Alkylzinc-mediated addition of alkynes to N-tosylaldimines: enantioselective synthesis of (E)-(2-En-3-ynyl) -amines

Article abstract of DOI:10.1002/adsc.200900219

An alkylzinc-mediated simple and efficient procedure for the catalytic enantioselective synthesis of N-tosyl-(E)-(2-en-3-ynyl)-amines has been developed. The method works well with various N-tosylaldimines and alkynes.

Full text of DOI:10.1002/adsc.200900219

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DOI: 10.1002/adsc.200900219
Alkylzinc-Mediated Addition of Alkynes to N-Tosylaldimines:
Enantioselective Synthesis of (E)-(2-En-3-ynyl)-amines
Chao Yin,a Xiu-Qin Hu,a Xin-Ping Hui,a and Peng-Fei Xua,*
a
State Key Laboratory of Applied Organic Chemistry, College of Chemistry and Chemical Engineering, Lanzhou
University, Lanzhou 730000, Peopleꢀs Republic of China
Fax : (+86)-931-891-5557; e-mail: xupf@lzu.edu.cn
Received: April 2, 2009; Published online: June 23, 2009
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adsc.200900219.
Abstract: An alkylzinc-mediated simple and effi-
cient procedure for the catalytic enantioselective
synthesis of N-tosyl-(E)-(2-en-3-ynyl)-amines has
been developed. The method works well with vari-
ous N-tosylaldimines and alkynes.
al. reported a highly enantioselective zinc/BINOL-
catalyzed alkynylation of N-sulfonylaldimines.[4m]
Recently, we have developed a novel method
wherein chiral imines 1 were used to furnish N-tert-
butylsulfinyl-(E)-(2-en-3-ynyl)-amines
2 with high
yields and enantioselectivities (Scheme 1).[10] We hy-
Keywords: alkynes; alkynylzinc reagents; asymmet-
ric synthesis; N-tosylaldimines; propargylic amines
À
The development of new methods that lead to C C
bond formation by addition of nucleophiles to reac-
tive functions, such as C=O and C=N double bonds, is
fundamentally important in chemical synthesis.[1] In
this field, the addition of an acetylenic reagent to car-
bonyl compounds or imines is one of the most impor-
tant objectives, and the resulting propargylic alcohols
or amines are versatile building blocks for the prepa-
Scheme 1. Addition of alkynes to N-tert-butylsulfinylimines.
ration of natural products, pharmaceuticals and plant pothesized that, in this process, the nitrogen-zinc
protective agents.[2] Some excellent on promotion of bond is very important, the zinc can coordinate with
the reactions of acetylenes with imines in high yields the alkyne and activate it to afford the p-complex
and enantioselectivities are known. In this context, which undergoes attack by another dialkynylzinc. Al-
the most reliable and efficient method for the prepa- though this method failed to work with two different
ration of propargylic amines is the addition of an ap- alkynes to afford diversified amines, it provided us
propriate alkynyl-metal to achiral imines or imines with an opportunity to develop a highly efficient al-
bearing chiral auxiliaries.[2b,3] The leading studies of kylzinc-mediated alkyne-imine addition. In this paper,
this kind of reaction have been carried out by Car- the catalytic enantioselective synthesis of (E)-(2-en-3-
reira et al. using zinc-mediated alkyne additions.[4] ynyl)-amines has been carried out using BINOL-type
Copper-catalyzed alkyne additions, disclosed by Li et ligands and N-tosylaldimines, and we found that the
al., also played a prominent role.[5] There have been a reaction of alkynes with N-tosylaldimine furnished N-
few examples of direct additions of alkynes to C=N tosyl-(E)-(2-en-3-ynyl)-amines in good yields and high
electrophiles, in which an Ir,[6] Zr,[7] Ag[8] or Au[9] enantiomeric excesses in the presence of dimethyl-
complex was used as a catalyst instead of a zinc or zinc. Herein, we wish to report the results.
copper complex. Recently, Bolmꢀs group has de-
First, we examined the racemic synthesis of a 2-en-
scribed the dimethylzinc-mediated addition of termi- 3-ynyl-amine. In an initial experiment, N-tosylbenzal-
nal alkynes to imines without any ligands,[4l] Pedro et dimine was added to a mixture phenylacetylene and
diethylzinc under reflux to give a mixture of 4 and 6
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Alkylzinc-Mediated Addition of Alkynes to N-Tosylaldimines
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Table 1. Addition of phenylacetylene to N-tosylbenzaldimine. (Screening of reaction conditions).
4/5[a]
4/6[a]
Yield of 4 [%]
ꢀ
Entry
Dialkylzinc (equiv.)
PhC CH (equiv.)
1
2
3
4
ZnEt2 (4)
ZnEt2 ( 4)
ZnMe2 (2)
ZnMe2 (3)
ZnMe2 (2)
ZnMe2 (2)
ZnMe2 (2)
4
8
2
3
4
4
4
–
–
1:4
4:1
>99:1
<1:99
<1:99
3:1
5:1
–
–
–
60
72
19
79
96
–
5
6[b]
7[c]
–
-
–
[a]
1
The ratio was detemined by H NMR (400 MHz).
THF as solvent.
Dioxane as solvent.
[b]
[c]
(Table 1, entries 1 and 2).[11] When ZnMe2 was used
instead of ZnEt2, the 1,2-addition product 5 was
found to be the major product (Table 1, entry 3). An
excellent result was observed for the reaction with 2
equivalents of ZnMe2 and 4 equivalents of alkyne,
and the desired product 4a was obtained in 96% yield
(Table 1, entry 5). The solvent had a strong effect on
this reaction. When the reaction was performed in
THF or 1,4-dioxane, under the same conditions only
the compound 5 was found (Table 1, entries 6 and 7).
With these conditions in hand, we turned our atten-
tion to the enantioselective addition reaction and var-
ious ligands L1–L5 were chosen. We found that the
desired products were formed with low ee values by
using L1 (19% ee) and L2 (25% ee). Then we
changed to use BINOL-type ligands, which led to in-
creased enantioselective excesses, and the best result
was obtained when the ligand L5 was used (87%
yield and 93% ee) (Table 2).
Table 2. Enantioselective addition of phenylacetylene to N-
tosylaldimine (3a). (Ligand optimization).[a]
To test the general applicability, a series of func-
tionalized N-tosylaldimines and alkynes were used.
To be delighted, as shown in Table 3, the reaction
works with a variety of aromatic and heteroaromatic
N-tosylaldimines, and with different alkynes, provid-
ing the desired products with good yields (up to 92%
yield) and high enantiomeric excesses (82–99% ee).
The sterically hindered aldimines gave higher ee
values, while benzaldimines bearing electron-rich
groups resulted in decreased enantioselectivities. For
example, o-methyl-substituted benzaldimine afforded
a 99% ee, but p-methoxy-substituted benzaldimine
gave 82% ee (Table 3, entries 3 and 8). It is more im-
portant that this method works with two different al-
kynes affording diversified amines (Table 3, en-
tries 13–15).
Entry
L
Yield [%][b]
ee [%][c]
1
2
3
4
5
L1
L2
L3
L4
L5
77
84
88
85
87
19
À25
38
20
93
[a]
The reaction was performed with 1 mmol ZnMe2 and
2 mmol alkyne.
Isolated yields.
[b]
[c]
Enantioselective excess was determined by HPLC.
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Chao Yin et al.
Table 3. Enantioselective addition of alkynes to N-tosylaldimines. (Substrate scope of alkynes and aldimines).[a]
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Entry
R1
R2
R3
Product
Yield [%][b]
ee [%][c]
1
2
3
4
5
6
7
8
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
n-C5H11
TMS
n-C5H11
Ph
Ph
7a
7b
7c
7d
7e
7f
7g
7h
7i
7j
7k
7l
7m
7n
7o
87
88
84
92
86
90
86
82
88
73
72
51
64
57
80
93
87
99
93
95
91
94
82
94
84
92
85
92
94
91
4-MeC6H4
2-MeC6H4
4-ClC6H4
2-ClC6H4
4-BrC6H4
2-BrC6H4
4-MeOC6H4
2-FC6H4
2-furyl
Ph
9
Ph
Ph
10
11
12
13
14
15
n-C5H11
TMS
Ph
n-C5H11
Ph
Ph
Ph
Ph
Ph
4-MeOC6H4
[a]
See Supporting Information for details: entries 1–12 used Method A, entries 13–15 used Method B.
Isolated yields.
The ee values were determined by HPLC.
[b]
[c]
To study the mechanism, we carried out deuterium- alkyne and dimethyzinc. First, the 1,2-addition of al-
labelling studies. When the reaction of 3a with phe- kynylzinc to 3a afforded a p-complex intermediate
nylacetylene was quenched with D2O, the ratio of H T1,[2b,4m] which underwent an attack by another alkyn-
to D of the double bond was 100:0. When the reac-
ACHTUNGTERNUNyNG lzinc to form a cyclic intermediate T2 under reflux
tion was performed with deuterated phenylacetylene conditions. The carbon-zinc bond could be cleaved by
and 3a then quenched with D2O and H2O, the ratios excess phenylacetylene to give the intermediate T3.
of H to D of the double bond were 3 to 97 and 4 to Then, the reaction was quenched with HCl to give the
96, respectively.
product 7a. (Scheme 2) In support of this postulate,
Our hypothesis is that alkynylzinc was formed in we used (S)-propargylamine 5 and 4-methoxyphenyl-
situ in analogy to the known chemistry of terminal
Scheme 2. Proposed mechanism.
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Alkylzinc-Mediated Addition of Alkynes to N-Tosylaldimines
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Scheme 3. Mechanism study.
(5 mL), extracted with diethyl ether (3ꢂ20 mL), dried over
MgSO4 and concentrated under reduced pressure. Purifica-
tion by flash chromatography on silica gel afforded com-
pounds 7m–o.
ACHTUNGTRENNUNG
acetylene as the starting materials,[4m] the amine 7o
was obtained in 86% yield. (Scheme 3)
The S configuration of the product was determined
by comparing its [a]D value with the derivative de-
scribed in the literature[10] (see Supporting Informa-
tion).
In summary, we have developed a simple and effi-
cient procedure for catalytic enantioselective synthe-
sis of N-tosyl-(E)-(2-en-3-ynyl)-amines by the alkyl-
zinc-mediated addition of alkynes to N-tosylaldimines
in excellent ee values (82–99%). In particular, this
method could be used to deal with two different al-
kynes to give diversified (E)-(2-en-3-ynyl)-amines suc-
cessfully. The synthetic applications and the further
mechanism study for this reaction are under investiga-
tion.
Acknowledgements
We thank the National Natural Science Foundation of China
(NSFC
20772051,
20702022),
the
“973”
Project
(2009CB626604) and the “111” program for financial sup-
port.
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