Photoredox C-F Quaternary Annulation Catalyzed by a Strongly Reducing Iridium Species

Article abstract of DOI:10.1021/acscatal.7b03089

We report a fac-Ir(ppy)₃?-Ir^II-Ir^III photocatalytic cycle involving t-BuOK as the terminal reductant in a visible-light-induced sp² C-F quaternary annulation reaction that proceeds in yields up to 98%. Because of the high activity of the Ir^II(ppy)₃ catalyst, even at a loading of 50 ppm, the annulation reaction was able to compete with an uncatalyzed nucleophilic aromatic substitution reaction. The annulation reaction was stereoconvergent, and an annulated product was synthesized with complete retention of enantiomeric excess.

Full text of DOI:10.1021/acscatal.7b03089

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Letter
Photoredox C–F Quaternary Annulation Catalyzed
by a Strongly Reducing Iridium Species
Peng Dai, Junyu Ma, Wenhao Huang, Wenxin Chen, Na
Wu, Shengfu Wu, Ying Li, Xu Cheng, and Renxiang Tan
ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.7b03089 • Publication Date (Web): 22 Dec 2017
Downloaded from http://pubs.acs.org on December 22, 2017
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ACS Catalysis
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Photoredox C–F Quaternary Annulation Catalyzed by a Strongly
Reducing Iridium Species
a,b
b
b
b
b
b
b
Peng Dai , Junyu Ma , Wenhao Huang , Wenxin Chen , Na Wu , Shengfu Wu , Ying Li , Xu
b,c,d
a,c
Cheng *, Renxiang Tan *
a Institute of Functional Biomolecules, State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing,
2
10023 China
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b Institute of Chemistry and Biomedical Sciences, School of Chemistry and Chemical Engineering, Jiangsu Key Laboratory
of Advanced Organic Materials, Nanjing University, Nanjing, 210023 China
c State Key Laboratory Cultivation Base for TCM Quality and Efficacy, Nanjing University of Chinese Medicine, Nanjing,
2
10023 China
d State Key Laboratory of Elementoꢀorganic Chemistry, Nankai University, Tianjin, 300071, China
II
III
ABSTRACT: We report a facꢀIr(ppy) *ꢀIr ꢀIr photocatalytic cycle involving tꢀBuOK as the terminal reductant in a visibleꢀlightꢀ
3
2
II
induced sp C–F quaternary annulation reaction that proceeds in yields up to 98%. Because of the high activity of the Ir (ppy) cataꢀ
3
lyst, even at a loading of 50 ppm, the annulation reaction was able to compete with an uncatalyzed nucleophilic aromatic substituꢀ
tion reaction. The annulation reaction was stereoconvergent, and an annulated product was synthesized with complete retention of
enantiomeric excess.
Keywords: Annulation, C–F bond activation, quaternary alkylation, photocatalysis, stereoconvergence
II
III
In photoredox catalysis, the redox potentials of the photoꢀ
catalyst at various stages of the catalytic cycle are important
considerations in reaction design and mechanism elucidaꢀ
Ir ꢀIr pathway. For this purpose, we chose orthoꢀfluoro benꢀ
zamide 1a as a substrate, for several reasons (Scheme 1b).
First, if 1a reacted with tꢀBuOK directly, no SET process
would take place; a nucleophilic aromatic substitution reaction
would occur instead (Table 1, entry 5). Second, even though
[1]
tion. The use of transitionꢀmetal complexes and organic
[2]
molecules as photoredox catalysts is well documented.
[
10]
Among the former, facꢀIr(ppy) has been shown to have a
photoredox activation of C–F bonds in multifluoroarenes,
3
IV/III*
[11] [12]
strongly reducing excited state (E1/2
= −1.73 V vs SCE)
gemꢀdifluoroalkenes,
been reported, cleavage of a sole sp C–F bond (E
and a trifluoromethyl group
have
< −1.9
V vs SCE for 1a; see SI, section 15) remains a challenge and
IV
III
2
red
and to undergo oxidative quenching events in Ir*ꢀIr ꢀIr cataꢀ
1
/2
[
3]
lytic cycle. If excitedꢀstate facꢀIr(ppy) underwent a reducꢀ
3
II
II
III
tive quenching event, the resulting Ir species, which is even
requires novel chemistry such as Ir*ꢀIr ꢀIr catalysis. Third,
an annulation reaction of 1a would afford a fused ring system
in a single step.
III/II
more highly reductive (E1/2
= −2.19 V vs SCE), could be
used to achieve otherwise challenging reactions. However, the
III*/II
transfer of an electron to excitedꢀstate facꢀIr(ppy) (E
=
O
H
O
3
1/2
Ir*
HE
+
0.31 V vs SCE), requires a strong electron donor. Recently, a
EtO
OEt
series of reports showed that Hantzsch esters can initiate sinꢀ
II
III
a)
IrII
N
H
Numerous reports
IrIV
gleꢀelectron transfer (SET) processes that lead to Ir*ꢀIr ꢀIr
redox cycles resulting in various novel transformations.
[
4]
Hantzsch ester (HE)
Electron and hydrogen-
atom donor
However, because HEs are prone to aromatization, transfer of
a hydrogen atom from the HE to the product is frequently
coupled to the SET process (Scheme 1a). This behavior limits
the utility of HEs for reactions in which hydrogen atom transꢀ
fer leads to undesirable side products. Therefore, to take adꢀ
fac-IrIII(ppy)3
fac-Ir(ppy)3*
t-BuOK
O
F
O
This work
t-BuOK enabled Ir*/IrII pathway
sp2 C-F quaternary annulation
without hydrogen atom donation
b)
N
N
IrII
II
vantage of the high reduction potential of an Ir species withꢀ
2a
1a
out accompanying hydrogen atom transfer, a new reducing
partner for facꢀIr(ppy) is necessary.
3
Scheme 1. Role of fac-Ir(ppy) and reducing Partners.
3
It has been shown that tꢀBuOK can donate an electron to
various substrates with a complexing reagent, and this ability
We began by carrying out reactions of 1a in the presence of
tꢀBuOK and facꢀIr(ppy) under visible light irradiation (Table
3
has been used to accomplish a variety of novel transforꢀ
[5]
1). Systematic screening of various reaction parameters reꢀ
vealed that the optimum irradiation source was warm white
LEDs, which not only delivered light but also elevated the
mations, including C–C coupling reactions,
photoreacꢀ
[6]
[7]
tions, and C–X bond formation reactions. In addition, Li
and coꢀworkers reported homolytic aromatic substitution
[
13]
temperature (to 70 °C). Under these conditions, reaction in
THF afforded 2a in 93% isolated yield in 3 h (entry 1). If tꢀ
BuOK was replaced with t-BuONa, no reaction occurred, a
result that we attributed to the weaker ionization potential of tꢀ
BuONa relative to that of tꢀBuOK (entry 2). Weaker bases
such as cesium carbonate did not work either (entry 3). When
we used cold white light, which had no significant heating
effect, the GC yield dropped considerably (to 63%, entry 4). In
the absence of light or photocatalyst, 3, produced from 1a by
means of a nucleophilic aromatic substitution reaction, was the
(HAS) reactions that are mediated by tꢀBuOK/facꢀIr(ppy) and
3
IV
III
[8]
that proceed via an Ir*ꢀIr ꢀIr pathwayr,ed which suggests that
[9]
the reduction potential of tꢀBuOK (E1/2 = 0.10 V vs SCE)
may be sufficient to accomplish reverse electron transfer. To
explore this possibility, we carried out a study of a facꢀ
II
III
Ir(ppy) *ꢀIr ꢀIr cycle involving tꢀBuOK.
3
To begin our inquiry, we needed an appropriate model reacꢀ
tion that would allow us to distinguish between reaction inꢀ
IV
III
duced by tꢀBuOK alone, an Ir*ꢀIr ꢀIr pathway, and an Ir*ꢀ
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Solvents other than THF
Page 2 of 5
[
14]
only product (entries 5 and 6).
substituted compound 1m gave regioisomers 2m and 2m′ in
52% and 38% yields, respectively; and reaction of 1n in
MTBE gave 2n in 29% yield. Substrates with paraꢀhalogen
substituents (1i and 1n) were highly labile during this transꢀ
formation: dehalogenation lowered the yield of desired prodꢀ
ucts 2i and 2n, and the major side product was 2a. In contrast,
metaꢀhalogen substituents, like that in 1m, survived the reacꢀ
tion conditions intact.
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
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3
3
3
3
3
3
3
3
4
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4
4
5
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5
5
5
5
5
5
5
5
6
were evaluated. MTBE gave comparable results, but no reacꢀ
tion occurred in DCE or DMSO, a solvent used by Li et al in
their HAS reaction. (entries 7–9). The reaction required 12 h
when the catalyst loading was 50 ppm, and an 88% isolated
yield of 2a was obtained.
[
8]
Table 1. Optimization of C–F Quaternary Annulation
a
Conditions
a
Table 2. Substrate Scope of Annulation Reaction
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
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0
1
2
3
4
5
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0
1
2
3
4
5
6
7
8
9
0
Deviation from standꢀ
ard conditions
b
Entry
Yield (%)
1
2
3
4
None
t-BuONa
Cs CO
100 (93)
NR
NR
2
3
Cold white light
63
5
No light, 12 h
6
7
8
9
No Ir(ppy)3
MTBE
3 (11%)
98
DCE
NR
DMSO
NR
c
1
0
50 ppm Ir(ppy)3
99 (88)
a
Standard conditions: 1a (0.2 mmol, 0.1 M), tꢀBuOK (1.2 equiv),
facꢀIr(ppy) (1 mol %), 70 °C heated with warm white LEDs , in
3
b
sealed tube, 3 h. GCꢀMS yields are provided, with isolated
c
yields in brackets. NR, no reaction. 12 h.
With the optimized conditions in hand, we explored the reꢀ
actions of other substrates 1 with an ortho C–F bond (Table 2).
Substrates with electronꢀdonating groups on the phenyl ring
(
1b–1d)underwent the annulation reaction, furnishing the corꢀ
responding products in excellent yields. Bocꢀprotected aniline
derivative 1e was transformed to 2e almost quantitatively, and
this reaction could be scaled up to 4 mmol to afford 1.08 g
(79%) of 2e. Annulation of 2,6ꢀdimethyl piperidine 1f gave 2f
in 94% yield, and substrate 1g, in which the piperidine moiety
was replaced with a diisopropyl amine moiety, also underwent
the annulation reaction, giving 2g in excellent yield. When a
monomethylꢀsubstituted piperidine group was introduced to
the substrate (1h), the product of regioselective reaction at the
tertiary carbon, 2h, was obtained. When the substrate had two
fluoro atoms (1i), annulation was accompanied by cleavage of
the other C–F when the reaction was carried out in THF.
However, by switching the solvent to MTBE, we were able to
obtain 2i in 34% yield. In addition to fluoroꢀsubstituted subꢀ
strates, we also evaluated a series of orthoꢀchloroꢀsubstituted
amides in this reductive photoredox annulation reaction. Subꢀ
strate 1j was as reactive as 1a and afforded 2a in 92% yield.
ortho-Chloroꢀsubstituted amide 1k, which has Nꢀsecꢀbutyl and
methyl substituents, was prepared and then subjected to the
annulation reaction conditions; this substrate was less reactive
than 1j, and 2k was obtained in 20% yield with about 50%
dechlorination product in 12 hours. Reaction of naphthalene
compound 1l produced two regioisomers, 2l and 2l′. Dichloroꢀ
a
Standard conditions: 1 (0.2 mmol, 0.1 M), tꢀBuOK (1.2 equiv),
facꢀIr(ppy) (1 mol %), THF, 70 °C (heated with warm white
LEDs), in sealed tube, 3 h; isolated yields after chromatography
are provided. MTBE was used instead of THF. 12 hours.
3
b
c
Because orthoꢀbromo benzoic acids are widely available, we
evaluated the compatibility of our annulation protocol with
[
15]
various orthoꢀbromoꢀsubstituted compounds (Table 3). Reꢀ
action of 1o (in which the fluorine atom in 1a is replaced by
bromine) gave 2a in excellent yield. In addition, substrates
1p–1r could be transformed to the corresponding tricyclic
products with similar yields and site selectivities to fluoro
compounds. Thiophene substrate 1s gave only a 10% yield of
[
16]
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desired product 2s; the low yield may have been due to high
a)
2a
b)
t-BuOH
HAT
1
2
3
4
5
6
7
8
9
ringꢀstrain during annulation. The ring strain was partially
relieved in the case of substrate 1t, which gave 2t in slightly
higher yield (30%). The structure of 2u was determined by
means of Xꢀray crystallographic analysis, which revealed that
the two methyl groups were cis to each other. . Substrate 1v,
which bears a pyridine moiety was converted to 2v as the only
product in excellent yield. In contrast, the yield of pyridine 2w
was poor due to decomposition to unidentified side products.
1a
t-BuOK
2
2
1
.5
.0
.5
O
t-BuO
-
N
t-BuO
SET
Ir*
IrII
H C
F-
O
O
hv
N
N
H
SET
A
B
f ac-Ir(ppy)
3
1.0
F
O
a
N
Table 3. Reactions of ortho-Bromo Benzamides
0
200
400
600
800
n/n (quencher/Ir)
1
a
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
O
Br
O
R4
R4 t-BuOK/f ac-Ir(ppy)
R1
3
N
Scheme 2. Emission Quenching and Plausible Reaction
a
Pathway. Emission quenching of fac-Ir(ppy)
BuOK. Plausible reaction pathway.
N
R1
Warm white light
R2
O
R3
THF, 70 o
C
R2
2
R3
3
by 1a and t-
b
1
O
O
N
Br
O
N
chiral substrate 4 (86% ee) to the photoredox catalysis condiꢀ
tions, we obtained 2a in 90% yield with 86% ee, suggesting
that reversible deprotonation of the carbon alpha to the nitroꢀ
gen atom did not occur. In addition, we carried out several
derivatization reactions of products 2. Specifically, the amide
group in 2a was reduced with borane to give amine 5 in 66%
yield, and 2d was transformed to corresponding coupling
product 8 in 63% yield over three steps. Removal of the Boc
group of 2e with TFA furnished aniline 9.
N
N
2p (65%)
2p' (29%)
1p O
2a (90%)
Br
O
O
N
O
O
O
N
O
N
N
N
H
1
q
2q (60%)
2q' (20%)
2p (66%)
2p' (29%)
O
O
O
O
F
O
O
O
N
N
N
O
N
Table 1
entry 1
N
N
a)
N
S
S
O
O
O
2r(58%)
2r' (34%)
2s (10%)
2t (30%)
4, 86% ee
O
1a (90%, 86% ee)
8 (74%)
F
S
O
N
Pd(PPh
3 4
) (4 mol %)
K CO (3 equiv)
b)
N
O
N
BH
3
(7.0 equiv)
N
2
3
N
O
O
THF, reflux, 40h
S
N
N
B(OH)2
N
5 (66%)
(1.5 equiv)
DMF/H O (10:1)
10 oC, 12 h
2
a
F
0
.4 mmol
2
2
u (rac, 52%) X-ray
1
2u' (18%)
2v (90%)
2w (35%)
O
N
O
O
1
2
) Tf O (1.2 equiv)
c)
N
Pyridine (15 equiv)
DCM, overnight
a
BBr
3
(2.0 equiv)
N
Standard conditions: 1 (0.2 mmol, 0.1 M), tꢀBuOK (1.2 equiv),
DCM, rt
2
2
) Tf O (1.2 equiv)
facꢀIr(ppy) (1 mol %), THF , 70 °C (heated with warm white
3
HO
O
rt, 1h
TfO
2
d
6
LEDs), in sealed tube, 3 h; isolated yields after chromatography
are provided.
7 (85%, in two steps)
0
.4 mmol
O
O
N
TFA (8 equiv)
DCM, rt, 2h
N
II
To determine whether the reaction proceeded via an Ir*/Ir
d)
O
O
cycle, we performed a emissionꢀquenching experiment at 70
C (Scheme 2a). Substantial quenching of excitedꢀstate
N
HN
2e
1 mmol
9
(91%)
°
Ir(ppy) by tꢀBuOK was observed, and no significant interacꢀ
3
Scheme 3. Synthetic Applications.
tion between 1a and the photocatalyst was detected. On the
basis of this result, we suggest that the reaction proceeds via
In addition to the CꢀF quaternary annulation reaction, we
explored the application of this facꢀIr(ppy) /tꢀBuOK in other
reactions (Table 4). 3ꢀFluoropyridine 10a could couple with
benezen at 100 C with 100 W white LEDs, giving biaryl
product 11a in 91% isolated yield. 3,5ꢀDifluoropyridine 10b
was transformed to 11b in 47%. Another substrate 10c bearing
a chloro atom was subjected to this photoredox reaction and
coupling product 11c was achieved in 87% yield with the
the pathway shown in Scheme 2b. First, electron transfer from
II
3
t-BuOK to excitedꢀstate Ir(ppy) * gives an Ir species, which
3
then transfers an electron to substrate 1a. Subsequent mesolyꢀ
o
2
[17]
sis of 1a generates sp carbon radical A and fluoride anion.
Then an intramolecular 1,5ꢀH shift results in the formation of
3
sp carbon radical intermediate B, and subsequent addition of
the carbon radical to the phenyl ring affords annulated species
C. Finally, hydrogen atom transfer furnishes product 2a.
o
LEDs used in Table 2 at 70 C.
We also explored some synthetic applications of this annulaꢀ
tion protocol (Scheme 3). Because the Xꢀray structure of 2t
indicated that the reaction gave products with cis methyl
groups, we hypothesized that stereoselectivity could be
achieved with an appropriate substrate. When we subjected
Table 4 Intermolecular Coupling Reaction with fac-
a
Ir(ppy) /t-BuOK
3
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fac-Ir(ppy)3
t-BuOK
(2) Prier, C. K.; Rankic, D. A.; MacMillan, D. W. C. Chem. Rev.
2013, 113, 5322.
3) Monos, T. M.; Stephenson, C. R. J. In Iridium(III) in Optoelec-
tronic and Photonics Applications; ZysmanꢀColman, E., Eds.; John
Wiley & Sons, Ltd. New York, 2017; p 541.
Ar
Ar-X +
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
white LEDs
benzene
(
1
0
11
product
substrate
product
substrate
(
4) (a) Rono, L. J.; Yayla, H. G.; Wang, D. Y.; Armstrong, M. F.;
N
F
F
Knowles, R. R. J. Am. Chem. Soc. 2013, 135, 17735. (b) Zhang, J.;
Li, Y.; Zhang, F.; Hu, C.; Chen, Y. Angew. Chem., Int. Ed. 2016, 55,
1872. (c) Wang, C.; Harms, K.; Meggers, E. Angew. Chem., Int. Ed.
F
N
N
N
2
016, 55, 13495. (d) Lee, K. N.; Lei, Z.; Ngai, M.ꢀY. J. Am. Chem.
11b (47%)b
1
0a
11a (91%)
11b
Soc. 2017, 139, 5003.
(5) (a) Sun, C.L.; Li, H.; Yu, D.G.; Yu, M.; Zhou, X.; Lu, X.Y.;
Huang, K.; Zheng, S.F.; Li, B.J.; Shi, Z.J. Nat. Chem. 2010, 2, 1044.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
N
(
b) Shirakawa, E.; Itoh, K.I.; Higashino, T.; Hayashi, T. J. Am. Chem.
N
Cl
11c (87%)c
Soc. 2010, 132, 15537. (c) Liu, W.; Cao, H.; Zhang, H.; Zhang, H.;
Chung, K. H.; He, C.; Wang, H.; Kwong, F. Y.; Lei, A. J. Am. Chem.
Soc. 2010, 132, 16737. (d) Studer, A.; Curran, D. P., Angew. Chem.,
Int. Ed. 2011, 50, 5018.(e) Zhou, S.; Doni, E.; Anderson, G. M.;
Kane, R. G.; MacDougall, S. W.; Ironmonger, V. M.; Tuttle, T.;
Murphy, J. A., J. Am. Chem. Soc. 2014, 136, 17818. (f) Zhang, L.;
Yang, H.; Jiao, L., J. Am. Chem. Soc. 2016, 138, 7151. (g) For
intramolecular CꢀC coupling mediated by tꢀBuOK: Masters, K.S.;
Bräse, S., Angew. Chem., Int. Ed. 2013, 52, 866, and references cited
therein.
1
0c
a
Standard conditions: 10 (0.2 mmol), tꢀBuOK (1.2 equiv), facꢀ
Ir(ppy) (1 mol %), benzene, 100ꢀ104 °C (heated with 100 W
white LEDs), in sealed tube, 6 h; isolated yields after chromatogꢀ
raphy are provided. with facꢀIr(ppy) (5 mol %) and tꢀBuOK
3
b
3
c
o
(
2.5 equiv). 70 C with warm white LEDs.
II
III
In summary, we have described a facꢀIr(ppy) *ꢀIr ꢀIr phoꢀ
3
tocatalytic cycle involving tꢀBuOK, an electron donor that
does not also donate a hydrogen atom, as the terminal reductꢀ
ant. This chemistry was used to carry out intramolecular C–F
quaternary annulation reactions, which proceeded in yields up
to 98%. This reaction was stereoconvergent, and substrate
control could be used to achieve enantioenriched annulation
products by means of the efficient protocol. Intermolecular Cꢀ
F coupling was also achieved with this catalysis.
(
6) For tꢀBuOK mediated reaction with light irradiation: Xu, Z.;
Gao, L.; Wang, L.; Gong, M.; Wang, W.; Yuan, R., ACS Catal. 2015,
5
, 45, and references cited therein.
(7) For CꢀX bond formation mediated by tꢀBuOK: Liu, W.ꢀB.;
Schuman, D. P.; Yang, Y.ꢀF.; Toutov, A. A.; Liang, Y.; Klare, H. F.
T.; Nesnas, N.; Oestreich, M.; Blackmond, D. G.; Virgil, S. C.;
Banerjee, S.; Zare, R. N.; Grubbs, R. H.; Houk, K. N.; Stoltz, B. M. J.
Am. Chem. Soc. 2017, 139, 6867, and references cited therein.
(
8) Cheng, Y.; Gu, X.; Li, P. Org. Lett. 2013, 15, 2664.
(9) Yi, H.; Jutand, A.; Lei, A. Chem. Commun. 2015, 51, 545.
(10) (a) Senaweera, S. M.; Singh, A.; Weaver, J. D. J. Am. Chem.
Soc. 2014, 136, 3002. (b) Arora, A.; Weaver, J. D. Acc. Chem. Res.
2016, 49, 2273. (c) Meyer, A. U.; Slanina, T.; Yao, C.ꢀJ.; König, B.
ACS Catal. 2016, 6, 369. (d). Liu, X.; Wang, Z.; Zhao, X.; Fu, X.
Inorg. Chem. Front. 2016, 3, 861. (e) Xie, J.; Rudolph, M.; Rominger,
F.; Hashmi, A. S. K. Angew. Chem., Int. Ed. 2017, 56, 7266.
ASSOCIATED CONTENT
Corresponding Author
*
*
rxtan@nju.edu.cn
chengxu@nju.edu.cn
Notes
(
11) Xie, J.; Yu, J.; Rudolph, M.; Rominger, F.; Hashmi, A. S. K.
Angew. Chem., Int. Ed. 2016, 55, 9416.
12) Li, L.; Xiao, T.; Chen, H.; Zhou, L. Chem. Eur. J. 2017, 23,
2249.
(13) For details, see SI, general procedure E.
14) If t-BuONa was used instead of t-BuOK, no S
The authors declare no competing financial interests.
(
Supporting Information
Experimental procedures, characterization of new compounds,
NMR spectra, GC and HPLC traces, UV–vis spectra, fluorescence
spectra, and crystal data. The Supporting Information is available
free of charge on the ACS Publications website at
http://pubs.acs.org.
(
N
Ar reaction
took place. It was possible due to the weaker ionization of t-BuONa
than that of t-BuOK in THF.
(15) (a) For examples of C–Br alkylation reactions, see: Wertjes,
W. C.; Wolfe, L. C.; Waller, P. J.; Kalyani, D. Org. Lett. 2013, 15,
5
986. (b) Bhakuni, B. S.; Yadav, A.; Kumar, S.; Patel, S.; Sharma, S.;
Kumar, S. J. Org. Chem. 2014, 79, 2944. (c) Chen, J.Q.; Wei, Y.L.;
Xu, G.Q.; Liang, Y.M.; Xu, P.F. Chem. Commun. 2016, 52, 6455.
(16) The order of reactivity of 1a < 1j < 1o (F < Cl < Br) was obꢀ
served. For details, see SI, section 10.
(17) We found the 2,6ꢀdisubstitution on the piperidine ring is
important to ensure the reacitivity. The possible reason was the steric
effect could enhance the distortion of CꢀX bond from the plane of
arene to effect the fragmentation.
ACKNOWLEDGMENT
This work was supported by the National Science Foundation of
China (nos. 21572099 and 21332005) and the Natural Science
Foundation of Jiangsu Province (no. BK20151379). Collaboraꢀ
tiveꢀInnovation team funding was highly appreciated. This study
was supported by the Open Project of State Key Laboratory Culꢀ
tivation Base for TCM Quality and Efficacy, Nanjing University
of Chinese Medicine (No. TCMQ & E 201702)
REFERENCES
(
1) Skubi, K. L.; Blum, T. R.; Yoon, T. P. Chem. Rev. 2016, 116,
10035.
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