Copper-catalyzed enantioselective synthesis of axially chiral allenes

Article abstract of DOI:10.1021/ol302790e

A simple copper-catalyzed enantioselective synthesis of axially chiral chloroallenes from the propargylic dichlorides is reported, employing a catalytic amount of easily prepared SimplePhos ligand. Exclusive formation of the desired allenes was observed with good enantioselectivities (ee's 62-96%). Further transformations to trisubstituted allenes or terminal alkynes with a propargylic quaternary carbon center keep a high level of enantiopurity.

Full text of DOI:10.1021/ol302790e

ORGANIC
LETTERS
2012
Vol. 14, No. 23
5880–5883
Copper-Catalyzed Enantioselective
Synthesis of Axially Chiral Allenes
†
Hailing Li, Daniel Muller, Laure Guenee, and Alexandre Alexakis*
†
‡
,†
€
ꢀ ꢀ
Department of Organic Chemistry, University of Geneva 30, and Laboratory of
Crystallography, University of Geneva 24, quai Ernest Ansermet CH-1211 Geneva 4,
Switzerland
alexandre.alexakis@unige.ch
Received October 11, 2012
ABSTRACT
A simple copper-catalyzed enantioselective synthesis of axially chiral chloroallenes from the propargylic dichlorides is reported, employing a
catalytic amount of easily prepared SimplePhos ligand. Exclusive formation of the desired allenes was observed with good enantioselectivities
(ee’s 62À96%). Further transformations to trisubstituted allenes or terminal alkynes with a propargylic quaternary carbon center keep a high level
of enantiopurity.
Allene compoundshavedrawn more and more attention
as a frequent building block and a versatile intermediate
for organic synthesis.1 Among the existing methodologies
for their preparation, the copper-mediated 1,3-substitu-
tion of carbon nucleophiles on propargylic electrophiles is
one of the most direct and efficient ways.2 Toward this
approach, asymmetric synthesis of chiral allenes has emerged
more than 20 years ago, starting from propargylic alcohol
derivatives, in most of the cases.3 Although stoichiometric
organocopper reagents were mainly used, catalytic versions
appeared recently.4À7 However, all these processes require
enantioenriched starting propargylic substrates; upon full
chirality transfer, the corresponding chiral allenes can be
formed with high enantiomeric excesses (Scheme 1, eq 1).
† Department of Organic Chemistry.
‡ Laboratory of Crystallography.
(1) Reviews and highlights on allenes: (a) Modern Allene Chemistry;
Krause, N., Hashmi, A. S. K., Eds.; Wiley-VCH: Weinheim, 2005. (b)
€
Hoffmann-Roder, A.; Krause, N. Angew. Chem., Int. Ed. 2004, 43, 1196–
1216. (c) Ma, S. Acc. Chem. Res. 2003, 36, 701–712. (d) Ma, S. Chem.
Rev. 2005, 105, 2829–2871. (e) Ma, S.; Negishi, E.-i. J. Am. Chem. Soc.
1995, 117, 6345–6357. (f) Hashmi, A. S. K. Angew. Chem., Int. Ed. 2000,
39, 3590–3593. (g) Yu, S.; Ma, S. Angew. Chem., Int. Ed. 2012, 51, 3074–
3112.
(4) Ohmiya, H.; Yokobori, U.; Makida, Y.; Sawamura, M. Org. Lett.
2011, 13, 6312–6315.
(5) Uehling, M. R.; Marionni, S. T.; Lalic, G. Org. Lett. 2011, 14,
362–365.
(6) Yang, M.; Yokokawa, N.; Ohmiya, H.; Sawamura, M. Org. Lett.
2012, 14, 816–819.
(7) Yokobori, U.; Ohmiya, H.; Sawamura, M. Organometallics
(2) Selected reviews on copper-mediated allene synthesis: (a) Krause,
€
Brummond, K. M.; DeForrest, J. E. Synthesis 2007, 2007, 795–818. (c)
Yu, S.; Ma, S. Chem. Commun. 2011, 47, 5384–5418.
N.; Hoffmann-Roder, A. Tetrahedron 2004, 60, 11671–11694. (b)
2012 DOI: 10.1021/om300552f.
(8) For selected reviews on copper-catalyzed AAA, see: (a) Alexakis,
A.; Malan, C.; Lea, L.; Tissot- Croset, K.; Polet, D.; Falciola, C. Chimia
2006, 60, 124–130. (b) Harutyunyan, S. R.; den Hartog, T.; Geurts, K.;
Minnaard, A. J.; Feringa, B. L. Chem. Rev. 2008, 108, 2824–2852. (c)
Alexakis, A.; Backvall, J. E.; Krause, N.; Pamies, O.; Dieguez, M. Chem.
Rev. 2008, 108, 2796–2823.
(3) (a) Alexakis, A.; Commerc-on, A.; Coulentianos, C.; Normant,
J. F. Tetrahedron 1984, 40, 715–731. (b) Elsevier, C. J.; Vermeer, P.
J. Org. Chem. 1989, 54, 3726–3730. (c) Alexakis, A.;Marek, I.;Mangeney,
P.; Normant, J. F. J. Am. Chem. Soc. 1990, 112, 8042–8047. (d) Buynak,
J. D.; Khasnis, D.; Bachmann, B.; Wu, K.; Lamb, G. J. Am. Chem. Soc.
1994, 116, 10955–10965. (e) Wan, Z.; Nelson, S. G. J. Am. Chem. Soc. 2000,
122, 10470–10471. (f) Dieter, R. K.; Yu, H. Org. Lett. 2001, 3, 3855–3858.
(g) Brummond, K. M.; Kerekes, A. D.; Wan, H. J. Org. Chem. 2002, 67,
5156–5163. (h) Zelder, C.; Krause, N. Eur. J. Org. Chem. 2004, 3968–3971.
(i) Tang, X.; Woodward, S.; Krause, N. Eur. J. Org. Chem. 2009, 2836–
2844. (j) Ye, J.; Li, S.; Chen, B.; Fan, W.; Kuang, J.; Liu, J.; Liu, Y.; Miao,
B.; Wan, B.; Wang, Y.; Xie, X.; Yu, Q.; Yuan, W.; Ma, S. Org. Lett. 2012,
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€
(9) For selected examples of prochiral allylic chloride substrates, see:
(a) Alexakis, A.; Malan, C.; Lea, L.; Benhaim, C.; Fournioux, X. Synlett
2001, 927–930. (b) Tissot-Croset, K.; Polet, D.; Alexakis, A. Angew.
Chem., Int. Ed. 2004, 43, 2426–2428. (c) Falciola, C. A.; Tissot-Croset,
K.; Reyneri, H.; Alexakis., A. Adv. Synth. Catal 2008, 350, 1090–1100.
(d) Li, H.; Alexakis, A. Angew. Chem., Int. Ed. 2012, 51, 1055–1058. (e)
~
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r
10.1021/ol302790e
Published on Web 11/12/2012
2012 American Chemical Society

Referring to the copper-catalyzed asymmetric allylic alky-
lation (AAA) for the prochiral allylic compounds,8,9
a
Table 1. Optimization of the Methodologya
similar process on prochiral propargylic compounds is
highly desirable, which could provide the chiral allenes
from nonchiral substrates in one single substitution step,
employing catalytic amount of copper salt and chiral
ligand.
Scheme 1. Prochiral Substrate for Allene Synthesis
Inspired by the recent work of Knochel et al.,10 the
prochiral 1,1-dichloro propargylic molecules drew our
attention by their facile preparation from the correspond-
ing propargylic aldehyde and are considered promising
substrates for the following catalytic process (Scheme 1,
eq 2). The desired product bearing a chlorine atom will
attract more interest for further functionalization compared
to allenes bearing only alkyl or aryl groups. Finally, it should
be mentioned that Woodward has recently attempted a
similar approach with diacetates instead of dichlorides;
however, no enantioselective version was reported.11
Herein, we report the first examples of copper-catalyzed
highly enantioselective 1,3-substitution on the aforemen-
tioned prochiral propargylic substrates, leading to the
exclusive formation of desired chloroallenes with high
enantiomeric excesses. By the selection of several easily
prepared chiral ligands, we managed to reach high level of
ee and obtained the desired products without other regio-
isomers. In addition, the family of alkyl Grignard reagent
was employed as nucleophile, which is advantageous over
other alkyl organometallic reagents such as organozinc
or organoaluminum due to its easy preparation and large
availability.
We started our investigation on 1,1-dichloro-3-cyclohexyl-
2-propyne as substrate (its synthesis is described in
the Supporting Information), under the reported optimized
conditions for copper-catalyzed asymmetric allylic alkylation
reactions,9b using copper(I) thiophenecarboxylate (CuTC)
as copper source, phosphoramidite L1 as chiral ligand, and
ethylmagnesium bromide as nucleophile in CH2Cl2 (Table 1,
entry 1). The reaction showed excellent regioselectivity,
affording exclusively the desired allene without formation
of 1,1-substitution regioisomer. However, the ee was not
ideal. AnotherdiastereoisomerL2 was equally tested under
the same conditions (entry 2) to exclude the possible
“matchÀmismatch effect” in the catalytic process.
catalyst
entrya
ligand L*
Cu salt
solvent
loading (%)
eeb (%)
1
2
L1
L2
L3
L3
L4
L4
L5
L5
L5
L5
L5
CuTC
CuTC
CuTC
CuTC
CuTC
CuTC
CuTC
CuTC
CuI
CH2Cl2
CH2Cl2
CH2Cl2
toluene
CH2Cl2
toluene
CH2Cl2
toluene
toluene
toluene
toluene
10
10
10
10
10
10
10
10
10
10
5
39
40
50
4
3
4
5
58
82
58
89
91
92
92
6
7
8
9
10
11
CuBr
CuBr
a Reaction conditions: the substrate (0.25 mmol) was added to a
solution of copper salt and chiral ligand in dry solvent at À78 °C. The
ethereal solution of Grignard reagent (1.2 equiv) was added dropwise
during 20 min, and the reaction mixture was stirred at À78 °C for 2 h.
The desired product was confirmed by 1H NMR. b Determined by GC
analysis using a chiral stationary phase. Cy = cyclohexyl.
Without having much success in terms of enantiomeric
excess on the trials with phosphoramidite ligands, we
switched to another family of chiral phosphorus ligand:
SimplePhos.12 The ligand screening startedwiththe readily
prepared L3, which showed good performances in some
asymmetric conjugated addition reactions.13 A promis-
ing value of 50% ee was achieved (entry 3). Switching
the solvent to toluene while keeping the same ligand led
to a dramatic drop of enantioselectivity (entry 4). In order
to emphasize the chiral information carried by the amine
moiety of the ligand, we envisaged that smaller sub-
stituents on phosphorus atom should enable more facile
binding of the complex to substrate and then increase the
enantioselective discrimination. For thisreason, the diethyl
(12) (a) Palais, L.; Mikhel, I. S.; Bournaud, C.; Micouin, L.; Falciola,
C. A.; Vuagnoux-d’Augustin, M.; Rosset, S.; Bernardinelli, G.; Alexakis,
A. Angew. Chem. Int. Ed 2007, 46, 7462–7465. (b) Palais, L.; Alexakis, A.
€
(10) Schade, M. A.; Yamada, S.; Knochel, P. Chem.;Eur. J. 2011,
17, 4232–4237.
Chem.;Eur. J. 2009, 15, 10473–10485. (c) Muller, D.; Alexakis, A. Org.
Lett. 2012, 14, 1842–1845.
€
(11) Asikainen, M.; Lewis, W.; Blake, A. J.; Woodward, S. Tetrahedron
Lett. 2010, 51, 6454–6456.
(13) Muller, D.; Tissot, M.; Alexakis, A. Org. Lett. 2011, 13,
3040–3043.
Org. Lett., Vol. 14, No. 23, 2012
5881

analogue L4 was also prepared and studied under the
similar conditions using two different solvents respectively
(entries 5 and 6). Surprisingly, at this time the choice of
toluene as solvent seemed to be essential and provided a
great improvement of ee. Finally, replacing the substituent
on P-atom of ligand by two tinier methyl groups (L5),
keeping toluene as solvent (entry 8), brought us a nice
breakthrough on selectivity: a very good ee of 89% was
obtained retaining the perfect regioselectivity. An optimi-
zation of the copper source showed that CuBr can still gain
3% of ee (entry 10). Because of its low price and large
availability, CuBr was chosen for the further investigation.
Lowering the catalyst loading from 10 to 5 mol % had no
influence on the outcome (entry 11). In addition, many
other classes of chiral ligands were equally investigated,
but no further improvement could be achieved (see the
Supporting Information).
Table 2. Scope of Grignard Reagentsa
entrya
R
product yield (%) ee[b] (%)
1
2
3
4
5
6
7
8
9
Et
2a
2b
2c
2d
2e
2f
84
92
84
84
92
88
84
82
nd
92
94
90
93
94
96
96
91
0
n-Bu
PhCH2CH2
i-Bu
CH2dC(CH3)CH2CH2
i-Pr
cyclopentyl
Me
2g
2h
t-Bu
With these optimized conditions in hand, a range of
alkyl Grignard reagents were introduced to form the
corresponding axially chiral allenes. The employment of
simple primary alkylmagnesium bromide afforded, in all
the studied cases, chiral chloroallenes with very good
enantioselectivities (Table 2, entries 1À3). A bulkier pri-
mary alkyl group, such as isobutyl, could also promote the
nucleophilic attack and keep high level of ee (entry 4). A
more vulnerable alkyl group bearing a remote double bond
had no interference to the selectivity and the yield (entry 5).
Interestingly, the introduction of a sterically demanding sec-
ondary alkyl group behaved even better, providing excel-
lent enantioselectivity (entry 6). Similar results were ob-
served in the case of the cyclopentyl group (entry 7). We
theorized that the secondary alkyl groups might have the
most suitable size when approaching the metalÀligand com-
plex. Finally, we intended to study the challenging methyl
nucleophile, which cannot be easily introduced to allylic
substrates under copper-catalyzed AAA conditions with
good selectivity. Fortunately, to our delight, in this case,
the methyl group attacked the substrate successfully and
formed the corresponding chloroallene as the only regio-
isomer with very nice enantioselectivity (entry 8). Consider-
ing the steric requirements of an sp carbon, as compared to
an sp2 carbon on allylic substrates, it is remarkable to
attain such high level of enantiocontrol on propargylic
substrate. As shown in the last entry, the use of t-BuMgBr
only led to racemic product (entry 9), which is also con-
ventional in copper-catalyzed asymmetric allylic alkylation.8
The generality of this methodology was exploited by
employing different 1,1-dichloro propargylic substrates
(Table 3). These substrates can be easily prepared from
the corresponding alkynes in only two single steps,10 which
facilitated our study on the scope of substrates (see the
Supporting Information). The acyclic aliphatic carbon
chain at the R position keeps the same reactivity with very
good enantioselectivity (entry 1). Introducing a terminal
chlorine atom on the carbon chain did not interfere
with the enantioselectivity (entry 2), while the obtained
allene, bearing two halogens, would be potentially useful
for synthetic purposes. Replacing the R group with a
bulkier alkyl group such as tert-butyl maintained the good
a Reaction conditions: the substrate (0.25 mmol) was added to a
solution of CuBr and chiral ligand in dry toluene at À78 °C. The ethereal
solution of Grignard reagent (1.2 equiv) was added dropwise during
20 min and the reaction mixture was stirred under À78 °C for 2 h. Full
conversion and the desired products were confirmed by 1H NMR.
[b] Determined by GC analysis using a chiral stationary phase.
selectivity (entry 3). With a more versatile R group such
as trimethylsilyl, the reaction still yielded a practical ee of
85% (entry 4). The resulting chiral allenylsilane moiety can
be widely used in organic transformations.14 Utilizing a
phenyl group on the substrate showed some limitations
for this methodology. The regioselectivity was never an issue;
however, the enantioselectivity decreased to 64% ee. Finally,
a protected alcohol functionality on the R group successfully
provided a valuable 2-allenic alcohol moiety albeit with a
moderate optical purity. The scaled-up reaction (2.0 mmol
substrate 1a) was carried out employing methyl Grignard
reagent leading to no change of enantioselectivity (90% ee)
and a good yield of 95% (see Supporting Information).
Table 3. Scope of 1,1-Dichloropropargylic Substratesa
entrya
R
subst product yield (%) eec (%)
1
n-pent
1b
1c
1d
1e
1f
2i
82
77
71
72
82
85
92
89
84
85
64
62
2
ClCH2CH2CH2CH2
2j
3
tBu
2k
2l
4b
5b
6
TMS
Ph
2m
2n
CH2O-t-Bu
1g
a Reaction conditions: the substrate (0.25 mmol) was added to a
solution of CuBr and chiral ligand in dry toluene at À78 °C. The ethereal
solution of Grignard reagent (1.2 equiv) was added dropwise during
20 min, and the reaction mixture was stirred under À78 °C for 2 h. The
desired products were confirmed by 1H NMR. b 1.05 equiv of Grignard
reagent was used in order to avoid the double alkylation as a side
reaction. c Determined by GC analysis using a chiral stationary phase.
5882
Org. Lett., Vol. 14, No. 23, 2012

To demonstrate the synthetic potential of the above
enantioenriched chloroallenes, we performed some further
transformations (Table 4). A simple and quickly accessible
application followed a typical procedure reported by
Knochel and co-workers on racemic chloroallene.10 To
our delight, during this process, no loss of enantiomeric
excesses was observed, and the chirality was fully transferred
to the products (entries 1À3) whether the aryl group was
introduced with electron-donating (ÀCH3, entry 2) or
electron-withdrawing (ÀF, entry 3) groups at the para
position.
Table 4. Copper-Catalyzed Transformations of Chloroallenea
entrya subst
R
solvent product yield (%) eeb (%)
An attempt to introduce the alkyl group under the same
conditions failed to afford the desired alkylated allene
compounds as successfully as in previous arylation cases.
Instead, the dechlorinated nonchiral allene was observed
as a major product when the reaction was preformed using
n-butyl Grignard reagent as the nucleophile. However,
when we simply changed the solvent from THF to dichloro-
methane, under similar conditions, the reaction led to al-
most exclusive formation of 1,3-substitution product on
the chloroallene, namely the terminal alkyne bearing a
stereogenic quaternary carbon center (entries 4À6). What
is exciting in this derivatization is that the reactions always
proceeded with full chirality transfer. In addition, com-
pared to the well-established method which suffered from
synthesizing the starting materials of high enantiomeric
purity, our methodology provides a more direct way for
the formation of all-carbon propargylic stereogenic center
through enantioselective propargylic substitution.15 This
nice approach to obtain the chiral terminal alkyne com-
pounds further increases the value of the chiral chloroal-
lene synthesis reported herein. From a synthetic point of
view, two more trials were focused on the silyl compound
2l; under the two different conditions, respectively, the
corresponding trisubstituted allenylsilane and propargyl-
silane were obtained in optically enriched form, which
represents the highly useful reagents in organic synthesis
(entries 7 and 8).16
1
2
3
4
5
6
7
8
2h
2h
2h
2h
2h
2h
2l
Ph
THF
3a
3b
3c
4a
4b
4c
5
85
85
84
89
97
79
75
87
90
90
90
90
90
90
83
83
p-tolyl THF
4-F-Ph THF
n-Bu
i-Bu
i-Pr
Ph
CH2Cl2
CH2Cl2
CH2Cl2
THF
2l
i-Bu
CH2Cl2
6
a Reaction conditions: the substrate (0.20 mmol) was added to a
mixture of CuCN and dry solvent at À20 °C (or 0 °C). The ethereal
solution of Grignard reagent (2 equiv in order to ensure the full conversion)
was added dropwise, the reaction mixture was warmed back to room
temperature and stirred during 2 h. The desired products were confirmed by
1H NMR. b Determined by GC analysis using a chiral stationary phase.
In conclusion, we have discovered a highly enantioselec-
tive synthesis of axially chiral chloroallenes, using a catalytic
amount of easily prepared SimplePhos ligand, as chiral
source, and readily available Grignard reagents as nucleo-
phile. These versatile compounds can be easily further trans-
formed to trisubstituted allenes or terminal alkynes with a
propargylic quaternary carbon center, keeping a high level
of enantiopurity. We believe this methodology makes a
useful contribution to asymmetric organic synthesis.
Acknowledgment. This work is supported by the Swiss
National Research Foundation (Grant No. 200020-126663)
and COST action D40 (SER Contract No. C07.0097). We
warmly thank Dr. Matthieu Tissot (University of Geneva)
for preparation of useful chemicals, Solvias for generous gift
of chiral ligands, BASF for the generous gift of chiral
amines, and Prof. P. Knochel (L. Maximilian University,
Munich, Germany) for fruitful discussions.
In order to have more insight to these products, alkyne
4a was subjected to “click” reaction conditions with
p-bromophenyl azide. X-ray diffraction on the resulting
crystalline product allowed the determination of the abso-
lute configuration (see the Supporting Information).
(14) For recent examples of chiral allenylsilanes, see: (a) Yokobori,
U.; Ohmiya, H.; Sawamura, M. Organometallics 2012 DOI: 10.1021/
om300552f. (b) Vyas, D. J.; Hazra, C. K.; Oestreich, M. Org. Lett. 2011, 13,
4462–4465. (c) Hazra, C. K.; Oestreich, M. Org. Lett. 2012, 14, 4010–4013
and references cited therein.
(15) Das, J. P.; Marek, I. Chem. Commun. 2011, 47, 4593–4623.
(16) (a) Masse, C. E.; Panek, J. S. Chem. Rev. 1995, 95, 1293–1316.
(b) Buckle, M. J. C.; Fleming, I.; Gil, S.; Pang, K. L. C. Org. Biomol.
Chem. 2004, 2, 749–769. (c) Carroll, L.; Pacheco, M. C.; Garcia, L.;
Gouverneur, V. Chem. Commun. 2006, 4113–4115.
Supporting Information Available. Experimental pro-
cedures, NMR spectra, and chiral separations for all
compounds. This material is available free of charge via
the Internet at http://pubs.acs.org.
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 23, 2012
5883