HETEROCYCLES

Short Paper | Regular issue | Vol. 85, No. 1, 2012, pp. 165-170
Received, 20th October, 2011, Accepted, 30th November, 2011, Published online, 6th December, 2011.
DOI: 10.3987/COM-11-12376

■ Synthesis of 1-Amino-1-aryl-1,2-dihydropyrrolo[3,4-c]pyridin-3-one Derivatives by the Reaction of 4-Lithiopyridine-3-carbonitrile with Aromatic Tertiary Amides

Kazuhiro Kobayashi,* Kazuhiro Nakagawa, and Taketoshi Kozuki

Division of Applied Chemistry, Department of Chemistry and Biotechnology, Graduate School of Engineering, Tottori University, 4-101 Koyama-minami, Tottori 680-8552, Japan

Abstract

A one-pot procedure for the preparation of 1-amino-1-aryl-1,2-dihydropyrrolo[3,4-c]pyridin-3-one derivatives from pyridine-3-carbonitrile and aromatic tertiary amides has been developed. Thus, the reaction of 4-lithiopyridine-3-carbonitrile, generated by the treatment of pyridine-3-carbonitrile with lithium 2,2,6,6-tetramethylpiperidide (LTMP), with aromatic tertiary amides in THF at –78 ˚C yields the pyrrolopyridinone derivatives in moderate yields.

In the course of our study on the development of new methods for the preparation of heterocyclic compounds, we became in need of 2-aroylpyridine-3-carbonitriles. So we attempted the reaction of 4-lithiopyridine-3-carbonitrile1 with N-methoxy-N-methylbenzamide. However, we were surprised to find that this reaction resulted in the formation of 1-methoxy(methyl)amino-1-phenyl-1,2-dihydropyrrolo-[3,4-c]pyridin-3-one. Herein, we wish to report the results of our study on the reaction of lithiopyridinecarbonitriles with aromatic tertiary amides, which offer a simple synthetic method for 1-amino-1-aryl-1,2-dihydropyrrolo[3,4-c]pyridin-3-one derivatives. The 1,2-dihydropyrrolo[3,4-c]-pyridine-3-one structure has been reported to be involved in the naturally occurring isoniazid–NAD(P) adducts.2 1,2-Dihydropyrrolo[3,4-c]pyridine-3-one derivatives have been mainly prepared by the reduction of pyrrolo[3,4-c]pyridine-1,3-diones.2,3 Recently, a method based on microwave-assisted intramolecular hetero-Diels-Alder cycloaddition of acetylenic pyrimidines has been reported.4 However, there have been no reports on the synthesis of this heterocyclic derivatives carrying an amino group at the 1-position.
First, the reaction of 4-lithiopyridine-3-carbonitrile with N-methoxy-N-methylbenzamide was examined under conditions illustrated in Scheme 1. Thus, the 4-position of pyridine-3-carbonitrile (1) was lithiated with 2 equivalents of lithium 2,2,6,6-tetramethylpiperidide (LTMP) in THF at –78 ˚C under Laurt’s conditions,2 and the resulting lithium product was allowed to react with two equivalents of N-methoxy-N-methylbenzamide at the same temperature for 30 min. Aqueous workup was followed by purification of the crude product by column chromatography on silica gel to give 1-methoxy(methyl)amino-1-aryl-1,2-dihydropyrrolo[3,4-c]pyridin-3-one (2a) in 49% yield as the only structurally defined isolated product. 4-Benzoylpyridine-3-carbonitrile was not obtained at all. The use of one equivalent of the amide gave a rather poorer yield (21%), and the use of three equivalents did not improve the yield. Determination of the structure of 2a was achieved on the basis of its spectral data. Mass spectrometry and elemental analysis established the molecular formula of the product to be C15H15N3O2. The IR spectrum showed absorption bands at 3187 and 1697 cm–1 due to N-H and C=O groups, respectively. The 13C NMR spectrum exhibited thirteen signals including a signal at 169.25 assignable to the amide carbonyl carbon. The 1H NMR spectral data are in good agreement with the structure of 2a (see Experimental section).

Encouraged by this result, the lithium product generated from 1 was then allowed to react with various tertiary amides. Using other nine aromatic tertiary amides, the corresponding 1-amino-1-aryl-1,2-dihydropyrrolo[3,4-c]pyridin-3-one derivatives (2) were obtained in moderate yields, as summarized in Scheme 1 as well. The results indicate that the yields of 1-methoxy(methyl)amino derivatives (2a-g) are somewhat higher than those of 1-dimethylamino derivatives (2h-j). This result may indicate that the methoxy group facilitates the rearrangement of 4 to 6 by stabilizing the transition state 5 shown below.
The formation of the products (2) from 1 and amides is thought to proceed as depicted in Scheme 2. The first step involves the addition of 3-cyanopyridin-4-yl anion to the carbonyl of the amides providing lithium alkoxide intermediate (3). Subsequent intramolecular addition of the alkoxide to the cyano function gave the lithioiminoether intermediate (4), of which rearrangement followed by protonation gives rise to 2. Similar iminoether rearrangement reactions have been reported previously;5 recently we have described the formation of 3-methyleneisoindolin-1-ones from the reaction of 2-formylbenzonitriles with dimethyloxosulfonium methylide via the corresponding imino anion intermediates.5c

When 1 was lithiated with two equivalents of LDA and treated with two equivalents of N-methoxy-N- methylbenzamide under the same conditions described above, the yields of the desired product (4a) decreased to 32%. The reaction of the lithium product, generated from 1 and LTMP under the same conditions, with N-methoxy-N-methylpropanamide led to the formation of an intractable mixture of products. The use of 1-benzoylpyrrolidine gave also a similar result. It should be noted that the uses of pyridine-2-carbonitrile and pyridine-4-carbonitrile in place of pyridine-3-carbonitrile resulted in the formation of complex reaction mixtures of products, from which no trace amounts of the corresponding pyrrolopyridinone derivatives were obtained.
In conclusion, we have shown that a range of 1-amino-1-aryl-1,2-dihydropyrrolo[3,4-c]pyridin-3-one derivatives can be prepared through the lithiation of pyridine-3-carbonitrile with LTMP followed by treatment with aromatic tertiary amides. The present procedure should be efficient and valuable in organic synthesis, because this type of 1,2-dihydro-3H-pyrrolo[3,4-c]pyridine-3-one derivatives are difficult to obtain by using previous reactions.

EXPERIMENTAL
The melting points were obtained on a Laboratory Devices MEL-TEMP II melting apparatus and are uncorrected. IR spectra were recorded with a Shimadzu FTIR-8300 spectrophotometer. The 1H NMR spectra were recorded using TMS as an internal reference with a JEOL ECP500 FT NMR spectrometer operating at 500 MHz or JEOL LA400FT NMR spectrometer operating at 400 MHz. The 13C NMR spectra were recorded in CDCl3 using TMS as an internal reference with a JEOL ECP500 FT NMR spectrometer operating at 125 MHz or JEOL LA400FT NMR spectrometer operating at 100 MHz. Low-resolution MS spectra (EI, 70 eV) were measured by a JEOL JMS AX505 HA spectrometer. TLC was carried out on a Merck Kieselgel 60 PF254. Column chromatography was performed using WAKO GEL C-200E. All of the organic solvents used in this study were dried over appropriate drying agents and distilled prior to use.
Starting Materials. N-Methoxy-N-methylbenzamides were prepared from the respective benzoyl chlorides and N,O-dimethylhydroxylamine hydrochloride by the standard method. n-BuLi was supplied by Asia Lithium Corporation. All other chemicals used in this study were commercially available.
Typical Procedure for the Preparation of 1,2-Dihydropyrrolo[3,4-c]pyridin-3-ones (2). 1-Methoxy(methyl)amino-1-phenyl-1,2-dihydropyrrolo[3,4-c]pyridin-3-one (2a). To a stirred solution of LTMP (2.0 mmol), generated from 2,2,6,6-tetramethylpiperidine and n-BuLi by the standard method, in THF (4 mL) at –78 ˚C was added a solution of 1 (0.10 g, 1.0 mmol) in THF (2 mL) dropwise. After 30 min, a solution of N-methoxy-N-methylbenzamide (0.35 g, 2.1 mmol) in THF (1 mL) was added and stirring was continued for an additional 30 min at the same temperature before saturated aqueous NH4Cl (15 mL) was added. The mixture was warmed to rt and the organic materials were extracted with AcOEt (3 × 10 mL). The combined extracts were washed with brine (10 mL) and dried over anhydrous Na2SO4. Evaporation of the solvent gave a residue, which was purified by preparative TLC on silica gel to give 2a (0.13 g, 49 %); a white solid; mp 157–158 ˚C (hexane–CH2Cl2); IR (KBr) 3187, 1697 cm–1; 1H NMR (400 MHz, CDCl3) δ 2.44 (s, 3H), 3.36 (s, 3H), 7.38–7.42 (m, 5H), 7.75–7.77 (m, 2H), 8.72 (d, J = 4.9 Hz, 1H), 9.04 (s, 1H); 13C NMR (100 MHz) δ 37.16, 60.30, 85.89, 117.91, 124.93, 125.74, 126.01, 128.91, 128.95, 140.95, 146.13, 152.63, 169.25; MS m/z 269 (M+, 0.37), 209 (100). Anal. Calcd for C15H15N3O2: C, 66.90; H, 5.61; N, 15.60. Found: C, 66.79; H, 5.55; N, 15.52.
1-Methoxy(methyl)amino-1-(3-methylphenyl)-1,2-dihydropyrrolo[3,4-c]pyridin-3-one (2b): a white solid; mp 168–170 ˚C (hexane–CH2Cl2); IR (KBr) 3185, 1694 cm–1; 1H NMR (400 MHz, CDCl3) δ 2.36 (s, 3H), 2.42 (s, 3H), 3.36 (s, 3H), 6.85 (br s, 1H), 7.16 (d, J = 7.8 Hz, 1H), 7.29 (t, J = 7.8 Hz, 1H), 7.42 (d, J = 5.4 Hz, 1H), 7.50 (s, 1H), 7.59 (d, J = 7.8 Hz, 1H), 8.71 (d, J = 5.4 Hz, 1H), 9.04 (s, 1H); 13C NMR (100 MHz) δ 21.55, 39.32, 60.29, 85.75, 117.93, 122.90, 123.54, 124.80, 125.82, 126.15, 128.85, 129.73, 138.74, 146.14, 152.70, 169.10; MS m/z 283 (M+, 0.46), 223 (100). Anal. Calcd for C16H17N3O2: C, 67.83; H, 6.05; N, 14.83. Found: C, 67.64; H, 6.14; N, 14.65.
1-Methoxy(methyl)amino-1-(4-methylphenyl)-1,2-dihydropyrrolo[3,4-c]pyridin-3-one (2c): a white solid; mp 70–72 ˚C (hexane–Et2O); IR (KBr) 3206, 1705 cm–1; 1H NMR (500 MHz, CDCl3) δ 2.34 (s, 3H), 2.42 (s, 3H), 3.36 (s, 3H), 7.01 (br s, 1H), 7.19 (d, J = 7.8 Hz, 2H), 7.41 (d, J = 5.0 Hz, 1H), 7.62 (d, J = 7.8 Hz, 2H), 8.71 (d, J = 5.0 Hz, 1H), 9.03 (s, 1H); 13C NMR (125 MHz) δ 21.01, 37.11, 60.30, 85.73, 117.85, 125.63, 125.93, 126.78, 129.16, 129.62, 138.91, 146.13, 152.63, 169.07; MS m/z 283 (M+, 0.42), 223 (100). Anal. Calcd for C16H17N3O2: C, 67.83; H, 6.05; N, 14.83. Found: C, 67.73; H, 6.04; N, 14.73.
1-(Biphenyl-4-yl)-1-methoxy(methyl)amino-1,2-dihydropyrrolo[3,4-c]pyridin-3-one (2d): a pale-yellow solid; mp 167–169 ˚C (hexane–CH2Cl2); IR (KBr) 3233, 1705 cm–1; 1H NMR (500 MHz, CDCl3) δ 2.46 (s, 3H), 3.40 (s, 3H), 7.11 (br s, 1H), 7.36 (t, J = 7.4 Hz, 1H), 7.42 (t, J = 7.4, 7.4 Hz, 2H), 7.46 (d, J = 5.2 Hz, 1H), 7.57 (d, J = 7.4 Hz, 2H), 7.65 (d, J = 8.1 Hz, 2H), 7.82 (d, J = 8.1 Hz, 2H), 8.74 (d, J = 5.2 Hz, 1H), 9.06 (s, 1H); 13C NMR (125 MHz) δ 37.20, 60.36, 85.73, 117.93, 125.90, 126.20, 127.04 (2C), 127.62, 127.66, 128.83, 137.76, 140.08, 141.91, 146.26, 152.77, 169.08; MS m/z 345 (M+, 0.21), 285 (100). Anal. Calcd for C21H19N3O2: C, 73.03; H, 5.54; N, 12.17. Found: C, 72.86; H, 5.66; N, 12.13.

1-(3-Chlorolphenyl)-1-methoxy(methyl)amino-1,2-dihydropyrrolo[3,4-c]pyridin-3-one (2e): a pale-yellow solid; mp 199–203 ˚C (hexane–CH2Cl2); IR (KBr) 3240, 1701, 1609 cm–1; 1H NMR (400 MHz, CDCl3) δ 2.42 (s, 3H), 3.38 (s, 3H), 7.01 (br s, 1H), 7.32–7.34 (m, 2H), 7.41 (d, J = 4.9 Hz, 1H), 7.63–7.64 (m, 1H), 7.79 (s, 1H), 8.75 (d, J = 4.9 Hz, 1H), 9.06 (s, 1H); 13C NMR (125 MHz) δ 36.53, 60.29, 85.33, 117.86, 123.88, 125.73, 126.11, 129.16, 130.20, 134.98, 140.12, 146.26, 152.94, 154.58, 168.72; MS m/z 303 (M+, 0.47), 243 (100). Anal. Calcd for C15H14ClN3O2: C, 59.31; H, 4.65; N, 13.83. Found: C, 59.25; H, 4.70; N, 13.58.
1-(4-Chlorolphenyl)-1-methoxy(methyl)amino-1,2-dihydropyrrolo[3,4-c]pyridin-3-one (2f): a white solid; mp 87–89 ˚C (hexane–CH2Cl2); IR (KBr) 3219, 1709 cm–1; 1H NMR (500 MHz, CDCl3) δ 2.40 (s, 3H), 3.37 (s, 3H), 7.01 (br s, 1H), 7.373 (d, J = 8.7 Hz, 2H), 7.374 (d, J = 5.0 Hz, 1H), 7.70 (d, J = 8.7 Hz, 2H), 8.74 (d, J = 5.0 Hz, 1H), 9.05 (s, 1H); 13C NMR (125 MHz) δ 37.04, 60.30, 85.58, 117.75, 125.93, 127.22, 129.09, 134.93, 137.53, 146.23, 152.74, 155.35, 169.37; MS m/z 303 (M+, 0.68), 243 (100). Anal. Calcd for C15H14ClN3O2: C, 59.31; H, 4.65; N, 13.83. Found: C, 59.18; H, 4.80; N, 13.55.
1-Methoxy(methyl)amino-1-(naphthalen-2-yl)-1,2-dihydropyrrolo[3,4-c]pyridin-3-one (2g): a white solid; mp 184–187 ˚C (hexane–CH2Cl2); IR (KBr) 3381, 1709 cm–1; 1H NMR (500 MHz, CDCl3) δ 2.45 (s, 3H), 3,38 (s, 3H), 7.10 (s, 1H), 7.49–7.52 (m, 3H), 7.82–7.85 (m, 2H), 7.91 (d, J = 9.2 Hz, 1H), 7.98 (d, J = 8.6 Hz, 1H), 8.12 (s, 1H), 8.71 (d, J = 5.2 Hz, 1H), 9.07 (s, 1H); 13C NMR (125 MHz) δ 37.19, 60.36, 85.95, 117.94, 123.56, 124.72, 125.90, 126.67, 126.78, 127.54, 128.27, 128.91, 133.08, 133.36, 136.11, 146.29 (2C), 152.71, 169.14; MS m/z 319 (M+, 0.90), 259 (100). Anal. Calcd for C19H17N3O2: C, 71.46; H, 5.37; N, 13.16. Found: C, 71.44; H, 5.45; N, 13.16.
1-Dimethylamino-1-phenyl-1,2-dihydropyrrolo[3,4-c]pyridin-3-one (2h): a pale-yellow solid; mp 212–214 ˚C (hexane–CHCl3); IR (KBr) 3173, 1699 cm–1; 1H NMR (500 MHz, CDCl3) δ 2.21 (s, 6H), 7.24 (br s, 1H), 7.32 (t, J = 7.3 Hz, 1H), 7.36–7.40 (m, 3H), 7,72 (d, J = 7.3 Hz, 2H), 8.70 (d, J = 5.0 Hz, 1H), 9.02 (s, 1H); 13C NMR (125 MH) δ 39.23, 85.34, 118.13, 125.66, 125.84, 128.84, 129.18, 139.96, 146.24, 152.76, 157.85, 169.58; MS m/z 253 (M+, 0.94), 193 (100). Anal. Calcd for C15H15N3O: C, 71.13; H, 5.97; N, 16.59. Found: C, 71.08; H, 6.01; N, 16.41.
1-(3-Chlorophenyl)-1-dimethylamino-1,2-dihydropyrrolo[3,4-c]pyridin-3-one (2i): a pale-yellow solid; mp 182–186 ˚C (hexane–CH2Cl2); IR (KBr) 3187, 1690 cm–1; 1H NMR (500 MHz, CDCl3) δ 2.20 (s, 6H), 6.99 (br s, 1H), 7.31–7.32 (m, 2H), 7.37 (dd, J = 5.2, 1.1 Hz, 1H), 7.58–7.60 (m, 1H), 7.74 (s, 1H), 8.73 (d, J = 5.2 Hz, 1H), 9.04 (s, 1H); 13C NMR (125 MHz) δ 39.23, 84.91, 118.05, 124.03, 125.49, 126.23, 129.10, 130.48, 135.30, 142.25, 146.42, 152.97, 157.21, 169.42; MS m/z 287 (M+, 0.66), 227 (100). Anal. Calcd for C15H14ClN3O: C, 62.61; H, 4.90; N, 14.60. Found: C, 62.38; H, 4.97; N, 14.41.
1-Dimethylamino-1-(3-methoxyphenyl)-1,2-dihydropyrrolo[3,4-c]pyridin-3-one (2j): a pale-yellow solid; mp 134–136 ˚C (hexane–CH2Cl2); IR (KBr) 3233, 1701 cm–1; 1H NMR (500 MHz, DMSO-d6) δ 2.04 (s, 6H), 3.75 (s, 3H), 6.88 (d, J = 6.9 Hz, 1H), 7.21–7.30 (m, 3H), 7.62 (d, J = 4.6 Hz, 1H), 8.69 (d, J = 4.6 Hz, 1H), 8.83 (s, 1H), 9.52 (s, 1H); 13C NMR (125 MHz) δ 38.76, 55.14, 84.31, 111.78, 113.61, 118.06, 118.34, 126.05, 129.96, 142.32, 145.04, 152.65, 157.30, 159.58, 168.05; MS m/z 283 (M+, 0.43), 223 (100). Anal. Calcd for C16H17N3O2: C, 67.83; H, 6.05; N, 14.83. Found: C, 67.83; H, 6.00; N, 14.89.

ACKNOWLEDGEMENT
We thank Mrs. Miyuki Tanmatsu of this university for recording mass spectra and performing combustion analyses.

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