Chiral diamine-copper(I) complexes as asymmetric catalysts in the enantioselective addition of phenylacetylene to imines

Article abstract of DOI:10.1055/s-2005-869896

The stereoselective addition of phenyl acetylene to imines, catalysed by chiral bis-amine-Cu(I) complexes was studied. The chiral ligands are either commercially available or easily prepared in one or two steps. This very convenient and extremely simple e

Full text of DOI:10.1055/s-2005-869896

SPECIAL TOPIC
1689
Chiral Diamine-Copper(I) Complexes as Asymmetric Catalysts in the
Enantioselective Addition of Phenylacetylene to Imines
C
S
opper(I)-Cat
i
alysed
m
Enantioselective
A
d
o
dition of Phe
n
nylacetylene
e
to Iminestta Orlandi, Federica Colombo, Maurizio Benaglia*
Centro di Eccellenza CISI, and Dipartimento di Chimica Organica e Industriale, Universita’ degli Studi di Milano, via Golgi 19,
0133 Milano, Italy
2
Fax +39(0250)314159; E-mail: maurizio.benaglia@unimi.it
Received 24 March 2005
We have recently demonstrated that enantiomerically
pure bis-imines copper(I) complexes are efficient cata-
lysts in the direct addition of phenyl and alkyl acetylene to
Abstract: The stereoselective addition of phenyl acetylene to im-
ines, catalysed by chiral bis-amine-Cu(I) complexes was studied.
The chiral ligands are either commercially available or easily pre-
pared in one or two steps. This very convenient and extremely sim-
1
3
imines. Copper(I) triflate complexes of enantiomerically
ple experimental procedure at room temperature allowed optically pure bis-imines derived from (R)-binaphthyl diamine
active propargyl amines to be obtained in good yields with enantio- have been shown to catalyse the formation of optically ac-
selectivities up to 70%.
tive propargyl amines at room temperature often in very
Key words: chiral bis-amines, copper complexes, propargyl- good yields and ee values of up to 81%.
amines, enantioselective catalysis, acetylene addition
Following our interest in developing new chiral Cu(I)
14
complexes in asymmetric catalysis, we decided to inves-
tigate the use of enantiomerically pure diamines as ligands
for the copper(I)-promoted addition of phenyl acetylene
Optically active propargylamines are synthetically versa-
tile intermediates for the construction of many biological-
15
to imines. We wish to report here the preliminary results
1
ly active nitrogen compounds and key intermediates for
of our study.
the synthesis of polyfunctional amino derivatives.2
In a series of explorative experiments, we found that
among the commercially available enantiomerically pure
Among the several synthetic methodologies available for
3
the preparation of these useful structures, the addition of
C -symmetric primary diamines, in our reaction condi-
2
an organometallic reagent to chiral imine derivatives still
tions, only (R)-binaphthyl diamine gave a complex with
4
represents an important method. However, the develop-
copper(I) triflate showing interesting catalytic proper-
ment of efficient catalytic enantioselective methods for
the preparation of enantiomerically enriched propargyl-
amines is a very appealing synthetic alternative.
16
ties. With only 10 mol% of catalyst, generated simply by
mixing an equimolar amount of copper triflate and (R)-bi-
naphthyl diamine, it was possible to promote the phenyl
5
While several catalytic methods are known to promote the acetylene addition to N-phenyl benzaldehyde imine (8), in
reaction of acetylenes with aldehydes in very high yields dichloromethane, to give the propargyl amine 9 in quanti-
6
and enantioselectivities, only very recently a few differ- tative yield and 45% ee. Among different solvents exam-
ent organometallic systems were reported to catalyse the ined, the catalytic system performed better in toluene
formation of enantiomerically enriched propargyl amines (Table 1, entry 3), where the product was obtained in
by employing acetylenic derivatives. Hoveyda and quantitative yield and 67% ee.
7
Snapper used a Zr(IV) complex in the presence of a chiral
The temperature seems to influence the reaction rate, but
amino acid-based ligand. Li developed a Cu(I) complex of
not the enantioselectivity of the process. Running the re-
8
pyridyl-bisoxazoline able to promote direct alkyne-imine
action at 0 °C lowered the yields (87% vs 99% in CH Cl ,
2
2
9
addition in toluene and in water. Knochel described the
and 47% vs 99% in toluene), but the enantioselectivities
remained virtually unchanged (Table 1, entry 1 vs 5, entry
addition of functionalised alkynes to enamines catalysed
by Cu(I) salts complexed to quinap, a mixed P,N-chiral
ligand. Lately Carreira developed a new atropisomeric
P,N ligand (pinap), structurally related to quinap, that
showed a similar reactivity and stereochemical efficiency
in promoting the CuBr-catalysed three-component
3
vs 6).
Among the different copper(I) salts tested, copper trifluo-
romethanesulfonate out-performed any other, affording
the product always with the highest enantioselectivity.
The use of chiral diamines as ligands in asymmetric catal-
ysis opens the attractive possibility to ultilise aqueous sol-
vents.17 Interestingly the binaphthyl diamine/copper(I)
complex was able to promote the reaction also in a tolu-
ene–water (9:1) mixture, affording the product 9 in very
good yield (91%) but diminished ee (Tables 1, 36% vs
1
0
reaction among dibenzylamine, an aldehyde and various
1
1
acetylenes. Finally, Jiang reported zinc acetylides addi-
tion to reactive ketoimines in the presence of a chiral ami-
1
2
no alcohol under mild reaction conditions.
6
7%, entry 4 vs 3).18
SYNTHESIS 2005, No. 10, pp 1689–1692
x
x.
x
x
.
2
0
0
5
Advanced online publication: 18.05.2005
DOI: 10.1055/s-2005-869896; Art ID: C03405SS
Georg Thieme Verlag Stuttgart · New York
©

1
690
S. Orlandi et al.
SPECIAL TOPIC
F5
R
R
R'
N
NH2
NH2
N
H
H
N
N
H
H
N
H
H
N
R'
F5
1
2
3
4
5
R = H
R = OH
R = OMe
6
7
R' = COCH3
R' = CH CH
2
3
Ph
Ligand 1–7 / Cu(OTf)
N
HN
Ph
H
8
9
Scheme 1 Chiral bis-amines employed in the Cu(I)-promoted addition of phenylacetylene to N-phenylbenzaldehyde imine (8).
Secondary amines were also tested as chiral ligands with Ligands 2–7 all showed a modest catalytic efficiency in
copper trifluoromethanesulfonate in the phenyl acetylene promoting the reaction, affording the product in the best
addition to imines. Ligands 2–5 were easily prepared by case with 55% yield (Table 1, entry 11, ligand 7). A free
1
9
13
20
reduction of the corresponding imines; ligand 6 was OH group on the ligand affects detrimentally its catalytic
obtained by reaction of diamine 1 with acetyl chloride; fi- ability (Table 1, entry 8); a methoxy group is tolerated,
nally, reduction of 6 with LiAlH afforded diamine 7 in but it has a negative influence on the stereoselectivity of
4
very high yield.
the process (Table 1, entry 9, 51% yield, 15% ee vs 67%
ee for entry 3). In any case the enantioselectivities were
very modest and clearly lower than those obtained with
the primary chiral diamine 1.
Table 1 Phenylacetylene Addition to Imine 8 Catalysed by Chiral
Bis-Diamine/Cu(I) Complexes
To further study the general applicability of this new cat-
alytic system, the methodology was then extended to dif-
ferently substituted imines (Scheme 2). The catalytic
system worked with imines modified both at the N-resi-
due or at the C-residue, affording products 16–21 in yields
from modest to excellent, and enantioselectivities up to
Entry Solvent
Catalyst
10 mol%)
Yield
(%)
ee
(%)
a
b
(
1
2
CH Cl2
1/Cu(OTf)
1/Cu(OTf)
1/Cu(OTf)
>99
25
45
14
67
36
41
67
<5
n.d.
15
<5
23
2
CH CN
3
7
0% (Table 2).
Toluene
>99
91
Substituents at the N-phenyl residue seem to have a nega-
tive effect on the enantioselectivity and sometimes on the
chemical efficiency as well of the process (Table 2, en-
tries 2 and 3). However, substituents are well-tolerated on
4
Toluene–H O (9:1) 1/Cu(OTf)
2
5c
6c
7
CH Cl2
1/Cu(OTf)
1/Cu(OTf)
2/Cu(OTf)
4/Cu(OTf)
5/Cu(OTf)
6/Cu(OTf)
7/Cu(OTf)
87
2
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
47
43
X
X
NH2
NH2
/
CuOTf
H
Ph
8
17
9
51
N
HN
Ph
1
0
43
Y
1
1
55
Y
a
1
Determined by H NMR on the crude reaction mixture and con-
1
0–15
1
6–21
firmed by silica gel flash column chromatography.
Determined by HPLC on a chiral stationary phase, DAICEL Chiral-
b
Scheme 2 Cu(I)-promoted addition of phenylacetylene to different-
ly substituted imines.
cel OD, hexane–i-PrOH, 95:5.
c
The reaction was run at 0 °C for 72 h.
Synthesis 2005, No. 10, 1689–1692 © Thieme Stuttgart · New York

SPECIAL TOPIC
Copper(I)-Catalysed Enantioselective Addition of Phenylacetylene to Imines
1691
the C-phenyl residue, with ee values constantly higher Phenylacetylene Addition to Imines; Typical Procedure
2
1
In a typical experimental procedure, Cu(OTf) (0.02 mmol) was add-
ed to a toluene solution (2 mL) of the chiral ligand (0.02 mmol) at
r.t. under a nitrogen atmosphere. After stirring for 10 min, imine 8
than 53% obtained (Table 2, entries 4–6).
It is worth mentioning that the diamine 1/Cu(I) complex
was also able to promote the addition of 4-bromophenyl (0.2 mmol) and phenylacetylene (0.3 mmol) were added. The reac-
acetylene to imine 8 to give the corresponding propargyl tion mixture was allowed to stir for 72 h at r.t., then it was filtered
through celite and purified by flash chromatography, if necessary.
amine in 33% yield and 51% ee.
For example, for compound 9:
1
Table 2 Phenylacetylene Addition to Imines 10–15 Catalysed by
/Cu(I)-Complex
H NMR: d = 7.77 (d, J = 8 Hz, 2 H), 7.40–7.30 (m, 5 H), 7.30–7.20
1
(m, 5 H), 6.80 (m, 3 H), 5.55 (s, 1 H), 4.05 (br s, 1 H).
Entry
X
Y
Product Isolated yield ee
a
b
(
%)
(%)
Acknowledgment
1
2
3
4
5
6
H
H
9
16
17
18
19
20
21
>99
>99
<10
>99
31
67
This work was supported by MIUR (Progetto Nazionale Stereosele-
zione in Sintesi Organica. Metodologie ed Applicazioni) and
C.I.N.M.P.I.S. (Consorzio Interuniversitario Nazionale Metodolo-
gie e Processi Innovativi di Sintesi).
H
4-OMe
27
H
2-OMe
n.d.
53
2-OMe
4-OMe
4-Me
2-Cl
H
H
H
H
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1
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(
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(
(
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4
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2
2
2
(
(
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(
1
H NMR: d = 7.33–7.00 (m, 8 H), 7.00–6.80 (m, 6 H), 6.70–6.50 (m,
6
H), 6.55 (br s, 2 H), 6.50 (br s, 2 H), 4.05 (s, 2 H), 3.90 (A proton
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Synthesis 2005, No. 10, 1689–1692 © Thieme Stuttgart · New York

1
692
S. Orlandi et al.
SPECIAL TOPIC
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(
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2
18% ee).
6
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(
Synthesis 2005, No. 10, 1689–1692 © Thieme Stuttgart · New York