination of the X-ray
structure of 28.
Supporting Information Available: Complete experi-
mental procedures and spectral and analytical data for all
reaction substrates and products. This material is available
free of charge via the Internet at http://pubs.acs.org.
OL017090C
(19) For examples where carbomagnesation products are reacted with
various electrophiles (other than oxygen), see ref 8b.
(20) Under conditions shown in eq 1, formation of carbomagnesation
products is less efficient with (ebthi)ZrCl2 (vs Cp2ZrCl2). Related studies
are in progress.
(21) For two representative examples, see: (a) Trost, B. M.; Toste, F.
D. J. Am. Chem. Soc. 1998, 120, 9074-9075. (b) Sato, K.; Yoshimura, T.;
Shindo, M.; Shishido, K. J. Org. Chem. 2001, 66, 309-314.
(17) Related studies with enantiomerically pure 14 are in progress.
(18) For examples of alkylation of alkylmetals with retention of
stereochemistry, see: (a) Jensen, F. R.; Nakamaye, K. L. J. Am. Chem.
Soc. 1966, 88, 3437-3438. (b) Hoffman, R. W.; Holzer, B. Chem. Commun.
2001, 491-492.
398
Org. Lett., Vol. 4, No. 3, 2002