Highly Robust Iron Catalyst System for Intramolecular C(sp3)?H Amidation Leading to γ-Lactams

Article abstract of DOI:10.1002/anie.202013499

Disclosed here is the use of an iron catalyst system for an intramolecular C?H amidation toward γ-lactam synthesis from dioxazolone precursors. (Phthalocyanine)Fe^IIICl was found to catalyze this cyclization with extremely high turnover numbers of up to 47 000 under mild and aerobic conditions. On the basis of experimental and computational mechanistic studies, the reaction is suggested to proceed by a stepwise radical pathway involving fast hydrogen atom abstraction followed by radical rebound. A plausible origin for the high turnover numbers along with air-compatibility is also rationalized.

Full text of DOI:10.1002/anie.202013499

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Accepted Article
Title: Highly Robust Iron Catalyst System for Intramolecular C(sp3)–H
Amidation Leading to γ-Lactams
Authors: Sukbok Chang and Jeonguk Kweon
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Highly Robust Iron Catalyst System for Intramolecular C(sp3)–H
Amidation Leading to -Lactams
Jeonguk Kweon [a,b] and Sukbok Chang [b,a,*]
Abstract: We herein disclose the use of an iron catalyst system for
an intramolecular C–H amidation toward γ-lactam synthesis from
dioxazolone precursors. (Phthalocyanine)Fe(III)Cl was found to
catalyze this cyclization with extremely high turnover numbers up to
47,000 under mild and aerobic conditions. On the basis of
experimental and computational mechanistic studies, the reaction
was suggested to proceed via a stepwise radical pathway involving
fast hydrogen atom abstraction followed by radical rebound. Plausible
origin of extremely high turnover numbers along with air-compatibility
was also rationalized.
Direct introduction of an amino group into hydrocarbon
backbones has been extensively investigated as the carbon-
nitrogen bonds are prevalent in pharmaceuticals and natural
products.[1] As a result, transition metal-catalyzed amino group
transfer is a promising approach especially for achieving high
regio- and stereoselectivity.[2] While precious metals have been
widely utilized for the C–H amination procedures, base metal
catalysts display distinctive advantages in terms of their natural
abundance and environmental sustainability.[3] In particular,
based on the various C–H oxygenation systems via well-
characterized iron oxo complexes,[4] their isolobal nitrenoid
intermediates have been regarded as an attractive “stepping
stones” to enable the C–N bond formation.[5]
On the other hand, construction of azacyclic structures via
C–H amination is an appealing synthetic strategy as it does not
require prefunctionalization of
the substrates.[6] Since the
Breslow’s pioneering works on the nitrene transfer using
(tetraphenylporphyrin)Fe(III) catalyst (5 mol%)[7] or isolated
cytochrome P450[8] to obtain cyclic sulfonyl amides, significant
advances have been made in the iron-catalyzed intramolecular
C–H amidation reactions (Scheme 1a). For instance, Che
employed a hepta-coordinated Fe(II) catalyst (5 mol%) for the
synthesis of 6-membered oxathiazinanes via in situ-generated
nitrene intermediate using hypervalent iodine as an oxidant at
80 °C.[9] The same group also reported the synthesis of pyrrolidine
derivatives from alkyl azides using NHC-porphyrin (NHC = N-
heterocyclic carbene) ligand system under the microwave
conditions.[10] White group achieved highly selective allylic C–H
amidation with a cationic (phthalocyanine)Fe(III) catalyst (10
mol%) under inert conditions.[11]
Scheme 1. a) Access to azacyclic compounds by Fe catalysis. b) Current
approach to γlactams from dioxazolones by a robust iron catalyst under air.
In 2013, Betley group prepared pyrrolidine derivatives from
aliphatic azides using an iron(II) dipyrinato catalyst (>10 mol%),[12]
proposing that it operates through an antiferromagnetically
coupled iron imido species in a quintet spin state (S = 2).[13] An
air-stable catalytic system allowing for the analogous pyrrolidine
synthesis was reported by van der Vlught et al. with redox-active
semiquinonato ligands (TON, up to 620).[14] Recently, Arnold[15]
and Fasan[16] independently demonstrated that cytochrome P450
derivatives, containing a heme-Fe(II) cofactor as catalytic center,
can construct carbon-nitrogen bonds under anaerobic conditions.
However, to our best knowledge, there is no example of iron-
catalyzed lactam synthesis via direct C–H amidation reaction
(Scheme 1a, bottom). In fact, Curtius type rearrangement of the
key acyl nitrenoid intermediate usually hampers the desired
nitrene insertion, leading the formation of isocyanate
byproducts.[17]
[a]
[b]
Department of Chemistry, Korea Advanced Institute of Science and
Technology (KAIST), Daejeon 34141 (Republic of Korea)
Center for Catalytic Hydrocarbon Functionalizations, Institute for Basic
Science (IBS), Daejeon 34141 (Republic of Korea)
E-mail: sbchang@kaist.ac.kr
Supporting information for this article is given via a link at the end of the
document.
Inspired by the precedent works on the oxygen and nitrogen
atom transfer processes using iron porphyrin derivatives, we
envisaged that analogous catalytic systems would mediate an
intramolecular C–H amidation to obtain γ-lactam compounds from
1
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10.1002/anie.202013499
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easily accessible dioxazolone precursors[18] via the acyl nitrenoid
intermediates. (Scheme 1b). While most known iron catalysis
requires anaerobic environment,[9, 11-12, 15-16] our current amidation
procedure with neutral (phthalocyanine)Fe(III)Cl catalyst is
operative under aerobic conditions with extremly high catalytic
turnover (up to 47,000). Experimental and computational studies
suggested that the key C–N bond-forming step proceeds in a
stepwise fashion through a radical intermediate, and the observed
high turnover numbers of the catalytic system was also
rationalized in terms of the oxygen durability and catalyst
regeneration.
performed under air, the catalytic reactivity was decreased (entry
4).[20]
Therefore, we envisioned that the higher-valent Fe(III)
analogue of PcFe(II) would permit better air-compatibility to the
current iron-catalyzed C–H amination, being less vulnerable to
the oxidative deactivation.[21] PcFe(III)Cl catalyst was found to be
also effective for the lactam cyclization under argon atmosphere
in the presence of NaSbF6 as the chloride abstractor (entry 5).
Other reaction solvents instead of HFIP were not effective for the
desired cyclization process (entries 6–11). It was found that the
NaSbF6 additive is not essential for the catalytic reactivity (entry
12). Moreover, the reaction was highly efficient with extremely low
catalyst loading under air atmosphere. For instance, excellent
product yield was obtained with 0.0055 mol% of PcFe(III)Cl
catalyst at 40 °C when the reaction was performed open to the air
(entry 13, TON = 15,000). The maximum turnover number was
determined to be 47,000 based on the product yield (entry 14),
which would be comparable to the reactivity of protein-based
catalyst system.[15b]
Table 1. Optimization of reaction conditions
We next explored the substrate scope under the currently
optimized aerobic reaction conditions (Table 2). It is noteworthy
that dioxazolones can be easily prepared in two steps from the
corresponding carboxylic acid feedstocks. The amination at the
benzylic C–H bonds proceeded with excellent turnover numbers,
and the efficiency was not significantly affected by the electronic
perturbation at the phenyl substituents (2–5) except the highly
electron-withdrawing CF3 group (6). Furthermore, high
diastereoselectivity was observed when a -methyl-substituted
dioxazolone was subjected to the reaction conditions (7,
d.r.>20:1). A benzofused lactam product 8 was efficiently
obtained also with excellent catalytic turnover (TON = 13,000).
Substrates bearing various types of aliphatic C–H bonds
were also smoothly cyclized. For instance, an amination at the
tertiary C–H bond afforded a spirocyclic lactam 9 with turnover
number of 1,300. Secondary methylene and primary methyl C–H
bonds were also readily amidated by the air-compatible
PcFe(III)Cl catalyst system (10–12). Moreover, polycyclic γ-
lactam skeletons were easily accessible by the current C–H
amidation approach (13–14). Interestingly, when an optically
active substrate (>99% ee) was subjected to the amidation
conditions, the lactam formation took place at the chiral C–H bond
without racemization (15, TON = 1,200). Dioxazolone compounds
bearing propargylic γ-C–H bonds were cyclized in the presence
of NaSbF6 additive (16–17). It should be noted that an
unprotected terminal alkyne functional group was tolerated under
the current aerobic reaction conditions. However, dioxazolone
bearing a thienyl moiety was converted to a solvent adduct only,
suggesting that the acyl nitrenoid intermediate undergoes a
Curtius rearrangement.
[Fe] cat.
(mol%)
Additive
(mol%)
Solvent
Yield[a]
(%)
Entry
1
PcFe(II) (5)
(TPP)Fe(III)Cl (5)
Fe(II)(PDP)(MeCN)2 (5)
PcFe(II) (5)
-
-
-
HFIP
HFIP
HFIP
HFIP
HFIP
CH2Cl2
THF
71 (<5)
9 (<5)
2
3
17 (<5)
45 (<5)
63 (<5)
34 (<5)
17 (29)
7 (80)
4[b]
5
PcFe(III)Cl (5)
NaSbF6 (5)
NaSbF6 (5)
NaSbF6 (5)
NaSbF6 (5)
NaSbF6 (5)
NaSbF6 (5)
NaSbF6 (5)
-
6
PcFe(III)Cl (5)
7
PcFe(III)Cl (5)
8
PcFe(III)Cl (5)
MeCN
C6H6
9
PcFe(III)Cl (5)
N.D. (>95)
<5 (92)
<5 (58)
62 (<5)
83 (<5)[c]
10
11
12
13[b]
PcFe(III)Cl (5)
PhCF3
PhCl
PcFe(III)Cl (5)
PcFe(III)Cl (5)
HFIP
HFIP
PcFe(III)Cl (0.0055)
-
14[b]
-
HFIP
52 (47)[d]
PcFe(III)Cl (0.0011)
[a] Determined by 1H-NMR analysis (internal standard: 1,1,2-trichloroethane).
The numbers in parentheses are the amounts of remaining starting material.
N.D.: Not detected. [b] Reaction was conducted under air. [c] Turnover number
(TON) was calculated to be 15,000 on the basis of the product formation. [d]
TON was 47,000.
At the outset, we envisioned that an iron(II) phthalocyanine
(Pc) complex, PcFe(II), would catalyze an intramolecular C–H
amidation via an acyl nitrenoid intermediate. When 3-
phenylpropyl dioxazolone 1 was employed as a model substrate,
PcFe(II) catalyst (5 mol%) provided the desired γ-lactam product
2 in high yield at 40 °C, using hexafluoro-2-propanol (HFIP) as the
reaction solvent under argon atmosphere (Table 1, entry 1). Other
types of iron complexes such as (TPP)Fe(III)Cl (H2TPP =
5,10,15,20-tetraphenylporphyrin)[7] and
species, Fe(II)(PDP)(MeCN)2 (PDP
ylmethyl)-2,2′-bipyrrolidine),[19] were less effective for the lactam
synthesis (entries 2 and 3, respectively). However, the high air-
sensitivity of PcFe(II) necessitates inert conditions to suppress
the catalyst deactivation (see the Supporting Information for
details). In fact, when the same reaction as of entry 1 was
Subsequently, we briefly examined the site selectivity
between potentially competing C–H bonds present in the same
molecule. When a dioxazolone substrate bearing both benzylic
and tertiary γ-C–H bonds was subjected to the catalytic conditions,
the cyclization was favored toward the benzylic position (B) over
the tertiary (T) site (18/19, 6.1:1). On the other hand, the
amination was almost exclusive at the benzylic position in the
presence of competing aliphatic 2° C–H bonds (20). Finally, the
current [PcFe(III)Cl]-catalyzed aerobic C–H amidation process
was shown to be readily performed in a gram scale (2, >99% yield,
TON of 18,000).
a
=
non-heme Fe(II)
N,N′-bis(pyridin-2-
2
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Table 2. Substrate scope of PcFe(III)Cl-catalyzed lactamization[a]
radical species formed by the iron catalyst. Moderate KIE values
were observed in both intra- and intermolecular competition of C–
H and C–D amination (kH/kD = 1.5 and 1.6, respectively, Scheme
2b). When 1.0 equiv of TEMPO was added as an external radical
scavenger, no TEMPO adduct was detected but diminished yield
of the lactam product was obtained (Scheme 2c). This result, in
parallel with the stereoretentive lactam cyclization (Table 2, 15),
led us to propose a rapid radical recombination after hydrogen
abstraction process.[22]
Scheme 2. a) Olefin isomerization test on a substrate bearing allylic C–H bonds.
b) Measurement of kinetic isotope effects (KIE). c) Radical trap experiment with
TEMPO.
To elucidate the mechanistic details, we conducted a series
of computational studies using a simplified ligand system (Pc′ =
5,10,15,20-tetraazoporphyrin). DFT calculations on the electronic
structures of the putative iron nitrenoid intermediate,
[Pc′FeCl(NR)] (R = COCH2CH2CH2C6H5) revealed that an
antiferromagentically coupled doublet (S
=
1/2, AF) is
thermodynamically most stable (Figure 1a). Mulliken spin density
on the Fe center and the axial nitrogen (Nax) atom was 1.891 and
–0.786, respectively, substantiating the intermediacy of an imidyl
radical species. In fact, the more soluble perchlorinated
analogous catalyst Cl16PcFe(III)Cl, which provided the lactam
product 2 from the dioxazolone substrate 1 in 51% yield with 5
mol% catalyst loading, displayed a distinctive organic radical
signal in the reaction mixture (g = 1.991, Figure 1b).[23] On the
other hand, the γ-hydrogen atom abstraction by the iron nitrenoid
was calculated to be almost barrierless (0.45 kcal/mol),
suggesting that radical mechanism is operative in the current
catalyst system. Furthermore, the significantly lower barrier of
HAA than that of the CO2 extrusion step (21.04 kcal/mol, Figure
S6) implies that the oxidative decarboxylation is rate-limiting step,
being in agreement with the moderate KIE values.[24]
To rationalize the plausible origin of the exceptionally high
turnover numbers in the current iron-catalyzed lactamization
process under aerobic conditions, further computational
corroborations were performed on the model catalyst species,
Pc′Fe. DFT calculations showed that while dioxygen binding to
the lower valent Fe(II) center is energetically favored by 9.65
kcal/mol to form an end-on superoxo species, the analogous
binding to the Fe(III) center turned out to be highly endergonic
(Figure 2a). This result implies that the high air-compatibility of the
[a] Reaction conditions: substrate (0.1 mmol) and PcFe(III)Cl (0.0055 mol%) in
HFIP (1.0 mL) for 12 h at 40 °C, open to the air. Isolation yields are reported.
Turnover numbers (TONs) based on the product formation are shown in the
parentheses. [b] 0.055 mol% of catalyst was used. [c] Substrate (0.2 mmol) and
HFIP (2.0 mL) were used. [d] 1.0 mol% of catalyst was used. [e] 0.50 mol% of
catalyst was used. [f] Substrate (0.15 mmol) and HFIP (1.5 mL) were used. [g]
5.0 mol% of catalyst and 5.0 mol% of NaSbF6 were used. [h] 1.0 mol% of
catalyst and 1.0 mol% of NaSbF6 were used. [i] Determined by 1H-NMR analysis
of the crude reaction mixture.
The mechanistic aspect of the C–N bond-forming step was
then investigated. When a substrate having a reactive allylic C–H
bond (Z)-22 was subjected to the reaction conditions, an olefin-
isomerized solvent adduct (E)-23 was obtained as an amide
byproduct (12%, Scheme 2a). This result suggested that a
stepwise process would be operative, presumably via an allylic
3
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Fe(III) catalyst system compared to the lower-valent Fe(II)
counterpart can be attributed to the energetically disfavored
oxygen binding which would lead to the oxidative
decomposition.[20]
Figure 1. a) Mulliken spin density plot of [Pc′FeCl(NR)]S=1/2 (α-spin density in
blue and β-spin density in green) and proposed hydrogen atom abstraction
(HAA) step. AF = Antiferromagnetically-coupled. b) Experimental (black) and
simulated (red, g = 1.991) X-band EPR spectrum of the reaction mixture using
Cl16PcFe(III)Cl.
The dependence of the substrate coordination on the
catalyst spin states was examined. The X-band EPR spectrum of
PcFe(III)Cl in a frozen HFIP solvent showed admixed spin states
of doublet and quartet, indicating the co-existance of the two
electronic configurations (Figure S4).[25] However, DFT
calculations revealed that the substrate coordination is
energetically downhill only in the doublet spin surface (Figure 2b).
Moreover, the calculated Fe–Nax bond length of the dioxazolone
adduct [Pc′FeCl-1] was significantly shorter in the doublet state
(2.158 Å) compared to that of the quartet counterpart (2.759 Å ),
further suggesting that the substrate coordination on the iron
metal center is favored in the doublet state.
Figure 2. a) Computational comparison of dioxygen binding between Fe(II) and
Fe(III) center of the model catalyst system, Pc′Fe. b) Free energy change of iron
catalyst species in the dioxazolone coordination depicted with Fe–Nax bond
length in doublet (S = 1/2) and quartet (S = 3/2) spin states. c) Electronic
configurations of the Pc′Fe-product adduct and the free energy change for the
product release in each spin state.
On the other hand, the presupposed product-catalyst
adduct [Pc′FeCl-(N-2)], was calculated to be most stable in the
intermediate quartet spin state (IS, S = 3/2), rather than in its lower
spin state (LS, S = 1/2, Figure 2c).[25] In the quartet spin state, the
Fe–N bond length is calculated to be significantly elongated
compared to that of the doublet analogue, as the Fe–Nax σ*
antibonding orbital is partially populated. Moreover, the product
dissociation from [Pc′FeCl-(N-2)] is thermodynamically favored
(ΔG = –17.39 kcal/mol, Figure 2c) in the quartet energy surface,
thereby preventing the product inhibition even in the presence of
large access amounts of the lactam species relative to the catalyst
loading. The similar tendency was also observed when the κO-
coordination mode of the product 2 was considered (Figure S8).
In fact, even in the presence of product 2 (1.0 equiv) separately
added to the reaction mixture, the PcFe(III)Cl catalyst still
displayed high turnover numbers (= 12,000) in a reaction of a
substrate 1, indicating that the product inhibition is not significant
during the course of reaction (see the Supporting Information).
The plausible mechanism of the current catalytic system can be
summarized in Scheme 3, showing that the key C–N bond
formation involves a radical intermediate in doublet spin surface
and that the facile product release for the catalyst takes place in
the quartet spin state.
Scheme 3. A plausible mechanistic pathway of the [PcFe(III)Cl]-catalyzed
intramolecular C–H amidation with dioxazolone substrates to produce γ-lactams.
In conclusion, we successfully developed a PcFe(III)Cl-
catalyzed intramolecular C–H amidation of dioxazolones to afford
γ-lactam products with extremely high turnover numbers under
aerobic conditions. The origin of the high catalytic activity was
rationalized by the facile spin interconversion of the iron species.
We believe that this study would pave a way for the use of easily
accessible 1st row transition metal catalyst systems for the direct
and practical C–H functionalizations.
4
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Acknowledgements
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This research was supported by the Institute for Basic Science
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helpful discussions and critical reading.
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Conflict of interest
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The authors declare no conflict of interest.
Keywords: Iron catalysis, nitrenoid transfer, aerobic conditions,
dioxazolones, -lactam synthesis
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10.1002/anie.202013499
Angewandte Chemie International Edition
COMMUNICATION
Entry for the Table of Contents
Jeonguk Kweon, and Sukbok Chang*
Page No. – Page No.
Highly Robust Iron Catalyst System
for Intramolecular C(sp3)–H
Amidation Leading to γ-Lactams
Herein, the highly robust air-stable iron-catalyzed C–H amidation is disclosed for the
synthesis of -lactams. A series of experimental and computational mechanistic
investigations suggested a radical stepwise pathway involving an imidyl nitrenoid
intermediate. The air compatibility and high turnover numbers (up to 47,000) of the iron
catalyst system were also rationalized by DFT calculations.
6
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