Hypervalent iodine-mediated Ritter-type amidation of terminal alkenes: The synthesis of isoxazoline and pyrazoline cores

Article abstract of DOI:10.3762/BJOC.14.89

Hypervalent iodine-mediated olefin functionalization provides a rapid gateway towards accessing both various heterocyclic cores and functional groups. In this regard, we have developed a Ritter-type alkene functionalization utilizing a PhI(OAc)₂

Full text of DOI:10.3762/BJOC.14.89

Hypervalent iodine-mediated Ritter-type amidation of terminal
alkenes: The synthesis of isoxazoline and pyrazoline cores
Sang Won Park‡1, Soong-Hyun Kim‡2, Jaeyoung Song2, Ga Young Park2, Darong Kim2,
Tae-Gyu Nam*1 and Ki Bum Hong*2
Letter
Open Access
Address:
Beilstein J. Org. Chem. 2018, 14, 1028–1033.
1Department of Pharmacy and Institute of Pharmaceutical Science
and Technology, Hanyang University, Ansan, Gyeonggi-do 15588,
Republic of Korea and 2New Drug Development Center (NDDC),
Daegu-Gyeongbuk Medical Innovation Foundation (DGMIF), 80
Cheombok-ro, Dong-gu, Daegu, Republic of Korea
doi:10.3762/bjoc.14.89
Received: 09 February 2018
Accepted: 27 April 2018
Published: 11 May 2018
Email:
This article is part of the Thematic Series "Hypervalent iodine chemistry in
organic synthesis".
Tae-Gyu Nam* - tnam@hanyang.ac.kr; Ki Bum Hong* -
kbhong@dgmif.re.kr
Guest Editor: T. Wirth
* Corresponding author ‡ Equal contributors
© 2018 Park et al.; licensee Beilstein-Institut.
License and terms: see end of document.
Keywords:
amido-amidation; hypervalent iodine; isoxazoline; metal-free;
oxyamidation; pyrazoline
Abstract
Hypervalent iodine-mediated olefin functionalization provides a rapid gateway towards accessing both various heterocyclic cores
and functional groups. In this regard, we have developed a Ritter-type alkene functionalization utilizing a PhI(OAc)2 ((diace-
toxyiodo)benzene, PIDA)/Lewis acid combination in order to access isoxazoline and pyrazoline cores. Based on allyl ketone
oximes and allyl ketone tosylhydrazones, we have developed an alkene oxyamidation and amido-amidation protocol en route to
accessing both isoxazoline and pyrazoline cores. Additionally, acetonitrile serves as both the solvent and an amine source in the
presence of this PIDA/Lewis acid combination. This operationally straightforward and metal-free protocol provides an easy access
to isoxazoline and pyrazoline derivatives.
Introduction
Isoxazoline and pyrazoline-containing heterocycles are abun- thetic chemists [12-15]. Among precedent synthetic methods,
dant in natural products and biologically active molecules [1-5]. the functionalization of unactivated olefins provides a rapid
Thus, these scaffolds are also important from the standpoint of construction of different heterocycles [16,17]. More specifi-
pharmaceutical and medicinal chemistry [6-11]. Not surprising- cally, the formation of isoxazoline and pyrazoline cores via
ly, the construction of diverse heterocyclic cores including isox- alkene heterofunctionalization of allyl ketone oximes and/or
azolines and pyrazolines has garnered much attention from syn- allyl ketone tosylhydrazones has been well documented [18-22].
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Beilstein J. Org. Chem. 2018, 14, 1028–1033.
For example, diverse halonium sources have been utilized for However, an attempted expansion of this methodology to allyl
the synthesis of isoxazolines via halocyclization. Furthermore, ketone oximes and allyl ketone tosylhydrazones proved unsuc-
transition metal-, visible light, and hypervalent iodine-mediated cessful under the previously reported reaction conditions (see
oxidative cyclization protocols provide isoxazoline backbones Supporting Information File 1, Table S1). Upon optimization
bearing diverse substituents such as –SR, -CF3, -OH and halo- with various oxidants and additives screened, it was found that
gens [23-27].
a Lewis acid additive can promote the olefin heterofunctional-
ization via a Ritter-type amidation using acetonitrile as both the
solvent and the amine source. Interestingly, this hypervalent
Results and Discussion
As depicted in Scheme 1, we have previously reported an inter-/ iodine-mediated Ritter-type oxyamidation of 1a proved less
intramolecular alkene diamination using either N-iodosuccin- efficient in the presence of solvent combinations with aceto-
imide (NIS) or a phenyliodine diacetate (PIDA)/halide additive nitrile, despite acetonitrile being used in vast excess (see Sup-
combination [28-30]. Vinylanilines and vinylaminopyridines in porting Information File 1, Table S1). Herein, we entail the first
combination with electron-rich, Brønsted basic amines were example of a hypervalent iodine(III)-mediated Ritter-type
converted to their corresponding indoline and azaindoline deriv- oxyamidation and amido-amidation of terminal alkenes in the
atives.
presence of a Lewis acid.
Optimization studies of this Ritter-type oxyamidation
commenced with oxidant screening in the presence of a
Lewis acid (Table 1). Without oxidant, the Ritter-type oxyami-
dation still proceeded to give 3a albeit in low yield (Table 1,
entry 1). The background reaction mediated by a Lewis acid
seemed plausible via an electrophilic activation of the double
bond. When the reaction is performed in the presence of hyper-
valent iodine reagents such as PIFA ([bis(trifluoroacet-
oxy)iodo]benzene), PhI(NPhth)2 and PIDP (bis(tert-butylcar-
bonyloxy)iodobenzene) much better yields were obtained
(Table 1, entries 2–4), with PhI(OAc)2 proving to be the best
Scheme 1: Hypervalent iodine-mediated heterofunctionalization of ter-
minal alkenes.
Table 1: Hypervalent iodine-mediated Ritter-type alkene oxyamidation.
entrya
oxidant (equiv)
additive (equiv)
T (°C)
yield of 3a (%)b
1
–
BF3·OEt2 (1.0)
BF3·OEt2 (1.0)
BF3·OEt2 (1.0)
BF3·OEt2 (1.0)
BF3·OEt2 (1.0)
BF3·OEt2 (1.0)
BF3·OEt2 (1.0)
BF3·OEt2 (1.0)
AlCl3 (1.0)
25
25
25
25
25
reflux
25
25
25
25
25
25
25
10
35
42
49
55
60
14
14
0
2
PhI(OCOCF3)2 (1.0)
PhI(NPhth)2 (1.0)
PIDP (1.0)
3
4
5
PhI(OAc)2 (1.0)
PhI(OAc)2 (1.0)
IBX (1.0)
6
7
8
DMP (1.0)
9
PhI(OAc)2 (1.0)
PhI(OAc)2 (1.0)
PhI(OAc)2 (1.0)
PhI(OAc)2 (1.0)
PhI(OAc)2 (1.0)
10
11
12
13
SnCl4 (1.0)
0
TiCl4 (1.0)
12
45
0
TMSOTf (1.0)
–
aAll reactions were performed on a 0.21 mmol scale (0.1 M) and with a standard 18 h reaction time. bIsolated yield.
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Beilstein J. Org. Chem. 2018, 14, 1028–1033.
(Table 1, entry 5). Refluxing conditions further improved the Next a series of allyl ketone oximes 1 were subjected to the op-
yield (Table 1, entry 6). Additionally, other cyclic hypervalent timized reaction conditions and the results are summarized in
iodine oxidants such as IBX (2-iodoxybenzoic acid) and DMP Scheme 2. Phenyl and electron-deficient aryl allyl ketone
(Dess–Martin periodinane) (Table 1, entries 7 and 8) gave simi- oximes showed robust reactivity as the corresponding products
lar yields to the background reaction. Lastly, a Lewis acid were obtained in good yields (3a–c, 3f) [31]. However, elec-
screen (Table 1, entries 9–12) was performed. Among the tested tron-rich aryl allyl ketone oximes such as 1d, 1e and 1g proved
Lewis acids, AlCl3, SnCl4, TiCl4, TMSOTf and BF3·Et2O, the inferior. Also the furan-substituted allyl ketone oxime deliv-
latter was found to be the best choice of additive. Remarkably, ered the desired product 3h albeit in a moderate yield. In addi-
the activation of PIDA by a Lewis acid (BF3·OEt2) seemed to tion, various alkyl allyl ketone oximes were investigated. While
be crucial for this Ritter-type oxyamidation to proceed (Table 1, cyclopropyl allyl ketone oxime 1m was converted to the corre-
entry 13). Based on these experiments, we chose the conditions sponding isoxazoline 3m in 20% yield, other alkyl allyl ketone
outlined in Table 1, entry 5 for our further investigations due to oximes afforded higher yields of the desired products. This ob-
the mild (room temperature) reaction conditions.
servation is ascribed differences in reactivity due to an in-
Scheme 2: Substrate scope of the Ritter-type oxyamidation: isoxazoline synthesis. All reactions were performed on a 0.21 mmol scale (0.1 M) and
with a standard 18 h reaction time.
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Beilstein J. Org. Chem. 2018, 14, 1028–1033.
creased steric bulk at the α-position (t-Bu > c-Hex > n-Oct > Based on these experimental data and previous reports [32,33],
n-Bu).
a plausible mechanism of the Ritter-type oxyamidation and
amido-amidation is proposed in Scheme 4. First, an activation
We next explored the hypervalent iodine-mediated Ritter-type of hypervalent iodine(III) by the Lewis acid generates the active
amido-amidation reaction in the presence of a Lewis acid in iodine(III) species A in situ. The resulting iodine(III) then, in
order to access pyrazoline cores (Scheme 3). A series of allyl turn, forms the electrophilic iodonium intermediate B with the
ketone tosylhydrazones 4 were subjected to the same reaction terminal alkene of the allyl ketone oxime or allyl ketone tosyl-
conditions. In general, the yields of the pyrazoline cores de- hydrazone. The subsequent 5-exo-type cyclization by nucleo-
creased marginally relative to the Ritter-type oxyamidation philic attack on the iodonium then leads to the isoxazoline or
reaction. Monosubstituted aryl allyl ketone tosylhydrazones pyrazoline cores (C) bearing the hypervalent iodine(III) group.
showed good reactivity and provided the pyrazoline hetero- Following iodine activation by the Lewis acid, the iodonium ion
cycles 5a–c in moderate yields (24–47%). On the other hand, D undergoes nucleophilic substitution with excess acetonitrile
disubstituted aryl allyl ketone tosylhydrazones 4d and 4e to form intermediate E. Then water can add to the correspond-
yielded the corresponding products in 28% and 26%, respec- ing nitrilium and subsequent tautomerization delivers isoxazo-
tively. The reaction of heteroaryl allyl ketone tosylhydrazones line 3 (X = O) and pyrazoline 5 (X = NTs) via a Ritter-type
such as 3-furyl allyl ketone tosylhydrazone 4f and 3-thiophenyl oxyamidation and amido-amidation.
allyl ketone tosylhydrazone 4g provided their desired products
in low yields. Lastly, alkyl allyl ketone tosylhydrazones 4h and Conclusion
4i seemed to maintain of the trend in which increased reactivity In summary, we have developed a hypervalent iodine(III)-medi-
is the result of increasing size of the alkyl side chain at the ated inter-/intramolecular Ritter-type oxyamidation and amido-
α-position (t-Bu > c-Hex).
amidation protocol in the presence of a Lewis acid. This trans-
Scheme 3: Substrate scope of Ritter-type amido-amidation: pyrazoline synthesis. All reactions were performed on a 0.21 mmol scale (0.1 M) and with
a standard 18 h reaction time.
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Scheme 4: Plausible mechanism of the hypervalent iodine(III)-mediated Ritter-type oxyamidation/amido-amidation in the presence of a Lewis acid.
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Rankin, F. W.; Tobin, A. E.; Emmett, G.; Lalka, G. K.; Sze, J. Y.;
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Experimental procedures, characterization data, and copies
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This work was supported by the research fund of Hanyang
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