Picolinate-Directed Arene meta-C-H Amination via FeCl3 Catalysis

Article abstract of DOI:10.1021/jacs.9b13753

Direct C-H functionalization of aromatic compounds is a powerful tool for organic synthesis; however, differentiation among the ubiquitous and often chemically similar C-H bonds remains a significant challenge. Conflation with coordinating or directing groups incorporated into the intended substrate has helped address these limitations, although access to remote sites remains limited. Herein, we report an operationally simple and sustainable direct meta-selective H₂N amination of benzylic and related aromatic picolinates under conditions mild enough to modify polyfunctional and late-stage molecules.

Full text of DOI:10.1021/jacs.9b13753

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Article
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Picolinate Directed Arene meta-C-H Amination via FeCl Catalysis
Raghunath R Anugu, Sailu Munnuri, and John R. Falck
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.9b13753 • Publication Date (Web): 22 Feb 2020
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Picolinate Directed Arene meta-C-H Amination via FeCl3 Catalysis
Raghunath Reddy Anugu, Sailu Munnuri and John R. Falck*
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Division of Chemistry, Departments of Biochemistry and Pharmacology, University of Texas Southwestern Medical
Center, Dallas, TX 75390, United States
ABSTRACT: Direct C-H functionalization of aromatic compounds is a powerful tool for organic synthesis; however,
differentiation amongst the ubiquitous and often chemically similar C-H bonds remains a significant challenge. Conflation
with coordinating or directing groups incorporated into the intended substrate has helped address these limitations,
although access to remote sites remains limited. Herein, we report an operationally simple and sustainable direct meta-
selective H2N-amination of benzylic and related aromatic picolinates under conditions mild enough to modify
polyfunctional and late stage molecules.
operationally simple, direct meta-selective H2N-amination of
benzylic and related aromatic picolinates at rt-40 °C mediated
by catalytic FeCl3 under an inert atmosphere (Fig. 1, Panel B).
This procedure contributes to the burgeoning list of iron-
catalyzed C–H functionalizations26a while concurrently
providing a high level of an otherwise elusive regioselectivity
not observed in operationally similar aminations.26b
1. INTRODUCTION
Arylamines are prominent structural motifs in a vast array of
medically and economically important substances.1
Traditionally, aminations of arenes utilized multi-step
sequences and/or harsh reagents2 (e.g., nitration/reduction),
rearrangements (Beckmann, Curtius), reactive intermediates
(benzynes3), or vicarious nucleophilic substitution (VNS) of
strongly electron-deficient arenes.4,5 These were largely
superseded by aminations6 via transition metal mediated cross-
couplings with pre-functionalized substrates (e.g., Ullman-
Goldberg,7 Chan-Evans-Lam,8 Hartwig/Buchwald9) or
reactions of aryl anions with electrophilic amination
reagents.10,11 In more recent years, direct C-H functionalization
procedures including aminations12 have gained widespread
acceptance and generally provide improved scope and
efficiency. To address the challenge of differentiating amongst
the various aromatic C-H bonds, which often have similar
reactivities, C-H functionalization methodologies have been
aided by embedded or introduced directing groups (DGs). This
furnishes an additional level of regioselectivity, primarily
proximal or ortho to the DGs, and in many cases can override
the innate electronic and/or steric positional preferences of the
aromatic substrate.13 Extensions to meta-selective C-H
functionalization, however, are more challenging due to spatial
and/or geometric constraints.14 The emergence of the
Catellani15 norbornene relay procedure,16,17 purpose-designed
U-shaped directing groups,18-20 and other approaches,21 have
proven effective for meta-functionalization in many instances.
Nevertheless, it was not until 2016 that Yu and colleagues22
achieved the first and only directed meta-selective C-H arene
amination (Fig. 1, Panel A). However, the Yu amination
requires an elevated temperature and long reaction time (100
°C, 24 h); subsequent removal of the directing group utilizes hot
hydrobromic acid (100 °C), conditions that can be anticipated
to significantly limit synthetic applications. Based upon our
prior investigations,23,24 we envisioned a more practical
aromatic electrophilic (SEAr) amination procedure exploiting a
weakly basic pyridyl directing group. Herein, we report25 an
A: meta-Amination via Catellani norbornene-mediated relay process
OMe
F3
C
NHCOAd
(10 mol%)
N
OH
OMe
N
OMe
N
DG
CO2Me
(1.5 equiv)
Me
Me
+
R1
OBz
N
Me
Me
X
X
R2
K2PO4 (3 equiv)
AgOAc (2 equiv)
R
R
Pd
Ln
Pd(OAc)2 (10 mol%)
DCM, 100 °C
24 h
X
R2N
N
X = O, tBocN
R1
R2
Wang, Li, Jain, Farmer, He, Shen, Yu22 (2016)
B: This work
R'
O
R'
O
H2N-OSO3H
FeCl3 (5 mol%)
O
N
O
O
N
N
Et3N, HFIP
0-40 °C
6-24 h
O
NH
R
R
NH2
meta
*meta-Selective
*Inexpensive
*Environmentally friendly, sustainable catalyst
*Operationally simple
*Commercial reagents
Proposed SEAr mechanism
Figure 1. Directed Arene C-H meta-Amination Procedures.
The meta-selective amination procedure reported by Yu and
colleagues22 (Panel A) is compared and contrasted with the
method described herein (Panel B).
2. RESULTS AND DISCUSSION
Using benzyl picolinate (1) as a model system, a screen of
common transition metal catalysts and known electrophilic
aminating agents was used to identify the combination of FeCl3
and commercial hydroxylamine-O-sulfonic acid27 (HOSA) as
optimum (Table 1). Most notably, spectral analyses of the crude
reaction mixtures revealed that, of the three possible
regioisomeric amination adducts, only meta-aminated 2 was
present (≥99% by 1H/13C NMR, identified as the N-
1
acetamide28); the structure of 2 was further confirmed by H
nOe after isolation. Using 1,1,1,3,3,3-hexafluoroisopropanol29
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(HFIP) as solvent and HOSA/Et3N (2 equiv each) at rt, 2 was
warmed to 40 °C, except for 3,4-dichloro 15 that proceeded at
rt. In this cohort, only 3-nitro-4-methoxy 16 was produced in
poor yield, although most of the starting material was
recovered.
1
2
3
4
5
6
7
8
obtained in 72% isolated yield (entry 6) accompanied by
unidentified, polar (baseline) material or 65% yield on a 5 mmol
scale; in the former scale, 1 was completely consumed whereas
5% of 1 was recovered in the 5 mmol scale. In contrast with the
Yu procedure,22 no bis-aminated aryl picolinate was observed.
Other organic and inorganic bases gave inferior results as did
other solvents including 2,2,2-trifluoroethanol, MeOH, and
CH2Cl2 as well as combinations with HFIP (see Supporting
Information). Of several alternative commercial nitrogen-
containing DGs, e. g., 1H-pyrrole-2-carboxylate, (S)-N-
methylprolinate, 2-pyridineacetate, and 2-(dimethylamino)
benzoate, only 1-isoquinolinecarboxylate was comparable to
picolinate, although cost considerations excluded it from
routine use. Removal of the picolinate directing group in 2 with
K2CO3 in MeOH/H2O (10:1) at rt furnished 3-aminobenzyl
alcohol in 81% yield.
Application to phenethyl picolinate led to a mixture of meta-
and para-amines 17a,b favoring the later by a factor of 2 (Table
2, Panel B). The appearance of this additional regioisomer is
presumably due to the extended reach of the ethyl appendage.
For phenpropyl picolinate, the distribution of meta-/para-
regioisomers in 18a,b moved closer to parity (1:1.2), but like its
benzylic counterpart 9, the reaction required 40 °C to reach
completion. This might indicate some catalytically
nonproductive bidentate binding of the FeCl3 by the ester and
picolinate.
To validate the utility of our methodology for applications to
late stage molecules and pharmaceuticals, several polycyclic
and multifunctional examples were examined (Table 2, Panel
C). Interestingly, 1- and 2-naphthylmethanols showed a
proclivity for functionalization of both rings giving rise to 19a,b
and 20a,b, respectively. 2-Biphenylmethanol yielded 21a,b as
a 3:1 mixture. This regioselectivity likely reflects the
orthogonal conformation of the two phenyl rings which brings
the distal ring into closer proximity to the picolinate iron-
nitrenoid chelate. The successful meta-selective aminations of
dipeptide 22 and pyrazine 23 also bode well for applications
with more complex systems.
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22
23
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Table 1. Directed meta-Amination Optimizationa
O
O
HOSA
O
O
catalyst
N
N
base
solvent
1
2
NH2
entry catalyst (mol%) solvent base temp (°C) time (h) yield (%)
1
2
3
4
5
6
7
8
9
Pd(OAc)2 (10)
Rh2(esp)2 (10)
Cu(OTf)2 (10)
Ni(OAc)2 (10)
FeBr3 (10)
FeCl3 (5)
HFIP
HFIP
HFIP
HFIP
HFIP
HFIP
HFIP
HFIP
TFE
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
CsOH
Et3N
40
40
40
40
40
23
23
23
40
40
23
23
24
24
24
24
24
10
33
33
24
24
26
16
<5
0
<5
0
30
72b
55
42
20
0
Scheme 1. Control Experiments
FeCl3 (1)
O
HOSA (2 equiv)
FeCl3 (0.1)
FeCl3 (10)
FeCl3 (5)
FeCl3 (5)
FeCl2 (10)
O
(a)
(b)
(c)
no reaction
N
Et3N (2 equiv)
HFIP, rt, 24 h
1
10
11
12
THF
HFIP
HFIP
O
O
FeCl3 (5 mol%)
HOSA (2 equiv)
Et3N (2 equiv)
30
66
O
O
no reaction
HFIP, rt-60 °C, 22 h
aSee Supporting Information for additional details. b65% yield
on 5 mmol scale, 5% of 1 recovered.
O
FeCl3 (5 mol%)
HOSA (2 equiv)
MeO
mix of aminobenzyl benzoates
(11%)
N
Et3N (2 equiv)
HFIP, rt, 10 h
(5 mol%)
A selection of representative benzyl picolinates was explored
to define the scope of the reaction (Table 2, Panel A) starting
with 4-methyl-, 2-methyl- and 2,6-dimethylbenzyl picolinates
that smoothly generated 3, a regioisomeric mixture of 4a,b
(6:1), and 5, respectively, overnight at rt. This series reveals
picolinate-guided electrophilic aminations are comparatively
unrestricted even if one or both ortho-positions bear
substituents since it likely involves direct addition to the
aromatic π-system (Fig. 1, Panel B). In contrast, methodology
that operates through a Catellani norbornene-palladacycle,15-17
templates,18,20,30,31 or other protocols32 to achieve meta-
selectivity typically generate only the less hindered meta-
isomer when one ortho-substituent is present, even if both meta-
positions are available for functionalization; if both ortho-
positions are occupied, their efficiencies suffer further and
product yields are reduced. Generation of 4-methoxy-
substituted adduct 6 in just 6 h is consistent with the influence
of a powerful electron-donating substituent on a SEAr
functionalization. Substitution at the benzylic position was well
tolerated, e.g., 7 and 8a,b, and had minimal influence on the
distribution of regioisomers (cf., 4a,b vs. 8a,b). The picolinate
of methyl (R)-mandelate, while more sluggish, still delivered a
O
O
O
FeCl3 (5 mol%)
HOSA (2 equiv)
O
O
(d)
(e)
mix of aminobenzyl benzoates
(0-5%)
N
Et3N (2 equiv)
HFIP, rt, 24 h
(5-100 mol%)
FeCl3 (5 mol%)
HOSA (2 equiv)
O
2
N
Et3N (2 equiv)
HFIP, rt, 23 h
TEMPO (1 equiv)
(41%)
1
O
O
Rh2(esp)2 (2 mol%)
MesSO3NH2 (1.5 equiv)
O
(f)
no reaction
N
N
F3CCH2OH, rt, 16 h
1
Cu(OTf)2 (10 mol%)
HOSA (1.5 equiv)
O
(g)
2
CsOH (1.5 equiv)
1,10-phen (10 mol%)
HFIP, rt, 16 h
(5%)
1
O
FeSO4 (5 mol%)
MsONH3OTf (1.5 equiv)
O
(h)
no reaction
N
ACN/H2O, rt, 24 h
1
Mes = mesitylene, phen = phenanthroline
Control experiments proved instructive in understanding the
requirements of the reaction. In the absence of FeCl3 catalyst
(Scheme 1a) or an attached picolinate directing group (Scheme
1b), the substrates, 1 and benzyl benzoate, were recovered
unreacted even after prolonged reaction times. A mixture of
regioisomeric aminobenzyl benzoates (11%) formed in the
presence of added methyl picolinate (5 mol%) (Scheme 1c);
however, there was no reaction in the presence of 1 equiv of
good yield of
9 whereas amination of benzaldehyde
cyanohydrin to 10 was modest, but provided ready access to a
useful masked aminated aldehyde. Arenes bearing electron-
withdrawing substituents, viz., 3-trifluoromethyl 11, 4-
carbomethoxy 12, 4-bromo 13, and 2-chloro (14a,b), were
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added methyl picolinate (see SI). To probe the possibility that
1
the che-
2
3
Table 2. Directed C-H meta-Amination of Picolinatesa
4
5
6
7
8
A: Benzyl Esters
Cmpd #:
isolated yield (regioisomer ratio), temp, time
Me
Me
DG
DG
DG
DG
DG
O
O
O
O
O
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
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50
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60
Me
Me
MeO
Me
NH2
: 75% (6:1)
rt, 16 h
NH2
: 70%
rt, 16 h
NH2
4a,b
NH2
NH2
3
5
6
: 78%
: 71%
rt, 16 h
rt, 6 h
Me
Me Me
Me
CO2Me
DG
DG
DG
DG
O
O
O
O
+
Me
NH2
: 68%
rt, 16 h
NH2
NH2
NH2
7
8a,b
9
: 75% (7:1)
: 71%
rt, 16 h
40 °C, 24 h
CN
O
DG
DG
DG
DG
F3C
O
O
O
Br
MeO2C
NH2
NH2
NH2
NH2
10
b
11
12
13
: 74%
: 41%
0 °C, 8 h
: 71%
: 51%
40 °C, 24 h
40 °C, 24 h
40 °C, 24 h
Cl
DG
Cl
Cl
DG
DG
DG
O2N
O
O
O
O
+
MeO
Cl
NH2
NH2
14a,b
NH2
NH2
b
15
: 43%
rt, 24 h
16
: 76% (9:1)
: 15%
40 °C, 24 h
40 °C, 16 h
B: Phenethyl and Phenpropyl Esters
isolated yield (regioisomer ratio), temp, time
Cmpd #:
CO2Et
CO2Et
O
O
DG
DG
DG
+
DG
O
O
+
H2N
H2N
NH2
NH2
b
c
b
17a,b
18a,b
: 64% (1:2)
: 66% (1:1.2)
40 °C, 24 h
rt, 18 h
C: Polycyclic/Multifunctional Esters
isolated yield (regioisomer ratio), temp, time
Cmpd #:
O
O
NH2
DG
DG
DG
DG
DG
DG
O
O
O
O
+
+
+
H2N
NH2
NH2
Br
19a,b
Br
20a,b
: 66% (1:1)
c
: 62% (1:1.5)
0 °C, 10 h
NH2
: 61% (3:1)
rt, 16 h
NH2
21a,b
O
DG
H
N
N
O
rt, 16 h
O
N
CO2Me
O
tBu
N
H
O
O
O
Me
DG
22
DG =
NH2
23
: 56%
NH2
N
: 72%
40 °C, 24 h
rt, 15 h
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b
c
aReaction conditions: FeCl3 (5 mol%), HOSA (2 equiv), Et3N (2 equiv), 0.1 M in HFIP. 4 equiv each of HOSA and Et3N. Ratio
1
unchanged after 10-fold dilution which is consistent with intramolecularly directed amination.
2
3
4
5
6
7
8
9
lated active iron-nitrenoid species may need the extra
stabilization provided by arene coordination, as suggested by a
reviewer, 3,5-dimethylbenzyl picolinate was used as a ligand
instead of methyl picolinate (Scheme 1d). A mixture of
regioisomeric aminobenzyl benzoates (5%) formed in the
presence of 5 mol% of 3,5-dimethylbenzyl picolinate; no
reaction in the presence of 50 and 100 mol% of 3,5-
dimethylbenzyl picolinate (see SI). We conclude from 1c and
1d that the picolinate directing group must be esterified to the
substrate and that it plays a decisive role both in facilitating
amination and as a meta-directing group. In the presence of
TEMPO (1 equiv), the yield of 2 was reduced to 41% (Scheme
1e). Additional studies would be needed to determine if radicals
have a role in the amination. An indication of the unique role of
iron in these processes is highlighted by the failure or low
conversion of 1 into 2 by other recently introduced transition
metalation-deprotonation (CMD);36 and (c) Heck-type
carbometallation-elimination,37 the electrophilic aromatic
substitution (SEAr) pathway [option (a)] is the most consistent
with the regioselectivities in Table 2 and the above KIE
measurements.
Scheme 3. Preparation and Evaluation of 1-Amino-
pyridinium 24 as a Potential Intermediate Leading to 2
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
FeCl3 (5 mol%)

O
+
2
2
HFIP
rt-40 °C
MesONH2
O
1
N
CH2Cl2
rt
FeCl3 (5 mol%)
H2N

OMes
Et3N
24
HFIP
rt-40 °C
metal C-H amination procedures including those mediated by
1-Amino-pyridinium
2,4,6-trimethylbenzenesulfonate
26b
Rh2(esp)2,23 Cu(OTf)2,24 and FeSO4
respectively).
(Schemes 1f,g,h,
(OMes) salt 24 was prepared according to literature
procedure34 and then heated with FeCl3, with and without
Et3N, for 24 h. No meta-amino adduct 2 was observed.
Scheme 2. Kinetic Isotope Effect Study
O
O
D
D
3. CONCLUSIONS
HOSA (0.5 equiv)
D
D
D
Et3N (0.5 equiv)
O
O
1
2
+
+
Classical electrophilic aromatic functionalizations are
associated with aggressive reagents and adherence to the
Crum‐Brown‐Gibson Substitution Rule38 (ortho/para vs meta).
Consequently, meta-functionalizations of electron-rich and
electron-neutral substrates are generally restricted or
unavailable. The results presented above demonstrate picolinate
directed C-H functionalizations can now be added to the options
for remote arene functionalization strategies.39 In light of its
atom- and cost-efficiencies, we anticipate this methodology will
find wide utility and encourage extensions to other C-H
functionalization processes.
N
N
FeCl3 (5 mol%)
D
D
D
HFIP
rt, 9 h
D
NH2
KH/KD = 1
Competitive amination of an equimolar mixture of 1 and benzyl-
2,3,4,5,6-d5 picolinate using FeCl3 (5 mol%) in HFIP (0.1 M) with
a limiting amount of amination reagent [HOSA (0.5 equiv), Et3N
(0.5 equiv)] at rt for 9 h. The ratio of 2 and 3-aminobenzyl-2,4,5,6-
d4 picolinate in the crude reaction product was measured by NMR.
To gain additional mechanistic insight, we measured the
kinetic isotope effect (KIE) of the amination. Such studies have
proven valuable for assessing mechanistic hypotheses in a wide
variety of transition metal-catalyzed reactions.33 An equimolar
mixture of 1 and its deuterated analog, benzyl-2,3,4,5,6-d5
picolinate, was subjected to competitive amination using FeCl3
(5 mol%) in HFIP (0.1 M) with a limiting amount of amination
reagent [HOSA (0.5 equiv) and Et3N (0.5 equiv)] at rt for 9 h
4. EXPERIMENTAL SECTION
General experimental considerations, procedures, analytical
chromatograms, and spectral data are provided in the
Supporting Information.
General amination procedure. To a stirring, 0 °C solution
of HOSA (0.4 mmol, 2 equiv) in HFIP (1.5 mL) was added Et3N
(0.4 mmol, 2 equiv). After 15 min, the picolinate ester (0.2
mmol, 1 equiv) in HFIP (0.5 mL) and anhydrous FeCl3 (5
mol%; n.b., deliquescent) were added sequentially. The
reaction was conducted at the temperature indicated in Table 2.
After complete consumption of the picolinate ester (6-24 h,
monitored by TLC), the reaction mixture was diluted with
CH2Cl2 (10 mL), washed with saturated aqueous Na2CO3 (10
mL), brine (10 mL), dried over anhydrous Na2SO4, and
concentrated in vacuo. The crude residue was purified on a
commercial pre-packed SiO2 column using a medium pressure,
automated chromatograph equipped with a UV detector and
eluted with MeOH/CH2Cl2 or EtOAc/hexanes to furnish
aminated picolinate(s) in the indicated yield(s). Variations in
reaction conditions are noted in the legend of Table 2 for select
substrates.
1
(Scheme 2). H/13C NMR analyses of the crude showed a 1:1
mixture of meta-aminated products for a KH/KD ratio of 1.
Similar kinetic isotope effects (KIE) have been reported for
related Rh2-,23 Cu(II)-,24 and Fe(II/III)-mediated26 reactions
indicating C-H cleavage is not the rate-determining step, thus
excluding organometallic C-H activation as a likely pathway.
An alternative pathway invokes an N-aminopyridinium salt,
generated in situ either directly from HOSA amination of the
picolinate nitrogen or with the assistance of the iron catalyst,
which serves as the actual amination intermediate. This was
evaluated by independent preparation of 24 following literature
procedure34 and its exposure to FeCl3, with and without Et3N,
in HFIP for 24 h with heating up to 40 °C (Scheme 3). No arene
amination was observed.
Of the most plausible remaining C-H functionalization
scenarios,35 viz., (a) picolinate directed, iron-nitrenoid
electrophilic aromatic substitution (SEAr); (b) concerted
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Amination and Its Application in Organic Synthesis. Tetrahedron
ASSOCIATED CONTENT
2019, 75, 130607. (d) Plietker, B.; Röske, A. Recent Advances in Fe-
Catalyzed C–H Aminations Using Azides as Nitrene Precursors. Catal.
Sci. Technol. 2019, 9, 4188–4197.
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SUPPORTING INFORMATION
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The Supporting Information is available free of charge on the
ACS Publications website at DOI:
(13) Henry, M. C.; Mostafa, M. A. B.; Sutherland, A.ꢀRecent
Advances in Transition-Metal-Catalyzed, Directed Aryl C–H/N–H
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Selective C–H Arylation via Pd/Norbornene Catalysis. J. Am. Chem.
Soc. 2015, 137, 5887–5890.
General
experimental
considerations,
procedures/characterization data, analytical chromatograms,
and scanned spectra (PDF)
AUTHOR INFORMATION
Corresponding Author
*j.falck@utsouthwestern.edu
ORCID
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Raghunath Reddy Anugu: 0000-0003-3868-1203
Sailu Munnuri: 0000-0001-5675-6032
John R. Falck: 0000-0002-9219-7845
Notes
(18) Tang, R.-Y.; Li, G.; Yu, J.-Q. Conformation-Induced Remote
meta-C–H Activation of Amines. Nature 2014, 507, 215–220.
(19) Lee, S.; Lee, H.; Tan, K. L. meta-Selective C–H
The authors declare no competing financial interests.
Functionalization Using
a Nitrile-Based Directing Group and
ACKNOWLEDGMENT
Cleavable Si-Tether. J. Am. Chem. Soc. 2013, 135, 18778–18781.
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meta-C–H Bonds Assisted by an End-On Template. Nature 2012, 486,
518–522.
(21) Hofmann, N.; Ackermann, L. meta-Selective C–H Bond
Alkylation with Secondary Alkyl Halides. J. Am. Chem. Soc. 2013,
135, 5877–5884.
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Yu, J.-Q. Ligand-Promoted meta-C–H Amination and Alkynylation. J.
Am. Chem. Soc. 2016, 138, 14092–14099.
(23) Paudyal, M. P.; Adebesin, A. M.; Burt, S. R.; Ess, D. H.; Ma, Z.;
Kürti, L.; Falck, J. R. Dirhodium Catalyzed C-H Arene Amination
Using Hydroxylamines. Science 2016, 353, 1144–1147.
(24) Munnuri, S.; Anugu, R. R.; Falck, J. R. Cu(II)-Mediated N–H
and N-Alkyl Aryl Amination and Olefin Aziridination. Org. Lett. 2019,
21, 1926–1929.
(25) Anugu, R. R.; Munnuri, S.; Falck, J. R. Directed meta C-H
Amination of Benzyl Picolates via FeCl3-Catalysis. Abstracts of
Papers, 258th ACS National Meeting & Exposition, San Diego, CA,
United States, August 25-29 (2019), MEDI-0253.
(26) (a) Shang, R.; Ilies, L.; Nakamura, E. Iron-Catalyzed C–H Bond
Activation. Chem. Rev. 2017, 117, 9086–9139. (b) Legnani, L.; Cerai,
G. P.; Morandi, B. Direct and Practical Synthesis of Primary Anilines
Through Iron-Catalyzed C–H Bond Amination. ACS Catal. 2016, 6,
8162–8165.
(27) Ma, Z.; Zhou, Z.; Kürti, L. Direct and Stereospecific Synthesis
of N‐H and N‐Alkyl Aziridines from Unactivated Olefins Using
Hydroxylamine‐O‐Sulfonic Acids. Angew. Chem. Int. Ed. 2017, 56,
9886–9890.
(28) Bowen, R. D.; Davies, D. E.; Fishwick, C. W. G.; Glasbey, T.
O.; Noyce, S. J.; Storr, R. C. Generation and Reactions of
Azaxylylenes. Tet. Lett. 1982, 23, 4501–4504.
(29) D'Amato, E. M.; Börgel, J.; Ritter, T. Aromatic C–H Amination
in Hexafluoroisopropanol. Chem. Sci. 2019, 10, 2424–2428.
(30) Wan, L.; Dastbaravardeh, N.; Li, G.; Yu, J.-Q. Cross-Coupling
of Remote meta-C–H Bonds Directed by a U-Shaped Template. J. Am.
Chem. Soc. 2013, 135, 18056–18059.
(31) Wang, P.; Farmer, M. E.; Huo, X.; Jain, P.; Shen, P.-X.; Ishoey,
M.; Bradner, J. E.; Wisniewski, S. R.; Eastgate, M. D.; Yu, J.-Q.
Ligand-Promoted meta-C–H Arylation of Anilines, Phenols, and
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(32) Phipps, R. J.; Matthew J.; Gaunt, M. J. A meta-Selective Copper-
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(33) Gómez-Gallego, M.; Sierra, M. A. Kinetic Isotope Effects in the
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Financial support provided by the Robert A. Welch
Foundation (I-0011), Dr. Ralph and Marian Falk Medical
Research Trust Bank of America, N.A., Trustee, and USPHS
NIH (RO1 HL139793). Dr. Adeniyi Michael Adebesin is
thanked for insightful advice and critical commentary.
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Temperature
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FeCl3, H2N-OSO3H
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Et3N, HFIP
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meta-selective operationally simple commercial reagents inexpensive sustainable
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