4-Alkenyl-2-aminothiazoles: Smart dienes for polar [4 + 2] cycloadditions

FULL PAPER

DOI: 10.1002/ejoc.201201185

4-Alkenyl-2-aminothiazoles: Smart Dienes for Polar [4+2] Cycloadditions

Mateo Alajarin,*^[a]Jose Cabrera,^[a]Pilar Sanchez-Andrada,^[a,b]Raul-Angel Orenes,^[c]and

Aurelia Pastor*^[a]

Dedicated to Professor Waldemar Adam on the occasion of his 75th birthday

Keywords: Cycloaddition / Cyclization / Nitrogen heterocycles / Zwitterions / Reaction mechanisms

An exhaustive investigation into the [4+2] cycloadditions of

4-alkenyl-2-aminothiazoles with a wide range of dienophiles

has been carried out. 4-Alkenyl-2-aminothiazoles act as good

in-out dienes, reacting with dienophiles bearing electron-

withdrawing groups. The heteroannulations, typically con-

ducted under mild conditions, were endo-selective when

cyclic dienophiles were used, and regioselective when the

reactions are conducted with unsymmetrical dienophiles.

low levels of endo selectivity and the lack of stereospecificity

in the reactions with certain acyclic dienophiles indicate a

stepwise mechanism with a zwitterion as the most plausible

intermediate. The course of the reaction changes when the

highly reactive PTAD and TCNE are used as dienophiles,

since in these cases, only addition products were obtained.

Calculations of the HOMO and LUMO energy values of rep-

resentative 4-alkenyl-2-aminothiazoles, and the results of π-

The endo-selective processes presumably take place by con- facial diastereoselective processes by using chiral substrates

certed but highly asynchronous mechanisms. In contrast, the

are also disclosed.

Introduction

systems to be prepared.^[5]Diverse polycyclic structures have

been synthesized in this way from vinylfurans,^[6]vinyl-

indoles,^[7]vinylpyrroles,^[8]and vinylimidazoles.^[9]

The Diels–Alder reaction, a [4π + 2π] cycloaddition, re-

sults in six-membered-ring products through carbon–car-

bon bond formation.^[1]This process has been extensively

investigated since its discovery, and a large number of vari-

ants are known.^[2]Nowadays, the Diels–Alder reaction con-

tinues to play a central role in the total syntheses of many

natural products, and also in the construction of a large

number of compounds of biological importance.^[3]

The use of heteroaromatic compounds as either the diene

or dienophile component is an area of great interest in

Diels–Alder chemistry.^[4]Aromatic vinyl heterocycles may

undergo Diels–Alder reaction as dienes by involving either

the aromatic nucleus (intra-annular addition) or the diene

moiety including the side-chain double bond (extra-annular

addition). In general, the latter mode of reaction is pre-

ferred, and this allows substituted condensed heterocyclic

In recent years, there has been considerable interest in

substituted and bicyclic derivatives of thiazoles, as the 1,3-

thiazole ring appears in a diverse range of natural products

and other biologically active compounds.^[10]For instance,

thiazolo[5,4-b]pyridin-5(4H)-one derivatives are efficient

HIV integrase strand-transfer inhibitors,^[11]2-aminothi-

azole derivatives are inhibitors of cdk5/p25, and thus are

potentially useful for the treatment of Alzheimer’s disease

and other neurodegenerative disorders,^[12]and 5-arylidene-

2-imino-4-thiazolidinones show significant levels of anti-in-

flammatory activity.^[13]Unfortunately, functionalization of

the thiazole ring is usually a difficult task, since, due to its

electron-deficient aromatic character, this heterocycle is

very reluctant to undergo electrophilic substitution or ad-

dition, or indeed cycloaddition across the formal C=C and

C=N double bonds.^[14]The loss of the aromaticity results

in reactions that are less exothermic than classical Diels–

Alder processes.^[15]In fact, only reactions with highly reac-

tive dienophiles have been described to date. These pro-

cesses lead to intermediate bicyclic products that sub-

sequently undergo chelotropic extrusion of sulfur^[16]or eli-

mination of a nitrile molecule.^[17]

[a] Department of Organic Chemistry, Faculty of Chemistry,

University of Murcia, Regional Campus of International

Excellence “Campus Mare Nostrum”,

30100 Murcia, Spain

Fax: +34-868884149

E-mail: alajarin@um.es

aureliap@um.es

[b] University Centre of Defence, at the Spanish Air Force

Academy, Base Aerea de San Javier, c/ Coronel Lopez

Peña s/n, 30720 Santiago de la Ribera, Murcia, Spain

[c] SAI, University of Murcia, Campus de Espinardo,

30100 Murcia, Spain

Recently, we have demonstrated that 4-alkenyl-2-methyl-

and 4-alkenyl-2-phenylthiazoles react with classical dieno-

philes such as maleimides,^[18]maleic anhydride,^[18]or 4-

phenyl-1,2,4-triazoline-3,5-dione (PTAD),^[19]which opens a

Supporting information for this article is available on the

WWW under http://dx.doi.org/10.1002/ejoc.201201185.

474

Eur. J. Org. Chem. 2013, 474–489

Cycloadditions of 4-Alkenyl-2-Aminothiazoles

new route to polyheterocyclic derivatives. Given the scarcity

4-Alkenyl-2-(dimethylamino)thiazole 1e was also synthe-

of reports of the participation of thiazoles in Diels–Alder sized using microwave irradiation (Scheme 2). Thiazole 1e

processes, and the significance of the thiazolyl moiety in was thus isolated in a yield comparable to that obtained in

medicinal chemistry, it seemed to be desirable to develop the thermal reaction, but in a shorter reaction time.

this area of synthetic chemistry. To expand the scope of

the [4+2] cycloaddition reactions of 4-alkenylthiazoles, we

decided to investigate the reactions of these substrates bear-

ing an amino group at 2-position, in the hope that this sub-

stitution pattern would activate the thiazole ring.^[14a,20]It is

well known that for normal-electron-demand Diels–Alder

reactions, an increase in the electron-rich character of the

diene and an increase in the electron-poor character of the

dienophile result in an enhancement of the charge transfer

Scheme 2. Synthesis of 4-alkenyl-2-aminothiazole 1e by MW irradi-

ation.

and a decrease in the activation barrier.^[21]Taking these

ideas into account, 4-alkenyl-2-aminothiazoles should be

much more reactive than their previously investigated 2-alk-

yl- and 2-aryl-substituted conterparts, and thus they would

potentially be able to participate as highly reactive dienes

in a more varied collection of Diels–Alder reactions.

In this paper, we disclose our findings regarding the syn-

thesis of 4-alkenyl-2-aminothiazoles and their reactivity as

dienes in [4+2] cycloaddition reactions with a wide range

Racemic 2-(dimethylamino)thiazoles 1f–h were easily

prepared from the corresponding α-chloro ketones (i.e., 2c–

e) and thiourea 3d (Scheme 3, Table 2). α-Chloro ketones

2c and 2e have been reported previously.^[19]The synthesis

of α-chloro ketone 2d is described in the Supporting Infor-

mation.

of dienophiles. Issues pertaining to stereocontrol and regi-

ochemistry are also discussed. Finally, we have investigated

some striking aspects of the mechanism, namely the opera-

tion of a concerted vs. a stepwise process.

Results and Discussion

Synthesis of 4-Alkenyl-2-aminothiazoles 1

Scheme 3. Synthesis of chiral 4-alkenyl-2-aminothiazoles 1f–h (2c:

R¹= Ph, R²= Me, 2d: R¹= Et, R²= Me, 2e: R¹,R²

=

The 4-alkenyl-2-aminothiazoles (i.e., 1a–e) were prepared

by a Hantzsch synthesis,^[22]by reacting previously reported

α-chloro ketones 2a–b with thioureas 3a–d at room tem-

perature (Scheme 1). Thiazoles 1a–e were isolated in yields

of 82–90% (Table 1). Thioureas 3, except for N,N-dimeth-

ylthiourea (3d), are commercially available. Thiourea 3d was

prepared following a previously reported method.^[16b]

CH₂OCH₂CH₂).

Table 2. Synthesis of chiral 4-alkenyl-2-aminothiazoles 1f–h.

Entry

R¹

R²

Product

Yield [%]

1

2

3

Ph

Et

Me

1f

1g

1h

87

60

62

–CH₂OCH₂CH₂–

Scheme 1. Synthesis of 4-alkenyl-2-aminothiazoles 1a–e (2a: R¹=

4-MeC₆H₄, 2b: R¹= 4-MeOC₆H₄, 3a: R²= NH₂, 3b: R²= NHPh,

3c: R²= NHMe, 3d: R²= NMe₂).

HOMO Energies of Thiazoles 1

The HOMO energies of the 4-alkenyl-2-amino-, 4-vinyl-

2-hydroxy-, and 4-vinyl-2-mercaptothiazoles (i.e., 1i–m; Fig-

ure 1) were obtained through single-point Hartree–Fock

(HF) calculations with the 6-31G basis set using B3LYP/6-

31G geometries, as this procedure has been shown to pro-

vide more accurate orbital energies than the B3LYP level.^[23]

The computed B3LYP/6-31G structures of thiazoles 1i–m

in their reactive s-cis conformations are shown in Figure 2.

In Table 3 we summarize the HOMO energies and the 2p_z

eigenvectors of the HOMOs of dienes 1i–m.

Table 1. Synthesis of 4-alkenyl-2-aminothiazoles 1a–e.

Entry

R¹

R²

Product

Yield [%]

1

2

3

4

5

4-MeC₆H₄

4-MeOC₆H₄

4-MeC₆H₄

NH₂

1a

1b

1c

1d

1e

82^[a]

83^[a]

90

NHPh

NHMe

NMe₂

86

88^[a]

[a] Previously described in ref.^[16b]

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475

M. Alajarin, A. Pastor et al.

FULL PAPER

in Table 3 show that the HOMO energy is slightly enhanced

by the presence of a phenyl group at C-1 (Figure 1 and

Table 3, entry 1), as was also found for the analogous 2-

phenyl-substituted thiazole.^[18]Finally, the introduction of

a hydroxy or thiol group at the 2-position did not result

in any significant increase of the HOMO energy (Table 3,

entries 4–5). Hence, we should expect that 4-alkenyl-2-

aminothiazoles behave as activated dienes in normal-elec-

tron-demand [4+2] cycloaddition reactions, but their reac-

tivities are predicted to be only slightly higher than those

of the 2-methyl and 2-phenyl derivatives.

Figure 1. Structures of 4-alkenyl-2-amino-, 2-hydroxy-4-vinyl-, and

2-mercapto-4-vinylthiazoles 1i–m.

[4+2] Cycloadditions of 4-Alkenyl-2-aminothiazoles 1a–e

The reactions of thiazoles 1a–e with N-phenylmaleimide

(NPM) or maleic anhydride (MA) were conducted in aceto-

nitrile at room temperature (Scheme 4). Under these con-

ditions, tetrahydropyrrolo[3,4-g]benzothiazole-6,8-diones

endo-4a–e and tetrahydrofuro[3,4-g]benzothiazole-6,8-dione

endo-4f were obtained in excellent yields (Table 4). Com-

pounds endo-4a–f are the result of a [4+2] cycloaddition

and a further 1,3-hydrogen migration. The possible pres-

ence of the primary cycloadducts or those resulting from a

further ene reaction with a second equivalent of dienophile

1

was ruled out by analysis of the H NMR spectra of the

crude products.^[18]As far as it could be determined, only

the stereoisomer deriving from an endo transition state is

formed in each case, as shown by the X-ray crystal structure

of 4e (see below).

Figure 2. Computed B3LYP/6-31G geometries of 4-alkenyl-2-

amino-, 2-hydroxy-4-vinyl-, and 2-mercapto-4-vinylthiazoles 1i–m

in their respective s-cis conformations.

Table 3. HOMO values for 4-alkenyl-2-amino-, 2-hydroxy-4-vinyl-,

and 2-mercapto-4-vinylthiazoles 1i–m in their respective s-cis con-

formations (for the numbering of the diene carbon atoms, see Fig-

ure 1).

Entry

Diene Eigenvalue [eV]

2p_zcoefficients

C-1

C-2

C-3 C-4

1

2

3

4

5

s-cis-1i

s-cis-1j

s-cis-1k

s-cis-1l

s-cis-1m

–7.40

–7.98

–7.84

–8.57

–8.56

–0.21

–0.20

–0.25

–0.24

–0.22 0.17 0.27

–0.14 0.23 0.33

–0.13 0.23 0.33

–0.18 0.25 0.32

–0.17 0.24 0.30

Scheme 4. Reactions of 4-alkenyl-2-aminothiazoles 1a–e with NPM

and MA (R¹and R²defined in Table 4).

Table 4. Reactions of 4-alkenylthiazoles 1a–e with NPM and MA.

Entry

R¹

R²

X

t [h] Product Yield [%]

According to the FMO theory, dienes with substituents

capable of donating electron density into the conjugated π-

system show higher reactivity in normal-electron-demand

Diels–Alder reactions.^[21,24]Thus, we used the computed

HOMO values of thiazoles 1i–m to predict their relative

reactivities. Contrary to our expectations, the presence of

an amino group induces only a slight increase in the

HOMO energies of 2-aminothiazoles 1i–k compared to

those of their 2-methyl- and 2-phenyl-substituted counter-

1

2

3

4

5

6

4-MeC₆H₄

NH₂

NPh 48 endo-4a

90

91

90

91

72

NHPh NPh 48 endo-4b

NHMe NPh 48 endo-4c

4-MeOC₆H₄NHMe NPh 48 endo-4d

4-MeC₆H₄

NMe₂NPh 48 endo-4e

NMe₂24 endo-4f

O

Notably, the reactions shown in Scheme 4 take place un-

parts.^[18]Thus, the HOMO value of 2-amino-4-vinylthiazole der exceedingly mild reaction conditions considering that

1j is –7.98 eV (Table 3, entry 2), whereas the previously re- the cycloaddition step involves the dearomatization of the

ported values for 2-phenyl- and 2-methyl-4-vinylthiazoles thiazole ring. For the sake of comparison, previously de-

are –8.01 eV and –8.41 eV, respectively.^[18]The data shown scribed reactions of 4-alkenyl-2-methyl- and 4-alkenyl-2-

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Cycloadditions of 4-Alkenyl-2-Aminothiazoles

phenylthiazoles with the same dienophiles had to be con- with the expected cycloadduct (i.e., 7ЈЈ) when DMMa was

ducted at 120 °C in the same solvent.^[18]This fact indicates used (Table 5, entries 1–4). The reactions with DMFu were

that 4-alkenyl-2-aminothiazoles 1 are considerably more re- also not diastereoselective (Table 5, entries 5 and 6), and no

active, despite the predictions done on the basis of their discrimination between the endo (7) and the exo (7Ј) ap-

HOMO levels.

proaches was seen.

Next, we investigated the reactions of 4-alkenyl-2-amino-

thiazole 1e with the highly reactive dienophiles PTAD and

tetracyanoethylene (TCNE). Much to our surprise, the ex-

pected [4+2] cycloadducts were not isolated in either case.

Instead, thiazoles 5 and 6, resulting from an initial electro-

philic addition of PTAD or TCNE to the C-5 atom of the

thiazole ring, were obtained (Scheme 5).

Table 5. Reactions of 4-alkenyl-2-aminothiazoles 1a and 1c–e with

dimethyl maleate (DMMa) and dimethyl fumarate (DMFu).

Entry

R¹

R²

X=X Yield [%] 7/7Ј/7ЈЈ^[a]

1

2

3

4

4-MeC₆H₄

4-MeC₆H₄NHMe DMMa

4-MeOC₆H₄NHMe DMMa

4-MeC₆H₄

4-MeC₆H₄NHMe DMFu

4-MeC₆H₄NMe₂DMFu

NH₂DMMa

35

64

72

93

43:00^[b]:57

36:10^[c]:54

42:00^[b]:58

23:28:49

a

b

c

NMe₂DMMa

d

5

6

81

96

41:59:00^[b]

b

d

47:53:00^[b]

[a] Determined by analysis of characteristics signals in the ¹H

NMR spectrum of the crude product (errorϮ5% of the stated

1

value). [b] Not detected in the H NMR spectrum of the reaction

mixture. [c] Not isolated, but detected in the ¹H NMR spectrum of

the reaction mixture.

Regioselectivity in the [4+2] Cycloadditions of 4-Alkenyl-2-

aminothiazoles with Unsymmetrical Dienophiles

The regioselectivity of this kind of Diels–Alder reactions

can be investigated by using unsymmetrical dienophiles. Ac-

cording to FMO theory, the regiochemistry of the Diels–

Alder reaction is controlled by the complementarity of the

frontier orbitals of the diene and the dienophile. Thus, more

effective overlap takes place between the ends of the two

components with the highest coefficients.^[1a]For 4-alkenyl-

2-aminothiazoles 1, the atom with the coefficient with the

highest absolute value is C-5 of the thiazole ring (labelled

as C-4 in Figure 1 and Table 3). Regarding the LUMO of

the dienophile, when an electron-withdrawing substituent is

present at the α-position, the atom with the highest coeffi-

cient is at the adjacent β-position.^[25]

Methyl acrylate, α-chloroacrylonitrile, ethyl 2,3-butadi-

enoate, and ethyl propiolate were chosen as model dieno-

philes to probe the regioselectivity of the cycloaddition re-

actions of 1. The reaction of 1c with a large excess of methyl

acrylate in acetonitrile under reflux led to cycloadducts 8a

and 8b, both as endo/exo mixtures, in a moderate overall

yield (Scheme 7). This process was highly regioselective, al-

though negligible endo/exo selectivities were observed for

both 8a and 8b. To avoid the undesired addition of the

dienophile to the amino group (cycloadducts endo-8b and

exo-8b), the reaction of dimethylamino derivative 1e with

methyl acrylate was conducted under analogous conditions,

Scheme 5. Reaction of 4-alkenyl-2-(dimethylamino)thiazole 1e with

PTAD and TCNE.

Next, the reactions of 4-alkenylthiazoles 1a–e with di-

methyl maleate (DMMa) and dimethyl fumarate (DMFu)

were explored. These reactions were conducted in acetoni-

trile under reflux for 48 h (Scheme 6, Table 5). That higher

reaction temperatures and a large excess of dienophile

(15 equiv.) were required is consistent with the lower reac-

tivity of DMMa or DMFu arising from their acyclic struc-

tures. The reaction products, dimethyl 4,5,6,7-tetrahydro-

benzothiazole-6,7-dicarboxylates 7, 7Ј, and 7ЈЈ, are the re-

sult of a Diels–Alder cycloaddition followed by a 1,3-hydro-

gen migration. Notably, no reaction was observed when 4-

alkenyl-2-(phenylamino)thiazole 1b was used as starting

material (result not shown). The cycloadditions of thiazoles

1a and 1c–e with DMMa were not stereospecific. Thus,

cycloadducts 7 and/or 7Ј, in which the two carboxymethyl

substituents have a trans arrangement, were isolated along

giving

a mixture of endo-8c and exo-8c exclusively

(Scheme 8).

The reaction of 1e with α-chloroacrylonitrile was carried

out in acetonitrile at reflux temperature (Scheme 9). Cy-

cloadduct 9 was isolated in good yield as a single re-

gioisomer. The formation of 9 was highly diastereoselective,

Scheme 6. Reactions of 4-alkenyl-2-aminothiazoles 1a and 1c–e

with dimethyl maleate (DMMa) and dimethyl fumarate (DMFu)

(R¹, R²and X=X defined in Table 5).

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M. Alajarin, A. Pastor et al.

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Scheme 9. Reaction of 4-alkenyl-2-(dimethylamino)thiazole 1e with

α-chloroacrylonitrile, ethyl 2,3-butadienoate, and ethyl propiolate.

The unequivocal assignment of 10 was established on the basis of

a cross-peak between C-7a and the protons of the methyl group

attached to the benzothiazole ring, observed in its 2D HMBC spec-

trum (see next section).

Scheme 7. Reaction of 4-alkenyl-2-(methylamino)thiazole 1c with

methyl acrylate. Diastereomeric ratio determined by analysis of

1

characteristic signals in the H NMR spectrum of the crude prod-

uct (errorϮ5% of the stated value).

[4+2] Cycloadditions of Chiral 4-Alkenyl-2-aminothiazoles

The reactions of 1f–h, which contain a chiral carbon

atom in the 4-alkenyl side chain, with NPM were initially

carried out in acetonitrile at room temperature (Scheme 10

and Table 6, entries 1–3). Under these conditions, tetra-

hydropyrrolo[3,4-g]benzothiazole-6,8-diones endo-4g–i and

endo-4gЈ–iЈ were obtained as 50:50 mixtures of dia-

stereomers. We were unable to separate these mixtures, ex-

cept for endo-4g and endo-4gЈ, whose separation could be

achieved by chromatographic techniques. The use of a less

polar reaction solvent, such as toluene, resulted in a slight

diastereomeric excess (Table 6, entry 4). The relative config-

uration of the chiral centres of the major diastereomer was

not assigned, due to the low levels of diastereoselectivity

(see below).

Scheme 8. Reaction of 4-alkenyl-2-(dimethylamino)thiazole 1e with

methyl acrylate. Diastereomeric ratio determined by analysis of

1

characteristic signals in the H NMR spectrum of the crude prod-

uct (errorϮ5% of the stated value).

and a single diastereoisomer was formed exclusively. Thi-

azole 1e also reacted with allenyl and alkynyl dienophiles

such as ethyl 2,3-butadienoate and ethyl propiolate to give

ethyl 4,5-dihydrobenzothiazole-6-carboxylate derivatives 10

and 11 in good yields (Scheme 9).

This study thus corroborates that the reactions of 4-alk-

enyl-2-aminothiazoles 1 with unsymmetrical dienophiles are

regioselective. It must be also stressed that substrates 1 react

with NPM, MA, dimethyl fumarate, dimethyl maleate,

methyl acrylate, and other typical dienophiles with the ex-

clusive participation of the side-chain double bond (extra-

annular addition). Therefore, these reactions may be also

described as site-selective.

Scheme 10. Reactions of chiral 4-alkenyl-2-aminothiazoles 1f–h

with NPM (R¹and R²defined in Table 6).

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Cycloadditions of 4-Alkenyl-2-Aminothiazoles

Table 6. Reactions of chiral 4-alkenyl-2-aminothiazoles 1f–h with

NPM.

Entry R¹

R²

Solvent t [h] endo-4/endo-4Ј^[a]

Yield [%]

1

2

3

4

Ph

Et

Me

MeCN 72

MeCN 16

50:50

g

h

i

80^[b]

80^[c]

99^[c]

–

CH₂OCH₂CH₂MeCN 48

Ph Me toluene 72

50:50

60:40^[d]

g

[a] Determined by analysis of characteristic signals in the ¹H NMR

spectrum of the crude product (errorϮ5% of the stated value).

[b] The diastereomeric mixture was separated and the two dia-

stereomers were isolated in 42 and 38% yield. [c] Inseparable dia-

stereomeric mixture. [d] The relative configurations of the major

and minor diastereomers are unassigned.

Structural and Configurational Assignment

The relative configuration of endo-4e was unequivocally

established by single-crystal X-ray analysis (see Supporting

Information). The configurational assignment of com-

pounds endo-4a–d and endo-4f was done by comparison of

their ¹H NMR spectroscopic data with that of endo-4e. The

coupling constants between protons 5-H/5a-H and 5a-H/

8a-H were especially informative, being in the ranges 4.2–

5.6 and 7.6–8.0 Hz, respectively. The overlapping of the res-

1

onances of protons 5-H, 5a-H, and 8a-H in the H NMR

spectra of endo-4g–i and endo-4gЈ–iЈ hampered an unam-

biguous assignment. Nevertheless, bearing in mind that re-

actions of achiral 1a–e with NPM were completely endo-

selective, the mixtures of diastereomers obtained in the re-

actions of 1f–h with NPM, namely endo-4g–i and endo-4gЈ–

iЈ, were assigned to result from an endo approach of the

dienophile to the two diastereotopic faces of the diene.

The relative stereochemistry of 7, 7Ј, and 7ЈЈ was estab-

lished on the basis of the values of the coupling constants

between the protons of the six-membered ring, and of sig-

nificant cross-peaks in their respective ¹H,¹H-NOESY spec-

tra (Figure 3). We worked on the basis that cycloadducts 7,

7Ј, and 7ЈЈ would, in solution, have the half-chair conforma-

Figure 3. Significant coupling constants (red colour, dashed arrows

[Hz]) and NOE effects (blue colour, solid arrows) for the assign-

ment of the relative configuration of cycloadducts 7, 7Ј, and 7ЈЈ.

tion shown in Figure 3.^[7d]The most significant coupling 7-H and 4Ј-H/6-H, which suggest that 4Ј-H and 6-H adopt

constants for these assignments are those between protons a 1,3-cis arrangement. Finally, the lack of a cross-peak be-

6-H/5-H and 6-H/7-H. For stereoisomers 7, the coupling tween H_orthoand 7-H in the spectrum of 7bЈЈ is consistent

constants between these pairs of protons have values in the with the relative configuration assigned with the aid of the

ranges 11.3–11.4 and 9.3–9.9 Hz, respectively, indicating coupling constants.

that 5-H, 6-H, and 7-H adopt 1,2-transdiaxial arrange-

Some of the resonances for the protons of the six-mem-

ments.^[7d]For cycloadducts 7Ј, the coupling constants be- bered rings in the H NMR spectra of the endo/exo struc-

tween 6-H/7-H are between 8.8 and 8.9 Hz, which is consis- tures of 8a–c were partially overlapping, which hampered

tent with a relative trans arrangement, and the J values for the unequivocal configurational assignment of these struc-

the pairs of protons 5-H/6-H, 4-H/5-H, and 4’-H/5-H indi- tures. Unfortunately, the NOESY spectrum of endo-8a did

cate a cis arrangement for 5-H and 6-H (Figure 3).^[7d]Fi- not reveal conclusive information. Nevertheless, their struc-

nally, all of the J values for the 5-H, 6-H, and 7-H protons tures were tentatively attributed by comparison of selected

in stereoisomers 7ЈЈ are lower than 7 Hz, which indicates coupling constants with those of 7, 7Ј and 7ЈЈ (see Exp.

1

that they have relative 1,2-cis arrangements.^[7d]

The most representative contacts shown in the H,¹H-

Sect.).

1

The structures of regioisomers 9, 10, and 11 were un-

NOESY spectra of 7b, 7dЈ, and 7bЈЈ (Supporting Infor- equivocally identified according to the pattern of coupling

mation) are also shown in Figure 3. The cross-peaks ob- of the protons in the six-membered rings. It was not pos-

served between the 5-H/7-H and 4Ј-H/6-H pairs of protons sible to determine the relative configuration of the two chi-

in the spectrum of 7b are consistent with the assignment ral centres in 9. Nevertheless, on the basis of previous re-

based on the coupling constants. Regarding 7dЈ, the most ports,^[26]the relative configuration of 9 was tentatively as-

relevant contacts are those shown between protons H_ortho

/

signed by considering a “chloro-endo” approach of the di-

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479

M. Alajarin, A. Pastor et al.

FULL PAPER

enophile. This assumption is supported by the fact that the reactions of the 4-alkenyl-2-aminothiazoles 1a–e with NPM

resonances of the aromatic protons of the p-tolyl substitu- and MA. Nevertheless, the transition states for these pro-

ent at the 5-position of the benzothiazole ring are shifted cesses may be highly asynchronous, due to the unsymmetri-

by more than 0.2 ppm to higher frequencies in compound cal nature of the dienes.^[21,28]Based on the electron-donat-

9 compared to tetrahydrobenzothiazoles endo-8. This para- ing character of the amino group of the diene, formation

magnetic shift could be induced by the anisotropic effect of the C-5(thiazole ring)–C(NPM) bond should be more

of the nitrile functionality in the adjacent pseudoequatorial advanced in the putative transition state. This fact would

position (Figure 4).

explain the lack of π-facial diastereoselectivity observed in

the reactions of thiazoles 1f–h with NPM. In order to ratio-

nalize the observed results, we propose an endo approach

of NPM to conformers A and B of 1f–h (Scheme 11). In

structures A and B, the largest group (R¹) would be located

antiperiplanar to the approaching trajectory of the dieno-

phile.^[29]In principle, the transition state resulting from the

approach of NPM to conformer A would be favoured, as

the hydrogen atom is placed at the inside position, thus avo-

iding 1,3-allylic strain.^[30]The lack of diastereoselectivity

may be explained by considering the highly asynchronous

nature of the transition states shown in Scheme 11. In these

transition states, the bond forming adjacent to the ste-

reogenic centre is longer, and so the influence of the chiral

substituent would be minimal, thus it would be unable to

induce facial differentiation.

Figure 4. Proposed preferred conformations for compounds endo-

1

8 and 9 on the basis of their H NMR spectroscopic data.

Finally, the structural determination of cycloadduct 10

was done taking into account the information contained in

1

the 2D HMQC, 2D HMBC and H,¹H-NOESY spectra.

The appearance of a cross-peak relating the protons of the

methyl group attached to the benzothiazole ring with C-7a

in the 2D HMBC experiment was the key evidence in its

unambiguous assignment (Scheme 9).

Proposed Mechanism for the [4+2] Cycloadditions of 4-

Alkenyl-2-aminothiazoles 1a–h with Dienophiles

In a previous paper, we proposed that [4+2] cycload-

ditions of 4-alkenyl-2-methyl- and 4-alkenyl-2-phenylthi-

azoles with dienophiles is

a concerted HOMO_diene–

LUMO_dienophile-controlled process.^[18]According to FMO

theory, the presence of the amino group at C-2 of the thi-

azole ring in 4-alkenylthiazoles 1 should result in an in-

crease in reactivity in normal-electron-demand Diels–Alder

reactions.^[24]In fact, computed HOMO values of represen-

Scheme 11. Suggested mechanism for the formation of cycload-

ducts endo-4g–i and endo-4gЈ–iЈ (R¹and R²defined in Tables 2 and

6).

Several experimental observations indicate a change from

tative 4-alkenyl-2-aminothiazoles 1i–m are slightly higher a concerted cycloaddition process to a stepwise mechanism

than those of reported 4-alkenyl-2-methyl- and 4-alkenyl-2- in the reactions of 4-alkenyl-2-aminothiazoles 1 with the

phenylthiazoles. However, this slight increase does not re- acyclic dienophiles tested. That appropriate substitutents

flect the dramatic enhancement of reactivity shown by on the diene and the dienophile can favour the stabilization

dienes 1a–e (Scheme 4). This experimental evidence reveals of charges of opposite signs and change the mechanism

that factors other than the HOMO values, such as polar from concerted to stepwise is supported by previous

effects, may come into play.^[27]As Domingo and co-workers work.^{[21,27–28,31]}We propose the mechanism shown in

stated, the feasibility of a Diels–Alder reaction is mainly Scheme 12 to explain the reactions of thiazoles 1 with acy-

related to the polar character of the process, described by clic dienophiles of generic structure X=Y. As we stated

the charge transfer at the corresponding TS.^[21]

above, C-5 of the thiazole ring is activated by the presence

On the basis of the stereospecificity and high endo selec- of the amino group. The increase in electron density at this

tivity observed, we propose a concerted mechanism for the position is substantiated by the fact that the resonances of

480

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Eur. J. Org. Chem. 2013, 474–489

Cycloadditions of 4-Alkenyl-2-Aminothiazoles

the C-5 protons are shifted to lower frequencies than those hydrogen migration, intermediate 16 would eliminate a mo-

of unsubstituted thiazoles in their respective NMR spec- lecule of hydrogen cyanide. Previous reports have shown

tra.^[16b]The nucleophilic attack of C-5 of the thiazole, at that other 2-aminothiazoles react easily with TCNE to give

the most electron-deficient position of the dienophile would analogous products.^[14a]In a more general sense, dienes

give zwitterionic intermediate 12. This process would be as- with substituents that are able to stabilize zwitterionic inter-

sisted by the lone pair of the amino group at C-2. The low mediates usually react with TCNE to give the correspond-

reactivity shown by thiazole 1b in its reactions with DMMa ing addition products, followed by β-elimination of hydro-

and DMFu (see above) supports the important role of this gen cyanide.^[35]

electron pair, which in compound 1b is partially delocalized

over the phenyl group attached to the amino functionality.

Scheme 13. Proposed mechanism for the formation of compound

6.

In contrast to the other cyclic dienophiles tested, PTAD

reacted with 1e to give the corresponding addition product

(i.e., 5). This change in the course of the reaction may be

Scheme 12. General mechanism for the reactions of 4-alkenyl-2-

aminothiazoles 1 with acyclic dienophiles.

explained by taking into account the stabilization of zwit-

terionic intermediate 18 by delocalization of the negative

charge into the urea fragment. This extra stabilization

The zwitterionic intermediate (i.e., 12) may react further

by either of two alternative routes depending on the nature

of the dienophile (Scheme 12). The cyclization of 12 would

lead to the formal [4+2] cycloadduct (i.e., 13). A consecu-

would increase the lifetime of 18, favouring the 1,3-hydro-

gen migration to the nitrogen atom.^[14a]

tive 1,3-hydrogen migration, favoured by the rearomatiza-

tion of the thiazole ring, would give the final cyclic product

(i.e., 15). The 1,3-hydrogen shift may be intermolecular,

since a concerted reaction is expected to have a very high

activation barrier.^[32]This migration step,^[33]which may

have a polar character, would also be favoured by the pres-

ence of the amino functionality at C-2. We propose that the

hydrogen atom migrates with a positive charge density. The

negative charge generated at the carbon atom to which it

was initially bonded would be stabilized by the adjacent

2) Stereospecificity and endo/exo Stereoselectivity

sulfur atom.^[34]Moreover, the lone pair of the exocyclic ni-

It is commonly accepted that in most Diels–Alder reac-

tions, the two new σ-bonds are formed in a concerted, al-

though not necessarily synchronous, manner. This requires

the diene to adopt an s-cis conformation. Consistent with

this mode of addition, Diels–Alder reactions are generally

stereospecific, i.e. the configurations of both diene and di-

enophile components are “retained” in the adduct.^[1]

The most revealing facts about stereochemical aspects of

the [4+2] cycloaddition processes of thiazoles 1, in terms

of elucidation of the mechanism, come from their reactions

trogen would be delocalized over the unsaturated fragment

of the bicyclic structure in 13, so increasing the basic char-

acter of C-5 (see structure 13 in Scheme 12) and facilitating

the migration of the hydrogen atom as a proton. Alterna-

tively, 12 would experience a 1,3-hydrogen migration lead-

ing to the corresponding addition product (i.e., 14). The

following findings support the proposal of a stepwise [4+2]

cycloaddition for this group of reactions.

1) Chemoselectivity

In the tricyanovinylation reaction of 1e, the formation of with DMMa (Scheme 6 and Table 5). In a concerted pro-

zwitterionic intermediate 16 would presumably be preceded cess, the reactions of thiazoles 1 with DMMa should be

by a charge-transfer π complex 17 (Scheme 13).^[14a]Inter- stereospecific and lead to tetrahydrobenzothiazoles 7ЈЈ

mediate 16 would gain extra stabilization arising from the (endo attack) and/or 7ЈЈЈ (exo attack) shown in Figure 5.

two electron-withdrawing nitrile groups. Following the 1,3- However, besides diastereoisomer 7ЈЈ, which retains the cis

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481

M. Alajarin, A. Pastor et al.

FULL PAPER

arrangement of the two carboxylate groups, diastereoiso-

The isolation of diastereomeric mixtures of compounds

mers 7 and 7Ј were isolated, in which these two substituents 8a–c, which were assigned as endo-8a–c and exo-8a–c, is

have a trans arrangement (Table 5). The lack of stereospeci- also consistent with the involvement of zwitterionic species

ficity in the reactions with DMMa shows that the cycload- of general structure 12 (Scheme 12). Surprisingly, the for-

dition must be a stepwise process, with the configurational mation of cycloadduct 9 from α-chloroacrylonitrile was

stability of the chiral carbanion in the corresponding inter- completely diastereoselective. Probably, steric hindrance in

mediate (i.e., 12) (Scheme 12) being diminished under the the ionic intermediate makes rotation about single bonds

harsh reaction conditions.

slower than ring closure, and the initial relative configura-

tion is preserved.^[1b]

3) Regioselectivity

The proposed stepwise mechanism is also consistent with

the regioselectivity observed in the reactions of thiazole 1e

with methyl acrylate, α-chloroacrylonitrile, ethyl 2,3-butadi-

enoate, and ethyl propiolate. The structures of the resulting

cycloadducts (i.e., 8–11) would be the result of the nucleo-

philic attack of C-5 of thiazole 1e at the most electron-de-

ficient position of the dienophile. Therefore, the regioselec-

tivity is fully controlled by the resonance effect of the amino

group at C-2.

The formation of ethyl 4,5-dihydrobenzothiazole-6-carb-

oxylate 10 may be explained by the reaction of 1e with the

more electron-deficient double bond of the allene, i.e. the

C-2=C-3 bond, to give [4+2] cycloaddition product 21, fol-

lowed by two consecutive 1,3-hydrogen migrations via inter-

mediates 22 or 23 (Scheme 15). The isomerization of an

exocyclic double bond to an endocyclic one (transforma-

tions 21Ǟ23 and 22Ǟ10) has previously been observed in

cycloadducts resulting from the Diels–Alder reactions of

2,3-butadienoates with other dienes.^[37]

Figure 5. Expected cycloadducts (7ЈЈ and 7ЈЈЈ) for a concerted

[4+2] cycloaddition of 4-alkenyl-2-aminothiazoles 1 with DMMa.

The possibility of the isomerization of DMMa to give

DMFu under the reaction conditions can be discounted,

bearing in mind the different results obtained in the reac-

tions of 1b and 1d with DMMa and DMFu. The reactions

of 1b and 1d with DMMa led to mixtures of 7, 7Ј, and 7ЈЈ,

whereas those with DMFu gave mixtures of 7 and 7Ј only

(compare entries 2 and 4 with entries 5 and 6 in Table 5).

As expectedly the ¹H NMR spectrum of a sample of

DMMa heated in refluxing acetonitrile for 48 h showed the

total absence of DMFu.

The reaction of 1e with DMFu was also carried out in a

protic solvent in an attempt to trap putative zwitterionic

intermediate 19 (Scheme 14).^[36]However, we observed the

exclusive formation of cycloadducts 7 and 7Ј, suggesting

that the lifetime of zwitterionic intermediate 19 is rather

short, and that the intramolecular cyclization takes place

before the intermolecular 1,3-hydrogen migration occurs.

Scheme 15. Alternative sequence of steps for the formation of 10

via intermediates 21–23.

Conclusions

We have demonstrated that 4-alkenyl-2-aminothiazoles 1

can be prepared in an efficient manner, and they behave as

effective dienes in [4+2] cycloadditions. The reactions of 1

with classical electron-poor dienophiles, except for PTAD

and TCNE, are site-selective, since only the diene moiety

that comprises the formal ring C=C and the side-chain

double bond is involved (extra-annular addition). The iso-

Scheme 14. Reaction of 1e with dimethyl fumarate in ethanol as

solvent, and structure of putative zwitterionic intermediate 19.

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Cycloadditions of 4-Alkenyl-2-Aminothiazoles

product precipitated from the reaction mixture, and it was filtered

and dried under vacuum. The mother liquors were evaporated un-

der vacuum and further product was precipitated by addition of

Et₂O. R_f= 0.17 (2:1 EtOAc/n-hexane), yield 90% (0.263 g), m.p.

lated compounds are the result of a [4+2] cycloaddition

followed by a 1,3-hydrogen migration. The reactions with

PTAD and TCNE lead to addition products instead of the

corresponding [4+2] cycloadducts. The reactions with cy-

clic dienes such as NPM or MA are stereoselective, provid-

ing a single diastereoisomer derived from an endo transition

state. In this case, a concerted but highly asynchronous

mechanism is proposed.

249–251 °C (colourless needles, CHCl /Et O). IR (nujol): ν = 3450,

˜

3

2

3270, 1778, 1712, 1630, 1589, 1519, 1313, 1286, 1216, 1191, 1157,

695 cm^{–1 1}H NMR (CDCl₃, 400.91 MHz): δ = 2.30 (s, 3 H,

.

C₆H₄Me), 3.08 (dd, J = 5.8, J = 1.6 Hz, 2 H, 4-H, 4Ј-H), 3.70 (q,

J = 5.6 Hz, 1 H, 5-H), 3.79 (dd, J = 8.0, J = 5.4 Hz, 1 H, 5a-H),

4.21 (dt, J = 8.0, J = 1.6 Hz, 1 H, 8a-H), 5.02 (br. s, 2 H, NH₂),

Acyclic dienophiles such as DMMa and DMFu also re-

act, but require considerably more forcing reaction condi- 6.73–6.75 (m, 2 H), 7.07 (d, J = 8.2 Hz, 2 H), 7.12 (d, J = 8.2 Hz,

2 H), 7.27–7.32 (m, 3 H) ppm. ¹³C NMR (CDCl₃, 100.81 MHz): δ

tions. These processes are not stereospecific. The reactions

= 20.9 (q, C₆H₄Me), 29.7 (t, C-4), 39.4 (d, C-5), 41.3 (d, C-8a),

with unsymmetrical dienophiles such as methyl acrylate, α-

46.0 (d, C-5a), 110.9 (s, C-8b), 126.3 (2 d), 128.3 (2 d), 128.5 (d),

chloroacrylonitrile, ethyl 2,3-butadienoate, and ethyl pro-

128.9 (2 d), 129.2 (2 d), 131.2 (s), 136.9 (s), 137.1 (s), 147.6 (s, C-

piolate are highly regioselective, the exclusive regioisomer

3a), 167.9 (s, C-2), 174.4 (s, CO), 175.4 (s, CO) ppm. MS (EI,

being the result of the nucleophilic addition of C-5 of the

70 eV): m/z (%) = 390 (25) [M + 1]⁺, 389 (100) [M]⁺, 284 (33), 242

thiazole to the most electron-deficient position of the dien-

(72), 241 (42), 209 (22), 183 (25), 151 (31), 137 (40), 119 (26), 91

ophile. All the data compiled for the reactions with acyclic

(37). C₂₂H₁₉N₃O₂S (389.47): calcd. C 67.84, H 4.92, N 10.79, S

dienophiles suggest a stepwise mechanism for the [4+2]

cycloaddition step, with zwitterionic species as the most

plausible intermediates. Presumably, the resonance effect of

the amino group at C-2 of the thiazole ring is a key con-

trolling element for the reactivity and regioselectivity of this

type of cycloaddition.

The reactions of 4-alkenyl-2-aminothiazoles 1 with

dienophiles described here open up a new route to complex

polycyclic thiazole derivatives that are not easily accessible

by other methods.

8.23; found C 67.77, H 5.02, N 10.93, S 8.19.

(5R*,5aR*,8aS*)-5-(4-Methylphenyl)-7-phenyl-2-(phenylamino)-

4,5,5a,8a-tetrahydropyrrolo[3,4-g]benzothiazole-6,8-dione (endo-4b):

The solvent was evaporated to dryness and the residue was purified

by silica gel chromatography eluting with 1:2 EtOAc/n-hexane (R_f

= 0.29), yield 90% (0.314 g), m.p. 240–241 °C (colourless needles,

CHCl /Et O). IR (nujol): ν = 3360, 1782, 1698, 1603, 1544, 1526,

˜

3

2

1

1496, 1196, 1181, 744 cm^–1. H NMR (CDCl₃, 400.91 MHz): δ =

2.29 (s, 3 H, C₆H₄Me), 3.14 (dd, J = 5.8, J = 1.6 Hz, 2 H, 4-H +

4Ј-H), 3.71 (q, J = 5.6 Hz, 1 H, 5-H), 3.79 (dd, J = 8.0, J = 5.4 Hz,

1 H, 5a-H), 4.23 (dt, J = 8.0, J = 1.6 Hz, 1 H, 8a-H), 6.75–6.78

(m, 2 H), 7.05–7-12 (m, 5 H), 7.25–7.37 (m, 7 H), 7.47 (br. s, 1 H,

NH) ppm. ¹³C NMR (CDCl₃, 100.81 MHz): δ = 20.9 (q, C₆H₄Me),

30.0 (t, C-4), 39.7 (d, C-5), 41.4 (d, C-8a), 46.1 (d, C-5a), 110.1 (s,

C-8b), 118.8 (2 d), 123.5 (d), 126.3 (2 d), 128.4 (2 d), 128.5 (d),

128.8 (2 d), 129.3 (2 d), 129.6 (2 d), 131.5 (s), 137.0 (s), 137.1 (s),

140.1 (s), 147.9 (s, C-3a), 165.6 (s, C-2), 174.3 (s, CO), 175.3 (s,

CO) ppm. MS (EI, 70 eV): m/z (%) = 466 (32) [M + 1]⁺, 465 (100)

[M]⁺, 318 (39), 317 (29), 315 (20), 213 (37), 119 (25), 91 (36), 77

(43). C₂₈H₂₃N₃O₂S (465.57): calcd. C 72.23, H 4.98, N 9.03, S 6.89;

found C 72.01, H 5.13, N 8.94, S 6.90.

Experimental Section

General Remarks: IR spectra were recorded neat or as nujol emul-

sions. ¹H NMR spectra were recorded at 300, 401, or 600 MHz.

¹³C NMR spectra were recorded at 50, 75, or 101 MHz. Chemical

shifts are expressed in ppm, using TMS at δ = 0.00 ppm as an

1

internal reference for H spectra, and CDCl₃at δ = 77.1 ppm for

¹³C spectra. Mass spectra were recorded using EI (70 eV) or FAB⁺

(using 3-nitrobenzyl alcohol as matrix) ionization modes.

Synthesis of 4-Alkenyl-2-aminothiazoles 1a–h: Thiazoles 1a–b^[16b]

and 1e^[16b]are known compounds, and they were prepared follow-

ing methods previously described in the literature. The general pro-

cedure for the synthesis of thiazoles 1c–d and 1f–h and their struc-

tural characterization have been included in the Supporting Infor-

mation.

Synthesis of α-Chloro Ketones 2a–e: α-Chloro ketones 2a–b,^[18]

2c,^[19]and 2e^[19]are known compounds, and they were prepared

following methods previously described in the literature. The gene-

ral procedure for the synthesis of the α-chloro ketone 2d and its

structural characterization have been included in the Supporting

Information.

(5R*,5aR*,8aS*)-2-(Methylamino)-5-(4-methylphenyl)-7-phenyl-

4,5,5a,8a-tetrahydropyrrolo[3,4-g]benzothiazole-6,8-dione (endo-4c):

The product precipitated from the reaction mixture, and it was fil-

tered and dried under vacuum. The mother liquors were evapo-

rated, and further product was precipitated by the addition of ace-

tonitrile. R_f= 0.50 (EtOAc), yield 91% (0.275 g), m.p. 223–225 °C

(colourless needles, CHCl /Et O). IR (nujol): ν = 3209, 3113, 1716,

˜

3

2

1597, 1499, 1413, 1156, 1130, 757, 693 cm^–1. ¹H NMR (CDCl₃,

300.10 MHz): δ = 2.30 (s, 3 H, C₆H₄Me), 3.00 (s, 3 H, NHMe),

3.07 (dd, J = 6.0, J = 1.6 Hz, 2 H, 4-H + 4Ј-H), 3.68 (q, J = 5.7 Hz,

1 H, 5-H), 3.78 (dd, J = 8.0, J = 5.4 Hz, 1 H, 5a-H), 4.22 (dt, J =

8.0, J = 1.6 Hz, 1 H, 8a-H), 5.72 (br. s, 1 H, NH), 6.75–6.78 (m, 2

H), 7.07 (d, J = 8.4 Hz, 2 H), 7.13 (d, J = 8.4 Hz, 2 H), 7.26–7.35

(m, 3 H) ppm. ¹³C NMR (CDCl₃, 75.45 MHz): δ = 20.9 (q,

C₆H₄Me), 29.7 (t, C-4), 32.1 (q, NHMe), 39.4 (d, C-5), 41.4 (d, C-

8a), 46.1 (d, C-5a), 108.4 (s, C-8b), 126.3 (2 d), 128.3 (2 d), 128.5

(d), 128.8 (2 d), 129.2 (2 d), 131.3 (s), 136.96 (s), 137.03 (s), 147.9

(s, C-3a), 171.3 (s, C-2), 174.6 (s, CO), 175.5 (s, CO) ppm. MS (EI,

70 eV): m/z (%) = 404 (20) [M + 1]⁺, 403 (100) [M]⁺, 256 (43), 255

(26), 165 (32), 151 (43), 91 (25). C₂₃H₂₁N₃O₂S (403.50): calcd. C

Synthesis of Thioureas 3: Thioureas 3a–c are commercially avail-

able. N,N-Dimethylthiourea 3d was prepared following a previously

reported method.^[16b]

General Procedure for the Synthesis of endo-4: A solution of the

corresponding 4-alkenyl-2-aminothiazole (1; 0.75 mmol) and N-

phenylmaleimide (0.39 g, 2.25 mmol) in acetonitrile (10 mL) was

stirred at room temperature for 48 h. The isolation and purification

is described in each case.

(5R*,5aR*,8aS*)-2-Amino-5-(4-methylphenyl)-7-phenyl-4,5,5a,8a- 68.46, H 5.25, N 10.41, S 7.95; found C 68.11, H 5.37, N 10.52, S

tetrahydropyrrolo[3,4-g]benzothiazole-6,8-dione (endo-4a): The 8.09.

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M. Alajarin, A. Pastor et al.

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(5R*,5aR*,8aS*)-2-(Methylamino)-5-(4-methoxyphenyl)-7-phenyl-

4,5,5a,8a-tetrahydropyrrolo[3,4-g]benzothiazole-6,8-dione (endo-4d):

The solvent was evaporated to dryness, and the residue was crys-

tallized from 1:1 CH₂Cl₂/Et₂O. R_f= 0.10 (2:1 EtOAc/n-hexane),

yield 90% (0.283 g), m.p. 229–231 °C (colourless needles, CHCl₃/

4gЈ) or (5R*,5aS*,8aR*)-2-Dimethylamino-7-phenyl-5-[(1S*)-1-

phenylethyl]-4,5,5a,8a-tetrahydropyrrolo[3,4-g]benzothiazole-6,8-di-

one (endo-4gЈЈ): The solvent was evaporated to dryness, and the

residue was purified by silica gel chromatography eluting with 1:2

EtOAc/n-hexane (R_f= 0.17), yield 38% (0.123 g), m.p. 183–185 °C

Et O). IR (nujol): ν = 3211, 3110, 1711, 1594, 1514, 1256, (colourless needles, CHCl /n-hexane). IR (nujol): ν = 1714, 1556,

˜

2

3

1181 cm^–1

.

¹H NMR (CDCl₃, 400.91 MHz): δ = 2.99 (s, 3 H,

1494, 1282, 1220, 1190, 1026, 878, 816, 758, 729, 703 cm^{–1 1}H

.

NHMe), 3.05–3.08 (m, 2 H, 4-H + 4Ј-H), 3.70 (q, J = 5.6 Hz, 1 H,

5-H), 3.74–3.78 (m, 4 H, C₆H₄OMe + 5a-H), 4.22 (dt, J = 7.9, J

NMR (CDCl₃, 400.91 MHz): δ = 1.36 (d, J = 6.9 Hz, 3 H), 2.18–

2.27 (m, 1 H), 2.55 (ddd, J = 14.9, J = 12.2, J = 2.6 Hz, 1 H), 3.05–

= 1.4 Hz, 1 H, 8a-H), 5.81 (br. s, 1 H, NH), 6.77–6.81 (m, 4 H), 3.17 (m, 8 H), 3.80 (dq, J = 11.3, J = 6.9 Hz, 1 H), 3.91 (dm, J =

7.15 (d, J = 8.7 Hz, 2 H), 7.27–7.34 (m, 3 H) ppm. ¹³C NMR

7.6 Hz, 1 H), 7.14–7.17 (m, 2 H), 7.20–7.25 (m, 1 H), 7.29–7.41 (m,

(CDCl₃, 100.81 MHz): δ = 30.0 (t, C-4), 32.0 (q, NHMe), 39.1 (d, 7 H) ppm. ¹³C NMR (CDCl₃, 100.81 MHz): δ = 20.9 (q), 28.0 (t),

C-5), 41.2 (d, C-8a), 46.1 (d, C-5a), 55.2 (q, C₆H₄OMe), 108.3 (s, 40.0 (2 q), 40.3 (d), 42.1 (d), 42.2 (d), 42.7 (d), 109.7 (s), 126.3 (2

C-8b), 113.9 (2 d), 126.3 (2 d), 128.5 (d), 128.9 (2 d), 129.5 (2 d),

d), 126.4 (d), 127.4 (2 d), 128.3 (d), 128.7 (2 d), 128.8 (2 d), 131.5

131.3 (s), 132.1 (s), 147.9 (s, C-3a), 158.8 (s), 171.4 (s, C-2), 174.6 (s), 146.2 (s), 149.2 (s), 170.9 (s), 175.3 (s), 175.8 (s) ppm. MS (EI,

(s, CO), 175.6 (s, CO) ppm. MS (EI, 70 eV): m/z (%) = 420 (28) [M

+ 1]⁺, 419 (100) [M]⁺, 272 (37), 271 (25), 246 (24), 121 (45), 119

(20), 91 (21). C₂₃H₂₁N₃O₃S (419.50): calcd. C 65.85, H 5.05, N

10.02, S 7.64; found C 65.54, H 5.17, N 10.23, S 7.60.

70 eV): m/z (%) = 432 (48) [M + 1]⁺, 431 (100) [M]⁺, 258 (42), 257

(41), 205 (25), 179 (97), 164 (32), 136 (35), 109 (37), 105 (67), 88

(30), 77 (31). C₂₅H₂₅N₃O₂S (431.55): calcd. C 69.58, H 5.84, N

9.74, S 7.43; found C 69.47, H 5.96, N 9.64, S 7.72.

(5R*,5aR*,8aS*)-2-Dimethylamino-5-(4-methylphenyl)-7-phenyl-

4,5,5a,8a-tetrahydropyrrolo[3,4-g]benzothiazole-6,8-dione (endo-4e):

The product precipitated from the reaction mixture, and it was fil-

tered and dried under vacuum. The mother liquors were evaporated

to dryness, and further product was precipitated by the addition of

acetonitrile. R_f= 0.10 (1:1 EtOAc/n-hexane), yield 91% (0.285 g),

(5R*,5aS*,8aR*)-5-[(2S*)-2-Butyl]-2-dimethylamino-7-phenyl-

4,5,5a,8a-tetrahydropyrrolo[3,4-g]benzothiazole-6,8-dione and

(5R*,5aS*,8aR*)-5-[(2R*)-2-butyl]-2-dimethylamino-7-phenyl-

4,5,5a,8a-tetrahydropyrrolo[3,4-g]benzothiazole-6,8-dione (endo-4h

and endo-4hЈ): The solvent was evaporated to dryness, and the resi-

due was purified by silica gel chromatography eluting with 1:2

EtOAc/n-hexane (R_f= 0.17) to give a 50:50 mixture of dia-

stereomers, yield 80% (0.230 g), m.p. 154–156 °C (colourless need-

m.p. 231–233 °C (colourless needles, CHCl /Et O). IR (nujol): ν =

˜

3

2

1

1722, 1553, 1499, 1425, 1339, 1178, 822, 751, 690 cm^–1. H NMR

(CDCl₃, 400.91 MHz): δ = 2.30 (s, 3 H, C₆H₄Me), 3.09–3.17 (m, 8

H, NMe₂+ 4-H + 4Ј-H), 3.66 (q, J = 5.6 Hz, 1 H, 5-H), 3.76 (dd,

J = 7.9, J = 5.2 Hz, 1 H, 5a-H), 4.22 (d, J = 7.9 Hz, 1 H, 8a-H),

6.77–6.80 (m, 2 H), 7.07 (d, J = 8.0 Hz, 2 H), 7.14 (d, J = 8.0 Hz,

2 H), 7.25–7.32 (m, 3 H) ppm. ¹³C NMR (CDCl₃, 100.81 MHz): δ

= 20.9 (q, C₆H₄Me), 29.7 (t, C-4), 39.4 (d, C-5), 40.1 (2 q, NMe₂),

41.5 (d, C-8a), 46.0 (d, C-5a), 108.3 (s, C-8b), 126.3 (2 d), 128.2 (2

d), 128.4 (d), 128.7 (2 d), 129.1 (2 d), 131.3 (s), 136.8 (s), 137.2 (s),

148.7 (s, C-3a), 171.2 (s, C-2), 174.7 (s, CO), 175.5 (s, CO) ppm.

MS (EI, 70 eV): m/z (%) = 418 (26) [M + 1]⁺, 417 (100) [M]⁺, 270

(38), 269 (29), 179 (21), 165 (36), 119 (20), 91 (29). C₂₄H₂₃N₃O₂S

(417.51): calcd. C 69.04, H 5.55, N 10.06, S 7.68; found C 68.87,

H 5.59, N 10.34, S 7.58.

les, CHCl /Et O). IR (nujol): ν = 1705, 1545, 1498, 1417, 1196,

˜

3

2

1132, 763, 734 cm^–1. ¹H NMR (CDCl₃, 400.91 MHz): δ = 0.89–

0.97 (m, 6 H), 1.01 (d, J = 6.7 Hz, 3 H), 1.12 (d, J = 6.7 Hz, 3 H),

1.23–1.38 (m, 2 H), 1.67–1.85 (m, 4 H), 2.34–2.45 (m, 4 H), 2.95–

3.02 (m, 2 H), 3.08 (s, 12 H), 3.69–3.75 (m, 2 H), 4.12–4.14 (m, 2

H), 7.20–7.22 (m, 4 H), 7.31–7.36 (m, 2 H), 7.39–7.43 (m, 4 H)

ppm. ¹³C NMR (CDCl₃, 75.45 MHz): δ = 10.0 (q), 10.3 (q), 17.1

(q), 17.2 (q), 26.65 (t), 26.70 (t), 28.2 (t), 28.4 (t), 34.3 (d), 34.5 (d),

39.9 (d), 40.0 (d), 40.1 (4 q), 41.7 (d), 42.0 (d), 42.9 (d), 43.0 (d),

109.26 (s), 109.31 (s), 126.3 (2 d), 126.4 (2 d), 128.32 (d), 128.34

(d), 128.88 (2 d), 128.90 (2 d), 131.6 (2 s), 149.7 (s), 149.8 (s), 170.9

(2 s), 175.6 (s), 175.7 (s), 175.91 (s), 175.92 (s) ppm. MS (EI, 70 eV):

m/z (%) = 384 (56) [M + 1]⁺, 383 (93) [M]⁺, 326 (86), 195 (47), 179

(100), 142 (48), 136 (45), 109 (47). C₂₁H₂₅N₃O₂S (383.51): calcd. C

65.77, H 6.57, N 10.96, S 8.36; found C 65.43, H 6.73, N 11.23, S

8.40.

(5R*,5aS*,8aR*)-2-Dimethylamino-7-phenyl-5-[(1R*)-1-phenyleth-

yl]-4,5,5a,8a-tetrahydropyrrolo[3,4-g]benzothiazole-6,8-dione (endo-

4 g) or (5R*,5aS*,8aR*)-2-Dimethylamino-7-phenyl-5-[(1S*)-1-

phenylethyl]-4,5,5a,8a-tetrahydropyrrolo[3,4-g]benzothiazole-6,8-di-

one (endo-4gЈ): The solvent was evaporated to dryness, and the resi-

due was purified by silica gel chromatography eluting with 1:2

EtOAc/n-hexane (R_f= 0.20), yield 42% (0.136 g), m.p. 214–216 °C

(5R*,5aS*,8aR*)-2-Dimethylamino-5-[(3R*)-3-oxolanyl]-7-phenyl-

4,5,5a,8a-tetrahydropyrrolo[3,4-g]benzothiazole-6,8-dione and

(5R*,5aS*,8aR*)-2-dimethylamino-5-[(3S*)-3-oxolanyl]-7-phenyl-

4,5,5a,8a-tetrahydropyrrolo[3,4-g]benzothiazole-6,8-dione (endo-4i

and endo-4iЈ): The solvent was evaporated to dryness, and the resi-

due was purified by silica gel chromatography eluting with 3:1

EtOAc/n-hexane (R_f= 0.17) to give a 50:50 mixture of dia-

stereomers, yield 99% (0.295 g), m.p. 224–226 °C (colourless need-

(colourless needles, CHCl /n-hexane). IR (nujol): ν = 1708, 1553,

˜

3

1444, 1190, 1133, 757, 704 cm^–1. H NMR (CDCl₃, 400.91 MHz):

1

δ = 1.49 (d, J = 6.9 Hz, 3 H), 2.18–2.34 (m, 2 H), 3.41 (br. dd, J =

16.2, J = 4.2 Hz, 1 H), 3.01 (s, 6 H), 3.68 (dq, J = 10.6, J = 6.9 Hz,

1 H), 3.89 (ddd, J = 7.7, J = 4.2, J = 0.8 Hz, 1 H), 4.21 (dm, J =

7.7 Hz, 1 H), 7.17–7.30 (m, 7 H), 7.34–7.38 (m, 1 H), 7.41–7.46 (m,

2 H) ppm. ¹³C NMR (CDCl₃, 100.81 MHz): δ = 20.5 (q), 29.0 (t),

40.1 (2 q), 41.4 (d), 41.6 (d), 41.9 (d), 42.9 (d), 109.0 (s), 126.3 (2

d), 126.4 (d), 127.4 (2 d), 128.4 (d), 128.7 (2 d), 129.0 (2 d), 131.6

(s), 146.0 (s), 149.7 (s), 170.8 (s), 175.5 (s), 175.9 (s) ppm. MS (EI,

70 eV): m/z (%) = 431 (100) [M]⁺, 258 (41), 179 (71), 164 (36), 136

(34), 109 (40), 105 (57), 88 (31), 77 (37). C₂₅H₂₅N₃O₂S (431.55):

calcd. C 69.58, H 5.84, N 9.74, S 7.43; found C 69.42, H 5.90, N

9.79, S 7.32.

les, CHCl /Et O). IR (nujol): ν = 1710, 1549, 1493, 1415, 1195,

˜

3

2

1

1133, 1053, 738 cm^–1. H NMR (CDCl₃, 400.91 MHz): δ = 1.53–

1.73 (m, 2 H), 1.94–2.02 (m, 2 H), 2.17–2.25 (m, 1 H), 2.31–2.38

(m, 1 H), 2.47–2.56 (m, 2 H), 2.69 (br. dd, J = 16.4, J = 4.5 Hz, 1

H), 2.90 (br. dd, J = 16.5, J = 4.4 Hz, 1 H), 3.07 (s, 6 H), 3.08 (s,

6 H), 3.18–3.25 (m, 2 H), 3.36–3.42 (m, 2 H), 3.56–3.60 (m, 2 H),

3.79–3.87 (m, 2 H), 3.92–3.99 (m, 2 H), 4.09–4.19 (m, 3 H), 4.23

(t, J = 7.7 Hz, 1 H), 7.19 (m, 4 H), 7.32–7.37 (m, 2 H), 7.39–7.45

(m, 4 H) ppm. ¹³C NMR (CDCl₃, 100.81 MHz): δ = 29.4 (t), 29.6

(t), 31.4 (t), 32.3 (t), 39.0 (d), 39.1 (d), 40.05 (2 q), 40.07 (2 q), 41.2

(5R*,5aS*,8aR*)-2-Dimethylamino-7-phenyl-5-[(1R*)-1-phenyleth- (d), 41.4 (d), 42.38 (d), 42.42 (d), 43.1 (d), 43.2 (d), 68.3 (t), 68.4

yl]-4,5,5a,8a-tetrahydropyrrolo[3,4-g]benzothiazole-6,8-dione (endo- (t), 72.0 (t), 73.0 (t), 109.0 (s), 109.1 (s), 126.3 (4 d), 128.5 (2 d),

484

www.eurjoc.org

Eur. J. Org. Chem. 2013, 474–489

Cycloadditions of 4-Alkenyl-2-Aminothiazoles

129.0 (4 d), 131.5 (2 s), 148.6 (s), 148.8 (s), 170.9 (2 s), 175.1 (s),

175.2 (s), 175.6 (s), 175.7 (s) ppm. MS (EI, 70 eV): m/z (%) = 398

(25) [M + 1]⁺, 397 (87) [M]⁺, 327 (32), 326 (87), 205 (47), 179 (100).

C₂₁H₂₃N₃O₃S (397.50): calcd. C 63.45, H 5.83, N 10.57, S 8.07;

found C 63.23, H 6.00, N 10.72, S 7.99.

thiazole 1a–e (0.50 mmol) in acetonitrile (5 mL). The reaction mix-

ture was stirred under reflux for 48 h. The solvent was evaporated

to dryness and the residue was purified by silica gel chromatog-

raphy.

Dimethyl (5R*,6S*,7S*)-2-Amino-5-(4-methylphenyl)-4,5,6,7-tetra-

hydrobenzothiazole-6,7-dicarboxylate (7a): From dimethyl maleate:

2:1Ǟ3:1 EtOAc/n-hexane was used as eluent (R_f= 0.25 in 2:1

EtOAc/n-hexane), yield 20% (0.036 g) (7aЈЈ was also isolated in

15% yield, R_f= 0.18 in 2:1 EtOAc/n-hexane), m.p. 223–225 °C

(5R*,5aR*,8aS*)-2-Dimethylamino-5-(4-methylphenyl)-4,5,5a,8a-

tetrahydrofuro[3,4-g]benzothiazole-6,8-dione (endo-4f): Maleic anhy-

dride (0.04 g, 0.41 mmol) was added to a solution of 4-alkenyl-2-

dimethylaminothiazole 1e (0.10 g, 0.41 mmol) in dry acetonitrile

(10 mL). The reaction mixture was stirred at room temperature for

24 h. The solvent was evaporated to dryness, and the product was

(colourless needles, CHCl /Et O). IR (nujol): ν = 3425, 3281, 3106,

˜

3

2

1725, 1632, 1521, 1292, 1233, 1165, 999, 817 cm^–1. ¹H NMR

precipitated with dry Et₂O, yield 72% (0.101 g), m.p. 150–152 °C (CDCl₃, 600.13 MHz): δ = 2.32 (s, 3 H, C₆H₄Me), 2.82–2.90 (m, 2

(colourless prisms, CHCl /Et O). IR (nujol): ν = 1779, 1716, 1627,

H, 4-H + 4Ј-H), 3.21 (ddd, J = 11.3, J = 9.9, J = 6.3 Hz, 1 H, 5-

˜

3

2

1574, 1227 cm^–1. ¹H NMR (CDCl₃, 300.10 MHz): δ = 2.32 (s, 3 H, H), 3.28 (dd, J = 11.3, J = 9.9 Hz, 1 H, 6-H), 3.31 (s, 3 H, CO-

C₆H₄Me), 3.01–3.08 (m, 8 H, NMe₂+ 4-H + 4Ј-H), 3.39–3.46 (m, OMe), 3.71 (s, 3 H, COOMe), 4.26 (dt, J = 9.9, J = 2.3 Hz, 1 H,

1 H, 5-H), 3.83 (dd, J = 8.1, J = 4.2 Hz, 1 H, 5a-H), 4.31 (dt, J = 7-H), 4.90 (br. s, 2 H, NH₂), 7.12 (s, 4 H) ppm. ¹³C NMR (CDCl₃,

8.1, J = 1.8 Hz, 1 H, 8a-H), 7.14 (d, J = 8.1 Hz, 2 H), 7.20 (d, J =

8.1 Hz, 2 H) ppm. ¹³C NMR (CDCl₃, 75.45 MHz): δ = 20.7 (q,

C₆H₄Me), 28.1 (t), 37.7 (d), 39.9 (2 q), 42.3 (d), 46.7 (d), 106.0 (s,

100.81 MHz): δ = 21.1 (q), 33.9 (t), 43.8 (d), 44.8 (d), 50.2 (d), 51.6

(q), 52.5 (q), 113.0 (s), 127.6 (2 d), 129.1 (2 d), 136.8 (s), 138.0 (s),

146.5 (s), 167.2 (s), 171.7 (s), 173.8 (s) ppm. MS (EI, 70 eV): m/z

C-8b), 127.4 (2 d), 129.1 (2 d), 135.7 (s), 136.8 (s), 149.4 (s, C-3a), (%) = 360 (3) [M]⁺, 328 (15), 301 (25), 300 (98), 241 (100).

169.3 (s), 169.5 (s), 171.0 (s) ppm. MS (EI, 70 eV): m/z (%) = 341

(28) [M + 1]⁺, 342 (91) [M]⁺, 271 (47), 270 (100), 269 (100), 237

(33), 184 (33), 179 (74), 165 (100). C₁₈H₁₈N₂O₃S (342.41): calcd. C

63.14, H 5.30, N 8.18, S 9.36; found C 62.88, H 5.42, N 8.10, S

9.52.

C₁₈H₂₀N₂O₄S (360.43): calcd. C 59.98, H 5.59, N 7.77, S 8.90;

found C 59.81, H 5.69, N 7.90, S 8.99.

Dimethyl

(5R*,6S*,7S*)-2-Methylamino-5-(4-methylphenyl)-

4,5,6,7-tetrahydrobenzothiazole-6,7-dicarboxylate (7b): From di-

methyl maleate: 2:1 EtOAc/n-hexane was used as eluent (R_f= 0.24),

yield 24% (0.045 g) (7bЈЈ was also isolated in 40% yield, R_f= 0.12

in 2:1 EtOAc/n-hexane). From dimethyl fumarate: 81% combined

yield with 7bЈ, m.p. 213–214 °C (colourless needles, CHCl₃/Et₂O).

1-{2-Dimethylamino-4-[(E)-2-(4-methylphenyl)ethenyl]thiazol-5-yl}-

4-phenyl-1,2,4-triazolidin-3,5-dione (5): PTAD (0.07 g, 0.41 mmol)

was added to a solution of 4-alkenyl-2-dimethylaminothiazole 1e

(0.10 g, 0.41 mmol) in toluene (5 mL). After 5 min of stirring at

room temperature, the solvent was evaporated to dryness, and the

product was purified by silica gel chromatography eluting with 1:1

EtOAc/n-hexane (R_f= 0.29), yield 72% (0.123 g), m.p. 173–175 °C

IR (nujol): ν = 3205, 3102, 1730, 1592, 1407, 1293, 1234, 1165 cm^–1.

˜

¹H NMR (CDCl₃, 600.13 MHz): δ = 2.32 (s, 3 H, C₆H₄Me), 2.83–

2.90 (m, 2 H, 4-H + 4Ј-H), 2.96 (s, 3 H, NHMe), 3.21 (ddd, J =

11.4, J = 9.0, J = 7.3 Hz, 1 H, 5-H), 3.27 (dd, J = 11.4, J = 9.9 Hz,

1 H, 6-H), 3.31 (s, 3 H, COOMe), 3.72 (s, 3 H, COOMe), 4.27 (dt,

J = 9.9, J = 2.3 Hz, 1 H, 7-H), 5.14 (br. s, 1 H, NH), 7.10–7.13 (m,

4 H) ppm. ¹³C NMR (CDCl₃, 75.45 MHz): δ = 21.1 (q), 32.0 (q),

(colourless prisms, CHCl /Et O). IR (nujol): ν = 1762, 1695, 1555,

˜

3

2

1142, 800, 721 cm^–1. H NMR (CDCl₃, 400.91 MHz): δ = 2.36 (s,

1

3 H), 3.14 (s, 6 H), 6.80 (d, J = 15.8 Hz, 1 H), 7.14 (d, J = 8.0 Hz,

2 H), 7.36–7.49 (m, 6 H), 7.53–7.56 (m, 2 H), 8.50 (br. s, 1 H) ppm. 34.0 (t), 43.8 (d), 44.8 (d), 50.3 (d), 51.6 (q), 52.5 (q), 110.6 (s),

¹³C NMR (CDCl₃, 100.81 MHz): δ = 21.3 (q), 39.8 (2 q), 114.0 (s),

116.1 (d), 125.5 (2 d), 127.1 (2 d), 128.4 (d), 129.2 (2 d), 129.4 (2

d), 131.1 (s), 133.8 (s), 134.0 (d), 138.4 (s), 151.1 (s), 151.8 (s), 152.4

127.6 (2 d), 129.1 (2 d), 136.7 (s), 138.1 (s), 146.8 (s), 170.6 (s),

171.9 (s), 173.8 (s) ppm. MS (FAB⁺): m/z (%) = 375 (100) [M +

1]⁺. C₁₉H₂₂N₂O₄S (374.46): calcd. C 60.94, H 5.92, N 7.48, S 8.56;

(s), 168.7 (s) ppm. MS (FAB⁺): m/z (%) = 838 (36) [2M]⁺, 420 (74) found C 60.77, H 6.01, N 7.81, S 8.49.

[M + 1]⁺, 419 (100) [M]⁺. C₂₂H₂₁N₅O₂S (419.50): calcd. C 62.99,

H 5.05, N 16.69, S 7.64; found C 62.72, H 5.17, N 16.72, S 7.88.

Dimethyl

(5R*,6S*,7S*)-2-Methylamino-5-(4-methoxyphenyl)-

4,5,6,7-tetrahydrobenzothiazole-6,7-dicarboxylate (7c): From di-

methyl maleate: 2:1 EtOAc/n-hexane was used as eluent (R_f= 0.30),

yield 42% (0.082 g) (7cЈЈ was also isolated in 30% yield, R_f= 0.22

in 2:1 EtOAc/n-hexane), m.p. 208–210 °C (colourless needles,

2-Dimethylamino-5-(1,2,2-tricyanoethenyl)-4-[(E)-2-(4-methylphen-

yl)ethenyl]thiazole (6): TCNE (0.06 g, 0.50 mmol) was added to a

solution of 4-alkenyl-2-dimethylaminothiazole 1e (0.12 g,

0.50 mmol) in chloroform (5 mL). After 2 h of stirring at room CHCl /Et O). IR (nujol): ν = 3205, 3106, 1729, 1594, 1515, 1407,

˜

3

2

temperature, the solvent was evaporated to dryness, and the prod-

uct was purified by silica gel chromatography eluting with 1:1

EtOAc/n-hexane (R_f= 0.30), yield 43% (0.074 g), m.p. 218–220 °C

1350, 1299, 1247, 1229, 1165, 1027, 833, 730 cm^–1. ¹H NMR

(CDCl₃, 400.91 MHz): δ = 2.84–2.87 (m, 2 H, 4-H + 4Ј-H), 2.94

(s, 3 H, NHMe), 3.16–3.28 (m, 2 H, 5-H + 6-H), 3.32 (s, 3 H,

C₆H₄OMe), 3.72 (s, 3 H, COOMe), 3.79 (s, 3 H, COOMe), 4.27

(dt, J = 9.9, J = 2.3 Hz, 1 H, 7-H), 5.45 (br. s, 1 H, NH), 6.85 (d,

J = 8.7 Hz, 2 H), 7.16 (d, J = 8.7 Hz, 2 H) ppm. ¹³C NMR (CDCl₃,

100.81 MHz): δ = 32.0 (q), 34.1 (t), 43.4 (d), 44.8 (d), 50.4 (d), 51.7

(red needles, CHCl /Et O). IR (nujol): ν = 2207, 1594, 1355, 1307,

˜

3

2

1263, 808 cm^–1. ¹H NMR (CDCl₃, 300.10 MHz): δ = 2.39 (s, 3 H),

3.26 (br. s, 3 H), 3.47 (br. s, 3 H), 7.22 (d, J = 8.0 Hz, 2 H), 7.51

(d, J = 8.0 Hz, 2 H), 7.88–7.99 (m, 2 H) ppm. ¹³C NMR (CDCl₃,

75.45 MHz): δ = 21.6 (q), 40.0 (q), 40.8 (q), 73.7 (s), 114.2 (s), 114.3 (q), 52.4 (q), 55.2 (q), 110.6 (s), 113.8 (2 d), 128.7 (2 d), 133.2 (s),

(s), 114.4 (s), 116.8 (d), 117.3 (s), 126.0 (s), 128.5 (2 d), 129.9 (2 d), 146.8 (s), 158.6 (s), 170.6 (s), 171.9 (s), 173.9 (s) ppm. MS (EI,

132.7 (s), 141.3 (s), 143.9 (d), 166.3 (s), 171.5 (s) ppm. MS (FAB⁺):

70 eV): m/z (%) = 391 (6) [M + 1]⁺, 390 (7) [M]⁺, 358 (15), 331

m/z (%) = 346 (65) [M + 1]⁺, 345 (51) [M]⁺. C₁₉H₁₅N₅S (345.41): (30), 330 (100), 271 (89), 121 (55). C₁₉H₂₂N₂O₅S (390.46): calcd. C

calcd. C 66.07, H 4.38, N 20.27, S 9.28; found C 65.95, H 4.51, N

20.32, S 9.18.

58.45, H 5.68, N 7.17, S 8.21; found C 58.27, H 5.79, N 7.37, S

8.26.

Reactions of 4-Alkenyl-2-aminothiazoles 1a–e with Dimethyl Male-

ate and Dimethyl Fumarate: Dimethyl maleate or dimethyl fumarate

(1.08 g, 7.50 mmol) was added to a solution of 4-alkenyl-2-amino-

Dimethyl

(5R*,6S*,7S*)-2-Dimethylamino-5-(4-methylphenyl)-

4,5,6,7-tetrahydrobenzothiazole-6,7-dicarboxylate (7d): From di-

methyl maleate: 1:2Ǟ1:1 EtOAc/n-hexane was used as eluent (R_f

Eur. J. Org. Chem. 2013, 474–489

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485

M. Alajarin, A. Pastor et al.

FULL PAPER

= 0.35 in 1:2 EtOAc/n-hexane), yield 21% (0.041 g) (7dЈ and 7dЈЈ

were also isolated in 26 and 46% yields, respectively, R_f= 0.30 and

0.10, respectively, in 2:1 EtOAc/n-hexane). From dimethyl fumar-

ate: yield 39% (7dЈ was also isolated in 57% yield), m.p. 165–166 °C

yield, R = 0.25 in 2:1 EtOAc/n-hexane). IR (nujol): ν = 3425, 3346,

˜

f

3136, 1738, 1613, 1516, 1203, 1167, 1022, 817 cm^–1. ¹H NMR

(CDCl₃, 400.91 MHz): δ = 2.31 (s, 3 H, C₆H₄Me), 2.84 (dd, J =

17.7, J = 3.6 Hz, 1 H, 4-H), 2.94 (ddd, J = 17.7, J = 6.2, J = 2.2 Hz,

1 H, 4Ј-H), 3.48 (dd, J = 6.2, J = 5.1 Hz, 1 H, 6-H), 3.55 (br. s, 1

(colourless needles, CHCl /Et O). IR (nujol): ν = 1737, 1723, 1549,

˜

3

2

1224, 1168 cm^–1. ¹H NMR (CDCl₃, 600.13 MHz): δ = 2.32 (s, 3 H, H, 7-H), 3.61 (s, 3 H, COOMe), 3.70 (s, 3 H, COOMe), 3.86 (q, J

C₆H₄Me), 2.86–2.93 (m, 2 H, 4-H + 4Ј-H), 3.07 (s, 6 H, NMe₂), = 5.7 Hz, 1 H, 5-H), 5.22 (br. s, 2 H, NH₂), 7.07–7.14 (m, 4 H)

3.20 (ddd, J = 11.3, J = 9.3, J = 6.9 Hz, 1 H, 5-H), 3.27 (dd, J =

11.3, J = 9.8 Hz, 1 H, 6-H), 3.31 (s, 3 H, COOMe), 3.72 (s, 3 H, (t, C-4), 38.7 (d, C-5), 40.0 (d, C-7), 49.3 (d, C-6), 52.2 (q, CO-

ppm. ¹³C NMR (CDCl₃, 100.81 MHz): δ = 21.0 (q, C₆H₄Me), 29.7

COOMe), 4.27 (dt, J = 9.8, J = 2.3 Hz, 1 H, 7-H), 7.11 (s, 4 H)

ppm. ¹³C NMR (CDCl₃, 100.81 MHz): δ = 21.1 (q), 34.1 (t), 40.1

(2 q), 43.7 (d), 44.8 (d), 50.3 (d), 51.6 (q), 52.4 (q), 110.6 (s), 127.5

(2 d), 129.1 (2 d), 136.6 (s), 138.2 (s), 147.5 (s), 170.6 (s), 172.1 (s),

173.9 (s) ppm. MS (EI, 70 eV): m/z (%) = 389 (11) [M + 1]⁺, 388

(11) [M]⁺, 356 (13), 329 (34), 328 (100), 269 (77). C₂₀H₂₄N₂O₄S

(388.47): calcd. C 61.83, H 6.23, N 7.21, S 8.25; found C 61.69, H

6.29, N 7.37, S 8.17.

OMe), 52.4 (q, COOMe), 113.3 (s, C-7a), 127.0 (2 d), 129.4 (2 d),

136.6 (s), 139.4 (s), 144.6 (s, C-3a), 167.9 (s, C-2), 171.8 (s, CO-

OMe), 171.9 (s, COOMe) ppm. MS (EI, 70 eV): m/z (%) = 360 (23)

[M]⁺, 301 (35), 300 (52), 241 (100), 184 (30), 149 (23), 105 (27).

Dimethyl

(5R*,6R*,7S*)-2-Methylamino-5-(4-methylphenyl)-

4,5,6,7-tetrahydrobenzothiazole-6,7-dicarboxylate (7bЈЈ): From di-

methyl maleate: 2:1 EtOAc/n-hexane was used as eluent (R_f= 0.12),

yield 40% (0.075 g) (7b was also isolated in 24% yield, R_f= 0.24

Dimethyl

(5R*,6R*,7R*)-2-Methylamino-5-(4-methylphenyl)- in 2:1 EtOAc/n-hexane), m.p. 146–147 °C (colourless needles,

4,5,6,7-tetrahydrobenzothiazole-6,7-dicarboxylate (7bЈ): From di-

methyl fumarate: 1:1 EtOAc/n-hexane was used as eluent (R_f=

0.20). 81% combined yield (0.151 g) (compound 7bЈ was obtained

as a diastereomeric mixture with 7b, and the assignment could be

done since 7b had been obtained in pure form from the reaction

CHCl /n-pentane). IR (nujol): ν = 3205, 3110, 1732, 1557, 1209,

˜

3

1167, 1022 cm^–1. ¹H NMR (CDCl₃, 300.10 MHz): δ = 2.31 (s, 3 H,

C₆H₄Me), 2.83 (ddd, J = 17.6, J = 5.1, J = 1.5 Hz, 1 H, 4-H), 2.96

(ddd, J = 17.6, J = 6.3, J = 2.1 Hz, 1 H, 4Ј-H), 2.97 (s, 3 H,

NHMe), 3.47 (dd, J = 6.9, J = 5.1 Hz, 1 H, 6-H), 3.59 (s, 3 H,

COOMe), 3.60–3.62 (m, 1 H, 7-H), 3.70 (s, 3 H, COOMe), 3.86 (q,

J = 5.7 Hz, 1 H, 5-H), 5.35 (br. s, 1 H, NH), 7.09 (br. s, 4 H) ppm.

¹³C NMR (CDCl₃, 75.45 MHz): δ = 21.0 (q, C₆H₄Me), 30.4 (t, C-

4), 32.1 (q, NHMe), 38.9 (d, C-5), 40.3 (d, C-7), 49.4 (d, C-6), 52.1

(q, COOMe), 52.3 (q, COOMe), 111.3 (s, C-7a), 127.0 (2 d), 129.3

(2 d), 136.5 (s), 139.7 (s), 145.9 (s, C-3a), 170.9 (s, C-2), 172.0 (s,

1

with DMMa). H NMR (CDCl₃, 400.91 MHz): δ = 2.28 (s, 3 H,

C₆H₄Me), 2.93 (s, 3 H, NHMe), 2.98 (ddd, J = 17.1, J = 3.8, J =

1.7 Hz, 1 H, 4-H), 3.11 (ddd, J = 17.1, J = 6.3, J = 2.8 Hz, 1 H,

4Ј-H), 3.53 (dd, J = 8.9, J = 3.8 Hz, 1 H, 6-H), 3.65 (s, 3 H, CO-

OMe), 3.76 (s, 3 H, COOMe), 3.78 (dt, J = 6.3, J = 3.8 Hz, 1 H,

5-H), 3.83 (dt, J = 8.9, J = 2.3 Hz, 1 H, 7-H), 5.14 (br. s, 1 H,

NH), 6.93 (d, J = 8.0 Hz, 2 H), 7.03 (d, J = 8.0 Hz, 2 H) ppm. ¹³C COOMe), 172.1 (s, COOMe) ppm. MS (EI, 70 eV): m/z (%) = 374

NMR (CDCl₃, 100.81 MHz): δ = 21.0 (q, C₆H₄Me), 31.1 (t, C-4),

(44) [M]⁺, 315 (81), 314 (49), 255 (100), 230 (34), 198 (51), 105 (36).

32.1 (q, NHMe), 39.2 (d, C-5), 40.3 (d, C-7), 47.4 (d, C-6), 51.8 (q, C₁₉H₂₂N₂O₄S (374.46): calcd. C 60.94, H 5.92, N 7.48, S 8.56;

COOMe), 52.4 (q, COOMe), 110.8 (s, C-7a), 127.3 (2 d), 129.1 (2 found C 60.57, H 5.99, N 7.77, S 8.71.

d), 136.7 (s), 137.7 (s), 146.2 (s, C-3a), 171.1 (s, C-2), 172.50 (s,

Dimethyl

(5R*,6R*,7S*)-2-Methylamino-5-(4-methoxyphenyl)-

COOMe), 172.51 (s, COOMe) ppm.

4,5,6,7-tetrahydrobenzothiazole-6,7-dicarboxylate (7cЈЈ): From di-

Dimethyl (5R*,6R*,7R*)-2-Dimethylamino-5-(4-methylphenyl)- methyl maleate: 2:1 EtOAc/n-hexane was used as eluent (R_f= 0.22),

4,5,6,7-tetrahydrobenzothiazole-6,7-dicarboxylate (7dЈ): From di-

methyl maleate: 1:2Ǟ1:1 EtOAc/n-hexane was used as eluent (R_f

= 0.30 in 1:2 EtOAc/n-hexane), yield 26% (0.051 g) (7d and 7dЈЈ

were also isolated in 21 and 46% yields, respectively, R_f= 0.35 and

0.10, respectively, in 2:1 EtOAc/n-hexane). From dimethyl fumar-

ate: yield 57% (7d was also isolated in 39% yield), m.p. 151–153 °C

yield 30% (0.059 g) (7c was also isolated in 42% yield, R_f= 0.30

in 2:1 EtOAc/n-hexane), m.p. 84–86 °C. IR (nujol): ν = 3367, 3206,

˜

1

1733, 1512, 1259, 1026 cm^–1. H NMR (CDCl₃, 400.91 MHz): δ =

2.82 (ddd, J = 17.4, J = 4.7, J = 1.2 Hz, 1 H, 4-H), 2.97–2.92 (m,

4 H, 4Ј-H + NHMe), 3.45 (dd, J = 6.6, J = 5.0 Hz, 1 H, 6-H), 3.59

(s, 3 H, C₆H₄OMe), 3.60–3.62 (m, 1 H, 7-H), 3.70 (s, 3 H, CO-

OMe), 3.77 (s, 3 H, COOMe), 3.85 (m, 1 H, 5-H), 5.40 (br. s, 1 H,

NH), 6.82 (d, J = 8.7 Hz, 2 H), 7.11 (d, J = 8.7 Hz, 2 H) ppm. ¹³C

(colourless needles, CHCl /Et O). IR (nujol): ν = 1741, 1731, 1584,

˜

3

2

1559, 1343, 1324, 1226, 1170 cm^–1. ¹H NMR (CDCl₃,

400.91 MHz): δ = 2.28 (s, 3 H, C₆H₄Me), 3.03 (ddd, J = 17.1, J = NMR (CDCl₃, 100.81 MHz): δ = 29.3 (t, C-4), 32.0 (q, NHMe),

3.8, J = 1.6 Hz, 1 H, 4-H), 3.09 (s, 6 H, NMe₂), 3.15 (ddd, J = 38.4 (d, C-5), 40.2 (d, C-7), 49.4 (d, C-6), 52.0 (q, COOMe), 52.2

17.1, J = 6.2, J = 2.7 Hz, 1 H, 4Ј-H), 3.53 (dd, J = 8.8, J = 3.8 Hz, (q, COOMe), 55.2 (q, C₆H₄OMe), 110.9 (s, C-7a), 114.0 (2 d), 128.2

1 H, 6-H), 3.65 (s, 3 H, COOMe), 3.75 (s, 3 H, COOMe), 3.78 (dt,

(2 d), 133.6 (s), 145.8 (s, C-3a), 158.4 (s), 171.2 (s, C-2), 172.0 (s,

J = 6.2, J = 3.8 Hz, 1 H, 5-H), 3.84 (dt, J = 8.8, J = 1.8 Hz, 1 H, COOMe), 172.1 (s, COOMe) ppm. MS (EI, 70 eV): m/z (%) = 390

7-H), 6.93 (d, J = 8.1 Hz, 2 H), 7.03 (d, J = 8.1 Hz, 2 H) ppm. ¹³C (37) [M]⁺, 331 (67), 330 (31), 271 (67), 246 (53), 198 (47), 183 (33),

NMR (CDCl₃, 75.45 MHz): δ = 21.0 (q, C₆H₄Me), 31.6 (t, C-4),

39.3 (d, C-5), 40.1 (2 q, NMe₂), 40.4 (d, C-7), 47.4 (d, C-6), 51.8

(q, COOMe), 52.3 (q, COOMe), 111.1 (s, C-7a), 127.3 (2 d), 129.1

(2 d), 136.5 (s), 138.0 (s), 147.4 (s, C-3a), 170.4 (s, C-2), 172.6 (s,

COOMe), 172.7 (s, COOMe) ppm. MS (EI, 70 eV): m/z (%) = 389

(14) [M + 1]⁺, 388 (17) [M]⁺, 356 (17), 329 (38), 328 (100), 269

(82). C₂₀H₂₄N₂O₄S (388.47): calcd. C 61.83, H 6.23, N 7.21, S 8.25;

found C 61.64, H 6.33, N 7.31, S 8.29.

167 (32), 149 (100), 121 (92), 86 (73), 59 (81), 57 (74).

Dimethyl (5R*,6R*,7S*)-2-Dimethylamino-5-(4-methylphenyl)-

4,5,6,7-tetrahydrobenzothiazole-6,7-dicarboxylate (7dЈЈ): From di-

methyl maleate: 1:2Ǟ1:1 EtOAc/n-hexane was used as eluent (R_f

= 0.10 in 1:2 EtOAc/n-hexane), yield 46% (0.089 g) (7d and 7dЈ

were also isolated in 21 and 26% yields, respectively, R_f= 0.35 and

R_f= 0.30 in 2:1 EtOAc/n-hexane), m.p. 96–98 °C (colourless need-

les, CHCl /n-hexane). IR (nujol): ν = 1747, 1738, 1556, 1515, 1434,

˜

3

Dimethyl (5R*,6R*,7S*)-2-Amino-5-(4-methylphenyl)-4,5,6,7-tetra-

hydrobenzothiazole-6,7-dicarboxylate (7aЈЈ): From dimethyl male-

ate: 2:1Ǟ3:1 EtOAc/n-hexane was used as eluent (R_f= 0.18 in 2:1

EtOAc/n-hexane), yield 15% (0.027 g) (7a was also isolated in 20%

1345, 1261, 1202, 1166, 756 cm^–1. ¹H NMR (CDCl₃, 400.91 MHz):

δ = 2.30 (s, 3 H, C₆H₄Me), 2.86 (ddd, J = 17.5, J = 5.1, J = 1.5 Hz,

1 H, 4-H), 2.99 (ddd, J = 17.5, J = 6.2, J = 2.2 Hz, 1 H, 4Ј-H),

3.09 (s, 6 H, NMe₂), 3.45 (dd, J = 6.7, J = 5.0 Hz, 1 H, 6-H), 3.57

486

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Eur. J. Org. Chem. 2013, 474–489

Cycloadditions of 4-Alkenyl-2-Aminothiazoles

(s, 3 H, COOMe), 3.62–3.65 (m, 1 H, 7-H), 3.69 (s, 3 H, COOMe),

22.3 (t, C-7), 31.86 (t, C-4), 31.94 (t, CH₂CH₂), 38.9 (q, NMe), 40.2

(d, C-5), 45.1 (d, C-6), 48.8 (t, CH₂CH₂), 51.5 (q, COOMe), 51.8

3.86 (m, 1 H, 5-H), 7.08 (s, 4 H) ppm. ¹³C NMR (CDCl₃,

50.30 MHz): δ = 20.9 (q, C₆H₄Me), 30.7 (t, C-4), 38.8 (d, C-5), (q, COOMe), 114.2 (s, C-7a), 127.6 (2 d), 129.0 (2 d), 136.3 (s),

40.1 (2 q, NMe₂), 40.3 (d, C-7), 49.3 (d, C-6), 51.9 (q, COOMe),

52.1 (q, COOMe), 111.0 (s, C-7a), 127.0 (2 d), 129.2 (2 d), 136.2

(s), 139.7 (s), 146.8 (s, C-3a), 170.9 (s, C-2), 172.0 (s, COOMe),

138.4 (s), 145.4 (s, C-3a), 168.3 (s, C-2), 172.4 (s, COOMe), 173.5

(s, COOMe) ppm. MS (EI, 70 eV): m/z (%) = 403 (30) [M + 1]⁺,

402 (100) [M]⁺, 343 (28), 316 (37), 226 (28), 140 (42), 115 (29), 59

172.2 (s, COOMe) ppm. MS (EI, 70 eV): m/z (%) = 389 (25) [M + (33), 55 (34). C₂₁H₂₆N₂O₄S (402.51): calcd. C 62.66, H 6.51, N

1]⁺, 388 (81) [M]⁺, 329 (100), 269 (74), 244 (39), 212 (42), 197 (30). 6.96, S 7.97; found C 62.50, H 6.64, N 6.99, S 8.08.

C₂₀H₂₄N₂O₄S (388.47): calcd. C 61.83, H 6.23, N 7.21, S 8.25;

Methyl (5R*,6R*)-2-[(2-Methoxycarbonylethyl)methylamino]-5-(4-

found C 61.71, H 6.24, N 7.49, S 8.11.

methylphenyl)-4,5,6,7-tetrahydrobenzothiazole-6-carboxylate (exo-

Reaction of 4-Alkenyl-2-aminothiazoles 1c and 1e with Methyl 8b): 1:2Ǟ1:1 EtOAc/n-hexane was used as eluent (R_f= 0.31 in 1:2

Acrylate: Methyl acrylate (0.66 g, 7.65 mmol) was added to a solu-

tion of the 4-alkenyl-2-aminothiazole 1c or 1e (0.50 mmol) in

acetonitrile (5 mL). The reaction mixture was stirred under reflux

for 48 h. The solvent was removed, and the residue was purified by

silica gel chromatography.

EtOAc/n-hexane), yield 4% (0.008 g), m.p. 124–126 °C (colourless

needles, CHCl /Et O). IR (nujol): ν = 1730, 1547, 1332, 1296, 1206,

˜

3

2

1167, 1113, 1045, 811 cm^–1. H NMR (CDCl₃, 400.91 MHz): δ =

2.31 (s, 3 H, C₆H₄Me), 2.69 (t, J = 6.9 Hz, 2 H, CH₂CH₂), 2.74–

3.02 (m, 5 H, 4-H + 4Ј-H + 7-H + 7Ј-H + 5-H), 3.06 (s, 3 H,

NMe), 3.23–3.28 (m, 1 H, 6-H), 3.42 (s, 3 H, COOMe), 3.69 (s, 3

H, COOMe), 3.74 (t, J = 6.9 Hz, 2 H, CH₂CH₂), 7.10 (s, 4 H) ppm.

¹³C NMR (CDCl₃, 100.81 MHz): δ = 21.0 (q, C₆H₄Me), 26.5 (t),

31.9 (t, CH₂CH₂), 34.0 (t), 39.0 (q, NMe), 43.1 (d), 47.3 (d), 48.8

(t, CH₂CH₂), 51.5 (q, COOMe), 51.8 (q, COOMe), 113.5 (s, C-7a),

127.3 (2 d), 129.1 (2 d), 136.2 (s), 139.7 (s), 145.7 (s, C-3a), 168.2

(s, C-2), 172.3 (s, COOMe), 174.6 (s, COOMe) ppm. MS (EI,

70 eV): m/z (%) = 403 (35) [M + 1]⁺, 402 (100) [M]⁺, 316 (52), 226

(32), 168 (22), 167 (27), 140 (68), 115 (21). C₂₁H₂₆N₂O₄S (402.51):

calcd. C 62.66, H 6.51, N 6.96, S 7.97; found C 62.43, H 6.59, N

7.02, S 8.00.

1

Methyl (5R*,6S*)-2-Methylamino-5-(4-methylphenyl)-4,5,6,7-tetra-

hydrobenzothiazole-6-carboxylate (endo-8a): 1:2Ǟ1:1 EtOAc/n-

hexane was used as eluent (R_f= 0.08 in 1:2 EtOAc/n-hexane), yield

11% (0.017 g), m.p. 198–199 °C (colourless needles, CHCl₃/Et₂O).

IR (nujol): ν = 3209, 3117, 1734, 1599, 1410, 1306, 1233, 1167,

˜

1057, 1040, 821 cm^–1. ¹H NMR (CDCl₃, 600.13 MHz): δ = 2.28 (s,

3 H, C₆H₄Me), 2.68 (br. dd, J = 16.3, J = 9.9 Hz, 1 H, 7-H), 2.80

(dd, J = 16.3, J = 5.0 Hz, 1 H, 7Ј-H), 2.95 (s, 3 H, NMe), 2.98 (br.

d, J = 17.1 Hz, 1 H, 4-H), 3.09–3.13 (m, 2 H, 6-H + 4Ј-H), 3.65 (s,

3 H, COOMe), 3.72 (td, J = 6.5, J = 3.3 Hz, 1 H, 5-H), 5.82 (br.

s, 1 H, NH), 6.97 (d, J = 8.0 Hz, 2 H), 7.03 (d, J = 8.0 Hz, 2 H)

ppm. ¹³C NMR (CDCl₃, 100.81 MHz): δ = 21.0 (q, C₆H₄Me), 22.2

Methyl

(5R*,6S*)-2-Dimethylamino-5-(4-methylphenyl)-4,5,6,7-

(t, C-7), 31.7 (t, C-4), 32.0 (q, NMe), 40.1 (d, C-5), 45.1 (d, C-6), tetrahydrobenzothiazole-6-carboxylate (endo-8c): 1:2 EtOAc/n-hex-

51.5 (q, COOMe), 113.9 (s, C-7a), 127.6 (2 d), 129.0 (2 d), 136.4

(s), 138.3 (s), 144.9 (s, C-3a), 169.4 (s, C-2), 173.5 (s, COOMe) ppm.

ane was used as eluent (R_f= 0.18), yield 24% (0.040 g), m.p. 120–

121 °C (colourless needles, CHCl /Et O). IR (nujol): ν = 1731,

˜

3

2

MS (EI, 70 eV): m/z (%) = 316 (33) [M]⁺, 230 (21), 147 (43), 140 1556, 1336, 1249, 1229, 1196, 1167, 1125, 940, 822 cm^–1. H NMR

1

(27), 132 (30), 107 (67), 106 (100), 104 (25), 77 (27). C₁₇H₂₀N₂O₂S

(316.42): calcd. C 64.53, H 6.37, N 8.85, S 10.13; found C 64.24,

H 6.43, N 8.90, S 9.98.

(CDCl₃, 400.91 MHz): δ = 2.28 (s, 3 H, C₆H₄Me), 2.69 (ddt, J =

16.2, J = 9.7, J = 2.0 Hz, 1 H, 7-H), 2.81 (dd, J = 16.2, J = 5.1 Hz,

1 H, 7Ј-H), 2.99–3.06 (m, 1 H, 4-H), 3.08 (s, 6 H, NMe₂), 3.09–

3.17 (m, 2 H, 4Ј-H + 6-H), 3.64 (s, 3 H, COOMe), 3.72 (td, J =

6.5, J = 3.3 Hz, 1 H, 5-H), 6.97 (d, J = 8.1 Hz, 2 H), 7.03 (d, J =

8.1 Hz, 2 H) ppm. ¹³C NMR (CDCl₃, 50.30 MHz): δ = 21.0 (q,

C₆H₄Me), 22.3 (t, C-7), 31.9 (t, C-4), 40.2 (d, C-5), 40.3 (2 q,

NMe₂), 45.1 (d, C-6), 51.5 (q, COOMe), 114.1 (s, C-7a), 127.6 (2

d), 129.0 (2 d), 136.3 (s), 138.4 (s), 145.6 (s, C-3a), 169.5 (s, C-2),

173.6 (s, COOMe) ppm. MS (EI, 70 eV): m/z (%) = 331 (33) [M +

1]⁺, 330 (100) [M]⁺, 271 (35), 244 (28), 154 (81), 88 (24).

C₁₈H₂₂N₂O₂S (330.43): calcd. C 65.42, H 6.71, N 8.48, S 9.70;

found C 65.05, H 6.82, N 8.62, S 9.82.

Methyl (5R*,6R*)-2-Methylamino-5-(4-methylphenyl)-4,5,6,7-tetra-

hydrobenzothiazole-6-carboxylate (exo-8a): 1:2Ǟ1:1 EtOAc/n-hex-

ane was used as eluent (R_f= 0.13 in 1:2 EtOAc/n-hexane), yield

11% (0.017 g), m.p. 246–248 °C (colourless needles, CHCl₃/Et₂O).

IR (nujol): ν = 3210, 3111, 1723, 1597, 1407, 1304, 1230, 1168 cm^–1.

˜

¹H NMR (CDCl₃, 400.91 MHz): δ = 2.31 (s, 3 H, C₆H₄Me), 2.76

(ddm, J = 17.6, J = 10.9 Hz, 1 H, 4-H), 2.86–3.06 (m, 7 H, 4Ј-H

+ NMe + 7-H + 7Ј-H + 5-H), 3.28 (td, J = 10.2, J = 5.5 Hz, 1 H,

6-H), 3.42 (s, 3 H, COOMe), 5.31 (br. s, 1 H, NH), 7.11 (s, 4 H)

ppm. ¹³C NMR (CDCl₃, 100.81 MHz): δ = 21.0 (q), 26.5 (t), 32.1

(q), 33.9 (t), 43.0 (d), 47.4 (d), 51.5 (q), 113.4 (s), 127.3 (2 d), 129.2

(2 d), 136.3 (s), 139.7 (s), 145.2 (s), 169.2 (s), 174.6 (s) ppm. MS

(EI, 70 eV): m/z (%) = 317 (24) [M + 1]⁺, 316 (85) [M]⁺, 230 (91),

Methyl

(5R*,6R*)-2-Dimethylamino-5-(4-methylphenyl)-4,5,6,7-

tetrahydrobenzothiazole-6-carboxylate (exo-8c): 1:2 EtOAc/n-hex-

ane was used as eluent (R_f= 0.25), yield 32% (0.053 g), m.p. 169–

140 (100). C₁₇H₂₀N₂O₂S (316.42): calcd. C 64.53, H 6.37, N 8.85, 171 °C (colourless needles, CHCl /Et O). IR (nujol): ν = 1728,

˜

3

2

S 10.13; found C 64.29, H 6.39, N 8.97, S 10.21.

1589, 1556, 1515, 1296, 1194, 1166, 1128, 980, 813, 723, 708 cm^–1.

¹H NMR (CDCl₃, 400.91 MHz): δ = 2.31 (s, 3 H, C₆H₄Me), 2.75–

3.04 (m, 5 H, 4-H + 4Ј-H + 7-H + 7Ј-H + 5-H), 3.06 (s, 6 H,

NMe₂), 3.24–3.31 (m, 1 H, 6-H), 3.64 (s, 3 H, COOMe), 7.08–7.12

(m, 4 H) ppm. ¹³C NMR (CDCl₃, 50.30 MHz): δ = 21.0 (q), 26.4

(t), 34.0 (t), 40.2 (2 q), 43.1 (d), 47.4 (d), 51.5 (q), 113.4 (s), 127.3

(2 d), 129.1 (2 d), 136.2 (s), 139.8 (s), 145.8 (s), 169.5 (s), 174.6 (s)

ppm. MS (EI, 70 eV): m/z (%) = 331 (32) [M + 1]⁺, 330 (92) [M]⁺,

244 (54), 154 (100), 139 (21), 125 (20). C₁₈H₂₂N₂O₂S (330.43):

calcd. C 65.42, H 6.71, N 8.48, S 9.70; found C 65.22, H 6.79, N

8.69, S 9.54.

Methyl (5R*,6S*)-2-[(2-Methoxycarbonylethyl)methylamino]-5-(4-

methylphenyl)-4,5,6,7-tetrahydrobenzothiazole-6-carboxylate (endo-

8b): 1:2Ǟ1:1 EtOAc/n-hexane was used as eluent (R_f= 0.25 in

1:2 EtOAc/n-hexane), yield 9% (0.018 g), m.p. 57–59 °C (colourless

needles, CHCl /Et O). IR (nujol): ν = 1736, 1545, 1306, 1258, 1200,

˜

3

2

1

1167, 1113, 1044, 819, 732 cm^–1. H NMR (CDCl₃, 400.91 MHz):

δ = 2.29 (s, 3 H, C₆H₄Me), 2.65–2.72 (m, 3 H, 7-H + CH₂CH₂),

2.81 (dd, J = 16.2, J = 5.3 Hz, 1 H, 7Ј-H), 3.01 (dm, J = 17.1 Hz,

1 H, 4-H), 3.08–3.15 (m, 5 H, NMe + 4Ј-H + 6-H), 3.64 (s, 3 H,

COOMe), 3.70–3.71 (m, 4 H, 5-H + COOMe), 3.77 (m, J = 6.9 Hz,

2 H, CH₂CH₂), 6.97 (d, J = 8.1 Hz, 2 H), 7.04 (d, J = 8.1 Hz, 2 (5R*,6R*)-6-Chloro-2-dimethylamino-5-(4-methylphenyl)-7H-4,5-di-

H) ppm. ¹³C NMR (CDCl₃, 100.81 MHz): δ = 21.0 (q, C₆H₄Me), hydrobenzothiazole-6-carbonitrile (9): α-Chloroacrylonitrile (1.07 g,

Eur. J. Org. Chem. 2013, 474–489

www.eurjoc.org

487

M. Alajarin, A. Pastor et al.

FULL PAPER

12.27 mmol) was added to a solution of 4-alkenyl-2-aminothiazole

1e (0.20 g, 0.82 mmol) in acetonitrile (10 mL). The reaction mixture

was stirred under reflux for 48 h. The solvent was removed, and

the residue was purified by silica gel chromatography, eluting with

1:2 EtOAc/n-hexane (R_f= 0.33), yield 80% (0.218 g), m.p. 203–

Supporting Information (see footnote on the first page of this arti-

cle): contains the experimental procedure for the preparation of α-

chloro ketone 2d, a general procedure for the preparation of thi-

azoles 1c–d and 1f–h, the ¹H,¹H-NOESY spectra of 7b, 7dЈ, and

7bЈЈ, the X-ray structure of endo-4e, the cartesian coordinates, elec-

tronic energies, and imaginary frequencies of 4-alkenylthiazoles 1i–

m optimized at the B3LYP/6-31+G level, and copies of the ¹H

NMR and ¹³C NMR spectra of all new compounds.

205 °C (colourless prisms, CHCl /Et O). IR (nujol): ν = 1590, 1569,

˜

3

2

1135, 1044, 900, 814, 724 cm^–1. ¹H NMR (CDCl₃, 400.91 MHz): δ

= 2.36 (s, 3 H, C₆H₄Me), 3.08 (s, 6 H, NMe₂), 3.15 (br. dd, J =

17.4, J = 6.0 Hz, 1 H, 4-H), 3.23 (br. dd, J = 17.4, J = 8.8 Hz, 1

H, 4Ј-H), 3.38 (br. d, J = 16.0 Hz, 1 H, 7-H), 3.43 (dd, J = 8.8, J

= 6.0 Hz, 1 H, 5-H), 3.52 (br. d, J = 16.0 Hz, 1 H, 7Ј-H), 7.18 (d,

J = 8.0 Hz, 2 H), 7.32 (d, J = 8.0 Hz, 2 H) ppm. ¹³C NMR (CDCl₃,

100.81 MHz): δ = 21.1 (q, C₆H₄Me), 32.3 (t, C-4), 38.9 (t, C-7),

40.1 (2 q, NMe₂), 50.5 (d, C-5), 59.1 (s, C-6), 109.6 (s, CN), 117.9

(s, C-7a), 128.4 (2 d), 129.3 (2 d), 135.0 (s), 138.2 (s), 145.8 (s, C-

3a), 170.2 (s, C-2) ppm. MS (EI, 70 eV): m/z (%) = 333 (23) [M +

2]⁺, 331 (62) [M]⁺, 154 (100). C₁₇H₁₈ClN₃S (331.85): calcd. C 61.53,

H 5.47, N 12.66, S 9.66; found C 61.34, H 5.63, N 12.79, S 9.44.

Acknowledgments

This work was supported by the Spanish Ministerio de Educacion

y Ciencia (MEC) (project number CTQ2008-05827) and Fundacion

Seneca-CARM/ (project number 08661/PI/08).

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Ethyl

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benzothiazole-6-carboxylate (10): Ethyl 2,3-butadienoate (0.28 g,

2.45 mmol) was added to a solution of 4-alkenyl-2-aminothiazole

1e (0.20 g, 0.82 mmol) in acetonitrile (15 mL). The reaction mixture

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the residue was purified by silica gel chromatography, eluting with

1:5 EtOAc/n-hexane (R_f= 0.15), yield 66% (0.193 g), m.p. 114–

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˜

3

2

1

1505, 1324, 1245, 1225, 1195, 1128, 1093 cm^–1. H NMR (CDCl₃,

400.91 MHz): δ = 1.18 (t, J = 7.1 Hz, 3 H, COOCH₂CH₃), 2.25 (s,

3 H, C₆H₄Me), 2.50 (s, 3 H, C-7-Me), 3.00 (dd, J = 17.0, J =

2.2 Hz, 1 H, 4-H), 3.08 (s, 6 H, NMe₂), 3.21 (dd, J = 17.0, J =

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8.0 Hz, 2 H) ppm. ¹³C NMR (CDCl₃, 100.81 MHz): δ = 14.2 (q,

COOCH₂CH₃), 20.8 (q, C-7-Me), 20.9 (q, C₆H₄Me), 33.7 (t, C-4),

39.5 (d, C-5), 40.0 (2 q, NMe₂), 59.7 (t, COOCH₂CH₃), 117.9 (s,

C-7a), 121.2 (s, C-6), 127.0 (2 d), 128.8 (2 d), 135.5 (s), 140.9 (s, C-

7), 141.0 (s), 151.4 (s, C-3a), 167.8 (s, COOEt), 171.5 (s, C-2) ppm.

MS (EI, 70 eV): m/z (%) = 356 (52) [M]⁺, 284 (20), 283 (100).

C₂₀H₂₄N₂O₂S (356.47): calcd. C 67.38, H 6.79, N 7.86, S 9.00;

found C 67.03, H 6.92, N 8.04, S 8.89.

Ethyl

2-Dimethylamino-5-(4-methyphenyl)-4,5-dihydrobenzothi-

azole-6-carboxylate (11): Ethyl propiolate (0.48 g, 4.92 mmol) was

added to a solution of 4-alkenyl-2-aminothiazole 1e (0.20 g,

0.82 mmol) in acetonitrile (15 mL). The reaction mixture was

stirred under reflux for 48 h. The solvent was removed, and the

residue was purified by silica gel chromatography, eluting with 1:2

EtOAc/n-hexane (R_f= 0.35), yield 72% (0.202 g), m.p. 91–93 °C

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1425, 1309, 1246, 1281, 1216, 1191, 1095, 1034, 817, 721 cm^–1. H

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(100), 253 (30), 239 (33), 184 (39), 179 (37), 165 (38). C₁₉H₂₂N₂O₂S

(342.44): calcd. C 66.64, H 6.48, N 8.18, S 9.36; found C 66.32, H

6.59, N 8.23, S 9.29.

488

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Eur. J. Org. Chem. 2013, 474–489

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Received: September 4, 2012

Published Online: December 6, 2012

Eur. J. Org. Chem. 2013, 474–489

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489

Article Doi

4-Alkenyl-2-aminothiazoles: Smart dienes for polar [4 + 2] cycloadditions

DOI: 10.1002/ejoc.201201185

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