We have devised a room temperature process for the cyclopropanation of electron-poor olefins using unstabilised diazo compounds, generated under continuous flow conditions. This protocol was applied to a wide range of different diazo species to generate functionalised cyclopropanes which are valuable 3D building blocks.We are grateful to Pfizer Worldwide Research and Development
(CB, RJI and JMH), the Swiss National Science Foundation
(DNT), CAPES (RL, no 9865/13-6) and the EPSRC (SVL,
grant no EP/K0099494/1 and no EP/K039520/1) for financial
support.This is the final published article, originally published in Organic & Biomolecular Chemistry, 2015,13, 2550-2554 DOI: 10.1039/C5OB00019

Battilocchio, Claudio

Hawkins, Joel M

Ingham, Richard J

Labes, Ricardo

Ley, Steven V

Roda, Nuria M

Tran, Duc N

We have devised a room temperature process for the cyclopropanation of electron-poor olefins using unstabilised diazo compounds, generated under continuous flow conditions. This protocol was applied to a wide range of different diazo species to generate functionalised cyclopropanes which are valuable 3D building blocks

Apollo (Cambridge)

Organic &Biomolecular ChemistryCOMMUNICATIONCite this: Org. Biomol. Chem., 2015,13, 2550Received 6th January 2015,Accepted 6th January 2015DOI: 10.1039/c5ob00019jwww.rsc.org/obcCyclopropanation using flow-generated diazocompounds†Nuria M. Roda,a Duc N. Tran,a Claudio Battilocchio,a Ricardo Labes,aRichard J. Ingham,a Joel M. Hawkinsb and Steven V. Ley*aWe have devised a room temperature process for the cyclopropana-tion of electron-poor olefins using unstabilised diazo compounds,generated under continuous flow conditions. This protocol wasapplied to a wide range of different diazo species to generate func-tionalised cyclopropanes which are valuable 3D building blocks.IntroductionFlow chemistry is finding increasing use as an enabling tech-nology in both industrial and academic settings,1 providing anumber of advantages over traditional batch mode processesand thereby leading to a variety of interesting opportunities.Many reports to date have involved the adaptation of a singletransformation from batch to flow modes.2 From our perspec-tive, a more important goal would be the discovery of new pat-terns of reactivity. Using flow chemistry methods the space/time dynamics of a reaction profile can be adjusted along withother reaction parameters (i.e. pressure, temperature andmixing) that can be controlled accurately. New opportunitiesarise especially in harnessing reactive intermediates, whichcan be very challenging when using conventional methods. Ina flow mode, it is possible to continuously generate highlyreactive species free from contaminating reagents and thendeliver these to a reaction zone for combination with variouspartners to afford a range of products.Using this approach, we have previously established a con-tinuous process for the production of transient diazo specieson demand, as a class of interesting reactive building blocks(Scheme 1).3 Notably, this approach enabled the continuousgeneration of highly reactive intermediates and avoided thehazards associated with bulk handling of these species.4The cyclopropane ring features in many natural productsand often in bioactive and other functional materials due toits particular conformational constraints and properties.5Accordingly, cyclopropanation of olefins using stabilisedelectrophilic diazo compounds has been well studied. In par-ticular, transition-metal catalysis for the coupling of olefinsand diazo compounds are amongst the most well developedmethods for cyclopropane preparation.6 By contrast, unstabil-ised diazo compounds are underexplored. Interestingly, thishighly energetic species often demonstrates a reversed reactiv-ity pattern due to their amphiphilic character (Scheme 2).7Further to our initial investigations using the flow generate/translocate/react protocol for sp2–sp3 cross couplings, we envi-saged that the diazo species could react with different electronpoor olefins in order to give access to substituted cyclo-propanes, under mild conditions and without the need for anytransition metals in the coupling step. This method wouldScheme 1 Flow generation, translocation and reaction of diazointermediates.Scheme 2 Cyclopropanation of diazo species.†Electronic supplementary information (ESI) available. See DOI: 10.1039/c5ob00019jaInnovative Technology Centre, Department of Chemistry, University of Cambridge,Lensfield Road, Cambridge CB2 1EW, UK. E-mail: svl1000@cam.ac.uk; http://www.leygroup.ch.cam.ac.uk/bPfizer Worldwide Research and Development, Eastern Point Road, Groton,CT 06340, USA2550 | Org. Biomol. Chem., 2015, 13, 2550–2554 This journal is © The Royal Society of Chemistry 2015Open Access Article. Published on 07 January 2015. Downloaded on 19/03/2015 11:24:35.  This article is licensed under a Creative Commons Attribution-NonCommercial 3.0 Unported Licence.View Article OnlineView Journal  | View Issuerepresent an attractive alternative approach to the preparationof poly functional cyclopropanes.Results and discussionThe study commenced with the use of the readily preparedhydrazone 1a as model substrate for the reaction.8 We soonfound that in AcOEt as solvent, a consistent and clean streamof diazo compounds 2a was generated by passage through acolumn packed with activated manganese dioxide. As in pre-vious studies,3 the use of Hünig’s base was necessary to sup-press the formation of by-products. Using this protocol, wewere able to rapidly establish the cyclopropanation procedureusing the olefin substrate 3a. Under optimised conditions, asolution of 1a (0.1 M in AcOEt, 2 equiv. of DIPEA) was passedthrough a column reactor packed with activated MnO2. Theexiting stream of diazo (0.5 mL min−1) was combined with asolution of olefin (3a, 0.05 M in AcOEt, 0.5 mL min−1) aftermixing at a T-piece and then stirred at room temperature for2 h. With these optimised conditions, 4a was isolated in 89%yield (Scheme 3). The process was scaled up using a column of3 g MnO2 to produce 1.14 g of cyclopropane 4a (86% yield) inone run using only 1.2 equiv. of diazo compound. Notably, thetransformation was also achieved with high diastereoselectivity(10 : 1). No attempt was made at this stage to further increasethe scale of the reaction.With the aim of continuously processing material, webriefly investigated the flow cyclopropanation under differentconditions (i.e. temperature and residence time) and rapidlyfound that running the reaction continuously in a 20 mLScheme 3 Cyclopropanation reaction via the generate/translocate/react protocol (major isomer reported in scheme); a 0.2 mmol scale;b 4.25 mmol scale.Scheme 4 Flow diazo preparation and cyclopropanation sequenceusing: (a) a heated reactor coil; (b) direct evaporation.Table 1 Cyclopropanation of different diazo species with olefin 3aaEntrya Substrate Product Yieldb dr1 4a 89% 10 : 12 4b 99% 10 : 13 4c 97% 10 : 14 4d 89% 10 : 15 4e 80% 8 : 16 4f 79% 7 : 17 4g 59% 6 : 18 4h 99% 10 : 19 4i 39% 5 : 110 4j 55% 5 : 111 4k 63%c 5 : 1a 0.2 mmol scale. b Isolated yield after aqueous work-up and silica gelplug filtration. c Ratio of E/Z 3 : 1.Organic & Biomolecular Chemistry CommunicationThis journal is © The Royal Society of Chemistry 2015 Org. Biomol. Chem., 2015, 13, 2550–2554 | 2551Open Access Article. Published on 07 January 2015. Downloaded on 19/03/2015 11:24:35.  This article is licensed under a Creative Commons Attribution-NonCommercial 3.0 Unported Licence.View Article Onlinepolymer (PFA) coil at 60 °C, a continuous throughput of 0.93 gh−1 of material could be obtained. Notably, in addition to thiswe found that the combination of the two reaction streamsand the direct feed into a rotary evaporator gave complete con-version to the cyclopropyl derivative 4a in situ (Scheme 4).Next we wished to assess the scope of this new room temp-erature cyclopropanation process. Electron-withdrawing substi-tuents on the aryl ring of diazo species (Table 1) were welltolerated, giving cyclopropanes 4a, 4e and 4f in very goodyields (79–89%). Similarly, electron-donating groups also gen-erated cyclopropanes in high yields (4b–d, 89–99%). Impor-tantly, the steric hindrance exerted by ortho substituentsseems not to affect the reaction outcome, as illustrated bycomparison between 4c and 4d. This unusual feature of theprotocol contrasts with metal-catalysed procedures for cyclo-propanation.6 Heterocycles are well tolerated (4g, 4h) as is thepresence of unsaturation (4i and 4k). Notably, the use of theketone derivatives (Table 1, entry 10) gave an interesting 55%isolated yield of the product 4j, with a good level of diastereo-selectivity (5 : 1). One remarkable aspect of the protocol is thatall the products were obtained with good to excellentdiastereoselectivity (Table 1).Additionally, we were also pleased to find that increasingthe functional complexity of the olefinic partner did not affectthe outcome of the reaction as shown by reacting the diazospecies 2a with the more elaborate structures (i.e. 5, Scheme 5)which gave high yield of the corresponding cyclopropyl pep-tides 6a and 6b.We also decided to investigate the preparation of specifi-cally challenging, unstable and difficult to access cyclopropylcompounds, in particular substituted donor–acceptorcyclopropanes.9For example, the reaction of the diazo 2a with olefin 3c gave7a in 55% yield as a single diastereoisomer (Scheme 6).While this yield was lower than desired, the olefin startingmaterial had all been consumed. Further attempts withdifferent diazo species failed to give any isolable products. Wequickly realised the chemical sensitivity of this class of cyclo-propane products to silica gel chromatography and devised analternative “work-up” involving the use of LiAlH4 (Scheme 7) togive the corresponding diols which were readily isolated(Table 2). This 2-step transformation provides syntheticallyuseful yields with very high diastereoselectivities.Another valuable aspect of flow chemistry is associatedwith the advantages of continuously flowing material though amultistep sequence without the need to isolate intermediates.To showcase this aspect, we devised a 4-step sequence,whereby the use of a very cheap source of material (geraniol)would generate a more complex molecular product, 4k(Scheme 8).During optimisation of this procedure, we discovered thatan excess of MnO2 (7 g) was required for the complete oxi-dation of geraniol (delivered at 0.5 mL min−1 as a 0.2 M solu-Scheme 5 Diastereoselective cyclopropanation of dipeptide 5 to 6a/6b.Scheme 7 Diastereoselective cyclopropanation of 3b, followed byreduction to diol 8.Table 2 Cyclopropanation of different diazo species with olefin 3bafollowed by reduction to diol 8Entry Substrate Product Yieldb dr1 8a 48% >20 : 12 8b 55% >20 : 13 8c 58% >20 : 14 8d 40%c >20 : 1aOne-pot procedure at 0.2 mmol scale. b Isolated yield after aqueouswork-up and silica gel plug filtration. cRatio of E/Z 1.2 : 1.Scheme 6 Diastereoselective cyclopropanation of 3b.Communication Organic & Biomolecular Chemistry2552 | Org. Biomol. Chem., 2015, 13, 2550–2554 This journal is © The Royal Society of Chemistry 2015Open Access Article. Published on 07 January 2015. Downloaded on 19/03/2015 11:24:35.  This article is licensed under a Creative Commons Attribution-NonCommercial 3.0 Unported Licence.View Article Onlinetion in THF) to geranial (step 1).10 The output from thereagent column was collected in a reactor flask containing1.05 equiv. of hydrazine. After stirring for 2 h at room tempera-ture (step 2), the crude reaction mixture was pumped througha pre-activated column of MnO2 (1.0 mL min−1) to generatethe diazo intermediate (step 3). The MnO2 column served alsoto decompose any residual hydrazine.11 In-line IR monitoringat around 2070 cm−1 identified the diazo product exiting thereactor. This diazo stream was finally combined in a T-piecewith a stream (1.0 mL min−1) containing olefin 3a (step 4).Direct evaporation of the final reaction mixture in a rotaryevaporator gave 4k in good yield.ConclusionsIn conclusion, we devised a system that could deliver, rapidlyand efficiently, differently decorated cyclopropanes under flowconditions, with no need for precious metal catalysis andunder remarkable mild conditions (room temperature). Theprocess was successfully applied to a wide range of differentunstabilised nucleophilic diazo species which were combinedwith electron-poor olefins. In this work, we demonstrated howflow chemistry can serve as a discovery tool for generating newchemical reactivity windows to prepare valuable products. Thisapproach again exemplifies the opportunities that arise byusing flow chemistry methods.AcknowledgementsWe are grateful to Pfizer Worldwide Research and Develop-ment (CB, RJI and JMH), the Swiss National Science Foun-dation (DNT), CAPES (RL, no 9865/13-6) and the EPSRC (SVL,grant no EP/K0099494/1 and no EP/K039520/1) for financialsupport.Notes and references1 Selected recent reviews for chemical flow systems:(a) R. L. Hartman, J. P. McMullen and K. F. Jensen, Angew.Chem., Int. Ed., 2011, 50, 7502–7519; (b) J. Wegner,S. Ceylan and A. Kirschning, Adv. Synth. Catal., 2012, 354,17–57; (c) C. Wiles and P. Watts, Green Chem., 2012, 14,38–54; (d) L. Malet-Sanz and F. Susanne, J. Med. Chem.,2012, 55, 4062–4098; (e) I. R. Baxendale, J. Chem. Technol.Biotechnol., 2013, 88, 519–552; (f ) J. C. Pastre, D. L. Browneand S. V. Ley, Chem. Soc. Rev., 2013, 42, 8849–8869;(g) S. V. Ley, D. E. Fitzpatrick, R. J. Ingham andR. M. Myers, Angew. Chem., Int. Ed., 2014, 53, 2–17.2 Selected recent examples for chemical flow systems:(a) H. Kim, A. Nagaki and J.-I. Yoshida, Nat. Commun.,2011, 2, 264; (b) F. Levesque and P. H. Seeberger, Angew.Chem., Int. Ed., 2012, 51, 1706–1709; (c) B. J. Deadman,C. Battilocchio, E. Sliwinski and S. V. Ley, Green Chem.,2013, 15, 2050–2055; (d) Z. He and T. F. Jamison, Angew.Chem., Int. Ed., 2014, 53, 3353–3357; (e) M. Baumann andI. R. Baxendale, Beilstein J. Org. Chem., 2013, 9, 1613–1619;(f ) S. Newton, C. F. Carter, C. M. Pearson, L. de C. Alves,H. Lange, P. Thansandote and S. V. Ley, Angew. Chem., Int.Ed., 2014, 53, 4915–4920; (g) A. M. Nightingale,T. W. Phillips, J. H. Bannock and J. C. de Mello, Nat.Commun., 2014, 5, 3777; (h) X. Fan, V. Sans, P. Yaseneva,D. D. Plaza, J. Williams and A. Lapkin, Org. Process Res.Dev., 2012, 16, 1039–1042; (i) S. Glöckner, D. N. Tran,R. J. Ingham, S. Fenner, Z. E. Wilson, C. Battilocchio andS. V. Ley, Org. Biomol. Chem., 2015, 13, 207–214;( j) T. Ouchi, C. Battilocchio, J. M. Hawkins and S. V. Ley,Org. Process Res. Dev., 2014, 18, 1560–1566. Example of flowcyclopropanation using diazomethane: (k) F. Mastronardi,B. Gutmann and C. O. Kappe, Org. Lett., 2013, 15, 5590–5593.3 D. N. Tran, C. Battilocchio, S.-B. Lou, J. M. Hawkins andS. V. Ley, Chem. Sci., DOI: 10.1039/C4SC03072A.Scheme 8 Telescoped sequence for the preparation of cyclopropane amino acid 4k. a Yield following concentration, measured by 1H-NMR com-pared to an internal standard; b reaction run on 1 mmol scale.Organic & Biomolecular Chemistry CommunicationThis journal is © The Royal Society of Chemistry 2015 Org. Biomol. Chem., 2015, 13, 2550–2554 | 2553Open Access Article. Published on 07 January 2015. Downloaded on 19/03/2015 11:24:35.  This article is licensed under a Creative Commons Attribution-NonCommercial 3.0 Unported Licence.View Article Online4 Recent review about generation of diazo species in flow:B. J. Deadman, S. G. Collins and A. R. Maguire, Chem. –Eur. J., DOI: 10.1002/chem.201404348.5 Selected reviews on cyclopropanes: (a) W. A. Donaldson,Tetrahedron, 2001, 57, 8589–8627; (b) H. Lebel,J.-F. Marcoux, C. Molinaro and A. B. Charette, Chem. Rev.,2003, 103, 977–1050; (c) L. A. Wessjohann, W. Brandt andT. Thiemann, Chem. Rev., 2003, 103, 1625–1648;(d) F. Brackmann and A. de Meijere, Chem. Rev., 2007, 107,4493–4537.6 Selected recent examples for metal-catalysed cyclopropana-tion: (a) J.-J. Shen, S.-F. Zhu, Y. Cai, H. Xu, X.-L. Xie andQ.-L. Zhou, Angew. Chem., Int. Ed., 2014, 53, 13188–13191;(b) V. N. G. Lindsay, D. Fiset, P. J. Gritsch, S. Azzi andA. B. Charette, J. Am. Chem. Soc., 2013, 135, 1463–1470;(c) X. Xu, H. J. Lu, J. V. Ruppel, X. Cui, S. L. de Mesa,L. Wojtas and X. P. Zhang, J. Am. Chem. Soc., 2011, 133,15292–15295; (d) S. F. Zhu, X. Xu, J. A. Perman andX. P. Zhang, J. Am. Chem. Soc., 2010, 132, 12796–12799;(e) M. P. Doyle, Angew. Chem., Int. Ed., 2009, 48, 850–852.7 (a) M. Doyle, Acc. Chem. Res., 1986, 19, 348–356;(b) A. J. Padwa, Organomet. Chem., 2001, 617, 3–16;(c) M. Regitz and G. Mass, Diazo Compounds Properties andSynthesis, Academic Press, Inc., Orlando, 1986;(d) M. P. Doyle, M. A. McKervey and T. Ye, Modern CatalyticMethods for Organic Synthesis with Diazo Compounds, Wiley,New York, 1998; (e) J. N. Johnston, H. Muchalski andT. L. Troyer, Angew. Chem., Int. Ed., 2010, 49, 2290–2298;(f ) G. Maas, Angew. Chem., Int. Ed., 2009, 48, 8186–8195;(g) V. L. Rendina and J. S. Kingsbury, J. Org. Chem., 2012,77, 1181–1185; (h) A. J. Wommack and J. S. Kingsbury,J. Org. Chem., 2013, 78, 10573–10587; (i) T. L. Holton andH. Shechter, J. Org. Chem., 1995, 60, 4725–4729;( j) L. A. Adams, V. K. Aggarwal, R. V. Bonnert, B. Bressel,R. J. Cox, J. Shepherd, J. de Vicente, M. Walter,W. G. Whittingham and C. L. Winn, J. Org. Chem., 2003, 68,9433–9440.8 Hydrazones can be safely synthesised in flow manner start-ing from aldehydes/ketones and hydrazine. A preliminaryexample was shown in the telescoped synthesis of 4k(Scheme 8).9 Selected recent reviews for donor–acceptor cyclopropanes:(a) T. F. Schneider, J. Kaschel and D. B. Werz, Angew.Chem., Int. Ed., 2014, 53, 5504–5523; (b) M. A. Cavitt,L. H. Phun and S. France, Chem. Soc. Rev., 2014, 43,804–818.10 I. Hemeon, N. W. Barnett, N. Gathergood, P. J. Scammellsand R. D. Singer, Aust. J. Chem., 2004, 57, 125–128.11 I. Bhatnagar and M. V. George, J. Org. Chem., 1968, 33,2407–2411.Communication Organic & Biomolecular Chemistry2554 | Org. Biomol. Chem., 2015, 13, 2550–2554 This journal is © The Royal Society of Chemistry 2015Open Access Article. Published on 07 January 2015. Downloaded on 19/03/2015 11:24:35.  This article is licensed under a Creative Commons Attribution-NonCommercial 3.0 Unported Licence.View Article Online

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Cyclopropanation using flow-generated diazo compounds.

A practical and mild protocol for the cyclopropanation of unstabilised diazo compounds is reported.</p

Nuria M. Roda

Duc N. Tran

Claudio Battilocchio

Ricardo Labes

Richard J. Ingham

Joel M. Hawkins

Steven V. Ley

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Organic & Biomolecular Chemistry

Cyclopropanation using flow-generated diazo compounds

https://www.repository.cam.ac.uk/bitstream/handle/1810/247078/Roda%20et%20al_Cyclopropanation%20using%20flow-generated%20diazo%20compounds_2015_Organic%20and%20Biomolecular%20Chemistry.pdf?sequence=1&isAllowed=y

Cyclopropanation using flow-generated diazo compounds.

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