Solid phase-mediated synthesis of isonitriles

Article abstract of DOI:10.1016/S0040-4039(02)01672-6

Supported sulfonyl chlorides and microwave irradiation are an efficient combination for isonitrile synthesis.

Full text of DOI:10.1016/S0040-4039(02)01672-6

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 7201–7203
Solid phase-mediated synthesis of isonitriles
a
b
c
d
a,
Delphine Launay, Susan Booth, Ian Clemens, Andrew Merritt and Mark Bradley *
a
Combinatorial Centre of Excellence, Department of Chemistry, University of Southampton, Southampton SO17 1BJ, UK
b
Organon, Newhouse, Lanarkshire, Scotland, UK
Eli Lilly & Co., Lilly Research Centre, Erl Wood Manor, Windlesham, Surrey GU20 6PH, UK
c
d
GSK, Research and Development, Medicines Research Centre, Gunnels Wood Road, Stevenage SG1 2NY, UK
Received 12 February 2002; revised 2 August 2002; accepted 9 August 2002
Abstract—Supported sulfonyl chlorides and microwave irradiation are an efficient combination for isonitrile synthesis. © 2002
Elsevier Science Ltd. All rights reserved.
Multi-component reactions (MCRs) have become an
important constituent of the combinatorial chemist’s
arsenal, allowing large numbers of compounds to be
produced in a rapid parallel synthesis programme.
1
2
Thus, the Passerini and Ugi reactions, to name but
two, have become well established in library synthesis
3
programmes (Scheme 1).
One of the most important components of these reac-
tions, and one that is very limited in accessibility, is the
isonitrile. Isonitriles are especially important due to
their unusual bifunctional reactivity, acting as both a
nucleophile and an electrophile during the reaction.
There are numerous methods reported for isonitrile
Scheme 2. Solution synthesis of isonitiriles.
Work-up and purification of this reaction was problem-
atic due to the reactivity of the isonitriles. The use of a
polymer supported sulfonyl chloride therefore appeared
to offer a fast and efficient method of isonitrile genera-
tion, with just a simple filtration and acidic work-up (to
remove the pyridine) being involved. A number of
reactions were therefore investigated using a range of
formamides, as shown in Table 1 and Scheme 3.
4
synthesis, however, during the synthesis of a series of
isonitrile tags we became aware of the limited utility
and applicability of many current methods. Eventually
the synthetically most useful conditions, the treatment
of formamides with p-toluene sulfonyl chloride, were
5
identified and this led to the synthesis of a number of
isonitriles in reasonable yield and purity (Scheme 2).
Scheme 1. (a) Passerini and (b) Ugi reaction.
*
0
Corresponding author.
040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)01672-6

7
202
D. Launay et al. / Tetrahedron Letters 43 (2002) 7201–7203
Table 1.
Entry no.
Sulfonyl chloride resin (Novabiochem) (equiv.)
Pyridine (equiv. in DCM) Formamide
Isonitrileb (% purity)
1
2
3
4
5
6
7
8
3
3
9
3
3
6
6
6
3
3
3
3
3
3
Neat pyridine
Neat pyridine
Neat pyridine
B
A
11
49
50
66
74
100
100
27
100
81
100
100
95
A
A
A
A
A
B
A
B
C
D
E
F
10
50
50
100
50
50
50
50
50
50
50
a
9
a
10
11
12
13
14
a
a
a
a
18
a
Using the Smith Synthesiser, 100°C, 10 min.
Determined by RP-HPLC.
b
Scheme 3. Solid phase-mediated synthesis of isonitriles.
The reaction was successfully optimised with for-
mamide A using a gel based sulfonyl chloride resin
from Novabiochem (see entries 6 and 7 in Table 1) and
highly efficient and clean technique of synthesis for this
important class of compounds. Interestingly we
6
TM
observed that the use of a Smith Synthesiser
and
a limited quantity of pyridine, to give the isonitriles in
exceptional purity. Using microwave irradiation and 3
equiv. of sulfonyl chloride resin the method became
very reproducible and gave the desired product in good
to excellent purities for five out of the six substrates
microwave irradiation gave much faster reactions, while
maintaining product purity and in many cases
improved yields, thereby allowing rapid access to this
class of compounds for subsequent incorporation into a
range of compounds, including the synthesis of isoni-
trile tags, useful probes for a range of biological
processes.
7
investigated (see entries 9–14 in Table 1). Only reaction
with the formamide F gave poor conversion, pre-
sumably because the formamide here was more heavily
substituted and less benign than the other formamides
investigated.
Acknowledgements
The sulfonyl chloride resin was also quantitatively
regenerated (according to the results from microanaly-
sis) from the sulfonic acid resin by treatment with 5
We thank Personal Chemistry for the use of the Smith
Synthesiser . Work in the Combinatorial Centre of
Excellence is funded by GSK, AstraZeneca, Pfizer,
Roche, Eli-Lilly, Organon, NovaBiochem/Merck,
Amersham/Nycomed Amersham and through the JIF
initiative.
TM
equiv. of PCl in DMF at room temperature.
5
A solid phase-mediated synthesis of isonitriles using a
resin supported sulfonyl chloride has proven to be a

D. Launay et al. / Tetrahedron Letters 43 (2002) 7201–7203
7203
References
p-toluenesulfonyl chloride (0.77 mmol). After 5 min the ice
bath was removed and the mixture was stirred at room
temperature for 6 h. The yellow solution became slowly
brown. The solution was quenched with water (10 mL)
and extracted with DCM (3×15 mL). The organic layer
1
2
. Passerini, M. Gazz. Chim. Ital. 1921, 51, 126.
. Ugi, I.; Betz, W.; Fetzer, U.; Offermann, K. Chem. Ber.
961, 94, 2814–2816.
. (a) D o¨ mling, A.; Ugi, I. Angew. Chem., Int. Ed. 2000, 39,
168–3210; (b) Bauer, S. M.; Armstrong, R. W. J. Am.
1
3
was washed with a saturated aqueous solution of KH SO4
2
3
(2×15 mL), the extracts were dried (MgSO ), filtered,
4
Chem. Soc. 1999, 121, 6355–6366; (c) Weber, L.; Illgen, K.;
Almstetter, M. Synlett 1999, 3, 366–374; (d) D o¨ mling, A.;
Ugi, I. Angew. Chem., Int. Ed. 1993, 32, 563–564; (e)
D o¨ mling, A. Curr. Opin. Chem. Biol. 2000, 4, 318–323.
. For methods of isonitrile synthesis, see: (a) Kim, M.;
Euler, W. B.; Rosen, W. J. Org. Chem. 1997, 62, 3766–
concentrated and chromatographed on silica gel (hexane/
ethyl acetate, 9/1 then 8/2 and 7/3), to give 74 mg of a
yellow oil (yield=79%).
Typical solid-supported synthesis procedure. To
polystyrene sulfonyl chloride resin (414 mg, 1.2 mmol) in
dichloromethane (2.4 mL) were added 4-chlorobenzylfor-
mamide (68 mg, 0.40 mmol) and pyridine (1.58 mL, 20
mmol) in a sealed reaction vial. The reaction was per-
formed for 10 min at 100°C in the microwave reactor
Smith Synthesizer. The crude mixture was filtered with
dichloromethane (15 mL). The filtrate was poured into
water (15 mL) and extracted with dichloromethane (2×20
mL). After washings with an aqueous solution of potas-
sium hydrogensulfate (3×15 mL), the organic layer was
4
3
769; (b) Obrecht, R.; Herrmann, R.; Ugi, I. Synthesis
1
985, 400–402; (c) Kercher, T.; Livinghouse, T. J. Org.
Chem. 1997, 62, 805–812.
. Ho, T.-L.; Jana, G. H. J. Org. Chem. 1999, 64, 8965–8967.
. From Novabiochem. Sulfonyl chloride polystyrene resin
5
6
1
00–200 mesh. The polymer matrix is copoly(styrene–1%
DVB). Substitution: 2.9 mmol/g.
7
. Typical experimental procedure for the solution phase
synthesis. To a cooled and stirred solution of the for-
mamide B (0.31 mmol) in pyridine (3 mL) was added
dried over MgSO
and concentrated to afford 40 mg of the
4
expected compound, in 70% yield and 98% purity.