Synlett 2014; 25(6): 858-862
DOI: 10.1055/s-0033-1340670
letter
© Georg Thieme Verlag Stuttgart · New York

2,2,3-Tribromopropanal as a Versatile Reagent in the Skraup-Type Synthesis of 3-Bromoquinolin-6-ols

Clemens Lamberth*
a   Syngenta Crop Protection AG, Research Chemistry, Schaffhauserstr. 101, 4332 Stein, Switzerland   Fax: +41(62)8660860   Email: clemens.lamberth@syngenta.com
,
Fiona Murphy Kessabi
a   Syngenta Crop Protection AG, Research Chemistry, Schaffhauserstr. 101, 4332 Stein, Switzerland   Fax: +41(62)8660860   Email: clemens.lamberth@syngenta.com
,
Renaud Beaudegnies
a   Syngenta Crop Protection AG, Research Chemistry, Schaffhauserstr. 101, 4332 Stein, Switzerland   Fax: +41(62)8660860   Email: clemens.lamberth@syngenta.com
,
Laura Quaranta
a   Syngenta Crop Protection AG, Research Chemistry, Schaffhauserstr. 101, 4332 Stein, Switzerland   Fax: +41(62)8660860   Email: clemens.lamberth@syngenta.com
,
Stephan Trah
a   Syngenta Crop Protection AG, Research Chemistry, Schaffhauserstr. 101, 4332 Stein, Switzerland   Fax: +41(62)8660860   Email: clemens.lamberth@syngenta.com
,
Guillaume Berthon
a   Syngenta Crop Protection AG, Research Chemistry, Schaffhauserstr. 101, 4332 Stein, Switzerland   Fax: +41(62)8660860   Email: clemens.lamberth@syngenta.com
,
Fredrik Cederbaum
a   Syngenta Crop Protection AG, Research Chemistry, Schaffhauserstr. 101, 4332 Stein, Switzerland   Fax: +41(62)8660860   Email: clemens.lamberth@syngenta.com
,
Thomas Vettiger
b   Syngenta Crop Protection AG, Process Development, Breitenloh 5, 4333 Münchwilen, Switzerland
,
CS Prasanna
c   Syngenta Research and Technology Centre, Santa Monica Works, Corlim, Ilhas, Goa 401 110, India
› Author Affiliations
Further Information

Publication History

Received: 09 December 2013

Accepted after revision: 03 January 2014

Publication Date:
10 February 2014 (online)


Abstract

2,2,3-Tribromopropanal, a reagent which almost became forgotten in the chemical literature after its first application in the 1950s, is used for the one-step transformation of diversely substituted 4-nitro- and 4-methoxyanilines into 3-bromo-6-nitroquinolines and 3-bromo-6-methoxyquinolines. These intermediates are then converted, in one further step, into 3-bromoquinolin-6-ols, which may carry additional substituents at positions 7 and 8.

 
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  • 22 2,2,3-Tribromopropanal (2) Br2 (103 mL, 319 g, 2.0 mol) was added dropwise over 2 h to a solution of acrolein (1) (131 mL, 112 g, 2.0 mol) in DCE (320 mL) at r.t. During the addition, the color changed from colorless to orange and the reaction temperature was kept in the range 20–40 °C. Following addition, the mixture was stirred for 2 h at r.t., then another equivalent of Br2 (103 mL, 319 g, 2.0 mol) was added dropwise over 2 h. The red–brown mixture was stirred for 16 h at r.t., evaporated under reduced pressure, and the residue purified by Vigreux column distillation to deliver 2,2,3-tribromopropanal (2) (494 g, 1.68 mol, 84%) as a slightly yellowish liquid. Bp 80–85 °C (0.02 mbar); 1H NMR (400 MHz, CDCl3): δ = 4.23 (s, 2 H), 9.16 (s, 1 H).
  • 23 3-Bromo-8-methylquinolin-6-ol (5); Typical Procedures
    Method A
    3-Bromo-8-methyl-6-nitroquinoline (3)
    2,2,3-Tribromopropanal (2) (29.4 g, 0.1 mol) was added slowly to a suspension of 2-amino-5-nitrotoluene (15.2 g, 0.1 mol) in glacial AcOH (200 mL). The mixture was heated to 110 °C for 1 h, cooled to r.t. and filtered. The remaining solid was washed with Et2O, then suspended in H2O (150 mL) and treated with aq sat. NaHCO3 solution until a pH of 9 was reached. The suspension was transferred to a separating funnel and extracted with EtOAc (2 × 200 mL). The organic phase was dried over MgSO4 and evaporated under reduced pressure. The residue was purified by chromatography on silica gel, using EtOAc and heptane as eluents to afford 3-bromo-8-methyl-6-nitroquinoline (3) (20.7 g, 77 mmol, 77%) as yellow crystals.1H NMR (400 MHz, CDCl3): δ = 2.86 (s, 3 H), 8.35 (d, J = 2.1 Hz, 1 H), 8.47 (d, J = 2.0 Hz, 1 H), 8.54 (d, J = 2.2 Hz, 1 H), 9.06 (d, J = 2.1 Hz, 1 H).3-Bromo-8-methylquinolin-6-ol (5) Reduced Fe powder (15 g, 0.27 mol) was added in portions to a suspension of 3-bromo-8-methyl-6-nitroquinoline (3) (20.6 g, 77 mmol) in a mixture of EtOH (400 mL) and 37% aq HCl (2 mL) at r.t. The mixture was heated at reflux temperature for 2 h, during which time the color of the suspension changed from grey–yellow to red–brown. The mixture was cooled to 40 °C, filtered through Celite, and the filtrate diluted with EtOH, treated with silica gel and concentrated under reduced pressure. The residue was purified by chromatography on silica gel, using EtOAc and CH2Cl2 as eluents to deliver 6-amino-3-bromo-8-methylquinoline. This intermediate was suspended in a mixture of 85% aq phosphoric acid (125 mL) and H2O (12 mL), and heated to 180 °C in a tantalum pressure vessel for 72 h. Subsequently, the mixture was cooled to r.t. and added to H2O (250 mL). To this solution, 30% aq NaOH solution was added until a pH between 2–4 was reached. The resulting precipitate was filtered, washed with cold H2O and dried to give 3-bromo-8-methylquinolin-6-ol (5) (12.3 g, 52 mmol, 67%). 1H NMR (400 MHz, DMSO-d 6): δ = 2.64 (s, 3 H), 6.99 (d, J = 2.1 Hz, 1 H), 7.22 (d, J = 2.1 Hz, 1 H), 8.47 (d, J = 2.2 Hz, 1 H), 8.69 (d, J = 2.3 Hz, 1 H), 10.13 (s, 1 H). Method B 3-Bromo-6-methoxy-8-methylquinoline (4) 2,2,3-Tribromopropanal (2) (50.0 g, 0.18 mol) was added slowly to a suspension of 4-methoxy-2-methylaniline (25.0 g, 0.18 mol) in glacial AcOH (300 mL). The mixture was stirred for 6 h at r.t., then diluted with EtOAc (300 mL) and washed with H2O (2 × 100 mL), brine (100 mL) and 2 M NaOH solution (100 mL). The organic layer was dried over MgSO4 and evaporated under reduced pressure. The residue was purified by chromatography on silica gel, using EtOAc and heptane as eluents to yield 3-bromo-6-methoxy-8-methylquinoline (4) (20.5 g, 81 mmol, 45%). 1H NMR (400 MHz, CDCl3): δ = 2.73 (s, 3 H), 3.90 (s, 3 H), 6.82 (d, J = 2.0 Hz, 1 H), 7.21 (d, J = 2.1 Hz, 1 H), 8.17 (d, J = 1.9 Hz, 1 H), 8.76 (d, J = 2.0 Hz, 1 H). 3-Bromo-8-methylquinolin-6-ol (5)A mixture of 3-bromo-6-methoxy-8-methylquinoline (4) (14.0 g, 55 mmol) in 48% HBr (250 mL) was slowly heated to 110 °C, and kept at this temperature for 20 h. Subsequently, the mixture was cooled and filtered. The residue was washed with H2O, taken up in sat. aq NaHCO3 solution and filtered again. The solid was washed with H2O and dried under high vacuum to afford 3-bromo-8-methylquinolin-6-ol (5) (11.1 g, 47 mmol, 84%). The 1H NMR spectroscopic data of the sample of compound 5 was identical to that obtained using method A.