Development and application of a new general method for the asymmetric synthesis of (E)-(2-En-3-ynyl)-amines

Article abstract of DOI:10.1002/adsc.200800642

The first direct approach for the asymmetric synthesis of (E)-2-arylidene-1,4-diphenylbut-3-yn-1-amines by addition of alkynylzinc to chiral N-tert-butylsulfinylimines is reported with excellent diastereoselectivity and good yield. This asymmetric additio

Full text of DOI:10.1002/adsc.200800642

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DOI: 10.1002/adsc.200800642
Development and Application of a New General Method for the
Asymmetric Synthesis of (E)-(2-En-3-ynyl)-amines
Chao Yin,a Xin-Ping Hui,a,* Peng-Fei Xu,a,* Liang-Feng Niu,a Yong-Fei Chen,a
and Binghe Wangb
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
Department of Chemistry, Georgia State University, Campus Box 4098, Atlanta, GA 30302-4098, USA
b
Received: October 20, 2008; Revised: January 21, 2009; Published online: February 6, 2009
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adsc.200800642.
Abstract: The first direct approach for the asym-
metric synthesis of (E)-2-arylidene-1,4-diphenylbut-
3-yn-1-amines by addition of alkynylzinc to chiral
N-tert-butylsulfinylimines is reported with excellent
diastereoselectivity and good yield. This asymmetric
addition reaction provides a practical, economical
and concise synthesis of multifunctional molecules
with the 1,3-enyne side chain and an amino group.
In addition, this methodology can be applied to the
synthesis of substituted vinyl iodide compounds,
and substituted chiral dihydropyrroles.
metric synthesis of (E)-2-arylidene-1,4-diphenylbut-3-
yn-1-amines in high diastereoselectivity via the addi-
tion of alkynylzinc species to N-tert-butansulfinyl-
AHCTUNGTREGiNNUN mines, which are stable, easy to prepared, and widely
used for various applications.[5–9]
In our work, we used Ellmanꢀs enantiomerically
pure, R-configured N-tert-butanesulfinylimines, which
can be used as chiral nitrogen-containing intermedi-
ates for the preparation of a wide range of chiral
amines. The asymmetric addition of an alkynylzinc to
(R)-tert-butylsulfinylbenzaldimine (1a) led to the for-
mation of two major compounds, 2a and 3a. As
shown in Table 1, the amounts of ZnEt2 and alkyne
have a significant effect on the yield and the ratio of
2a to 3a, which increased significantly when the
amounts of phenylacetylene and diethylzinc increased
from 1 to 3 equivalents (Table 1, entries 1–3). Then,
we varied the ratio of phenylacetylene over diethyl-
Keywords: alkynes; asymmetric synthesis; cycliza-
tion; diethylzinc; N-tert-butanesulfinylimines
Multifunctional molecules with double and triple zinc (Table 1, entries 4, 5) and found that a ratio of
bonds and an amino group, such as 1,3-enynamines, 1:2.5:5 for the sulfinylimine, diethylzinc, and phenyl-
are important key building blocks for diversity-orient-
ACHTUNGTRENaNUGN cetylene gave the best results. Therefore, subsequent
ed organic synthesis; therefore, their efficient synthe- studies were conducted with 2.5 equivalents diethyl-
ses have attracted the interest of synthetic organic zinc and 5 equivalents phenylacetylene. Temperature
chemists.[1] 1,3-Enynamines were normally synthesized was also a crucial factor in this reaction. The reaction
by separate multistep processes.[1b,2] In particular, it is did not occur at ambient temperature or 608C; and it
difficult to synthesize chiral 1,3-enynamines with ste- gave a low 40% yield at 808C (Table 1, entries 6–8).
reocontrol. To the best of our knowledge, there was It was found that when the reactions were performed
only one report on the stereoselective synthesis of under reflux they gave high yield and diastereoselec-
chiral 1,3-enyne-containing a-amino acid esters, which tivity (Table 1, entries 3–5). Three solvents were ex-
were prepared by hydrogen-mediated reductive cou- amined and toluene was found to be the best choice
pling of 1,3-diynes and ethyl N-(tert-butylsulfinyl)imi- (Table 1, entries 5, 9, 10). Other additives, such as
noacetate using RhACHTUNTRGNEUNG(COD)2OTf and BIPHEP as cata- InCl3, Et2AlCl were studied; however, none of them
lysts.[3] Recently, Kazmaier, et al.[4] reported the con- worked as well as diethylzinc (Table 1, entries 11, 12).
venient synthesis of peptides containing a 1,3-enyne The reaction with dimethylzinc as additive gave lower
side chain by the Sonogashira reaction using the tran- ratios of 2a/3a and low yields (Table 1, entry 13).
sition metal catalysts Rh
ACHTUNGTREN(NUG COD)2OTf or PdACHTUNGTRENN(UGN PPh3)4. Therefore, the optimal conditions were those of
Herein, we report for the first time the efficient asym- entry 5 in Table 1, which led to the formation of 2a in
Adv. Synth. Catal. 2009, 351, 357 – 362
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357

Chao Yin et al.
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Table 1. Reaction optimization.
Entry
Additive (equiv.)
Temperature
2a/3a
Yield [%]
dr[a]
À ꢀ
Ph C CH (equiv.)
1
2
3
4
5
6
7
8
1
2
3
2
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
1
2
3
4
5
5
5
5
5
5
5
5
5
reflux
reflux
reflux
reflux
reflux
r.t.
608C
808C
reflux
reflux
reflux
reflux
reflux
10:1
28:1
34:1
50:1
50:1
N.R.
N.R.
10:1
N.R.
N.R.
N.R.
N.R.
25:1
19
65
90
87
93
–
–
40
–
–
–
–
87
>99:1
>99:1
>99:1
>99:1
>99:1
–
–
>99:1
–
–
–
9[b]
10[c]
11[d]
12[e]
13[f]
–
>99:1
[a]
1
Only one isomer was obtained and determined by H NMR (400 MHz) of the crude products.
[b]
[c]
[d]
[e]
[f]
Reaction was carried out in n-hexane.
Reaction was carried out in THF.
InCl3 as additive.
Et2AlCl as additive.
ZnMe2 as additive
high yield (93%) and excellent diastereoselectivity
(dr>99:1).
With the optimized reaction conditions in hand, a
survey of different N-tert-butanesulfinylimines was
carried out and the results are summarized in Table 2.
For the less sterically hindered 4-substituted N-tert-
butanesulfinylaldimines, excellent diastereoselectivi-
ties (dr>99:1) were achieved; however, the 2-substi-
tuted N-tert-butanesulfinylaldimines resulted in lower
diastereoselectivities except for 2-fluoro-N-tert-bu-
ACHTUNGTRENNUNGtanesulfinylaldimine. The diastereoselectivities were
excellent when aromatic and alphatic alkynes were
used (Table 2, entries 14 and 17). The addition reac-
tion to N-tert-butanesulfinylketoimine was also exam-
ined and compound 2p was not obtained; instead, N-
tert-buACHTUNGTRENNUNGtanesulfinylpropargylamine (3p) was obtained
in low yield and low diastereoselectivity (dr=87:13,
Table 2, entry 16).
The stereochemistry of the compound 2a was deter-
mined by X-ray crystallography on the basis of com-
pound 5.[10] (See Supporting Information) which was
derived from compound 2a in a two-step reaction se-
quence (Figure 1). A key feature of this methodology
is the use of the products 2 in subsequent transforma-
Figure 1. Synthesis and X-ray crystallography structure of
tions. For example, deprotection and acetylization can compound 5.
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General Method for the Asymmetric Synthesis of (E)-(2-En-3-ynyl)-amines
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Table 2. Asymmetric addition of phenylacetylene to chiral N-tert-butanesulfinylimines.[a]
Entry
R1
R3
2/3
Yield [%][b]
dr[c]
1
2
3
4
5
6
7
8
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
p-Cl-C6H4
C6H5
C6H5
n-C5H11
50:1
28:1
28:1
34:1
28:1
42:1
24:1
40:1
40:1
20:1
20:1
40:1
16:1
99:1
50:1
<1:99
25:1
93 (2a)
92 (2b)
86 (2c)
91 (2d)
88 (2e)
91 (2f)
88 (2g)
90 (2h)
86 (2i)
78 (2j)
85 (2k)
83 (2l)
60 (2m)
95 (2n)
94 (2o)
51 (3p)
81 (2q)
>99:1
>99:1
95:5
>99:1
95:5
p-CH3-C6H4
o-CH3O-C6H4
p-CH3O-C6H4
o-Cl-C6H4
m-Cl-C6H4
p-Cl-C6H4
o-F-C6H4
m-F-C6H4
o-Br-C6H4
naphthyl
n-butyl
p-Et2N-C6H4
C6H5
C6H5
C6H5
C6H5
97:3
>99:1
>99:1
>99:1
90:10
>99:1
>99:1
>99:1
>99:1
>99:1
87:13
9
10
11
12
13
14
15[d]
16[e]
17
>99:1
[a]
See Supporting Information for reaction details, R2 =H (entries 1–15); R2 =CH3 (entry 16).
Isolated yields of compound 2.
The dr values were determined by H NMR (400 MHz) of the crude materials.
(S)-tert-Butanesulfinylimine was used.
The dr value was determined on the basis of compound 3p.
[b]
[c]
[d]
[e]
1
be accomplished in high yields without loss of enan- D2O, the ratio of H to D of the double bond was 55
tioselectivity (Scheme 1).
to 45.[11] When the reaction was performed with deu-
To study the reaction mechanism, a series of experi- terated phenylacetylene and then quenched by D2O
ments was performed. There was no reaction when and H2O, the ratios of H to D of the double bond
1,4-diphenylbutanediyne and imine 1a were used as were 6 to 94 and 46 to 54, respectively.
starting materials, which indicated the 1,4-diphenylbu-
Our current hypothesis is that alkynylzinc is formed
tanediyne was not a intermediate. When we used in situ in analogy to the known chemistry of terminal
compound 3a instead of imine 1a as starting material, alkynes and dialkylzinc (Figure 2). First, the 1,2-addi-
no reaction was found which suggested the product 2a tion of alkynylzinc to 1a affords intermediate T1,
was not derived from 3a under this conditions. Then, which undergoes attack by another alkynylzinc to
we carried out deuterium labeling studies. When the form a cyclic intermediate T2.[1d,12] The carbon-zinc
reaction of 1a with phenylacetylene was quenched by and nitrogen-zinc bonds can be split by excess phenyl-
acetylene to give intermediates T3 and T3’. Then, the
reaction is quenched by H2O to give product 2a. In
support of this postulate, we examined the reactivity
of the proposed intermediate T3’, excess benzalde-
hyde was added to the reaction system after the addi-
tion reaction of alkynylzinc to N-tert-butanesulfinyl-
AHCTUNGTREGiNNUN mine was completed, the expected addition product,
compound 7 was obtained. Such results are consistent
with the formation of intermediate T3’; the N-attack
product (from T3) is an aza-hemiacetal, which is un-
stable under work-up conditions and product 2 was
Scheme 1. Conversion of the addition products.
Adv. Synth. Catal. 2009, 351, 357 – 362
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359

Chao Yin et al.
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Figure 2. Proposed mechanism.
obtained. The proposed mechanism also allows an ex- equiv.), compounds 7 and 10 were obtained in yields
planation for the predominant formation of 3p of 70% and 65%, respectively (Scheme 2). Compound
(Table 2, entry 16). In this case, the methyl group may 7 could be cyclized to compound 8 in the presence of
cause a steric hindrance problem and thus make it un- HAuCl4·4H2O; removal of the N-tert-butanesulfinyl
favorable for the formation of T2, which is essential group in 4M HCl afforded the chiral multi-substituted
for the formation of 2p.
dihydropyrrole 9 (Scheme 3).
We further exploited the utility of this methodolo-
In summary, we have successfully developed a
gy. When ZnEt2 (5 equiv.) and phenylacetylene (4 novel and direct approach for the asymmetric synthe-
equiv.) were used and the reaction mixture was sis of (E)-2-arylidene-1,4-diphenylbut-3-yn-1-amines
quenched with benzaldehyde (5 equiv.) or I2 (5 by addition of alkynylzinc to chiral N-tert-butanesul-
Scheme 2. Synthesis of compounds 7 and 10.
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Adv. Synth. Catal. 2009, 351, 357 – 362

General Method for the Asymmetric Synthesis of (E)-(2-En-3-ynyl)-amines
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Scheme 3. Gold-catalyzed cyclization of 7 to pyrrole 8.
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ACHTUNGTRENNUNGfinylimines. This asymmetric addition reaction pro-
vides a practical, efficient and concise synthesis of
multifunctional molecules, which offer attractive and
versatile reaction sites for further transformations.
The synthetic applications and the further mechanism
study for this reaction are in progress.
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Under a nitrogen atmosphere, toluene (3.0 mL), phenylace-
tylene (2.5 mmol, 275 mL) and diethylzinc (1.25 mmol,
1.25 mL) were combined in a Schlenk tube equipped with a
condenser, the reaction mixture was heated to reflux for 5 h
during which time a white precipitate was generated. Then
N-tert-butanesulfinyl imine (0.5 mmol, dissolved in 0.5 mL
toluene) was added, the solution was refluxed for another
12 h. After being cooled to ambient temperature, the reac-
tion was quenched by H2O, and extracted with diethyl ether
(3ꢂ15 mL), washed with brine (3ꢂ15 mL), dried with anhy-
drous Na2SO4, and concentrated under vacuum. The crude
product was purified by column chromatography (silica gel)
to give the products.
Acknowledgements
We are grateful for the financial support of the National Nat-
ural Science Foundation of China (NSFC 20772051,
20702022), the Program “111” and NCET-05–0880 from the
Ministry of Education of P. R. China.
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