Highly enantioselective copper-catalyzed allylic alkylation with phosphoramidite ligands

Article abstract of DOI:10.1002/adsc.200303207

New phosphoramidites were applied as chiral ligands in the Cu-catalyzed allylic alkylation with dialkylzinc reagents. A variety of substrates, reagents and chiral ligands were screened, resulting in improved catalytic methodology for allylic bromides in w

Full text of DOI:10.1002/adsc.200303207

FULL PAPERS
Highly Enantioselective Copper-Catalyzed Allylic Alkylation
with Phosphoramidite Ligands
Anthoni W. van Zijl, Leggy A. Arnold, Adriaan J. Minnaard, Ben L. Feringa*
Department of Organic and Molecular Inorganic Chemistry, Stratingh Institute, University of Groningen,
9747 AG Nijenborgh 4, The Netherlands
Fax: ( ‡ 31)-50-3634296, e-mail: Feringa@chem.rug.nl
Received: November 11, 2003; Accepted: February 21, 2004
Supporting Information for this article is available on the WWW under http://asc.wiley-vch.de/home/.
Abstract: New phosphoramidites were applied as Keywords: allylic alkylation; asymmetric catalysis;
chiral ligands in the Cu-catalyzed allylic alkylation copper; diorganozinc compounds; phosphoramidite
with dialkylzinc reagents. A variety of substrates, ligands; SN2'-substitution
reagents and chiral ligands were screened, resulting in
improved catalytic methodology for allylic bromides
in which enantioselectivities up to 88% were reached.
Introduction
distinct, proved to be more challenging, although very
good results have been attained recently.[4] A number of
Among the most important tools of the synthetic catalysts, including chiral W,[5] Ir,[6] Mo,[7] Pt[8] and Rh[9]
organic chemist are transition metal-catalyzed C C complexes, have been used for the enantioselective
À
bond forming reactions.[1] The allylic alkylation[2] holds a alkylation of monosubstituted allylic substrates, in some
prominent position due to its high versatility as the cases with excellent results. In all these reactions,
products can easily be further transformed and func- including those catalyzed by palladium, a soft stabilized
tionalized in a variety of ways. Moreover, it is possible to carbon nucleophile such as a malonate anion is used.
alkylate the substrate by two distinct pathways Hard organometallic-based nucleophiles, in order to
(Scheme 1). Direct displacement leads to a (SN2) directly introduce simple alkyl groups, have been used
substitution whereas the alternative pathway leads to only to a limited extent in asymmetric allylic alkylation
substitution at the g position (SN2'). When the substrate reactions with palladium.[3,10]
has different substituents at the a and g positions of the
allylic moiety, the two pathways lead to different substitution with hard or soft nucleophiles.[3,11] In a
products. palladium-catalyzed reaction the soft nucleophile will
Distinct mechanisms are proposed for nucleophilic
Control of the regio- and stereochemistry has been the approach the allyl moiety from the opposite side of the
focal point in research on the transition metal-catalyzed coordinated metal ion (path a), whereas in allylic
allylic alkylation and, in particular, the development of a alkylations with hard nucleophiles initial addition to
highly enantioselective version has enjoyed widespread the transition metal is followed by reductive elimination
attention in recent years.[3] A variety of chiral Pd (path b) (Scheme 2).[11]
catalysts has shown excellent enantioselectivities with
Nickel complexes have been used as catalyst in an
acyclic[3b] and cyclic[3d] substrates substituted identically enantioselective allylic alkylation with hard nucleo-
at both a and g positions. The formation of optically philes and although in some cases good selectivities have
active branched products from monosubstituted allylic been achieved with cyclic[12] and acyclic[13] substrates, in
substrates, where the two regioisomeric products are general the results have been disappointing.
Scheme 1.
Scheme 2.
Adv. Synth. Catal. 2004, 346, 413 420
DOI: 10.1002/adsc.200303207
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Anthoni W. van Zijl et al.
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Cu-catalysts have shown to be good candidates for
highly selective allylic substitution reactions with hard
nucleophiles,[14] but surprisingly, the enantioselective
copper-catalyzed allylic alkylation has not been studied
extensively.[15] B‰ckvall and van Koten et al. reported
the first asymmetric copper-catalyzed allylic alkyla-
tion,[16a] with Grignard reagents, using chiral thiolate
ligands, reaching enantioselectivities up to 64%.[16]
More recently the enantioselectivities could be im- Scheme 3.
proved using phosphites[17] and phosphoramidites[17b] as
chiral ligands.
Asymmetric copper-catalyzed allylic alkylations using Results and Discussion
dialkylzinc reagents[18] and chiral amine ligands resulted
in very high selectivities,[19] but only if the very bulky The relatively high enantiomeric excess obtained with
dineopentylzinc was used, as with diethylzinc only 44% simple dialkylzinc reagents was a major incentive to
ee was reached.
further improve our system for the allylic alkylation. To
Hoveyda and co-workers developed peptide-derived achieve maximum selectivity it was, however, necessary
Schiff base ligands and achieved up to 75% ee in to perform the reaction at a constant temperature of
the copper-catalyzed allylic alkylation of cinnamyl À 408C, because the enantioselectivity of the reaction
phosphates with diorganozinc reagents.[20a] The allylic turned out to be temperature dependent.[22] At that
alkylation of unsaturated esters with a phosphate temperature the reaction proceeds rather slowly, even
leaving group at the g position led to ees as high as with 5 mol % of catalyst, and in addition the melting
97%.[20b]
point of diglyme prevented further cooling to improve
Employing a ligand library, based on chiral sulfona- selectivity.[23]
mides,[21] enantioselectivities up to 88% were reached in
Preliminary experiments exploring the use of differ-
desymmetrization reactions of cyclic meso compounds ent copper salts for the allylic alkylation of cinnamyl
with two phosphate leaving groups in the allylic bromide 1a with diethylzinc showed that the use of
positions.[21b]
CuOTf[24] resulted in a higher asymmetric induction
Our group reported the copper-catalyzed asymmetric than CuBr¥ Me2S.[22] At À 40 to À 108C in diglyme,
allylic alkylation with dialkylzinc reagents and phos- CuBr¥ Me2S provides 2a with 64% ee and the use of
phoramidite ligands.[22] Using CuBr¥ Me2S in the pres- CuOTf resulted in 69% ee and a similar product ratio.
ence of ligand 4, cinnamyl bromide 1a could be alkylated Furthermore, it was found that THFas solvent improved
with high regioselectivity (84:16) and good enantiose- the SN2':SN2 ratio to 75:25 compared to a ratio of 57:43
lectivity (77%) (Scheme 3).
in diglyme. Therefore, further investigations with THF
We now report improved conditions for this allylic as solvent and CuOTf as copper salt were carried out.
alkylation, which result in higher reactivity, regioselec- The reactions were performed at À 408Cin the presence
tivity and enantioselectivity. Furthermore the scope of the catalyst prepared in situ from 1 mol % of CuOTf
with respect to substrates and dialkylzinc reagents was and 2 mol % of ligand 4. First a few variations in the
extended using this new procedure.
addition of diethylzinc were examined (Table 1).
Table 1. Variations in the addition of Et2Zn in Cu-catalyzed alkylation of cinnamyl bromide.
Entry
Reagent (solvent)
Yield [%][a, b]
SN2':SN2[a] (2:3)
ee [%][a]
1
2
3
4
5
Et2Zn (in hexanes)
Et2Zn (in toluene)
Et2Zn (neat)
96
96
92
96
86
85: 15
85: 15
85: 15
85: 15
85: 15
67
64
55
69
77
Et2Zn (in hexanes)[c]
Et2Zn (in hexanes)[c, d]
[a]
Determined by GC.
[b]
[c]
[d]
Product, remainder is starting material.
Reverse addition of starting materials.
Reaction performed at À 608C.
414
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Table 2. Screening of phosphoramidite ligands in the asymmetric Cu-catalyzed allylic alkylation.
Entry
Ligand (config.)[a]
Ref.[b]
Yield [%][c, d]
SN2':SN2[c] (2:3)
ee 2a [%][c]
Config. 2a
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
4 (Sa,R,R)
5 (Sa,S,S)
6 (Sa,R,R)
7 (Sa,S,S)
8 (Sa,R)
[26]
[26]
96
97
70
74
87
96
67
49
92
92
93
37
95
66
76
94
87
96
95
94
88
95
7
85: 15
79: 21
92: 8
69
30
60
75
48
0
58
30
24
39
7
43
82
45
65
20
3
(S)
(S)
(S)
(S)
(S)
[26]
e
94: 6
[27]
[27]
[26]
89: 11
78: 22
90: 10
90: 10
83: 17
82: 18
91: 9
84: 16
91: 9
91: 9
83: 17
89: 11
92: 8
91: 9
90: 10
91: 9
9 (Sa,S)
10 (Sa,S)
11 (Sa,R)
12 (Sa,S)
13 (Sa,S)
14 (S,S)
(S)
(S)
(S)
(S)
(R)
(R)
(S)
(R)
(S)
(S)
(R)
(R)
(S)
(S)
(S)
(R)
(S)
(R)
(S)
[27]
[e]
[e]
[e]
15 (S,S)
[28]
[27]
[27]
[27]
[29]
[29]
[29]
[29]
[29]
[30]
[30]
[30]
[30]
[30]
16 (Sa,R,R)
17 (Ra,S,S)
18 (Sa,R,R)
19 (R,R)
20 (R,R)
21 (R,R)
22 (R,R)
23 (R,R)
24 (Ra,Ra)
25 (Ra,Ra)
26 (Ra,Ra)
27 (Sa,Sa,S,S)
28 (Ra,Ra,S,S)
8
14
23
14
12
33
8
91: 9
89: 11
92: 8
90: 10
91: 9
98
94
5
[a]
Bidentate ligands 24 28 added in 1 mol %.
Reference to ligand preparation.
Determined by GC.
Product, remainder is starting material.
Ligand not reported before (see Supporting Information).
[b]
[c]
[d]
[e]
The reaction of cinnamyl bromide in THF at À 408C ligands used are depicted in Scheme 4. The results are
with diethylzinc as a hexane solution proceeded faster summarized in Table 2.
than in the original procedure, providing 2a/3a in 96%
Monodentate phosphoramidites 4 13[26,27] with a
yield after 18 h (Table 1, entry 1). Et2Zn as a toluene BINOL backbone (Table 2, entries 1 10) afforded 2a/
solution or neat Et2Zn did not improve the results 3a in yields that were generally, although not always,
(Table 1, entries 2 and 3), but on reverse addition[25] of good. The C C bond formation was always in favor of
À
the starting materials a small enhancement of ee was the SN2' product, with regioselectivities up to 94:6;
observed. Decreasing the temperature to À 608C re- although the enantioselectivities obtained by applying
sulted in an ee of 77%.
these ligands were highly varying. A ligand backbone
The finding that at À 608C and in the presence of only with(S)configurationleadstothe(S)configurationinthe
1 mol % catalyst 77% enantioselectivity is reached and product, but the type and configuration of the amine
still the reaction proceeds much faster than in our groupcanhavealargeinfluenceontheenantioselectivity.
original procedure, shows that a significant improve-
A few other monodentate ligands 14 18[27,28] with
ment has been reached and that allylic alkylation in THF N,N-bis(1-phenylethyl)amine attached to different
using CuOTf as the copper source is superior to the one backbones were subsequently screened (Table 2, entries
in diglyme with CuBr¥ Me2S.
11 15). The three ligands with aBINOL-type backbone
Using the improved reaction conditions, a screening gave similar results to the former ligands. The ligands
for more selective phosphoramidite ligands was exe- with a catechol (14, entry 11) and biphenyl (15, entry 12)
cuted. All reactions were performed at À 408C and the backbone are the only ligands in which the configuration
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Anthoni W. van Zijl et al.
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of the amine dictates the configuration of the product, cyclohexyl-substituted allylic bromides 1f and 1g were
but the low enantioselectivities actually show the applied. The results are summarized in Table 3.
necessity of a more bulky chiral backbone.
Good yields were obtained for the different para-
TADDOL-based phosphoramidites 19 23[29] as li- substituted cinnamyl bromides after 18 h (Table 3,
gands afforded 2a/3a in excellent yields and high entries 1 4). Due to volatility of the products, only
regioselectivities (around 90:10) (Table 2, entries 16
20). Unfortunately, low asymmetric induction was and 2c/3c (Table 3, entries 1 and 2). The less volatile
observed with all these ligands. compounds 2d/3d and 2e/3e, in contrast, were obtained
moderate isolated yields (54%) were obtained for 2b/3b
Bidentate BINOL-derived phosphoramidite ligands in 71% and 83% yield, respectively (Table 3, entries 3
24 28[30] were also used as ligands in the allylic and 4). The regio- and enantioselectivities obtained for
alkylation of cinnamyl bromide with diethylzinc (Ta- para-substituted cinnamyl bromides were similar. Using
ble 2, entries 21 25). Again, high yields and very good Pd[4a,32] and Ir[6a] catalysts, the regioselectivity was
2a/3a ratios (around 90:10) were obtained except for strongly dependent on the electronic properties of the
ligand 26 (Table 2, entry 23), which gave an unexpected para-substituents. In contrast, when using chiral Cu
low yield. The enantioselectivities found for the biden- catalysts on distinct substituted cinnamyl substrates, the
tate phosphoramidite ligands are remarkably low.
regioselectivity was found to be fairly constant, but then
In general monodentate phosphoramidites with a the enantioselectivity varied considerably.[17b,20a] It is
BINOL-type backbone are the most effective ligands therefore quite striking that both regio- and enantiose-
for this reaction. The best results were obtained with lectivity are constant in the present system.
ligand 4 and the new ligands 7 and 16 (Scheme 4). Using
Surprisingly, in case of naphthyl substituted allylic
ligand 7, 74% yield, an excellent ratio of 94:6 and an ee bromide 1f only 26% ee was observed using ligand
for 2a of 75% was found (Table 2, entry 4). It is 16. Ligand 4 resulted in a lower regioselectivity
interesting to note that 7, which has an (Sa,S,S) config- but a higher enantioselectivity of 67% was found
uration, gives better selectivities than its diastereomer, (Table 3, entry 6). In the allylic alkylation with cyclo-
which points to an opposite matched-mismatched effect hexyl substituted allylic bromide 1g, using ligand 16, the
to the other ligands, where the (Sa,R,R) or (Sa,R) is the ee found for 2g was only 53%, pointing to a considerable
matched diastereomer.[31] The reaction with bromide 1a effect of the nature of the R substituent in the allylic
and diethylzinc in the presence of CuOTf and 16 affords substrate.
2a/3a in 95% yield and aratio of 91:9 (Table 2, entry 13).
Subsequently, different diorganozinc reagents, includ-
The asymmetric induction improved to 82% and ing Et2Zn, i-Pr2Zn and n-Bu2Zn, were used to alkylate
because this is the highest enantioselectivity yet ob- cinnamyl bromide 1a at À 608C (Table 4). In the case of
served, further experiments were conducted using this diethyl- and dibutylzinc the yield was somewhat lower
ligand.
due to a slower reaction (entries 1 and 3), but the
A number of different allylic bromides were used as alkylation with diisopropylzinc reached full conversion
substrates in the copper-catalyzed allylic alkylation. within 18 h (entry 2). The SN2':SN2 ratio was excellent in
Cinnamyl bromide derivatives with different electron- all cases and similar high ees (86 88%) for all three
withdrawing substituents 1b e and naphthyl- and products were found.
Table 3. Different allylic bromides applied in the asymmetric Cu-catalyzed allylic alkylation.
Entry
R
Ligand
Yield [%][a, b,c]
SN2':SN2[a] (2:3)
ee 2b g [%][a, d]
1
2
3
4
5
6
7
p-Cl-C6H4
1b
1c
1d
1e
1f
1f
1g
16
16
16
16
16
4
81 (54)
89 (54)
98 (71)
91 (83)
98 (77)
96 (n.d.)
89 (57)
91: 9
91: 9
93: 7
91: 9
96: 4
88: 12
90: 10
78
77
77
81
26
67
53
p-CF3-C6H4
p-NO2-C6H4
p-MeO2C-C6H4
1-Naphthyl
1-Naphthyl
Cyclohexyl
16
[a]
Determined by GC.
Product, remainder is starting material.
Isolated yield in parentheses.
[b]
[c]
[d]
Branched products likely to have (S) configuration based on GC.
416
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Highly Enantioselective Copper-Catalyzed Allylic Alkylation
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Scheme 4. Chiral phosphoramidite ligands applied in Cu-catalyzed allylic alkylation.
As expected, lowering the temperature to À 608C tivity was also enhanced. Quite striking is the enantio-
raised the enantioselectivity as was observed with ligand selectivity, being independent of the nature of the Zn
4 (entry 5, Table 1), but with ligand 16 the regioselec- reagent, which holds promise for the applicability of a
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Anthoni W. van Zijl et al.
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Table 4. Different diorganozinc compounds applied at lower temperature in asymmetric Cu-catalyzed allylic alkylation.
Entry
R2Zn
Yield [%][a, b]
SN2':SN2[a] (2:3)
ee [%][a]
1
2
3
Et2Zn
i-Pr2Zn
n-Bu2Zn
74
94
58
93: 7
97: 3
91: 9
86
88
87c
[a]
Determined by GC.
Product, remainder is starting material.
Branched product likely to have (S) configuration based on GC.
[b]
[c]
(HRMS) were recorded on an AEI MS-902. HPLC analyses
were performed on a Waters 480 with an LC spectrophotom-
eter or a Waters 600E system controller with a Waters 991
photodiode array detector using different chiral columns that
are specified where necessary. 1H NMR, 13C NMR and
31P NMR spectra were recorded on a Varian Gemini-200
(50.32 MHz), Varian 300 (75.48 MHz) or Varian 500
(125.80 MHz) spectrometer in CDCl3. Chemical shift values
are denoted in d units (ppm) relative to residual solvent peaks
(CHCl3, d ˆ 7.24 ppm for protons, d ˆ 77 ppm for carbon
atoms and external H3PO4, d ˆ 0.0 ppm for phosphorus
atoms). GC measurements were performed either on an HP
5890 A, an HP 5890 series II or an HP6890 gas chromatograph
with flame ionization detector using different columns that are
specified where necessary.
large range of dialkylzinc reagents. Also interesting to
note is the fact that the higher reactivity of diisopropyl-
zinc does not hamper the selectivity, in fact, the reaction
is even slightly more selective than in the other cases,
giving 2h with high regioselectivity (97:3) and excellent
enantioselectivity (88% ee).
Conclusion
We have considerably improved the catalytic system for
the enantioselective copper-catalyzed allylic alkylation
with dialkylzinc reagents by changing the solvent and Cu
salt to THFand CuOTf, respectively, and employing the
new ligand 16.
We also showed that this system allows electronically
different substituted cinnamyl substrates to be alkylated
with equal selectivities, but that sterically distinct
substrates are likely to need a different ligand. Several
diorganozinc reagents can also be used with constant
high regio- and enantioselectivities, although the reac-
tivities differ somewhat.
The enantioselectivities are the highest achieved so
far in the copper-catalyzed allylic isopropylation and n-
butylation and especially for the n-butylation of allyl
halides the new catalytic system represents a substantial
improvement.
General Procedure for the Enantioselective Allylic
Alkylation
Under an argon atmosphere phosphoramidite ligand
(0.02 mmol,) and (CuOTf)2 ¥ C6H6 (0.01 mmol CuOTf) were
dissolved in 5 mL of THF and stirred for 10 min at room
temperature. After cooling the solution to the appropriate
temperature the allylic bromide (1 mmol) was added.[33] After
5 min R2Zn (1M in hexane, 1.2 mL, 1.2 mmol) was added and
the reaction mixture was stirred at the reported temperature
for 18 h. The reaction was quenched with 1 M aqueous H2SO4,
and the separated aqueous layer was extracted twice with
diethyl ether. The combined organic layers were treated with
Detailed mechanistic studies on the enantioselective brine, dried over MgSO4 and concentrated under vacuum.
copper-catalyzed allylic alkylation are currently in
progress.
(‡)-(S)-3-Phenyl-1-pentene (2a)
Purification by column chromatography (SiO2, ether/pentane,
Experimental Section
1:50, Rf ˆ 0.8) gave 118 mg (81%) of a mixture of 2a and 3a as a
colorless oil. NMR experiments were performed on the
mixture of products, but only data of the branched product
General Remarks
2a are given. [a]2D2: ‡ 40.48 (c 2.7, C6H6) with 58% ee (according
All solvents were reagent grade and were dried and distilled
before use. All solvents were stored under nitrogen. All
reactions were carried out under an argon atmosphere using
dried glassware (standard Schlenk procedures). Chromatog-
raphy: silica gel Merck Type 9385 230 400 mesh, TLC: silica
gel 60, Merck, 0.25 mm. Optical rotations were measured on a
Perkin-Elmer 241 MC (at room temperature). Mass spectra
to chiral GC). Proof of stereochemistry: literature value [a]2D2:
‡ 35.08 (c 6, C6H6)[34] is assigned to the (S) enantiomer with
61% ee. 1H NMR (200 MHz): d ˆ 7.32 7.18 (m, 5H), 5.95 (m,
1H), 5.02 (m, 2H), 3.14 (m, 1H), 1.70 (m, 2H), 0.87 (t, J ˆ
7.2 Hz, 3H); 13C NMR (200 MHz): d ˆ 144.4, 142.2, 128.3,
127.6, 126.1, 114.0, 51.7, 28.3, 12.1; MS (EI) for C11H14:
‡
m/z ˆ 146 (M) . Determination of the ee of 2a was performed
418
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Highly Enantioselective Copper-Catalyzed Allylic Alkylation
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by GC on a CP-Chiralsil-Dex CB, 25 m  0.25 mm column, He
flow 1.0 mL/min, isothermic 758C, tr ˆ 39.8 min for (R)-2a;
tr ˆ 40.5 min for (S)-2a.
124, 7256; bisoxazolines: d) F. Glorius, A. Pfaltz, Org.
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[8] a) J. M. Brown, J. E. MacIntyre, J. Chem. Soc. Perkin
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[9] T. Hayashi, A. Okada, T. Suzuka, M. Kawatsura, Org.
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General procedures and preparation of 2b, 2c, 2d, 2e, 2f, 2 g, 2 h
and 2i; synthesis of allylic bromides 1b, 1c, 1d, 1e, 1f and 1 g;
general procedure for preparation of phosphoramidite ligands
7, 12, 13 and 14.
[10] The highest enantioselectivity in a Pd-catalyzed allylic
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We thankIng. M. van Gelder for assistance with the GC and
HPLC analyses. Financial support from the Dutch Ministry of
Economic Affairs (EET project) and the Dutch Organisation
for Scientific Research (NWO-CW) is gratefully acknowledged.
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