Abstract
Continuous-flow processing approaches are having a significant impact on the way we devise and perform chemical synthesis. Flow chemistry has repeatedly demonstrated numerous improvements with respect to synthesis efficiency, process safety and ease of reaction scale-up. In recent years flow chemistry has been applied with remarkable success to the generation of valuable target structures across a range of industries from basic bulk chemical manufacture and materials development to flavours, food and cosmetic applications. However, due to its earlier implementation, it has found so far many more advocates in areas of medicinal and agrochemical research and manufacture. In this review article, we summarise the key developments that continuous-flow synthesis has had in the area of saturated heterocycles, specifically focusing on approaches that generate these important entities from acyclic precursors.
Keywords
- Continuous processing
- Flow chemistry
- Heterocycles
- Synthesis
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References
Fanelli F, Parisi G, Degennaro L, Luisi R (2017) Beilstein J Org Chem 13:520–542. https://doi.org/10.3762/bjoc.13.51
Ley SV, Fitzpatrick DE, Myers RM, Battilocchio C, Ingham RJ (2015) Angew Chem Int Ed 54:10122–10137. https://doi.org/10.1002/anie.201501618
Fitzpatrick DE, Battilocchio C, Ley SV (2016) ACS Cent Sci 2:131–138. https://doi.org/10.1021/acscentsci.6b00015
Newman SG, Jensen KV (2013) Green Chem 15:1456–1472. https://doi.org/10.1039/C3GC40374B
Baxendale IR, Brocken L, Mallia CJ (2013) Green Process Synth 2:211–230. https://doi.org/10.1515/gps-2013-0029
Baxendale IR (2013) J Chem Technol Biotechnol 88:519–552. https://doi.org/10.1002/jctb.4012
Ley SV (2012) Chem Rec 2:378–390. https://doi.org/10.1002/tcr.201100041
Wegner J, Ceylan S, Kirschning A (2011) Chem Commun 47:4583–4592. https://doi.org/10.1039/C0CC05060A
Hartman RL, Jensen KV (2009) Lab Chip 9:2495–2507. https://doi.org/10.1039/B906343A
Hessel V (2009) Chem Eng Technol 32:1655–1681. https://doi.org/10.1002/ceat.200900474
Razzaq T, Glasnov TN, Kappe CO (2009) Chem Eng Technol 32:1702–1716. https://doi.org/10.1002/ceat.200900272
Razzaq T, Kappe CO (2010) Chem Asian J 5:1274–1289. https://doi.org/10.1002/asia.201000010
Ceylan S, Coutable L, Wegner J, Kirschning A (2011) Chem Eur J 17:1884–1893. https://doi.org/10.1002/chem.201002291
Hessel V, Kralisch D, Kockmann N (eds) (2015) Novel process windows: innovative gates to intensified and sustainable chemical processes. Weinheim, Wiley-VCH
Webb D, Jamison TF (2010) Chem Sci 1:675–680. https://doi.org/10.1039/C0SC00381F
Wegner J, Ceylan S, Kirschning A (2012) Adv Synth Catal 354:17–57. https://doi.org/10.1002/adsc.201100584
Britton J, Raston CL (2017) Chem Soc Rev 46:1250–1271. https://doi.org/10.1039/C6CS00830E
Anderson NG (2001) Org Process Res Dev 5:613–621. https://doi.org/10.1021/op0100605
Movsisyan M, Delbeke EIP, Berton JKET, Battilocchio C, Ley SV, Stevens CV (2016) Chem Soc Rev 45:4892–4928. https://doi.org/10.1039/C5CS00902B
Baumann M, Baxendale IR (2015) Beilstein J Org Chem 11:1194–1219. https://doi.org/10.3762/bjoc.11.134
Gutmann B, Cantillo D, Kappe CO (2015) Angew Chem Int Ed 54:6688–6798. https://doi.org/10.1002/anie.201409318
Porta R, Benaglia M, Puglisi A (2016) Org Process Res Dev 20:2–25. https://doi.org/10.1021/acs.oprd.5b00325
Baumann M, Baxendale IR, Ley SV (2011) Mol Divers 15:613–630. https://doi.org/10.1007/s11030-010-9282-1
Glasnov TN, Kappe CO (2011) J Heterocyl Chem 48:11–29. https://doi.org/10.1002/jhet.568
Movsisyan M, Moens M, Stevens C (2016) In: Scriven EFV, Ramsden CA (eds) Advances in heterocyclic chemistry: flow synthesis of heterocycles, vol 119. Elsevier, Amsterdam, pp 22–57
Lovering F, Bikker J, Humblet C (2009) J Med Chem 52:6752–6756. https://doi.org/10.1021/jm901241e
Lovering F (2013) Med Chem Commun 4:515–519. https://doi.org/10.1039/C2MD20347B
Birudukota NVS, Frankea R, Hofer B (2016) Org Biomol Chem 14:3821–3837. https://doi.org/10.1039/C5OB02539G
Karawajczyk A, Giordanetto F, Benningshof J, Hamza D, Kalliokoski T, Pouwer K, Morgentin R, Nelson A, Müller G, Piechot A, Tzalis D (2015) Drug Discov Today 20:1310–1316. https://doi.org/10.1016/j.drudis.2015.09.009
Musio B, Mariani F, Sliwinski EP, Kabeshov MA, Odajima H, Ley SV (2016) Synthesis 48:3515–3526. https://doi.org/10.1055/s-0035-1562579
Mastronardi F, Gutmann B, Kappe CO (2013) Org Lett 15:5590–5593. https://doi.org/10.1021/ol4027914
Brzozowski M, O’Brien M, Ley SV, Polyzos A (2015) Acc Chem Res 48:346–362. https://doi.org/10.1021/ar500359m
Mallia CJ, Baxendale IR (2016) Org Process Res Dev 20:327–360. https://doi.org/10.1021/acs.oprd.5b00222
Britton J, Jamison TF (2017) Angew Chem Int Ed 56:8823–8827. https://doi.org/10.1002/anie.201704529
Cludius-Brandt S, Kupracz L, Kirschning A (2013) Beilstein J Org Chem 9:1745–1750. https://doi.org/10.3762/bjoc.9.201
Grafton M, Mansfield AC, Fray MJ (2010) Tetrahedron Lett 51:1026–1029. https://doi.org/10.1016/j.tetlet.2009.12.071
Baumann M, Baxendale IR, Ley SV (2010) Synlett 5:749–752. https://doi.org/10.1055/s-0029-1219344
Baumann M, Baxendale IR, Kuratli C, Ley SV, Martin RE, Schneider J (2011) ACS Comb Sci 13:405–413. https://doi.org/10.1021/co2000357
Baumann M, Baxendale IR, Kirschning A, Ley SV, Wegner J (2011) Heterocycles 82:1297–1316. https://doi.org/10.3987/COM-10-S(E)77
Yoshida J (2005) Chem Commun 41:4509–4516. https://doi.org/10.1039/B508341A
Suga S, Tsutsi Y, Nagaki A, Yoshida J (2005) Bull Chem Soc Jpn 78:1206–1217. https://doi.org/10.1246/bcsj.78.1206
Lau S-H, Galvan A, Merchant RR, Battilocchio C, Souto JA, Berry MB, Ley SV (2015) Org Lett 17:3218–3221. https://doi.org/10.1021/acs.orglett.5b01307
Griesbaum K, Liu X, Kassiaris A, Scherer M (1997) Liebigs Ann Recueil 1381–1390
Bogdan AR, James K (2011) Org Lett 13:4060–4063. https://doi.org/10.1021/ol201567s
Fernandez-Suarez M, Wong SYF, Warrington BH (2002) Lab Chip 2:170–174. https://doi.org/10.1039/B202324E
Yoshida J (2010) Chem Rec 10:332
Yoshida J, Takahashi Y, Nagaki A (2013) Chem Commun 49:9896–9904. https://doi.org/10.1039/C3CC44709J
Tsoung J, Wang Y, Djuric SW (2017) React Chem Eng 2:458–461. https://doi.org/10.1039/C7RE00058H
Martin RE, Morawitz F, Kuratli C, Alker AM, Alanine AI (2012) Eur J Org Chem 47–52. https://doi.org/10.1002/ejoc.201101538
Snyder DA, Noti C, Seeberger PH, Schael F, Bieber T, Ehrfeld W (2005) Helv Chim Acta 88:1–9. https://doi.org/10.1002/hlca.200490304
Wiles C, Watts P (2011) Micro reaction technology in organic synthesis. CRC Press, Boca Raton
Hallmark B, Mackley MR, Gadala-Maria F (2005) Adv Eng Mater 7:545–547. https://doi.org/10.1002/adem.200400154
Hornung CH, Mackley MR, Baxendale IR, Ley SV (2007) Org Process Res Dev 11:399–405. https://doi.org/10.1021/op700015f
McMullen JP, Jensen KF (2011) Org Process Res Dev 15:398–407. https://doi.org/10.1021/op100300p
Baxendale IR (2015) Chem Eng Technol 38:1713–1716. https://doi.org/10.1002/ceat.201500255
Baxendale IR, Hornung C, Ley SV, Molina JMM, Wikström A (2013) Aust J Chem 66:131–144. https://doi.org/10.1071/CH12365
Kappe CO, Dallinger D, Murphree SS (2009) Practical microwave synthesis for organic chemists; strategies, instruments and protocols. Wiley-VCH Verlag GmbH, Weinheim. ISBN: 978-3-527-32097-4
Baxendale IR, Hayward JJ, Ley SV (2007) Comb Chem High Throughput Screen 10:802–836. https://doi.org/10.2174/138620707783220374
Baxendale IR, Pitts MR (2006) Chimica Oggi Chem Today 24:41–45
Saaby S, Baxendale IR, Ley SV (2005) Org Biomol Chem 3:3365–3368. https://doi.org/10.1039/b509540a
Bogaert-Alvarez RJ, Demena P, Kodersha G, Polomski RE, Soundararajan N, Wang SSY (2001) Org Process Res Dev 5:636–645. https://doi.org/10.1021/op0100504
Hook BDA, Dohle W, Hirst PR, Pickworth M, Berry MB, Booker-Milburn KI (2005) J Org Chem 70:7558–7564. https://doi.org/10.1021/jo050705p
Lainchbury MD, Medley MI, Taylor PM, Hirst P, Dohle W, Booker-Milburn KI (2008) J Org Chem 73:6497–6505. https://doi.org/10.1021/jo801108h
Elliott LD, Berry M, Harji B, Klauber D, Leonard J, Booker-Milburn KI (2016) Org Process Res Dev 20:1806–1811. https://doi.org/10.1021/acs.oprd.6b00277
Blackham EE, Booker-Milburn KI (2017) Angew Chem 56:6613–6616. https://doi.org/10.1002/anie.201701775
Mukae H, Maeda H, Nashihara S, Mizuno K (2007) Bull Chem Soc Jpn 80:1157–1161. https://doi.org/10.1246/bcsj.80.1157
Shvydkiv O, Nolan K, Oelgemöller M (2011) Beilstein J Org Chem 7:1055–1063. https://doi.org/10.3762/bjoc.7.121
DeLaney EN, Lee DS, Elliott LD, Jin J, Booker-Milburn KI, Poliakoff M, George MW (2017) Green Chem 19:1431–1438. https://doi.org/10.1039/C6GC02888H
Baumann M, Baxendale IR (2016) Synlett 27:159–163. https://doi.org/10.1055/s-0035-1560391
Hsueh N, Clarkson GJ, Shipman M (2015) Org Lett 17:3632–3635. https://doi.org/10.1021/acs.orglett.5b01777
Hsueh N, Clarkson GJ, Shipman M (2016) Org Lett 18:4908–4911. https://doi.org/10.1021/acs.orglett.6b02349
Baumann M, Baxendale IR, Ley SV (2008) Synlett 14:2111–2114. https://doi.org/10.1055/s-2008-1078026
Baumann M, Baxendale IR, Martin LJ, Ley SV (2009) Tetrahedron 65:6611–6625. https://doi.org/10.1016/j.tet.2009.05.083
Battilocchio C, Baumann M, Baxendale IR, Biava M, Kitching MO, Ley SV, Martin RE, Ohnmacht SA, Tappin NDC (2012) Synthesis 44:635–647. https://doi.org/10.1055/s-0031-1289676
Baumann M, Baxendale IR, Brasholz M, Hayward JJ, Ley SV, Nikbin N (2011) Synlett 22:1375–1380. https://doi.org/10.1055/s-0030-1260573
Fernandez A, Levine ZG, Baumann M, Sulzer-Mosse S, Sparr C, Schläger S, Metzger A, Baxendale IR, Ley SV (2013) Synlett 24:514–518. https://doi.org/10.1055/s-0032-1318109
Glöckner S, Tran DN, Ingham RJ, Fenner S, Wilson ZE, Battilocchio C, Ley SV (2015) Org Biomol Chem 13:207–214. https://doi.org/10.1039/C4OB02105C
Kim H, Nagaki A, Yoshida J (2011) Nat Commun 2:264–272. https://doi.org/10.1038/ncomms1264
Carter CF, Baxendale IR, O’Brien M, Pavey JBJ, Ley SV (2009) Org Biomol Chem 7:4594–4597. https://doi.org/10.1039/B917289K
Carter CF, Baxendale IR, Pavey JBJ, Ley SV (2010) Org Biomol Chem 8:1588–1595. https://doi.org/10.1039/B924309G
Prosa N, Turgis R, Piccardi R, Scherrmann M-C (2012) Eur J Org Chem 2188–2200. https://doi.org/10.1002/ejoc.201101726
Bremner WS, Organ MG (2007) J Comb Chem 9:14–16. https://doi.org/10.1021/cc060130p
Briggs ME, Slater AG, Lunt N, Jiang S, Little MA, Greenaway RL, Hasell T, Battilocchio C, Ley SV, Cooper AI (2015) Chem Commun 51:17390–17393. https://doi.org/10.1039/C5CC07447A
Spaccini R, Liguori L, Punta C, Bjorsvik H-R (2012) ChemSusChem 5:261–265. https://doi.org/10.1002/cssc.201100262
Mikami K, Islam MN, Yamanaka M, Itoh Y, Shinoda M, Kudo K (2004) Tetrahedron Lett 45:3681–3683. https://doi.org/10.1016/j.tetlet.2004.02.157
Yamamoto H, Sasaki I, Hirai Y, Namba K, Imagawa H, Nishizawa M (2009) Angew Chem Int Ed 48:1244–1247. https://doi.org/10.1002/anie.200804641
Hafez AM, Taggi AE, Dudding T, Lectka T (2001) J Am Chem Soc 123:10853–10859. https://doi.org/10.1021/ja016556j
Izquierdo J, Pericas MA (2016) ACS Catal 6:348–356. https://doi.org/10.1021/acscatal.5b02121
Wang S, Izquierdo J, Rodríguez-Escrich C, Pericàs MA (2017) ACS Catal 7:2780–2785. https://doi.org/10.1021/acscatal.7b00360
Osorio-Planes L, Rodriguez-Escrich C, Pericas MA (2016) Cat Sci Technol 6:4686–4689. https://doi.org/10.1039/C6CY00473C
Kreituss I, Bode JW (2017) Nat Chem 9:446–452. https://doi.org/10.1038/nchem.2681
Tsubogo T, Oyamada H, Kobayashi S (2015) Nature 520:329–332. https://doi.org/10.1038/nature14343. Scheme updated based upon presented material at the international conference on organic synthesis 21, IIT Bombay, India, December 2016
Drop M, Bantreil X, Grychowska K, Mahoro GU, Colacino E, Pawlowski M, Martinez J, Subra G, Zajdel P, Lamaty F (2017) Green Chem 19:1647–1652. https://doi.org/10.1039/C7GC00235A
Comer E, Organ MG (2005) J Am Chem Soc 127:8160–8167. https://doi.org/10.1021/ja0512069
Lim J, Lee SS, Ying JY (2010) Chem Commun 46:806–808. https://doi.org/10.1039/B917986K
Clarke AK, James MJ, O'Brien P, Taylor RJK, Unsworth WP (2016) Angew Chem Int Ed 55:13798–13802. https://doi.org/10.1002/anie.201608263
Correia CA, Gilmore K, McQuade DT, Seeberger PH (2015) Angew Chem 54:4945–4948. https://doi.org/10.1002/anie.201411728
Ouchi T, Battilocchio C, Hawkins JM, Ley SV (2014) Org Process Res Dev 18:1560–1566. https://doi.org/10.1021/op500208j
Ötvös SB, Mandity IM, Fülöp F (2011) Mol Divers 15:605–611. https://doi.org/10.1007/s11030-010-9276-z
Brasholz M, Von Känel K, Hornung CH, Saubern S, Tsanaktsidis J (2011) Green Chem 13:1114–1117. https://doi.org/10.1039/C1GC15107J
Chieffi G, Braun M, Esposit D (2015) ChemSusChem 8:3590–3594. https://doi.org/10.1002/cssc.201500804
Conde E, Rivilla I, Larumbe A, Cossío FP (2015) J Org Chem 80:11755–11767. https://doi.org/10.1021/acs.joc.5b01418
Viviano M, Milite C, Rescigno D, Castellano S, Sbardella GA (2015) RSC Adv 5:1268–1273. https://doi.org/10.1039/C4RA13392G
Wiles C, Hammond MJ, Watts P (2009) Beilstein J Org Chem 5(27). https://doi.org/10.3762/bjoc.5.26
Kee S-P, Gavriilidis A (2009) Org Process Res Dev 13:941–951. https://doi.org/10.1021/op800276a
McPake CB, Murray CB, Sandford G (2009) Tetrahedron Lett 50:1674–1676. https://doi.org/10.1016/j.tetlet.2008.12.073
Kestenbaum H, Lange de Oliveira A, Schmidt W, Schüth F, Ehrfeld W, Gebauer K, Löwe H, Richter T, Lebiedz D, Untiedt I, Züchner H (2002) Ind Eng Chem Res 41:710–719. https://doi.org/10.1021/ie010306u
Markowz G, Schirrmeister S, Albrecht J, Becker F, Schütte R, Caspary KJ, Klemm E (2005) Chem Eng Technol 28:459–464. https://doi.org/10.1002/ceat.200407146
Alves L, Desidera AL, de Oliveira KT, Newton S, Ley SV, Brocksom T (2015) Org Biomol Chem 13:7633–7642. https://doi.org/10.1039/C5OB00525F
Ushakov DB, Gilmore K, Seeberger PH (2014) Chem Commun 50:12649–12651. https://doi.org/10.1039/C4CC04932B
Ullah F, Samarakoon T, Rolfe A, Kurtz RD, Hanson PR, Organ MG (2010) Chem Eur J 16:10959–10962. https://doi.org/10.1002/chem.201001651
Fagnoni M, Bonassi F, Palmieri A, Protti S, Ravelli D, Ballini R (2014) Adv Synth Catal 356:753–758. https://doi.org/10.1002/adsc.201300859
Cerra B, Mangiavacchi F, Santi C, Lozza AM, Gioiello A (2017) React Chem Eng 2:467–471. https://doi.org/10.1039/C7RE00083A
Yamada YMA, Torii K, Uozumi Y (2009) Beilstein J Org Chem 5(18). https://doi.org/10.3762/bjoc.5.18
Kopetzki D, Levesque F, Seeberger PH (2013) Chem Eur J 19:5450–5456. https://doi.org/10.1002/chem.201204558
Levesque F, Seeberger PH (2012) Angew Chem Int Ed 51:1706–1709. https://doi.org/10.1002/anie.201107446
Kouridaki A, Huvaere K (2017) React Chem Eng 2:590–597. https://doi.org/10.1039/C7RE00053G
Ziegenbalg D, Kreisel G, Weiß D, Kralisch D (2014) Photochem Photobiol Sci 13:1005–1015. https://doi.org/10.1039/C3PP50302J
Bourne RA, Han X, Poliakoff M, George MW (2009) Angew Chem Int Ed 48:5322–5325. https://doi.org/10.1002/anie.200901731
Fukuyama T, Kobayashi M, Rahman MT, Kamata N, Ryo I (2008) Org Lett 10:533–536. https://doi.org/10.1021/ol702718z
Bou-Hamdan FR, Lévesque F, O’Brien AG, Seeberger PH (2011) Beilstein J Org Chem 7:1124–1129. https://doi.org/10.3762/bjoc.7.129
Zhang X, Stefanick S, Villani FJ (2004) Org Process Res Dev 8:455–460. https://doi.org/10.1021/op034193x
Treece JL, Goodell JR, Velde DV, Porco JA, Aubé J (2010) J Org Chem 75:2028–2038. https://doi.org/10.1021/jo100087h
McCaw PG, Buckley NM, Eccles KS, Lawrence SE, Maguire AR, Collins SG (2017) J Org Chem 82:3666–3679. https://doi.org/10.1021/acs.joc.7b00172
Silva BV, Violante FA, Pinto AC, Santos LS (2011) Rapid Commun Mass Spectrom 25:423–428. https://doi.org/10.1002/rcm.4869
Buono FG, Eriksson MC, Yang B-S, Kapadia SR, Lee H, Brazzillo J, Lorenz JC, Nummy L, Busacca CA, Yee N, Senanayake C (2014) Org Process Res Dev 18:1527–1534. https://doi.org/10.1021/op500263m
Payne GB (1967) J Org Chem 32:3351–3355. https://doi.org/10.1021/jo01286a017
Mandrelli F, Buco A, Piccioni L, Renner F, Guelat B, Martin B, Schenkel B, Venturoni F (2017) Green Chem 19:1425–1430. https://doi.org/10.1039/C6GC02840C
Baxendale IR, Deeley J, Griffiths-Jones CM, Ley SV, Saaby S, Tranmer GK (2006) Chem Commun:2566–2568. https://doi.org/10.1039/B600382F
Baxendale IR, Griffiths-Jones CM, Ley SV, Tranmer GK (2006) Synlett:427–430. https://doi.org/10.1055/s-2006-926244
Kamptmann S, Ley SV (2015) Aust J Chem 68:693–696. https://doi.org/10.1071/CH14530
Lücke D, Dalton T, Ley SV, Wilson ZE (2016) Chem Eur J 22:4206–4217. https://doi.org/10.1002/chem.201504457
Brasholz M, Macdonald JM, Saubern S, Ryan JH, Holmes AB (2010) Chem Eur J 16:11471–11480. https://doi.org/10.1002/chem.201001435
Rao ZX, Patel B, Monaco A, Cao ZJ, Barniol-Xicota M, Pichon E, Ladlow M, Hilton ST (2017) Eur J Org Chem. https://doi.org/10.1002/ejoc.201701111. Early view
Battilocchio C, Baxendale IR, Biava M, Kitching MO, Ley SV (2012) Org Process Res Dev 16:798–810. https://doi.org/10.1021/op300084z
Adamo A, Beingessner RL, Behnam M, Chen J, Jamison TF, Jensen KF, Monbaliu J-CM, Myerson AS, Revalor EM, Snead DR, Stelzer T, Weeranoppanant N, Wong SY, Zhang P (2016) Science 352:61–67. https://doi.org/10.1126/science.aaf1337
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Baumann, M., Baxendale, I.R. (2018). Flow Chemistry Approaches Applied to the Synthesis of Saturated Heterocycles. In: Sharma, U., Van der Eycken, E. (eds) Flow Chemistry for the Synthesis of Heterocycles. Topics in Heterocyclic Chemistry, vol 56. Springer, Cham. https://doi.org/10.1007/7081_2018_16
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