Indian Journal of Chemistry Vol. 438, May 2004, pp. 927-935

3,6-Dibenzoxyl-l,2-pyridazine: A new versatile benzoyl transferring agent for NH2, -OH and -SH benzoylations

Sabir Hu ssa in Mashraqui * & Jadhav Latika Shivaji Dcpartmcnt of Chcmistry, University of Mumbai , Vidya nagari , Sa ntac ru z (E). Mumbai 400098, India. E-mail shmas hraqui @y ahoo.com

Received 14 Jalli/ar.\' 2003: accepted (revised) 22 August 2003

A ncwly sy nthcs izcd 3,6-d ibenzoxy l- I ,2-pyridazinc 3 has becn in vcstigatcd for its potential to transfcr th e ben zoyl

group to va ri ou s orga ni c substrates ca rry ing - NH2, - OH and - SH groups. The be nzoy l transfer is fairly general in scope. occurs un der convenient condition s and provides good to exce llent yields of benzoy lated products. Moreovcr, by ch oos ing proper conditions, it is poss ible to achieve chemose lec tive be nzoy lation in bi-functional molecules . For instan ce, N­ benzoy lation of aro matic amincs ea n bc sc lec ti ve ly accomplished over th at of aliphatic amincs and vice versa by manipulating reac ti on conditions. Selccti vc N- or O-bcnzoylat ion in aminoph enols is also po ss ible. Although. not studied in detail, we find that dibenzoate 3 ca n also be used to effect C-benzoylation of reac ti ve phcnols and ketones, as excmplified by th e C-benzoylation of resorcin ol and acetoph enonc. res pec tivel y. Dibcnzoate 3. besidcs being a crys tallinc, easy to handle, so lid possesscs twice th c potcntial as an acy l ca rri er comparcd to thc other kn own acy l ca rriers. These fcatures makc 3 as an attractive choice for man y applica ti ons pertaining to benzoy l tran sfcr reac ti ons.

IPC: InLCI.7 C 070237/00

l2 Acylations of heteroatom functional groups viz. literature as acyl transferring agents . These systems am ine, alcohols, phenols etc . are frequentl y encou n­ take advantage of highly polarized -COR or S-COR tered in the practice of synthetic organ ic chemi stry, linkages, wherein th e nucleophilic attack on th e acy l particularly with regard to derivatiza ti ons, protection moiety is facilitated by th e stabili zed azolate or and functional group interconversions I . Des pite thiolate anion acting as a leaving group. Many of repertoire of methods available for heteroatom th ese acyl carriers also offer advan tages in terms of 2 6 acy lations . , there ex ists a continuing interes t to stabi I ity, hi gh acy I tran sfer potential and mi Id develop new :lcy lating agents, acti vators or catal ys ts cond itions. to ac hieve se lecti vi ty, con trol and mi Id reacti on Preparation and structure of 3,6-dibenzoxyl-I,2- 7 cond itions . Traditional acylating agents name ly, acid pyn"d azme" 3 . D unn . g our wor k on acy I ca rn' ersI '} , we chl orides and ac id an hydrides or mixed anhydrides have re cently demonstrated th e potential of monoacyl are un stab le and to xic substances, pos ing storage and hyd raz ides i .j (R= CH 3 or C6 Hs), derived from handling problems. Although acy lat ion of amines are chea ply availab le maleic hydrazide 1 as versatile acyl known to be spo ntaneo us, th ose of comparati vel y less transferring agent in man y applications under conven­ nucleophilic phenols, al cohol s and thiol s are not ient conditions. The use of maleic hyd razide 1 as an spontaneous processes. requ iring base, Lewis ac id or acy l ca rrier was bD sed on th e ass umption th at its hi gh B metal ion catalysis for acy lations to occur . On th e aci dity (pKa =13 )1 5 would provide a dri ving force for other hand, acy lat ions via tran ses terification and the easy nu cleophilic displacement of th e mal eic hy­ aminolys is are preperat ive ly less attracti ve since draz ide anion during acy lations. We report here in the being equilibrium processes , th ey genera lly afford sy nthes is of hitherto unreported dibenzoyl maleic hy­ I ess san. sf' actory conversI. onsY·IO . drazide 3 and its successful implementation as a ver­ Late ly, a number of so lid acy l carriers based on sat ile ben zoy l transferring agent to a variety of het­ acyl derivati ves of azole rings and its analogs, name ly eroatolll fun cti onal groups (-NH2, -OH, -SH) as illus­ imidazo le, benzimidazole and benzotriazo le ha ve trated in th e generali zed reactions depicted in the been developed I I . In add ition, a limited nu mber of S­ Scheme I. acy l derivati ves of 2-merca tptobenzothiazo le and 2- Dibenzoyl ma leic hydrazide 3 was readi ly prepared mercaptobenzoxazole have also been described in th e by react ing 1 with ca. 2.5 equivalent of benzoy l 928 INDIAN J. CHEM .. SEC B, MA Y 2004

0 II OH O-C-R ¢NI ~H ¢NI ~H 0 0 1 2

0 0 OH II II O-C-Ph O-C-Ph 0 II PhCOCII Py N-C-Ph I ~H • I I or or ¢N ...-;N I ~-C--Ph ¢OI ~-C-P h ¢N ¢N II II 0 0 0 O-C-Ph 0 0 II 0 1 3 3a 3b

0 0 3/0MF II II RNH21 ArNH2 • RNHC-Ph l ArNHC-Ph See Table I

3/0MF+EhN .. ~ ~ ROH 1 ArOH ROC-R 1 ArOC- Ph See Table II o _3=-:...-1O=-:..:.M:..:c F N_.... ArSg-Ph ArSH _+:.....:::Et:.>.3:....: See Table II Scheme I chloride in dry pyridine (O°C- 80-90°C, 5 hr) . The put together leave 3 as the most fa vo ured structure for dibenzoate 3 was isolated as a fine needle shaped, the dibenzoate. colourless solid from chloroform, mp 143-46°C in N-BenzoyJation of amines with 3. In anticipation 68% yield. As expected of a dibenzoate structure, the that both the benzoy l groups of 3 would be compound analyzed correctly for its molecular transferred, th e molar proportion of the latter with formula Ci sHI ZN20 4 and showed M+ at mlz 320. A respect to nucleophili c substrate was taken in 1: 2-2.5 priori , three structures (3, 3a and 3b) are conceivable, ratio . To start with, we set-up as a test case th e depending upon whether "0" and or "N" acylations reaction of dibenzoate 3 with an aromatic amine, have occurred. However, the structure 3 is clearly aniline (1 :2.5 ratio) in different solvents , namely ev ident from the 13C NMR and IR spectral data. The glaci al aceti c ac id, DMF, THF and CH3CN to proton decoupled 13C NMR spectrum revealed only evaluate the suitability and efficacy of the medium. seven carbon signals, thereby supporti ng a The reactions were heated uniformly fo r 1 hr at 80- sy mmetrical structure, either 3 or 3b for thi s 90°C and the product analysis by HPLC revealed compound. However, th e appearance of a single hi ghes t conversion to anil ide of 61 % in acetic ac id I absorption band at 1755 cm- in its IR spectrum medium followed by DMF (46%), whereas THF and undoubtedly points to the presence of - O-CO-Ph CI-I 3CN produced in sign ificant conversions «10%) . rather than the -N-CO-Ph linkage. These evidences Heatin g the reacti ons eith er in acetic acid or DM F for MASHRAQUI el al.: 3,6-DIBENZOXYL-1 ,2-PYRIDAZINE AS BENZOYL TRANSFERRING AGENT 929 ca. 3 hr led to nearly quantitative formation of benza­ piperidine or benzyl amine (pKa > LO)16 failed to nilide product. The faster rate of acyl transfer in acetic undergo benzoylation in acetic acid presumably as a acid may be attributed to the formation of hydrogen result of deactivation on account of extensive bonding involving both the ring nitrogen and the protonation. For thi s reason and to maintain neutral carbonyl oxygen in dibenzoate 3. The H-bond conditions, we have preferred to use DMF as th e induced increased electrophilicity of the acyl group solvent of choice. would be expected to facilitate the nucleophilic attack To evaluate the general scope of the reaction, we to give higher conversions in the acidic medium. ]t submitted a number of aromatic and aliphatic amines may be noted that being weak bases, aromatic amines, to benzoylation with 3 in DMF solvent and results are sLich as aniline (pKa = 4.60)16 are not appreciably collected in the Table I. All the reactions were carried protonated in weak acid such as acetic acid (pKa = out using 5 mmoles of dibenzoate 3 and lO­ 4.7)1 7 and therefore no noticeable deactivation is IS mmoles of the amine substrate to ensure complete observed under the weakly acidic medium of acetic transfer of both the benzoyl groups. The reactions are ac id. However, more basic aliphatic amines such as completed during 3-6 hr of heating at 80-90°C

Table I- N-Benzoylation" of aromatic and aliphatic ami nes with 3

c Entry Substrate Benzoylated product b Time(hr) Yi eld 80-90°C (%)

I C6HSNH 2 C6HSNHCOC6Hs 3 89

2 4-MeC6H4NH 2 4-MeC6H4N HCOC6HS 3 9 1 3 4-CIC r, H4NH 2 4-CIC6H.jN HCOC6Hs 5 87 4 4-02NC6H4NH 2 4-02NC6 H.jNHCOC6HS 6 65

5 4-HOC6H4N H2 4-HOC6H4NHCOC6HS 4 69

6 2- HOC6H4N H2 2-HOC6 H4NHCOC6 HS 4 72

7 4-H02CC6H4NH 2 4-H02CC6H4NHCOC6Hs 4 77

8 2- H02CC6H4NH 2 2-H02CC6H4NHCOC6HS 4 88

9 C6HsNHNH2 C6HSNHNHCOC6HS 3 92

10 5 82 CQ:::::,.. u CQ:::::,.. U NH2 NHCOCoH,

H (rNHCOC6 5 II (r" I NH 2 " I 6 78 :::::,.. :::::,..

12 (eI N~ NH 2 (eI N~ N H COC6 H , 6 75 :::::,.. s :::::,.. s

13 CoHsCH 2NH 2 CoHsCH2NHCOC6Hs 3 87 14 /\ /\ 3 70 0 NH o N - COC"H, "----I "----I .

15 (C6 HsCH 2h NH (C6 HsCH2)2NCOC6Hs 5 66 16 C6HsCH 2CH 2NH 2 C6HsCH2CH2NHCOC6H s 3 80

17 C6 HI IN H Cr, HI IN HCOC6 HS 3 81 d 18 H2N(CH 2)3NH 2 C6HsCON H(CH3)3NHCOC6Hs 4 78 (a) benzoy lati ons were carried out usin g 5 mm ole of 3 and 12- 15 mm ole of amine in DMF unless stated other- wi se. (b) Products are characteri zed by elemental analysis, mp and superimpossable IR data with authenti c sa mpl es. (e) Yi elds refer to TLC homogeneous product. (d) 6 1l11l10le of 3 and 5 mll10l e of diamine used. 930 INDIAN J. CHEM .. SEC B. M A Y 2004 depending upon th e structure of th e substrates and the tion of 2-aminothiophenol shown in the (Eq. 2) also iso lated yields of N-benzoylated products ran ge from afforded the cycli ze d product, 2-phenyl benzothiazo le 65-96%. The high yields clearly indica te that both th e albeit in moderate yield of 36%, along with unidenti­ benzoyl groups are being effective ly transferred. fied products. H owever, the reaction of 2-am ino­ Multifunctional am ino-ph enols such as 2- and 4- phenol under th e above condition did not proceed be­ aminophenols were found to reac t selectively with 3 yond the initi al, N-benzoylation stage (68 %) with no at th e - NH1 group to afford the corresponding trace of the cyclized product, 2-pheny l benzoxazole benzamide (enteries 5 and 6) without detectabl e 0- (Eq. 3). This res ul t is not surprising since th e cycliza­ benzoylation being observed. Aromatic aminoac ids, tion of 2-aminophenol with carboxylic ac id deriva­ 2- and 4-arninobenzoic acids also successfully tives to form 2-ary l/a lkyl benzoxazoles has been re­ participated in the benzoylation to give good yields of ported to occur on ly under strong ac id co nditions at th e corresponding N-benzoyl products (e ntries 7 and elevated temperatures 18. 8. Table I ). In many cases, product iso lation simply In order to probe i f am ino acids cou ld be benzoy­ con sisted of diluting th e reacti on with water to ob tain lated with 3, we studied the benzoy lation of a model th e prec ipitate of th e crude benzoy l deri va ti ve, which amino ac id, glycine. We made several mod ificat ions co uld be purified by crystallizati on. in th e reacti on co nditions i.e., DMF/~ , DMF-Et, N/.6.. N-benzoyl transfer to am ino group appended to the NMP/pyridin e/~ etc, but were of no ava il. The fa ilure heterocyclic rings also occurred read ily in satisfactory to effect benzoylation of glycine co uld be attributed to yields (entries II and 12). The reaction of 1,2- (i) its existence in th e less reac ti ve, + NH 3 CH 2 CO ~ ' bifunctional amines, such as 1,2-phenylene diamine, zwitteri onic form and or (ii) inso lubility of glycine in 2-aminothiophenol and 2-aminophenol was also sub­ the given reacti on medium. In order to circumvent jected to benzoy lation with 3 as shown in th e the se problems, we attempted th e reac ti on of glycine Scheme II. We carried out th ese reactions in acetic in the aqueous alka line medium. Accordingly, diben­ ac id med ium in anticipation that subsequent to zoa te 3 and glyc ine were taken in 80% aq . DMF to benzoylat ion, ac id cata lys is might enforce ring clo­ which 5% aOH ~o lution was added dropwise at sure to provide the co rresponding heteroannulation room temperature w ith vigorous stirring during 30 products. Indeed , for the case of 1,2-phenylene di a­ min to get a final alka line p H . The react ion mixture mine (Eq. 2), we d;d obtain the ex pected cyclized was further stirred at room temperature for 6 hr, product, 2-phenyl benzimidazole as the major product cooled and ac idified w ith dil. HCI to produce a co l­ in 45 % yield (unoptimized) along with the co rre­ ourless precipitate. The product after filtrati on ami sponding dibenzamide in 20% yield (Eq. 1). The reac- crystallization from aq. alcohol was identified as th e

0 (XNH-C-PhII 3 /CH3COOH (XN + ((H' • I >-Ph ... ( I ) 80-g0oe ~ N NH2 NH-C-Ph I II H 0 45 % N 20 % I >-Ph 80-g0oe (X ... (2) ~ S

36 %

.. . (3)

68 %

Scheme II M AS HR AQUI el 01. : 3,6-DIBENZOXYL- 1,2- PYRIDAZINE AS BENZO YL T RANSFERRI NG AGENT 931 desired hippuric acid (65%). The success of thi s reac­ line with the above reasoning, we have exploited th is tion suggests that under proper set of conditio ns, ben­ reacti vity profil e to effect selecti ve benzoylation of zoylati on of other amino acids o ught to be possible in e ither aromati c or aliphati c amine in a mix ture con­ reasonable yields. taining both amines. W hen an equimolar mi xture of p­ Benzoylation of phenols and alcohols. Attempted toluidine and benzyl amine are all owed to react "vith benzoyl transfer reacti ons to phenols or alcohols with 3 dibenzoate 3 in neutral DMF solvent, indeed as ex­ were un successful in DMF solvent alone which is in pected the product exclusively deri ved from the ben­ agreement with our experience with mono-acyl maleic zoylati o n of benzyl amine (80% yield ; Eq. 1) is hydrazides 213b. In these cases, base catalysis either formed. But, when the same reactio n was conducted using pyridine or tri ethyl amine was an essential in glacial acetic acid, we coul d obtain the benzoyl requi rement to effect acylati ons. Accordingly, we derivati ve of toluidine in 84% yield wi thout detect­ perfo rmed benzoylati on of phenols and alcohols with 3 able benzoylati o n of benzyl amine. We anti cipate that in DMF medium contain ing Et3N as the base. Under such chemoselecti vity should be possibl e in in­ these conditions, benzoylation of phenols and alcohols tramolecul ar situati o ns as well. occurred smoothly upon heating. The reacti on was The selecti ve benzoylation of amino function in found to be general and results obtained with vari ous preference to the pheno li c gro up has already been phenols and alcohols are coll ected in the Table II. The demo nstrated, where in under neutral conditio n amino yields of the benzoylated products, although not group is benzoylated leavin g the phenoli c - O H intact optimized are generall y sati sfactory. The benzoylati on (see Table I , entri es 5 and 6)). In order to achi eve the of isovanillol with di benzoate 3 proceeded to give a reverse selecti vity i. e., to preferenti ally benzoylate crystalline product, identified as the monobenzoate pheno li c -OH in the presence of - NH2, we perfo rmed product (entry 9). Indeed, as expected, in this molecule the benzoylatio n of p-amin ophenol as a representati ve the more basic phenolic functi on reacts preferentiall y case, in dry DMF containing a strong base potassium over the less reactive pri mary alcoho l. Dihydric t-butox ide. It was anti cipated th at the phenolate anion phenols, resorci nol and hydroquinol (entries 6 and 7) as generated by phenol deprotonation would react faster well as diols (entries 14 and 15) were all readily with 3 under kineti call y controll ed process over th e dibenzoylated in good to excell ent yields. Cholesterol amino functi o n. Indeed, in keeping with thi s rationale, was converted into cholesteryl benzoate in 65 % yield. we isolated the O-benzoyl deri vati ve of p­ Likewise, th iophenols also underwent benzoylati on in aminophenol with good chemoselecti vity (67 % yield, good yields (entries 16 and 17). However, we are yet to Scheme III, Eq. 3) alo ng w ith N-benzoyl product be­ find suitable conditions that woul d all ow us to ing fo rmed as a minor product (7%). successfull y perform benzoylati on of sugar substrates C-Acylations of phenol and ketone. Although not i.e., glucose, fructose etc. stu died in detai l, we have also looked at the possibil­ Selective acylations under controlled conditions. ity of carryi ng out C-benzoylati on on reacti ve phenols Chemoselectivi ty in acylatio n of bifunctional mole­ and enoli zable ketones with 3. As representati ve case, cules is of in terest in many appli cations in synthetic the C-benzoylati on of a reacti ve phenol, namely re­ organi c chemistri. Selective acylati o ns of pri mary sorcinol 4 was attempted wi th dibenzoate 3 in the alcohol in the presence of secondary or terti ary alco­ presence of an excess of anhydro us Z nC I2. T he reac­ hol and that of amino function in the presence of phe­ tion mi xture was heated at 120-30D C fo r 6 hr. The no li c group have been well -documented in th e litera­ desired C-benzoylated product 5 coul d indeed be ob­ tu re. In the present work, we have attempted to tained tho ugh in a modcst yield of 35 % after reaction achieve selective acylation of (i) ali phati c vs aromatic work-up and pu ri ficatio n. We have also successfully amines and (ii) amine vs phenol under appropriate used dibenzoate 3 to effect benzoylati on of acetophe­ condi ti ons. no ne 6 as a model ketone. Towards this end, 6 was Aliphati c amines, being more basic (p Ka 9 to 12) added to a solution of dry THF containing a slight exhibit better nucleophili city than aromatic amines excess of potassium t- butoxide at ODe. The resulting (pKa 4 to 5)16 Thus, under the neutral conditi o ns ali­ enol ate was reacted with an equimolar quantity of phatic amines woul d react preferentiall y over the less dibenzoate 3. From th e reacti on, after work-up and reactive aromatic amines. On the other hand, under Si0 2 column puri fication, we could successfull y iso­ acidic condition, the more basic aliphati c amines are late the desired product, dibenzoyl meth ane 7 in a rendered in active owin g to extensive pro tonati o n. In modest yie ld of 34% (Scheme IV). 932 INDIAN 1. CHEM .. SEC B. MA Y 2004

Table II- Benzoylationa of phenols. alcohols and thiols with 3

d Entry Substrate Acylated product C Time(hr) Yield 75-80°C (%)

I C6HsOH C6HsOCOC6 HS 6 90 2 4-MeC6H4OH 4-MeC6H4OCOC6 HS 6 87

3 4-BrC6 H4OH 4-BrC6H4OCOC6 HS 6 92

4 4-02NC6 H4OH 4-02NC6 H4OCOC6Hs 8 78

5 6 89 en::::,." .6' O H en::::,." .6' OCOCJ i 5

6b 6 80

HO OH HsC"OCO 0 OCOC H5 0 6

7b 6 87 HO-o-OH H5C"OCO-o-OCOC6H5

OH OCOC"H5 8 5 68

Q-COOH Q-COOH

9 4 72

::::,." OH ::::,." OCOC()i 5 ~OC H) ~OC Ii)

10 CH)OH CH)OCOC6HS 4 93

11 C6 HsCH2OH C6 HsCH20COC6Hs 4 90 12b 4 87 HOH2C-o-CH20 H HsCoOCO H2C-o-CH20COC6H5

13 Cholesterol Cholesterol benzoate 6 62 b 14 (HO-CH2CH2)20 (C6HsOCOCH2CH 2h O 6 80 b 15 (HO-CH2CH2h S (C6 HsOCOCH2CH2h S 6 78

16 Cr, HsSH C6 HsSCOC6HS 4 69

17 4-MeC6 H4SH 4-MeC6 H4SCOC6 HS 4 78 a) Unless stated oth erwise benzoylati ons were conducted with 5 mmole of 3 and 12- 15 mmoles of ph enol. alcohol or thiophenol in DMF containing Et)N( 1-1 .5mL) as the base. (b) 5 mmoles of substrates and 6 mmoles of 3 used. (c) All benzoylated products arc characteri zed by elemental analysis. mp and or supcrimpossablc IR spectra with authentic samples. (d) Yi elds (unoptimized refer to TLC homogencous products.

Mechanistically, the benzoyl transfer occurs in in a slower reaction the second benzoyl group is also stepwise manner, the first benzoyl group is transferred transferred to complete the benzoylation process. faster than the second group. This is borne out in the reaction of amjnes as well as phenols, since we could Conclusion detect the formation of mono benzoyl maleic hy­ In conclusion, we have reported the synthesis of drazide 2 (R=C6Hs) as the intermediate by TLC com­ dibenzoate 3 from cheaply available maleic hydrazide parison with the authentic sample of 2. Subsequently, and studied its general potential in benzoyl transfer MASHRAQUI et al.: 3,6-DlBENZOXYL- 1, 2-PYRIDAZINE AS BENZOYL T RANSFERRING AGENT 933

... (1) 80- gooe

3 I DMF ... (2) 80- gooe

NH?

3/THF • + Q(C H3hCOK, RT ¢ .. . (3) OH O-C-Ph II 0 67 % 7 %

Scheme III

3 I A nhyd ZnCl2 • 120De , 35%

3 I NaH ITHF • oDe - RT, 34% 6 7

Scheme IV reacti o ns to vari ous substrates carry ing - NH2' -OH, benzoylati o ns. It has been also possible to carry o ut and - SH functionalities. The scope of 3 as a be nzoyl e ither N- o r O-benzoylati o n in aminophenols under carri er is further e nhanced in view of its successful specifi c conditions. It is worthy to note th at the applicati o n in C-benzoylati o ns reactions as we ll. The dibenzoate 3 is a crystalline, stable solid which benzoyl transfer to amino-compounds occurs under makes sto rage and handling easy with the added neutral conditio ns, whereas base catalysis is required ad vantages of mild reacti o n conditions and generally to pro mote the reacti on with phe nolic and a lcoho li c good yi e lds. Finall y, dibenzoate 3 possesses twice substrates. C hemoselective N-benzoyl ati o n of the potenti al as th e benzoyl transferring agent aromati c amines can be selecti vely accomplished in compared to other known acy l carri ers, which should aceti c acid medium, while in neutra l DMF solvent make 3 as a pote nti all y attracti ve choice fo r many more basic ali phati c amines undergo selecti ve applicati ons. 934 INDIAN J. CHEM .. SEC B. M A Y 2004

Experimental Section. R eaction of 1,2-phenylene diamine with diben­ The melting points were determined on a Gallenk­ zoate 3 . Formation of 2-phenyl benzimidazole. To a amp melting-point apparatus and are uncorrected. IR solution o f 3 (1.60 g, 5 mI11o les) in glacial acetic acid spectral data were recorded on a Shimadzu FTIR - (15 mL) was added 1,2 -phenylene diamine (1.10 g. 10 4200 Spectrophotometer as a KBr d isk; IH NMR mmoles). The reacti on was heated at 80-90°C for 6 hI'. pectra o n Vari an EM-360-L, 60 MHz, and 300 MHz After all owing the reaction to cool to RT the reacti on Spectrometers with tetramethyl sil ane as the intern al was poured over cold water and basified with aq. standard ; and Mass Spectra on a GCMS-QP 5050A Na2C03. T he precipitated soli d was filtered, dried and Shimadzu spectrophotometer. subj ected to Si02 column chromatograph y. Elution Preparation of 3,6-dibenzoxyl-I,2-pyridazine 3. w ih C HCI ., gave 2-phenyl benzimidazole in 45% To a well stirred mi xture of maleic hydrazide (J 2.0 g, yield, mp 294-96°C (l it. mp 296-97°C). Further e lu ­ 0.1 0 mol) in dry pyridine (80 mL) was added dropwise tion with 5% mcth anol in chl oroform eluted ou t l J benzoyl chl ori de (35.0 g, 0.25 mol) during 15 -20 min dibenzamide in 20% yie ld. Illp 30 I-305°C, dec.(lit ' • at ODe. The reaction temperature was maintained be­ mp 306°C), dec. Reaction of 2-mercaptoaniline wi th dibenzoatc tween 0-5°C for 2 hr and th en at room temperature for 3: Prepara tion of 2-phenyl benzothiazole. The reac­ 2 hr and fina ll y heated at 80-90DC for 30 min. T he re­ tion of dibenzoate 3 wlth 2-mercaptoan iline was car­ action mixture was poured onto cru shed ice. The pre­ ri ed out as describcd for I ,2-phcnylene diamine. The cipitated solid was fi ltered, washed sequentially with work-up of th e reaction gave a crude product which cold di!. HCI , 5% aq. NaHC0 and water. Ai r drying of 3 on crystal Ii zati o n from aq. alcohol g ve colourl ess the solid foll owed by two crystalli zati ons fro m chl oro­ crysta ls of 2-phe nyl benzothiazole, mp 112-14"C form gave colourl ess fi ne needl es of dibenzoate 3 in 20 (lit . mp j 14"C), yield 36% . 68% yield, mp 143-46°e. (Found: C, 67.35; H , 3.82: Selective N-benzoylation of aromatic a mine: N, 8.70. Calc. fo r Cl s HI 2 N 2 0~: C, 67.50; H, 3.75; N, P,-eparation of benzylamide. T o a solution of equi­ 8.75%). MS: mlz 32 1 (M++J), 320, 2 17, 105; IR (KBr), l I110lar amount of an iline (1.02 g, I j mI11o les) and ben­ 3035, 1755, 1335, 1510, 1287, 111 0. 890 cm· ; IH zyl amin e ( 1.2 g, II I11I11o les) in glacial acetic acid ( 15 NMR (300 MHz, CDCl ): 6.8- 8. 1 (m, C H=CH and 3 8 I11L ) was added dibenzoate 3 ( 1. 6 g, 5 mmoles) and Ar- H); 13C NMR C DC I3): 8 164. 16, 160.64, 134.54, the reaction mixture was heated at 80-90°C for 3 hr. 130.65,128.82, 127.96, 125.05. The usual work-up o f the reaction, followed by crys·· Typical procedure for benzoylation of amines. talli zation of the crude product gave benzamide in To a sol uti on of di benzoate 3 (1.6 g, 5 ml11olcs) in 67% yield. The N-benzoyl product derived from ben­ DMF ( 10 mL) was added freshl y distilled aniline zyl amin e coul d not be detected by TLC anal ysis. (1. 13 g, 11 mmoles). The reaction was heated at 80- Selective N-benzoylation of aliphatic amine: 90DC for 3 hr whereby the reaction was judged to be Preparation of benzamide. To a solution of anil in e complete by TLC analysis. The reaction was diluted and benzyl amine ( I I mmoles each) in DMF ( 15 mL) wih water, th e precipitated solid filtered and washed was added dibenzoate 3 (1 .60 g, 5 mmoles) and the sequentially with 5% HCI , 5% NaHC03 and water. reaction was heated at 80-90"C for 3 hr. The usual The crude benzanilide was crystalli zed from aq. alco­ work-up of the reaction, fo ll owed by crystallization of hol to g iv e colourless solid of benzamide, mp 162- the crude product from I: I ethyl acetate-petroleum 63°C (89% yield). ether gave N-benzoyl deri vati ve of benzy l amine, mp Typical procedure for benzoyla tion of phenols 104-07°e. a nd alcohols. p-Bromophenol (1 .90 g, II mmoles) C hemoselective O-benzoylation of p-amino­ dibenzoate 3 ( 1.6 g, 5 ml11oles ) were dissolved in phenol. 4-Aminophenol ( 1.l6 g, II mmoles) wa~ DMF (10 mL) containing 1.0 I11L of (C2 HShN. The added at RT to a sol ution of dry THF (15 mL) con­ reaction was heated at 75-80°C for 5 hr whereby the taining an excess of potassium I-butoxide (1.94 g, 15 reaction was judged to be complete by TLC analysis. mmoles). After the reaction had been stirred at RT fo r The reacti on mixture was worked-up as descri bed 10 min, it was cooled in ice and dibenzoate 3 ( 1.60 g, above and th e crude product crystallized from aq. al­ 5 mmoles) was added all at once. The reaction was cohol to give colourl ess cry stals of p-bromophenyl th en put in an oil-bath kept at 80-90°C for 4 hr. The benzoate (entry 3, Table II) in 92% yie ld, mp 99- usual work-up of the reacti on afforded crude product 10 1°C, (litiS. mp 102°C). whi ch was subjected to SiOl column chromatog raphic MASHRAQUI el 01.: 3, 6-DIBENZOXYL- I ,2-PYRIDAZINE AS BENZOYL TRANSFERRING AGENT 935 purification. Elution with 1:4 ethy acetate (b) Barret A G M & Braddoe k D C, J Chelll Soc, Chelll COIII ­ -pet. eth er first eluted out 4-hydroxybenzamide, mp. /111111 . 24 . 1997 . 351. (c) Ishihara K, Ku bota M & Yamamoto H. SYlllell . 1996.265. 2 13- 14°C in 7% yield. Further elution with the same (d) Izumi J. Shiina I & Mukaiyam a T. Chelll Lell , 1995.1-+1 . solvent system gave the desired O-benzoyl product, 4- (e) Iqbal J & Srivastav a R R, J Org Chelll , 57, 1992, 200 1. amino phenyl benzoate, mp 213-14°C, as a major (I) Katritzky A R. Hai-Ying He & Suzuki K, J Org Ch elll. 65, product in 65 % yield . 2000, 8210. (g) Lin M Y & Raj an Babu T V. Org Lell , 2, 2000 , 1000. C-Acylatioll of resorcinol: Preparation of res­ 8 (a) Scri ven E F V. Chelll Soc Rev. 12. 1983, 129 . benzophenonc. An intimate mixture of dibenzoate 3 (b) Steglich W & Holre G, All gel\' Chelll lilt Ed Ell gi. 17, (3.20 g, 10 mIlloles), resorcinol ( 1.65 g, 15 mmoles) 1978, 569. and fresh ly fused ZnCl2 (5.0 g) was healed in an oil­ 9 (a) Laroc k R C. COlll prehell Sil"e Orgallic Trall.~/o nll at iolls, bath at 120nC for 7 hr. The reaction mixture, after VCH, New York , 1989 pp 98 1. (b) M arch J, Ad,'wlced Orgallic Chelllistry. 3rd Ed. (Wiley cooling to RT was decomposed with di!. HCI and ex­ Easter Lid. New Delhi) pp 370. tracted with ethyl acetate. The organic extract was 10 (a) Nico laou K C, Telrahe£il-.JII , 33 , 1977. 68 3. dried over anhyd. a 2 S0 ~, concentrated and the crude (b) M asa mune S, Bates G S & Corcoran J W, All gell' Chelll 1111 £d Ell gl, 16, 1977. 585. product purified over Si02 column chromatography. II (a) Bhujanga Ra o K S, Rao C G & Singh B B, J Ch elll Res (S) Eluti on with I: 1 ethyl acetate-petroleum eth er gave 1992. 196. the required product, resbenzophenone in 35% yield, (b) Ton·ini. Zecchini G P, Agros i F & Paradasi M P. mp 139-41 °C (I it21. mp 142-44°C ). .I Helerocyl Chelll , 23, 1986. 1459. C-Acylation of acetophenone: P.·eparation of (c) Kuni eda T, M ori T, Higuchi T & Hirobe M , Telroh edro ll Lell, 26, 1985, 1977. dibenzoyl methane. To a solution of acetophenone (d) Mitsuru U & Imai S K, Sylllh esis. 1981 , 99 1-93. ( 1.16 g, 10 mmoles) in anhyd. THF was added (el Bott a M, Salad ino R, Gcnlile G, Summa V & Nocolelli R. potassium !-butoxide ( l.Og) at One. The reaction was Tel rahedroll. 50, 1994. 3603. stirred at thi s temperature for 10 min and then (f') Kaminska J E & Kaminski J Z. SYll lh esis, 1999. 593 . dibenzoate 3 ( 1.6 g, 5 mmoles) was added all al once. (g) Iwata C. Watan abe M , Okamoto S, Fujimoto M & Sakae M , Heleroc.,'c!es, 27 . 1988,323. The reaction was graduall y all owed to warm up to RT (h) Sakakibara T, Watabe Y, Yamada M & Sudoh R, BIIII Soc and then kept overnight. The deep yell ow reaction Ch elll Jpll , 6 1. 1988, 247 . mixture was acidified with di!. HCI and extracted with (i) Katritzky A R. Yand B & Semezin D, .I Org Chelll , 62. CH2Cb, washed wih water and dried over anhyd. 1997,726. a2S04. The organi c extract was stripped off the (j) Nair P G & Jos hua C P, Chelll IlId, 1974, 704. (k) Franc P, Si ovenko P & M arijan K, Helem cycles. 54. 200 I. solvent by distillation and the crude oi ly product 1011 -20. purified by Si02 column chromatography (1:4 ethy l (I) AI-Sehemi A G. Atkin son R S, Fawcell J & Ru ssell D R. acetate-pet. ether) to obtain dibenzoyl methane in Telrahedroll Lell , 41 , 2000, 2239. 34% yield, mp 80-82°C, (lit22 mp 82°C). 12 (a ) Mitsuru U, Kouji S & Yos hi o I. SYlllhesis, 12,1981. 99 1- 93. (b) Mitsuru U, Akira S & Yoshi o I, J Poly Sci PolY'1I Ch elll. References 1978, 475 , I (a) Kocienski Philip & Georg Thieme Verlag, 13 (a) MashraCJui S H, Niranlar S S & Bi swas M M , Illd .I Chelll Prolecli ve Croups (Stuttgart, New York) 1999. (B) 34, 1995, 1102. (b) Greene T W & Wuts P G M , Prolecli ve Crollps ill Or­ (b) Mashraqui S H & Shi vaji J L. .I Ch elll /?es(s ), in press. nd gallic SYlllh esis, 2 Edn. (Wiley, New york), 1991. 14 (a) Feuer H & Rubin stein H, .I Alii Ch elll Soc, 80. 1958, 5873 . (c) Satchell D P N, QII(/I"I Rev (Londoll ), 16, 1963. 160. (b) Stefyne D & Howa rd W L , J Org Chelll. 19, 1953. 115. (d) Haslam, Tetrahedmn. 36. 1980. 2409. 15 Karritzky A R & Rees C W, COlllprehell sive Heterocyclic (e) Kaminski Z J, SYllthesis . 1987, 9 17. Ch elllistry. (Pergamon Press) Vol. 3, 1984, p 4 .. (I) Hughes D L, Org React. 40, 1992, 33 5. 16 Carey F A. Orgallic Chellli.wrv, 3rd Ed . (Tata McGraw- HilI. 2 Smith M J. Moffit J G & Khorana H G. J Alii Chelll Soc, 80. New Delhi) 1996, p 77 6. 1958, 6204. 17 Carey F A, Organic Ch emislry, 3rd Ed. (Tala McGraw-Hili, 3 Mukaiyama T. Angell' Chelll lilt £d £lIgl, j 8, 1970, 70. New Delhi) 1996. p 90 I . 4 Slaab S, Allgew Chelll Inl £d £ lI g/, 1960,35 1. 18 Vogel I, Tex!book ofPraCl ical Orgallic Chelllislr)" (Longman. 5 Zbigniew J & Kaminski Z J, Tetrahedroll Lell., 26, 1985, London), 5\1 ' edn ., 1989. p.1 3 10. 2901 . 19 Mazurkiewicz R, MOllatsh Chel1l , 119, 1988, 1279. 6 Ikegami S, Uchiyama H, Hayama H , Katsuki T & Yamaguchi 20 Chapman & Hall, Dicliollarv of Orgallic Compoullds, 6'h Ed. M, Tetrahedroll, 44, 1988. 5333 . Vo1.5 , P-O-01401. 7 (a) Katrittzk y R, Yand B & Semenzin D. J OrM Chelll , 62 , 2 1 Cevin eR.J AIII CheIllSoc, 67 , 1945 . 1510. 1997, 726-728. 22 Konig, Ch elll Bel', 39, 1906,4027.