An Enantioconvergent Benzylic Hydroxylation Using a Chiral Aryl Iodide in a Dual Activation Mode

Article abstract of DOI:10.1021/acscatal.0c02321

The application of a triazole-substituted chiral iodoarene in a direct enantioselective hydroxylation of alkyl arenes is reported. This method allows the rapid synthesis of chiral benzyl alcohols in high yields and stereocontrol, despite its nontemplated nature. In a cascade activation consisting of an initial irradiation-induced radical C-H-bromination and a consecutive enantioconvergent hydroxylation, the iodoarene catalyst has a dual role. It initiates the radical bromination in its oxidized state through an in-situ-formed bromoiodane and in the second, Cu-catalyzed step, it acts as a chiral ligand. This work demonstrates the ability of a chiral aryl iodide catalyst acting both as an oxidant and as a chiral ligand in a highly enantioselective C-H-activating transformation. Furthermore, this concept presents an enantioconvergent hydroxylation with high selectivity using a synthetic catalyst.

Full text of DOI:10.1021/acscatal.0c02321

Subscriber access provided by Caltech Library
Letter
An Enantioconvergent Benzylic Hydroxylation
Using a Chiral Aryl Iodide in a Dual Activation Mode
Ayham H. Abazid, Nils Clamor, and Boris Johannes Nachtsheim
ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.0c02321 • Publication Date (Web): 02 Jul 2020
Downloaded from pubs.acs.org on July 3, 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
An Enantioconvergent Benzylic Hydroxylation Using a Chiral Aryl
Iodide in a Dual Activation Mode
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
Ayham H. Abazid,a Nils Clamora and Boris J. Nachtsheima*
University of Bremen, Institute of Organic and Analytical Chemistry, Leobener Straße 7, 28359 Bremen, Germany
nachtsheim@uni-bremen.de
KEYWORDS Chiral Alcohols, Enantioselective Oxidation, Enantioconvergent Catalysis, Hypervalent Iodine, Photochemistry
ABSTRACT: The application of a triazole-substituted chiral iodoarene in a direct enantioselective hydroxylation of alkyl
arenes is reported. This method allows the rapid synthesis of chiral benzyl alcohols in high yields and stereocontrol despite
its non-templated nature. In a cascade activation comprising of an initial irradiation-induced radical C-H-bromination and a
consecutive enantioconvergent hydroxylation, the iodoarene catalyst has a dual role. It initiates the radical bromination in
its oxidized state through an in situ formed bromoiodane and in the second, Cu-catalyzed step, it acts as a chiral ligand. This
work demonstrates the ability of a chiral aryl iodide catalyst acting both, as an oxidant and as a chiral ligand in a highly
enantioselective C-H-activating transformation. Furthermore, this concept presents an enantioconvergent hydroxylation
with high selectivity using a synthetic catalyst.
unknown.17 During our systematic studies of N-
heterocycle-stabilized iodanes (NHIs),18 we recently
introduced triazole-substituted aryl iodides 1 (Figure 1) as
chiral iodane-precursors and successfully verified their
excellent performance in a plethora of enantioselective
oxidative transformations.19 In a new approach we herein
demonstrate their unique ability to act in a dual way,
initially as a iodane-based halogen donor for a non-
stereoselective radical-mediated halogenation and as a
chiral ligand in a so far undescribed enantioconvergent
hydroxylation.20,21
INTRODUCTION
The direct hydroxylation of C(sp3)−H bonds is one of the
most efficient reactions to introduce molecular complexity
into unfunctionalized bulk chemicals.1,2 Once introduced,
the resulting alcohols are either a fundamental part of the
desired target molecule or they can be readily transformed
into other useful functionalities. Hydroxylations of benzylic
C(sp3)−H bonds are of particular interest due to the
intrinsic reactivity of the benzylic C-H bond allowing a
highly regioselective C-H activation in the presence of
other aliphatic C-H bonds.3,4 Based on cytochrome P-450
oxygenases as natural blueprint,5 a variety of chiral metal-
I
OTIPS
R
porphyrine
complexes
were
developed
for
Bn
N
enantioselective hydroxylations.6 In a first report in 1989
by Groves and co-workers chiral iron porphyrins could be
applied in combination with iodosobenzene as an oxygen-
donor to hydroxylate ethyl benzene in 40% yield and 41%
ee.7 Template-directed procedures give excellent
selectivities although only well-selected substrates that
can non-covalently interact with the chiral catalyst
through hydrogen-bonding patterns can be addressed
efficiently.8,9 It is surprising, that even more than three
decades after the initial finding of Groves, simple alkyl
benzenes are still difficult to hydroxylate in good yields
and enantioselectivities through purely synthetic
catalysts.10,11 Hypervalent iodine reagents are commonly
used oxidants for oxidative couplings and in group- and
oxygen transfer reactions.12,13,14 They can be also applied in
benzylic hydroxylations as demonstrated by Groves in his
early report as well as in high valent transition metal
chemistry15 and in photoredox catalysis.16 The use of chiral
iodanes or their aryl iodide precursors in catalytic
enantioselective benzylic hydroxylations is so far
N
N
1
1a
1b
: R=OMe
: R=H
X, [O]
X
[M], [O]
N*
Ar
I+ N*
Ar
HO [M]
I
Halogen
-donor
Chiral
Ligand
H
X
OH

Ar
hv
Ar
Ar
Non-selective
C-H-Activation
Enantioconvergent
Hydroxylation
known
unknown
Figure 1. Working model for the dual activation of alkyl
arenes using catalysts of type 1.
Combining 1 with a co-oxidant and a halogen anion
should initially form a stabilized halogen(aryl)--iodane,
to initiate the C-H-activation and then ligate a transition
ACS Paragon Plus Environment

ACS Catalysis
electron rich ethyl arenes were investigated. 4-Methyl- and
Page 2 of 9
metal during the second, enantioconvergent, reaction step.
The combination of bromide sources and aryl--iodanes is
known to activate benzylic C-H-bonds through in situ
formation of bromo-iodanes followed by a light-induced
homolytic cleavage of the labile I-Br-bond.22
1
2
3
4
4-methoxy-substituted derivatives reacted superior giving
the desired benzyl alcohols 3b and 3c in high yields and
96% and 95% ee. Free hydroxy groups are tolerated as
well giving 3d-3f in still good yields and 72%-87% ee.
5
6
7
8
The effect of electron withdrawing groups at the arene
was then investigated. All possible bromo-substituted
isomers reacted well giving 3g-3i in overall good yields of
76-79% with the best enantioselectivity being observed
for the 3-Br-derivative (95%). Ethyl-substituted nitro
arenes gave compounds 3j and 3k in even better yields (90
and 89%) and excellent 93% and 95% ee. Synthetically
versatile nitriles and free carboxylic acids are also well
tolerated yielding benzyl alcohols 3l and 3m in good yields
and 83% and 95% ee. Indane and tetrahydronaphthalene
give 3n and 3o in 79% and 77% yield with 85% and 95%
ee. For these substrates, small amounts of dihydroxylation
products (<10% were observed). Next, the aliphatic side
chain of the ethyl benzene was varied. nPropyl- and nbutyl
benzene gave 3p and 3q in yields and selectivities
comparable to the model substrate. The same was
observed for 1,2-diphenylethane giving 3r in 79% and
93% ee. 2-Phenyl acetic acid yielded (R)-mandelic acid 3s
in 64% and 88% ee. Next, multiple bond substitution in the
benzylic side chain was examined. Once again, the method
showed a high robustness among those substrates.
RESULTS AND DISCUSSION
Based on the fact that many radical-mediated
enantioconvergent substitutions, in particular alkylations
of secondary alkyl halides, can be catalyzed by Cu(I)-
salts,23,24 CuBr was initially used as additive, acting as the
bromide donor and the transition metal-catalyst. To test
our hypothesis, the direct hydroxylation of ethyl benzene
2a was investigated (Table 1). As expected, under heating
in DCM no reaction was observed (entry 1). To our delight,
irradiation with a blue LED (465 nm) gave the desired
product (R)-3a in 68% yield and 71% ee using 150 mol%
CuBr (entry 2). While aromatic solvents such as toluene
give a diminished yield and selectivity (entry 3) using
acetonitrile gave (R)-3a in 75% yield and 90% ee (entry
4). Since the Cu(I)-additive should initially only act as an
activator for I-Br-bond activation, it should be sufficient to
add catalytic amounts of CuBr and another, cheaper,
bromide source in stoichiometric quantities. Indeed, if only
20 mol% of CuBr in combination with 1.5 equiv. of NaBr as
additive was used, the reaction still proceeds with almost
the same outcome (entry 5). Under these conditions
catalyst loading of 1a could be decreased to 15 mol%
without affecting yield and selectivity (entry 6). Under
strictly dry reaction conditions (entry 7) no product
formation was observed which implies water as the
hydroxy source in this process. In agreement with our
recent findings, catalyst 1b, without the important ortho-
substituent at the aryl iodide, performs worse (entry 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
Scheme 1. Substrate Scope.
Table 1. Optimization of the reaction conditions.
cat. 1a
, CuBr, NaBr
OH
mCPBA (2.5 equiv)
Ph
Ph
(R)-3a
solvent (0.1 M), rt, blue led
2a
entry
1aa
CuBra
NaBra solvent
t
yield
[%]
ee
[%]
[h]
12
20
30
14
14
14
14
8
1b
2
20
20
20
20
20
15
15
15
150
150
150
150
20
0
0
DCM
DCM
0
-
68
25
75
74
74
0
71
40
90
90
90
0
3
0
PhMe
4
0
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
5
150
150
150
150
6c
7d
8e
20
20
20
48
63
amol%. bThe reaction was performed at 60 °C for 12 hr
without light. cThese conditions will be further referred as
“optimized conditions”. ddry acetonitrile and water-free
mCPBA were used in the reaction. ecatalyst 1b was used
instead of 1a.
Under these optimized conditions, the applicable
substrate scope was examined (Scheme 1). Initially, simple
ACS Paragon Plus Environment

Page 3 of 9
ACS Catalysis
It was also of interest whether the applied reaction
1a
(15 mol%)
CuBr (20 mol%)
NaBr (1.5 equiv.)
1
2
3
4
5
6
7
8
conditions allow the regioselective C-H-activation of the
benzyl C-H-bond in the presence of tertiary C-H-bonds -
also potential hot spots for the initial radical-mediated
halogenation. Therefore, substrate 2aa was submitted to
our optimized reaction conditions and indeed a mixture of
the isomers 3aa and 3ab in a ratio of 7:1 and 95% ee for
(R)-3aa was observed (Scheme 2). Thus, activation of the
benzylic C-H is strongly favored.
OH
(Het)Ar
R
(Het)Ar
OH
R
mCPBA (2.5 equiv)
MeCN (0.1 M), rt, blue led
2
3
OH
EWG
EDG
After this comprehensive elaboration of the substrate
scope we intended to get a deeper understanding of the
underlying reaction mechanism and in particular, proof
the initially proposed dual role of the catalyst in this
process and the unique enantioconvergent hydroxylation.
For the first step, the radical-mediated halogenation, a
brominated catalyst must be formed with a labile I-Br
bond that breaks homolytic to induce the radical-mediated
benzyl C-H-abstraction. Treatment of 1a with NaBr and
mCPBA allowed us to isolate a white solid which was
identified via NMR and MS as being the brominated
derivative 1a-Br (Scheme 3 – a). Treatment of 2a with this
compound without a Cu-source under light irradiation
yielded the benzyl bromide 4 in a very clean reaction and
72% yield as a racemate (b). Even if benzyl bromide would
be formed enantioenriched, its known tendency to
racemize in polar solvents would yield the racemate under
the given reaction conditions.25 This experiment implies,
that once the benzyl bromide is formed, the second step of
the transformation must be an enantioconvergent reaction
in which irradiation should not be essential anymore. To
verify this hypothesis, 2a was reacted again using the
optimized conditions, but with only 4h of light irradiation
followed by further stirring for 4 h in the dark (c). Under
these conditions the desired benzyl alcohol was observed
in nearly the same yield and enantioselectivity as under
full-time irradiation.
9
3b
(EDG = 4-Me): 83%, 96% ee
(EDG = 4-OMe): 95%, 95%ee
(EDG = 2-OH): 58%, 84% ee
(EDG = 4-OH): 76%, 72%ee
(EDG = 3-OH): 68%, 87% ee
3g
3h
3i
3j
3k
3l
(EWG = 4-Br): 76%, 87%ee
(EWG = 2-Br): 77%, 84% ee
(EWG = 3-Br): 79%, 95% ee
(EWG = 4-NO2): 90%, 93% ee
(EWG = 2-NO2): 89%, 95% ee
(EWG = 4-CN): 84%, 83% ee
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
3c
3d
3e
3f
OH
3m
(EWG = 4-CO2H): 74%, 95% ee
3p
(R = Et): 85%, 93%ee
OH
3q
3r
(R = nPr): 77%, 85% ee
(R = CH2Ph): 79%, 93% ee
n
R
Ph
Ph
3n
3o
(n = 1): 79%, 85% ee
(n =2): 77%, 95% ee
OH
3s:
64% 88% ee
CO2H
OH
OH
(X=O): no reaction
(X=S): 54%, 89% ee
Ph
3v
X
3t
: 72%, 83% ee
OH
HO
3w
3x
(2-pyridyl): 63%, 78% ee
(4-pyridyl): 57%, 87% ee
Ph
N
3u:
61%, 90% ee
OH
N
3y:
48%, 80% ee
NH
O
Allyl benzene was directly hydroxylated to yield the allyl
alcohol 3t in 83% ee. Propargyl alcohol 3u was isolated
with even higher selectivities of 90% ee, although the yield
was lower (61%), probably due to a slight decomposition
of the delicate propargylic alcohol. Finally, a variety of
ethyl-substituted heterocycles as substrates were
investigated. 2-Ethyl furane did not result in product
formation due to decomposition of the starting material.
The corresponding thiophene gave 3v in 89% ee and 54%
yield. Even ethyl pyridines were tolerated under the
Scheme 3. Bromination with isolated catalyst 1a-Br to
prove the first step of the dual activation mechanism.
1a
NaBr
mCPBA
(a)
CH3CN
Br I+
mCBA-
OTIPS
MeO
Bn
N
Br
N
1a-Br
N
Ph
applied
oxidative
conditions,
despite
potential
(±)-4
Ph
, 72%
oxygenations of the ring nitrogen giving 2- and 4-pyridyl-
substituted alcohols 3w and 3x in moderate yields and
78% and 87% ee. Even 4-ethyl quinazolinone could be
directly hydroxylated to 3y with 80% ee.
blue led, CH3CN, 4 h
2a
no CuBr
optimized
conditions
dark
+ CuBr
dark
- CuBr
(b)
(e)
(d)
OH
Scheme 2. Investigating the regioselectivity.
optimized conditions
Ph
4 h irradiation, 4 h dark
OH
H
(R)-3a
optimized conditionsa
(c)
c
: 75%, 88% ee
Ph
Ph
Ph
H
OH
d
e
: 74%, 87% ee
: 53%, 18% ee
2aa
(R)-3aa
3ab
79%, 95 ee%
( 7
Next, 4 was treated under the optimized conditions,
without irradiation (d). Here, 3a was isolated in almost the
same quantities and ee-values as in the previous
experiments. The necessity of CuBr as additive which was
intended to catalyze exclusively the second step was
:
1 )
a Slight deviation: reaction temperature was decreased to 0
°C after 4 h.
ACS Paragon Plus Environment

ACS Catalysis
Page 4 of 9
the induced hypervalent twist.26 However, NMR-experiments
questioned as well. When the reaction was repeated,
without adding CuBr (e), 3a could still be isolated in 53%
yield, however, nearly as a racemate (18% ee). From these
experiments it was concluded that Cu is not necessary for
the initial C-H activation but plays a fundamental role in
the enantioconvergent hydroxylation. Here, 1a must act as
a N-ligand coordinating through its triazole functionality,
and therefore no oxidative conditions should be necessary.
Further control experiments were performed starting from
racemic 4 under our optimized conditions, without the
addition of mCPBA, but adding either CuBr or CuBr2
(Scheme 4 – a and b). In both experiments no conversion
to 3a was observed. Thus, even in the second step the
oxidant is necessary, but not just to oxidize the Cu(I)-
species. Obviously a hypervalent iodine compound must be
important as well in the enantioconvergent step.
1
2
3
4
5
6
7
8
strongly support a hydroxylation under reductive collapse of
the iodane as exemplified by 13C chemical shifts of the
characteristic iodine-bound aryl signal (Figure 2). This ipso-
carbon in 1a (blue) and the meta-carbon (green) have typical
chemical shifts of approx. 90 and 110 ppm (a). Upon addition
of mCPBA to yield 1a-OH as a mixture of different isomers,
both signals clearly disappear and shift downfield to > 115
ppm (b). Addition of CuBr regenerates 1a demonstrated by
the reappearance of both signals (c).
A significant line
broadening of the signals in the corresponding proton NMR
implies the existence of paramagnetic Cu(II) in the reaction
mixture (see ESI). The transient formation of Cu(III)-species,
for example as a Cu(III)-hydroxy should also be considered.
Unfortunately, Cu-triazole complexes could not be isolated
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
and
therefore
in
depth
understanding
of
the
enantioconvergent step remains elusive.
Scheme 4. Control experiments to elucidate the stereo-
convergent hydroxylation.
(a)
no mCPBA
1a
1a
, CuBr
(15 mol%)
(20 mol%)
(b)
no mCPBA
a
b
c
OH
Br
no
reaction
, CuBr
(15 mol%)
2 (20 mol%)
Ph
(R)-3a
Ph
(±)-4
(c)
mCPBA,
CuBr
(20 mol%)
5
(15 mol%)
Br
OTIPS
MeO
Bn
N
N
N
Figure 2. 13C-NMR-shifts for in situ oxidation of 1a
between 85-112 ppm. (a) 1a alone. (b) 1a+mCPBA. (c) 1a
+ mCPBA + CuBr.
As a further support the chiral bromobenzene 5 was
prepared. Aryl bromides cannot be oxidized with mCPBA
into a hypervalent state and therefore, as observed, no
reaction should occur (c). For gaining more insights about
the potential active oxidation state of the involved Cu-
species, this experiment was repeated starting from benzyl
bromide under oxidative conditions but now adding CuBr2
instead of CuBr (Scheme 5). Under these conditions 3a was
isolated in slightly lower yields (61%) but in similar
enantioselectivity (85% ee). When CuBr2 was used in
stoichiometric amounts without mCPBA no reaction was
observed. Thus the co-oxidant is either involved in
formation of even higher oxidized Cu(III)-hydroxy-
complexes and/or a second iodane formation.
However, based on the initial control experiments the
catalytic cycle as shown in Scheme 6 is proposed. In the
initial irradiation-mediated cycle (Scheme 6 - a) 1a is
oxidized into the hydroxyiodobenzene 1a-OH. Ligand
exchange with NaBr gives the bromoiodobenze 1a-Br
which underlies rapid I-Br bond cleavage under irradiation
yielding a bromine radical and the radical cation 1a-RC.
Radical benzylic bromination initiated by either species
converts the alkyl benzene into the benzyl bromide as a
racemate. In the second cycle (Scheme 6 - b) 1a is oxidized
again in the initial-step to 1a-OH. The iodane then
hydroxylates the Cu-salt either yielding a chiral Cu(II) or a
Cu(III)-hydroxy complex 1a-Cu-OH.
Scheme 5. Enantioconvergent hydroxylation with
a
CuBr2.
Scheme 6. Mechanistic proposal.
2.5 equiv. mCPBA
OH
Br
1a
, CuBr
2 (20 mol%)
(15 mol%)
Ph
Ph
(±)-4
optimized conditions
dark
(R)-3a
61%, 85% ee
aReaction conditions: (±)-4 (0.11 mmol), CH3CN (0.1 M).
A hydroxylated catalyst 1a-OH could not be isolated as a pure
substrate for further control experiment due to its high
reactivity based on the ortho-effect of the methoxy group and
ACS Paragon Plus Environment

Page 5 of 9
ACS Catalysis
mCBA-
I+
1
2
3
4
Br
MeO
OTIPS
NaOH
Bn
N
N
N
NaBr
1a-Br
5
6
7
8
mCBA-
mCBA-
I+
I+
OTIPS
HO
MeO
OTIPS
(a)
Blue
Led
MeO
Bn
N
Bn
N
N
N
N
N
9
1a-RC
Br
+
1a-OH
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
H
Ph
I
OTIPS
mCPBA
2a
MeO
Br
Bn
N
N
N
Ph
(±)-4
1a
OH
mCPBA
mCBA-
Ph
(R)-3a
I
OTIPS
(b)
Dark
I+
MeO
HO
MeO
OTIPS
Bn
N
N
N
Bn
N
N
N
Ln Cu(II/III)
L=Br-, mCBA-
OH
1a-Cu-OH
1a-OH
Cu(I/II)Ln
Depending on the oxidation state of the active Cu-
complex, either a radical or a SN-type enantioconvergent
hydroxylation with the emerging benzyl bromide from
cycle (a) yields (R)-3a. In a potential radical pathway a
benzylic radical could be trapped by the chiral Cu(II)-
complex to form a chiral Cu(III)-complex which collapses
in a final reductive elimination to give the chiral benzyl
alcohol. Even though deep mechanistic details of the
second step remain elusive it can be concluded that, due to
the high racemization tendency of 4, this overall reaction is
a stereomutative enantioconvergent reaction.
ACS Paragon Plus Environment

ACS Catalysis
Page 6 of 9
(1) (a) Bryliakov, K. P. Catalytic Asymmetric Oxygenations with
the Environmentally Benign Oxidants H2O2 and O2. Chem. Rev.
2017, 117, 11406. (b) Cernak, T.; Dykstra, K. D.; Tyagarajan, S.;
Vachal, P.; Krska, S. W. The Medicinal Chemist’s Toolbox for Late
Stage Functionalization of Drug-like Molecules. Chem. Soc. Rev.
2016, 45, 546.
(2) White, M. C.; Zhao, J. Aliphatic C–H Oxidations for Late-Stage
Functionalization. J. Am. Chem. Soc. 2018, 140, 13988.
(3) Genovino, J.; Sames, D.; Hamann, L. G.; Touré, B. B. Accessing
Drug Metabolites via Transition-Metal Catalyzed C−H Oxidation:
The Liver as Synthetic Inspiration. Angew. Chem. Int. Ed. 2016, 55,
14218.
1
2
3
4
5
6
7
8
CONCLUSIONS
In conclusion this work demonstrates the ability of
chiral aryl iodides substituted with N-heterocycles to be
used in enantioselective benzylic hydroxylations through a
double role, acting as oxidant and as a chiral ligand in a
consecutive reaction sequence consisting of a benzyl
bromination and
verification of (±)-benzyl bromide as
a
Cu-mediated substitution. The
reaction
a
9
intermediate verifies that the second, Cu-mediated
reaction, is an enantioconvergent hydroxylation. The
reaction tolerates a wide variety of substrates including
electron rich and electron poor alkyl benzenes, exocyclic -
bonds as well as alkyl-substituted N-heterocycles.
Furthermore, a high regioselectivity for the benzylic C-H-
bond in the presence tertiary C-H-bonds was observed.
This reaction cascade offers great potential for other
enantioselective oxidative benzylic C-H-activations,
although the mechanism of the enantioconvergent step
still needs to be further elaborated.
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
(4) (a) Das, A.; Nutting, J. E.; Stahl, S. S. Electrochemical C–H
Oxygenation and Alcohol Dehydrogenation involving Fe-oxo
Species using Water as the Oxygen Source. Chem. Sci. 2019, 10,
7542. (b) Tanwar, L.; Börgel, J.; Ritter, T. Synthesis of Benzylic
Alcohols by C–H Oxidation. J. Am. Chem. Soc. 2019, 141, 17983.
(5) (a) Fasan, R. Tuning P450 Enzymes as Oxidation Catalysts.
ACS Catal. 2012, 2, 647. (b) Denisov, I. G.; Makris, T. M.; Sligar, S.
G.; Schlichting, I. Structure and Chemistry of Cytochrome P450.
Chem. Rev. 2005, 105, 2253.
(6) (a) Guo, M.; Corona, T.; Ray, K.; Nam, W. Heme and
Nonheme High-Valent Iron and Manganese Oxo Cores in
Biological and Abiological Oxidation Reactions. ACS Cent. Sci.
2019, 5, 13. (b) Petsi, M.; Zografos, A. L. Advances in Catalytic
Aerobic Oxidations by Activation of Dioxygen-Monooxygenase
Enzymes and Biomimetics. Synthesis 2018, 50, 4715. (c) Adam, S.
M.; Wijeratne, G. B.; Rogler, P. J.; Diaz, D. E.; Quist, D. A.; Liu, J. J.;
Karlin, K. D. Synthetic Fe/Cu Complexes: Toward Understanding
Heme-Copper Oxidase Structure and Function. Chem. Rev. 2018,
118, 10840.
AUTHOR INFORMATION
Corresponding Author
* nachtsheim@uni-bremen.de
Author Contributions
(7) Groves, J. T.; Viski, P. Asymmetric Hydroxylation by a Chiral
Iron Porphyrin. J. Am. Chem. Soc. 1989, 111, 8537.
(8) Carboni, S.; Gennari, C.; Pignataro, L.; Piarulli, U.
The manuscript was written by BJN. Experimental work was
performed by AHA and NC. All authors have given approval to
the final version of the manuscript.
Supramolecular
Ligand–Ligand
and
Ligand–Substrate
Interactions for Highly Selective Transition Metal Catalysis.
Dalton Trans 2011, 40, 4355.
Orcid
Boris J. Nachtsheim: 0000-0002-3759-2770
Ayham H. Abazid: 0000-0002-4204-4701
Nils Clamor: 0000-0002-7290-4792
(9) (a) Burg, F.; Breitenlechner, S.; Jandl, C.; Bach, T.
Enantioselective Oxygenation of Exocyclic Methylene Groups by a
Manganese Porphyrin Catalyst with a Chiral Recognition Site.
Chem. Sci. 2020, 11, 2121. (b) Burg, F.; Bach, T. Lactam Hydrogen
Bonds as Control Elements in Enantioselective Transition-Metal-
Catalyzed and Photochemical Reactions. J. Org. Chem. 2019, 84,
8815. (c) Burg, F.; Gicquel, M.; Breitenlechner, S.; Pothig, A.; Bach,
T. Site- and Enantioselective C-H Oxygenation Catalyzed by a
Chiral Manganese Porphyrin Complex with a Remote Binding Site.
Angew. Chem. Int. Ed. 2018, 57, 2953. (d) Frost, J. R.; Huber, S. M.;
Breitenlechner, S.; Bannwarth, C.; Bach, T. Enantiotopos-Selective
Funding Sources
This work is support by the DFG (Deutsche
Forschungsgemeinschaft – Grant NA 955/3-1).
Notes
The authors declare no competing financial interests.
C-H Oxygenation Catalyzed by
a Supramolecular Ruthenium
Complex. Angew. Chem. Int. Ed. 2015, 54, 691.
ABBREVIATIONS
mCPBA: meta-Chloroperbenzoic acid; mCBA: meta-
Chlorobenzoic acid; DCM: Dichloromethane
(10) Hartwig, J. F.; Larsen, M. A. Undirected, Homogeneous C-H
Bond Functionalization: Challenges and Opportunities. ACS Cent.
Sci. 2016, 2, 281.
(11) (a) Betori, R. C.; May, C. M.; Scheidt, K. A. Combined
Photoredox/Enzymatic C-H Benzylic Hydroxylations. Angew.
Chem. Int. Ed. 2019, 58, 16490. (b) Ottenbacher, R. V.; Talsi, E. P.;
Rybalova, T. V.; Bryliakov, K. P. Enantioselective Benzylic
Hydroxylation of Arylalkanes with H2O2 in Fluorinated Alcohols in
the Presence of Chiral Mn Aminopyridine Complexes.
ChemCatChem 2018, 10, 5323. (c) Talsi, E. P.; Samsonenko, D. G.;
Ottenbacher, R. V.; Bryliakov, K. P. Highly Enantioselective C−H
Oxidation of Arylalkanes with H2O2 in the Presence of Chiral Mn-
Aminopyridine Complexes. ChemCatChem 2017, 9, 4580. (d)
Gross, Z.; Ini, S. Asymmetric Catalysis by a Chiral Ruthenium
Porphyrin: Epoxidation, Hydroxylation, and Partial Kinetic
Resolution of Hydrocarbons. Org. Lett. 1999, 1, 2077. (e) Hamada,
T.; Irie, R.; Mihara, J.; Hamachi, K.; Katsuki, T. Highly
Enantioselective Benzylic Hydroxylation with Concave Type of
(Salen)manganese(III) Complex. Tetrahedron 1998, 54, 10017. (f)
ASSOCIATED CONTENT
Supporting Information. The Supporting Information is
available free of charge on the ACS Publications website at
DOI: XXX.
Including all experimental procedures and characterization
data.
ACKNOWLEDGMENT
Ayham Abazid acknowledges the State of Bremen for a
Scholars at Risk Fund.
REFERENCES
ACS Paragon Plus Environment

Page 7 of 9
ACS Catalysis
Hamachi, K.; Irie, R.; Katsuki, T. Asymmetric Benzylic Oxidation
Oxidations. Angew. Chem. Int. Ed. 2020, 59, 1479. (b) Hempel, C.;
Using a Mn-salen Complex as Catalyst. Tetrahedron Lett. 1996, 37,
4979.
(12) Hypervalent Iodine Chemistry; Wirth, T., Ed.; Top. Curr.
Chem. 373; Springer: Cham, 2016. pp. 1-166.
(13) Zhdankin, V. V. Hypervalent Iodine Chemistry: Preparation,
Structure and Synthetic Applications of Polyvalent Iodine
Compounds; John Wiley & Sons Inc: Chichester, West Sussex,
2014. pp. 145-336.
Maichle-Mössmer, C.; Pericàs, M. A.; Nachtsheim, B. J. Modular
1
2
3
4
5
6
7
8
Synthesis
of
Triazole-Based
Chiral
Iodoarenes
for
Enantioselective Spirocyclizations. Adv. Synth. Catal. 2017, 359,
2931.
(20) (a) Bhat, V.; Welin, E. R.; Guo, X.; Stoltz, B. M. Advances in
Stereoconvergent Catalysis from 2005 to 2015: Transition-Metal-
Mediated Stereoablative Reactions, Dynamic Kinetic Resolutions,
and Dynamic Kinetic Asymmetric Transformations. Chem. Rev.
2017, 117, 4528. (b) Bartlett, S. L.; Johnson, J. S. Synthesis of
Complex Glycolates by Enantioconvergent Addition Reactions.
Acc. Chem. Res. 2017, 50, 2284. (c) Mohr, J. T.; Moore, J. T.; Stoltz,
B. M. Enantioconvergent Catalysis. Beilstein J. Org. Chem. 2016, 12,
2038.
(14) (a) Hyatt, I. F. D.; Dave, L.; David, N.; Kaur, K.; Medard, M.;
Mowdawalla, C. Hypervalent Iodine Reactions Utilized in ´Carbon–
Carbon Bond Formations. Org. Biomol. Chem. 2019, 17, 7822. (b)
Budhwan, R.; Yadav, S.; Murarka, S. Late Stage Functionalization
of Heterocycles using Hypervalent Iodine(III) Reagents. Org.
Biomol. Chem. 2019, 17, 6326. (c) Lee; Choi; Hong. Alkene
Difunctionalization Using Hypervalent Iodine Reagents: Progress
and Developments in the Past Ten Years. Molecules 2019, 24,
2634. (d) Reddy Kandimalla, S.; Prathima Parvathaneni, S.;
Sabitha, G.; Subba Reddy, B. V. Recent Advances in Intramolecular
Metal-Free Oxidative C-H Bond Aminations Using Hypervalent
Iodine(III) Reagents. Eur. J. Org. Chem. 2019, 2019, 1687. (e) Xing,
L.; Zhang, Y.; Du, Y. Hypervalent Iodine-Mediated Synthesis of
Spiroheterocycles via Oxidative Cyclization. Curr. Org. Chem.
2019, 23, 14. (f) Ghosh, M. K.; Rajkiewicz, A. A.; Kalek, M.
Organocatalytic Group Transfer Reactions with Hypervalent
Iodine Reagents. Synthesis 2019, 51, 359. (g) Hari, D. P.;
Caramenti, P.; Waser, J. Cyclic Hypervalent Iodine Reagents:
Enabling Tools for Bond Disconnection via Reactivity Umpolung.
Acc. Chem. Res. 2018, 51, 3212. (h) Elsherbini, M.; Wirth, T.
Hypervalent Iodine Reagents by Anodic Oxidation: A Powerful
Green Synthesis. Chem. Eur. J. 2018, 24, 13399. (i) Boelke, A.;
Finkbeiner, P.; Nachtsheim, B. J. Atom-Economical Group-Transfer
Reactions with Hypervalent Iodine Compounds. Beilstein J. Org.
Chem. 2018, 14, 1263. (j) Yoshimura, A.; Yusubov, M. S.; Zhdankin,
V. V. Synthetic Applications of Pseudocyclic Hypervalent Iodine
Compounds. Org. Biomol. Chem. 2016, 14, 4771. (k) Li, Y.; Hari, D.
P.; Vita, M. V.; Waser, J. Cyclic Hypervalent Iodine Reagents for
Atom-Transfer Reactions: Beyond Trifluoromethylation. Angew.
Chem. Int. Ed. 2016, 55, 4436. (l) Yoshimura, A.; Zhdankin, V. V.
Advances in Synthetic Applications of Hypervalent Iodine
Compounds. Chem. Rev. 2016, 116, 3328.
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
(21) (a) Chang, C.-H.; Sathishkumar, N.; Liao, Y.-T.; Chen, H.-T.;
Han, J.-L. Solvent-Dependent Enantiodivergent Friedel-Crafts
Reaction of Arylsulfonyl Indoles with 1-Naphthols. Adv. Synth.
Catal. 2020, 362, 903. (b) Huo, H.; Gorsline, B. J.; Fu, G. C. Catalyst-
controlled Doubly Enantioconvergent Coupling of Racemic Alkyl
Nucleophiles and Electrophiles. Science 2020, 367, 559. (c) Zeng,
G.; Li, Y.; Qiao, B.; Zhao, X.; Jiang, Z. Photoredox Asymmetric
Catalytic Enantioconvergent Substitution of 3-Chlorooxindoles.
Chem. Commun. 2019, 55, 11362. (d) Schwarzwalder, G. M.;
Matier, C. D.; Fu, G. C. Enantioconvergent Cross-Couplings of Alkyl
Electrophiles: The Catalytic Asymmetric Synthesis of
Organosilanes. Angew. Chem. Int. Ed. 2019, 58, 3571. (e) Iwamoto,
T.; Okuzono, C.; Adak, L.; Jin, M.; Nakamura, M. Iron-Catalysed
Enantioselective Suzuki-Miyaura Coupling of Racemic Alkyl
Bromides. Chem. Commun. 2019, 55, 1128. (f) Zhang, X.; Ren, J.;
Tan, S. M.; Tan, D.; Lee, R.; Tan, C.-H. An Enantioconvergent
Halogenophilic Nucleophilic Substitution (SN2X) Reaction. Science
2019, 363, 400. (g) Wendlandt, A. E.; Vangal, P.; Jacobsen, E. N.
Quaternary Stereocentres via an Enantioconvergent Catalytic SN1
Reaction. Nature 2018, 556, 447. (h) Mixdorf, J. C.; Sorlin, A. M.;
Zhang, Q.; Nguyen, H. M. Asymmetric Synthesis of Allylic Fluorides
via Fluorination of Racemic Allylic Trichloroacetimidates
Catalyzed by a Chiral Diene-Iridium Complex. ACS Catal. 2018, 8,
790. (i) Schäfer, P.; Sidera, M.; Palacin, T.; Fletcher, S. P.
Asymmetric Cross-Coupling of Alkyl, Alkenyl and (Hetero)aryl
Nucleophiles with Racemic Allyl Halides. Chem. Commun. 2017,
53, 12499.
(22) (a) Dohi, T.; Takenaga, N.; Goto, A.; Fujioka, H.; Kita, Y.
Clean and Efficient Benzylic C−H Oxidation in Water Using a
Hypervalent Iodine Reagent: Activation of Polymeric
Iodosobenzene with KBr in the Presence of Montmorillonite-K10.
J. Org. Chem. 2008, 73, 7365. (b) Tohma, H.; Maegawa, T.;
Takizawa, S.; Kita, Y. Facile and Clean Oxidation of Alcohols in
Water Using Hypervalent Iodine(III) Reagents. Adv. Synth. Catal.
2002, 344, 328. (c) Amey, R. L.; Martin, J. C. Synthesis and
Reaction of Substituted Arylalkoxyiodinanes: Formation of Stable
Bromoarylalkoxy and Aryldialkoxy Heterocyclic Derivatives of
Tricoordinate Organoiodine(III). J. Org. Chem. 1979, 44, 1779.
(23) Gu, Q.-S.; Li, Z.-L.; Liu, X.-Y. Copper(I)-Catalyzed
Asymmetric Reactions Involving Radicals. Acc. Chem. Res. 2020,
53, 170.
(15) Sousa e Silva, F. C.; Tierno, A. F.; Wengryniuk, S. E.
Hypervalent Iodine Reagents in High Valent Transition Metal
Chemistry.
Molecules
2017,
22,
DOI:
10.3390/molecules22050780.
(16) Wang, L.; Liu, J. Synthetic Applications of Hypervalent
Iodine(III) Reagents Enabled by Visible Light Photoredox
Catalysis. Eur. J. Org. Chem. 2016, 2016, 1813.
(17) (a) Parra, A. Chiral Hypervalent Iodines: Active Players in
Asymmetric Synthesis. Chem. Rev. 2019, 119, 12033. (b) Flores,
A.; Cots, E.; Bergès, J.; Muñiz, K. Enantioselective Iodine(I/III)
Catalysis in Organic Synthesis. Adv. Synth. Catal. 2019, 361, 2. (c)
Ghosh, S.; Pradhan, S.; Chatterjee, I.
A Survey of Chiral
Hypervalent Iodine Reagents in Asymmetric Synthesis. Beilstein J.
Org. Chem. 2018, 14, 1244. (d) Claraz, A.; Masson, G. Asymmetric
Iodine
Catalysis-mediated
Enantioselective
Oxidative
(24) (a) Bartoszewicz, A.; Matier, C. D.; Fu, G. C.
Enantioconvergent Alkylations of Amines by Alkyl Electrophiles:
Copper-Catalyzed Nucleophilic Substitutions of Racemic α-
Halolactams by Indoles. J. Am. Chem. Soc. 2019, 141, 14864. (b)
Kainz, Q. M.; Matier, C. D.; Bartoszewicz, A.; Zultanski, S. L.; Peters,
J. C.; Fu, G. C. Asymmetric Copper-Catalyzed C-N Cross-Couplings
Induced by Visible Light. Science 2016, 351, 681. (c) Ratani, T. S.;
Bachman, S.; Fu, G. C.; Peters, J. C. Photoinduced, Copper-
Catalyzed Carbon–Carbon Bond Formation with Alkyl
Electrophiles: Cyanation of Unactivated Secondary Alkyl
Chlorides at Room Temperature. J. Am. Chem. Soc. 2015, 137,
13902. (d) Do, H.-Q.; Bachman, S.; Bissember, A. C.; Peters, J. C.; Fu,
G. C. Photoinduced, Copper-Catalyzed Alkylation of Amides with
Transformations. Org. Biomol. Chem. 2018, 16, 5386.
(18) (a) Boelke, A.; Nachtsheim, B. J. Evolution of N-
Heterocycle-Substituted Iodoarenes (NHIAs) to Efficient
Organocatalysts
in
Iodine(I/III)-Mediated
Oxidative
Transformations. Adv. Synth. Catal. 2020, 362, 184. (b) Boelke, A.;
Vlasenko, Y. A.; Yusubov, M. S.; Nachtsheim, B. J.; Postnikov, P. S.
Thermal Stability of N-Heterocycle-Stabilized Iodanes
– A
Systematic Investigation. Beilstein J. Org. Chem. 2019, 15, 2311.
(c) Boelke, A.; Lork, E.; Nachtsheim, B. J. N-Heterocycle-Stabilized
Iodanes: From Structure to Reactivity. Chem. Eur. J. 2018, 24,
18653.
(19) (a) Abazid, A. H.; Nachtsheim, B. J. A Triazole-Substituted
Aryl Iodide with Omnipotent Reactivity in Enantioselective
ACS Paragon Plus Environment

ACS Catalysis
Page 8 of 9
Unactivated Secondary Alkyl Halides at Room Temperature. J. Am.
Chem. Soc. 2014, 136, 2162.
(25) Li, C.; Zhang, Y.; Sun, Q.; Gu, T.; Peng, H.; Tang, W.
Transition-Metal-Free Stereospecific Cross-Coupling with
Alkenylboronic Acids as Nucleophiles. J. Am. Chem. Soc. 2016, 138,
10774.
of Ketones: Refining the stereoinduction model. Tetrahedron:
Asymmetry 2013, 24, 1193. (b) Guilbault, A.-A.; Legault, C. Y.
Drastic Enhancement of Activity in Iodane-Based α-
Tosyloxylation of Ketones: Iodine(III) Does the Hypervalent
Twist. ACS Catal. 2012, 2, 219.
1
2
3
4
5
6
(26) (a) Thérien, M.-È.; Guilbault, A.-A.; Legault, C. Y. New Chiral
Iodooxazoline Catalysts for the I(III)-Mediated α-Tosyloxylation
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
ACS Paragon Plus Environment

Page 9 of 9
ACS Catalysis
[O], [M]-Br
[O], Cu-catalyst
H
Br
OH
1
2
3
4
5
6
Radical
Bromination
Enantioconvergent
Hydroxylation
Ar
R
Ar
I
R
Ar
R
up to
96% ee!
OTIPS
N
MeO
Bn
N
N
7
Ar*-I
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