Synthesis of monofluorooxazoles with quaternary C-F centers through photoredox-catalyzed radical addition of methylene-2-oxazolines

Article abstract of DOI:10.1039/d0ob00267d

A novel photoredox-catalyzed radical addition of methylene-2-oxazolines has been developed under visible light irradiation to synthesize monofluorooxazoles with a quaternary carbon center using 2-bromo-2-fluoro-3-oxo-3-phenylpropionates as radical source. This method with a simple protocol, scalability and high yield offers a facile path to get diverse monofluorinated oxazoles with quaternary C-F centers, which are a class of highly valuable motifs and synthons.

Full text of DOI:10.1039/d0ob00267d

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Synthesis of monofluorooxazoles with quaternary C‐F centers
through photoredox‐catalyzed radical addition of methylene‐2‐
oxazolines
Received 00th January 20xx,
Accepted 00th January 20xx
Gui‐Ting Song,†a,b Chuan‐Hua Qu,†,a Jin‐Hong Chen,a Zhi‐Gang Xu,a Cheng‐He Zhou,*,b and Zhong‐
DOI: 10.1039/x0xx00000x
Zhu Chen*,a
A novel photoredox‐catalyzed radical addition of methylene‐2‐
oxazolines has been developed under visible light irradiation to
synthesize monofluorooxazoles with a quaternary carbon center
using 2‐bromo‐2‐fluoro‐3‐oxo‐3‐phenylpropionates as radical
source. This method with simple protocol, scalability and high yield
offers a facile path to get diverse monofluorinated oxazoles with
quaternary C‐F centers, which are a class of highly valuable motifs
and synthons.
The most prescribed, best performing, and bestselling drugs are
usually those fluorine‐containing pharmaceutical agents.1 Indeed,
the selective incorporation of fluorine into organic compounds
generally leads to an improved membrane permeability and higher
stability toward oxidative degradation,2,3 thus arousing a great
interest in the synthesis of fluorine‐containing compounds.4 In
particular, compounds with a quaternary C‐F center are of high
pharmaceutical potential.1a,b,5 Therefore, the synthesis of
monofluoro compounds containing quaternary carbon centers has
attracted the attention of many synthetic chemists.6 However, there
are still very limited approaches to allow the catalytic synthesis of C‐
F quaternary carbons. Thus, it would be highly desirable to develop
a novel alternative method for preparing compounds with C‐F
quaternary carbon centers. Notably, oxazole is an important
heterocycle present in a variety of natural products and biologically
active compounds,7 as exemplified by anti‐diabetic agent AD‐5061,8a
anti‐mycobacterial texaline8b as well as anti‐inflammatory8c and
bronchodilator 4‐aminooxazoles8d (Figure 1). Consequently, the
combination of a C‐F quaternary carbon center and an oxazole unit
through photoredox catalyzed monofluoroalkylation of methylene‐
2‐oxazolines could enrich the diversity of oxazoles, which in turn
could provide novel bioactivities for drug discovery campaign.
Fig.1 Representative biologically active molecules containing oxazole
motif.
Carbon‐carbon bond formation plays a pivotal role in synthetic
organic and medicinal chemistry, and accordingly, many protocols to
construct new carbon‐carbon bonds have been developed. One of
the unique protocols for catalytic C‐C bond construction is
photoredox catalyzed radical addition with π acceptors, such as
alkenes, arenes, alkynes, isocyanides, and imines.9 The protocol is
mild and versatile, and typically produces carbon radical quickly at
room temperature. Although various carbon radicals have been
adopted to this conversion, the 2‐fluoro‐3‐oxo‐3‐phenylpropanoate‐
type radical has rarely been reported to undergo such
transformation. In our previous work, we developed an electron
catalyzed radical cyclization of methylene‐2‐oxazolines protocol
a. College of Pharmacy, National & Local Joint Engineering Research Center of
Targeted and Innovative Therapeutics, Chongqing Key Laboratory of Kinase
Modulators as Innovative Medicine, Chongqing University of Arts and Sciences,
Chongqing 402160, China.
b. Institute of Bioorganic & Medicinal Chemistry, Key Laboratory of Applied Chemistry
of Chongqing Municipality, School of Chemistry and Chemical Engineering,
Southwest University, Chongqing 400715, China.
Scheme 1 Cascade C(sp3)‐CF and aromatization of methylene‐2‐
oxazolines.
† These authors contributed equally.
Electronic Supplementary Information (ESI) available: Experimental details and
spectroscopic characterization information. See DOI:10.1039/x0xx00000x
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Journal Name
(Scheme 1a).10a In line with our interest in the development of 1, entry 9), we examined the substrate scope of methylene‐2‐
methods for the synthesis of fluoroorganic compounds,10 herein, we oxazolines 1 and 2‐bromo‐2‐fluoro ‐3‐oxo‐3‐phenylpropanoate 2a.
report an unprecedented approach towards the synthesis of As shown in Scheme 2, the presence of a substituent on the aryl ring
fluorinated oxazole with a quaternary C‐F center using ethyl 2‐ of methylene‐2‐oxazolines 1 had no significant effect for reaction
bromo‐2‐fluoro‐3‐oxo‐3‐phenylpropanoate as radical CFR1R2 source yield. The reaction of methylene‐2‐oxazolines 1 with an electron‐
via
aromatization of methylene‐2‐oxazolines (Scheme 1b). This strategy at the para position furnished the corresponding products 3a‐e with
provides a facile approach to highly‐valued oxazole derivatives. 71‐83% yields. Gratifyingly, methylene‐2‐oxazolines possessing
a photoredox catalyzed tandem radical addition and donating group, electron‐withdrawing group or just hydrogen atom
At the outset, the reaction of methylene‐2‐oxazoline 1a with ethyl various halogens (such as fluorine, chlorine, bromine, iodine) with
2‐bromo‐2‐fluoro ‐3‐oxo‐3‐phenylpropanoate 2a was chosen as a various substitution patterns were well‐compatible, and the desired
model system to optimize the reaction conditions (Table 1). A products 3f‐3i could be obtained in moderate to good yields. It was
mixture of 1a and 2a in dichloromethane was exposed to 1 mol% fac‐ worth noting that methylene‐2‐oxazolines derived from polycyclic
Ir(ppy)3 in the presence of Na2CO3 at room temperature under visible arenes 3j were also well‐tolerated. It was noteworthy that heteroaryl
light irradiation. The desired product 3a was then isolated in 78% derived methylene‐2‐oxazolines were also good substrates for this
yield along with the cyclization product 3a' (Table 1, entry 1). transformation (3k‐3m). Alicyclic substituted methylene‐2‐
Because of this promising result, screening of various solvents oxazolines could also serve as efficient reaction partners and
indicated that other solvents (such as (CH2)Cl2, DMF, DMA, THF, and furnished the corresponding monofluoroalkylated oxazoles 3n and
MeCN) also worked well, but the yields are lower (Table 1, entries 2‐ 3o in good yields.
6). The screening of bases showed that K3PO4 was the best with 80%
yield (Table 1, entry 9). Other bases such as K3CO3, Cs2CO3, KOAc and
NaBF4 were less effective (entries 7‐8 and 10‐11). Control
Table 2 Scope with respect to methylene‐2‐oxazolinesa,b
experiments indicated that visible light irradiation, photocatalyst and
base were critical for this transformation (Table 1, entries 12‐14). The
reaction could not proceed smoothly when other photocatalysts
were tested (Table 1, entries 15‐17).
O
O
Table 1 Optimization of reaction conditionsa
3a, R=CH3, 80%
3b, R=H, 71%
3c, R=F,
83%
F
F
Br
O
COOEt
O
COOEt
3d, R=Cl, 77%
3e, R=CF3, 79%
N
N
R
3f, 76%
O
O
O
Entry
Photocatalyst
Solvent
Base
Yield(3a)b Yield(3a')b
F
F
F
F
O
Cl
O
O
O
COOEt
COOEt
COOEt
I
1
2
3
4
fac‐Ir(ppy)3
fac‐Ir(ppy)3
fac‐Ir(ppy)3
fac‐Ir(ppy)3
CH2Cl2
(CH2)2Cl2
DMF
Na2CO3
Na2CO3
Na2CO3
Na2CO3
78%
71%
46%
42%
16%
13%
trace
trace
N
N
N
Cl
F
3g, 68%
3i, 61%
3h, 71%
O
O
DMA
O
5
6
7
8
9
10
11
12c
13
14
15
fac‐Ir(ppy)3
fac‐Ir(ppy)3
fac‐Ir(ppy)3
fac‐Ir(ppy)3
fac‐Ir(ppy)3
fac‐Ir(ppy)3
fac‐Ir(ppy)3
fac‐Ir(ppy)3
\
THF
Na2CO3
Na2CO3
K2CO3
Cs2CO3
K3PO4
KOAc
NaBF4
K3PO4
K3PO4
\
75%
73%
69%
47%
80%
74%
48%
trace
trace
<20%
trace
<10%
<10%
20%
17%
<10%
<10%
trace
\
F
O
N
F
COOEt
F
O
COOEt
O
COOEt
MeCN
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
O
N
N
O
S
O
3j, 69%
3l,
67%
3k, 63%
O
O
O
F
O
N
COOEt
F
O
COOEt
F
O
COOEt
\
\
\
N
N
N
fac‐Ir(ppy)3
[Ru(bpy)3]PF6
[IrdF(CF3)(ppy)2(dtb
bpy)]PF6
3m, 62%
3n, 84%
3o, 85%
K3PO4
aUnless otherwise noted, all reactions were performed with 1 (0.2 mmol), 2a
(0.3 mmol), fac‐Ir(ppy)3 (1 mol%) and K3PO4 (0.4 mmol) in CH2Cl2 (1 mL) under
33W fluorescent light bulb at room temperature with Ar atmosphere for 12‐
24 h. bYields are reported for the isolated products based on 1.
16
17
CH2Cl2
CH2Cl2
K3PO4
K3PO4
<10%
trace
\
\
Eosin Y
aUnless otherwise noted, all reactions were performed with 1a (0.2 mmol),
2a (0.3 mmol), base (0.4 mmol) and photocatalyst (1.0 mol%) in solvent (1.0
mL) under 33W fluorescent light bulb at room temperature with Ar
atmosphere for 12 h. bIsolated yield based on 1a. cIn the dark.
Next, the substrate scope of keto esters
2 was explored to
examine their applicability in our system (Scheme 3). Keto
esters with various halogens, such as fluorine, chlorine,
bromine, iodine, which were useful modules for further
functionalization, were well‐compatible, and the desired
With the optimized reaction conditions for the synthesis of
fluorinated oxazole containing a quaternary C‐F center in hand (Table
2 | J. Name., 2012, 00, 1‐3
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products 4a‐4d could be obtained in 66% to 81% yields. alkyl radical II. At this stage, intermediate II is oxidized to the β‐
Electron‐donating methyl at the para or meta position monofluoroalkylated carbocation intermediate III by fac‐[Ir4+(ppy)3]
proceeded well with 1a to deliver the expected products 4e and (+0.77V vs. SCE in CH3CN). Ultimately, monofluoroalkylated oxazole
4f in 72% and 76% yield, respectively. The reaction also 3a is formed by deprotonation in the presence of base. Alternatively,
occurred smoothly with methyl ketoate to obtain product 4g in intermediate II would also proceed through a radical cyclization
77% yield. Especially, keto ester with heteroaromatic ring was pathway, with concomitant production of the cyclohexadienyl
also effective in undergoing the radical reaction to deliver 4h
.
radical IV. Further SET‐oxidation and deprotonation will give product
Importantly, this transformation was scalable. The reaction 3a'. In addition, radical chain mechanism could not be ruled out. The
of 1a (0.52 g) with 2a (1.3 g) was conducted under the standard intermediate II could transfer one electron (SET) to the bromo
conditions, providing 3a (0.99 g) in the isolated yields of 87%, derivative forming the radical I and the intermediate III.
demonstrating that this process is practical and reliable
(Scheme 2, eqn.(1)).
Table 3 Scope with respect to monofluorobromoacyl arenesa,b
Scheme 2 (1) Gram‐scale reaction and (2) radical trapping experiment.
aUnless otherwise noted, all reactions were performed with 1a (0.2 mmol), 2
(0.3 mmol), fac‐Ir(ppy)3 (1.0 mol%) and K3PO4 (0.4 mmol) in CH2Cl2 (1.0 mL),
under 33W fluorescent light bulb at room temperature with Ar atmosphere
Scheme 3 Proposed mechanism.
for 12‐24 h. bYields are reported for the isolated products based on 1a.
In conclusion, an efficient methodology of the photoredox‐
catalyzed monofluoroalkylation of methylene‐2‐oxazolines via
tandem radical addition and aromatization has been developed. This
To shed light on the reaction mechanism, we conducted a radical
trapping experiment with the presence of the radical scavenger
2,2,6,6‐tetramethylpiperdine 1‐oxyl (TEMPO). When this radical
inhibitor TEMPO was introduced into a solution of methylene‐2‐
oxazoline 1a, keto ester 2a, K3PO4, and the photocatalyst fac‐Ir(ppy)3
in CH2Cl2, the reaction was completely inhibited, which indicates that
a radical process is operating (Scheme 2, eqn.(2)).
Based on our findings and previous studies,9a,10a,11 a mechanism
for the monofluoroalkylation of methylene‐2‐oxazolines was
proposed (Scheme 3). Initially, irradiation of the heteroleptic fac‐
[Ir3+(ppy)3] with visible light results in a metal to ligand charge‐
transfer (MLCT) process, which furnishes an excited state fac‐
[Ir3+(ppy)3]*, which can undergo oxidative quenching in the presence
of α‐bromo‐α‐monofluoro keto ester as an appropriate electron
acceptor via a single electron transfer (SET) process with the
formation of the strongly oxidizing fac‐[Ir4+(ppy)3] and radical I.
Subsequently, the electrophilic radical I will attack the carbon–
carbon double bond of the methylene‐2‐oxazoline 1a to give the oxy‐
method provides
a
facile path to diverse substituted
monofluorinated oxazoles with quaternary C‐F centers, which are a
class of highly valued structural motifs and novel synthons. The
synthesis proceeds rapidly under visible light irradiation and
demonstrated a broad substrate scope with high functional group
compatibility. Further applications of α‐monofluoro keto ester
radicals in organic synthesis are underway in our laboratory.
Acknowledgements
We gratefully acknowledge the Science and Technology Research
Program of Chongqing Municipal Education Commission
(KJQN201901345, KJQN201901346), Chongqing Natural Science
Foundation Postdoctoral Science Foundation Project (cstc2019jcyj‐
bshX0053), and the Scientific Research Foundation of the Chongqing
University of Arts and Sciences (R2019FXY11).
This journal is © The Royal Society of Chemistry 20xx
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Li, Z. Chen and Z. Xu, Org. Lett., 2019, 21, 8169; (c) C. Qu, P.
Conflicts of interest
There are no conflicts to declare.
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4 | J. Name., 2012, 00, 1‐3
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Synthesis of monofluorooxazoles with quaternary C-F centers through
photoredox-catalyzed radical addition of methylene-2-oxazolines
Gui-Ting Song,†a,b Chuan-Hua Qu,†a Jin-Hong Chen,a Zhi-Gang Xu,a Cheng-He Zhou,b,* and
Zhong-Zhu Chena,*
A photoredox-catalyzed radical addition of methylene-2-oxazolines has been developed under
visible light irradiation to synthesize monofluorooxazoles with quaternary C-F centers using 2-
bromo-2-fluoro-3-oxo-3-phenylpropionates as radical source.
EtOOC
F
O
fac-Ir(ppy)3
R2
Br
radical addition
O
+
O
O
COOEt
F
N
R1
N
R1
R2
cascade pathway
mild condition
a quaternary C-F center construction
excellent reaction selectivity