Efficient synthesis of primary selenocarboxylic amides by reaction of nitriles with phosphorous(V) selenide

Article abstract of DOI:10.1055/s-2002-35604

The reaction of nitriles with P₂Se₅ in the presence of EtOH/H₂O afforded a variety of primary selenocarboxylic amides.

Full text of DOI:10.1055/s-2002-35604

LETTER
1983
Efficient Synthesis of Primary Selenocarboxylic Amides by Reaction of
Nitriles with Phosphorous(V) Selenide
Efficient
S
ynthesis
a
of Primary
r
Selenoc
l
a
rboxy
h
lic Amides einz Geisler,* Anke Jacobs, Andreas Künzler, Manuela Mathes, Ilona Girrleit, Birgit Zimmermann,
Ehrenfried Bulka, Wolf-Diethard Pfeiffer, Peter Langer*
Institut für Chemie und Biochemie der Ernst-Moritz-Arndt-Universität Greifswald, Soldmannstr. 16, 17487 Greifswald, Germany
Received 25 September 2002
+ H2O
Abstract: The reaction of nitriles with P2Se5 in the presence of
EtOH/H2O afforded a variety of primary selenocarboxylic amides.
P2Se5
H2Se
Ph
- H3PO4
Key words: cyclizations, heterocycles, nitriles, selenium, synthetic
methodology
Se
NH2
P2Se5
Ph C N
EtOH, H2O
1a
2a (84%)
Selenium containing heterocycles are of considerable cur-
rent interest, due to their pharmacological activity. A
prominent example is the antitumor and antiviral active C-
glycosyl selenazole selenazofurin.1 In contrast to their sul-
fur analogues, there exist only limited methods for the
synthesis of N,Se-heterocycles, e. g. 1,3-selenazoles.2
Many syntheses rely on the use of primary seleno-ureas
and selenocarboxylic amides. However, these important
building blocks are not readily available and there are
many drawbacks of known synthetic procedures. Seleno-
carboxylic amides have been prepared by reaction of ni-
triles with H2Se, NaSeH,3a generated by NaBH4/Se,3 by
use of Se/CO,4 and tris(trimethylsilyl)-monoselenophos-
phate.5 These methods are restricted mainly to aryl substi-
tuted derivatives or require toxic or not readily available
reagents. An alternative synthesis of selenocarboxylic
amides relies on the reaction of nitriles with Al2Se3 in the
presence of Et3N/pyridine/H2O.6 Unfortunately, many
yields given in this paper could not be reproduced in our
hands (vide infra).7
P2Se5
O
O
EtOH
reflux
Br
Ph
Ph
NH2
Ph
4
S
Se
Ph
NH2
Ph
N
5
3a (87%)
Scheme 1 Synthesis of selenocarboxylic amides by reaction of
nitriles with P2Se5
transformed into 1,3-selenazoles by reaction with -bro-
moketones.
Our initial attempts to prepare primary selenocarboxylic
amides by reaction of carboxylic amides with P2Se5 were
unsuccessful under a variety of conditions (variation of
the stoichiometry, solvent, temperature, reaction time and
additives such as HCl, NaOH, Ph3P or PCl3).8,9 We have
eventually found that primary selenocarboxylic amides
can be prepared in good yields by reaction of nitriles with
P2Se5.10 Slow addition of water to the reaction mixture re-
sulted in formation of small amounts of hydrogen selenide
in situ which subsequently added to the nitrile. During the
optimization of the reaction the following parameters
proved important (Table 1): a) use of 0.4 equivalents of
P2Se5 (corresponding to 2.0 equiv of selenium), b) slow
addition of water or P2Se5 to the reaction mixture, c) use
of EtOH/H2O, d) reaction time and temperature, e) crys-
tallization solvent (Table 2). An attempt to directly use a
mixture of the elements (P/Se = 2:5) rather than P2Se5
proved unsuccessful. The cyclization of 2a with -bro-
moacetophenone afforded 1,3-selenazole 3a in 87%
yield.11
Herein, we wish to report a new method for the synthesis
of primary selenocarboxylic amides by reaction of nitriles
with P2Se5 in the presence of EtOH/H2O (Scheme 1).
From a preparative viewpoint, our methodology is more
convenient and reliable than the use of Al2Se3 and is less
toxic than CO, NaSeH or H2Se. In addition, P2Se5 is much
easier and more reliably available in pure form and is less
prone to hydrolysis than Al2Se3. It can be handled in pres-
ence of air and stored for a long time under inert atmo-
sphere.7 Our methodology allows the preparation of a
great variety of selenocarboxylic amides. The yields ob-
tained for known products are in many cases better than
those reported for other methods. In addition, a number of
novel functionalized derivatives were prepared with good
chemoselectivity. The selenocarboxylic amides prepared
represent versatile synthetic building blocks and were
In order to study the preparative scope of our methodolo-
gy, the substituents of the nitrile were systematically var-
ied (Scheme 2, Table 2). The reaction of benzonitrile and
2-tolylnitrile with P2Se5 afforded selenocarboxylic
amides 2a and 2b, respectively. Starting with acetonitrile
Synlett 2002, No. 12, Print: 02 12 2002.
Art Id.1437-2096,E;2002,0,12,1983,1986,ftx,en;D18602ST.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0936-5214

1984
K. Geisler et al.
LETTER
Table 1 Optimization of the Synthesis of 2a
Entry
Educt
1a
1a
1a
1a
4
Reagent
Al2Se3
P2Se5
P2Se5
P2Se5
P2Se5
P2Se5
P/Sec
Equiv
1.4
0.4
0.4
0.2
0.4
0.4
0.4
0.4
0.4
0.4
Additive
t (h)
2
Temp.
reflux
reflux
reflux
reflux
reflux
reflux
reflux
reflux
reflux
20 °C
(%)a
1
NEt3/pyridine/H2O
NEt3/pyridine/H2O
EtOH/H2O
49
72
84
55
0
2
2
3
2
4
EtOH/H2O
2
b
5
2
b
6
5
2
0
7
1a
1a
1a
1a
EtOH/H2O
EtOH/H2O
EtOH/H2O
EtOH/H2O
2
9
8
P2Se5
P2Se5
P2Se5
0.5
12
12
34
27
0
9
10
a Isolated yields.
b Various conditions, see text.
c Mixture P/Se = 2:5
corresponding nitriles 1o–q. The reaction of P2Se5 with
functionalized aromatic nitriles afforded products 2r–v
with very good chemoselectivity. Seleno-urea (2x) and se-
lenoglycin amide (2y), which represents to our knowledge
the first amino acid derived selenocarboxylic amide, were
successfully prepared from cyanamide and aminoacetoni-
trile, respectively. The cyclization of selenocarboxylic
amides 2 with -bromoketones afforded a variety of 1,3-
selenazoles 3 (Scheme 2, Table 2).11
Se
P2Se5
R1 C N
R1
NH2
EtOH, H2O
1a-y
2a-y
O
Br
R2
EtOH, reflux
Se
R2
R1
N
3a-y
We have reported a chemoselective, convenient and reli-
able synthesis of a variety of selenocarboxylic amides in-
cluding a number of novel functionalized derivatives. The
yields obtained for known products compare well to those
reported for other methods. Selenocarboxylic amides rep-
resent useful building blocks for the synthesis of 1,3-se-
lenazoles and other pharmacologically relevant N/Se-
heterocycles.
Scheme 2 Synthesis of selenocarboxylic amides and 1,3-selen-
azoles
and propionitrile, selenocarboxylic amides 2c and 2d
were prepared, respectively. Alkyl-substituted derivatives
are generally rather unstable and difficult to prepare. Se-
lenocarboxylic amide 2e was prepared from phenylaceto-
nitrile. The use of Al2Se3, following the protocol reported
by Cohen,6 proved unsatisfactory in our hands: selenocar-
boxylic amides 2a–e were isolated in only 49%, 14%, 7%,
3% and 21% yields, respectively. The reaction of P2Se5
with dibenzylacetonitrile afforded selenocarboxylic
amide 2f. Products 2g–i were prepared from pyridyl sub-
stituted nitriles. The novel functionalized selenocarboxy-
lic amides 2j–m, containing a nitrile, carboxylic acid,
ester and guanidine moiety, were prepared from 1j–m
with very good chemoselectivity. A protection of the
functional groups was not required. Selenation of malonic
dinitrile afforded the novel difunctional derivative 2n.
Phenylethenyl-, tert-butyl- and naphthyl-substituted sele-
nocarboxylic amides 2o–q could be prepared from the
Acknowledgment
Financial support from the Fonds der Chemischen Industrie e. V.
(Liebig-scholarship and funds for P. L.) and from the Deutsche For-
schungsgemeinschaft (Heisenberg-scholarship and funds for P. L.)
is gratefully acknowledged.
References
(1) Goldstein, B. M.; Kennedy, S. D.; Hennen, W. J. J. Am.
Chem. Soc. 1990, 112, 8265; and references cited therein.
(2) (a) Larsen, R. In Comprehensive Heterocyclic Chemistry II,
Vol. 3; Shinkai, I., Ed.; Elsevier Science: Oxford, 1996,
Chap. 8. (b) Wirth, T. Organoselenium Chemistry, Modern
Developments in Organic Synthesis; Springer: Berlin, 2000.
(c) Koketsu, M.; Nada, F.; Ishihara, H. Synthesis 2002, 195;
and references cited therein.
Synlett 2002, No. 12, 1983–1986 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
Efficient Synthesis of Primary Selenocarboxylic Amides
1985
Table 2 Yields of Selenocarboxylic Amides 2 and 1,3-Selenazoles 3
2/3
a
b
c
R1
Appearance (Crystallization solvent) Mp (°C)
% (2)a
84
30
27
20
40
81
37
18
36
41
47
33
55
52
42
58
35
22
48
57
73
70
26
37
59
R2
% (3)a
87
93
53
61
100
61
93
61
81
–
Ph
Golden needles (C6H6/PE)
Yellow needles (C6H6/PE)
Colorless prisms (C6H6)
Colorless prisms (C6H6)
Colorless needles (C6H6/PE)
Yellow prisms (C6H6/PE)
Colorless needles (C6H6/PE)
Golden needles (EtOH)
Orange lamella (DMF/H2O)
Brown needles (EtOH)
Yellow prisms (EtOH)
Colorless liquid
125–126
109–111
125–126
56–57
Ph
2-(H3C)C6H4
Me
Ph
4-BrC6H4
d
e
Et
Me
PhCH2
92–93
Ph
f
Ph2CH
148–150
143–144
146–147
142–143
108–109
120–122
Dec.
H
g
h
i
2-Pyridyl
3-Pyridyl
4-Pyridyl
(NC)CH2
H2NC(=O)CH2
(EtO2C)CH2
H2NC(=NH)NH
H2NC(=Se)CH2
PhCH=CH
tBu
Ph
4-BrC6H4
4-BrC6H4
j
–
k
l
Ph
95
74
–
4-(O2N)C6H4
m
n
o
p
q
r
Grey prisms (EtOH)
162–164
Dec.
–
Yellow needles (DMF/CHCl3)
Colorless liquid
–
–
Dec.
Me
61
–
Colorless needles (C6H6)
Yellow prisms (EtOH)
Yellow prisms (EtOH)
Yellow lamella (toluene/PE)
Yellow needles (H2O)
Colorless needles (C6H6)
132–133
130–132
127–128
106–108
175–176
94–96
–
1-Naphthyl
4-(H2N)C6H4
2-(HO)C6H4
4-(HO)C6H4
4-ClC6H4CH2
Ph
80
87
29
25
73
86
54
87
–
Ph
s
H
t
H
u
v
w
x
y
4-BrC6H4
4-(H3C)C6H4
4-BrC6H4
Ph
4-(O2N)C6H4CH2 Yellow needles (EtOH)
219–221
130–133
204–206
195–197
Cyclohexyl
H2N
Colorless needles (C6H6)
Colorless needles (H2O)
Colorless needles (EtOH)
b
(H2N)CH2
–
a Isolated yields of free amide.
b Isolated yield of hydrobromide.
(3) (a) Lai, L.-L.; Reid, D. H. Synthesis 1993, 870.
(b) Klayman, D. L.; Griffins, T. S. J. Am. Chem. Soc. 1973,
95, 197. (c) For the use of LiAlH4/Se, see: Ishihara, H.;
Koketsu, M.; Fukuta, Y.; Nada, F. J. Am. Chem. Soc. 2001,
123, 8408. (d) Also see: Koketsu, M.; Fukuta, Y.; Ishihara,
H. Tetrahedron Lett. 2001, 42, 6333.
(4) Ogawa, A.; Miyaka, J.; Karasaki, Y.; Murai, S.; Sonoda, N.
J. Org. Chem. 1985, 50, 384.
(5) Kaminski, R.; Glass, R. S.; Skowronska, A. Synthesis 2001,
1308.
often not complete and strongly depends on the particle size
of aluminum and on many other parameters: Brauer, B.
Handbuch der präparativen anorganischen Chemie; Ferd.
Enke Verlag: Stuttgart, 1960, 732. (b) It is necessary, but
extremely difficult to remove remaining aluminum. In
addition, Al2Se3 is very prone to hydrolysis and has to be
handled with great care (glove box). Since it has to be used
as a powder, substantial decomposition readily occurs and
impurities cannot be separated.
(8) For the synthesis of thioamides from amides, see: Raucher,
(6) Cohen, V. J. Synthesis 1978, 668.
S.; Klein, P. J. Org. Chem. 1981, 46, 3558.
(7) This can have several reasons: (a) We have found that the
aluminothermic formation of Al2Se3 from the elements is
Synlett 2002, No. 12, 1983–1986 ISSN 0936-5214 © Thieme Stuttgart · New York

1986
K. Geisler et al.
LETTER
(9) For the synthesis of N,N-disubstituted selenocarboxylic
amides, see: (a) Collhard-Charon, C.; Renson, M. Bull. Soc.
Chim. Belg. 1963, 72, 304. (b) Jensen, K. A.; Nielsen, P. H.
Acta Chim. Scand. 1966, 20, 597. (c) See also: Sukhai, R.
S.; de Jong, R.; Brandsma, L. Synthesis 1977, 888.
NH), 6.78–7.22 (m, 4 H, Ar), 8.20 (br, 1 H, NH). 13C NMR
(C6D6, 75 MHz): c 19.67 (CH3), 125.67, 125.68, 126.22,
126.24, 128.99, 130.70 (Ar), 210.46 (C=Se). IR (KBr, cm–1):
1620 (s), 1420 (s), 1290 (m), 1265 (w), 1230 (w), 1155 (w),
1130 (w), 1045 (w), 855 (m). MS (70 eV): m/z (%): 199
(100, M+). Anal. calcd. for C8H9NSe (198.13): C 48.50, H
4.58, N 7.07, Se 38.86; found C 48.50, H 4.30, N 7.10, Se
39.50. All new compounds gave satisfactory analytical or
high resolution mass data.
Synthesis of P2Se5: A mixture of red phosphorous and grey
selenium powder was heated in a tube with minor Bunsen
burner flame until the reaction was complete. The reaction
mixture was grounded and powdered to give P2Se5 as a grey
solid. For comparison, see: Kudchadker, M. V.; Zingaro, R.
A.; Irgolic, K. J. Can. J. Chem. 1968, 46, 1415.
(10) General procedure for the preparation of selenocarboxylic
amides: Method A (for 2a–2t): An ethanol solution (15–30
mL) of the nitrile (50 mmol) and of freshly prepared P2Se5
(9.1 g, 20 mmol) was refluxed. Subsequently, water (3–6
mL) was added dropwise during 2–3 h. After cooling, the
solution was filtered and water was added to the filtrate
which resulted in precipitation of the selenocarboxylic
amide 2. In some cases, the aqueous layer was extracted with
ether or benzene. The combined organic layers were dried
(Na2SO4), filtered and concentrated. Cooling (dry ice) or
addition of petroleum ether resulted in crystallization of the
product. The crude product was dried (desiccator, P2O5) and
crystallized from the solvent indicated (Table 2).
(11) Typical procedure for the preparation of 1,3-selenazoles: An
EtOH solution (20 mL) of selenobenzamide (1.84 g, 10
mmol) and -bromoacetophenone (1.99 g, 10 mmol) was
stirred under evolution of heat. After cooling, the mixture
was poured into H2O. The precipitated product was filtered
off and recrystallized from EtOH to give 3a as colorless
lamella (2.47 g, 87%).
Method B (for 2u–2y): The nitrile (50 mmol) was dissolved
in ethanol (15–30 mL) and water (3–6 mL). To the refluxing
solution was added freshly prepared P2Se5 (9.1 g, 20 mmol)
in small portions during 2–3 h. The solution was cooled and
filtered. Water was added to the filtrate which resulted in
precipitation of the selenocarboxylic amide 2. In some cases,
the aqueous layer was extracted with benzene. The
Spectroscopic data of 2,4-diphenyl-1,3-selenazole (3a): mp:
99 °C. 1H NMR (CDCl3, 300 MHz): 7.38–8.01 (m, 10 H,
Ar), 8.06 (s, 1 H, 5-H). 2J (SeH) = 58.3 Hz. 13C NMR
(CDCl3, 75 MHz): c 118.26, 126.72, 127.08, 127.91,
128.70, 128.97, 130.21, 135.42, 136.41, 156.93, 173.87. 77Se
NMR (CDCl3, 100% Me2Se): 712.69 (2JSe-H = 58.3 Hz). IR
(KBr, cm–1): 3114 (m), 1598 (s), 1509 (s), 1481 (s), 1442 (s),
1279 (m), 1152 (m), 1071 (m), 1043 (s), 1027 (m), 952 (s).
MS (70 eV): m/z (%): 285 (59, M+), 182 (100), 102 (86).
Anal. calcd. for C15H11NSe (284.22): C 63.39, H 3.90, N
4.93; found C 63.45, H 3.92, N 4.91. All new compounds
gave satisfactory analytical or high resolution mass data.
combined organic layers were dried (Na2SO4), filtered and
concentrated. Cooling (dry ice) or addition of petroleum
ether resulted in crystallization of the product. The crude
product was dried (exsiccator, P2O5) and crystallized from
the solvent indicated (Table 2). For 2x, only water was used
as the solvent. In case of 2x and 2y, the hot solution was
filtered without prior cooling. Concentration of the filtrate
resulted in precipitation of the pure product.
Spectroscopic data of 2-methyl-selenobenzamide (2b): 1H
NMR (C6D6, 300 MHz): 2.15 (s, 3 H, CH3), 5.90 (br, 1 H,
Synlett 2002, No. 12, 1983–1986 ISSN 0936-5214 © Thieme Stuttgart · New York