Reaction of o -(oxiranylmethyl)benzonitriles with sodium borohydride or Grignard reagent/CuI: a new synthesis of substituted 3-alkyl-3,4-dihydroisocoumarins

. A new method for the synthesis of substituted 3-alkyl-3,4-dihydroisocoumarins is described. o -(Oxiranylmethyl)benzonitriles, prepared from isovanillin in five steps, when reacted with nucleophiles such as sodium borohydride or phenylmagnesium chloride/CuI, undergo an intramolecular cyclization to yield the target compounds in good yields, in one pot.


Introduction
3,4-Dihydroisocoumarins (DHIC), otherwise named 3,4-dihydroisochromen-1-ones, are abundantly distributed in a wide range of natural sources.For examples, DHIC isolated from Kigelia pinnata, 1 Hydrangea macrophylla, 2 Cape aloe, 3 Montrouziera sphaeroidea, 4 Aloe hildebrandtii, 5 Cassia siamea, 6 Caryocar glabrum, 7 as well as others have been reported.Furthermore, certain DHIC from natural sources have broadly biological activities.DHIC such as isolated from Xyris pterygoblephara exhibiting antifungi activity, 8 from Aloe vera exhibiting binding activity with human serum albumin, 9 from Fusarium verticillioides exhibiting antimalarial, antitubercular and antifungal activities, 10 as well as others.On the other hand, DHIC also play an important core structure for many biologically active compounds.For instance, AI-77-B, a naturally-occurring DHIC which chemically belongs to the amicoumacin family, was isolated from different Bacillus genera exhibiting an antiulcerogenic activity without common side effects. 11Because of diverse biological activities, a number of synthetic strategies for DHIC have been developed.The major methods reported include the use of the Heck-Matsuda reaction, 12 radical cyclization mediated by titanocene(III) chloride, 13 cyclization of αlithiated 2-toluenecarboxylates, 14 coupling of vinylic halides or triflates with o-(1-alkenyl)benzoic acids, 15 the successive lateral and ortho-lithiations of 4,4-dimethyl-2-(o-toyl)oxazoline, 16 as well as others.However, those reported methods have some disadvantages including tedious reaction conditions, inaccessible starting materials or reagents, and low yields.Therefore, the development of a mild and efficient method for DHIC is requisite and of interest.On the other hand, the ring-opening of epoxides by various nucleophiles to yield diverse organic compounds has been well documented in organic synthesis. 17The addition of various nucleophiles to cyano groups has also been well described. 18However, studies on the addition of various nucleophiles to aryl compounds with an adjacent epoxy and cyano substituents has seldom been examined.In our previous study, we reported the reaction of o-(oxiranylmethyl)benzonitrile intermediates with TBAB/NaCN to yield various substituted 3,4-dihydroisoquinolin-1-ones. 19Continuing our work on benzoheterocycles, 20 we herein report the synthesis of substituted 3-alkyl-3,4dihydroisocoumarins from the reaction of o-(oxiranylmethyl)benzonitriles with nucleophiles such as sodium borohydride and Grignard reagent in the presence of copper iodide (Scheme 1).Scheme 1. Synthesis of 3-alkyl-3,4-dihydroisocoumarins from o-(oxiranylmethyl)benzonitriles with NaBH4 and C6H5MgCl/CuI nucleophiles.

Results and Discussion
In order to optimize the reaction conditions, compound 2a used as a model reaction was allowed to react with NaBH4 under various conditions.The given results showed that 5,6-dimethoxy-3methyldihydroisochroman (3a) together with 1-(2,3-dimethoxy-6-cyanophenyl)-2-propanol (5a) were formed in varying ratios.Compound 3a was produced through a domino sequence, involving ring-opening of the epoxide, followed by the intramolecular cyclization of the forming alkoxide anion with the cyano functional group, and then hydrolysis.Compound 5a was formed by simple ring opening of the epoxide by NaBH4.The results of this model reaction are compiled in Table 1.Based on the results reported in Table 1, we concluded that ethanol (entries 1-4) is a better solvent than methanol (entries 5-6) and anhydrous ethanol (entries 4, 7) is the best solvent for the reaction.Three quivalents of NaBH4 (entry 7) is better than 1 or 1.5 equivalents of NaBH4 (entries 1-6), and heating under reflux is better than reaction at room temperature for the production of 3. Thus, the use of excess NaBH4 (3.0 equiv.) in refluxing ethanol (entry 7) gives a high yield (80%) of 3a from 2a.Based on these conditions, o-(oxiranylmethyl)benzonitriles 2a-d gave the target compounds 3a-d in high yields (80-87%), in the one pot procedure.
All spectral data, such as IR, 1 H-NMR, 13 C-NMR, EI-MS, and HRMS or EA, are consistent with the 3-methyl-3,4-dihydroisocoumarin structures (3a-d).The IR spectrum of compound 3a, for example, showed absorption at 1707 cm -1 (C=O) and the 1 H-NMR spectrum exhibited a doublet signal of methyl group bonded to C-3 (J 6.2 Hz at  1.46); two double doublet signals at 2.66 and 3.13 which respectively have coupling constants J 16.8, 11.4 and 16.8, 3.2 Hz assigned to H-4a and H-4b; two singlet methoxy signals at  3.78 and 3.89; a one proton signal at  4.59 coupled to neighboring protons assigned as H-3; and two aromatic protons at 6.88, and 7.82 with the same coupling constant J 8.4 Hz indicating their ortho relationship.In the 13 C-NMR twelve lines are observed consistent with that required for the structure.The HRMS (m/z 222.0887) and EA (C, 65.01; H, 6.41) are consistent with the structure.To increase the diversity, o-(oxiranylmethyl)benzonitriles (2a-d) were allowed to react with Grignard reagent phenylmagnesium chloride/CuI.At the start of this study, 2a was reacted with phenylmagnesium chloride under various conditions to yield the desired 3-benzyl-5,6-dimethoxydihydroisochroman 4a and the results are shown in Table 2.As shown in Table 2, in the absence of CuI, 4a was formed in the low yield (16%) (entry 1) with the exception of entry 5 (11%) which was carried out for a shorter reaction time.This suggests the importance of CuI.A lower amount of Grignard reagent C6H5MgCl (entries 1-5) gave 4a in low to modest yields (11-66%).On the other hand the reaction of 2a with excess C6H5MgCl (2.4 equiv)/CuI (0.5 equiv) in refluxing THF (entry 6) for 24 hr provided the highest yield for 4a (86%).These conditions were employed for the synthesis of 3-benzyl-3,4dihydroisocoumarins 4a-d from o-(oxiranylmethyl)benzonitriles 2a-d, in yields of 85-90%.
The spectral data including IR, 1 H-NMR, 13 C-NMR, EI-MS, and HRMS or EA are all consistent with those required for the proposed 5-alkoxy-3-benzyl-6-methoxy-3,4dihydroisocoumarin structures 4a-d.The IR spectrum of compound 4a, for example, shows absorption at 1717 cm -1 (C=O) indicating the presence of carbonyl group.The indicating the presence of aromatic protons of benzyl group.In the 13 C-NMR spectrum of compound 4a shows sixteen lines which is consistent with carbon numbers required for the structure 4a.Besides, the data of HRMS (m/z 298.1204) and elemental analysis (C, 72.19; H, 6.03), all data are correct and consistent with the data required for compound 4a.

Conclusions
We have successfully prepared diverse 3-substituted 3,4-dihydroisocoumarins from the reaction of o-(oxiranylmethyl)benzonitriles with nucleophiles (NaBH4 or Grignard reagent/CuI).This reaction demonstrates that epoxide ring of o-(oxiranylmethyl)benzonitrile opened by nucleophile to give alkoxide anion which attacks the neighboring nitrile to effect the intramolecular cyclization, and this is followed by hydrolysis to yield a series of substituted 3-alkyl-3,4dihydroisocoumarins.

Experimental Section
General.Melting points were measured with Yanaco micro melting-point apparatus. 1H-NMR and 13 C-NMR spectra were obtained on a Varian Unity plus 400 Spectrometer.Chemical shifts were measured in parts per million with respect to TMS.IR spectra were run on a Perkin-Elmer spectrometer (System 2000 FT-IR, series No. 35575).Elemental analyses were recorded on a Heraeus CHN-O Rapid analyzer.Mass spectra were recorded on a Chem/HP/middle spectrometer connected to a Hewlett Packard series II model gas-liquid chromatography.HRMS spectra were performed on a JEOL JMS SX/SX 102A instrument.Silica gel (230-400 mesh) for column chromatography and the pre-coated silica gel plates (60 F-254) for TLC were purchased from E. Merck Co. UV light (254 nm) was used to detect spots on TLC plates after development.

Table 1 .
The reaction of compound 2a with NaBH4 under various conditions to yield 3a and 5a a Determined by isolated yields; b Anhydrous solvent was used.

Table 2 .
The reaction of compound 2a with C6H5MgBr under various conditions to yield 4a a Isolated yield from column chromatography, other by products being neglected.