The generation and reactivity of two model vinyl carbenoids from gem-dibromoalkenes 1 were studied in microflow systems. From substrate 1a (R = Ph, CF3), the lithium-bromine exchange could be simply performed within 30 ms at 20 °C with very good E-selectivity whereas the reaction was unselective under batch conditions, even at −78 °C. Moreover, the unstable carbenoid generated from 1b (R = Ph, H) could be trapped as the major product while only the Fritsch-Buttemberg-Wiechell rearrangement product was obtained in a flask under cryogenic conditions.
This is a preview of subscription content, log in to check access.
Buy single article
Instant access to the full article PDF.
Price includes VAT for USA
Knorr R (2004) Alkylidenecarbenes, Alkylidenecarbenoids,† and competing species: which is responsible for Vinylic Nucleophilic substitution, [1 + 2] Cycloadditions, 1,5-CH insertions, and the Fritsch−Buttenberg−Wiechell rearrangement? Chem. Rev. 104(9):3795–3850. https://doi.org/10.1021/cr030616h
Capriati V, Florio S (2010) Anatomy of long-lasting love affairs with Lithium Carbenoids: past and present status and future prospects. Chem. Eur. J. 16(14):4152–4162. https://doi.org/10.1002/chem.200902870
Chelucci G (2012) Synthesis and metal-catalyzed reactions of gem-Dihalovinyl systems. Chem. Rev. 112(3):1344–1462. https://doi.org/10.1021/cr200165q
Harada T, Katsuhira T, Hattori K, Oku A (1994) Stereochemistry in Carbenoid formation by bromine/Lithium and bromine/zinc exchange reactions of gem-Dibromo compounds. Tetrahedron 50(27):7987–8002. https://doi.org/10.1016/S0040-4020(01)85284-4
Fürst R, Rinner U (2013) Synthesis of an advanced intermediate of the Jatrophane Diterpene Pl-4: a Dibromide coupling approach. J. Organomet. Chem. 78(17):8748–8758. https://doi.org/10.1021/jo401480t
Mizuta S, Otaki H, Kitamura K, Nishi K, Watanabe K, Makau JN, Hashimoto R, Usui T, Chiba K (2016) 3,3-Dibromo-2-Trifluoromethyl Acrylic Acid Ethyl Ester: A Versatile Platform for the Stereoselective Preparation of Functionalized-α-Trifluoromethyl α,β-Unsaturated Lactones and Trifluoromethyl Pyrazolinones. Org Chem Front 3(12):1661–1667. https://doi.org/10.1039/C6QO00360E
Wirth T (2017) Novel organic synthesis through ultrafast chemistry. Angew. Chem. Int. Ed. 56(3):682–684. https://doi.org/10.1002/anie.201609595
Yoshida J (2008) Flash chemistry: fast organic synthesis in microsystems. Wiley, Hoboken
Yoshida J, Kim H, Nagaki A (2017) “Impossible” chemistries based on flow and micro. J Flow Chem 7(3):60–64. https://doi.org/10.1556/1846.2017.00017
Usutani H, Tomida Y, Nagaki A, Okamoto H, Nokami T, Yoshida J (2007) Generation and reactions of O-Bromophenyllithium without Benzyne formation using a microreactor. J. Am. Chem. Soc. 129(11):3046–3047. https://doi.org/10.1021/ja068330s
Nagaki A, Matsuo C, Kim S, Saito K, Miyazaki A, Yoshida J (2012) Lithiation of 1,2-Dichloroethene in flow microreactors: versatile synthesis of alkenes and alkynes by precise residence-time control. Angew. Chem. Int. Ed. 51(13):3245–3248. https://doi.org/10.1002/anie.201108932
Kim H, Nagaki A, Yoshida J (2011) A flow-microreactor approach to protecting-group-free synthesis using Organolithium compounds. Nat. Commun. 2:264. https://doi.org/10.1038/ncomms1264
Nagaki A, Ichinari D, Yoshida J (2014) Three-component coupling based on flash chemistry. Carbolithiation of Benzyne with functionalized Aryllithiums followed by reactions with electrophiles. J. Am. Chem. Soc. 136(35):12245–12248. https://doi.org/10.1021/ja5071762
Kim H, Min K-I, Inoue K, Im DJ, Kim D-P, Yoshida J (2016) Submillisecond organic synthesis: outpacing fries rearrangement through microfluidic rapid mixing. Science 352(6286):691–694. https://doi.org/10.1126/science.aaf1389
Sam B, Montgomery TP, Krische MJ (2013) Ruthenium catalyzed reductive coupling of paraformaldehyde to Trifluoromethyl Allenes: CF3-bearing all-carbon quaternary centers. Org. Lett. 15(14):3790–3793. https://doi.org/10.1021/ol401771a
Khan ZA, Wirth T (2009) Synthesis of indene derivatives via electrophilic cyclization. Org. Lett. 11(1):229–231. https://doi.org/10.1021/ol8024956
Morken PA, Bachand PC, Swenson DC, Burton DJ (1993) Synthesis of Fluorinated 1,2,3-Butatrienes from .Alpha.-Halovinyl Organometallic Reagents. J. Am. Chem. Soc. 115(13):5430–5439. https://doi.org/10.1021/ja00066a011
Hamdoun G, Sebban M, Cossoul E, Harrison-Marchand A, Maddaluno J, Oulyadi H (2014) 1 H pure shift DOSY: a Handy tool to evaluate the aggregation and solvation of Organolithium derivatives. Chem. Commun. 50(31):4073–4075. https://doi.org/10.1039/C4CC00111G
Reich HJ (2013) Role of Organolithium aggregates and mixed aggregates in Organolithium mechanisms. Chem. Rev. 113(9):7130–7178. https://doi.org/10.1021/cr400187u
Stanetty P, Mihovilovic MD (1997) Half-lives of Organolithium reagents in common ethereal solvents. J. Organomet. Chem. 62(5):1514–1515. https://doi.org/10.1021/jo961701a
The authors gratefully acknowledge the European France-(Manche)-England cross-border cooperation program INTERREG IV A “AI-CHEM CHANNEL” and INTERREG V A “LABFACT”, co-financed by ERDF, for financial support. The authors from Normandie Université also thank the Tremplin Carnot I2C, the Labex SYNORG (ANR-11-LABX-0029) and the Région Normandie. K.P. is grateful to Ministerio de Educación Superior, Ciencia y Tecnología of the Dominican Republic for fellowship (CALIOPE programme). J.L. is grateful to Dr. M. De Paolis and Prof. H. Oulyadi for fruitful discussion and assistance.
Conflict of interest
On behalf of all authors, the corresponding author states that there is no conflict of interest.
This article is dedicated to the memory of Prof. Jun-ichi Yoshida
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Electronic supplementary material
About this article
Cite this article
Picard, B., Pérez, K., Lebleu, T. et al. Bromine-lithium exchange on gem-dibromoalkenes part 1: batch vs microflow conditions. J Flow Chem 10, 139–143 (2020). https://doi.org/10.1007/s41981-019-00057-6
- Fritsch-Buttemberg-Wiechell rearrangement
- Organolithium compounds