Reaction of amphipathic-type thioester and amine with hydrophobic effect in water

Article abstract of DOI:10.1055/s-0030-1261165

The title reaction was studied using sodium 3-(1-oxododec-1-yl)thio- and 3-(1-oxohept-1-yl)thiopropanoate with various chain lengths of amines. The yields of the amides were found to depend on both the chain length of the thioester and that of amine, suggesting the presence of hydrophobic interaction. The amides were obtained in better yields after addition of sodium fluoride. Acylation (dodecanoylation) of some hydrophobic amino acids was also studied to obtain the corresponding amides. Georg Thieme Verlag Stuttgart - New York.

Full text of DOI:10.1055/s-0030-1261165

LETTER
2035
Reaction of Amphipathic-Type Thioester and Amine with Hydrophobic Effect
in Water
R
A
eactionof Amph
t
ipathic-
s
Type Thio
u
ester and
A
s
mine inW
h
a
ter i Torihata, Chiaki Kuroda*
Department of Chemistry and Research Center for Smart Molecules, Rikkyo University, Nishi-Ikebukuro, Toshima-ku,
Tokyo 171-8501, Japan
Fax +81(3)39852396; E-mail: chkkuroda@grp.rikkyo.ne.jp
Received 18 April 2011
planned to use amphipathic thioesters 6 and 7, which have
Abstract: The title reaction was studied using sodium 3-(1-oxo-
dodec-1-yl)thio- and 3-(1-oxohept-1-yl)thiopropanoate with vari-
ous chain lengths of amines. The yields of the amides were found to
depend on both the chain length of the thioester and that of amine,
both a hydrophobic alkyl chain and a hydrophilic carbox-
ylate moiety, in place of 1 and 2, respectively. Herein we
report that the reaction proceeds even with hydrophilic
suggesting the presence of hydrophobic interaction. The amides amines including butylamine and cyclohexylamine to
were obtained in better yields after addition of sodium fluoride. yield the corresponding amides.
Acylation (dodecanoylation) of some hydrophobic amino acids was
6
7
Each of compounds 6 and 7 were prepared by acylation
of 3-mercaptopropanoic acid with lauroyl chloride or hep-
tanoyl chloride, respectively, followed by titration with
also studied to obtain the corresponding amides.
Key words: amines, amides, amino acids, thioesters, hydrophobic
effect
8
NaOH. Initially, amidation of 6 with amines having var-
ious chain length of alkyl group (3a–h) was studied, and9
the results are summarized in Scheme 2 and Table 1.
When an aqueous suspension of 6 and octylamine (3c)
was stirred for 24 hours at ambient temperature, N-octyl-
dodecanamide (4c) was afforded in 94% yield (entry 3).
Shorter amines such as butylamine (3a) and hexylamine
Organic reactions in aqueous media have been extensive-
ly developed because of convenience, harmlessness and
unique chemical behavior. Formation of amides from
1
thioesters and amines is one of the fundamental reactions
in biological chemistry. The reaction is one of the practi-
(
3b) also reacted under the same reaction condition to
2
cal methods in peptide synthesis. In aqueous organic
give 4a and 4b in 45% and 97% yields, respectively (en-
tries 1 and 2). In the previous method involving S-dodecyl
dodecanethioate (1), short-chain amines 3b,c did not react
at all despite the reaction being carried out under refluxing
chemistry, reaction of activated thioester is also reported.3
Kinoshita and Kunieda’s group reported dimerization and
polymerization reactions of thioalanine or thioglycine S-
dodecyl ester in water in the presence of a weak amine.4
We recently reported hydrophobic effect in the reaction of
S-dodecyl dodecanethioate (1) or heptanethioate (2) with
5
condition. Compounds 3d–h reacted with thioester 6, af-
fording the corresponding amides 4d–h in good yields
(
entries 4–8). Cyclohexylamine (3i) also reacted with 6, to
5
n-alkylamine 3. The reaction occurred without the aid of
give amide 4i albeit in a low yield (entry 9). Since water-
soluble amines such as 3a,b,i reacted, it was suggested
that the solubility of amine in water is not a main factor to
determine the occurrence of the reaction. The low yield of
any surfactant or organic solvent, and the yield of the
products 4 or 5 depended primarily on the chain length of
amine (Scheme 1). Namely, long-chain alkylamine (n
>12) afforded the corresponding amide in good yield,
4
i is probably due to steric hindrance.
while no amide was obtained from amine having shorter
alkyl chain (n = 6, 8) or cyclohexylamine.
O
O
H2O
R2
COO Na
2
R1
S
+
R NH2
R1
N
O
O
H
H2O
6 R1 = n-C11H23
4a–i R1 = n-C11H23
n-C12H25
n-CnH2n+2
3a–i
+
n-CnH2n+2NH2
R
S
R
N
1
5a–h R1 = n-C6H13
7
R
= n-C6H13
H
1
2
R = n-C11H23
R = n-C6H13
3
4 R = n-C11H23
5 R = n-C6H13
Scheme 2
Scheme 1
Compound 7 afforded amides 5a–h after reaction with the
corresponding amines under the same reaction conditions
Since thioesters 1 and 2 are hydrophobic molecules, the
above results led us to suspect that hydrophobic interac-
tion was not enough between water-soluble short-chain
amines and the water-insoluble thioesters. Thus, we
(
Table 1, entries 10–17). Difference in yields between 6
and 7 was obvious. Namely, the long-chain amines were
acylated in moderate yields when reacted with 7 (entries
1
2–17), while the short-chain amines were acylated in
only low yields (entries 10 and 11). The results indicate
that the yield of the product depends primarily on the
chain length of the thioester, suggesting the presence of
hydrophobic interaction. Compound 6 forms micelle un-
SYNLETT 2011, No. 14, pp 2035–2038
Advanced online publication: 10.08.2011
DOI: 10.1055/s-0030-1261165; Art ID: U03611ST
x
x
.x
x
.2
0
1
1
©
Georg Thieme Verlag Stuttgart · New York

2
036
A.Torihata, C. Kuroda
LETTER
der the reaction conditions (CMC = 2.6 mM, determined Table 2 Salt Effect in the Reaction of Thioester 6/7 and Amine 3a
by electric conductivity method), while 7 dissolves in wa-
Entry
Thioester Amine
Salt
Product
Yield (%)b
ter to form a clear solution.
1
2
3
4
5
6
7
8
9
6
6
6
6
7
7
7
7
7
7
7
7
3a
3a
3i
NaCl
NaF
NaCl
NaF
NaF
NaF
NaF
NaF
NaF
NaF
NaF
NaF
4a
82
89
39
59
67
91
88
75
82
83
74
57
Table 1 Amidation Reaction of Thioester 6/7 with Amine 3a
4a
Entry
Thioester Amine R¢
Product Yield (%)b
4i
1
2
3
4
5
6
7
8
9
6
6
6
6
6
6
6
6
6
7
7
7
7
7
7
7
7
3a
3b
3c
3d
3e
3f
n-Bu
4a
4b
4c
4d
4e
4f
45
97
94
84
89
93
77
77
9
3i
4i
n-C H
6
11
17
19
3a
3b
3c
3d
3e
3f
5a
n-C H
8
5b
5c
n-C H
9
n-C H
10
21
23
25
29
5d
5e
n-C H
11
3g
3h
3i
n-C H
4g
4h
4i
12
1
1
0
1
2
5f
n-C H
14
3g
3h
5g
cyclohexyl
n-Bu
1
5h
1
1
1
1
1
1
1
0
1
2
3
4
5
6
7
3a
3b
3c
3d
3e
3f
5a
5b
5c
5d
5e
5f
7
a
All the reactions were carried out under the same conditions as men-
tioned in the footnote a of Table 1. Molar ratio of 6/3 or 7/3 = 1:2.
Isolated yield.
n-C H
16
36
20
36
45
50
36
6
11
17
19
b
n-C H
8
12
n-C H
amide 9a in 21% yield after one day (entry 1). A similar
result was obtained for the reaction of 8b with 6 giving
9
n-C H
13
10
21
23
25
29
9
3
b (entry 2). When sodium fluoride was added (entries
and 4) or the reaction temperature was raised to 70 °C
n-C H
11
(
entries 5 and 6), 9a,b were obtained in better yields. In
contrast, compound 7 did not react with 8a at all even after
the reaction was heated to 70 °C.
3g
3h
n-C H
5g
5h
12
1
n-C H
14
a
Each substrate was mixed in distilled H O and stirred for 24 h at r.t.
2
(CH2)n
O
2
H O
H2N
Molar ratio of 6/3 or 7/3 = 1:2. Concentration of 6 or 7 = 13 mM.
6
+
n-C6H13
b
Isolated yield.
O
8
8
a n = 1
b n = 2
O
(
CH2)n
O
The effect of salts was examined with the expectation that
the hydrophobic effect would be increased. Sodium chlo-
ride and sodium fluoride were individually added to the
reaction mixture of thioester 6 with hydrophilic amines
6 13
n-C H
n-C11H23
N
H
O
9
9
a n = 1
b n = 2
Scheme 3
3
a,i, from which the amidation reaction proceeded in low
or moderate yields without additive (see Table 1, entries 1
and 9). The results of the salt effect are shown in Table 2.
The yield of 4a or 4i increased after the addition of sodium
chloride or sodium fluoride, the latter of which was a little
more effective. Amidation of 7 was also improved by the
addition of sodium fluoride to obtain 5 in acceptable
yields for synthetic purpose (entries 5–12).
Table 3 Amidation of Thioester 6 with Glycine or b-Alanine Hexyl
Estersa
Entry Substrate Temperature Time
h)
Additive Product Yield
b
(
(%)
1
2
3
4
5
6
8a
8b
8a
8b
8a
8b
r.t.
24
24
24
24
18
18
–
9a
9b
9a
9b
9a
9b
21
38
84
80
65
79
The reactions of 6 with functionalized amine, acylation
r.t.
–
(
dodecanoylation) reaction of glycine and b-alanine hexyl
r.t.
NaF
NaF
–
esters 8a and 8b were next studied (Scheme 3). Com-
pounds 8a,b were prepared as triflate from 1-hexanol and
r.t.
1
0
glycine or b-alanine, respectively. The reaction of 8a,b
70 °C
70 °C
1
1
with 6 is summarized in Table 3. When 8a was treated
with 6 under the same reaction conditions as described
above (r.t., 24 h), the reaction proceeded slowly to give
–
a
Molar ratio of 6/8 = 1:2.
Isolated yield.
b
Synlett 2011, No. 14, 2035–2038 © Thieme Stuttgart · New York

LETTER
Reaction of Amphipathic-Type Thioester and Amine in Water
2037
(
6) Kurooka, S.; Hashimoto, M.; Tomita, M.; Maki, A.;
R
H2O
n-C11H23
O
R
Yoshimura, Y. J. Biochem. 1976, 79, 533.
O
6
+
–1 1
H2N
n-C6H13
O
(7) Compound 7: IR (KBr): 1684, 1566, 1425 cm . H NMR as
N
n-C6H13
carboxylic acid (CDCl ): d = 0.88 (t, J = 6.4 Hz, 3 H), 1.21–
O
H
3
O
1.37 (m, 6 H), 1.59–1.70 (m, 2 H), 2.55 (t, J = 7.5 Hz, 2 H),
1
0a–d
1
1a–d
13
2
.69 (t, J = 6.9 Hz, 2 H), 3.11 (t, J = 6.9 Hz, 2 H). C NMR
as carboxylic acid (CDCl ): d = 14.0, 22.4, 23.5, 25.5, 28.6,
3
Scheme 4
3
1.4, 34.2, 44.0, 177.2, 199.3. MS (FAB): m/z = 263 [M +
+
+
+
Na] , 241 [M + H] . HRMS (FAB): m/z [M + H] calcd for
Table 4 Amidation of Thioester 6 with Some Hydrophobic Amino
C H O NaS: 241.0874; found: 241.0865.
1
0
18
3
Acid Hexyl Estersa
(8) Dellaria, J. F. Jr.; Nordeen, C.; Swett, L. R. Synth. Commun.
986, 16, 1043.
9) Typical Procedure for the Amidation Reaction: Thioester
(0.065 mmol) was added to a stirred mixture of amine 3
0.13 mmol) in H O (5 mL), and the mixture was stirred at
1
Entry
Substrate R (parent amino acid)
Product Yield (%)b
(
6
1
2
3
10a
10b
10c
10d
Me CH (valine)
11a
11b
11c
11d
69
61
83c
73
2
(
2
r.t. for 24 h. The mixture was extracted with Et O, and the
Me CHCH (leucine)
2
2
2
ethereal layer was washed with aq NaHCO solution, and
3
MeEtCH (isoleucine)
Bn (phenylalanine)
dried over Na SO . After evaporation of the solvent, the
2
4
product was purified by silica gel column chromatography
using hexane–EtOAc as eluent.
4
(
10) (a) Iimura, S.; Manabe, K.; Kobayashi, S. Chem. Commun.
002, 94. (b) Bodanszky, M. Int. J. Pept. Protein Res. 1984,
23, 111.
a
All the reactions were carried out at 70 °C for 18 h. Molar ratio of 6/
0 = 1:2.
Isolated yield.
Epimerization was not observed.
2
1
b
c
(11) An aqueous solution of NaOH (0.5 M, 0.26 mL) was added
in the reaction of 8 triflate (0.13 mmol) with 6 (0.065 mmol).
(
12) Compound 9a: mp 60–61 °C. IR (KBr): 3315, 1739, 1647,
–
1 1
1
3
1
2
552, 1213 cm . H NMR (CDCl ): d = 0.88 (t, J = 7.0 Hz,
Similarly, hydrophobic amino acid hexyl esters 10a–d
were acylated to afford the corresponding amides 11a–
3
H), 0.89 (t, J = 7.0 Hz, 3 H), 1.23–1.39 (m, 22 H), 1.55–
.69 (m, 4 H), 2.24 (t, J = 7.4 Hz, 2 H), 4.04 (d, J = 5.0 Hz,
1
4–17
d
in good yields (Scheme 4 and Table 4). These re-
13
H), 4.15 (t, J = 6.7 Hz, 2 H), 5.94 (br, 1 H). C NMR
sults suggest that amphipathic-type thioester is a useful
acylating agent of amino acid derivative in water. The
lower reactivity of amino acid derivative, in comparison
to alkylamine, is probably due to low nucleophilicity of
the amino group. The pKa value of the amino group in
amino acid is generally lower than that in alkylamine.
(
2
CDCl ): d = 14.0, 14.1, 22.5, 22.7, 25.4, 25.6, 28.4, 29.2,
3
9.3 (2 × C), 29.4, 29.6 (2 × C), 31.3, 31.9, 36.4, 41.3, 65.7,
+
170.3, 173.2. EIMS: m/z = 341 [M ], 201, 118. HRMS: m/z
[M + H] calcd for C20
+
H40NO : 342.3008; found: 342.3002.
3
(
13) Compound 9b: mp 45–46 °C. IR (KBr): 3296, 1732, 1639,
–
1 1
1
3
552, 1186 cm . H NMR (CDCl ): d = 0.88 (t, J = 6.7 Hz,
3
H), 0.89 (t, J = 6.2 Hz, 3 H), 1.22–1.37 (m, 22 H), 1.55–
In conclusion, various chain lengths of amines were acy-
lated by amphipathic thioester 6 or 7 in water. The yields
of the amides were dependent primarily on the chain
length of the thioester. In contrast to the previous method
1.69 (m, 4 H), 2.15 (t, J = 7.5 Hz, 2 H), 2.53 (t, J = 5.9 Hz, 2
H), 3.52 (q, J = 5.9 Hz, 2 H), 4.09 (t, J = 6.8 Hz, 2 H), 6.07
1
3
(
2
3
br, 1 H). C NMR (CDCl ): d = 14.0, 14.1, 22.5, 22.7, 25.6,
3
5.7, 28.5, 29.3 (3 × C), 29.5, 29.6 (2 × C), 31.4, 31.9, 34.0,
+
4.7, 36.8, 173.0, 173.2. EIMS: m/z = 355 [M ], 215, 132.
5
using S-alkylthioester 1 or 2, amides were successfully
+
HRMS: m/z [M + H] calcd for C H NO : 356.3165;
2
1
42
3
synthesized from hydrophilic short-chain amines. The
present method will be useful in the acylation of amines in
water.
found: 356.3134.
14) Compound 11a: oil. IR (NaCl): 3307, 1736, 1651, 1539,
(
–
1 1
1198 cm . H NMR (CDCl ): d = 0.88 (t, J = 6.8 Hz, 3 H),
3
0
.89 (t, J = 6.8 Hz, 3 H), 0.90 (d, J = 7.0 Hz, 3 H), 0.94 (d,
J = 7.0 Hz, 3 H), 1.22–1.39 (m, 22 H), 1.59–1.69 (m, 4 H),
2.10–2.21 (m, 1 H), 2.23 (t, J = 7.7 Hz, 2 H), 4.07–4.18 (m,
References and Notes
2
1
2
3
3
3
H), 4.58 (dd, J = 4.6, 8.8 Hz, 1 H), 5.94 (br d, J = 9.0 Hz,
(
1) (a) Organic Reactions in Water; Lindström, U. M., Ed.;
Blackwell Publishing: Oxford, 2007. (b) Li, C.-J. Chem.
Rev. 1993, 93, 2023. (c) Li, C.-J.; Chen, L. Chem. Soc. Rev.
1
3
H). C NMR (CDCl ): d = 14.0, 14.1, 17.7, 18.9, 22.5,
3
2.7, 25.6, 25.7, 28.5, 29.2, 29.3 (2 × C), 29.5, 29.6 (2 × C),
1.3, 31.4, 31.9, 36.8, 56.8, 65.4, 172.4, 173.0. EIMS: m/z =
2
006, 35, 68. (d) Lindström, U. M. Chem. Rev. 2002, 102,
+
+
83 [M ], 254. HRMS: m/z [M + H] calcd for C H NO :
2
3
46
3
2751.
84.3478; found: 384.3478.
(
2) (a) Kent, S. B. H. Chem. Soc. Rev. 2009, 38, 338.
b) Noren, C. J.; Wang, J.; Perler, F. B. Angew. Chem. Int.
(
15) Compound 11b: oil. IR (NaCl): 3288, 1741, 1651, 1543,
(
–
1 1
1
0
192 cm . H NMR (CDCl ): d = 0.88 (t, J = 6.8 Hz, 3 H),
3
Ed. 2000, 39, 450. (c) Weber, A. L.; Orgel, L. E. J. Mol.
Evol. 1979, 13, 193.
3) Nambu, H.; Hata, K.; Matsugi, M.; Kita, Y. Chem. Eur. J.
.89 (t, J = 6.8 Hz, 3 H), 0.94 (d, J = 6.3 Hz, 3 H), 0.95 (d,
J = 6.0 Hz, 3 H), 1.23–1.39 (m, 23 H), 1.46–1.72 (m, 6 H),
.21 (t, J = 7.5 Hz, 2 H), 4.12 (t, J = 5.8 Hz, 2 H), 4.65 (dt,
(
(
2
2005, 11, 719.
1
3
J = 5.0, 8.7 Hz, 1 H), 5.84 (br d, J = 8.0 Hz, 1 H). C NMR
4) (a) Kawabata, Y.; Kinoshita, M. Makromol. Chem. 1975,
(
CDCl ): d = 14.0, 14.1, 22.1, 22.5, 22.7, 22.8, 24.9, 25.5,
3
176, 49. (b) Kawabata, Y.; Kinoshita, M. Makromol. Chem.
2
3
2
3
5.6, 28.4, 29.2, 29.3 (2 × C), 29.5, 29.6 (2 × C), 31.3, 31.9,
1
975, 176, 2797. (c) Kawabata, Y.; Kinoshita, M.
+
6.6, 41.9, 50.6, 65.5, 172.8, 173.4. EIMS: m/z = 397 [M ],
Makromol. Chem. 1975, 176, 2807.
+
68, 86. HRMS: m/z [M + H] calcd for C H NO :
2
4
48
3
(
5) Torihata, A.; Kuroda, C. Bull. Chem. Soc. Jpn. 2010, 83,
98.3634; found: 398.3616.
1534.
Synlett 2011, No. 14, 2035–2038 © Thieme Stuttgart · New York

2
038
A.Torihata, C. Kuroda
LETTER
(
16) Compound 11c: oil. IR (NaCl): 3300, 1738, 1653, 1537,
(17) Compound 11d: mp 45–46 °C. IR (KBr): 3326, 1732, 1645,
–1
1
–1 1
1
192 cm . H NMR (CDCl ): d = 0.88 (t, J = 6.9 Hz, 3 H),
1523, 1209 cm . H NMR (CDCl ): d = 0.88 (t, J = 6.6 Hz,
3
3
0.89 (t, J = 6.8 Hz, 3 H), 0.90 (d, J = 6.8 Hz, 3 H), 0.93 (t,
3 H), 0.90 (t, J = 6.0 Hz, 3 H), 1.23–1.38 (m, 22 H), 1.52–
1.68 (m, 4 H), 2.17 (t, J = 7.6 Hz, 2 H), 3.11 (dd, J = 5.8, 14.0
Hz, 1 H), 3.14 (dd, J = 6.0, 14.0 Hz, 1 H), 4.04–4.15 (m, 2
J = 7.2 Hz, 3 H), 1.22–1.40 (m, 24 H), 1.58–1.72 (m, 4 H),
1
1
.83–1.94 (m, 1 H), 2.22 (t, J = 7.6 Hz, 2 H), 4.11 (dt, J =
0.7, 6.7 Hz, 1 H), 4.14 (dt, J = 10.7, 6.7 Hz, 1 H), 4.62 (dd,
H), 4.90 (dt, J = 7.7, 6.0 Hz, 1 H), 5.90 (br d, J = 8.0 Hz, 1
1
3
13
J = 4.6, 8.5 Hz, 1 H), 5.97 (br d, J = 8.5 Hz, 1 H). C NMR
H), 7.08–7.34 (m, 5 H). C NMR (CDCl ): d = 14.0, 14.1,
3
(
CDCl ): d = 11.6, 14.0, 14.1, 15.4, 22.5, 22.7, 25.2, 25.5,
22.5, 22.7, 25.5, 25.6, 28.4, 29.2, 29.3 (2 × C), 29.4, 29.6 (2
× C), 31.3, 31.9, 36.6, 38.0, 52.9, 65.7, 127.0, 128.5 (2 × C),
3
2
3
2
3
5.7, 28.5, 29.2, 29.3 (2 × C), 29.5, 29.6 (2 × C), 31.3, 31.9,
+
+
6.8, 38.1, 56.1, 65.4, 172.3, 172.8. EIMS: m/z = 397 [M ],
129.3 (2 × C), 136.0, 171.8, 172.6. EIMS: m/z = 431 [M ],
+
+
68, 86. HRMS: m/z [M + H] calcd for C H NO :
232, 120. HRMS: m/z [M + H] calcd for C H NO :
2
4
48
3
27 46
3
98.3634; found: 398.3647.
432.3478; found: 432.3491.
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