952
J.Org. Chem., Vol. 42, No. 6, 1977
Schaffner-Sabba,Tomaselli, Henrici, and Renfroe
(2) P. W. Trown, H. F. Lindh, K. P. Milstrey, V. M. Gallo, B. R. Mayberry, H.L Lindsay, and P. A. Miller, Antimicrob. Ag. Chemother., 225 (1968). (3) K. C. Murdock, J. Med. Chem., 17, 827 (1974). (4) Mammalian metabolism of 7 via an arene oxide pathway would conceivably produce an aranotin; see, for example, D. M., Jerina, H.Yagi, and J. W. Daly, Heterocycles, 1, 267 (1973); D. M. Jerina and J. W. Daly, Science, 185, 573 (1974). (5) An account of another attempt to prepare 7 from 8 was found during this work: J. Yoshimura, Y. Sugiyama, and H. Nakamura, Bull. Chem. SOC.Jpn., 46, 2850 (1973). (6) Y. Kishi, T. Fukuyama, and S. Nakatsuka, J. Am. Chem. SOC.,95, 6492 (1973). (7) T. Hino and T. Sato, Chem. Pharm. Bull., 22, 2866 (1974).
(8) T. Sasaki, Chem. Ber., 54, 163 (1921). (9) Melting points are uncorrected. NMR spectra were recorded on a Varian T-60 instrument and are reported in parts per million from internal tetramethylsilane. Infrared and mass spectra were recorded on Perkin-Elmer 137 and CEC-1 1OB instruments, respectively. Elemental analyses were conducted under the supervision of Dr. F. Scheidl of our microanalytical laboratory. (10) K. W. Blake and P. E. Sammes, J. Chem SOC.C, 980 (1970). (11) A synthesis of this compound from indole-2-carbonyl chloride was reported subsequent to the submission of this manuscript: R. J. Boatman and H.W. Whitlock, J. Org. Chem., 41, 3050 (1976). (12) G. Germain, P. Main, and M. M. Woolfson, Acta Crystallogr., Sect. A, 27, 368 (1971).
Synthesis and Chemistry of Cyclic Sulfoximines’ Karl Schaffner-Sabba,2Hollis Tomaselli, Berndt Henrici, and H. B. Renfroe* Research Department, Pharmaceutical Diuision, C I R A - G E I G Y Corporation, Ardsley, New York 10.702 Received October 6 , 1976 T h e synthesis of 1,2,4-thiadiazine 1-oxides, w h i c h are cyclic sulfoximines exemplified b y 16, 19,27, a n d 30, is reported. A l k y l a t i o n of 16 w i t h m e t h y l iodide-NaH gives 20, which in turn can be converted t o 21; 16 o n treatment w i t h t r i e t h y l o x o n i u m tetrafluoroborate gives 27. T h e unsaturated but nonaromatic 1,2,4-thiadiazine 1-oxide 30 can be prepared by t h e action of e t h y l iodide on the silver salt o f 27. T h a t 27 a n d 30 are ylidic in nature is shown by t h e i r ‘H a n d 13C NMR spectra, which are discussed, a n d their a b i l i t y t o undergo electrophilic substitution in the same manner as thiabenzene 1-oxides. T h e mass spectra of the various thiadiazine 1-oxides show i m p o r t a n t fragm e n t a t i o n pathways involving p h e n y l m i g r a t i o n from sulfur t o the adjacent carbon. These migrations are n o t imp o r t a n t in the spectra of t h e open-chain intermediates.
The chemistry of sulfoximines has been the focus of much attention in the past several years, and two reviews of this developing area of organosulfur chemistry have recently appeared.3 Part of the interest in the chemistry of sulfoximines, which are capable of wide structural variations, has been concerned with the synthesis of heterocycles containing this functionality. Two arrangements are possible: (a) with the S=N moiety exocyclic to the ring, and (b) with the S=N moiety an integral part of the ring.4 We report here the synthesis and chemistry of 1,2,4-thiadiazine 1-oxides, which are sulfoximine heterocycles that exemplify the second category. Reported syntheses of sulfoximine heterocycles such as 1” and 26 have utilized an existing sulfoximine unit around which to construct a ring. Our initial synthetic goal which would provide access to the thiadiazine 1-oxide system was a diketo structure represented by 3. The successful preparation of such 0
Scheme I
0
0
C,H,S-CH,
I1
NH
0
7
1
2
3
a dione was accomplished similarly by starting from an intact sulfoximine. Scheme I depicts initial unsuccessful approaches. The carboxamidosulfoximine 5 was envisioned as a useful intermediate not only for the synthesis of the dione 3, but also, by reaction with formic acid, nitrous acid, or reduction-carbonylation, for the generation of other heterocycles as well. Attempted conversion of the corresponding sulfoxide 4l to 5 by the standard reaction with hydrazoic acida gave exclusively the Pummerer rearrangement product, diphenyl disulfide (6).Use of the versatile but unstable amino transfer reagent 0-mesitylsulfonylhydroxylamine (MSH)g did provide the desired intermediate 5 but in less than acceptable yields.
N-COLCHl
II
N-COCH
10
i“””
12
I
2. eo,
0
R“,
-
0 -
II
C,H,S”CO,H
II
N-CO,CH, 11
“KN-R 0
13
Synthesis and Chemistry of Cyclic Sulfoximines Some effort was made to prepare the ester 8 which would then be converted to 5. The known and readily accessible methylphenylsulfoximinelO 7, on conversion to the dianion and treatment with 1 equiv of methyl chloroformate, gave little of the desired 8, however. An attempted modification of the well-known preparation of sulfones,ll where the sulfinamide 9 rather than sodium benzenesulfinate was reacted with methyl bromoacetate, did not yield 8. Sulfoximine 7 was easily converted to the methoxycarbonyl derivative 10 in good yield. The anion of 10,generated with LDA, could be carboxylated giving the free acid 11 (39%),stable toward decarboxylation, but offering no advantage over the corresponding ester prepared directly (Scheme 11).Finally, later it was found that 10 could undergo condensation with DMF acetal in a manner similar to that of ketones12 and the enaminosulfoximine 12, a quite stable yellow solid, was formed in 50% yield. All attempts to convert 12 to 13 (R = H or alkyl) by amination with ammonia, ammonium acetate, amines, or triethyloxonium tetrafluoroborate (Meerwein reagent) followed by ammonia failed. A successful approach to the thiadiazine system was devised (Scheme 11) which took advantage of the ability of 10 to unScheme I1 0
II
- 71
C H SnCO&H,
LLDA
lo
N\
COzCHj
14 p
R
0
0
J. Org. Chem., Vol. 42, No. 6,1977 953 1675 cm-l. The NMR spectrum shows an exchangeable proton at 6 10.8 and geminal protons a t 6 4.91 ( J = 17 Hz), which are exchanged rapidly by DzO in MenSO-dG or immediately if acid or base are added. The AB quartet a t 6 4.91 collapses to a broad singlet a t 100 "C which becomes a sharper singlet at 150 "C while the phenyl protons remain sharp and clear. On cooling to room temperature the original quartet is restored. Although no enol is detected, the collapse of the quartet on heating is consistent with chemical averaging through the enol form which becomes rapid at elevated temperature. 13CNMR spectra which define 16 are seen in Chart I. In the mass spectrum of 16 a base peak of mle 91 correChart I.
I3C
Chemical Shifts (ppm from Me,Si) of 1 6 in Me,SO-d, Chemical shift, ppm 52.8 129.8 135.3
k,"
3i 0
152.3 161.5
t
Assignment C-6 c-9, c-11 C-8, C-12 c-7. c-10 c-3,c - 5
sponding to C7H7 suggests a migration of the phenyl moiety from sulfur to carbon. Oae et al.I5 have reported the migration of aryl groups from sulfur to nitrogen in the mass spectra of aryl alkyl sulfoximines. This migration of phenyl to carbon appears to be electron impact induced and is characteristic of all 1,2,4-thiadiazine I-oxides discussed in this paper. The migration was of little or no significance in the spectra of the open-chain intermediates. Alkylation of 16 is shown in Scheme 111. Treatment of 16 with 1 equiv of NaH and CHJ yielded a mixture of several Scheme I11
21
20
0
1I 5~1
C H S-CH,Li
17
0
II
'
N-COLCHI
c H S-CONHCH,
'iXH i 18
22
NKN-cHJ 0
r
o
1
0
19
dergo acylation on carbon. Inverse addition of the lithio derivative of 10 to 1equiv of methyl chloroformate gave in good yield, the ester 14,which could be aminated with ammonia or methylamine in good yields providing the amides 15. Cyclization of 15a with sodium methoxide gave the 1,2,4-thiadiazinedione 1-oxide 16 in 47% yield along with 2-5% of the methanolysis product 17.'" Attempted cyclization of 15b with sodium methoxide gave only the methanolysis product 18 (55%). Apparently methanolysis in this case competes effectively with cyclization with the more bulky see-amide anion. When sodium hydride in DMF was employed, however, cyclization readily occurred yielding the N-methyl dione 19 (75%). Interestingly, when 15a was subjected to these same conditions only a 31% yield of 16 was obtained along with a surprising 43% of The dione 16 (as well as 19) is essentially nonenolic; the infrared spectrum indicates carbonyl absorption at 1705 and
23
24a,R = CLHj b,R = C,H,
major components probably due to indiscriminate alkylation at several sites. With 2 equiv of base and CHJ a 37% yield of 20 could be isolated from a mixture. This geminally dialkylated product could be converted smoothly to the trimethyl dione 21 in 70% yield. In spite of geminal methyl groups, fragmentations of mle 119, ascribable to [CGH~C(CH:&]+ resulting from phenyl migration, are seen in the spectra of 20 [25%of base peak at 125 (CsHsSzO+)]and 21 [loo% of base peak relative to mle 125 (75%)]. A shorter approach to N-substituted diones like 24 was attempted by acylation of the lithio derivative of 10 with
J . Org. Chem., Vol. 42, No. 6, 1977
954
Schaffner-Sabba, Tomaselli, Henrici, and Renfroe
isocyanates. Cyclization was envisioned as occurring directly via 23, a similar intermediate to the anion involved in the cyclization of 15b to 19, to give 24. Indeed, 24a and 24b were obtained but only in very low yields and all attempts to improve this process failed. Attention was then focused on the conversion of the dione 16 (Scheme IV) to the dichloro derivative 25. The displaceScheme IV 0
0
-
t 16
0 Et Ot
4
0
!!yo
C H$ 1
NaH CHJ
All data indicated that only one ethyl group had entered the new molecule. The indicated ylidic polarization (structure, Chart 11) imparts anionic character to carbon 6, shielding it, and explains the unusually high field value for an otherwise vinylic carbon which might be expected to resonate in the 100-140-ppm range. A less plausible structure was 29 which would have resulted from a phenyl migration and change in oxidation state of sulfur during the reaction. The phenylbound carbon of 29 could possibly resonate in the 50-60-ppm range, and the molecule might give rise to the phenylketene fragment, mle 118. The coupling constant JI'C-H for carbon 6 has a value of 179.9 Hz which should exclude any structure containing an sp"-hybridized carbon such as in 29. The J II(--H for carbon 6 in 16 i s 146.0 Hz. However, in order to rule out unequivocally 29 and N-alkylated possibilities shown in Chart 111, a simple hydrolysis with 16% hydrobromic acid a t room Chart 111
C f i H 5 b o
__t
aq HBr
N\
NH
Y bEt
6Et
27
HBr L 2. Et1
28
dEt A
I
6Et B
bEt
c
0
0 0 D E F temperature was attempted and, indeed, 16 was isolated in 33% yield. The result of this experiment supports structure 27 and definitely rules out structure 29, as well as D and E (Chart 111).The phenyl migration seen in the mass spectrum of 27 then must occur in the spectrometer as it does with 16, 19,20,21, and 28. Methylation of 27 with NaH-methyl iodide gave the same product 28, in good yield, as that obtained from 19 and triethyloxonium tetrafluoroborate. Compound 28, similarly, could be hydrolyzed t o 19. T h e methyl group of 28 is unequivocally placed on nitrogen at position 4 since 19 was derived from 15 which had been prepared from 14 and methylamine. This is important if one considers the near identity of the l,''CNMR spectra of 27 and 28 (Chart 11)which suggests structure 27 for the Meerwein product rather than the tautomers A and B (Chart 111).A chemical shift difference of 7.7 ppm between carbon 6 in 27 and in 30 (Chart IV and Scheme IV) argues against the enol tautomer A (Chart 111).Carbon 6 in A should not be so dissimilar from that of 30. Other possibilities in Chart I11 which may be ruled out are C (no methylene protons in the NMR spectrum) and F (it would be difficult to account for the C"6O fragment and the unusually high ylidic shielding (Chart 11) of carbon 6 ' 9 ) . The pathway for formation of 27 and 28 can be seen in Scheme V. Polarization of the acylsulfoximide grouping is strong (31) and provides as the most choice site for attack by the oxonium species the carbonyl oxygen of position 3 leading via 32 to 27 and 28. Some precedent exists for this as shown by the acylation of the ylide 33 with phenyl isocyanate to give 0
dEt
29
30
ment of the halogens in 25 could then be studied, and their reductive removal to yield the basic 1,2,4-thiadiazine 1-oxide 26 attempted. All efforts to convert 16 to 25 with SOC12, POCl:3, etc., gave unstable yellow mixtures which eluded characterization. Reaction of 16 with 2 equiv of Meerwein reagent, in an attempt to prepare a dialkoxy version of 25 (i.e., 30) gave a new substance in 80% yield which could be assigned the structure 27. This new substance showed a one-proton singlet a t 6 4.33 that was exchanged with NaOD and DCl. The mass spectrum indicated an M+ peak a t mle 252 and a base peak a t mle 118 which was shown by high resolution to be CnHhO, most probably attributable to C6H&H=C=O, and NMR a second peak a t mle 90 corresponding to C;.Hs. The spectrum (Chart 11) showed an important peak a t 59.4 ppm. Chart 11. I3C Chemical Shifts (ppm from Me,Si) of 27 and 28 in Me,SO-d,
OCH,CH, 13
Chemical shift, ppm R = H ( 2 7 ) R = CH, (28) 13.9 13.8 27.0 59.4 59.3 64.9 66.3 126.5 129.2 129.3 132.9 133.0 143.9 143.8 157.3 157.8 159.4
14
Assignment carbon no. 14 15 6 13 9,ll 8, 1 2 10 7 3, 5
34.10
The action of the Meerwein reagent on the dimethyl dione 20 gave a mixture of several components, and in reaction with the open-chain intermediates 14 and 15 no ylidic product similar to 34 was isolated. Reaction of 27 or its sodium salt with 1 equiv of the Meerwein reagent gave a mixture of at least
four major products which was not pursued. The desired product 30, a probable component of this mixture, could be
J.Org. Chem., Vol. 42, No. 6, 1977 955
Synthesis and Chemistry of Cyclic Sulfoximines
Scheme VI
Scheme V
r
n
i
IL
O j-
J
31
o s
0
35,R = CH,OC,H,
32
36,X = Br,NO,
08 I N(CH,),
34
33
prepared from 27 by first obtaining the silver salt and treating this in ether a t room temperature with ethyl iodide." The 'H NMR spectrum of 30 shows two nearly identical methylenes and two identical methyls which indicates that the new ethyl group is also on oxygen and not nitrogen. This structure, as might be expected from the electronic nature of 27 and from l'> shows chemical and physical propprevious reports,' erties consistent with ylidic character. The 'C NMR spectrum (Chart IV) shows the ylidic anionic shielding at carbon 6 which Chart I V . '% Chemical Shifts (ppm from Me,&) of 30 in Me ,Sod,
I
OCH2CHj 13
Chemical shift, p p m
14.29 63.02 67.13 126.89 129.253 133.19 142.89 161.59 168.58
14
Assignment
14, 16 13 15 6
9,ll 8, 12 10 7 5
3
resonates at 67.13 ppm (JI'C-H = 184.4 Hz)."' This is 7.7 ppm lower field than the same carbon in 27 (Chart 11) and is presumably due to the distribution of electron density not only a t C-6 but also to the nitrogens a t positions 2 and 4. In 27 electron density is more localized a t C-6. This is also reflected in the proton chemical shifts of 27 and 30 since the proton a t C-6 appears at 6 4.90 with 30 vs. 6 4.33 with 27. The mass spectrum shows, in addition to M+ a t mle 280, a base peak a t mle 118 indicative of the phenyl migration discussed previously. The mass spectrum is best interpreted, however, as a loss of ethylene from the molecular ion to generate the M+ of 27 followed by the fragmentation of that species. The ylidic nature of thiabenzenes and thiabenzene 1-oxides is now well known, and ylidic electrophilic substitution in the 1-oxides has recently been reported" as shown by the conversion of 35 to 36. In a similar manner, compound 27 was smoothly brominated by bromine in CHzClp giving the 6bromo derivative 37a in 87% yield. Likewise, nitration was accomplished in 13%yield with acetyl nitrate producing the 6-nitro derivative 37b. Attempts to reduce the nitro group of 37b with hydrogen on Zn/HOAc failed. Bromination of 30 yielded as the only isolated product a substance best charac-
37a,X = Br b,X =NO,
38
terized as the dihydrobromide of 38.22An attempt to hydrolyze 30 to 16, as had been accomplished with 27, produced a mixture from which neither 16 nor 27 could be clearly identified. In summary, physical properties such as '"C NMR spectra and lH NMR spectra, and chemical properties such as electrophilic substitution and deuterium exchange a t C-7, indicate 27 and 30 to be ylidic 1,2,4-thiadiazine 1-oxides.
Experimental Section All melting and boiling points are uncorrected. NMR spectra were determined on Varian A-60D and CFT-20 spectrometers and are reported in 6 units using tetramethylsilane as an internal reference. Infrared spectra were recorded on a Perkin-Elmer Model 137 spectrophotometer. Mass spectra were taken on an AEI-MS902 and are reported as m / e with relative intensity (percent of base peak) in parentheses. Extractions were usually worked up by washing, finally. with a saturated NaCl solution, drying over MgSOi followed by vacuum filtration, and evaporation of solvent under water pressure vacuum on a Rotavapor a t 25-60 "C. S-Methyl-S-phenyl-N-methoxycarbonylsulfoximine (10). T o a solution of 79.47 g (0.512 mol) of 7 in 400 ml of anhydrous dimethoxyethane was added under nitrogen at ambient temperature 30.86 g (0.768 mol) of 50% sodium hydride in portions. After complete addition the slurry was stirred for 2.5 h before the dropwise addition of 72.50 g (0.768 mol) of methyl chloroformate over 1 h. This slurry was stirred for 12-15 h. Suspended solid was removed by filtration, and the filtrate concentrated in vacuo t o a yellow residue which was dissolved in 500 ml of CHCl:,. This solution was washed with 100 ml of water and with saturated NaCl ( 2 X 100 ml). The organic layer was dried, filtered, and concentrated in vacuo leaving a pale yellow solid which was washed with petroleum ether and recrystallized from ethyl acetate to give off-white crystals, 65.4 g (59.9%):mp 97-98 "C;".' NMR (MenSO-dG) 6 7.5-8.0 (m, 5 ArH), 3.38 and 3.41 ( 2 s, -SCH:t and NC0,CH;r); IR (Nujol) 1675 (s), 1260 (s), 1220 cm-' (s);m / e (re1 intensity) M+ not observed, 198 (1001,182(95). S-Carboxymethyl-S-phenyl-N-methoxycarbonylsulfoximine (11). A solution of 77.7 g of isopropylcyclohexylamine in 300 ml of dry T H F was cooled to -10 "C and was treated with 324 ml of 2.25 M n-butyllithium in hexane. This solution was stirred for 1 h a n d to this was added at -70 "C 50.4g of 10 in 400 ml of THF. This mixture was stirred for 2 h at -70 OC and transferred in portions (carefully to control foaming) to a second flask containing 1800 g of dry ice; the resulting slurry was stirred for 15 h and allowed to come to ambient temperature. To this was added 600 ml of water and, after vigorous mixing, the upper organic layer was separated. The aqueous layer was extracted several times with 50-ml portions of ether, then made acidic with acetic acid and extracted several times with CHCl,{.The CHCl
