Synthesis of 3-nitropyrrolidines via dipolar cycloaddition reactions using a modular flow reactor

Article abstract of DOI:10.1055/s-0029-1219344

The generation and subsequent use of unstabilised azomethine ylides in dipolar cycloaddition reactions within a flow microreactor is demonstrated. The 3-nitropyrrolidines produced were furthermore subjected to chemoselective hydrogenation reactions using

Full text of DOI:10.1055/s-0029-1219344

LETTER
749
Synthesis of 3-Nitropyrrolidines via Dipolar Cycloaddition Reactions Using a
Modular Flow Reactor
S
ynthesis of 3-Nitropy
a
rrolidines rcus Baumann, Ian R. Baxendale, Steven V. Ley*
Innovative Technology Centre, Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge, CB2 1EW, UK
Fax +44(1223)767798; E-mail: svl1000@cam.ac.uk
Received 20 November 2009
This modular platform consists of a dual pumping unit
Abstract: The generation and subsequent use of unstabilised
which delivers the dissolved starting materials into a mix-
ing device and directs the combined reaction stream
azomethine ylides in dipolar cycloaddition reactions within a flow
microreactor is demonstrated. The 3-nitropyrrolidines produced
were furthermore subjected to chemoselective hydrogenation reac-
through a selection of convection flow coils (CFC) and/or
tions using the H-Cube® system. To ensure product purities in ex- glass tubes13 filled with solid-supported reagents and
cess of 90–95%, immobilised scavengers were successfully
employed.
scavengers that can be maintained at a desired tempera-
ture and pressure. Furthermore, this system can be run
Key words: microreactor, flow chemistry, pyrrolidine, dipolar cy-
cloaddition, solid-supported reagents
with the Flow Commander software also available from
Vapourtec12 allowing for the use of a front-end liquid han-
dler and a UV-directed fraction collector.
The synthesis of highly functionalised heterocyclic com-
pounds is of central importance to most modern medicinal
chemistry programmes1 since these building blocks are
readily manipulated to compounds with favourable phar-
macophoric properties. Accordingly, the synthetic chem-
ist is expected to deliver these entities in a flexible, high-
yielding fashion yet avoiding time-consuming purifica-
tion procedures as well as hazardous or obnoxious chem-
ical inputs wherever possible.2 In recent studies we3 and
others4 have attempted to address some of these issues by
using modular flow reactors in concert with automation
methods and in-line immobilised reagents and scavengers
packed into glass columns to effect clean product forma-
tion.
H
O
N
N
N
N
N
H
OH
N
N
N
H
H
nicotine
L-proline
L-prolinyl tetrazole
O
H
O
NH
Ar
HO
OTMS
Ar
NH2
O
N
N
N
H
NC
H
vildagliptin
Jörgensen's catalyst
levetiracetam
Figure 1 Biologically and synthetically interesting pyrrolidines
We have already demonstrated the success of these meth-
ods in the preparation of various heterocyclic scaffolds
such as oxazoles,5 oxazolines,6 pyrazoles,7 triazoles,8 thi-
azoles, and imidazoles9 using a variety of flow microreac-
tors. Here we show how these devices can be applied
further to the efficient assembly of 3-nitropyrrolidines and
related structures as potentially useful building blocks for
synthesis since pyrrolidine-based compounds have been
shown to display a wide variety of biological activities.10
These structures can be found in alkaloids such as nicotine
or in amino acids typified by proline, as well as many drug
substances such as the anticonvulsant Levetiracetam or
the oral antihyperglycemic agent Vildagliptin (Figure 1).
In addition, many chiral pyrrolidines have been described
as privileged structures with numerous applications in the
field of asymmetric organocatalysis.11
For the preparation of 3-nitropyrrolidine derivatives and
in order to access more structural variety in the pyrroli-
dine ring, we have chosen to use a dipolar cycloaddition
process involving nonstabilised azomethine ylides and ni-
tro alkenes.14 This reaction also readily allows for the sub-
sequent differentiation of both nitrogen functionalities
and hence increases the flexibility towards any subse-
quent transformation (Scheme 1).
In order to perform initial cycloaddition studies, toluene
was selected as the preferred solvent to dissolve both the
nitro alkene as well as the commercially available N-(meth-
oxymethyl)-N-(trimethylsilyl)benzylamine coupling part-
ner at concentrations up to 0.2 M. The further addition of
1.0 equivalent of TFA to the nitro alkene solution was
found to be crucial in order to generate the dipole even at
the elevated temperatures of the flow reaction. When
these stock solutions were mixed in a standard static mix-
ing tee and flowed through a 10 mL CFC heated to
120 °C, with a residence time of between 30–90 minutes,
the corresponding 3-nitropyrrolidine was formed. Subse-
quent optimisation led to the observation that acetonitrile,
in most cases, was a superior solvent to toluene as it was
In our investigations below we make use of the R2+/R4
flow system commercially available from Vapourtec.12
SYNLETT 2010, No. 5, pp 0749–0752
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6.
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Advanced online publication: 25.01.2010
DOI: 10.1055/s-0029-1219344; Art ID: D33709ST
© Georg Thieme Verlag Stuttgart · New York

750
M. Baumann et al.
LETTER
more easily removed, and the starting materials could be By being able to carefully adjust the reaction parameters
prepared at higher concentrations (up to 0.5 M). Further- of the flow reactor more sensitive nitropyrrolidines such
more, real time product analysis via LC-MS was more as those with labile halides on heterocyclic ring systems
convenient in acetonitrile as opposed to toluene due to the (1, 2, and 5) or the bicyclic octahydroisoindoline deriva-
high UV absorption of the toluene signal at key monitor- tive 3 could also be readily obtained in high yield.
ing wavelengths.
Having prepared this first set of nitropyrrolidine deriva-
tives we wished to further simplify our protocol by avoid-
ing the use of the strong TFA acid in order to generate the
reactive dipole. In relation to some of our earlier studies
on monolithic reactor cartridges we were attracted by the
concept of a reloadable fluoride monolith which we had
previously found very powerful in a number of trifluo-
romethylation reactions using Ruppert’s reagent (TMS-
CF3) in a flow process.17b After preparation and charging
of this ion-exchange monolith according to previously
published literature procedures3e,16,17 we started our inves-
tigations in the azomethine ylid cycloaddition chemistry.
We were pleased to confirm that indeed high conversions
of the starting materials could be achieved even at reduced
temperatures of between 50–80 °C in comparison to our
original procedure. Furthermore, we were able to reduce
the overall reaction time including the QP-BZA-assisted
removal of excess nitro alkene starting material to less
than one hour. Using the fluoride monolith also resulted in
increased yields of 3-nitropyrrolidine products when
compared to the previous method using TFA (Figure 3,
compounds 1, 3, 9). Encouraged by these new results we
expanded the initial work by varying the type of dipolaro-
phile. Again, a small collection of differently substituted
pyrrolidine products was prepared (Figure 3) including
interesting substituents such as sulfonates, phosphonates,
and esters. Starting from D-menthyl acrylate we also in-
vestigated the impact of a chiral auxiliary on the diastere-
omeric ratio of the product outcome. However, under all
conditions evaluated (time, temperature, stoichiometry,
and solvent modifications) only a 1:1 mixture of diastereo-
mers was ever observed by NMR analysis.
Scheme 1 Optimised flow set-up for formation of 3-nitropyrrolidines
We have also shown that by passing the exiting flow
stream through a glass column packed with an immobil-
ised benzylamine scavenger resin (QP-BZA,15 2.5 equiv)
followed by a plug of silica gel (1 cm path length), it was
possible to remove any unreacted nitro alkene and simul-
taneously release the desired nitropyrrolidine from its ini-
tially formed TFA salt. By using the above set of
conditions a small collection of 3-nitropyrrolidines
(Figure 2) was quickly generated using temperatures
ranging from 60–120 °C and affording high-purity prod-
ucts in good isolated yields.
O2N
O2N
Br
N
Bn
MeO
N
S
Bn
N
Cl
1, 76%
2, 77%
NO2
O
Bn
NO2
Bn
NO2
N
Bn
N
N
N
Bn
N
O
OBn
O
N
H
F
Cl
O
P
Bn
Bn
O
O
3, 74%
5, 82%
4, 79%
EtO
OEt
MeO
F3CO
O2N
NO2
NO2
11, 86%
12, 89%
13, 92%
O
N
Bn
N
N
Bn
Bn
O
N
Bn
O
S
Bn
N
6, 87%
7, 81%
8, 91%
O
O
O2N
Bn
NO2
N
14, 83%
15, 87%
Bn
NO2
Cl
N
N
O2N
O2N
Br
Bn
N
Bn
N
O2N
9, 91%
H
10, 93%
9, 88%
S
Bn
1, 83%
3, 84%
Figure 2 Collection of 3-nitropyrrolidines prepared in flow
Figure 3 Pyrrolidines prepared using a fluoride monolith in flow
Synlett 2010, No. 5, 749–752 © Thieme Stuttgart · New York

LETTER
Synthesis of 3-Nitropyrrolidines
751
To further elaborate these 3-nitropyrrolidine derivatives
into other building blocks we exploited their inherent
chemoselectivity. This was accomplished by selective hy-
drogenation of the nitro group over the benzyl group using
the H-Cube® flow hydrogenator.18 Employing an ethanol–
ethyl acetate (1:1 mixture) solvent system the clean reduc-
tion of the nitro group to the corresponding amine was
achieved on passage through a Raney Nickel filled car-
tridge at 60 °C in the presence of catalytic amounts of ace-
tic acid (Figure 4).
References and Notes
(1) (a) Name Reactions in Heterocyclic Chemistry; Li, J. J., Ed.;
John Wiley and Sons, Inc.: Hoboken / NJ, 2005. (b) The
Organic Chemistry of Drug Design and Drug Action, 2nd
ed.; Silverman, R. B., Ed.; Elsevier Academic Press: New
York, 2004. (c) Heterocyclic Chemistry, 4th ed.; Joule, J. A.;
Mills, K., Eds.; Blackwell Publishing: Cambridge MA,
2008. (d) The Practice of Medicinal Chemistry, 3rd ed.;
Wermuth, C. G., Ed.; Elsevier Academic Press: Burlington
MA, 2008.
(2) (a) Ley, S. V.; Baxendale, I. R. Chimia 2008, 63, 162.
(b) Baxendale, I. R.; Hayward, J. J.; Lanners, S.; Ley, S. V.;
Smith, C. D. In Microreactors in Organic Synthesis and
Catalysis; Wirth, T., Ed.; Wiley-VCH: Weinheim, 2008,
Chap. 4.2, 84–122. (c) Baxendale, I. R.; Hayward, J. J.; Ley,
S. V.; Tranmer, G. K. ChemMedChem 2007, 2, 768.
(d) Baxendale, I. R.; Pitts, M. R. Chem. Today 2006, 24, 41.
(3) (a) Sedelmeier, J.; Ley, S. V.; Baxendale, I. R. Green Chem.
2009, 11, 683. (b) Baxendale, I. R.; Ley, S. V.; Mansfield,
A. C.; Smith, C. D. Angew. Chem. Int. Ed. 2009, 48, 4017.
(c) Baxendale, I. R.; Ley, S. V.; Schou, S. C.; Sedelmeier, J.
Chem. Eur. J. 2010, 16, 89. (d) Sedelmeier, J.; Ley, S. V.;
Baxendale, I. R. Green Chem. 2009, 11, 683. (e) Baumann,
M.; Baxendale, I. R.; Ley, S. V.; Nikbin, N.; Smith, C. D.
Org. Biomol. Chem. 2008, 6, 1587. (f) Baumann, M.;
Baxendale, I. R.; Ley, S. V.; Nikbin, N.; Smith, C. D.;
Tierney, J. P. Org. Biomol. Chem. 2008, 6, 1577.
OBn
Cl
F3CO
Bn
Bn
N
N
Bn
N
H2N
18, 93%
H2N
H2N
16, 95%
17, 97%
Figure 4 Raney nickel mediated reduction of nitropyrrolidines
Alternatively, when the flow catalyst cartridge was filled
with 10% Pd on charcoal both reduction of the nitro group
and concomitant removal of the benzyl protecting group
can be realised. All of the resulting 3-aminopyrrolidines
were obtained with no loss of stereochemical integrity in
very good yields and purities after removal of the acetate
counterion. This was easily achieved by elution of the out-
put stream through a column of polymer-supported
carbonate19 (1.0 equiv based on 3-nitropyrrolidine starting
material) followed by solvent removal (Figure 5).
(g) Carter, C. F.; Baxendale, I. R.; O’Brien, M.; Pavey, J. B.
J.; Ley, S. V. Org. Biomol. Chem. 2009, 7, 4594.
(h) Hornung, C. H.; Mackley, M. R.; Baxendale, I. R.; Ley,
S. V. Org. Process Res. Dev. 2007, 11, 399. (i) Baxendale,
I. R.; Ley, S. V.; Smith, C. D.; Tranmer, G. K. Chem.
Commun. 2006, 4835. (j) Baxendale, I. R.; Griffiths-Jones,
C. M.; Ley, S. V.; Tranmer, G. K. Synlett 2006, 427.
(k) Baxendale, I. R.; Deeley, J.; Griffiths-Jones, C. M.; Ley,
S. V.; Saaby, S.; Tranmer, G. K. Chem. Commun. 2006,
2566.
MeO
OH
NH2
(4) (a) Kirschning, A.; Solodenko, W.; Mennecke, K. Chem.
Eur. J. 2006, 12, 5972. (b) Brandt, J. C.; Wirth, T. Beilstein
J. Org. Chem. 2009, 5, 30. (c) Razzaq, T.; Glasnov, T. N.;
Kappe, C. O. Eur. J. Org. Chem. 2009, 1321. (d) Mason, B.
P.; Price, K. E.; Steinbacher, J. L.; Bogdan, A. R.; McQuade,
D. T. Chem. Rev. 2007, 107, 2300. (e) Hafez, A. M.; Taggi,
A. E.; Dudding, T.; Lectka, T. J. Am. Chem. Soc. 2001, 123,
10853. (f) Grant, D.; Dahl, R.; Cosford, N. D. P. J. Org.
Chem. 2008, 73, 7219. (g) Gustafsson, T.; Pontén, F.;
Seeberger, P. H. Chem. Commun. 2008, 1100. (h) Sahoo,
H. R.; Kralj, J. G.; Jensen, K. F. Angew. Chem. Int. Ed. 2007,
46, 5704. (i) Jähnisch, K.; Hessel, V.; Löwe, H.; Baerns, M.
Angew. Chem. Int. Ed. 2004, 43, 406. (j) Kulkami, A. A.;
Kalyani, V. S.; Joshi, R. A.; Joshi, R. R. Org. Process Res.
Dev. 2009, 13, 999. (k) Hübner, S.; Bentrup, U.; Budde, U.;
Lovis, K.; Dietrich, T.; Freitag, A.; Küpper, L.; Jähnisch, K.
Org. Process Res. Dev. 2009, 13, 952. (l) Petersen, T. P.;
Ritzén, A.; Ulven, T. Org. Lett. 2009, 11, 5134.
NH
NH
NH
NH
H2N
H
H2N
H2N
21, 93%
19, 90%
20, 97%
22, 95%
Figure 5 Pd/C-mediated reduction and debenzylation of 3-nitro-
pyrrolidines
In summary, we have demonstrated a particularly conve-
nient preparation of 3-nitropyrrolidines and related com-
pounds using a flow chemical reactor and appropriate
inline workup cartridges to avoid conventional clean up
procedures.20 The further elaboration of the products by
chemoselective hydrogenation chemistry using a flow hy-
drogenator was also achieved to give a new range of
building blocks for organic synthesis programmes.
(5) Baumann, M.; Baxendale, I. R.; Ley, S. V.; Smith, C. D.;
Tranmer, G. K. Org. Lett. 2006, 8, 5231.
(6) Baumann, M.; Baxendale, I. R.; Ley, S. V. Synlett 2008,
2111.
Acknowledgment
We gratefully acknowledge financial support from the Cambridge
European Trust and the Ralph Raphael Studentship award (to
M.B.), the Royal Society (to I.R.B.), and the BP endowment (to
S.V.L.).
(7) Smith, C. J.; Iglesias-Sigüenza, F. J.; Baxendale, I. R.; Ley,
S. V. Org. Biomol. Chem. 2007, 5, 2758.
(8) Smith, C. D.; Baxendale, I. R.; Lanners, S.; Hayward, J. J.;
Smith, S. C.; Ley, S. V. Org. Biomol. Chem. 2007, 5, 1559.
(9) Baxendale, I. R.; Ley, S. V.; Smith, C. D.; Tamborini, L.;
Voica, A.-F. J. Comb. Chem. 2008, 10, 851.
(10) Nájera, C.; Sansano, J. M. Org. Biomol. Chem. 2009, 7,
4567.
Synlett 2010, No. 5, 749–752 © Thieme Stuttgart · New York

752
M. Baumann et al.
LETTER
(11) (a) Mukherjee, S.; Yang, J. W.; Hoffmann, S.; List, B. Chem.
Rev. 2007, 107, 5471. (b) MacMillan, D. W. C. Nature
(London) 2008, 455, 304.
(12) Vapourtec R2+/R4 units are available from Vapourtec Ltd,
Place Farm, Ingham, Suffolk, IP31 1NQ, UK. Website:
http://www.vapourtec.co.uk.
(20) In a typical flow experiment stock solutions of the alkene
component (1.5 equiv, containing 1.0 equiv TFA in MeCN)
and N-(methoxymethyl)-N-(trimethylsilyl)benzylamine (1.0
equiv in MeCN) were prepared and injected into the two
individual sample loops of the R2+ unit of the Vapourtec
system. The resulting streams were mixed in a static mixing
tee and then directed into a flow coil (10 mL volume, 1.0 mm
i.d., temperature 60–120 °C) mounted on the R4 unit to give
residence times between 30–90 min depending on the
reactivity of the substrate used. After leaving this coil the
reaction mixture was directed into a glass column (typically
10 cm length, 10 mm bore) containing the scavenging resin
(QP-BZA, 2.5 equiv and a 1 cm plug of silica). The purified
product was then collected and isolated after solvent
removal.
(13) Commercially available Omnifit® glass chromatography
columns with adjustable height-end pieces(plunger).
Typically, the polymer-supported reagent is placed in an
appropriately sized Omnifit column®, usually 10 mm bore
by 150 mm length, or shorter and the plungers are adjusted
to relevant bed heights and the polymer swelled/washed with
solvent. Website: http://www.omnifit.com.
(14) (a) Bigotti, S.; Malpezzi, L.; Molteni, M.; Mele, A.; Panzeri,
W.; Zanda, M. Tetrahedron Lett. 2009, 50, 2540.
(b) Wright, S. W.; Ammirati, M. J.; Andrews, K. M.;
Brodeur, A. M.; Danley, D. E.; Doran, S. D.; Lillquist, J. S.;
Liu, S.; McClure, L. D.; McPherson, R. K.; lson, T. V.;
Orena, S. J.; Parker, J. C.; Rocke, B. N.; Soeller, W. C.;
Soglia, C. B.; Treadway, J. L.; VanVolkenburg, M. A.;
Zhao, Z.; Cox, E. D. Bioorg. Med. Chem. Lett. 2007, 17,
5638. (c) Bucsh, R. A.; Domagla, J. M.; Laborde, E.; Sesnie,
J. C. J. Med. Chem. 1993, 36, 4139.
For Experiments Involving the Use of the Fluoride
Monolith
The two starting materials were dissolved at the same
concentrations in MeCN and injected into the two
corresponding sample loops of the R2+ [alkene 1.5 mmol in
MeCN and N-(methoxymethyl)-N-(trimethylsilyl)benzyl-
amine 1.0 mmol in MeCN]. After mixing both streams in a
T-piece the resulting mixture was directed into the fluoride
monolith (in a column; 10 cm length, 15 mm bore, ca. 12
mmol fluoride) heated between 50–80 °C with a combined
flow rate of 200 mL/min. The exiting stream was then passed
through a glass column (10 cm length, 10 mm bore)
containing the scavenging resin (QP-BZA, 2.5 equiv) for
final in-line purification.
For the chemoselective reduction of 3-nitropyrrolidines
using the H-Cube® system in full hydrogen mode the starting
material was dissolved in a EtOH–EtOAc (1:1) solvent
system (0.2–0.5 M; containing catalytic amounts of AcOH)
and passed through the appropriate catalyst cartridge heated
to 60 °C with a flow rate of 1.0 mL/min. In order to remove
the acetate counterion the out flow stream is subsequently
directed through a glass column containing 1 equiv polymer-
supported carbonate.19
(15) QuadraPure benzylamine (QP-BZA) is a high-loading
scavenger commercially available from Reaxa. Website:
http://www.reaxa.com.
(16) Nikbin, N.; Ladlow, M.; Ley, S. V. Org. Process Res. Dev.
2007, 11, 458.
(17) (a) Baxendale, I. R.; Ley, S. V.; Lumeras, W.; Nesi, M.
Comb. Chem. High Throughput Screening 2002, 5, 197.
(b) Baumann, M.; Baxendale, I. R.; Martin, L. J.; Ley, S. V.
Tetrahedron 2009, 65, 6611.
(18) The H-Cube® flow hydrogenator is commercially available
from ThalesNano Nanotechnology Inc., Graphisoft Park,
H-1031 Budapest, Záhony u. 7, Hungary; Website: http://
www.thalesnano.com.
(19) MP-carbonate is a basic anion-exchange resin (3.2 mmol/g)
commercially available from Biotage. Website: http://
www.biotage.com.
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