Bromoacetaldehyde Diethyl Acetal

SYNLETT0936-52141437-2096 © Georg Thieme Verlag Stuttgart · New York 2015, 26, 2185–2186 2185 spotlight

Syn lett J. Gotkowska Spotlight

Joanna Gotkowska Joanna Gotkowska was born in Zgierz (Poland) in 1985. She received her M.Sc. in chemistry in 2009 working in the group of Professor Bioorganic Chemistry Laboratory, Faculty of Pharmacy, Medical University of Lodz, Bogusław Kryczka at the University of Lodz Muszynskiego 1, 90-151 Lodz, Poland (Poland). Currently, she is continuing her re- [email protected] search at the Bioorganic Chemistry Laboratory, Faculty of Pharmacy, Medical University of Lodz, Published online: 12.08.2015 working in the group of Assistant Professor Dor- DOI: 10.1055/s-0034-1381164; Art ID: st-2015-v0522-v ota G. Piotrowska. Her research interests focus on synthesis of novel isoxazolidine analogues of homo-N-nucleos(t)ides.

Introduction O OEt Me CH + NBr Bromoacetaldehyde diethyl acetal (1) is widely used in OEt chemistry for the synthesis of a variety of antibiotics (in- 2 O cluding erythromycin and cephalosporins) and other drugs. O 1. EtOH 2. HBr, EtOH It is an important and highly reactive bifunctional com- Me C O CH CH2 + Br2 BrCH2CH(OEt)2 3 pound with a good leaving group and a masked aldehyde 1 function. It can be used as a starting material in a variety of Me O Me EtOH 1 2 + reactions to provide N-alkylated compounds, lactams, al- OO Br2 dehydes,3 oximes,4 azides,5 and acyclic di-/polyselenides.3 Me 4 Preparation Scheme 1

Bromoacetaldehyde diethyl acetal (1) is commercially available and can be prepared by several procedures: from diethylacetal 2 and bromosuccinimide,6 from vinyl acetate 3 with bromine in ethanol,7 and from 2,4,6-trimethyl-1,3,5- trioxane 4 with bromine in ethanol.8

Table 1 Use of Bromoacetaldehyde Diethyl Acetal

(A) The reaction of bromoacetaldehyde diethyl acetal 1 with iso-bu- O 1. LDA, THF, Δ tyronitrile 5 afforded dihydrofuranone 6 in high yield. Reductive OEt Δ 2. HCl, AcOH, H2O, O amination of 6 with N-benzyl-N-(2-phenylethyl)amine led to an es- Br + CN ter after EDCI/HOBt-assisted coupling with benzyl alcohol. The oxi- OEt HO dative N-debenzylation with CAN allowed to cleanly convert the 6 1 5 86% yield ester into lactam 7.2 O four steps Ph N This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. 40% yield 7

H N (B) Diaryl-1,2,4-triazoles 11 bearing an N-hydroxyurea moiety can SH 2 be obtained in a reaction sequence beginning with the preparation O N N HO N of oxime 9 from bromoacetal 1, followed by the bromide displace- N ment in 9 after reaction with the thiol 10, and a two-step installa- tion of a carbamoyl fragment.4 S OEt R 10 R Br N N ⋅ HCl + NH2OH HCl N OH Br N OEt 1 89

11 R R 38–63% yield

Syn lett J. Gotkowska Spotlight

um azide 12. The Staudinger–aza-Wittig reaction of 13 with cyclo- R O HN hexane-1,3-dione 14 (R = H) afforded an enamine, which upon R 14 treatment with TFA gave 6,7-dihydro-1H-indol-4(5H)-one 15 OEt OEt Ph3P, THF (R = H). Application of substituted 1,3-dicarbonyl compounds 14 ex- Br + NaN3 N3 R OEt OEt O panded the scope of this efficient approach to a variety of pyrroles.5 R 1 12 13 15 96% yield 92% yield

(D) Dicyano acetal 17 was prepared from 1 and malononitrile 16, 1. thiourea, t-BuOK and was further transformed into a pyrimidine derivative, a precur- CN EtOH, Δ 2. HCl, H O, NaOH, Δ N sor to 7H-pyrrolo[2,3-d]pyrimidin-4-amine 18.9 K2CO3 2 N OEt NC DMF, Δ NC 3. Raney-Ni, H2O, Δ NH2 Br + OEt NC EtO OEt 47% yield HN 1 16 17 54% yield 18

(E) Regioselective alkylation of resacetophenone 19 with 1 afforded O Me O Me compound 20. Under acidic conditions, an intermediate aldehyde HO HO was formed from which substituted benzofuran derivative was ob- OEt K2CO3 DMF, Δ tained. Baker–Venkataraman rearrangement followed by acid-cata- Br + lyzed cyclization led to the formation of furanoflavonoids 21.10 OEt OEt OH O EtO 1 19 20 1. A 15 H+, PhMe, Δ 90% yield 2. ArCOCl, pyridine O 3. pyridine, t-BuOK O Ar 4. H2SO4, AcOH, Δ

46% yield 21 O

(F) The Michaelis–Arbusov reaction of bromoacetal 1 with triethyl OEt O OEt + phosphite 22 gave phosphonate 23, which was transformed into (E)- Br P(OEt)3 (EtO)2P diethyl 2-ethoxyvinylphosphonate and further into a vinylphos- OEt OEt phate. The latter compound served as an efficient acceptor in the 1 22 23 81% yield synthesis of acyclic nucleoside phosphonates 24.11

five steps O base (EtO)2P OH O 17% yield 24

(G) Bromoacetal 1 was applied as a starting material in the synthesis 1. DMF, K2CO3, H2O, Δ OEt OEt of the Se-protected selenide 26, which after acidic hydrolysis was 2. NaBH4, EtOH, PG-X + KSeCN used in the Ugi four-component reaction using carboxylic acid, iso- Br Se OEt 25 PG OEt nitrile, and ammonium chloride (as a source of ammonia) to form 1 26 3 bisamide 27 as selenocysteine dipeptides. PGSe 76–99% yield O H two steps N R1 N R2 H O 27 25–85% yield This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited.

References

(1) Yu, Q.; Carlsen, P. Molecules 2008, 13, 701. (7) McElvain, S. M.; Kundiger, D. Org. Synth. 1943, 23, 8. (2) Davies, S. G.; Mortimer, D. A. B.; Mulvaney, A. W.; Russell, A. J.; (8) Baganz, H.; Dossow, K. H.; Hohmann, W. Chem. Ber. 1953, 86, Skarphedinsson, H.; Smith, A. D.; Vickers, R. J. Org. Biomol. 148. Chem. 2008, 6, 1625. (9) Jung, M.-H.; Kim, H.; Choi, W.-K.; El-Gamal, M. I.; Park, J.-H.; Ho (3) Abbas, M.; Wessjohann, L. A. Org. Biomol. Chem. 2012, 10, 9330. Yoo, K.; Bo Sim, T.; Ha Lee, S.; Baek, D.; Hah, J.-M.; Cho, J.-H.; Oh, (4) Jiang, B.; Huang, X.; Yao, H.; Jiang, J.; Wu, X.; Jiang, S.; Wang, Q.; Ch.-H. Bioorg. Med. Chem. Lett. 2009, 19, 6538. Lu, T.; Xu, J. Org. Biomol. Chem. 2014, 12, 2114. (10) Dixit, M.; Tripathi, B. K.; Tamrakar, A. K.; Srivastava, A. K.; (5) Bellur, E.; Yawer, M. A.; Hussain, I.; Riahi, A.; Fatunsin, O.; Kumar, B.; Goel, A. Bioorg. Med. Chem. 2007, 15, 727. Fischer, C.; Langer, P. Synthesis 2009, 2, 227. (11) Dayde, B.; Benzaria, S.; Pierra, C.; Gosselin, G.; Surleraux, D.; (6) Keiko, N. A.; Stepanowa, L. G.; Kleptsova, E. A.; Vdovina, G. P.; Volle, J. N.; Pirat, J. L.; Virieux, D. Org. Biomol. Chem. 2012, 10, Odegova, T. F. Pharm. Chem. J. 2009, 43, 202. 3448.