Microwave Promoted Transcarbamylation Reaction of Sulfonylcarbamates under Continuous-Flow Conditions

Article abstract of DOI:10.1021/acs.oprd.5b00323

Successful conditions for the transcarbamylation/transesterification reaction of sulfonylcarbamates with alcohols by microwave heating under continuous-flow conditions were developed. After optimization of the processes, two series of O-alkylsulfonylcarbamates were obtained in high yields and purities using microwave transparent borosilicate tube reactors. In order to also illustrate the usefulness of the protocol in a medicinal chemistry context, the methodology was used for the synthesis of three angiotensin II type 2 receptor ligands.

Full text of DOI:10.1021/acs.oprd.5b00323

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Communication
Microwave Promoted Transcarbamylation Reaction of
Sulfonylcarbamates Under Continuous-Flow Conditions
Ilze Kumpina, Rebecka Isaksson, Jonas Savmarker, Johan Wannberg, and Mats Larhed
Org. Process Res. Dev., Just Accepted Manuscript • DOI: 10.1021/acs.oprd.5b00323 • Publication Date (Web): 28 Dec 2015
Downloaded from http://pubs.acs.org on January 3, 2016
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Microwave Promoted Transcarbamylation Reaction of
Sulfonylcarbamates Under ContinuousꢀFlow Conditions
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Ilze Kumpiņa†, Rebecka Isaksson†, Jonas Sävmarker‡, Johan Wannberg§, Mats Larhed§,
∗
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†Organic Pharmaceutical Chemistry, Department of Medicinal Chemistry
Uppsala University
‡Beijer Laboratory, Department of Medicinal Chemistry, Uppsala Biomedical Center,
Uppsala University
§Department of Medicinal Chemistry, Science for Life Laboratory, Uppsala University
Boxꢀ574, SEꢀ751 23 Uppsala, Sweden
*Corresponding author
Mats.larhed@orgfarm.uu.se
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Abstract
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Successful
conditions
for
the
transcarbamylation/transesterification
reaction
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of sulfonylcarbamates with alcohols by microwave heating under continuousꢀflow conditions
were developed. After optimization of the processes, two series of ꢀalkylsulfonylcarbamates
O
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were obtained in high yields and purities using microwave transparent borosilicate tube
reactors. In order to also illustrate the usefulness of the protocol in a medicinal chemistry
context, the methodology was used for the synthesis of three angiotensin II type 2 receptor
ligands.
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Keywords continuousꢀflow, transcarbamylation, sulfonylcarbamates, microwave, angiotensin
II AT2 receptor ligands
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Introduction
Microwave (MW) heating has become a widely used method for smallꢀscale batch synthesis
in many research laboratories and pharmaceutical companies.1ꢀ5 Microwave irradiation in
general provides a faster heating rate of the reaction mixture compared to conventional
heating methods, thus reducing the reaction time.6ꢀ8 Pressurized reactions in sealed process
vials using purposeꢀbuilt MWꢀreactors also allow for remote and safe increase of the
temperature well above the atmospheric boiling point of the solvent. In many examples
improved yields and high reaction selectivities have been observed.9
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While many reactions have been performed on a small scale using microwave heating, few
have been further developed into large scale synthesis due to the physical limitation of
microwave heating; the penetration depth of only a few centimeters and the limited
dimensions of standing wave cavities.6,10 One technology which is gaining importance to
overcome these obstacles is continuousꢀflow (CF) synthesis which has been used successfully
for a large number of different organic transformations.11ꢀ22 CF systems has been developed in
parallel with MW instruments and has attracted significant interest due to the advantages in
safety, handling and scale out possibilities.7 Our laboratory has previously described a
purposeꢀbuilt system which combines CF with nonꢀresonant MW heating23ꢀ26 as compared to
the traditional wall heating utilized in most CF setups. The combination of these techniques
allow not only for improved safety and high process temperatures but also for quick changes
of the reaction temperature.18 The homogeneous heating through the 200 mm long microwave
transparent borosilicate tube reactor is achieved through a uniformly distributed axial MW
field.
Because of the short overall process time, additional reaction parameters such as choice of
solvent, molar ratio of reactants, reagent concentrations and temperature can be quickly
investigated. This advantage significantly speeds up the overall time required for reaction
optimization.
The reninꢀangiotensin system (RAS) plays an important role in bloodꢀpressure regulation and
fluid/electrolyte balance. The main effector of RAS is the octaꢀpeptide angiotensin II (AngII)
which binds to angiotensin II type 1 receptor (AT1R) and type 2 receptor (AT2R).27 While the
function of the AT1R has been extensively studied, the role of AT2R has long been debated
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and is still today not fully understood; it has been suggested to act opposing to AT1R,
exerting antiꢀinflammatory properties, as well as promoting neuroprotection and neuronal
regeneration.27
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Figure 1. Structure of AT2R agonist C21
The C21ꢀclass (also known as the M24ꢀclass) of AT2R agonists contain an essential acidic
alkyl (arylsulfonyl)carbamate functionality (Figure 1).28ꢀ30 Since previous studies have shown
the importance of the specific structure of the alkoxy sideꢀchain for AT2R activity,27ꢀ30 we
were interested in identifying swift methods for introduction of different alkoxy groups.
Interestingly, by leaving a sample of C21 in methanol over the weekend, it was discovered
that a fraction of the
Oꢀbutyl group had been exchanged by an Oꢀmethyl functionality. A
literature survey did not reveal any previous examples of such an alkoxyꢀtoꢀalkoxy
transcarbamylation/transesterification reaction with sulfonylcarbamates. Only a single
reported example with no yield provided were found where a similar aryloxyꢀtoꢀalkoxy
transformation had been achieved.31 In this paper Hirama et al. reported the heating of methyl
N
ꢀ(2,4,6ꢀtribromophenoxycarbonyl)sulfamate with (Z)ꢀ3ꢀhexenꢀ1ꢀol, producing (Z)ꢀ((hexꢀ3ꢀ
enꢀ1ꢀyloxy)carbonyl)sulfamate. Thus, to the best of our knowledge, transcarbamylation of
alkyl sulfonylcarbamates using aliphatic alcohols to exchange the alkoxy group in an alkyl
sulfonylcarbamate has not yet been reported.
We hereby report that model alkyl tosylcarbamates can be rapidly prepared from methyl
tosylcarbamate under acid/base free conditions in high yields using a CFꢀMW system. The
optimized procedures were carried out at 160ꢀ220 °C using flow rates of 0.5 or 1.0 mL/min
and a 200×2 mm borosilicate tube reactor with a total volume of 0.63 mL (the MW field zone
is the central 100 mm of the reactor, providing a heated volume of 0.31 mL). Both neat
conditions and the use of acetonitrile as coꢀsolvent proved to be highly productive. To further
explore the structureꢀactivity relationship (SAR) of AT2R ligands we decided to utilize the
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CFꢀMW system to introduce variations in the alkoxy substituent of C21. Transcarbamylation
of the sulfonylcarbamate provided a straightforward and effective transformation through
which different alkoxy moieties could be smoothly introduced.
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Results and discussion
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nꢀButanol was selected as a representative alcohol for optimization of the reaction conditions
(Table 1, entry 1). First, methyl tosylcarbamate (
1
) in nꢀbutanol was subjected to MW heating
2 mm borosilicate reactor.
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at 120 C at a flow rate of 1.0 mL/min employing the 200
×
Unfortunately, we detected only 33% of butyl tosylcarbamate (2a) product and 67% of
unreacted starting material according to LCꢀMS analysis. Increasing reaction temperature to
160ꢀ200 oC gave full conversion to 2a in 98% and 95% isolated yield, respectively. At higher
temperatures we could start observing decomposition of 1.
After achieving high yields in the initial model experiments, we decided to further investigate
the scope and limitations of the CFꢀMW promoted transcarbamylation reaction employing a
flow of 1.0 mL/min. As the instrumentation allowed us to reach stable reaction temperatures
within a short amount of time (<30 s), the washꢀout period became the time limiting factor (3
min). Hence, we decided to perform a fast temperature optimization for each alcohol (Table
1).
Table 1.CFꢀMW transcarbamylation of methyl tosylcarbamate (1) using neat alcohols
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a
1
Yield of the isolated product (>95% pure by H NMR). No column chromatography necessary. Neat reaction
conditions: a stock solution of methyl tosylcarbamate 1 (0.04 M) in appropriate alcohol was pumped through the
b
200×2 mm borosilicate reactor (0.63 mL) at a flow rate of 1.0 mL/min. Purified by column chromatography.
c
Scale out. A stock solution of 1 (0.1 M) in nꢀbutanol was pumped through the 200×2 mm borosilicate (0.63 mL)
reactor at a flow rate of 1.0 mL/min, collecting 45 mL of reaction mixture at 180 oC for 45 min. The alcohol was
evaporated and the remaining residue was purified by column chromatography to yield 2a as colorless oil (1.10
g, 91%).
In general, good to excellent conversions where achieved when increasing the temperature as
the rate to reach equilibrium was enhanced.
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However, as observed with nꢀbutanol, higher temperatures caused slight decomposition also
with other alcohols. Notably, isoꢀbutanol gave significantly lower yields than secꢀbutanol, 43ꢀ
75% of 2b and 86ꢀ97% of 2c, respectively, due to unidentified byproduct formation (Table 1,
entry 2 and 3). The length of the alkyl chain did not seem to affect product yields (Table 1,
entry 4ꢀ6). Unsaturated product 2g was obtained in 89ꢀ91% yield with no detected double
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o
bond isomerization when the reaction reached full conversion at 160ꢀ180 C (Table 1, entry
o
7). Benzyl alcohol reached a maximum yield of 74% 2h at 180ꢀ200 C (Table 1, entry 8).
Higher productivity could not be obtained due to several low percentage sideꢀproducts in the
reaction mixtures. N,Nꢀdimethylaminoethanol showed no problems with reactivity, affording
80% of 2i. Cyclopropylmethanol gave best outcome (93% 2j) at the somewhat lower
temperature of 160 oC (Table 1, entry 10).
To investigate the test reactions robustness and continuousꢀflow potential we scaledꢀout the
o
reaction with
n
ꢀbutanol at 180 C for 45 min to produce larger quantities of the previously
isolated 2a. In order to shorten the time and to increase the output we used a higher
concentration of in the stock solution (0.1 M) but kept the flow rate at 1.0 mL/min. After 45
1
min processing we collected and isolated 1.10 g, 91% of 2a, corresponding to a productivity
of 5.4 mmol/h. (Table 1, entry 1) Thus, the output was improved and the increased
concentration of the reaction mixture was not limiting the yields.
The potential application in medicinal chemistry projects was next investigated. To save
expensive reactants and to speed up the process, reactions using a coꢀsolvent were studied.
After a quick experimental investigation it became clear that acetonitrile was a highly suitable
solvent due to the ability to solvate the starting material, easy handling and low cost.
The initial reaction with a 0.2 M solution of
1 in a mixture of acetonitrile and nꢀbutanol (12
o
mol equiv to
1
) at 160ꢀ180 C resulted in 47ꢀ49% isolated yield of 2a at a flow rate of 1.0
mL/min (not shown in Table 2). By elevating the temperature to 180ꢀ200 oC and reducing the
flow rate to 0.5 mL/min, yield increased to 71ꢀ74% (not shown in Table 2). The highest yields
o
were isolated when the reaction was performed at 200 and 220 C with a flow rate of 0.5
mL/min and when 28 mol equiv of nꢀbutanol was used, maintaining the concentration of
1 at
0.2 M, providing 80 and 81% yield of 2a (Table 2, entry 1). Thus, the use of acetonitrile as a
coꢀsolvent resulted in only slightly lower yield of 2a compared to the neat alcohol reaction.
This encouraged us to evaluate isoꢀ and tertꢀbutanol as reaction partners in acetonitrile
solution, yielding 63% of 2b and 53% of 2k (Table 2, entry 2 and 8).
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The diluted alcohol solutions used in CFꢀMW reactions did not give as much reactant saving
as expected. Therefore, it was decided to try injecting the reactant through a 1.0 mL loop in a
flow of carrier solvent. In continuous acetonitrile flow of 0.5 and 1.0 mL/min at 160 oC, a 1.0
mL solution of
1
in nꢀbutanol was injected, furnishing an isolated yield of 63% and 67% of
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2a, respectively (Table 2, entry 1). By increasing the temperature to 180 C, the outcome
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improved to 80% and 85% 2a. At 200 and 220 C, the isolated yields were 81% and 72%,
respectively (Table 2, entry 1).
Please note that no precise measurements of the concentration profile was conducted. We
assume that the injected plug was tailing due to axial dispersion and back mixing as a result of
a laminar flow with a parabolic velocity profile throughout the system. In addition, turbulence
from the junctions should further hamper the survival of the plug. No CF reactions were
attempted using conventional heating due to high temperatures and pressures.
Table 2. CFꢀMW transcarbamylation of methyl tosylcarbamate (1) with different alcohols in
acetonitrile
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a
b
Yield of the isolated product, purified by column chromatography (>95% pure by 1H NMR). Reaction
conditions: a solution of methyl tosylcarbamate 1 (0.2 M) in appropriate alcohol (28 mol equiv) and acetonitrile
was pumped through the 200×2 mm borosilicate reactor (0.63 mL) at a flow rate of 0.5 mL/min. Reaction
c
conditions: a stock solution of methyl tosylcarbamate 1 (0.2 M) in appropriate alcohol (29ꢀ49 mol equiv) was
injected (1.0 mL) in acetonitrile flow pumped through the 200×2 mm borosilicate reactor (0.63 mL) at a flow
d
rate of 1.0 mL/min. 0.5 mL/min.e1.5 mL/min.
The loop injection methodology was next extended to other alcohols. We did not observe any
issues regarding the conversion by using a carrier solvent. Overall the yields after CFꢀMW
processing using the injection method were 62ꢀ85% (Table 2) compared to 74ꢀ98% from
running reactions in neat alcohol (Table 1).
Transcarbamylation of the carbamate was then explored using the AT2R agonist C21 (3,
Table 3) as the starting material.27,28 Waste of this relatively expensive reactant was
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minimized by applying a protocol using the 1.0 mL loop to inject compound
3 dissolved in
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the appropriate alcohol (~0.2 M), with the carrier solvent being the identical alcohol reactant.
The temperature was kept constant at 180 °C employing a flow of 1.0 mL/min for the
alcohols. The products were purified using preparative reverseꢀphase HPLC due to poor
separation with flash chromatography. The results are summarized in Table 3.
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Table 3. CFꢀMW transcarbamylative synthesis of AT2R ligands.
a
For biological data see reference.32 Reaction conditions: a solution of 3 (~ 0.2 M) in appropriate alcohol (100ꢀ59
mol equiv) was injected in the system using a 1 mL loop and subsequently pumped through the 200×2 mm
borosilicate reactor (0.63 mL) with the same alcohol as the carrier solvent at a flow rate of 1.0 mL/min. The
product was purified using preperative reverseꢀphase HPLC.
The isolated yields of 4aꢀc ranged from 41ꢀ64%. Only in the case of 4c was the conversion of
the starting material close to complete according to LCꢀMS analysis. The reactions were not
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further optimized but it is likely that the somewhat low yields were a consequence of
incomplete conversions (Table 3, entries 1 and 2) and repeated HPLC purification.
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Conclusion
A previously undescribed CFꢀMW promoted transcarbamylation/transesterification protocol
which is fast, efficient and can be scaledꢀout for the synthesis of a wide range of alkyl
(arylsulfonyl)carbamates was developed. Easily available and cheap acetonitrile could be used
as coꢀsolvent/carrier for the CFꢀMW process with excellent results. The methodology was
further used for synthesis of three biologically active angiotensin II AT2R ligands. The high
safety, fast heating and smooth processing at high temperatures were identified as important
advantages with the purpose built CFꢀMW system. We are currently exploring the
development of the corresponding batch transcarbamylation methology.
Experimental section
General information
Microwaveꢀassisted continuous flow reactions were performed using a WaveCraft
ArrheniusOne. The continuous flow pumping was provided via a Shimadzu LCꢀ10AD HPLC
pump. The employed tube reactors were made out of borosilicate with a length of 200 mm,
inner diameter of 2 mm and volume of 0.63 mL; the MW filed zone is the central 100 mm
(0.31 mL). The temperature of the reactor was determined using an Optris CT infrared (IR)
sensor (Optris GmbH, Berlin, Germany). Analytical TLC was performed on silica gel 60 Fꢀ
254 plates and visualized with UV light (λ = 254 nM). Flash column chromatography was
performed on silica gel 60 (40ꢀ63 µm). Analytical LC–MS was performed using electrospray
ionization (ESI) and a C18 column (50×3.0 mm, 2.6 µm particle size, 100 Å pore size) with
MeCN/H2O in 0.05% aqueous HCOOH as the mobile phase at a flow rate of 1.5 mL/min. All
final compounds were ≥95% pure as determined by NMR. Preparative reverseꢀphase HPLC
was performed on a C18 column (MachereyꢀNagel VP 125/21 Nucleodur C18 HTec 5 µm)
using MeCN/H2O (0.05% HCOOH) as a mobile phase with UV (254 nm) detection. All
reagents and solvents were commercially available and were used as received.
General procedure for CFꢀMW transcarbamylation of 1 using neat alcohols (Table 1). A
stock solution of methyl tosylcarbamate (0.04 M) in the appropriate alcohol was prepared and
then pumped at a flow rate of 1.0 mL/min through the 200
×
2 mm borosilicate reactor at the
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temperature of 140ꢀ210 °C. Next, 5 mL of the crude reaction mixture at each temperature was
collected and concentrated to yield the desired product.
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General procedure for CFꢀMW transcarbamylation of 1 using injection methodology (Table
2). A stock solution of methyl tosylcarbamate (0.2 M) in appropriate alcohol was prepared
and then injected (1.0 mL) in an acetonitrile flow of 1.0 mL/min and then pumped through the
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200×2 mm borosilicate reactor at the temperature of 180 and 200 °C. Next, 6ꢀ8 mL of the
crude reaction mixture at each temperature was collected, concentrated and thereafter
subjected to silica gel column chromatography using a petrol ether/ethyl acetate mixture (4:1)
to yield the desired product.
Procedure for CFꢀMW transcarbamylation of 3 using injection methodology (Table 3)
Compound was dissolved in 1.0 mL of alcohol and injected via the loop (1.0 mL) using the
same alcohol as carrier solvent, with a flow rate of 1.0 mL/min. The mixture was pumped
through the 200 2 mm borosilicate reactor at 180 °C. Next, 30 mL of the crude reaction
.
3
×
mixture was collected, concentrated and thereafter purified using preparative reverseꢀphase
HPLC.
Procedure for batch preparation of methyl tosylcarbamate (1
).33 In oven dried flask
4ꢀmethylbenzenesulfonamide (5.03 g, 29.4 mmol) was dissolved in dry DCM (40 mL), cooled
to 0 oC (ice bath) and triethylamine (12.0 mL, 85.2 mmol) was dropwise added. After 10 min
o
methyl chloroformate (2.5 mL, 32.3 mmol) was added dropwise at 0 C. The reaction was
thereafter stirred at 0 oC for 30min, then for 2h at room temperature. The mixture was diluted
with DCM, extracted with 1 M HCl (80 mL), water (80 mL), brine (80 mL), dried over
MgSO4, filtered and evaporated. The obtained oil was purified by column chromatography
(20ꢀ40% ethyl acetate in petroleum ether) to yield the desired product (4.75 g, 70%).
Acknowledgment
This work was supported by a travel grant from 7th Framework Program Project InnovaBalt
(REGPOTꢀCTꢀ2013ꢀ316149ꢀInnovaBalt), by the Kjell and Märta Beijer Foundation and by
Uppsala University.
Supporting Information
Experimental procedures and copies of spectra. This material is available free of charge via
the Internet at http://pubs.acs.org.
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Author information
Corresponding Author
*Eꢀmail: mats.larhed@orgfarm.uu.se
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Notes
The authors declare no competing financial interest.
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