An Effective [FeIII(TF4DMAP)Cl] Catalyst for C-H Bond Amination with Aryl and Alkyl Azides

Article abstract of DOI:10.1021/acs.orglett.8b03765

[Fe^III(TF₄DMAP)Cl] can efficiently catalyze intermolecular sp³ C-H amination using aryl azides and intramolecular sp³ C-H amination of alkyl azides in moderate-to-high product yields. At catalyst loading down to 1 mol %, the reactions display high chemo- and regioselectivity with broad substrate scope and are effective for late-stage functionalization of complex natural/bioactive molecules.

Full text of DOI:10.1021/acs.orglett.8b03765

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
An Effective [FeIII(TF4DMAP)Cl] Catalyst for C−H Bond Amination
with Aryl and Alkyl Azides
Yi-Dan Du,†,§ Zhen-Jiang Xu,§ Cong-Ying Zhou,†,‡ and Chi-Ming Che*,†,‡,§
†State Key Laboratory of Synthetic Chemistry and Department of Chemistry, The University of Hong Kong, Pokfulam Road, Hong
Kong, China
‡HKU Shenzhen Institute of Research & Innovation, Shenzhen 518053, China
§Shanghai-Hong Kong Joint Laboratory in Chemical Synthesis, Shanghai Institute of Organic Chemistry, 354 Feng Lin Road,
Shanghai 200032, China
S
* Supporting Information
ABSTRACT: [FeIII(TF4DMAP)Cl] can efficiently catalyze intermolecular sp3 C−H amination using aryl azides and
intramolecular sp3 C−H amination of alkyl azides in moderate-to-high product yields. At catalyst loading down to 1 mol %, the
reactions display high chemo- and regioselectivity with broad substrate scope and are effective for late-stage functionalization of
complex natural/bioactive molecules.
sources with high selectivity and broad substrate scope
(covering complex molecules/natural products) is highly
appealing. Our recent work revealed that [FeIII(TF4DMAP)-
Cl]12 (Figure 1, TF4DMAP = meso-tetrakis(o,o,m,m-tetra-
fluoro-p-(dimethylamino)phenyl)porphyrinato dianion) is effi-
cient in catalyzing anti-Markovnikov oxidation of terminal aryl
alkenes to aldehydes with H2O2 as a terminal oxidant,13 which
involves a reactive iron−oxo porphyrin intermediate. This
atalytic C−H amination with nitrene sources represents a
Cgeneral and efficient approach to the formation of C−N
bonds, which are ubiquitous in molecules of pharmaceutical
and/or biological interest.1 The ubiquity of chemically similar
C−H bonds in complex molecules presents major challenges
for site-selective C−H amination, including direct functional-
ization of C−H bonds, via nitrene insertion, for late-stage
modification of natural products.2 Among generally used
nitrene sources (e.g., N-arylsulfonylimino phenyliodinanes,3
bromamine-T,4 chloramine-T,5 and organic azides6), organic
azides offer a broad nitrene scope and high atom efficiency.
Transition-metal catalysts are well documented to be effective
for the decomposition of these nitrene sources to generate
metal−nitrene intermediates.7 Compared with other transi-
tion-metal catalysts, iron complexes are inexpensive and
biocompatible and often exhibit unique catalytic activity in
nitrene insertion reactions of organic azides.8−10,11b,d−k For
example, iron−dipyrrinato complex9 and N-heterocyclic
carbene iron(III) porphyrin10 were found to be effective for
C−H amination of alkyl azides, which remain a formidable
challenge for the commonly used Rh and Cu catalysts. In view
of the importance of iron catalysts in C−H amination via
nitrene transfer,8−11 the development of a more efficient iron
catalyst for C−H amination using organic azides as nitrene
Figure 1. Structure of iron porphyrin [Fe(TF4DMAP)Cl].
Received: November 24, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b03765
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Letter
finding promoted us to examine the catalytic activity of this
complex in isoelectronically related nitrene transfer/insertion
reactions. Herein, we report an efficient C−H amination with
aryl and alkyl azides catalyzed by [FeIII(TF4DMAP)Cl] under
thermal conditions and its application in derivatization of
natural products.
Scheme 2. Amination of Benzylic C−H Bonds with Aryl
a
Azides
At the outset, we evaluated the catalytic activity of
[FeIII(TF4DMAP)Cl] in the C−H amination of ethylbenzene
(1a) with 3,5-bis(trifluoromethyl)phenyl azide (2a); the
desired amine 3a was obtained in 91% isolated yield when
the reaction was performed in DCE at 120 °C for 12 h. Under
the optimized reaction conditions, we investigated the scope of
aryl azides as the nitrene source using 1a as a model substrate
(Scheme 1). High yields (67−84%) of C−H amination
a
Scheme 1. Scope of Aryl Azides.
a
Conditions: 1 (5.0 mmol), 2 (0.5 mmol), [Fe(TF4DMAP)Cl] (1
mol %), 4 Å MS (120 mg), DCE (2.0 mL), under argon, 120 °C;
b
isolated yield; 2.5 mmol of substrate was used.
adjacent to oxygen atom, benzylic C−H bonds were
preferentially aminated in good-to-high yields (3s−v). The
electron-withdrawing substituent on the phenyl ring was found
to reduce the activity of benzylic C−H bonds, leading to low
product yields (3w−y). This is in agreement with the
electrophilic nature of the reactive iron−imido/nitrene
intermediate.
a
Conditions: 1a (5.0 mmol), 2 (0.5 mmol), [Fe(TF4DMAP)Cl] (1
mol %), 4 Å MS (120 mg), DCE (2.0 mL), under argon, 120 °C;
isolated yield.
products were obtained for mono-para-substituted aryl azides
(3b−d). 3,5-Dichlorophenyl azide (2e) and 2,4,6-trichlor-
ophenyl azide (2f) afforded the corresponding amines 3e and
3f in 76% and 79% yield, respectively. When aryl azides
containing electron-donating substituent(s) (2g and 2h) were
used as the nitrene sources, the corresponding amines 3g and
3h were obtained in moderate yields. The beneficial effect of
incorporating multi-electron-withdrawing substituents was also
demonstrated in the reactions of 2,3,5,6-tetrafluoro- and
pentafluorophenyl azides (2i, 2j) which afforded the
corresponding amines in high yields (3i, 83%; 3j, 88%).
We further investigated the scope of C−H amination under
the optimized conditions. As depicted in Scheme 2, when
benzylic C−H bonds were subjected to the reaction with aryl
azide 2a or 2j as nitrene source, the corresponding C−H
amination products (3k−y) were obtained in 20−98% yields.
It is noteworthy that for 4-methylanisole, containing a primary
benzylic C−H bond, the C−H amination proceeded smoothly
in 67% yield (3p). The reaction protocol also worked well for
tertiary benzylic C−H bonds as shown in the cases of 3q (98%
yield) and 3r (62% yield). When the substrates had both
benzylic C−H bonds and tertiary C−H bonds or C−H bonds
Given the good results of benzylic C−H bond amination, we
then investigated the application of the amination for
unactivated C−H bonds (Scheme 3). Tetrahydrofuran was
reactive toward the C−H amination, giving the corresponding
products in 67−75% yields (4a, 4b). Tetrahydropyran and 1,4-
dioxane also worked well with 2a to give 4c and 4d in 65% and
60% yield, respectively. Treatment of cyclooctane with 2j in
the presence of [Fe(TF4DMAP)Cl] (3 mol %) gave C−H
amination product 4e in 60% yield. When 1°, 2°, or 3°
aliphatic C−H bonds and C−H bonds adjacent to the oxygen
atom were present in the substrates, the Fe(III)-catalyzed C−
H amination occurred at 3 °C−H bond preferentially and in
40−72% yields (4f−o). The site selectivity of the C−H
amination for the substrates bearing multiple 3° C−H bonds
was also examined by using two derivatives of dihydroci-
tronellol, each containing two 3° C−H sites. In both cases, the
amination was favored at the site distal to the electron-
withdrawing group (bromo or acetate, 4p, 4q). This
regioselectivity could be attributed to the electron deactivation
of the C(3)−H bond by an electron-withdrawing group.
B
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a
Scheme 3. Amination of Unactivated C−H Bonds with Aryl
Table 1. Intramolecular C−H Amination of Alkyl Azide
a b
,
Azides
a
Conditions A: 1 (1.0 mmol), 2 (0.2 mmol), [Fe(TF4DMAP)Cl] (3
mol %), 4 Å MS (120 mg), DCE (1.0 mL), under argon, 120 °C;
b
isolated yield; Conditions B: the same as A except using neat 1 (1.0
mL) without DCE.
The intramolecular C−H amination of alkyl azides9a,c,10,11g,i
is challenging because of the facile 1,2-hydride shift of the
alkylnitrene intermediate. Our recent work10 revealed that the
N-heterocyclic carbene iron(III) porphyrin [FeIII(TDCPP)-
(IMe)2]I (TDCPP = meso-tetrakis(2,6-dichlorophenyl)-
porphyrinato dianion) can efficiently catalyze intramolecular
C−H amination of a broad array of alkyl azides. However, 10
mol % catalyst loading was required to guarantee high
substrate conversion and product yields for the reaction.
This promoted us to test the catalytic activity of [Fe-
(TF4DMAP)Cl] for the intramolecular C−H amination of
alkyl azides with lower catalyst loading. As depicted in Table 1,
a variety of alkyl azides underwent intramolecular C−H
amination in the presence of 3 mol % of [Fe(TF4DMAP)Cl] in
45−90% isolated yields. It is noteworthy that when alkyl azide
5f was used, the six-membered piperidine product was
selectively formed in 62% yield, showcasing the strong
preference for amination at the 3° C−H bond (entry 6,
Table 1). For secondary alkyl azides 5g and 5h, the
corresponding pyrrolidines were obtained in 78−90% yields
a
Conditions: 2 (0.3 mmol), [Fe(TF4DMAP)Cl] (3 mol %), Boc2O
(0.36 mmol), 4 Å MS (120 mg), DCE (2.0 mL), under argon, 120
°C; isolated yield. dr = 4.2:1.
b
(entries 7 and 8, Table 1). Notably, when a cyclic secondary
alkyl azide 5i was subjected to the reaction, a tropane
derivative with a bicyclic structure prevalent in a wide range of
alkaloids was isolated in 62% yield (entry 9, Table 1).
Similarly, the α-azido ketone 5j gave a tropane analogue in
86% yield, which is an important intermediate for the synthesis
C
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of cocaine. Interestingly, a secondary alkyl azide 5k derived
from L-menthol underwent intramolecular amination exclu-
sively at a 1° C−H bond to give the cis-octahydroindole in 45%
yield with a dr ratio of 4.2:1 (entry 11, Table 1), revealing that
primary unactivated aliphtic C−H bonds are also amenable for
amination in this protocol when competing secondary or
tertiary C−H bonds are inaccessible. For substrate 5l bearing a
cyclopropyl ring at C4, the iron-porphyrin-catalyzed reaction
gave the pyrrolidine 6l in 78% yield, with no cyclopropyl ring-
2j completely shut down the reaction, with no amination
product 3j observed (Scheme 5a). Second, the amination of a
Scheme 5. Reaction Mechanism Study
1
opening product(s) observed in the crude H NMR spectra.
This is indicative of a concerted or very fast radical rebound
mechanism for the C−H amination.
The high efficiency of the [FeIII(TF4DMAP)Cl] catalyst was
further demonstrated by its applicability to the late-stage
functionalization of complex natural product derivatives, which
possess various C−H bonds and functional groups (Scheme
4). With 2j as the nitrene source, Ac-diosgenin (7) underwent
Scheme 4. Late-Stage C−H Functionalization of Natural
Product Derivatives
mixture of ethylbenzene and ethylbenzene-d10 with 2a gave a
kinetic isotope effect (KIE, kH/kD) of ∼8.4 (Scheme 5b),
suggesting that C−H bond cleavage is the rate-determining
step. The KIE value is in the range of kH/kD ∼5−13 reported
for the H atom abstraction by metal−nitrene/imido com-
plexes.14,15 Third, when (−)-β-pinene 11 was subjected to the
reactions with three different azides 2a, 2i, and 2j separately,
two types of allylic C−H aminated products were observed in
each case (Scheme 5c), with the major ones presumably arising
from a radical rearrangement or an alkene aziridination and
subsequent ring-opening process.11b
In summary, we have demonstrated that [FeIII(TF4DMAP)-
Cl] can efficiently catalyze C−H amination of aryl azides and
alkyl azides with broad substrate scope and with high chemo-
and regioselectivity. The catalytic system is highly effective for
amination of a variety of sp3 C−H bonds including unactivated
aliphatic C−H bond, benzylic C−H bond, allylic C−H bond,
and 1°−3° C−H bonds. This catalytic protocol is also
applicable to late-stage amination of complex natural product
derivatives.
amination exclusively at the allylic C−H bond remote from the
−OAc group, resulting in 75% isolated yield with a dr ratio of
2:1; Me-estrone (8) reacted exclusively at the benzylic C−H
bond with azide 2j, giving the desired amine 8a and its imine
analogue 8b in 40% and 10% yield, respectively, while
amination of TBS-estrone with azide 2a gave amine 9a and
the corresponding imine 9b in 25% and 37% yield, respectively
(no imine products were observed for the examples in
Schemes 2 and 3 under the reaction conditions indicated
therein). For the reaction of racemic DL-α-tocopherol acetate
(10), the desired benzylic C−H amination products 10a (cis)
and 10b (trans) were isolated in a combined 30% yield with a
dr ratio of 1.5:1, along with 30% of imine product 10c.
Several experiments were performed to shed light on the
mechanism of the catalytic C−H amination process. First,
addition of TEMPO to a standard reaction mixture of 1a and
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.8b03765.
■
S
Detailed experimental procedures, characterization of
new compounds, and copies of NMR spectra (PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: cmche@hku.hk.
ORCID
Cong-Ying Zhou: 0000-0002-2235-6070
Chi-Ming Che: 0000-0002-2554-7219
D
DOI: 10.1021/acs.orglett.8b03765
Org. Lett. XXXX, XXX, XXX−XXX

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Letter
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Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by the Hong Kong Research Grants
Council General Research Fund (17303815, 17301817), the
National Natural Science Foundation of China (NSFC
21472216, 21472159), and the CAS-Croucher Funding
Scheme for Joint Laboratories and Basic Research Program-
S h e n z h e n F u n d ( J C Y J 2 0 1 6 0 2 2 9 1 2 3 5 4 6 9 9 7 ,
JCYJ20170412140251576, and JCYJ20170818141858021).
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