T. Morimoto et al. / Tetrahedron Letters 48 (2007) 3093–3095
3095
Table 1. Copper-catalyzed enantioselective conjugate addition of
diethylzinc to 2-cyclohexen-1-onea
References and notes
1. For a review, see: Alexakis, A.; Benhaim, C. Eur. J. Org.
Chem. 2002, 3221.
2. Escher, I. H.; Pfaltz, A. Tetrahedron 2000, 56, 2879.
3. Hu, X.; Chen, H.; Zhang, X. Angew. Chem., Int. Ed. 1999,
38, 3518.
4. Hu, Y.; Liang, X.; Wang, J.; Zheng, Z.; Hu, X. J. Org.
Chem. 2003, 68, 4542.
5. Morimoto, T.; Mochizuki, N.; Suzuki, M. Tetrahedron
Lett. 2004, 45, 5717.
O
O
+ Et2Zn
Cu(OTf)2 - Ligand 5a-i
*
Entry
Ligand
Conv.b (%)
eec (%)
Config.d
1
2
3
4
5
6
7
8
9
5a
5b
5c
5d
5e
5f
100
100
100
72
100
41
48
100
98
41
44
33
8
94
28
7
R
S
S
R
R
R
R
R
R
6. Uozumi, Y.; Tanahashi, A.; Lee, S.-Y.; Hayashi, T. J. Org.
Chem. 1993, 58, 1945.
7. Preparation of a typical ligand 5e: To a mixture of (R)-
20-(diphenylphosphoryl)-1,10-binaphthyl-2-ol (6) (120 mg,
0.26 mmol) and K2CO3 (219 mg, 1.6 mmol) in acetone
(3 mL) was added 2-dimethylaminoethyl chloride
(114 mg, 0.78 mmol). The mixture was stirred and heated
under reflux for 13 h and cooled to room temperature.
The solvent was removed and the residue was dissolved
in a saturated solution of Na2CO3. The aqueous solution
was extracted with AcOEt. The organic phase was
washed with H2O and brine, dried over MgSO4, and
concentrated under reduced pressure. The crude product
was purified by chromatography on silica gel with
MeOH to yield (R)-2-(20-diphenylphosphoryl)-1,10-
binaphthyl-2-yloxy-N,N-dimethylethanamine as a white
solid (121 mg, 88%). To a mixture of (R)-2-(20-diphenyl-
phosphoryl)-1,10-binaphthyl-2-yloxy-N,N-dimethylethan-
amine (80 mg, 0.148 mmol) and triethylamine (0.42 mL,
3.0 mmol) in xylene (3.3 mL) was added trichlorosilane
(0.08 mL, 0.74 mmol) at 0 ꢁC, the mixture was refluxed
under Ar for 18 h. After being cooled to room temper-
ature, the mixture was treated with 30% NaOH. The
mixture was stirred and heated at 80 ꢁC for 1 h under
Ar, cooled, and extracted with AcOEt. The organic
phase was washed with a saturated solution of Na2CO3
and brine, dried over MgSO4, and concentrated under
reduced pressure. The crude product was purified by
chromatography on silica gel with MeOH to yield (R)-20-
(diphenylphosphino)-1,10-binaphthyl-2-ol (5e) as a white
solid (68 mg, 88%). 1H NMR (CDCl3, 500 MHz) d: 1.87
(3H · 2, s), 2.09–2.14 (1H, m), 2.21–2.26 (1H, m), 3.75–
3.79 (1H, m), 3.93–3.97 (1H, m), 6.09 (1H, d,
J = 7.9 Hz), 7.06–7.09 (3H, m), 7.14–7.26 (11H, m),
7.32 (1H, d, J = 8.5 Hz), 7.42–7.46 (2H, m), 7.83, 7.86
(3H, m), 7.97 (1H, d, J = 9.1 Hz). Selected 13C NMR
5g
5h
5i
84
6
a Reaction conditions: Cu(OTf)2 (0.005 mmol), 5 (0.01 mmol), 2-
cyclohexen-1-one (0.5 mmol), Et2Zn (0.75 mmol, 0.75 mL of 1 M
hexane solution); CH2Cl2 (1.5 mL); 0 ꢁC; 5 h.
b Conversion determined by GC.
c Ee determined by GC using a c-DEX 225 column.
d The absolute configuration was assigned by GC analysis in com-
parison with an authentic sample.
Table 2. Screening of reaction conditions for copper-catalyzed conju-
gate addition using ligand 5ea
Entry Cu salt
Solvent Temp (ꢁC) Conv. (%) eeb (%)
1
2
3
4
5
6
7
8
9
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Toluene
Et2O
CH2Cl2
CH2Cl2
CH2Cl2
0
0
0
rt
ꢀ5
100
100
100
100
100
94
100
100
100
100
89
88
94 (87)c
94
99
CH2Cl2 ꢀ20
73
96
(CuOTf)2Ætol CH2Cl2
0
0
0
0
CuTCd
CuTC
CuTC
CH2Cl2
Toluene
Et2O
86
77
75
10
a Under the similar reaction conditions described in a footnote of
Table 1 (except solvent, temp, or copper salt).
b The absolute configuration of all the products was R.
c Compound 5e: 1.5 mol %.
d CuTC: copper(I) thiophene-2-carboxylate.
(CDCl3, 125 MHz) d: 45.57, 57.62, 67.14. IR (cmꢀ1
)
ligand 5e. However, the enantioselectivity was modest
(film): 2343.8, 2361.2, 2770.1, 2851.1, 2920.5, 2955.2,
3055.5, 3069.0. FAB-MS: 562 (MH+). [a]D +40.9 (c 0.85,
CHCl3).
(49% ee).
In conclusion, we have developed several new P,O,N-
type ligands and found that the simplest one bearing
an O-(dimethylamino)ethyl group is efficient for a
copper-catalyzed enantioselective conjugate addition to
2-cyclohexen-1-one.8
8. A P,OH-type ligand bearing a di-n-butylphosphino group
was reported to be efficient for copper-catalyzed enantio-
selective conjugate addition of diethylzinc to linear enones:
Ito, K.; Eno, S.; Saito, B.; Katsuki, T. Tetrahedron Lett.
2005, 46, 3981.