Tandem Thioacylation-Intramolecular Hydrosulfenylation of Propargyl Amines – Rapid Access to 2-Aminothiazolidines

DOI: 10.1002/ejoc.201801505

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Heterocyclic Synthesis*

Tandem Thioacylation-Intramolecular Hydrosulfenylation of

Propargyl Amines – Rapid Access to 2-Aminothiazolidines

Ravi P. Singh,^[a]Delphine Gout,^[b]and Carl J. Lovely*^[a]

Abstract: An investigation directed towards the preparation of ing chromatographic purification and is in fact facilitated by

α-substituted propargyl thioureas from the corresponding silica gel. Control reactions and monitoring the progress of the

propargylamine resulted in a tandem thioacylation/anti-hydro- reaction by NMR spectroscopy clearly indicate that the cycliza-

sulfenylation and the formation of the corresponding thiazol- tion is relatively slow until either purification or the introduction

idine in excellent (46–98 %) yields rather than the anticipated of silica gel results in cyclization. Subsequently, it was found

thiourea. Initial interpretation of this outcome was formulated that even the parent system afforded the thiazolidine when the

in terms of the highly substituted nature of the α-carbon of reaction was conducted on silica gel. Overall, the reaction is

these amines resulting in steric acceleration, however, even sim- tolerant of a variety of substitution patterns, internal and termi-

ple propargylamines engage in this chemistry. In light of these nal alkynes and isothiocyanates providing rapid access to 2-

observations, it was determined subsequently that the forma- aminothiazolidines.

tion of the thiourea is quite rapid, but cyclization occurred dur-

Introduction

tailed in this paper, accessing the requisite propargyl-substi-

tuted thioureas via the standard methods we had already em-

ployed for guanidine and urea synthesis were complicated by

unanticipated events.^[7]

Alkynes have proven to be pivotal functional groups in the con-

text of complex molecule synthesis, in particular, the stereo-

and regiocontrolled addition of E⁺/Nu^–across the triple bond

have been particularly enabling. When this is rendered intra-

molecular, the construction of cyclic, including heterocyclic sys-

tems can be accomplished readily. We have been interested for

several years in the utility of such chemistries for the construc-

tion of alkaloids belonging to the oroidin^[1]and Leucetta family

of marine sponge metabolites.^[2]In the context of an investiga-

tion towards the total synthesis of two members of the Leucetta

alkaloids^[2–3]spirocalcaridine A (3) and B (4),^[4]we have re-

ported recently a tandem oxidative amination dearomatizing

spirocyclization (TOADS) of propargyl guanidines 1 (X = NCO₂R)

for construction of the ABC rings,^[5]rapidly providing the com-

plete natural product framework 2 in one synthetic operation

which takes advantage of this feature of alkyne reactivity (Fig-

ure 1).^[6]As part of this initial investigation, we extended this

tandem cyclization process to the participation of ureas 1 (X =

O) which led to the formation of the corresponding spiro

iminooxazole 2 in good yields.^[5]Our intent was to extend fur-

ther this general process to thioureas 1 (X = S) as a means to

access the related spiro iminothiazole, however, as will be de-

Figure 1. Dearomatizing spirocyclization approach to the complete frame-

work of spirocalcaridine A and B.

[a] Department of Chemistry and Biochemistry,University of Texas Arlington,

700 Planetarium Place, Arlington, TX 76019-0065, USA

E-mail: lovely@uta.edu

https://www.uta.edu/chemistry/faculty/carl_lovely.php

[b] Center for Nanostructured Materials, University of Texas Arlington,

700 Planetarium Place, Arlington, TX 76019-0065, USA

E-mail: delphine.gout@uta.edu

Specifically, instead of isolating the thiourea 1 (X = S), we

obtained thiazolidines in excellent yields instead. The conver-

sion of propargylamines and isothiocyanates to the thiazolidine

or thiazole has been known for a number of years (see

Scheme 1),^[8]however, generally relatively forcing conditions

(heating neat,^[8]refluxing in toluene^[9]or microwave irradia-

tion)^[10]were employed. While these reactions are experimen-

Supporting information and ORCID(s) from the author(s) for this article are

available on the WWW under https://doi.org/10.1002/ejoc .201801505.

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Scheme 1. Overview of prior thiazolidine synthesis from propargylamines.

tally convenient, depending upon the structures of the precur- (Scheme 2).^[7]Specifically, upon treatment of propargylamine 5

sors, there can be issues with aromatization and formation of with phenyl isothiocyanate in dichloromethane at room tem-

other by-products.^[10]Two recent reports from the Dethe group perature for 2 h, a single product was obtained in 93 % yield

have shown that thiazolidines can be obtained in good yields after chromatographic purification on silica gel. It was initially

via a three component coupling under copper(I) catalysis,^[11,12]assigned as the expected thiourea 6a but upon its subjection

including asymmetric variants, and through heating (35–50 °C) to the oxidative conditions with iodosobenzene diacetate

neat mixtures of the amine and isothiocyanate.^[13]In these lat- (IBDA) to effect dearomatization only unreacted starting mate-

ter reports, no examples of either terminal alkynes, N-unsubsti-

tuted propargylamines, or systems lacking substituents at the

propargylic carbon were described. Herein, we describe the dis-

covery and development of a synthetic method that delivers

the vinylidene substituted thiazoline from a propargylamine

and an isothiocyanate as the exclusive product mediated by

silica gel. The method has broad substrate scope and provides

access to heterocycles primed for further elaboration.

Results and Discussion

In the previously reported dearomatization chemistry from our

group, the requisite cyclization substrates 1 were prepared from

the corresponding N-methyl propargylamine 5 (obtained via a

three-component coupling) by treatment with isothioureas and

HgO (guanidines) or isocyanates (ureas) without event, but

the reaction with isothiocyanates took a different course

Scheme 2. Synthesis of thiazolidine during attempt to prepare thiourea 6a.

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1

rial was recovered. Upon closer analysis of the H and ¹³C NMR

data for the molecule we had assigned as 6a it became clear

that the product was, in fact, the thiazolidine 7a resulting from

the tandem thio acylation and subsequent anti-hydrosulfenyl-

ation of the alkyne. Propargylamine 5 was reacted with several

different isothiocyanates possessing varying electronic charac-

teristics and in each case, cyclization occurred to afford the cor-

responding heterocycle 7b–k in good yield (entries 1–10,

Table 1).^[14]Each thiazolidine derivative was obtained as the

Z-isomer; this was established either through X-ray crystallogra-

phy (7b, Figure 2) or a ROESY experiment (7a), the others were

assigned by analogy (see also Table 2, Table 3, Table 4, and

Table 5).

Figure 2. X-ray crystal structure of thiazolidine 7b.

Table 1. Thiazolidines 7b–k^[a]from propargylamine 5.

Table 2. Thiazolidines 11a–d^[a]and thiazolidinones 12a–d^[b]obtained from

propargylamine 10.

[a] Propargylamine 5 (1 equiv.), isothiocyanate (1 equiv.), CH₂Cl₂, r.t., 2 h then

slurry on silica gel for column chromatography.

[a] Isothiocyanate (1 equiv.) was added to amine 10 (1 equiv.) in CH₂Cl₂was

stirred at r.t. for 2 h then slurried on silica gel for column chromatography.

[b] 11a–d were dissolved in CDCl₃and allowed to stand open to the air at

r.t. for 1–3 days.

Initially, we were surprised by the observation of cyclization

products as these reaction conditions are exceptionally mild,

occurring at room temperature over a few hours. It was hypoth-

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Table 3. Thiazolidines 17a–d derived from 3-phenylpropargylamine (16) and

Table 5. Evaluation of solids to promote the cyclization reaction.^[a]

isothiocyanates.^[a]

Entry

Conditions

29a:31a:33a^[b]

1

CH₂Cl₂

1:2:2

2

Silica gel

1:0:0

3

4

5

6

7

8

Alumina (Neutral)

Alumina (Acidic)

Alumina (Basic)

Celite

Molecular Sieves

Sand

1:0:0

3:1:0.5

1:1:0.5

4:1:0

9

Silica gel in CH₂Cl₂

Amberlyst

Dowex

Neat

1:1:1

na

2:1:1

1:1:0.1

1:1:0^[c]

30a:32a:34a

0:1:0

4:1:0.5

10

11

12

13

14

15

16

CH₂Cl₂

Neat

Silca gel

[a] Reactions were performed on 25 mg scale on solid (1.75 g/mmol) for

2 h. [b] Product ratios obtained from ¹H NMR spectroscopy of crude reaction

mixtures. [c] This reaction was conducted at 40 °C.

prepared according to the method of Looper and coworkers

(Scheme 3) and evaluated in this chemistry.^[15]Specifically, the

terminal acetylene 8 was subjected to a copper-mediated

three-component coupling with formaldehyde and the N-allyl

methylamine derivative to produce the propargylamine 9. Pd-

Catalyzed deallylation then provided the requisite amine 10 in

good yield. This substrate upon exposure to isothiocyanates de-

livered the corresponding thiazolidine 11a–d (Table 2) in mod-

est to good yield as single stereoisomers as established by X-

ray crystallography of thiazolidine 11b. Interestingly, these com-

pounds underwent slow air oxidation to the corresponding

4-thiazolone 12a–d (Table 2) upon standing for a few days in

[a] Isothiocyanate (1 equiv.) was added to amine 16 (1 equiv.) in CH₂Cl₂was

stirred at r.t. for 2 h then slurried on silica gel for column chromatography.

Table 4. Synthesis of thiazolidines 22b–d and 24 from Dethe's substrates 19

and 23.^[a]

[a] Isothiocyanate (1 equiv.) was added to amine 19 or 23 (1 equiv.) in CH₂Cl₂

was stirred at r.t. for 2 h then slurried on silica gel for column chromatogra-

phy.

esized, initially, that it was conceivable that cyclization was facil-

itated by reactive rotamer effects due to the aryl substitution

on the propargylic carbon and the enhanced nucleophilicity of

sulfur compared to oxygen and nitrogen in the corresponding

urea and guanidine. To address the issue of steric effects en-

hancing the rate, the less-substituted propargylamine 10 was

Scheme 3. Preparation and reaction of p-anisylpropargylamine 10.

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solution. This was evident from the disappearance of the meth-

1

ylene group in the H NMR spectra, the appearance of a carb-

onyl absorption in the IR spectrum and finally confirmation

through X-ray crystallography of compound 12b. No attempt

was made to optimize this transformation, but presumably,

these thiazolones form via an autoxidation pathway.

There was still suspicion in our minds that even the N-methyl

propargylic amine was undergoing this cyclization reaction be-

cause of reactive rotamer effects, specifically due to the N-

methyl group and thus we decided to subject primary prop-

argylamines to this chemistry. We prepared the phenyl prop-

argylamine 16 from the corresponding bromide 14 via Gabriel

chemistry (14→15→16, Scheme 4a) and subjected this sub-

strate to reaction with the same group of isothiocyanates used

with 10.^[16]Amine 16 upon exposure to isothiocyanates also

delivered the corresponding thiazolidine 17a–d (Table 3) in

moderate yield as single stereoisomers as established by X-ray

crystallography of thiazolidines 17a and 17c. Interestingly,

Castagnolo has reported similar reactions of propargylamine 16

with isothiocyanates under microwave conditions with pTsOH

as a catalyst, but these reactions delivered imidazo-2-thione

derivatives in modest yields rather than the 2-aminothiazole

derivatives.^[10]In addition to the thiazolidines, with phenyl iso-

thiocyanate, we observed the formation of a small amount of a

2:1 adduct 18 where the thiazolidine ring nitrogen underwent

addition to provide 18,^[17]which was confirmed through X-ray

crystallography (Scheme 4b). The yields of this series of thiazol-

idines were lower than those reported in Table 1 and Table 2

as propargylamine 16 was somewhat unstable.

The facility of these cyclization reactions, irrespective of the

substitution patterns, was somewhat surprising based on exist-

ing precedent. As noted in the introduction (Scheme 1), there

are prior reports of reactions of simple propargylamines^[18]re-

acting with isothiocyanates giving 2-aminothiazolidines but

Scheme 4. (a) Synthesis and cyclization of phenylpropargylamine. (b) Struc-

ture and X-ray structure of bis addition product 18.

these earlier methods either rely on Thorpe-Ingold type acceler- tained and thus the reaction pathway observed by us is com-

ation,^[8]much more forcing conditions (e.g., heat or microwave plementary.^[20]Interestingly, according to this same report,

irradiation)^[19]or require lengthier reaction times in comparison when the reaction of 19 is conducted in DMF in the absence

to our observations where a thiazolidine is obtained under ex- of NaOH the corresponding thiourea was obtained (cf. 19→21,

ceptionally mild conditions (r.t. for 2 h).^[9–11]In contrast, Dethe Scheme 5). However, in our hands, subjection of propargyl-

and coworkers have shown that when various propargylamines amine 5 to these conditions described by Dethe (PhNCS, DMF)

and isothiocyanates are reacted in DMF with NaOH as base the also resulted in the formation of the cyclization product 7a after

corresponding imidazothione (cf. 19→20, Scheme 5) is ob- purification, although it is not necessary to run the reaction for

Scheme 5. Divergent reaction pathways of propargylamine 19 with phenyl isothiocyanate.

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12 h, similar results are obtained after 2 h. For comparative was present which resembled the spectroscopic data for 22a.

purposes and to convince ourselves that our observation with The presence of impurities suggested that this discrepancy be-

5 was not simply an anomaly, we prepared propargylamine 19 tween the data was attributable to the fact that Dethe and

reported by Dethe and co-workers and subjected it to reaction coworkers did not purify the product, but rather report both

with phenyl isothiocyanate in DMF, surprisingly this also led to the yield and spectroscopic data for the crude product; this is

a thiazolidine, 22a in our hands. We found also that treatment not explicitly stated in the provided supporting information but

of 19 with phenyl isothiocyanate in dichloromethane for 2 h at assumed based on our own experience (vide infra and Figure 3).

room temperature resulted in the formation of the thiazolidine When we repeated the reaction of 19 with phenyl isothio-

22a in good yield. This cyclization pathway appears to be gen- cyanate in either dichloromethane or DMF and examined the

eral with amine 19 for the same types of isothiocyanates we ¹H and ¹³C NMR spectrum of the crude reaction mixture, our

have investigated previously delivering thiazolidines 22b–d data were a much closer match for that reported in the litera-

(Table 4).^[13]While our own investigation was continuing, the ture.^[20]Interestingly, in Dethe's recent report they describe the

Dethe lab reported that heating neat mixtures of propargyl- reaction of 23 under nominally similar conditions to ours but

amines, including 19, and an isothiocyanate does afford the requiring 12 h and affording 24 in 85 % yield after purifica-

corresponding thiazolidine, and we were able to reproduce tion.^[13]Repetition of this reaction in our hands, but with only

this.^[13]However, the divergence in product formation between 2 h reaction time, delivered 24 (Table 4) in essentially the same

the two labs on reaction of propargylamine 19 and phenyliso- yield.

thiocyanate when conducted in solution was troubling and we

To begin to get a better understanding of what exactly is

going on in these reactions, we chose to monitor the progress

wished to elucidate the source of the discrepancy.

1

We closely examined the corresponding H NMR spectrum of the reaction by NMR spectroscopy. Indeed, when the reac-

from our synthesis of 22a and that accompanying the pub- tions of propargylamine 19 with phenyl isothiocyanate were

lished synthesis of 21;^[20]it was clear immediately that the two conducted in CD₂Cl₂, [D₇]DMF (shown) or [D₆]benzene and

products were different, however, on closer inspection of the monitored by ¹H NMR spectroscopy showed relatively rapid and

spectra reported by Dethe, at least one additional compound complete formation of the thiourea after 2 h and subsequently

Figure 3. Time course of reaction between propargylamine 19 and phenyl isothiocyanate in [D₇]DMF analyzed by ¹H NMR spectroscopy.

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Figure 4. Time course of reaction between propargylamine 23 and phenyl isothiocyanate in CD₂Cl₂analyzed by ¹H NMR spectroscopy.

slower cyclization. For example, propargylamine 19 with phenyl time, when known mixtures of thiourea and thiazolidine (estab-

isothiocyanate in [D₇]DMF (Figure 3), shows the formation of lished by NMR spectroscopy) were analyzed by TLC only one

the thiourea 25a is fairly rapid and appears to be complete product was observed (other than a small amounts of unre-

after 2 h. The characteristic vinylidine signal δ_Hd= 6.75 grows acted isothiocyanate); in other words the TLC mobility of the

in much more slowly and is present to the extent of ca. 20 % thiourea appeared to be identical to the TLC mobility of the

after 12 h. These data show clearly that under these reaction thiazolidine. In retrospect, this was deemed to be unlikely as

conditions the thiourea is the major but not the only product the hydrogen-bond donor properties of the thiourea were ex-

formed and that prior to work-up the thiazolidine 22a is only a pected to result in a relatively polar molecule and thus we con-

minor component of the reaction mixture. As noted above, cluded that all of these observations were pointing to the possi-

Dethe and coworkers reported the high yield formation of thi- bility that these cyclizations were facilitated by silica gel during

azolidine 24 after 12 h reaction time in CH₂Cl₂from propargyl- the purification.

amine 23 and phenyl isothiocyanate. Examination of this reac-

tion in CD₂Cl₂by ¹H NMR spectroscopy (Figure 4) exhibited

similar characteristics to the reaction of 19, the formation of

the thiazolidine was incomplete after 12 h, although it starts to

appear in the spectra after 3 h (Figure 4). It also appears that

the formation of the thiourea is slower in dichloromethane than

in DMF as there is still unreacted propargylamine 19. In the

case of substrate 5, the thiourea 6a formation was complete in

less than one hour followed by slower cyclization (ca. 90 % after

12 h). This latter observation suggests that there is some accel-

eration of the cyclization due to substituent effects.^[8]

To test the hypothesis that silica gel was accelerating this

cyclization,^[21]we took the crude reaction mixture formed from

a reaction between propargylamine 5 and phenyl isothio-

cyanate after 2 h and then analyzed it by ¹H NMR spectroscopy.

This analysis revealed that the mixture contained ca. 40 % of

desired product 7a with ca. 60 % of the intermediate thiourea

6a remaining unreacted. This same reaction mixture was then

subjected to purification by column chromatography on silica

gel which produced the thiazolidine in 89 % yield as the only

product. Similarly, we evaluated the reactions of both 19 and

23 with phenyl isothiocyanate in solution for 2 h, quantified

Taken in concert, these results are interesting because they the compositions of the crude reaction mixture by ¹H NMR

suggest that the cyclization occurs predominantly after work- spectroscopy (vide infra) and then these mixtures were purified

up and most likely during purification by chromatography on by silica gel chromatography affording the corresponding thi-

silica gel and, in order for the generally good isolated yields, azolidines 22a (from 19) in 91 % yield and 24 (from 23) also in

must be occurring quite rapidly. A further observation with 91 % yield as the only products. Specifically, in the case of the

propargylamine 5 was confounding and surprising to us at this reaction of 19 with phenyl isothiocyanate, after 2 h in solution,

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a mixture comprising thiazolidine 22a (12 %), thiourea 25a

(80 %) and unreacted amine 19 (8 %) was obtained prior to

purification. Similarly, amine 23 and phenyl isothiocyanate af-

forded a mixture of the thiazolidine 24 (15 %), the thiourea 26

(64 %) and unreacted starting amine 23 (21 %) prior to purifica-

tion. Alternatively, conducting the reactions of all three amines

with phenyl isothiocyanate directly on silica gel without using

any solvent demonstrated that the reactions were essentially

complete in 2 h (eluted with 10 % MeOH in CH₂Cl₂, concen-

trated by blowing dry nitrogen and analyzed) by ¹H NMR spec-

troscopy) and on purification by chromatography provided the

expected thiazolidines in good yields, similar to those reported

in Table 1 and Table 4. The NMR investigation and the latter

control experiments where the composition of the crude prod-

ucts was established prior to purification show clearly that the

cyclization reaction is quite slow and in some cases the forma-

tion of the thiourea is incomplete after 2 h, but these reactions

are going to completion upon exposure to silica gel. It was

obvious from these experiments that the rate of the reaction

was increased by the presence of the silica gel, but it was not

clear whether this was simply an acid-catalyzed process or per-

haps a proximity-induced effect.

Scheme 6. Selected optimization of reaction conditions for propargylamines

27 and 28 and X-ray structure of compound 33b.

The fact that these reactions appeared to benefit from accel-

eration from silica gel was a potentially useful observation as

two sets of substrates, specifically N-methyl propargylamine 27

and the unsubstituted congener 28, afforded either mixtures of

the thiazolidine 29a, thiourea 31a and the thioimidazoline 33a

(entry 1, Table 5) or gave the thiourea 32a respectively (entry

14, Table 5) in the absence of SiO₂(Scheme 6). In the case of

33a, the initial product undergoes tautomerization to 33b upon

purification by chromatography, established by X-ray crystallog-

raphy, presumably a reflection of the greater aromaticity of

imidazoles versus thiazoles. Gratifyingly, when we evaluated N-

methyl propargylamine with phenyl isothiocyanate on silica gel

(entry 2, Table 5), the reaction produced the thiazolidine 29a

exclusively. Alumina (acidic, basic and neutral) gave similar re-

sults to silica gel (entries 3–5, Table 5). Celite, sand and molec-

ular sieves, on the other hand, provided a mixture of products

(entries 6–8, Table 5). Interestingly, when the reaction was con-

ducted in solution with a suspension of silica gel (entry 9,

Table 5), the reaction resulted in the formation of a mixture of

the thiourea and thiazolidine. Use of solid acid supports did not

afford any reaction, presumably, the amine is protonated and

trapped. Attempts to perform the reaction using neat reagents

resulted in mixtures of products (entries 12–13, Table 5)

whether the reaction was performed at room temperature or

40 °C. While an exhaustive screen was not conducted, the par-

ent propargylamine 29 showed similar trends as the N-methyl

derivative. Neat reaction along with the reaction in CH₂Cl₂pro-

duced the thiourea as a major product (entries 14 and 15).

Whereas silica gel supported reaction produced the desired thi-

azolidine 30a, along with smaller amounts of the thiourea 32a

and the 2-thioimidazoline 34a (entry 16).

ditions (Scheme 6). Likewise, a series of thiazolidines was pre-

pared from propargylamine itself under identical conditions af-

fording the corresponding thiazolidines 30a–d in good yields

(Table 6). Under the mild conditions employed the double bond

does not migrate into the ring to generate the aromatic system

which is in contrast to previous reports of the reaction of these

reagents.^[19]X-ray crystallography of adducts 30a and 30d

clearly show the presence of the vinylidene moiety and the

fact that the imino moiety exists as the E-isomer, presumably

reflecting the reduced steric environment around the thiazol-

idine nitrogen. The isolated yield of 30a appears to be higher

than expected from the experiment described in Table 5 (entry

16), but we attribute this to the cyclization continuing during

the purification process. The reactions with propargylamine 10

were repeated on silica gel and it was found that all four thi-

azolidines 11a–d were obtained in >80 % yields, reflecting im-

proved efficiency. In contrast, when the cyclizations involving

amine 16 were repeated on silica gel, no improvements were

obtained, perhaps due to increasing decomposition and there

was a small increase in the formation of the 2:1 adduct, cf.

compound 18 (Scheme 3b) The facile formation of the thiazol-

idine in the presence of silica gel suggests that the cyclization

is mediated by solid support, whether this is a proximity effect

caused by coordination of nitrogen to the surface or whether

it is as a solid acid is not totally clear. The mildly acidic nature of

silica gel is well appreciated and has been exploited in synthetic

organic chemistry.^[22]The NMR experiments discussed above

indicate that thiourea 38 formation is relatively rapid but in the

absence of any external catalyst, the cyclization is slow

(Scheme 7). In the presence of silica gel, either added to the

reaction mixture or exposure during purification^[23]of the crude

reaction mixture results in rate enhancement. With the excep-

tion of the terminal alkynes (R³= H) prior protonation of the

Based on these observations, we evaluated the direct appli-

cation of reagents to silica gel followed by stirring the resulting

mixture for 2 h. A series of N-methyl thiazolidines 29a–d alkyne would potentially lead to regioisomeric vinyl carbo-

(Table 6) were prepared in good isolated yields using these con- cations or in some cases (R³= Ar) the wrong isomer for forma-

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tion of the thiazolidine, therefore we propose that a π-complex

39 is formed which activates the triple bond to nucleophilic

attack by sulfur affording 40. Proton transfer then completes

the process and provides the thiazolidine.^[24]It is also feasible

that the propargylamine nitrogen coordinates to the silica gel

surface which in effect functions as a large substituent and in-

creases the population of the reactive rotamer, further facilitat-

ing the reaction.

Table 6. Silica gel promoted hydrothiolation of terminal propargylamines.^[a]

Scheme 7. Putative mechanism for the formation of the thiazole.

urea 6a resulted in the isolation of the intermediate imidazolyl-

substituted thiourea 42 but not the required thiourea 6a

(Scheme 8). However, upon treatment with the more nucleo-

philic p-anisidine, the same thiazolidine product 7d as isolated

previously (see Scheme 2 and Scheme 8) was obtained in good

yield. Interestingly, attempts to convert the intermediate imid-

[a] To a vigorously stirred suspension of silica gel (1.75 g/mmol) was added

the propargylamine (0.72 mmol) in CH₂Cl₂(0.2 mL) and then the isothio-

cyanate (1 equiv.) was added dropwise. After 2 h of stirring at r.t., the residue

was purified.

We very much wanted to access thioureas derived from

propargylamine 5 to evaluate our TOADS chemistry and thus

sought an alternative approach. Accordingly, we decided to ex-

plore the preparation and reaction of the imidazolyl thiourea

derivative 42 in Scheme 8 which would be accessed from the

corresponding amine 5 and thiocarbonyl diimidazole (TCDI). In-

terestingly, an attempt to access the phenyl-substituted thio-

Scheme 8. Thiazolidine 7d formation via the action of TCDI.

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silica gel and then purified by flash chromatography to afford the

thiazolidine.

azolyl thiourea 42 into either the requisite thiourea 6 or thi-

azolidine 7 were not successful with either aniline or anisidine.

Suggesting that anisidine was converted into the correspond-

ing imidazolyl thiourea or isothiocyanate prior to reaction with

propargylamine 5. As noted above, access to mixtures of the

thiourea and thiazolidines was possible if purification was

avoided. Such a mixture was exposed to a mixture of IBDA,

HFIP, Cs₂CO₃(standard conditions for TOADS), but rather than

obtaining the dearomatization product, the thiazolidine was the

only isolable product.^[25]

General Procedure (B): To vigorously stirred silica gel (1.75 g/

mmol), a solution of propargylamine (50 mg, 0.72 mmol) in CH₂Cl₂

(0.2 mL) and isothiocyanate (0.72 mmol) was added dropwise. The

resulting slurry was stirred at r.t. for 2 h. After removal of the solvent

by rotary evaporation, the crude product was then purified by flash

chromatography to afford the thiazolidine.

General Procedure (C): Thiazolidines (50 mg) were dissolved in

CDCl₃(1 mL) and left open to the atmosphere for 1–3 days. After

concentration, the crude product was purified by column chroma-

tography to afford the oxidized product.

(Z)-N-Phenyl-4-(4-methoxybenzyl)-5-((Z)-4-methoxybenzylid-

ene)-3-methylthiazolidin-2-imine (7a): Synthesized following

general procedure A, (125 mg, 0.42 mmol), purified by column chro-

matography (ethyl acetate/hexanes = 3:7) to afford compound 7a

Conclusions

In summary, we have found that a wide variety of thiazolidines

can be prepared in generally good to excellent yields via a tan-

dem thioacylation-hydrosulfenylation of propargylamines and

that these reactions are promoted by silica gel.^[26]The reaction

has a broad substrate scope with regard to both the propargyl-

amine and the isothiocyanate. Initial uncertainty surrounding

the preparation and lifetime of the thiourea intermediate was

clarified when it was determined that the intramolecular hydro-

sulfenylation can be catalyzed by silica gel. The thiourea can be

prepared by using short reaction times and avoiding purifica-

tion. Initial attempts to engage crude samples of thiourea 6a

in TOADS chemistry were thwarted by the facile hydrosulfenyl-

ation reaction leading to a thiazolidine 7a; indeed out of the

systems investigated, propargylamine 5 upon conversion to the

intermediate thiourea underwent cyclization to the correspond-

ing thiazolidine most rapidly in the absence of silica gel. Our

investigations to circumvent this are ongoing, as well as efforts

to exploit the potentially useful thiazolidine derivatives and we

will report these efforts in due course.

1

(158 mg, 87 %) as a light-yellow gum. H NMR: 7.28 – 7.24 (m, 2H),

7.09 (d, J = 8.5 Hz, 4H), 7.05 (tt, J = 8.5, 1.2 Hz, 1H), 6.89 (dd, J =

8.5, 1.2 Hz, 2H), 6.85 – 6.81 (m, 4H), 6.15 (s, 1H), 4.58 (td, J = 5.1,

1.2 Hz, 1H), 3.80 (s, 3H), 3.76 (s, 3H), 3.23 (s, 3H), 3.06 – 3.05 (d, J =

5.1 Hz, 2H). ¹³C NMR: 158.8, 158.7, 156.6, 150.9, 131.2, 130.0, 129.3,

129.0, 128.5, 127.8, 123.4, 122.6, 121.0, 114.1, 113.9, 71.2, 55.4, 40.0,

32.6. FT-IR (neat, cm^–1): 2951, 2931, 2834, 1610, 1584, 1508, 1461,

+

1300, 1244, 1175, 1028. HR-MS (m/z): calcd. for [M + H]

C₂₆H₂₆N₂O₂S, 431.1788, found 431.1792.

(Z)-N-(2,6-Dimethylphenyl)-4-(4-methoxybenzyl)-5-((Z)-4-

methoxybenzylidene)-3-methylthiazolidin-2-imine (7b): Synthe-

sized following general procedure A, (125 mg, 0.42 mmol), purified

by column chromatography (ethyl acetate/hexanes = 3:7) to afford

compound 7b (176 mg, 91 %) as a yellow solid. m.p. 74–78 °C. ¹H

NMR: 7.09 (dd, J = 8.6, 1.6 Hz, 4H), 6.97 (d, J = 8.6 Hz, 2H), 6.89 –

6.85 (m, 1H), 6.83–6.80 (m, 4H), 6.26 (s, 1H), 4.67 (t, J = 4.0 Hz, 1H),

3.79 (s, 3H), 3.77 (s, 3H), 3.25 (s, 3H), 3.13 – 3.02 (m, 2H), 2.08 (s, 3H),

1.92 (s, 3H). ¹³C NMR: 158.7, 158.6, 155.4, 148.9, 131.2, 130.6, 130.1,

129.8, 129.3, 128.6, 127.8, 127.6, 123.0, 120.4, 114.1, 114.0, 71.1, 55.4,

55.3, 40.3, 32.2, 18.3, 18.2. FT-IR (neat, cm^–1): 2918, 2832, 1656, 1609,

1508, 1462, 1380, 1249, 1175, 1031, 766. HR-MS (m/z): calcd. for [M

+

Experimental Section

+ H] C₂₈H₃₀N₂O₂S, 459.2101, found 459.2106.

All reagents were purchased from commercial suppliers and were

used as received unless otherwise noted. Solvents were dried either

by distillation over appropriate drying agents: tetrahydrofuran was

distilled from sodium/benzophenone ketyl; acetonitrile, benzene,

diethyl ether, and dichloromethane were dried using an alumina-

based solvent purification system. ¹H and ¹³C NMR (δ in ppm) spec-

tra were recorded in CDCl₃(unless otherwise noted) at 500 and

125.8 MHz, respectively (unless otherwise noted). Residual CHCl₃

(Z)-N-(4-tert-Butylphenyl)-4-(4-methoxybenzyl)-5-((Z)-4-me-

thoxybenzylidene)-3-methylthiazolidin-2-imine (7c): Synthe-

sized following general procedure A, (125 mg, 0.42 mmol), purified

by column chromatography (ethyl acetate/hexanes = 3:7) to afford

compound 7c (185 mg, 90 %) as a yellow solid. m.p. 60–65 °C. ¹H

NMR: 7.27 – 7.24 (m, 2H), 7.12 – 7.06 (m, 4H), 6.85 – 6.81 (m, 4H),

6.81 – 6.77 (m, 2H), 6.14 (s, 1H), 4.56 (td, J = 5.1, 1.2 Hz, 1H), 3.80

(s, 3H), 3.77 (s, 3H), 3.19 (s, 3H), 3.04 (d, J = 5.1 Hz, 2H), 1.31 (s, 9H).

¹³C NMR: 158.7, 158.6, 155.6, 148.6, 145.7, 131.2, 130.5, 129.3, 128.7,

127.9, 125.8, 121.7, 120.7, 114.0, 113.8, 70.8, 55.3, 40.0, 34.3, 32.4,

31.6. FT-IR (neat, cm^–1): 2957, 2836, 1594, 1508, 1460, 1246, 1174,

1028, 835. HR-MS (m/z): calcd. for [M + H] ⁺C₃₀H₃₄N₂O₂S, 487.2414,

found 487.2415.

1

(δ = 7.26) was utilized as reference for H NMR spectra and carbon

absorption of CDCl₃(δ = 77.0) as internal reference for ¹³C NMR

were used. Infrared spectra were recorded neat using an ATR-FT-IR

spectrometer. High-resolution mass spectra (HR-MS) were measured

in the Shimadzu Center for Advanced Analytical Chemistry at UT

Arlington. Analytical thin layer chromatography (TLC) was per-

formed on silica gel 60F₂₅₄aluminum pre-coated plates (0.25 mm

layer). All chromatographic purifications were performed using ICN

silica gel (230–400 mesh).

(Z)-N-(4-Methoxyphenyl)-4-(4-methoxybenzyl)-5-((Z)-4-

methoxybenzylidene)-3-methylthiazolidin-2-imine (7d): Synthe-

sized following general procedure A, (125 mg, 0.42 mmol), purified

by column chromatography (ethyl acetate/hexanes = 3:7) to afford

1

General Procedure (A): To a stirred solution of propargylamine

(125 mg, 0.42 mmol) in CH₂Cl₂(2.0 mL) was added isothiocyanate

(0.42 mmol). The resulting reaction mixture was stirred at r.t. for

compound 7d (162 mg, 83 %) as a light-yellow gum. H NMR: 7.12

– 7.07 (m, 4H), 6.84 (d, J = 2.2 Hz, 2H), 6.81 (d, J = 2.2 Hz, 2H), 6.80

(d, J = 1 Hz, 4H), 6.13 (s, 1H), 4.54 (t, J = 5.7 Hz, 1H), 3.79 (s, 3H),

2 h. A slurry was made by adding silica gel (2 g/mmol) to the reac- 3.77 (s, 3H), 3.76 (s, 3H), 3.18 (s, 3H), 3.03 (d, J = 5.7 Hz, 2H). ¹³C

tion mixture and then the solvent was removed by rotary evapora- NMR: 158.7, 158.6, 156.4, 155.7, 145.1, 131.2, 130.4, 129.3, 128.6,

tion. The resulting mixture was applied to the top of the column of

127.9, 123.2, 120.7, 114.2, 114.0, 113.8, 71.0, 55.5, 55.4, 40.0, 32.4.

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FT-IR (neat, cm^–1): 2954, 2933, 2836, 1609, 1509, 1463, 1243, 1158, 2H), 7.46 (d, J = 7.4 Hz, 1H), 7.41 (t, J = 7.4 Hz, 2H), 7.27 – 7.20 (m,

1030, 819. HR-MS (m/z): calcd. for [M + H] ⁺C₂₇H₂₈N₂O₃S, 461.1893, 2H), 7.01 (d, J = 7.4 Hz, 2H), 6.85 (d, J = 8.2 Hz, 2H), 6.75 (d, J =

found 461.1897.

7.4 Hz, 2H), 6.03 (s, 1H), 4.48 (m, 1H), 3.76 (s, 3H), 3.71 (s, 3H), 3.29

(s, 3H), 3.09–3.06 (m, 1H), 2.94–2.90 (m, 1H). ¹³C NMR: 175.4, 168.4,

158.9, 158.8, 136.7, 132.0, 131.2, 131.1, 131.0, 129.8, 128.2, 128.1,

127.0, 122.8, 114.1, 113.9, 69.4, 55.4, 55.2, 39.9, 33.8. FT-IR (neat, cm^–

¹): 3191, 2835, 1716, 1665, 1604, 1508, 1463, 1374, 1245, 1174, 1027,

702. HR-MS (m/z): calcd. for [M + H]⁺C₂₇H₂₆N₂O₃S, 459.1737, found

459.1737.

(Z)-N-(4-nitrophenyl)-4-(4-methoxybenzyl)-5-((Z)-4-methoxy-

benzylidene)-3-methylthiazolidin-2-imine (7e): Synthesized fol-

lowing general procedure A, (125 mg, 0.42 mmol), purified by col-

umn chromatography (ethyl acetate/hexanes = 3: 7) to afford com-

pound 7e (155 mg, 77 %) as a yellow solid. m.p. 60–64 °C. ¹H NMR:

8.11 (d, J = 8.9 Hz, 2H), 7.07 (d, J = 8.9 Hz, 2H), 7.05 (d, J = 8.9 Hz,

2H), 6.93 (d, J = 8.9 Hz, 2H), 6.84 (d, J = 8.9 Hz, 2H), 6.83 (d, J =

8.9 Hz, 2H), 6.24 (s, 1H), 4.65 (t, J = 4.9 Hz, 1H), 3.79 (s, 3H), 3.77 (s,

3H), 3.25 (s, 3H), 3.11 – 3.05 (m, 2H). ¹³C NMR: 159.0, 158.9, 143.4,

131.1, 129.3, 129.2, 128.5, 128.0, 127.1, 125.1, 122.9, 122.1, 114.2,

113.9, 113.9, 71.3, 55.4, 55.3, 40.1, 32.7. FT-IR (neat, cm^–1): 2914,

2834, 1610, 1561, 1508, 1459, 1325, 1245, 1172, 1027. HR-MS (m/z):

calcd. for [M + H]⁺C₂₆H₂₅N₃O₄S, 476.1639, found 476.1638.

(Z)-N-Allyl-4-(4-methoxybenzyl)-5-((Z)-4-methoxybenzylidene)-

3-methylthiazolidin-2-imine (7j): Synthesized following general

procedure A, (125 mg, 0.42 mmol), purified by column chromatog-

raphy (ethyl acetate/hexanes = 3:7) to afford compound 7j (113 mg,

1

68 %) as a light-yellow gum. H NMR: 7.17 (d, J = 8.7 Hz, 2H), 7.04

(d, J = 8.7 Hz, 2H), 6.88 (d, J = 8.7 Hz, 2H), 6.78 (d, J = 8.7 Hz, 2H),

6.05 (s, 1H), 5.91 (ddt, J = 17.1, 10.5, 5.3 Hz, 1H), 5.17 (dq, J = 17.1,

1.8 Hz, 1H), 5.04 (dq, J = 10.5, 1.8 Hz, 1H), 4.43 (ddd, J = 6.8, 4.1,

1.2 Hz, 1H), 3.82 (dt, J = 5.3, 1.8 Hz, 2H), 3.80 (s, 3H), 3.77 (s, 3H),

3.04 (s, 3H), 3.01 (dd, J = 13.5, 4.3 Hz, 1H), 2.89 (dd, J = 13.5, 4.3 Hz,

1H). ¹³C NMR: 158.6, 158.5, 156.3, 136.8, 131.1, 130.1, 129.4, 128.8,

128.3, 120.8, 114.6, 114.0, 113.7, 70.9, 56.9, 55.4, 55.3, 39.8, 32.3. FT-

IR (neat, cm^–1): 3025, 2917, 2834, 1610, 1508, 1459, 1242, 1177,

1025. HR-MS (m/z): calcd. for [M + H]⁺C₂₃H₂₆N₂O₂S, 395.1788, found

395.1798.

(Z)-N-(3,4-Bis(trifluoromethyl)phenyl)-4-(4-methoxybenzyl)-5-

((Z)-4-methoxybenzylidene)-3-methylthiazolidin-2-imine (7f):

Synthesized following general procedure A, (125 mg, 0.42 mmol),

purified by column chromatography (ethyl acetate/hexanes = 3:7)

to afford compound 7f (191 mg, 80 %) as a light-yellow gum. ¹H

NMR: 7.48 (s, 1H), 7.21 (s, 2H), 7.07 (dd, J = 8.7, 6.0 Hz, 4H), 6.84 (dd,

J = 8.7, 6.0 Hz, 4H), 6.25 (s, 1H), 4.64 (t, J = 5.4 Hz, 1H), 3.79 (s, 3H),

3.78 (s, 3H), 3.21 (s, 3H), 3.12 – 3.01 (m, 2H). ¹³C NMR: 159.0, 158.9,

132.0 (q, J = 33.1 Hz), 131.2, 130.9, 129.3, 128.9, 128.1, 127.1, 123.5

(q, J = 271 Hz), 122.8, 121.8, 116.4, 114.2, 114.1, 113.8, 71.2, 55.4,

55.2, 40.2, 32.3. FT-IR (neat, cm^–1): 2933, 2839, 1596, 1510, 1463,

1369, 1274, 1248, 1167, 1122, 1030. HR-MS (m/z): calcd. for [M + H]⁺

C₂₈H₂₄N₂O₂F₆S, 567.1535, found 567.1533.

(Z)-N-(4-Bromo-2-trifluoromethoxyphenyl)-4-(4-methoxy-

benzyl)-5-((Z)-4-methoxybenzylidene)-3-methylthiazolidin-2-im-

ine (7k): Synthesized following general procedure A, (125 mg,

0.42 mmol), purified by column chromatography (ethyl acetate/hex-

anes = 3:7) to afford compound 7k (190 mg, 76 %) as a light-yellow

1

gum. H NMR: 7.34 – 7.33 (m, 1H), 7.38 – 7.26 (m, 1H), 7.06 (dd, J =

(Z)-N-(3-Chloro-4-methylphenyl)-4-(4-methoxybenzyl)-5-((Z)-4-

methoxybenzylidene)-3-methylthiazolidin-2-imine (7g): Synthe-

sized following general procedure A, (125 mg, 0.42 mmol), purified

by column chromatography (ethyl acetate/hexanes = 3:7) to afford

8.9, 5.3 Hz, 4H), 6.83 (dd, J = 5.3, 8.9 Hz, 4H), 6.73 (d, J = 8.9 Hz,

1H), 6.19 (s, 1H), 4.61 (t, J = 6.0 Hz, 1H), 3.79 (s, 3H), 3.78 (s, 3H),

3.19 (s, 3H), 3.04 (d, J = 6.0 Hz, 2H). ¹³C NMR: 158.8, 158.7, 157.4,

143.8, 142.1, 142.0, 131.1, 130.5, 129.3, 129.2, 128.3, 127.5, 125.5,

125.1, 121.3, 120.7 (q, J = 256.6 Hz), 114.9, 114.1, 113.8, 71.2, 55.4,

55.3, 40.0, 32.3. FT-IR (neat, cm^–1): 2934, 2837, 1599, 1509, 1463,

1243, 1159, 1028. HR-MS (m/z): calcd. for [M + H]⁺C₂₇H₂₄N₂O₃F₃SBr,

593.0716, found 593.0723.

1

compound 7g (160 mg, 79 %) as a yellow solid. m.p. 58–60 °C. H

NMR: δ 7.10–7.06 (m, 5H), 6.85 (d, J = 2.2 Hz, 1H), 6.85 – 6.82 (m,

4H), 6.66 (dd, J = 8.0, 2.2 Hz, 1H), 6.16 (s, 1H), 4.56 (t, J = 4.5 Hz,

1H), 3.81 (s, 3H), 3.76 (s, 3H), 3.17 (s, 3H), 3.05 – 2.99 (m, 2H), 2.32

(s, 3H). ¹³C NMR δ 158.8, 158.7, 156.8, 150.3, 134.2, 131.2, 131.1,

130.3, 129.9, 129.3, 128.4, 127.6, 123.0, 121.1, 120.8, 114.1, 113.8,

71.1, 55.5, 55.4, 40.1, 32.4, 19.6. FT-IR (neat, cm^–1): 2998, 2834, 1618,

1592, 1508, 1438, 1388, 1245, 1175, 1030, 813. HR-MS (m/z): calcd.

for [M + H]⁺C₂₇H₂₇N₂O₂SCl, 479.1555, found 479.1562.

(Z)-N-Phenyl-5-((Z)-4-methoxybenzylidene)-3-methylthiazol-

idin-2-imine (11a): Synthesized following general procedure A,

(50 mg, 0.28 mmol), purified by column chromatography (ethyl

acetate/hexanes = 3:7) to afford compound 11a (67 mg, 76 %) as a

1

light-yellow gum. H NMR: 7.30 (dd, J = 8.4, 7.4 Hz, 2H), 7.19 (d, J =

(Z)-N-Benzyl-4-(4-methoxybenzyl)-5-((Z)-4-methoxybenzyl-

idene)-3-methylthiazolidin-2-imine (7h): Synthesized following

general procedure A, (125 mg, 0.42 mmol), purified by column chro-

matography (ethyl acetate/hexanes = 3:7) to afford compound 7h

(171 mg, 91 %) as a light-yellow gum. ¹H NMR ([D₄]methanol) δ

7.20 (t, J = 7.0 Hz, 2H), 7.14–7.11 (m, 3H), 7.07 (d, J = 7.0 Hz, 2H),

6.97 (d, J = 8.6 Hz, 2H), 6.81 (d, J = 8.6 Hz, 2H), 6.71 (d, J = 8.6 Hz,

2H), 6.23 (s, 1H), 4.50 (t, J = 4.1 Hz, 1H), 4.25 (ABq, J_AB= 14.9 Hz,

V_AB= 39.1 Hz, 2H), 3.68 (s, 3H), 3.66 (s, 3H), 2.99 (s, 3H), 2.97 – 2.86

(m, 2H). ¹³C NMR ([D₄]methanol): δ 159.2, 158.8, 158.7, 140.3, 131.0,

129.2, 128.6, 128.0, 127.7, 127.2, 126.4, 121.0, 113.8, 113.4, 70.8, 57.9,

54.6, 54.5, 39.6, 31.6. FT-IR (neat, cm^–1): 2931, 2834, 1602, 1508,

1451, 1358, 1244, 1174, 1026, 813. HR-MS (m/z): calcd. for [M + H]⁺

C₂₇H₂₈N₂O₂S, 445.1944, found 445.1950.

8.4 Hz, 2H), 7.07 (tt, J = 7.4, 1.1 Hz, 1H), 6.97 (dd, J = 8.4, 1.1 Hz,

2H), 6.84 (d, J = 8.4 Hz, 2H), 6.47 (t, J = 2.0 Hz, 1H), 4.42 (d, J =

2.0 Hz, 2H), 3.78 (s, 3H), 3.12 (s, 3H). ¹³C NMR: 158.6, 156.6, 151.5,

129.2, 129.1, 128.6, 126.4, 123.3, 122.4, 119.6, 114.1, 59.5, 55.4, 33.1.

FT-IR (neat, cm^–1): 3001, 2929, 2834, 1622, 1584, 1508, 1460, 1247,

1175, 1027, 765. HR-MS (m/z): calcd. for [M + H]⁺C₁₈H₁₈N₂OS,

311.1213, found 311.1202. Note: The yield was improved (98 %)

when the reaction was done following general procedure B.

(Z)-N-(2,6-Dimethylphenyl)-5-((Z)-4-methoxybenzylidene)-3-

methylthiazolidin-2-imine (11b): Synthesized following general

procedure A, (50 mg, 0.28 mmol), purified by column chromatogra-

phy (ethyl acetate/hexanes = 2: 8) to afford compound 11b (67 mg,

1

70 %) as a light-yellow gum. H NMR: 7.15 (d, J = 8.8 Hz, 2H), 7.03

(d, J = 7.8 Hz, 2H), 6.91 (t, J = 7.8 Hz, 1H), 6.83 (d, J = 8.8 Hz, 2H),

6.46 (bs, 1H), 4.46 (s, 2H), 3.77 (s, 3H), 3.16 (s, 3H), 2.15 (s, 6H). ¹³C

NMR: 158.6, 156.1, 148.9, 129.8, 129.3, 128.6, 127.9, 126.4, 123.1,

119.4, 114.1, 60.1, 55.3, 33.0, 18.3. FT-IR (neat, cm^–1): 2963, 2913,

2833, 1646, 1623, 1585, 1508, 1461, 1248, 1176, 1033, 773. HR-MS

(m/z): calcd. for [M + H]⁺C₂₀H₂₂N₂OS, 339.1526, found 339.1517.

(Z)-N-Benzoyl-4-(4-methoxybenzyl)-5-((Z)-4-methoxybenzyl-

idene)-3-methylthiazolidin-2-imine (7i): Synthesized following

general procedure A, (125 mg, 0.42 mmol), purified by column chro-

matography (ethyl acetatehexanes = 3:7) to afford compound 7i

1

(166 mg, 86 %) as a light-yellow gum. H NMR: 8.30 (d, J = 8.2 Hz,

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Note: The yield was improved (99 %) when the reaction was done (q, J = 210.4 Hz), 121.9, 118.2 (q J = 3.7 Hz), 117.4, 114.8, 55.5, 29.7.

following general procedure B.

FT-IR (neat, cm^–1): 2840, 1711, 1626, 1593, 1510, 1366, 1277, 1181,

1122, 1021. HR-MS (m/z): calcd. for [M + H]⁺C₂₀H₁₄N₂O₂F₆S,

461.0758, found 461.0772.

(Z)-N-(3,5-Bis(trifluoromethyl)phenyl)-5-((Z)-4-methoxybenzyl-

idene)-3-methylthiazolidin-2-imine (11c): Synthesized following

general procedure A, (50 mg, 0.28 mmol), purified by column chro-

matography (ethyl acetate/hexanes = 1:3) to afford compound 11c

(83 mg, 65 %) as a light-yellow gum. ¹H NMR ([D₄]methanol): 7.54

(s, 1H), 7.38 (s, 2H), 7.10 (d, J = 8.8 Hz, 2H), 6.81 (d, J = 8.8 Hz, 2H),

6.50 (s, 1H), 4.41 (s, 2H), 3.68 (s, 3H), 3.03 (s, 3H). ¹³C NMR (125 MHz,

[D₄]methanol): 158.9, 158.6, 153.3, 132.0 (q, J = 32.8 Hz), 128.9,

128.2, 124.2, 123.4 (q, J = 270.3 Hz), 122.7, 120.5, 115.7 (q, J =

4.1 Hz), 113.7, 59.1, 54.3, 37.6, 31.7. FT-IR (neat, cm^–1): 2921, 2837,

1621, 1593, 1509, 1370, 1165, 1120, 1026, 842. HR-MS (m/z): calcd.

for [M + H]⁺C₂₀H₁₆N₂OF₆S, 447.0960, found 447.0968. Note: The

yield was improved (99 %) when the reaction was done following

general procedure B.

(Z)-2-(Allylimino)-5-((Z)-4-methoxybenzylidene)-3-methylthi-

azolidin-4-one (12d): Synthesized following general procedure C,

(50 mg, 0.18 mmol), purified by column chromatography (ethyl

acetate/hexanes = 1:9) to afford compound 12d (7 mg, 14 %, 54 %

brsm) as an off white solid. m.p. 80–82 °C. ¹H NMR: 7.69 (s, 1H), 7.49

(d, J = 8.8 Hz, 2H), 6.98 (d, J = 8.8 Hz, 2H), 6.01 (ddt, J = 17.1, 10.4,

5.4 Hz, 1H), 5.30 (dq, J = 10.3, 1.6 Hz, 1H), 5.18 (dq, J = 10.3, 1.6 Hz,

1H), 4.07 (dt, J = 5.4, 1.6 Hz, 2H), 3.86 (s, 3H), 3.34 (s, 3H). ¹³C NMR:

167.1, 160.8, 134.7, 131.9, 130.1, 126.7, 116.2, 114.6, 55.5, 55.0, 29.6.

FT-IR (neat, cm^–1): 3079, 2923, 2848, 1702, 1647, 1631, 1597, 1508,

1412, 1359, 1293, 1253, 1173, 1102. HR-MS (m/z): calcd. for [M + H]⁺

C₁₅H₁₆N₂O₂S, 289.1010, found 289.1002.

(Z)-N-Phenyl-5-((Z)-benzylidene)thiazolidin-2-imine (17a): Syn-

thesized following general procedure A, (50 mg, 0.38 mmol), puri-

fied by column chromatography (ethyl acetate/hexanes = 1:4) to

afford compound 17a (48 mg, 48 %) as a light-yellow solid. m.p.

128–130 °C. ¹H NMR: 7.38 – 7.25 (m, 8H), 7.22 (t, J = 7.2 Hz, 1H),

7.09 (tt, J = 7.6, 1.2 Hz, 1H), 6.57 (t, J = 2.1 Hz, 1H), 4.87 (s, 2H). ¹³C

NMR: 158.0, 136.4, 129.3, 128.9, 128.7, 128.5, 127.7, 126.9, 125.4,

123.7, 121.0, 118.9, 63.1. FT-IR (neat, cm^–1): 3372, 3247, 3021, 2923,

2853, 1607, 1590, 1531, 1494, 1444, 1315, 1263, 1176, 1032, 828,

749. HR-MS (m/z): calcd. for [M + H]⁺C₁₆H₁₄N₂S, 267.0955, found

267.0932.

(Z)-N-Allyl-5-((Z)-4-methoxybenzylidene)-3-methylthiazolidin-2-

imine (11d): Synthesized following general procedure A, (100 mg,

0.57 mmol), purified by column chromatography (ethyl acetate) to

afford compound 11d (86 mg, 55 %) as a light-yellow gum. ¹H NMR:

7.31 – 7.24 (m, 2H), 6.91 (d, J = 8.8 Hz, 2H), 6.50 (s, 1H), 5.96 (ddt,

J = 16.8, 11.8, 5.4 Hz, 1H), 5.25 (dq, J = 16.8, 1.8 Hz, 1H), 5.09 (ddd,

J = 11.8, 3.1, 1.8 Hz, 1H), 4.33 (d, J = 1.8 Hz, 2H), 3.91 (dt, J = 5.4,

1.8 Hz, 2H), 3.82 (s, 3H), 3.02 (s, 3H). ¹³C NMR: 158.6, 157.2, 136.7,

129.3, 128.8, 126.4, 119.5, 114.9, 114.1, 59.5, 57.1, 55.4, 33.1. FT-IR

(neat, cm^–1): 2952, 2835, 1649, 1602, 1509, 1416, 1298, 1250, 1176,

1029, 854. HR-MS (m/z): calcd. for [M + H]⁺C₁₅H₁₈N₂OS, 275.1218,

found 275.1210. Note: The yield was improved (80 %) when the

reaction was done following general procedure B.

(Z)-N-(2,6-Dimethylphenyl)-5-((Z)-benzylidene)thiazolidin-2-

imine (17b): Synthesized following general procedure A, (50 mg,

0.38 mmol), purified by column chromatography (ethyl acetate/hex-

anes = 3:7) to afford compound 17b (52 mg, 46 %) as an off-white

solid. m.p. 85–90 °C. ¹H NMR: 7.30 (d, J = 7.6 Hz, 2H), 7.25 – 7.14

(m, 3H), 7.09 – 7.02 (m, 3H), 6.51 (s, 1H), 4.71 (s, 2H), 2.24 (s, 6H).

¹³C NMR: 149.9, 136.1, 133.3, 129.2, 128.6, 128.2, 127.8, 126.9, 126.2,

125.3, 119.4, 60.5, 18.4. FT-IR (neat, cm^–1): 3024, 2913, 2849, 1655,

1620, 1466, 1444, 1319, 1273, 1175, 1091, 766, 690. HR-MS (m/z):

calcd. for [M + H]⁺C₁₈H₁₈N₂S, 295.1263, found 295.1266.

(Z)-2-(Phenylimino)-5-((Z)-4-methoxybenzylidene)-3-methylthi-

azolidin-4-one (12a): Synthesized following general procedure C,

(60 mg, 0.19 mmol), purified by column chromatography (ethyl

acetate/hexanes = 1:19) to afford compound 12a (11 mg, 17 %,

60 % brsm) as a light-yellow solid. m.p. 146–148 °C (lit.^[27]m.p.

146 °C). ¹H NMR: 7.71 (s, 1H), 7.39 (td, J = 7.1, 1.1 Hz, 4H), 7.21–7.18

(m, 1H), 7.02 (dd, J = 8.4, 1.1 Hz, 2H), 6.91 (d, J = 8.4 Hz, 2H), 3.82

(s, 3H), 3.45 (s, 3H). ¹³C NMR: 167.2, 160.9, 151.4, 148.4, 131.9, 130.8,

129.4, 126.5, 124.9, 121.3, 118.9, 114.6, 55.5, 29.7. FT-IR (neat, cm^–1):

3054, 2948, 2836, 1703, 1637, 1593, 1509, 1412, 1364, 1253, 1182,

1023. HR-MS (m/z): calcd. for [M + Na]⁺C₁₈H₁₆N₂O₂S, 347.0825,

found 347.0834.

(Z)-N-(3,5-Di(trifluoromethyl)phenyl)-5-((Z)-benzylidene)thi-

azolidin-2-imine (17c): Synthesized following general procedure

A, (50 mg, 0.38 mmol), purified by column chromatography (ethyl

acetate/hexanes = 3: 7) to afford compound 17c (78 mg, 50 %) as

an off-white solid. m.p. 178–180 °C. ¹H NMR: 7.59 (s, 2H), 7.57 (s,

1H), 7.50 – 7.32 (m, 2H), 7.31 – 7.20 (m, 3H), 6.62 (t, J = 2.5 Hz, 1H),

4.74 (d, J = 2.5 Hz, 2H). ¹³C NMR: 159.9, 148.2, 135.7, 132.5 (q, J =

33.2 Hz), 128.8, 127.8, 127.5, 123.3 (q, J = 271 Hz), 121.4, 120.8,

116.8 (q, J = 4.1 Hz), 57.9. FT-IR (neat, cm^–1): 3031, 2918, 2867, 2833,

1651, 1598, 1475, 1367, 1273, 1177, 1116, 948. HR-MS (m/z): calcd.

for [M + H]⁺C₁₈H₁₂N₂F₆S, 403.0698, found 403.0701.

(Z)-2-(Dimethylphenylimino)-5-((Z)-4-methoxybenzylidene)-3-

methylthiazolidin-4-one (12b): Synthesized following general pro-

cedure C, (60 mg, 0.17 mmol), purified by column chromatography

(ethyl acetate/hexanes = 1:19) to afford compound 12b (13 mg,

20 %, 57 % brsm) as an off-white solid. m.p. 168–172 °C. ¹H NMR:

7.71 (s, 1H), 7.36 (d, J = 8.9 Hz, 2H), 7.09 (d, J = 8.2 Hz, 2H), 7.01

(dd, J = 8.2, 6.8 Hz, 1H), 6.90 (d, J = 8.9 Hz, 2H), 3.81 (s, 3H), 3.50 (s,

3H), 2.13 (s, 6H). ¹³C NMR: 167.3, 160.9, 151.2, 145.9, 131.9, 130.7,

130.6, 128.5, 128.3, 126.4, 124.4, 119.1, 114.6, 55.5, 29.6, 18.0. FT-IR

(neat, cm^–1): 3065, 2946, 2836, 1697, 1633, 1589, 1509, 1461, 1255,

1181, 1030, 764. HR-MS (m/z): calcd. for [M + H]⁺C₂₀H₂₀N₂O₂S,

353.1318, found 353.1311.

(Z)-N-Allyl-5-((Z)-benzylidene)thiazolidin-2-imine (17d): Synthe-

sized following general procedure A, (50 mg, 0.38 mmol), purified

by column chromatography (ethyl acetate/hexanes = 3:7) to afford

compound 17d (54 mg, 62 %) as a light-yellow gum. ¹H NMR: 7.38

– 7.33 (m, 2H), 7.28 (d, J = 7.2 Hz, 2H), 7.20 (tt, J = 7.2, 1.2 Hz, 1H),

6.55 (t, J = 1.9 Hz, 1H), 5.93 (ddt, J = 17.1, 10.3, 5.5 Hz, 1H), 5.26

(dq, J = 17.1, 1.9 Hz, 1H), 5.17 (dq, J = 10.3, 1.6 Hz, 1H), 4.95 (d, J =

1.9 Hz, 2H), 3.98 (dt, J = 5.5, 1.6 Hz, 2H). ¹³C NMR: 158.8, 139.6,

136.7, 134.2, 128.6, 127.6, 126.6, 117.9, 116.7, 69.2, 46.7. FT-IR (neat,

cm^–1): 3206, 2922, 2853, 1615, 1543, 1493, 1239, 1073, 912, 717. HR-

MS (m/z): calcd. for [M + H]⁺C₁₃H₁₄N₂S, 231.0955, found 231.0935.

(Z)-2-(Bistrifluoromethylphenylimino)-5-((Z)-4-methoxybenzyl-

idene)-3-methylthiazolidin-4-one (12c): Synthesized following

general procedure C, (50 mg, 0.11 mmol), purified by column chro-

matography (ethyl acetate/hexanes = 0.5:9.5) to afford compound

12c (9 mg, 17 %, 67 % brsm) as off-white solid. m.p. 146–148 °C. ¹H

NMR: 7.78 (s, 1H), 7.68 (s, 1H), 7.46 (s, 2H), 7.40 (d, J = 8.8 Hz, 2H),

6.95 (d, J = 8.8 Hz, 2H), 3.83 (s, 3H), 3.44 (s, 3H). ¹³C NMR: 166.8,

161.4, 153.9, 149.8, 132.8 (q, J = 33.3 Hz), 132.5, 132.1, 125.9, 123.3

(Z)-5-((Z)-benzylidene)-N-phenyl-2-(phenylimino)thiazolidine-3-

carbothioamide (18): Synthesized following general procedure A,

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(50 mg, 0.38 mmol), purified by column chromatography (ethyl J = 8.7, 3.3, 1.0 Hz, 1H), 4.07 (d, J = 15.4 Hz, 1H), 3.98 (ddt, J = 8.7,

acetate/hexanes = 1: 9) to afford compound 18 (13 mg, 9 %) as an

4.6, 1.7 Hz, 2H), 1.79 (dtt, J = 8.7, 4.6, 1.7 Hz, 1H), 1.70 (ddd, J =

13.6, 8.1, 3.5 Hz, 1H), 1.58 (ddd, J = 13.6, 8.1, 3.5 Hz, 1H), 0.93 (d,

off-white solid. m.p. 146–150 °C. ¹H NMR: 7.59 (d, J = 9.1 Hz, 2H),

7.40 (td, J = 8.3, 3.1 Hz, 4H), 7.34 (t, J = 7.9 Hz, 2H), 7.27–7.23 (m, J = 6.6 Hz, 3H), 0.87 (d, J = 6.6 Hz, 3H). ¹³C NMR: 137.3, 136.8, 136.0,

4H), 7.20 (d, J = 7.9 Hz, 2H), 7.10 – 7.01 (m, 2H), 6.67 (d, J = 2.4 Hz,

133.8, 128.7, 128.6, 128.2, 128.1, 127.4, 127.2, 120.9, 114.7, 64.8, 56.7,

1H), 5.59 (d, J = 2.4 Hz, 2H). ¹³C NMR: 178.2, 156.8, 147.7, 138.7,

47.4, 42.2, 23.9, 23.8, 22.5. FT-IR (neat, cm^–1): 3026, 2954, 2925, 2867,

135.3, 129.6, 128.9, 128.8, 127.9, 127.7, 126.6, 125.7, 125.2, 123.2, 1648, 1617, 1543, 1493, 1399, 1280, 993, 909, 730, 693. HR-MS (m/z):

121.7, 121.5, 61.6. FT-IR (neat, cm^–1): 3080, 2918, 2849, 1603, 1565,

1488, 1450, 1396, 1317, 1188, 1063, 881, 744. HR-MS (m/z): calcd.

for [M + H]⁺C₂₃H₁₉N₃S₂, 402.1093, found 402.1090.

calcd. for [M + H]⁺C₂₄H₂₈N₂S, 377.2046, found 377.2045.

(Z)-N-Phenyl-5-methylidene-3-methylthiazolidin-2-imine (29a):

Synthesized following general procedure B, (50 mg, 0.72 mmol),

purified by column chromatography (ethyl acetate/hexanes =

1.5:8.5) to afford compound 29a (115 mg, 78 %) as a colorless gum.

¹H NMR: 7.31 – 7.25 (m, 2H), 7.07 – 7.02 (m, 1H), 6.94 (dd, J = 8.4,

1.2 Hz, 2H), 5.18 (q, J = 2.1 Hz, 1H), 5.06 (td, 2.3, 1.5 Hz, 1H), 4.23 (t,

J = 2.3 Hz, 2H), 3.06 (s, 3H). ¹³C NMR: 156.9, 151.9, 137.6, 129.0,

123.3, 122.2, 105.4, 58.0, 33.1. FT-IR (neat, cm^–1): 3055, 2914, 2848,

1647, 1617, 1572, 1466, 1419, 1376, 1272, 1190, 1066, 946, 847,

774. HR-MS (m/z): calcd. for [M + H]⁺C₁₁H₁₂N₂S, 205.0794, found

205.0793.

(Z)-N-Phenyl-3-benzyl-5-((Z)-benzylidene)-4-isobutylthi-

azolidin-2-imine (22a):^[13]Synthesized following general proce-

dure A, (100 mg, 0.36 mmol), purified by column chromatography

(ethyl acetate/hexanes = 3:7) to afford compound 22a (135 mg,

1

91 %) as a light-yellow gum. H NMR: 7.40 (m, 4H), 7.37 – 7.32 (m,

5H), 7.27 (dd, J = 8.4, 1.5 Hz, 2H), 7.24 – 7.20 (m, 1H), 7.11 (tt, J =

7.6, 1.5 Hz, 1H), 7.05 (dd, J = 8.4, 1.5 Hz, 2H), 6.45 (s, 1H), 5.53 (d,

J = 15.3 Hz, 1H), 4.42 (ddd, J = 7.5, 3.2, 0.9 Hz, 1H). 4.22 (d, J =

15.3 Hz, 1H), 1.92 – 1.80 (m, 2H), 1.68 (ddd, J = 13.9, 8.5, 3.2 Hz,

1H), 1.01 (d, J = 6.5 Hz, 3H), 0.95 (d, J = 6.5 Hz, 3H). ¹³C NMR:

155.9, 151.3, 137.0, 133.7, 129.1, 128.9, 128.7, 128.2, 128.1, 127.7,

127.5, 123.3, 122.4, 121.2, 65.2, 47.5, 42.5, 24.0, 23.9, 22.7. FT-IR

(neat, cm^–1): 3026, 2954, 2925, 2867, 1634, 1614, 1585, 1489, 1446,

1216, 1071, 750. HR-MS (m/z): calcd. for [M + H]⁺C₂₇H₂₈N₂S,

413.2046 , found 413.2056.

(Z)-N-(2,6-Dimethylphenyl)-5-methylidene-3-methylthiazolidin-

2-imine (29b): Synthesized following general procedure B, (50 mg,

0.72 mmol), purified by column chromatography (ethyl acetate/hex-

anes = 1:9) to afford compound 29b (127 mg, 76 %) as a colorless

1

gum. H NMR: 7.02 (d, J = 7.4 Hz, 2H), 6.92 – 6.89 (m, 1H), 5.17 (q,

J = 2.1 Hz, 1H), 5.01 (q, J = 2.4 Hz, 1H), 4.26 (t, J = 2.1 Hz, 2H), 3.11

(s, 3H), 2.16 (s, 6H). ¹³C NMR: 156.7, 149.5, 137.7, 129.7, 127.9, 123.2,

105.2, 58.7, 33.1, 18.2. FT-IR (neat, cm^–1): 3058, 2914, 2848, 1648,

1617, 1578, 1466, 1238, 1162, 1066, 950, 848, 766. HR-MS (m/z):

calcd. for [M + H]⁺C₁₃H₁₆N₂S, 233.1107, found 233.1109.

(Z)-N-(2,6-Dimethylphenyl)-3-benzyl-5-((E)-benzylidene)-4-iso-

butylthiazolidin-2-imine (22b): Synthesized following general pro-

cedure A, (100 mg, 0.36 mmol), purified by column chromatography

(ethyl acetate/hexanes = 3:7) to afford compound 22b (138 mg,

1

87 %) as a light-yellow gum. H NMR: 7.41 (m, 4H), 7.36 – 7.29 (m,

(Z)-N-(3,5-Bis(trifluoromethyl)phenyl-5-methylidene-3-methyl-

thiazolidin-2-imine (29c): Synthesized following general proce-

dure B, (50 mg, 0.72 mmol), purified by column chromatography

(ethyl acetate/hexanes = 1:9) to afford compound 29c (220 mg,

3H), 7.25 – 7.18 (m, 3H), 7.09 (d, J = 7.3 Hz, 1H), 7.05 (d, J = 7.3 Hz,

1H), 6.95 (t, J = 7.3 Hz, 1H), 6.43 (s, 1H), 5.56 (d, J = 15.4 Hz, 1H),

4.51 (ddd, J = 6.8, 3.0, 1.1 Hz, 1H), 4.27 (d, J = 15.4 Hz, 1H), 2.27 (s,

3H), 2.13 (s, 3H), 1.87 (ddd, J = 14.9, 7.3, 1 Hz, 2H), 1.73 – 1.66 (m,

1H), 1.03 (d, J = 6.4 Hz, 3H), 0.97 (d, J = 6.4 Hz, 3H). ¹³C NMR: 155.2,

1

90 %) as a colorless gum. H NMR: 7.51 (s, 1H), 7.37 (s, 2H), 5.26 (q,

J = 2.1 Hz, 1H), 5.13 (q, J = 2.4 Hz, 1H), 4.32 (t, J = 2.1 Hz, 2H), 3.08

137.2, 135.8, 133.8, 128.8, 128.7, 128.2, 128.1, 128.0, 127.6, 127.1, (s, 3H). ¹³C NMR: 158.2, 153.0, 136.2, 132.1 (q, J = 32.8 Hz), 123.4 (q,

123.1, 120.7, 65.9, 47.3, 42.7, 24.0, 23.9, 23.0, 18.5, 18.4. FT-IR (neat, J = 271 Hz), 122.6, 116.3 (q, J = 4.0 Hz), 106.4, 58.0, 33.0. FT-IR (neat,

cm^–1): 3025, 2952, 2918, 2867, 1641, 1617, 1586, 1492, 1397, 1281,

cm^–1): 2923, 2872, 1642, 1618, 1595, 1425, 1366, 1272, 1119, 966,

1212, 1154, 752, 692. HR-MS (m/z): calcd. for [M + H]⁺C₂₉H₃₂N₂S, 845, 702. HR-MS (m/z): calcd. for [M + H]⁺C₁₃H₁₀F₆N₂S, 341.0542,

441.2359, found 441.2357.

found 341.0539.

(Z)-N-Allyl-5-methylidene-3-methylthiazolidin-2-imine (29d):

Synthesized following general procedure B, (50 mg, 0.72 mmol),

purified by column chromatography (ethyl acetate/hexanes = 1:3)

to afford compound 29d (96 mg, 79 %) as a light-yellow gum. ¹H

NMR: 5.93 – 5.83 (m, 1H), 5.19 – 5.13 (m, 2H), 5.09 – 5.06 (m, 1H),

5.01 (dq, J = 10.2, 1.6 Hz, 1H), 4.07 (t, J = 2.2 Hz, 2H), 3.75 (dt, J =

5.4, 1.6 Hz, 2H), 2.87 (s, 3H). ¹³C NMR: 157.2, 137.7, 136.7, 114.7,

105.3, 57.9, 57.5, 33.1. FT-IR (neat, cm-1): 3077, 2921, 2866, 2807,

1649, 1616, 1580, 1416, 1236, 1106, 913, 857, 654. HR-MS (m/z):

calcd. for [M + H]⁺C₈H₁₂N₂S, 169.0794, found 169.0799.

(Z)-N-(3,5-Di(trifluoromethylphenyl)-3-benzyl-5-((Z)-benzyl-

idene)-4-isobutylthiazolidin-2-imine (22c): Synthesized following

general procedure A, (100 mg, 0.36 mmol), purified by column chro-

matography (ethyl acetate/hexanes = 3:7) to afford compound 22c

(186 mg, 94 %) as a light-yellow gum. ¹H NMR (500 MHz, [D₄]meth-

anol): 7.57 (s, 1H), 7.41 (s, 2H), 7.38–7.37 (m, 4H), 7.29 (t, J = 7.7 Hz,

3H), 7.20 (d, J = 7.7 Hz, 3H), 6.60 (s, 1H), 5.30 (d, J = 15.3 Hz, 1H),

4.53 (ddd, J = 7.8, 3.4, 1.4 Hz, 1H), 4.37 (d, J = 15.3 Hz, 1H), 1.89 –

1.74 (m, 2H), 1.71 (m, 1H), 0.94 (d, J = 6.4 Hz, 3H), 0.91 (d, J = 6.4 Hz,

3H). ¹³C NMR (125 MHz, [D₄]methanol): 158.0, 153.2, 136.6, 135.5,

132.2, 131.9, 131.5, 128.6, 128.3, 127.9 (q, J = 326 Hz), 127.8, 127.7,

127.5, 127.3, 122.5, 122.4, 115.7 (q, J = 4.0 Hz), 65.9, 41.9, 23.7, 22.7,

21.5. FT-IR (neat, cm^–1): 2957, 2927, 2870, 1636, 1597, 1494, 1369,

1276, 1172, 1132. HR-MS (m/z): calcd. for [M + H]⁺C₂₉H₂₆F₆N₂S,

549.1800, found 549.1830.

(E)-N-Phenyl-5-methylidenethiazolidin-2-imine (30a):^{[9–10, 28]}

Synthesized following general procedure B, (50 mg, 0.9 mmol), puri-

fied by column chromatography (ethyl acetate/hexanes = 1.5:8.5)

to afford compound 30a (138 mg, 80 %) as a light-brown solid. m.p.

1

104–108 °C (Lit.^[9]m.p. 113 °C). H NMR: 7.32 – 7.25 (m, 2H), 7.22 –

7.16 (m, 2H), 7.06 (m, 1H), 5.21 (q, J = 2.2 Hz, 1H), 5.15 – 5.10 (m,

1H), 4.61 (t, J = 2.2 Hz, 2H). ¹³C NMR: 159.6, 145.6, 143.9, 129.2,

123.7, 121.4, 104.3, 58.3. FT-IR (neat, cm^–1): 3242, 3191, 3027, 2856,

1590, 1550, 1492, 1444, 1314, 1077, 1037, 747. HR-MS (m/z): calcd.

for [M + H]⁺C₁₀H₁₀N₂S, 191.0637, found 191.0630.

(Z)-N-Allyl-3-benzyl-5-((Z)-benzylidene)-4-isobutylthiazolidin-2-

imine (22d): Synthesized following general procedure A, (100 mg,

0.36 mmol), purified by column chromatography (ethyl acetate/hex-

anes = 3:7) to afford compound 22d (95 mg, 70 %) as a light-yellow

1

gum. H NMR: 7.41 – 7.31 (m, 6H), 7.30 – 7.24 (m, 4H), 6.42 (s, 1H),

5.99 (ddt, J = 17.1, 10.2, 5.2 Hz, 1H), 5.36 (d, J = 15.4 Hz, 1H), 5.24

(dq, J = 17.1, 1.9 Hz, 1H), 5.08 (dq, J = 10.2, 1.9 Hz, 1H), 4.28 (ddd,

(E)-N-(2,6-Dimethylphenyl)-5-methylidenethiazolidin-2-imine

(30b): Synthesized following general procedure B, (25 mg,

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0.45 mmol), purified by column chromatography (ethyl acetate/hex-

anes = 1.5:8.5) to afford compound 30b (64 mg, 65 %) as a white

0840509). We thank Maciej Kukula in the Shimadzu Center for

Advanced Analytical Chemistry for obtaining the HRMS data

reported in this manuscript. We are grateful to Taru Bharadwaj

(Welch Summer Scholar 2016) for some preliminary experi-

ments.

1

solid. m.p. 94–98 °C. ¹H NMR: H NMR: 7.02 (d, J = 7.6 Hz, 2H), 6.96

(dd, J = 7.6, 6.6 Hz, 1H), 6.43 (bs, 1H), 5.14 (q, J = 2.1 Hz, 1H), 5.02

(bs, 1H), 4.42 (bs, 2H), 2.21 (s, 6H). ¹³C NMR: 145.4, 143.0, 132.2,

128.1, 124.8, 104.6, 60.5, 55.8, 18.3. FT-IR (neat, cm^–1): 3171, 3095,

2900, 2836, 1652, 1619, 1586, 1463, 1277, 1172, 1075, 774. HR-MS

(m/z): calcd. for [M + H]⁺C₁₂H₁₄N₂S, 219.0950, found 219.0943.

Keywords: Cyclization · Alkynes · Heterocycles ·

(E)-N-(3,5-Bis(trifluoromethyl)phenyl)-5-methylidenethiazol- Isothiocyanates · Synthetic methods

idin-2-imine (30c): Synthesized following general procedure B,

(25 mg, 0.45 mmol), purified by column chromatography (ethyl

[1] a) T. Lindel, Alkaloids 2017, 77, 117–219; b) Y. Ma, S. De, C. Chen, Tetrahe-

acetate/hexanes = 1.5:8.5) to afford compound 30c (115 mg, 78 %)

as a white solid. m.p. 80–82 °C. ¹H NMR: 7.54 (s, 1H), 7.49 (s, 2H),

6.90 (bs, 1H), 5.27 (q, J = 2.2 Hz, 1H), 5.17 (q, J = 2.5 Hz, 1H), 4.45

(t, J = 2.5 Hz, 2H). ¹³C NMR: 161.8, 149.7, 140.3, 132.4 (q, J = 32.9 Hz),

123.2 (q, J = 271.1 Hz), 121.9, 116.9 (q, J = 3.8 Hz), 106.4, 54.0. FT-

IR (neat, cm^–1): 3092, 2851, 2828, 1648, 1610, 1483, 1378, 1352,

1175, 1117. HR-MS (m/z): calcd. for [M + H] ⁺C₁₂H₈F₆N₂S, 327.0385,

found 327.0383.

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(E)-N-Allyl-5-methylidenethiazolidin-2-imine (30d):^[9–10]Synthe-

sized following general procedure B, (25 mg, 0.45 mmol), purified

by column chromatography (ethyl acetate/hexanes = 3:7) to afford

compound 30d (47 mg, 67 %) as a white solid. m.p. 96–98 °C (lit.^[9]

1

m.p. 92–94 °C). H NMR: 5.87 (ddt, J = 17.1, 10.3, 5.5 Hz, 1H), 5.21

(dq, J = 17.1, 1.4 Hz, 1H), 5.12 (dq, J = 10.3, 1.4 Hz, 2H), 5.08 (td, J =

2.8, 1.4 Hz, 1H), 4.67 (t, J = 2.8 Hz, 2H), 4.55 (bs, 1H), 3.88 (dt, J =

5.5, 1.4 Hz, 2H). ¹³C NMR: 158.5, 148.8, 134.4, 116.5, 102.5, 67.0, 46.6.

FT-IR (neat, cm-1): 3186, 3003, 2891, 2838, 1623, 1551, 1415, 1294,

1237, 1069, 1025, 841, 643, 593. HR-MS (m/z): calcd. for [M + H]⁺

C₇H₁₀N₂S, 155.0637, found 155.0629.

Synthesis of 1,4-dimethyl-3-phenyl-1,3-dihydro-2H-imidazole-

2-thione (33b): Synthesized following general procedure B, ¹H

NMR: 7.51 – 7.47 (m, 2H), 7.43 (t, J = 7.4 Hz, 1H), 7.27 (dd, J = 8.2,

1.2 Hz, 2H), 6.53 (d, J = 1.2 Hz, 1H), 3.61 (s, 3H), 1.90 (s, 3H). ¹³C

NMR: 163.5, 136.7, 129.5, 129.1, 128.4, 126.1, 115.3, 34.9, 10.9. FT-IR

(neat, cm^–1): 3058, 2914, 2848, 1648, 1617, 1578, 1466, 1238, 1162,

1066, 950, 848, 766. HR-MS (m/z): calcd. for [M + H]⁺C₁₁H₁₂N₂S,

204.0721, found 204.0692.

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Synthesis of thiocarbonyl intermediate: To a stirred solution of

propargylamine 5 (120 mg, 0.40 mmol) in CH₂Cl₂(2.0 mL) at r.t.

was added Et₃N (124 mg, 1.21 mmol) followed by the addition of

thiocarbonyldiimidazole (73 mg, 0.40 mmol). After 12 h, the reac-

tion mixture was diluted with water (5 mL) and CH₂Cl₂(5 mL), two

layers were separated. The aqueous part was back extracted with

CH₂Cl₂(2x10 mL). Combined organic extracts were washed with

brine (20 mL), dried with sodium sulfate and concentrated under

reduced pressure. The thus obtained crude material was purified by

column chromatography (MeOH/CH₂Cl₂= 1:9) to afford the thio-

urea 35 (112 mg, 68 %) as an off-white solid. m.p. 118–120 °C. ¹H

NMR: 7.62 (bs, 1H), 7.37 (d, J = 9.1 Hz, 4H), 7.03 (bs, 2H), 6.84 (d, J =

9.1 Hz, 4H), 3.79 (s, 3H), 3.77 (s, 3H), 3.34–3.12 (m, 5H). ¹³C NMR:

179.2, 160.2, 159.1, 133.4, 130.2, 129.8, 127.5, 119.5, 114.3, 114.2,

113.7, 87.4, 82.8, 58.2, 55.4, 55.4, 37.4. FT-IR (neat, cm^–1): 3168, 3115,

2922, 2839, 2222, 1604, 1523, 1454, 1368, 1290, 1240, 1168, 1069,

1024, 835, 744. HR-MS (m/z): calcd. for [M + Na]⁺C₂₃H₂₃N₃O₂S,

428.1403, found 428.1414.

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Acknowledgments

This work has been supported by the Robert A. Welch Founda-

tion (Y-1362). NMR spectra were obtained on instruments pur-

chased with grants from the NSF (CHE-0234811 and CHE-

Eur. J. Org. Chem. 0000, 0–0

www.eurjoc.org

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thiocyanate under Dethe′s recently reported conditions (neat, 40 °C) and

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ynes appear to cyclize under both the Dethe conditions and the condi-

tions reported herein, terminal alkynes do not cyclize under neat reac-

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[25] In unpublished work, we have discovered that simple thioureas engage

in oxidative dearomatization reactions and so failure of these systems

reflects the nucleophilicity of sulfur. For comparative purposes, thio-

carbamates related to 5 do participate in the dearomatization pathway

and this presumably reflects the attenuated nucleophilicity of the sulfur

in this functional group.

Received: October 3, 2018

Eur. J. Org. Chem. 0000, 0–0

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Heterocyclic Synthesis*

A metal-free coupling reaction be-

tween propargylamines and isothio-

cyanates affords good yields of vinyl-

idene substituted thiazolidines. Con-

trol reactions suggest that these reac-

tions are in fact mediated by silica gel.

A broad substrate scope and a variety

of substitution patterns are accessible.

R. P. S. D. Gout, C. J. Lovely* ........ 1–16

Tandem Thioacylation-Intramolec-

ular Hydrosulfenylation of Prop-

argyl Amines – Rapid Access to 2-

Aminothiazolidines

DOI: 10.1002/ejoc.201801505

Eur. J. Org. Chem. 0000, 0–0

www.eurjoc.org

16

Article Doi

Tandem Thioacylation-Intramolecular Hydrosulfenylation of Propargyl Amines – Rapid Access to 2-Aminothiazolidines

DOI: 10.1002/ejoc.201801505

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