Asymmetric addition of arylboronic acids to cumulene derivatives catalyzed by axially chiral N-heterocyclic carbene-Pd2+ Complexes

Article abstract of DOI:10.1002/chem.201100703

Cumulene+carbene=chirality! Asymmetric additions of boronic acids to cumulene derivatives, catalyzed by an N-heterocyclic carbene-palladium complex, provide the desired allenic products in good to excellent yields and moderate to good enantioselectivities

Full text of DOI:10.1002/chem.201100703

DOI: 10.1002/chem.201100703
Asymmetric Addition of Arylboronic Acids to Cumulene Derivatives
Catalyzed by Axially Chiral N-Heterocyclic Carbene–Pd2+ Complexes
Zhen Liu, Peng Gu, and Min Shi*[a]
Cumulenes can serve as extremely versatile building
blocks for rapid construction of molecular complexity in or-
ganic synthesis, because of their unique reactivities in many
organic reactions.[1] Moreover, some natural products with a
cumulenic structure have been recently discovered.[2,3] Al-
though their novel chemical properties have been extensive-
ly explored, thus far, the applications of unsymmetrical cu-
Scheme 1. Chiral, cationic, NHC–Pd2+–diaqua complexes 1a and 1b.
Bn=benzyl, TfO=triflate.
mulene derivatives in asymmetric catalysis have not been re-
ported.[4]
Catalytic, asymmetric, conjugate addition of organoboron
reagents to activated alkenes is an efficient method for con-
struction of chiral, enantioenriched compounds by using
achiral precursors.[5] To date, several examples on addition
of organoboronic acids to allenes catalyzed by palladium
have been reported.[6a–d] Moreover, the enantioselective ad-
dition of organoboronic reagents to allenic compounds cata-
lyzed by palladium[6e–m] or rhodium[7] has also been success-
fully developed to provide chiral allylic or allenic products
in good yields and good ee values. But, to the best of our
knowledge, the use of cumulene derivatives as substrates in
this asymmetric reaction still remains unexplored. Herein,
we report the first examples of asymmetric addition of aryl-
boronic acids to cumulene derivatives catalyzed by axially
chiral, N-heterocyclic carbene (NHC)–Pd2+–diaqua com-
plexes 1a and 1b (Scheme 1).[8]
À
of arylpalladium species at the C3 C4 double bond
(Table 1, entry 1 and Scheme 4).[1a,7,9] The examination of
various bases and solvents as well as the reaction tempera-
ture revealed that this asymmetric addition reaction should
be carried out in dioxane with Et3N (2.0 equiv) at 508C, to
give 3a in 96% yield and 90% ee (Table 1, entries 2–9). The
chiral NHC–Pd complex 1b as the catalyst produced 3a in
85% yield and 88% ee under identical conditions (Table 1,
entry 10).
Table 1. Optimization of the reaction conditions of NHC–Pd-catalyzed,
asymmetric addition of phenylboronic acid to 2a.
Initially, we utilized ethyl-2-methyl-5,5-diphenylpenta-
2,3,4-trienoate 2a and phenylboronic acid (2.0 equiv) as sub-
strates in the presence of K3PO4 (5.0 equiv) as a base with
NHC–Pd-complex 1a (5 mol%) as the catalyst to examine
the reaction outcome. It was delightful to find that the inser-
Entry
T [8C]
Base
Solvent
t [h]
Yield [%][a] ee [%][b]
1
2
3
4
5
6
7
80
80
80
80
50
50
50
50
50
50
K3PO4
K2CO3
dioxane 10
dioxane 10
89
92
93
96
95
61
91
96
81
85
18 (R)[c]
40 (R)
18 (R)
82 (R)
82 (R)
18 (R)
78 (R)
90 (R)
78 (R)
88 (R)
DIPEA[d] dioxane 12
À
tion of an arylpalladium species into the C2 C3 double
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
dioxane 10
dioxane 10
THF
bond of 2a took place smoothly to afford allenic product 3a
in 89% yield and 18% ee at 808C in dioxane along with a
trace amount of achiral product derived from the insertion
24
24
toluene
8[e]
9[f]
10[e,g]
dioxane 10
dioxane 48
dioxane 48
[a] Isolated yields. [b] Determined by chiral HPLC. [c] The absolute con-
figuration was determined by X-ray diffraction of 7a. [d] DIPEA=N,N-
diisopropylethylamine. [e] 2.0 equiv of Et3N was used. [f] 1.0 equiv of
Et3N was used. [g] NHC–Pd complex 1b was used as the catalyst.
[a] Dr. Z. Liu, P. Gu, Prof. Dr. M. Shi
State Key Laboratory of Organometallic Chemistry
Shanghai Institute of Organic Chemistry
Chinese Academy of Sciences, 345 Lingling Road
Shanghai 200032 (P.R. China)
Fax : (+86)21-64166128
E-mail: Mshi@mail.sioc.ac.cn
Having established the optimal reaction conditions, we
next investigated the scope and limitations of this asymmet-
ric hydroarylation with a variety of boronic acids and cumu-
lene derivatives 2a–h. We found that the corresponding ad-
Supporting information for this article, including experimental details,
characterization data, chiral HPLC, and X-ray crystallographic files
(CIF), is available on the WWW under http://dx.doi.org/10.1002/
chem.201100703.
5796
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Chem. Eur. J. 2011, 17, 5796 – 5799

COMMUNICATION
ducts 3b–k and 3m–w were produced in good to excellent
yields (up to 95%) and good to excellent ee values (up to
94%) with aromatic boronic acids with diverse substituents
on the phenyl ring and heterocyclic 3- or 2-thienylboronic
acid (Table 2, entries 1–10 and 12–22). In the case of phenyl-
formed into interesting chiral building blocks. As shown in
Scheme 3, reduction of 3a and 3i with LiAlH4 produced 4a
and 4i in good yields. Products 4a and 4i underwent AuIII-
catalyzed cyclization to give 3,6-dihydropyrans 5a and 5i in
excellent yields along with retained chirality.[10] The six-
membered, cyclic compound 5a
could be further converted to
Table 2. NHC–Pd complex 1a-catalyzed asymmetric hydroarylation of 2a–h with various boronic acids.
the functionalized, chiral alde-
hyde 6a through ozonization to
give 92% yield and 90% ee.
These reactions can also be per-
formed on a 2.0 mmol scale,
giving 5a and 5i in similar
yields along with the same ee
values (see the Supporting In-
formation for details). The
asymmetric bromoetherification
of 4a could also be achieved to
afford product 7a in 64% yield
and 90% ee with a Pd/Cu-bi-
metallic catalytic system in the
presence of lithium bromide.
The ee value of 7a was deter-
mined after debromination
(Scheme 3).[11] The absolute
configuration of 3 was unequiv-
ocally determined by a single-
crystal X-ray structural analysis
of 7a (Figure 1, also see the
Supporting Information).
Entry
R1
R2
R3
t [h]
Yield [%][a]
ee [%][b]
1
2
3
4
5
6
7
8
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
4-FC6H4
4-FC6H4
4-ClC6H4
4-ClC6H4
4-BrC6H4
4-PhC6H4
3-Br-4-MeOC6H3
Me (2a)
Me (2a)
Me (2a)
Me (2a)
Me (2a)
Me (2a)
Me (2a)
Me (2a)
Me (2a)
Me (2a)
Me (2a)
Et (2b)
Et (2b)
Et (2b)
Ph (2c)
Me (2d)
Me (2d)
Me (2e)
Me (2e)
Me (2 f)
Me (2g)
Me (2h)
4-MeC6H4
4-MeOC6H4
4-EtC6H4
4-tBuC6H4
4-PhC6H4
4-ClC6H4
3-MeC6H4
2-naphthyl
3-thienyl
2-thienyl
2-trans-phenylvinyl
C6H5
4-PhC6H4
2-naphthyl
C6H5
4-MeOC6H4
3-MeOC6H4
C6H5
10
10
10
48
10
24
10
10
10
48
24
24
24
12
12
12
12
12
12
12
12
12
95 (3b)
87 (3c)
93 (3d)
85 (3e)
95 (3 f)
81 (3g)
88 (3h)
91 (3i)
91 (3j)
51 (3k)
67 (3l)
88 (3m)
89 (3n)
86 (3o)
83 (3p)
91 (3q)
92 (3r)
93 (3s)
92 (3t)
69 (3u)
89 (3v)
91 (3w)
93 (R)
91[c] (R)
92 (R)
92 (R)
94 (R)
87[c] (R)
92[c] (R)
92[c] (R)
88 (R)
9
10
11
12
13
14
15
16
17
18
19
20
21
22
88 (R)
50[c] (R)
91[c] (R)
88[c] (R)
84[c] (R)
78[c,d] (R)
91[c] (R)
93[c] (R)
91[c] (R)
93[c] (R)
92[c] (R)
86[c] (R)
85[c] (R)
2-naphthyl
4-MeOC6H4
4-MeOC6H4
C6H5
A plausible catalytic cycle is
outlined in Scheme 4.[1a,7,8,12]
The first step is the formation
[a] Isolated yields. [b] Determined by chiral HPLC. [c] The reaction was carried out at 808C. [d] 1.0 equiv
Et3N was used.
of [Pd
(NHC)(OH)]+ (A) from
ACHTUNGTRENNUNG
vinylboronic acid, the desired product 3l was obtained in
67% yield and 50% ee at 808C, presumably because the in
situ generated phenylvinylpalladium species is not stable
under the conditions used (Table 2, entry 11). As for 4-tert-
butylphenyl boronic acid and 2-thienyl boronic acid, the re-
actions were performed for 48 h, because these boronic
acids are not very reactive due to steric and electronic prop-
erties (Table 2, entries 4 and 10). In most cases, the reaction
was carried out at 808C. With 2 mol% of catalyst loading,
the reaction became sluggish.
the cationic [PdAHCUTNGREN(NUG NHC)ACTHUNGTRENNNUG
(H2O)2]2+ (1) in the presence of a
base. Transmetalation of arylboronic acid with palladium-
species A gives arylpalladium-complex B. The crucial step is
À
the regioselective insertion of B into the C2 C3 double
Cumulene 2i with two aliphatic substituents (R1 =Me)
completely changed regioselectivity to give the achiral prod-
uct 3x in 50% yield (Scheme 2).
The obtained, optically active, allenic products 3a–w are
synthetically useful compounds, which can be easily trans-
Scheme 2. NHC–Pd complex 1a-catalyzed hydroarylation of 2i with phe-
Scheme 3. Synthetic manipulations of chiral adducts 3a and 3i. AIBN=
nylboronic acid.
azobisisobutyronitrile.
Chem. Eur. J. 2011, 17, 5796 – 5799
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www.chemeurj.org
5797

M. Shi et al.
Concerning the formation of the achiral 3x in the case of
cumulene 2I, with two aliphatic substituents (R1 =Me), it
seems to us that the b-allenic ester is formed first, which
then suffers isomerization to the more stable conjugate
diene under the basic reaction conditions. This isomerization
is facilitated by the presence of the rather small methyl
groups at the allene terminus.[13]
In conclusion, we have developed the first examples of
asymmetric addition of arylboronic acids to cumulene deriv-
atives catalyzed by chiral, cationic, C2-symmetric, NHC–
Pd2+–diaqua complexes, affording allenic esters in good to
excellent yields and moderate to good enantioselectivities.
Further transformation of these optically active, allenic ad-
ducts to useful chiral products, with good yields and retained
chirality, have also been demonstrated. Further optimization
of this interesting catalytic system and elucidation of the de-
tailed mechanism are in progress in our group.
Figure 1. ORTEP drawing of 7a.
Experimental Section
General procedure: In a dried Schlenk
tube, catalyst (0.005 mmol), arylboron-
ic acids (0.2 mmol), cumulene deriva-
tives (0.1 mmol), and Et3N (27.7 mL,
0.2 mmol) were dissolved in 1,4-diox-
ane (1.0 mL) in an argon atmosphere.
The reaction solution was stirred at
the appointed temperature. After the
reaction had run to completion (moni-
tored by TLC), the solvent was re-
moved under vacuum and the residue
was purified by flash column chroma-
tography on silica gel eluted with ethyl
acetate/petroleum ether (1:200 v/v) to
afford the products.
Acknowledgements
We thank the National Basic Research
Program
of
China
ACHTUNGTRENNUNG(973)-
2010CB833302, and the National Nat-
ural Science Foundation of China for
financial support (21072206, 20472096,
20902019,
20872162,
20672127,
20821002, 20732008, and 20702059).
Keywords: allenic compounds ·
boronic acids
cumulene
·
carbenes
·
·
derivatives
Scheme 4. A plausible reaction mechanism.
palladium
bond of diaryl-substituted cumulene-derivatives 2a–i to give
intermediate C-I, presumably due to electronic properties.
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Chem. Eur. J. 2011, 17, 5796 – 5799

Palladium-Catalyzed Asymmetric Addition
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Received: March 8, 2011
Published online: April 18, 2011
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ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
5799