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 Hussa in Mashraqui * & Jadhav Latika Shivaji

Dcpartmcnt of Chcmistry, University of Mumbai , Vidyanagari , Santac ruz (E). Mumbai 400098, India. E-mail shmashraqui @yahoo.com

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

A ncwly synthcsizcd 3,6-d ibenzoxy l- I ,2-pyridazinc 3 has becn in vcstigatcd for its potential to transfcr the benzoyl group to various organic substrates carry ing - NH2, - OH and - SH groups. The benzoy l transfer is fairly general in scope. occurs under conven ient conditions and prov ides good to exce llent y ields of benzoy lated products. Moreovcr, by choos ing proper conditions, it is poss ible to achieve chemoselective benzoy lation in bi-functional molecules . For instance, N­benzoy lation of aromatic amincs ean bc sclecti ve ly accompli shed over that of aliphati c amincs and vice versa by manipulating reacti on conditions. Selccti vc N- or O-bcnzoy lat ion in aminophenols is also poss ibl e. Although. not studied in detail , we find that dibenzoate 3 can also be used to effect C-benzoylation of reac ti ve phcnols and ketones, as excmplified by the C-benzoylation of resorcinol and acetophenonc. respectivel y. Dibcnzoate 3. besidcs being a crys tallinc, easy to handle, solid possesscs twice thc potcntia l as an acy l ca rri er comparcd to thc other known acy l carri ers. These fcatures makc 3 as an attractive choice for many appli ca ti ons pertaining to benzoy l tran sfcr reac ti ons.

IPC: InLCI.7 C 070237/00

Acylations of heteroatom functional groups viz. amine, alcohols, phenols etc . are frequentl y encoun­tered in the practice of synthetic organ ic chemi stry, part icularly with regard to derivati zati ons, protection and functional group interconversions I . Despite repertoire of methods available for heteroatom acy lations2

.6

, there ex ists a cont inuing interest to develop new :lcy lating agents, acti vators or catal ys ts to achieve selecti vi ty , con trol and mi Id reacti on cond itions7

. Traditional acylating agents namely, acid chlorides and acid anhydrides or mixed anhydrides are unstab le and toxic substances, pos ing storage and handling problems. Although acy lat ion of amines are known to be spontaneous, those of comparati vel y less nucleophili c phenols, alcohol s and thiol s are not spontaneous processes. requ iring base, Lewis acid or metal ion catalysis for acy lations to occurB

. On the other hand, acy lat ions via tran sesterifi cation and aminolys is are preperat ive ly less attract i ve since being equilibrium processes, they genera ll y afford I . f' . Y·IO ess sans actory conversIons .

Lately, a number of so lid acy l carri ers based on acyl derivati ves of azole rings and its analogs, namely imidazole, benzimidazole and benzotriazo le have been developed I I . In add ition, a limited nu mber of S­acy l derivati ves of 2-mercatptobenzothi azo le and 2-mercaptobenzoxazo le have also been described in the

literature as acyl transferring agents l2. These systems

take advantage of highly polari zed -COR or S-COR linkages, wherein the nucleophilic attack on the acy l moiety is facilitated by the stabili zed azolate or thiolate anion acting as a leaving group. Many of these acyl carri ers also offer advan tages in terms of stabi I ity , high acy I tran sfer potential and mi Id cond itions.

Preparation and structure of 3,6-dibenzoxyl-I ,2-"d " 3 D . k I ' I } pyn azme . unng our wor on acy carn ers ' , we

have recent ly demonstrated the potential of monoacyl hyd razides i .j (R= CH 3 or C6Hs), derived from cheaply availab le maleic hydrazide 1 as versatile acyl transferring agent in many applications under conven­ient cond iti ons. The use of maleic hyd razide 1 as an acy l carri er was bDsed on the assumption that its high acidity (pKa =13 )1 5 would provide a dri ving force for the easy nucleophili c displacement of the maleic hy­drazide anion during acy lations. We report herein the sy nthes is of hitherto unreported dibenzoyl maleic hy­drazide 3 and its successful implementat ion as a ver­sat ile benzoy l transferring agent to a variety of het­eroatolll functi onal groups (-N H2, -OH , -SH) as ill us­trated in the generali zed reactions depicted in the Scheme I.

Dibenzoyl maleic hydrazide 3 was readi ly prepared by react ing 1 w ith ca. 2.5 equivalent of benzoy l

928 INDIAN J. CHEM .. SEC B, MA Y 2004

0 II

OH O-C-R

¢N I ~H ¢N I ~H

0 0

1 2

0 0 OH II II

O-C-Ph O-C-Ph 0 ¢O ¢N ¢N ¢N II

I ~H PhCOCII Py N-C-Ph • I I or I ~-C--Ph or

I ~-C-Ph ...-;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

~ ~ ROC- R 1 ArOC- Ph ROH 1 ArOH 3/0MF+EhN ..

See Table II

o ArSH _3=-:...-1 O=-:..:.M:..:cF_+:.....:::Et:.>.3:....:N_.... ArSg- Ph

See Table II

Scheme I

chloride in dry pyridine (O°C- 80-90°C, 5 hr) . The dibenzoate 3 was isolated as a fine needle shaped, colourless solid from chloroform, mp 143-46°C in 68% yield. As expected of a dibenzoate structure, the compound analyzed correctly for its molecular formula Ci sHI ZN20 4 and showed M+ at mlz 320. A priori , three structures (3, 3a and 3b) are conceivable, depending upon whether "0" and or "N" acylations have occurred. However, the structure 3 is clearly ev ident from the 13C NMR and IR spectral data. The proton decoupled 13C NMR spectrum revealed only seven carbon signals, thereby supporti ng a sy mmetrical structure, either 3 or 3b for thi s compound. However, the appearance of a single absorption band at 1755 cm-I in its IR spectrum undoubtedly points to the presence of - O-CO-Ph rather than the -N-CO-Ph linkage. These evidences

put together leave 3 as the most fa voured structure for the dibenzoate.

N-BenzoyJation of amines with 3. In anticipation that both the benzoy l groups of 3 would be transferred, the molar proportion of the latter with respect to nucleoph ili c substrate was taken in 1: 2-2.5 ratio . To start with, we set-up as a test case the reaction of dibenzoate 3 with an aromatic amine, aniline (1 :2.5 ratio) in different solvents , namely glacial aceti c ac id, DMF, THF and CH3CN to evaluate the suitability and efficacy of the medium. The reacti ons were heated uniformly fo r 1 hr at 80-90°C and the product analysis by HPLC revealed hi ghest conversion to anil ide of 61 % in acetic ac id medium followed by DMF (46%), whereas THF and CI-I3CN produced insign ificant conversions «10%) . Heating the reac ti ons either in acetic acid or DMF for

MASHRAQUI el al.: 3,6-DIBENZOXYL-1 ,2-PYRIDAZINE AS BENZOYL TRANSFERRING AGENT 929

ca. 3 hr led to nearly quantitative formation of benza­nilide product. The faster rate of acyl transfer in acetic acid may be attributed to the formation of hydrogen bonding involving both the ring nitrogen and the carbonyl oxygen in dibenzoate 3. The H-bond induced increased electrophilicity of the acyl group would be expected to facilitate the nucleophilic attack to give higher conversions in the acidic medium. ]t may be noted that being weak bases, aromatic amines, sLich as aniline (pKa = 4.60)16 are not appreciably protonated in weak acid such as acetic acid (pKa = 4.7)17 and therefore no noticeable deactivation is observed under the weakly acidic medium of acetic ac id. However, more basic aliphatic amines such as

piperidine or benzyl amine (pKa > LO)16 failed to undergo benzoylation in acetic acid presumably as a result of deactivation on account of extensive protonation. For thi s reason and to maintain neutral conditions, we have preferred to use DMF as the solvent of choice.

To evaluate the general scope of the reaction , we submitted a number of aromatic and aliphatic amines to benzoylation with 3 in DMF solvent and results are collected in the Table I. All the reactions were carried out using 5 mmoles of dibenzoate 3 and lO­IS mmoles of the amine substrate to ensure complete transfer of both the benzoyl groups. The reactions are completed during 3-6 hr of heating at 80-90°C

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

Entry Substrate Benzoylated product b Time(hr) Yieldc

80-90°C (%)

I C6HSNH2 C6HSNHCOC6Hs 3 89

2 4-MeC6H4NH2 4-MeC6H4N HCOC6HS 3 9 1

3 4-CICr, H4NH2 4-CIC6H.jN HCOC6Hs 5 87

4 4-02NC6H4NH2 4-02NC6H.jNHCOC6HS 6 65

5 4-HOC6H4N H2 4-HOC6H4NHCOC6HS 4 69

6 2-HOC6H4N H2 2-HOC6H4NHCOC6HS 4 72

7 4-H02CC6H4NH2 4-H02CC6H4NHCOC6Hs 4 77

8 2- H02CC6H4NH2 2-H02CC6H4NHCOC6HS 4 88

9 C6HsNHNH2 C6HSNHNHCOC6HS 3 92

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

NH2 NHCOCoH,

II (rNH 2 (rNHCOC6H5

" I " I 6 78 :::::,.. :::::,..

12 (eN (eN I ~NH2 I ~NHCOC6H , 6 75 :::::,.. s :::::,.. s

13 CoHsCH2NH2 CoHsCH2NHCOC6Hs 3 87

14 /\ /\ 3 70 0 NH o N - COC" H, "----I "----I .

15 (C6 HsCH 2h NH (C6HsCH2)2NCOC6Hs 5 66

16 C6HsCH2CH2NH2 C6HsCH2CH2NHCOC6Hs 3 80

17 C6HI IN H Cr,HI IN HCOC6 HS 3 81

18d H2N(CH2)3NH2 C6HsCON H(CH3)3NHCOC6Hs 4 78

(a) benzoy lations were carried out using 5 mmole of 3 and 12- 15 mmole of amine in DMF unless stated other-wi se. (b) Products are characteri zed by elemental analysis, mp and superimpossable IR data with authentic sampl es. (e) Yields 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 the structure of the substrates and the isolated yields of N-benzoylated products range from 65-96%. The high yields clearly indicate that both the benzoyl groups are being effect ive ly transferred. Multifunctional amino-phenols such as 2- and 4-aminophenols were found to react selectively w ith 3 at the - NH1 group to afford the corresponding benzamide (enteries 5 and 6) w ithout detectable 0-benzoy lation being observed. Aromatic aminoacids, 2- and 4-arninobenzoic acids also successfully participated in the benzoylation to give good y ields of the corresponding N-benzoyl products (entri es 7 and 8. Table I ). In many cases, product iso lation simply consisted of diluting the reacti on with water to obtain the prec ipitate of the crude benzoy l deri vati ve, which could be purifi ed by crysta lli zati on.

N-benzoyl transfer to amino group appended to the heterocyc lic rings also occurred read il y in satisfactory y ields (entries II and 12). The reaction of 1,2-bi functional amines, such as 1,2-pheny lene diamine, 2-aminothiophenol and 2-aminophenol was also sub­jected to benzoy lation with 3 as shown in the Scheme II. We carried out these react ions in acet ic acid medium in anticipation that subsequent to benzoy lat ion, acid cata lys is might enforce ring clo­sure to provide the correspond ing heteroannulation products. Indeed, for the case of 1,2-pheny lene di a­mine (Eq. 2) , we d;d obtain the expected cyclized product, 2-phenyl benzimidazole as the major product in 45 % yield (unoptimized) along with the corre­sponding dibenzamide in 20% y ield (Eq. 1). The reac-

tion of 2-aminothiophenol shown in the (Eq. 2) also afforded the cycli zed product, 2-pheny l benzothiazo le albeit in moderate y ield of 36%, along w ith unidenti­fied products. H owever, the reaction of 2-am ino­phenol under the above condition did not proceed be­yond the ini ti al, N-benzoy lation stage (68%) w ith no trace of the cycli zed product, 2-pheny l benzoxazole (Eq. 3). This resul t is not surprising since the cycliza­tion of 2-aminophenol with carboxyl ic ac id deriva­tives to form 2-ary l/a lkyl benzoxazoles has been re­ported to occur on ly under strong ac id condit ions at elevated temperatures 18.

In order to probe i f amino acids cou ld be benzoy­lated with 3, we studied the benzoy lation of a model amino ac id, glyc ine. We made several mod ificat ions in the reacti on conditions i.e., DMF/~, DMF-Et,N/.6.. NMP/pyridine/~ etc, but were of no ava il. The fa ilure to effect benzoylation of glyc ine could be attributed to ( i) its existence in the less reacti ve, +NH 3CH2CO~ ' zw itteri onic form and or (ii ) inso lubility of glycine in the given reacti on medium. In order to circumvent these problems, we attempted the reacti on of glyc ine in the aqueous alka line medium. Accordingly, diben­zoate 3 and glyc ine were taken in 80% aq . DMF to which 5% aOH ~olution was added dropwi se at room temperature w ith vigorous sti rring during 30 min to get a fina l alka line p H . The react ion mixture was further stirred at room temperature for 6 hr, cooled and ac idified w ith dil. HCI to produce a co l­ourless precipitate. The product after filtrati on ami crystalli zation from aq. alcohol was identified as the

0 II

((H' 3 /CH3COOH (XN (XNH-C-Ph • I >-Ph + ... ( I ) 80-g0oe ~ N

NH2 NH-C-Ph I II H 0

45 % 20 %

80-g0oe I >-Ph (XN

~ S . .. (2)

36 %

.. . (3)

68 %

Scheme II

MASHRAQU I el 01. : 3,6-DIBENZOXYL- 1 ,2-PYRIDAZINE AS BENZOYL TRANSFERRI NG AGENT 931

des ired hippuric ac id (65%). The success of thi s reac­tion suggests that under proper set of conditio ns, ben­zoy lation of other amino ac ids o ught to be poss ible in reasonable y ie lds.

Benzoylation of phenols and alcohols. Attempted benzoy l transfer reactions to pheno ls or alcohols with 3 were unsuccessfu l in DM F solvent alone which is in agreement with our ex perience with mono-acy l maleic hydrazides 213b. In these cases, base catalys is e ither using pyridine or tri ethyl amine was an essential requi rement to effect acy lati ons. Accord ing ly, we perfo rmed benzoylation of pheno ls and alcoho ls with 3 in DMF medium contain ing Et3N as the base. Under these conditions, benzoy lation of phenols and alcoho ls occurred smoothly upon heating. The reaction was found to be general and results obtai ned with various phenols and alcohols are collected in the Table II . The yields of the benzoy lated products, although not optimized are genera ll y sati sfactory. The benzoy lation of isovanillol with di benzoate 3 proceeded to give a crysta lline product, identif ied as the monobenzoate product (entry 9). Indeed, as expected, in this molecule the more bas ic phenolic function reacts preferentia ll y over the less reactive pri mary alcoho l. Dihydric phenols, resorci nol and hydroq uino l (entries 6 and 7) as well as diols (en tries 14 and 15) were all readi ly dibenzoy lated in good to excellent yields. Cholesterol was converted into cholesteryl benzoate in 65 % yie ld. Likewise, th iopheno ls also underwent benzoy lation in good yields (entries 16 and 17). However, we are yet to find su itable condi tions that wo ul d a llow us to successfully perform benzoy lation of sugar substrates i.e., glucose, fructose etc.

Selective acylations under controlled conditions. Chemoselectivi ty in acylatio n of bifunctional mo le­cules is of in terest in many appli cations in sy nthet ic organic chemistri. Selective acy latio ns of pri mary alcohol in the presence of secondary or terti ary alco­hol and that of amino function in the presence of phe­no lic group have been well -documented in the litera­tu re. In the present work, we have attempted to achieve se lective acy lation of (i) a li phatic vs aromatic am ines and (ii) am ine vs phenol under appropri ate condi tions.

Aliphati c am ines, being more bas ic (p Ka 9 to 12) exhibit better nucleophili c ity than aromatic amines (pKa 4 to 5)16 Thus, under the neutral cond iti o ns a li­phatic am ines would react preferentia ll y over the less reactive aromatic amines. On the other hand, under acidic condit ion, the more bas ic a liphati c amines are rendered in active ow ing to ex tensive pro tonatio n. In

line w ith the above reasoning, we have exploited th is reacti vity profile to effect selecti ve benzoy lat ion of e ithe r aromati c or a liphati c amine in a mix ture con­taining both amines. W hen an equimo lar mi xture of p­to luidine and benzy l amine are allowed to reac t "vith dibenzoate 3 in neutra l DMF solvent, indeed as ex­pected the product exclusively de ri ved from the ben­zoy lati o n of benzy l amine (80% y ie ld ; Eq . 1) is for med . But, when the same reactio n was conducted in glac ia l acetic ac id, we could obtain the benzoyl derivati ve of to luidine in 84% yie ld wi thout detect­able benzoy latio n of benzy l amine. We anti cipate that such chemoselecti vity should be poss ibl e in in­tramolecul ar situatio ns as well.

The selecti ve benzoy lation of amino funct ion in prefe rence to the pheno li c gro up has a lready been demo nstrated, where in under neutra l conditio n am ino group is benzoy lated leaving the phenolic - O H intact (see Table I , entri es 5 and 6)). In order to achieve the reverse selecti vity i. e ., to preferenti a lly benzoy late pheno lic -OH in the presence of - NH2, we perfo rmed the benzoy latio n of p-aminopheno l as a representati ve case, in dry DMF conta ining a strong base potassium t-butox ide. It was anti c ipated that the pheno late anion generated by pheno l deprotonation would react faste r w ith 3 under kine ti ca ll y contro lled process over the am ino fun ctio n. Indeed, in keeping with thi s rationale, we isolated the O-benzoy l deri vati ve of p­aminopheno l with good chemoselecti vity (67% y ield, Scheme III , Eq. 3) a lo ng w ith N-benzoyl product be­ing fo rmed as a minor product (7%).

C-Acylations of phenol and ketone. A lthough not stud ied in detai l, we have a lso looked at the possibil­ity of carryi ng out C-benzoy lation on reacti ve phenols and enoli zable ketones with 3. As representati ve case, the C-benzoy lati on of a reacti ve phenol, namely re­sorc ino l 4 was attempted wi th dibenzoate 3 in the presence of an excess of anhydro us Z nC I2. T he reac­

tion mi xture was heated at 120-30DC fo r 6 hr. The des ired C-benzoy lated product 5 could indeed be ob­tained tho ugh in a modcst y ie ld of 35 % after reaction work-u p and pu ri ficat io n. We have a lso successfully used dibenzoate 3 to effect benzoy lation of acetophe­no ne 6 as a model ketone. Towards this end, 6 was added to a soluti on of dry TH F containing a slight

excess of potass ium t - butox ide at ODe. The resulting eno l ate was reacted with an equimo lar qu antity of d ibenzoate 3. From the reac ti on, after work-up and S i0 2 col umn puri fication, we could successfully iso­late the des ired product, dibenzoyl methane 7 in a modest yie ld of 34% (Scheme IV).

932 INDIAN 1. CHEM .. SEC B. MA Y 2004

Table II- Benzoylationa of phenols. alcohols and thiol s with 3

Entry Substrate Acyla ted product C Time(hr) Yieldd

75-80°C (%)

I C6HsOH C6HsOCOC6HS 6 90 2 4-MeC6H4OH 4-MeC6H4OCOC6 HS 6 87

3 4-BrC6H4OH 4-BrC6H4OCOC6HS 6 92

4 4-02NC6H4OH 4-02NC6H4OCOC6Hs 8 78

5 en en 6 89

::::,." .6' OH ::::,." .6' OCOCJi 5

6b 0 0 6 80

HO OH HsC"OCO OCOC6 H5

7b

HO-o-OH H5C"OCO-o-OCOC6H5

6 87

OH OCOC"H5 8

Q-COOH Q-COOH

5 68

9

~ ~ 4 72

::::,." OH ::::,." OCOC()i 5

OC H) OC Ii)

10 CH)OH CH)OCOC6HS 4 93

11 C6HsCH2OH C6HsCH20COC6Hs 4 90

12b

HOH2C-o-CH20 H HsCoOCOH2C-o-C H20COC6 H5

4 87

13 Cholesterol Cholesterol benzoate 6 62

14b (HO-CH2CH2)20 (C6HsOCOCH2CH 2h O 6 80

15b (HO-C H2CH2h S (C6HsOCOCH2CH 2h S 6 78

16 Cr,HsSH C6HsSCOC6HS 4 69

17 4-MeC6H4SH 4-MeC6H4SCOC6HS 4 78

a) Unless stated otherwise benzoy lations were conducted with 5 mmole of 3 and 12- 15 mmoles of phenol. alcohol or thiopheno l 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 e lemental analysi s. mp and o r supcrimpossab lc IR spectra with authentic samples. (d) Yie lds (uno ptimized re fer to TLC homogencous products.

Mechanistically, the benzoyl transfer occurs in stepwise manner, the first benzoyl group is transferred faster than the second group. Thi s is borne out in the reaction of amjnes as well as phenols, since we could detect the formation of mono benzoyl maleic hy­drazide 2 (R=C6Hs) as the intermediate by TLC com­parison with the authentic sample of 2. Subsequently ,

in a slower reaction the second benzoyl group is a lso transferred to complete the benzoylation process.

Conclusion In conclusion, we have reported the synthes is of

dibenzoate 3 from cheap ly available maleic hydrazide and studied its general potential in benzoyl transfer

MASHRAQUI et al.: 3,6- DlBENZOXYL- 1 ,2-PYRIDAZINE AS BENZO YL T RANSFERRING AGENT 933

... (1) 80- gooe

3 I DMF ... (2)

80- gooe

Q NH?

3/THF • ¢ + (C H3hCOK , RT .. . (3)

OH O-C-Ph II 0

67 % 7 %

Scheme III

3 I Anhyd 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, and - SH func tionaliti es . The scope of 3 as a be nzoy l carri e r is furth er e nhanced in view of its success ful applicatio n in C-benzoy lati o ns reac tion s as we ll. The benzoy l tran s fe r to amino -co mpounds occurs under neutra l conditi o ns, w hereas base cata lys is is required to pro mote the reac ti on with phe no lic and a lcoho li c substrates . C hemoselective N-benzoyl ati o n of aromatic amines can be selec ti ve ly acco mpli shed in aceti c ac id medium, w hil e in neutra l DMF so lvent more bas ic a li phatic amines undergo selec ti ve

benzoy lati o ns. It has been also poss ibl e to carry o ut e ither N- o r O -benzoy lati o n in aminopheno ls under spec ifi c co nditi ons . It is worthy to note th at the dibenzoate 3 is a c rys ta lline , stable so lid whi ch makes sto rage and handling easy with the added ad vantages of mild reac ti o n conditi ons and generally good yi e lds. Fi na ll y, dibenzoate 3 possesses tw ice the potenti a l as th e benzoyl transferrin g agent compared to o the r known acy l carri e rs, which shou ld make 3 as a po te nti a ll y attracti ve cho ice fo r many appli ca ti ons .

934 INDIAN J. CHEM .. SEC B. MA Y 2004

Experimental Section. The melting points were determined on a Gall enk­

amp melting-point apparatus and are uncorrected . IR spectral data were recorded on a Shimadzu FTIR -4200 Spectrophotometer as a KBr d isk; I H NMR pectra o n Va ri an EM-360-L, 60 MH z, and 300 MH z

Spectrometers with tetramethy l s il ane as the inte rna l standard ; and Mass Spectra on a GCMS-QP 5050A Shimadzu spectrophotometer.

Preparation of 3,6-dibenzoxyl-I ,2-pyridazine 3. To a well stirred mi xture of maleic hydrazide (J 2.0 g, 0 .1 0 mol) in dry pyridine (80 mL) was added dropwise benzoyl chlo ride (35.0 g, 0.25 mol) during 15-20 min

at ODe. The reaction temperature was mainta ined be­

tween 0-5°C for 2 hr and then at room temperature for

2 hr and fina ll y heated at 80-90DC for 30 min. T he re­action mixture was poured onto crushed ice. The pre­c ipitated solid was fi ltered, washed sequentially with cold di!. HCI , 5% aq. NaHC03 and water. Ai r drying of the solid foll owed by two crystalli zations fro m chloro­form gave colourl ess fi ne needles of dibenzoate 3 in

68% yield, mp 143-46°e. (Found : C, 67 .35; H , 3.82: N, 8.70. Calc. fo r Cl sHI 2N20~: C , 67.50; H, 3.75; N, 8.75%). MS : mlz 32 1 (M++J) , 320, 2 17, 105; IR (KB r), 3035, 1755, 1335, 1510, 1287 , 111 0. 890 cm·l; IH

NMR (300 MHz, CDCl3): 8 6 .8- 8. 1 (m, C H=CH and Ar- H); 13C NMR C DC I3): 8 164. 16, 160.64, 134.54, 130.65,128.82, 127.96, 125.05.

Typical procedure for benzoylation of amines. To a sol uti on of di benzoate 3 (1.6 g, 5 ml11olcs) in DMF ( 10 mL) was added freshly distilled aniline (1. 13 g, 11 mmoles). The reaction was hea ted at 80-

90DC for 3 hr whereby the reaction was judged to be complete by TLC ana lys is. The reaction was diluted wih water, the precipi tated solid filte red and washed sequentially with 5% HCI , 5% NaHC03 and water. The crude benzanilide was crysta lli zed from aq. alco­hol to g ive co lourless so lid of benzamide, mp 162-63°C (89% yie ld).

Typical procedure for benzoyla tion of phenols a nd alcohols. p-Bromophenol (1 .90 g, II mmoles) dibenzoate 3 ( 1.6 g, 5 ml11oles ) were dissolved in DMF (10 mL) containing 1.0 I11L of (C2 HShN. The reaction was heated at 75-80°C for 5 hr whereby the reaction was judged to be complete by TLC analysis. The reaction mixture was worked-up as desc ri bed above and the crude product crystall ized from aq. al­cohol to g ive colourl ess c rysta ls of p-bromophenyl benzoate (entry 3, Table II) in 92% y ie ld, mp 99-101°C, (liti S. mp 102°C) .

R eaction of 1,2-phenylene diamine with diben­zoate 3 . Formation of 2-phenyl benzi midazole. To a soluti on o f 3 (1.60 g, 5 mI11o les) in glac ial acetic ac id (15 mL) was added 1 ,2-pheny lene diamine (1.10 g. 10 mmo les). The reac ti on was heated at 80-90°C for 6 hI'. After a llowing the reaction to cool to RT the reac tion was poured over co ld water and bas ified with aq. Na2C03. T he precip itated so li d was f iltered , dried and subj ected to Si02 colum n chromatograph y. Eluti on w ih C HCI., gave 2-pheny l benzimidazole in 45 % y ie ld, mp 294-96°C (l it. mp 296-97°C) . Furthe r e lu ­tion with 5 % mcthanol in chl oroform e luted ou t dibenzamide in 20% y ie ld. Illp 30 I-305°C, dec. (lit l'J•

mp 306°C), dec . Reaction of 2-mercaptoaniline wi th dibenzoatc

3: Prepara tion of 2-phenyl benzothiazole. The reac­tion of dibenzoate 3 wl th 2- mercaptoan iline was car­ri ed out as describcd for I ,2-phcny lene d iamine. The work- up of th e react ion gave a crude product which on crystal I iza tio n from aq. alcoho l g ve colou rl ess crysta ls of 2-phe ny l benzoth iazole, mp 112-14"C (lit20

. mp j 14"C), y ie ld 36% . Selective N-benzoylation of aromatic a mine:

P,-eparation of benzylamide. T o a so lut ion of equ i­I110lar amoun t of an iline (1.02 g, I j mI11o les) and ben­zyl am ine ( 1.2 g, II I11I11o les) in g lacia l acet ic ac id ( 15 I11L) was added dibenzoate 3 ( 1.6 g, 5 mmo les) and the reaction mixture was heated at 80-90°C for 3 hr. The usual work-up o f the reaction, followed by crys·· ta lli zation of the crude product gave benzamide in 67 % y ie ld. The N-benzoyl product derived f rom ben ­zy l am ine coul d not be detected by TLC anal ysi s.

Selective N-benzoylation of aliphatic amine: Preparation of benzamide. To a solution of anil ine and benzyl amine ( I I mmoles each) in DMF ( 15 mL) was added dibenzoate 3 (1 .60 g, 5 mmoles) and the reaction was heated at 80-90"C for 3 hr. The usual work-up of the react ion, fo ll owed by c rystallization of the crude product from I: I ethyl acetate-petroleum ether gave N-benzoy l deri vati ve of ben zy l amine, mp 104-07°e.

C hemoselective O-benzoylation of p-amino­phenol. 4-Aminophenol ( 1.l6 g, II mmoles) wa~

added at RT to a sol ution of dry THF (15 mL) con­taining an excess of potass ium I-butoxide (1.94 g, 15 mmo les). After the reaction had been stirred at RT fo r 10 min , it was cooled in ice and diben zoate 3 ( 1.60 g, 5 mmo les) was added all at once. The reac tion was then put in an oil-ba th kept at 80-90°C for 4 hr. The usua l work-up of the reaction afforded c rude product whi ch was subjected to SiOl column chro matog raphi c

MASHRAQUI el 01.: 3,6-DIBENZOXYL- I ,2-PYRIDAZINE AS BENZOYL TRANSFERRING AGENT 935

purification. E lutio n with 1:4 ethy acetate -pet. ether first e luted out 4-hydroxybenzamide, mp. 2 13- 14°C in 7% yie ld . Further e luti on with the same solvent system gave the desired O-benzoy l product , 4-amino phenyl benzoate, mp 213-14°C, as a major product in 65 % yield .

C-Acylatioll of r esorcinol: Preparation of r es­benzophenonc. An intimate mixture of d ibenzoate 3 (3.20 g, 10 mIlloles), resorc inol ( 1.65 g, 15 mmoles) and fresh ly fused ZnCl2 (5 .0 g) was healed in an oil­bath at 120nC for 7 hr. The reaction mixture, after cooling to RT was decomposed with di!. HCI and ex­tracted with ethyl acetate. The o rganic extract was dried over anhyd . a2S0~, concentrated and the crude product purifi ed over Si02 column chromatography. Eluti on with I: 1 ethy l acetate-petroleum e ther gave the required product, resbenzophenone in 35% yield , mp 139-41 °C (I it21. mp 142-44°C ).

C-Acylation of acetophenone: P.·eparation of dibenzoyl methane. To a solut ion of acetophenone ( 1.16 g, 10 mmoles) in anhyd . THF was added potassium !-butoxide ( l.Og) at One. The react ion was stirred at thi s temperature for 10 min and then dibenzoate 3 ( 1.6 g, 5 mmoles) was added all al o nce. The reaction was gradua ll y a llowed to warm up to RT and then kept overnight. The deep ye llow react ion mixture was acidified with di!. HCI and ex tracted with CH2Cb, washed wih wate r and dried over anhyd.

a2S04. The organic extract was stripped off the solvent by distillation and the crude oi ly product purified by Si02 column chromatography (1:4 ethy l acetate-pet. ether) to obtain dibenzoyl methane in 34% yield, mp 80-82°C, (lit22 mp 82°C).

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