Mild and Chemoselective Thioacylation of Amines Enabled by the Nucleophilic Activation of Elemental Sulfur

Article abstract of DOI:10.1021/jacs.0c03256

A mild and chemoselective method for the thioacylation of amines using α-keto acids and elemental sulfur has been developed. The key to the success of this transformation is the nucleophilic activation of elemental sulfur by thiols such as 1-dodecanethiol

Full text of DOI:10.1021/jacs.0c03256

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Communication
Mild and Chemoselective Thioacylation of Amines
Enabled by the Nucleophilic Activation of Elemental Sulfur
Masato Saito, Sho Murakami, Takeshi Nanjo, Yusuke Kobayashi, and Yoshiji Takemoto
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.0c03256 • Publication Date (Web): 21 Apr 2020
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Journal of the American Chemical Society
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Mild and Chemoselective Thioacylation of Amines Enabled by the Nu-
cleophilic Activation of Elemental Sulfur
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Masato Saito, Sho Murakami, Takeshi Nanjo, Yusuke Kobayashi, and Yoshiji Takemoto*
Graduate School of Pharmaceutical Sciences, Kyoto University, Yoshida, Sakyo-ku, Kyoto 606-8501, Japan
Supporting Information Placeholder
ABSTRACT: A mild and chemoselective method for the thioacylation of amines using -ketoacids and elemental sulfur has
been developed. The key to success for this transformation is the nucleophilic activation of elemental sulfur by thiols such
as 1-dodecanethiol. A variety of functional groups, including unprotected hydroxyl, carboxyl, amide, sulfide, and tertiary
amine moieties are tolerated under the applied reaction conditions. To demonstrate the advantages of this method com-
pared to conventional O-S exchange reactions using Lawesson’s reagent or P2S5, thioamide moieties were introduced site-
specifically into biologically active compounds.
Thioamide moieties are commonly encountered in syn-
thetic intermediates. Their synthetic validity is due to their
unique reactivity and their ability to serve as building
blocks in the synthesis of S-containing heterocycles such
as thioazoles and thioazolines.1,2 In addition, thioamides
are regarded as bioisosteres of amides that exhibit in-
creased resistance to enzymatic hydrolysis;3 many articles
have described an improved biological activity of pharma-
ceuticals upon replacing amide with thioamide groups.4
For instance, thioacyl lysine derivatives possess signifi-
cantly improved anticancer properties compared to acyl ly-
sines.4a Furthermore, Petersson reported that the incorpo-
ration of thioamides into peptides provides stability
against hydrolysis by proteases without any loss of biolog-
ical activity.4b Although various methods for the synthesis
of valuable thioamides have been developed, reliable
methods for the site-specific installation of thioamides
with good functional-group compatibility remain elusive.5-
Scheme 1. Decarboxylative thioacylation strategies
7
Conventionally, O-S exchange reactions in oligoamides
are accomplished with Lawesson’s reagent or P2S5, albeit
that this generally results in a mixture of partially con-
verted oligothioamides that may, depending on the reac-
tion conditions, contain unreacted amides (Scheme 1A).5
While the Willgerodt–Kindler reaction and many varia-
tions thereof (Scheme 1B)6 require only carbonyl com-
pounds, amines, and elemental sulfur, most of these reac-
tions proceed exclusively under relatively harsh conditions
and exhibit a severely limited substrate scope. Even though
significant effort has been devoted to solving these funda-
mental problems,7 the reported methods often suffer from
poor site-selectivity and functional-group compatibility.
Accordingly, mild and efficient reactions for the chemose-
lective formation of thioamides with broad functional-
group tolerance are highly desirable.
Herein, we propose such a chemoselective synthesis of
thioamides under mild conditions, inspired by our previ-
ous work on the decarboxylative synthesis of amides8,9 us-
ing α-ketoacids, amines, and t-butylhydroperoxide (TBHP)
via the nucleophilic addition of TBHP to imine intermedi-
ate A. We envisaged that thioamides could potentially be
obtained using a nucleophilic sulfurizing oxidant of the
type R-Sn-S-H instead of TBHP (Scheme 1C). Alas, com-
pared to electrophilic sulfurizing reagents, such nucleo-
philic reagents are scarce.10 Accordingly, we planned to ac-
tivate elemental sulfur using nucleophiles (Nu) to generate
nucleophilic sulfurizing species B, which bears a Nu-Sn-S-
H moiety. However, elemental sulfur11 is generally stable
under ambient conditions, and its activation usually re-
quires harsh conditions (acids, bases, or radical initiators
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Page 2 of 7
at high temperatures). In order to effectively produce thi-
(nC12H25SH)) significantly improved the reaction at room
temperature and afforded 3 in excellent yield (entries 6-8).
Considering price and odor, we chose nC12H25SH as the op-
timal additive (entry 8).13 While the reaction proceeded
with as little as 10 mol% nC12H25SH (entry 9), the thioacyla-
1
2
3
4
oamides, we activated elemental sulfur under mild condi-
tions using strong or soft nucleophiles such as thiols or
phosphines (Nu = S, P). Furthermore, chalcogen–chalco-
gen interactions12 are expected to aid the nucleophilic acti-
vation of elemental sulfur using thiols (Nu = S).
n
5
tion was hampered by an excess of C12H25SH (entry 10);
6
7
8
9
this may indicate that excess thiol causes a fragmentation
of S8 to produce unreactive species. Next, we considered
the solvent; DMF produced 3 in high yield (entry 11),
whereas less polar solvents such as toluene and dichloro-
methane produced 3 in merely low yield, even in the pres-
ence of thiols (entries 12, 13), which can be explained by the
poor solubility of S8 in these solvents. Finally, we substi-
tuted elemental sulfur with several different polysulfides in
order to gain further insights on the reactive species in this
thioacylation reaction (entries 14, 15). While commercially
available dialkyltetrasulfide 4 was not effective for the thi-
oacylation, 3 was produced in 74% yield using dia-
ryltetrasulfide 5.14 These results suggest that thiols activate
polysulfide S-S bonds and attack the α-sulfur of tetrasul-
fides to provide reactive RSSSH species.15
Table 1. Optimization of the reaction conditions for
the decarboxylative thioacylation
10
11
12
13
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51
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60
S source
(mmol)
Yield
(%)a
17
Entry
Additive
Solvent
THF
1
S8 (0.3)b
S8 (0.3)b
S8 (0.3)b
S8 (0.3)b
S8 (0.3)b
S8 (0.3)b
S8 (0.3)b
S8 (0.3)b
S8 (0.3)b
S8 (0.3)b
S8 (0.3)b
S8 (0.3)b
S8 (0.3)b
4 (0.1)
None
2
None
THF/Py 12
3
DMAP
THF
THF
THF
THF
THF
THF
THF
THF
DMF
PhMe
CH2Cl2
THF
THF
12
With the optimum reaction conditions in hand, we in-
vestigated the substrate scope of the thioamidation reac-
tion between α-ketoacids and amines in order to verify the
chemoselectivity and functional-group tolerance (Table 2).
α-Ketoacids with linear or branched alkyl substituents pro-
vided thioamides 6 and 7 in good yield (Table 2A). In con-
trast, α-ketoacids derived from benzoic acids produced thi-
oamides 8 and 9 in moderate yield, even when heated,
which is presumably due to their lower reactivity. Interest-
ingly, when oxaloacetic acid was used as an acyl source,
thioacetylated 10 was obtained in 70% yield via decarbox-
ylation. Our general thioamidation protocol is also appli-
cable to substrates with unprotected OH groups (11). Next,
we explored the scope with respect to amines. Cyclohexyl-
amine, and secondary cyclic amines, such as piperidine and
morpholine, provided thioamides 12-14 in 78-100% yield. In
addition, primary amines that bear an additional tertiary
amine, iodine, fluorine, or chlorine group(s) provided thi-
oamides 15-18 in good yield. Although the aniline deriva-
tives showed lower nucleophilic activity, p-toluidine pro-
duced thioanilide 19 in 47% yield. As unsaturated bonds in
e.g. alkynes react with elemental sulfur under basic condi-
tions, we also tested alkynes and olefins under the opti-
mized reaction conditions, which provided 20-24 in 47-
81% yield. It should be noted here that 20-24 contain un-
protected hydroxyl and carboxyl groups, which could po-
tentially be functionalized by coupling and/or substitution
reactions. Finally, amoxapine, an antidepressant drug, fur-
nished thioamidated derivative 25 in 84% yield, which of-
fers a method for prodrug synthesis via thioacylation.16
4
PCy3
trace
0
5
Ph2P(O)H
Cysteine
PhSH
6
96
7
quant.
84 (91c)
84
8
nC12H25SH
nC12H25SH
nC12H25SH
nC12H25SH
nC12H25SH
nC12H25SH
nC12H25SH
nC12H25SH
9d
10e
11
12
13
14
15
21
86
16
23
trace
74
5 (0.1)
aThe yield was determined by 1H NMR spectroscopy using di-
methyl terephthalate as the internal standard. bThe number of
c
mmols was calculated as the number of S atoms. Isolated
yield. d10 mol% nC12H25SH was employed. e10 equiv. nC12H25SH
was employed.
Initially, the reaction conditions were optimized using
α-ketoacid 1, phenethylamine 2, and elemental sulfur as
substrates (Table 1). When the reaction was carried out in
THF without an additive, the obtained yield of the desired
product (3) was low (entry 1). Subsequently, we examined
nucleophilic additives using THF as the solvent (entries 2-
8). Although pyridine, DMAP, and PCy3 did not improve
the yield of 3 at room temperature (entries 2-4), the addi-
tion of thiols (cysteine, thiophenol, and 1-dodecanethiol
To further investigate the functional-group tolerance,
we applied various amino-acid derivatives as nucleophiles.
Esters of phenylalanine, leucine, and alanine were thioac-
ylated under the optimized conditions to produce 26-28 in
66-77% yield, even when in-situ-neutralized amine hydro-
chloride salts were employed in the reaction. Bulkier
amino acids, such as valine, tertiary leucine, and isoleucine
motifs, provided 29-31 in 56-75% yield.
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Table 2. Substrate scope of the decarboxylative thioacylationa
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
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19
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24
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aIsolated yield. bThe reaction was performed at 50 °C. cThe reaction was performed in DMF. dOxaloacetic acid was used as the α-
i
f
ketoacid. eAmine hydrochloride salt (0.10 mmol) and Pr2NEt (0.10–0.20 mmol) were used. α-Ketoacid (0.10 mmol), amine (0.12
g
mol), and 5-tert-butyl-2-methylbenzenethiol (0.10 mmol) were reacted in DMF/CS2 (9:1). A solution of the amine and the thiol
was added dropwise over 4 hours at 80 °C. hDr values were estimated by chiral SFC analysis. iThe reaction was performed at 80 °C.
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Scheme 2. Synthetic applications of the decarboxylative thioacylation of aminesa
1
2
3
4
5
6
7
8
9
10
11
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13
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15
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aIsolated yield. bThe reaction was performed at 80 °C. cThe reaction was performed at 50 °C.
Notably, methionine derivative 32 was obtained in 64%
yield without oxidation of the sulfide moiety. In addition,
this reaction was applicable to amino acids with unpro-
tected hydroxyl groups (serine, threonine, and tyrosine) to
produce thioamides 33-35 in good yield. Proline, N-unpro-
tected histidine, tryptophan, and dipeptide derivatives fur-
nished thioacylated 36-39 in 51-77% yield. Moreover, the
thioacylation using an -ketoacid derived from Cbz-leu-
cine enabled the rapid preparation of peptide thioamide 40.
(Scheme 2A). Furthermore, the synthesis of thioacylated
lysine compounds, which exhibit anticancer properties,
was also accomplished using this thioacylation (Scheme
2B).4a,d Under the optimized conditions, the amine moiety
of a lysine residue was thioacylated using an α-ketoacid de-
rived from myristic acid to obtain thiomyristoyl lysine
(TM) compound 51 in 80% yield. The synthesis of thioam-
ide analogues 52-54 with different thioacyl groups was
straightforward, as various α-ketoacids are commercially
available or easily prepared.23 Finally, we wanted to
demonstrate the synthetic advantages of our decarboxyla-
tive thioacylation compared to conventional O-S exchange
reactions (Scheme 2C). The decarboxylative thioamidation
between 1 and 55 produced thioamide 57 in 64% yield,
while the O-S exchange reaction of 56 using Lawesson’s re-
agent resulted in a mixture of 57-59 (mono- or di-thioam-
ides), which is due to the similar reactivity of the amides.
These results strongly indicate that this decarboxylative
thioacylation strategy is a powerful tool for the selective
introduction of a thioamide moiety into molecules that
contain several amide bonds.
Subsequently, we applied this method to synthesize thi-
oamide analogues of pharmaceutical compounds that con-
tain amide groups (Table 2B). A transcriptional antiestro-
gen17 S-analogue (41), an analgesic18 S-analogue (42), a hu-
man dihydroorotate dehydrogenase inhibitor19 analogue
(43), and a selective σ1 agonist20 analogue (44) were ob-
tained in 40-82% yield. Notably, our thioamidation proto-
col is highly reliable and scalable; for example, 41 could be
produced on the gram scale (79% yield, 2.9 g) without the
need for any special operational requirements or safety
measures.
To demonstrate its synthetic utility, we applied this
chemoselective thioacylation reaction to the synthesis of
several biologically active compounds (Scheme 2A and 2B).
Thiazoline scaffolds with an aromatic ring at the C-2 posi-
tion are common in various biologically active compounds,
including natural products such as pulicatins21 and the
highly potent human peroxisome proliferator-activated re-
ceptor-δ agonist.22 The decarboxylative thioacylation be-
tween 45 and threonine derivative 46 furnished thioamide
47 in 71% yield, which was directly converted into thia-
zoline 49 after treatment with N,N-diethylaminosulfur tri-
fluoride (DAST), followed by reduction with DIBAL-H
In conclusion, we have developed a mild and highly
chemoselective method for the thioacylation of amines
with -ketoacids. The key to this methodology is the effi-
cient activation of elemental sulfur under mild conditions
by thiols. These conditions tolerate a wide variety of func-
tional groups that include unprotected alcohols, phenols,
unsaturated bonds, and carboxylic acids. We believe that a
site-selective introduction of thioamide moieties into bio-
logically active compounds, including peptides and pro-
teins, will promote structure–activity-relationship and
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Journal of the American Chemical Society
gate Addition of Terminal Alkynes to α,β-Unsaturated Thioam-
drug-discovery studies. Studies of this nature are currently
in progress in our laboratory.
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Org. Lett. 2012, 14, 440-443. (h) Pourvali, A.; Cochrane, J. R.; Hut-
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Verma, P.; Xia, G.; Yu, J.-Q. Enantioselective Amine α-Function-
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Rapid, Traceless, AgI-Promoted Macrocyclization of Peptides Pos-
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and Chemoselective Transformations of Thioamides with De-
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Wang, M.; Price, I. R.; Cao, J.; Yang, M.; Zhang, X.; Lin, H. A Small-
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ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the
ACS publications website.
Experimental procedures and analytical data for all new com-
pounds (PDF)
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AUTHOR INFORMATION
Corresponding Author
*E-mail: takemoto@pharm.kyoto-u.ac.jp
ORCID
Masato Saito: 0000-0001-7908-0776
Takeshi Nanjo: 0000-0002-5679-6701
Yusuke Kobayashi: 0000-0003-3074-7378
Yoshiji Takemoto: 0000-0003-1375-3821
Notes
The authors declare no competing financial interests.
ACKNOWLEDGMENTS
This work was supported by JSPS KAKENHI grants
JP16H06384 and JP18K14865. The authors gratefully
acknowledge a Grant for Basic Science Research Projects from
The Sumitomo Foundation (T.N.), the Hoansha Foundation
for a research grant (Y.K.), and a Grant-in-Aid for JSPS Fellows
(M.S.).
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Aqueous Compatible Protocol to Both Alkyl and Aryl Thioamide
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(10) Although a stable reagent containing an R-Sn-S-H structure
has not been reported, amines are expected to activate elemental
sulfur and provide a nucleophilic sulfurizing oxidant under the
proposed mechanisms of Willgerodt–Kindler-type reactions,
which generally require high temperature; for details, see: ref 6.
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(23) α-Ketoacids are easily prepared from the corresponding car-
boxylic acids through a two-step homologation using sulfur ylide,
and more than one hundred α-ketoacids are commercially availa-
ble. For further details, see ref. 9c and the Supporting Information.
(13) We confirmed that the combination of 1-dodecanthiol and el-
emental sulfur did not produce S3 radical anion species, although
many reports on the activation of elemental sulfur under basic
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