Visible Light-Induced Aromatic Difluoroalkylation

Article abstract of DOI:10.1002/adsc.201400542

Difluoroalkylated aromatics are important structural motifs in pharmaceutical and agrochemical applications. Herein, we report their synthesis by a mild, efficient, and convenient method using visible light photoredox catalysis. A variety of unactivated aromatics were difluoroalkylated with ethyl 2-bromo-2,2-difluoroacetate (BrCF₂CO₂Et) in the presence of the triscyclometalated Ir complex fac-[Ir(ppy)₃] under visible light irradiation at room temperature. It is shown that reaction outcomes containing the CF₂CO₂Et moiety can be converted to a variety of other CF₂-containing aromatics, demonstrating the synthetic utility of the present method.

Full text of DOI:10.1002/adsc.201400542

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DOI: 10.1002/adsc.201400542
Visible Light-Induced Aromatic Difluoroalkylation
Jaehun Jung,a Eunjin Kim,a Youngmin You,b,* and Eun Jin Choa,c,*
a
Department of Bionanotechnology, Hanyang University, Ansan, Kyeonggi-do 426-791, Republic of Korea
Department of Advanced Materials Engineering for Information and Electronics, Kyung Hee University, Yongin,
b
Kyeonggi-do 446-701, Republic of Korea
E-mail: odds2@khu.ac.kr
Department of Chemistry and Applied Chemistry, Hanyang University, Ansan, Kyeonggi-do 426-791, Republic of Korea
c
Fax : (+82)-31-400-5457; e-mail: echo@hanyang.ac.kr
Received: June 13, 2014; Revised: July 2, 2014; Published online: && &&, 0000
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201400542.
Abstract: Difluoroalkylated aromatics are impor-
tant structural motifs in pharmaceutical and agro-
chemical applications. Herein, we report their syn-
thesis by a mild, efficient, and convenient method
using visible light photoredox catalysis. A variety of
unactivated aromatics were difluoroalkylated with
ethyl 2-bromo-2,2-difluoroacetate (BrCF2CO2Et) in
the presence of the triscyclometalated Ir complex
ficient and environmentally friendly transformations.
Visible-light photoredox catalysis emerges as the
promising alternative to the existing methods, as re-
cently demonstrated by the Qing group and the Wang
group for the difluoroalkylation of electron-rich het-
eroaromatics [Figure 2, Eq. (3)].[6] Herein, we present
a strategy for the difluoroalkylation of aromatics em-
ploying ethyl 2-bromo-2,2-difluoroacetate in the pres-
ence of a triscyclometalated Ir catalyst as the visible
light photoredox catalyst [Figure 2, Eq. (4)].[7,8] This
radical-based reaction does not require prefunctional-
ization of the aromatics and proceeds under mild re-
action conditions (room temperature/pressure). Mech-
anistic studies have also been performed to establish
that the key catalytic process of the photoredox cata-
lytic cycle involves oxidative quenching of the photo-
excited catalyst. In addition, the synthetic utility of
the products was demonstrated by their modification
into various CF2-containing molecules.
fac-[IrACHTUNGTRENNUNG(ppy)3] under visible light irradiation at room
temperature. It is shown that reaction outcomes
containing the CF2CO2Et moiety can be converted
to a variety of other CF2-containing aromatics, dem-
onstrating the synthetic utility of the present
method.
Keywords: aromatics; difluoroalkylation; heteroaro-
matics; iridium; visible light
We started the investigation of aryl difluoroalkyla-
tion using 1,4-dimethoxybenzene 1a as a model com-
The incorporation of fluoroalkyl groups into organic pound
and
ethyl
2-bromo-2,2-difluoroacetate
molecules has been of great importance due to their (BrCF2CO2Et) to produce the difluoroalkylated prod-
impact on the physical and biological properties of uct 2a (Table 1). The reaction mixture in DMF was
the material.[1] In particular, difluoroalkylation to gen- photoirradiated under blue LEDs (7 W) at room tem-
ꢀ
ꢀ
ꢀ
erate compounds containing CF2H or various CF2
groups has been useful in the preparation of pharma- bases. It was found that the use of fac-[IrAHCUTNGTRENNUNG
perature with different photoredox catalysts and
(ppy)3] and
ceuticals, agrochemicals, sugars, and enzyme inhibi- KO-t-Bu produced the best yields among various
tors.[2] Introduction of a functionalized CF2 moiety combinations involving the catalysts {[Ru
G
ꢀ
such as CF2CO2Et not only can alter the properties [Ru
G
[IrACTHUNGRTENNU(G ppy)2ACHTUNGTRENUN(NG dtbbpy)]PF6,
of the molecules but can also provide a CF2 building
ACHTUNGTRENNUNG
block because the moiety can undergo further modifi- throline, ppy=2-phenylpyridinato, dtbbpy=di-tert-
cation into various CF2-containing functional groups butyl-2,2’-bipyridine, dFppy=2-(1,4-difluorophenyl)-
such as a difluoromethyl group (CF2H), as shown in pyridinato} and bases (TMEDA, DBU, K3PO4, and
Figure 1.[3,4]
K2HPO4) (entries 1–9). The effects of other parame-
While a variety of difluoroalkylation methods have ters, such as solvents, concentrations, and the stoichi-
been demonstrated including transition metal-cata- ometry of the reagents on the reaction, were also ex-
lyzed or UV-mediated processes [Figure 2, Eq. (1) amined.[9] The reaction showed the best reactivity
and Eq. (2)],[5] it is still desirable to develop more ef- with 3 mol% fac-[Ir
ACTHNUTRGNEUNG(ppy)3], 3 equivalents of
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Figure 1. Aryl-CF2CO2Et as a CF2 building block.
Figure 2. Methods for the synthesis of aryl-CF2CO2Et compounds.
BrCF2CO2Et, and 1.5 equivalents of KO-t-Bu in
With the optimized conditions in hand, we evaluat-
DMSO at a concentration of 0.25M (entries 10–16). ed the utility of our difluoroalkylation method with
Control experiments showed that the reaction re- a broad range of non-prefunctionalized aromatics
quired both visible light[10] and a photocatalyst (en- (Table 2). This mild and convenient method allowed
tries 17 and 18).
for the difluoroalkylation of a variety of electron-rich
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Visible Light-Induced Aromatic Difluoroalkylation
Table 1. Optimization of reaction conditions for the synthesis of difluoroalkylated
aromatics.[a]
[a]
Reaction conditions: 1a (0.1 mmol), BrCF2CO2Et (0.3 mmol).
[b]
The yields were determined by gas chromatography and 19F NMR spectrosco-
py with internal standards of dodecane and 4-fluorotoluene, respectively.
aromatics with high efficiencies. The regioselectivity low conversion rate (30% after 18 h). In addition, aro-
pattern observed in the transformation was consistent matics containing alkenyl substituents did not under-
with that anticipated for a radical mediated aromatic go selective aryl-difluoroalkylation because the
substitution process.[8a,11,12] Alkyl and alkoxy substitu- alkene moiety was also reactive toward a radical-
ꢀ
ents such as OMe worked as ortho/para-directing mediated process with the CF2 radical. As an exam-
groups in the process with the electron-deficient ple, the reaction of 1-methoxy-4-vinylbenzene provid-
carbon-centered CF2 radical.[13] The selective addition ed a mixture of products from bromodifluoroalkyla-
of CCF2CO2Et at the ortho/para positions of the aro- tion,[8b,c] alkenyl-difluoroalkylation, and aryl-difluor-
matics can occur due to the favorable formation of oalkylation.[14]
more stable conjugated radical and carbocation inter-
To gain insight into the reaction mechanism, we
mediates. In addition to the regioselectivity, another conducted Stern–Volmer experiments for 50 mM fac-
salient feature of this transformation is the lower re- [Ir
ACHTUNGTRENNUNG
activity of the difluoroalkylated product toward the [IrAHCTUNGTRENNUNG
second reaction resulting in monodifluoroalkylation. time-correlated single-photon-counting (TCSPC)
In the same context, difluoroalkylation of electron-de- technique after nanosecond photoexcitation at
ficient aromatics was unsuccessful, and the reaction of 377 nm with varying concentrations of BrCF2CO2Et.
less electron-rich substrates such as toluene showed As shown in [Figure 3 (a)], the phosphorescence life-
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Table 2. Difluoroalkylation of aromatics.[a]
[a]
[b]
[c]
Reaction conditions: 1 (0.5 mmol), BrCF2CO2Et (1.5 mmol), 18–24 h.
The given yields are isolated yields obtained by the average of two runs.
The ratios were determined by 19F NMR spectroscopy, gas chromatography,
and NOE experiments.
[d]
The minor regioisomeric position is labelled with “*”.
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Visible Light-Induced Aromatic Difluoroalkylation
Figure 3. Phosphorescence quenching experiments for 50 mM fac-[Ir
30 mM BrCF2CO2Et and (b) 30 mM KO-t-Bu (triangles) or 30 mM TMEDA (circles). Phosphorescence decay traces of fac-
[Ir(ppy)3] were monitored at lem =520 nm after the nanosecond pulsed excitation (temporal resolution=8.0 ns) under lex =
377 nm. Inset Figure is a plot of electron transfer rate (1/t ꢀ1/t0; where t and t0 are phosphorescence lifetimes of fac-[Ir-
(ppy)3] in the presence and absence of BrCF2CO2Et, respectively) as a function of the concentration of BrCF2CO2Et. The
ACHTUNGRTENUN(NG ppy)3] in Ar-saturated DMSO solutions with (a) 0–
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
gray line is a linear fit of the data points, and the slope corresponds to the rate constant for electron transfer (keT =1.5ꢁ
108 mꢀ1 sꢀ1).
time (tobs) decreases in proportion with the concentra-
tion of BrCF2CO2Et. This decrease in tobs is due to
electron transfer from the photoexcited Ir complex to
BrCF2CO2Et and is caused by the fact that the driving
force for the one-electron transfer is as high as
1.34 eV (see the Supporting Information, Figure S1,
for details of the calculation). The rate constant for
electron transfer (keT) was determined to be 1.5ꢁ
108 Mꢀ1 sꢀ1 [Figure 3 (a)], approaching the diffusion-
limited regime. In sharp contrast, the phosphores-
cence decay trace is not affected by the presence of
30 mM TMEDA and 30 mM KO-t-Bu [Figure 3 (b)].
These results indicate that reductive quenching of the
photoexcited Ir complex by the one-electron donor
(i.e., TMEDA) can be ignored, and that the photoca-
talytic step does not involve participation of the
Brønsted base (i.e., KO-t-Bu).
Figure 4. Proposed mechanism for the aryl-difluoroalkyla-
tion.
Based on these results, we propose a plausible
mechanism for the difluoroalkylation of aromatics The addition of CCF2CO2Et to an aromatic compound
(Figure 4). Photoexcitation of fac-[Ir
visible light produces [Ir(IV)ppyCꢀ
a metal-to-ligand charge-transfer (MLCT) transi- a one-electron transfer from 1A to [Ir(IV)
tion.[15] This transient species is oxidatively quenched generates [Ir
(III)(ppy)3] and forms a carbocation in-
by one-electron transfer to BrCF2CO2Et, producing termediate. Subsequent deprotonation by ꢀO-t-Bu
[Ir(IV)
(ppy)3]+ and the key intermediate CCF2CO2Et. completes the reaction providing the desired difluor-
ACHUTGTNNERNUG(III)HCATUNGTERN(NUGN ppy)3] by generates the difluoroalkylated radical species 1A
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
A
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
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Table 3. Difluoroalkylation of heteroaromatics.[a,b]
[a]
Reaction conditions: 3 (1.0 mmol), BrCF2CO2Et (2.0 mmol), TEA or K3PO4
(2.0 mmol), 16–18 h.
The given yields are isolated yields based on an average of two runs.
The minor regioisomeric position is labelled with “*”, and the ratio was deter-
mined by 19F NMR spectroscopy and gas chromatography.
[b]
[c]
oakylated product 2 [pathway (a)]. Alternatively, de- fluoroalkylated products in good to excellent yields
protonation of 1A can occur to produce the radical with high regioselectivities.
anion species 1B.[16] Reductive one-electron transfer
to [Ir(IV)ACHTUNGTRENNUNG AHCTUNGTERG(NNUN III)ACTHUNGTREN(NNGU ppy)3] and obtained from our methodology, a difluoroalkylated
To demonstrate the synthetic utility of the products
(ppy)3]+ regenerates [Ir
yields 2 [pathway (b)]. It is also noted that radical compound 2a was shown to be successfully trans-
propagation between BrCF2CO2Et and 1A or 1B formed into a variety of CF2-containing compounds
cannot be ruled out, although the mechanism requires by conventional organic reactions (Scheme 1). Besides
further resolution.
a known process from RCF2CO2Et to RCF2H by hy-
Difluoroalkylation was also applied to heteroaro- drolysis and decarboxylation,[5c] we conducted the fol-
matics, and the process was optimized (see the Sup- lowing reactions and generated three kinds of CF2-
porting Information, Tables S2 and S3). The reactivity compounds in excellent yields: (a) hydride reduction,
of heteroaromatics was higher than that of aromatics, (b) Grignard reaction, and (c) amide formation via
requiring less catalyst loading and less BrCF2CO2Et. nucleophilic acyl substitution with NH3.[17]
As for heteroaryl difluoroalkylation, TEA and K3PO4
In summary, an efficient and convenient method
were used as bases and DMF was used as the solvent. for the synthesis of difluoroalkylated aromatics, which
A variety of heterocycles were reacted with the radi- are important structural motifs in pharmaceutical and
cal (CCF2CO2Et) which was generated in the presence agrochemical products, has been developed by visible-
of 1 mol% fac-[Ir
ble light irradiation (Table 3). The keT value for one- omatics, including heteroaromatics, were difluoroalky-
electron transfer from the photoexcited fac-[Ir(ppy)3] lated with BrCF2CO2Et as the CF2R source in the
to BrCF2CO2Et was determined employing the presence of fac-[Ir(ppy)3] under visible-light irradia-
ACHTUNGERTN(NUNG ppy)3] in DMF (0.25M) under visi- light photoredox catalysis. A variety of unactivated ar-
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
TCSPC technique to be 3.1ꢁ108 mꢀ1 sꢀ1 (Supporting tion at room temperature. Stern–Volmer experiments
Information, Figure S2). The use of TEA showed the suggested that the photoredox catalytic cycle involved
best reactivity in the reaction of pyrroles (4a) and in- an oxidative quenching pathway. In addition, the syn-
doles (4b, 4c), while K3PO4 was used for furans (4d), thetic utility of the products was demonstrated by
thiophenes (4e), benzothiophenes (4f), and benzofur- their modification into various CF2-containing mole-
ans (4g). Reactions were highly efficient and gave di- cules through conventional organic reactions. We an-
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Visible Light-Induced Aromatic Difluoroalkylation
Scheme 1. Versatile transformations of 2a. Reaction conditions: (a) NaBH4 (1.5 equiv.), EtOH, 24 h. (b) MeMgBr
(2.1 equiv.), THF, 08C ! room temperature, 3 h. (c) NH3, MeOH, room tempeature, 13 h.
ticipate that our protocol will be an efficient and con-
venient alternative to conventional difluoroalkylation
methods.
dried over MgSO4, concentrated in vacuo, and purified by
flash column chromatography to give the heteroaryl-
CF2CO2Et compound.
Experimental Section
Acknowledgements
Synthesis of Ar-CF2CO2Et Compounds
This work was supported by the National Research Founda-
tion of Korea (NRF) [NRF-2014R1A1A1A05003274, NRF-
2014-011165, and NRF-2012M3A7B4049657 (Nano Material
Technology Development Program)] and the TJ Science Fel-
lowship of the POSCO TJ Park Foundation.
An oven-dried, resealable test tube equipped with a magnet-
ic stir bar was charged with an aromatic compound
(0.5 mmol), sealed with a silicone septa screw-cap, and de-
gassed by alternating vacuum evacuation and argon backfill.
A solution of fac-[IrACTHNUTRGNE(UGN ppy)3] (3.0 mol%, 0.015 mmol) in
DMSO (2.0 mL, 0.25M) and KO-t-Bu (1.5 equiv.,
0.75 mmol) was then added to the tube. BrCF2CO2Et
(3 equiv., 1.5 mmol) was then added into the reaction mix-
ture. The test tube was stirred under argon and irradiated by
blue LEDs at room temperature. The reaction was allowed
to proceed for 18–24 h, and reaction progress was checked
by TLC or gas chromatography. The reaction mixture was
then diluted with ethyl acetate and washed with an NH4Cl
solution and brine. The organic layers were dried over
MgSO4, concentrated under vacuum, and purified by flash
column chromatography to give the aryl-CF2CO2Et com-
pound.
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An oven-dried, resealable test tube equipped with a magnet-
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sealed with a silicone septa screw-cap, and degassed by al-
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ꢀ
ꢀ
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ACHTUNGTRENNUNG
ꢀ
ꢀ
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COMMUNICATIONS
Visible Light-Induced Aromatic Difluoroalkylation
Adv. Synth. Catal. 2014, 356, 1 – 9
9
Jaehun Jung, Eunjin Kim, Youngmin You,* Eun Jin Cho*
Adv. Synth. Catal. 0000, 000, 0 – 0
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
9
ÞÞ
These are not the final page numbers!