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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: [email protected]; 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
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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
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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 ©
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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
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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
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-
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.
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Organic & Biomolecular Chemistry Paper
This journal is © The Royal Society of Chemistry 2013 Org.
Biomol. Chem., 2013, 11, 2766–2771 | 2771
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