Catalytic Synthesis of N-Heterocycles via Direct C(sp3)-H Amination Using an Air-Stable Iron(III) Species with a Redox-Active Ligand

Article abstract of DOI:10.1021/jacs.7b00270

Coordination of FeCl₃ to the redox-active pyridine-aminophenol ligand NNO^H2 in the presence of base and under aerobic conditions generates FeCl₂(NNO^ISQ) (1), featuring high-spin Fe^III and an NNO^ISQ radical ligand. The complex has an overall S = 2 spin state, as deduced from experimental and computational data. The ligand-centered radical couples antiferromagnetically with the Fe center. Readily available, well-defined, and air-stable 1 catalyzes the challenging intramolecular direct C(sp³)-H amination of unactivated organic azides to generate a range of saturated N-heterocycles with the highest turnover number (TON) (1 mol% of 1, 12 h, TON = 62; 0.1 mol% of 1, 7 days, TON = 620) reported to date. The catalyst is easily recycled without noticeable loss of catalytic activity. A detailed kinetic study for C(sp³)-H amination of 1-azido-4-phenylbutane (S₁) revealed zero order in the azide substrate and first order in both the catalyst and Boc₂O. A cationic iron complex, generated from the neutral precatalyst upon reaction with Boc₂O, is proposed as the catalytically active species.

Full text of DOI:10.1021/jacs.7b00270

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Article
Catalytic Synthesis of N-Heterocycles via Direct C(sp3)-H Amination
using an Air-stable Iron(III) Species with a Redox-Active Ligand
Bidraha Bagh, Daniël L. J. Broere, Vivek Sinha, Petrus F. Kuijpers, Nicolaas van
Leest, Bas de Bruin, Serhiy Demeshko, Maxime A. Siegler, and Jarl Ivar van der Vlugt
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.7b00270 • Publication Date (Web): 15 Mar 2017
Downloaded from http://pubs.acs.org on March 16, 2017
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Journal of the American Chemical Society
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Catalytic Synthesis of N-Heterocycles via Direct C(sp3)−H
Amination using an Air-stable Iron(III) Species with a Redox-
Active Ligand
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Bidraha Bagh,† Daniël L. J. Broere,† Vivek Sinha,† Petrus F. Kuijpers,† Nicolaas P. van Leest,† Bas
de Bruin,*,† Serhiy Demeshko,# Maxime A. Siegler,‡ Jarl Ivar van der Vlugt*,†
†Homogeneous, Bioinspired and Supramolecular Catalysis, van ‘t Hoff Institute for Molecular Sciences, University
of Amsterdam, Science Park 904, 1098 XH, Amsterdam, the Netherlands.
#Institüt für Anorganische Chemie, Georg-August-Universität Göttingen, Tammannstraße 4, 37077 Göttingen,
Germany.
‡Small Molecule X-ray Crystallography, Department of Chemistry, John Hopkins University, Baltimore MD 21218,
USA.
ABSTRACT: Coordination of FeCl3 to the redox-active pyridine-aminophenol ligand NNOH2 in the presence of base and
under aerobic conditions generates FeCl2(NNOISQ) (1), featuring high spin FeIII and an NNOISQ radical ligand. The com-
plex has an overall S = 2 spin state, as deduced from experimental and computational data. The ligand-centered radical
couples anti-ferromagnetically with the Fe center. Readily available, well-defined and air-stable 1 catalyzes the challeng-
ing intramolecular direct C(sp3)-H amination of unactivated organic azides to generate a range of saturated N-
heterocycles with the highest TON (1 mol% 1, 12 h, TON = 62; 0.1 mol% 1, 7 d, TON = 620) reported to date. The catalyst is
easily recycled without noticeable loss of catalytic activity. A detailed kinetic study for C(sp3)−H amination of 1-azido-4-
phenylbutane (S1) revealed zero order in azide substrate and first order in both catalyst and Boc2O. A cationic iron com-
plex, generated from the neutral precatalyst upon reaction with Boc2O, is proposed as the catalytically active species.
INTRODUCTION
coupling under strongly basic conditions (Scheme 1b).5
Recently, transition metal catalyzed (predominantly pal-
ladium) amination has emerged for the activation of ali-
phatic C-H bonds, which typically requires an electron-
withdrawing directing group (Scheme 1c).6 Lastly, nitrene
(in situ generated) insertion into a C(sp3)-H bond is an
efficient and perhaps the best studied approach for
C(sp3)−N bond formation (Scheme 1d). Nitrenes can ei-
ther be generated from amines by utilizing a combination
of PhI(OAc)2 and MgO or from activatived, non-aliphatic
organic azides (e.g. sulfonyl azide, aryl azide) or iminoio-
dinanes in the presence of transition metal catalysts. 7
The development of efficient methods for the formation
of carbon−nitrogen (C−N) bonds is one of the most cru-
cial task in chemical synthesis. The installment of C−N
bonds by direct functionalization of C(sp3)−H bonds is a
powerful and atom-efficient transformation for chemical
synthesis. Although the direct installation of nitrogen into
a C(sp3)–H bond is extremely challenging due to the
thermodynamic and kinetic stability of the C(sp3)–H
bond, intra- and intermolecular C(sp3)-H amination has
seen much progress in the last decade.1 Particularly, in-
tramolecular C(sp3)−H amination as an atom-economical
strategy has found extensive applications for the con-
struction of varieties of important N-heterocycles.2 Four
main strategies have been developed for the construction
of C(sp3)−H bonds by direct, intramolecular amination of
either activated or unactivated C(sp3)−H bonds. A crucial
advance in intramolecular C(sp3)–H amination can be
traced back to the Hofmann-Löffler-Freytag (HLF) reac-
tion, developed in the early 1880s with the initial discov-
ery by Hofmann.3 N-halogenated amines are utilized as
starting materials in HLF reactions and the generally ac-
Scheme 1. Intramolecular C(sp3)-H amination strate-
gies for the formation of N-heterocyles.
cepted mechanism involves
a free radical pathway
(Scheme 1a).4 Another effective method involves the oxi-
dation of C,N-dianions generated by successive deproto-
nation of an N–H and a C–H bond, followed by oxidative
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Unfortunately, most of the existing C–H amination
strategies involve directing groups, pre-oxidation of sub-
strates, or external chemical oxidants, leading to poor
atom economy and waste generation. In contrast, in situ
generation of a metal-bound nitrene species from readily
available aliphatic organoazides, releasing only molecular
nitrogen as side product, followed by selective insertion
into a C(sp3)−H bond would constitute an efficient ap-
proach for catalytic C-H amination. Synthesis of N-
heterocycles via direct C(sp3)−H amination using aliphatic
azide substrates is an appealing strategy, given that N-
heterocycles are prevailing building blocks in natural
products, pharmaceuticals and functional materials (Fig-
ure 1a).8 Recently, two reports appeared on air-sensitive
FeII-catalyzed direct C(sp3)−H amination of linear azides
to give saturated Boc-protected N-heterocycles, propos-
edly proceeding via an FeIII-nitrene radical intermediate
(Figure 1b).9,10 Apart from these systems featuring a redox-
active metal center (‘metalloradical’ approach),11 our
group recently demonstrated the catalytic PdII-mediated
C(sp3)−H amination of aliphatic azide to pyrrolidine, albe-
it with very modest turnover. This system operates via
single electron transfer from an aminophenol-derived
redox-active ligand to the substrate to generate a Pd-
bound nitrene-substrate radical and the one-electron oxi-
dized iminosemiquinonato (ISQ) ligand radical (Figure
1b).12 Herein we discuss the synthesis and detailed charac-
terization of a bench-stable iron(III) complex with a re-
dox-active NNO ligand. This air-stable iron species is an
effective and recyclable catalyst for direct C(sp3)−H ami-
nation of aliphatic azides to N-heterocycles with much
improved TON’s compared to the existing catalysts.
tion of NEt3 in air resulted in the paramagnetic dark green
1
2
3
4
5
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solid 1 in good yield (Scheme 2). UV-vis spectroscopy
supports the imino-semiquinonato (ISQ) ligand oxidation
state (λmax = 740 nm, ε = 8.37 x 103 M−1 cm−1).13-16 Magnetic
susceptibility measurements of 1 at 298 K using the Evans’
method revealed an effective magnetic moment (μeff) of
4.86 μB, thus indicating an S = 2 ground state, which is
consistent with a high spin FeIII–center (d5) that is strong-
ly anti-ferromagnetically coupled with a ligand centered
NNOISQ radical. Temperature dependent solid state
SQUID measurement and zero-field 57Fe Mössbauer spec-
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troscopy confirmed the total S = 2 ground state (χMT = 3.7
cm3 mol–1 K or eff = 5.44 μB) and an FeIII oxidation state (δ
ꢀ
= 0.42 mm/s, ΔEQ= 0.85 mm/s), respectively (Figure 2).17
Scheme 2. Synthesis of 1, with representation of three
possible oxidation states of NNO.
tBu
tBu
tBu
tBu
tBu
OH
O
tBu
O
O
O
tBu
t
Bu
tBu
tBu
1. FeCl3, air
MeOH, ꢀ 80 o
C
Cl
Cl
N
Fe
N
N
N
NH
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
2. NEt3, MeOH
air, ꢀ 80 oC ꢀ r.t.
N
N
N
N
N
FeCl2(NNOISQ) (1)
NNOAP
NNOISQ
NNOIBQ
NNOH2
1.002
4.00
3.50
3.00
2.50
2.00
1.50
1
0.998
0.996
0.994
0.992
0.99
1.00
0
-4.8
-2.8
-0.8
1.2
3.2
50
100
150
200
Figure 2. Solid state characterization of 1 by (a) variable
temperature SQUID magnetometry and (b) zero-field 57Fe
Mössbauer spectroscopy at 80 K.
a)
Pyrrolidineꢀcontaing natural products:
O
Pyrrolidineꢀcontaing pharmaceuticals:
COOH
OMe
H
N
COOH
N
N
N
H
N
N
N
Me
N
Me
O
(Proline)
(Hygrine)
(Dihydroshihunine)
H
O
N
N
Cl
COOH
N
H
N
N
N
Cl
H
NAc
Me
N
N
COOH
(Kv1.5 potassium
blocker)
(Glucokinase activator)
(Nicotine)
(Nornicotine)
(Kainic acid)
b) Catalytic C(sp3)ꢀH bond amination:
Catalyst
C6H6, heat
Boc
N
N3
Ph
+
Boc2O
Ph
Catalyst by Betley et al.
Catalyst by van der Vlugt et al.
Catalyst by Lin et al.
Present catalyst
tBu
tBu
[CoCp2]
Me
Cl
Cl
tBu
O
tBu
O
FeII
Figure 3. (a) Displacement ellipsoid plot (50% probability
level) of 1; hydrogen atoms and lattice solvent molecules
omitted for clarity. Selected bond lengths (Å) and angles (°):
Fe(1)-Cl(1) 2.2512(4); Fe(1)-Cl(2) 2.2366(4); Fe(1)-O(1)
1.9572(10); Fe(1)-N(1) 2.0136(12); Fe(1)-N(2) 2.1024(11); C(1)-
O(1) 1.2809(17); C(6)-N(1) 1.3390(17); C(1)-C(6) 1.4634(18);
O(1)-Fe(1)-N(1) 78.99(4); N(1)-Fe(1)-N(2) 77.56(4); O(1)-Fe(1)-
N(2) 156.18(4); Cl(1)-Fe(1)-Cl(2) 117.32(2). DFT (M06, def2-
TZVP) calculated spin density plot of (b) ground state of 1 (S
= 2) (c) high spin state of 1 (S = 3).
II
III Cl
Fe
Ph
N
N
N
Pd Cl
N
N
N
N
Me
Me
Me
Me
II
Cl
Me
Me
Fe
N
(
= MOF)
Cl
Reaction conditions:
Boc2O (10 eq.), 90 o
Reaction conditions:
Reaction conditions:
Boc2O (1 eq.), 100 oc, 24 h
Catalyst (10 mol%)
Reaction conditions:
Boc2O (1 eq.), 65 oc, 12 h
Catalyst (10 mol%)
c
Boc2O (1 eq.), 100 oc, 12 h
48 h, Catalyst (5 mol%)
Yield: 90 %, TON ~ 18
(Homogeneous system:
Yield: 31 %, TON ~ 6)
Catalyst (1 mol%)
Yield: 62 %, TON ~ 62
Yield: 10 %, TON ~ 2
Yield: 57 %, TON ~ 6
Figure 1. (a) Pyrrolidine-containing natural products and
pharmaceuticals and (b) catalysts for direct C(sp3)−H amina-
tion of 1-azido-4-phenylbutane as benchmark substrate.
The formulation of 1 as FeIIICl2(NNOISQ) was further
confirmed by single crystal X-ray structure determination
(Figure 3a). The geometry around iron (τ of 0.52) is in-
termediate between trigonal bipyramidal and square py-
ramidal. The iron-ligand bond lengths (Fe-O 1.9572(10);
RESULTS AND DISCUSSION
The ligand NNOH2 is readily accessible following a liter-
ature procedure.12a Coordination of the neutral ligand
NNOH2 to FeCl3 in MeOH at −80 °C followed by the addi-
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Fe-N 2.0136(12) Å) as well as ligand-based interatomic
Figure 4. (a) Cyclic voltammogram of 1 in CH2Cl2 (1 × 10−3
M), scan rate 100 mV s−1 vs. Fc/Fc+ on Pt-disk. (b) Displace-
ment ellipsoid plot (50% probability level) of 2 (one of two
independent molecules is shown); hydrogen atoms and lat-
tice solvent molecules omitted for clarity. Selected bond
lengths (Å) and angles (°): Fe(1)-O(1A) 1.9267(17); Fe(1)-O(1B)
1.9144(17); Fe(1)-N(1A) 1.890(2); Fe(1)-N(1B) 1.877(2); Fe(1)-
N(2A) 1.968(2); Fe(1)-N(2B) 1.957(2); C(1A)-O(1A) 1.314(3);
C(1B)-O(1B) 1.324(3); C(6A)-N(1A) 1.367(3); C(6B)-N(1B)
1.375(3); C(1A)-C(6A) 1.433(4); C(1B)-C(6B) 1.439(3); O(1A)-
Fe(1)-N(1A) 83.32(8); O(1B)-Fe(1)-N(1B) 84.24(8); N(1A)-Fe(1)-
N(2A) 81.62(10); N(1B)-Fe(1)-N(2B) 82.31(9); O(1A)-Fe(1)-
N(2A) 164.94(9); O(1B)-Fe(1)-N(2B) 166.04(9); N(1A)-Fe(1)-
N(1B) 177.21(9).
1
2
3
4
5
6
7
8
distances (O1-C1 1.2809(17); N1-C6 1.3390(17) Å) are char-
acteristic for the ISQ ligand oxidation state.14,18-20 A Met-
rical Oxidation State (MOS) value of ‒0.69 (± 0.04)19 was
determined for the NNOISQ ligand of 1. DFT calculations
(b3-lyp, def2-TZVP) show a broken-symmetry S = 2 spin
state (<S2> = 6.8) as the ground state (see SI). The energy
difference between the broken-symmetry S = 2 ground
state (Figure 3b) and the high-spin S = 3 excited state
(Figure 3c) is calculated to be +5.3 kcal mol-1 by DFT. The
spin-density plot for S = 2 (Figure 3b) clearly illustrates
the observed anti-ferromagnetic coupling between the
NNO radical fragment and the Fe center via the coordi-
nated N and O atoms. A Lӧwdin population analysis22 (see
SI) shows that the Fe center has a total spin equivalent to
4 unpaired electrons.
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We set out to investigate the activity of well-defined
air-stable 1 for catalytic C(sp3)−H amination, using 1-
azido-4-phenylbutane (S1) as standard substrate and di-
tert-butyl dicarbonate (Boc2O) as in situ protecting group
to avoid catalyst deactivation by pyrrolidine coordination
(Table 1). Heating an equimolar mixture of both reagents
(100 ꢀmol) at 100 °C in benzene for 24 h in the presence of
10 mol% 1 as catalyst in a pressure tube resulted in com-
plete conversion of S1 to the desired Boc-protected pyrrol-
idine P1a (70 %) and Boc-protected amine P1b (30%) as
side-product (entry 1). Lowering the catalyst loading to 5
mol% led to a slightly different product ratio of 63:37 for
P1a: P1b (entry 2).
Cyclic voltammetry of 1 in CH2Cl2 solution revealed
quasi-reversible one-electron oxidation and reduction
events at + 0.51 V and - 0.74 V vs. Fc/Fc+, respectively
(Figure 4a). Chemical oxidation of 1 using silver salts like-
ly afforded Cl─ abstraction but no clean species was ob-
tained. Chemical reduction of 1 using CoCp2 led to for-
mation of homoleptic FeII(NNOISQ)2 (2). The latter species
does not reform FeIII(NNOISQ) upon re-oxidation. The
homoleptic complex 2 was characterized by single crystal
X-ray structure determination (Figure 4b and SI). Two
crystallographically independent molecules of 2 were
found in the asymmetric unit (P21/n). The geometry
around each Fe-metal center is distorted octahedral, with
meridionally coordinated NNO ligands. The iron-ligand
bond lengths, angles and interatomic distances within the
NNO moieties are very similar for both molecules and
suggestive of the ISQ ligand oxidation state.14,18-20 The
iron-ligand bond lengths in complex 2 (average bond dis-
tances: Fe-O 1.928 Å, Fe-Nimino 1.884 Å, Fe-Npyridyl 1.963 Å)
are slightly shorter then in heteroleptic complex 1 (Fe-O
1.957 Å, Fe-Nimino 2.014 Å, Fe-Npyridyl 2.102 Å). On the con-
trary, the ligand-based interatomic distances in 2 (average
bond distances: C-O 1.320 Å, C-Nimino 1.368 Å) are slightly
longer than those in complex 1 (C-O 1.281 Å, C-Nimino 1.339
Å). Chemical oxidation of 2 with AgBF4 resulted in the
formation of [FeIII(NNOISQ)2]BF4 (3a), which was structur-
ally characterized (see SI for details). The chloride deriva-
tive of this homoleptic FeIII-system, [FeIII(NNOISQ)2]Cl
(3b), was accessible directly by heating a mixture of FeCl3
and NNOH2 (2 molar equiv.) at reflux in the presence of
NEt3 under aerobic conditions.
Table 1. Performance of 1 in intramolecular C(sp3)−H
amination of aliphatic azide S1 to P1a and P1b.
Entry
1
Boc2O
Temp. Time P1a (%)
P1b
(mol%) (equiv) (°C)
(h)
24
24
24
24
24
24
24
2
(%)
1
10
5
1
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
70 (67a)
63 (60a)
62
30
37
38
38
38
37
35
32
37
37
17
2
3‡
1
5
1
4
2
1
62
5
1
1
62
6†
7*
8
5
5
10
1
63
5
65
5
55
9
10‡
5
1
3
63
5
1
3
63
12
2
1
3
38
13
14‡
2
1
6
62
38
38
38
38
32
6
2
1
6
62
15
1
1
12
12
12
24
48
62
16≠
17‡,≠
18≠
19≠
1
1
62
1
1
52
0.1
0.1
1
11
1
23
13
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