2-Chloro-4-iodopyridine-3-carboxaldehyde synthesis

Yield:153034-90-3 54%

Reaction Conditions:

Stage #1: 2-chloro-4-iodopyridinewith lithium diisopropyl amide in tetrahydrofuran at -78; for 3 h;
Stage #2: formic acid ethyl ester in tetrahydrofuran at -78; for 1.5 h;

Steps:

Step 1:2-Chloro-4-iodonicotinaldehyde

A mixture of 2-chloro-3-iodopyridine(5.0g, 21mmol) in dry THF (30 mL) was slowly added to a cold (-78°C) solution oflithiumdiisopropylamide(15 mL, 30mmol) in dry THF (50 mL). The resulting mixture was stirred for 3h at this temperature.Ethylformate(4.0g, 54mmol) wasthenadded.Stirring continued for 1.5 h at the same temperature.Water (10 mL) was added to quench the reaction, and then theresultingmixture was warmed toroom temperature.2 MHCl(50 mL) was added and then the THF was removed under reduced pressure.The aqueous residue was extracted withethyl acetate(2 x 50 mL).The combined organic extracts were washed with brine, dried over Na₂SO₄andconcentrated under reduced pressure.The residuewas purified on silica gel(diethyl ether/petroleum ether1:4)to give the desired product as a yellow solid(3.0 g, 54% yield).HNMR(500 MHz, CDCl₃):δ10.22(s, 1H), 8.09(d, J =5.0Hz, 1H), 7.95(d,J =5.0Hz, 1H).

References:

Liang, Jun;Van Abbema, Anne;Balazs, Mercedesz;Barrett, Kathy;Berezhkovsky, Leo;Blair, Wade S.;Chang, Christine;Delarosa, Donnie;DeVoss, Jason;Driscoll, Jim;Eigenbrot, Charles;Goodacre, Simon;Ghilardi, Nico;MacLeod, Calum;Johnson, Adam;Bir Kohli, Pawan;Lai, Yingjie;Lin, Zhonghua;Mantik, Priscilla;Menghrajani, Kapil;Nguyen, Hieu;Peng, Ivan;Sambrone, Amy;Shia, Steven;Smith, Jan;Sohn, Sue;Tsui, Vickie;Ultsch, Mark;Williams, Karen;Wu, Lawren C.;Yang, Wenqian;Zhang, Birong;Magnuson, Steven [Bioorganic and Medicinal Chemistry Letters,2017,vol. 27,# 18,p. 4370 - 4376] Location in patent:supporting information