Improved synthesis of phenylethylamine derivatives by Negishi cross-coupling reactions

Article abstract of DOI:10.1016/j.tet.2010.09.074

Trifluoroacetamido-protected β-aminoalkylzinc iodides undergo Negishi cross-coupling reaction with aryl iodides in moderate to excellent yields (42-84%) based on the corresponding trifluoroacetamido-protected β-aminoalkyl iodides, employing a catalyst pre

Full text of DOI:10.1016/j.tet.2010.09.074

Tetrahedron 66 (2010) 9175e9181
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Improved synthesis of phenylethylamine derivatives by Negishi cross-coupling
reactions
y
*
Craig M.L. Goddard, Ahmad Reza Massah , Richard F.W. Jackson
Department of Chemistry, Dainton Building, The University of Sheffield, Brook Hill, Sheffield, S3 7HF, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 17 July 2010
Received in revised form 6 September 2010
Accepted 20 September 2010
Available online 24 September 2010
Trifluoroacetamido-protected
b-aminoalkylzinc iodides undergo Negishi cross-coupling reaction with
aryl iodides in moderate to excellent yields (42e84%) based on the corresponding trifluoroacetamido-
protected -aminoalkyl iodides, employing a catalyst prepared in situ from Pd2(dba)3 and SPhos (1:2 M
b
ratio). In general, meta- and para-substituted aryl iodides give good results using relatively low levels of
catalyst [0.25 mol % Pd2(dba)3], but more hindered ortho-substituted examples require higher catalyst
loadings. The preparation of trifluoroacetamido-protected b-aminoalkyl iodides is straightforward, and
the intermediates are significantly more stable than the corresponding Boc-protected derivatives.
Ó 2010 Elsevier Ltd. All rights reserved.
1. Introduction
available straightforwardly from amino acids. The yields in the
Pd-catalysed Negishi cross-coupling were generally moderate,4 al-
Chiral primary amines 1 continue to attract attention as syn-
thetic targets. A very recent review highlighted approaches, which
involve an asymmetric step, specifically N-acylenamide and en-
amine reduction, reductive amination and imine reduction.1 These
approaches are least effective when the two substituents are of
comparable steric bulk (R1eR2), since facial discrimination is then
more challenging. As an alternative to the asymmetric synthesis
approach, methods have been developed, which rely on use of the
chiral pool, for example, by reaction of carbon nucleophiles with
enantiomerically pure aziridines 2, generally prepared from enan-
tiomerically pure amino acids, leading to amines of general struc-
ture 3.2,3 This method is in principle appropriate for making chiral
primary amines when the two substituents are of comparable steric
bulk.
though they were based on the more valuable protected
amine, and therefore also reflect the efficiency of the zinc insertion
process, as well as the tendency of protected -aminoalkylzinc io-
dides to undergo -elimination.
b-iodo-
b
b
NHBoc
X
BF3
K
PGHN
R1
4
7
X = Ar
5, X = ZnI
6
, X = I
Related
b-benzamidoethylzinc iodides had been prepared by
Knochel, and converted into the corresponding zinc/copper re-
agents by transmetallation with CuCN$2LiCl prior to subsequent
allylation.6 More recently, Molander has shown that very stable
NH2
R2
NH2
potassium
b-aminoethyltrifluoroborates 7 can undergo efficient
NTs
R3
SuzukieMiyaura cross-coupling with aryl halides and triflates,7,8
R1
R1
R1
3
R1 ~ R2
although this method has not yet been applied to substituted chi-
ral potassium b-aminoalkyltrifluoroborates.
1
2
We have recently uncovered computational and (circumstan-
tial) experimental evidence that a combination of internal co-
ordinating groups, and Lewis basic solvents, can promote (partial)
ionisation of the zinc iodine bond in alkylzinc iodides, forming tight
ion pairs.9,10 Such behaviour provides a credible explanation for the
high functional group tolerance of alkylzinc iodides, as well as the
Some time ago, we reported that enantiomerically pure phen-
ylethylamines 4 could be prepared by Pd-catalysed Negishi cross-
coupling of chiral non-racemic
iodides.4,5 The protected
-aminoalkylzinc iodides are prepared
from the corresponding protected -iodoamines 6, themselves
b-aminoalkylzinc iodides 5 with aryl
b
b
(relative) stability of
We have also shown that replacement of the Boc-protecting group
by the more electron withdrawing TFA group results in -amino-
alkylzinc iodides that can be more reactive in Negishi cross-cou-
pling reactions, but are also substantially more stable towards
b-aminoalkylzinc iodides towards elimination.
* Corresponding author. Tel.: þ44 114 222 9464; fax: þ44 114 222 9303; e-mail
b
address: r.f.w.jackson@shef.ac.uk (R.F.W. Jackson).
y
Present address: Department of Chemistry, Islamic Azad University, Shahreza
Branch, Shahreza Isfahan, P.O. Box 86145-311, Iran.
0040-4020/$ e see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.09.074

9176
C.M.L. Goddard et al. / Tetrahedron 66 (2010) 9175e9181
b
-elimination.11 The reason for this, at first sight, counterintuitive
2. Results and discussion
result is that the mechanism of the
b-elimination is altered by the
change in protecting group. Specifically, the Boc-protected
b
-ami-
Prior to exploring the influence of the TFA-protecting group, the
application of the catalyst derived from Pd2(dba)3/SPhos to the
cross-coupling of the zinc reagent derived from the Boc-protected
noalkylzinc iodide 8 (derived from aspartic acid) decomposes by
a first order process, which we have proposed to occur by a syn-
elimination promoted by coordination of the electron-rich carba-
mate carbonyl group to zinc (Eq. 1), needed to compensate for the
(partial) ionisation of the zinceiodine bond. In contrast, the anal-
b-aminoalkyl iodide 14 was investigated. In our previous studies,
Negishi cross-coupling of this reagent with 4-iodotoluene using
Pd2(dba)3/(o-tol)3P as catalyst gave the product 15 in 59% yield.4
Use of Pd2(dba)3/SPhos under comparable conditions showed
a modest, but probably significant, improvement in yield to 66%
(Scheme 2).
ogous TFA-protected b-aminoalkylzinc iodide 9 undergoes elimi-
nation by a second order process,11 required because the less
electron-rich TFA-carbonyl group is now unable to coordinate
sufficiently strongly to the alkylzinc iodide to promote elimination,
which therefore probably proceeds through the dialkylzinc reagent
10 (Eq. 2).
Me
NHBoc
I
BocHN
Ph
1) Zn, I2, DMF
Ph
2) SPhos/Pd2dba3
4-MeC6H4-I
14
15, 66%
b-aminoalkylzinc iodide.
Scheme 2. Cross-coupling of Boc-protected
The TFA-protected phenylalanine and valine-derived iodides 16
and 17 were selected to exemplify our approach, and were
straightforwardly prepared from the corresponding amino alcohols
by TFA-protection14 and iodination (Scheme 3). The yields in the
iodination step are consistently higher than those obtained for
iodination of the corresponding Boc-protected derivatives,4 partly
because the TFA-iodides are more stable than the corresponding
Boc-iodides.
Furthermore, we have very recently established that Buchwald’s
biarylphosphine ligands (specifically SPhos 11)12 in combination
with Pd2(dba)3 are effective for the Negishi cross-coupling of the
serine-derived organozinc reagent 12 with aryl halides, giving high
yields of phenylalanine derivatives 13, and in many cases permit-
ting lower levels of Pd to be used (Scheme 1).13 It therefore
appeared that an investigation of the synthesis of chiral phenyl-
I2, PPh3,
H2N
R
TFAHN
R
imidazole TFAHN
TFAA
NEt3
OH
OH
I
R
R = PhCH2
R = Pr
16, R = PhCH2 (84%)
18, R = PhCH2 (95%)
i
i
i
17, R = Pr (70%)
19, R = Pr (85%)
ethylamines by Negishi cross-coupling of TFA-protected b-amino-
Scheme 3. Preparation of trifluoroacetamido iodides.
alkylzinc iodides with aryl iodides, catalysed by Pd2(dba)3/SPhos
would be fruitful. We report here the results of this study.
Conversion of the iodides 16 and 17 into the organozinc reagents
20 and 21, respectively, was carried out using zinc activated with
iodine, in DMF as solvent. Although we had established that
Pd2(dba)3 was superior to Pd(OAc)2 in the synthesis of phenylala-
nine derivatives by Negishi coupling,13 these two sources of palla-
dium were initially compared, since Knochel had successfully used
a combination of Pd(OAc)2 and SPhos for related Negishi coupling
reactions.15e17 Nevertheless, as is evident from Table 1, entry 1, the
use of Pd2(dba)3 (2.5 mol %) in combination with SPhos (5 mol %)
NHBoc
CO2Me
NHBoc
1. Zn*, DMF
Ar
I
PCy2
OMe
11
CO2Me
12
2. ArX, Pd2(dba)3
SPhos
MeO
13
Scheme 1. Use of SPhos to prepare phenylalanine derivatives.
Table 1
Synthesis of N-TFA-protected phenylalanine derivatives 22 and 23
Entry
1
Aryl iodide
Iodoamine
Product
Yield (%) method Aa
74 (55)c
Yield (%) method Bb
70
22a
22b
2
3
72
60
65
50
22c
22d
4
84
72

C.M.L. Goddard et al. / Tetrahedron 66 (2010) 9175e9181
9177
Table 1 (continued)
Entry
Aryl iodide
Iodoamine
Product
Yield (%) method Aa
Yield (%) method Bb
5
22e
61
32
6
7
8
22f
68
80
70
35
71
67
22g
22h
9
22i
67
42
10
11
23a
23b
63
70
58
42
12
23c
57
37
13
14
23d
23e
74
42
d
d
15
23f
51
61
d
16
23g
60
a
Method A: iodoamine (1 mmol), aryl iodide (1.3 mmol), SPhos (5 mol %), Pd2dba3 (2.5 mol %), Zn (3 mmol), DMF (1 mL).
Method B: iodoamine (1 mmol), aryl iodide (1.3 mmol), SPhos (0.5 mol %), Pd2dba3 (0.25 mol %), Zn (3 mmol), DMF (0.3 mL).
Using Pd(OAc)2 (5 mol %) in place of Pd2dba3 (2.5 mol %).
b
c
gave a higher yield than was obtained with Pd(OAc)2, so all sub-
4-iodophenol,18 presumably due to competitive protonation by the
phenolic proton under conditions with lower catalyst concentra-
tion, and therefore a reduced rate of cross-coupling. It is appro-
priate to highlight that the amount of solvent employed under
conditions B corresponds to approximately 4 mol of DMF for each
mole of organozinc reagent. The DMF is therefore best considered
as a stoichiometric reagent, acting as a ligand for zinc.
sequent reactions were conducted using Pd2(dba)3. Cross-coupling
of zinc reagent 20 with a range of aryl iodides, using Pd2(dba)3
(2.5 mol %) in combination with SPhos (5 mol %) as catalyst
(method A), proceeded to give the phenylethylamine derivatives 22
in good yield (Scheme 4, Table 1), representing a substantial im-
provement on the previous method that we have reported using
Boc-protected reagents.4 Analogous couplings of the valine-derived
organozinc iodide 21 gave the products 23 (Table 1). In general,
only a marginal decrease in yield was observed when the catalyst
loading was reduced by a factor of 10, and the amount of solvent
also substantially reduced (0.3 mL of DMF per mmol, method B).
As we had previously observed, this decrease in yield was more
pronounced for ortho-substituted aryl iodides, and also for
Zn, I2
DMF
TFAHN
R
TFAHN
R
20, R = PhCH2 Pd2dba3
21, R = Pr
TFAHN
R
ArI
I
ZnI
Ar
SPhos
16, R = PhCH2
17, R = iPr
22, R = PhCH2
23, R = Pr
i
i
Scheme 4. Negishi cross-coupling of trifluoroacetamido zinc iodides.

9178
C.M.L. Goddard et al. / Tetrahedron 66 (2010) 9175e9181
3. Conclusions
FTIR (nmax/cmꢁ1): 3298, 3100, 2954, 1698, 1564, 1178; dH (400 MHz,
CDCl3) 2.82 (1H, dd, J 14.0, 8.0, CHAHBPh), 2.92 (1H, dd, J 14.0, 6.0,
CHAHBPh), 3.14 (1H, dd, J 10.5, 4.0, CHAHBI), 3.35 (1H, dd, J 10.5, 4.0,
CHAHBI), 3.94e3.86 (1H, m, CHNHTFA), 6.23e6.33 (1H, br, NH),
TFA-protected b-aminoalkylzinc iodides are easy to prepare and
react with good to excellent yields in Negishi cross-coupling re-
actions with aryl iodides, catalysed by a combination of Pd2(dba)3
and SPhos. In the case of 4- and 3-substituted aryl iodides, low
loadings of catalyst (0.5 mol % Pd) are sufficient to achieve satis-
factory results. In addition the key TFA-iodides are more efficiently
prepared, and substantially more stable, than the corresponding
Boc-iodides, so it is clear that TFA is an excellent choice of pro-
tecting group for the synthesis of phenylethylamines using the
Negishi coupling.
7.16e7.30 (5H, m, Ph); dC (100 MHz, CDCl3) 10.4, 39. 9, 50.7, 115.6 (q,
22
J 286), 127.5, 129.0, 129.1, 135.6, 156.5 (q, J 35); [
a]
þ16.9 (c 1.0,
D
CHCl3); m/z (ES) Found: MHþ 357.9912. C11H12NOIF3 requires MHþ
357.9916.
4.2.2. (S)-(ꢁ)-2,2,2-Trifluoro-N-(1-iodo-3-methylbutane-2-yl)acet-
amide 17. General iodination procedure was followed using
(S)-2,2,2-trifluoro-N-(1-hydroxy-3-methylbutane-2-yl)acetamide
19 (1.99 g, 10.0 mmol) and gave, after purification by silica gel
column (5% ethyl acetate in petroleum ether), the iodide (2.35 g,
70%) as a white solid; mp 114e116 ꢀC; FTIR (nmax/cmꢁ1): 3274, 3106,
2974, 1700, 1562; 1162; dH (400 MHz, CDCl3) 0.99 (3H, d, J 6.6,
CH3CH), 1.05 (3H, d, J 6.6, CH3CH), 1.83e1.97 (1H, m, (CH3)2CH), 3.38
(1H, dd, J 10.6, 4.8, CHAHBI), 3.46 (1H, dd, J 10.6, 3.5, CHAHBI),
3.48e3.54 (1H, m, CHNHTFA), 6.20e6.36 (1H, br, NH); dC (100 MHz,
4. Experimental
4.1. General
All reagents used were obtained commercially and were not
purified further. The SPhos was obtained from two sources, Alfa
AesarÒ and AldrichÒ; the SPhos obtained from AldrichÒ was ground
before use. All solvents used were of HPLC quality and purchased
from Fischer ScientificÒ. Petroleum ether refers to the fraction that
boils in the range of 40e60 ꢀC. The DMF was distilled from calcium
CDCl3) 9.8, 18.3, 19.0, 32.3, 55.2, 115.0 (q, J 288), 158 (q, J 37);
22
[a
]
ꢁ42.0 (c 1.0, CHCl3); m/z (ES) Found: MHþ 309.9918.
D
C7H11NOIF3 requires MHþ 309.9916.
ꢀ
hydride and kept under an inert atmosphere over 4 A molecular
4.3. Cross-coupling reaction: method A
sieves. All columns were monitored using TLC, on pre-coated silica
plates, TLC plates visualised by Ultra Violet light and potassium
permanganate dip. Flash column chromatography was performed
under pressure, using silica gel 60 from Davisil Fluorochem. 1H and
13C NMR spectra were recorded on a Bruker AV-400 spectrometer
at room temperature. Samples were dissolved in CDCl3. Coupling
constants are measured in Hertz and are quoted to the nearest
0.1 Hz and chemical shifts are quoted in parts per million relative to
the residual chloroform peak. Melting points were determined
using a Linkham HFS91 heating stage, with a TC92 controller. The
temperatures are uncorrected. Optical rotations were determined
using an AA-10 Automatic Polarimeter, at 589 nm. High-resolution
mass spectra were recorded using a MicroMass LCT operating in
electrospray (ES) mode. Infra red spectra were measured on a Per-
kineElmer Paragon RX I FT-IR spectrophotometer. Wavenumbers
are quoted to the nearest whole number. The TFA-protected phe-
nylalaninol derivative 18 was prepared by the literature method,14
and the corresponding valinol derivative 1919 was prepared by
a minor modification of the literature method,14 using a smaller
molar excess of trifluoroacetic anhydride (1.2 equiv rather than
1.4 equiv).
Zinc dust (190 mg, 3 mmol) was added to a flame dried, nitrogen
purged side arm round bottom flask. Dry DMF (1 mL) was added via
syringe followed by
a catalytic amount of iodine (40 mg,
0.15 mmol). A colour change of the DMF was observed from
colourless to yellow and back again. (S)-2,2,2-Trifluoro-N-(1-iodo-
3-phenylpropan-2-yl)acetamide 16 (356 mg, 1 mmol) or (S)-2,2,2-
trifluoro-N-(1-iodo-3-methylbutane-2-yl)acetamide 17 (309 mg,
1 mmol) was added immediately followed by a catalytic amount of
iodine (40 mg, 0.15 mmol). The solution was stirred at room tem-
perature and gave a noticeable exotherm. When the solution had
cooled Pd2dba3 (22 mg, 0.025 mmol), SPhos (21 mg, 0.05 mmol)
and aryl iodide (1.3 mmol) were added to the flask and left to stir at
room temperature overnight, under positive pressure of nitrogen.
The crude reaction mixture was applied directly to a silica gel
column to afford the purified cross-coupled product.
4.4. Cross-coupling reaction: method B
Zinc dust (190 mg, 3 mmol) was added to a flame dried, nitrogen
purged side arm round bottom flask. Dry DMF (0.3 mL) was added
via syringe followed by a catalytic amount of iodine (40 mg,
0.15 mmol). A colour change of the DMF was observed from
colourless to yellow and back again. (S)-2,2,2-Trifluoro-N-(1-iodo-
3-phenylpropan-2-yl)acetamide 16 (356 mg, 1 mmol) or (S)-2,2,2-
trifluoro-N-(1-iodo-3-methylbutane-2-yl)acetamide 17 (309 mg,
1 mmol) was added immediately followed by a catalytic amount of
iodine (40 mg, 0.15 mmol). The solution was stirred at room tem-
perature and gave a noticeable exotherm. In a separate flame dried
nitrogen purged flask Pd2dba3 (11 mg, 0.0125 mmol), was added
followed by dry DMF (0.25 mL). In a separate flame dried nitrogen
purged flask, SPhos (11 mg, 0.025 mmol) was added followed by
dry DMF (0.25 mL). Once the zinc insertion has cooled the palla-
4.2. Iodination procedure
The alcohol (10.0 mmol) was added by syringe over 30 min to
a stirred solution of triphenylphosphine (2.75 g, 10.5 mmol), im-
idazole (0.71 g, 10.5 mmol) and iodine (2.66 g, 10.5 mmol) in dry
CH2Cl2 (30 mL) under nitrogen at room temperature and the re-
action mixture was left overnight. The precipitate was removed by
filtration, the filtrate concentrated under reduced pressure and the
residue dissolved in ethyl acetate (150 mL). The insoluble material
was removed by filtration and the filtrate was washed with satu-
rated sodium thiosulfate solution (50 mL) and brine (50 mL), dried
over MgSO4 and evaporated under reduced pressure. The crude
product was purified by silica gel column chromatography.
dium solution (50 mL, 0.0025 mmol) and SPhos solution (50 mL,
0.005 mmol) were added via syringe followed by aryl iodide
(1.3 mmol). The reaction was allowed to stir at room temperature
overnight under positive pressure of nitrogen. The crude reaction
mixture was applied directly to a silica gel column to afford the
purified cross-coupled product.
4.2.1. (S)-(þ)-2,2,2-Trifluoro-N-(1-iodo-3-phenyl-propan-2-yl)acet-
amide 16. General iodination procedure was followed using
(S)-2,2,2-trifluoro-N-(1-hydroxy-3-phenylpropan-2-yl)acetamide
18 (2.35 g, 10.0 mmol) and gave, after purification by silica gel
column (5% ethyl acetate in petroleum ether), the iodide (3.0 g,
84%) as a white solid; mp 132e133 ꢀC; Rf 0.54 (20% EtOAc in petrol);
4.4.1. (S)-(ꢁ)-2,2,2-Trifluoro-N-(1-(4-methoxyphenyl)-3-phenyl-
propan-2-yl)acetamide 22a. General cross-coupling method A was

C.M.L. Goddard et al. / Tetrahedron 66 (2010) 9175e9181
9179
followed using 4-iodoanisole (304 mg, 1.3 mmol) and gave, after
purification by silica gel column (5% ethyl acetate in petroleum
ether), the title compound (249 mg, 74%) as a white solid.
in petrol); FTIR (nmax/cmꢁ1): 3302, 3030, 2933,1698,1562,1162, 878,
757; dH (400 MHz, CDCl3) 2.26 (3H, s, CH3), 2.69e2.82 (3H, m), 2.86
(1H, dd, J 14.0, 6.5), 4.32e4.42 (1H, m, CHNHTFA), 5.9e5.97 (1H, br,
NH), 6.99 (2H, d, J 8.0, C6H4eCH3), 7.04e7.28 (7H, m, ArH); dC
General cross-coupling method B was followed using 4-iodoa-
nisole (304 mg, 1.3 mmol) and gave, after purification by silica gel
column (5% ethyl acetate in petroleum ether), the title compound
(236 mg, 70%) as a white solid; mp 141.5e143 ꢀC; Rf 0.44 (20% EtOAc
in petrol); FTIR (nmax/cmꢁ1): 3311, 3021, 2958, 1691, 1609, 1555,
1510, 1215, 1125, 1152, 1030, 840, 808; dH (400 MHz, CDCl3) 2.80
(1H, dd, J 15.0, 7.0), 2.83 (1H, dd, J 15.0, 7.0), 2.90 (1H, dd, J 14.0, 6.0),
2.95 (1H, dd, J 14.0, 6.0), 3.82 (3H, s, OCH3), 4.39e4.49 (1H, m,
CHNHTFA), 5.97e6.05 (1H, br, NH), 6.86e6.91 (2H, m, C6H4eOCH3),
7.09e7.13 (2H, m, C6H4eOCH3), 7.17e7.37 (5H, m, Ph); dC (100 MHz,
(100 MHz, CDCl3) 21.0, 38.9, 39.3, 52.4, 115.7 (q, J 287), 127.0, 128.7,
22
129.1, 129.2, 129.4, 133.5, 136.6, 136.7, 156.6 (q, J 37); [
a
]
ꢁ2.0 (c
D
1.01, CHCl3); m/z (ES) Found: MHþ 322.14.34. C18H19NOF3 requires
MHþ 322.1419.
4.4.5. (S)-(þ)-2,2,2-Trifluoro-N-(1-phenyl-3-o-tolylpropan-2-yl)
acetamide 22e. General cross-coupling method A was followed
using 2-iodotoluene (166 mL, 1.3 mmol) and gave, after purification
by silica gel column (5% ethyl acetate in petroleum ether), the title
compound (196 mg, 61%) as a white solid.
CDCl3) 38.5, 39.3, 52.5, 55.3, 114.1, 118.6 (q, J 287), 127.0, 128.6, 128.7,
22
129.2, 130.2, 136.7, 156.6 (q, J 37), 158.6; [
a
]
D
ꢁ2.0 (c 1.01, CHCl3);
General cross-coupling method B was followed using 2-iodo-
toluene (166 mL, 1.3 mmol) and gave, after purification by silica gel
m/z (ES) Found: MHþ 338.1352. C18H19NO2F3 requires MHþ
338.1368.
column (5% ethyl acetate in petroleum ether), the title compound
(103 mg, 32%) as a white solid; mp 142.5e143.5 ꢀC; Rf 0.57 (20%
EtOAc in petrol); FTIR (nmax/cmꢁ1): 3306, 3024, 2925, 1697, 1559,
1163, 877, 749; dH (400 MHz, CDCl3) 2.27 (3H, s, CH3), 2.82 (1H, dd, J
14.0, 8.0), 2.86e3.00 (3H, m), 4.35e4.46 (1H, m, CHNHTFA),
6.06e6.13 (1H, br, NH), 7.05e7.35 (9H, m, ArH); dC (100 MHz, CDCl3)
4.4.2. (S)-(ꢁ)-2,2,2-Trifluoro-N-(1-(3-methoxyphenyl)-3-phenyl-
propan-2-yl)acetamide 22b. General cross-coupling method A was
followed using 3-iodoanisole (155
purification by silica gel column (5% ethyl acetate in petroleum
ether), the title compound (242 mg, 72%) as a white solid.
General cross-coupling method B was followed using 3-iodoa-
mL, 1.3 mmol) and gave, after
19.4, 37.3, 39.9, 51.8, 115.7 (q, J 287), 126.1, 127.0, 127.1, 128.8, 129.2,
22
129.7, 130.8, 135.1, 136.4, 136.8, 156.7 (q, J 37); [
a
]
D
þ19.1 (c 1.0,
nisole (155
m
L, 1.3 mmol) and gave, after purification by silica gel
CHCl3); m/z (ES) Found: MHþ 322.1414. C18H19NOF3 requires MHþ
column (5% ethyl acetate in petroleum ether), the title compound
(219 mg, 65%) as a white solid; mp 137.2e138.5 ꢀC; Rf 0.46 (20%
EtOAc in petrol); FTIR (nmax/cmꢁ1): 3028, 2929, 1699, 1610, 1584,
1455, 1260, 1220, 1165, 1057, 876, 782, 754; dH (400 MHz, CDCl3)
2.75 (1H, dd, J 14.0, 7.0), 2.77 (1H, dd, J 14.0, 7.0), 2.84 (1H, dd, J 12.0,
6.5), 2.87 (1H, dd, J 12.0, 6.5), 3.73 (3H, s, OCH3), 4.34e4.44 (1H, m,
CHNHTFA), 5.90e5.99 (1H, br, NH), 6.63e6.65 (1H, m, C6H4eOCH3),
6.67e6.76 (2H, m, C6H4eOCH3), 7.09e7.29 (6H, m, ArH); dC
(100 MHz, CDCl3) 39.4, 52.4, 55.2, 112.4, 114.9, 115.7 (q, J 286), 121.5,
127.0, 128.8, 129.2, 129.8, 136.7, 138.2, 156.6 (q, J 37), 159.9, one
322.1419.
4.4.6. (S)-(þ)-2,2,2-Trifluoro-N-(1-(4-hydroxyphenyl)-3-phenyl-
propan-2-yl)acetamide 22f. General cross-coupling method A was
followed using 4-iodophenol (287 mg, 1.3 mmol) and gave, after
purification by silica gel column (10% ethyl acetate in petroleum
ether), the title compound (220 mg, 68%) as a white solid.
General cross-coupling method B was followed using 4-iodo-
phenol (287 mg, 1.3 mmol) and gave, after purification by silica gel
column (10% ethyl acetate in petroleum ether), the title compound
(113 mg, 35%) as a white solid; mp 163.0e164.5 ꢀC; Rf 0.22 (20%
EtOAc in petrol); FTIR (nmax/cmꢁ1): 3382, 3321, 3030, 2930, 1692,
1601, 1556, 1511, 1218, 1163, 1103, 825, 750, 659; dH (400 MHz,
CD3COCD3) 2.80e3.04 (4H, m, PhCH2NHTFACH2eC6H4eOH),
4.32e4.43 (1H, m, CHNHTFA), 6.74e6.79 (2H, m, C6H4eOH),
7.05e7.10 (2H, m, C6H4eOH), 7.18e7.31 (5H, m, Ph), 8.19 (1H, s, OH),
8.22e8.30 (1H, br, NH); dC (100 MHz, CD3COCD3) 40.0, 40.6, 54.6,
signal not observed; [
a
]
22 ꢁ1.0 (c 1.01, CHCl3); m/z (ES) Found: MHþ
D
338.1378. C18H19NO2F3 requires MHþ 338.1368.
4.4.3. (S)-(ꢁ)-2,2,2-Trifluoro-N-(1-(2-methoxyphenyl)-3-phenyl-
propan-2-yl)acetamide 22c. General cross-coupling method A was
followed using 2-iodoanisole (169
mL, 1.3 mmol) and gave, after
purification by silica gel column (5% ethyl acetate in petroleum
ether), the title compound (202 mg, 60%) as a white solid.
General cross-coupling method B was followed using 2-iodoa-
116.0, 117.0 (q, J 287), 127.2, 129.1, 129.7, 130.0, 131.0, 139.3, 156.9,
22
157.0 (q, J 37); [
a
]
þ2.0 (c 1.01, acetone); m/z (ES) Found: MHþ
D
nisole (169
mL, 1.3 mmol) and gave, after purification by silica gel
324.1221. C17H17NO2F3 requires MHþ 324.1211.
column (5% ethyl acetate in petroleum ether), the title compound
(167 mg, 50%) as a white solid; mp 137e139 ꢀC; Rf 0.49 (20% EtOAc
in petrol); FTIR (nmax/cmꢁ1): 3310, 3028, 2963, 1694, 1614, 1556,
1254, 1219, 1174, 1151, 1030, 837, 809, 754; dH (400 MHz, CDCl3)
2.75e2.90 (3H, m), 3.06 (1H, dd, J 14.0, 5.5), 3.82 (3H, s, OCH3),
4.21e4.32 (1H, m, CHNHTFA), 6.85e6.92 (2H, m, C6H4eOCH3),
6.98e7.02 (1H, m, C6H4eOCH3), 7.19e7.36 (m, 7H, ArH); dC
(100 MHz, CDCl3) 33.3, 40.14, 53.9, 55.2, 110.5, 115.9 (q, J 286), 121.2,
4.4.7. (S)-(þ)-2,2,2-Trifluoro-N-(1-(4-fluorophenyl)-3-phenyl-
propan-2-yl)acetamide 22g. General cross-coupling method A was
followed using 4-fluoroiodobenzene (150 mL, 1.3 mmol) and gave,
after purification by silica gel column (5% ethyl acetate in petroleum
ether), the title compound (260 mg, 80%) as a white solid.
General cross-coupling method B was followed using 4-fluo-
roiodobenzene (150 mL, 1.3 mmol) and gave, after purification by
125.6, 126.8, 128.5, 128.6, 129.5, 131.4, 137.3, 156.7 (q, J 37), 157.0;
silica gel column (5% ethyl acetate in petroleum ether), the title
compound (231 mg, 71%) as a white solid; mp 150.5e152 ꢀC; Rf 0.49
(20% EtOAc in petrol); FTIR (nmax/cmꢁ1): 3304, 3031, 2934, 1697,
1561, 1509, 1223, 1159, 877, 829, 750, 724; dH (400 MHz, CDCl3) 2.79
(1H, dd, J 13.5, 7.5), 2.82 (1H, dd, J 13.5, 7.5), 2.90 (1H, dd, J 14.0, 6.0),
2.92 (1H, dd, J 14.0, 6.0), 4.36e4.46 (1H, m, CHNHTFA), 6.10e6.20
(1H, br, NH), 6.96e7.36 (8H, m, ArH); dC (100 MHz, CDCl3) 38.7, 39.5,
52.6, 115.6 (d, J 21), 115.6 (q, J 286), 127.1, 128.8, 129.2, 130.6 (d, J 8),
22
[
a]
ꢁ24.9 (c 1.0, CHCl3); m/z (ES) Found: MHþ 338.1361.
D
C18H19NO2F3 requires MHþ 338.1368.
4.4.4. (S)-(ꢁ)-2,2,2-Trifluoro-N-(1-phenyl-3-p-tolylpropan-2-yl)
acetamide 22d. General cross-coupling method A was followed
using 4-iodotoluene (283 mg, 1.3 mmol) and gave, after purification
by silica gel column (5% ethyl acetate in petroleum ether), the title
compound (270 mg, 84%) as a white solid.
General cross-coupling method B was followed using 4-iodoto-
luene (283 mg, 1.3 mmol) and gave, after purification by silica gel
column (5% ethyl acetate in petroleum ether), the title compound
(231 mg, 72%) as a white solid; mp 165e166.5 ꢀC; Rf 0.58 (20% EtOAc
132.5, 136.5, 156.7 (q, J 37), 161.9 (d, J 246); [
a]
22 þ4.0 (c 1.0, CHCl3);
D
m/z (ES) Found: MHþ 326.1166. C17H16NOF4 requires MHþ 326.1168.
4.4.8. (S)-(ꢁ)-Methyl 4-(3-phenyl-2-(2,2,2-trifluoro-acetamido)pro-
pyl)benzoate 22h. General cross-coupling method A was followed

9180
C.M.L. Goddard et al. / Tetrahedron 66 (2010) 9175e9181
using methyl 4-iodobenzoate (340 mg, 1.3 mmol) and gave, after
purification by silica gel column (5% ethyl acetate in petroleum
ether), the title compound (255 mg, 70%) as a white solid.
in petrol); FTIR (nmax/cmꢁ1) 3308, 3102, 2979, 2879, 1699, 1558,
1370, 1161, 860, 770; dH (400 MHz, CDCl3) 0.88 (3H, d, J 6.8, CH3CH),
0.94 (3H, d, J 6.8, CH3CH), 1.71e1.83 (1H, m, (CH3)2CH), 2.25 (3H, s,
PhCH3), 2.63 (1H, dd, J 14.1, 8.0, CHAHBeAr), 2.81 (1H, dd, J 14.1, 5.8,
CHAHBeAr), 3.95e4.05 (1H, m, CHNHTFA), 5.81e5.95 (1H, br, NH),
6.97 (2H, d, J 8.0, Ar), 7.04 (2H, d, J 8.0, Ar); dC (100 MHz, CDCl3) 17.5,
General cross-coupling method B was followed using methyl
4-iodobenzoate (340 mg, 1.3 mmol) and gave, after purification by
silica gel column (5% ethyl acetate in petroleum ether), the title
compound (244 mg, 67%) as a white solid; mp 166.5e168 ꢀC; Rf 0.32
(20% EtOAc in petrol); FTIR (nmax/cmꢁ1): 3296, 3100, 2954, 1717,
1701, 1611, 1557, 1280, 1177, 1154, 1104, 970, 880, 751; dH (400 MHz,
CDCl3) 2.82 (1H, dd, J 14.0, 7.5), 2.92 (1H, dd, J 14.0, 7.5), 2.96 (1H,
dd, J 14.0, 6.0), 3.02 (1H, dd, J 14.0, 6.0), 3.94 (3H, s, CO2CH3),
4.45e4.55 (1H, m, CHNHTFA), 5.96e6.04 (1H, br, NH), 7.16e7.20
(2H, m, C6H4eCO2CH3), 7.25e7.38 (5H, m, Ph), 8.00e8.04 (2H, m,
C6H4eCO2CH3); dC (100 MHz, CDCl3) 39.5, 39.6, 52.1, 52.3, 115.6 (q, J
286), 127.2, 128.8, 129.0, 129.2, 129.2, 130.0, 136.3, 142.2, 156.7 (q, J
19.6, 21.0, 30.6, 37.3, 56.5, 116.0 (q, J 288), 128.9, 129.3, 133.9, 136.4,
22
158.0 (q, J 37); [
a
]
D
ꢁ27 (c 1.0, CHCl3); m/z (ES) Found: MHþ
274.1412. C14H19NOF3 requires MHþ 274.1419.
4.4.12. (R)-(ꢁ)-2,2,2-Trifluoro-N-(1-(4-methoxyphenyl)-3-methyl-
butan-2-yl)acetamide 23c. General cross-coupling method A was
followed using 4-iodoanisole (304 mg, 1.3 mmol) and gave, after
purification by silica gel column (5% ethyl acetate in petroleum
ether), the title compound (165 mg, 57%) as a white solid.
35),166.6; [
a
]
22 ꢁ1.0 (c 1.01, CHCl3); m/z (ES) Found: MHþ 366.1325.
General cross-coupling method B was followed using 4-iodoa-
nisole (304 mg, 1.3 mmol) and gave, after purification by silica gel
column (5% ethyl acetate in petroleum ether), the title compound
(106 mg, 37%) as a white solid; mp 121e123 ꢀC; Rf 0.44 (30% EtOAc
in petrol); FTIR (nmax/cmꢁ1) 3293, 3107, 2969, 2878, 1670, 1558,
1365, 1255, 1158, 858; dH (400 MHz, CDCl3) 0.88 (3H, d, J 6.8,
CH3CH), 0.94 (3H, d, J 6.8, CH3CH), 1.70e1.83 (1H, m, CH3CH), 2.61
(1H, dd, J 14.1, 8.0, CHAHBeAr), 2.80 (1H, dd, J 14.1, 5.7, CHAHBeAr),
3.72 (3H, s, OCH3), 3.93e4.02 (1H, m, CHNHTFA), 5.81e5.93 (1H, br,
NH), 6.74e6.79 (2H, m, Ar), 6.98e7.02 (2H, m, Ar), dC (100 MHz,
CDCl3) 17.6, 19.5, 30.7, 36.8, 55.2, 56.7, 114.1, 116.0 (q, J 288), 129.1,
D
C19H19NO3F3 requires MHþ 366.1317.
4.4.9. (S)-(ꢁ)-2,2,2-Trifluoro-N-(1-(naphthalen-1-yl)-3-phenyl-
propan-2-yl)acetamide 22i. General cross-coupling method A was
followed using 1-iodonaphthalene (190
mL, 1.3 mmol) and gave,
after purification by silica gel column (5% ethyl acetate in petroleum
ether), the title compound (239 mg, 67%) as a white solid.
General cross-coupling method B was followed using 1-iodo-
naphthalene (190 mL, 1.3 mmol) and gave, after purification by silica
gel column (5% ethyl acetate in petroleum ether), the title com-
pound (150 mg, 42%) as a white solid; mp 174.0e175.5 ꢀC; Rf 0.51
(20% EtOAc in petrol); FTIR (nmax/cmꢁ1): 3328, 3030, 2929, 1698,
1549,1450,1203,1149, 913, 870, 796, 778, 700; dH (400 MHz, CDCl3)
2.95 (1H, dd, J 14.0, 7.5), 3.01 (1H, dd, J 14.0, 6.5), 3.32e3.42 (2H, m),
4.50e4.61 (1H, m, CHNHTFA), 6.05e6.15 (1H, br, NH), 7.16e7.20
(2H, m, Ph), 7.24e7.36 (4H, m, Ph, Naph), 7.39e7.44 (1H, m, Naph),
7.47e7.56 (2H, m, Naph), 7.79 (1H, d, J 8.0, Naph), 7.85e7.89 (1H, m,
Naph), 7.95e7.99 (1H, m, Naph); dC (100 MHz, CDCl3) 36.9, 39.7,
130.0, 156.0 (q, J 37), 158.5; [
a]
22 ꢁ25 (c 1.0, CHCl3); m/z (ES) Found:
D
MHþ 290.1358. C14H19NO2F3 requires MHþ 290.1368.
4.4.13. (R)-(ꢁ)-2,2,2-Trifluoro-N-(1-(3-methoxyphenyl)-3-methyl-
butan-2-yl)acetamide 23d. General cross-coupling method A was
followed using 3-iodoanisole (155 mL, 1.3 mmol) and gave, after
purification by silica gel column (5% ethyl acetate in petroleum
ether), the title compound (214 mg, 74%) as a white solid; mp
102e103 ꢀC; Rf 0.45 (30% EtOAc in petrol); FTIR (nmax/cmꢁ1) 3299,
2970, 2845, 1696, 1558, 1261, 1176, 891, 725; dH (400 MHz, CDCl3)
0.88 (3H, d, J 6.8, CH3CH), 0.93 (3H, d, J 6.8, CH3CH), 1.71e1.84 (1H,
m, CH3CH), 2.63 (1H, dd, J 14.1, 8.6, CHAHBeAr), 2.82 (1H, dd, J 14.1,
5.5, CHAHBeAr), 3.70 (3H, s, OCH3), 3.96e4.05 (1H, m, CHNHTFA),
6.11e6.21 (1H, br, NH), 6.61e6.71 (3H, m, Ar), 7.09e7.16 (1H, m, Ar);
dC (100 MHz, CDCl3) 17.6, 19.5, 30.8, 37.7, 55.1, 56.5, 112.2, 114.7,
52.4, 119.6 (q, J 286), 123.4, 125.3, 125.9, 126.5, 127.1, 127.5, 128.0,
22
128.8, 129.0, 129.2, 132.0, 133.0, 134.0, 136.7, 157.0 (q, J 37); [a]
D
þ25.1 (c 1.0, CHCl3); m/z (ES) Found: MHþ 358.1436. C21H19NOF3
requires MHþ 358.1419.
4.4.10. (R)-(ꢁ)-2,2,2-Trifluoro-N-(3-methyl-1-phenylbutan-2-yl)
acetamide 23a. General cross-coupling method A was followed
using iodobenzene (145
m
L, 1.3 mmol) and gave, after purification
115.0 (q, J 288), 121.4, 129.6, 138.7, 156.0 (q, J 37), 159.8; [
a]
22 ꢁ20 (c
D
by silica gel column (5% ethyl acetate in petroleum ether), the title
compound (163 mg, 63%) as a white solid.
1.0, CHCl3); m/z (ES) Found: MHþ 290.1366C14H19NO2F3 requires
MHþ 290.1368.
General cross-coupling method B was followed using iodo-
benzene (145
m
L, 1.3 mmol) and gave, after purification by silica gel
4.4.14. (R)-(ꢁ)-2,2,2-Trifluoro-N-(1-(2-methoxyphenyl)-3-methyl-
butan-2-yl)acetamide 23e. General cross-coupling method A was
followed using 2-iodoanisole (169 mL, 1.3 mmol) and gave, after
column (5% ethyl acetate in petroleum ether), the title compound
(151 mg, 58%) as a white solid; mp 115e117 ꢀC; Rf 0.53 (30% EtOAc in
petrol); FTIR (nmax/cmꢁ1) 3308, 3102, 2976, 2876, 1699, 1558, 1370,
1161, 851, 757; dH (400 MHz, CDCl3) 0.98 (3H, d, J 6.8, CH3CH), 1.04
(3H, d, J 6.8, CH3CH), 1.81e1.95 (1H, m, (CH3)2CH), 2.75 (1H, dd, J
14.0, 8.3, CHAHBPh), 2.96 (1H, dd, J 14.0, 5.6, CHAHBPh), 4.07e4.17
(1H, m, CHNHTFA), 5.95e6.09 (1H, br, NH), 7.13e7.36 (5H, m, Ph); dC
(100 MHz, CDCl3) 17.6, 19.5, 30.8, 37.8, 56.6, 116.0 (q, J 288), 126.8,
purification by silica gel column (5% ethyl acetate in petroleum
ether), the title compound (122 mg, 42%) as a white solid; mp
102e103 ꢀC; Rf 0.45 (30% EtOAc in petrol); FTIR (nmax/cmꢁ1) 3297,
3107, 2973, 2845, 1696, 1564, 1261, 1167, 891, 722; dH (400 MHz,
CDCl3) 0.93 (3H, d, J 6.8, CH3CH), 0.94 (3H, d, J 6.8, CH3CH),
1.84e1.97 (m, 1H, CH3CH), 2.68 (1H, dd, J 13.8, 4.3, CHAHBeAr),
2.80 (1H, dd, J 13.8, 10.7, CHAHBeAr), 3.77 (3H, s, OCH3), 3.82e3.92
(m, 1H, CHNHTFA), 6.75e7.2 (m, 5H, NH and Ar); dC (100 MHz,
CDCl3) 18.3, 18.5, 30.9, 31.7, 55.2, 57.6, 110.3, 116.0 (q, J 288), 121.1,
128.6, 129.0, 137.2, 158.0 (q, J 37); [
a
]
22 ꢁ21 (c 1.0, CHCl3); m/z (ES)
D
Found: MHþ 260.1268. C13H17NOF3 requires MHþ 260.1262.
4.4.11. (R)-(ꢁ)-2,2,2-Trifluoro-N-(3-methyl-1-p-tolylbutan-2-yl)
acetamide 23b. General cross-coupling method A was followed
using 4-iodotoluene (283 mg, 1.3 mmol) and gave, after purification
by silica gel column (5% ethyl acetate in petroleum ether), the title
compound (191 mg, 70%) as a white solid.
General cross-coupling method B was followed using 4-iodo-
toluene (283 mg, 1.3 mmol) and gave, after purification by silica gel
column (5% ethyl acetate in petroleum ether), the title compound
(115 mg, 42%) as a white solid; mp 149e150 ꢀC; Rf 0.55 (30% EtOAc
126.1, 128.3, 131.0, 157.0 (q, J 37), 157.1; [
a
]
22 ꢁ47.4 (c 1.01, CHCl3);
D
m/z (ES) Found: MHþ 290.1359 C14H19NO2F3 requires MHþ
290.1368.
4.4.15. (R)-(ꢁ)-Methyl 4-(3-methyl-2-(2,2,2-trifluoro-acetamido)bu-
tyl)benzoate 23f. General cross-coupling method A was followed
using methyl 4-iodobenzoate (340 mg, 1.3 mmol) and gave, after
purification by silica gel column (5% ethyl acetate in petroleum
ether), the title compound (162 mg, 51%) as a white solid; mp

C.M.L. Goddard et al. / Tetrahedron 66 (2010) 9175e9181
9181
129e131 ꢀC; Rf 0.31 (10% EtOAc in petrol); FTIR (nmax/cmꢁ1) 3295,
Acknowledgements
3106, 2955, 2884, 1707, 1696, 1561, 1373, 1277, 1157, 882, 766; dH
(400 MHz, CDCl3) 0.91 (3H, d, J 6.8, CH3CH), 0.95 (3H, d, J 6.8,
CH3CH), 1.72e1.85 (1H, m, CH3CH), 2.71 (1H, dd, J 14.1, 8.7,
CHAHBeAr), 2.93 (1H, dd, J 14.1, 5.6, CHAHBeAr), 3.84 (3H, s,
CO2CH3), 4.00e4.10 (1H, m, CHNHTFA), 5.87e5.97 (1H, br, NH),
7.15e7.19 (2H, m, Ar), 7.88e7.92 (2H, m, Ar); dC (100 MHz, CHCl3)
We thank Dr. Ian Rilatt for preliminary experiments, and the
Islamic Azad University, Shahreza Branch, for financial support
during a period of sabbatical leave (Ahmad Reza Massah). We also
thank a referee for helpful comments on the manuscript.
17.6, 19.5, 31.3, 37.9, 52.1, 56.6, 116.0 (q, J 288), 128.6, 129.0, 129.9,
22
References and notes
143.0, 158.0 (q, J 37), 166.9; [
a
]
D
ꢁ12.2 (c 1.01, CHCl3); m/z (ES)
Found: MHþ 318.1318. C15H19NO3F3 requires MHþ 318.1317.
1. Nugent, T. C.; El-Shazly, M. Adv. Synth. Catal. 2010, 352, 753e819.
2. Nenajdenko, V. G.; Karpov, A. S.; Balenkova, E. S. Tetrahedron: Asymmetry 2001,
12, 2517e2527.
3. Seo, H.; Hirsch-Weil, D.; Abboud, K. A.; Hong, S. J. Org. Chem. 2008, 73,1983e1986.
4. Hunter, C.; Jackson, R. F. W.; Rami, H. K. J. Chem. Soc., PerkinTrans.12000, 219e223.
5. Deboves, H. J. C.; Hunter, C.; Jackson, R. F. W. J. Chem. Soc., Perkin Trans. 1 2002,
733e736.
4.4.16. (R)-(ꢁ)-2,2,2-Trifluoro-N-(1-(4-fluorophenyl)-3-methyl-
butan-2-yl)acetamide 23g. General cross-coupling method A was
followed using 1-fluoro-4-iodobenzene (289 mg, 1.3 mmol) and
gave, after purification by silica gel column (5% ethyl acetate in
petroleum ether), the title compound (169 mg, 61%) as a white
solid.
6. Duddu, R.; Eckhardt, M.; Furlong, M.; Knoess, H. P.; Berger, S.; Knochel, P.
Tetrahedron 1994, 50, 2415e2432.
7. Molander, G. A.; Vargas, F. Org. Lett. 2007, 9, 203e206.
8. Molander, G. A.; Jean-Gerard, L. J. Org. Chem. 2007, 72, 8422e8426.
9. Caggiano, L.; Jackson, R. F. W.; Meijer, A.; Pickup, B. T.; Wilkinson, K. A.
Chem.dEur. J. 2008, 14, 8798e8802.
10. Dreiocker, F.; Oomens, J.; Meijer, A.; Pickup, B. T.; Jackson, R. F. W.; Schafer, M.
J. Org. Chem. 2010, 75, 1203e1213.
11. Rilatt, I.; Jackson, R. F. W. J. Org. Chem. 2008, 73, 8694e8704.
12. Milne, J. E.; Buchwald, S. L. J. Am. Chem. Soc. 2004, 126, 13028e13032.
13. Ross, A. J.; Lang, H. L.; Jackson, R. F. W. J. Org. Chem. 2010, 75, 245e248.
14. Wiktelius, D.; Luthman, K. Org. Biomol. Chem. 2007, 5, 603e605.
15. Manolikakes, G.; Schade, M. A.; Hernandez, C. M.; Mayr, H.; Knochel, P. Org. Lett.
2008, 10, 2765e2768.
General cross-coupling method B was followed using 1-fluoro-
4-iodobenzene (289 mg, 1.3 mmol) and gave, after purification by
silica gel column (5% ethyl acetate in petroleum ether), the title
compound (167 mg, 60%) as a white solid; mp 116e117 ꢀC; Rf 0.47
(30% EtOAc in petrol); FTIR (nmax/cmꢁ1) 3304, 3103, 2970, 2879,
1697, 1557, 1365, 1211, 1158, 861, 727; dH (400 MHz, CDCl3) 0.88
(3H, d, J 6.8, CH3CH), 0.93 (3H, d, J 6.8, CH3CH), 1.70e1.83 (1H, m,
CH3CH), 2.59 (1H, dd, J 14.1, 8.8, CHAHBeAr), 2.84 (1H, dd, J 14.1,
5.4, CHAHBeAr), 3.91e4.01 (1H, m, CHNHTFA), 6.13e6.23 (1H, br,
NH), 6.86e6.93 (2H, m, Ar), 7.00e7.07 (2H, m, Ar); dC (101 MHz,
CDCl3) 17.5, 19.5, 30.9, 37.0, 56.7, 115.4 (d, J 21), 116.0 (q, J 288),
16. Manolikakes, G.; Hernandez, C. M.; Schade, M. A.; Metzger, A.; Knochel, P. J. Org.
Chem. 2008, 73, 8422e8436.
17. Manolikakes, G.; Dong, Z. B.; Mayr, H.; Li, J. S.; Knochel, P. Chem.dEur. J. 2009,
15, 1324e1328.
18. Jackson, R. F. W.; Rilatt, I.; Murray, P. J. Org. Biomol. Chem. 2004, 2, 110e113.
19. Kostyanovsky, R. G.; Lenev, D. A.; Krutius, O. N.; Stankevich, A. A. Mendeleev
Commun. 2005, 140e141.
130.4 (d, J 8), 133.0, 156.7 (q, J 37), 161.7 (d, J 245); [
a
]
22 ꢁ13 (c 1.0,
D
CHCl3); m/z (ES) Found: MHþ 278.1166 C13H16NOF4 requires MHþ
278.1168.