Cation Radical Accelerated Nucleophilic Aromatic Substitution via Organic Photoredox Catalysis

Article abstract of DOI:10.1021/jacs.7b10076

Nucleophilic aromatic substitution (S_NAr) is a direct method for arene functionalization; however, it can be hampered by low reactivity of arene substrates and their availability. Herein we describe a cation radical-accelerated nucleophilic aromatic substitution using methoxy- and benzyloxy-groups as nucleofuges. In particular, lignin-derived aromatics containing guaiacol and veratrole motifs were competent substrates for functionalization. We also demonstrate an example of site-selective substitutive oxygenation with trifluoroethanol to afford the desired trifluoromethylaryl ether.

Full text of DOI:10.1021/jacs.7b10076

Subscriber access provided by READING UNIV
Communication
Cation Radical-Accelerated Nucleophilic Aromatic
Substitution via Organic Photoredox Catalysis
Nicholas E. S. Tay, and David A Nicewicz
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.7b10076 • Publication Date (Web): 25 Oct 2017
Downloaded from http://pubs.acs.org on October 25, 2017
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 free 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 accessible to all
readers and 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.
Journal of the American Chemical Society 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 6
Journal of the American Chemical Society
1
2
3
4
5
6
7
8
9
Cation Radical Accelerated Nucleophilic Aromatic Substitution via
Organic Photoredox Catalysis
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
Nicholas E. S. Tay, David A. Nicewicz*
Department of Chemistry, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, 27599ꢀ3290, United
States
Supporting Information Placeholder
catalysis6,7, with notable exceptions utilizing harsh acidic8 or
ABSTRACT: Nucleophilic aromatic substitution (SNAr) is a
direct method for arene functionalization, however it can be hamꢀ
basic conditions.9 Our proposed transformation presents an
alternative paradigm for CꢀO bond functionalization via mild,
transition metalꢀfree catalysis.
A. Nucleophilic aromatic substitution (SNAr) for C(sp2)–OR activation?
pered by low reactivity of arene substrates and their availability.
Herein we describe a cation radicalꢀaccelerated nucleophilic aroꢀ
matic substitution using methoxyꢀ and benzyloxyꢀ groups as nuꢀ
cleofuges. In particular, ligninꢀderived aromatics containing guaiꢀ
acol and veratrole motifs were competent substrates for functionꢀ
alization. We also demonstrate an example of siteꢀselective substiꢀ
tutive oxygenation with trifluoroethanol to afford the desired triꢀ
fluoromethylaryl ether.
Nu
OR
Nu
OR
Nu
–OR
R
R
R
Meisenheimer complex
Requires electron deficient arenes (R = NO2, F, SO2R; X = F or Cl)
B. Activation of C(sp2)–OR Bonds by Cation Radical Accelerated-SNAr:
One of the most direct means of benzenoid functionalization is
nucleophilic aromatic substitution (SNAr). Mechanistically,
this transformation occurs by an additionꢀelimination sequence
via a Meisenheimer complex and allows for selective cleavage
of C–F or C–Cl bonds (Figure 1). Despite its prevalence in
medicinal chemistry,1 the utility of SNAr is limited to select
aromatics and heteroaromatics, as the formation of the
Meisenheimer complex is highly endergonic and its stabilizaꢀ
tion requires electronꢀwithdrawing groups at either the ortho
or para positions of the arene2.
Nu
Me
MeO
acridinium
acridinium
Me
NuH
+
-MeOH
455 nm LEDs
Me
• selective for OMe and OBn groups
• guaiacol and veratrole motifs accessible
• amination and oxygenation
N
R
R1
R1
BF4
Anisole Charge Density
Proposal:
OMe
HNu OMe
NuH
Nu
We have established a research program studying the reactiviꢀ
ty of arene cation radicals, generated by organic photooxidaꢀ
tion catalysts, that undergo a series of C–H functionalization
reactions with nucleophiles such as azoles, ammonia and cyaꢀ
nide.3,4 These reactions proceed via photoinduced electron
transfer (PET) from the aromatic substrate to an excitedꢀstate
acridinium photooxidant to generate arene cation radicals. The
natural population analysis (NPA) of anisole, a prototypical
substrate in the aforementioned reactions, reveals a buildup of
charge density in the cation radical at the methoxyꢀbearing
carbon atom as well as the para- and orthoꢀcarbon atꢀ
oms(Figure 1).5 Cation radical 1 is anticipated to be susceptiꢀ
ble to reversible nucleophilic attack at either the ipso-, paraꢀ
or ortho- positions relative to the methoxy group. We hypothꢀ
esized that if a terminal oxidant is omitted, ipso σꢀcomplex 2
could undergo rearomatization after methanol extrusion to
give an overall inverse electronꢀdemand SNAr affording 3.
This is in contrast to the previous C–H functionalization pathꢀ
ways that occur via the paraꢀ or ortho-addition intermediates,
as a second, irreversible oxidation step is required to form
these adducts.3 Herein, we describe the development of a genꢀ
eral means for activation of alkoxy arenes toward SNAr via
single electron oxidation. Current methods for CꢀO bond funcꢀ
tionalization of aryl methyl ethers rely primarily on nickel
2
1
–MeOH
+e–
Ground State
- 0.100
Radical Cation
0.580
3
Figure 1. (A) Challenges to using alkoxy arenes in SNAr chemisꢀ
try (B) A proposal for a photoredoxꢀcatalyzed cation radicalꢀ
accelerated SNAr.
We began our studies with 2,4ꢀdichloroanisole as the aromatic
substrate and imidazole as the nucleophilic coupling partner,
using the acridinium photocatalyst A previously utilized in our
arene CꢀH amination3 and cyanation4 protocols (Table S1).10
Successful formation of the desired aminated arene 4 in a 95%
yield (isolated yield = 79%) was realized with an excess of
imidazole in an equivolume mixture of 2,2,2ꢀtrifluoroethanol
(TFE) and 1,2ꢀdichloroethane (DCE) under anaerobic condiꢀ
tions. Control experiments established the importance of acriꢀ
dinium photocatalyst A as the amination product was not
formed in the absence of light and photocatalyst, and deꢀ
creased yields were observed with less structurally robust acꢀ
ridinium derivatives (catalysts BꢀC).11 Additionally, we reaꢀ
soned that formation of the ipso- product was promoted by the
exclusion of oxygen from the system, as downstream aryl
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 2 of 6
aromatization and deprotonation pathways for CꢀH amination chlorinated N-arylimidazoles 9 and 10 in excellent yield. We
1
2
3
4
5
6
7
8
would be eliminated. As anticipated, conducting the reaction
under aerobic conditions displayed the sensitivity of the sysꢀ
tem to oxygen, as decreased yields were observed.
were pleased to find that monoꢀsubstituted 4ꢀchloroanisole and
2ꢀchloroanisole, as well as unsubstituted anisole provided the
ipsoꢀaminated products in excellent to moderate yields (11 to
13). The latter two results are especially interesting as they
display complementary selectivity to our previously reported
CꢀH amination protocol. We were also able to transform sevꢀ
eral substituted methoxynaphthalenes to their N-
The optimized conditions were then successfully applied to a
range of halogenated methoxyarenes, a substrate limitation
under current nickelꢀcatalyzed conditions.12 2,4 Diꢀ
halogenated anisoles were successfully transformed to correꢀ
sponding N-arylimidazoles (5 to 8) in good yield, with a tolerꢀ
ance for brominated and fluorinated anisoles observed (Chart
1). Interestingly, substitutive defluorination for 7 and 8 was
observed under our reaction conditions, but its extent was subꢀ
stitutionꢀdependent and an independent SNAr pathway for this
competitive transformation was ruled out as defluorinative
SNAr was not observed in the absence of light or acridinium
(Table S6).13
naphthylimidazole
imidazolyl)naphthalene
counterparts,
as
and
1ꢀchloroꢀ2ꢀ(1ꢀ
1ꢀcyanoꢀ2ꢀ(1ꢀ
14
9
imidazolyl)naphtalene 15 were obtained in good and excellent
yields respectively. Additionally, we discovered the amenabilꢀ
ity of benzyl aryl ethers as nucleofuges in this transformation,
with 1ꢀ(benzyloxy)ꢀ2,4ꢀdichlorobenzene affording the adduct
16 in excellent yield.
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
Guaiacol and veratrole are monomeric units obtained from
lignin valorization processes14,15 and their catechol core is
prevalent in numerous plant and animal metabolites. Despite
Monoꢀchlorinated, 2,4ꢀsubstituted anisoles were also excellent
substrates for this transformation, yielding the corresponding
Chart 1. Arene substrate scope for photoredox-catalyzed cation radical accelerated SNAr.
Reactions were run in a 1:1 mixture of 1,2ꢀdichloroethane (DCE) and 2,2,2ꢀtrifluoroethanol (TFE) at [0.1 M] with respect to the arene. a26% of defluoriꢀ
native amination product observed, see SI for details. bTwo side products (11% combined) observed, see SI for details. c10 mol % catalyst A used. d9:1
DCE:TFE solvent system. ‡ Loss of –OBn.
2
ACS Paragon Plus Environment

Page 3 of 6
Journal of the American Chemical Society
their structural ubiquity in natural and synthetic molecules, We then sought to probe the applicability of this system to the
1
2
3
4
5
6
7
8
selective Oꢀalkyl CꢀO substitutions in these motifs are elusive.
Upon applying our reaction conditions to methyl veratrate, we
observed a 92% yield for the aminated products 17, with a 7:1
C4:C3 selectivity. Veratronitrile, 3,4ꢀdimethoxyphenyl triflate
and veratraldehyde also provided the desired N-arylimidazoles
(18 to 20). While OMeꢀsubstitution at C4 was typically faꢀ
vored in accordance with computationally predicted NPA valꢀ
ues,16 we observed a regioselectivity switch for veratraldeꢀ
hyde. We hypothesize that this divergence results from hemiꢀ
acetal formation in the presence of TFE, for which NPA valꢀ
ues predict a regioselectivity preference for C3 over C4.17
lateꢀstage functionalization of complex molecules. A protected
methoxynoradrenalone derivative was converted to the 3ꢀ and
4ꢀ(1ꢀimidazolyl) noradrenalone derivatives 32 and 33 respecꢀ
tively, with partial selectivity for C3ꢀsubstitution as predicted
by NPA values. Tyrosine and LꢀDOPA methyl ester derivaꢀ
tives were regioselectively transformed to the aminated adꢀ
ducts 34 and 35 in moderate to good yields. We also demonꢀ
strate the first example of selective aryl CꢀN formation beꢀ
tween the imidazole moiety of Bocꢀhistidine methyl ester and
the methoxyarene component of PhthꢀOꢀmethyltyrosine meꢀ
thyl ester 36.
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
Triisopropylsilyl (TIPS) and benzylꢀprotected methyl isovanilꢀ
late underwent selective ipsoꢀOMe amination to yield 21 and
22 in excellent yield. Interestingly, selective OMeꢀ substituꢀ
tion was observed for 3ꢀ(benzyloxy)ꢀ4ꢀmethoxyphenyl triflate
when using a 9:1 DCE:TFE solvent mixture (23). Selective C3
amination was observed for Oꢀbenzylvanillin isomers (24 and
25), which corroborates the regioselectivity preferences for
veratraldehyde. Benzylꢀprotected acetovanillone and isoacetoꢀ
vanillone were also aminated in excellent yields (26 to 29),
albeit with limited C4:C3 selectivity. We hypothesize that the
absence of regioselectivity in these examples may arise from
increased difficulty of hemiacetal formation for the acetapheꢀ
nones. Heterocycles containing the veratrole core were also
selectively aminated with imidazole at the 7ꢀposition, yielding
single regioisomers for 4ꢀchloroꢀ6,7ꢀdimethoxyquinoline 30
and 6,7ꢀdimethoxyisoquinoline 31.
A range of Nꢀheterocyclic nucleophiles were found to be
competent coupling partners for our transformation. Pyrazoles
successfully formed the CꢀN adduct with 2,4 dichloroanisole
in moderate to excellent yields (Table 1, 37 to 41). Interestingꢀ
ly, we observed the formation of a single regioisomer (39, 40)
when using 3ꢀmethylpyrazole as the nucleophile, and conꢀ
firmed its identity as the less hindered CꢀN adduct 40 by xꢀray
crystallography. Benzimidazoles were also compatible with
our reaction conditions, furnishing N-arylbenzimidazoles
(NAB) 42 and 43 in moderate yields. The formation of the
unsymmetrial NABs 43 are especially interesting, as the azole
component is a key feature of a potential therapeutic for neuꢀ
rodegenerative diseases18; thus our synthetic method would
enable arene diversification of the parent benzimidazole. Bocꢀ
histidine methyl ester was also a compatible nucleophile, afꢀ
fording the CꢀN adduct 44 as a single regioisomer in moderate
yield. Lastly, triazoles were competent coupling partners as
the unsubstituted and amino acid derived triazoles furnished
the desired products 45 and 46. The product regioselectivities
for 44 and 46 suggest a spatial preference for the unhindered
azole tautomer, and future work will elucidate the nature of
this selectivity.
Table 1. Nucleophile scope of cation radical-accelerated
SNAr.
Cl
Cl
5 mol % catalyst A
Nuc
MeO
455 nm LEDs
1:1 DCE:TFE, 24 h
33 °C, N2
Nuc
H
+
R
R
Two nonꢀNꢀheterocyclic nucleophiles were found to be comꢀ
petent coupling partners. Aniline synthesis was accomplished
using ammonium carbamate under an anaerobic version of our
previously reported arene amination conditions3, generating 47
in a moderate yield. Additionally, we report the suitability of
TFE as a nucleophile under our conditions. The incorporation
of trifluoroethyl groups into pharmaceuticals is known to inꢀ
crease their lipophilicity and metabolic stability19, and methꢀ
ods for generating trifluoroethylarylethers proceed via copperꢀ
catalysis with aryl halides19 or tetrafluoroborates20 as the couꢀ
pling partners. We display the first example (to the best of our
knowledge) of methoxyarene coupling with trifluoroethanol,
as 2,4ꢀdichloroanisole was converted to the trifluoroꢀ
ethylarylether 48 in 44% yield in the presence of the exogeꢀ
nous base 1,1,3,3ꢀtetramethylguanidine.
1.1 - 4.0 eq.
1.0 eq.
Cl
Me
Me
N
N
Cl
N
Cl
N
N
N
N
Cl
Me
Cl
N
tBu
Cl
Cl
39: 96% yield
one isomer
37: 94% yield
38: 74% yield
40: 92% yield
one isomer
O
MeO2C
N
H
NHBoc
Cl
Me
Cl
N
Cl
N
N
Cl
Cl
N
2
N
N
N
1
N
Me
Cl
Cl
Cl
Cl
44: 41% yielda
one isomer
43: 41% yielda
1.9:1 (N1:N2)
41: 33% yield
42: 54% yield
Sequential CꢀH functionalization and SNAr reactions were
possible using naproxen methyl ester to first afford a cyaꢀ
nation adduct (S30) followed by the SNAr conditions with
imidazole to give 49, thus displaying the complementarity of
our arene functionalization protocols for lateꢀstage modificaꢀ
tions of complex arenes (Figure 2A). Finally, we also display
an example of selective CꢀO bond cleavage in a βꢀOꢀ4’ lignin
model substrate S32, where highly selective Oꢀ4’ cleavage
furnishes 50 in a 51% yield (Figure 2B). Confirmation of the
bond selectivity was shown using the deuterated analog S41,
which provided 51 in a comparable yield. This selectivity
complements current redoxꢀneutral lignin depolymerization
CO2Bn
NHBoc
Cl
N
N
N
Cl
Cl
Cl
O
N
H2N
F3C
Cl
47: 45% yielda,d 48: 44% yielda,e
N
N
Cl
45: 58% yielda,b
Cl
Cl
46: 27% yielda,c
one isomer
Reactions run in a 1:1 mixture of DCE:TFE [0.1 M] with respect to the
arene. a0.10 eq. of catalyst A. bTrifluorotoluene (TFT) as solvent. cReacꢀ
tion run in a 1:1 DCE:TFT. dReaction run in 10:1 DCE:H2O with 8.0 eq.
of ammonium carbamate. eReaction run in TFE with 3.0 eq. of 1,1,3,3ꢀ
tetramethylguanidine.
3
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 4 of 6
methods involving photoredox catalysis, in which βꢀOꢀ4’ linkꢀ
methoxyphenyl triflate was subjected to a 1:1 DCE:TFE solꢀ
ages are common cleavage targets.21
vent system (Fig. S12), the product of C3ꢀsubstitution, 19b
was observed in addition to the aforementioned C4ꢀ
substitution adduct 23 in a 2.5:1 C4:C3 ratio. We hypothesize
that increasing the concentration of the highly ionizing and
polar TFE24 stabilizes the radical cation resonance forms such
that the two most stable cationic sites are available for nucleoꢀ
philic attack.
1
2
3
4
5
6
7
8
While the mechanism of this transformation is currently under
examination, we were interested in probing the viability of the
arene radical cation, as it is the key reactive intermediate in
our aforementioned proposal. Since both 2,4ꢀdichloroanisole
and imidazole [Ep/2 = +2.04 V and Ep/2 = +1.15 V vs. SCE,
respectively, Fig. S8]22 are capable of reductively quenching
catalyst A (E* = +2.15 V), product formation could potenꢀ
Given these observations, we proposed that Mes-Acr+* oxiꢀ
dizes the anisole derivative leading to 52 (Figure 2C). Addiꢀ
tion of the nucleophile at the methoxyꢀbearing carbon gives
rise to 53, which undergoes loss of MeOH and is reduced by
Mes-Acrꢀ, leading to the final SNAr adduct.
red
tially occur via the arene or imidazole radical cation. Substitutꢀ
ing acridinium A for a less oxidizing iridiumꢀbased photocataꢀ
lyst D (E* [IrIII*/IrII] = +1.68 V vs. SCE)23 yielded no desired
product (Table S1, entry 16). This result indicates that an elecꢀ
trophilic aromatic substitutionꢀlike mechanism involving the
methoxyarene and an open shell imidazole species is unlikely,
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
Overall, we have demonstrated the applicability and practicaliꢀ
ty of cationꢀaccelerated SNAr for the formation of Nꢀ
arylazoles, anilines and trifluoroethylarylethers from the parꢀ
ent methoxyarenes and benzyloxyarenes. The accessibility of
guaiacol and veratrole moieties should enable the functionaliꢀ
zation of ligninꢀbased substrates as well as lateꢀstage diversifiꢀ
cation of complex molecules with these motifs. Together, our
photoredoxꢀcatalyzed strategy offers a new approach to CꢀO
bond functionalization and we anticipate that the mildness of
this protocol will enable adoption for a range of applications.
A.
CO2Me
Me
CO2Me
Me
5 mol % catalyst A
3.0 eq. TMSCN
MeO
MeO
MeCN/pH 9 buffer
S30
455 nm LEDs, O2
CN
67 % yield
Naproxen methyl ester
CO2Me
10 mol % catalyst A
4.0 eq. imidazole
Me
N
N
DCE:TFE (1:1; 0.1 M)
455 nm LEDs, N2
49: 94 % yield
CN
ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at http://pubs.acs.org.
B.
ꢀꢁO-4’ cleavage
OMe
N
O
10 mol % catalyst A
4.0 eq. imidazole
OMe
3
1
2
MeO
MeO
O
N
4
R
DCE:TFE (1:1; 0.1 M)
455 nm LEDs, N2
R
O
O-4’
cleavage
O
50: R = Me; 51% yield
51: R = CD3; 48% yield
Experimental procedures, spectral data and computational results
for all new compounds (PDF)
Four potential sites for C-O clevage
Me
C.
*
ACKNOWLEDGMENT
OMe
Me
Financial support was provided by the National Institutes
of Health (NIGMS R01 GM120186) and the David and
Lucile Packard Foundation. N.E.S.T is grateful for an NSF
Graduate Fellowship. IR was performed in the UNC EFRC:
Center for Solar Fuels, an Energy Frontier Research Center
funded by the U.S. Department of Energy, Office of Basic
Energy Sciences (DEꢀSC0001011).
Me
t-Bu
N
Ph
t-Bu
–e–
Mes-Acr+*
h
+e–
OMe
Me
52
Me
Mes-Acr•
Me
Me
Me
Me
REFERENCES
NH
t-Bu
N
t-Bu
Ph
N
Mes-Acr+
t-Bu
N
Ph
(1) Brown, D. G.; Boström, J. J. Med. Chem. 2016, 59, 4443–4458.
(2) Carey, F. A.; Sundberg, R. J. 5th ed.; Springer, 2008.
(3) Romero, N. A.; Margrey, K. A.; Tay, N. E.; Nicewicz, D. A.
Science 2015, 349, 1326–1330.
(4) McManus, J. B.; Nicewicz, D. A. J. Am. Chem. Soc. 2017, 139,
2880–2883.
(5) Margrey, K. A.; McManus, J. B.; Bonazzi, S.; Zecri, F.; Niceꢀ
wicz, D. A. J. Am. Chem. Soc. 2017, 139, 11288–11299.
(6) Cornella, J.; Zarate, C.; Martin, R. Chem Soc Rev 2014, 43,
8081–8097.
(7) Tobisu, M.; Chatani, N. Acc. Chem. Res. 2015, 48, 1717–1726.
(8) Mishra, A. K.; Verma, A.; Biswas, S. J. Org. Chem. 2017, 82,
3403–3410.
(9) Kaga, A.; Hayashi, H.; Hakamata, H.; Oi, M.; Uchiyama, M.;
Takita, R.; Chiba, S. Angew. Chem. Int. Ed. 2017, 56, 11807–11811.
(10) See the Supporting Information for more details on the optiꢀ
mization of the reaction conditions.
(11) Romero, N. A.; Nicewicz, D. A. Chem. Rev. 2016, 116,
10075–10166.
t-Bu
–e–
- MeOH
NH
N
N
N
53
OMe
13
Figure 2. A) Sequential complementary photoredoxꢀcatalyzed
arene functionalizations. B) Selective Oꢀ4’ CꢀO bond cleavage
in a βꢀOꢀ4’ lignin model substrate. C) Proposed mechanism.
and that the arene radical cation is crucial for arene amination.
We were also interested in probing the identity of the nucleoꢀ
fuge upon arene aromatization. When 1ꢀ(benzyloxy)ꢀ2,4ꢀ
dichlorobenzene was subjected to reaction conditions, we obꢀ
served the presence of benzyl alcohol as the only byꢀproduct
of the reaction, indicating that the nucleofuge is unaltered upꢀ
on expulsion from arene (Figs. S9 ꢀ S11). Lastly, we note the
presence of a solvent effect with TFE. When 3ꢀ(benzyloxy)ꢀ4ꢀ
(12) Zarate, C.; Nakajima, M.; Martin, R. J. Am. Chem. Soc. 2017,
139, 1191–1197.
4
ACS Paragon Plus Environment

Page 5 of 6
Journal of the American Chemical Society
(13) 2ꢀchloroꢀ4ꢀfluoroanisole provided 26% of substitutive defluorꢀ
(18) Tardiff, D. F.; Jui, N. T.; Khurana, V.; Tambe, M. A.; Thompꢀ
son, M. L.; Chung, C. Y.; Kamadurai, H. B.; Kim, H. T.; Lancaster,
A. K.; Caldwell, K. A.; Caldwell, G. A.; Rochet, J. C.; Buchwald, S.
L.; Lindquist, S. Science 2013, 342, 979–983.
ination product whereas 4ꢀchloroꢀ2ꢀfluoroanisole only yielded 5% of
the analogous byꢀproduct. See the Supporting Information for more
details.
1
2
3
4
5
6
7
8
9
(14) Guillén, M. D.; Manzanos, M. J. Food Chem. 2002, 79, 283–
292.
(15) Key, R. E.; Bozell, J. J. ACS Sustain. Chem. Eng. 2016, 4,
5123–5135.
(16) The regioselectivities observed generally correlate with NPA
analysis, where the most electrophilic site on the radical cation is
preferentially substituted. Examples of these correlations are in the
Supporting Information.
(17) No selectivity preference for C3 over C4 for substrate 20 was
observed by NPA analysis, but the hemiacetal of 20 formed with TFE
shows a preference for C3 substitution. See the Supporting Inforꢀ
mation (Figures S3, S14 and S15) for more details.
(19) Vuluga, D.; Legros, J.; Crousse, B.; BonnetꢀDelpon, D. Eur. J.
Org. Chem. 2009, 2009, 3513–3518.
(20) Quach, T. D.; Batey, R. A. Org. Lett. 2003, 5, 1381–1384.
(21) Kärkäs, M. D.; Matsuura, B. S.; Monos, T. M.; Magallanes,
G.; Stephenson, C. R. J. Org. Biomol. Chem. 2016, 14, 1853–1914.
(22) Roth, H. G.; Romero, N. A.; Nicewicz, D. A. Synlett 2016, 27,
714–723.
(23) Choi, G. J.; Zhu, Q.; Miller, D. C.; Gu, C. J.; Knowles, R. R.
Nature 2016, 539, 268–271.
(24) Eberson, L.; Hartshorn, M. P.; Persson, O.; Radner, F. Chem.
Commun. 1996, 2105–2112.
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
5
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 6 of 6
1
2
3
4
5
6
7
8
9
Nuc
OMe
organic photooxidant
R
R
455 nm LEDS
N2
48 examples
+ Nuc
via
H
OMe
H
Nuc
H
Nuc
OMe
radical cation
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
Meisenheimer complex
6
ACS Paragon Plus Environment