Eight-membered Rings with One Sulfur Atom

9.20 Eight-membered Rings with One Sulfur Atom JOSEPH E. TOOMEY, JR Reilly Industries, Inc., Indianapolis, IN, USA 9.20.1

INTRODUCTION

449

9.20.1.1

Scope of Chapter

450

9.20.1.2

Nomenclature

450

9.20.2

THEORETICAL METHODS

451

9.20.3 EXPERIMENTAL STRUCTURAL METHODS 9.20.3.1 X-ray Diffraction Studies 9.20.3.2 NMR Studies 9.20.3.3 Ultraviolet Spectra

451 451 452 452

9.20.4

453

THERMODYNAMIC ASPECTS

9.20.4.1 9.20.4.2 9.20.4.3

Physical Properties Solubilities Conformational Studies

453 453 453

9.20.5

REACTIVITY OF FULLY CONJUGATED RINGS

453

9.20.6

REACTIVITY OF NONCONJUGATED RINGS

453

9.20.7

REACTIVITY OF SUBSTITUENTS ATTACHED TO RING CARBON ATOMS

455

9.20.8

REACTIVITY OF SUBSTITUENTS ATTACHED TO RING HETEROATOMS

455

9.20.9

RING SYNTHESES

455

9.20.9.1 9.20.9.2 9.20.9.3 9.20.9.4

9.20.1

Fully Conjugated Rings Dihydro Derivatives Tetrahydro Derivatives Fully Saturated Derivatives

455 456 457 457

INTRODUCTION

This ring system was reviewed in the first edition of Comprehensive Heterocyclic Chemistry (CHEC-I) <84CHEC-I(7)692> and covered the literature up to 1982. This chapter will cover the intervening time through 1994. In general, medium sized ring heterocycles are somewhat hard to make, and there is not a large body of synthetic literature on eight-membered rings with one sulfur atom. Compounds, that are reported, are sparse compared to the more numerous five- and sixmembered ring heterocycles. 449

450 9.20.1.1

Eight-membered Rings with One Sulfur Atom Scope of Chapter

Synthesis of the fully conjugated parent heterocycle, 2//-thiocin (1), has not been reported, although there are reported syntheses of the saturated heterocycle, thiocane (2) (b.p. 71°C/10 torr, 196-198°C/767 torr; nD20 0.9910 g cm" 3 ) <53M1206>.

Chapter coverage includes compounds containing ring (1), dihydro-derivatives, tetrahydroderivatives, and the saturated heterocycle (2) and its derivatives, along with corresponding benzofused ring systems and ring ketones. Since some pertinent material overlaps with the previous review <84CHEC-I(7)692>, some published material is repeated when it is appropriate to the discussion.

9.20.1.2

Nomenclature

IUPAC nomenclature (B-79MI920-01 > is generally followed using numbering shown in (1) and (2). The fully unsaturated heterocycle (1) is always named "thiocin", but nonconjugated S-heterocycles are sometimes named as "thiacyclooctene", and the saturated heterocycle (2) is usually named "thiocane", or sometimes "thiacyclooctane". Occasionally, benzo fused ring systems are named as the "thia" analogue of the all-carbon aromatic ring system. There are no aromatic eight-membered ring structures. To achieve aromaticity in an eight membered ring with three C = C ' s , two of the eight atomic centers would have to supply either two rilled /7-orbitals or two empty /7-orbitals, achieving a lOre electron or (>n electron system, respectively; this is quite unlikely. For example, a priori, anion (3) might be incorrectly thought to satisfy the An+ 2 rule for aromaticity, with ten n electrons participating (one sulfur lone pair is assumed to participate). Furthermore, eight-membered rings have great difficulty achieving planar configuration, defeating any incipient aromatic stabilization.

Because (2) has a plane of symmetry through C-5 and S-l, there are only five possible monosubstituted derivatives, neglecting conformational isomers; whereas (1) has no such plane of symmetry and all eight possible monosubstituted derivatives are possible. In addition to conformational isomers (axial-equatorial or cis-trans), there is one nonconjugated tautomer of (1), the 4//-thiocin (4). There are no reports of ring (4) except for benzo-fused thiocins and a reported spiro compound (see Section 9.20.3.3). For tetrahydro derivatives, particularly 2//-3,4,7,8-tetrahydrothiocin (5) for example, there is the possibility of cis-trans isomerizations of the double bond.

Oxo-derivatives include the known sulfoxide (6) and sulfone (7), as well as 5-thiocanone (8) (b.p. 120-123°C/19 torr: m.p. 52-53°C; v (CC14) 1703, 1408 cm" 1 ; X (cyclohexane) 226 nm, (water) 242 nm; n 3.81 D), and the sulfoxide of (8), (9) (m.p. 91-92°C; v (CHC13) 1750-1710 cm"') <62JA370l, 81SC231). Other isomers of (8) are known, such as 3-thiocanone (10) (b.p. 66-68°C/0.4 torr),

Eight-membered Rings with One Sulfur Atom

451

4-thiocanone (11) (b.p. 75°C/1.0 torr), and the sulfone of 4-thiocanone, (12) (m.p. 133°C) <77CB1O69>. However, 2-thiocanone (13) is not known. Some benzo-fused derivatives of the parent heterocycles and their oxo-derivatives have been reported.

9.20.2

THEORETICAL METHODS

There are no studies on these ring systems having been reported with the exception of force-field calculations on dibenzo fused dihydrothiocins reviewed in CHEC-I.

9.20.3 EXPERIMENTAL STRUCTURAL METHODS Most studies (x-ray diffraction and NMR) have focused on determining the conformation of the eight-membered ring.

9.20.3.1

X-ray Diffraction Studies

Diffraction data gave information about solid state structures and conformations, which may be significantly different from solution conformations. Possible conformations of eight-membered rings were reviewed in the first edition of this work <84CHEC-I(7)692> and will not be repeated here. Many eight-membered ring compounds seem to show boat-chair conformation, and 5-thiocanone (8) is one such example of a thiocane compound <80JOC1224>. Three new reports for nonconjugated thiocins have appeared and, surprisingly, two of the three, (14) (m.p. 186°C; m/e 359, 327, 326, 300, 171, 96) (81ACR1134, 81ACS197) and (15) <93MC114>, show boat-boat conformations. The third report is for the bridged compound (16) (m.p. 192-195°C) which is constrained to a boat-boat conformation <87CCC228l>. One diffraction study was for cw,rra«.s-dihydrothiocin derivative (17) (m.p. 144-145 °C; v 1710,

HON

NC

(15)

(16)

452

Eight-membered Rings with One Sulfur Atom

1670 cm"1) <84JA1341> which showed a twisted diene conformation <82JA6842>. Conformation of (17) allowed a [1,5] sigmatropic shift to form the cw,c«-isomer (m.p. 77-79 °C; v 1720 cm"1) <84JA1341> on heating.

MeO2C MeO2C

(17)

9.20.3.2 NMR Studies Proton NMR data for thiocane (2) consists of adsorptions expected for aliphatic, cyclic thioethers: 1.2-1.5 S for ring protons on carbons not alpha to sulfur and 2.5-3.0 6 for protons on carbons alpha to sulfur <80JOC3613>. Benzo fusion, (18), shifts the protons of the alpha carbon down slightly (3.13 <5), along with the protons beta to ring fusion and beta to sulfur (1.65-1.77 S) <82ACS(B)56i>. Proton spectra for thiocins and their nonconjugated, or partly-reduced, derivatives are typical of unsaturated, nonaromatic, cyclic thioethers.

(18)

Some benzo-fused, eight-membered ring, methyl-substituted sulfur ylides can show methyl resonance at unusually low values: S 1.8-2.0 if the ylide methyl group can be shielded by the benzene ring in a predominant conformation <82CC1O6O, 84CPB4360). This would be expected to extend to other alkyl group substituted, benzo-fused ylides. Oxygenation of ring carbons or sulfur brings about expected consequences to proton spectra: increased, proximal deshielding resulting in larger 3 values. Dynamic NMR data was used to assess conformations and symmetry present in solution. It can reveal differences in conformation due to solvent effects, and the activation energy for interconversion of conformers can be determined. This area was reviewed in the first edition (84CHEC1(7)692> and will not be repeated here.

9.20.3.3 Ultraviolet Spectra There are no studies of simple thiocins or reduced analogues, most being benzo-fused multicyclic ring systems. A spiro compound (19) (m.p. 133-134°C; v 3420, 1740, 1735, 1720, 1695 cm"1; m/e 495, 464, 436, 404, 376, 323, 292, 277) shows Amax at 243 nm and 202 nm, log e = 4.24 and 4.49, respectively <87AP(320)455>. Symmetrical 5-thiocanone (8) exhibits a maxima at between 226 nm and 242 nm depending on the polarity of the solvent used, water solvent giving rise to the higher X max <60JA4075>. R

MeO2C MeO2C

CO2Me

(19) R = Bul

Eight-membered Rings with One Sulfur Atom 9.20.4 9.20.4.1

453

THERMODYNAMIC ASPECTS Physical Properties

Thiocin derivatives are solids with melting points generally between 100^200 °C; on occasion, benzo fusion can cause a drop in the melting point to slightly below 100°C. Sulfoxide and sulfone derivatives tend to be even more crystalline than the parent thiocins. Thiocanones have low melting points and may be liquids at ambient temperatures. If materials are purified by distillation, it is usually at pressures under 1.0 torr. Dipole moments are generally not measured, but 5-thiocanone (8) has one of 3.8 D <60JA4075>.

9.20.4.2

Solubilities

Thiocins as a general rule are sparingly soluble in alkanes, but are soluble in most other organic solvents, including chlorinated hydrocarbons and benzenoids. Thiocanones are less soluble in the weakly polar solvents than are thiocins.

9.20.4.3

Conformational Studies

This was reviewed in CHEC-I. There have been no further studies except those reported in Section 9.20.3.

9.20.5

REACTIVITY OF FULLY CONJUGATED RINGS

2//-Thiocin (1) is expected to be a reactive molecule similar to unsaturated, noncyclic ethers. As such, the ring should be readily reactive to a wide range of reagents like electrophiles, nucleophiles, oxidizing agents, reducing agents, free radicals, and strong acids. There are, however, no reports studying the chemistry of (1), its benzo-fused derivatives, or other derivatives.

9.20.6

REACTIVITY OF NONCONJUGATED RINGS

In this section, we will treat both reduced or partially reduced thiocins, which may be conjugated but not fully so. Reactivity of some thiocanes, tetrahydrothiocins, and benzo-fused analogues were reviewed in the first edition. For the most part, reactivity and chemistry of those rings systems are that which are expected from their carbocyclic counterparts, with few exceptions. £ran,s-Cycloalkene (17), which is in equilibrium with cyclobutene (20), undergoes thermal ring opening in a conrotatory fashion in the dark. However, in the presence of light, an unprecedented [1,5] hydrogen shift occurs to give (21) (m.p. 77-79°C; v 1720 cm" 1 ) (Scheme 1) <82JA6842,84JA1341>. MeO2C

conrotatory

|

|

CO2Me (20) Scheme 1

Annelation of rings onto a thiocanone can be accomplished. Reaction of 5-thiocanone (8) with a secondary amine forms enamine (22) (R = Me; b.p. 80-85°C/0.2 torr; 'H-NMR (CDC13) 4.35 (1 H, m, =CH—)), which in turn can react with aryl azides to generate the tetrahydrothiocino[4,5-af]1,2,3-triazole ring system (23) (Ar = 4-nitrophenyl; m.p. 197°C) (Scheme 2) <84JHCll2l>. By

454

Eight-membered Rings with One Sulfur Atom

reacting enamine (22) with an aryl isocyanate instead of an azide, tetrahydrothiocino[4,5-d] isoxazoles (24) (Ar = 4-nitrophenyl; m.p. 140°C) can be produced.

R,NH

i, ArN3

(8) 53-60%

ii, HC1, EtOH

R2N (22) i, ArCNO, Et3N ii, HC1, EtOH

Scheme 2

Annelation of 3-thiocanone (10) (m.p. 30°C; nD20 1.5073) was accomplished by making the semicarbazone, (25) and (26) (mixture; m.p. 174°C; v (KBr) 3450, 3370, 3150, 2920, 1690, 1580, 1460,1420 cm~'), followed by oxidation with selenium dioxide to form either tetrahydrothiocino[3,2fi?]-l,2,3-selenadiazole ring system (27) (oil; v 2920, 2850, 1440, 1330, 1300, 1275, 1250 cm" 1 ) or tetrahydrothiocino[3,4-i]-l,2,3-selenadiazole ring system (28) (m.p. 62°C; v (KBr) 2915,2840,1440, 1310, 1270, 760 cm" 1 ) (Scheme 3) <89LA435>. m-Semicarbazone (25) gave rise to [3,2-J] ring fusion (27), and fraws-semicarbazone (26) gave rise to [3,4-rf] ring fusion (28). Both (27) and (28) could be thermally decomposed to l-thia-2-cyclooctyne (29) (v 2910, 2840, 2200, 1650, 1435, 750 cm" 1 ) or l-thia-3-cyclooctyne (30), respectively.

H2NNH-CONH2 91% combined N-NHCONH, (10)

(25)

H2NOCHN (26)

SeO2, H+

SeO2> H+ 1.7%

160 "C 35%

160 °C

(30)

Scheme 3

Eight-membered Rings with One Sulfur Atom

455

In a variant of the Hantzch ester synthesis for dihydropyridines <1882LA(215)1>, the sulfone of (10), (31), can behave as a substitute for the normally used acetoacetic ester component (Equation (1)) <94JHC351>.

CO2R +

ArCHO

CO2R

+

(1) H2N

9.20.7 REACTIVITY OF SUBSTITUENTS ATTACHED TO RING CARBON ATOMS Substituent chemistry is expected from analogous reactions of those substituents on other saturated cyclic hydrocarbons. Presence of the heteroatom in the ring does not confer any unique chemical properties compared to noncyclic analogues.

9.20.8

REACTIVITY OF SUBSTITUENTS ATTACHED TO RING HETEROATOMS

Reported 5-substituents are restricted to oxygen or alkyl groups. Both have the expected reactivity patterns of sulfones or sulfonium compounds. The presence of a ring formed from two substituents on the sulfur atom does not confer any special reactivity to S-substituents.

9.20.9

RING SYNTHESES

In general, reduced and nonconjugated thiocins are not made from parent thiocins. There are different synthetic approaches depending on the degree of unsaturation in the heterocyclic ring.

9.20.9.1

Fully Conjugated Rings

Thiocin derivatives are most often made by addition of alkynes to enamine structures, followed by cyclization. For example, enamine of thiochroman-4-one, (32), gives benzothiocin (14) on addition of dimethyl acetylenedicarboxylate (DMAD) (Equation (2)) <82ACS(B)435>. Use of the enamine from thiochroman-3-one also gives (14) <81ACS(B)197>.

(14)

(2)

(32)

Addition of DMAD to enaminothione (33) gave the nonconjugated 4//-thiocin (19) (Equation (3)) <87AP(320)455>.

MeO2C R (33) R = Bu'

CO2Me

(19)

(3)

Eight-membered Rings with One Sulfur Atom

456

Diphenylethyne can be inserted into a palladium compound to yield the benzothiocin (34) <87JOM(321)C13>.

Ph

9.20.9.2

Dihydro Derivatives

Like other types of unsaturated ylides, sulfonium ylides having an a-ethynyl group undergo a [2,3]-sigmatropic rearrangement to give a ring expanded product via an allene intermediate. Ylide (35) gave the 2i/-3,4-dihydrothiocin derivative (36) (Scheme 4) <82H(19)2147>.

1,3-shift

[2,3]

CO2Et

33-68%

EtO2C (35)

Diaryl sulndes bearing an acyl group on one ring and an ester group for intramolecular condensation gave the dibenzo-4//-5,6-dihydrothiocindione ring systems. In an improvement over the use of alkyllithium bases on diaryldiesters, Hellwinkel and Bohnet were able to react sodium hydride, in refiuxing toluene, with 2-acetyl-2'-carboxymethyldiphenyl sulfide (37) to give diketone (38) (m.p. 106-108°C; v 1690, 1675, 1667 cm" 1 ) in 65% yield (Equation (4)) <87CBll5l>.

CO2Me

COMe

i,NaH ii, H2O

(4)

65%

(37)

DMAD undergoes [2 + 3] cycloaddition with unsaturated, cyclic sulfoxides, such as (39), to give dihydrothiocin S-monoxides, such as (40) (m.p. 108 °C; v 1060-1045 cm" 1 ; 'H-NMR (CDC13) 5 5.82 (1 H, m), 6.57 (1 H, m), 3.85 (3 H, s), 3.68 (3 H, s), 3.30 (2 H, m), 2.38 (4 H, m)), via what is believed to be the bicyclic intermediate (41) (Scheme 5) <80AG849>.

MeO2C MeO2C II

CO2Me

- CO2Me

110°C OMe

o

(40)

(39) Scheme 5

Eight-membered Rings with One Sulfur Atom 9.20.9.3

457

Tetrahydro Derivatives

The five-membered ring sulfonium salt (42), of specific stereochemistry, can be expanded to 2/73,4,7,8-tetrahydrothiocin (43) (R = CH 3 OCH 2 O; b.p. 90-110°C/0.05 torr; v 1710 cm- 1 ) through ylide (44) (Scheme 6), albeit in low (36%) yield <89JA842l>. CO2Et K2CO3

CO2Et

CO2Et

(42)

(44) Scheme 6

A higher yield (66%) route by the same authors to a similarly-substituted tetrahydrothiocin (45) utilized the open chain sulfonium salt (46) (Equation (5)). Proposed mechanisms involved a fivemembered ring sulfonium ylide identical to (44), except that RO was replaced with BzO. CO2Et

OBz Nal, 2,6-lutidine

(5) CO2Et

25 °C

BzO (45)

9.20.9.4

Fully Saturated Derivatives

Thiocanes are synthesized by the displacement of a halide from 1,7-dihaloheptane derivatives using NaSH, as a nucleophile. A recent improvement (47% yield) in the synthesis of the parent thiocane (2) avoids the need for high dilution and uses NaSH on solid support alumina <92TL7709>. The dihaloheptane chain can contain keto groups. In a variant synthetic scheme, not involving solid support, a lower yield (30%) of 3-thiocanone (10) resulted from using NaSH in ethanol solvent <89SC557>.

Copyright © 1996 Elsevier Ltd.

Comprehensive Heterocyclic Chemistry II