Enantioselective alkynylation to aldimines catalyzed by chiral 2,2′-di(2-aminoaryloxy)-1,1′-binaphthyl-copper(I) complexes

Article abstract of DOI:10.1016/j.tetlet.2007.11.032

The enantioselective alkynylation of aldimines with terminal acetylenes catalyzed by chiral Cu(I) complexes with (R)-2,2′-di(2-aminoaryloxy)-1,1′-binaphthyl ligands (7) was examined. Chiral C₂-symmetric N,N-ligands 7, which have primary aniline

Full text of DOI:10.1016/j.tetlet.2007.11.032

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Tetrahedron Letters 49 (2008) 379–382
Enantioselective alkynylation to aldimines catalyzed by chiral
2,20-di(2-aminoaryloxy)-1,10-binaphthyl-copper(I) complexes
Manabu Hatano, Takafumi Asai and Kazuaki Ishihara*
Graduate School of Engineering, Nagoya University, Furo-cho, Chikusa, Nagoya 464-6603, Japan
Received 19 September 2007; revised 25 October 2007; accepted 6 November 2007
Available online 26 November 2007
Abstract—The enantioselective alkynylation of aldimines with terminal acetylenes catalyzed by chiral Cu(I) complexes with (R)-2,20-
di(2-aminoaryloxy)-1,10-binaphthyl ligands (7) was examined. Chiral C2-symmetric N,N-ligands 7, which have primary aniline
moieties, were readily prepared from inexpensive (R)-1,10-binaphthol (BINOL) as a chiral source. In particular, the reaction of
N-benzylidenebenzeneamine 1a with phenylacetylene 2a proceeded smoothly in the presence of 5 mol % of (CuOTf)2ÆC6H5CH3
and 10 mol % of (R)-7d at room temperature for 24 h, and the corresponding propargylamine 3a was obtained with up to 82% ee.
Ó 2007 Elsevier Ltd. All rights reserved.
Catalytic enantioselective addition to C@N bonds
provides a versatile method for synthesizing chiral
nitrogen-containing scaffolds in biologically active
compounds and natural products.1 In particular, prop-
argylamines (3) are some of the most important nitro-
gen-containing compounds,2 and can be obtained by
the alkynylation of aldimines (1) with terminal acety-
lenes (2) via C–H bond activation and C–C bond forma-
tion (Scheme 1).3,4 To date, a variety of chiral Cu(I or
II) complexes have been developed in these catalyses,
and chiral P,N-ligands such as QUINAP5 and PINAP6
and chiral N,O-ligands such as amino acids7 and amino
alcohols8 have been found to be effective. Chiral N,N-
ligands or N,N,N-ligands such as binaphthyldiimines9
and PYBOXes10 have also been established. Although
chiral aniline derivatives as C2-symmetric N,N-ligands
are promising ligands for activating Cu(I or II) in gen-
eral,11 examples have been limited to the pioneering
work by Benaglia et al.12 who used chiral binaphthyl-
diamine. We report here the Cu(I)-catalyzed enantio-
selective alkynylation of aldimines with terminal
acetylenes by using chiral 2,20-di(2-aminoaryloxy)-1,10-
binaphthyl ligands (7), particularly with primary aniline
moieties, which are readily prepared from inexpensive
1,10-binaphthol (BINOL) as a chiral source.
In our preliminary study, we first examined the catalytic
enantioselective alkynylation of N-benzylidenebenzene-
amine (1a) with phenylacetylene (2a) (1.5 equiv) in the
presence of 10 mol % each of Cu(OTf)2 and the com-
mercially available chiral primary N,N-ligands (4, 5,
and 6a) in CH2Cl2 at room temperature (Table 1).
(R,R)-1,2-Diphenylethanediamine (4) and (R,R)-1,2-
cyclohexanediamine (5) gave the corresponding product
(3a) in low yield in an almost racemic manner (entries 1
and 2). In sharp contrast to 4 and 5, binaphthyldiamine
(6a) showed a significant improvement in both yield and
enantioselectivity as reported by Benaglia et al.9,12 using
CuOTf (entry 3). Binaphthyldiamine-derivatives with no
N-substitutions (6b and 6c) also promoted the reactions,
although the enantioselectivities were moderate (36–48%
ee) (entries 4 and 5). However, N,N0-disubstituted bi-
naphthyldiamine derivatives such as 6d and 6e did not
work well even though they had the same axially chiral
binaphthyl backbone as 6a. Therefore, in this catalysis,
primary aniline derivatives (ArNH2) should work effec-
tively as chiral N,N-ligands, compared to other more
basic primary alkylamines (RNH2) or less basic second-
ary anilines (ArNHR0) and acidic sulfonamides
(ArNHSO2R0).13
R2
cat. Cu(I or II)
chiral ligands
R2
HN
N
R3
+
H
R1
R1
H
*
R3
1
2
3
Scheme 1. Cu(I or II)-catalyzed enantioselective alkynylations of
aldimines with terminal alkynes.
*
Corresponding author. Tel.: +81 52 789 3331; fax: +81 52 789
3222; e-mail: ishihara@cc.nagoya-u.ac.jp
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.11.032

380
M. Hatano et al. / Tetrahedron Letters 49 (2008) 379–382
Table 1. Enantioselective phenylacetynylation to 1a catalyzed by
chiral primary diamine-Cu(II) complexes
Table 2. Enantioselective phenylacetynylation to 1a catalyzed by (R)-
7ÆCu(I) complexes
Cu(OTf)2 (10 mol %)
ligand (10 mol %)
Ph
(CuOTf)2·C6H5CH3
Ph
H
HN
Ph
N
Ph
(5 mol %)
Ph
H
H
Ph
(1.5 equiv)
2a
HN
Ph
+
N
(
R)-7 (10 mol %)
H
Ph
(
S
)
CH2Cl2, rt
Ph
+
(
R
)
(1.5 equiv)
Ph
3a
1a
toluene, rt, 24 h
Ph
Ph
3a
1a
2a
Entry
Ligand
Time (h)
Yield (%)
ee (%)
Entry
Ligand
Yield (%)
ee (%)
1
2
3
4
5
6
7
4
24
24
24
24
7
26
12
99
31
100
24
5
5
0
61
36
48
0
1
2
3
4
5
6
7
7a
7b
7c
7d
7e
7f
72
89
75
73
12
34
12
73
75
71
82
37
9
5
6a
6b
6c
6d
6e
48
48
3
7g
12
Me
5
4
Ph
Ph
NH2
NH2
NH2
NH2
NH2
NH2
NH2
NH2
6
3
2
1
O
NH2
O
O
NH2
NH2
O
O
NH2
NH2
4
5
6a
6b
O
NH2
Br
Br
NH2
NH2
NHPh
NHPh
NHTf
NHTf
Me
7a
7b
7c
Cl
Cl
6c
6d
6e
F
O
O
NH2
NH2
O
O
NH2
NH2
O
O
NH2
NH2
Based on our preliminary hypothesis, we prepared chiral
primary aniline 7 with a binaphthyl backbone as C2-
symmetric chiral N,N-ligands according to the reported
procedure (Scheme 2 and Table 2).14 From commer-
cially available (R)-BINOL or (R)-H8-BINOL, 7a–g
were readily obtained in 74–>99% yields in two steps.
F
Cl
Cl
7e
7f
7d
CF3
To our delight, the catalytic enantioselective alkynyl-
ation of 1a with 2a (1.5 equiv) in the presence of
5 mol % of (CuOTf)2ÆC6H5CH3 and 10 mol % of 7a in
toluene at room temperature for 24 h gave 3a in 72%
yield with 73% ee (Table 2, entry 1). Compound 7b with
an (R)-H8-binaphthyl backbone was also effective, and
3a was obtained with 75% ee (entry 2). The effects of
Cl
O
O
NH2
NH2
Cl
CF3
7g
R
K2CO3 (2.1 equiv)
(R)-BINOL
+
DMF, 80 ˚C, 16 h
94–>99%
substitution in the aniline moiety were examined. We
found that substitution at the 5-position with an elec-
tron-withdrawing group such as Cl in 7d was better than
an electron-donating group such as Me in 7c, and we
finally obtained 3a in 73% yield with up to 82% ee (entry
4).15 Other substitutions with electron-withdrawing
groups at the 3-, 4-, or 6-position as in 7e–g did not
work well (entries 5–7).
F
NO2
(2 equiv)
R
R
O
O
NO2
NO2
O
O
NH2
NH2
Pd/C, H2 (5 atm)
THF, rt, 72 h
With the optimized conditions with (CuOTf)2ÆC6H5CH3
and 7d, we next examined the generality of the alkynyl-
ation to aldimines (1) (Table 3). Other terminal acetyl-
enes such as 1-bromo-4-ethynylbenzene (2b) and
trimethylsilylacetylene (2c) had low reactivities (0–16%
yield), although 3b was obtained with 71% ee (entries
2 and 3). Next, other aldimines (1b–e) with substitutions
at the p-position of R1 and/or R2 moieties in 1a were
R
R
7a (>99%), 7b (>99%),
7c (84%), 7d (>99%),
7e (74%), 7f (94%),
7g (82%)
Scheme 2. Preparation of chiral 2,20-di(2-aminoaryloxy)-1,10-binaph-
thyl ligand (7) with primary aniline moieties.

M. Hatano et al. / Tetrahedron Letters 49 (2008) 379–382
Table 3. Enantioselective acetynylation to aldimines 1 catalyzed by (R)-7dÆCu(I)
381
(CuOTf)2·C6H5CH3
(5 mol %)
R2
R2
H
HN
R1
N
H
R3
(
R)-7d (10 mol %)
+
R1
(1.5 equiv)
toluene, rt, 24 h
3
R3
1
2
Entry
1 (R1, R2)
2 (R3)
3
Yield (%)
ee (%)
1
2
3
4
5
6
7
8
9
1a (Ph, Ph)
1a (Ph, Ph)
1a (Ph, Ph)
1b (Ph, p-FC6H4)
1c (Ph, p-MeC6H4)
1d (p-MeOC6H4, p-ClOC6H4)
1e (p-ClC6H4, p-MeOC6H4)
1f (2-Naph, Ph)
1g (2-Furyl, Ph)
1h (Ph, Boc)
2a (Ph)
3a
3b
3c
3d
3e
3f
73
16
0
28
27 [58]a
11
19 [57]a
48
82 (R)
71
—
2b (p-BrC6H4)
2c (TMS)
2a (Ph)
2a (Ph)
2a (Ph)
2a (Ph)
2a (Ph)
2a (Ph)
2a (Ph)
48
75 [78]a
50
3g
3h
3i
74 (R) [71]a
74
33
29
56
16
10
3j
a Reactions were examined in the presence of (CuOTf)2ÆC6H5CH3 (10 mol %) and (R)-7d (20 mol %) for 48 h.
examined. The enantioselectivities were decreased to 48–
50% ee when aldimines 1b and 1d with N-R2 bearing an
electron-withdrawing group were used (entries 4 and 6).
However, good enantioselectivities (74–75% ee) were
observed for 1c and 1e when an electron-donating group
was introduced to N-R2 (entries 5 and 7). Compound
1f, which was derived from 2-naphthaldehyde,
also gave the corresponding adduct 3h in moderate yield
with good enantioselectivity (74% ee) (entry 8), while 1g,
which was derived from 2-furaldehyde, gave the corre-
sponding adduct 3i with 33% ee (entry 9). N-Boc aldim-
ine 1h gave adduct 3j in 16% yield with 29% ee. Running
the reaction for longer times (48 h) with a higher catalyst
loading (20 mol %) improved the yield and the enantio-
selectivities (see the brackets in Table 3). Products 3e
and 3g were obtained in 58% yield with 78% ee and
57% yield with 71% ee, respectively (entries 5 and 7).
Finally, we considered mechanistic aspects including
transition states in the reaction between 1a and 2a with
a (R)-7dÆCu(I) complex as a working model. In the tran-
sition states, four-coordinated Cu(I) intermediates are
postulated, and si-face attack (TS-1) should be favored
to avoid steric repulsion between aldimine 1a and the
aniline moieties of 7d (TS-2) (Fig. 1). Probably, 5-Cl
in 7d would partially have a steric and/or electronic
effect to control the aniline and naphthyl rings in a
face-to-edge relationship.16 Moreover, we cannot
completely deny the possibility that 5-Cl para to the
NH2 group effectively enhanced the Lewis acidity of
the Cu(I) center, and thus other possible transition
states that could provide the corresponding propargyl-
amine 3a with low enantioselectivities are effectively
prevented. Eventually, (R)-3a10e could be obtained with
release from the catalyst, and coordinatively unsatu-
rated active Cu(I) intermediates towards the C–H
activation of 2a would be regenerated.
Cl
In summary, the Cu(I)-catalyzed enantioselective
alkynylations of aldimines with terminal acetylenes
were achieved by using chiral 2,20-di(2-aminoaryloxy)-
1,10-binaphthyl ligands 7. The chiral N,N-ligands 7,
which have primary aniline moieties, were readily pre-
pared from inexpensive BINOL as a chiral source. In
particular, the reaction of aldimine 1a with phenylacetyl-
ene 2a proceeded smoothly in the presence of 10 mol %
each of Cu(I) precursor and (R)-7d at room temperature
for 24 h, and the corresponding propargylamine 3a was
obtained with up to 82% ee in 73% yield. Further studies
towards other catalytic enantioselective reactions
including the process of C–H bond activation/C–C bond
formation are in progress.
NH2
O
Cu
N
O
Ph
(R)-3a
H2N
H
Cl
si-face
TS-1 (favored
)
Cl
re-face
H
NH2
O
(S)-3a
Cu
N
O
Ph
Acknowledgments
H2N
Cl
Financial support for this project was provided by
Grant-in-Aid for Young Scientists B (19750072) of
MEXT, Toray Science Foundation, and Toyoaki Scho-
larship Foundation.
TS-2 (disfavored
Figure 1. Proposed transition states.
)

382
M. Hatano et al. / Tetrahedron Letters 49 (2008) 379–382
6. Kno¨pfel, T. F.; Aschwanden, P.; Ichikawa, T.; Watanabe,
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Lett. 2004, 45, 8705; (b) Colombo, F.; Benaglia, M.;
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Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/j.tetlet.
2007.11.032.
References and notes
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15. Representative reaction procedure (Table 2, entry 4):
(CuOTf)2ÆC6H5CH3 (25.8 mg, 0.05 mmol) and (R)-2,20-
di(2-amino-5-chlorophenoxy)-1,10-binaphthyl (7d) (53.7
mg, 0.10 mmol) were mixed in a pyrex Schlenk tube at
room temperature under nitrogen atmosphere. To the
mixture was added freshly distilled and well-degassed
toluene (10 mL), and this solution was stirred for 30 min at
that temperature. Then, phenylacetylene (2a) (153.2 mg,
1.5 mmol) and N-benzylidenebenzeneamine (1a) (181.2
mg, 1.0 mmol) were added, and the mixture was stirred
at room temperature for 24 h. The resulting mixture was
then filtered through a pad of Celite and purified by neutral
silica gel column chromatography (eluent: hexane/EtOAc),
to give the desired propargylamine (3a) in 73% yield
(206.9 mg). The enantiomeric purity was determined by
HPLC on chiral column (OD-H) (82% ee, R).
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