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Hydrophosphonodifluoromethylation of Alkenes via Thiyl-Radical/Photoredox Catalysis Wenhao Huang, Jingzhi Chen, Daocheng Hong, Wenxin Chen, Xu Cheng, Yuxi Tian, and Guigen Li J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.7b02354 • Publication Date (Web): 20 Dec 2017 Downloaded from http://pubs.acs.org on December 21, 2017
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The Journal of Organic Chemistry is published by the American Chemical Society. 1155 Sixteenth Street N.W., Washington, DC 20036 Published by American Chemical Society. Copyright © American Chemical Society. However, no copyright claim is made to original U.S. Government works, or works produced by employees of any Commonwealth realm Crown government in the course of their duties.
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The Journal of Organic Chemistry
Hydrophosphonodifluoromethylation of Alkenes via ThiylRadical/Photoredox Catalysis Wenhao Huang,[a] Jingzhi Chen,[a] Daocheng Hong,[b] Wenxin Chen,[a] Xu Cheng,*[ac] Yuxi Tian,*[b] and Guigen Li[a] [a] Institute of Chemistry and Biomedical Science, School of Chemistry and Chemical Engineering, Nanjing University, Nanjing, China [b] Key Laboratory of Mesoscopic Chemistry of MOE, School of Chemistry and Chemical Engineering, Nanjing University, Nanjing, China [c] State Key Laboratory of Elemento-organic Chemistry, Nankai University, Tianjin, China E-mail:
[email protected];
[email protected];
Abstract: Visible-light-induced catalytic hydrophosphonodifluoromethylation of mono- and disubstituted alkenes using bromodifluoromethanephosphonate with a Hantzsch ester as the terminal reductant is reported. The combination of thiyl-radical catalysis with photoredox catalysis was important for achieving good chemoselectivity and high yields.
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Introduction Hantzsch esters (HEs) have been shown to act as efficient terminal reductants in a number of visiblelight-induced reactions. Owing to their unique dihydropyridine structure, HEs can donate an electron in several ways. For example, in photoredox catalysis,1 a HE can transfer an electron to the photocatalyst and become a cationic radical.2 Alternatively, in the absence of a photocatalyst, a HE can absorb visible light, and the resulting excited-state species can then transfer an electron directly to a substrate via a socalled encounter complex.3 In 2016, we reported a thiyl-radical-catalyzed photoreductive reaction employing a HE as a terminal reductant.4 In this reaction, the HE reacts with the thiyl radical by means of a hydrogen atom transfer process and forms a neutral radical, a key intermediate that is reductive enough to initiate an electron transfer process. On the basis of these results, we hypothesized that thiylradical catalysis could be linked to transition-metal catalysis via a HE to achieve novel transformation. 5
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The Journal of Organic Chemistry
Scheme 1. Strategies for constructing sp3 C–CF2PO(OEt)2 bonds.
a) Established chemistry: 1) Anionic nucleophilic addition 6 X R' R
MCF2PO(OEt)2
R 2) Transition-metal catalysis O
N
R'
X
Y
Y
CF2PO(OEt)2
7
4,4'-diMeO-bpy (5 mol %) NiCl2•DMe (2 mol %)
+ BrCF2PO(OEt)2 + ArB(OH)2
CF2PO(OEt)2 N
base, O
3) PC*/PC+ photoredox catalysis 9
R2 N
O 2
R
2 mol % f ac-Ir(ppy)3
+ BrCF2PHO(OEt)2
N
O
R1
base, blue LED
R1
CF2PO(OEt)2
4) Radical ATRA reaction 8,11 +
R
AIBN, n-Bu3SnH,
+ PhXCF2PO(OEt)2 X = Se or S
b)
2
R 2
R
R
or UV irradiation
F F + EtO P EtO O
CF2PO(OEt)2
R
X = Br or I R
X
Na2S2O4
XCF2PO(OEt)2
Br
HE PC* RS PC-
EtO OEt P O F F
H R2
CF2PO(OEt)2
1
R
O
O
EtO
OEt N H HE
pharmaceutical scaffold, this work F F O
O
O NH2
N
N
OH P O OH
O F N N
BZN TLR7 agonist
N
3
F OH P OH O
N Cl PNP inhibitor
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O F
H N
O
N
F
O P HO OH
F
Anti-HCMV agent
3
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To test this hypothesis, we explored a hydrophosphonodifluoromethylation reaction of alkenes. Although there are several well-documented methods for introducing a difluorophosphonomethyl group at an sp3 carbon—including nucleophilic addition, transition-metal catalysis, photoredox catalysis, and radical addition (Scheme 1)—none of these methods have successfully been used to accomplish hydrophosphonodifluoromethylation. For example, anionic nucleophilic addition requires a strong base or a stoichiometric amount of metal to generate a difluorophosphonomethyl anion, and an electrophilic reagent is necessary.6 For transition-metal catalysis, the transition-metal species must undergo further functionalization after insertion of the M–CF2PO(OEt)2 group into the alkene double bond.7 Use of the radical-addition procedure usually results in halogen atom transfer radical addition, and therefore an additional step is necessary to remove the halogen atom.8 In photoredox catalysis, a PC*/PC+ (PC = photocatalyst) pathway (oxidative quenching) frequently leads to oxidation of the radical intermediate.9 In comparison with the many successful examples of hydrotrifluoromethylation reactions,10 there have been only a few reports of hydrophosphonodifluoromethylation reactions; these reactions require a Se/Sn reagent or UV irradiation and are applicable only to pure alkene or enol ether substrates.11 Because many pharmaceutical molecules bear a difluoromethane phosphate group, an efficient catalytic hydrophosphonodifluoromethylation protocol that is compatible with a variety of functionality is highly desirable.12 Herein we report that combining a thiyl-radical-catalyzed hydrogen atom transfer of a HE with
a
PC–/PC*
catalytic
cycle
provides
a
chemoselective
method
for
the
direct
hydrophosphonodifluoromethylation of alkenes. The method does not require strongly basic conditions, and direct installation of the hydrogen atom avoids the innate halogen atom transfer radical addition pathway. In addition, the substrate scope of the method shows good potential for use in pharmaceutical contexts.
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The Journal of Organic Chemistry
Results and Discussion Table 1. Optimization of Reaction Conditions
Entry Variation from optimized conditions a
a
Yield (%) b
1
None
99 (64)
2
fac-Ir(ppy)3 (1 mol %)
100
3
No photocatalyst
ND
4
No HSAcOMe
