Enantioselective copper-catalyzed allylic alkylation with dialkylzincs using phosphoramidite ligands

Article abstract of DOI:10.1021/ol0156289

Matrix presented In the presence of a catalytic amount of copper salts, cinnamyl halides undergo a regio- and enantioselective S_N2′ alkylation with dialkylzincs using chiral phosphoramidites as ligands. An S_N2′:S_N2 ratio o

Full text of DOI:10.1021/ol0156289

ORGANIC
LETTERS
2001
Vol. 3, No. 8
1169-1171
Enantioselective Copper-Catalyzed
Allylic Alkylation with Dialkylzincs Using
Phosphoramidite Ligands
,†
Hinke Malda, Anthoni W. van Zijl, Leggy A. Arnold, and Ben L. Feringa*
Department of Organic and Molecular Inorganic Chemistry, Stratingh Institute,
UniVersity of Groningen, Nijenborgh 4, 9747 AG Groningen, The Netherlands
feringa@chem.rug.nl
Received January 30, 2001
ABSTRACT
In the presence of a catalytic amount of copper salts, cinnamyl halides undergo a regio- and enantioselective SN2′ alkylation with dialkylzincs
using chiral phosphoramidites as ligands. An SN2′:SN2 ratio of 85:15 and enantiomeric excesses up to 77% for the chiral SN2′ products are
found. Variation of solvent and reaction temperature revealed that the highest regio- and enantioselectivities are found using coordinating
solvents of −40 °C.
Transition metal mediated carbon-carbon bond formations
are among the most versatile synthetic methodologies in
contemporary organic chemistry.1 In recent years, the alky-
lation of allylic substrates has attracted much attention in
approaches toward branched, chiral products.2 Several highly
selective palladium-catalyzed allylic substitutions using ma-
lonates as carbon nucleophiles have been described.1,3,4 Van
Koten and Ba¨ckvall reported the first asymmetric copper-
catalyzed allylic alkylation using Grignard reagents albeit
with moderate enantioselectivities.5 Recently, Du¨bner and
Knochel6 introduced a highly regioselective copper-catalyzed
alkylation method with dineopentylzinc employing chiral
ferrocenylamines as ligands resulting in SN2′ products with
up to 98% ee.
However, highly enantioselective allylic alkylation with
nonsterically demanding (linear) alkylzinc reagents remains
a major challenge. In this Letter, we report an asymmetric
copper(I)-catalyzed allylic alkylation with dialkylzincs and
cinnamyl bromide resulting in ee’s up to 77%. This selectiv-
ity is achieved using 1 mol % of catalyst, prepared in situ
from CuBr‚Me2S and a chiral phosphoramidite ligand (1a,
Figure 1). These ligands are known to give excellent
† Fax: Int. code +(50) 3634296. Tel.: Int. code +(50) 3634278.
(1) (a) Beller, M.; Bolm, C. In Transition Metals for Organic Synthesis;
Wiley: VCH: Weinheim, 1998. (b) Trost, B. M.; Van Vranken, D. L. Chem.
ReV. 1996, 96, 395-422. (c) Catalytic Asymmetric Synthesis; Ojima, I.,
Ed.; VHC: New York, 1993. (d) Jacobsen, E. N.; Pfaltz, A.; Yamamoto,
Y. ComprehensiVe Asymmetric Catalysis I, II, III; Springer-Verlag: Berlin,
Heidelberg, 1999.
(2) (a) Magid, R. M. Tetrahedron 1980, 36, 1901-1930 and references
therein. (b) Meuzelaar, G. J.; Karlstrom, A. S. E.; Persson, E. S. M.; Del
Villar, A.; Van Koten, G.; Ba¨ckvall, J.-E. Tetrahedron 2000, 56, 2895-
2903. (c) Ba¨ckvall, J.-E.; Selle´n, M. J. Chem. Soc., Chem. Commun. 1987,
827-829. (d) Ba¨ckvall, J.-E.; Selle´n, M.; Grant, B. J. Am. Chem. Soc. 1990,
112, 6615-6621. (e) Ba¨ckvall, J.-E.; Persson, E. S. M.; Bombrun, A. J.
Org. Chem. 1994, 59, 4126-4130. (f) Persson, E. S. M.; Ba¨ckvall, J.-E.
Acta Chem. Scand. 1995, 49, 899. (g) Underliner, T. L.; Paisley, S. D.;
Schmitter, J.; Lesheski, L.; Goering, H. L. J. Org. Chem. 1989, 54, 2369-
2374. (h) Bartels, B.; Helmchen, G. Chem. Commun. 1999, 741-742.
(3) (a) Pre´tot, R.; Pfalz, A. Angew. Chem., Int. Ed. 1998, 37, 323-325.
(b) Hayashi, T.; Kishi, K.; Yamamoto, A.; Ito, Y. Tetrahedron Lett. 1990,
31, 1743-1746. (c) Hayashi, T.; Ohno, A.; Lu, S.-j.; Matsumoto, Y.;
Fukuyo, E.; Yanagi, K. J. Am. Chem. Soc. 1994, 116, 4221-4226. (d)
Hayashi, T.; Kawatsura, M.; Uozumi, Y. Chem. Commun. 1997, 561-562.
(e) Trost, B. M.; Toste, F. D. J. Am. Chem. Soc. 1998, 120, 9074-9075.
(4) Reiser, O. Angew. Chem. 1993, 105, 576; Angew. Chem., Int. Ed.
Engl. 1993, 32, 547-551.
(5) Van Klaveren, M.; Persson, E. S. M.; Del Villar, A.; Grove, D. M.;
Ba¨ckvall, J.-E.; Van Koten, G. Tetrahedron Lett. 1995, 36, 3059-3062.
(6) Du¨bner, F.; Knochel, P. Tetrahedron Lett. 2000, 41, 9233-9237.
10.1021/ol0156289 CCC: $20.00 © 2001 American Chemical Society
Published on Web 03/21/2001

perature 70% conversion was reached after 2 d. A 75:25
mixture of regioisomers was found with an enantiomeric
excess of 17% for the SN2′ product. These observations
initiated a more detailed investigation of the optimal solvent,
reaction conditions, and chiral ligands.
Diglyme gave the highest ee for the allylic alkylation with
2a (Table 1, entry 8), for the various solvents examined,
although the highest regioselectivity was observed using THF
(Table 1, entry 4). Noncoordinating solvents such as toluene
and CH2Cl2 showed low regioselectivity and almost no
asymmetric induction for the SN2′ product (Table 1, entries
2 and 3). Among the different cinnamyl halides tested,
cinnamyl bromide turned out to be the most reactive and
selective starting material (Table 1, entry 12).
The allylic acetate and phosphate were not reactive under
these reaction conditions even after 2 days at room temper-
ature (Table 1, entries 9 and 10). Furthermore, a number of
phosphoramidite ligands were tested in the allylic alkylation
(Table 1, entries 12-16). Using ligand 1a, carrying a chiral
bis[(R)-1-phenylethyl]amine moiety, and CuBr‚Me2S in the
reaction of cinnamyl bromide with diethylzinc, the corre-
sponding SN2′ product was obtained with an enantioselec-
tivity of 64% (Table 1, entry 12).13 The other phosphora-
midites, with different stereochemistries or different chiral
amines (1b-1e), resulted in lower enantioselectivities. When
the reaction was carried out at a constant low reaction
Figure 1. Phosphoramidite ligands.
selectivities in the copper-catalyzed 1,4-addition of diorga-
nozinc compounds to cyclic and acyclic enones,7 cyclohexa-
dienones,8 R,â-unsaturated nitro-esters,9 nitro-olefins,10 and
cyclic 1,3-diene-epoxides11 as well as in the asymmetric
rhodium-catalyzed hydrogenation.12
The preliminary reactions were carried out with cinnamyl
chloride (2a), diethylzinc, 1 mol % of CuBr‚Me2S, and 2
mol % of ligand 1a in THF. The initial temperature of the
alkylation was -40 °C, and upon warming to room tem-
Table 1. Enantioselective Copper-Catalyzed Allylic Alkylation with Dialkylzincs Using Phosphoramidites 1a-1e as Ligands: Effect
of the Solvent, Leaving Group, Ligand, and Temperature
entry
substrate
X
R
solvent
Et2O
toluene
CH2Cl2
THF
L*
3:4
convna (%)
yielda of 3 (%)
ee of 3 (%)
1
2
3
4
5
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
2a
2a
2a
2a
2a
2a
2a
2b
2c
2d
2e
2e
2e
2e
2e
2e
2e
2e
2e
2e
Cl
Cl
Cl
Cl
Cl
Cl
Cl
OAc
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Me
Me
Bu
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1b
1c
1d
1e
1a
1a
1a
1a
1a
47:53
59:41
62:38
75:25
52:48
57:43
57:43
100b
100
100
70b
100
85b
90b
0c
0c
90
100
79
96
98
73
35d
70d,e
40
44d,e
65
nd
27
84
nd
63
nd
57
nd
<5
<5
17
17
22
28
1,4-dioxane
DME
diglyme
diglyme
diglyme
diglyme
diglyme
diglyme
diglyme
diglyme
diglyme
diglyme
diglyme
diglyme
diglyme
diglyme
OP(O)(OEt)2
I
66:34
84:16
68:32
78:22
73:27
72:28
85:15
84:16
nd
24
90
70
23
63
62
32
54
nd
nd
nd
63
64
25
31
12
13
77
77
11
24
71
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
49:51
84:16
a Determined by GC. b Conversion after 2 d. c After 18 h at -10 °C, the reaction was stirred at rt for 2 d. d Reaction performed at a constant temperature
of -40 °C. e 5 mol % of catalyst was used.
1170
Org. Lett., Vol. 3, No. 8, 2001

temperature of -40 °C, an enantioselectivity of 77% was
found. Using 5 mol % instead of 1 mol % of catalyst, the
conversion of the starting material can be increased from
35% to 70% (Table 1, entry 18).
To establish the regio- and enantioselectivity during the
progress of the allylic alkylation, the reaction of 2e with Et2-
Zn, catalyzed by CuBr‚Me2S (5 mol %)/1a (15 mol %), at
constant temperature (-40 °C), was followed in time. The
conversion, the relative amount of SN2′ product, and the
enantiomeric excess were monitored, and the results are
presented in Figure 2. The time profile of the reaction reveals
In addition to diethylzinc, different dialkylzincs were also
used in the allylic alkylation with cinnamyl bromide. With
dimethylzinc, 40% conversion was found after 18 h with no
regioselectivity and 11% ee (24% ee at constant -40 °C)
for the (SN2′) product (Table 1, entries 19 and 20). Dibu-
tylzinc gives a regioselectivity similar to that of diethylzinc
in this reaction with 71% ee for the (SN2′) product but with
a lower conversion rate (Table 1, entry 21).
Besides CuBr‚Me2S for the in situ preparation of the
catalyst, different copper(I) and copper(II) salts were also
used in the allylic alkylation (Table 2). Copper(I) cyanide
Table 2. Enantioselective Copper-Catalyzed Allylic Alkylation
with Cinnamyl Bromide and Diethylzinc Using Phosphoramidite
1a as a Ligand. The Effect of the Copper(I) and Copper(II)
Salts
Figure 2. Time profile of the conversion, the regioselectivity, and
the enantiomeric excess of the allylic alkylation.
that the reaction is fast at the beginning and slows down
after 3 h. The relative amount of SN2′ product is almost
constant during the reaction. A striking feature is the fact
that the enantiomeric excess increased in time. Because no
blank reaction occurs (Table 2, entry 10), this feature
indicates that different catalytic species are present at the
early stage of the reaction. The nature of the catalytic species
involved is subject to a current detailed investigation.
In conclusion, we found a new enantioselective copper-
catalyzed alkylation of cinnamyl bromides with dialkylzincs
by applying phosphoramidites as chiral ligands. The product
3 was obtained in a good yield with enantiomeric excesses
up to 77%. This is, to the best of our knowledge, the highest
ee obtained in a copper-catalyzed catalytic allylic alkylation
using unbranched organometallic reagents.
yield of
ee of
entry
Cu salt
CuI
CuCN
CuBr
Cu(F-acac)b
CuBr.Me2S
Cu(OTf)2
CuBr2
Cu(OAc)2
CuOTf
SN2′:SN2
convn (%)
3 (%)
3 (%)
1
2
3
4
5
6
7
8
9
76: 24
94: 6
41
69
80
54
100
51
79
63
69
1
36
nd
nd
50
nd
48
75
nd
60
62
3
79: 21
81: 19
84: 16
81: 19
79: 21
79: 21
85: 15
63
62
64
64
12
60
69
10a
a No ligand was used in this reaction. b (F-acac) is trifluoroacetylacetate.
Acknowledgment. Financial support by the ministry of
economic affairs (EET grant) is gratefully acknowledged.
OL0156289
gives a remarkable high ratio of regioisomers, but very little
enantioselectivity for the major (SN2′) product (Table 2, entry
2). The highest enantiomeric excess (69%) was observed
using copper(I) triflate with a conversion of 69% within 18
h (Table 2, entry 9). Notable is the finding that CuBr‚Me2S
complex gives a higher conversion than the pure CuIBr salt
(Table 2, entries 5 and 3). Furthermore, a few experiments
employing different organometallic reagents were carried out.
In contrast to Grignard reagents (EtMgBr), which show no
selectivity at all under these reaction conditions, EtZnCl
results in a regioselectivity of 79% for the SN2′ product with
an enantiomeric excess of 49%.
(9) Versleijen, J. P. G.; Van Leusen, A. M.; Feringa, B. L. Tetrahedron
Lett. 1999, 40, 5803-5806.
(10) Alexakis, A.; Benhaim, C. Org. Lett. 2000, 2, 2579-2581.
(11) Badalassi, F.; Crotti, P.; Macchia, F.; Pineschi, M.; Arnold, A.;
Feringa, B. L. Tetrahedron Lett. 1998, 39, 7795-7798.
(12) Van den Berg, M.; Minnaard, A. J.; Schudde, E. P.; Van Esch, J.;
De Vries, A. H. M.; De Vries, J. G.; Feringa, B. L. J. Am. Chem. Soc.
2000, 122, 11539-11540.
(13) Typical procedure for enantioselective allylic alkylation (Table
2, entry 5): Under an argon atmosphere the phosphoramidite ligand 1a
(5.4 mg, 0.01 mmol) and CuBr‚Me2S (1 mg, 0.005 mmol) were dissolved
in diglyme (5 mL) and stirred for 10 min at room temperature. To the cooled
solution (-40 °C) was added Et2Zn (1 M in hexane, 0.6 mL, 74 mg, 0.6
mmol). After 5 min 2e (99 mg, 0.5 mmol) was added and the reaction was
allowed to warm to -10 °C over 18 h. The mixture was quenched with 1
M aqueous H2SO4, and the separated aqueous layer was extracted 2 times
with diethyl ether. The combined organic layers were treated with brine,
dried over MgSO4, and concentrated in vacuo. After purification by column
chromatography (SiO2, diethyl ether:pentane, 1:50), the products 3 and 4
were obtained in 81% yield. The enantiomeric excess of 3 was determined
by gas chromatography (chiral column Betadex 120, 30m, 0.25 mm, oven
temperatre ) 75 °C, tr(3) ) 39.8 and 40.5 min) to be 64%.
(7) (a) Arnold, L. A.; Imbos, R.; Mandoli, A.; De Vries, A. H. M.; Naasz,
R.; Feringa, B. L. Tetrahedron 2000, 56, 2865-2878. (b) Feringa, B. L.
Acc. Chem. Res. 2000, 33, 346-353.
(8) Imbos, R.; Brilman, M. H. G.; Pineschi, M.; Feringa, B. L. Org.
Lett. 1999, 1, 623-625.
Org. Lett., Vol. 3, No. 8, 2001
1171