The rapid generation of isothiocyanates in flow

Article abstract of DOI:10.3762/bjoc.9.184

Isothiocyanates are versatile starting materials for a wide range of chemical reactions. However, their high nucleophilic susceptibility means they are best prepared and used immediately. We report here on a flow platform for the fast and efficient formation of isothiocyanates by the direct conversion of easily prepared chloroximes. To expedite this chemistry a flow insert cartridge containing two immobilised reagents is used to affect the chemical transformation which typically eliminates the requirements for any conventional work-up or purification of the reaction stream.

Full text of DOI:10.3762/bjoc.9.184

The rapid generation of isothiocyanates in flow
Marcus Baumann and Ian R. Baxendale*
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2013, 9, 1613–1619.
Department of Chemistry, University of Durham, South Road, Durham
DH1 3LE, United Kingdom
doi:10.3762/bjoc.9.184
Received: 20 June 2013
Accepted: 23 July 2013
Published: 08 August 2013
Email:
Ian R. Baxendale* - i.r.baxendale@durham.ac.uk
* Corresponding author
This article is part of the Thematic Series "Chemistry in flow systems III".
Guest Editor: A. Kirschning
Keywords:
chloroxime; dipolar cycloaddition; flow chemistry; flow synthesis;
immobilised reagents; isothiocyanate; nitrile oxide
© 2013 Baumann and Baxendale; licensee Beilstein-Institut.
License and terms: see end of document.
Abstract
Isothiocyanates are versatile starting materials for a wide range of chemical reactions. However, their high nucleophilic
susceptibility means they are best prepared and used immediately. We report here on a flow platform for the fast and efficient
formation of isothiocyanates by the direct conversion of easily prepared chloroximes. To expedite this chemistry a flow insert
cartridge containing two immobilised reagents is used to affect the chemical transformation which typically eliminates the require-
ments for any conventional work-up or purification of the reaction stream.
Introduction
Flow based chemical synthesis is playing an increasingly flow chemistry is moving from an academic curiosity to
pivotal role within the chemical sciences as it facilitates a more become a common tool in many synthesis laboratories paral-
versatile and responsive workflow. It encompasses many leling the emergence and adoption of another enabling techno-
aspects of synthesis from the rapid and on-demand preparation logy, the microwave reactor [17].
of important building blocks to the development of multi-step
sequences leading to advanced chemical structures and more An area which has benefited significantly from the many recent
direct scaling of bulk producing reactions [1-10]. Consequently, developments in our understanding of flow chemistry is the
the chemical literature is growing at a precipitous rate with synthesis of reactive precursors and handling of sensitive inter-
numerous examples of key chemical transformations having mediates [18-23]. However, despite the breadth of chemistries
been further optimised or improved upon when conducted already explored there are certain functional transformations
within a pseudo-/continuous flow process [11,12]. From a syn- notably absent, one particular class of important building blocks
thesis perspective the majority of these endeavours have been which has received less attention are isothiocyanates. These
directed at enhancing specific reaction safety profiles, identi- species are widely utilised as valuable starting materials for
fying new reaction sequences or generating improvements to many thiourea-based organocatalysts [24-26], numerous hetero-
well-known yet cumbersome transformations [13-16]. Indeed, cyclic entities [27-29] as well as important entry points towards
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other key functional groups such as isocyanides [30,31], guan- of strategies to minimise this side reaction have been attempted.
idines [32,33] and thiosemicarbazides [34]. Due to the limited These include the use of highly diluted reaction mixtures, the
commercial availability of diversely functionalised isothio- use of large excesses of the corresponding dipolarophile
cyanates chemists normally pursue a de novo synthesis, which partner, as well as the slow addition of reagents to create
most commonly involves the condensation of an amine with limiting concentrations of the active 1,3-dipole. Despite these
thiophosgene or carbon disulfide [35,36], both reagents causing efforts, the side reaction is still seen and there normally remains
safety concerns due to the formation of toxic, malodorous and/ the requirement for time consuming purifications such as
or extremely corrosive byproducts (Scheme 1a). An underutil- column chromatography in order to isolate pure products.
ised alternative sequence is the 1,3-dipolar cycloaddition reac-
tion between a nitrile oxide and a thiourea compound which Immobilised reagents have shown great promise as enabling
initially generates an unstable 1,4,2-oxathiazoline intermediate technologies when incorporated in flow reactors to aid in the
that readily rearranges into urea and eliminates the desired processing, work-up and purification of reaction sequences [40-
isothiocyanate product [37,38] (Scheme 1b).
44]. In addition they have been successfully utilised in order to
render dipolar cycloaddition reactions involving azomethine
ylides [45,46] as well as nitrile oxides [47,48] more practical for
generating important heterocyclic scaffolds such as
pyrrolidines, isoxazolines and their derivatives [49-52]. We
therefore considered that it should be possible to develop a mild
and practical flow-based process to form isothiocyanates from
the corresponding reactive nitrile oxide intermediates.
Our strategy makes use of two immobilised reagents (a weak
base and a functionalised thiourea) placed as a 1:1-mixture
within a single glass reactor cartridge (Scheme 2). The immob-
ilised base affects the in situ formation of the reactive nitrile
oxide from the chloroxime which is immediately captured by
the local tethered thiocarbonyl dipolarophile. Consequently, this
approach significantly minimises the formation of the furoxan
Scheme 1: Strategies towards isothiocyanates.
Whilst this approach appears on initial inspection to be very byproduct by creating a scenario of pseudo high dilution of the
attractive it is somewhat hampered by the requirement to access nitrile oxide whilst allowing a concurrent high local concentra-
the reactive nitrile oxide species, which once formed is prone to tion of the dipolarophile. Additionally the immobilised supports
undergo fast dimerisation leading to furoxan byproducts (see act as excellent sequestering agents for trapping even the small
Table 1) [39]. In fact this facile dimerisation reaction is regu- quantities of polar impurities within the matrix thus allowing
larly reported as troublesome in many reactions that progress for the isolation of the desired isothiocyanate product in high
through nitrile oxide intermediates. As a consequence a number purity after only simple solvent removal.
Scheme 2: Flow approach towards isothiocyanates.
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Results and Discussion
column at a flow rate of 0.2 mL/min equating to an average
Initially a set of batch experiments was performed using residence time of 10 minutes. After passing a 100 psi backpres-
(4-bromophenyl)chloroxime 1a as the substrate, which was effi- sure regulator the typically colourless reaction mixture was
ciently prepared on gram scale from the corresponding benzal- collected yielding the product after evaporation of the solvent.
dehyde via oxime formation and subsequent NCS-mediated 1H NMR experiments were used to determine the product com-
chlorination [53]. Screening different solvents (MeCN, acetone, position and purity and pleasingly revealed complete conver-
EtOAc, MeOH and iPrOH) and immobilised thiourea species sion of the substrates into the desired isothiocyanate product in
(QP-TU [54] and QS-MTU [55]) showed that the desired trans- high yield and purity as summarised in Table 2.
formation can be effected with either immobilised thiourea
source and furthermore tolerates a wide range of the solvents, The reactions demonstrate a high tolerance for both electron
with MeCN being identified as the best option. The choice of poor and electron rich aromatic substrates (Table 2, entries 1–8)
base was found to be of particular importance given that solu- which all delivered the desired isothiocyanates reliably in high
tion phase bases tested (NEt3 or DBU even using slow addition) yield and purity. Furthermore, aliphatic chloroximes were found
immediately generated substantial quantities of a white precip- to work equally well, efficiently generating the corresponding
itate, which was later identified as the undesired furoxan isothiocyanate products again in high yields and purities
byproduct (Table 1). In order to evaluate conditions to minimise (Table 2, entries 9–12). When using single diastereoisomers of
this side reaction we studied several immobilised bases α-chiral chloroximes the desired isothiocyanate product was
including QP-DMA (benzyldimethylamine resin) and SiO2-pyr. correspondingly isolated as a single isomer (by 1H NMR)
The latter allowed for the isolation of the desired isothio- suggesting a concerted reaction pathway to be in operation.
cyanate in high yield and with very little contamination by the Importantly, more complex substrates (i.e. N-chloro-
furoxan byproduct.
pyrrolidines, Table 2, entries 13–15) can be subjected to the
reaction conditions in order to not only install the desired
We translated the outcome of these preliminary results into a isothiocyanate functionality but through concomitant elimina-
flow protocol using a commercially available Vapourtec R tion affect the formation of a cyclic imine, which is very
series flow reactor [56] which was operated with MeCN as the attractive as it allows subsequent diversification of these poly-
system solvent. Stock solutions of the chloroxime starting ma- functionalised heterocyclic building blocks. Overall, this exem-
terials were prepared in the same solvent (0.25–0.5 M) and plifies how the presented methodology can enable the rapid
injected into a sample loop (2–10 mL size). Both the solid construction of scaffolds with unprecedented substitution
supported base (SiO2-pyr) and immobilised thiourea species patterns, which hold great interest due to their potential as
(QP-TU or QS-MTU) were blended (by shaking), filled into an highly decorated entities.
glass column (10 cm length, 6.6 mm i.d., 1:1 ratio, 1.2 equiv
each species) and the column inserted into a glass heating jacket The most noteworthy feature of this flow protocol is its effi-
which was maintained at 50 °C. The flow stream of the sub- ciency and simplicity allowing the desired product to be isol-
strate was subsequently directed through the heated reactor ated following only solvent removal. The incomplete recovery
Table 1: Screening of different bases for the formation and conversion of nitrile oxides in batch:
Entry
Base
Ratio isothiocyanate/furoxan
Comments
1
2
3
4
NEt3 (0.2 M in MeCN)
DBU (0.2 M in MeCN)
QP-DMA
1:1
dropwise addition of base
dropwise addition of base
portionwise addition of base
portionwise addition of base
1:1
2.2:1
>4:1
SiO2-pyr
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Table 2: Isothiocyanates prepared in flow.
Entry
Starting material
Product
Isolated yield [%]
Scale [mmol]
93a
84a
1.0
5.0
1
1b
2
3
4
89a
91a
78a
1.0
1.0
0.7
2b
3b
4b
5
6
76a
94a
0.5
1.0
5b
6b
7
8
91a
85a
0.5
1.0
7b
8b
9b
9
89a
84a
0.8
0.8
10
10b
11b
11
81a
0.8
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Table 2: Isothiocyanates prepared in flow. (continued)
12
87a
1.0
12b
13b
13
14
73b,c
0.5
0.5
71b,c
14b
15
76b,c
0.75
15b
aPurity > 90% by 1H NMR. bPurified by SiO2 column chromatography. c2.5 equiv of SiO2-pyridine used.
of material in these reactions can be accounted for by small
Supporting Information
amounts of the furoxan dimer which forms yet is trapped within
the reactor column, thus evading its tedious removal via
subsequent column chromatography. In addition our study
demonstrates that thiourea – either immobilised on a poly-
styrene-type support (QP-TU) or on silica gel (QS-MTU) –
serves as an efficient source of a sulfur atom. Given the higher
loading of QP-TU (~5.5 mmol/g) compared to QS-MTU
(~1.5 mmol/g) as well as its lower cost, QP-TU might be
considered the more economical option, however, with the pri-
mary focus of this study being the small scale generation of
valuable novel isothiocyanate products, this would only become
relevant at larger scales (>100 g).
Supporting Information File 1
Experimental part.
[http://www.beilstein-journals.org/bjoc/content/
supplementary/1860-5397-9-184-S1.pdf]
Acknowledgements
We would like to express our gratitude to the Royal Society for
funding to support this research.
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