Table 4 Preparation of nitriles via microwave heating
Equivalents of
reagent
GC
GC
Purity (%)
a
Entry
1
Amide
Product
Conversion (%)
3.5
3.5
>99
95
2
3
>99
>99
>99
3.5
98
a
Reaction conditions: toluene, 1-ethyl-3-methyl-1H-imidazolium hexafluorophosphate, 200 ЊC, 15 minutes.
facilitate complete conversion than secondary amides. In the
case of N-phenylamides, the reaction was markedly slower than
for amides bearing simple N-alkyl substituents. However, if a
larger excess of reagent was used, even these reactions could be
driven to completion (Table 3, entry 8).
15 T. Sifferlen, M. Rueping, K. Gademann, B. Jaun and D. Seebach,
Helv. Chim. Acta, 1999, 82, 2067.
1
1
1
6 B. S. Pedersen, S. Scheibye, N. H. Nilsson and S.-O. Lawesson,
Bull. Soc. Chim. Belg., 1977, 87, 223.
7 B. S. Pedersen and S.-O. Lawesson, Bull. Soc. Chim. Belg., 1977, 86,
6
93.
In all cases investigated, primary amides gave clean conver-
sion to the corresponding nitriles under microwave heating
8 J. Perregaard, I. Thomsen and S.-O. Lawesson, Bull. Soc. Chim.
Belg., 1977, 87, 321.
32
(
Table 4). The improved results were thought to be due to the
19 S. Scheibye, B. S. Pedersen and S.-O. Lawesson, Bull. Soc. Chim.
Belg., 1977, 87, 229.
20 J. Perregaard, B. S. Pedersen and S.-O. Lawesson, Acta Chem.
Scand., 1977, B31, 460.
higher temperature driving even the reaction with benzamide to
the nitrile.
In conclusion, a new polymer-supported thionating reagent
has been developed as an easily handled, low odour alternative
to Lawesson’s reagent. Its use has been demonstrated in the
conversion of secondary or tertiary amides to thioamides and
primary amides to nitriles. The benefits of microwave tech-
nology have been illustrated and the use of a small amount of
ionic liquid to promote efficient heating in such systems has
been proven to be effective.
2
1 Typical experimental procedure: Ethyl dichlorothiophosphate
12 ml, 90 mmol) was added dropwise to a suspension of N-(2-
(
aminoethyl)aminomethyl polystyrene (NovaBiochem, 9.35 g, 2.8
Ϫ1
mmol g , 21 mmol) in pyridine (150 ml) at 0 ЊC. The resulting
suspension was allowed to warm to room temperature and then
shaken at room temperature for 4 hours. Following filtration and
washing with dichloromethane (5 × 200 ml) and diethyl ether
(5 × 200 ml) residual solvent was removed in vacuo to yield the
polymeric reagent as an orange solid; Found: S, 5.8%, P, 5.9%;
Ϫ1
Ϫ1
Loading: 1.8 mmol g ; νmax (single bead)/cm 3090, 2850, 1676,
1623, 1603, 1494, 1454, 1115, 1029, 761.
Acknowledgements
2
2 Loading of the resin was calculated from sulfur and phosphorous
elemental analysis.
We would like to thank BBSRC and Novartis for a Research
Fellowship (S. V. L.) and a CASE award (A. G. L.). Also, we
thank AstraZeneca for generous additional funding (R. I. S.).
23 Example thioamide formation (conventional heating): Thiophos-
phorylated amine resin (466 mg, 0.84 mmol) was added in one por-
tion to a solution of N,N-dimethylbenzamide (28 mg, 0.19 mmol) in
toluene (3.0 ml). The resulting suspension was heated without
agitation to 90 ЊC for 14 hours. Further reagent (256 mg, 0.46 mmol)
was then added and the suspension was heated at 90 ЊC for a further
16 hours. The reaction mixture was then cooled to room temper-
ature and filtered through a short pad of silica gel (eluent: diethyl
ether). The solvent was then evaporated under reduced pressure,
giving the corresponding thioamide (99%) as a yellow solid; (GC)
Notes and references
1
S. V. Ley, I. R. Baxendale, R. N. Bream, P. S. Jackson, A. G. Leach,
D. A. Longbottom, M. Nesi, J. S. Scott, R. I. Storer and S. J. Taylor,
J. Chem. Soc., Perkin Trans. 1, 2000, 3815.
2
M. J. Astle, in Ion Exchangers in Organic and Biochemistry,
ed. C. Calmon and T. R. E. Kressman, Interscience, New York, 1957
and references cited therein.
Ϫ1
98%; νmax(film)/cm 1518 (C᎐S); δ (400 MHz; CDCl , Me Si)
H
3
4
7.40–7.26 (5 H, m, Ph), 3.59 (3 H, m, NCH ), 3.15 (3 H, s, NCH );
3
3
3
4
R. B. Merrifield, J. Am. Chem. Soc., 1963, 85, 2149.
S. V. Ley, M. H. Bolli, B. Hinzen, A. G. Gervois and B. J. Hall,
J. Chem. Soc., Perkin Trans. 1, 1998, 2239.
δ (100 MHz; CDCl , Me Si) 201.4 (C᎐S), 143.4 (Ph), 128.5 (Ph),
C
3
4
128.3 (Ph), 125.7 (Ph), 44.1 (CH ), 43.2 (CH ); m/z (EI) 165.0618
3
3
ϩ
(M Ϫ C H NS requires 165.0612).
9
11
5
6
L. M. Gayo, Biotech. Bioeng., 1998, 61, 95.
24 Although the new polymer-supported reagent itself has only a
low odour, one should be aware that the low molecular weight
thioamides did themselves have a strong odour.
J. J. Parlow, R. V. Devraj and M. S. South, Curr. Opin. Chem. Biol.,
1
999, 3, 320.
7
8
9
M. Caldarelli, J. Habermann and S. V. Ley, J. Chem. Soc., Perkin
Trans. 1, 1999, 107.
F. Haunert, M. H. Bolli, B. Hinzen and S. V. Ley, J. Chem. Soc.,
Perkin Trans. 1, 1998, 2235.
M. Caldarelli, J. Habermann and S. V. Ley, Bioorg. Med. Chem.
Lett., 1999, 9, 2049.
25 Example nitrile formation (conventional heating): Thiophosphoryl-
ated amine resin (490 mg, 0.88 mmol) was added in one portion to
a solution of 4-methoxybenzamide (30 mg, 0.20 mmol) in toluene
(3.0 ml). The resulting suspension was heated without agitation to
90 ЊC for 14 hours. Further reagent (278 mg, 0.50 mmol) was then
added and the suspension was heated at 90 ЊC for a further 16 hours.
The reaction mixture was then cooled to room temperature and
filtered through a short pad of silica gel (eluent: diethyl ether). The
solvent was then evaporated under reduced pressure, giving the
corresponding nitrile (99%) as a colourless solid; (GC) 98%;
1
1
1
0 J. Habermann, S. V. Ley and J. S. Scott, J. Chem. Soc., Perkin Trans.
1
, 1999, 1253.
1 S. V. Ley, O. Schücht, A. W. Thomas and P. J. Murray, J. Chem. Soc.,
Perkin Trans. 1, 1999, 1251.
2 J. Habermann, S. V. Ley and R. Smits, J. Chem. Soc., Perkin Trans.
Ϫ1
νmax(film)/cm 1518 (C᎐S); δ (400 MHz; CDCl , Me Si) 7.58 (2 H,
H
3
4
1
, 1999, 2421.
d, J 9.0, Ph), 6.95 (2 H, d, J 9.0, Ph), 3.88 (3 H, s, OCH ); δ (100
3 C
1
1
3 I. R. Baxendale and S. V. Ley, Bioorg. Med. Chem. Lett., 2000, 1.
4 A. W. Hofmann and S. Gabriel, Chem. Ber., 1892, 25, 1578;
The Chemistry of Heterocyclic Compounds, Vol. 35, Thiazole and
its derivatives, Part 1, ed. J. V. Metzger, John Wiley and Sons,
New York, 1979, p. 180.
MHz; CDCl , Me Si) 162.9 (Ph), 134.0 (Ph), 119.2 (CN), 114.7 (Ph),
3 4
104.0 (Ph), 55.5 (CH ).
3
26 S. Caddick, Tetrahedron, 1995, 51, 10403.
27 A. de la Hoz, A. Diaz-Ortis, A. Moreno and F. Langa, Euro J. Org.
Chem., 2000, 3659.
3
60
J. Chem. Soc., Perkin Trans. 1, 2001, 358–361