Domino-Fluorination-Protodefluorination Enables Decarboxylative Cross-Coupling of α-Oxocarboxylic Acids with Styrene via Photoredox Catalysis

Article abstract of DOI:10.1021/acs.joc.7b01054

Domino-fluorination-protodefluorination decarboxylative cross-coupling of α-keto acids with styrene has been developed via photoredox catalysis. The critical part of this strategy is the formation of the carbon-fluorine (C-F) bond by the capture of a carbon-centered radical intermediate, which will overcome side reactions during the styrene radical functionalization process. Experimental studies have provided evidence indicating a domino-fluorination-protodefluorination pathway with α-keto acid initiating the photoredox cycle. The present catalytic protocol also affords a novel approach for the construction of α,β-unsaturated ketones under mild conditions.

Full text of DOI:10.1021/acs.joc.7b01054

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Article
Domino-fluorination-protodefluorination enables decarboxylative cross-
coupling of #-oxocarboxylic acids with styrene via photoredox catalysis
Muliang Zhang, Junwei Xi, Rehanguli Ruzi, Nan Li, Zhongkai Wu, Weipeng Li, and Chengjian Zhu
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.7b01054 • Publication Date (Web): 15 Aug 2017
Downloaded from http://pubs.acs.org on August 16, 2017
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The Journal of Organic Chemistry
Dominoꢀfluorinationꢀprotodefluorination enables decarboxylaꢀ
tive crossꢀcoupling of αꢀoxocarboxylic acids with styrene via phoꢀ
toredox catalysis
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Muliang Zhang,† Junwei Xi,† Rehanguli Ruzi,† Nan Li,† Zhongkai Wu,† Weipeng Li,† Chengjian Zhu*†‡
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† State Key Laboratory of Coordination Chemistry, Jiangsu Key Laboratory of Advanced Organic Materials, School of
Chemistry and Chemical Engineering, Nanjing University, Nanjing 210093, China
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‡State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Shanghai 200032, Chiꢀ
na. Eꢀmail: cjzhu@nju.edu.cn
RECEIVED DATE (to be automatically inserted after your manuscript is accepted if required according to the
journal that you are submitting your paper to)
ABSTRACT
Domino-fluorination-protodefluorination enables decarboxylative cross-coupling
O
base, cat. Ir
Selectfluor
O
Ar1
Ar2
+
Ar1
Ar2
OH
Blue LEDs
O
54 - 84% yield
Strategy: photoredox catalysis combined with radical fluorination
Dominoꢀfluorinationꢀprotodefluorination decarboxylative crossꢀcoupling of αꢀketo acids with styrene has been deꢀ
veloped via photoredox catalysis. The critical part of this strategy is the formation of the carbonꢀfluorine (CꢀF) bond by
the capture of a carbonꢀcentered radical intermediate, which will overcome side reactions during the styrene radical
functionalization process. Experimental studies have provided evidence indicating a dominoꢀfluorinationꢀ
protodefluorination pathway, with αꢀketo acid initiating the photoredox cycle. The present catalytic protocol also afꢀ
fords a novel approach for the construction of α,βꢀunsaturated ketones under mild conditions.
INTRODUCTION
Carboxylic acids are widely available in great structural diversity, and their conversion into valuable chemical prodꢀ
ucts such as bioactive natural compounds and biofuels represents an important goal.1 Accompanied by a latent and easꢀ
ily removable carboxylate group to direct reactivity,2 carboxylic acids have been extensively developed to engage this
kind of compounds in new catalytic organic transformations.3 Since Myers first reported palladium catalyzed decarꢀ
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boxylative Heckꢀtype olefination (Scheme 1 A),4 transitionꢀmetalꢀcatalyzed decarboxylative coupling reactions have
been wellꢀdeveloped for modern organic synthesis.5 While broadly used, most of the reactions still require high temꢀ
perature, strong oxidant and harsh reaction conditions, which are often incompatible with many sensitive functional
groups. Radical reactions are also widely used to construct carbonꢀcarbon (CꢀC) or carbonꢀheteroatom (CꢀHet) bonds
in organic synthesis.6 In particular, electrophilic fluorine sources Nꢀfluorobenzenesulfonimide (NFSI) and Selectfluor
can effectively fluorinate alkyl radicals, compared to the traditional methods for fluorine incorporation,7 and elegant
solutions to introduce fluorine into a carbon skeleton structure using a free radical strategy have been reported (Scheme
1 B).8 Meanwhile, visibleꢀlight mediated photoredox catalysis has emerged as a valuable platform for its unique ability
to induce single electron transfer (SET) processes that allow the invention of many significant new chemical reactions.9
The application of this strategy to radical decarboxylation functionalization has led to the discovery of novel reactiviꢀ
ties and improved reaction conditions.10
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Scheme 1. A) Palladium catalyzed decarboxylative Heckꢀtype olefination. B) Free radical methods for fluorine incorꢀ
poration. C) Our strategy for photoredox catalysis decarboxylative crossꢀcoupling combined with radical fluorination.
Prompted by the effectiveness of these two kinds of catalytic modes, we recognized that a novel decarboxylative
crossꢀcoupling strategy could be achieved via an alternative mechanistic pathway. We wondered whether attempts to
combine photoredox catalysis with radical fluorination resulted in a direct and mild route to α,βꢀunsaturated ketones
by decarboxylative coupling of simple αꢀketo acids and styrene, a transformation that to our knowledge has not yet
been described (Scheme 1 C). The critical part of this strategy is the formation of a new CꢀF bond by the capture of a
carbonꢀcentered radical intermediate derived from radical addition and unique challenges with regard to unproductive
oxidation,11 dimerization12 and nucleophilic trapping13 during the styrene functionalization process are well addressed
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by fluorine atom transfer from Selectfluor to the benzylic radical. In addition, decarboxylation of αꢀketo acids produces
acyl radicals without the aid of other reagents.14 Sequential elimination of hydrogen fluoride offers doubleꢀbond formꢀ
ing events because of the presence of a driving force to generate conjugated system. Moreover, a variety of naturally
occurring and manꢀmade compounds that show extraordinary biological and pharmacological activity (e.g., anticancer,
antimicrobial, antioxidant, antiinflammatory) are in possess of α,βꢀunsaturated ketone core structures.15 Based on our
interest in photocatalytic research,16 we herein detail the successful execution of this design principle, and present a
new mechanism for the production of α,βꢀunsaturated ketones under mild reaction conditions.
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RESULTS AND DISCUSSION
We first explored this dominoꢀfluorinationꢀprotodefluorination decarboxylative crossꢀcoupling reaction of benzoꢀ
ylformic acid 1a with 4ꢀmethylstyrene 2b in the presence of the photocatalyst facꢀIr(ppy)3 (I), Selectfluor and Na2HPO4
at room temperature. To our delight, we observed the formation of the desired ketone product 3a (Table 1, entry 1,
23% yield) in a 1:1 mixture of H2O/CH3CN (0.1 M) under irradiation with visible light from blue LEDs (5 W, λmax
=
455 nm). Encouraged by this promising result, we then screened a series of photocatalysts (I ꢀ IV) and found
Ir[dF(CF3)ppy]2(dtbbpy)PF6 (IV) was designated as the suitable one with 54% yield (entries 2 ꢀ 4). Examination of a
range of bases revealed that two equivalents of sodium acetate was superior (81% yield) with respect to reaction effiꢀ
ciency (entries 5ꢀ8). When we used other fluorine sources such as NFSI, no desired product could be observed (entry
9). The key role of water and acetonitrile as the solvent mixture was shown when either of these two solvents were
used independently (entries 10 and 11). Finally, control experiments confirmed the requirement of a photocatalyst, and
a light source in this new decarboxylative crossꢀcoupling protocol (entries 12 and 13).
Table 1. Optimization studies.a
entry
photocat.
base
F source
Selectfluor
Selectfluor
Selectfluor
Selectfluor
Selectfluor
Selectfluor
Selectfluor
Selectfluor
NFSI
solvent
yieldb
23
34
20
54
43
18
81
64
0
1
2
3
4
5
6
7
8
9
I
Na2HPO4
Na2HPO4
Na2HPO4
Na2HPO4
NaHCO3
Na2CO3
NaOAc
CH3CN/H2O
CH3CN/H2O
CH3CN/H2O
CH3CN/H2O
CH3CN/H2O
CH3CN/H2O
CH3CN/H2O
CH3CN/H2O
CH3CN/H2O
II
III
IV
IV
IV
IV
IV
IV
K2HPO4
NaOAc
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10
11
IV
IV
NaOAc
NaOAc
NaOAc
NaOAc
Selectfluor
Selectfluor
Selectfluor
Selectfluor
CH3CN
H2O
34
0
1
2
3
4
12
none
IV
CH3CN/H2O
CH3CN/H2O
12
0
13c
5
6
7
8
[a] The reactions were carried out with 1a (0.2 mmol), 2b (0.4 mmol, 2.0 equiv), base (0.4 mmol, 2.0 equiv), photocatalyst (0.002 mmol, 2
mol %), solvent (2 mL), Selectfluor (0.5 mmol, 2.5 equiv), at room temperature, 5 W blue LEDs, 36 h. [b] Isolated yields. [c] Reaction
performed in the absence of light. [d] I = facꢀIr(ppy)3, II = Ir(ppy)2(dtbbpy)PF6, III = Ru(bpy)3(PF6)2, IV = Ir[dF(CF3)ppy]2(dtbbpy)PF6.
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With the optimized reaction conditions shown above, we studied other substrates in this dominoꢀfluorinationꢀ
protodefluorination decarboxylative crossꢀcoupling of αꢀketo acids and styrene. First, the scope of the αꢀoxocarboxylic
acid substrate was investigated (Scheme 2). As for the effect of electronic properties of the substituents on the phenyl
ring, benzoylformic acids bearing an electronꢀrich group (4ꢀmethyl or 4ꢀmethoxyl) yielded α,βꢀunsaturated ketones 3b
and 3c smoothly, and electronꢀdeficient (4ꢀhalogen substituents or 4ꢀtrifluoromethyl) acid derivatives yielded desired
products (3d–h) in yields of 61 – 78%. The substrate with aryl iodide functional group sensitive to transitionꢀmetal
catalysis remained intact in this reaction (3g), which provides the possibility for further functionalization. Metaꢀ(methyl,
methoxyl, bromo) substituted αꢀoxo acids were similarly found to be suitable substrates for this transformation and
gave the desired ketones (3iꢀk) in good yield. For the orthoꢀsubstituted or sterically bulky substrate, the reaction delivꢀ
ered the corresponding products (3m and 3n) with 80% and 84% yields, respectively, which may be due to radical reꢀ
action. Moreover, when heterocyclic 2ꢀfuranyl, 2ꢀthienyl, and 2ꢀnaphthylꢀsubstituted αꢀoxo acids were used, the unꢀ
saturated ketones (3oꢀq) were also obtained.
Scheme 2. Scope of αꢀketo acid in this decarboxylative crossꢀcoupling reaction
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O
Me
Ir[dF(CF3)ppy]2(dtbbpy)PF6
NaOAc, Selectfluor
1
2
3
4
5
6
7
O
+
R
OH
O
R
5 W Blue LEDs
Me
O
1
2b
3
O
O
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Me
Me
OMe
Me
Me
Me
Me
Me
Cl
3b, 79%, 30ha
3c, 71%, 48h
3a, 81%, 30h
O
O
O
Br
F
3d, 78%, 30h
3e, 76%, 30h
3f, 67%, 48h
O
O
O
Me
Me
Me
I
Me
CF3
Br
3g, 70%, 30h
3h, 61%, 48h
3i, 82%, 30h
O
Br
O
O
OMe
Me
Me
Me
Me
Me
Me
3l, 54%, 48h
3j, 58%, 30h
3k, 70%, 48h
O
O
O
Me
O
Me
3m, 80%, 30h
O
Me
Me
3n, 84%,30h
O
Me
3o, 53%, 48h
S
Me
Me
3p, 57%, 48h
3q, 50%, 48h
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Reaction conditions: 1 (0.2 mmol), 2b (0.4 mmol, 2.0 equiv), Ir[dF(CF3)ppy]2(dtbbpy)PF6 (0.002 mmol, 2 mol %),
NaOAc (0.4 mmol, 2.0 equiv), CH3CN/H2O (V/V = 1:1, 2 mL), Selectfluor ( 0.5 mmol, 2.5 equiv), at room temperaꢀ
ture, 5 W blue LEDs, 30 ꢀ 48 h. aReaction carried out on 5 mmol scale.
Encouraged by the above promising results obtained, we further applied the optimized reaction conditions to
investigate the substrate scope of alkenes, and the results are summarized in Scheme 3. A series of styrenes, with
various substituents on the aromatic ring, were found to be suitable candidates to offer the desired ketones in good
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yields. Styrenes having halogen substituents such as fluoro, chloro and bromo groups afforded the corresponding prodꢀ
ucts (4bꢀd). Paraꢀphenylstyrene also reacted with αꢀoxocarboxylic acid under the standard reaction conditions to afꢀ
ford the coupling product (4e) in 65% yield. Notably, a metaꢀchloro (4g) or orthoꢀbromo (4h) substituent on the phenyl
ring of styrenes could also be well tolerated. The styrenes with more substituents (methyl, chloro) on the phenyl ring
were used, they all underwent the decarboxylative crossꢀcoupling with αꢀoxocarboxylic acids, yielding α,βꢀunsaturated
ketone products (4lꢀk) in 60 – 83% yields.
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Scheme 3. Scope of styrene in this decarboxylative crossꢀcoupling reaction.
O
Me
Ir[dF(CF3)ppy]2(dtbbpy)PF6
NaOAc, Selectfluor
O
O
+
R
OH
R
5 W Blue LEDs
Me
O
4
2
1b
O
O
Cl
Me
Me
Me
F
Me
Me
4a, 70%, 30h
4b, 72%, 30h
4c, 74%, 30h
O
O
O
Me
Me
Me
Br
Cl
Ph
4f, 81%, 30h
4e, 65%, 48h
4d, 62%, 48h
O
O
O
Cl
Me
Me
Br
Me
Me
4g, 58%, 48h
Cl
4h, 50%, 48h
4I, 60%, 48h
O
O
Me
Me
Me
Me
4j, 83%, 30h
4k, 82%, 30h
Reaction conditions: 1b (0.2 mmol), 2 (0.4 mmol, 2.0 equiv), Ir[dF(CF3)ppy]2(dtbbpy)PF6 (0.002 mmol, 2 mol %),
NaOAc (0.4 mmol, 2.0 equiv), CH3CN/H2O (V/V = 1:1, 2 mL), Selectfluor ( 0.5 mmol, 2.5 equiv), at room temperaꢀ
ture, 5 W blue LEDs, 30 ꢀ 48 h.
To gain mechanistic insight into the visibleꢀlightꢀmediated photoredox catalysis for dominoꢀfluorinationꢀ
protodefluorination decarboxylative crossꢀcoupling, the radical scavenger TEMPO (2, 2, 6, 6ꢀtetramethylꢀ1ꢀ
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piperidinyloxy) was introduced into the photochemical system, and the reaction was completely restrained under optiꢀ
mized reaction conditions, indicating that a SET radical process is operating (Scheme 4 a). To test if the benzylic radiꢀ
cal derived from radical addition of acyl radical to styrene undergo the direct oxidation and deprotonation to release the
final product, we used TBHP to replace Selectfluor and observed no ketone product (Scheme 4 b).17 These experiꢀ
mental results suggested Selectfluor was not simply an oxidant for participating in the photocatalytic cycle, but might
contribute to decarboxylative crossꢀcoupling process. In the absence of base, we monitored the acylfluorinated product
of styrenes in the reaction mixture by NMR spectrum although only a small amount. (Scheme 4 c), which implied that
5a may be the reaction intermediate and unstable to eliminate hydrogen fluoride in the presence of base.18 Finally, we
performed fluorescence quenching experiments with the Ir[dF(CF3)ppy]2(dtbbpy)PF6 as photocatalyst ( See: Supportꢀ
ing Information). The results of a series of Stern−Volmer quenching studies revealed the initiation point of the photoꢀ
redox catalytic cycle likely began with the oxidation of αꢀketo acids.
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Scheme 4. Mechanistic investigation of the decarboxylative crossꢀcoupling reaction.
On the basis of the experimental results and literature reported,19 a possible mechanism is shown in Scheme 5. Unꢀ
der visibleꢀlight irradiation, the photocatalyst Ir[dF(CF3)ppy]2(dtbbpy)PF6 (1) leads to the formation of a longꢀlived
excited state Ir*III (2), undergoing a metal to ligand chargeꢀtransfer (MLCT) process. Ir*III (2) can serve as an efficient
oxidizing agent to oxide αꢀketo acid by a SET process with the reduced IrII (3) species. The corresponding carboxyl
radical species would quickly extrude CO2 to give the acyl radical species 6. The radical addition of 6 to styrene 2b
delivers the critical benzylic radical 7. At this stage, direct fluorine atom transfer from Selectfluor to the benzylic radiꢀ
cal 7 is proposed to construct the CꢀF bond with concomitant generation of the corresponding Selectfluor radical cation
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9. Subsequently, radical cation 9 would act as an oxidant to complete the photoredox cycle as a suitable electron accepꢀ
tor in the conversion of reduced state IrII (3) to the ground state IrIII (1) species. The acylfluorinated product 5a is unꢀ
stable to eliminate hydrogen fluoride in the presence of base, delivering the final α,βꢀunsaturated ketone product 3a.
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4
5
6
7
8
9
Scheme 5. Possible reaction mechanism
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In conclusion, we have developed a visibleꢀlightꢀmediated photoredox catalysis protocol for dominoꢀfluorinationꢀ
protodefluorination decarboxylative crossꢀcoupling of αꢀketo acids with styrene. Challenges associated with styrene
functionalization process were efficiently overcome by rapid fluorine atom transfer from Selectfluor to the benzylic
radical combined with photoredox catalysis. This dominoꢀfluorinationꢀprotodefluorination catalytic strategy provides a
novel pathway for the construction of α,βꢀunsaturated ketones, with a variety of functional groups tolerated on both αꢀ
keto acids and styrene. Extending this method to other challenging reaction systems is currently being explored in our
laboratory.
EXPERIMENTAL SECTION
General Information: All regents were AR regents commercial available. Phenylglyoxylic acid 1a was purchased
from SigmaꢀAldrich. Other keto acids 1 were prepared from the corresponding methyl ketones according to the reportꢀ
ed procedure.20 Styrenes 2 were purchased from TCI, Alfa or Acros. All of other commercially available compounds
were used without further purification. Thin Layer Chromatography (TLC) was used to detect the progress of reactions
and to separate products. HRMS data were recorded by a TOF LC/MS. Melting points (mp) were determined with a
1
digital electrothermal apparatus without further correction. H NMR, 13C NMR and 19F NMF spectra were recorded
using 400 MHz spectrometer at room temperature, with TMS as internal standard. Chemical shifts (δ) are determined
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in ppm downfield from tetramethylsilane. Abbreviations for signal couplings are: s, singlet; d, doublet; t, triplet; m,
multiplet.
1
2
3
4
5
6
7
8
General procedure for the decarboxylative cross coupling of αꢀketo acids with styrene: A 10 mL ovenꢀdried
Schlenkꢀtube was charged with photocatalyst Ir[dF(CF3)ppy]2(dtbbpy)PF6 (0.004 mmol, 0.02 equiv), the corresponding
keto acid (1, 0.2 mmol), Selectfluor (0.5 mmol, 2.5 equiv.), and NaOAc (0.4 mmol, 2.0 equiv). The tube was evacuated
and backfilled with Ar (three times), Styrenes (2, 0.4 mmol, 2.0 equiv.) in CH3CN/H2O (1:1, 2 mL) were added by syꢀ
ringe under Ar. The tube was then sealed and was placed at a distance (app. 5 cm) from 5W blue LEDs lamb, and the
mixture was stirred for 30 ꢀ 48 h at room temperature. The resulting mixture was diluted with EtOAc (15 mL). The
organic layers were washed with H2O and brine, dried over anhydrous Na2SO4 and the solvent was then removed unꢀ
der vacuo. The residue was purified with chromatography column on silica gel (gradient eluent of EtOAc/petroleum
ether: 1/200 to 1/100) to give the corresponding products 3 or 4.
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o
1
(E)ꢀ1ꢀphenylꢀ3ꢀ(pꢀtolyl)propꢀ2ꢀenꢀ1ꢀone (3a) (36.0 mg, 81% yield). White solid; mp: 113ꢀ114 C; H NMR (400
MHz, Chloroformꢀd) δ 8.05 ꢀ 7.97 (m, 2H), 7.79 (d, J = 15.7 Hz, 1H), 7.61 ꢀ 7.44 (m, 6H), 7.22 (d, J = 8.0 Hz, 2H),
2.38 (s, 3H). 13C NMR (100 MHz, Chloroformꢀd) δ 190.7, 145.0, 141.1, 138.4, 132.7, 132.2, 129.7, 128.6, 128.5,
128.5, 21.6. HRMS (ESI) Calcd for C16H15O [M+H]+: 223.1177, found: 223.1178.
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(E)ꢀ1,3ꢀdiꢀpꢀtolylpropꢀ2ꢀenꢀ1ꢀone (3b): (912 mg, 79% yield). White solid; mp: 128ꢀ130 C; H NMR (400 MHz,
Chloroformꢀd) δ 7.93 (d, J = 6.4 Hz, 2H), 7.78 (d, J = 15.7 Hz, 1H), 7.56 ꢀ 7.43 (m, 3H), 7. 30 ꢀ7.20 (m, 4H), 2.42 (s,
3H), 2.38 (s, 3H). 13C NMR (100 MHz, Chloroformꢀd) δ 190.1, 144.5, 143.5, 141.0, 135.8, 132.3, 129.7, 129.3, 128.6,
128.5, 121.1, 21.7, 21.6. HRMS (ESI) Calcd for C17H17O [M+H]+: 237.1274, found: 237.1276.
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(E)ꢀ1ꢀ(4ꢀmethoxyphenyl)ꢀ3ꢀ(pꢀtolyl)propꢀ2ꢀenꢀ1ꢀone (3c): (35.8mg, 71% yield). White solid; mp: 156ꢀ158 C; H
NMR (400 MHz, Chloroformꢀd) δ 8.12 ꢀ 7.96 (m, 2H), 7.78 (d, J = 15.6 Hz, 1H), 7.60 ꢀ 7.44 (m, 3H), 7.21 (d, J = 7.9
Hz, 2H), 7.04 ꢀ 6.89 (m, 2H), 3.87 (s, 3H), 2.38 (s, 3H). 13C NMR (100 MHz, Chloroformꢀd) δ 188.8, 163.4, 144.1,
140.8, 132.4, 131.2, 130. 8, 129.7, 128.4, 120.8, 113.8, 55.5, 21.5. HRMS (ESI) Calcd for C17H16O2 [M+H]+:
252.1150, found: 252.1154.
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(E)ꢀ1ꢀ(4ꢀfluorophenyl)ꢀ3ꢀ(pꢀtolyl)propꢀ2ꢀenꢀ1ꢀone (3d): (37.4mg, 78% yield). White solid; mp: 124ꢀ126 C; H
NMR (400 MHz, Chloroformꢀd) δ 7.99 ꢀ 7.89 (m, 2H), 7.70 (d, J = 15.6 Hz, 1H), 7.44 (d, J = 8.0 Hz, 2H), 7.36 (d, J =
15.6 Hz, 1H), 7.22 ꢀ 6.99 (m, 4H), 2.29 (s, 3H). 13C NMR (100 MHz, Chloroformꢀd) δ 188.9, 165.5(d, J = 254.2 Hz),
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145.2, 141.2, 134.7, 132.1, 131.1 (d, J = 9.2 Hz), 129.8, 128.5, 120.6, 115.7 (d, J = 21.8 Hz), 21.6. 19F NMR (376 MHz,
Chloroformꢀd) δ ꢀ105.73. HRMS (ESI) Calcd for C16H14FO [M+H]+: 241.1023, found: 241.1025.
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(E)ꢀ1ꢀ(4ꢀchlorophenyl)ꢀ3ꢀ(pꢀtolyl)propꢀ2ꢀenꢀ1ꢀone (3e): (38.9 mg, 76% yield). White solid; mp: 158ꢀ160 C; H
NMR (400 MHz, Chloroformꢀd) δ 8.00 ꢀ 7.90 (m, 2H), 7.79 (d, J = 15.7 Hz, 1H), 7.54 (d, J = 8.1 Hz, 2H), 7.49 ꢀ 7.39
(m, 3H), 7.24 (t, J = 8.4 Hz, 2H), 2.39 (s, 3H). 13C NMR (100 MHz, Chloroformꢀd) δ 189.3, 145.5, 141.4, 139.1, 136.7,
132.0, 129.9, 129.7, 128.9, 128.6, 120.5, 21.6. HRMS (ESI) Calcd for C16H14ClO [M+H]+: 257.0728, found: 257.0728.
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(E)ꢀ1ꢀ(4ꢀbromophenyl)ꢀ3ꢀ(pꢀtolyl)propꢀ2ꢀenꢀ1ꢀone (3f): (40.2 mg, 67% yield). White solid; mp:160ꢀ163 C; H
NMR (400 MHz, Chloroformꢀd) δ 7.95 ꢀ 7.83 (m, 2H), 7.79 (d, J = 15.7 Hz, 1H), 7.67 ꢀ 7.61 (m, 2H), 7.54 (d, J = 8.1
Hz, 2H), 7.43 (d, J = 15.7 Hz, 1H), 7.23 (d, J = 8.0 Hz, 2H), 2.39 (s, 3H). 13C NMR (100 MHz, Chloroformꢀd) δ 189.5,
145.5, 141.4, 137.1, 132.0, 131.9, 130.1, 129.8, 128.6, 127.7, 120.5, 21.6. HRMS (ESI) Calcd for C16H14BrO [M+H]+:
301.0223, found: 301.0227.
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(E)ꢀ1ꢀ(4ꢀiodophenyl)ꢀ3ꢀ(pꢀtolyl)propꢀ2ꢀenꢀ1ꢀone (3g): (48.7mg, 70% yield). White solid; mp:156ꢀ158 C; H NMR
(400 MHz, Chloroformꢀd) δ 7.86 (d, J = 8.4 Hz, 2H), 7.79 (d, J = 15.7 Hz, 1H), 7.72 (d, J = 8.4 Hz, 2H), 7.54 (d, J =
8.1 Hz, 2H), 7.42 (d, J = 15.7 Hz, 1H), 7.23 (d, J = 8.0 Hz, 2H), 2.40 (s, 3H). 13C NMR (100 MHz, Chloroformꢀd) δ
189. 8, 145.6, 141.4, 137.9, 137.6, 132.0, 129.9, 129.8, 128.6, 120.4, 100.5, 21.6. HRMS (ESI) Calcd for C16H14IO
[M+H]+: 349.0084, found: 349.0086.
(E)ꢀ3ꢀ(pꢀtolyl)ꢀ1ꢀ(4ꢀ(trifluoromethyl)phenyl)propꢀ2ꢀenꢀ1ꢀone (3h): (35.4mg, 61% yield). White solid; mp: 145ꢀ147
oC; 1H NMR (400 MHz, Chloroformꢀd) δ 8.00 (d, J = 8.1 Hz, 2H), 7.76 ꢀ 7.60 (m, 3H), 7.46 (d, J = 8.1 Hz, 2H), 7.35
(d, J = 15.7 Hz, 1H), 7.15 (d, J = 8.0 Hz, 2H), 2.31 (s, 3H). 13C NMR (100 MHz, Chloroformꢀd) δ 189.7, 146.2, 141.7,
141.2, 133.9 (q, J = 32.6 Hz), 131.8, 129.8, 128.7, 128.6, 125.6 (q, J = 3.7 Hz), 123.7 (q, J = 272.7 Hz), 120.6, 21.6.
19F NMR (376 MHz, Chloroformꢀd) δ ꢀ62.96. HRMS (ESI) Calcd for C17H14F3O [M+H]+: 291.0991, found: 291.0994.
(E)ꢀ1ꢀ(mꢀtolyl)ꢀ3ꢀ(pꢀtolyl)propꢀ2ꢀenꢀ1ꢀone (3i): (38.7 mg, 82% yield). White solid; mp: 68ꢀ70oC; 1H NMR (400 MHz,
Chloroformꢀd) δ 7.85 ꢀ 7.69 (m, 3H), 7.53 (d, J = 8.1 Hz, 2H), 7.48 (d, J = 15.7 Hz, 1H), 7.37 (d, J = 5.2 Hz, 2H), 7.21
(d, J = 8.0 Hz, 2H), 2.43 (s, 3H), 2.38 (s, 3H). 13C NMR (100 MHz, Chloroformꢀd) δ 190.8, 144.8, 141.1, 138.4, 133.5,
132.2, 129.0, 128.5, 128.5, 125.7, 121.3, 21. 6, 21.4. HRMS (ESI) Calcd for C17H17O [M+H]+: 237.1274, found:
237.1276.
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(E)ꢀ1ꢀ(3ꢀmethoxyphenyl)ꢀ3ꢀ(pꢀtolyl)propꢀ2ꢀenꢀ1ꢀone (3j): (29.2 mg, 58% yield). White solid; mp: 48ꢀ50 C; H
NMR (400 MHz, Chloroformꢀd) δ 7.79 (d, J = 15.7 Hz, 1H), 7.62 ꢀ 7.51 (m, 4H), 7.47 (d, J = 15.7 Hz, 1H), 7.40 (t, J
= 7.9 Hz, 1H), 7.22 (d, J = 8.0 Hz, 2H), 7.17 ꢀ 7.09 (m, 1H), 3.88 (s, 3H), 2.39 (s, 3H). 13C NMR (100 MHz, Chloroꢀ
formꢀd) δ 190.4, 159.9, 145.0, 141.1, 139.8, 132.2, 129.7, 129.6, 128.5, 121.2, 121.0, 119.2, 112.7, 55.5, 21.6. HRMS
(ESI) Calcd for C17H16O2 [M+H]+: 252.1150, found: 252.1154.
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(E)ꢀ1ꢀ(3ꢀbromophenyl)ꢀ3ꢀ(pꢀtolyl)propꢀ2ꢀenꢀ1ꢀone (3k): (42.0 mg, 70% yield). white solid; mp:132ꢀ134 C; H
NMR (400 MHz, Chloroformꢀd) δ 8.13 (t, J = 1.7 Hz, 1H), 7.92 (dt, J = 7.8, 1.3 Hz, 1H), 7.80 (d, J = 15.7 Hz, 1H),
7.73 ꢀ 7.64 (m, 1H), 7.54 (d, J = 8.1 Hz, 2H), 7.46 ꢀ 7.33 (m, 2H), 7.23 (d, J = 8.0 Hz, 2H), 2.39 (s, 3H). 13C NMR
(100 MHz, Chloroformꢀd) δ 189.1, 145.8, 141.5, 140.2, 135.5, 131.9, 131.5, 130.2, 129.8, 128.6, 127.0, 122.9, 120.4,
21.6. HRMS (ESI) Calcd for C16H14BrO [M+H]+: 301.0223, found: 301.0224.
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(E)ꢀ1ꢀ(2ꢀbromophenyl)ꢀ3ꢀ(pꢀtolyl)propꢀ2ꢀenꢀ1ꢀone (3l): (32.4 mg, 54% yield). White solid; mp: 135ꢀ138 C; H
NMR (400 MHz, Chloroformꢀd) δ 7.63 (d, J = 8.2 Hz, 1H), 7.48 ꢀ 7.35 (m, 5H), 7.34 ꢀ 7.28 (m, 1H), 7.19 (d, J = 8.0
Hz, 2H), 7.04 (d, J = 16.1 Hz, 1H), 2.37 (s, 3H). 13C NMR (100 MHz, Chloroformꢀd) δ 194.7, 146.9, 141.6, 141.3,
133.4, 131.7, 131.3, 129.8, 129.2, 128.7, 127.3, 125.2, 119.5, 21.6. HRMS (ESI) Calcd for C16H14BrO [M+H]+:
301.0223, found: 301.0226.
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(E)ꢀ1ꢀ(2,4ꢀdimethylphenyl)ꢀ3ꢀ(pꢀtolyl)propꢀ2ꢀenꢀ1ꢀone (3m): (40.0 mg, 80% yield). White solid; mp: 100ꢀ104 C;
1H NMR (400 MHz, Chloroformꢀd) δ 7.49 ꢀ 7.41 (m, J = 7.7 Hz, 4H), 7.30 ꢀ 6.94 (m, 5H), 2.43 (s, 3H), 2.37 (s, 6H).
13C NMR (100 MHz, Chloroformꢀd) δ 196.08, 145.4, 141.0, 140.8, 137.4, 136.3, 132.2, 132.1, 129.7, 128.6, 128.4,
126.1, 125.8, 21.5, 21.4, 20.4. HRMS (ESI) Calcd for C18H19O [M+H]+: 251.1430, found: 251.1432.
(E)ꢀ1ꢀmesitylꢀ3ꢀ(pꢀtolyl)propꢀ2ꢀenꢀ1ꢀone (3n): (44.4 mg, 84% yield). White solid; mp: 56ꢀ58 oC; 1H NMR (400 MHz,
Chloroformꢀd) δ 7.40 (d, J = 8.1 Hz, 2H), 7.21 ꢀ 7.07 (m, 3H), 6.94 ꢀ 6.80 (m, 3H), 2.37 (s, 3H), 2.32 (s, 3H), 2.19 (s,
6H). 13C NMR (100 MHz, Chloroformꢀd) δ 201.6, 146.9, 141.4, 138.3, 137.2, 134.1, 131.7, 129.7, 128.5, 128.4, 127.5,
21.6, 21.2, 19.4. HRMS (ESI) Calcd for C19H21O [M+H]+: 265.1587, found: 265.1589.
(E)ꢀ1ꢀ(furanꢀ2ꢀyl)ꢀ3ꢀ(pꢀtolyl)propꢀ2ꢀenꢀ1ꢀone (3o): (22.5 mg, 53% yield). White solid; mp: 96ꢀ98 oC; 1H NMR (400
MHz, Chloroformꢀd) δ 7.86 (d, J = 15.8 Hz, 1H), 7.64 (d, J = 2.3 Hz, 1H), 7.55 (d, J = 8.1 Hz, 2H), 7.41 (d, J = 15.8
Hz, 1H), 7.32 (d, J = 3.6 Hz, 1H), 7.22 (d, J = 8.0 Hz, 2H), 6.58 (dd, J = 3.6, 1.7 Hz, 1H), 2.39 (s, 3H). 13C NMR (100
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MHz, Chloroformꢀd) δ 178.1, 153.8, 146.4, 144.1, 141.2, 132.1, 129.7, 128.6, 120.2, 117.3, 112.5, 21.6. HRMS (ESI)
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(E)ꢀ1ꢀ(thiophenꢀ2ꢀyl)ꢀ3ꢀ(pꢀtolyl)propꢀ2ꢀenꢀ1ꢀone (3p): (26.0 mg, 57% yield).White solid; mp:112ꢀ114 C; H NMR
(400 MHz, Chloroformꢀd) δ 7.94 ꢀ 7.76 (m, 2H), 7.66 (dd, J = 4.9, 1.0 Hz, 1H), 7.53 (d, J = 8.1 Hz, 2H), 7.38 (d, J =
15.6 Hz, 1H), 7.24 ꢀ 7.13 (m, 3H), 2.38 (s, 3H). 13C NMR (100 MHz, Chloroformꢀd) δ 182.1, 145.7, 144.2, 141.2,
133.7, 132.0, 131.7, 129.7, 128.5, 128.2, 120.6, 21.6. HRMS (ESI) Calcd for C14H13OS [M+H]+: 229.0682, found:
229.0685.
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(E)ꢀ1ꢀ(naphthalenꢀ2ꢀyl)ꢀ3ꢀ(pꢀtolyl)propꢀ2ꢀenꢀ1ꢀone (3q): (27.2 mg, 50% yield). White solid; mp: 141ꢀ143 C; H
NMR (400 MHz, Chloroformꢀd) δ 8.53 (s, 1H), 8.10 (dd, J = 8.6, 1.7 Hz, 1H), 8.02 ꢀ 7.81 (m, 4H), 7.72 ꢀ 7.49 (m, 5H),
7.24 (d, J = 7.3 Hz, 2H), 2.40 (s, 3H). 13C NMR (100 MHz, Chloroformꢀd) δ 190.4, 144.9, 141.1, 135.7, 135.5, 132.6,
132.3, 129.7, 129.8, 129.5, 128.6, 128.3, 127.8, 126.8, 124.6, 121.1, 21.6. HRMS (ESI) Calcd for C20H16O [M+H]+:
272.1201, found: 272.1204.
(E)ꢀ3ꢀphenylꢀ1ꢀ(pꢀtolyl)propꢀ2ꢀenꢀ1ꢀone (4a): (31.1 mg, 70% yield). White solid; mp: 48ꢀ50 oC; 1H NMR (400 MHz,
Chloroformꢀd) δ 7.94 (d, J = 8.2 Hz, 2H), 7.80 (d, J = 15.7 Hz, 1H), 7.65 ꢀ 7.62 (m, 2H), 7.53 (d, J = 15.7 Hz, 1H),
7.42 – 7.39 (m, 3H), 7.29 (d, J = 8.0 Hz, 2H), 2.43 (s, 3H). 13C NMR (100 MHz, Chloroformꢀd) δ 190.0, 144.4, 143.7,
135.6, 135.0, 130.4, 129.4, 128.9, 128.7, 128.4, 122.1, 21.7. HRMS (ESI) Calcd for C16H15O [M+H]+: 223.1177,
found: 223.1179.
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(E)ꢀ3ꢀ(4ꢀfluorophenyl)ꢀ1ꢀ(pꢀtolyl)propꢀ2ꢀenꢀ1ꢀone (4b): (34.6 mg, 72% yield). White solid; mp:152ꢀ154 C; H
NMR (400 MHz, Chloroformꢀd) δ 7.93 (d, J = 6.7 Hz, 2H), 7.77 (d, J = 15.7 Hz, 1H), 7.67 ꢀ 7.58 (m, 2H), 7.47 (d, J =
15.7 Hz, 1H), 7.30 (d, J = 7.3 Hz, 2H), 7.16 ꢀ 7.05 (m, 2H), 2.43 (s, 3H). 13C NMR (100 MHz, Chloroformꢀd) δ 189.8,
164.0 (d, J = 251.6 Hz), 143.7, 143.1, 135.5, 131.3 (d, J = 2.8 Hz), 130.3 (d, J = 8.5 Hz), 129.4, 128.6, 121.8, 116.1 (d,
J = 21.9 Hz), 21.7. 19F NMR (376 MHz, Chloroformꢀd) δ ꢀ109.25. HRMS (ESI) Calcd for C16H14FO [M+H]+: 241.1023,
found: 241.1025.
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(E)ꢀ3ꢀ(4ꢀchlorophenyl)ꢀ1ꢀ(pꢀtolyl)propꢀ2ꢀenꢀ1ꢀone (4c): (37.9 mg, 74% yield). White solid; mp: 147ꢀ149 C; H
NMR (400 MHz, Chloroformꢀd) δ 7.93 (d, J = 8.2 Hz, 2H), 7.75 (d, J = 15.7 Hz, 1H), 7.60 ꢀ 7.47 (m, 3H), 7.39 (d, J =
8.5 Hz, 2H), 7.31 (d, J = 8.1 Hz, 2H), 2.44 (s, 3H). 13C NMR (100 MHz, Chloroformꢀd) δ 189.7, 143.9, 142.9, 136.3,
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135.5, 133.5, 129.6, 129.4, 129.2, 128.7, 122.5, 21.7. HRMS (ESI) Calcd for C16H14ClO [M+H]+: 257.0728, found:
257.0728.
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(E)ꢀ3ꢀ(4ꢀbromophenyl)ꢀ1ꢀ(pꢀtolyl)propꢀ2ꢀenꢀ1ꢀone (4d): (37.3 mg, 62% yield). White solid; mp: 132ꢀ134 C; H
NMR (400 MHz, Chloroformꢀd) δ 7.93 (d, J = 8.2 Hz, 2H), 7.73 (d, J = 15.7 Hz, 1H), 7.61 ꢀ 7.45 (m, 5H), 7.31 (d, J =
8.0 Hz, 2H), 2.44 (s, 3H). 13C NMR (100 MHz, Chloroformꢀd) δ 189.7, 143.8, 142.9, 135.5, 133.9, 132.2, 129.8, 129.4,
128.7, 124.6, 122.6, 21.7. HRMS (ESI) Calcd for C16H14BrO [M+H]+: 301.0223, found: 301.0227.
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(E)ꢀ3ꢀ([1,1'ꢀbiphenyl]ꢀ4ꢀyl)ꢀ1ꢀ(pꢀtolyl)propꢀ2ꢀenꢀ1ꢀone (4e): (38.7 mg, 65% yield). White solid; mp:112ꢀ114 C; H
NMR (400 MHz, Chloroformꢀd) δ 7.95 (d, J = 8.2 Hz, 2H), 7.84 (d, J = 15.7 Hz, 1H), 7.71 (d, J = 8.3 Hz, 2H), 7.66 ꢀ
7.60 (m, 4H), 7.57 (d, J = 15.7 Hz, 1H), 7.45 (t, J = 7.5 Hz, 2H), 7.37 (t, J = 7.3 Hz, 1H), 7.30 (d, J = 8.0 Hz, 2H),
2.43 (s, 3H). 13C NMR (100 MHz, Chloroformꢀd) δ 189.9, 143.9, 143.7, 143.2, 140.2, 135.7, 133.9, 129.4, 128.9,
128.7, 127.9, 127.6, 127.1, 121.9, 21.7. HRMS (ESI) Calcd for C22H18O [M+H]+: 298.1358, found: 298.1359.
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(E)ꢀ3ꢀ(mꢀtolyl)ꢀ1ꢀ(pꢀtolyl)propꢀ2ꢀenꢀ1ꢀone (4f): (38.2 mg, 81% yield). White solid; mp: 83ꢀ84 C; H NMR (400
MHz, Chloroformꢀd) δ 7.94 (d, J = 8.2 Hz, 2H), 7.78 (d, J = 15.7 Hz, 1H), 7.52 (d, J = 15.7 Hz, 1H), 7.45 (d, J = 6.6
Hz, 2H), 7.34 ꢀ 7.27 (m, 3H), 7.22 (d, J = 7.5 Hz, 1H), 2.44 (s, 3H), 2.40 (s, 3H). 13C NMR (100 MHz, Chloroformꢀd)
δ 190.1, 144.6, 143.6, 138.6, 135.7, 134.9, 131.3, 129.3, 129.1, 128.8, 128.7, 125.7, 121.9, 21.7, 21.4.
(E)ꢀ3ꢀ(3ꢀchlorophenyl)ꢀ1ꢀ(pꢀtolyl)propꢀ2ꢀenꢀ1ꢀone (4g): (29.7 mg, 58% yield). White solid; mp: 71ꢀ73 C; 1H NMR
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(400 MHz, Chloroformꢀd) δ 7.94 (d, J = 8.2 Hz, 2H), 7.73 (d, J = 15.7 Hz, 1H), 7.64 (s, 1H), 7.56 ꢀ 7.46 (m, 2H), 7.39
ꢀ 7.21 (m, 4H), 2.45 (s, 3H). 13C NMR (100 MHz, Chloroformꢀd) δ 189.6, 143.9, 142.6, 136.9, 135.4, 134.9, 130.2,
130.2, 129.4, 128.7, 127.8, 126.8, 123.3, 21.7. HRMS (ESI) Calcd for C16H14ClO [M+H]+: 257.0728, found: 257.0729.
(E)ꢀ3ꢀ(2ꢀbromophenyl)ꢀ1ꢀ(pꢀtolyl)propꢀ2ꢀenꢀ1ꢀone (4h): (30.0 mg, 50% yield). White solid; mp: 44ꢀ46 oC; 1H NMR
(400 MHz, Chloroformꢀd) δ 8.11 (d, J = 15.7 Hz, 1H), 7.93 ꢀ 7.91 (m, 2H), 7.71 (dd, J = 7.8, 1.5 Hz, 1H), 7.60 (d, J =
9.1 Hz, 1H), 7.41 (d, J = 15.7 Hz, 1H), 7.36 ꢀ 7.15 (m, 4H), 2.41 (s, 3H). 13C NMR (100 MHz, Chloroformꢀd) δ 189.8,
143.9, 142.7, 135.3, 135.1, 133.5, 131.3, 129.4, 128.8, 127.9, 127.7, 125.9, 125.1, 21.7. HRMS (ESI) Calcd for
C16H14BrO [M+H]+: 301.0223, found: 301.0227.
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(E)ꢀ3ꢀ(3,5ꢀdichlorophenyl)ꢀ1ꢀ(pꢀtolyl)propꢀ2ꢀenꢀ1ꢀone (4i): (34.8 mg, 60% yield). White solid; mp: 148ꢀ150 C; H
NMR (400 MHz, Chloroformꢀd) δ 8.07 (d, J = 15.7 Hz, 1H), 7.91 (d, J = 8.2 Hz, 2H), 7.67 (d, J = 8.5 Hz, 1H), 7.51 ꢀ
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7.40 (m, 2H), 7.32 ꢀ 7.24 (m, 3H), 2.42 (s, 3H). 13C NMR (100 MHz, Chloroformꢀd) δ 189.5, 144.1, 138.8, 136.3,
136.0, 135.2, 131.9, 130.1, 129.4, 128.8, 128.5, 127.5, 124.9, 21.7. HRMS (ESI) Calcd for C16H13Cl2O [M+H]+:
291.0338, found: 291.0339.
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(E)ꢀ3ꢀ(3,4ꢀdimethylphenyl)ꢀ1ꢀ(pꢀtolyl)propꢀ2ꢀenꢀ1ꢀone (4j): (41.5 mg, 83% yield). White solid; mp:118ꢀ120 C; H
NMR (400 MHz, Chloroformꢀd) δ 7.93 (d, J = 8.2 Hz, 2H), 7.76 (d, J = 15.7 Hz, 1H), 7.48 (d, J = 15.7 Hz, 1H), 7.43 ꢀ
7.34 (m, 2H), 7.28 (d, J = 7.9 Hz, 2H), 7.16 (d, J = 7.7 Hz, 1H), 2.42 (s, 3H), 2.29 (s, 3H), 2.28 (s, 3H). 13C NMR (100
MHz, Chloroformꢀd) δ 190.1, 144.7, 143.5, 139.8, 137.2, 135.8, 132.7, 130.3, 129.6, 129.3, 128.6, 126.1, 21.7, 19.9,
19.8. HRMS (ESI) Calcd for C18H19O [M+H]+: 251.1430, found: 251.1432.
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(E)ꢀ3ꢀ(3,5ꢀdimethylphenyl)ꢀ1ꢀ(pꢀtolyl)propꢀ2ꢀenꢀ1ꢀone (4k): (41.0 mg, 82% yield). White solid; mp: 115ꢀ117 oC; 1H
NMR (400 MHz, Chloroformꢀd) δ 7.94 (d, J = 8.2 Hz, 2H), 7.75 (d, J = 15.7 Hz, 1H), 7.51 (d, J = 15.7 Hz, 1H), 7.33 ꢀ
7.22 (m, 4H), 7.04 (s, 1H), 2.43 (s, 3H), 2.35 (s, 3H). 13C NMR (100 MHz, Chloroformꢀd) δ 190.1, 144.8, 143.5, 138.5,
135.7, 134.9, 132.3, 129.3, 128.7, 126.3, 121.9, 21.7, 21.2. HRMS (ESI) Calcd for C18H19O [M+H]+: 251.1430, found:
251.1431.
ACKNOWLEDGMENT
We gratefully acknowledge the National Natural Science Foundation of China (21474048, 21372114 and
21672099 ).
Supporting Information:
1H and 13C NMR spectra of compounds. This material is available free of charge via the Internet at http://pubs.acs.org.
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