Enantioselective copper-catalysed allylic alkylation of cinnamyl chlorides by Grignard reagents using chiral phosphine-phosphite ligands

Article abstract of DOI:10.1002/adsc.201000213

The copper(I)-catalysed S_N2'-type allylic substitution of E-3-aryl-allyl chlorides (cinnamyl chlorides) using Grignard reagents represents a powerful method for the synthesis of compounds carrying a benzylic stereocentre. By screening a small library of modular chiral phosphine-phosphite ligands a new copper(I)-based catalyst system was identified which allows the performance of such reactions with exceptional high degrees of regio- and enantioselectivity. Best results were obtained using TADDOLderived ligands (3 mol%), copper(I) bromide?dimethyl sulfide (CuBr?SMe₂) (2.5 mol%) and methyl tert-butyl ether (MTBE) as a solvent. Various (1- alkyl-allyl)benzene derivatives were prepared with up to 99% ee (GC) in isolated yields of up to 99%. In most cases the product contained less than 3% of the linear regioisomer (except for ortho-substituted substrates). Both electron-rich and electron-deficient cinnamyl chlorides were successfully employed. The absolute configuration of the products was assigned by comparison of experimental and calculated CD spectra. The substrates were prepared from the corresponding alcohols by reaction with thionyl chloride. Initially formed mixtures of regioisomeric allylic chlorides were homogenised by treatment with CuBr?SMe₂ (2.5 mol%) in the presence of triphenyl phosphine (PPh₃) (3 mol%) in MTBE at low temperature to give the pure linear isomers. In reactions with methylmagnesium bromide (MeMgBr) an ortho-diphenylphosphanyl-arylphosphite ligand with an additional phenyl substituent in ortho'-position at the aryl backbone proved to be superior. In contrast, best results were obtained in the case of higher alkyl Grignard reagents (such as ethyl-, n-butyl-, isopropyl-, and 3-butenylmagnesium bromides) with a related ligand carrying an isopropyl substituent in ortho'-position. The method was tested on a multimmol scale and is suited for application in natural product synthesis.

Full text of DOI:10.1002/adsc.201000213

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DOI: 10.1002/adsc.201000213
Enantioselective Copper-Catalysed Allylic Alkylation of
Cinnamyl Chlorides by Grignard Reagents using Chiral
Phosphine-Phosphite Ligands
Wibke Lçlsberg,a Shute Ye,a and Hans-Gꢀnther Schmalza,*
a
Department fꢀr Chemie, Universitꢁt zu Kçln, Greinstraße 4, 50939 Kçln, Germany
Fax : (+49)-221-470-3064; phone: (+49)-221-470-3063; e-mail: schmalz@uni-koeln.de
Received: March 18, 2010; Revised: July 8, 2010; Published online: August 16, 2010
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adsc.201000213.
Abstract: The copper(I)-catalysed SN2’-type allylic spectra. The substrates were prepared from the cor-
substitution of E-3-aryl-allyl chlorides (cinnamyl responding alcohols by reaction with thionyl chlo-
chlorides) using Grignard reagents represents a pow- ride. Initially formed mixtures of regioisomeric allyl-
erful method for the synthesis of compounds carry- ic chlorides were homogenised by treatment with
ing a benzylic stereocentre. By screening a small li- CuBr·SMe2 (2.5 mol%) in the presence of triphenyl
brary of modular chiral phosphine-phosphite ligands phosphine (PPh3) (3 mol%) in MTBE at low temper-
a new copper(I)-based catalyst system was identified ature to give the pure linear isomers. In reactions
which allows the performance of such reactions with with methylmagnesium bromide (MeMgBr) an
exceptional high degrees of regio- and enantioselec- ortho-diphenylphosphanyl-arylphosphite ligand with
tivity. Best results were obtained using TADDOL- an additional phenyl substituent in ortho’-position at
derived ligands (3 mol%), copper(I) bromide·di- the aryl backbone proved to be superior. In contrast,
methyl sulfide (CuBr·SMe2) (2.5 mol%) and methyl best results were obtained in the case of higher alkyl
tert-butyl ether (MTBE) as a solvent. Various (1- Grignard reagents (such as ethyl-, n-butyl-, isopro-
alkyl-allyl)benzene derivatives were prepared with pyl-, and 3-butenylmagnesium bromides) with a re-
up to 99% ee (GC) in isolated yields of up to 99%. lated ligand carrying an isopropyl substituent in
In most cases the product contained less than 3% of ortho’-position. The method was tested on a multi-
the linear regioisomer (except for ortho-substituted mmol scale and is suited for application in natural
substrates). Both electron-rich and electron-deficient product synthesis.
cinnamyl chlorides were successfully employed. The
absolute configuration of the products was assigned Keywords: allylic substitution; asymmetric catalysis;
by comparison of experimental and calculated CD chiral P,P ligands; copper(I); Grignard reagents
Introduction
organo-zinc[6] or Grignard reagents.[7] Recently,
Grignard reagents were used in the Cu-catalysed sub-
The development of efficient protocols for catalytic stitution of b-disubstituted allylic halides and 1,4-
enantioselective C C bond formation is a central task dihalo-2-butenes.[8]
À
of chemical synthesis research.[1] While considerable
As summarized in recent reviews[2,9] a variety of
progress has been made towards the development of chiral catalysts have been employed in these reac-
metal-catalysed allylic substitution reactions in gener- tions. A preformed arenethiolato-Cu(I) complex was
al, comparably few copper-based methods have been used by Bꢁckvall and van Koten;[5a,b] however, cata-
established allowing the use of organometallic re- lysts are usually prepared in situ from a Cu(I) salt and
agents.[2] Early studies on the regioselectivity of the a chiral ligand, such as ferrocenyl-based thiolates,[5c]
reaction of allylic esters with cuprates[3] paved the amino-diphosphanes,[7e] phosphoramidites,[7a–d,8], spiro-
way for the development of asymmetric[4] and even phosphoramidites,[6d] aminoalkyl-phosphites,[7a,b] or N-
catalytic asymmetric methods.[5] Later, allylic halides heterocyclic carbenes.[10]
were also employed in enantioselective copper-cata-
While high enantioselectivities (up to 99% ee) were
lysed SN2’-type allylic alkylations mainly using observed in certain cases, the applicability of the
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Wibke Lçlsberg et al.
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methodology in the context of complex synthesis is namyl chlorides by alkyl Grignard reagents – as a
still limited. An example is the Cu-catalysed reaction general enantioselective entry to various arene build-
of cinnamyl chlorides with MeMgBr where the enan- ing blocks with a benzylic chirality centre.
tioselectivity drops from 96% to 66% ee on introduc-
tion of an ortho-substitutent.[7c] Also, regioselectivities
are frequently unsatisfactory and rarely exceed 90%. Results and Discussion
Therefore, the search for new efficient catalyst sys-
tems also tolerating a broader substrate scope still In the present study, fourteen phosphine-phosphite li-
represents an important goal.
gands (1a–n) were tested (Figure 2). These ligands
We have recently developed a new class of chiral were all prepared from the corresponding substituted
phosphine-phosphite ligands of type 1 (Figure 1) phenols in up to 60% overall yield following the es-
tablished four-steps protocol.[11c] Most of the ligands
used contain a diphenylphosphanyl tooth. Only ligand
1i carries a bis-3,5-dimethyl-4-methoxyphosphine unit
to probe a system with different electronic and steric
properties at this position. To build up the phosphite
unit, either (R,R)-TADDOL[16] or (S)-BINOL[17] were
used as chiral diol. In awareness of the crucial impor-
Figure 1. Phenol-derived modular ligands of type 1.
tance of the substituents at the central arene ring (es-
pecially in ortho-position to the oxy-functionali-
ty)[11b,13,14] on the ligand performance, a set of differ-
which are readily synthesized from a phenol and a ently substituted phenols was employed for the ligand
chiral diol (such as BINOL or TADDOL).[11] The synthesis.
modular nature of these ligands not only allows the
As a substrate for an initial ligand screening we se-
synthesis of whole ligand libraries but also facilitates lected commercial trans-cinnamyl chloride (5) and
the optimisation of the ligand structure for individual studied the regio- and enantioselectivity of its reac-
reactions. So far, these ligands were applied with out- tion with methyl-magnesium bromide (according to
standing success in the Rh-catalysed asymmetric hy- Scheme 2) using either Cu(I)-thiophene carboxylate
droboration of styrenes,[11b,12] the Cu-catalysed asym- (CuTC)[18] or CuBr·SMe2 as the Cu source.
metric 1,4-addition of Grignard reagents to enones,[13]
and the Rh-catalysed asymmetric hydroformylation of
styrene.[14]
Encouraged by these results and in continuation of
our interests in the field of marine diterpenoid total
synthesis[15] we envisioned to exploit these ligands in
the enantioselective synthesis of substituted (1-
methyl-allyl)benzenes (such as 4) by means of a Cu-
catalysed allylic substitution. As shown in Scheme 1,
compound 4 would represent an attractive precursor
Scheme 2. The parent reaction investigated in this study.
for organoboron intermediates of type 3 from which
the calamenene 2 is accessible in a few efficient
steps.[12]
The results of the first screening of our prototype li-
We here disclose the details of a study which has brary, summarised in Table 1, clearly revealed the po-
led to the identification of highly selective new cata- tential of the phosphine-phosphite ligands of type 1
lyst systems (exploiting ligands of type 1) for the Cu- for Cu-catalysed allylic substitution reactions using
catalysed enantioselective allylic substitution of cin- Grignard reagents. Best results were obtained with li-
gands 1c and 1h, which both gave a very good enan-
tioselectivity (94% ee) and a satisfying (ca. 9:1) regio-
selectivity (g-selectivity) in favour of the desired
branched product 6a. Again, a dramatic impact of the
the substituent(s) at the ligand backbone (especially
in the ortho position to the phosphite unit) was
found, as the comparison of the results obtained with
ligands 1a–1h confirms. In contrast to the Cu(I)-cata-
lysed 1,4-addition to cyclic enones,[13] ligands 1e and
1f (with a bulky tert-butyl substituent in the ortho-po-
sition) exhibited only a moderate enantioselectivity.
Scheme 1. The (1-methyl-allyl)benzene derivative 4 as a pre-
cursor for 2 and related terpenoids.
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Enantioselective Copper-Catalysed Allylic Alkylation of Cinnamyl Chlorides by Grignard Reagents
Figure 2. Phosphine-phosphite ligands of type 1 used in the present study.
Also noteworthy is the fact that the TADDOL-de- identified as the preferred source of Cu(I). Remarka-
rived ligands generally performed much better than bly, best results were achieved in MTBE, and, accord-
the BINOL-derived ligands (1j–1n). The influence of ingly, this solvent was used in all further experiments.
the specific copper source on the selectivities was not
The outstanding selectivity in the synthesis of 6a
sufficiently pronounced to allow any conclusions at under the above-mentioned conditions (Table 2;
this stage. Noteworthy is also the fact that the R-con- entry 9) was obtained using a 2.5-fold excess of the
figurated enantiomer (R-6a) was preferentially Grignard reagent in the presence of 5% of the cata-
formed in all experiments (for the assignments, see lyst. To further improve the method (also from an
below).
ecological point of view) we were interested in reduc-
We selected the “phenyl-substituted” ligand 1h for ing the amount of catalyst and Grignard reagent to a
the further optimisation of the reaction conditions. minimum. As shown in Table 3 it was indeed possible
After confirming the high selectivity initially obtained to reduce the amount of Grignard reagent to
with this ligand (Table 1; entry 16) on a 3.3 mmol 1.2 equivalents and to halve the amount of catalyst
scale (using 500 mg of 5), we next investigated the in- without losing selectivity (entry 3). Further reduction
fluence of the solvent. Besides CH2Cl2 (used initially), of the catalyst load to 1.25 equivalents, however, led
we tested THF, its less coordinating 2-methyl ana- to lower (still remarkable) selectivities.
logue (MeTHF),[13] Et2O, and methyl tert-butyl ether
In another series of experiments (Table 4) the
(MTBE). As the results shown in Table 2 indicate, we effect of the reaction temperature was briefly studied.
obtained excellent enantioselectivities (up to >99% By successively increasing the temperature in steps of
ee) and regioselectivities (up to 98/2) in the less coor- 208C a continuous decrease of regio- as well as of
dinating ethereal solvents. Moreover, CuBr·SMe2 was enantioselectivity was observed. Nevertheless, the fact
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Table 1. Performance of different ligands of type 1 in the
Cu-catalysed reaction of 5 with MeMgBr according to
Scheme 2 under standard conditions in CH2Cl2.[a]
Table 2. Influence of the solvent on the Cu-catalysed reac-
tion of 5 with MeMgBr according to Scheme 2 in the pres-
ence of ligand 1h.[a]
Entry
Ligand
Cu(I) source
6a/6b[b]
ee [%][b]
Entry
Solvent
CH2Cl2
Cu(I) source
6a/6b[b]
ee [%][b]
1
2
3
4
5
6
7
8
1a
CuBr·SMe2
CuTC
CuBr·SMe2
CuTC
CuBr·SMe2
CuTC
CuBr·SMe2
CuTC
CuBr·SMe2
CuTC
CuBr·SMe2
CuTC
CuBr·SMe2
CuTC
CuBr·SMe2
CuTC
CuBr·SMe2
CuTC
CuBr·SMe2
CuTC
CuBr·SMe2
CuTC
CuBr·SMe2
CuTC
CuBr·SMe2
CuTC
CuBr·SMe2
CuTC
59/51
2/98
15
30
56
49
95
94
75
36
61
43
62
61
73
5
94
94
86
85
23
11
0
1
2
3
4
5
6
7
8
CuBr·SMe2
CuTC
CuBr·SMe2
CuTC
CuBr·SMe2
CuTC
CuBr·SMe2
CuTC
88/12
93/7
94
94
39
19
>99
58
99
97
>99
99
1b
1c
1d
1e
1f
1g
1h
1i
65/35
75/25
88/12
80/20
45/55
25/75
77/23
51/49
98/2
84/16
29/71
3/97
88/12
93/7
THF
10/90
24/76
81/19
48/52
96/4
86/14
98/2
MeTHF
Et2O
9
9
10
MTBE
CuBr·SMe2
CuTC
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
93/7
[a]
Conditions: 5 (300 mmol), Cu(I) source (5 mol%), ligand
1h (6 mol%) in solvent (2 mL) at À788C, addition of
MeMgBr in CH2Cl2 over 7 h.
The 6a/6b ratio and the enantiomeric excess (ee) of 6a
were determined by CG analysis; the conversion of 5
was always >99%. Values given are the average of two
independent experiments.
[b]
94/6
93/7
1j
10/90
29/71
11/89
24/76
14/86
12/88
20/80
40/60
7/93
Table 3. Influence of the catalyst loading on the Cu-cata-
lysed reaction of 5 with MeMgBr according to Scheme 2 in
the presence of ligand 1h.[a]
1k
1l
3
22
7
3
2
Entry Cu(I)
[mol%]
Ligand
[mol%]
MeMgBr
(equiv.)
6a/
ee
6b[b] [%][b]
1m
1n
1
2
3
4
5
5
2.5
2.5
1.9
6
3
3
1.7
1.5
2.5
5
1.2
1.2
1.2
98/2 >99
98/2 >99
98/2 >99
98/2 98
2
1
20/80
[a]
Conditions: 5 (300 mmol), Cu(I) source (5 mol%), ligand
(6 mol%) in CH2Cl2 (2 mL) at À788C, addition of
MeMgBr in CH2Cl2 over 7 h.
The 6a/6b ratio and the enantiomeric excess (ee) of 6a
were determined by CG analysis; the conversion of 5
was always >99%. Values given are the average of two
independent experiments. In all experiments R-6a was
formed as the major enantiomer.
1.25
87/13 98
[a]
[b]
Conditions:
5 (300 mmol), CuBr·SMe2, ligand 1h in
MTBE (2 mL) at À788C, slow addition of MeMgBr in
CH2Cl2 over 7 h.
[b]
The 6a/6b ratio and the enantiomeric excess (ee) of 6a
were determined by CG analysis; the conversion of 5
was always >99%. Values given are the average of two
independent experiments.
that useful regio- and enantioselectivities were still
obtained at 08C (or even at 208C) convincingly re- products of type 8 were frequently obtained as insep-
flects the robustness of the reaction system.
arable mixtures together with the isomeric allylic
chlorides of type 9 (for instance in the case of com-
pounds 10, 12, 14, 26 and 28). However, this problem
was solved by simply stirring an MTBE solution of
the mixtures with catalytic amounts of CuBr·SMe2
Substituted Cinnamyl Chlorides
Having developed efficient and reliable conditions for and PPh3 at À788C. Under these conditions, an iso-
the reaction of 5 as the parent substrate we next merisation-equilibration process[21] cleanly produced
turned our attention to the study of other trans-cin- the thermodynamically more stable linear allylic
namyl chlorides (8) with different substitution pat- chlorides (8), which could then be isolated in pure
terns at the arene ring (see Table 5). The required al- form.
lylic chlorides (8) were prepared from the correspond-
Substrate 24 (with a triple substituted double bond)
ing cinnamic acid derivatives (7) by reduction of an in was synthesised from 4-tert-butylbenzaldehyde
situ-activated derivative[19] and subsequent treatment through aldol condensation with propionaldehyde,
of the intermediate allylic alcohols with thionyl chlo- followed by reduction and chlorination (Scheme 3). In
ride in ether[20] (Scheme 3). As a complication, the the case of 24 only a 1:1 mixture of regioisomeric al-
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Enantioselective Copper-Catalysed Allylic Alkylation of Cinnamyl Chlorides by Grignard Reagents
Table 4. Influence of the reaction temperature on the Cu-
catalysed reaction of 5 with MeMgBr according to Scheme 2
in the presence of ligand 1h.[a]
precedented employment of substrates with reactive
functional groups such as ester or cyano (entries 9
and 10). All in all, the results shown in Table 5 docu-
ment a useful scope of differently substituted trans-
cinnamyl chlorides (8), which can be transformed
using the standard protocol. Further improvement of
the selectivity may even be achieved in specific cases
by individual optimisation of the reaction conditions.
Entry
Temp. [8C]
6a/6b[b]
ee [%][b]
1
2
3
4
5
6
À78
À60
À40
À20
0
98/2
97/3
89/11
95/5
91/9
89/11
99
95
92
94
92
86
20
Variation of the Grignard Reagent
[a]
Conditions: 5 (300 mmol), CuBr·SMe2 (2.5 mol%), ligand
1h (3 mol%) in MTBE (2 mL), slow addition of
MeMgBr in CH2Cl2 over 7 h.
The 6a/6b ratio and the enantiomeric excess (ee) of 6a
were determined by CG analysis; the conversion of 5
was always >99%. Values given are the average of two
independent experiments.
Having demonstrated that the standard catalyst
system developed (based on ligand 1h) allows for the
Cu-catalysed allylic substitution of a broad range of
substrates of type 8 in a highly selective fashion using
methylmagnesium bromide, we were also interested
in the question whether different Grignard reagents
can also be employed.
[b]
In a first experiment using the parent substrate 5
and EtMgBr the expected product (30a) was obtained
in high yield and with excellent g-selectivity; however,
the enantioselectivity was only 66% ee (Table 6,
entry 1). At this point we remembered that ligand 1c
had shown a similar performance as 1h in the initial
ligand screening (Table 1). Therefore, we tested this
less bulky ligand (1c) in the reaction of cinnamyl
chloride 5 with EtMgBr and were pleased to find a
significantly improved enantioselectivity of 85% ee
(Table 6, entry 2).
Scheme 3. Preparation of substituted cinnamyl chlorides.
Conditions: a) NEt3, THF, ethyl chloroformate; b) NaBH4
THF, then MeOH; c) SOCl2, Et2O; d) CuBr·SMe2
(2.5 mol%), PPh3, (3 mol%), MTBE, À788C.
As Table 6 also shows, the reaction of 5 with n-
butyl-MgBr (as a higher n-alkyl Grignard reagent)
proceeded under the same conditions with a remark-
lylic chlorides was obtained after isomerisation of the able g-selectivity but with only 76% ee (Table 6,
initial 1.4:1 mixture with CuBr·SMe2 and PPh3. The entry 3). In contrast, 3-butenyl-MgBr afforded the
isomerisation of 28 lead to a 2:1 mixture in favour of corresponding product (32a) with virtually perfect
the branched allylic chloride.
enantioselectivity and a respectable regioselectivity of
The differently substituted cinnamyl chlorides (10, 94:6 (Entry 4). Finally, it was found that isopropyl-
12, 14, 16, 18, 20, 22, 24, 26 and 28) were then reacted MgBr (as a sterically more demanding, secondary
with MeMgBr in the presence of CuBr·SMe2 Grignard reagent) reacted with high g-selectivity to
(2.5 mol%) and ligand 1h (3 mol%), according to the give the branched hydrocarbon 33a with an enantiose-
optimum conditions for the parent substrate
5
lectivity of 82% ee.
(Table 3; entry 3). Much to our satisfaction we found
that under these standard conditions all substrates af-
forded the desired branched substitution products in Configuration Assignments
high yield with good to excellent selectivity. As the
results given in in Table 5 reveal, all para- or meta- The absolute configuration of 6a and the various allyl-
substituted substrates gave rise to high enantio- (96– ic substitution products given in Table 5 and Table 6
99% ee) and regioselectivities (ꢀ94:6). While a low was assigned by comparison of experimental and cal-
regioselectivity was observed for the ortho-chloro- culated circular dichroism (CD) spectra. For this pur-
substituted substrate 12, the result obtained for the pose, the CD spectra of these compounds in MeOH
ortho-methoxycinnamyl chloride (18) is still in a suita- were calculated through time-dependent density-func-
ble range for possible synthetic applications.
tional theory (TDDFT)[22] using Gaussian ꢃ03W[23]
,
The reaction of compound 24 to give 25a (Table 5, the B3LYP functional[24] and the TZVP basis set.[25]
entry 8) deserves attention because it suggests that This methodology had previously been used success-
cinnamyl chlorides with a substituent in the b-position fully for the prediction of CD spectra of related chiral
are also suitable substrates. Noteworthy is also the un- benzene derivatives.[26]
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Wibke Lçlsberg et al.
Table 5. CuI)-catalysed reaction of substituted cinnamyl chlorides with MeMgBr in the presence of ligand 1h.[a]
FULL PAPERS
Entry Substrate
Product
Yield[b] Regioselectivity (g/a)[c] ee [%][c] Configuration[d]
1
2
3
4
5
10
12
14
16
18
11a
93
99
99
82
93
94/6
97
87
97
98
93
R
S
13a
15a
17a
19a
55/45
98/2
R
R
R
99/1
85/15
6
20
21a
99
98/2
99
R
7
22
24
23a
25a
100
86
99/1
96
94
R
R
8[e]
87/13
9
26
28
27a
29a
76
98
97/3
97/3
99
84
R
R
10[f]
[a]
Conditions: substrate (300 mmol), CuBr·SMe2 (2.5 mol%), ligand 1h (3 mol%) in MTBE (2 mL), slow addition of
MeMgBr (1.2 equiv.) in CH2Cl2 over 7 h. Conversion was >99%.
Yield of isolated products (g+a) after purification by filtration over silica gel.
The ratio of regioisomers and the enantiomeric excess (ee) of the g-product were determined by CG analysis; the conver-
sion of substrate was always >99%. Values given are the average of two independent experiments.
The absolute configuration was determined by correlation of experimental and calculated CD spectra.
In this case, the substrate (24) was employed as a 1.4:1 mixture of the regioisomeric allylic chlorides (compare Scheme 3).
In this case, the substrate (28) was employed as a 2:1 mixture of the regioisomeric allylic chlorides (compare Scheme 3).
[b]
[c]
[d]
[e]
[f]
1
As an illustration, the measured and calculated CD brational contributions of the arene via Lb transi-
spectra of compounds (R)-15a and (R)-33a are depict- tions, which change their sign depending on the tem-
ed in Figure 3. The clear consensus in the region from perature and therefore are of little value for the con-
1
210 nm to 235 nm (emerging from La transitions) in- figuration assignment.[26d,27] The thus determined ab-
dicates them in both cases belonging to the same solute configurations are in agreement with the litera-
enantiomer.[26c,d] Meanderings in the area of smaller ture for compounds 6a, 15a, 17a, 23a, 30a, 31a, and
wavelengths (>240 nm) arise from weak contrary vi- 32a based on the sign of the [a]D values.[28] The only
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Enantioselective Copper-Catalysed Allylic Alkylation of Cinnamyl Chlorides by Grignard Reagents
disagreement was found for compound 33a. We ob-
tained this product with an enantiomeric purity of
82% ee (GC) and the sample (containing 2% of the
achiral linear regioisomer) showed a positive [a]D20
value of +42 (c 1.22 in CHCl3). In trust of the CD
correlation (Figure 3), we suggest that the (+)-enan-
tiomer is (R)-configurated which contradicts the pre-
vious assignment.[29]
Conclusions
The Cu(I)-catalysed SN2’-type allylic substitution of
cinnamyl chlorides by Grignard reagents was investi-
gated using chiral phosphine-phosphite ligands of
type 1. By screening a small prototype ligand library
we identified the two TADDOL-derived ligands 1c
and 1h as being particularly powerful. Under opti-
mised conditions the reaction of the parent substrate
5 with MeMgBr could be performed with an unprece-
dented degree of regio- and enantioselectivity. Fur-
thermore it was shown that the protocol developed
allows the use of a rather broad scope of substituted
cinnamyl chlorides and of different Grignard re-
agents.
We are confident that the modular nature of the li-
Figure 3. Calculated (line) and experimental (dotted) CD
spectra of compounds 15a (top) and 33a (bottom) in MeOH.
gands and their ease of preparation offer promising
options for the optimisation of individual transforma-
tions in the context of future applications, for in-
stance, in the synthesis of bioactive compounds proc-
essing a benzylic stereocentre.
Table 6. Cu(I)-catalysed reaction of the parent cinnamyl chloride (5) with different Grignard reagents in the presence of li-
gands 1h and 1c, respectively.[a]
Entry RMgBr
Product
Ligand Yield[b] Regioselectivity (g/a)[c] ee [%][c] Configuration
1
2
Et-MgBr
Et-MgBr
1h
1c
90
88
99/1
94/6
66
85
R
R
30a
31a
3
4
n-Bu-MgBr
1c
1c
1c
100
100
99
99/1
94/6
98/2
76
R
R
R
3-butenyl-MgBr 32a
>99
82
5
i-Pr-MgBr
33a
[a]
Conditions: 5 (300 mmol), CuBr·SMe2 (2.5 mol%), ligand 1c or 1h (3 mol%) in MTBE (2 mL), slow addition of RMgBr in
CH2Cl2 over 7 h. Conversion was >99%.
Yields of isolated products (g+a) after purification by filtration over silica gel.
The ratio of regioisomers and the enantiomeric excess (ee) of the g-product were determined by CG analysis; the conver-
sion of substrate was always >99%. Values given are the average of two independent experiments.
[b]
[c]
Adv. Synth. Catal. 2010, 352, 2023 – 2031
ꢂ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
2029

Wibke Lçlsberg et al.
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Typical Procedure for the Cu(I)-Catalysed
Asymmetric Allylic Substitution using Grignard
Reagents
A dry argon-flushed, 100-mL Schlenk flask was charged
with a chiral ligand of type 1 (24.6 mmol, 3 mol%) and
CuBr·SMe2 (20.5 mmol, 2.5 mol%) dissolved in 5.5 mL of
dry MTBE. The mixture was stirred for 30 min at room tem-
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10 min the solution was cooled to À788C and 0.45 mL of
MeMgBr (2.21M in Et2O) (0.99 mmol, 1.2 equiv.) diluted in
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before the reaction was quenched with 0.1 mL of 1M HCl
and the mixture was allowed to warm to room temperature.
After addition of 15 mL of Et2O and 10 mL of 1M HCl the
layers were separated and the aqueous layer was re-extract-
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washed with 15 mL of brine, dried over MgSO4, filtered and
concentrated under vacuum. The product was purified by fil-
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Acknowledgements
This work was carried out in the context of Cost D40 and
was (in part) supported by the European Commission (Lig-
bank). We would like to thank the Chemetall GmbH, Frank-
furt, for generous gifts of chemicals. In addition, we would
like to gratefully acknowledge Dr. Dirk Blunk for valuable
advice concerning the calculation of CD spectra.
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