Indian Journal of Chemistry Vol. 40B, January 200 I, pp. 5-10

Synthesis of macrocycles derived from vanillin and isovanillin

Sukeerthi Kumar & Sabir H Mashraqui*

Department of Chemistry, University of Mumbai, Vidyanagari, Santacruz (E)

Mumbai 400098, India.

E-mail : shmashraqui @yahoo.com

Received 26 April 1999; accepted (revised) II lilly 2000

Readily available van illin 1 and isovanillin 2 have been exploited for the first time to synthesise thia and aza-bridged macroeyclcs. Utilising a co mmon approach, 1 and 2 are first converted into the corresponding key intermediates, dicholoro compounds 5 and 10. Cyclocondensations of these molecules wi th Na2S under high di lution provide thia-bridged macroeycles 6 and 11 and with p-toluenesulphonamide under basic condition, the aza-bridged macrocyc les 7 and 12, respectively arc obtained. The structu res arc fully supported by elemental analysis, mass and hi gh resolution NMR data. Variable NMR measurements on 6 and 11 suggest that these macrocyc les are conformationally mobi le even at -55 °C on the NMR time sca le.

Since the di scovery of crown ethers by Pederson I, there has been synthesized a phenomenal number of crown ethers and macrocyclic systems to study relationship between their structures and physical properties. Consequently, during the past 4 decades, a vast body of literatu re has accumulated on wide ranging app lications of crown ethers in different areas of chemistry which include metal ion complexation, host guest interactions, phase transfer catalysis, biosensors and enzyme models2.

We recently reported the synthes is of a number of polyoxa-, oxathi a- and oxaaza-macrocycles using readily accessible building blocks, bisphenol-A and bisnaphthol 3. Literature revealed, to our surpri se, that commercially readi ly avai lable vanillin 1 and isovanillin 2, despite being endowed with suitable reactive functionalities have not hitherto been exploited in the synthesis of macrocycles. In context to our interest in macrocycles, we now report fo r the first time application of vanillin 1 and isovanillin 2 towards the synthesis of new macrocyclic systems.The strategy consists of first forming a single bridge by self coupling of 1 or 2 via alkylations at their phenolic function with a su itable bisalkylating agent to form the corresponding dimeric aldehydes . The bis-aldehydes in turn can be transformed into the reactive benzyl halides to be used for the final macrocyclization by reacting wi th suitable bisnucleophilic sulphur and nitrogen reagents to form thi a- and aza-bridged macrocycles .

Macrocycles derived from vanillin (Scheme I). In persuit of the above strategy, vanillin 1 was first

reacted with diethylene glycol ditosylate~ (2: 1 ratio) under K2C03-DMF condition to afford the required bis-aldehyde 3 as a crystalline solid in 58 % yield. Reduction of 3 with NaBH4 in dry methanol produced the corresponding bis-diol 4 (85 % yield) which on treatment with an excess of SOCl2 in dry ch loroform gave dichloro compound 5 as a colourless solid, mp 94-96 °C in 56 % yield .

With dichloro compound 5 in hand , the thia macrocyclization with Na2S.9H20 was carri ed out in benzene-ethanol solvent system under high di lut ion cond ition. The crude product obtained upon work up was purified by Si02 column chromatography to result in the isolat ion of a single low polar crystalline solid, mp 96-98 °C in 29 % yield. The structure 6 was assigned to thi s compound on the basis of elemental analysis and spectral data. The compound (C2oH240 SS) showed M+ at mlz 376 and its IH NMR spectrum (200 MHz) revealed a combined signal at 8 3.7 (5H) due to both the -OCH3 and PhCH2S- protons on account of accidentally identical chemical shi fts for these protons. Triplets centered at 8 4.2 and 3.8 (J = 5Hz each) can be assigned to PhOClhCH2- and PhOCH 2CHr protons, respectively . The aromatic H-5 and H-6 appeared each as a doublet at 8 6.4 and 86.3 (J = 8 Hz each) and the H-3 is seen as a singlet at 8 6.6. These spectral data fully support I: 1 macroeycl ic structure 6 for this compound.

In order to synthesize the azabridged macrocycle, dichloride 5 was allowed to react with an equivalent amount of p-toluenesulphonamide in K2C0 3 - DMF

6 INDIAN J CHEM. SEC B. JANUARY 2001

11.111 . ----3

6

7

4.X=OH 5 . X-CI

Ts = p- CH3-CSH4-S02

Reagents: I) ( TsOCH2CHz)20 I Anhyd K2C0:J1 80-8SoC I Dry DMF I 40hr.

II ) NaBH.1 Dry MeOH I R.T / 4hr. III) SOCIzl Dry CHCI, 160-6SoC 16hr.

IV) Na2S. 9H20 I C6H6-EtOH 160-6SoC I 14hr.

V) p-CHJ-C~-S02-NH21 Anhyd K2COJ I Dry DMF I 80-90oC I 18hr.

Scheme I

system. Purification of the crude product over Si02 column chromatography gave a co lourless, crystalline solid , mp J 62-65 DC. Elemental ana lysis (C27 H3I N07S) together with the presence of M+ at mlz 513 suggested 1: 1 macrocyclic structure 7 for this compound. In support of the structure 7, its IH NMR (300 M Hz) showed singlets at 8 2.48 and 4.26 for ArCH) and ArCH2N< protons, respecti vely. Interestingly, protons belonging to the methoxyl and bridged ArOCH2CHr O- appeared together in the form of a single resonance (a sing let) at 8 3.70 on account of accidentally identical chemical shi fts; the absence of coupling between the four ArOCH2CH20-protons though surprising is not without precedences. The aromatic H-5 and H-6 protons of the phenoxy 1 ring appear each as a doublet at 8 6.5 and 6.27 (J = 6 Hz) , respectively and the H-3 is found as a singlet at 8 6.68. The aromatic protons of p-toluene-sulphonamide ring form a double doublet at 8 7.38

and 7.78 (J = 6 Hz) . These data fully endorse structure 7 fo r this compound.

Macrocycles derived from isovanillin (Scheme II) . The same sequence of reactions as discussed above for the macrocycles 6 and 7 was followed for developing macrocycles from isovanillin 2. Accordingly, isovanillin 2 was first converted into bis-aldehyde 8 by reacting with diethylene glycol ditosylate. Reduction of 8 by NaBH4 followed by trea tment of the resulting diol 9 with SOC12 in chloroform provided the dichloride 10 as a crystalline solid . Finally, the macrocyclization of 10 with Na2S.9H20 in benzene-ethanol afforded after work-up and Si02 column chromatography, a colourless crystalline solid , mp 104-05 DC in 13 % yield .

The compound showed M+ at m/z 376 and its elemental analys is (C2oH240 SS) suggested I: I macrocyclic structure 11 fo r this compound . In conformity with structure 11 , its IH NMR spectrum

KUMA R el al.: SY NTHESIS OF MACROCYCLES 7

()OCH:! ~ OHC~OH

2

11

9 , X ~ OH 10 , X : CI

12

Reagents: As described for Scheme-I

Scheme II

(200 MH z) revealed singlets for -OCH3 and -SCH2 at 8 3.88 and 3.42, respecti vely whereas A rOCH2CH20-protons appeared as a triplets each at 8 4.36 and 3.84 (J = 5 Hz each). The aromatic protons H-3 and H-4 are di scernible as a doublet each at 8 6.87 and 7.06, respecti vely (J = 7 Hz each) and the H-6 is found as a singlet at 86.97 .

The cycl izati on of dichloride 10 with p-toluenesulphonamide was performed under the conditions described fo r 7. Chromatographic pu ri fication of the crude gave a colourless crystalline solid , m,p, 126-28 °C in 17 .5 % yield. The I: 1 macrocyc lic structure 12 was readily apparent from the appearance of M+ at mlz 51 3 and its NMR revealed singlets at 8 2.46, 3.83 and 4. 14 ass ingnable to ArCH3, A r-O-CH3 and >N-CH2' respectively. For the bridge A rOCH2CH 20- protons, two triplets are seen at 8 3.78 and 4.30 (J = 6Hz each).The aromati c H-3 and H-4 appeared as an overlapping double doublets between 8 6.72 to 6.82 , whereas H-6 can be located as a singlet at 8 6.9. The aromatic protons

11a 11b

Figure- I

belonging to the tosy l group appeared as a doublet each (J = 7 Hz) at 8 7.33 and 7.77.

It may be noted that the two aromati c ri ngs in macrocycle 6 are locked essentia ll y in (near) parallel oreintation by virtue of their pw·a-bridgi ng6. Thus, on account of the ring anisotropic effect, the aromatic protons (8 6.3 to 6.60) as wel l as the methoxyl protons (8 3.70) in macrocycle 6 ex peri ence upfield shift in contrast to its meta-bridged analog 11 which shows aromati c protons at re latively lower fie ld in the

8 INDIAN J CHEM. SEC B. JANUARY 2001

region between 8 6.87 to 7.06 and the methoxyl protons at 8 3.88. For macrocycle 11, the two aromatic rings are probably held in the more stable anti conformat ion lla rather than the syn form lIb (Figure 1) to avoid energeticall y unfavourable 1t-1t repulsion. Such anti-orientation of bridged aromatic nuclei is of common occurrence in lIl-cyclophanes.6.7

In both vanillin and isovani llin seri es, 1: 1 cyclocondensation seems to be the prefeITed mode of cycli zati on to form only monothia- (6 and 11) and monoaza macrocycles (7 and 12). No 2:2 condensed marcocycles arising out of condensation of 2 molecul es of dichlorides 5 or 10 with 2 equivalents of either Na2S or p-toluenesulphonamide could be isolated or detected in the crude reaction mixtures. Evidently, the diethyleneoxy bridge is long and flexible enough to allow the penultimate intermediate to adopt a relat ively st rain free fo lded conformation to faci litate I: 1 macrocycliza tion. Indeed, the strain free nature of macrocyc!es 6, 7, 11 and 12 is ev ident from the fact that these molecules are undergoi ng facil e bridge as well as ring rotations as indicated by the appearance of sharp singlets assoc iated with benzylic and methoxy l protons (average conformation) on the NMR time scale at room temperature. Variable temperature NM R measurements carried out on thi a-bridged macrocycles 6 and 11 showed no change in the spectra from room temperature down to -55 DC, thereby implying very low energy barrier to conformational flipping processes8. Experimental Section

Melting points were determined using apparatus employing electrical heating , and are uncorrected. IR spectra were recorded in KBr pellet on a Shimadzu FrlR -4200. IH NMR spectra were scanned on a Varian EM-360L at 60 MHz or Varian VR-300s at 200 MHz with TMS as the intern al standard . TLC were carried out on manually coated silica plates (3 x 10 cm) using Acme TLC silica gel.

Preparation of bis-aldehyde 3. Diethyleneglycol ditosylate (8.28 g , 20 mmo!es), vanillin 1 (6.08 g, 40 mmoles) and anhydrous K2C03 (5.42 g, 40 mmoles) were added to dry DMF (100 mL). The reaction mixture was stirred and heated at 80-90 DC for 40 hr. The reac tion mixture was diluted with cold water and the precipitated so lid fi ltered, washed with water and dried in open air. The solid was rec rystalli sed from eth anol to give co lourless crystals of 3 in 58% yi eld (4 .34 g) , mp1 20-22 °C (Found: C, 64.56 ; H, 5.38. C2oHn 0 7 requ ires C, 64.17 ; H, 5.88%) ; lR (KBr):

3000,1680, 1580, 1260,1140,1020, 875, 725 cm-I; IH NMR (CDCl]): 8 4.1(s, 6H, -OCH3), 4.2 (t, 4H, 1=5 Hz, Ph-OCHr CHr O), 4.45 (t, 4H, 1=5 Hz, Ph-O-CHr CH2-) 7.0- 7.7 (m, 6H, Ar-H) and 10.0 (s, 2H, -CHO).

Preparation of bis-diol 4. Bis-aldehyde 3 (2 .5 g, 6.68 mmoles) in dry methano l (100 mL) was st irred and cooled to 10-15DC. NaBH4 (1.84 g) was added portion wise over a period of 1 hr. After addition was completed, the reaction mi xture was stirred at room temperature fo r 4 hr. The methanol was boiled off and the residual oil was treated with cold water to produce a solid. Crystalli zation from ethy l (Icetate afforded whi te crystals of 4 in 85% yield (2. 15 g) , mp 104-08 DC (Fou nd: C, 63.98; H, 6.42. C2oH;'60 7 requires C, 63.49 ; H, 6.88%); IR(KBr): 3450,3000,1510,1420, 1260, 11 20, 1100, 800 cm-I; IH NMR (CDCI3): 84. 1 (s, 6H, -OeI·h), 4.2 (t, 4H, J= 5 Hz, PhO -CH 2-CH2- ), 4.4 (t, 4H, 1= 5 Hz, Ph-O- CHrCHr ) , 4.7 (s,6 H, Ph-CH2-0H) and 6.9-7.3 (m, GH, Ar-H).

Preparation of dichloride S. Diol 4 ( 1.89 g, 5 mmoles) was dissolved in dry chloroform (50 mL) and to thi s SOCI2 (1.5 mL) was added at room temperature. The reaction was then refl uxed for 6 hr. The reaction mi xture was concentrated to give an oily product which solidified on cooling. Crystalli sa ti on fro m petroleum ether (60-80 DC fract ion) provided white crystals of 5 in 56% yield (1.1 5 g), mp 94-95 °C (Found: C, 57.35 ; H, 5.92 ; CI , 17 .42 . C2oH240 sCI2 requires C, 57.83 ; H, 5.78 ; CI, 17. 11 %); IR (KBr): 3000, 1600,1520,1280, 1240,11 20, 101 5,700 cm- I; IH NMR (CDCl3) 8 4. 1 (s, 6H, -OCH3), 4.2 (t, 4H, 1= 5 Hz, PhO -CH 2-CHr ), 4.5 (t, 4H, 1 = 5 Hz, Ph-O- CHrCHr ), 4.8 (s, 4H, -CH2-CI ) and 6.9-7.3 (m, 6H , Ar-H).

Synthesis of thia-bridged rnauocycles 6. Dichloride 5 (0.828 g, 2 mmoles), was di sso lved in benzene ( 150mL) and added dropwise to a stirred solution of I: I ethanol-benzene (20Cl mL) containing Na2S.9H 20 (0.75 g) and cetyl tri methyl ammoniulll bromide(25mg) as the phase transfer catalyst at 60-65DC over a period of 6 hr. The reaction was refluxed further for 8 hr. After cooling to room temperature, the reaction mixture was fi ltered over a pad of celite. The crude product obtained upon concentration was subjected to SiOl chromatography (petrol eum ether-ethyl acetate ; 85: 15 v/v as eluen t) and further recrystallised (petroleum ether-ethy l acetate) to provide wh ite crystals of 6, mp 96-98 "c in 29% yield (0.2 18 g).(Found: C, 63.42 ; H, 6.72 ; S, 8.2 1. Clol-bOsS requires C, 63.83 ; H, 6.38; S, 8.5 1 %); IR

KUMAR el aJ.: SYNTHESIS OF MACROCYCLES 9

(KBr): 3000, 1610, 1600, 1520, 1470, 1460, 1420, 1340, 1260, 1230, 1160, 1140, 1000, 1040, 970, 850, 810 cm- I; IH NMR (CDCI3) as described in the text; MS: m Iz 376(100%), 281, 239, 209,195,137,121,77 and 65.

Synthesis of aza-bridged macrocycles 7. A solution of dichloride 5 (0.828 g, 2 mmoles) and p-toluene sulphonamide (0.342 g, 2 mmoles) in dry DMF (70 mL) was added to a stirred solution of DMF (30 mL) containing anhydrous K2C03 (1.5 g) at 80 to 90°C over a period of 8 hr. The reaction was further heated for 10 hr, then diluted with cold water and extracted with methylene chloride. The methylene chloride extract was washed with water and dried over Na2S04. The semisolid residue obtained upon concentration was subjected to Si02 column chromatgraphy (C HCI3 as eluent) and the solid obtained was recrystallised from ethanol to provide white crystals of 7 in 28 % yield (0.293 g), mp 162-64 °C (Found: C, 63.48 ; H, 6.24 ; N, 2.53 ; S, 6.56 . C27H3I0 7NS requires C, 63.16 ; H, 6.04 ; N, 2.73 ; S, 6.24 %) ; IR (KBr): 3000, , 1590, 1520, 1460, 1440, 1420, 1260, 1240, 1220, 1140, 1120, 1020, 1000, 800 cm- I; IH NMR (CDCI3 ; 300 MHz) as described in the text; MS: m Iz 513 (100%), 358, 357, 137,9 1 and 28.

Preparation of bis-aldehyde 8. Using the method described for 3 , isovanillin 2 (3 .04 g, 20 mmoles) was reacted with diethylene glycol ditosylate (4.14 g, 10 mmoles) in the presence of anhydrous K2C03 (2.76 g, 20 mmoles) in dry DMF (25 mL).The solid obtained upon work-up was crystalli sed from ethanol to obtain white crystals in 84% yield (3.15 g), mp 11 8-20 °C (Fou nd: C, 64.55 ; H, 5 .38 . C2oHn 0 7 requires C,64.17; H,5 .88%); lR(KBr): 2900,1700,1600, 1500, 1440, 1350, 1260, 1150, 1110, 800 cm- I ; IH NMR

(C DCl3): 84.0 (s, 6H, -OCH3) , 4.1 (t, 4H, J = 5 Hz, PhO -CHr CH2-), 4.3 (t, 4H, J = 5 Hz, Ph-O- CHr CH2-) , 6.9-7.7 (m, 61-1, Ar-H) and 9.73 (s, 21-1, -CHO).

Preparation of bis-diol 9. As described for 4, bis-aldehyde 8 (4.114 g) was reduced using NaBI-I4 (3 .5 g) in dry methanol. The solid obtained upon work-up was crysta lli sed from ethy l acetate to provide white crystals of 9 in 58% yie ld (2.4 g), mp 68-70 °C (Found: C, 63.88 ; H, 6.94. C201-12607 requires C, 63.49 ; 1-1, 6.88%) ; IR(KBr): 3400, 3000, 1600, 1510, 1420, J280, 1140, 1110, 800 cm- I; I H NMR (CDCl3 + DMSO-d6) : 8 3.66 (s, 6H, -OCH3) , 8 3.7 (t, 4H, J = 5 Hz, PhO -CHr Cfh-) , 3.9 (t, 41-1, J = 5 Hz,

Ph-O- CH2-CI-I 2-), 4.0 (s, 2H, -OH ), 4.43 (s, 4H, -CH20H) and 6.8-7.2 (m, 61-1, Ar-H).

Preparation of dichloride 10. Dichloride 10 was prepared from diol 9 (1.89 g. 5 mmoles) using the same conditions described for 5. The solid obtained upon work-up was crystallised from diisopropyl ether to provide white crystals of lOin 58% yield (1.2 g) , mp 84-86 °C (Found: C, 57.42 ; H, 5.35 ; CI , 17.23 . C2oH240 sCI2 requires C, 57.83 ; H, 5.78 ; CI , 17.11 %); IR (KBr): 3000, 1600, 1510, 1450, 1420, 1280, 1240, 1120, 1020, 840, 700, 610 cm- I; 11-1

NMR(CDCb): 8 3.6 (s, 61-1, -OCH3), 3.8 (t, 41-1, J = 5 Hz, PhO -CHr CI-I 2-), 4.0 (t, 4H, J = 5 Hz, Ph-O-C1-h-CH2-), 4.3 (s, 41-1, -CH2-CI) and 6.8-7.1(m, 6H , Ar-Hl.

Synthesis of thia-bridged macrocycle 11 . The compound 11 was prepared by the cyc lisation of dichloride 10 (0.828 g, 2 mmoles) with Na2S.9H20 (0.75 g) in benzene-ethanol solvent system under the same condition as described for 6 . After work-up, the crude product was subjected to Si02 column chromatograpy (petroleum ether-CHCl3; 75:25 v/v as eluent).The solid obtained was recrystallised from ethanol to provide white crystals of 11 in 12.6% yield (0.095 g) , mp 104-05°C (Found: C, 63.42 ; H, 6.09 ; S, 8.63 . C2oH240 SS requires C, 63.83 ; H, 6.38 ; S, 8.51 %) ; IR (KBr): 3000, 2950, 1600, 1510, 1460, 1440, 1420, 1370, 1340, 1270, 1220, 1160, 11 40, 1090, 1040, 910, 820 cm- I; 11-1 NMR (200 MHz; CDCI3) as described in the text; MS: 376(100%), 137 and 28.

Synthesis of aza-bridged macrocycles 12. For the synthesis of 12, cyclisation of 10 (0 .828g, 2 mmol es) with p-toluene sulphonamide (0.342 g , 2 mmoles) was carried out as described for 7 in dry DMF (160 mL) using anhydrous K2C03 (1.38 g, 10 mmoles) as the base. The crude product obtained after work-up was purified by Si02 column chromatography (CHCI 3 as eluent) and recrystallised from ethanol to provide white crystals of 12 in 17.5% yield (0.18 g) , mp 126-28 °C (Found: C, 63.58 ; H, 6.24 ; N, 2.43 ; S, 6.04 . C27H3I 0 7NS requires C, 63.16; H, 6.04; N, 2.73 ; S, 6.24%) ; IR(KBr): 3000, 2900, 16 10, 1590, 1520, 1440, 1350, 1330, 1300, 1260, 1230, 1160, 1140, 1120, 1100,1020, 910,810,770 cm- I; IH NMR (200 Ml-lz; CDCb) as described in the text. MS : mlz 51 3 (100%),460,376,358,33 1,281,227, 195, 163,137 and 79 .

10 INDIAN J CHEM. SEC B, JANUARY 2001

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