Nickel-BINAP catalyzed enantioselective α-arylation of α-substituted γ-butyrolactones

Article abstract of DOI:10.1021/ja017545t

A Ni(0)-BINAP system is utilized for the highly enantioselective α-arylation of α-substituted γ-butyrolactones with aryl chlorides and bromides. α-Quaternization is achieved in moderate to excellent yields. Furthermore, the rate accelerating effect caused by the addition of Zn(II) salts is investigated. Copyright

Full text of DOI:10.1021/ja017545t

Published on Web 03/14/2002
Nickel-BINAP Catalyzed Enantioselective r-Arylation of r-Substituted
γ-Butyrolactones
Dirk J. Spielvogel and Stephen L. Buchwald*
Department of Chemistry, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139
Received November 14, 2001
Scheme 1 R-Arylation of R-Substituted γ-Butyrolactones
Recently, the Pd-catalyzed R-arylation of ketones and related
compounds has received a great deal of attention. A number of
Pd(0)-based systems have been reported that are useful for intra-
and intermolecular versions of this process.1 The enantioselective
construction of quaternary centers by R-arylation/vinylation meth-
odology has also been detailed.1c,2
Herein, we disclose that a Ni(0)-BINAP system can be used
for the highly enantioselective R-arylation of R-substituted γ-bu-
tyrolactones with aryl chlorides and bromides. We also report an
accelerating effect caused by the addition of zinc(II) salts. Initial
experiments, using conditions similar to those employed in Pd(0)-
based procedures,2a focused on the coupling of R-methyl-γ-buty-
rolactone 1a and 2-bromonaphthalene with NaOt-Bu as base.
Unfortunately, this protocol resulted primarily in reduction of the
aryl bromide. Upon changing the base from NaOt-Bu to NaHMDS,
the efficient formation of product was realized. After some
experimentation, we found that the Pd-catalyzed arylation proceeded
with moderate yield and enantioselectivity. Substitution of Pd(0)
with Ni(0) proved to be instrumental for the production of highly
enantiomerically enriched products.3 Thus, using 5 mol % Ni[(S)-
BINAP](COD), prepared in situ from Ni(COD)2, provided the
arylation products with high ee values, albeit in low yields (Table
1, entries 1 and 3). The increase in enantioselectivity may be due
to a greater stereochemical communication between ligand and
substrate(s) that results from the smaller Ni-center. Aryl chlorides
can be utilized with comparable reaction rates, less reduction, and
minimally lower enantioselectivities compared to aryl bromides
(entry 4); no anisole is detected in the reactions to yield (-)-3 (entry
4). Furthermore, at low conversions (-)-3 is formed quantitatively.
Attempts to accelerate the reaction by increasing the quantity of
catalyst to 10 mol % were marginally successful (entry 5).
To facilitate the experimental procedure we envisioned the in
situ zinc reduction of (BINAP)NiBr2. To probe the effect of the
salt that would be formed, 15 mol % of ZnBr2 was added as a
THF solution to the reaction mixture as previously prepared (entry
4). Pleasingly, a dramatic increase in both the rate of the reaction
and the isolated yield of the product was observed (entries 2 and
6).
Scheme 2. Palladium-Catalyzed R-Arylation of 1a
Table 1. Nickel-Catalyzed R-Arylation of 1aa
With this method, a variety of electron-rich and electron-poor
aryl halides with meta or para substituents can be successfully
coupled with excellent enantioselectivities (90-97%). The yields
differ due to the extent of reduction of the aryl halide. The reaction
conditions allow for the presence of ethyl esters and silyl ethers
(Table 1, entries 10 and 13). Unfortunately, ortho-substituted aryl
halides gave none of the desired product.
To determine the absolute stereochemistry of (-)-2, we sought
to convert the lactone by treatment with 4-iodoaniline to the cor-
responding anilide. Surprisingly, reaction under Weinreb’s condi-
tions yielded lactam (-)-11.4 X-ray analysis of (-)-11 revealed
a Conditions: 5 mol % of Ni(COD)2, 8.5 mol % of (S)-BINAP, 2 equiv
of 1a, 2.3 equiv of NaHMDS, 15 mol % of ZnBr2, 1 equiv of ArX (0.25
mmol), 0.75 mL of toluene, 0.25 mL of THF, 17-20 h, 60 °C. b Isolated
yield. c Determined by HPLC. d GC yield. e 0 mol % of ZnBr2, 1 mL of
toluene. f 10 mol % of Ni(COD)2, 17 mol % of (S)-BINAP. g 80 °C. h 1
mmol of ArCl, 2 mmol of 1a, 2 mmol of NaHMDS.
the absolute stereochemistry to be (S) as shown in Scheme 3.5
Notably, the sense of induction observed with the Ni(S)-(BINAP)
* Address correspondence to this author. E-mail: sbuchwal@mit.edu.
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10.1021/ja017545t CCC: $22.00 © 2002 American Chemical Society

C O M M U N I C A T I O N S
Scheme 3. Determination of Absolute Stereochemistry
ploying 1 equiv of the Na-enolate of 1a provide similar yields as
reactions with 2 equiv of Na-enolate to which 1 equiv of ZnBr2
was added.
To further examine the scope of the enantioselective lactone aryl-
ation, the reactions with R-benzyl- (1b), R-allyl- (1c), and R-propyl-
γ-butyrolactone (1d) were investigated. The arylation of 1b-d
proceeded with good enantioselectivities (83-96%). The system
is, however, sensitive to the size of the R-substituent. Thus, longer
reaction times or higher reaction temperatures were necessary with
1b-c, resulting in lower yields (Table 2, entries 2, 3, and 5). The
terminal olefin moiety of 1c also lends itself to side reaction(s),
thus decreasing the isolated yield of the desired product (entries
4-6).12
a Conditions: 10 mol % of Ni(COD)2, 17 mol % of (S)-BINAP, 2 equiv
of lactone, 2.3 equiv of NaHMDS, 15 mol % of ZnBr2, 1 equiv of ArCl
(0.25 mmol), 0.75 mL of toluene, 0.25 mL of THF, 17-20 h. b Isolated
yield. c Determined by HPLC. d GC yield. e 5 mol % of Ni(COD)2, 8.5
mol % of (S)-BINAP. f 0.5 mmol of 1c, 0.575 mmol of NaHMDS, 0.75
mmol of ArCl.
Chart 1. Influence of Zn(II) Stoichiometrya
In summary, the application of a Ni(BINAP) system for the
R-arylation of R-substituted γ-butyrolactones has been described.
Coupled with an accelerating effect of Zn(II) salts, R-quaternization
is achieved with high enantioselectivities and moderate to excellent
yields. Future work will focus on expanding the scope of this
enantioselective arylation system. Elucidation of the exact role of
Zn(II) as well as investigations into the stereochemical comple-
mentarity of Pd(S)-BINAP and Ni(S)-BINAP are in progress.
a Conditions: 5 mol % Ni(COD)2, 8.5 mol % (S)-BINAP, 2 equiv of
1a, 2.3 equiv of NaHMDS, ZnBr2, 1 equiv of 3-chloroanisole (0.25 mmol),
0.75 mL of toluene, 0.25 mL of THF, 3 h, 60 °C.
Table 2. Nickel-Catalyzed R-Arylation of 1b, 1c, and 1da
Acknowledgment. We thank the National Institute of Health
(GM 46059) for support of this work. We are grateful for continuing
support of our programs from Pfizer, Merck and Bristol-Myers
Squibb. We thank Dr. Gregory Hughes for helpful discussions.
D.J.S. thanks the German Academic Exchange Service (DAAD)
for a postdoctoral fellowship.
Supporting Information Available: Experimental procedures and
characterization data for all unknown compounds (PDF). This material
is available free of charge via the Internet at http://pubs.acs.org.
References
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L13. For recent reviews on the enantioselective construction of quarternary
centers see: (d) Trost, B. M.; Lee, C. In Catalytic Asymmetric Synthesis;
Ojima, I., Ed.; Wiley & Sons: New York, 2000; Chapter 8E. (e) Donde,
Y.; Overman, L. E. In Catalytic Asymmetric Synthesis; Ojima, I., Ed.;
Wiley & Sons: New York, 2000; Chapter 8G. (f) Corey, E. J.; Guzman-
Perez, A. Angew. Chem., Int. Ed. Engl. 1998, 37, 388-401.
(3) Ni(0)-mediated R-arylations have been detailed: (a) Cristau, H. J.; Vogel,
R.; Taillefer, M.; Gadras, A. Tetrahedron Lett. 2000, 41, 8457-8460.
(b) Semmelhack, M. F.; Chong, B. P.; Stauffer, R. D.; Chong, A.; Jones,
L. D. J. Am. Chem. Soc. 1975, 97, 2507-2516.
(4) (a) Basha. A.; Lipton, M.; Weinreb, S. M. Tetrahedron Lett. 1977, 48,
4171-4174. (b) For a similar lactone-to-lactam conversion see: Takano,
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(5) Configurations of (-)-3-(-)-13 are assigned by analogy to (-)-(S)-2.
(6) For Chart 2 see Supporting Information.
(7) Greenwood, N. N.; Earnshaw, A. Chemistry of the Elements; Pergamon
Press: New York, 1984; Chapter 29.
system in the formation of 2 and 3 was opposite to that observed
with Pd(S)-(BINAP) (see Scheme 2 and Table 1, entries 1 and 3).
To gain further insight into the accelerating effect of ZnBr2 in
the reaction of 1a with 3-chloroanisole, the process was examined
with use of different Zn(II) salts6 and with varying concentrations
of ZnBr2 (see Chart 1). Comparable accelerating effects are
observed with ZnBr2, ZnCl2, Zn(OTf)2, and Zn(Ot-Bu)2. Strongly
ionic (ZnF2)7 and more covalent (ZnI2)7 additives show no
influence.8 The enantioselectivity is independent of the zinc(II) salt
employed. Variation of the [ZnBr2] reveals an accelerating effect
at catalytic quantities (5-30 mol %) and an inhibiting effect at
stoichiometric quantities (>120 mol %).
(8) The use of THF as a cosolvent is necessary to observe the ZnBr2-based
rate acceleration. Both ZnF2 and Zn(OTf)2 show poor solubility in THF
and toluene. Addition of 15 mol % ZnBr2 to the Pd-catalyzed reaction of
1a with 3-bromoanisole (2.5 mol % Pd2(dba)3, 9 mol % (S)-BINAP) also
leads to an improved yield ((+)-3: y ) 58%, ee ) 54%).
On the basis of these results and those described by others,9 it
seems reasonable that ZnBr2 acts as a Lewis acid that facilitates
bromide abstraction from (BINAP)Ni(Ar)(Br) to form a cationic
[(BINAP)Ni(Ar)]+ species that subsequently undergoes transmeta-
lation more rapidly. The inhibition observed with stoichiometric
Zn(II) may be due to the formation of a less reactive zinc eno-
late.10,11 This is in agreement with the finding that reactions em-
(9) Majumdar, K. K.; Cheng, C.-H. Org. Lett. 2000, 15, 2295-2298.
(10) Rathke, M. W.; Weipert, P. Compr. Org. Synth. 1991, 2, Chapter 1.8.
(11) Ni(0)-catalyzed C-C bond formation utilizing organozincs: (a) Lipschutz,
B. H.; Blomgren, P. A.; Kim, S.-K. Tetrahedron Lett. 1999, 40, 197-
200. (b) Fauvarque, J. F.; Jutand, A. J. Organomet. Chem. 1979, 177,
273-281.
(12) 1H NMR and mass spectra analysis of the crude reaction mixture suggest
the formation of small amounts of Heck reaction products.
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