Copper-Catalyzed Propargylic Substitution of Dichloro Substrates: Enantioselective Synthesis of Trisubstituted Allenes and Formation of Propargylic Quaternary Stereogenic Centers

Article abstract of DOI:10.1002/chem.201404668

An easy and versatile Cu-catalyzed propargylic substitution process is presented. Using easily prepared prochiral dichloro substrates, readily available Grignard reagents together with catalytic amount of copper salt and chiral ligand, we accessed a range of synthetically interesting trisubstituted chloroallenes. Substrate scope and nucleophile scope are broad, providing generally high enantioselectivity for the desired 1,3-substitution products. The enantioenriched chloroallenes could be further transformed into the corresponding trisubstituted allenes or terminal alkynes bearing all-carbon quaternary stereogenic centers, through the copper-catalyzed enantiospecific 1,1/1,3-substitutions. The two successive copper-catalyzed reactions could be eventually combined into a one-pot procedure and different desired allenes or alkynes were obtained respectively with high enantiomeric excesses.

Full text of DOI:10.1002/chem.201404668

DOI: 10.1002/chem.201404668
Full Paper
&
Asymmetric Catalysis
Copper-Catalyzed Propargylic Substitution of Dichloro Substrates:
Enantioselective Synthesis of Trisubstituted Allenes and
Formation of Propargylic Quaternary Stereogenic Centers
Hailing Li,[a] David Grassi,[a] Laure Guꢀnꢀe,[b] Thomas Bꢁrgi,[c] and Alexandre Alexakis*[a]
Abstract: An easy and versatile Cu-catalyzed propargylic
substitution process is presented. Using easily prepared pro-
chiral dichloro substrates, readily available Grignard reagents
together with catalytic amount of copper salt and chiral
ligand, we accessed a range of synthetically interesting tri-
substituted chloroallenes. Substrate scope and nucleophile
scope are broad, providing generally high enantioselectivity
for the desired 1,3-substitution products. The enantio-
enriched chloroallenes could be further transformed into the
corresponding trisubstituted allenes or terminal alkynes
bearing all-carbon quaternary stereogenic centers, through
the copper-catalyzed enantiospecific 1,1/1,3-substitutions.
The two successive copper-catalyzed reactions could be
eventually combined into a one-pot procedure and different
desired allenes or alkynes were obtained respectively with
high enantiomeric excesses.
Introduction
Since their discovery by Jacobus H. van’t Hoff, allene com-
pounds have drawn more and more attention owing to their
interesting properties and synthetic utility; one of the most
highlighted characteristics is their potential axial chirality.[1] Re-
garding their synthetic importance, and in order to gain more
insight on this family of compounds, their asymmetric synthe-
sis has become a must to access enantiomerically enriched ax-
ially chiral allenes.[2]
Scheme 1. Comparison of asymmetric allylic (a) and propargylic (b) substitu-
tion. a) Asymmetric allylic substitution introduces central chirality; b) asym-
metric propargylic substitution introduces axial chirality.
Although the introduction of central chirality can be ach-
ieved by asymmetric allylic substitution,[3] the asymmetric
propargylic substitution are often performed to generate the
chiral allenes (Scheme 1).[4]
To synthesize chiral allenes, most strategies to date have
been based on the chirality transfer from enantioenriched
propargyl compounds [Scheme 2, eq. (A)].[5] Recently, the
groups of Woodward[6] and Knochel[7] reported respectively the
use of propargyl diacetates and propargyl dichlorides as pro-
chiral substrates for allene synthesis [Scheme 2, eq. (B)]. How-
ever, in both studies, stoichiometric amounts of copper salts
were employed and no example of an asymmetric version has
been reported. Inspired by these studies, we intended to com-
bine these two approaches, namely to use prochiral substrates
and to perform the reaction under catalytic conditions.
In a previous study, our group reported the first enantio-
selective synthesis of chiral chloroallenes under the copper-cat-
alyzed conditions [Scheme 2, eq. (C)]. A simple and useful ap-
plication of this allene synthesis was demonstrated in the ste-
reospecific copper-catalyzed 1,1/1,3 substitutions [Scheme 2,
eq. (D)].[8]
[a] Dr. H. Li, Dr. D. Grassi, Prof. Dr. A. Alexakis
Department of Organic Chemistry, University of Geneva
Quai Ernest Ansermet 30, 1211 Geneva 4 (Switzerland)
Fax: (+41)22-379-32-15
Owing to the facile racemization in the presence of copper
salt and relative instability of this family of molecules, the
scope of an asymmetric allene synthesis is highly important
and worth extensive study. Herein we aim at further extending
the scope of substrates and nucleophiles. The investigation of
further transformations and limitations are equally presented.
By simply placing different substituents (R1) on the prochiral
substrate, introducing different alkyl groups (R2) by Grignard
reagents, we can obtain diverse substitution patterns on the
chloroallenes and further substitution can install R3 groups in
a 1,1- or 1,3-regioselective manner, affording the correspond-
E-mail: alexandre.alexakis@unige.ch
[b] Dr. L. Guꢀnꢀe
Laboratory of Crystallography, University of Geneva
Quai Ernest Ansermet 30, 1211 Geneva 4 (Switzerland)
[c] Prof. Dr. T. Bꢁrgi
Department of Physical Chemistry, University of Geneva
Quai Ernest Ansermet 30, 1211 Geneva 4 (Switzerland)
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201404668.
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First of all, the substrate 1a
was subjected to the conven-
tional conditions for the copper-
catalyzed asymmetric allylic alky-
lation (AAA) using chiral phos-
phoramidite ligand L1.[9] We ob-
served exclusive formation of
the 1,3-substituion product,
namely the desired chloroallene
2a, with 48% ee (Table 1,
entry 1). No trace of other regio-
isomer was detected. Based on
this preliminary result, we con-
tinued to study the ligand effect.
Several different phosphorami-
dite ligands were tested, as well
as the chiral catalyst-substrate
Scheme 2. Proposed approach for enantioselective allene synthesis.
“match/mismatch
effect”
ing trisubstituted allenes or terminal alkynes (Scheme 2). In
short, this study represents a versatile and tunable synthesis of
chiral allenes and alkynes bearing quaternary carbon centers at
propargylic position.
(Table 1, entries 1–4). The enantiomeric excess was limited to
59% (Table 1, entry 9) as the highest value for this family of li-
gands (Table 1, entries 5–12). The ferrocene-based phosphorus
ligands[10] were taken into consideration. Different sub-families
were investigated, such as Josiphos (Table 1, entries 14 and
15),[11] Taniaphos (Table 1, entry 13),[11] Mandyphos, and Wal-
phos (see the Supporting Information). The best result was ob-
tained with Josiphos L14, which gave 56% ee (Table 1,
entry 15). Among the available ferrocene-based ligands, no fur-
ther improvement could be obtained. Inspired by the work of
asymmetric allylic alkylation using N-heterocyclic carbenes
(NHCs) as ligands, several NHCs were used as ligands in the
Results and Discussion
Optimization of the reaction conditions
The optimization started with an extensive screening of chiral
ligands under copper-catalyzed conditions (Figure 1).
Figure 1. Chiral ligands used in this optimization.
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ed from one of the simplest air-stable SimplePhos ligands L19
(Table 1, entry 25), and screened several different ligands,
which are illustrated by replacing the two phenyl groups on
the phosphorus atom by other substituents (L20, L21, L22;
Table 1, entries 26–30), or replacing the phenyl groups on the
chiral amine moiety by 2-naphthyl groups (L23, L24, L25, L26;
Table 1, entries 31–36). Knowing that toluene could be used as
a decent nonpolar solvent that was known to sometimes pro-
mote high enantioselectivity in conjugate addition process-
es,[17] our reaction was tested in toluene to see the influence
(Table 1, entries 34 and 36). A series of ligands that have previ-
ously been used for the asymmetric conjugate addition reac-
tions were also studied here (Table 1, entries 31–37). Finally, we
managed to increase the ee to 75% with ligand L26 and tolu-
ene as solvent (Table 1, entry 36). We have also adjusted the
copper salt/ligand ratio from 1:1.1 to 1:2, whereby ee de-
creased from 75% to 70% (Table 1, entry 37). For a complete
list of the tested ligands, see the Supporting Information.
Screening of the copper source (Table 2) further increased
the ee to 79% by using copper iodide (Table 2, entry 8). Reduc-
ing the catalyst loading led to a reasonable drop in enantio-
selectivity (Table 2, entry 10). The influence of copper source
on this transformation was relatively minor. All of the tested
cases gave ee values higher than 70%, with only one exception
(53% ee with Cu(OAc)2; Table 2, entry 4).
Table 1. Preliminary ligand screening.
Entry[a]
Ligand L*
Cu salt
Solvent
ee [%][b]
1
2
3
4
5
6
7
8
L1
L2
L3
L4
L5
L6
L7
L8
L9
CuTC
CuTC
CuTC
CuTC
CuTC
CuTC
CuTC
CuTC
CuTC
CuTC
CuTC
CuTC
CuTC
CuTC
CuTC
CuTC
CuTC
No Cu
CuTC
CuTC
CuTC
CuTC
CuTC
CuTC
CuTC
CuTC
CuTC
CuTC
CuTC
CuTC
CuTC
CuTC
CuTC
CuTC
CuTC
CuTC
CuTC
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
toluene
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
Et2O
48
ꢀ50
ꢀ8
ꢀ51
44
40
ꢀ14
51
9
ꢀ59
ꢀ38
ꢀ13
ꢀ55
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37[d]
L9
L10
L11
L12
L13
L14
L15
L16
L16
L16
L17
L17
L17
L17
L18
L19
L20
L20
L21
L21
L22
L23
L24
L25
L25
L26
L26
L26
[c]
–
7
56
ꢀ5
ꢀ65
ꢀ10
ꢀ28
55
0
20
18
43
ꢀ46
ꢀ48
ꢀ26
ꢀ61
0
0
54
47
57
Et2O
CH2Cl2
THF
Et2O
toluene
CH2Cl2
CH2Cl2
CH2Cl2
toluene
CH2Cl2
toluene
toluene
CH2Cl2
CH2Cl2
CH2Cl2
toluene
CH2Cl2
toluene
toluene
Table 2. Copper source screening.
Entry[a]
Cu salt
ee [%][b]
20
66
75
70
1
2
3
4
5
6
7
8
CuTC
CuBr
CuCl
Cu(OAc)2
Cu(OTf)2
(CuOTf)2·C7H8
(CuOTf)2·C6H6
CuI
75
70
71
53
78
76
70
79
78
73
[a] Reaction conditions: The substrate (0.25 mmol) was added to a solu-
tion of copper salt and chiral ligand in dry solvent at ꢀ788C. The ethereal
solution of Grignard reagent (1.2 equiv) was added dropwise and the re-
action mixture was stirred at ꢀ788C for 2 h. The desired product was
confirmed by 1H NMR spectroscopy and not isolated; [b] determined by
GC analysis using a chiral stationary phase; [c] no conversion; [d] copper
salt/chiral ligand ratio=1:2.
9
10[c]
CuNaph
CuI
[a] Reaction conditions: The substrate (0.10 mmol) was added to a solu-
tion of copper salt and ligand L26 in dry toluene at ꢀ788C. The ethereal
solution of Grignard reagent (1.2 equiv) was added dropwise and the re-
action mixture was stirred at ꢀ788C for 2 h. The desired product was
confirmed by 1H NMR spectroscopy and not isolated; [b] determined by
GC analysis using a chiral stationary phase; [c] 5 mol% catalyst loading.
copper-catalyzed process (Table 1, entry 16, 17, and 19)[12] as
well as the copper-free conditions (Table 1, entry 18),[13] giving
a maximum of 65% ee (Table 1, entry 17); however this ee is
still not enough for an efficient synthetic methodology. We
then turned to biphenyl/binaphthyl-based ligands (Table 1, en-
tries 20 and 24), the best result, 55% ee obtained with simple
(R)-BINAP L17, was promising. However, solvent screening
brought no improvement (Table 1, entries 20–23).
Subsequently, solvent screening was carried out, retaining
the combination of L26 and CuI (Table 3). Different mixtures of
solvents with different ratios were studied (Table 3, entries 2–
7), as well as the polar ethereal solvents (Table 3, entries 8–10).
Toluene remained the best choice among all tested cases.
After ligand screening, copper salt screening and solvent
screening, under the preliminarily optimized conditions (CuI/
L26 in toluene) a modest level of enantioselectivity (79% ee)
Finally, we focused our attention on another family of phos-
phorus ligands, SimplePhos,[14] which is not commonly used for
substitution reactions,[15] but has been extensively studied in
the copper-catalyzed conjugate addition system.[14a,16] We start-
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isolated, but, according to the previous synthesis procedure, it
was air sensitive and readily decomposed on silica gel. Finally,
we found that flash column chromatography on Al2O3 could
easily afford the desired ligand, and it decomposed much
more slowly in diethyl ether than in dichloromethane when we
extracted the solution and purified it by column chromatogra-
phy. With this knowledge, we have managed to isolate the
ligand L27 in a practical yield of 60% and been able to study
its influence on the catalysis. However, for further optimization,
we decided to change the model substrate from 1a to 1b, to
decrease the volatility, for easier isolation and purification. The
results for this final stage formal optimization are assembled in
Table 4.
Table 3. Solvent screening.
Entry[a]
Solvent
ee [%][b]
1
2
3
4
5
6
7
8
9
10
toluene
79
76
70
79
38
44
72
toluene/CH2Cl2 4:1
toluene/CH2Cl2 1:1
toluene/hexane 1:1
toluene/pentane 1:2
Et2O/pentane 1:1
toluene/hexane 1:2
Et2O
[c]
–
A set of two diastereomers of phosphoramidite ligands L1
and L2 were tested (Table 4, entries 1 and 2). The ee values
were relatively low. SimplePhos ligand L25 and ent-L26 were
studied in both CH2Cl2 and toluene as solvent (Table 4, en-
tries 3–6). The enantioselectivity could be improved to 82% ee
with ent-L26 (Table 4, entry 6). The use of ligand L27 led to
a major improvement in terms of enantioselectivity (89% ee;
Table 4, entry 8). A simple representative screening of the
copper source (Table 4, entries 9 and 10) established the final
optimized conditions to be the combination of cheap salt CuBr
with easily prepared chiral ligand L27 in toluene and the cata-
lyst loading could be further decreased to 5 mol% while re-
taining the same enantiomeric excess (Table 4, entry 11).
THF
MTBE
0
58
[a] Reaction conditions: The substrate (0.10 mmol) was added to a solu-
tion of CuI and ligand L26 in dry solvent at ꢀ788C. The ethereal solution
of Grignard reagent (1.2 equiv) was added dropwise and the reaction
mixture was stirred at ꢀ788C for 2 h. The desired product was confirmed
by 1H NMR spectroscopy and not isolated; [b] determined by GC analysis
using a chiral stationary phase; [c] no conversion.
for the allene synthesis was achieved. As there was still much
room for optimization, we tried to understand the trend in
SimplePhos ligand screening and intended to replace the two
ethyl groups on L26 by methyl groups. This ligand, L27
(Table 4), was previously generated in situ and used for the
ring-opening of polycyclic hydrazines.[15a,c] L27 could also be
Scope of Grignard reagents
Under the optimized conditions, a broad range of Grignard re-
agents was used as nucleophile to install different alkyl groups
on the chloroallenic moiety. This methodology benefits from
the large availability and easy preparation of Grignard re-
agents, and showed a substantial diversity in terms of nucleo-
philes. The primary alkyl Grignard reagents generally led to
high enantioselectivities, with ee values ranging between 90%
and 94% (Table 5, entries 1–5). We introduced different-sized
aliphatic alkyl chains (Table 5, entries 1, 2 and 4) and an alkyl
group bearing a phenyl ring (Table 5, entry 3) or a terminal
double bond (Table 5, entry 5). As widely known for copper-
catalyzed asymmetric allylic alkylation reactions, the allyl group
may cause regioselectivity issues and a similar trend was also
observed here (Table 5, entry 6). The use of allyl Grignard’s
chloride analogue further lowered both regio- and enantiose-
lectivities (Table 5, entry 7). Unexpectedly, the benzyl group,
which should behave similarly to allyl in copper-catalyzed sub-
stitution, worked relatively well, providing exclusive SN2’ prod-
uct with a practical ee of 71% (Table 5, entry 8). Secondary
alkyl groups could also be introduced, with even higher enan-
tioselectivities regardless of their increased bulkiness (Table 5,
entries 9 and 10). Comparison of entries 10 and 11 clearly
shows an influence of the counterion in the Grignard reagent,
which was also the case for entries 6 and 7. The use of cyclo-
pentyl magnesium chloride (Table 5, entry 11) instead of bro-
mide (Table 5, entry 10) decreased the ee by 20%. The method-
ology was also applied to the conventionally challenging re-
agent MeMgBr and it was remarkable to obtain high enantio-
Table 4. Final stage formal optimization.
Entry[a] Ligand L* Cu salt Solvent Catalyst loading [%] ee [%][b]
1
2
3
4
5
6
7
8
L1
L2
L25
CuTC
CuTC
CuTC
CuTC
CuTC
CuTC
CuTC
CuTC
CuI
CH2Cl2
CH2Cl2
CH2Cl2
toluene 10
CH2Cl2 10
toluene 10
CH2Cl2 10
toluene 10
toluene 10
toluene 10
10
10
10
39
40
50
4
58
82
58
89
91
92
92
L25
ent-L26
ent-L26
L27
L27
L27
9
10
11
L27
L27
CuBr
CuBr
toluene
5
[a] Reaction conditions: The substrate (0.25 mmol) was added to a solu-
tion of copper salt and chiral ligand in dry solvent at ꢀ788C. The ethereal
solution of Grignard reagent (1.2 equiv) was added dropwise during
20 min and the reaction mixture was stirred at ꢀ788C for 2 h. The desired
1
product was confirmed by H NMR spectroscopy and not isolated; [b] de-
termined by GC analysis using a chiral stationary phase. Cy=cyclohexyl.
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Table 5. Scope of Grignard reagents.
Entry[a]
RMgX or RLi
Product
Yield [%]
ee [%][b]
1
2
3
4
5
6
7
8
EtMgBr
nBuMgBr
PhCH2CH2MgBr
iBuMgBr
CH2 =C(CH3)CH2CH2MgBr
allylMgBr
allylMgCl
benzylMgBr
iPrMgBr
cPentylMgBr
cPentylMgCl
MeMgBr
2b
2c
2d
2e
2 f
2g
2g
2h
2i
2j
2j
2k
–
–
84
92
84
84
92
n.d.[c]
n.d.[d]
85
88
84
92
82
n.d.
n.d.[e]
n.d.[f]
92
94
90
93
94
58
12
71
96
96
76
91
0
9
10
11
12
13
14
15
Scheme 3. Synthetic pathway for substrate preparation.
tBuMgBr
PhMgBr
nBuLi
–
23
2c
[a] Reaction conditions: the substrate (0.25 mmol) was added to a solution
of CuBr and chiral ligand L27 in dry toluene at ꢀ788C. The ethereal solu-
tion of Grignard reagent (1.2 equiv) was added dropwise over 20 min and
the reaction mixture was stirred under ꢀ788C for 2 h. Full conversion
and the desired products were confirmed by 1H NMR spectroscopy;
[b] determined by GC analysis using a chiral stationary phase; [c] regioiso-
mer g/a=1:1.3; [d] regioisomer g/a=1:2.1; [e] unidentified mixture;
[f] full conversion, desired product not isolated.
control on this type of propargylic substrate (Table 5 entry 12).
Attempts with tert-butyl or phenyl reagents were unsuccessful
(Table 5, entries 13 and 14). One more example, using a organo-
lithium reagent as nucleophile,[18] gave full conversion with the
desired allene as major product, although the enantiomeric
excess was quite poor (Table 5, entry 15).
Substrate scope
The generality of this enantioselective allene synthesis method
was exploited by extending the scope of 1,1-dichloro-
propargylic substrates. The advantage of this family of prochi-
ral substrates is their easy preparation;[7] a two-step synthetic
sequence from commercially available alkynes, with only one
purification by flash column chromatography, can afford differ-
ent propargyl dichlorides in moderate to good yields
(Scheme 3). The first step was the formation of corresponding
conjugated ynal from the alkyne, without purification, the
second step involved a double chlorination of the crude ynal
using PCl5 and provided the desired dichloro substrate 1.
These propargyl dichlorides were then subjected to copper-
catalyzed substitution reactions under the previously estab-
lished conditions, leading to the formation of the correspond-
ing chloroallenes in most cases. Various linear aliphatic alkyl
groups could be present in the substrate and showed good se-
lectivities (Scheme 4, 2l, 2m). Similar substrate 1d, bearing
a terminal chlorine atom, was also tolerated. The resulting
allene 2n, which bears two halogens, would be potentially
synthetically useful. Cases where the R group was a secondary
Scheme 4. Substrate scope.
alkyl afforded the desired allenes with very good ee values
(Scheme 4, 2c, 2o, ent-2j), whereas further increasing the
steric bulk to tertiary alkyl (tBu) slightly decreased the ee to
84% (Scheme 4, 2p). Silyl-substituted allenes imply interesting
and important synthetic potential.[5d,19] Through our methodol-
ogy, the trimethylsilyl (TMS)-substituted chloroallene 2q could
be obtained with good yield and a decent ee of 85%. Increas-
ing the size of the silyl group from TMS to triethylsilyl (TES) in
the substrate negatively influenced the enantioselectivity and
the ee value decreased to 72% (Scheme 4, 2r). The bulkier tri-
isopropylsilyl (TIPS) group greatly decreased the reactivity
under these conditions. We had to warm up the reaction to
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room temperature to achieve some conversion; however, the
resulting product 2s was racemic. The phenyl-substituted sub-
strate led to only moderate enantioselectivity (Scheme 4, 2t).
We then tested the influence of substituents on the aromatic
ring with different electronic effects. Electron-donating groups,
such as para-methyl, had no influence on enantiomeric excess
(Scheme 4, 2u), whereas the electron-withdrawing group para-
trifluoromethyl improved the ee value from 64% to 82%
(Scheme 4, 2v). An example with protected alcohol functionali-
ty was also studied; an a-alkoxyallenylic compound was ob-
tained, albeit with moderate ee (Scheme 4, 2w). Finally, one
more substrate 1m was prepared for the synthesis of vinyl-
allenic compound 2x in good yield and good enantioselectivi-
ty.
Table 6. Copper-catalyzed transformation of chloroallenes.
Entry[a] Nucleophile Solvent Product
Yield [%]
ee [%][b]
1
2
3
4
5
6
7
8
PhMgBr
PhMgBr
THF
CH2Cl2
THF
CH2Cl2
THF
THF
CH2Cl2
CH2Cl2
THF
3a
3a
3e
4b
3 f
3 f
4b
91
87
<80
89
58
90
60
80
90
87
88
87.5
2-Naphtyl
nBuMgBr
nBuMgBr
nBuMgCl
nBuMgCl
vinylMgCl
vinylMgCl
vinylMgBr
n.d.
n.d.
Ratio 3/5 1/0.18 Low conv. n.d.
Ratio 3/5 1/1.35 Low conv. n.d.
Ratio 3/5 1/0.48 Low conv. n.d.
–
–
–
–
–
Further transformations of chiral chloroallenes
9
10
11
12
13
14
15
THF
By employing this synthetic method, we could easily prepare
trisubstituted chiral allenic compounds bearing a chlorine
atom, which renders the resultant molecules ready for further
transformations. To demonstrate the application and impor-
tance of the synthetic system, we performed some simple
metal-catalyzed reactions on the reactive allenic chloride
moiety.
ethynylMgBr THF
No conv.
No conv.
No conv.
No conv.
No conv.
–
–
–
–
–
iPrZnBr
iPrZnBr
nBuLi
THF
CH2Cl2
CH2Cl2
THF
nBuLi
[a] Reaction conditions: The substrate (0.10 mmol) was added to a mixture
of CuCN and dry solvent at 08C. The ethereal solution of Grignard re-
agent was added dropwise, the reaction mixture was warmed up to
room temperature and stirred during 2 h or overnight. The desired prod-
ucts were confirmed by 1H NMR spectroscopy; [b] determined by GC
analysis using a chiral stationary phase.
First of all, we tried palladium-catalyzed coupling reactions
(Scheme 5). Under the conventional conditions, we carried out
Suzuki[13f] and Sonogashira[20] couplings on 2k aimed at instal-
ling phenyl and trimethylsilylethynyl respectively on the allene
by replacing the chlorine atom. In the case of the Suzuki cou-
pling, total racemization was observed in the desired product
by a 1,1-substitution in THF keeping the same level of enantio-
purity as the starting chloroallene (Table 6, entry 1). The bulkier
1-naphthyl group could also be installed on the same starting
material, albeit with a slightly lower ee (Table 6, entry 3). The
preliminary attempt to introduce the alkyl group under the
same conditions failed to afford the desired alkylated allene
compound 3 as successfully as in previous arylation cases. In-
stead, a substantial amount of dechlorinated nonchiral allene 5
was detected when performing the reaction with n-butyl
Grignard reagent. However, when we simply changed the sol-
vent from THF to CH2Cl2, under similar conditions, the reaction
led to almost exclusive formation of 1,3-substitution product 4.
Therefore, the nBu group was installed in a 1,3-substitution
manner using CH2Cl2 as solvent affording terminal alkyne 4b
with a propargylic quaternary carbon center (Table 6, entry 4).
When we subjected the phenyl Grignard to chloroallene in
CH2Cl2, no trace of the corresponding alkyne was detected.
The reaction still formed exclusively the aryl allene 3a, albeit
partially racemized. The ee value dropped from 90% to 60%
(Table 6, entry 2). Furthermore, efforts were made to enable
1,1-alkylation. We found that slow addition and careful control
of the amount of nucleophile substantially minimzed the side
reaction, namely the formation of reduced allene 5. Product
formation could then be easily controlled by a simple change
of solvent; alkyne 4b in CH2Cl2 (Table 6, entry 4) and alkylated
allene 3 f in THF (Table 6, entry 5). The ee values always re-
mained at high levels in these transformations. We also studied
the halogen effect of the Grignard reagents in the substitution
Scheme 5. Pd-catalyzed coupling reactions on chloroallene.
3a and the reaction provided a complex mixture. The tested
Sonogashira coupling afforded the desired product 3b in 82%
yield, albeit partially racemized. The ee value decreased from
90% in the starting material 2k to 36% in the resulting allene
3b.
Without having obtained promising results from the prelimi-
nary tests on Pd-catalyzed coupling systems, we turned to
copper-catalyzed substitution reactions of these enantio-
enriched chloroallenes. Based on the previous report on the
copper-catalyzed substitution of racemic chloroallenes by
Knochel et al.,[7] we applied this simple and quickly accessible
procedure to our enantiomerically enriched allenes. The
phenyl group could be introduced to the allene 2k (90% ee)
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reaction using nBuMgCl instead of nBuMgBr in both solvents
(Table 6, entries 6 and 7). Similar enantioselectivities were ob-
tained, suggesting that the counterion of the Grignard reagent
was not crucial in this case. Attempts to install challenging
groups by means of the Grignard reagent, such as vinyl
(Table 6, entries 8–10) and ethynyl (Table 6, entry 11), were un-
successful. Other organometallic reagents, such as organozinc
reagent (Table 6, entries 12 and 13) and organolithium reagent
(Table 6, entries 14 and 15) were tested in both THF and CH2Cl2
respectively, although almost no conversion took place in all of
these cases.
Copper-catalyzed one-pot sequence
Considering that the enantioselective synthesis of chloroal-
lenes and the 1,1-arylation or 1,1/1,3-alkylation of chloroallenes
were both under copper-catalyzed conditions, we intended to
combine these two steps into a one-pot sequence. For this
one-pot process, we could start with the allene synthesis reac-
tion in toluene using an alkyl Grignard reagent, then add the
necessary solvent and another Grignard reagent to promote
the follow-up alkylation or arylation. Three representative ex-
amples are shown in Scheme 6. We subjected substrate 1b to
the previously optimized conditions, leading to the in situ gen-
eration of chiral allene 2k. In the same reaction medium,
a second solvent (THF or CH2Cl2) was introduced to promote
the following substitution step, giving rise to 3a, 3 f, or 4b
(depending on choice of solvent or Grignard reagent;
Scheme 6). The switch of solvents allowed access to the trisub-
stituted aryl/alkyl allenes or terminal alkyne in high enantiopur-
ity levels. This methodology provides an easy access to chiral
allene and alkyne synthesis, with flexible choice of different
substituents pattern in the products.
With the systematic study, we established a relatively tuna-
ble enantioselective synthesis for trisubstituted aryl allenes, tri-
substituted alkylated allenes, and terminal alkynes with quater-
nary stereogenic carbon centers (see examples in Figure 2).[21]
Different aryl groups with different steric or electronic effects
could be introduced highly enantiospecifically (3a, 3c–e). Pri-
mary, secondary, and tertiary alkyl groups were installed by
1,1-substitution in THF providing the corresponding allenes
(3 f–i) while primary and secondary alkyls could also go
through 1,3-substitution on chloroallenes in CH2Cl2 to form al-
kynes (4b–d). Allyl Grignard worked well in this reaction, with
good yield and total chirality transfer (3j). We could even syn-
thesize highly bulky compounds with a sterically congested
quaternary carbon center, such as 4e. Versatile and synthetical-
ly useful moieties, such as propargyl silyl 4a and allenyl silyl
3k,[22] were readily prepared from the common chloroallene
2q. A simple change of solvents, from CH2Cl2 to THF, led to
the formation of both compounds 4a and 3k respectively.
Determination of the absolute configuration
X-ray crystallography approach
To gain more insight into these products, 4b was subjected to
“click chemistry”. Under Sharpless’ conditions, using a catalytic
amount of CuSO4,[23] the terminal alkyne 4b underwent Huis-
gen cycloaddition with para-bromophenyl azide to form the
corresponding 1,2,3-triazole
(Scheme 7).
6
X-ray diffraction on the result-
ing crystalline product 6 allowed
the determination of the abso-
lute configuration of the stereo-
genic carbon center, which was
defined as S (Figure 3).
Supposing that this quaterna-
ry carbon center was intact
during the Huisgen cycloaddi-
tion process, the quaternary
carbon center in the alkyne 4b
was established as S as well. Ac-
cording to the previous work of
Corey[24] and Caporusso[25] on
the substitution reactions of
bromoallenes, we assumed that,
in our case, the nucleophilic
attack still followed the reported
anti-SN’ manner (Scheme 7). In
this way, we attributed the abso-
lute configuration of the axially
chiral chloroallene compound
2k as R. In the case of 1,1-substi-
tution, knowing also that nucle-
ophiles have a preference for
anti-type substitutions, we pre-
Figure 2. Formation of enantioenriched allenes and alkynes.
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vertical axis uppermost, the more
polarizable substituent in the hor-
izontal axis is to the right, then
a clockwise screw pattern of po-
larizability will obtain and the
enantiomer should be dextrorota-
tory; if the more polarizable sub-
stituent in the horizontal axis is to
the left, then an anticlockwise
screw pattern of polarizability will
obtain and the enantiomer
should be laevorotatory.”[26]
Two reported examples are
shown in the Table 7, entries 1
and 2. Based on the previously
established relative polarizability
order, the molecules were
placed accordingly with the view
along the orthogonal axes, and
the screw patterns corresponded
well with the sign of optical ro-
tation. Therefore, we selected
several representative examples
Scheme 6. Copper-catalyzed one-pot sequence.
Scheme 7. Formation of the 1,2,3-triazole 6.
Table 7. Absolute configuration prediction by Lowe’s extension of Brew-
ster’s rules.
Entry[a] Absolute config- Polarizability View along the or-
uration order thogonal axes
Sign of
½aꢁD
Cl>Me>
tBu>H
1[a]
2[a]
3[b]
4[b]
5[b]
6[b]
7[b]
(ꢀ)
(ꢀ)
(ꢀ)
(+)
(ꢀ)
(+)
(ꢀ)
Me>tBu>H
Cl>Cy>
Me>H
Cl>nBu>
tBu>H
Figure 3. X-ray crystal structure of 6.
Cl>Cy>
nBu>H
sumed that the aryl allenes 3a and alkyl allene 3 f have the de-
picted stereochemistry, while the other chiral allene com-
pounds and alkynes are assigned by inference (Figure 2).
Ph>Cy>
Me>H
Cy>Me,
Cy>nBu>H
Lowe’s empirical approach
[a] Previously reported; [b] synthesized in our study.
Based on Lowe’s extension of Brewster’s rules,[26] the absolute
configuration of allenes could be predicted according to the
relative polarizability of the substituents and the signs of opti-
cal rotation (Table 7):
which were synthesized in our study, and illustrated them in
the same manner. The predicted absolute configurations
matched well with the results obtained from X-ray crystallogra-
phy (Table 7, entries 3–7).
“If the allenes are viewed along their orthogonal axes, then the
handedness of the screw pattern of polarizability is determined
as follows. If by placing the more polarizable substituent in the
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Vibrational circular dichroism spectra approach
ate would bias a certain conformation in the presence of the
chiral phosphorus ligand (Figure 5). Upon the anti-selective ox-
idative addition process, the CuIII intermediate C would be
formed, which could then undergo a reductive elimination to
obtain the desired chloroallene P and regenerate the CuI spe-
cies A.
The infrared (IR) spectra and vibrational circular dichroism
(VCD) spectra[27] of the chloroallene 2k and phenyl allene 3a
were measured respectively to establish the absolute configu-
rations by comparing the measured spectra with their calculat-
ed counterparts (Figure 4).
The proposed transition state models for intermediate B are
shown in Figure 5. The two naphthyl groups intend to present
The IR spectra are very well reproduced by the calculations.
For the chloroallene 2k, knowing that the S-enantiomer was
used for calculation, based on the comparison, the opposite
absolute configuration R can be assigned for 2k. As for phenyl
allene 3a, the absolute configuration can be assigned as S,
which is the same enantiomer used in the calculation (see the
Supporting Information for detailed discussion). Overall, the re-
sults are in good agreement with what we expected according
to previous approaches and further confirmed the absolute
configurations of the molecules synthesized in this study.
Proposed mechanism for chloroallene formation
We propose a possible mechanism for this enantioselective
propargylic substitution. In the case of halogen atoms as leav-
ing group, an anti-SN’/reductive elimination sequence was en-
visaged (Scheme 8).[4c,28] The complexation of the initial cop-
per(I) species A with the propargylic substrate S led to the for-
mation of copper coordination intermediate B. This intermedi-
Scheme 8. Proposed mechanism.
Figure 4. Experimental (lower) and calculated (upper) IR and VCD spectra.
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over alumina previously activated at 3508C during 12 h under ni-
trogen before use. Reaction progress was monitored by thin-layer
chromatography (TLC) or GC-MS Hewlett Packard (EI mode)
HP6890–5973. TLC was performed using silica gel precoated alumi-
num plates purchased from Sigma–Aldrich and visualized by UV
fluorescence or KMnO4 staining. Flash column chromatography
1
was performed using silica gel 32–63 mm, 60 ꢃ. H (400 MHz), 13C
(101 MHz), 31P (162 MHz) and 19F (376 MHz) NMR spectra were re-
corded on a Bruker 400F NMR in CDCl3 or C6D6, and chemical shifts
(d) are given in ppm relative to residual CHCl3 or C6HD5. Multiplicity
is indicated as follows: s (singlet), d (doublet), t (triplet), q (quartet),
m (multiplet), dd (doublet of doublets), dt (doublet of triplets), ddd
(doublet of doublets of doublets), brs (broad singlet). Coupling
constants are reported in Hertz (Hz). Optical rotations were record-
ed on a PerkinElmer 241 polarimeter at 258C in a 10 cm cell in the
stated solvent; ½aꢁD values are given in 10ꢀ1 degcm2 gꢀ1 (concentra-
tion c given as g per 100 mL). Enantiomeric excesses were deter-
mined by chiral GC measurement either on a HP6890 (H2 as vector
gas) or HP6850 (H2 as vector gas) with the stated column. Temper-
ature programs are described as follows: initial temperature (8C)—
initial time (min)—temperature gradient (8Cminꢀ1)—final tempera-
ture (8C); retention times (tR) are given in minutes. Enantiomeric ex-
cesses were also determined by Chiral SFC measurement on
a Berger SFC with the stated column. The chiral phosphoramidite
ligands[9,29] NHC ligands,[13h,30,31] and Simplephos ligands[14] were
prepared according to the reported procedures. Josiphos, Tania-
phos, Mandyphos, and Walphos ligands were provided by Solvias
as a gift. CuTC, CuCN, CuBr, CuI, Cu(OAc)2, Cu(OTf)2, (CuOTf)2·C7H8,
(CuOTf)2·C6H6 was purchased from FrontierScientific, Sigma–Aldrich
or Alfa-Aesar and used as received. Copper(II) naphthenate (77% in
mineral spirits; 8% Cu) was purchased from Strem and used as
a solution in pentane (3.2 g of the green viscous oil was dissolved
in 50 mL pentane).
Figure 5. Models for enantiodiscrimination.
a parallel conformation in order to favor p–p stacking interac-
tion, the conformation of the gem-chloro carbon center would
favor transition state TS1 due to lower steric hindrance. In the
meantime, the methyl group on the phosphorus atom could
also influence the enantioselectivity as we can see the interac-
tion between the front methyl group on the P atom with the
upper H or Cl atom in this model. This could be an explanation
for the fact that during ligand optimization process, replacing
the methyl groups by bulkier alkyls (ethyl or n-butyl) lowered
the enantiomeric excesses.
Conclusions
In conclusion, we have reported a versatile and tunable syn-
thetic methodology for the enantioselective synthesis of chiral
allenes and terminal alkynes. The copper-catalyzed 1,3-propar-
gylic substitution employed a catalytic amount of the cheap
copper source CuBr and an easily accessible SimplePhos ligand
L27, with a range of readily available Grignard reagents as nu-
cleophiles. The prochiral propargyl dichloride substrates were
easily synthesized in two steps from commercially available al-
kynes with only one purification. The 1,3-substitutions were
observed exclusively to afford the chloroallenes with high
enantioselectivities up to 96% ee. A simple and useful applica-
tion of this chiral allene synthesis was demonstrated in the ste-
reospecific copper-catalyzed 1,1/1,3-substitution. By simply
changing the nucleophiles or the solvents, we could gain
access to different trisubstituted aryl or alkyl allenes (by 1,1-
substitution in THF) and terminal alkynes (by 1,3-substitution
in CH2Cl2). Synthetically valuable allenyl and propargyl silanes
were synthesized in high optical purity through this methodol-
ogy. The value of this study was further amplified by combin-
ing the two copper-catalyzed reactions into a one-pot process
and the enantioinduction remained high for this sequence. In
summary, this work represents an important contribution to
the asymmetric syntheses of allenes and terminal alkynes.
Representative procedure for SimplePhos ligand synthesis
1,1-Dimethyl-N,N-bis((R)-1-(naphthalen-2-yl)ethyl)phosphanamine
(L27): To a 100 mL flask was added (R)-bis[(R)-1-(naphthalen-2-yl)e-
thyl]amine (1.59 g, 4.8 mmol, 1.0 equiv) and THF (15 mL). The solu-
tion was cooled down to ꢀ788C under nitrogen in an acetone/dry
ice bath. nBuLi was added dropwise to the solution at ꢀ788C (the
color of the solution turned from yellow to red orange). Once addi-
tion had finished, the reaction mixture was stirred at the same
temperature for a further 10 min (longer time would lead to the
decomposition of the deprotonated amine) before adding PCl3
(0.42 mL, 4.8 mmol, 1.0 equiv). An aliquot of reaction mixture was
collected for analysis by 31P NMR spectrocopy (in [D6]benzene).
Upon full consumption of PCl3, MeLi solution (1.6m in Et2O, 6.9 mL,
11.04 mmol, 2.3 equiv) was introduced to the flask, and the reac-
tion mixture was allowed to warm back to 08C and stirred for a fur-
ther 20–30 min. Excess of the organolithium reagent was neutral-
ized by adding several drops of MeOH. The resulting solution was
quenched by water and the aqueous phase was extracted with
Et2O (3ꢄ25mL). The combined organic phases were dried over
Na2SO4 and concentrated under reduced pressure. A fast column
chromatography purification on Al2O3 (eluent=9:1 pentane/Et2O;
Rf =0.85) provided the desired product L27 (1.13 g, 60% yield) as
a white solid. 1H NMR (400 MHz, CDCl3): d=7.73–7.71 (m, 2H),
7.58–7.55 (m, 4H), 7.44–7.37 (m, 6H), 7.15 (dd, J=8.6, 1.8 Hz, 2H),
4.58–4.50 (m, 2H), 1.76 (d, J=6.9 Hz, 6H), 1.33 (d, J=6.2 Hz, 3H),
1.21 ppm (d, J=5.9 Hz, 3H); 13C NMR (101 MHz, CDCl3): d=142.0,
133.2, 132.4, 128.0, 127.5, 127.3, 127.2, 126.0, 125.7, 125.5, 53.5 (d,
J=6.5 Hz), 21.5 (d, J=9.1 Hz), 17.7 (d, J=18.2 Hz), 17.1 ppm (d, J=
Experimental Section
General remarks: All reactions were carried out under argon atmos-
phere with flame-dried glasswares. Solvents were dried by filtration
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14.5 Hz); 31P NMR (162 MHz, CDCl3): d=13.47 ppm. The spectral
data are in full agreement with those reported in the literature.[14b]
124.8, 90.0, 41.7, 32.1, 32.0, 26.46, 26.42, 26.3, 24.6, 12.1 ppm;
HRMS (EI) calcd for C11H17Cl [M]+ 184.1013, found 184.1011.
Representative procedure for the copper-catalyzed 1,1-ary-
lation of chloroallenes
Representative procedure for substrate synthesis
(3,3-Dichloroprop-1-yn-1-yl)cyclohexane (1b): To a solution of cy-
clohexylacetylene (2.61 mL, 20 mmol, 1.0 equiv) in Et2O (16 mL) at
ꢀ408C was added dropwise nBuLi solution (1.6m in hexane,
12.5 mL, 20 mmol, 1 equiv) followed by the addition of anhydrous
DMF (2.4 mL, 30 mmol, 1.5 equiv) in one portion. The clear reaction
mixture was allowed to warm up to room temperature and stirred
for 30 min. The solution was then poured into a biphasic mixture
of aqueous 10% KH2PO4 solution (100 mL) and Et2O (80 mL) at
08C. The mixture was stirred vigorously, and layers were parti-
tioned. The aqueous phase was extracted with Et2O (3ꢄ50 mL).
The organic phases were combined, dried over Na2SO4, filtered,
and concentrated under reduced pressure. The crude 3-cyclohexyl-
propiolaldehyde obtained was used in the following chlorination
step without further purification. The crude aldehyde (calculated as
20 mmol, 1.0 equiv) was dissolved in dry CH2Cl2 (40 mL) and
cooled to ꢀ208C. PCl5 (6.2 g, 30 mmol, 1.5 equiv) was added por-
tionwise and the reaction mixture was stirred overnight. It was
quenched by solid NaHCO3 (8.4 g, 100 mmol, 5.0 equiv) at ꢀ208C
followed by water. The mixture was allowed to warm back to room
temperature. Additional NaHCO3 was added to completely neutral-
ize the solution. The aqueous phase was extracted with CH2Cl2 (3ꢄ
50mL). The organic phases were combined, dried over Na2SO4, fil-
tered, and concentrated under reduced pressure. Purification by
flash column chromatography on silica gel (eluent=pentane; Rf =
0.83) provided the desired compound 1b (3.01 g, 79% overall
yield over 2 steps) as a slightly yellow liquid. 1H NMR (400 MHz,
CDCl3): d=6.28 (d, J=1.8 Hz, 1H), 2.54–2.48 (m, 1H), 1.84–1.77 (m,
2H), 1.74–1.66 (m, 2H), 1.54–1.43 (m, 3H), 1.38–1.29 ppm (m, 3H);
13C NMR (101 MHz, CDCl3): d=96.2, 76.6, 56.3, 31.9, 29.2, 25.8,
24.8 ppm; HRMS (EI) calcd for C9H12Cl2 [M]+ 190.0311, found
190.0306.
(S)-(3-Cyclohexylbuta-1,2-dien-1-yl)benzene (3a): A dried argon-
flushed Schlenk tube was charged with CuCN (2.7 mg, 15 mol%)
and the chloroallene 2k (34.1 mg, 0.2 mmol, 1.0 equiv) in THF
(2 mL) at 08C. PhMgBr (1m in THF, 0.4 mL, 0.4 mmol, 2.0 equiv) was
added dropwise to the solution. The reaction mixture was allowed
to warm back to room temperature and the reaction progress was
monitored by TLC. Once full conversion had been achieved, the re-
action mixture was quenched by saturated aqueous NH4Cl solution
and the aqueous phase was extracted with Et2O (2ꢄ5mL). The
combined organic phases were dried over Na2SO4, concentrated
under reduced pressure, and purified by flash column chromatog-
raphy on silica gel (eluent=pentane; Rf =0.69). Product 3a was
obtained as a colorless oil (0.0385 g, 91% yield, S-enantiomer,
90% ee). The enantiomeric excess was determined by GC on
a chiral stationary phase (column: Hydrodex b-6-TBDMS, method:
60-0-1-170-5, tR =86.81, 87.19 min). ½aꢁ2D0 =+233.3 (c=0.53 in
CHCl3; 1H NMR (400 MHz, CDCl3): d=7.32–7.26 (m, 4H), 7.20–7.14
(m, 1H), 6.08 (p, J=2.8 Hz, 1H), 1.94–1.85 (m, 3H), 1.82 (d, J=
2.8 Hz, 3H), 1.77–1.73 (m, 2H), 1.69–1.63 (m, 1H), 1.35–1.11 ppm
(m, 5H); 13C NMR (101 MHz, CDCl3): d=202.4, 136.3, 128.63, 128.61,
126.47, 126.43, 109.1, 94.6, 42.3, 32.3, 32.1, 26.6, 26.4, 17.4 ppm;
HRMS (EI) calcd for C16H20 [M]+ 212.1560, found 212.1560.
Representative procedure for the copper-catalyzed 1,1-alky-
lation of chloroallenes
(S)-Octa-2,3-dien-2-ylcyclohexane (3 f):
A
dried argon-flushed
Schlenk tube was charged with CuCN (2.7 mg, 15 mol%) and the
chloroallene 2k (34.1 mg, 0.2 mmol, 1.0 equiv) in THF (2 mL) at
08C. nBuMgBr (3.2m in Et2O, 0.08 mL, 0.24 mmol, 1.2 equiv) was
added dropwise to the solution during 30 min. The reaction mix-
ture was allowed to warm back to room temperature and the reac-
tion progress was monitored by TLC. Once full conversion had
been achieved, the reaction mixture was quenched by saturated
aqueous NH4Cl solution and the aqueous phase was extracted
with Et2O (2ꢄ5mL). The combined organic phases were dried over
Na2SO4, concentrated under reduced pressure, and purified by
flash column chromatography on silica gel (eluent=pentane; Rf =
0.63). Product 3 f was obtained as a colorless oil (0.0222 g, 58%
yield, S-enantiomer, 87% ee). The enantiomeric excess was deter-
mined by GC on a chiral stationary phase (column: Hydrodex b-3P,
method : 60-0-1-110-0-20-170-5, tR =46.73, 48.23 min). ½aꢁ2D0 =+44.9
Representative procedure for the copper-catalyzed propar-
gylic substitution of 1,1-dichloro substrates
(R)-(1-Chloropenta-1,2-dien-3-yl)cyclohexane (2b): A dried Schlenk
tube was charged with CuBr (1.8 mg, 5 mol%) and the chiral
ligand L27 (5.4 mg, 5.5 mol%) in toluene (2 mL). The mixture was
stirred at room temperature for 10 min. The 1,1-dichloroalkyne 1b
(47.8 mg, 0.25 mmol, 1.0 equiv) was introduced dropwise and the
reaction mixture was stirred at room temperature for a further
5 min before being cooled to ꢀ788C in an acetone/dry ice cold
bath. The ethyl Grignard reagent (3m in Et2O, 0.1 mL, 0.30 mmol,
1.2 equiv) was added manually during 20 min. Once the addition
was complete the reaction mixture was stirred at ꢀ788C for 2 h.
The reaction was quenched by adding saturated aqueous solution
of NH4Cl. Et2O was added and the aqueous phase was separated
and extracted with diethyl ether (3ꢄ2 mL). The combined organic
phases were washed with brine (3 mL), dried over anhydrous
Na2SO4, filtered and concentrated under reduced pressure. The
crude product was purified by column chromatography on silica
gel using (eluent=pentane; Rf =0.76), and the desired product 2b
was isolated as a colorless oil. (0.039 g, 84% yield, R-enantiomer,
92% ee). The enantiomeric excess was determined by GC on
a chiral stationary phase (column: Hydrodex b-3P, method: 60-0-1-
110-0-20-170-5, tR =48.20, 49.14 min). ½aꢁ2D0 =ꢀ86.3 (c=0.50 in
1
(c=0.60 in pentane); H NMR (400 MHz, CDCl3): d=5.02 (tp, J=5.6,
2.8 Hz, 1H), 1.95 (q, J=6.5 Hz, 2H), 1.82–1.68 (m, 5H), 1.67 (d, J=
2.8 Hz, 3H), 1.40–1.02 (m, 9H), 0.90 ppm (t, J=7.1 Hz, 3H);
13C NMR (101 MHz, CDCl3): d=200.7, 104.6, 90.9, 41.8, 32.2, 32.1,
31.6, 29.3, 26.7, 26.6, 22.4, 17.9, 14.1 ppm; HRMS (EI) calcd for
C14H24 [M]+ 192.1873, found 192.1870.
Representative procedure for the copper-catalyzed 1,3-alky-
lation of chloroallenes
(S)-(3-methylhept-1-yn-3-yl)cyclohexane (4b): A dried argon-flushed
Schlenk tube was charged with CuCN (2.7 mg, 15 mol%) and the
chloroallene 2k (34.1 mg, 0.2 mmol, 1.0 equiv) in CH2Cl2 (2 mL) at
08C. nBuMgBr (3.9m in Et2O, 0.1 mL, 0.4 mmol, 2.0 equiv) was
added dropwise to the solution. The reaction mixture was allowed
to warm back to room temperature and the reaction progress was
1
CHCl3); H NMR (400 MHz, CDCl3): d=6.08–6.06 (m, 1H), 2.13–2.06
(m, 2H), 1.90–1.73 (m, 5H), 1.67–1.63 (m, 1H), 1.31–1.10 (m, 5H),
1.03 ppm (t, J=7.3 Hz, 3H); 13C NMR (101 MHz, CDCl3): d=198.2,
Chem. Eur. J. 2014, 20, 1 – 14
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monitored by TLC. Once full conversion had been achieved, the re-
action mixture was quenched by saturated aqueous NH4Cl solution
and the aqueous phase was extracted with Et2O (2ꢄ5mL). The
combined organic phases were dried over Na2SO4, concentrated
under reduced pressure, and purified by flash column chromatog-
raphy on silica gel (eluent=pentane; Rf =0.95). Product 4b was
obtained as a colorless oil (0.0342 g, 89% yield, S-enantiomer,
90% ee). The enantiomeric excess was determined by GC on
a chiral stationary phase (column: Hydrodex b-6-TBDMS: method
60-0-1-110-0-20-170-5, tR =47.34, 47.86 min). ½aꢁ2D0 =+2.7 (c=0.49
concentrated under reduced pressure, and purified by flash
column chromatography on silica gel (eluent=pentane; Rf =0.95).
Product 4b was obtained as a colorless oil (0.0431 g, 90% yield).
Acknowledgements
This work is supported by the Swiss National Research Founda-
tion (grant No. 200020-126663). The authors warmly thank Dr.
D. Mꢁller (Univ. of Geneva) for preparation of useful chemicals,
Solvias for generous gift of chiral ligands, BASF for the gener-
ous gift of chiral amines and Prof. P. Knochel (L. Maximilian
Univ., Munich, Germany) for fruitful discussion.
1
in CHCl3); H NMR (400 MHz, CDCl3): d=2.07 (s, 1H), 1.93–1.89 (m,
1H), 1.80–1.76 (m, 3H), 1.68–1.63 (m, 1H), 1.49–1.05 (m, 15H),
0.92 ppm (t, J=7.1 Hz, 3H). 13C NMR (101 MHz, CDCl3): d=91.4,
69.1, 45.6, 38.8, 38.3, 28.2, 27.4, 27.0, 26.98, 26.9, 26.7, 23.5, 23.46,
14.3 ppm. HRMS (EI) calcd for C11H17 [MꢀC3H7]+ 149.1325, found
149.1323.
Keywords: allenes · asymmetric catalysis · copper · Grignard
reagents · P ligands
Representative procedure for the one-pot copper-catalyzed
sequence to generate chiral allenes
[1] Reviews and highlights on allenes: a) Modern Allene Chemistry (Eds.: N.
Krause, A. S. K. Hashmi), Wiley-VCH, Weinheim, 2005; b) A. Hoffmann-
Rçder, N. Krause, Angew. Chem. 2004, 116, 1216–1236; Angew. Chem.
Int. Ed. 2004, 43, 1196–1216; c) A. Hoffmann-Rçder, N. Krause, Angew.
Chem. 2002, 114, 3057–3059; Angew. Chem. Int. Ed. 2002, 41, 2933–
2935; d) S. Ma, Acc. Chem. Res. 2003, 36, 701–712; e) S. Ma, Chem. Rev.
2005, 105, 2829–2871; f) S. Ma, E.-i. Negishi, J. Am. Chem. Soc. 1995,
117, 6345–6357; g) A. S. K. Hashmi, Angew. Chem. 2000, 112, 3737–
3740; Angew. Chem. Int. Ed. 2000, 39, 3590–3593; h) S. Yu, S. Ma,
Angew. Chem. 2012, 124, 3128–3167; Angew. Chem. Int. Ed. 2012, 51,
3074–3112.
[2] For selected reviews on allene synthesis: a) N. Krause, A. Hoffmann-
Rçder, Tetrahedron 2004, 60, 11671–11694; b) K. M. Brummond, J. E. De-
Forrest, Synthesis 2007, 795–818; c) S. Yu, S. Ma, Chem. Commun. 2011,
47, 5384–5418. For recent advances in catalytic allene synthesis, see:
d) R. K. Neff, D. E. Frantz, ACS Catal. 2014, 4, 519–528, and the referen-
ces therein.
[3] a) Transition Metal Catalyzed Enantioselective Allylic Substitution in Or-
ganic Synthesis Vol. 38 (Ed.: U. Kazmaier), Springer, Berlin Heidelberg,
2012 and the references therein. For selected reviews on copper-cata-
lyzed asymmetric allylic alkylation (AAA), see: b) A. Alexakis, C. Malan, L.
Lea, K. Tissot-Croset, D. Polet, C. Falciola, Chimia 2006, 60, 124–130;
c) S. R. Harutyunyan, T. den Hartog, K. Geurts, A. J. Minnaard, B. L. Ferin-
ga, Chem. Rev. 2008, 108, 2824–2852; d) A. Alexakis, J. E. Bꢅckvall, N.
Krause, O. Pamies, M. Dieguez, Chem. Rev. 2008, 108, 2796–2823; e) O.
Baslꢀ, A. Denicourt-Nowicki, C. Crꢀvisy, M. Mauduit in Copper-Catalyzed
Asymmetric Synthesis (Eds.: A. Alexakis, N. Krause, S. Woodward), Wiley-
VCH, Weinheim, 2014, pp. 85–126.
(S)-(3-Cyclohexylbuta-1,2-dien-1-yl)benzene (3a): A dried Schlenk
tube was charged with CuBr (1.8 mg, 5 mol%) and the chiral
ligand L27 (5.4 mg, 5.5 mol%) in toluene (2 mL). The mixture was
stirred at room temperature for 10 min. The 1,1-dichloro alkyne 1b
(47.8 mg, 0.25 mmol, 1.0 equiv) was introduced dropwise and the
reaction mixture was stirred at room temperature for a further
5 min before being cooled to ꢀ788C in an acetone/dry ice cold
bath. The methyl Grignard reagent (3.2m in Et2O, 0.09 mL,
0.30 mmol, 1.2 equiv) was added manually during 20 min. Once
the addition was complete the reaction mixture was stirred at
ꢀ788C for 2 h. The reaction was monitored by TLC to achieve full
conversion of the starting material. THF (1 mL) was introduced and
PhMgBr (2.8m in THF, 0.18 mL, 0.5 mmol, 2.0 equiv) was added
dropwise to the solution. The reaction mixture was allowed to
warm back to room temperature and the reaction progress was
monitored by TLC. Once full conversion had been achieved, the re-
action mixture was quenched by saturated aqueous NH4Cl solution
and the aqueous phase was extracted with Et2O (2ꢄ5mL). The
combined organic phases were dried over Na2SO4, concentrated
under reduced pressure, and purified by flash column chromatog-
raphy on silica gel using (eluent=pentane; Rf =0.69). Product 3a
was obtained as a colorless oil (0.0376 g, 71% yield).
Representative procedure for the one-pot copper-catalyzed
sequence to generate chiral alkynes
[4] a) A. Alexakis, A. CommerÅon, C. Coulentianos, J. F. Normant, Tetrahe-
dron 1984, 40, 715–731; b) C. J. Elsevier, P. Vermeer, J. Org. Chem. 1989,
54, 3726–3730; c) A. Alexakis, I. Marek, P. Mangeney, J. F. Normant, J.
Am. Chem. Soc. 1990, 112, 8042–8047; d) J. D. Buynak, D. Khasnis, B.
Bachmann, K. Wu, G. Lamb, J. Am. Chem. Soc. 1994, 116, 10955–10965;
e) Z. Wan, S. G. Nelson, J. Am. Chem. Soc. 2000, 122, 10470–10471;
f) R. K. Dieter, H. Yu, Org. Lett. 2001, 3, 3855–3858; g) K. M. Brummond,
A. D. Kerekes, H. Wan, J. Org. Chem. 2002, 67, 5156–5163; h) C. Zelder,
N. Krause, Eur. J. Org. Chem. 2004, 3968–3971; i) X. Tang, S. Woodward,
N. Krause, Eur. J. Org. Chem. 2009, 2836–2844; j) J. Ye, S. Li, B. Chen, W.
Fan, J. Kuang, J. Liu, Y. Liu, B. Miao, B. Wan, Y. Wang, X. Xie, Q. Yu, W.
Yuan, S. Ma, Org. Lett. 2012, 14, 1346–1349; k) A. Nakatani, K. Hirano, T.
Satoh, M. Miura, Org. Lett. 2012, 14, 2586–2589.
[5] For recent examples of copper-catalyzed asymmetric allene synthesis,
see: a) H. Ohmiya, U. Yokobori, Y. Makida, M. Sawamura, Org. Lett. 2011,
13, 6312–6315; b) M. R. Uehling, S. T. Marionni, G. Lalic, Org. Lett. 2012,
14, 362–365; c) M. Yang, N. Yokokawa, H. Ohmiya, M. Sawamura, Org.
Lett. 2012, 14, 816–819; d) U. Yokobori, H. Ohmiya, M. Sawamura, Orga-
nometallics 2012, 31, 7909–7913. For a palladium-catalyzed asymmetric
allene synthesis from racemic substrates, see: e) Y. Wang, W. Zhang, S.
Ma, J. Am. Chem. Soc. 2013, 135, 11517–11520.
A dried Schlenk tube was charged with CuBr (1.8 mg, 5 mol%) and
the chiral ligand L27 (5.4 mg, 5.5 mol%) in toluene (2 mL). The
mixture was stirred at room temperature for 10 min. The 1,1-di-
chloro alkyne 1b (47.8 mg, 0.25 mmol, 1.0 equiv) was introduced
dropwise and the reaction mixture was stirred at room tempera-
ture for a further 5 min before being cooled to ꢀ788C in an ace-
tone/dry ice cold bath. The methyl Grignard reagent (3.2m in Et2O,
0.09 mL, 0.30 mmol, 1.2 equiv) was added manually during 20 min.
Once the addition was complete the reaction mixture was stirred
at ꢀ788C for 2 h. The reaction was monitored by TLC to achieve
full conversion of the starting material. CH2Cl2 (1.5 mL) was intro-
duced and nBuMgBr (3.2m in THF, 0.16 mL, 0.5 mmol, 2.0 equiv)
was added dropwise to the solution. The reaction mixture was al-
lowed to warm back to room temperature and the reaction prog-
ress was monitored by TLC. Once full conversion had been ach-
ieved, the reaction mixture was quenched by saturated aqueous
NH4Cl solution and the aqueous phase was extracted with Et2O
(2ꢄ5mL). The combined organic phases were dried over Na2SO4,
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[6] M. Asikainen, W. Lewis, A. J. Blake, S. Woodward, Tetrahedron Lett. 2010,
51, 6454–6456.
[16] For selected examples, see : a) D. Mꢁller, A. Alexakis, Chem. Commun.
2012, 48, 12037–12049; b) L. Palais, A. Alexakis, Chem. Eur. J. 2009, 15,
10473–10485; c) D. Mꢁller, A. Alexakis, Org. Lett. 2012, 14, 1842–1845;
d) D. Mꢁller, A. Alexakis, Chem. Eur. J. 2013, 19, 15226–15239.
[17] D. Mꢁller, M. Tissot, A. Alexakis, Org. Lett. 2011, 13, 3040–3043.
[18] For the example using organolithium as nucleophile in the copper-cata-
lyzed allylic substitution, see M. Pꢀrez, M. FaÇanꢇs-Mastral, P. H. Bos, A.
Rudolph, S. R. Harutyunyan, B. L. Feringa, Nat. Chem. 2011, 3, 377–381.
[19] For recent examples of chiral allenylsilane synthesis, see ref. [5d] and:
a) D. J. Vyas, C. K. Hazra, M. Oestreich, Org. Lett. 2011, 13, 4462–4465;
b) C. K. Hazra, M. Oestreich, Org. Lett. 2012, 14, 4010–4013; and refer-
ences therein.
[20] T. J. J. Mꢁller, M. Ansorge, Chem. Ber./Recueil 1997, 130, 1135–1139.
[21] J. P. Das, I. Marek, Chem. Commun. 2011, 47, 4593–4623.
[22] a) C. E. Masse, J. S. Panek, Chem. Rev. 1995, 95, 1293–1315; b) M. J. C.
Buckle, I. Fleming, S. Gil, K. L. C. Pang, Org. Biomol. Chem. 2004, 2, 749–
769; c) L. Carroll, M. C. Pacheco, L. Garcia, V. Gouverneur, Chem.
Commun. 2006, 4113–4115.
[7] M. A. Schade, S. Yamada, P. Knochel, Chem. Eur. J. 2011, 17, 4232–4237.
[8] H. Li, D. Mꢁller, L. Guꢀnꢀe, A. Alexakis, Org. Lett. 2012, 14, 5880–5883.
[9] a) K. Tissot-Croset, D. Polet, A. Alexakis, Angew. Chem. 2004, 116, 2480–
2482; Angew. Chem. Int. Ed. 2004, 43, 2426–2428; b) H. Li, A. Alexakis,
Angew. Chem. 2012, 124, 1079–1082; Angew. Chem. Int. Ed. 2012, 51,
1055–1058.
[10] For selected examples using ferrocene-based phosphorus ligands in the
copper-catalyzed AAA, see: a) F. Dꢁbner, P. Knochel, Angew. Chem.
1999, 111, 391–393; Angew. Chem. Int. Ed. 1999, 38, 379–381; b) F.
Dꢁbner, P. Knochel, Tetrahedron Lett. 2000, 41, 9233–9237; c) H. K.
Cotton, J. Norinder, J.-E. Bꢅckvall, Tetrahedron 2006, 62, 5632–5640.
[11] For selected examples using Josiphos or Taniaphos in the copper-cata-
lyzed AAA with Grignard reagents, see: a) F. Lꢆpez, A. W. van Zijl, A. J.
Minnaard, B. L. Feringa, Chem. Commun. 2006, 409–411; b) M. Gianneri-
ni, M. FaÇanꢇs-Mastral, B. L. Feringa, J. Am. Chem. Soc. 2012, 134, 4108–
4111.
[12] For selected examples using NHC ligands in copper-catalyzed AAA, see
a) S. Tominaga, Y. Oi, T. Kato, D. K. An, S. Okamoto, Tetrahedron Lett.
2004, 45, 5585–5588; b) A. O. Larsen, W. Leu, C. N. Oberhuber, J. E.
Campbell, A. H. Hoveyda, J. Am. Chem. Soc. 2004, 126, 11130–11131;
c) J. J. Van Veldhuizen, J. E. Campbell, R. E. Giudici, A. H. Hoveyda, J. Am.
Chem. Soc. 2005, 127, 6877–6882; d) Y. Lee, K. Akiyama, D. G. Gilling-
ham, M. K. Brown, A. H. Hoveyda, J. Am. Chem. Soc. 2008, 130, 446–
447; e) T. Jennequin, J. Wencel-Delord, D. Rix, J. Daubignard, C. Crꢀvisy,
M. Mauduit, Synlett 2010, 1661–1665.
[13] For selected examples using NHC carbene ligands under copper-free
AAA conditions, see: a) Y. Lee, A. H. Hoveyda, J. Am. Chem. Soc. 2006,
128, 15604–15605; b) Y. Lee, B. Li, A. H. Hoveyda, J. Am. Chem. Soc.
2009, 131, 11625–11633; c) C. M. Latham, A. J. Blake, W. Lewis, M. Law-
rence, S. Woodward, Eur. J. Org. Chem. 2012, 699–707; d) J.-N. Levy,
C. M. Latham, L. Roisin, N. Kandziora, P. D. Fruscia, A. J. P. White, S.
Woodward, M. J. Fuchter, Org. Biomol. Chem. 2012, 10, 512–515; e) O.
Jackowski, A. Alexakis, Angew. Chem. 2010, 122, 3418–3422; Angew.
Chem. Int. Ed. 2010, 49, 3346–3350; f) D. Grassi, A. Alexakis, Org. Lett.
2012, 14, 1568–1571; g) D. Grassi, H. Li, A. Alexakis, Chem. Commun.
2012, 48, 11404–11406; h) D. Grassi, C. Dolka, O. Jackowski, A. Alexakis,
Chem. Eur. J. 2013, 19, 1466–1475.
[23] V. V. Rostovtsev, L. G. Green, V. V. Fokin, K. B. Sharpless, Angew. Chem.
2002, 114, 2708–2711; Angew. Chem. Int. Ed. 2002, 41, 2596–2599.
[24] E. J. Corey, N. W. Boaz, Tetrahedron Lett. 1984, 25, 3059–3062.
[25] a) A. M. Caporusso, C. Polizzi, L. Lardicci, Tetrahedron Lett. 1987, 28,
6073–6076; b) A. M. Caporusso, C. Polizzi, L. Lardicci, J. Org. Chem.
1987, 52, 3920–3923; c) C. Polizzi, C. Consoloni, L. Lardicci, A. M. Capor-
usso, J. Organomet. Chem. 1991, 417, 289–304; d) A. M. Caporusso, S.
Filippi, F. Barontini, P. Salvadori, Tetrahedron Lett. 2000, 41, 1227–1230;
e) A. M. Caporusso, L. A. Aronica, R. Geri, M. Gori, J. Organomet. Chem.
2002, 648, 109–118; f) A. M. Caporusso, A. Zampieri, L. A. Aronica, D.
Banti, J. Org. Chem. 2006, 71, 1902–1910.
[26] a) J. H. Brewster, J. Am. Chem. Soc. 1959, 81, 5475–5483; b) G. Lowe,
Chem. Commun. 1965, 411–413.
[27] T. B. Freedman, X. L. Cao, R. K. Dukor, L. A. Nafie, Chirality 2003, 15,
743–758.
[28] I. Marek, P. Mangeney, A. Alexakis, J. F. Normant, Tetrahedron Lett. 1986,
27, 5499–5502.
[29] A. Alexakis, D. Polet, S. Rosset, S. March, J. Org. Chem. 2004, 69, 5660–
5667.
[30] H. Clavier, L. Coutable, L. Toupet, J.-C. Guillemin, M. Mauduit, J. Organo-
met. Chem. 2005, 690, 5237–5254.
[14] a) L. Palais, I. S. Mikhel, C. Bournaud, L. Micouin, C. A. Falciola, M. Vuag-
noux-d’Augustin, S. Rosset, G. Bernardinelli, A. Alexakis, Angew. Chem.
2007, 119, 7606–7609; Angew. Chem. Int. Ed. 2007, 46, 7462–7465;
b) D. Mꢁller, L. Guꢀnꢀe, A. Alexakis, Eur. J. Org. Chem. 2013, 6335–6343.
[15] a) C. Bournaud, C. Falciola, T. Lecourt, S. Rosset, A. Alexakis, L. Micouin,
Org. Lett. 2006, 8, 3581–3584; b) R. Millet, L. Gremaud, T. Bernardez, L.
Palais, A. Alexakis, Synthesis 2009, 2101–2112; c) L. Palais, C. Bournaud,
L. Micouin, A. Alexakis, Chem. Eur. J. 2010, 16, 2567–2573.
[31] D. Martin, S. Kehrli, M. d’Augustin, H. Clavier, M. Mauduit, A. Alexakis, J.
Am. Chem. Soc. 2006, 128, 8416–8417.
Received: July 31, 2014
Published online on && &&, 0000
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FULL PAPER
&
Asymmetric Catalysis
H. Li, D. Grassi, L. Guꢀnꢀe, T. Bꢁrgi,
A. Alexakis*
&& – &&
Copper-Catalyzed Propargylic
Substitution of Dichloro Substrates:
Enantioselective Synthesis of
Trisubstituted Allenes and Formation
of Propargylic Quaternary Stereogenic
Centers
A range of chiral allenes and terminal
alkynes are synthesized highly enantio-
selectively. Starting from prochiral di-
chloro substrate bearing substituent R1,
different alkyl groups R2 are introduced
providing chiral chloroallenes. Further
substitution reaction installs R3 groups
highly stereospecifically and demon-
strates diverse substitution patterns.
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