SimplePhos monodentate ligands: Synthesis and application in copper-catalyzed reactions

Article abstract of DOI:10.1002/anie.200702186

(Chemical Equation Presented) A simple choice: Ligands termed Simple-Phos (L*), based on a chiral amino and flexible aryl groups on the phosphorus atom, induce high enantioselectivity in the copper-catalyzed conjugate addition and allylic substitution of dialkyl zinc and trialkyl aluminum reagents (see scheme; CuTC = copper thiophene carboxylate).

Full text of DOI:10.1002/anie.200702186

Communications
DOI: 10.1002/anie.200702186
Asymmetric Catalysis
SimplePhos Monodentate Ligands: Synthesis and Application in
Copper-Catalyzed Reactions**
Latitia Palais, Igor S. Mikhel, ChloØe Bournaud, Laurent Micouin, Caroline A. Falciola,
Magali Vuagnoux-dꢀAugustin, StØphane Rosset, GØrald Bernardinelli, and Alexandre Alexakis*
The design of chiral ligands is the key to attaining high
asymmetric induction in transition-metal-catalyzed reactions.
Subtle changes in the conformational, steric, and/or electronic
properties of the chiral ligand can often lead to dramatic
variation of the reactivity and enantioselectivity. As a result of
strong substrate dependence in most cases, tunable and
readily synthesized ligands are desirable to obtain high
enantioselectivities.
the Cu-catalyzed enantioselective conjugate 1,4-addition of
dialkyl zinc to a variety of Michael acceptors. In the course of
our studies to find new types of efficient chiral ligands, we
report herein the modification of the biphenol moiety of
phosphoramidite ligands.
Keeping in mind that the induced helicity, promoted by
the amine part, is the most important point, we sought to
replace the biphenol unit by other aromatic groups that might
adopt a helical conformation. Thus, we modified the biphenol
core by ring expansion (L2), by opening the biphenol unit
(L3), or by creating a phosphinamine-type ligand with two
phenyl groups on the phosphorus atom (L4; Scheme 2). These
Nowadays, asymmetric copper-catalyzed conjugate addi-
tion and allylic substitution are well-developed methodolo-
À
gies for creating C C bonds. Many efforts have been made in
designing efficient systems and identifying new ligands to
improve enantioselectivities.[1]
Among the most efficient ligands, those based on the
atropoisomerism[2] of a binaphthol[3] or a biphenol[4] moiety
play a prominent role. We have demonstrated that phosphor-
amidite ligands based on the atropoisomerically flexible
biphenol unit are also excellent ligands (Scheme 1). Thus,
the atropoisomerism of the biphenol part of the ligand
induced by the amine moiety allows high enantioselectivity in
Scheme 2. Newly synthesized ligands.
new ligands were tested for the addition of Et2Zn to 2-
cyclohexenone (1) catalyzed by copper thiophene carboxylate
(CuTC) to compare their efficiency (Table 1).
Table 1: Addition of Et2Zn to 2-cyclohexenone (1) catalyzed by CuTC in
the presence of various ligands L*.
Scheme 1. Conformational atropoisomerism of L1.
[*] L. Palais, I. S. Mikhel, C. Bournaud, C. A. Falciola,
M. Vuagnoux-d’Augustin, S. Rosset, Dr. G. Bernardinelli,
Prof. Dr. A. Alexakis
Entry
Ligand
Conversion [%][a]
ee [%][b]
DØpartement de Chimie Organique
UniversitØ de Gen›ve
30 quai Ernest Ansermet, 1211 Geneve 4 (Switzerland)
Fax: (+41)223-793-215
1
2
3
4
L1
L2
L3
L4
>99
>99
>95
>99
96
35
22
71
E-mail: alexandre.alexakis@chiorg.unige.ch
Dr. L. Micouin
UniversitØ RenØ Descartes
[a] Determined by GC-MS. [b] Determined by chiral GC.
Laboratoire de Chimie Pharmaceutique
4 Avenue de l’Observatoire, 75270 Paris Cedex 06 (France)
[**] The authors thank the Swiss National Research Foundation (grant
no. 200020-113332) for financial support, and BASF for a generous
gift of chiral amines.
The ring expansion in L2 or the opening of the biphenol
unit in L3 resulted in lower enantioselectivities, probably
because the degree of flexibility allowed by these systems is
too high. However, ligand L4 afforded a significantly better
Supportinginformation for this article is available on the WWW
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Table 2: Synthesis of SimplePhos–borane ligands by the two pathways.
enantioselectivity of up to 71% ee
(Table 1, entry 4). This interesting
result introduced a novel class of
chiral phosphorus ligands. Contrary
to biphenol-based ligands, the chir-
ality was induced by the helicity of
the two aryl groups, which were also
chirally flexible as tropos ligands
(Scheme 3).
To our surprise, ligand L4 has
not been previously described. For
convenience, we called the class for
which L4 is the first example Sim-
plePhos. The potential modularity
of this phosphinamine ligand is
worth mentioning, and lies in the
flexible variation of the amine
moiety and separately the aryl
groups on the phosphorus atom.
Entry
Ligand
Ar1
Ar2
R
Yield [%][c]
1
2
3
4
5
6
7
8
9
L4[a]
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Me
Me
Et
Me
Me
Me
Me
Me
Me
68
82
84
58
41
78
94
67
25
L4-BH3
L5-BH3
L6-BH3
L7-BH3
L8[b]
o-OMe(C6H4)
2-naphthyl
1-naphthyl
Ph
Ph
Ph
L9[b]
p-tolyl
xylyl
m-CF3(C6H4)
L10[b]
L11-BH3
[a] Synthesized without addition of borane complex. [b] Free ligand was obtained exclusively; protection
with borane did not work. [c] Yield of isolated product.
stable towards oxidation in the solid state but slightly air-
sensitive in solution. Although traces of oxide do not impede
catalysis, we decided to protect our ligands with borane[5] to
form phosphine–borane complexes, which are air-stable and
readily purified by chromatography on alumina. Note, how-
ever, that hindered ligands, such as L8, L9, and L10, are
perfectly stable and do not easily form the borane complexes.
For the other strategy (pathway 2), the same methodology
as for the synthesis of phosphoramidite ligands was used.
After formation of the aminophosphine dichloride, prepared
in situ from bis[(S)-1-phenylethyl]amine and a solution of
PCl3/Et3N, three equivalents of aryl Grignard reagent (pre-
pared in THF) were added to form the free ligand after one
night under reflux. Ligands L9 and L10 (Table 2, entries 7 and
8) were not protected, because they crystallized spontane-
ously in pentane without oxidation. Ligand L11 (Table 2,
entry 9) could not be protected in situ and needed prior
filtration on neutral alumina under an inert atmosphere.
Attempts to obtain suitable crystals for X-ray analysis of
L4 in various solvents (pentane, hexane, cyclohexane) were
unsuccessful. However, crystallization of L4-BH3 in hexane
provided suitable white needles and the molecular structure is
shown in Figure 1.
Scheme 3. Interconversion of helicity in L4.
The SimplePhos ligands can bear similar or different R1
groups. The substituents on these aromatic rings can exert a
steric influence when placed in the ortho or meta position.
Although it is known that phosphine–borane complexes
may be directly used in catalysis,[5] the results obtained with
L4-BH3 were clearly inferior to those with unprotected L4.
Thus, these ligands need prior deprotection for copper-
catalyzed reactions. The deprotection reaction, performed
with ten equivalents of morpholine in Et2O at room temper-
ature, afforded the free ligands with very high yields
(Table 3).
All the newly synthesized ligands were screened in
conjugate addition[1] (CuTC, 5 mol%; L*, 10 mol%) and in
allylic substitution.[6] Preliminary tests of the addition of
Et2Zn to 2-cyclohexenone (1) are summarized in Table 4.
Among the variations on the amine part, ligand L7 (2-
naphthyl substituent) afforded the best result, with complete
conversion and a very high ee value of up to 95% (Table 4,
They can also exert an electronic effect (for example, CF3 or
OMe) or a coordination effect (for example, o-OMe). On the
amine part, C2 symmetry is not a requirement. Again, steric as
well as electronic or coordination effects can be brought
about by variation of R2 and R3. Thus, the modularity of the
SimplePhos family is remarkable.
SimplePhos ligands were prepared via two pathways, by
starting from a chiral C2-symmetric amine (Table 2). For the
first synthesis, ligands L4 to L8 (Table 2, entries 2–6) were
obtained by deprotonation of the chiral amine by BuLi
followed by the addition of Ph2PCl (pathway 1). Ligand L4 is
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Table 5: Addition of AlEt3 to 3-methylcyclohex-2-enone catalyzed by
CuTC in the presence of various SimplePhos ligands.
Entry
Ligand
Conversion [%][a]
ee [%]
1
2
3
4
5
6
7
8
L4
L5
L6
L7
L8
L9
L10
L11
85
90
93
86
93
70
90
86
80
>99 (71)
98 (73)
>99
Figure 1. ORTEP plot of the structure of ligand L4-BH3.
99
>99 (60)
>99 (81)
82
Table 3: Deprotection of borane ligands by morpholine.
[a] Yield of isolated product in parentheses.
methyl-2-cyclohexenone (3), gave at best 96% ee with a
Entry
Ligand
Ar1
Ar2
R
Yield [%][a]
biphenol-based
phosphoramidite
ligand
L12
(see
Scheme 4).[7] Conversely, two SimplePhos ligands, L5 and,
again, L7, had close ee values of 93% (Table 5, entries 2 and
4).
1
2
3
4
L5
L6
L7
L11
Ph
Ph
Ph
Ph
Et
98
93
97
83
o-OMe(C6H4)
2-naphthyl
Ph
Me
Me
Me
m-CF3(C6H4)
An even more demanding substrate was tested: 3-phenyl-
2-cyclohexenone (5; Scheme 4). The addition of Me3Al gave
72% ee with the phosphoramidite ligand L12. Both the
[a] Yield of isolated product.
Table 4: Addition of Et2Zn to 2-cyclohexenone (1) catalyzed by CuTC in
the presence of SimplePhos ligands.
Entry
Ligand
Conversion [%]
ee [%]
1
2
3
4
5
6
7
8
L4
L5
L6
L7
L8
L9
L11
L11
97
>99
>99
>99
>99
>99
>99
>99
80
81
63
95
70
67
73
90
Scheme 4. Addition of AlMe3 to 3-phenyl-2-cyclohexenone (5).
entry 4). As we observed previously for biphenol-based
phosphoramidite ligands, an increase of the steric bulk on
the amine favors enantioselectivity. Furthermore, replace-
ment of the two phenyl groups by bulkier electron-rich p-tolyl
or xylyl groups (Table 4, entries 6 and 7) is less favorable than
replacement by an electron-withdrawing group (m-CF3-
(C6H4); Table 4, entry 8). This surprising electronic effect
could not be observed with phosphoramidite ligands. Cyclo-
heptenone gave similar results, the best ligand being L7
(92% ee). Although these SimplePhos ligands do not induce
the highest recorded ee values, they lie among the best 10%
for this conjugate addition.
conversion and the enantioselectivity were better with the
SimplePhos ligand L10. The addition of a methyl group has
never been described with this substrate, and our SimplePhos
ligand seemed to be very efficient for this catalytic system.
In the allylic substitution, tests were carried out on our
latest substrate, 1,4-dibromobutene (7; Scheme 5).[8] Again,
SimplePhos ligands compare favorably with the best phos-
phoramidite ligand (91% ee[8]).
A last example shows the efficiency of SimplePhos ligands
in allylic substitution (Table 6). We have previously reported,
in collaboration with Micouin,[9] the reaction of trialkyl
aluminum reagents on bicyclic hydrazines. In this reaction,
we demonstrated that phosphoramidite ligands were cleaved
by these reagents in noncoordinating solvents, such as toluene
or dichloromethane. The use of SimplePhos ligands could
avoid this problem. Indeed, not only were SimplePhos ligands
Another, more demanding copper-catalyzed conjugate
addition was tested: the addition of AlEt3 to trisubstituted
cyclohexenones to induce the formation of stereogenic
quaternary carbon centers (Table 5). The test substrate, 3-
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Experimental Section
Synthesis of ligand L4-BH3: BuLi (1.25m solution in hexane, 1 equiv)
was added dropwise to a stirred solution of bis[(S)-1-phenylethyl]-
amine (1 equiv) in THF at À708C under an inert atmosphere. The
reaction mixture was stirred at À708C for 10 min, then allowed to
warm to room temperature. After stirring for 2 h, the mixture was
cooled to À708C and a solution of Ph2PCl (1 equiv) in THF was
slowly added dropwise. The reaction mixture was allowed to warm to
room temperature and stirred overnight. Then, a solution of borane–
dimethylsulfide complex (2 equiv) was added at room temperature
and the reaction mixture was stirred overnight. After evaporation of
the solvent under vacuum, the desired ligand was purified by flash
chromatography on neutral alumina with toluene as solvent.
Scheme 5. Enantioselective CuTC-catalyzed allylic alkylation of 1,4-
dibromo-2-butene (7) with a Grignard reagent.
Table 6: Desymmetrization of polycyclic hydrazines with AlMe3 in the
presence of phosphoramidite-based ligands or Simplephos ligands.
Received: May 17, 2007
Published online: August 14, 2007
Keywords: asymmetric catalysis · conjugate addition · copper ·
.
enones · P ligands
[1] For reviews, see: a) A. Alexakis, C. Benhaim, Eur. J. Org. Chem.
2002, 3221 – 3223; b) N. Krause, A. Hoffmann-Röder, Synthesis
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353; d) M. P. Sibi, S. Manyem, Tetrahedron 2000, 56, 8033 – 8061.
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de Vries, J. Am. Chem. Soc. 2000, 122, 11539 – 11540.
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Benhaim, Synlett 2001, 1375 – 1378; b) A. Alexakis, D. Polet, S.
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Merd›s, D. Moulin, N. Riegel, S. Thorimbert, J. P. GenÞt, J.
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Croset, D. Polet, C. Falciola, Chimia 2006, 60, 124 – 130; b) H.
Yorimitsu, K. Oshima, Angew. Chem. 2005, 117, 4509 – 4513;
Angew. Chem. Int. Ed. 2005, 44, 4435 – 4439.
Entry
Substrate
Ligand
Yield [%]
ee [%]
1
2
3
4
5
6
7
8
9
9
9
9
9
9
11
11
11
11
L13
L14
L4
86
85
78
81
85
94
90
85
12
67 (À)
85 (+)
90 (À)
94 (À)
88 (À)
79 (À)
89 (À)
86 (À)
78 (À)
L7
L10
L13
L4
L7
L10
[7] A. Alexakis, M. dꢀAugustin, L. Palais, Angew. Chem. 2005, 117,
1400 – 1402; Angew. Chem. Int. Ed. 2005, 44, 1376 – 1378.
[8] A. Alexakis, C. A. Falciola, Angew. Chem. 2007, 119, 2673 – 2676;
Angew. Chem. Int. Ed. 2007, 46, 2619 – 2622.
[9] a) L. Micouin, A. Alexakis, C. Bournaud, C. Falciola, T. Lecourt,
S. Rosset, Org. Lett. 2006, 8, 3581 – 3584. See also: b) M. Pineschi,
F. Del Moro, P. Crotti, F. Macchia, Org. Lett. 2005, 7, 3605 – 3609.
untouched, but also they afforded significantly higher enan-
tioselectivities (compare entries 1, 2, and 6 with entries 4 and
7 of Table 6).
In conclusion, we have described a novel class of chiral
monodentate phosphorus ligands, termed SimplePhos. This
family of chiral ligands is highly modular, versatile, and easy
to synthesize. Preliminary tests in copper-catalyzed reactions
showed that they are equal to or better than phosphoramidite
ligands. Other applications in asymmetric synthesis are in
progress and will be reported in due course.
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