A highly practical approach to chiral homoallylic-homopropargylic amines via aza-Barbier reaction

Article abstract of DOI:10.1016/j.tetlet.2016.03.103

The first access to chiral homoallylic-homopropargylic amine bearing two contiguous stereocenters has been well accomplished via zinc-promoted aza-Barbier reaction. N-tert-Butanesulfinyl ketimines are well-tolerated substrates, providing the tertiary amin

Full text of DOI:10.1016/j.tetlet.2016.03.103

Accepted Manuscript
A Highly Practical Approach to Chiral Homoallylic-homopropargylic Amines
via aza-Barbier Reaction
Bin-Hua Yuan, Zhi-Cheng Zhang, Wen-Jie Liu, Xing-Wen Sun
PII:
S0040-4039(16)30333-1
DOI:
http://dx.doi.org/10.1016/j.tetlet.2016.03.103
TETL 47491
Reference:
Tetrahedron Letters
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Revised Date:
Accepted Date:
17 February 2016
28 March 2016
31 March 2016
Please cite this article as: Yuan, B-H., Zhang, Z-C., Liu, W-J., Sun, X-W., A Highly Practical Approach to Chiral
Homoallylic-homopropargylic Amines via aza-Barbier Reaction, Tetrahedron Letters (2016), doi: http://dx.doi.org/
10.1016/j.tetlet.2016.03.103
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A Highly Practical Approach to Chiral
Homoallylic-homopropargylic Amines via
aza-Barbier Reaction
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Bin-Hua Yuan, Zhi-Cheng Zhang, Wen-Jie Liu, Xing-Wen Sun

1
Tetrahedron Letters
A Highly Practical Approach to Chiral Homoallylic-homopropargylic Amines via
aza-Barbier Reaction
Bin-Hua Yuan, Zhi-Cheng Zhang, Wen-Jie Liu, and Xing-Wen Sun
Department of Chemistry, Fudan University, 220 Handan Road, Shanghai 200433, P. R. China
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
The first access to chiral homoallylic-homopropargylic amine bearing two contiguous
stereocentes has been well accomplished via zinc-promoted aza-Barbier reaction. N-tert-
Butanesulfinyl ketimines are well-tolerated substrates, providing the tertiary amines in high
yields and with excellent diastereoselectivities. 3,4-Dihydro-2H-pyrroles could be prepared in
high efficiency by cyclization of the corresponding amines.
Available online
2009 Elsevier Ltd. All rights reserved.
Keywords:
aza-Barbier reaction
homoallylic-homopropargylic amine
N-tert-butanesulfinyl imine
Homopropargylic amines are widely utilized in the
construction of natural products,1 pharmaceutical molecules and
N-tert-Butanesulfinyl imines can provide unique reactivity
and stereoselectivity in various reactions and prove to be
extremely versatile chiral reagents.16 Our group has made
continuing efforts in the asymmetric synthesis of various amines
using this chiral reagent in past several years.17 We have found
that various allylzinc reagents or allylindium reagents formed in
situ could react with N-tert-butanesulfinyl imines via aza-Barbier
reaction leading to a diversity of homoallylic amines. For
example, remarkable controlled stereoselectivity reversal was
achieved in Zn-promoted allylation of N-tert-butanesulfinyl
imines by simply changing the solvent.17a Futhermore, it is worth
noting that we also reported an asymmetric propargylation of N-
tert-butanesulfinyl ketimines using 3-bromo-1-trimethylsilyl-1-
propyne to generate chiral quaternary stereocenter-containing
homopropargylic amines in good yields and with excellent
diastereoselectivities (Scheme 1a).17g Based on our previous
a wide range of heterocyclic compounds, such as pyrrolines,2,3
4
pyrroles,
piperidines,5 tetrahydropyridines,6 and other
chemicals.7 Pyrrolines are especially critical intermediates in
pharmaceutical industry since they can be conveniently
transformed to pyrroles and pyrrolidines. Accordingly,
asymmetric synthesis of homopropargylic amines has attracted
considerable attention in recent years.8 In these advancements,
addition of nucleophilic reagents to imines has been
demonstrated as an elegant approach. Nucleophilic reagents
include allenylborane,9 allenylzinc,10 allenyltin,11 allenylsilane,12
propargyl bromide,13 silylated propargyl bromide,14 etc.15
However, in most cases, the use of unstable nucleophilic reagents
or the formation of allene byproducts simultaneously in
progargylation limits their applications. On the other hand, to the
best of our knowledge, there is rare approach for the preparation
of enantioenriched homopropargylic amine bearing two
contiguous stereocenters in one-pot fashion to date. Therefore,
studies, here we report
a novel method to synthesize
homopropargylic amines bearing two contiguous stereocenters
and homoallylic units.
developing
new
method
to
build
enantioenriched
homopropargylic amines, especially for tertiary amines
containing two vicinal stereocenters, is still in high demand.
———
 Corresponding author. Tel.: +86-21-6564-2406; e-mail: sunxingwen@fudan.edu.cn

2
Tetrahedron
14
rt
2.0
0.5
82
90:10
a
Reaction was performed with imine 1b (0.20 mmol) and Zn/2a in 4 mL
THF for 24 hours unless otherwise noted. b Isolated yield. c Determined by 1H
NMR and LC-MS of the crude products. d DMF as solvent. e 4 mL of DMF
f
was used as solvent and 2 equiv of LiCl was added. 8 mL of THF as solvent.
g 2 equiv of LiCl was added.
Better diastereoselectivity (90:10) was observed when 0.5 to
2.0 equiv of water was added and 0.5 equiv of water afforded the
best yield (67%) (entries 6-8). Although reducing temperature
and concentration improved diastereoselectivity slightly, obvious
decrease of the yield were observed (entry 9-11). Besides, the
presence of LiCl in THF solvent only complicated the reaction
(entry 12). Whereafter, we increased the amount of zinc and
allylic bromide reagent 2a in order to get higher yield (entries 13
and 14). Finally, we selected entry 13 as the optimized reaction
conditions (80%, dr 90:10).
Scheme 1. Asymmetric construction of homoallylic-
homopropargylic amines
We contrived to utilize γ-ethynl substituted allylic bromide 2
as the allylic reagent to react with N-tert-butanesulfinyl imines to
afford homopropargylic amines, while vinyl groups are
introduced as well (Scheme 1b).
With the optimized conditions in hand, we turned our attention
to the substrate scope and generality of the reaction. As
We preliminarily utilized γ-phenylethynl allylic bromide 2a
and N-tert-butanesulfinyl imine 1b to examine the reaction. 2a
could be easily prepared from methyl propiolate in 40% overall
yield (Z/E 12:1) over four steps18. As shown in table 1, the
reaction proceeded smoothly in the presence of 2 equiv of zinc
powder with γ-phenylethynl allylic bromide 2a and afford the
desired products in high yield (99%) but with poor
diastereoselectivity (75:25) under argon at room temperature.
The similar result was observed by reducing the amount of 2a to
1.5 equiv (Table 1, entries 1 and 2). When the amount of 2a was
reduced to 1.1 equiv, dr increased to 80:20 with the decrease of
yield to 82% (entry 3). Changing the solvent to DMF or adding
LiCl did not influence the result positively (entries 4 and 5).
According to our previous work,17a,17d,17e,17g the content of water
could have a subtle impact on both yield and diastereoselectivity
of the aza-Barbier-type allylation. Therefore, we subsequently
screened the effect with regard to the amount of water.
summarized in scheme 2,
a wide range of (R)-N-tert-
butanesulfinyl imines 1 were examined to react with γ-ethynl
allylic bromide 2 in the presence of zinc powder and water in
THF at room temperature.
Table 1. Screening and optimization of the reaction conditions
T
Zn/2a
(eq)
H2O
(eq)
Yield
(%)b
Entrya
drc
(oC)
1
rt
rt
rt
rt
rt
rt
rt
rt
rt
0
2.0
1.5
1.1
1.1
2.0
1.1
1.1
1.1
1.1
1.1
1.1
1.1
1.5
-
99
99
82
72
64
48
56
67
51
47
26
37
80
75:25
74:26
80:20
complex
65:35
90:10
90:10
90:10
91:9
2
-
3
-
4d
5e
6
-
1.0
2.0
1.0
0.5
0.5
0.5
0.5
0.5
0.5
Scheme
2.
Asymmetric
synthesis
of
homoallylic-
homopropargylic amines
7
8
9f
10
11
12g
13
92:8
-20
rt
rt
93:7
complex
90:10

3
1H-pyrrole derivatives cannot be generated by treatment of
homoallylic-homopropargylic amine 3a with several different
Lewis acids. Then, the tert-butanesulfinyl group was removed
by 2 mol/L HCl in dioxane in nearly quantitative yield. After
alkalization, the free amines were subjected to 10 mol%
AgOAc in MeCN at room temperature. A series of 3,4-
dihydro-2H-pyrrole derivatives 4b, 4i, 4k, 4n and 4o were
obtained successfully via 5-endo-dig cyclization and
subsequent isomerization from initially produced enamines to
imines, which were accordant with the previous reports by
other groups3 (Scheme 4).
(1S, 2R)-anti-3j
(1S, 2S)-syn-3g’
Figure 1. X-ray crystal structure of (1S, 2R)-anti-3j and (1S, 2S)-
syn-3g’
To our delight, all the reactions went smoothly and afforded
the desired homoallylic-homopropargylic amines in good to
excellent yields and with good to excellent diastereoselectivities
(Scheme 2). For aldimines, we found that position and electronic
property of substituent on the aryl-ring did not significantly
affect either reactivity or selectivity of the reaction (3a-3h).
Notably, ketimine substrates, including naphthalenyl methyl and
furyl methyl ketimines, were competent to approach excellent
diastereoselectivities (>95:5 dr) (3i-3m). Besides, methyl and
fluorine atom on the benzene ring of allylation reagent 2 were
well tolerated (3n and 3o). Pleasingly, γ-heptynl allylic bromide
reacting with aldimine 1a also afforded corresponding amine 3p,
which made this method more versatile (3p). Unfortunately,
aliphatic sulfinyl imines could only give poor diastereoselectivity.
The absolute structures of obtained products were identified
unambiguously through X-ray crystallography of 3j19a and 3g’19b
(the minor product in reaction for 3g) (Figure 1).
The outcome of stereochemistry of the products were
consistent with the transition state model proposed previously.17e
A six-membered cyclic chair-form transition state model is
preferred wherein zinc is presumed to coordinate both to the
imine nitrogen and the sulfinyl oxygen. Compared to chair-form
transition, boat-form transition is obviously unfavored because of
the steric repulsion between the ethynyl group and the imine aryl
group (Scheme 3).
Scheme 4. Synthesis of 3,4-dihydro-2H-pyrrole derivatives
In conclusion, we have developed a Zn-promoted aza-Barbier-
type reaction to asymmetric synthesis of a broad spectrum of
homoallylic-homopropargylic amines bearing two contiguous
stereocenters using γ-ethynyl allylic bromide as allylation reagent
in mild conditions. It is notable that N-tert-butanesulfinyl
ketimines are outstandingly amenable to this approach. Besides,
cyclization of deprotected homopropargylic amines can afford
3,4-dihydro-2H-pyrrole derivatives, which are believed to be
useful building blocks in the synthesis of some bioactive
compounds.
Acknowledgments
Financial support from the National Nature Science
Foundation of China (No. 21472019) is gratefully acknowledged.
The authors are also thankful to Dr. Xiao-Di Yang for her
assistance with X-ray crystallography.
Supplementary data
Supplementary data associated with this article can be found,
in the online version, at
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5
Highlights
A Highly Practical Approach to Chiral
Homoallylic-homopropargylic Amines
via aza-Barbier Reaction
Bin-Hua Yuan, Zhi-Cheng Zhang, Wen-Jie Liu,
and Xing-Wen Sun

The first access to chiral homoallylic-
homopropargylic amine bearing two contiguous
stereocentes.


A novel allylic bromide was illustrated in aza-
Barbier reaction.
Enantioenriched 3,4-dihydro-2H-pyrroles was
prepared in high efficiency via 5-indo-dig pathway.
———
 Corresponding author. Tel.: +86-21-6564-2406; e-mail:
sunxingwen@fudan.edu.cn