Cyclopropyl Thioethers, New Inputs for Palladium Catalyzed Ring Opening of Cyclopropanes

Article abstract of DOI:10.1021/acs.oprd.9b00444

We present herein a new palladium-catalyzed ring opening of cyclopropane-substituted thioethers. The study involves an intramolecular trapping of an intermediate aryl palladium to afford thiochromene derivatives. In contrast to the analogous cyclopropylam

Full text of DOI:10.1021/acs.oprd.9b00444

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Communication
Cyclopropyl thioethers, new inputs for Palladium
catalyzed ring-opening of cyclopropanes
Sudipta Ponra, Aude Nyadanu, Na Pan, Elodie Martinand-Lurin, Alexandra
Savy, Maxime R. Vitale, Laurent El Kaim, and Laurence Grimaud
Org. Process Res. Dev., Just Accepted Manuscript • DOI: 10.1021/acs.oprd.9b00444 • Publication Date (Web): 21 Nov 2019
Downloaded from pubs.acs.org on November 24, 2019
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Cyclopropyl thioethers, new inputs for Palladium
catalyzed ring-opening of cyclopropanes
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Sudipta Ponra,‡ Aude Nyadanu,¥ Na Pan,†# Elodie Martinand-Lurin,† Alexandra Savy,†
Maxime Vitale,‡ Laurent El Kaim¥* and Laurence Grimaud. †*
AUTHOR ADDRESS
‡ Institut de Recherche de Chimie Paris, PSL Université Paris – Chimie ParisTech –
CNRS –UMR 8247, 11 rue Pierre et Marie Curie, 75005 Paris, France.
¥ Laboratoire de Synthèse Organique (LSO), CNRS, Ecole Polytechnique, ENSTA
Paris-UMR 7652, Institut Polytechnique de Paris, 828 Bd des Maréchaux, 91128
Palaiseau, France.
# Shanghai Engineering Research Center of Molecular Therapeutics and New Drug
Development, SCME, East China Normal University, 3663 Zhongshanbei Road, 200062,
Shanghai, China.
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†
Laboratoire des biomolécules, Sorbonne Université – Ecole Normale Supérieure –
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CNRS, 24 Rue Lhomond, 75005 Paris, France.
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TOC
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via
Pd(OAc)2 (5 mol%)
PtBu3.HBF4 (10 mol%)
S
S
S
R
R
K2CO3 (2.0 equiv)
Pd Br
L
Br
DMF, MW, 180 o
C
up to 95% yield
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ABSTRACT. We present herein a new palladium-catalyzed ring-opening of
cyclopropane-substituted thioethers. The study involves an intramolecular trapping of an
intermediate aryl palladium to afford thiochromene derivatives. In contrast to the
analogous cyclopropylamines which led to efficient ring-opening using
triphenylphosphine as ligand for palladium, good yields for cyclopropyl thioethers required
the use of bulkier electron-donating phosphines, such as tri-tertbutylphosphine.
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KEYWORDS : Cyclopropane, ring-opening, thioether, palladium catalysis,
thiochromene.
Introduction
Due to high steric constraint with angles close to 60° instead of the standard tetrahedral
geometry around the carbon atom, cyclopropanes constitute a unique class of reactive
alkanes. According to their substitution pattern, a wide range of experimental conditions
has been disclosed for their ring-opening and subsequent trapping by a nucleophile, an
electrophile or a dipolarophile.1 Among the various methods, metal-catalyzed processes
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were highly successful for the ring-opening of alkylidene- or vinyl-cyclopropanes.2 Since
the 70s, alkoxycyclopropanes3 have attracted much attention with the pioneering work of
Nakamura and Kuwajima who disclosed the first Pd-catalyzed opening of a silylated
alkoxycyclopropane and trapping of the resulting homoenolate.4 Comparatively, the
metal-catalyzed ring-opening of aminocyclopropanes5 has significantly received less
attention. Along with some acid-triggered6 and oxidative ring-openings,7 Pd-catalyzed
conditions have been reported a few years ago by our group and others to propose
efficient syntheses of benzo-fused oxa- and aza-heterocycles (Scheme 1, eq. (a) & (b)).8
In contrast, the corresponding ring-opening of cyclopropyl thioethers has been scarcely
reported9 and, to the best of our knowledge, there is no example of such a metal-
catalyzed approach.
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Considering this lack, we decided to study the likelihood of an intramolecular trapping of
cyclopropyl thioethers, as previously disclosed for oxa- and aza- analogues,4c,8 as a
means to generate valuable 4H-thiochromenes in a very efficient and straightforward
manner (Scheme 1, eq. (c)).
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ROC cascade of silyloxy cyclopropanes: 4(c)
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TMSO
Pd(OAc)2, PPh3
O
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TBAF.H2O
eq. (a)
CH3CN, 80°C
Br
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92%
ROC cascade of aminocyclopropanes:8
R
R
N
R
N
O
N
O
O
Pd cat, base
Br
eq. (b)
+
This work:
Pd(OAc)2 (5 mol%)
S
S
eq. (c)
PtBu3.HBF4 (10 mol%)
K2CO3 (2.0 equiv)
DMF, MW, 180 oC
Br
R
R
Scheme 1. Palladium triggered ring-opening/cyclization of RO, R2N and RS-tethered
cyclopropanes
Results and Discussion
Following our past interest in the ring-opening of aminocyclopropanes, experimental
conditions close to those developed previously were tested first. For this purpose, 2-
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bromophenyl cyclopropyl thioether 1a was prepared through the alkylation of the 2-bromo
thiophenol under classical basic reaction conditions.10 The mercaptocyclopropane 1a
was then treated in the presence of 5 mol% of PdCl2(PPh3)2 in wet acetonitrile with 2
equiv of cesium carbonate under microwave irradiation at 130 °C for 20 min (entry 1,
Table 1).11 Nevertheless, no reaction occurred under these conditions, even when
increasing the reaction temperature up to 180 °C. Faced to such an absence of reactivity,
we thus decided to use a commercially available Pd(0) source, with the hope to boost the
expected catalytic activity. For this purpose, Pd2(dba)3 was selected as catalyst and
different ligands were tested next. In order to perform the reaction at higher temperature,
N,N-dimethylformamide was selected as solvent. Poor conversions were observed at 180
°C with common phosphines such as triphenylphosphine, tri-ortho-tolylphosphine and
dppf (entries 2-4, Table 1). Based on the hypothesis that these disappointing results could
result from a sluggish oxidative addition arising from the electron-donating effect of the
thiocyclopropyl moiety, conditions close to those reported for the cross-coupling of aryl
chlorides12 were enforced (entry 5, Table 1). To our delight, the use of tri(tert-
butyl)phosphine turned out to be highly beneficial, leading to a 66% of conversion after
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only 20 min. Unfortunately, longer reaction time induced a significantly higher level of
competititive decomposition. Several bases were then assessed (entries 8-10, Table 1)
and potassium carbonate turned out to give the best results. Indeed, tertiary amine bases
showed prone to partially induce the undesired isomerization of C=C bond (entries 8 and
10, Table 1). N,N-dimethylformamide and N,N-dimethylacetamide gave similar results
(entries 5-6, Table 1) but acetonitrile reduced conversion (entry 7, Table 1). Finally,
sources of Pd(II) were tested with tri-tertbutylphosphine (entries 11-12, Table 1) and,
pleasingly, complete conversion was achieved starting with Pd(OAc)2. With these
optimized conditions, the desired thiochromene 2a was isolated in 70% yield.
Surprisingly, all trials to give higher yields failed, even when the crude NMR of the reaction
mixture was very clean. This behavior was attributed to the air sensitivity of the 2a during
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1
the purification process. Indeed, after 24 h at room temperature, the H NMR spectrum
unmistakably showed a prominent level of product decomposition.
Table 1. Optimization of the reaction conditions.
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Pd cat (5 mol%)
S
S
Ligand (10 mol%)
base (2 equiv)
DMF, W
Br
1a
2a
20 min, 180 °C
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Entry
Cat.
Ligand
Base
Conversion[a]
(isolated yields %)
0%[b]
1
2
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8
PdCl2(PPh3)2
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
-
Cs2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
PPh3
4%
14%
P(o-tol)3
dppf
0%
P(tBu)3.HBF4
P(tBu)3.HBF4
P(tBu)3.HBF4
P(tBu)3.HBF4
66%
68%[c]
<5%[d]
60%[e]
N
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Pd2(dba)3
Pd2(dba)3
PdCl2
P(tBu)3.HBF4
P(tBu)3.HBF4
P(tBu)3.HBF4
P(tBu)3.HBF4
TMEDA
iPr2NEt
K2CO3
K2CO3
46%
66%[f]
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6%
Pd(OAc)2
100% (70%)[g]
[a] Evaluated by 1H NMR. [b] performed in MeCN at 130 °C. [c] performed in DMA
instead of DMF. [d] performed in MeCN. [e] Product obtained as a 1:1 mixture of two
regiomers. [f] Product obtained as a 2:1 mixture of two regioisomers. [g] Yields did not
exceed 20% when performed under thermic conditions (oil bath).
In order to assess the scope of this new Pd-catalyzed ring-opening of cyclopropyl
thioethers, a wider set of starting materials were prepared. They were synthesized by
either direct alkylation of o-bromothiophenol derivatives with bromo cyclopropane10 or
bromination of the corresponding cyclopropane arylthioether13 (Scheme 2). After
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electrophilic aromatic acylation of products 1c and 1d, substrates 1b an 1e-i were thereby
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obtained.
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R = H
(ii)
R
SH
Br
S
R
S
(i)
R'
Br
Br
O
1a
1b
R = H, 52%
R = Cl, 38%
1c
1d
R' = Me, 45%
R' = Bn, 86%
S
SH
S
(iii)
(i)
R
Br
R
R
1e
1f
R = Me, 62%
R = Et, 43%
R = i-Pr, 74%
R = Me, 89%
R = Et, 61%
1g
1h
1i
R = i-Pr, 45%
R = tBu, 78%
R = 3,4-OMe, 95%
t
R = Bu, 90%
R = 4,5-(OMe)2, 56%
Conditions
: (i) bromocyclopropane (1.3 equiv), K2CO3 (1.5 equiv), DMF, 24h
(ii) R'COCl (5 equiv), AlCl3 (1.2 equiv), CHCl3, 0 oC to rt, 3h. (iii) Br2 (1.6 equiv), CHCl3, 0
oC to rt, 6h.
Scheme 2. Starting material syntheses.
With the set of optimized conditions in hand, we investigated the scope and limitations
of the Pd-catalyzed reaction (scheme 3). Electron-poor starting materials afforded the
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corresponding thiochromenes in low yields due to fast decomposition of the crude
mixture. Indeed, compounds 2b and 2c gave very low isolated yields of the corresponding
thiochromenes and 2d -obtained from 1d- decomposed under the reaction conditions.
The presence of an acyl group in 2c provoked the isomerization of the double bond in the
final product probably due to enhanced conjugation of the resulting regiomer. However,
for electron-rich arylthioethers, the desired thiochromenes 2e-2i were obtained in fair to
good yields. Moreover, the reaction can be performed on the gram scale and 2a was
isolated with a slightly reduced 55% yield.
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Pd(OAc)2 (5 mol%)
PtBu3.HBF4 (10 mol%)
S
S
R
R
K2CO3 (2.0 equiv)
DMF, MW, 180 oC, 20 min
Br
1
2
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S
S
Cl
S
R
O
a
b
2b
(5%)
2a
2c
2d
(70%)
S
R = Me
R = Bn
(33%,regiomers 2.5:1)
decomposition
MeO
MeO
S
2e
R = Me
2f
R = Et (95%)
R = i-Pr
R = t-Bu
(74%)
2g
2h
(89%)
(66%)
R
2i
(54%)
a 55% for gram scale of starting material
b The minor regiomer is the one with the C=C bond conjugated with the aromatic core
Scheme 3. Scope of the reaction.
To the best of our knowledge, this reaction constitutes the first example of metal
triggered ring-opening of non-substituted cyclopropyl thioethers. The reaction turned out
to be less general than those relying on oxygen- or nitrogen-based derivatives. However,
this method provides an unparalleled and straightforward access to thiochromenes,
structures that have been narrowly reported in the literature so far and for which scarce
synthetic routes have been described.14 Worthy of note, thiochromenes are direct
precursors of thiochromane derivatives, many of which possess interesting biological
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properties encompassing anti-hypertensive ((-)-tertatolol), antibacterial and antifungal
activities (Scheme 4).15-17
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O
O
S
R
Ph
N
OH
S
H
S
N
O
R = H, OMe, Cl
(-)-tertatolol
noncardioselective beta-blocker11
Antifungal12
Antibacterial13
Scheme 4. Thiochromanes with biological activities.
Finally, by analogy to our previous work and related studies,8 we propose the following
mechanistic scenario (Scheme 5). Upon oxidative addition of the starting arylbromide 1a
onto an in situ generated monoligated Pd(0) complex, the resulting aryl-Pd(II)
intermediate A would then evolve through an intramolecular ring-enlargement process,
which would likely be assisted by the nucleophilic character of the neighbouring sulfur
atom. This key event would induce the formation of the 7-membered palladacycle B
which, upon reductive elimination and carbonate-promoted proton abstraction, would
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allow the formation of the thiochromene 2a. While we previsouly demonstrated that the
palladium-catalyzed ring opening of aminocyclopropyl derivatives is rather facile as
compared to that of the cyclopropyl thioethers,8(b) we suggest that, in the latter case, the
oxidative addition onto Pd(0) is rather a sluggish step. Indeed, as often observed in the
case of reluctant oxidative additions, the very electron-rich phosphine ligand P(tBu)3 is
compulsory for obtaining satisfactory results. Hence, the presence of the sulfur atom in
ortho position of the bromine atom probably increases the electron density of the aromatic
ring to such an extent that the oxidative addition is dramatically hampered. On the other
hand, the necessity of using an electron rich phosphine ligand such as P(tBu)3 may
decrease the electrophilic character of the palladium center in intermediate A and,
consequently, might render the rearrangement process more difficult. Further
mechanistic studies are ongoing and will be reported in due course.
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Pd(OAc)2, P(tBu)3
S
S
K2CO3 (1 equiv)
6
7
8
DMF, 180°C,
µW, 20 min
Br
2a
1a
B-H
9
B
R.E.
Pd(0)L
L = P(tBu)3
O.A.
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Pd(0)L
B = CO32
S
S
thio-assisted
ring-opening
Pd Br
L
Pd
L
A
B
Scheme 5. Mechanistic proposal.
Conclusions
To conclude, we have reported here the first Pd-catalyzed ring opening of
thiocyclopropanes. The ability of sulfur to act as ligand for transition metals and potentially
disturb the ring opening process was among some of the questions raised by the project.
The moderate yield and lower scope of the fragmentation of thiocyclopropanes compared
to the related nitrogen derivatives may be related to such interactions. Anyhow our results
shed the light on an unusual fragmentation process that could find further applications
using either palladium for the formation of monocyclic thioheterocycles or even other
transition metals. Further directions involving competing CH activations of
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thiocyclopropanes as observed for amino analogues might be also interesting to
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Experimental Section
All reactions were performed under argon atmosphere. Solvents were distilled or
purified with a purification system using activated alumina columns before use. All
products were purified by flash chromatography using silica gel (230-400 mesh). 1H-NMR
and 13C-NMR were recorded in CDCl3 with chemical shifts reported for 1H NMR relative
to residual CHCl3 peak (7.26 ppm). For 13C NMR, chemical shifts were reported relative
to the central peak of CDCl3 (77.16 ppm). HRMS data for new compounds were obtained
electrospray ionization method coupled to a LTQ-Orbitrap high resolution detector in
positive mode. All microwave reactions were carried out using Anton Paar Microwave
Synthesis Reactor (Monowave 300). Unless otherwise noted, all the reagents were
ordered and used without further purification.
General procedure for the alkylation reaction:10 To a stirred solution of substituted
thiophenol (1.0 mmol) and K2CO3 (1.50 equiv) in dry DMF (2 mL) under argon atmosphere
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was added bromocyclopropane (1.3 equiv). The mixture was heated at 120 oC for 24 h
and then cooled to room temperature. After TLC shows complete conversion of thiols the
crude reaction mixture was diluted with methyl tert-butyl ether, excess K2CO3 was
removed by filtration and washed with saturated Na2CO3 solution (3 x 5 mL). After
separation of organic layer the aqueous phase was then extracted with methyl tert-butyl
ether (2 x 20 mL) and the combined organic extracts washed by water (5 x 40 mL) and
brine (40 mL) before being dried over MgSO4. After filtration and evaporation of the
solvents under reduced pressure, the crude material was purified by flash column
chromatography on silica gel to afford the desired cyclopropyl(phenyl)sulfane derivative
1.
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General procedure for bromination reaction:13 Under argon atmosphere
cyclopropyl(phenyl)sulfane derivative (1.0 mmol) was dissolved in 2 mL CHCl3 and stirred
at 0 oC for 10 minutes. To this ice cold solution, Br2 (1.6 equiv) was added dropwise and
after addition the reaction mixture was stirred at room temperature for further 6 h. After
TLC showed complete conversion of cyclopropyl(phenyl)sulfane derivative, the crude
reaction mixture was quenched with saturated Na2S2O3 solution (10 mL) and diluted with
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CH2Cl2 (15 mL). After separation of organic layer the aqueous phase was then extracted
with CH2Cl2 (2 x 20 mL) and the combined organic extracts washed by water (40 mL) and
brine (40 mL) before being dried over MgSO4. After filtration and evaporation of the
solvents under reduced pressure, the crude material was purified by flash column
chromatography on silica gel to afford the desired brominated product 1.
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General procedure for acylation reaction: In an oven dried flask under argon
atmosphere were sequentially introduced AlCl3 (1.2 equiv), acyl chloride (5.0 equiv), 2 mL
CHCl3 and stirred at 0 oC for 15 minutes. To this ice cold solution (2-
bromophenyl)(cyclopropyl)sulfane (1.0 mmol) was added dropwise and after addition the
reaction mixture was stirred at room temperature for further 3 h. After TLC shows
complete conversion of (2-bromophenyl)(cyclopropyl)sulfane derivative, the crude
reaction mixture was quenched with ice water (5 mL) and neutralized by HCl until pH = 2.
The whole mixture was diluted with CH2Cl2 (10 mL) and after separation of organic layer
the aqueous phase was extracted with CH2Cl2 (2 x 20 mL) and the combined organic
extracts washed by water (40 mL) and brine (40 mL) before being dried over MgSO4.
After filtration and evaporation of the solvents under reduced pressure, the crude material
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was purified by flash column chromatography on silica gel to afford the desired acylated
product.
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(2-Bromophenyl)(cyclopropyl)sulfane (1a): Starting from 2-bromothiophenol (189 mg,
118 µL, 1.0 mmol) and bromocyclopropane (157 mg, 104 µL, 1.3 mmol) and following the
general
procedure
of
cyclopropanation
reaction,
the
desired
(2-
bromophenyl)(cyclopropyl)sulfane 1a was obtained as a colorless oil (120 mg, 52% yield).
1H NMR (300 MHz, CDCl3) δ 7.57-7.48 (m, 2H), 7.30 (td, J = 7.8, 1.2 Hz, 1H), 7.00 (td, J
= 7.7, 1.5 Hz, 1H), 2.14 (tt, J = 7.4, 4.4 Hz, 1H), 1.14 (td, J = 6.6, 4.9 Hz, 2H), 0.78-0.69
(m, 2H); 13C NMR (75 MHz, CDCl3) δ 140.5, 132.6, 127.7, 126.4, 125.7, 120.7, 11.9, 8.5;
HRMS (ESI) m/z: [M]+● calcd for C9H9BrS 227.9608, found: 227.9609.
(2-Bromo-5-chlorophenyl)(cyclopropyl)sulfane (1b): Starting from 2-bromo-5-
chlorobenzenethiol (223.5 mg, 1.0 mmol) and bromocyclopropane (157 mg, 104 µL, 1.3
mmol) and following the general procedure of cyclopropanation reaction, the desired (2-
bromo-5-chlorophenyl)(cyclopropyl)sulfane 1b was obtained as colorless oil (100 mg,
1
38% yield). H NMR (300 MHz, CDCl3) δ 7.48 (d, J = 2.4 Hz, 1H), 7.39 (d, J = 8.4 Hz,
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1H), 6.97 (dd, J = 8.4, 2.4 Hz, 1H), 2.18-2.06 (m, 1H), 1.24-1.13 (m, 2H), 0.80-0.66 (m,
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2H); C NMR (75 MHz, CDCl3) δ 142.8, 134.0, 133.5, 125.9, 125.8, 118.3, 11.9, 8.6;
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HRMS (ESI) m/z: [M]+● calcd for C9H8BrClS 261.9219, found: 261.9218.
1-(3-Bromo-4-(cyclopropylthio)phenyl)ethanone (1c): Starting from acetyl chloride (392
mg, 355 µL, 5.0 mmol) and following the general procedure of acylation reaction, the
desired 1-(3-bromo-4-(cyclopropylthio)phenyl)ethanone 1c was obtained as grey colored
crystalline solid (121 mg, 45% yield), mp 66-68 oC. 1H NMR (300 MHz, CDCl3) δ 8.06 (d,
J = 1.8 Hz, 1H), 7.87 (dd, J = 8.3, 1.8 Hz, 1H), 7.61 (d, J = 8.3 Hz, 1H), 2.56 (s, 3H), 2.15
(tt, J = 7.4, 4.4 Hz, 1H), 1.24-1.15 (m, 2H), 0.81-0.73 (m, 2H); 13C NMR (75 MHz, CDCl3)
δ 196.0, 147.8, 134.7, 132.4, 127.4, 125.6, 120.3, 26.5, 11.8, 8.6; HRMS (ESI) m/z: [M]+●
calcd for C11H11BrOS 269.9714, found: 269.9715.
1-(3-Bromo-4-(cyclopropylthio)phenyl)-2-phenylethanone
(1d):
Starting
from
phenylacetyl chloride (773 mg, 622 µL, 5.0 mmol) and following the general procedure of
acylation reaction, the desired 1-(3-bromo-4-(cyclopropylthio)phenyl)-2-phenylethanone
1d was obtained as a grey colored crystalline solid (298 mg, 86% yield), mp 92-94 oC. 1H
NMR (300 MHz, CDCl3) δ 8.11 (d, J = 1.8 Hz, 1H), 7.91 (dd, J = 8.3, 1.8 Hz, 1H), 7.59 (d,
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J = 8.3 Hz, 1H), 7.39-7.19 (m, 5H), 4.21 (s, 2H), 2.22-2.05 (m, 1H), 1.23-1.13 (m, 2H),
0.80-0.68 (m, 2H); 13C NMR (75 MHz, CDCl3) δ 195.6, 148.0, 134.4, 134.1, 132.7, 129.5,
128.9, 127.8, 127.1, 125.6, 120.4, 45.5, 11.8, 8.6; HRMS (ESI) m/z: [M]+● calcd for
C17H15BrOS 346.0027, found: 346.0018.
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(2-Bromo-4-methylphenyl)(cyclopropyl)sulfane (1e): Starting from 4-methylthiophenol
(500 mg, 4.03 mmol) and following the general procedure of cyclopropanation reaction,
the desired cyclopropyl(p-tolyl)sulfane was obtained as colorless oil (590 mg, 89% yield).
1H NMR (300 MHz, CDCl3) δ 7.29 (d, J = 8.2 Hz, 2H), 7.12 (d, J = 8.0 Hz, 2H), 2.33 (s,
13
3H), 2.20 (tt, J = 7.4, 4.4 Hz, 1H), 1.09-0.99 (m, 2H), 0.76-0.64 (m, 2H); C NMR (75
MHz, CDCl3) δ 135.1, 129.6, 127.4, 21.0, 12.8, 8.6; HRMS (ESI) m/z: [M]+● calcd for
C10H12BrS 164.0660, found: 164.0660. Starting from cyclopropyl(p-tolyl)sulfane (490 mg,
2.98 mmol) and following the general procedure of bromination reaction, the desired (2-
bromo-4-methylphenyl)(cyclopropyl)sulfane 1e was obtained as colorless oil (453 mg,
1
62% yield). H NMR (300 MHz, CDCl3) δ 7.42 (d, J = 8.1 Hz, 1H), 7.34 (d, J = 1.0 Hz,
1H), 7.11 (ddd, J = 8.0, 1.8, 0.7 Hz, 1H), 2.30 (s, 3H), 2.14 (tt, J = 7.4, 4.4 Hz, 1H), 1.17-
1.05 (m, 2H), 0.79-0.64 (m, 2H); 13C NMR (75 MHz, CDCl3) δ 136.7, 136.1, 133.2, 128.7,
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126.7, 120.9, 20.6, 12.2, 8.5; HRMS (ESI) m/z: [M]+● calcd for C10H11BrS 241.9765,
found: 241.9759.
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(2-Bromo-4-ethylphenyl)(cyclopropyl)sulfane (1f): Starting from 4-ethylthiophenol (1.00
g, 7.20 mmol) and following the general procedure of cyclopropanation reaction, the
desired cyclopropyl(4-ethylphenyl)sulfane was obtained as colorless oil (785 mg, 61%
yield). 1H NMR (300 MHz, CDCl3) δ 7.33 (d, J = 8.2 Hz, 2H), 7.15 (d, J = 8.2 Hz, 2H), 2.64
(q, J = 7.6 Hz, 2H), 2.20 (tt, J = 7.4, 4.4 Hz, 1H), 1.25 (t, J = 7.6 Hz, 3H), 1.10-1.00 (m,
13
2H), 0.75-0.66 (m, 2H) ; C NMR (75 MHz, CDCl3) δ 141.3, 135.2, 128.3, 127.1, 28.3,
15.6, 12.5, 8.5 ; HRMS (APPI) m/z: [M]+● calcd for C11H14S : 178.0816, found:178.0813.
Starting from cyclopropyl(4-ethylphenyl)sulfane (763 mg, 4.30 mmol) and following the
general
procedure
of
bromination
reaction,
the
desired
(2-bromo-4-
ethylphenyl)(cyclopropyl)sulfane 1f was obtained as colorless oil (471 mg, 43% yield). 1H
NMR (300 MHz, CDCl3) δ 7.45 (d, J = 8.1 Hz, 1H), 7.37 (d, 1.8 Hz, 1H), 7.14 (dd, J = 8.0,
1.8 Hz, 1H), 2.60 (q, J = 7.6 Hz, 2H), 2.19-2.09 (m, 1H), 1.22 (t, J = 7.6 Hz, 3H), 1.16-
1.07 (m, 2H), 0.78-0.69 (m, 2H) ; 13C NMR (75 MHz, CDCl3) δ 142.3, 136.8, 131.9, 127.3,
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126.5, 120.7, 27.9, 15.4, 11.9, 8.4 ; HRMS (APPI) m/z: [M]+● calcd for C11H13BrS :
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255.9921, found : 255.9922.
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(2-Bromo-4-isopropylphenyl)(cyclopropyl)sulfane
(1g):
Starting
from
4-
isopropylthiophenol (1.00 g, 6.60 mmol) and following the general procedure of
cyclopropanation reaction, the desired cyclopropyl(4-isopropylphenyl)sulfane was
obtained as colorless oil (565 mg, 45% yield). 1H NMR (300 MHz, CDCl3) δ 7.34 (d, J =
8.3 Hz, 2H), 7.19 (d, J = 8.3 Hz, 2H), 2.90 (hept, J = 6.9 Hz, 1H), 2.21 (tt, J = 7.4, 4.4 Hz,
1H), 1.27 (d, J = 6.9 Hz, 6H), 1.10-1.01 (m, 2H), 0.76-0.68 (m, 2H) ; 13C NMR (75 MHz,
CDCl3) δ 145.9, 135.3, 127.0, 126.8, 33.6, 24.0, 12.4, 8.4 ; HRMS (APPI) m/z: [M]+● calcd
for C12H16S
:
192.0973, found: 192.0971. Starting from cyclopropyl(4-
isopropylphenyl)sulfane (487 mg, 2.50 mmol) and following the general procedure of
bromination reaction, the desired (2-bromo-4- isopropylphenyl)(cyclopropyl)sulfane 1g
was obtained as colorless oil (507 mg, 74% yield). 1H NMR (300 MHz, CDCl3) δ 7.46 (d,
J = 8.1 Hz, 1H), 7.37 (d, J = 1.9, 1H), 7.17 (dd, J = 8.1, 1.9 Hz, 1H), 2.85 (hept, J = 6.9
Hz, 1H), 2.17-2.10 (m, 1H), 1.23 (d, J = 6.9 Hz, 6H), 1.16-1.07 (m, 2H), 0.77-0.69 (m,
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2H) ; 13C NMR (75 MHz, CDCl3) δ 147.1, 136.9, 130.6, 126.5, 125.9, 120.7, 33.4, 23.8,
11.9, 8.4 ; HRMS (APPI) m/z: [M]+● calcd for C12H15BrS: 270.0078, found: 270.0082.
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(2-Bromo-4-tert-butylphenyl)(cyclopropyl)sulfane
(1h):
Starting
from
4-tert-
butylbenzenethiol (1.34 mL, 8.0 mmol) and following the general procedure of
cyclopropanation reaction, the desired (4-tert-butylphenyl)(cyclopropyl)sulfane was
obtained as colorless oil (1.28 g, 78% yield). 1H NMR (300 MHz, CDCl3) δ 7.33 (s, 4H),
2.19 (tt, J = 7.4, 4.4 Hz, 1H), 1.32 (s, 9H), 1.10-1.00 (m, 2H), 0.74-0.65 (m, 2H); 13C NMR
(75 MHz, CDCl3) δ 148.4, 135.3, 126.9, 125.9, 34.5, 31.5, 27.1, 12.6, 8.6; HRMS (ESI)
m/z: [M]+● calcd for C13H18S 206.1129, found: 206.1124. Starting from (4-tert-
butylphenyl)(cyclopropyl)sulfane (400 mg, 1.94 mmol) and following the general
procedure
of
bromination
reaction,
the
desired
(2-bromo-4-tert-
butylphenyl)(cyclopropyl)sulfane 1h was obtained as colorless oil (496 mg, 90% yield).
1H NMR (300 MHz, CDCl3) δ 7.53 (d, J = 2.2 Hz, 1H), 7.51 (dd, J = 8.2 Hz, 1H), 7.34 (dd,
J = 8.2, 2.2 Hz, 1H), 2.14 (tt, J = 7.4, 4.4 Hz, 1H), 1.31 (s, 9H), 1.17-1.08 (m, 2H), 0.78-
0.68 (m, 2H); 13C NMR (75 MHz, CDCl3) δ 149.6, 136.9, 129.8, 126.4, 125.0, 120.8, 34.5,
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(2-Bromo-4,5-dimethoxyphenyl)(cyclopropyl)sulfane
(1i):
Starting
from
3,4-
dimethoxybenzenethiol (170 mg, 145 µL, 1.0 mmol) and following the general procedure
of cyclopropanation reaction, the desired cyclopropyl(3,4-dimethoxyphenyl)sulfane was
obtained as slightly grey colored crystalline solid (200 mg, 95% yield), mp 82-84 C. 1H
o
NMR (300 MHz, CDCl3) δ 7.01-6.90 (m, 2H), 6.82 (d, J = 8.3 Hz, 1H), 3.87 (s, 3H), 3.86
(s, 3H), 2.19 (tt, J = 7.4, 4.4 Hz, 1H), 1.00 (td, J = 6.5, 4.8 Hz, 2H), 0.73-0.63 (m, 2H); 13C
NMR (75 MHz, CDCl3) δ 149.3, 147.8, 129.5, 120.9, 112.3, 112.0, 56.2, 56.0, 13.9, 8.6;
HRMS (ESI) m/z: [M]+● calcd for C11H14O2S 210.0715, found: 210.0705. Starting from
cyclopropyl(3,4-dimethoxyphenyl)sulfane (200 mg, 0.95 mmol) and following the general
procedure
of
bromination
reaction,
the
desired
(2-bromo-4,5-
dimethoxyphenyl)(cyclopropyl)sulfane 1i was obtained as white colored amorphous solid
o
1
(496 mg, 56% yield), mp 93-95 C. H NMR (300 MHz, CDCl3) δ 7.10 (s, 1H), 7.02 (s,
1H), 3.89 (s, 3H), 3.85 (s, 3H), 2.19 (tt, J = 7.4, 4.4 Hz, 1H), 1.14-1.04 (m, 2H), 0.81-0.68
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(m, 2H); 13C NMR (75 MHz, CDCl3) δ 149.0, 147.8, 130.7, 116.2, 112.4, 111.7, 56.4, 56.3,
13.1, 8.6; HRMS (ESI) m/z: [M]+● calcd for C11H13BrO2S 287.9820, found: 287.9826.
General procedure for Pd-catalyzed cyclopropane ring opening reaction (2): In an oven
dried microwave glass vial reactor under argon atmosphere sequentially introduced
substituted (2-bromophenyl)(cyclopropyl)sulfane 1 (1.0 mmol), DMF (2 mL) and
degassed with argon for 20 minutes. To this reaction mixture Pd(OAc)2 (0.05 equiv),
PtBu3.HBF4 (0.1 equiv), K2CO3 (2 equiv) were carefully introduced. The whole reaction
mixture was heated under microwave irradiation at 180 oC for 20 minutes. After TLC
shows complete conversion of (2-bromophenyl)(cyclopropyl)sulfane derivative the crude
reaction mixture was diluted with Et2O (10 mL) and H2O (10 mL). After separation of
organic layer the aqueous phase was further extracted with Et2O (2 x 20 mL) and the
combined organic extracts washed by water (5 x 40 mL) and brine (40 mL) before being
dried over MgSO4. After filtration and evaporation of the solvents under reduced pressure,
the crude material was purified by flash column chromatography on silica gel to afford the
desired thiopyran derivative 2.
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4H-Thiochromene (2a): Starting from (2-bromophenyl)(cyclopropyl)sulfane 1a (100 mg,
0.436 mmol), Pd(OAc)2 (4.9 mg, 0.021 mmol), PtBu3.HBF4 (12.6 mg, 0.044 mmol), K2CO3
(121 mg, 0.872 mmol) and following the general procedure of cyclopropane ring opening
reaction, the desired 4H-thiochromene 2a was obtained as colorless oil (45 mg, 70%
yield). The same reaction performed using 1g of 1a, Pd(OAc)2 (49 mg, 0.22 mmol) and
PtBu3.HBF4 (128 mg, 0.44 mmol), K2CO3 (1.20g, 8.72 mmol) to give 356 mg of 2a (55%).
1H NMR (400 MHz, CDCl3) δ 7.20-7.16 (m, 1H), 7.11-7.00 (m, 3H), 6.32 (dt, J = 9.1, 1.1
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Hz, 1H), 5.95 (dt, J = 9.1, 4.7 Hz, 1H), 3.30 (d, J = 4.7 Hz, 2H); C NMR (101 MHz,
CDCl3) δ 132.6, 132.2, 128.7, 126.7, 126.6, 126.5, 122.4, 120.9, 31.7; HRMS (ESI) m/z:
[M]+● calcd for C9H8S 148.0347, found: 148.0332.
7-Chloro-4H-thiochromene
(2b):
Starting
from
(2-bromo-5-
chlorophenyl)(cyclopropyl)sulfane 1b (150 mg, 0.57 mmol), Pd(OAc)2 (12.8 mg, 0.057
mmol), PtBu3.HBF4 (33.0 mg, 0.114 mmol), K2CO3 (157 mg, 1.14 mmol) and following the
general procedure of cyclopropane ring opening reaction for 1 h, the desired 7-chloro-4H-
1
thiochromene 2b was obtained as colorless oil (5 mg, 5% yield). H NMR (400 MHz,
CDCl3) δ 7.18 (s, 1H), 7.03 (d, J = 8.1 Hz, 1H), 6.94 (d, J = 8.1 Hz, 1H), 6.44 (d, J = 9.8
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Hz, 1H), 5.94 (dt, J = 9.8, 5.0 Hz, 1H), 3.45 (d, J = 5.0 Hz, 2H); C NMR (101 MHz,
CDCl3) δ 133.7, 133.3, 130.7, 129.1, 128.5, 126.9, 125.8, 122.0, 25.1; HRMS (ESI) m/z:
[M]+● calcd for C9H7ClS 181.9957, found: 181.9952.
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6-Methyl-4H-thiochromene
(2e):
Starting
from
(2-bromo-4-
methylphenyl)(cyclopropyl)sulfane 1e (120 mg, 0.493 mmol), Pd(OAc)2 (5.6 mg, 0.025
mmol), PtBu3.HBF4 (14.3 mg, 0.049 mmol), K2CO3 (136 mg, 0.986 mmol) and following
the general procedure of cyclopropane ring opening reaction, the desired 6-methyl-4H-
1
thiochromene 2e was obtained as colorless oil (59 mg, 74% yield). H NMR (400 MHz,
CDCl3) δ 7.05 (d, J = 7.9 Hz, 1H), 6.91-6.83 (m, 2H), 6.31 (dd, J = 9.0, 1.0 Hz, 1H), 5.95-
5.90 (m, 1H), 3.25 (d, J = 4.5 Hz, 2H), 2.22 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 136.5,
132.5, 129.4, 128.7, 127.3, 126.4, 122.3, 121.0, 31.6, 21.0; HRMS (ESI) m/z: [M]+● calcd
for C10H10S 162.0503, found: 162.0497.
6-Ethyl-4H-thiochromene
(2f):
Starting
from
(2-bromo-4-
ethylphenyl)(cyclopropyl)sulfane 1f (202 mg, 0.79 mmol), Pd(OAc)2 (8.8 mg, 0.039 mmol),
PtBu3.HBF4 (22.9 mg, 0.079 mmol), K2CO3 (217 mg, 1.57 mmol) and following the general
procedure of cyclopropane ring opening reaction, the desired 6-ethyl-4H-thiochromene 2f
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