C-H Amination of Arenes with Hydroxylamine

Article abstract of DOI:10.1021/acs.orglett.0c00598

This Letter describes the development of a Ti^III-mediated reaction for the C-H amination of arenes with hydroxylamine. This reaction is applied to a variety of electron-rich (hetero)arene substrates, including a series of natural products and pharmaceuticals. It offers the advantages of mild conditions (room temperature), fast reaction rates (<30 min), compatibility with ambient moisture and air, scalability, and the use of inexpensive commercial reagents.

Full text of DOI:10.1021/acs.orglett.0c00598

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Letter
C−H Amination of Arenes with Hydroxylamine
Yi Yang See and Melanie S. Sanford*
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ABSTRACT: This Letter describes the development of a TiIII-
mediated reaction for the C−H amination of arenes with
hydroxylamine. This reaction is applied to a variety of electron-
rich (hetero)arene substrates, including a series of natural products
and pharmaceuticals. It offers the advantages of mild conditions
(room temperature), fast reaction rates (<30 min), compatibility
with ambient moisture and air, scalability, and the use of inexpensive commercial reagents.
niline derivatives (ArNH2) appear in a wide variety of
Aspecialty chemicals, materials, natural products, and
pharmaceuticals.1 As such, synthetic methods for the formation
of ArNH2 are highly sought-after in organic synthesis. In
general, the most common approaches involve transition-metal
catalyzed cross-coupling,2 arene nitration/reduction,3 and
arene C−H amination protocols.4−6 However, due to high
reagent/catalyst costs as well as reactivity concerns, process-
scale preparations of ArNH2 still largely rely on nitration of the
corresponding aromatic precursor followed by hydrogenation
to yield the aniline products (Figure 1A).7
We sought to develop a practical alternative to nitration/
reduction that enables the direct conversion of arenes (Ar−H)
to ArNH2. Recent reports have shown that O-protected
hydroxylamine derivatives (e.g., A−D in Figure 1B) are
effective reagents for Fe-catalyzed arene C−H amination.4−6
A key step of these reactions involves Fe-mediated N−O bond
cleavage to release an aminyl radical (H2N•). This radical
(and/or its conjugate acid H3N•+) then reacts with the arene
substrate, ultimately affording an aniline product.8 While this is
a conceptually attractive approach, in practice current methods
are limited by the requirement for an electron-withdrawing
substituent on oxygen to facilitate N−O bond scission.9 These
functionalized hydroxylamine derivatives can be expensive
and/or require multistep synthesis, thus rendering them less
practical for larger scale applications. Herein, we develop a
method that accesses an analogous reaction manifold using the
commodity chemical hydroxylamine as the aminating reagent
(Figure 1C). This transformation is high yielding, inexpensive,
Figure 1. (A) Synthetic approaches to Ar−NH2. (B) Reagents for
Ar−H amination. (C) This work: H2NOH as a reagent for C−H
amination.
and scalable and thus offers a complement to existing C−H
amination methods as well as more traditional nitration/
reduction sequences.
Pioneering early work by Keller, Kovacic, and Minisci
demonstrated the feasibility of the TiIII-mediated amination of
electron-rich arenes using hydroxylamine.10−13 However, these
early examples were very limited due to their narrow substrate
scope, low yields, formation of side products, and the
requirement for large excesses of arene substrate.14 For
Received: February 14, 2020
https://dx.doi.org/10.1021/acs.orglett.0c00598
© XXXX American Chemical Society
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Letter
example, under Minisci’s original reaction conditions (using
excess arene in methanol), the TiCl3-mediated amination of
anisole (1, 4 equiv) with hydroxylamine (1 equiv) afforded
<18% yield of aniline 2 (based on hydroxylamine as the
limiting reagent; Figure 2, entry 1). To address these
limitations, we initially evaluated a series of first row transition
metal salts (e.g., Ti, V, Cr, Mn, Fe, Co, Ni, Cu) as redox
mediators for this transformation. Among these, only titanium-
(III) salts proved effective. Extensive optimization revealed
that several factors have a favorable impact on the rate and
yield of the reaction (Figure 2). These include the use of (1)
sulfuric acid as an additive,15 (2) high concentration of the
arene, (3) acetonitrile or acetic acid as solvent, and (4) slow
addition of TiIII (as a solution in HCl). Overall, the optimal
conditions were found to involve the slow addition of TiCl3 to
a mixture of arene substrate (1 equiv), hydroxylamine
hydrochloride (2 equiv), and sulfuric acid (10 equiv) in
acetonitrile at room temperature. This afforded a combined
76% yield of 2 (76% isolated, 1:2.2 ortho-/para-isomer, 5:2
mono-/diamination).16 Importantly, these conditions employ
the arene substrate as the limiting reagent and afford <5% side
products (the mass balance is predominantly starting material).
The reaction does not require the exclusion of air/moisture,
and it affords comparable yield upon scaling from 1 to 10
mmol (vide infra). Furthermore, reaction progress can be
conveniently monitored by the decolorization of the unreacted
TiIII.
We next examined the reactivity of a panel of arene
substrates under the optimized reaction conditions (Scheme
1). Good to excellent yields were obtained with various mono-,
di-, and trisubstituted arenes bearing electron-donating
substituents. In contrast, less electron-rich arenes (e.g.,
benzene) afforded low yields (see p S10 for substrates that
afforded yields of ≤10%). As with anisole, small amounts
a
Figure 2. Reaction optimization. Conditions: substrate (0.2 mmol),
NH2OH·HCl (0.4 mmol), TiCl3 (0.4 mmol, added over 20 min),
MeCN (2.0 mL) unless stated otherwise. b GC yield, mono-/
diamination, ortho/para isomer observed; see Supporting Information
for complete details.
Scheme 1. Substrate Scope of C−H Amination
B
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(typically ≤20% yield) of diamination products were also
observed for some substrates (see Supporting Information for
details). Generally, 2−3 equiv of hydroxylamine hydrochloride
were required to achieve maximum yield. Functional groups
such as ethers, esters, amides, free amines, chlorides, and
bromides were tolerated. Several heterocyclic arenes under-
went ring amination to afford thiophene 11 and benzathiazoles
22 and 23. The observed selectivities are in line with those
reported for other C(sp2)−H amination reactions with aminyl
radicals.4−6 The reaction is sensitive to sterics, with C−H
amination occurring preferentially at sterically less encumbered
sites (for example, see 4 and compare 8 with 17). In cases
where low solubility of the substrate resulted in precipitation
(e.g., 23), additional volumes of acetonitrile, hydroxylamine
hydrochloride, and sulfuric acid were added to maximize
conversions. Acetonitrile was found to be the most general
solvent, but the use of acetic acid significantly improved the
conversion with several substrates (e.g., 14, 18, 26).
Several pharmaceuticals and natural products with denser
and more complex substitution patterns were also effective
substrates. Notably, arene amination was selective for the more
electron-rich ring in azipiprazole (27). While some of the more
complex substrates afforded mixtures of isomeric products (24
and 27), these examples demonstrate the potential for applying
this method in the late stage C−H amination of relatively
complex intermediates.17
no consumption of the starting material nor formation of any
aminated products (Figure 3C). Inner-sphere electron transfer
then likely occurs, resulting in N−O bond homolysis. This
would release a Ti(IV) oxo species along with the aminyl
radical. This electrophilic radical can then engage electron-rich
arene substrates by analogy to literature reports.4−6,12
Competition experiments between p-xylene-H10 and p-xylene-
D
10 show a competition isotope effect (kH/kD) of 1.00 (Figure
3D), which is consistent with an aromatic substitution pathway
wherein C−H cleavage occurs after the rate- and product-
determining step.18,19 Notably, the electron-rich product of
these transformations is expected to be deactivated toward
further amination due to protonation of the aniline under the
reaction conditions. This likely explains why monoamination
predominates in all of these systems, despite the presence of an
excess of hydroxylamine and Ti(III) under our standard
conditions.16
Overall, this report describes the development/optimization
of a method for the direct C−H amination of electron-rich
arenes using hydroxylamine. This protocol uses an inexpensive
and commercially available mediator (TiIIICl3) and is
insensitive to adventitious moisture and air. Furthermore, the
reaction is readily scaled without significant adjustment to the
reaction conditions. Given the operational simplicity and wide
availability of the reagents, this transformation offers a
potentially attractive complement to nitration/reduction
sequences.
As shown in Figure 3A, this procedure is readily scalable. For
instance, the C−H amination to form 17, an intermediate in
ASSOCIATED CONTENT
* Supporting Information
■
sı
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c00598.
Procedure details and NMR spectra (PDF)
AUTHOR INFORMATION
Corresponding Author
■
Melanie S. Sanford − Department of Chemistry, University of
Michigan, Ann Arbor, Michigan 48109, United States;
orcid.org/0000-0001-9342-9436; Email: mssanfor@
umich.edu
Author
Yi Yang See − Department of Chemistry, University of Michigan,
Ann Arbor, Michigan 48109, United States
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c00598
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
Figure 3. (A) Scale up of reaction. (B−D) Mechanism studies.
■
We gratefully acknowledge funding from Dow through the
University Partnership Initiative. We also thank Dr. Matthew S.
Remy (Dow Chemical Company) for helpful discussions.
the synthesis of tamibarotene, was scaled from 1 to 10 mmol
without additional optimization. A slight exotherm of the scale-
up reaction was noted, but this was easily controlled by
adjusting the rate of TiIII addition and/or by external cooling.
Mechanistically, we propose that hydroxylamine interacts
with the oxophilic TiIII via the free hydroxyl group (Figure
3B).10−15 This proposal is supported by control studies with
O-substituted hydroxylamines and/or hydrazine, which show
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