Cu-catalyzed enantioselective 1,4-additions of aryl-Grignard reagents to cyclohexenone in the presence of TADDOL-derived phosphane-phosphite ligands

Article abstract of DOI:10.1002/ejoc.201101258

Asymmetric conjugate additions (1,4-additions) of aryl-Grignard reagents to cyclohex-2-enone, currently a more or less unsolved challenge, were investigated. For this purpose, a small library of phenol-derived chiral phosphane-phosphite ligands containing TADDOL- or BINOL-based phosphite moieties was evaluated. These ligands are easily prepared by a short modular scheme previously developed in this laboratory. Two particularly powerful ligands (4a and 4b, both TADDOL-derived and each possessing a bulky tert-butyl substituent ortho to the phosphite group) were identified. Conditions were optimized with use of the addition of (4-methoxyphenyl)magnesium bromide to cyclohexenone as a standard reaction system. Under optimized conditions [CuBr·SMe ₂ (4 mol-%), ligand 4a (6 mol-%), 2-methyl-THF, -78 °C, slow addition of Grignard reagent] the 1,4-product was obtained with high enantioselectivity (up to 95 % ee) and good regioselectivity (r.r. = 90:10). The scope of the method was probed with different aryl-Grignard reagents. It was found that reagents with electron-donating substituents in meta- or para-positions performed particularly well, whereas the presence of F or CF ₃ substituents led to decreased ee values. Only ortho-substituted aryl-Grignard reagents did not give rise to useful results. A series of phosphane-phosphite ligands were also tested in the Rh-catalyzed 1,4-addition of phenylboronic acid to cyclohexenone, but enantioselectivities did not exceed 70 % ee in this case. The difficult task of employing aryl-Grignard reagents in Cu-catalyzed enantioselective 1,4 addition reactions was achieved with the assistance of readily accessible chiral modular P,P ligands. High enantioselectivities were obtained in a number of synthetically relevant cases. Copyright

Full text of DOI:10.1002/ejoc.201101258

FULL PAPER
DOI: 10.1002/ejoc.201101258
Cu-Catalyzed Enantioselective 1,4-Additions of Aryl-Grignard Reagents to
Cyclohexenone in the Presence of TADDOL-Derived Phosphane-Phosphite
Ligands
Qaseem Naeemi,[a] Mehmet Dindarog˘lu,[a] Darius P. Kranz,[a] Janna Velder,[a] and
Hans-Günther Schmalz*[a]
Dedicated to Professor Mohammed A. Omary[‡]
Keywords: Asymmetric catalysis / C–C bond formation / Conjugate addition / Copper / P ligands
Asymmetric conjugate additions (1,4-additions) of aryl-Grig-
nard reagents to cyclohex-2-enone, currently a more or less
unsolved challenge, were investigated. For this purpose, a
small library of phenol-derived chiral phosphane-phosphite
ligands containing TADDOL- or BINOL-based phosphite
moieties was evaluated. These ligands are easily prepared
by a short modular scheme previously developed in this labo-
ratory. Two particularly powerful ligands (4a and 4b, both
[CuBr·SMe2 (4 mol-%), ligand 4a (6 mol-%), 2-methyl-THF,
–78 °C, slow addition of Grignard reagent] the 1,4-product
was obtained with high enantioselectivity (up to 95% ee) and
good regioselectivity (r.r. = 90:10). The scope of the method
was probed with different aryl-Grignard reagents. It was
found that reagents with electron-donating substituents in
meta- or para-positions performed particularly well, whereas
the presence of F or CF3 substituents led to decreased ee
TADDOL-derived and each possessing a bulky tert-butyl values. Only ortho-substituted aryl-Grignard reagents did
substituent ortho to the phosphite group) were identified.
Conditions were optimized with use of the addition of (4-
methoxyphenyl)magnesium bromide to cyclohexenone as a
standard reaction system. Under optimized conditions
not give rise to useful results. A series of phosphane-phos-
phite ligands were also tested in the Rh-catalyzed 1,4-ad-
dition of phenylboronic acid to cyclohexenone, but enantio-
selectivities did not exceed 70% ee in this case.
Introduction
Conjugate additions (1,4-additions) of carbon nucleo-
philes to α,β-unsaturated carbonyl compounds belong
among the most valuable methods for carbon-carbon bond
formation in organic synthesis. Because a new chirality cen-
ter can be formed in the course of such a reaction, the de-
velopment of enantioselective protocols has been a chal-
lenge for organic chemists for more than three decades.[1]
Of particular synthetic importance are Cu-catalyzed ad-
ditions of organometallic reagents (R–M) to cyclic enones,
a process that also represents the benchmark reaction in the
development of new efficient catalyst systems (Scheme 1).[2]
Although catalytic asymmetric 1,4-additions of organo-
zinc and aluminum reagents in a highly enantioselective
manner have been achieved through the use of chiral phos-
phorus ligands,[2,3] the employment of Grignard reagents,
which are readily available, safer, and much easier to handle,
Scheme 1. Cu-catalyzed 1,4-additions to cyclic enones.
remained on open challenge for many years, because the
reported methods were limited to specific substrates and/or
did not reliably proceed with useful levels of enantio-
selectivity.[4] In 2004, an important breakthrough was dis-
closed by Feringa and co-workers, who identified
TaniaPhos (1, Figure 1)[5] and JosiPhos (2)[6] as useful li-
gands for Cu-catalyzed 1,4-additions of alkylmagnesium
halides to cyclic enones with enantioselectivities of up to
96% ee.[7] More recently, Alexakis and co-workers also re-
[a] Department für Chemie, Universität zu Köln,
Greinstr. 4, 50939 Köln, Germany
Fax: +49-221-470-3064
E-mail: schmalz@uni-koeln.de
[‡] Head of Organic Chemistry Department, Kabul University
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201101258.
Figure 1. Chiral ligands used by others in the enantioselective Cu-
catalyzed 1,4-addition of Grignard reagents.
Eur. J. Org. Chem. 2012, 1179–1185
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H.-G. Schmalz et al.
FULL PAPER
ported high selectivities in such reactions in the presence THF)[13] as the most promising solvent.[11,12] The reactions
of the amino-phosphane SimplePhos[8] or of N-heterocyclic were conducted at –78 °C with slow addition of a solution
carbene (NHC) ligands such as 3, the latter even allowing of the aryl-Grignard reagent by syringe pump over a period
the synthesis of β,β-disubstituted cyclic ketones (generation of 2 h, followed by stirring for 1 h at the same temperature.
of quaternary centers).[9]
After addition of aqueous NH4Cl and extraction with
We have recently introduced phenol-derived phosphane- MTBE the solution was passed through a small amount of
phosphite ligands of type 4 (Scheme 2), which are readily silica and analyzed by chromatography with use of a chiral
synthesized in a modular fashion through the use of a chiral stationary phase. Peaks were assigned by use of authentic
diol (such as TADDOL or BINOL) as a source of chiral- reference samples.
ity.[10] Some of these ligands turned out to perform particu-
The results of the first ligand screening are summarized
larly well in Cu-catalyzed enantioselective 1,4-additions of in Table 1. Firstly, it should be noted that the transforma-
Grignard reagents to cyclohexenone[11] and other cyclic en- tions proceeded smoothly in all cases with good to excellent
ones.[12] As a major advantage, it was also possible to trans- degrees of regioselectivity in favor of the (R-configured)
fer branched (secondary) alkyl groups, as well as alkenyl 1,4-addition products 6a. The minor 1,2-addition products
and phenyl residues, with high selectivity, thus overcoming (rac-7a) were always formed as racemic mixtures. As in our
a major limitation of the known catalyst systems.
earlier study, even seemingly similar ligands (varying only
in the backbone substitution) performed rather differently.
Best results with respect both to the enantioselectivity (up
to 95%) and to conversion were obtained with the TAD-
DOL-based ligands 4a and 4b, each bearing a bulky tert-
butyl substituent ortho to the phosphite moiety. Interest-
ingly, a different R1 substituent (methyl) was preferred in
the BINOL-based set of ligands. However, ligand 4g, the
best one of this series, was less effective than 4a and 4b,
which accordingly were selected for further investigations.
Scheme 2. Modular phosphane-phosphite ligands of type 4.
Because of the great synthetic relevance of 3-aryl-substi-
tuted cycloalkanones, we decided to explore the applica-
bility of our ligands in enantioselective 1,4-additions of dif-
ferent aryl-Grignard reagents, primarily with use of cyclo-
hexenone as a model substrate. Here we report the results
of this study, which provided valuable insights into the
scope and limitations of the methodology.
Table 1. Results of the primary ligand screening.[a]
Entry
Ligand (L*)
6a/7a[b] Conversion [%][c] ee of 6a [%][b]
Results and Discussion
1
2
3
4
5
6
7
8
4a
4b
4c
4d
4e
4f
4g
4h
4i
95:5
93:7
98:2
96:4
98:2
93:7
98:2
98:2
97:3
96:4
98:2
93:7
90
90
60
66
78
56
63
60
63
59
82
59
95
90
21
53
7
45
73
13
17
24
19
23
The investigation was started with the screening of a
small ligand library consisting of the ligands shown in Fig-
ure 2, all prepared as previously reported.[10b]
9
10
11
12
4j
4k
4l
[a] Reaction conditions: chiral ligand (6 mol-%), CuBr.SMe2
(4 mol-%), slow addition of Grignard reagent (0.1–0.5 m, 1.5 equiv.)
over 2 h at –78 °C, then 1 h further stirring. [b] Determined by GC
(FID) with a BGB 176 SE column. [c] Determined by GC from the
relative amount of remaining 5.
Under the optimized conditions (ligand 4a) the synthesis
of 6a could also be performed on a preparative scale to give
the pure product 6a with 95% ee and in 60% isolated yield
after separation of the byproduct rac-7a by careful flash
chromatography. Using the same conditions, we then inves-
Figure 2. Various ligands of type 4 used in the present study. R1 to
R4 = H unless otherwise indicated.
As a standard reaction system we selected the addition tigated the performance of a variety of different aryl-Grig-
of (4-methoxyphenyl)magnesium bromide to cyclohexenone nard reagents (Table 2). In all cases, arylmagnesium brom-
(5) in the presence of CuBr·SMe2 (4 mol-%) and a chiral ides were prepared in 2-Me-THF and treated with cyclohex-
ligand (6 mol-%) with use of 2-methyl-tetrahydrofuran (Me- enone under the standard conditions in the presence of 4a
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Enantioselective 1,4-Additions of Aryl-Grignard Reagents
or 4b as chiral ligand. Initially, both ligands were tested for
each reagent, but only the (reproduced) results for the better
ligand are given in Table 2.
Table 2. Addition of various aryl-MgBr reagents to cyclohex-
enone.[a] For the products’ structures, see Figure 3.
Entry
L*
6/7[b]
Product
Yield [%][c]
ee of 6 [%][d]
1
2
3
4
5
6
7
8
4a
4a
4b
4b
4b
4a
4a
4b
4a
4a
4b
4b
4b
91:9
6a
6b
6c
6d
6e
6f
6g
6h
6i
60
50
76
59
54
(50)
(52)
61
63
(23)
69
95
92
95
13
15
15
10
85
77
13
65
65
83
90:10
90:10
80:20
75:25
79:21
82:18
79:21
84:16
80:20
90:10
82:18
90:10
Figure 3. Various 3-arylcyclohexanones prepared as detailed in
Table 2.
9
10
11
12
13
6j
6k
6l
68
61
6m
[a] Reaction conditions: chiral ligand (6 mol-%), CuBr.SMe2
(4 mol-%), slow addition of Grignard reagent (0.1–0.5 m, 1.5 equiv.)
over 2 h at –78 °C, then 1 h further stirring. [b] Determined by GC–
MS. [c] Isolated yield (yields given in brackets determined by GC).
[d] Determined by chiral GC (FID).
As can be seen from Table 2, the expected 1,4-addition
products (Figure 3) were obtained in all cases investigated,
although with varying yields and enantiomeric purities. Ex-
cellent regio- and enantioselectivities were observed with
PhMgBr or with aryl-Grignard reagents containing elec-
tron-donating substituents in their para-positions (Entries 1
to 3). In addition, electron-rich 3,5-disubstituted aryl-Grig-
nard reagents also afforded the products with high selectivi-
ties (Entries 8 and 9). In contrast, the use of 2-substituted
aryl-Grignard reagents resulted in low enantioselectivities,
probably for steric reasons (Entries 6 and 7). In general,
fluorinated or trifluoromethylated (i.e., electron-poor) rea-
gents also afforded the products with low enantioselectivi-
ties (Entries 4, 5, and 10). Synthetically useful results were
in turn obtained with (3,4-methylenedioxyphenyl)-MgBr, 2-
naphthyl-MgBr, and 4-vinylphenyl-MgBr (Entries 11 to 13).
The absolute configurations – R – of the 1,4-addition
Figure 4. Experimentally measured and calculated (dotted line) CD
spectra of compounds 6a and 6c in CH3CN.
The somewhat disappointing results obtained for aryl-
products of type 6 obtained with ligands 4a/4b were deter- Grignard reagents bearing electron-withdrawing (fluoro or
mined by circular dichroism (CD) spectroscopy. Each sam- trifluoromethyl) substituents prompted us to investigate
ple showed a positive cotton effect at about 290 to 300 nm. briefly whether these reactions could possibly be better con-
By comparison of the experimentally measured CD spectra ducted with use of ligands other than 4a or 4b. Taking the
(in CH3CN) with the corresponding spectra calculated addition of (4-F3C-phenyl)-MgBr to cyclohexenone as a
through time-dependent density functional theory model we tested the effects of TaniaPhos (1), JosiPhos (2),
(TDDFT,[14] with use of Gaussian 03W,[15] the B3LYT func- and the TADDOL-derived phosphane-phosphite ligands 4c
tional,[16] and the TZVP basis set[17]) a reliable assignment and 4f (Table 3). However, none of these ligands afforded
was possible, as demonstrated in Figure 4 for compounds the 1,4-addition product 6e with useful levels of regio- and
6a and 6c.
enantioselectivity.
Eur. J. Org. Chem. 2012, 1179–1185
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Table 3. Performance of different ligands (L*) in the 1,4-addition shi-style Rh-catalyzed 1,4-additions. We therefore also
of 4-CF3-C6H4MgBr to 2-cyclohexenone.[a]
briefly tested the performance of ligands 4a to 4k in the
reaction between cyclohexenone (5) and phenylboronic acid
(Table 4).
Table 4 indicates that the tested ligands of type 4 again
performed rather differently. The best result (70% ee) was
obtained with the BINOL-derived ligand 4j, bearing a
phenyl substituent in the R1 position (Entry 10). However,
the comparison with BINAP (Entry 13)[20] immediately
shows that the phosphane-phosphite ligands of type 4 do
not appear to be particularly promising in Rh-catalyzed
conjugate additions of arylboronic acids to enones.
Entry
L*
6e/7e
Conversion [%]
ee [%][b]
1
2
3
4
5
1
2
4c
4f
4a
50:50
44:56
45:55
41:59
80:20
97
98
90
95
90
9
19
30
23
13
[a] Reaction conditions: chiral ligand (6 mol-%), CuBr·SMe2
(4 mol-%), slow addition of Grignard reagent (0.1–0.5 m; 1.5 equiv.)
over 2 h at –78 °C, then 1 h further stirring. [b] Determined by chi-
ral GC.
Conclusions
We have investigated the performance of modular phos-
phane-phosphite ligands of type 4 in catalytic enantioselec-
tive 1,4-arylations with use of cyclohex-2-enone (5) as a rel-
evant model substrate. As a most important result we were
able to demonstrate that some of these ligands (especially
4a and 4b) allow (for the first time) Cu-catalyzed 1,4-ad-
ditions of aryl-Grignard reagents to be achieved with useful
levels of regio- and enantioselectivity (up to 95% ees). The
scope of the method was evaluated by testing differently
substituted aryl-Grignard reagents, and it was shown that
electron-donating substituents in para- or meta-positions
were tolerated well, whereas for fluoro- and CF3-substituted
aryl-Grignard reagents unsatisfactory selectivities were ob-
tained. In view of the good availability of Grignard reagents
and the low cost of copper, we are optimistic that the
method will find application in certain cases as an alterna-
tive to the (much more expensive) Rh-catalyzed 1,4-ad-
ditions of arylboronic acids. It also should be mentioned
that the modular nature of the phosphane-phosphite li-
gands of type 4 is a valuable pre-condition for further li-
gand optimization (for individual transformations).[21] Also,
as we have shown in a separate study, the developed proto-
col is also applicable to other cyclic α,β-unsaturated carb-
onyl compounds.[12]
Despite the fact that our method does not allow fluori-
nated aryl groups to be transferred in a useful manner, the
high selectivities found for ligands 4a/4b in the Cu-catalyzed
1,4-additions of various (more electron-rich) aryl-Grignard
reagents (Table 2) represent an important improvement and
await future application in organic synthesis.
One competing methodology for conjugate additions of
aryl groups to α,β-unsaturated carbonyl compounds (in-
cluding cyclic enones) is, of course, the Rh-catalyzed reac-
tions of arylboronic acids, first introduced by Hayashi and
Miyaura.[18] In the presence of chiral diphosphanes (such
as BINAP) or chiral diene ligands the products are often
obtained with excellent yields and enantioselectivities.[19] In
this context we were interested to find out whether or not
our ligands (of type 4) could possibly also be used in Haya-
Table 4. Performance of ligands of type 4 in the Rh-catalyzed 1,4-
addition of phenylboronic acid to cyclohexenone.
Experimental Section
Entry
L*
Temp. [°C] Time [h] Conversion
ee [%]
General: All reactions were conducted under argon in heat-dried
glassware with use of standard Schlenk techniques. Anhydrous 2-
Me-THF was obtained by distillation from sodium benzophenone
1
2
3
4
5
6
7
8
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
4j
4j
4k
4l
100
100
100
100
100
100
100
100
100
100
100
(MW)
100
100
100
5
5
5
5
5
5
5
2
5
5
16
1
5
5
5
22
20
10
12
21
33
12
12
28
34
66
28
23
15
80
12
10
55
10
9
7
8
8
57
70
68
59
13
17
96
1
ketyl. H NMR and 13C NMR spectra were recorded in CDCl3 at
1
600 MHz for H and 150 MHz for 13C. Proton shifts are reported
in ppm (δ) downfield from TMS and were determined by reference
to the residual solvent peak (CHCl3, 7.24 ppm or 77.0 ppm, respec-
tively). Infrared (IR) spectra were recorded with a Paragon 100
FT IR instrument (Perkin–Elmer). Optical rotations were mea-
sured with a Perkin–Elmer 343 polarimeter, concentrations (c) are
given in g/100 mL. All Grignard solutions were synthesized from
the corresponding alkyl bromides in 2-Me-THF. Reactions were
monitored by GC–MS with an Agilent GC 6890N gas chromato-
graph, a HP 5973N mass selective detector, and a HP7683 GC
autosampler. A HP-5MS column (30 mϫ0.25 mm) was used.
Enantiomeric ratios were determined by HPLC or GC analysis
9
10
11
12
13
14
15
(S)-BINAP
MW = microwave; conditions: 0.5–0.8 bar, 120–150 °C, 300 W
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Enantioselective 1,4-Additions of Aryl-Grignard Reagents
with an Agilent GC 6890N gas chromatograph and a BGB 176 SE
column (30 mϫ0.25 mm), a 6-TBDMS-2,3-Me-β-CD (50% in VO
1701, 10/94 BG) column (25 mϫ0.25 mm), or a Lipodex A column
(50 mϫ0.25 mm). A MAT 900S (Finnigan) mass spectrometer was
used for DIP-MS mass spectra. CD spectra were determined in
CH3CN with a Jasco J-180 CD-spectropolarimeter [concentrations
(c) are given in mgmL–1].
ligand 4b (110 mg, 0.12 mmol), and cyclohex-2-enone (5, 0.20 mL,
2.1 mmol) in 2-Me-THF (7 mL) was treated with a solution
(0.31 m, 10 mL, 3.15 mmol) of (4-fluorophenyl)magnesium bromide
in 2-Me-THF. After chromatography (CH2Cl2/cyclohexane 2:3, Rf
= 0.10) the product 6d (228 mg, 59%) was obtained as a colorless
oil. (13% ee; determined by chiral GC). 1H NMR (600 MHz,
CDCl3): δ = 1.67–1.84 (m, 2 H), 2.0–2.16 (m, 2 H), 2.28–2.58 (m,
4 H), 2.92–3.0 (m, 1 H), 6.94–7.01 (m, 2 H), 7.11–7.19 (m, 2
H) ppm. 13C NMR (150 MHz, CDCl3): δ = 25.3, 32.8, 41.0, 43.9,
General Procedure
– 1,4-Additions on a Preparative Scale:
CuBr·SMe2 (0.04 equiv.) and a chiral ligand (0.06 equiv.) were dis-
solved in dry 2-Me-THF under argon and the resulting mixture
was allowed to stir for 15 min at room temp. After addition of
cyclohexenone (1.0 equiv.) the mixture was cooled to –78 °C and a
diluted solution of an aryl-Grignard reagent (1.5 equiv. [Ar-MgX]
= 0.1–0.5 molL–1) was slowly added by syringe pump over a period
of 2 h. The mixture was stirred for another 1 h and then quenched
with aqueous NH4Cl solution. The layers were separated and the
aqueous phase was extracted with tert-butyl methyl ether (MTBE).
The combined organic layers were dried with MgSO4 and filtered
through a short pad of silica, and the solvent was evaporated under
reduced pressure. The crude product was finally purified by flash
chromatography.
2
3
49.0, 115.3 (d, JF-C = 21.1 Hz), 127.9 (d, JF-C = 7.6 Hz), 140.0,
1
160.6 (d, JF-C = 244.0 Hz), 210.6 ppm. 19F NMR (282 MHz,
CDCl ): δ = –116.43 (s, 1 F) ppm. IR (neat): ν = 3040 (w), 2936
˜
3
(m), 2864 (w), 1707 (s), 1602 (m), 1508 (s), 1446 (w), 1418 (w), 1314
(w), 1246 (m), 1219 (s), 1158 (m), 1104 (w), 883 (w), 829 (s) cm–1.
Retention times (BGB 176 SE, initial temp. 40 °C, rate
0.2 °C min–1, final temp. 170 °C): 71.8 min (minor)/72.3 min
(major). HRMS: calcd. for C12H13FO 188.10; found 192.09.
(R)-3-(4-Trifluoromethylphenyl)cyclohexanone (6e): As described in
the General Procedure,
a solution of CuBr·SMe2 (17.3 mg,
0.084 mmol), ligand 4b (111 mg, 0.126 mmol), and cyclohex-2-en-
one (5, 0.20 mL, 2.1 mmol) in 2-Me-THF (7 mL) was treated with
a solution (0.39 m, 8 mL, 3.15 mmol) of [4-(trifluoromethyl)-
phenyl]magnesium bromide in 2-Me-THF. After chromatography
(EtOAc/cyclohexane 2:8; Rf = 0.17) the product 6e (264 mg, 54%)
was obtained as a colorless oil (15% ee; determined by chiral GC).
1H NMR (600 MHz, CDCl3): δ = 1.71–1.87 (m, 2 H), 2.06–2.19
(m, 2 H), 2.31–2.61 (m, 4 H), 3.01–3.11 (m, 1 H), 7.33 (d, J =
8.1 Hz, 2 H), 7.58 (d, J = 8.1 Hz, 2 H) ppm. 13C NMR (150 MHz,
(R)-3-(4-Methoxyphenyl)cyclohexanone (6a): As described in the
General Procedure, a solution of CuBr·SMe2 (82.2 mg, 0.4 mmol),
ligand 4a (497 mg, 0.6 mmol), and cyclohex-2-enone (5, 0.96 mL,
10 mmol) in 2-Me-THF (10 mL) was treated with a solution of (4-
methoxyphenyl)magnesium bromide (0.44 m, 34 mL, 15 mmol) in
2-Me-THF. After chromatography (EtOAc/cyclohexane 1:9; Rf =
0.14) the product 6a (120 mg, 60%) was obtained as a colorless oil
(95% ee; determined by chiral GC). [α]λ (20 °C, CH2Cl2, c = 0.40 g/
1
CDCl3): δ = 25.3, 32.4, 41.0, 44.4, 48.4, 125.6 (q, JF-C = 271 Hz),
3
2
125.5 (q, JF-C = 4 Hz), 126.8, 128.8 (q, JF-C = 32.4 Hz), 126.9,
100 mL): [α]589 = +14.2, [α]546 = +21.0, [α]405 = +138.5, [α]365
=
148.1, 210.1 ppm. 19F NMR (282 MHz, CDCl3): δ = –62.46 (s, 3
+333.3, [α]334 = +1017.5. CD (c = 0.29 mgmL–1 in CH3CN): Θ (γ)
= +14.46 (290 nm). 1H NMR (600 MHz, CDCl3): δ = 1.69–1.82
(m, 2 H), 2.01–2.13 (m, 2 H), 2.34–2.53 (m, 4 H), 2.92–2.96 (m, 1
H), 3.76 (s, 3 H), 6.85 (d, J = 8.7 Hz, 2 H), 7.12 (d, J = 8.7 Hz, 2
H) ppm. 13C NMR (150 MHz, CDCl3): δ = 25.4, 32.9, 41.1, 43.8,
F) ppm. IR (neat): ν = 2939 (w), 1709 (s), 1617 (m), 1419 (m), 1322
˜
(s), 1161 (m), 1112 (s), 1067 (s), 1017 (m) cm–1. Retention times
(BGB 176 SE, initial temp. 40 °C, rate 0.2 °C min–1, final temp.
170 °C): 71.8 min (minor)/72.3 min (major). HRMS: calcd. for
C13H13F3O 242.09; found 242.00.
49.1, 55.1, 113.9, 127.4, 136.4, 158.1, 211.0 ppm. IR (neat): ν =
˜
2932 (m), 2833 (w), 2861 (w), 1705 (s), 1609 (m) 1582(s), 1510 (s),
1444 (m), 1303 (m), 1222 (s), 1176 (s), 1030 (s), 825 (s) cm–1. Reten-
tion times (6-TBDMS-2,3-Me-β-CD, initial temp, 80 °C, rate
0.7 °C min–1, final temp. 180 °C): 105.6 min (minor)/106.0 min
(major). HRMS: calcd. for C13H16O2 204.12; found 204.11.
(R)-3-(3,5-Dimethylphenyl)cyclohexanone (6h): As described in the
General Procedure,
a
solution of CuBr·SMe2 (17.3 mg,
0.084 mmol), ligand 4b (111 mg, 0.126 mmol), and cyclohex-2-en-
one (5, 0.202 mL, 2.1 mmol) in 2-Me-THF (7 mL) was treated with
a solution (0.139 m, 22 mL, 3.15 mmol) of (3,5-dimethylphenyl)-
magnesium bromide in 2-Me-THF (2 mL). After chromatography
(CH2Cl2/cyclohexane 2:3, Rf = 0.22) the product 6h (258 mg, 61%)
was obtained as an oil (85% ee; determined by chiral GC), [α]λ
(20 °C, CH2Cl2, c = 0.9 g/100 mL): [α]589 = +13.5 [α]546 = +24,
[α]405 = +139, [α]365 = +294, [α]334 = +129. CD (c = 0.65 mgmL–1
in CH3CN): Θ (γ) = +5.86 (292 nm). 1H NMR (600 MHz, CDCl3):
δ = 1.71–1.86 (m, 2 H), 2.03–2.16 (m, 2 H), 2.30 (s, 6 H), 2.36–2.58
(m, 4 H), 2.89–2.99 (m, 1 H), 6.83 (s, 2 H), 6.87 (s, 1 H) ppm. 13C
NMR (150 MHz, CDCl3): δ = 21.4, 25.5, 32.8, 41.1, 44.6, 48.9,
(R)-3-(p-Tolyl)cyclohexanone (6c): As described in the General Pro-
cedure, a solution of CuBr·SMe2 (82.2 mg, 0.4 mmol), ligand 4b
(531 mg, 0.6 mmol), and cyclohex-2-enone (5, 0.96 mL, 10 mmol)
in 2-Me-THF (10 mL) was treated with a solution of p-tolylmagne-
sium bromide (0.37 m, 40 mL, 15 mmol) in 2-Me-THF. After
chromatography (EtOAc/cyclohexane 1:9; Rf = 0.14) the product
6c (143 mg, 76%) was obtained as a white solid (95% ee; deter-
mined by chiral GC). [α]λ (20 °C, CHCl3, c = 0.25 g/100 mL): [α]589
= +12, [α]546 = +21, [α]405 = +139, [α]365 = +334, [α]334 = +1029.
CD (c = 0.25 mgmL–1 in CH3CN): Θ (γ) = +13.9 (290 nm). 1H
NMR (600 MHz, CDCl3): δ = 1.71–1.81 (m, 2 H), 2.03–2.16 (m, 2
H), 2.32 (s, 3 H), 2.37–2.56 (m, 4 H), 2.91–3.2 (m, 1 H), 7.11–7.16
(m, 4 H) ppm. 13C NMR (150 MHz, CDCl3): δ = 20.9, 25.4, 32.8,
124.3, 128.2, 138.1, 144.3, 211.1 ppm. IR (neat): ν = 3006 (w), 2933
˜
(m), 2860 (m), 1708 (s), 1601 (s), 1446 (m), 1420 (m), 1220 (m), 847
(m), 830 (m), 703 (s) cm–1. Retention times (6-TBDMS-2,3-Me-β-
CD, initial temp, 80 °C, rate 0.2 °C min–1, final temp. 180 °C):
58.0 min (minor)/58.5 min (major). HRMS: calcd. for C14H18O
202.14; found 202.13.
41.1, 44.3, 49.0, 128.0, 129.2, 136.1, 146.9, 211.1 ppm. IR (neat): ν
˜
= 2946 (m), 2861 (w), 1695 (s), 1514 (m), 1418 (m), 1312 (m), 1220
(m), 882 (m), 820 (s) cm–1. Retention times (6-TBDMS-2,3-Me-β-
CD, initial temp, 80 °C, rate 0.7 °C min–1, final temp. 180 °C):
209.7 min (minor)/210.2 min (major). HRMS: calcd. for C13H16O
188.12; found 188.12.
(R)-3-(3,5-Dimethoxyphenyl)cyclohexanone (6i): As described in the
General Procedure,
a
solution of CuBr·SMe2 (17.3 mg,
0.084 mmol), ligand 4a (113 mg, 0.126 mmol), and cyclohex-2-en-
one (5, 0.202 mL, 2.1 mmol) in 2-Me-THF (7 mL) was treated with
a solution (0.134 m, 23 mL, 3.15 mmol) of (3,5-dimethoxyphenyl)-
magnesium bromide in 2-Me-THF. After chromatography
(R)-3-(4-Fluorophenyl)cyclohexanone (6d): As described in the Ge-
neral Procedure, a solution of CuBr·SMe2 (17.3 mg, 0.084 mmol),
Eur. J. Org. Chem. 2012, 1179–1185
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1183

H.-G. Schmalz et al.
FULL PAPER
(CH2Cl2/cyclohexane 2:3, Rf = 0.14) the product 6i (309 mg, 63%)
was obtained as a colorless oil (77% ee; determined by chiral GC),
(0.33 m, 9.5 mL, 13.15 mmol) of (4-vinylphenyl)magnesium brom-
ide in 2-Me-THF. After chromatography (EtOAc/cyclohexane 2:8;
Rf = 0.21) the product 6m (270 mg, 61%) was obtained as a yellow
oil (83% ee; determined by chiral HPLC). [α]λ (20 °C, CH2Cl2, c =
[α]λ (20 °C, CH2Cl2, c = 1.0 g/100 mL). [α]589 = +11.2 [α]546
=
+20.4, [α]405 = +138, [α]365 = +274, [α]334 = +119. CD (c =
0.56 mgmL–1 in CH3CN): Θ (γ) = +9.8 (292 nm). 1H NMR 1.05 g/100 mL): [α]589 = +1.5 [α]546 = +1.8 [α]405 = +15.1 [α]365
=
(600 MHz, CDCl3): δ = 1.69–1.77 (m, 1 H), 1.78–1.84 (m, 1 H), +39.1. CD (c = 0.52 mgmL–1 in CH3CN): Θ (γ) = +37.3 (297 nm).
2.04–2.06 (m, 1 H), 2.10–2.14 (m, 1 H), 2.41–2.44 (m, 1 H), 2.45–
2.50 (m, 1 H), 2.54–2.57 (m, 1 H), 2.89–2.94 (m, 1 H), 3.76 (s, 6
H), 6.32 (t, J = 2.4 Hz, 1 H), 6.35 (d, J = 2.3, 2 H) ppm. 13C NMR
(150 MHz, CDCl3): δ = 25.4, 32.5, 41.4, 44.9, 90.5, 91.1, 98.1,
1H NMR (600 MHz, CDCl3): δ = 1.72–1.86 (m, 2 H), 2.04–2.07
(m, 1 H), 2.12–2.15 (m, 1 H), 3.33–3.39 (m, 1 H), 2.43–2.46 (m, 1
H), 2.50–2.53 (m, 1 H), 2.55–2.59 (m, 1 H), 2.96–3.01 (m, 1 H),
5.52 (d, J = 11.3 Hz, 1 H), 5.72 (d, J = 17.1 Hz, 1 H), 6.70 (dd, J
104.7, 109.0, 111.8, 123.4, 126.4, 135.7, 135.8, 146.7, 160.9, = 17.7, 10. 9 Hz 1 H), 7.71 (d, J = 7.9 Hz, 2 H), 7.36 (d, J = 8.4 Hz,
210.8 ppm. IR (neat): ν = 2986 (w), 2935 (m), 2833 (w), 1706 (s),
2 H) ppm. 13C NMR (150 MHz, CDCl3): δ = 25.4, 32.7, 41.2, 44.4,
˜
1593 (s), 1457 (s), 1426 (s), 1353 (m), 1316 (s), 1260 (m), 1193 (s),
48.8, 113.6, 126.4, 126.7, 136.1, 136.3, 143.9, 210.9 ppm. IR (neat):
1148 (s), 1060 (s), 827 (s), 695 (s) cm–1. Retention times (6- ν = 2932 (m), 1706 (s), 1603 (w), 1502 (m), 1448 (s), 1439 (m),
˜
TBDMS-2,3-Me-β-CD, initial temp, 70 °C, rate 0.5 °C min–1, final
temp. 180 °C): 71.8 min (minor)/72.3 min (major). HRMS: calcd.
for C14H18O3 234.13; found 234.126.
1233 (s), 1033 (s) cm–1. Retention times (HPLC I, Merck–Hitachi,
hexane/propan-2-ol, 90:10, initial temp. r.t., flow: 1.00 mL min–1):
10.60 min (major)/15.2 min (minor). HRMS: calcd. for C14H16O
200.1201; found 200.120.
(R)-3-(3,4-Methylenedioxyphenyl)cyclohexanone (6k): As described
in the General Procedure, a solution of CuBr·SMe2 (17.3 mg,
0.084 mmol), ligand 4b (111 mg, 0.126 mmol), and cyclohex-2-en-
one (5, 0.20 mL, 2.1 mmol) in 2-Me-THF (7 mL) was treated with
a solution (0.45 m, 7 mL, 3.15 mmol) of [3,4-(methylenedioxy)-
phenyl]magnesium bromide in 2-Me-THF. After chromatography
(EtOAc/cyclohexane 1:9, Rf = 0.22) the product 6k (304 mg, 69%)
was obtained as a yellow oil (65% ee; determined by chiral GC).
Supporting Information (see footnote on the first page of this arti-
1
cle): Copies of H and 13C NMR spectra and chromatograms (ee
analysis) for compounds 6a, 6b, 6c, 6d, 6g, 6h, 6j, 6k, and 6l.
Acknowledgments
This work was carried out in the context of COST D40. We would
like to gratefully acknowledge the Deutscher Akademischer Aus-
tauschdienst (DAAD) for a PhD scholarship award to Q. N. We
also would like to thank Chemetall GmbH, Frankfurt/Main, for
generous gifts of Grignard reagents, Andreas Adler for HPLC mea-
surements, and Dr. Tobias Robert for valuable discussions and ad-
vice.
[α]λ (20 °C, CH2Cl2, c = 0.825 g/100 mL): [α]589 = –10.6 [α]546
=
–10.6. CD (c = 0.62 mgmL–1 in CH3CN): Θ (γ) = +14.46 (290 nm).
1H NMR (600 MHz, CDCl3): δ = 1.69–1.80 (m, 2 H), 2.01–2.04
(m, 1 H), 2.09–2.13 (m, 1 H), 2.31–2.36 (m, 1 H), 2.41–2.46 (m, 2
H), 2.52–2.55 (m, 1 H), 2.88–2.93 (m, 1 H), 5.91 (s, 2 H), 6.64 (dd,
J = 8.0, 1.5 Hz, 1 H), 6.70 (d, J = 1.4 Hz, 1 H), 6.74 (d, J = 8.0 Hz,
1 H) ppm. 13C NMR (150 MHz, CDCl3): δ = 25.4, 33.0, 41.1, 44.5,
49.3, 100.9, 107.0, 108.3, 119.4, 138.4, 146.1, 147.8, 210.9 ppm. IR
(neat): ν = 2932 (w), 1706 (s), 1603 (w), 1502 (m), 1484 (s), 1033
˜
[1] For reviews on asymmetric 1,4-additions in general, see: a) H.-
G. Schmalz, in: Comprehensive Organic Synthesis, vol. 4 (Eds.:
B. M. Trost, I. Fleming), Pergamon, Oxford, 1991, pp. 199–
236; b) B. E. Rossiter, N. M. Swingle, Chem. Rev. 1992, 92,
771–806; c) N. Krause, A. Hoffmann-Röder, Synthesis 2001,
171–196; d) J. Christoffers, G. Koripelly, A. Rosiak, M. Rössle,
Synthesis 2007, 1279–1300.
[2] For reviews on Cu-catalyzed enantioselective 1,4-additions, see:
a) F. López, A. J. Minaard, B. L. Feringa, Acc. Chem. Res.
2007, 40, 179–188; b) M. S. Harutyunyan, T. den Hartog, K.
Geurts, A. J. Minnard, B. L. Feringa, Chem. Rev. 2008, 108,
2824–2852; c) A. Alexakis, J. E. Bäckvall, N. Krause, O. Pam-
ies, M. Dieguez, Chem. Rev. 2008, 108, 2796–2823; d) T. Jer-
phagnon, M. G. Pizzuti, A. J. Minnaard, B. L. Feringa, Chem.
Soc. Rev. 2009, 38, 1039–1075; e) T. Thaler, P. Knochel, Angew.
Chem. 2009, 121, 655–658; Angew. Chem. Int. Ed. 2009, 48,
645–648.
[3] For selected publications, see: a) B. L. Feringa, Acc. Chem. Res.
2000, 33, 346–353; b) I. H. Escher, A. Pfaltz, Tetrahedron 2000,
56, 2879–2888; c) S. J. Degrado, H. Mizutani, A. H. Hoveyda,
J. Am. Chem. Soc. 2001, 123, 755–756; d) M. T. Reetz, A. Gos-
berg, D. Moulin, Tetrahedron Lett. 2002, 43, 1189–1191; e)
P. K. Fraser, S. Woodward, Chem. Eur. J. 2003, 9, 776–783; f)
A. Alexakis, V. Albrow, K. Biswas, M. d’Augustin, O. Prietob,
S. Woodward, Chem. Commun. 2005, 2843–2845; g) L. Su, X.
Li, W. L. Chan, X. Jia, A. S. C. Chan, Tetrahedron: Asymmetry
2003, 14, 1865–1869; for a review on the use of Al-organyls
see: h) P. von Zezschwitz, Synthesis 2008, 1809–1831.
(s) cm–1. Retention times (BGB 176 SE, initial temp. 40 °C, rate
0.2 °C min–1, final temp. 170 °C): 71.8 min (minor)/72.3 min
(major). HRMS: calcd. for C13H16O3 218.094; found 218.095.
(R)-3-(2-Naphthyl)cyclohexanone (6l): As described in the General
Procedure, a solution of CuBr·SMe2 (17.3 mg, 0.084 mmol), ligand
4b (111 mg 0.126 mmol), and cyclohex-2-enone (5, 0.20 mL,
2.1 mmol) in 2-Me-THF (7 mL) was treated with a solution
(0.56 m, 5.6 mL, 3.15 mmol) of 2-naphthylmagnesium bromide in
2-Me-THF. After chromatography (EtOAc/cyclohexane 1:9; Rf =
0.28) the product 6l (306 mg, 68%) was obtained as a white solid
(65% ee; determined by chiral HPLC), [α]λ (20 °C, CH2Cl2, c =
0.98 g/100 mL): [α]589 = +6.5 [α]546 = +6.6 [α]405 = +93.5 [α]365
=
+254. CD (c = 0.63 mgmL–1 in CH3CN): Θ (γ) = +40.6 (292 nm).
1H NMR (600 MHz, CDCl3): δ = 1.77–1.86 (m, 1 H), 1.91–1.99
(m, 1 H), 2.14–2.20 (m, 1 H), 2.38–2.44 (m, 1 H), 2.46–2.41 (m, 1
H), 2.60–2.69 (m, 2 H), 3.14–3.20 (m, 1 H), 7.34–7.36 (d, J =
8.3 Hz, 1 H), 7.41–7.48 (m, 2 H), 7.63 (s, 1 H), 7.72–7.71 (m, 3
H) ppm. 13C NMR (150 MHz, CDCl3): δ = 25.5, 32.6, 41.2, 44.7
48.8, 124.7, 125.6, 126.1, 127.6, 128.3, 132.3, 133.4, 141.6, 210.9
(s) ppm. IR (neat): ν = 3040 (w), 2930 (w), 2860 (w), 1703 (s), 1630
˜
(w), 1259 (m), 1220 (m), 1017 (m), 813 (s), 745 (s) cm–1. Retention
times (HPLC I, Merck–Hitachi, hexane/propan-2-ol, 99:01, initial
temp. r.t., flow: 1.00 mL min–1): 27.32 min (minor)/31.47 min
(major, R). HRMS: calcd. for C16H16O 224.1201; found 224.120.
[4] a) K.-H. Ahn, R. B. Klassen, S. J. Lippard, Organometallics
1990, 9, 3178–3181; b) D. M. Knotter, F. Lambert, M.
van Klaveren, M. D. Janssen, G. Van Koten, Tetrahedron:
Asymmetry 1991, 2, 1097–1100; c) M. Spescha, G. Rihs, Helv.
Chim. Acta 1993, 76, 1219–1230; d) Q.-L. Zhou, A. Pfaltz, Tet-
(R)-3-(4-Vinylphenyl)cyclohexanone (6m): As described in the Gene-
ral Procedure, a solution of CuBr·SMe2 (17.3 mg, 0.084 mmol), li-
gand 4b (111 mg, 0.126 mmol), and cyclohex-2-enone (5, 0.20 mL,
2.1 mmol) in 2-Me-THF (7 mL) was treated with a solution
1184
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Eur. J. Org. Chem. 2012, 1179–1185

Enantioselective 1,4-Additions of Aryl-Grignard Reagents
rahedron 1994, 50, 4467–4478; e) D. Seebach, G. Jaeschke, A.
Pichota, L. Audergon, Helv. Chim. Acta 1997, 80, 2515–2519;
f) E. L. Stangeland, T. Sammakia, Tetrahedron 1997, 53,
16503–16510; g) M. Kanai, Y. Nakagawa, K. Tomioka, Tetra-
hedron 1999, 55, 3843–3854; h) L. Braga, S. J. N. Silva, D. S.
Lüdtke, R. L. Drekener, C. C. Silveira, J. B. T. Rocha, L. A.
Wessjohann, Tetrahedron Lett. 2002, 43, 7329–7331; see also:
i) S. Woodward, Angew. Chem. 2005, 117, 5696–5698; Angew.
Chem. Int. Ed. 2005, 44, 5560–5562.
T. Ireland, G. Grossheimann, C. Wieser-Jeunesse, P. Knochel,
Angew. Chem. 1999, 111, 3397–3400; Angew. Chem. Int. Ed.
1999, 38, 3212–3215.
A. Togni, C. Breutel, A. Schnyder, F. Spindler, H. Laudert, A.
Tijani, J. Am. Chem. Soc. 1994, 116, 4062–4066.
a) F. López, S. R. Harutyunyan, A. J. Minnaard, B. L. Feringa,
J. Am. Chem. Soc. 2004, 126, 12784–12785; b) B. L. Feringa,
R. Badorrey, D. Peña, S. R. Harutyunyan, A. J. Minaard, Proc.
Natl. Acad. Sci. USA 2004, 101, 5834–5838.
L. Palais, A. Alexakis, Tetrahedron: Asymmetry 2009, 20, 2866–
2870.
a) S. Kehrli, D. Martin, D. Rix, M. Mauduit, A. Alexakis,
Chem. Eur. J. 2010, 16, 9890–9904; b) M. Tissot, A. Perez-
Hernandez, D. Müller, M. Mauduit, A. Alexakis, Org. Lett.
2011, 13, 1524–1527; for a review, see: c) C. Hawner, A.
Alexakis, Chem. Commun. 2010, 46, 7295–7306.
G. A. Peterson, H. Nakatsuji, M. Hada, M. Ehara, K. Toyota,
R. Fukuda, J. Hasegawa, M. Ishida, T. Nakajima, Y. Honda,
O. Kitao, H. Nakai, M. Klene, X. Li, J. E. Knox, H. P. Hratch-
ian, J. B. Cross, C. Adamo, J. Jaramillo, R. Gomperts, R. E.
Stratmann, O. Yazyev, A. J. Austin, R. Cammi, C. Pomelli,
J. W. Ochterski, P. Y. Ayala, K. Morokuma,G. A. Voth, P. Sal-
vador, J. J. Dannenberg, V. G. Zakrzewski, S. Dapprich, A. D.
Daniels, M. C. Strain, O. Farkas, D. K. Malick, A. D. Rabuck,
K. Raghavachari, J. B. Foresman, J. V. Ortiz, Q. Cui, A. G. Ba-
boul, S. Clifford, J. Cioslowski, B. B. Stefanov, G. Liu, A. Lia-
shenko, P. Piskorz, I. Komaromi, R. L. Martin, D. J. Fox, T.
Keith, M. A. Al-Laham, C. Y. Peng, A. Nanayakkara, M.
Challacombe, P. M. W. Gill, B. Johnson, W. Chen, M. W.
Wong, C. Gonzalez, J. A. Pople, Gaussian 03, revision d.02,
Gaussian Inc., Pittsburgh PA, 2003.
[5]
[6]
[7]
[16] a) A. D. Becke, J. Chem. Phys. 1993, 98, 5648; b) A. D. Becke,
J. Chem. Phys. 1993, 98, 1372; c) P. J. Stephens, F. J. Devlin,
C. F. Chabalowski, M. J. Frisch, J. Phys. Chem. 1994, 98,
11623.
[17] The TZVP is a triple-ζ basis set with polarization functions.
[18] a) M. Sakai, H. Hayashi, N. Miyaura, Organometallics 1997,
16, 4229–4231; b) Y. Takaya, M. Ogasawara, T. Hayashi, M.
Sakai, J. Am. Chem. Soc. 1998, 120, 5579–5580; c) T. Hayashi,
M. Takahashi, Y. Takaya, M. Ogasawara, J. Am. Chem. Soc.
2002, 124, 5052–5058.
[19] For selected work on Rh-catalyzed 1,4-additions of arylboronic
acids, see: a) M. T. Reetz, D. Mouline, A. Gosberg, Org. Lett.
2001, 3, 4083; b) M. Kuriyama, K. Nagai, K. Yamada, Y.
Miwa, T. Taga, K. Tomiaka, J. Am. Chem. Soc. 2002, 124,
8932; c) R. Amangul, V. Michelet, J.-P. Genet, Synlett 2002,
1791; d) J.-G. Boiteau, R. Imbose, A. J. Minnaard, B. L. Fer-
inga, Org. Lett. 2003, 5, 681; for reviews, see: e) T. Hayashi, K.
Kaori, Chem. Rev. 2003, 103, 2829–2844; f) A. Gutnov, Eur. J.
Org. Chem. 2008, 4547–4554; g) H. J. Edwards, J. D. Hargrave,
S. D. Penrose, C. G. Frost, Chem. Soc. Rev. 2010, 39, 2093–
2105.
[20] A. Miyashita, A. Yasuda, H. Takaya, K. Toriumi, T. Ito, T.
Souchi, R. Noyori, J. Am. Chem. Soc. 1980, 102, 7932–7934.
[21] The increasing importance of phosphite-containing ligands in
enantioselective metal catalysis is reflected in a series of recent
reviews, see: a) H. F. Pérez, P. Etayo, A. Panossian, A. V.-Fer-
ran, Chem. Rev. 2011, 111, 2119–2176; b) P. W. N. M.
van Leeuwen, P. C. J. Kamer, C. Claver, O. Pàmies, M. Dièguez,
Chem. Rev. 2011, 111, 2077–2188; c) H. W. Lam, Synthesis
2011, 13, 2011–2043.
[8]
[9]
[10] a) F. Blume, S. Zemolka, T. Fey, R. Kranich, H.-G. Schmalz,
Adv. Synth. Catal. 2002, 344, 868–883; b) J. Velder, T. Robert,
I. Weidner, J.-M. Neudörfl, J. Lex, H.-G. Schmalz, Adv. Synth.
Catal. 2008, 350, 1309–1315; for selected applications, see: c)
S. Werle, T. Fey, J.-M. Neudörfl, H.-G. Schmalz, Org. Lett.
2007, 9, 3555–3558; d) T. Robert, Z. Abiri, J. Wassenaar, S.
Romanski, J.-M. Neudörfl, H.-G. Schmalz, J. N. H. Reek, Or-
ganometallics 2010, 29, 478–483; e) W. Lölsberg, S. Ye, H.-G.
Schmalz, Adv. Synth. Catal. 2010, 352, 2023–2031.
[11] T. Robert, J. Velder, H.-G. Schmalz, Angew. Chem. 2008, 120,
7832–7835; Angew. Chem. Int. Ed. 2008, 47, 7718–7721.
[12] Q. Naeemi, T. Robert, D. P. Kranz, J. Velder, H.-G. Schmalz,
Tetrahedron: Asymmetry 2011, 22, 887–892.
[13] D. F. Aycock, Org. Process Res. Dev. 2007, 11, 156–159.
[14] K. Krohn, I. Kock, B. Elsässer, U. Flörke, B. Schulz, S. Dra-
eger, G. Pescitelli, S. Antus, T. Kurtán, Eur. J. Org. Chem. 2007,
1123–1129.
[15] M. J. Frisch, G. W. Trucks, H. B. Schlegel, G. E. Scuseria,
M. A. Robb, J. R. Cheeseman, J. A. Montgomery Jr, T. Vreven,
K. N. Kudin, J. C. Burant, J. M. Millam, S. S. Iyengar, J. Tom-
asi, V. Barone, B. Mennucci, M. Cossi, G. Scalmani, N. Rega,
Received: August 29, 2011
Published Online: December 23, 2011
Eur. J. Org. Chem. 2012, 1179–1185
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
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