2-Alkylidene-4-oxothiazolidine Vinyl Bromides: Versatile Precursors for C(5) Functionalization via Pyridine-Assisted Bromine Transfer

Abstract

A series of structurally diverse vinyl bromides, derived from push-pull 2-alkylidene-4-oxothiazolidines, undergoes pyridine-assisted bromine transfer from the C=C bond to the C(5) position, enabling different C(5) functionalization. The type of the product depends on the C(5) substituent and, in some cases, the transformation is affected by the substituent at the C=C bond.

push-pull alkenes - 2-alkylidene-4-oxothiazolidines - pyridine - bromine transfer - functionalization

References and Notes

<A NAME="RG36905ST-1">1</A> Pontillo J. Chen C. Bioorg. Med. Chem. Lett.  2005,  15:  1407 

<A NAME="RG36905ST-2">2</A> Bellur E. Langer P. Synlett  2004,  2169 

<A NAME="RG36905ST-3">3</A> Kulesza A. Ebetino FH. Mishra RK. Cross-Doersen D. Mazur AW. Org. Lett.  2003,  5:  1163 

<A NAME="RG36905ST-4">4</A> Foote KM. Hayes CJ. John MP. Pattenden G. Org. Biomol. Chem.  2003,  1:  3917 

<A NAME="RG36905ST-5">5</A> Kuethe JT. Wong A. Wu J. Davies IW. Dormer PG. Welch CJ. Hillier MC. J. Org. Chem.  2002,  67:  5993 

<A NAME="RG36905ST-6">6</A> Rossi R. Bellina F. Carpita A. Synlett  1996,  356 

<A NAME="RG36905ST-7">7</A> Torri S. Xu LH. Okumoto H. Synlett  1991,  695 

<A NAME="RG36905ST-8">8</A> Cocco MT. Congiu C. Onnis V. Ianelli S. Heterocycles  2004,  63:  259 

<A NAME="RG36905ST-9">9</A> Kameswaran V. Jiang B. Synthesis  1997,  530 

<A NAME="RG36905ST-10">10</A> Akiyama T. Simeno F. Murakami M. Yoneda F. J. Am. Chem. Soc.  1992,  114:  6613 

<A NAME="RG36905ST-11">11</A> Singh G. Ila H. Junjappa H. Synthesis  1985,  165 

<A NAME="RG36905ST-12">12</A> Haddad N. Abramovich Z. Ruhman I. Tetrahedron Lett.  1996,  37:  3521 

<A NAME="RG36905ST-13">13</A> Seebach D. Gysel U. Job K. Beck AK. Synthesis  1992,  39 

<A NAME="RG36905ST-14">14</A> Medici A. Fogagnolo M. Pedrini P. Dondoni A. J. Org. Chem.  1982,  47:  3844 

<A NAME="RG36905ST-15">15</A> Marković R. Baranac M. Synlett  2000,  607 

<A NAME="RG36905ST-16">16</A> Marković R. D˛ambaski Z. Baranac M. Tetrahedron  2001,  57:  5833 

<A NAME="RG36905ST-17">17</A> Maki J. Sako M. Tanabe M. Suzuki M. Synthesis  1981,  462 

<A NAME="RG36905ST-18">18</A>

Typical Procedure for Synthesis of 2-Bromo-2-(4-oxo-thiazolidin-2-ylidene)- N -(2-phenylethyl)ethanamide ( 5b). To a suspension of 1 mmol of the parent 4-oxothiazolidine in CHCl₃ (37 mL) 2% bromine solution in the same solvent (ca. 1 equiv of bromine) was added dropwise under reflux until complete disappearance of the starting material. The progress of the reaction was monitored by TLC. The reaction mixture was evaporated to dryness, EtOH (2-3 mL) and a few drops of H₂O were added and bromide was allowed to crystallize in a freezer. In the case of preparation of vinyl bromides 6a-e, EtOH (50 mL) was used as a solvent and bromine addition was carried out at ca. -5 °C. The reaction mixture was evaporated to several mL, a certain amount of H₂O was added and bromides were allowed to crystallize in a freezer. Only vinyl bromide 6b was isolated by extraction with CH₂Cl₂ and could not be crystallized. All crystallized vinyl bromides 5a-e and 6a-e were isolated as pure substances.
Spectroscopic Data for (Z)- and (E)-5b.
¹H NMR (200 MHz, DMSO-d ₆): δ (Z isomer) = 2.78 (t, 2 H, CH₂Ph, J = 7.3 Hz), 3.33-3.43 (m, 2 H, NCH₂), 3.95 (s, 2 H, CH₂S), 7.19-7.34 (m, 5 H, Ph), 7.84 (t, 1 H, NH_amide, J = 5.6 Hz), 11.37 (s, 1 H, NH_lactam); δ (E-isomer) = CH₂Ph and NCH₂ are shielded, 3.79 (s, 2 H, CH₂S), Ph is shielded, 7.17 (t, 1 H, NH_amide, J = 5.2 Hz), 10.93 (s, 1 H, NH_lactam). ¹³C NMR (50.3 MHz, DMSO-d ₆ ): δ (Z-isomer) = 33.2 (CH₂S), 35.1 (CH₂Ph), 41.4 (NCH₂), 84.2 (=CBr), 126.3 (p-Ph), 128.6 (o-Ph), 128.8 (m-Ph), 139.4 (C1-Ph), 152.8 (C=), 163.3 (CO_amide), 173.3 (CO_lactam); δ (E isomer) = 33.8 (CH₂S), 35.4 (CH₂Ph), 41.4 (NCH₂), 80.0 (=CBr), 126.3 (p-Ph), 128.6 (o-Ph), 128.8 (m-Ph), 139.4 (C1-Ph), 149.9 (C=), 163.3 (CO_amide), 174.3 (CO_lactam). IR (KBr, Z and E): ν = 3360, 3139, 3022, 1723, 1615, 1585, 1517, 1452, 1431, 1350, 1312, 1257, 1219, 1190, 887, 786, 750, 699 cm^-1. MS (CI): m/z = 341/343 [M + 1]. UV (DMSO, Z and E): λ_max (ε) = 296.6 nm (18.900). Anal. Calcd for C₁₃H₁₃BrN₂O₂S: C, 45.76; H, 3.84; N, 8.21; S, 9.40. Found: C, 45.94; H, 3.90; N, 8.16; S, 9.56.

<A NAME="RG36905ST-19">19</A> Satzinger G. Justus Liebigs Ann. Chem.  1963,  665:  150 

<A NAME="RG36905ST-20">20</A> Satzinger G. Liebigs Ann. Chem.  1978,  473 

<A NAME="RG36905ST-21">21</A> Zaleska B. Ciez D. Winnik W. Chaczatrion K. Pharmazie  1995,  50:  537 

<A NAME="RG36905ST-22">22</A> Baranac M. PhD Thesis   University of Belgrade; Serbia and Montenegro: 2005. 

<A NAME="RG36905ST-23">23</A>

Typical Procedure for Synthesis of ( Z )-[4-Oxo-5-(pyr-idinium-1-yl)thiazolidin-2-ylidene] -N -(2-phenyl-ethyl)ethanamide Bromide ( 7b) by Pyridine-Assisted Bromine Transfer Reaction. To a suspension of 1.48 mmol of vinyl bromide 5b (0.505 g) in CHCl₃ (31 mL) a tenfold molar excess of pyridine was added and mixture refluxed for 7 d. Reaction mixture was then cooled to r.t. and evaporated to dryness under reduced pressure. Column chromatography (SiO₂, MeOH as an eluent) of the crude product yielded 7b (0.541 g, 87%) as a pale brown solid. ¹H NMR (200 MHz, DMSO-d ₆): δ = 2.75 (t, 2 H, CH₂Ph, J = 7.2 Hz), 3.31-3.40 (m, 2 H, NCH₂), 5.94 (s, 1 H, =CH), 7.09 (s, 1 H, CHS), 7.17-7.35 (m, 5 H, Ph), 8.24 (t, 2 H, m-pyridine, J = 7.2 Hz), 8.33 (t, 1 H, NH_amide, J = 5.4 Hz), 8.75 (t, 1 H, p-pyridine, J = 7.8 Hz), 9.30 (d, 2 H, o-pyridine, J = 5.6 Hz), 12.30 (br s, 1 H, NH_lactam). ¹³C NMR (50.3 MHz, DMSO-d ₆): δ = 35.4 (CH₂Ph), 40.4 (NCH₂), 71.8 (CHS), 96.5 (=CH), 126.4 (p-Ph), 128.6 (o-Ph), 128.7 (m-pyridine), 128.9 (m-Ph), 139.7 (C1-Ph), 144.8 (o-pyridine), 146.3 (C=), 148.0 (p-pyridine), 166.4 (CO_amide), 168.2 (CO_lactam). IR (KBr): ν = 3271, 3051, 3025, 1722, 1656, 1597, 1545, 1484, 1448, 1298, 1246, 1198, 1173, 832, 754, 703 cm^-1. ESI-MS: m/z 340 [M⁺], 261.

<A NAME="RG36905ST-24">24</A> Marković R. Pavlovich JG. Baranac M. Phosphorus, Sulfur Silicon Relat. Elem.  2005,  180:  1411 

<A NAME="RG36905ST-25">25</A> Hutchinson REJ. Tarbell DS. J. Org. Chem.  1969,  34:  66 

<A NAME="RG36905ST-26">26</A> Lane TH. Speier JL. Org. Chem.  1976,  41:  2714 

<A NAME="RG36905ST-27">27</A> Anders E. Hertlein K. Meske H. Synthesis  1990,  323 

<A NAME="RG36905ST-28">28</A> Katritzky AR. Marson CM. Angew. Chem., Int. Ed. Engl.  1984,  23:  420 ; and references cited therein

<A NAME="RG36905ST-29">29</A>

Typical Procedure for Synthesis of ( Z , E )-(5-Morpholino-4-oxothiazolidin-2-ylidene)- N -(2-phenylethyl)ethan-amide ( 9b). A mixture of the crude pyridinium salt 7b (94.3 mg) and morpholine (0.08 mL, 0.91 mmol) in CHCl₃ (8.7 mL) was stirred at r.t. for 6.5 h in dry atmosphere. After evaporation of the solvent under reduced pressure, the residue was purified by column chromatography (SiO₂, gradient toluene-EtOAc, 4:6 v/v to pure EtOAc) to give a pale yellow solid as a mixture of isomers (Z)- and (E)-9b (69.4 mg, 87% based on vinyl bromide 5b). ¹H NMR (200 MHz, DMSO-d ₆): δ (Z isomer) = 2.24-2.30 (m, 2 H, NCH_ax), 2.62-2.74 (m, 4 H, NCH_eq and CH₂Ph), 3.24-3.34 (m, 2 H, NCH₂), 3.57-3.60 (m, 4 H, CH₂O), 5.30 (s, 1 H, CHS), 5.58 (s, 1 H, =CH), 7.16-7.34 (m, 5 H, Ph), 7.90 (t, 1 H, NH_amide, J = 5.5 Hz), 11.42 (s, 1 H, NH_lactam); δ (E isomer) = 2.21-2.31 (m, 2 H, NCH_ax), 2.57-2.76 (m, 4 H, NCH_eq and CH₂Ph), NCH₂ is shielded, 3.61 (t, 4 H, CH₂O, J = 4.4 Hz), 5.23 (s, 1 H, =CH), 5.72 (s, 1 H, CHS), 7.16-7.34 (m, 5 H, Ph), 8.02 (t, 1 H, NH_amide, J = 5.6 Hz), 11.70 (s, 1 H, NH_lactam). ¹³C NMR (50.3 MHz, DMSO-d ₆): δ (Z isomer) = 35.6 (CH₂Ph), 40.4 (NHCH₂), 48.4 (CH₂N), 65.9 (CH₂O), 72.6 (CHS), 94.5 (=CH), 126.3 (p-Ph), 128.6 (o-Ph), 128.8 (m-Ph), 139.8 (C1-Ph), 148.1 (C=), 166.3 (CO_amide), 171.7 (CO_lactam); δ (E isomer) = 35.3 (CH₂Ph), 40.3 (NHCH₂), 48.6 (CH₂N), 65.8 (CH₂O), 75.1 (CHS), 92.7 (=CH), 126.4 (p-Ph), 128.6 (o-Ph), 128.8 (m-Ph), 139.6 (C1-Ph), 147.7 (C=), 166.8 (CO_amide), 170.0 (CO_lactam). IR (KBr, Z and E): ν = 3437, 3267, 3212, 3077, 1718, 1635, 1565, 1454, 1280, 1249, 1113, 858, 831, 768, 703 cm^-1. MS (CI): m/z 348 [M + 1]. UV (DMSO, Z and E): λ_max (ε) = 283.8 nm (25.700). Anal. Calcd for C₁₇H₂₃N₃O₄S (9b·H₂O): C, 55.87; H, 6.34; N, 11.50; S, 8.77. Found: C, 55.90; H, 6.34; N, 11.42; S, 9.05.

<A NAME="RG36905ST-30">30</A> Katritzky AR. Bapat JB. Blade RJ. Leddy BP. Nie P.-L. Ramsden CA. Thind SS. J. Chem. Soc., Perkin Trans. 1  1979,  418 

<A NAME="RG36905ST-31">31</A> Gromov SP. Kurchavov NA. Eur. J. Org. Chem.  2002,  4123 

<A NAME="RG36905ST-32">32</A> Van der Plas HC. J. Heterocycl. Chem.  2000,  37:  427