Base-Catalyzed Transesterification of Thionoesters

Article abstract of DOI:10.1021/acs.joc.8b02260

Here we report a convenient synthesis of thionoesters by base-catalyzed transesterification. Benzyl and alkyl thionobenzoates and thionoheterobenzoates were efficiently prepared using various alcohols catalyzed by the corresponding sodium alkoxide. This methodology features a broad substrate scope, good to excellent yields, short reaction times, while simultaneously driving the reaction toward completion through the removal of the methanol byproduct. We also report the conversion of a small collection of thionobenzoates into the corresponding α,α-difluorobenzyl ethers to demonstrate the conversion of alcohols into difluorobenzyl or difluoroheterobenzyl ethers, a process that could prove useful for lead optimization in medicinal chemistry.

Full text of DOI:10.1021/acs.joc.8b02260

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Article
Base-Catalyzed Transesterification of Thionoesters
Josiah J. Newton, Robert Britton, and Chadron Mark Friesen
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b02260 • Publication Date (Web): 20 Sep 2018
Downloaded from http://pubs.acs.org on September 20, 2018
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Base-Catalyzed Transesterification of Thionoesters
Josiah J. Newton,†‡ Robert Britton† and Chadron M. Friesen‡
†Department of Chemistry, Simon Fraser University, Burnaby, British Columbia, Canada, V5A 1S6
‡Department of Chemistry, Trinity Western University, Langley, British Columbia, Canada, V2Y 1Y1
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ABSTRACT: Here we report a convenient synthesis of thionoesters by baseꢀcatalyzed transesterification. Benzyl and alkyl thionoꢀ
benzoates and thionoheterobenzoates were efficiently prepared using various alcohols catalyzed by the corresponding sodium
alkoxide. This methodology features a broad substrate scope, good to excellent yields, short reaction times, while simultaneously
driving the reaction towards completion through the removal of the methanol byproduct. We also report the conversion of a small
collection of thionobenzoates into the corresponding α,αꢀdifluorobenzyl ethers to demonstrate the conversion of alcohols into
difluorobenzyl or difluoroheterobenzyl ethers, a process that could prove useful for lead optimization in medicinal chemistry.
Introduction
ters, application of this reaction to diversity oriented or library
synthesis can be timeꢀconsuming and present challenges in
isolation. For example, thionation of benzoyl esters requires 8
or more hours in refluxing xylene and up to 24 h in toluene.12
Additionally, the purification of thionoester products often
requires tedious precipitation of and extensive chromatogꢀ
raphy to completely remove Lawesson’s reagent and reaction
byproducts. While alternative and more convenient strategies
for thionoester synthesis have been reported, these processes
require additional synthetic steps in the preparation of activatꢀ
ed precursors (Scheme 2 c)13, d)14, e)15).16 It has also been
shown that thionoesters can be prepared through the sulfhyꢀ
drolysis of orthoesters17 or from ferrocenyl carbene complexꢀ
es.18
Thionoesters are the thiocarbonyl analogue of esters, and
are of interest due to their unique reactivity. For example, thiꢀ
onoesters can be fluorinated by Deoxofluor®1 to provide
difluoroalkyl ethers or readily isomerized to the corresponding
thioesters (Scheme 1).2,3 Thionoesters also serve as ether preꢀ
cursors through reduction by the use of Raney Nickel4 or tribuꢀ
tyltin hydride.5 Recently, it has been shown that thionoesters
can be converted into 1,4,2ꢀoxathiazoles,6 which are of interest
as motifs for drug discovery.7
Scheme 1: Common reactions of thionoesters.
Curiously, while the synthesis of thioamides from thionoesꢀ
ters has been reported extensively, the use of alcohols as nuꢀ
cleophiles for the transesterification of thionoesters is exꢀ
tremely rare.19,20,21 Early research involving transesterification
of dithiobenzoyl acetic acid suggested to us that transesterifiꢀ
cation should provide a straightforward means to rapidly diꢀ
versify thionoesters.8,22 In addition, exchange reactions with
dithioesters and alcohols have been reported.23,24 It was also
demonstrated that αꢀoxoꢀdithioesters will undergo transesteriꢀ
fication yielding thionoesters.16,25 One notable use of this stratꢀ
egy is in the total synthesis of clostrubin, where the resulting
thionoester was a BartonꢀKellogg olefination as a key step in
the synthesis.26
While historically thionoesters were accessed from a Pinner
alkyl imidate, which is cleaved with H2S and pyridine,8,9 they
are now generally prepared from their corresponding ester,
through the aid of Lawesson’s reagent (Scheme 2 b)).10,11
While this process offers access to a wide range of thionoesꢀ
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reaction enabled the rapid assembly of wide range of functionꢀ
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ally diverse thionoesters that may otherwise be incompatible
with standard reagents used in the conversion of esters to thioꢀ
noesters (e.g., Lawesson’s reagent).
Scheme 2: Synthesis of thionobenzoates.
Table 1: Baseꢀcatalyzed transesterification of methylꢀ
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thionobenzoatea,b
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Considering the above, we envisioned a streamlined syntheꢀ
sis of structurally diverse thionoesters could be achieved
through a straightforward transesterification reaction from a
starting methyl thionoester. Here, transesterification would be
promoted by the removal of methanol. While clearly products
of transesterification of thionoesters could be accessed using
one of the strategies outlined in Scheme 2 or reagents such as
thiobenzoyl chloride27, transesterification offers the advantage
of being a mild reaction that involves no byproduct formation,
and minimal required purification. To explore this process, we
began by examining the transesterification of methylthionoꢀ
benzoate (14).
Results and Discussion
As highlighted in Table 1, the transesterification of methylꢀ
thionobenzoate is generally a rapid and robust reaction. Each
reaction was carried out in a solution (~0.7 M) of the required
alcohol with the addition of a catalytic amount of the correꢀ
sponding alkoxide at 75 °C. In most cases we observed excelꢀ
lent conversion after only 15 minutes, with only small increasꢀ
es in yield with extended time. It should be noted that many
thiocarbonyl compounds are sensitive to moisture or photoꢀ
oxidation. While thionoesters are more stable than thioketones
or thioaldehydes, we observed the slow hydrolysis of thioꢀ
noesters into the corresponding ester when stored as aqueous
solutions for extended periods of time. As summarized in Taꢀ
ble 1, a variety of primary and secondary alcohols (e.g., 15a-
15ab) were successfully transformed into their thionoester
derivatives. The possibility of exploiting this transformation
for more interesting substrates was also considered, and we
were pleased to find that benzyl alcohols, cyclohexanol, as
well as shortꢀchain PEG alcohols were all compatible. Transꢀ
esterification with diols also provided monomeric products
(e.g., 15q, 15r and 15s), which is useful for further derivatizaꢀ
tion. We note that tertiary alcohols, phenols, 2ꢀhaloethanols
and 2ꢀphenylethanol were all incompatible with this process.
Despite these limitations, this straightforward and convenient
a Reaction conditions: methyl thionobenzoate (1.0 mmol) and the
described alcohol (1.5 mL) were mixed and then treated with the
corresponding sodium alkoxide (0.2 mmol) and heated at 75 °C
c
for 15 min. b Isolated yields; reaction time = 2 h; d reaction time
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f
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= 3 h; e reaction on 0.5 mmol scale; reaction time = 30 min;
reaction time = 1 h.
Finally, in an effort to demonstrate the utility of this proꢀ
cess, we examined the conversion of a small collection of
readily available thionoesters into the corresponding α,αꢀ
difluorobenzyl ethers, as shown in Table 3. Thus, starting with
methylthionobenzoate, transesterification followed by fluoriꢀ
nation using reaction conditions reported by Kuroboshi,28,29 we
were able to rapidly access the difluorobenzylethers 18a-18d.
As such, this process may prove useful for the conversion of
alcohols into difluorobenzyl or difluoroheterobenzyl ethers, a
process that could prove useful for lead optimization in medicꢀ
inal chemistry.30–32
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Having established a wide scope of compatible alcohols, we
next examined a range of alkyl, alkenyl and heteroaryl thioꢀ
noesters (Table 2). Here, we found that the transformation of a
variety of methyl thionoesters could be directly converted into
a broad array of thionoesters using this convenient process. Of
note, the reaction was compatible with furans, thiophenes,
pyrroles, pyridines, pyrazines, indoles, indazoles, and cinꢀ
namates.
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Table 2: Baseꢀcatalyzed transesterification of hetꢀ
Table 3: Synthesis of α,αꢀdifluorobenzyl ethers.
eroaryl and alkyl thionoestersa,b
In summary, we developed a convenient and rapid method
of preparing thionoesters from primary and secondary alcohols
through baseꢀcatalyzed transesterification with methyl thioꢀ
noesters. This process is robust and tolerates a wide range of
alcohols and thionoesters.
Experimental Section
General Information. All solvents, reagents and starting materiꢀ
als were purchased from Sigma Aldrich, Anachemia, Fisher Sciꢀ
entific, EMD, Alfa Aesar, AK Sci, or BDH and were used without
further purification. Flash chromatography was carried out with
Sigma Aldrich highꢀpurity grade 60 Å silica gel (70ꢀ230 mesh), or
Silicycles 60 Å silica gel (70ꢀ230 mesh) using a forced flow of
eluent. All reported yields are isolated yields.
Bruker ASCEND III 400 MHz with Bruker AVANCE III 400
MHz running TopSpin 3.1.6 were employed as required for
obtaining solutionꢀstate NMR data. Nuclear magnetic resoꢀ
nance (NMR) spectra were recorded using CDCl3 (CDCl3).
Signal positions (δ) are given in parts per million from tetraꢀ
methylsilane (δ 0). Coupling constants (J values) are given in
1
Hertz (Hz) and are reported to the nearest 0.1 Hz. H NMR
spectral data are tabulated in the order: multiplicity (s, singlet;
d, doublet; t, triplet; q, quartet; quint, quintet; sext, sextet; sept,
septet; m, multiplet), coupling constants, number of protons.
Highꢀresolution mass spectrometry was performed on an Agꢀ
ilent 6210 TOF LC/MS or a Bruker MaXis Impact TOF
LC/MS.
a Reaction conditions: a mixture of the thionoester (1.0 mmol) and
the required alcohol (1.5 mL) was treated with the corresponding
b
O-Methyl benzothioate (14)12. Methyl benzoate (13.602 g, 99
mmol) was refluxed with Lawesson’s reagent (40.468 g, 100
mmol) in xylenes (150 mL) for 8 h. The crude solution apꢀ
peared orange, and upon cooling, much of the Lawesson’s
sodium alkoxide (0.2 mmol) and heated at 75 °C for 15 min;
isolated yields; c 0.2 mmol thionoester; d reaction time = 30 min; e
reaction time = 1 h; 0.5 mmol thionoester; g 2.0 mmol thionoesꢀ
f
ter; h 0.1 mmol thionoester; I reaction time = 2.5 h.
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reagent precipitated out. The resulting solution was diluted O-(2-Methylpropyl) benzothioate (15f). Purification by colꢀ
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with 150 mL of hexanes to precipitate any residual Lawesꢀ
son’s reagent. The Lawesson's solution was filtered, and residꢀ
ual solvent was evaporated. The resulting solution was puriꢀ
fied by column chromatography on silica gel (100% hexane),
umn chromatography on silica gel (100% pentane), afforded
the desired product 15f as a yellow liquid (120 mg, 63%
yield). 1HꢀNMR (400 MHz, CDCl3)
δ 8.24 (d, J = 8.4 Hz, 2H),
7.57 (t, J = 7.4 Hz, 1H), 7.43 (t, J = 7.8 Hz, 2H), 4.48 (d, J =
6.5 Hz, 2H), 2.37ꢀ2.23 (m, 1H), 1.13 (d, J = 6.7 Hz, 6H) ;13C
to yield O-methyl benzothioate as an orange liquid (9.694 g,
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64% yield). HꢀNMR (400 MHz, CDCl3)
δ 8.19 (d, J = 8.5
NMR (101 MHz, CDCl3)
δ 211.6, 138.5, 132.7, 128.7, 128.1,
78.8, 27.8, 19.4; HRMS (ESI): calcd for C11H15OS+ [M+H+]:
Hz, 2H), 7.53 (t, J = 7.4 Hz, 1H), 7.38 (t, J = 7.8 Hz, 2H), 4.30
(s, 3H); 13C NMR (101 MHz, CDCl3)
128.8, 128.1, 59.3.
δ
212.3, 138.2, 132.7,
195.0838, found 195.0839.
O-pentyl benzothioate (15g)33. Purification by column chromaꢀ
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General Procedure for Synthesis of Thionobenzoates. 0.2
mmol of sodium metal was added to in 1.5 mL of the alcohol,
and mixed until it had completely dissolved. To the solution
was added O-methyl benzothioate (0.152 g, 1 mmol), and the
mixture was heated at 75°C for 15 minutes, uncapped. Residuꢀ
al volatiles were evaporated, and the crude reaction mixture
was purified by column chromatography on silica gel to obtain
the pure product.
tography on silica gel (100% pentane), afforded the desired
product 15g as a yellow liquid (193 mg, 94% yield). HꢀNMR
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(400 MHz, CDCl3)
δ 8.19 (d, J = 8.1 Hz, 2H), 7.53 (t, J = 7.4
Hz, 1H), 7.39 (t, J = 7.8 Hz, 2H), 4.66 (t, J = 6.6 Hz, 2H), 1.92
(quint, J = 7.0 Hz, 2H), 1.53ꢀ1.37 (m, 2H), 0.95 (t, J = 7.1 Hz,
3H); 13C NMR (101 MHz, CDCl3)
128.7, 128.1, 72.9, 28.3, 28.0, 22.4, 14.0.
δ 211.7, 138.5, 132.6,
O-(3-Methylbutyl) benzothioate (15h)34. Purification by colꢀ
umn chromatography on silica gel (100% pentane), afforded
the desired product 15h as a yellow liquid (174 mg, 84%
O-Ethyl benzothioate (15a)6. Purification by column chromaꢀ
tography on silica gel (100% pentane), afforded the desired
product 15a as a yellow liquid (130 mg, 72% yield).1HꢀNMR
yield). 1HꢀNMR (400 MHz, CDCl3)
δ 8.10 (d, J = 8.4 Hz, 2H),
(400 MHz, CDCl3)
δ 8.10 (d, J = 8.4 Hz, 2H), 7.43 (t, J = 7.4
7.45 (t, J = 7.4 Hz, 1H), 7.31 (t, J = 7.8 Hz, 2H), 4.63 (t, J =
6.5 Hz, 2H), 1.84ꢀ1.71 (m, 3H), 0.93 (t, J = 6.4 Hz, 6H); 13C
Hz, 1H), 7.29 (t, J = 7.8 Hz, 2H), 4.64 (q, J = 7.1 Hz, 2H),
1.43 (t, J = 7.1 Hz, 3H); 13C NMR (101 MHz, CDCl3)
δ
NMR (101 MHz, CDCl3)
71.5, 37.0, 25.4, 22.6.
δ 211.6, 138.5, 132.6, 128.7, 128.1,
211.6, 138.5, 132.7, 128.7, 128.1, 68.6, 13.8.
O-Propyl benzothioate (15b)13. Purification by column chroꢀ
O-hexyl benzothioate (15i). Purification by column chromaꢀ
matography on silica gel (100% pentane), afforded the desired
tography on silica gel (100% pentane), afforded the desired
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product 15b as a yellow liquid (116 mg, 64% yield). HꢀNMR
product 15i as a yellow liquid (214 mg, 96% yield). HꢀNMR
(400 MHz, CDCl3)
δ 8.19 (d, J = 8.3 Hz, 2H), 7.53 (t, J = 7.4
(400 MHz, CDCl3)
δ 8.10 (d, J = 4.2 Hz, 2H), 7.44 (t, J = 7.4
Hz, 1H), 7.38 (t, J = 7.8 Hz, 2H), 4.63 (q, J = 6.6 Hz, 2H),
Hz, 1H), 7.30 (t, J = 7.8 Hz, 2H), 4.58 (t, J = 6.7 Hz, 2H), 1.83
(quin, J = 7.1 Hz, 2H), 1.43 (quin, J = 7.5 Hz, 2H), 1.33ꢀ1.25
(m, 2H), 0.84 (t, J = 7.1 Hz, 3H); 13C NMR (101 MHz, CDCl3)
1.94 (sext, J = 7.1 Hz, 2H), 1.09 (t, J = 7.4, 3H); 13C NMR
(101 MHz, CDCl3)
21.8, 10.7.
δ 211.7, 138.5, 132.6, 128.7, 128.1, 74.3,
δ
211.6, 138.5, 132.6, 128.7, 128.1, 72.9, 31.5, 28.3, 25.9,
22.6, 14.0; HRMS (ESI): calcd for C13H19OS+ [M+H+]:
223.1151, found 223.1140.
O-(1-methylethyl) benzothioate (15c)13. Purification by column
chromatography on silica gel (100% pentane), afforded the
desired product 15c as a yellow liquid (124 mg, 66% yield).
O-heptyl benzothioate (15j). Purification by column chromaꢀ
1HꢀNMR (400 MHz, CDCl3)
δ 8.09 (d, J = 8.4 Hz, 2H), 7.44
tography on silica gel (100% pentane), afforded the desired
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(t, J = 7.4 Hz, 1H), 7.30 (t, J = 7.3 Hz, 2H), 5.80 (sept, J = 6.2
product 15j as a yellow liquid (186 mg, 78% yield). HꢀNMR
Hz, 1H), 1.40 (d, J = 6.2 Hz, 6H);13C NMR (101 MHz,
(400 MHz, CDCl3)
δ 8.22 (d, J = 8.4 Hz, 2H), 7.56 (t, J = 7.4
CDCl3) δ 210.8, 139.0, 132.5, 128.8, 128.0, 75.6, 21.2.
Hz, 1H), 7.42 (t, J = 7.8 Hz, 2H), 4.70 (t, J = 6.6 Hz, 2H), 1.95
(quin, J = 7.1 Hz, 2H), 1.57ꢀ1.33 (m, 8H), 0.94 (t, J = 6.9 Hz,
O-butyl benzothioate (15d)13. Purification by column chromaꢀ
3H); 13C NMR (101 MHz, CDCl3)
δ 211.6, 138.5, 132.6,
tography on silica gel (100% pentane), afforded the desired
128.7, 128.1, 72.9, 31.6, 29.0, 28.3, 26.2, 22.6, 14.1; HRMS
(ESI): calcd for C14H21OS+ [M+H+]: 237.1308, found
237.1289.
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product 15d as a yellow liquid (150 mg, 72% yield). HꢀNMR
(400 MHz, CDCl3)
Hz, 1H), 7.38 (t, J = 7.8 Hz, 2H), 4.67 (t, J = 6.5 Hz, 2H), 1.90
(quint, J = 7.1 Hz, 2H), 1.55 (m, 2H), 1.01 (t, J = 1.0, 3H); 13
δ 8.18 (d, J = 8.4 Hz, 2H), 7.53 (t, J = 7.4
C
O-octtyl benzothioate (15k). Purification by column chromaꢀ
NMR (101 MHz, CDCl3)
72.6, 30.4, 19.5, 13.8.
δ 211.7, 138.5, 132.6, 128.7, 128.1,
tography on silica gel (100% pentane), afforded the desired
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product 15k as a yellow liquid (136 mg, 55% yield). HꢀNMR
(400 MHz, CDCl3)
δ 8.22 (d, J = 8.4 Hz, 2H), 7.56 (t, J = 7.4
O-(1-Methylpropyl) benzothioate (15e). Purification by colꢀ
umn chromatography on silica gel (100% pentane), afforded
the desired product 15e as a yellow liquid (156 mg, 83%
Hz, 1H), 7.42 (t, J = 7.8 Hz, 2H), 4.70 (t, J = 6.6 Hz, 2H), 1.94
(quin, J = 7.1 Hz, 2H), 1.57ꢀ1.29 (m, 10H), 0.93 (t, J = 6.9 Hz,
3H); 13C NMR (101 MHz, CDCl3)
δ 211.6, 138.5, 132.6,
yield). 1HꢀNMR (400 MHz, CDCl3)
δ 8.17 (d, J = 8.4 Hz, 2H),
128.7, 128.1, 72.9, 31.8, 29.3, 29.2, 28.3, 26.2, 22.6, 14.1;
HRMS (ESI): calcd for C15H23OS+ [M+H+]: 251.1464, found
251.1483.
7.51 (t, J = 7.4 Hz, 1H), 7.37 (t, J = 7.7 Hz, 2H), (sext, J = 6.2
Hz, 1H), 1.96ꢀ1.74 (m, 2H), 1.42 (d, J = 6.2 Hz, 3H), 1.01 (t, J
= 7.5 Hz, 3H); 13C NMR (101 MHz, CDCl3)
δ 211.0, 139.0,
132.5, 128.8, 128.0, 80.2, 28.6, 18.6, 9.7; HRMS (ESI): calcd
O-dodecyl benzothioate (15l). Purification by column chroꢀ
matography on silica gel (100% pentane), afforded the desired
for C11H15OS+ [M+H+]: 195.0838, found 195.0838.
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product 15l as a yellow liquid (119 mg, 39% yield). HꢀNMR
O-(2-Hydroxypropyl) benzothioate (15r)17. Reaction continued
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7
8
for 2h. Purification by column chromatography on silica gel
(20:80 EtOAc/pentane), afforded the desired product 15r as a
yellow liquid (159 mg, 75% yield). 1HꢀNMR (400 MHz,
(400 MHz, CDCl3)
δ 8.21 (d, J = 8.4 Hz, 2H), 7.56 (t, J = 7.4
Hz, 1H), 7.41 (t, J = 7.8 Hz, 2H), 4.69 (t, J = 6.6 Hz, 2H), 1.94
(quin, J = 7.1 Hz, 2H), 1.54ꢀ1.29 (m, 18H), 0.91 (t, J = 6.9 Hz,
3H); 13C NMR (101 MHz, CDCl3)
δ 211.7, 138.5, 132.6,
CDCl3)
δ 8.17 (d, J = 8.4 Hz, 2H), 7.53 (t, J = 7.4 Hz, 1H),
7.38 (d, J = 7.8 Hz, 2H), 4.82 (t, J = 6.2 Hz, 2H), 3.85 (t, J =
128.7, 128.1, 73.0, 31.9, 29.3, 29.7, 29.6, 29.5, 29.4, 29.3,
28.3, 26.2, 22.7, 14.1; HRMS (ESI): calcd for C19H31OS+
[M+H+]: 307.2090, found 307.2066.
6.2, 2H), 2.16 (quint, J = 6.2, 2H), 1.91 (br, 1H); 13C NMR
(101 MHz, CDCl3)
59.5, 31.4.
δ 211.7, 138.3, 132.8, 128.7, 128.1, 69.5,
O-benzyl benzothioate (15m)13. Purification by column chroꢀ
matography on silica gel (100% pentane), afforded the desired
product 15m as a yellow liquid (122 mg, 53% yield). 1HꢀNMR
(400 MHz, CDCl3)
Hz, 1H), 7.48 (d, J = 7.8 Hz, 2H), 7.44ꢀ7.36 (m, 5H), 5.71 (s,
2H); 13C NMR (101 MHz, CDCl3)
211.1, 138.3, 135.3,
9
O-(2-(2-Hydroxyethoxy)ethyl) benzothioate (15s). Reaction
continued for 2h. Purification by column chromatography on
silica gel (20:80 EtOAc/pentane), afforded the desired product
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
δ 8.21 (d, J = 8.4 Hz, 2H), 7.53 (t, J = 7.4
1
15s as a yellow liquid (198 mg, 89% yield). HꢀNMR (400
MHz, CDCl3)
δ 8.19 (d, J = 8.4 Hz, 2H), 7.54 (t, J = 7.4 Hz,
δ
1H), 7.39 (d, J = 7.8 Hz, 2H), 4.83 (t, J = 4.7 Hz, 2H), 3.98 (t,
J = 4.7, 2H), 3.77 (br, 2H), 3.68 (t, J = 4.44, 2H), 2.15 (br,
132.9, 128.9, 128.7, 128.5, 128.4, 128.1, 74.1.
O-(4-methylbenzyl) benzothioate (15n). Reaction continued
for 2h. Purification by column chromatography on silica gel
(100% pentane), afforded the desired product 15n as a yellow
liquid (172 mg, 70% yield). HꢀNMR (400 MHz, CDCl3)
1H); 13C NMR (101 MHz, CDCl3)
δ 211.4, 138.2, 132.9,
128.8, 128.1, 72.5, 71.7, 71.4, 68.7, 61.8; HRMS (ESI): calcd
for C11H15O3S+ [M+H+]: 227.0736, found 227.0710.
1
δ
O-2-(2-(2-Methoxyethoxy)ethoxy)ethyl benzothioate (15t).
Reaction continued for 2h. Purification by column chromatogꢀ
raphy on silica gel (100% pentane), afforded the desired prodꢀ
uct 15t as a yellow liquid (198 mg, 89% yield). 1HꢀNMR (400
8.23 (d, J = 8.4 Hz, 2H), 7.56 (t, J = 6.9 Hz, 1H), 7.40 (d, J =
7.5 Hz, 4H), 7.26 (d, J = 7.8 Hz, 2H), 5.70 (s, 2H), 2.42 (s,
3H); 13C NMR (101 MHz, CDCl3)
δ 211.2, 138.4, 138.3,
132.8, 132.3, 129.4, 128.9, 128.6, 128.1, 74.2, 21.3; HRMS
(ESI): calcd for C15H15OS+ [M+H+]: 243.0838, found
243.0817.
MHz, CDCl3)
δ 8.13 (d, J = 8.4 Hz, 2H), 7.46 (t, J = 7.4 Hz,
1H), 7.31 (d, J = 7.8 Hz, 2H), 4.75 (t, J = 4.7 Hz, 2H), 3.90 (t,
J = 4.7, 2H), 3.69ꢀ3.67 (m, 2H), 3.63ꢀ3.58 (m, 4H), 3.48ꢀ3.46
O-(2,5-dimethoxybenzyl) benzothioate (15o). Reaction continꢀ
ued for 2h. Purification by column chromatography on silica
gel (100% pentane), afforded 15n as a yellow solid. Recrystalꢀ
lization out of pentane afforded yellow flakey crystals. Crysꢀ
(m, 2H), 3.30 (s, 3H); 13C NMR (101 MHz, CDCl3)
δ 211.4,
138.3, 132.8, 128.9, 128.1, 71.9, 71.6, 70.8, 70.7, 70.6, 68.8,
59.1; HRMS (ESI): calcd for C14H21O4S+ [M+H+]: 285.1155,
found 285.1129.
1
talline mp 69ꢀ71 °C; Amorphous mp 65ꢀ66 °C. HꢀNMR (400
O-Cyclohexyl benzothioate (15u)35. Reaction continued for 2h.
Purification by column chromatography on silica gel (100%
MHz, CDCl3)
δ 8.23 (d, J = 8.4 Hz, 2H), 7.55 (t, J = 7.4 Hz,
1H), 7.40 (d, J = 7.9 Hz, 2H), 7.06 (s, 1H), 7.40 (d, J = 7.9 Hz,
2H), 5.74 (s, 2H), 3.85 (s, 3H), 3.82 (s, 3H); 13C NMR (101
pentane), afforded the desired product 15u as a yellow liquid
1
(154 mg, 67% yield). HꢀNMR (400 MHz, CDCl3)
δ 8.21 (d,
MHz, CDCl3)
δ 211.3, 153.5, 151.9, 138.5, 132.7, 128.9,
J = 8.3 Hz, 2H), 7.55 (t, J = 7.4 Hz, 1H), 7.41 (d, J = 7.8 Hz,
2H), 5.73 (quint, J = 4.1 Hz, 1H), 2.12ꢀ2.04 (m, 2H), 1.89ꢀ
1.73 (m, 4H), 1.67ꢀ1.43 (m, 4H ); 13C NMR (101 MHz,
128.1, 124.7, 116.0, 113.9, 111.7, 69.7, 56.1, 55.8; HRMS
(ESI): calcd for C16H17O3S+ [M+H+]: 289.0893, found
289.0871.
CDCl3)
23.6.
δ 210.6, 139.0, 132.5, 128.8, 128.0, 80.1, 30.8, 25.5,
O-(3-Phenylpropyl) benzothioate (15p). Purification by colꢀ
umn chromatography on silica gel (100% pentane), afforded
the desired product 15p as a yellow liquid (198 mg, 79%
O-((3-methyloxetan-3-yl)methyl) benzothioate (15v). Reaction
continued for 1h. Purification by column chromatography on
silica gel (10:90 EtOAc/pentane), afforded the desired product
15v as a dark green liquid (168 mg, 76% yield). 1H NMR
(400 MHz, CDCl3) δ 8.26 – 8.15 (m, 2H), 7.56 (t, J = 7.4
Hz, 1H), 7.41 (t, J = 7.9 Hz, 2H), 4.71 (s, 2H), 4.70 (d, J =
6.0 Hz, 2H), 4.53 (d, J = 6.0 Hz, 2H), 1.50 (s, 3H); 13C
NMR (101 MHz, CDCl3) δ 211.4, 138.3, 133.1, 128.9,
128.4, 79.9, 77.2, 76.6, 39.6, 21.7; HRMS (ESI): calcd for
C12H15O2S+ [M+H+]: 223.0787, found 223.0788.
1
yield). HꢀNMR (400 MHz, CDCl3)
δ 8.16 (d, J = 8.2 Hz,
2H), 7.53 (t, J = 7.4 Hz, 1H), 7.38 (d, J = 7.8 Hz, 2H), 7.32ꢀ
7.28 (m, 2H), 7.24ꢀ7.19 (m, 2H), 4.68 (t, J = 6.4 Hz, 2H),
2.84 (t, J = 7.6 Hz, 2H), 2.28ꢀ2.21 (m, 2H); 13C NMR (101
MHz, CDCl3)
δ 211.5, 141.1, 138.4, 132.7, 128.7, 128.6,
128.5, 128.1, 126.1, 72.0, 32.5, 30.0; HRMS (ESI): calcd for
C16H17OS+ [M+H+]: 257.0995, found 257.1015.
O-(2-Hydroxyethyl) benzothioate (15q)17. Reaction continued
for 3h. Purification by column chromatography on silica gel
(20:80 EtOAc/pentane), afforded the desired product 15q as a
yellow liquid (113 mg, 61% yield). 1HꢀNMR (400 MHz,
O-(2-(pyridin-2-yl)ethyl) benzothioate (15w). Reaction continꢀ
ued for 1h. Purification by column chromatography on silica
gel (20:80 EtOAc/pentane), afforded the desired product 15w
as a swamp green liquid (136 mg, 53% yield). 1H NMR (400
MHz, CDCl3) δ 8.58 (ddd, J = 4.9, 1.8, 1.0 Hz, 1H), 8.15 –
8.06 (m, 2H), 7.64 (td, J = 7.6, 1.8 Hz, 1H), 7.51 (t, J = 7.4
Hz, 1H), 7.38 – 7.32 (m, 2H), 7.27 (d, J = 7.7 Hz, 1H), 7.17
(ddd, J = 7.7, 4.9, 1.2 Hz, 1H), 5.07 (t, J = 6.7 Hz, 2H),
CDCl3)
δ 8.19 (d, J = 8.0 Hz, 2H), 7.54 (t, J = 7.4 Hz, 1H),
7.39 (d, J = 7.8 Hz, 2H), 4.80 (t, J = 4.6 Hz, 2H), 4.10 (br,
2H), 2.02 (br, 1H); 13C NMR (101 MHz, CDCl3)
138.2, 133.0, 128.8, 128.2, 73.6, 60.8.
δ 211.5,
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 6 of 12
3.40 (t, J = 6.7 Hz, 2H); 13C NMR (101 MHz, CDCl3) δ
211.4, 158.0, 149.8, 138.5, 136.6, 132.8, 128.8, 128.2,
123.5, 121.9, 77.2, 71.6, 37.2.HRMS (ESI): calcd for
C14H14NOS+ [M+H+]: 244.0791, found 244.0791.
mixture was purified by column chromatography on silica gel
to obtain the pure product.
1
2
3
4
5
6
7
8
Ester (10 mmol) was mixed with Lawesson’s reagent (10
mmol, 4.045 g) in xylenes (9 mL) and heated at 150°C, until
conversion to the thionoester slowed to a halt, as monitored by
TLC and/or GCꢀMS. Upon cooling, much of the Lawesson’s
reagent precipitated out. The resulting solution was diluted
with 10 mL of hexanes (or 10 mL of ethyl acetate if the startꢀ
ing ester was insoluble in hexanes) to precipitate any residual
Lawesson’s reagent. The resulting solution was filtered
through a cotton plug, and residual solvent was evaporated.
The resulting solution was purified by column chromatogꢀ
raphy on silica gel, to yield the pure product.
O-(6-chlorohexyl) benzothioate (15x). Reaction continued for
1h. Purification by column chromatography on silica gel (5:95
EtOAc/pentane), afforded the desired product 15x as a dark
orange liquid (164 mg, 61% yield). 1H NMR (400 MHz,
CDCl3) δ 8.18 (dd, J = 8.5, 1.3 Hz, 2H), 7.54 (t, J = 7.4
Hz, 1H), 7.40 (dd, J = 8.5, 7.2 Hz, 2H), 4.67 (t, J = 6.5 Hz,
2H), 3.56 (t, J = 6.6 Hz, 2H), 1.94 (p, J = 6.9 Hz, 2H), 1.83
(p, J = 7.0 Hz, 2H), 1.55 (p, J = 3.6 Hz, 4H);13C NMR (101
MHz, CDCl3) δ 211.7, 138.5, 132.8, 128.8, 128.2, 77.2,
72.7, 45.1, 32.6, 28.3, 26.7, 25.7. HRMS (ESI): calcd for
C13H18ClOS+ [M+H+]: 257.0761, found 257.0759.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
O-methyl furan-2-carbothioate (16a). Reaction continued for
3h. Purification by column chromatography on silica gel (5:95
EtOAc/pentane), afforded the desired product 16a as an orꢀ
ange liquid (0.696 g, 48% yield). 1HꢀNMR (400 MHz, CDCl3)
O-(3-(trimethylsilyl)propyl) benzothioate (15y). Reaction conꢀ
tinued for 30 minutes. Purification by column chromatography
on silica gel (5:95 EtOAc/pentane), afforded the desired prodꢀ
uct 15y as a yellow liquid (206 mg, 84% yield). 1H NMR
(400 MHz, CDCl3) δ 8.26 – 8.12 (m, 2H), 7.53 (t, J = 7.4
Hz, 1H), 7.39 (dd, J = 8.4, 7.2 Hz, 2H), 4.64 (t, J = 6.9 Hz,
2H), 1.98 – 1.85 (m, 2H), 0.69 – 0.60 (m, 2H), 0.05 (s, 9H);
13C NMR (101 MHz, CDCl3) δ 211.7, 138.7, 132.8, 128.8,
128.2, 77.2, 75.4, 23.1, 12.8, ꢀ1.6; HRMS (ESI): calcd for
C13H21OSSi+ [M+H+]: 253.1077, found 253.1060.
δ
7.52 (br, 1H), 7.16 (d, J = 3.5 Hz, 1H), 6.42 (dd, J = 3.0
Hz, 1.6 Hz, 1H), 4.13 (s, 3H); 13C NMR (101 MHz, CDCl3)
197.7, 153.0, 146.8, 116.7, 112.6, 57.9.
δ
Oꢀmethyl furanꢀ3ꢀcarbothioate (16b)5. Reaction continued for 3h.
Purification by column chromatography on silica gel (5:95
EtOAc/pentane), afforded the desired product 16b as an or-
1
ange liquid (0.871 g, 62% yield). H-NMR (400 MHz, CDCl3)
δ
7.97 (dd, J = 1.5 Hz, 0.7 Hz, 1H), 7.28 (t, J = 1.7 Hz, 1H),
6.75 (dd, J = 1.8 Hz, 0.6 Hz, 1H), 4.10 (s, 3H); 13C NMR (101
O-(3-(pyridin-4-yl)ethyl) benzothioate (15z). Reaction continꢀ
ued for 1h. Purification by column chromatography on silica
gel (gradient elution from 10:90 to 70:30 EtOAc/pentane),
afforded the desired product 15z as an amberꢀcolored liquid
(159 mg, 60% yield). 1H NMR (400 MHz, CDCl3) δ 8.53
(d, J = 5.1 Hz, 2H), 8.20 – 8.08 (m, 2H), 7.55 (t, J = 7.4
Hz, 1H), 7.39 (t, J = 7.8 Hz, 2H), 7.17 (d, J = 5.9 Hz, 2H),
4.69 (t, J = 6.3 Hz, 2H), 2.85 (d, J = 7.7 Hz, 2H), 2.33 –
2.21 (m, 2H).13C NMR (101 MHz, CDCl3) δ 211.4, 150.1,
150.0, 138.3, 133.0, 128.8, 128.3, 124.0, 77.2, 71.5, 32.0,
29.0. HRMS (ESI): calcd for C15H16NOS+ [M+H+]: 258.0947,
found 258.0950.
MHz, CDCl3)
δ 205.6, 145.7, 143.6, 129.6, 110.2, 58.0;
HRMS (ESI): calcd for C6H7O2S+ [M+H+]: 143.0161, found
143.0155.
Oꢀmethyl thiopheneꢀ2ꢀcarbothioate (16c)36. Reaction continued
for 3h. Purification by column chromatography on silica gel
(5:95 EtOAc/pentane), afforded the desired product 16c as an
orange liquid (1.518 g, 99% yield). 1H-NMR (400 MHz,
CDCl3)
Hz, 1.3 Hz, 1H), 7.06 (m, 1H), 4.22 (s, 3H); 13C NMR (101
MHz, CDCl3) 203.5, 144.9, 133.7, 131.9, 128.1, 58.6.
δ 7.85 (dd, J = 3.8 Hz, 1.3 Hz, 1H), 7.54 (dd, J = 5.0
δ
Oꢀmethyl thiopheneꢀ3ꢀcarbothioate (16d). Reaction continued for
3h. Purification by column chromatography on silica gel (5:95
EtOAc/pentane), afforded the desired product 16d as an orange
O-(1H,1H,2H,2H-perfluoro-1-octyl) benzothioate (15ab).
Reaction continued for 30 minutes. Purification by column
chromatography on silica gel (10:90 Et2O/petroleum ether),
afforded the desired product 15ab as a blackꢀgreen liquid (300
mg, 70% yield). 1H NMR (400 MHz, CDCl3) δ 8.18 (d, J =
7.1 Hz, 2H), 7.56 (t, J = 7.4 Hz, 1H), 7.40 (dd, J = 8.3, 7.4
Hz, 2H), 4.99 (t, J = 6.3 Hz, 2H), 2.76 (tq, J = 18.2, 6.3 Hz,
2H); 13C NMR (101 MHz, CDCl3) δ 210.6, 137.8, 133.1,
128.8, 128.2, 120.7 – 107.5 (m), 63.6 (t, J = 4.0 Hz), 30.3
(t, J = 21.8 Hz); 19F NMR (376 MHz, CDCl3) δ ꢀ80.8 (tt, J
= 9.9, 2.6 Hz), ꢀ112.7 – ꢀ113.5 (m), ꢀ121.4 – ꢀ122.1 (m), ꢀ
122.4 – ꢀ123.1 (m), ꢀ123.2 – ꢀ123.8 (m), ꢀ125.6 – ꢀ126.6
(m); HRMS (ESI): calcd for C15H9F13OS+ [M+H+]: 485.0239,
found 485.0237.
1
liquid (0.975 g, 62% yield). HꢀNMR (400 MHz, CDCl3) δ 8.12
(dd, J = 3.1 Hz, 1.2 Hz, 1H), 7.67(dd, J = 5.1 Hz, 1.2 Hz, 1H),
7.23 (dd, J = 5.1 Hz, 3.1 Hz, 1H), 4.22 (s, 3H); 13C NMR (101
MHz, CDCl3) δ 205.8, 142.9, 130.4, 128.5, 125.5, 58.5; HRMS
(ESI): calcd for C6H7O1S2+ [M+H+]: 158.9933, found 158.9927.
O-methyl 1-methyl-1H-pyrrole-2-carbothioate (16e). Reaction
continued for 1h. Purification by column chromatography on
silica gel (5:95 EtOAc/pentane), afforded the desired product
16d as a yellow liquid (0.873 g, 56% yield). 1H NMR (400
MHz, CDCl3) δ 7.20 (dd, J = 4.1, 1.9 Hz, 1H), 6.80 (t, J =
2.1 Hz, 1H), 6.09 (dd, J = 4.1, 2.5 Hz, 1H), 4.16 (s, 3H),
3.96 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 200.4, 133.6,
131.8, 120.1, 108.4, 57.1, 38.8. HRMS (ESI): calcd for
C7H10NOS+ [M+H+]: 156.0478, found 156.0472.
General Procedure for Synthesis of Methyl Heteraryl thio-
noesters. 0.2 mmol of sodium metal was added to in 1.5 mL
of the alcohol, and mixed until it had completely dissolved. To
the solution was added O-methyl benzothioate (0.152 g, 1
mmol), and the mixture was heated at 75°C for 15 minutes.
Residual volatiles were evaporated, and the crude reaction
O-methyl pyridine-3-carbothioate (16f)37. Reaction continued
for 3h. Purification by column chromatography on silica gel
(20:80 EtOAc/pentane), afforded the desired product 16f as a
dark orange liquid (0.154 g, 10% yield). Low yields occur
ACS Paragon Plus Environment

Page 7 of 12
The Journal of Organic Chemistry
Methyl 1-methyl-1H-indazole-3-carboxylate (8)40. Methylꢀ1Hꢀ
with unprotected Nꢀheterocycles. 1H NMR (400 MHz,
1
2
3
4
indazoleꢀ3ꢀcarboxylate (0.922 g, 5.2 mmol) was dissolved in 8
mL of DMF with K2CO3 (4.674 g, 33.8 mmol), and to it was
added 1.5 mL of iodomethane (24 mmol). The solution was
magnetically stirred and heated at 60°C for 4 hours. The reꢀ
sulting solution was diluted in water and extracted with ethyl
acetate. The resulting organic layers were combined, and
washed twice with water, and dried over sodium sulfate. The
resulting solution was filtered, concentrated, and white crysꢀ
tals of 8 slowly formed from the resulting solution over the
next few days (0.834 g, 84% yield). 1H NMR (400 MHz,
CDCl3) δ 8.2 (dt, J = 8.2, 1.0 Hz, 1H), 7.5 – 7.4 (m, 2H),
7.3 (dt, J = 7.9, 3.9 Hz, 1H), 4.2 (s, 3H), 4.0 (s, 3H);13C
NMR (101 MHz, CDCl3) δ 163.1, 141.2, 134.6, 127.1,
123.9, 123.3, 122.3, 109.6, 77.2, 52.2, 36.5.
CDCl3) δ 9.35 (dd, J = 2.2, 0.7 Hz, 1H), 8.79 (dd, J = 4.9,
1.7 Hz, 1H), 8.56 – 8.42 (m, 1H), 7.38 (ddd, J = 8.1, 4.9,
0.7 Hz, 1H), 4.32 (s, 3H); 13C NMR (101 MHz, CDCl3) δ
209.1, 152.0, 148.5, 137.1, 133.9, 123.2, 59.5.
5
6
7
8
O-methyl pyrazine-2-carbothioate (16g). Reaction continued
for 1h. Purification by column chromatography on silica gel
(20:80 EtOAc/pentane), afforded the desired product 16g,
which was concentrated in vacuo, and placed in the freezer to
facilitate crystallization, affording a dark brown waxy crystalꢀ
line solid (0.100g, 7% yield). mp 115ꢀ117 °C. 1H NMR (400
MHz, CDCl3) δ 9.46 (d, J = 1.4 Hz, 1H), 8.74 (d, J = 2.4
Hz, 1H), 8.67 (dd, J = 2.4, 1.5 Hz, 1H), 4.40 (s, 3H); 13C
NMR (101 MHz, CDCl3) δ 207.3, 148.5, 146.5, 145.4,
143.5, 60.0. HRMS (ESI): calcd for C6H7N2OS+ [M+H+]:
155.0274, found 155.0270.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
O-methyl 1-methyl-1H-indazole-3-carbothioate (16l). Reaction
was conducted on a 3 mmol scale. Reaction continued for 2h.
Purification by column chromatography on silica gel (20:80
EtOAc/pentane), but the resulting product was contaminated
with Lawesson’s reagent. The columned product was disꢀ
solved in 10 mL of methanol, filtered, and concentrated. The
resulting residue was filtered through a plug of silica with
50/50 DCM/pentane, and concentrated, affording yellow crysꢀ
talline 16l (0.297 g, 47% yield). mp 54ꢀ56 °C. 1H NMR (400
MHz, CDCl3) δ 8.5 (dt, J = 8.2, 1.0 Hz, 1H), 7.5 – 7.4 (m,
2H), 7.4 (dt, J = 8.0, 3.9 Hz, 1H), 4.4 (s, 3H), 4.2 (s, 3H);
13C NMR (101 MHz, CDCl3) δ 203.9, 142.4, 141.4, 127.0,
124.0, 123.6, 123.4, 109.6, 77.2, 58.2, 36.6; (ESI): calcd for
C10H11N2OS+ [M+H+]: 207.0587, found 207.0580.
O-methyl 1-methyl-1H-indole-2-carbothioate (16h). Reaction
was conducted on a 2 mmol scale. Reaction continued for 1h.
Purification by column chromatography on silica gel (20:80
EtOAc/pentane), afforded the desired product 16h as a yellow
crystalline solid (0.079 g, 18% yield). Additional thionoester
was contaminated with starting ester in later fractions, and was
1
abandoned. mp 70ꢀ72 °C. H NMR (400 MHz, CDCl3) δ
7.66 (d, J = 8.0 Hz, 1H), 7.47 (s, 1H), 7.39 – 7.31 (m, 2H),
7.13 (ddd, J = 7.9, 5.7, 2.2 Hz, 1H), 4.27 (s, 3H), 4.07 (s,
3H); 13C NMR (101 MHz, CDCl3) δ 202.5, 140.6, 138.2,
125.8, 125.6, 122.8, 120.8, 111.5, 110.5, 58.0, 32.9. HRMS
(ESI): calcd for C11H12NOS+ [M+H+]: 206.0634, found
206.0626.
General Procedure for Transesterification of Heteroaryl
Thionoesters. 0.2 mmol of sodium metal was added to in 1.5
mL of the alcohol, and mixed until it had completely disꢀ
solved. To the solution was added the heteroaryl thionoester (1
mmol), and the mixture was heated at 75°C for 15 minutes,
uncapped. The crude reaction mixture was purified by column
chromatography on silica gel to obtain the pure product.
O-methyl cyclohexanecarbothioate (16i)38. Reaction continued
for 2h. Purification by column chromatography on silica gel
(100% pentane), afforded the desired product 16i as a yellow
liquid (0.619 g, 33% yield). 1H NMR (400 MHz, CDCl3) δ
4.06 (s, 3H), 2.68 (tt, J = 11.7, 3.4 Hz, 1H), 1.96 – 1.89 (m,
2H), 1.79 (dt, J = 11.8, 2.9 Hz, 2H), 1.70 – 1.64 (m, 1H),
1.57 – 1.45 (m, 2H), 1.33 – 1.18 (m, 3H); 13C NMR (101
MHz, CDCl3) δ 229.4, 58.7, 54.7, 32.4, 25.8.
O-butyl furan-2-carbothioate (17a.). Purification by column
chromatography on silica gel (5:95 EtOAc/pentane), afforded
O-methyl hexanethioate (16j)36. Reaction continued for 2h.
Purification by column chromatography on silica gel (100%
pentane), afforded the desired product 16j as a lightꢀbrown
liquid (0.337 g, 25% yield). The product is volatile, and should
be used within a few days of preparation, as it slowly decomꢀ
poses and will fume in air. 1H NMR (400 MHz, CDCl3) δ
4.07 (s, 3H), 2.73 (t, J = 7.6 Hz, 2H), 1.74 (p, J = 7.5 Hz,
2H), 1.35 – 1.29 (m, 4H), 0.90 (t, J = 6.7 Hz, 3H); 13C
NMR (101 MHz, CDCl3) δ 225.4, 58.9, 46.7, 31.0, 28.4,
22.4, 13.9.
the desired product 17a as a yellow liquid (154 mg, 90%
1
yield). HꢀNMR (400 MHz, CDCl3)
δ 7.60 (dd, J = 1.7 Hz,
0.8 Hz, 1H), 7.23 (dd, J = 3.6 Hz, 0.7 Hz, 1H), 6.50 (dd, J =
3.5 Hz, 1.7 Hz, 1H), 4.63 (t, J = 6.6 Hz, 2H), 1.85 (quin; J =
7.1 Hz, 2H), 1.50 (sext, J = 7.5 Hz, 2H), 0.99 (t, J = 7.4 Hz,
3H); 13C NMR (101 MHz, CDCl3)
δ 197.4, 153.2, 146.8,
116.3, 112.5, 71.3, 30.3, 19.3, 13.8; HRMS (ESI): calcd for
C9H13O2S+ [M+H+]: 185.0631, found 185.0620.
O-butyl furan-3-carbothioate (17b.). Purification by column
chromatography on silica gel (5:95 EtOAc/pentane), afforded
the desired product 17b as a yellow liquid (193 mg, 94%
O-ethyl (E)-3-phenylprop-2-enethioate (16k)39. Reaction
continued for 30 minutes. Purification by column chromatogꢀ
raphy on silica gel (5:95 EtOAc/pentane), afforded the desired
product 16k as a dark red/orange liquid (0.753 g, 39% yield).
1
yield). HꢀNMR (400 MHz, CDCl3)
δ 8.04 (dd, J = 1.4 Hz,
0.6 Hz, 1H), 7.36 (t, J = 1.8 Hz, 1H), 6.83 (dd, J = 1.8 Hz, 0.6
Hz, 1H), 4.59 (t, J = 6.6 Hz, 2H), 1.83 (quin; J = 7.1 Hz, 2H),
1.49 (sext, J = 7.4 Hz, 2H), 0.99 (t, J = 7.4 Hz, 3H); 13C NMR
1HꢀNMR (400 MHz, CDCl3)
δ 7.69 (d, J = 15.8 Hz, 1H),
(101 MHz, CDCl3)
δ 205.1, 145.6, 143.5, 129.9, 110.1, 71.3,
7.55 (m, 2H), 7.37 (m, 3H), 7.01 (d, J = 15.8 Hz, 1H), 4.63 (t,
30.3, 19.4, 13.8; HRMS (ESI): calcd for C9H13O2S+ [M+H+]:
J = 7.09 Hz, 2H), 1.47 (q, J = 7.09 Hz, 3H); 13C NMR (101
185.0631, found 185.0627.
MHz, CDCl3)
68.9, 13.9.
δ 210.4, 140.4, 134.8, 130.3, 129.0, 128.4,
O-butyl thiophene-2-carbothioate (17c.). Purification by colꢀ
umn chromatography on silica gel (5:95 EtOAc/pentane), afꢀ
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The Journal of Organic Chemistry
Page 8 of 12
2.5 Hz, 1H), 4.75 (t, J = 4.7 Hz, 2H), 3.96 (s, 3H), 3.90 (t, J
= 4.7 Hz, 2H), 3.77 – 3.72 (m, 2H), 3.64 (t, J = 4.2 Hz,
2H), 2.09 (br, 1H). 13C NMR (101 MHz, CDCl3) δ 199.4,
133.7, 132.1, 121.0, 108.8, 77.2, 72.4, 69.2, 69.0, 61.9,
38.9. HRMS (ESI): calcd for C10H16NO3S+ [M+H+]: 230.0845,
found 230.0853.
forded the desired product 17c as a yellow liquid (143 mg,
1
1
2
3
4
5
6
7
8
69% yield). HꢀNMR (400 MHz, CDCl3)
δ 7.84 (dd, J = 3.8
Hz, 1.3 Hz, 1H), 7.53 (dd, J = 5.0 Hz, 1.2 Hz, 1H), 7.05 (dd, J
= 5.0 Hz, 3.8 Hz, 1H), 4.62 (t, J = 6.5 Hz, 2H), 1.85 (quin; J =
7.0 Hz, 2H), 1.51 (sext, J = 7.5 Hz, 2H), 0.99 (t, J = 7.4 Hz,
3H); 13C NMR (101 MHz, CDCl3)
δ 203.0, 145.3, 133.5,
131.5, 128.1 72.0, 30.3, 19.4, 13.8; HRMS (ESI): calcd for
C9H13OS2+ [M+H+]: 201.0402, found 201.0394.
O-(2-(2-hydroxyethoxy)ethyl) pyridine-3-carbothioate (17i).
Reaction conducted on a 0.22 mmol scale. Reaction continued
for 30 minutes. Purification by column chromatography on
silica gel (100% EtOAc), afforded the desired product 17i as a
yellow liquid (46 mg, 92% yield). 1H NMR (400 MHz,
CDCl3) δ 9.35 (dd, J = 2.2, 0.7 Hz, 1H), 8.79 (dd, J = 4.9,
1.7 Hz, 1H), 8.56 – 8.42 (m, 1H), 7.38 (ddd, J = 8.1, 4.9,
0.7 Hz, 1H), 4.32 (s, 3H); 13C NMR (101 MHz, CDCl3) δ
209.1, 152.0, 148.5, 137.1, 123.2, 59.5. HRMS (ESI): calcd
for C10H14NO3S+ [M+H+]: 228.0689, found 228.0691.
O-butyl thiophene-3-carbothioate (17d.). Purification by colꢀ
umn chromatography on silica gel (5:95 EtOAc/pentane), afꢀ
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
forded the desired product 17d as a yellow liquid (178 mg,
1
89% yield). HꢀNMR (400 MHz, CDCl3)
δ 8.12 (dd, J = 3.1
Hz, 1.2 Hz, 1H), 7.67 (dd, J = 5.1 Hz, 1.2 Hz, 1H), 7.23 (dd, J
= 5.1 Hz, 3.1 Hz, 1H), 4.61 (t, J = 6.6 Hz, 2H), 1.86 (quin; J =
7.1 Hz, 2H), 1.51 (sext, J = 7.5 Hz, 2H), 1.00 (t, J = 7.4 Hz,
3H); 13C NMR (101 MHz, CDCl3)
δ 205.2, 143.2, 130.2,
128.4, 125.4 71.8, 30.4, 19.4, 13.8; HRMS (ESI): calcd for
C9H13OS2+ [M+H+]: 201.0402, found 201.0383.
O-(2-(2-hydroxyethoxy)ethyl) pyrazine-2-carbothioate (17j).
Reaction conducted on a 0.23 mmol scale. Reaction continued
for 30 minutes. Purification by column chromatography on
silica gel (100% EtOAc), afforded the desired product 17j as
an orange/brown oil (33 mg, 64% yield). 1H NMR (400 MHz,
CDCl3) δ 9.42 (d, J = 1.4 Hz, 1H), 8.71 (d, J = 2.5 Hz,
1H), 8.66 – 8.57 (m, 1H), 4.91 – 4.80 (m, 2H), 4.06 – 3.97
(m, 2H), 3.78 – 3.75 (m, 2H), 3.70 – 3.66 (m, 2H), 2.02 (br,
1H). 13C NMR (101 MHz, CDCl3) δ 206.7, 148.6, 147.0,
146.8, 145.7, 143.6, 77.2, 72.8, 72.4, 68.3, 61.8. HRMS
(ESI): calcd for C9H13N2O3S+ [M+H+]: 229.0641, found
229.0631.
O-(2-(2-hydroxyethoxy)ethyl) furan-2-carbothioate (17e).
Reaction continued for 30 minutes. Purification by column
chromatography on silica gel (50:50 EtOAc/pentane), afforded
the desired product 17e as a yellow liquid (194 mg, 90%
yield). 1H NMR (400 MHz, CDCl3) δ 7.71 – 7.43 (m, 1H),
7.28 (d, J = 3.6 Hz, 1H), 6.51 (dd, J = 3.6, 1.7 Hz, 1H),
5.01 – 4.57 (m, 2H), 3.98 – 3.90 (m, 1H), 3.82 – 3.70 (m,
2H), 3.70 – 3.64 (m, 2H), 2.18 (s, 1H); 13C NMR (101
MHz, CDCl3) δ 196.8, 153.0, 147.0, 117.1, 112.7, 72.5,
70.1, 68.6, 61.7.; HRMS (ESI): calcd for C9H13O4S+ [M+H+]:
217.0529, found 217.0507.
O-(2-(2-hydroxyethoxy)ethyl)
1-methyl-1H-indole-2-
O-(2-(2-hydroxyethoxy)ethyl) furan-3-carbothioate (17f). Reꢀ
action continued for 30 minutes. Purification by column
chromatography on silica gel (50:50 EtOAc/pentane), afforded
carbothioate (17k.). Reaction conducted on a 0.21 mmol scale.
Reaction continued for 30 minutes. Purification by column
chromatography on silica gel (50:50 EtOAc/pentane), afforded
the desired product 17k. as a yellow liquid (56 mg, 93%
yield). 1H NMR (400 MHz, CDCl3) δ 7.24 (dd, J = 4.1, 1.9
Hz, 1H), 6.81 (dd, J = 2.1 Hz, 1H), 6.10 (dd, J = 4.1, 2.5
Hz, 1H), 4.75 (t, J = 4.7 Hz, 2H), 3.96 (s, 3H), 3.90 (t, J =
4.7 Hz, 2H), 3.77 – 3.72 (m, 2H), 3.64 (t, J = 4.2 Hz, 2H),
2.09 (br, 1H); 13C NMR (101 MHz, CDCl3) δ 201.6, 140.6,
138.2, 125.9, 125.8, 122.8, 120.9, 112.3, 110.6, 72.4, 70.2,
68.7, 61.8, 33.0. HRMS (ESI): calcd for C14H18NO3S+
[M+H+]: 280.1002, found 280.1001.
the desired product 17f as a yellow liquid (135 mg, 57%
1
yield). HꢀNMR (400 MHz, CDCl3)
δ 8.08 (dd, J = 1.5 Hz,
0.7 Hz, 1H), 7.37 (t, J = 1.7 Hz, 1H), 6.85 (dd, J = 2.0 Hz, 0.6
Hz, 1H), 4.66 (t, J = 4.7 Hz, 2H), 4.76 (t; J = 4.7 Hz, 2H), 3.92
(t, J = 4.7 Hz, 2H), 3.76 (t, J = 4.4 Hz, 2H), 3.66 (t, J = 4.5 Hz,
2H), 2.17 (br, 1H); 13C NMR (101 MHz, CDCl3) δ 204.7,
145.9, 143.6, 129.6, 110.2, 72.5, 70.2, 68.7, 61.7.; HRMS
(ESI): calcd for C9H13O4S+ [M+H+]: 217.0529, found
217.0504.
O-(2-(2-hydroxyethoxy)ethyl) thiophene-3-carbothioate (17g).
Reaction continued for 30 minutes. Purification by column
chromatography on silica gel (50:50 EtOAc/pentane), afforded
O-(2-(2-hydroxyethoxy)ethyl)-1-methyl-1H-pyrrole-2-
carbothioate (17l). Reaction continued for 1h. Purification by
column chromatography on silica gel (20:80 EtOAc/pentane),
afforded the desired product 17l as a yellow liquid (266 mg,
92% yield). 1H NMR (400 MHz, CDCl3) δ 7.28 – 7.21 (m,
1H), 7.02 – 6.94 (m, 1H), 6.86 – 6.84 (m, 1H), 6.78 (t, J =
2.2 Hz, 1H), 6.08 (dd, J = 4.1, 2.5 Hz, 1H), 5.64 (s, 2H),
3.88 (s, 3H), 3.81 (s, 3H), 3.77 (s, 3H); 13C NMR (101
MHz, CDCl3) δ 199.4, 153.4, 152.0, 133.7, 131.6, 125.1,
120.9, 116.2, 114.0, 111.5, 108.5, 67.7, 56.0, 55.8, 38.7.
HRMS (ESI): calcd for C15H18NO3S+ [M+H+]: 292.1002,
found 292.0992.
the desired product 17g as a yellow liquid (159 mg, 66%
1
yield). HꢀNMR (400 MHz, CDCl3)
δ 8.16 (dd, J = 3.1 Hz,
1.1 Hz, 1H), 7.68 (dd, J = 5.1 Hz, 1.1 Hz, 1H), 7.24 (dd, J =
5.1 Hz, 3.1 Hz, 1H), 4.66 (t, J = 4.7 Hz, 2H), 3.94 (t; J = 4.6
Hz, 2H), 3.67 (m, 2H), 3.66 (t, J = 4.5 Hz, 2H), 2.15 (m, 1H);
13C NMR (101 MHz, CDCl3)
δ 204.8, 142.9, 130.6, 128.5,
125.6, 72.5, 70.7, 68.7, 61.8; HRMS (ESI): calcd for
C9H13O3S2+ [M+H+]: 233.0301, found 233.0292.
O-(2-(2-hydroxyethoxy)ethyl)-1-methyl-1H-pyrrole-2-
carbothioate (17h). Reaction continued for 1h. Purification by
column chromatography on silica gel (50:50 EtOAc/pentane),
afforded the desired product 17h as a yellow liquid (208 mg,
91% yield). 1H NMR (400 MHz, CDCl3) δ 7.24 (dd, J = 4.1,
1.9 Hz, 1H), 6.81 (dd, J = 2.1 Hz, 1H), 6.10 (dd, J = 4.1,
O-(2-(2-hydroxyethoxy)ethyl) cyclohexanecarbothioate (17m).
Reaction conducted on a 0.52 mmol scale. Reaction continued
for 30 minutes. Purification by column chromatography on
silica gel (50:50 EtOAc/pentane), afforded the desired product
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The Journal of Organic Chemistry
O-(3-phenylpropyl) 1-methyl-1H-indole-2-carbothioate (17r).
17m as a yellow liquid (90 mg, 74% yield). 1H NMR (400
1
2
3
4
5
6
7
8
Reaction conducted on a 0.46 mmol scale. Reaction continued
for 1h. Purification by column chromatography on silica gel
(5:95 EtOAc/pentane), afforded the desired product 17r as a
yellow crystalline solid (103 mg, 72% yield). mp 57ꢀ58 °C.
1H NMR (400 MHz, CDCl3) δ 7.71 (dd, J = 8.1, 1.1 Hz,
1H), 7.49 (s, 1H), 7.43 – 7.31 (m, 4H), 7.30 – 7.24 (m, 3H),
7.17 (ddd, J = 8.0, 5.8, 2.1 Hz, 1H), 4.73 (t, J = 6.4 Hz,
2H), 4.11 (s, 3H), 2.88 (dd, J = 8.6, 6.8 Hz, 2H), 2.35 –
2.21 (m, 2H); 13C NMR (101 MHz, CDCl3) δ 201.8, 141.0,
140.6, 138.4, 128.6, 128.4, 126.2, 125.8, 125.7, 122.8,
120.8, 111.5, 110.5, 70.9, 33.0, 32.6, 30.1. HRMS (ESI):
calcd for C19H20NOS+ [M+H+]: 310.1260, found 310.1254.
MHz, CDCl3) δ 4.54 (t, J = 4.7 Hz, 2H), 3.78 (t, J = 4.7
Hz, 2H), 3.72 – 3.63 (m, 2H), 3.60 – 3.52 (m, 2H), 2.62 (tt,
J = 11.6, 3.4 Hz, 1H), 2.03 (s, 1H), 1.91 – 1.82 (m, 2H),
1.72 (td, J = 12.0, 2.9 Hz, 2H), 1.64 – 1.58 (m, 1H), 1.45
(qd, J = 12.3, 3.1 Hz, 2H), 1.32 – 1.05 (m, 4H).13C NMR
(101 MHz, CDCl3) δ 228.7, 72.3, 70.7, 68.6, 61.7, 54.7,
32.5, 25.8, 25.7. C11H21O3S+ [M+H+]: 233.1206, found
233.1200.
9
O-(2-(2-hydroxyethoxy)ethyl) hexanethioate (17n). Reaction
conducted on a 0.58 mmol scale. Reaction continued for 30
minutes. Purification by column chromatography on silica gel
(50:50 EtOAc/pentane), afforded the desired product 17n as a
yellow liquid (74 mg, 58% yield). 1H NMR (400 MHz,
CDCl3) δ 4.61 (t, J = 4.7 Hz, 2H), 3.85 (t, J = 4.7 Hz, 2H),
3.81 – 3.71 (m, 2H), 3.68 – 3.57 (m, 2H), 2.75 (t, J = 7.7
Hz, 2H), 2.11 (s, 1H), 1.75 (p, J = 9.8, 7.3 Hz, 2H), 1.37 –
1.29 (m, 4H), 0.92 – 0.87 (m, 3H); 13C NMR (101 MHz,
CDCl3) δ 224.6, 72.4, 71.0, 68.5, 61.7, 46.9, 31.0, 28.4,
22.3, 13.9. C10H21O3S+ [M+H+]: 221.1206, found 221.1205.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
O-(but-3-en-1-yl) 1-methyl-1H-indazole-3-carbothioate (17s).
Reaction conducted on a 0.18 mmol scale. Reaction continued
for 30 minutes. Purification by column chromatography on
silica gel (20:80 EtOAc/pentane), afforded the desired product
17s as a yellow crystalline solid (43 mg, 94% yield). mp 34ꢀ
1
35 °C. H NMR (400 MHz, CDCl3) δ 8.3 (dd, J = 8.2, 1.0
Hz, 1H), 7.4 – 7.3 (m, 2H), 7.3 (dtd, J = 8.0, 3.9, 0.9 Hz,
1H), 5.9 (ddt, J = 17.0, 10.3, 6.7 Hz, 1H), 5.2 (dd, J = 17.2,
1.7 Hz, 1H), 5.1 (dd, J = 10.2, 1.5 Hz, 1H), 4.8 (t, J = 6.8
Hz, 2H), 4.1 (s, 3H), 2.7 (dt, J = 6.8 Hz, 2H); 13C NMR
(101 MHz, CDCl3) δ 203.8, 142.8, 141.4, 134.0, 126.9,
123.8, 123.4, 122.3, 117.8, 109.6, 77.2, 70.6, 36.7, 32.9;
HRMS (ESI): calcd for C13H15N2OS+ [M+H+]: 247.0900,
found 247.0904.
O-(2-(2-hydroxyethoxy)ethyl)-(Z)-3-phenylprop-2-enethioate
(17o). Reaction continued for 1h. Purification by column
chromatography on silica gel (50:50 EtOAc/pentane), afforded
the desired product 17o as a dark red/orange liquid (120 mg,
1
52% yield). HꢀNMR (400 MHz, CDCl3)
δ 7.75 (d, J = 15.8
Hz, 1H), 7.56 (m, 2H), 7.38 (m, 3H), 7.05 (d, J = 15.8 Hz,
1H), 4.75 (t, J = 4.7 Hz, 2H), 3.93 (t, J = 4.7 Hz, 2H), 3.78 (t,
J = 4.5 Hz, 2H), 3.67 (t, J = 4.5 Hz, 2H), 2.04 (br, 1H); 13C
O-(pent-4-en-1-yl) 1-methyl-1H-indazole-3-carbothioate (17t).
Reaction conducted on a 0.18 mmol scale. Reaction continued
for 30 minutes. Purification by column chromatography on
silica gel (20:80 EtOAc/pentane), afforded the desired product
17t as an orange liquid (35 mg, 75% yield). 1H NMR (400
MHz, CDCl3) δ 8.4 (d, J = 8.2 Hz, 1H), 7.5 – 7.4 (m, 2H),
7.4 – 7.3 (m, 1H), 5.9 (ddt, J = 16.9, 10.1, 6.6 Hz, 1H), 5.1
(dq, J = 17.1, 1.6 Hz, 1H), 5.0 (dq, J = 10.2, 1.3 Hz, 1H),
4.8 (t, J = 6.8 Hz, 2H), 4.2 (s, 3H), 2.3 (td, J = 7.5, 6.1 Hz,
2H), 2.1 (p, J = 6.8 Hz, 2H); 13C NMR (101 MHz, CDCl3)
δ 203.9, 142.8, 141.4, 137.5, 126.9, 123.9, 123.4, 122.5,
115.7, 109.6, 77.2, 71.0, 36.7, 30.4, 27.7; HRMS (ESI):
calcd for C14H17N2OS+ [M+H+]: 261.1056, found 261.1059.
NMR (101 MHz, CDCl3)
δ 210.3, 141.5, 134.7, 130.4, 129.0,
128.6, 72.4, 70.7, 68.8, 61.8, 53.4; HRMS (ESI): calcd for
C13H17O3S+ [M+H+]: 253.0893, found 253.0860.
O-(2,5-dimethoxybenzyl) (E)-3-phenylprop-2-enethioate (17p).
Reaction continued for 1h. Purification by column chromatogꢀ
raphy on silica gel (50:50 EtOAc/pentane), afforded the deꢀ
sired product 17p as a dark red/orange liquid (252 mg, 71%
yield). 1H NMR (400 MHz, CDCl3) δ 7.73 (d, J = 15.8 Hz,
1H), 7.59 – 7.51 (m, 2H), 7.41 – 7.34 (m, 3H), 7.07 (d, J =
15.8 Hz, 1H), 7.04 – 6.96 (m, 1H), 6.92 – 6.83 (m, 2H),
5.63 (s, 2H), 3.83 (s, 3H), 3.79 (s, 3H); 13C NMR (101
MHz, CDCl3) δ 210.2, 153.5, 151.9, 141.0, 134.8, 130.3,
128.9, 128.9, 128.4, 124.8, 116.0, 114.0, 111.7, 69.0, 56.2,
55.8. HRMS (ESI): calcd for C18H19O3S+ [M+H+]: 315.1049,
found 315.1036.
O-(3-hydroxypropyl)
1-methyl-1H-indazole-3-carbothioate
(17u). Reaction conducted on a 0.22 mmol scale. Reaction
continued for 2.5h. Purification by column chromatography on
silica gel (50:50 EtOAc/pentane), afforded the desired prodꢀ
uct, which was still contained 1,3ꢀpropanediol which was exꢀ
tracted with a several small portions with water, from a soluꢀ
tion in diethyl ether. The solution was dried over sodium sulꢀ
fate, filtered, and concentrated in vacuo, affording the desired
product 17u as a yellow oil, which crystallized after several
days (48 mg, 87% yield). mp 89ꢀ90 °C. 1H NMR (400 MHz,
CDCl3) δ 8.5 (dd, J = 8.2, 1.0 Hz, 1H), 7.5 – 7.5 (m, 2H),
7.4 (dt, J = 8.0, 3.9 Hz, 1H), 5.0 (t, J = 6.1 Hz, 2H), 4.2 (s,
3H), 3.9 – 3.9 (m, 4H), 2.4 (s, 1H), 2.3 (q, J = 6.0 Hz, 2H);
13C NMR (101 MHz, CDCl3) δ 203.3, 142.4, 141.5, 127.0,
124.0, 123.4, 123.1, 109.7, 77.2, 69.2, 60.3, 36.7, 31.6;
HRMS (ESI): calcd for C12H15N2O2S+ [M+H+]: 251.0849,
found 251.0852.
O-(but-3-en-1-yl) 1-methyl-1H-pyrrole-2-carbothioate (17q)
Reaction conducted on a 2.19 mmol scale. Reaction continued
for 1h. Purification by column chromatography on silica gel
(5:95 EtOAc/pentane), afforded the desired product 17q as a
yellow liquid (241 mg, 56% yield). 1H NMR (400 MHz,
CDCl3) δ 7.23 (dd, J = 4.1, 2.0 Hz, 1H), 6.79 (dd, J = 2.0
Hz, 1H), 6.09 (dd, J = 4.1, 2.0 Hz, 1H), 5.88 (ddt, J = 17.0,
10.3, 6.6 Hz, 1H), 5.18 (dq, J = 17.0, 1.6 Hz, 1H), 5.12 (dd,
J = 10.3, 1.6 Hz, 1H), 4.65 (t, J = 6.6 Hz, 2H), 3.94 (s, 3H),
2.61 (qt, J = 6.6, 1.4 Hz, 2H); 13C NMR (101 MHz, CDCl3)
δ 199.7, 134.3, 133.8, 131.6, 120.8, 117.3, 108.6, 69.6,
38.9, 32.9. HRMS (ESI): calcd for C10H14NOS+ [M+H+]:
196.0791, found 196.0785.
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The Journal of Organic Chemistry
Page 10 of 12
O-(3-phenylpropyl)
1-methyl-1H-indazole-3-carbothioate
MHz, CDCl3) δ 133.5 (t, J = 31.8 Hz), 130.7, 128.4, 125.3
(t, 3.7 Hz), 122.8, 121.6 106.3 (m,
1
2
3
4
5
6
7
8
(17v). Reaction conducted on a 0.23 mmol scale. Reaction
continued for 1h. Purification by column chromatography on
silica gel (15:85 EtOAc/pentane), afforded the desired product
17v as a yellow oil, which crystallized after several days (63
J
=
–
CF2CF2CF2CF2CF2CF3), 56.0 (t, J = 5.9 Hz), 31.3 (t, J =
21.8 Hz); 19F NMR (376 MHz, CDCl3) δ ꢀ70.3 (s), ꢀ80.8
(tt, J = 10.1, 2.6 Hz), ꢀ120.3 – ꢀ106.0 (m), ꢀ121.9 (t, J =
14.4 Hz), ꢀ122.6 – ꢀ123.1 (m), ꢀ123.3 – ꢀ123.8 (m), ꢀ125.8
– ꢀ126.4 (m). HRMS (ESI): calcd for C15H9F15ONa+
[M+Na+]: 513.0306, found 513.0308.
1
mg, 87% yield). mp 109ꢀ111 °C. H NMR (400 MHz,
CDCl3) δ 8.4 (dt, J = 8.3, 1.1 Hz, 1H), 7.5 – 7.4 (m, 2H),
7.4 – 7.3 (m, 3H), 7.3 – 7.2 (m, 2H), 4.8 (t, J = 6.7 Hz, 2H),
4.2 (s, 3H), 2.9 (dd, J = 8.7, 6.7 Hz, 2H), 2.4 – 2.3 (m,
2H);13C NMR (101 MHz, CDCl3) δ 203.8, 142.8, 141.5,
141.2, 128.7, 128.6, 127.0, 126.3, 123.9, 123.3, 122.5,
109.7, 77.2, 70.9, 36.7, 32.5, 30.1; HRMS (ESI): calcd for
C18H19N2OS+ [M+H+]: 311.1213, found 311.1211.
2-((phenylcarbonothioyl)oxy)ethyl acetate (17w). 15q was
dissolved in 1 mL of dichloromethane to which acetic anhyꢀ
dride was added (0.104 g, 1.02 mmol), followed by the addiꢀ
tion of a catalytic amount of 4ꢀdimethylaminoꢀpyridine (2 mg,
0.016 mmol). The mixture was stirred at room temperature for
15 minutes, and the crude reaction mixture was filtered
through a plug of silica, eluted with 20/80 ethyl acetate penꢀ
tane. The solvent was removed in vacuo, yielding 17w as a
yellow liquid (59 mg, 91% yield). In a test experiment without
the dimethylaminopyridine, no reaction was observed by TLC
even after 3 hours. 1H NMR (400 MHz, CDCl3) δ 8.19 (dd,
J = 8.4, 1.2 Hz, 2H), 7.55 (t, J = 7.4 Hz, 1H), 7.40 (t, J =
7.8 Hz, 2H), 4.88 – 4.81 (m, 2H), 4.58 – 4.53 (m, 2H), 2.11
(s, 3H); 13C NMR (101 MHz, CDCl3) δ 211.1, 170.8, 138.0,
133.0, 128.9, 128.1, 70.0, 61.7, 20.9; HRMS (ESI): calcd for
C11H13O3S+ [M+H+]: 225.0580, found 225.0580.
9
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60
General Procedure for Oxidative Fluorodesulfuration of
Thionoesters. Thionoester (0.2 mmol) was dissolved in 1 mL
of DCM, and to the solution was added HF/pyridine(70/30,
0.05 mL) was subsequently added. The solution was magnetiꢀ
cally stirred until homogenous, and Nꢀiodosuccinimide was
added in one portion (0.5 mmol). The solution quickly turned
black and was allowed to stir at room temperature for 15
minutes. The resulting solution neutralized dropwise with Naꢀ
HCO3 sat’d water until slightly basic, and the iodine liberated
in the reaction was quenched with sodium thiosulfate. The
organic layer was separated, and the aqueous layer was exꢀ
tracted with 3x1 mL of dichloromethane. The organic layers
were combined, dried over sodium sulfate, filtered, and the
solvent was evaporated in vacuo. The crude reaction mixture
was purified by column chromatography on silica gel to yield
the desired product.
2-(difluoro(phenyl)methoxy)ethyl acetate (18d). Purification
by column chromatography on silica gel (5:95 Et2O/pentane),
afforded the desired product 18d as a colorless liquid (11 mg,
25% yield). 1H NMR (400 MHz, CDCl3) δ 7.7 – 7.6 (m,
2H), 7.5 – 7.4 (m, 3H), 4.4 – 4.3 (m, 2H), 4.2 – 4.2 (m,
2H), 2.1 (s, 3H).13C NMR (101 MHz, CDCl3) δ 171.0,
133.9 (t, J = 32.1 Hz), 130.8, 128.5, 125.6 (t, J = 3.7 Hz),
123.0, 62.7, 62.0 (t, J = 6.0 Hz), 21.0. 19F NMR (376 MHz,
4-(3-(difluoro(phenyl)methoxy)propyl)pyridine (18a). Purifiꢀ
cation by column chromatography on silica gel (Gradient eluꢀ
tion from 20:80 to 50/50 EtOAc/pentane), afforded the desired
product 18a as a colorless liquid (21 mg, 40% yield). 1H
NMR (400 MHz, CDCl3) δ 8.5 (d, J = 4.9 Hz, 2H), 7.7 –
7.6 (m, 2H), 7.5 – 7.4 (m, 3H), 7.1 (d, J = 6.1 Hz, 2H), 4.1
(t, J = 6.2 Hz, 2H), 2.8 (t, J = 7.7 Hz, 2H), 2.1 – 2.0 (m,
2H); 13C NMR (101 MHz, CDCl3) δ 150.5, 149.9, 134.3 (t,
J = 32.6 Hz), 130.7, 128.5, 125.5 (t, J = 3.7 Hz), 124.1,
62.9 (t, J = 5.9 Hz), 31.6, 29.9; HRMS (ESI): calcd for
C15H16F2NO+ [M+H+]: 264.1194, found 264.1197.
+
CDCl3) δ ꢀ69.4; HRMS (ESI): calcd for C11H12F2NaO3
[M+Na+]: 253.0647, found 253.0641.
ASSOCIATED CONTENT
Supporting Information
(The Supporting Information is available free of charge on the
ACS Publications website.
1Hꢀ,13Cꢀ, and 19FꢀNMR spectra for all compounds (PDF)
(((6-chlorohexyl)oxy)difluoromethyl)benzene (18b). Purificaꢀ
tion by column chromatography on silica gel (5:95
Et2O/pentane), afforded the desired product 18b as a colorless
liquid (13 mg, 38% yield). 1H NMR (400 MHz, CDCl3) δ
7.65 – 7.58 (m, 2H), 7.50 – 7.38 (m, 3H), 4.04 (t, J = 6.5
Hz, 2H), 3.55 (t, J = 6.7 Hz, 2H), 1.80 (p, J = 6.7 Hz, 2H),
1.73 (p, J = 6.6 Hz, 2H), 1.53 – 1.43 (m, 4H). 13C NMR
(101 MHz, CDCl3) δ 134.4 (t, J = 32.8 Hz), 130.4, 128.3,
125.4 (t, J = 3.7 Hz), 122.9, 63.7 (t, J = 5.9 Hz), 45.0, 32.5,
29.1, 26.5, 25.2. 19F NMR (376 MHz, CDCl3) δ ꢀ69.2.
HRMS (ESI): calcd for C13H17ClF2ONa+ [M+Na+]: 285.0828,
found 285.0819.
AUTHOR INFORMATION
Corresponding Authors
* Eꢀmail: chad.friesen@twu.ca.
ORCID
Josiah Newton: 0000ꢀ0003ꢀ1718ꢀ4750
Robert Britton: 0000ꢀ0002ꢀ9335ꢀ0047
Chadron M. Friesen: 0000ꢀ0001ꢀ9955ꢀ5695
Notes
((1H,1H,2H,2H-perfluoro-1-octyl)difluoromethyl)benzene
(18c). Purification by column chromatography on silica gel
(5:95 Et2O/pentane), afforded the desired product 18c as a
colorless liquid (60 mg, 64 % yield). 1H NMR (400 MHz,
CDCl3) δ 7.7 – 7.6 (m, 2H), 7.6 – 7.3 (m, 3H), 4.4 (t, J =
6.7 Hz, 2H), 2.6 (tt, J = 18.1, 6.6 Hz, 2H). 13C NMR (101
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
This work was supported by grants by the MJ Murdock Charitable
Trust and Natural Sciences and Engineering Research Council,
DiscoveryꢀGrant Program (RGPINꢀ2015ꢀ05513). R. B. acknowlꢀ
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Page 11 of 12
The Journal of Organic Chemistry
edges support from an NSERC Discovery Grant and a Michael
Smith Foundation for Health Research Career Scholar Award.
Effective Thiobenzoylation Reagent. Bull. Korean
Chem. Soc. 2002, 23 (7), 1029–1030.
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Katritzky, A. R.; Witek, R. M.; RodriguezꢀGarcia,
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