Continuous Flow Multi-Step Organic Synthesis
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Webb, Damien, and Timothy F. Jamison. “Continuous Flow
Multi-step Organic Synthesis.” Chemical Science 1.6 (2010): 675.
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http://dx.doi.org/10.1039/C0SC00381F
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Royal Society of Chemistry, The
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Continuous Flow Multi-Step Organic Synthesis
Damien Webb, Timothy F. Jamison
Received (in XXX, XXX) Xth XXXXXXXXX 200X, Accepted Xth XXXXXXXXX 200X First published on the web Xth XXXXXXXXX 200X
DOI: 10.1039/b000000x
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A recently developed strategy for multi-step synthesis is the use of continuous flow techniques to combine multiple synthetic steps into a single continuous operation. In this mini-review we discuss the current state of the art in this field.
Introduction
The multi-step synthesis of complex organic compounds from
10
simpler precursors is one of the outstanding accomplishments of synthetic organic chemistry. Through the development and invention of synthesis strategies, methods and technologies, increasingly complex molecules can be assembled with designed structures and functions for a variety of medicinal,
15
agrochemical and materials applications. However, despite significant advances, organic synthesis is still largely considered an inefficient and unsustainable practice that is highly labour- and resource-intensive.1
The traditional pathway for multi-step synthesis proceeds by
20
the batchwise and iterative step-by-step transformation of starting materials into desired products (Figure 1(a)). Typically, after the completion of each synthetic step (A+B→C, C→D and D→E), products are isolated from the reaction mixture and purified to remove any undesired
25
components that might interfere with the subsequent synthetic transformations. Although this approach is the foundation on which modern synthesis has been built, such an approach is time-consuming, often wasteful and in stark contrast to the single-cell multi-step biosynthetic pathways found in nature.2
30
Figure 1 Synthesis strategies.
Currently, the ideal laboratory synthesis3 (Figure 1(b)) is
unlikely to be achieved in practice, although a number of
35
innovative strategies have been developed to increase synthetic efficiency.4 A recently introduced method for
streamlining multi-step syntheses is the use of continuous flow techniques5 to combine multiple synthetic steps into a
single continuous reactor network, thereby circumventing the
40
need to isolate intermediate products (Figure 1(c)). In this mini-review we detail some recent developments in the field of multi-step continuous flow synthesis6 and discuss select
contemporary examples of this emerging technology.
Multi-Step Flow Synthesis
45Solution-based approaches
Synthetic chemists have long known that telescoping can be an effective tactic for truncating a multi-step synthesis.7
Telescoping reaction sequences typically involves the consecutive addition of reagents and/or catalysts to a reactor
50
in order to initiate further transformations of intermediate products or to achieve in situ quenching of reactive species. This strategy is well suited to flow chemistry and a number of reports employing solution-based systems have been disclosed.
55
The Yoshida group has published several examples outlining the use of highly reactive and unstable organolithium compounds for multi-step synthesis under continuous flow conditions.8 For example, o-dibromobenzene could be
effectively coupled with two different electrophiles via
60
sequential halogen–lithium exchange reactions in an extremely fast yet controlled manner (Scheme 1).9 The
authors used flow reactors constructed from stainless steel micromixers and tubes, whilst the reagent streams were driven by syringe pump devices. The success of these protocols is
65
attributed to effective temperature and residence time10 (t R)
control that allows the unstable intermediates to be rapidly transferred to the next stage of the reactor before decomposition can occur.
70
Scheme 1 Generation and reaction of o-bromophenyllithium
species using flow chemistry (Yoshida).
E A
B
C D
A E
A + B reaction 1 C reaction 2 D reaction 3 E
step-by-step batch synthesis intermediates C and D isolated and purified
one-step to E economic synthesis
C and D not isolated multiple steps in 1 operation (a) traditional approach
(b) 'ideal' synthesis
(c) continuous flow multi-step synthesis
Br Br n-BuLi TMSCl TMS OH Ph PhCHO n-BuLi –78 °C tR = 0.82 s –78 °C tR = 6.93 s 0 °C tR = 0.49 s 0 °C tR = 1.57 s 74%
= the introduction of an input stream to the reactor network tR = residence time in the reactor (see ref. 10)
in THF in hexane
Recently, the McQuade group reported a synthesis of the non-steroidal anti-inflammatory drug ibuprofen using continuous flow methods (Scheme 2).11 The three-step synthesis (Friedel–
Crafts acylation, 1,2-migration and ester hydrolysis) was linked into a single continuous system and provided ibuprofen
5
in 51% isolated yield following off-line workup and crystallisation of the exiting flow stream.
10
Scheme 2 Continuous flow synthesis of ibuprofen (McQuade).
The ability to perform multi-step reactions in an uninterrupted continuous fashion may also be beneficial for medicinal chemistry applications.12 Cosford recently described a
continuous two-step synthesis of a focused 13-membered
15
library of imidazo[1,2-a]pyridine-2-carboxamides (Scheme 3).13 No isolation of the carboxylic acid intermediate was
required and a final off-line purification of the crude reaction mixture provided the targets. For their work the authors used the commercially available Syrris AFRICA flow system.14
20
Scheme 3 Synthesis of a Mur ligase inhibitor using multi-step
continuous flow synthesis (Cosford).
25
Continuous separation and distillation
Although the telescoping processes described above are effective, they are not without limitations. A significant drawback is that excess reagents are often required, whilst the requirement for careful route design to ensure downstream
30
reagent compatibility is an added challenge. The integration of solution-based quenching with subsequent phase separation operations into flow systems would therefore greatly expand the utility of this new technology.
The Jensen group reported the integration of microfluidic
35
biphasic extraction systems with microreactors for the multi-step synthesis of carbamates (Scheme 4).15 A microseparator
incorporating a hydrophobic membrane was designed and used to successfully remove the aqueous stream and thus any water-soluble components.16
40
Scheme 4 Continuous carbamate synthesis involving multiple
reactions and separations (Jensen).
45
The Jensen group added a further instrument to the flow toolbox with the development of a microfluidic distillation unit capable of performing an in-line solvent switch.Working in conjunction with the Buchwald laboratory, a two-step flow sequence to prepare enol ethers was developed (Scheme 5).17
50
A bespoke silicon device was employed to carry out a continuous distillation of a binary solvent mixture (dichloromethane/DMF).18
55
Scheme 5 Continuous synthesis of an enol-ether involving
liquid–liquid separation and continuous solvent exchange (Jensen and Buchwald).
Solid-supported multi-step flow synthesis
60
The use of supported reagents, catalysts and scavengers in synthesis is well documented and has proven to be an extremely advantageous technology in the modern laboratory.19 The combination of immobilized reagents with
flow reactors20 has great potential for revolutionising the
65
synthesis process.21
The Ley group has pioneered the use of solid-supported reagents, catalysts and scavengers to facilitate organic synthesis and has an expanding portfolio of work in the area of continuous flow multi-step synthesis.22 Indeed, the group’s
70
2006 synthesis of the complex natural product oxomaritidine is currently the most elaborate example of continuous flow multi-step synthesis to date (Scheme 6).23 Employing a variety
of supported reagents and catalysts, including the commercially available H-Cube hydrogenator,24 seven
75
synthetic steps were orchestrated into a single reactor network to afford the target in excellent yield (>40%) and purity (>90%). H2O O TfOH OH O 20 eq. KOH 150 °C tR = 5 min 0 °C 50 °C tR = 2 min 65 °C tR = 3 min 51% after recrystallization 1 eq. PhI(OAc)2 1 eq. 1 eq. 5 eq. 4 eq. HC(OMe)3 in MeOH in MeOH/H2O N NH2 DIPEA HOBt, EDC (1.2 eq. in DMF) O Br HO O OH N H MeO2C H2N N N OH O HN CO2Me 100 °C tR = 20 min 75 °C tR = 15 min 46% HN 1 eq. in DMF 1.2 eq. in DMF 2 eq. in DMF R O Cl 1.1 eq. NaN3 (aq.)
liquid-liquid
separation separationgas-liquid
R'OH N H R O OR' 105 °C acyl azide formation RT Curtius rearrangement RT 1 eq. in toluene aqueous extract N2 Tf2O in CH2Cl1 liquid-liquid separation HCl (aq.) micro-distillation OH DIPEA DMF and N2 On-Bu t-Bu Pd(OAc)2, dppp, NEt3 t-Bu On-Bu triflate
formation reactionHeck
aqueous extract N2 + CH2Cl2
in CH2Cl2
Scheme 6 Continuous flow synthesis of oxomaritidine (Ley). PS
= polymer supported.
The development of catalytic process is integral to the future of synthesis25 and so the use of solid-supported catalysts for
5
muliple steps in flow systems is particularly attractive. Using an electroosmotic flow-driven miniaturized flow reactor, Watts recently reported the use of two solid-supported catalysts in series for the two-step synthesis of analytically pure α,β-unsaturated compounds (Scheme 7).26
10
Scheme 7 Continuous two-step synthesis of α,β-unsaturated
compounds using supported catalysts (Watts).
15
In many instances, such as the synthesis of pharmaceuticals, the quality of the final product of a synthetic route must meet stringent purity standards. An effective method for achieving in-line purification in flow-mode is the integration of
solid-20
supported scavengers to selectively remove unwanted components of the flow stream.
The Ley group recently reported on the multi-step synthesis of triazoles27 using the commercially available flow system from
Vapourtec28 (Scheme 8). Following three chemical
25
transformations (oxidation, homologation and ‘click’ triazole formation) the flowing solution was subsequently pumped through a variety of strategically positioned solid-supported scavengers to sequester any fouling components. This effectively provided the desired product in excellent purity
30
and without recourse to traditional column chromatography.29
Scheme 8 Three-step continuous flow synthesis of a triazole
35
employing a variety of immobilized reagents and scavengers (Ley).
The Lectka group has described the use of sequentially linked jacketed glass columns for catalytic and enantioselective multi-step flow synthesis and reported a continuous route to
40
the metalloproteinase inhibitor BMS-275291 (Scheme 9).30
The use of scavenger columns eliminated the need for batch purification of the eluting flow stream. In their approach the flow streams were purely gravity-driven and Celite® was
employed to control the column residence times. Remarkably
45
impressive yields and selectivities were observed.
Scheme 9 Synthesis of BMS-275291 using a column-based
50
system incorporating resin-bound reagents and scavengers (Lectka).
In a further example of a multiphase continuous flow system, Ulven reported the preparation of a 15-membered library of potential chemokine receptor ligands (Scheme 10).31 Three
55
separate building blocks were combined in three distinct reaction steps, whilst two scavenger resins were employed to remove any unreacted substrates. Semi-automatic purification of the crude products allowed a high compound throughput, further underscoring the potential of continuous flow
multi-60 Br HO PS-NMe3N3 OH MeO OMe PS-TPAP PS-PhP(n-Bu)2 H-Cube! F3C O O O CF3 MeO OMe N H HO PS-NMe3OH N MeO MeO O H oxomaritidine Si-amine PS-PIFA I OC(O)CF3 OC(O)CF3 80 °C 70 °C RT then 55 °C 35 °C 4:1 MeOH/H2O PS-PIFA Si-amine N H NH2 Si in 1:1 MeCN/THF in THF solvent switch to CH2Cl2 5 eq. in CH2Cl2 PS-SO3H Si-piperazine OMe OMe O OEt N O OEt N S O2N S NO2 >99% yield >99% purity 1:1 in MeCN Me O N2 P(O)(OMe)2 Ph F N3 PS-TEMPO OH 1.2 eq. KOtBu in MeOH QP-TU QP-BZA PS-NMe2 PS-SO3H Ph N N N F 60 °C 100 °C 70 °C SO3O N Me Me Me Me N H S NH2 55% tR = 48 min PS-TEMPO QP-TU 1 eq. 2 eq. 2 eq. PS-NMe2•CuI NH2 QP-TU all in MeCN O Cl Cl Cl Cl Cl Cl N N O Me O Me Me Cl O PS-organocat. PS-piperazine H2N N H Me O t-Bu O OH FMocHN s-Bu PS-CDI PS-trisamine H N N H Me O t-Bu O N H s-Bu O HS N N O O Me Me dr 91.5:8.534% N • N H N N H2N NH2 O O N OMe N H
PS-CDI PS-trisamine PS-organocat.
BMS-275291 celite! PS-NMe3SH 2.25 eq. in THF 2.25 eq. in THF 1 eq. in THF 1.05 eq. in THF
step synthesis as a tool for the drug discovery process.
5
Scheme 10 Three-step continuous flow synthesis of receptor
ligands (Ulven).
Finally, immobilized enzymes have also been integrated into continuous flow systems. Ley and co-workers reported the preparation of the natural product grossamide using a
10
continuous flow reactor system (Scheme 11).32 An initial
peptide coupling protocol,33 was followed by a peroxidase
catalysed dimerization to deliver the neolignan natural product.
15
Scheme 11 A multi-step continuous synthesis of grossamide
using an immobilised horseradish peroxidase (Ley).
Summary and Outlook
20In this mini-review we hope to have demonstrated that the use of continuous flow methods for multi-step organic synthesis is a burgeoning and exciting area of research that has the potential to greatly simplify and improve the synthesis process. Indeed, with the promise of economic and safety
25
benefits, pharmaceutical manufacturers have begun to investigate and implement continuous manufacturing as a viable alternative to the traditional batchwise synthesis of API’s.32 Although many challenges remain, continuous flow
multi-step synthesis may be a key breakthrough technology
30
for enabling the efficient preparation of complex substances.
References
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35
35, 686; (c) T. Hudlicky, Chem. Rev., 1996, 96 , 3.
2 P. M. Dewick, Medicinal Natural Products: A Biosynthetic
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3 P. A. Wender and B. L. Miller in Connectivity Analysis and
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4 For a review on cascade reactions in total synthesis see: K. C. Nicolaou, D. J. Edmonds and P. G. Bulger, Angew. Chem., Int. Ed.,
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2006, 45, 7134; for C–H functionalisation methods see the thematic issue: Chem. Rev., 2010, 110, 575; for a review on enantioselective cascade catalysis see: A. M. Walji and D. W. C. MacMillan, Synlett, 2007, 10, 1477; for protecting-group-free synthesis see: R. W. Hoffmann, Synthesis, 2006, 21, 3531; for a discussion of one-pot
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Bogdan and D. T. McQuade, Chem. Rev., 2007, 107, 2300; (d) K. Geyer, T. Gustafsson and P. H. Seeberger, Synlett, 2009, 15, 2382 (e) A. Kirschning, W. Solodenko and K. Mennecke, Chem. Eur. J., 2006,
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Symposium, Systems Chemistry, 2008, 65; (h) K. Jähnisch, V. Hessel,
H. Löwe, M. Baerns, Angew. Chem., Int. Ed., 2004, 43, 406. 6 In this mini-review we use the term ‘continuous flow synthesis’ to
mean a synthetic process where chemical reactions are run using a continuously flowing stream. This definition is thus irrespective of
70
the reactor type used and the scale involved.
7 N. G. Anderson, Practical process research & development, Academic Press, San Diego, Calif. ; London, 2000.
8 J.-i. Yoshida, A. Nagaki and T. Yamada, Chem. Eur. J. 2008, 14, 7450.
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9 H. Usutani, Y. Tomida, A. Nagaki, H. Okamoto, T. Nokami and J.-i. Yoshida, J. Am. Chem. Soc., 2007, 129, 3046.
10 In flow chemisty, residence time (tR) is the time that a reaction
solution spends inside a reactor and is a consequence of the flow rate. 11 R. B. Andrew, L. P. Sarah, C. K. Daniel, J. B. Steven and D. T.
80
McQuade, Angew. Chem., Int. Ed., 2009, 48, 8547.
12 For a discussion see: S. Y. F. Wong-Hawkes, J. C. Matteo, B. H. Warrington and J. D. White in New Avenues to Efficient Chemical
Synthesis, 2007, Springer Berlin, Heidelberg, pp. 39–55.
13 A. Herath, R. Dahl and N. D. P. Cosford, Org. Lett., 2009, 12, 412.
85
14 Website: http://www.syrris.com/
15 H. R. Sahoo, J. G. Kralj, K. F. Jensen, Angew. Chem., Int. Ed. 2007,
46, 5704. For an alternative flow approach to carbamates using
solid-supported reagents see: M. Baumann, I.R. Baxendale, S.V. Ley, N. Nikbin and C.D. Smith, Org. Biomol. Chem., 2008, 6, 1587 and M.
90
Baumann, I.R. Baxendale, S.V. Ley, N. Nikbin, C.D. Smith and J.P. Tierney, Org. Biomol. Chem., 2008, 6, 1577. For a very recent example of continuous separations see: T. Tricotet and D. F. O’Shea,
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16 J. G. Kralj, H. R. Sahoo and K. F. Jensen, Lab Chip, 2007, 7, 256.
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17 R. L. Hartman, J. R. Naber, S. L. Buchwald and K. F. Jensen, Angew.
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18 R. L. Hartman and K. F. Jensen, Lab Chip, 2009, 9, 2495. For a recently reported method for performing an in-line solvent switch as part of a multi-step flow sequence see: M. D. Hopkin, I. R. Baxendale
100
and S. V. Ley, Chem. Commun., 2010, 46, 2450.
PS-trisamine CbzN NH N R CO H-cube! Br R' N N R' O H N R 75 °C PS-NMM 11-96% after semiautomatic flash chromatography N O 75 °C 75 °C tR = 7 min PS-NMM PS-trisamine 1 eq. in DMF 1.5 eq. in DMF 1.5 eq. in DMF tR = 6 min MeO HO O OH DIPEA PyBroP PS-HOBt HO NH2 PS-SO3H H2O2•urea, pH 4.5 buffer PS-enzyme O O HN O N H OH OH MeO HO grossamide PS-HOBt N N N OH in THF in DMF
19 For a comprehensive compendium see: S. V. Ley, I. R. Baxendale, R. N. Bream, P. S. Jackson, A. G. Leach, D. A. Longbottom, M. Nesi, J. S. Scott, R. I. Storer and S. J. Taylor, J. Chem. Soc., Perkin Trans. 1, 2000, 3815. For other perspectives see: D. C. Sherrington, J. Polym.
Sci., Part A: Polym. Chem., 39, 2001, 2364 and P. Hodge, Chem. Soc.
5
Rev., 26, 1997, 487.
20 (a) S. Ley et al., PCT Int. Appl., W09958475, 1999; (b) I. R. Baxendale and S. V. Ley in New Avenues to Efficient Chemical
Synthesis, 2007, Springer Berlin, Heidelberg, pp. 151–185.; (c) P.
Hodge, Curr. Opin. Chem. Biol., 2003, 7, 362. For further discussions
10
see references 5(e) and 19. 21 P. Kundig, Science, 314, 430.
22 For the most recent review of the group’s work see reference 5(g). 23 I. R. Baxendale, J. Deeley, C. M. Griffiths-Jones, S. V. Ley, S. Saaby
and G. K. Tranmer, Chem. Commun., 2006, 2566.
15
24 Website: http://www.thalesnano.com/products/h-cube
25 R. Noyori, Nature Chem., 1, 5.
26 C. Wiles, P. Watts and S. J. Haswell, Lab Chip, 2007, 7, 322. It is noteworthy that even ‘traditional’ synthesis laboratories have begun to embrace multi-step flow chemistry, see: A. W. Pilling, J. Boehmer
20
and D. J. Dixon, Angew. Chem., Int. Ed., 2007, 46, 5428.
27 I. R. Baxendale, S. V. Ley, A. C. Mansfield and C. D. Smith, Angew.
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28 Website: http://www.vapourtec.co.uk/
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25
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30
31 T. P. Petersen, A. Ritzen and T. Ulven, Org. Lett., 2009, 11, 5134. 32 I. R. Baxendale, C. M. Griffiths-Jones, S. V. Ley and G. K. Tranmer,
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35
34 D. M. Roberge, B. Zimmermann, F. Rainone, M. Gottsponer, M. Eyholzer and N. Kockmann, Org. Process Res. Dev., 2008, 12, 905.