J . Org. Chem., Vol. 44, No. 4 , 1979 477
Substituted 4-l'hianones and 4-Thianols (18) V. Baliah and T . Chellathurai, lndian J. Chem., 9, 424 (1971). (19) lbrahim El-Sayod,El-Kholy. and Fathi Kame1 Rafa, Tetrahedron Lett., 1437 (1965). (20) P. Y. Johnson and G. A . Berchtold. J. Org. Chem., 35, 584 (1970). (21) F. Arndt and J. Pusch, 13er., 5 8 , 1646 (1925).
(22) C. A. R. Baxter and D. A. Whiting, J. Chem. SOC.C, 1174 (1968). (23) F. R. Japp and W. Maitland, J. Chem. SOC.,1473 (1904). (24) V. Harak and M. Cermy. Collect. Czech. Chem. Commun., 18, 379 (1953). (25) M. Blasubramanian and A. D'Souza, Tetrahedron, 24, 5399 (1968).
Preparation and Stereochemistry of Some Substituted 4-Thianones and 4-Thianols. Single-Crystal Analysis of r-2,trans-6-Diphenyl-cis-3-methyl-4-thianone and r-2,trans-6-Diphenyl-cis-3-ethyl-4-thianone K. Ramalingam and K. D. Berlin* D e p a r t m e n t of Chemistry, Ohlahoma S t a t e University, Stillwater, Ohlahoma 74074
R. A. Loghry a n d Dick van der Helm* D e p a r t m e n t of Chemistry, University of Oklahoma, N o r m a n , Ohlahoma 73069
N . Satyamurthy Department of Chemistry, P.S.G. College of Arts and Sciences, Coimbatore, India Received M a y 30, 1978
A number of substituted 4-thianones and 4-thianols have been prepared. Methods of formation, IR, 'H NMR, and 13C NMR analysis indicated the conformation of the heterocyclic ring in the cases studied to be predominantly 3-methyl- and r-2,trans-6-diphenyl-cis-3-ethyl-4-thiof the chair form. The structures of r-2,trans-6-diphenyl-cisanone were determined by single-crystal X-ray diffraction studies. The space group for the two compounds is I b a 2 , with unit cemll dimensions of a = 39.389, b = 10.5224, and c = 7.1062 8, for the methyl derivative and a = 39.414, b = 10.8315, and c = 7.3941 8, for the ethyl derivative. The structures were solved from diffractometer data and refined to R - values of 0.060 and 0.058, respectively. Simple six-membered sulfur heterocyclics are known to R e s u l t s a n d Discussion exist mostly in t h e chair conformation.l-s In contrast, a few T h e preparation of 2,6-diphenyl-4-thianone was first resix-membered nitrogen heterocyclics with a preferred boat ported by Arndt and co-workers.12 T h e reaction of dibenzconformation are recorded. For example, p s e u d ~ t r o p i n e , ~ alacetone with H2S in t h e presence of sodium acetate leads phenyl 3a-phenyl-3P-tropanyl ketone,1° and 1,2,2,6,6-pento the formation of both cis- and trans-2,6-diphenyl-4-thitamethyl-4-phenyl-4-piperidinol'have been reported to exist anone. Although this method gives good yields, it is limited in the boat form. In connection with a study on 13C NMR by the number of appropriate precursors available, such as 1 spectra of some substituted thiane derivatives, we had a n and 2. In the present investigation, the unsymmetrical distyryl occasion to prepare a number of substituted 4-thianones and ketones 2c a n d 2d were prepared by t h e condensation of mo4-thianols and certain derivatives thereof. We now report the nobenzilidine derivatives la and l b with benzaldehyde in the methods of preparation a n d present evidence for the configpresence of aqueous sodium hydroxide under controlled uration and conformation of the saturated sulfur heterocycles. conditions. Incidentally, t h e reaction of benzaldehyde a n d T h e first single-crystal analysis of a substituted 4-thianone methyl ethyl ketone with concentrated hydrochloric acid has is also recorded. been reported by MetayerI3 to furnish 2d as a side product.
"+ 0
A'
c,H;
l a , R = CH, b, R = C,H, 0
0022-326317911944-0477$01.00/0
la (or l b )
1. NaOHIHz0
2c (or 2d)
2 . CfiH5CHO
In our hands, reaction of unsymmetrical 1,4-pentadien%one (2c) with H2S in the presence of sodium acetate or Triton B led to the formation of both r-2,cis-6-diphenyltrans-3-methyl-4-thianone (3c) and r-2.trans-6-diphenylcis- 3-methyl-4-thianone (4b), but under different conditions. Higher ratio of baseldienone concentration, lower temperature, and shorter reaction time favored the formation of thermodynamically less stable 4b. If the concentration of the sodium acetate was decreased a n d the temperature of the reaction a n d the heating time were both increased, the 3c predominated. T h e syntheses for 3a-e and 4a-c were similar, and details are in the Experimental Section. S t e r e o c h e m i s t r y of the 4-Thianones. If the chair conformation is assumed for the heterocyclic ring, the two aryl groups and t h e methyl group in 3c or the ethyl group in 3d
C 1979 American Chemical Society
478
J . Org. ['hem., Vol. 44, No. 4 , 1979
Ramalingam et al. on dipole moment data.15 Although the assignment may be correct, it seemed that X-ray analysis of a crystal of a member of this family would permit possible correlations with other related systems in an unequivocal fashion. Thus, we have obtained X-ray diffraction d a t a on single crystals of 4b and 4c; t h e d a t a are given later in this paper. To the best of our knowledge, these d a t a are the first for 4-thian0nes.1~Examination of the torsional angles S(l)-C(2)-C(3)-C(l3) and C(7)-C(2)-C(3)-H(3) for 4b (or 4c) confirms t h a t the methyl (or ethyl) group occupies an equatorial position and the phenyl group a t C(2) is axial. T h e value of torsional angle C(4)-c(5)-C(6)-C(15) is proof for the equatorial C6Hs-C(6)
R'
0 H
c
H
bond. Hence, the structure of the methyl-substituted isomer is 4b. In each case, the phenyl at C(2) is axially disposed while t h e methyl or ethyl a t C(3) is in an equatorial position. T h e phenyl group a t C(6) is equatorially situated in both molecules
might be expected to occupy more stable equatorial positions. H This seems reasonable in view of the conditions used in the synthesis. Detailed information regarding t h e configuration in the solid state. (since 3c and 3d have syn-arranged phenyl groups, we have Stereochemistry of Reduction with LiA1H4. T h e relabeled them as cis compounds) of thianones 3c and 3d can duction of ketones 3b-e was carried out using LiAlH4 in ether. be gleaned by analysis of the l H NMR spectrum. T h e signals A summary of these results to give 7-9 are in Tables I and V. a t 6 3.90 (d, J = 11.5 Hz) and 4.24 (dd, J = 11.5 and 3.5 Hz) for It will be seen t h a t on reduction with LiAlH4 the thianone 3b 3c correspond t o protons bonded t o C(2) and C(6), respecafforded predominantly the more stable equatorial alcohol tively. T h e observed large coupling constant J H ( ~ ~=)11.5 , H ( ~7a~along ) with axial alcohol 8a presumably with the structures Hz certainly suggests that the phenyl group and methyl group are in equatorial positions. T h e coupling constants J H ( , ~ ~ ) , H ( ~ ~ ) and J H ( ~ ~(11.5 ),H and(3.5 ~ Hz), ~ ) which are typical for vicinal and J g a u c h e in t h e chair conformacoupling constants Jallti tion,14 indicate that the proton a t C(6) is in the axial position. T h e IH N M R spectra of protons bonded to C(2) and C(6) in 3c and 3d are quite similar, indicating that the two derivatives probably have t h e same conformation. However, three additional structures 4bf-4b"' should be considered for t r a n s isomer 4b. Ring reversal can convert 4b
4b'
4b"
into a mirror image of 4b", and t h e same relationship is true for 4b' and 4b"'. Unfortunately, it was not possible to assess the relative stereochemistry of the compounds 4b or 4c by 'H NMR analysis. I t has been reported t h a t trans-2,6-diphenyl-4-thianone {4a) exists in a nonchair conformation, based
J . Org. Chem., Vol. 44, No. 4, 1979 479
Substituted 1-Thianones and 4-Thianols
Table I. Substituted 4-Thianols and Corresponding Acetates IR C-0 compd stretch, cm-l
Y
9
a, G = S , R = CH,,Z = H G = S,R = C,H,,Z = H c . G = SO,, R = CH,,Z = H i d . C; = SO', R = C,H,,Z = H e. G = S,R = CH,,Z = C(O)CH, f , G = S,R = C,H,,Z = C(O)CH, g, G = SO,, R = CH,,Z = C(O)CH, il. G = SO,, R = C,H,, Z = C(O)CH,
13,
shown. However, LiAlH4 reduction of thianones 3c-e afforded a more severe mixture of t h e axial and equatorial alcohols. T h e reduction of 3e with LiAlH4 produced epimeric alcohols 7d (45%) and 8d (47%). T h e small preponderance of t h e less stable axial alconol8d in t h e reduction of Be may indicate
7a 7b 7c 7d 7h 7i 8a 8b 8c 8d
1031 1036
8h
1020
8i 9a 9b 9e 9f
1020
yield, o/o
mp. "C
formulaf
e e
194-195" 154-155" 124-16' 93-94" 97-98" 114-116" 160-161' 157-1X3' 89-90 64-65" 88-89" 119-121d 144-146"
C19H2203S
e e
70 70 e e e
e
68 73 e e
1038 1038
76 84
C18H200S
CigHl20S CiJHitQS C~uHz202S C~IH~~O~S
C1gH2203S CiVH200S Cidb20S CiJHisOS C~HZLO?S CzlH240jS ClaHqOS
121-122" 133-1J5d
C1gHIj.X
106-107"
CIIH?JO~S
C>~HL~O~S
a Recrystallized from aqueous ethanol Recrystallized from benzene-petroleum ether (60-80 "C) Recrystallized from hexane. Recrystallized from ethanol. e The yields for the thianols depend upon the reducing conditions (see Table V) f Satisfactory analytical values (10.35% for C, H. or c, H. S)were reported for all compounds (Ed.).
(IH 7d
I
H
?'H
I
OH
8d
that the axial methyl group in 3e slightly hinders the approach of the reagent from the axial side. Preferential approach of the hydride from the equatorial side should therefore lead t o more of t h e less stable thianol8d with a n axial hydroxyl group. T h e ratio is similar to that for the axial (55%) and equatorial (45%) isomers repcrted for the LiA1H4 reduction of analogously constituted ::8,X,5-trimethylcyclohexanone.1i T h e reduction of each of t h e thianones 4b and 4c with LiAlH4 gave exclusively one alcohol (9a or 9b). IR and NMR analysis of these alcohols and kinetics of acetylationls indicated a n equat,orial (orientation of the hydroxyl group in both cases. Scale models suggest hindrance t o t h e axial approach t o t h e hydride ion, and the exclusive formation of the equatorial alcohol!; was surprising. However, a similar observation was made by Baliah a n d c o - w o r k e r ~who , ~ ~ observed mostly equatorial alcohol (9096)in t h e reduction via LiA1H4 of trans-2,6-dipheny1-4-thianone (4a). Although alcohols 9a and 9b seem reasonable as illustrated, a preliminary X-ray diffraction anabysis of single crystals of t h e ethyl compound indicates t h a t the structure is 9b.'8 Thus, in t h e reduction of 4c, hydride transfer may come via an equatorial approach and the resulting alcohol may then undergo ring reversal t o give 9b. T h e same appears true for 4b ..+ 9a', now under study. Oxidation of thianones 3c, 3d, 4b, and 4c with H z 0 2 yields the sulfones !;a, 5b, 6a, and 6b, respectively. Also with H 2 0 2 thianols 7a, 7b, 7c, 8a, 8b, and 8c give sulfones 7e-g and 8e-g. T h e acetates '7j and 7k as well as 8j and 8k are easily prepared for characterization purposes from 7f, 7g, 8f, and 8g. Similar derivatives o r the trans alcohol 9 (recall t h a t t h e structures may be better represented as 9') are found in Table IV also. In order t o simplify the spectral analysis for reduction products therefrom, Ra was deuterated a t t h e (Y positions t o give 10a. T h e same procedure gave ketones lob and 10c from 3c and 3e, respectively. Reduction of 10a with LiA1H4 in ether produced l l h and 12b i n a 1.84:lratio similar t o t h a t found
10
12
11
K"'
K"'
H
OH
H
# ] "R
s R'
R' D
6R""
K""
11'
12
a , R = R"' = C 6 H5 ,, R' = R" = H;R"" = D b, R = R"' = C,H 5 ,, R' = R" = H;R"" = CH, c , R = C 6 H5 ,, R'= H;R" = R"' = CH,;R"" = D
+
in a similar reduction of 3b 7b 8b (Table V). In view of the finding13 t h a t 4e gave 9b, we cannot eliminate from consideration that 11' and 12' may be the products from reduction of 10b rather t h a n l l b and 12b, and this will be investigated. Meerwein-Ponndorf-Verley Reduction of 4-Thianones. Under Meerwein-Ponndorf--Verley (MPW reduction conditions using aluminum isopropoxide a n d isopropyl alcohol, each of the 4-thianones 3b-c afforded isomeric alcohols (Table V). On chromatography over alumina, t h e axial alcohols were eluted first. In general, cyclohexanols with a n equatorial hydroxyl group are more strongly adsorbed t h a n those with a n axial hydroxyl group.?() 2L' Generally, t h e MPV reduction is considered t o proceed through a cyclic transition state.xl,24 On this two cyclic transition states (13 and 14) can be envisioned for t h e reduction of thianone 3e. Courtauld models revealed a greater steric hindrance t o t h e axial approach of t h e hydride in 11 than to the equatorial approach in 13. Accordingly, it is reasonable t h a t thianone 3e, with the ring anchored in a single chair conformation, should lead to more of the axial alcohol 8d t h a n t h a t with a n equatorial alcohol 7d. These expectations are confirmed in t h e -+
480
J . Org. Chtm., Vol. 44, No. 4 , 1979
Ramalingam e t al.
Table 11. IR and 'H NMR Dataa for Substituted 4-Thianols
b
compd
IR C-0 stretch, cm-___
H(2)
H(3)
H(4)
7a
1040
4.06 (dd)
1.65-2.57 (m)
3.82 (s)
7b
1025
7c
1041
7d
104(1
8a
1031
8b
990
8c
1020
H(5)
3.44 ( t ) = 20.0 Hz)
2.00-2.35 (m)
3.98 (d) 2.48-2.66 (m) 3.70 ( t ) b J =: 11.0 Hz (Wl/z = 20.0 Hz)
1.94-2.40 (m)
3.71 (d) 2.41-2.60 (m) J = 11.50 Hz
1.78 (t) J = 6.0 Hz 4.44-4.59 (m) 2.11-2.25 (m)
4.21 (d) J =: 12.0 Hz
2.36 (m)
4.27 (d) 2.40-2.56 (m) J =: 11.0 Hz
(W1/2
3.78-4.08 (m)
1.98-2.15 (m) 2.44-2.52 (m)
4.44 (s) overlapped with H(2,6) 4.13 (br s) ( W ~ /=Z7.0 Hz)
2.15-2.30 (m)
4.44 (br s) 7.0 Hz)
1.88-2.18 (m)
overlapped with H(6)
2.08-2.12 (m)
(W1/2 =
8d
1040 1018
9a
106B
4.12 (d) 2.18-2.28 (m) J = 3.0 Hz
3.91 (quint)
2.30-2.46 (m)
9b
1054
4.10 (d) 2.04-2.25 (m) J = 5.0 Hz
overlapped with H(2)
2.39 (t) J = 5.0 Hz
1.88 (t) J = 4.5 Hz
H(6)
other
1.56 (s, 1 H, OH) 3.73 ( s , 6 H , 0 C H 3 ) 6.70-6.78 (d, 4 H, Ar H) 7.25-7.35 (d, 4 H, Ar H) 4.12 (dd) 0.88 (d, 3 H , CH3) J = 2.5 Hz 1.92 ( s , 1 H, OH) J = 10.0 Hz 7.20-7.42 (m, 10 H, Ar H ) 4.10 (dd) 0.77 (t, 3 H, CH2CH3) J = 2.5 Hz 1.10-1.50 (m, 2 H , CHzCH3) J = 10.0 Hz 1.67 (s, 1 H , OH) 7.20-7.40 (m, 10 H, Ar H) 4.03 (dd) 1.34 [s, 3 H, CH3(a)] 1.47 [s. 3 H, CH3(e)] 1.60 (s, 1 H, OH) 7.19-7.42 (m, 5 H , Ar H) 1.61 ( s , 1 H, OH) 3.77 ( s . 6 H , 0 C H 3 ) 6.78-6.87 (d, 4 H, Ar H) 7.24-7.32 (d, 4 H, Ar H) 4.58 (dd) 0.82 (d, 3 H, CH3) J = 5.0 Hz J = 7.00 Hz J = 10.0 Hz 1.78 ( 5 , 1 H, OH) 7.20-7.42 (m, 10 H, Ar H) 4.60 (dd) 0.77 (t, :3 H, CHzCH3) J = 5.0 Hz 1.10-1.50 (m, 2 H. CH2CH3) J = 12.0 Hz 7.20-7.44 (m, 10 H, Ar H ) 4.33-4.48 (m) 1.24 [s, 3 H, CH3(e)] 1.66 [s, 3 H, CH3(a)] OH overlapped with CH3(a) 7.19-7.48 (m, 5 H, Ar H) 4.34 (t) 0.96 (d, J = 7 Hz, 3 H, CH3) J = 5.0 Hz 1.60 (s, 1 H, OH) 7.20-7.70 (m, 10 H, Ar H ) 4.51 (t) 0.77 (t,3 H. CHzCH3) J = 5.0 Hz 1.22-1.7 (m, 2 H, CHzCH3) 7.18-7.64 (m, 10 H. Ar H)
0 NMR values are in 5 Abbreviations used: s, singlet: d. doublet; dd, doublet of doublet; t , triplet; m, multiplet: quint, quintet. Complex triplet.
13
CH
14
present study (see Table V). As the apparent degree of steric hindrance around t h e carbonyl increases, owing t o t h e proximity of t h e bulky alkyl groups, t h e yield of t h e axial isomer increases. This is supported by t h e present investigation. In contrast t o the above observation, Hardy and Wickerz5report a high yield (75%) of cis-3,3,5-trimethylcyclohexanol (with a n equatorial hydroxyl) in t h e reduction of 3,3,5-trimethylcyclohexanone by t h e M P V method. However, in analyzing t h e isomer ratio of t h e products, t h e possibility of isomeriza-
tion of t h e less stable axial alcohol t o a more stable epimer under equilibrating conditions (aluminum isopropoxideisopropyl alcohol) should be examined. In order t o substantiate this, t h e axial thianols have been allowed to equilibrate under M P V conditions employing aluminum isopropoxide, isopropyl alcohol, a n d acetone for 140 h. I t is found t h a t thianols 8a-d epimerize t o the corresponding equatorial isomers, which are obtained in high yield after chromatography of t h e equilibration mixture. However, it is also observed t h a t no epimerization occurs during MPV reduction in t h e present study (within a reaction time of 6 h). It is noteworthy also t h a t thianones 4b and 4c gave exclusively t h e alcohol with t h e equatorially substituted hydroxyl group as discussed from the same reduction with LiAlH4. Stereochemistry of the 4-Thianols. I t has been demonstrated t h a t t h e carbon-oxygen stretching frequency for a n equatorial hydroxy group (near 1040 cm-l) is greater than t h a t for a n axial hydroxy group (1000 cm-1).26-28 T h e C-0 stretching frequencies for t h e thianols are listed in Table 11. T h e observation of t h e position of this band can be of considerable aid in t h e determination of t h e stereochemical configuration of t h e hydroxyl group in t h e 4-thianols. It can be seen from Table I1 t h a t t h e thianols with a n equatorial hydroxyl group give a n absorption band a t higher frequency compared t o its epimer with a n axial hydroxyl group. T h e stereochemistry of the thianols has been further confirmed by a study of their lH N M R spectra and kinetics of
J . Org. Chem., Vol. 44, No. 4, 1979 481
Substituted 4-Thianones and 4-Thianols
T a b l e 111. Physical D a t a f o r 4-Thianone 1,l-Dioxides IR, cm-'
-soy
yield,
compd
C=-0
asym
sym
%
mp, "C
5a 5a 6a 6b
I721 I721 1709 17 18
1326 1330 1318 1318
1136 1138 1124 1126
80" 90 " 85a
201-203 202-204 202-204 171-173
Crystallized from aqueous ethanol.
Satisfactory analytical values (f0.3% for C, H) were reported for all compounds (Ed.).
IR, cm-l
-so2-
yield,
compd
C-0
asym
sym
7e 7f 7g 7j 7k 8e 8f 8g
1064
1297 1370 1307 1295 1312 1300 1299 1294 1316 1299 1295 1295 1300 1302
1130 1149 1136 1135 1134 1134 1I49 1133 1138 1142 1117 1117 1125 1124
8k 9c 9d 9g
9h
CIXH1803S C19H2003S Ci~Hi803S CigHzoW
Table IV. 4-Thianol 1,l-Dioxides a n d Corresponding Acetates
~-
8j
86a
formulab
1010
1058 104-1
10313 103 1 1003 1026 1020 1027 1065 1064 1045 10511
0x3
80 72 88 72 83 78 80 86 70 81 7'
1 1
90 67 86
mp, "C 295297" 282-283" (dec) 234-236 252-253a 189- 191b 222-224a 338-341" 264-2Gh 185-1870 194-196O 198.5-201.56 217-219.56 206-208" 200-201a
formula' C19H220$ Ci~Hio03S Cd2203S C~OHZZO~S C21H2404S C 19H2205S CiaHzoOsS C19H2203S C'oH2204S C~IH~~OJS C 18H2003S CigH2203S C2oHz208 Cz1H240jS
a Recrystallized from ethanol. Recrystallized from aqueous ethanol. Satisfactory analytical values (f0.3%for (1.H) were reported for all compounlis.
Table V. Composition of t h e P r o d u c t s from t h e Reduction of 4-Thianones thianones reduced 3b 3c 3d 3e Ib IC
3b 3C 3d 3e Ib IC
total crude product, 90 87 98 92 98 95
oc
unreduced thianone, %
yield (%) of epimeric thianols axial equatorial
reduction with MPV 50 (sa) 8 66 (8b) 4 65 (8c) 3 76 (8d) 25 50
reduction with LiAlH4 3 8 15 4 31 2 47 91 2 96 3
9.5 92 94 96
15 (7a) 13 (7b) 20 (7c) 10 (7d) 71 (9a) 43 (9b) 90 35 56 45 91 92
acetylation with acetic anhydride in pyridine.18 T h e 'H N M R spectral data of the epimeric thianols are summarized in Table 11. Significant information regarding the configuration of the hydroxyl group may be deduced from the chemical shift data of t h e H(4) proton. T h e points of interest in these spectra are t h e half-widths of bands for t h e H ( 4 ) h y d r ~ g e n . 'It ~ can be seen from Table I1 that the half-width signals for axial alcohols 8 b a n d 8c are 7 Hz as compared t o about 20 Hz for t h e corresponding equa1,orial epimers 7 b and 7c. T h e H(4) axial hydrogens of the equatorial alcohols 7 b and 7c are more strongly coupled with t h e neighboring hydrogens t h a n are t h e equatorial H(4) hydrogens in axial alcohols 8 b and 8c. T h e spectra of t h e equatorial thianols 7 b a n d 7c also show signals for t h e
H(4) axial hydrogen more downfield compared t o those for t h e epimeric axial alcohols with a n equatorial H(4) hydrogen (see Table 11). S i n g l e - C r y s t a l Analysis of 4 b a n d 4c. Single crystals of 4 b a n d 4c, m p 150-152 and 120-121 "C, respectively, were grown from different solvents. T h e basic stereochemistry of both sulfides is identical as shown in t h e stereoview of single molecules in Figure 1. Axial disposition of the phenyl group occurs a t C(2) in each system along with a n equatorial phenyl group at C(6). An equatorial methyl or ethyl substituent is confirmed a t C(3) in 4b and 4c, respectively. Figure 2 contains t h e bond distances, while Figure 3 displays the corresponding bond angles. Torsional angles are given in Table VI. Average torsional angles of 55.5 a n d 55.0" for 4 b and 4c, respectively, are slightly smaller t h a n t h a t reported for cyclohexane (55.9")
