From Propargylic Alcohols to Substituted Thiochromenes: Gem-Disubstituent Effect in Intramolecular Alkyne Iodo/hydroarylation

Article abstract of DOI:10.1021/acs.joc.1c00333

This work describes the 6-endo-dig cyclization of S-aryl propargyl sulfides to afford 2H-thiochromenes. The substitution at the propargylic position plays a crucial role in allowing intramolecular silver-catalyzed alkyne hydroarylation and N-iodosuccinimide-promoted iodoarylation. Additionally, a PTSA-catalyzed thiolation reaction of propargylic alcohols was developed to synthesize the required tertiary S-aryl propargyl ethers. The applicability of merging these two methods is demonstrated by synthesizing the retinoic acid receptor antagonist AGN194310.

Full text of DOI:10.1021/acs.joc.1c00333

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Article
From Propargylic Alcohols to Substituted Thiochromenes: gem-
Disubstituent Effect in Intramolecular Alkyne Iodo/hydroarylation
́
Noelia Velasco, Anisley Suárez, Fernando Martínez-Lara, Manuel Angel Fernández-Rodríguez,
Roberto Sanz,* and Samuel Suárez-Pantiga*
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ABSTRACT: This work describes the 6-endo-dig cyclization of S-
aryl propargyl sulfides to afford 2H-thiochromenes. The sub-
stitution at the propargylic position plays a crucial role in allowing
intramolecular silver-catalyzed alkyne hydroarylation and N-
iodosuccinimide-promoted iodoarylation. Additionally, a PTSA-
catalyzed thiolation reaction of propargylic alcohols was developed
to synthesize the required tertiary S-aryl propargyl ethers. The
applicability of merging these two methods is demonstrated by
synthesizing the retinoic acid receptor antagonist AGN194310.
Scheme 1. Selected Methodologies for Synthesizing 2H-
Thiochromenes
INTRODUCTION
■
Propargyl N-aryl amines and O-aryl ethers are versatile and
precious building blocks.1 The intramolecular alkyne arylation2
of these building blocks provides straightforward access to
relevant heterocycles such as hydroquinolines and chro-
menes,3,4 without requiring a previous arene ortho function-
alization. By contrast, this strategy involving C−H bond
functionalization remains almost unexplored when applied to
the synthesis of 2H-thiocromenes from the related thioethers.5
Intramolecular alkyne hydroarylation of S-aryl propargyl
thioethers has been scarcely reported and limited to propargyl
Claisen rearrangement using terminal alkynes under harsh
reaction conditions (Scheme 1a).6 This rearrangement delivers
a reactive allene intermediate7 that evolves into the
thiochromene. Therefore, the synthesis of substituted 2H-
thiochromenes is commonly accomplished by using thiosali-
cylaldehydes and alkenes in the presence of an organocatalyst
(Scheme 1b).8
Alternative classical strategies that do not require ortho
prefunctionalization are based on multistep sequences to afford
a 4-thiochromanone intermediate.9 Subsequent alcohol for-
mation followed by elimination generates the 2H-thiochro-
mene. This strategy has been employed to synthesize retinoic
acid receptor (RAR) antagonist AGN194310 (Scheme 1c).10
Therefore, a more straightforward synthesis of thiochromenes
through alkyne arylation of S-aryl propargyl thioethers under
mild reaction conditions will be highly appealing.
desulfurative halogenation reactions.11 Additionally, in a
seminal contribution of the activation of propargyl thioethers
Received: February 10, 2021
The lack of electrophilic alkyne arylation methodologies of
S-aryl propargyl thioethers is particularly surprising. A possible
explanation could be that the sulfur atom favors competitive
reaction pathways other than alkyne arylation. For instance, S-
phenyl alkyl thioethers react with halonium ions enabling
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by π-acids,12 Wang has reported a thiirenium ion formation
after alkyne activation (Scheme 2a). Then, this intermediate
these types of compounds bearing a quaternary center at the
propargylic position have been reported. Despite the advances
achieved in the thiolation of propargyl alcohols,5,15 mainly
secondary propargylic alcohols have been used. Although an
acid catalyst can easily activate tertiary alcohols, the
propargylic substitution reaction is more challenging. The
generated tertiary propargyl cation intermediate, which could
be more adequately represented as an allenium ion, evolves
rapidly in different alternative reaction pathways from
propargylic substitution, such as competitive elimination or
SN′ reactions forming allenes.16 Moreover, thiols could react
with propargylic alcohols through other different reactivity
patterns that do not implicate a carbocation at the propargylic
position, like hydrothiolation of alkynes.17 Whereas thiolation
of tertiary propargyl alcohols was efficiently accomplished
using alkyl thiols,15a,c,f with less nucleophilic thiophenols the
reaction takes place with low yields.12 Remarkably, in two
recent reports, few examples of S-aryl propargyl thioethers
were efficiently synthesized from tertiary propargyl alcohols
and an excess of thiophenol (2−3 equiv) by using catalytic
amounts of a bimetallic Ir−Sn complex18 or a lithium
triflimidate salt.19 To this end, and on the basis of our
previous experience in the direct nucleophilic substitutions of
propargylic alcohols,15c,16,20 we evaluated the propargylation of
thiophenols employing p-toluenesulfonic acid monohydrate (1,
PTSA) as a promising, cheap, and easily accessible catalyst.
After some optimization,21 this simple Brønsted acid proved to
be an efficient catalyst for accomplishing thiolation of a variety
of tertiary propargylic alcohols 3 with different thiols 2
(Scheme 3). When dimethyl-substituted propargylic alcohol 3a
was tested, under standard conditions using 5 mol % 1 in
nitromethane, the desired S-aryl propargyl thioether 4aa was
obtained in high yields.
Scheme 2. Alternative Reactivity of Propargyl Sulfides with
π-Acid Metal Catalysts
evolves through 1,2 migration of the thio group to generate
highly reactive metal−carbene species.13 Considering these
reports, we hypothesized that tertiary propargyl sulfides,
because of the gem-dimethyl effect,14 could react with an
adequate alkynophilic reagent affording 2H-thiochromenes by
favoring electrophilic alkyne arylation over other competitive
pathways. Herein, we report the synthesis of 2H-thiochro-
menes through iodocyclization or hydroarylation of S-aryl
propargyl thioethers (Scheme 2b).
RESULTS AND DISCUSSION
■
Synthesis of Tertiary S-Aryl Propargyl Thioethers. To
tackle our proposed idea, we need to start from tertiary S-aryl
propargyl thioethers. However, few examples for synthesizing
Scheme 3. Synthesis of Propargyl Thioethers 4 from Thiols 2 and Tertiary Propargyl Alcohols 3
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The reaction seemed to be quite general with various
thioarenes bearing different electron-donating, neutral, and
moderate electron-withdrawing substituents at the para
position (4ab−ae, 4jc, 4jk, and 4kd), although a slightly
lower yield was observed with a methoxy substituent (4ab).
Functional groups at the ortho (4af, 4ag, and 4kl) or meta
(4ah) position were well tolerated. Interestingly, thionaphthols
(4ai and 4aj) also underwent the PTSA-catalyzed thiolation
reaction. Next, we studied different alcohols. Modifications
over a methyl group at the propargylic position revealed that
phenyl (4ba) and vicinal (4ca) methoxy groups were
compatible with the nucleophilic substitution reaction. Diaryl-
and dicyclopropyl-substituted tertiary alcohols proved to be
more challenging, though the desired propargyl thioethers 4da
and 4ea were accessible. Other alcohols bearing one
cyclopropyl substituent at the propargylic position also reacted
with thiols, providing the desired products (4fa and 4ga).
Propargylic alcohols 3 derived from cyclohexanone performed
well, affording the corresponding thioethers in high yields (4ha
and 4ia). Substrates bearing methoxy groups in the arene
moiety R3 were suitable substrates for the thiolation reaction
with different thioarenes (4ja, 4jc, 4jk, 4ka, 4kd, and 4kl).
Curiously, a methoxy group at the meta position of the arene
attached to the alkyne (4ka) provides higher yields than the
related substrate bearing a methoxy group at the para position
(4aj). Presumably, this moderate difference might be caused
by a stronger stabilization of the carbocation intermediate that
slows the nucleophilic attack and allows competitive reaction
pathways.22 The method was also productive with tertiary
alcohols bearing an alkyl group as the alkyne substituent (4la)
as well as with alkyl thiols (4bm and 4fn). In addition, to
demonstrate the practicability of the method, the reaction was
scaled up, affording gram amounts of 4aa (3.78 g, 71% yield)
and 4ad (5.21 g, 79% yield).
Synthesis of 2H-Thiochromenes. Once we established
an efficient and easily scalable methodology for synthesizing S-
aryl propargyl thioethers, we investigated an intramolecular
arylation procedure to obtain the desired 2H-thiochromenes.
We nonetheless have foreseen that a combination of a suitable
electrophilic agent with adequate S-aryl propargyl thioethers
will be decisive in achieving the alkyne arylation. As we have
already postulated, the Thorpe−Ingold effect could favor the
6-endo-dig cyclization.
To test our hypothesis, we initially focused on electrophilic
iodonium reagents based on our previous experience in
iodocarbocyclizations.23 Dimethyl-substituted propargylic thi-
oether 4aa, the analogous propargyl unsubstituted compound
5, and secondary propargyl sulfide 6 were evaluated with N-
iodosuccinimide (NIS) (Scheme 4). Whereas the reaction of
4aa with NIS gave rise to the desired 3-iodothiochromene 7aa,
primary and secondary propargyl thioethers 5 and 6 afforded
only disulfide and multiple byproducts, possibly derived from
sulfur−halogen substitution;11 the thiochromenes were not
observed. This differentiated reactivity of 4aa suggests a crucial
gem-dimethyl effect.
Once we demonstrated the feasibility of the process, we
continued with the optimization (Table 1). An increase in
Table 1. Optimization of the Reaction Conditions for the
a
Iodocarbocyclization Reaction of 4aa
b
entry
I+ source
equiv
solvent
additive
yield (%)
1
2
NIS
NIS
NIS
NIS
NIS
I2
1.1
1.3
1.1
1.3
1.3
1.3
1.3
1.3
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
−
−
51
76 (74)
c
d
3
BF3·Et2O
BF3·Et2O
AcOH
−
Na2CO3
K2CO3
56
60
50
−
32
35
e
4
e
5
6
e
7
e
I2
I2
8
a
Reaction conditions: 4aa (0.1 mmol) and NIS (0.13 mmol) in
b
CH2Cl2 (1 mL). Determined by 1H NMR using CH2Br2 as the
c
internal standard. Yield after column chromatography in parentheses.
d
e
With 0.11 mmol of additive. With 0.13 mmol of additive.
reaction time and a slight excess of NIS provide 3-
iodothiochromene 7aa in higher yields (entries 1 and 2).
Lewis or Brønsted acid additives (entries 3−5) do not
positively impact the reaction. Other possible iodonium
sources, such as molecular iodine in the absence (entry 6) or
presence of carbonates (entries 7 and 8), were less efficient.
When NBS and NCS replaced NIS, no desired thiochromenes
were obtained. Instead, the corresponding disulfide and
multiple byproducts possibly derived from sulfur−halogen
substitution11 and elimination reactions were obtained.
Next, a selection of S-aryl propargyl thioethers 4 was
subjected to the optimized reaction conditions (Table 1, entry
2), affording various 3-iodothiochromenes 7 (Scheme 5).
Electron-donating and neutral groups (7aa, 7ab, and 7ae) at
the para position of the thioaryl moiety (R4) gave rise to the
corresponding 3-iodothiochromenes in high yields. Moderate
electron-withdrawing groups such as halogens at the para
(7ac−ad and 7kd) and ortho (7kl) position are also well-
tolerated. Interestingly, iodoarylation of 4aj takes place
selectively in the most activated position of the 2-thionaphthol
moiety. Additionally, thioether 4ai also provided access to a
tricyclic scaffold (7ai). Modification over the propargylic
position was also accomplished, affording spirocyclic com-
pound 7ia. Alkynes bearing methoxy-functionalized arenes in
R3 also delivered the desired thiochromenes in variable yields
(7ka, 7kd, and 7kl).
Scheme 4. Preliminary Studies of Intramolecular
Iodoarylation of S-Aryl Propargyl Thioethers
Once we studied the electrophilic iodoarylation of thioethers
4, we envisioned that metal π-acid catalysts might behave like
iodonium reagents allowing the alkyne hydroarylation reaction
(Table 2).21 Considering the extraordinary ability of gold(I)
complexes to activate alkynes,2b,24 we decided to start our
study by employing these types of catalysts. Initial assays with
IPrAuNTf2 complexes were unfruitful (entry 1). Gratifyingly,
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(entries 7 and 8). Next, we studied the nature of the silver
catalyst (entries 9−11). Silver salts bearing a less coordinating
counteranion gave rise to 8aa in poor yields (entries 9 and 10),
possibly due to their lower stability, which results in the
formation of a silver mirror. Finally, Brønsted acids were also
checked as suitable catalysts. Triflic acid proved to be effective,
although lower yields were achieved, presumably due to the
degradation of 4aa into a diverse variety of unidentified
byproducts (entries 12−14).
Scheme 5. Synthesis of Iodothiochromene Derivatives 7
from Propargyl Thioethers 4
With optimized reaction conditions in hand, we decided to
evaluate the reactivity of a selection of tertiary propargyl
thioethers 4 (Scheme 6). The hydroarylation was efficiently
Scheme 6. Synthesis of Thiochromene Derivatives 8
a
through Hydroarylation of Propargyl Thioethers 4
Table 2. Optimization of the Reaction Conditions for the
a
Hydroarylation Reaction of 4aa
b
entry
catalyst
mol %
temp
t (h)
yield (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
IPrAuNTf2
IPrAuCl/AgOTf
AgOTf
AgOTf
AgOTf
5
5
5
5
5
5
5
5
5
5
5
5
1
0.5
reflux
reflux
reflux
reflux
rt
24
5
1
−
80
79
c
5
86 (83)
a
The reaction was performed at 110 °C under microwave irradiation.
24
24
5
5
5
5
5
5
5
−
65
45
28
8
5<
21
40
36
19
AgOTf
60
Bi(OTf)3
Sc(OTf)3
AgSbF6
AgBF4
AgNTf2
TfOH
reflux
reflux
reflux
reflux
reflux
reflux
reflux
reflux
achieved when the thioaryl moiety bears electron-donating or
neutral groups (8aa, 8ab, 8ae, 8ah, 8ah′, 8ha, 8ja, and 8jk),
whereas substrates bearing moderate electron-withdrawing
groups (4ac and 4ad) were not productive, affording
inseparable mixtures of various compounds. The deactivation
of the arene makes other alternative reaction pathways
competitive. As expected, substitution at the meta position of
the thioaryl fragment afforded a mixture of the two different
possible regioisomeric thiochromenes 8ah and 8ah′ (∼2:1)
derived from the 6-endo cyclization. Analogous behavior was
observed utilizing propargyl thioether 4aj obtained from 2-
thionaphthol. In this case, linear 8aj and angular 8aj′
thiochromenes were obtained in a 1.2:1 mixture. Propargyl
sulfide 4ai derived from 1-thionaphthol gave rise to the
complementary angular 2H-thiochromene 8ai. Activated
alkynes bearing methoxy-functionalized arene substituents
also underwent hydroarylation (8ha, 8ja, and 8jk). Similar to
iodocarbocyclization, a spiro[cyclohexane-1,2′-thiochromene]
(8ha) could also be accessed.
d
d
d
TfOH
TfOH
d
14
24
a
b
c
Reaction conditions: 4aa (0.1 mmol) in 1,2-dichloroethane (1 mL).
Determined by 1H NMR using CH2Br2 as an internal standard.
d
Yield after column chromatography in parentheses. No full
conversion of 4aa was achieved.
cationic gold complexes generated in situ using silver triflate as
a halide scavenger could promote the cyclization generating
the desired thiochromene 8aa (entry 2). However, control
experiments with the silver salt revealed that AgOTf is indeed
the catalyst (entries 3−6).25 Other metal triflates also afforded
the desired thiochromene 8aa, although in lower proportions
D
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a
Scheme 7. Synthesis of pan-RAR Antagonist AGN194310 16
a
Reaction conditions: (a) 1 mol % PdCl2(PPh3)2, 1 mol % CuI, DIPA, 60 °C; (b) 5 mol % PTSA/MeNO2, rt; (c) ethyl 4-ethynylbenzoate 13, 5
mol % PdCl2(MeCN)2, 10 mol % PtBu3, 5 mol % CuI, Et3N, reflux; (d) 10 mol % AgOTf, 128 °C, MW (150 W), 25 min/1,2-DCE; (e) NaOH,
2:1 THF/Et2O, rt.
Synthesis of AGN194310. To further demonstrate the
potential of our methodology, we decided to implement the
developed process to synthesize relevant biologically active
compounds. Pan-RAR antagonist AGN194310 is a thiochro-
mene derivative that possesses significant activity in RAR
signaling10,26 and anticancer activity.27 This compound has
been synthesized in 11 steps with an overall yield of 3.5%,
involving a critical 4-thiochromenone intermediate.10 In this
context, we envisaged that the combination of PTSA-catalyzed
thiolation of tertiary propargylic alcohols followed by alkyne
hydroarylation could significantly shorten the previously
established synthetic route (Scheme 7).
The strategy features cheap and readily available starting
materials. At the outset, the Sonogashira cross-coupling
between commercially available 2-methyl-3-butyn-2-ol 9 and
1-bromo-4-ethylbenzene 10 led quantitatively to 11. PTSA-
catalyzed thiolation gave rise to the corresponding tertiary S-
aryl propargyl thioether 12 in high yield. Not surprisingly, the
alkyne hydroarylation reaction to access the thiochromene core
was inefficient with this substrate, likely due to the
incompatibility between the bromo-substituted S-aryl prop-
argyl thioethers and the silver catalyst used in the process.
Another Sonogashira coupling occurred before the final
cyclization to circumvent this issue, furnishing an alternative
propargyl sulfide 14 bearing two differentiated alkynes. After
careful tuning of the reaction conditions, using microwave
irradiation and AgOTf (10 mol %) as a catalyst, selective
activation of the propargyl alkyne occurs to generate the
thiochromene core. Finally, using a well-established method-
ology for the ester’s deprotection allowed us to obtain
AGN194310. This synthetic sequence affords the pan-RAR
antagonist in only five steps in a 22% overall yield.
EXPERIMENTAL SECTION
■
General Methods. All reactions involving air-sensitive com-
pounds were carried out under a N2 atmosphere (99.99%). All
glassware was oven-dried (120 °C), evacuated, and purged with
nitrogen. Temperatures were reported as bath temperatures. All
common reagents and solvents were obtained from commercial
suppliers and used without further purification. Non-commercially
available propargyl alcohols were prepared following previously
described procedures: addition of alkynyl organometallic to a
carbonyl16c,28 and/or Sonogashira cross-coupling reaction.29 Solvents
were dried following standard methods. Hexane and ethyl acetate
were purchased as extra pure grade reagents and used as received.
TLC was performed on alumina-backed plates coated with silica gel
60 with the F254 indicator; the chromatograms were visualized by UV
light (254 nm) and/or by staining with a Ce/Mo reagent,
anisaldehyde, or phosphomolybdic acid solution and subsequent
heating. Rf values refer to silica gel. Flash column chromatography was
carried out on silica gel 60, 230−400 mesh. 1H and 13C NMR spectra
were recorded on a Varian Mercury-Plus (300 MHz for 1H, 75.4 MHz
for 13C) or Bruker Avance (300 MHz for H, 75.4 MHz for 13C, 282
1
MHz for 19F) spectrometer at room temperature. NMR splitting
pattern abbreviations are as follows: s, singlet; br s, broad singlet; d,
doublet; dd, doublet of doublets; dt, doublet of triplets; ddd, doublet
of doublet of doublets; t, triplet; td, triplet of doublets; q, quartet;
quint, quintet; sext, sextet; m, multiplet. Chemical shifts are reported
in parts per million using the residual solvent peak as a reference
1
1
(CDCl3, H δ 7.26 and 13C δ 77.16; DMSO-d6, H δ 2.50 and 13C δ
39.50; acetone-d6, 1H δ 2.05 and 13C δ 206.26, 29.84), and the
multiplicities of 13C signals were determined by DEPT experiments.
GC-MS spectra were recorded on an Agilent 6890N/5973
Network GC System, equipped with an HP-5MS column or a
Thermo 1300GC instrument equipped with an MS 7000ISQ
STDNOVPI MS detector, using Chromeleon software. Low-
resolution electron impact mass spectra (EI-LRMS) were obtained
at 70 eV on a mass spectrometer, and only the molecular ions and/or
base peaks, as well as significant peaks in MS, are given. High-
resolution mass spectrometry (HRMS) was carried out on a 6545 Q-
TOF (Agilent) mass spectrometer (ESI or APCI as ion source) as
specified.
CONCLUSIONS
■
In summary, herein, we have described the first electrophilic
iodo- and hydroarylation of S-aryl propargyl thioethers to
synthesize densely substituted 2H-thiochromenes by using NIS
and a silver salt as the electrophilic reagent and catalyst,
respectively. The applicability of this method was demon-
strated by the synthesis of the highly selective retinoic acid
receptor antagonist AGN194310. Upon application of this
strategy, the synthesis was considerably shortened from 11 to 5
steps. The gem-disubstituent effect plays a crucial role in
favoring 6-endo-dig iodo and hydroarylation reactions. The
absence of substituents at the propargylic position makes other
alternative reaction pathways competitive. Additionally, we
have developed a reliable, easily scalable methodology for
synthesizing the required S-aryl propargyl thioethers bearing a
quaternary center at the propargylic position by employing
PTSA as a cheap and readily available catalyst.
Reactions were carried out in common Pyrex round-bottom flasks,
and those performed under microwave irradiation in 10 mL
microwave vials crimped on top with 20 mm Sil/PTFE septa.
When needed, pH values were determined using pH indicator strips
(pH 0−14 Universal indicator paper, Merck MColorpHaspt).
Microwave irradiation was realized with a CEM Discover S-Class
Reactor with a single-mode microwave cavity producing continuous
irradiation. Temperature measurements were conducted using an IR
sensor located below the microwave cavity floor, and reaction times
refer to the total hold time at the indicated temperature. The
maximum wattage supplied was 220 W.
General Procedure A for the Synthesis of Propargyl
Sulfides 4 from Alcohols 3. Thiol 2 (1.3 equiv, 0.56 mmol) and
p-toluenesulfonic acid (4 mg, 0.02 equiv, 5 mol %) were sequentially
added to a solution of the corresponding propargyl alcohol 3 (1 equiv,
0.4 mmol) in MeNO2 (0.8 mL, 0.5 M). The mixture was allowed to
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stir at rt for 30 min, until full depletion of the alcohol was determined
by TLC (spots were visualized using Ce/Mo reagent and heat as the
staining agent). Then, the reaction was quenched by the addition of
aqueous NaOH (0.5 M, 10 mL) and CH2Cl2 (2 mL). The separated
aqueous phase was extracted with CH2Cl2 (3 × 10 mL). The
combined organic layers were dried over anhydrous Na2SO4, filtered,
and concentrated under reduced pressure. The residue was purified by
column chromatography on silica gel (eluent, hexane/EtOAc
mixture), affording the corresponding propargyl sulfides 4.
previously described data.19 LRMS (EI) m/z (%): 143 (100), 128
(64), 115 (31), 65 (28), 252 (M+, 3).
(2-Bromophenyl) (2-Methyl-4-phenylbut-3-yn-2-yl) Sulfide (4af).
Compound 4af was prepared according to general procedure A
(reaction time, 2 h). The crude product was purified by flash column
chromatography on silica gel (hexane), affording pure 4af (82% yield,
1
110 mg). Yellow liquid. Rf = 0.2 (hexane). H NMR (300 MHz,
CDCl3): δ 8.02 (dd, J = 7.72, 1.69 Hz, 1H), 7.72 (dd, J = 7.93, 1.35
Hz, 1H), 7.44−7.40 (m, 2H), 7.37−7.32 (m, 4H), 7.23 (td, J = 7.86,
1.70 Hz, 1H), 1.77 (s, 6H). 13C{1H} NMR (75.4 MHz, CDCl3): δ
137.9 (CH), 134.6 (C), 133.4 (CH), 131.7 (2 × CH), 131.0 (C),
130.1 (CH), 128.4 (2 × CH), δ 128.3 (CH), 127.5 (CH), 123.3 (C),
93.6 (C), 83.9 (C), 44.3 (C), 30.8 (2 × CH3). LRMS (EI) m/z (%):
143 (100), 128 (30), 251 (13), 108 (12), 330 (M+, 10). HRMS (ESI
+) m/z: [M + H]+ calcd for C17H16BrS, 331.0151; found, 331.0149.
(2-Chlorophenyl) (2-Methyl-4-phenylbut-3-yn-2-yl) Sulfide
(4ag). Compound 4ag was prepared according to general procedure
A (reaction time, 2 h). The crude product was purified by flash
column chromatography on silica gel (hexane), affording pure 4ag
(2-Methyl-4-phenylbut-3-yn-2-yl) (p-Tolyl) Sulfide (4aa). Com-
pound 4aa was prepared according to general procedure A (reaction
time, 30 min). The crude product was purified by flash column
chromatography on silica gel (hexane), affording pure 4aa (81% yield,
1
87 mg). Pale yellow liquid. Rf = 0.22 (hexane). H NMR (300 MHz,
CDCl3, 25 °C): δ 7.69−7.66 (m, 2H), 7.46−7.42 (m, 2H), 7.38−7.33
(m, 3H), 7.25−7.22 (m, 2H), 2.44 (s, 3H), 1.71 (s, 6H). 13C{1H}
NMR (75.4 MHz, CDCl3): δ 139.3 (C), 137.1 (2 × CH), 131.6 (2 ×
CH), 129.4 (2 × CH), 129.0 (C), 128.2 (2 × CH), 128.0 (CH),
123.4 (C), 94.2 (C), 83.2 (C), 42.5 (C), 30.4 (2 × CH3), 21.4
(CH3). LRMS (EI) m/z (%): 143 (100), 128 (36), 233 (14), 251
(12), 266 (M+, 10). HRMS (ESI+) m/z: [M + H]+ calcd for C18H19S,
267.1202; found, 267.1205.
1
(75% yield, 86 mg). Yellow oil. Rf = 0.23 (hexane). H NMR (300
MHz, CDCl3): δ 8.03−8.01 (m, 1H), 7.57−7.54 (m, 1H), 7.46−7.43
(m, 2H), 7.37−7.34 (m, 5H), 1.79 (s, 6H). 13C{1H} NMR (75.4
MHz, CDCl3): δ 139.8 (C),138.4 (CH), 132.1 (C), 131.5 (2 × CH),
130.1 (CH), 129.9 (CH), 128.2 (2 × CH), 128.1 (CH), 126.7 (CH),
123.1 (C), 93.5 (C), 83.7 (C), 44.1 (C), 30.7 (2 × CH3). LRMS (EI)
m/z (%): 143 (100), 128 (40), 77 (13), 127 (12), 286 (M+, 3).
HRMS (ESI+) m/z: [M + H]+ calcd for C17H16ClS, 287.0656; found,
287.0652.
(3-Methoxyphenyl) (2-Methyl-4-phenylbut-3-yn-2-yl) Sulfide
(4ah). Compound 4ah was prepared according to general procedure
A (reaction time, 2 h). The crude product was purified by flash
column chromatography on silica gel (20:1 hexane/EtOAc), affording
pure 4ah (68% yield, 73 mg). Yellow oil. Rf = 0.35 (20:1 hexane/
EtOAc). 1H NMR (300 MHz, CDCl3): δ 7.48−7.45 (m, 2H), 7.42−
7.41 (m, 1H), 7.39−7.34 (m, 5H), 7.04−7.00 (m, 1H), 3.77 (s, 3H),
1.76 (s, 6H). 13C{1H} NMR (75.4 MHz, CDCl3): δ 159.3 (C), 133.6
(C), 131.5 (2 × CH), 129.2 (CH), 128.9 (CH), 128.2 (2 × CH),
128.0 (CH), 123.2 (C), 121.5 (CH), 115.3 (CH), 94.1 (C), 83.3 (C),
55.1 (CH3), 42.5 (C), 30.5 (2 × CH3). 139 LRMS (EI) m/z (%): 143
(100), 138 (33), 267 (22), 282 (M+, 15). HRMS (ESI+) m/z: [M +
H]+ calcd for C18H19OS, 283.1151; found, 283.1155.
(4-Methoxyphenyl) (2-Methyl-4-phenylbut-3-yn-2-yl) Sulfide
(4ab). Compound 4ab was prepared according to general procedure
A (reaction time, 30 min). The crude product was purified by flash
column chromatography on silica gel (50:1 hexane/EtOAc), affording
pure 4ab (58% yield, 65 mg). Pale yellow oil. Rf = 0.12 (50:1 hexane/
EtOAc). 1H NMR (300 MHz, CDCl3): δ 7.68−7.62 (m, 2H), 7.42−
7.36 (m, 2H), 7.34−7.30 (m, 3H), 6.95−6.90 (m, 2H), 3.85 (s, 3H),
1.65 (s, 6H). 13C{1H} NMR (75.4 MHz, CDCl3): δ 160.8 (C), 138.8
(2 × CH), 131.6 (2 × CH), 128.3 (2 × CH), 128.0 (CH), 123.4 (C),
114.1 (2 × CH), 94.2 (C), 83.3 (C), 55.4 (CH3), 42.7 (C), 30.3 (2 ×
CH3), one C peak missed due to overlapping. LRMS (EI) m/z (%):
128 (100), 175 (67), 115 (50), 77 (50), 282 (M+, 27). HRMS (ESI+)
m/z: [M + H]+ calcd for C18H19OS, 283.1151; found, 283.1156.
(4-Chlorophenyl) (2-Methyl-4-phenylbut-3-yn-2-yl) Sulfide (4ac).
Compound 4ac was prepared according to general procedure A
(reaction time, 2 h). The crude product was purified by flash column
chromatography on silica gel (hexane), affording pure 4ac (81% yield,
1
90 mg). Pale yellow solid. Mp: 49−51 °C. Rf = 0.24 (hexane). H
NMR (300 MHz, CDCl3): δ 7.72−7.71 (m, 1H), 7.69−7.68 (m, 1H),
7.44−7.39 (m, 3H), 7.37−7.34 (m, 4H), 1.71 (s, 6H). 13C{1H} NMR
(75.4 MHz, CDCl3): δ 138.2 (2 × CH), 135.6 (C), 131.5 (2 × CH),
131.1 (C), 128.7 (2 × CH), 128.3 (2 × CH), 128.1 (CH), 123.1 (C),
93.7 (C), 83.6 (C), 42.9 (C), 30.4 (2 × CH3). LRMS (EI) m/z (%):
143 (100), 128 (32), 286 (M+, 5). HRMS (ESI+) m/z: [M + H]+
calcd for C17H16ClS, 287.0656; found, 287.0651.
(2-Methyl-4-phenylbut-3-yn-2-yl) (Naphthalen-1-yl) Sulfide
(4ai). Compound 4ai was prepared according to general procedure
A (reaction time, 2 h). The crude product was purified by flash
column chromatography on silica gel (hexane), affording pure 4ai
1
(83% yield, 102 mg). Orange oil. Rf = 0.22 (hexane). H NMR (300
MHz, CDCl3): δ 8.96−8.93 (m, 1H), 8.18−8.10 (m, 1H), 8.02−7.94
(m, 2H), 7.65−7.54 (m, 3H), 7.34−7.30 (m, 3H), 7.26−7.23 (m,
2H), 1.80 (s, 6H). 13C{1H} NMR (75.4 MHz, CDCl3): δ 137.1
(CH), 136.4 (C), 134.0 (C), 131.3 (CH), 130.2 (CH), 130.1 (C),
128.1 (CH), 127.9 (CH), 127.7 (CH), 127.1 (CH), 126.4 (CH),
125.9 (CH), 125.1 (CH), 123.0 (C), 94.0 (C), 83.5 (C), 43.7 (C),
30.8 (2 × CH3). LRMS (EI) m/z (%): 143 (100), 115 (50), 302 (M+,
35). HRMS (ESI+) m/z: [M + H]+ calcd for C21H19S, 303.1202;
found, 303.1201.
(4-Bromophenyl) (2-Methyl-4-phenylbut-3-yn-2-yl) Sulfide
(4ad). Compound 4ad was prepared according to general procedure
A (reaction time, 2 h). The crude product was purified by flash
column chromatography on silica gel (hexane), affording pure 4ad
1
(79% yield, 102 mg). White oil. Rf = 0.5 (hexane). H NMR (300
MHz, CDCl3): δ 7.63−7.58 (m, 2H), 7.55−7.50 (m, 2H), 7.41−7.33
(m, 5H), 1.68 (s, 6H). 13C{1H} NMR (75.4 MHz, CDCl3): δ 138.4
(2 × CH).131.8 (C), 131.8 (2 × CH), 131.6 (2 × CH), 128.4 (2 ×
CH), 128.2 (CH), 124.0 (C), 123.1 (C), 93.7 (C), 83.7 (C), 42.9
(C), 30.5 (2 × CH3). LRMS (EI) m/z (%): 143 (100), 128 (38), 108
(15), 330 (M+, 5). HRMS (ESI+) m/z: [M + H]+ calcd for
C17H16BrS, 331.0151; found, 331.0149.
(2-Methyl-4-phenylbut-3-yn-2-yl) (Naphthalen-2-yl) Sulfide
(4aj). Compound 4aj was prepared according to general procedure
A (reaction time, 2 h). The crude product was purified by flash
column chromatography on silica gel (hexane), affording pure 4aj
(71% yield, 88 mg). Colorless solid. Mp: 62−64 °C. Rf = 0.16
(2-Methyl-4-phenylbut-3-yn-2-yl) (Phenyl) Sulfide (4ae). Com-
pound 4ae was prepared according to general procedure A (reaction
time, 30 min). The crude product was purified by flash column
chromatography on silica gel (hexane), affording pure 4ae (70% yield,
1
(hexane). H NMR (300 MHz, CDCl3): δ 8.40 (s, 1H), 7.97−7.92
(m, 4H), 7.63−7.60 (m, 2H), 7.52−7.48 (m, 2H), 7.41−7.38 (m,
3H), 1.85 (s, 6H). 13C{1H} NMR (75.4 MHz, CDCl3): δ 136.8
(CH), 133.6 (CH), 133.4 (C), 133.4 (C), 131.5 (2 × CH), 131.0
(C), 128.2 (2 × CH), 128.0 (CH), 128.0 (CH), 127.9 (CH), 127.7
(CH), 126.8 (CH), 126.3 (CH), 123.2 (C), 94.1 (C), 83.6 (C), 42.9
(C), 30.6 (2 × CH3). LRMS (EI) m/z (%): 143 (100), 115 (43), 128
(40), 302 (M+, 37). HRMS (ESI+) m/z: [M + H]+ calcd for C21H19S,
303.1202; found, 303.1203.
1
71 mg). Pale yellow liquid. Rf = 0.23 (hexane). H NMR (300 MHz,
CDCl3): δ 7.71−7.75 (m, 2H), 7.35−7.43 (m, 6H), 7.28−7.33 (m,
2H), 1.67 (s, 6H). 13C{1H} NMR (75.4 MHz, CDCl3, 25 °C): δ
137.1 (2 × CH), 132.6 (C), 131.6 (2 × CH), 129.2 (CH), 128.6 (2 ×
CH), 128.3 (2 × CH), 128.1 (CH), 123.4 (C), 94.1 (C), 83.4 (C),
42.7 (C), 30.6 (2 × CH3). NMR data are in full agreement with
F
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(2,4-Diphenylbut-3-yn-2-yl) (p-Tolyl) Sulfide (4ba). Compound
4ba was prepared according to general procedure A (reaction time, 30
min). The crude product was purified by flash column chromatog-
raphy on silica gel (hexane), affording pure 4ba (90% yield, 120 mg).
procedure A (reaction time, 2 h). The crude product was purified by
flash column chromatography on silica gel (20:1 hexane/EtOAc),
affording pure 4ga (65% yield, 84 mg). Colorless oil. Rf = 0.37 (20:1
hexane/EtOAc). 1H NMR (300 MHz, CDCl3): δ 7.65−7.61 (m, 2H),
7.33−7.28 (m, 2H), 7.17−7.16 (m, 2H), 6.88−6.82 (m, 2H), 3.83 (s,
3H), 2.4 (s, 3H), 1.66 (s, 3H), 1.24−1.15 (m, 1H), 0.63−0.46 (m,
4H). 13C{1H} NMR (75.4 MHz, CDCl3): δ 159.5 (C), 139.2 (C),
137.4 (2 × CH), 133 (2 × CH), 129.2 (2 × CH), 128.6 (C), 115.4
(C), 113.9 (2 × CH), 87.9 (C), 85.1 (C), 55.4 (CH3), 49.6 (C), 29.4
(CH3), 21.4 (CH3), 21.1 (CH), 3.6 (CH2), 2.5 (CH2). LRMS (EI)
m/z (%): 91 (100), 231 (76), 199 (64), 115 (61), 322 (M+, 20).
HRMS (ESI+) m/z: [M + H]+ calcd for C21H23OS, 323.1464; found,
323.1466.
1
Colorless oil. Rf = 0.17 (hexane). H NMR (300 MHz, CDCl3, 25
°C): δ 7.68−7.64 (m, 2H), 7.44−7.42 (m, 2H), 7.35−7.29 (m, 8H),
7.08−7.05 (m, 2H), 2.34 (s, 3H), 2.02 (s, 3H). 13C{1H} NMR (75.4
MHz, CDCl3): δ 142.6 (C), 139.4 (C), 136.9 (2 × CH), 131.5 (2 ×
CH), 129. (C), 129.0 (2 × CH), 128.2 (2 × CH), 128.1 (CH), 128.0
(2 × CH), 127.3 (CH), 126.8 (2 × CH), 123.2 (C), 91.9 (C), 86.8
(C), 50.2 (CH), 29.9 (CH3), 21.3 (CH3). LRMS (EI) m/z (%): 205
(100), 127 (18), 328 (M+, 14). HRMS (ESI+) m/z: [M + H]+ calcd
for C23H21S, 329.1358; found, 329.1361.
(1-Methoxy-2,4-diphenylbut-3-yn-2-yl) (p-Tolyl) Sulfide (4ca).
Compound 4ac was prepared according to general procedure A
(reaction time, 30 min). The crude product was purified by flash
column chromatography on silica gel (50:1 hexane/EtOAc), affording
pure 4ac (65% yield, 92 mg). Orange oil. Rf = 0.23 (50:1 hexane/
EtOAc). 1H NMR (300 MHz, CDCl3): δ 7.77−7.74 (m, 2H), 7.47−
7.44 (m, 2H), 7.41−7.40 (m, 1H), 7.39−7.31 (m, 7H), 7.09 (d, J =
7.8 Hz, 2H), 4.09 (d, J = 9.7 Hz, 1H), 3.91 (d, J = 9.7 Hz, 1H), 3.45
(s, 3H), 2.36 (s, 3H). 13C{1H} NMR (75.4 MHz, CDCl3): δ 139.6
(C), 139.4 (C), 137.3 (2 × CH), 131.8 (2 × CH), 129.3 (2 × CH),
128.4 (2 × CH), 128.3 (2 × CH), 128.3 (2 × CH), 128.1 (C), 127.8
(2 × CH), 123.2 (C), 89.4 (C), 88.5 (C), 79.0 (CH2), 59.9 (CH3),
55.1 (C), 21.4 (CH3). LRMS (EI) m/z (%): 207 (100), 221 (49),
299 (38), 281 (33), 358 (M+, 5). HRMS (ESI+) m/z: [M + H]+ calcd
for C24H23OS, 359.1464; found, 359.1466.
{1-[(4-Methoxyphenyl)ethynyl]cyclohexyl} (p-Tolyl) Sulfide (4ha).
Compound 4ha was prepared according to general procedure A
(reaction time, 2 h). The crude product was purified by flash column
chromatography on silica gel (10:1 hexane/EtOAc), affording pure
4ha (84% yield, 113 mg). Pale yellow liquid. Rf = 0.39 (10:1 hexane/
EtOAc). 1H NMR (300 MHz, CDCl3): δ 7.66−7.62 (m, 2H), 7.39−
7.34 (m, 2H), 7.21−7.19 (m, 2H), 6.90−6.85 (m, 2H), 3.84 (s, 3H),
2.41 (s, 3H), 2.09−2.04 (m, 2H), 1.78−1.65 (m, 7H), 1.36−1.31 (m,
1H). 13C{1H} NMR (75.4 MHz, CDCl3): δ 159.4 (C), 139.2 (C),
137.3 (2 × CH), 133.0 (2 × CH), 129.3 (2 × CH), 128.2 (C), 115.8
(C), 113.9 (2 × CH), 91.0 (C), 85.3 (C), 55.4 (CH3), 48.3 (C), 38.8
(2 × CH2), 25.7 (CH2), 23.8 (2 × CH2), 21.4 (CH3). LRMS (EI) m/
z (%): 91 (100), 213 (91), 336 (M+, 89). HRMS (ESI+) m/z: [M +
H]+ calcd for C22H25OS, 337.1621; found, 337.1626.
[1-(Phenylethynyl)cyclohexyl] (p-Tolyl) Sulfide (4ia). Compound
4ia was prepared according to general procedure A (reaction time, 2
h). The crude product was purified by flash column chromatography
on silica gel (hexane), affording pure 4ia (87% yield, 106 mg).
(3-Phenyl-1,1-di-p-tolylprop-2-yn-1-yl) (p-Tolyl) Sulfide (4da).
Compound 4da was prepared according to general procedure A
(reaction time, 30 min). The crude product was purified by flash
column chromatography on silica gel (hexane), affording pure 4da
1
Colorless oil. Rf = 0.59 (hexane). H NMR (300 MHz, CDCl3): δ
1
(53% yield, 87 mg). Yellow oil. Rf = 0.18 (hexane). H NMR (300
7.66−7.63 (m, 2H), 7.44−7.41 (m, 2H), 7.35−7.33 (m, 3H), 7.22−
7.19 (m, 2H), 2.42 (s, 3H), 2.13−2.04 (m, 2H), 1.81−1.66 (m, 7H),
1.37−1.33 (m, 1H). 13C{1H} NMR (75.4 MHz, CDCl3): δ 139.2
(C), 137.3 (2 × CH), 131.6 (2 × CH), 129.3 (2 × CH), 128.3 (2 ×
CH), 128 (C), 127.9 (CH), 123.7 (C), 92.6 (C), 85.5 (C), 48.1 (C),
38.8 (2 × CH2), 25.6 (CH2), 23.7 (2 × CH2), 21.4 (CH3). LRMS
(EI) m/z (%): 115 (100), 79 (92), 155 (88), 141 (81), 306 (M+, 71).
HRMS (ESI+) m/z: [M + H]+ calcd for C21H23S, 307.1515; found,
307.1519.
MHz, CDCl3): δ 7.62 (d, J = 8.3 Hz, 4H), 7.42−7.38 (m, 2H), 7.35−
7.32 (m, 3H), 7.29−7.27 (m, 2H), 7.15 (d, J = 8.1 Hz, 4H), 7.02 (d, J
= 7.9 Hz, 2H), 2.37 (s, 6H), 2.33 (s, 3H). 13C{1H} NMR (75.4 MHz,
CDCl3): δ 139.7 (2 × C), 139.0 (C), 137.1 (CH), 136.3 (2 × CH),
131.7 (2 × CH), 129.9 (2 × C),129.1 (2 × CH), 128.9 (4 × CH),
128.7 (C), 128.3 (4 × CH), 128.2 (2 × CH), 123.4 (C), 91.6 (C),
88.8 (C), 59.2 (C), 21.4 (CH3), 21.2 (2 × CH3). HRMS (ESI+) m/z:
[M + H]+ calcd for C30H27S, 419.1828; found, 419.1833.
(1,1-Dicyclopropyl-3-phenylprop-2-yn-1-yl) (p-Tolyl) Sulfide
(4ea). Compound 4ea was prepared according to general procedure
A (reaction time, 2 h). The crude product was purified by flash
column chromatography on silica gel (hexane), affording pure 4ea
[4-(4-Methoxyphenyl)-2-methylbut-3-yn-2-yl] (p-Tolyl) Sulfide
(4ja). Compound 4ja was prepared according to general procedure
A (reaction time, 1 h). The crude product was purified by flash
column chromatography on silica gel (20:1 hexane/EtOAc), affording
pure 4ja (75% yield, 89 mg). Yellow oil. Rf = 0.38 (20:1 hexane/
1
(64% yield, 80 mg). Yellow oil. Rf = 0.12 (hexane). H NMR (300
1
MHz, CDCl3): δ 7.65 (d, J = 7.02 Hz, 2H), 7.36−7.28 (m, 5H), 7.15
(d, J = 7.9 Hz, 2H), 2.39 (s, 3H), 1.32−1.23 (m, 2H), 0.62−0.40 (m,
8H). 13C{1H} NMR (75.4 MHz, CDCl3): δ 139.2 (C), 137.8 (2 ×
CH), 131.6 (2 × CH), 129.0 (2 × CH), 128.6 (C), 128.3 (2 × CH),
128.2 (CH), 123.0 (C), 86.8 (C), 85.4 (C), 56.2 (C), 21.5 (CH3),
20.3 (2 × CH), 2.6 (2 × CH2), 2.6 (2 × CH2). LRMS (EI) m/z (%):
195 (100), 136 (54), 318 (M+, 19). HRMS (APCI+) m/z: [M + H]+
calcd for C22H23S, 319.1515; found, 319.1519.
EtOAc). H NMR (300 MHz, CDCl3): δ 7.61 (d, J = 8.00 Hz, 2H),
7.34−7.31 (m, 2H), 7.21−7.18 (m, 2H), 6.85 (d, J = 8.8 Hz, 2H),
3.83 (s, 3H), 2.41 (s, 3H), 1.65 (s, 6H). 13C{1H} NMR (75.4 MHz,
CDCl3): δ 159.4 (C), 139.3 (C), 137.1 (2 × CH), 133 (2 × CH),
129.4 (2 × CH), 129.2 (C), 115.6 (C), 113.9 (2 × CH), 92.7 (C),
83.1 (C), 55.4 (CH3), 42.7 (C), 30.6 (2 × CH3), 21.4 (CH3). LRMS
(EI) m/z (%): 173 (100), 115 (23), 128 (22), 296 (M+, 7). HRMS
(ESI+) m/z: [M + H]+ calcd for C19H21OS, 297.1308; found,
297.1311.
(4-Chlorophenyl) [4-(4-Methoxyphenyl)-2-methylbut-3-yn-2-yl]
Sulfide (4jc). Compound 4jc was prepared according to general
procedure A (reaction time, 2 h). The crude product was purified by
flash column chromatography on silica gel (20:1 hexane/EtOAc),
affording pure 4jc (82% yield, 103 mg). Orange oil. Rf = 0.38 (20:1
hexane/EtOAc). 1H NMR (300 MHz, CDCl3): δ 7.66−7.61 (m, 2H),
7.36−7.28 (m, 4H), 6.88−6.83 (m, 2H), 3.83 (s, 3H), 1.64 (s, 6H).
13C{1H} NMR (75.4 MHz, CDCl3): δ 159.6 (C), 138.2 (2 × CH),
(2-Cyclopropyl-4-phenylbut-3-yn-2-yl) (p-Tolyl) Sulfide (4fa).
Compound 4fa was prepared according to general procedure A
(reaction time, 2 h). The crude product was purified by flash column
chromatography on silica gel (hexane), affording pure 4fa (66% yield,
1
71 mg). Pale yellow oil. Rf = 0.19 (hexane). H NMR (300 MHz,
CDCl3): δ 7.72 (d, J = 8.10 Hz, 2H), 7.44−7.42 (m, 2H), 7.37−7.35
(m, 3H), 7.24 (d, J = 7.9 Hz, 2H), 2.45 (s, 3H), 1.74 (s, 3H), 1.30−
1.23 (m, 1H), 0.71−0.54 (m, 4H). 13C{1H} NMR (75.4 MHz,
CDCl3): δ 139.2 (C), 137.4 (2 × CH), 131.5 (2 × CH), 129.1 (2 ×
CH), 128.7 (C), 128.2 (2 × CH), 128.0 (CH), 123.2 (C), 89.4 (C),
85.2 (C), 49.3 (C), 29.3 (CH3), 21.2 (CH), 21.0 (CH3), 3.6 (CH2),
2.5 (CH2). LRMS (EI) m/z (%): 154 (100), 169 (98), 141 (78), 292
(M+, 8). HRMS (ESI+) m/z: [M + H]+ calcd for C20H21S, 293.1358;
found, 293.1361.
135.7 (C), 133 (2 × CH), 131.3 (C), 128.8 (2 × CH), 115.3 (C),
114.0 (2 × CH), 92.2 (C), 83.6 (C), 55.4 (CH3), 43.1 (C), 30.6 (2 ×
CH3). LRMS (EI) m/z (%): 173 (100), 128 (20), 115 (19), 316 (M+,
3). HRMS (ESI+) m/z: [M + H]+ calcd for C18H18ClOS, 317.0761;
found, 317.0764.
[2-Cyclopropyl-4-(4-methoxyphenyl)but-3-yn-2-yl] (p-Tolyl) Sul-
fide (4ga). Compound 4ga was prepared according to general
N-(4-{[4-(4-Methoxyphenyl)-2-methylbut-3-yn-2-yl]thio}phenyl)-
acetamide (4jk). Compound 4jk was prepared according to general
G
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procedure A (reaction time, 2 h). The crude product was purified by
flash column chromatography on silica gel (2:1 hexane/EtOAc),
affording pure 4jk (70% yield, 95 mg). Pale yellow oil. Rf = 0.12 (2:1
hexane/EtOAc). 1H NMR (300 MHz, CDCl3): δ 8.04 (s, 1H), 7.61−
7.57 (m, 2H), 7.54−7.50 (m, 2H), 7.28−7.25 (m, 2H), 6.80−6.77
(m, 2H), 3.76 (s, 3H), 2.13 (s, 3H), 1.58 (s, 6H). 13C{1H} NMR
(75.4 MHz, CDCl3): δ 168.9 (C), 159.4 (C), 139.1 (2 × CH),137.9
(C), 132.9 (2 × CH), 127.5 (C), 119.6 (2 × CH), 115.3 (C), 113.9
(2 × CH), 92.5 (C), 83.2 (C), 55.3 (CH3), 42.9 (C), 30.4 (2 × CH3),
24.6 (CH3). LRMS (EI) m/z (%): 173 (100), 205 (92), 115 (67), 43
(64), 339 (M+, 15). HRMS (ESI+) m/z: [M + H]+ calcd for
C20H22NO2S, 340.1366; found, 340.1372.
h). The crude product was purified by flash column chromatography
on silica gel (hexane), affording pure 4bm (58% yield, 61 mg). Yellow
oil. Rf = 0.22 (hexane). H NMR (300 MHz, CDCl3): δ 7.83−7.80
1
(m, 2H), 7.56−7.53 (m, 2H), 7.42−7.36 (m, 5H), 7.32−7.28 (m,
1H), 2.77−2.68 (m, 1H), 2.54−2.45 (m, 1H), 2.00 (s, 3H), 1.56−
1.47 (m, 2H), 1.28−1.23 (m, 18H), 0.91 (t, J = 6.73 Hz, 3H).
13C{1H} NMR (75.4 MHz, CDCl3): δ 144.1 (C), 132.3 (2 × CH),
128.9 (2 × CH), 128.8 (2 × CH), 128.5 (C), 127.8 (CH), 127.1 (2 ×
CH), 123.8 (C), 92.4 (C), 86.1 (C), 47.1 (C), 32.5 (CH2), 32.1
(CH2), 32.0 (CH2), 30.2 (2 × CH2), 30.1 (CH2), 30.0 (CH2), 29.9
(CH2), 29.7 (CH2), 29.6 (CH2), 29.3 (CH2), 14.7 (CH3), 13.3
(CH3). LRMS (EI) m/z (%): 402 (100), 57 (60), 43 (38), 71 (35),
406 (M+, 5). HRMS (ESI+) m/z: [M + H]+ calcd for C28H39S,
407.2767; found, 407.2770.
[4-(3-Methoxyphenyl)-2-methylbut-3-yn-2-yl] (p-Tolyl) Sulfide
(4ka). Compound 4ka was prepared according to general procedure
A (reaction time, 1 h). The crude product was purified by flash
column chromatography on silica gel (20:1 hexane/EtOAc), affording
pure 4ka (93% yield, 110 mg). Yellow oil. Rf = 0.31 (20:1 hexane/
Benzyl(2-cyclopropyl-4-phenylbut-3-yn-2-yl) Sulfide (4fn). Com-
pound 4fn was prepared according to general procedure A (reaction
time, 2 h). The crude product was purified by flash column
chromatography on silica gel (hexane), affording pure 4fn (71% yield,
81 mg). Yellow oil. Rf = 0.17 (hexane). 1H NMR (300 MHz, CDCl3):
δ 7.61−7.57 (m, 2H), 7.44−7.23 (m, 6H), 7.16−7.09 (m, 2H), 2.37
(s, 2H), 1.62 (s, 3H), 1.21−1.12 (m, 1H), 0.55−0.45 (m, 4H).
13C{1H} NMR (75.4 MHz, CDCl3): δ 139.3 (C), 137.5 (2 × CH),
131.5 (2 × CH), 129.2 (2 × CH), 128.7 (CH), 128.3 (2 × CH),
128.1 (CH), 123.3 (C), 89.5 (C), 85.2 (C), 49.5 (C), 29.3 (CH2),
21.5 (CH), 21.0 (CH3), 3.7 (CH2), 2.5 (CH2). LRMS (EI) m/z (%):
169 (100), 141 (78), 292 (M+, 12). HRMS (APCI+) m/z: [M + H]+
calcd for C20H21S, 293.1358; found, 293.1356.
1
EtOAc). H NMR (300 MHz, CDCl3): δ 7.63 (d, J = 7.9 Hz, 2H),
7.26−7.20 (m, 3H), 7.00 (d, J = 7.6 Hz, 1H), 6.92−6.87 (m, 2H),
3.83 (s, 3H), 2.41 (s, 3H), 1.66 (s, 6H). 13C{1H} NMR (75.4 MHz,
CDCl3): δ 159.3 (C), 139.4 (C), 137.2 (2 × CH), 129.4 (2 × CH),
129.3 (CH), 129.0 (C), 124.4 (C), 124.1 (CH), 116.4 (CH), 114.6
(CH), 94.0 (C), 83.2 (C), 55.3 (CH3), 42.5 (C), 30.43 (2 × CH3),
21.4 (CH3). LRMS (EI) m/z (%): 173 (100), 281 (23), 115 (18),
296 (M+, 16). HRMS (ESI+) m/z: [M + H]+ calcd for C19H21OS,
297.1308; found, 297.1311.
(4-Bromophenyl) [4-(3-Methoxyphenyl)-2-methylbut-3-yn-2-yl]
Sulfide (4kd). Compound 4kd was prepared according to general
procedure A (reaction time, 2 h). The crude product was purified by
flash column chromatography on silica gel (20:1 hexane/EtOAc),
affording pure 4kd (70% yield, 102 mg). Pale yellow oil. Rf = 0.36
Gram Scale Synthesis of Selected Propargyl Sulfides 4. To a
solution of propargyl alcohol 2-methyl-4-phenylbut-3-yn-2-ol 3a (3.2
g, 1 equiv, 20 mmol) in MeNO2 (40 mL, 0.5 M) were added p-
toluenethiophenol 2a (3.23 g, 1.3 equiv, 26 mmol) or p-
bromothiophenol 2d (3.12 mL, 1.3 equiv, 26 mmol) and p-
toluenesulfonic acid 1 (76 mg, 0.02 equiv, 5 mol %). The resulting
mixture was stirred at rt for 30 min. After the alcohol was consumed,
the reaction was quenched with aqueous NaOH (0.5 M, 50 mL). The
separated aqueous phase was extracted with CH2Cl2 (3 × 50 mL).
The combined organic layers were dried with anhydrous Na2SO4 and
concentrated under reduced pressure. The residue was purified by
silica gel column chromatography (eluent, hexane/EtOAc mixture) to
afford the corresponding propargyl sulfides: (2-methyl-4-phenylbut-3-
yn-2-yl) (p-tolyl) sulfide 4aa (3.78 g, 71% yield) or (2-bromophenyl)
(2-methyl-4-phenylbut-3-yn-2-yl) sulfide 4ad (5.21 g, 79% yield).
Synthesis of (3-Phenylprop-2-yn-1-yl) (p-Tolyl) Sulfide 5.
Primary propargyl sulfide 1-methyl-4-[(3-phenyl-2-propyn-1-yl)thio]-
benzene 5 (CAS Registry No. 2306760-67-6) was prepared via a
modified version of a previously described procedure.30 Compound 2-
propynyl p-tolyl sulfide31 (0.36 g, 1.1 equiv, 2.2 mmol) was dissolved
in diisopropylamine (4 mL, 0.5 M). Then iodobenzene (0.22 mL, 1
equiv, 2 mmol), PdCl2Ph3 (28 mg, 2 mol %), and CuI (7.6 mg, 2 mol
%) were sequentially added. The reaction mixture was allowed to stir
at rt for 3 h. The crude was quenched by addition of brine. The
separated aqueous phase was extracted with Et2O (3 × 10 mL). The
combined organic layers were dried over anhydrous Na2SO4 and
concentrated under reduced pressure. The residue was purified by
silica gel column chromatography (eluent hexane) to afford the
corresponding propargyl sulfide 5, 1-methyl-4-[(3-phenyl-2-propyn-1-
yl)thio]benzene (0.31 g, 65% yield, CAS Registry No. 2306760-67-6).
NMR data are in full agreement with previously described data.30
1-Methyl-4-[(3-phenyl-2-propyn-1-yl)thio]benzene (5). Brown
1
(20:1 hexane/EtOAc). H NMR (300 MHz, CDCl3): δ 7.62−7.57
(m, 2H), 7.54−7.50 (m, 2H), 7.30−7.21 (m, 1H), 7.00−6.97 (m,
1H), 6.92−6.88 (m, 2H), 3.83 (s, 3H), 1.67 (s, 6H). 13C{1H} NMR
(75.4 MHz, CDCl3): δ 159.4 (C), 138.4 (2 × CH), 131.8 (C), 131.7
(2 × CH), 129.4 (CH), 124.1 (CH), 124.0 (C), 116.0 (CH), 114.8
(CH), 93.4 (C), 83.7 (C), 55.3 (CH3), 42.9 (C), 30.5 (2 × CH3),
one C peak missing due to overlapping. LRMS (EI) m/z (%): 173
(100), 115 (18), 128 (15), 368 (M+, 8). HRMS (ESI+) m/z: [M +
H]+ calcd for C18H18BrOS, 361.0256; found, 361.0254.
(2-Fluorophenyl) [4-(3-Methoxyphenyl)-2-methylbut-3-yn-2-yl]
Sulfide (4kl). Compound 4kl was prepared according to general
procedure A (reaction time, 2 h). The crude product was purified by
flash column chromatography on silica gel (20:1 hexane/EtOAc),
affording pure 4kl (67% yield, 81 mg). Pale yellow oil. Rf = 0.33 (20:1
hexane/EtOAc). 1H NMR (300 MHz, CDCl3): δ 7.80−7.74 (m, 1H),
7.44−7.36 (m, 1H), 7.23−7.13 (m, 3H), 6.97−6.94 (m, 1H), 6.89−
6.84 (m, 2H), 3.79 (s, 3H), 1.70 (s, 6H). 13C{1H} NMR (75.4 MHz,
CDCl3): δ 164 (C, JC−F = 247.6 Hz), 159.2 (CH), 139.9 (CH), 131.8
(C, JC−F = 8.2 Hz), 129.3 (CH), 124.1 (CH, JC−F = 4.1 Hz), 124.0 (2
× CH), 119.4 (C, JC−F = 18.3 Hz), 116.4 (CH), 115.8 (CH, JC−F
=
24.1 Hz), 114.6 (CH), 93.1 (C), 83.4 (C), 55.2 (CH3), 43.7 (C),
30.6 (2 × CH3). 19F NMR (282 MHz, CDCl3): δ −105.0. HRMS
(ESI+) m/z: [M + H]+ calcd for C18H18FOS, 301.1057; found,
301.1061.
(2-Methyloct-3-yn-2-yl) (p-Tolyl) Sulfide (4la). Compound 4la
was prepared according to general procedure A (reaction time, 4 h).
The crude product was purified by flash column chromatography on
silica gel (50:1 hexane/CH2Cl2), affording pure 4la (73% yield, 72
1
1
mg). Colorless oil. Rf = 0.33 (50:1 hexane/CH2Cl2). H NMR (300
oil. Rf = 0.17 (hexane). H NMR (300 MHz, CDCl3): δ 7.50−7.49
MHz, CDCl3): δ 7.51 (d, J = 8.1 Hz, 2H), 7.15 (dt, J = 7.8, 0.7 Hz,
2H), 2.37 (s, 3H), 2.17 (t, J = 7.0 Hz, 2H), 1.54−1.28 (m, 10H), 0.90
(t, J = 7.2 Hz, 3H). 13C{1H} NMR (75.4 MHz, CDCl3): δ 139.1 (C),
136.9 (2 × CH), 129.4 (C), 129.3 (2 × CH), 84.8 (C), 83.6 (C), 42.4
(C), 31.0 (CH2), 30.9 (2 × CH3), 22.1 (CH2), 21.4 (CH3), 18.6
(CH2), 13.8 (CH3). LRMS (EI) m/z (%): 123 (100), 246 (M, 55),
231 (30), 216 (33). HRMS (APCI+) m/z: [M + H]+ calcd for
C16H23S, 247.1515; found, 247.1519.
(m, 2H), 7.46−7.41 (m, 2H), 7.35−7.33 (m, 3H), 7.23−7.20 (m,
2H), 3.86 (s, 2H), 2.41 (s, 3H). 13C{1H} NMR (75.4 MHz, CDCl3):
δ 137.4 (C), 137.7 (2 × CH), 137.7 (2 × CH), 137.4 (C), 131.6 (2 ×
CH), 131.5 (C), 129.8 (2 × CH), 128.3 (2 × CH), 128.2 (CH),
123.1 (C), 85.6 (C), 83.7 (C), 24.6 (CH2), 21.2 (CH3). LRMS (EI)
m/z (%): 115 (100), 89 (21), 238 (M+, 20).
Synthesis of (1,3-Diphenylprop-2-yn-1-yl) (p-Tolyl) Sulfide
6. Compound 6 was prepared according to general procedure A. The
crude product was purified by flash column chromatography on silica
gel (hexane), affording pure 6 (88% yield, 111 mg).
(2,4-Diphenylbut-3-yn-2-yl) (Dodecyl) Sulfide (4bm). Compound
4bm was prepared according to general procedure A (reaction time, 2
H
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(1,3-Diphenylprop-2-yn-1-yl) (p-Tolyl) Sulfide (6). Pale yellow
liquid. Rf = 0.18 (hexane). 1H NMR (300 MHz, CDCl3): δ 7.56−7.35
(m, 12H), 7.19 (d, J = 7.9 Hz, 2H), 5.26 (s, 1H), 2.42 (s, 3H).
13C{1H} NMR (75.4 MHz, CDCl3): δ 138.8 (C) 138.4 (C), 135.1 (2
× CH), 131.7 (2 × CH), 129.7 (C), 129.5 (2 × CH), 128.5 (2 ×
CH), 128.3 (3 × CH), 128.2 (2 × CH), 127.8 (CH), 123.1 (C),87.7
(C), 86.9 (C), 44.7 (CH), 21.3 (CH3). LRMS (EI) m/z (%): 191
(100), 314 (M+, 35), 207 (18). HRMS (ESI+) m/z: [M + H]+ calcd
for C22H19S, 315.1202; found, 315.1203.
(C), 55.2 (C), 24.5 (2 × CH3), one C peak is missing due to
overlapping. LRMS (EI) m/z (%): 458 (100), 456 (M+, 84), 331
(45). HRMS (APCI+) m/z: [M + H]+ calcd for C17H15BrIS,
456.9117; found, 456.9117.
3-Iodo-2,2-dimethyl-4-phenyl-2H-thiochromene (7ae). Com-
pound 7ae was prepared according to general procedure B. The
crude product was purified by flash column chromatography on silica
gel (hexane), affording pure 7ae (74% yield, 56 mg). Pale yellow oil.
1
Rf = 0.33 (hexane). H NMR (300 MHz, CDCl3): δ 7.42−7.40 (m,
1H), 7.39−7.37 (m, 1H), 7.36−7.35 (m, 1H), 7.33−7.31 (m, 2H),
7.30−7.27 (m, 2H), 7.26−7.25 (m, 1H), 7.23−7.19 (m, 1H), 1.32 (s,
6H). 13C{1H} NMR (75.4 MHz, CDCl3): δ 153.2 (C), 152.5 (C),
142.6 (C), 134.9 (C), 129.1 (2 × CH), 128.8 (2 × CH), 127.6 (CH),
127.3 (CH), 126.4 (CH), 123.5 (CH), 121.5 (CH), 109.1 (C), 55.2
(C), 24.6 (2 × CH3). LRMS (EI) m/z (%): 378 (M+, 100), 251 (39),
142 (30). HRMS (ESI+) m/z: [M + H]+ calcd for C17H16IS,
379.0012; found, 379.0006.
General Procedure B for the Synthesis of Iodothiochro-
menes 7 by Iodoarylation of Propargyl Thioethers 4. N-
Iodosuccinimide (58.5 mg, 1.3 equiv, 0.23 mmol) was added to a
solution of propargyl thioether 4 (1 equiv, 0.2 mmol) in CH2Cl2 (2
mL, 0.1 M) at 0 °C. The reaction mixture was allowed to warm to rt.
Then the reaction mixture was allowed to stir overnight (24 h) until
the full depletion of the propargyl sulfide was determined by GC-MS.
The reaction was quenched by the addition of saturated aqueous
Na2S2O3 (10 mL). The aqueous phase was extracted with CH2Cl2 (3
× 10 mL). The combined organic layer was dried over anhydrous
Na2SO4, filtered, and concentrated under reduced pressure. Then, the
residual succinimide was precipitated by the addition of Et2O (10
mL) to the crude. The solids were filtered off through a plug of Celite
and washed thoroughly with Et2O (3 × 30 mL). The filtrate was
concentrated in vacuo, affording crude 3-iodothiochromenes 7, which
were purified by column chromatography on silica gel (eluent,
hexane/EtOAc mixture) to afford the corresponding pure thiochro-
menes 7.
3-Iodo-2,2-dimethyl-4-phenyl-2H-benzo[h]thiochromene (7ai).
Compound 7ai was prepared according to general procedure B.
The crude product was purified by flash column chromatography on
silica gel (hexane), affording pure 7ai (60% yield, 52 mg). Pale yellow
1
oil. Rf = 0.26 (hexane). H NMR (300 MHz, CDCl3): δ 8.51−8.47
(m, 1H), 7.91−7.88 (m, 1H), 7.79−7.76 (m, 1H), 7.65−7.57 (m,
2H), 7.56−7.53 (m, 2H), 7.42−7.36 (m, 3H), 7.34−7.33 (m, 1H),
1.23 (s, 6H). 13C{1H} NMR (75.4 MHz, CDCl3): δ 153.4 (C), 152.7
(C), 142.6 (C), 134.1 (C), 132.9 (C), 131.2 (C), 128.7 (2 × CH),
128.1 (CH), 127.3 (2 × CH), 126.7 (CH), 126.4 (CH), 125.6 (CH),
125.1 (CH), 123.4 (CH), 121.3 (CH), 107.0 (C), 55.4 (C), 24.7 (2
× CH3). LRMS (EI) m/z (%): 301 (100), 284 (98), 428 (M+, 82).
HRMS (ESI+) m/z: [M + H]+ calcd for C21H18IS, 429.0168; found,
429.0165.
3-Iodo-2,2,6-trimethyl-4-phenyl-2H-thiochromene (7aa). Com-
pound 7aa was prepared according to general procedure B. The crude
product was purified by flash column chromatography on silica gel
(hexane), affording pure 7aa (75% yield, 58 mg). Yellow oil. Rf = 0.28
(hexane). 1H NMR (300 MHz, CDCl3): δ 7.41−7.38 (m, 2H), 7.37−
7.34 (m, 1H), 7.33−7.29 (m, 1H), 7.28−7.25 (m, 2H), 7.11−7.08
(m, 2H), 2.34 (s, 3H), 1.31 (s, 6H). 13C NMR (75.4 MHz, CDCl3): δ
153.7 (C), 152.5 (C), 142.7 (C), 131.0 (C), 129.8 (2 × CH), 129.3
(2 × CH), 128.7 (C), 127.4 (CH), 127.3 (CH), 123.5 (CH), 121.4
(CH), 108.1 (C), 55.1 (C), 24.7 (2 × CH3), 21.2 (CH3). LRMS (EI)
m/z (%): 392 (M+, 100), 393 (23), 265 (18). HRMS (ESI+) m/z:
[M + O + H]+ calcd for C18H18ISO+, 409.0119; found, 409.0122.32
3-Iodo-6-methoxy-2,2-dimethyl-4-phenyl-2H-thiochromene
(7ab). Compound 7ab was prepared according to general procedure
B. The crude product was purified by flash column chromatography
on silica gel (hexane), affording pure 7ab (71% yield, 58 mg). Yellow
2-Iodo-2,2-dimethyl-1-phenyl-3H-benzo[f ]thiochromene (7aj).
Compound 7aj was prepared according to general procedure B.
The crude product was purified by flash column chromatography on
silica gel (hexane), affording pure 7ai (62% yield, 54 mg). Pale yellow
1
oil. Rf = 0.19 (hexane). H NMR (300 MHz, CDCl3): δ 7.92−7.65
(m, 4H), 7.58−7.30 (m, 7H), 1.35 (s, 6H). 13C{1H} NMR (75.4
MHz, CDCl3): δ 153.0 (C), 152.6 (C), 142.6 (C), 133.8 (C), 132.3
(C), 132.0 (C), 128.7 (CH), 127.9 (CH), 127.6 (CH), 127.4 (CH),
127.3 (CH), 127.0 (CH), 126.9 (CH), 126.7 (CH), 126.7 (CH),
125.9 (CH), 123.6 (CH), 121.5 (CH), 109.3 (C), 55.2 (C), 24.6 (2
× CH3). LRMS (EI) m/z (%): 301 (100), 284 (90), 428 (M+, 70).
HRMS (APCI+) m/z: [M + H]+ calcd for C21H18IS, 429.0168; found,
429.0172.
1
oil. Rf = 0.26 (hexane). H NMR (300 MHz, CDCl3): δ 7.39−7.36
(m, 3H), 7.34−7.25 (m, 3H), 6.85−6.82 (m, 2H), 3.81 (s, 3H), 1.27
(s, 6H). 13C{1H} NMR (75.4 MHz, CDCl3): δ 159.1 (C), 154.5 (C),
152.5 (C), 142.7 (C), 132.4 (2 × CH), 127.3 (CH), 127.2 (CH),
124.8 (C), 123.3 (CH), 121.3 (CH), 114.7 (2 × CH), 105.9 (C),
55.5 (CH3), 55.0 (C), 24.9 (2 × CH3). LRMS (EI) m/z (%): 408
(M+, 100), 281 (76), 142 (50). HRMS (ESI+) m/z: [M + H]+ calcd
for C18H18IOS, 409.0118; found, 409.0108.
3′-Iodo-6′-methyl-4′-phenylspiro[cyclohexane-1,2′-thiochro-
mene] (7ia). Compound 7ia was prepared according to general
procedure B. The crude product was purified by flash column
chromatography on silica gel (hexane), affording pure 7ia (63% yield,
1
56 mg). Pale yellow oil. Rf = 0.48 (hexane). H NMR (300 MHz,
CDCl3): δ 7.80 (d, J = 7.50 Hz, 1H), 7.46−7.39 (m, 2H), 7.34−7.29
(m, 1H), 7.16−7.12 (m, 2H), 7.07 (d, J = 8.2 Hz, 2H), 2.33 (s, 3H),
2.11−2.01 (m, 2H), 1.96−1.79 (m, 5H), 1.50−1.42 (m, 1H), 1.28−
1.25 (m, 2H). 13C{1H} NMR (75.4 MHz, CDCl3): δ 153.8 (C),
151.3 (C), 143.3 (C), 135.7 (C), 132 (C), 129.8 (2 × CH), 128.7
(CH), 127.6 (2 × CH), 126.6 (CH), 124.1 (CH), 123.8 (CH), 110.9
(C), 58.5 (CH), 31.9 (2 × CH2), 25.1 (CH2), 22.6 (2 × CH2), 21.1
(CH3). LRMS (EI) m/z (%): 182 (100), 141 (58), 181 (57), 432
(M+, 52). HRMS (ESI+) m/z: [M − I]+ calcd for C21H21S, 305.1364;
found, 305.1358.
6-Chloro-3-iodo-2,2-dimethyl-4-phenyl-2H-thiochromene (7ac).
Compound 7ac was prepared according to general procedure B. The
crude product was purified by flash column chromatography on silica
gel (hexane), affording pure 7ac (70% yield, 59 mg). Pale yellow oil.
1
Rf = 0.44 (hexane). H NMR (300 MHz, CDCl3): δ 7.41−7.29 (m,
5H), 7.26−7.21 (m, 3H), 1.30 (s, 6H). 13C{1H} NMR (75.4 MHz,
CDCl3): δ 152.6 (C), 152.4 (C), 142.4 (C), 133.6 (C), 132.2 (C),
129.8 (2 × CH), 129.2 (2 × CH), 127.8 (CH), 127.4 (CH), 123.7
(CH), 121.5 (CH), 110.0 (C), 55.2 (C), 24.5 (2 × CH3). LRMS (EI)
m/z (%): 412 (M+, 100), 285 (62), 142 (53). HRMS (APCI+) m/z:
[M + H]+ calcd for C17H15ClIS, 412.9622; found, 412.9620.
3-Iodo-4-(3-methoxyphenyl)-2,2,6-trimethyl-2H-thiochromene
(7ka). Compound 7ka was prepared according to general procedure
B. The crude product was purified by flash column chromatography
on silica gel (100:1 hexane/EtOAc), affording pure 7ka (61% yield,
6-Chloro-3-iodo-2,2-dimethyl-4-phenyl-2H-thiochromene (7ad).
Compound 7ad was prepared according to general procedure B. The
crude product was purified by flash column chromatography on silica
gel (hexane), affording pure 7ad (67% yield, 63 mg). Yellow oil. Rf =
1
52 mg). Colorless oil. Rf = 0.21 (100:1 hexane/EtOAc). H NMR
(300 MHz, CDCl3): δ 7.32−7.38 (m, 1H), 7.21−7.24 (m, 2H),
7.03−7.09 (m, 3H), 6.85−6.89 (m, 1H), 3.90 (s, 3H), 2.32 (s, 3H),
1.39 (s, 6H). 13C{1H} NMR (75.4 MHz, CDCl3): δ 155.1 (C), 144.2
(C), 138.2 (C), 136.2 (C), 131.3 (CH), 132.1 (CH), 129.8 (CH),
128.9 (CH), 128.4 (CH), 122.3 (C), 116.2 (CH), 112.2 (C), 110
(CH), 108.9 (C), 55.8 (CH3), 55.6 (C), 25.9 (CH3), 21.8 (2 × CH3).
1
0.6 (hexane). H NMR (300 MHz, CDCl3): δ 7.32−7.42 (m, 6H),
7.16−7.20 (m, 2H), 1.31 (s, 6H). 3C{1H} NMR (75.4 MHz, CDCl3):
δ 152.4 (C), 142.4 (C), 134.3 (C), 132.1 (2 × CH), 129.9 (2 × CH),
127.8 (CH), 127.4 (CH), 123.7 (CH), 121.5 (CH), 120.0 (C), 110.0
I
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LRMS (EI) m/z (%): 295 (100), 422 (M+, 86), 299 (78), 128 (74).
HRMS (APCI+) m/z: [M − I]+ calcd for C19H19OS, 295.1157;
found, 295.1152.
6-Bromo-3-iodo-4-(3-methoxyphenyl)-2,2-dimethyl-2H-thio-
chromene (7kd). Compound 7kd was prepared according to general
procedure B. The crude product was purified by flash column
chromatography on silica gel (hexane), affording pure 7kd (72% yield,
68 mg). Colorless oil. Rf = 0.21 (hexane). 1H NMR (300 MHz,
CDCl3): δ 7.32−7.37 (m, 3H), 7.11−7.15 (m, 2H), 7.04 (d, J = 7.4
Hz, 1H), 6.86 (d, J = 8.2 Hz, 1H), 3.89 (s, 3H), 1.36 (s, 6H).
13C{1H} NMR (75.4 MHz, CDCl3): δ 159.6 (C), 144.7 (C), 143.7
The crude product was purified by flash column chromatography on
silica gel (hexane), affording pure 8ab (64% yield, 36 mg). Pale yellow
oil. Rf = 0.13 (hexane). H NMR (300 MHz, CDCl3): δ 7.38−7.35
1
(m, 3H), 7.32−7.29 (m, 2H), 6.99 (d, J = 8.6 Hz, 1H), 6.93 (d, J =
2.7 Hz, 1H), 6.59−6.63 (m, 1H), 5.71 (s, 1H), 3.83 (s, 3H), 1.50 (s,
6H). 13C{1H} NMR (75.4 MHz, CDCl3): δ 158.9 (C), 141.3 (C),
138.6 (C), 134.8 (C), 131.4 (CH), 129.3 (2 × CH), 129.1 (CH),
128.3 (2 × CH), 127.5 (CH), 126.4 (C), 112.7 (CH), 111.4 (CH),
55.5 (CH3), 41.3 (C), 29.1 (2 × CH3). LRMS (EI) m/z (%): 267
(100), 268 (18), 282 (M+, 14). HRMS (ESI+) m/z: [M + H]+ calcd
for C18H19OS, 283.1151; found, 283.1158.
2,2-Dimethyl-4-phenyl-2H-thiochromene (8ae). Compound 8ae
(CAS Registry No. 132007-64-8) was prepared according to general
procedure C. The crude product was purified by flash column
chromatography on silica gel (hexane), affording pure 8ae (78% yield,
40 mg). NMR spectra are in accordance with previously described
(C), 134.2 (C), 132.3 (CH), 132.1 (CH), 130 (CH), 129.7 (CH),
122.2 (CH), 120 (C), 114 (CH), 111.9 (C), 108.9 (CH), 106.5 (C),
55.8 (CH3), 54.6 (C), 24.7 (2 × CH3). LRMS (EI) m/z (%): 299
(100), 488 (44), 486 (M+, 43). HRMS (APCI+) m/z: [M + H]+
calcd for C18H17BrIOS, 486.9223; found, 486.9223.
data.33 Pale yellow oil. Rf = 0.25 (hexane). H NMR (300 MHz,
1
8-Fluoro-3-iodo-4-(3-methoxyphenyl)-2,2-dimethyl-2H-thio-
chromene (7kl). Compound 7kl was prepared according to general
procedure B. The crude product was purified by flash column
chromatography on silica gel (100:1 hexane/EtOAc), affording pure
7kl (54% yield, 45 mg). Colorless oil. Rf = 0.29 (100:1 hexane/
EtOAc). 1H NMR (300 MHz, CDCl3): δ 7.26−7.18 (m, 3H), 7.12−
7.01 (m, 2H), 6.95 (d, J = 2.4 Hz, 1H), 6.89 (dd J = 8.2, 2.4 Hz, 1H),
3.90 (s, 3H), 1.30 (s, 6H). 13C{1H} NMR (75.4 MHz, CDCl3): δ
162.3 (C), 159.6 (C), 159.0 (C), 152.6 (C), 144.3 (C, JC−F = 73.3
Hz), 131.0 (CH), 128.3 (CH, JC−F = 7.6 Hz), 124.5 (CH, JC−F = 3.7
Hz), 122.1 (CH), 121.8 (C), 115.8 (CH, JC−F = 21.6 Hz), 113.7
(CH), 108.7 (CH), 108.3 (C), 55.8 (CH3), 54.6 (C), 24.7 (2 ×
CH3). 19F{1H} NMR (282 MHz, CDCl3): δ −110. LRMS (EI) m/z
(%): 299 (100), 426 (M+, 42), 300 (14). HRMS (ESI+) m/z: [M +
H]+ calcd for C18H17FIOS, 427.0023; found, 427.0023.
General Procedure C for the Synthesis of Thiochromenes 8
by Hydroarylation of Propargyl Thioethers 4. Propargyl sulfide
4 (1 equiv, 0.2 mmol) was dissolved in 1,2-dichloroethane (1 mL, 0.2
M). Then AgOTf (2.6 mg, 0.05 equiv, 0.01 mmol) was added at once.
The obtained suspension was allowed to stir at 85 °C in a preheated
bath until full depletion of the propargyl thioether was determined by
GC-MS. Then, the reaction mixture was allowed to cool to rt, and
hexane (2 mL) was added. The mixture was filtered through a plug of
silica and washed with hexane. The filtrate was concentrated under
reduced pressure. The crude was purified by column chromatography
on silica gel (eluent, hexane/EtOAc mixture) to afford the
corresponding thiochromenes 8.
General Procedure D for the Synthesis of Thiochromenes 8
by Hydroarylation of Propargyl Thioethers 4 under Micro-
wave Irradiation. Propargyl sulfide 3 (1 equiv, 0.2 mmol) was
dissolved in 1,2-dichloroethane (1 mL, 0.2 M) in a microwave tube.
Then catalyst AgOTf (2.6 mg, 0.05 equiv, 0.01 mmol) was added at
once. The obtained suspension was heated under microwave
irradiation at 110 °C for 10 min. Then, the reaction mixture was
allowed to cool to rt, and hexane (2 mL) was added. The mixture was
filtered through a plug of silica and washed with hexane. The filtrate
was concentrated under reduced pressure. The crude was purified by
column chromatography on silica gel (eluent, hexane/EtOAc
mixture) to afford the corresponding thiochromenes 8.
CDCl3): δ 7.40−7.37 (m, 4H), 7.33−7.29 (m, 2H), 7.30−7.14 (m,
1H), 7.07−7.04 (m, 2H), 5.84 (s, 1H), 1.50 (s, 6H). 13C{1H} NMR
(75.4 MHz, CDCl3): δ 141 (C), 138.8 (C), 133.7 (C), 132.1 (C),
129.2 (2 × CH), 128.2 (2 × CH), 128.1 (CH), 127.9 (CH), 127.8
(CH), 127.6 (CH), 127.5 (CH), 125.0 (CH), 40.7 (C), 28.9 (2 ×
CH3). LRMS (EI) m/z (%): 237 (100), 238 (17), 252 (M+, 13).
7-Methoxy-2,2-dimethyl-4-phenyl-2H-thiochromene (8ah).
Compound 8ah was prepared according to general procedure D.
The crude product (as a 1.2:1 8ah/8ah′ mixture) was purified by
flash column chromatography on silica gel (hexane), affording 8ah
(with small traces of 8ah′) (45% yield, 26 mg). Brown oil. Rf = 0.15
(hexane). 1H NMR (300 MHz, CDCl3): δ 7.63−7.60 (m, 1H), 7.42−
7.30 (m, 5H), 6.95 (d, J = 2.7 Hz, 1H), 6.85 (dd, J = 8.2, 2.7 Hz, 1H),
6.05 (s, 1H), 3.85 (s, 3H), 1.51 (s, 6H). 13C{1H} NMR (75.4 MHz,
CDCl3): δ 157.7 (C), 138.4 (C), 133.6 (C), 132.9 (C), 132.2 (CH),
128.6 (2 × CH), 128.3 (CH), 128.2 (CH), 127.5 (C), 126.8 (2 ×
CH), 112.8 (CH), 111.0 (CH), 55.5 (CH3), 37.4 (C), 28.8 (2 ×
CH3). LRMS (EI) m/z (%): 267 (100), 224 (19), 268 (19), 282 (M+,
3). HRMS (ESI+) m/z: [M + H]+ calcd for C18H19OS, 283.1151;
found, 283.1156.
5-Methoxy-2,2-dimethyl-4-phenyl-2H-thiochromene (8ah′).
Compound 8ah′ was prepared according to general procedure D.
The crude product was purified by flash column chromatography on
silica gel (hexane), affording pure 8ah′ (with small traces of 8ah)
1
(35% yield, 20 mg). Brown oil. Rf = 0.18 (hexane). H NMR (300
MHz, CDCl3): δ 7.57−7.54 (m, 2H), 7.38−7.34 (m, 3H), 7.12 (t, J =
8 Hz, 1H), 6.84 (dd, J = 7.9, 1.2 Hz, 1H), 6.75 (dd, J = 8.1, 1.0 Hz,
1H), 5.73 (s, 1H), 3.86 (s, 3H), 1.60 (s, 6H). 13C{1H} NMR (75.4
MHz, CDCl3): δ 159.1 (C), 138.6 (C), 131.4 (C), 130.4 (CH), 128.6
(2 × CH), 128.2 (CH), 127.2 (CH), 126.9 (C), 126.3 (2 × CH),
125.7 (C), 118.9 (CH), 110.1 (CH), 55.4 (CH3), 37.7 (C), 29.9 (2 ×
CH3). LRMS (EI) m/z (%): 267 (100), 252 (25), 268 (17), 282 (M+,
6). HRMS (ESI+) m/z: [M + H]+ calcd for C18H19OS, 283.1151;
found, 283.1154.
2,2-Dimethyl-4-phenyl-2H-benzo[h]thiochromene (8ai). Com-
pound 8ai was prepared according to general procedure C. The
crude product was purified by flash column chromatography on silica
gel (hexane), affording pure 8ai (65% yield, 39 mg). Yellow oil. Rf =
1
2,2,6-Trimethyl-4-phenyl-2H-thiochromene (8aa). Compound
8aa was prepared according to general procedure C. The crude
product was purified by flash column chromatography on silica gel
(hexane), affording pure 8aa (83% yield, 42 mg). Pale yellow oil. Rf =
0.24 (hexane). H NMR (300 MHz, CDCl3): δ 8.37−8.34 (m, 1H),
7.83−7.80 (m, 1H), 7.56−7.51 (m, 3H), 7.42−7.38 (m, 3H), 7.36−
7.32 (m, 2H), 7.23 (d, J = 8.7 Hz, 1H), 5.94 (s, 1H), 1.56 (s, 6H).
13C{1H} NMR (75.4 MHz, CDCl3): δ 141.3 (C), 139.9 (C), 133.1
(CH), 130.9 (C), 130.4 (C), 129.7 (C), 129.4 (2 × CH), 128.5 (C),
128.3 (3 × CH), 127.6 (CH), 126.4 (CH), 126.3 (CH), 125.8 (CH),
125.5 (CH), 124.3 (CH), 41.0 (C), 28.7 (2 × CH3). LRMS (EI) m/z
(%): 287 (100), 207 (62), 302 (M+, 44). HRMS (ESI+) m/z: [M +
H]+ calcd for C21H19S, 303.1202; found, 303.1202.
1
0.31 (hexane). H NMR (300 MHz, CDCl3): δ 7.37−7.33 (m, 3H),
7.31−7.28 (m, 2H), 7.19 (d, J = 1.8 Hz, 1H), 6.94 (d, J = 7.9 Hz,
1H), 6.85 (dd, J = 8.1, 1.8 Hz, 1H), 5.77 (s, 1H), 2.33 (s, 3H), 1.48
(s, 6H). 13C{1H} NMR (75.4 MHz, CDCl3): δ 141.3 (C) 138.8 (C),
137.8 (C), 132.8 (CH), 130.5 (C), 129.4 (2 × CH), 128.8 (C), 128.5
(CH), 128.3 (2 × CH), 127.8 (CH), 127.5 (CH), 126.0 (CH), 40.9
(C), 29.1 (2 × CH3), 21.2 (CH3), LRMS (EI) m/z (%): 251 (100),
250 (20), 266 (M+, 13). HRMS (ESI+) m/z: [M + H]+ calcd for
C18H19S, 267.1202; found, 267.1203.
5-Methoxy-2,2-dimethyl-4-phenyl-2H-thiochromene (8aj). Com-
pound 8aj was prepared according to general procedure C. The crude
(as a 1.25:1 8aj/8aj′ mixture) was purified by flash column
chromatography on silica gel (hexane), affording pure 8aj (with
small traces of 8aj′) (35% yield, 22 mg). Light brown solid. Mp: 88−
90 °C. Rf = 0.20 (hexane). 1H NMR (300 MHz, CDCl3): δ 8.40−8.37
6-Methoxy-2,2-dimethyl-4-phenyl-2H-thiochromene (8ab).
Compound 8ab was prepared according to general procedure D.
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(m, 1H), 7.85−7.82 (m, 1H), 7.62−7.59 (m, 1H), 7.57−7.48 (m,
3H), 7.44−7.42 (m, 2H), 7.37−7.34 (m, 2H), 7.25 (d, J = 8.6 Hz,
1H), 5.81 (s, 1H), 1.58 (s, 6H). 13C{1H} NMR (75.4 MHz, CDCl3):
δ 141.3 (C), 139.8 (C), 133.0 (2 × CH), 130.8 (C), 130.3 (C), 129.3
(2 × CH), 128.3 (2 × CH), 127.6 (CH), 126.8 (C), 126.7 (C), 126.3
(CH), 126.2 (CH), 125.7 (CH), 125.4 (CH), 124.2 (CH), 40.9 (C),
28.6 (2 × CH3). LRMS (EI) m/z (%): 287 (100), 288 (20), 302 (M+,
17). HRMS (ESI+) m/z: [M + H]+ calcd for C21H19S, 303.1202;
found, 303.1203.
3,3-Dimethyl-1-phenyl-3H-benzo[f]thiochromene (8aj′). Com-
pound 8aj′ was prepared according to general procedure C. The
crude product was purified by flash column chromatography on silica
gel (hexane), affording pure 8aj′ (with small traces of 8aj) (33% yield,
19 mg). Cream-colored solid. Mp: 87−89 °C. Rf = 0.17 (hexane). 1H
NMR (300 MHz, CDCl3): δ 7.80−7.79 (m, 2H), 7.71 (d, J = 8.5 Hz,
1H), 7.57 (d, J = 8.5 Hz, 1H), 7.29−7.26 (m, 5H), 7.13−7.07 (m,
2H), 6.08 (s, 1H), 1.50 (s, 6H). 13C{1H} NMR (75.4 MHz, CDCl3):
δ 143.5 (C), 139.1 (C), 135.5 (CH), 134.8 (C), 132.9 (C), 129.8
(C), 128.5 (2 × CH), 128.4 (CH), 128.1 (CH), 127.9 (C), 127.8 (2
× CH), 127.7 (CH), 127.1 (CH), 126.2 (CH), 125.1 (CH), 124.5
(CH), 41.2 (C), 27.6 (2 × CH3). LRMS (EI) m/z (%): 287 (100),
302 (M+, 31). HRMS (ESI+) m/z: [M + H]+ calcd for C21H19S,
303.1202; found, 303.1203.
4′-(4-Methoxyphenyl)-6′-methylspiro[cyclohexane-1,2′-thio-
chromene] (8ha). Compound 8ha was prepared according to general
procedure C. The crude product was purified by flash column
chromatography on silica gel (100:1 hexane/EtOAc), affording pure
8ha (61% yield, 41 mg). Colorless oil. Rf = 0.23 (100:1 hexane/
EtOAc). 1H NMR (300 MHz, CDCl3): δ 7.26−7.22 (m, 2H), 7.22−
7.21 (m, 1H), 6.97−6.94 (m, 1H), 6.93−6.89 (m, 2H), 6.87−6.84
(m, 1H), 5.82 (s, 1H), 3.87 (s, 3H), 2.33 (s, 3H), 1.91−1.69 (m, 8H),
1.61−1.56 (m, 2H), 13C{1H} NMR (75.4 MHz, CDCl3): δ 159.2
(C), 138.3 (C), 137.6 (C), 133.9 (C), 132.8 (C), 131.4 (C), 131.2
(C), 130.5 (2 × CH), 128.7 (CH), 127.8 (CH), 126.0 (CH), 113.7
(2 × CH), 55.4 (CH3), 45.4 (C), 37.0 (CH2), 29.1 (CH2), 25.9
(CH2), 21.9 (2 × CH2), 21.2 (CH3). LRMS (EI) m/z (%): 293
(100), 336 (M+, 40). HRMS (ESI+) m/z: [M + H]+ calcd for
C22H25OS, 337.1621; found, 337.1628.
and 2-methylbut-3-yn-2-ol 9 (2.33 mL, 1.2 equiv, 24 mmol) were
dissolved in diisopropylamine (40 mL, 0.5 M). Then PdCl2(PPh3)2
(140 mg, 1 mol %) and CuI (38 mg, 1 mol %) were added to the
mixture. The obtained solution was heated at 60 °C overnight in an
oil bath. The crude was quenched with brine (50 mL), and the
separated aqueous phase was extracted with Et2O (3 × 50 mL). The
combined organic layers were dried with anhydrous Na2SO4 and
concentrated under reduced pressure, and the filtrate was
concentrated under reduced pressure. Then, the crude product was
purified by silica gel column chromatography (eluent, 10:1 hexane/
EtOAc mixture) to afford the alkynol 4-(4-ethylphenyl)-2-methylbut-
3-yn-2-ol34 11 (1.74 g, 98% yield, CAS Registry No. 155105-68-3).
4-(4-Ethylphenyl)-2-methylbut-3-yn-2-ol (11).34 Yellow liquid. Rf
1
= 0.3 (10:1 hexane/AcOEt). H NMR (300 MHz, CDCl3): δ 7.39−
7.35 (m, 2H), 7.17−7.12 (m, 2H), 2.66 (q, J = 7.6 Hz, 2H), 1.66 (s,
6H), 1.25 (t, J = 7.6 Hz, 3H), one H corresponding to the OH group
is missing, NMR spectra match those previously reported.34 13C{1H}
NMR (75.4 MHz, CDCl3): δ 144.6 (C), 127.8 (2 × CH), 131.6 (2 ×
CH), 120.0 (C), 93.2 (C), 82.3 (C), 65.6 (C), 31.6 (2 × CH3), 28.8
(CH2), 15.4 (CH3). LRMS (EI) m/z (%): 43 (100), 173 (52), 115
(30), 188 (M+, 12).
Synthesis of AGN 194310 and Synthesis of (4-Bromophen-
yl) [4-(4-Ethylphenyl)-2-methylbut-3-yn-2-yl] Sulfide (12).
First, p-bromothiophenol 2e (1.97 g, 1.3 equiv, 10.4 mmol) and p-
toluenesulfonic acid 1 (76 mg, 5 mol %) were added to a previously
prepared solution of alkynol 11 (1.46 g, 1 equiv, 8 mmol) in MeNO2
(20 mL, 0.5 M). The mixture was allowed to stir for 30 min until full
depletion of the alcohol was determined by TLC; spots were
visualized using UV−vis and a Ce/Mo reagent as the staining agent.
Then, the reaction was quenched by the addition of aqueous NaOH
(0.5 M, 30 mL). The separated aqueous phase was extracted with
CH2Cl2 (3 × 30 mL). The combined organic layers were dried over
anhydrous Na2SO4, filtered, and concentrated under reduced
pressure. The residue was purified by silica gel column chromatog-
raphy (eluent, hexane) to afford pure propargyl sulfide 12 (1.81 g,
70% yield).
(4-Bromophenyl) [4-(4-Ethylphenyl)-2-methylbut-3-yn-2-yl] Sul-
1
fide (12). Yellow liquid. Rf = 0.26 (hexane). H NMR (300 MHz,
4-(3-Methoxyphenyl)-2,2,6-trimethyl-2H-thiochromene (8ja).
Compound 8ja was prepared according to general procedure C.
The crude product was purified by flash column chromatography on
silica gel (40:1 hexane/EtOAc), affording pure 8ja (52% yield, 32
mg). Pale yellow oil. Rf = 0.25 (40:1 hexane/EtOAc). 1H NMR (300
MHz, CDCl3): δ 7.25−7.21 (m, 2H), 7.20−7.19 (m, 1H), 6.99−6.96
(m, 1H), 6.94−6.90 (m, 2H), 6.89−6.85 (m, 1H), 5.74 (s, 1H), 3.86
(s, 3H), 2.19 (s, 3H), 1.47 (s, 6H). 13C{1H} NMR (75.4 MHz,
CDCl3): δ 159.2 (C), 138.3 (C), 137.7 (C), 133.7 (C), 133.1 (C),
132.1 (CH), 130.7 (C), 130.4 (2 × CH), 129.4 (C), 128.5 (CH),
127.8 (CH), 126.0 (CH), 113.7 (CH), 55.5 (CH3), 41.0 (C), 29.1 (2
× CH3), 21.2 (CH3). LRMS (EI) m/z (%): 281 (100), 282 (20), 296
(M+, 11). HRMS (ESI+) m/z: [M + H]+ calcd for C19H21OS,
297.1309; found, 297.1308.
CDCl3): δ 7.78−7.62 (m, 2H), 7.60−7.56 (m, 2H), 7.31−7.27 (m,
2H), 7.17−7.14 (m, 2H), 2.67 (q, J = 7.7 Hz, 2H), 1.64 (s, 6H), 1.26
(t, J = 7.6 Hz, 3H). 13C{1H} NMR (75.4 MHz, CDCl3): δ 144.6 (C),
138.4 (2 × CH), 131.9 (C), 131.8 (2 × CH), 131.6 (2 × CH), 128.0
(2 × CH), 124.0 (C), 120.3 (C), 92.9 (C), 83.8 (C), 43.0 (C), 30.6
(2 × CH3), 28.9 (CH2), 15.5 (CH3). LRMS (EI) m/z (%): 171
(100), 128 (24), 141 (17), 358 (M+, 2). HRMS (APCI+) m/z: [M +
H]+ calcd for C19H20BrS+, 359.0464; found, 359.0461.
Synthesis of AGN 194310 and Synthesis of Ethyl 4-[(4-{[4-
(4-Ethylphenyl)-2-methylbut-3-yn-2-yl]thio}phenyl)ethynyl]-
benzoate 14. Anhydrous triethylamine (8 mL, 0.25 M) was added
to a mixture of propargyl sulfide 12 (716 mg, 1 equiv, 2 mmol) and
ethyl 4-ethynylbenzoate35 13 (522 mg, 1.5 equiv, 3.0 mmol) under a
N2 atmosphere. Then, PdCl2(MeCN)2 (26 mg, 5 mol %), tri-tert-
butylphosphonium tetrafluoroborate (58 mg, 10 mol %), and CuI (19
mg, 5 mol %) were added to the solution. This mixture was allowed to
stir at 85 °C overnight (14 h) in an oil bath. The reaction was
quenched by the addition of brine (10 mL). The separated aqueous
phase was extracted with Et2O (3 × 10 mL). The combined organic
layers were dried over anhydrous Na2SO4, filtered, and concentrated
under reduced pressure. Then, the crude product was purified by
silica gel column chromatography (eluent, 20:1 hexane/EtOAc
mixture) to afford ethyl 4-[(4-{[4-(4-ethylphenyl)-2-methylbut-3-yn-
2-yl]thio}phenyl)ethynyl]benzoate 14 (750 mg, 83% yield).
N-[4-(4-Methoxyphenyl)-2,2-dimethyl-2H-thiochromen-6-yl]-
acetamide (8jk). Compound 8jk was prepared according to general
procedure C. The crude product was purified by flash column
chromatography on silica gel (2:1 hexane/EtOAc), affording pure 8jk
1
(56% yield, 38 mg). Yellow oil. Rf = 0.42 (2:1 hexane/EtOAc). H
NMR (300 MHz, CDCl3): δ 7.54−7.53 (m, 1H), 7.24−7.20 (m, 3H),
7.04 (d, J = 8.5 Hz, 1H), 6.94−6.90 (m, 2H), 5.74 (s, 1H), 3.86 (s,
3H), 2.19 (s, 3H), 1.47 (s, 6H), one H corresponding to the NH
group is missing. 13C{1H} NMR (75.4 MHz, CDCl3): δ 168.3 (C),
138 (C), 159.3 (C), 132.1 (C), 130.4 (2 × CH), 129.8 (CH), 128.7
(C), 128.5 (CH), 118.6 (CH), 117.8 (C), 116.4 (C), 114.1 (CH),
113.7 (2 × CH), 55.5 (CH3), 53.9 (CH3), 41.0 (C), 29.1 (2 × CH3).
LRMS (EI) m/z (%): 324 (100), 282 (20), 325 (19), 339 (M+, 13).
HRMS (ESI+) m/z: [M + H]+ calcd for C20H22NO2S, 340.1366;
found, 340.1370.
4-[(4-{[4-(4-Ethylphenyl)-2-methylbut-3-yn-2-yl]thio}phenyl)-
ethynyl]benzoate (14). Pale yellow oil. Rf = 0.23 (20:1 hexane/
1
EtOAc). H NMR (300 MHz, CDCl3): δ 1.26 (t, J = 7.6 Hz, 3H),
1.44 (t, J = 7.1 Hz, 3H), 1.68 (s, 6H), 2.67 (q, J = 7.6 Hz, 2H), 4.42
(q, J = 7.1 Hz, 2H), 7.18−7.15 (m, 2H), 7.33−7.31 (m, 2H), 7.64−
7.54 (m, 4H), 7.75−7.72 (m, 2H), 8.09−8.06 (m, 2H). 13C{1H}
NMR (75.4 MHz, CDCl3): δ 166.1 (C) 144.5 (C), 136.5 (2 × CH),
134.0 (C), 131.7 (2 × CH), 131.6 (2 × CH), 131.5 (2 × CH), 130.1
Synthesis of AGN 194310 and Synthesis of 4-(4-Ethyl-
phenyl)-2-methylbut-3-yn-2-ol (11). In a Schlenk flask under a N2
atmosphere, 1-bromo-4-ethylbenzene 10 (2.7 mL, 1 equiv, 20 mmol)
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(C), 129.6 (2 × CH), 127.9 (2 × CH), 127.7 (C), 123.4 (C), 120.3
(C), 93.0 (C), 91.9 (C), 90.2 (C), 83.8 (C), 61.2 (CH2), 43.1 (C),
30.7 (2 × CH3), 28.9 (CH2), 15.5 (CH3), 14.4 (CH3). LRMS (EI)
m/z (%): 420 (100), 151 (51), 150 (38), 452 (M+, 3). HRMS (ESI+)
m/z: [M + H]+ calcd for C30H29O2S, 453.1902; found, 453.1883.
Synthesis of AGN 194310 and Synthesis of Ethyl 4-{[4-(4-
Ethylphenyl)-2,2-dimethyl-2H-thiochromen-6-yl]ethynyl}-
benzoate 15. To a solution of propargyl sulfide 14 (181 mg, 1 equiv,
0.4 mmol) in 1,2-dichloroethane (2 mL, 0.2 M) was added AgOTf
(5.2 mg, 10 mol %). The reaction mixture was heated under
microwave irradiation (128 °C, 150 W, 20 min). After that, the crude
was allowed to cool to room temperature, hexane (4 mL) was added,
and the mixture was filtered through a plug of silica and washed with
hexane. The filtrate was concentrated under reduced pressure. The
residue was purified by silica gel column chromatography (eluent,
20:1 hexane/EtOAc mixture) to afford ethyl 4-{[4-(4-ethylphenyl)-
2,2-dimethyl-2H-thiochromen-6-yl]ethynyl}benzoate 15 (98 mg, 55%
yield, CAS Registry No. 229961-27-7). NMR data were in full
agreement with previously reported spectra.10
4-{[4-(4-Ethylphenyl)-2,2-dimethyl-2H-thiochromen-6-yl]-
ethynyl}benzoate (15). Pale yellow oil. Rf = 0.28 (20:1 hexane/
AcOEt). 1H NMR (300 MHz, CDCl3): δ 8.07−8.03 (m, 2H), 7.61−
7.51 (m, 4H), 7.23−7.20 (m, 4H), 7.09 (d, J = 8.1 Hz, 1H), 5.88 (s,
1H), 4.41 (q, J = 7.1 Hz, 2H), 2.72 (q, J = 7.6 Hz, 2H), 1.50 (s, 6H),
1.43 (t, J = 7.1 Hz, 3H), 1.30 (t, J = 7.6 Hz, 3H). 13C{1H} NMR
(75.4 MHz, CDCl3): δ 166.2 (C),138.5 (C), 137.9 (C), 134.5 (C),
133.8 (C), 133.5 (C), 132.3 (C), 131.6 (2 × CH), 131.5 (C), 131.0
(CH), 130.0 (C), 127.9 (2 × CH), 127.8 (CH), 121.9 (CH), 129.6
(2 × CH), 129.3 (2 × CH), 128.3 (CH), 92.1 (C), 89.6 (C), 61.3
(CH2), 41.0 (C), 29.0 (2 × CH3), 28.7 (CH2), 15.7 (CH3), 14.5
(CH3).
8ah, 8ah′, 8ai, 8aj, 8aj′, 8ha, 8ja, 8jk, 11, 12, 13, 14, 15,
and 16 (ZIP)
FAIR data, including the primary NMR FID files, for
compounds 4al, 7aj, and 7ka (ZIP)
AUTHOR INFORMATION
■
Corresponding Authors
́
Samuel Suárez-Pantiga − Area de Química Orgánica,
Departamento de Química, Facultad de Ciencias,
Universidad de Burgos, 09001 Burgos, Spain; orcid.org/
0000-0002-4249-7807; Email: svsuarez@ubu.es
́
Roberto Sanz − Area de Química Orgánica, Departamento de
Química, Facultad de Ciencias, Universidad de Burgos,
09001 Burgos, Spain; orcid.org/0000-0003-2830-0892;
Email: rsd@ubu.es
Authors
́
Noelia Velasco − Area de Química Orgánica, Departamento
de Química, Facultad de Ciencias, Universidad de Burgos,
09001 Burgos, Spain
Anisley Suárez − Area de Química Orgánica, Departamento
de Química, Facultad de Ciencias, Universidad de Burgos,
09001 Burgos, Spain
Fernando Martínez-Lara − Area de Química Orgánica,
Departamento de Química, Facultad de Ciencias,
Universidad de Burgos, 09001 Burgos, Spain
́
́
́
Manuel Angel Fernández-Rodríguez − Departamento de
Synthesis of AGN 194310 and Synthesis of 4-{[4-(4-
Ethylphenyl)-2,2-dimethyl-2H-thiochromen-6-yl]ethynyl}-
benzoic Acid 16. A solution of thiochromene 15 (90 mg, 0.2 mmol)
in THF (2 mL) was treated with aqueous NaOH (2 mL, 4 M). The
solution was allowed to stir at rt overnight. Then, the mixture was
acidified with HCl [10% (w/w) aqueous solution]. The separated
aqueous phase was extracted with EtOAc (3 × 10 mL). The combined
organic layers were washed with water and brine, dried over
anhydrous Na2SO4, filtered, and concentrated under reduced
pressure. The residue was purified by silica gel column chromatog-
raphy (eluent, 100:1:5 CH2Cl2/MeOH/HCOOH), affording retinoid
acid antagonist AGN194310 16 (62 mg, 73% yield, CAS Registry No.
229961-45-9). NMR data were in full agreement with previously
reported data.10
4-{[4-(4-Ethylphenyl)-2,2-dimethyl-2H-thiochromen-6-yl]-
ethynyl}benzoic Acid (16, AGN194310). Pale yellow oil that solidifies
upon refrigeration. Rf = 0.28 (100:1:5 CH2Cl2/MeOH/HCOOH).
1H NMR [300 MHz, (CD3)2CO]: δ 8.09 (d, J = 8.4 Hz, 2H), 7.72−
7.69 (m, 2H), 7.59−7.58 (m, 1H), 7.59−7.58 (m, 1H), 7.33−7.28
(m, 3H), 7.24−7.21 (m, 2H), 7.10 (d, J = 8.1 Hz, 2H), 5.97 (s, 1H),
2.71 (d, J = 7.6 Hz, 2H), 1.49 (s, 6H), 1.27 (t, J = 7.6 Hz, 3H), one H
corresponding to the COOH group is missing. 13C{1H} NMR [75.4
MHz, (CD3)2CO]: δ 167.1 (C), 144.8 (C), 139.0 (C),138.6 (C),
135.6 (C), 134.9 (C), 134.3 (C), 133.1 (C), 132.5 (2 × CH), 131.4
(CH), 130.7 (2 × CH), 129.9 (2 × CH), 129.1 (CH), 128.8 (2 ×
CH), 128.6 (CH), 128.3 (C), 122.7 (CH), 92.3 (C), 90.2 (C), 41.6
(C), 29.2 (CH2), 29.0 (2 × CH3), 16.1 (CH3).
Química Orgánica y Química Inorgánica, Instituto de
Investigación Química “Andrés M. del Río” (IQAR),
Universidad de Alcalá (IRYCIS), 28805 Madrid, Spain;
orcid.org/0000-0002-0120-5599
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.joc.1c00333
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The authors gratefully acknowledge Junta de Castilla y León
and FEDER (BU291P18 and BU049P20) and Ministerio de
Ciencia e Innovación and FEDER (CTQ2016-75023-C2-1-P)
for financial support. The project leading to these results has
received funding from “la Caixa” Foundation, under Agree-
ment LCF/PR/PR18/51130007> (CAIXA-UBU001). N.V.,
F.M.-L., and S.S.-P. thank Junta de Castilla y León and FSE
and FEDER for predoctoral (N.V. and F.M.-L.) and
postdoctoral (S.S.-P.) contracts, respectively.
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ASSOCIATED CONTENT
■
sı
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.joc.1c00333.
1
Copies of H and 13C{1H} NMR spectra for all new
compounds (PDF)
FAIR data, including the primary NMR FID files, for
compounds 4aa−4aj, 4ba, 4bm, 4aa−4ka, 4jc, 4jk, 4kd,
4kl, 4fn, 5, 6, 7aa−7ae, 7ai, 7ia, 7kd, 7kl, 8aa, 8ab, 8ae,
L
https://doi.org/10.1021/acs.joc.1c00333
J. Org. Chem. XXXX, XXX, XXX−XXX

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pubs.acs.org/joc
Article
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