Synthesis of new derivatives of copper complexes of Josiphos family ligands for applications in asymmetric catalysis

Article abstract of DOI:10.1039/c4cy00180j

A series of new copper complexes containing chiral ferrocenyl diphosphine ligands of the Josiphos family have been prepared. These complexes have been studied in the catalytic asymmetric 1,2-addition of Grignard reagents to enones and aromatic ketones. Variation of the electronic and steric properties of the ligand resulted in a positive effect in the regio- and enantioselectivity of Grignard reagents to α-H-substituted enones using the ligand in which tert-butyl substituents were introduced in the diarylphosphine moiety. The copper complexes were also successfully applied in the catalytic asymmetric conjugate addition of Grignard reagents to enoates. No increase of enantioselectivity was observed in the catalytic asymmetric addition of linear Grignard reagents, compared to that of the commercially available ligand rev-Josiphos. The Royal Society of Chemistry 2014.

Full text of DOI:10.1039/c4cy00180j

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Synthesis of new derivatives of copper complexes
of Josiphos family ligands for applications in
asymmetric catalysis†
Cite this: Catal. Sci. Technol., 2014,
4, 1997
*
*
R. Oost, J. Rong, A. J. Minnaard and S. R. Harutyunyan
A series of new copper complexes containing chiral ferrocenyl diphosphine ligands of the Josiphos family
have been prepared. These complexes have been studied in the catalytic asymmetric 1,2-addition of
Grignard reagents to enones and aromatic ketones. Variation of the electronic and steric properties of the
ligand resulted in a positive effect in the regio- and enantioselectivity of Grignard reagents to α-H-substituted
enones using the ligand in which tert-butyl substituents were introduced in the diarylphosphine moiety. The
copper complexes were also successfully applied in the catalytic asymmetric conjugate addition of Grignard
reagents to enoates. No increase of enantioselectivity was observed in the catalytic asymmetric addition of
linear Grignard reagents, compared to that of the commercially available ligand rev-Josiphos.
Received 11th February 2014,
Accepted 23rd March 2014
DOI: 10.1039/c4cy00180j
www.rsc.org/catalysis
that changing the steric properties and tuning the electronic
properties of the ligand will improve the regioselectivity of
Introduction
Ferrocenyl based ligands, in particular diphosphines, are
amongst the most important of chiral ligands in transition
metal catalysis.1 Josiphos, the primus inter pares of the
ferrocenyl diphosphines, provides high activity and enantio-
selectivity in a wide range of catalytic transformations,
including hydrogenations,2 Buchwald–Hartwig aminations,3
and Cu-catalyzed conjugate reductions4 as well as additions.5
However, fine-tuning of the steric and electronic properties
of these ligands is often needed to achieve the desired excel-
lent catalytic performance in a specific reaction or for a spe-
cific substrate.
the reaction in favour of the 1,2-addition to non-substituted
enones by affecting the equilibrium between the intermediate
π- and σ-complexes.9
Here, we report the synthesis of five new Cu-complexes of
Josiphos-type ligands, Cu-L1–L5, and their application in
the Cu-catalyzed 1,2-addition of Grignard reagents to enones
and aromatic ketones as well as in the 1,4-addition to
α,β-unsaturated esters (Fig. 1).
Recently, we demonstrated that rev-Josiphos, in combina-
tion with a Cu(I)-salt, catalyzes the 1,2-addition of Grignard
reagents to enones and aromatic ketones.6–8 This strategy pro-
vides direct access to chiral tertiary alcohols with excellent yields
and enantioselectivities (>95%). During this research we found
that in the addition to enones, the α-substituent on the olefin
plays an important role in the 1,2- versus 1,4-regioselectivity,
with excellent 1,2-selectivity observed only with α-bromo and
α-methyl substituted enones. For non-substituted enones, a
mixture of 1,2- and 1,4-addition products is obtained, both
with low enantioselectivities.
Fig. 1 Representative ligands of Josiphos family.
Results
Synthesis of Cu-L1–L5
The most direct approach to improve catalyst performance
is through fine-tuning of the ligand structure. We envisioned
Josiphos-type ligands are readily accessible via a two-step syn-
thesis starting from enantiomerically pure Ugi's amine.10 Due
to the stepwise introduction of the phosphine substituents,
fine tuning of the ligands is achieved by variation in the sub-
stituents on each of the phosphorus atoms. An alternative
approach is to modify Josiphos-type ligands by increasing the
steric bulk of the ferrocenyl side-chain.11
Stratingh Institute for Chemistry, University of Groningen, Nijenborg 4, 9747 AG,
Groningen, The Netherlands. E-mail: S.Harutyunyan@rug.nl, A.J.Minnaard@rug.nl
† Electronic supplementary information (ESI) available. See DOI: 10.1039/
c4cy00180j
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Scheme 2 Introduction of a diadamantylphosphine group in the ligand
structure.
Scheme 1 General procedure for the synthesis of copper complexes
of rev-Josiphos derivatives.
The copper(I) complexes of the Josiphos-type ligands were
synthesized using a modification of the procedure reported by
Togni et al. for the synthesis of ferrocenyl ligands (Scheme 1).12
The phosphines were introduced in two steps starting from
(S)-Ugi's amine, in turn prepared in four steps from ferrocene.13
In the first step, (S)-Ugi's amine was diastereoselectively
ortho-lithiated followed by reaction with chlorodicyclohexyl-
phosphine to provide aminophosphine 1 in 78% yield.14 The
dimethylamino moiety was then substituted with the corre-
sponding secondary phosphane, with retention of configura-
tion,15 to give the desired Josiphos-type ligand. As for Josiphos,
these ferrocenyl diphosphines were bench-stable, but oxidized
slowly in air. Therefore all ligands, without further isolation/
purification, were reacted with CuBr·SMe2 in CH2Cl2 at room
temperature to form their corresponding copper(I) complexes
(Scheme 1). The complexes were stable in air and moisture for
several months at room temperature. If needed, the copper
could be removed quantitatively by treatment with ethylene-
diamine to recover the corresponding free ligand.16
Scheme 3 Synthesis of Cu-L5. a) 1 eq. isovaleryl chloride, 1 eq. AlCl3,
DCM, rt, 3 h; b) 1.2 eq. BH3·SMe2, 30 mol% (S)-2-methyl-5,5-diphenyl-
3,4-propano-1,3,2-oxazaborolidine, THF, 0 °C, 2 h; c) Ac2O, pyridine,
rt, 30 h; d) aq. HNMe2, MeOH, rt, 30 h; e) first 1.2 eq. sec-BuLi, Et2O,
0 °C, then 2 eq. Cy2PCl, rt, overnight; f) first 1 eq. Ph2PH, AcOH, 90 °C,
5 h, then 1 eq. CuBr·SMe2, CH2Cl2, rt, 2 h.
(Scheme 3). Ketone 2 was obtained in 68% yield by Friedel–
Crafts acylation of ferrocene with isovaleryl chloride. Chiral
alcohol 3 was obtained by enantioselective reduction with
borane–dimethyl sulfide at 0 °C in THF in the presence of
30 mol% of (S)-2-methyl-5,5-diphenyl-3,4-propano-1,3,2-
oxazaborolidine. The enantiomeric excess of 3, determined by
HPLC, was 98% after recrystallization. Acetylation of 3 with
Ac2O in pyridine afforded acetate 4. The conversion of acetate
4 to amine 5 was accomplished in good yield by treatment
with aqueous dimethylamine in methanol following the pro-
cedure of Ugi.9
As with Ugi's amine, ferrocenyl amine 5 can undergo diastereo-
selective ortho-lithiation. This reaction was carried out with
sec-butyllithium in ether at 0 °C. The use of an excess of chloro-
dicyclohexylphosphine was necessary to obtain 6 in acceptable
yields and high diastereoselectivities (>95%). The dimethyl-
amino group was then substituted with diphenylphosphine
in acetic acid according to Togni's procedure,12 and Cu-L5
was formed in 42% yield (Scheme 3).
In the synthesis of Cu-L2, substitution of the dimethyl-
amino moiety for bis(3,5-di(trifluoromethyl)phenyl)phosphine
did not proceed with full retention of configuration, which is
in good agreement with earlier observations,17 with a diaste-
reomeric ratio of 8 : 1 determined by 31P-NMR spectroscopy.
However, the diastereomers of the copper complexes could
be separated by flash-chromatography over silica gel.
We attempted to introduce a sterically more demanding
phosphine, i.e. diadamantylphosphine, in place of a dicyclo-
hexylphosphine moiety to understand the influence of steric
encumbrance at the other phosphine group on the reactivity/
selectivity of the copper complexes in addition reactions.19
However, the reaction of ortho-lithiated Ugi's amine with
diadamantylphosphine chloride did not yield the desired
product (Scheme 2). Despite several efforts, we were not able
to introduce this phosphine on the ortho-position, presum-
ably due to steric bulk.
Application of Cu-L1–L5 in catalysis
The Cu-catalyzed 1,2-additions of both iBuMgBr and EtMgBr
to enone 7 were chosen as model reactions in the evaluation
of the catalytic activity/selectivity of Cu-L1–L5. The 1,2-addi-
tion product of iBuMgBr was obtained with 90% ee using Cu-
rev-Josiphos (Table 1, entry 1). Similar results were obtained
with Cu-L1 that contains electron donating substituents in
the diarylphosphine moiety (entry 2). However, with electron-
withdrawing substituents, e.g., in Cu-L2, the reaction yielded
the same result as in the blank reaction (entry 3). A consider-
able decrease of enantioselectivity in the reactions catalysed
The copper complex of the isobutyl analogue of rev-
Josiphos Cu-L5 was prepared to study the effect of an
increase in steric interactions in the backbone of the ligand
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Table 1 Complexes Cu-L1–L5 studied in the 1,2-addition reactions of
iBuMgBr and EtMgBr to α-Br-substituted enones
Table 2 Complexes Cu-L1–L5 studied in the 1,2-addition reactions of
RMgBr to α-H-substituted enones
Entrya
Catalyst
RMgBr
12 : 13 : 14b
12 (ee)c,d
Entrya
Catalyst
RMgBr
8 : 9 : 10b
8 (ee)c,d
1
2
3
4
5
6
7
Cu-rev-Josiphos
Cu-rev-Josiphos
Cu-L1
Cu-L2
Cu-L3
EtMgBr
16 : 84 : 0
29 : 64 : 6
19 : 70 : 11
5 : 95 : 0
8 : 75 : 17
43 : 56 : 1
28 : 48 : 24
14
28
12
n.d.
31d
54
9
1
2
3
4
5
6
7
8
Cu-rev-Josiphos
Cu-L1
Cu-L2
Cu-L3
Cu-L4
Cu-L5
Cu-rev-Josiphos
Cu-L1
Cu-L2
Cu-L3
iBuMgBr
iBuMgBr
iBuMgBr
iBuMgBr
iBuMgBr
iBuMgBr
EtMgBr
EtMgBr
EtMgBr
EtMgBr
EtMgBr
EtMgBr
97 : 1 : 2
99 : 1 : 0
25 : 25 : 50
71 : 26 : 3
97 : 2 : 1
78 : 4 : 18
98 : 1 : 1
96 : 4 : 0
87 : 12 : 1
90 : 0 : 10
86 : 13 : 1
99 : 1 : 0
90
87
Racemic
27e
60
iBuMgBr
iBuMgBr
iBuMgBr
iBuMgBr
iBuMgBr
iBuMgBr
Cu-L4
Cu-L5
34
23
11
a
Reaction conditions: addition of 1.2 equiv. RMgBr to a 0.15 M solution
9
17e
b
of 11 in tBuOMe at −78 °C in the presence of 5 mol% Cu-L1–L5. The
10
11
12
6e
ratio of 12 :13 :14 was determined by GC analysis. c Enantioselectivity of
Cu-L4
Cu-L5
10
14
d
12 was determined by HPLC analysis. The opposite enantiomer was
obtained.
a
Reaction conditions: addition of 1.2 equiv. RMgBr to a 0.15 M solution
b
of 7 in tBuOMe at −78 °C in the presence of 5 mol% Cu-L1–L5. The
c
ratio of 8:9:10 was determined by GC analysis. Enantioselectivity of
d
the use of electron withdrawing groups in Cu-L2 (entry 4) affects
the regioselectivity drastically, with almost full 1,4-selectivity
albeit as a racemate. As in the previous case, Cu-L3 led to the
1,2-addition product with the opposite configuration in 31% ee
(entry 5). Importantly an increase in 1,2-selectivity as well as in
enantioselectivity was observed with Cu-L4 (43% and 54%,
respectively, entry 6). Comparison of the results of entries 3
and 6 (Table 2) indicates that the steric hindrance, rather than
the change in electronic properties of the diarylphosphine moiety,
plays a dominant role in the regio- and enantioselectivity.
The catalytic system was also applied in the 1,2-addition
of Grignard reagents to aryl alkyl ketones. In previous studies
it was found that although the yields were excellent, high
enantioselectivities were obtained only with bulkier Grignard
reagents.8 The addition of EtMgBr to ketone 15 catalysed by
Cu-rev-Josiphos provided only 22% ee (Table 3). The
8 was determined by HPLC analysis. The absolute configuration of
8 is R (ref. 20). e The opposite enantiomer was obtained.
by Cu-L3–L5 compared to that by Cu-rev-Josiphos (entries 4–6)
coincides with an increase in the steric encumbrance of the
ligands. Interestingly, with Cu-L3, the product obtained has the
opposite configuration to that obtained with Cu-rev-Josiphos
(entry 4).
In the addition of EtMgBr to α-Br-substituted enones,
where the Cu-rev-Josiphos only gives 23% ee (Table 1, entry 7),
we found that all complexes, Cu-L1–L5, provide a low ee as well
(entries 8–12). Surprisingly, Cu-L2 catalyses this reaction with
good 1,2-selectivity and 17% ee (entry 9). These data indicate
that neither an increase in steric bulk on the diarylphosphine
nor the introduction of an isobutyl substituent in the backbone
increases the enantioselectivity in the copper-catalyzed 1,2-addition
to enones. Changing the electronic properties of the copper
complexes also leads to a small decrease in enantioselectivity
compared to Cu-rev-Josiphos. Despite the low enantioselectivity,
it is interesting to note that once again both Cu-L2 and Cu-L3
provide the product with the opposite configuration compared
with Cu-rev-Josiphos.
Table 3 Complexes Cu-L1–5 studied in the 1,2-addition reactions of
EtMgBr to 15
In the addition of Grignard reagents to α-H-substituted
enones, regioselectivity is an important issue. Research over
the last 80 years has established that copper(I) based reagents and
catalysts are the primary synthetic tool to obtain 1,4-selectivity.
The use of Cu-rev-Josiphos and EtMgBr led to only 16% 1,2-
addition product (Table 2, entry 1). Changing the Grignard
reagent to the β-branched iBuMgBr increased the 1,2-selectivity
to 29% (entry 2). This indicates that not only the α-substituent
determines the regioselectivity but also the steric hindrance of
the Grignard reagent is important. Therefore we chose to use
iBuMgBr for our screening.
Entrya
Catalyst
RMgBr
16 : 17b
16 (ee)c
1
2
3
4
5
6
Cu-rev-Josiphos
Cu-L1
Cu-L2
Cu-L3
Cu-L4
EtMgBr
EtMgBr
EtMgBr
EtMgBr
EtMgBr
EtMgBr
99 : 1
87 : 13
99 : 1
90 : 10
56 : 44
71 : 29
22
9
14d
16d
Racemic
Racemic
Cu-L5
a
Reaction conditions: addition of 1.2 equiv. EtMgBr to a 0.15 M solution
b
of 15 in tBuOMe at −78 °C in the presence of 5 mol% Cu-L1–L5. The
c
ratio of 16 :17 was determined by GC analysis. Enantioselectivity of 16
d
We found that an electron donating substituent in Cu-L1
does not change the regioselectivity considerably. In contrast,
was determined by HPLC analysis. The opposite enantiomer was
obtained.
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Table 4 Complexes Cu-L1–L5 studied in the 1,4-addition reactions of
EtMgBr to 18
constant to copper(I). This in turn results in reduced catalytic
activity, and therefore, the overall selectivity of the reaction
decreases due to an increase in the relative contribution of the
non-catalysed 1,2- and 1,4-additions as well as the 1,2-reduction.
Increasing steric interactions both at the phosphine moie-
ties (Cu-L3–L5) and at the chiral carbon center results in a pro-
nounced decrease in enantiofacial discrimination (Table 1).
The data obtained with catalysts Cu-L1–L5 in the additions
to aryl alkyl ketone 15 did not, however, show an obvious corre-
lation. In all of the cases very low stereoselectivity was observed,
and in the case of Cu-L4 and Cu-L5, lower catalytic activity
was apparent from the increased extent of the 1,2-reduction
to yield 17 (Table 3).
Entrya
Catalyst
RMgBr
Yieldb (%)
19 (ee)c
1
2
3
4
5
6
Cu-rev-Josiphos
Cu-L1
Cu-L2
Cu-L3
Cu-L4
EtMgBr
EtMgBr
EtMgBr
EtMgBr
EtMgBr
EtMgBr
94
95
97
95
56
96
98
96
88
7
70
81
Cu-L5
a
Reaction conditions: addition of 19 to a 0.3 M solution of EtMgBr
b
in DCM at −78 °C in the presence of 5 mol% Cu-L1–L5. Conversion
One of the goals of this study was to understand the factors
that govern the regioselectivity observed in the addition of
Grignard reagents to α-H-substituted enones. Research efforts
over the last decades have shown that, in the case of Cu-catalysed
reactions, 1,4-addition of organometallic reagents is the most
common pathway. In our previous studies with chiral ferrocenyl
ligands, we have observed this trend. Using Cu-rev-Josiphos as a
catalyst in the addition of Grignard reagents to α-H-substituted
enones provided mainly 1,4-product 13 (Table 2, entries 1 and 2).
When testing our new catalysts Cu-L1–L5 in this transforma-
tion, we were pleased to find that both the regioselectivity and
enantioselectivity of the 1,2-addition reaction greatly increased
using catalyst Cu-L4, which bears a sterically hindered and
electron rich phosphine moiety (Table 2, entry 6). From a mech-
anistic perspective, it is well established that transmetallated
Cu-species are capable of forming π-complexes with a conju-
gated double bond followed by oxidative addition to form a
σ-complex and reductive elimination to yield the 1,4-addition
product.5 However recently it has been shown that trans-
metallated Cu-species are capable of π-complex formation with
a conjugated carbonyl moiety also.25 Our present empirical data
indicate that the presence of an α-substituent at the enone 7
destabilizes the formation of π- and σ-complexes with a conju-
gated double bond. This most likely drives the Cu-catalyst to
form π-complexes with the carbonyl of the enone, followed by
formation of the 1,2-addition product (Table 1). Therefore high
1,2-selectivity has been obtained with most of the catalysts
studied. In contrast, in the case of α-H-substituted enone 11,
such substrate control is absent and the reaction proceeds
via π- and σ-complexes followed by 1,4-product formation.
However when sterically hindered and electron rich catalyst
Cu-L4 was used for the first time a clear catalyst control over the
regio- and stereoselectivity of the addition was observed. This
conclusion is supported by consideration of the data obtained
regarding the 1,4-addition of EtMgBr to α,β-unsaturated esters.
Most of the ligands were found to be excellent catalysts
in regard to 1,4-selectivity, while Cu-L4 provided both lower
1,4-selectivity and lower enantioselectivity (Table 4, entry 5).
c
determined by GC analysis. Enantioselectivity of 19 was determined
by GC analysis on a chiral phase (B-PM).
complexes Cu-L1–L5 were screened in the same reaction. As
in the addition to enones, enantioselectivities decreased com-
pared to Cu-rev-Josiphos and the configuration of the product
changed for Cu-L2 and Cu-L3. With Cu-L4 and Cu-L5, only
racemic products were obtained with lower regioselectivities
(entries 5 and 6).
The new complexes were also studied in a reaction in which
Cu-rev-Josiphos provides excellent results, the 1,4-addition of
EtMgBr to α,β-unsaturated esters (Table 4).21
All of the new complexes provided good yields, and most
of them provided good enantioselectivities also. Complex
Cu-L1 provided, as in the 1,2-additions, similar results to
those obtained with rev-Josiphos (entry 2). The other com-
plexes provide good enantioselectivities, but less than that
obtained with the Cu-rev-Josiphos. Cu-L3 showed only 7%
enantioselectivity (entry 4). Interestingly, Cu-L4 provided low
1,4-regioselectivity (entry 5). This result correlates well with
relatively good 1,2-selectivity obtained using the same complex
in the addition of Grignard reagents to α-H-substituted enones
(Table 2, entry 6).
Discussion
In the present contribution several electronically and sterically
distinct Cu-complexes have been synthesized and tested as
catalysts in enantioselective 1,2- and 1,4-additions of Grignard
reagents to carbonyl compounds. From the data obtained in
the addition of iBuMgBr and EtMgBr to α-Br-substituted
enones, one can conclude that increasing the electron donating
properties of one of the phosphine moieties of the catalyst
(Cu-L1) does not affect, substantially, the performance of the cat-
alyst when compared with that observed using Cu-rev-Josiphos
(Table 1, entries 1 and 2). By contrast, introducing electron-
withdrawing groups at the phosphine moiety decreases the
regioselectivity as well as the stereoselectivity in the 1,2-addition
reaction (Table 1, compare entries 1 and 7 with entries 3 and 9).
We surmise that reducing the electron density at the phosphine
moiety has a negative effect on the ligands' association
Conclusions
We report here the synthesis of five new copper complexes of
rev-Josiphos-type ligands with a variation in steric and electronic
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properties. We successfully introduced electron donating,
electron withdrawing and bulky substituents on the phos-
phines as well as a bulky substituent in the backbone. These
complexes have been applied to the 1,2- and 1,4-additions of
alkyl magnesium reagents to enones. We found that in the
1,2-addition to α-H-substituted enones, the Cu-L4 with bulky
tert-butyl and electron donating methoxy groups on the aromatic
ring provides higher regio- and enantioselectivities compared to
Cu-rev-Josiphos. Copper complexes were also successfully
applied in the 1,4-addition of EtMgBr to an α-H-substituted
enone: methyl cinnamate. While all newly synthesized catalysts
provided high 1,4-selectivity, Cu-L4 was found to give lower
regio- and enantioselectivity. These results provide further
insight into how to optimise catalyst design towards better
1,2-selectivity with α-H-substituted enones. In the 1,2-addition
to aromatic ketones complexes Cu-L1–L5 did not improve
the enantioselectivity of linear Grignard reagents. Further
investigations to increase the enantioselectivity of linear
Grignard reagents and to design better 1,2-selective catalysts
are currently underway.
separated. The aqueous layer was extracted three times with
CH2Cl2 (4 mL) and the combined organic layers were dried
over MgSO4. The solvent was removed under reduced pres-
sure and the residue was purified by column chromatography
(SiO2, pentane/Et2O 5 : 1) to give compound 1 as an orange
1
solid (0.39 g, 78%). H-NMR (CDCl3): δ 0.9–2.0 (m, 25H), 2.08
(s, 6H), 2.35 (s, 1H), 4.03 (s, 5H), 4.08 (s, 1H), 4.24 (d, 2H).
13C-NMR (CDCl3): δ 9.0, 26.8 (d, J = 11.6 Hz), 27.6 (d, J = 8.3 Hz),
27.9 (d, J = 12.3 Hz), 28.1 (d, J = 7.1 Hz), 28.6, 28.7, 28.8,
31.0 (d, J = 9.8 Hz), 32.6 (d, J = 16.7 Hz), 32.8 (d, J = 18.5 Hz),
34.2 (d, J = 8.3 Hz), 36.7 (d, J = 12.3 Hz), 39.6, 56.8 (d, J = 8 Hz),
67.5, 68.7 (d, J = 3 Hz), 70.0, 70.3, 79.1, 95.6. 31P-NMR (CDCl3):
δ – 11.3 (s).
4-Methylvalerylferrocene 2 (ref. 23)
Isovaleryl chloride (2 mL, 16.1 mmol) was added to a suspen-
sion of aluminium(III) chloride (2.3 g, 17 mmol) in CH2Cl2
(35 mL) at 0 °C. This solution was added to a solution of ferro-
cene (3.0 g, 16.1 mmol) in CH2Cl2 (35 mL) at 0 °C. The reaction
mixture was warmed to rt and stirred for 3 h. The reaction was
quenched by adding ice-cold water (50 mL) at 0 °C. The phases
were separated and the aqueous phase was extracted with
CH2Cl2 (3 × 50 mL). The organic layers were washed with
saturated K2CO3 solution, brine and water. The organic layer
was dried over MgSO4 and concentrated in vacuo. The crude
product was purified by column chromatography (SiO2, pentane/
Et2O 9 : 1). Pure 3 was isolated as an orange solid (2.95 g, 68%).
1H-NMR (CDCl3): δ 0.98 (d, 6H, J = 6.5 Hz), 2.26 (app. nonet,
1H, J = 6.5 Hz), 2.55 (d, 2H, J = 6.5 Hz), 4.20 (s, 5H), 4.49
(s, 2H), 4.78 (s, 2H). 13C-NMR (CDCl3): 23.1 (2CH3), 25.2 (CH),
49.0 (CH2), 69.5 (2CH), 69.9 (5CH), 72.3 (2CH), 79.9 (C) 203.7
(CO).
Experimental
General
All reactions were carried out under a nitrogen atmosphere
using oven-dried glassware and using standard Schlenk tech-
niques. Dichloromethane, THF and tBuOMe were used from
the solvent purification system. (S)-Ugi's amine13 and 7 (ref. 22)
were prepared according to literature procedures. All other
starting materials and Grignard reagents were purchased from
Aldrich (iBuMgBr (2 M in Et2O) and EtMgBr (3 M in Et2O)).
Chromatography was performed on silica gel (230–400 mesh).
Thin-layer chromatography was performed on silica plates.
Compounds were visualized by UV and cerium/molybdenum
or potassium permanganate staining. Progress and conversion
of the reaction were determined by GC-MS. Mass spectra
were recorded on a mass spectrometer using an Orbitrap
analyser. 1H, 13C, 19 F and 31P spectra were recorded on 400 and
100.59 MHz using CDCl3 as solvent. Chemical shift values are
reported in ppm with the solvent resonance as the internal
standard (CHCl3: δ 7.26 for 1H, δ 77.0 for 13C). Data are reported
as follows: chemical shifts, multiplicity (s = singlet, d = doublet,
t = triplet, q = quartet, br = broad, m = multiplet), coupling
constants (Hz), and integration. Optical rotations were measured
on a polarimeter with a 10 cm cell (c given in grams per
100 mL). Enantiomeric excesses were determined by chiral GC
or HPLC analysis.
(S)-Ferrocenyl-3-methylbutanol 3
A stirred solution of 0.56 g of (R)-2-methyl-5,5-diphenyl-3,4-
propano-1,3,2-oxazaborolidine (3 mmol, 30 mol%) in 5 mL of
THF was cooled to 0 °C, and 0.6 mL of borane–Me2S solution
(1.2 mmol, 2 M in THF) was added. After 15 min, a solution
of 2 (1.63 g, 6 mmol) in 20 mL of THF and, separately, a
borane–Me2S solution (2.4 mL, 4.8 mmol, 2 M in THF) were
simultaneously added slowly over a period of 1 h at 0 °C. The
reaction mixture was stirred for 1 h at 0 °C before it was
quenched with 5 mL of MeOH. The solution was concen-
trated under reduced pressure and the crude product was
purified by column chromatography (pentane/EtOAc 4 : 1)
and recrystallized from hot hexane. Pure 3 was obtained as an
orange solid (1.82 g, 58%, 98% ee). The enantiomeric ratio was
determined by chiral HPLC analysis, Chiralcel OD-H column,
n-heptane–i-PrOH 98 : 2, 40 °C, detection at 254 nm, retention
(R)-1-Dicyclohexylphosphano-2-[α-(S)-(N,N-
dimethylamino)ethyl]ferrocene 1 (ref. 12)
1
sec-Butyllithium (1.4 M in cyclohexane, 0.9 mL, 1.26 mmol)
was added to a solution of Ugi's amine (0.3 g, 1.09 mmol) in
Et2O (4 mL) at 0 °C. After 2 h, chlorodicyclohexylphosphane
(0.3 mL, 1.3 mmol) was added at 0 °C and the solution was
allowed to warm up to rt and stirred overnight. Saturated
aqueous Na2CO3 (3 mL) was added and the layers were
times (min): 16.9 (major) and 18.3 (minor). H-NMR (CDCl3):
δ 0.91 (t, J = 5.5 Hz, 6H), 1.41 (m, 1H), 1.62 (m, 1H), 1.76 (m, 2H),
4.21 (s, 2H), 4.25 (s, 5H), 4.29 (s, 2H). 13C-NMR (CDCl3): δ 22.4
(CH3), 23.6 (CH3), 25.1 (CH), 47.5 (CH2), 61.7 (CHOH), 66.1
(2CH), 67.8 (5CH), 69.1 (2CH), 95.8 (C). HRMS (ESI+) calcd for
C15H19Fe [M − OH]+ 255.08307, found 255.082.
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(S)-Ferrocenylethyl-3-methylpropyl acetate 4
(R)-1-[(SP)-2-(Dicyclohexylphosphino)ferrocenyl]-ethyl-
(di-4-methoxyphenyl)phosphine Cu-L1
mixture of (150 mg, 0.33
Ferrocenyl alcohol 3 (0.94 g, 3.5 mmol) was dissolved in
10 mL of pyridine. Acetic anhydride (5 mL, 53 mmol) was
added and the solution was stirred for 30 hours at room tem-
perature. Volatiles were removed under vacuum (0.7 mm Hg,
5 h). Without further purification, pure 4 was obtained as an
orange solid (1.1 g, quantitative). 1H-NMR (CDCl3): δ 0.95
(dd, 6H), δ 1.62 (m, 2H), 1.79 (m, 1H), 2.04 (s, 3H), 4.12
(s, 7H) 4.16 (s, 1H), 4.26 (s, 1H), 5.85 (dd, 1H). 13C-NMR
(CDCl3): 21.5 (CH), 22.1 (CH3), 23.7 (CH3), 24.9 (CH2), 44.0
(CH3), 66.5 (CH), 68.0 (CH), 68.2 (CH), 68.3 (CH), 68.9 (CH),
70.5 (CH), 88.45 (C). 170.8 (CO). HRMS (ESI+) calcd for
C15H19Fe [M − OAc]+ 255.08307, found 255.082.
A
1
mmol)
and
bis(4-methoxyphenyl)phosphine (82 mg, 0.33 mmol) in acetic
acid (5 mL) was degassed three times and stirred for 5 h at
90 °C under nitrogen atmosphere. The solvent was removed
under reduced pressure and the yellow residue was dissolved
in CH2Cl2. The organic layer was washed with saturated aque-
ous Na2CO3, brine and H2O. The organic layer was dried on
MgSO4 and the solvent was removed under reduced pressure.
The crude product was dissolved in CH2Cl2 (5 mL) and
CuBr·SMe2 (68 mg, 0.33 mmol, 1 equiv.) was added. The mixture
was stirred at rt for 2 h. The solvent was removed in vacuo and
the product was purified by column chromatography
(SiO2, pentane/Et2O 5 : 1), and recrystallization from methanol
1
(S)-[3-(N,N-Dimethylamino)isobutyl]ferrocene 5
gave Cu-L1 as an orange solid (85 mg, 32%). H-NMR (CDCl3):
δ 1.0–2.0 (m, 25H), 3.76 (s, 3H, OMe), 3.80 (s, 3H, OMe), 4.04
(s, 5H, Cp), 4.21 (s, 1H, Cp), 4.29 (m, 1H, Cp), 4.33 (s, 1H, Cp)
6.83 (dd, 4H, J = 8.5, 57.3 Hz), 7.52 (dt, J = 8.8, 97.7 Hz, 4H).
13C-NMR (CDCl3): δ 17.7 (s, CH3), 26.2 (d, J = 29.1 Hz), 26.9
(d, J = 12.1), 27.4 (d, J = 12.3), 28.2, 28.3, 30.5 (d, J = 8.7 Hz), 30.7
(d, J = 5.5 Hz), 31.9 (d, J = 10.0 Hz), 34.5 (d, J = 10.8 Hz), 35.4
(d, J = 6.0 Hz), 35.6 (d, J = 6.3), 39.5 (d, J = 6.6 Hz), 39.6 (d, J = 6.7),
55.4 (d, J = 8.7 Hz), 69.0, 69.6, 70.1, 70.3, 73.6, 74.8 (d, J = 18.2 Hz),
77.4, 93.3 (dd, J = 17.4, 7.1 Hz), 114.4 (dd, J = 37.2, 9.6 Hz),
121.7 (dd, J = 22.3, 6.9 Hz), 124.1 (dd, J = 20.5, 10.5 Hz), 135.7
(dt, J = 13.5, 5.3 Hz), 161.1 (d, J = 30 Hz). 31P-NMR (CDCl3):
To a solution of 4 (1.09 g, 3.45 mmol) in MeOH (10 mL),
dimethylamine (10 mL, 40% in water) was added. The reaction
was stirred for 30 hour at room temperature. Then, the solu-
tion was diluted with ether (100 mL) and water (50 mL). The
organic layer was separated, dried over MgSO4 and filtered.
The solvent was removed in vacuo. Pure 5 was obtained as dark
1
brown oil (1.03 g, quantitative). H-NMR (CDCl3): δ 1.01 (dd,
J = 3.9, 6.5 Hz, 6H), 1.70 (m, 2H), 1.91 (m, 1H), 1.97 (s, 6H),
3.46 (dd, J = 3.1, 11.4 Hz, 1H), 4.0–4.1 (m, 9H). 13C-NMR
(CDCl3): δ 21.9 (CH), 24.5 (CH3), 24.9 (CH3), 40.6 (CH2), 40.7
(2CH3), 60.6 (CH), 67.1 (CH), 67.3 (CH), 67.6 (CH), 68.8 (5CH),
69.5(CH), 85.4 (C). HRMS (ESI+) calcd for C15H19Fe [M − NMe2]+
255.08307, found 255.082.
δ −11.66. [α]D = −2.8 (c = 1, CH2Cl2). HRMS (ESI+) calcd for
20
C38H48BrCuFeO2P2 [M]+, 796.09529, found 796.094.
(R)-1-[(SP)-2-(Dicyclohexylphosphino)ferrocenyl]-ethyl-di[3,5-
bis-(trifluoromethyl)phenyl]phosphine Cu-L2
(R)-1-Dicyclohexylphosphano-2-[α-(S)-(N,N-
dimethylamino)isobutyl]ferrocene 6
Prepared according to the procedure described above from 1
(300 mg, 0.65 mmol), bis(3,5-di(trifluoromethyl)phenyl)phosphine
(300 mg, 0.65 mmol) and CuBr·SMe2 (134 mg, 0.65 mmol).
Purified on column chromatography (SiO2, pentane/Et2O 5:1) to
give compound Cu-L2 as an orange solid (176 mg, 25%). 1H-NMR
(CDCl3): δ 1.0–2.0 (m, 25H), 3.86 (q, 1H), 4.12 (s, 1H), 4.18
(s, 5H), 4.23 (s, 1H), 4.30 (s, 1H), 7.35 (s, 1H), 7.85 (s, 1H), 7.89
(s, 2H), 8.28 (s, 2H). 13C-NMR (CDCl3): δ 16.9 (s, CH3), 25.9 (m),
26.6 (m), 27.3 (m), 28.3 (d, J = 15.7 Hz), 29.5 (m), 31.2 (s), 34.5 (s),
35.9 (m), 41.2 (m), 68.8 (s), 69.9 (s), 70.2 (s, 5CH), 71.4 (s, 1CH),
74.6 (s, 1CH), 77.4 (s, 1C), 91.3 (d, 1C), 122.5 (s), 123.0 (dq,
J = 273, 30.4 Hz, 4CF3), 124.4 (s), 131.5 (dq, J = 33.9, 7.2 Hz),
132.2 (m), 136.5 (br. s). 31P-NMR (CDCl3): δ −9.53 (br. d,
J = 149.9 Hz), −14.31(br. d, J = 155.3 Hz). 19F-NMR (CDCl3):
sec-Butyllithium (1.4 M in cyclohexane, 0.86 mL, 1.2 mmol)
was added to a solution of 5 (0.3 g, 1 mmol) in Et2O (2 mL) at
0 °C. After 2 h, chlorodicyclohexylphosphane (0.5 mL, 2 mmol)
was added at 0 °C and the solution was allowed to warm up to
rt and stirred overnight. Saturated aqueous Na2CO3 (3 mL) was
added and the layers were separated. The aqueous layer was
extracted three times with CH2Cl2 (4 mL) and the combined
organic layers were dried over MgSO4. The solvent was removed
under reduced pressure and the residue was purified by col-
umn chromatography (SiO2, pentane/Et2O 10 : 1) to give com-
pound 6 as an orange solid (0.29 g, 59%). 1H-NMR (CDCl3):
δ 1.03 (dd, J = 5.7, 33.3 Hz, 6H), 1.1–2.0 (m, 25H), 2.19 (s, 6H),
3.96 (m, 1H), 4.04 (s, 5H), 4.08 (s, 1H), 4.21 (m, 2H). 13C-NMR
(CDCl3): δ 22.6 (s, 2CH3), 24.6 (s, 1CH2), 26.3 (s, 1CH2), 26.8
(d, J = 15.4 Hz, 1CH2), 27.6 (d, J = 8 Hz, 1CH2), 28.0 (s, 1CH2),
28.1 (d, J = 4.6, 1CH2), 28.6 (d, J = 12.6, 1CH2), 29.1 (m, 1CH2),
30.8 (m, 1CH2), 32.6 (d, J = 16.9 Hz, 1CH2), 32.9 (d, J = 18.6 Hz,
1CH2), 36.3 (d, J = 12.7 Hz, 1CH2), 39.4 (s, 1CH2), 40.2 (s, 1CH),
46.3 (s, 1CH), 58.2 (s, 1CH), 67.5 (m, CH), 68.6 (d, J = 3.5 Hz, CH),
70.0 (s, 5CH), 70.6 (m, CH), 77.4 (s, 1C), 79.4 (s, 1C). 31P-NMR
(CDCl3): δ −11.88 (s). HRMS (ESI+) calcd for C29H47FeNP [M + H]+
496.27901, found 496.278.
20
δ −63.1 (d, J = 16.0 Hz). [α]D = −40.4 (c = 1, CH2Cl2). HRMS
(ESI+) calcd for C40H40F12FeP2Cu [M]+, 929.1054, found 929.104.
(R)-1-[(Sp)-2-(Dicyclohexylphosphino)ferrocenyl]-ethyl-
(di-o-tolyl)phosphine Cu-L3
Prepared according to the procedure described above from 1
(218 mg, 0.48 mmol), di(o-tolyl)phosphine (18 mg, 0.53 mmol)
and CuBr·SMe2 (100 mg, 0.49 mmol). Purified on column chro-
matography (SiO2, pentane/Et2O 5 : 1) to give compound Cu-L3
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as an orange solid (275 mg, 75%). 1H-NMR (CDCl3): δ 1–2.6
(m, 31H), 3.65 (q, 1H), 4.21 (s, 5H), 4.29 (s, 1H), 4.34 (s, 2H),
6.9–7.3 (m, 8H). 13C-NMR (CDCl3): δ 15.5 (d, J = 4.5 Hz, CH3),
23.2 (d, J = 15.2 Hz, CH2), 23.4 (d, J = 11.5 Hz, CH2), 26.0
(d, J = 8.2 Hz, CH2), 27.0 (d, J = 12.3 Hz, CH2), 27.3 (t, J = CH),
27.8 (d, J = 13.9 Hz, CH2), 28.2 (s), 29.8 (m), 30.9 (d, J = 8.6 Hz,
CH2), 31.7 (d, J = 11.6 Hz, CH2), 34.5 (d, J = 15.5 Hz, CH2), 38.4
(d, J = 11.6 Hz, CH2), 68.8 (d, J = 3.8 Hz, 1CH), 70.1 (s, 5CH),
70.5 (d, J = 7.7 Hz, 1CH), 74.1 (s, 1CH), 74.8 (d, J = 17.9 Hz,
1CH), 77.4 (s, 1CH), 91.5 (d, Cp), 125.2 (d, J = 4.2, Hz, Ar), 125.9
(d, J = 5.0 Hz, Ar), 127.5 (dd, J = 3.9, 20.0 Hz, 1C), 129.6 (s, Ar),
129.8 (s, Ar), 130.3 (dd, J = 7.5, 17.1 Hz, 1C), 131.1 (d, J = 7.7 Hz,
Ar), 131.5 (m, Ar), 131.8 (d, J = 6.2 Hz, Ar), 133.5 (s, 1CH), 142.5
(d, J = 16.9 Hz, 1C), 143.6 (d, J = 19.5 Hz, 1C). 31P-NMR (CDCl3):
δ −10.2 (d, J = 181.7 Hz), −19.9 (br. d, J = 184.8 Hz). [α]D20 = +17.0
(c = 1, CH2Cl2). HRMS (ESI+) calcd for C38H48BrCuFeP2 [M]+,
764.1054, found 764.101.
128.5 (m, 2CH), 128.7 (d, J = 9.0 Hz, 2CH), 129.2 (d, J =
8.1 Hz, 2CH), 130.3 (d, J = 45.8 Hz, 2CH), 134.1 (m, 2CH).
31P-NMR (CDCl3): δ −9.53 (d), −14.31 (br). [α]D = +59.2
20
(c = 0.25, CH2Cl2). HRMS (ESI+) calcd for C40H40F12FeP2Cu [M]+,
778.1211, found 778.117.
General procedure for the copper-catalyzed 1,2-addition of
Grignard reagents to ketones6
A Schlenk tube equipped with septum and stirring bar was
charged with Cu-L (7.5 μmol, 5 mol%). Dry tBuOMe (1.5 mL)
was added and the solution was stirred under nitrogen at rt
for 15 min. Then, the corresponding ketone (0.15 mmol in
0.5 mL of tBuOMe) was added and the resulting solution was
cooled to −78 °C. In a separate Schlenk flask, the correspond-
ing Grignard reagent (0.18 mmol, 1.2 eq., in Et2O) was diluted
with tBuOMe (to a combined volume of 1 mL) under nitrogen
and added dropwise to the reaction mixture over 3 h using a
syringe pump. Once the addition was complete, the reaction
mixture was monitored by TLC and GC-MS. The reaction was
quenched by the addition of MeOH (1 mL) and saturated aqueous
NH4Cl (2 mL), the mixture was warmed to rt and diluted with
Et2O, and the layers were separated. The aqueous layer was
extracted with Et2O (3 × 5 mL), the combined organic layers
were dried with anhydrous Na2SO4 and filtered, and the solvent
was evaporated in vacuo. Gas chromatography analysis was
carried out to determine the 1,2-addition, 1,4-addition and
1,2-reduction ratio on a sample which was passed through a
short plug of silica gel to remove copper residues. The crude
product was purified by flash chromatography on silica gel
using mixtures of n-pentane and Et2O as the eluent.
(R)-1-[(SP)-2-(Dicyclohexylphosphino)ferrocenyl]-ethyl-[di(3,5-
di-tert-butyl-4-methoxyphenyl)phosphine Cu-L4
Prepared according to the procedure described above
from
1
(150 mg, 0.33 mmol), bis(3,5-di-tert-butyl-4-
methoxyphenyl)chlorophosphine (82 mg, 0.33 mmol) and
CuBr·SMe2 (68 mg, 0.33 mmol). Purified on column chroma-
tography (SiO2, pentane/Et2O 5 : 1) to give compound Cu-L4 as
an orange solid (202 mg, 60%). 1H-NMR (CDCl3): δ 1.0–2.0
(m, 25H), 1.29 (s, 18H, tBu), 1.41 (s, 18H, tBu), 3.42 (m, 1H, CH),
3.59 (s, 3H, OMe), 3.66 (s, 3H, OMe), 4.07 (s, 5H, Cp), 4.26
(s, 1H, Cp), 4.31 (m, 2H, Cp), 7.23 (d, 2H, J = 12.5, Ar), 7.57
(d, 2H, J = 19 Hz, Ar). 13C-NMR (CDCl3): δ 16.4, 23.2, 31.7
(d, J = 19.1 Hz), 32.6 (d, J = 11.5 Hz), 32.9, 33.6 (d, J = 14.3 Hz),
34.0, 36.0 (dd, J = 22.1, 6.2 Hz), 37.3 (d, J = 11.2 Hz), 37.9
(d, J = 6.36 Hz), 40.3 (d, J = 10.3 Hz), 41.0 (dd, J = 14.0, 5.5 Hz),
41.7 (d, J = 14 Hz), 44.5 (dd, J = 11.1, 5.6 Hz), 51.9, 70.0 (d, J =
5.3 Hz), 74.3 (d, J = 3.3 Hz), 75.6, 76.1 (t, J = 5.9 Hz), 77.0, 79.1,
80.1, 80.2, 83.0, 99.0, 110.77, 138.2 (dd, J = 60.7, 16.6 Hz), 149.5
(dd, J = 34.2 ,9.2 Hz), 166.6 (d, J = 40 Hz). 31P-NMR (CDCl3):
(Z)-2-Bromo-3,5-dimethyl-1-phenylhex-1-en-3-ol 8a6
Using the general procedure: reaction was performed with
iBuMgBr and 7. 1H-NMR (CDCl3): δ 1.0 (dd, J = 6.8 Hz, 6H),
1.60 (s, 3H), 1.66 (dd, J = 6.1, 13.9 Hz, 1H), 1.82 (app. nonet,
J = 6.5 Hz, 1H), 1.90 (dd, J = 5.5, 14.1 Hz, 1H), 1.99 (br. s, 1H)
7.25 (s, 1H), 7.31 (m, 1H), 7.38 (t, J = 7.3 Hz, 2H), 7.56
(d, J = 7.9 Hz, 2H). 13C-NMR (CDCl3): δ 24.46 (CH3), 24.54 (CH3),
24.71 (CH), 29.0 (CH3), 49.3 (CH2), 77.8 (C), 126.4 (CH), 127.9
(CH), 128.3(2CH), 129.2(2CH), 134.9 (C), 136.5 (C). Enantiomeric
excess was determined by chiral HPLC analysis, Chiralcel AD-H
column, n-heptane/i-PrOH 98 : 2, 40 °C, detection at 240 nm,
retention times (min): 17.9 (minor) and 21.3 (major).
20
δ −9.53, −14.31. [α]D = −40.8 (c = 1, CH2Cl2). HRMS (ESI+)
calcd for C54H80BrCuFeO2P2 [M]+, 1020.3457, found 1020.346.
(R)-1-[(SP)-2-(Dicyclohexylphosphino)ferrocenyl]isobutyl-
diphenylphosphine Cu-L5
Prepared according to the procedure described above from 6
(220 mg, 0.44 mmol), diphenylphosphine (0.08 mL, 0.44 mmol)
and CuBr·SMe2 (90 mg, 1 eq.) . Purified on column chromatog-
raphy (SiO2, pentane/Et2O 5 : 1) to give compound Cu-L5 as an
orange solid (144 mg, 42%). 1H-NMR (CDCl3): δ 0.62 (d, 3H,
CH3), 0.75 (d, 3H, CH3), 1.0–2.0 (m, 25H), 3.75 (s, 5H, Cp), 4.18
(s, 1H, Cp), 4.25 (s, 1H, Cp), 4.34 (s, 1H, Cp), 7.2–7.5 (m, 6H, Ar),
7.69 (bs, 2H, Ar), 7.95 (bs, 2H, Ar). 13C-NMR (CDCl3): δ 21.4,
23.4, 25.5, 26.2 (d, J = 16.6 Hz), 27.2 (d, J = 11.6 Hz), 27.7 (m),
28.4 (d, J = 16.9 Hz), 29.3 (s), 29.9 (s), 30.5, 30.7, 33.3
(d, J = 14.3 Hz), 34.2 (d, J = 12.1 Hz), 36.5 (m), 39.3 (t, J = 9.0 Hz),
43.7 (m), 46.1 (s), 68.7 (s, CH), 70.1 (s, 5CH), 72.1 (s, CH), 72.6
(s, CH), 77.4 (s, C), 93.8 (d, J = 21.5 Hz, C), 125.7 (s, C),
(Z)-2-Bromo-3-methyl-1-phenylpent-1-en-3-ol 8b6
Using the general procedure: the reaction was performed
with EtMgBr and 7. 1H-NMR (CDCl3): δ 0.92 (t, J = 7.4 Hz,
3H), 1.56 (s, 3H), 1.86 (m, 3H), 7.18 (s, 1H), 7.29 (m, 1H), 7.36
(t, J = 7.5 Hz, 2H), 7.55 (d, J = 7.8 Hz, 2H). 13C-NMR (CDCl3):
δ 8.3, 27.3, 33.9, 77.7, 127.0, 127.9, 128.3, 129.3, 134.3, 136.4.
Enantiomeric excess was determined by chiral HPLC analysis,
Chiralcel AD-H column, n-heptane/i-PrOH 98 : 2, 40 °C, detec-
tion at 240 nm, retention times (min): 25.7 (minor) and 27.5
(major).
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(E)-3,5-Dimethyl-1-phenylhex-1-en-3-ol 12 (ref. 23)
(30 m × 0.25 mm), 90 °C, retention times (min): 37.7 (minor)
and 38.6 (major).
Using the general procedure: the reaction was performed with
iBuMgBr and 11. H-NMR (CDCl3): δ 0.91 (t, J = 6.8 Hz, 6H),
1
1.37 (s, 3H), 1.56 (m, 2H), 1.78 (app. nonet, J = 6.5 Hz, 1H) 6.24 Acknowledgements
(d, J = 16.4 Hz, 1H), 6.54 (d, J = 16.2 Hz, 1H), 7.2–7.4 (m, 5H).
Financial support from the Netherlands Organization for
Scientific Research (NWO-Vidi, S.R.H.) is acknowledged.
13C-NMR (CDCl3): δ 24.4 (CH3), 24.5 (CH3), 24.6 (CH), 29.2
(CH3), 51.5 (CH2), 73.7 (C), 126.3 (2CH), 126.4 (CH), 127.2
(2CH), 128.5 (CH), 137.1 (CH), 137.2 (CH). Enantiomeric excess
was determined by chiral HPLC analysis, Chiralcel AD-H column, Notes and references
n-heptane/i-PrOH 98 : 2, 40 °C, detection at 240 nm, retention
times (min): 21.2 (minor) and 22.2 (major).
1 H.-U. Blaser, B. Pugin, F. Spindler, E. Mejía and A. Togni, in
Privileged Chiral Ligands and Catalysts, ed. Q.-L. Zhou,
Wiley_VCH, Weinheim, Germany, 1st edn, 2011, pp. 93–136.
2 N. C. Zanetti, F. Spindler, J. Spencer, A. Togni and G. Rihs,
Organometallics, 1996, 15, 860–866.
2-(3,5-Bis(trifluoromethyl)phenyl)butan-2-ol 16 (ref. 8)
Using the general procedure: the reaction was performed
with EtMgBr and 15. 1H-NMR (CDCl3): δ 0.80 (t, J = 7.5 Hz, 3H),
1.58 (s, 3H), 1.85 (m, 3H), 7.74 (s, 1H), 7.88 (s, 2H). 13C-NMR
(CDCl3): δ 8.2 (CH3), 30.1 (CH3), 36.9 (CH2), 74.9 (C), 120.8
(q, J = 3.9 Hz, 2C), 122.4 (CH), 125.1 (CH), 125.6 (CH), 131.6
(q, J = 33.3 Hz, 2CF3), 150.7 (C). Enantiomeric excess was
determined by chiral HPLC analysis, Chiralcel OD-H column,
n-heptane/i-PrOH 99.5 : 0.5, 40 °C, detection at 240 nm, reten-
tion times (min): 17.8 (minor) and 18.4 (major).
3 Q. Shen, S. Shekar, J. P. Stambuli and J. F. Hartwig, Angew.
Chem., Int. Ed., 2005, 44, 1371–1375; A. H. Roy and
J. F. Hartwig, J. Am. Chem. Soc., 2003, 125, 8704–8704.
4 B. H. Lipshutz and J. M. Servesko, Angew. Chem., Int. Ed., 2003,
42, 4789–4792; B. H. Lipshutz, J. M. Servesko and B. R. Taft,
J. Am. Chem. Soc., 2004, 126, 8352–8353; B. H. Lipshutz,
N. Tanaka, B. R. Taft and C.-T. Lee, Org. Lett., 2006, 8, 1963–1966.
5 S. R. Harutyunyan, T. den Hartog, K. Geurts, A. J. Minnaard
and B. L. Feringa, Chem. Rev., 2008, 108, 2824–2852;
F. Bilčík, M. Drusan, J. Marák and R. Šebesta, J. Org. Chem.,
2012, 77, 760–765.
General procedure for copper-catalyzed 1,4-addition to
α,β-unsaturated esters21
6 A. V. R. Madduri, A. J. Minnaard and S. R. Harutyunyan,
Org. Biomol. Chem., 2012, 10, 2878–2884.
7 A. V. R. Madduri, A. J. Minnaard and S. R. Harutyunyan,
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A Schlenk tube equipped with septum and a stirring bar was
charged with Cu-L (5 μmol, 5 mol%). Dry CH2Cl2 (1 mL) was
added and the solution was stirred under nitrogen at rt for
5 min. The mixture was cooled to −78 °C and EtMgBr (0.3 mmol,
3.0 M solution in Et2O) was added. After stirring for 5 min, a
solution of 18 (19 mg, 0.10 mmol) in CH2Cl2 (0.25 mL) was
added dropwise to the reaction mixture over 1 h using a syringe
pump. Once the addition was complete, the reaction mixture
was monitored by TLC and GC-MS. The reaction was quenched
by the addition of MeOH (1 mL) and saturated aqueous NH4Cl
(2 mL), the mixture was warmed to rt and diluted with CH2Cl2,
and the layers were separated. The aqueous layer was extracted
with CH2Cl2 (3 × 5 mL), the combined organic layers were dried
with anhydrous MgSO4 and filtered, and the solvent was evapo-
rated in vacuo. Gas chromatography analysis was carried out to
determine the 1,2-addition and 1,4-addition ratio on a sample
which was passed through a short plug of silica gel to remove
copper residues. The crude product was purified by flash chro-
matography on silica gel using mixtures of n-pentane and Et2O
as the eluent.
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Methyl-3-phenylpentanoate 19 (ref. 24)
Using the general procedure: the reaction was performed with
EtMgBr and 18. 1H-NMR (CDCl3): δ 0.74 (t, J = 7.5 Hz, 3H),
1.63 (m, 2H), 2.58 (m, 2H), 2.95 (q, J = 7.1 Hz, 1H), 3.50 (s, 3H),
7.1 (m, 3H), 7.20 (m, 2H). 13C-NMR (CDCl3): δ 12.1 (CH3), 29.3
(CH2), 41.5 (CH2), 44.1 (CH), 51.7 (CH3), 126.6 (CH), 127.7
(CH), 128.6 (CH), 144.1 (C), 173.2 (C). Enantiomeric excess was
determined by chiral GC analysis, Chiraldex B-PM column
16 F. Caprioli, A. V. R. Madduri, A. J. Minnaard and
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E. Bappert, P. Polleux, J. Medlock and A. Zanotti-Gerosa,
PCT Int. Appl., WO 2009090251, 2009.
2004 | Catal. Sci. Technol., 2014, 4, 1997–2005
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Paper
19 The rev-Josiphos ligand in which cyclohexyl groups are
substituted with tert-butyl groups is commercially available.
However our preliminary screening of the copper complex of
this ligand in 1,2-addition reactions to enones and aromatic
ketones resulted in a drastic loss of enantioselectivity.
20 Z. Wu, A. V. R. Madduri, S. R. Harutyunyan and A. J. Minnaard,
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21 F. López, S. R. Harutyunyan, A. Meetsma, A. J. Minnaard and
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This journal is © The Royal Society of Chemistry 2014
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