Functionalization of [2.2]Paracyclophanes via a Reductive Sulfanylation Reaction

Article abstract of DOI:10.1021/acs.joc.0c02235

An expeditious route to planar chiral sulfur-based scaffolds has been achieved in two operational steps from cheap and commercial [2.2]paracyclophane hydrocarbon. The sulfur atom was introduced in a specific benzylic position of the [2.2]paracyclophane according to a reductive sulfanylation reaction, which proceeds under two complementary reaction conditions with either the BF3·OEt2/Et3SiH or TFA/BH3·THF combinations. The study was completed by the development of a highly efficient resolution approach by HPLC.

Full text of DOI:10.1021/acs.joc.0c02235

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Functionalization of [2.2]Paracyclophanes via a Reductive
Sulfanylation Reaction
Damien Deschamps, Jean-Franco̧ is Lohier, Christopher J. Richards, Annie-Claude Gaumont,
́
and Stephane Perrio*
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ABSTRACT: An expeditious route to planar chiral sulfur-based
scaffolds has been achieved in two operational steps from cheap and
commercial [2.2]paracyclophane hydrocarbon. The sulfur atom was
introduced in a specific benzylic position of the [2.2]paracyclophane
according to a reductive sulfanylation reaction, which proceeds under
two complementary reaction conditions with either the BF3·OEt2/
Et3SiH or TFA/BH3·THF combinations. The study was completed by
the development of a highly efficient resolution approach by HPLC.
always possible to transfer well-established aromatic chemistry
to the [2.2]PCP series, without being faced with low yields,
uncontrolled regioselectivities, or unusual reactivities. As a
consequence, special efforts are often required for optimiza-
tion. Furthermore, [2.2]PCP derivatives exhibit a unique
reactivity related to strong transannular interactions.
INTRODUCTION
■
Discovered by Brown and Farthing1 70 years ago, [2.2]-
paracyclophane ([2.2]PCP) is the parent hydrocarbon of a
fascinating family of organic scaffolds (Figure 1).2 It involves a
Inspired by our continuous interest in sulfur chemistry,6 we
previously described the results of our investigations
concerning the synthesis and the applications of monosub-
stituted sulfur-based [2.2]paracyclophanes.7 In the targeted
structures, the heteroatom atom was directly attached to one
aromatic deck of the [2.2]PCP (Y = SR1, Figure 1).
Considering the attractive reactivity of benzylic sulfur
derivatives,8 we decided to turn out attention toward
[2.2]PCP platforms, in which the sulfur center is located
further from the ring, at a lateral benzylic position (Y =
CH2SR1, Figure 1).9 However, to the best of our knowledge,
literature precedents for this subclass of [2.2]PCP-based
synthons remain surprisingly elusive. There are two common
methodologies for the synthesis of such scaffolds, both of
which provide racemic products. The most conventional one
consists of a substitution reaction with the displacement of a
benzylic halogen atom in the presence of a nucleophilic sulfur
source10 (Scheme 1a), whereas the other takes profit of the
Figure 1. Parent [2.2]paracyclophane and planar chiral monosub-
stituted derivatives
compact arrangement of two cofacially stacked and strongly
interacting benzene units, linked together at the para positions
by ethylene groups. The unique structural, physical, and
electronic properties of [2.2]PCP derivatives have resulted in
significant attention.3 They have been successfully applied in
numerous fields, such as energy materials, functional poly-p-
xylylene (parylene) coatings, π-stacked polymers, and exten-
sively used in asymmetric synthesis and catalysis.4 Indeed, an
important facet of [2.2]PCP chemistry is related to the
inherent planar chirality of these systems. The presence of a
single substituent on the [2.2]PCP skeleton breaks the plane of
symmetry of the molecule and generates enantiomers (Figure
1). As no asymmetric synthesis methods are available from the
achiral [2.2]PCP hydrocarbon, approaches to enantiopure
samples rely predominantly on the efficient resolution of
racemates.5
specific reactivity of thiocarbonyl derivatives with the so-called
11
̈
benzylic Schonberg rearrangement (thione-thiol transforma-
tion, Scheme 1b).
Received: September 16, 2020
Despite the recent progress reported in selective function-
alization of the [2.2]PCP core, unsolved synthetic challenges
still remain, mainly due to the resistance they often exhibit for
conventional chemical transformations.3a Arguably, it is not
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Scheme 1. Literature Background and Strategy of this Work
Table 1. Optimization of the Reaction Conditions for the
Reductive Sulfanylation
a
entry
acid (equiv)
reductant (equiv)
solvent
yield (%)
1
2
3
4
5
6
7
8
BF3·2H2O (2.1)
BF3·OEt2 (2.1)
BF3·OEt2 (1.1)
BF3·OEt2 (1.1)
BF3·OEt2 (1.1)
BF3·OEt2 (1.1)
CF3CO2H (15)
CF3CO2H (15)
CF3CO2H (15)
CH3CO2H (15)
CF3SO3H (15)
CF3CO2H (5)
CF3CO2H (1.1)
Et3SiH (1.5)
Et3SiH (1.5)
Et3SiH (1.5)
Et3SiH (1.5)
Et3SiH (1.5)
Et3SiH (1.5)
BH3·pyridine (1)
BH3·Me2S (1)
BH3·THF (1)
BH3·THF (1)
BH3·THF (1)
BH3·THF (1)
CH2Cl2
CH2Cl2
CH2Cl2
DCE
PhMe
75
83
85 (83)
b
c
71
75
d
80
85
THF
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
b
9
92 (88)
10
11
12
13
e
45
65 (80)
f
Considering the versatile potential of these targets merging
[2.2]PCP and benzylic heteroatom functionalities,12 the
development of a direct and practical strategy based on
regioselective C−S bond formation on the [2.2]PCP platform
is still warranted. An interesting feature would be to involve a
readily available [2.2]PCP precursor, which could be prepared
through a limited number of steps from the inexpensive and
commercial [2.2]PCP hydrocarbon. As it is well established
that the introduction of a carbonyl function to the [2.2]PCP
core can be directly achieved through an electrophilic
substitution, we postulated that a reductive reaction
approach13 could then allow incorporation of the sulfur atom
(Scheme 1c). Indeed, the reductive sulfanylation is an elegant
but overlooked reaction, which involves the reduction of a
thionium14 species, formed from an aldehyde or ketone in the
presence of a thiol and an activator. A limited number of
examples, employing a Lewis/Brønsted acid with either a
hydrosilane or borane reductant, have been described.13,14 In
light of this, we present the results of our investigations.
BH3·THF (1)
g
a
b
Optimization with 0.25 mmol of 1. In brackets, reaction on a 1.2
mmol scale. DCE = 1,2-dichloroethane. Complex mixture. No
reaction. In brackets, reaction with a concentration of 1 M.
Reduction of 1 into the corresponding primary alcohol.
c
d
e
f
g
significant improvement to an 83% yield (entry 2). A similar
reaction efficiency was observed employing a single equivalent
of the BF3·OEt2 activator (entry 3). The effect of the solvent
was then investigated. Whereas slightly lower yields (71 and
75%) were observed in 1,2-dichloroethane and toluene (entries
4 and 5), the reaction failed completely in a THF solution
(entry 6).
We also explored activation by a Brønsted acid in the
presence of a borane reductant. The use of a large excess of
trifluoroacetic acid (TFA, 15 equiv) and BH3·pyridine adduct
(1 equiv) in CH2Cl2 furnished 2a in a nice 80% yield (entry 7).
A screening of other boron reagents and Brønsted acids was
then investigated (entries 8−11). The best result was obtained
in the presence of the TFA/BH3·THF combination (92%
yield, entry 9). Reducing the amount of TFA to 5 equiv had a
detrimental effect on the reaction efficiency (65% yield, entry
12). However, increasing the concentration of aldehyde 1 from
0.25 to 1 M led to a much better 80% yield (entry 12). Finally,
the use of a single equivalent resulted in no product 2a
formation (entry 13). To summarize, the conditions of entries
3 and 9 in Table 1 were determined to be optimal for the
synthesis of 2a. In both cases, no erosion of reaction efficiency
was noticed when experiments were carried out on a larger 1.2
mmol scale (entries 3 and 9).
With optimal conditions in hand (conditions A with BF3·
OEt2/Et3SiH and B with TFA/BH3·THF), the reaction scope
with respect to the thiol was then investigated, as shown in
Scheme 2. To our delight, the four aliphatic mercaptans tested
reacted smoothly to afford the desired [2.2]PCP-based sulfides
2b−e in good to excellent yields (64−99%). Worthy of note is
the remarkable tolerance of the process to the ester function,
with 2e formed in a quantitative yield (conditions A). A
comparison of the results obtained with both protocols shows
the following trends. The use of conditions A is preferable with
primary thiols (2d and 2e), while conditions B brought about
superior results with secondary, tertiary, and aromatic thiols
RESULTS AND DISCUSSION
The racemic [2.2]paracyclophane-4-carboxaldehyde 1 was
■
prepared in a single operational step (Rieche formylation)
from parent [2.2]PCP, as previously described by Brase.15 The
̈
synthesis was easily scaled up and allowed the isolation of ∼10
g of the substrate, from a single batch, in an excellent 85%
yield.
In the initial study, thiophenol was chosen as the model
sulfur reactant to optimize the reaction conditions (Table 1).
In the first experiment (0.25 mmol scale), a stoichiometric
amount of thiol and 1 was solubilized at 0 °C in CH2Cl2 (0.25
M). The reaction mixture was then reacted with commercial
BF3·2H2O complex (2.1 equiv). After 5 min of reaction,
triethylsilane (1.5 equiv) was added, and the reaction mixture
was stirred at room temperature for 3 h. Analysis of the crude
1
mixture by H NMR clearly indicated the formation of the
anticipated [2.2]PCP thioether 2a, according to the presence
of the diagnostic AX pattern of the diastereotopic protons of
2
the CH2S group (δ = 3.83 and 4.11 ppm, J = 12.4 Hz).
Purification by chromatography on silica gel led to the
isolation of 2a in a satisfactory 75% yield (entry 1). The
structure was then confirmed by X-ray crystal structure
analysis. Switching to BF3·OEt2 as the Lewis acid furnished a
B
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Information for additional details of the transition state
model).
Scheme 2. Substrate Scope through Variation of the Thiol
Cross-experiments were then investigated with stoichiomet-
ric amounts of the [2.2]PCP-based aldehyde 1, ketone 3, and
thiophenol (see the Supporting Information). Under the BF3·
OEt2/Et3SiH conditions, the reductive sulfanylation is totally
chemoselective for the aldehyde function (ratio 2a/4a of
100:0). The reaction led essentially to the isolation of the
phenylsulfanyl [2.2]PCP 2a. With the TFA/BH3·THF system,
competing reactivity of the acetyl group was observed, but the
process is still highly in favor of the formyl substituent (ratio
2a/4a of 88:12).
The highly efficient formation of sulfanyl ester 2e provided
great opportunities to use this functionalized [2.2]PCP
derivative as a generally usable sulfur building block, through
a methodology productively used in our group before7a,b,17 and
which consists of a retro-Michael reaction and further
electrophilic trapping of the generated anion. Accordingly,
the treatment of 2e at low temperature (−78 °C) with a 1 M
solution of t-BuOK in THF (1.2 equiv) afforded the
corresponding benzylic thiolate (Scheme 4a). In situ quench
a
In brackets, yield at the 7.5 mmol scale.
(2a−c). To explore the synthetic utility of the method, a scale-
up reaction (7.5 mmol) of the [2.2]PCP derivative 1a with 3-
sulfanylpropionic acid methyl ester (R1 = (CH2)2CO2Me) was
then conducted under conditions A, delivering 2.4 g of
thioether 2e in an excellent 94% yield.
We turned our attention to extending the scope of this
reductive sulfanylation reaction to the acetyl [2.2]PCP 3, this
offering a strategic entry to [2.2]PCP derivatives displaying
both planar and central chirality (Scheme 3). This starting
Scheme 4. Useful Transformations of Sulfanyl Ester 2e
Scheme 3. Extension to 4-Acetyl[2.2]paracyclophane 3
a
b
c
With 1.2 equiv of t-BuOK. With 2 equiv of t-BuOK. Diacel
Chiralpak IA column (id,4.6 mm), n-heptane/EtOH (60:40 ratio),
and a flow rate of 1.0 mL/min.
material was prepared in a 68% yield by Friedel−Crafts
acylation of [2.2]PCP with acetyl chloride/AlCl3 in dry
dichloromethane.16 A preliminary set of experiments employ-
ing thiophenol rapidly indicated that the TFA/BH3·THF
system was more appropriate in this series (see the Supporting
Information). Furthermore, a decrease in the amount of TFA
to 5 equiv markedly improved the reaction efficiency. The
anticipated thioether 4a was isolated in a pleasing 88% yield, as
a mixture of two diastereoisomers in a 93/7 ratio. The
products were readily separated by column chromatography on
silica gel. Much to our delight, we succeeded in growing single
crystals of the major diastereoisomer of 4a, suitable for an X-
ray diffraction analysis from which the relative (SP,R)*
stereochemistry was unambiguously assigned. tert-Butanethiol
and isopropanethiol gave the desired products 4b and 4c, in
79% and 85% yields, respectively, along with a similar level of
diastereoselectivity (ratios of ∼85:15). Separation of the
diastereoisomers was again efficient on silica gel, and the
configurations were unambiguously assigned according to
analytical similarities previously observed with 4a (see the
Supporting Information). To rationalize the preference for the
(SP, R)* configured products, we suggest that the reaction
proceeds via thionium conformer I, with an attack of the
reductant opposite to the CH2CH2 bridge (see the Supporting
with iodomethane led to 2f in a nice 79% yield. Notably, the
synthesis of 2f would have been problematic using the
reductive sulfanylation reaction directly, as the use of gaseous
methanethiol would have been required. Alternatively,
quenching with an aqueous HCl solution afforded thiol 5 in
an 80% yield. Thus, the precursor 2e can be regarded as a
valuable modular [2.2]PCP-based building block.
As already mentioned, approaches to enantiopure samples
rely predominantly on the efficient resolution of racemates,
which can be tedious, especially when larger quantities are
needed. We attempted the resolution of our racemate ( )-2e
on an analytic scale by chiral high-performance liquid
chromatography (HPLC). Using a Diacel Chiralpak IA column
(id,4.6 mm), with a mixture of n-heptane and EtOH in a 60:40
ratio (v/v) and a flow rate of 1.0 mL/min, a tremendous
difference in retention times of 12 min for enantiomer (RP)-2e
and (SP)-2e was observed, resulting in a baseline separation of
the two enantiomers (see the Supporting Information). These
conditions were then successfully applied on a semipreparative-
scale, from 1.5 g of starting material (Scheme 4b). This
allowed the isolation of 596 mg of (RP)-(−)-2e (tR = 5.96 min,
80%, ee > 99%) and 613 mg of (SP)-(+)-2e (tR = 17.91 min,
82%, ee > 99%) (see the Supporting Information). Conversion
C
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successively added TiCl4 (17.6 g, 92.8 mmol, 2 equiv, 10.2 mL) and
Cl2CHOCH3 (4.5 mL, 50.8 mmol, 1 equiv). The resulting mixture
was allowed to warm up slowly to room temperature and then stirred
at this temperature for 6 h. Water (450 mL) was then added and
stirring was maintained for 2 h. The reaction mixture was extracted
with CH2Cl2, and the combined organic phases were dried over
MgSO4, filtered, and evaporated. The resulting solid was purified by
column chromatography on silica gel with dichloromethane as an
eluent to obtain the desired aldehyde 1. Yield: 85% (9.61 g, 0.04
mol). White solid. Mp: 148−149 °C (lit.15 mp: 159 °C). TLC
(CH2Cl2/pentane, 80:20) Rf = 0.59. 1H NMR (400 MHz, CDCl3): δ
9.96 (s, 1H), 7.01 (d, J = 1.8 Hz, 1H), 6.73 (dd, J = 7.8 and 1.8, 1H),
6.61−6.54 (m, 2H), 6.49 (dd, J = 7.8 and 1.6, 1H), 6.44 and 6.39 (AB
part of ABXY pattern, J = 7.8 and 1.6, 1H each), 4.10 (ddd, J = 12.2,
10.3 and 1.8, 1H), 2.91−3.31 (m, 7H). 13C{1H} NMR (101 MHz,
CDCl3): δ 192.1, 143.4, 140.8, 139.5, 139.6, 138.2, 136.7, 136.5,
136.3, 133.4, 133.1, 132.5, 132.3, 35.4, 35.3, 35.1, 33.8. IR (cm−1) ν:
719, 795, 875, 906, 1227, 1410, 1590, 1677 (CO), 2751, 2850,
2925. MS (EI): m/z (%) 236 (84), 144 (21), 132 (21), 104 (100), 78
(38). HRMS (ESI): calcd for C17H17O [M + H]+, 237.1279; found,
237.1268.
into the corresponding thiols, according to the aforementioned
retro-Michael reaction, was then carried out with the individual
enantiomers of 2e. This allowed the isolation of each
enantiomer of thiol 5 in good yields (79% and 76%), as
enantiopure products (see the Supporting Information). A
single crystal suitable for X-ray diffraction analysis was
obtained on the enantiopure thiol, derived from the first-
eluting enantiomer of sulfanyl ester 2e obtained by chiral
HPLC, and this established the configuration unambiguously
as (RP) (Flack parameter = −0.01). Given the wide reactivity
of the sulfanyl group, this highly efficient resolution process
provides a promising entry to a collection of sulfur-based
[2.2]PCP derivatives in both enantiomeric forms.18
CONCLUSIONS
■
In conclusion, through combining a Friedel−Crafts reaction
and a reductive sulfanylation, we have developed a reliable and
high yielding method, which permits functionalization of the
[2.2]PCP architecture at a specific benzylic position. Two
complementary reaction conditions, promoted by either BF3·
OEt2/Et3SiH or TFA/BH3·THF combinations, were devel-
oped. The methodology allowed efficient and straightforward
access to a collection of relevant planar chiral sulfur-based
[2.2]paracyclophanes. Furthermore, a highly efficient late-stage
resolution of the planar chirality led to the isolation, in
enantiopure forms, of both enantiomers of the related
mercaptan, which can then serve as a versatile building block
in the synthesis of more elaborated [2.2]PCP derivatives.
These original scaffolds with the key features they display
possess many application options that are to be explored.
4-Acetyl[2.2]paracyclophane (3).16 In two-necked round-bot-
tomed flask, equipped with a nitrogen inlet, a solution of
[2.2]paracyclophane (4.16 g, 20 mmol, 1 equiv) in dry CH2Cl2 (22
mL) was cooled to −50 °C. A solution of acetyl chloride (3 mL, 42
mmol, 2.1 equiv) and AlCl3 (4.67 g, 35 mmol, 1.75 equiv) was added
dropwise. After stirring at −50 °C for 15 min, the reaction mixture
was allowed to warm to −20 °C and stirred at this temperature for an
additional 15 min. The resulting mixture was poured into an aqueous
6 N HCl solution (20 mL). The organic layer was separated, and the
aqueous layer was extracted with CH2Cl2 (2 × 30 mL). The organic
fractions were combined, dried over MgSO4, filtered, and evaporated
to dryness. The resulting crude product was then purified by column
chromatography on silica gel (CH2Cl2/EtOAc, 99:1) to afford the
expected ketone 3. Yield: 68% (3.40 g, 13.6 mmol). White solid. Mp:
100−101 °C (lit.16 mp: 107−109 °C). TLC (CH2Cl2/EtOAc, 99:1)
EXPERIMENTAL SECTION
■
1
Rf = 0.7. H NMR (400 MHz, CDCl3): δ 6.93 (d, J = 1.8, 1H), 6.66
General Experimental. Dry THF and CH2Cl2 were obtained by
a passage down an activated alumina column. All other reagents and
solvents were used as purchased from commercial sources. All
reactions were performed in oven-dried glassware, under an
atmosphere of dry nitrogen. Due to the stench of thiols, all glassware
and syringes were washed with bleach after use. Low reaction
temperatures stated were those of the reaction mixtures. Reactions
were purified by column chromatography with silica gel Si 60 (0.040−
0.063 mm). Thin-layer chromatography was carried out on silica gel
60 F254 (1.1 mm) with spot detection under UV light or by I2
oxidation. Melting points were obtained on a capillary apparatus and
are uncorrected. All chemical shifts (δ) and coupling constants (J) in
the NMR spectra are quoted in parts per million (ppm) and hertz
(Hz), respectively. The following abbreviations are used to designate
the multiplicity of the signals: s = singlet; d = doublet; t = triplet; m =
multiplet; and combinations thereof. The chemical shifts are
calibrated to TMS (δ H 0.00) or residual proton and carbon
resonances of the solvent CDCl3 (δ H 7.26 and δ C 77.16). IR spectra
were recorded on an ATR-FT-IR instrument equipped with a
diamond ATR probe. Mass spectra were obtained with a QTOF LC/
MS instrument. Semipreparative separations of enantiomers were
carried out on a chromatographic system with a 5 mL sample loop,
equipped with a photodiode array detector (200−400 nm), and an IA
column (5 mm; size 250 mm × 20 mm). Enantiomeric excesses were
determined by chiral HPLC equipped with a photodiode array
detector (200−400 nm) and an IA column (5 mm; size 250 mm ×
4.6 mm). In all cases, the analysis was calibrated with a sample of the
racemate. Optical rotations are reported in deg dm−1 cm3 g−1 and
were measured at room temperature (20 °C) on a polarimeter using a
1 mL cell with a 1 dm path length at 589 nm (sodium D light).
Synthesis of the [2.2]PCP-Based Precursors. [2.2]-
Paracyclophane-4-carboxaldehyde (1).15 The synthesis was carried
out as reported in the literature. To a solution of [2.2]paracyclophane
(10 g, 48 mmol, 1 equiv) in CH2Cl2 (450 mL) cooled to 0 °C, were
(dd, J = 7.9 and 1.8, 1H), 6.58−6.49 (m, 4H), 6.39 (dd, J = 7.9 and
1.9), 3.98 (ddd, J = 12.6, 7.0 and 4.6, 1H), 3.25−3.11 (m, 4H), 3.10−
2.97 (m, 2H), 2.90−2.79 (m, 1H), 2.47 (s, 3H). 13C{1H} NMR (101
MHz, CDCl3): δ 200.5, 141.8, 140.5, 140.0, 139.4, 138.1, 136.65,
136.60, 134.4, 133.3, 133.1, 132.3, 131.4, 36.3, 35.4, 35.3, 35.1, 29.0.
IR (cm−1) ν: 731, 793, 854, 902, 1185, 1266, 1349, 1552, 1679
(CO), 2888, 2850, 2922, 2951. HRMS (ESI): calcd for C18H19O
[M + H]+: 251.1436; found, 251.1441.
Synthesis of the [2.2]PCP-Based Sulfides 2. General
Procedure A: BF3·OEt2/Et3SiH-Mediated Reductive Sulfanylation.
In a two-necked round-bottomed flask, equipped with a nitrogen inlet,
a 0.25 M solution of [2.2]paracyclophane-4-carboxaldehyde 1 (1
equiv) in CH2Cl2 and the appropriate thiol (1.1 equiv) were
successively introduced. The stirred mixture was then charged
successively dropwise with BF3·OEt2 (1.1 equiv) and triethylsilane
(1.5 equiv). The reaction was then stirred at room temperature for an
additional 3 h. After the addition of a saturated NaHCO3 aqueous
solution, extraction with CH2Cl2 (20 mL), the organic layer was
washed with H2O (20 mL). The collected aqueous layers were
extracted with CH2Cl2 (2 × 20 mL). The organic fractions were
combined, dried over MgSO4, filtered, and evaporated to dryness. The
resulting crude product was then purified by column chromatography
on silica gel to afford the anticipated sulfide 2.
General Procedure B: CF3CO2H/BH3·THF-Mediated Reductive
Sulfanylation. In a two-necked round-bottomed flask, equipped with
a nitrogen inlet, a 0.25 M solution of [2.2]paracyclophane-4-
carboxaldehyde 1 (1 equiv) in CH2Cl2 and the appropriate thiol
(1.1 equiv) were introduced. The stirred mixture was then charged
dropwise successively with trifluoroacetic acid (15.6 equiv) and BH3·
THF (1.1 equiv). The reaction was then stirred at room temperature
for an additional hour. After the addition of an aqueous saturated
NaHCO3 solution, extraction with CH2Cl2 (20 mL), the organic layer
was washed with H2O (20 mL). The collected aqueous layers were
D
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extracted with CH2Cl2 (2 × 20 mL). The organic fractions were
combined, dried over MgSO4, filtered, and evaporated to dryness. The
resulting crude product was then purified by column chromatography
on silica gel to afford the anticipated sulfide 2.
4-(Dodecylsulfanyl)methyl[2.2]paracyclophane (2d). The com-
pound was obtained following general procedure A from aldehyde 1
(150 mg, 0.63 mmol), dodecane-1-thiol (R1 = CH3(CH2)11, 166 μL,
0.70 mmol), BF3·OEt2 (86 μL, 0.70 mmol), and triethylsilane (152
μL, 0.94 mmol) in CH2Cl2 (2.5 mL). Yield: 97% (259.4 mg, 0.61
mmol). The compound was obtained following general procedure B
4-(Phenylsulfanyl)methyl[2.2]paracyclophane (2a). The com-
pound was obtained following general procedure A from aldehyde 1
(150 mg, 0.63 mmol), thiophenol (R1 = Ph, 71 μL, 0.70 mmol), BF3·
OEt2 (86 μL, 0.70 mmol), and triethylsilane (152 μL, 0.94 mmol) in
CH2Cl2 (2.5 mL). Yield: 85% (177.9 mg, 0.54 mmol). The
compound obtained following general procedure B from aldehyde 1
(59 mg, 0.25 mmol), thiophenol (R1 = Ph, 28 μL, 0.275 mmol),
trifluoroacetic acid (300 μL, 3.9 mmol), and BH3·THF (1 M solution,
275 μL, 0.275 mmol) in CH2Cl2 (1 mL). Yield: 92% (76 mg, 0.54
mmol). White solid. Mp: 88−89 °C. TLC (pentane/CH2Cl2, 70:30)
Rf = 0.56. 1H NMR (500 MHz, CDCl3): δ 7.34−7.23 (m, 4H), 7.22−
7.15 (m, 1H), 6.72 (dd, J = 7.8 and 1.8, 1H), 6.58 (dd, J = 7.8 and =
1.8, 1H), 6.55−6.48 (m, 3H), 6.45 (dd, J = 7.8 and 1.8, 1H), 6.37 (s,
1H), 4.11 (d, J = 12.4, 1H), 3.83 (d, J = 12.4, 1H), 3.43 (ddd, J =
13.7, 10.8 and 6.0, 1H), 3.22−3.12 (m, 1H), 3.12−2.93 (m, 5H), 2.86
(ddd, J = 13.7, 10.8 and 6.0, 1H). 13C{1H} NMR (101 MHz, CDCl3):
δ 140.2, 139.7, 139.4, 138.1, 137.1, 136.2, 135.3, 135.0, 133.5, 133.4,
132.3, 132.0, 129.6, 129.0, 128.9, 126.2, 38.1, 35.4, 35.1, 34.5, 33.4. IR
(cm−1) ν: 714, 796, 897, 1412, 1485, 1592, 2849, 2922, 3006. HRMS
(ESI): calcd for C23H22NaS [M + Na]+, 353.1340; found, 353.1338.
4-(tert-Butylsulfanyl)methyl[2.2]paracyclophane (2b). Obtained
following the general procedure A from aldehyde 1 (150 mg, 0.63
mmol), tert-butanethiol (R1 = t-Bu, 78 μL, 0.70 mmol), BF3·OEt2 (86
μL, 0.70 mmol) and triethylsilane (152 μL, 0.94 mmol) in CH2Cl2
(2.5 mL). Yield: 64% (125.62 mg, 0.40 mmol). Obtained following
general procedure B from aldehyde 1 (118 mg, 0.5 mmol), t-
butanethiol (R1 = t-Bu, 62 μL, 0.55 mmol), trifluoroacetic acid (580
μL, 7.5 mmol), and BH3·THF (1 M solution, 550 μL, 0.55 mmol) in
CH2Cl2 (2 mL). Yield: 72% (112 mg, 0.36 mmol). White solid. Mp:
from aldehyde 1 (118 mg, 0.5 mmol), dodecane-1-thiol (R1
=
CH3(CH2)11, 132 μL, 0.55 mmol), trifluoroacetic acid (580 μL, 7.5
mmol), and BH3·THF (1 M solution, 550 μL, 0.5 mmol) in CH2Cl2
(2.2 mL). Yield: 84% (177 mg, 0.42 mmol). White solid. Mp: 54−55
1
°C. TLC (pentane/CH2Cl2, 80:20) Rf = 0.45. H NMR (400 MHz,
CDCl3): δ 6.68 (dd, J = 7.9 and 1.6, 1H), 6.56−6.41 (m, 5H), 6.28 (s,
1H), 3.71 (d, J = 13.2, 1H), 3.52−3.43 (m, 1H), 3.40 (d, J = 13.2,
1H), 3.24−3.13 (m, 1H), 3.12−2.94 (m, 5H), 2.93−2.81 (m, 1H),
2.32 (t, J = 7.4, 2H), 1.58−1.44 (m, 2H), 1.39−1.19 (m, 18H), 0.92
(t, J = 6.9, 3H). 13C{1H} NMR (101 MHz, CDCl3): δ 139.9, 139.6,
139.4, 137.95, 137.90, 135.25, 135.20, 133.5, 133.3, 132.2, 131.5,
129.0, 35.4, 35.2, 35.1, 34.5, 33.5, 32.0, 31.7, 29.85, 29.80, 29.7, 29.6,
29.55, 29.50, 29.3, 29.0, 22.8, 14.3. IR (cm−1) ν: 717, 798, 872, 903,
945, 1412, 1432, 1464, 1593, 2850, 2919, 2949, 3007. HRMS (ESI):
calcd for C29H42NaS [M + Na]+, 445.2905; found, 445.2925.
3-([2.2]Paracyclophan-4-yl)methylsulfanylpropionic Acid Methyl
Ester (2e). The compound was obtained following general procedure
A from aldehyde 1 (150 mg, 0.63 mmol), 3-sulfanylpropionic acid
methyl ester (R1 = (CH2)2CO2Me, 77 μL, 0.70 mmol), BF3·OEt2 (86
μL, 0.70 mmol), and triethylsilane (152 μL, 0.94 mmol) in CH2Cl2
(2.5 mL). Yield: 99% (213.5 mg, 0.63 mmol). The compound was
obtained following general procedure B from aldehyde 1 (118 mg, 0.5
mmol), 3-sulfanylpropionic acid methyl ester (R1 = (CH2)2CO2Me,
61 μL, 0.55 mmol), trifluoroacetic acid (580 μL, 7.5 mmol), and BH3·
THF (1 M solution, 550 μL, 0.55 mmol) in CH2Cl2 (2 mL). Yield:
79% (135 mg, 0.4 mmol). White solid. Mp: 58−59 °C. TLC
1
(pentane/EtOAc, 80:20) Rf = 0.45. H NMR (400 MHz, CDCl3): δ
6.65 (dd, J = 7.8 and 1.8, 1H), 6.55−6.43 (m, 4H), 6.41 (dd, J = 7.8
and 1.8, 1H), 6.26 (s, 1H), 3.72 (d, J = 13.3, 1H), 3.67 (s, 3H), 3.42*
(d, J = 13.3, 1H), 3.48−3.39* (m, 1H) (* signals overlapping), 3.22−
3.12 (m, 1H), 3.12−2.94 (m, 5H), 2.86 (ddd, J = 13.6, 10.2 and 6.2,
1H), 2.61−2.57 (m, 2H), 2.51−2.46 (m, 2H). 13C{1H} NMR (101
MHz, CDCl3): δ 172.4, 140.0, 139.5, 139.3, 137.9, 137.2, 135.3,
135.1, 133.5, 133.3, 132.2, 131.7, 128.9, 51.8, 35.3, 35.2, 35.0, 34.5,
34.4, 33.4, 26.4. IR (cm−1) ν: 715, 794, 1238, 1344, 1434, 1592, 1724
(CO), 2851, 2924, 3005. MS (ESI): m/z (%) 703 [(2M + Na)+,
1
81−82 °C. TLC (pentane/CH2Cl2, 80:20) Rf = 0.34. H NMR (400
MHz, CDCl3): δ 6.70 (dd, J = 7.8 and 1.6, 1H), 6.54 and 6.50 (AB
part of ABMX pattern, JAB = 7.9, JAM = 1.6 and JBX = 1.7, 2H), 6.48−
6.41 (m, 3H), 6.31 (s, 1 H), 3.71 (d, J = 12.0, 1H), 3.47* (d, J = 12.0,
1H), 3.53−3.42* (m, 1H) (* signals overlapping), 3.23−3.13 (m,
1H), 3.13−2.93 (m, 5H), 2.88 (ddd, J = 13.5, 10.8 and 6.3, 1H), 1.35
(s, 9H). 13C{1H} NMR (101 MHz, CDCl3): δ 140.0, 139.7, 139.4,
137.9, 137.5, 135.3, 135.1, 133.5, 133.4, 132.3, 131.6, 128.9, 42.6,
35.4, 35.1, 34.6, 33.5, 32.4, 31.0. IR (cm−1) ν: 715, 796, 870, 903,
1159, 1363, 1411, 1434, 1458, 1593, 2853, 2923, 3007. HRMS (ESI):
calcd for C21H26NaS [M + Na]+, 333.1653, found 333.1663. Anal.
Calcd for C21H26S: C, 81.23; H, 8.44; S, 10.33. Found: C, 81.42; H,
8.31; S, 10.30.
+
31], 363 [(M + Na)+, 100], 341 [(MH) , 38], 231 (29), 221 (79).
HRMS (ESI): calcd for C21H25O2S [M + H]+, 341.1575; found,
341.1576. Anal. Calcd for C21H24O2S: C, 74.08; H, 7.11; S, 9.42.
Found: C, 74.00; H, 7.17; S, 9.83.
Gram-Scale Synthesis of 2e. A two-necked round-bottomed flask,
equipped with a nitrogen inlet, was charged successively with
[2.2]paracyclophane-4-carboxaldehyde 1 (1.77 g, 7.5 mmol, 1
equiv), 3-sulfanylpropionic acid methyl ester (918 μL, 8.25 mmol
1.1 equiv), and CH2Cl2 (30 mL). The resulting mixture cooled in an
ice bath, and BF3·OEt2 (1.02 mL, 8.25 mmol, 1.1 equiv) was added.
After 5 min, triethylsilane (1,815 mL, 11,25 mmol, 1.5 equiv) was
added. After removal of the cold bath, the reaction mixture was
allowed to stir at room temperature for 3 h. After the addition of a
saturated NaHCO3 aqueous solution, extraction with CH2Cl2 (20
mL), the organic layer was washed with H2O (2 × 20 mL). The
collected aqueous layers were extracted with CH2Cl2 (3 × 20 mL).
The organic fractions were combined, dried over MgSO4, filtered, and
evaporated to dryness. The resulting crude product was then purified
by column chromatography on silica gel with pentane/ethyl acetate
(9:1) to give sulfide 2e (2.4 g, 94%).
Synthesis of the [2.2]PCP-Based Sulfides 4. General
Procedure. In a two-necked round-bottomed flask, equipped with a
nitrogen inlet, a 0.25 M solution of 4-acetyl[2.2]paracyclophane 3 (1
equiv) in CH2Cl2 and the appropriate thiol (1.1 equiv) were
introduced. The stirred mixture was successively charged dropwise
with trifluoroacetic acid (5 equiv) and BH3·THF (1.1 equiv). The
reaction was then stirred at room temperature for an additional hour.
After the addition of a saturated NaHCO3 aqueous solution,
4-(Isopropylsulfanyl)methyl[2.2]paracyclophane (2c). The com-
pound was obtained following general procedure A from aldehyde 1
(59 mg, 0.25 mmol), isopropanethiol (R1 = i-Pr, 26 μL, 0.275 mmol),
BF3·OEt2 (33 μL, 0.275 mmol), and triethylsilane (60 μL, 0.375
mmol) in CH2Cl2 (1 mL). Yield: 61% (45 mg, 0.15 mmol). The
compound was obtained following general procedure B from aldehyde
1 (118 mg, 0.5 mmol), isopropanethiol (R1 = i-Pr, 52 μL, 0.55 mmol),
trifluoroacetic acid (580 μL, 7.5 mmol), and BH3·THF (1 M solution,
550 μL, 0.55 mmol) in CH2Cl2 (2.2 mL). Yield: 85% (126 mg, 0.425
mmol). White solid. Mp: 49−51 °C. TLC (pentane/CH2Cl2, 4:1) Rf
1
= 0.30. H NMR (400 MHz, CDCl3): δ 6.69 (dd, J = 7.9 and 1.7,
1H), 6.55 and 6.50 (AB part of ABMX pattern, JAB = 7.8, JAM = 1.7
and JBX = 1.8, 2H), 6.48−6.45 (m, 2H), 6.43 (dd, J = 7.9 and 1.8,
1H), 6.30 (s, 1H), 3.72 (d, J = 13.2, 1H), 3.45* (d, J = 13.2, 1H),
3.53−3.44* (m, 1H) (* signals overlapping), 3.24−3.13 (m, 1H),
3.13−2.94 (m, 5H), 2.87 (ddd, J = 13.5, 10.7 and 6.1, 1H), 2.69 (sept,
J = 6.8, 1H), 1.24 (d, J = 6.8, 3H), 1.21 (d, J = 6.8, 3H). 13C{1H}
NMR (101 MHz, CDCl3): δ 139.9, 139.6, 139.4, 137.95, 137.90,
135.3, 135.0, 133.5, 133.3, 132.2, 131.5, 128.9, 35.4, 35.1, 34.6, 34.5,
34.1, 33.5, 23.4 (a single signal for the two CH3 of the i-Pr group). IR
(cm−1) ν: 715, 795, 870, 900, 1051, 1154, 1241, 1411, 1451, 1593,
2853, 2924, 2951. HRMS (ESI): calcd for C20H24NaS [M + Na]+,
319.1496; found, 319.1504.
E
https://dx.doi.org/10.1021/acs.joc.0c02235
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
1
extraction with CH2Cl2 (20 mL), the organic layer was washed with
H2O (20 mL). The collected aqueous layers were extracted with
CH2Cl2 (2 × 20 mL). The organic fractions were combined, dried
over MgSO4, filtered, and evaporated to dryness. The resulting crude
product was then purified by column chromatography on silica gel to
afford the anticipated sulfide 4.
solid. Mp: 128−129 °C. TLC (pentane/CH2Cl2, 4:1) Rf = 0.62. H
NMR (400 MHz, CDCl3): δ 6.56−6.50 (m, 3H), 6.46−6.37 (m, 4H),
4.04 (q, J = 6.8, 1H), 3.64−3.55 (m, 1H), 3.24−2.86 (m, 7H), 2.78
(sept, J = 6.7, 1H), 1.75 (d, J = 6.8, 3H), 1.27 (d, J = 6.7, 3H), 1.12
(d, J = 6.7, 3H). 13C{1H} NMR (101 MHz, CDCl3): δ 140.6, 140.0,
139.7, 139.5, 137.8, 135.5, 133.6, 133.0, 132.1, 131.8, 130.0, 129.9,
39.0, 35.5, 35.4, 34.9, 33.7 (2 signals overlapping), 23.8, 23.6, 19.7. IR
(cm−1) ν: 750, 764, 861, 1260, 1275, 1452, 1592, 2854, 2925, 2954,
3007. HRMS (ESI): calcd for C21H26NaS [M + Na]+, 333.1653;
found, 333.1652. (Sp, S)*-4c (minor diastereoisomer). White solid.
4-[1′-(Phenylsulfanyl)ethyl][2.2]paracyclophane (4a). The com-
pound was obtained following the general procedure from ketone 3
(500 mg, 2 mmol), thiophenol (R1 = Ph, 215 μL, 2.1 mmol),
trifluoroacetic acid (750 μL, 10 mmol), and BH3·THF (1 M solution,
2.1 mL, 2.1 mmol) in CH2Cl2 (10 mL) as a mixture (93:7 ratio) of
diastereoisomers. Yield: 88% (604 mg, 1.76 mmol). Separation was
achieved by column chromatography on silica gel (pentane/CH2Cl2,
90:10). (Sp,R)*-4a (major diastereoisomer). White solid. Mp: 111−
1
Mp: 62−63 °C. TLC (pentane/CH2Cl2, 4:1) Rf = 0.82. H NMR
(400 MHz, CDCl3): δ 6.88 (d, J = 7.9, 1H), 6.60−6.52 (m, 3H), 6.47
(d, J = 7.9, 1H), 6.39−6.33 (m, 2H), 4.07 (q, J = 6.8, 1H), 3.43−3.32
(m, 1H), 3.21−2.86 (m, 8H), 1.51 (d, J = 6.4, 3H), 1.42 (d, J = 6.8,
3H), 1.37 (d, J = 6.8, 3H). 13C{1H} NMR (101 MHz, CDCl3): δ
142.1, 140.3, 139.6, 139.1, 136.1, 135.3, 133.3, 132.8, 132.5, 132.2,
131.8, 130.3, 39.6, 35.5, 35.3, 35.2, 34.2, 33.2, 25.5, 23.9, 23.8. IR
(cm−1) ν: 750, 764, 1049, 1260, 1275, 1454, 1593, 2854, 2924, 2956,
3006. HRMS (ESI): calcd for C21H26NaS [M + Na]+, 333.1653;
found, 333.1667.
1
112 °C. TLC (pentane/CH2Cl2, 90:10) Rf = 0.08. H NMR (400
MHz, CDCl3): δ 7.36−7.30 (m, 2H), 7.29−7.24 (m, 3H), 6.55−6.46
(m, 5H), 6.40−6.35 (m, 1H), 6.29 (s, 1H), 4.33 (q, J = 6.8, 1H), 3.66
(ddd, J = 13.6, 10.1 and 1.9, 1H), 3.27−3.17 (m, 1H), 3.15−2.88 (m,
6H), 1.67 (d, J = 6.8, 3H). 13C{1H} NMR (101 MHz, CDCl3): δ
140.0, 139.75, 139.70, 139.5, 138.3, 135.6, 134.8, 133.7, 133.5, 133.1,
132.15, 132.10, 130.4, 129.6, 128.8, 127.6, 44.5, 35.4, 35.3, 34.7, 33.9,
19.1. IR (cm−1) ν: 738, 861, 1180, 1372, 1412, 1437, 1477, 1583,
1592, 2852, 2926, 3008. HRMS (ESI): calcd for C24H24NaS [M +
Na]+, 367.1496; found, 367.1499. (Sp,S)*-4a (minor diaster-
eoisomer). Colorless oil. TLC (pentane/CH2Cl2, 90:10) Rf = 0.16.
1H NMR (400 MHz, CDCl3): δ 7.67−7.63 (m, 2H), 7.44−7.38 (m,
2H), 7.35−7.29 (m, 1H), 6.91−6.86 (m, 1H), 6.69 (s, 1H), 6.60−
6.58 (m, 2H), 6.46−6.39 (m, 3H), 4.46 (q, J = 6.7, 1H), 3.41 (ddd, J
= 13.2, 9.3 and 3.7, 1H), 3.22−3.09 (m, 4H), 3.07−2.91 (m, 3H),
1.32 (d, J = 6.7, 3H). 13C{1H} NMR (101 MHz, CDCl3): δ 141.1,
140.5, 139.6, 139.1, 136.4, 136.2, 135.4, 133.3, 132.8, 132.6, 132.45,
132.40, 132.2, 130.1, 129.2, 127.3, 45.1, 35.6, 35.35, 35.30, 33.1, 25.3.
IR (cm−1) ν: 731, 860, 907, 1057, 1368, 1441, 1437, 1478, 1583,
2852, 2923, 3007. HRMS (ESI): calcd for C24H24NaS [M + Na]+,
367.1496; found, 367.1508.
Transformation of Sulfanyl Ester 2e. 4-(Methylsulfanyl)-
methyl[2.2]paracyclophane (2f). In a two-necked round-bottomed
flask, equipped with a nitrogen inlet, sulfanyl ester 2e (194.7 mg, 0.57
mmol, 1 equiv) was diluted in dry THF (3 mL). After cooling to −78
°C, t-BuOK (686 μL of a 1 M solution in THF, 1.2 equiv) was added
dropwise. The reaction was stirred at −78 °C for 30 min, and
iodomethane (39 μL, 0.63 mmol, 1.1 equiv) was added. After
additional stirring for 20 min at −78 °C, water was added, and the
reaction mixture was allowed to warm to room temperature. Volatiles
were removed under reduced pressure, and the aqueous phase was
extracted twice with CH2Cl2. The collected organic layers were dried
over MgSO4 and concentrated under a vacuum. The resulting crude
product was then purified by column chromatography on silica gel
(pentane/CH2Cl2, 70:30) to afford the expected sulfide 2f. Yield: 79%
(120.5 mg, 0.45 mmol). White solid. Mp: 83−84 °C. TLC (pentane/
CH2Cl2, 70:30) Rf = 0.32. 1H NMR (400 MHz, CDCl3): δ 6.67 (dd, J
= 7.9 and 1.7, 1H), 6.56−6.45 (m, 4H), 6.43 (dd, J = 7.8 and 1.7,
1H), 6.27 (s, 1H), 3.71 (d, J = 13.4, 1H), 3.50−3.41 (m, 1H), 3.35 (d,
J = 13.4, 1H), 3.23−3.14 (m, 1H), 3.13−2.95 (m, 5H), 2.87 (ddd, J =
13.6, 10.8 and 6.2, 1H), 1.92 (s, 3H). 13C{1H} NMR (101 MHz,
CDCl3): δ 139.9, 139.6, 139.4, 137.9, 137.4, 135.25, 135.20, 133.5,
133.3, 132.2, 131.6, 129.0, 37.1, 35.4, 35.0, 34.4, 33.4, 15.1. IR (cm−1)
ν: 716, 753, 795, 868, 906, 1237, 1411, 1426, 1592, 2850, 2924, 3006,
3030. HRMS (ESI): calcd for C18H20NaS [M + Na]+, 291.1183;
found, 291.1194. Anal. Calcd for C18H20S: C, 80.55; H, 7.51; S, 11.94.
Found: C, 80.24; H, 7.51; S, 12.28.
([2.2]Paracyclophan-4-yl)methanethiol (( )-5). In a two-necked
round-bottomed flask, sulfanyl ester ( )-2e (345.5 mg, 1.01 mmol, 1
equiv) was diluted in dry THF (5 mL). After cooling to −78 °C, t-
BuOK (2 mL of a 1 M solution in THF, 2 equiv) was added dropwise.
The reaction mixture was stirred at −78 °C for 30 min and then
directly poured onto an aqueous 1 M HCl solution (20 mL). The
resulting mixture was extracted with CH2Cl2 (3 × 20 mL), and the
collected organic layers were dried over MgSO4 and concentrated
under a vacuum. The resulting crude product was then purified by
column chromatography on silica gel (pentane/CH2Cl2, 80:20) to
afford the expected thiol ( )-5. Yield: 80% (204.2 mg, 0.80 mmol).
White solid. Mp: 143−144 °C. TLC (pentane/CH2Cl2, 80:20) Rf =
0.22. 1H NMR (400 MHz, CDCl3): δ 6.63 (dd, J = 7.8 and 1.8, 1H),
6.53−6.44 (m, 4H), 6.41 (dd, J = 7.8 and 1.8, 1H), 6.30 (s, 1H), 3.73
(dd, J = 13.1 and 7.2, 1H), 3.49−3.38 (m, 2H), 3.23−3.13 (m, 1H),
3.12−2.94 (m, 5H), 2.93−2.82 (ddd, J = 13.6, 10.8 and 6.1, 1H), 1.54
(t, J = 7.2, 1H). 13C{1H} NMR (101 MHz, CDCl3): δ 140.5, 140.3,
139.7, 139.4, 137.1, 135.5, 134.1, 133.6, 133.4, 132.3, 131.8, 128.9,
35.4, 35.1, 34.5, 33.3, 27.8. IR (cm−1) ν: 638, 794, 871, 1239, 1412,
1497, 1591, 2539, 2849, 2924. HRMS (ESI): calcd for C17H18NaS [M
+ Na]+, 277.1027; found, 277.1026. Anal. Calcd for C17H18S: C,
80.27; H, 7.13; S, 12.60. Found: C, 79.81; H, 7.31; S, 12.22.
Resolution Protocol of Sulfanyl Ester ( )-2e by Semi-
preparative HPLC. The racemic sulfanyl ester ( )-2e (1.50 g, 4.41
4-[1′-(tert-Butylsulfanyl)ethyl]-[2.2]paracyclophane (4b). The
compound was btained following the general procedure from ketone
3 (125 mg, 0.5 mmol), t-butanethiol (R1 = t-Bu, 62 μL, 0.55 mmol),
trifluoroacetic acid (193 μL, 2.5 mmol, 5 equiv), and BH3·THF (1 M
solution, 550 μL, 0.55 mmol) in CH2Cl2 (2 mL) as a mixture (85:15
ratio) of diastereoisomers. Yield: 79% (128 mg, 0.395 mmol).
Separation was achieved by column chromatography on silica gel
(pentane/CH2Cl2, 4:1). (Sp,R)*-4b (major diastereoisomer). White
1
solid. Mp: 117−118 °C. TLC (pentane/CH2Cl2, 4:1) Rf = 0.64. H
NMR (400 MHz, CDCl3): δ 6.60−6.53 (m, 3H), 6.45−6.36 (m, 4H),
4.11 (q, J = 6.9, 1H), 3.60−3.51 (m, 1H), 3.25−2.89 (m, 7H), 1.84
(d, J = 6.9, 3H), 1.33 (s, 9H). 13C{1H} NMR (101 MHz, CDCl3): δ
141.5, 139.9, 139.7, 139.4, 137.0, 135.6, 133.4, 132.9, 132.1, 131.9,
130.3, 130.1, 43.9, 38.8, 35.5, 35.3, 35.1, 33.6, 31.9, 22.5. IR (cm−1) ν:
750, 764, 794, 860, 1161, 1260, 1275, 1370, 1457, 1593, 2854, 2895,
2924, 3006. HRMS (ESI): calcd for C22H28NaS [M + Na]+,
347.1809; found, 347.1812. (Sp,S)*-4b (minor diastereoisomer).
White solid. Mp: 109−110 °C. TLC (pentane/CH2Cl2, 4:1) Rf =
1
0.84. H NMR (400 MHz, CDCl3): δ 6.95 (d, J = 7.8, 1H), 6.63−
6.55 (m, 2H), 6.50 (s, 1H), 6.43 (d, J = 7.8, 1H), 6.35−6.29 (m, 2H),
4.09 (q, J = 6.8, 1H), 3.44−3.35 (m, 1H), 3.23−3.03 (m, 4H), 3.00−
2.86 (m, 3H), 1.54 (s, 9H), 1.45 (d, J = 6.8, 3H). 13C{1H} NMR (101
MHz, CDCl3): δ 142.8, 140.2, 139.6, 139.0, 135.35, 135.30, 133.5,
132.6, 132.5, 132.1, 131.8, 130.1, 43.8, 38.6, 35.5, 35.25, 35.20, 33.0,
32.3, 29.1. IR (cm−1) ν: 750, 764, 1055, 1159, 1261, 1275, 1363,
1457, 1592, 2854, 2924. HRMS (ESI): calcd for C22H28NaS [M +
Na]+, 347.1809; found, 347.1804.
4-[1′-(Isopropylsulfanyl)ethyl]-[2.2]paracyclophane (4c). The
compound was obtained following the general procedure from ketone
3 (125 mg, 0.5 mmol), isopropanethiol (R1 = i-Pr, 52 μL, 0.55 mmol),
trifluoroacetic acid (193 μL, 2.5 mmol, 5 equiv), and BH3·THF (1 M
solution, 550 μL, 0.55 mmol) in CH2Cl2 (2 mL) as a mixture (86:14
ratio) of diastereoisomers. Yield: 85% (131 mg, 0.425 mmol).
Separation was achieved by column chromatography on silica gel
(pentane/CH2Cl2, 4:1). (Sp,R)*-4c (major diastereoisomer). White
F
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Article
mmol) was dissolved in the minimum amount of a 60:40 n-heptane/
ethanol mixture. Aliquots of the resulting solution were repeatedly
injected into the semipreparative HPLC apparatus equipped with an
IA column (5 μm; size = 250 mm × 20 mm) eluting with 60:40 n-
heptane/ethanol at 1 mL min−1 (20 °C) and with UV monitoring at
229 nm. The collected fractions of each enantiomer, eluted at 5.96
and 17.91 min, were concentrated in vacuo. Individual fractions of
enantiomers thus isolated were reinjected onto an analytical chiral IA
column (5 μm; size 250 mm × 4.6 mm) to determine their
enantiomeric purity. The absolute configuration within (−)-2e and
(+)-2e was unambiguously assigned by chemical correlation to the
related thiols (vide infra).
(RP)-(−)-2e was the first-eluted fraction in a total yield of 596 mg
(1.75 mmol, 100% ee). HPLC: tR = 5.96 min (IA column (5 μm; size
= 250 mm × 4.6 mm); flow rate = 1.0 mL min−1; n-heptane/ethanol
60:40; 20 °C, 229 nm). [α]2D0 −14.2 (c 0.01, CHCl3). Other spectral
data are similar to those previously given for the racemic sample.
(SP)-(+)-2e was the second-eluted fraction in a total yield of 613
mg (1.80 mmol, 100% ee). HPLC: tR = 17.91 min (IA column (5 μm;
size = 250 mm × 4.6 mm); flow rate = 1.0 mL min−1; n-heptane/
ethanol 60:40; 20 °C, 229 nm). [α]2D0 +13.9 (c 0.01, CHCl3). Other
spectral data are similar to those previously given for the racemic
sample.
Authors
Damien Deschamps − Normandie Univ, ENSICAEN,
UNICAEN, CNRS, LCMT, 14000 Caen, France
Jean-Franco̧ is Lohier − Normandie Univ, ENSICAEN,
UNICAEN, CNRS, LCMT, 14000 Caen, France
Christopher J. Richards − School of Chemistry, University of
East Anglia, Norwich NR4 7TJ, United Kingdom;
orcid.org/0000-0001-7899-4082
Annie-Claude Gaumont − Normandie Univ, ENSICAEN,
UNICAEN, CNRS, LCMT, 14000 Caen, France
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.joc.0c02235
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We acknowledge financial support from ERDF funding (ISCE-
Chem & INTERREG IVa program), CNRS, and Synorg Labex
(ANR-11-LABX-0029). We thank Julien Del Corpo and
Romain Saubion (ENSICAEN) for contributing to the
optimization of the protocols.
Deprotection into Enantiopure Thiols 5. The deprotection
was carried out as described before with the racemic material, and the
configuration of both enantiomers was unambiguously assigned by X-
ray crystallography.
(RP)-(−)-5 was obtained from sulfanyl ester (RP)-(−)-2e. Yield:
79% (50.2 mg, 0.197 mmol, 100% ee). White solid. Mp: 143−144 °C.
Spectral data are similar to those previously given for the racemic
sample. HPLC: tR = 4.72 min (IA column (5 μm; size = 250 mm ×
4.6 mm); flow rate = 1.0 mL min−1; n-heptane/EtOH 80:20; 20 °C,
210 nm). [α]2D0 −37.6 (c 0.01, CHCl3).
(SP)-(+)-5 was obtained from sulfanyl ester (SP)-(+)-2e. Yield:
76% (48.2 mg, 0.189 mmol, 100% ee). White solid. Mp: 143−144 °C.
Spectral data are similar to those previously given for the racemic
sample. HPLC: tR = 6.38 min (IA column (5 μm; size = 250 mm ×
4.6 mm); flow rate = 1.0 mL min−1; n-heptane/EtOH 80:20; 20 °C,
210 nm). [α]2D0 +36.3 (c 0.01, CHCl3).
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The Supporting Information is available free of charge at
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Optimization of the reaction conditions; stereochemical
assignment; transition state model; cross-experiments;
chemoselectivity, crystallographic data for 2a, 4a, and
(RP)-5; HPLC chromatographs; NMR spectra for all
new products (PDF)
Accession Codes
CCDC 1909740−1909742 contain the supplementary crys-
tallographic data for this paper. These data can be obtained
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emailing data_request@ccdc.cam.ac.uk, or by contacting The
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AUTHOR INFORMATION
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Corresponding Author
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Stephane Perrio − Normandie Univ, ENSICAEN,
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Email: stephane.perrio@ensicaen.fr
G
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