Catalytic asymmetric γ-alkylation of carbonyl compounds via stereoconvergent suzuki cross-couplings

Article abstract of DOI:10.1021/ja2079515

With the aid of a chiral nickel catalyst, enantioselective γ- (and I-) alkylations of carbonyl compounds can be achieved through the coupling of γ-haloamides with alkylboranes. In addition to primary alkyl nucleophiles, for the first time for an asymmetric cross-coupling of an unactivated alkyl electrophile, an arylmetal, a boronate ester, and a secondary (cyclopropyl) alkylmetal compound are shown to couple with significant enantioselectivity. A mechanistic study indicates that cleavage of the carbon-halogen bond of the electrophile is irreversible under the conditions for asymmetric carbon-carbon bond formation.

Full text of DOI:10.1021/ja2079515

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Catalytic Asymmetric γ-Alkylation of Carbonyl Compounds via
Stereoconvergent Suzuki Cross-Couplings
Susan L. Zultanski and Gregory C. Fu*
Department of Chemistry, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, United States
S Supporting Information
b
obtained for a range of alkylÀalkyl Suzuki cross-couplings
(Table 1).6 Diphenylamides are attractive carboxylic acid
derivatives, since reduction and acyl transfer reactions proceed
smoothly (eqs 3À57).
ABSTRACT: With the aid of a chiral nickel catalyst,
enantioselective γ- (and δ-) alkylations of carbonyl com-
pounds can be achieved through the coupling of γ-halo-
amides with alkylboranes. In addition to primary alkyl
nucleophiles, for the first time for an asymmetric cross-
coupling of an unactivated alkyl electrophile, an arylmetal, a
boronate ester, and a secondary (cyclopropyl) alkylmetal
compound are shown to couple with significant enantio-
selectivity. A mechanistic study indicates that cleavage of the
carbonÀhalogen bond of the electrophile is irreversible
under the conditions for asymmetric carbonÀcarbon bond
formation.
n comparison with α- and β-alkylation reactions,1 the range of
I
useful methods for the catalytic enantioselective incorporation
of alkyl substituents γ to a carbonyl group is rather limited.2 One
unexplored approach to this objective is the asymmetric coupling of
a γ-halocarbonyl compound with an alkylmetal reagent (eq 1).3,4
As illustrated in Table 1, asymmetric γ-alkylations of a range of
unactivated racemic secondary γ-chloroamides can be achieved
with an array of alkylboranes, furnishing the alkylÀalkyl Suzuki
coupling products with good enantioselectivity. A wide variety of
functional groups are compatible with the reaction conditions,
including an acetal, silyl ether, aryl ether,8 indole, and aryl
To date, effective enantioselective cross-couplings of unacti-
vated alkyl electrophiles have been described only for secondary
homobenzylic bromides, acylated halohydrins (and one homo-
logue), and β-haloanilines; in each instance, a primary alkylmetal
reagent has served as the nucleophilic coupling partner.5 In this
report, we establish that a chiral nickel catalyst can achieve stereo-
convergent alkylation reactions of γ-halocarbonyl compounds
(eq 2), and we provide the first example of an asymmetric cross-
coupling of an unactivated alkyl electrophile with a secondary
(cyclopropyl) alkylmetal reagent.
fluoride.9 Both of the catalyst components (NiBr2 diglyme and
3
ligand 1) are commercially available.
With respect to the electrophile, the scope of these asym-
metric alkylations is not limited to cross-couplings of γ-chloro-
diphenylamides. Thus, the corresponding bromides are also
suitable electrophiles (eq 6; not optimized). Furthermore, under
the standard conditions, good ee was observed for the stereo-
convergent coupling of a homologue of a γ-chloroamide, thereby
achieving enantioselective δ-alkylation (eq 7).10 Finally, the
carbonyl group need not be a diphenylamide;11 for example,
the cross-coupling of a γ-chloro Weinreb amide12 proceeded
with promising ee, and a preliminary study provided evidence
In early studies, we determined that, when the carbonyl
Received: August 22, 2011
group is an N,N-diphenylamide, good ee’s and yields can be
Published: September 13, 2011
r
2011 American Chemical Society
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Journal of the American Chemical Society
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Table 1. Catalytic Enantioselective γ-Alkylation of N,
N-Diphenylamides via Stereoconvergent Suzuki Cross-
Couplings of Secondary Alkyl Chloridesa
Scheme 1. Outline of a Possible Reaction Pathwaya
a For the sake of simplicity, all of the elementary steps are drawn as
irreversible.
expansion in the scope of asymmetric cross-couplings of unac-
tivated alkyl electrophiles.
a For the reaction conditions, see eq 2. All data are averages of
two experiments. b Yields of purified products. c 20% NiBr2 diglyme
3
and 24% 1 were used. d The reaction was conducted in i-Pr2O at
60 °C.
that enhanced enantioselectivity should be possible through fur-
ther optimization (eq 8).
Our current working hypothesis regarding the pathway for
these Suzuki reactions is depicted in Scheme 1. This builds on
pioneering mechanistic studies of nickel/terpyridine-catalyzed
Negishi cross-couplings of unactivated alkyl halides by Vicic14a
and Phillips.14b Interestingly, the computational investigation by
Phillips suggests that the formation of B may be reversible for the
coupling of MeZnI and i-PrI, specifically, that ΔGq = 11 kcal/mol
for B f A and ΔGq = 13 kcal/mol for B f C.
To gain insight into whether the initial step of oxidative
addition (A f B) is reversible under our Suzuki cross-coupling
conditions, we monitored the reaction of each enantiomer of a
γ-haloamide and observed essentially no erosion in the ee of the
electrophile during the course of the reaction (eq 12). This is
consistent with the conclusion that halide abstraction (A f B) is
irreversible, in contrast to the results of Phillips' study of a Negishi
reaction.15,16
With respect to the nucleophilic coupling partner, previous
studies of asymmetric cross-couplings of unactivated secondary
electrophiles have focused exclusively on primary alkyl-(9-BBN)
derivatives.5 We obtained encouraging enantioselectivities when
a γ-chloroamide was coupled with an arylborane (eq 9), a
boronate ester (eq 10), or a secondary (cyclopropyl) alkylborane
(eq 11).13 These data illustrate the potential for an important
In conclusion, we have developed a method for the catalytic
enantioselective γ- (and δ-) alkylation of carbonyl compounds
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Journal of the American Chemical Society
COMMUNICATION
through the cross-coupling of γ-haloamides with alkylboranes.
With regard to the family of products that is generated, this study
differs from previous reports of asymmetric couplings of unac-
tivated secondary alkyl electrophiles, which furnished substituted
benzenes, protected alcohols, and anilines. Both alkyl chlorides
and alkyl bromides are suitable electrophilic cross-coupling
partners, and for the first time an arylmetal, a boronate ester,
and a secondary (cyclopropyl) alkylmetal compound are shown
to serve as nucleophilic partners and to couple with substantial
enantioselectivity. A mechanistic study indicates that carbonÀ
halogen bond cleavage is irreversible under the reaction condi-
tions. Further investigations of cross-couplings of alkyl electro-
philes are underway.
virtually constant. (e) For a substrate bearing a methyl group α to the
amide, one isomer of the product was observed when the “matched”
ligand was employed, and a 1.7:1 ratio of diastereomers was generated
when the “mismatched” ligand was used (substrate control). (f) In
addition to the desired cross-coupling, minor amounts of the electro-
phile undergo β-elimination and hydrodehalogenation.
(7) For zirconium-catalyzed transamidation, see: Stephenson, N. A.;
Zhu, J.; Gellman, S. H.; Stahl, S. S. J. Am. Chem. Soc. 2009, 131,
10003–10008.
(8) For leading references on nickel-catalyzed Suzuki reactions of
aryl alkyl ethers, see: Yu, D.-G.; Li, B.-J.; Shi, Z.-J. Acc. Chem. Res. 2010,
43, 1486–1495.
(9) For examples of nickel-catalyzed Suzuki reactions of aryl fluor-
ides (perfluorinated arenes), see: Schaub, T.; Backes, M.; Radius, U.
J. Am. Chem. Soc. 2006, 128, 15964–15965.
(10) Under the standard conditions (eq 2), a β-chloroamide is not a
suitable coupling partner because of its propensity to lose HCl and form
an α,β-unsaturated amide.
(11) Under the standard cross-coupling conditions (eq 2), a variety
of dialkyl and diarylamides cross-coupled with ee’s 1À15% lower than
those for the diphenylamide.
(12) For a review of the utility of Weinreb amides in organic
synthesis, see: Balasubramaniam, S.; Aidhen, I. S. Synthesis 2008,
3707–3738.
(13) On the other hand, (9-BBN)-cyclopentyl is not a suitable
substrate under these conditions.
(14) (a) Jones, G. D.; Martin, J. L.; McFarland, C.; Allen, O. R.; Hall,
R. E.; Haley, A. D.; Brandon, R. J.; Konovalova, T.; Desrochers, P. J.;
Pulay, P.; Vicic, D. A. J. Am. Chem. Soc. 2006, 128, 13175–13183. (b) Lin,
X.; Phillips, D. L. J. Org. Chem. 2008, 73, 3680–3688.
(15) An alternative but in our view less likely explanation is that
interconversion of A and B proceeds without erosion of the enantio-
meric excess of the electrophile.
(16) For related studies addressing the potential reversibility of
oxidative addition for nickel-catalyzed cross-couplings of activated alkyl
halides, see: (a) Suzuki reactions of α-haloamides (irreversible oxidative
addition): Lundin, P. M.; Fu, G. C. J. Am. Chem. Soc. 2010, 132,
11027–11029. (b) Negishi reactions of benzylic halides (computa-
tional study; reversible oxidative addition): Lin, X.; Sun, J.; Xi, Y.; Liu,
D. Organometallics 2011, 30, 3284–3292.
’ ASSOCIATED CONTENT
S
Supporting Information. Experimental procedures, com-
b
pound characterization data, and crystallographic data (CIF).
This material is available free of charge via the Internet at http://
pubs.acs.org.
’ AUTHOR INFORMATION
Corresponding Author
gcf@mit.edu
’ ACKNOWLEDGMENT
Support has been provided by the National Institutes of
Health (National Institute of General Medical Sciences, Grant
R01-GM62871), a Merck Summer Fellowship (S.L.Z.), and a
Robert T. Haslam Graduate Fellowship (S.L.Z.).
’ REFERENCES
(1) (a) For leading references on catalytic, enantioselective
α-alkylation reactions, see: MacMillan, D. W. C.; Watson, A. J. B.
α-Functionalization of Carbonyl Compounds. In Science of Synthesis; De
Vries, J. G., Molander, G. A., Evans, P. A., Eds.; Thieme: Stuttgart,
Germany, 2010; Vol. 3, pp 677À745. (b) For leading references on
catalytic enantioselective β-alkylation reactions, see: Nguyen, B. N.; Hii,
K. K.; Szymanski, W.; Janssen, D. B. Conjugate Addition Reactions. In
Science of Synthesis; De Vries, J. G., Molander, G. A., Evans, P. A., Eds.;
Thieme: Stuttgart, Germany, 2010; Vol. 1, pp 571À688.
(2) For a recent example, see: Smith, S. W.; Fu, G. C. J. Am. Chem.
Soc. 2009, 131, 14231–14233.
(3) For leading references on metal-catalyzed alkylÀalkyl cross-
couplings, see: Rudolph, A.; Lautens, M. Angew. Chem., Int. Ed. 2009,
48, 2656–2670.
(4) For leading references on enantioselective cross-couplings of
alkyl electrophiles, see: (a) Glorius, F. Angew. Chem., Int. Ed. 2008,
47, 8347–8349. (b) Owston, N. A.; Fu, G. C. J. Am. Chem. Soc. 2010,
132, 11908–11909.
(5) (a) Saito, B.; Fu, G. C. J. Am. Chem. Soc. 2008, 130, 6694–6695.
(b) Reference 4b. (c) Lu, Z.; Wilsily, A.; Fu, G. C. J. Am. Chem. Soc. 2011,
133, 8154–8157.
(6) Notes: (a) The catalytic enantioselective γ-alkylation illustrated
in entry 4 of Table 1 proceeded in 79% yield with 89% ee on a gram scale
(1.1 g of product). (b) The cross-coupling depicted in entry 3 of Table 1
proceeded in 57% yield with 89% ee when conducted with a lower
catalyst loading (5% NiBr2 diglyme/6% 1 on a 0.5 mmol scale).
3
(c) Under the standard conditions (eq 2), essentially no carbonÀcarbon
bond formation was observed in the absence of NiBr2 diglyme or ligand 1.
3
(d) During the course of a γ-alkylation, the unreacted electrophile
remains essentially racemic (<5% ee), and the ee of the product is
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