Iron porphyrin catalysed light driven C-H bond amination and alkene aziridination with organic azides

Article abstract of DOI:10.1039/d0sc00784f

Visible light driven nitrene transfer and insertion reactions of organic azides are an attractive strategy for the design of C-N bond formation reactions under mild reaction conditions, the challenge being lack of selectivity as a free nitrene reactive intermediate is usually involved. Herein is described an iron(iii) porphyrin catalysed sp³ C-H amination and alkene aziridination with selectivity by using organic azides as the nitrogen source under blue LED light (469 nm) irradiation. The photochemical reactions display chemo- and regio-selectivity and are effective for the late-stage functionalization of natural and bioactive compounds with complexity. Mechanistic studies revealed that iron porphyrin plays a dual role as a photosensitizer and as a catalyst giving rise to a reactive iron-nitrene intermediate for subsequent C-N bond formation.

Full text of DOI:10.1039/d0sc00784f

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DOI: 10.1039/D0SC00784F
ARTICLE
Iron porphyrin catalysed light driven C-H bond amination
and alkene aziridination with organic azides
Yi-Dan Du,a Cong-Ying Zhou,ac Wai-Pong To,a Hai-Xu Wanga and Chi-Ming Che*ab
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
Visible light driven nitrene transfer and insertion reactions of organic azides is an attractive strategy for the design of C-N
bond formation reactions under mild reaction conditions, the challenge being lack of selectivity as free nitrene reactive
intermediate is usually involved. Herein is described an iron(III) porphyrin catalysed sp3 C–H amination and alkene
aziridination with selectivity by using organic azides as nitrogen source under blue LED light irradiation. The photochemical
reactions display chemo- and regio-selectivity and are effective for the late-stage functionalization of natural and bioactive
compounds with complexity. Mechanistic studies revealed that iron porphyrin plays a dual role as a photosensitizer as well
as
a
catalyst giving rise to reactive iron-nitrene intermediate for subsequent C-N bond formation.
bonds in a selective manner. As metal-nitrenes are envisioned
to display higher selectivity than free nitrenes, photochemical
generation of reactive metal-nitrene species from organic
Introduction
The development of efficient methods for selective C-N bond
formation under mild reaction conditions is important in
organic synthesis owing to ubiquity of amino group in
bioactive natural products and pharmaceuticals. Nitrene C-H
insertion and alkene aziridination are powerful methods for
installing amino group into organic molecules.1 In this regard,
there is burgeoning interest to use organic azides as nitrene
source as only nitrogen gas is produced as a by-product and
external oxidant is not required. However, nitrene transfer
reactions of organic azides, especially for intermolecular
reactions, often require elevated temperature, which may limit
the substrate scope and product selectivity, as well as increase the
chance for competitive side reactions. Photochemical activation of
organic azides offers a potential solution to this issue. As examples,
Yoon and co-workers found that irradiation of azidoformates
and alkenes with visible light in the presence of
[Ir(ppy)2(dttbpy)]PF6 led to aziridination products at room
temperature.2a König and co-workers employed [Ru(bpy)3](Cl)2
as photosensitizer to achieve an sp2 C-H amidation of electron-
rich heteroaromatics with benzoyl azides under visible light
irradiation.2c These reactions proceed via free nitrene
intermediate generated through energy transfer from triplet
excited states of transition metal sensitizers to organic azides.
While free nitrenes react efficiently with organics, their high
reactivity and short lifetime present significant hurdles for the
reactions with relatively unreactive sp3 C-H bond or multi C-H
azides would be appealing. We are attracted to the works of
Newcomb and co-workers on the generation of reactive iron-
oxo species for C–H hydroxylation through light irradiation of
- 3
iron porphyrins in the presence of ClO4 . A collaborative work
by Martin-Diaconescu, Neese, Roithova, Bill, Lloret-Fillol,
Costas and their co-workers reported the generation of iron-
nitrido species by photolysis of an iron-azide complex bearing
a pentadentate aminopyridine ligand.4 Abu-Omar and co-
workers disclosed the first examples of mononuclear imido
complexes of manganese(V) and chromium(V) corroles under
photolytic or thermal conditions.5 We conceive that
metalloporphyrins with labile axial coordination sites are
potential appealing catalysts for visible-light driven nitrene C–
H insertion and aziridination with organic azides,6 in which
metalloporphyrin acts as photosensitizer and at the same time
captures free nitrene to give reactive metal-nitrene/imido
intermediate. Herein is described
a
light induced
intermolecular sp3 C-H bond amination and alkene
aziridination with organic azides and intramolecular sp3 C-H
bond amination of alkyl azides catalysed by iron porphyrin
(Scheme 1). Robert and co-workers reported an iron(III)
porphyrin that catalyses light-induced CO2 reduction to CO.7a
Draksharapu, Gruden, Browne and co-workers reported a non-
Previous work:
photosensitizer
H
visible light
R
N
N3R
or RN
RHN
H
This work:
a. State Key Laboratory of Synthetic Chemistry, Department of Chemistry, The
University of Hong Kong, China. E-mail: cmche@hku.hk
Cl
NR
Fe
Fe
b. HKU Shenzhen Institute of Research & Innovation, Shenzhen, China.
c. Present address: College of Chemistry and Materials Science, Jinan University,
Guangzhou, China.
NHR
N3R
visible light
L
† Electronic Supplementary Information (ESI) available: Experimental details and
characterization of products. See DOI: 10.1039/x0xx00000x
Scheme 1 C–H amination with organic azides by iron porphyrin photocatalysis.
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heme iron photocatalyst for light driven aerobic oxidation of To investigate whether metal-nitrene intermediate was
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methanol.7b
involved in this light driven C-H DOaIm: 10in.1a0t3io9/nD,0SCs0e0v7e8r4aFl
experiments were conducted. [1] The kinetic isotope effect
(KIE) was examined by the reaction of ethylbenzene, d10-
ethylbenzene and arylazide 2a under the photocatalytic
conditions (Scheme 3A). A kH/kD value of 6.5 was obtained.
This KIE value in the range of 5-11 observed in transition metal
porphyrin catalysed sp3 C-H amination is supportive of metal-
nitrene intermediate that reacts with C-H bond via a H-atom
abstraction mechanism.10 Bettinger and co-workers found that
a free nitrene (R2BN:) generated from the photolysis of
azidoboranes can undergo intermolecular insertion into a C-H
bond of cyclohexane. The KIE value was measured to be
1.35.10d [2] To examine if the reaction involves radical chain
mechanism, the quantum yields (QY) of these photo-
chemical reactions have been estimated by using potassium
Results and discussion
Reaction conditions and mechanism of iron-porphyrin
photocatalysis
At the outset, we examined a panel of iron porphyrins for light
driven C-H amination of indane 1a with 3,5-
bis(trifluoromethyl)phenyl azide 2a (Scheme 2). The reaction
was conducted at 25-35oC with blue LED (469 nm) irradiation.
Fe(TTP)Cl,
Fe(p-Cl-TPP)Cl,
Fe(TMP)Cl,
Fe(p-F-TPP)Cl,
Fe(TDCPP)Cl, Fe(TDCDMAP)Cl, Fe(F20TPP)Cl and Fe(TF4DMAP)Cl
gave C-H amination product 3a in 12-99% yields with
Fe(TF4DMAP)Cl 8 being the most effective one (99% yield in 24
h; 93% yield in 15 h; Table S1 in ESI†). No reaction was
observed in the absence of iron porphyrin catalyst or blue LED
irradiation revealing that both iron porphyrin catalyst and light
are indispensable in the photochemical C-H amination
reaction. The photo-stability of Fe(TF4DMAP)Cl and
Fe(F20TPP)Cl in deaerated DCE was examined. As portrayed in
Fig. S1 and S2 respectively, the UV-visible absorption spectra
of these two complexes remained unchanged upon blue LED
irradiation for at least 18 hours. An iron(II) porphyrin
CF3
A
HN
CF3
CF3
F3C
N3
5.0 eq.
1 mol% Fe(TF4DMAP)Cl
+
D
D
o
D
4 A MS, DCE, 25-35oC
D
D
D
D
HN
CF3
CD3
CF3
Blue LED
D
D
D
mono(dialkylcarbene) complex, Fe(F20TPP)(Ad) (Ad
=
2-
CD3
D
KIE= 6.5
D
adamantylidene),9 also catalysed the reaction to give 3a in 98%
yield. [Fe(F20TPP)]2(μ-O), which was slowly converted to
Fe(F20TPP)Cl upon light irradiation (Fig. S3), is another effective
catalyst affording 3a in 96% yield. Other Ru, Mn, Co and Ir
porphyrins were less effective giving 3a in 15% to 82% yields
along with by-product 3,5-bis(trifluoromethyl)aniline 4a in 8-
50% yields. Other iron complexes supported by non-porphyrin
N4/N5 ligands failed to give the desired C-H amination product
under the same reaction conditions. In the absence of
molecular sieves, the product yield dropped to 30%. The use of
free porphyrin H2TF4DMAP or [Ru(bpy)3](Cl)2•6H2O as
photosensitizer furnished 3a in 10% and 15% yield,
respectively. When Rh2(OAc)4 was used as catalyst, no reaction
was observed under the same condition. The photochemical
reaction could also take place to give 3a in 93% yield under
thermal condition with Fe(TF4DMAP)Cl as catalyst but at a
reaction temperature of 120 oC. When the reaction was
performed under irradiation of green LED (530 nm) for 36 h, 3a
was obtained in 25% yield.
D
5.0 eq.
B
CF3
F3C
N3
HN
CF3
CF3
3a
, 70%
1 mol% Fe(TF4DMAP)Cl
+
F
o
F
4 A MS, DCE, 25-35oC
F
F
F
F
NH2
F
Blue LED
HN
F
F
F
3c
, 15%
Scheme 3 Mechanistic study.
CF3
F3C
+
N3
HN
1 mol% Fe(D4-por*)Cl,
o
CF3
4 A MS, DCE, 25-35oC
Blue LED, 48 h
CF3
1a
2a
3a
82%, 20% ee
Ts
N
1 mol% Fe(D4-por*)Cl,
TsN3
Ph
+
o
4 A MS, DCE, 25-35oC
Blue LED, 60 h
Ph
11d
49%, 35% ee (12 h, 44%, 42% ee)a
CF3
F3C
N3
F3C
NH2
Scheme
4
Asymmetric C-H amination and aziridination catalysed by chiral iron
1 mol% cat.
HN
+
porphyrin. a 5 mol% catalyst was used.
+
o
4 A MS, DCE
CF3
CF3
2a
Ph
Blue LED
25-35oC
CF3
4a
1 mol% Fe(TF4DMAP)Cl
Ph
Ph
1a
Ar-N3
N
Ar
+
3a
NMe2
F
o
4 A MS, DCE, 25-35oC
Ph
F
F
2a
Blue LED
CF3
CF3
Me2N
F
12
, 60%
F
F
Ar =
N
Ph
F
F
F
F
Cl
R
1 mol% Fe(TF4DMAP)Cl
Fe
N
N
N
Ar
Ar-N3
+
o
4 A MS, DCE, 25-35oC
Ph
N
R
2a
Blue LED
13
14
F
F
, R = Ph , 90%
, R = Me, 87%
F
F
Me2N
NMe2
Scheme
Fe(TF4DMAP)Cl.
5
Stereospecific aziridination of alkenes and arylazide 2a catalysed by
F
F
Fe(TF4DMAP)Cl
Scheme 2 C-H amination of indane 1a with azide 2a and structure of Fe(TF4DMAP)Cl.
2 | J. Name., 2012, 00, 1-3
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ferrioxalate as a chemical actinometer. It was found that the condition led to poor yield of the C-H amination product 3k.
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QY for the reaction of styrene and 2a was 12% while that of No reaction was observed when tosyl azide,
DOI: 10.1039/D0dSCip0h0e78n4yFl
indane and 2a was 5.5%. A lower QY of 3.5% was found phosphorylazide or benzylazide was used as nitrene source.
with Fe(3,5-DitBu-Chenphyrin)Cl 11 instead of Fe(TF4DMAP)Cl as With azide 2a as nitrene source, the scope of hydrocarbons
the photocatalyst. Since the QY values of these reactions were was examined. As shown in Table 2, azide 2a underwent
less than 100%, the photochemical reaction is less likely to nitrene insertion to benzylic C-H bond of a range of substrates
involve a radical chain mechanism.12 [3] The cross-over including ethylbenzene, tetralin, diphenylmethane, fluorene,
reaction of indane with 2a and 2,3,4,5,6-pentafluoroaniline xanthene, isochroman to give the amination products in good
gave C-H amination products 3a and 3c in 70% and 15% yield, to high yields (5a-5l). For substituted ethylbenzenes, both
respectively, suggesting the involvement of indane radical electron-donating and -withdrawing groups (4-methoxy, 4-
intermediate (Scheme 3B). [4] When the photochemical C-H methyl, 4-chloride) led to high product yields (5g-5j). When
amination of indane with arylazide 2a was performed with isopentylbenzene which bears both benzylic and tertiary C-H
chiral
Fe(D4-por*)Cl
(H2(D4-por*)
=
meso-tetrakis- bonds was used as substrate, the reaction took place regio-
{(1R,4S,5S,8R)-1,2,3,4,5,6,7,8-octahydro-1,4:5,8-dimethano-
anthracen-9-yl}-porphyrin) catalyst, the C-H aminated product
3a was obtained in 82% yield and with 20% ee (Scheme 4).
With Fe(D4-por*)Cl as catalyst, the reaction of styrene with
TsN3 led to aziridine 11d in 49% and with 34% ee. This result is
comparable to our previous work in which stoichiometric
reaction of styrene with Ru(D4-por*)(NTs)2 gave 11d in 27%
ee.13 [5] MALDI-MS analysis of stoichiometric reaction of
selectively at the benzylic C-H bond over tertiary C-H bond (5k).
Table 1 Scope of organic azides under photocatalytic condition a
NHR
1 mol% Fe(TF4DMAP)Cl
R
N3
+
o
4 A MS, DCE, 25-35oC
2b-r
1a
3b-r
Blue LED
Cl
F
F
F
F
F
HN
HN
HN
HN
Fe(TF4DMAP)Cl and azide 2a showed
a m/z signal at
Cl
F
F
F
F
F
1355.1475, corresponding to the iron-nitrene/imido
formulation (Fig. S4). [6] The aziridination of alkenes and 2a
under the photocatalytic conditions displayed good
stereospecificity, giving cis-aziridines from cis-alkenes and
trans-aziridines from trans-alkenes in up to 90% yield (Scheme
3c
, 96%
3d
, 94%
3e, 60%
3b
, 93%
Me
F
CF3
Br
OMe
HN
HN
HN
HN
Me
3f
3g
, 55%
, 38%
5), which favours the involvement of
a metal-nitrene
3h
, 27%
3i
, <5%
O
O
CCl3
intermediate rather than a free triplet nitrene. [7] We
attempted to detect if any short-lived species would be
generated from iron(III) porphyrin chloride complexes
(Fe(TF4DMAP)Cl and Fe(F20TPP)Cl) upon photo-excitation in the
presence of azide 2a by nanosecond time-resolved absorption
spectroscopy. Transient signal of spectral change at 350-420
nm was observed 1 μs after laser flash and which decayed
back to initial base line after 25 μs; such signal was not
observed for photoexcitation of the iron porphyrin complex in
the absence of azide 2a under the same conditions. But as the
signal was close to the laser excitation wavelength of 355 nm
and relatively weak, it would be difficult to make any
conclusive statement. These results altogether suggest that in
the iron porphyrin catalysed light driven C-H amination, a
reactive metal-nitrene/imido species was generated in the
course of photolysis.
With the optimal condition, the scope of organic azides for the
iron porphyrin-catalysed light driven sp3 C-H amination was
examined by using indane as substrate. As shown in Table 1,
electron-withdrawing substituents (CF3, F and Cl) of aryl azides
facilitated the intermolecular C-H amination leading to high
yield of products (93-96%, 3b-3d). For aryl azides having only
one electron-withdrawing substituent, C-H amination products
were obtained in moderate yields (27-60%, 3e-3h). Electron-
donating substituent (OMe) was found to disfavour the
reaction resulting in poor product yield (<5%, 3i). It is worth
noting that azidoformate Troc-N3 was also reactive in the
photocatalytic C-H amination giving 3j in 54% yield. The use of
3,5-bis(trifluoromethyl)benzoyl azide under the photocatalytic
HN
HN
CF3
O
F3C
,19%
3j
, 54%
3k
a
Reactions were run under argon with 0.5 mmol of the azide, 5.0 mmol of
indane, 5 × 10−3 mmol of the catalyst (1 mol% with respect to the azide) and 120
mg 4 Å MS in 2.0 mL of anhydrous DCE in 10.0 mL sealed tube. The tube was
irradiated with blue LED at 25-35oC.
In the case of methyl (S)-2-(4-isobutylphenyl)propanoate which
has two electronically different benzylic C-H bonds, the C-H
amination took place at the more electron-rich C-H bond (5l).
This photochemical C-H amination is also applicable to allylic
C-H bonds. The reaction of cyclohexa-1,4-diene with 2a gave
the allylic C-H amination product 5m in 70% yield. Allylbenzene
gave a mixture of C-H aminated isomeric products (5na, 5nb).
The reaction of 1-(allyloxy)-4-(prop-1-en-2-yl)benzene
proceeded with high chemo- and regio-selectivity to give 5o in
35% yield. When 2,3-dimethylbuta-1,3-diene was subjected to
the photocatalysis, a 7-membered heterocycle product 5p was
isolated in 78% yield. The reaction also took place at allylic C-H
bond of -unsaturated aldehydes and -unsaturated
ketones in good product yields (5q-5s). When cyclic 2-
norbornene was used, bridged secondary C-H amination
product 5t was obtained in 52% yield with endo:exo ratio of
3:1 along with aziridination product in 12% yield. No allylic C-H
amination product was observed.
We next examined the photocatalytic C-H amination of
tetrahydrofuran and unactivated C-H bonds, the
functionalization of which is a challenge. Tetrahydrofuran was
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J. Name., 2013, 00, 1-3 | 3
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tube was irradiated with blue LED at 25-35oC. b 5 mol% catalyst was used.
reactive under the photocatalytic condition giving the
amination product 6a in 61% yield (Table 2). The reaction of
cyclooctane with 2a proceeded smoothly to give 6b in 40%
yield. When the substrate contains tertiary, secondary and
primary C-H bonds, the photocatalytic amination preferentially
occurred at tertiary C-H bond over secondary and primary C-H
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bonds (6c-6g). We also investigated the DreOgI:io10s.e10le3c9t/iDv0itSyC0o0f7t8h4eF
photochemical C-H amination of substrates bearing multiple
tertiary C–H centers. When dihydrocitronellyl acetate or
dihydrocitronellyl bromide was subjected to the photochemical
C-H amination, the reaction occurred preferentially at the
tertiary C–H bond remote from the electron-withdrawing
group (acetate or bromo, 6h, 6i). This regioselectivity could be
attributed to the deactivation of C(3)-H bond by the electron-
withdrawing group.
To our surprise, the α-C-H bond of ketone, which is generally
thought to be deactivated by carbonyl moiety, could also be
aminated. Treatment of 1-phenylbutan-2-one with 2a and a
catalytic amount of iron porphyrin at room temperature under
blue LED irradiation afforded α-C-H amination product 6l in
40% yield. Likewise, 2,4-dimethylpentan-3-one and 5-
methylhexan-2-one gave α-C-H aminated products 6m and 6n
in 50% and 36% yield, respectively. No reaction was found
when methyl 2-phenylacetate was used. These results suggest
that 2a might react with the enol form of ketone to afford an
aziridine which underwent ring-opening to give final α-C-H
amination product.14
Table 2 Fe(TF4DMAP)Cl-catalysed intermolecular C-H amination with organic azide 2a
under photocatalytic conditiona
CF3
H
NHAr
R2
1 mol% Fe(TF4DMAP)Cl
Ar-N3
Ar =
+
R1
R2
R1
o
4 A MS, DCE, 25-35oC
5a-5w
6a-6n
1b-1z
2a
Blue LED
CF3
NHAr
NHAr
NHAr
NHAr
O
5d
, 70%
5a
, 91%
5b
, 80%
5c
, 78%
NHAr
O
NHAr
NHAr
5g
5h
, X = OMe, 90%,
, X = Me, 81%,
, X = H, 83%
5i
5j
O
, X = Cl, 82%
X
5f
, 66%
5e
, 74%
NHAr
CO2Me
Ph
Intramolecular C-H amination of alkyl azides
5k
, 82%
NHAr
5l
, 54%
We next used the photocatalysis for intramolecular C−H
NHAr
amination of alkyl azides15,16 to form imidazolidines,17
a
NHAr
NHAr
Ph
5na
versatile class of intermediates in organic synthesis. As shown
in Table 3, a variety of N-containing alkyl azides underwent C-H
amination to give the corresponding imidazolidines in 45-98%
yield. It is noteworthy that when 1-(2-azidoethyl)indoline was
subjected to the photolysis, an indole product was obtained in
95% yield presumably derived from ring-opening of the imida-
,35%
5m
, 70%
+
O
Ph
NHAr
,15%
5nb
5o
, 35%
O
O
CF3
H
NHAr
N
H3C
H3C
ArHN
H
H
CF3
5r
, 60%, dr = 2.6:1
5p
, 78%
Table 3 Fe(TF4DMAP)Cl-catalysed intramolecular C-H amination of N-containing alkyl
azides under photocatalytic conditiona
5q
, 35%
NHAr
O
R2
ArHN
R1
+
N
1 mol% Fe(TF4DMAP)Cl
NAr
NR2
R1
5t
, 52%,
12%
o
1.2 eq. Boc2O, 4A MS
N
5s
, 85%
endo: exo = 3:1
N3
DCE, 25-35oC
Blue LED
Boc
Me
NHAr
O
7
8
Me
NHAr
NHAr
, 61%
Entry
1
Substrate
Product
Yield (%)
NHAr
55%
6a
b
Boc
6b
, 40%
6c
, 41% (45%)
6d,
ArHN
N
N3
N
H
NHAr
N
75
NHAr
MeO2C
Boc
BzO
7a
MeO2C
8a
b
6g
, 35%
6f
, 30%
6e
, 27% (35%)
Boc
N
N3
ArHN
N
ArHN
7
3
H
OAc
N
3
7
Br
2
70
78
Boc
6h
, 56% (C7: C3 = 5.3 :1)
6i
, 45%
OMe
Ph
OMe
8b
NHAr
O
7b
NHAr
F3C
N
OBz
H
6j
, 37%
N3
Ph
N
6k
, 50%
Ph
N
N
NHAr
NHAr
NHAr
3
4
Boc
Ph
Ph
8c
O
6m
7c
O
O
6n
, 36%
, 50%
6l
, 40%
Ph
N3
a
Me
61; 30b
Reactions were run under argon with 0.5 mmol of the azide, 5.0 mmol of the
substrates, 5 × 10−3 mmol of the catalyst (1 mol% with respect to the azide)
and 120 mg 4 Å MS in 2.0 mL of anhydrous DCE in 10.0 mL sealed tube. The
Ph
N
N
N
Boc
8d
Me
4 | J. Name., 2012, 00, 1-3
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7d
9b
10b
View Article Online
DOI: 10.1039/D0SC00784F
N
O
3
100
92 (85)
Boc
N
N
5
45
N
N3
O
N3
Boc
7e
9c
8e
3
10c
Boc
N
O
Boc
4
5
100
100
82 (77)
84 (77)
N
N3
6
7
98
95
N
N
O
O
8f
N3
7f
9d
4
10d
H
N
N
O
N3
Boc
N
Boc
N3
N
8g
7g
5
Boc
10e
O
N
8
55
9e
O
N3
O
N3
Boc
6
100
90 (82)
7h
8h
N
O
a Reactions were run under argon with 0.3 mmol of the azide, Boc2O (0.36 mmol),
3 × 10−3 mmol of the catalyst (1 mol% with respect to the azide) and 120 mg 4 Å
MS in 2.0 mL of anhydrous DCE in 10.0 mL sealed tube. The tube was irradiated
8
10f
9f
b
with blue LED at 25-35oC. Isolated yields are shown. [Fe(F20TPP)Cl] was used as
the catalyst. Yields were determined by 1H NMR spectroscopy.
a Reactions were run under argon with 0.3 mmol of the azide, Boc2O (0.36 mmol),
9 × 10−3 mmol of the catalyst (3 mol% with respect to the azide) and 120 mg 4 Å
MS in 2.0 mL of anhydrous DCE in 10.0 mL sealed tube. The tube was irradiated
with blue LED at 25-35oC. Isolated yields are shown in the brackets.
zolidine product (entry 7). For the reaction of O-containing
alkyl azide 7h, a 1,3-oxazinane derivative 8h was obtained in
55% yield (entry 8).
Intramolecular C-H amination of α-azidoketones
Derivatization of natural products
Nitrogen bridged bicyclic moiety is prevalent in naturally
occurring alkaloids.18 This valuable scaffold can be constructed
by our iron-catalysed light driven C-H amination of -
azidoketones. As shown in Table 4, various medium-sized
cyclic -azidoketones underwent intramolecular C-H
amination to give the corresponding nitrogen bridged bicyclic
compounds in 42-85% yields (entry 1-6). It is noteworthy that
2-azidocyclohexan-1-one failed to give intramolecular C-H
amination product, suggesting that the ring strain affected the
reactivity.
As the photocatalysis can be performed under mild conditions
and with high regio- and chemo-selectivity, we conceive that
this methodology has the potential to selectively aminate C-H
bond of other complex natural products which possess various
C-H bonds and functional groups. We first examined the C-H
amination of Ac-Cholesterol that contains a total of 48 C–H
bonds, 22 of which are secondary, and 7 tertiary and 4 allylic
(Scheme 6A). Under the photochemical condition, Ac-
Cholesterol underwent amination exclusively at the allylic C-H
bond remote from the electron-withdrawing group -OAc in
77% isolated yield with a dr ratio of 4.5:1. Fe(F20TPP)Cl also
catalysed the light-driven amination of Ac-Cholesterol with
52% product yield. Similar to Cholesterol, the reaction of Bz-
Diosgenin gave allylic C-H bond aminated product 16 in 60%
isolated yield with a dr ratio of 3:1 when 2b was used as the
nitrene source (Scheme 6B). Amination of the C-H bond
adjacent to oxygen atom was not observed. When 2a was used
as the nitrene source, the corresponding amination product
was obtained in 78% yield with a dr ratio of 7:1. Treatment of
an Estrone derivative (Scheme 6C) with 2a and Fe(TF4DMAP)Cl
under the photocatalytic condition gave an allylic amination
product 18 in 79% yield. Likewise, a double allylic amination of
a Progesterone derivative (Scheme 6D) was observed in 28%
yield. When (−)-ambroxide was subjected to the photolysis,
the C-H amination occurred at the C-H bond adjacent to O
atom giving imine product 20 in 23% yield with a recovery of
45% starting material (Scheme 6E). Treatment of (+)-
Table 4 Fe(TF4DMAP)Cl-catalysed intramolecular C-H amination of -azidoketones
under photocatalytic conditiona
Boc
O
3 mol% Fe(TF4DMAP)Cl
N
N3
O
o
1.2 eq. Boc2O, 4A MS
n
DCE, 25-35oC
Blue LED, 10 h
0-1
1-8
9
10
Entry
Substrate
Product
Conv.
(%)
Yield
(%)
O
1
70
46 (42)
N3
N
Boc
O
10a
9a
O
Boc
2
100
90 (80)
N
N3
O
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ARTICLE
Journal Name
Nootkatone with 2a under the photochemical condition gave an form metal-nitrene intermediate for subsequent C-N bond
View Article Online
3
DOI: 10.1039/D0SC00784F
aziridination product in 30% yield.
formation. A variety of sp C-H bonds can be aminated in good
to high yields and with excellent regioselectivity. The reactivity
trend of C-H bonds for the photocatalytic amination was found
to be benzylic ≈ allylic > tertiary > secondary > primary C-H
bond. The method is also effective for selective late stage C-H
amination of complex natural products. The photochemical
reaction herein developed has several eco-friendly advantages
including: 1) using organic azides as aminating agents, 2) using
catalysts of biocompatible and earth abundant iron, and 3)
using blue LED light as energy source. Nonetheless the use of
DCE as solvent is not desirable feature and work to use
environmental benign solvent system to replace DCE is needed
to further improve this iron porphyrin catalysed
photochemical amination reaction. The chiral Fe(D4-por*)Cl
can catalyse the light driven C-H amination and alkene
aziridination with moderate enantioselectivity. To our
knowledge, this work represents the first examples of visible
light driven sp3 C-H amination and alkene aziridination with
organic azides by iron porphyrin photocatalysis.
A
AcO
AcO
F3C
N3
H
H
F3C
F3C
H
H
H
2 mol% Fe-catalyst
NHH
o
4 A MS, DCE, 25-35oC
CF3
Blue LED
1.5 eq.
15
Fe(TF4DMAP)Cl: 77%, dr = 4.5 :1
Fe(F20TPP)Cl: 52%, dr = 3.3 :1
Ac-Cholesterol
BzO
B
BzO
R
R
H
H
H
R
N3
H
H
2 mol% Fe(TF4DMAP)Cl
NHH
+
H
H
o
4A MS, DCE, 25-35oC
R
H
H
Blue LED, 48 h
O
O
O
O
1.5 eq.
16
R = Cl, , 60%, dr = 3:1, 18% r.s.m.
(59%, dr = 3:1,35% r.s.m.)[b]
Bz-Diosgenin
17
R = CF3, , 60%, dr = 3:1, 10% r.s.m.,
(78%, dr = 7:1, 7% r.s.m.)[b]
MeO
C
F3C
N3
H
2 mol% Fe(TF4DMAP)Cl
H
H
o
4 A MS, DCE, 25-35oC
H
H
H
CF3
1.5 eq.
MeO
Blue LED
Estrone
derivative
Conflicts of interest
There are no conflicts to declare.
CF3
HN
18
, 79%
CF3
D
CF3
O
F3C
F3C
N3
H
2 mol% Fe(TF4DMAP)Cl
Acknowledgements
This work was supported by National Natural Science Foundation of
China (NSFC 91856203 and 21472159), Basic Research Program-
HN
HN
CF3
H
H
o
4 A MS, DCE, 25-35oC
CF3
1.5 eq.
Blue LED
Progesterone
derivative
H
H
H
F3C
Shenzhen
Fund
(JCYJ20170412140251576
and
O
JCYJ20180508162429786), Hong Kong Research Grants Council
General Research Fund (17301817, 17303815) and “Laboratory for
Synthetic Chemistry and Chemical Biology” funded by
Health@InnoHK of Innovation and Technology Commission, Hong
Kong Special Administrative Region.
19
, 28%
CF3
E
N
O
CH3
H
F3C
+
N3
O
3 mol% Fe(TF4DMAP)Cl
CH3
H
CF3
CH3
o
4A MS, DCE, 25-35oC
CH3
H
CF3
2 eq.
Blue LED, 48 h
20
, 23%
H
45% rsm
(-)-Ambroxide
dr = 3.5:1
F
F3C
F3C
N3
O
Notes and references
CF3
3 mol% Fe(TF4DMAP)Cl
O
+
o
4A MS, DCE, 25-35oC
1
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N
CF3
1.5 eq.
Blue LED, 48 h
(+)-Nootkatone
21
, 30%
Scheme
6 Late-stage diversification of complex molecules via [Fe(TF4DMAP)Cl]-
catalysed C–H amination. [a] The reaction was conducted with 2 mol% of catalyst and
irradiated for 48 h. [b] The reaction was conducted with 5 mol% of catalyst and
irradiated for 24 h. r.s.m.= reaction starting material
2
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Conclusions
In summary, we have demonstrated that the iron porphyrin
Fe(TF4 DMAP)Cl is an efficient catalyst for selective
intermolecular C-H amination and alkene aziridination of
organic azides and intramolecular sp3 C-H bond amination of
alkyl azides under blue LED light irradiation. Mechanistic study
revealed that Fe(TF4DMAP)Cl played a dual role in the
reactions acting as a photosensitizer as well as a catalyst to
6 | J. Name., 2012, 00, 1-3
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ARTICLE
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DOI: 10.1039/D0SC00784F
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