Are Aminomethyl Thioesters Viable Intermediates in Native Chemical Ligation Type Amide Bond Forming Reactions?

Article abstract of DOI:10.1071/CH18198

The condensation of N-mercaptomethyl amines and thioesters is a potential route to amides, via aminomethyl thioester intermediates, in a native chemical ligation type process followed by self-cleavage of the 'mercaptomethyl' auxiliary. This paper describes investigations towards the preparation of aminomethyl thioesters, and subsequent conversion into amides, from a three-component coupling of formaldehyde, a thioacid, and an amine. Our studies suggest that while such intermediates may be formed en route to amides, no advantages are offered over the direct reaction of the amine and thioacid precursors.

Full text of DOI:10.1071/CH18198

RESEARCH FRONT
CSIRO PUBLISHING
Aust. J. Chem.
Full Paper
https://doi.org/10.1071/CH18198
Are Aminomethyl Thioesters Viable Intermediates in Native
Chemical Ligation Type Amide Bond Forming Reactions?
A
A
A B
,
Carlie L. Charron, Jade M. Cottam Jones, and Craig A. Hutton
A
School of Chemistry and Bio21 Institute, University of Melbourne, Parkville, Vic. 3010,
Australia.
B
Corresponding author. Email: chutton@unimelb.edu.au
The condensation of N-mercaptomethyl amines and thioesters is a potential route to amides, via aminomethyl thioester
intermediates, in a native chemical ligation type process followed by self-cleavage of the ‘mercaptomethyl’ auxiliary. This
paper describes investigations towards the preparation of aminomethyl thioesters, and subsequent conversion into amides,
from a three-component coupling of formaldehyde, a thioacid, and an amine. Our studies suggest that while such
intermediates may be formed en route to amides, no advantages are offered over the direct reaction of the amine and
thioacid precursors.
Manuscript received: 2 May 2018.
Manuscript accepted: 28 June 2018.
Published online:
27 July 2018.
Introduction
Intriguingly, the S-acetyl mercaptomethylamine intermedi-
ates 4 in this process are similar to the postulated thioester
intermediate that would be formed through the NCL-type
ligation of a mercaptomethylamine and a thioester. Further-
more, attempted isolation of the S-acetyl mercaptomethyl-
amines 4 often leads to conversion into the corresponding
amide 6,[28–30] providing evidence that such an acyl transfer
process with cleavage of the ‘auxiliary’ is viable.
Accordingly, we were keen to investigate potential routes to
an efficient preparation of S-acyl mercaptomethylamines 9 as
intermediates in an amide ligation process related to NCL. Two
approaches were envisaged – through a hydroxymethylamine 2
and a thioacid, or through a hydroxymethylthioester 8 and an
amine (Scheme 3).[27,31]
Amide bonds are the fundamental links between amino acid
residues in peptides and proteins, which are crucial in virtually
all biological processes.[1–3] Numerous chemoselective meth-
ods for synthesising amide bonds have been developed using
amine surrogates and carboxylic acid derivatives as coupling
partners.[1,4,5] Many of these methods have been inspired by
‘thiol capture’ ligation processes[6,7] such as native chemical
ligation (NCL).[8,9]
Native chemical ligation has revolutionised the chemical
synthesis of peptides and proteins from smaller peptide frag-
ments.[10–14] NCL was initially limited to the coupling of
peptides possessing an N-terminal cysteine (Scheme 1a); how-
ever, more recent advances have led to modified coupling
partners, including the use of b- and g-mercapto amino acid
derivatives[10,15–18] and thiol auxiliaries appended to the
N-terminal amine.[19–25] Thiol auxiliaries employed in NCL-
type ligations are usually ortho-mercaptobenzyl groups or
substituted 1- or 2-aryl-2-mercaptoethyl groups.[19,20] Auxiliary
cleavage is required after the ligation step, normally through
acid-catalysed or reductive benzyl group cleavage or a radical
b-scission process (Scheme 1b).
Results and Discussion
N-Hydroxymethylamine Approach
The hydroxymethylamine–thioacid approach to an S-acyl mer-
captomethylamine was first investigated, using benzylamine 12
and thioacetic acid 3 as a model system. Hydroxymethylamines 2
are normally prepared by reaction of the corresponding amine 1
with formaldehyde.[27–30] Such hydroxymethylamines 2 are typ-
ically not isolated but are reacted directly to generate substitution
products. Accordingly, benzylamine 12 was first treated with
formaldehyde before thioacetic acid 3 was added to the mixture.
Numerous conditions were examined in which the stoichi-
ometry and reaction time were varied, with moderate to good
yields obtained in virtually all cases, suggesting this may be a
viable pathway to amide formation (Table 1). The use of other
amines (aniline, cyclohexylamine) also proceeded in moderate–
good yield (Table 2) and non-polar solvents gave better yields
than polar solvents (Table 3). However, a control reaction in
which formaldehyde was omitted generated the amide 13 in
Ideally, a self-cleaving auxiliary that is stable when present
on the amine starting material – but labile in the amide product –
would allow for a one-step ligation/cleavage process.[26]
A
mercaptomethyl auxiliary is a potential self-cleaving auxiliary,
as an N-mercaptomethyl amide should extrude CH2S to generate
the amide product.[27] However, the mercaptomethylamines 5
required as starting materials in an NCL-type ligation are not
necessarily stable. Mercaptomethylamines 5 have been pre-
pared from Mannich-type reactions of amines 1, formaldehyde,
and thioacetic acid 3 (presumably via the intermediate iminium
species), followed by hydrolysis of the resultant S-acetyl mer-
captomethylamine 4 (Scheme 2).[27]
Journal compilation ꢀ CSIRO 2018
www.publish.csiro.au/journals/ajc

B
C. L. Charron, J. M. Cottam Jones, and C. A. Hutton
(a)
(b)
O
O
O
O
H
H
N
peptide 1
peptide 1
N
H2N
HS
peptide 2
HN
peptide 2
HS
SR
O
SR
RЈ
RЈ
RЉ
thioester exchange
thioester exchange
O
H
N
O
peptide 1
HN
peptide 2
S
H2N
peptide 2
O
RЈ
H
RЉ
peptide 1
N
S
S–N acyl transfer
RЈ
SH
O
O
O
S–N acyl transfer
H
peptide 1
peptide 1
N
N
peptide 2
O
O
RЉ
H
H
N
RЈ
RЈ
peptide 1
N
peptide 2
auxiliary cleavage
RЈ
O
H
HS
H
N
N
peptide 2
RЉ
Scheme 1. (a) Traditional NCL between C-terminal thioester and N-terminal cysteine coupling partners. (b) NCL using thiol auxiliaries
followed by auxiliary cleavage yielding an amide bond.
ϩ
R
N
H
CH2O
R
R
NaOH
AcSH
RNH2
N
H
N
H
AcS
HS
3
R
1
4
5
N
H
HO
(–CH2S)
Δ
2
AcHN–R
6
Scheme 2. Mercaptomethylamines via hydroxymethylamines and thioacetic acid.
O
3 occurs at a sufficient rate such that no involvement of the
S-acyl mercaptomethylamine intermediate 9 need be invoked.
Direct acylation of amines by thioacids has been observed, but in
polar solvents usually requires additives such as HOBt, CuII, or
I2 to facilitate the process.[32–37]
RNH2
SH
RЈ
1
7
CH2O
CH2O
O
R
HO
N
H
S
OH
S-Hydroxymethyl Thioester Approach
RЈ
2
8
Investigations next turned to studying the reaction of a hydro-
xymethylthioester 8 and an amine 1. Hydroxymethylthioesters 8
have been prepared through heating a neat mixture of thioacids
and formaldehyde.[31] Accordingly, S-hydroxymethyl thioace-
tate 14 was prepared from thioacetic acid and formaldehyde and
used directly in amidation reactions (Scheme 4).
RЈCOSH
RNH2
O
S
R
N
H
RЈ
9
Treatment of the hydroxymethyl thioester 14 with benzyl-
amine 12 was investigated under a variety of conditions. Use of
dioxane and dioxane–water solvent mixtures gave varied
results; while only a low yield was obtained in dioxane, use of
10 % aqueous dioxane gave a reasonably good yield (58 %) of
the amide 13 after 3 h (Table 4, entry 2). Further increases in
water content resulted in decreased yield (Table 4, entries 3–5).
These effects may be related to the solubility of the reagents. Use
of other solvents gave low to moderate yields of the amide
(Table 4, entries 6–11).
O
N
O
(–CH2S)
R
R
N
RЈ
RЈ
H
SH
10
11
Scheme 3. Two approaches to synthesising S-acyl mercaptomethylamines
9 as ligation intermediates.
good yield and shorter reaction time than in the presence of
formaldehyde (Table 1, entries 9, 10). It is apparent that under
these conditions direct acylation of the amine 12 by the thioacid
Formation of the amide in these reactions can potentially
proceed via the mercaptomethylamine intermediate 9 or by
direct amination of the thioester 14, as for the previous approach

Aminomethylthioesters En Route to Amides?
C
O
O
O
CH2O
34 %
Ph
NH2
Table 1. Optimisation of amide 13 production from benzylamine 12
and thioacetic acid 3
12
N
H
13
SH
S
OH
Ph
O
3
14
i) CH2O
H2N
Ph
N
H
13
Ph
ii) AcSH
Scheme 4. Synthesis of S-hydroxymethyl thioacetate 14 followed by
12
3
reaction with benzylamine.
EntryA Equiv. 12 Equiv. 3 Equiv. CH2O Time [h] Yield [%]
Table 4. Effect of solvent on yield of amide
1
1
1
1
1
1
1
1
1
1
1
1
1
1
2
1
1
1
1
2
2
2
2
0
0
18
48
3
61
86
46
46
47
31
67
89
2
O
O
O
CH2O
34 %
Ph
NH2
5
12
S
N
H
OH
Ph
SH
6
18
96
18
22
4
3
14
7
13
8
9
EntryA
Solvent
dioxane
Yield [%]
10
1
18
58
54
27
28
18
2
AReaction conditions: 12 þ CH2O (0.1 M), room temperature, 10 min,
then 3.
2
dioxane/water (9 : 1)
dioxane/water (8 : 2)
dioxane/water (7 : 3)
dioxane/water (5 : 5)
MeOH
3
4
5
6
Table 2. Effect of amine coupling partner on yield of amide
7
CH3CN
8
CH2Cl2
14
41
17
9
O
i) CH2O
9
DMF
H2N
R
N
R
10
11
DMSO
ii) AcSH
H
H2O
3
AReaction conditions: 14 þ 12 (0.1 M), room temperature, 3 h.
EntryA
R
Yield [%]
1
2
3
Bn
46
23
91
Ph
NH2
O
cyclohexyl
Ph
O
12
N
H
SEt
Ph
4:1 dioxane/H2O
5 %
AReaction conditions: 2 equiv. CH2O, 10 min, then 1 equiv. AcSH, 3 h, room
temperature.
15
13
Scheme 5. Synthesis of amides from S-ethyl thioester 15.
14 is simply more activated due to the inductive effect of the
electronegative oxygen atom.
Table 3. Effect of solvent on yield of amide
O
i) CH2O
We next investigated an aminomethyl thioester 18, which
could potentially undergo a similar substitution as the hydro-
xymethyl thioester 14 to generate the required intermediate.
Direct amination of the dimethylaminomethyl thioester 18
should be disfavoured compared with the hydroxymethyl thioe-
ster 14 on both steric and electronic grounds.
H2N
Ph
N
H
Ph
ii) AcSH
12
3
13
EntryA
Solvent
Yield [%]
1
2
3
4
5
6
CH2Cl2
CH3CN
Dioxane
DMF
99
94
87
55
38
19
The dimethylaminomethyl thioester 18 was prepared
in good yield by treatment of potassium thioacetate 16 with
N,N-dimethylmethyleneammonium iodide 17 (Scheme 6).
Treatment of the dimethylaminomethyl thioester 18 with ben-
zylamine 12 gave only 19 % of the desired amide 13, higher than
from the S-ethyl system 15 but lower than from the S-hydroxy-
methyl compound 14. It is difficult to determine whether this
reflects a decreased propensity to form the mercaptomethyl
amine intermediate or a decreased rate of direct amination.
Finally, N-methylation of the dimethylaminomethyl thioe-
ster 18 generated the trimethylammoniomethyl thioester 19.
Reaction of this thioester 19 with benzylamine 12 gave the
amide 13 in good yield under a range of conditions (Table 5).
Yet again, however, it is possible that the increased reactivity of
the thioester 19 could be due to the inductive effect of the
positively charged ammonium group increasing the reactivity of
the thioester in a direct amination pathway, rather than an
DMSO
MeOH
AReaction conditions: 12 (1 equiv.) þ CH2O (2 equiv. 0.1 M), room tem-
perature, 10 min, then 1 equiv. AcSH, 3 h, rt.
(Tables 1–3). In order to assist in delineating these mechanisms,
reaction of benzylamine 12 with the isosteric S-ethyl thioacetate
15 was undertaken in 20 % aqueous dioxane (Scheme 5). Use of
the S-ethyl thioester 15 gave only 5 % yield of the amide 13,
compared with 54 % from the hydroxymethyl thioester 14,
providing circumstantial support for a different reaction mecha-
nism. It is possible, however, that the hydroxymethyl thioester

D
C. L. Charron, J. M. Cottam Jones, and C. A. Hutton
ϩ
Ϫ
General Procedure for Amine Acetylation via
N-Hydroxymethylamine Intermediate
N
I
O
O
O
12
17
S
N
N
H
Ph
SK
4:1 dioxane/H2O
19 %
To a solution of paraformaldehyde in dioxane (0.1 M), various
amines (Tables 1 and 2) were added and allowed to stir at room
temperature for 10 min before thioacetic acid was added drop-
wise. Reactant quantities and reaction time were varied to opti-
mise reaction conditions (Table 1). The reaction mixture was
concentratedunder vacuum andpurified by flash chromatography
in diethyl ether and ethyl acetate. The product was characterised
by 1H and 13C NMR spectroscopy and mass spectrometry.
76 %
18
16
13
MeI 64 %
12
Ϫ
O
I
ϩ
N
S
19
Scheme 6. Synthesis of amides from an aminomethyl thioester.
N-Benzylacetamide 13
dH (CDCl3) 2.03 (s, 3H), 4.41 (d, J 5.5, 2H), 5.79 (s, 1H), 7.27–
7.36 (m, 5H). dC 23.3 (CH3), 43.8 (CH2), 127.5 (CH), 127.8
(CH), 128.7 (CH), 138.2 (C), 169.8 (C). HRMS m/z 150.0914;
calcd for C9H12ONþ [M þ H]þ 150.0919.
Table 5. Effect of solvent on yield of amide from trimethylammonio-
methyl thioester
Ϫ
O
O
I
Ph
NH2
ϩ
N
12
S
N
H
Ph
N-Cyclohexylacetamide
19
13
dH (CDCl3) 1.04–1.18 (m, 2H), 1.28–1.39 (m, 2H), 1.58–1.61
(m, 2H), 1.66–1.71 (m, 2H), 1.87–1.91 (m, 2H), 1.93 (s, 1H),
3.70–3.76 (m, 1H), 5.46 (s, 1H). dC 23.6 (CH3), 24.6 (CH2), 25.5
(CH2), 33.2 (CH2), 48.2 (CH2), 169.1 (C). HRMS m/z 142.1228;
calcd for C8H16ONþ [M þ H]þ 142.1226.
EntryA
Solvent
dioxane
Yield [%]
1
2
3
4
5
6
7
8
9
61
70
50
40
63
36
70
11
43
dioxane/water (9 : 1)
dioxane/water (8 : 2)
dioxane/water (7 : 3)
dioxane/water (5 : 5)
MeOH
N-Phenylacetamide
dH (CDCl3) 2.16 (s, 3H), 7,10 (t, J, 1H), 7.31 (t, J, 2H), 7.49 (d, J,
2H). dC 24.6 (CH3), 119.9 (CH), 124.3 (CH), 129.0 (CH), 137.9
(CH), 168.5 (C). HRMS m/z 136.0758; calcd for C8H10ONþ
[M þ H]þ 136.0757.
CH3CN
CH2Cl2
DMF
General Procedure for N-Benzylacetamide Synthesis via
N-Hydroxymethyl Amine Intermediate
AReaction conditions: 19 þ 12 (0.1 M), room temperature, 3 h.
Paraformaldehyde (6 mmol, 2 equiv.) was suspended in various
solvent mixtures (0.1 M) as listed in Table 3. Benzylamine
(3 mmol, 1 equiv.) was added to the reaction and stirred at room
temperature for 10 min before thioacetic acid (3 mmol, 1 equiv.)
was added dropwise. The reaction was left at room temperature
for 3 h before concentrating the solvent under vacuum and
purification with flash chromatography.
increase in the rate of substitution to generate the mercapto-
methylamino intermediate 9.
Conclusion
Numerous precursors to S-acylmercaptomethylamines have been
investigated as model systems to validate the NCL-type ligation
of such precursors with subsequent extrusion of CH2S, thereby
providing a one-pot ligation–auxiliary cleavage protocol. The
most reactive of these precursors – the trimethylammoniomethyl
thioester 19 – generates N-benzylamide in similar yield and at a
similar rate to the reaction of benzylamine and thioacetic acid.
As such, whether or not these reactions are proceeding via the
proposed S-acylmercaptomethylamine thioester intermediates
(i.e. 9), withsubsequentacyltransferand extrusionofCH2S, there
seems little advantage in preparing such reactive intermediates
when simpler, direct processes suffice.
S-Hydroxymethylthioacetate 14
Paraformaldehyde (16 mmol, 1 equiv.) was added to an oven-
dried 10 mL round bottom flask and purged with nitrogen.
Thioacetic acid (16 mmol, 1 equiv.) was added dropwise and
slowly warmed until the paraformaldehyde dissolved (,708C).
After 3 h, the reaction mixture was dissolved in dichloromethane
(20 mL) and extracted with distilled water (3 ꢀ 20 mL). The
organic layer was collected and dried with MgSO4, filtered, and
concentrated under vacuum to yield a yellow oil. The crude
product was characterised and used without further purification.
Total yield 606 mg (34 %). dH (CDCl3) 2.39 (s, 3H), 3.45 (s, 1H),
5.04 (d, J 6.4, 2H). dC (CDCl3) 31.4 (CH3), 64.4 (CH2), 198.9 (C).
HRMS m/z 107. 0164; calcd for C3H7O2Sþ [M þ H]þ 107.0166.
Experimental
Materials and Methods
Chemicals were purchased from Sigma Aldrich, Fisher
Scientific, Merck, and Honeywell and used without further
purification. TLC was performed on pre-coated silica gel 60F254
plates (Merck). Flash chromatography was performed on
silica gel 40–63 mm using compressed air. NMR spectra were
recorded on an Agilent MR400 (400 MHz) apparatus. Mass
spectra were recorded using a NanoLC/OrbiTrap Fusion Lumos
spectrometer.
General Procedure for N-Benzylacetamide Synthesis via
S-Hydroxymethyl Thioester Intermediate
S-Hydroxymethyl thioester 14 (0.5 mmol, 1 equiv.) was sus-
pended in various solvent mixtures (0.1 M) as listed in Table 4.
Benzylamine (0.5 mmol, 1 equiv.) was added to the reaction and
stirred at room temperature for 3 h. The reactions were tracked
by TLC using 4 : 1 ethyl acetate/hexanes (Rf 0.3). The solvent

Aminomethylthioesters En Route to Amides?
E
was concentrated under vacuum and purified by flash chroma-
tography using a 4 : 1 ethyl acetate/hexane solvent system. The
final products were fully characterised and yields are reported in
Table 4.
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Synthesis of Dimethylaminomethyl Thioester 18
N,N-Dimethylmethyleneammonium iodide 17 (0.8 mmol, 1
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and stirred vigorously at room temperature overnight. The
reaction mixture was passed through a cotton plug to remove
any insoluble materials before concentrating the solvent under
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characterised and used without further purification. Total yield
86 mg (80 %). dH (CDCl3) 2.22 (s, 1H), 2.40 (s, 3H) 4.56 (6H, s).
dC (CDCl3) 31.7 (CH3), 42.4 (CH3), 62.4 (CH2), 196.8 (C).
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Crude dimethylaminomethyl thioester 18 (4.1 mmol, 1 equiv.)
was dissolved in dry diethyl ether (0.1 M) in an oven-dried flask
under a stream of Ar. Methyl iodide (21 mmol, 5 equiv.) was
added dropwise The reaction mixture was stirred under argon in
the dark for 18 h. The insoluble product was collected as the
iodine salt using a sintered glass funnel. The product was
washed with cold diethyl ether and dried under vacuum. The
final product was fully characterised and used without further
purification. Total yield: 739 mg (64 %). dH (CDCl3) 2.55 (s,
3H), 3.15 (s, 9H), 4.91 (s, 2H). dC (CDCl3) 30.5 (CH3), 53.1
(CH3), 62.3 (CH2), 192.3 (C). HRMS m/z 148.0791; calcd for
C6H15ONSþ [M þ H]þ 148.0791.
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The solvent was concentrated under vacuum and purified by
flash chromatography using a 4 : 1 ethyl acetate/hexane solvent
system. The final products were fully characterised and yields
are reported in Table 5.
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Supplementary Material
1H and 13C NMR spectra for compounds 13, 14, 18, and 19 are
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Conflicts of Interest
The authors declare no conflicts of interest.
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Acknowledgements
This work was supported by the Australian Research Council.
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