Amine-bis(phenolate) Iron(III)-Catalyzed Formal Hydroamination of Olefins

Article abstract of DOI:10.1002/asia.201501098

A practical synthesis of highly functionalized amines by the formal hydroamination reaction of alkenes with nitroarenes catalyzed by an air stable amine-bis(phenolate) iron(III) complex is reported. The reaction uses an easily handled silane, low catalyst loadings, and mild reaction conditions. A wide range of substrates are transformed with synthetically useful yields (21 examples).

Full text of DOI:10.1002/asia.201501098

DOI: 10.1002/asia.201501098
Communication
Hydroamination
Amine-bis(phenolate) Iron(III)-Catalyzed Formal Hydroamination
of Olefins
Kailong Zhu, Michael P. Shaver,* and Stephen P. Thomas*[a]
Abstract: A practical synthesis of highly functionalized
amines by the formal hydroamination reaction of alkenes
with nitroarenes catalyzed by an air stable amine-bis(phe-
nolate) iron(III) complex is reported. The reaction uses an
easily handled silane, low catalyst loadings, and mild reac-
tion conditions. A wide range of substrates are trans-
formed with synthetically useful yields (21 examples).
The efficient synthesis of functionalized amines is of great im-
portance as these substrates are key components of natural
products, pharmaceuticals, fine chemicals, materials, and agro-
chemicals.[1] Conventional methods for amine synthesis include
amine-carbonyl reductive amination,[2] amine N-alkylation by
hydrogen autotransfer,[3] and transition-metal-catalyzed CÀN
cross-coupling [Eq. (1)–(3), Scheme 1].[4] Given the limitations
of these methods, including their low functional group toler-
ance, new methods with a wide substrate scope and mild reac-
tion conditions are still required. Very recently, Baran and co-
workers reported a practical formal hydroamination of alkenes
with nitroarenes catalyzed by Fe(acac)3 using phenylsilane as
the stoichiometric reducing agent [Eq. (4), Scheme 1].[5] Based
on experimental observations and previous mechanistic stud-
ies on related systems,[6] a radical reaction pathway was pro-
posed: an in situ generated hydrido–iron complex transfers
a hydrogen atom to the alkene to give an alkyl radical, which
undergoes N-alkylation of a nitrosoarene, generated in situ by
hydrido–iron-mediated nitroarene reduction. The reaction
showed good functional group tolerance including substrates
bearing an amide, ketone, halide, and alcohol functionalities,
showcasing this as a potent tool for the construction of highly
functionalized amines. Excellent regioselectivity for amination
at the most substituted carbon center was observed for this
radical reaction, in contrast to transition-metal-catalyzed hydro-
amination reactions, in which strict control of regioselectivity
remains challenging. However, the high catalyst loading
Scheme 1. Methods for the construction of heavily functionalized amines.
(30 mol%) and reaction temperature (608C) diminish the over-
all reaction efficiency. Our success with amine-bis(phenolate)
iron(III) catalyzed hydrosilylation[7] and mediation of radical re-
actions such as atom transfer radical polymerization[8] suggest-
ed these could be ideal catalysts for this formal hydroamina-
tion process. In addition, the synthesis of amine-bis(phenolate)
iron(III) complexes is straightforward and they are highly stable
towards air and moisture.[9]
In our most recent work, we demonstrated that amine-bis-
(phenolate) iron(III) complexes showed excellent catalytic activ-
ity for the chemoselective reduction of nitroarenes to the cor-
responding anilines using triethoxysilane as the reducing
agent.[10] Excellent functional group tolerance (22 examples)
and high isolated yields of amine (up to 98%) were obtained
under mild conditions (Scheme 2). Here we extend the applica-
tion of this catalyst system to the formal hydroamination of al-
kenes with nitroarenes.
[a] K. Zhu, Dr. M. P. Shaver, Dr. S. P. Thomas
School of Chemistry
The reaction of 4-nitrothioanisole 1 and 2-methyl-2-butene
A using phenylsilane as the reducing agent was chosen as the
model reaction to establish optimal reaction conditions
(Table 1). When the reaction was carried out in EtOH at 608C
with two equivalents of PhSiH3 and three equivalents of
alkene, the nitroarene was completely consumed in 1 h, and
a mixture of N,O-dialkylated adduct 2, aniline 5a and a small
Joseph Black Building
University of Edinburgh
David Brewster Road, Edinburgh, EH9 3FJ (United Kingdom)
E-mail: michael.shaver@ed.ac.uk
stephen.thomas@ed.ac.uk
Supporting information for this article can be found under http://
dx.doi.org/10.1002/asia.201501098.
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ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Communication
such as toluene and acetonitrile gave low conversions (Table 1,
entries 4 and 5). Replacing the furanyl donor with an amine
moiety, Cat II, gave 35% of the hydroamination product 4a
along with 40% of aniline 5a using one equivalent of silane at
room temperature (Table 1, entry 6). Under the same reaction
conditions, Fe(acac)3 produced just 15% of the hydroamination
product (Table 1, entry 7), thus showing the benefit imparted
by the amine-bis(phenolate) ligand. The nature of the silane
was important as polymethylhydrosiloxane (PMHS) was less re-
active, giving the hydroamination product 4a in only 20%
yield along with 30% of aniline 5a (Table 1, entry 8). These op-
timized conditions give similar or improved isolated yields to
those previously reported using 30 mol% Fe(acac)3 while offer-
ing an improvement in catalyst loading and reaction
temperature.
Scheme 2. Amine-bis(phenolate) iron(III) complexes as efficient catalysts for:
a) nitroarene reduction and b) olefin formal hydroamination.
Table 1. Optimization of Hydroamination Conditions.[a]
With optimized reaction conditions developed, the substrate
scope of this iron-catalyzed olefin formal hydroamination was
investigated. Seven different olefins were tested with an array
of nitroarenes bearing different arene substituents. Using tri-
substituted alkene A, a range of nitroarenes were explored as
reaction partners. Nitroarenes bearing electron-donating
groups (4a–4c), halide substituents (4d–4 f), and electron-
withdrawing groups (4g) were all tolerated under the devel-
oped reaction conditions to give the corresponding amines in
synthetically useful isolated yields (Table 2). In all cases, the re-
action was chemoselective for hydroamination without any
deleterious side-reactions, such as protodehalogenation[11] or
reductive amination, observed. Nitrobenzene was also a suita-
ble substrate, giving the hydroamination product 4h in 58%
isolated yield. It was noteworthy that a nitroarene bearing
a carbonyl group was also tolerated without any reduction at
the ketone (4i), suggesting good chemoselectivity for the cata-
lyst. Olefin B, bearing a free alcohol was also investigated, suc-
cessfully reacting with nitroarenes bearing a halide (4j, 4k),
electron-withdrawing (4l), and electron-donating substituents
(4m). In these cases, significantly higher isolated yields were
obtained than those using olefin A. By using 2-chloro-5-nitro-
pyridine, a moderate yield of formal hydroamination was ob-
tained with alkene B (4n). Amine 4o can be prepared using
either alkene C or E. When terminal alkene C was used, the hy-
droamination product 4n was isolated in 51% yield. However,
when the sterically hindered alkene E was used, the same
product 4o was isolated in just 26% yield. Cyclic olefin D gave
the corresponding product in 48% yield (4p). When olefin F
was used, the highly hindered amine 4q was prepared in 53%
yield, a product challenging to make using other methods. It
should be noted that in all cases, the reaction takes place on
the more hindered site of the olefin, thus supporting the previ-
ously hypothesized radical pathway.
Entry
Variation from standard condition
4a [%][b]
5a [%][b]
1
2
3
4
5
6
7
8
none
r.t. instead of 608C
40
45
51
30
25
22
r.t. 1.0 equiv of PhSiH3
Toluene instead of EtOH
MeCN instead of EtOH
Cat II, rt, 1.0 equiv of PhSiH3
Fe(acac)3, rt, 1.0 equiv of PhSiH3
PMHS (6.0 equiv), 2 h
low conversion
low conversion
35
15
20
40
65
30
[a] All reactions were carried out using 0.3 mmol of 4-nitrothioanisole.
[b] Yield of isolated product. rt=room temperature.
amount of the hydroamination product 4a was produced. Zinc
and aqueous hydrochloric acid were subsequently added, con-
verting intermediate 2 into the hydroamination product 4a in
40% isolated yield after the Zn/HCl work up (Table 1, entry 1).
As expected, aniline 5a was also isolated in 30% yield from
the direct reduction reaction of the nitroarene (Table 1,
entry 1). The reaction temperature was then lowered to room
temperature in a bid to reduce the amount of direct nitroarene
reduction, a reaction that generally requires elevated tempera-
tures. Indeed, a slightly higher yield of the hydroamination
product 4a was obtained at room temperature and the rela-
tive amount of aniline 5a was reduced (Table 1, entry 2). Inter-
estingly, under these reaction conditions hydroxylamine 3 was
observed as the major intermediate, presumably as a product
of the addition of alkyl radical to the nitrosoarene, but without
any O-alkylation. Reducing the amount of silane from two
equivalents to one equivalent gave an even higher yield of the
hydroamination product 4a (Table 1, entry 3). Other solvents
Using olefin G, which bears a distal carbonyl functionality, N-
arylpiperidines were formed by a formal hydroamination/re-
ductive amination cascade process (6a–6c). In these cases, ni-
troarenes with an electron-donating group gave the N-arylpi-
peridine products 6a and 6b in 45% and 51% yield, respec-
tively, while a nitroarene with an electron-withdrawing sub-
stituent gave a reduced amount of hydroamination product
6c (Scheme 3).
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Communication
Table 2. Substrate Scope.[a]
Scheme 3. Synthesis of N-arylpiperidine with nitroarene and olefin G.[a]
[a] Unless otherwise noted, all reactions were carried out using three equiva-
lents of olefin (0.9 mmol), two equivalents of PhSiH3 (0.6 mmol), one equiva-
lent of nitroarene (0.3 mmol), 0.02 equivalents of catalyst (0.006 mmol) in
1.5 mL EtOH at room temperature for 2 h. Zn (20.0 equiv) and HCl (2N,
3.0 mL) were then added and the mixture was stirred for another 1 h at
608C. Yields are those of the isolated product. [b] One equivalent of PhSiH3,
1 h.
lane as the reducing agent. The reaction requires just
2.0 mol% catalyst, as low as one equivalent of silane, and oper-
ates at room temperature. A wide range of substrates were tol-
erated with synthetically useful yields (21 examples, up to 76%
yield). We continue to explore catalyst design in this formal hy-
droamination reaction and the application of these exceptional
catalysts in other such radical reactions.
Experimental Section
General Hydroamination Procedure: Alkene (0.9 mmol, 3.0 equiv)
and PhSiH3 (1.0 or 2.0 equiv) were added to a solution of the nitro
compound (0.3 mmol, 1.0 equiv) and catalyst (2.8 mg, 0.006 mmol,
2.0 mol%) in EtOH (1.5 mL). The resulting mixture was stirred at
room temperature until full consumption of the staring nitro com-
pound was observed as indicated by TLC. Zinc (390 mg, 6.0 mmol,
20 equiv) and aqueous HCl (2N, 3.0 mL) were added to the reac-
tion mixture. After stirring at 608C for another 1 h, the reaction
mixture was cooled to room temperature and filtered through
Celite and the filter cake washed with EtOAc. The filtrate was col-
lected and saturated aqueous NaHCO3 solution added until strong-
ly basic and then extracted with EtOAc three times. The combined
organic phases were washed with brine, dried (Na2SO4), and con-
centrated under reduced pressure. The crude product purified by
flash column chromatography using petroleum spirit/ethyl acetate.
Acknowledgements
[a] Unless otherwise noted, all reactions were carried out using three
equivalents of olefin (0.9 mmol), two equivalents of PhSiH3 (0.6 mmol),
one equivalent of nitroarene (0.3 mmol), 0.02 equiv of catalyst
(0.006 mmol) in EtOH (1.5 mL) at room temperature for 2 h. Zn
(20.0 equiv) and HCl (2N, 3.0 mL) were then added and the mixture
stirred for another 1 h at 608C. Yields are those of the isolated product.
[b] 1.0 equiv of PhSiH3, 1 h. [c] 608C, 1 h.
MPS and SPT thank the University of Edinburgh for Chancel-
lor’s Fellowships and the School of Chemistry for continued
support. MPS thanks the Framework Program 7 for a Marie
Curie Career Integration Grant (FP7-PEOPLE-2013-CIG-618372)
and the EPSRC for a research grant (EP/M000842/1). SPT
thanks the Royal Society for a University Research Fellowship.
KZ thanks the China Scholarship Council and the University of
Edinburgh for an academic scholarship. We thank Prof. Jason
B. Love for useful discussions.
In conclusion, we have reported that an amine-bis(pheno-
late) iron(III) complex can be used as an efficient catalyst for
olefin formal hydroamination with nitroarenes using phenylsi-
Chem. Asian J. 2016, 11, 977 – 980
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Communication
von Wangelin, Angew. Chem. Int. Ed. 2015, 54, 11906–11908; Angew.
Chem. 2015, 127, 12074–12076.
Keywords: amine-bis(phenolate) · hydroamination · iron ·
radicals · silanes
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Manuscript received: October 9, 2015
Accepted Article published: February 11, 2016
Final Article published: March 1, 2016
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