Synthesis 2009(8): 1265-1270  
DOI: 10.1055/s-0028-1088029
PAPER
© Georg Thieme Verlag Stuttgart ˙ New York

Synthesis of Masked Vicinal Amino Aldehydes of Pyrrolizine and Pyrrolo [1,2-c]thiazole Series

Anton V. Tverdokhlebov*a, Alexander V. Denisenkob, Andrey A. Tolmacheva,b, Yulian M. Volovenkob, Svetlana V. Shishkinac, Oleg V. Shishkinc
a Enamine Ltd., Alexandra Matrosova str. 23, 01103, Kiev, Ukraine
Fax: +38(044)5373253; e-Mail: atver@univ.kiev.ua;
b Kiev National Taras Shevchenko University, Volodimirska str. 62, 01033, Kiev, Ukraine
c STC ‘Institute for Single Crystals’, NAS of Ukraine, 60 Lenina ave., 61001, Kharkiv, Ukraine

Further Information

Publication History

Received 29 September 2008
Publication Date:
25 March 2009 (online)

Abstract

Acylation of (1,3-dihydro-1,3-dimethyl-2H-benzimidazol-2-ylidene)acetonitrile with mixed anhydrides of N-Boc proline and 4-thiazolidinecarboxylic acid was found to proceed at the exocyclic carbon atom yielding the corresponding C-acyl derivatives. Removal of the protecting group with equimolar amount of hydrochloric acid effected simultaneous cyclization affording 2-(3-amino-5,6,7,7a-tetrahydro-1-oxo-1H-pyrrolizin-2-yl)- and 2-(5-amino-7,7a-dihydro-7-oxo-1H,3H-pyrrolo[1,2-c]thiazol-6-yl)-1,3-dimeth­ylbenzimidazolium chlorides. Reduction of the prepared salts with sodium borohydride resulted in 3-amino-2-(2,3-dihydro-1,3-di­methyl-1H-benzimidazol-2-yl)-5,6,7,7a-tetrahydro-1H-pyrrolizin-1-one and 5-amino-6-(2,3-dihydro-1,3-dimethyl-1H-benzimidazol-2-yl)-1,7a-dihydro-3H,7H-pyrrolo[1,2-c]thiazol-7-one, respectively. These compounds were shown to be masked aldehydes. Their reactions with phenylhydrazine and hydroxylamine yielded corresponding hydrazones and oximes, whereas condensation with malononitrile furnished 2-amino-5a,6,7,8-tetrahydro-5-oxo-5H-pyrido[3,2-b]pyrrolizine-3-carbonitrile and 2-amino-5a,6-dihydro-5H,8H-thiazolo[3′,4′:1,5]pyrrolo[2,3-b]pyridine-3-carbonitrile.

Vicinal (hetero)aromatic amino aldehydes are powerful synthons in heterocyclic chemistry. [¹] However, within the pyrrole series these derivatives are poorly represented, [²] whereas for the fused pyrroles like pyrrolizine they are hitherto unknown. Among all isomeric aminopyrrolizines, the 3(5)-substituted derivatives are of especial interest because of their structural relation to jenamidines alkaloid family. [³] At the same time the 3(5)-aminopyrrolizines are the least investigated in comparison with other amines of this structural framework. Only a few syntheses have been reported, [³-5] and most of them included various intramolecular nucleophilic additions of nitrogen or carbon to the nitrile group. [³] [4] Furthermore, attempts of electrophilic introduction of nitrogen functionalities into the pyrrolizine were examined, [5] but sometimes it was complicated with formation of a mixture of positional isomers. [5a]

In turn, 2(6)-formylpyrrolizines are the least studied derivatives among all the isomeric aldehydes of the pyrrolizine series. To the best of our knowledge, there are only 5 papers dealing with these compounds, [6] while more than 50 publications are devoted to other aldehydes of this structural framework. The single relatively general approach to pyrrolizine-2(6)-carboxaldehydes is the reaction of 2-acylpyrrole derivatives with acrolein [6a] [b] or its equivalents. [6c] Evidently, this method is incompatible with the presence of an amino group. A few less common syntheses known [6d] [e] also do not tolerate amine functionality. Hence, the 3-aminopyrrolizine-2-carboxaldehyde moiety represents a synthetic challenge we decided to meet.

N,N′-Dimethylbenzimidazolium moiety is an equivalent of the aldehyde functionality. [7] Its reduction to 2,3-dihydro derivative provides the masked formyl group, [7] which can be liberated by hydrolytic cleavage, if necessary. [7a] Recently we have applied such an approach to the preparation of 2-aminopyrrole-3-carboxaldehyde derivatives 1 (Figure  [¹] ) by reduction of the corresponding benzimidazolium salt precursors 2. [8] The latter were obtained in two steps from the nitrile 3 (Scheme  [¹] ) by means of C-acylation with chloroacetyl chloride followed by amination with primary amines. [8] As a continuation of our research in this field, the utility of the compound 3 for the synthesis of vicinal amino aldehyde derivatives of fused pyrroles has been studied, and the results obtained are reported herein.

Figure 1 3-Carboxaldehyde derivatives 1 and their precursors 2 (R is alkyl or substituted phenyl)

Scheme 1

Compound 3 reacts with certain electrophiles at the exocyclic carbon atom. [8] [9] Its reaction with mixed anhydrides of Boc-protected proline (4a, n = 1) and pipecolic acid (4b, n = 2) occurs smoothly affording derivatives 5a,b in 70-80% yields. The anhydrides 4a,b were generated in situ from the appropriate acids and ethyl chloroformate. It is noteworthy that previously the mixed anhydrides of protected proline were used for acylation of diazomethane only. [¹0] Other C-acyl derivatives were prepared by either Claisen type condensation of proline esters [¹¹] and imidazolides [¹²] or addition of organometallics to appropriate esters, [¹³] Weinreb amides, [¹4] and carboxylates. [¹5] Furthermore, the carbodiimide assisted acylation of certain phosphorus ylides was reported. [¹6] Thus, the present reaction has revealed applicability of mixed anhydrides of α-amino acids for acylation of the enamine type carbon.

Deprotection of the compounds 5a,b with an equimolar amount of hydrochloric acid furnished the benzimidazolium salts 6a,b in nearly quantitative yield. Obviously, derivatives 6 are formed through the hydrogen chloride assisted intramolecular addition of the liberated amine to the nitrile, which is accompanied by the transfer of charge to the benzimidazole moiety. Moreover, the sequence was successfully extended to the cysteine derived anhydride 7, thus leading to the salt 9 via the intermediate compound 8. The S,N-acetal fragment in the derivatives 8 and 9 survived completely the hydrolytic conditions of deprotection-cyclization step.

The structure of the compounds prepared 6 and 9 was initially deduced from their ¹H and ¹³C NMR spectra and then confirmed unambiguously by X-ray crystallographic study carried out for the derivative 6a (Figure  [²] ).

Figure 2 X-ray molecular structure of compound 6a˙2H2O with the atom numbering used in the crystallographic analysis

Further, reduction of the quaternary salts 6 and 9 was examined (Scheme  [²] ). Treatment of compounds 6a and 9 with excess sodium borohydride in methanol resulted in the masked amino aldehyde derivatives of pyrrolizine 10 and pyrrolo[1,2-c]thiazole 11 in moderate yields (30-40%). It should be noted that in the case of pyrroles 2 the yield of the reduction was at least twice higher. [8] Nonetheless, at the expense of the good yields on the previous steps, the method allows preparation of the target compounds 10 and 11 in 20-25% overall yield from the starting nitrile 3. However, in the case of indolizine derivative 6b even traces of the appropriate products like 10 and 11 were not detected in the reaction mixture and the starting salt 6b was completely recovered. [¹7] The reason for the different behavior of compound 6b is unclear. Nevertheless, we have noted the difference in the chemical shifts of 2-C of benzimidazolium moiety in derivatives 6a, 9 and 6b. Thus, in the ¹³C NMR spectra of compounds 6a and 9 this signal was observed at 170.8 and 170.6 ppm, respectively, whereas for the derivative 6b it appeared at 162.6 ppm. So far as the chemical shift value could be considered as indirect measure of electrophilicity of the appropriate carbon atom, these data showed lower reactivity of compound 6b compared to 6a and 9 thus agreeing with the experiment. Perhaps, another geometry of the molecule 6b results in different conjugation degree between the two bicyclic parts, thus influencing the reactivity. For more detailed conclusions the quantum chemical calculations are required.

Scheme 2 X = CH2 (10, 12, 14, 16); S (11, 13, 15, 17). Reagents and conditions: (i) PhNHNH2˙HCl, EtOH, reflux; (ii) NH2OH˙HCl, EtOH, reflux; (iii) cat. NH4Cl, CH2(CN)2, EtOH, reflux.

The amino aldehyde nature of the derivatives 10 and 11 was demonstrated by several transformations. Thus, their treatment with phenylhydrazine afforded the corresponding hydrazones 12 and 13. Similarly, the oximes 16 and 17 were obtained by reaction with hydroxylamine. Finally, the ammonium chloride catalyzed condensation with malononitrile yielded derivatives of tricyclic systems 14 and 15. It is noteworthy that compound 15 is the representative of the novel hitherto unknown heterocyclic skeleton of thiazolo[3′,4′:1,5]pyrrolo[2,3-b]pyridine. At the same time the pyrido[3,2-b]pyrrolizine system 14 is little known. To the best of our knowledge only four derivatives of this structural framework have been reported to date. [¹8]

In summary, the present investigation has resulted in the preparation of the first examples of vicinal amino aldehydes of the pyrrolizine and pyrrolo[1,2-c]thiazole series. Moreover, during the synthesis the acylation of the enamine type carbon with mixed anhydrides of N-protected α-amino acids has been carried out for the first time, thus revealing the principal applicability of the mixed anhydrides for C-acylations. Compound 3 turned out to be suitable starting material for the synthesis of amino aldehyde derivatives of monocyclic [8] and fused pyrroles. However, some limitations of the method have been also found. At present the dependence of the reduction of the salts of type 6,9 on the size and nature of the fused ring remains vague. Therefore, further research in the field is in progress.

The starting nitrile 3 was prepared according to the described procedure. [9a] N-Boc proline, pipecolic acid, and 4-thiazolidinecarboxylic acid were obtained as reported. [¹9] All melting points were determined in open capillary tubes in a Thiele apparatus and are uncorrected. Elemental analyses were performed at the microanalytical department of the Institute of Organic Chemistry, NAS, Kiev, Ukraine. ¹H and ¹³C NMR spectra were recorded on a Varian Unity plus 400 spectrometer (400 MHz for ¹H and 100 MHz for ¹³C) in DMSO-d 6. Chemical shifts (δ) are given in ppm downfield from internal Me4Si. J values are in Hz. The purity of all compounds obtained was checked by ¹H NMR and LC/MS on an Agilent 1100 instrument.

Nitriles 5a,b and 8; General Procedure

Ethyl chloroformate (0.77 g, 7.1 mmol) was added dropwise to an ice-cooled and stirred solution of the appropriate N-Boc amino acid (7.1 mmol) and Et3N (0.98 mL, 7.1 mmol) in anhyd dioxane (15 mL). After the addition was complete, the mixture was stirred at 10-15 ˚C for 1h. Then compound 3 (1.02 g, 5.5 mmol) was added in one portion and resulting mixture was slowly heated up to the boiling point and stirred at reflux for 1 h. Upon cooling the precipitated Et3N˙HCl was removed by filtration and the dioxane was evaporated to dryness in vacuo. The residue was triturated with H2O (20 mL), filtered, and recrystallized from aq i-PrOH to give derivatives 5a,b and 8.

2-[Cyano(1,3-dihydro-1,3-dimethyl-2 H -benzimidazol-2-ylidene)acetyl]-1-pyrrolidinecarboxylic Acid t -Butyl Ester (5a)

Yield: 1.64 g (78%); mp 128 ˚C (H2O-i-PrOH).

¹H NMR: δ = 1.41 (s, 9 H, t-C4H9), 1.84-1.94 (m, 3 H, 3,3,4-H), 2.31 (m, 1 H, 4-H), 3.39-3.49 (m, 2 H, 5-CH2), 3.74 (s, 6 H, 2 NCH3), 4.73 (m, 1 H, 2-H), 7.40 (m, 2 H, HAr), 7.61 (m, 1 H, HAr), 7.67 (m, 1 H, HAr).

¹³C NMR: δ = 24.0 (4-CH2), 28.6 [C(CH3)3], 31.1 (3-CH2), 33.3 (2 NCH3), 47.2 (5-CH2), 56.9 (CCN), 61.7 (2-CH), 78.7 [C(CH3)3], 112.1 (4,7-CBim), 121.9 (CN), 125.1 (5,6-CBim), 132.3 (3a,7a-CBim), 153.0 (2-CBim), 153.8 (COO), 189.7 (C=O).

Anal. Calcd for C21H26N4O3: C, 65.95; H, 6.85; N, 14.65. Found: C, 66.01; H, 6.82; N, 14.50.

2-[Cyano(1,3-dihydro-1,3-dimethyl-2 H -benzimidazol-2-ylidene)acetyl]-1-piperidinecarboxylic Acid t -Butyl Ester (5b)

Yield: 1.59 g (73%); mp 119 ˚C (H2O-i-PrOH).

¹H NMR: δ = 1.47 (s, 9 H, t-C4H9), 1.67-1.76 (m, 4 H, 4,5-CH2), 1.92 (m, 1 H, 3-H), 2.33 (m, 1 H, 3-H), 3.46 (m, 1 H, 6-H), 3.79 (s, 6 H, 2 NCH3), 3.96 (m, 1 H, 6-H), 5.23 (m, 1 H, 2-H), 7.44 (m, 4 H, HAr).

¹³C NMR: δ = 19.9 (4-CH2), 24.9 (5-CH2), 28.1 (3-CH2), 28.6 [C(CH3)3], 33.3 (2 N CH3), 42.1 (6-CH2), 43.0 (2-CH), 56.2 (CCN), 78.9 [C(CH3)3], 112.1 (4,7-CBim), 121.8 (CN), 125.2 (5,6-CBim), 132.4 (3a,7a-CBim), 153.1 (2-CBim), 155.6 (COO), 191.0 (C=O).

Anal. Calcd for C22H28N4O3: C, 66.65; H, 7.12; N, 14.13. Found: C, 66.60; H, 7.30; N, 14.20.

4-[Cyano(1,3-dihydro-1,3-dimethyl-2 H -benzimidazol-2-ylidene)acetyl]-3-thiazolidinecarboxylic Acid t -Butyl Ester (8)

Yield: 1.87 g (85%); mp 103 ˚C (H2O-i-PrOH).

¹H NMR: δ = 1.48 (s, 9 H, t-C4H9), 3.28 (dd, ² J = 11.5 Hz, ³ J = 5.5 Hz, 1 H, 5-H), 3.57 (m, 1 H, 5-H), 3.81 (s, 6 H, 2 NCH3), 4.61 (d, J = 6.5 Hz, 1 H, 2-H), 4.75 (m, 1 H, 4-H), 5.28 (d, J = 6.5 Hz, 1 H, 2-H), 7.45-7.48 (m, 4 H, HAr).

¹³C NMR: δ = 28.5 [C(CH3)3], 33.3 (2 NCH3), 35.3 (5-CH2), 50.0 (4-CH), 57.2 (CCN), 64.3 (2-CH2), 80.1 [C(CH3)3], 112.2 (4,7-CBim), 121.6 (CN), 125.3 (5,6-CBim), 132.3 (3a,7a-CBim), 152.5 (2-CBim), 153.1 (COO), 186.9 (C=O).

Anal. Calcd for C20H24N4O3S: C, 59.98; H, 6.04; N, 13.99; S, 8.01. Found: C, 59.92; H, 6.17; N, 13.90; S, 7.77.

Benzimidazolium Chlorides 6a,b and 9; General Procedure

A solution of the appropriate compound 5a,b, 8 (3 mmol) and concd HCl (0.33 mL) in i-PrOH (10 mL) was refluxed for 30-40 min. After cooling, the solid formed was filtered and washed with cold i-PrOH (5 mL) yielding pure derivatives 6a,b, 9. i-PrOH filtrate was evaporated to dryness in vacuo and the residue was crystallized from anhyd MeCN affording additional portion of compounds 6a,b, 9.

2-(3-Amino-5,6,7,7a-tetrahydro-1-oxo-1 H -pyrrolizin-2-yl)-1,3-dimethyl-3 H -benzimidazolium Chloride (6a)

Yield: 0.92 g (96%); mp >300 ˚C (i-PrOH).

¹H NMR: δ = 1.60 (m, 1 H, 6-H), 2.10-2.17 (m, 3 H, 6,7,7-H), 3.37 (m, 2 H, 5-CH2), 3.79 (s, 3 H, NCH3), 3.83 (s, 3 H, NCH3), 4.11 (dd, J = 9.5, 6.5 Hz, 1 H, 7a-H), 7.57 (m, 2 H, HAr), 7.91 (m, 2 H, HAr), 8.41 (s, 1 H, NH2), 8.62 (s, 1 H, NH2).

¹³C NMR: δ = 26.9 (6-C), 27.9 (7-C), 32.8 (NCH3), 33.2 (NCH3), 47.9 (5-C), 70.5 (7a-C), 79.5 (2-C), 112.8 (4-CBim), 113.1 (7-CBim), 125.9 (5-CBim), 126.0 (6-CBim), 132.3 (3a-CBim), 132.5 (7a-CBim), 147.3 (3-C), 170.8 (2-CBim), 191.3 (1-C=O).

Anal. Calcd for C16H19ClN4O: C, 60.28; H, 6.01; N, 17.57; Cl, 11.12. Found: C, 60.09; H, 5.82; N, 17.38; Cl, 11.37.

X-ray Crystal Structure [²0]

Suitable crystals of 6a were grown from aq EtOH in the form of hydrate with two molecules of H2O. Intensities of 28391 reflections (5137 independent, Rint = 0.038) were measured with ‘Xcalibur-3’ diffractometer operating in the ω-2Θ scan mode, 2Θmax = 60˚, and using graphite monochromated MoKα radiation (λ = 0.71073 Å). Crystal data: C16H19ClN4O˙2H2O, Mr = 354.83, monoclinic, a = 13.820(1), b = 9.191(1), c = 13.976(1) Å, β = 97.43(1)˚, V = 1760.4(1) ų, T = 293 K, space group P21/n, Z = 4, µ(MoKα) = 0.239 mm. The structure was solved by direct method using SHELXTL program package. [²¹] Positions of hydrogen atoms were located from electron density difference maps and refined by riding model with Uiso = nUeq of the carrier atom (n = 1.5 for methyl groups and n = 1.2 for the rest of hydrogens). Hydrogen atoms participating in hydrogen bonds were refined isotropically. Full-matrix least-squares refinement against F² in anisotropic approximation for nonhydrogen atoms using 5061 reflections was converged to R1 = 0.038, wR2 = 0.105 [for 2504 reflections with F>4σ(F)], S = 0.851.

2-(3-Amino-1,5,6,7,8,8a-hexahydro-1-oxo-2-indolizin-yl)-1,3-dimethyl-3 H -benzimidazolium Chloride (6b)

Yield: 0.99 g (99%); mp 245-246 ˚C (MeCN).

¹H NMR: δ = 1.36 (m, 2 H, 7-CH2), 1.52 (m, 1 H, 6-H), 1.73 (m, 1 H, 6-H), 1.85 (m, 1 H, 8-H), 2.06 (m, 1 H, 8-H), 3.04 (m, 1 H, 5-H), 4.32 (m, 1 H, 5-H), 4.72 (m, 7 H, 2 NCH3, 8a-H), 7.59 (m, 2 H, HAr), 7.91 (m, 2 H, HAr), 8.19 (s, 2 H, NH2).

¹³C NMR: δ = 22.8 (7-C), 25.9 (8-C), 28.9 (6-C), 33.0 (2 NCH3), 41.9 (5-C), 64.2 (8a-C), 76.9 (2-C), 113.0 (4-CBim), 113.1 (7-CBim), 125.9 (5-CBim), 126.0 (6-CBim), 132.4 (3a-CBim), 132.5 (7a-CBim), 147.6 (3-C), 162.6 (2-CBim), 189.9 (1-C=O).

Anal. Calcd for C17H21ClN4O: C, 61.35; H, 6.36; N, 16.83; Cl, 10.65. Found: C, 61.45; H, 6.22; N, 16.93; Cl, 10.53.

2-(5-Amino-7,7a-dihydro-7-oxo-1 H ,3 H -pyrrolo[1,2- c ]thiazol-6-yl)-1,3-dimethyl-3 H -benzimidazolium Chloride (9)

Yield: 0.96 g (95%); mp 302 ˚C (i-PrOH).

¹H NMR: δ = 3.10 (dd, ² J = 11.5 Hz, ³ J = 6.0 Hz, 1 H, 1-H), 3.30 (dd, ² J = 11.5, ³ J = 9.0 Hz, 1 H, 1-H), 3.82 (s, 6 H, 2 NCH3), 4.32 (d, J = 10.5 Hz, 1 H, 3-H), 4.38 (dd, ³ J = 6.0 Hz, ³ J = 9.0 Hz, 1 H, 7a-H), 5.04 (d, J = 10.5 Hz, 1 H, 3-H), 7.59-7.62 (m, 2 H, HAr), 7.92-7.94 (m, 2 H, HAr), 8.74 (s, 1 H, NH2), 9.13 (s, 1 H, NH2).

¹³C NMR: δ = 31.4 (1-C), 32.8 (NCH3), 33.1 (NCH3), 50.7 (3-C), 71.0 (7a-C), 80.0 (6-C), 113.1 (4-CBim), 113.3 (7-CBim), 126.2 (5-CBim), 126.3 (6-CBim), 132.3 (3a-CBim), 132.5 (7a-CBim), 146.5 (5-C), 170.6 (2-CBim), 189.5 (7-C=O).

Anal. Calcd for C15H17ClN4OS: C, 53.49; H, 5.09; N, 16.63; Cl, 10.52; S, 9.52. Found: C, 53.68; H, 4.87; N, 16.70; Cl, 10.54; S, 9.31.

Pyrrolizine 10 and Pyrrolo[1,2- c ]thiazole 11; General Procedure

NaBH4 (0.45 g, 14 mmol) was added in portions to a stirred and ice-cooled solution of the salts 6a or 9 (3.5 mmol) in MeOH (15 mL). After the addition was complete, the stirring was continued for 1 h and then the mixture was left overnight. The precipitate formed was filtered, washed with H2O (10 mL) and recrystallized from i-PrOH to give derivatives 10, 11.

3-Amino-2-(2,3-dihydro-1,3-dimethyl-1 H -benzimidazol-2-yl)-5,6,7,7a-tetrahydro-1 H -pyrrolizin-1-one (10)

Yield: 0.32 g (32%); mp 185 ˚C (i-PrOH).

¹H NMR: δ = 1.38 (m, 1 H, 6-H), 1.96 (m, 3 H, 6,7,7-H), 2.45 (s, 3 H, NCH3), 2.48 (s, 3 H, NCH3), 3.16 (m, 2 H, 5-CH2), 3.70 (m, 1 H, 7a-H), 4.58 (s, 1 H, 2-CHBim), 6.41 (m, 2 H, HAr), 6.58 (m, 2 H, HAr), 7.59 (br s, 2 H, NH2).

¹³C NMR: δ = 27.3 (6-C), 27.4 (7-C), 33.6 (NCH3), 33.7 (NCH3), 47.8 (5-C), 69.2 (7a-C), 84.7 (2-CBim), 88.3 (2-C), 106.8 (4-CBim), 107.2 (7-CBim), 119.3 (5-CBim), 119.6 (6-CBim), 143.0 (3a-CBim), 143.3 (7a-CBim), 174.5 (3-C), 195.2 (1-C=O).

Anal. Calcd for C16H20N4O: C, 67.58; H, 7.09; N, 19.70. Found: C, 67.81; H, 7.10; N, 19.70.

5-Amino-6-(2,3-dihydro-1,3-dimethyl-1 H -benzimidazol-2-yl)-1,7a-dihydro-3 H ,7 H -pyrrolo[1,2- c ]thiazol-7-one (11)

Yield: 0.43 g (41%); mp 172-173 ˚C (i-PrOH).

¹H NMR: δ = 2.44 (s, 3 H, NCH3), 2.47 (s, 3 H, NCH3), 2.94 (dd, ² J = 11.5 Hz, ³ J = 3.5 Hz, 1 H, 1-H), 3.17 (dd, ² J = 11.5 Hz, ³ J = 9.5 Hz, 1 H, 1-H), 3.95 (dd, ³ J = 3.5, 9.5 Hz, 1 H, 7a-H), 4.10 (d, J = 11.0 Hz, 1 H, 3-H), 4.57 (s, 1 H, 2-CHBim), 4.77 (d, J = 11.0 Hz, 1 H, 3-H), 6.43 (m, 2 H, HAr), 6.59 (m, 2 H, HAr), 6.74 (br s, 1 H, NH2), 7.94 (br s, 1 H, NH2).

¹³C NMR: δ = 32.2 (1-C), 33.5 (NCH3), 33.8 (NCH3), 51.7 (3-C), 69.7 (7a-C), 84.4 (2-CBim), 90.5 (6-C), 107.0 (4-CBim), 107.2 (7-CBim), 119.4 (5-CBim), 119.6 (6-CBim), 142.9 (3a-CBim), 143.3 (7a-CBim), 173.6 (5-C), 193.5 (7-C=O).

Anal. Calcd for C15H18N4OS: C, 59.58; H, 6.00; N, 18.53; S, 10.60. Found: C, 59.60; H, 5.84; N, 18.33; S, 10.46.

Phenylhydrazones 12, 13 and Oximes 16, 17; General Procedure

A solution of compound 10, 11 (2 mmol) and phenylhydrazine hydrochloride (0.37 g, 2.6 mmol) or hydroxylamine hydrochloride (0.18 g, 2.6 mmol) in EtOH (5 mL) was refluxed for 0.5 h. Upon cooling, the solid precipitated was filtered, washed with H2O (5 mL) and recrystallized from the appropriate solvent yielding derivatives 12, 13 or 16, 17.

3-Amino-5,6,7,7a-tetrahydro-1-oxo-1 H -pyrrolizine-2-carbox­aldehyde Phenylhydrazone (12)

Yield: 0.34 g (66%); mp 229-230 ˚C (i-PrOH).

¹H NMR: δ = 1.35 (m, 1 H, 6-H), 1.98 (m, 3 H, 6,7,7-H), 3.21 (m, 1 H, 5-H), 3.26 (m, 1 H, 5-H), 3.74 (m, 1 H, 7a-H), 6.61 (t, J = 7.0 Hz, 1 H, 4-HPh), 6.81 (d, J = 7.0 Hz, 2 H, 2,6-HPh), 7.13 (t, J = 7.0 Hz, 2 H, 3,5-HPh), 7.58 (s, 1 H, NH2), 7.67 (s, 1 H, N=CH), 8.22 (s, 1 H, NH2), 9.46 (s, 1 H, NH).

¹³C NMR: δ = 26.9 (6-C), 27.7 (7-C), 47.7 (5-C), 69.5 (7a-C), 93.1 (2-C), 111.7 (2,6-CPh), 117.7 (4-CPh), 129.5 (3,5-CPh), 135.1 (1-CPh), 146.6 (N=CH), 172.0 (3-C), 192.5 (1-C=O).

Anal. Calcd for C14H16N4O: C, 65.61; H, 6.29; N, 21.86. Found: C, 65.49; H, 6.07; N, 21.80.

5-Amino-7,7a-dihydro-7-oxo-1 H ,3 H -pyrrolo[1,2- c ]thiazole-6-carboxaldehyde Phenylhydrazone (13)

Yield: 0.37 g (67%); mp 257-258 ˚C (EtOH).

¹H NMR: δ = 2.92 (m, 1 H, 1-H), 3.18 (m, 1 H, 1-H), 4.00 (m, 1 H, 7a-H), 4.20 (d, J = 11.5 Hz, 1 H, 3-H), 4.81 (d, J = 11.5 Hz, 1 H, 3-H), 6.63 (t, J = 6.5 Hz, 1 H, 4-HPh), 6.85 (d, J = 6.5 Hz, 2 H, 2,6-HPh), 7.14 (t, J = 6.5 Hz, 2 H, 3,5-HPh), 7.67 (s, 1 H, N=CH), 7.79 (s, 1 H, NH2), 8.57 (s, 1 H, NH2), 9.61 (s, 1 H, NH).

¹³C NMR: δ = 31.8 (1-C), 51.6 (3-C), 70.0 (7a-C), 94.4 (6-C), 111.8 (2,6-CPh), 118.0 (4-CPh), 129.5 (3,5-CPh), 133.8 (1-CPh), 146.3 (N=CH), 171.2 (5-C), 191.0 (7-C=O).

Anal. Calcd for C13H14N4OS: C, 56.92; H, 5.14; N, 20.42; S, 11.69. Found: C, 56.74; H, 4.97; N, 20.27; S, 11.60.

3-Amino-5,6,7,7a-tetrahydro-1-oxo-1 H -pyrrolizine-2-carbox­aldehyde Oxime (16)

Yield: 0.22 g (60%); mp 220-221 ˚C (i-PrOH).

¹H NMR: δ = 1.33 (m, 1 H, 6-H), 1.97 (m, 3 H, 6,7,7-H), 3.16 (m, 1 H, 5-H), 3.22 (m, 1 H, 5-H), 3.73 (m, 1 H, 7a-H), 7.17 (s, 1 H, NH2), 7.66 (s, 1 H, N=CH), 8.20 (s, 1 H, NH2), 10.00 (s, 1 H, OH).

¹³C NMR: δ = 26.9 (6-C), 27.8 (7-C), 47.6 (5-C), 69.7 (7a-C), 90.3 (2-C), 142.9 (N=CH), 172.2 (3-C), 192.4 (1-C=O).

Anal. Calcd for C8H11N3O2: C, 53.03; H, 6.12; N, 23.19. Found: C, 52.87; H, 6.19; N, 23.20.

5-Amino-7,7a-dihydro-7-oxo-1 H ,3 H -pyrrolo[1,2- c ]thiazole-6-carboxaldehyde Oxime (17)

Yield: 0.25 g (63%); mp 242-243 ˚C (EtOH).

¹H NMR: δ = 2.88 (m, 1 H, 1-H), 3.17 (m, 1 H, 1-H), 4.00 (m, 1 H, 7a-H), 4.17 (d, J = 10.5 Hz, 1 H, 3-H), 4.75 (d, J = 10.5 Hz, 1 H, 3-H), 7.43 (s, 1 H, NH2), 7.67 (s, 1 H, N=CH), 8.56 (s, 1 H, NH2), 10.22 (s, 1 H, OH).

¹³C NMR: δ = 31.7 (1-C), 51.2 (3-C), 70.2 (7a-C), 91.6 (6-C), 142.1 (N=CH), 171.5 (5-C), 190.8 (7-C=O).

Anal. Calcd for C7H9N3O2S: C, 42.20; H, 4.55; N, 21.09; S, 16.09. Found: C, 42.16; H, 4.79; N, 21.10; S, 16.24.

Pyrido[3,2- b ]pyrrolizine 14 and Thiazolo[3′,4′:1,5]pyrrolo[2,3- b ]pyridine 15; General Procedure

A solution of compound 10, 11 (2 mmol), malononitrile (0.17 g, 2.6 mmol) and NH4Cl (0.01 g, 0.2 mmol) in EtOH (5 mL) was refluxed for 1 h. After cooling, the precipitate formed was filtered, washed with H2O (10 mL) and recrystallized from aq DMF affording derivatives 14,15.

2-Amino-5a,6,7,8-tetrahydro-5-oxo-5 H -pyrido[3,2- b ]pyrrolizine-3-carbonitrile (14)

Yield: 0.17 g (40%); mp 260 ˚C (DMF-H2O).

¹H NMR: δ = 1.25 (m, 1 H, 7-H), 2.20 (m, 3 H, 7,6,6-H), 3.09 (m, 1 H, 8-H), 3.28 (m, 1 H, 8-H), 4.53 (dd, J = 10.0, 6.0 Hz, 1 H, 5a-H), 8.00 (s, 1 H, 4-H), 8.16 (s, 1 H, NH2), 8.27 (s, 1 H, NH2).

¹³C NMR: δ = 24.1 (7-C), 27.1 (6-C), 47.2 (8-C), 74.6 (5a-C), 83.1 (3-C), 108.3 (4a-C), 117.4 (CN), 141.7 (4-C), 163.9 (2-C), 173.8 (9a-C), 193.6 (5-C=O).

Anal. Calcd for C11H10N4O: C, 61.67; H, 4.71; N, 26.15. Found: C, 61.53; H, 4.73; N, 26.20.

2-Amino-5a,6-dihydro-5-oxo-5 H ,8 H -thiazolo-[3′,4′:1,5]pyrrolo[2,3- b ]pyridine-3-carbonitrile (15)

Yield: 0.32 g (68%); mp 207 ˚C (DMF-H2O).

¹H NMR: δ = 2.92 (m, 1 H, 6-H), 3.28 (m, 1 H, 6-H), 4.33 (m, 2 H, 5a-H, 8-H), 4.94 (d, J = 9.0 Hz, 1 H, 8-H), 8.04 (s, 1 H, 4-H), 8.18 (br s, 2 H, NH2).

¹³C NMR: δ = 31.5 (6-C), 49.6 (8-C), 71.4 (5a-C), 85.2 (3-C), 106.5 (4a-C), 117.2 (CN), 140.6 (4-C), 164.5 (2-C), 172.5 (9a-C), 193.7 (5-C=O).

Anal. Calcd for C10H8N4OS: C, 51.71; H, 3.47; N, 24.12; S, 13.80. Found: C, 51.70; H, 3.64; N, 24.19; S, 13.94.

    References

  • 1 For a review, see: Caluwe P. Tetrahedron  1980,  36:  2359 
  • 2 Eger K. Pfahl JG. Folkers G. Roth HJ. J. Heterocycl. Chem.  1987,  24:  425 
  • 3a Snider BB. Duvall JR. Sattler I. Huang X. Tetrahedron Lett.  2004,  45:  6725 
  • 3b Snider BB. Duvall JR. Org. Lett.  2005,  7:  4519 
  • 3c Duvall JR. Wu F. Snider BB. J. Org. Chem.  2006,  71:  8579 
  • 4a Volovenko YuM. Shokol TV. Babichev FS. Dopov. Akad. Nauk Ukr. RSR, Ser. B.  1986,  2:  35 ; Chem. Abstr. 1987, 107, 163331
  • 4b Volovenko YuM. Chem. Heterocycl. Compd. (Engl. Transl.)  1997,  33:  854 ; Khim. Geterotsikl. Soedin. 1997, 975
  • 4c Hartke K. Radau S. Liebigs Ann. Chem.  1974,  2110 
  • 4d Fares V. Flamini A. Poli N. J. Am. Chem. Soc.  1995,  117:  11580 
  • 4e Bonamico M. Fares V. Flamini A. Imperatori P. Poli N. Angew. Chem., Int. Ed. Engl.  1989,  28:  1049 
  • 4f Fares V. Flamini A. Poli N. J. Chem. Res., Synop.  1995,  228 
  • 4g Bonamico M. Fares V. Flamini A. Giuliani AM. Imperatori P. J. Chem. Soc., Perkin Trans. 2  1988,  1447 
  • 4h Collange E. Flamini A. Poli R. J. Phys. Chem.  2002,  A106:  200 
  • 4i Flamini A. Fares V. Capobianchi A. Valentini V. J. Chem. Soc., Perkin Trans. 1  2001,  3069 
  • 5a Yang Z. Zhang S. J. Indian Chem. Soc.  2002,  79:  698 
  • 5b Sun G. Yang Z. Zhang S. J. Indian Chem. Soc.  2003,  80:  851 
  • 6a Varlamov AV. Borisova TN. Bonifas N. Chernyshev AI. Alexandrov GG. Voskresensky LG. Chem. Heterocycl. Compd. (Engl. Transl.)  2004,  40:  166 ; Khim. Geterotsikl. Soedin. 2004, 201
  • 6b Clare BW. Ferro V. Skeleton BW. Stick RV. White AH. Aust. J. Chem.  1993,  46:  805 
  • 6c Abbiati G. Casoni A. Canevari V. Nava D. Rossi E. Org. Lett.  2006,  8:  4839 
  • 6d Hamersma JAM. Nossin PMM. Speckamp WN. Tetrahedron  1985,  41:  1999 
  • 6e Dannhardt G. Lehr M. Arch. Pharm. (Weinheim, Ger.)  1988,  321:  545 
  • 7a Craig JC. Ekwuribe NN. Fu CC. Walker KAM. Synthesis  1981,  303 
  • 7b Ramos JM. Tarazi M. Wuest JD. J. Org. Chem.  1987,  52:  5437 
  • 7c Katritzky AR. Aslan DC. Oniciu DC. Tetrahedron: Asymmetry  1998,  2245 
  • 7d Lee I.-SH. Jeoung EH. Kreevoy MM. J. Am. Chem. Soc.  1997,  119:  2722 
  • 7e Lee I.-SH. Jeoung EH. J. Org. Chem.  1998,  63:  7275 
  • 8 Tverdokhlebov AV. Denisenko AV. Tolmachev AA. Volovenko YuM. Synthesis  2007,  1811 
  • 9a Rudnev MI. Kurbatov VP. Chub NK. Osipov OA. J. Gen. Chem. USSR (Engl. Transl.)  1988,  58:  2077 ; Zh. Obshch. Khim. 1988, 58, 2334
  • 9b Zakhs ER. Ponyaev AI. Subbotina MA. El’tsov AV. Russ. J. Gen. Chem. (Engl. Transl.)  2001,  71:  1076 ; Zh. Obshch. Khim. 2001, 71, 1142
  • 9c Zakhs ER. Subbotina MA. El’tsov AV. J. Org. Chem. USSR (Engl. Transl.)  1979,  15:  178 ; Zh. Org. Khim. 1979, 15, 200
  • 10a Gavai AV. Vaz RJ. Mikkilineni AM. Roberge JY. Liu Y. Lawrence RM. Corte JR. Yang W. Bednarz M. Dickson JK. Ma Z. Seethala R. Feyen JHM. Bioorg. Med. Chem. Lett.  2005,  15:  5478 
  • 10b Bures F. Kulhanek J. Tetrahedron: Asymmetry  2005,  16:  1347 
  • 10c Bernard E. Vanderesso R. Tetrahedron Lett.  2004,  45:  8603 
  • 10d Vasanthakumar G.-R. Patil BS. Suresh Babu VV. J. Chem. Soc., Perkin Trans. 1  2002,  2087 
  • 10e Lakeev SN. Mullagalin IZ. Galin FZ. Majdanova IO. Abdullin MF. Russ. Chem. Bull.  2002,  51:  2230 ; Izv. Akad. Nauk Ser. Khim. 2002, 2071
  • 10f Wallen EAA. Christiaans JAM. Saario SM. Forsberg MM. Venäläinen JI. Paso HM. Männistö PT. Gynther J. Bioorg. Med. Chem.  2002,  10:  2199 
  • 10g Harrison JR. O’Brien P. Porter DW. Smith NM. J. Chem. Soc., Perkin Trans. 1  1999,  3623 
  • 10h Plucinska K. Liberek B. Tetrahedron  1987,  43:  3509 
  • 10i Fujimoto K. Iwano Y. Hirai K. Sugawara S. Chem. Pharm. Bull.  1986,  34:  999 
  • 11a Wada CK. Holms JH. Curtin ML. Dai Y. Florjancic AS. Garland RB. Guo Y. Heyman HR. Stacey JR. Steinman DH. Albert DH. Bouska JJ. Elmore IN. Goodfellow CL. Marcotte PA. Tapang P. Morgan DW. Michaelides MR. Davidsen SK. J. Med. Chem.  2002,  45:  219 
  • 11b Koskinen AMP. Kallatsa OA. Tetrahedron  2003,  59:  6947 
  • 11c Verbicky CA. Zercher CK. J. Org. Chem.  2000,  65:  5615 
  • 11d Yuste F. Ortiz B. Carrasco A. Peralta M. Quintero L. Sanchez-Obregon R. Walls F. Garcia Ruano JL. Tetrahedron: Asymmetry  2000,  11:  3079 
  • 11e Wittenberger SJ. J. Org. Chem.  1996,  61:  356 
  • 12a Bal G. Van der Veken P. Antonov D. Lambeir A.-M. Grellier P. Croft SL. Augustyns A. Halmers A. Bioorg. Med Chem. Lett.  2003,  13:  2875 
  • 12b Hoffman RV. Tao J. J. Org. Chem.  1999,  64:  126 
  • 13a Chen P. Cheng PTN. Spergel SH. Zahler R. Wang X. Thottathil J. Barrish JC. Polniaszek RP. Tetrahedron Lett.  1997,  38:  3175 
  • 13b De Luca L. Giacomelli G. Porcheddu A. Org. Lett.  2001,  3:  1519 
  • 13c Heathcock CH. von Geldern TW. Heterocycles  1987,  25:  75 
  • 13d Elliott RL. Kopecka H. Lin N.-H. He Y. Garvey DS. Synthesis  1995,  772 
  • 14a De Luca L. Giacomelli G. Taddei M. J. Org. Chem.  2001,  66:  2534 
  • 14b Knight JG. Ley SV. Tetrahedron Lett.  1991,  32:  7119 
  • 15a Overman LE. Lesuisse D. Tetrahedron Lett.  1985,  26:  4167 
  • 15b Evans DA. Nelson JV. Vogel E. Taber TR. J. Am. Chem. Soc.  1981,  103:  3099 
  • 15c Goldstein SW. Overman LE. Rabinowitz MH. J. Org. Chem.  1992,  57:  1179 
  • 16a Aitken RA. Karodia N. Massil T. Young RJ. J. Chem. Soc., Perkin Trans. 1  2002,  533 
  • 16b Aitken RA. Karodia N. J. Chem. Soc., Chem. Commun.  1996,  2079 
  • 18a Nomura Y. Bando T. Takeuchi Y. Tomoda S. Bull. Chem. Soc. Jpn.  1984,  57:  1271 
  • 18b Laduree D. Robba M. Heterocycles  1984,  22:  303 
  • 19a Harris BD. Bhat KL. Joullie M. Heterocycles  1986,  24:  1045 
  • 19b Swarbrick ME. Gosselin F. Lubell WD. J. Org. Chem.  1999,  64:  1993 
  • 19c Oiry J. Pue JY. Fatome M. Sentenac-Roumanou H. Lion C. Imbach JL. Eur. J. Med. Chem.  1992,  27:  809 
  • 21 Sheldrick G. M. SHELXTL PLUS. PC version. A System of Computer Programs for the Determination of Crystal Structure from X-ray Diffraction Data. Rev. 5.1.   University of Göttingen; Germany: 1998. 
17

To be precise, the material recovered from the reaction exhibited the same ¹H and ¹³C NMR spectra as that of compound 6b, but differed in melting point and elemental analysis, having significant lack of Cl. Probably, it was a mixture of the salts 6b with different counterions, namely chloride, hydroxide, and, maybe, borate. Treatment of this material with HCl afforded compound 6b identical with the authentic sample in all parameters.

20

Full crystallographic parameters have been deposited at the Cambridge Crystallographic Data Centre under reference number CCDC 702208. These data can be obtained free of charge at www.ccdc.cam.ac.uk/conts/retrieving.html [or from the Cambridge Crystallographic Data Centre, 12, Union Road, Cambridge CB2 1EZ, UK; fax: +44(1223)336-033; e-mail: deposit@ccdc.cam.ac.uk].

    References

  • 1 For a review, see: Caluwe P. Tetrahedron  1980,  36:  2359 
  • 2 Eger K. Pfahl JG. Folkers G. Roth HJ. J. Heterocycl. Chem.  1987,  24:  425 
  • 3a Snider BB. Duvall JR. Sattler I. Huang X. Tetrahedron Lett.  2004,  45:  6725 
  • 3b Snider BB. Duvall JR. Org. Lett.  2005,  7:  4519 
  • 3c Duvall JR. Wu F. Snider BB. J. Org. Chem.  2006,  71:  8579 
  • 4a Volovenko YuM. Shokol TV. Babichev FS. Dopov. Akad. Nauk Ukr. RSR, Ser. B.  1986,  2:  35 ; Chem. Abstr. 1987, 107, 163331
  • 4b Volovenko YuM. Chem. Heterocycl. Compd. (Engl. Transl.)  1997,  33:  854 ; Khim. Geterotsikl. Soedin. 1997, 975
  • 4c Hartke K. Radau S. Liebigs Ann. Chem.  1974,  2110 
  • 4d Fares V. Flamini A. Poli N. J. Am. Chem. Soc.  1995,  117:  11580 
  • 4e Bonamico M. Fares V. Flamini A. Imperatori P. Poli N. Angew. Chem., Int. Ed. Engl.  1989,  28:  1049 
  • 4f Fares V. Flamini A. Poli N. J. Chem. Res., Synop.  1995,  228 
  • 4g Bonamico M. Fares V. Flamini A. Giuliani AM. Imperatori P. J. Chem. Soc., Perkin Trans. 2  1988,  1447 
  • 4h Collange E. Flamini A. Poli R. J. Phys. Chem.  2002,  A106:  200 
  • 4i Flamini A. Fares V. Capobianchi A. Valentini V. J. Chem. Soc., Perkin Trans. 1  2001,  3069 
  • 5a Yang Z. Zhang S. J. Indian Chem. Soc.  2002,  79:  698 
  • 5b Sun G. Yang Z. Zhang S. J. Indian Chem. Soc.  2003,  80:  851 
  • 6a Varlamov AV. Borisova TN. Bonifas N. Chernyshev AI. Alexandrov GG. Voskresensky LG. Chem. Heterocycl. Compd. (Engl. Transl.)  2004,  40:  166 ; Khim. Geterotsikl. Soedin. 2004, 201
  • 6b Clare BW. Ferro V. Skeleton BW. Stick RV. White AH. Aust. J. Chem.  1993,  46:  805 
  • 6c Abbiati G. Casoni A. Canevari V. Nava D. Rossi E. Org. Lett.  2006,  8:  4839 
  • 6d Hamersma JAM. Nossin PMM. Speckamp WN. Tetrahedron  1985,  41:  1999 
  • 6e Dannhardt G. Lehr M. Arch. Pharm. (Weinheim, Ger.)  1988,  321:  545 
  • 7a Craig JC. Ekwuribe NN. Fu CC. Walker KAM. Synthesis  1981,  303 
  • 7b Ramos JM. Tarazi M. Wuest JD. J. Org. Chem.  1987,  52:  5437 
  • 7c Katritzky AR. Aslan DC. Oniciu DC. Tetrahedron: Asymmetry  1998,  2245 
  • 7d Lee I.-SH. Jeoung EH. Kreevoy MM. J. Am. Chem. Soc.  1997,  119:  2722 
  • 7e Lee I.-SH. Jeoung EH. J. Org. Chem.  1998,  63:  7275 
  • 8 Tverdokhlebov AV. Denisenko AV. Tolmachev AA. Volovenko YuM. Synthesis  2007,  1811 
  • 9a Rudnev MI. Kurbatov VP. Chub NK. Osipov OA. J. Gen. Chem. USSR (Engl. Transl.)  1988,  58:  2077 ; Zh. Obshch. Khim. 1988, 58, 2334
  • 9b Zakhs ER. Ponyaev AI. Subbotina MA. El’tsov AV. Russ. J. Gen. Chem. (Engl. Transl.)  2001,  71:  1076 ; Zh. Obshch. Khim. 2001, 71, 1142
  • 9c Zakhs ER. Subbotina MA. El’tsov AV. J. Org. Chem. USSR (Engl. Transl.)  1979,  15:  178 ; Zh. Org. Khim. 1979, 15, 200
  • 10a Gavai AV. Vaz RJ. Mikkilineni AM. Roberge JY. Liu Y. Lawrence RM. Corte JR. Yang W. Bednarz M. Dickson JK. Ma Z. Seethala R. Feyen JHM. Bioorg. Med. Chem. Lett.  2005,  15:  5478 
  • 10b Bures F. Kulhanek J. Tetrahedron: Asymmetry  2005,  16:  1347 
  • 10c Bernard E. Vanderesso R. Tetrahedron Lett.  2004,  45:  8603 
  • 10d Vasanthakumar G.-R. Patil BS. Suresh Babu VV. J. Chem. Soc., Perkin Trans. 1  2002,  2087 
  • 10e Lakeev SN. Mullagalin IZ. Galin FZ. Majdanova IO. Abdullin MF. Russ. Chem. Bull.  2002,  51:  2230 ; Izv. Akad. Nauk Ser. Khim. 2002, 2071
  • 10f Wallen EAA. Christiaans JAM. Saario SM. Forsberg MM. Venäläinen JI. Paso HM. Männistö PT. Gynther J. Bioorg. Med. Chem.  2002,  10:  2199 
  • 10g Harrison JR. O’Brien P. Porter DW. Smith NM. J. Chem. Soc., Perkin Trans. 1  1999,  3623 
  • 10h Plucinska K. Liberek B. Tetrahedron  1987,  43:  3509 
  • 10i Fujimoto K. Iwano Y. Hirai K. Sugawara S. Chem. Pharm. Bull.  1986,  34:  999 
  • 11a Wada CK. Holms JH. Curtin ML. Dai Y. Florjancic AS. Garland RB. Guo Y. Heyman HR. Stacey JR. Steinman DH. Albert DH. Bouska JJ. Elmore IN. Goodfellow CL. Marcotte PA. Tapang P. Morgan DW. Michaelides MR. Davidsen SK. J. Med. Chem.  2002,  45:  219 
  • 11b Koskinen AMP. Kallatsa OA. Tetrahedron  2003,  59:  6947 
  • 11c Verbicky CA. Zercher CK. J. Org. Chem.  2000,  65:  5615 
  • 11d Yuste F. Ortiz B. Carrasco A. Peralta M. Quintero L. Sanchez-Obregon R. Walls F. Garcia Ruano JL. Tetrahedron: Asymmetry  2000,  11:  3079 
  • 11e Wittenberger SJ. J. Org. Chem.  1996,  61:  356 
  • 12a Bal G. Van der Veken P. Antonov D. Lambeir A.-M. Grellier P. Croft SL. Augustyns A. Halmers A. Bioorg. Med Chem. Lett.  2003,  13:  2875 
  • 12b Hoffman RV. Tao J. J. Org. Chem.  1999,  64:  126 
  • 13a Chen P. Cheng PTN. Spergel SH. Zahler R. Wang X. Thottathil J. Barrish JC. Polniaszek RP. Tetrahedron Lett.  1997,  38:  3175 
  • 13b De Luca L. Giacomelli G. Porcheddu A. Org. Lett.  2001,  3:  1519 
  • 13c Heathcock CH. von Geldern TW. Heterocycles  1987,  25:  75 
  • 13d Elliott RL. Kopecka H. Lin N.-H. He Y. Garvey DS. Synthesis  1995,  772 
  • 14a De Luca L. Giacomelli G. Taddei M. J. Org. Chem.  2001,  66:  2534 
  • 14b Knight JG. Ley SV. Tetrahedron Lett.  1991,  32:  7119 
  • 15a Overman LE. Lesuisse D. Tetrahedron Lett.  1985,  26:  4167 
  • 15b Evans DA. Nelson JV. Vogel E. Taber TR. J. Am. Chem. Soc.  1981,  103:  3099 
  • 15c Goldstein SW. Overman LE. Rabinowitz MH. J. Org. Chem.  1992,  57:  1179 
  • 16a Aitken RA. Karodia N. Massil T. Young RJ. J. Chem. Soc., Perkin Trans. 1  2002,  533 
  • 16b Aitken RA. Karodia N. J. Chem. Soc., Chem. Commun.  1996,  2079 
  • 18a Nomura Y. Bando T. Takeuchi Y. Tomoda S. Bull. Chem. Soc. Jpn.  1984,  57:  1271 
  • 18b Laduree D. Robba M. Heterocycles  1984,  22:  303 
  • 19a Harris BD. Bhat KL. Joullie M. Heterocycles  1986,  24:  1045 
  • 19b Swarbrick ME. Gosselin F. Lubell WD. J. Org. Chem.  1999,  64:  1993 
  • 19c Oiry J. Pue JY. Fatome M. Sentenac-Roumanou H. Lion C. Imbach JL. Eur. J. Med. Chem.  1992,  27:  809 
  • 21 Sheldrick G. M. SHELXTL PLUS. PC version. A System of Computer Programs for the Determination of Crystal Structure from X-ray Diffraction Data. Rev. 5.1.   University of Göttingen; Germany: 1998. 
17

To be precise, the material recovered from the reaction exhibited the same ¹H and ¹³C NMR spectra as that of compound 6b, but differed in melting point and elemental analysis, having significant lack of Cl. Probably, it was a mixture of the salts 6b with different counterions, namely chloride, hydroxide, and, maybe, borate. Treatment of this material with HCl afforded compound 6b identical with the authentic sample in all parameters.

20

Full crystallographic parameters have been deposited at the Cambridge Crystallographic Data Centre under reference number CCDC 702208. These data can be obtained free of charge at www.ccdc.cam.ac.uk/conts/retrieving.html [or from the Cambridge Crystallographic Data Centre, 12, Union Road, Cambridge CB2 1EZ, UK; fax: +44(1223)336-033; e-mail: deposit@ccdc.cam.ac.uk].

Figure 1 3-Carboxaldehyde derivatives 1 and their precursors 2 (R is alkyl or substituted phenyl)

Scheme 1

Figure 2 X-ray molecular structure of compound 6a˙2H2O with the atom numbering used in the crystallographic analysis

Scheme 2 X = CH2 (10, 12, 14, 16); S (11, 13, 15, 17). Reagents and conditions: (i) PhNHNH2˙HCl, EtOH, reflux; (ii) NH2OH˙HCl, EtOH, reflux; (iii) cat. NH4Cl, CH2(CN)2, EtOH, reflux.