Regio- and stereocontrolled introduction of secondary alkyl groups to electron-deficient arenes through copper-catalyzed allylic alkylation

Article abstract of DOI:10.1002/anie.201200809

Copper-catalyzed allylic alkylation of azoles, a pyridine N-oxide, and fluoroarenes with secondary allylic phosphates proceeded under mild reaction conditions with excellent γ-E-selectivity. The reactions with enantioenriched allylic phosphates proceeded

Full text of DOI:10.1002/anie.201200809

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DOI: 10.1002/anie.201200809
Allylic Alkylation
Regio- and Stereocontrolled Introduction of Secondary Alkyl Groups
to Electron-Deficient Arenes through Copper-Catalyzed Allylic
Alkylation**
Yusuke Makida, Hirohisa Ohmiya,* and Masaya Sawamura*
Heteroarenes are important structural motifs found in many
pharmaceuticals, agrochemicals and natural products.[1]
Accordingly, the development of efficient methods for
heteroarene functionalization is important. Although there
are various methods for accessing functionalized hetero-
arenes, the C-alkylation of these species is still severely
limited in scope. Indeed, conventional methods involving
stoichiometric metalation of electron-deficient heteroarenes
followed by trapping with alkyl halides or pseudo halides are
Scheme 1. g-Selective allyl–aryl or allyl–heteroaryl couplings. LG=leav-
ing group.
generally difficult because heteroarylmetal species are unsta-
ble compared with arylmetals.[2] Friedel–Crafts-type reactions
also allow for alkylation, but these methods are only
applicable to electron-rich heteroarenes.[3] Recently, transi-
À
tion-metal-catalyzed Csp2 H functionalizations of (hetero)-
arenes, such as alkene hydro(hetero)arylations[4,5] or cou-
plings with alkyl halides,[6,7] have been introduced as new
approaches for heteroarene C-alkylation. However, even with
these methods the introduction of secondary alkyl groups is
quite difficult.[5,8] In particular, the stereocontrolled introduc-
tion of a secondary alkyl group remains underdeveloped,
although it was achieved in the intramolecular alkene hydro-
arylations of Ellman, Bergman and co-workers.[9]
generation of heteroarylcopper(I) species that are reactive in
the g-selective allyl–aryl coupling (Scheme 1b).[11]
Herein we report a Cu-catalyzed allylic alkylation of
electron-deficient heteroarenes with internal secondary
allylic phosphates, which proceeded with excellent g-regio-
selectivity and E-stereoselectivity.[12–15] This copper catalyst
system was similarly applicable to fluoroarenes. Furthermore,
the reaction of enantioenriched secondary allylic phosphates
proceeded with 1,3-anti stereoselectivity to afford the corre-
sponding alkylated (hetero)arenes with a controlled secon-
dary stereogenic center. Thus, this Cu-catalyzed alkylation is
a straightforward method for the stereocontrolled introduc-
tion of secondary alkyl groups to electron-deficient (hetero)-
arenes.
Specifically, the g-substitution reaction of 4-phenyloxa-
zole (1a; 0.6 mmol) with Z allylic phosphate 2a (0.5 mmol) in
the presence of CuCl (10 mol%) and LiOtBu (0.5 mmol) in
THF (1 mL) at 408C for 10 h afforded alkylated arene
product 3aa in 78% yield (87% conversion) with excellent
regio- (3aa/3aa’ 99:1) and stereoselectivities (E/Z > 99:1)
[Eq. (1)].[16,17] On the other hand, the reaction of the isomeric
Earlier, we reported organoboron-based PdII- or CuI-
catalyzed approaches for the allylic alkylation of arenes
(Scheme 1a).[10] High g-regioselectivity, 1,3-anti or syn ste-
reoselectivities, and broad functional group compatibilities
are all attractive features of these approaches. Therefore, the
extension of these organoboron-based approaches to the
alkylation of heteroarenes might be expected. We did not
take this approach, however, because we knew that a-
borylheteroarenes are generally unstable and difficult to
prepare. Instead, we envisioned that the base-assisted direct
cupration of heteroarenes under the conditions of Daugulis
might be effective and more straightforward for the catalytic
[*] Y. Makida, Prof. Dr. H. Ohmiya, Prof. Dr. M. Sawamura
Department of Chemistry, Faculty of Science
Hokkaido University, Sapporo, 060-0810 (Japan)
E-mail: ohmiya@sci.hokudai.ac.jp
sawamura@sci.hokudai.ac.jp
Homepage: http://barato.sci.hokudai.ac.jp/~orgmet/index.php
[**] This work was supported by Grants-in-Aid for Scientific Research (B)
and for Young Scientists (B), JSPS. We thank MEXT for financial
support in the form of a Global COE grant (Project No. B01:
Catalysis as the Basis for Innovation in Materials Science). Y.M.
thanks JSPS for scholarship support.
substrate 2a’ proceeded with slightly decreased g-selectivity
to afford 3aa and 3aa’ in a 5:95 ratio [Eq. (2)]. The slight
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201200809.
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Table 1: Cu-catalyzed allylic alkylation with 1a.[a]
difference in the regioselectivities of the isomeric substrates
indicates that the relative steric demands of the a- and
g-substituents perturb the regioselectivity to some extent.
However, these results indicate that a useful level of
g-selectivity is obtainable, even when unfavorable steric
effects are present.
Several observations concerning the optimum reaction
conditions for the reaction between 1a and 2a’, [Eq. (2)] are
to be noted: No reaction occurred when KOtBu was used as
a base or in the absence of CuCl. The use of CuOAc, CuOTf,
or CuI instead of CuCl resulted in decreased yields and
regioselectivities (70%, 12:88; 73%, 13:87; 71%, 23:77,
respectively). Also, allylic substrates with carbonate or
acetate leaving groups were not reactive at all.
Entry Arene Phosphate Product[b]
Yield
[%][c]
g/a[d]
1
2
1a
1a
2b
2c
81
73
>99:1
96:4
3
1a
2d
63
92:8
4[e]
5[f]
1a
1a
2e
2 f
45
61
>99:1
>99:1
The steric effects of the a- and g-substituents of allylic
phosphates 2 (Scheme 2) on the reactivity and regioselectivity
6
7
1a
1a
2g
2h
53
92
–
–
[a] Reaction conditions: 1a (0.24 mmol), 2 (0.2 mmol), CuCl (10 mol%),
LiOtBu (0.2 mmol) in THF (0.4 mL) at 408C for 10 h. [b] Isomeric ratio
(E/Z) >99:1. [c] Yield of isolated product. [d] Determined by 1H NMR or
GC analysis of the crude product. [e] The reaction was carried out at
608C. [f] The reaction was carried out on a 1.0 mmol scale at 608C.
esters, CF3, MeO, and Cl, were also compatible (Table 2,
entries 1–4, 6, and 9–11).
Various azole derivatives were used (Table 2).[19] The
reaction of 4-phenyloxazole derivative 1b with a CF3 sub-
stituent at the para position of the phenyl group occurred with
a high g-selectivity (97:3; entry 3). Substitution with a MeO
group (1c), however, decreased the g-selectivity to 88%
(entry 4). Benzoxazole derivatives 1d and 1e were effective
in the reaction with 2a and afforded 3da and 3ea, respec-
tively, with 96% g-selectivity (entries 5 and 6). Ring sub-
stitution with a Ph group was also tolerated at the 5-position
of the oxazole, as shown in the reaction of 1 f (entry 7). A
sulfur-containing heterocycle, 4-methylthiazole (1g), reacted
in moderate yield (60%) with excellent g-regioselectivity
(> 99:1; entry 8). The reaction between 2-(4-chlorophenyl)-
1,3,4-oxadiazole (1h) and 2a afforded 3ha in 83% yield with
95% g-regioselectivity (entry 9). The oxadiazole 1h reacted
with 2b in 96% g-selectivity (entry 10).
The method was also applicable to a pyridine N-oxide
derivative (entries 11 and 12). The reaction of 2-phenyl-
pyridine N-oxide (1i) with 2b occurred at the 6-position of the
pyridine to afford the corresponding product 3ib in high yield
(92%) with excellent g-selectivity (> 99:1; entry 11). Replac-
ing the g-Me substituent of 2b with a sterically more
demanding butyl group (2c) did not affect the excellent
g-selectivity (> 99:1; entry 12).
Scheme 2. Allylic phosphates used. TIPS=triisopropylsilyl,
TBDMS=tert-butyldimethylsilyl.
were further evaluated and the results are shown in Table 1,
entries 1–5.[18] As the g-substituent became bulkier
(Me <Bu <iBu), the regioselectivity gradually decreased
(99 > 96 > 92%) with decreasing product yields (81 > 73 >
63%; entries 1–3). On the other hand, allylic phosphates 2e
and 2 f, bearing sterically more demanding groups (iPr or
cyclohexyl) in place of the a-PhCH2CH2 substituent of 2b,
underwent the reaction with excellent g-selectivity (> 99:1;
entries 4 and 5).
Cyclic allylic phosphates also served as substrates
(Table 1, entries 6 and 7). Oxazole 1a reacted with 2-cyclo-
hexenyl phosphate (2g) to provide the product in a decent
yield (53%; entry 6). The reaction of 1a with seven-mem-
bered cyclic phosphate 2h was more effective, providing the
product in 92% yield (entry 7).
The copper-catalyzed method has also been extended to
the reaction of fluoroarenes (Table 3). Pentafluorobenzene
(1j) reacted efficiently with 2b to afford 3jb in 93% yield
with 90% g-selectivity (entry 1). The reaction of 1j with the
a-isopropyl allylic phosphate 2e showed excellent regio-
selectivity (87% yield, g/a > 99:1; entry 2). The cyclic allylic
The Cu-catalyzed allylation was applicable to a range of
heteroarenes (1) and allylic phosphates (2) as shown in
Table 2. Functional groups on 1 or 2, such as silyl ethers,
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Table 2: Cu-catalyzed allylic alkylation with various heteroarenes.[a]
Table 3: Cu-catalyzed allylic alkylation with various fluoroarenes.[a]
Entry Arene
Phosphate Product[b]
Yield g/a[d]
Entry Arene
Phosphate Product[b]
Yield g/a[d]
[%][c]
[%][c]
1
2
1a
1a
2i
2j
61
80
>99:1
>99:1
1
2b
93
90:10
2
3
4
1j
1j
2e
2g
2b
87 >99:1
3
2b
82
97:3
78
88
–
4
5
6
2b
2a
2a
55
77
50
88:12
96:4
96:4
94:6
5
2b
2e
67
92:8
7
2b
2b
52[f] >99:1
6[e]
73 >99:1
8[e]
60
83
>99:1
[a] Reaction conditions: 1 (0.24 mmol), 2 (0.2 mmol), CuCl (10 mol%),
LiOtBu (0.2 mmol) in THF (0.4 mL) at 408C for 10 h. [b] Isomeric ratio
(E/Z) >99:1. [c] Yield of isolated product. [d] Determined by 1H NMR or
GC analysis of the crude product. [e] The reaction was carried out in
toluene.
9
2a
95:5
10
11
1h
1i
2b
2b
86
92
96:4
>99:1
syn 92:8; entry 3). These results demonstrate that, despite
some erosion of enantiomeric purity, the copper-catalyzed
allylic alkylation allows the construction of a stereogenic
center at the position a to electron-deficient heteroaromatic
rings, which is rare and difficult to obtain by other methods.[9]
As shown in Table 4, entries 4–7, the reaction of fluoro-
arenes with enantioenriched allylic phosphates also pro-
ceeded with 1,3-anti stereochemistry. Specifically, the reac-
tions of pentafluorobenzene (1j) or 2,3,5,6-tetrafluoro-
pyridine (1m) with enantioenriched (S)-(Z)-2e (99% ee),
which has a-iPr and g-Me groups gave enantioenriched (R)-
(E)-3je (99% ee) and (À)-(E)-3me (95% ee) with 1,3-anti
stereochemistry (anti/syn > 98:2), respectively (Table 2,
entries 4 and 5).[20] The reaction of the fluoroarene 1k with
(S)-(Z)-2b (98% ee) also gave excellent chirality transfer
(92% ee, anti/syn 97:3; entry 6). The reaction of pentafluoro-
benzene (1j) with (S)-(Z)-2k (95% ee), which has a siloxy-
methyl group at the g-position, afforded (+)-(E)-3jk with
90% ee (anti/syn 97:3; entry 7).
The active organocopper species is likely a monoorgano-
heterocuprate ([ArCuOtBu]À) rather than a neutral organo-
copper(I) species (LnCuAr), because LiOtBu is not basic
enough to lithiate the (hetero)arenes and LiOtBu is present in
an excess relative to copper during the catalytic reaction.[22]
This assumption is also supported by the fact that the
g-regioselectivities were generally high, but not always
perfect. This rationale comes from our previous observation
that the Cu-catalyzed allyl–alkyl coupling between allylic
phosphates and alkylboranes occurred with perfect g-selec-
12
2c
60
>99:1
[a] Reaction conditions: 1 (0.24 mmol), 2 (0.2 mmol), CuCl (10 mol%), LiOtBu
(0.2 mmol) in THF (0.4 mL) at 408C for 10 h. [b] Isomeric ratio (E/Z) >99:1.
[c] Yield of isolated product. [d] Determined by 1H NMR or GC analysis of the crude
product. [e] The reaction was carried out at 608C. [f] Yield determined by NMR
analysis. Significant amounts of unidentified compounds were also detected.
phosphate 2g coupled with 1j to give the product in good
yield (entry 3). The tetrafluoroarenes 1k and 1l, bearing CF3
and MeO groups, respectively, and 2,3,5,6-tetrafluoropyridine
(1m) also served as suitable fluoroarene substrates (entries 4–
6).
The alkylation of azole derivatives with enantioenriched
allylic phosphates proceeded with 1,3-anti stereochemistry,
allowing the stereocontrolled introduction of secondary alkyl
groups (Table 4, entries 1–3). Specifically, the alkylation of
4-phenyloxazole (1a) with (S)-(Z)-2b (98% ee), which has a-
PhCH2CH2 and g-Me substituents, proceeded with 90% anti
stereoselectivity, affording (R)-(E)-3ab with 79% ee
(entry 1). More efficient chirality transfer occurred in the
reaction of 1a with (S)-(Z)-2a’ (96% ee), which has a-Me and
g-Bu substituents, giving (À)-(E)-3aa’ with 85% ee (anti/syn
94:6; entry 2).[20,21] The reaction of the oxadiazole 1h with (S)-
(Z)-2a’ (96% ee) afforded (À)-(E)-3ha’ with 81% ee (anti/
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Table 4: Chirality transfer.[a]
([ArCuOtBu]À,A). Subsequently, A forms diaste-
Entry Arene Phosphate Product[b]
Yield
[%][c]
g/a[d]
ee [%][e]
(anti/syn)
reomeric p-complexes B (path a) or B’ (path b)
with an allylic phosphate (2), in which the copper
atom is anti to the leaving group (OP). Owing to the
difference in the strength of the trans effect, iso-
mer B is more reactive than B’. Thus, the oxidative
addition of B through transition state C(TS) is
predominant. This oxidative addition affords (s-
(S)-(Z)-2b
79
(90:10)
1
2
1a
1a
40
58
>99:1
98% ee
(S)-(Z)-2a’
96% ee
85
(94:6)
95:5
enyl)copper(III) species D (enyl[s+p] complex),
g
À
which has a C Cu s bond. Finally, reductive elim-
ination of D results in forming the g-coupling
product 3-g. The occasional incomplete g-selectivity
suggests the minor involvement of path b, in which
the diastereomeric p-complex B’ leads to enyl[s+p]
complex D’, which forms the a-coupling product 3-a.
In summary, we have developed a Cu-catalyzed
allylic alkylation reaction of azoles (oxazoles, an
oxadiazole, and a thiazole), a pyridine N-oxide
derivative, and fluoroarenes with internal secondary
allylic phosphates that proceeds under mild reaction
conditions with excellent g and E-selectivities. The
reaction with enantioenriched allylic phosphates
proceeded with 1,3-anti stereoselectivity to generate
an allylic stereogenic center at the position a to the
aromatic ring. Accordingly, the Cu-catalyzed reac-
tion is a straightforward and powerful method for the
stereocontrolled introduction of secondary alkyl
groups to electron-deficient arenes.
(S)-(Z)-2a’
96% ee
81
(92:8)
3
4
5
6
1h
1j
87
87
73
88
88:12
>99:1
>99:1
94:6
(S)-(Z)-2e
99% ee
99
(>99:1)
(S)-(Z)-2e
99% ee
95
(98:2)
1m
1k
(S)-(Z)-2b
98% ee
92
(97:3)
(S)-(Z)-2k
95% ee
90
(97:3)
7
1j
91
>99:1
[a] The reaction was carried out with 1 (0.24 mmol), 2 (0.2 mmol), CuCl (10 mol%),
LiOtBu (0.2 mmol) in toluene (entries 1–3 and 5; 0.4 mL) or THF (entries 4, 6, and
7; 0.4 mL) at 408C for 10 h. [b] Isomeric ratio (E/Z) >99:1. [c] Yield of isolated
product. [d] Determined by 1H NMR or GC analysis of the crude product. [e] The ee
values were determined by chiral-phase HPLC analysis.
Received: January 30, 2012
Published online: March 13, 2012
Keywords: allylic alkylation · azoles · copper ·
.
heteroarenes · regioselectivity
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According to DFT studies by Nakamura et al. on the
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mechanism shown in Scheme 3 for the present Cu-catalyzed
reaction. The catalytic cycle is initiated by a LiOtBu-assisted
À
C H cupration of a (hetero)arene to produce a heterocuprate
À
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À
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[8] Wang and co-workers achieved secondary benzylation and
allylation of 1,3-azoles through a Cu-catalyzed reaction with
N-tosylhydrazones: a) X. Zhao, G. Wu, Y. Zhang, J. Wang, J.
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[16] Allylic alcohols with a Z configuration are readily obtainable
though Z-selective reductions of the corresponding propargylic
alcohols.
[17] To our surprise, the E-isomer of 2a showed no reactivity under
the same conditions. Partial alcoholysis of 2a to the correspond-
ing allylic alcohol was observed.
[10] For Pd- and Cu-catalyzed g-selective and stereospecific allyl–
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[18] The reaction between 1a and a Z allylic phosphate bearing an
aryl group at the g-position resulted in no reaction. Z Allylic
phosphates bearing an aryl group at the a-position were too
unstable to prepare.
[19] Reactions with imidazole derivatives were unsuccessful.
[20] See the Supporting Information for experiments to determine
the absolute configurations of (R)-(E)-3ab and (R)-(E)-3je.
[21] Evaluation of the product enantiomeric excess values for the
reactions of azole 1a with different reaction times and con-
versions confirmed that no racemization of (R)-(E)-3ab oc-
curred under the reaction conditions. This suggests moderate
diastereotopic face selectivity in the reaction between the
heteroarylcopper(I) species and the allylic phosphate. Studies
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Angewandte
Chemie
for improving the efficiency of 1,3-chirality transfer in reactions
with heteroarenes are under way.
cupration of electron-deficient arenes, see: Ref. [11], and
references therein.
[22] Treatment of 1a with LiOtBu (1:1) in THFat 408C for 1 h or 10 h
followed by quenching with D2O resulted in no deuterated
product. These results indicate that the heteroaryllithium does
not form in a meaningful amount in the Cu-catalyzed allylic
[23] a) N. Yoshikai, S.-L. Zhang, E. Nakamura, J. Am. Chem. Soc.
2008, 130, 12862 – 12863; b) M. Yamanaka, S. Kato, E. Naka-
mura, J. Am. Chem. Soc. 2004, 126, 6287 – 6293; for a review, see:
c) N. Yoshikai, E. Nakamura, Chem. Rev. 2012, DOI: 10.1021/
cr200241f.
alkylation. For
a discussion of the LiOtBu-assisted direct
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