HETEROCYCLES

Paper | Special issue | Vol. 90, No. 2, 2015, pp. 1135-1141
Received, 11th July, 2014, Accepted, 29th July, 2014, Published online, 13th August, 2014.
DOI: 10.3987/COM-14-S(S)82

■ Oxidative 1,1’-Coupling of Highly Alkylated 2-Methoxycarbonylazulenes

Ryszard Ostaszewski and Hans-Jürgen Hansen*

Institute of Organic Chemistry, University of Zürich, Winterthurerstrasse 190, CH-8057 Zürich, Switzerland

Abstract

The oxidation of highly alkylated methyl azulene-2-carboxylates 1b – 1d and a dimethyl azulene-1,2-dicarboxylate 1a with TEMPO (2,2,6,6-tetramethyl-piperidine-1-oxyl) in the presence of Et2O·BF3 ((diethyloxonio)trifluoroborate) in benzene at 5 °C leads in moderate yield to the corresponding 1,1’-biazulene-carboxylates 2a – 2d (Table 1).

INTRODUCTION
As for arene couplings,1 there are principally two procedures which can be applied for the synthesis of 1,1’-biazulenes, i.e. the classical Ullmann coupling2 or its modern transition metal variants (see, e.g.3) as well as oxidative coupling reactions (see, e.g.4-6). The exposure to air of guaiazulene, when absorbed on silica gel, is already sufficient to form 3,3’-biguaiazulene (5,5'-diisopropyl-3,3',8,8'-tetramethyl-1,1'-biazulene) as main product beside higher oxidation products,7 and benzo[a]azulene with MnO2-C (C = activated carbon) as catalyst8 as well as azuleno[1,2-b]thiophene with N-iodosuccinimide (NIS) as oxidant9 are converted to the corresponding biazulenes in good yields. In general, higher alkylated azulenes combine readily in their radical cation state to the corresponding biazulenium forms, which by loss of two protons yield biazulenes.10 With the exception of ethyl 2-aminoazulene-1-carboxylate,10,11 which indeed carries a strong π-donor group next to the carboxy group, it seems that the oxidative coupling of azulenes with electron-acceptor substituents at the 5-membered ring such as alkoxycarbonyl groups at C(2) or C(1) and C(2) has not been tried.12-14 The AM1 calculated structure of such kind of 1,1’-biazulene-2,2’-dicarboxylate is displayed in Figure 1. Most interesting is the fact that the energetically relaxed structure of it possesses almost perpendicularly oriented azulene halves with MeO of the ester groups in syn-orientation and outward position. The distance of their O-atoms amounts to 426 pm, i.e., a distance for possibly further interactions. In the following, we describe our experiment to synthesize the envisaged 1,1’-biazulene-2,2’-dicarboxylates.

RESULTS AND DISCUSSION
We investigated the oxidative coupling of three methyl azulene-2-carboxylates 1b – 1d and dimethyl azulene-1,2-dicarboxylate 1a (Figure 2). Azulene-1,2-dicarboxylates are by-products of Hafner’s heptalene synthesis starting with azulenes and dimethyl acetylenedicarboxylate.17,18 Treatment of the azulene-1,2-dicarboxylates with phosphoric acid (see19,20) leads to selective demethoxycarbonylation at C(1).21 We had 1a and the corresponding dimethyl dicarboxylates for 1b – 1d from our former work on the thermal reaction of azulenes and dimethyl acetylenedicarboxylate at hand.23,24

We chose 1a as model substrate for our screening experiments of its oxidative 1,1’-didehydrodimerization (Scheme 2). As a result, we found that typical oxidants for inter- and intramolecular benzene coupling reactions such as CoF3, Th(OC(O)CF3)3, RuO2, VOX3 (X = F, Cl), PhI(OAc)2/Et2O·BF3 or PhI(OC(O)CF3)2/Et2O·BF3, and DDQ in diverse solvents gave no didehydro-dimer 2a at all.

Finally, we checked the oxidant system PhI(OAc)2/Et2O·BF3 again, but this time in the presence of 1 eq. of FeCl3 in benzene at 5 °C and, indeed, for the first time, we found 15% of 2a in the reaction mixture. A further experiment showed that the catalytic system worked also without PhI(OAc)2, thus resulting in the formation of 2a in an almost equal yield of 12%. On the other hand, FeCl3 alone, also when adsorbed on silica gel, did not lead to the formation of 2a in benzene. In view of the fact that Et2O·BF3 seemed to play the role of an enhancer for the 1,1’-coupling reaction 1a → 2a with oxidants such as FeCl3, we looked for another organic oxidant and selected 2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPO).25 Again, we observed that TEMPO alone in benzene does not cause the 1,1’-coupling of 1a. However, in the presence of Et2O·BF3, we found 12% of 2a. Following experiments with TEMPO and varying amounts of Et2O·BF3 led with all azulenecarboxylates 1a – 1d to the corresponding biazulenes 2a – 2d. The experimental results are listed in Table 1.26,27
All 4 dimers could be obtained in crystalline form. But none of the crystals of 2a – 2d were suitable for an X-ray crystal structure analysis. The elemental analysis indicated that three of the crystallized dimers contained water, which could not be removed by drying in vacuo, in a molar ratio of 1 : 1 (2a, 2d) or 0.5 : 1 (2c). Nevertheless, the MS spectra of all 4 dimers showed the correct molecular mass as well as the expected 1H- and the related 13C-NMR spectra.
Most interesting is the observation that Et2O·BF3 is a necessary co-catalyst (enhancer) for the oxidants TEMPO or FeCl3. We suppose that in the loosely coordinating solvent benzene Et2O·BF3 transfers BF3 to the oxyl O-atom of TEMPO and that it is this species, which snatches an electron from the azulene π-skeleton, thus leading to 1-((trifluoroboryl)oxy)-2,2,6,6-tetramethylpiperidine anion and the corres-ponding azulenium ion, which then dimerizes. As a result, biazulenes 2 are formed, accompanied by 2 eq. HF and 2 eq. 1-((difluoroboryl)oxy)-2,2,6,6-tetramethylpiperidine. Obviously, FeCl3 and Et2O·BF3 in benzene co-operates in a similar manner, thus leading to FeCl2+ as crucial oxidant for the azulene-2-carboxylates 1.

EXPERRIMENTAL
General: See.28,29
Oxidative 1,1’-coupling of the methyl azulenecarboxylates 1a – 1d. – TEMPO (0.312 g, 2.0 mmol) was dissolved in benzene (5 mL). The solution was cooled to 5 °C, and the respective azulenecarboxylate 1 (1.0 mmol), dissolved in benzene (5 mL), was added under stirring and an N2 atmosphere. Then, Et2O·BF3 (0.284 g, 2.0 mmol) was put in drop by drop. After 1 h stirring at 5 °C, the cooling bath was removed and stirring was continued for 3 h. The reaction was quenched by addition of a saturated aqueous Na2CO3 solution (15 mL). The phases were separated and the water phase extracted 3 times with AcOEt (3 x 15 mL). The combined organic phases were washed with water (2 x 10 mL) and dried (MgSO4). The crude product, left after evaporation, was further dried in vacuo (0.06 Torr, 1 h) in order to remove non-reacted TEMPO together with its respective amine. Non-reacted azulenecarboxylates and other by-products were removed by flash chromatography (Et2O/AcOEt) on silica gel. Yields of the pure didehydro-dimers 2 are listed in Table 1.
Experiments with the other oxidants were performed in the same manner.
Data of tetramethyl 4,4',6,6',8,8'-hexamethyl-[1,1'-biazulene]-2,2',3,3'-tetracarboxylate (2a): mp 207.1–208.0 °C (Et2O/AcOEt). Rf (hexane/AcOEt 1:1) 0.46. IR (CHCl3): 1720s (C=O). 1H-NMR (300 MHz, CDCl3): 7.11 (s, H–C(5,5’)); 6.96 (s, H–C(7,7’)); 3.92 (s, CH3OOC–C(3,3’)); 3.44 (s, CH3OOC–C(2,2’)); 2.90 (s, CH3–C(4,4’)); 2.56 (s, CH3–C(6,6’)); 2.15 (s, CH3–C(8,8’)). 1H-NOE (CDCl3): 2.15 ↔ 6.96; 2.56 ↔ 6.96 + 7.11; 2.90 ↔ 3.92 + 7.11. 13C-NMR (75 MHz, CDCl3): 170.04, 166.37 (O=C–C(2,2’,3,3’)); 152.89, 150.11, 149.65, 136.33, 134.90, 132.66, 126.88, 121.27 (C(1,1’,3a,3’a – 8a,8’a)); 52.20, 51.39 (CH3OOC–C(2,2’,3,3’)); 28.45, 28.07, 27.22 (CH3–C(4,4’,6,6’,8’,8’)). EI-MS (570.64): 571 (M+, 100), 539 ([M – CH3O]+, 74). The elemental analysis indicated the presence of one H2O in the crystals of 2a (C34H34O8 + H2O), 588.65): Anal. Calcd for C34H34O6: C 69.37, H 6.16. Found: C 69.29, H 6.34.
Data of dimethyl 3,3',4,4',6,6',8,8'-octamethyl-[1,1'-biazulene]-2,2'-dicarboxylate (2b): mp 205.3–206.2 °C (Et2O/hexane). Rf (hexane/AcOEt 4:1) 0.22. IR (CHCl3): 1714s (C=O). 1H-NMR (300 MHz, CDCl3): 7.77 (s, 2H, H–C(5,5’)); 6.64 (s, 2H, H–(7,7’)); 3.41 (s, CH3COO–C(2,2’)); 3.02 (s, 6H, CH3–C(3)); 2.87 (s, 6H, CH3–C(4,4’)); 2.44 (s, 6H, CH3–C(6)); 2.03 (s, 6H, CH3–C(8,8’)). 13C-NMR (75 MHz, CDCl3): 169.00 (O=C–C(2,2’); 51.21 (CH3OOC–C(2,2’)); 28.99, 28.20, 27.62, 17.56 (CH3–C(3,3’,4,4’,6,6’,8,8’)). EI-MS (482.62): 482 (M+, 100). Anal. Calcd for C32H34O4: C 79.64, H 7.10. Found C 79.51, H 7.48.
Data of dimethyl 4,4',6,6',8,8'-hexamethyl-[1,1'-biazulene]-2,2'-dicarboxylate (2c): mp 227.0–227.5 °C (AcOEt/hexane). Rf (hexane/Et2O 1:1) 0.31. IR (CHCl3): 1715s. 1H-NMR (300 MHz, CDCl3): 7.90 (H–C(3,3’)); 6.97 (s, H–C(5,5’)); 6.79 (s, H–(7,7’)); 3.58 (s, CH3COO–C(2,2’)); 2.91 (s, CH3–C(4,4’)); 2.53 (s, CH3–C(6,6’)); 2.03 (s, CH3–C(8,8’)). 1H-NOE (CDCl3): 7.90 ↔ 2.91, 3.58; 2.91 ↔ 7.90, 6.97; 2.53 ↔ 6.79; 2.03 ↔ 6.79. 13C-NMR (75 MHz, CDCl3): 166.40 (C=O, C(2,2’)); 130.67, 127.57, 117.66 (C(3,3’,5,5’,7,7’)): 51.20 (CH3OOC–C(2,2’)); 28.74, 27.24, 25.67 (CH3–C(4,4’,6,6’,8,8’)). CI-MS (454.57): 455 (M+), 423 ([M – CH3OH]+, 61). The elemental analysis indicated the presence of 0.5 H2O in the crystals of 2a (C60H60O8 + H2O), 927.15): Anal. Calcd for C60H60O8: C 77.73, H 6.74. Found: C 77.80, H 6.38.
Data of dimethyl 6,6'-di(tert-butyl)-3,3',4,4',8,8'-hexamethyl-[1,1'-biazulene]-2,2-dicarboxylate (2d): mp 120.0–122.0 °C (AcOEt/hexane). Rf (hexane/AcOEt 1:1) 0.23. IR (CHCl3): 1712s. 1H-NMR (300 MHz, CDCl3): 7.00 (s, H–C(5,5’)); 6.86 (s, H–C(7,7’)); 3.42 (s, CH3OOC–C(2,2’)); 3.06 (s, CH3–C(4,4’)); 2.86 (s, CH3–C(3,3’)); 2.09 (s, CH3–C(8)); 1.38 (s, (CH3)3–C(6,6’)). 1H-NOE (CDCl3): 2.86 ↔ 3.06, 3.42; 7.00 ↔ 3.06, 1.38; 6.86 ↔ 2.09, 1.38. 13C-NMR (75 MHz, CDCl3): 169.09 (C=O, C(2,2’)); 125.54, 125.33 (C(5,5’,7,7’)); 51.19 (CH3OOC–C(2,2’)); 38.20 ((CH3)3C–C(6,6’)); 29.55, 28.27, 27.60 (CH3–C(3,3’,4,4’,8,8’)); 17.48 ((CH3)3C–C(6,6’)). EI-MS (566.86): 566 (M+, 100). The elemental analysis indicated the presence of one H2O in the crystals of 2d (C38H46O8 + H2O), 584.88): Anal. Calcd for C36H46O8: C 78.04, H 8.27. Found: C 78.32, H 8.53.

ACKNOWLEDGEMENT
Support of this work by the Swiss National Science Foundation is gratefully acknowledged.

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