HETEROCYCLES

Paper | Regular issue | Vol. 78, No. 5, 2009, pp. 1223-1233
Received, 26th November, 2008, Accepted, 25th December, 2008, Published online, 29th December, 2008.
DOI: 10.3987/COM-08-11610

■ Synthesis and Retro Aza Diels-Alder Reaction of Some New Isoquinuclidine Derivatives

Liliana Marzorati,* Patrícia Busko Di Vitta, Blanka Wladislaw, Julio Zukerman Schpector, and Claudio Di Vitta*

Chemistry Institute of the University of São Paulo, Av. Prof. Lineu Prestes 748, 05508-000, São Paulo, Brazil

Abstract

N-Benzyl- and N-(α-methoxycarbonylethyl)-2,4,6-triphenyl-1,2-dihydropyridines were submitted to Diels-Alder reactions with maleic anhydride or N-phenylmaleimide yielding, diastereoselectively, the corresponding endo-anti adducts. These novel isoquinuclidines showed to be resistant to N-alkylation or N-protonation, undergoing an unexpected fragmentation via a retro aza Diels-Alder process.

INTRODUCTION
As an ongoing project aiming the preparation of new chiral phase-transfer catalysts, presenting a rigid cyclic structure, we decided to investigate the Diels-Alder (DA) reactions of chiral N-substituted-1,2-dihydropyridines with suitable dienophiles, a well established route for constructing the isoquinuclidine skeleton. In the literature, modest to good π-facial diastereoselectivities were observed for DA reactions of 1,2-dihydropyridines I and II bearing a stereogenic center either at the exocyclic substituent attached to the nitrogen atom1 or at C-2 of the 1,2-dihydropyridine ring.2 However, to our knowledge, there is no literature report on this kind of reaction involving 1,2-dihydropyridines of type III, with two stereocenters, one at C-2 and the other at the nitrogen substituent.

RESULTS AND DISCUSSION
In an attempt to prepare new dienes of type II and III, N-benzyl-2,4,6-trimethylpyridinium and N-(±)-(α-methoxycarbonylethyl)-2,4,6-trimethylpyridinium tetrafluoroborates3 were submitted to reduction with NaBH4, but complex mixtures of products were obtained in both cases. However, using the same reducing agent, N-benzyl-2,4,6-triphenyl-1,2-dihydropyridine 1a was successfully prepared.4 In order to test the reactivity of this kind of azadiene, we performed the DA reaction of 1a with maleic anhydride and N-phenylmaleimide (Scheme 1). Although some decrease of reactivity would be expected, due to the presence of the electron withdrawing phenyl groups, the DA reactions proceeded smoothly for each dienophile, yielding, in each case, only one adduct (2a (85%) or 3a (90%)). This result prompted us to perform the reduction of N-(±)-(α-methoxycarbonylethyl)-2,4,6-triphenylpyridinium tetrafluoroborate with NaBH4. The non-isolable epimeric equimolar mixture of the resulting 1,2-dihydropyridines 1b was submitted to reaction with maleic anhydride or N-phenylmaleimide, yielding the new racemic diastereoisomeric DA adducts 2b (20%) and 2b’ or 3b (35%) and 3b’ (20%), respectively (Scheme 1).

These newly prepared isoquinuclidines were fully characterized by 1H NMR (Table 1).

In order to access the stereochemical features of such adducts, we turned our attention to the coupling constant between H-1 and H-2. Although for analogous adducts the observed value of ca. 3 Hz has been considered5 as indicative of an endo configuration, the inspection of molecular models for compounds 2 and 3 indicates that very similar J1,2 values would be expected for the endo and exo isomers. Moreover, for compounds 2 and 3, besides assigning an endo or exo configuration, it would be necessary to determine the relative position of H-9, that could point either towards the olefinic bond (syn-orientation) or opposite to it (anti-orientation). In this sense, it should be mentioned that, for similar compounds, Krow et al.2 found that the reduction of the olefinic bond of a syn-adduct, using Pd/C and hydrogen, gave rise to a product for which the resonance signal of syn H-9 was shifted downfield relatively to the same signal in the original adduct. Coherently, no such effect was observed upon hydrogenation of the anti-oriented adduct. In our case, hydrogenation of the olefinic double bond of isoquinuclidines 3b and 3b’ showed to be completely stereoselective, yielding the new saturated compounds 4b (50%) and 4b’ (50%), for which some selected 1H NMR data are presented in Table 2.

For compounds 3b and 4b or 3b’ and 4b’, close values for the H-9 chemical shifts were observed. This fact suggests that H-9, in compounds 3b and 3b’, is not affected by the double bond anisotropy and, therefore, must be anti-oriented. Additionally, as an evidence for the endo configuration of 3b and 3b’, it should be pointed out that the hydrogenated analogs (4b and 4b’) present a long range coupling (ca. 3 Hz) between H-6 and one of the methylene protons at C-10. Such coupling can only be attributed to a W conformation of the four sigma bonds, linking exo-H-6 and H-10b (Figure 1). Furthermore, for compounds 4b and 4b’, the magnitude of the coupling constants between H-10b and H-11 (ca. 12 Hz) indicates that they are eclipsed, as a result of an exo hydrogen addition to the double bond of adducts 3b and 3b’.

The above arguments seemed to support an endo-anti stereochemistry for adducts 2 and 3. In fact, this configuration was further confirmed by single crystal X-ray analysis of adducts 2a and 3b (Figure 2).

As for the origin of the high endo-anti-diastereoselectivity of the DA reactions of 2,4,6-triphenyl-1,4-dihydropyridines 1, we believe that it could be attributed to: (i) the low reactivity of dienes 1, due to conjugation between the dihydropyridine ring double bonds and the two 4,6-phenyl π-density,6 and (ii) the steric hindrance to the syn approach of the dienophile, due to the presence of the phenyl group at C-2 of the diene.
As a next step for the construction of the molecular framework of the model catalyst, we attempted the alkylation of the isoquinuclidine nitrogen. Adducts 3a and 3b failed to react with MeI, at room temperature, with complete recovery of the starting material. Surprisingly, the reaction of the same adducts with Me2SO4, under reflux in MeCN, afforded a mixture containing benzaldehyde. The lack of NMR proton signals attributable to the isoquinuclidine nitrogen substituent suggested the occurence of a retro aza Diels-Alder reaction7 (Scheme 2). In fact, diene 58 could be isolated (55%) from the crude reaction mixture. It should be noted that uppon treatment of a CHCl3 solution of adducts 3a or 3b with TFA, at room temperature, the retro aza Diels-Alder reaction was still observed.

As previously reported, hindered N-substituted 2-azanorbornenes are prone to heterocycloreversion.7b In order to try to cicumvent such drawback, the less hindered DA adduct 6 was prepared (43%), and submitted to reaction with TFA (Scheme 3), affording the corresponding stable isoquinuclidinium salt 7. For the obtained product, the observed deshielding of the 9, 9’, 1, 2, 6, and benzylic protons, and the change in multiplicity of the Hb signal (d in 6; dd in 7; see Figure 3) were consistent with the protonation of the isoquinuclidine nitrogen.

Inspired by this promissing result, we attempted the methylation of 6 with Me2SO4/MeCN. However, heterocycloreversion was again observed, probably driven by the high stability of the highly conjugated diene 5.

CONCLUSION
The easy cycloreversion of this kind of adducts precluded the preparation of isoquinuclidinium salts, as originally planned. However, such reaction could find application in the synthetic functionalization of primary amines9 and aminoacids,10 having the amino group temporarily locked into a pyridinium salt ring. Efforts in this sense are in progress in our laboratory.

EXPERIMENTAL
Commercial reagents were used without further purification. 1H and 13C NMR spectra were recorded, respectively, at 200 MHz (Bruker AC 200) or 300 MHz (Varian Inova) and at 50 or 75 MHz. All spectra are reported in δ (ppm) relative to TMS. N-Benzyl-2,4,6-triphenyl-1,2-dihydropyridine was prepared according to the literature procedure.4
N-(±)-(α-Methoxycarbonylethyl)-2,4,6-triphenyl-pyridinium tetrafluoroborate. To a stirred solution of 4.2 g (30 mmol) of L-alanine methyl ester hydrochloride in 100 mL of CH2Cl2, Et3N (6.1 g; 60 mmol) was added, followed by 2,4,6-triphenylpyrilium tetrafluoroborate (12 g; 30 mmol; via goose-neck). Each portion of this salt was added after complete dissolution of the previous one. After stirring for 2 h at rt, acetic acid (3.6 g; 60 mmol) was added. Stirring was maintained for 2 h, the solvent removed under reduced pressure and the resulting oily residue was treated with Et2O and washed with water. Crystallization from EtOH yielded a colorless solid (50 % yield); mp 219-220 oC; 1H NMR (CDCl3): δ 7.93 (s, 2H, Ar), 7.84 - 7.52 (m, 15H, Ar), 5.56 (q, 1H, J = 7.2 Hz), 3.68 (s, 3H), 1.50 (d, 3H, J = 7.2 Hz); Anal. Calcd for C27H24NO2BF4: C, 67.38; H, 5.03; N, 2.91. Found: C, 67.30; H, 4.96; N, 3.15
N-(±)-(α-Methoxycarbonylethyl)-2,4,6-triphenyl-1,2-dihydropyridines. To a stirred solution of N-(±)-(α-methoxycarbonylethyl)-2,4,6-triphenylpyridinium tetrafluoroborate (4.8 g; 10 mmol) in MeCN/MeOH (1 : 1), NaBH4 (0.38 g; 10 mmol) was added, in small portions via goose-neck, at 0 oC, and under N2 atmosphere. The resulting mixture was further stirred for 1 h. After removing the solvent under reduced pressure, and adding Et2O, the mixture was eluted through a pad of SiO2. Concentration of the organic extract yielded a yellow oil as an equimolar mixture of the expected diastereoisomeric dihydropyridines, that was submitted, without separation, to the subsequent DA reaction; 1H NMR (CDCl3): δ 7.76 - 7.73 (m, 2H, Ar), 7.63 - 7.51 (m, 10H, Ar), 7.39 - 7.18 (m, 18H, Ar), 6.08 (d, 1H, J = 1.5 Hz), 5.98 (d, 1H, J = 1.5 Hz), 5.87 (dd, 1H, J = 6.6 and 1.2 Hz), 5.74 (dd, 1H, J = 6.6 and 1.2 Hz), 5.28 (d, 1H, J = 6.6 Hz), 5.15 (d, 1H, J = 6.6 Hz), 4.19 (q, 1H, J = 6.6 Hz), 3.93 (q, 1H, J = 7.2 Hz), 3.63 (s, 3H), 3.46 (s, 3H), 1,48 (d, 3H, J = 7.2 Hz), 1.30 (d, 3H, J = 6.6 Hz); 13C NMR (CDCl3): δ 173.6, 173.1, 146.0, 145.1, 143.9, 137.8 (2C), 136.1, 129.1, 129.0, 128.8 (2C), 128.6, 128.5, 128.4, 128.3, 128.0, 127.9, 127.7, 127.4, 127.3, 127.2, 127.0 (2C), 126.7, 126.5, 126.0 (2C), 124.8, 124.2, 108.9, 108.2, 58.9, 56.4, 56.3, 55.0, 52.0, 51.9, 16.4, 16.2
N-Benzyl-2,4-diphenyl-1,2-dihydropyridine. 0.85 g (2.1 mmol) of N-benzyl-2,4-diphenyl-1,2-pyridinium tetrafluoroborate was dissolved in MeCN/MeOH (1 : 1), and the resulting solution, maintained under nitrogen atmosphere, was cooled to 0 oC. To this mixture was added an aqueous solution of KOH (0.12 g; 2.0 mmol) and NaBH4 (0.079 g; 2.0 mmol). After stirring for 2 min., the reaction mixture was poured into Et2O. The ethereal phase was washed with water, dried over MgSO4, and concentrated under reduced pressure. The crude resulting solid (0.36 g), impurified with some tetrahydropyridine, was submitted to the DA reaction; 1H NMR (CDCl3): δ 7.64 - 7.22 (m, 15H, Ar), 5.80 (d, 1H, J = 1.5 Hz), 5.30 (m, 1H), 4.07 (s, 2H), 4.06 (d, 2H); 13C NMR (CDCl3): δ 149.5, 139.8, 139.3, 137.7, 137.3, 129.0, 128.8, 128.6, 128.5, 128.4, 128.3 (2C), 128.0, 127.5, 127.0, 125.7, 108.5, 104.8, 54.2, 48.8
DA reactions-Typical Procedure
A mixture of N-benzyl-2,4,6-triphenyl-1,2-dihydropyridine (1a; 0.16 g; 0.40 mmol) and maleic anhydride (0.040 g; 0.40 mmol), in Et2O (2 mL), was stirred overnight. The suspended solid was filtered and crystallized (MeCN) yielding 2a, as white crystals (85% yield); mp 205 - 207 oC; 1H NMR (CDCl3): δ 7.97 (dd, 2H, Ar, J = 8.7 and 1.5 Hz), 7.56 - 6. 34 (m, 19H, Ar and olefinic), 4.50 (d, 1H, J = 8.3 Hz), 4.00 (d, 1H, J = 2.1 Hz), 3.84 - 3.78 (m, 1H), 3.78 (d, 1H, J = 12 Hz), 3.71 (dd, 1H, J = 8.3 and 3.0 Hz), 3.15 (d, 1H, J = 12 Hz); 13C NMR (CDCl3): δ 171.3, 170.2, 142.8, 141.9, 140.3, 137.6, 136.6, 133.2, 129.8, 129.2, 128.4, 128.3, 127.6, 127.0, 126.7, 125.3, 66.1, 65.6, 56.4, 44.4, 44.3, 43.0. Anal. Calcd for C34H27NO3: C, 82.09; H, 5.47; N, 2.82. Found: C, 81.71; H, 5.55; N, 2.85
Adduct 3a was prepared analogously by using N-phenylmaleimide (90 % yield); mp 200 - 201 oC; 1H NMR (CDCl3): δ 8.06 (d, 2H, Ar, J = 8.1 Hz), 7.53 - 6.83 (m, 24H, Ar), 4.47 (d, 1H, J = 8.0 Hz), 4.10 (d, 1H, J = 2.4 Hz), 3.93 - 3.91(m, 1H), 3.88 (d, 1H, J = 12 Hz), 3.63 (dd, 1H, J = 8.0 and 2.7 Hz), 3.27 (d, 1H, J = 12 Hz); 13C NMR (CDCl3): δ 176.4, 175.8, 143.4, 141.3, 141.2, 138.2, 136.9, 132.7, 131.7, 130.1, 129.2, 128.9, 128.5, 128.3, 128.0, 127.5, 127.4, 127.0, 126.7, 126.4, 126.3, 125.2, 66.8, 65.9, 56.6, 45.0, 43.8, 42.3; Anal. Calcd for C40H32N2O2: C, 83.89; H, 5.59; N, 4.90. Found: C, 83.80; H, 5.83; N, 4.72
Adduct 2b was prepared in a similar manner, by using N-(±)-(α-methoxycarbonylethyl)-2,4,6-triphenyl-1,2-dihydropyridines and maleic anhydride. It was isolated in 20 % yield by treating the diastereoisomers mixture with MeOH; mp 216 - 220 oC; 1H NMR (C6D6): δ 7.80 - 7.00 (m, 15H, Ar), 6.90 (d, 1H, J = 2.1 Hz), 4.90 (d, 1H, J = 2.4 Hz), 4.09 (dd, 1H, J = 8.4 and 3.0 Hz), 3.90 - 3.82 (m, 1H), 3.69 (s, 3H), 3.25 (q, 1H, J = 7.5 Hz), 0.90 (d, 3H, J = 7.5 Hz)
Adducts 3b and 3b’ were prepared by reaction of N-(±)-(α-methoxycarbonylethyl)-2,4,6-triphenyl-1,2-dihydropyridines (3.9 g; 10 mmol) with N-phenylmaleimide (1.7 g; 10 mmol), in Et2O (20 mL). The solid mixture of adducts 3b and 3b’ was dissolved in hot MeOH. Slow concentration of the methanolic solution resulted in the separation of 3b (35%) and 3b’ (20%). Each isolated adduct was crystallized from MeCN, yielding white crystals.
3b: mp 200 - 203 oC; 1H NMR (CDCl3): δ 7.98 (m, 2H, Ar), 7.48 - 6.81 (m, 19H, Ar), 4.51 (d, 1H, J = 2.4 Hz), 4.38 (d, 1H, J = 8.1 Hz), 3.97 - 3.94 (m, 1H), 3.59 (dd, 1H, J = 7.8 and 2.7 Hz), 3.40 (q, 1H, J = 6.6 Hz), 2.87 (s, 3H), 1.22 (d, 3H, J = 6.6 Hz); 13C NMR (CDCl3): δ 176.4, 174.9, 173.0, 142.7, 140.3, 139.5, 136.9, 133.3, 131.5, 128.9, 128.5, 128.4, 128.3, 128.1, 127.8, 127.2, 127.0, 126.3, 125.2, 65.3, 58.8, 53.3, 51.0, 46.0, 45.1, 44.1, 12.6
3b’: mp 204 - 207 oC; 1H NMR (C6D6): δ 8.08 (s, 2H, Ar), 7.95 - 6.79 (m, 19H, Ar), 5.21 (d, 1H, J = 2.4 Hz), 4.53 (d, 1H, J = 7.8 Hz), 4.25 - 4.18 (m, 1H), 4.13 (dd, 1H, J = 8.1 and 3.0 Hz), 3.57 (q, 1H, J = 7.5 Hz), 3.34 (s, 3H), 0.90 (d, 3H, J = 7.5 Hz); 13C NMR (C6D6): δ 177.1, 176.5, 175.6, 145.6, 140.7, 140.1, 137.0, 132.9, 131.7, 129.7, 128.8, 128.3, 128.2, 128.0, 127.9, 126.8, 126.4, 125.1, 65.3, 58.9, 55.0, 51.5, 45.8, 44.9, 43.9, 20.0; Anal. Calcd for C37H32N2O4: C, 78.15; H, 5.67; N, 4.93. Found: C, 78.14; H, 5.61; N, 4.96
Adduct 6 was prepared in 43 % yield, according to the typical procedure; mp 126 - 129 oC; 1H NMR (CDCl3): δ 7.60 (dd, 2H, Ar, J = 8.4 and 5.0 Hz), 7.59 - 7.21 (m, 17H, Ar), 6.89 (dd, 2H, Ar, J = 7.5 and 6.0 Hz), 3.90 (bs, 1H), 3.86 (d, 1H, J = 8.4 Hz), 3.78 (d, 1H, J = 13 Hz), 3.39 (dd, 1H, J = 8.4 and 3.3 Hz), 3.27 (dd, 1H, J = 10 and 2.1 Hz), 2.84 (d, 1H, J = 13 Hz), 2.39 (dd, 1H, J = 10 and 2.7 Hz); 13C NMR (CDCl3): δ 176.6, 174.3, 142.8, 139.4, 139.3, 137.0, 131.7, 128.9 (2C), 128.5, 128.4, 128.2, 128.1, 127.8, 126.8, 126.4, 125.8, 124.8, 64.1, 57.7, 54.6, 52.8, 43.6, 47.0; Anal. Calcd for C34H28N2O2·H2O: C, 79.35; H, 5.88; N, 5.44. Found: C, 79.56; H, 5.85; N, 5.21
Hydrogenation of adducts 3b and 3b’. Adduct 3b or 3b’ (0.10 g; 0.18 mmol), in MeOH (250 mL), was submitted to hydrogenation using 0.077 g of 5 % Pd/C and hydrogen in a Parr apparatus. After shaking for 20 h, the catalyst was removed by filtration over Celite,® and the methanolic solution was concentrated. The resulting oily crude product was treated with MeOH yielding a white solid.
Adduct 4b was obtained in 50 % yield after crystallization from MeCN; mp 218 - 222 oC; 1H NMR (CDCl3/C6D6): δ 8.10 - 6.37 (m, 20H, Ar), 4.48 (d, 1H, J = 2.7 Hz), 3.70 (dd, 1H, J = 10 and 2.7 Hz), 3.36 (q, 1H, J = 6.9 Hz), 3.40 - 3.24 (m, 2H), 3.15 (dd, 1H, J = 10 and 2.1 Hz), 2.89 (s, 3H), 2.79 (ddd, 1H, J = 14, 12 and 3.0 Hz), 2.40 (dd, 1H, J = 14 and 6.6 Hz), 0.92 (d, 3H, J = 6.9 Hz); 13C NMR (CDCl3/C6D6): δ 175.4, 175.2, 172.5, 142.9, 140.5, 140.1, 131.8, 130.5, 129.2, 129.1, 128.3, 128.0, 127.9, 127.3, 127.6, 127.4, 127.3, 127.0, 126.8, 126.4, 125.8, 125.7, 63.1, 62.2, 54.9, 50.5, 45.6, 45.3, 40.1, 37.1, 31.4, 13.0
Adduct 4b’ was obtained in 50 % yield after crystallization from MeCN; mp 213 - 225 oC; 1H NMR (CDCl3): δ 7.95 - 6.40 (m, 20H, Ar), 5.07 (d, 1H, J = 3.1 Hz), 4.29 (dd, 1H, J = 9.7 and 3.0 Hz), 3.91 (dd, 1H, J = 9.7 and 2.8 Hz), 3.65 (s, 3H), 3.50 - 3.42 (m, 1H), 3.36 - 3.28 (m, 1H), 3.32 (bq, 1H, J = 7.5 Hz), 2.97 (ddd, 1H, J = 14, 11 and 3.0 Hz), 2.49 (dd, 1H, J = 14 and 6.2 Hz), 0.88 (d, 3H, J = 7.5 Hz); 13C NMR (CDCl3): δ 176.8, 176.5, 176.4, 145.4, 140.8, 140.6, 131.6, 129.4, 128.8, 128.6, 128.4 (2C), 128.2, 128.1, 127.9, 127.8 (2C), 127.1, 126.8, 126.5, 126.0 (2C), 63.2, 62.4, 56.3, 51.4, 44.9, 44.7, 40.5, 37.3, 31.5, 19.2
Retro aza DA reaction. A solution of adduct 3a (0.11 g; 2.0 mmol), in 2 mL of CHCl3, was treated, at rt, with 22 µL of CF3CO2H (0.033 g; 3.0 mmol). The reaction was monitored by TLC (hexane : EtOAc; 9:1) until complete consumption of the adduct. A yellow oil was obtained after removal of the solvent, and purified by column chromatography (hexane : EtOAc; 9:1) yielding 5, as a yellow solid (0.043 g; 1.1 mmol; 55%); mp 171.5 - 173 oC; 1H NMR (CDCl3): δ 7.80 - 7.50 (m, 15H, Ar), 6.80 (d, 1H, J = 2.9 Hz), 4.00 (dd, 1H, J = 17 and 8.6 Hz), 3.40 (dd, 1H, J = 17 and 8.6 Hz), 2.90 (td, 1H, J = 17, 17 and 2.9 Hz); 13C NMR (CDCl3): δ 174.7, 165.8, 145.1, 144.8, 138.8, 136.0, 132.2, 129.6, 129.2, 128.9, 128.3, 127.9, 126.6, 126.5, 125.9, 117.1, 40.8, 27.0; Anal. Calcd for C26H19NO2: C, 82.76; H, 5.04; N, 3.71. Found: C, 82.15; H, 5.14; N, 3.64.

ACKNOWLEDGMENTS
This work was supported by FAPESP, CAPES and CNPq.

References

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3. N-Benzyl-2,4,6-trimethylpyridinium tetrafluoroborate was prepared by reacting 2,4,6-trimethylpyrilium tetrafluoroborate with benzylamine, in EtOH, at rt, for 6 h. By pouring the reaction mixture into Et2O, a colorless solid (47% yield) was collected by filtration, and crystallyzed from EtOH; mp 124 - 125 °C; 1H NMR (CDCl3): δ 7.62 (s, 2H, Ar), 7.37 - 7.35 (m, 3H, Ar), 6.89 - 6.86 (m, 2H, Ar), 5.76 (s, 2H), 2.71 (s, 6H), 2.58 (s, 3H); 13C NMR (CDCl3): δ 159.0, 154.9, 131.5, 129.6, 128.8, 128.6, 125.0, 55.0, 21.4, 20.8; Anal. Calcd for C15H18NBF4: C, 60.20; H, 6.02; N, 4.68. Found: C, 60.21; H, 6.03; N, 4.83; N-(±)-(α-methoxycarbonylethyl)-2,4,6-trimethylpyridinium tetrafluoroborate was prepared as follows: a mixture of 2 equiv. of alanine and 1 equiv. of 2,4,6-trimethylpyrilium tetrafluoroborate in water was heated under reflux for 5 h. After removal of water, the residue was extracted with hot EtOH. Concentration of the ethanolic solution afforded a white solid identified as the double salt [(C8H11NCHMeCO2).(C8H11NCHMeCO2H)+]BF4- (30 % yield) after crystallyzation from EtOH/Et2O; mp 155 - 157 °C (decomp.); 1H NMR (D2O): δ 7.74 (s, 4H, Ar), 5.62 (q, 2H, J = 7.0 Hz), 2.64 (bs, 12H), 2.36 (s, 6H), 2.78 (d, 6H, J = 7.0 Hz); 13C NMR (D2O): δ 173.2, 158.9, 155.5, 129.8, 128.6, 62.8, 21.7, 21.0, 20.8, 15.8; Anal. Calcd for C22H31N2O4BF4; C, 55.67; H, 6.59; N, 5.91. Found: C, 55.44; H, 6.48; N, 6.12; this salt was treated with excess of Me2SO4 and an equimolar amount of K2CO3, in MeOH. After heating under reflux for 4 h, the reaction mixture was poured into Et2O, and the precipitate was recrystallized from EtOH/Et2O yielding an hygroscopic white solid (100% yield); 1H NMR (D2O): δ 7.44 (s, 2H, Ar), 5.60 (q, 1H, J = 7.0 Hz), 3.70 (s, 3H), 2.63 (bs, 6H), 2.36 (s, 3H), 1.80 (d, 3H, J = 7.0 Hz); 13C NMR (D2O): δ 173.4, 159.7, 154.8, 129.5, 128.5, 62.7, 54.2, 20.8, 20.6, 15.7 .
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