The irradiation of (Z)-2-phenyl-4-aryliden-5(4H)-thiazolones 2 with blue light (465 nm) in CH2Cl2 solution promotes [2 + 2]-photocycloaddition of the exocyclic C═C bonds and the formation of the dispirocyclobutanes 3. This reaction takes place with high stereoselectivity, given that the ε-isomer (1,3 head-to-tail syn coupling) is formed in more than 90% yield in most of the cases. However, irradiation of 5(4H)-thiazolones 2 with blue light (456 nm) in dry MeOH in the presence of BF3·OEt2 leads to the monospirocyclobutanes 4 with full stereoselectivity, also affording the ε-isomer. A ring-opening reaction of only one of the thiazolone rings appears to have taken place in 4 upon methanolysis, leading to the corresponding ester and thioamide groups. The treatment of free 4-aryliden-5(4H)-thiazolones 2 with a base in alcohol (NaOR/ROH) also produces a ring-opening reaction of the heterocycle by methanolysis, although, under these reaction conditions, further intramolecular S-attack at the exocyclic C(H)═C bond and cyclization is observed, forming the dihydrothiazoles 5 or 6 as mixtures of cis (RS/SR)- and trans (RR/SS)-isomers with high diastereomeric excess. trans-(RR/SS)-Dihydrothiazoles 6 can be isolated as pure diastereoisomers by column chromatography. Surprisingly, dihydrothiazoles 5 can also be obtained by the treatment of 4-aryliden-5(4H)-thiazolones 2 with BF3·OEt2 in methanol in the absence of a base.
The irradiation of (Z)-2-phenyl-4-aryliden-5(4H)-thiazolones 2 with blue light (465 nm) in CH2Cl2 solution promotes [2 + 2]-photocycloaddition of the exocyclic C═C bonds and the formation of the dispirocyclobutanes 3. This reaction takes place with high stereoselectivity, given that the ε-isomer (1,3 head-to-tail syn coupling) is formed in more than 90% yield in most of the cases. However, irradiation of 5(4H)-thiazolones 2 with blue light (456 nm) in dry MeOH in the presence of BF3·OEt2 leads to the monospirocyclobutanes 4 with full stereoselectivity, also affording the ε-isomer. A ring-opening reaction of only one of the thiazolone rings appears to have taken place in 4 upon methanolysis, leading to the corresponding ester and thioamide groups. The treatment of free 4-aryliden-5(4H)-thiazolones 2 with a base in alcohol (NaOR/ROH) also produces a ring-opening reaction of the heterocycle by methanolysis, although, under these reaction conditions, further intramolecular S-attack at the exocyclic C(H)═C bond and cyclization is observed, forming the dihydrothiazoles 5 or 6 as mixtures of cis (RS/SR)- and trans (RR/SS)-isomers with high diastereomeric excess. trans-(RR/SS)-Dihydrothiazoles 6 can be isolated as pure diastereoisomers by column chromatography. Surprisingly, dihydrothiazoles 5 can also be obtained by the treatment of 4-aryliden-5(4H)-thiazolones 2 with BF3·OEt2 in methanol in the absence of a base.
The [2 + 2]-photocycloaddition
reaction is a powerful synthetic
tool for the tailored and versatile preparation of cyclobutanes by
the C—C coupling of olefinic C=C bonds.[1] The relevance of the cyclobutane ring resides in its presence
as a common structural motif in natural products or synthetic compounds
with strong pharmacological activity. Some examples of relevant cyclobutanes
can be found in Figure .[2−7] Moreover, cyclobutanes are also interesting synthetic intermediates
as they show a particular reactivity due to the high ring strain.[8−11]
Figure 1
Cyclobutanes
with important pharmacological activity.
Cyclobutanes
with important pharmacological activity.Figure also shows
that these cyclobutanes contain many chiral centers. The development
of methods for control of the stereoselectivity during cyclobutane
synthesis has attracted substantial attention.[12−15] However, for photochemical processes,
a high stereoselectivity is only achieved when the reactions take
place in the solid state and topochemical Schmidt’s conditions
are achieved. This is the case, for instance, for the synthesis of
α-truxillic (Figure b) and β-truxinic acid derivatives.[16−18] In general,
the [2 + 2]-photocycloadditions performed in solution suffer a lack
of stereoselectivity, and the use of auxiliary reagents such as chiral
templates, sensitizers or catalysts, is mandatory.[19−31]We are interested in a particular family of cyclobutanes,
namely,
1,3-diaminotruxillic derivatives (Figure ), which are well-known because of their
antinociceptive activity. A renewed interest in these compounds has
arisen over the past few years because truxillic derivatives have
been shown to be FABP (fatty acid binding protein) inhibitors and
are responsible for the cellular reuptake of anandamide (an endocannabinoid
neurotransmitter).[32−36] As a result, they are promising candidates in efficient treatments
for chronic pain.[37] However, this is not
the only outstanding pharmacological activity of truxillic derivatives
as they have also been recently shown to be the only nonpeptidic GLP-1R
(glucagon-like peptide receptor) agonists for the treatment of type
2 diabetes mellitus.[38−40]
Figure 2
Context of this work, comparison with previous work and
main achievements.
Context of this work, comparison with previous work and
main achievements.As a result of this interest,
we have developed different methodologies
for the stereoselective synthesis of 1,3-diaminotruxillic derivatives
(Figure ). Among these,
the direct irradiation of (Z)-4-aryliden-5(4H)-oxazolones 1 shows high simplicity and versatility,
together with some degree of stereoselectivity (Figure , past work, path a).[41] Thus, we have shown that the [2 + 2]-photocycloaddition
of oxazolones 1 can occur using low-power (less than
20W), blue light (465 nm) irradiation sources. This method works for
oxazolones bearing electron-donating and electron-withdrawing substituents
and gives quantitative yields of cyclobutanes in almost all cases
studied. However, it requires long reaction times (up to 3 days) and
affords up to four different stereoisomers, although one of them (ε)
is obtained in 50–90% abundance with respect to the other isomers.
This method has been complemented with another, three-step strategy
in which a palladium complex behaves as a template, thus allowing
the isolation of 1,3-diaminotruxillic derivatives with good yields
as single isomers (Figure , past work, path b).[42−45]The (Z)-4-arylidene-5(4H)-thiazolones 2 are the sulfur counterparts
of 4-arylidene-5(4H)-oxazolones 1. Despite
the structural analogy, unsaturated
5(4H)-thiazolones are less well-known, and their
synthetic potential is underdeveloped.[46,47] Sulfur-containing
drugs exhibit remarkable pharmacological activity, and as such, they
are targets of particular interest from the point of view of pharmaceutical
companies.[48] Proof of this interest is
the fact that there are at least 249 sulfur-containing drugs approved
by the US Food and Drug Administration (FDA).[49] Thiazolones have received some attention as sulfur-containing drugs,
initially during the study of penicillin (it was believed that the
active substance contained a thiazolone ring rather than a thiazolidine),[50,51] and more recently as promising anticancer compounds.[52] Due to the close relationship between 5(4H)-oxazolones 1 and 5(4H)-thiazolones 2, the interesting reactivity of oxazolones to give 1,3-diaminotruxillic
derivatives observed in our previous studies,[41−45] the interest in sulfur-containing compounds due to
their interesting pharmacological properties, and the complete absence
of previous studies in this area, we have studied the reactivity of
(Z)-4-arylidene-5(4H)-thiazolones 2 in [2 + 2]-photocycloaddition reactions and in ring-opening
reactions upon alcoholysis (Figure , this work). With the aim of further exploring the
chemical possibilities of these substrates, and taking into account
the known influence of Lewis acids on photochemical reactions[26,28,53−62] (acceleration and/or change in the orientation and selectivity of
the reactions), we have examined both processes (ring opening and
photocycloaddition) in the presence of a simple Lewis acid, namely
BF3, and present the results obtained below.
Results and Discussion
Synthesis
of (Z)-4-Arylidene-5(4H)-thiazolones 2 and [2 + 2]-Photocycloaddition by Direct
Irradiation
The thiazolones 2a–2o used
in this work are shown in Figure . Synthesis was carried out following the same experimental
procedure reported by Rao and Filler,[46] which in turn were based on the original work of Behringer et al.[63,64] Following this method, the treatment of oxazolones 1a–1o with thioacetic acid in the presence of substoichiometric amounts
of NEt3 gave the corresponding thiazolones 2a–2o as air- and moisture-stable solids. Thiazolones 2a–2o contain electron-withdrawing or electron-donating substituents at
different positions of the 4-arylidene ring in order to cover the
widest scope. Thiazolones 2a–2c have been described
previously, although 2b was prepared using a different
method,[65,66] and although thiazolones 2e, 2f, 2g, 2h, and 2j appear in Scifinder, there are either no references associated with
their synthesis or no details can be found in the corresponding literature.
As such, they are fully characterized here (see Supporting Information).
Figure 3
Thiazolones 2a–2o used
in this work and synthetic
method.
Thiazolones 2a–2o used
in this work and synthetic
method.The HRMS (ESI+) spectra
of 2a–2o show peaks in agreement with the stoichiometries
proposed in Figure . In addition, the 1H NMR spectra of 2a–2o show a pattern
of peaks quite similar to that of the oxazolone precursors 1a–1o, with only the signal due to the ortho-H of the
2-Ph ring in 2a–2o showing a downfield shift with
respect to the same signal in 1a–1o. The 13C NMR spectra of 2a–2o, in which the
signal due to the S—C (=O) carbon appears
around 195 ppm, downfield shifted by more than 20 ppm with respect
to the O—C (=O) carbonyl carbon peak (around
170 ppm), are much more informative.Solutions of thiazolones 2a–2o in CH2Cl2 were then irradiated
with blue light (465 nm) at room
temperature using the irradiation setup described in the Experimental Section (PCB with 24 blue LEDs). This
irradiation promoted the [2 + 2]-photocycloaddition of the exocyclic
C=C bond of thiazolones 2 and formation of the
corresponding cyclobutanes 3 (Figure ), which were isolated as air-stable solids
after solvent evaporation and recrystallization from CH2Cl2/n-pentane.
Figure 4
[2 + 2]-Photocycloaddition
of 4-arylidene-5(4H)-thiazolones 2 to
give cyclobutanes 3.
[2 + 2]-Photocycloaddition
of 4-arylidene-5(4H)-thiazolones 2 to
give cyclobutanes 3.The optimum reaction time for full conversion of 2 using
the PCB, as determined by 1H NMR monitoring, was
72 h. This reaction time can be shortened to 24 h if a Kessil lamp
(456 nm) is used instead, probably due to the higher photonic flux
of the latter. The reaction also takes place in other solvents (for
instance, methanol), giving the same yield of cyclobutanes 3. Identical results were obtained in CH2Cl2 in the presence or absence of oxygen. No photocycloaddition was
observed for 2i and 2l, and partial conversion
was obtained for 2h, despite the photonic flux used.
The scope of the reaction (Figure ) appears to be general as it takes place with full
conversions and very good yields of isolated products in the presence
of either electron-donating (Me, OMe) or electron-withdrawing (F,
Cl, Br, NO2, CF3) substituents. A change in
position of the substituents (ortho vs para) in the 4-arylidene ring is well tolerated (compare 3e with 3j or 3f with 3k), as
is the presence of two substituents in the meta-
and para-positions (3m–3o).
Figure 5
Scope of the [2 + 2]-photocycloaddition of thiazolones 2 to give cyclobutanes 3.
Scope of the [2 + 2]-photocycloaddition of thiazolones 2 to give cyclobutanes 3.NMR analysis of the cyclobutanes 3 represented in Figures and 5 showed that they were mainly obtained as single isomers (3a, 3g, 3h) or as mixtures of two
isomers with molar ratios of 80:20 or higher (3b, 3d, 3e, 3f, 3m, 3n, 3o; see Table and Experimental Section).
Given that the photocycloaddition of thiazolones 2 can
afford up to 11 different isomers, the stereoselectivity of the process
presented here is remarkable. A comparison of these results with those
obtained with related substrates shows that the use of thiazolones
results in a more selective process. For instance, we have reported
the synthesis of cyclobutanes by direct [2 + 2]-photocycloaddition
of 4-arylidene-5(4H)-oxazolones 1 (Figure , past work, path
a).[41] This reaction takes place for only
a narrow range of substituents, and the corresponding cyclobutanes
were obtained as mixtures of four different isomers with similar molar
ratios. However, in the case of the thiazolones studied here, the
scope is much wider, and the stereoselectivity is markedly higher.
Table 1
Yields of Cyclobutanes 3, Obtained as
Mixtures of Isomers, and Composition of the Mixtures
3a
3b
3c
3d
3e
3f
3g
3h
3j
3k
3m
3n
3o
yield
82
100
100
100
85
92
100
80a
95
98
100
100
90
ε (%)
100
90
59
91
96
83
100
100
71
65
85
91
94
α (%)
0
10
25
9
4
17
0
0
29
35
15
9
6
others (%)
9:7
Maximum conversion achieved.
Maximum conversion achieved.The NMR data for all cyclobutanes 3 studied showed
the presence of species with high symmetry but were not conclusive
because several isomers could fit with the experimental NMR data.
As such, full characterization of the main isomer for cyclobutanes 3 was achieved by determining the X-ray crystal structures
of derivatives 3g, 3h, and 3m, which are shown in Figures , 7, and 8,
respectively.
Figure 6
X-ray crystal structure of cyclobutane 3g. Thermal
ellipsoids are drawn at 50% probability.
Figure 7
X-ray
crystal structure of cyclobutane 3h. Thermal
ellipsoids are drawn at 50% probability.
Figure 8
X-ray
crystal structure of cyclobutane 3m. Thermal
ellipsoids are drawn at 50% probability.
X-ray crystal structure of cyclobutane 3g. Thermal
ellipsoids are drawn at 50% probability.X-ray
crystal structure of cyclobutane 3h. Thermal
ellipsoids are drawn at 50% probability.X-ray
crystal structure of cyclobutane 3m. Thermal
ellipsoids are drawn at 50% probability.All structures clearly show the formation of the cyclobutane core
by [2 + 2]-cycloaddition of the respective thiazolones. The isomer
characterized in all three cases is the ε-isomer (ε),
according to the isomer assignment of Stoermer and Bachér,[67,68] which is formed by the 1,3-head-to-tail coupling of two Z-thiazolones in a syn orientation. This
ε-isomer is the same as that characterized as the major isomer
in the [2 + 2]-photocycloaddition of oxazolones, thus suggesting that
the dimerization of oxazolones and thiazolones follows the same orientation.
The three structures are very similar, with the cyclobutane core showing
the 1,2-cis-2,3-cis-3,4-cis configuration. The cyclobutane rings are not planar
and exhibit dihedral angles of C1-C2-C101-C2 (3g) = 18.1(3)°,
C1-C9-C18-C26 (3h) = 19.7(3)°, and C2-C10-C2-C10
(3m) = 22.4(3)°, which are similar to those found
in related cyclobutanes.[41] In addition,
the values for the remaining bond distances (Å) and angles (°)
are in the usual range of values found in the literature for related
structural arrangements.[38,41,43,69−74]The characterization of the main isomer in compounds 3g, 3h, and 3m as the ε-isomer
allows
us to extrapolate this assignment to the remaining cyclobutanes 3 prepared here even though we were unable to characterize
them all by X-ray diffraction. An additional argument in this direction
is the comparison of the NMR chemical shifts for the 1H
and 13C nuclei of the cyclobutane ring in 3, which exhibit values that appear in very narrow ranges, thereby
suggesting quite similar environments.
Effect of Lewis Acids (BF3) on the [2 + 2]-Photocycloaddition
of Thiazolones 2
As mentioned in the Introduction,
the presence of Lewis acids can change the rate, orientation, and/or
selectivity of a given reaction.[23,28,53−62] In order to determine the influence of Lewis acids in this particular
photochemical reaction, we irradiated suspensions of selected examples
of thiazolones 2 with blue light (Kessil lamp, 456 nm),
in methanol, in the presence of BF3·OEt2. The optimized amount of BF3·OEt2 was
four equivalents with respect to thiazolone 2. After
irradiation for 24 h, the conversion of 2 was complete,
and cyclobutanes 4 (represented in Figure ) were isolated by simple filtration of the
resulting suspensions (see Experimental Section and Supporting Information). The full
characterization of these cyclobutanes 4 showed that
they were obtained as single isomers in all cases studied (see below).
As such, the reaction in the presence of a Lewis acid (BF3) gives a cyclobutane with the same orientation as in its absence
but with full stereoselectivity, thereby improving our previous results.
However, no acceleration was observed. As a result, a more restricted
scope was examined.
Figure 9
Photocycloaddition of thiazolones 2 in methanol
in
the presence of the Lewis acid BF3·OEt2
Photocycloaddition of thiazolones 2 in methanol
in
the presence of the Lewis acid BF3·OEt2The characterization of compounds 4 by HRMS and NMR
spectroscopy clearly shows the formation of a cyclobutane core in
which one of the thiazolones remains unchanged while the other has
undergone a ring-opening reaction by methanolysis, thus giving the
corresponding ester and thioamide fragments. The HRMS data for cyclobutanes 4a, 4b, 4d, and 4e reflect
the dimerization of the corresponding thiazolones 2 and
the incorporation of a molecule of methanol for each dimer of cyclobutane.
The 1H NMR spectra of 4a–4e show signals
corresponding to the presence of a single isomer in each case; in
other words, the reaction is totally stereoselective for the cases
studied. The ring-opening reaction is evidenced by the observation
of peaks due to the ester fragment (at around 3.8 ppm) and the NH
proton (a broad signal at around 8.5–8.7 ppm) with a relative
intensity of 3:1. The presence of a single peak for the two chemically
equivalent cyclobutane CH protons (4.8–4.9 ppm, relative intensity
2) shows that, despite the loss of symmetry produced by the ring-opening
reaction, the two ArC(H) groups of the cyclobutane are still equivalent.
The 13C NMR spectra of 4a–4e also show
signals in agreement with the ring-opening reaction of the only heterocycle.
In this respect, peaks at around 205–206 (SC=O) and
166–167 ppm (SC=N) suggest the presence of a thiazolone
ring, while peaks at around 198 (HNC=S) and 169 ppm (COO) confirm
the presence of ester and thioamide groups. Moreover, three different
signals are observed for the cyclobutane ring, one for the two chemically
equivalent CH carbons (in the 55 ppm region) and two for the quaternary
carbons (at about 90 and 67 ppm).As discussed for cyclobutanes 3, there is more than
one isomer whose structure fits with the HRMS and NMR data for cyclobutanes 4. In this case, there are four possible structures (syn-ε, syn-epi, anti-epi, and syn-peri);[41] therefore, the X-ray crystal structure of 4b was determined
to complete the structural characterization. Crystals were obtained
by slow diffusion of n-pentane into a solution of
crude 4b in CH2Cl2 at −18
°C, and the structure obtained is shown in Figure .
Figure 10
X-ray crystal structure
of cyclobutane 4b. Thermal
ellipsoids are drawn at 50% probability.
X-ray crystal structure
of cyclobutane 4b. Thermal
ellipsoids are drawn at 50% probability.The structure of cyclobutane 4b shows that the isomer
obtained is the ε-isomer, which is formed by the 1,3-head-to-tail
coupling of two thiazolones in a syn orientation.
The cyclobutane core of 4b is not planar, showing a value
for the C4-C1-C2-C3 dihedral angle of 19.1(1)°, which is identical
to those found in the structures of 3g, 3h, and 3m. Other internal parameters of the cyclobutane
ring are also identical (within experimental error) to those found
in 3g, 3h, and 3m. The structure
also confirms the ring-opening reaction by methanolysis at one of
the thiazolones and the corresponding presence of ester and thioamide
fragments, both of which show bond distance and angle values in agreement
with those found in the literature for similar types of bonds.[74]In light of the crystal structure of 4b, it can be
concluded that photocycloaddition in methanol in the presence of BF3 gives cyclobutanes 4, and that cyclobutanes 3 are formed in the absence of BF3. This reaction
takes place with exactly the same orientation because the same isomer
out of the 11 possible cyclobutane isomers is obtained in both cases
(ε-isomer). However, the reaction affords slightly different
compounds as 3 contains two unaltered thiazolone rings,
whereas 4 contains only one. This suggests that the Lewis
acid BF3 has a small but important influence as, although
neither the rate nor the orientation of the reaction are affected,
the ring-opening reaction is favored in the presence of the Lewis
acid.We have studied the interaction between thiazolones 2 and BF3 in MeOH both in the ground state and
in the excited
state. Thiazolone 2b was selected as a representative
example. To analyze the interaction in the ground state, a solution
of 2b in CD3OD was treated with increasing
amounts of BF3·OEt2 until the molar ratio
1:4 was reached, and the result of each addition was monitored by 1H NMR spectroscopy (see Supporting Information). A comparison of the NMR spectra showed that there is no detectable
interaction on the NMR time scale as all spectra were identical, and
no signal underwent a change in its chemical shift. This suggests
that either the interaction is very weak or it occurs to such a small
extent that it cannot be detected by NMR spectroscopy. As for the
excited state, the fluorescence of thiazolone 2b was
examined in the absence and presence of BF3·OEt2 (Supporting Information) in methanol.
Thiazolone 2b is fluorescent and shows an emission maximum
at 459 nm when excited at 390 nm. After the addition of BF3·OEt2 (1–4 equiv), no changes were detected
in either the maximum of the emission or its intensity. These results
suggest that the Lewis acid does not have a marked influence on either
the excited state or the ground state. However, the different structure
of cyclobutanes 3 and 4 shows that an interaction
with the Lewis acid must occur at some point in the reaction, and
given the lack of reaction observed between 2b and BF3, this probably occurs after the formation of cyclobutane 3. To check this, we treated cyclobutane 3a with
BF3·OEt2 in methanol for 24 h at room temperature
and in the dark. The formation of 4a was evident after
this time, thus suggesting that the role of BF3 is related
to the promotion of the ring-opening reaction, as shown in Figure , rather than to
the [2 + 2]-photocycloaddition.
Figure 11
Proposal of the mechanism for the BF3-promoted ring-opening
reaction.
Proposal of the mechanism for the BF3-promoted ring-opening
reaction.
Ring-Opening Reaction of
Thiazolones 2: Synthesis
of 4,5-Dihydrothiazoles (5, 6) and Thiazoles
(7)
The easy ring-opening reaction undergone
by 3 to give 4 prompted us to study the
opening of the remaining thiazolone ring in 4. The opening
of both heterocycles should produce cyclobutanes structurally analogous
to diaminotruxillic bis-amino acids but containing sulfur in their
structure. In a first attempt, we tested the classical process, namely,
heating cyclobutanes 3c and 3d with a catalytic
amount of a base (NaOMe) in alcohol (MeOH).[75] Surprisingly, this reaction afforded the 4,5-dihydrothiazoles 5c and 5d as a mixture of cis- and trans-diastereoisomers, as shown in Figure (upper reaction).
Figure 12
Synthesis
of 4,5-dihydrothiazoles 5 by treatment of
cyclobutanes 3 with NaOMe in MeOH.
Synthesis
of 4,5-dihydrothiazoles 5 by treatment of
cyclobutanes 3 with NaOMe in MeOH.The transformation shown in the upper reaction of Figure suggests that the reaction
is most likely related to the intrinsic reactivity of the exocyclic
C(H)=C bond in thiazolone 2 rather than to that
of the cyclobutane skeleton in 3. For that reason, we
studied the reactivity of thiazolones 2c and 2d with NaOMe in MeOH as a solvent, and the results are also shown
in Figure (lower
reaction). As expected, the treatment of 2c and 2d with base in alcohol gave the dihydrothiazoles 5c and 5d in virtually the same yields and diastereomeric
excess as obtained when 3c and 3d were used
as precursors instead. This suggests that, when heating under basic
conditions, cyclobutanes 3 are not stable and a retro-[2
+ 2] reaction can take place to regenerate thiazolones 2, which subsequently react with a base to give 5.Compounds 5c and 5d were characterized
by HRMS and NMR spectroscopy. The 1H NMR spectra show two
characteristic AB spin systems centered around 5.4 ppm, assigned to
the two aliphatic protons of the (N)CH—CH (S) moiety. The value
of the 3JHH coupling constant
between these two protons is diagnostic for the determination of the
configuration of each diastereoisomer. Thus, the major species shows
a value for the 3JHH coupling constant of 6.5
Hz, which is typical for trans geometries, whereas
the value found for the minor isomer is around 10 Hz, thus suggesting
a cis arrangement.[76] The
higher abundance of the trans-isomer is in good agreement
with the lower intramolecular repulsions in this isomer. These two
protons correlate (1H–13C HSQC spectra)
with two C atoms at around 87 (CHN) and 55 ppm (CHS), thus showing
their aliphatic character. In addition, the peak at around 194–196
ppm for thiazolones 2 (around 205–208 ppm in cyclobutanes 3), assigned to the thiocarbonyl group (S—C=O),
has disappeared, and a new peak is now observed in the 170–172
ppm region. This suggests the formation of a new heterocycle, namely
the 4,5-dihydrothiazole shown in Figure .This synthetic method for the preparation
of dihydrothiazoles from
4-arylidene-5(4H)thiazolones 2 is novel
as, to the best of our knowledge, only one previous example has been
reported in the literature.[77] In that case,
the reaction was performed using NaOH in water to afford the corresponding
carboxylic acid.[77] Dihydrothiazoles are
interesting materials due to their properties, and different synthetic
methods have been reported for their preparation, most of them starting
from aminothiols.[78−89] Dihydrothiazoles are versatile intermediates for the synthesis of
high-value-added compounds, for instance β-cysteine and derivatives,[90−94] are present in flavours[95] and in natural
products,[96−99] and show a remarkable pharmacological activity.[100−102] For all of these reasons, we decided to explore this almost unprecedented
synthesis of dihydrothiazoles from thiazolones 2 in more
detail. The results are presented in Figure .
Figure 13
Reactivity of thiazolones 2 with
base in alcohol to
give dihydrothiazoles (5 and 6) and thiazoles
(7). Yields (%) correspond to the pure isolated trans-isomer.
Reactivity of thiazolones 2 with
base in alcohol to
give dihydrothiazoles (5 and 6) and thiazoles
(7). Yields (%) correspond to the pure isolated trans-isomer.The treatment of thiazolones 2 with NaEtO in ethanol
at reflux temperature gave the corresponding dihydrothiazoles 6, as shown in Figure . After the reaction, the ethanol was evaporated to
dryness, the residue was extracted with CH2Cl2, and all insoluble materials were removed by filtration. Evaporation
of the solvent gave an oily residue, which was shown by 1H NMR spectroscopy to be a mixture of the two diastereoisomers of
dihydrothiazoles 6 in a trans/cis molar ratio in the range 86:14 to 90:10. As such, the
reaction takes place with a remarkable diastereomeric excess, which
is even higher than when methanol was used as a solvent. The major trans-isomer could be isolated in pure form from that mixture
by column chromatography (see Experimental Section), while the minor cis-isomer could not be isolated
in sufficient quantity to be characterized in most cases. The reaction
shows an adequate scope, as it works in moderate to good yields for
both electron-donating (6c, 6i, 6m) and electron-withdrawing (6h, 6n) substituents
in the 5-aryl ring. In addition, the reaction tolerates substituents
at the ortho-, meta-, and para-positions of the aryl ring. In the case of thiazolone 2n, the formation of the thiazole 7n as the major
reaction product was observed. This compound was also purified and
separated from 6n by column chromatography. The absence
of the diagnostic AB spin system at around 5.3–5.4 ppm in the 1H NMR spectrum of 7n, and the corresponding carbons
at 86 ppm and 55 ppm in the 13C NMR spectrum, as well as
the presence of two new quaternary C atoms at 142 ppm, confirms the
formation of thiazole 7n, the molecular structure of
which determined by X-ray diffraction methods (Figure ). The formation of thiazole 7n in the reaction medium is likely due to aerobic oxidation of the
precursor dihydrothiazole, which is a well-known reaction.[103] When microwaves were used instead of a conventional
heating source, as in the case of the 4-NO2-substituted
thiazolone 2g, complete transformation into thiazole 7g was observed in just one minute, thus meaning that formation
of the dihydrothiazole is accelerated, as is its oxidation. For that
reason, only conventional heating was used.The mechanism proposed
for the synthesis of dihydrothiazoles 5 or 6 from thiazolones 2 is shown
in Figure . The
reaction seems to start with a nucleophilic attack of the alkoxide
at the carbonyl carbon to form the corresponding ester group and the
thioamidate fragment. Subsequent intramolecular S-attack of the sulfide
at the C(H) carbon of the exocyclic C(H)=C double bond, followed
by protonation of the stabilized enolate generated, results in the
formation of the final dihydrothiazoles.
Figure 14
Mechanistic proposal
for the synthesis of dihydrothiazoles 5 (or 6) from thiazolones 2.
Mechanistic proposal
for the synthesis of dihydrothiazoles 5 (or 6) from thiazolones 2.The easy ring-opening reactions undergone by cyclobutanes 3 to give cyclobutanes 4 shown in Figures and 11 suggest that
the Lewis acid BF3 fosters the attack of
nucleophiles at the carbonyl carbon, which should, in principle, favor
the formation of dihydrothiazoles from thiazolones. With this in mind,
we attempted the reaction of thiazolones 2 with methanol,
in the presence of the Lewis acid BF3·OEt2 and in the absence of a base. The results of these reactions are
shown in Figure .
Figure 15
Reactivity of thiazolones 2 with MeOH in the presence
of BF3; synthesis of dihydrothiazoles 5.
Reactivity of thiazolones 2 with MeOH in the presence
of BF3; synthesis of dihydrothiazoles 5.The treatment of thiazolones 2 with
BF3·OEt2 (4 equiv) in methanol at reflux
temperature
for 18 h resulted in the formation of the corresponding dihydrothiazoles 5 in good to moderate yields. The reaction does not take place
at room temperature, with thiazolone 2 being recovered
unchanged. At shorter reaction times (2 h) in refluxing methanol,
we observed low conversions (less than 10%), along with the formation
of 5 in a more or less equimolar mixture of the two diastereoisomers
(range between 1.2:1 to 1.5:1). No reaction was observed in refluxing
methanol in the absence of BF3. As such, in the presence
of BF3, both high temperatures and long reaction times
are needed to achieve full conversion of thiazolones 2 into dihydrothiazoles 5, although a base is no longer
required. The reaction is tolerant to the presence of electron-donating
(Me, OMe) and electron-withdrawing (F, Cl, Br, CF3) substituents
at different positions of the aryl ring, thus meaning that the reaction
shows an adequate scope. The main difference between this process
and the reaction performed in the presence of a base (Figures and 13) is the diastereoselectivity, which is moderate to high in the presence
of a base but very low or even nonexistent in the presence of BF3. Unfortunately, we have no reasonable explanation for this
finding. Our mechanistic proposal to explain the role of the Lewis
acid in this reaction is presented in Figure . Coordination of the carbonyl oxygen to
BF3 increases the electrophilic character of the carbonyl
carbon (as in Figure ), which is, therefore, more susceptible to attack by methanol. The
decoordination of BF3 is followed by the formation of the
sulfide, which can attack the exocyclic C(H)=C bond (see Figure ).
Figure 16
Mechanistic proposal
for the formation of dihydrothiazoles in the
presence of BF3.
Mechanistic proposal
for the formation of dihydrothiazoles in the
presence of BF3.
Conclusion
In summary, new (Z)-4-aryliden-5(4H)-thiazolones 2 have been prepared by treatment
of oxazolones
with thioacetic acid. These thiazolones have been shown to be convenient
and versatile precursors for the synthesis of a wide variety of carbo-
and heterocycles with high selectivity. The irradiation of thiazolones 2 with blue light (465 nm) results in the formation of diaminotruxillic-type
cyclobutanes 3 by head-to-tail 1,3-syn coupling [2 + 2]-photocycloaddition of thiazolones 2. The reaction shows a high stereoselectivity as cyclobutanes 3 are obtained mostly as the ε isomer. When the photochemical
reaction is performed in the presence of a Lewis acid (BF3·OEt2), the reaction follows the same orientation
(head-to-tail 1,3-coupling), but an additional ring-opening reaction
is observed, due to bonding of the BF3, thus giving a different
family of truxillic cyclobutanes 4. The role of the Lewis
acid is to foster the electrophilic character of the carbonyl carbon,
thereby favoring the ring-opening reaction. In addition, treatment
of 2 with base NaOR in alcohol ROH affords dihydrothiazoles 5, 6 via a ring-opening reaction followed by
S-intramolecular attack at the exocyclic C(H)=C bond. The reaction
is highly stereoselective, with the trans-isomer
being obtained as a major isomer in all cases studied. Dihydrothiazoles 5 can also be obtained by treatment of the thiazolone 2 with alcohol in the presence of BF3 but in the
absence of a base. In this case, the reaction shows a broader scope,
and it seems that the role of BF3 is to increase the electrophilic
character of both the carbonyl carbon and the vinyl carbon.
Experimental Section
General Methods
All solvents used are commercial-grade
and were used as received. All reactions were performed at open-air
without special caution against the moisture and oxygen, except the
syntheses of compounds 4, which were carried out under
Ar atmosphere using dry and deoxygenated methanol. Flash column liquid
chromatographies were performed on silica gel (70–230 μm)
or aluminum oxide 90 neutral (50–200 μm), eluting with
the solvents specified on each case. Elemental analyses (CHNS) were
carried out on a Perkin-Elmer 2400 Series II microanalyzer. Infrared
spectra (4000–380 cm–1) were recorded on
a Perkin-Elmer Spectrum-100 IR spectrophotometer. 1H, 13C, and 19F NMR spectra were recorded in CDCl3 or CD2Cl2 solutions at 25 °C on
Bruker AV300 or AV500 spectrometers (δ in ppm, J in Hz) at 1H operating frequency of 300.13 or 500.13
MHz, respectively. 1H and 13C spectra were referenced
using the solvent signal as internal standard, while 19F spectra were referenced to CFCl3. The assignment of 1H NMR peaks has been performed through standard 2D 1H–COSY (2K points in t2 using
a spectral width of 12 ppm; 128 t1 experiments
were recorded and zero-filled to 1K; for each t1 value, two scans were signal-averaged using a recycle delay
of 1 s) and selective 1D 1H-NOESY experiments. Typical mixing times
in the case of selective 1D-NOESY experiments were in the range 1.0–2.0
s, as a function of the irradiated signal. These values of optimized
mixing times were set equal to the longitudinal relaxation time T1, determined using the inversion–recovery
sequence. The 13C NMR peaks were identified using standard 1H–13C edited-HSQC and 1H–13C HMBC 2D experiments. In both cases, 4K points in t2 using spectral widths of 10 ppm (1H) and 200 ppm (13C) were used, with averaged values of
the coupling constants 1JCH = 145 Hz and long-range JCH = 10 Hz. Typically, 128 t1 experiments were recorded and zero-filled to 1 K. For each t1 value, 8 (HSQC) or 32 (HMBC) scans were signal-averaged
using a recycle delay of 1 s. ESI (ESI+) mass spectra were
recorded using an Esquire 3000 ion-trap mass spectrometer (Bruker
Daltonic GmbH) equipped with a standard ESI/APCI source. Samples were
introduced by direct infusion with a syringe pump. Nitrogen served
both as the nebulizer gas and the dry gas. MALDI mass spectra were
recorded using a Bruker MicroFlexTM or a Bruker AutoFlexTMIII spectrometer, equipped with a time-of-flight mass analyzer,
and using DIT (dithranol) as a matrix. The sample was dissolved in
CH2Cl2. The HRMS mass spectra were recorded
using a MicroToF Q, API-Q-ToF ESI with a mass range from 20 to 3000 m/z and mass resolution of 15000 (fwhm).
The absorption spectra in the UV–visible region were measured
on a Thermo Scientific Evolution 600 UV–vis spectrophotometer
using quartz SUPRAXIL cuvettes, light path 10 mm. The oxazolones 1a–1o used as starting materials were synthesized according
to published methods.[104−113]
Irradiation Setup
The irradiation setup consists of
a round-bottom flask irradiated by either a printed circuit board
(PCB) formed by 24 LEDs bulbs (Topbright) of a 10 mm diameter, each
irradiating at 465 nm, or a commercial Kessil lamp irradiating at
456 nm. The LEDs are serially connected in blocks of 6. The output
power per LED unit (blue, 465 nm) is 250 kmcd. The optical output
power of the PCB of LEDs measured with a photometer (PM100D, Thorlabs)
was 1 W, so the maximal power provided by the PCB is 24 W. The PCB
(dimensions: 7 cm × 6 cm) and the flask are placed inside a custom-built
setup for fixing the light source and the sample container and dissipate
the excess heating. A concave mirror is placed in front of the PCB
to maximize the light that irradiates the LEDs. The Kessil lamp is
the PR160L-456 nm model, with a maximal power of 40 W. The intensity
of the lamp can be tuned, and different powers were tested. Those
specified in each case gave the maximum yield.
X-ray Crystallography
Single crystals of 3g, 3h, 4b, and 7n of suitable
quality for X-ray diffraction measurements were grown by slow diffusion
of n-pentane into CH2Cl2 solutions
of the crude product at −18 °C for several weeks, while
those of 3m were obtained by slow evaporation of a solution
of the product in CH2Cl2. A single crystal was
mounted in each case at the end of a quartz fiber in a random orientation.
The crystal was fixed to the fiber with epoxy resin (3g) or covered with perfluorinated oil and placed under a cold stream
of N2 gas (3h, 3m, 4b, 7n). The data collections were performed at 293(2)
K on an Oxford Diffraction Xcalibur Sapphire3 diffractometer (3g) or at 100(2) K on Bruker D8 Venture (3h, 3m) or Bruker APEX CCD (4b, 7n)
diffractometers using graphite-monochromated Mo Kα radiation
(λ = 0.71073 Å). A hemisphere of data was collected based
on ω-scan and φ-scan runs. The diffraction frames were
integrated using the programs CrysAlis RED[114] and SAINT,[115] and the integrated intensities
were corrected for absorption with SADABS.[116] The structures were solved and developed by Fourier methods.[117] All non-hydrogen atoms were refined with anisotropic
displacement parameters. The H atoms were placed at idealized positions
and treated as riding atoms. Each H atom was assigned an isotropic
displacement parameter equal to 1.2 times the equivalent isotropic
displacement parameter of its parent atom. The structures were refined
to Fo2, and all reflections were used in the
least-squares calculations.[118] CCDC 1912941 (3g), 1912942 (7n), 1958992 (3h), 1958993 (3m), and 1999650 (4b) contains the supplementary crystallographic
data for this paper and can be obtained free of charge from The Cambridge
Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
General Procedure for the Synthesis of (Z)-2-Phenyl-4-aryliden-5(4H)-thiazolones 2a–2o
The synthesis of the thiazolones 2a–2o has
been carried out following the same experimental procedure as that
reported by Rao and Filler,[46] which in
turn is based in the original work of Behringer et al.[63,64] Thiazolones 2a–2c have been previously described,
although 2b was prepared using a different method.[65,66] Thiazolones 2e, 2f, 2g, 2h, and 2j appear on Scifinder, but either no
references are associated with their synthesis, or no details of their
preparation and characterization can be found in the literature associated.
Therefore, we present here the full synthesis and characterization
of thiazolones 2d–2o.
General Procedure for the
[2 + 2]-Photocycloaddition of 4-Arylidene-2-phenyl-5(4H)-thiazolones 2: Synthesis of Cyclobutanes 3a–3o
A solution of the 4-arylidene-2-phenyl-5(4H)-thiazolones 2a–2o (∼1 mmol)
in 10 mL of CH2Cl2 was irradiated for 24–72
h with the blue light (465 nm) provided by the PCB of 24 LEDs while
stirred at room temperature. The progress of the reaction was followed
by 1H NMR. After 72 h, the conversion of thiazolones 2a–2o into cyclobutanes 3a–3o was
complete (exceptions are indicated). The solvent was then evaporated
to dryness, and the yellow solid residue was characterized by NMR
as the cyclobutanes 3a–3o. In almost all cases,
the ε-isomer appeared as the major isomer (>90% molar ratio)
with minor amounts (<10%) of other isomers (exceptions are indicated).
For that reason, only the ε-isomer is fully characterized.
Numbering of Cyclobutanes 3a–3o, Exemplified
with 3a
Following the general method, thiazolone 2c (300 mg, 1.01 mmol) was reacted in CH2Cl2 with
blue light for 72 h to give 3c as a yellow solid. Cyclobutane 3c was obtained as a mixture of four isomers in 59:25:9:7
molar ratio. Obtained: 300 mg (100% yield). Only the major ε-isomer
was fully characterized. 1H NMR (CD2Cl2, 300.13 MHz): δ = 7.99 (m, 2H, Ho, Ph), 7.60–7.58
(m, 3H, Hm, Hp, Ph), 7.52 (AA′BB′
spin system, 2H, Ho, C6H4), 6.75
(AA′BB′ spin system, 2H, Hm, C6H4), 4.64 (s, 1H, H-C6,12), 3.69 (s, 3H, -OCH3). 13C{1H} NMR (CD2Cl2, 75.5 MHz): δ = 207.8 (SC = O, C4,11), 164.6 (SC = N, C2,9),
159.4 (C-OCH3),133.4 (Ci, Ph), 132.3 (2C, Co, C6H4), 131.9 (Cp, Ph),
128.9 (2C, Cm, Ph), 128.2 (2C, Co, Ph), 124.7
(Ci, C6H4), 113.0 (2C, Cm, C6H4), 91.7 (Cq, C5,7), 57.9 (CH,
C6,12), 55.0 (OCH3). HRMS (ESI+) [m/z]: calcd for [C34H26N2NaO4S2]+ = [M + Na]+, 613.1232; found, 613.1237.
6,12-Bis(4-fluorophenyl)-2,9-diphenyl-3,10-dithia-1,8-diazadispiro-[4.1.47.15]dodeca-1,8-diene-4,11-dione 3d
Following the general method, thiazolone 2d (300 mg, 1.06 mmol) was reacted in CH2Cl2 with
blue light for 72 h to give 3d as a yellow solid. Cyclobutane 3d was obtained as a mixture of two isomers in 91:9 molar
ratio. Obtained: 298 mg (99% yield). Only the major ε-isomer
was fully characterized. 1H NMR (CD2Cl2, 300.13 MHz): δ = 7.97 (m, 2H, Ho, Ph), 7.63–7.55
(m, 2H, Ho, C6H4 + 2H, Hm, Ph + 1H, Hp, Ph), 6.92 (t, 2H, Hm, C6H4, 3JHH = 3JFH = 8.73 Hz), 4.69
(s, 1H, H-C6,12). 13C{1H} NMR (CD2Cl2, 75.5 MHz): δ = 207.3 (SC = O, C4,11), 165.5
(SC = N, C2,9), 162.5 (d, C-F, 1JFC = 247 Hz),
133.2 (Ci, C6H4), 132.9 (d, 2C, Co, C6H4,3JFC =
8.3 Hz), 132.5 (Cp, Ph), 129.0 (2C, Cm, Ph),
128.4 (Ci, Ph), 128.2 (2C, Co, Ph), 114.6 (d,
2C, Cm, C6H4,2JFC = 21.3 Hz), 90.9 (Cq, C5,7), 57.4 (CH, C6,12). 19F NMR (CD2Cl2, 282.4 MHz) δ = −114.13
(tt, 3JFH = 8.68 Hz, 4JFH = 3.36 Hz). HRMS (ESI+) [m/z]: calcd for [C32H20F2N2NaO2S2]+ = [M + Na]+, 589.0826; found, 589.0812.
6,12-Bis(4-chlorophenyl)-2,9-diphenyl-3,10-dithia-1,8-diazadispiro-[4.1.47.15]dodeca-1,8-diene-4,11-dione 3e
Following the general method, thiazolone 2e (300 mg, 1.00 mmol) was reacted in CH2Cl2 with
blue light for 72 h to give 3e as a yellow solid. Cyclobutane 3e was obtained as a mixture of two isomers in a 96:4 molar
ratio. Obtained: 255 mg (85% yield). Only the major ε-isomer
was fully characterized. 1H NMR (CDCl3, 500.13
MHz): δ = 7.89 (m, 2H, Ho, Ph), 7.59–7.52
(m, 3H, Hm+Hp, Ph), 7.47 (m, 2H, Ho, C6H4), 7.14 (m, 2H, Hm, C6H4), 4.63 (s, 1H, H-C6,12). 13C{1H} NMR (CDCl3, 125.76 MHz): δ = 207.3 (SC
= O, C4,11), 165.6 (SC = N, C2,9), 134.3 (C-Cl, C6H4), 133.2 (Ci, Ph), 132.5 (Cp, Ph), 132.4
(2C, Co, C6H4), 130.7 (Ci, C6H4), 129.0 (2C, Cm, Ph), 128.3
(2C, Co, Ph), 128.1 (2C, Cm, C6H4), 90.7 (Cq, C5,7), 57.5 (CH, C6,12). HRMS (ESI+) [m/z]: calcd for [C32H20Cl2N2NaO2S2]+ = [M + Na]+, 621.0241; found, 621.0233.
Following the general method, thiazolone 2o (300 mg, 1.00 mmol) was reacted in CH2Cl2 with
blue light for 72 h to give 3o as a yellow solid. Cyclobutane 3o was obtained as the mixture of two isomers in 94:6 molar
ratio. Obtained: 271 mg (90% yield). Only the major ε-isomer
was fully characterized. 1H NMR (CDCl3, 500.13
MHz): δ = 7.91 (m, 2H, Ho, Ph), 7.65 (td, 1H, H6, C6H3, 3JHH = 4JFH = 9.5
Hz, 4JHH = 2.2 Hz), 7.61–7.53
(m, 3H, Hp + Hm, Ph), 7.12 (dt, 1H, H2, C6H3, 3JHF = 8.7 Hz, 4JHH = 2.2 Hz), 6.94 (q, 1H, H5, C6H3, 3JHF = 4JHF = 3JHH = 9.5 Hz), 4.59 (s, 1H, H-C6,12). 13C{1H}
NMR (CDCl3, 125.76 MHz): δ = 206.9 (SC = O, C4,11),
166.3 (SC = N, C2,9), 150.4 (dd, C4-F, 1JCF = 253.2 Hz, 2JCF = 14.7 Hz), 149.5 (dd, C3-F, 1JCF = 249.6 Hz, 2JCF = 15.3 Hz), 132.9 (Ci, Ph), 132.7 (Cp, Ph), 129.2 (2C, Cm, Ph), 128.9 (m, C1, C6H3), 128.3 (2C, Co, Ph), 127.1
(t, C2, C6H3, 2JCF = 3JCF = 5.3 Hz), 120.7 (t, C6, C6H3, 2JCF = 3JCF = 10.06 Hz), 116.6 (dd, C5, C6H3, 2JFC = 14.13 Hz, 3JCF = 3.64 Hz), 90.5 (Cq,
C5,7), 56.8 (CH, C6,12). 19F{1H} NMR (CDCl3, 282.4 MHz) δ = −137.37 (d, 3JFF = 9.6 Hz), −137.33 (d, 3JFF = 9.6 Hz). HRMS (ESI+) [m/z]: calcd for [C32H18F4N2NaO2S2]+ = [M + Na]+,
625.0644; found, 625.0640.
General Procedure for the
[2 + 2]-Photocycloaddition of 4-Arylidene-2-phenyl-5(4H)-thiazolones 2 in the Presence of BF3: Synthesis
of Cyclobutanes 4a–4e
To
a suspension of the thiazolones 2a–2e (around
0.38 mmol) in dry deoxygenated methanol (3 mL) under an
Ar atmosphere, BF3·OEt2 was added (200
μL, 1.621 mmol). The resulting suspension was irradiated for
24 h with the blue light provided by a Kessil lamp (PR160L, 40 W).
The distance between the sample and the lamp is 5 cm, and the power
of the lamp is fixed at 50% to avoid the overheating of the sample.
After the reaction time, the solid in suspension is filtered, washed
with MeOH, dried in vacuo, and characterized as cyclobutanes 4a–4e.
Numbering of Cyclobutanes 4a–4e, Exemplified
with 4a
Methyl 1,3-Bis(4-chlorophenyl)-8-oxo-6-phenyl-2-phenylthioamido-7-thia-5-azaspiro[3.4]oct-5-ene-2-carboxylate 4e
Following the general method, thiazolone 2e (100.37 mg, 0.336 mmol) and BF3·OEt2 (200 μL, 1.621 mmol) in dry and deoxygenated methanol
(3 mL) were irradiated with blue light (456 nm; 100% intensity in
this case to maximize the conversion) for 24 h to give cyclobutane 4e as a yellow solid. Compound 4e was recrystallized
from CH2Cl2/n-pentane. Obtained:
32.27 mg (31% yield). 1H NMR (CDCl3, 300.13
MHz): δ = 8.53 (s, 1H, NH), 7.67 (m, 2H, Ho, NCS-Ph),
7.64 (m, 2H, Ho, NCS-Ph), 7.57 (m, 1H, Hp, NCS-Ph),
7.53–7.44 (m, 3H, Hp, Hm, NCS-Ph), 7.40
(t, 2H, Hm, NCS-Ph), 7.29 (d, 4H, Hm, C6H4Cl, 2JHH = 8.5 Hz), 7.18 (d, 4H, Ho, C6H4Cl, 2JHH = 8.53 Hz), 4.86
(s, 2H, H-C1,3), 3.88 (s, 3H, OMe). 13C{1H}
NMR (CDCl3, 75.5 MHz): δ = 205.8 (SC = O, C8), 198.1
(NC = S, C9), 169.4 (COO), 167.4 (SC = N, C6), 140.9 (Ci, C6/C9-Ph), 134.4 (Cp, C1,3-C6H4Cl), 133.1 (Cp, CH, C6/C9-Ph), 131.7 (Cp, CH,
C6/C9-Ph), 132.6 (Ci, C6/C9-Ph), 132.4 (Ci,
C1,3-C6H4Cl), 130.7 (Co, C1,3-C6H4Cl), 129.4 (Cm, CH, C6/C9-Ph) 128.9
(Cm, C1,3-C6H4Cl), 128.9 (Cm, CH, C6/C9-Ph), 128.1 (Co, CH, C6/C9-Ph), 126.4 (Co, CH, C6/C9-Ph), 90.4 (Cq, C4), 67.6 (Cq, C2), 54.3 (CH, C1,3), 52.2 (OMe). HRMS (ESI+) [m/z]: calcd for [C33H24Cl2N2O3S2Na]+ = [M + Na]+, 653.0498; found, 653.0506.
Reaction of Cyclobutanes 3c and 3d with NaOMe in MeOH
To a suspension of the cyclobutanes 3c or 3d (150 mg) in methanol (10 mL) was added
NaOMe (10 mg). The resulting mixture was heated in an oil bath at
60 °C for 30 min. After the reaction time, the resulting solution
was evaporated to dryness, and the residue was extracted with CH2Cl2 (2 × 15 mL). Any insoluble solid in the
CH2Cl2 was removed by filtration. The organic
phase was washed with H2O (10 mL), dried with anhydrous
MgSO4, and evaporated to dryness, giving dihydrothiazoles 5c or 5d as yellow oils. Obtained: 168 mg (5c, 92% yield); 166 mg (5d, 94% yield). Compounds 5c and 5d were characterized by NMR methods as
the mixture of the two possible diastereoisomers trans (RR/SS) and cis (RS/SR) in trans/cis = 86:14 (5c) and 81:19 (5d) molar ratios.
General
Procedure for the Synthesis of trans-(RR/SS) Ethyl 5-Aryl-2-phenyl-4,5-dihydrothiazole-4-carboxylates 6
All syntheses of trans-(RR/SS) ethyl 5-aryl-2-phenyl-4,5-dihydrothiazole-4-carboxylates 6 were performed using the same experimental method, which
is detailed here for the synthesis of 6c. To a suspension
of thiazolone 2c (600 mg, 2.03 mmol) in 10 mL of ethanol
was added NaOEt (10 mg, 0.09 mmol). The resulting mixture was refluxed
(80 °C) in an oil bath for 2 h, then left to reach room temperature.
The resulting solution was evaporated to dryness. The orange oily
residue was extracted with CH2Cl2 (25 mL), removing
all insoluble material by filtration. The clear solution was evaporated
to dryness, and the residue was characterized by NMR as the dihydrotiazol 6c (mixture of the two diastereoisomers), although impure.
Therefore, trans-(RR/SS)-6c (the main component of the mixture) was purified
by column chromatography using silica gel as support and a mixture
of n-hexane/Et2O (8:1) as an eluent. The
band collected under these conditions is trans-(RR/SS)-6c. Obtained: 411 mg
(58% yield).
Following the general procedure, thiazolone 2m (150 mg, 0.51 mmol) was reacted with NaOEt (10 mg, 0.09
mmol) for 4 h in refluxing EtOH (10 mL) to give, after chromatographic
purification using silica gel as support and n-hexane/Et2O (8:1) as an eluent, trans-(RR/SS)-6m as a yellow oil. Obtained:
129 mg (75% yield). 1H NMR (CDCl3, 300.13 MHz):
7.94 (d, 2H, Ho, Ph, 3JHH = 6.8 Hz), 7.53–7.43 (m, 3H, Hp + 2Hm, Ph), 7.19 (s, 1H, H2, C6H(Me)2),
7.16, 7.12 (AB spin system, 2H, H5 + H6, 3JHH = 7.5 Hz, C6H(Me)2),
5.41 (AB spin system, CH, 3JHH = 6.6 Hz), 5.36 (AB spin system, CH, 3JHH = 6.6 Hz), 4.31 (q, 1H, OCHCH3, 3JHH = 7.1 Hz), 4.29 (q, 1H, OCHCH3, 3JHH = 7.1 Hz), 2.27 (s, 6H, 2CH3),
1.33 (t, 3H, OCH2CH, 3JHH =
7.1 Hz). 13C{1H} NMR (CDCl3, 75.5
MHz): 170.4 (NCS), 170.4 (COO), 137.8, 137.3, 136.7 (3Cq, C1, C3, C4, CH3(Me)2),
132.7 (Ci, Ph), 131.8 (Cp, Ph), 130.2 (CH, C6/C5, C6H3(Me)2), 128.7 (Co, Ph), 128.7 (CH, C2, C6H3(Me)2), 128.6 (Cm, Ph), 124.9
(CH, C6/C5, C6H3(Me)2), 86.6 (NCH), 61.9 (OCH2), 56.5 (SCH), 19.8 (CH3), 19.5 (CH3), 14.2 (OCH2CH). HRMS (ESI+) [m/z]: calcd for [C20H22NO2S]+ = [M + H]+, 340.1366; found, 340.1359.
trans-(RR/SS) Ethyl 5-(3,4-Dichlorophenyl)-2-phenyl-4,5-dihydrothiazole-4-carboxylate
(6n) and Ethyl 5-(3,4-Dichlorophenyl)-2-phenylthiazole-4-carboxylate
(7n)
Following the general procedure, thiazolone 2n (270 mg, 0.81 mmol) was reacted with NaOEt (10 mg, 0.09
mmol) for 2 h in refluxing EtOH (10 mL) to give a waxy orange solid.
This solid is composed of dihydrothiazole 6n and thiazole 7n. These compounds were separated and purified by column
chromatography using silica gel as support. Using a mixture of n-hexane/Et2O (4:1) as an eluent, the thiazole 7n eluted first. Evaporation of the solvent gave pure 7n as white crystals. Obtained: 128 mg (42% yield). Further
elution with the same mixture of solvents gave trans-(RR/SS)-6n as a yellow
oil. Obtained: 70 mg (24% yield)
Microwave Synthesis of
Methyl 5-(4-Nitrophenyl)-2-phenyl-4,5-thiazole-4-carboxylate 7g
To a suspension of thiazolone 2g (300
mg, 0.97 mmol) in methanol (5 mL) was added NaOMe (9 mg). The mixture
was heated in a microwave oven (150 W, 70 °C) for 1 min. After
the reaction time, the solvent was evaporated to dryness, and the
solid residue was extracted with CH2Cl2 (10
mL). The resulting suspension was filtered through a Celite pad, and
the Celite was washed with additional CH2Cl2 (20 mL). The clear solution was evaporated to dryness, and the crude
was characterized by NMR and was shown to contain thiazole 7g. Compound 7g was purified by column chromatography
(silica gel; n-hexane/Et2O = 5:1 as an
eluent), giving pure 7g as white crystals. Obtained:
64 mg (20% yield). 1H NMR (CDCl3, 300.13 MHz):
δ = 8.33 (AB spin system, 2H, H3+H5, C6H4NO2), 8.02 (m, 2H, Ho,
Ph), 7.74 (AB spin system, 2H, H2+H6, C6H4NO2), 7.51 (m, 3H, Hp+Hm, Ph), 3.91 (s, 3H, OMe). 13C{1H} NMR
(CDCl3, 75.5 MHz): 167.6 (NCS), 162.3 (CO), 148.1 (C, S-C
= ), 143.1 (C4-N, C6H4NO2), 141.9 (C, N-C = ), 137.0 (C1, C6H4NO2), 132.3 (Ci, Ph), 131.2 (Cp,
Ph), 131.0 (C2/C6, C6H4NO2), 129.2 (Cm, Ph), 126.7 (Co,
Ph), 123.4 (C3/C5, C6H4NO2), 52.6 (OCH3). HRMS (ESI+) [m/z]: calcd for [C17H12N2NaO4S]+ = [M + Na]+, 363.0415; found, 363.0410.
Synthesis of Dihydrothiazole
Derivatives (cis/trans)-5 through Ring-Opening Reaction
without a Base in the Presence of BF3 (General Procedure)
All syntheses of (cis/trans)-methyl
5-aryl-2-phenyl-4,5-dihydrothiazole-4-carboxylates (cis/trans)-5 were performed using the
same experimental method, which is detailed here for the synthesis
of 5a. To a suspension of the thiazolone 2a (100.7 mg, 0.38 mmol) in methanol (5 mL) was added BF3·OEt2 (200 μL, 1.621 mmol). The resulting mixture
was heated in an oil bath at a reflux temperature with stirring for
18 h. After the reaction time, the solvent was evaporated to dryness,
and the oily residue was dissolved in CH2Cl2 (5 mL). This solution was washed with H2O (3 × 2
mL), dried with anhydrous MgSO4, and evaporated to dryness,
giving 5a as the mixture of the two diastereoisomers trans (RR/SS) and cis (RS/SR) in a 1:1 molar
ratio. Obtained: 83.04 mg (74% yield)
Following the general procedure, thiazolone 2d (102.0 mg, 0.360 mmol) was reacted with BF3·OEt2 (200 μL, 1.621 mmol) for 18 h in refluxing MeOH (5
mL) to give (cis/trans)-5d (1:1.1 molar ratio) as a yellow oil. In this case, further chromatographic
purification was necessary to separate 5d from starting
thiazolone 2d. The chromatographic purification was started
using silica as support and n-hexane/Et2O (9:1) as an eluent. Using these conditions, only the thiazolone 2d was eluted. Then the solvent was changed, and 2-propanol
was employed. Using these conditions, the dihydrothiazole 5d was obtained as a yellow oil after solvent evaporation. Obtained:
81 mg (71% yield). 1H NMR (CDCl3, 300.13 MHz):
δ = 7.99 (m, Ho, NCS-Ph), 7.93 (m, Ho,
NCS-Ph), 7.55–7.43 (m, Hp+Hm, NCS-Ph,
both isomers), 7.40 (m, Ho, C6H4F),
7.28 (m, Ho, C6H4F), 7.06 (tt, Hm, C6H4F, 3JHF =
8.6 Hz, 4JHH = 2.1 Hz), 6.97
(tt, Hm, C6H4F, 3JHF = 8.7 Hz, 4JHH =
2.0 Hz), 5.57 (d, NCH, 3JHH = 8.9 Hz, cis-isomer), 5.47 (d, SCH, 3JHH = 6.5 Hz, trans-isomer), 5.35 (d, NCH, 3JHH = 6.5 Hz, trans-isomer), 5.26 (d, SCH, 3JHH = 8.9 Hz, cis-isomer),
3.85 (s, OMe, trans-isomer). 3.43 (s, OMe, cis-isomer). 13C{1H} NMR (CDCl3, 75.5 MHz): δ = 170.7 (COO), 170.5 (SC = N), 170.4
(SC = N), 169.3 (COO), 162.6 (d, Cp-F, C6H4F, 1JCF = 247.4 Hz),
162.6 (d, Cp-F, C6H4F, 1JCF = 247.7 Hz), 136.2 (d, Ci, C6H4F, 4JCF = 3.3 Hz), 134.1 (d, Ci, C6H4F, 4JCF = 3.5 Hz), 132.6 (2Ci, NCS-Ph, both isomers ovelapped), 132.1, 132.0 (2Cp, NCS-Ph, both isomers), 129.8(d, Co, C6H4F, 3JCF = 8.3 Hz),
129.3(d, Co, C6H4F, 3JCF = 8.3 Hz), 128.9, 128.8, 128.7, 128.7 (Co, Cm, NCS-Ph, both isomers), 116.0 (d, Cm, C6H4F, 2JCF = 21.7 Hz), 115.4 (d, Cm, C6H4F, 2JCF = 21.7 Hz),
86.8 (NCH, trans-isomer), 84.1 (NCH, cis-isomer), 56.0 (SCH, trans-isomer), 55.2 (SCH, cis-isomer), 53.0 (OMe). 52.0 (OMe). 19F NMR(CDCl3, 282.40 MHz): δ = −113.67 (tt, 3JFH = 8.6 Hz, 4JFH = 3.3 Hz), −113.23 (tt, 3JFH = 8.5 Hz, 4JFH = 3.3 Hz). HRMS (ESI+) [m/z]: calcd for [C17H15FNO2S]+ = [M + H]+, 316.0802; found, 316.0796.
(cis/trans)-Methyl 5-(4-Chlorophenyl)-2-phenyl-4,5-dihydrothiazole-4-carboxylate 5e
Following the general procedure, thiazolone 2e (300.6 mg, 1.00 mmol) was reacted with BF3·OEt2 (600 μL, 4.863 mmol) for 18 h in refluxing MeOH (15
mL) to give (cis/trans)-5e (1:1.7 molar ratio) as a yellow oil. In this case, chromatographic
purification was carried out to separate (cis/trans)-5e from thiazolone 2e and
to further separate cis-5e from trans-5e. The chromatographic purification
was started using silica as support and n-hexane/Et2O (9:1) as an eluent. Using these conditions, only the thiazolone 2e was eluted. Then the solvent was changed, and a mixture, n-hexane/ethyl acetate (8:2), was used as an eluent. Compound trans-5e eluted first and was obtained as a
yellow oil after solvent evaporation (obtained: 90 mg, 27% yield).
Compound cis-5e eluted in a second fraction
and was obtained as a yellow oil after solvent evaporation (obtained:
54 mg, 16% yield). 1H NMR (CDCl3, 300.13 MHz):
δ = 7.95 (m, Ho, NCS-Ph), 7.89 (m, Ho,
NCS-Ph), 7.55–7.40 (m, Hm, Hp, NCS-Ph
both isomers), 7.33 (d, Ho, Hm, C6H4Cl), 7.22 (d, Ho, Hm, C6H4Cl), 5.56 (d, NCH, 3JHH = 8.9 Hz, cis-isomer), 5.42 (d, SCH, 3JHH = 6.4 Hz, trans-isomer), 5.32 (d, NCH, 3JHH = 6.4 Hz, trans-isomer), 5.21 (d, SCH, 3JHH = 8.9 Hz, cis-isomer),
3.82 (s, OMe, trans-isomer), 3.42 (s, OMe, cis-isomer). 13C{1H} NMR (CDCl3, 75.5 MHz): δ = 170.7 (SC = N), 170.7 (SC = N), 170.6
(COO), 169.3 (COO), 138.2 (Ci, C6H4Cl), 136.9 (Ci, C6H4Cl), 134.4 (Cp, C6H4Cl), 134.2 (Cp, C6H4Cl), 132.5 (Ci, NCS-Ph, both isomers),
132.2(Cp, NCS-Ph), 132.1 (Cp, NCS-Ph), 129.4,
128.9 (Co, Cm C6H4Cl),
129.3, 129.0 (Co, Cm C6H4Cl), 128.8, 128.8 (Co, Cm, NCS-Ph), 128.8,
128.8 (Co, Cm, NCS-Ph), 86.6 (NCH, trans-isomer), 83.9 (NCH, cis-isomer), 56.0 (SCH, trans-isomer), 55.2 (SCH, cis-isomer),
53.1 (OMe, trans-isomer), 52.2 (OMe, cis-isomer). HRMS (ESI+) [m/z]: calcd for [C17H14ClNO2SNa]+ = [M + Na]+, 354.0326; found, 354.0325.
Authors: Haohua Huo; Xiaodong Shen; Chuanyong Wang; Lilu Zhang; Philipp Röse; Liang-An Chen; Klaus Harms; Michael Marsch; Gerhard Hilt; Eric Meggers Journal: Nature Date: 2014-11-06 Impact factor: 49.962
Authors: Elena Serrano; Alberto Juan; Angel García-Montero; Tatiana Soler; Francisco Jiménez-Márquez; Carlos Cativiela; M Victoria Gomez; Esteban P Urriolabeitia Journal: Chemistry Date: 2015-11-24 Impact factor: 5.236
Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6
Figure 7
Figure 8
Figure 9
Figure 10
Figure 11
Figure 12
Figure 13
Figure 14
Figure 15
Figure 16