Copper-catalyzed asymmetric allylic alkylation of racemic cyclic substrates: Application of dynamic kinetic asymmetric transformation (DYKAT)

Article abstract of DOI:10.1002/adsc.200900790

The copper-catalyzed asymmetric allylic alkylation (AAA) is of great interest in organic synthesis. This reaction was extensively studied using a broad range of substrates, ligands and organometallic reagents. However, the use of racemic substrates was still limited. Although some processes of kinetic resolution are reported in the literature, no examples of quantitative deracemization are described as is the case for the Pd-catalyzed allylic alkylation. We present here a full account of our investigations through the development of the first example of such a process in copper-catalyzed AAA. High enantioselectivities (up to 99% ee), scope of the reaction and mechanistic considerations are reported herein.

Full text of DOI:10.1002/adsc.200900790

FULL PAPERS
DOI: 10.1002/adsc.200900790
Copper-Catalyzed Asymmetric Allylic Alkylation of Racemic
Cyclic Substrates: Application of Dynamic Kinetic Asymmetric
Transformation (DYKAT)
Jean-Baptiste Langloisa and Alexandre Alexakisa,*
a
Department of Organic Chemistry, University of Geneva, Quai Ernest Ansermet, 30, 1211 Geneva 4, Switzerland
Fax : (+41)-22-379-3215; phone: (+41)-22-379-6522; e-mail: alexandre.alexakis@unige.ch
Received: November 12, 2009; Published online: February 9, 2010
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adsc.200900790.
Abstract: The copper-catalyzed asymmetric allylic al- ent here a full account of our investigations through
kylation (AAA) is of great interest in organic syn- the development of the first example of such a pro-
thesis. This reaction was extensively studied using a cess in copper-catalyzed AAA. High enantioselectiv-
broad range of substrates, ligands and organometallic ities (up to 99% ee), scope of the reaction and mech-
reagents. However, the use of racemic substrates was anistic considerations are reported herein.
still limited. Although some processes of kinetic res-
olution are reported in the literature, no examples of Keywords: allylic alkylation; allylic compounds;
quantitative deracemization are described as is the asymmetric catalysis; copper; nucleophilic substitu-
case for the Pd-catalyzed allylic alkylation. We pres- tion
Introduction
substitution, many examples of DYKAT exist in the
literature but no report has yet described its use in
The copper-catalyzed allylic alkylation reaction has Cu-catalyzed AAA.[7] Two years after the seminal
received a broad attention during the past three de- work of Bꢀckvall,[8] we have communicated a highly
cades.[1] In combination with non-stabilized nucleo- enantioselective example of DYKAT (up to 92% ee)
philes, this reaction allowed for the introduction of in this chemistry.[9] Further improvements of the pro-
simple alkyl groups in the allylic position. Copper is cess, extension of the scope and mechanistic consider-
known particularly to involve a clean SN2’ displace- ations are reported herein.
ment of the leaving group.[2] For this reason, the reac-
tion has been applied extensively to prochiral sub-
strates, leading to the formation of a stereogenic Results and Discussion
center. The enantiocontrol of this center has been the
subject of many studies and a very high level of enan- Development of the Methodology and Optimization
tioselectivity has been finally observed in this reac- of the Reaction
tion.[3] On the other hand, the use of substrates bear-
ing a racemic stereocenter was far less studied. Some We started our study with the reaction of the phene-
processes of kinetic resolution are reported in the lit- thylmagnesium bromide on different substrates cata-
erature and, to the best of our knowledge, only one lyzed by a combination of copper(I) thiophene-2-car-
example involves a regiodivergent kinetic resolu- boxylate (CuTC, 5 mol%) and L1 (5.5 mol%) in
tion.[4,5] Thus, developing a process of quantitative CH2Cl2 (Table 1). At ꢀ788C, cyclohex-2-en-1-yl ace-
asymmetric allylic alkylation (AAA) starting from a tate 1 or methyl carbonate 2 led to conversions of 70
racemic substrate was of great interest for such a re- and 83%, respectively, but product 8 was recovered in
action. In 1999, Trost introduced the concept of dy- a racemic form (entries 1 and 2, Table 1). In spite of
namic kinetic asymmetric transformation (DYKAT) complete conversions, low enantiomeric excesses
allowing for the transformation of both enantiomers were observed with phosphonite 3 and phosphonate 4
of a racemic substrate in a highly enantioenriched (entries 3 and 4). Product (R)-8 was formed in inter-
product.[6] Initially designed for Pd-catalyzed allylic esting enantioselectivities of 53 and 78% ee when
Adv. Synth. Catal. 2010, 352, 447 – 457
ꢁ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
447

Jean-Baptiste Langlois and Alexandre Alexakis
Table 2. Screening of different solvents.[a]
FULL PAPERS
Table 1. Screening of different leaving groups.[a]
Entry
Solvent
Conversion [%][b]
ee [%][c]
1
2
3
4
5
6
7
DCM
Et2O
THF
MeTHF
i-Pr2O
MTBE
Toluene
>99
>99
>99
>99
40
78 (R)
4 (R)
0
0
26 (R)
70 (R)
6 (R)
83
>99
[a]
Reaction conditions: racemic substrate 6 (0.5 mmol) was
added to solution of CuTC (5 mol%) and L1
a
(5.5 mol%) in dry solvent (2 mL). The reaction mixture
was cooled to ꢀ788C and the Grignard reagent (1M in
Et2O, 1.5 equiv.) was added dropwise.
Conversion relative to the formation of 8, determined by
GC-MS.
[b]
[c]
Entry X
Substrate t
Conversion
ee
[h] [%][b]
[%][c]
Determined by GC on a chiral stationary phase.
1
2
3
4
5
6
7
8
OAc
OCO2Me
OP(O)Ph2
OP(O)
Cl
1
2
3
4
5
6
6
7
15 70
15 83
0
4 (R)
8 (R)
14 (R)
53 (R)
78 (R)
28 (R)
3
3
2
1
1
–
>99
Table 3. Screening of chiral ligands.[a]
(OEt)2
>99
>99
>99
>99
0[e]
Entry
Ligand
Conversion [%][b]
ee [%][c]
Br
Br[d]
OTf
1
2
3
4
5
6
7
8
L1
L2
L3
L4
L5
L6
L7
L8
>99
>99
>99
>99
>99
>99
>99
>99
78 (R)
18 (R)
32 (R)
76 (R)
78 (S)
92 (R)
4 (R)
[e]
–
[a]
Reaction conditions: racemic substrate (0.5 mmol) was
added to a solution of CuTC and L1 in dry CH2Cl2
(2 mL). The reaction mixture was cooled to ꢀ788C and
the Grignard reagent (1M in Et2O, 1.5 equiv.) was added
dropwise.
Conversion relative to the formation of 8, determined by
GC-MS.
Determined by GC on chiral stationary phase.
TBAI (1 equiv) was added.
[b]
8 (R)
[a]
Reaction conditions: racemic substrate 6 (0.5 mmol) was
added to a solution of CuTC (5 mol%) and chiral ligand
(5.5 mol%) in dry CH2Cl2 (2 mL). The reaction mixture
was cooled to ꢀ788C and the Grignard reagent (1M in
Et2O, 1.5 equiv.) was added dropwise.
Conversion relative to the formation of 8, determined by
GC-MS.
Determined by GC on a chiral stationary phase.
[c]
[d]
[e]
The formation of 8 was not observed.
[b]
[c]
chloride 5 and bromide 6 were used (entries 5 and
6).[10] In situ formation of the allylic iodide, by addi-
tion of tert-butylammonium iodide (TBAI) to sub-
strate 6, failed to improve this result (entry 7). No re- tained, respectively (entries 4 and 5). Low enantioin-
action of alkylation occured with triflate 7, likely due duction was achieved in toluene (entry 6).
to a competitive elimination reaction (entry 8). Clear-
The stereochemical outcome of the reaction was
ly, the reactivity of the substrate was closely related next studied in the presence of various phosphorami-
to the enantioselectivity of the product. Thus, bro- dite ligands (Table 3, Figure 1). Ligand L2, which is a
mide 6 was chosen to pursue our investigations.
diastereoisomer of L1, led to a mismatch situation
The reaction was conducted in different solvents (18% ee, entry 2, Table 3). A second match/mismatch
but dichloromethane (DCM) appeared to be the sol- pair was observed with ligands L3 and L4, which gave
vent of choice (entry 1, Table 2). Coordinating sol- the alkylation product in 32 and 76% ee, respectively
vents, such as diethyl ether (Et2O), tetrahydrofuran (entries 3 and 4). Interestingly, the absolute configura-
(THF) and MeTHF afforded product 8 in a racemic tion of the product 8 remains the same with all these
form (entries 2–4).[11] It is worthy of note that the re- ligands (entries 1 to 4). Use of ligand L5 resulted in
action mixture always contained a small amount of similar ee (78%, entry 5) and confirmed that the abso-
Et2O coming from the solution of the Grignard re- lute configuration of the product is linked to the con-
agent. All our efforts to remove it were unfruitful. figuration of the amine part of the ligand. L6 was
Using bulkier diisopropyl ether (i-Pr2O) and methyl found to be the most effective ligand for this reaction,
tert-butyl ether (MTBE), 26 and 70% ee were ob- providing (R)-8 in 92% ee (entry 6). Poor enantiose-
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Adv. Synth. Catal. 2010, 352, 447 – 457

Copper-Catalyzed Asymmetric Allylic Alkylation of Racemic Cyclic Substrates
Figure 1. Phosphoramidite and Simplephos ligands.
lectivities were obtained with tropos ligand[12] L7 and mained low (entries 9 and 10).[16] Different N-hetero-
Simplephos ligand[13] L8 (entries 7 and 8).
cyclic carbenes were also surveyed in this reaction but
Although phosphoramidites gave the best results, always led to poorly enantioenriched product (see
other ligands were evaluated. As biphosphine ligands Supporting Information).
proved to be efficient in many reactions catalyzed by
Among all these ligands, phosphoramidites were by
copper,[14] (R)-BINAP L9 was tested (Figure 2). Using far the most effective for this reaction. For example,
a small excess of ligand compared to copper (L/Cu= ligand L6, providing quantitatively product (R)-8 in
1.1), complete conversion and promising enantioselec- 92% ee, was particularly noteworthy. With this result
tivity were obtained (48% ee, entries 1 and 2, in hand, we decided to further optimize the reaction
Table 4). Varying the electronic and steric properties using the commercially available phosphoramidite L1.
of this ligand led to lower ees (entries 3 and 4). The The influence of the concentration of the reaction
same trend was observed with (R)-Difluorphos L12 mixture was studied (entry 1, Table 5). The enantio-
and (R)-Synphos L13 (entries 5 and 6).[15] Then, we meric excess rose to 86% when the reaction mixture
turned our attention to ferrocene-based biphosphine was diluted from 0.18M to 0.1M (entry 2). Further
ligands. Bisdiphenyl-Walphos L14 and Taniaphos L15 decrease of the reaction concentration did not im-
proved to be weakly reactive (entries 7 and 8). Bisdi- prove this value (entry 3). In such conditions, differ-
cyclohexyl-Josiphos L16 and Taniaphos L17 led to ent sources of copper were investigated. CuCl, CuBr,
better conversions although the enantioselectivies re- CuBr·SMe2 and CuACTHNURGTNEUNG(OAc)2 gave comparable results to
Figure 2. Chiral biphosphine ligands.
Adv. Synth. Catal. 2010, 352, 447 – 457
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449

Jean-Baptiste Langlois and Alexandre Alexakis
FULL PAPERS
Table 4. Screening of biphosphine ligands.[a]
Table 5. Screening of copper sources and final optimiza-
AHCTUNGTRENNUNG
tions.[a]
Entry
Ligand
Conversion [%][b]
ee [%][c]
Entry
CuX
Conversion [%][b]
ee [%][c]
1
2
3
4
5
6
7
8
9
10
L9[d]
L9
>99
>99
>99
>99
>99
>99
40
7
93
>99
34 (S)
48 (S)
6 (S)
36 (S)
8 (S)
12 (S)
32 (S)
6 (R)
38 (S)
28 (S)
1
2
3
4
5
6
7
8
CuTC[d]
CuTC
>99
>99
>99
>99
>99
>99
>99
>99
>99
>99
>99
>99
>99
>99
78 (R)
86 (R)
86 (R)
82 (R)
82 (R)
80 (R)
82 (R)
28 (R)
56 (R)
92 (R)
80 (R)
92 (R)
94 (R)
93 (R)
L10
L11
L12
L13
L14
L15
L16
L17
CuTC[e]
CuCl
CuBr
CuBr·SMe2
Cu
CuCN
Cu(OTf)2
ACHTUNGERTN(NUNG OAc)2
9
ACHTUNGTRENNUNG
10
11
12
13
14
CuI
[a]
Reaction conditions: racemic substrate 6 (0.5 mmol) was
added to a solution of CuTC (5 mol%) and chiral ligand
(5.5 mol%) in dry CH2Cl2 (2 mL). The reaction mixture
was cooled to ꢀ788C and the Grignard reagent (1M in
Et2O, 1.5 equiv.) was added dropwise.
Conversion relative to the formation of 8, determined by
GC-MS.
Determined by GC on a chiral stationary phase.
L/Cu=1.5.
CuI[f]
CuTC[g]
CuTC[d,f,g]
CuI[d,g]
[b]
[a]
Reaction conditions: racemic substrate 6 (0.5 mmol) was
added to a solution of CuX (5 mol%) and L1 (5.5 mol%)
in dry CH2Cl2 (4 mL). The reaction mixture was cooled
to ꢀ788C and the Grignard reagent (1M in Et2O,
1.5 equiv.) was added dropwise.
Conversion relative to the formation of 8, determined by
GC-MS.
Determined by GC on a chiral stationary phase.
0.18M in 6.
0.07M in 6.
L6 was used.
7.5 mol% catalyst loading.
[c]
[d]
[b]
CuTC (entries 4–7). The enantioselectivity dropped
when CuCN and Cu(OTf)2 were employed (entries 8
[c]
[d]
[e]
[f]
AHCTUNGTRENNUNG
and 9). CuI was found to be the best copper source
for this reaction and 92% ee was attained (entry 10).
Its use in combination with L6, surprisingly led to a
lower enantioselectivity (entry 11)! The last improve-
ment of the methodology was made by increasing the
catalyst loading from 5 to 7.5 mol% (entries 12–14).
[g]
tyl)cyclohex-1-ene 11 was obtained in 91% yield and
Finally, a set of three different methods was devel- 90% ee (entry 2). In spite of their volatility, (S)-3-
oped, providing (R)-8 in excellent enantiomeric ex- ethyl- and (S)-3-butylcyclohex-1-enes 12 and 13 were
cesses (Scheme 1).
isolated in good yields and excellent enantiomeric ex-
cesses after derivatization into corresponding mix-
tures of diastereoisomeric epoxides (entries 3 and
4).[17] A Grignard reagent containing a tertiary double
bond could be introduced in 92% ee (entry 5). How-
ever, a very sluggish reaction occurred when allylmag-
Application of the Methodology and Generality of
the Reaction
With these optimal conditions in hand, we started to nesium bromide was tested.[18] Increasing the steric
probe the reaction scope by the addition of various bulk of the alkyl group led to lower enantioinduction.
primary alkyl Grignard reagents to racemic substrate Thus, the use of benzyl- and neopentylmagnesium
6 (Table 6). Using Method A, (R)-3-(4-tert-butoxybu- bromides afforded products 15 and 16 in 28% ee (en-
Scheme 1. Optimized methods A, B and C.
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Adv. Synth. Catal. 2010, 352, 447 – 457

Copper-Catalyzed Asymmetric Allylic Alkylation of Racemic Cyclic Substrates
Table 6. Scope of primary alkyl Grignard reagents.[a]
Table 7. Scope of secondary, tertiary and aryl Grignard re-
agents.[a]
Entry
R
Product
Yield [%][b]
ee [%][c]
Entry S.[b]
R
P.[c] Yield [%][d] ee [%][e]
1
2
3
4
5
6
7
8
9
c-Pent
i-Pr
t-Bu
20
21
22
23
20
20
20
20
20
85
68 (R)
40 (R)
50 (S)
0[e]
68 (R)
68 (R)
68 (R)
66 (R)
74 (R)
1
2
3
4
5
6
7
8
9
10
6
6
6
6
6
6
6
6
9
PhCH2CH2
8
95
92 (R)
90 (R)
90 (S)
92 (S)
92 (R)[g]
28 (R)
28 (R)
8 (S)
86[d]
80[d]
97
t-BuO
Et
N
11 91
12 79[f]
Ph
n-Bu
13 81[f]
c-Pent[f]
c-Pent[g]
c-Pent[h]
c-Pent[i]
c-Pent[j]
G
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
Me2C=CHCH2CH2 14 87
PhCH2
15 81
16 90
17 89
18 93
19 98
t-BuCH2
Me3SiCH2
[h]
AHCTUNGTRENNUNG
PhCH2CH2
44 (R)
38 (R)
[a]
10 PhCH2CH2
Method A: racemic substrate 6 (0.5 mmol) was added to
a solution of CuTC (7.5 mol%) and L1 (8.3 mol%) in
dry CH2Cl2 (4 mL). The reaction mixture was cooled to
ꢀ788C and the Grignard reagent (1M in Et2O,
1.2 equiv.) was added dropwise.
Yield of isolated product. Conversion relative to the for-
mation of the product is given in parentheses.
Determined by GC on chiral stationary phase after deri-
vatization of a sample of the isolated product into the
corresponding epoxides.
[a]
Reaction conditions: racemic substrate (0.5 mmol) was
added to solution of CuTC (7.5 mol%) and L1
(8.3 mol%) in dry CH2Cl2 (4 mL). the reaction mixture
was cooled to ꢀ788C and the Grignard reagent (1M in
Et2O, 1.2 equiv.) was added dropwise.
Substrate.
a
[b]
[c]
[b]
[c]
[d]
[e]
Product.
Yield of isolated product.
Determined by GC on chiral stationary phase after deri-
vatization of a sample of isolated product into corre-
sponding epoxides.
Isolated yield of the corresponding diastereoisomeric ep-
oxides obtained after treatment with mCPBA.
Determined by GC on chiral stationary phase.
Me3SiCH2MgCl was used.
[d]
Isolated yield of the corresponding diastereoisomeric ep-
oxides obtained after treatment with mCPBA.
Determined by SFC on a chiral stationary phase.
L/Cu=1.5.
[e]
[f]
[g]
[h]
[i]
[f]
The reaction was performed at ꢀ958C.
[g]
[h]
10 mol% catalyst loading.
Methoc C.
Method B.
[j]
tries 6 and 7). Only 8% ee was observed for the for-
mation of (S)-(cyclohex-2-enylmethyl)trimethylsilane
17, suggesting that both steric and electronic proper- has not a notable influence on the selectivity of the
ties of the alkyl Grignard reagent have an influence reaction (entry 5). The conversion was complete at
on the stereochemical outcome of the reaction ꢀ958C but the enantioselectivity remained the same
(entry 8). Substrates with different ring sizes were (entry 6). Using 10 mol% of catalyst loading or the
also surveyed. 3-Bromocyclopent-1-ene 9 and 3-bro- Method C did not improve this result (entries 7 and
mocyclohept-1-ene 10 gave products 18 and 19 in low 8). Thanks to the Method B, the product 20 was ob-
enantioselectivities (entries 9 and 10).[19]
tained in a slightly better ee of 74% (entry 10).
Although the hindrance of the Grignard reagent
To further extend the generality of this method, the
seemed to have a detrimental effect on the enantiose- reaction conditions were applied to an acyclic sub-
lectivity of the product, secondary, tertiary and aryl strate. Unfortunately, the poor enantioselectivity ob-
Grignard reagents were examined in more detail tained with 3-bromo-1,3-diphenylprop-1-ene 24 en-
(Table 7). (R)-3-Cyclopentylcyclohex-1-ene 20 was couraged us to continue our study with various cyclic
isolated in good yield and 68% ee (entry 1).[20] Isopro- substrates (Scheme 2). Thus, the six-membered ring
pylmagnesium bromide afforded products 21 in 40% backbone was derivatized with different substitution
ee (entry 2). The introduction of a tertiary alkyl group patterns (Table 8).
gave similar result and (S)-3-tert-butylcyclohex-1-ene
6-Bromo-1-methylcyclohex-1-ene 26 led to product
22 was provided with 50% ee (entry 3). A racemate 32 in almost quantitative yield and 18% ee (entry 1).
was recovered using phenylmagnesium bromide Conjugated substrates 27 and 28 affected dramatically
(entry 4). The addition of cyclopentylmagnesium bro- the reaction outcome and alkylation products were af-
mide was chosen as a model reaction for further in- forded in 0 and 26% ee, respectively (entries 2–5).
vestigations. Increasing the amount of chiral ligand However, the non-coordinating and weakly electron-
Adv. Synth. Catal. 2010, 352, 447 – 457
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Jean-Baptiste Langlois and Alexandre Alexakis
FULL PAPERS
Scheme 3. AAA of compound 39.
in 94% yield and excellent enantiomeric excess of
97.5% (entry 11). This result prompted us to evaluate
a 5-monosubstituted substrate. Thus, 3-bromo-5-meth-
ylcyclohex-1-ene 39 was synthesized as a 1/3 mixture
of cis/trans isomers and submitted to the reaction con-
ditions (Scheme 3).[21] Product 40 was obtained as a
3/1 mixture of cis/trans isomers demonstrating that
the reaction proceeded via a clean inversion proce-
dure. Surprisingly, a match/mismatch situation oc-
curred, providing product cis-40 in 94% ee whereas
product trans-40 was obtained in only 70% ee.
Scheme 2. Various cyclic and acyclic substrates.
Table 8. Extension of the reaction scope.[a]
From a synthetic point of view, the methyl unit is
the most valuable alkyl group. Unfortunately, its in-
troduction via an asymmetric allylic alkylation is
often poorly reactive and poorly selective. To date,
several examples of methylation are reported but few
of them are efficient for both methyl and other alkyl
groups.[22] This reaction was tested in the present con-
ditions (Table 9). Methylmagnesium bromide was
found to be a very efficient reaction partner and (R)-
Ent. S. Method R1
R2 P. Yield [%][b] ee [%][c]
1
2
3
4
5
6
7
8
26
27
27
28
28
29
29
A
C
B
C
B
C
B
Me
CN
CN
CO2Et
CO2Et
Ph
H
H
H
H
H
H
H
H
H
H
32 95
33 86
33 67
34 88
34 82
35 65
35 85
36 81
37 61
37 83
18 (ꢀ)[d]
0
0
8 (ꢀ)
26 (ꢀ)
22 (ꢀ)
82 (ꢀ)
78 (ꢀ)
36 (+)[f]
38 (+)[f]
97.5 (S)[d]
Ph
Ph
29 B[e]
Table 9. Asymmetric allylic methylation.[a]
9
10
11
30
30
31
C
B
B
Br
Br
H
Me 38 94
[a]
Method A: CuTC (7.5 mol%), L1 (8.3 mol%), 0.1M in
substrate; Method B: CuTC (7.5 mol%), L6 (8.3 mol%),
0.18M in substrate; Method C: CuI (7.5 mol%), L1
(8.3 mol%), 0.18M in substrate.
Entry Substrate
R
H
Product Yield [%][b] ee [%]
[b]
[c]
[d]
Yield of isolated product.
Determined by SFC on s chiral stationary phase.
Determined by GC on a chiral stationary phase after de-
rivatization of a sample of isolated product into the cor-
responding epoxides.
n-BuMgBr was used.
Determined by GC on a chiral stationary phase.
1
2
3
4
6
41
99[c]
80
99 (R)[d]
97 (ꢀ)[e]
80 (ꢀ)[f]
60 (R)[d]
29
30
10
Ph 42
Br 43
H
70
44
96[c]
[e]
[f]
[a]
Method B: racemic substrate (0.5 mmol) was added to a
solution of CuTC (7.5 mol%) and L6 (8.3 mol%) in dry
CH2Cl2 (2 mL). The reaction mixture was cooled to
ꢀ788C and the Grignard reagent (3M in Et2O,
1.2 equiv.) was added dropwise.
Yield of isolated product.
Yield determined by GC-MS using 1-methylcyclohexane
as internal standard.
Determined by GC on a chiral stationary phase after de-
rivatization of a sample of the isolated product into the
corresponding epoxides.
Determined by SFC on a chiral stationary phase.
Determined by a GC on chiral stationary phase.
withdrawing phenyl group was a good substitution
pattern for this reaction. Using the Method B, 2-
phenyl-3-phenethylcyclohex-1-ene 35 was isolated in
85% yield and 82% ee (entry 7). 78% ee was obtained
when n-butylmagnesium bromide was used with this
substrate (entry 8). Synthetically interesting substrate
30 gave a clean allylic alkylation in 38% ee (entries 9
and 10). 3-Bromo-5,5-dimethylcyclohex-1-ene 31
proved to be a very efficient substrate, providing 38
[b]
[c]
[d]
[e]
[f]
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Adv. Synth. Catal. 2010, 352, 447 – 457

Copper-Catalyzed Asymmetric Allylic Alkylation of Racemic Cyclic Substrates
Table 10. Effect of styrene on the reaction.[a]
3-methylcyclohex-1-ene 41 was provided in quantita-
tive yield and perfect enantioselectivity of 99% ee
(entry 1). Excellent enantioselection was also ob-
served for the methylation of 6-bromo-1-phenylcyclo-
hex-1-ene 29 (97% ee, entry 2). Substrate 30 gave an
interesting enantiomeric excess of 80% (entry 3).
Only 60% ee was obtained with the seven-membered
ring substrate 10 (entry 4). Clearly, the use of a
methyl group matched perfectly with the reaction re-
quirements (low steric hindrance of the alkyl group).
Entry
Styrene [equiv.][b]
Conversion [%][c]
ee [%][d]
1
2
3
4
0
>99
>99
>99
>99
78 (R)
92 (R)
92 (R)
92 (R)
3
0[e]
3[e]
Mechanistic Considerations
[a]
Reaction conditions: racemic substrae 6 (0.5 mmol) was
added to solution of CuTC (5 mol%) and L1
Having established the scope of the reaction, we fo-
cused our attention on the reaction mechanism. To
elucidate the reaction pathway, a number of ap-
proaches have to be considered including a dynamic
kinetic resolution (DKR, path a), an enantioselective
radical process (path b) or a copper-catalyzed dynam-
ic kinetic asymmetric transformation (DYKAT, path
c).[23]
Path a implied that both enantiomers of the race-
mic substrate are in rapid equilibrium and that only
one of them undergoes the copper-catalyzed AAA.
This pathway could be supported by the fact that al-
lylic bromides are known to perform an allylic rear-
a
(5.5 mol%) in dry CH2Cl2 (2 mL). The reaction mixture
was cooled to ꢀ788C and the Grignard reagent (1M in
Et2O, 1.2 equiv.) was added dropwise.
Styrene was added at ꢀ788C before the Grignard re-
agent.
Conversion relative to the formation of product 8, deter-
mined by GC-MS.
Determined by GC on a chiral stationary phase after de-
rivatization of a sample of isolated product into the cor-
responding epoxides.
[b]
[c]
[d]
[e]
Method A was used.
rangement at room temperature.[24] Such a process complex 48 (K3, K4 >k5, k6). Then, the system is dis-
cannot be completely ruled out, even if it seems un- placed through the intermediate with the lower free
likely that the racemization of the substrate occurred energy for the formation of the product (k5 ¼k6). In-
fast enough in the reaction conditions (ꢀ788C, <1 h). terestingly, different results are observed in the pres-
The huge difference in reactivity observed when al- ent process depending on the nature of the substrate.
lylic halides (5, 6) are used instead of activated allylic Low reactive substrates, such as acetate 1, lead to the
alcohols (1–4) leads us to consider a possible radical formation of product 8 in racemic form whereas
pathway. Indeed, an enantioselective radical process model substrate 6 affords the alkylation product in
(path b) allowing for deracemization of allylic sub- high enantioselectivity (up to 94% ee).
strates has been already described in Ni catalysis and
might be envisaged in Cu chemistry.[25] To evaluate explain this peculiarity. In the first, the equilibration
this alternative, some experiments were conducted in between the Cu(III) intermediates is assumed to take
Two distinct possibilities have to be considered to
AHCTUNGTRENNUNG
the presence of a radical scavenger (Table 10).[26] place only if the reductive elimination is rate limiting
When styrene was added to the model reaction, under (k1, k2 @k5, k6). In the case of the low reactive sub-
non-optimized conditions, the enantiomeric excess in- strate 1, the reductive elimination is expected to
creased from 78 to 92% (entries 1 and 2). Using opti- occur fast, providing 49 virtually with no equilibra-
mized Method A, the addition of styrene did not tions of the intermediates. On the other hand, sub-
affect the reaction outcome (entries 3 and 4). These strate 6 undergoes rapid oxidative addition allowing
experiments confirm the presence of a radical path- for a p-allyl equilibration. Consequently, enantioen-
way in the process, certainly initiated by the in situ re- riched 49 could be obtained in quantitative yield if
duction of a small amount of copper(II) present in k5 ¼k6.
the initial catalyst. Fortunately, this competing path-
However, it is accepted in the literature that the
(III) intermediates are in rapid equilibrium what-
way is only a minor background reaction and is avoid- CuACHTUNGTRENNUNG
ed by using the optimized conditions (dilution, high ever the substrate used.[1f,28] This leads us to the
catalyst loading).
second possibility, which is based on the properties of
Having excluded pathways a and b, the possibility the allylic ion pairs 46 and 47. After the oxidative ad-
of a DYKAT was studied (Figure 3). In such a situa- dition step, all substrates lead to similar CuACTHUNRTGNE(GNU III) inter-
tion, according to the Curtin–Hammett principle,[27] mediates. These intermediates differ only by the
two diastereoisomeric s-allylcopper complexes (46 nature of the counter anion X. However, this differ-
and 47) are in rapid equilibrium via a meso-p-allyl ence can change the reactivity profile of the reac-
Adv. Synth. Catal. 2010, 352, 447 – 457
ꢁ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
453

Jean-Baptiste Langlois and Alexandre Alexakis
FULL PAPERS
Figure 3. Plausible reaction mechanism (R=alkyl or aryl group, k=constant rate, K=equilibrium constant, S=solvent).
tion.[29] Thus, the Cu
ACTHNUTRGNE(NUG III) intermediates stemming presence of CuCN instead of CuTC. The temperature
from the ionization of allylic acetate 1 may have close was increased to ꢀ508C due to the poor reactivity of
rates of elimination (X=OAc, k5 ꢁk6) while 6 would this catalyst. Copper cyanide is known to avoid the
lead to intermediates with different ones (X=Br, k5 ¼ equilibration of the Cu
ACHTUNGTRNE(NUNG III) intermediates by increas-
k6). It may also be speculated that bidentate anions ing the rate of the reductive elimination step.[30] These
(such as acetates or carbonates) may slow down the conditions led to the formation of product 8 in com-
equilibria K3 and K4, thus leading to lower enantiose- plete conversion and 1-deuterated compound 8a was
lectivities.
recovered as the sole isomer. Clearly, the use of
To gain more insight into the reaction mechanism, CuTC implies the formation of a p-allyl whatever the
deuterium-labeling experiments were carried out nature of the substrate. These results strongly support
(Scheme 4). 1-Deuteriocyclohex-2-en-1-yl acetate 1-d1 the second approach of the DYKAT process. The
was submitted to the reaction conditions (Method A). enantioselectivity of the system is due to the nature
In such conditions, racemic 8 was obtained in 60% of the allylic ion pairs, which could induce different
conversion in 18 h. Interestingly, the resulting alkyla- rates of reductive elimination.
tion product was a 45/55 mixture of the 1- and 3-deu-
terated adducts (8a and 8b). It is worthy of note that
the recovered starting material remains intact, avoid- Conclusions
ing the possibility of a copper-catalyzed racemization
of the substrate. This observation suggests that the re- In conclusion, we have disclosed a process of quanti-
action mechanism involves the formation of a p-allyl tative asymmetric allylic alkylation of racemic sub-
intermediate. Then, the reaction was repeated in the strates in copper catalysis. This identified process was
Scheme 4. Deuterium-labeling experiments.
454
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Adv. Synth. Catal. 2010, 352, 447 – 457

Copper-Catalyzed Asymmetric Allylic Alkylation of Racemic Cyclic Substrates
DCM (2 mL) and the solution was stirred for 10 min at
further applied to a range of cyclic substrates. A very
high level of enantioselectivity was achieved for the
addition of primary alkyl Grignard reagents (up to
97.5% ee). Of particular interest was the addition of
MeMgBr, which afforded ees up to 99%. On the
other hand, sterically hindered Grignard reagents
proved to be less efficient. Indeed, this type of nucle-
room temperature. Then, the substrate (0.5 mmol) was
added and the solution was cooled to ꢀ788C. After 10 min
at this temperature, the alkylmagnesium bromide solution
(1M in Et2O, 0.6 mL, 0.6 mmol, 1.2 equiv.) was added drop-
wise and the reaction mixture was stirred for 1 h. The reac-
tion was quenched with an aqueous solution of HCl 1M
(15 mL) and extracted with Et2O (15 mL). Organic layer
was washed with HCl 1M (15 mL) and brine (15 mL), dried
over Na2SO4, filtered and concentrated under vacuum. The
crude mixture was purified on silica gel chromatography
column (pentane). The desired product was recovered as a
colorless liquid. For experimental details, see Supporting In-
formation.
ophile provided hindered CuACTHNUTRGNEUGN(III) intermediates favor-
ing the reductive elimination. Finally, a systematic
study of the reaction mechanism allowed us to define
this process as the first example of DYKAT in
copper-catalyzed asymmetric allylic alkylation. Fur-
ther applications of this process are the subject of on-
going work.
Acknowledgements
Experimental Section
The authors thank the Swiss National Research Foundation
(grant No. 200020-126663) and COST action D40 (SER con-
tract No. C07.0097) for financial support, as well as BASF
for the generous gift of chiral amines.
Typical Procedures for Asymmetric Allylic
Alkylation of Cyclic Racemic Substrates
Method A: In a flame-dried Schlenk tube under an argon
atmosphere, CuTC (7.2 mg, 0.038 mmol, 0.075 equiv.) and
L1 (22.2 mg, 0.041 mmol, 0.083 equiv.) were dissolved in dry
DCM (4 mL) and the solution was stirred for 10 min at References
room temperature. Then, the substrate (0.5 mmol) was
added and the solution was cooled to ꢀ788C. After 10 min
at this temperature, the alkylmagnesium bromide solution
(1M in Et2O, 0.6 mL, 0.6 mmol, 1.2 equiv.) was added drop-
wise and the reaction mixture was stirred for 1 h. The reac-
tion was quenched with an aqueous solution of HCl 1M
(15 mL) and extracted with Et2O (15 mL). The organic layer
was washed with HCl 1M (15 mL) and brine (15 mL), dried
over Na2SO4, filtered and concentrated under vacuum.
Crude mixture was purified on silica gel chromatography
column (pentane). The desired product was recovered as a
colorless liquid. A sample of the isolated product was treat-
ed with mCPBA and Na2HPO4 in DCM. After 1 h, Et2O
(10 mL) was added and the reaction was quenched with an
aqueous solution of saturated Na2S2O3. The organic layer
was washed two times with an aqueous solution of NaOH
1M, dried over Na2SO4, filtered and concentrated under
vacuum. The crude mixture of two diastereoisomeric epox-
ides was directly analyzed in chiral GC.
Method B: CuTC (7.2 mg, 0.038 mmol, 0.075 equiv.) and
L6 (22.6 mg, 0.041 mmol, 0.083 equiv.) were dissolved in dry
DCM (2 mL) and the solution was stirred for 10 min at
room temperature. Then, the substrate (0.5 mmol) was
added and the solution was cooled to ꢀ788C. After 10 min
at this temperature, the alkylmagnesium bromide solution
(1M in Et2O, 0.6 mL, 0.6 mmol, 1.2 equiv.) was added drop-
wise and the reaction mixture was stirred for 1 h. The reac-
tion was quenched with an aqueous solution of HCl 1M
(15 mL) and extracted with Et2O (15 mL). Organic layer
was washed with HCl 1M (15 mL) and brine (15 mL), dried
over Na2SO4, filtered and concentrated under vacuum. The
crude mixture was purified on silica gel chromatography
column (pentane). The desired product was recovered as a
colorless liquid.
[1] a) H. L. Goering, V. D. Singleton, J. Org. Chem. 1983,
48, 1531; b) C. C. Tseng, S. D. Paisley, H. L. Goering, J.
Org. Chem. 1986, 51, 2884; c) J. E. Bꢀckvall, M. Sellen,
B. Grant, J. Am. Chem. Soc. 1990, 112, 6615; d) J. E.
Bꢀckvall, E. S. M. Persson, A. Bombrun, J. Org. Chem.
1994, 59, 4126; e) S. Mori, E. Nakamura, K. Moroku-
ma, J. Am. Chem. Soc. 2000, 122, 7294; f) M. Yamana-
ka, S. Kato, E. Nakamura, J. Am. Chem. Soc. 2004, 126,
6287.
[2] For anti SN2’ see: a) H. L. Goering, V. D. Singleton, J.
Am. Chem. Soc. 1976, 98, 7854; b) H. L. Goering, S. S.
Kantner, J. Org. Chem. 1984, 49, 422; c) C. C. Tseng,
S. J. Yen, H. L. Goering, J. Org. Chem. 1986, 51, 2892.
For syn SN2’ see: d) P. Barsanti, V. Calo, L. Lopez, G.
Marchese, F. Naso, G. Pesce, J. Chem. Soc. Chem.
Commun. 1978, 1085; e) S. Valverde, M. Bernabe, S.
Garciaochoa, A. M. Gomez, J. Org. Chem. 1990, 55,
2294; f) Gallina, P. G. Ciattini, J. Am. Chem. Soc. 1979,
101, 1035; g) B. Breit, P. Demel, Adv. Synth. Catal.
2001, 343, 429; h) P. Demel, M. Keller, B. Breit, Chem.
Eur. J. 2006, 12, 6669.
[3] For former papers: a) M. Vanklaveren, E. S. M. Pers-
son, A. Delvillar, D. M. Grove, J. E. Bꢀckvall, G.
Vankoten, Tetrahedron Lett. 1995, 36, 3059; b) F.
Dubner, P. Knochel, Angew. Chem. 1999, 111, 391;
Angew. Chem. Int. Ed. 1999, 38, 379; c) H. Malda,
A. W. van Zijl, L. A. Arnold, B. L. Feringa, Org. Lett.
2001, 3, 1169; d) A. Alexakis, C. Malan, L. Lea, C.
Benhaim, X. Fournioux, Synlett 2001, 927. For reviews
on recent advances see: e) A. Alexakis, J. E. Bꢀckvall,
N. Krause, O. Pamies, M. Dieguez, Chem. Rev. 2008,
108, 2796; f) C. A. Falciola, A. Alexakis, Eur. J. Org.
Chem. 2008, 3765; g) A. Alexakis, C. Malan, L. Lea, K.
Tissot-Croset, D. Polet, C. Falciola, Chimia 2006, 60,
124; h) S. R. Harutyunyan, T. den Hartog, K. Geurts,
Method C: CuI (7.1 mg, 0.038 mmol, 0.075 equiv.) and L1
(22.2 mg, 0.041 mmol, 0.083 equiv.) were dissolved in dry
Adv. Synth. Catal. 2010, 352, 447 – 457
ꢁ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
455

Jean-Baptiste Langlois and Alexandre Alexakis
FULL PAPERS
A. J. Minnaard, B. L. Feringa, Chem. Rev. 2008, 108,
2824, and references cited therein; i) Z. Lu, S. M. Ma,
Angew. Chem. 2008, 120, 264; Angew. Chem. Int. Ed.
2008, 47, 258; j) H. Yorimitsu, K. Oshima, Angew.
Chem. 2005, 117, 4509; Angew. Chem. Int. Ed. 2005, 44,
4435.
Shimizu, Angew. Chem. 2004, 116, 2278; Angew. Chem.
Int. Ed. 2004, 43, 2228; b) F. Lopez, S. R. Harutyunyan,
A. Meetsma, A. J. Minnaard, B. L. Feringa, Angew.
Chem. 2005, 117, 2812; Angew. Chem. Int. Ed. 2005, 44,
2752; c) T. Llamas, R. G. Arrayas, J. C. Carretero,
Angew. Chem. 2007, 119, 3393; Angew. Chem. Int. Ed.
2007, 46, 3329; d) S. Y. Wang, S. J. Ji, T. P. Loh, J. Am.
Chem. Soc. 2007, 129, 276; e) H. Ito, Y. Kosaka, K.
Nonoyama, Y. Sasaki, M. Sawamura, Angew. Chem.
2008, 120, 7534; Angew. Chem. Int. Ed. 2008, 47, 7424;
f) Y. Du, L. W. Xu, Y. Shimizu, K. Oisaki, M. Kanai,
M. Shibasaki, J. Am. Chem. Soc. 2008, 130, 16146; g) T.
den Hartog, S. R. Harutyunyan, D. Font, A. J. Min-
naard, B. L. Feringa, Angew. Chem. 2008, 120, 404;
Angew. Chem. Int. Ed. 2008, 47, 398.
[4] a) F. Badalassi, P. Crotti, F. Macchia, M. Pineschi, A.
Arnold, B. L. Feringa, Tetrahedron Lett. 1998, 39, 7795;
b) F. Gini, F. Del Moro, F. Macchia, M. Pineschi, Tetra-
hedron Lett. 2003, 44, 8559; c) R. Millet, A. Alexakis,
Synlett 2007, 435; d) R. Millet, A. Alexakis, Synlett
2008, 1797. For a review see: e) M. Pineschi, New J.
Chem. 2004, 28, 657.
[5] a) M. Pineschi, F. Del Moro, P. Crotti, V. Di Bussolo, F.
Macchia, J. Org. Chem. 2004, 69, 2099; b) O. Equey, A.
Alexakis, Tetrahedron: Asymmetry 2004, 15, 1531.
[6] a) B. M. Trost, F. D. Toste, J. Am. Chem. Soc. 1999, 121,
3543; b) B. M. Trost, R. C. Bunt, R. C. Lemoine, T. L.
Calkins, J. Am. Chem. Soc. 2000, 122, 5968; c) B. M.
Trost, M. R. Machacek, H. C. Tsui, J. Am. Chem. Soc.
2005, 127, 7014. For a review see: d) B. M. Trost, D. R.
Fandrick, Aldrichimica Acta 2007, 40, 59.
[7] For recent applications of DYKAT see: a) E. Reyes, A.
Cordova, Tetrahedron Lett. 2005, 46, 6605; b) A. Yama-
guchi, S. Matsunaga, M. Shibasaki, J. Am. Chem. Soc.
2009, 131, 10842; c) K. Leijondahl, L. Boren, R. Braun,
J. E. Bꢀckvall, J. Org. Chem. 2009, 74, 1988; d) D. S.
Reddy, N. Shibata, J. Nagai, S. Nakamura, T. Toru,
Angew. Chem. 2009, 121, 817; Angew. Chem. Int. Ed.
2009, 48, 803.
[15] The authors thank Prof. Dr. J. P. GenÞt and Dr. V.
Vidal-Ratovelomanana for a generous gift of ligands
L12 and L13.
[16] Ligands L14 to L17 were generously donated by Sol-
vias.
[17] See Experimental Section.
[18] According to the work of Bꢀckvall, the reaction of al-
lylmagnesium bromide led to poor conversion and low
ee (60% after 18 h, 54% ee). A. S. E. Karlstrom, J. E.
Bꢀckvall, Chem. Eur. J. 2001, 7, 1981.
[19] Monitoring the reaction of substrate 9 by 31P NMR,
showed that the chiral ligand was damaged.
[20] To determine the absolute configuration of the prod-
ucts stemming from the addition of secondary or terti-
ary alkyl-Grignard reagents to substrate 6, the follow-
ing procedure was carried out. 3-(S)-Cyclohexyl-1,7-oc-
tadiene (78% ee) was prepared according to a reported
procedure. (K. Tissot-Croset, D. Polet, S. Gille, C.
Hawner, A. Alexakis, Angew. Chem. 2004, 116, 2480–
2482; Angew. Chem. Int. Ed. 2004, 43, 2426–2428).
This product underwent a ring closing metathesis by
treatment with Grubbs catalyst first generation, afford-
ing 3-(R)-cyclohexylcyclohexene {[a]2D5: ꢀ51.3 (c 0.99 in
CHCl3, 78% ee)}. In the present case, cyclohexylmagne-
sium bromide was directly added to racemic substrate 6
under the conditions of Method A. 3-(R)-cyclohexylcy-
clohexene was obtained {[a]2D5: ꢀ42 (c 1.0 in CHCl3,
70% ee)}. This represents an important correction com-
pared to our previous report (see ref.[9]), where the ab-
solute configurations were wrongly assigned.
[8] J. Norinder, J. E. Bꢀckvall, Chem. Eur. J. 2007, 13,
4094.
[9] J. B. Langlois, A. Alexakis, Chem. Commun. 2009,
3868.
[10] Absolute configuration of product 8 was assigned by
comparison of optical rotation of product 12 with the
one reported in the literature {[a]2D5: ꢀ58.4 (c 1.2 in tol-
uene, 88% ee}; Lit. [a]25: +77 [(c 1.0 in toluene, 100%
ee) for (R)-3-ethylcycloDhex-1-ene]. G. Buono, C. Siv, G.
Peiffer, C. Triantaphylides, J. Org. Chem. 1985, 50,
1782; G. Consiglio, O. Piccolo, L. Roncetti, F. Morandi-
ni, Tetrahedron 1986, 42, 2043. It was assumed that all
products stemming from the addition of a primary
alkyl-Grignard reagents to substrate 6 have the same
absolute configuration. This represents an important
correction compared to our previous report (see ref.[9]),
where the absolute configurations were wrongly as-
signed.
[21] A. Vallribera, N. Serra, J. Marquet, M. Morenomanas,
Tetrahedron 1993, 49, 6451; see also ref.[1b]
[22] Selected examples of Cu-catalyzed asymmetric allylic
methylation: a) U. Piarulli, P. Daubos, C. Claverie, M.
Roux, C. Gennari, Angew. Chem. 2003, 115, 244;
Angew. Chem. Int. Ed. 2003, 42, 234; b) K. E. Murphy,
A. H. Hoveyda, J. Am. Chem. Soc. 2003, 125, 4690;
c) K. Tissot-Croset, A. Alexakis, Tetrahedron Lett.
2004, 45, 7375; d) F. Lopez, A. W. van Zijl, A. J. Min-
naard, B. L. Feringa, Chem. Commun. 2006, 409; e) A.
Novak, M. J. Calhorda, P. J. Costa, S. Woodward, Eur.
J. Org. Chem. 2009, 898; f) W. P. Hong, A. El-Awa,
P. L. Fuchs, J. Am. Chem. Soc. 2009, 131, 9150.
[11] a) J. E. Bꢀckvall, M. Sellen, B. Grant, J. Am. Chem.
Soc. 1990, 112, 6615; b) E. S. M. Persson, J. E. Bꢀckvall,
Acta Chim. Scand. 1995, 49, 899.
[12] a) A. Alexakis, S. Rosset, J. Allamand, S. March, F.
Guillen, C. Benhaim, Synlett 2001, 1375; b) A. Alexa-
kis, D. Polet, S. Rosset, S. March, J. Org. Chem. 2004,
69, 5660.
[13] a) L. Palais, I. S. Mikhel, C. Bournaud, L. Micouin,
C. A. Falciola, M. Vuagnoux-d’Augustin, S. Rosset, G.
Bernardinelli, A. Alexakis, Angew. Chem. 2007, 119,
7606; Angew. Chem. Int. Ed. 2007, 46, 7462; b) L.
Palais, A. Alexakis, Chem. Eur. J. 2009, 15, 10473.
[14] Selected examples of process using a combination of
biphosphine ligand and copper: a) B. H. Lipshutz, H.
[23] For information about DKR and DYKAT see: a) K.
Faber, Chem. Eur. J. 2001, 7, 5004; b) J. Steinreiber, K.
Faber, H. Griengl, Chem. Eur. J. 2008, 14, 8060.
456
asc.wiley-vch.de
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Adv. Synth. Catal. 2010, 352, 447 – 457

Copper-Catalyzed Asymmetric Allylic Alkylation of Racemic Cyclic Substrates
[24] G. S. Hammond, J. Warkentin, J. Am. Chem. Soc. 1961,
83, 2554.
[29] a) A. Streitwieser, E. G. Jayasree, S. S. H. Leung,
G. S. C. Choy, J. Org. Chem. 2005, 70, 8486; b) A.
Streitwieser, E. G. Jayasree, F. Hasanayn, S. S. H.
Leung, J. Org. Chem. 2008, 73, 9426.
[25] S. Son, G. C. Fu, J. Am. Chem. Soc. 2008, 130, 2756.
[26] For an example of the use of styrene as radical scav-
enger see: K. Y. Li, A. Alexakis, Angew. Chem. 2006,
118, 7762; Angew. Chem. Int. Ed. 2006, 45, 7600.
[27] J. I. Seeman, Chem. Rev. 1983, 83, 83.
[30] a) J. P. Gorlier, L. Hamon, J. Levisalles, J. Wagnon, J.
Chem. Soc. Chem. Commun. 1973, 88; b) J. P. Marino,
D. M. Floyd, Tetrahedron Lett. 1979, 675; c) H. L.
Goering, S. S. Kantner, J. Org. Chem. 1984, 49, 422;
d) H. L. Goering, C. C. Tseng, J. Org. Chem. 1983, 48,
3986.
[28] In particular cases the leaving group avoids the forma-
tion of a p-allyl, see ref.[2g]
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