Hydroxylamine-O -sulfonic acid — a versatile synthetic reagent
Raymond G. Wallacef School of Chemistry Brunei University Uxbridge, Middlesex UBS 3PH Great Britain
imidazoli nones and related derivatives are time to these various modes of reaction. discussed in the review. Many of these The uses of HOSA as a reagent are organiz preparations can be carried out in high ed below according to the different syn yield, thetic transformations that it can bring about. Hydroxylamine-Osulfonic acid, NHj-OSOjH (abbreviated to HOSA in Probably by far the most well known this article) has become in recent years and explored reactions of HOSA are commercially available. Although much animation reactions, illustrating elec fruitful chemistry has been carried out us trophilic attack by HOSA, with amination ing HOSA, to this author's knowledge, on nitrogen being the most important, there has been no systematic review in although a significant number of English* of its use as a synthetic reagent. It animations on both carbon and sulfur have is a chemically interesting compound been reported, Amination on phosphorus because of the ability of the nitrogen center also occurs. to act in the role of both nucleophile and AMINATION electrophile, dependent on circumstances, Synopsis (a) At a nitrogen atom and thus it has proved to be a reagent of Hydroxylamine-0-sulfonic acid (0 Preparation of mono- and di- great synthetic versatility. (HOSA) has only recently become widely substituted hydrazines and trisubstituied commercially available despite the fact that H,N-Nu hydrazinium salts it has proved to be a valuable synthetic reagent in preparative organic chemistry. (as an electrophilic X Ji-H • ^N-NH, Unfortunately, however, information center) | Nu regarding the use of HOSA in organic syn 0 \ l* thesis has remained scattered in the -N • -N-NH H,NOS-OH a literature, and it is to focus attention on the ' ii versatility and potential of this reagent that 0 Monosubstituted hydrazines can be this information has been brought together E prepared in yields of the order of 50% by now in the form of a short review article. 1 treatment of a primary amine with HOSA (as a nucleophilic • in aqueous solution in the presence of base Important among the areas of applica center) Q (eq. I),2_s Similarly, secondary amines tion of HOSA are aminationand reductive E-N-0-3-OH react to give 1,1-disubstituted hydrazines dea mi nation reactions, nitrile and oxime M (eq. 2)S* formation, and the preparation of amides H O and diazo compounds. These and other Besides being directly involved in reac An alternative route for mono- or di- reactions, including the use of HOSA for tions, it may serve as an in xiiu source of substituted hydrazines uses an aqueous the synthesis of heterocycles such as ox- other chemical entities [e.g., imene) which solution of the amine and a ketone, or the aziridines, diaziridines, pyrroles, isothi- then undergo reaction with a given sub strate. Reference will be made from lime to +On secondment from the Cancer Research Cam azoles, benzisoxazoles, benzodiazepines, paign's Gray Laboratory, Mounl Vernon Hospilat, isothiazolo- and pyrazolopyridines, and 'For a short review in Japanese see ref. I. Northwood, Middlesex I1A6 2RN. 1980 by Aldrich Chemical Company, Inc. Aldrichimica Ada. Vol 13. No. I, 1980 3 corresponding SchhTs base, instead of !he amine alone and involves diaziridine ring RNH HOSA/KOH/HjO ^ formation (vide infra) which avoids the use RNHNHj R=CH3 49-53% (eq. 1) * 70"/10 m in " of a considerable excess of amine to sup R=C6H5 81-68% press further reaction of the hydrazine product and has additional advantages (for HOSA/KOH/H,0 a discussion see reference 6 and references (n-C^jNH 75V40m-^> (rt-C^NNH, 34% («,. 2) ciled therein). I.lj-Trisubstituied hydrazinium salts
are formed when ternary amines are (CH3)3N |i)HOS^KOH^OM > (cH^NHi(- 85% (eq.3) treated with HOSA under basic conditions in aqueous or alcoholic media{eqs.3,4).'1^' (ii) Masked hydrazines - amination on the nitrogen heteroatom of nitrogen CH3 HOSA/EtOH heterocycies (CH^NfCHjjOH —£ HO(CH2)2-N*-NH2 SO; % (eq. 4) rellux/5mlfi 66 Ql-NH, CH, J2 \\ + NH, NNH, 26% (eq. 5) Many nitrogen helerocycles can be o OVIhr 0 aminated on nitrogen using HOSA. These include azetidine,"pyridine,4'5 quinoline,4S pyridazine,9 pyrimidine,' pyrazine,^ 10 t! IJIi (i) HOSA/H;O/90°/30min tetrazole, indole, "> benzimidazole, (ii) KjCOj/room lemp. ec 6 triazine,'4 benzoxazole," and purine12-'*' (iii) HI/-20°/1hr Nf .- 63-72% < "- ' ring systems (eqs. 5-16). (The pyrimidine NHj ring system, however, will often undergo ring opening and rearrangement reactions as alternative reaction pathways:9 a specific example of this is given under mis (t) HOSA/KOH/H;0/eO°/45 min cellaneous reactions.) Here, as in the syn (ii) Hl/-10°/lhr thesis of the simple hydrazines, the ni OH trogen of the HOSA acts as an elect rophilic center in the reaction.
In the case of the 1-aminopyridinium (i) HOSA/KOH/H,O/70°/4hr (eq. 8) 4 cation, -' 1-aminoindole." and 1,2-di- N ^J-rH <'» HI N'' "-n3 aminobenzimidazole" especially, the 7 ,- R=CH3 56% method constitutes an important NH; ' R=CH30 50% preparative procedure since the reaction either fails with other reagents (pyridine) or N' the HOSA synthesis provides a more HOSA/NaOH straightforward route to the compounds in
question (indole, benzimidazole). I- p" R-H, R"=NH2 Aminobenzotriazole14 forms a convenient benzyne precursor. •>• 7fKi (Hi) Preparation of 2-tetrazenes (i) HOSA/KOH/H3O/70°/dhr (II) HI (VH • (WNV) <«^N i ' R,=Ri=H 34% NHj R,=Ra=CH3 55% Piperidine and pipercolines react with
HOSA in aqueous solution, in the presence M R NH "I) *\ HOSA/Na;CQ3(pH 7-8)/H,0 "Tj N' * of sodium hydroxide, to give 1,1,4,4-tetra- ill sfi 70-75° 20min/at retlux, 20-30min ~ [^ ^(Jj substituted 2-tetrazenes (eq. 17).I! Pre sumably, the simple hydrazine is initially 35% (eq.11) formed and is subsequently oxidized to the tetrazene. "r=i (b) At a carbon atom R=n-C3H7 26% HOSA will aminate on aliphatic, aromatic and heterocyclic carbon atoms under a variety of conditions. HOSA/KOH/DMF . (i) Aliphatic carbon ! I ; room temp./1hr X (eq. 12) J,u R'=R2=H 96% -C-H -C-NH2 nz ™ R<=CHiC6H5, Ri=H 84%
4 Atdrhhinm-a Ada. Vol. li, No. I. 1980 One of the most successful of these procedures is the elegant one-step synthesis HOSA/KOH/H,0 ^ of a-amino acids from carboxylic acids. room temp. " {eq. 13) The acid is lithiated in a mixed solvent :D> system and afterwards treated with HOSA R,=H, =H 76% (eq. 18)IK to give the a-amino acid. HOSA will also aminate active methylene com pounds as is demonstrated in the synthesis N •I N of substituted pyrroles" from /3-keto esters HOSA/KOH/HsO (^ (eq. 14) and ,8-diketones. 60° > cK N," NH2 [iff Aromatic carbon C l ~» )>" NH, HOSA >< (no details) (eq. 15) Two main methods have been employed i to bring about direct animation in NH H 2 aromatic systems using HOSA. In both cases the yields tend to be on the low side. The first employs aluminum chloride as a catalyst and has been fairly extensively T || V HQSA/pH >7- investigated by Keller™ and Kovacic.2' There appears to be a number of points of (eq. 16) variance between the work of the two authors. The precise animating species is OHOO-H IOH not known. Examples from both authors' work are given below (eqs. I9.20).-"-3' almost quantitative "Note: pH 2-4 gives C-8 ami nation The second method is a homolytic animation procedure developed by Minisci
R2 p» pi pi and his co-workers," whereby what is f* ,R' thought to beaprotonated amino radical is R'-ZfJ-H HOSA/NaOH/H^ tf/"""^-^-/"^. (eq. 17) generated in a redox system (H,N- 60-70" /2hr •OSO,H/Fe") at room temperature and this then attacks an aromatic substrate. R1=R2=R3^H 18% Yields of between 10 and 40% of mono- aminated product are reported {eq. 21). (In RCH^CH •-iN^PQ./HMPT/THF-he-ane > RCHUCOiU HOSA ^ many instances the yields are quantitative -15°/2hr with respect to the aromatic substrate ac (eq. 18) tually consumed.) In certain cases the reac RCH(NH2)CO,H R=C6H5 83% tion shows a degree of stereospecificity.
A third method,21 from the very recent CH, literature, is based on H.C. Brown's HOSA/AICI, H,N 21% (eq. 19) procedure for the conversion of alkenes via 95-105°/30min CH, thcorganoborane to aliphatic amines (vide infra). If an ary] orgaiioboraue is sub stituted for the alkyl borane in the reaction (the paper gives triphenyiborane as an ex ample - prepared from phenylmagnesium HOSA/AICI, bromide and boron trifluoride) an aryl- 50% (eq. 20) amine is produced (eq. 22). The disadvan 100-105° /30m in & tage of the method is that, unlike trialkyl boranes. which utilize two of the three alkyl groups in amine formation, triphenyi borane uses only one phenyl group and OCHj thus the overall yield with regard to anima tion on the aromatic ring is not high, HOSA/FegSOj/MeOH NHj (eq. 21) foom temp./15min 34% (iitf Heterocyclic carbon (with respect to HOSA) )C-U Jc-NHj
HOSA/diglyme Certain heterocyeles will react with M^B CSHSNH, 35% (eq. 22) 100"/24hr HOSA to give a C-.substituted amino derivative. For instance. 1.3-dimethyl- Akfrwhimiea Aaa. Vol. IJ, No. I. 1980 5 uracil reacts with HOSA at pH 2 over 40 That the mechanism of some of these (eq. 25).Jft However, prolonged treatment hours to give the C-amino product in reactions may be one of addition followed with HOSA (70°,4hours)givesprincipally almost quantitative yield (eq. 23).M Guan- by elimination is suggested by the fact that ihe 4-aminoquina7oline and no dihydro osine (eq. 16) aminaies at the 8-position"1 quinazolines, unsubstituted in the 4- compound. (Interestingly, ben imidazoles atpH 2-4(70°)and 5-nitroquinoline(<;/: 8- position, react with HOSA at 60-65° over and orf/w-disubsiituted benzenes are also hydroxyquinoline) animates at the 6- and 5-10 minutes to give A'-(3,4-dihydro-4- products of the reaction under these con 8-positions under basic conditions (eq. quinazolinylJhydroxylamine-O-sulfonic ditions)." 24)» acids, which can be isolated in good yield (c) At a sulfur atom =S and -S" >• -S~NHj (eq. 23) S-NHr , Amination of sulfur in a variety of organic situations can be tarried out using NO: HOSA. Thus thiols!ones),37 thioacids," thioamides,2''2, dithioacids2* and thio- ethers1" undergo amination to give the cor responding hydrosulfamines and hydro- (eq. 24) sulfonium salts (eqs. 26-30), The yields for the reactions arc generally good and, as with most HOSA transformations, the ex perimental procedure is relatively simple. Sulfilimines, in particular, have proved 10 be very useful intermediates in organic synthesis.51 (d) At a phosphorus atom (eq. 25)
p 60-65°/5-10m in < R ra N ^ R=H, CH3 50-88% P. Triphenylphospliine, when treated with CN HOSA in methanol, gives triphenylphos- HOSA/Na0H{NHa)/KHCO3/Hj,0/Et0H phiminium hydrogen sulfate (eq. 31) in room temp./15min (eq. 26) 69% yield." I H R,=CH„ R^H, Ra=C6H5 80%
HOSA/MaOMe/MeOH Two methods of bringing about the R,S R2SNHt SO4 room tern p./several hr (eq. 27) transformation RNH; - RH using HOSA R-C;H5 59% are available: an indirect method via the sulfonamide" and a direct route10 which has appeared in the literature only recently. ArCOSNa HOSA/NapH/H^O ^ ArCOSNHI Ar-3,4-CI2C6H3 95% (eq. 28) <20° At-2-)uroyl 70% Reductive deamination refers to the transformation of an amine to a product ot lower oxidation level (in the sense propos HOSA/NaOH/H,0 RCSNHAr >• RC(=NAr)SNH, (eq. 29) ed by Robinson) and involves the net <20° replacement of an amino group by R=CH,, Ar=C H 88% 6 s hydrogen. HOSA/NaOH/H,0 In the indirect route,11 a primary ArCSSNa ArCSSNH, <20° (eq. 30) aliphatic or aromatic amine is treated with Ar=4-CIC6H, 87% sulfonyl chloride (typically benzene-, p- toluene- or methanesulfonyl chloride) in HOSA/MeOH dry pyridine and the mixture warmed on a (C^P 7> [(CSHJJJPNHJ HSOi 69% (eq. 31) room (emp./5mi steam bath. The sulfonamide, which is isolated, is dissolved in NaOH and then R'SOjO/pyridine HOSA/NaOH/H^O/ElOH treated with HOSA and the reaction mix RNH, >• RNHSOiR' RH steam bath/30min distill y ture distilled to give the alkane or arene. (room temp if ft'-CHJ (eq. 32) Yields of product are usually high(eq. 32).
R=CSH5CH„ R'=C6H5 85% Doldouras and Kollonitsch" have R=n-C6H,3, R'=4-CH3C6H0 >90% shown that there is no need to proceed via the sulfonamide, since the primary amine
RNH HOSA'NaOH/HjO . RH R-(CHs)5C02H 55% (eq 331 will react directly with 2-3 molar * uV1.5hr ^* R=2-CO!HC6H4 72% equivalents of HOSA, in the presence of
6 Atdrwhimha Acta, Vol. 13. No. I, I9H0 base, at 0°, to give the deaminated product
in yields in excess of 50% (eq. 33). The H OS A/(N H 30 H) sSCV VNaO H/H ;0 HOjCCHCCOiH > H0 C(CHJ) COJH 77% (eq. 34) authors have shown that (he reaction 20°/3hr 2 2 works tor a variety of structural types in cluding amines containing other func ; HQSA/iNH3OH);S04 /NaOH/H;0 tionalities, and claim that it is a selective NO,CiH4CH=CHCOIH and general method. They have coined the 40"/6hr (eq. 35) name 'hydrodeamination' for the process NOaCjH^CH^COjH 87% and furthermore have illustrated how it may be extended totheconversions RNH; - RD and RT. HOSA/NaOMe/MeOH 30-40% (eq. 36) room temp /16hr In both methods a common mono- substituted diimide (RN=NH) is pro posed as an intermediate (their mode of formation differing) which readily decom H OS A/Me OH poses to RH and nitrogen. CH,OH REDUCTION (eq. 37) HOSA alone, or in conjunction with R1 + R other reagents, provides under basic con N^ CHfOH ditions a source of diimide which will 55% 25% reduce double bonds. Thus, HOSA with 95% cyclohexanone gives l.l-dihydroxyazo- R=7-CI, R,=2-CH3 cyclohexane, an unstable substance, which, if allowed to decompose at room _ HOSA/mineral oil . temperature (which it does rapidly by way n-CsH„CO,H i70"-i80°/g.5h, • n-CsH„NH2 23% (eq. 36) of diimide) in the presence ofquinone or of azobenzene, yields hydroquinone and COjH NH, hydrazobenzene respectively.l-s HOSAand HOSA/PPA (CH30): > (CH30). (eq. 39) hydroxy la mine sulfate together form an in 115-120°/1hr 4-met boxy 35% situ source of diimide capable of selectively x=1,2,3 2,4-dlmethoxy 25% hydrogenating conjugated multiple bonds (eqs. 34, 35).> Using HOSA alone, Appel hr and Buchner" give examples of the reduc *VC=CH, (ii;;] *!ffriHOSA/ai reflu*/3hr rrr • RVCHCH,™, (eq. 40) tion of both conjugated and noncon- 1 fl ---7)-C6H13, Ri-H 64% jugated multiple bonds but the yields tend R'=CeH5, R*=CHj 58% to be lower (eq. 36), CHj CH, HYDROXYMETHYLATION (i) NaBH /BF elfierale/dfglyme/ioom lemp./3hr ,-NH, 4 3 (eq. 41) (ii) HOSA/l00°/3hr ™ 5B% )f~H • ^C-CHjOH anhydride) with HOSA in mineral oil at Quinolines can be hydroxy methylated in trifluoride etherate to the alkene and 160-180° (eq. 38)Wor polyphosphoricaeid sodium borohydride in diglymc. The reac the 2- and/or 4-position using HOSA in w ,x at 115-125° (eq. 39). However, the con methanol (eq. 37). The discovery arose tion is highly steieospeeific as is ditions for this transformation clearly still when a desired amination on nitrogen us demonstrated in the conversion of nor- need to be optimized. ing the standard HOSA method could not bornenc and a-pincne to the isomerically be achieved owing to insolubility of some Addition to double bonds pure fAD-norbornylamine and isopino- campheylamine. respectively.4- Occasion quinolines in the aqueous medium and, as a Alkenes result, the solvent was changed to ally a rearranged amination product is observed ,J' methanol. The reaction has been found to (0 ^^ • >—
AUrkhinika Acta, i'ol. li. So. I. I'M) 1 Aryl alkyl ketones, under the above con HOSA/FeCI;/MeOH RCH=CH, RCHCICH,NH, -n-CtH3 8% (eq. 42) ditions (eq. 51), yield N-aryl aliphatic 0° =C6H5 13% amides, again in good yields." According to Sherk et a/.,4K diaryl CH=CH2 J/^YCHCHJNH; HOSA/FeSOa/MeOH ketones do not react under these con OCH, (eq. 13) ditions, but Ho49 has reported the forma u tion of amides in tetrahydrofuran. Schmidt- and Beckmann-type mechanisms CSCH CCI=CHNHj are proposed for these rearrangement reac HOSA/FeCI,/MeOH H,0 tions, the precise details of which have not been resolved.4*'4* (eq. 14) In a very recent extension of this syn 50 NH, thetic transformation, Olah and Fung QT" have shown that alicyclic ketones can be converted to their corresponding lactams, in high yield, by heating the ketone and HOSA/K£CQ3 or KOAc R,R C=0 t fj°/1min >• R,R;C-NOSO,K HOSA under reflux in formic acid for 55% (eq. 45) several hours (eq. 52). Benzophenone, un R,=CHjC02CH3, R2= CH, 55% der similar conditons, gives benzanilide in 68% yield.50 HOSA/HjO ArCHO ArCH=NOSG,H Examines room temp. ' Ar=subst. benzene, (eq. 46) pyridine or imidazole* •R.G. Wallace, unpublished observations. >=CH(NR2) ^JCH-CN Examples are given in eq. 42. It would the important factor being for them to be An additional nitrile synthesis using appear that ihe amino group attaches itself sufficiently rigorous to bring about the HOSA has recently been reported.5' This to the least-substituted carbon atom. The elimination of sulfuric acid from the in time the precursor is an enamine. The addition differs from the organoborane termediate oxime-O-sulfonate, method is extremely useful since enamines method in not being stereospecific. can be prepared readily from a variety of If addition is carried out in methanolic (Hi) >=0 -> ^>=N-OH active methylene compounds and ketones. solution with FeS0 instead of FeCl , an The enamine and HOSA are stirred 4 2 Aliphatic ketones react exothermically amino ether is produced (eq. 43)ia and if together for 1 hour at room temperature, when warmed together with HOSA in a sodium azide is also present an azido amine whereby the nitrile is obtained in good water bath to give the corresponding oxime is formed.45 yield (eq. 53). in very good yield (eq. 50).41t The reaction is Phenylacetylene with FeCb yields «- accompanied by the loss of nitrogen. Forster reaction chlorophenylacetaldehyde by hydrolysis of N OH the corresponding intermediate enamine >o > " >"> -N (eq. 44)." C'v) >o Oximes react with HOSA in aqueous H 52 Carbonyt compounds base to give diazo compounds. Thus. Aliphatic aldehydes
HOSA/H3O w R^n-CBH13 87% (0 >=0 ^>=N-OS03X RCN (eq. 47) RCHO 20-40°/20min * R^HOCHj 71% Both ketones and aldehydes read with Aromatic or heteroaromatic aldehydes HOSA to give oxime-O-sulfonic acids and (i) HOSA/HjO/room temp Ar=4-CH C H„ 85% ArCHO >• ArCN 3 6 (eq. 48) salts (eqs, 45. 46)."'" In the case ofketones (ii) 65V30min Ar=3-CH30, 4-CH3CBH3 89% and some aldehydes, these derivatives can Aromatic or heteroaromatic aldehydes be isolated and are well defined, reasonably stable, crystallizable solids. They can be (i) HOSA/HjO/AryO' CHO CN 3-cyano 76% (eq. 49) prepared in good yield and undergo a (ii) Na?C03/NaOH/<5° variety of further reactions. This transfor N ^N mation illustrates the alternative role of the HOSA HOSA nitrogen as nucleophile. RR'C=O RR'C=NOH Ri=CH3 90% (eq. 50) A (water bath)' CH3, R>=C(CH3)3 85% The condensation reaction to give the oxime-0-sulfonicacid or salt forms a com Ar^ HOSA ArNH^ mon first stage in a number of related and SC=0 Ar -CgHj, H— CHj 90% (eq.51) c=o A {water bath)' -4-CH OC H , R-CH 90% synthetically very useful transformations. Ar 3 6 a 3
/^CH2 («) -CHO -CN HOSA/HCO;H MM Aldehydes, in aqueous solution/suspen at reflux/3-7hr NH (eq. 52) sion, can be smoothly converted in high C^0 n=3-10 **° n=10 87% yield into nilriles (of the same carbon number) wild HOSA.?'"'' The precise con Ar. HOSA/H,0 -> "CHCN Ar-4-N0,CH*Ri=C=CHI , 78% ditions depend on ihe nature of the R:C-CHNR'; r (eq. 53) aldehyde (details are given in eqs. 47-491. room temp /1h r R' Ar-4-pyridyl, R1 = CH3 68%
8 Aldrkhimka Ada, Vol. 13. No. I. I9H0 fluorenone oxime gives diazofluorene in R" 60% yield and benzophenone oxime gives HOSA/NaOH/H,0 R'-C-C=CH-C-R" R'-C-C=CH-C-R"' diphenyldiazomethane (30%). The reac 4V2hr (eq. 54) NOH II tion also works well for fully conjugated o o a,^-unsaturated 1,4-ketoximes (eq. 54)." R-=C*H* R =CH3, R =H 78% Fragmentation reactions csc /^NOH A * - - In a sagacious extension of the diazo functionality formation reaction just described, Wieland, Kaufmann and Es- HON (eq. 55) chenmoser51 have demonstrated in the field of steroidal chemistry the facile conver sion of an a./?-oxido oxime toanalkynone (eq. 55). A further example and a discus O^ ,0 62% sion of the mechanism of the reaction is given in a later paper.ss
Miscellaneous HOSA/MaOMe/THF C.HrN=0 (eq. 56) (i) -N=0 ->• -N=N=N room lemp. CBK-N=N=N 25% Nitrosobenzene will react with HOSA in tetrahydrofuran in the presence of base to CH, CH, give phenyl azide(<;/l Forster reaction) (eq. HOSA/KOH/HjO 56).sh > L | 91% (eq-57) 70-72°/4hr (ii) N-Oxideformation CHp^N Certain 4-substituted pyridines' and O condensed pyrimidines (quinazolines)31' react with HOSA to give N-oxides. For ex ample, 4,6-dimethylpyrimidine, with the CH^,=o HOSA/2NNaOH/E»,Q CH^f" g6% potassium salt of HOSA in aqueous methanol over 4 hours at 70°-72°. gives 4,6-dimeihylpyrimidine-l-oxide (eq. 57),u HOSA/RNH;/H;Q A mechanism involving addition of e< 59 HOSA, followed by ring opening and then 0"/overnight R-H 61-70% ( I- > R=CH, 62% recyclization and, finally, loss of sulfur '3 62 Vo trioxide and ammonia is proposed for the 11 react ion. NH, [oom CHjCOCHjCOR temp./overnight ~ CH,COCHCOR HETEROCYCLIC FORMA •] (eq. 60) TION CH*. ,COR (a) Cyclization reactions RCO^N^ CH3 R-OCH3 34% Oxaziridines H R=CH3 28% The oxaziridine ring system can be HOSA/H,0 NC^_ NH, prepared by the reaction of HOSA with an NC-C=C.R, : M If (eq. 61) aliphatic ketone"" or benzaldehyde ''> in NC' "^c room temp72hr R,=CH ca.85% RJ\; ;S N 3 2/V NaOH at 6-8°. Thus, 3-ethyl-3-methyl- M=Na, K R^SCH, ca.70% oxaziridine is obtained in 96% yield (eq. reviews by Scrtmitzl,'<'4 who notes that by 58)" from 2-butanone. The oxaziridine is one-step method for the preparation of 1964. fifty or so diaziridines had been stable only at very low temperature. More tetrasubstituted pyrroles. A /J-diketo com prepared by the HOSA method. stable oxaziridines are generally obtained pound is treated with HOSA in aqueous potassium carbonate solution overnight to by acylating (he unsubstituted oxaziridine The diaziridine is formed by reaction of give a symmetrically substituted pyrrole in situ.™ HOSA with ketone/ammonia mixtures. (yields 28-34%, eq. 60). Pyrroline is formed Setoffs bases or a mixture of a carbonyl Diaziridines in low yield when HOSA is treated with compound and a primary amine. A typical Related to the preparation of ox NaOMe in methanol in the presence of 1,3- synthetic procedure, described in Organic 6 aziridines and probably another of the 1 biitadiene." The 1,4-addiiion of imene Syntheses? is illustrated in eq. 59. The most widely explored areas of HOSA (NH) to the diene is invoked in this reac diaziridines may easily be oxidized to chemistry has been the synthesis of tion. 1 diazirines. diaziridines. Both simple * and complex Isotkiazoles diaziridines such as those with steroidal61 and multifused''1 ring structures have been The pyrrole system Dicyanothioalkene salts* (eq. 61, these described. Principal references are given in Tamura-e; aV have described a simple " I he yields ftommoiiocyiiiHiLompiiundsarc very low
•Mtlrichimica Acta. I <,!. I J. \o. I. I9H0 can easily be prepared in yields of over 70% by the thioacylation of malononitrile by es ters of dithiocarboxylic, thionocarboxylic, (i> HOSA/Na^SO./MjO/tew min o N 95% (eq. 62) x ant hie or trithioearbonic acids at room (ii) NaHCOyH;0/CH;Clj/1hr temperature) react with HOSA in aqueous solution to give 3-aminoisothiazoles.67M! The yield of crude reaction product is generally good but isolation of the pure HOSA _Ar 14% (eq-63) isothiazole may in some cases present NHAr N Ar=CfiH= technical difficulties. CHO Ar-4-NOjC6H4 7%
Bmzisoxazoles R' R1 Kemp and WoodwardM have described ^Yj-^is-CN HOSA/KHCOj/NaOH/HgO/EtOH ^ "t^il rf^1 how benzisoxazole can be prepared in 95% , room temp715min r (eq. 64) yield when sa I icy] aldehyde is combined with HOSA in water, followed by treat jll R'=R3=CHa, R*=H 72% ment with sodium bicarbonate for 1 hour at room temperature (eq, 62). A similar preparation was reported eleven years after |i) HOSA/H;Q/ and/or by employing mesitylsulfonyl- U hydroxylamine in place of HOSA in the ^f HOSA/NaOH/H.O [^V"\ 87% (eq. 68) reaction (yields up to 76%). a 60 7OV3Omi 1 The proposed mechanism for the N^H - ' ' W^r/ cyclization involves a ring expansion step; an additional benzodiazepine ring syn HOSA/NaOH/H;0 32% (eq. 69) thesis, which is a direct ring expansion of a 60-70" preformed starting material, is described a little later, Isothiazolopyridines HOSA/PPA In an extension of the isothiazole syn (CH30)x 80-110° /2-3.5hr (OCH,),, (eq. 70) thesis described above, 3-cyanopyridine-2- (CH30) ihiones are found to cyclize on treatment K =1,2,3 24-45% with HOSA in the presence of base to give 3-aminoisothiazolo[5.4-/>]pyridines (eq. Dibenzo-[l, 4]-diazepinex ring contraction reaction to give 27 74 64). The yields in this reactionaregood. Treatment of /V-methylacridinium imidazolin-2-ones in high yield. Thus, 5.6-diphenyl-l,2,4-tria7in-3-one gives 4,5- Pyrazolopyridines derivatives with HOSA in absolute methanol containing 30% ammonia for 3-4 diphenylimidazolin-2-one (68%), 1,2,4- Pyridines with a /J-carbonyl functionali hours al room temperature results in an ex benzotria7in-3-one gives benzimidazolin- ty in the 2-position undergo ring closure pansion of the heterocyclic ring. The 2-one (87%, eq, 68) and phenanthro[9,IO- with HOSA to give pyrazolo[l,5-«]- e]-[],2,4]tria7.in-3-one (requiring 7 7 resulting 5-methyldiben/o(/>.(']-( MHi- pyridines (eqs. 65.66) "- - in good yield. The azepines7J are obtained in variable yield aqueous/ethanolic NaOH) gives 1,3- reaction would seem to occur by eleo (eq. 67). dihydrophenanthro[9.IO- 10 Aldrkhimica Acta. Vol. 13. No. I. I9H0 u to give oxindole in .12% yield (eq. 69), 93, 1024(1973), About the Author 26) K. Kiisuga, M. Hirobe, and T. Okamotu. ibid.. 94, Dr. Wallace is a research scientist work MISCELLANEOUS 945(1974). 27) K. Gewald, U, Schleget, and H. SchaTer, / Praki. ing for the Cancer Research Campaign. He Most of the preceding reactions describ Chem.. 317, 959(1975), obtained his B.Sc. degree from Southamp ed have involved the incorporation of the 28) M.S. Raasch, J. Org. Chem., 37, 3820(1972), ton University in 1968 and subsequently nitrogen of the HOSA in the reaction 29) W. Walter and CO. Meese, Justus Liebigs Ann. carried out his Ph.D. research at the product. One reaction whicli differs from Chem., 7S3, 169(1971). School of Pharmacy. Portsmouth all of these is that between aromatic ethers 30) T. Appel and W. Buchner, Chem. Ber., 95, 849 (1962). Polytechnic. His main interests lie in the and HOSA in polyphosphoric acid. Here, .11) Y. Tamura, .1. Minamikawa. and M. Ideda. Syn area of heterocyclic chemistry and in par sulfur is incorporated and the product is a thesis. I (1977). ticular he is concerned with the synthesis of diarylsulfonefeq. 70)." It is suggested that 32) R. Appel, W. Buchner.andE Qutb.Jialui Liehigs hypoxic cell radiosensitizers for use in HOSA is cleaved to give H,S0 and it is Ann. Chem.. 618,53(1958). 4 33} A. Nickon and A.S. Hill, J. Am. Chem. Soc. 86. cancer therapy. He holds a Visiting further reaction of this that gives rise to the 1152 (1964). Research Fellowship at Brunei University. sulfone. 34) G.A. DoldograsandJ.Kollonitsch, ibid., 100. 342 (1978). Aldrich offers HOSA and many of the CONCLUSIONS 35) E. Sehmilz, R. Ohme, and S. Schramm, Angen- Chtm.. Int. Ed. Engl.. 2, 157(1963). reagents cited by Dr. Wallace; HOSA has proved to be a reagent of 36} W. Diirckheimer, Justus Liebigs Ann. Chem.. 721, diverse synthetic utility, its multifarious 240(1969). uses having been amply illustrated in the 37) R. Appel and W. BUchner, ibid.. 654, I (1962). foregoing paragraphs. Such versatility is a 38) M.H. Palmer and P.S. Mclntyre, Tetrahedron leu.. 2147(1968). consequence of the inherent ability of 39) G.B. Bachman and J.E. Goldmaclier, J. Org. HOSA to act as both a nucleophile and Chem., 29, 2576(1964). electrophile and also to provide an in situ 40) G.P. Dhareshwar and B.D. Hosangadt, Indian J. source of other chemical entities, factors Chem.. 11, 716(1973) referred to at the beginning of this article. 41) H.C. Brown, W.R. Heydkamp, E. Breuer, and W.S. Murphy, J. Am. Chem. Soc.. 86, .1565(1964). These properties have led to its exploita 42) M.W. Raihke, N, Inoue, K.R. Varma, and H.C. tion in such a variety of situations. Brown, ibid.M, 2871 (1966). 43) I..A. Levy and I.. Fishbcin. Tetrahedron leu., Clearly there is scope for its application 3771(1969). in further organic transformations, and in 44) K Mimsciand K. Galli, ibid., 1679(1965). particular, it must have a further part to 45) F. Minisci, R. Galli, and M. Cecere. Chim. Ind. {Milan). 48, 1,12(1966). play in new heterocyclic syntheses. 46) P.A.S. Smith, J. Am. Chem. Soc., 70,323(1948). 47) J. Streith and C. Fizet, Hetv. Chim. Acta, 59, 2786 ACKNOWLEDGMENT (1976); Tetrahedron leu., 3187 (1974), 1 wish to thank the Cancer Research 48) J.K. Sandford, FT. Blair, i Arroya, and K..W. Campaign for financial support. Sherk, J. Am. Chem. Soc., 67, 1941 (1945). 49) H.-F. Ho. Diss. Abslr. Int. B, 10. 456,1 (1970). References: 50) G.A Olah and A.P. Fung, Synthesis, 537(1979). I) M. Takcishi. Yuki Gosei Kagatu Kvokai Shi. 28, 51) H. Biere and R, Russc, Tetrahedron Leu., 1361 1171 (1970). (1979). 2} F. Sommer, O.F. Schultz, and M. Nassau, Z. 52) J. Meinwald, P.G. Gassman. and E.G. Miller, J. Anorg. Allg. Chem., 147. 142(1925). Am. Chem. Soe., 81. 4751 (1959). Last year, Professor G.R. Wyatt of the 3) O. tiever and K. Hayes, J. Org. Chem., 14. 813 53) I. Scverin. P. Adhikary, and 1. Briiutigam. Chem. (1949). Her.. 109. 1179(1976). Department of Biology at Queen's U niver- 4) R. Crdsl and A. Meuwscn, Chem. Ber., 92, 2521 54) P. Wieland, H. Kaufmann, and A. Eschcnmoser, sity wrote to me suggesting that we make 7- (1959). Helv. Chim. Ada. SO, 2108 (1967). etho>;y-rj-methoxy-2,2-dimethylchromene 5) R. Gosl and A. Megwsen. Org. Svnth..ii, 1 (196.1). 55) P. Wieland and H. KauTmann, ibid., 56, 2044 (Ethoxy-Precocenc). "The substance has 6) R. Ohme and A Zubek in "Preparative Organic (1973). Chemistry," G. Hilgetag and A. Martini. Eds., 56) J.-P Anselmeand N. Koga, Chem. Comniun. 443 activity as a'precocene'or specific cytotox John Wiley and Sons. New York, N.Y., 1972, p (1970), ic agent for the corpus allatum of insects, 586. 57) E. SehmiK, R. Ohme, and S.Schramm, 2. Chem., which stops ihe production of the juvenile 7) W. Kldtzer. Monatsh. Chem., »7, 1120(1966). 3, 190(1963). hormone and thus brings about precocious 8) K. Kirsie, W. Liiitke, and P. Rademaeher, Angen: 58) E. Schmitz, R. Ohme, and S. Schramm, Chem. Chem.. Int. Ed. Engl.. 17, 680 (1978). Iler.,97. 2521 (1964). metamorphosis and prevents reproductive 9) K. Kasuga, M. Hirobe, and T. Okamoto. Chem. 59) E Schmitz, R. Ohme, and S. 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Chem.,2,83(1963). 192 (1965); C.W. Recs and R.C Storr, ibid.. 193 65) E. Schmitz and K. Ohme, Org. Smth.. 45, 83 our research." (1965). (1965) 15} R.S. Atkinson and C.W. Reeti. ibiil., 1230(1967). 66) R Appe! and O, Biiehner, Angen: Chem.. hit HI. Ethoxy-Precocene seems a very exciting 16} Y. Kawa/oe and G.-F Huang, Chem Pharm. Lngl.. 1. 332(1962). compound, related to the anti-juvenile hor Bull, 20. 2073(1972). 67) K.HarlkeandL Peshkar, ibid., ft, 83 (1967). mones Precocene I and II. which we have 17) R. Slradi. Ani Accad. Nas. Umei, CI. Sci. Fa.. 68) K tlartkeandl. Peshkar, Arch. Phorm. \ H-ein- been making for some time. And so we Mat. Nat.. Rend.. 43, 350 (1967). heim. OV;.]. 301.661 (1968) IN) S. Yamada, I" Oguri. and I Shuiin, ./. Chem 69) U.S. Kemp and R.B.Woodward, Telrahedron.il. made it. .Vw. Chew. Common. i>2MW2t. 3019(1965). 19) Y. Tamma. S. Kaio. and M. Ikeda. Chem. Ind. 701 J. Sitwiriski, Roe:. Chem.. SO, 2005 (1976). (London). 767(1971). 71) J. Stmth and C FizcL. Tetrahedron Lett.. 1297 20) R.N Keller and P.A..S. Smith. J. Am. Chen,. Site.. (1977). 66. 1122(1944). 72) H Ochi. T. Miyasaka, K. Kanada. and K. Ara- 21) P. Kovacicand R.P. Dennett, ibid.. 83,221 (1961) kawa. Bull. Chem. Soe. Jpn., 49, 1980(1976), 22) K. Miniso, Srnthesis. I (1973). 73) M. Hirobcand T.Ozawa. Tetrahedron leu., 4493 23) G.W. KabalkaandJ.W. Ferrell, Si-ni/i. Commun.. (1971). 9,443(1979). 74) C.W. Rees and A.A. Sale. J. Chem. Sw.. Perkin 24) M. Maeda and Y. Kawapoe, Tetrahedron Lett.. Trans. I. 545 (1973). 2751 (1973). 751 G.P. Dhareshwar and B.D Hosangadi, Indian J. It was no bother at all, just a pleasure to 25) M. Hasegawa and I. Okamoto, Yakugaku Zasshi. Chem.. II, 718(1973). be able to help. Aldrkhimka Acta, Vol. 13, No. I. 1980 II