3-Chloropropionyl Chloride

SYNLETT0936-52141437-2096 © Georg Thieme Verlag Stuttgart · New York 2015, 26, 2049–2050 2049 spotlight

Syn lett M. Grabkowska-Drużyc Spotlight

Magdalena Grabkowska-Drużyc Magdalena Grabkowska-Drużyc was born in Sta- rachowice (Poland) in 1985. She received her M.Sc. in chemistry in 2009 working in the group Bioorganic Chemistry Laboratory, Faculty of Pharmacy Medical University of Lodz, of Professor Grzegorz Mlostoń at the University Muszyńskiego 1, 90-151 Lodz, Poland of Lodz (Poland). She has been employed as a [email protected] Teaching Assistant at the Bioorganic Chemistry Laboratory, Faculty of Pharmacy, Medical Uni- Published online: 23.07.2015 versity of Lodz since 2010 under the guidance DOI: 10.1055/s-0034-1381100; Art ID: st-2015-v0521-v of Dr. Dorota G. Piotrowska. Her research inter- ests focus on the synthesis of new isoxazolidine analogues of C-nucleotides of the potential anti- cancer and antiviral activity.

Introduction preparation of acyl chlorides can also be applied: the reac- tion of acrylic acid (3) or 3-chloropropionic acid (4) with Acyl chlorides are highly reactive derivatives of carbox- thionyl chloride, phosphoryl chloride, phosgene, or phos- ylic acids and therefore are applied widely in acylations. phorus trichloride. 3-Chloropropionyl chloride is an important bifunctional reagent. It is capable of acylation and possesses a 2-chloro- O SOCl2 ethyl fragment (CH2CH2Cl), which can be subjected to nu- O cleophilic substitution and serves as a masked vinyl group. 2 SOCl2 or POCl3 O O It can be used as a starting material in many reactions to or COCl2 construct a variety of (hetero)cyclic compounds. HO Cl Cl 3 1 Preparation O SOCl2 or PCl3 HO Cl 3-Chloropropionyl chloride (1) is commercially avail- 4 able and can be prepared from β-propiolactone (2) and thi- Scheme 1 onyl chloride.1 Other standard methods available for the

Table 1 Use of 3-chloropropionyl chloride

(A) The Friedel–Crafts acylation of tert-butylbenzene (5) with 1. AlCl , CH Cl , 0 °C O 3 2 2 3-chloropropionyl chloride (1) followed by cyclization provid- 2. H2SO4, 90 °C + ed indanone 6, which was further transformed into urea derivative Cl Cl 36% yield 2 7, a potent TRPV1 antagonist. 5 6 1 O

HN NH This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. 28% yield (four steps) N N 7 H

(B) A novel high-yielding one-pot microwave-assisted synthesis R R O O of condensed 5-substituted pyranoisoquinoline-1,6-diones 9 from O 2-substituted isoquinoline-1,3-diones 8 and 3-chloropropionyl N N + NaH, THF chloride (1) was reported.3 Cl Cl O MW O 1875–88% yield 9 O R = hydrogen, halogen, alkyl or alkoxy

Cl OH (C) Aouf et al. reported the titanium tetrachloride mediated addition SiMe3 of 3-chloropropionyl chloride (1) to 2,3,6,7-tetramethyl-1,8- O TiCl4, MeNO2 + bis(trimethylsilyl)-octa-2,6-diene (10) leading to cyclopentanol de- CH Cl Cl Cl 2 2 rivative 11, which contains three quaternary carbons.4 Me3Si 44% yield 1 10 11

Syn lett M. Grabkowska-Drużyc Spotlight

(D) Acylation of 2-aminophenol (12) with 3-chloropropionyl chlo- O NH2 N 1. EtOAc, Et3N, Δ ride (1), followed by cyclization in the presence of polyphosphoric + 2. PPA, 110 °C acid (PPA), gave benzoxazole 13, which was further reacted with Cl Cl OH O Cl 4-chlorophenyl-1-piperazine to yield the target benzo[d]oxazole 11312 5 analogue 14, a selective dopamine D4 receptor ligand. 1-(4-chlorophenyl)piperazine MeCN, K2CO3, KI, Δ 58% yield N

O N N Cl 14

1 (E) Acylation of substituted nitriles 15 with 3-chloropropionyl chlo- R CN 1 1. K CO R C(O)NH2 O R1 CN 2 3 2 ride (1) and subsequent intramolecular cyclization afforded 2-aryl- R 2 2. TEBA, K CO N H2SO4 R 2-pyrrolidinecarbonitriles 16 which were subsequently hydrolysed + 2 3 N Cl Cl HN 2 92–98% yield 70–87% yield to 2-aryl-2-pyrrolidinecarboxamides 17, showing moderate anti- R O cancer activity.6 1 15 16 17 O R1, R2 = aryl

(F) 3-Chloropropionyl chloride (1) was applied in the preparation of 1. CH2Cl2, py, –15 °C O MeO MeO 2. THF, NaH, 40 °C O intermediate 19 in the synthesis of cephalotaxine (20). The γ-lact- + NH N Cl Cl 56% yield am ring in 19 was constructed in a two-step sequence involving N- MeO MeO 7 19 acylation and intramolecular alkylation. 1 18 O O

O O N 81% yield (four steps) O 20

(G) Ozcan et al. reported the synthesis of oxadiazoloisopropylamide OH O Cl N 23 as potent and noncovalent proteasome inhibitor. O-Acylation of N O N N-hydroxyamidine 21 with 3-chloropropionyl chloride (1) and sub- 1. CH2Cl2, r.t. NH2 2. toluene, Δ sequent intramolecular cyclization afforded the intermediate oxadi- Cl Cl + 8 21 62% yield 22 azole 22, which was further transformed into 23 in good yield. 1

1. NH 2 , K2CO3, MeCN, Δ N O O 2. 2-(p-tolyloxy)acetyl chloride O N N Et3N, THF, r.t. 75% yield 23

(H) The synthesis of 2-imidazolidinones 25 and 26 (potential TACE O H inhibitors) started with the preparation of an unstable isocyanate 1. NaN Ar N O 3 N 24 by reacting 3-chloropropionyl chloride (1) with sodium azide.9 2. Δ N OH OCN O 25 Cl Cl 70% yield Cl 25: 27% yield or 1 24 (four steps) O 26: 29% yield (four steps) Ar OH N N O 26 This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited.

References

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