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Unexpected Thorpe Reaction of an α-Alkoxynitrile

Department of Medicinal Chemistry, University of Szeged, Dóm tér 8., H-6720 Szeged, Hungary
Molecules 2000, 5(2), 127-131;
Submission received: 19 January 2000 / Accepted: 14 February 2000 / Published: 17 February 2000


α-Alkoxynitrile 1 in the presence of tris(methylthio)methyllithium 2 at –78°C gave the dimer 5 instead of the expected C1-elongated product 3. The formation of com-pound 5 is explained in terms of anion formation and self-condensation, a variant of the Thorpe reaction. Scrutinizing the 1H NMR spectra revealed that the enamine tautomer 5b is predominant over the imine 5a in the solvents investigated.


Nitrile 1 (Scheme 1) was obtained en route to acyclic analogues of the C-nucleoside tiazofurin [1]. This compound was deemed to be a good starting material for the synthesis of α-keto ester 4 via in-termediate 3. This assumption was based on analogy with the Grignard reaction of nitriles giving rise to ketones [2] or the Blaise reaction (Reformatsky reaction of nitriles affording β-keto esters) [3].
For the required carboxylate anion synthon different tris(alkylthio or arylthio)methyllithiums, de-rived from tris(alkyl or arylthio)methanes [4], were used successfully in the C1 elongation of ketones [5] and lactones [6]. Most often [tris(methylthio)methyl]lithium (2) was applied which is stable up to –40°C [7]. The obtained trithioorthoesters can be transformed into the corresponding esters using the common mercury(II) salt-assisted demercaptalisation procedure. In principle, alkyl chloroformates could also be employed as C1 synthons. However, in the single reported Reformatsky-type reaction of ethyl chloroformate with ethyl acetoacetate in the presence of a zinc-copper couple leading to diethyl 2-hydroxy-2-methylsuccinate, the yield was rather low (20%) [8]. In a recent application, ethyl chloro-formate was allowed to react with methyl phenylglyoxylate in a titanium(IV)-promoted reaction to af-ford ethyl methyl 2-hydroxy-2-phenylmalonate in 60% yield [9].

Results and Discussion

Nitrile 1 was allowed to react with compound 2 at –78°C for 4 h. Contrary to our expectations, compound 3 was not obtained. The isolated substance exhibited surprisingly complicated 1H NMR spectra in different solvents, according to the microanalysis it contained no sulfur and its elemental composition was identical with that of nitrile 1. Its low-voltage (15 eV) EI mass spectrum showed a molecular ion at m/z 622 (the molecular mass of the starting nitrile is 311) and a fragmentation pattern compatible only with the dimeric structures 5a and 5b. Scrutiny of the 1H NMR spectrum revealed that the substance exists as an enamine (5b) rather than an imine (5a). The IR spectrum also confirmed the presence of a nitrile group (νCN 2180 cm-1).
The literature search for precedents (Beilstein’s CrossFire 4.0, release BS9902PRPR using Beilstein Commander 4.0) showed that α-alkoxynitriles react normally with Grignard reagents [10] while orga-nolithium [11] and organosodium compounds [12,13] provoke self-condensation. This can be ex-plained by the strong basicity of organolithiums and the result is, just as in the above instance, the spe-cial case of the well-known Thorpe reaction [14] (Scheme 2).
It is noteworthy that even acetonitrile tends to react abnormally with Grignard reagents, e.g. with phenylmagnesium bromide, only 42% of the expected acetophenone has been obtained along with 32% of benzene [15]. Nitriles lacking α-hydrogens react normally and afford ketones.



To tris(methylthio)methane [4] (0.927 g, 6.0 mmol) dissolved in anhydrous THF (2.0 mL) was added butyllithium (1.26 M solution, 5.20 mL, 6.60 mL) at -78°C under nitrogen. Nitrile 1 [1] (1.40 g, 4.5 mmol) dissolved in anhydrous THF (10.0 mL) was added dropwise to this solution after 20 min and kept at –78°C for 4 h. The reaction mixture was quenched at –60°C with satd. NH4Cl solution. Af-ter allowing to warm up to room temperature, the mixture was diluted and extracted with chloroform (25 mL). The aqueous phase was extracted with chloroform (2 × 50 mL). The combined organic phases were dried (MgSO4) and evaporated in vacuo. Chromatographic purification using 20% (v/v) ethyl acetate in hexanes afforded 3-amino-2,4-bis{2-(benzyloxy)-1-[(benzyloxy)methyl]-ethoxy}-2-butene-nitrile (5, 0.56 g, 40%) as a yellow oil.

Spectral Data

IR (KBr, ν, cm-1): 3450m, 3330m, 3020m, 2910s, 2860s, 2180m, 1680m, 1493m, 1450m, 1090m.
1H NMR (CDCl3, 200 MHz, δ, ppm): 3.55 (d, J 6 Hz, 4 H, 2 x CH2); 3.65 (d, J 6 Hz, 4 H, 2 x CH2); 3.71 (m, 1 H, CH); 3.94 (m, 1 H, CH); 4.37 (s, 2 H, 4-CH2); 4.49 (s, 4 H, 2 x PhCH2); 4.52 (s, 4 H, 2 x PhCH2); 5.45 (br s, exchangeable with D2O, 2 H, NH2); 7.30 (m, 20 H, 4 x C6H5).
1H NMR (DMSO-d6, 200 MHz, δ, ppm): 3.52 (d, J 5 Hz, 4 H, 2 x CH2); 3.65 (d, J 5 Hz, 4 H, 2 x CH2); 3.72 (m, 1 H, CH); 3.88 (m, 1 H, H); 4.20 (s, 2 H, 4-CH2); 4.45 (s, 8 H, 4 x PhCH2); 6.00 (br s, exchangeable with D2O, 2 H, NH2); 7.30 (m, 20 H, 4 x C6H5).
EI-MS (15 eV, m/z, %): 622 (5, M+); 531 (1, M-91); 418 (4); 387 (4); 367 [4, M-CH(CH2OBn)2]; 331 (6); 292 (9); 278 (24); 220 (14); 181 (75); 102 (88); 91 (100, C7H7+).
Anal. calcd. for C38H42N2O6 (622.750): C, 73.29; H, 6.80; N, 4.50; found: C, 73.49; H, 6.71; N, 4.18.

References and Notes

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  • Samples Availability: not available.
Scheme 1.  
Scheme 1.  
Molecules 05 00127 sch001
Scheme 2.  
Scheme 2.  
Molecules 05 00127 sch002

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Kovács, L. Unexpected Thorpe Reaction of an α-Alkoxynitrile. Molecules 2000, 5, 127-131.

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Kovács L. Unexpected Thorpe Reaction of an α-Alkoxynitrile. Molecules. 2000; 5(2):127-131.

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Kovács, Lajos. 2000. "Unexpected Thorpe Reaction of an α-Alkoxynitrile" Molecules 5, no. 2: 127-131.

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