Enantioselective, Aerobic Copper-Catalyzed Intramolecular Carboamination and Carboetherification of Unactivated Alkenes

Article abstract of DOI:10.1021/acscatal.0c02607

Reduction of waste is an important goal of modern organic synthesis. We report herein oxidase reactivity for enantioselective intramolecular copper-catalyzed alkene carboamination and carboetherification reactions where previously used stoichiometric MnO2

Full text of DOI:10.1021/acscatal.0c02607

Subscriber access provided by the University of Exeter
Letter
Enantioselective, Aerobic Copper-Catalyzed Intramolecular
Carboamination and Carboetherification of Unactivated Alkenes
Tomasz Wdowik, Samuel L. Galster, Raul Carmo, and Sherry R Chemler
ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.0c02607 • Publication Date (Web): 16 Jul 2020
Downloaded from pubs.acs.org on July 16, 2020
Just Accepted
“Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted
online prior to technical editing, formatting for publication and author proofing. The American Chemical
Society provides “Just Accepted” as a service to the research community to expedite the dissemination
of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts appear in
full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been fully
peer reviewed, but should not be considered the official version of record. They are citable by the
Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered to authors. Therefore,
the “Just Accepted” Web site may not include all articles that will be published in the journal. After
a manuscript is technically edited and formatted, it will be removed from the “Just Accepted” Web
site and published as an ASAP article. Note that technical editing may introduce minor changes
to the manuscript text and/or graphics which could affect content, and all legal disclaimers and
ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors or
consequences arising from the use of information contained in these “Just Accepted” manuscripts.
is published by the American Chemical Society. 1155 Sixteenth Street N.W.,
Washington, DC 20036
Published by American Chemical Society. Copyright © American Chemical Society.
However, no copyright claim is made to original U.S. Government works, or works
produced by employees of any Commonwealth realm Crown government in the course
of their duties.

Page 1 of 9
ACS Catalysis
1
2
3
4
5
6
7
8
9
Enantioselective, Aerobic Copper-Catalyzed Intramolecular
Carboamination and Carboetherification of Unactivated
Alkenes
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Tomasz Wdowik, Samuel L. Galster, Raul L. L. Carmo, and Sherry R. Chemler*
Department of Chemistry, State University of New York at Buffalo, Buffalo, New York 14260, United States
KEYWORDS: asymmetric catalysis, copper, aerobic oxidation, carboamination, carboetherification, alkene
ABSTRACT: Reduction of waste is an important goal of modern organic synthesis. We report herein oxidase reactivity for
enantioselective intramolecular copper-catalyzed alkene carboamination and carboetherification reactions where
previously used stoichiometric MnO2 has been replaced with oxygen. This substitution was risky as the reaction mechanism
is thought to involve C–C bond formation via addition of alkyl carbon radicals to arenes. Such intermediates are also
susceptible to C–O bond formation via O2 addition. Control of absolute stereochemistry under aerobic conditions was also
uncertain. The oxidative cyclization efficiencies appear to track with the ease of the radical addition to the arenes.
Oxygen is the most abundant element in the Earth's crust, and
the third-most abundant element in the universe. It plays an
essential role in biological processes such as cellular
respiration, and is incorporated in a vast majority of
biomolecules. It is also considered an ideal oxidant because of
its low cost, high abundance, high atom economy, and the
non-toxic character of its reaction byproducts. Consequently,
much effort has been devoted to the study and understanding
of aerobic processes designed by nature as well as the chemical
industry.1,2 In these processes, oxygen can act as either an
oxidant that is reduced to water (oxidase-like activity), a
reagent that is incorporated into the final product (oxygenase-
like activity), or both.3,4 The sustainable nature of aerobic
oxidations can be further enhanced by developing catalytic
reactions that rely on earth-abundant transition metals like
copper.3, 5-7
homolysis of the resulting alkyl-Cu(II) bond, and oxidation of
the subsequent primary radical intermediate with molecular
oxygen to generate N-heterocyclic aldehydes, γ-lactams and γ-
lactones (Scheme 1A).11a Copper halides, e.g. CuCl,11a or copper
carboxylates11b,c are the most effective pre-catalysts reported
for such transformations.
Advances in copper-catalyzed alkene heterofunctionalization
reactions that enable the synthesis of ethers and amine
derivatives and that require either external oxidants or pre-
oxidized reagents have been reported.8 Stoichiometric
oxidants and reagents that have been applied include MnO2,8a
hypervalent
iodine
reagents,8b-g
Ag2CO3,8d
hydroxylamines,8i-k
N-
fluorobenzenesulfonamide,8c,h
diaziradinones,8l peroxides,8m-o and K2S2O8.8p Several of these
transformations are thought to involve carbon radical
intermediates. The application of air or oxygen as
stoichiometric oxidant in copper-catalyzed alkene
heterofunctionalizations that do not incorporate the oxygen
moiety into the product (oxidase function) are uncommon,9
and enantioselective examples are even more rare.10
Scheme 1. Copper-catalyzed difunctionalization of alkenes
Our attempts to render our aminooxygenation reaction
enantioselective using chiral bis(oxazoline) ligands (Figure 1)
met with promising, yet limited success (ca. 45% ee).11a The
poor enantioselectivity was disappointing because, prior to
this oxygenase work, we had developed
enantioselective intramolecular aminooxygenation reaction
using 2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPO) as the
We recently explored aerobic copper-catalyzed oxygenase-
like activity in the oxidative cyclization of alkenols and alkenyl
sulfonamides.11a These reactions are thought to involve
copper-catalyzed heterocyclization onto the alkene,
a
highly
1
ACS Paragon Plus Environment

ACS Catalysis
Page 2 of 9
radical trap, [Cu(4R,5S)-Ph-Box](OTf)2 as catalyst and O2 as
a drawback were these reactions performed on large scale.
Given our recent promising results in the oxygenase-type
aminooxygenations,11a we decided, then, to reinvestigate
stoichiometric oxidant (Scheme 1B).10 We hypothesized that
TEMPO radical served as an intermediary oxidant between
Cu(I) and O2, effecting turnover to Cu(II), since the copper-
catalyzed aminooxygenation worked well (at small scale) with
excess TEMPO in the absence of O210 and related aerobic [Cu]-
catalyzed oxidative aminations are aided by catalytic
TEMPO.12
1
2
3
4
5
6
7
8
molecular
oxygen
as
stoichiometric
oxidant
for
enantioselective copper-catalyzed carboamination and
carboetherification reactions (Scheme 1C).16
Our initial investigation into copper-catalyzed oxidase-type
reactions focused on the conversion of 4-pentenylsulfonamide
1 to sultam 2. Under O2 (1 atm) we had previously observed
that either aldehyde 4 or -lactam 5 could be formed
preferentially using CuCl as pre-catalyst, where the preference
for 4 or 5 largely depended on the presence or absence of
ligand, e.g. the achiral bis(oxazoline), L1 (Table 1, entries 1 and
2).9a By comparison, the reaction catalyzed by Cu(OTf)2•L1
under O2 provided ca. 25% of 4, 18% of 5, 57% of substrate 1
and trace sultam 2 (Table 1, entry 3). We speculated that the
amount of sultam 2 could be further enhanced by lowering the
O2 concentration from 100% to ca. 21% (air) or 10%. Lowering
the O2 concentration should kinetically disfavor the
intermolecular reaction of the carbon radical intermediate
with oxygen, while maintaining oxygen facilitated oxidation of
copper(I) to copper(II) that is necessary for catalytic turnover.
This concept was examined under a variety of conditions
employing both achiral and chiral ligands (Table 1).
Concurrently, we developed a series of enantioselective
copper-catalyzed intramolecular carboamination and
carboetherification reactions using manganese(IV) oxide
(MnO2) as stoichiometric oxidant (bottom of Scheme 1).13 In
2007, we reported the enantioselective carboamination of
alkenes towards sultams.13a In this reaction the primary carbon
radical adds to the aromatic ring of the N-tosyl group and,
after rearomatization, leads to a sultam. A similar concept was
used in the synthesis of hexahydro-1H-benz[f]indoles.13b
Related hexahydronaphtho[2,3-b]furans were obtained via
doubly intramolecular carboetherication of alkenes.13c,d While
this latter reaction was primarily explored in its racemic
variant,13c a few examples suggested the enantioselective
potential of this transformation.13d More recently, an
enantioselective intramolecular carboetherication of 1,1-
disubstituted alkenes towards spirocyclic ethers was
disclosed.13e
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Table 1. Optimization for carboamination, sultam 2a
In our initial investigation with the [Cu(R,R)-Ph-Box](OTf)2
catalyzed enantioselective alkene carboamination, for the
formation of chiral sultams, MnO2 was identified as the best
oxidant for optimal yield and enantioselectivity.13a Use of O2
as oxidant led to very poor reactivity in this system. Related
enantioselective copper-catalyzed alkene diamination
reactions have also been developed where MnO2 was also
employed.14 Interestingly, while (t-BuO)2 was an effective
oxidant for a related copper-catalyzed alkene diamination
reaction, the products were racemic.14 Additionally, use of
copper(II) carboxylates as precatalyst with (R,R)-Ph-Box also
resulted in racemic product formation in our carboamination
and carboetherification reactions.13a,13c Thus, we conclude
both the copper(I/II) counterion [OTf versus Cl or OC(O)R]
and the stoichiometric oxidant [MnO2 or O2/TEMPO versus
(t-BuO)2] are important factors that impact product
enantioselectivity. Based on our aminooxygenations involving
TEMPO and O2 (Scheme 1B), we were optimistic that if good
turnover efficiency could be achieved with O2 as sole oxidant,
then under such conditions an enantioselective alkene
aminofunctionalization could also be developed. However, in
the absence of TEMPO, enantioselectivity with use of O2 as
sole oxidant was not a foregone conclusion as it or its
byproducts could potentially coordinate to the copper center
and disrupt the enantioselectivity-determining step.
entr
y
Cu salt
L
oxidan
t
tim
e
(h)
products
, yield
(%)
ee
2
(%
)
111a
211a
311a
--
L1
L1
100%
O2
5
4: 62
n.a
.
CuCl
(20
mol%)
100%
O2
20
20
4: 20b; 5:
n.a
.
CuCl
(20
mol%)
80b
100%
O2
4: 25b; 5:
18%b; 1:
57%b;
n.a
.
Cu(OTf)
2
(20
mol%)
trace 2 b
4
5
L1 10% O2
in N2
7
2: 63%
n.a
.
CuCl
(15
mol%)
L1
L1
air
air
24
24
1b: 9, 2b:
44, 3: 17
n.a
.
CuCl
(20
mol%)
6c
CuCl
(20
2: 50, 3:
n.a
.
Figure 1. Bis(oxazoline) ligands used in this study
18
mol%)
The use of stoichiometric MnO2 as oxidant contributes
negatively to the E-factor of these reactions,15 which would be
2
ACS Paragon Plus Environment

Page 3 of 9
ACS Catalysis
7c
8d
9c
10
L1
none
17
7
mostly 1
n.a
.
here.11a) After switching back to copper(I) chloride, we
CuCl
(15
mol%)
1
2
3
4
5
6
7
8
observed improved reactivity with L3, however, the
enantioselectivity was still low (entry 11). We hypothesize that
the chloride diminishes asymmetric induction, perhaps by
serving as an extra ligand on [Cu] in the enantioselectivity-
determining aminocupration step.8a We speculated that silver
triflate could sequester chloride and therefore minimize
aminochlorination 3, and possibly increase enantioselectivity.
Indeed, we found that the addition of AgOTf (40 mol%) to the
carboamination reaction (Table 1, entry 12) resulted in 27%
yield of sultam 2, formed in 89% ee. The remainder of the
material was primarily substrate 1 (54%). Despite the fact that
only good reactivity or high enantioselectivity could be
achieved for this system, the copper turnover under aerobic
carboamination conditions was established.
We hypothesized that substrates that could undergo the
product-forming C–C bond formation (carbon radical
addition to pendant arene) more readily might display better
reactivity under the aerobic conditions. The anaerobic
copper-catalyzed carboamination towards fused ring N-
heterocycles (cf. 6  7) exhibited excellent yields and
enantioselectivity and was compatible with a wide range of
functional groups.13b Therefore, it was reasonable to develop
an aerobic variant of the carboamination reaction for alkenes
6. To our delight, a racemic reaction using CuCl•L1 under air
provided the product with quantitative yield (Table 2, entry 1).
Following this result, a series of chiral copper complexes were
tested under the same conditions. A summary of these
experiments is presented in Table 2.
L1 10% O2
1: 89, 3: 5 n.a
CuCl
(15
mol%)
in N2
.
L
2
10% O2
in N2
22
24
1b: 49, 2b:
23, 3b: 8,
4b: 16
29
CuCl
(15
mol%)
9
L3
dried
air
1 (no
reaction)
n.a
.
Cu(OTf)
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
2
(20
mol%)
11
CuCl
(20
mol%)
CuCl
L3
L3
dried
air
24
24
2: 56, 3:
18, 4: 5
29
89
12e
dried
air
2b: 27, 1b:
54, 4: 4
(20
mol%) +
AgOTf
(40
mol%)
a Ligand (L) loading = 1.1 x copper salt loading. Reactions run
on 0.19 mmol of 1 in PhCH3 (0.1 M w/r to 1). Yields are of
isolated products unless otherwise noted. bYields are
estimated based on NMR ratio. c Solvent = PhCF3 (0.1 M w/r
to 1). d K2CO3 (1 equiv) was included in the reaction. e 4% of
the corresponding 2-hydroxymethyl-N-sulfonylpyrrolidine
was also obtained.
Table 2. Optimization of aerobic carboamination of
alkenes towards fused ring N-heterocyclesa
Employing CuCl•L1 as pre-catalyst,11a we were delighted to find
we could obtain racemic sultam 2 in moderate to good yields
both under air (filling headspace of a pressure tube) and 10%
oxygen in nitrogen (balloon, 1 atm) atmosphere (Table 1,
entries 4-6). It should be noted that at lower reaction
temperatures the amount of aldehyde 4 increases (not
shown). A control experiment was also performed to verify
whether oxygen is necessary for reaction completion (entry 7).
Post-reaction TLC indicated mostly starting material, while
traces of sultam 2 and chloride 3 were also visible in the crude
NMR spectrum. In addition, when the aerobic reaction was
performed in the presence of K2CO3 (1 equiv), little conversion
was observed (entry 8). It is likely K2CO3 impedes the reaction
by sequestering the required protons for the conversion of O2
to H2O. Switching to the chiral ligand (R,R)-Ph-Box, L2 (see
Figure 1 for structure), one of the ligands optimal for the
previously reported anaerobic (MnO2 oxidant) copper-
catalyzed alkene carboamination conditions13a resulted in
poor reactivity and enantioselectivity (entry 9). Additionally,
carboamination was accompanied by competitive reactions:
aminochlorination 3 as well as aminooxygenation 4. We
investigated copper(II) triflate, the optimal copper source for
many of the enantioselective alkene difunctionalizations we
had developed under anaerobic conditions and those where
TEMPO was used as co-oxidant under aerobic conditions
(Scheme 1). Unfortunately, no conversion was observed even
when copper(II) triflate was combined with (4R,5S)-bis-Ph-
Box, L3, a frequently superior chiral ligand17 with better
solubility in organic solvents (entry 10). (We note that the
organic soluble Cu(CH3CN)4PF6 had demonstrated low
conversion of 1 to 4 in our previous study, so it was not applied
entry
1
Cu salt
L
oxidant
air
yield 7a
(%)
ee
(%)
L1
97
n.a.
CuCl
(20 mol%)
2
3
4
5
6
7
CuCl
(20 mol%)
CuCl
L4
L5
L1
air
air
ca. 73
ca. 67
ca. 76c
68c
<5
-45
n.a.
87
(20 mol%)
Cu(OTf)2
(20 mol%)
Cu(OTf)2
(20 mol%)
Cu(OTf)2
(20 mol%)
Cu(OTf)2
(20 mol%)
airb
airb
airb
L2
L3
97
93
L3 10% O2
97
92
in N2
8
9
Cu(OTf)2
(15 mol%)
Cu(OTf)2
(10 mol%)
L3 10% O2
in N2
L3 10% O2
in N2
93
89
95
94
a Ligand (L) loading = 1.1 x Cu salt loading. Reactions run on
0.19 mmol of 6a at 0.1 M. bDried air. cUnreacted 6a (about 25%)
was also obtained.
3
ACS Paragon Plus Environment

ACS Catalysis
Page 4 of 9
Chiral ligands that enabled good reactivity, i.e., (R,R)-Bn-Box,
1
L4 and (4S,5R)-bis-Ph-Box, L5, offered no or poor
enantioselectivity when combined with CuCl (entry 2 and 3).
The reactivity of the catalytic system based on an achiral box
ligand suffered somewhat, once chloride was replaced with
triflate (97% vs. 76% yield). Surprisingly, the opposite was true
for chiral ligands, where great improvement of reactivity and,
particularly, enantioselectivity was observed (entries 5–9).
Using L3, we were able to achieve the same level of yields and
enantiomeric excesses as in the original MnO2-based
protocol.13a It is also worth mentioning that because of the
increased lipophilicity of [Cu]•L3 complex (in comparison to
[Cu]•L2), the more expensive trifluorotoluene solvent, used in
the original studies, could be replaced with less polar toluene.
While running the reaction under air was convenient from the
operational point of view and did not result in unwanted
oxygenase-like activity (which would result in aldehydes or
alcohols), performing the reaction on a larger scale could
present a challenge due to the flammability risk associated
with exposing toluene to oxygen at elevated temperatures.18
To address this problem, we lowered the oxygen
concentration to the level below limiting oxygen
concentration for toluene in similar conditions (10% oxygen in
nitrogen).18 This change did not affect the reaction, leading to
the most optimal conditions for aerobic carboamination
towards fused-ring heterocycles (entry 7). We could also lower
the catalyst loading from 20 to 15 mol% and even 10 mol%
without diminishing selectivity and minimally diminishing
efficiency (entries 8–9). The scope of this aerobic copper-
catalyzed enantioselective carboamination reaction was
explored as illustrated in Chart 1.
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
aConditions from Table 2, entry 7 were used.
Chart 1. Reaction scope of aerobic enantioselective
arboamination of N-(4-pentenyl)arylsulfonamidesa
The reaction is compatible with both electron withdrawing
and electron donating substituents on both the aromatic ring
that serves as radical acceptor and the sulfonamide arene (Ts
and Ns). This carboamination protocol gave yields and
selectivities comparable to the conditions that previously
employed MnO2 as oxidant.13b Additionally, product 7f was
generated for the first time to illustrate the compatibility of
synthetically useful silyl ethers in this transformation. The
enantiomers of 7f were inseparable using several chiral HPLC
methods, so the % ee of 7f was not obtained, unfortunately.
We next expanded our enantioselective aerobic copper-
catalyzed investigations to intramolecular carboetherication
of alkenols to access fused-ring ethers.13c,d Since the analogous
enantioselective anaerobic (using MnO2 oxidant) alkene
carboetherifications had required (S,S)-t-Bu-Box, L6, for
optimal enantioselectivity in our previous studies (limited to
3 examples),13d reaction conditions were reinvestigated for the
aerobic process using alkenol 8a (Table 3).
Table 3. Optimization of aerobic carboetherification
of alkenes towards fused ring O-heterocyclesa
4
ACS Paragon Plus Environment

Page 5 of 9
ACS Catalysis
entry
Cu salt
L
oxidant additive yield
(%)
ee
(%)
1
2
3
4
5
6
7
8
9
1
L6
L6
air
airb
none
32
<5
CuCl
CuCl
2
AgOTf
(40
mol%)
AgOTf
(40
mol%)
AgOTf
(30
mol%)
AgOTf
(20
40
-62
3
4
5
CuCl
CuCl
CuCl
CuCl
L2
L2
L2
L2
airb
airb
airb
65
70
51
90
90
89
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
mol%)
none
6
7
airb
airb
airb
airb
30
30c
55
81
85
-67
90
87
Cu(OTf)2 L6
Cu(OTf)2 L2
Cu(OTf)2 L3
none
none
none
none
8
9
10
Cu(OTf)2 L3 10% O2
81
86
in N2
Cu(OTf)2 L3 10% O2
in N2
11d
none
60
85
aLigand (L) loading = 1.1 x Cu salt loading. Reactions run on
0.19 mmol of 8a at 0.1 M. bDried air. c 52% of 8a was recovered.
dReaction run in toluene.
aConditions: Table 3, entry 10. bL6 was used.
When the best ligand in the related anaerobic studies,13d L6,
was combined with copper(I) chloride, a racemic mixture of
9a was obtained (Table 3, entry 1). Addition of silver triflate
dramatically improved enantioselectivity (to 62% ee, entry 2).
The same level of reactivity and enantioselectivity was
observed when copper(II) triflate was used (entry 7). It
appears, however, that in this particular reaction, the
bis(oxazoline) ligand has more effect on enantioselectivity
than the copper source, as comparable values of ee (85%–90%)
were obtained with CuCl (entry 6), CuCl/AgOTf (entries 3–5),
and Cu(OTf)2 (entry 8) when the ligand was L2. These data
could mean that the alcohol substrate is more effective at
displacing the chloride, compared to the sulfonamide. An
improvement of reactivity was achieved with the more
lipophilic (4R,5S)-bis-Ph-Box, L3, whose use resulted in 81%
yield and 87% ee (entry 9). Changing the oxidant from air to
10% oxygen in nitrogen had virtually no effect on the reaction
(entry 10), and it was used as a safe oxidant in studies exploring
the substrate scope of this transformation (Chart 2).
Changing from a tertiary alcohol substrate, producing 9a, to a
primary alcohol substrate, producing 9b, resulted in
diminished enantioselectivity, though L6 gave superior results
to L3 (Chart 2). The alcohol sterics were also important to the
enantioselectivity in the anaerobic copper-catalyzed
carboetherification variant.13d Both electron-donating and
electron-withdrawing arene substituents were compatible,
including substrates with more readily activated groups such
as bromide 9c and silyl ether 9e (both functionalities are
newly demonstrated herein for this carboetherification
reaction). While the aryl substituents did impact the
enantioselectivity, (±10% ee) there was no clear trend.
The aerobic copper-catalyzed enantioselective synthesis of
spirocyclic
ethers13e
was
explored
next.
Aerobic
spirocyclization was deemed feasible upon successful
conversion of alkenol 10 to spirocycle 11 catalyzed by CuCl•L1
(Table 4, entry 1). Re-optimization of the enantioselective
carboetherification, however, was required because the
conditions optimal for the fused-ring synthesis [Table 3, entry
10, use of Cu(OTf)2•L3] did not provide any spirocycle 11, but
rather produced a hydroetherification/cyclization product
(Table 4, entry 2). Application of a hindered pyridine base (1
equiv) as additive (to sequester any strong acid, e.g. HOTf) led
to minimal conversion to a mixture of hydroetherification and
spirocycle products (ca. 5%, Table 4, entry 3). Fortunately,
changing to (R,R)-Ph-Box, L2, led to 29% isolated 11 albeit in
22% ee (Table 4, entry 4). More encouragingly, changing to
(S,S)-t-Bu-Box, L6, provide 30% of 11 in 72% ee (Table 4, entry
5). Given the poor yields, use of the potentially more robust
pre-catalyst CuCl was investigated further. While the CuCl•L2
pre-catalyst, in the presence of AgOTf additive gave a much
improved 81% yield of 11, it was practically racemic (Table 4,
entry 6). Further screening revealed that use of
CuCl•L6/AgOTf could give spirocycle 11 in 30% isolated yield
in 90% ee. Although the remainder of the mass was largely
starting 10, longer reaction time under these conditions did
not lead to higher yields (Table 4, entry 10). Use of the less
sterically hindered (S,S)-i-Pr-Box, L7, did not improve
conversion either (Table 4, entry 11).
Table 4. Optimization of aerobic carboetherification
of alkenol towards spirocyclic ethersa
Chart 2. Reaction scope of aerobic enantioselective
carboetherification of alkenolsa
5
ACS Paragon Plus Environment

ACS Catalysis
Page 6 of 9
intermolecular carboetherification under aerobic conditions
are being made.
1
In conclusion, an aerobic protocol for copper-catalyzed
enantioselective carboamination and carboetherication of
alkenes has been developed. The efficiency and selectivity of
the reactions vary with copper pre-catalyst, chiral ligand, and
substrate structure. For fused-ring heterocycle synthesis, the
reaction offers high yields and enantioselectivity and uses
industrially-friendly 10% oxygen in nitrogen as an oxidant and
Cu(OTf)2 as pre-catalyst.18 This methodology can be extended
towards the synthesis of sultams and spirocyclic ethers
although the efficiencies of these processes are lower. For
these less efficient transformations, the CuCl/AgOTf-based
pre-catalyst is more effective, likely due to its higher stability
in a reaction that creates water as a byproduct. Under the
aerobic conditions, the copper catalyst likely becomes inactive
over time, so a more stable catalyst, and substrates that react
with higher rate, positively impact the efficiency of the
reaction. This research adds new reactions to a growing
arsenal of aerobic transformations and provides access to
chiral saturated heterocycles potentially useful in medicinal
chemistry endeavors.
2
3
4
5
6
7
8
9
entr
y
Cu salt
CuCl
L
Additive
yield (%)
ee
(%
)
1
L1
none
none
22
n.a
.
2
Cu(OTf) L3
not
n.a
.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
obtained
2
b
3
Cu(OTf) L3
2,6-di-t-Bu-4-
methylpyridin
trace
n.a
.
2
e
4
5
Cu(OTf) L2
none
29
-22
72
2
Cu(OTf)
L
6
L2
none
30c
2
6
7
CuCl
AgOTf
AgOTf
81
-10
CuCl
L3
not
n.a
.
obtained
AUTHOR INFORMATION
b
8
9
CuCl
CuCl
CuCl
CuCl
L
6
L
6
L
6
L7
none
n.d.
32
-2
90
79
70
Corresponding Author
*E-mail: schemler@buffalo.edu.
AgOTf
AgOTf
AgOTf
ORCID
10d
33
Tomasz Wdowik: 0000-0002-9840-1501
Sherry R. Chemler: 0000-0001-6702-5032
Raul L. L. Carmo: 0000-0001-9917-5422
11
26
aLigand (L) loading = 1.1 x Cu salt loading. Reactions run on
0.19 mmol of 10 at 0.1 M. racemic
bA
hydroetherification/cyclization product (ca. 50%) was
obtained. c 48% of starting 10 was recovered. d Reaction time
was 48 h.
Funding Sources
National Institutes of Health (GM 078383).
Notes
The authors declare no competing financial interest.
Although no conditions delivering both high reactivity and
enantioselectivity were found, the conditions from Table 4,
entry 9 were used for other alkenes to expand the substrate
scope of the reaction (Chart 3).13e Aerobic carboetherication
for formation of a six-membered ring is also feasible:
morpholine 12 was obtained in 40% isolated yield along with
28% of the recovered starting alkenol. Bis-heterospirocycle 13
was formed in similar yield and excellent enantioselectivity.
ABBREVIATIONS
Ar = aryl
Bn = benzyl
ee = enantiomeric excess
HPLC = high-performance liquid chromatography
i-Pr – isopropyl
Me = methyl
MS = molecular sieves
n.d. = not determined
n.a. = not applicable
Chart 3. Reaction scope of aerobic enantioselective
spirocyclization of alkenolsa
NMR = nuclear magnetic resonance
Ns = p-nitrobenzenesulfonyl
Ph = phenyl
TBS = tert-butyldimethylsilyl
t-Bu = tert-butyl
TEMPO = 2,2,6,6-tetramethylpiperidine-1-oxyl
Tf = trifluoromethylsulfonyl
TLC = thin layer chromatography
Ts = p-toluenesulfonyl
aConditions: Table 4, entry 9
Extension of the methodology to intermolecular C-C bond
forming reactions, such as addition of the carbon radical
intermediate to styrenes,13d has thus far been limited by the
proclivity of the radical acceptor styrenes to undergo
oxidation to aldehydes and ketones under the copper-
catalyzed aerobic conditions.19 Further efforts to achieve
ASSOCIATED CONTENT
Supporting Information
6
ACS Paragon Plus Environment

Page 7 of 9
ACS Catalysis
Angew. Chem. Int. Ed. 2014, 53, 2034-2036. l) Zhu, Y.; Cornwall, R.
The Supporting Information is available free of charge on the
ACS Publications website at DOI:
G.; Du, H.; Zhao, B.; Shi, Y., Catalytic Diamination of Olefins via
N-N Bond Activation, Acc. Chem. Res. 2014, 47, 3665-3678. m)
Chatalova-Sazepin, C.; Wang, Q.; Sammis, G. M.; Zhu, J., Copper-
catalyzed intermolecular carboetherification of unactivated
alkenes by alkyl nitriles and alcohols, Angew. Chem. Int. Ed. 2015,
54, 5443-5446. n) Liu, R.; Wang, Z.; Wei, B.; Zhang, J.; Zhou, B.;
Han, B., Cu-Catalyzed aminoacyloxylation of unactivated alkenes
of unsaturated hydrazones with manifold carboxylic acids toward
ester-functionalized pyrazolines, Org. Lett. 2018, 20, 4183-4186. o)
Xiong, Y.; Zhang, B.; Yu, Y.; Weng, J.; Lu, G., Construction of
sulfonyl phthalides via copper-catalyzed oxysulfonylation of 2-
vinylbenzoic acids with sodium sulfinates, J. Org. Chem. 2019, 84,
13465-13472. p) Zhang, H.; Mao, L.; Yang, B.; Yang, S., Copper-
catalyzed radical cascade cyclizations for the synthesis of
phosphorated indolines, Chem. Commun. 2015, 51, 4101-4105.
(9) Racemic Cu-catalyzed aerobic alkene difunctionalization and
related transformations: a) Oxyamination (with KI additive): Wu,
F.; Steward, S.; Ariyarathna, J. P.; Li, W. Aerobic copper-catalyzed
alkene oxyamination for amino lactone synthesis, ACS Catal.,
2018, 8, 1921-1925. b) Sulfenoamination: Ni, Y.; Zuo, H.; Li, Y.; Wu,
Y.; Zhong, F., Copper-catalyzed regioselective intramolecular
electrophilic sulfenoamination via Lewis acid activation of
disulfides under aerobic conditions, Org. Lett. 2018, 20, 4350-4353.
c) Iodolactonization: Aerobic catalytic features in photoredox-
and copper-catalyzed iodolactonization reactions, Org. Lett. 2018,
20, 6462-6466. d) Oxyamination (with KI additive): Wu, F.;
Ariyaratha, J. P.; Alom, N.; Kaur, N.; Li, W., Oxyamination of
unactivated alkenes with electron-rich amines and acids via a
catalytic triiodide intermediate, Org. Lett. 2020, 22, 884-890. e)
Liu, R.; Wei, D.; Han, B.; Yu, W., Copper-catalyzed oxidative
oxyamination/diamination of internal alkenes of unsaturated
oximes with simple amines, ACS Catal. 2016, 6, 6525-6530.
(10) Fuller, P. H.; Kim, J. W.; Chemler, S. R., Copper catalyzed
enantioselective intramolecular aminooxygenation of alkenes. J.
Am. Chem. Soc. 2008, 130, 17638-17639.
(11) a) Wdowik, T.; Chemler, S. R., Direct synthesis of 2-
formylpyrrolidines, 2-pyrrolidinones and 2-dihydrofuranones via
aerobic copper-catalyzed aminooxygenation and dioxygenation
of 4-pentenylsulfonamides and 4-pentenylalcohols. J. Am. Chem.
Soc. 2017, 139, 9515-9518. Related oxygenase reactions: b) Li, J.;
Wei, J.; Zhu, B.; Wang, T.; Jiao, N., Cu-catalyzed oxygenation of
alkene-tethered amides with O2 via unactivated C=C bond
cleavage: a direct approach to cyclic imides, Chem. Sci. 2019, 10,
9099. c) Liu, Z.; Wang, P.; Ou, H.; Yan, Z.; Chen, S.; Tan, X.; Yu,
D.; Zhao, X.; Mu, T., Preparation of cyclic imides from alkene-
tethered amides: application of homogeneous Cu(II) catalytic
systems, RSC Adv., 2020, 10, 7698.
(12) Liwosz, T. W.; Chemler, S. R., Copper-catalyzed synthesis of
N-aryl and N-sulfonyl indoles from 2-vinylanilines with O2 as
terminal oxidant and TEMPO as co-catalyst. Synlett 2015, 26, 335-
339.
(13) a) Zeng, W.; Chemler, S. R., Copper(II)-catalyzed
enantioselective intramolecular carboamination of alkenes, J. Am.
Chem. Soc. 2007, 129, 12948-12948. b) Miao, L.; Haque, I.;
Manzoni, M. R.; Tham, W. S.; Chemler, S. R., Diastereo- and
1
2
3
4
5
6
7
8
Experimental procedures and characterization of
new compounds (PDF)
NMR spectra (PDF)
ACKNOWLEDGMENT
We thank the National Institutes of Health for financial
support (GM 078383).
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
REFERENCES
(1) Cavani, F.; Teles, J. H., Sustainability in catalytic oxidation: an
alternative approach or a structural evolution? Chemsuschem
2009, 2, 508-534.
(2) Caron, S.; Dugger, R. W.; Ruggeri, S. G.; Ragan, J. A.; Ripin, D.
H. B., Large-scale oxidations in the pharmaceutical industry.
Chem. Rev. 2006, 106, 2943-2989.
(3) McCann, S. D.; Stahl, S. S., Copper-catalyzed aerobic
oxidations of organic molecules: pathways for two-electron
oxidation with a four-electron oxidant and a one-electron redox-
active catalyst. Acc. Chem. Res. 2015, 48, 1756-1766.
(4) Liang, Y. J.; Wei, J. L.; Qiu, X.; Jiao, N., Homogeneous
oxygenase catalysis. Chem. Rev. 2018, 118, 4912-4945.
(5) Wendlandt, A. E.; Suess, A. M.; Stahl, S. S., Copper-catalyzed
aerobic oxidative C–H functionalizations: trends and mechanistic
insights. Angew. Chem. Int. Ed. 2011, 50, 11062-11087.
(6) Trammell, R.; Rajabimoghadam, K.; Garcia-Bosch, I., Copper-
promoted functionalization of organic molecules: from
biologically relevant Cu/O2 model systems to organometallic
transformations. Chem. Rev. 2019, 119, 2954-3031.
(7) Allen, S. E.; Walvoord, R. R.; Padilla-Salinas, R.; Kozlowski, M.
C., Aerobic copper-catalyzed organic reactions. Chem. Rev. 2013,
113, 6234-6458.
(8) a) Chemler, S. R.; Karyakarte, S. D.; Khoder, Z. M.,
Stereoselective and regioselective synthesis of heterocycles via
copper-catalyzed additions of amine derivatives and alcohols to
alkenes, J. Org. Chem. 2017, 82, 11311-11325. b) Zhu, X.; Chiba, S.,
Copper-catalyzed oxidative carbon–heteroatom bond formation:
a recent update, Chem. Soc. Rev. 2016, 45, 4504-4523. c) Wang, F.;
Chen, P.; Liu, G. Copper-catalyzed radical relay for aymmetric
radical transformations, Acc. Chem. Res. 2018, 51, 2036-2046. d)
Zhu, R.; Buchwald, S. L., Versatile enantioselective synthesis of
functionalized
lactones
via
copper-catalyzed
radical
oxyfunctionalization of alkenes, J. Am. Chem. Soc. 2015, 137, 8069-
8077. e) Lu, M.; Wang, C.; Loh, T., Copper-catalyzed vicinal
oxyazidation and diazidation of styrenes under mild conditions:
access to alkyl azides, Org. Lett. 2015, 17, 6110-6113. f) Fumagalli,
G.; Rabet, P. T. G.; Boyd, S.; Greaney, M. F., Three-component
azidation of styrene-type double bonds: light-switchable behavior
of a copper photoredox catalyst, Angew. Chem. Int. Ed. 2015,
54,11481-11484. g) Nakanishi, M.; Minard, C.; Retailleau, P.; Cariou,
K.; Dodd, R. H., Copper(I) catalyzed regioselective asymmetric
alkoxyamination of aryl enamide derivatives, Org. Lett. 2011, 13,
5792-5795. h) Li, Y.; Zheng, G.; Zhang, Q., Copper-catalyzed
aminooxygenation of styrenes with N-fluorobenzenesulfonimide
and N-hydroxylphthalimide derivatives, Beilstein J. Org. Chem.
2015, 11, 2721-2726. i) Benkovics, T.; Du, J.; Guzei, I. A.; Yoon, T. P.,
Anionic halocuprate(II) complexes as catalysts for the
oxaziridine-mediated aminohydroxylation of olefins, J. Org.
Chem. 2009, 74, 5545-5552. j) Hemric, B. N.; Shen, K.; Wang, Q.,
Copper-catalyzed amino lactonization and amino oxygenation of
alkenes using O-benzoylhydroxylamines, J. Am. Chem. Soc. 2016,
138, 5813-5816. k) Hesp, K. D., Copper-catalyzed regio- and
enantioselective hydroamination of alkenes with hydroxylamines,
enantioselective
copper-catalyzed
intramolecular
carboamination of alkenes for the synthesis of hexahydro-1H-
benz[f]indoles, Org. Lett. 2010, 12, 4739-4741. c) Miller, Y.; Miao,
L.; Hosseini, A. S.; Chemler, S. R., Copper-catalyzed
intramolecular alkene carboetherification: synthesis of fused-ring
and bridged-ring tetrahydrofurans, J. Am. Chem. Soc. 2012, 134,
12149-12156. d) Bovino, M. T.; Liwosz, T. W.; Kendel, N. E.; Miller,
Y.; Tyminska, N.; Zurek, E.; Chemler, S. R., Enantioselective
copper-catalyzed carboetherification of unactivated alkenes,
Angew. Chem. Int. Ed. 2014, 53, 6383-6387. e) Karyakarte, S. D.;
7
ACS Paragon Plus Environment

ACS Catalysis
Page 8 of 9
Um, C.; Berhane, I. A.; Chemler, S. R., Synthesis of spirocyclic
(17) Sequeira, F. C.; Bovino, M. T.; Chipre, A. J.; Chemler, S. R.,
Multigram synthesis of a chiral substituted indoline via copper-
catalyzed alkene aminooxygenation. Synthesis 2012, 44, 1481-1484.
(18) Osterberg, P. M.; Niemeier, J. K.; Welch, C. J.; Hawkins, J. M.;
Martinelli, J. R.; Johnson, T. E.; Root, T. W.; Stahl, S. S.,
Experimental limiting oxygen concentrations for nine organic
solvents at temperatures and pressures relevant to aerobic
oxidations in the pharmaceutical industry, Org. Process Res. Dev.
2015, 19, 1537-1543.
(19) Hossain, M. M.; Shyu, S. G., Selective copper(II)-catalyzed
aerobic oxidative cleavage of aromatic gem-disubstituted alkenes
to carbonyl compounds under neutral and mild conditions,
Tetrahedron 2014, 70, 251-255.
ethers by enantioselective copper-catalyzed carboetherification of
alkenols, Angew. Chem. Int. Ed. 2018, 57, 12921-12924.
(14) Turnpenny, B. W.; Chemler, S. R., Copper-Catalyzed Alkene
Diamination: Synthesis of Chiral 2-Aminomethylindolines and
Pyrrolidines, 2014, Chem. Sci. 5, 1786-1793.
1
2
3
4
5
6
7
8
(15) Sheldon, R. A., The E factor: fifteen years on, Green Chemistry
2007, 9, 1273-1283.
(16) a) Curran, D. P.; Keller, A. I. Radical additions of aryl iodides
are facilitated by oxidative rearomatization with dioxygen, J. Am.
Chem. Soc. 2006, 128, 13706-13707. b) Chen, F.; Lai, S.; Zhu, F.;
Meng, Q.; Jiang, Y.; Yu, W.; Han, B., Cu-Catalyzed radical cascade
annulations of alkyne-tethered N-alkoxyamides with air: facile
access to isoxazolidine/1,2-oxazinane-fused isoquinolin-1(2H)-
ones, ACS Catal. 2018, 8, 8925-8931.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
8
ACS Paragon Plus Environment

Page 9 of 9
ACS Catalysis
Table of Contents Only
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
9
ACS Paragon Plus Environment