Chemistry of the β-thiolactones: Substituent and solvent effects on thermal decomposition and comparison with the β-lactones

Article abstract of DOI:10.1021/jo500577c

The synthesis of a series of di-, tri-, and tetraalkyl β-thiolactones and β-lactones is described as well as their thermal decomposition with extrusion of carbon oxysulfide and carbon dioxide in two solvents of opposite polarities. The β-thiolactones are

Full text of DOI:10.1021/jo500577c

Article
pubs.acs.org/joc
Chemistry of the β‑Thiolactones: Substituent and Solvent Effects on
Thermal Decomposition and Comparison with the β‑Lactones.
Amandine Noel,† Bernard Delpech,† and David Crich*,‡
†Centre de Recherche de Gif, Institut de Chimie des Substances Naturelles, CNRS, Avenue de la Terrasse, 91190 Gif-sur-Yvette,
France
‡Department of Chemistry, Wayne State University, 5101 Cass Avenue, Detroit, Michigan 48202, United States
S
* Supporting Information
ABSTRACT: The synthesis of a series of di-, tri-, and tetraalkyl β-thiolactones
and β-lactones is described as well as their thermal decomposition with extrusion
of carbon oxysulfide and carbon dioxide in two solvents of opposite polarities. The
β-thiolactones are considerably more thermally stable than the β-lactones and
require higher temperatures for efficient decomposition in both solvents, whatever
the degree of substitution. The results are interpreted in terms of a zwitterionic
mechanism for fragmentation with a change in the rate-determining step between
the two series.
regioselectivities of simple model β-lactones and β-thiolactones
toward ring-opening by thiols and amines.39
INTRODUCTION
■
The β-lactones (2-oxetanones) have enjoyed considerable
interest from the synthetic organic and medicinal chemistry
communities over a period of many years because of their
interesting and varied reactivity patterns.1−8 Interest in the
medicinal chemistry of the β-lactones continues apace with the
recent discovery of potent proteasome inhibitors based upon
them,9−20 and their recent application as potent inhibitors for a
number of bacterial virulence factors.21−23 Indeed, it is this
interest that is currently driving efforts toward more effective
stereocontrolled syntheses of this class of molecule.11,24−27
In our laboratory, on the other hand, we are interested in the
possible use of β-thiolactones as surrogates for β-lactones and
β-lactams in bioorganic and medicinal chemistry.28,29 The
chemistry of the β-thiolactones (2-thietanones) has been much
less investigated than that of the β-lactones and β-lactams but
has the potential to be equally rich and varied,30,31 with possible
applications in bioorganic and medicinal chemistry. Toward
this end, we have synthesized a series of cognate β-lactones, β-
thiolactones, and β-lactams and have investigated their relative
abilities to inhibit porcine pancreatic lipase,29 cysteine proteases
(cathepsins B and L),28 and the proliferation of various human
cancer cell lines.28,29 In earlier work, the β-thiolactones have
been exploited as β-mercaptopropionamide precursors by
virtue of their ability to acylate amines.32−37 They also were
shown to undergo nucleophilic ring-opening on prolonged
exposure to hydrogen sulfide in the presence of base,38
although it is not known whether this process takes place by
acylation of sulfide anion or by SN2-like attack of sulfide at C4,
as has been shown to be the case for thiolate anions.36 In order
to better understand the relative reactivities of β-lactones and β-
thiolactones toward external nucleophiles and to identify their
relative merits for application in biological systems, we
conducted a systematic comparison of the reactivities and
In furtherance of our studies on the bioorganic and medicinal
chemistry of the β-thiolactones, we now turn to a comparison
of the thermal stability of the β-thiolactones and of the β-
lactones with respect to the extrusion of carbon oxysulfide and
carbon dioxide, respectively. Since it was postulated by
Erlenmeyer in 188040 and observed by Einhorn in 1883,41
one of the most-studied reactions of the β-lactones is the
thermal extrusion of carbon dioxide to give alkenes with
retention of configuration.1−4,8 The decarboxylation mecha-
nism, which is first-order in β-lactone,42,43 has been widely
studied and, while both concerted pathways and diradical
intermediates have been considered and excluded,44,45 is widely
held on the basis of solvent,46−48 reaction volume,48
substituent,45,49−53 kinetic,49 and computational evidence54−56
to involve a zwitterionic intermediate formed by initial cleavage
of the O1−C4 bond (Scheme 1, X = O).
Scheme 1. Zwitterion Mechanism for β-Lactone and β-
Thiolactone Fragmentation
The complementary extrusion of carbon oxysulfide (COS)
from a β-thiolactone was first suggested by Staudinger for the
case of tetraaryl β-thiolactones formed by the cycloaddition of
diarylthioketones with diphenyl ketene.57 Subsequent work by
Kohn et al. confirmed this result58 and corrected an earlier
report suggesting that the initial cycloaddition proceeded to
Received: March 11, 2014
Published: April 9, 2014
© 2014 American Chemical Society
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give the 3-thietanone regioisomer rather than the β-
thiolactones.59 Notably, 3,3-bis(4-dimethylaminophenyl)-4,4-
diphenyl-2-thietanone was shown to afford the tetraaryl alkene
on heating to 60 °C in a sealed tube.58 The extrusion of COS in
ethanol at reflux from a spirocyclic β-thiolactone generated by
cycloaddition of diphenyl ketene with N-methyl monothioph-
thalimide was later shown by Coyle et al. to take place
quantitatively in ethanol at reflux.60 The formal loss of COS
from peraryl-β-thiolactones may also be induced by nucleo-
philic attack on the carbonyl carbon, albeit through an
alternative mechanism involving cleavage of the C1−C4
bond, followed by elimination of a thiocarboxylate.61 Formal
loss of COS from tetraphenyl β-thiolactone is also observed on
treatment with Raney nickel and its equivalents and, in low
yield, on oxidation with mCPBA.61
In spite of these reports on the extrusion of COS from β-
thiolactones carrying multiple aromatic substituents, to the best
of our knowledge, there are no comparable studies on the
parallel decomposition of alkyl-substituted β-thiolactones.
Accordingly, in this article, we direct our attention to the
synthesis and thermal decomposition of the alkyl-substituted β-
thiolactones and cognate β-lactones. In addition to providing
information on the thermal stability of the β-thiolactones, the
solvent dependence of the decomposition of the β-thiolactones
and β-lactones provides a means of probing the mechanisms of
extrusion of COS and CO2 (Scheme 1, X = S and O,
respectively).
ing29,63−66 of β-lactone 4 with cesium thioacetate in DMF
afforded the 3-acetylthio acid 5, which was converted to the
corresponding thiol acid 6 with hydrazine hydrate so as to
avoid competing elimination. Nevertheless, thiol acid 6 was
obtained as a 83:17 mixture of diastereomers, which arose from
either a base-catalyzed epimerization or an elimination−
readdition pathway. Carbodiimide ring closure of a diaster-
eomerically enriched sample of 6 in the presence of
pentafluorophenol, going via the intermediacy of the
pentafluorophenyl ester, then gave the cis-configured β-
thiolactone 7 as a 93:7 mixture of cis:trans-isomers in excellent
yield. The relative stereochemistry of 7 rests on the strong
correlation between the two lactone ring protons and that
between the two methylene groups directly appended to the
lactone in the NOESY spectrum. On deprotonation with
LiHMDS and quenching at −78 °C with acetic acid, 7 was
converted to an inseparable 4:1 mixture of β-thiolactones 7 and
8 favoring the trans-isomer 8 (Scheme 2). In light of
subsequent alkylations of 4 and 7, it is probable that this
selectivity is the result of equilibration during the work-up
procedure.
The trans-disubstituted β-lactone 4 and the cis-disubstituted
β-thiolactone 7 were deprotonated with lithium amide bases
and the resulting enolates were alkylated with methyl iodide at
−78 °C to the corresponding 3,3,4-trisubstituted systems 9 and
10 as inseparable mixtures of stereoisomers (Scheme 3) in
Scheme 3. Synthesis of 3,3,4-Trisubstituted β-Lactone 9 and
β-Thiolactone 10
RESULTS AND DISCUSSION
■
Synthesis. 6-(p-Anisyl)hexanoic acid 1 was converted in the
standard manner to the 2-pyridyl thioester 2 and the phenyl
thioester 3. Following the method of Romo et al.,62 2 was
converted to the corresponding O-triethylsilyl monothio ketene
acetal and then allowed to react with propanal in the presence
of zinc chloride to afford a 3,4-trans-disubstituted β-lactone 4
(Scheme 2). The configuration of the trans-lactone 4 was
deduced by NOESY measurements; in particular, the
methylene group of the ethyl substituent was correlated with
the enolizable hydrogen adjacent to the carbonyl group,
whereas the two lactone ring hydrogens were only very weakly
correlated with each other. Invertive nucleophilic ring-open-
good yield. In both cases, the alkylation took place with
moderate selectivity on the opposite face of the enolate from
the existing C4 substituent, as was confirmed for both
compounds by NOESY measurements. A regioisomeric 3,4,4-
trisubstituted-β-lactone 11 was readily accessed in good yield
by reaction of the lithium enolate of 3 with 2-butanone
according to the method of Danheiser and Nowick (Scheme
4).67
Scheme 2. Preparation of cis- and trans-3,4-Disubstituted
β‑Lactones 4 and β-Thiolactones 7 and 8
Scheme 4. Synthesis of 3,4,4-Trisubstituted β-Lactone 11
Condensation of the lithium enolate of tert-butyl 6-(p-
anisyl)hexanoate 12 with 2-adamantanone and with 2-
adamantanethione68 gave the β-hydroxy and β-mercapto esters
13 and 14, which were converted to the corresponding acids 15
and 16 with trifluoroacetic acid in dichloromethane (Scheme
5). Intriguingly, attempted isolation of the mercapto ester 14
resulted in considerable retro-thioaldolization, and it was,
therefore, converted in situ to the acid 16. In contrast, the
corresponding hydroxyl ester 13 was readily isolated and
characterized. The difference in reactivity between the hydroxyl
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stituted systems where both ring closure and alkylation were
notably easier in the thiolactone case.
Scheme 5. Synthesis of 3,4,4-Trisubstituted β-Lactone 17
and β-Thiolactone 18
Extrusion Reactions. Studies on the thermal stability of the
various β-lactones and β-thiolactones were conducted in dilute
solution in two solvents: fluorinert [Fc-70, (C5F11)3N] and 1-
butyl-3-methylimidazolium hexafluorophosphate [BMIM PF6],
the one being extremely nonpolar and the other highly polar,72
with neither being miscible with toluene. An experimental
protocol was established whereby the substrate was heated in
dilute solution in the reaction solvent to the temperature of
choice in the presence of the internal standard 1,3,5-
trimethoxybenzene, and aliquots were withdrawn periodically
for examination. The analytical procedure involved extraction
of the aliquot at room temperature with a standard volume of
toluene, concentration under vacuum, and dissolution in
acetonitrile before examination by RP-UPLC with detection
by UV and mass spectrometry with atmospheric pressure
chemical ionization (APCI). Experiments conducted on a larger
scale enabled the isolation and characterization of the olefinic
products resulting from extrusion of CO2 or COS and, thus, the
provision of authentic samples for the kinetic runs.
After a preliminary survey of decomposition temperatures of
the various substrates at hand, 120 °C was selected as the most
appropriate for the comparison as it provoked fragmentation of
most substrates on a practical time scale. Fragmentations were
conducted in duplicate in dilute solution, leading to the first-
order rate constants and half-lives presented in Table 1. With
the exception of β-thiolactones 8 and 10, which did not
fragment under these conditions, all pyrolyses conducted in this
manner were clean with the anticipated olefin being the only
observable product. No evidence was found for alternative
modes of decomposition such as those that are known to occur
for the β-thiolactones on photolysis.73
and mercapto series was also evident in the cyclization step.
Thus, whereas cyclization of the hydroxyl acid 15 to the β-
lactone 17 required considerable optimization and screening of
coupling reagents, the formation of the β-thiolactone 18 from
the mercapto acid 16 proceeded smoothly under the same
conditions applied to obtain the less substituted system 7.
Furthermore, even under the optimal conditions using 4-
nitrobenzenesulfonyl chloride as condensation reagent, cycliza-
tion of 15 to give the β-lactone was accompanied by the
formation of the formal extrusion product 19 (Scheme 5).
Alkylation of the trisubstituted systems 17 and 18 was then
employed to access the tetraalkyl substituted β-lactone 20 and
the β-thiolactone 21 (Scheme 6). Again, a significant difference
Rate constants for the various β-lactones studied at 120 °C
span a range of more than 2 orders of magnitude with the 3,4-
disubstituted and 3,3,4-trisubstituted systems 4 and 9 having
the longest half-lives and the tetrasubstituted system 20 the
shortest (Table 1, entries 1−10). An interesting pattern of
solvent dependence was observed for the β-lactones with the
3,4-disubstituted system 4 showing no measurable change in
extrusion rate with solvent (Table 1, entries 1 and 2) and the
3,3,4-trisubstituted system 9 showing only a modest accel-
eration on going to the more polar solvent (Table 1, entries 3
and 4), while the 3,4,4-trisubstituted system 11 displayed a
much greater correlation between solvent polarity and reaction
rate (Table 1, entries 5 and 6). This pattern of reactivity is most
consistent with a mechanism for extrusion that displays little
change in polarization between the substrate and the transition
state, namely, a concerted mechanism, with polar character, as
in Scheme 1, only becoming apparent when stepwise cleavage
of a tertiary C−O bond is involved. The 3,4,4-trisubstituted β-
lactone 17, based on the adamantylidene skeleton, showed only
a modest solvent dependence (Table 1, entries 7 and 8),
reflecting the greater degree of substitution of the intermediate
cation than that derived from the acyclic counterpart 11 (Table
1, entries 5 and 6). The higher degree of substitution in the
adamantylidene system provides additional stabilization to any
intermediate cation and shields it to a greater extent from the
surrounding medium, thereby reducing dependence on solvent
polarity, consistent with earlier work documenting the lack of
solvent participation in the solvolysis of 2-adamantanyl
derivatives74 and with the greater stability of the 2-adamantanyl
cations than simple tertiary aliphatic carbenium ions.75−80
Scheme 6. Synthesis of Tetrasubstituted β‑Lactone 20 and β-
Thiolactone 21
in reactivity was apparent with attempted alkylation of 17,
being attended by extensive decarboxylation under the
conditions applied successfully to 18 (Scheme 6). Ultimately,
alkylation of 17 was achieved by use of the phosphazene base
P4-t-Bu69 at −100 °C, as recommended by Schwesinger70 and
employing dimethyl sulfate as alkylating agent,71 but never-
theless with a very modest yield (Scheme 6).
In this manner, a series of di-, two sets of tri-, and one pair of
tetraalkyl substituted β-lactones and the corresponding β-
thiolactones were prepared for studies of thermal stability.
Although the chemistry employed in these preparations was
mostly straightforward, several interesting points emerged,
most notably for the 3,4,4-trisubstituted and the tetrasub-
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Table 1. First-Order Rate Constants and Half-Lives for the Thermal Fragmentation of β-Lactones and β-Thiolactones at 120
a
°C
a
Substrate employed as a mixture of stereoisomers, leading to a mixture of stereoisomeric products reflecting the initial substrate mixture.
Interestingly, however, a significant solvent dependence
returned with the tetrasubstituted system 20, which is
nevertheless based on the adamantylidene framework (Table
1, entries 9 and 10) to which we return below.
solvent effects observed is noteworthy and reveals differences
between the β-lactones and the β-thiolactones. Most note-
worthy is the manner in which the tetrasubstituted β-
thiolactone 21 shows no solvent dependence (Table 1, entries
17 and 18), while its β-lactone analogue 20 (Table 1, entries 9
and 10) decomposes considerably faster in the more polar
solvent. In contrast with these observations, the two 3,4,4-
trisubstituted systems 17 and 18 both show a modest solvent
dependence (Table 1, entries 7, 8, 15, and 16).
The ensemble is best considered in terms of either a stepwise
mechanism with a zwitterionic intermediate (Scheme 1) or a
concerted mechanism with a highly asynchronous transition
state (Scheme 7). The differences between the various systems
In the β-thiolactone series, neither the 3,4-di- nor the 3,3,4-
trisubstituted systems 8 and 10, respectively (Table 1, entries
11−14) showed any appreciable decomposition at the standard
temperature of 120 °C in either solvent. In further experiments
intended to determine the decomposition temperature of
compounds 8 and 10, both were found to be stable on heating
neat at 230 °C under an inert atmosphere for multiple hours.
The 3,4,4-trisubstituted system 18 underwent decomposition to
the alkene in both solvents at this temperature (Table 1, entries
15 and 16), albeit more than a hundred-fold more slowly than
the β-lactone analogue 17 (Table 1, entries 7 and 8). The
decomposition of 18 showed only a modest solvent depend-
ence, consistent with that seen with the β-lactone congener 17.
Finally, the tetrasubstituted β-thiolactone 21 underwent
decomposition (Table 1, entries 17 and 18) more rapidly
than the trisubstituted analogue 18 but, again, more than 100-
fold more slowly than the direct β-lactone analogue 20.
Unexpectedly, in view of the high solvent dependence observed
for the tetrasubstituted β-lactone 20 (Table 1, entries 9 and
10), decomposition of the tetrasubstituted β-thiolactone 21 was
not influenced by the polarity of the solvent (Table 1, entries
17 and 18).
Scheme 7. Concerted Mechanism and Asynchronous
Transition State for Decomposition of β-Lactones and β-
Thiolactones
can then be accounted for either by changes in the rate-
determining step for the stepwise mechanism or by changes in
the degree of asynchronicity for the concerted mechanism.
For the stepwise mechanism with the zwitterionic
intermediate, solvent effects can be expected to operate on
both reaction steps. The use of a more polar solvent is expected
to accelerate the initial cleavage of the C−X bond through
stabilization of the polar zwitterion. However, for a given
carbon skeleton, the accelerating effect of the polar solvent on
this first step is expected to be less important for the β-
thiolactones than for the β-lactones as thiocarboxylates are
In general, it is very clear that the β-thiolactones, whatever
their degree of substitution, are much more thermally stable
than comparable β-lactones. It is also clear that the alkyl-
substituted β-thiolactones studied here decompose by thermal
extrusion of carbon oxysulfide to give alkenes and that the
alternative pathway considered by early workers in the field
with conjugated systems according to which thioketones and
ketenes are the main products is not operative. The pattern of
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more stable than carboxylates81,82 and, therefore, less
susceptible to stabilization by polar solvents. Fragmentation
of the zwitterionic intermediates to the alkenes and OCX
also will be influenced by solvent polarity in a different manner
according to X. Thus, for X = O, this step, which proceeds with
a loss of polarity, should be faster in less polar solvents. On the
other hand, when X = S, the products retain substantial polarity
owing to the formation of carbon oxysulfide with its dipole
moment of 0.72 D units,83 leading to the prediction of
accelerated fragmentation in polar solvents. Overall, for the β-
lactones, the two individual steps in the stepwise mechanism
are expected to experience opposite effects from an increase in
solvent polarity and, therefore, the nature of the observed effect
will depend on which step is rate-limiting. In the case of the β-
thiolactones, both steps of the stepwise mechanism are
expected to be accelerated in the more polar medium.
The weakness of C−S σ-bonds compared to their C−O
counterparts84,85 and the higher acidity of thioacids than
carboxylic acids81,82 suggest that heterolysis of the C−S bond in
the β-thiolactones will be considerably easier than that of the
C−O bond in the β-lactones. On the other hand, the
thiocarbonyl bond in carbon oxysulfide (73.7 kcal·mol−1)84 is
much weaker than the carbonyl bond in carbon dioxide (127.2
kcal·mol−1),84 indicating that loss of COS from a β-thiolactone-
derived zwitterionic intermediate will be slower than that of
CO2 from the analogous β-lactone-derived zwitterion. It is
conceivable, therefore, that there is a change of rate-limiting
step in the stepwise mechanism on replacement of the ring
oxygen by a sulfur atom. In the case of the β-lactone, the initial
cleavage of the C−O leading to the zwitterion would be rate-
limiting and followed by rapid loss of CO2, whereas, in the case
of the β-thiolactone, rapid C−S bond scission leads to a
zwitterion whose decomposition to the alkene and COS is slow
and rate-limiting. In both cases, formation of the zwitterion is
expected to be reversible.
mmol) in CH2Cl2 (81 mL) were added oxalyl chloride (2.12 mL, 24.3
mmol) and a catalytic amount of anhydrous DMF at room
temperature, and the reaction mixture was stirred for 30 min. The
solvent was evaporated under reduced pressure. To the oil residue was
added a solution of 2-mercaptopyridine (2.16 g, 19.4 mmol) in
CH2Cl2 (81 mL), followed by Et3N (4.52 mL, 32.4 mmol) at 0 °C.
The reaction mixture was stirred at room temperature for 2 h and then
quenched with 1 M HCl and neutralized by washing with saturated
NaHCO3. The organic layers were combined and evaporated. After
purification by flash chromatography (80:20 heptane/AcOEt), the
desired product was obtained as a yellow oil (3.7 g, 73%); IR υmax
1
(cm−1) 2929, 2854, 1704, 1611, 1572, 1511; H NMR (300 MHz,
CDCl3) δ 8.61 (d, J = 4.3 Hz, 1 H), 7.73 (t, J = 7.6 Hz, 1 H), 7.59 (d, J
= 7.6 Hz, 1 H), 7.25−7.32 (m, 1 H), 7.08 (d, J = 8.1 Hz, 2 H), 6.82 (d,
J = 8.1 Hz, 2 H), 3.79 (s, 3 H), 2.69 (t, J = 7.6 Hz, 2 H), 2.55 (t, J = 7.6
Hz, 2 H), 1.76 (quint., J = 7.6 Hz, 2 H), 1.61 (quint., J = 7.6 Hz, 2 H),
1.40 (quint., J = 7.6 Hz, 2 H); 13C NMR (75 MHz, CDCl3) δ 196.5
(C), 157.7 (C), 151.7 (C), 150.4 (CH), 137.1 (CH), 134.5 (C), 130.1
(CH), 129.2 (2 CH), 123.4 (CH), 113.7 (2 CH), 55.3 (CH3), 44.1
(CH2), 34.7 (CH2), 31.3 (CH2), 28.5 (CH2), 25.3 (CH2); MS (ES+)
m/z (%) 316.1 (100, [M + H]+); ESI-TOF-HRMS calcd for
C18H22NO2S (M + H) 316.1371, found 316.1375.
S-Phenyl 6-(4-Methoxyphenyl)hexanethioate (3). To a stirred
solution of (1)86 (4 g, 18.00 mmol) in CH2Cl2 (90 mL) were added
oxalyl chloride (2.4 mL, 27.96 mmol) and a catalytic amount of
anhydrous DMF at room temperature. The reaction mixture was
stirred for 30 min, and the solvent was evaporated under reduced
pressure. To the stirred oil residue was added thiophenol (2.21 mL,
21.59 mmol) in CH2Cl2 (90 mL), followed by Et3N (5 mL, 35.87
mmol) at 0 °C. The reaction mixture was stirred at room temperature
for 2 h and then quenched with 1 M HCl and neutralized by washing
with saturated NaHCO3. The organic layers were combined and
evaporated. After purification by flash chromatography (50/50
heptane/CH2Cl2), the desired product was obtained as a yellow oil
(5.16 g, 91%); IR υmax (cm−1) 2933, 2857, 1707, 1612, 1584, 1512; 1H
NMR (300 MHz, CDCl3) δ 7.40 (s, 5 H), 7.09 (d, J = 8.3 Hz, 2 H),
6.83 (d, J = 8.3 Hz, 2 H), 3.79 (s, 3 H), 2.65 (t, J = 7.5 Hz, 2 H), 2.57
(t, J = 7.5 Hz, 2 H), 1.74 (quint, J = 7.5 Hz, 2 H), 1.62 (quint, J = 7.5
Hz, 2 H), 1.42 (quint., J = 7.5 Hz, 2 H); 13C NMR (75 MHz, CDCl3)
δ 197.5 (C), 157.7 (C), 134.5 (C, 2 CH), 129.3 (2 CH), 129.2 (C, 2
CH), 129.1 (CH), 113.7 (2 CH), 55.3 (CH3), 43.6 (CH2), 34.7
(CH2), 31.3 (CH2), 28.5 (CH2), 25.4 (CH2); MS (ES+) m/z (%)
332.1 (100, [M + NH4]+); ESI-TOF-HRMS calcd for C19H26NO2S
(M + NH4) 332.1684, found 332.1670.
Regarding the concerted mechanism with the asynchronous
transition state, fragmentation of both the β-lactones and the β-
thiolactones is expected to be accelerated in polar solvents
owing to stabilization of the polar transition state.
The lack of a consistent pattern of solvent effects for either
the β-lactones or the β-thiolactones suggests that the concerted
mechanism is not operative. Rather, it seems likely that the
stepwise mechanism with the zwitterionic intermediates is the
preferred pathway with changes in the rate-determining step
being caused by subtle changes in substrate structure and
possibly by solvent.
trans-4-Ethyl-3-(4-(4-methoxyphenyl)butyl)oxetan-2-one
(4). To a stirred solution of 1 M LiHMDS in hexane (3.7 mL, 3.7
mmol) at −78 °C was added dropwise a solution of (2) (500 mg, 1.6
mmol) in CH2Cl2 (8 mL). The reaction mixture was stirred for 30 min
at −78 °C, and TESCl (0.54 mL, 3.2 mmol) was added dropwise. The
reaction mixture was stirred at −78 °C for 1 h and then quenched with
a pH 7 buffer solution. The organic layer was separated, dried over
Na2SO4, and evaporated. Propanal (0.1 mL, 1.39 mmol) and a solution
of crude S-pyridin-2-yl 6-(4-methoxyphenyl)hexanethioate triethylsilyl
enol ether (680 mg, 1.58 mmol) in CH2Cl2 (7.2 mL) were added
dropwise to a suspension of ZnCl2 (393 mg, 2.88 mmol, freshly fused
under vacuum) at room temperature. The reaction mixture was stirred
at room temperature for 2.5 h. A PBS buffer (pH 7) was added to the
reaction mixture, which was stirred for 25 min. The product was
extracted with CH2Cl2 and dried over Na2SO4, and the solvents were
evaporated. After purification on silica (80:20 heptane/AcOEt), the
desired product was obtained as a colorless oil (155.3 mg, 37%); IR
CONCLUSION
■
The di-, tri-, and tetraalkyl substituted β-thiolactones require
significantly higher temperature than the corresponding β-
lactones for the thermal extrusion of carbon oxysulfide and
carbon dioxide, respectively. This finding, coupled with
differences in the influences of solvent polarity on the extrusion
reactions, suggests that the decomposition of the β-thiolactones
and of the β-lactones is best interpreted in terms of stepwise
fragmentation mechanisms involving zwitterionic intermediates
with the rate-determining step, ring-opening, or expulsion of
COS or CO2 being dependent on the nature of the heteroatom,
S or O.
1
υmax (cm−1) 2930, 1814, 1611, 1511; H NMR (500 MHz, CDCl3) δ
7.08 (d, J = 8.3 Hz, 2 H), 6.83 (d, J = 8.3 Hz, 2 H), 4.10−4.18 (m, 1
H), 3.79 (s, 3 H), 3.11−3.20 (m, 1 H), 2.57 (t, J = 7.7 Hz, 2 H), 1.78−
1.95 (m, 2 H), 1.69−1.78 (m, 2 H), 1.53−1.69 (m, 2 H), 1.32−1.53
(m, 2 H), 0.99 (t, J = 7.1 Hz, 3 H); 13C NMR (75 MHz, CDCl3) δ
171.4 (C), 157.8 (C), 134.1 (C), 129.2 (2 CH), 113.8 (2 CH), 79.1
(CH), 55.6 (C), 55.3 (CH), 34.6 (CH2), 31.3 (CH2), 27.8 (CH2),
27.5 (CH2), 26.5 (CH2), 9.1 (CH3); MS (ES+) m/z (%) 547.3 (10,
EXPERIMENTAL SECTION
■
S-Pyridin-2-yl 6-(4-Methoxyphenyl)hexanethioate (2). To a
stirred solution of 6-(4-methoxyphenyl)hexanoic acid86 (3.6 g, 16.2
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[2M + Na]+), 285.1 (100, [M + Na]+); ESI-TOF-HRMS calcd for
C16H22NaO3 (M + Na) 285.1467, found 285.1473.
3.79 (s, 3 H), 3.62 (ddd, J = 8.4, 6.4, 3.6 Hz, 0.8 H), 3.53 (ddd, J =
11.2, 7.4, 3.6 Hz, 0.2 H), 3.15 (ddd, J = 8.9, 5.6, 3.5 Hz, 0.8 H), 2.56 (t,
J = 7.5 Hz, 2 H), 1.53−2.05 (m, 6 H), 1.50−1.36 (m, 2 H), 1.03 (t, J =
7.5 Hz, 0.6 H), 1.01 (t, J = 7.5 Hz, 2.4 H); 13C NMR (75 MHz,
CDCl3) δ 195.3 (0.2 C), 194.4 (0.8 C), 157.7 (C), 134.2 (C), 129.2 (2
CH), 113.7 (2 CH), 73.9 (0.8 CH), 70.4 (0.2 CH), 55.2 (CH3), 42.4
(0.8 CH2), 40.9 (0.2 CH2), 34.7 (CH2), 31.4 (CH2), 30.7 (CH2), 27.4
(0.2 CH2), 26.2 (0.8 CH2), 25.9 (0.8 CH2), 25.8 (0.2 CH2), 13.1 (0.2
CH3), 13.0 (0.8 CH3); MS (ES+) m/z (%) 579.3 (15, [2M + Na]+),
301.1 (100, [M + Na]+), 296.2 (60, [M + NH4]+); ESI-TOF-HRMS
calcd for C16H22NaO2S (M + Na) 301.1238, found 301.1236.
(S*)-2-((S*)-(1-(Acetylthio)propyl)-6-(4-methoxyphenyl)-
hexanoic Acid (5). To a solution of (4) (531 mg, 2.02 mmol) in
DMF (4.04 mL) was added cesium ethanethioate (1.05 g, 5.07 mmol),
and the reaction mixture was stirred at room temperature for 22 h.
The mixture was acidified with 1 M HCl and was then extracted with
ether and dried over Na2SO4. The desired product was obtained after
purification on a silica cartridge (70:30 heptane/AcOEt) as a yellow oil
1
(418.8 mg, 61%); IR υmax (cm−1) 3100, 2932, 1705, 1690; H NMR
(300 MHz, CDCl3) δ 8.93 (br s, 1 H), 7.08 (d, J = 8.0 Hz, 2 H), 6.82
(d, J = 8.0 Hz, 2 H), 4.13 (q, J = 7.2 Hz, 0.1 H, AcOEt), 3.78 (s, 3 H),
3.70−3.77 (m, 1 H), 2.50−2.65 (m, 3 H), 2.34 (s, 3 H), 2.05 (s, 0.1 H,
AcOEt), 1.71−1.82 (m, 2 H), 1.54−1.67 (m, 4 H), 1.30−1.49 (m, 2
H), 0.97 (t, J = 7.4 Hz, 3 H); 13C NMR (75 MHz, CDCl3) δ 195.1
(C), 179.4 (C), 157.7 (C), 134.5 (C), 129.2 (2 CH), 113.7 (2 CH),
60.4 (2 CH2, AcOEt), 55.3 (CH3), 49.5 (CH), 47.4 (CH), 34.7
(CH2), 31.5 (CH2), 30.7 (CH3), 29.5 (CH2), 27.1 (CH2), 25.5 (CH2),
14.2 (2 CH3, AcOEt) 11.5 (CH3); MS (ES−) m/z (%) 337.1 (100, [M
− H]−); ESI-TOF-HRMS calcd for C18H25O4S (M − H) 337.1474,
found 337.1459.
4-Ethyl-3-(4-(4-methoxyphenyl)butyl)-3-methyloxetan-2-
one (9). A solution of 0.6 M LDA (7.5 mL, 4.5 mmol) in THF was
added dropwise to a solution of (4) (534 mg, 2.0 mmol) in THF (6.7
mL) at −78 °C. The reaction mixture was stirred at this temperature
for 30 min, and freshly distilled MeI (0.44 mL, 6.9 mmol) was added.
The reaction was slowly warmed up to room temperature for 2.5 h.
The mixture was then cooled down to −78 °C, and acetic acid was
added. The mixture was extracted with AcOEt, washed with saturated
Na2CO3 and then brine, and dried over Na2SO4. The solvent was
removed under vacuo. The desired product was obtained after
purification on a silica cartridge (85:15 heptane/AcOEt) as a colorless
oil (394.6 mg, 70%, unlike/like 4:1); IR υmax (cm−1) 2937, 1815, 1612,
(S*)-2-((S*)-1-Mercaptopropyl)-6-(4-methoxyphenyl)-
hexanoic Acid (6). To a solution of (5) (410 mg, 1.2 mmol) in
CH3CN (24 mL) was added hydrazine monohydrate (0.12 mL, 2.4
mmol), and the reaction mixture was stirred at 0 °C for 1.5 h. The
mixture was acidified with 1 M HCl. The product was extracted with
CH2Cl2 and dried over Na2SO4, and the solvent was evaporated. The
desired product was obtained as a yellow oil (S*,S*/S*,R* = 83/17)
without further purification (342.4 mg, 96%); IR υmax (cm−1) 3100,
1
1512; H NMR (300 MHz, CDCl3) δ 7.08 (d, J = 8.0 Hz, 2 H), 6.83
(d, J = 8.0 Hz, 2 H), 4.17 (dd, J = 9.1 Hz, 5.5 Hz, 0.2 H), 4.11 (dd, J =
9.6 Hz, 4.6 Hz, 0.8 H), 3.78 (s, 3 H), 2.50−2.63 (m, 2 H), 1.47−1.85
(m, 8 H), 1.38 (s, 2.4 H), 1.24 (s, 0.6 H), 1.03 (t, J = 7.3 Hz, 2.4 H),
1.01 (t, J = 7.3 Hz, 0.6 H); 13C NMR (75 MHz, CDCl3) δ 175.0 (C),
157.7 (C), 134.2 (0.8 C), 134.1 (0.2 C), 129.2 (2 CH), 113.7 (2 CH),
85.4 (0.8 CH), 82.8 (0.2 CH), 57.0 (0.2 C), 56.4 (0.8 C), 55.2 (CH3),
35.7 (0.2 CH2), 34.7 (0.8 CH2), 32.0 (0.8 CH2), 31.7 (0.2 CH2), 30.0
(CH2), 23.8 (CH2), 23.4 (0.8 CH2), 19.8 (CH2), 14.1 (0.2 CH2), 10.0
(0.8 CH3), 9.9 (0.2 CH3); MS (APCI) m/z (%) 277.2 (85, [M + H]+),
318.2 (100, [M + H + CH3CN]+); ESI-TOF-HRMS calcd for
C17H25O3 (M + H) 277.1804, found 277.1794.
4-Ethyl-3-(4-(4-methoxyphenyl)butyl)-3-methylthietan-2-
one (10). To a solution of (7) (168 mg, 0.6 mmol) in THF (16.7 mL)
was added 1 M LiHMDS in hexane (0.9 mL, 0.93 mmol) at −78 °C,
and the mixture was stirred at this temperature for 1 h. TMEDA (0.14
mL, 0.93 mmol) and distilled MeI (0.19 mL, 3.0 mmol) were added at
−78 °C, and the reaction mixture was allowed to warm up to −40 °C
and was stirred at this temperature for 12 h. Acetic acid was added at
this temperature. The organic layer was washed with saturated
Na2CO3 and dried over Na2SO4, and the solvent was removed in
vacuo. The desired product was obtained as a yellow oil without
further purification (164.7 mg, 94%, 7:3 unlike/like); IR υmax (cm−1)
2934, 2856, 1740, 1612, 1511; 1H NMR (300 MHz, CDCl3) δ 7.08 (d,
J = 8.4 Hz, 2 H), 6.82 (d, J = 8.4 Hz, 2 H), 3.79 (s, 3 H), 3.24 (dd, J =
10.6, 4.5 Hz, 0.3 H), 3.17 (dd, J = 11.5, 4.1 Hz, 0.7 H), 2.50−2.64 (m,
2 H), 1.41−2.02 (m, 8 H), 1.35 (s, 2.1 H), 1.24 (s, 0.9 H), 1.00 (t, J =
7.3 Hz, 3 H); 13C NMR (75 MHz, CDCl3) δ 198.7 (0.3 C), 198.4 (0.7
C), 157.7 (C), 134.4 (0.7 C), 134.3 (0.3 C), 129.2 (2 CH), 113.7 (2
CH), 74.7 (0.3 C), 74.2 (0.7 C), 55.2 (CH3), 49.9 (0.7 CH), 46.9 (0.3
CH), 37.9 (CH2), 34.7 (CH2), 32.2 (0.7 CH2), 32.1 (0.3 CH2), 25.8
(0.7 CH2), 25.0 (0.3 CH2), 24.3 (0.7 CH2), 23.4 (0.3 CH2), 22.3 (0.7
CH3), 16.5 (0.3 CH3), 13.3 (CH3); MS (ES+) m/z (%) 310.2 (100,
[M + NH4]+); ESI-TOF-HRMS calcd for C17H28NO2S (M + NH4)
310.1841, found 310.1827.
1
2929, 2856, 1703, 1612; H NMR (300 MHz, CDCl3) δ 9.67 (br s, 1
H), 7.08 (d, J = 8.1 Hz, 2 H), 6.82 (d, J = 8.1 Hz, 2 H), 3.78 (s, 3 H),
2.92−3.03 (m, 1 H), 2.73−2.60 (m, 3 H), 2.00 (s, 1 H), 1.69−1.83
(m, 2 H), 1.21−1.68 (m, 6 H), 1.05 (t, J = 7.4 Hz, 3 H); 13C NMR (75
MHz, CDCl3) δ 180.3(C), 157.6 (C), 134.5 (C), 129.2 (2 CH), 113.7
(2 CH), 55.2 (CH3), 52.4 (CH), 44.3 (CH), 34.7 (CH2), 31.5 (CH2),
29.8 (CH2), 28.9 (CH2), 27.1 (CH2), 11.8 (CH3); MS (ES−) m/z (%)
589.3 (100, [2M − 3H]−); ESI-TOF-HRMS calcd for C32H45O6S2
(2M − 3H) 589.2658, found 589.2648.
cis-4-Ethyl-3-(4-(4-methoxyphenyl)butyl)thietan-2-one (7).
To a solution of (6) (330 mg, 1.11 mmol) in CH2Cl2 (5.6 mL)
were added to EDCI·HCl (427.3 mg, 2.23 mmol) and pentafluor-
ophenol (246.1 mg, 1.34 mmol) at 0 °C and the mixture was stirred at
0 °C for 1 h 30. The mixture was quenched with 1 M HCl and
extracted with CH2Cl2, dried over Na2SO4 and the solvent was
removed. The desired product was obtained after purification on a
silica cartridge (90:10 heptane/AcOEt) as a colorless oil (302.8 mg,
98%) in the form of a 93/7 cis/trans mixture; IR υmax (cm−1) 2932,
1
2858, 1749, 1612, 1512; H NMR (300 MHz, CDCl3) δ 7.08 (d, J =
8.6 Hz, 2 H), 6.82 (d, J = 8.6 Hz, 2 H), 4.12 (q, J = 7.5 Hz, 1 H), 3.79
(s, 3 H), 3.53 (ddd, J = 11.4, 7.4, 4.1 Hz, 1 H), 2.56 (t, J = 7.6 Hz, 2
H), 1.27−2.08 (m, 8 H), 1.06 (t, J = 7.0 Hz, 3 H); 13C NMR (75
MHz, CDCl3) δ 195.3 (C), 157.7 (C), 134.3 (C), 129.2 (2 CH), 113.7
(2 CH), 70.4 (CH), 55.2 (CH3), 40.9 (CH), 34.6 (CH2), 31.5 (CH2),
27.4 (CH2), 26.2 (CH2), 25.8 (CH2), 13.1 (CH3); MS (ES+) m/z (%)
579.3 (15, [2M + Na]+), 301.1 (100, [M + Na]+), 296.2 (60, [M +
NH4]+); ESI-TOF-HRMS calcd for C16H22NaO2S (M + Na)
301.1238, found 301.1236.
trans-4-Ethyl-3-(4-(4-methoxyphenyl)butyl)thietan-2-one
(8). To a −78 °C solution of (7) (270 mg, 0.97 mmol) in THF (26.9
mL) was added 1 M LiHMDS in hexane (1.46 mL, 1.46 mmol), and
the reaction mixture was stirred at −78 °C for 1 h. Tetramethylethy-
lenediamine (0.22 mL, 1.46 mmol) was then added at −78 °C, and the
mixture was stirred for an additional 30 min, after which the solution
was quenched with acetic acid (0.17 mL, 2.97 mmol). The reaction
mixture was neutralized with a saturated Na2CO3, and the product was
extracted with ether. The solvent was removed under vacuo. The
desired product was obtained as a mixture of cis/trans thiolactones
(20/80) and as a colorless oil (263.8 mg, 98%); IR υmax (cm−1) 2930,
2856, 1747, 1612, 1583, 1511; 1H NMR (300 MHz, CDCl3) δ 7.08 (d,
J = 8.6 Hz, 2 H), 6.83 (d, J = 8.6 Hz, 2 H), 4.12 (q, J = 7.9 Hz, 0.2 H),
4-Ethyl-3-(4-(4-methoxyphenyl)butyl)-4-methyloxetan-2-
one (11). To a stirred solution of 0.6 M LDA in THF (4.7 mL, 2.82
mmol) at −78 °C was added dropwise a solution of (3) (809 mg, 2.57
mmol) in THF (1.2 mL). The reaction mixture was stirred for 30 min
at −78 °C, and 2-butanone (0.23 mL, 2.57 mmol) was added
dropwise. The reaction was stirred at −78 °C for 30 min and then
allowed to warm up to 0 °C. The reaction was quenched with half-
saturated aqueous ammonium chloride. The mixture was poured into a
separatory funnel containing hexane/water (1:1). The aqueous layer
was extracted with hexane, and the combined organic layers were
washed successively with aqueous NaHCO3 and brine and then was
dried over Na2SO4 and evaporated. After a purification on a silica
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cartridge (95:5 heptane/AcOEt), the desired product was obtained as
J = 13.2 Hz, 1 H), 2.16 (br d, J = 13.2 Hz, 1 H), 1.97 (br s, 2 H),
1.50−1.89 (m, 15 H), 1.29−1.46 (m, 2 H); 13C NMR (75 MHz,
CDCl3) δ 181.2 (C), 157.7 (C), 134.5 (C), 129.2 (2 CH), 113.7 (2
CH), 75.4 (C), 55.2 (CH3), 49.0 (CH), 38.1 (CH), 37.8 (CH2), 34.8
(CH2), 34.3 (CH), 33.7 (CH2), 33.4 (CH), 33.0 (CH2), 32.6 (CH2),
31.6 (CH2), 27.4 (CH2), 27.1 (CH), 26.9 (CH), 25.5 (CH2); MS
(ES−) m/z (%) 371.2 (100, [M − H]−), 743.5 (15, [2M − H]−); ESI-
TOF-HRMS calcd for C23H31O4 (M − H) 371.2222, found 371.2223.
2-(2-Mercaptoadamantan-2-yl)-6-(4-methoxyphenyl)-
hexanoic Acid (16). To a solution of (12) (315.7 mg, 1.13 mmol) in
dry THF/cyclohexane (4:1, 2.6 mL) at −78 °C was added 0.6 M LDA
in THF (2 mL, 1.2 mmol). The mixture was stirred at −78 °C for 40
min, and a solution of adamantan-2-thione (200 mg, 1.2 mmol) in
THF (3.6 mL) was added. The cold bath was removed, and the
reaction mixture was stirred at room temperature for 2 h. The reaction
mixture was diluted with CH2Cl2, and 1 M HCl was added. The
organic phase was extracted with CH2Cl2 and washed with brine, dried
over Na2SO4, filtered, and concentrated. To this crude product in
CH2Cl2 (0.5 mL) was added TFA (0.5 mL). The reaction mixture was
stirred at room temperature for 2 h. CH2Cl2 was added and the
mixture was concentrated to dryness; this was repeated twice. After
purification on a silica cartridge (90:10 heptane/AcOEt), the desired
product was obtained as a white solid (193.2 mg, 44%, mp = 134.1−
a mixture of unlike/like (70:30) isomers and as a colorless oil (425 mg,
1
60%); IR υmax (cm−1) 2973, 2934, 2859, 1811, 1612, 1512; H NMR
(500 MHz, CDCl3) δ 7.08 (d, J = 8.6 Hz, 2 H), 6.83 (d, J = 8.6 Hz, 2
H), 3.80 (s, 3 H), 3.20 (t, J = 8.0 Hz, 0.3 H), 3.15 (t, J = 8.0 Hz, 0.7
H), 2.59 (t, J = 7.5 Hz, 2 H), 1.09−2.56 (m, 7 H), 1.54 (s, 1 H), 1.44
(s, 2 H), 1.25−1.42 (m, 1 H), 1.04 (t, J = 7.3 Hz, 1 H), 0.98 (t, J = 7.3
Hz, 2 H); 13C NMR (75 MHz, CDCl3) δ 171.7 (C), 157.8 (C), 134.1
(C), 129.2 (2 CH), 113.7 (2 CH), 82.6 (0.7 C), 82.3 (0.3 C), 58.9
(0.3 CH), 56.5 (0.7 CH), 55.2 (CH3), 34.6 (CH2), 33.7 (0.7 CH2),
31.4 (0.3 CH2), 31.3 (0.7 CH2), 27.9 (0.3 CH2), 27.2 (0.3 CH2), 27.0
(0.7 CH2), 24.9 (0.7 CH2), 24.2 (0.3 CH2), 24.1 (0.3 CH3), 18.9 (0.7
CH3), 8.4 (0.7 CH3), 7.9 (0.3 CH3); MS (ES+) m/z (%) 277.1 (100,
[M + H]+); ESI-TOF-HRMS calcd for C17H25O3 (M + H) 277.1804,
found 277.1802.
tert-Butyl 6-(4-Methoxyphenyl)hexanoate (12). To a stirred
solution of 6-(4-methoxyphenyl)hexanoic acid (4.8 g, 21.6 mmol) in
CH2Cl2 (108 mL) were added oxalyl chloride (2.8 mL, 32.1 mmol)
and a catalytic amount of anhydrous DMF at room temperature. The
reaction mixture was stirred for 30 min, and the solvent was
evaporated under reduced pressure. To the stirred oil residue was
added tert-butanol (108 mL), followed by Et3N (6.0 mL, 43.0 mmol),
at room temperature. The reaction mixture was stirred at this
temperature for 2 h and then quenched with 1 M HCl and neutralized
by washing with saturated NaHCO3. The organic layer was
evaporated. The desired product was obtained as a yellow oil (5.51
g, 92%); IR υmax (cm−1) 2977, 2932, 2857, 1728, 1613, 1513; 1H NMR
(300 MHz, CDCl3) δ 7.08 (d, J = 8.4 Hz, 2 H), 6.82 (d, J = 8.4 Hz, 2
H), 3.78 (s, 3 H), 2.55 (t, J = 7.5 Hz, 2 H), 2.20 (t, J = 7.5 Hz, 2 H),
1.53−1.67 (m, 4 H), 1.43 (s, 9 H), 1.23−1.40 (m, 2 H); 13C NMR (75
MHz, CDCl3) δ 173.2 (C), 157.6 (C), 134.7 (C), 129.2 (2 CH), 113.6
(2 CH), 79.9 (C), 55.2 (CH3), 35.5 (CH2), 34.8 (CH2), 31.4 (CH2),
28.6 (CH2), 28.1 (3 CH3), 25.0 (CH2); MS (ES+) m/z (%) 296.2
(100, [M + NH4]+); ESI-TOF-HRMS calcd for C17H30NO3 (M +
NH4) 296.2226, found 296.2221.
1
134.4 °C); IR υmax (cm−1) 3100, 2941, 2908, 2866, 1697, 1512; H
NMR (300 MHz, CDCl3) δ 8.05 (br s, 1 H), 7.08 (d, J = 8.6 Hz, 2 H),
6.82 (d, J = 8.6 Hz, 2 H), 3.78 (s, 3 H), 3.44 (dd, J = 11.6, 2.4 Hz, 1
H), 2.52−2.69 (m, 3 H), 2.50 (s, 1 H), 2.35 (br d, J = 13.7 Hz, 2 H),
1.91−2.03 (m, 3 H), 1.87 (br s, 2 H), 1.20−1.76 (m, 12 H); 13C NMR
(75 MHz, CDCl3) δ 179.5 (C), 157.7 (C), 134.5 (C), 129.2 (2 CH),
113.7 (2 CH), 57.1 (C), 55.3 (CH3), 50.4 (CH), 39.1 (CH2), 38.7
(CH), 35.5 (CH), 34.8 (CH2), 34.4 (CH2), 34.0 (CH2), 33.01 (CH2),
32.97 (CH2), 31.7 (CH2), 27.7 (CH2), 27.4 (CH), 27.1 (CH2), 26.7
(CH); MS (ES−) m/z (%) 387.2 (100, [M − H]−); ESI-TOF-HRMS
calcd for C23H31O3S (M − H) 387.1994, found 387.1994.
3′-(4-(4-Methoxyphenyl)butyl)spiro[adamantane-2,2′-oxe-
tan]-4′-one (17). 4-Nitrobenzenesulfonyl chloride (357.3 mg, 1.61
mmol) and triethylamine (0.37 mL, 2.65 mmol) were added to a
solution of (15) (500 mg, 1.34 mmol) in CH2Cl2 (6.7 mL) at 0 °C.
The reaction mixture was stirred at 0 °C for 2 h and at room
temperature overnight. The mixture was quenched with 1 M HCl and
extracted with CH2Cl2. The solution was dried over Na2SO4, and the
solvent was removed. The desired product was obtained, after
purification on a silica cartridge (90:10 heptane/AcOEt), as a white
solid (186 mg, 39%, mp = 82.7−83.5 °C); IR υmax (cm−1) 2909, 2856,
1810, 1612, 1511; 1H NMR (300 MHz, CDCl3) δ 7.09 (d, J = 8.6 Hz,
2 H), 6.82 (d, J = 8.6 Hz, 2 H), 3.78 (s, 3 H), 3.04 (dd, J = 10.5, 5.3
Hz, 1 H), 2.52−2.64 (m, 2 H), 2.14 (br s, 1 H), 2.10 (br d, J = 13.2
Hz, 1 H), 2.04 (br d, J = 13.2 Hz, 1 H), 1.58−1.94 (m, 16 H), 1.43−
1.54 (m, 1H); 13C NMR (75 MHz, CDCl3) δ 172.3 (C), 157.7 (C),
134.4 (C), 129.2 (2 CH), 113.7 (2 CH), 86.5 (C), 57.5 (CH), 55.2
(CH3), 38.8 (CH), 36.6 (CH2), 34.8 (CH), 34.7 (CH2), 34.4 (CH2),
33.3 (CH2), 33.0 (CH2), 32.9 (CH2), 31.6 (CH2), 27.1 (CH2), 26.8
(CH), 26.2 (CH), 24.5 (CH2) ; MS (APCI) m/z (%) 355.2 (70, [M +
H]+), 396.3 (100, [M + H + CH3CN]+); ESI-TOF-HRMS calcd for
C23H31O3 (M + H) 355.2273, found 355.2270, calcd for C25H34NO3
(M + H + CH3CN) 396.2539, found 396.2540.
tert-Butyl 2-(2-Hydroxyadamantan-2-yl)-6-(4-methoxy-
phenyl)hexanoate (13). To a solution of (12) (1 g, 3.59 mmol)
in dry THF (8.2 mL) at −78 °C was added 0.6 M LDA in THF (6.4
mL, 3.84 mmol). The mixture was stirred at −78 °C for 40 min. A
solution of adamantan-2-one (573 mg, 3.81 mmol) in THF (9.6 mL)
was added. The cold bath was removed, and the reaction mixture was
stirred at room temperature for 2 h. The reaction mixture was diluted
with CH2Cl2, and 1 M HCl was added. The product was extracted
with AcOEt. The organic phase was washed with brine, dried over
Na2SO4, filtered, and concentrated. The crude product was purified on
a silica cartridge (95:5 heptane/AcOEt) to give the desired product as
a colorless oil (1.22 g, 79%); IR υmax (cm−1) 3500, 2906, 2857, 1699,
1612, 1512; 1H NMR (300 MHz, CDCl3) δ 7.07 (d, J = 8.4 Hz, 2 H),
6.81 (d, J = 8.4 Hz, 2 H), 3.77 (s, 3 H), 3.48 (br s, 1 H), 2.99 (dd, J =
11.4, 4.0 Hz, 1 H), 2.54 (t, J = 7.9 Hz, 2 H), 2.31 (d, J = 13.2 Hz, 1 H),
2.23 (d, J = 13.2 Hz, 1 H), 1.85−2.12 (m, 4 H), 1.47−1.85 (m, 12 H),
1.43 (s, 9 H), 1.18−1.36 (m, 2 H); 13C NMR (75 MHz, CDCl3) δ
176.8 (C), 157.7 (C), 134.5 (C), 129.2 (2 CH), 113.7 (2 CH), 81.4
(C), 75.1 (C), 55.2 (CH3), 49.0 (CH), 38.3 (CH2), 38.0 (CH), 34.8
(CH2), 34.2 (CH2), 33.7 (CH2), 33.4 (2 CH2), 33.1 (CH2), 32.6
(CH2), 31.5 (CH2), 28.2 (3 CH3), 27.3 (CH2), 27.11 (CH), 27.08
(CH), 25.7 (CH2); MS (ES+) m/z (%) 355.2 (75, [M − OH −
C4H8]+), 451.3 (100, [M + Na]+); ESI-TOF-HRMS calcd for
C27H40NaO4 (M + Na) 451.2824, found 451.2806.
2-(5-(4-Methoxyphenyl)pentylidene)adamantane (19). This
compound was obtained as a byproduct on formation of 17 described
above. It was isolated after purification on a silica cartridge (95:5
heptane/AcOEt) as a colorless oil (349.9 mg, 70%); IR υmax (cm−1)
2-(2-Hydroxyadamantan-2-yl)-6-(4-methoxyphenyl)-
hexanoic Acid (15). To a solution of (13) (1.19 g, 2.78 mmol) in
CH2Cl2 (1.9 mL) was added TFA (1.9 mL). The reaction mixture was
stirred at room temperature for 1 h, and the solvent was evaporated.
The residue was treated with CH2Cl2 and concentrated to dryness, and
the process was repeated twice. After purification on a silica cartridge
(85:15 heptane/AcOEt), the desired product was obtained as a white
solid (972.7 mg, 94%, mp = 93.9−95.3 °C); IR υmax (cm−1) 3500,
1
2906, 2848, 1613, 1512; H NMR (300 MHz, CDCl3) δ 7.09 (d, J =
8.7 Hz, 2 H), 6.82 (d, J = 8.7 Hz, 2 H), 5.01 (t, J = 7.3 Hz, 1 H), 3.79
(s, 3 H), 2.79 (br s, 1 H), 2.54 (t, J = 7.6 Hz, 2 H), 2.30 (br s, 1 H),
1.51−2.06 (m, 16 H), 1.35 (quint., J = 7.6 Hz, 2 H); 13C NMR (75
MHz, CDCl3) δ 157.6 (C), 147.5 (C), 135.0 (C), 129.2 (2 CH), 116.1
(CH), 113.6 (2 CH), 55.2 (CH3), 40.6 (CH), 39.9 (2 CH2), 39.0
(CH), 37.4 (CH2), 34.9 (CH2), 32.1 (2 CH2), 31.2 (CH2), 29.9
(CH2), 28.7 (2 CH), 26.3 (CH2); MS (APCI) m/z (%) 310.2 (100,
[M+.]), 311.2 (92, [M + H]+), 328.2 (90, [M + NH4]+), 352.3 (85, [M
1
2908, 2858, 1699, 1612, 1511; H NMR (300 MHz, CDCl3) δ 9.51
(br s, 1 H), 7.07 (d, J = 8.5 Hz, 2 H), 6.82 (d, J = 8.5 Hz, 2 H), 3.78 (s,
3 H), 3.17 (dd, J = 11.7, 3.7 Hz, 1 H), 2.50−2.61 (m, 2 H), 2.22 (br d,
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+ H + CH3CN]+); ESI-TOF-HRMS calcd for C22H30O (M+.)
310.2297, found 310.2297.
6.82 (d, J = 8.7 Hz, 2 H), 5.27−5.51 (m, 2 H), 3.79 (s, 3 H), 2.55 (t, J
= 7.1 Hz, 2 H), 1.93−2.05 (m, 4 H), 1.52−1.65 (m, 2 H), 1.36−1.44
(m, 2 H), 0.96 (t, J = 7.7 Hz, 3 H); 1H NMR (500 MHz, C6D6) 7.01
(d, J = 8.2 Hz, 2 H), 6.81 (d, J = 8.2 Hz, 2 H), 5.36−5.50 (ABt, J =
14.8, 5.4 Hz, 2 H), 3.35 (s, 3 H), 2.48 (t, J = 7.7 Hz, 2 H), 1.90−2.01
(m, 4 H), 1.56 (quint., J = 7.7 Hz, 2 H), 1.36 (quint., J = 7.7 Hz, 2 H),
0.95 (t, J = 7.7 Hz, 3 H); 13C NMR (75 MHz, CDCl3) δ 157.6 (C),
134.9 (C), 132.1 (CH), 129.2 (2 CH), 129.1 (CH), 113.7 (2 CH),
55.3 (CH3), 34.9 (CH2), 32.4 (CH2), 31.2 (CH2), 29.2 (CH2), 25.6
(CH2), 14.0 (CH3); MS (APCI) m/z (%) 218.2 (100, [M+.]), 219.2
(30, [M + H]+); ESI-TOF-HRMS calcd for C15H22O (M+.) 218.1671,
found 218.1671.
1-Methoxy-4-(5-methyloct-5-en-1-yl)benzene (23). Com-
pound (9) (unlike/like 80:20) (53.2 mg, 0.19 mmol) was heated in
FC-70 (1 mL) at 120 °C overnight to give, after purification on a silica
cartridge (98:2 heptane/AcOEt), the desired product as a colorless oil
(11.4 mg, 26%, Z/E (80:20)) and the starting material (38.8 mg); IR
υmax (cm−1) 2960, 1613, 1512; 1H NMR (300 MHz, CDCl3) δ 7.10 (d,
J = 8.4 Hz, 2 H), 6.83 (d, J = 8.4 Hz, 2 H), 5.12 (t, J = 7.3 Hz, 1 H),
3.79 (s, 3 H), 2.56 (t, J = 7.8 Hz, 2 H), 1.91−2.08 (m, 4 H), 1.66 (s,
2.4 H), 1.50−1.62 (m, 2.6 H), 1.34−1.48 (m, 2 H), 0.93 (t, J = 7.3 Hz,
3 H); 13C NMR (75 MHz, CDCl3) δ 157.6 (C), 134.9 (C), 134.7 (C),
129.2 (2 CH), 127.1 (0.8 CH), 126.4 (0.2 CH), 113.7 (2 CH), 55.3
(CH3), 39.4 (0.2 CH2), 35.0 (CH2), 31.5 (1.6 CH2), 31.3 (0.2 CH2),
27.6 (0.8 CH2), 27.5 (0.2 CH2), 23.4 (CH3), 21.15 (0.8 CH2), 21.07
(0.2 CH2), 14.7 (0.8 CH3), 14.4 (0.2 CH3); MS (APCI) m/z (%)
274.2 (100, [M + H + CH3CN]+), 232.2 (30, [M+.]), 233.2 (20, [M +
H]+); ESI-TOF-HRMS calcd for C16H25O ([M + H]+.) 233.1905,
found 233.1915.
3′-(4-(4-Methoxyphenyl)butyl)spiro[adamantane-2,2′-thie-
tan]-4′-one (18). A solution of (16) (90 mg, 0.23 mmol) in CH2Cl2
(1 mL) was added to EDCI·HCl (155.3 mg, 0.81 mmol) and C6F5OH
(44.7 mg, 0.24 mmol) at 0 °C. The reaction mixture was stirred at 0
°C for 5 h. The mixture was quenched with 1 M HCl and extracted
with CH2Cl2 and dried over Na2SO4, and the solvent was removed.
The desired product was obtained after purification on a silica
cartridge (98:2 heptane/AcOEt) as a white solid (73.3 mg, 86%, mp =
1
79.2−80.7 °C); IR υmax (cm−1) 2906, 2853, 1739, 1612, 1511; H
NMR (300 MHz, CDCl3) δ 7.09 (d, J = 8.6 Hz, 2 H), 6.82 (d, J = 8.6
Hz, 2 H), 3.79 (s, 3 H), 3.47 (dd, J = 10.1, 5.5 Hz, 1 H), 2.47−2.66
(m, 2 H), 2.27 (br s, 1 H), 1.97−2.10 (m, 2 H), 1.68−1.97 (m, 15 H),
1.53−1.68 (m, 2 H); 13C NMR (75 MHz, CDCl3) δ 195.9 (C), 157.7
(C), 134.5 (C), 129.2 (2 CH), 113.7 (2 CH), 73.3 (CH), 59.6 (C),
55.2 (CH3), 42.2 (CH), 37.14 (CH2), 37.07 (CH2), 36.3 (CH2), 35.7
(CH2), 35.1 (CH), 34.8 (CH2), 33.7 (CH2), 31.8 (CH2), 27.32
(CH2), 27.25 (CH), 27.1 (CH2), 25.9 (CH); MS (APCI) m/z (%)
371.2 (100, [M + H]+); ESI-TOF-HRMS calcd for C23H31O2S (M +
H) 371.2045, found 371.2034.
3′-(4-(4-Methoxyphenyl)butyl)-3′-methylspiro[adamantane-
2,2′-oxetan]-4′-one (20). Dimethyl sulfate (0.11 mL, 1.16 mmol)
was added to a solution of (17) (132 mg, 0.37 mmol) in THF (1.2
mL), and the mixture was cooled to −100 °C. Phosphazene base P4-t-
Bu (1 M in hexane) (0.75 mL, 0.75 mmol) was added at this
temperature, and the reaction mixture was stirred for 1 h and allowed
to warm up to room temperature for 18 h. The reaction was quenched
at room temperature with acetic acid. After extraction with CH2Cl2,
the organic phase was washed with saturated aqueous Na2CO3 and
then brine and dried over Na2SO4. The solvent was removed under
vacuo. The desired product was obtained, after purification on a silica
cartridge (95:5 heptane/AcOEt), followed by HPLC (95:5 heptane/
AcOEt), as a white solid (30.2 mg, 22%, mp = 72.3−73.6 °C); IR υmax
(cm−1) 2916, 2858, 1810, 1612, 1512; 1H NMR (300 MHz, CDCl3) δ
7.08 (d, J = 8.4 Hz, 2 H), 6.82 (d, J = 8.4 Hz, 2 H), 3.78 (s, 3 H),
2.48−2.66 (m, 2 H), 2.27 (br s, 1 H), 2.22 (br s, 1 H), 1.44−2.15 (m,
18 H), 1.35 (s, 3 H); 13C NMR (75 MHz, CDCl3) δ 175.5 (C), 157.8
(C), 134.5 (C), 129.2 (2 CH), 113.8 (2 CH), 89.5 (C), 57.4 (C), 55.3
(CH3), 36.6 (CH2), 35.1 (CH2), 35.0 (CH2), 34.9 (CH2), 33.9 (CH),
33.67 (CH2), 33.65 (CH2), 33.4 (CH), 32.4 (CH2), 31.6 (CH2), 26.5
(CH), 26.1 (CH), 24.4 (CH2), 15.1 (CH3); MS (APCI) m/z (%)
323.2 (99, [M − CO2H]+), 324.2 (25, [M − CO2]+), 369.2 (100, [M
+ H]+); ESI-TOF-HRMS calcd for C24H33O3 (M + H) 369.2430,
found 369.2433.
3′-(4-(4-Methoxyphenyl)butyl)-3′-methylspiro[adamantane-
2,2′-thietan]-4′-one (21). LDA in THF 0.6 M (5.0 mL, 3.00 mmol)
and MeI (0.93 mL, 15.1 mmol) were added to a 0.2 M solution of
(18) (559 mg, 1.51 mmol) in THF (7.5 mL) at −78 °C, and the
mixture was allowed to warm up to −40 °C and stirred for 3 h at that
temperature. The reaction was quenched with acetic acid, and the
organic phase was washed with saturated Na2CO3, which was extracted
with CH2Cl2. After evaporation of the solvent, the product was
purified using HPLC (95:5 heptane/AcOEt). The desired product was
obtained as a colorless oil (265.1 mg, 46%); IR υmax (cm−1) 2908,
2853, 1729, 1612, 1584, 1511; 1H NMR (300 MHz, CDCl3) δ 7.08 (d,
J = 8.7 Hz, 2 H), 6.82 (d, J = 8.7 Hz, 2 H), 3.78 (s, 3 H), 2.48−2.65
(m, 2 H), 2.40 (br s, 1 H), 2.30 (br s, 1 H), 1.69−2.00 (m, 14 H),
1.49−1.68 (m, 4 H), 1.35 (s, 3H); 13C NMR (75 MHz, CDCl3) δ
198.9 (C), 157.5 (C), 134.3 (C), 129.0 (2 CH), 113.5 (2 CH), 72.7
(C), 64.8 (C), 55.0 (CH3), 37.7 (CH2), 37.4 (CH2), 37.2 (CH), 37.1
(CH2), 35.9 (CH2), 35.7 (CH), 35.1 (CH2), 34.7 (CH2), 34.5 (CH2),
32.3 (CH2), 26.8 (CH), 26.0 (CH), 24.3 (CH2), 17.4 (CH3); MS
(APCI) m/z (%) 384.2 (25, [M+.]), 385.2 (75, [M + H]+), 426.2 (100,
[M + H + CH3CN]+), 769.4 (10, [2M + H]+); ESI-TOF-HRMS calcd
for C24H33O2S (M + H) 385.2201, found 385.2206.
1-Methoxy-4-(6-methyloct-5-en-1-yl)benzene (24). Com-
pound (11) (unlike/like 70:30) (57.9 mg, 0.21 mmol) was heated in
FC-70 (1 mL) at 120 °C overnight to give, after purification on a silica
cartridge (98:2 heptane/AcOEt), the desired product as a colorless oil
(29.4 mg, 60%, Z/E (70:30)) and the starting material (23.2 mg); IR
1
υmax (cm−1) 2963, 2928, 1613, 1512; H NMR (300 MHz, CDCl3) δ
7.10 (d, J = 8.6 Hz, 2 H), 6.83 (d, J = 8.6 Hz, 2 H), 5.05−5.16 (m, 1
H), 3.79 (s, 3 H), 2.56 (t, J = 7.7 Hz, 2 H), 1.94−2.08 (m, 4 H), 1.68
(s, 1 H), 1.54−1.67 (m, 2 H), 1.60 (s, 2 H), 1.29−1.44 (m, 2 H), 0.99
(t, J = 7.5 Hz, 2 H), 0.97 (t, J = 7.5 Hz, 1 H); 13C NMR (75 MHz,
CDCl3) δ 157.6 (C), 137.1 (0.3 C), 136.9 (0.7 C), 135.0 (C), 129.2 (2
CH), 124.3 (0.3 CH), 123.1 (0.7 CH), 113.7 (2 CH), 55.2 (CH3),
35.0 (CH2), 32.4 (0.3 CH2), 31.4 (CH2), 29.7 (0.3 CH2), 29.5 (0.7
CH2), 27.7 (0.7 CH2), 27.5 (0.3 CH2), 24.8 (0.7 CH2), 22.9 (0.7
CH3), 15.9 (0.3 CH3), 12.8 (CH3); MS (APCI) m/z (%) 274.2 (100,
[M + H + CH3CN]+), 233.2 (50, [M + H]+), 232.2 (30, [M+.]); ESI-
TOF-HRMS calcd for C16H25O (M + H) 233.1905, found 233.1907.
2-(6-(4-Methoxyphenyl)hexan-2-ylidene)adamantane (25).
Compound (20) (55.3 mg, 0.15 mmol) was heated in FC-70 (1
mL) at 200 °C overnight to give, after purification on a silica cartridge
(98:2 heptane/AcOEt), the desired product as a colorless oil (34 mg,
1
70%); IR υmax (cm−1) 2905, 2847, 1613, 1512; H NMR (300 MHz,
CDCl3) δ 7.10 (d, J = 8.6 Hz, 2 H), 6.83 (d, J = 8.6 Hz, 2 H), 3.79 (s,
3 H), 2.83 (br s, 2 H), 2.56 (t, J = 7.6 Hz, 2 H), 2.02 (t, J = 7.6 Hz, 2
H), 1.81 (br s, 2 H), 1.77−1.88 (m, 6 H), 1.51−1.73 (m, 6 H), 1.61 (s,
3 H), 1.31−1.44 (m, 2 H); 13C NMR (75 MHz, CDCl3) δ 157.6 (C),
140.1 (C), 135.0 (C), 129.2 (2 CH), 120.5 (C), 113.6 (2 CH), 55.3
(CH3), 39.3 (2 CH2), 38.9 (2 CH2), 37.3 (CH2), 35.0 (CH2), 33.4
(CH2), 32.9 (CH), 32.7 (CH), 31.5 (CH2), 28.4 (CH2), 28.2 (2 CH),
17.6 (CH3); MS (APCI) m/z (%) 324.2 (100, [M+.]), 325.2 (90, [M +
H]+), 366.3 (30, [M + H + CH3CN]+); ESI-TOF-HRMS calcd for
C23H33O (M + H) 325.2531, found 325.2516.
ASSOCIATED CONTENT
■
S
* Supporting Information
(E)-1-Methoxy-4-(oct-5-en-1-yl)benzene (22). Compound (4)
(30 mg, 0.11 mmol) was heated neat at 150 °C for 4 h to give the
desired product as a yellow oil (18.6 mg, 75%); IR υmax (cm−1) 2930,
1612, 1512; 1H NMR (300 MHz, CDCl3) δ 7.09 (d, J = 8.7 Hz, 2 H),
Copies of the 1H and 13C NMR spectra of all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
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Article
(33) Moynihan, H. A.; Roberts, S. M. J. Chem. Soc., Perkin Trans 1
1994, 797−805.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: dcrich@chem.wayne.edu.
(34) Lin, C.-E.; Garvey, D. S.; Janero, D. R.; Letts, L. G.; Marek, P.;
Richardson, S. K.; Serebryanik, D.; Shumway, M. J.; Tam, S. W.;
Trocha, A. M.; Young, D. V. J. Med. Chem. 2004, 47, 2276−2282.
(35) Ramirez, J.; Yu, L.; Li, J.; Braunschweiger, P. G.; Wang, P. G.
Bioorg. Med. Chem. Lett. 1996, 6, 2575−2580.
(36) Crich, D.; Sana, K. J. Org. Chem. 2009, 74, 3389−3393.
(37) Lee, H. B.; Park, H.-Y.; Lee, B.-S.; Kim, Y. G. Magn. Reson.
Chem. 2000, 38, 468−471.
Notes
The authors declare no competing financial interest.
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