Acylmethanesulfonamides as new acylating agents for primary amines

Article abstract of DOI:10.1016/j.tetlet.2004.05.073

A new, simple and efficient procedure for the preparation of secondary amides through internal condensation of acylmethanesulfonamides ammonium salts is described. The selective acylation of mixed primary-secondary amines could be an attractive application of the new method.

Full text of DOI:10.1016/j.tetlet.2004.05.073

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 5375–5378
Acylmethanesulfonamides as new acylating
agents for primary amines
Silvia Coniglio,a,* Andrea Aramini,a M. Candida Cesta,a Sandro Colagioia,a
Roberto Curti,a Fabrizio D’Alessandro,a Gaetano D’Anniballe,b Valerio D’Elia,a
Giuseppe Nano,a Valerie Orlandoa and Marcello Allegrettia,*
aDompꢀe Research and Development, Chemistry Department, Dompꢀe S.p.A., Via Campo di Pile, 67100 L’Aquila, Italy
bDompꢀe Research and Development, Analytical Department, Dompꢀe S.p.A., Via Campo di Pile, 67100 L’Aquila, Italy
Received 1 April 2004; revised 14 May 2004; accepted 17 May 2004
Abstract—A new, simple and efficient procedure for the preparation of secondary amides through internal condensation of acyl-
methanesulfonamides ammonium salts is described. The selective acylation of mixed primary–secondary amines could be an
attractive application of the new method.
ꢀ 2004 Elsevier Ltd. All rights reserved.
1. Introduction
belonging to the class of 2-phenylpropionylmethane-
sulfonamides.6
Polyamines are frequently used intermediates in organic
synthesis and selective derivatization of the amino
groups generally requires complex multi-step protection/
deprotection methods.1 Monoacylation of mixed pri-
mary–secondary diamines poses considerable difficulties
and, by consequence, a wide number of strategies have
been proposed in order to approach this synthetic
challenge.2–5
2. Results and discussion
Repertaxin ((R)-4-isobutyl-a-methylphenylacetyl metha-
nesulfonamide) is currently under clinical investigation
for the prevention of delayed graft function during organ
transplant and its L-lysine salt is actually under evalua-
tion as a pharmaceutically acceptable salt for infusion
administration.
In this letter, we describe a novel method for the highly
chemoselective acylation of primary amino groups in
mixed primary–secondary diamines. This new method is
based on the unusual property of alkyl ammonium salts
of acylmethanesulfonamides to undergo internal con-
densation under thermal conditions. Our work has been
inspired by the study of a novel class of IL-8 inhibitors
Repertaxin
L-lysine salt 1 is an amorphous, highly
hygroscopic powder with melting point 85–90 ꢁC. Sta-
bility studies on the ‘raw material’ have pointed out the
time-dependent formation of traces (Table 1) of the
amides 2 and 3 as the only degradation side products.
H3N+
H
N
S
O
O
O
O
O
N
S
NH3+
O
O
Repertaxin
O
1
Keywords: Acylmethanesulfonamides; Mixed primary–secondary amine;
Condensation reaction.
In stressed conditions, the amount of these products
significantly enhanced and meaningful conversion of the
* Corresponding authors. Tel.: +39-862-338422; fax: +39-862-338219;
e-mail: marcello.allegretti@dompe.it
0040-4039/$ - see front matter ꢀ 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.05.073

5376
S. Coniglio et al. / Tetrahedron Letters 45 (2004) 5375–5378
Table 1. Stability studies on repertaxin
L
-lysine salt
Entry
Starting material
Reaction conditions (T/time)
Recovered starting material (%)
2 (%)
3 (%)
1
2
3
4
5
1
1
1
1
Rt/24 h
Rt/2 yr
>99.5
95.2
80.4
32.7
95
0.1
0.7
0.0
0.2
50 ꢁC/24 h
100 ꢁC/24 h
100 ꢁC/24 h
15.1
51.3
3.1
3.8
13.5
0.8
Ibuprofen L-lysine salt
starting material into the condensation by-products (2
and 3) occurred at T ¼ 100 ꢁC after 3 h.
Based on these preliminary observations, more experi-
ments have been performed in order to explore further
applications of this reaction. Ammonium salts have
been prepared simply by mixing acylmethanesulfon-
amides with the desired amine in dichloromethane; after
solvent evaporation the crude has been heated at
T ¼ 120 ꢁC for 3 h in a drying oven. Standard condi-
tions have been selected in order to compare the reac-
tivity of representative substrates (Table 2). Linear and
branched amines (entries 1–5) react in high yield to give
the corresponding amides. The wide applicability of the
reaction is supported by the high reactivity of
methanesulfonamides derived from alkyl, benzyl (6) and
benzoic acids.
COO-
H
H
N
N
NH3+
NH3+
O
O
COO-
2
3
It has been observed that the formation of 2 and 3 is
always accompanied by a proportional weight loss of
the raw. This suggests the removal of methanesulfon-
amide by sublimation as the reaction driving force.
Compounds 2 and 3 seem to be directly obtained from
internal condensation as in the solid state (Table 1, entry
3) as in the melted state (Table 1, entry 4). The relative
ratio of the amides 2 and 3 is plausibly due to the dif-
ferent basicity, nucleophilicity and steric hindrance of
the lysine amino groups. Internal condensation of car-
boxylate ammonium salts is a well known reaction7 but
its synthetic applications are actually limited by low
yields. In agreement with this, in fact, only low amounts
of 2 and 3 have been detected by heating the related
H
N
S
O
O
O
6
The reaction has been also successfully applied to the
acylation of aminoalcohols (entries 6 and 7).
carboxylic acid, ibuprofen L-lysine salt (Table 1, entry
5). The proposed reaction mechanism for the internal
condensation of acylmethanesulfonamides ammonium
salts is depicted in Scheme 1.
The most interesting application of this procedure, still
under evaluation, is the selective acylation of mixed
primary–secondary amines. As shown in Table 3,
probably due to the additional steric hindrance, sec-
ondary ammonium salts (entries 1 and 2) do not react in
the reaction conditions. The reaction sensitivity to steric
factors allows the discrimination between primary and
secondary amino groups in mixed diamines.
Methanesulfonamide displacement is highly favored by
the proximity of the reactive centers in the constrained
salified form. Ions solvation disfavors internal conden-
sation step; in fact the heating of solutions of repertaxin
L
-lysine salt in water or in dipolar solvents does not
afford 2 and 3. As previously mentioned, harvesting of
methanesulfonamide by sublimation has been supposed
strongly to contribute to drive the reaction equilibrium.
In agreement with this, homologues 4 and 5 show only
poor reactivity in the reaction conditions.
When N-propylaminoethylamine has been reacted with
1 equimolar amount of 6 (entry 3) only traces of the
condensation product have been isolated. This result is
in agreement with the higher basicity of the secondary
amino group. By contrast, when both the amino groups
were salified (entries 4 and 5), due to the steric hindrance
of the secondary amino groups, the selective acylation of
the primary group occurred in a quantitative manner.
H
N
H
N
S
S
O
O
O
O
O
O
N-Acyl-N-arylmethanesulfonamides have been previ-
ously reported5 as highly reactive N-acylating reagents.
These reagents show good chemoselectivity in the acyl-
ation of hindered amines mainly in force of the bulkiness
of the leaving group. We have herein described for the
first time the internal condensation of N-acylmethane-
sulfonamides ammonium salts. This reaction, although
requiring relatively harsh conditions, is still extremely
sensitive to the steric effects. The ionic interaction
between the reagents has been proposed as the crucial
factor in determining the observed selectivity.
4
5
O
O
O
O
CH3SO2NH2
O
-
O
O
S
S
R
N
CH3
R1
R
N
H
CH3
R
N
H
N
+
R1
H
R1
N
H
H
H
H
Scheme 1.

S. Coniglio et al. / Tetrahedron Letters 45 (2004) 5375–5378
Table 2. Internal condensation of acylmethanesulfonamides with primary aminesa
5377
O
O
O
O
S
O
O
∆
R
N
R'
-
+
S
N+
H
R
N
H
R'
H
NH2
H
Entry
1
Reagent
Amine
Product
Yield (%)
90
O
O
O
O
.
S
H2N
N
H3C
N
H
H
H
N
2
6
85
H2N
H2N
O
O
O
O
O
S
3
4
91
88
N
N
H
H
H
N
NH2
6
6
6
O
O
NH2
H
N
5
75
85
H
N
OH
6b
OH
H2N
O
OH
N
OH
7c
6
70
OH
O
H2N
HO
OH
a All the internal salts at T ¼ 120 ꢁC are in the melted state.
b In the reaction conditions a small amount of the cyclization product, oxazole, has been isolated.
c After 3 h a 1:1 mixture of amide and oxazole derivative was observed. Prolonging the reaction time the oxazole derivative is obtained as main
product.
Table 3. Internal condensation of acylmethanesulfonamides with secondary and mixed primary–secondary aminesa
Entry
Reagent
Reagent/Amine ratio
Amine
Product
Yield (%)
0
O
O
O
O
S
1b
1:1
CH3
N
N
N
H
H
2b
3c
4c
5c
6
6
6
6
1:1
1:1
2:1
2:1
0
<5
98
90
N
N
H
O
O
H
H
N
N
N
H
H2N
H
H
N
N
N
H2N
H
O
O
H
N
H
N
NH
NH2
a All the internal salts at T ¼ 120 ꢁC are in the melted state.
b General procedure (Method A).
c General procedure (Method B).

5378
S. Coniglio et al. / Tetrahedron Letters 45 (2004) 5375–5378
Summarizing, this new procedure can be considered a
new alternative to classical methods for acylation of
primary amino groups. The full scope of the reaction
remains to be exploited but the high reaction chemo-
selectivity with mixed primary–secondary amines sug-
gests interesting potential synthetic applications.
3.1.1.6. [4-(Hydroxymethyl)-2-(4-isobutylbenzyl)-4,5-
1
dihydro-1,3-oxazol-4- yl]methanol (Table 2, entry 7). H
NMR (CDCl3, 300 MHz): d 7.21 (d, 2H, J ¼ 7 Hz), 7.10
(d, 2H, J ¼ 7 Hz), 4.2 (d, 2H, J ¼ 2 Hz), 3.82 (s, 2H),
3.62 (dd, 2H, J1 ¼ 11 Hz, J2 ¼ 2 Hz), 3.48 (d, 2H,
J ¼ 11 Hz), 2.44 (d, 2H, J ¼ 7 Hz), 1.79 (m, 1H), 1.59
(br s, 2H, OH), 0.89 (d, 6H, J ¼ 7 Hz).
3. Experimental section
3.1. General procedure
3.1.2. Method B (reaction with mixed primary–secondary
amines)
3.1.2.1.
2-[(4-Isobutyl)phenyl]-N-[2-N-propylamino-
3.1.1. Method A (reaction with primary amines)
ethyl]acetamide (Table 3, entry 4). N-Propylethylenedi-
amine (0.1 mL, 0.81 mmol) was added to a stirred
solution of 6 (0.44 g, 1.62 mmol) in CH2Cl2 at rt. After
1 h the solvent was evaporated and the residue heated
for 3 h at T ¼ 120 ꢁC in a drying oven. After cooling at
room temperature, the reaction mixture was dissolved in
CH2Cl2 (10 mL) and washed with 0.5 M NaOH
(2 · 5 mL) and then with water (2 · 10 mL), dried over
Na2SO4 and evaporated under reduced pressure to
give pure 2-[(4-isobutyl)phenyl]-N-[2-N-propylamino-
ethyl]acetamide as a yellow oil (0.21 g, 0.79 mmol) in
3.1.1.1. 2-[(4-Isobutyl)phenyl]-N-butyl acetamide (Ta-
ble 2, entry 2). Butylamine (73 lL, 0.74 mmol) was added
to a stirring solution of 6 (0.2 g, 0.74 mmol) in CH2Cl2 at
rt. After 1 h, the solvent was distilled off and the residue,
2-[(40-isobutyl)phenyl]acetyl methanesulfonamide butyl-
ammonium salt, was heated for 3 h at T ¼ 120 ꢁC in a
drying oven. After cooling at room temperature, the
reaction mixture was dissolved in CH2Cl2 (10 mL) and
washed with water (2 · 5 mL), dried over Na2SO4. After
solvent evaporation under reduced pressure pure 2-[(4-
isobutyl)phenyl]-N-butyl acetamide was obtained as a
1
98% yield. H NMR (CDCl3, 300 MHz): d 7.14 (d, 2H,
1
yellow oil (0.154 g, 0.629 mmol) in 85% yield. H N MR
J ¼ 7 Hz), 7.03 (d, 2H, J ¼ 7 Hz), 5.90 (br s, 1H,
CONH), 4.20 (br s, 1H, NH), 3.50 (s, 2H), 3.35 (m, 2H),
2.65 (d, 2H, J ¼ 7 Hz), 2.45 (m, 4H), 1.79 (m, 1H), 1.35
(m, 2H), 0.97–0.86 (m, 9H).
(CDCl3, 300 MHz): d 7.16 (d, 2H, J ¼ 7 Hz), 7.04 (d,
2H, J ¼ 7 Hz), 5.22 (br s, 1H, CONH), 3.82 (s, 2H), 3.18
(m, 2H), 2.50 (d, 2H, J ¼ 7 Hz), 1.85 (m, 1H), 1.38 (m,
2H), 1.22 (m, 2H), 0.97–0.86 (m, 9H).
3.1.2.2. 2-[(4-Isobutyl)phenyl]-N-pyrrolidin-3-yl acet-
1
amide (Table 3, entry 5). H NMR (CDCl3, 300 MHz):
d 7.10 (d, 2H, J ¼ 7 Hz), 7.01 (d, 2H, J ¼ 7 Hz), 5.50 (br
s, 1H, CONH), 4.2 (br s, 1H, NH), 3.85 (m, 1H), 3.80 (s,
2H), 2.85 (m, 2H), 2.75 (m, 2H), 2.35 (d, 2H, J ¼ 7 Hz),
1.75 (m, 1H), 1.55 (m, 2H), 0.89 (d, 6H, J ¼ 7 Hz).
3.1.1.2. N-Butylbenzamide (Table 2, entry 3). 1H
NMR (CDCl3, 300 MHz): d 7.90 (d, 2H, J ¼ 7 Hz),
7.45–7.30 (m, 3H, J ¼ 7 Hz), 6.05 (br s, 1H, CONH),
3.45 (m, 2H), 1.60 (m, 2H), 1.25 (m, 2H), 0.91 (t, 3H,
J ¼ 7 Hz).
3.1.1.3.
2-[(4-Isobutyl)phenyl]-N-isoamylacetamide
1
(Table 2, entry 4). H NMR (CDCl3, 300 MHz): d 7.15
(d, 2H, J ¼ 7 Hz), 7.06 (d, 2H, J ¼ 7 Hz), 5.31 (br s, 1H,
CONH), 3.80 (s, 2H), 2.95 (m, 2H), 2.55 (d, 2H,
J ¼ 7 Hz), 1.90–1.80 (m, 2H), 1.36 (m, 2H, J ¼ 7 Hz),
1.01–0.90 (m, 12H, J ¼ 7 Hz).
References and notes
1. Lochner, M.; Geneste, H.; Hesse, M. Helv. Chim. Acta
1998, 81, 2270–2281.
2. Pittelkow, M.; Lewinsky, R.; Christensen, J. B. Synthesis
2002, 15, 2195–2202.
3. Xu, D.; Prasad, K.; Repic, O.; Blacklock, T. J. Tetrahedron
Lett. 1995, 36, 7357–7360.
3.1.1.4. 2-[(4-Isobutyl)phenyl]-N-cyclohexylacetamide
1
(Table 2, entry 5). H NMR (CDCl3, 300 MHz): d 7.20
(d, 2H, J ¼ 7 Hz), 7.09 (d, 2H, J ¼ 7 Hz), 5.25 (br s, 1H,
CONH), 3.20 (m, 1H), 3.76 (s, 2H), 2.55 (d, 2H,
J ¼ 7 Hz), 1.90–1.65 (m, 5H), 1.40–0.90 (m, 12H).
ꢁꢁ
ꢂ
ꢁꢁ
ꢁ
4. Koscova, S.; Budesinsky’, M.; Hodacova, J. Collect. Czech.
ꢂ
Chem. Commun. 2003, 68, 744–750.
5. (a) Kondo, K.; Sekimoto, E.; Miki, K.; Murakami, Y. J.
Chem. Soc., Perkin Trans. 1 1998, 2973–2974; (b) Kondo,
K.; Sekimoto, E.; Nakao, J.; Murakami, Y. Tetrahedron
2000, 56, 5843–5856.
6. Allegretti, M.; Cesta, M. C.; Colotta F.; Mantovanini, M.;
Bizzarri, C.; Porzio, S.; Sabbatini, W.; Bertini, R.; Caselli,
G.; Gandolfi, C. A. WO 0024710, 2000.
3.1.1.5. 2-[(4-Isobutyl)phenyl]-N-(2-hydroxyethyl)acet-
amide (Table 2, entry 6). 1H NMR (CDCl3, 300 MHz): d
7.15 (d, 2H, J ¼ 7 Hz), 7.05 (d, 2H, J ¼ 7 Hz), 5.70 (br s,
1H, CONH), 3.81 (s, 2H), 3.58 (m, 2H), 3.28 (m, 2H),
2.35 (d, 2H, J ¼ 7 Hz), 1.75 (m, 1H), 0.82 (d, 6H,
J ¼ 7 Hz).
7. Beckwith, A. L. J. In Zabicky The Chemistry of Amides;
Wiley-Interscience: New York, 1970; p 105.