Oxidation reactions in segmented and continuous flow chemical processing using an N -(tert -Butyl)phenylsulfinimidoyl chloride monolith

Article abstract of DOI:10.1055/s-0030-1259923

A supported version of N-(tert-butyl)phenylsulfinim-idoyl chloride on a monolithic material is described, which can be incorporated into a flow chemical processing arrangement to oxidise a variety of substrates in both stoichiometric and catalytic processes to yield products in high yields and in high purity after in-line workup. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-0030-1259923

LETTER
869
Oxidation Reactions in Segmented and Continuous Flow Chemical Processing
Using an N-(tert-Butyl)phenylsulfinimidoyl Chloride Monolith
M
onolithic
N
-
tert
-
e
Butylpheny
i
lsulfin
k
imidoyl Chlo
o
ride for OxidationsLange, Matthew J. Capener, Alexander X. Jones, Catherine J. Smith, Nikzad Nikbin, Ian R. Baxendale,
Steven V. Ley*
Innovative Technology Centre, Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge, CB2 1EW, UK
Fax +44(1223)336442; E-mail: svl1000@cam.ac.uk
Received 1 February 2011
therefore chosen for this study using a monolithic sup-
Abstract: A supported version of N-(tert-butyl)phenylsulfinim-
port.13
idoyl chloride on a monolithic material is described, which can be
incorporated into a flow chemical processing arrangement to oxi-
dise a variety of substrates in both stoichiometric and catalytic pro-
cesses to yield products in high yields and in high purity after in-line
workup.
Two different routes to this monolithic N-(tert-butyl)phe-
nylsulfinimidoyl chloride (M1) have been investigated
(Scheme 1). Route A employs the monomeric version of
sulfenamide 2 in which the crucial sulfur–nitrogen bond is
already established. After the polymerisation event, the
monolithic sulfenamide M3 requires oxidation with N-
tert-butyl-N,N-dichloroamine14 or N-chlorosuccinimide
(NCS). Route B was designed by close analogy to the
published procedure for the original reagent.10 Here, the
sulfur–nitrogen bond has to be established once the mono-
lith has been formed in order to yield the sulfinimidoyl
chloride functionality. Although route A delivers the
monolithic species M3, we found that route B gave easier
access in terms of synthetic effort necessary to yield the
monomeric starting materials (see Supporting Informa-
tion).
Key words: oxidation, monolith, flow chemistry, polymer-
supported reagents, catalysis
Immobilised reagents, whether on organic or inorganic
supports, are ideally suited for use in continuous or seg-
mented flow chemical processing.1 Among these poly-
mer-supported reagents, monoliths,2 defined as single
pieces of uniformly porous material made from organic or
inorganic monomers upon precipitation polymerisation,
can offer superior chemical efficiency over commonly
used bead-based materials.2k–p This is due to mass transfer
being governed by convective flow rather than diffusion,
and by low void volume.1,2 The well-defined porous struc-
ture of monolithic materials exhibits a greater surface
functionality and generally allows for higher loadings.
Their rigid structure is maintained across a wide range of
solvents and conditions due to the high degree of cross
linking, thereby facilitating multistep chemical transfor-
mations in continuous or under segmented flow condi-
tions.2
S
Br
NHt-Bu
a–c
route A
1
2
d
S
NCS
or
t-BuNCl2
NHt-Bu
R1
R2
M
M
X
M3
f
Cl
S
g
Several types of polymer-supported reagents or otherwise
solid-supported oxidants are known for performing heter-
ogeneous oxidation reactions.2j,3–9 However, a versatile
and robust oxidant on a monolithic support could have nu-
merous applications for continuous flow processes. An
oxidant on monolithic support has been reported by
Kirschning and co-workers.2j Ideally, the monolithic oxi-
dant should be able to perform a wide range of oxidation
reactions and preferably should adhere to current environ-
mental standards, being regenerable, atom-efficient, and
not engaging heavy metals in the process.
base
+
Nt-Bu
R1
R2
M1
XH
X = O, NR3
f
S
Br
a, e
route B
O
M
1
M2
Scheme
1
Formations and reactions of monolithic N-(tert-
butyl)phenylsulfinimidoyl chloride (M1). Reagents and conditions:
(a) i) n-BuLi, THF–hexanes (1:1), –78 °C, 2 h; ii) S8, THF–hexanes
(1:1), –10 °C, 20 min; iii) Ac2O, THF–hexanes (1:1), –78 °C to r.t.,
12 h, 72%; (b) i) (MeO)2Sn(n-Bu)2, THF, r.t.; ii) FeCl3, THF, r.t., 18
h, 37%; (c) CuI (10 mol%), TMEDA (10 mol%), t-BuNH2, O2 (air
stream), DMSO, 65 °C, 12–24 h, 20–60%; (d) DVB, AIBN (cat.),
hexane–dodecanol (1:2), 80 °C, Vapourtec R4 convection heater, 24
h; (e) DVB, AIBN (cat.), dodecanol, 80 °C, Vapourtec R4 convection
heater, 24 h; (f) t-BuNCl2 or NCS (2.1 M in CH2Cl2 in sample loop),
PhMe, 0.05 mL/min, 90 °C, multiple runs (see schemes in Tables 1
and 2 for setup); (g) see scheme in Table 1 for both setup and reagents
and conditions.
N-(tert-Butyl)phenylsulfinimidoyl chloride, initially re-
ported by Mukaiyama and co-workers in 2000,10 and since
then applied in various oxidative transformations,10–12 was
SYNLETT 2011, No. 6, pp 0869–0873
x
x.
x
x.
2
0
1
1
Advanced online publication: 16.03.2011
DOI: 10.1055/s-0030-1259923; Art ID: S01211ST
© Georg Thieme Verlag Stuttgart · New York

870
H. Lange et al.
LETTER
Monomeric S-4-vinylphenyl ethanethioate was obtained Functionalisation of the thioacetate monoliths M2 was
from p-bromostyrene (1) according to the literature achieved in flow using N-tert-butyl-N,N-dichloroamine.14
protocol15 and was readily polymerised (typically on a 3.9 Portions (2 mL) of a ca. 2 M solution of the amine in
mmol scale) using 1,4-divinyl-benzene as cross-linker, 1- dichloromethane were injected into a 2 mL sample loop
dodecanol as porogen and 2,2¢-azobis(isobutyronitrile) and pumped through the heated (90 °C) monolith using
(AIBN) as radical initiator to yield thioacetate monolith toluene as the system solvent (Scheme 1, step f). Upon
M2 (Scheme 1). The resulting monolith was then routine- successful functionalisation, the initially off-white mono-
ly washed with toluene at 65 °C to remove any porogen lith M2 turns bright yellow, namely, the colour of the
and any residual monomeric species. Both 1H NMR spec- original reagent10 (Figure 1, left and centre). Multiple ox-
troscopic analysis of the toluene washings and elemental idation reactions using one newly synthesised monolith
analysis of a monolith M2 confirmed complete incorpora- M1 (see Supporting Information) as well as regeneration
tion of both the monomeric S-4-vinylphenyl ethanethioate experiments suggest a minimum functional loading of M1
and the cross-linker. The monolith exhibited very good around 30% with respect to the acetate functionalities the-
linear correlations16 between flow rates and back pres- oretically present in M2. The results suggest that some of
sures when incorporated in a continuous flow configura- the thioacetate groups are inaccessible to the dichloroam-
tion using commercially available equipment.17,18 ine reagent and therefore remain unchanged. Some of the
Thioacetate monoliths were prepared in different sizes functionalised sites, however, might also be inaccessible
with an average reproducibility rate of better than 80%.
for oxidation reactions, thereby making interpretation ad-
ditionally difficult. An exact determination of the loading
of M1 via elemental analysis was not feasible, as the
Table 1 Results Obtained Using N-(tert-Butyl)phenylsulfinimidoyl Chloride Monolith M1 in Segmented Flow Oxidation Reactionsa
...
R2
R1
(0.25 mmol)
XH
M
0.025 mL/min
M1
R2
2 mL
CH2Cl2
CH2Cl2
100 psi
R1
X = O, NR3
X
2 mL
temp.
0.025 mL/min
M
DIPEA (2 equiv)
M3
Entry
Substrate
Temp (°C)
Product
Conv. (%)b
1
2
3
4
–78
0
30
0
34
93c
OH
O
~80d
89e
O2N
O2N
O
OH
5
6
0
0
>95
85
OH
O
OH
O
7
8
0
25
30
95
9f
0
90–95
N
N
H
a Reaction conditions: as outlined in the scheme; typically, 0.25–0.5 mmol experiments were run.
b Determined by 1H NMR spectroscopy.
c Yield after chromatography.
d Indications of overoxidation to the acid are present.
e Yield after in-line purification using an A15/A21 mixture; purity >90%.
f 1,8-Diazabicyclo[5.4.0]undec-7-ene (DBU) was used as a base.
Synlett 2011, No. 6, 869–873 © Thieme Stuttgart · New York

LETTER
Monolithic N-tert-Butylphenylsulfinimidyl Chloride for Oxidations
871
sulfinimidoyl species itself is air- and moisture-sensitive. to the original monomeric species. Increased temperatures
It is noteworthy, however, that the monolithic species M1 are needed to successfully oxidise aliphatic alcohols. Ad-
can be stored in a sealed Omnifit® glass column for weeks ditionally, amines were also oxidised successfully to their
without a significant loss of activity.
corresponding imines (Table 1, entry 9). Upon continued
use, the monolith changes colour from yellow to light
brown (Figure 1, on the right), visually indicating its re-
duction to the N-tert-butylphenylsulfenamide monolith
M3.
The use of polymeric oxidant M1 was then examined with
respect to its scope and limitations (Table 1), using dry
solvent and starting from conditions reported earlier for a
bead version of the reagent.13 To obtain optimum temper-
atures for the reactions, warming of the monolith was Given that conversions are high, an in-line purification us-
achieved using the built-in heating device,17,18 whereas ing an Omnifit® column packed with a mixture of A15/
the Omnifit® column containing the monolith was simply A21 resins maintained at ambient temperature was used to
submerged into a cooling bath to achieve low tempera- scavenge the byproducts (ammonium chloride and resid-
tures. Control experiments were performed to ensure that ual alcohol) to give the carbonyl compounds in good
the oxidations were accomplished by the sulfinimidoyl yields and purities >90% (Table 1, entry 4).
species and were not a result of the flow conditions chosen
(see Supporting Information).
Regeneration and reactivation of the spent monolith M1
back to the active form M3 can be achieved by passage of
Following optimisation (Table 1, entries 1–3, 7, 8), it is solutions of either N-tert-butyl-N,N-dichloroamine14 or
apparent that benzylic and allylic alcohols can be readily NCS through the column. Due to solubility issues, regen-
oxidized in good conversions at 0 °C (Table 1, entries 1– eration was typically achieved by pumping 2 mL portions
6). The fact that only low conversion was observed when of a 2 M solution of N-tert-butyl-N,N-dichloroamine
the monolith was cooled to –78 °C proves the expected through the monolith at elevated temperatures (50 °C) at
lower reactivity of the monolithic reagent when compared low flow rates (0.05 mL/min).
Table 2 Results Obtained Using N-(tert-Butyl)phenylsulfenamide Monolith M3 together with N-tert-Butyl-N,N-dichloroamine as Co-oxi-
dant in Segmented Flow Oxidation Reactionsa
R2
R1
XH (0.25 mmol)
DIPEA (2 equiv)
M
M3
R2
CH2Cl2
CH2Cl2
2 mL
2 mL
100 psi
R1
X
50 °C
M
X = O, NR3
t-BuNCl2 (4.4 equiv)
M1
Entry
Substrate
Flow rate (mL/min)
Product
Conv. (%)b
OH
O
1
0.025
0.025
86c
trace
2d
O2N
O2N
OH
OH
O
O
3
4
0.025
0.025
56
49
O
N
O
5
0.025
0.04
31
82
OH
O
6e
N
H
a Reaction conditions: as outlined in the scheme; typically, 0.25–0.5 mmol experiments were run.
b Determined by 1H NMR spectroscopy.
c Yield after chromatography.
d NCS was used as co-oxidant.
e 1,8-Diazabicyclo[5.4.0]undec-7-ene (DBU) was used as a base.
Synlett 2011, No. 6, 869–873 © Thieme Stuttgart · New York

872
H. Lange et al.
LETTER
monolith M1, which was cooled to 0 °C using an ice-water bath
(flow rate per pump 0.025 mL min–1) using dry CH2Cl2 as the sys-
tem solvent. The exiting stream is collected for 3–4 h, and the re-
sulting organic phase is concentrated in vacuo to yield the crude
products. Some of the crude products have been additionally puri-
fied via column chromatography on silica gel, using Et2O–light PE.
In-Line Workup
To achieve an in-line workup, a scavenger system is used that catch-
es the ammonium salts formed during the reaction. Additionally,
small amounts of residual alcohol species can be retained. An Om-
nifit® column of appropriate size (typically the same size as the col-
umn for the monolith itself) is filled with a mixture of a polymer-
supported base, here A21 (polymer-supported trimethylamine), and
a polymer-supported acid, here A15 (polymer-supported sulfonic
acid). The scavenger column is placed in-line behind the monolith.
The column can be placed in a heating jacket and maintained at
25 °C (using the Vapourtec R4 unit17 or the Uniqsis FlowSyn18 col-
umn heater).
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
Figure 1 Thioacetate monolith M2 (left), N-(tert-butyl)phenylsulfi-
nimidoyl chloride monolith M1 (centre), N-(tert-butyl)phenylsulfen-
amide monolith M3 (right)
Acknowledgment
The authors thank the Alexander von Humboldt Foundation, the
EPSRC, the Royal Society, and the BP Endowment for funding.
When considering larger-scale applications in flow, it
would be convenient to employ monolith M3 and a suit-
able co-oxidant simultaneously rather than to regenerate
different batches of the monolith. A screening of potential
co-oxidants revealed once more that problems arose
mainly due to poor solubility and/or limited reactivity on
the solid phase. NCS and N-tert-butyl-N,N-dichloroamine
were identified as the most efficient reagents, and the
combination of M3 (fully depleted M1) and dichloroam-
ine was used for the flow oxidation of a range of activated
and nonactivated alcohols (Table 2, see Supporting Infor-
mation for details).
References and Notes
(1) Recent reviews on flow chemistry and the use of supported
reagents in flow chemistry: (a) Baumann, M.; Baxendale, I.
R.; Ley, S. V. Mol. Diversity 2011, in press; DOI: 10.1007/
s11030-010-9282-1. (b) Webb, D.; Jamison, T. F. Chem.
Sci. 2010, 1, 675. (c) Mak, X. Y.; Laurino, P.; Seeberger, P.
H. Beilstein J. Org. Chem. 2009, 5, No. 19. (d) Kirschning,
A. Beilstein J. Org. Chem. 2009, 5, No. 15. (e) Baxendale,
I. R.; Hayward, J. J.; Lanners, S.; Ley, S. V.; Smith, C. D.
Heterogeneous Reactions, In Microreactors in Organic
Synthesis and Catalysis; Wirth, T., Ed.; Wiley-VCH:
Weinheim, 2008, Chap. 4.2, 84. (f) Ley, S. V.; Baxendale, I.
R. Chimia 2008, 62, 162. (g) Baxendale, I. R.; Hayward, J.
J.; Ley, S. V. Comb. Chem. High Throughput Screen. 2007,
10, 802. (h) Ley, S. V.; Baxendale, I. A.; Bream, R. N.;
Jackson, P. S.; Leach, A. G.; Longbottom, D. A.; Nesi, M.;
Scott, J. S.; Storer, R. I.; Taylor, S. J. J. Chem. Soc., Perkin
Trans. 1 2000, 3815.
The experiments discussed above were repeated multiple
times by reusing a single monolith fabricated as described
earlier (3.9 mmol functional groups). Those experiments
show that the monoliths can be used for transformations
that exceed the amounts of functionalised groups avail-
able on the initial monolith.
(2) Monolithic materials have been employed in other work:
(a) Smith, C. J.; Smith, C. D.; Nikbin, N.; Ley, S. V.;
Baxendale, I. R. Org. Biomol. Chem. 2011, 9, 1927.
(b) Baumann, M.; Baxendale, I. R.; Kirschning, A.; Ley, S.
V.; Wegner, J. Heterocycles 2011, 82, 1297. (c) Baumann,
M.; Baxendale, I. R.; Ley, S. V. Synlett 2010, 749.
In summary, a polystyrene-based monolithic version of N-
(tert-butyl)phenylsulfinimidoyl chloride (M1) has been
established, that oxidises a broad range of substrates both
when applied in stoichiometric and catalytic amounts.
Adding an in-line purification step, oxidation products
can be obtained in high yields and high purity.
(d) Baumann, M.; Baxendale, I. R.; Ley, S. V.; Nikbin, N.;
Smith, C. D. Org. Biomol. Chem. 2008, 6, 1587. (e)Nikbin,
N.; Ladlow, M.; Ley, S. V. Org. Process Res. Dev. 2007, 11,
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S. V.; Vicent, M. J. Green Chem. 2006, 8, 717. (h) Kunz,
U.; Schönfeld, H.; Kirschning, A.; Solodenko, W.
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G.; Harders, J.; Hoffmann, N.; Hoffmann, U.; Schönfeld, H.;
General Procedure for Segmented Flow Oxidation Reactions
Using M1
Solutions (2 mL each) of alcohol (0.25 mmol, 1.00 equiv) and i-
Pr2NEt (0.5 mmol, 2.00 equiv) in dry CH2Cl2 were prepared under
argon and were either loaded into 2 mL injection loops of a pre-
dried19 Vapourtec R2+ unit17 or loaded into 2 mL injection loops of
a pre-dried19 Uniqsis FlowSyn.18 The solutions were mixed in a
T-piece, and the resulting reaction stream was pumped through the
Synlett 2011, No. 6, 869–873 © Thieme Stuttgart · New York

LETTER
Monolithic N-tert-Butylphenylsulfinimidyl Chloride for Oxidations
873
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Vapourtec Ltd, Park Farm Business Centre, Fornham St
Genevieve, Bury St Edmunds, Suffolk, IP28 6TS, UK.
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