Iron-Catalyzed Primary C—H Amination of Sulfamate Esters and Its Application in Synthesis of Azetidines?

Article abstract of DOI:10.1002/cjoc.202000299

The direct amination of unactivated primary C—H bonds is extremely challenging due to their inert nature. Herein, we report an intramolecular primary C—H amination of sulfamate esters using an iron catalyst derived from iron(II) triflate and bipyridine. An array of oxathiazinanes were synthesized in moderate to good yields, which were further converted into biologically important azetidines by a one-pot procedure. This research demonstrates the potential of applying simple nitrogen ligands in iron-catalyzed C—H functionalization and offers an accessible alternative to state-of-the-art iron-nitrene chemistry.

Full text of DOI:10.1002/cjoc.202000299

Chinese Journal
of Chemistry
CJC
中 国 化 学 - An International Journal
Accepted Article
Title: Iron-Catalyzed Primary C–H Amination of Sulfamate Esters and Its Application
in the Synthesis of Azetidines
Authors: Yan Zhang, Dayou Zhong, Muhammad Usman, Peng Xue, and Wen-Bo Liu*
This manuscript has been accepted and appears as an Accepted Article online.
This work may now be cited as: Chin. J. Chem. 2020, 38, 10.1002/cjoc.202000299.
The final Version of Record (VoR) of it with formal page numbers will soon be
published online in Early View: http://dx.doi.org/10.1002/cjoc.202000299.
ISSN 1001-604X • CN 31-1547/O6
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Chinese Journal
of Chemistry
Iron catalysis, Primary C–H activation, Amination, Heterocycle, Azetidine
Concise Report
CJC
中
国 化 学 - An International Journal
Iron-Catalyzed Primary C–H Amination of Sulfamate Esters and Its
Application in the Synthesis of Azetidines
Yan Zhang, Dayou Zhong, Muhammad Usman, Peng Xue, and Wen-Bo Liu*
Sauvage Center for Molecular Sciences, Engineering Research Center of Organosilicon Compounds & Materials (Ministry of Education), College of Chemistry
and Molecular Sciences, Wuhan University, Wuhan, Hubei 430072, China
Cite this paper: Chin. J. Chem. 2019, 37, XXX—XXX. DOI: 10.1002/cjoc.201900XXX
Summary of main observation and conclusion The direct amination of unactivated primary C–H bonds is extremely challenging due to their inert nature.
Here we report an intramolecular primary C–H amination of sulfamate esters using an iron catalyst derived from iron(II) triflate and bipyridine. An array of
oxathiazinanes were synthesized in moderate to good yields, which were further converted into biologically important azetidines by a one-pot procedure.
This research demonstrates the potential of applying simple nitrogen ligands in iron-catalyzed C–H functionalization and offers an accessible alternative to
state-of-the-art iron-nitrene chemistry.
Remarkably,
a bis-NHC-stabilized iron(III) porphyrin catalyst,
Background and Originality Content
[Fe(TDCPP)(IMe)2]I, was developed by Che et al. enabling the
amination of inert aliphatic C–H bonds in good yields.[5c] In 2017,
amination of aryl azides was disclosed by the Plietker group using
a nucleophilic iron catalyst Bu4N[Fe(CO)3(NO)] (Scheme 1D).[11]
Scheme 1 Transition-metal-catalyzed nitrene insertion of primary C–H
Nitrogen-containing heterocycles are omnipresent in many
synthetic intermediates, natural products, and pharmaceuticals.[1]
In last several decades, considerable endeavors have been
committed to develop efficient methods toward their synthesis.[2]
As one of the most straightforward and economical methods,
direct C–H amination of ubiquitous hydrocarbons by means of
transition metal mediated nitrene insertion has drawn numerous
attentions of the community.[3,4] Significant advances have been
achieved albeit primarily employing source-limited metals (i.e.,
rhodium, iridium, and ruthenium).[3g–3n] Recently, remarkable
examples of non-precious metal-catalyzed nitrene insertion
reactions[4] have been emerged as a powerful C–N bond formation
method by the contributions of Che,[5] White,[6] Zhang,[7] Betley,[8]
and other.[4,9]
To date, the nitrene insertion reactions of aliphatic C(sp3)–H
bonds are mainly limited to activated substrates such as allylic and
benzylic C–H bonds.[3,4] Amination of unactivated aliphatic C–H
bonds is of substantial challenge owing to their thermodynamic
stability, in particular for primary C–H bonds with a bond-
dissociation energy (BDE) of 100.5 kcal/mol.[10] Only a handful of
examples capable of primary C–H amination have been known.
Driver and co-workers realized an intramolecular reaction of aryl
azides catalyzed by a thermally robust Rh(II) complex for the
synthesis of indolines (Scheme 1A).[3i] In 2010, the Zhang group
reported an excellent cobalt-catalyzed amination of the primary C–
H bond of phosphoryl azides (Scheme 1B).[7a] In 2013, the Betley
group employed an iron(II)-dipyrrinato catalyst [(AdDPClAr)FeCl(OEt2)]
to achieve the amination of a variety of C–H bonds, but exhibited
poor reactivity toward primary C–H bonds (Scheme 1C).[8b]
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10.1002/cjoc.202000299
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Yan Zhang et al.
Concise Report
bonds
conditions (see Tables S1–S6 in the SI for details). The
representative results were outlined in Table 1. Among the
examined ligands (entries 1–7, and Table S1), tridentate ligands
(L1–L3) generally showed inferior reactivity to bidentate ligands
(L4–L7). Aminopyridine-type ligands, previously used in iron-
catalyzed amination of sulfamate esters and sulfonamides,[12]
resulted in poor reactivity. We were delighted to find that the use
of bipyridine L4 offered 60% NMR yield of the desired
oxathiazinane 2a (entry 4). Examination of 1,10-phenanthroline-
type ligands (L5–L7) revealed that dichloro-substituted L7 is more
efficient (entry 7). Although slightly lower yield was obtained with
L4 in comparison with L7 (60% vs 63%, entries 4 vs 7), we decided
to use L4 as the ligand for further optimization due to its readily
availability and low cost. A number of oxidants were tested, and
PhI(OCOCF3)2 was found superior. Further examination of iron
sources, solvents, and temperature (entries 11–15) revealed that
the use of Fe(OTf)2 at 100 °C in acetonitrile improved the isolation
yield to 81%, which was identified as the optimal reaction
conditions (entry 15). Control experiment without the use of ligand
resulted in no product formation (entry 16).
Table 1 Condition optimizations
entrya
1
iron salt
Fe(ClO4)2
Fe(ClO4)2
Fe(ClO4)2
Fe(ClO4)2
Fe(ClO4)2
Fe(ClO4)2
Fe(ClO4)2
Fe(ClO4)2
Fe(ClO4)2
Fe(ClO4)2
FeCl2
ligand (x mol%)
L1 (20)
L2 (20)
L3 (20)
L4 (30)
L5 (30)
L6 (30)
L7 (30)
L4 (30)
L4 (30)
L4 (30)
L4 (30)
L4 (30)
L4 (30)
L4 (30)
L4 (30)
–
oxidant
2a (%)b
20
Additionally,
a notable manganese-catalyzed amination of
PhI(OCOCF3)2
PhI(OCOCF3)2
PhI(OCOCF3)2
PhI(OCOCF3)2
PhI(OCOCF3)2
PhI(OCOCF3)2
PhI(OCOCF3)2
PhI(OAc)2
sulfamate esters under mild conditions was accomplished by the
White group in 2015, and a wide range of substrates were tolerated
in excellent reactivity and selectivity (Scheme 1E).[6b]
2
11
3
28
60 (55)c
Utilizing abundant iron salts and readily available nitrogen
ligands to generate the active iron catalysts in situ has advantages
in practical synthesis due to their easy accessibility.[12] Seminal
reports using the “iron salt + ligand” protocol were independently
disclosed by the Che[12a] and Chan[12b] groups. In 2019, our group
developed an iron/aminopyridine-catalyzed amination of aliphatic
secondary and tertiary C–H bonds.[13] Encouraged by these results,
we sought to further expand this simple iron system to realize more
challenging primary C–H amination (Scheme 1F). Herein, we report
the successful development of an intramolecular primary C–H
bond amination of sulfamate esters using an iron catalyst derived
from Fe(OTf)2 and bipyridine. Furthermore, a variety of azetidines,
a conformationally rigid scaffold widely existed in potential drug
candidates and other bio-important compounds,[14] are accessed
from the amination products.
4
5
52
6
44
7
63
8
22
9
PhI(DMM)
33
10
11
12
13
14
15d
16e
PhI(OPiv)2
21
PhI(OCOCF3)2
PhI(OCOCF3)2
PhI(OCOCF3)2
PhI(OCOCF3)2
PhI(OCOCF3)2
PhI(OCOCF3)2
33c
48c
70c
73c
81c
N.D.
Fe(acac)2
Fe(OAc)2
Fe(OTf)2
Fe(OTf)2
Fe(OTf)2
Results and Discussion
We commenced our studies with 2-methyl-2-phenylpropyl
sulfamate ester 1a as a model substrate to optimize reaction
aReaction conditions: 1a (0.2 mmol), iron salt (0.02mmol, 10 mol%), oxidant
(0.4 mmol), and 4 Å MS (50 mg) in MeCN (2 mL) at 80 °C for 3 h. bNMR yield
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Iron-Catalyzed Primary C–H Amination of Sulfamate Esters and Its Application in the Synthesis of Azetidines
Chin. J. Chem.
using 1,3,5-trimethoxybenzene as an internal standard. cIsolated yield.
d100 °C. PhI(DMM), phenyliodonium dimethylmalonate.[15] eWithout ligand.
N.D., not detected.
Scheme 2 Investigation of site selectivity
Table 2 Substrate scopea
Systematic studies by White and Che disclosed that the
reactivity trends of amination using both heme-like[6a] and
nonheme[5b] iron catalysts are in accordance to the C−H bond
dissociation energies. The selectivity of this method toward
sulfamate esters with multiple C–H bond types were also studied
(Scheme 2). The amination of substrate 1m, bearing both
propargylic and primary C–H bonds, occurred at the propargylic site
exclusively to provide 2m in moderate yield (Scheme 2A).
Treatment of substrate 1n under the standard conditions delivered
a 5:2 mixture of secondary C–H versus primary C–H amination
products (Scheme 2B). Although sterically hindered, tertiary C–H
amination is much more preferred over primary C–H amination, as
showcasing by the reactions of substrates 1o and 1p (Scheme 2C).
Moreover, with substrate 1q, six-membered ring oxathiazinae 2q is
formed preferentially over the five-membered ring product 2q’
(Scheme 2D). Those trends of selectivity, intrinsically driven by the
substrates themselves, are in line with previous observations.[5b,6a]
a Reaction conditions: 1 (0.4 mmol), Fe(OTf)2 (0.04 mmol, 10 mol%), L4 (0.12
mmol, 30 mol%), PhI(OCOCF3)2 (0.8 mmol), and 4 Å MS (100 mg) in MeCN
(4 mL) at 100 °C for 3 h. b 0.2 mmol scale.
Next, the substrate scope was explored (Table 2). Substrates
(1b–1f) bearing electron-deficient groups, such as F, Cl, and Br, on
the aryl ring generated the corresponding oxathiazinanes 2b–2f in
65–82% yields. Substrate 1g containing an α-naphthyl group,
provided the corresponding product 2g in 59% yield. para-Isobutyl-
and para-methyl-substituted 2-aryl-2-methylpropyl sulfamates (2h,
2i) were also investigated and resulted in moderate yields (44–
50%). Previously, synthesis of oxathiazinane 2j from the
corresponding starting material 1j catalyzed by an iron
phthalocyanine catalyst ([FePc]·SbF6) resulted in only 3% yield.[6b]
An significant improvement (64% yield) was achieved by the use of
According to the literature precedent[5b,c,8b]
, a possible
reaction pathway was proposed (Scheme 3). Treatment of
substrate 1 with PhI(OCOCF3)2 generates compound II, which upon
reacts with the iron catalyst I leading to the formation of an imido-
iron species III together with iodobenzene. Then direct C–H
insertion or H-atom abstraction/radical recombination[5c,8b] of III
yields the desired product 2 and regenerates the catalyst.
a
manganese
tert-butylphthalocyanine
catalyst
([Mn(tBuPc)]·SbF6).[6b] By contrast, our chemistry afforded 2j in 82%
yield under the standard reaction conditions. Additionally, an
ester-containing substrate 1k was also tolerated delivering the
oxathiazinane 2k in 53% yield. Secondary alcohol-derived
sulfamate substrate 1l was compatible to form the corresponding
product 2l in 44% yield. A sulfonamide substrate was also
subjected to the standard reaction conditions, but failed to afford
any desired product (Scheme S1 in the SI).
Chin. J. Chem. 2019, 37, XXX－XXX
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Yan Zhang et al.
Concise Report
Scheme 3 Proposed reaction pathway
Table 3 One-pot synthesis of azetidines from oxathiazinanesa
As showcased in literature, oxathiazinanes are valuable
intermediates for heterocycles,[16a] 1,3-amino ethers,[16b] and other
bioactive targets.[16] To further demonstrate the utility of this iron-
catalyzed amination reaction, a one-pot procedure was used to
convert oxathiazinanes synthesized above to azetidines,
a
structurally and biologically important class of N-heterocyclic
compounds.[14] Protection of the amination products 2 with CbzCl
afforded N-Cbz oxathiazinanes 3. Without chromatographic
purification of the intermediates 3, NaI was added followed by NaH
to generate azetidines 4 through sequential ring-opening/ring-
closing steps.[17] As shown in Table 3, the azetidines 4a–4m were
synthesized in 50–79% yields by this one-pot procedure.
Delightedly, 3,3-dimethylazetidine 4j was also generated in 51%
yield. Notably, 3,3-dimethyl-azetidine is an important pattern in a
number of biologically active molecules, such as an dopamine
receptor antagonist zetidoline,[14c] a PDE4 inhibitor,[14d] and an
acetylcholine receptor agonist[14e] as shown in Figure 1.
aReaction conditions: 2 (0.1 mmol), CbzCl (0.2 mmol), NaH (0.2 mmol in THF
(1 mL) at room temperature for 30 min; NaI (0.15 mmol) in DMF (1 mL) at
60 °C for 1 h, then NaH (0.3 mmol) at 40 °C for 3 h. b0.2 mmol.
Figure 1 Selected examples of biologically relevant azetidines.
Conclusions
In summary, we have developed an iron-catalyzed
intramolecular primary C–H amination of sulfamate esters. A range
of oxathiazinanes were produced in moderate to good yields using
an iron catalyst derived from Fe(OTf)2 and bipyridine. The synthetic
utility of the amination reaction to construct azetidines is
demonstrated by
a one-pot procedure. Given the readily
availability and high reactivity of the catalyst toward aliphatic
substrates, this method offers a practical alternative to heterocycle
synthesis.
Experimental
General procedure for Fe-catalyzed C–H amination.
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Iron-Catalyzed Primary C–H Amination of Sulfamate Esters and Its Application in the Synthesis of Azetidines
Chin. J. Chem.
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11951.
O
O
m
ol%)
mol%)
Me
R1
R3
Fe(OTf)2 (10
L4
S
HN
O
(30
OSO2NH2
equiv)
PhI(OCOCF3)2 (2.0
MS, MeCN, 100 °C, 3 h
R2
R2
1
4
Å
R1 R3
2
To a 10 mL vial equipped with a magnetic stirring bar were
added Fe(OTf)2 (14.2 mg, 0.04 mmol, 10 mol%), L4 (18.7 mg, 0.12
mmol, 30 mol%), and 2 mL of MeCN. After the mixture was stirred
at 30 °C for 30 min, substrate 1 (0.4 mmol), PhI(OCOCF3)2 (344.0
mg, 0.8 mmol, 2 equiv), 4 Å MS (100 mg), and another 2 mL of
MeCN were added. Then the vial was sealed and the mixture was
stirred at 100 °C for 3 h. The reaction was cooled to room
temperature, filtered through a pad of celite, and washed with
CH2Cl2 (3 × 5 mL). The filtrate was concentrated under reduce
pressure, and the residue was purified by flash chromatography on
silica gel (200 ~ 300 mesh) to give the desired products 2.
Supporting Information
The supporting information for this article is available on the
WWW under https://doi.org/10.1002/cjoc.2018xxxxx.
Acknowledgement
We thank the NSFC (Nos. 21971198 and 21772148) and Wuhan
University (WHU) for financial support.
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Concise Report
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(The following will be filled in by the editorial staff)
Manuscript received: XXXX, 2019
Manuscript revised: XXXX, 2019
Manuscript accepted: XXXX, 2019
Accepted manuscript online: XXXX, 2019
Version of record online: XXXX, 2019
www.cjc.wiley-vch.de
© 2019 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2019, 37, XXX－XXX
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Iron-Catalyzed Primary C–H Amination of Sulfamate Esters and Its Application in the Synthesis of Azetidines
Chin. J. Chem.
Entry for the Table of Contents
Page No.
Iron-Catalyzed Primary C–H Amination of
Sulfamate Esters and Its Application in the
Synthesis of Azetidines
An iron-catalyzed intramolecular primary C–H amination of sulfamate esters using bipyridine ligand
has been reported for the construction of oxathiazinanes. A series of azetidines have been
synthesized as well from the amination product in a one-pot procedure.
Yan Zhang, Dayou Zhong, Muhammad Usman,
Peng Xue, and Wen-Bo Liu*
Chin. J. Chem. 2019, 37, XXX－XXX
© 2019 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.cjc.wiley-vch.de
This article is protected by copyright. All rights reserved.