Organic &Biomolecular Chemistry

PAPER

Cite this: Org. Biomol. Chem., 2013, 11,2766

Received 22nd January 2013,Accepted 26th February 2013

DOI: 10.1039/c3ob40140e

www.rsc.org/obc

Direct acylation of N-benzyltriflamides from the alcoholoxidation level via palladium-catalyzed C–H bondactivation†

Jihye Park,a Aejin Kim,a Satyasheel Sharma,a,b Minyoung Kim,a Eonjeong Park,a

Yukyoung Jeon,a Youngil Lee,b Jong Hwan Kwak,a Young Hoon Junga

and In Su Kim*a

A palladium-catalyzed ortho-acylation of N-benzyltriflamides from the alcohol oxidation level via C–H

bond activation is described. These transformations have been applied to a wide range of substrates, and

typically proceed with excellent levels of chemoselectivity and with high functional group tolerance.

Introduction

Transition-metal-catalyzed cross-coupling reactions haveemerged as a powerful tool available to produce structurallydiverse organic molecules.1 In particular, carbon–carboncross-coupling reactions involving selective C–H bond acti-vation have become an attractive variant of traditional cross-coupling reactions, because such methods avoid multisteppreparation of preactivated starting materials and productionof stoichiometric metallic waste. Thus, cross-coupling reac-tions via C–H bond activation can lead to an improved overallefficiency of the desired transformation.2

Recently, transition-metal-catalyzed oxidative acylations ofaromatic C–H bonds with aldehydes as coupling partners haveemerged as a promising set of carbon–carbon bond formationreactions.3 A wide range of directing groups, such as pyri-dines,4 amides,5 oximes,6 acetanilides,7 and indole,8 havebeen used for C–H bond activation. Decarboxylative acylationsof aromatic C–H bonds using α-keto acids as acyl surrogateshave been also reported.9 Although the acylation reactionsusing aldehydes or α-keto acids as coupling partners havebeen well documented, the reactions between the aromaticC–H bonds and alcohols remain relatively unexplored. In 2011,Li et al. first reported an oxidative acylation of arylpyridines fromthe alcohol oxidation level via palladium-catalyzed C–H bondactivation (Fig. 1).10 Yuan and coworkers also demonstrated a

palladium-catalyzed oxidative C–H bond acylation of acetani-lides with benzylic alcohols.11 These protocols are truly cataly-tic alternatives to Friedel–Crafts acylation. More importantly,this method provides direct access to aryl ketones, which areimportant scaffolds and synthetic precursors in natural pro-ducts, pharmaceuticals, and functional materials.12

Alcohols have long served as versatile substrates for the con-struction of carbon frameworks. Notably, alcohols are availableat low cost in great structural diversity, and are easy to storeand handle. Thus, alcohols can be reliable candidates for theacylation reaction because alcohols can be readily oxidizedinto aldehydes under metal catalysis.13

A triflamide directing group on catalytic C–H bond function-alization was first introduced by Yu et al.,14 and can be con-verted to a range of synthetically useful functional groups.14b

Herein, we disclose the palladium-catalyzed ortho-acylation ofN-benzyltriflamides with benzylic alcohols and aliphatic alco-hols using tert-butyl hydroperoxide (TBHP) as a convenientoxidant from the alcohol oxidation level.

Fig. 1 Pd-catalyzed oxidative acylation of sp2 C–H bonds from the alcoholoxidation level.

†Electronic supplementary information (ESI) available: 1H and 13C NMR copiesof all products. See DOI: 10.1039/c3ob40140e

aSchool of Pharmacy, Sungkyunkwan University, Suwon 440-746, Republic of Korea.

E-mail: insukim@skku.edu; Fax: +82 31 292 8800; Tel: +82 31 290 7788bDepartment of Chemistry, University of Ulsan, Ulsan 680-749, Republic of Korea

2766 | Org. Biomol. Chem., 2013, 11, 2766–2771 This journal is © The Royal Society of Chemistry 2013

Publ

ishe

d on

26

Febr

uary

201

3. D

ownl

oade

d by

Sun

gkyu

nkw

an U

nive

rsity

on

30/0

5/20

13 0

2:45

:18.

View Article OnlineView Journal | View Issue

www.rsc.org/obchttp://dx.doi.org/10.1039/c3ob40140ehttp://pubs.rsc.org/en/journals/journal/OBhttp://pubs.rsc.org/en/journals/journal/OB?issueid=OB011017

Results and discussion

In our initial study, N-(2-methoxybenzyl)triflamide (1a) andbenzyl alcohol (2a) were chosen as model substrates for opti-mizing the reaction conditions, and the selected results aresummarized in Table 1. To our delight, the combination of Pd(OAc)2 and TBHP in DMF promoted the coupling of 1a and 2ato provide our desired product 3a in 24% yield (Table 1, entry1). In the absence of either Pd(OAc)2 or TBHP, no couplingproduct 3a was observed. After screening of solvents underotherwise identical conditions, MeCN was found to be themost effective solvent in this coupling reaction, affording theproduct 3a in 46% yield, whereas other solvents such as THFand DCE were less effective in the coupling reaction (Table 1,entries 2–4). Screening of the oxidant showed that TBHP issuperior to other oxidants such as Ag2CO3, (NH4)2S2O8 and(PhCOO)2 (Table 1, entries 5–7).

Further study showed that the AcOH additive displayedincreased catalytic activity, but the TFA additive was lesseffective under the present conditions (Table 1, entries 8–9).Logically, it was thought that the formation of 3a can beincreased by the amount of oxidant and alcohol substrate.Indeed, treatment of 4 equiv. of TBHP provided the acylatedcompound 3a in 62% yield. After further optimization, thebest results were obtained by the use of 6 equiv. of 2a underotherwise identical conditions, affording the desired arylketone 3a in high yield (72%), as shown in entry 12.

With the optimal reaction conditions in hand, we set out toexplore the scope and limitation of the alcohol substrates(Table 2). The coupling of N-benzyltriflamide 1a and benzylicalcohols 2b–2f with electron-rich and electron-deficient groups(OMe, Me, CF3, F and Cl) at the para- and meta-positions wasfound to be favored in the acylation reaction to afford the

corresponding products 3b–3f in good yields. Notably, thechloro moiety on the aromatic ring was tolerated under thesecoupling conditions and offers versatile synthetic functionalityfor further elaboration. The ortho-substituted benzylic alcohols2g and 2h were also found to be favored in this catalyst system.In addition, 2-naphthylmethanol (2i) was smoothly convertedto the corresponding product 3i in 64% yield. To our pleasure,this transformation is not limited to benzylic alcohols. Ali-phatic alcohol 2j participated in the oxidative coupling tofurnish 3j, albeit with a decreased reactivity.

To further evaluate the substrate scope of this process, arange of N-benzyltriflamides 1b–1j and N-phenethyltriflamides1k and 1l was screened to couple with 4-methoxybenzylalcohol (2b) under optimal reaction conditions, as shown inTable 3. The coupling of benzylic alcohol 2b and N-benzyltri-flamides 1b–1f with an electron-donating group (Me) andhalogen groups (F and Cl) at the ortho- and meta-positions wasfound to be favored in the acylation reaction to afford the cor-responding products 4b–4f, whereas the reaction of 1g with anelectron-withdrawing group (CF3) at the meta-position wasfound to be relatively less reactive under these reaction con-ditions. Notably, the reaction of meta-substituted N-benzyltri-flamides preferentially occurred at the more stericallyaccessible position to afford the corresponding products as asingle regioisomer owing to the steric effect that caused inter-ference with either the formation of the cyclopalladated inter-mediate or the approach of the acyl radical into thepalladacycle intermediate. However, symmetric N-benzyltrifla-mide 1h afforded a separable mixture of monoacylatedproduct 4h and bisacylated compound 4hh with a 1 : 1 ratio.

Table 1 Selected optimization of reaction conditionsa

Entry Oxidant (equiv.) Additive Solvent Yieldb (%)

1 TBHP (3) DMF 242 TBHP (3) THF 43 TBHP (3) DCE Trace4 TBHP (3) MeCN 465 Ag2CO3 (3) MeCN N.R.6 (NH4)2S2O8 (3) MeCN N.R.7 (PhCOO)2 (3) MeCN 158 TBHP (3) AcOH MeCN 549 TBHP (3) TFA MeCN 3410 TBHP (4) AcOH MeCN 6211c TBHP (4) AcOH MeCN 6612d TBHP (4) AcOH MeCN 72

a Reaction conditions: 1a (0.3 mmol), 2a (0.9 mmol), Pd(OAc)2 (10 mol%), oxidant (quantity noted), additive (50 mol%), solvent (1 mL) at120 °C for 40 h in pressure tubes. b Isolated yield by flash columnchromatography. c 2a (1.2 mmol). d 2a (1.8 mmol).

Table 2 Scope of alcoholsa

a Reaction conditions: 1a (0.3 mmol), 2a–2j (1.8 mmol), Pd(OAc)2(10 mol%), TBHP (1.2 mmol), AcOH (50 mol%), MeCN (1 mL) at120 °C for 40 h in pressure tubes. b Isolated yield by flash columnchromatography.

Organic & Biomolecular Chemistry Paper

This journal is © The Royal Society of Chemistry 2013 Org. Biomol. Chem., 2013, 11, 2766–2771 | 2767

Publ

ishe

d on

26

Febr

uary

201

3. D

ownl

oade

d by

Sun

gkyu

nkw

an U

nive

rsity

on

30/0

5/20

13 0

2:45

:18.

View Article Online

http://dx.doi.org/10.1039/c3ob40140e

Heterocyclic triflamide 1i was also found to be reactive underthese reaction conditions. Finally, α-substituted N-benzyltrifla-mide 1j and N-phenethyltriflamides 1k and 1l also participatedin the oxidative coupling to furnish the corresponding pro-ducts 4j–4l with a slightly decreased reactivity.

Some control experiments were performed to obtainmechanistic insight. Treatment of N-benzyltriflamide 1a andbenzyl alcohol (2a) in the presence of the radical scavengerascorbic acid furnished the drastically reduced formation ofthe product 3a.6a,15 This result indicates that the reaction mayproceed through a radical pathway. To further support themechanistic pathway, some related experiments were per-formed. Benzyl alcohol (2a) was converted to the correspond-ing benzaldehyde in the presence of TBHP irrespective ofwhether Pd(OAc)2 was present or not. However, no acylationreaction between N-benzyltriflamide 1a and benzaldehyde wasobserved in the absence of TBHP even though a stoichiometricamount of Pd(OAc)2 was used.

On the basis of these collective data, a plausible mechan-ism is proposed (Scheme 1). First, a coordination of the Natom of 1a to Pd(II) and the subsequent cyclopalladationaffords a palladacycle I.16 At the same time, the alcohol can beoxidized to the corresponding aldehyde by TBHP and thet-BuȮ radical reacts with TBHP to generate the t-BuOȮradical,17 which can abstract an H atom from the aldehyde togive a reactive acyl radical.18 The palladacycle I can react withan acyl radical to provide the Pd(III) or Pd(IV) intermediate II,19

which can undergo reductive elimination to afford our product3a, and the Pd(II) catalyst is regenerated.

Conclusions

In conclusion, we demonstrated a Pd-catalyzed ortho-acylationof N-benzyltriflamides with benzylic and aliphatic alcoholsfrom the alcohol oxidation level via C–H bond activation.Further applications of this transformation to the total syn-thesis of biologically active compounds and more detailedmechanistic investigations are underway.

ExperimentalGeneral methods

Commercially available reagents were used without additionalpurification, unless otherwise stated. Sealed tubes (13 ×100 mm2) were purchased from Fischer Scientific and dried inan oven overnight and cooled under a stream of nitrogen priorto use. Thin layer chromatography was carried out using platescoated with Kieselgel 60F254 (Merck). For flash column chrom-atography, E. Merck Kieselgel 60 (230–400 mesh) was used.Nuclear magnetic resonance spectra (1H and 13C NMR) wererecorded on a Bruker Unity 400 MHz spectrometer for CDCl3solutions and chemical shifts are reported as parts per million(ppm) relative to, respectively, residual CHCl3 δH (7.24 ppm)and CDCl3 δC (77.2 ppm) as internal standards. Resonance pat-terns are reported with the notations s (singlet), d (doublet),t (triplet), q (quartet), sp (septet), and m (multiplet). Inaddition, the notation br is used to indicate a broad signal.Coupling constants (J) are reported in hertz (Hz). IR spectrawere recorded on a Varian 2000 Infrared spectrophotometerand are reported in cm−1. High-resolution mass spectra(HRMS) were recorded on a JEOL JMS-600 spectrometer.

General procedure for the synthesis of N-benzyltriflamides (1a–1l)

N-Benzyltriflamides were prepared from the correspondingbenzylamines and trifluoromethanesulfonic anhydride asdescribed in previous literature.14b

Table 3 Scope of N-benzyltriflamidesa

a Reaction conditions: 1b–1l (0.3 mmol), 2b (1.8 mmol), Pd(OAc)2(10 mol%), TBHP (1.2 mmol), AcOH (50 mol%), MeCN (1 mL) at120 °C for 40 h in pressure tubes. b Isolated yield by flash columnchromatography. c Combined yield of monoacylated product 4h andbisacylated compound 4hh.

Scheme 1 Plausible reaction mechanism.

Paper Organic & Biomolecular Chemistry

2768 | Org. Biomol. Chem., 2013, 11, 2766–2771 This journal is © The Royal Society of Chemistry 2013

Publ

ishe

d on

26

Febr

uary

201

3. D

ownl

oade

d by

Sun

gkyu

nkw

an U

nive

rsity

on

30/0

5/20

13 0

2:45

:18.

View Article Online

http://dx.doi.org/10.1039/c3ob40140e

Typical procedure for the acylation of N-benzyltriflamides

To an oven-dried sealed tube with 2-methoxybenzyltriflamide(1a) (80.8 mg, 0.3 mmol, 100 mol%), Pd(OAc)2 (6.6 mg,0.03 mmol, 10 mol%), TBHP (0.22 mL, 1.2 mmol, 400 mol%,5.5 M in decane), and AcOH (9 μL, 0.15 mmol, 50 mol%) inCH3CN (1 mL) was added benzyl alcohol (2a) (194.7 mg,1.8 mmol, 600 mol%). The reaction mixture was stirred at120 °C for 40 h. After cooling to room temperature, the reac-tion mixture was evaporated onto silica gel. Purification of theproduct by column chromatography (SiO2: n-hexanes–EtOAc)provided 3a (80.5 mg) in 72% yield.

1,1,1-Trifluoro-N-(6-benzoyl-2-methoxybenzyl)methanesulfo-namide (3a). Rf = 0.51 (n-hexanes–EtOAc = 4 : 1);

1H NMR(400 MHz, CDCl3) δ 7.79 (d, J = 7.4 Hz, 2H), 7.61 (t, J = 7.4 Hz,1H), 7.46 (t, J = 7.8 Hz, 2H), 7.37 (t, J = 8.0 Hz, 1H), 7.11 (d, J =8.0 Hz, 1H), 7.00 (d, J = 7.6 Hz, 1H), 6.28 (t, J = 5.9 Hz, 1H),4.48 (d, J = 6.1 Hz, 2H), 3.92 (s, 3H); 13C NMR (100 MHz,CDCl3) δ 198.3, 158.1, 139.7, 137.0, 133.7, 130.6, 129.1, 128.5,124.1, 122.3, 119.7 (q, JC–F = 319.5 Hz), 113.9, 56.0, 39.7; IR(KBr) ν 3306, 2946, 2844, 1655, 1582, 1461, 1420, 1374, 1285,1193, 1145, 1002, 949, 836 cm−1; HRMS (EI) Calcd forC16H14F3NO4S [M]

+ 373.0595, found 373.0591.1,1,1-Trifluoro-N-(2-methoxy-6-(4-methoxybenzoyl)benzyl)-

methanesulfonamide (3b). Rf = 0.45 (n-hexanes–EtOAc =4 : 1); 1H NMR (400 MHz, CDCl3) δ 7.78 (d, J = 7.8 Hz, 2H), 7.36(t, J = 7.6 Hz, 1H), 7.08 (d, J = 8.2 Hz, 1H), 6.92–6.99 (m, 3H),6.35 (br, 1H), 4.43 (s, 2H), 3.91 (s, 3H), 3.87 (s, 3H); 13C NMR(100 MHz, CDCl3) δ 196.7, 164.2, 158.1, 140.3, 133.2, 129.7,129.0, 123.8, 121.8, 119.7 (q, JC–F = 319.6 Hz), 113.8, 113.4,55.9, 55.6, 39.8; IR (KBr) ν 3303, 2942, 2844, 1646, 1510, 1462,1421, 1374, 1316, 1289, 1263, 1229, 1189, 1164, 1145, 1089,999, 848 cm−1; HRMS (EI) Calcd for C17H16F3NO5S [M]

+

403.0701, found 403.0702.1,1,1-Trifluoro-N-(2-methoxy-6-(4-(trifluoromethyl)benzoyl)-

benzyl)methanesulfonamide (3c). Rf = 0.50 (n-hexanes–EtOAc= 3 : 1); 1H NMR (400 MHz, CDCl3) δ 7.89 (d, J = 7.6 Hz, 2H),7.72 (d, J = 7.6 Hz, 2H), 7.39 (t, J = 7.4 Hz, 1H), 7.14 (d, J = 8.0Hz, 1H), 6.95 (d, J = 7.4 Hz, 1H), 6.20 (br, 1H), 4.51 (s, 2H),3.93 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 197.0, 158.3, 140.0,138.7, 134.8 (q, JC–F = 32.6 Hz), 130.8, 129.2, 125.5 (q, JC–F =3.6 Hz), 124.8, 123.5 (q, JC–F = 271.5 Hz), 122.3, 119.6 (q, JC–F =319.4 Hz), 114.4, 56.1, 39.6; IR (KBr) ν 3309, 3078, 2947, 2846,1659, 1597, 1462, 1374, 1285, 1231, 1193, 1089, 1001, 947,803 cm−1; HRMS (EI) Calcd for C17H13F6NO4S [M]

+ 441.0469,found 441.0466.

1,1,1-Trifluoro-N-(2-methoxy-6-(4-fluorobenzoyl)benzyl)-methanesulfonamide (3d). Rf = 0.48 (n-hexanes–EtOAc =4 : 1); 1H NMR (400 MHz, CDCl3) δ 7.86–7.88 (m, 2H), 7.43 (d,J = 7.6 Hz, 1H), 7.15–7.19 (m, 3H), 7.01–7.04 (m, 1H), 6.28 (br s,1H), 4.51 (s, 2H), 3.97 (s, 3H); 13C NMR (100 MHz, CDCl3) δ196.6, 166.1 (d, JC–F = 254.7 Hz), 158.2, 139.4, 133.4 (d, JC–F =5.0 Hz), 133.3, 129.2, 124.0, 121.9, 119.7 (q, JC–F = 319.6 Hz), 115.7(d, JC–F = 21.8 Hz), 113.9, 56.0, 39.7; IR (KBr) ν 3313, 2926, 1665,1584, 1414, 1326, 1284, 1192, 1141, 1066, 948, 859 cm−1; HRMS(EI) Calcd for C16H13F4NO4S [M]

+ 391.0501, found 391.0503.

1,1,1-Trifluoro-N-(2-methoxy-6-(3-methylbenzoyl)benzyl)-methanesulfonamide (3e). Rf = 0.45 (n-hexanes–EtOAc =4 : 1); 1H NMR (400 MHz, CDCl3) δ 7.61 (s, 1H), 7.55 (d, J =7.4 Hz, 1H), 7.34–7.43 (m, 3H), 7.11 (d, J = 8.0 Hz, 1H), 6.99 (d,J = 7.4 Hz, 1H), 6.28 (br s, 1H), 4.46 (s, 2H), 3.92 (s, 3H), 2.39(s, 3H); 13C NMR (100 MHz, CDCl3) δ 198.5, 158.1, 139.9,138.5, 137.1, 134.6, 130.9, 129.1, 128.3, 128.1, 124.1, 122.3,119.7 (q, JC–F = 319.5 Hz), 113.8, 56.0, 39.7, 21.3; IR (KBr) ν3314, 2948, 1652, 1584, 1461, 1421, 1374, 1287, 1230, 1191,1145, 1051, 961, 795 cm−1; HRMS (EI) Calcd for C17H16F3NO4S[M]+ 387.0752, found 387.0763.

1,1,1-Trifluoro-N-(2-methoxy-6-(3-chlorobenzoyl)benzyl)-methanesulfonamide (3f ). Rf = 0.45 (n-hexanes–EtOAc =4 : 1); 1H NMR (400 MHz, CDCl3) δ 7.76 (s, 1H), 7.65 (d, J =7.6 Hz, 1H), 7.57 (d, J = 7.8 Hz, 1H), 7.38–7.42 (m, 2H), 7.13(d, J = 8.1 Hz, 1H), 6.98 (d, J = 7.4 Hz, 1H), 6.16 (br s, 1H), 4.85(s, 2H), 3.93 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 196.7, 158.2,138.9, 138.6, 134.8, 133.6, 130.4, 129.8, 129.3, 128.7, 124.3,122.2, 119.7 (q, JC–F = 319.7 Hz), 114.3, 56.1, 39.7; IR (KBr) ν3317, 2968, 1660, 1585, 1462, 1421, 1374, 1284, 1192, 1086,957, 794 cm−1; HRMS (EI) Calcd for C16H13ClF3NO4S [M]

+

407.0206, found 407.0211.1,1,1-Trifluoro-N-(2-methoxy-6-(2-methoxybenzoyl)benzyl)-

methanesulfonamide (3g). Rf = 0.43 (n-hexanes–EtOAc =4 : 1); 1H NMR (400 MHz, CDCl3) δ 7.44 (t, J = 7.6 Hz, 1H), 7.38(d, J = 7.6 Hz, 1H), 7.20–7.24 (m, 1H), 6.85–7.02 (m, 1H), 6.35(br s, 1H), 4.54 (d, J = 5.6 Hz, 2H), 3.85 (s, 3H), 3.61 (s, 3H); 13CNMR (100 MHz, CDCl3) δ 199.1, 158.5, 157.8, 141.2, 133.8,131.1, 129.1, 128.3, 123.6, 122.5, 120.5, 119.8 (q, JC–F = 319.8Hz), 114.3, 111.9, 56.0, 55.7, 39.4; IR (KBr) ν 3303, 2942, 2844,1646, 1510, 1462, 1421, 1374, 1316, 1289, 1263, 1229, 1189,1164, 1145, 1089, 999, 848 cm−1; HRMS (EI) Calcd forC17H16F3NO5S [M]

+ 403.0701, found 403.0700.1,1,1-Trifluoro-N-(2-methoxy-6-(2-fluorobenzoyl)benzyl)-

methanesulfonamide (3h). Rf = 0.48 (n-hexanes–EtOAc =4 : 1); 1H NMR (400 MHz, CDCl3) δ 7.60–7.67 (m, 2H), 7.40 (t,J = 7.7 Hz, 1H), 7.30 (t, J = 7.4 Hz, 1H), 7.14–7.19 (m, 2H),7.05 (d, J = 7.4 Hz, 1H), 6.32 (br s, 1H), 4.64 (s, 2H), 3.96(s, 3H); 13C NMR (100 MHz, CDCl3) δ 195.7, 161.1 (d, JC–F =254.8 Hz), 158.1, 140.1, 134.8 (d, JC–F = 8.6 Hz), 131.7,129.4, 126.6 (d, JC–F = 11.7 Hz), 124.4 (d, JC–F = 3.7 Hz), 123.9,122.5 (d, JC–F = 2.1 Hz), 119.7 (q, JC–F = 319.5 Hz), 116.6(d, JC–F = 21.5 Hz), 114.9, 56.1, 39.4; IR (KBr) ν 3313, 2926,1665, 1584, 1414, 1326, 1284, 1192, 1141, 1066, 948, 859 cm−1;HRMS (EI) Calcd for C16H13F4NO4S [M]

+ 391.0501, found391.0503.

1,1,1-Trifluoro-N-(2-methoxy-6-(2-naphthoyl)benzyl)methane-sulfonamide (3i). Rf = 0.35 (n-hexanes–EtOAc = 4 : 1);

1H NMR(400 MHz, CDCl3) δ 8.20 (s, 1H), 7.86–7.96 (m, 4H), 7.60–7.63(m, 2H), 7.53–7.55 (m, 1H), 7.05–7.23 (m, 2H), 6.35 (br, 1H),4.50 (s, 2H), 3.95 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 198.2,158.2, 140.0, 135.8, 134.3, 132.1, 129.7, 129.1, 129.0, 128.6,127.9, 127.0, 125.3, 124.2, 122.3, 119.7 (q, JC–F = 319.6 Hz),113.9, 56.0, 39.8; IR (KBr) ν 3306, 3061, 2943, 1152, 1466, 1373,1291, 1192, 1082, 934, 867 cm−1; HRMS (EI) Calcd forC20H16F3NO4S [M]

+ 423.0752, found 423.0754.

Organic & Biomolecular Chemistry Paper

This journal is © The Royal Society of Chemistry 2013 Org. Biomol. Chem., 2013, 11, 2766–2771 | 2769

Publ

ishe

d on

26

Febr

uary

201

3. D

ownl

oade

d by

Sun

gkyu

nkw

an U

nive

rsity

on

30/0

5/20

13 0

2:45

:18.

View Article Online

http://dx.doi.org/10.1039/c3ob40140e

1,1,1-Trifluoro-N-(2-methoxy-6-(hexanoyl)benzyl)methane-sulfonamide (3j). Rf = 0.55 (n-hexanes–EtOAc = 4 : 1);

1H NMR(400 MHz, CDCl3) δ 7.37–7.41 (m, 1H), 7.29 (br s, 1H), 7.07 (brs, 1H), 6.31 (br s, 1H), 4.50 (s, 2H), 3.87 (s, 3H), 2.89 (br, 2H),1.68 (br, 2H), 1.31 (br, 4H), 0.88 (br, 3H); 13C NMR (100 MHz,CDCl3) δ 205.9, 158.1, 139.9, 129.6, 123.6, 120.7, 119.7 (q,JC–F = 319.6 Hz), 114.6, 56.1, 41.4, 39.2, 31.4, 24.1, 22.4, 13.9;IR (KBr) ν 3316, 2959, 2933, 2861, 1681, 1584, 1461, 1376,1229, 1192, 1146, 1050, 878 cm−1; HRMS (CI) Calcd forC15H21F3NO4S [M + H]

+ 368.1143, found 368.1139.1,1,1-Trifluoro-N-(2-(4-methoxybenzoyl)-6-methylbenzyl)-

methanesulfonamide (4b). Rf = 0.45 (n-hexanes–EtOAc =4 : 1); 1H NMR (400 MHz, CDCl3) δ 7.79 (d, J = 8.8 Hz, 2H), 7.40(d, J = 7.4 Hz, 1H), 7.23–7.31 (m, 2H), 6.94 (d, J = 8.8 Hz, 2H),6.50 (br, 1H), 4.31 (s, 2H), 3.87 (s, 3H), 2.53 (s, 3H); 13C NMR(100 MHz, CDCl3) δ 197.8, 164.2, 139.5, 139.2, 133.8, 133.5,133.2, 129.8, 128.0, 127.7, 119.7 (q, JC–F = 320.0 Hz), 113.8,55.6, 43.3, 19.5; IR (KBr) ν 3289, 2964, 2844, 1641, 1598, 1420,1372, 1263, 1229, 1189, 1029, 947, 848 cm−1; HRMS (EI) Calcdfor C17H16F3NO4S [M]

+ 387.0752, found 387.0754.1,1,1-Trifluoro-N-(2-fluoro-6-(4-methoxybenzoyl)benzyl)-

methanesulfonamide (4c). Rf = 0.48 (n-hexanes–EtOAc =4 : 1); 1H NMR (400 MHz, CDCl3) δ 7.82 (d, J = 8.8 Hz, 2H),7.44–7.49 (m, 1H), 7.28–7.37 (m, 2H), 7.00 (d, J = 8.8 Hz, 2H),6.70 (t, J = 6.0 Hz, 1H), 4.49 (d, J = 6.0 Hz, 2H), 3.92 (s, 3H); 13CNMR (100 MHz, CDCl3) δ 196.0 (d, JC–F = 2.4 Hz), 164.5, 161.1(d, JC–F = 250.0 Hz), 140.2 (d, JC–F = 2.0 Hz), 133.3, 129.7 (d, JC–F= 8.6 Hz), 129.3, 126.3 (d, JC–F = 3.4 Hz), 123.4 (d, JC–F = 16.0Hz), 119.6 (q, JC–F = 319.3 Hz), 119.0 (d, JC–F = 23.0 Hz), 114.0,55.7, 38.8 (d, JC–F = 5.6 Hz); IR (KBr) ν 3297, 2919, 2848, 1644,1598, 1459, 1377, 1288, 1230, 1171, 1060, 953, 848 cm−1;HRMS (EI) Calcd for C16H13F4NO4S [M]

+ 391.0501, found391.0499.

1,1,1-Trifluoro-N-(2-chloro-6-(4-methoxybenzoyl)benzyl)-methanesulfonamide (4d). Rf = 0.40 (n-hexanes–EtOAc =4 : 1); 1H NMR (400 MHz, CDCl3) δ 7.77 (d, J = 8.8 Hz, 2H), 7.60(d, J = 7.6 Hz, 1H), 7.31–7.38 (m, 2H), 6.95 (d, J = 8.8 Hz, 2H),6.44 (t, J = 6.0 Hz, 1H), 4.53 (d, J = 6.0 Hz, 2H), 3.88 (s, 3H); 13CNMR (100 MHz, CDCl3) δ 196.1, 164.6, 141.0, 136.5, 133.3,132.8, 132.6, 129.2, 129.1, 128.4, 119.7 (q, JC–F = 319.8 Hz),114.0, 55.7, 43.3; IR (KBr) ν 3292, 2926, 2846, 1644, 1597, 1511,1424, 1376, 1264, 1159, 1028, 944, 848 cm−1; HRMS (EI) Calcdfor C16H13ClF3NO4S [M]

+ 407.0206, found 407.0206.1,1,1-Trifluoro-N-(2-(4-methoxybenzoyl)-5-methylbenzyl)-

methanesulfonamide (4e). Rf = 0.45 (n-hexanes–EtOAc =4 : 1); 1H NMR (400 MHz, CDCl3) δ 7.80 (d, J = 8.8 Hz, 2H),7.29–7.43 (m, 2H), 7.25–7.28 (m, 1H), 6.98 (d, J = 8.8 Hz, 2H),6.80 (br, 1H), 4.34 (s, 2H), 3.92 (s, 3H), 2.47 (s, 3H); 13C NMR(100 MHz, CDCl3) δ 197.3, 164.0, 143.0, 136.7, 134.9, 133.0,132.4, 131.4, 130.1, 128.5, 119.6 (q, JC–F = 319.2 Hz), 113.8,55.6, 47.3, 21.4; IR (KBr) ν 3302, 2918, 2848, 1640, 1600, 1510,1419, 1262, 1231, 1170, 1059, 955, 849 cm−1; HRMS (EI) Calcdfor C17H16F3NO4S [M]

+ 387.0752, found 387.0753.1,1,1-Trifluoro-N-(2-(4-methoxybenzoyl)-5-chlorobenzyl)-

methanesulfonamide (4f ). Rf = 0.45 (n-hexanes–EtOAc =4 : 1); 1H NMR (400 MHz, CDCl3) δ 7.74 (d, J = 8.3 Hz, 2H), 7.54

(s, 1H), 7.38–7.44 (m, 2H), 6.95 (d, J = 8.3 Hz, 2H), 6.70 (br,1H), 4.29 (s, 2H), 3.88 (s, 3H); 13C NMR (100 MHz, CDCl3) δ196.2, 164.4, 138.4, 138.1, 136.0, 133.1, 132.2, 131.7, 129.4,119.6 (q, JC–F = 318.8 Hz), 114.0, 55.7, 46.7; IR (KBr) ν 3302,2928, 1644, 1571, 1421, 1374, 1293, 1231, 1150, 1121, 1062,935, 848 cm−1; HRMS (EI) Calcd for C16H13ClF3NO4S [M]

+

407.0206, found 407.0211.1,1,1-Trifluoro-N-(2-(4-methoxybenzoyl)-5-(trifluoromethyl)-

benzyl)methanesulfonamide (4g). Rf = 0.50 (n-hexanes–EtOAc= 3 : 1); 1H NMR (400 MHz, CDCl3) δ 7.76–7.80 (m, 3H), 7.69 (d,J = 8.0 Hz, 1H), 7.59 (d, J = 8.0 Hz, 1H), 6.96 (d, J = 8.4 Hz, 2H),6.60 (br s, 1H), 4.37 (s, 2H), 3.89 (s, 3H); 13C NMR (100 MHz,CDCl3) δ 196.0, 164.7, 141.1, 137.2, 133.5 (q, JC–F = 33.0 Hz),133.2, 130.7, 128.9, 128.4 (q, JC–F = 3.5 Hz), 125.0 (q, JC–F =3.5 Hz), 123.2 (q, JC–F = 271.1 Hz), 119.6 (q, JC–F = 318.8 Hz),114.1, 55.7, 46.7; IR (KBr) ν 3309, 3078, 2947, 2846, 1659, 1597,1462, 1374, 1285, 1231, 1193, 1089, 1001, 947, 803 cm−1; HRMS(EI) Calcd for C17H13F6NO4S [M]

+ 441.0469, found 441.0466.1,1,1-Trifluoro-N-(4-methoxy-2-(4-methoxybenzoyl)benzyl)-

methanesulfonamide (4h). Rf = 0.45 (n-hexanes–EtOAc = 3 : 1);1H NMR (400 MHz, CDCl3) δ 7.74 (d, J = 8.8 Hz, 2H), 7.405 (d, J =8.4 Hz, 1H), 6.98–7.00 (m, 1H), 6.87–6.90 (m, 3H), 6.61 (t, J =6.0 Hz, 1H), 4.21 (d, J = 6.1 Hz, 2H), 3.82 (s, 3H), 3.73 (s, 3H); 13CNMR (100 MHz, CDCl3) δ 196.9, 164.2, 158.7, 139.0, 133.1, 133.0,129.6, 128.5, 119.6 (q, JC–F = 318.9 Hz), 116.7, 116.6, 113.9, 55.7,55.6, 46.6; IR (KBr) ν 3283, 2924, 2847, 1646, 1599, 1510, 1422,1294, 1230, 1192, 1146, 1032, 959, 849 cm−1; HRMS (CI) Calcdfor C17H17F3NO5S [M + H]

+ 404.0780, found 404.0781.1,1,1-Trifluoro-N-(4-methoxy-2,6-bis(4-methoxybenzoyl)benzyl)-

methanesulfonamide (4hh). Rf = 0.20 (n-hexanes–EtOAc =3 : 1); 1H NMR (400 MHz, CDCl3) δ 7.83 (d, J = 8.8 Hz, 4H), 7.00(s, 2H), 6.95 (d, J = 8.8 Hz, 4H), 6.57 (t, J = 6.0 Hz, 1H), 4.31 (d,J = 6.0 Hz, 2H), 3.87 (s, 6H), 3.77 (s, 3H); 13C NMR (100 MHz,CDCl3) δ 196.0, 164.5, 157.8, 142.5, 133.2, 129.4, 125.5, 119.6 (q,JC–F = 319.9 Hz), 116.4, 114.0, 55.8, 55.6, 42.0; IR (KBr) ν 2938,2843, 1599, 1511, 1423, 1258, 1169, 1029, 961, 847 cm−1; HRMS(CI) Calcd for C25H23F3NO7S [M + H]

+ 538.1147, found 538.1147.1,1,1-Trifluoro-N-((3-(4-methoxybenzoyl)thiophen-2-yl)methyl)-

methanesulfonamide (4i). Rf = 0.45 (n-hexanes–EtOAc = 4 : 1);1H NMR (400 MHz, CDCl3) δ 7.80 (d, J = 8.3 Hz, 2H), 7.22–7.28(m, 2H), 7.10 (br, 1H), 6.96 (d, J = 8.3 Hz, 2H), 4.58 (s, 2H),3.88 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 190.7, 163.8, 144.8,138.7, 132.4, 130.5, 130.4, 124.4, 119.6 (q, JC–F = 318.8 Hz),113.8, 55.6, 41.1; IR (KBr) ν 3301, 2935, 1631, 1599, 1510, 1422,1376, 1283, 1261, 1230, 1191, 1173, 1058, 868 cm−1; HRMS (EI)Calcd for C14H12F3NO4S2 [M]

+ 379.0160, found 379.0158.(S)-1,1,1-Trifluoro-N-(1-(2-(4-methoxybenzoyl)phenyl)ethyl)-

methanesulfonamide (4j). Rf = 0.50 (n-hexanes–EtOAc = 5 : 1);1H NMR (400 MHz, CDCl3) δ 7.80 (d, J = 8.8 Hz, 2H), 7.36–7.54(m, 5H), 6.97 (d, J = 8.8 Hz, 2H), 4.79–4.86 (m, 1H), 3.90 (s,3H), 1.47 (d, J = 7.1 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ199.1, 164.4, 141.6, 136.7, 133.3, 131.8, 131.3, 130.0, 129.9,119.5 (q, JC–F = 318.9 Hz), 113.9, 56.1, 55.7, 22.5; IR (KBr) ν3225, 2923, 2851, 1647, 1597, 1426, 1377, 1262, 1193, 1152,1028, 932, 848 cm−1; HRMS (EI) Calcd for C17H16F3NO4S [M]

+

387.0752, found 387.0753.

Paper Organic & Biomolecular Chemistry

2770 | Org. Biomol. Chem., 2013, 11, 2766–2771 This journal is © The Royal Society of Chemistry 2013

Publ

ishe

d on

26

Febr

uary

201

3. D

ownl

oade

d by

Sun

gkyu

nkw

an U

nive

rsity

on

30/0

5/20

13 0

2:45

:18.

View Article Online

http://dx.doi.org/10.1039/c3ob40140e

1,1,1-Trifluoro-N-(2-methoxy-6-(4-methoxybenzoyl)phenethyl)-methanesulfonamide (4k). Rf = 0.45 (n-hexanes–EtOAc = 3 : 1);1H NMR (400 MHz, CDCl3) δ 7.95 (s, 1H), 7.80 (d, J = 8.2 Hz,2H), 7.28 (t, J = 8.0 Hz, 1H), 7.03 (d, J = 8.2 Hz, 1H), 6.89–6.93(m, 3H), 3.88 (s, 3H), 3.86 (s, 3H), 3.58–3.59 (m, 2H), 2.87–2.90(m, 2H); 13C NMR (100 MHz, CDCl3) δ 198.1, 164.5, 158.3,139.7, 133.6, 129.8, 127.4, 125.1, 124.6, 121.4, 119.7 (q, JC–F =317.8 Hz), 113.8, 112.6, 55.6, 43.0, 26.3; IR (KBr) ν 2924, 1936,1596, 1460, 1373, 1318, 1264, 1222, 1185, 1095, 965, 852 cm−1;HRMS (EI) Calcd for C18H18F3NO5S [M]

+ 417.0858, found417.0868.

1,1,1-Trifluoro-N-(2-fluoro-6-(4-methoxybenzoyl)phenethyl)-methanesulfonamide (4l). Rf = 0.45 (n-hexanes–EtOAc = 3 : 1);1H NMR (400 MHz, CDCl3) δ 7.78–7.84 (m, 3H), 7.24–7.35 (m,2H), 7.15 (d, J = 7.5 Hz, 1H), 6.94 (d, J = 8.2 Hz, 2H), 3.88 (s,3H), 3.59–3.63 (m, 2H), 2.93–2.96 (m, 2H); 13C NMR (100 MHz,CDCl3) δ 196.6 (d, JC–F = 2.6 Hz), 164.7, 161.9 (d, JC–F = 246.5Hz), 140.1 (d, JC–F = 3.2 Hz), 133.6, 129.3, 128.0 (d, JC–F =8.7 Hz), 125.4 (d, JC–F = 3.4 Hz), 124.5 (d, JC–F = 16.2 Hz), 119.7(q, JC–F = 319.6 Hz), 118.1 (d, JC–F = 22.4 Hz), 113.9, 55.7, 43.5,25.5 (d, JC–F = 2.9 Hz); IR (KBr) ν 2926, 1937, 1596, 1456, 1374,1264, 1220, 1186, 1081, 958, 853, 772 cm−1; HRMS (EI) Calcdfor C17H15F4NO4S [M]

+ 405.0658, found 405.0666.

Acknowledgements

This work was supported by the National Research Foundationof Korea (no. 2010-0002465) funded by the Ministry of Edu-cation, Science and Technology.

Notes and references

1 For recent reviews on C–C cross-coupling reactions, see:(a) J. Magano and J. R. Dunetz, Chem. Rev., 2011, 111, 2177;(b) N. Rodriguez and L. J. Goossen, Chem. Soc. Rev., 2011,40, 5030; (c) G. C. Fortman and S. P. Nolan, Chem. Soc. Rev.,2011, 40, 5151; (d) C. Liu, H. Zhang, W. Shi and A. Lei,Chem. Rev., 2011, 111, 1780.

2 For recent reviews on C–H bond activation, see:(a) L. Ackermann, Chem. Rev., 2011, 111, 1315;(b) S. H. Cho, J. Y. Kim, J. Kwak and S. Chang, Chem. Soc.Rev., 2011, 40, 5068; (c) J. Wencel-Delord, T. Dröge, F. Liuand F. Glorius, Chem. Soc. Rev., 2011, 40, 4740;(d) O. Baudoin, Chem. Soc. Rev., 2011, 40, 4902;(e) J. L. Bras and J. Muzart, Chem. Rev., 2011, 111, 1170.

3 For a recent review on catalytic acylation of sp2 C–H bonds,see: C. Pan, X. Jia and J. Cheng, Synthesis, 2012, 44, 677.

4 (a) X. Jia, S. Zhang, W. Wang, F. Luo and J. Cheng, Org.Lett., 2009, 11, 3120; (b) O. Baslé, J. Bidange, Q. Shuai andC.-J. Li, Adv. Synth. Catal., 2010, 352, 1145.

5 (a) J. Park, E. Park, A. Kim, Y. Lee, K.-W. Chi, J. H. Kwak,Y. H. Jung and I. S. Kim, Org. Lett., 2011, 13, 4390;(b) S. Sharma, E. Park, J. Park and I. S. Kim, Org. Lett.,2012, 14, 906; (c) S. Sharma, J. Park, E. Park, A. Kim,

M. Kim, J. H. Kwak, Y. H. Jung and I. S. Kim, Adv. Synth.Catal., 2013, 355, 332.

6 (a) C.-W. Chan, Z. Zhou, A. S. C. Chan and W.-Y. Yu, Org.Lett., 2010, 12, 3926; (b) Y. Yang, B. Zhou and Y. Li, Adv.Synth. Catal., 2012, 354, 2916.

7 (a) Y. Wu, B. Li, F. Mao, X. Li and F. Y. Kwong, Org. Lett.,2011, 13, 3258; (b) C.-W. Chan, Z. Zhou and W.-Y. Yu, Adv.Synth. Catal., 2011, 353, 2999; (c) C. Li, L. Wang, P. Li andW. Zhou, Chem.–Eur. J., 2011, 17, 10208.

8 B. Zhou, Y. Yang and Y. Li, Chem. Commun., 2012, 48, 5163.9 (a) P. Fang, M. Li and H. Ge, J. Am. Chem. Soc., 2010, 132,

11898; (b) M. Li and H. Ge, Org. Lett., 2010, 12, 3464;(c) M. Kim, J. Park, S. Sharma, A. Kim, E. Park, J. H. Kwak,Y. H. Jung and I. S. Kim, Chem. Commun., 2013, 49, 925;(d) J. Park, M. Kim, S. Sharma, E. Park, A. Kim, S. H. Lee,J. H. Kwak, Y. H. Jung and I. S. Kim, Chem. Commun., 2013,49, 1654.

10 F. Xiao, Q. Shuai, F. Zhao, O. Baslé, G. Deng and C.-J. Li,Org. Lett., 2011, 13, 1614.

11 Y. Yuan, D. Chen and X. Wang, Adv. Synth. Catal., 2011,353, 3373.

12 (a) G. Sartori and R. Maggi, Advances in Friedel-Crafts Acyl-ation Reactions, CRC Press, FL, 2010; (b) G. A. Olah, Friedel-Crafts Chemistry, Wiley, New York, 1973.

13 For selected reviews, see: (a) G. E. Dobereiner andR. H. Crabtree, Chem. Rev., 2010, 110, 681; (b) G. Guillena,D. J. Ramón and M. Yus, Angew. Chem., Int. Ed., 2007, 46,2358; (c) G. Tojo and M. Fernández, Oxidation of Alcohols toAldehydes and Ketones, Springer, Berlin, Germany, 2006;(d) J. F. Bower, I. S. Kim, R. L. Patman and M. J. Krische,Angew. Chem., Int. Ed., 2009, 48, 34.

14 For ortho-iodination and alkenylation of N-benzyltrifla-mides, see: (a) J.-J. Li, T.-S. Mei and J.-Q. Yu, Angew. Chem.,Int. Ed., 2008, 47, 6452; For ortho-fluorination of N-benzyl-triflamides, see: (b) X. Wang, T.-S. Mei and J.-Q. Yu, J. Am.Chem. Soc., 2009, 131, 7520.

15 J. J. Warren and J. M. Mayer, J. Am. Chem. Soc., 2010, 132,7784.

16 For a review on palladacycles, see: J. Dupont, C. S. Consortiand J. Spencer, Chem. Rev., 2005, 105, 2527.

17 (a) A. J. Catino, J. M. Nichols, H. Choi, S. Gottipamula andM. P. Doyle, Org. Lett., 2005, 7, 5167; (b) E. C. McLaughlin,H. Choi, K. Wang, G. Chiou and M. P. Doyle, J. Org. Chem.,2009, 74, 730.

18 For a review of acyl radicals, see: (a) C. Chatgilialoglu,D. Crich, M. Komatsu and I. Ryu, Chem. Rev., 1999, 99,1991; For recent selected examples of acyl radicals, see:(b) Z. Shi and F. Glorius, Chem. Sci., 2013, 4, 829; (c) Z. Liu,J. Zhang, S. Chen, E. Shi, Y. Xu and X. Wan, Angew. Chem.,Int. Ed., 2012, 51, 3231.

19 (a) N. R. Deprez and M. S. Sanford, J. Am. Chem. Soc., 2009,131, 11234; (b) J. M. Racowski, A. R. Dick andM. S. Sanford, J. Am. Chem. Soc., 2009, 131, 10974;(c) D. C. Powers and T. Ritter, Nat. Chem., 2009, 1, 302;(d) D. C. Powers, M. A. L. Geibel, J. E. M. N. Klein andT. Ritter, J. Am. Chem. Soc., 2009, 131, 17050.

Organic & Biomolecular Chemistry Paper

This journal is © The Royal Society of Chemistry 2013 Org. Biomol. Chem., 2013, 11, 2766–2771 | 2771

Publ

ishe

d on

26

Febr

uary

201

3. D

ownl

oade

d by

Sun

gkyu

nkw

an U

nive

rsity

on

30/0

5/20

13 0

2:45

:18.

View Article Online

http://dx.doi.org/10.1039/c3ob40140e