Carboxyl activation via silylthioesterification: One-pot, two-step amidation of carboxylic acids catalyzed by non-metal ammonium salts

Article abstract of DOI:10.1016/j.tetlet.2015.09.050

The first organo-catalyzed silylthioesterification of a carboxylic acid and a commercially available mercaptoorganosilane results in the in situ production of an O-silylthionoester. Subsequent amine addition forms amides in an operationally simple one-pot procedure without removal of water. The scope and efficiency of these reactions with respect to the catalyst, carboxylic acid, amine, [Si-S] moiety, and solvent are investigated. A number of functionalities are tolerated in the two-step amidation including alkene, alkyne, alkyl and aryl halides, benzylic ethers, and heterocycles with free coordinating sites.

Full text of DOI:10.1016/j.tetlet.2015.09.050

Tetrahedron Letters 56 (2015) 6034–6037
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Carboxyl activation via silylthioesterification: one-pot, two-step
amidation of carboxylic acids catalyzed by non-metal ammonium
salts
b,
Angus A. Lamar a, , Lanny S. Liebeskind
⇑
⇑
a Department of Chemistry and Biochemistry, The University of Tulsa, 800 South Tucker Drive, Tulsa, OK 74104, USA
b Sanford S. Atwood Chemistry Center, Emory University, 1515 Dickey Drive, Atlanta, GA 30322, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
The first organo-catalyzed silylthioesterification of a carboxylic acid and a commercially available mer-
captoorganosilane results in the in situ production of an O-silylthionoester. Subsequent amine addition
forms amides in an operationally simple one-pot procedure without removal of water. The scope and effi-
ciency of these reactions with respect to the catalyst, carboxylic acid, amine, [Si–S] moiety, and solvent
are investigated. A number of functionalities are tolerated in the two-step amidation including alkene,
alkyne, alkyl and aryl halides, benzylic ethers, and heterocycles with free coordinating sites.
Ó 2015 Elsevier Ltd. All rights reserved.
Received 4 September 2015
Accepted 15 September 2015
Available online 21 September 2015
Keywords:
Direct amidation
Thiosilane
Thiol ester
Ammonium salt catalysis
Thioesterification
Much effort has been dedicated to amide bond construction,
especially in attempts to address problems concerning cost and
atom-economy.1 Several systems have recently been employed to
catalyze a direct amidation of ꢀ1:1 ratios of RCOOH and RNH2
(including B(III) reagents, metal salts, inorganic acids, and other
heterogeneous materials), though many of these systems require
long reaction times, high temperatures, high dilution (at lower
temperatures), and/or the removal of water either azeotropically
in high boiling solvents or with molecular sieves.2,3 However, the
most widely employed coupling methods require a stoichiometric
activating agent.4 These reactions are frequently hindered by the
use of an excess of reagent and/or strictly anhydrous conditions,
and are accompanied by the formation of by-products and large
amounts of chemical waste which can be difficult to separate.
From a synthetic perspective, silylthiols have been largely unex-
plored as reagents when compared to analogous organic thiols. The
relatively weak Si–S bond (ꢀ300 kJ/mol)5 and the oxophilicity of
silicon lead to highly reactive molecules with intriguing potential
in organic synthesis. To date, the [Si–S] moiety has been used pri-
marily in the production of silanethiolato complexes of main group
elements and transition-metals for the synthesis of heterometallic
clusters.6 Only a few examples of the utilization of [Si–S] units as
reagents for functional transformations have been reported. For
example, thiosilanes have been used for C–O bond cleavage
(oxirane ring-opening),7 as masking agents of carbonyl groups,8
and in reactions with acid halides to form thiol esters.9
Recently, our research group has discovered that O-silylthio-
noesters, generated by silylation of thiol acids (prepared in two
steps from carboxylic acids using traditional coupling agents),
serve as a functionally unique, activated carboxyl unit compared
to analogous O-alkylthionoesters (Scheme 1).10 The kinetically
formed S-silylthiol ester undergoes a thermodynamically driven
tautomerization of the triorganosilicon group from sulfur to
oxygen to form an O-silylthionoester. These O-silylthionoester
species react with amines to generate oxoamides exclusively due to
a subsequent O- to S-silatropic migration, while O-alkylthionoesters
react with amines to produce thioamide linkages. Following this
finding, we aimed to explore the use of thiosilane units as a direct
and atom-economical means of generating these unique function-
alities from carboxylic acids (Scheme 2).
Intrigued by the possibility of a silylthioesterification of a car-
boxylic acid, we were inspired by the bulky diarylammonium
(DPAT) and pentafluorophenyl ammonium (PFPAT) (thio)esterifi-
cation catalysts of Ishihara,11 Tanabe,12 and others2c (Fig. 1).
Though sterically encumbered alcohol substrates have been
shown to be far less reactive with these catalysts in
esterifications,2c the elongated Si–SH bond13 (as compared to
C–OH) may increase the nucleophilic viability of the bulky silylthiols
in silylthioesterification attempts. Herein we report the employ-
ment of a commercially available mercaptoorganosilane for an
⇑
Tel.: +1 918 631 3024; fax: +1 918 631 3404 (A.A.L.); tel.: +1 404 727 6604;
fax: +1 404 767 6586 (L.S.L.).
E-mail address: angus-lamar@utulsa.edu (A.A. Lamar).
http://dx.doi.org/10.1016/j.tetlet.2015.09.050
0040-4039/Ó 2015 Elsevier Ltd. All rights reserved.

A. A. Lamar, L. S. Liebeskind / Tetrahedron Letters 56 (2015) 6034–6037
6035
Scheme 3. Formation of O-silylthionoester.14
Table 1
Survey of [Si–S] reagents and catalysts
Scheme 1. Differential reactivity of thionoesters.
Entry
[Si–S]
Solvent
Catalyst (10 mol %)
% yielda
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
None
None
Xylenes
Xylenes
Xylenes
Xylenes
Xylenes
Xylenes
Xylenes
C6H5CF3
Toluene
Heptane
Cyclohexane
Xylenes
Xylenes
Xylenes
Xylenes
Xylenes
Xylenes
Xylenes
Xylenes
Xylenes
None
PFPAT
None
PFPAT
5b
Trace
12
Ph3SiSH
Ph3SiSH
Ph3SiSH
Ph3SiSH
Ph3SiSH
Ph3SiSH
Ph3SiSH
Ph3SiSH
Ph3SiSH
Me3Si–S–SiMe3
Ph2MeSiSH
iPr3SiSH
(tBuO)3SiSH
Ph3SiOH
Ph3SiSH
Ph3SiSH
Ph3SiSH
Ph3SiSH
4c
PFPAT
47d
21
PFPATe
PFPATf
40
20
15
8
PFPAT
PFPAT
PFPAT
PFPAT
PFPAT
PFPAT
PFPAT
PFPAT
Scheme 2. Direct formation of a reactive O-silylthionoester species via silylthioes-
terification of a carboxylic acid.
Trace
0g
Traceg
9
Trace
Trace
6
18
21
PFPAT
[C6F5NH3]+[OTos]À
DPAT
[Mes2NH2]+[OTf]À
[Ph2NH2]+[OTos]À
3
a
b
c
d
e
f
Determined by GCMS using (4-tBuPh)2 as internal standard.
BnNH2 was added in the first step and heated 24 h at 60 °C.
All reagents added at once, refluxed for 2 h then at 60 °C for an additional 8 h.
Similar yield obtained using ‘wet’ xylene.
5 mol % PFPAT.
Figure 1. Examples of ammonium salt esterification catalysts.
intermediary production of an O-silylthionoester from a carboxylic
acid with organic ammonium salt catalysts and subsequent atom-
economical amidation with a nearly equimolar amount of amine.
This represents the first example of O-silylthionoester formation
directly from a carboxylic acid via silylthioesterification, and the
first usage of a silylthiol as an amidation coupling agent.
20 mol % PFPAT.
Only hydrolysis of [Si–S] was observed.
g
xylenes without removal of water, followed by BnNH2 addition
and heating at 60 °C for 4–12 h (1 pot).
In our initial investigations, we sought to isolate O-silylthio-
noesters from carboxylic acids prior to amine addition (Scheme 3).
Though evidence of formation of O-silylthionoester and expulsion
of water was observed by 13C NMR and IR (see Supporting Informa-
tion), purification and quantification of these compounds proved
challenging. For this reason, an in situ reaction with an amine
(1 pot, 2-step) was envisioned as a proof of concept in order to
quantify the resulting isolable amide product.
To begin our investigation of amide formation, c-C6H11-COOH
was chosen as a modestly encumbered test substrate (Table 1).
In a series of control experiments (entries 1–4), the exclusion of
silylthiol and/or catalyst from the reaction in Step 1 resulted in
minor yield of amide formation, presumably due to catalyst
quenching upon amine addition and a negligible background direct
condensation reaction at 60 °C over ꢀ8 h. The reaction was then
optimized by varying the stoichiometry of substrates, as well as
the solvent (xylenes, trifluoromethyltoluene, toluene, heptane,
cyclohexane), temperature, and reaction time to produce the
following operationally simple condition: RCOOH/Ph3SiSH/
ammonium salt catalyst (1:1:0.1, respectively), 2 h in refluxing
Under the best conditions found in the study, a series of differ-
ent ‘Si–S’ units were tested using known pentafluorophenylammo-
nium triflate (PFPAT)12 as catalyst (Table 1, entries 12–15). Since it
has been shown that thiosilanes are prone to hydrolysis or alcohol-
ysis under acidic conditions,15,16 and that sterically bulky silyl
groups are known to enhance stability of the silylthiol to hydroly-
sis,16–18 we tested iPr3SiSH and (tBuO)3SiSH.16 As expected, the less
sterically hindered ‘Si–S’ substrates that were tested hydrolysed
immediately in the acidic conditions (entries 12 and 13), whereas
the bulky iPr3SiSH and hydrolytically stable (tBuO)3SiSH16 were not
as effective as the air stable, commercially available solid Ph3SiSH,
implying a balance for the silylthiol substrate between stability to
undesired hydrolysis and S-nucleophilicity to generate S-silyl
thioesters. A reaction time of two hours in Step 1 proved to be
important, as hydrolysis of Ph3SiSH (and the resulting thionoester)
increased over time as observed by GCMS, but was sufficiently low
at shorter reaction times even in undried solvent. The observed
triphenylsilanol by-product was also tested as
a possible
activating agent in the reaction, but no amide formation resulted
(entry 16).

6036
A. A. Lamar, L. S. Liebeskind / Tetrahedron Letters 56 (2015) 6034–6037
Table 3
Several ammonium catalysts (entries 17–20) were then synthe-
Effect of amine in 2-step amidation of hydrocinnamic acid19
sized11,12 and tested with Ph3SiSH. An attractive feature of the
ammonium salt catalysts is their ability to promote esterifications
without azeotropic or chemical removal of water. PFPAT was found
to be the most effective catalyst tested, even in the presence of
undried solvent. Bulky diarylammonium salts (entries 18–20) were
less effective than PFPAT, but all of the [OTf]À containing catalysts
were more effective than the background reaction in which
catalyst was excluded (entry 3). Catalysts containing the [OTos]À
counteranion in the ammonium salt proved to be less efficient than
the background.
Entry
1
R1R2NH
BnNH2
Product
Isol. % yield
4—76
The substrate scope of carboxylic acid of the reaction was then
investigated using BnNH2 employing the best conditions revealed
in Table 1 (Table 2).
The best yields (56–80%) were obtained from sterically accessi-
ble 1° alkyl and benzylic carboxylic acids. As steric bulk increases
in 2° and 3° carboxylic acids, the efficiency of the 2-step amidation
sequence decreases. A number of functionalities are tolerated
including alkene, alkyne, alkyl and aryl halides, benzylic ethers,
2
3
4
BnMeNH
16—63
17—42
18—42
and heterocycles. The enantiopure (R)-(À)-a-methoxyphenylacetic
acid was tested to determine if racemization would occur during
the reaction pathway, and complete retention of configuration
(>99%) of the amide product 15 was observed by comparison to
the isolated racemate using chiral HPLC. In addition, the nature
of the amine nucleophile was briefly examined (Table 3). As
expected, sterically hindered 2° and 3° amines (entries 2 and 3)
resulted in lower yields than 1° BnNH2 (entry 1), and the electron
deficient and less nucleophilic 2-pyridylamine (entry 4) resulted in
a lower yield over the same standard reaction time.
The mechanistic pathway (Scheme 4) is believed to proceed in a
similar fashion to analogous PFPAT-catalyzed (thio)esterifications
of carboxylic acids and alcohols/thiols. The catalyst is presumed
to produce a hydrophobic environment2c,12 in order to promote
the silylthioesterification of the carboxylic acid with Ph3SiSH,
Scheme 4. Presumed mechanistic pathway.
resulting in
a S-silylthioester (not observed) which rapidly
tautomerizes to the O-silylthionoester isomer through S- to
O-silatropy. Upon amine addition, a tetrahedral intermediate is
presumed formed from which a second silyl migration occurs
from O to S to expel a [Si–S] unit and produce the oxoamide.
In conclusion, the first example of silylthioesterification of a
carboxylic acid to produce a O-silylthionoester via silatropic migra-
tion has been described. This reactive intermediate was used as a
proof of concept to form amides in an operationally convenient
2-step, 1-pot method without removal of water with a range of
amines and carboxylic acids. Although the yields of the product
amides are not competitive with the best systems currently avail-
able for amidation, this work represents a novel usage of a class of
[Si–S]-containing molecules that may presage the development of
more uniquely selective and efficient reactions that include, and
extend beyond, the formation of amide bonds. The commercially
available Ph3SiSH reagent, while susceptible to hydrolysis over
longer reaction times, is sufficiently stable in the reaction, even
in undried solvent, and serves as a good nucleophile despite the
steric bulk of the triarylsilyl group. Attempts were not made to
recover Ph3SiSH upon completion of the reaction, however, the
hydrolysed Ph3SiOH was observed in examples following purifica-
tion by chromatography. Further explorations into the utility of
silylthiols as reagents for other organic transformations as well
as investigations toward an enhanced and/or recyclable silylthiol
for amidation are currently underway.
Table 2
2-Step amidation of carboxylic acids19
Acknowledgment
This work was supported by Grant GM043107, awarded by
National Institute of General Medical Sciences, DHHS.

A. A. Lamar, L. S. Liebeskind / Tetrahedron Letters 56 (2015) 6034–6037
6037
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14. General procedure for preparation of O-silylthionoester: to a flame-dried flask
was added NaSSiR3 (0.33 mmol) and dry toluene (2-4 mL). The mixture was
stirred at rt under argon for 15 min. Then R’COCl (0.33 mmol) was added via
syringe and a reflux condenser was attached. The solution was heated to reflux
under argon with stirring overnight. The reaction was then cooled to room
temperature and solvent was removed under vacuum. Dry hexanes were
added, solids were removed via filtration and washed with hexanes, and the
combined filtrate was concentrated under vacuum. The O-silylthionoester
products were analyzed without additional purification.
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added carboxylic acid (0.4 mmol), Ph3SiSH (116 mg; 0.4 mmol), PFPAT (14 mg;
0.04 mmol), and xylenes (2 mL). The flask was purged with argon, and a reflux
condenser was attached. The solution was refluxed under argon with stirring
for 2 h. The reaction was then cooled to 60 °C and amine (0.5 mmol;
1.25 equiv) was added at once (via gas-tight syringe for liquid amines) and
the reaction was stirred under argon at 60 °C for approximately 8 hours
(typically 6–14 h). The reaction was then cooled to room temperature, solvent
was removed under vacuum, and the crude was purified directly via flash
chromatography (typically using an eluant of DCM, then increasing polarity
gradually to 20% EtOAc/DCM unless otherwise stated). Products 3,20a 4,20b 5,20c
7,20d 8,20e 9,3e 11,20f 12,20g 13,10 14,20h 15,20i 16,20j 17,20k and 1820l are all
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reported data.
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Guo, F.-R.; Wang, X.-C.; Huo, P.-F.; Bi, H.-P.; Guan, Z.-H.; Liang, Y.-M. Org. Lett.
2009, 11, 5726–5729; (e) Sarakinos, G.; Corey, E. J. Org. Lett. 1999, 1, 1741–
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all products (1H NMR and 13C NMR; crude IR of O-silylthionoester
intermediate; and HPLC chromatogram of racemic and enantiop-
ure 15)) associated with this article can be found, in the online
version, at http://dx.doi.org/10.1016/j.tetlet.2015.09.050.
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