N-Acyltrifluoromethanesulfonamides as new chemoselective acylating agents for aliphatic and aromatic amines

Article abstract of DOI:10.1016/j.tet.2006.03.097

This work describes advances in the study of the internal condensation of ammonium salts of N-acylsulfonamides. N-Acyltrifluoromethanesulfonamides show considerable advantages over the non fluorinated analogues by virtue of their higher reactivity and aci

Full text of DOI:10.1016/j.tet.2006.03.097

Tetrahedron 62 (2006) 5608–5616
N-Acyltrifluoromethanesulfonamides as new chemoselective
acylating agents for aliphatic and aromatic amines
Sophie Guillard, Andrea Aramini, Maria C. Cesta, Sandro Colagioia, Silvia Coniglio,
Filippo Genovese, Giuseppe Nano, Emanuela Nuzzo, Valerie Orlando and Marcello Allegretti
*
´
Chemistry Department, Dompe Research and Development, Dompe pha.r.ma s.p.a., Via Campo di Pile, 67100 L’Aquila, Italy
´
Received 13 March 2006; accepted 30 March 2006
Available online 2 May 2006
Abstract—This work describes advances in the study of the internal condensation of ammonium salts of N-acylsulfonamides. N-Acyltrifluoro-
methanesulfonamides show considerable advantages over the non fluorinated analogues by virtue of their higher reactivity and acidity. The
reaction chemoselectivity has been investigated using a wide range of amines. The sensitivity of the reaction to steric and electronic effects
confirms the potential application of these reagents in chemoselective acylation of polyamines.
Ó 2006 Elsevier Ltd. All rights reserved.
1. Introduction
Chemoselective acylation of mixed primary–secondary
amines is a synthetic challenge and, to date, a wide range
of strategies have been used to address this problem;2–6 the
observed chemoselectivity suggests promising applications
of this process, but the relatively harsh conditions strongly
limit the scope of the reaction. Here we report the efforts
at extending the reactivity studies with the aim to select
optimised conditions for the process.
We have recently reported1 that alkylammonium salts of
acylmethanesulfonamides undergo internal condensation to
give the corresponding amide derivatives under thermal con-
ditions (T¼120 ꢀC, 3 h, 80 mmHg). The proposed reaction
mechanism is depicted in Scheme 1.
O
O
O
O
CF3SO2NH2
O
-
O
O
S
S
2. Results and discussion
R
N
CF3
R1
CF3
R
N
H
R
N
H
N
+
R1
N
H
The aim of the present study is to evaluate acyltrifluoro-
methanesulfonamides in comparison with related acyl-
methanesulfonamides as novel acylating reagents for the
amino group (Fig. 1).
R1
H
H
H
H
Scheme 1.
The ionic interaction between the reagents is the crucial
reaction step and, furthermore, methanesulfonamide har-
vesting by sublimation strongly contributes to drive the
reaction equilibrium. These preliminary reactivity studies
clearly demonstrate that the proximity of the reactive centres
strongly influences the steric requirements of the reaction. In
fact, secondary ammonium salts do not evolve to the corre-
sponding amides and selective monoacylation of mixed
primary–secondary amines has been reported to proceed in
good yields.
The rationale behind this choice is based on the following
considerations: (1) the marked acidity of the amide hydrogen
should favour the acid–base interaction with low-basicity
amines; (2) the electron-withdrawing effect of the fluorine
atoms should enhance the reactivity of the electrophilic
centre and (3) the higher vapour tension of trifluoromethane-
sulfonamide as compared to methanesulfonamide should
positively influence the reaction course.
In Table 1, a comparison between the reactivity of 2-(4-
isobutylphenyl)-N-(methylsulfonyl)acetamide
1 and its
trifluoromethyl analogue 2 is described. As previously
reported, 1 significantly undergoes internal condensation
only when heated under vacuum in the absence of solvent
(entries 1 and 2). On the contrary, comparable yields are
obtained when 2 is heated either neat (entry 3) or in toluene
Keywords: Alkylammonium salts; N-Acyltrifluoromethanesulfonamides;
Chemoselective acylation; Mixed primary–secondary amines.
* Corresponding author. Tel.: +39 0862338212; fax: +39 0862338219;
e-mail: marcello.allegretti@dompe.it
0040–4020/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2006.03.097

S. Guillard et al. / Tetrahedron 62 (2006) 5608–5616
5609
H
we reported the lack of reactivity of secondary ammonium
salts of 1, but further experiments revealed that by prolong-
ing the reaction time under the fusion conditions, small
amount of the condensation product occurs. On the contrary,
2 shows a marked reactivity towards secondary amines; in
fact, the reactions with pyrrolidine (entry 5) and N-butyl-
methylamine (entry 6) proceed in appreciable yield. The
higher reactivity of 2 is in agreement with the increased
electrophilic character of the carbonyl group.
H
N
N
CF3
S
S
O
O
O
O
O
O
2
1
H
N
O
H
N
S
O
O
O
S
O
F
F
S
O
O
O
O
O
F
4
3
On the basis of the mechanistic hypothesis, the acid–base
interaction between the reagents is a crucial step for the
reaction course (Table 3). Accordingly, low-basicity amines,
such as anilines, fail to react with 1 since the formation of
the ion-pair is highly disfavoured (entries 1 and 2). Heating
a 1:1 mixture of the reagents does not lead to appreciable
amounts of the amide products. The modest acidity increase
caused by electron-withdrawing ring substituents, in com-
pounds 3 and 4, does not significantly enhance the reactivity
of the substrates (entries 3 and 4).
F
F
H
N
F
H
N
F
F
S
F
S
O
O
O
O
O
O
6
5
F
H
F
F
N
S
O
O
O
Unlike the corresponding methanesulfonamide, 2 reacts
with aniline to give the corresponding anilide (entry 5).
This result is in agreement with the higher acidity and reac-
tivity of the substrate. Substitution in the para position of the
aniline ring with electron-withdrawing or electron-releasing
groups does not markedly influence the reaction outcome
(entries 6–8), whereas substituents in the ortho position
clearly depress the aniline reactivity (entries 9–11). The
observed trend highlights the importance of steric hindrance.
The absolute unreactivity of 2,6-difluoroaniline (entry 12)
could be explained by the low basicity and nucleophilicity
of the amino group. 2,6-Difluoroaniline is, in fact, signifi-
cantly less basic than the other tested anilines (pKa¼2.47).
As reported for dialkyl amines, N-methylaniline is moder-
ately reactive in our conditions (entry 13), while the more
sterically congested 2-methyl-N-methylaniline fails to afford
the desired condensation product (entry 14).
7
Figure 1. Substrates used as acylating agents.
Table 1. Reactivity of 1 and 2 with butylamine invarious reaction conditions
Entry Reagent
Amine
H2N
Reaction conditions
Yield (%)
90
Neat/T¼120 ꢀC/4 h,
1
2
1
1
80 mmHg
Toluene/reflux/8 h
0
90
80
10
H2N
Neat/T¼120 ꢀC/4 h,
3
4
2
2
H2N
H2N
80 mmHg
Toluene/reflux/8 h
5
6
2
2
2
Toluene/rt/3 d
H2N
H2N
H2N
Toluene/T¼30 ꢀC/1 h Tracesa
Toluene/T¼30 ꢀC/1 h 10a
The above results confirm the hypothesis that acyltrifluoro-
methanesulfonamides, due to their increased reactivity,
may constitute a valuable alternative to acylmethanesulfon-
amides as an activated intermediates for amide synthesis.
7
a
The different yield is due to different work-up procedure (see text).
As a next step, we have verified if the enhanced reactivity of
the substrate could be detrimental to the chemoselectivity of
the reaction (Table 4).
solution (entry 4). A low but significant conversion is
obtained by stirring a toluene solution of the salt at room tem-
perature for several days (entry 5). The results in entries 6 and
7 confirm the sublimation of the trifluoromethanesulfon-
amide as the crucial event for the reaction proceeding. In
fact, after 1 h at T¼30 ꢀC (entry 6) only traces of the product
are detected (GC–MS analysis) in the crude reaction mixture,
whereas a subsequent analysis after simple solvent evapora-
tion shows a consistent increase of yield (entry 7).
When a two-fold molar excess of 2 reacts with N-propylami-
noethylamine, the amine reagent is efficiently transformed
(90% conversion yield) to give a 70:30 mixture of the amide
products 2-(4-isobutylphenyl)-N-[2-(propylamino)ethyl]-
acetamide A and N-(2-aminoethyl)-2-(4-isobutylphenyl)-
N-propylacetamide B. Using a 1:1 ratio of the reagents,
the reaction proceeds with high chemoselectivity (A/B
ratio¼97:3) although in lower yield (60%) (entries 1 and 2).
To explore the reactivity of acyltrifluoromethanesulfon-
amides, several ammonium salts, prepared by mixing 2
with the desired amine in toluene, have been treated under
the selected conditions (Table 2).
No traces of the diacylated compound are detectable. The
surprising lack of reactivity of the primary amino group of
B could be due to the engagement of a stable intramolecular
interaction with the electrophilic carbonyl group. In fact, the
only product detected in the reaction mixture is C (Fig. 2).
Prolonging the reaction time to 24 h a 70:30 mixture of the
Primary amines (entries 1–4) afford the corresponding
amides in moderate to good yields. In our previous paper,

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S. Guillard et al. / Tetrahedron 62 (2006) 5608–5616
Table 2. Reactivity of 2 with alkylamines in the selected conditions
H
H
N
CF3
N
toluene /∆ / 8h
S
R'
+
CF3SO2NH2
+
R'NH2
O
O
O
O
Entry
1
Amine
Product
Yield (%)
80
H
N
H2N
O
O
O
O
H
N
2
3
90
H2N
H2N
H
N
95a
H
N
4
5
35
40
45
H2N
N
HN
O
N
6
HN
O
a
Reaction conditions: xylene/reflux/8 h.
products A/C is obtained. This result supports the hypothe-
sis, confirming a marked tendency of B to the cyclisation.
benzylamine with the enantiopure substrates 6 and 7
(Table 5).
The lower reactivity of a-branched-amines (Table 2, entry 4)
suggests an additional steric effect induced by the hindrance
on the a-carbon of the amine reagent. To explore this
hypothesis, 2 has been reacted with a 1:1 mixture of butyl-
amine and racemic a-methylbenzylamine. The 80:20 ratio
between the products confirms the high sensitivity of the
reaction to steric effects (Table 4, entry 3).
On the basis of the described steric effect, it was conceivable
to expect a different reactivity of the R and S enantiomers.
The four pure diastereomers have been singularly synthe-
sised, as reference compounds for the following reaction
products, by reacting 6 and 7 with the commercially avail-
able pure (R)(+) and (S)(ꢁ)-a-methylbenzylamines. Starting
material 6 and the final diastereomeric product have been
proved stable to epimerisation in the reaction conditions
(reflux, toluene, 48 h, triethylamine as non reactive amine).
Keeping this in mind we have reasoned that the steric
hindrance at the carbon next to the carbonyl group could
also play a role on the substrate reactivity. With the aim to
address this issue, 2-(4-isobutylphenyl)propionyltrifluoro-
methanesulfonamide 5 has been synthesised and reacted
with several amines. Interestingly, a dramatic decrease in
reactivity has been observed on moving from linear (entry 4)
to branched primary amines (entry 5), whereas pyrrolidine
proves unreactive under our standard conditions (entry 6).
The same competition experiment described in entry 3 has
been performed with 5 and higher chemoselectivity has
been observed (entry 7). The results of the experiments in
Table 4 confirm that steric hindrance at both the a-carbons
next to the reactive centres strongly affects the reactivity of
the substrate.
The reaction of 6 with racemic a-methylbenzylamine affords
the diastereoisomers (2R,1R) with 80% diastereomeric
excess but with a modest conversion yield (20%) and high
recovery of the starting material (Table 5, entry 1). Prolong-
ing the reaction time to 24 h (entry 2) the yield increases up
to 82% without significant change in the enantiodiscrimina-
tion of the reaction. Analogous results have been obtained
when substrates 7 and 5 have been, respectively, reacted with
racemic and enantiopure a-methylbenzylamines (entries
4–6).
3. Conclusions
As a final step of this work, wehave investigated the diastereo-
differentiation of the process reacting racemic a-methyl-
Summarizing, this work describes our advances in the
study of the internal condensation of ammonium salts of

S. Guillard et al. / Tetrahedron 62 (2006) 5608–5616
5611
Table 3. Reaction of acylsulfonamides with aniline derivatives
Entry
Reagent
Amine
Product
Yield (%)
N.d.a
H
N
1
1
H2N
O
H
N
O
O
H2N
H2N
2
3
1
3
N.d.
O
O
O
O
H
N
Tracesb
O
O
O
H
N
O
H2N
O
F
4
4
Tracesb
F
F
O
S
O
H
N
H2N
5
6
2
2
70
80
O
H
N
H2N
COOCH3
O
COOCH3
H
N
H2N
Br
7
8
2
2
75
71
O
Br
O
H
N
O
H2N
O
H
N
H2N
H2N
9
2
2
59
37
O
O
Cl
O
Cl
H
N
10
O
F
H
N
11
12
2
2
Tracesb
Tracesb
H2N
H2N
O
O
F
F
H
N
F
H
N
N
13
2
30
O
O
N
H
N
14
2
N.d.
a
N.d.: not detected.
Detected by GC–MS analysis.
b

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S. Guillard et al. / Tetrahedron 62 (2006) 5608–5616
Table 4. Reactivity of acyltrifluoromethanesulfonamides with amines in standard conditions
Entry
Reagent
Amine
Ratio
Productsa
Conversion
yield (%)b
NH2
H
N
H
N
N
H
N
N
O
H2N
1
2
2:1
+
90
O
O
A
B
(70:30)
NH2
H
N
H
N
N
H
2
2
1:1
60
H2N
O
+
A
B
(97:3)
H
H
N
N
+
H2N
3
2
1:1
89
NH2
+
O
O
(80:20)
H
N
4
5
5
5
1:1
1:1
92
20
H2N
O
H
N
H2N
O
HN
N
6
7
5
5
1:1
1:1
N.d.c
O
H
H
N
+
N
73
H2N
NH2
+
O
O
(95:5)
a
Yields of isolated products are calculated after purification by flash chromatography.
Conversion yields are calculated on recovered starting materials.
N.d.: not detected.
b
c
N-acylmethanesulfonamides.N-Acyltrifluoromethanesulfon-
amides show considerable advantages over their non fluori-
nated analogues by virtue of their higher reactivity and
acidity. The results in Table 5 are not optimal in terms of
stereoselectivity, but they are encouraging and further studies
on more hindered substrates could provide access to interest-
ing synthetic applications.
4. Experimental
4.1. General
Thin-layer chromatography was carried out with Macherey-
Nagel-DURASIL-25 silica gel plates. Nuclear magnetic
resonance (NMR) spectra were recorded on a Bruker
ARX-300 MHz spectrometer. Column chromatography
was performed on silica gel (300–400 mesh). IR spectra
were recorded on Perkin–Elmer Spectrum One FTIR Spec-
trometer. GC–MS analysis was performed using a Thermo-
Finnigan Trace 2030 UP MS chromatograph (analytical
column: RTX-5MS) and a ThermoFinnigan DSQ 250 spec-
trometer. Uncorrected melting points were performed on
a Buchi 530 apparatus. Elemental analyses were within
ꢂ0.4% of the theoretical values calculated for C, H and N
N
N
C
Figure 2. 2-(4-Isobutylbenzyl)1-propyl-4,5-dihydro-1H-imidazole (C).

S. Guillard et al. / Tetrahedron 62 (2006) 5608–5616
5613
Table 5. Stereoselective reaction of N-acyltrifluoromethanesulfonamides with racemic and chiral a-methylbenzylamine
H
H
N
CF3
N
H2N
S
O
+
O
O
O
Entry
1
Reagent
Amine
Reaction conditions
Toluene/reflux/8 h
Products
de (%)a
Yield (%)
20
H
N
6
80
40
30
40
40
40
H2N
O
(2R, 1R)
H
N
2
3
4
5
6
6
7
5
5
Toluene/reflux/24 h
Toluene/reflux/24 h
Toluene/reflux/24 h
Toluene/reflux/24 h
Toluene/reflux/24 h
82
85
78
74
70
H2N
H2N
O
(2R, 1R)
H
N
O
(2 eq.)
(2R, 1R)
H
N
H2N
H2N
O
(2S, 1S)
H
N
O
(2S, 1S)
H
N
6
H2N
O
(2R, 1R)
a
Diastereoisomeric excess is calculated by chromatography purification of the products.
and is reported only with symbols. Commercially available
reagents and solvents were used as received.
(CDCl3) d 7.20–7.10 (m, 4H), 3.80 (s, 2H), 3.18 (s, 3H), 2.00
(d, J¼7 Hz, 2H), 1.92–1.83 (m, 1H), 0.90 (d, J¼7 Hz, 6H);
IR (Nujol, cmꢁ1) n 3345, 2980, 1680, 1500, 1380, 1130;
EIMS m/z 269 (M+). Anal. Calcd for C13H19NO3S: C,
57.97; H, 7.11; N, 5.20; S, 11.90. Found: C, 57.96; H,
7.09; N, 5.21; S, 11.89.
4.1.1. 2-(4-Isobutylphenyl)-N-(methylsulfonyl)acetamide
(1). 1,10-carbonyldiimidazole (CDI) (0.930 g, 5.73 mmol)
was added to a solution of 4-isobutylphenyl acetic acid7
(1.00 g, 5.21 mmol) in dry CH2Cl2 (25 mL) and the result-
ing solution was stirred for 30 min. Triethylamine
(1.5 mL, 10.42 mmol) and methanesulfonamide (0.850 g,
10.42 mmol) were consecutively added and the solution
stirred for 12 h at room temperature. After cooling to 0 ꢀC,
a KH2PO4 buffer solution (pH 2.4, 20 mL) was added and
the two phases were separated. The aqueous phase was
extracted with CH2Cl2 (3ꢃ25 mL) and the collected organic
extracts washed with brine (2ꢃ15 mL) and dried over
Na2SO4. Solvent removal under reduced pressure afforded
a crude residue, which after purification by flash chromato-
graphy (eluent mixture CHCl3/MeOH 9:1), afforded the pure
compound 1 (1.05 g, yield 75%) as a colourless oil. 1H NMR
4.1.2. 2-(4-Isobutylphenyl)-N-[trifluromethylsulfonyl]-
acetamide (2). Following the same procedure described for
1 and starting from 4-isobutylphenyl acetic acid (1.00 g,
5.21 mmol), compound 2 was prepared using commercial
trifluoromethanesulfonamide. The pure compound 2 was
obtained (0.84 g, yield 50%) as a pale yellow solid. Mp
1
107–109 ꢀC; H NMR (CDCl3) d 7.20–7.10 (m, 4H), 3.80
(s, 2H), 2.00 (d, J¼7 Hz, 2H), 1.92–1.83 (m, 1H), 1.60–
1.50 (br s, 1H, CONH), 0.90 (d, J¼7 Hz, 6H); IR (Nujol,
cmꢁ1) n 3345, 2980, 1680, 1500, 1380, 1130; EIMS m/z
323 (M+). Anal. Calcd for C13H19NO3S: C, 57.97; H, 7.11;
N, 5.20; S, 11.90. Found: C, 58.00; H, 7.08; N, 5.19; S, 11.91.

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S. Guillard et al. / Tetrahedron 62 (2006) 5608–5616
4.1.3. 2-(3-Benzoylphenyl)-N-(methylsulfonyl)acetamide
(3). Following the same procedure as described for 1 and
starting from commercial 2-(3-benzoylphenyl)acetic acid
(1.00 g, 4.16 mmol), compound 3 was prepared. The pure
compound 3 (1.05 g, yield 75%) was obtained as a yellow
4.2. General procedure for the preparation of amides
The selected amine (1.0 mmol) was added to a solution of
N-acylmethanesulfonamide (compounds 1–4, 1.0 mmol)
or N-acyltrifluoromethanesulfonamide (compounds 5–7,
1.0 mmol) in toluene (5 mL). The resulting solution was
refluxed for 8 h. After cooling to room temperature, toluene
was removed under reduced pressure and the residue diluted
with CH2Cl2 (10 mL) and washed with a KH2PO4 buffer
solution (pH 2.4, 3ꢃ10 mL). After drying over Na2SO4 the
organic phase was evaporated under reduced pressure and
pure arylamides were obtained by flash chromatography of
the crude residue.
1
oil. H NMR (DMSO-d6) d 8.28 (s, 1H), 8.20 (d, J¼7 Hz,
1H), 8.02 (d, J¼7 Hz, 1H), 7.80–7.67 (m, 4H+NH), 7.50
(m, 2H), 3.38 (m, 5H); IR (neat, cmꢁ1) n 3150, 3000,
1650, 1450, 750; EIMS m/z 317 (M+). Anal. Calcd for
C16H15NO4S: C, 60.55; H, 4.76; N, 4.41; S, 10.10. Found:
C, 60.56; H, 4.73; N, 4.45; S, 10.09.
4.1.4. 4-{2-[(Methylsulfonyl)amino]-2-oxoethyl}phenyl
trifluoromethanesulfonate (4). Following a synthetic pro-
cedure as already described8 compound 4 was prepared
from commercially available 4-hydroxyphenylacetic acid.
The pure compound 4 (1.48 g, yield 78%) was obtained as
4.2.1. N-Butyl-2-(4-isobutylphenyl)-N-acetamide (Table
1, entry 4). White solid (eluent mixture n-hexane/EtOAc
1
9:1); yield 80%; mp 57–58 ꢀC; H NMR (CDCl3) d 7.20–
1
7.05 (m, 4H), 5.30 (br s, 1H, CONH), 3.55 (s, 2H), 3.21–
3.14 (m, 2H), 2.50 (d, J¼7 Hz, 2H), 1.92–1.83 (m, 1H),
1.44–1.35 (m, 2H), 1.25 (m, 2H), 0.97–0.85 (m, 9H); IR
(Nujol, cmꢁ1) n 3368, 2950, 1670, 1460; EIMS m/z 247
(M+). Anal. Calcd for C16H25NO: C, 77.68; H, 10.19; N,
5.66. Found: C, 77.70; H, 10.15; N, 5.68.
colourless oil. H NMR (CDCl3) d 7.38 (d, J¼7 Hz, 2H),
7.18 (d, J¼7 Hz, 2H), 4.95 (br s, 1H+CONH), 3.80 (s,
2H), 3.18 (s, 3H); IR (Nujol, cmꢁ1) n 3345, 2980, 1685,
1500, 1380, 1130; EIMS m/z 361 (M+). Anal. Calcd for
C10H10F3NO6S2: C, 33.24; H, 2.79; F, 15.77; N, 3.88;
S, 17.75. Found: C, 33.25; H, 2.76; F, 15.79; N, 3.87; S,
17.78.
4.2.2. N-Benzyl-2-(4-isobutylphenyl)acetamide (Table 2,
entry 2). White solid (eluent mixture n-hexane/EtOAc
9:1); yield 90%; mp 100–103 ꢀC; 1H NMR (CDCl3)
d 7.30–7.20 (m, 4H), 7.15–7.05 (m, 5H), 5.60 (br s, 1H,
CONH), 4.40 (d, J¼5 Hz, 2H), 3.55 (s, 2H), 2.55 (d,
J¼7 Hz, 2H), 1.90–1.82 (m, 1H), 0.85 (d, J¼7 Hz, 6H); IR
(Nujol, cmꢁ1) n 3368, 2950, 1670, 1460; EIMS m/z 281
(M+). Anal. Calcd for C19H23NO: C, 81.10; H, 8.24; N,
4.98. Found: C, 81.11; H, 8.19; N, 5.01.
4.1.5. 2-(4-Isobutylphenyl)-N-[(trifluoromethyl)sulfo-
nyl]propanamide (5). Following the same procedure as
described for 1 and starting from the commercially available
reagents4-isobutylphenylpropionicacid(1.00 g, 4.85 mmol)
and trifluoromethanesulfonamide (1.44 g, 9.7 mmol), com-
pound 5 (1.26 g, yield 80%) was obtained as yellow oil. 1H
NMR (CDCl3) d 7.20–7.08 (m, 4H), 3.75 (q, J¼7 Hz, 1H),
2.50 (d, J¼7 Hz, 2H), 1.92–1.83 (m, 1H), 1.50 (d, J¼7 Hz,
3H), 0.90 (d, J¼7 Hz, 6H); IR (neat, cmꢁ1) n 3345, 2980,
1670, 1500, 1380, 1130; EIMS m/z 337 (M+). Anal.
Calcd for C14H18F3NO3S: C, 49.84; H, 5.38; F, 16.89; N,
4.15; S, 9.50. Found: C, 49.86; H, 5.36; F, 16.91; N, 4.14;
S, 9.52.
4.2.3. 2-(4-Isobutylphenyl)-N-(1-phenylethyl)acetamide
(Table 2, entry 4). White solid (eluent mixture CHCl3/
CH3OH 98:2); yield 35%; mp 89–92 ꢀC; 1H NMR (CDCl3)
d 7.32–7.20 (m, 4H), 7.18–7.05 (m, 5H), 5.55 (br s, 1H,
CONH), 5.15–5.04 (m, 1H), 3.50 (s, 2H), 2.50 (d, J¼7 Hz,
2H), 1.92–1.83 (m, 1H), 1.35 (d, J¼7 Hz, 3H), 0.90 (d,
J¼7 Hz, 6H); IR (Nujol, cmꢁ1) n 3368, 2950, 1670, 1460;
EIMS m/z 295 (M+). Anal. Calcd for C20H25NO: C, 81.31;
H, 8.53; N, 4.74. Found: C, 81.34; H, 8.49; N, 4.70.
4.1.6. (2R)-2-(4-Isobutylphenyl)-N-[(trifluoromethyl)sul-
fonyl]propanamide (6). Compound 6 was synthesised as
1
described in Ref. 9. [a]2D0 ꢁ80.5 (c 1, CH3OH); H NMR
(CDCl3) d 7.20–7.08 (m, 4H), 3.75 (q, J¼7 Hz, 1H), 2.50
(d, J¼7 Hz, 2H), 1.92–1.83 (m, 1H), 1.50 (d, J¼7 Hz,
3H), 0.90 (d, J¼7 Hz, 6H); IR (neat, cmꢁ1) n 3345, 2980,
1670, 1500, 1380, 1130; EIMS m/z 337 (M+). Anal. Calcd
for C14H18F3NO3S: C, 49.84; H, 5.38; F, 16.89; N, 4.15;
S, 9.50. Found: C, 49.85; H, 5.35; F, 16.92; N, 4.16; S,
9.48.
4.2.4. 1-[(4-Isobutylphenyl)acetyl]pyrrolidine (Table 2,
entry 5). Colourless oil (eluent mixture n-hexane/EtOAc
9:1); yield 40%; 1H NMR (CDCl3) d 7.20 (d, J¼7 Hz,
2H), 7.05 (d, J¼7 Hz, 2H), 3.63 (s, 2H), 3.49 (t, J¼7 Hz,
2H), 3.43 (t, J¼7 Hz, 2H), 2.45 (d, J¼7 Hz, 2H), 1.70–
1.76 (m, 5H), 0.90 (d, J¼7 Hz, 6H); IR (neat, cmꢁ1
)
n 2950, 1670, 1460; EIMS m/z 245 (M+). Anal. Calcd for
C16H23NO: C, 78.32; H, 9.45; N, 5.71. Found: C, 78.33;
H, 9.48; N, 5.73.
4.1.7. (2S)-2-(4-Isobutylphenyl)-N-[(trifluoromethyl)sul-
fonyl]propanamide (7). Compound 7 was synthesised fol-
lowing the same procedure as described for 6 and starting
from the commercially available reagent (2S)-2-(4-isobutyl-
4.2.5. N-Butyl-2-(4-isobutylphenyl)-N-methylacetamide
(Table 2, entry 6). Colourless oil (eluent mixture n-hex-
ane/EtOAc 9:1); yield 80%; 1H NMR (CDCl3) d 7.20–7.05
(m, 4H), 3.55 (s, 2H), 3.15–3.10 (m, 5H), 2.50 (d, J¼7 Hz,
2H), 1.92–1.83 (m, 1H), 1.44–1.35 (m, 2H), 1.30–1.20 (m,
2H), 0.97–0.85 (m, 9H); IR (neat, cmꢁ1) n 3368, 2950,
1670, 1460; EIMS m/z 261 (M+). Anal. Calcd for
C17H27NO: C, 78.11; H, 10.41; N, 5.36. Found: C, 78.13;
H, 10.39; N, 5.38.
1
phenyl)propionic acid. [a]2D0 +79 (c 1, CH3OH); H NMR
(CDCl3) d 7.20–7.08 (m, 4H), 3.75 (q, J¼7 Hz, 1H), 2.50
(d, J¼7 Hz, 2H), 1.92–1.83 (m, 1H), 1.50 (d, J¼7 Hz,
3H), 0.90 (d, J¼7 Hz, 6H); IR (neat, cmꢁ1) n 3345, 2980,
1670, 1500, 1380, 1130; EIMS m/z 337 (M+). Anal. Calcd
for C14H18F3NO3S: C, 49.84; H, 5.38; F, 16.89; N, 4.15;
S, 9.50. Found: C, 49.87; H, 5.35; F, 16.91; N, 4.17; S,
9.48.

S. Guillard et al. / Tetrahedron 62 (2006) 5608–5616
5615
4.2.6. 2-(4-Isobutylphenyl)-N-phenylacetamide (Table 3,
entry 5). White solid (eluent mixture n-hexane/EtOAc
9:1); yield 70%; mp 110–112 ꢀC; 1H NMR (CDCl3)
d 7.30–7.20 (m, 4H), 7.15–7.05 (m, 5H), 6.90 (br s, 1H,
CONH), 3.36 (s, 2H), 2.51 (d, J¼7 Hz, 2H), 1.90 (m, 1H),
0.93 (d, J¼7 Hz, 6H); IR (Nujol, cmꢁ1) n 3368, 2950,
1670, 1460; EIMS m/z 267 (M+). Anal. Calcd for
C18H21NO: C, 80.86; H, 7.92; N, 5.24. Found: C, 80.89;
H, 7.88; N, 5.27.
n-hexane/EtOAc 9:1); yield 30%; 1H NMR (CDCl3) d 7.40–
7.30 (m, 3H), 7.15 (d, J¼7 Hz, 2H), 7.05–6.90 (m, 4H), 3.45
(s, 2H), 3.30 (s, 3H), 2.42 (d, J¼7 Hz, 2H), 1.92–1.83 (m,
1H), 0.85 (d, J¼7 Hz, 6H); IR (neat, cmꢁ1) n 3368, 2950,
1670, 1460; EIMS m/z 281 (M+). Anal. Calcd for
C19H23NO: C, 81.10; H, 8.24; N, 4.98. Found: C, 81.08;
H, 8.20; N, 5.01.
4.2.13. 2-(4-Isobutylphenyl)-N-[2-(propylamino)ethyl]-
acetamide (Table 4, compound A). Pale yellow oil (eluent
mixture n-hexane/EtOAc 8:2); H NMR (CDCl3) d 7.18–
1
4.2.7. Methyl 4-{[(4-isobutylphenyl)acetyl]amino}ben-
zoate (Table 3, entry 6). Pale yellow oil (eluent mixture
n-hexane/EtOAc 8:2); yield 80%; 1H NMR (CDCl3) d 8.00
(d, J¼7 Hz, 2H), 7.50 (d, J¼7 Hz, 2H), 7.28–7.15 (m,
4H), 3.90 (s, 3H), 3.80 (br s, 1H, CONH), 3.65 (s, 2H),
2.55 (d, J¼7 Hz, 2H), 1.85–1.78 (m, 1H), 0.90 (d, J¼7 Hz,
6H); IR (neat, cmꢁ1) n 3300, 2950, 1680, 1460; EIMS m/z
325 (M+). Anal. Calcd for C20H23NO3: C, 73.82; H, 7.12;
N, 4.30. Found: C, 73.83; H, 7.10; N, 4.31.
7.12 (m, 4H), 6.05 (br s, 1H, CONH), 3.50 (s, 2H), 3.30–
3.25 (m, 2H), 2.74–2.66 (m, 2H), 2.45–2.52 (m, 4H),
1.92–1.83 (m, 1H), 1.62 (br s, 1H, NH), 1.48–1.30 (m,
2H), 0.95–0.80 (m, 9H); IR (neat, cmꢁ1) n 3360, 3060,
1914, 1643, 1456, 1233, 650; ESIMS m/z 276 (M+). Anal.
Calcd for C17H28N2O: C, 73.87; H, 10.21; N, 10.13. Found:
C, 73.88; H, 10.23; N, 10.15.
4.2.14. N-(2-Aminoethyl)-2-(4-isobutylphenyl)-N-propyl-
acetamide (Table 4, compound B). Pale yellow oil (eluent
mixture n-hexane/EtOAc 8:2); 1H NMR (CDCl3) d 7.02 (m,
4H), 3.50 (t, J¼7 Hz, 2H), 3.45 (s, 2H), 3.35 (m, 2H), 3.20
(t, J¼7 Hz, 2H), 2.50 (d, J¼7 Hz, 2H), 2.05 (br s, 2H, NH2),
1.85 (m, 1H), 1.50 (m, 2H), 1.02–0.92 (m, 9H); IR (neat,
cmꢁ1) n 3345, 2950, 1670, 1460; ESIMS m/z 276 (M+).
Anal. Calcd for C17H28N2O: C, 73.87; H, 10.21; N, 10.13.
Found: C, 73.89; H, 10.24; N, 10.09.
4.2.8. N-(4-Bromophenyl)-2-(4-isobutylphenyl)acet-
amide (Table 3, entry 7). White solid (eluent mixture
n-hexane/EtOAc 9:1); yield 75%; mp 135–137 ꢀC; 1H
NMR (CDCl3) d 7.40–7.30 (m, 4H), 7.27–7.12 (m, 4H),
7.00 (br s, 1H, CONH), 3.65 (s, 2H), 2.50 (d, J¼7 Hz, 2H),
n 3300, 2950, 1680, 1460; EIMS m/z 345/347 ([79/81Br]
M+). Anal. Calcd for C18H20BrNO: C, 62.44; H, 5.82; Br,
23.08; N, 4.05. Found: C, 62.46; H, 5.79; Br, 23.10; N, 4.04.
1.92–1.83 (m, 1H), 0.90 (d, J¼7 Hz, 6H); IR (Nujol, cmꢁ1
)
4.2.15. 2-(4-Isobutylbenzyl)-1-propyl-4,5-dihydro-1H-
imidazole (compound C). Colourless oil (eluent mixture
n-hexane/EtOAc 8:2); 1H NMR (CDCl3) d 7.19 (d,
J¼7 Hz, 2H), 7.09 (d, J¼7 Hz, 2H), 3.78 (t, J¼10 Hz, 2H),
3.62 (s, 2H), 3.35 (t, J¼10 Hz, 2H), 2.97 (t, J¼7 Hz, 2H),
2.48 (d, J¼7 Hz, 2H), 1.92–1.83 (m, J¼7 Hz, 1H), 1.35–
1.28 (m, J¼7 Hz, 2H), 0.90 (d, J¼7 Hz, 6H), 0.75 (t,
J¼7 Hz, 3H); IR (neat, cmꢁ1) n 2957, 1605, 1460, 1125;
ESIMS m/z 258 (M+). Anal. Calcd for C17H26N2: C, 79.02;
H, 10.14; N, 10.84. Found: C, 79.05; H, 10.12; N, 10.83.
4.2.9. N-(4-Ethoxyphenyl)-2-(4-isobutylphenyl)acet-
amide (Table 3, entry 8). Yellow oil (eluent mixture
n-hexane/EtOAc 85:15); yield 71%; 1H NMR (CDCl3)
d 8.00 (br s, 1H, CONH), 7.55 (d, J¼7 Hz, 2H), 7.10–7.01
(m, 4H), 6.95 (d, J¼7 Hz, 2H), 3.75 (q, J¼7 Hz, 2H), 3.65
(s, 2H), 2.50 (d, J¼7 Hz, 2H), 1.92–1.83 (m, 1H), 1.45
n 3368, 2950, 1670, 1460; EIMS m/z 311 (M+). Anal. Calcd
for C20H25NO2: C, 77.14; H, 8.09; N, 4.50. Found: C, 77.15;
H, 8.13; N, 4.48.
(t, J¼7 Hz, 3H), 0.90 (d, J¼7 Hz, 6H); IR (neat, cmꢁ1
)
4.2.16. (2R)-2-(4-Isobutylphenyl)-N-[(1R)-1-phenyl-
ethyl]propanamide (Table 5, entry 1). White solid (eluent
mixture n-hexane/EtOAc 7:3); mp 107–109 ꢀC; [a]D20 +22.6
(c 1, CH3OH); 1H NMR (CDCl3) d 7.30–7.05 (m, 9H), 5.50
(br s, J¼7 Hz, 1H, CONH), 5.14–5.07 (m, 1H), 3.55 (q,
J¼7 Hz, 1H), 2.47 (d, J¼7 Hz, 2H), 1.92–1.83 (m,
J¼7 Hz, 1H), 1.51 (d, J¼7 Hz, 3H), 1.39 (d, J¼7 Hz, 3H),
0.91 (d, J¼7 Hz, 6H); IR (neat, cmꢁ1) n 3286, 2950, 2864,
1642, 1540, 1447; EIMS m/z 309 (M+). Anal. Calcd for
C21H27NO: C, 81.51; H, 8.79; N, 4.53. Found: C, 81.55;
H, 8.77; N, 4.51.
4.2.10. 2-(4-Isobutylphenyl)-N-(2-methylphenyl)acet-
amide (Table 3, entry 9). White solid, (eluent mixture
n-hexane/EtOAc 9:1); yield 59%; mp 110–111 ꢀC; 1H
NMR (CDCl3) d 7.95 (d, J¼7 Hz, 1H), 7.23–7.00 (m, 7H),
6.85 (br s, 1H, CONH), 3.70 (s, 2H), 2.50 (d, J¼7 Hz,
2H), 1.85–1.80 (m, 4H), 0.85 (d, J¼7 Hz, 6H); IR (Nujol,
cmꢁ1) n 3368, 2950, 1670, 1460; EIMS m/z 281 (M+).
Anal. Calcd for C19H23NO: C, 81.10; H, 8.24; N, 4.98.
Found: C, 81.12; H, 8.21; N, 4.95.
4.2.11. N-(2-Chlorophenyl)-2-(4-isobutylphenyl)acet-
amide (Table 3, entry 10). Yellow oil (eluent mixture n-hex-
ane/EtOAc 9:1); yield 37%; 1H NMR (CDCl3) d 8.05 (br s,
1H, CONH), 7.58 (d, J¼7 Hz, 1H), 7.35 (d, J¼7 Hz, 1H),
7.25–7.00 (m, 6H), 3.68 (s, 2H), 2.50 (d, J¼7 Hz, 2H),
n 3368, 2950, 1670, 1460; EIMS m/z 300/302 ([35/37Cl]
M+). Anal. Calcd for C18H20ClNO: C, 71.63; H, 6.68; Cl,
11.75; N, 4.64. Found: C, 71.63; H, 6.68; Cl, 11.75; N, 4.64.
4.2.17. (2S)-2-(4-Isobutylphenyl)-N-[(1S)-1-phenylethyl]-
propanamide (Table 5, entry 4). White solid (eluent mix-
ture n-hexane/EtOAc 7:3); mp 108–110 ꢀC; [a]D20 ꢁ23.2 (c
1
1, CH3OH); H NMR (CDCl3) d 7.30–7.05 (m, 9H), 5.50
1.92–1.83 (m, 1H), 0.90 (d, J¼7 Hz, 6H); IR (neat, cmꢁ1
)
(br s, J¼7 Hz, 1H, CONH), 5.14–5.07 (m, 1H), 3.55 (q,
J¼7 Hz, 1H), 2.47 (d, J¼7 Hz, 2H), 1.92–1.83 (m,
J¼7 Hz, 1H), 1.51 (d, J¼7 Hz, 3H), 1.39 (d, J¼7 Hz, 3H),
0.91 (d, J¼7 Hz, 6H); IR (neat, cmꢁ1) n 3286, 2950, 2864,
1642, 1540, 1447; EIMS m/z 309 (M+). Anal. Calcd for
C21H27NO: C, 81.51; H, 8.79; N, 4.53. Found: C, 81.52;
H, 8.81; N, 4.50.
4.2.12. 2-(4-Isobutylphenyl)-N-methyl-N-phenylacet-
amide (Table 3, entry 13). Light brown oil (eluent mixture

5616
S. Guillard et al. / Tetrahedron 62 (2006) 5608–5616
Sekimoto, E.; Nakao, J.; Murakami, Y. Tetrahedron 2000, 56,
5843–5856.
References and notes
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