Reaction of" sulfenes" with aryl nitrones and N-phenylhydroxyl-amines

J. F. King and T. Durst, ibid., 44, 409 (1966); (0) F. Eloy and A. Van. Overstrseten, Bull. SOC. Chim. Belges. 76, 63 (1967); U. S. Patent 3,420,849. ...
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Vol. 34, No. IO,October 1969

“SULFENES”3097

Reaction of “Sulfenes” with Aryl Nitrones and N-Phenylhydroxylamines to Form Benzoxathiazepines and o-Aminophenol Derivatives, Respectively WILLIAME. TRUCE, J. W. FIELDHOUSE, D. J. VRENCUR, J. R. NORELL, R. W. CAMPBELL, AND D. G. BRADY Department of Chemistry, Purdue University, Lafayette, Indiana 4Y907 Received November 26, 1968

4,5-Dihydr0-4-aryl-3H-l,2,Bbenzoxathiazepine2,a-dioxides are prepared by the reaction of diary1 nitrones with alkanesulfonyl chlorides and triethylamine. The seven-membered-ring azasultone structural assignment is supported by spectral data, chemical degradation, and alternate syntheses. A mechanism for the formation of the azasultone is proposed on the basis of 180-1abeling studies. The analogous rearrangement of N-phenylhydroxylamines to 0-aminophenol derivatives under like conditions was shown by l*O-labelingstudies to involve a different mechanism.

The intermediacy of sulfenes (R2C=S02) in the alcoholysis of alkanesulfonyl chlorides in the presence of tertiary amines and deuterium-labeled alcohols (ROD) was demonstrated by the formation of monodeuterated sulfonate esters; no di- or trideuteration was observed. Also, when an alkanesulfonyl chloride is treated with triethylamine in the presence of “nucleophilic” olefins such as enamines, ketene acetals, and ketene N,O-acetals, cycloaddition of the “sulfene” intermediate to the olefin results, and thietane 1,l-dioxides generally are f ~ r m e d . Although ~ sulfene readily undergoes 1,2 or 1,4 cycloaddition, there is only one known example of a 1,3 cycl~addition.~Attempts to effect cycloaddition of sulfene to l,&dipolar nitrile oxides resulted in the sulfonate esters of a-chloroaldoximes.5 Another 1,a-dipolar system with a considerable propensity for cycloaddition is a nitrone or ani1 N-oxide (A). 1,3 cycloaddition has been reported to occur belt2

this reactivity of nitrones toward l,&dipolar cycloaddition, we studied their behavior in sulfene systems.l 6 When equimolar quantities of N, a-diphenyl nitrone and triethylamine were stirred at room temperature in benzene, and a solution of methanesulfonyl chloride in benzene was added drpowise, there was immediate precipitation of triethylammonium chloride. A crystalline product, of elemental analysis and molecular weight consistent with the expected 1:l adduct 1, was obtained from the solution (eq 1). However, the spec-

0

‘DN7

/

A

\

tween nitrones and methylene phosphoranes,6 Michael olefins,? alkenes,* enamines, enynes,lo, sulfinylamines,l1 acetylenic carboxylic esters, l2 ketene acetals,13 isocya n a t e ~ , isothi~cyanates,~~ ’~ and ynamines.l6 In view of (1) W. E. Truce and R. W. Campbell, J . Amer. Chem. Soc., 88, 3599 (1966). (2) J. F. King and T. Durst, ibid., 87, 5684 (1965). (3) For a review of sulfene reactions, see G. Opita, Angew. Chem., 79, 161 (1967); Angew. Chem. Intern, Ed. Enel., 6, 107 (1967). (4) 8.Rossi and 8.Maiorana, Tetrahedron Lett., 263 (1966). (5) (a) W. E.Truce and A. R. Naik, Can. J . Chem., 44, 297 (1966); (b) J. F. King and T. Durst, ibid., 44, 409 (1966); (0) F. Eloy and A. Van Overstrseten, Bull. SOC.Chim. Belges. 76, 63 (1967); U. S. Patent 3,420,849 (1966). (6) J. WuB and R. Hubgen, Angew. Chem., 79,472(1967);Angew. Chem. Intern. Ed. Enol., 6 , 457 (1967). (7) B. G. Murray and A. F. Turner, J . Chem. SOC.,C , 1338 (1966). (8)J. Hamer and A. Macaluao, Chem. Reo., 64, 473 (1964). (9) Y. Nomura, F.Furusaki, and Y. Takevichi. Bull. Chem. SOC.J a p . , 40, 1740 (1967). (10) (a) V. N. Christokletov and A. A. Petrov, Zh. Obahch. Khim., 84, 2385 (1962); J . Gen. Chem. USSR,84, 2353 (1962). (11) (a) R. Albrecht and G . Kresse, Chem. Ber., 98, 1205 (1965); (b) B. P. Stark and M. H. G. Ratcliffe, J . Chem. SOC.,2640 (1964). (12) R. Huisgen and H . Seidl, Tetrahedron Lett., 2019 (1963). (13) R. Scarpati and 9. Santacroce, Gam. Chim. Itat., 96, 375 (1966). (14) (a) R. Grsshey, R. Huisgen, and H. Leitermann, Tetrahedron Lett., No. 12,9 (1960). (b) G. E . Utainger and F. A. Regenass, Helu. Chim. Acta, 117, 1892 (1954). (0) J. Thesing and W. Birrenberg, Chem. Ber., 94, 1748 (1959). (d) R. Hukgen, Angew. Chem., 76, 604 (1963);Angew. Chem. Intern. Ed. E n Z . , 4, 565 (1963).

tral properties of the crystalline adduct agree not with 1, but with the isomeric structure 2. Although the infrared spectrum exhibits strong absorptions at 7.30 and 8.65 p (S020), a weak absorption at 3.00 p can be attributed to NH or OH. Furthermore, the nmr spectrum is complex, consisting of a series of sharp singlets and a conical peak between 6 3.30 and 4.10 (3 H), two doublets centered at 4.68 (J = 2.2 cps) and 4.85 (J = 2.2 cps) (1 H), a multiplet at 6.68-7.30 (4 H), and a singlet at 7.4 (5 H). The nmr spectrum of 1 would be expected to display ten aromatic protons instead of the observed nine. Treatment of N-(2-methylphenyl)-a- phenyl nitrone with ethanesulfonyl chloride and triethylamine gave a crystalline adduct 3 whose nmr spectrum shows a singlet at 6 7.4 (5 H), a multiplet at 6.70-7.25 (3 H), and other peaks due to aliphatic and amino protons. This suggests that the N-phenyl ring is trisubstituted, while the a-phenyl ring remains monosubstituted. These reactions are summarized below (eq 2 and 3), and the (15) H. G. Viehe, Angew. Chem., 79, 744 (1967); Angew. Chem. Intern. E d . En&, 6, 767 (1967). (16) (a) W.E. Truce, J. R. Norell, R. W. Campbell, D. G. Brady, and J. W. Fieldhouse, Chem. Ind. (London), 1870 (1965). (b) W.E. Truce and J. W. Fieldhouse, Abstracts, 154th National Meeting of the American Chemical Society, Chicago, Ill., Sept 1967,No. S 45; See also ref 50.

3098 TRUCE, FIELDHOUSE, VRENCUR, NORELL,CAMPBELL, AND BRADY physical properties and spectra of the products are consistent with structures 2 and 3. Adducts 2 and 3 [CHa=SOJ

---+

Cd%\

H-y

H-

/N

H (2)

/%-* 0 0

0

2

+ [CH&H+3OJ

----t.

The Journal of Organic Chemistry

of an amine to an alp-unsaturated sulfonyl system,lQ resulting in the formation of an a,@-unsaturatedsulfonate ester (Scheme I). Reduction of a,p-unsaturated sulfones to the corresponding saturated sulfides by lithium aluminum hydride has been reported by several workers.20 The corresponding a,@-unsaturatedsulfide was unaffected by the same conditions. These authors conclude that the sulfonyl group polarizes the double bond so that attack by hydride is possible, resulting in a sulfonyl stabilized carbanion. Precedence for the final reduction step in the proposed mechanism can be found in the work of Strating and Backer who found that phenyl methanesulfonate is reduced by lithium aluminum hydride to phenol and methanethiol.21 Compound 2 was independently synthesized and interrelated by a number of alternative procedures as shown in Scheme 11. Bromination of 2 gives three different products depending upon conditions, i.e. , eq 5-7. The analytical and spectral data agree well with 0

t

3

could result from rearrangement of the initial cycloadduct, the oxathiazole, as illustrated for the format.ion of 2 (eq 4). This rearrangement is analogous to that

H

I

6

H(f

No

H

I

reported by Boyland" for N-phenylhydroxylamine-0sulfonic acid. That 2 contains an NH rather than an OH group is shown by acetylation to give an amide (4) having a carbonyl absorption at 6.0 p , whereas aryl acetates give carbonyl absorptions at 5.7 p.I* The presence of three replaceable hydrogens, one on nitrogen and two a to the sulfonyl group, was demonstrated by the conversion of 2 into its corresponding trimethyl derivative by treatment with 3 equiv of sodium amide in liquid ammonia followed by reaction with 3 equiv of methyl iodide. Azasultone 2 was reductively cleaved using lithium aluminum hydride in tetrahydrofuran or dioxane giving 2-phenylethanethiol, 2-aminophenol, and hydrogen. We know of no published examples of G N bond cleavage in a phenyl benzyl amine by lithium aluminum hydride. Since the previously described alkylation on carbon using strong base indicates that the formation of a sulfonyl stabilized carbanion is possible, anion formation with attendant hydrogen evolution may be the initial step in the reduction. The next step in the reduction is postulated to be the reverse of the addition

structures 5, 6, and 7. Eloy and Van Over~traeten~ reported the formation of 6 under similar conditions and have also prepared 6 from the reaction of N-(4-bromophenyl)-a-pheny1 nitrone , methanesulfonyl chloride, and triethylamine. To extend the scope of this cyclization to include the preparation of other seven-membered-ring azasultones, various nitrones and several sulfonyl chlorides were employed as summarizedin Table I, p 3100. Several attempts were made to establish the intermediacy of the oxathiazole 1. For example, in attempts to preclude subsequent rearrangement of the oxathiazole, N-(2,6-dimethylphenyl)-a-phenyl nitrone, and N-methyl-a-phenyl nitrone were treated with methanesulfonyl chloride and triethylamine. I n both

(17) E. Boyland and R . Nery, J . Chem. Soc., 5217 (1962). (18) L. J. Bellamy, "The Infrared Spectra of Complex Molseules," 2nd ad, John Wiley & Son,Inc., New York, N. Y., 1958, pp 182,213.

(19) 8.T. McDowell and C. J. M. Stirling, J . Cham. Soc., B , 343 (1967). (20) (a) F. G. Bordwell and W. H. McKeltin. J . Amer. Chsm. SOC.,78, 2251 (1961); (b) G. Van Zyl and R. Koster, J . Org. Chem., a@,3568 (1984). (21) J. Strating and H. J. Backer, Rec. Trar. Chim., (19, 638 (1960).

7

Voi. 94, No. 10, October 1969

“SULFENES” 3099

SCHEME I

N-phenylhydroxylamine has been added to many activated double bonds.2a We have found that N-phenylhydroxylaminereadily adds to benzenesulfonylethylene, p-toluenesulfonylethylene, and p-tolyl trans-gstyrenesulfonate giving the corresponding 2-(N-phenylhydroxy1amine)ethanesulfonylderivative24(eq 8). CsH5NHOH

+ RCH=CHSOzR’

---f

OH

I

C ~ H ~ N C H R C H Z S O(8) ~~’

M

I

It was anticipated that the reaction of N-phenylhydroxylamine with 0-styrenesulfonyl chloride would result in the formation of oxathiazole 1 as shown in eq 9.

+ 8

SCHEME I1

CH3

I

C6HSNHOH

C6HSNHOH

-

+

+ CeH,CH=CHSO2F

Ac,O

Et,O

I

CjH5NCHCH2S02F

I

OH 9

4

/ NaOH, H,O-dioxane, 50‘

n

attempts only low yields of acyclic decomposition products were obtained ; 2-amino-2-phenylethanesulfonic acid was obtained in both cases, together with traces of formaldehydeand N-methylbenzamidein the latter. The second attempt at isolation of an oxathiazole 2,2-dioxide involved the addition of N-phenylhydroxylamine to an a,p-unsaturated sulfonyl chloride. The addition of hydroxylamine and methylhydroxylamine to vinyI sulfones has been reported by Sayigh,12while

Oxathiazole 1 was not isolated, but only the rearranged adduct 2. When the same reaction was carried out using 8-styrenesulfonyl fluoride the sulfonyl fluoride (9) corresponding to 8 was isolated and character(22) A. A. R. Sayigh, H. Ulrich, and M. Green, J . Or& Chem., 49, 2042 (19~. (23) 3. Enrico, aal.2. Chim. It&., 68, 488 (1938). (24) J. W. Fieldhouse, Ph.D. Thesis. Purdue University, Lafayette, Ind., 196s.

3100

The Journal of Organic Chemistry

FIELDHOUSE, VRENCUR, NORELL, CAMPBELL, AND BRADY

TRUCE,

TABLEI BENZOXATHIAZEPINES Nitrones

0

R'CsH4

\

/"

/"="., CsHiRl H

Sulfonyl chloridea R'CHaSOzCI

Registry no.

Benzoxathiasepinea Yield, Mp,

%

OC

-Calcd, C

% H

N

.

-Found, %----H N

I

C

S

5172-50-9 60 160 61.07 4.76 5.09 11.65 61.09 R2 = H R3 = H 4-NO2; R2 = 3-C1 Ra = H 20646-62-2 87' 201-203 47.40 3.13 7.90 9.04 47.5 25 205 59.98 4.03 9.33 10.67 59.6 R3 H 20646-63-3 H ; R2 = 3-0-N R3 = H 16261-43-1 52 235-236 52.49 3.78 8.75 10.01 52.66 4-NOz; Rz H 20646-78-0 72 148-149 52.49 3.78 8.75 10.01 52.56 3-NO2; Rz = H R3 = H 20646-65-5 52b 253-254 47.40 3.13 7.90 9.04 47.67 = 4-NO2; R2 = 4-C1 R3 = H 20646-66-6 = H ; Rz = 4-C1 R3 = H 59' 157-158 54.28 3.91 4.52 10.35 54.54 20646-67-7 35 151 66.44 4.65 4.31 9.85 66.51 = benzo[b]; Rz = H R3 = H R3 = H 16261-42-0 62' 54.28 3.91 4.52 10.35 54.02 168.5 = 4-Cl; R2 H 167-168 62.26 5.23 4.84 11.08 61.99 20646-69-9 58 = 4-CH3; Ra = H R3 = H 57.32 4.13 4.78 10.93 57.43 20646-70-2 53' 173-174 4-F; R2 = H R3 = H 20646-71-3 611 209 47.42 3.42 3.95 9.05 47.26 = 4-Br; R2 = H R3 = H 20646-72-4 62g 151-152 54.28 3.91 4.52 10.35 54.35 = 2-C1; R2 = H R3 = H 59.98 4.03 9.33 10.67 60.19 20646-73-5 45 263-264 = 4 - e N ; Rz = H R3 = H R3 = CHI 20646-74-6 37 159-166 62.26 5.20 4.84 11.08 62.27 R2 = H 20646-75-7 18 145-147 63.34 5.65 4.62 10.57 63.24 = H ; R2 = 2-C& R3 = CH3 20646-76-8 24 185-190 63.34 5.65 4.62 10.57 63.24 = 4-CH3; R2 = H R3 CH3 69.02 5.24 3.84 8.77 68.87 21 199-200 = 4-CH3; R2 = H R3 = CsHs 20646-77-9 = R2 = H R3 = Br 20647-16-9 26* 133-135 47.5 3.39 3.96 9.05 47.7 a Calcd: C1, 10.0. Found: C1,10.3. a Calcd: C1, 10.0. Found: C1,10.20. Calcd: C1, 11.44. Found: C1, 11.44. Found: C1, 11.71. e Calcd: F, 6.48. Found: F, 6.67. f Calcd: Br, 22.56. Found: Br, 22.45. Found: C1, 11.21. * Calcd: Br, 22.56. Found: Br, 22.70.

R' R' R' R' R' R' R' R1 R' R' Rl R' R' R' R' R' R' R' R'

= = = =

ized. When it was treated with a benzene solution of triethylamine, only azasultone 2 could be isolated.26 One question that remains unanswered is the nature of the rearrangement of oxathiazole 1 to azasultone 2. There are a t least three pathways by which rearrangement can occur (Scheme 111). The asterisk in the diagram signifies l80label and the dotted lines represent the bonds being formed or broken in the transition state. In pathway a, the transition state is pictured as being a four-membered ring involving the nitrogen, the original nitrone oxygen, and two carbon atoms of the benzene ring. By using l8O-labeled nitrone, the final azasultone should contain all the excess l80in the phenolic oxygen. Lithium aluminum hydride reduction should give 2aminophenol which is enriched with l80to the same extent as the starting nitrone. I n pathway b, the transition state is pictured as a six-membered ring. Complete rearrangement to azasultone would result in no excess '80 being present in the phenolic oxygen, as determined by cleavage to 2-aminophenol. Pathway c represents complete cleavage of the N-0 bond, and hence scrambling of all l80present. Cleavage of the azasultone would give 2-aminophenol containing one-third of the excess ' 8 0 originally incorporated in the nitrone. The 'So analyses were determined by comparison of the R/I: and XI 2 peaks in the mass spectrum of both labeled and unlabeled rnateriah26 As shown in Table 11, trial 1 resulted in 78% retention of the excess while

+

(25) A n alternate mechanism shown below was precluded on the basis that 10 was synthesized and did not cyclize to I under the conditions of the formation of 8.

C6H5NHOH

+

C6H5CH=CHS02CI

[C6Hp"H2CH=CHC6H,]

---c

10

(26) L. A. Neiman, V. I . Maimind, and M. M. Shemyakin, Tetrahedron

Lett., 3157 (1965).

S

4.72 4.97 11.57 3.42 7.74 8.78 4.10 9.30 10.91 3.99 8.84 9.93 4.00 8.72 9.86 3.22 7.70 9.18 3.89 4.29 10.54 4.74 4.40 9.81 4.05 4.38 10.51 5.30 4.63 11.21 4.16 11.03 3.42 3.78 9.06 3.83 4.39 10.41 4.13 9.31 10.56 5.53 4.81 11.36 5.70 4.91 10.82 5.94 4.43 10.53 5.48 3.85 8.70 3.58 4.23 9.29 C1, 11.15. Calcd: Calcd: C1, 11.44.

TABLE I1 COMPOUNDS USED I N THE REARRANGEMENT OF DIARYL NITRONE~

+

2/P, %Labeled Unlabeled

-P Compound

A

Trial 1 1.74 0.72 1.02 Nitrobenzene N-Phenyl-a-(4-fluorophenyl) nitrone 2.39 1.35 1.04 1.28 0.47 0.81 2-Aminophenol Trial 2 Nitrobenzene 4.62 0.72 3.90 N-Phenyl-a-(4-fluorophenyl) nitrone 4.81 1.35 3.46" 2-Aminophenol 3.31 0.46 2.85 a The reduction of nitrobenzene-180 to N-phenylhydroxylamine-180 in HzIsO is knownz7 to result in a 229" loss of " 0 ; the formation of a nitrone from N-phenylhydroxylamine-'SO is known*s to result in retention of 1 0 0 ~ 1o8 0 .

trial 2 resulted in 82.5% retention of the excess lSO. This indicates that pathway a is predominantly (80% of the reaction) being followed, i e . , a four-memberedring transition state is occurring, with the other 20% of the reaction occurring through pathway b or c.28 (27) S. Oae, T. Fukumoto, and M. Yamagami, Bull. Chem. SOC.J a p . , 96, 728 (1963). (28) An alternative explanation involves an ion pair which can either immediately attack the ortho position of the benzene ring or first rotate 120° and then attack the ortho position of the benzene ring. The 80% retention of 1 8 0 and 20% loss of 180 could then be rationalized if kattaok > hot.

Vol. 94, No. 10, October 1969

'SULFENES" 3 101 SCHEME I11

*h

A Framework Molecular Model indicates that the nitrone oxygen is about half as far from the ortho position of the benzene ring as the sulfonyl oxygens, which are effectively held back by the five-membered ring. This suggests that rearrangement of an acyclic N-sulR fonyloxyaniline (C~HSNOSO~R), where the constriction of the five-membered ring is absent, to the corresponding Zaminophenol may involve attachment of a sulfonyl oxygen to the benzene ring. Work carried out by Lwowski, et aZ.,2sand confirmed in this laboratory, has substantiated this point. Lwowski studied the reaction of p-nitrobenzenesulfonyl chloride -lSO with Nbenzoyl-N-phenylhydroxylamine in the presence of triethylamine and found that all of the phenolic oxygen in the resulting o-hydroxybenaanilide (eq 10) was ori-

H O

H O

i (29) G . T. Tisue, M . (1968).

Gr898m8UU, and

W. Lwowski, Tetrahedron, 314, 999

ginally part of the sulfonyl oxygens. We have studied the reaction of N-phenylhydroxylamine-180with methanesulfonyl chloride in the presence of triethylamine (eq 11). Here, the N-methanesulfonyl-o-aminophenol

ONHGH + + CH3S02Cl

Et,N

3

contained no excess l80as determined by mass spectral analysis. These results are in agreement with the sixmembered-ring transition state proposed by Lwowski, et al.29 In summary, various diary1 nitrones react with sulfene in poor to excellent yields, depending on the substituent on the a-phenyl ring and the nature of the sulfonyl chloride. The probability of an intermediate 1,2,5-oxathiazole 2,2-dioxide was demonstrated. Its rearrangement to an aaasultone was shown to proceed predominantly via a four-membered-ring transition state probably owing to the inherent steric restrictions. In contrast to the rearrangement of the 1,2,5-0xathiazole, the rearrangement of N-sulfonyloxyanilines proceeds via a six-membered-ring transition state.

3102 TRUCE, FIELDHOUSE, VRENCUR, NORELL, CAMPBELL, AND BRADY

The Journal of Organic Chemistry

Anal. Calcd for C ~ ~ H l ~ N O sC, S : 64.38; H, 6.00; N, 4.40, S, 10.10; mol wt, 317. Found: C, 64.05; H, 5.93; N, 4.45; Materials.-Triethylamine (Matheson Coleman and Bell, bp Sj10.04;- mol wt, 323. 88-90') was used as obtained. a-Toluenesulfonyl chloride and Reduction of 2 with Lithium Aluminum Hvdride.-To a stirred methanesulfonyl chloride were Eastman Kodak White Label solution of 3.00 g (0.0109 mol) of 2 in 40 ml of dry tetrahydrograde and were used without further purification. Anhydrous furan, 0.42 g (0.011 mol) of lithium aluminum hydride suspended diethyl ether (Mallinckrodt) and benzene (Baker Analyzed reain 40 ml of tetrahydrofuran was added dropwise. A vigorous gent) were used as obtained. Tetrahydrofuran (Fisher Certified evolution of hydrogen gas resulted. After stirring 24 hr a t room Reagent) was purified by distilling it from lithium aluminum hytemperature, 10% sulfuric acid was cautiously added until a dride. Other starting materials were prepared according to the neutral solution resulted; 100 ml of water was then added; references cited. These included bromomethanesulfonyl chloand the solution was extracted with chloroform. The combined ride,81 bp 87-89' (15 mm), n% 1.5620; p-styrenesulfonyl chloextracts were dried (NazS04) and evaporated in vacuo, and the ride,az mp 89-90'; and N-aceto-N-phenylhydroxylamine,aa mp resulting oil was triturated with a few drops of chloroform and 66-67 O . later hexane, giving a pale yellow solid. Sublimation a t 125' The nitrones used were prepared by warming ethanolic solu(0.2 mm) gave 0.48 g (44%) of 2-aminophenol, mp 169-170'. tions of equimolar quantities of aldehyde and hydroxylamine for The neutral aqueous solution was acidified to pH 1 and extracted several minutes; cooling gave solids which were recrystallized with chloroform, and the extracts were added to the mother from alcohols or benzene-hexane in yields of 50-90%. liquors of 2-aminophenol. Evaporation in vacuo and distillation General Procedure for the Reaction of Alkanesulfonyl Chlogave 0.45 g 2-phenylethanethiol, bp 85' (10 mm) [lit. bp 133rides and Diary1 Nibones.-All glassware was oven dried before 140' (55 mm),34 bp 95-98' (12 mm)as],which gave an infrared use, and reactions were carried out under an atmosphere of dry spectrum identical with that of an authentic sample. nitrogen. A solution of 0.01-0.03 mol of nitrone in 200-300 Reaction of N-Phenylhydroxylamine and p-Styrenesulfonyl ml of benzene was prepared in a 500-ml three-neck flask equipped Chloride.-To a solution of 1.28 g (0.0118 mol) of N-phenylwith two dropping funnels and a mechanical stirrer. If solution hydroxylamine in 100 ml of dry ether, a solution of 2.38 g (0.0118 was not complete at room temperature, external heat was applied mol) of p-styrenesulfonyl chloride in 30 ml of ether was added as necessary. Equivalent amounts of alkanesulfonyl chloride dropwise. After 24 hr of stirring a t room temperature, a brown and triethylamine, each in 50 ml of benzene, were added simulgum separated from the colorless solution; it was not charactaneously over a period of 0.5 hr. During the course of the terized. The ethereal solution was filtered and allowed to evapslightly exothermic reaction, triethylammonium chloride preorate a t room temperature. Crystals separated slowly from the cipitated and an intense color often developed. The reaction resulting purple oil. Addition of a small amount of 2-propanol mixture was stirred for 2-48 hr after the addition was complete. facilitated crystallization. Filtration gave 1.90 g (58.5%).of At this time, the reaction mixture was filtered, resulting in 704,5-dihydro-4-phenyl-3H-1,2,5-benzoxathiazepine 2,a-dioxide 99% yields of triethylammonium chloride. The filtrate was (2), identical in all respects with that prepared by the reaction of evaporated in vacuo yielding highly colored oils which were inN,a-diphenyl nitrone, methanesulfonyl chloride, and triethylduced to crystallize by adding small amounts of ethanol or methamine. anol. Cooling and filtration usually gave pure product (not anaReaction of N-Phenylhydroxylamine and p-Styrenesulfonyl lytically pure) on which the yield is based. A second crop of Fluoride.-To a solution of 1.50 g (0.00806 mol) of p-styreneazasultone could often be obtained by concentration of the mother sulfonyl fluoride in 50 ml of ether was added dropwise a solution liquors. The residual oils, which were not characterized, showed of 0.88 g (0.00806 mol) of N-phenylhydroxylamine in 50 ml of only ionic sulfonate bands in the ir spectrum. ether. After 24 hr of stirring at room temperature, a small Reaction of Acetic Anhydride with 4,5-Dihydro-4-phenyl-JH- amount of dark solid was filtered and discarded, 50 ml of heptane 1,2,5-Benzoxathiazepine 2,2-Dioxide @).-A solution of 2.00 g was added to the filtrate, and the diethyl ether was removed by (0.00727 mol) of 2 in 25 ml of acetic anhydride was refluxed for gentle heating. I n two crops, 2.2 g (92%) of pale yellow 2-(N7 hr. Evaporation in vacuo gave a solid which was recrystallized phenylhydroxylamino)-2-phenylethanesulfonylfluoride (9) was from methanol giving 1.50 g (65%) of 5-acetyl-4,5-dihydro-4obtained: mp 84-86'dec; ir (Nujol) 2.80 (OH), 6.22 (C=C), and phenyl-3H-1,2,5-benzoxathiazepine2,a-dioxide (4): mp 164.57.10, 8.30 p (SOZF); nmr (CClr) 6 3.50-6.00 (m, 3, CHCHt165.5'; ir (Nujol) 6.00 (C=O), 7.25, 7.30, 8.50, 8.60 (SOZO), SOtF), and 6.70-7.50 (m, 11, aromatic and OH). and 7.60 p (CN); nmr (CDCla) 8 1.87 (8, 3, CHa), 3.36 (t, 2, Anal. Calcd for CIdHi4FNOaS: C, 56.89; H, 4.78; F, J = 7 CPS, CHzSOzO), 6.19 (t, 1, J = 7 CPS, H--CN), 7.27 6.44; N, 4.75; S, 10.83. Found: C, 57.03; H, 4.93; F, (s,5, aromatic), and 7.43 (s,4, aromatic). 6.40; N, 4.71; S, 10.64. Anal. Calcd for ClsH16NOS: C, 60.50; H, 4.73; N, 4.41; Reaction of 2-(N-Phenylhydroxylamino)-2-phenylethanesulmol wt, 317. Found: C, 60.44; H, 4.83; N, 4.38; mol wt, fonyl Fluoride with Triethylamine.-To a solution of 0.270 g 317. (0.000915 mol) of the sulfonyl fluoride in 50 ml of benzene was Reaction of 2 with Sodium Amide and Methyl Iodide.-To added dropwise a solution of 0.10 g (0.0010 mol) of triethylamine 0.0066 mol of sodium amide in 200 ml of liquid ammonia was in 25 ml of benzene. During the course of 4 hr of stirring at room added 0.60 g (0.0022 mol) of 2. After 10 min of stirring, 0.060 temperature, a dark oil separated from the solution. At this mol of methyl iodide dissolved in 50 ml of ether was added droptime, the reaction mixture was washed with 100 ml of 1% HCl wise over a 10-min period. The reaction mixture was stirred for and then 100 ml of HzO, dried (NazS04), and evaporated in 10 hr, during which time the ammonia was allowed to evaporate vacuo. The resulting oil crystallized upon the addition of 2 ml slowly. The solid remaining was washed with 50 ml of water, of ethanol yielding 0.170 g (67%) of 2, mp 160-160.5', identical decolorized, and recrystallized from methanol giving 0.234 g in all respects with an authentic sample. (34%) of 4,5-dihydro-4-phenyl-3,3,5-trimethyl-3H-l,2,5-benzoxReaction of 2-Hydroxyacetanilide and fI-Styrenesulfonyl Chloathiazepine 2,a-dioxide: mp 138.5-140.0'; ir (Nujol) 6.20 ride in the Presence of Dilute Sodium Hydroxide.-A solution of (C=C) and 7.40, 8.50 p (SOzO); nmr (CDClr) 6 1.40 (s, 3, B), 3.33 g (0.0165 mol) of P-styrenesulfonyl chloride and 2.48 g 1.80 ( 8 , 3, C), 2.81 (s, 3, NCHa), 4.32 (s, 1, H-C-N), and 6.67(0.0165 mol) of 2-hydroxyacetanilide in 36 ml of dioxane was 7.50 (m, 9, aromatic protons). heated to 50' as 14 ml of 10% sodium hydroxide was added dropwise. The solution was immediately poured into 200 ml of ice water giving a yellow oily solid, which was recrystallized from \ / CH. methanol (three times) giving 1.35 g (26%) of the N-acetylbenzoxathiazepine4, identical with that prepared from 2 and acetic CHa' ' :' \ anhydride. B C Reaction of 2-Hydroxyacetanilide with 8-Styrenesulfonyl Chloride in the Presence of Triethylamine.-To a solution of 1.51

Experimental Sectionao

(30) All melting points and boiling points are uncorrected. Infrared spectra were recorded with a Perkin-Elmer Infracord spectrophotometer. Nuclear magnetic resonance spectra were recorded on a Varian A-80 with tetramethylailane as internal standard. Mass spectra were recorded with a Hitschi RMU-6A spectrometer at 7 to 15 eV. Microanalyses were performed by Dr. C. 9.Yeh and associates. (31) W. E. Truce, D. J. Abraham, and P. Son, J . Otg. Chem., 82, 990 (1967).

(32) C.9.Rondestvedt, "Organic Syntheses," Coll. Vol. IV, John Wiley & Sons,Inc., New York, N. Y., 1963, p 846. (33) V. Priyadarshini and 8. G. Tandon, J . Chem. Eng. Data, 13, 143 (1967). (34) C. Djerassi, M. Gorman, F. X. Markley, and E. B. Oldenburg. J . Amsr. Chem. SOC.,77,568 (1955). (35) M. Kulka, Can. J . Chem., $4, 1093 (1956).

Vol. $4, No. 10,October 1969 g (0.010 mol) of 2-hydroxyacetanilide and 1.01 g (0.010 mol) of

triethylamine in 100 ml of benzene a t 65’ was added dropwise a solution of 2.03 g (0.010 mol) of @-styrenesulfonylchloride in 40 ml of benzene. After 11 hr of stirring a t 65’, 1.20 g (88%) of triethylammonium chloride was collected by filtration. The filtrate was evaporated in uacuo yielding an oil that was crystallized and then recrystallized from 2-propanol. 2-Acetamidophenyl 8-styrenesulfonate i2.45 g (77%)] wm obtained: mp 108.5-109.0”; ir (Nujol) 3.05 (NH), 5.95, 6.00 (C==O), 7.30, 8.35, 8.45, 8.50, 8.60 (SOa), 10.20 p (trans C=C); nmr (CDCla) 6 1.94 (s, 3, CHs), 6.78-8.20 (m, 12, aromatic, olefinic and amide protons). The olefinic protons are distinguishable as doublets (J = 15cps) a t 6 6.88 and 7.52. Anal. Calcd for CleHlsN04S: C, 60.50; H. 4.73; N, 4.41; S, 10.10; mol wt, 317. Found: C, 60.44; H, 4.79; N, 4.44; S, 10.04; mol wt, 321. Reaction of N-Aceto-N-phenylhydroxylaminewith 8-Styrenesulfonyl Chloride in the Presence of Triethylamine.-To a solution of 0.60 g (0.0040 mol) of N-aceto-N-phenylhydroxylamine and 0.40 g (0.0040 mol) of triethylamine in benzene a t 72” was added dropwise a solution of 0.81 g (0.0040 mol) of @-styrenesulfonyl chloride in benzene. After 18 hr of stirring a t 72’, 0.48 g (88%) of triethylammonium chloride was isolated by filtration. From the filtrate was obtained 0.47 g (37%) of 2acetamidophenyl 8-styrenesulfonate, identical with that prepared directly above. Cyclization of 2-Acetamidophenyl 8-Styrenesulfonate with 10% Sodium Hydroxide.-A solution of 1.75 g (0.55 mol) of 2-acetamidophenyl 8-styrenesulfonate in 15 ml of dioxane was heated to 50’ as 7 ml of 10% sodium hydroxide solution was added. After 2 hr of stirring a t 50”, the reaction mixture was poured into 150 ml of ice water. Filtration and drying gave 0.60 g (34%) of the N-acetylbenzoxathiazepine 4, identical with that prepared from 2 and acetic anhydride. Reaction of 2 with Bromine in Refluxing Carbon Tetrachloride. -A solution of 0.500 g (0.00182 mol) of 2 in 50 ml of carbon tetrachloride was heated to reflux and a solution of 0.280 g (0.00175 mol) of bromine in 50 ml of carbon tetrachloride was then added slowly. After 1 hr a t reflux the reaction mixture was stirred a t room temperature for 12 hr giving 0.30 g of a pale yellow solid, mp 195-196’. Recrystallization from methanol gave 4-phenyl-3H-1,2,5-benzoxathiazepine-N-oxide 2,a-dioxide (5): mp 170’; ir (Nujol) 6.20, 6.30 (C=C), 6.35 (C=N), 7.25, 7.30, 7.40, 7.50, 8.45, 8.55 (SOZO), and 8.20 p (NO); nmr (CDCla) 6 4.54 (s,2, CHZSOZO), 7.35-8.30 (m, 9, aromatic). An analytical sample was prepared by column chromatography on alumina with 3: 1 hexane-benzene as eluent. Anal. Calcd for Cl4HtlNO4S: C, 58.10; H, 3.81; N, 4.85; S, 11.07; mol wt, 289. Found: C, 57.89; H, 3.93; N, 4.68; S, 11.16; molwt, 287. Reaction of 2 with Bromine in Refluxing Chloroform.-A solution of 1.00 g (0.00364 mol) of 2 in 100 ml of chloroform was heated to reflux and a solution of 0.655 g (0.00409 mol) bromine in 50 ml of chloroform was then added dropwise. Hydrogen bromide was evolved during the addition. After being stirred a t reflux for 1 hr, the bright yellow solution was washed with 100 ml of concentrated sodium bisulfite solution, dried (MgSOd), decolorized, and evaporated in vacuo. A yellow solid resulted, which was recrystallized from methanol giving 0.77 g (59%) of 8-bromo-4,5-dihydro-4-phenyl-3H-1,2,5-benzoxathiazepine 2,2dioxide ( 6 ) : mp 165’ (lit.6cmp 161-162’); ir (Nujol) 3.00,3.05 (NH), 6.25, 6.35 (C=C), and 7.30, 7.48, 8.60 p (SOZO); nmr

“SULFENES”3103 (CDClr) 6 3.30-4.20 (m, 3-CHaSOzO and NH), 4.62-4.77 (m, 0.5, CsHbCH), 4.81-4.92 (m, 0.5, CeH.&H), 6.60-7.27 (m, 3) and 7.40 (s,5 aromatic). Am2. Calcd for C14HlpBrNOoS: C, 47.50; H, 3.39; Br, 22.60; N, 4.00; S, 9.05; mol wt, 354. Found: C, 47.26; H, 3.40; Br, 22.40; N, 3.98; S, 9.13; molwt, 354. Reaction of 2 with 2 Mol of Bromine in Refluxing Carbon Tetrachloride.-A solution of 1.00 g (0.00364 mol) of 2 in 100 ml of carbon tetrachloride was heated to reflux and a solution of 1.310 g (0.00728 mol) of bromine in 100 ml of carbon tetrachloride was then added dropwise. An orange precipitate formed which dissolved after 12 hr a t reflux giving a clear yellow solution. Evaporation in uacuo gave a yellow oil which crystallized upon trituration with methanol and cooling. Two recrystallizations from methanol gave 0.50 g (39%) of 8-bromo-4-phenyl-5H-1,2,5benzoxathiazepine 2,a-dioxide (7): mp 165’ dec; ir (Nujol) 3.00 (NH), 6.25 (C=C aromatic), 6.38 (C=C, olefin), and 7.40, 8.45, 8.52, 8.67 I( (Sogo); nmr (CDCla) 6 6.16 (s,1, C=C-H), 7.30-7.69 (m, 8, aromatic protons), and 7.78-8.21 (m, 1, NH). Anal. Calcd for C14HloBrNOaS: C, 48.00; H, 2.87; N, 3.98; Br, 22.70; S, 9.10; mol wt, 353. Found: C, 48.28; H, 2.98; Br, 22.70; S, 8.83; mol wt, 343. Preparation of Labeled Materials.-In a typical experiment, 2.0 g of potassium nitrate, 4.0 g of l80-labeled H20 (Bio Rad Laboratories), and 0.1 ml of concentrated nitric acid were sealed in an ampoule and heated to 70’ for 40 hr.S6 The tube was then cooled and opened, and the depleted HZO-‘~O was distilled. This recovered H20-180 was then allowed to exchange with a second 2.0-g portion of potassium nitrate under the same conditions. The labeled potassium nitrate thus obtained, 3.80 g (0.038 mol), was ground to a fine powder and suspended in 30 ml of benzene (Baker Spectroscopic grade) and the benzene suspension was cooled to 5’; 2.0 g (0.015 mol) of anhydrous aluminum chloride was added portionwise during a 20-min period,37while an internal temperature of 5-10’ was maintained. At the end of 3 hr of stirring a t 5’, 10 ml of H2O was added. The benzene layer was separated and the aqueous layer was extracted three times with 10 ml of benzene. The combined benzene extracts were evaporated in uacuo and the residue was steam distilled yielding 1.5 g of nitrobenzene-l80 (32a/,based on potassium nitrate). Following this method, from H20-1.6%180, nitrobeneene1.2%180 was prepared; from H20-10%180, nitrobenzene5.7%]80 was prepared. The nitrobenzene was reduced to Nphenylhydroxylamine by known methods.a8 The nitrone was prepared as described above.

Registry N o . 4 , 16261-61-3; 5, 20647-18-1; 6, 16261-57-7; 7,20647-20-5; 9,20647-23-8; 4,bdihydro4-phenyl- 3,3,5- trimethyl- 3H - 1,2,5- benxoxathiazepine 2,2-dioxide, 20647-22-7; 2-acetamidophenyl p-styrenesulfonate, 20647-21-6. Acknowledgment.-This investigation was supported by Public Health Service Grant No. CA-04536-09 and National Science Foundation Grant No. GP-7909. (36) M. Anbar, H. Halmann, and S. Pinchas, J . Chen. Soc., 1242 (1960). (37) A. V. Topchiev, “Nitration of Hydrocarbons,” Pergamon Press, New York, N. Y . , 1959, p 283 IT. (38) 0.Kamm. ‘‘Organic Syntheses.” Coll. Vol. I. John Wilev & Sons, Inc., New York. N. Y., 1964, p 445.