Catalyst-controlled reverse selectivity in C-C bond formation: NHC-Cu-catalyzed α-selective allylic alkylation with organolithium reagents

Article abstract of DOI:10.1039/c5cc01521a

An efficient and highly α-selective copper-catalyzed allylic alkylation of allylic halides with organolithium reagents is presented. The use of N-heterocyclic carbenes as ligands is key to reverse the common γ-selectivity of this transformation and gives rise to the corresponding linear products with high levels of regioselectivity.

Full text of DOI:10.1039/c5cc01521a

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Catalyst-Controlled Reverse Selectivity in C-C Bond
Formation: NHC-Cu-Catalyzed α-Selective Allylic
Alkylation with Organolithium Reagents
Cite this: DOI: 10.1039/x0xx00000x
Stefano F. Pizzolato,a Massimo Giannerini,a Pieter H. Bos,a Martín Fañanás-
Mastral*a,b and Ben L. Feringa*a
Received 00th January 2012,
Accepted 00th January 2012
DOI: 10.1039/x0xx00000x
www.rsc.org/
regiocontrol could be achieved due to the particular nature of the
leaving group and by careful choice of the copper salt.10 Hoveyda
and coworkers showed cases of α-selective Cu-catalyzed allylation
with allenyl- and vinyl-boronic esters.11
An efficient and highly α-selective copper-catalyzed allylic
alkylation of allylic halides with organolithium reagents is
presented. The use of N-heterocyclic carbenes as ligands is
key to reverse the common
and gives rise to the corresponding linear products with high
levels of regioselectivity
γ-selectivity of this transformation
The development of general Cu-mediated α-AA methodology
under strict catalytic control using simple allyl bromides remains an
important goal. As part of our research program toward direct
catalytic cross-coupling reactions of organolithium reagents,12,13 we
explored Cu-catalyzed α-allylic alkylation with these highly reactive
organometallic reagents. Organolithium reagents represent a highly
valuable class of compounds in organic chemistry due to their low
cost, versatility and ease of preparation.14 However, their
applicability in catalytic transformations has been limited by their
intrinsic high reactivity. Recently, we described the first general γ-
selective Cu-catalyzed asymmetric AA with organolithium reagents
(Scheme 1a).12a Based on a judicious choice of the reaction
conditions (low temperature, slow addition of the organolithium
reagents, non-polar solvent) and of the catalytic system (CuBr·SMe2,
diphosphine or phosphoramidite ligand) notorious side product
formation can be avoided and the γ-selective reaction proceeds with
excellent levels of chemo-, regio- and enantioselectivity. As the
reactivity of organolithium reagents is highly dependent on the
solvent,14,15 it is desirable to design a Cu-catalyzed α-selective AA
by a simple catalyst variation and not by a change of solvent or
reaction conditions, which could lead to the formation of undesired
side products.
.
Complete control over the product distribution of a catalytic
reaction, i.e. catalyst-controlled selectivity, is a major goal in organic
synthesis.1 Besides chemo-, enantio- and diastereoselectivity, the
control over regioselectivity is an important parameter in catalyst
design.2 Ideally, depending on the synthetic demand, regioselectivity
should be switchable by simple catalyst modifications in reactions in
which the substrate can undergo competing regiodivergent pathways.
The nucleophilic displacement with allylic substrates, i.e. allylic
substitution, represents
a clear example of a regiodivergent
transformation.3 Unsymmetrical allylic compounds feature two
distinct reactive sites (α and γ position) susceptible to either SN2 or
SN2’ type nucleophilic displacement.
Different transition metals have been used to catalyze the allylic
substitution reaction.4 Among them, Pd and Cu are probably the
most common ones for the formation of C-C bonds. Pd-catalyzed
allylic alkylation (AA) has proven to be very effective for the
formation of the α-substituted product, mostly used in combination
with stabilized nucleophiles.5 Cu-catalyzed AA is characterized by
the use of non-stabilized organometallic reagents and usually
proceeds with high γ-selectivity.6 A myriad of enantioselective
versions of the Cu-catalyzed asymmetric allylic alkylation has been
α
-selective AA
b) (this
γ
work)
-selective AAA
12a)
a)
(ref
+
R2Li
R1
Br
CuBr•SMe
mol%)
developed, covering
a wide range of allylic systems and
2 (5
CuBr•SMe
mol%)
2 (5
or
organometallic reagents.6 In spite of these findings, Cu-catalyzed α-
selective AA have been rarely reported.7-11 Specifically, changing
the reaction conditions (solvent, copper salt, ligand, temperature)
and leaving group led, in a number of cases, to an inversion of the
regioselectivity giving rise to the formation of mainly the α-
substituted product.7-9 In 1990 Bäckvall and co-workers studied the
diphosphine
ligand
phosphoramidite
mol%)
CH2Cl2, -80 °C
NHC
mol%)
ligand
(5.5
(5.5
CH2Cl2, -80 °C
R2
R1
R2
to >99:1
R1
α
α
:
γ
up
:
γ
to >99:1
up
e.r.
to 99:1
up
regiocontrol in Cu-catalyzed AA with Grignard reagents8 and Scheme 1 Catalyst-controlled regioselectivity in Cu-catalyzed AA
subsequently reported an α-selective AA for the synthesis of α- with organolithium reagents.
methyl substituted carboxylic acids.9 Recently, Wu and coworkers
specifically developed an α-selective Cu-catalyzed allylic alkylation
Herein we present catalytic methodology for the Cu-catalyzed α-
with Grignard reagents of phosphorothioate esters in which total selective AA of allylic halides with organolithium reagents (Scheme
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1b). The reaction affords functionalized linear allylic products in is also important to note that the nature of the heterocyclic carbene
high yields and represents an efficient and selective catalytic C(sp3)- (imidazolium vs. imidazolinium) does not have an influence on the
C(sp3) cross-coupling method for these highly reactive compounds.16 outcome of the reaction Finally, the use of the diphenyl-substituted
Bidentate or highly hindered NHC ligands have been used in the NHC L9 also led to excellent levels of regioselectivity (entry 10).
field of Cu-catalyzed asymmetric γ-selective AA with
organometallic reagents.17-20 However, based on our experience with
Table 2 Ligand Screening.
CuBr.SMe2 5
organolithium reagents12 and the anticipated key role of the
mol%
nBu
mol%
L
5.5
electronic nature of the ligand in determining the regioselectivity of
the allylic alkylation, we reasoned that the use of a strong σ-donating
carbene21 ligand could affect the course of the reaction. We started
our investigation applying the same conditions previously reported
for the asymmetric γ-selective AA of allyl bromides with
organolithium reagents12a using CuBr·SMe2 in CH2Cl2 at -80 °C to
establish solely the effect of the ligand modification on the reaction.
Imidazolium salt L1 (see Table 2) was treated with NaOtBu to
generate the free carbene ligand in situ. Interestingly the reaction of
1a showed a completely inverted regioselectivity with the linear
product 2a being dominant (Table 1, entry 1, α:γ = 95:5). This data,
compared with the results arising from various reactions in the
absence of ligand (Table 1, entry 2), copper salt (entry 3) or both
(entry 4), showed that, due to the extreme reactivity of alkyllithium
reagents, the combination of copper with the carbene ligand is
essential for achieving the high α-selectivity and preventing the
formation of multiple side products.22
nBu
nBuLi
1.5
+
Ph
+
Br
Ph
Ph
CH2Cl2 80 oC
,
-
1a
2a
3a
equiv
X
X
R
N
R
N
N
N
R
BF4
R
=
N
=
=
=
=
=
L1:
L2:
L6:
L7:
R
R
Adamantyl, X BF4
R
R
Mes, X Cl
N
i
=
=
=
=
=
=
BF4
X
BF4
2-( Pr)C6H4,
X
Cy,
L3: R
X
L8: R
iPr)
Cl
=
=
2C6
H3, X
Mes,
i
Cl
2,6-(
=
L4:
L5:
R
R
2-( Pr)C6H4, X Cl
iPr) C H3, X Cl
L9
=
2,6-(
2
6
Entrya
2a:3ab
Entrya
6
7
2a:3ab
85:15
95:5
L
L
1c
2
95:5
95:5
98:2
92:8
95:5
L1
L1
L2
L3
L4
L5
L6
L7
L8
L9
3
4
5
8
94:6
9c
10
70:30
98:2
a
Reaction conditions: 0.3 mmol of 1a, 0.015 mmol of CuBr·SMe2 and 0.0165 mmol of
L in 2 ml of dry CH2Cl2 cooled at -80 oC. nBuLi (0.45 mmol, 1.6 M in hexane) diluted
Table 1 Role of Cu complex and NHC ligand in the α-selective AA
of allyl bromides with organolithium reagents
with dry hexane (final conc. 0.45 M) added over 3 h. Reaction mixture stirred for 2 h at -
c
80 oC. b Determined by GC and 1H-NMR analysis. Carbene ligand was preformed
Cu salt /
nBu
ligand
NaOtBu
using 0.0165 mmol of NaOtBu .
Ph
Ph
Ph
nBuLi
1.5
Ph
nBu
product
Ph
+
+
+
Br
Ph
CH2Cl2, 80 oC
-
1a
equiv
α−
γ−
product
4
2a
Ph
3a
Having established the optimized conditions (see SI for further
details), we set out to explore the scope of this Cu-catalyzed α-
selective AA. We chose the readily available ligand L2 as it showed
excellent selectivity during the ligand screening. This α-selective AA
protocol proved to be very efficient for a variety of organolithium
reagents. Both long and short alkyllithium reagents were suitable
reagents for the cross-coupling with cinnamyl bromide 1a (Table 3,
entries 1-5). secBuLi could also be used providing high
regioselectivity (entry 6). Substrates bearing different electron
withdrawing groups also react with total regioselectivity giving rise
to the corresponding linear products 2 in very good yields in all
cases (entries 7-10). Importantly, no traces of side products resulting
from halogen/lithium exchange were observed when aromatic
halides were used (entries 7 and 8). The chemoselectivity of this
system was further tested using the ester containing substrate 1e. It
should be emphasized that no 1,2-addition to the ester took place and
only the corresponding linear product was obtained when ligand L7
was used, thus showing the high activity of the catalytic system
(entry 10). The same ligand was optimal for the catalytic cross-
substitution
products
Homocoupling
products
Allylic
Entrya
Cu Salt
CuBr·SMe2
CuBr·SMe2
-
-
Ligand
Conv. (%)b
full
full
80
2a:3a:4b
95:5:-
73:17:10
49:18:33
48:16:36
1
L1
-
L1
-
2c
3d
4e
83
a
Reaction conditions: 0.015 mmol (5.0 mol%) of CuBr·SMe2, 0.0165 mmol (5.5 mol%)
of L1 and 0.0165 mmol (5.5 mol%) of NaOtBu in 1 mL of dry CH2Cl2 cooled at -80
C.
A solution of 0.3 mmol of 1a in 1 mL of dry CH2Cl2 added to the cooled mixture. nBuLi
(0.45 mmol, 1.6 M in hexane) diluted with dry hexane (final conc. 0.45 M) added over 3
h. Reaction mixture further stirred for 2 h at -80 oC. b Determined by GC and 1H-NMR. c
L1 and NaOtBu omitted. d CuBr·SMe2 omitted. e CuBr·SMe2,L1 and NaOtBu omitted.
̊
Encouraged by the excellent selectivity shown by ligand L1, we
examined a series of commercially available imidazolinium or
imidazolium salts bearing different substituents at the nitrogen atoms
(Table 2). First of all, we could further simplify the procedure
exploiting the basicity of the organolithium compounds. By slowly
n
coupling of BuLi with electron rich o-OMe-substituted cinnamyl
n
adding BuLi to a mixture of copper salt, imidazolium salt L1 and
bromide 1f (entry 11) and functionalized allyl bromides 1g and 1h
(entries 12 and 13). In the latter cases a slight decrease in the
regioselectivity was observed but complete chemoselectivity
remained. The alkylation of alkyl-substituted allyl bromide 1i
proceeded with lower selectivity but still led to preferential α-
substitution when ligand L9 was used (entry 14). Finally, the α-
selective AA of the less reactive allyl chlorides is illustrated by the
reaction between cinnamyl chloride 1j and nBuLi (entry 15),
affording the corresponding linear product with excellent selectivity.
We also studied the Cu-catalyzed α-selective AA of Z-cinnamyl-
substrate 1a, we obtained 2a without any erosion of selectivity, thus
avoiding the use of NaOtBu (entries 1 and 2). This result shows that
the formation of the carbene takes place before any other process
happens in the reaction medium. The screening showed that the use
of ligands bearing alkyl substituent at the nitrogen atoms led almost
exclusively to the formation of the linear product 2a (entries 1-3). In
particular the use of CuBr·SMe2 and L2 gave SN2 product 2a with
98% selectivity in 78% isolated yield (vide infra). A significant
effect of steric hindrance was observed when ligands bearing aryl
substituents were used. While the reaction was still highly α-
selective when mesityl- (L3 and L6, entries 4 and 7) and 2-
isopropylphenyl (L4 and L7, entries 5 and 8) substituted ligands
were used, ligands bearing the bulkier 2,6-diisopropylphenyl group
showed a decrease in regioselectivity (L5 and L8, entries 6 and 9). It
n
n
bromide 1k using both BuLi and HexLi (Scheme 2). Remarkably,
the reaction proceeded in both cases without isomerization of the
double bond as the Z/E ratio of the starting material remained
unaltered in the product.23
2 | J. Name., 2012, 00, 1-3
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Table 3 Reaction scope.
allyl complex B which competes with product formation (Scheme
3).24a Assuming the formation of a SN2’ σ-allyl complex A in our
catalytic system,6,25,26,27 the complete absence of isomerization might
suggest a very fast rearrangement to a π-allyl intermediate C. This
rearrangement would be faster than reductive elimination which is
probably slowed down by the electron-rich character of the carbene
ligand,28 thus precluding the formation of the SN2’ product. Further
isomerization of C and reductive elimination would give rise to the
linear product 2. A direct SN2 reaction has also to be considered as
an explanation for the observed retention of olefin geometry.29 The
role of the ligand is pivotal in dictating the selective delivery of the
alkyl unit on the α-allylic position (as previously highlighted, see
Table 1, the reaction performed without the presence of ligand L1
proceeds with low selectivity).
CuBr.SMe2 5
mol%
mol%
R1
L
5.5
Ligand
R1Li
+
R
R1
+
R
X
R
CH2Cl2, -80 °C
2
3
1
Yield
(%)c
Entrya
1
R1
2:3b
1
L
Br
nBu
98:2
78
L2
1a
1a
1a
1a
1a
1a
2
Et
iBu
96:4
97:3
98:2
91:9
90:10
60
L2
L2
L2
L2
L9
3
76
4
nHex
Me
secBu
70
5d
6
99e
50f
I
H
[CuI]-R
O.A.
[Cu
]
Br
[CuIII
]
R
III
R.E.
R
Ph
Ph
R
Ph
Ph
1k
Br
[CuIII
]
[Cu
]
Ph R
2o-p
7
8
9
nBu
nBu
nBu
98:2
98:2
98:2
86
86
75
R.E.
A
C
[CuI]
L2
L2
L2
1b
1c
1d
Cl
Br
H
Ph
R
Br
Br
Br
Ph
R.E. Ph
Ph
Ph
H
[CuIII
]
[CuIII
]
[Cu]
[CuIII
R
]
R
R
R
=
L2
Cu
[CuI]
B
Scheme 3 Mechanistic pathways in allylic alkylation.
F3C
MeO
In conclusion, we have been able to reverse the regioselectivity of
the Cu-catalyzed AA of allyl halides with organolithium reagents by
using a catalyst comprising of CuBr·SMe2 and an NHC ligand. The
reaction affords linear allylic products with excellent regioselectivity
in high yields, thus representing an efficient and selective catalytic
C(sp3)-C(sp3) cross-coupling of these highly reactive compounds.
Furthermore, the catalytic system exhibits a remarkable functional
group tolerance (ether, ester, halide) and allows the alkylation of
both E and Z allyl halides without any olefin isomerization.
10g
nBu
99:1
72
L7
1e
O
Br
11
12
nBu
nBu
98:2
83
90
L7
L7
1f
O
BnO
Br
85:15
1g
O
7
13g
nBu
90:10
72h
O
Br
L7
1h
Notes and references
Br
14
15
nBu
nBu
75:25
94:6
95
85
L9
L9
a
1i
Stratingh Institute for Chemistry, University of Groningen, Nijenborgh
4, 9747 AG, Groningen (The Netherlands); e-mail: b.l.feringa@rug.nl.
Cl
b
1j
Present address: Center for Research in Biological Chemistry and
a
Reaction conditions: see Table 2. b Determined by GC and 1H-NMR analysis. c Yield
Molecular Materials (CIQUS), University of Santiago de Compostela,
15782 Santiago de Compostela (Spain); e-mail: martin.fananas@usc.es.
The Netherlands Organization for Scientific Research (NWO-CW),
National Research School Catalysis (NRSC-C), Ministry of Education
Culture and Science (Gravitation program 024.601035) are acknowledged
for financial support.
d
e
f
of isolated product. MeLi was diluted with dry toluene. Conversion. Racemic
product was obtained using chiral ligand L9. g 1.05 equiv of nBuLi was used. h Yield of
isolated linear product.
CuBr.SMe2 5
mol%
:
=
=
Z E 94:6
mol%
L2
5.5
Ph
Ph
Ph
:
nBuLi
1.3
94:6
α:γ
+
+
CH2Cl2, -80 o
C
Electronic Supplementary Information (ESI) available: General
procedures, optimization tables, experimental and spectroscopic data for
all compounds. See DOI: 10.1039/c000000x/
nBu Yield: 77%
Br
equiv
2o
1k
=
Z E 94:6
CuBr.SMe2 5
mol%
mol%
:
=
=
Z E 86:14
α:γ
L2
5.5
Ph
nHexLi
1.3
93:7
nHex Yield: 63%
CH2Cl2, -80 o
C
1
J. Mahatthananchai, A. M. Dumas and J. W. Bode, Angew. Chem.
Int. Ed., 2012, 51, 10954-10990.
Br
equiv
2p
1k
:
=
Z E 86:14
Reaction conditions: see Table 2. Z:E and α:γ ratios determined by GC and 1H-NMR
analysis. Yield of isolated product.
2
3
B. M. Trost, Science, 1983, 219, 245-250.
(a) B. M. Trost and D. L. van Vranken, Chem. Rev., 1996, 96, 395-
422; (b) R. M. Magid, Tetrahedron, 1980, 36, 1901-1930.
(a) E. N. Jacobsen, A. Pfaltz and H. Yamamoto, Comprehensive
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(b) Z. Lu and S. Ma, Angew. Chem. Int. Ed., 2008, 47, 258-297. (c)
U. Kazmaier, Transition Metal Catalyzed Allylic Substitution in
Organic Synthesis, Springer-Verlag, Berlin, 2012.
Scheme 2 Olefin geometry retention in the Cu-catalyzed α-selective
AA of Z-cinnamyl-bromide 1k.
4
5
Interestingly, isomerization of cis-double bonds has been
observed in previous examples of Cu-mediated α-selective allylic
alkylation of cinnamyl substrates.24 The double bond isomerization
was proposed to arise from an initial SN2’-selective formation of a σ-
allyl complex A and a subsequent C-C bond rotation leading to π-
(a). B. M. Trost and M. L. Crawley, Chem. Rev., 2003, 103, 2921-
2944; (b) A. Pfaltz and W. J. Drury, Proc. Natl. Acad. Sci. USA 2004,
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For reviews see: (a) Karlström, A. S. E.; Bäckvall, J. E. in Modern 17 For selected examples using Grignard reagents see: (a) M. Magrez,
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11 Developing Cu-catalyzed γ-selective allylic alkylation methodologies
with organoboron compounds, Hoveyda and coworkers found
variable amounts of linear product by employing monodentate NHC- 20 For Cu-free asymmetric allylic alkylation with Grignard reagents
ligands in combination with allenyl and vinyl boronic esters: (a) B.
Jung and A. H. Hoveyda, J. Am. Chem. Soc., 2012, 134, 1490-1493;
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12 For examples of Cu-catalyzed asymmetric AA with organolithium
47-82.
reagents, see: (a) M. Pérez, M. Fañanás-Mastral, P. H. Bos, A. 22 A complex mixture of products was always obtained when other
Rudolph, S. R. Harutyunyan and B. L. Feringa, Nat. Chem., 2011,
3
,
solvents were used in the absence of copper complex. See Supporting
Information for further details.
377-381; (b) M. Fañanás-Mastral, M. Pérez, M.; P. H. Bos, A.
Rudolph, S. R. Harutyunyan and B. L. Feringa, Angew. Chem. Int. 23 In preliminary studies, a Z:E = 68:32 mixture of o-methoxycinnamyl
Ed., 2012, 51, 1922-1925; (c) P. H. Bos, A. Rudolph, M. Pérez, M.
Fañanás-Mastral, S. R. Harutyunyan and B. L. Feringa, Chem.
Commun., 2012, 48, 1748-1750; (d) M. Pérez, M. Fañanás-Mastral,
bromide was converted into a Z:E = 68:32 mixture of the
corresponding alkylated linear product, with a regioselectivity of α:γ
= 97:3. See Supporting Information for further details.
V. Hornillos, A. Rudolph, P. H. Bos, S. R. Harutyunyan and B. L. 24 (a) H. L. Goering and S. Kantner, J. Org. Chem., 1983, 48, 721-724;
Feringa, Chem. Eur. J., 2012, 18, 11880-11883; (e) S. Guduguntla,
(b) T. Spangenberg, A. Schoenfelder, B. Breit and A. Mann, Eur. J.
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M. Fañanás-Mastral and B. L. Feringa, J. Org. Chem., 2013, 78
,
8274-8280.
25 P.-F. Larsson, P.-O. Norrby and S. Woodward, in Copper-Catalyzed
Asymmetric Synthesis (A. Alexakis, N. Krause and S. Woodward,
Eds.), Wiley-VCH, Weinheim, 2014, Chapter 12.
13 For Pd-catalyzed cross-coupling of organolithium reagents, see: (a)
S. Murahashi, M. Yamamura, K. Yanagisawa, N. Mita and K.
Kondo, J. Org. Chem., 1979, 44, 2408-2417; (b) M. Giannerini, M. 26 (a) M. Yamanaka, S. Kato and E. Nakamura, J. Am. Chem. Soc.
Fañanás-Mastral and B. L. Feringa, Nat. Chem., 2013,
5
, 667-672; (c)
2004, 126, 6287-6293; (b) N. Yoshikai, S. L. Zhang and E.
Nakamura, J. Am. Chem. Soc., 2008, 130, 12862-12863; (c) N.
Yoshikai and E. Nakamura, Chem. Rev., 2012, 112, 2339-2372.
V. Hornillos, M. Giannerini, C. Vila, M. Fañanás-Mastral and B. L.
Feringa, Org. Lett., 2013, 15, 5114-5117; (d) M. Giannerini, M.
Fañanás-Mastral and B. L. Feringa, Angew. Chem. Int. Ed., 2013, 52
13329-13333; (e) C. Vila, M. Giannerini, V. Hornillos, M. Fañanás-
Mastral and B. L. Feringa, Chem. Sci., 2014, , 1361-1367.
14 (a) The Chemistry of Organolithium Compounds; Z. Rappoport and I.
,
27 A plausible alternative pathway could involve the formation of an
intermediate enyl[σ+π] Cu(III) complex. See reference 26a.
5
28 C. S. J. Cazin, N-Heterocyclic Carbenes in Transition Metal
Catalysis and Organocatalysis, Springer, Berlin, 2011.
Marek (Eds.), Wiley-VCH, Weinheim, 2004. (b) Lithium Compounds 29 Direct SN2 displacement without the presence of
a
Cu(III)
in Organic Synthesis; R. Luisi and V. Capriati (Eds.) Wiley-VCH,
Weinheim, 2014.
intermediate is unlikely, as even simple SN2 reactions of alkyl
halides, performed with cuprates, are still proposed to proceed
through oxidative addition to afford Cu(III) species, based on a
number of earlier studies. For mechanistic studies on Cu-catalyzed
allylic substitutions, see Ref. 26. For NMR-detection of Cu(III)-
intermediates in substitution reactions of alkyl halides with Gilman
cuprates: T. Gärtner, W. Henze and R. M. Gschwind, J. Am. Chem.
Soc., 2007, 129, 11362.
15 V. H. Gessner, C. Däschlein and C. Strohmann, Chem. Eur. J., 2009,
15, 3320-3334.
16 For representative examples of C(sp3)-C(sp3) cross-couplings of allyl
substrates with other organometallic reagents, see: (a) S. Son and G.
C. Fu, J. Am. Chem. Soc., 2008, 130, 2756-2757; (b) K. Endo, T.
4 | J. Name., 2012, 00, 1-3
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