Study on the reaction mechanism of Heck-oxyarylation of 2 H -chromenes

The Heck-oxyarylation reaction of deuterium labeled 2 H -chromenes ( 12 , 15 ) has been studied whose synthesis was achieved in four steps starting from the readily available 7-benzyloxychromane ( 9 ). Since the deuterium label was not affected in the course of the oxyarylation, the formation of the neutral achiral intermediate 7 could be ruled out as a possible reaction pathway and a reason for the lack of enantioselectivity in asymmetric Heck-oxyarylations. This also allowed the simple synthesis of 6a-and 11a-deutero-3-benzyloxypterocarpanes ( 13a , b ).


Introduction
Pterocarpans are naturally occurring plant products carrying a cis-fused benzofuranylbenzopyran ring system.Many of them are phytoalexins, which are produced in plants during infections by fungi, bacteria or viruses and subsequently act as protective agents for plants 1 .While some pterocarpans have antifungal 2 and oestrogenic activity 3 others have been reported to inhibit HIV-1 in cell cultures 4 and to possess significant snake or spider inhibition venom activity 5 .
On the basis of data published in the literature, 26 the displacement step may take place via (i) cationic (5→6) (ii) neutral (5→7) or a palladium containing cyclic intermediate (5→8) as shown in Figure 2. Since no or very moderate (ee%<10) asymmetric induction could be observed by us 17 in the presence of chiral bidentate phosphine ligands, such as CHIRAPHOS, NORPHOS, TRIPHOS and R-(+)-BINAP, it could be assumed that this reaction takes place through parallel pathways and the main pathway involves an achiral intermediate 7, where the chirality introduced by chiral ligands of Pd(0) is lost.
In order to obtain aunambiguous evidence about this assumption, 2H-chromenes (12,15) labeled with deuterium at C-3 or C-4 have been synthesized and their transformation to the corresponding pterocarpans were studied.

Results and Discussion
According to the proposed mechanism shown in Figure 1 and 2, it seemed reasonable to prepare compounds in which a D atom was introduced at C-3 or at C-4 of the 2H-chromene skeleton (1).For this purpose 7-benzyloxychromone (9) was reduced by lithium aluminium hydride in tetrahydrofuran at -60 ºC resulting in 7-benzyloxychromanone (10a) 18 in 70% yield, whose hydrogens at C-3 could be exchanged (10a→10b) using the method published by Mioskowski et al 27 (Scheme 2).Since the 1 H NMR monitoring of 10a in CDCl 3 at room temperature has clearly indicated that in the presence 10 mol% triazabicyclo [4.4.0] dec-5-ene (TBD) the deuterium incorporation has reached 99% in 12h, then the target molecule (10b) could be simply isolated in 88% yield.Subsequently, 10b was reduced by lithium aluminium hydride in ether at room temperature resulting in the corresponding chromane-4-ol (11), whose dehydratation was performed by some drops of diluted hydrochloric acid in acetone at 56 ºC affording the C-3 deuterium labeled 2H-chromene 12 in an overall yield 46%.The deuterium content of 12 has been determined by 1 H NMR as 75%.The Heck-oxyarylation of 12 was performed with 2a or 2b under the standard conditions [in case of 2a: PdCl 2 /LiCl, acetone, r.t.; in case of 2b: Pd(C 6 H 6 CN) 2 Cl 2 , Ag 2 CO 3 , Ph 3 P, THF, at 65 ºC or [bmim] [PF 6 ], at 100 ºC] to result in 3benzyloxypterocarpan (13a) in 30-40% yield whose 1 H NMR spectrum has clearly indicated the presence of the C-6a deuterium with 75% abundance.Since the deuterium incorporation of the chromene ring did not change in the course of the oxyarylation, contrast to our earlier assumption, the formation of the neutral achiral intermediate 7 must have been ruled out as a possible reaction pathway.It is also noteworthy that the oxyarilation of C-4 labeled 15 possessing 100% deuterium incorporation with 2a or 2b (R'=H) took place in a similar manner to give 13b with unchanged deuterium incorporation.The 1 H NMR spectra of 13a and 13b has also been found identical with those of compounds prepared by us in different synthetic route. 28ince the absence of an asymmetric Heck-oxyarylation can not be attributed to the formation of achiral intermediate 7, further efforts are required to find suitable chiral inductor and to optimize circumstances.It is also noteworthy that our efforts to increase the yield of the oxyarylation carried out in DMF or NMP in the presence of a palladacycle, such as trans-di(µ-acetato)-bis[o-(di-o-tolylphosphino)benzyl]dipalladium(II) prepared according to the literature 29 were unsuccessful.Surprisingly, no transformation could be observed in these solvents, although palladacycletes have been found highly efficient catalysts for Heck vinylation of aryl halides under these conditions. 30Moreover the yield of the oxyarylation described in general procedure b of the experimental section could not be improved by microwave irradiation either.Work on this project is in progress in our laboratory.

Experimental Section
General Procedures.All reagents and organic compounds were purchased from Sigma Aldrich.

7-Benzyloxy-4-deutero-2H-chromene (15)
To stirred solution of 10a (132 mg, 0.52 mmol) in dry Et 2 O (10 ml) LiAlD 4 (28 mg, 0.66 mmol) was added at 0 °C.After 30 min.the reaction mixture was quenched with sat.aqueous NH 4 Cl (20 ml) and the organic layer was separated and the water phase was extracted with Et 2 O (3x10 ml).The combined organic phase was washed with brine and dried (Na 2 SO 4 ), whose evaporation resulted in 14 as a colorless solid (132 mg).It was dissolved in acetone (5 ml) and heated in the presence of one drop 10% HCl for 3 hours.After neutralization with Et 3 N, the reaction mixture was diluted with water and extracted with dichloromethane (3x5 ml).The organic layer was washed with brine and dried (Na 2 SO 4 ).Evaporation of the solvent gave an oil (70 mg), which was purified by preparative TLC (n-hexane:ethyl acetate = 3:1) to give 15 of m.p. 59-60 °C (55 mg, 44%), as a colorless solid incorporation has been determination by 1 H-NMR to be 99%. 1

Figure 2 .
Figure 2. Possible pathways of the displacement step.