Asymmetric copper-catalyzed addition of grignard reagents to aryl alkyl ketones

Article abstract of DOI:10.1002/anie.201109040

Chiral tertiary alcohols: A copper(I) catalyst with a chiral ferrocenyl diphosphine ligand facilitates the additive-free 1,2-addition of readily available Grignard reagents to aromatic ketones, thus providing access to chiral tertiary alcohols with excellent yields and enantioselectivities. Copyright

Full text of DOI:10.1002/anie.201109040

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DOI: 10.1002/anie.201109040
Asymmetric Catalysis
Asymmetric Copper-Catalyzed Addition of Grignard Reagents to Aryl
Alkyl Ketones**
Ashoka V. R. Madduri, Syuzanna R. Harutyunyan,* and Adriaan J. Minnaard*
Tertiary alcohols are ubiquitous in natural products and
pharmaceutical compounds. Therefore, methods for the
enantioselective preparation of their chiral congeners are
a necessity.[1,2] The synthesis of enantiopure secondary
alcohols is well established by mature strategies, such as the
asymmetric hydrogenation of ketones with transition metals
and enzymes[3] followed by dynamic kinetic resolution of the
corresponding racemates. However, these strategies do not
apply for tertiary alcohols.[4] Even the resolution of racemic
tertiary alcohols with lipases or esterases is generally not
efficient.[5] The most straightforward method to prepare
enantiopure tertiary alcohols would be the catalytic asym-
metric addition of organometallic reagents to ketones.[6,1c] For
the addition of alkyl groups, this notion has led to several
studies in which dialkylzinc and organotitanium reagents
were used effectively.[2] In contrast, readily available Grignard
reagents have only been used in conjunction with stoichio-
metric amounts of a chiral ligand.[7] This is not surprising, as
the uncatalyzed addition of the Grignard reagent is a formi-
dable competitor.[8] Indeed, catalytic non-asymmetric addi-
tion of Grignard reagents to ketones has only recently
become possible using Zinc(II) salts as catalysts.[9]
Very recently, we have shown that, counterintuitively,
copper–diphosphine catalysts can be used for the enantiose-
lective 1,2-addition of Grignard reagents to enones.[10]
Although the conjugated double bond is thought to play
a major role in the course of that reaction, we nevertheless
used this catalyst system to study the unprecedented asym-
metric addition of Grignard reagents to aryl alkyl ketones.
Initial experiments were carried out using acetophenone
as the substrate and CuBr·SMe2 as the metal precursor. In the
absence of ligand, the reaction with 2-ethylbutylmagnesium
bromide in tert-butyl methyl ether at various temperatures
provided only small amounts of the addition product. The
main products were phenethyl alcohol, as a result of
Meerwein–Ponndorf–Verley reduction, and unreacted start-
ing material, which is probably due to enolization.[11]
A
subsequent ligand screening involved a variety of chiral
ligands, including monodentate phosphoramidites and biden-
tate diphosphines.[12] Josiphos-type ligand (S,RFe)-L1 turned
out to be far superior, both in terms of yield and enantiose-
lectivity; a maximum ee of 82% with an excellent 96% yield
was obtained at À788C (Table 1, Entry 1). This result
indicates that the catalyst has a particularly high turnover
frequency and outcompetes the uncatalyzed addition reac-
tion, as well as reduction and enolization, at this temperature.
We were delighted to find that this positive outcome is
representative for a broad spectrum of substituted acetophe-
nones (Table 1). Upon addition of the same Grignard reagent,
2-ethylbutylmagnesium bromide, good to excellent enantio-
selectivities were obtained in combination with high yields of
isolated products. Surprisingly, no clear trends were observed
that relate the steric and electronic effects of the substituents
to the enantioselectivity. Para and meta substituents have
small but significant effects on the ee. Also, remarkably,
a bromo substituent does not suffer from metal–halogen
exchange. Notable results are 3-trifluoromethyl acetophe-
none 1i with an excellent ee of 96% and 3-methoxyaceto-
phenone 1h with a decreased yield and an ee of 54%. Also
remarkable are the excellent enantioselectivities obtained for
3,5-ditrifluoromethyl acetophenone (1p, 98%), 3,4-dichloro
acetophenone (1n, 96%), and 3,5-difluoro acetophenone (1o,
92%). An ortho-bromo substituent is also well-tolerated (1m,
95% ee), although the yield is decreased.
This addition of Grignard reagents to ketones, an
archetypical organic chemistry reaction, can now be carried
out in a catalytic asymmetric manner (Scheme 1). The use of
Scheme 1. Catalytic asymmetric addition of Grignard reagents to aryl
alkyl ketones.
a copper catalyst based on a chiral Josiphos-type diphosphine
ligand, in tert-butyl methyl ether, provides excellent yields
and enantiomeric excesses (> 95%) in the addition of
branched alkyl Grignard reagents to aryl alkyl ketones.
[*] A. V. R. Madduri, Dr. S. R. Harutyunyan, Prof. A. J. Minnaard
Stratingh Institute for Chemistry, University of Groningen
Nijenborgh 7, 9747 AG, Groningen (The Netherlands)
E-mail: s.harutyunyan@rug.nl
A small extension of the study shows that the reaction is
limited neither to methyl-substituted ketones nor to phenyl-
substituted ketones. Thus, upon addition, trifluoromethyl
propiophenone 1k gives an ee of 84% (Entry 11). This is
a result comparable to acetophenone (ee 82%, Entry 1), but
lower than trifluoromethyl acetophenone 1i (ee 96%,
Entry 9). A diminished enantioselectivity was obtained with
2-acetonaphthone 1q, but 1-acetonaphthone 1r gave an
a.j.minnaard@rug.nl
[**] We thank Dr. B. Pugin (Solvias) for the generous gift of a ligand kit
for initial screening.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201109040.
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Table 1: Catalytic asymmetric addition of 2-ethylbutylmagnesium bromide to aryl alkyl ketones.
Entry[a]
1
ee (yield)[b–d]
2
Entry
1
ee (yield)[b–d]
2
Entry
15
1
ee (yield)[b–d]
2
1
2a, 82 (96)
2b, 76 (85)
8[e]
2h, 54 (87)
2o, 92 (96)
2p, 98 (95)
2[e]
9
2i, 96 (95)
2j, 76 (90)
16[g]
3
2c, 76 (93)
10[e]
17[e]
2q, 66 (91)
4
2d, 76 (95)
2e, 86 (91)
11
2k, 84 (97)
2l, 70 (84)
18
2r, 95 (71)
2s, 80 (88)
5[e]
12[e]
19[e]
6
2 f, 84 (97)
2g, 90 (96)
13[f]
2m, 95 (61)
2n, 96 (96)
20
2t, 76 (96)
7[e]
14
21[h]
2u, rac. (75)
[a] Conditions: CuBr·SMe2 (5 mol%), (S,RFe)-L1 (6 mol%), Grignard reagent (1.25 equiv; 0.1m in tBuOMe), À788C, 5–10 h. [b] All conversions >98%
(GC-MS). [c] Regio- and enantioselectivities determined by chiral-phase HPLC analysis. [d] Yield of isolated product. [e] Reaction performed at À608C.
[f] iBuMgBr was used. [g] The reaction was also performed on a 4 mmol scale and resulted in 91% yield and 97% ee. [h] Phenylmagnesium bromide
was used.
excellent ee of 95% (Entries 17 and 18). Even 2-acetoan-
thracenone 1s is a suitable substrate for the reaction (80% ee,
88% yield). Heteroaromatic substituents are also allowed, as
in the case of 2-thiophenyl methyl ketone 1t. Additions to
alkyl alkyl ketones (not depicted) and the addition of
phenylmagnesium bromide (2u, Entry 21) both afforded
racemic product.
The scope in terms of Grignard reagents was then studied
(Table 2), using 1p as the substrate. Although the yields are
invariably excellent, bulkier Grignard reagents, such as those
with branched alkyl groups, are required to obtain high
enantioselectivities. Methylmagnesium bromide is inactive
and ethylmagnesium bromide gives only 22% ee (Entry 1).
With butenylmagnesium bromide the ee rises to 44%, with
phenylethylmagnesium bromide 68% ee is obtained, and the
enantioselectivity of the reaction reaches 95% with isobutyl-
magnesium bromide (Entries 2–4). The addition of 2-ethyl-
butylmagnesium bromide, 2-ethylhexylmagnesium bromide,
and cyclohexylmethylmagnesium bromide were very reward-
ing as well, each affording the corresponding alcohol in 98%
ee (Entries 5–7).
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Table 2: Catalytic asymmetric addition of Grignard reagents to 3,5-
ditrifluoromethyl acetophenone (1p).
by exploring the addition of alkyl alkyl ketones and the use of
linear Grignard reagents are ongoing.
Experimental Section
General procedure for the 1,2-addition of Grignard reagents to
ketones: CuBr·SMe2 (0.015 mmol, 3.08 mg, 5 mol%) and ligand
(S,RFe)-L1 (0.018 mmol, 6 mol%) were added to a Schlenk tube
equipped with septum and stirring bar. Dry tBuOMe (3 mL) was
added and the solution was stirred under nitrogen at room temper-
ature for 15 min. The ketone (0.3 mmol) in tBuOMe (1 mL) was
added and the resulting solution was cooled to À788C. The desired
Grignard reagent (0.36 mmol, 1.2 equiv, in Et2O) was diluted with
tBuOMe (combined volume of 1 mL) under nitrogen and added to
the reaction mixture over 15 min. Once the addition was complete,
the reaction mixture was monitored by TLC and GC-MS. After
completion, the reaction was quenched by the addition of MeOH
(1 mL) and saturated aqueous NH4Cl (2 mL), and then warmed to
room temperature, whereupon it was diluted with Et2O and the layers
were separated. The aqueous layer was extracted with Et2O (3 ꢀ
5 mL) and the combined organic layers were dried with anhydrous
Na2SO4, filtered, and the solvent was evaporated in vacuo. The crude
product was purified by flash chromatography on silica gel using
mixtures of n-pentane and Et2O as the eluent.
Entry[a]
1
RMgBr
3, ee (yield)[b–d]
3a, 22 (94)
2
3
4
5
6
3b, 44 (92)
3c, 68 (93)
3d, 95 (95)
2p, 98 (95)
3e, 98 (91)
7
8
3 f, 98 (97)
3g, 74 (86)
Received: December 21, 2011
Published online: February 14, 2012
[a] Conditions: CuBr·SMe2 (5 mol%), (S,RFe)-L1 (6 mol%), RMgBr
(1.25 equiv; 0.1m in tBuOMe), À788C, 5-10 h. [b] All conversions >98%
(GC-MS).[c] Regio- and enantioselectivities determined by chiral-phase
HPLC analysis. [d] Yield of isolated product. Cy=cyclohexyl.
Keywords: 1,2-addition · aromatic ketones ·
asymmetric catalysis · chiral tertiary alcohols · copper
.
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alkyl group transfer step is presented in
Scheme 2. We surmise that, upon reac-
tion of the Grignard reagent with the
chiral copper bromide complex, a new
transmetalated species is formed
wherein the alkyl moiety is more reac-
tive than in the original Grignard
reagent. Furthermore, this species is
capable of double activation of the
substrate via a pseudo-chair transition
state: Lewis acid activation of the car-
Scheme 2. Proposed
transition state for
the reaction.
bonyl moiety through the Mg2+ and activation of the carbonyl
double bond by copper in analogy with the coordination
mode of organocopper species reported recently by Bertz
et al.[13]
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suitable for use in the synthesis of naturally occurring
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