A new chiral 2-sulfonylamino-2′-phosphino-1,1′-binaphthyl ligand for highly enantioselective copper-catalyzed conjugate addition of diethylzinc to benzylideneacetones

Article abstract of DOI:10.1016/j.tetlet.2004.05.101

A new axially chiral phosphine-sulfonamide ligand was prepared via a chiral component (R)-2-amino-2′-diphenylphosphinyl-1,1′-binaphthyl, which was conveniently synthesized through a new route involving hydrolysis of (R)-2-cyano-2′-phosphinyl-1,1′-binaphth

Full text of DOI:10.1016/j.tetlet.2004.05.101

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 5717–5722
A new chiral 2-sulfonylamino-20-phosphino-1,10-binaphthyl ligand
for highly enantioselective copper-catalyzed conjugate addition of
diethylzinc to benzylideneacetones
Toshiaki Morimoto,* Nobuhiro Mochizuki and Masato Suzuki
School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Shizuoka-shi 422-8526, Japan
Received 8 April 2004;revised 30 April 2004;accepted 17 May 2004
Available online 15 June 2004
Abstract—A new axially chiral phosphine–sulfonamide ligand was prepared via a chiral component (R)-2-amino-20-diphenyl-
phosphinyl-1,10-binaphthyl, which was conveniently synthesized through a new route involving hydrolysis of (R)-2-cyano-20-
phosphinyl-1,10-binaphthyl followed by Hofmann rearrangement of the amide group. The new ligand was found to be very efficient
in copper-catalyzed enantioselective conjugate addition of diethylzinc to acyclic enones such as benzylideneacetones, providing very
high enantioselectivity up to 99% ee.
Ó 2004 Elsevier Ltd. All rights reserved.
The enantioselective conjugate addition of organomet-
allics to a,b-unsaturated carbonyl and related com-
pounds is an important strategy for the construction of
chiral carbon–carbon bonds in the synthesis of optically
pure compounds including physiologically active ones.1
For practical and theoretical purposes the development
of chiral catalyst systems has been widely investigated,
and several efficient catalysts using copper complexes of
chiral ligands have been developed in the reaction of
dialkylzinc with enones.1;2 Several types of chiral phos-
phorous ligands, such as phosphoramidites,3 phosph-
ites,4 P,N ligands,5 and some others,6 have been found
to be highly efficient (>90% ee) in copper-catalyzed
conjugate addition of diethylzinc to cyclic enones.
However, only a few types of ligands are efficient for the
reaction of acyclic enones such as chalcones and benz-
ylideneacetones.3c;d;5b;e;f;i–m;6c
of diethylzinc.5c As an extension of the utility of the
chiral component we developed novel chiral P,N ligands
3, 4 by condensation of the component with 2-pyridine-
carboxaldehyde and 2-picolinic acid or their analogs,5c;g
and found that the 2-pyridylmethyleneamino derivatives
3 are the most efficient ligands in copper-catalyzed
enantioselective conjugate addition of diethylzinc to
2-cyclohexen-1-one, providing high enantioselectivity up
to 91–95% ee. However, these ligands could not give
high enantioselectivity in the reaction of acyclic enones
such as chalcone (71% ee) and benzylideneacetone (48%
ee) (Fig. 1).
R
N
PPh2
R'SO2NH
PPh2
R
2
Several years ago, we prepared amidine 1a and imine 1b
derivatives of a chiral component (S)-2-(amino)alkyl-
phosphine and found that they are useful ligands in
palladium-catalyzed enantioselective allylic alkylation7
but not efficient in copper-catalyzed conjugate addition
R=Me2N : 1a
R=p-Me2NC6H4: 1b
O
NH PPh2
N
PPh2
N
R
N
R
Keywords: Chiral binaphthyl ligand;Copper catalyst;Conjugate
addition;Enantioselectivity;Enones.
4
3
* Corresponding author. Tel./fax: +81-54-2645740;e-mail: morimtt@
u-shizuoka-ken.ac.jp
Figure 1. P,N ligands derived from b-aminoalkylphosphine.
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.05.101

5718
T. Morimoto et al. / Tetrahedron Letters 45 (2004) 5717–5722
On the other hand, N-monosubstituted sulfonamide was
first found in 1996 to accelerate the copper-catalyzed
conjugate addition of dialkylzinc to enones,8 and chiral
mono- or bis-sulfonamides were employed as the ligands
for the copper-catalyzed enantioselective conjugate
addition, though the enantioselectivity was low (ꢀ32%
or ꢀ28% ee).9a;b A series of efficient chiral ligands, N-
alkyl-b-(N0-salicylideneamino)alkanesulfonamides, was
later developed by high-throughput screening of a
parallel library.6a In 1990 we developed a novel type
of chiral ligands, 2-(sulfonylamino)alkylphosphines 2,
which were found to be efficient in enantioselective
palladium-catalyzed hydrosilylation and Heck-type
hydroarylation of olefins.10 In a previous symposium,5g
we reported that N-alkylsulfonyl derivatives 2 of the
chiral aminophosphine component are effective for
the copper-catalyzed conjugate addition to a cyclic
enone, giving good enantioselectivity. Very recently,
an analogous trifluoromethylsulfonyl derivative of a
2-(amino)alkylphosphine was reported to be a highly
efficient ligand for copper-catalyzed conjugate
addition to cyclic enones.5h However, the N-sulfonyl
ligands 2 derived from (S)-2-(amino)alkylphosphines
could not give high enantioselectivity in the reaction
of acyclic enones such as chalcone and benzylidene-
acetone.
The preparation of an axially chiral aminophosphine
component, (R)-2-amino-20-diphenylphosphino-1,10-bi-
naphthyl (MAP), was first reported by Vyskocil et al.11
starting from (R)-2-amino-20-hydroxy-1,10-binaphthyl
(NOBIN). (R)- and (S)-NOBIN were prepared by cou-
pling of 2-naphthylamine and 2-naphthol with CuCl2 in
the presence of (R)-1-phenylethylamine followed by re-
peated diastereoselective crystallization,12 or obtained
from racemic NOBIN by resolution with (1S)- or (1R)-
camphor-10-sulfonic acid.13 Later, Singer and Buchwald
reported the preparation of (R)-NOBIN via palladium-
catalyzed amination of O-protected (R)-BINOL mono-
triflate with benzophenone imine.14 (S)-NOBIN was
recently prepared via (S)-O-methyl NOBIN obtained by
Curtius rearrangement of (S)-20-methoxy-1,10-binaph-
thyl-2-carboxylic acid, which was synthesized by dia-
stereoselective nucleophilic aromatic substitution of a
())-menthyl naphthalenecarboxylate with a Grignard
reagent.15 However, there are several drawbacks to the
above procedures for the preparation of enantiopure
MAP via NOBIN such as low overall yield and the
necessity for tedious optical resolution, and, therefore,
the development of new efficient methodology is still
desired. We report herein a convenient preparation of an
N-sulfonyl derivative 11 of the chiral binaphthyl com-
ponent (R)-MAP from (R)-BINOL 5 and its use as
an efficient ligand in copper-catalyzed enantioselective
conjugate addition of diethylzinc to acyclic enones such
as benzylideneacetone and its analogs.
We then envisioned that the introduction of sulfonyl
groups to other chiral aminophosphine components
might be useful for developing more efficient ligands
in the metal-catalyzed conjugate addition to acyclic
enones. Since an axially chiral binaphthyl skeleton
has been well documented to construct an effective
chiral template, chiral 1,10-binaphthyl derivatives
bearing both a 2-sulfonylamino group and a 20-
diphenylphosphino group were designed as efficient
ligands.
The synthetic route of the new P,N-type ligand 11 is
described in Scheme 1. The chiral component, (R)-2-
amino-20-dipenylphosphinyl-1,10-binaphthyl 9 was con-
veniently prepared via a known compound, (R)-2-cya-
no-20-diphenylphosphinyl-1,10-binaphthyl 6. According
to the procedure of Hayashi and co-workers,16 the tri-
flate of (R)-1,10-bi-2-naphthol (BINOL) 5 was catalyti-
1) Tf2O
2) Ph2POH, Pd cat.
3) KCN, Ni cat.
OH
NaOH, H2O2
CN
CONH2
OH
P(O)Ph2
P(O)Ph2
in EtOH
5
6
7
Br2, NaOMe
in MeOH
TolSO2Cl
in pyridine
KOH
NHCO2Me
P(O)Ph2
NH2
P(O)Ph2
8
9
HSiCl3, NEt3
in xylene
NHSO2Tol
P(O)Ph2
NHSO2Tol
PPh2
10
Scheme 1. Synthesis of a phosphine–sulfonamide ligand 11.
11

T. Morimoto et al. / Tetrahedron Letters 45 (2004) 5717–5722
5719
cally converted to a monophosphinylation product,
which was allowed to react with potassium cyanide in
the presence of a nickel catalyst, affording (R)-2-cyano-
20-diphenylphosphinyl-1,10-binaphthyl 6 in high overall
yield. Several attempts to achieve acid or alkaline
hydrolysis of the cyano compound 6 with sulfuric acid
or sodium hydroxide failed. However, we were able to
accomplish the hydrolysis of 6 to the corresponding
amide 7 in 96% yield by prolonged heating with alkaline
hydrogen peroxide in ethanol. Modified Hofmann
rearrangement17 of the amide 7 with bromine and so-
dium methoxide in methanol yielded the methoxycar-
bamoyl derivative 8 (92%),18 which was converted to the
corresponding amine derivative 9 (97%) by alkaline
hydrolysis. N-Sulfonylation with p-toluenesulfonyl
chloride in pyridine gave the 2-tosylamino-20-phosphinyl
derivative 10 (90%).19 The phosphinyl group of 10 was
reduced with trichlorosilane to afford the aimed P,N-
type ligand, (R)-2-p-tosylamino-20-diphenylphosphino-
1,10-binaphthyl 11 (97%).20
Some different copper salts also showed high enantio-
selectivity at 0 °C. To the best of our knowledge, the
enantioselectivity of up to 96–99% ee thus obtained with
ligand 11 is the highest among the reported data for the
enantioselective conjugate addition of diethylzinc to
benzylideneacetone.
As an extension of the substrate, several para-, meta-,
and ortho-substituted benzylideneacetones 12b–f were
selected and allowed to react with diethylzinc at 0 °C in
toluene in the presence of copper triflate (0.5 mol %) and
ligand 11 (1 mol %). The results are summarized in
Table 2. The reactions with substituted benzylidene-
acetones 12b–e afforded the corresponding products
in high enantioselectivity (95–97% ee), though the ee
with a methylenedioxy derivative 12f was somewhat
lower.23
In conclusion, we have synthesized a new chiral
binaphthyl ligand bearing both a phosphino group and
a sulfonylamino group through a convenient route
involving hydrolysis and Hofmann rearrangement. We
also presented an application of the new ligand to the
copper-catalyzed enantioselective conjugate addition of
diethylzinc to an acyclic enone, benzylideneacetone,
where very high enantioselectivity (94–99% ee) was
obtained even under various reaction conditions (sol-
vent: toluene, dichloromethane, ether;temperature: )20
to 20 °C;Cu: 0.5–2 mol %). Several substituted benzyl-
ideneacetones were also converted to the corresponding
conjugate addition products with high enantioselectivity
(84–98% ee). Further investigation is in progress to
reveal the scope and utility of the ligand and some other
ligands derived from the synthetic intermediates, and to
apply the present reaction to the synthesis of physio-
logically active compounds.
The copper-catalyzed enantioselective conjugate addi-
tion of diethylzinc to benzylideneacetone 12a was cho-
sen as a model reaction for evaluation of the capability
of the newly prepared chiral ligand 11.21 The effects of
different reaction parameters were investigated for sol-
vents, temperatures, amounts of copper salt and 11, and
different copper salts. The results are summarized in
Table 1. High ee values (96–99% ee) were obtained by
using the ligand 11 (5 mol %) and copper triflate
(2 mol %) at 0 °C in all the solvents (toluene, dichloro-
methane, and ether) used.22 Even when the amount
of copper triflate was reduced to 0.5 mol % (ligand
1 mol %), the high enantioselectivity was maintained
along with good yield of the product. The ee values at
0 °C were generally better than those at )20 and 20 °C.
Table 1. Copper-catalyzed enantioselective conjugate addition of diethylzinc to benzylideneacetone 12aa
O
O
Cu salt - Ligand 11
+
Et Zn
2
13a
12a
Entry
Cu salt (mol %)
Ligand 11/Cu
Solvent
Temp. (°C)
Yield (%)b
ee (%)b
Config.c
1
Cu(OTf)2 (2)
Cu(OTf)2 (2)
2.5:1
2.5:1
2.5:1
2.5:1
2.5:1
1.5:1
2:1
Toluene
CH2Cl2
Et2O
0
0
33
72
71
62
32
71
80
80
55
43
74
61
36
99
98
96
94
94
96
97
96
97
96
96
97
94
R
R
R
R
R
R
R
R
R
R
R
R
R
2
3
Cu(OTf)2 (2)
Cu(OTf)2 (2)
0
4
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
20
)20
0
5
Cu(OTf)2 (2)
Cu(OTf)2 (1)
6
7
Cu(OTf)2 (0.5)
(CuOTf)2ÆTol (1)
(CuOTf)2ÆTol (1)
(CuOTf)2ÆTol (1)
Cu(OAc)2ÆH2O (2)
Cu(OAc)2ÆH2O (2)
Cu(OAc)2ÆH2O (2)
0
8
2.5:1
1.5:1
2.5:1
2.5:1
1.5:1
2.5:1
0
9
0
10
11
12
13
)20
0
0
)20
a Reaction conditions: benzylideneacetone 12a (0.5 mmol), diethylzinc (0.75 mmol, 0.75 mL of 1 M hexane solution);solvent (3 mL);5 h.
b Yield and ee determined by GC (capillary column: Supelco c-DEX 225) using n-dodecane as an internal standard.
c The absolute configuration was assigned by comparison of specific rotation data.

5720
T. Morimoto et al. / Tetrahedron Letters 45 (2004) 5717–5722
Table 2. Copper-catalyzed enantioselective conjugate addition of diethylzinc to benzylideneacetones 12a–fa
O
O
Cu(OTf) - Ligand 11
2
+
Et Zn
2
Ar
Ar
*
12a-f
13a-f
ee (%)c
Entry
1
Ar
Product
Yield (%)b
63
Config.e
13a
96
95
96
97
R
f
2
3
4
Me
MeO
Cl
13b
13c
13d
50
44
50
)
f
)
f
)
f
5
6
13e
13f
51
49
98
+
Cl
O
O
f
84d
)
a Reaction conditions: Cu(OTf)2 (0.005 mmol), 11 (0.01 mmol), 12 (1.0 mmol), Et2Zn (1.5 mmol, 1.5 mL of 1 M hexane solution);toluene (6 mL);0 °C;
5 h.
b Yield based on the isolated product.
c ee determined by GC using a c-DEX 225 column.
d ee determined by HPLC using a Chiralcel OJ column.
e The absolute configuration was assigned by comparison of specific rotation data.
f Sign of the optical rotation of addition product.
2623;(b) Choi, Y. H.;Choi, J. Y.;Yang, H. Y.;Kim, Y.
H. Tetrahedron: Asymmetry 2002, 13, 801–804;(c) Alexa-
Acknowledgements
kis, A.;Benhaim, C.;Rosset, S.;Humam, M.
J. Am.
Chem. Soc. 2002, 124, 5262–5263;(d) Watanabe, T.;
This work was partially supported by a Grant-in-Aid for
Scientific Research from Japan Society of the Promotion
of Science (No. 13672225). The authors are grateful to
Dr. Mitsuo Uchida and Mrs. Ayako Satoh for the
measurement of FAB-MS and the microanalysis,
respectively.
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(CHCl3) 2996, 1725, 1508 cmÀ1;FAB-MS
m=z 528
([MH]+). Anal. Calcd for C34H26NO3PÆH2O: C,
74.85;H, 5.17;N, 2.57. Found: C, 74.72;H, 4.95;N,
2.22.
19. (R)-2-p-Tolylsulfonylamino-20-diphenylphosphinyl-1,10-
binaphthyl 10: To a dichloromethane (3.0 mL) solution of
(R)-2-amino-20-diphenylphosphinyl-1,10-binaphthyl 9 (85
mg, 0.18 mmol), which was prepared by alkaline hydroly-
sis of 8, was added pyridine (0.1 mL), and cooled in an ice-
bath. To the cooled solution was added a pyridine
(0.1 mL) solution of p-toluenesulfonyl chloride (69 mg,
0.36 mmol) and the mixture was stirred for 3 h. The
reaction mixture was acidified with hydrochloric acid
(1 M) and extracted with AcOEt (30 mL). The combined
organic layers were washed with saturated NaHCO3 and
brine, dried over MgSO4, filtered, and concentrated in
vacuo. The crude product was purified by silica gel column
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chromatography (toluene/AcOEt ¼ 20/1) to yield 10
26
(102 mg, 90%) as a solid. ½aŠ )28.6 (c 1.0, CHCl3); 1H
D
A.;Uda, T.;Morimoto, T.
Tetrahedron: Asymmetry
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1999, 10, 4501–4511;(f) Saitoh, A.;Achiwa, K.;
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1H);IR (CHCl ) 1159 cmÀ1;FAB-MS m=z 624 ([MH]+).
3
Anal. Calcd for C39H30NO3PSÆH2O: C, 72.99;H, 5.03;N,
2.18. Found: C, 72.89;H, 4.87;N, 1.81.
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20. (R)-2-p-Tolylsulfonylamino-20-diphenylphosphino-1,10-bi-
naphthyl 11: To a cooled xylene (5.0 mL) solution of 10
(102 mg, 0.16 mmol) in a pressure tube was added tri-
ethylamine (0.46 mL, 3.27 mmol) and trichlorosilane
(0.08 mL, 0.82 mmol). After ventilation with Ar, the
mixture was stirred and heated at 130 °C for 5 h. The
reaction mixture was cooled and 30% NaOH was added.
The mixture was heated at 60 °C for 0.5 h under Ar. After
cooling to room temperature, the mixture was extracted
with AcOEt. The combined organic layers were washed
with saturated NaHCO3 and brine, dried over MgSO4,
filtered, and concentrated in vacuo. The crude product was
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2863.
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purified by silica gel column chromatography (toluene) to
25
afford 11 (96 mg, 97%) as a white solid. ½aŠ )21.4 (c 1.0,
D
CHCl3); 1H NMR (CDCl3) d 2.30 (s, 3H), 6.06 (s, 1H),
6.49–7.99 (m, 26H);IR (CHCl 3) 1163 cmÀ1;FAB-MS
m=z 608 ([MH]+). Anal. Calcd for C39H30NO2PS: C, 77.08;
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2.10.
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Tetrahedron:
21. Typical procedure for the copper-catalyzed conjugate
addition: The reaction was carried out under an argon
atmosphere. The catalyst solution was prepared in situ by
stirring 0.5 mol % of Cu(OTf)2 (0.005 mmol) and 1 mol %
of ligand 11 (0.01 mmol) in dry, degassed toluene (3 mL)
for 30 min. The catalyst solution was cooled to 0 °C and a
solution of benzylideneacetone 12 (1 mmol) in toluene
(3 mL) was added followed by addition of a solution
of diethylzinc in hexane (1.0 M, 1.5 mL, 1.5 mmol) and
n-dodecane (0.5 mmol) as an internal standard. After
stirring for 5 h at 0 °C, the reaction mixture was quenched
with 1 N aqueous HCl and extracted with ether. The
combined organic layers were washed with brine,
dried over MgSO4, filtered, and concentrated in vacuo.
The crude product was purified by silica gel column
chromatography (hexane/AcOEt ¼ 3/1) to give the corre-
sponding 1,4-addition product, 4-phenylhexan-2-one 13.
The yields and the ee values of the addition products were
determined by GC analysis (before or after purification)
with a chiral capillary column, Superco c-DEX 225 or
HPLC analysis with a chiral column, Daicel Chiralcel
OJ.
16. (a) Uozumi, Y.;Tanahashi, A.;Lee, S.-Y.;Hayashi, T. J.
Org. Chem. 1993, 58, 1945–1948;(b) Uozumi, Y.;Suzuki,
N.;Ogiwara, A.;Hayashi, T. Tetrahedron 1994, 50, 4293–
4302.
17. Nagai, H.;Matsuo, M.;Matsuda, T. Kogyokagaku Zasshi
1964, 67, 1248.
18. (R)-2-N-Carbomethoxyamino-20-diphenylphosphinyl-1,10-
binaphthyl 8: To a methanol (1 mL) solution of (R)-2-
carbamoyl-20-diphenylphosphinyl-1,10-binaphthyl 7 (137
mg, 0.28 mmol), which was prepared by hydrolysis of
(R)-2-cyano-20-diphenylphosphinyl-1,10-binaphthyl 6 with
alkaline hydrogen peroxide in ethanol at 50–60 °C for
1 d, was added a solution of sodium methoxide in
methanol (1 M solution, 0.82 mL, 0.82 mmol). The meth-
anol solution was ice-cooled with stirring and a methanol
solution of bromine (0.5 M, 0.55 mL, 0.28 mmol) was
added dropwise. The mixture was gradually heated up to
65 °C during 1 h and kept at the same temperature for
15 min. The solvent was removed by evaporation and
saturated NaHCO3 was added. The mixture was extracted
with AcOEt. The combined organic layers were washed
with brine, dried over MgSO4, filtered, and concentrated
in vacuo. The crude product was purified by silica gel
22. The highest ee value was obtained in toluene, though it
was not clearly explained that the yield of the product in
toluene was lower than those obtained in other solvents or
by using smaller molar ratios of the ligand to copper
triflate. The lower yield may be rationalized by the
column chromatography (AcOEt) to give 8 (134 mg, 92%)
24
D
3.58 (s, 3H), 6.49–7.97 (m, 22H), 8.69 (br s, 1H);IR
as a solid. ½aŠ )135.8 (c 1.0, CHCl3); 1H NMR (CDCl3) d

5722
T. Morimoto et al. / Tetrahedron Letters 45 (2004) 5717–5722
explanation that a considerable part of copper complexes
23. For further evaluation of the ligand, the reaction of
a representative cyclic enone, 2-cyclohexen-1-one with
diethylzinc was also carried out under similar conditions,
affording (R)-3-ethylcyclohexan-1-one in lower selectivity
(52% ee).
(higher ratios of ligand to copper: 2/1 or/and more)
formed are less active (aggregated, less soluble in toluene;
less active as a catalyst for the conjugate addition but
active for by-reactions).