The use of copper flow reactor technology for the continuous synthesis of 1,4-Disubstituted 1,2,3-triazoles

Article abstract of DOI:10.1002/adsc.200800758

A library of 1,4-disubstituted 1,2,3-tri-azoles was synthesized using a copper flow reactor. Organic azides, generated in situ from alkyl halides and sodium azide, were reacted with acetylenes using the copper-catalyzed Huisgen 1,3-dipolar cy-cloaddition.

Full text of DOI:10.1002/adsc.200800758

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DOI: 10.1002/adsc.200800758
The Use of Copper Flow Reactor Technology for the Continuous
Synthesis of 1,4-Disubstituted 1,2,3-Triazoles
Andrew R. Bogdana and Neal W. Sachb,*
a
Cornell University, Department of Chemistry and Chemical Biology, Ithaca, NY 14853, USA
Pfizer Inc., Global Research and Development, Medicinal Chemistry, 10777 Science Centre Drive, San Diego, CA 92121,
b
USA
Fax : (+1)-858-678-8244; phone: (+1)-858-622-7938; e-mail: neal.sach@pfizer.com
Received: December 8, 2008; Revised: March 12, 2009; Published online: April 6, 2009
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adsc.200800758.
Abstract: A library of 1,4-disubstituted 1,2,3-tri-
ACHTUNGTRENNUNGazoles was synthesized using a copper flow reactor.
Flow chemistry is an important, emerging field that
pushes the boundaries of organic synthesis by access-
ing so-called ꢀforbidden chemistriesꢁ through unparal-
leled reaction control.[6] The numerous advantages of
running reactions in flow are often attributed to the
large surface area-to-volume ratios.[6c] Small dimen-
sions lead to good mixing[7] and the superb heat trans-
fer within these systems enables excellent control of
exotherms, limiting the impact of runaway reac-
tions.[6b] Back-pressure regulation technology enables
solvent boiling suppression and reaction kinetics can
be substantially increased.[8] In addition, scale-up be-
comes a facile process compared with batch systems
and output is measured as a function of time rather
than batch size.[9]
Organic azides, generated in situ from alkyl halides
and sodium azide, were reacted with acetylenes
using the copper-catalyzed Huisgen 1,3-dipolar cy-
cloaddition. This process eliminates both the han-
dling of organic azides and the need for additional
copper catalyst and permits the facile preparation
of numerous triazoles in a continuous flow process.
Keywords: click chemistry; flow chemistry; hetero-
geneous catalysis; high-throughput screening; high-
throughput synthesis; microreactors
Realizing the benefits of flow chemistry we sought
to explore a one-pot click methodology (Scheme 1).
The click reaction between organic azides and acety-
lenes has gained a considerable amount of attention
since its discovery in 2001.[1] The resulting 1,2,3-tri-
ACHTUNGTRENNUNGazoles are an interesting class of heterocycles, as they
have found use in many biological applications, anti-
fungal agents, as well as dyes.[2] Chemists are attracted
to click chemistry in drug discovery due to its high de-
pendability, its appeal to combinatorial chemistry, and
its compatibility with biological systems.[3]
Scheme 1. The one-pot click reaction.
Whilst acetylenes can be readily prepared using Organic azides could be generated in small volumes
high-yielding methodologies such as the Sonogashira from their corresponding alkyl halides at high temper-
coupling, azide preparation is more problematic. atures and immediately reacted with acetylenes. By
Azides are a class of compounds known to readily de- adopting this approach we hoped to overcome the
compose[4] and as such their preparation and isolation safety and supply issues of azides and dramatically in-
must be handled with care, particularly on scale.
crease the monomers available to us, enabling a great-
Eliminating the need to isolate azides would be a er number of triazoles to be synthesized.
significant advantage and while reports have shown
We report herein the rapid synthesis of a 1,4-disub-
that alkyl azides can be generated in situ prior to the stituted 1,2,3-triazole library in a flow reactor using
copper-catalyzed cycloaddition, these methodologies this one-pot click methodology. A copper flow reactor
have either been slow or relied on microwave tech- has been developed to catalyze the reaction, enabling
nology.[5]
triazoles to be synthesized from simple starting mate-
rials without the need for additional catalyst. The
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Andrew R. Bogdan and Neal W. Sach
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Figure 1. Conjure flow reactor, schematic drawing.
facile scale-up of one triazole is also demonstrated,
and the application of this technology to drug discov-
ery is discussed.
The Conjure flow reactor (Figure 1) was designed
to operate on a scale suitable for both medicinal
chemistry and process research. The instrument
adopts a segmented flow approach versus a continu-
ous stream approach in order to minimize material
consumption and limit reaction size. Reaction seg-
ments are separated by an immiscible fluorous spacer,
perfluoromethyldecalin, that prevents segment diffu-
sion and reaction trailing.[10,11] Using this approach,
multiple segments can flow through the reactor at any
one time, maximizing the systemꢁs efficiency and per-
mitting rapid library development (medicinal chemis-
try) or reaction optimization (process research).
The reactor diskette consists of a reaction coil
made of copper, Hastelloy or PTFE tubing placed be-
tween two copper plates (Figure 2). Multiple seg-
ments can be passed through the system sequentially
since the internal volume of the reactor diskette
ranges from 2–10 mL and reaction segments are on
the order of 400 mL.
Heterogeneous catalysis has been used extensively
in flow systems and has proven to be highly recyclable
and selective.[12] Realizing that even Cu(0) sources
such as copper wire[1b] and copper metal turnings[5a]
had been effectively used as catalysts for the click re-
action, we had a reactor diskette prepared from
copper. Using this method, we envisioned that no ad-
ditional copper catalyst would be necessary, removing
a level of complexity from the system. Indeed, when
reaction segments containing sodium azide, an alkyl
halide, and acetylene in DMF were passed through
Figure 2. a) A reactor diskette with the top copper plate re-
moved, exposing the copper tubing within (0.75 mm i.d.). b)
An assembled reactor diskette for the flow reactor
(145 mmꢃ165 mmꢃ5 mm).
the copper flow reactor, high conversions were ob- thermal conditions.[14] The copper reactor was used to
tained within 5 min.[13] Replacing the copper reactor catalyze hundreds of reactions, never showing a loss
with a Hastelloy reactor diskette prohibited the reac- of catalytic activity[15] and was also shown to effective-
tion, confirming the necessity of the copper and prov- ly catalyze other copper-mediated reactions such as
ing the triazole formation was not occurring under the Sonogashira and Ullman couplings.
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The Use of Copper Flow Reactor Technology for the Continuous Synthesis
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Scheme 2. The optimized one-pot click reaction using 4-ethynyltoluene and 2-bromoethanol.
We optimized the one-pot click methodology using tions resulting in low yields, an optimization could be
4-ethynyltoluene, 2-bromoethanol and sodium azide carried out in order to increase the yield. In this proof
in DMF (Scheme 2).[16] By varying the residence time, of concept work, the optimization conditions from the
reactor temperature, and equivalents of alkyl azide, DOE between 4-ethynyltoluene and 2-bromoethanol
we were able to rapidly obtain optimal reaction con- were the only conditions used. The click methodology
ditions using minimal amounts of material.[17] By link- worked for aliphatic and aromatic acetylenes, as well
ing the instrumentꢁs analytical output to DOE soft- as primary and secondary alkyl halides. Low molecu-
ware such as Design Expertꢄ, reports are generated lar weight azides such as azidoethane and 3-azidooxe-
after the optimization, dictating the optimal reaction tane were also used safely in the Conjure flow reac-
conditions for this transformation (see Supporting In- tor.
formation).
The batch scale-up of processes involving energetic
Using these conditions, a library was prepared intermediates such as organic azides can be dangerous
using six different acetylenes, six different alkyl hal- as high concentrations can accumulate, thus creating
ides, and sodium azide (Figure 3). It should be noted an explosion hazard. Such reactions can require ex-
tensive process safety investigation and costly custom
engineered facilities. In flow this danger is significant-
ly reduced as scale-up is a function of time and flow
rate and the volume of active chemistry remains
small. Through this principle, processes developed
using flow technology on a small scale can subse-
quently be used to prepare larger scale batches as
compounds move through development, minimizing
process development and capital equipment costs.
To demonstrate the preparative capability of the
Conjure flow reactor, the click reaction between 4-
ethynyltoluene and N-ethylchloroacetamide was
scaled-up (Table 1). The stoichiometry was adjusted
such that only 1 equivalent of alkyl azide was generat-
ed, thus limiting excess azide (either organic or inor-
ganic) in the output stream. After 12 min, 115 mg
(60%) of triazole 5 were isolated after the simple
work-up of aqueous precipitation and filtration. If run
continuously, this output extrapolates to generating
575 mg of product per hour, or 13.8 g of product per
day (Table 1).
In summary, we have developed a one-pot click re-
action using a copper flow reactor that permits the in
situ generation of organic azides and facile prepara-
Figure 3. Alkyl halides and terminal acetylenes used for the
triazole library.
tion of triazole libraries. The use of a custom engi-
neered copper reactor serves as the catalyst to facili-
that the preparation of six acetylene source vials tate the cycloaddition. Reactions are readily scaled up
(0.25M in DMF), six alkyl halide source vials (0.5M with fewer safety concerns than the corresponding
in DMF) and a sodium azide source vial (0.5M in batch processes. The high-throughput, automated
DMF/H2O 4:1 v/v) was the only chemical handling nature of the instrument greatly adds to the appeal of
necessary to run the library synthesis. Using the opti- this process and this technology is currently being em-
mized conditions for the flow click methodology, ployed in the drug discovery process to rapidly syn-
thirty triazoles were synthesized in a matter of hours thesize vast numbers of compounds towards flow dis-
in modest to excellent yield (Figure 4).[18] For reac- covery.[10a]
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Andrew R. Bogdan and Neal W. Sach
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1
Figure 4. The 1,4-disubstituted 1,2,3-triazoles synthesized using the Conjure flow reactor. Yields determined by H NMR
using an internal standard.
um lock channel and z-gradient (Protasis MRM Division,
Savoy, IL). The spectrometer was equipped with a CTC
Experimental Section
HTC-PAL autosampler (Leap Technologies, Carrboro, NC).
Samples were prepared using DMSO-d6 spiked with the in-
ternal standard 2,5-dimethylfuran. Peaks were referenced to
2,5-dimethylfuran (5.8 ppm for 1H). LC/MS analyses were
carried out using an Agilent Technologies HPLC (Agilent
Technologies 1200 Series diode array detector, Agilent Tech-
nologies 1200 Series column heater, Agilent 1100 Series
General Remarks
1
All reagents and solvents were used as received. H NMR
analysis was carried out using a capillary NMR probe (Pro-
tasis MRM Division, Savoy, IL) on a Varian Inova spec-
trometer with a Larmor frequency of 499.667 MHz. The ca-
pillary NMR probe consisted of a 5 mL flow cell (active
volume 2.5 mL) double-tuned to H and 13C with a deuteri-
1
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The Use of Copper Flow Reactor Technology for the Continuous Synthesis
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Table 1. Triazole synthesis scale-up.
nology. We acknowledge Professor Valery V. Fokin and Dr.
Jason E. Hein of the Scripps Research Institute for helpful
discussions on click chemistry, Professor D. Tyler McQuade
of Florida State University for valuable comments during the
preparation of the manuscript, Dr. Wei Wang for assistance
1
with H NMR, and Dr. Elizabeth Farrant for discussions on
fluorous spacer technology. We gratefully acknowledge the
Pfizer Student Employment Program for financial support
(to A.R.B.).
Time
Triazole Output
12 min
1 hour
1 day
115 mg[a]
575 mg
13.8 g
[a]
References
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Typical Experimental Procedure for Triazole Library
Synthesis
4-Ethynyltoluene (133.3 mL, 0.25M in DMF, 0.033 mmol, 1.0
equiv.), ethyl iodide (133.3 mL, 0.5M in DMF, 0.066 mmol,
2.0 equiv.), and NaN3 (133.3 mL, 0.5M in DMF/H2O 4:1 v/v,
0.066 mmol, 2.0 equiv.) were aspirated from their respective
source vials, mixed through a PFA mixing tube (0.2 mm
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flow reactor set at 1508C at a rate of 400 mLminÀ1 (5 min
residence time). Reaction segments were collected in a 96-
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resin. Segments were filtered, concentrated, and analyzed
1
using H NMR.
Experimental Procedure for Scaled-Up Triazole
Synthesis
4-Ethynyltoluene (133.3 mL, 1.0M in DMF, 0.1333 mmol, 1.0
equiv.), N-ethylchloroacetamide (133.3 mL, 1.0M in DMF,
0.1333 mmol, 1.0 equiv.), and NaN3 (133.3 mL, 1.0M in
DMF/H2O 4:1 v/v, 0.1333 mmol, 1.0 equiv.) were aspirated
from their respective source vials, mixed through a PFA
mixing tube (0.2 mm i. d.), and loaded into an injection
loop. Six reaction segments were injected into the flow reac-
tor set at 1508C, passed through the reactor at 200 mLminÀ1
(10 min residence time) and collected in a reaction vial con-
taining heptane and water. The yellow precipitate was col-
lected by filtration, washed with water (2ꢃ), heptane (2ꢃ)
and dried under vacuum to afford triazole 5; yield: 115 mg
(60%).
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Experimental procedures, DOE data, and compound char-
acterization data are available in the Supporting Informa-
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MS and NMR.
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