Continuous Flow Multi-Step Organic Synthesis
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Citation
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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Continuous Flow Multi-Step Organic Synthesis
Damien Webb, Timothy F. Jamison
5
Received (in XXX, XXX) Xth XXXXXXXXX 200X, Accepted Xth XXXXXXXXX 200X
First published on the web Xth XXXXXXXXX 200X
DOI: 10.1039/b000000x
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
10
15
20
25
30
The multi-step synthesis of complex organic compounds from
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,
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
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
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
(a) traditional approach
A
+
B
reaction 1
40
45
reaction 2
D
reaction 3
50
55
E
step-by-step batch synthesis
intermediates C and D isolated and purified
65
(b) 'ideal' synthesis
E
A
Multi-Step Flow Synthesis
Solution-based approaches
60
C
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
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.
one-step to E
economic synthesis
(c) continuous flow multi-step synthesis
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
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.
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
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
attributed to effective temperature and residence time10 (tR)
control that allows the unstable intermediates to be rapidly
transferred to the next stage of the reactor before
decomposition can occur.
70
A
C
D
Br
E
B
Br
C and D not isolated
multiple steps in 1 operation
Figure 1 Synthesis strategies.
35
Currently, the ideal laboratory synthesis3 (Figure 1(b)) is
unlikely to be achieved in practice, although a number of
innovative strategies have been developed to increase
synthetic efficiency.4 A recently introduced method for
This journal is © The Royal Society of Chemistry [year]
in THF
PhCHO
n-BuLi
TMSCl
in THF
in hexane
in THF
tR = 0.82 s
tR = 6.93 s
tR = 0.49 s
tR = 1.57 s
–78 °C
–78 °C
0 °C
0 °C
n-BuLi
in hexane
TMS
OH
Ph
74%
= the introduction of an input stream to the reactor network
tR = residence time in the reactor (see ref. 10)
Scheme 1 Generation and reaction of o-bromophenyllithium
species using flow chemistry (Yoshida).
Journal Name, [year], [vol], 00–00 | 1
5
Recently, the McQuade group reported a synthesis of the nonsteroidal 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
in 51% isolated yield following off-line workup and
crystallisation of the exiting flow stream.
O
20 eq. KOH
in MeOH
in MeOH/H2O
H2O
1 eq.
RT
tR = 5 min
tR = 2 min
150 °C
TfOH
5 eq.
45
tR = 3 min
50 °C
O
65 °C
51% after recrystallization
0 °C
50
10
Scheme 2 Continuous flow synthesis of ibuprofen (McQuade).
15
20
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
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
O
HO
tR = 15 min
100 °C
75 °C
Br
O
N
N
CO2Me
HN
65
HN
1.2 eq. in DMF
25
Scheme 3 Synthesis of a Mur ligase inhibitor using multi-step
continuous flow synthesis (Cosford).
70
Continuous separation and distillation
30
35
40
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
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
biphasic extraction systems with microreactors for the multistep 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
2 | Journal Name, [year], [vol], 00–00
HCl (aq.)
triflate
formation
DMF and N2
in DMF
liquid-liquid
separation
microdistillation
aqueous extract
N2 + CH2Cl2
Heck
reaction
On-Bu
t-Bu
Scheme 5 Continuous synthesis of an enol-ether involving
liquid–liquid separation and continuous solvent exchange (Jensen
and Buchwald).
O
46%
N2
Tf2O in CH2Cl1
55
2 eq. in DMF
HOBt, EDC
(1.2 eq. in DMF)
tR = 20 min
OH
DIPEA
DIPEA
N
OR'
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
A bespoke silicon device was employed to carry out a
continuous distillation of a binary solvent mixture
(dichloromethane/DMF).18
in CH2Cl2
OH
1 eq. in DMF
RT
N
H
Scheme 4 Continuous carbamate synthesis involving multiple
reactions and separations (Jensen).
t-Bu
60
NH2
R
On-Bu
N
H
OH
O
gas-liquid
separation
Pd(OAc)2, dppp, NEt3
MeO2C
H2N
Curtius
liquid-liquid rearrangement
separation
105 °C
aqueous extract
OH
1 eq.
acyl azide
formation
1.1 eq. NaN3 (aq.)
1 eq. PhI(OAc)2
4 eq. HC(OMe)3
O
R'OH
R
Cl
1 eq. in toluene
75
Solid-supported multi-step flow synthesis
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
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
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
synthetic steps were orchestrated into a single reactor network
to afford the target in excellent yield (>40%) and purity
(>90%).
This journal is © The Royal Society of Chemistry [year]
HO
HO
Br
PS-NMe3N3
PS-PhP(n-Bu)2
70 °C
RT then 55 °C
in 1:1 MeCN/THF
P(O)(OMe)2
Me
H-Cube!
N2
N
H
OH
MeO
PS-TPAP
OMe
MeO
O
OMe
in THF
4:1 MeOH/H2O
O
MeO
PS-NMe3OH
H
MeO
1.2 eq. KOtBu
in MeOH
O
F3C
solvent switch to
CH2Cl2
F
Ph
55%
80 °C
Me
Me
oxomaritidine
Me
N
H
OC(O)CF3
Si
35
Scheme 6 Continuous flow synthesis of oxomaritidine (Ley). PS
= polymer supported.
5
10
NH2
QP-TU
QP-TU
NH2
Si-amine
PS-PIFA
NH2
Me
PS-TEMPO
I
F
S
SO3 O N
N
H
PS-SO3H
2 eq.
all in MeCN
PS-PIFA
OC(O)CF3
PS-NMe2
N
35 °C
N
QP-BZA
N
N
Ph
CF3
QP-TU
70 °C
OH
2 eq.
5 eq. in CH2Cl2
Si-amine
N3
PS-NMe2•CuI
100 °C
60 °C
O
O
tR = 48 min
PS-TEMPO
1 eq.
The development of catalytic process is integral to the future
of synthesis25 and so the use of solid-supported catalysts for
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
40
45
Scheme 8 Three-step continuous flow synthesis of a triazole
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
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
impressive yields and selectivities were observed.
OMe
S
OMe
O2N
N
PS-SO3H
N
O
Si-piperazine
s-Bu
OEt
O
S
1:1 in MeCN
O
NO2
OEt
1.05 eq. in THF
Me
>99% yield
>99% purity
Me
20
25
30
Scheme 7 Continuous two-step synthesis of α,β-unsaturated
compounds using supported catalysts (Watts).
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 solidsupported 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
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
and without recourse to traditional column chromatography.29
Me
N
H
t-Bu
1 eq. in THF
PS-CDI
PS-trisamine
Cl
2.25 eq. in THF
celite!
PS-organocat.
PS-NMe3SH
PS-piperazine
O
Cl
Cl
O s-Bu
Cl
HS
Cl
N
H
Cl
2.25 eq. in THF
N
O
Me
N
t-Bu
N
H
Me
BMS-275291
O
Me
O
H
N
O
Cl
34%
dr 91.5:8.5
OMe
•
N
H2N
H
N
PS-CDI
50
60
NH2
N
N
55
This journal is © The Royal Society of Chemistry [year]
O
N
O
H2N
O
N
Me
15
O
OH
FMocHN
N
PS-trisamine
O
H
N
O
PS-organocat.
Scheme 9 Synthesis of BMS-275291 using a column-based
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
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 multiJournal Name, [year], [vol], 00–00 | 3
step synthesis as a tool for the drug discovery process.
References
1
R'
CbzN
35
Br
2
1.5 eq. in DMF
NH
1 eq. in DMF
tR = 7 min
tR = 6 min
H-cube!
PS-trisamine
PS-NMM
75 °C
R
N
C
75 °C
O
40
3
PS-trisamine
75 °C
1.5 eq. in DMF
N
R'
H
N
N
11-96%
after semiautomatic
flash chromatography
R
4
O
45
N
O
PS-NMM
50
5
Scheme 10 Three-step continuous flow synthesis of receptor
ligands (Ulven).
10
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
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.
55
5
60
15
O
MeO
HO
65
H2O2•urea, pH 4.5 buffer
OH
PS-HOBt
PS-SO3H
PS-enzyme
6
PyBroP
DIPEA
in DMF
70
NH2
OH
HN
O
HO
OH
O
in THF
7
N
H
HO
8
O
MeO
grossamide
75
9
10
OH
N
N
N
PS-HOBt
80
11
12
Scheme 11 A multi-step continuous synthesis of grossamide
using an immobilised horseradish peroxidase (Ley).
85
20
25
30
Summary and Outlook
In 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
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
for enabling the efficient preparation of complex substances.
4 | Journal Name, [year], [vol], 00–00
13
14
15
90
95
16
17
18
100
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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
synthesis see: S. J. Broadwater, S. L. Roth, K. E. Price, M. Kobaslija
and D. T. McQuade, Org. Biomol. Chem., 2005, 3, 2899; for
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For recent reviews on flow chemistry see: (a) T. Wirth,
Microreactors in organic synthesis and catalysis, Wiley-VCH,
Weinheim, 2008; (b) R. L. Hartman and K. F. Jensen, Lab Chip,
2009, 9, 2495; (c) B. P. Mason, K. E. Price, J. L. Steinbacher, A. R.
Bogdan and D. T. McQuade, Chem. Rev., 2007, 107, 2300; (d) K.
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12, 5972; (f) C. Wiles and P. Watts, Eur. J. Org. Chem., 2008, 10,
1655; (g) S. V. Ley and I. R. Baxendale in Proceedings of Bosen
Symposium, Systems Chemistry, 2008, 65; (h) K. Jähnisch, V. Hessel,
H. Löwe, M. Baerns, Angew. Chem., Int. Ed., 2004, 43, 406.
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
the reactor type used and the scale involved.
N. G. Anderson, Practical process research & development,
Academic Press, San Diego, Calif. ; London, 2000.
J.-i. Yoshida, A. Nagaki and T. Yamada, Chem. Eur. J. 2008, 14,
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H. Usutani, Y. Tomida, A. Nagaki, H. Okamoto, T. Nokami and J.-i.
Yoshida, J. Am. Chem. Soc., 2007, 129, 3046.
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.
R. B. Andrew, L. P. Sarah, C. K. Daniel, J. B. Steven and D. T.
McQuade, Angew. Chem., Int. Ed., 2009, 48, 8547.
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.
A. Herath, R. Dahl and N. D. P. Cosford, Org. Lett., 2009, 12, 412.
Website: http://www.syrris.com/
H. R. Sahoo, J. G. Kralj, K. F. Jensen, Angew. Chem., Int. Ed. 2007,
46, 5704. For an alternative flow approach to carbamates using solidsupported reagents see: M. Baumann, I.R. Baxendale, S.V. Ley, N.
Nikbin and C.D. Smith, Org. Biomol. Chem., 2008, 6, 1587 and M.
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,
Chem. Eur. J., DOI: 10.1002/chem.200903284.
J. G. Kralj, H. R. Sahoo and K. F. Jensen, Lab Chip, 2007, 7, 256.
R. L. Hartman, J. R. Naber, S. L. Buchwald and K. F. Jensen, Angew.
Chem., Int. Ed., 2010, 122, 911.
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
and S. V. Ley, Chem. Commun., 2010, 46, 2450.
This journal is © The Royal Society of Chemistry [year]
5
10
15
20
25
30
35
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,
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Sci., Part A: Polym. Chem., 39, 2001, 2364 and P. Hodge, Chem. Soc.
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
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.
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
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.
Chem., Int. Ed., 2009, 48, 4017.
28 Website: http://www.vapourtec.co.uk/
29 For a discussion of this work see: P. S. Seeberger, Nature Chem., 1,
258.
30 S. France, D. Bernstein, A. Weatherwax and T. Lectka, Org. Lett.,
2005, 7, 3009. For a review of the Lectka groups work in this area
see: A. M. Hafez, A. E. Taggi and T. Lectka, Chem. Eur. J., 2002, 8,
4114.
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,
Synlett, 2006, 3, 427.
33 I. R. Baxendale, S. V. Ley, C. D. Smith and G. K. Tranmer, Chem.
Commun., 2006, 4835.
34 D. M. Roberge, B. Zimmermann, F. Rainone, M. Gottsponer, M.
Eyholzer and N. Kockmann, Org. Process Res. Dev., 2008, 12, 905.
This journal is © The Royal Society of Chemistry [year]
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