Catalytic asymmetric cross-couplings of racemic α-bromoketones with arylzinc reagents

Article abstract of DOI:10.1002/anie.200804888

(Chemical Equation Presented) Nickel box: The first catalytic asymmetric method for cross-coupling arylzinc reagents with α-bromoketones has been developed (see scheme). This stereoconvergent carbon-carbon bond-forming process occurs under unusually mild conditions and without activators, thereby allowing the generation of potentially labile tertiary stereocenters.

Full text of DOI:10.1002/anie.200804888

Communications
DOI: 10.1002/anie.200804888
Cross-Coupling
Catalytic Asymmetric Cross-Couplings of Racemic a-Bromoketones
with Arylzinc Reagents**
Pamela M. Lundin, Jorge Esquivias, and Gregory C. Fu*
Many interesting target molecules include ketones that bear
an a-aryl substituent, making the development of methods for
the synthesis of this structural motif an active area of
investigation.[1] For example, extensive efforts have recently
been devoted to the discovery of palladium catalysts for the
cross-coupling of ketones with aryl halides in the presence of
a Brønsted base (path A in Scheme1; through an enolate).[2]
couplings.[7] In the case of a-haloesters, we were able to
subsequently develop a catalytic asymmetric a-arylation
process that furnished tertiary stereocenters [Eq. (1);
TBAT= [F2SiPh3]À [NBu4]+].[8] However, we could not
apply this method to corresponding Hiyama arylations of
a-haloketones, presumably because of the Brønsted basic
reaction conditions.[9,10]
Unlike cross-coupling processes such as the Hiyama and
Suzuki reactions, which often employ Lewis or Brønsted basic
activators, the Negishi reaction typically proceeds without an
additive,[11,12] thereby making it an attractive starting point for
the development of a method for the catalytic asymmetric
a-arylation of ketones to generate (potentially labile) tertiary
stereocenters. Herein, we establish that a nickel/pybox 2
catalyst can indeed achieve enantioselective cross-couplings
of racemic a-bromoketones with arylzinc reagents under very
mild conditions with a good ee value and yield [Eq. (2)].[13,14]
Scheme 1. Methods for synthesizing ketones having a-aryl substitu-
tents.
Furthermore, in the case of a,a-disubstituted ketones, cata-
lytic asymmetric a-arylations have been described wherein
quaternary stereocenters are generated with excellent enan-
tioselectivity.[3,4] Unfortunately, these methods cannot be
applied to the asymmetric synthesis of more commonly
encountered tertiary stereocenters, because of the propensity
of a-arylketones, such as 1, to enolize under the reaction
conditions.[5,6]
Alternatively, an umpolung arylation process, whereby a
ketone bearing an a leaving group reacts with an arylmetal
reagent, could provide the target a-arylketone (path B in
Scheme1). Until recently, there were no examples of palla-
dium- or nickel-catalyzed cross-couplings between secondary
a-halocarbonyl compounds and arylmetals (metal = B, Si, Sn,
or Zn). In 2007, we reported that a nickel catalyst can achieve
Hiyama arylation reactions with a wide array of electrophiles,
including secondary a-halocarbonyl compounds, and Lei and
co-workers later described a nickel-based method for Suzuki
The data in Table 1 illustrate the role that various reaction
parameters play in determining the efficiency of this stereo-
convergent Negishi a-arylation of ketones. Cross-coupling
does not occur if NiCl2·glyme is omitted (Table 1, entry 2),
whereas carbon–carbon bond formation does proceed in the
absence of ligand 2[15] (Table 1, entry 3). Pybox ligands other
than 2 furnish lower ee values and yields (Table 1, entries 4
and 5), as do solvents other than a glyme/THF mixture
(Table 1, entries 6–8). At room temperature, the catalyst
system is somewhat less effective than at À30 8C (Table 1,
entry 9).
[*] P. M. Lundin, Dr. J. Esquivias, Prof. Dr. G. C. Fu
Department of Chemistry, Massachusetts Institute of Technology
Cambridge, MA 02139 (USA)
Fax: (+1)617-324-3611
E-mail: gcf@mit.edu
[**] Support has been provided by the National Institutes of Health
(National Institute of General Medical Sciences, grant R01-
GM62871), Merck Research Laboratories, Novartis, and the
Spanish Department of Science (fellowship for J.E.).
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.200804888.
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Table 1: Catalytic asymmetric arylations of racemic a-bromoketones:
Effect of reaction parameters.
(Table 3). Very good ee values and useful yields are observed
with a variety of a-alkyl substituents, including those that are
functionalized (Table 3, entries 2 and 3) and b branched
Table 3: Catalytic asymmetric arylations of racemic a-bromoketones:
Variation of the electrophile.
Entry Variation from the “standard” conditions ee [%] Yield [%][a]
1
2
3
4
5
6
7
8
9
none
no NiCl2·glyme
no (+)-2
Ph-pybox, instead of (+)-2
iPr-pybox, instead of (+)-2
glyme only
THF only
DMF, instead of glyme/THF
RT
94
–
–
71
73
–
87
–
87
<5
55
54
6
<5
52
<5
81
Entry
Ar
R
ee [%]
Yield [%][a]
1
2
Ph
Ph
Ph
Ph
Et
94
95
92
95
–
72
75
96
86
76
90
89
<5
80
CH2Ph
CH2CH2Cl
iBu
iPr
Me
Me
Me
Me
Me
3[b]
4[c]
5
89
Ph
[a] The yield was determined by using GC methods with a calibrated
internal standard.
6
2-F-C6H4
2-Et-C6H4
4-MeO-C6H4
4-F3C-C6H4
2-thienyl
7[b]
8
79
90
9
10
87 (89)[c]
96
76 (82)[c]
81
All data are the average of two experiments. [a] Yield of purified product.
[b] Run at À20 8C. [c] Ar2Zn (1.1 equiv) was used rather than ArZnI.
By using our optimized method, we can achieve Negishi
cross-couplings of racemic 2-bromopropiophenone with an
array of arylzinc reagents with excellent ee values and good
yields (Table 2),[16] although the efficiency of the process is
(Table 3, entry 4); however, if R is large, little of the cross-
coupling product is formed (Table 3, entry 5). If the aryl group
of the ketone is bulky, the reaction proceeds with moderate
enantioselectivity (Table 3, entries 6 and 7). In contrast, good
ee values are observed regardless of whether the group is
electron-rich (Table 3, entry 8) or electron-poor (Table 3,
entry 9). A thiophene is compatible with this nickel-based
coupling process (Table 3, entry 10).[18]
Table 2: Catalytic asymmetric arylations of racemic a-bromoketones:
Variation of the nucleophile.
In conclusion, we have developed the first catalytic
asymmetric method for cross-coupling arylmetal reagents
with a-haloketones, specifically, the NiCl2·glyme/2-catalyzed
reaction of arylzincs with racemic secondary a-bromoketones.
This stereoconvergent carbon–carbon bond-forming process
occurs under unusually mild conditions (À30 8C and no
activators), thereby allowing the generation of potentially
labile tertiary stereocenters. Ongoing efforts are directed at
expanding the scope of cross-coupling reactions of alkyl
electrophiles.
Entry
Ar
ee [%]
Yield [%][a]
1
2
3
Ph
96 (95[b])
–
86 (88[b])
<5
88
2-MeO-C6H4
3-Me-C6H4
3-MeO-C6H4
4-F-C6H4
4-MeO-C6H4
4-Me2N-C6H4
4-MeS-C6H4
94
94
96
96
93
96
4[b]
5
87
74
93
85
6
7
8
71
All data are the average of two experiments. [a] Yield of purified product.
[b] Ar2Zn (1.1 equiv) was used, rather than ArZnI.
Experimental Section
General Procedure: A solution of the arylmagnesium bromide
(1.6 mmol; 1.6 equiv) was added to a solution of ZnI2 (510 mg,
1.6 mmol; 1.6 equiv) in THF (final concentration of ArZnI = 0.20m)
under argon. The mixture was stirred for 40 min at room temperature
(a precipitate is immediately observed), and then it was cooled to
À30 8C. NiCl2·glyme (11.0 mg, 0.050 mmol; 0.050 equiv) and (+)-2
(29.9 mg, 0.065 mmol; 0.065 equiv) were added to an oven-dried
50 mL flask. The flask was purged with argon, and then the a-
bromoketone (1.0 mmol; 1.0 equiv) and glyme (13.5 mL) were added
in that order. This solution was stirred at room temperature for
20 min, and then it was cooled to À30 8C. The suspension of ArZnI
(6.5 mL, 1.3 mmol; 1.3 equiv) was added dropwise over 3 min, and the
reaction mixture was stirred at À30 8C for 4 h. The reaction was then
sensitive to the steric demand of the nucleophile (Table 2,
entry 2). The organozinc substrate can include a range of
functional groups, such as OR, halogen, NR2, and SR groups.
Diarylzinc reagents (Ar2Zn) and arylzinc iodides (ArZnI)
generally furnish similar enantioselectivities and yields (e.g.,
Table 2, entry 1).[17] The a-arylated ketone is stable to
racemization under these conditions.
We have examined the scope of this method for the
catalytic asymmetric a-arylation of ketones not only with
respect to the nucleophile (Table 2), but also the electrophile
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quenched with saturated ammonium chloride (10 mL). The reaction
[10] For asymmetric Negishi alkylations of a-haloamides, see: C.
Fischer, G. C. Fu, J. Am. Chem. Soc. 2005, 127, 4594 – 4595.
[11] For reviews of cross-coupling reactions, see: a) Metal-Catalyzed
Cross-Coupling Reactions (Eds.: A. de Meijere, F. Diederich),
Wiley-VCH, New York, 2004; b) Handbook of Organopalla-
dium Chemistry for Organic Synthesis (Ed.: E.-i. Negishi), Wiley
Interscience, New York, 2002.
mixture was diluted with Et2O (50 mL) and distilled water (10 mL).
The organic layer was separated, washed with brine (10 mL), dried
over magnesium sulfate, and concentrated. The product was purified
by flash column chromatography.
Received: October 6, 2008
[12] For a review of the Negishi reaction, see: E.-i. Negishi, Q. Hu, Z.
Huang, G. Wang, N. Yin in The Chemistry of Organozinc
Compounds (Eds.: Z. Rappoport, I. Marek), Wiley, New York,
2006, chap. 11.
Published online: November 28, 2008
Keywords: asymmetric catalysis · enantioselectivity · ketones ·
.
nickel · zinc
[13] For additional examples of nickel-catalyzed enantioselective
cross-coupling reactions of activated and unactivated alkyl
electrophiles, see: a) alkylation of benzylic halides: F. O. Arp,
G. C. Fu, J. Am. Chem. Soc. 2005, 127, 10482 – 10483; b) alky-
lation of allylic chlorides: S. Son, G. C. Fu, J. Am. Chem. Soc.
2008, 130, 2756 – 2757; c) alkylation of homobenzylic bromides:
B. Saito, G. C. Fu, J. Am. Chem. Soc. 2008, 130, 6694 – 6695;
d) alkynylation of benzylic bromides: J. Caeiro, J. P. Sestelo,
L. A. Sarandeses, Chem. Eur. J. 2008, 14, 741 – 746; e) arylation
of propargylic halides: S. W. Smith, G. C. Fu, J. Am. Chem. Soc.
2008, 130, 12645 – 12647.
[14] For a recent overview of asymmetric cross-couplings of secon-
dary alkyl electrophiles, see: F. Glorius, Angew. Chem. 2008, 120,
8474 – 8476; Angew. Chem. Int. Ed. 2008, 47, 8347 – 8349.
[15] Ligand 2 can be synthesized in one or two steps from a
commercially available amino alcohol and a commercially
available pyridine derivative (see the Supporting Information).
[16] Notes: a) In preliminary studies under our standard conditions,
a-chloroketones and heteroarylzinc reagents were not suitable
substrates (low yield or ee values); b) During the course of the
cross-coupling, the ee value of the unreacted a-bromoketone
was less than 5%, and the ee value of the product was essentially
constant.
[17] Notes: a) The use of less than 1.1 equivalent of Ar2Zn (2.2 equiv
of the Ar group) leads to significantly lower yields. Therefore, we
generally employ ArZnI (1.3 equiv) as the arylating agent;
b) We prepared ArZnI by the reaction of a Grignard reagent
with ZnI2. In preliminary experiments, we observed that arylzinc
halides produced by zinc insertion into aryl halides may also be
employed, whereas the use of commercially available arylzinc
halides led to lower yields.
[18] In a preliminary study, we obtained 72% ee and 68% yield in a
Negishi phenylation of racemic 2-bromocyclohexanone. To the
best of our knowledge, there has been no previous report of a
catalytic asymmetric arylation of a dialkylketone (see referen-
ces [3] and [4]).
[1] For some leading references, see: J. M. Fox, X. Huang, A.
Chieffi, S. L. Buchwald, J. Am. Chem. Soc. 2000, 122, 1360 –
1370.
[2] For overviews, see: a) Reference [1]; b) D. A. Culkin, J. F.
Hartwig, Acc. Chem. Res. 2003, 36, 234 – 245.
[3] For key studies, as well as references to the synthesis and utility
of enantioenriched a-arylketones, see: a) J. Ahman, J. P. Wolfe,
M. V. Troutman, M. Palucki, S. L. Buchwald, J. Am. Chem. Soc.
1998, 120, 1918 – 1919; b) T. Hamada, A. Chieffi, J. Ahman, S. L.
Buchwald, J. Am. Chem. Soc. 2002, 124, 1261 – 1268; c) X. Liao,
Z. Weng, J. F. Hartwig, J. Am. Chem. Soc. 2008, 130, 195 – 200.
[4] For a nickel-catalyzed process, see: G. Chen, F. Y. Kwong, H. O.
Chan, W.-Y. Yu, A. S. C. Chan, Chem. Commun. 2006, 1413 –
1415.
[5] pKa (acetone): 26.5; pKa (PhCH2COCH3): 19.8 (values in
DMSO taken from: F. G. Bordwell, S. Zhang, X.-M. Zhang,
W.-Z. Liu, J. Am. Chem. Soc. 1995, 117, 7092 – 7096).
[6] For examples of methods for the asymmetric synthesis of cyclic
a-arylketones wherein the a carbon is a tertiary stereocenter,
see: a) C. H. Cheon, H. Yamamoto, J. Am. Chem. Soc. 2008, 130,
9246 – 9247; b) V. K. Aggarwal, B. Olofsson, Angew. Chem. 2005,
117, 5652 – 5655; Angew. Chem. Int. Ed. 2005, 44, 5516 – 5519;
c) Y.-M. Shen, B. Wang, Y. Shi, Angew. Chem. 2006, 118, 1457 –
1460; Angew. Chem. Int. Ed. 2006, 45, 1429 – 1432; d) D.
Soorukram, P. Knochel, Angew. Chem. 2006, 118, 3768 – 3771;
Angew. Chem. Int. Ed. 2006, 45, 3686 – 3689.
[7] N. A. Strotman, S. Sommer, G. C. Fu, Angew. Chem. 2007, 119,
3626 – 3628; Angew. Chem. Int. Ed. 2007, 46, 3556 – 3558. For a
subsequent study of Suzuki reactions, see: C. Liu, C. He, W. Shi,
M. Chen, A. Lei, Org. Lett. 2007, 9, 5601 – 5604.
[8] X. Dai, N. A. Strotman, G. C. Fu, J. Am. Chem. Soc. 2008, 130,
3302 – 3303.
[9] We believe that, in certain cases, even the product of the Hiyama
arylation illustrated in Equation (1) may be susceptible to
racemization (e.g., with Ar= 4-F3C-C6H4; see footnote 7a of
reference [8]).
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