Organoselenium-Catalyzed Oxidative Allylic Fluorination with Electrophilic N-F Reagent

Article abstract of DOI:10.1021/acscatal.7b03829

An efficient route of organoselenium-catalyzed oxidative allylic fluorination has been developed. In this transformation, bulky electrophilic fluorinating reagent N-fluoro-2,4,6-trimethylpyridinium triflate (TMFP-OTf) was employed as the oxidant and fluorine source. Notably, TEMPO as an additive affects the fluorination and leads to better substrate scope and excellent functional group tolerance. By this protocol, a variety of allylic fluorides were synthesized in good to excellent yields. The obtained allylic fluorides could be converted into vinyl fluorides efficiently in the presence of an appropriate base.

Full text of DOI:10.1021/acscatal.7b03829

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Letter
Organoselenium-Catalyzed Oxidative Allylic
Fluorination with Electrophilic N–F Reagent
Ruizhi Guo, Jiachen Huang, and Xiaodan Zhao
ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.7b03829 • Publication Date (Web): 29 Dec 2017
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ACS Catalysis
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Organoselenium-Catalyzed Oxidative Allylic Fluorination with
Electrophilic N–F Reagent
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Ruizhi Guo, Jiachen Huang, and Xiaodan Zhao*
Institute of Organic Chemistry & MOE Key Laboratory of Bioinorganic and Synthetic Chemistry, School of Chemistry, Sun
Yat-Sen University, Guangzhou 510275, P. R. China
ABSTRACT: An efficient route of organoselenium-catalyzed oxi-
dative allylic fluorination has been developed. In this transfor-
R2
H
mation, bulky electrophilic fluorinating reagent N-fluoro-2,4,6-
trimethylpyridinium triflate (TMFP-OTf) was employed as the oxi-
dant and fluorine source. Notably, TEMPO as an additive affects
the fluorination and leads to better substrate scope and excellent
functional group tolerance. By this protocol, a variety of allylic
fluorides were synthesized in good to excellent yields. The obtained
allylic fluorides could be converted into vinyl fluorides efficiently
in the presence of an appropriate base.
F
RSeSeR (10 mol %)
TEMPO, N
R2
R1
R3
R1
R3
F
21 examples
up to 98% yield
N-F reagent as oxidant and fluorine source
KEYWORDS: selenium catalysis, alkene, electrophilic fluorinating reagents, fluorination, allylic reaction
(a) As the oxidant and nitrogen source
Owing to the occurrence of allylic fluoride moiety in pharma-
cat.
ceuticals and agrochemicals, efficient synthesis of allylic fluo-
rides has drawn considerable attention in the past decades.1,2 In
general, these molecules were prepared through allylic substi-
tution of prefunctionalized substrates.3 Considering step econ-
omy, methods for manipulating alkenes to directly construct
allylic fluorides via C–H bond cleavage are more attractive.4,5
In this scenario, a few distinct strategies via transition metal
catalysis have been developed recently. For example, Lectka
has disclosed a copper catalyzed C–H abstraction/fluorination
strategy to prepare allylic fluorides with electrophilic N–F
reagent as a fluorine source.5c Subsequently, an elegant work
of palladium catalyzed allylic C–H fluorination with
Et3N·3HF as a nucleophilic fluorinating reagent has been
demonstrated by Doyle.5d As a supplement, organocatalysis
strategy has been utilized in this allylic fluorination as well,
but successful examples are rare.5e-g Despite these important
advances, some drawbacks such as poor operational conven-
ience and narrow substrate scope remain. For the purpose of
synthetic divergence, developing new methods that allow effi-
cient allylic fluorination of diversified alkenes in a simple
operational way is highly desirable.
Electrophilic selenium catalysis (ESC) through selenenylation-
deselenenylation process has emerged as a powerful tool for
organic synthesis owing to its unique advantages including
simplicity for operation, mild conditions, and excellent regio-
and stereoselectivity.6-9 Particularly, the combination of ESC
and electrophilic N–F reagents in selective functionalization of
alkenes and dienes has been developed by our group and oth-
ers in the past few years.8,9 By this protocol, a variety of valu-
able compounds such as aminated and pyridinated compounds,
N- and O-heterocycles and dichlorides could be efficiently
accessed. In these transformations, N–F reagents served as the
N(SO2Ph)2
N(SO2Ph)2
RSeSeR
or
N-F reagent
cat.
RSeSeR
X-
N
N-F reagent
(b) Only as an oxidant
cat.
NuH
Nu
Nu
Nu
RSeSeR
n
or
or
3
2
3
N-F reagent
1
1
2
cat.
RSeSeR
Cl
N-F reagent
"Cl-"
Cl
(c) This work: As the oxidant and fluorine source
cat.
RSeSeR
F
H
reagent
N
F
TEMPO
Scheme 1. Application of N–F Reagents in Organoselenium
Catalysis
oxidant and nitrogen source (Scheme 1a)8a,d,9a or only as an
oxidant (Scheme 1b).8b,c,9b-e However, the employment of N–F
reagents as a fluorinating reagent in selenium catalysis is un-
precedented so far. Although selenium-catalyzed fluorination
with N–F reagents has been our goal, we have never observed
fluorinated products in our previous studies.8 We believed that
it was possible to achieve organoselenium-catalyzed oxidative
allylic fluorination using N–F reagents as the oxidant and fluo-
rine source based on the reports in the literature, in which an
active species [RSeF] in situ generated was utilized in the
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fluoroselenenylation of alkenes,10,11 and PhSe group could be
formed was selected as the model substrate (Table 1). Initially,
common N–F reagents such as Selectfluor, NFSI and FP-OTf
were tested in the presence of a catalytic amount of PhSeSePh
under N2 atmosphere. Not surprisingly, the desired product
was not formed at all (entries 1-3). Instead, some hydroxylated
and aminated byproducts were observed.7e,8d,9a Other commer-
cial available pyridinium derivatives were further evaluated.
However, highly reactive N-fluoro-2,6-dichloropyridinium
triflate (DCFP-OTf) afforded several unidentified fluorides
(entry 4). To our delight, the desired allylic fluoride 2a was
formed in 83% yield when N-fluoro-2,4,6-trimethylpyridinium
triflate (TMFP-OTf) was utilized as the oxidant (entry 5). This
result is in accordance with our assumption that bulky 2,4,6-
collidine concomitantly generated in the reaction is a weak
nucleophile and base so that the side reactions can be sup-
pressed and the fluorination occurs smoothly. After the suita-
ble oxidant was identified, several polar aprotic solvents were
screened to improve the fluorination (entries 6-9). The yield
was slightly better when ClCH2CH2Cl was used as the solvent
(entry 6). Furthermore, TMFP-BF4 was less effective due to
the low solubility of this reagent in ClCH2CH2Cl (entry 10).
Additional nucleophilic fluorine sources such as Et3N·3HF
and pyridine·HF led to lower yields or almost no desired
product (entries 11 and 12). When less PhSeSePh was em-
ployed, the desired product was decreased (entry 13) and no
product was detected in the absence of PhSeSePh (entry 14).
More N–F reagent slightly increased the yield (entry 15). It is
noteworthy that all the reactions had to be performed under N2
atmosphere to avoid the formation of hydroxylated byproduct.
When the reaction was run under air, the yield dramatically
dropped (entry 16).13 The concentration of reaction is also
important for the reactivity of fluorination. Lower concentra-
tion resulted in worse reactivity.
eliminated under certain oxidative conditions.12c,e,i
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In light of the literature, the implementation of allylic fluor-
ination through ESC was mainly plagued by three issues: (i) In
the stoichiometric fluoroselenenylation, the involved reactive
intermediate [RSeF] is unstable and has not been identified
yet.12 (ii) Nitrogen-containing groups from N–F reagents8d,9a
and trace water7e,9a in the reaction are strongly competitive
nucleophiles in contrast to F-. In the literature, high dosage of
nucleophilic fluorides had to be employed in order to promote
fluorination.11e,i If using N–F reagents, the amount of F- only
equivalent to catalyst could be generated and its concentration
may be too low to trigger the fluorination. (iii) The nucleo-
philicity of F- could be weakened by weak acid or H-bond
donor. To overcome these issues, a suitable oxidative system
that can not only generate the [RSeF] species smoothly but
also ensure the nucleophilicity of fluorine anion is crucial.
Very recently, we discovered that N-fluoro-2,4,6-
trimethylpyridinium salts can efficiently and solely serve as an
oxidant for organoselenium-catalyzed regioselective C(sp2)–H
pyridination of 1,3-dienes using exogenous pyridine sources
(Scheme 1a).8d Inspired by this result, we envisioned that
bulky N–F reagent might be an ideal candidate to serve as the
oxidant and fluorine source. Herein, we report a strategy to
construct allylic fluorides via organoselenium catalyzed oxida-
tive allylic fluorination of alkenes with bulky N–F reagent and
TEMPO (Scheme 1c).
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Table 1. Condition Evaluationa
H
F
PhSeSePh (10 mol %)
OMe
OMe
Ph
Ph
N-F reagent, additive
solvent, rt, 20 h
O
O
1a
2a
Me
Table 2. Effect of TEMPO in Allylic Fluorinationa
O O
Cl
Ph
Ph
N
S
S
N
N
Cl
Me
X
N
Cl
OTf
N
Me
N
O
O
2BF4
OTf
F
F
F
F
F
NFSI
Selectfluor
DCFP-OTf
FP-OTf
X = OTf, TMFP-OTf
BF4, TMFP-BF4
yield (%)b
entry
1
2
oxidant
Selectfluor
NFSI
additive
solvent
CH2Cl2
CH2Cl2
-
-
0
0
3
FP-OTf
-
CH2Cl2
0
4
5
6
7
8
9
10
11
12
13c
14d
15e
16 f
DCFP-OTf
TMFP-OTf
TMFP-OTf
TMFP-OTf
TMFP-OTf
TMFP-OTf
TMFP-BF4
TMFP-OTf
TMFP-OTf
TMFP-OTf
TMFP-OTf
TMFP-OTf
TMFP-OTf
-
-
-
-
-
-
-
CH2Cl2
CH2Cl2
ClCH2CH2Cl
CHCl3
MeCN
CH3NO2
ClCH2CH2Cl
ClCH2CH2Cl
ClCH2CH2Cl
ClCH2CH2Cl
ClCH2CH2Cl
ClCH2CH2Cl
ClCH2CH2Cl
0
83
84(85)
59
56
trace
52
47
trace
66
0
Et3N·3HF
pyridine·HF
-
-
-
-
aConditions: 1a (0.05 mmol), RSeSeR (10 mol %), TMFP-OTf
(0.1 mmol), TEMPO (0.025 mmol), ClCH2CH2Cl (350 μL), rt, 20
h, under N2 atmosphere. Yields indicated in the parenthesis were
obtained under the similar conditions without TEMPO (0.06
mmol TMFP-OTf was used). Yields were determined by 19F
NMR with PhCF3 as the internal standard.
86
22
aConditions: 1a (0.05 mmol), PhSeSePh (10 mol %), oxidant
(0.06 mmol), additive (0.10 mmol), solvent (350 μL), rt, 20 h,
b
under N2 atmosphere. Determined by 19F NMR with PhCF3 as
the internal standard. Isolated yield on 0.1 mmol scale is in the
With the above conditions in hand, we attempted to investi-
gate the substrate scope of this fluorination (see Supporting
Information). A variety of aryl-substituted olefinic esters were
successful to form the corresponding products in good yields
ranging from 67-88% under the conditions. However, when
the functional group tethering to the double bond on substrates
c
d
e
parenthesis. PhSeSePh, 5 mol %. No PhSeSePh. TMFP-OTf, 2
equiv. fUnder air.
To commence allylic fluorination, (E)-methyl 4-phenylbut-
3-enoate (1a) with ester group which can be further trans-
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ACS Catalysis
was changed to the other electron-withdrawing groups such as
diselenide catalyst C4 was used in order to obtain higher
yields. Sometimes reaction temperature was raised slightly to
consume all the starting materials (2e and 2m). It is noted that
fluorination of olefinic nitrile generated Z- and E-isomer prod-
ucts (2o, E/Z = 3:1), which is different from the cases of other
substrates. Furthermore, trisubstituted olefinic esters were
compatible with the conditions (2p-r, 74-77%). Alkyl-
substituted alkenes also underwent fluorination to give prod-
ucts efficiently (2s-u, 59-69%).14 Interestingly, when trifluo-
romethylsulfone 3 was treated with N–F reagent, cinnamyl
aldehyde (4) was obtained in excellent yield instead of allylic
fluoride (Eq. 1). Currently, the mechanism for the formation of
this aldehyde is not so clear.
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amide, sulfone, phosphonate and nitrile, the fluorination was
ineffective to occur and the desired products were obtained
only in trace or moderate yields. We realized that the fluorina-
tion of these substrates was suppressed presumably by the
inefficiency of turnover-limiting deselenenylation process.9e
To overcome this issue, various diselenides were evaluated in
order to accelerate the oxidation of selenide moiety in inter-
mediate. However, no distinct improvement was afforded (Ta-
ble 2) and the decomposition of diarylmethyl diselenides into
selenium was observed. In order to eliminate catalyst decom-
position, several additives were further screened and it was
found that allylic fluoride 2a could be generated in highest
yield when BnSeSeBn (C7) was combined with TEMPO (0.5
equiv) and TMFP-OTf (2 equiv) (Table 2). Other electron-rich
diselenides (2-MeOC6H4Se)2 (C4) and (3-MeOC6H4Se)2 (C5)
were effective under this condition as well (Table 2).
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Table 4. Synthesis of Vinyl Fluorides via Olefin Isomeriza-
tiona
F
F
DBU (20 mol %)
CH2Cl2, rt, 2 h
Ph
EWG
OMe
Ph
EWG
Table 3. Substrate Scope of Allylic Fluorinationa
2
5
Me
F
F
F
F
R2
H
F
R2
R1
O
C7 (10 mol %)
OBn
N
+
Ph
Ph
Ph
Ph
R1
R3
R3
TEMPO (0.5 equiv)
ClCH2CH2Cl, rt, 20 h
O
Me
N
Me
OTf
O
O
O
5c, 83%
5a, 99%
5b, 99%
1
2
F
TMFP-OTf
F
F
R =
F
2e, 77%b,c
2f, 88%
H,
2a, 92%
4-CF3,
4-F,
SO2Ph
5d, 99%b
Ph
CN
Ph
PO(OEt)2
5f, 98%
2-Me, 2b, 83%
OMe
4-Cl, 2g, 98%
4-Br
2c, 46%
5e, 86%
3-Me,
R
2h, 84%b,d
4-Ph 2d, 67%b
O
aConditions: 2 (0.08 mmol), DBU (0.016 mmol), CH2Cl2 (1.0
F
F
F
Me
mL), rt, 2 h. bTriethylamine (1 equiv) was used instead of DBU.
O(L-Menthyl)
O
OBn
N
Me
Ph
Ph
Ph
O
O
O
The obtained allylic fluorides are valuable building blocks
due to the convenient transformation of their double bond
moiety. For example, vinyl fluorides could be efficiently gen-
erated via olefin isomerization of the corresponding allylic
fluorides in the presence of an appropriate base (Table 4).15
Various phenyl-substituted vinyl fluorides with different pen-
dent functional groups were synthesized in excellent yields
through this process and only Z-isomer was observed (5a-f,
83-99%).
2k, 60%
2i, 97%
2j (dr = 1:1), 89%
F
F
F
O
N
Ph
R'
Ph
Ph
CN
2m, R' = SO2Ph, 97%b,c,e
2n, R' = PO(OEt)2, 59%b
O
O
2l, 74%
2o, 71% (E/Z = 3:1)b
Me
F
Me
F
Me
Me
F
OMe
OMe
OBn
OBn
OBn
Ph
Ph
O
O
O
2r, 74%b
2q, 77%b
2p, 76%
O
F
F
Me
F
N
O
Et
Me
O
O
2s, 59%b
2t, 68%b
2u, 69%b
aConditions: 1 (0.1 mmol), C7 (10 mol %), TMFP-OTf (0.2
mmol), TEMPO (0.05 mmol), ClCH2CH2Cl (500 μL), rt, 20 h,
b
c
under N2 atmosphere. C4 (10 mol%) was used. At 40 °C for 48
h. dReaction time, 48 h. eTMFP-OTf, 3 equiv.
F
Then, we turned our attention to elucidating the mechanism.
To exclude the possibility that TEMPO was oxidized by N–F
reagent to form oxoammonium salt which might serve as a co-
oxidant16,17 to affect the reaction, bench stable
[TEMPO+][TfO-] was tested. The yield of allylic fluoride 2a
was reduced to 56% when it was utilized as an additive instead
of TEMPO (Eq. 2). Further analysis of the equimolar mixture
of BnSeSeBn and TMFP-OTf was found that BnSeSeBn
mainly decomposed into selenium after 1 h and only 36% of
BnSeSeBn remained.18 However, more than twofold
BnSeSeBn was detected when the reaction with this mixture
was conducted in the presence of TEMPO (see Supporting
x
C7 (10 mol %)
Ph
SO2CF3
(1)
TMFP-OTf (1.2 equiv)
Ph
SO2CF3
TEMPO (0.5 equiv)
ClCH2CH2Cl (0.2 M)
rt, 20 h
3
Ph
O
4, 92%
Consequently, the substrate scope was refreshed under the
new conditions and became broader (Table 3). The fluorina-
tion of aryl-substituted olefinic esters, amides, sulfones, phos-
phonates and nitriles proceeded smoothly to afford the corre-
sponding products in moderate to excellent yields (2a-o, 46-
98%). For the formation of some products, electron-rich
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Information). These results disclose that free TEMPO as an
Corresponding Author
1
2
3
4
5
6
7
8
additive is possible to inhibit the deactivation of BnSeSeBn
during the fluorination. Then, we attempted to detect fluorose-
lenenylated intermediate in order to confirm the generation of
[RSeF] species indirectly. Intermediate 6 was observed in 20%
NMR yield when PhSeSePh (1.0 equiv), TMFP-OTf (1.2
equiv) and NaF (2 equiv) were added to the reaction (Eq. 3). If
NaF was absent, only trace 6 was observed.19 This evidence
shows that diselenide might undergo the Se-Se bond cleavage
to form [RSeF] in the initial of reaction.
*E-mail: zhaoxd3@mail.sysu.edu.cn
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
We thank Sun Yat-Sen University, the “One Thousand Youth
Talents” Program of China and the Natural Science Foundation of
Guangdong Province (Grant No. 2014A030312018) for financial
support.
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Se
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TMFP-OTf
TEMPO
Me
BnSeSeBn
TMFP-OTf
+ 2a
Me
OTf
2,4,6-collidine + BnSeOTf
Me
N
BnSeF
H
1a
2,4,6-collidine
F
+
Se
Ph
COOMe
Ph
COOMe
TfO-
F-
Se
Bn
Bn
F
I
III
2,4,6-collidine
TMFP-OTf
Fluorination
F
Ph
COOMe
II
SeBn
Scheme 2. Proposed Reaction Mechanism
Based on the mechanistic studies of this and previous
works,8d a possible mechanism is proposed (Scheme 2). The
reaction is initiated by the oxidative cleavage of diselenide to
generate electrophilic [BnSeF] and BnSeOTf. The species
[BnSeF] reacts with olefinic ester 1a to form seleniranium ion
I. After ring-opening by the nucleophilic attack of fluorine
anion, fluoroselenenylated intermediate II is formed. Then,
oxidation of the BnSe group on II by TMFP-OTf leads to the
formation of intermediate III. The desired product 2a and
[BnSeF] are generated after subsequent H-elimination with the
assistance of weak base. The role of TEMPO is possible to
inhibit the decomposition of BnSeSeBn to selenium that is
incompetent to trigger the fluorination. It is noted that the ini-
tiation of the reaction via Se(IV) species cannot be ruled out
although the fluorination via Se(II) species is more reasonable.
In summary, we have disclosed a new route to synthesize
allylic fluorides with bulky electrophilic TMFP-OTf through
electrophilic selenium catalysis (ESC). The N–F reagent
serves as the oxidant and fluorine source. The combination of
electron-rich diselenide with TEMPO improves the reactivity
of fluorination, and is crucial for the excellent functional
group tolerance and better substrate scope.
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ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: XXX
Experimental details, characterization data, mechanistic
studies and NMR spectra of new compounds.
AUTHOR INFORMATION
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(18) Usually, BnSeSeBn was observed after our catalytic reactions
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failed to occur when selenium was employed as the catalyst instead of
diselenide.
(19) It failed to trap fluoroselenenylated intermediate with
BnSeSeBn due to the instability of the intermediate.
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