Aminolysis of 3-Phenyl propylthiol esters leading to diverse sets of amides

Article abstract of DOI:10.1080/00397910802663352

3-Phenyl propylthiol esters were investigated as "activatable" solution phase linkers. These linkers can be activated with silver salts and upon treatment with amines can be converted to the corresponding amides. Under unactivated conditions, the linker i

Full text of DOI:10.1080/00397910802663352

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Aminolysis of 3-Phenyl
Propylthiol Esters Leading to
Diverse Sets of Amides
Mirosław J. Tomaszewski a , Pandiaraju Subramanian
a & Vijayaratnam Santhakumar a
a Department of Medicinal Chemistry, AstraZeneca
Research and Development, Montreal, Quebec,
Canada
Published online: 16 Jun 2009.
To cite this article: Mirosław J. Tomaszewski , Pandiaraju Subramanian &
Vijayaratnam Santhakumar (2009): Aminolysis of 3-Phenyl Propylthiol Esters Leading
to Diverse Sets of Amides, Synthetic Communications: An International Journal for
Rapid Communication of Synthetic Organic Chemistry, 39:14, 2614-2624
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Synthetic Communications1, 39: 2614–2624, 2009
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910802663352
Aminolysis of 3-Phenyl Propylthiol Esters
Leading to Diverse Sets of Amides
Mirosław J. Tomaszewski, Pandiaraju Subramanian,
and Vijayaratnam Santhakumar
Department of Medicinal Chemistry, AstraZeneca Research and
Development, Montreal, Quebec, Canada
Abstract: 3-Phenyl propylthiol esters were investigated as ‘‘activatable’’ solution
phase linkers. These linkers can be activated with silver salts and upon treatment
with amines can be converted to the corresponding amides. Under unactivated
conditions, the linker is stable to a variety of reagents and reaction conditions
including treatment with amines.
Keywords: Activatable linkers, amides synthesis, solid phase synthesis, thioesters
INTRODUCTION
A powerful means of achieving diverse combinatorial libraries is to
introduce structural diversity concomitant with cleaving the product
from the resin. For example, tetrafluorophenol esters,[1] oximes,[2] and
Marshal linker[3] are all solid-supported linkers for tethering acids to a
solid support that can afford a number of different amides upon cleavage
with amines. Treatment of these solid supports with amines cleaves the
linker and affords the desired amide products; however, the use of amines
or other nucleophiles in steps other than the cleavage step is precluded
because of the activated nature of these linkers. Barn and coworkers[4]
Received July 28, 2008.
Address correspondence to Vijayaratnam Santhakumar, Department of
Medicinal Chemistry, AstraZeneca Research and Development, 7171 Frederick-
Banting, Montreal, Quebec H4S 1Z9, Canada. E-mail: v.santhakumar@
astrazeneca.com
2614

Aminolysis of 3-Phenyl Propylthiol Esters
2615
Scheme 1. Catch and release process on solid support.
have shown that a Wang ester linkage, which is stable to a number of
nucleophiles including amines, can be activated with AlCl3 and can
afford the corresponding amides upon addition of amines. Because
strong Lewis acids are not compatible with a number of functional
groups typically found in heavily functionalized molecules, we were inter-
ested in developing a stable linker system that can afford amides under
more mild conditions.
There are literature reports that thioesters can be converted into
amides in the presence of silver[5] or mercury salts,[6] and this linker has
been utilized in the solid-phase synthesis of peptides.[7] We were inter-
ested in further exploring the potential of this linker in the synthesis of
diverse sets of amides. Our initial studies with thioesters on solid support
were hampered because of the labile nature of these linkers to amines
even under unactivated conditions. We thereby undertook a systematic
study to evaluate the potential of thioesters as activatable linkers. Our
plan was to first study the thioester linkage in solution, wherein conveni-
ent methods of quantification exist, and then apply it to solid-phase
synthesis as illustrated in Scheme 1. Herein, we report our solution-phase
studies.
RESULTS AND DISCUSSION
After screening a variety of thioesters, we were pleased to find that 3-phe-
nyl propylthiol esters possessed the sought-after linker qualities. 3-Phenyl
propylthiol ester can be activated with AgOTf=K3PO4 and undergo a
smooth reaction with amines, affording the corresponding amides.
Importantly, however, in the absence of the activator, the thiol esters
do not react with amines. The best conversions to amides were obtained
by treating 3-phenyl propylthiol ester with amines in the presence of
AgOTf (3 eq.) and K3PO4 (3 eq.) in acetonitrile at 70ꢀC for 24 h. Silver
triflate turned out to be the activator of choice from a number of thiophi-
lic reagents including Ag2CO3, Ag2O, FeSO4, FeCl3, FeBr3, HgCl2, and
Cu(OAc)2. Although AgOAc was found to be as equally effective as
AgOTf, the better solubility profile of AgOTf meant that this particular

2616
M. J. Tomaszewski, P. Subramanian, and V. Santhakumar
Table 1. Variation of carboxy group in thioesters
Thioester
Yield (%)
84
89
98
88
92
89
(Continued )

Aminolysis of 3-Phenyl Propylthiol Esters
2617
Table 1. Continued
Thioester
Yield (%)
83
91
87
74
silver salt was selected for further study. Meanwhile, K3PO4 in
acetonitrile was determined to be the best base=solvent combination.
Other solvents tried were tetrahydrofuran (THF), dimethylformamide
(DMF), dimethylsulfoxide (DMSO), and dioxane; other bases tried were
K2CO3, Cs2CO3, NEt3, and diisopropylethyl amine (DIPEA).
We were interested in determining the scope of the reaction by
varying the carboxy group. Using 4-benzyl piperidine as a representative
secondary amine, a variety of 3-phenyl propylthiol esters were studied as
summarized in Table 1. Aliphatic, electron-deficient and electron-rich
aromatic, and hetero aromatic 3-phenyl propylthiol esters were efficiently
converted to the corresponding amides under the condition developed.
Although some substrates reacted even at room temperature, it was most
convenient to run the reactions at 70ꢀC to ensure complete conversions.
The scope of amines tolerated in this reaction was studied next.
Using p-iodophenyl thioester as the common substrate, primary amines
and both cyclic and acyclic secondary amines were found to be good
substrates for converting thioesters into amides (Table 2).
We also investigated the compatibility of 3-phenylpropanethiol
linker to four different reactions: reductive amination, amide formation,
and Stille and Suzuki coupling reactions. The reductive amination of
benzaldehyde thioester with primary and secondary amines using
NaBH(OAc)3 in CH2Cl2 at room temperature overnight is summarized

2618
M. J. Tomaszewski, P. Subramanian, and V. Santhakumar
Table 2. Amidation of thioester with a variety of amines
Amine
Yield (%)
79
74
89
84
88
(Continued )

Aminolysis of 3-Phenyl Propylthiol Esters
2619
Table 2. Continued
Amine
Yield (%)
79
90
81
in Table 3. There was no premature cleavage of the thioester linker under
these conditions.
The stability of 3-phenyl propylthiol ester was then investigated
under the standard amide coupling reaction. As shown in Scheme 2,
3-phenyl propylthiol ester was treated with trifluoroacetic acid (TFA)
to give the corresponding amine, which was subjected to standard peptide
coupling conditions, affording the desired amide in 92% yield. Once
again, the thioester linker remained intact during this transformation.
3-Phenyl propylthiol esters were also found to be compatible with Stille
and Suzuki cross-coupling reactions (Scheme 3). p-Iodobenzoyl thioester
ester undergoes a Stille cross-coupling reaction with PhSnBu3, affording
the biaryl product. This same thiol ester participated in an efficient
Suzuki cross-coupling reaction with p-tolyl boronic acid in the presence
of a palladium catalyst. The product from the Suzuki coupling reaction,
obtained in 93% yield, was treated with 4-benzyl piperidine under the
activated condition developed to give the corresponding amide in quan-
titative yield. Interestingly, Liebeskind and coworkers[8] have reported
that thioesters can be converted into the corresponding ketones with aryl
boronic acids in the presence of a palladium catalyst and copper salts. In

2620
M. J. Tomaszewski, P. Subramanian, and V. Santhakumar
Table 3. Reductive amination reaction displaying the stability of thioester linker
to treatment with amines under ‘‘unactivated’’ conditions
Amine
Yield (%)
52
88
68
79
57

Aminolysis of 3-Phenyl Propylthiol Esters
2621
Scheme 2. Amide coupling reaction.
our case, no ketone product was observed, presumably because of the
absence of copper salt.
In conclusion, we have demonstrated that 3-phenyl propane thiol
esters can be utilized as stable linkers in solution-phase chemistries. This
linker tolerates a number of reaction conditions including reductive ami-
nation, Stille and Suzuki coupling, Boc cleavage, and amide coupling.
Equally importantly, these thiol esters can be activated with silver acetate
at the appropriate point in the synthesis and be efficiently converted to
the corresponding amides. Further exploration of the solid-supported
version of this work using silica-bound propylthiol is in progress and will
be reported in due course.
Scheme 3. Suzuki and Stille coupling reactions.

2622
M. J. Tomaszewski, P. Subramanian, and V. Santhakumar
EXPERIMENTAL
Representative Procedure for the Synthesis of Thiocarbamates
(Tables 1 and 2)
Triethyl amine (10 mmol) and dimethylaminopyridine (25 mg) were
added to a solution of acid chloride (3.6 mmol) in dichloromethane
(25 mL) at 0ꢀC followed by 3-phenypropyl thiol (3.6 mmol), and the
resulting mixture was stirred at room temperature overnight. The reac-
tion mixture was concentrated under reduced pressure, and the residue
was purified by flash chromatography.
Representative Procedure for the Synthesis of Amides
from Thiocarbamates (Tables 1 and 2)
Amine (0.36 mmol), anhydrous silver trifluoromethanesulfonate
(0.9 mmol), and potassium phosphate (0.9 mmol) were added to a stirred
solution of 3-phenylpropyl thiocarbamate (0.3 mmol) in acetonitrile
(3 mL). After 16 h at 70ꢀC, the reaction mixture was filtered through a
plug of silica gel (5 g), eluted with acetonitrile (10–15 mL), and concen-
trated under reduced pressure. Then the crude product was purified by
column chromatography to afford the corresponding amide.
Representative Procedure for the Reductive Amination
Reactions (Table 3)
The amine (1 mmol) was added to a solution of the S-(3-phenylpropyl)
4-formylbenzenecarbothioate (0.3 mmol) in dichloromethane (5 mL)
and stirred at room temperature overnight. NaCN(BH)3 (1.5 mmol)
was added to the reaction mixture and heated at reflux overnight. After
the usual aqueous workup, the crude product was purified by flash
chromatography.
Synthesis of tert-Butyl 4-(3-Phenylpropylsulfanylcarbonyl)piperidine-
1-carboxylate
O-(7-Azabenzotriazol-1-yl)-N,N,N0,N0-tetramethyluronium
hexafluoro-
phosphate (HATU) (5 mmol) was added to a solution of 1-tert-
butoxycarbonylpiperidine-4-carboxylic acid (5 mmol), 3-phenylpropane
thiol (4 mmol), and diisopropylethyl amine (10 mmol) in dimethyl acetamide

Aminolysis of 3-Phenyl Propylthiol Esters
2623
(10 mL), and the resulting mixture was stirred at room temperature over-
night. After the usual aqueous workup, the residue was purified by flash
chromatography eluting with 10% ethyl acetate in hexane to give tert-butyl
4-(3-phenylpropylsulfanylcarbonyl)piperidine-1-carboxylate (91%).
Synthesis of 4-(3-Phenylpropylsulfanylcarbonyl)piperidine
A solution of tert-butyl 4-(3-phenylpropylsulfanylcarbonyl)piperidine-
1-carboxylate (0.3 mmol) in 5% trifluroacetic acid in dichloromethane
(10 mL) was stirred at room temperature overnight. Solvent was removed
under reduced pressure, and the residue was used for the subsequent step
without further purification.
Synthesis of S-(3-Phenylpropyl) 1-(3-Bromobenzoyl)piperidine-
4-carbothioate
HATU (0.5 mmol) was added to a solution of 4-(3-phenylpropylsulfanyl-
carbonyl)piperidine (0.5 mmol), 3-bromobenzoic acid (0.5 mmol), and
diisopropylethyl amine (1.5 mmol) in dimethyl acetamide (5 mL), and
the resulting mixture was stirred at room temperature overnight. After
the usual aqueous workup, the residue was purified by flash chromato-
graphy eluting to give S-(3-phenylpropyl) 1-(3-bromobenzoyl)
piperidine-4-carbothioate (92%).
Synthesis of S-(3-Phenylpropyl) 4-(p-Tolyl)benzenecarbothioate
p-Tolyl boronic acid (0.7 mmol) was added to a solution of S-(3-
-phenylpropyl) 4-iodobenzenecarbothioate (0.5 mmol), Pd2(dba)3
(5 mol%) tributylphosphine (15 mol%), and potassium fluoride (KF)
(1.5 mmol) in THF (5 mL), and the resulting mixture was heated at
45 ꢀC overnight. After the usual aqueous workup, the residue was puri-
fied by flash chromatography eluting to give S-(3-phenylpropyl)
4-(p-tolyl)benzenecarbothioate (93%).
Synthesis of (4-Benzyl-1-piperidyl)-[4-(p-tolyl)phenyl]methanone
Following the general procedure described previously for the synthesis of
amides from thiocarbamates, (4-benzyl-1-piperidyl)-[4-(p-tolyl)phenyl]

2624
M. J. Tomaszewski, P. Subramanian, and V. Santhakumar
methanone was made starting from S-(3-phenylpropyl) 4-(p-tolyl)
benzenecarbothioate.
S-(3-Phenylpropyl) 4-Phenylbenzenecarbothioate
Phenyltributyl tin (0.6 mmol) was added to a solution of S-(3-
-phenylpropyl) 4-iodobenzenecarbothioate (0.5 mmol), Pd2(dba)3
(5 mol%), and tributylphosphine (15 mol%) in N-methyl pyrolidinone
(NMP) (5 mL), and the resulting mixture was heated at 90ꢀC overnight.
After the usual aqueous workup, the residue was purified by flash
chromatography eluting to give S-(3-phenylpropyl) 4-phenylbenzenecar-
bothioate (53%).
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