Catalytic asymmetric alkynylation of C1-substituted C,N-cyclic azomethine imines by CuI/chiral bronsted acid co-catalyst

Article abstract of DOI:10.1002/anie.201104017

It all adds up: The title reaction was developed for the synthesis of chiral tetrahydroisoquinoline derivatives with a tetrasubstituted carbon center at the C1-position (see scheme, Bz=benzoyl, pybox=2,6-bis(2-oxazolinyl)pyridine) . The reaction was facilitated effectively by the co-catalyst system composed of copper(I)/Ph-pybox and an axially chiral dicarboxylic acid.

Full text of DOI:10.1002/anie.201104017

Communications
DOI: 10.1002/anie.201104017
Asymmetric Catalysis
Catalytic Asymmetric Alkynylation of C1-Substituted C,N-Cyclic
Azomethine Imines by CuI/Chiral Brønsted Acid Co-Catalyst**
Takuya Hashimoto, Masato Omote, and Keiji Maruoka*
Biologically active tetrahydroisoquinolines having a chiral
stereocenter at the C1-position are commonly found in nature
and also in synthetic molecules,[1] and therefore, the catalytic
asymmetric synthesis of these valuable building blocks has
been explored as a worthwhile research area during the past
decade.[2] In addition to asymmetric hydrogenation,[3] cata-
We report herein, the exploration of our alkynylation as a
novel direct catalytic asymmetric method to provide a variety
of chiral C1-alkynyl tetrahydroisoquinolines.[9] This investi-
gation led to the discovery of a highly enantioselective
alkynylation of azomethine imines catalyzed by a CuI/Ph-
pybox complex (pybox = 2,6-bis(2-oxazolinyl)pyridine). This
reaction has a remarkably broad substrate scope in terms of
the aromatic substituents of the azomethine imines and the
terminal alkynes. Although we faced the difficulty of attaining
high enantioselectivity when using C1-substituted azomethine
imines for the challenging formation of a tetrasubstituted
carbon center, this issue could be successfully overcome by
the addition of an axially chiral dicarboxylic acid, originally
developed in this laboratory,[10] as a key co-catalyst.
We commenced the study by screening the commercially
available chiral ligands that are commonly used in copper-
catalyzed asymmetric transformations, for the reaction of
C,N-cyclic azomethine imine 1a and phenylacetylene
(Table 1).[11] Among the chiral bis(oxazoline) and pybox
ligands that were examined at 20 mol% catalyst loading,
(R,R)-Ph-pybox L5 exhibited the best results, giving 2a in
90% yield with 95% ee (Table 1, entries 2–6). The amount of
the catalyst could then be decreased to 5 mol% without
compromising the yield or selectivity (Table 1, entry 7). The
choice of the copper source also had a significant impact on
À
lytic asymmetric C C bond formation by nucleophilic addi-
tion to dihydroisoquinolines or isoquinolines has been given
much attention in this regard.[4] Despite these efforts, there
has been only one early report, by Shibasaki and co-workers
in 2001, wherein dihydroisoquinolines having two different
functionalities at the C1-position (tetrasubstituted carbon
center) could be successfully generated in a catalytic asym-
metric manner.[4b] Although a decade has passed since their
pioneering discovery, no viable alternative to achieve this goal
has emerged to date.[5]
During our studies on the use of C,N-cyclic azomethine
imines (e.g. 1a; Scheme 1) in the context of catalytic
asymmetric 1,3-dipolar cycloadditions,[6] we became aware
of their unique ability to act as prochiral electrophiles to
dihydroisoquinolines. Namely, the copper-catalyzed reaction
of 1a with phenylacetylene furnished the alkynylation
product and not the [3 + 2] cycloadduct, in contrast to the
reaction of N,N’-cyclic azomethine imines, reported by Fu.[7]
Although the asymmetric alkynylation of N-alkyl and N-aryl
dihydroisoquinolinium salts has already been reported as a
comparable method by Schreiber and Taylor, and Li and co-
workers, respectively, these studies exhibited rather limited
substrate scope or only modest selectivity.[8] What is even
more important is the inability of this procedure to construct
an asymmetric tetrasubstituted carbon center; Schreiber and
Taylor only reported a racemic product, thus clearly leaving
room for further development.
Table 1: Optimization of the reaction conditions.[a]
Entry
Metal
Ligand
Yield [%][b]
[ee] [%][c]
1
2
3
4
5
6
CuOAc
CuOAc
CuOAc
CuOAc
CuOAc
CuOAc
CuOAc
CuBr
none
L1
L2
L3
L4
L5
L5
L5
L5
99
>99
43
66
74
90
99
>99
>99
–
72
45
31
52
95
96
27
4
7[d]
8
Scheme 1. 1,3-Dipolar cycloaddition versus alkynylation. Bz=benzoyl.
9
CuI
[a] Performed with 1a (0.10 mmol) and phenylacetylene (0.30 mmol) in
the presence of the copper source (0.020 mmol) and the ligand
(0.022 mmol). [b] Yield of the isolated product. [c] Determined by HPLC
analysis on a chiral stationary phase. [d] Performed with 5 mol% CuOAc
and 5.5 mol% L5. Bn=benzyl.
[*] Dr. T. Hashimoto, M. Omote, Prof. Dr. K. Maruoka
Department of Chemistry, Graduate School of Science
Kyoto University, Sakyo, Kyoto, 606-8502, (Japan)
E-mail: maruoka@kuchem.kyoto-u.ac.jp
[**] This work was partially supported by a Grant-in-Aid for Scientific
Research from the MEXT (Japan). M.O. thanks the Research
Fellowships of JSPS for Young Scientists.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201104017.
8952
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2011, 50, 8952 –8955

Table 3: Optimization of the reaction conditions for the formation of the
the enantioselectivity as observed in the use of copper
bromide and iodide (Table 1, entries 8 and 9).
tetrasubstituted carbon center.[a]
We then examined the substrate scope of this asymmetric
alkynylation, as shown in Table 2. Initially, the reaction
tolerance to the substituent on the aromatic ring of the
azomethine imines was investigated because most of the
previous reports on the catalytic asymmetric synthesis of di-
or tetra-hydroisoquinolines failed to clarify this point. C,N-
Cyclic azomethine imines bearing a methyl group at the 5-, 6-,
7-, or 8-positions could be converted into the corresponding
products with ee values ranging from 85 to 94%, thus proving
the high reaction tolerance to the position of the substituent
(Table 2, entries 1–4). In addition, this catalytic system could
also be applied to azomethine imines having either electron-
donating or electron-withdrawing functionalities on the
aromatic ring (Table 2, entries 5–8). In almost all cases, the
products could be obtained in nearly quantitative yields by
using two equivalents of the terminal alkyne. With regard to
the variation of terminal alkynes, aryl, alkenyl, alkyl, and silyl
acetylenes could be utilized to give the products in high yields
and enantioselectivities (Table 2, entries 10–18), with 2-tolyl-
acetylene and 1-heptyne being the only two exceptions
(Table 2, entries 9 and 17).
entry
ligand
(R)-5
Yield [%][b]
[ee] [%][c]
1
2
3
4
5
6
7
8
9
L5
L1
L5
L5
L5
L5
L5
ent-L5
L6
none
none
>99
trace
96
97
94
94
99
67
68
68
–
76
54
88
(R)-5a
(R)-5b
(R)-5c
(R)-5d
(R)-5e
(R)-5e
(R)-5e
94
94
À44
12
[a] Reaction conditions: 3a (0.30 mmol), phenylacetylene (0.60 mmol),
CuOAc (0.015 mmol), ligand (0.0165 mmol) and (R)-5 (0.018 mmol).
[b] Yield of the isolated product. [c] Determined by HPLC analysis on a
chiral stationary phase.
Prompted by this success, we looked at the more
challenging task of asymmetric alkynylation of C1-substituted
azomethine imine 3a, with the aim of constructing a chiral
tetrasubstituted carbon center (Table 3). Gratifyingly, the
reaction proceeded smoothly to give the alkynylated com-
pound 4a in good yield, although the enantioselectivity
remained at a moderate level (Table 3, entry 1). A re-
examination of the chiral ligands was unfruitful, as demon-
strated by the sluggish reaction when using bis(oxazoline) L1
(Table 3, entry 2). Accordingly, we then focused on the
development of an alternative strategy to improve the
enantioselectivity; this strategy took into consideration the
catalytic cycle, which likely involves an acid-base concerted
process.[12] As shown in Scheme 2, the formation of the copper
Table 2: Catalytic asymmetric alkynylation of C,N-cyclic azomethine
imines.[a]
Entry
R1
R2
Yield [%][b]
[ee] [%][c]
1
2
3
4
5
6
7
8
5-Me (1b)
6-Me (1c)
7-Me (1d)
8-Me (1e)
6-Br (1 f)
7-Br (1g)
6-MeO (1h)
7-MeO2C (1i)
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
>99 (2b)
>99 (2c)
>99 (2d)
>99 (2e)
>99 (2 f)
96 (2g)
91
94
85
90
93
94
89
89
43
94
95
90
94
91
89
90
75
96
Scheme 2. Tentative catalytic cycle.
acetylide from the terminal alkyne and copper acetate would
liberate acetic acid and this free acetic acid would protonate
azomethine imine. Thus, electrophilically activated azome-
thine imine I would then react with nucleophilic copper
acetylide. Based on the assumption of this tentative catalytic
cycle, it can be envisaged that the replacement of the role of
acetic acid by a chiral Brønsted acid would open an attractive
way to enhance the selectivity. On the assumption that a more
acidic chiral Brønsted acid, which is simply added to the
reaction flask, would exchange with acetic acid in situ without
the need for the preformation of a new copper/chiral
Brønsted acid complex, we initiated the addition of some
representative axially chiral dicarboxylic acids (R)-5 as co-
catalysts.[10,13,14] As anticipated, this investigation revealed the
high dependence of the enantioselectivity on the 3,3’-sub-
>99 (2h)
93 (2i)
9
H (1a)
2-tolyl
3-tolyl
4-tolyl
4-BrC6H4
4-MeOC6H4
cyclohexenyl
cyclohexyl
cyclopropyl
C5H11
TMS
>99 (2j)
>99 (2k)
>99 (2l)
>99 (2m)
>99 (2n)
88 (2o)
82 (2p)
>99 (2q)
94 (2r)
10
11
12
13
14
15
16
17
18
H
H
H
H
H
H
H
H
H
89 (2s)
[a] Reaction conditions: 1 (0.30 mmol), terminal alkyne (0.60 mmol),
CuOAc (0.015 mmol) and L5 (0.0165 mmol). [b] Yield of the isolated
product. [c] Determined by HPLC analysis on a chiral stationary phase.
Angew. Chem. Int. Ed. 2011, 50, 8952 –8955
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8953

Communications
stituents of the chiral dicarboxylic acids; the highest catalytic
activity could be attained by using either (R)-5d or (R)-5e
(Table 3, entries 3–7).[15] The enantioselectivity of the process
could be drastically improved from 68% ee to 94% ee, just by
adding 6 mol% of the catalyst. Owing to the greater general-
ity of (R)-5e, which became apparent in the later study, we
chose the combination of L5 and (R)-5e as the optimized
reaction conditions. Using the diastereomeric pair composed
of ent-L5 and (R)-5e as the chiral catalyst had an adverse
effect on the reactivity, and the opposite enantiomer (4a) was
obtained in diminished yield and modest ee value (Table 3,
entry 8). The role of the dicarboxylic acid was evaluated to be
supplementary, given the fact that the use of achiral pybox
ligand L6 (see, Table 1) in conjunction with (R)-5e resulted in
poor stereoinduction (Table 3, entry 9).
With the optimized reaction conditions for the formation
of the tetrasubstituted carbon center established, the sub-
strate scope of the asymmetric alkynylation of C1-substituted
C,N-cyclic azomethine imines was investigated (Table 4). A
variety of terminal alkynes could be incorporated to generate
a tetrasubstituted carbon center at the C1-position with high
enantioselectivity (Table 4, entries 1–6). Notably, the chain
length of the C1 substituent had only minimal impact on the
reactivity and selectivity (Table 4, entries 7–10). These estab-
lished reaction conditions were then applied in the alkyny-
lation of C1-unsubstituted azomethine imine 1a and 1-
heptyne, to give an improvement in the enantioselectivity
(Table 4, entry 11, for comparison, see Table 2, entry 17).
To remove the benzamide group of the products to access
chiral tetrahydroisoquinolines we performed two synthetic
applications. As shown in Scheme 3, after the hydrogenation
À
Scheme 3. N N Bond cleavage of the product.
A synthetic procedure exploiting the alkyne and the
benzamide moiety to give a tetrahydroisquinoline with an
additional stereocenter was developed using 4a as the starting
material (Scheme 4). A copper-catalyzed cyclization of 4a
proceeded to give dihydropyrazole 7, which upon hydro-
genation furnished pyrazoline 8 with modest diastereoselec-
À
tivity. Subsequent cleavage of the N N bond led to 9, thus
incorporating the amide nitrogen in the product.[16]
Scheme 4. Incorporation of the benzamide in the alkyne moiety.
In conclusion, we succeeded in developing a direct
catalytic asymmetric alkynylation using C,N-cyclic azome-
thine imines as a novel prochiral electrophile to give chiral
tetrahydroisoquinoline derivatives. The procedure estab-
lished herein offered two distinct advantages, which have
not been realized by precedents. One advantage is the broad
substrate scope with regard to both the prochiral electrophiles
and the alkynes. The other, more important advantage is the
capability to construct a tetrasubstituted carbon center at the
C1-position by applying a catalyst system composed of
copperI/pybox and an axially chiral dicarboxylic acid. To the
best of our knowledge, this is the first catalytic asymmetric
À
of the alkyne moiety of 2a, the N N bond could be easily
cleaved by SmI2 to give the tetrahydroisoquinoline 6 in 69%
(2 steps).
Table 4: Catalytic asymmetric alkynylation of C1-substituted C,N-cyclic
azomethine imines.[a]
=
reaction wherein terminal alkynes directly add to the C N
double bond to give a chiral tetrasubstituted carbon center
with high enantioselectivity.[17,18]
Received: June 12, 2011
Published online: August 10, 2011
Entry
R1
R2
Yield [%][b]
[ee] [%][c]
1
2
3
4
5
6
7
8
Me (3a)
Me
Me
Me
Me
Me
Et (3b)
Et
Bu (3c)
Bu
H (1a)
4-tolyl
97 (4b)
>99 (4c)
>99 (4d)
90 (4e)
98 (4 f)
89 (4g)
86 (4h)
84 (4i)
93
94
95
92
89
88
94
90
88
79
88
4-BrC6H4
4-MeOC6H4
cyclohexenyl
cyclopropyl
C5H11
Ph
C5H11
Ph
C5H11
Keywords: alkynylation · asymmetric catalysis ·
.
chiral brønsted acid · copper · nitrogen heterocycles
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