Cycloaddition Reaction of Ethyl Thioxoacetate and the Dienamine Derived from Pummerer’s Ketone

e use of Bunte salt (1), for example, the ethyl ester as precursors of thioaldehydes, for example, ethyl thioxoacetate, was described by the german chemist Hans Bunte [1, 2]. is early work employed symmetrical dienes as trapping agents, the one exception being thebaine. Kirby and coworkers [3–8] reported the formation of ethyl thioxoacetate (3) from sulphonyl chloride (2) by elimination of hydrogen chloride with triethylamine. e thioaldehyde was trapped by a variety of 1,3-dienes such as 2,3-dimethylbutadiene (4), cyclohexadiene(5), anthracene (6a), 9,10-anthracene (6b), and thebaine (7). e cycloadducts of the corresponding dienes (8), (9), (10), and (11) were obtained in high yields, as it is shown in Scheme 1. e major thebaine cycloadduct (11) was found to be unstable. When it was heated under re�ux in toluene for 8 h, it was converted in high yield into the isomer (12) indicating that the cycloadduct (11) had been formed under kinetic control. Y. Watanabe and T. Skakibara [9] treated 1,4-diacetoxy1,3-butadiene (13) with ethyl thioxoacetate (3) derived in situ from thioglycolate [10], and obtained an inseparable mixture of threoand erythro-isomers in 68% yield Scheme 2. Recently, we reported [11] that treatment of the transient thioaldehyde (3) with unsymmetrical diene 1-methoxy-1,3cyclohexadiene (15) gave the cycloadducts (16) and (17) in good yield in an endo : exo ratio of 4 : 1, Scheme 3. e aim of the present study is to extend and explore the regiochemistry and stereochemistry of the reaction of ethyl thioxoacetate (3) with unsymmetrical diene, which is the dienamine (19) derived from Pummerer’s ketone.


Introduction
e use of Bunte salt (1), for example, the ethyl ester as precursors of thioaldehydes, for example, ethyl thioxoacetate, was described by the german chemist Hans Bunte [1,2].is early work employed symmetrical dienes as trapping agents, the one exception being thebaine.
e major thebaine cycloadduct (11) was found to be unstable.When it was heated under re�ux in toluene for 8 h, it was converted in high yield into the isomer (12) indicating that the cycloadduct (11) had been formed under kinetic control.
Recently, we reported [11] that treatment of the transient thioaldehyde (3) with unsymmetrical diene 1-methoxy-1,3cyclohexadiene (15) gave the cycloadducts ( 16) and (17) in good yield in an endo : exo ratio of 4 : 1, Scheme 3. e aim of the present study is to extend and explore the regiochemistry and stereochemistry of the reaction of ethyl thioxoacetate (3) with unsymmetrical diene, which is the dienamine (19) derived from Pummerer's ketone.

Cycloaddition Reaction of Ethyl ioxoacetate and the
Dienamine Derived from Pummerer's Ketone.With the aim of extending the study of thioxoacetate ester reactions with unsymmetrical conjugated dienes, a diene substituted in the 2-H position with an amino group was selected.e compound chosen was the dienamine (19) prepared [12] from the readily accessible enone, Pummerer's ketone (18) (Scheme 4).
e dienamine was formed as oil, from the ketone and pyrrolidine in methanol, as described in reference [12], and used immediately without puri�cation.e Bunte salt (1) was treated with triethylamine in ethanol-benzene in the presence of 1 mol equivalent of the dienamine (19) and calcium chloride dihydrate for 3 days.en the mixture was workedup under acidic conditions, which could be hydrolysed to the enamine (20) to give the cycloadduct (21) as a gum in 20% yield (Scheme 5).e yield of this product was increased to 40% by using 3 mol equivalents of the  e molecular formula of the cycloadduct ( 5) was iden-ti�ed by accurate mass measurement.e fragmentation patterns are discussed in (Table 3).e presence of the carbonyl groups was con�rmed by i. r. spectroscopy� a strong band at  1730 cm −1 was attributed to both carbonyl groups.e structure of the adduct (21), with the exception of stereochemistry, was assigned on the basis of the 1 H n.m.r.spectrum.e 90 MHz spectrum distinguishes between the 2 possible regioisomers (21) and (22) as shown in Scheme 6.
e 4a-H signal,  4,86 (d, j 4.0 Hz), is easily recognized by its low �eld position, similar to that of the corresponding signal,  4,65, in Pummerer's ketone (18), arising from deshielding by the inductive e�ect of oxygen.is allows identi�cation of the signal for 4-H,  3.35 (d, j 4Hz), since no other signals have this splitting.e fact that this signal is a clean doublet discounts structure (22), since 4-H would be coupled with 11-H.It was not possible to established the stereochemistry (i.e., with of 4, racemic, diastereoisomers (21) is, assuming that the cis ring fusion of Pummerer's ketone is maintained) from the 90 MHz spectrum (Scheme 7).
However, the 200 MHz spectrum and the nuclear overhauser (n.o.e) studied (Tables 1 and 2) established the structure (21) unambiguously.e structure (21) can be distinguished from (21a) by the long-range "W" coupling, J 1.3 Hz, between H-11 and 2-H.is coupling would not be expected in the isomer (21a   ese observations establish the relative stereochemistry at the centers 11, 1, and 9b and also con�rm the regiochemistry.When the cycloadduct (21) was hydrolysed with 1.03 M sodium hydroxide in tetrahydrofuran at room temperature the acid (23) was obtained as a gum in 83% yield (Scheme 8).
e molecular formula, C 16 H 16 O 4 S, was determined by accurate mass measurementas shown in Table 4. e i. r. spectrum showed a broad, strong band at  1730 cm −1 , arising from the ketonic and carboxylic carbonyl groups.e 1 H n.m.r.spectra of the ester (21) and the acid (23) were closely similar, apart from the replacement of ethoxyl signals by a broad hydroxyl signal, which disappeared upon exchange with deuterium oxide.
It was hoped that a crystalline product, suitable for combustion analysis, would be obtained.However, so far the acid (23) has resisted crystallization.e formation of predominantly only one (21) of eight possible diastereoisomers requires comment.Vedejs et al. reported [13] a related cycloaddition reaction.ey found that the thioaldehydes having electron-withdrawing groups (ZCHS; Z=CN, CO 2 CH 3 , or COCH 3 ), generated from the phenacyl sulphides, could be trapped by 2-ethoxybutadiene to give Diels-Alder adducts.e compounds with sulphur attached to C (1) of the diene were found to be formed predominantly.is regiochemistry corresponds to that observed in the reaction of thioxoacetate and the dienamine (19).e unusually high endo selectivity of the latter reaction could be due to the strong steric repulsion between the 9bmethyl and ester groups in the exo isomer.Finally, attack by the thioaldehyde on the dienamine (19) has occurred cis to the 9b-methyl group and 4a-hydrogen atom and trans to the larger 9b-aryl group and 4a-oxygen atom.e 200 MHz 1 H n.m.r spectrum showed weak signals that could represent another isomer, but otherwise the reaction was remarkably stereo-and region-selective.

Preparation of the Cycloadduct Ketone 21 Using 3 mol
Equivalents of the Bunte Salt.e Bunte salt (3) (0.743 g, 3.35 mmol) and calcium chloride dihydrate (0.493 g, 3.35 mmol) were dissolved in ethanol (15 mL).A mixture of the dienamine (19) (0.299 g, 1.12 mmol) and triethylamine (0.339 g, 3.35 mmol) was added to the salt mixture.e reaction mixture was stirred at room temperature for 4 days then was worked up and chromatographed as described before to give the ketone (21) (0.12 g, 33.4%).e 1 H n.m.r.spectrum was identical obtained by using 1 mol equivalent of the Bunte salt.
3.4.Hydrolysis of the Ester 21. 1.03 M sodium hydroxide (1 mL) was added to a solution of the ester (21) (40 mg, 0.12 mmol) in tetrahydrofuran (2 mL) and the mixture was stirred at room temperature overnight.Aer 24 h the solution was concentrated with slight heating under reduced pressure.e resulting aqueous solution was concentrated, washed with ether (5 × 10 mL), then acidi�ed with 5% hydrochloric acid (2 mL) and aer extracted with ether (5 × 10 mL).e ethereal extracts were washed with brine (5 mL), dried (MgSO 4 ), and evaporated under reduced pressure with slight heating to give the acid (23) (30 mg, 83%) as an amorphous solid.
). Importantly, this is supported by n.o.e experiments.us, irradiation at  4.11 (11-H) increased the intensity of the singlet centered at  1.63 (9b-Me).Conversely, the doublet at  4.11 (11-H) increased in intensity when the methyl group,  1.63 was irradiated.