Thioesterifications Free of Activating Agent and Thiol: A Three-Component Reaction of Carboxylic Acids, Thioureas, and Michael Acceptors

Article abstract of DOI:10.1002/adsc.201500426

An amine-catalyzed, one-pot synthesis of thioesters directly from carboxylic acids, thioureas, and Michael acceptors is described. This process was further improved by use of 1-[2-(methylamino)ethyl]-3-phenylthiourea (4) as the catalyst. Aromatic and aliphatic carboxylic acids with functional groups are compatible with this process, and both α,β-unsaturated esters and ketones can be the Michael acceptors for this reaction. The progress of this reaction was monitored by ¹H NMR, and a reaction mechanism is proposed.

Full text of DOI:10.1002/adsc.201500426

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DOI: 10.1002/adsc.201500426
Thioesterifications Free of Activating Agent and Thiol: A Three-
Component Reaction of Carboxylic Acids, Thioureas, and
Michael Acceptors
Sharada Prasanna Swain,a Yen-Lin Chou,a and Duen-Ren Houa,*
a
Department of Chemistry, National Central University, Jhong-Li City, Taoyuan, Taiwan, 32001
Fax: (+886)-3-422-7664; phone: (+ 886)-3-427-9442; e-mail: drhou@ncu.edu.tw
Received: April 29, 2015; Revised: June 1, 2015; Published online: August 18, 2015
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201500426.
Abstract: An amine-catalyzed, one-pot synthesis of
thioesters directly from carboxylic acids, thioureas,
and Michael acceptors is described. This process
was further improved by use of 1-[2-(methylami-
no)ethyl]-3-phenylthiourea (4) as the catalyst. Aro-
matic and aliphatic carboxylic acids with functional
groups are compatible with this process, and both
a,b-unsaturated esters and ketones can be the Mi-
chael acceptors for this reaction. The progress of
this reaction was monitored by 1H NMR, and a reac-
tion mechanism is proposed.
ported by Cai et al., demonstrated that thioesters
could be produced from a one-pot, three-component
reaction of organic halides, aromatic acyl halides, and
thiourea as the source of the sulfur atom
(Scheme 1).[16]
Herein, we report a new thioesterification of car-
boxylic acids in which the adducts of thioureas and
Michael acceptors activate the carboxylic acids and
also provide the corresponding thiolate to generate
the thioesters. This one-pot, three-component reac-
tion is performed under mild conditions and is free of
the use of reactive, often foul-smelling thiols and the
activating reagents frequently required for the thioes-
terification of carboxylic acids. We have found that
the efficiency of this process is further improved by
addition of a catalytic amount of compound 4, a conju-
gate of a thiourea and a secondary amine.
Keywords: Michael addition; multicomponent reac-
tion; organic catalysis; thioesterification
Thiourea and its derivatives have been widely ap-
Thioesters (thiol esters) are useful building blocks for plied as powerful catalysts in organocatalytic reac-
organic synthesis[1,2] and the chemical synthesis of pro- tions.[17] However, when various thioureas, such as
teins.[3] They serve as activated carboxylic acids and N,N’-diphenylthiourea (3a), were screened in an at-
are often used as acyl transfer agents for various nu-
cleophiles, or precursors to generate radicals.[4,5] For
example, native chemical ligation (NCL), a powerful
chemical method to synthesize proteins, employs the
reaction between an N-terminal cysteine peptide and
a C-terminal peptide thioester.[3,6] In addition, a,b-un-
saturated thioesters are often good substrates in
asymmetric 1,4-addition reactions.[7] Some thioesters
also possess biological activities and medicinal poten-
tial.[8,9]
The conventional methods for generating thioesters
are: (i) the activation of carboxylic acids with carbo-
diimides or N-acylbenzotriazoles followed by the ad-
dition of thiols[10] and (ii) the reaction of acyl halides
with thiols.[11] Recent progress in the preparation of
thioesters includes the acid-catalyzed, direct conden-
sation of carboxylic acids and thiols,[12] and various
coupling reactions, mainly mediated by metal com-
plexes.[13–15] An interesting development, recently re- Scheme 1. Synthesis of thioesters using thiourea.
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Thioesterifications Free of Activating Agent and Thiol
tempt to prepare the Michael adduct of benzoic acid solvents such as toluene and DMF were compatible
(1a) and ethyl acrylate (2a) [Eq. (1)], the results were with this reaction (entries 9 and 10), and the reaction
unsatisfactory. We felt that this addition process time could be shortened to 10 h by increasing the re-
might be improved by the addition of amines to give action temperature, by using solvents with higher
the more nucleophilic benzoate anion. Thus, a mixture boiling points (entries 9 and 11). However, the reac-
of 1a, 2a, 3a and dibutylamine was heated at 408C for tion failed in THF, methanol, or aqueous DMF solu-
24 h [Eq. (2)]. We were pleased to find that the thio- tion (entries 12–14). N,N’-Dimethylthiourea (3b),
ester 5a was isolated in 30% yield along with the aza- commercially available as is 3a, was also a suitable
Michael adduct, ethyl 3-(dibutylamino)propanoate source of the sulfur atom (entries 15 and 16). The low
(52%).[18] The thioester 5a was unambiguously charac- yield for the reaction involving 3b in CH2Cl2
terized by NMR and IR spectroscopy and mass analy- (entry 15) is likely due to its low solubility at the reac-
sis.[19]
tion temperature (408C) used.
The scope of the reaction is summarized in Table 2.
o-Toluic acid (1b), 3,4- and 2,6-dimethylbenzoic acids
(1c and 1d) gave satisfactory yields (entries 1–3).
Both electron-rich and electron-deficient benzoic
acids can be the substrates for this reaction, as shown
for 4-methoxy- and 4-nitrobenzoic acids (1e and 1f,
entries 4 and 5). 2-Iodobenzoic acid (1g) gave a mod-
erate yield (entry 6). Both 1- and 2-naphthoic acids
are also good substrates (entries 7 and 8). The results
obtained from the naphthoic acids 1h and 1i and the
dimethylbenzoic acids 1c and 1d suggest that the
steric environment around the carboxyl group has
little influence on the reaction. The thioesterification
also proceeded well for 4-methoxyphenylacetic acid
(1j) and Boc-l-phenylalanine (1k), in both of which
the carboxyl groups are not conjugated to the aromat-
ic systems (entries 9 and 10). Aliphatic carboxylic
acids, such as 1l and 1m, were also compatible with
the reaction, although the yields were lower (en-
We were intrigued by the unexpected formation of tries 11 and 12). In addition to the acrylates 2a and
5a, and the results of optimizing this thioesterification 2b, other Michael acceptors including the a,b-unsatu-
are summarized in Table 1. We observed that the thio- rated ketones 2c and 2d and dimethyl fumarate (2e)
esters were unstable and often lost during their isola- provided the corresponding thioesters (entries 13–16).
tion, so the reported yields were determined by Phenyl vinyl ketone[20] (2c) provided the best yields
1H NMR analysis of the crude products with an inter- among the Michael acceptors screened, and also re-
nal standard (anisole); isolated yields, shown in pa- sulted in increased yields of the thioesters derived
rentheses, were obtained after column chromatogra- from the aliphatic carboxylic acids 1l and 1m (en-
phy. Varying the stoichiometry of the reagents or di- tries 17 and 18) as compared those obtained with 2a
butylamine gave very limited improvements in yields (entries 11 and 12). The successful thioesterification
(entries 1–4). The idea of constraining the role of the of 1n and 1k suggests that biomolecules with the
secondary amine as a basic catalyst, rather than as the amide or carbamate functional groups, for example,
nucleophile, prompted us to explore the conjugate of protected peptides, could be potential substrates for
an amine and a thiourea to facilitate this reaction. this reaction.
Indeed, the yield of 5a increased to 72% when we
When the thioester 5ka was further reacted with
used 4, derived from addition of N-methylethylenedi- (S)-1-phenylethanamine, amide 6 was obtained as
amine to phenyl isothiocyanate, in place of dibutyl-
amine and thiourea 3a as the 28 amine base and the
source of the sulfur atom, respectively (entry 5). The
yield rose further to 81% when the acrylate 2a was
the limiting reagent (entry 6). We subsequently found
that the same result could be obtained by using a cata-
lytic amount of 4 (20 mol%), accompanied with
excess thiourea 3a (entry 7). However, further reduc-
ing the quantity of 4 to 10 mol% was not productive
(entry 8). In addition to CH2Cl2, other polar, aprotic
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Table 1. Reaction optimizations for the thioesterification of 1a
[a]
[a]
[a]
[a]
[a]
Entry
1a
2a
3a
(n-Bu)2NH
4
Solvent
Yield [%][b]
1
2
3
4
5
6
7
8
1.0
1.0
1.0
1.0
1.0
1.5
1.5
1.0
1.5
1.5
1.5
1.5
1.5
1.5
1.0
1.5
1.0
1.0
1.5
1.5
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.5
1.0
1.5
–
1.0
1.0
1.0
0.2
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
toluene
DMF
toluene
THF
MeOH
DMF(aq)
CH2Cl2
toluene
30 (15)
31 (15)
25 (10)
20 (5)
72 (50)
81 (55)
80 (55)
45 (25)
78
80
81
0
0
1.5
1.5
0.2
0.1
0.2
0.2
0.2
0.2
0.2
0.2
0.2
0.2
–
1.5
1.0
1.5
1.5
1.5
1.5
1.5
1.5
9[c]
10
11[d]
12
13
14
15
16[g]
[e]
0
25
80
1.0[f]
1.5[f]
[a]
Equivalents of the reagent used.
[b]
[c]
[d]
[e]
[f]
As calculated from 1H NMR spectra utilizing anisole as an internal standard; isolated yields shown in parentheses.
Reaction conducted at 508C, 24 h.
Reaction conducted at 908C, 10 h.
DMF/H2O, v/v=1:1.
N,N’-Dimethylthiourea was used.
808C.
[g]
a single product and no diastereomeric isomer was
observed in 13C NMR. This result suggests that the
optical purity of 1k was preserved during this thioes-
terification [Eq. (3)].
Scheme 2. One-pot synthesis of amide 12.
The effectiveness of this methodology was shown
by the gram-scale synthesis of 5ba (1.45 g, 56% yield)
and the one-pot synthesis of N-benzyl-3-methylbutan-
amide (7) in 65% isolated yield (Scheme 2).
The proposed mechanism for the reaction is shown
in Scheme 3 and is consistent with the following ob-
servations. Monitoring of the reaction of 1m, 2c, 3a,
1
and 4 by H NMR spectroscopy showed that an inter-
mediate was first generated and reached its highest
Scheme 3. A plausible reaction mechanism for the thioester-
concentration in 6 h (Figure 1). Then the formation of ification.
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Table 2. Thioesterification of carboxylic acids [a]
entry
Carboxylic acid
Michael acceptor
Thioester
Yield [%][b]
84 (60)
1
2a
2
3
4
2a
2a
2a
72 (55)
68 (52)
81 (62)
5
2a
60 (41)
6
2a
2a
52 (30)
70 (46)
7[c]
8[c]
2a
2a
75 (52)
80 (58)
9[c]
10[c]
11
2a
2a
65 (40)
50 (25)
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Table 2. (Continued)
entry
Carboxylic acid
Michael acceptor
Thioester
Yield [%][b]
64 (40)
12
2a
13
1a
1a
1a
75 (51)
85 (62)
60 (42)
14[d]
15[d]
16[c]
1a
46 (20)
17[d]
18
1l
2c
2c
70 (45)
85 (66)
1m
19
2d
55 (35)
[a]
Thiourea 3a was applied; reaction in toluene, 808C, 24 h.
Yields determined by H NMR spectroscopic analysis; isolated yields shown in parentheses.
Reaction in toluene, 808C, 48 h.
Reaction in CH2Cl2, 408C, 48 h
[b]
[c]
[d]
1
the product 5mc was observed, accompanied with convenient synthesis of thioesters of biological or
a decrease in the intermediate. The intermediate was chemical interest.
isolated and characterized as compound 8 (R2 =R’=
Ph) through its synthesis by addition of thiourea 3a to
phenyl vinyl ketone (2c).[19,21] Subsequent addition of
isovaleric acid (1m) and 4 (20 mol%) to the solution
Experimental Section
of 8 also provided thioester 5mc. In this mechanism,
the addition/substitution of the carboxylate to 8 gives
Typical Procedure for the Synthesis of Thioesters
carbamimidate 10 and thiolate 11, which further react
to produce thioesters and stable ureas.
To a solution of benzoic acid (1a, 184.4 mg, 1.51 mmol),
ethyl acrylate (2a, 100.9 mg, 1.01 mmol), and N,N’-diphe-
nylthiourea (3a, 1.51 mmol, 1.5 equiv.) in toluene (5.0 mL)
was added thiourea catalyst 4 (42.3 mg, 0.20 mmol). The re-
action was heated in an oil bath (808C) for 24 h, and then
the excess solvent was evaporated under vacuum. The crude
product was purified by column chromatography (SiO2:
EtOAc/n-hexane, 1:5; Rf =0.76) to give thioester 5a as a col-
orless oil; yield: 131.2 mg (0.55 mmol, 55%). 1H NMR
(300 MHz, CDCl3): d=7.93 (d, J=7.2 Hz, 2H), 7.54 (t, J=
7.3 Hz, 1H), 7.41 (t, J=7.6 Hz, 2H), 4.18 (q, J=7.2 Hz,
2H), 3.29 (t, J=6.9 Hz, 2H), 2.69 (t, J=6.9 Hz, 2H), 1.21 (t,
In summary, this new method for preparing thioest-
ers is free of the troublesome thiols and activating re-
agents generally required for the thioesterification of
carboxylic acids. Instead, both the thioureas and the
a,b-unsaturated esters are easy to handle, inexpensive
and commercially available. Both aromatic and ali-
phatic carboxylic acids with functional groups are
compatible with this process. The proposed reaction
mechanism is supported by the identified reaction in-
termediate. Thus, this reaction provides a metal-free, J=7.2 Hz, 3H); 13C NMR (75 MHz, CDCl3): d=191.5,
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N-Benzyl-3-methylbutanamide (7)[22]
To a solution of isovaleric acid 1m (58.2 mg, 0.57 mmol), 1-
phenylprop-2-en-1-one 2c (50.2 mg, 0.38 mmol), and N,N’-di-
phenylthiourea 3a (130.1 mg, 0.57 mmol) in toluene
(1.5 mL) was added thiourea catalyst
4
(16.5 mg,
0.08 mmol). The reaction mixture was heated in an oil bath
(808C) for 24 h, cooled to room temperature, treated with
benzylamine 11 (61.1 mg, 0.57 mmol) and then heated in an
oil bath (408C) for 24 h. Then excess solvent was evaporated
under vacuum. The crude product was purified by column
chromatography (SiO2: EtOAc/n-hexane, 1:2; Rf 0.42) to
give 12 as a light yellow solid; yield: 47.5 mg (0.25 mmol,
1
65%). H NMR (300 MHz, CDCl3): d=7.31–7.25 (m, 5H),
5.69 (s, 1H), 4.43 (d, J=5.7 Hz, 2H), 2.17–2.09 (m, 1H),
2.06 (d, J=7.2 Hz, 2H), 0.95 (d, J=7.2 Hz, 6H). The spec-
troscopic data are consistent with the reported values.[22]
3-Oxo-3-phenylpropyl N,N’-Diphenylcarbamimido-
thioate (8)
To
a solution of 1-phenylprop-2-en-1-one 2c (15.2 mg,
0.115 mmol) in toluene (0.5 mL) was added N,N’-diphe-
nylthiourea 3a (26.2 mg, 0.115 mmol). The reaction mixture
was heated in an oil bath (808C) for 5 h, and then the excess
solvent was evaporated under vacuum. The crude product
was purified by column chromatography (SiO2: EtOAc/n-
hexane, 1:4; Rf =0.62) to give compound 8 as a yellow solid;
yield: 29.5 mg (0.081 mmol, 71%); mp 104.0–105.08C.
1H NMR (300 MHz, CDCl3): d=7.90–7.89 (m, 3H), 7.53–
7.41 (m, 5H), 7.19–7.15 (m, 3H), 6.74–6.64 (m, 4H), 3.61 (t,
J=6.0 Hz, 2H), 3.27 (t, J=6.0 Hz, 2H); 13C NMR (75 MHz,
CDCl3): d=199.1, 147.3, 136.6, 133.2, 129.5, 129.2, 128.5,
127.9, 117.8, 113.2, 38.8, 37.4; HR-MS (FAB+): m/z=
360.1293, calcd. for [M]+ (C22H20N2OS): 360.1296.
Figure 1. Reaction progress of the thioesterification moni-
tored by 1H NMR spectroscopy (808C, 300 MHz);[19] 1m
(1.0 mmol), 2c (1.0 mmol), 3a (1.0 mmol) and 4 (0.2 mmol in
toluene-d8 (1.0 mL).
Acknowledgements
171.7, 136.7, 133.4, 128.6, 127.2, 60.7, 34.4, 24.0, 14.1; IR
(neat): n=2981 (m), 2360 (m), 1735 (s), 1664 (s), 1207 (s),
912 (s), 690 (s) cmÀ1; HR-MS (ESI+): m/z=261.0556, calcd.
for [M+Na]+ (C12H14O3NaS): 261.0561.
Financial support from the Ministry of Science and Technolo-
gy, Taiwan (NSC 101-2113M-008-002), is gratefully acknowl-
edged. We thank Prof. John C. Gilbert, Santa Clara Universi-
ty, for helpful comments. Thanks are also due to the Institute
of Chemistry, Academia Sinica and the Valuable Instrument
Center at National Central University, Taiwan, for mass anal-
ysis.
1-(2-(Methylamino)ethyl)-3-phenylthiourea (4)
To
3.24 mmol),
3.24 mmol) in THF (5.0 mL) was added triethylamine
a
solution of N-methylethane-1,2-diamine (15.2 mg,
and phenyl isothiocyanate (438.5 mg,
(328.3 mg, 3.24 mmol). The reaction mixture was stirred at References
room temperature for 18 h, and then the excess solvent was
evaporated under vacuum. The crude product was purified
by column chromatography (SiO2: MeOH/EtOAc, 1:4; Rf =
0.35) to give compound 4 as a white solid; yield: 549.5 mg
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(2.62 mmol, 81%); mp 161.0–163.08C; H NMR (300 MHz,
CDCl3): d=7.33–7.32 (m, 4H), 7.21–7.18 (m, 1H), 7.09 (s,
1H), 4.39 (s, 1H), 3.65 (t„ J=6.3 Hz, 2H), 3.01 (t„ J=
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