Copper-Catalyzed Cope-Type Hydroamination of Nonactivated Olefins toward Cyclic Nitrones: Scope, Mechanism, and Enantioselective Process Development

Article abstract of DOI:10.1002/chem.201902683

The catalytic synthesis of cyclic nitrones, an important type of functional molecules for both synthetic chemistry and related fields, remains underdeveloped. Herein we report the copper-catalyzed Cope-type hydroamination of oximes with pendant nonactivated olefins, which enables facile access to a series of five- and six-membered cyclic nitrones under mild conditions. In this study, heterocycle-tethered oximes were employed in the Cope-type hydroamination reaction for the first time. High enantioselectivity was achieved for carbon-tethered γ,δ-vinyl oximes to afford enantioenriched five-membered cyclic nitrones. The results of preliminary mechanistic studies indicate a mononuclear catalytic species and a unified catalytic pathway over a large temperature range.

Full text of DOI:10.1002/chem.201902683

A Journal of
Accepted Article
Title: Cu-Catalyzed Cope-Type Hydroamination of Non-activated
Olefins toward Cyclic Nitrones: Scope, Mechanism and
Enantioselective Process Development
Authors: Jinbo Zhao, Mengru Zhang, Shuang Liu, Hexin Li, Yajing
Guo, Na Li, Meihui Guan, Haroon Mehfooz, and Qian Zhang
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To be cited as: Chem. Eur. J. 10.1002/chem.201902683
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10.1002/chem.201902683
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Cu-Catalyzed Cope-Type Hydroamination of Non-activated
Olefins toward Cyclic Nitrones: Scope, Mechanism and
Enantioselective Process Development
Mengru Zhang,[a]†Shuang Liu,[a]†Hexin Li,[a]Yajing Guo,[a] Na Li,[a]Meihui Guan,[a] Haroon Mehfooz,[a]
Jinbo Zhao*[a] and Qian Zhang*[a,b]
Abstract: Catalytic synthesis of cyclic nitrones, an important type of
functional molecules for both synthetic chemistry and related fields,
O
O
remains underdeveloped. Herein we report the Cu-catalyzed Cope-
type hydroamination of oximes with pendant non-activated olefins
enables facile access to a series of 5- and 6-membered cyclic nitrones
under mild conditions. Heterocycle-tethered oximes were
incorporated to the Cope-type hydroamination for the first time. High
enantioselectivity was realized for carbon-tethered γ,δ-vinyl oximes to
afford enantioenriched five-membered nitrones. Preliminary
mechanistic studies indicate a mononuclear catalytic species and a
unified catalytic pathway over a large temperature range.
N
O
NH
N
O
OH
N
HO
HO
O
CO2H
OH
DMPO
bioorthogonal agents
immino-spin trapping agent
O
OH
HO
H
OH
OH
N
O
N
N
N
N
HO
O
synthetic intermediate
()-Peganumine E
Figure 1. Selected Nitrone-based Functional Molecules, Therapeutic Agents,
Synthetic Intermediates and Natural Products.
Introduction
Cyclic nitrone and their immediate derivatives have received
increasing attention for their occurrence in natural products,1 and
their role as key intermediates for the preparation of N-
heterocycles,2,3therapeutic immuno-spin-trapping reagents,4,5
liquid crystal materials, and paramagnetic modification agents, et.
al. (Figure 1). A striking contrast to their multifaceted application
is the limited number and diversity of these compounds available
owing to the paucity of catalytic strategies for their preparation.
Accessing chiral cyclic nitrones mainly hinges on non-catalytic
diastereoselective transformations from electrophile-induced
annulation processes, via either substrate control6 or reagent
control.7 A recent advance used chiral pool strategy with natural
carbohydrate derived chiral backbone as template for substrate
control.8Catalytic asymmetric transformations represent a highly
efficient, cost-effective and versatile solution to chiral nitrone
synthesis, but relevant protocols are rare.9-12 Highly
enantioselective catalytic synthesis of chiral cyclic nitrones
remains highly underdeveloped.
Cope-type hydroamination has gained increasing attention over
the past decades as a unique alternative to the traditional
hydroamination paradigm.13,14Variants with sp3-hybridized N-
nucleophiles, such as hydroxyl amine, hydrazine, et. al., has
received significant attention and was systematically investigated
in the past two decades, both experimentally15-22 and
theoretically.23,24These
efforts
culminated
in
highly
enantioselective versions to be developed by the
Beauchemin22and Jacobson25 groups with organocatalysts,
demonstrating the feasiblity of catalytic strategies for this
traditionally thermal proess. On the other hand, since the seminal
reports of Bishop26and Grigg27, Cope-type hydroaminations of
sp2-hybridized N- nucleophiles remain highly underdeveloped,28-
32
likely due to their attenuated reactivity. Furthermore, the
charge-separated property of the products of these sp2-hybridized
N-nucleophiles (such as nitrone for the reaction of oxime)
indicates further thermodynamic unfavourability, exacerbating the
situation for the development of effective catalytic protocols. In
this context, a notable recent advance by Chiba et. al. employed
inorganic base to facilitate the annulation of γ, δ-vinyl oxime
toward formation of 5-membered cyclic nitrones.30 Under these
conditions, oximes bearing tethered styrene-type activated olefins
were shown to be highly yielding, while those bearing terminal,
non-activated alkene moieties were much less reactive even
under forcing conditions (Scheme 1, a).To date, general
applicable catalytic strategies for efficient Cope-type
hydroamination of sp2-hybridized N-sources remains lacking.
[a]
[b]
Ms. M. Zhang, Ms S. Liu, Mr. H. Li, Ms Y. Guo, Ms N. Li, Ms M.
Guan, Mr. H. Mehfooz, Prof. J. Zhao, Prof. Q. Zhang
Key Laboratory of Functional Molecule Synthesis of Jilin Province,
Department of Chemistry
Northeast Normal University
5268 Renmin Street, Changchun, Jilin, P. R. China 130024
E-mail: zhaojb100@nenu.edu.cn; zhangq651@nenu.edu.cn
Prof. Q. Zhang
State Key Laboratory of Organometallic Chemistry
Shanghai Institute of Organic Chemistry, Chinese Academy of
Sciences
345 Lingling Road, Shanghai, P. R. China 200032
†These authors contributed equally.
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10.1002/chem.201902683
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We recently reported the CuI-catalyzed Cope-type
hydroamination of oxime with the highly strained cyclopropene
proceeds with high efficiency,12 demonstrating that π-activation
by transition metal is a feasible catalytic strategy. Despite of this
advance, the reaction of non-activated olefins is more challenging
due to thermodynamic unfavourability. We envisioned that the
catalyst-controlled cyclization of the readily available alkenyl
oximes may provide highly efficient synthesis of cyclic nitrones
that can be rendered asymmetric, provided that a viable catalytic
activation of the non-activated olefins can be realized. Herein we
show that with the appropriate choice of supporting ligands, a CuI-
based catalytic system can catalyze vinyl oximes tethered by an
array of scaffolds toward the construction of various 5- and 6-
membered cyclic nitrones with high level of conversion. This
catalytic protocol displays unparalleled substrate profile and
offers highly enantioselective conditions for the synthesis of
carbon-tethered 5-membered cyclic nitrones under mild
conditions (Scheme 1, b).
Entry[a]
Cat.
CuCl
CuCl
--
Ligand
Temp./oC
Conv.
80%
0
Yieldb
55%
0
1
2
3
4
Dppbz (L1)
--
25
25
25
25
Dppbz (L1)
0
0
CuCl
rac-BINAP
(L2)
< 5%
trace
5
CuCl
PCy3 (L3)
25
25
25
25
25
25
25
60
80
>99%
99%
69%
85%
87%
trace
trace
trace
90%
88%
>99%
6
CuCl
dcype (L4)
7
CuCl
IMes (L5)
98%
8
CuTC
L5
L5
L5
L5
L5
L5
<5 %
< 5%
< 5%
97%
(a) Base promoted annulation: 2014, Chiba et. al. (ref. 30)
9
Cu(OTf)2
CuBr2
R
R
10
11
12
13
O
HO
Ar
N
N
K3PO4 or NaOt-Bu
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
heat
Ar
R = aryl, 60oC, high yield
H, 140oC, fair yield
>99%
>99%
(b)
Catalyzed intramolecular Cope-type hydroamination (this work)
HO

O
R'
N
R'
N
( )
O
n
R
Ar
N
[a] Reactions were performed on 0.20 mmol scale. [b] NMR Yields versus
an internal standard of CH2Br2.
Ar
R
R
Cu
R
R
HO
n = 1, 2
30-120oC
Me
N
gave higher conversion and yields, with IMes retrieving the
highest 98% conversion and 87% yield (entries 4-7, Table 1). With
this ligand, Cu(OAc)2 demonstrates superior reactivity (entries 8-
11). Upon elevation of temperature, Cu(OAc)2/IMes catalyzed
reaction reached full conversion at 60oC or above, and gave
excellent yields of 4a (entries 12-13).
Ar
N
R
R'
O
N
O
N
 Non-activated olefin
 Mild conditions
 Diversity
R'
N
Ar
N
R
OH
N
X
n
Stereocontrol
Scheme 1. Cope-type Hydroamination of Oxime: Base-Promoted Reaction (a)
and a Cu-Catalyzed Variant (b, this work).
Under the optimized condition (entry 13, Table 1) a variety of
germinal dimethyl substituted carbon-tethered γ-alkenyl oximes
delivered the expected 5-membered cyclic nitrones uneventfully
in high yields (Scheme 2). The reactivity is insensitive to the
electronic properties of substituents, and4b-4j were all delivered
in excellent yields (83-99%). The reaction can also be
uneventfully scaled up to gram scale, as a 10 mmol (2.37 g) scale
reaction of oxime 1d catalyzed by 2 mol% CuCl and3 mol% IMes
at 80oC efficiently deliveredthe product 4d in 80% yield (1.90
g).Furthermore, naphthyl (4k, 4l) and thienyl (4m) substrates
gave nearly quantitative yields. Alkyl substitution of the olefin at
the terminal carbon led to compromised reactivity, as the
substrate bearing a cis-internal olefin required higher temperature
(120oC) to react, albeit still delivered the expected product 4n in
a good yield of 67%. Similarly, a substrate bearing a ring-fused
cis-1,2-olefin also delivered the product 4o in a good yield of 69%.
In contrast, substrate bearing a phenyl substitution at this position
retrieved a high yield of 87% (4p). In this case, activation by
coordination is not as dramatic as for the mono-substituted
terminal alkene, and base-promoted cyclization may account for
part of the reactivity. To our delight, alkyl substitution at the
internal olefinic carbon seems to exert less significant impact, as
Results and Discussion
We set out to examine the reactivity of readily available γ,δ-
alkenyl oxime 1a to probe the feasibility of activating non-
activated olefin in an intramolecular setting. Remarkably,
treatment of 1a with catalytic CuCl/dppbz and 30 mol% NaOt-Bu
in toluene led to efficient cyclization with a high conversion and
moderate yield even at room temperature (entry 1, Table 1)!
Notably, for these substrates the base-promoted conditions only
provided moderate yields at 140oC.31 Control experiments with
copper salt or ligand alone led to no conversion (entries 2-3),
indicative of dramatic ligand accelerated catalysis (LAC).33 The
reactions promoted by more electron-rich ligands
Table 1.Optimization of Cu-Catalyzed Annulation of γ-Alkenyl Oxime 1a.a
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4q, which bears a tertiary α-carbon, was produced in a high 87%
yield at 80oC.
We believe the lower conversion may arise from the unfavorable
thermodynamics for non-activated olefins compared to the highly
strained cyclopropene,34 and/or the likely strong product inhibition,
as indicated by the highly efficiency of CuI-catalyzed 1,3-dipolar
cycloadditions of nitrones.35,36 To probe the favorability of this
intramolecular version vs intermolecular reaction with the strained
cyclopropene, as well as the relative favorability of Thorpe-Ingold
effect on the reactivity of intramolecular cyclization, we performed
We then examined the effects of tether on the reactivity. While
not surprisingly a substrate bearing sterically highly similar R3 and
R4 (R3 = Me, R4 = allyl) afforded product 4r in a high yield but low
diastereocontrol, the oxime bearing an α-phenyl substituent
afforded the product 4s in 74% yield and > 95/5 d.r., whose trans
configuration is supported by NOESY ananlysis, showing the
strong 1,3-diastereocontrol exerted by the α-phenyl group. 1-
Indanone derived substrate failed to deliver the expected product
4teven at 120oC, indicating that for effective coordination
activation, some degree of conformational flexibility is required.
Furthermore, substrates without germinal dimethyl substitution
α-to the oxime moiety were also viable under the catalyzed
conditions but resulted in lower conversions. As such, compound
5a could only be obtained in 55% conversion and 52% yield
catalyzed by Cu(OAc)2/dppbz at 70oC for 24h in the presence of
3 equiv. of t-BuOH as additive (entry 1, Table 2).
the
following
competing
experiments
cyclopropene
(Scheme
showed
2).
clear
Competitionbetween1aand
preference in favor of intermolecular process, although as
expected, the intramolecular process still contributed to an
appreciable degree (29% yield of 4a, eq. 1, Scheme3). In contrast,
the intramolecular cyclization of substrate 1s which lacks
germinal dimethyl substitution was much more sluggish in the
presence of cyclopropene (eq. 2, Scheme 3). These results
highlight the challenge for the effective catalysis of non-activated
olefins, even in intramolecular settings, especially for the
substrates that lack germinal dimethyl substitution.
R4
R3
Cu(OAc)2 (5 mol%)
IMes (6 mol%)
HO
Me
N
HO
O
Ph
Me
CuCl (5 mol%)
IMes (6 mol%)
N
O
Ph Me
O
NaOt-Bu (30 mol%)
N
R4
+
N
N
Ar
+
eq. 1
Toluene, 80oC
N2
NaOt-Bu (30 mol%)
Tol, 30oC, N2
R2 R1
Ph
R3
Ph
R1
Ph
R2
Ph
1a
1
4
4a, 29%
5a, 57%
O
O
O
N
Me
O
CuCl (5 mol%)
dcype (6 mol%)
N
N
OH
O
N
Ph
Me
N
N
Ph Me
O
N
+
eq. 2
+
NaOt-Bu (30 mol%)
t-BuOH (3 equiv.)
Tol, 30oC, N2
Ph
Ph
Ph
Ph
Me
Cl
1w
MeO
6a
, <10%
5b, 63%
1s
4d, 98% (80%)[a]
21% recovered s.m. (
)
4c, 95%
4b, 99%
4a, 99%
O
N
O
Scheme 3. Competition experiments.
O
N
O
N
N
Ph
F3C
F
F3CO
Me
Accordingly, we briefly re-optimized the conditions for these
substrates. As can be seen from Table 2, the conversion for6acan
be improved to 80% (yield was also 80%) with electron-rich
bidentate alkyl phosphine ligand dcypeL4 (entry 2). To further
improve the conversion, we surmised that addition of additives
that can bind to Cu salts can facilitate the catalyst’s ligand
exchange process to liberate it from product-bound form to re-
enter the catalytic cycle. Indeed, some olefin and alkyne additives
were found to have moderate effects on the conversion. Of note,
trans-stilbene also showed improvement of the conversion to 90%,
and gave the highest yield among the additives evaluated (entry
5). The effect of diphenyl acetylene was almost as effective as
trans-stilbene, with the conversion being >95% (entry 7). A higher
loading (10 equiv.) of diphenyl acetylene did not retard the
catalytic reaction but showed less obvious improvement to the
yield (entry 8). Thus, the condition of entry 7 in Table 2was
adopted in the subsequent scope studies.
4h, 95%
g,
4
83%
4e, 99%
4f, 85%
O
N
O
O
N
O
N
N
Cl
4j, 95%
4l
N
, 99%
Ph
4k, 99%
4i, 93%
H
H
Et
O
N
O
O
N
O
N
Ph
Ph
4n, 67%[b]
Ph
H
S
4p
, 87%
[b]
4m
4o
, 59%
, 98%
(from E-alkene)
(from Z-alkene)
CH3
H
O
N
O
N
O
O
N
N
nOe
Ph
Ph
Ph
H
Ph
4t, 0%[b]
This condition can be applied to a variety of substituted oximes
bearing aryls and heteroaryls of distinct electronic characters,
which all proceeded with high conversion and yields (Scheme
4).37Substitution at ortho-position is also nicely accommodated (6j,
75%). Similar to that observed above, the reaction of substrate
bearing a methyl substitution at the internal carbon of the olefin
moiety is equally facile (6n, 87% yield), while
4r,95%,[c] 1.14/1 d.r. 4s, 74%, > 95/5 d.r.
4q, 87%
Scheme 2. Scope of Thorpe-Ingold type carbon-tethered γ -Alkenyl
Oximes.Conditions: oxime (0.20 mmol), Cu(OAc)2 (5 mol%), IMes(6 mol%),
NaOt-Bu (30 mol%), toluene [0.1M], 80oC, N2. [a] Yield of 10 mmol scale
reaction. [b] Performed at 120oC. [c] Performed at 30oC with dppbz as ligand.
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substitution at the terminal carbon led to no reaction even at
elevated temperature of 120oC (6o, 0%).
Table 2. Ligand and Additive Effect on Cu-Catalyzed Annulation of γ-Alkenyl
Oxime1s.
We also examined the reactivity of δ,ε-alkenyl oxime under
Cu(OAc)2/IMes catalysis, but found that one-carbon homologated
six-membered cyclic nitrones 6pcould not be cyclized with this
protocol even at 120oC. In contrast, the product 4u, which
contains geminal dimethyl substitution α to the oxime, could be
obtained with 99% yield at this temperature (Scheme 5),
highlighting the significance of conformational effect.
Entry[a]
Ligand
Additive (equiv.)
Conv./%[a]
Yield/%[b]
1
2
3
4
Dppbz (L1)
dcype (L4)
IMes (L5)
--
--
--
--
55
52
80
52
0
80
Me
5% Cu(OAc)2
6% IMes
NOH
1zm
NOH
O
N
74
NaOt-Bu (30 mol%)
t-BuOH (3 equiv.)
toluene, 120oC
Ph
Ph
6p
, trace
P(3,5-di-CF3-
C6H3)3 (L6)
< 5%
Me
5% Cu(OAc)2
6% IMes
O
N
5
6
7
8
dcype (L4)
dcype (L4)
dcype (L4)
dcype (L4)
trans-stilbene (1)
4-F-styrene (1)
PhC≡CPh (1)
PhC≡CPh (10)
90
88
74
86
82
NaOt-Bu (30 mol%)
t-BuOH (3 equiv.)
toluene, temperature
Ph
Ph
75
4u
1u
80oC, 19%
>95
>95
100oC, 68% (75% conv.)
120oC, 99%
Scheme 5. Reactivity of δ,ε-alkenyl oximes.
[a] Determined by 1H NMR of crude reaction mixture. [b] Isolated yields.
R1
R4
R1
R4
The scope of the current transformation also encompasses N-
tethered substrates, such as N-hydroxy-N’-allyl
arylarboximidamides to access imidazoline-N-oxides
Cu(OAc)2 (5 mol%)
dcype (6 mol%)
NaOt-Bu (30 mol%)
HO
O
N
N
R3
R2
2
7
R3
PhCCPh (1.0 equiv.)
t-BuOH (3 equiv.)
Ar
Ph
(Scheme 5). To our delight, these compounds demonstrate
superior reactivities compared to carbon-tethered γ,δ-alkenyl
oximes, i.e., the reaction of 2a catalyzed by CuCl/dppbz afforded
the expected product 7a in 89% yield with > 95% conversion at
50oC. An examination of the N-substituent indicated that N-t-butyl
derivative afforded cyclization product 7c in a high yield of 97%.
Under the above conditions, a series of N-tert-butyl substrates
were efficiently transformed to the products, in typically > 95%
conversion and high yields, including various substituted aryl (7d-
i) and naphthyl (7j) bearing vinyl oximes, demonstrating
insensitivity to electronic perturbation caused by substituents on
the aryl group. The mild reaction conditions also enable
successful cyclization to construct tertiary C-N bond, as
demonstrated by 7k. Notably, our recent studies showed that
these compounds show different selectivity in Pd(0)-catalyzed
annulation, in favor of O-annulation.38
2
n
n
R
Toluene, 80oC, N2
1
6
n = 0, 1
O
O
O
O
N
N
N
N
Ph
MeO
F
Me
t-Bu
6c
[a]
6a, 86%
[a]
6d
, 54%
6b
, 75% (95%)
, 93% (98%)
O
N
O
N
O
N
O
N
F3C
6f, 83% (98%)[a]
Cl
MeS
6e
, 85%
6g
, 79%
6h, 71% (83%)[a]
O
O
N
N
O
O
N
N
Br
Cl
Me
Cl
, 90% (98%)
[a]
[a]
6i
, 72%
6l
, 67% (86%)
6j, 75%
6k
Furthermore, ring fused N-tethered vinyl oximes can also be
efficiently promoted to cyclize under the identical mild conditions
as for the N-hydroxy-N’-allyl arylcarboximidamides (Scheme 6).
Hence, as representative examples, benzene-fused and
pyrrolyl/indolyl substituted oximes bearing various substituents
uneventfully delivered the tricyclic nitrones 8a-c and 9a-g in good
to high yields. Notably, the reactivity of oximes with disubstituted
olefins also gave the expected products in good yields as well (9b
and 9g). Functionalities such as iodine can be nicely tolerated,
allowing for further elaboration. Here, it is worthwhile to note the
marked differential reactivities of carbon-tethered δ,ε-alkenyl
O
N
n-C7H15
O
N
O
N
Ph
Ph
S
[b]
6n, 87% (99%)[a]
0%
6o,
6m, 88%
Scheme 4. Scope of non-Thorpe-Ingold type carbon-tethered γ -Alkenyl
Oximes.[a] Conversions were reported in parentheses where incomplete
conversion was observed. [b] Performed at 120oC.
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Me
Scheme 6. Scope of Benzene- and N-heterocycle Fused δ-alkenyl Oximes.[a]
Cu(OAc)2 (5 mol%)
dppbz (6 mol%)
NaOt-Bu (30 mol%)
toluene, 50oC
N2
HO R'
R'
O
Performed at 70oC.
N
N
Ar
N
N
Ar
R
R
7
2
oxime (0% for 6p even at 120oC) with that of the arene- and
heteroarene fused alkenyl oxime (high yield of 7-9 at 50oC). We
hypothesize that conformational effects may play a pivotal role for
the catalytic reactivity.
To demonstrate the role of the catalytic system, cyclization of
representative oximes under base-promoted or simple heating
conditions were performed. These reactions only led to no
conversion or decomposition of starting materials (Scheme 6),
showing the essential role of catalysts.
O
O
N
O
N
N
Ph
N
N
N
R
Ph
Et
allyl, 7a, 89%
7b
Bn, , 87%
R =
7e
7d, 96%
, 90%
7c
t-Bu, , 97%
O
N
O
N
O
N
N
N
N
Cl
F
F3C
O
NOH
N
7f, 74%
7g, 90%
7h, 75%
base: n.r.
Ph
heating: n.r.
Ph
O
N
6a
O
N
OH
O
O
N
N
N
N
Br
base: dec.
N
N
30 mol% KOt-Bu
toluene, 110 oC, 13 h
N
Ph
Ph
tBu
7c
NOH
N
tBu
O
OR heating, toluene
120oC, 24 h
7i, 89%
7k
, 75%
7j, 85%
N
base: n.r.
Ph
8a
Scheme 5. Scope of N-hydroxy-N’-allyl arylarboximidamides for the synthesis
of imidazole N-oxides.
Me
Me
OH
O
N
N
base: dec.
heating: dec.
N
N
9a
Scheme 7. Control experiments.
Table 3. Catalytic Highly Enantioselective Synthesis of Cyclic Nitrones Enabled by Chiral Ligands.Optimization of Cu-Catalyzed Annulation of γ-Alkenyl
Oxime1a.[a]
Entry
1
Catalyst
CuCl
Ligand
Solvent
Toluene
Additive
--
Yield/%[b]
69
e.r.[c]
L6
65:35
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2
CuCl
L7
L8
L9
L10
L9
L9
L9
L9
L9
L9
L9
L9
L9
L9
L9
L9
L9
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
THF
--
93
64:36
75:25
87:13
70:30
86:14
--
3
CuCl
--
79
4
CuCl
--
78
5
CuCl
--
> 99
27
6
CuBr
--
7
CuI
--
trace
82
8
Cu(OAc)2
Cu(OTf)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
--
87:13
81:19
73:27
82:18
86:14
73:27
95:5
9
--
75
10
11
12
13
14
15
16
17
18
--
96
Et2O
--
97
MTBE
Dioxane
CyH
--
46
--
93
--
32
CyH
--
68
90:10
92:8
CyH
t-BuOH (1 equiv.)
t-BuOH (2 equiv.)
t-BuOH (3 equiv.)
81 (89)[d]
83 (93) [d]
85 (94) [d]
CyH
91:9
CyH
92:8
[a] Conditions: oxime (0.20 mmol), Cu (0.01 mmol, 5 mol%), L (0.012 mmol, 6 mol%), NaOt-Bu, additive (if applicable), solvent (2 mL), 10oC, 24 h.[b] Isolated
yields. [c] Enantioselectivities were determined by HPLC on a chiral stationary phase. [d] Values in parentheses are conversion of the reaction based on
recovered starting material.
The effect of asymmetric induction with chiral ligands was
subsequently investigated with the model reaction of 1a following
the establishment of the substrate scope and the factors
controlling the reactivity (Table 3). Evaluation of ligand structure
revealed DuPhos and BPE types ligands to be promising, with
(R,R)-Ph-BPE L9 giving (+)-4a in 87:13 e.r. (entry 4, Table 3). The
pre-catalysts were also important for the conversion and
enantiocontrol, among which Cu(OAc)2 was found to be more
competent in both reactivity and enantioselection (entries 5-9). A
remarkable effect on the enantioselectivity was also noted:
ethereal solvents tend to give higher conversion with lower
enantioselectivities, while non-polar cyclohexane (CyH) delivered
the product with high enantiocontrol (95:5 e.r.) but a low
conversion of 32% (entry 14). Alcoholic additives were then added
to improve the conversion in CyH (entries 16-18). To our delight,
with 3 equiv. of t-BuOH the reaction can reach 94% conversion,
retrieving product (+)-4ain 85% yield and 92:8 e.r. (entry 18).
Under these optimized conditions, a plethora of carbon tethered
alkenyl oximes undergo ligand-prompted Cu-catalyzed cyclization
to afford the corresponding chiral 5-membered cyclic nitrones with
high enantiomeric ratios (Scheme 8). Tolerated functionalities
include various halides, fluorine, methylthio group, et. al. Notably,
the reaction of oximes displaying α,α-dimethyl substitution can
reach high conversion at 10 oC, a temperature under which
substrates without the dimethyl substituents were more reluctant
to cyclize. These latter substrates can undergo efficient
cyclization at 50oC to deliver the products 6 in good conversions
and high level of enantiocontrol.39Generally, the enantioselectivity
remained high irrespective of the electronic properties of the
substituents on the aryl groups. Furthermore, the enantioselective
conditions are efficient for the establishment of tertiary center by
activating olefins bearing alkyl substitution at the internal olefinic
carbon (4p). However, the enantiocontrol for other types of
substrates, such as aza-, benzo- and heterocycle-fused
substrates remains low with a variety of commonly used ligand
scaffolds. Further studies are warranted and are currently
underway.
We subsequently performed some preliminary studies to gain
mechanistic insights of the reaction. Upon monitoring the
enantioselectivity of the cyclization product vs the
enantioselectivity of the catalyst, a linearrelationship between the
enantiomeric excess of the catalyst andthat of the product was
observed (Figure 3, left). The lack of non-linear effect suggests
that neithercatalyst aggregation nor dimer formation is present.40
In addition, Eyring plot of the enantioselectivities of reactions
performed within a large temperature range (–20 ~ 80 oC)
displayed good linearity (Figure 3, right), suggesting of a unified
mechanism operates over this large temperature range,41 and
that no appreciable competing background reaction is present, as
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10.1002/chem.201902683
Chemistry - A European Journal
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solvent clusters that affected the enthalpy-entropy control of the
enantioselective process.43
Ph
Me
HO
Ph
R''
O
*
R''
N
Cu
L9
N
P
P
Ar
A mechanistic hypothesis was proposed (Figure 4) based on
our previous work and the experimental evidence gained herein.
First, the reaction of oxime (as exemplified with 1s), base and
copper catalyst CuL*X affords adduct A, with subsequent
association of the olefin to form π-complex B. Ligand promoted
inner-sphere metalla-retro-Cope cyclization to forge the key C–N
bond, leading to alkyl copper species C. Protonation of the latter
either with t-BuOH or with the substrate oxime can deliver the final
product 6a and regenerate catalyst for the next cycle. Unlike the
reaction of cyclopropene, herein, especially for the carbon-
tethered substrates which lacks germinal di-substitution, the
addition of alkyne as additive is necessitated to possibly
accelerate the catalyst’s ligand exchange process to liberate it
from the product-bound species D to re-enter the next cycle.
Ar
Ph
Ph
L9
R' R'
R'
R'
Me
Me
Me
Me
O
O
O
O
*
*
*
*
N
N
N
N
Me
MeO
Cl
4d
F
4c
(+)-4e, 95%, 93:7 er
(+)- , 80%, 91:9 er
(+)- , 96%, 99.4:0.6 er
Me
4b
(+)- , 57%, 92:8 er
Me
Me
Me
O
O
*
O
*
O
*
*
N
N
N
N
Cl
Ph
F3CO
F3C
4i
(+)-4h, 57%, 92:8 er (+)- , 85%, 84:16 er
4g
(+)-4f, 89%, 91:9 er
(+)- , 49%, 87:13 er
Me
Me
O
*
O
Me
*
O
N

O
N
*
N
N
Me
Ph
Ph
S
[a]
(+)-6a, 58%, 85:15 er
4p
(+)- , 57%, 89:11 er
4m
(+)-
, 45%, 91:9 er
4j
(+)- , 75%, 82:18 er
H
O
N
Me
Me
Me
Me
O
O
O
*
*
O
*
*
N
N
N
N
Ph
6a
Me
F3C
Cl
Ph
Ph
t-Bu
CuL
N
H
6b
(+)-6c, 54%, 92:8 er
(-)-6f, 44%, 88:12 er
(-)- , 50%, 88:12 er
(+)-6e, 53%, 89:11 er
O
Ph
Ph
NOH
1s
Me
Me
Me
Me
CuL
O
O
O
O
*
*
*
*
Ph
N
Ph
N
N
N
NaOt-Bu
t-BuOH
D
F
Br
Cl
P
P
MeS
(+)-6g, 68%, 88:12 er
Cl
O
N
Cu
Cy2P
Cu
O
(-)-6h, 53%, 89:11 er (-)-6i, 51%, 85:15 er
(+)-6k, 78%, 89:11 er

PCy2
Ph
N
C
Scheme 8. Substrate Scope of the Enantioselective Intramolecular Cope-type
Hydroamination of Alkenyl oximes 1. Conditions: oxime 1 (0.20 mmol), Cu (5
mol%), L9 (0.012 mmol, 6 mol%), NaOt-Bu (0.06 mmol, 30 mol%), t-BuOH (0.60
mmol, 3 equiv.), CyH (2 mL), N2.For 4, the reactions were performed with
Cu(OAc)2 at 10oC; for 6, the reactions were performed with CuCl at 30oC for 12
h, then 50oC, 12 h. [a] L8 was used as ligand.
Ph
A

P
O

Ph
n
N
Cu
P
o
i
t
a
Cy2P
x
e
l
p
C
u
PCy2
m
o
O
N
metalla-retro-Cope
intermediate
c
-

Ph
B
Figure 4. A plausible mechanism.
Conclusions
In conclusion, a CuI-based catalytic system is proven effective
for intramolecular Cope-type hydroamination of oxime with non-
activated olefins, enabling efficient access to a variety of 5- and
6-membered cyclic nitrones that are otherwise challenging to
attain or intangible. For the first time, aza- and heterocycle fused
vinyl oximes were incorporated into the reactivity domain of Cope-
type hydroamination, expanding the diversity and accessibility of
cyclic nitrones. Moreover, high enantioselectivities were also
achieved for carbon-tethered 5-membered nitrones, representing
the first example of high enantioselective catalytic cyclic nitrones
synthesis from alkenyl oximes. Mechanistic studies suggest a
mononuclear catalytic species and a unified catalytic pathway
over a large temperature range. Further studies are underway in
our laboratory to expand this strategy to other types of substrates.
Figure 3. Mechanistic studies. Non-linear effect (left) and Eyring plot (right) of
the reaction of 1acatalyzed by CuCl/(R, R)-Ph-BPE to form (+)-4a at various
temperatures in toluene.
observed experimentally.From the Eyring plot, differential
activation parameters (ΔΔH≠ = ‒0.70 kcal/mol; ΔΔS≠ = ‒0.55
cal/mol·K) can be facily extracted.This relatively small differential
activation enthalpy and especially smalldifferntial activation
entropy indicate that the enthalpy term plays a more dominant role
in the the stereodiscrimination process.42The appreciable solvent
effect on the enantiocontrol likely arises from the formation of
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10.1002/chem.201902683
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[19] J.Moran, S. I.Gorelsky, E.Dimitrijevic, M.-E.Lebrun, A.-C.Bédard, C.Séguin,
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Entry for the Table of Contents (Please choose one layout)
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A Cu(I)-based catalyst system
enables Cope-type hydroamination of
several distinct types of vinyl oximes
under mild conditions, offering access
to cyclic nitrones otherwise
Mengru Zhang,Shuang Liu,Hexin Li,
Yajing Guo, Na Li, Meihui Guan, Haroon
Mehfooz, Jinbo Zhao* and Qian Zhang*
Page No. – Page No.
inaccessible via traditional protocols
and allows for highly enantioselective
synthesis of 5-membered cyclic
nitrones.
Cu-Catalyzed Cope-Type
Hydroamination of Non-activated
Olefins toward Cyclic
Nitrones:Scope, Mechanism and
Enantioselective Process
Development
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