Tributyltin hydride and 1-ethylpiperidine hypophosphite mediated intermolecular radical additions to 2,4,6-trichlorophenyl vinyl sulfonate

Article abstract of DOI:10.1016/j.tetlet.2007.10.030

2,4,6-Trichlorophenyl vinyl sulfonate smoothly undergoes intermolecular radical addition under mild initiation conditions mediated by tributyltin hydride and 1-ethylpiperidine hypophosphite (EPHP) to generate a range of functionalised alkyl sulfonamide pr

Full text of DOI:10.1016/j.tetlet.2007.10.030

Available online at www.sciencedirect.com
Tetrahedron Letters 48 (2007) 8926–8929
Tributyltin hydride and 1-ethylpiperidine hypophosphite
mediated intermolecular radical additions to
2,4,6-trichlorophenyl vinyl sulfonate
Oluwabusola Edetanlen-Elliot, Richard J. Fitzmaurice, Jonathan D. Wilden
and Stephen Caddick*
Department of Chemistry, University College London, Christopher Ingold Laboratories, 20 Gordon Street,
London, WC1H 0AJ, UK
Received 5 September 2007; revised 26 September 2007; accepted 4 October 2007
Available online 9 October 2007
Abstract—2,4,6-Trichlorophenyl vinyl sulfonate smoothly undergoes intermolecular radical addition under mild initiation condi-
tions mediated by tributyltin hydride and 1-ethylpiperidine hypophosphite (EPHP) to generate a range of functionalised alkyl
sulfonamide precursors. This methodology can be used to prepare bifunctional pentafluorophenyl/2,4,6-trichlorophenyl sulfonates
in good yields.
Ó 2007 Published by Elsevier Ltd.
Sulfonamides are a common structural feature in a large
range of important pharmaceuticals with a wide range
of biological activities.1 To date, the most commonly
used synthetic method to make sulfonamides involves
reaction of nucleophiles such as amines with sulfonyl
chlorides.2 Although this method is efficient the forma-
tion of the sulfonyl chloride is often not routine requir-
ing harsh oxidising or strongly Lewis acidic conditions.3
Previously, we have described the use of pentafluoro-
phenyl (PFP) sulfonates as a shelf stable alternative to
sulfonyl chlorides.4,5 This functional group readily
undergoes reaction with amines to generate sulfon-
amides and this can be achieved under aqueous condi-
tions. For example, PFP vinyl sulfonate undergoes
clean intermolecular radical addition using Bu3SnH as
the chain carrier to generate alkyl PFP sulfonates. Sub-
sequent aminolysis has been used to derive a range of
sulfonamides in good yields.5
for PFP-sulfonates.6 As part of the development of the
chemistry of TCP-sulfonates we now report radical
additions to TCP vinyl sulfonate, an electron-deficient
alkene, which is air and moisture stable. These radical
additions are mediated by both Bu3SnH and 1-ethyl-
piperidine hypophosphite (EPHP) and provide a simple
and effective synthetic route to functionalised alkyl-
TCP-sulfonates and a variety of sulfonamides that can
be derived thereof.
Generation of the key TCP-vinyl sulfonate 1 was readily
achieved. Addition of a solution of 2,4,6-trichloro-
phenol and triethylamine in dichloromethane to com-
mercially available 2-chloroethane-1-sulfonyl chloride
2 at low temperature gave TCP-vinyl sulfonate 1 in good
yield (Scheme 1).
Initially, we evaluated a range of conditions for the rad-
ical addition of simple radicals generated from iodides
Despite the utility of PFP-sulfonates we have spent con-
siderable effort in finding alternatives, which address
issues of cost and toxicity and we recently introduced
2,4,6-trichlorophenyl (TCP) sulfonates as a replacement
Cl
O O
a
O O
S
S
Cl
O
Cl
Cl
2
Cl
Keywords: Radical addition; Tributyltin hydride; EPHP; TCP-sulfo-
nate; Sulfonamide.
1
*
Scheme 1. Reagents and conditions: (a) TCPOH, NEt3, CH2Cl2,
À10 °C, 82%.
Corresponding author. Tel./fax: +44 0 20 7679 4694; e-mail:
s.caddick@ucl.ac.uk
0040-4039/$ - see front matter Ó 2007 Published by Elsevier Ltd.
doi:10.1016/j.tetlet.2007.10.030

O. Edetanlen-Elliot et al. / Tetrahedron Letters 48 (2007) 8926–8929
8927
Table 1. Optimisation of EPHP mediated addition to TCP vinyl
sulfonate
Table 2. Substrate scope of EPHP–BEt3/air mediated additions
RI, EPHP, BEt3/air
O O
S
O O
S
RI, EPHP,
O
O
O O
DCM, 0 oC,10 min
TCPO
TCPO
R
S
S
TCPO
TCPO
R
BEt3/air, solvent
Entry RI
Product
Yield
(%)
Entry
RI
EPHP
(equiv)
Solvent
Temperature
(°C)
Yield
(%)
O
O
O
1
2
3
4
5
6
7
8
iPrI
iPrI
iPrI
iPrI
tBuI
tBuI
tBuI
tBuI
5
5
5
5
5
3
7.5
10
Dioxane
Dioxane
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
22
22
22
0
0
0
<5a
47
43
62
59
50
64
63
I
S
S
S
1
64
TCPO
O
I
2
62
51
TCPO
0
0
O
O
3
4
I
I
TCPO
a BEt3 omitted. Yield estimated by integration of the crude H NMR.
1
O
O
S
72
TCPO
to TCP vinyl sulfonate (Table 1). We were particularly
keen to utilise EPHP as a non-toxic alternative to
Bu3SnH as radical chain carrier in an analogous fashion
to that reported previously.7 Optimisation of the reac-
tion conditions for the free radical addition of primary,
secondary and tertiary radicals to TCP vinyl sulfonate
indicated that higher concentrations of chain carrier
gave higher yields (Table 1, entries 6–8) although the
maximum yield was achieved at 7.5 equiv of EPHP
(Table 1, entry 7). In addition, air alone did not initiate
the free radical chain effectively (Table 1, entry 1) how-
ever triethylborane/air mixture at low temperature was
found to proceed smoothly. This was best achieved via
bubbling a volume of air through the reaction solution
under a static inert atmosphere.
O
O
S
5
6
7
8
33
I
TCPO
CO2Me
NHBoc
CO2Me
NHBoc
O
O
O
O
<5a
27
I
I
S
S
S
TCPO
O
Cl
TCPO
Cl
O
I
CO2Me
<5a
CO2Me
TCPO
a Yield estimated by integration of the crude 1H NMR.
Our optimised EPHP conditions were then applied to a
range of radical precursors and the efficiency of the
addition evaluated (Table 2). These reactions were par-
ticularly facile requiring a reaction time of a few hours
and the major side products, hypophosphite derived,
could be removed with an aqueous work-up. It should
be noted however that column chromatography was
often required in the case of primary alkyl halides to
remove ethyl radical addition by-products. The yields
were generally moderate to good, although, with the
primary alkyl halides, as expected, lower yields were
observed. In the case of an amino acid derived iodide
(Table 2, entry 6) significant amounts of the reduced
iodide, vinyl sulfonate, ethyl radical addition and the
product from elimination of HI were obtained even at
low temperatures. In general it is notable that the reac-
tion proceeds much better with alkyl iodides than with
alkyl bromides.
Using Bu3SnH as the chain carrier initiated with AIBN
in refluxing toluene (Method A), we found that this
intermolecular addition led to the corresponding alkyl
sulfonate esters in moderate to good yields (Table 3).
Initiation with BEt3/air coupled with an improved puri-
fication protocol resulted in improved yields with simple
alkyl sulfonates (Table 3, entries 1, 3, 4 and 6) and it was
notable that secondary and tertiary bromides gave
acceptable yields (Table 3, entries 2 and 7). We believe
a significant proportion of this increase in yield was
due to a more facile purification protocol involving
column chromatography on KF or K2CO3 doped silica
as described by Harrowven.8
The functional group tolerance of this intermolecular
radical addition route to TCP vinyl sulfonates is exem-
plified in reactions in the presence of esters, silyl ethers,
aryl halides, acids, alcohols and other alkyl halides
(Table 3). Also noteworthy is the addition of the radical
generated from BocHN–A(I)–OMe, which was unsuc-
cessful with EPHP as the chain carrier but was achieved,
albeit in low yield, in the presence of Bu3SnH (Table 3,
entry 9). However, as before significant amounts of
reduced halide and HI elimination products were iso-
lated and in the case of BEt3/air activation, the ethyl
addition product. The relatively low yields in the case
of the BEt3/air activation with the more complicated
substrates (Table 3, entries 9–16) can be attributed to
Although the use of EPHP as a chain carrier in radical
additions to TCP vinyl sulfonate was successful, prob-
lems with the efficiency of the reaction particularly with
less readily generated radicals limited the scope of the
methodology. In particular, we wanted a single set of
reliable conditions which could be used to access rapidly
a range of alkyl TCP sulfonates. In order to expand the
generality of the reaction we returned to the more facile
Bu3SnH as the radical chain carrier under both AIBN
and BEt3/air initiation (Table 3).

8928
O. Edetanlen-Elliot et al. / Tetrahedron Letters 48 (2007) 8926–8929
Table 3. Bu3SnH mediated radical additions to TCP vinyl sulfonate
RX
O
O
O O
S
S
TCPO
TCPO
Method A or B
R
Entry
Product
Yield (%)
Method Aa
74
Method Bb
88
O O
S
1
2
TCPO
O O
S
—
64
TCPO
O O
S
3
4
5
74
53
—
88
57
19
TCPO
O
O
S
TCPO
O
O
O
S
TCPO
O
S
6
7
72
—
88
44
TCPO
O
O
S
TCPO
O
O
S
8
9
65
37
37
20
TCPO
CO2Me
NHBoc
O
O
S
S
TCPO
O
O
10
11
12
13
50
58
—
—
48
0
CO2Me
TCPO
O
O
S
CO2H
OH
TCPO
O
O
S
38
44
TCPO
O
O
S
S
TCPO
OTBDMS
O
O
Cl
14
15
16
—
48
40
36
32
9
TCPO
O
O
S
S
Cl
TCPO
O
O
TCPO
Cl
a 3 equiv RX, 0.05 equiv AIBN, 2.5 equiv Bu3SnH, MePh, 110 °C, 2 h.
b 2 equiv RX, 3 equiv Bu3SnH, 1 equiv BEt3, air, CH2Cl2, 0 °C to rt, 18 h.

O. Edetanlen-Elliot et al. / Tetrahedron Letters 48 (2007) 8926–8929
8929
O
O
double intermolecular radical addition to prepare
bifunctional TCP/PFP sulfonates, which we envisage
will be of significant utility as building blocks in two-
directional synthesis.
3, n = 1
4, n = 2
S
Cl
TCPO
n
a
b
Acknowledgements
O O
S
5, n = 1, 89%
6, n = 2, 84%
I
TCPO
We gratefully acknowledge the financial support of
EPSRC, and BBSRC for support of our programme.
We also gratefully acknowledge AstraZeneca, Glaxo-
SmithKline, Novartis and CEM Microwave Technology
(UK). We gratefully acknowledge the EPSRC mass
spectrometry service at Swansea for provision of mass
spectra.
n
O
O
O O
S
S
OPFP
TCPO
n
Method A
49%
66%
Method B
38%
41%
References and notes
7, n = 1
8, n = 2
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Scheme 2. Reagents and conditions: (a) NaI, butanone, 120 °C (MW)
30 min; (b) Method A or B (see footnote Table 3).
a significant proportion of competing ethyl radical
addition.
Encouraged by these results we also wished to prepare
bifunctional alkyl TCP/alkyl PFP via a double radical
addition protocol (Scheme 2). Conversion of 3 and 4
to iodides 5 and 6 was best achieved via microwave heat-
ing with NaI in butanone. The elevated temperatures
accessed using microwave conditions resulted in com-
plete reaction after 30 min compared to 18 h in refluxing
acetone. Radical addition to PFP vinyl sulfonate using 5
and 6 gave the desired bifunctional TCP/PFP sulfonates
7 and 8 in moderate yields. As expected from our model
studies an excess of Bu3SnH was required and initiation
with AIBN in refluxing toluene proved more effective,
particularly in the case of 8.
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Wadman, S. N.; Wilden, J. D. Tetrahedron Lett. 2004, 45,
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In conclusion, we have succeeded in carrying out inter-
molecular radical additions to TCP vinyl sulfonate using
stannane mediated or stannane-free conditions to give
alkyl sulfonates. Notably, we were able to carry out a