Cu-Catalyzed Enantioselective Reductive Coupling of 1,3-Dienes and Aldimines

Article abstract of DOI:10.1021/acs.orglett.8b03216

Catalytic chemo- and enantioselective generation of 1,3-disubstituted allyl-Cu complexes from a Cu-H addition to 1,3-dienes followed by in situ reactions with aldimines to construct homoallylic amines is presented. The method is distinguished by an unprec

Full text of DOI:10.1021/acs.orglett.8b03216

Letter
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
pubs.acs.org/OrgLett
Cu-Catalyzed Enantioselective Reductive Coupling of 1,3-Dienes
and Aldimines
Mingfeng Li, Jiping Wang, and Fanke Meng*
State Key Laboratory of Organometallic Chemistry, Center for Excellence in Molecular Synthesis, Shanghai Institute of Organic
Chemistry, Chinese Academy of Sciences, 345 Lingling Road, Shanghai 200032, China
*
S Supporting Information
ABSTRACT: Catalytic chemo- and enantioselective generation of 1,3-disub-
stituted allyl−Cu complexes from a Cu−H addition to 1,3-dienes followed by in
situ reactions with aldimines to construct homoallylic amines is presented. The
method is distinguished by an unprecedented pathway to generate enantiomeri-
cally enriched allyl−Cu species, allowing reactions with a wide range of aldimines
in high chemo-, site-, diastereo-, and enantioselectivity. Functionalization provides
useful building blocks that are otherwise difficult to access.
omoallylic amines exist in structures of many biologically
active molecules and serve as precursors for the
preparation of a range of N-containing molecules.
Scheme 1. Cu-Catalyzed Enantioselective Reductive
Coupling of Alkene and Imine
H
1
,2
Consequently, general methods for the synthesis of homo-
allylic amines in enantiomerically pure form have been
considered to be an important goal in organic synthesis.
Although approaches for catalytic enantioselective allylation of
3
aldimines have significantly advanced, the need to utilize
stoichiometric quantities of an organometallic reagent is a
limitation of these processes, and one or multiple additional
synthetic operations are required to synthesize an organo-
metallic reagent. In addition, the variety of allyl groups that can
be introduced is limited due to the restriction of the available
methods to prepare allyl reagents. In particular, synthesis of an
enantioenriched allyl reagent and its utility in metal-catalyzed
allylation of imines is rare. Therefore, catalytic generation of
allyl nucleophiles from easily accessible alkenes and their in
situ use for addition to imines could obviate these drawbacks.
The utility of carbon-based nucleophiles formed from alkenes
for addition to carbonyls promoted by noble metal catalysts
4
(
Rh, Ru, and Ir) has been pioneered by Krische. While these
processes have been successful for enantioselective addition to
5
aldehydes, only a few examples of enantioselective addition to
6
imines have been reported. Alternatively, the development of
protocols using catalysts derived from earth-abundant metals
attracts much attention. In particular, Cu-catalyzed enantiose-
lective coupling of alkenes and imines represents an important
aldimines can proceed rapidly; (2) the regioselectivity of
Cu−H addition to 1,3-dienes (4,3-addition vs 4,1-addition)
and the following addition to imines (which to participate in
the addition, I or II) has to be well regulated by the catalyst;
(3) the enantioselectivity of generation of the secondary allyl−
Cu complex and subsequent addition to imines has to be
controlled by the single catalyst; (4) the catalyst has to
promote the imine addition rapidly enough to avoid possible
method for the preparation of enantioenriched amines
7
(
Scheme 1a−c). Although there are a few protocols on Cu-
catalyzed enantioselective borylative allylation of imines using
allenes or 1,3-dienes, the generation of enantioenriched
8
secondary allyl−Cu complexes from Cu−H addition to 1,3-
dienes and their in situ use in imine addition remains
9
−11
undisclosed.
1
2
racemerization (Scheme 1d). Herein, we outline an
Such a process allows the introduction of functionalized allyl
groups that are otherwise difficult to access. The challenges
include the following: (1) the catalyst has to control the
chemoselectivity, as competitive Cu−H reduction of the
Received: October 9, 2018
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b03216
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Table 1. Optimization of Conditions
a
b
b
c
entry
ligand
solvent
silane
yield of 3a (%)
3a/4a
dr
er
1
2
3
4
5
6
7
8
9
5a
5b
5c
5d
5e
5f
5g
5g
5g
5g
5g
5g
5g
5g
5a
5g
THF
THF
THF
THF
THF
THF
THF
(MeO) MeSiH
<2
<2
30
40
24
<2
71
<2
34
47
23
51
53
53
53
75
<2:98
<2:98
32:68
60:40
33:67
<2:98
74:26
<2:98
38:62
47:53
31:69
58:42
57:43
55:45
58:42
76:24
NA
NA
>98:2
79:21
66:33
NA
88:12
NA
82:18
80:20
81:19
81:19
79:21
80:20
81:19
88:12
NA
NA
99:1
87:13
89:11
NA
99:1
NA
99:1
99:1
98:2
99:1
99:1
99:1
99:1
>99:1
2
(MeO) MeSiH
2
(MeO) MeSiH
2
(MeO) MeSiH
2
(MeO) MeSiH
2
e
e
(MeO) MeSiH
2
(MeO) MeSiH
2
e
e
CH CN
(MeO) MeSiH
3
2
CH Cl
(MeO) MeSiH
2
2
2
10
11
12
13
14
15
16
CyH
(MeO) MeSiH
2
Et O
(MeO) MeSiH
2
2
toluene
dioxane
THF
THF
THF
(MeO) MeSiH
2
(MeO) MeSiH
2
(EtO) MeSiH
2
PMHS
d
(MeO) MeSiH
2
a
Yield of both isolated diastereomers from column chromatography. Further recrystallization can easily remove minor diastereomer in high yield.
b
1
c
d
e
Determined by analysis of H NMR spectra of unpurified mixtures. Determined by analysis of HPLC spectra. 2.0 equiv of diene were used. Not
available.
unprecedented protocol for catalytic enantioselective forma-
tion of a unique secondary allyl−Cu complex followed by an
addition to aldimines to afford homoallylic amines that are
otherwise difficult to access in high efficiency, chemo-, regio-,
and stereoselectivity.
Our investigations began with screening a variety of ligands
for the reaction of 1,3-diene 1a and aldimine 1b in the
presence of 5.0 mol % Cu(OAc)2 and 5.0 equiv of
allylation of imines that resulted in only 4,3-addition products
8a
being formed, the 4,1-addition mode occurred exclusively to
afford homoallylic amine 3a, indicating that only allyl−Cu
complex I participated in the imine addition step (Scheme 1d).
In addition, the configuration of alkene in 3a is exclusively E,
which is different from those generated from reactions with
10b
CO2.
With the optimal conditions in hand, we investigated the
scope of aldimines. As shown in Scheme 2, reactions of aryl-
substituted aldimines that contain electron-donating (3b, 3d−
e), electron-withdrawing (3c, 3f−j), and halogen groups (3e−
h) afforded exclusive 4,1-addition products in 60−85% yields,
86:14−99:1 dr, and 97:3−99:1 er. Aldimines substituted with
sterically congested aryl groups were transformed in 71−77%
yields, 92:8−97:3 dr, and 99:1−>99:1 er (3k−m). A variety of
heterocycles were well tolerated (3n−s). Transformation of
alkyl-substituted aldimines provided 4,1-addition products 3t−
u in 70−75% yields, 75:25−90:10 dr, and 98:2 er.
We further explored the scope of 1,3-dienes. As indicated in
Scheme 3, reaction of dienes substituted with electron-rich
(6a, 6e), electron-deficient (6b−d, 6h), halogen-containing
(6a−c, 6f−g), and sterically congested (6i−j) aryl groups
afforded homoallyic amines in 71−97% yields, 80:20−99:1 dr,
and 97:3−>99:1 er. A wide range of heterocycles were well
tolerated (6k−o). When alkyl-substituted dienes were used in
the reaction, only a product from the imine reduction was
observed, probably due to the lower reactivity of alkyl-
(
MeO) MeSiH (Table 1). Cu complexes derived from
2
bisphosphines 5a and 5b did not promote the reductive
allylation (entries 1 and 2). Only a product 4a from reduction
of aldimine was observed. A reaction in the presence of a Cu
complex formed from sterically congested bisphosphine 5c
afforded homoallylic amine 3a in 30% yield, >98:2 dr, and 99:1
er, although the chemoselectivity was low (entry 3). Further
studies revealed that no improvement was made on chemo-,
diastereo-, and enantioselectivity by Cu complexes derived
from phosphines 5d−f (entries 4−6). Transformation of 1a
and 2a promoted by a Cu complex generated from Ph-BPE 5g
delivered 3a (CCDC 1859782) in 71% yield, 88:12 dr, and
9
9:1 er (entry 7). Optimization of solvents indicated that
reaction that was performed in THF provided the best yield
and stereoselectivity for 3a (entries 8−13). Changing the
silane to (EtO) MeSiH or PMHS resulted in erosion of yield
2
and stereoselectivity (entries 14−15). Increasing the equivalent
of diene slightly improved the chemoselectivity (entry 16). It is
noteworthy that, in contrast to previous work on borylative
B
DOI: 10.1021/acs.orglett.8b03216
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
a
Scheme 2. Scope of Aldimines
Scheme 3. Scope of 1,3-Dienes
a
The reactions were performed under a N2 atmosphere. See
b
a
Supporting Information (SI) for details. 3.0 equiv of diene were
The reactions were performed under a N atmosphere. See SI for
2
b
used.
details. 3.0 equiv of dienes were used.
substituted dienes in the Cu−H addition step, resulting in
domination of reduction of imine.
Scheme 4. Gram Scale Reaction and Functionalization
The reaction can be conducted on multigram scale with a
.5 mol % catalyst loading without any erosion of yield and
0
stereoselectivity (eq 1). One of the advantages of the
phosphinoyl group is the ease of deprotection. The
phosphinoyl group of the homoallylic amine 3d was cleaved
13
with 4.0 M HCl solution in MeOH (eq 2). As shown in
Scheme 4, the multifunctional homoallylic amine can be
further transformed into useful building blocks (Scheme 4).
Acylation of the amine with acryloyl chloride followed by ring
closing metathesis promoted by Ru complex 9 afforded δ-
14
lactam 11 in 53% overall yield. Allylation of the Boc amide 8
followed by ring closing metathesis in the presence of Ru
complex 9 delivered tetrahydropyridine 10 in 58% overall
1
5,16
yield, >99:1 dr and >99:1 er.
Tetrahydropyridines and
17
piperidines commonly exist in biologically active molecules.
The alkene moiety can be dihydroxylated to generate
aminoalcohol 12 (CCDC 1859783) in 58:42 dr with 48%
yield of the major diastereomer as a single enantiomer. The
18
alkene moiety can be converted to other olefins. Switching
the methyl group on the alkene to a functionalizable ester
moiety through a one-pot ozonolysis followed by a Wittig
19
reaction led to 13 in 40% overall yield as a single enantiomer.
The proposed catalytic cycle is shown in Scheme 5. The
addition of Cu−H complex III to diene 1a afforded allyl−Cu
complex IV, which reacted with phosphinoyl imine 2a directly
without isomerization to V, probably due to the high affinity of
3a
the phosphonoyl group to the metal center. Once allyl−Cu
complex IV was generated, a fast intramolecular C−C bond
forming reaction occurred before possible isomerization and
C
DOI: 10.1021/acs.orglett.8b03216
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 5. Proposed Catalytic Cycle
ACKNOWLEDGMENTS
■
This work was financially supported by the State Key
Laboratory of Organometallic Chemistry, the Shanghai
Institute of Organic Chemistry, the “Hundred Talents Plan”
of Chinese Academy of Sciences, the “Thousand Youth
Talents Plan”, the Shanghai Sailing Program (Grant No.
1
7YF1424100), the National Natural Science Foundation of
China (Grant No. 21702222), the Science and Technology
Commission of Shanghai Municipality (Grant No.
1
7JC1401200), and the Strategic Priority Research Program
of the Chinese Academy of Sciences (Grant No.
XDB20000000).
racemerization, delivering exclusive 4,1-addition product VI.
Protonation of the Cu−N bond by t-BuOH released the
product 3a and generated Cu complex VII, which underwent
σ-bond metathesis with silane to regenerate Cu−H complex
III. Two transition states of allylation are shown in Scheme 5
to illustrate the stereoselectivity. In TS2, the proximity of the
large phosphonoyl group and the phosphine ligand on Cu
leads to the steric repulsion and raised the energy of such a
pathway. In the absence of such a disadvantageous interaction,
a pathway through TS1 that led to the major diastereomer 3a
was favored.
In conclusion, we developed an unprecedented protocol of
catalytic enantioselective generation of chiral secondary allyl−
Cu complexes through Cu−H addition to 1,3-dienes followed
by their in situ addition to aldimines, providing a wide range of
homoallylic amines in high chemo-, regio-, diastereo-, and
enantioselectivity. The reactions were performed with easily
accessible starting materials in the presence of a readily
available phosphine−Cu complex. Functionalization of the
product afforded a variety of useful building blocks that are
otherwise difficult to access. Further investigations on
expanding the scope of alkenes to generate enantiomerically
enriched organometallic complexes are underway.
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AUTHOR INFORMATION
Corresponding Author
■
*
1
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E-mail: mengf@sioc.ac.cn.
ORCID
Fanke Meng: 0000-0003-1009-631X
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