Reactivity of (Z)-4-Aryliden-5(4 H)-thiazolones: [2 + 2]-Photocycloaddition, Ring-Opening Reactions, and Influence of the Lewis Acid BF3

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Reactivity of (Z)‑4-Aryliden-5(4H)‑thiazolones: [2 + 2]-

Photocycloaddition, Ring-Opening Reactions, and Inﬂuence of the

Lewis Acid BF₃

Sonia Sierra, David Dalmau, Sheila Higuera, Dar í o Cort é s, Olga Crespo, Ana I. Jimenez, Alexandra Pop,

Cristian Silvestru, and Esteban P. Urriolabeitia *

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ABSTRACT: The irradiation of (Z)-2-phenyl-4-aryliden-5(4H)-

thiazolones 2 with blue light (465 nm) in CH₂Cl₂solution 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·OEt₂leads 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·OEt₂in methanol

in the absence of a base.

We are interested in a particular family of cyclobutanes,

namely, 1,3-diaminotruxillic derivatives (Figure 2), 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).³²⁻³⁶As a result, they

are promising candidates in eﬃcient treatments for chronic

pain.³⁷However, this is not the only outstanding pharmaco-

logical 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

INTRODUCTION

■

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

1.²⁻⁷Moreover, cyclobutanes are also interesting synthetic

intermediates as they show a particular reactivity due to the

high ring strain.⁸⁻¹¹

Figure 1 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.¹²⁻¹⁵However, for photochemical pro-

cesses, 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 1b) and β-

truxinic acid derivatives.¹⁶⁻¹⁸In 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

Received: June 21, 2021

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A

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Figure 1. Cyclobutanes with important pharmacological activity.

Figure 2. Context of this work, comparison with previous work and main achievements.

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Figure 3. Thiazolones 2a−2o used in this work and synthetic method.

Figure 4. [2 + 2]-Photocycloaddition of 4-arylidene-5(4H)-thiazolones 2 to give cyclobutanes 3.

As a result of this interest, we have developed diﬀerent

methodologies for the stereoselective synthesis of 1,3-

diaminotruxillic derivatives (Figure 2). 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 2, past work, path a).⁴¹Thus, 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 2, 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.⁴⁸Proof of this

interest is the fact that there are at least 249 sulfur-containing

drugs approved by the US Food and Drug Administration

(FDA).⁴⁹Thiazolones 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),^50,51and more recently as promising

anticancer compounds.⁵²Due 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,⁴¹⁻⁴⁵the 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]-photocycload-

dition reactions and in ring-opening reactions upon alcoholysis

(Figure 2, 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 3.

Synthesis was carried out following the same experimental

procedure reported by Rao and Filler,⁴⁶which in turn were

based on the original work of Behringer et al.^63,64Following

this method, the treatment of oxazolones 1a−1o with

thioacetic acid in the presence of substoichiometric amounts

of NEt₃gave 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,^65,66and

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).

The HRMS (ESI⁺) spectra of 2a−2o show peaks in

agreement with the stoichiometries proposed in Figure 3. In

1

addition, the H 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

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Figure 5. Scope of the [2 + 2]-photocycloaddition of thiazolones 2 to give cyclobutanes 3.

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

a

yield

ε (%)

α (%)

82

100

0

100

90

10

100

59

25

100

91

9

85

96

4

92

83

17

100

0

80

100

0

95

71

29

98

65

35

100

85

15

100

91

9

90

94

6

others (%)

9:7

a

Maximum conversion achieved.

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 CH₂Cl₂were 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 4), which were isolated as air-stable solids after

solvent evaporation and recrystallization from CH₂Cl₂/n-

pentane.

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 CH₂Cl₂in 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 5)

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).

The optimum reaction time for full conversion of 2 using the

1

PCB, as determined by H NMR monitoring, was 72 h. This

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NMR analysis of the cyclobutanes 3 represented in Figures 4

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 1 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 2, 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.

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 6, 7, and 8, respectively.

Figure 7. X-ray crystal structure of cyclobutane 3h. Thermal ellipsoids

are drawn at 50% probability.

Figure 6. X-ray crystal structure of cyclobutane 3g. Thermal ellipsoids

are drawn at 50% probability.

Figure 8. 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),

cyclobutane core showing the 1,2-cis-2,3-cis-3,4-cis conﬁgu-

ration. 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.⁴¹In 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 arrange-

ments.^{38,41,43,69−74}

according to the isomer assignment of Stoermer and

67,68

́

Bacher,

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

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Figure 9. Photocycloaddition of thiazolones 2 in methanol in the presence of the Lewis acid BF₃·OEt₂

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

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);⁴¹therefore, 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 CH₂Cl₂at

−18 °C, and the structure obtained is shown in Figure 10.

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 meth-

anolysis 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

1

comparison of the NMR chemical shifts for the H 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]-Photo-

cycloaddition 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·OEt₂was four equivalents with

respect to thiazolone 2. After irradiation for 24 h, the

conversion of 2 was complete, and cyclobutanes 4

(represented in Figure 9) 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.

The 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

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

1

cyclobutane. The H 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

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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·OEt₂in

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 BF₃is related to the promotion of the ring-opening

reaction, as shown in Figure 11, rather than to the [2 + 2]-

photocycloaddition.

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).⁷⁵Surprisingly, this reaction aﬀorded the 4,5-

dihydrothiazoles 5c and 5d as a mixture of cis- and trans-

diastereoisomers, as shown in Figure 12 (upper reaction).

The transformation shown in the upper reaction of Figure

12 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 12 (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 +

Figure 10. X-ray crystal structure of cyclobutane 4b. Thermal

ellipsoids are drawn at 50% probability.

only one. This suggests that the Lewis acid BF₃has 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

BF₃in 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·OEt₂until

the molar ratio 1:4 was reached, and the result of each addition

1

was monitored by H 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.

Figure 11. Proposal of the mechanism for the BF₃-promoted ring-opening reaction.

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Figure 12. Synthesis of 4,5-dihydrothiazoles 5 by treatment of cyclobutanes 3 with NaOMe in MeOH.

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.

2] reaction can take place to regenerate thiazolones 2, which

subsequently react with a base to give 5.

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 12.

This synthetic method for the preparation of dihydrothia-

zoles 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.⁷⁷In that case, the reaction was

performed using NaOH in water to aﬀord the corresponding

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 ³J_HHcoupling constant between these

two protons is diagnostic for the determination of the

conﬁguration of each diastereoisomer. Thus, the major species

3

shows a value for the J_HHcoupling 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.⁷⁶The higher abundance of the trans-isomer is

in good agreement with the lower intramolecular repulsions in

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Figure 14. Mechanistic proposal for the synthesis of dihydrothiazoles 5 (or 6) from thiazolones 2.

Figure 15. Reactivity of thiazolones 2 with MeOH in the presence of BF₃; synthesis of dihydrothiazoles 5.

carboxylic acid.⁷⁷Dihydrothiazoles are interesting materials

due to their properties, and diﬀerent synthetic methods have

been reported for their preparation, most of them starting from

aminothiols.⁷⁸⁻⁸⁹Dihydrothiazoles are versatile intermediates

for the synthesis of high-value-added compounds, for instance

β-cysteine and derivatives,⁹⁰⁻⁹⁴are present in ﬂavours⁹⁵and in

natural products,⁹⁶⁻⁹⁹and show a remarkable pharmacological

activity.^100−102For 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 13.

The treatment of thiazolones 2 with NaEtO in ethanol at

reﬂux temperature gave the corresponding dihydrothiazoles 6,

as shown in Figure 13. 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 H NMR spectroscopy to be a mixture of the two

1

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

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Figure 16. Mechanistic proposal for the formation of dihydrothiazoles in the presence of BF₃.

compound was also puriﬁed and separated from 6n by column

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 12 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 16. Coordination of the carbonyl oxygen to BF₃

increases the electrophilic character of the carbonyl carbon (as

in Figure 11), which is, therefore, more susceptible to attack by

methanol. The decoordination of BF₃is followed by the

formation of the sulﬁde, which can attack the exocyclic

C(H)C bond (see Figure 14).

chromatography. The absence of the diagnostic AB spin

1

system at around 5.3−5.4 ppm in the H 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 13). 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.¹⁰³When 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 dihydrothia-

zoles 5 or 6 from thiazolones 2 is shown in Figure 14. 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.

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

The easy ring-opening reactions undergone by cyclobutanes

3 to give cyclobutanes 4 shown in Figures 9 and 11 suggest

that the Lewis acid BF₃fosters 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·OEt₂and in

the absence of a base. The results of these reactions are shown

in Figure 15.

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

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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 CH₂Cl₂solutions 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 N₂gas (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 RED¹¹⁴and

SAINT,¹¹⁵and the integrated intensities were corrected for

absorption with SADABS.¹¹⁶The structures were solved and

developed by Fourier methods.¹¹⁷All 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.

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. Dihydrothia-

zoles 5 can also be obtained by treatment of the thiazolone 2

with alcohol in the presence of BF₃but in the absence of a

base. In this case, the reaction shows a broader scope, and it

seems that the role of BF₃is 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

1

spectrophotometer. H, ¹³C, and ¹⁹F NMR spectra were recorded in

CDCl₃or CD₂Cl₂solutions 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 t₁experiments were recorded

and zero-ﬁlled to 1K; for each t₁value, 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 t₂using spectral widths of 10

ppm (¹H) and 200 ppm (¹³C) were used, with averaged values of the

2

The structures were reﬁned to F_o, and all reﬂections were used in the

least-squares calculations.¹¹⁸CCDC 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,⁴⁶which in turn is based in the

original work of Behringer et al.^63,64Thiazolones 2a−2c have been

previously described, although 2b was prepared using a diﬀerent

method.^65,66Thiazolones 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.

1

n

coupling constants J_CH= 145 Hz and long-range J_CH= 10 Hz.

Typically, 128 t₁experiments were recorded and zero-ﬁlled to 1 K.

For each t₁value, 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 MicroFlex^TMor a Bruker

AutoFlex^TMIII 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

(Z)-4-(4-Fluorobenzylidene)-2-phenyl-5(4H)-thiazolone 2d. The

oxazolone 1d (2.5 g, 9.3 mmol), thioacetic acid (2.0 mL, 28.4 mmol)

and NEt₃(0.1 mL) were heated in an oil bath at 70 °C while stirred

for 18 h. During this time the oxazolone dissolved, giving a dark

solution, and after some minutes a deep-colored solid precipitated.

After the reaction time the mixture was left to reach room

temperature and ethanol (30 mL) was added to complete the

precipitation. The yellow solid thus formed was ﬁltered, washed

thoroughly with ethanol (120−150 mL) until the characteristic smell

of thioacetic acid disappeared, dried by suction, and characterized as

1

2d. Obtained: 1.64 g (62% yield). H NMR (CD₂Cl₂, 300.13 MHz):

δ = 8.30 (dd, 2H, H₂/H₆, C₆H₄F, ³J_HH= 8.7 Hz, ⁴J_HF= 5.7 Hz), 8.00

(d, 2H, H_o, Ph, ³J_HH= 6.5 Hz), 7.61−7.50 (m, 3H, H_p+2H_m,Ph), 7.18

3

(t, 2H, H₃/H₅, J_HH≈ J_HF= 8.7 Hz), 7.17 (s, 1H, H_vinyl). ¹⁹F NMR

(CD₂Cl₂, 282.4 MHz): δ = −107.41 (tt, ³J_FH= 8.7 Hz, ⁴J_FH= 3.1 Hz).

¹³C{¹H} NMR (CD₂Cl₂, 75.5 MHz): δ = 194.7 (CO), 167.6 (NCS),

1

165.0 (d, C₄F, J_CF= 254 Hz), 146.4 (=C), 136.0 (d, 2CH, C₂/C₆,

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

³J_FC= 8.7 Hz), 133.9 (C, C_i, Ph), 133.3 (CH, C_p, Ph), 130.8 (d, C,

C₁, C₆H₄F, ⁴J_FC= 3.3 Hz), 130.0 (d, CH, C_vinyl, ⁵J_FC= 1.7 Hz), 129.6

(2CH, C_m, Ph), 128.8 (2CH, C_o, Ph), 116.7 (d, 2CH, C₃/C₅, C₆H₄F,

²J_FC= 22.0 Hz). HRMS (ESI⁺) [m/z]: calcd for [C₁₆H₁₀FNNaOS]⁺=

[M + Na]⁺, 306.0359; found, 306.0349. IR (ν, cm⁻¹): 1682 (CO, vs).

(Z)-4-(4-Chlorobenzylidene)-2-phenyl-5(4H)-thiazolone 2e. Thia-

zolone 2e was obtained following the same experimental procedure

than the described for 2d. Therefore, oxazolone 1e (2.5 g, 8.8 mmol)

was reacted with thioacetic acid (2 mL) and NEt₃(0.1 mL) for 18 h

at 70 °C to give 2e as a deep yellow solid. Obtained: 1.55 g (59%

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yield). H NMR (CD₂Cl₂, 300.13 MHz): δ = 8.25 (AA′BB′ spin

C-OMe, C₆H₄OMe), 145.7 (=C), 133.6 (C_i, Ph), 133.5 (CH, C₆,

C₆H₄OMe), 133.2 (CH, C₄/C₅, C₆H₄OMe), 132.4 (CH, C_p, Ph),

128.9 (2CH, C_m, Ph), 128.2 (2CH, C_o, Ph), 125.4 (CH, C_vinyl), 122.9

(C₁, C₆H₄OMe), 121.0 (CH, C₄/C₅, C₆H₄OMe), 110.8 (CH, C₃,

C₆H₄OMe), 55.7 (OMe). HRMS (ESI⁺) [m/z]: calcd for

[C₁₇H₁₃NNaO₂S]⁺= [M + Na]⁺, 318.0559; found, 318.0555.

(Z)-4-(2-Chlorobenzylidene)-2-phenyl-5(4H)-thiazolone 2j. Thia-

zolone 2j was obtained following the same experimental procedure

than the described for 2d. Therefore, oxazolone 1j (2.5 g, 8.8 mmol)

was reacted with thioacetic acid (2 mL) and NEt₃(0.1 mL) for 18 h

3

system, 2H, H₃/H₅, C₆H₄Cl,), 8.04 (dd, 2H, H_o, Ph, J_HH= 8.2 Hz,

⁴J_HH= 1.5 Hz), 7.64−7.55 (m, 3H, H_p+2H_m,Ph), 7.48 (AA′BB′ spin

system, 2H, H₂/H₆, C₆H₄Cl), 7.18 (s, 1H, H_vinyl). ¹³C{¹H} NMR

(CD₂Cl₂, 75.5 MHz): δ = 194.1 (CO), 167.5 (NCS), 146.4 (=C),

137.3 (C, C₄, C₆H₄Cl), 134.2 (2CH, C₃/C₅, C₆H₄Cl), 133.3 (C₁,

C₆H₄Cl), 132.9 (CH, C_p, Ph), 132.4 (C_i, Ph), 129.2 (CH, C_vinyl),

129.2 (2CH, C₂/C₆, C₆H₄Cl), 129.0 (2CH, C_m, Ph), 128.3 (2CH, C_o,

Ph). HRMS (ESI⁺) [m/z]: calcd for [C₁₆H₁₀ClNNaOS]⁺= [M +

Na]⁺, 322.0064; found, 322.0053.

at 70 °C to give 2j as a yellow solid. Obtained: 0.98 g (36% yield). ¹H

(Z)-4-(4-Bromobenzylidene)-2-phenyl-5(4H)-thiazolone 2f. Thia-

zolone 2f was obtained following the same experimental procedure

than the described for 2d. Therefore, oxazolone 1f (2.5 g, 7.6 mmol)

was reacted with thioacetic acid (2 mL) and NEt₃(0.1 mL) for 18 h

at 70 °C to give 2f as a deep yellow solid. Obtained: 1.19 g (45%

3

NMR (CDCl₃, 300.13 MHz): δ = 8.95 (dd, 1H, H₆, C₆H₄Cl, J_HH

=

4

7.8 Hz, J_HH= 2.0 Hz), 8.01 (m, 2H, H_o, Ph), 7.75 (s, 1H, H_vinyl),

7.62−7.34 (m, 6H, H_p(Ph) + 2H_m(Ph) + H₃/H₄/H₅(C₆H₄Cl)).

¹³C{¹H} NMR (CDCl₃, 75.5 MHz): δ = 194.2 (CO), 168.3 (NSC),

147.2 (=C), 137.5, 131.8 (C_i/C₂, C₆H₄Cl), 133.9 (CH, C₆, C₆H₄Cl),

133.3 (C_i, Ph), 133.0 (CH, C_p, Ph), 131.7, 130.0, 127.1 (CH, C₃/C₄/

C₅, C₆H₄Cl), 129.0 (2CH, C_m, Ph), 128.4 (2CH, C_o, Ph), 126.0 (CH,

C_vinyl). HRMS (ESI⁺) [m/z]: calcd for [C₁₆H₁₀ClNNaOS]⁺= [M +

Na]⁺, 322.0064; found, 322.0072.

1

yield). H NMR (CDCl₃, 300.13 MHz): δ = 8.13 (d, 2H, H₃+ H₅,

C₆H₄Br, ³J_HH= 8.5 Hz), 8.01 (d, 2H, H_o, Ph, ³J_HH= 6.7 Hz), 7.61 (d,

2H, H₂+ H₆, C₆H₄Br, ³J_HH= 8.5 Hz), 7.57−7.51 (m, 3H, H_p+ 2H_m,

Ph), 7.16 (s, 1H, H_vinyl). ¹³C{¹H} NMR (CDCl₃, 75.5 MHz): δ =

194.5 (CO), 167.7 (NCS), 146.7 (=C), 134.5 (2CH, C₃+ C₅,

C₆H₄Br), 133.5 (C₁, C₆H₄Br), 133.0 (CH, C_p, Ph), 132.8 (C_i, Ph),

132.4 (2CH, C₂+ C₆, C₆H₄Br), 129.8 (CH, C_vinyl), 129.2 (2CH, C_m,

Ph), 128.5 (2CH, C_o, Ph), 126.3 (C₄, C-Br, C₆H₄Br). HRMS (ESI⁺)

[m/z]: calcd for [C₁₆H₁₀BrNNaOS]⁺= [M + Na]⁺, 365.9559; found,

365.9551.

(Z)-4-(2-Bromobenzylidene)-2-phenyl-5(4H)-thiazolone 2k.

Thiazolone 2k was obtained following the same experimental

procedure than the described for 2d. Therefore, oxazolone 1k (2.5

g, 7.6 mmol) was reacted with thioacetic acid (2 mL) and NEt₃(0.1

mL) for 18 h at 70 °C to give 2k as a deep yellow solid. Obtained:

1

1.02 g (39% yield). H NMR (CDCl₃, 300.13 MHz): δ = 8.92 (dd,

(Z)-4-(4-Nitrobenzylidene)-2-phenyl-5(4H)-thiazolone 2g. Thia-

zolone 2g was obtained following the same experimental procedure

than the described for 2d. Therefore, oxazolone 1g (2.5 g, 8.5 mmol)

was reacted with thioacetic acid (2 mL) and NEt₃(0.1 mL) for 18 h

at 70 °C to give 2g as a deep yellow solid. Obtained: 1.02 g (38%

yield). ¹H NMR (CDCl₃, 300.13 MHz): δ = 8.45 (AA′BB′ spin

system, 2H, H₃/H₅, C₆H₄NO₂), 8.35 (AA′BB′ spin system, 2H, H₂/

1H, H₃, C₆H₄Br, ³J_HH= 8.0 Hz, ⁴J_HH= 1.7 Hz), 8.01 (dd, 2H, H_o, Ph,

³J_HH= 8.2 Hz, ⁴J_HH= 1.5 Hz), 7.70 (s, 1H, H_vinyl), 7.68 (dd, 1H, H₆,

C₆H₄Br, ³J_HH= 8.0 Hz, ⁴J_HH= 1.2 Hz), 7.60−7.45 (m, 4H, H_p+ 2H_m

3

(Ph) + H₄(C₆H₄Br)), 7.30 (td, 1H, H₅, C₆H₄Br, J_HH= 8.0 Hz, ⁴J_HH

= 1.7 Hz). ¹³C{¹H} NMR (CDCl₃, 75.5 MHz): δ = 194.1 (CO),

168.3 (NCS), 147.2 (=C), 134.0 (CH, C₃, C₆H₄Br), 133.4 (CH, C₅/

C₆, C₆H₄Br), 133.3 (C_i, Ph), 133.0 (CH, C_p, Ph), 131.9 (CH, C₅/C₆,

C₆H₄Br), 129.0 (2CH, C_o, Ph), 128.8 (CH, C_vinyl), 128.4 (2CH, C_m,

Ph), 128.3 (2 overlapped carbons, C₁+C₂, C₆H₄Br), 127.7 (CH, C₄,

C₆H₄Br). HRMS (ESI⁺) [m/z]: calcd for [C₁₆H₁₀BrNNaOS]⁺= [M

+ Na]⁺, 365.9559; found, 365.9548.

3

H₆, C₆H₄NO₂), 8.07 (d, 2H, H_o, Ph, J_HH= 7.2 Hz), 7.66−7.57 (m,

3H, H_p+2H_m,Ph), 7.24 (s, 1H, H_vinyl). ¹³C{¹H} NMR (CDCl₃, 75.5

MHz): δ = 195.3 (CO), 169.1 (NCS), 148.4 (C₄, C₆H₄NO₂), 139.7

(C₁, C₆H₄NO₂), 133.5 (CH, C_p, Ph), 133.3 (2CH, C₃/C₅,

C₆H₄NO₂), 129.2 (2CH, C_m, Ph), 128.6 (2CH, C_o, Ph), 127.0

(CH, C_vinyl), 123.9 (2CH, C₂/C₆, C₆H₄NO₂). Due to low solubility

some quaternary ¹³C signals (Ci of Ph and = C of the arylidene

fragment) were missing. HRMS (ESI+) [m/z]: calcd for

[C₁₆H₁₀N₂NaO₃S]⁺= [M + Na]⁺, 333.0310; found, 333.0317. IR

(ν, cm⁻¹): 1696 (vs).

(Z)-4-(3,4-Dimethoxybenzylidene)-2-phenyl-5(4H)-thiazolone 2l.

Thiazolone 2l was obtained following the same experimental

procedure than the described for 2d. Therefore, oxazolone 1l (2.5

g, 8.1 mmol) was reacted with thioacetic acid (2 mL) and NEt₃(0.1

mL) for 18 h at 70 °C to give 2l as a deep orange solid. Obtained:

1.59 g (60% yield). ¹H NMR (CDCl₃, 300.13 MHz): δ = 8.29 (s, 1H,

(Z)-4-(4-Triﬂuoromethylbenzylidene)-2-phenyl-5(4H)-thiazolone

2h. Thiazolone 2h was obtained following the same experimental

procedure than the described for 2d. Therefore, oxazolone 1h (2.5 g,

7.9 mmol) was reacted with thioacetic acid (2 mL) and NEt₃(0.1

mL) for 18 h at 70 °C to give 2h as a pale-yellow solid. Obtained:

1.84 g (70% yield). ¹H NMR (CDCl₃, 300.13 MHz): δ = 8.34

(AA′BB′ spin system, 2H, H₂/H₆, C₆H₄CF₃), 8.01 (dd, 2H, H_o, Ph,

³J_HH= 8.2 Hz, ⁴J_HH= 1.5 Hz), 7.72 (AA′BB′ spin system, 2H, H₃/H₅,

3

H₂, C₆₃H₃), 7.97 (d, 1H, H_o, Ph, J_HH= 7.2 Hz), 7.60 (d, 1H, H₆,

C₆H₃, J_HH= 8.4 Hz), 7.55−7.48 (m, 3H, 2H_m+ H_p(Ph)), 7.20 (s,

3

1H, H_vinyl), 6.94 (d, 1H, H₅, C₆H₃, J_HH= 8.4 Hz), 4.02 (s, 3H,

OMe), 3.97 (s, 3H, OMe). ¹³C{¹H} NMR (CDCl₃, 75.5 MHz): δ =

194.4 (CO), 165.1 (NCS), 152.3, 149.1 (2C, C₃+C₄, C₆H₃), 144.5

(=C), 133.6 (C_i, Ph), 132.3 (CH, C₆, C₆H₃), 131.7 (CH, C_vinyl),

129.0 (2CH, C_m,Ph), 128.9 (CH, C_p, Ph), 127.8 (2CH, C_o, Ph),

127.0 (C, C₁, C₆H₃), 114.5 (CH, C₂, C₆H₃), 110.9 (CH, C₅, C₆H₃),

56.0 (OCH₃), 55.8 (OCH₃). HRMS (ESI⁺) [m/z]: calcd for

[C₁₈H₁₅NNaO₃S]⁺= [M + Na]⁺, 348.0665; found, 348.0659. IR

(ν, cm⁻¹): 1704 (vs), 1677.

C₆H₄CF₃), 7.60−7.50 (m, 3H, H_p+2H_m,Ph), 7.19 (s, 1H, H_vinyl). ¹⁹F

NMR (CDCl₃, 282.4 MHz): δ = −62.97 (s). ¹³C{¹H} NMR (CDCl₃,

75.5 MHz): δ = 194.4 (CO), 168.9 (NCS), 147.7 (=C), 137.1 (q, C₁,

5

C₆H₄CF_3,J_CF= 1.4 Hz), 133.3 (CH, C_p, Ph), 133.2 (C_i, Ph), 133.1

(2CH, C₂/C₆, C₆H₄CF₃), 132.2 (q, C, C₄, C₆H₄CF_3,J_CF= 43 Hz),

129.2 (2CH, C_m, Ph), 128.7 (CH, C_vinyl), 128.6 (2CH, C_o, Ph), 125.8

(2CH, C₃/C₅, C₆H₄CF_3,J_CF= 3.8 Hz), 120.4 (q, CF₃, J_CF= 272

Hz). Anal. Calcd for C₁₇H₁₀F₃NOS: C, 61.26; H, 3.02; N, 4.20; S,

9.62. Found: C, 60.94; H, 3.12; N, 3.91; S, 9.93.

2

(Z)-4-(3,4-Dimethylbenzylidene)-2-phenyl-5(4H)-thiazolone 2m.

Thiazolone 2m was obtained following the same experimental

procedure than the described for 2d. Therefore, oxazolone 1m (2.5

g, 9.0 mmol) was reacted with thioacetic acid (2 mL) and NEt₃(0.1

mL) for 18 h at 70 °C to give 2m as a yellow solid. Obtained: 1.18 g

3

1

(Z)-4-(2-Methoxybenzylidene)-2-phenyl-5(4H)-thiazolone 2i.

Thiazolone 2i was obtained following the same experimental

procedure than the described for 2d. Therefore, oxazolone 1i (2.5

g, 8.9 mmol) was reacted with thioacetic acid (2 mL) and NEt₃(0.1

mL) for 18 h at 70 °C to give 2i as a pale-yellow solid. Obtained: 0.80

g (30% yield). ¹H NMR (CDCl₃, 300.13 MHz): δ = 8.95 (d, 1H, H₆,

C₆H₄OMe, ³J_HH= 7.8 Hz), 8.02 (d, 2H, H_o, Ph, ³J_HH= 6.5 Hz), 7.90

(s, 1H, H_vinyl), 7.57−7.42 (m, 4H, H_p(Ph) + 2H_m(Ph) + H₄/H₅

(44% yield). H NMR (CDCl₃, 300.13 MHz): δ = 8.09 (d, 1H, H₆,

3

C₆H₃, J_HH= 8.0 Hz), 8.05−8.02 (m, 3H, H₅(C₆H₃)+ 2H_o(Ph)),

7.59−7.52 (m, 3H, H_p+ 2H_m, Ph), 7.29 (s, 1H, H₂, C₆H₃), 7.23 (s,

1H, H_vinyl), 2.37 (s, 3H, Me, C₆H₃(Me)₂), 2.36 (s, 3H, Me,

C₆H₃(Me)₂). ¹³C{¹H} NMR (CDCl₃, 75.5 MHz): δ = 194.7 (CO),

165.7 (NCS), 145.5 (=C), 141.2 (C, C₆H₃), 137.2 (C, C₆H₃), 134.6

(CH, C₅, C₆H₃), 133.6 (C_i, Ph), 132.4 (CH, C_vinyl), 131.9 (CH, C_p,

Ph), 131.5 (C, C₆H₃), 131.0 (CH, C₆, C₆H₃), 130.4 (CH, C₂, C₆H₃),

128.9 (2CH, C_m, Ph), 128.1 (2CH, C_o, Ph), 20.2 (CH₃), 19.9 (CH₃).

HRMS (ESI⁺) [m/z]: calcd for [C₁₈H₁₅NNaOS]⁺= [M + Na]⁺,

316.0767; found, 316.0771. IR (ν, cm⁻¹): 1687 (vs), 1652.

3

(C₆H₄OMe)), 7.12 (t, 1H, H₄/H₅, C₆H₄OMe, J_HH= 7.6 Hz), 6.94

(d, 1H, H₃, C₆H₄OMe, ³J_HH= 8.3 Hz), 3.92 (s, 3H, OMe). ¹³C{¹H}

NMR (CDCl₃, 75.5 MHz): δ = 194.6 (CO), 165.9 (NSC), 160.1 (C₂,

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(Z)-4-(3,4-Dichlorobenzylidene)-2-phenyl-5(4H)-thiazolone 2n.

Thiazolone 2n was obtained following the same experimental

procedure than the described for 2d. Therefore, oxazolone 1n (2.5

g, 7.9 mmol) was reacted with thioacetic acid (2 mL) and NEt₃(0.1

mL) for 18 h at 70 °C to give 2n as a yellow solid. Obtained: 1.74 g

(m, 5H, H_m, H_p, NCS-Ph; H_o, Ph), 7.20 − 7.12 (m, 3H, H_m, H_p, Ph),

4.71 (s, 1H, CH_,H-C(6,12)). ¹³C{¹H} NMR (CDCl₃, 75.5 MHz): δ =

208.0 (SC = O, C4,11), 164.9 (SC = N, C2,9), 133.6 (C_i, Ph), 132.7

(C_i, Ph), 132.3 (C_p, CH, Ph), 131.1 (CH, Ph), 129.0 (CH, Ph), 128.5

(C_o, CH, C2,9-Ph), 128.2 (C_p, CH, Ph), 128.0 (CH, Ph), 91.3 (C_q,

C5,7), 58.5 (CH, C6,12). HRMS (ESI⁺) [m/z]: calcd for

[C₃₂H₂₃N₂O₂S₂]⁺=[M + H]⁺, 531.1195, found 531.1203.

1

(66% yield). H NMR (CDCl₃, 300.13 MHz): δ = 8.49 (d, 1H, H₂,

4

C₆H₃Cl₂, J_HH= 1.9 Hz), 8.06−8.02 (m, 3H, H₅/H₆(C₆H₃Cl₂) +

2H_o(Ph)), 7.63−7.55 (m, 4H, H₅/H₆(C₆H₃Cl₂) + 2H_m+ H_p(Ph)),

7.12 (s, 1H, H_vinyl). ¹³C{¹H} NMR (CDCl₃, 75.5 MHz): δ = 194.1

(CO), 168.5 (NCS), 147.1 (=C), 145.1 (C, C₆H₃Cl₂), 135.3 (C,

C₆H₃Cl₂), 134.2 (CH, C₆, C₆H₃Cl₂), 133.7 (2C overlapped, C_i(Ph)

+ C (C₆H₃Cl₂)), 133.1 (CH, C₅, C₆H₃Cl₂), 131.9 (CH, C₂,

C₆H₃Cl₂), 130.8 (CH, C_p,Ph), 129.1 (2CH, C_o,Ph), 128.4 (2CH,

C_m,Ph), 127.8 (CH, C_vinyl). HRMS (ESI⁺) [m/z]: calcd for

[C₁₆H₉Cl₂NNaOS]⁺= [M + Na]⁺, 355.9665; found, 355.9664. IR

(ν, cm⁻¹): 1699 (vs), 1683.

2,9-Diphenyl-6,12-di-p-tolyl-3,10-dithia-1,8-diazadispiro-

[4.1.4⁷.1⁵]-dodeca-1,8-diene-4,11-dione 3b. Following the general

method, thiazolone 2b (300 mg, 1.07 mmol) was reacted in CH₂Cl₂

with blue light for 72 h to give 3b as a yellow solid. Cyclobutane 3b

was obtained as a mixture of two isomers in 90:10 molar ratio.

Obtained: 300 mg (100% yield). Only the major ε-isomer was fully

characterized. ¹H NMR (CD₂Cl₂, 300.13 MHz): δ = 7.98 (m, 2H, H_o,

Ph), 7.59 (m, 3H, H_m, H_p, Ph), 7.41 (AA′BB′ spin system, 2H, H_o,

C₆H₄), 7.02 (AA′BB′ spin system, 2H, H_m, C₆H₄), 4.65 (s, 1H, H-

C6,12), 2.21 (s, 3H, CH₃). ¹³C{¹H} NMR (CD₂Cl₂, 75.5 MHz): δ =

207.8 (SC = O, C4,11), 164.6 (SC = N, C2,9), 137.9 (C-CH₃),133.3

(C_i, Ph), 132.2 (C_p, Ph), 130.6 (2C, C_m, C₆H₄), 129.6 (C_i, C₆H₄),

128.9 (2C, C_m, Ph), 128.4 (2C, C_o, C₆H₄), 128.3 (2C, C_o, Ph), 91.2

(C_q, C5,7), 58.1 (CH, C6,12), 20.7 (CH₃). HRMS (ESI⁺) [m/z]:

calcd for [C₃₄H₂₆N₂NaO₂S₂]⁺= [M + Na]⁺, 581.1333; found,

581.1329.

(Z)-4-(3,4-Diﬂuorobenzylidene)-2-phenyl-5(4H)-thiazolone 2o.

Thiazolone 2o was obtained following the same experimental

procedure than the described for 2d. Therefore, oxazolone 1o (2.5

g, 8.8 mmol) was reacted with thioacetic acid (2 mL) and NEt₃(0.1

mL) for 18 h at 70 °C to give 2o as a yellow solid. Obtained: 0.98 g

1

(37% yield). H NMR (CDCl₃, 300.13 MHz): 8.43 (ddd, 1H, H₂,

3

4

C₆H₃F₂, J_FH= 11.7 Hz, J_FH= 8.0 Hz, J_HH= 1.9 Hz), 8.04 (d, 2H,

H_o, Ph, ³J_HH= 6.7 Hz), 7.81 (m, 1H, H₅, C₆H₃F₂), 7.63−7.54 (m, 3H,

H_p+ 2H_m, Ph), 7.28 (t, 1H, H₆, C₆H₃F₂, ³J_HH≈ ⁴J_FH= 8.5 Hz), 7.15

(s, 1H, H_vinyl). ¹⁹F NMR (CDCl₃, 282.40 MHz): δ = −131.30 (dddd,

1F, F₄, ³J_FF= 21.0 Hz, ³J_FH= 14.1 Hz, ⁴J_FH= 8.0 Hz, ⁴J_FH= 6.0 Hz),

−135.95 (ddd, 1F, F₃, ³J_FF= 21.0 Hz, ³J_FH= 14.1 Hz, ⁴J_FH= 6.0 Hz).

¹³C{¹H} NMR (CDCl₃, 75.5 MHz): δ = 194.2 (CO), 168.1 (NCS),

6,12-Bis(4-methoxyphenyl)-2,9-diphenyl-3,10-dithia-1,8-diaza-

dispiro-[4.1.4⁷.1⁵]dodeca-1,8-diene-4,11-dione 3c. Following the

general method, thiazolone 2c (300 mg, 1.01 mmol) was reacted in

CH₂Cl₂with 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

1

2

major ε-isomer was fully characterized. H NMR (CD₂Cl₂, 300.13

152.2 (dd, C, C₃/C₄, C₆₁H₃F₂, J_CF= 272 Hz, J_CF= 13.3 Hz), 150.2

2

(dd, C, C₃/C₄, C₆H₃F₂, J_CF= 272 Hz, J_CF= 13.3 Hz), 146.5 (=C),

MHz): δ = 7.99 (m, 2H, H_o, Ph), 7.60−7.58 (m, 3H, H_m, H_p, Ph),

7.52 (AA′BB′ spin system, 2H, H_o, C₆H₄), 6.75 (AA′BB′ spin system,

2H, H_m, 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),

133.2 (C, C_i, Ph), 133.0 (CH, C_p, Ph), 131.0 (dd, C, C₁, C₆H₃F₂, ³J_CF

= 4.1 Hz), 130.2 (dd, CH, C₅, C₆H₃F₂, ²J_CF= 6.6 Hz, ³J_CF= 3.4 Hz),

129.1 (2CH, C_m, Ph), 128.4 (2CH, C_o, Ph), 128.3 (CH, C_vinyl), 121.1

(d, CH, C₂, C₆H₃F₂, ²J_CF= 18.7 Hz), 117.7 (d, CH, C₆, C₆H₃F₂, ²J_CF

= 17.8 Hz). HRMS (ESI⁺) [m/z]: calcd for [C₁₆H₁₀F₂NOS]⁺= [M +

H]⁺, 302.0445; found, 302.0446.

164.6 (SC = N, C2,9), 159.4 (C-OCH₃),133.4 (C_i, Ph), 132.3 (2C,

C_o, C₆H₄), 131.9 (C_p, Ph), 128.9 (2C, C_m, Ph), 128.2 (2C, C_o, Ph),

124.7 (C_i, C₆H₄), 113.0 (2C, C_m, C₆H₄), 91.7 (C_q, 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-diazadis-

piro-[4.1.4⁷.1⁵]dodeca-1,8-diene-4,11-dione 3d. Following the gen-

eral method, thiazolone 2d (300 mg, 1.06 mmol) was reacted in

CH₂Cl₂with 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

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 CH₂Cl₂was 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

1

followed by H 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.

1

was fully characterized. H NMR (CD₂Cl₂, 300.13 MHz): δ = 7.97

(m, 2H, H_o, Ph), 7.63−7.55 (m, 2H, H_o, C₆H₄+ 2H, H_m, Ph + 1H,

H_p, Ph), 6.92 (t, 2H, H_m, C₆H₄, ³J_HH= ³J_FH= 8.73 Hz), 4.69 (s, 1H,

H-C6,12). ¹³C{¹H} NMR (CD₂Cl₂, 75.5 MHz): δ = 207.3 (SC = O,

1

C4,11), 165.5 (SC = N, C2,9), 162.5 (d, C-F, J_FC= 247 Hz), 133.2

3

(C_i, C₆H₄), 132.9 (d, 2C, C_o, C₆H_4,J_FC= 8.3 Hz), 132.5 (C_p, Ph),

129.0 (2C, C_m, Ph), 128.4 (C_i, Ph), 128.2 (2C, C_o, Ph), 114.6 (d, 2C,

2

C_m, C₆H_4,J_FC= 21.3 Hz), 90.9 (C_q, C5,7), 57.4 (CH, C6,12). ¹⁹F

4

NMR (CD₂Cl₂, 282.4 MHz) δ = −114.13 (tt, ³J_FH= 8.68 Hz, J_FH

=

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-diazadis-

piro-[4.1.4⁷.1⁵]dodeca-1,8-diene-4,11-dione 3e. Following the gen-

eral method, thiazolone 2e (300 mg, 1.00 mmol) was reacted in

CH₂Cl₂with 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, H_o, Ph), 7.59−7.52 (m, 3H, H_m+H_p, Ph), 7.47 (m, 2H, H_o,

C₆H₄), 7.14 (m, 2H, H_m, 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 (C_i, Ph), 132.5 (C_p, Ph), 132.4

(2C, C_o, C₆H₄), 130.7 (C_i, C₆H₄), 129.0 (2C, C_m, Ph), 128.3 (2C, C_o,

Ph), 128.1 (2C, C_m, C₆H₄), 90.7 (C_q, C5,7), 57.5 (CH, C6,12).

Numbering of Cyclobutanes 3a−3o, Exempliﬁed with 3a.

2,6,9,12-Tetraphenyl-3,10-dithia-1,8-diazadispiro[4.1.4⁷.1⁵]-do-

deca-1,8-diene-4,11-dione 3a. Following the general method,

thiazolone 2a (300 mg, 1.13 mmol) was reacted in CH₂Cl₂with

blue light for 24 h to give 3a as a yellow solid. Compound 3a was

recrystallized in a mixture CH₂Cl₂/n-pentane, the ε-isomer was

obtained selectively. Obtained: 245.4 mg (82% yield). ¹H NMR

(CDCl₃, 300.13 MHz): δ = 7.90 (m, 2H, H_o, NCS-Ph), 7.54−7.48

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HRMS (ESI⁺) [m/z]: calcd for [C₃₂H₂₀Cl₂N₂NaO₂S₂]⁺= [M + Na]⁺,

621.0241; found, 621.0233.

molar ratio. Obtained: 295 mg (98% yield). In this case, well-

separated peaks were observed for the two isomers, allowing their full

1

6,12-Bis(4-bromophenyl)-2,9-diphenyl-3,10-dithia-1,8-diazadis-

piro-[4.1.4⁷.1⁵]dodeca-1,8-diene-4,11-dione 3f. Following the gen-

eral method, thiazolone 2f (300 mg, 0.87 mmol) was reacted in

CH₂Cl₂with blue light for 72 h to give 3f as a yellow solid.

Cyclobutane 3f was obtained as a mixture of two isomers in 83:17

molar ratio. Obtained: 276 mg (92% yield). Only the major ε-isomer

was fully characterized. ¹H NMR (CDCl₃, 300.13 MHz): δ = 7.89 (m,

2H, H_o, Ph), 7.57−7.51 (m, 3H, H_m+ H_p, Ph), 7.41 (m, 2H, H_o,

C₆H₄), 7.30 (m, 2H, H_m, C₆H₄), 4.63 (s, 1H, H-C6,12). ¹³C{¹H}

NMR (CDCl₃, 75.5 MHz): δ = 207.3 (SC = O, C4,11), 165.8 (SC =

N, C2,9), 133.3 (C_i, Ph), 132.8 (2C, C_o, C₆H₄), 132.6 (C_p, Ph), 131.4

(C_i, C₆H₄), 131.2 (2C, C_m, C₆H₄), 129.2 (2C, C_m, Ph), 128.4 (2C,

C_o, Ph), 122.8 (Br-C_p, C₆H₄), 90.7 (C_q, C5,7), 57.7 (CH, C6,12).

Anal. Calcd for C₁₆H₁₀BrNOS: C, 55.83; H, 2.93; N, 4.07; S, 9.31.

Found: C, 56.18; H, 2.63; N, 4.08; S, 9.67.

characterization. Major isomer (ε-isomer) H NMR (CDCl₃, 500.13

3

4

MHz): δ = 8.32 (dd, 1H, H₆, C₆H₄, J_HH= 8.1 Hz, J_HH= 1.7 Hz),

7.87 (m, 2H, H_o, Ph), 7.58−7.48 (m, 3H, H_p+H_m, Ph; overlapped

3

4

with minor isomer), 7.43 (dd, 1H, H₃, C₆H₄, J_HH= 7.9 Hz, J_HH

=

1.2 Hz), 7.14 (td, 1H, H₅, C₆H₄, ³J_HH= 7.8 Hz, ⁴J_HH= 1.3 Hz), 6.97

3

4

(td, 1H, H₄, C₆H₄, J_HH= 7.8 Hz, J_HH= 1.7 Hz), 5.62 (s, 1H, H-

C6,12). ¹³C{¹H} NMR (CDCl₃, 125.76 MHz): δ = 206.2 (SC = O,

C4,11), 165.6 (SC = N, C2,9), 134.5 (C₆, C₆H₄), 133.4 (C_i,

Ph),132.5 (C₃, C₆H₄), 132.3 (C_p, Ph), 132.1 (C_i, C₆H₄), 129.5 (C₄,

C₆H₄), 128.9 (2C, C_m, Ph; overlapped with minor isomer), 128.2

(2C, C_o, Ph), 126.4 (C₅, C₆H₄), 125.9 (Br-C₂, C₆H₄), 90.5 (C_q,

C5,7), 55.4 (CH, C6,12). Minor isomer (α-isomer) ¹H NMR

(CDCl₃, 500.13 MHz): δ = 8.62 (dd, H₆, C₆H₄, ³J_HH= 8.0 Hz, ⁴J_HH

=

2.2 Hz), 7.96 (m, H_o, Ph), 7.58−7.48 (m, H_p+H_m, Ph; overlapped

with major isomer), 7.46 (dd, 1H, H₃, C₆H₄, ³J_HH= 8.0 Hz, ⁴J_HH= 1.1

Hz), 7.35 (td, 1H, H₅, C₆H₄, ³J_HH= 7.7 Hz, ⁴J_HH= 1.3 Hz), 7.09 (td,

1H, H₄, C₆H₄, ³J_HH= 7.8 Hz, ⁴J_HH= 1.7 Hz), 5.91 (s, 1H, H-C6,12).

¹³C{¹H} NMR (CDCl₃, 125.76 MHz): δ = 205.8 (SC = O, C4,11),

164.9 (SC = N, C2,9), 134.0 (C₆, C₆H₄), 133.5 (C_i, Ph),133.3 (C_i,

C₆H₄), 132.6 (C₃, C₆H₄), 132.3 (C_p, Ph), 129.5 (C₄, C₆H₄), 128.9

(2C, C_m, Ph, overlapped), 128.5 (2C, C_o, Ph), 127.0 (C₅, C₆H₄),

125.4 (Br-C₂, C₆H₄), 88.7 (C_q, C5,7), 54.9 (CH, C6,12). Anal. Calcd

for C₁₆H₁₀BrNOS: C, 55.83; H, 2.93; N, 4.07; S, 9.31. Found: C,

55.79; H, 2.91; N, 4.05; S, 9.62.

6,12-Bis(4-nitrophenyl)-2,9-diphenyl-3,10-dithia-1,8-diazadis-

piro-[4.1.4⁷.1⁵]dodeca-1,8-diene-4,11-dione 3g. Following the gen-

eral method, thiazolone 2g (300 mg, 0.94 mmol) was reacted in

CH₂Cl₂with blue light for 72 h to give 3g as a yellow solid.

Cyclobutane 3g was obtained as a single isomer (ε-isomer).

1

Obtained: 298 mg (100% yield). H NMR (CD₂Cl₂, 300.13 MHz):

δ = 8.06 (m, 2H, H_m, C₆H₄), 7.95 (m, 2H, H_o, Ph), 7.77 (m, 2H, H_o,

C₆H₄), 7.65−7.56 (m, 3H, H_p+ H_m, Ph), 4.84 (s, 1H, H-C6,12).

¹³C{¹H} NMR (CD₂Cl₂, 75.5 MHz): δ = 206.5 (SC = O, C4,11),

167.0 (SC = N, C2,9), 147.7 (C₆H₄, C-NO₂), 139.2 (C_i, C₆H₄), 132.9

(C_p, Ph), 132.7 (C_i, Ph), 131.9 (2C, C_o, C₆H₄), 129.1 (2C, C_m, Ph),

128.3 (2C, C_o, Ph), 122.9 (2C, C_m, C₆H₄), 89.7 (C_q, C5,7), 57.1

(CH, C6,12). HRMS (ESI⁺) [m/z]: calcd for [C₃₂H₂₀N₄NaO₆S₂]⁺=

[M + Na]⁺, 643.0716; found, 643.0708.

6,12-Bis(3,4-dimethylphenyl)-2,9-diphenyl-3,10-dithia-1,8-diaza-

dispiro-[4.1.4⁷.1⁵] dodeca-1,8-diene-4,11-dione 3m. Following the

general method, thiazolone 2m (300 mg, 1.02 mmol) was reacted in

CH₂Cl₂with blue light for 72 h to give 3m as a yellow solid.

Cyclobutane 3m was obtained as the mixture of two isomers in 85:15

molar ratio. Obtained: 299 mg (100% yield). Only the major ε-isomer

was fully characterized. ¹H NMR (CDCl₃, 500.13 MHz): δ = 7.93 (m,

2H, H_o, Ph), 7.55−7.49 (m, 3H, H_p+H_m, Ph), 7.34−7.28 (m, 2H, H₂

+ H₆, C₆H₃), 6.91 (d, 1H, H₅, C₆H₃, ³J_HH= 7.83 Hz), 4.61 (s, 1H, H-

C6,12), 2.11 (s, 3H, C₃-Me), 2.09 (s, 3H, C₄-Me). ¹³C{¹H} NMR

(CDCl₃, 125.76 MHz): δ = 208.0 (SC = O, C4,11), 164.2 (SC = N,

C2,9), 136.4 (C₁, C₆H₃), 135.7 (C₄, C₆H₃), 133.7 (C_i, Ph), 132.5 (C₂,

C₆H₃), 132.0 (C_p, Ph), 130.0 (C₃, C₆H₃), 129.0 (C₅, C₆H₃), 128.8

(2C, C_m, Ph), 128.6 (C₆, C₆H₃), 128.3 (2C, C_o, Ph), 91.6 (C_q, C5,7),

58.3 (CH, C6,12), 19.7 (C₃-Me), 19.4 (C₄-Me). HRMS (ESI⁺) [m/

z]: calcd for [C₃₆H₃₀N₂NaO₂S₂]⁺= [M + Na]⁺, 609.1646; found,

609.1651.

6,12-Bis(4-triﬂuoromethylphenyl)-2,9-diphenyl-3,10-dithia-1,8-

diazadispiro[4.1.4⁷.1⁵] dodeca-1,8-diene-4,11-dione 3h. Following

the general method, thiazolone 2h (300 mg, 0.90 mmol) was reacted

in CH₂Cl₂with blue light for 72 h to give a maximal conversion of 3h

of 80% as a single isomer (ε-isomer). Further irradiation of the

solution did not improved the conversion. Obtained: 241 mg. The

1

remaining thiazolone 2h proved to be diﬃcult to be separated. H

NMR (CDCl₃, 500.13 MHz): δ = 7.89 (m, 2H, H_o, Ph), 7.63 (m, 2H,

H_o, C₆H₄), 7.60−7.53 (m, 3H, H_p+ H_m, Ph), 7.44 (m, 2H, H_m,

C₆H₄), 4.75 (s, 1H, H-C6,12). ¹³C{¹H} NMR (CDCl₃, 125.7 MHz):

δ = 207.1 (SC = O, C4,11), 166.3 (SC = N, C2,9), 136.2 (C_i, C₆H₄),

133.1 (C_i, Ph), 132.8 (C_p, Ph), 131.4 (2C, C_o, C₆H₄), 130.5 (q, C-

CF₃, ²J_CF= 66.6 Hz), 129.3 (2C, C_m, Ph), 128.4 (2C, C_o, Ph), 125.0

6,12-Bis(3,4-dichlorophenyl)-2,9-diphenyl-3,10-dithia-1,8-diaza-

dispiro-[4.1.4⁷.1⁵]dodeca-1,8-diene-4,11-dione 3n. Following the

general method, thiazolone 2n (300 mg, 0.90 mmol) was reacted in

CH₂Cl₂with blue light for 72 h to give 3n as a yellow solid.

Cyclobutane 3n was obtained as the mixture of two isomers in 91:9

molar ratio. Obtained: 298 mg (100% yield). Only the major ε-isomer

3

1

(q, 2C, C_m, C₆H₄, J_CF= 3.7 Hz), 124.0 (q, CF₃, J_CF= 272.2 Hz),

90.5 (C_q, C5,7), 57.7 (CH, C6,12). ¹⁹F NMR (CDCl₃, 282 MHz) δ =

−62.72 (s, CF₃). HRMS (ESI⁺) [m/z]: calcd for

[C₃₄H₂₀F₆N₂NaO₂S₂]⁺= [M + Na]⁺, 689.0752; found, 689.0768.

6,12-Bis(2-chlorophenyl)-2,9-diphenyl-3,10-dithia-1,8-diazadis-

piro-[4.1.4⁷.1⁵]dodeca-1,8-diene-4,11-dione 3j. Following the gen-

eral method, thiazolone 2j (300 mg, 1.00 mmol) was reacted in

CH₂Cl₂with blue light for 72 h to give 3j as a yellow solid.

Cyclobutane 3j was obtained as the mixture of two isomers in 71:29

molar ratio. Obtained: 285 mg (95% yield). Only the major ε-isomer

1

was fully characterized. H NMR (CD₂Cl₂, 300.13 MHz): δ = 7.99

4

(m, 2H, H_o, Ph), 7.91 (d, 1H, H₂, C₆H_3,J_HH= 2.0 Hz), 7.66−7.56

(m, 3H, H_p+H_m, Ph), 7.42 (dd, 1H, H₆, C₆H₃, ³J_HH= 8.4 Hz, ⁴J_HH

=

3

2.1 Hz), 7.29 (d, 1H, H₅, C₆H_3,J_HH= 8.4 Hz), 4.62 (s, 1H, H-C6,12).

¹³C{¹H} NMR (CD₂Cl₂, 75.5 MHz): δ = 206.7 (SC = O, C4,11),

1

was fully characterized. H NMR (CDCl₃, 500.13 MHz): δ = 8.19

166.6 (SC = N, C2,9), 133.6 (C₂, C₆H₃), 132.8 (C_p, Ph), 132.4 (C₄,

C₆H₃), 132.2 (2C, C_i(Ph)+C₁(C₆H₃)), 131.6 (C₃, C₆H₃), 130.6 (C₆,

C₆H₃), 129.7 (C₅, C₆H₃), 129.1 (2C, C_m, Ph), 128.3 (2C, C_o, Ph),

89.9 (C_q, C5,7), 56.7 (CH, C6,12). HRMS (ESI⁺) [m/z]: calcd for

[C₃₂H₁₈Cl₄N₂NaO₂S₂]⁺= [M + Na]⁺, 688.9461; found, 688.9466.

6,12-Bis(3,4-diﬂuorophenyl)-2,9-diphenyl-3,10-dithia-1,8-diaza-

dispiro-[4.1.4⁷.1⁵] dodeca-1,8-diene-4,11-dione 3o. Following the

general method, thiazolone 2o (300 mg, 1.00 mmol) was reacted in

CH₂Cl₂with 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, H_o, Ph), 7.65 (td, 1H, H₆, C₆H₃, ³J_HH= ⁴J_FH= 9.5 Hz, ⁴J_HH= 2.2

3

4

(dd, 1H, H₆, C₆H₄, J_HH= 7.0 Hz, J_HH= 2.3 Hz), 7.87 (m, 2H, H_o,

Ph), 7.58−7.46 (m, 3H, H_m+H_p, Ph, overlapped with minor isomer),

7.24 (dd, 1H, H₃, C₆H₄, ³J_HH= 7.0 Hz, ⁴J_HH= 1.9 Hz), 7.06 (td, 2H,

H₄, H₅, C₆H₄, ³J_HH= 7.0 Hz, ⁴J_HH= 1.9 Hz), 5.54 (s, 1H, H-C6,12).

¹³C{¹H} NMR (CDCl₃, 125.7 MHz): δ = 206.3 (SC = O, C4,11),

165.6 (SC = N, C2,9), 134.9 (C₁, C₆H₄), 134.0 (C₆, C₆H₄), 133.4

(C_i, Ph), 132.3 (C_p, Ph), 130.4 (C₂, C₆H₄), 129.2, 125.8 (2C, C₄, C₅,

C₆H₄), 129.1 (C₃, C₆H₄), 128.9 (2C, C_m, Ph), 128.2 (2C, C_o, Ph),

90.4 (C_q, C5,7), 53.0 (CH, C6,12). HRMS (ESI⁺) [m/z]: calcd for

[C₃₂H₂₀Cl₂N₂NaO₂S₂]⁺= [M + Na]⁺, 621.0241; found, 621.0238.

6,12-Bis(2-bromophenyl)-2,9-diphenyl-3,10-dithia-1,8-diazadis-

piro-[4.1.4⁷.1⁵] dodeca-1,8-diene-4,11-dione 3k. Following the

general method, thiazolone 2k (300 mg, 0.87 mmol) was reacted in

CH₂Cl₂with blue light for 72 h to give 3k as a yellow solid.

Cyclobutane 3k was obtained as the mixture of two isomers in 65:35

Hz), 7.61−7.53 (m, 3H, H_p+ H_m, Ph), 7.12 (dt, 1H, H₂, C₆H₃, ³J_HF

=

4

3

4

3

8.7 Hz, J_HH= 2.2 Hz), 6.94 (q, 1H, H₅, C₆H₃, J_HF= J_HF= J_HH

9.5 Hz), 4.59 (s, 1H, H-C6,12). ¹³C{¹H} NMR (CDCl₃, 125.76

N

https://doi.org/10.1021/acs.joc.1c01458

J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

pubs.acs.org/joc

Article

MHz): δ = 206.9 (SC = O, C4,11), 166.3 (SC = N, C2,9), 150.4 (dd,

C₄-F, ¹J_CF= 253.2 Hz, ²J_CF= 14.7 Hz), 149.5 (dd, C₃-F, ¹J_CF= 249.6

Hz, J_CF= 15.3 Hz), 132.9 (C_i, Ph), 132.7 (C_p, Ph), 129.2 (2C, C_m,

C1,3), 53.0 (OMe), 21.3 (Me). HRMS (ESI⁺) [m/z]: calcd for

[C₃₅H₃₀N₂O₃S₂Na]⁺= [M + Na]⁺, 613.1590; found, 613.1588.

Methyl 1,3-Bis(4-ﬂuorophenyl)-8-oxo-6-phenyl-2-phenylthioa-

mido-7-thia-5-azaspiro[3.4]oct-5-ene-2-carboxylate 4d. Following

the general method, thiazolone 2d (100.61 mg, 0.355 mmol) and BF₃·

OEt₂(200 μL, 1.621 mmol) in dry and deoxygenated methanol (3

mL) were irradiated with blue light (456 nm) for 24 h to give

cyclobutane 4d as a yellow solid. Compound 4d was recrystallized

2

Ph), 128.9 (m, C₁, C₆H₃), 128.3 (2C, C_o, Ph), 127.1 (t, C₂, C₆H₃,

3

2

3

²J_CF= J_CF= 5.3 Hz), 120.7 (t, C₆, C₆H₃, J_CF= J_CF= 10.06 Hz),

2

3

116.6 (dd, C₅, C₆H₃, J_FC= 14.13 Hz, J_CF= 3.64 Hz), 90.5 (C_q,

C5,7), 56.8 (CH, C6,12). ¹⁹F{¹H} NMR (CDCl₃, 282.4 MHz) δ =

3

−137.37 (d, J_FF= 9.6 Hz), −137.33 (d, J_FF= 9.6 Hz). HRMS

(ESI⁺) [m/z]: calcd for [C₃₂H₁₈F₄N₂NaO₂S₂]⁺= [M + Na]⁺,

625.0644; found, 625.0640.

1

from CH₂Cl₂/n-pentane. Obtained: 34.99 mg (33% yield). H NMR

(CDCl₃, 300.13 MHz): δ = 8.54 (s, 1H, NH), 7.67 (m, 2H, H_o, NCS-

Ph), 7.64 (m, 2H, H_o, NCS-Ph), 7.57 (m, 1H, H_p, NCS-Ph), 7.54−

7.42 (m, 3H, H_p, H_m,NCS-Ph), 7.39 (t, 2H, H_m, NCS-Ph), 7.35 (m,

4H, H_o, C₆H₄F), 6.90 (t, 4H, H_m, C₆H₄F), 4.88 (s, 2H, H-C1,3), 3.88

(s, 3H, OMe). ¹³C{¹H} NMR (CDCl₃, 75.5 MHz): δ = 205.9 (SC =

O, C8), 199.0 (NC = S, C9), 169.5 (COO), 167.2 (SC = N, C6),

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·OEt₂was 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.

1

162.7 (d, C-F, C1,3-C₆H₄F, J_FC= 248.21 Hz), 140.9 (C_i, C6/C9-

Ph), 133.0 (C_p, CH, C6/C9-Ph), 132.7 (2C overlapped, C_i, C6/C9-

Ph + C_i, C1,3-C₆H₄F), 131.7 (C_p, CH, C6/C9-Ph), 131.2 (d, C_o,

3

C1,3-C₆H₄F, J_FC= 8.04 Hz), 129.4 (C_m, CH, C6/C9-Ph), 128.8

(C_m, CH, C6/C9-Ph), 128.1 (C_o, CH, C6/C9-Ph), 126.4 (C_o, CH,

2

C6/C9-Ph), 115.7 (d, C_m, C1,3-C₆H₄F, J_FC= 21.32 Hz), 90.6 (C_q,

C4), 67.7 (C_q, C2), 54.2 (CH, C1,3), 53.2 (OMe). ¹⁹F NMR

(CDCl₃, 282.40 MHz) δ = −113.18 (tt, ³J_FH= 8.8 Hz, ⁴J_FH= 3.7 Hz).

HRMS (ESI⁺) [m/z]: calcd for [C₃₃H₂₅F₂N₂O₃S₂]⁺= [M + H]⁺,

599.1269; found, 599.1262.

Methyl 1,3-Bis(4-chlorophenyl)-8-oxo-6-phenyl-2-phenylthioa-

mido-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-

Numbering of Cyclobutanes 4a−4e, Exempliﬁed with 4a.

Methyl 8-Oxo-1,3,6-triphenyl-2-phenylthioamido-7-thia-5-azas-

piro[3.4]-oct-5-ene-2-carboxylate 4a. Following the general method,

thiazolone 2a (299.6 mg, 1.13 mmol) and BF₃·OEt₂(600 μL, 4.863

mmol) were irradiated with blue light (456 nm) for 24 h in dry and

deoxygenated methanol (9 mL) to give cyclobutane 4a as a pale-

1

pentane. Obtained: 32.27 mg (31% yield). H NMR (CDCl₃, 300.13

MHz): δ = 8.53 (s, 1H, NH), 7.67 (m, 2H, H_o, NCS-Ph), 7.64 (m,

2H, H_o, NCS-Ph), 7.57 (m, 1H, H_p, NCS-Ph), 7.53−7.44 (m, 3H, H_p,

H_m,NCS-Ph), 7.40 (t, 2H, H_m, NCS-Ph), 7.29 (d, 4H, H_m, C₆H₄Cl,

2

²J_HH= 8.5 Hz), 7.18 (d, 4H, H_o, C₆H₄Cl, J_HH= 8.53 Hz), 4.86 (s,

1

yellow solid. Obtained: 185.1 mg (59% yield). H NMR (CDCl₃,

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 (C_i, C6/C9-Ph), 134.4 (C_p, C1,3-

C₆H₄Cl), 133.1 (C_p, CH, C6/C9-Ph), 131.7 (C_p, CH, C6/C9-Ph),

132.6 (C_i, C6/C9-Ph), 132.4 (C_i, C1,3-C₆H₄Cl), 130.7 (C_o, C1,3-

C₆H₄Cl), 129.4 (C_m, CH, C6/C9-Ph) 128.9 (C_m, C1,3-C₆H₄Cl),

128.9 (C_m, CH, C6/C9-Ph), 128.1 (C_o, CH, C6/C9-Ph), 126.4 (C_o,

CH, C6/C9-Ph), 90.4 (C_q, C4), 67.6 (C_q, C2), 54.3 (CH, C1,3), 52.2

300.13 MHz): δ = 8.66 (s, 1H, NH), 7.68 (d, 2H, H_o, NCS-Ph), 7.65

(m, 2H, H_o, NCS-Ph), 7.54 (t, 1H, H_p, NCS-Ph), 7.50−7.42 (m, 3H,

H_p, H_m, NCS-Ph), 7.42−7.33 (m, 6H, H_mNCS-Ph, H_oPh), 7.24−

7.15 (m, 6H, H_m, H_p, Ph), 4.94 (s, 2H, H-C1,3), 3.88 (s, 3H, OMe).

¹³C{¹H} NMR (CDCl₃, 75.5 MHz): δ = 206.3 (SC = O, C8), 199.0

(NC = S, C9), 169.7 (COO), 166.5 (SC = N, C6), 141.2 (C_i, C6-

Ph), 133.0 (C_i, C9-Ph), 132.7 (C_p, CH, C6-Ph), 132.5 (C_i, C1,3-Ph),

131.4 (C_p, CH, C9-Ph), 129.5 (C_o, CH, C1,3-Ph), 129.2 (C_p, CH,

C1,3-Ph), 128.7 (C_m, CH, C6-Ph), 128.7 (C_m, CH, C1,3-Ph), 128.2

(C_m, CH, C9-Ph), 128.2 (C_o, CH, C6-Ph), 126.5 (C_o, CH, C9-Ph),

90.8 (C_q, C4), 67.8 (C_q, C2), 55.0 (CH, C1,3), 53.1 (OMe). HRMS

(ESI⁺) [m/z]: calcd for [C₃₃H₂₇N₂O₃S₂]⁺= [M + H]⁺, 563.1463;

found, 563.1457.

(OMe). HRMS (ESI⁺) [m/z]: calcd for [C₃₃H₂₄Cl₂N₂O₃S₂Na]⁺

=

[M + Na]⁺, 653.0498; found, 653.0506.

Synthesis of Dihydrothiazoles (5 and 6) and Thiazoles (7)

through a Ring-Opening Reaction Promoted by a Base. 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 CH₂Cl₂was

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.

Methyl 8-Oxo-6-phenyl-2-phenylthioamido-1,3-di-p-tolyl-7-

thia-5-azaspiro[3.4]oct-5-ene-2-carboxylate 4b. Following the

general method, thiazolone 2b (99.84 mg, 0.358 mmol) and BF₃·

OEt₂(200 μL, 1.621 mmol) were irradiated with blue light (456 nm)

for 24 h in dry and deoxygenated methanol (3 mL) to give

cyclobutane 4b as a yellow solid. Compound 4b was recrystallized

1

from CH₂Cl₂/n-pentane. Obtained: 41.1 mg (39% yield). H NMR

(CDCl₃, 300.13 MHz): δ = 8.64 (s, 1H, NH), 7.72 (m, 2H, H_o, NCS-

Ph), 7.68 (m, 2H, H_o, NCS-Ph), 7.55 (m, 1H, H_p, NCS-Ph), 7.50−

7.43 (m, 3H, H_p, H_m,NCS-Ph), 7.37 (t, 2H, H_m, NCS-Ph),7.27 (d,

3

4H, H_m, C₆H₄Me, J_HH= 7.7 Hz), 7.00 (d, 4H, H_o, C₆H₄Me, J_HH

=

7.7 Hz), 4.87 (s, 2H, H-C1,3), 3.86 (s, 3H, OMe), 2.24 (s, 6H, Me).

¹³C{¹H} NMR (CDCl₃, 75.5 MHz): δ = 206.5 (SC = O, C8), 198.9

(NC = S, C9), 169.8 (COO), 166.1 (SC = N, C6), 141.4 (C_i, C6/C9-

Ph), 138.5 (C_i, C1,3-C₆H₄Me), 138.0 (C_p, C1,3-C₆H₄Me), 133.1 (C_i,

C6/C9-Ph), 132.6 (C_p, CH, C6/C9-Ph), 131.3 (C_p, CH, C6/C9-Ph),

129.4 (C_o,C1,3-C₆H₄), 129.4 (C_m, C1,3-C₆H₄), 129.2(C_m, CH, C6/

C9-Ph), 128.7 (C_m, CH, C6/C9-Ph), 128.2 (C_o, CH, C6/C9-Ph),

126.6 (C_o, CH, C6/C9-Ph), 91.1 (C_q, C4), 67.8 (C_q, C2), 54.9 (CH,

trans-(RR/SS) Methyl 5-(4-Methoxyphenyl)-2-phenyl-4,5-dihy-

1

drothiazole-4-carboxylate 5c. H NMR (CDCl₃, 300.13 MHz): δ

= 7.92 (d, 2H, H_o, Ph, ³J_HH= 7 Hz), 7.52−7.46 (m, 3H, H_p+H_m, Ph),

7.35 (AA′BB′ spin system, 2H, H_o, C₆H₄), 6.89 (AA′BB′ spin system,

3

2H, H_m, C₆H₄), 5.45, 5.35 (AB spin system, 2H, H₄+H₅, J_HH= 6.6

Hz), 3.83 (s, 3H, CO₂Me), 3.81 (s, 3H, OMe).). ¹³C{¹H} NMR

(CDCl₃, 75.5 MHz): δ = 170.8 (CO₂Me), 170.4 (SC = N), 159.5

(C_p-OMe, C₆H₄), 132.7, 132.2 (2C, C_i(C₆H₄+ Ph)), 131.8 (C_p, Ph),

O

https://doi.org/10.1021/acs.joc.1c01458

J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

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Article

128.7 (C_o, C₆H₄), 128.6 (C_o, Ph), 128.6 (C_m, Ph), 114.3 (C_m, C₆H₄),

86.6 (C4), 56.3 (C5), 55.3 (OMe), 52.8 (CO₂Me). HRMS (ESI⁺)

[m/z]: calcd for [C₁₈H₁₈NO₃S]⁺= [M + H]⁺, 328.1002; found,

328.1010.

mg, 0.09 mmol) for 2 h in reﬂuxing EtOH (10 mL) to give, after

chromatographic puriﬁcation using silica gel as support and n-hexane/

Et₂O (11:1) as an eluent, trans-(RR/SS)-6i as a yellow oil. Obtained:

1

140 mg (80% yield). H NMR (CDCl₃, 300.13 MHz): δ = 7.93 (dd,

2H, H_o, Ph, ³J_HH= 8.2 Hz, ⁴J_HH= 1.4 Hz), 7.51 (tt, 1H, H_p, Ph, ³J_HH

trans-(RR/SS) Methyl 5-(4-Fluorophenyl)-2-phenyl-4,5-dihydro-

1

4

3

thiazole-4-carboxylate 5d. H NMR (CDCl₃, 300.13 MHz): δ =

= 8.2 Hz, J_HH= 1.4 Hz), 7.44 (t, 2H, H_m, Ph, J_HH= 8.2 Hz), 7.39

3

4

(dd, 1H, H₆, C₆H₄OMe, ³J_HH= 7.7 Hz, ⁴J_HH= 0.7 Hz), 7.29 (td, 1H,

H₅, C₆H₄OMe, J_HH= 7.7 Hz, J_HH= 0.7 Hz), 6.96 (td, 1H, H₄,

C₆H₄OMe, J_HH= 7.7 Hz, J_HH= 0.7 Hz), 6.92 (d, 1H, H₃,

7.92 (dd, 2H, H_o, Ph, J_HH= 6.8 Hz, J_HH= 1.2 Hz), 7.50−7.44 (m,

3

4

3H, H_p+H_m, Ph), 7.41 (m, 2H, H_o, C₆H₄), 7.02 (dd, 2H, H_m,

3

4

3

4

C₆H_4,J_HH₃= 8.7 Hz, J_FH= 2.4 Hz), 5.46, 5.33 (AB spin system, 2H,

H₄+H₅, J_HH= 6.5 Hz), 3.81 (s, 3H, CO₂Me). ¹³C{¹H} NMR

(CDCl₃, 75.5 MHz): δ = 170.6 (CO₂Me), 170.2 (SC = N), 162.4 (d,

4

3

C₆H₄OMe, J_HH= 0.7 Hz), 5.81 (AB spin system, 1H, NCH, J_HH

=

5.1 Hz), 5.45 (AB spin system, 1H, SCH, ³J_HH= 5.1 Hz), 4.29 (q, 2H,

1

3

C_p-F, C₆H₄, J_CF= 248.21 Hz), 136.1 (C_i, C₆H₄), 132.5 (C_i, Ph),

OCH₂CH₃, J_HH= 7.1 Hz), 3.87 (s, 3H, OMe), 1.33 (t, 3H,

3

OCH₂CH₃, ³J_HH= 7.1 Hz). ¹³C{¹H} NMR (CDCl₃, 75.5 MHz): δ =

131.9 (C_p, Ph), 129.2 (d, C_o, C₆H₄, J_CF=8.3 Hz), 128.7 (C_o, Ph),

128.6 (C_m, Ph), 115.9 (d, C_m, C₆H₄, ²J_CF= 21.9 Hz), 86.7 (C4), 55.9

(C5), 52.9 (CO₂Me). ¹⁹F NMR (CDCl₃, 282 MHz) δ = −113.15 (tt,

170.9 (NCS), 170.4 (COO), 156.5 (C₂-OMe, C₆H₄OMe), 132.9 (C_i,

Ph), 131.6 (C_p, Ph), 129.2 (C₄/C₅, C₆H₄OMe), 128.8 (C₁,

C₆H₄OMe), 128.7 (C_o, Ph), 128.5 (C_m, Ph), 127.8 (C₆,

C₆H₄OMe), 121.0 (C₄/C₅, C₆H₄OMe), 110.7 (C₃, C₆H₄OMe),

84.4 (CH, NCH), 61.7 (OCH₂), 55.5 (CH₃, OMe), 50.4 (CH,

SCH), 14.2 (CH₃). HRMS (ESI⁺) [m/z]: calcd for

[C₁₉H₁₉NNaO₃S]⁺= [M + Na]⁺, 364.0983; found, 364.0978.

trans-(RR/SS) Ethyl 5-(3,4-Dimethylphenyl)-2-phenyl-4,5-dihy-

drothiazole-4-carboxylate 6m. 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:

CF, J_FH= 8.09 Hz, J_FH= 4.86 Hz). HRMS (ESI⁺) [m/z]: calcd for

3

4

[C₁₇H₁₃FNO₂S]⁺= [M − H]⁺, 314.0657; found, 314.0649.

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-carbox-

ylates 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).

1

129 mg (75% yield). H NMR (CDCl₃, 300.13 MHz): 7.94 (d, 2H,

3

H_o, Ph, J_HH= 6.8 Hz), 7.53−7.43 (m, 3H, H_p+ 2H_m, Ph), 7.19 (s,

1H, H₂, C₆H₃(Me)₂), 7.16, 7.12 (AB spin system, 2H, H₅+ H₆, ³J_HH

3

= 7.5 Hz, C₆H₃(Me)₂), 5.41 (AB spin system, CH, J_HH= 6.6 Hz),

3

5.36 (AB spin system, CH, J_HH= 6.6 Hz), 4.31 (q, 1H, OCH₂CH₃,

³J_HH= 7.1 Hz), 4.29 (q, 1H, OCH₂CH₃, ³J_HH= 7.1 Hz), 2.27 (s, 6H,

3

2CH₃), 1.33 (t, 3H, OCH₂CH₃, J_HH= 7.1 Hz). ¹³C{¹H} NMR

(CDCl₃, 75.5 MHz): 170.4 (NCS), 170.4 (COO), 137.8, 137.3, 136.7

(3C_q, C₁, C₃, C₄, C₆H₃(Me)₂), 132.7 (C_i, Ph), 131.8 (C_p, Ph), 130.2

(CH, C₆/C₅, C₆H₃(Me)₂), 128.7 (C_o, Ph), 128.7 (CH, C₂,

C₆H₃(Me)₂), 128.6 (C_m, 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 (OCH₂CH₃). HRMS (ESI⁺) [m/z]: calcd for [C₂₀H₂₂NO₂S]⁺=

trans-(RR/SS) Ethyl 5-(4-Methoxyphenyl)-2-phenyl-4,5-dihydro-

thiazole-4-carboxylate 6c. ¹H NMR (CDCl₃, 300.13 MHz): δ =

3

7.92 (d, 2H, H_o, Ph, J_HH= 6.9 Hz), 7.52−7.36 (m, 3H, H_p+ H_m,

Ph), 7.34 (d, 2H, H₂, H₆, C₆H₄OMe, ³J_HH= 8.7 Hz), 6.89 (d, 2H, H₃,

H₅, C₆H₄OMe, ³J = 8.7 Hz), 5.43 (AB spin system, 1H, SCH, ³J_HH

=

3

6.7 Hz), 5.32 (AB spin system, 1H, NCH, J_HH= 6.7 Hz), 4.29 (q,

[M + H]⁺, 340.1366; found, 340.1359.

3

2H, OCH₂CH₃, J_HH= 7.1 Hz), 3.82 (s, 3H, OMe), 1.32 (t, 3H,

trans-(RR/SS) Ethyl 5-(3,4-Dichlorophenyl)-2-phenyl-4,5-dihy-

drothiazole-4-carboxylate (6n) and Ethyl 5-(3,4-Dichlorophenyl)-

2-phenylthiazole-4-carboxylate (7n). Following the general proce-

dure, 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)

OCH₂CH₃, ³J_HH= 7.1 Hz). ¹³C{¹H} NMR (CDCl₃, 75.5 MHz): δ =

170.3 (CO), 170.3 (NCS), 159.5 (C₄, C₆H₄OMe), 132.8 (C_i, Ph),

132.3 (C_1,C₆H₄OMe), 131.7 (CH, C_p, Ph), 128.7 (CH, C_o, Ph),

128.7 (2CH, C₂+C₆, C₆H₄OMe), 128.6 (2CH, C_m, Ph), 114.3 (2CH,

C₃+C₅, C₆H₄OMe), 86.8 (CH, NC4H), 61.8 (CH₂), 56.5 (CH,

SC5H), 55.3 (OMe), 14.2 (CH₃). HRMS (ESI⁺) [m/z]: calcd for

[C₁₉H₁₉NNaO₃S]⁺= [M + Na]⁺, 364.0983; found, 364.0983.

trans-(RR/SS) Ethyl 5-(4-Triﬂuoromethylphenyl)-2-phenyl-4,5-

dihydrothiazole-4-carboxylate 6h. Following the general procedure,

thiazolone 2h (192 mg, 0.58 mmol) was reacted with NaOEt (10 mg,

0.09 mmol) for 2 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)-6h as a waxy orange solid.

Obtained: 166.5 mg (76% yield). ¹H NMR (CDCl₃, 300.13 MHz): δ

Ethyl 5-(3,4-Dichlorophenyl)-2-phenyl-4,5-dihydrothiazole-4-

1

carboxylate (6n). H NMR (CDCl₃, 300.13 MHz): δ = 7.93 (d,

3

2H, H_o, Ph, ³J_HH= 7.0 Hz), 7.55−7.43 (m, 5H, H_p+H_m(Ph) + H₅+

= 7.93 (d, 2H, H_o, Ph, J_HH= 7.0 Hz), 7.65−7.46 (m, 7H, H_p+H_m,

Ph; H_2,6+H_3,5, C₆H₄CF₃), 5.49 (AB spin system, 1H, SCH, ³J_HH= 6.3

H₆(C₆H₃Cl₂)), 7.28 (s, 1H, H₂, C₆H₃Cl₂), 5.39 (AB spin system, 1H,

3

Hz), 5.36 (AB spin system, 1H, NCH, J_HH= 6.3 Hz), 4.31 (q, 2H,

SCH, J_HH= 6.3 Hz), 5.31 (AB spin system, 1H, NCH, J_HH= 6.3

3

OCH₂CH₃, J_HH= 7.1 Hz), 3.87 (s, 3H, OMe), 1.33 (t, 3H,

Hz), 4.31 (q, 1H, OCH₂CH₃, J_HH= 7.1 Hz), 4.29 (q, 1H,

OCH₂CH₃, ³J_HH= 7.1 Hz). ¹³C{¹H} NMR (CDCl₃, 75.5 MHz): δ =

3

OCH₂CH₃, J_HH= 7.1 Hz), 1.34 (t, 3H, OCH₂CH₃, J_HH= 7.1 Hz).

¹³C{¹H} NMR (CDCl₃, 75.5 MHz): 173.6 (NCS), 169.9 (CO),

140.5 (C₁, C₆H₃Cl₂), 132.2 (CH, C₅/C₆, C₆H₃Cl₂), 131.0 (CH, C₅/

C₆, C₆H₃Cl₂), 129.6 (C_p, Ph), 128.8 (C_o, Ph), 128.7 (C_m, Ph), 126.6

(CH, C₂, C₆H₃Cl₂), 86.1 (NCH), 62.2 (OCH₂), 55.4 (SCH), 14.1

(CH₃). Signals due to C₃and C₄(C₆H₃Cl₂) and to the C_ipso(Ph)

were not observed. HRMS (ESI⁺) [m/z]: calcd for

[C₁₈H₁₆Cl₂NO₂S]⁺= [M + H]⁺, 380.0279; found, 380.0289.

170.3 (NCS), 169.8 (CO), 144.4 (C₁, C₆H₄CF₃), 132.3 (C_i, Ph),

2

132.1 (C_p, Ph), 130.4 (q, C₄-CF₃, J_CF= 40 Hz), 128.8 (C_o, Ph),

128.7 (C_m, Ph), 128.0 (C₂+C₆, C₆H₄CF₃), 126.0 (C₃+C₅, C₆H₄CF₃,

³J_CF= 3.8 Hz), 123.5 (CF₃, ¹J_CF= 272 Hz), 86.4 (CH, NC4H), 62.1

(CH₂), 55.9 (CH, SC5H), 14.1 (CH₃). ¹⁹F NMR (CDCl₃, 282.4

MHz): δ = −62.70 (s, CF₃). HRMS (ESI⁺) [m/z]: calcd for

[C₁₉H₁₅F₃NO₂S]⁺= [M − H]⁺, 378.0781; found, 378.0797.

trans-(RR/SS) Ethyl 5-(2-Methoxyphenyl)-2-phenyl-4,5-dihydro-

thiazole-4-carboxylate 6i. Following the general procedure,

thiazolone 2i (150 mg, 0.51 mmol) was reacted with NaOEt (10

Ethyl 5-(3,4-Dichlorophenyl)-2-phenylthiazole-4-carboxylate

1

(7n). H NMR (CDCl₃, 300.13 MHz): δ = 8.01 (m, 2H, H_o, Ph),

4

7.67 (d, 1H, H₂, C₆H₃Cl₂, J_HH= 2 Hz), 7.54−7.48 (m, 4H, H_p+H_m

P

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J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

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3

(Ph) + H₅(C₆H₃Cl₂)), 7.40 (dd, 1H, H₆, C₆H₃Cl₂, J_HH= 8.3 Hz,

⁴J_HH= 2.1 Hz), 4.35 (q, 2H, OCH₂CH₃, ³J_HH= 7.1 Hz), 1.31 (t, 3H,

OCH₂CH₃, ³J_HH= 7.1 Hz). ¹³C{¹H} NMR (CDCl₃, 75.5 MHz): δ =

(d, NCH, ³J_HH= 6.6 Hz, trans-isomer), 5.23 (d, SCH, ³J_HH= 8.9 Hz,

cis-isomer), 3.82 (s, OMe, trans-isomer), 3.40 (s, OMe, cis-isomer),

2.34 (s, Me), 2.30 (s, Me). ¹³C{¹H} NMR (CDCl₃, 75.5 MHz): δ =

170.9 (SC = N), 170.8 (SC = N), 170.6 (COO), 169.5 (COO), 138.3

(C_p, C₆H₄Me), 138.2 (C_p, C₆H₄Me), 137.4 (C_i, C₆H₄Me), 135.2 (C_i,

C₆H₄Me), 132.7 (C_i, NCS-Ph, both isomers, overlapped), 132.0,

131.9 (2C_p, NCS-Ph, both isomers), 129.8, 129.2, 128.9, 128.8, 128.7

(2C overlapped), 127.8, 127.5 (C_o, C_m, NCS-Ph + C_o, C_m, C₆H₄Me),

86.6 (NCH, trans-isomer), 84.0 (NCH, cis-isomer), 56.6 (SCH, trans-

isomer), 55.8 (SCH, cis-isomer), 53.0 (OMe, trans-isomer), 52.0

(OMe, cis-isomer), 21.3 (Me), 21.2 (Me). HRMS (ESI⁺) [m/z]:

calcd for [C₁₈H₁₇NO₂SNa]⁺= [M + Na]⁺, 334.0872; found,

334.0877.

166.8 (NCS), 161.9 (CO), 142.6, 142.2 (S-C=C-N), 133.5 (C,

C₆H₃Cl₂), 132.5, 132.5 (2C, C-Cl, C₆H₃Cl₂), 131.8 (CH, C₂,

C₆H₃Cl₂), 130.9 (C_p, Ph), 130.5 (C_i, Ph), 130.1 (CH, C₅, C₆H₃Cl₂),

129.3 (CH, C₆, C₆H₃Cl₂), 129.0 (C_m, Ph), 126.9 (C_o, Ph), 61.5

(CH₂), 14.1 (CH₃). HRMS (ESI⁺) [m/z]: calcd for

[C₁₈H₁₃Cl₂NNaO₂S]⁺= [M + Na]⁺, 399.9942; found, 399.9945.

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%

(cis/trans)-Methyl 2-Phenyl-5-(4-methoxyphenyl)-4,5-dihydro-

thiazole-4-carboxylate 5c. Following the general procedure,

thiazolone 2c (100.3 mg, 0.34 mmol) was reacted with BF₃·OEt₂

(200 μL, 1.621 mmol) for 18 h in reﬂuxing MeOH (5 mL) to give

(cis/trans)-5c (1:1.1 molar ratio) as a yellow oil. In this case, further

chromatographic puriﬁcation was necessary to separate 5c from

starting thiazolone 2c. The chromatographic puriﬁcation was started

using silica as support and n-hexane/Et₂O (9:1) as an eluent. Using

these conditions, only the thiazolone 2c was eluted. Then the solvent

was changed, and 2-propanol was employed. Using these conditions,

the dihydrothiazole 5c was obtained as a yellow oil after solvent

evaporation. Obtained: 42.7 mg (38% yield). ¹H NMR (CDCl₃,

300.13 MHz): δ = 7.96 (m, H_o, NCS-Ph), 7.90 (m, H_o, NCS-Ph),

7.54−7.41 (m, H_m, H_p, NCS-Ph, both isomers), 7.32 (d, H_o,

1

yield). H NMR (CDCl₃, 300.13 MHz): δ = 8.33 (AB spin system,

2H, H₃+H₅, C₆H₄NO₂), 8.02 (m, 2H, H_o, Ph), 7.74 (AB spin system,

2H, H₂+H₆, C₆H₄NO₂), 7.51 (m, 3H, H_p+H_m, 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 (C_i, Ph), 131.2 (C_p, Ph), 131.0 (C₂/

C₆, C₆H₄NO₂), 129.2 (C_m, Ph), 126.7 (C_o, 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 per-

formed 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)

3

C₆H₄OMe, J_HH= 8.1 Hz), 7.19 (d, H_o, C₆H₄OMe, J_HH= 8.1 Hz),

6.87−6.78 (d, H_m, C₆H₄OMe, ³J_HH= 8.0 Hz), 5.53 (d, NCH, ³J_HH

=

3

8.9 Hz, cis-isomer), 5.43 (d, SCH, J_HH= 6.5 Hz, trans-isomer), 5.34

(d, NCH, ³J_HH= 6.6 Hz, trans-isomer), 5.23 (d, SCH, ³J_HH= 8.9 Hz,

cis-isomer), 3.81 (s, OMe, trans-isomer), 3.79, 3.76 (2s, OMe, both

isomers), 3.41 (s, OMe, cis-isomer). ¹³C{¹H} NMR (CDCl₃, 75.5

MHz): δ = 171.0 (SC = N), 170.9 (SC = N), 170.8 (COO), 169.4

(COO), 159.5 (C_p, C₆H₄OMe), 159.5 (C_p, C₆H₄OMe), 132.6 (C_i,

NCS-Ph, both isomers), 132.2 (C_i, C₆H₄OMe), 132.0 (C_p, NCS-Ph),

131.9 (C_p, NCS-Ph), 130.0 (C_i, C₆H₄OMe), 129.1 (C_o, C₆H₄OMe),

128.8 (C_o, C₆H₄OMe), 128.7, 128.6 (C_o, C_m, NCS-Ph, both isomers),

114.4 (C_m, C₆H₄OMe), 113.7 (C_m, C₆H₄OMe), 86.3 (NCH, trans-

isomer), 83.8 (NCH, cis-isomer), 56.2 (SCH, trans-isomer), 55.4

(SCH, cis-isomer), 55.3 (OMe), 55.2 (OMe), 52.9 (COOMe).), 52.0

(COOMe). HRMS (ESI⁺) [m/z]: calcd for [C₁₈H₁₇NO₃SNa]⁺= [M

+ Na]⁺, 350.0821; found, 350.0823.

(cis/trans)-Methyl 5-(4-Fluorophenyl)-2-phenyl-4,5-dihydrothia-

zole-4-carboxylate 5d. 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, H_o, NCS-Ph), 7.93 (m, H_o, NCS-Ph), 7.55−7.43

(m, H_p+H_m, NCS-Ph, both isomers), 7.40 (m, H_o, C₆H₄F), 7.28 (m,

H_o, C₆H₄F), 7.06 (tt, H_m, C₆H₄F, ³J_HF= 8.6 Hz, ⁴J_HH= 2.1 Hz), 6.97

(cis/trans)-Methyl 2,5-Diphenyl-4,5-dihydrothiazole-4-carboxy-

late 5a. H NMR (CDCl₃, 300.13 MHz): δ = 7.96 (m, H_o, NCS-

Ph), 7.90 (m, H_o, NCS-Ph), 7.52−7.21 (m, H_m+H_p, NCS-Ph,

H_o+H_m,+H_p, Ph, both isomers), 5.55 (d, NCH, J_HH= 9.0 Hz, cis-

1

3

isomer), 5.45 (d, SCH, J_HH= 6.5 Hz, trans-isomer), 5.37 (d, NCH,

³J_HH= 6.5 Hz, trans-isomer), 5.23 (d, SCH, ³J_HH= 9.0 Hz, cis-isomer),

3.79 (s, OMe, trans-isomer), 3.34 (s, OMe, cis-isomer). ¹³C{¹H}

NMR (CDCl₃, 75.5 MHz): δ = 170.7 (SC = N), 170.7 (COO), 170.5

(SC = N), 169.2 (COO), 140.3, 138.1 (C_i, Ph, both isomers), 132.5

(C_i, NCS-Ph, overlapped), 132.0, 131.9 (2C_p, NCS-Ph, both

isomers), 129.0, 128.8, 128.7, 128.6, 128.6, 128.4, 127.9, 127.5 (C_o,

C_m, NCS-Ph; C_o, C_m, Ph; both isomers), 128.4, 128.2 (C_p, Ph both

isomers), 86.5 (NCH, trans-isomer), 83.9 (NCH, cis-isomer), 56.6

(SCH, trans-isomer), 55.8 (SCH, cis-isomer), 52.9 (OMe, trans-

isomer), 51.9 (OMe, cis-isomer). HRMS (ESI⁺) [m/z]: calcd for

[C₁₇H₁₆NO₂S]⁺= [M + H]⁺, 298.0896; found, 298.0893.

(tt, H_m, C₆H₄F, ³J_HF= 8.7 Hz, ⁴J_HH= 2.0 Hz), 5.57 (d, NCH, ³J_HH

=

3

8.9 Hz, cis-isomer), 5.47 (d, SCH, J_HH= 6.5 Hz, trans-isomer), 5.35

(d, NCH, ³J_HH= 6.5 Hz, trans-isomer), 5.26 (d, SCH, ³J_HH= 8.9 Hz,

cis-isomer), 3.85 (s, OMe, trans-isomer). 3.43 (s, OMe, cis-isomer).

(cis/trans)-Methyl 2-Phenyl-5-(p-tolyl)-4,5-dihydrothiazole-4-

carboxylate 5b. Following the general procedure, thiazolone 2b

(101.4 mg, 0.363 mmol) was reacted with BF₃·OEt₂(200 μL, 1.621

mmol) for 18 h in reﬂuxing MeOH (5 mL) to give (cis/trans)-5b

¹³C{¹H} NMR (CDCl₃, 75.5 MHz): δ = 170.7 (COO), 170.5 (SC =

1

N), 170.4 (SC = N), 169.3 (COO), 162.6 (d, C_p-F, C₆H₄F, J_CF

=

1

(1:1.1 molar ratio) as a yellow oil. Obtained: 80 mg (71% yield). H

247.4 Hz), 162.6 (d, C_p-F, C₆H₄F, J_CF= 247.7 Hz), 136.2 (d, C_i,

4

NMR (CDCl₃, 300.13 MHz): δ = 7.98 (m, H_o, NCS-Ph), 7.91 (m,

H_o, NCS-Ph), 7.55−7.41 (m, H_m, H_p, NCS-Ph, both isomers), 7.30

C₆H₄F, J_CF= 3.3 Hz), 134.1 (d, C_i, C₆H₄F, J_CF= 3.5 Hz), 132.6

(2C_i, NCS-Ph, both isomers ovelapped), 132.1, 132.0 (2C_p, NCS-Ph,

3

(d, H_o, C₆H₄Me, J_HH= 8.1 Hz), 7.16 (d, H_o, H_m, C₆H₄Me, J_HH

=

both isomers), 129.8(d, C_o, C₆H₄F, J_CF= 8.3 Hz), 129.3(d, C_o,

7.8 Hz), 7.06 (d, H_m, C₆H₄Me, ³J_HH₃= 8.1 Hz), 5.55 (d, NCH, ³J_HH

C₆H₄F, J_CF= 8.3 Hz), 128.9, 128.8, 128.7, 128.7 (C_o, C_m, NCS-Ph,

3

2

8.9 Hz, cis-isomer), 5.44 (d, SCH, J_HH= 6.6 Hz, trans-isomer), 5.36

both isomers), 116.0 (d, C_m, C₆H₄F, J_CF= 21.7 Hz), 115.4 (d, C_m,

Q

https://doi.org/10.1021/acs.joc.1c01458

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2

C₆H₄F, J_CF= 21.7 Hz), 86.8 (NCH, trans-isomer), 84.1 (NCH, cis-

(cis/trans)-Methyl 5-(2-Bromophenyl)-2-phenyl-4,5-dihydrothia-

zole-4-carboxylate 5k. Following the general procedure, thiazolone

2k (100.4 mg, 0.293 mmol) was reacted with BF₃·OEt₂(200 μL,

1.621 mmol) for 18 h in reﬂuxing MeOH (5 mL) to give (cis/trans)-

5k (1:0.8 molar ratio) as a yellow oil. In this case, further

chromatographic puriﬁcation was necessary to separate 5k from

starting thiazolone 2k. The chromatographic puriﬁcation was started

using silica as support and n-hexane/Et₂O (9:1) as an eluent. Using

these conditions, only the thiazolone 2k was eluted. Then the solvent

was changed, and 2-propanol was employed. Using these conditions,

the dihydrothiazole 5k was obtained as a yellow oil after solvent

evaporation. Obtained: 30 mg (27% yield). ¹H NMR (CDCl₃, 300.13

MHz): δ = 7.93 (m, H_o, NCS-Ph), 7.90 (m, H_o, NCS-Ph), 7.59 (dd,

H₃, C₆H₄Br, ³J_HH= 8.0 Hz, ⁴J_HH= 1.2 Hz), 7.55−7.52 (m, H_p, NCS-

Ph, both isomers, H₃, C₆H₄Br), 7.49−7.42 (m, H_m, NCS-Ph, H₆,

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

3

4

3

4

(tt, J_FH= 8.6 Hz, J_FH= 3.3 Hz), −113.23 (tt, J_FH= 8.5 Hz, J_FH

=

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-dihydrothia-

zole-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

3

4

C₆H₄Br; both isomers), 7.30 (td, H₅, C₆H₄Br, J_HH= 7.5 Hz, J_HH

=

3

4

1.2 Hz), 7.22 (td, H₅, C₆H₄Br, J_HH= 7.4 Hz, J_HH= 1.2 Hz), 7.15

(td, H₄, C₆H₄Br, ³J_HH= 8.0 Hz, ⁴J_HH= 1.7 Hz), 7.10 (td, H₄, C₆H₄Br,

³J_HH= 7.4 Hz, J_HH= 1.7 Hz), 5.91 (d, SCH, J_HH= 9.1 Hz, cis-

4

3

isomer), 5.89 (d, SCH, J_HH= 4.5 Hz, trans-isomer), 5.66 (d, NCH,

³J_HH= 9.1 Hz, cis-isomer), 5.47 (d, NCH, J_HH= 4.5 Hz, trans-

3

1

mg, 16% yield). H NMR (CDCl₃, 300.13 MHz): δ = 7.95 (m, H_o,

NCS-Ph), 7.89 (m, H_o, NCS-Ph), 7.55−7.40 (m, H_m, H_p, NCS-Ph

both isomers), 7.33 (d, H_o, H_m,C₆H₄Cl), 7.22 (d, H_o, H_m, C₆H₄Cl),

5.56 (d, NCH, J_HH= 8.9 Hz, cis-isomer), 5.42 (d, SCH, J_HH= 6.4

Hz, trans-isomer), 5.32 (d, NCH, J_HH= 6.4 Hz, trans-isomer), 5.21

isomer), 3.83 (s, OMe, trans-isomer), 3.40 (s, OMe, cis-isomer).

¹³C{¹H} NMR (CDCl₃, 75.5 MHz): δ = 170.9 (SC = N), 170.8 (SC

3

= N), 170.4 (COO), 169.2 (COO), 140.2 (C₁, C₆H₄Br), 137.9 (C₁,

C₆H₄Br), 133.2 (C₃, C₆H₄Br), 132.8 (C₃, C₆H₄Br), 132.7 (C_i, NCS-

Ph), 132.6 (C_i, NCS-Ph), 132.1 (C_p, NCS-Ph), 132.1 (C_p, NCS-Ph),

129.8 (C_4,C₆H₄Br), 129.7 (C_4,C₆H₄Br), 129.2, 128.9 (C_o, C_m, NCS-

Ph, both isomers), 128.8 (C₆, C₆H₄Br), 128.8 (C₆, C₆H₄Br), 128.5

(C₅, C₆H₄Br), 128.1 (C₅, C₆H₄Br), 123.8 (C₂-Br, C₆H₄Br), 123.7

(C₂-Br, C₆H₄Br), 85.1 (NCH, trans-isomer), 82.6 (NCH, cis-isomer),

55.3 (SCH, trans-isomer), 54.5 (SCH, cis-isomer), 53.1 (OMe, trans-

isomer), 52.0 (OMe, cis-isomer). HRMS (ESI⁺) [m/z]: calcd for

[C₁₇H₁₄BrNO₂SNa]⁺= [M + Na]⁺, 397.9821; found, 397.9808.

(cis/trans)-Methyl 5-(3,4-Dimethylphenyl)-2-phenyl-4,5-dihydro-

thiazole-4-carboxylate 5m. Following the general procedure,

thiazolone 2m (101.73 mg, 0.347 mmol) was reacted with BF₃·

OEt₂(200 μL, 1.621 mmol) for 18 h in reﬂuxing MeOH (5 mL) to

give (cis/trans)-5m (1:0.8 molar ratio) as a yellow oil. Obtained: 95

3

(d, SCH, ³J_HH= 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 (C_i,

C₆H₄Cl), 136.9 (C_i, C₆H₄Cl), 134.4 (C_p, C₆H₄Cl), 134.2 (C_p,

C₆H₄Cl), 132.5 (C_i, NCS-Ph, both isomers), 132.2(C_p, NCS-Ph),

132.1 (C_p, NCS-Ph), 129.4, 128.9 (C_o, C_mC₆H₄Cl), 129.3, 129.0

(C_o, C_mC₆H₄Cl), 128.8, 128.8 (C_o, C_m, NCS-Ph), 128.8, 128.8 (C_o,

C_m, 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.

(cis/trans)-Methyl 5-(4-Triﬂuoromethylphenyl)-2-phenyl-4,5-di-

hydrothiazole-4-carboxylate 5h. Following the general procedure,

thiazolone 2h (103.60 mg, 0.311 mmol) was reacted with BF₃·OEt₂

(200 μL, 1.621 mmol) for 18 h in reﬂuxing MeOH (5 mL) to give

(cis/trans)-5h (1:2.1 molar ratio) as a yellow oil. In this case, further

chromatographic puriﬁcation was necessary to separate 5h from

starting thiazolone 2h. The chromatographic puriﬁcation was started

using silica as support and n-hexane/Et₂O (9:1) as an eluant. Using

these conditions, only the thiazolone 2h was eluted. Then the solvent

was changed, and 2-propanol was employed. Using these conditions,

the dihydrothiazole 5h was obtained as a yellow oil after solvent

evaporation. Obtained: 38 mg (34% yield). ¹H NMR (CDCl₃, 300.13

MHz): δ = 7.95 (m, H_o, NCS-Ph), 7.91 (m, H_o, NCS-Ph), 7.61 (d,

1

mg (84% yield). H NMR (CDCl₃, 300.13 MHz): δ = 7.98 (m, 2H,

NCS-Ph), 7.92 (m, H_o, NCS-Ph), 7.55−7.41 (m, H_m, H_p, NCS-Ph,

both isomers), 7.18 (s, H₂, C₆H₃(Me)₂), 7.14−7.12 (m, H₅, H₆,

C₆H₃(Me)₂), 7.03 (s, H₂, C₆H₃(Me)₂), 7.02 (m, H₅, H₆,

3

C₆H₃(Me)₂), 5.55 (d, NCH, J_HH= 9.0 Hz, cis-isomer), 5.43 (d,

3

SCH, J_HH= 6.7 Hz, trans-isomer), 5.38 (d, NCH, J_HH= 6.7 Hz,

trans-isomer), 5.22 (d, SCH, ³J_HH= 9.0 Hz, cis-isomer), 3.82 (s, OMe,

trans-isomer), 3.42 (s, OMe, cis-isomer), 2.25 (s, Me, trans-isomer).

2.20 (s, Me, cis-isomer). ¹³C{¹H} NMR (CDCl₃, 75.5 MHz): δ =

170.9 (COO + SC = N, overlapped), 170.6 (SC = N), 169.4 (COO),

137.7 (C_i, C₆H₃(Me)₂), 137.4, 136.9, 136.8, 136.7 (C_q, C₃, C₄,

C₆H₃(Me)₂both isomers), 135.5 (C_i, C₆H₃(Me)₂), 132.7 (C_i, NCS-

Ph), 132.7 (C_i, NCS-Ph), 131.9 (C_p, NCS-Ph), 131.9 (C_p, NCS-Ph),

130.3, 129.7, 125.3, 124.3 (C₅, C₆, C₆H₃(Me)₂, both isomers), 129.0,

128.9, 128.6 (C_o, C_m, NCS-Ph, both isomers), 128.7 (C₂,

C₆H₃(Me)₂), 128.7 (C₂, C₆H₃(Me)₂), 86.5 (NCH, trans-isomer),

83.8 (NCH, cis-isomer), 56.5 (SCH, trans-isomer), 55.7 (SCH, cis-

isomer), 52.9 (OMe, trans-isomer), 51.9 (OMe, cis-isomer), 19.9,

19.8, 19.5, 19.5 (Me). HRMS (ESI⁺) [m/z]: calcd for

[C₁₉H₁₉NO₂SNa]⁺= [M + Na]⁺, 348.1029; found, 348.1032.

3

H_m, C₆H₄-CF_3,J_HH= 8.1 Hz, both isomers), 7.54−7.50 (m, H_p,

NCS-Ph both isomers, H_o, C₆H₄-CF₃), 7.40−7.42 (m, H_m, NCS-Ph,

3

both isomers), 7.39 (d, 2H, H_o, C₆H₄-CF_3,J_HH= 8.2 Hz), 5.60 (d,

NCH, ³J_HH= 8.9 Hz, cis-isomer), 5.49 (d, SCH, ³J_HH= 6.4 Hz, trans-

3

isomer), 5.35 (d, NCH, J_HH= 6.4 Hz, trans-isomer), 5.28 (d, SCH,

³J_HH= 8.9 Hz, cis-isomer), 3.83 (s, OMe, trans-isomer), 3.39 (s, OMe,

cis-isomer). ¹³C{¹H} NMR (CDCl₃, 75.5 MHz): δ = 173.4 (SC = N),

172.4 (SC = N), 170.1 (COO), 168.5 (COO), 144.0 (C_i, C₆H₄-CF₃),

141.5 (C_i, C₆H₄-CF₃), 133.2 (C_p, NCS-Ph), 132.9 (C_p, NCS-Ph),

2

131.5 (C_i, NCS-Ph), 131.3 (C_i, NCS-Ph), 130.9 (q, C_p-CF₃, J_CF

=

ASSOCIATED CONTENT

* Supporting Information

The Supporting Information is available free of charge at

https://pubs.acs.org/doi/10.1021/acs.joc.1c01458.

2

■

32.9 Hz), 130.8 (q, C_p-CF₃, J_CF= 32.9 Hz), 129.1, 129.1 (C_o, C_m,

NCS-Ph), 129.0, 129.0 (C_o, C_m, NCS-Ph), 128.6 (C_o, C₆H₄-CF₃),

128.1 (C_o, C₆H₄-CF₃), 126.3 (q, C_m, C₆H₄-CF₃, ³J_CF= 3.7 Hz), 125.7

(q, C_m, C₆H₄-CF₃, J_CF= 3.7 Hz), 122.2 (q, CF₃, J_CF= 272 Hz),

122.1 (q, CF₃, J_CF= 272 Hz), 85.1 (NCH, trans-isomer), 82.2

(NCH, cis-isomer), 55.8 (SCH, trans-isomer), 55.0 (SCH, cis-isomer),

53.4 (OMe, trans-isomer), 52.3 (OMe, cis-isomer). ¹⁹F NMR(CDCl₃,

282.40 MHz): δ = −62.76 (s), −62.70 (s). HRMS (ESI⁺) [m/z]:

calcd for [C₁₈H₁₄F₃NO₂SNa]⁺= [M + Na]⁺, 388.0590; found,

388.0584.

sı

3

1

Copies of ¹H and ¹³C NMR spectra for all new

compounds, copies of the absorption (UV−vis) spectra

of thiazolones 2 and selected cyclobutanes 3, NMR

spectra, and UV−vis spectra of 2b in the presence of BF₃

(PDF)

R

https://doi.org/10.1021/acs.joc.1c01458

J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

pubs.acs.org/joc

Article

Accession Codes

REFERENCES

■

CCDC 1912941−1912942, 1958992−1958993, and 1999650

contain the supplementary crystallographic data for this paper.

These data can be obtained free of charge via www.ccdc.ca-

m.ac.uk/data_request/cif, or by emailing data_request@ccdc.

cam.ac.uk, or by contacting The Cambridge Crystallographic

Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax:

+44 1223 336033.

(1) Poplata, S.; Tröster, A.; Zou, Y.-Q.; Bach, T. Recent Advances in

the Synthesis of Cyclobutanes by Olefin [2 + 2] Photocycloaddition

Reactions. Chem. Rev. 2016, 116, 9748−9815.

(2) Dembitsky, V. M. Naturally Occurring Bioactive Cyclobutane-

Containing (CBC) Alkaloids in Fungi, Fungal Endophytes, and

Plants. Phytomedicine 2014, 21, 1559−1581.

(3) Marson, C. M. New and Unusual Scaffolds in Medicinal

Chemistry. Chem. Soc. Rev. 2011, 40, 5514.

(4) Kim, J.; Bogdan, D. M.; Elmes, M. W.; Awwa, M.; Yan, S.; Che,

J.; Lee, G.; Deutsch, D. G.; Rizzo, R. C.; Kaczocha, M.; Ojima, I.

Incarvillateine Produces Antinociceptive and Motor Suppressive

Effects via Adenosine Receptor Activation. PLoS One 2019, 14,

No. e0218619.

(5) Tsai, I.-L.; Lee, F.-P.; Wu, C.-C.; Duh, C.-Y.; Ishikawa, T.; Chen,

J.-J.; Chen, Y.-C.; Seki, H.; Chen, I.-S. New Cytotoxic Cyclobutanoid

Amides, a New Furanoid Lignan and Anti-Platelet Aggregation

Constituents from Piper arborescens . Planta Med. 2005, 71, 535−542.

(6) Fan, Y.-Y.; Zhang, H.; Zhou, Y.; Liu, H.-B.; Tang, W.; Zhou, B.;

Zuo, J.-P.; Yue, J.-M. Phainanoids A-F, A New Class of Potent

Immunosuppressive Triterpenoids with an Unprecedented Carbon

Skeleton from Phyllanthus Hainanensis . J. Am. Chem. Soc. 2015, 137,

138−141.

(7) Li, J.; Gao, K.; Bian, M.; Ding, H. Recent advances in the total

synthesis of cyclobutane-containing natural products. Org. Chem.

Front. 2020, 7, 136−154.

(8) Reissig, H. U.; Zimmer, R. Thrilling Strain! Donor-Acceptor-

Substituted Cyclobutanes for the Synthesis of (Hetero)Cyclic

Compounds. Angew. Angew. Chem., Int. Ed. 2015, 54, 5009−5011.

(9) Hu, J. -L.; Wang, L. J.; Xu, H.; Xie, Z. W.; Tang, Y. Highly

Diastereoselective and Enantioselective Formal [4 + 3] Cycloaddition

of Donor-Acceptor Cyclobutanes with Nitrones. Org. Lett. 2015, 17,

2680−2683.

(10) Perrotta, D.; Racine, S.; Vuilleumier, J.; de Nanteuil, F.; Waser,

J. [4 + 2]-Annulations of Aminocyclo-butanes. Org. Lett. 2015, 17,

1030−1033.

(11) Stevens, A. C.; Palmer, C.; Pagenkopf, B. L. The Formal [4 + 3]

Cycloaddition between Donor- Acceptor Cyclobutanes and Nitrones.

Org. Lett. 2011, 13, 1528−1531.

(12) Hu, J.-L.; Feng, L.-W.; Wang, L.; Xie, Z.; Tang, Y.; Li, X.

Enantioselective Construction of Cyclobutanes: A New and Concise

Approach to the Total Synthesis of (+)-Piperarborenine B. J. Am.

Chem. Soc. 2016, 138, 13151−13154.

(13) Gutekunst, W. R.; Baran, P. S. Applications of C-H

Functionalization Logic to Cyclobutane Synthesis. J. Org. Chem.

2014, 79, 2430−2452.

(14) Parella, R.; Gopalakrishnan, B.; Babu, S. A. Direct Bis-Arylation

of Cyclobutanecarboxamide via Double C-H Activation: An Auxiliary-

Aided Diastereoselective Pd-Catalyzed Access to Trisubstituted

Cyclobutane Scaffolds Having Three Contiguous Stereocenters and

an All-cis Stereochemistry. J. Org. Chem. 2013, 78, 11911−11934.

(15) Panish, R. A.; Chintala, S. R.; Fox, J. M. A Mixed-Ligand Chiral

Rhodium(II) Catalyst Enables the Enantioselective Total Synthesis of

Piperarborenine B. Angew. Chem., Int. Ed. 2016, 55, 4983−4987.

(16) Cohen, M. D.; Schmidt, G. M. J.; Sonntag, F. I. 384.

Topochemistry. Part II. The photochemistry of trans-cinnamic acids.

J. Chem. Soc. 1964, 2000−2013.

(17) Schmidt, G. M. J. Photodimerization in the solid state. Pure

Appl. Chem. 1971, 27, 647−678.

(18) Ramamurthy, V.; Venkatesan, K. Photochemical reactions of

organic crystals. Chem. Rev. 1987, 87, 433−481.

(19) Alonso, R.; Bach, T. A Chiral Thioxanthone as an Organo-

catalyst for Enantioselective [2 + 2] Photocycloaddition Reactions

Induced by Visible Light. Angew. Chem., Int. Ed. 2014, 53, 4368−

4371.

(20) Huo, H.; Shen, X.; Wang, C.; Zhang, L.; Röse, P.; Chen, L.-A.;

Harms, K.; Marsch, M.; Hilt, G.; Meggers, E. Asymmetric photoredox

transition-metal catalysis activated by visible light. Nature 2014, 515,

100−103.

AUTHOR INFORMATION

■

Corresponding Author

Esteban P. Urriolabeitia − Instituto de Síntesis Química y

Catálisis Homogénea, ISQCH (CSIC-Universidad de

Zaragoza), 50009 Zaragoza, Spain; orcid.org/0000-

0001-9779-5820; Email: esteban@unizar.es

Authors

Sonia Sierra − Instituto de Síntesis Química y Catálisis

Homogénea, ISQCH (CSIC-Universidad de Zaragoza),

50009 Zaragoza, Spain

David Dalmau − Instituto de Síntesis Química y Catálisis

Homogénea, ISQCH (CSIC-Universidad de Zaragoza),

50009 Zaragoza, Spain

Sheila Higuera − Instituto de Síntesis Química y Catálisis

Homogénea, ISQCH (CSIC-Universidad de Zaragoza),

50009 Zaragoza, Spain

Darío Cortés − Instituto de Síntesis Química y Catálisis

Homogénea, ISQCH (CSIC-Universidad de Zaragoza),

50009 Zaragoza, Spain

Olga Crespo − Instituto de Síntesis Química y Catálisis

Homogénea, ISQCH (CSIC-Universidad de Zaragoza),

50009 Zaragoza, Spain; orcid.org/0000-0001-9522-

5840

Ana I. Jimenez − Instituto de Síntesis Química y Catálisis

Homogénea, ISQCH (CSIC-Universidad de Zaragoza),

50009 Zaragoza, Spain

Alexandra Pop − Supramolecular Organic and

Organometallic Chemistry Centre, Department of Chemistry,

Faculty of Chemistry and Chemical Engineering, Babes-

Bolyai University, 400028 Cluj−Napoca, Romania

Cristian Silvestru − Supramolecular Organic and

Organometallic Chemistry Centre, Department of Chemistry,

Faculty of Chemistry and Chemical Engineering, Babes-

Bolyai University, 400028 Cluj−Napoca, Romania;

orcid.org/0000-0001-5124-9525

̧

Complete contact information is available at:

https://pubs.acs.org/10.1021/acs.joc.1c01458

Notes

The authors declare no competing ﬁnancial interest.

ACKNOWLEDGMENTS

■

We thank the Gobierno de Aragón-FSE (Spain, research

groups Aminoácidos y Péptidos E19_20R and Química de Oro

y Plata E07_20R) and the Spanish Government (Agencia

Estatal de Investigación: projects nos. PID2019-106394GB-I00

and PID2019-104379RB-C21) for funding. A.P. is grateful for

ﬁnancial support of the Romanian Ministry of Education and

Research through the grant PN-III-P1-1.1-MC-2018-2580. S.S.

thanks gobierno de Aragón-FSE for a Ph.D. fellowship.

S

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The Journal of Organic Chemistry

pubs.acs.org/joc

Article

(21) Du, J.; Skubi, K. L.; Schultz, D. M.; Yoon, T. P. A Dual

Catalysis Approach to Enantioselective [2 + 2] Photocycloadditions

Using Visible Light. Science 2014, 344, 392−396.

(38) Liu, Q.; Li, N.; Yuan, Y.; Lu, H.; Wu, X.; Zhou, C.; He, M.; Su,

H.; Zhang, M.; Wang, J.; Wang, B.; Wang, Y.; Ma, D.; Ye, Y.; Weiss,

H. C.; Gesing, E. R. F.; Liao, J.; Wang, M. W. Cyclobutane Derivatives

As Novel Nonpeptidic Small Molecule Agonists of Glucagon-Like

Peptide-1 Receptor. J. Med. Chem. 2012, 55, 250−267.

(39) Chen, D.; Liao, J.; Li, N.; Zhou, C.; Liu, Q.; Wang, G.; Zhang,

R.; Zhang, S.; Lin, L.; Chen, K.; Xie, X.; Nan, F.; Young, A. A.; Wang,

M.-W. A nonpeptidic agonist of glucagon-like peptide 1 receptors

with efficacy in diabetic db/db mice. Proc. Natl. Acad. Sci. U. S. A.

2007, 104, 943−948.

(40) de Graaf, C.; Donnelly, D.; Wootten, D.; Lau, J.; Sexton, P. M.;

Miller, L. J.; Ahn, J.-M.; Liao, J.; Fletcher, M. M.; Yang, D.; Brown, A.

J. H.; Zhou, C.; Deng, J.; Wang, M. W. Glucagon-Like Peptide-1 and

Its Class B G Protein-Coupled Receptors: A Long March to

Therapeutic Successes. Pharmacol. Rev. 2016, 68, 954−1013.

(41) García-Montero, A.; Rodríguez, A. M.; Juan, A.; Velders, A. H.;

Denisi, A.; Jiménez-Osés, G.; Gómez-Bengoa, E.; Cativiela, C.;

Gómez, M. V.; Urriolabeitia, E. P. Metal-Free [2 + 2]-Photo-

cycloaddition of (Z )-4-Aryliden-5(4 H )-Oxazolones as Straightforward

Synthesis of 1,3-Diaminotruxillic Acid Precursors: Synthetic Scope

and Mechanistic Studies. ACS Sustainable Chem. Eng. 2017, 5, 8370−

8381.

(42) Roiban, D.; Serrano, E.; Soler, T.; Grosu, I.; Cativiela, C.;

Urriolabeitia, E. P. Unexpected [2 + 2] C-C bond coupling due to

photocycloaddition on orthopalladated (Z )-2-aryl-4-arylidene-5(4 H )-

oxazolones. Chem. Commun. 2009, 4681−4683.

(43) Serrano, E.; Juan, A.; García-Montero, A.; Soler, T.; Jiménez-

Marquez, F.; Cativiela, C.; Gómez, M. V.; Urriolabeitia, E. P.

Stereoselective Synthesis of 1,3-Diaminotruxillic Acid Derivatives: An

Advantageous Combination of C-H-ortho -Palladation and On-Flow

[2 + 2]-Photocycloaddition in Microreactors. Chem. - Eur. J. 2016, 22,

144−152.

(22) Brimioulle, R.; Lenhart, D.; Maturi, M. M.; Bach, T.

Enantioselective Catalysis of Photochemical Reactions. Angew.

Chem., Int. Ed. 2015, 54, 3872−3890.

(23) Brimioulle, R.; Bauer, A.; Bach, T. Enantioselective Lewis Acid

Catalysis in Intramolecular [2 + 2] Photocycloaddition Reactions: A

Mechanistic Comparison between Representative Coumarin and

Enone Substrates. J. Am. Chem. Soc. 2015, 137, 5170−5176.

(24) Coote, S. C.; Pothig, A.; Bach, T. Enantioselective Template-

Directed [2 + 2] Photocycloadditions of Isoquinolones: Scope,

Mechanism and Synthetic Applications. Chem. - Eur. J. 2015, 21,

6906−6912.

(25) Zhao, G.; Yang, C.; Sun, H.; Lin, R.; Xia, W. (+)-Camphor

Derivative Induced Asymmetric [2 + 2] Photoaddition Reaction. Org.

Lett. 2012, 14, 776−779.

(26) Tröster, A.; Alonso, R.; Bauer, A.; Bach, T. Enantioselective

Intermolecular [2 + 2] Photocycloaddition. Reactions of 2(1 H )-

Quinolones Induced by Visible Light Irradiation. J. Am. Chem. Soc.

2016, 138, 7808−7811.

(27) Poplata, S.; Bach, T. Enantioselective Intermolecular [2 + 2]

Photocycloaddition Reaction of Cyclic Enones and its Application in

a Synthesis of (-)-Grandisol. J. Am. Chem. Soc. 2018, 140, 3228−3231.

(28) Leverenz, M.; Merten, C.; Dreuw, A.; Bach, T. Lewis Acid

Catalyzed Enantioselective Photochemical Rearrangements on the

Singlet Potential Energy Surface. J. Am. Chem. Soc. 2019, 141, 20053−

20057.

(29) Nikitas, N. F.; Gkizis, P. L.; Kokotos, C. G. Thioxanthone: a

powerful photocatalyst for organic reactions. Org. Biomol. Chem. 2021,

19, 5237−5253.

(30) Sicignano, M.; Rodríguez, R. I.; Alemán, J. Recent Visible Light

and Metal Free Strategies in [2 + 2] and [4 + 2] Photocycloadditions.

Eur. J. Org. Chem. 2021, 2021, 3303−3321.

(44) Carrera, C.; Denisi, A.; Cativiela, C.; Urriolabeitia, E. P.

Functionalized 1,3-Diaminotruxillic Acids by Pd-Mediated C-H

Activation and [2 + 2]-Photocycloaddition of 5(4 H )-Oxazolones.

Eur. J. Inorg. Chem. 2019, 2019, 3481−3489.

(45) Urriolabeitia, E. P.; Sánchez, P.; Pop, A.; Silvestru, C.; Laga, E.;

Jiménez, A. I.; Cativiela, C. Synthesis of esters of diaminotruxillic bis-

amino acids by Pd-mediated photocycloaddition of analogs of the

Kaede protein chromophore. Beilstein J. Org. Chem. 2020, 16, 1111−

1123.

(31) Marra, I. F. S.; de Almeida, A. M.; Silva, L. P.; de Castro, P. P.;

Correa, C. C.; Amarante, G. W. Stereoselective Intermolecular [2 + 2]

̈

Cycloadditions of Erlenmeyer-Plochl Azlactones Using Visible Light

Photoredox Catalysis. J. Org. Chem. 2018, 83, 15144−15154.

(32) Berger, W. T.; Ralph, B. P.; Kaczocha, M.; Sun, J.; Balius, T. E.;

Rizzo, R. C.; Haj-Dahmane, S.; Ojima, I.; Deutsch, D. G. Targeting

Fatty Acid Binding Protein (FABP) Anandamide Transporters - A

Novel Strategy for Development of Anti-Inflammatory and Anti-

Nociceptive Drugs. PLoS One 2012, 7, No. e50968.

(46) Filler, R.; Rao, Y. S. New Aspects of the Chemistry of 5-

Thiazolones. J. Org. Chem. 1962, 27, 3730−3731.

(33) Yan, S.; Elmes, M. W.; Tong, S.; Hu, K.; Awwa, M.; Teng, G. Y.

H.; Jing, Y.; Freitag, M.; Gan, Q.; Clement, T.; Wei, L.; Sweeney, J.

M.; Joseph, O. M.; Che, J.; Carbonetti, G. S.; Wang, L.; Bogdan, D.

M.; Falcone, J.; Smietalo, N.; Zhou, Y.; Ralph, B.; Hsu, H.-C.; Li, H.;

Rizzo, R. C.; Deutsch, D. G.; Kaczocha, M.; Ojima, I. SAR studies on

truxillic acid mono esters as a new class of antinociceptive agents

targeting fatty acid binding proteins. Eur. J. Med. Chem. 2018, 154,

233−252.

(34) Kaczocha, M.; Rebecchi, M. J.; Ralph, B. P.; Teng, Y.-H. G.;

Berger, W. T.; Galbavy, W.; Elmes, M. W.; Glaser, S. T.; Wang, L.;

Rizzo, R. C.; Deutsch, D. G.; Ojima, I. Inhibition of Fatty Acid

Binding Proteins Elevates Brain Anandamide Levels and Produces

Analgesia. PLoS One 2014, 9, No. e94200.

(47) Barrett, G. C. The Chemistry of 1,3-Thiazolinone ⇌ Hydroxy-

1,3-Thiazole Systems. Tetrahedron 1980, 36, 2023−2058.

(48) Feng, M.; Tang, B.; Liang, S. H.; Jiang, X. Sulfur-Containing

Scaffolds in Drugs: Synthesis and Application in Medicinal Chemistry.

Curr. Top. Med. Chem. 2016, 16, 1200−1216.

(49) Scott, K. A.; Njardarson, J. T. Analysis of US FDA-Approved

Drugs Containing Sulfur Atoms. Top. Curr. Chem. 2018, 376, 5−34.

(50) Clarke, H. T.; Johnson, J. R.; Robinson, R. In Chemistry of

Penicillin; Clarke, H. T., Ed.; Princeton University Press: New Jersey,

2016.

(51) Thiazole and Its Derivatives: Part 1. In The Chemistry of

Heterocyclic Compounds; Metzger, J. V., Ed.; John Wiley & Sons: New

York, 1979; Vol. 34.

(35) Ojima, I.; Deutsch, D.; Kaczocha, M.; Berger, W. T.; Rizzo, R.;

Balius, T. E. Alpha and gamma-truxillic and derivatives and

pharmaceutical compositions thereof, US Patent US 10213406 B2,

US Patent Application Publication US2019/0201365 A1.

(36) Kim, J.; Bogdan, D. M.; Elmes, M. W.; Awwa, M.; Yan, S.; Che,

J.; Lee, G.; Deutsch, D. G.; Rizzo, R. C.; Kaczocha, M.; Ojima, I.

Incarvillateine produces antinociceptive and motor suppressive effects

via adenosine receptor activation. PLoS One 2019, 14, No. e0218619.

(37) Priebe, A.; Hunke, M.; Tonello, R.; Sonawane, Y.; Berta, T.;

Natarajan, A.; Bhuvanesh, N.; Pattabiraman, M.; Chandra, S. Ferulic

acid dimer as a non-opioid therapeutic for acute pain. J. Pain Res.

2018, 11, 1075−1085.

(52) El-Naggar, A. M.; Eissa, I. H.; Belal, A.; El-Sayed, A. A. Design,

Eco-Friendly Synthesis, Molecular Modeling and Anticancer Evalua-

tion of Thiazol-5(4 H )-Ones as Potential Tubulin Polymerization

Inhibitors Targeting the Colchicine Binding Site. RSC Adv. 2020, 10,

2791−2811.

(53) Lewis, F. D.; Howard, D. K.; Oxman, J. D. Lewis Acid Catalysis

of Coumarin Photodimerization. J. Am. Chem. Soc. 1983, 105, 3344−

3345.

(54) Lewis, F. D.; Oxman, J. D.; Gibson, L. L.; Hampsch, H. L.;

Quillen, S. L. Lewis Acid Catalysis of Photochemical Reactions. 4.

Selective Isomerization of Cinnamic Esters. J. Am. Chem. Soc. 1986,

108, 3005−3015.

T

https://doi.org/10.1021/acs.joc.1c01458

J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

pubs.acs.org/joc

Article

(55) Lewis, F. D.; Quillen, S. L.; Hale, P. D.; Oxman, J. D. Lewis

Acid Catalysis of Photochemical Reactions. 7. Photodimerization and

Cross-Cycloaddition of Cinnamic Esters. J. Am. Chem. Soc. 1988, 110,

1261−1267.

(56) Lewis, F. D.; Barancyk, S. V. Lewis Acid Catalysis of

Photochemical Reactions. 8. Photodimerization and Cross-Cyclo-

addition of Coumarin. J. Am. Chem. Soc. 1989, 111, 8653−8661.

(57) Lewis, F. D.; Elbert, J. E.; Upthagrove, A. L.; Hale, P. D. Lewis

Acid Catalysis of Photochemical Reactions. 9. Structure and

Photoisomerization of (E )- and (Z )-Cinnamamides and Their

Lewis Acid Complexes. J. Org. Chem. 1991, 56, 553−561.

(58) Lewis, F. D.; Oxman, J. D.; Huffman, J. C. Photodimerization

of Lewis Acid Complexes of Cinnamate Esters in Solution and the

Solid State. J. Am. Chem. Soc. 1984, 106, 466−468.

(59) Brimioulle, R.; Guo, H.; Bach, T. Enantioselective Intra-

molecular [2 + 2] Photocycloaddition Reactions of 4-Substituted

Coumarins Catalyzed by a Chiral Lewis Acid. Chem. - Eur. J. 2012, 18,

7552−7560.

(60) Yoon, T. P. Photochemical Stereocontrol Using Tandem

Photoredox-Chiral Lewis Acid Catalysis. Acc. Chem. Res. 2016, 49,

2307−2315.

phosphate-catalyzed Erlenmeyer reaction. Tetrahedron Lett. 2010,

51, 625.

(76) Lee, S.-H.; Yoon, J.; Nakamura, K.; Lee, Y.-S. Efficient

Syntheses and Ring-Opening Reactions of trans - and cis -Oxazoline-5-

carboxylates. Org. Lett. 2000, 2, 1243−1246.

(77) Nitz, T. J.; Lindsey, J.; Stammer, C. H. An excursion into the

synthesis of potential angiotensin converting enzyme inhibitors. J. Org.

Chem. 1982, 47, 4029−4032.

(78) Gaumont, A.-C.; Gulea, M.; Levillain, J. Overview of the

chemistry of 2-thiazolines. Chem. Rev. 2009, 109, 1371−1401.

(79) Alsharif, Z. A.; Alam, M. A. Modular synthesis of thiazoline and

thiazole derivatives by using a cascade protocol. RSC Adv. 2017, 7,

32647−32651.

(80) Mollo, M. C.; Bisceglia, J. A.; Kilimciler, N. B.; Mancinelli, M.;

Orelli, L. R. Microwave-Assisted Synthesis of 2-Substituted 2-

Thiazolines and 5,6-Dihydro-4H-1,3-thiazines. Synthesis 2020, 52,

1666−1679.

(81) You, S.-L.; Razavi, H.; Kelly, J. W. A Biomimetic Synthesis of

Thiazolines Using Hexaphenyloxo-diphosphonium Trifluorometha-

nesulfonate. Angew. Chem., Int. Ed. 2003, 42, 83−85.

(82) Liu, J.; Wen, Y.; He, F.; Gao, L.; Gao, L.; Wang, J.; Wang, X.;

Zhang, Y.; Hu, L. Ruthenium(II)-catalyzed C-O/C-S cyclization for

the synthesis of 5-membered O-containing and S-containing hetero-

cycles. Org. Chem. Front. 2019, 6, 846−851.

(61) Daub, M. E.; Jung, H.; Lee, B. J.; Won, J.; Baik, M.-H.; Yoon, T.

P. Enantioselective [2 + 2] Cycloadditions of Cinnamate Esters:

Generalizing Lewis Acid Catalysis of Triplet Energy Transfer. J. Am.

Chem. Soc. 2019, 141, 9543−9547.

(83) Bengtsson, C.; Nelander, H.; Almqvist, F. Asymmetric

Synthesis of 2,4,5-Trisubstituted Δ²-Thiazolines. Chem. - Eur. J.

2013, 19, 9916−9922.

(62) Poplata, S.; Bauer, A.; Storch, G.; Bach, T. Intramolecular [2 +

2] Photocycloaddition of Cyclic Enones: Selectivity Control by Lewis

Acids and Mechanistic Implications. Chem. - Eur. J. 2019, 25, 8135−

8148.

(84) Dunbar, K. L.; Scharf, D. H.; Litomska, A.; Hertweck, C.

Enzymatic Carbon-Sulfur Bond Formation in Natural Product

Biosynthesis. Chem. Rev. 2017, 117, 5521−5577.

̈

(63) Behringer, H.; Stein, H. W. Uber die Umsetzung von

̈

Azlactonen mit Thiosauren. (Vorlaufige Mitteilung). Chem. Ber.

1949, 82, 209−212.

(85) Vorbru

̈

ggen, H.; Krolikiewicz, K. A simple synthesis of Δ²-

oxazines, Δ²-oxazines, Δ²-thiazolines and 2-substituted benzoxazoles.

Tetrahedron 1993, 49, 9353−9372.

(64) Behringer, H.; Jepson, J. B. Notiz zur Reaktion von Azlactonen

̈

mit Thiosauren. Chem. Ber. 1952, 85, 138.

(86) Charette, A. B.; Chua, P. Mild Method for the Synthesis of

Thiazolines from Secondary and Tertiary Amides. J. Org. Chem. 1998,

63, 908−909.

(65) Coutouli-Argyropoulou, E.; Thessalonikeos, E. Reactions of

nitrile oxides and nitrile imines with 4-arylidene-2-phenyl-5(4 H )-

thiazolones. Liebigs Ann. Chem. 1990, 1990, 1097−1100.

(87) Lemercier, B. C.; Pierce, J. G. Synthesis of Thiazolines by

Copper Catalyzed Aminobromination of Thiohydroximic Acids. Org.

Lett. 2014, 16, 2074−2076.

(66) Chandrasekhar, S.; Srimannarayana, M. The Erlenmeyer

synthesis with a thioazlactone. ARKIVOC 2009, 12, 290−295.

̈

(67) Stoermer, R.; Bachér, F. Uber die Konfiguration der Truxin-

(88) Liu, B.; Davis, R.; Joshi, B.; Reynolds, D. W. Phosphine-

Catalyzed Annulation of Thioamides and 2-Alkynoates: A New

Synthesis of Thiazolines. J. Org. Chem. 2002, 67, 4595−4598.

(89) Raman, P.; Razavi, H.; Kelly, J. W. Titanium(IV)-Mediated

Tandem Deprotection-Cyclodehydration of Protected Cysteine N -

Amides: Biomimetic Syntheses of Thiazoline- and Thiazole-

Containing Heterocycles. Org. Lett. 2000, 2, 3289−3292.

(90) Cook, A. H.; Harris, G.; Heilbron, S. Studies in the azole series.

Part V. A synthesis of β -phenylcysteine. J. Chem. Soc. 1948, 1060−

1065.

(91) Doyle, F. P.; Holland, D. O.; Mamalis, P.; Norman, A.

Thiazolidines. Part V. Synthesis of β -alkylcysteines. J. Chem. Soc.

1958, 4605−4614.

(92) Holland, D. O.; Mamalis, P. Thiazolidines. Part IV. Further

Reactions of 2-Methylthio-5-phenylthiazoline-4-carboxylic Acid. J.

Chem. Soc. 1958, 4601−4605.

(93) Kim, T.-S.; Lee, Y.-J.; Jeong, B.-S.; Park, H.; Jew, S.

Enantioselective Synthesis of (R )- and (S )-)-Alkylcysteines via

Phase-Transfer Catalytic Alkylation. J. Org. Chem. 2006, 71, 8276−

8278.

(94) Vanderhaeghe, H.; Thomis, J. Preparation and Properties of 5-

Phenylphenoxymethylpenicillin. J. Med. Chem. 1975, 18, 486−490.

(95) Adams, A.; De Kimpe, N. Chemistry of 2-Acetyl-1-pyrroline, 6-

Acetyl-1,2,3,4-tetrahydropyridine, 2-Acetyl-2-thiazoline, and 5-Acetyl-

2,3-dihydro-4H-thiazine: Extraordinary Maillard Flavor Compounds.

Chem. Rev. 2006, 106, 2299−2319.

(96) McKeever, B.; Pattenden, G. Total synthesis of trunkamide A, a

novel thiazoline-based prenylated cyclopeptide metabolite from

Lissoclinum sp. Tetrahedron 2003, 59, 2713−2727.

̈

und Truxillsauren (VI). Ber. Dtsch. Chem. Ges. B 1922, 55, 1860−

1882.

̈

(68) Stoermer, R.; Bachér, F. Zur Stereoisomerie der Truxillsauren

̈

und uber die Auffindung der letzten Saure dieser Gruppe (VIII). Ber.

Dtsch. Chem. Ges. B 1924, 57, 15−23.

(69) Runcevski, T.; Blanco-Lomas, M.; Marazzi, M.; Cejuela, M.;

Sampedro, D.; Dinnebier, R. E. Following a Photoinduced

Reconstructive Phase Transformation and its Influence on the Crystal

Integrity: Powder Diffraction and Theoretical Study. Angew. Chem.,

Int. Ed. 2014, 53, 6738−6742.

(70) Liang, S.; Liu, S.-X.; Jin, H.-Z.; Shan, L.; Yu, S.-C.; Shen, Y.-H.;

Li, H.-L.; Wu, Q.-Y.; Zhang, W.-D.; Sun, Q.-Y. Two novel

innovanoside dimers from Daphne aurantiaca and a concise total

synthesis of diinnovanoside A. Chem. Commun. 2013, 49, 6968−6970.

(71) Wheeler, K. A.; Wiseman, J. D.; Grove, R. C. Enantiocontrolled

solid-state photodimerizations via a chiral sulfonamide-cinnamic acid.

CrystEngComm 2011, 13, 3134−3137.

(72) Grove, R. C.; Malehorn, S. H.; Breen, M. E.; Wheeler, K. A. A

photoreactive crystalline quasiracemate. Chem. Commun. 2010, 46,

7322−7324.

(73) Gnanaguru, K.; Ramasubbu, N.; Venkatesan, K.; Ramamurthy,

V. A study on the photochemical dimerization of coumarins in the

solid state. J. Org. Chem. 1985, 50, 2337−2346.

(74) Allen, F. H.; Kennard, O.; Watson, D. G.; Brammer, L.; Orpen,

A. G.; Taylor, R. Tables of bond lengths determined by X-ray and

neutron diffraction. Part 1. Bond lengths in organic compounds. J.

Chem. Soc., Perkin Trans. 2 1987, S1−S19.

(75) Cleary, T.; Brice, J.; Kennedy, N.; Chávez, F. One-pot process

to Z -α -benzoylamino-acrylic acid methyl esters via potassium

U

https://doi.org/10.1021/acs.joc.1c01458

J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

pubs.acs.org/joc

Article

(97) Schmidt, E. W.; Nelson, J. T.; Rasko, D. A.; Sudek, S.; Eisen, J.

A.; Haygood, M. G.; Ravel, J. Patellamide A and C biosynthesis by a

microcin-like pathway in Prochloron didemni , the cyanobacterial

symbiont of Lissoclinum patella. Proc. Natl. Acad. Sci. U. S. A. 2005,

102, 7315−7320.

(98) Miura, C.; Kiyama, M.; Iwano, S.; Ito, K.; Obata, R.; Hirano,

T.; Maki, S.; Niwa, H. Synthesis and luminescence properties of

biphenyl-type firefly luciferin analogs with a new, near-infrared light-

emitting bioluminophore. Tetrahedron 2013, 69, 9726−9734.

(99) Wipf, P.; Reeves, J. T.; Day, B. W. Chemistry and Biology of

Curacin A. Curr. Pharm. Des. 2004, 10, 1417−1437.

(100) Havrylyuk, D.; Roman, O.; Lesyk, R. Synthetic approaches,

structure activity relationship and biological applications for

pharmacologically attractive pyrazole-pyrazoline-thiazolidine-based

hybrids. Eur. J. Med. Chem. 2016, 113, 145−166.

(101) Tan, F.; Shi, B.; Li, J.; Wu, W.; Zhang, J. Design and Synthesis

of New 2-Aryl-4,5-dihydro-thiazole Analogues: In Vitro Antibacterial

Activities and Preliminary Mechanism of Action. Molecules 2015, 20,

20118−20130.

(102) Jin, Z. Muscarine, imidazole, oxazole and thiazole alkaloids.

Nat. Prod. Rep. 2009, 26, 382−445.

(103) Huang, Y.; Gan, H.; Li, S.; Xu, J.; Wu, X.; Yao, H. Oxidation

of 4-carboxylate thiazolines to 4-carboxylate thiazoles by molecular

oxygen. Tetrahedron Lett. 2010, 51, 1751−1753.

̈

(104) Plöchl, J. Ueber Phenylglycidasaure (Phenyloxacrylsaure). Ber.

Dtsch. Chem. Ges. 1883, 16, 2815; Ber. Dtsch. Chem. Ges. 1884, 17,

1616.

̈

(105) Erlenmeyer, E. Ueber die Condensation der Hippursaure mit

̈

Phtalsaureanhydrid und mit Benzaldehyd. Justus Liebigs Annalen der

Chemie 1893, 275, 1.

(106) Carter, H. E. Azlactones , Chapter 5 of the book series. Organic

Reactions 2004, 3, 198.

(107) Filler, R. Adv. Heterocycl. Chem.; Katrizky, A. R., Ed.; Academic

Press: New York, 1954; Chapter 4, p 75.

(108) Rao, Y. S.; Filler, R. Geometric Isomers of 2-Aryl(Aralkyl)-4-

arylidene(alkylidene)-5(4 H )-oxazolones. Synthesis 1975, 12, 749.

(109) Rao, Y. S.; Filler, R. Oxazolones. In Chem. Heterocycl. Compd.;

Turchi, I. J., Ed.; John Wiley & Sons: New York, 1986; Vol. 45, pp

361.

(110) Cativiela, C.; Díaz de Villegas, M. D.; Meléndez, E. On the

synthesis of geometric isomers of 2-methyl (or phenyl)-4-[α -

arylethylidene]-5(4 H )-oxazolones. J. Heterocycl. Chem. 1985, 22,

1655.

(111) Bautista, F. M.; Campelo, J. M.; García, A.; Luna, D.; Marinas,

J. M.; Romero, A. A. Study on dry-media microwave azalactone

synthesis on different supported KF catalysts: influence of textural and

acid-base properties of supports. J. Chem. Soc., Perkin Trans 2 2002,

227.

(112) Roiban, G-D.; Soler, T.; Contel, M.; Grosu, I.; Cativiela, C.;

Urriolabeitia, E. P. Reactivity of Unsaturated 5(4 H )-Oxazolones with

Hg(II) Acetate: Synthesis of Methyl N -Benzoylamino-3-arylacrylates.

Synth. Commun. 2012, 42, 195−203.

(113) Mesaik, M. A.; Rahat, S.; Khan, K. M.; Ullah, Z.; Choudary,

M. I.; Murad, S.; Ismail, Z.; Rahman, A. U.; Ahmad, A. Synthesis and

immunomodulatory properties of selected oxazolone derivatives.

Bioorg. Med. Chem. 2004, 12, 2049.

(114) CrysAlis RED, version 1.171.27p8; Oxford Diﬀraction Ltd.:

Oxford, 2005.

(115) SAINT Software Reference Manuals, Version 5.0; Bruker

Analytical Xray Systems, Inc.: Madison, WI, 2000.

(116) Sheldrick, G. M. SADABS, Program for absorption and other

̈

corrections; Gottingen University, 1996.

(117) Sheldrick, G. M. SHELXS-86, Phase annealing in SHELX -90:

direct methods for larger structures. Acta Crystallogr., Sect. A: Found.

Crystallogr. 1990, A46, 467.

(118) Sheldrick, G. M. SHELXL-97, A short history of SHELX. Acta

Crystallogr., Sect. A: Found. Crystallogr. 2008, A64, 112.

V

https://doi.org/10.1021/acs.joc.1c01458

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Reactivity of (Z)-4-Aryliden-5(4 H)-thiazolones: [2 + 2]-Photocycloaddition, Ring-Opening Reactions, and Influence of the Lewis Acid BF3

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