One-Pot Generation of C≡X Bonds from Methyl 2-Siloxycyclopropane­carboxylates: Simple Syntheses of Functionalized Nitriles and Alkynes

Abstract

Starting from methyl 2-siloxycyclopropanecarboxylates simple and efficient one-pot procedures are described that lead to β-cyanoesters and methoxycarbonyl-substituted terminal alkynes. The prepared functionalized alkynes were subjected to typical transformations such as [3+2] cycloaddition providing triazole derivatives, Sonogashira coupling, Au-catalyzed hydrophosphorylation or a copper-catalyzed coupling of methyl diazoacetate furnishing alkyne 14 and allene derivative 15. The Pauson–Khand reaction of the enyne 4c afforded a diastereomeric mixture of methyl 5-oxohexahydropentalen-2-carboxylate 16 in moderate yield.

Key words

cyclopropanes - nitriles - alkynes - Bestmann–Ohira reagent - Click reaction - Pauson–Khand reaction - enol phosphates

• References and Notes


The term donor–acceptor cyclopropane was introduced in this report:
• 1a Reissig H.-U, Hirsch E. Angew. Chem., Int. Ed. Engl. 1980; 19: 813 ; Angew. Chem. 1980 , 92, 839

Earlier examples of this class of cyclopropanes are certainly known. See:
• 1b Cram DJ, Ratajczak A. J. Am. Chem. Soc. 1968; 90: 2198
• 1c Cram DJ, Yankee EW. J. Am. Chem. Soc. 1970; 92: 6329

For first synthetic applications also see:
• 1d Wenkert E. Acc. Chem. Res. 1980; 13: 27

For reviews on d–a cyclopropanes, see:
• 2a Reissig H.-U. Top. Curr. Chem. 1988; 144: 73
• 2b Reissig H.-U, Zimmer R. Chem. Rev. 2003; 103: 1151
• 2c Gnad F, Reiser O. Chem. Rev. 2003; 103: 1603
• 2d Yu M, Pagenkopf BL. Tetrahedron 2005; 61: 321
• 2e De Simone F, Waser J. Synthesis 2009; 3353
• 2f Carson CA, Kerr MA. Chem. Soc. Rev. 2009; 38: 3051
• 2g Schneider TF, Kaschel J, Awan SL, Dittrich B, Werz DB. Chem. Eur. J. 2010; 16: 11276
• 2h Mel’nikov MYa, Budynina EM, Ivanova OA, Trushkov IV. Mendeleev Commun. 2011; 21: 293
• 2i Cavitt MA, Phun LH, France S. Chem. Rev. Soc. 2014; 43: 804
• 2j Schneider TF, Kaschel J, Werz DB. Angew. Chem. Int. Ed. 2014; 53: 5504 ; Angew. Chem. 2014, 126, 5608

For a seminal theoretical study on d–a cyclopropanes, see:
• 2k Schneider TF, Werz DB. Org. Lett. 2011; 13: 1848
• 3 Grimm EL, Reissig H.-U. J. Org. Chem. 1985; 50: 242
• 4 Reichelt I, Reissig H.-U. Synthesis 1984; 786
• 5a Beyzavi MH, Lentz D, Reissig H.-U, Wiehe A. Eur. J. Org. Chem. 2013; 269
• 5b Beyzavi MH, Nietzold C, Reissig H.-U, Wiehe A. Adv. Synth. Catal. 2013; 355: 1409
• 6a Özbek H, Veljkovic IS, Reissig H.-U. Synlett 2008; 3145
• 6b Ngo TH, Berndt H, Lentz D, Reissig H.-U. J. Org. Chem. 2012; 77: 9676
• 6c Ngo TH, Berndt H, Wilsdorf M, Lentz D, Reissig H.-U. Chem. Eur. J. 2013; 19: 15155
• 7 Zimmer R, Ziemer A, Gruner M, Brüdgam I, Hartl H, Reissig H.-U. Synthesis 2001; 1649
• 8 Veljkovic I, Zimmer R, Reissig H.-U, Brüdgam I, Hartl H. Synthesis 2006; 2677

For other selected publications dealing with in situ generation of 1,4-dicarbonyl compounds from d–a cyclopropanes and their functionalizations in one-pot procedures, see:
• 9a Brückner C, Reissig H.-U. J. Org. Chem. 1988; 53: 2440
• 9b Brückner C, Reissig H.-U. Liebigs Ann. Chem. 1988; 465
• 9c Brückner C, Suchland B, Reissig H.-U. Liebigs Ann. Chem. 1988; 471
• 9d Ullmann A, Schnaubelt J, Reissig H.-U. Synthesis 1998; 1052
• 9e Patra PK, Reissig H.-U. Eur. J. Org. Chem. 2001; 4195
• 10a Gladow D, Reissig H.-U. Helv. Chim. Acta 2012; 95: 1818
• 10b Gladow D, Reissig H.-U. Synthesis 2013; 45: 2179
• 10c Gladow D, Reissig H.-U. J. Org. Chem. 2014; 79: 4492

For a comprehensive overview on the use of nitriles in organic chemistry, see:
• 11a Science of Synthesis . Vol. 19. Murahashi S.-I. Georg Thieme Verlag; Stuttgart: 2004

For selected recent publications dealing with the nitrile synthesis from aldoximes, see:
• 11b Bad MN. S, Behrouz S, Nekoei A.-R. Synlett 2012; 23: 1191
• 11c Dev D, Palakurthy NB, Kumar N, Mandal B. Tetrahedron Lett. 2013; 54: 4397
• 11d Patil UB, Shendage SS, Nagarkar JM. Synthesis 2013; 45: 3295
• 11e Yu L, Li H, Zhang X, Ye J, Liu J, Xu Q, Lautens M. Org. Lett. 2014; 16: 1346 ; and references cited in these reports
• 12 The subsequent formation of the corresponding amidoximes from nitriles and hydroxylamine was not observed. For a related reference, see: Lin C.-C, Hsieh T.-H, Liao P.-Y, Liao Z.-Y, Chang C.-W, Shih Y.-C, Yeh W.-H, Chien T.-C. Org. Lett. 2014; 16: 892

Alkylated methyl cyclopropanecarboxylates 1 are easily accessible by deprotonation at C-1 followed by reaction with suitable alkyl halides such as MeI or allyl bromide. See:
• 13a Reissig H.-U, Böhm I. J. Am. Chem. Soc. 1982; 104: 1735
• 13b Reichelt I, Reissig H.-U. Chem. Ber. 1983; 116: 3895
• 13c Reichelt I, Reissig H.-U. Liebigs Ann. Chem. 1984; 531
• 14 Gilbert JC, Weerasooriya U. J. Org. Chem. 1982; 47: 1837
• 15a Müller S, Liepold B, Roth GJ, Bestmann HJ. Synlett 1996; 521
• 15b Pietruszka J, Witt A. Synthesis 2006; 4266
• 16a Brimioulle R, Bach T. Science 2013; 342: 840
• 16b Barbero A, Cuadrado P, Fleming I, González AM. J. Chem. Soc., Perkin Trans. 1 1993; 1657
• 16c Cordes C, Prelog V, Troxler E, Westen HH. Helv. Chim. Acta 1968; 51: 1663

For selected applications of alkynoic acid derivatives, see:
• 17a Ojima I. Pure Appl. Chem. 2002; 74: 159
• 17b Ji X, Zhou Y, Wang J, Zhao L, Jiang H, Liu H. J. Org. Chem. 2013; 78: 4312
• 17c Nagendiran A, Verho O, Haller C, Johnston EV, Bäckvall J.-E. J. Org. Chem. 2014; 79: 1399
• 17d For a total synthesis of (+)-lupinine using alkyne 4d, see ref. 16a.
• 18 For the enyne ring-closing metathesis of 4d leading to exo-methylene-functionalized cyclohexene product, see: Lee Y.-J, Schrock RR, Hoveyda AH. J. Am. Chem. Soc. 2009; 131: 10652
• 19a Chan TR, Hilgraf R, Sharpless KB, Fokin VV. Org. Lett. 2004; 6: 2853

For a recent review, see:
• 19b Berg R, Straub BF. Beilstein J. Org. Chem. 2013; 9: 2715
• 20 El Meslouti A, Beaupère D, Demailly G, Uzan R. Tetrahedron Lett. 1994; 35: 3913
• 21 Moinizadeh N, Klemme R, Kansy M, Zimmer R, Reissig H.-U. Synthesis 2013; 45: 2752
• 22a Lee PH, Kim S, Park A, Chary BC, Kim S. Angew. Chem. Int. Ed. 2010; 49: 6806 ; Angew. Chem. 2010, 122, 6958

For a similar hydrophosphorylation of terminal alkynes, see:
• 22b Nun P, Egbert JD, Oliva-Madrid M.-J, Nolan SP. Chem. Eur. J. 2012; 18: 1064

For reviews on synthesis and recent application of enol phosphates, see:
• 23a Lichtenthaler FW. Chem. Rev. 1961; 61: 607
• 23b Occhiato EG. Mini-Rev. Org. Chem. 2004; 1: 149
• 23c Protti S, Fagnoni M. Chem. Commun. 2008; 3611
• 23d Knappke CE. I, Jacobi von Wangelin A. Chem. Soc. Rev. 2011; 40: 4948
• 23e Sellars JD, Steel PG. Chem. Soc. Rev. 2011; 40: 5170
• 23f Li B.-J, Yu D.-G, Sun C.-L, Shi Z.-J. Chem. Eur. J. 2011; 17: 1728
• 23g Song R.-J, Liu Y.-Y, Wu J.-C, Xie Y.-X, Deng G.-B, Yang X.-H, Liu Y, Li J.-H. Synthesis 2012; 44: 1119

For recent contributions on enol phosphates, see:
• 23h Krawczyk E, Mielniczak G, Owsianik K, Luczak J. Tetrahedron: Asymmetry 2012; 23: 1480
• 23i Barthes N, Grison C. Bioorg. Chem. 2012; 40: 48
• 24 Kumaraswamy G, Jayaprakash N, Balakishnan G. Org. Biomol. Chem. 2011; 9: 7913

For reviews, see:
• 25a Pauson PL. Tetrahedron 1985; 41: 5855
• 25b Schore NE. Chem. Rev. 1988; 88: 1081
• 25c Rodríguez Rivero M, Adrio J, Carretero JC. Synlett 2005; 26 ; and references cited herein

For selected examples, see:
• 25d Paquette LA, Borrelly S. J. Org. Chem. 1995; 60: 6912
• 25e Zimmer R, Buchholz M, Collas M, Angermann J, Homann K, Reissig H.-U. Eur. J. Org. Chem. 2010; 4111
• 26 Typical Procedure for Methyl 3-Cyano-2,3-dimethyl-butanoate (2c): A mixture of cyclopropane 1c (1.15 g, 5.00 mmol) and NH₂OH·HCl (486 mg, 7.00 mmol) in formic acid (5 mL) was heated at 100 °C for 6 h. After cooling to r.t. the solution was neutralized with 2 N NaOH solution followed by extraction with CH₂Cl₂ (3 × 30 mL). Purification by kugelrohr distillation (80 °C, 1.3 mbar) afforded β-cyanoester 2c (524 mg, 68%) as a colorless liquid. ¹H NMR (400 MHz, CDCl₃): δ = 1.28 (d, J = 7.2 Hz, 3 H, Me), 1.34, 1.39 (2 × s, 2 × 3 H, Me), 2.51 (q, J = 7.2 Hz, 1 H, CH), 3.67 (s, 3 H, OMe). ¹³C NMR (125.8 MHz, CDCl₃): δ = 13.7 (q, Me), 24.0, 25.3 (2 × q, Me), 34.5 (s, CMe₂), 47.1 (d, CH), 51.8 (q, OMe), 123.2 (s, CN), 172.9 (s, CO₂Me). IR (ATR): 2985–2845 (C–H), 2240 (C≡C), 1740 (C=O) cm^–1. HRMS (ESI–TOF): m/z [M + Na]⁺ calcd for C₈H₁₃NNaO₂: 178.0838; found: 178.0839. Typical Procedure for Methyl 3-Methylpent-5-yne-carboxylate (4a): To a suspension of K₂CO₃ (819 mg, 5.93 mmol) in MeOH (6 mL) reagent 3 (452 mg, 2.35 mmol) and siloxycyclopropane 1a (684 mg, 3.56 mmol) were added at r.t. After stirring overnight, 5% aq NaHCO₃ solution (10 mL) and Et₂O (50 mL) were added. After separation of the phases, the aqueous phase was extracted with Et₂O (3 × 50 mL). The combined organic layers were dried with Na₂SO₄, filtered and carefully concentrated. Column chromatography (silica gel, Et₂O) followed by careful removal of the solvent (ca 500 mbar; bath temp: 35 °C) provided 4a ^16b (362 mg, 98%) as a pale yellow liquid. ¹H NMR (400 MHz, CDCl₃): δ = 1.21 (d, J = 7.0 Hz, 3 H, Me), 2.03 (d, J = 2.5 Hz, 1 H, 5-H), 2.36 (dd, J = 6.0, 12.5 Hz, 1 H, 2-H), 2.52 (dd, J = 5.7, 12.5 Hz, 1 H, 2-H), 2.87–2.95 (m, 1 H, 3-H), 3.65 (s, 3 H, OMe). ¹³C NMR (125.8 MHz, CDCl₃): δ = 20.6 (q, Me), 22.7 (d, C-3), 41.2 (t, C-2), 51.7 (q, OMe), 68.9 (s, C-4), 87.1 (d, C-5), 171.8 (s, C-1). Typical Procedure for Methyl 3-(1-Benzyl-1H-1,2,3-triazol-4-yl)-3-butanoate (5a): To a solution of the alkyne 4a (0.072 g, 0.571 mmol) in MeCN (10 mL) benzyl azide (0.051 g, 0.380 mmol), TBTA (0.028 g, 0.053 mmol), Et₃N (5 μL, 0.053 mmol), and CuI (0.010 g, 0.053 mmol) were added at r.t. and stirred overnight. After filtration of the mixture (silica gel), concentration in vacuo and purification by column chromatography (silica gel, hexanes–EtOAc, 8:1 → 2:1) afforded the product 5a (0.071 g, 72%) as a yellow oil. ¹H NMR (400 MHz, CDCl₃): δ = 1.30 (d, J = 7.0 Hz, 3 H, Me), 2.51 (dd, J = 7.6, 15.8 Hz, 1 H, 2-H), 2.78 (dd, J = 7.0, 15.8 Hz, 1 H, 2-H), 3.42 (sextet, J = 7.0 Hz, 1 H, 3-H), 3.59 (s, 3 H, OMe), 5.45 (s, 2 H, NCH₂), 7.20–7.23, 7.31–7.34 (2 × m, 2 × 3 H, =CH, Ph). ¹³C NMR (100.5 MHz, CDCl₃): δ = 20.1 (q, Me), 27.8 (d, CH), 40.9 (t, CH₂), 51.4 (q, OMe), 53.9 (t, CH₂Ph), 120.0 (d, =CH), 127.9, 128.5, 129.0, 134.8 (3 × d, s, Ph), 151.9 (s, =C), 172.6 (s, C=O). IR (ATR): 3140–2845 (=C–H, C–H), 1735 (C=O) cm^–1. HRMS (ESI–TOF): m/z [M + Na]⁺ calcd for C₁₄H₁₇N₃NaO₂: 282.1213; found: 282.1222. Diphenyl 4-(Diphenoxyphosphoryloxy)-3-methylpent-4-enoate (12): Alkyne 4a (0.051 g, 0.405 mmol) was dissolved in toluene (2 mL) and diphenyl phosphate 11 (0.084 g, 0.338 mmol), AgPF₆ (0.004 g, 0.017 mmol) and Ph₃AuCl (0.008 g, 0.017 mmol) were added. The solution was stirred at r.t. overnight. After filtration through a pad of silica gel (EtOAc), the filtrate was concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel, hexanes–EtOAc, 6:1 → 2:1) to afford 12 (0.095 g, 75%) as a yellow oil. ¹H NMR (500 MHz, CDCl₃): δ = 1.08 (d, J = 6.8 Hz, 3 H, Me), 2.23 (dd, J = 8.2, 15.3 Hz, 1 H, CH₂), 2.53 (dd, J = 6.2, 15.3 Hz, 1 H, CH₂), 2.79–2.87 (m, 1 H, CH), 3.65 (s, 3 H, OMe), 4.66, 5.02 (m_c, 2 × 1 H, =CH₂), 7.16–7.25, 7.32–7.36 (2 × m, 2 × 3 H, 2 × 2 H, Ph). ¹³C NMR (125.8 MHz, CDCl₃): δ = 17.6 (q, Me), 35.5 (dd, ³ J _CP = 7.3 Hz, CH), 38.4 (t, CH₂), 51.6 (q, OMe), 96.9 (td, ³ J _CP = 2.1 Hz, =CH₂), 120.1 (dd, ³ J _CP = 5.2 Hz, Ph), 125.5 (d, Ph), 129.8 (d, Ph), 150.4 (d, ² J _CP = 7.3 Hz, Ph), 157.7 (d, ² J _CP = 9.3 Hz, =C), 172.1 (s, CO₂). IR (ATR): 2955–2850 (=C–H, C–H), 1740 (C=O), 1665 (C=C), 1300 (P–O) cm^–1. HRMS (ESI–TOF): m/z [M + H]⁺ calcd for C₁₉H₂₂O₆P: 377.1149; found: 377.1127. HRMS (ESI–TOF): m/z [M + Na]⁺ calcd for C₁₉H₂₁NaO₆P: 399.0968; found: 399.0946. HRMS (ESI–TOF): m/z [M + K]⁺ calcd for C₁₉H₂₁KO₆P: 415.0707; found: 415.0682. Methyl 5-Oxo-1,2,3,3a,4,5-hexahydropentalen-2-carboxylate (16): Enyne 4e (0.177 g, 1.16 mmol) was dissolved in Et₂O (16 mL). After addition of Co₂(CO)₈ (0.398 g, 1.16 mmol), the solution was stirred for 15 h at r.t. under an Ar atmosphere. The solution was then filtrated through neutral alumina (Et₂O) and the filtrate was concentrated to dryness. The resulting crude product was dissolved in CH₂Cl₂ (10 mL) and NMO (0.178 g, 2.37 mmol) was added in one portion at 0 °C. The solution was stirred at this temperature for 18 h and then treated with 10% HCl solution (1 mL). The separated organic phase was washed with brine (2 × 3 mL) and dried (Na₂SO₄). After removal of the solvent under reduced pressure, the residue was purified by column chromatography (hexanes–EtOAc, 4:1) to afford bicyclic product 16 (0.104 g, 50%; 2 diastereomers = 60:40) as a colorless oil. ¹H NMR (500 MHz, CDCl₃): δ = 1.37–1.52 (m, 2 H, CH₂), 2.04 (dd, J = 3.1, 18.1 Hz, 0.6 H, CH₂), 2.12 (dd, J = 3.4, 18.1 Hz, 0.4 H, CH₂), 2.42–2.50, 2.57–2.65, 2.84–3.11, 3.19–3.29 (4 × m, 0.6 H, 0.4 H, 3 H, 1 H, CH, CH₂), 3.69, 3.72 (2 × s, 1.2 H, 1.8 H, OMe), 5.89, 5.91 (2 × m_c, 0.6 H, 0.4 H, =CH). ¹³C NMR (125.8 MHz, CDCl₃): δ = 30.0*, 30.3, 34.4, 35.2*, 42.0*, 42.2 (6 × t, CH₂), 43.3, 44.0*, 44.4, 46.6* (4 × d, CH), 52.1*, 52.2 (2 × q, OMe), 125.1, 125.6* (2 × d, =CH), 174.6*, 175.8 (2 × s, CO₂Me), 187.3*, 188.1 (2 × s, =C), 209.8*, 210.2 (2 × s, C=O); signals of the minor diastereomer are marked with *. IR (ATR): 3140–2860 (=C–H, C–H), 1730 (C=O) cm^–1. HRMS (ESI–TOF): m/z [M + H]⁺ calcd for C₁₀H₁₃O₃: 181.0859; found: 181.0860. HRMS (ESI–TOF): m/z [M + Na]⁺ calcd for C₁₀H₁₂NaO₃: 203.0679; found: 203.0685. HRMS (ESI–TOF): m/z [M + K]⁺ calcd for C₁₀H₁₂KO₃: 219.0418; found: 219.0426.