Syntheses of N-substituted thymine thioacetamides. A novel approach to site selective acylation of diaminoalkanes

Article abstract of DOI:10.1016/S0040-4020(00)00704-3

A new series of N-substituted thiocarbamoyl derivatives containing histamine, tryptamine, and other moieties having at least one amino group attached to an aliphatic chain, has been synthesized from (1-thyminyl)thioacetamide in good isolated yields (69-86%). N-[2-(4-Imidazolyl)ethyl](1-thyminyl)thioacetamide was hydrolyzed to its amide on prolonged heating in water. Ammonium sulfide (20-22% solution in water) has found interesting new applications in the efficient synthesis of N-[2-(3-indolyl)ethyl](1-thyminyl)thioacetamide and site selective acylation of diaminoalkanes, starting directly from nitriles. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4020(00)00704-3

TETRAHEDRON
Pergamon
Tetrahedron 56 (2000) 7981±7986
Syntheses of N-Substituted Thymine Thioacetamides. A Novel
Approach to Site Selective Acylation of Diaminoalkanes
*
Jarosøaw Spychaøa
Â
Adam Mickiewicz University, Department of Chemistry, Grunwaldzka 6, 60-780 Poznan, Poland
Received 30 May 2000; revised 17 July 2000; accepted 3 August 2000
AbstractÐA new series of N-substituted thiocarbamoyl derivatives containing histamine, tryptamine, and other moieties having at least one
amino group attached to an aliphatic chain, has been synthesized from (1-thyminyl)thioacetamide in good isolated yields (69±86%). N-[2-(4-
Imidazolyl)ethyl](1-thyminyl)thioacetamide was hydrolyzed to its amide on prolonged heating in water. Ammonium sul®de (20±22%
solution in water) has found interesting new applications in the ef®cient synthesis of N-[2-(3-indolyl)ethyl](1-thyminyl)thioacetamide
and site selective acylation of diaminoalkanes, starting directly from nitriles. q 2000 Elsevier Science Ltd. All rights reserved.
Introduction
purposes.3 The corresponding products 3 were obtained by
re¯uxing readily available (1-thyminyl)thioacetamide (1)
with a primary amine 2 in ethanol by employing approxi-
mately equimolar quantities of the reactants. The bases used
included several mono-substituted aliphatic diamines,
histamine, tryptamine, and 4-aminophenethylamine. Puri®-
cation was effected by recrystallization from methanol or
water. The products were isolated as free bases or their
hydrochloride salts. N-substituted thioamides can be readily
hydrolyzed by the action of bases.4 N-[2-(4-Imidazolyl)-
ethyl](1-thyminyl)thioacetamide (3e) lost sulfur by itself,
simply by heating in water for an extended time (an imida-
zole residue as a desulfurizing agent). Therefore, care must
be taken when crystallizing the products having basic
groups from water. It is of interest to note that thioacetamide
3a did not show any tendency to cyclize into a N-methyl-
tetrahydropyrimidine derivative, even after long re¯uxing.
As will be shown below, a simple and general procedure is
ef®cient for the formation of 3.
The search for new thymine chemotherapeutical agents, has
stimulated tremendous efforts towards the synthesis of
nucleoside analogues over the past decade. In general,
these compounds have been designed as antimetabolites
through isosteric substitution or through modi®cation of
the sugar moiety.1 Considerable interest has been focused
on different sulfur analogues.2 Hitherto, no report has been
encountered on the preparation of N-substituted thymine
thioacetamides which would deal with a study of the
Wallach reaction.
Results and discussion
The preparation of the new title compounds is outlined in
Scheme 1. The substitution of one amino group by another
one to form N-substituted thioamides was used for synthetic
Scheme 1.
Keywords: Wallach reaction; thioamides; amides; uracils.
* Corresponding author. Tel.: (4861)8291370; fax: (4861)8658008.
0040±4020/00/$ - see front matter q 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(00)00704-3

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J. Spychal¤a / Tetrahedron 56 (2000) 7981±7986
Scheme 2. (1) Addition; (2) substitution of the amino group; (3) hydrolysis.
Scheme 3.
In contrast to literature data,5 the above examples support a
general mechanism. Treatment of a nitrile with one
equivalent of ammonium sul®de yields a primary thio-
amide,6,7 which on successive treatment with an appropriate
primary amine affords N-substituted thioamide. The forma-
tion of products is dependent on the nature of the N-sub-
stituents. For RˆNH2 the amide was found to be the only
product and N-substituted thioamide was only an inter-
mediate in the reaction, the elimination of hydrogen sul®de
was performed by re¯uxing in aqueous solution (see a
reaction sequence in Scheme 2. It has been suggested
previously that the reaction proceeds via a N-substituted
simple amidine intermediate (instead of a N-substituted
thioamide) followed by a nucleophilic substitution of the
mercapto group. This suggestion was supported by the
fact that simple amidines can be obtained sometimes by
treating some nitriles or thioamides with ammonium sul®de
or amines, respectively.8 1-(4-Amidinobutyl)thymine (6)
was also isolated from a mixture of 1-(4-cyanobutyl)-
thymine (5) and an excess of aqueous ammonium sul®de-
pyridine after prolonged standing at room temperature.
However, the syntheses of 3, 10, and 12 require heating
under re¯ux and therefore, no simple amidine intermediate
was observed. Formation of 4-(thiocarbamoyl)benzamide
(8) from 4-amidinobenzamide (7) and aqueous (NH4)2S
even at room temperature indicates why no evidence of
the simple amidine intermediate was obtained (Scheme 3).
This result is in accord with previous observations.9
Commercially available 20±22% ammonium sul®de
aqueous solution has already found applications for the
preparation of several unsubstituted thioamides.6,7 As
will be shown below in Scheme 4, N-[2-(3-indolyl)-
ethyl](1-thyminyl)thioacetamide (3f) can be readily
prepared by direct reaction of a nitrile with a primary mono-
amine in the presence of small excess of (NH4)2S in water-
ethanol. This procedure is an example of the synthesis of
N-substituted thioamides by the use of nitriles under
aqueous conditions. Other literature reactions took the
same course under anhydrous conditions.10
Unfortunately, the above new method offers no advantage
for the preparation of all products 3. When a basic group
was attached to the N-substituent, self-desulfurization
occurred under the reaction conditions. The amide 10
resulted in good yield from a site selective reaction of 9
with ethylenediamine in ethanol-ammonium sul®de,
20±22% solution in water. Such a reaction was to be
expected in view of an earlier published work.5 It has
recently been shown that a similar reaction proceeded
under anhydrous conditions and afforded cyclized amidines
upon substitution and cyclization (N-substituted thioamide
intermediate was involved in the reaction).11,12 Syntheses
from (1-uracilyl and 1-thyminyl)acetonitriles (9) are
presented in Scheme 4.
The application of the (NH4)2S-acylation method was
Scheme 4.
Scheme 5.

J. Spychal¤a / Tetrahedron 56 (2000) 7981±7986
7983
extended for the preparation of a new dicationic diaryl furan
molecule. 2,5-Bis{4-[N-(3-amino-2-hydroxypropyl)carba-
moyl]phenyl}furan dihydrochloride (12) was obtained in
excellent 91% yield in a one-step reaction starting from
2,5-bis(4-cyanophenyl)furan (11) and 1,3-diamino-2-hydroxy-
propane (Scheme 5).
after the heating had begun. After cooling in the refrigerator,
the solid was ®ltered off, washed with cold water, and
recrystallized from hot water (3e), methanol (3b, 3c, 3d,
3f, 3g), methanol/2-propanol (3a) to afford colourless crys-
tals. The free base 3a was not cyclized on re¯uxing for
additional twenty hours in ethanol and only the starting
material was recovered. 3a was acidi®ed with 1N hydro-
chloric acid. The solution was evaporated to dryness and
the residue recrystallized from methanol. Product precipi-
tated out on cooling as a white solid.
Conclusion
In conclusion, the procedures presented appear to offer
considerable utility for the simple synthesis of a new series
of 1-substituted thymines from readily available substrates
by using the Wallach reaction. An alternative preparative
route was available for some of these products. (1-Uracilyl
and 1-thyminyl)acetonitriles found here new applications as
site selective acylating agents for the synthesis of mono-
substituted diaminoalkanes. The procedure presented was
particularly advantageous in the preparation of the more
substituted diamide derivative. The products of these reac-
tions are valuable for the general mechanism. An analytical
reagent-(NH4)2S, 20±22% solution in water, proved to be a
useful tool in organic syntheses.
N-[3-(Methylamino)propyl](1-thyminyl)thioacetamide
hydrochloride (3a ´ HCl). 75%; mp 250±2518C (dec.); dH
1.76 (d, 3H, Jˆ0.9 Hz, CH3), 2.70±2.90 (m, 6H,
CH2CH2NH1HCH3), 3.32 (t, 2H, Jˆ6.4 Hz, CH2CH2N),
3.94 (dt, 2H, Jˆ5.8, 5.8 Hz, CSNHCH2), 4.62 (s, 2H,
NCH2CS), 7.46 (d, 1H, Jˆ1.2 Hz, C6H), 10.49 (m, 2H,
CSNH, intramolecular (d1)SvC(d2)´´´´´´´´´H1NHCH3
bonds), 11.29 (br s, 1H, N3H); dC 11.8, 39.9, 42.2 (double
intensity), 53.6, 55.8, 108.1, 142.6, 151.2, 164.8, 199.0; dH
[D2O, (CH3)3Si(CH2)3SO3Na] 1.90 (s, 3H, CH3), 2.87±3.02
(m, 5 H, CH2CH2NCH3), 3.51 (t, 2H, Jˆ6.2 Hz, CH2CH2N),
4.13 (t, 2H, Jˆ6.2 Hz, CSNHCH2), 4.75 (s, 2H, NCH2CS),
7.45 (d, 1H, Jˆ1.1 Hz, C6H); dC (D2O, (CH3)3Si(CH2)3-
SO3Na) 14.0, 43.0, 45.7, 45.8, 57.4, 59.6, 113.4, 146.0,
154.9, 169.4, 202.0; HRMS (EI): M1, found 270.1156.
C11H18N4O2S requires 270.1151. The product gave a nega-
tive ninhydrin test for primary amine.
Experimental
Melting points are uncorrected and were determined by
using Boetius melting-point apparatus. NMR spectra were
recorded on Varian Gemini 300 MHz (75.5 MHz for 13C)
spectrometer in DMSO-d6 with TMS as a standard (unless
indicated otherwise), while IR spectra on a FT-IR Bruker
113 V spectrometer. High resolution mass spectra were
made in AMD 402 or 602 mass spectrometers by using EI
or FAB modes, respectively. Thin-layer chromatography
was performed with Merck silica gel 60F254 glass plates
(0.25 mm thickness) in three solvent systems: 44:8:1,
11:4:1, or 7:5:2 CHCl3±CH3OH±NH4OH (chloroform was
distilled from P2O5). All compounds showed a single spot
on TLC visualized with UV absorption (254 nm). The
primary amines gave a positive reaction with 0.2% nin-
hydrin ethanolic solution. Amines 2 [a) N-methylpropane-
diamine, b) 3-(dimethylamino)propylamine, c) 1-(2-amino-
ethyl)piperidine, d) 4-(2-aminoethyl)morpholine, e) hista-
mine, f) tryptamine, g) 2-(4-aminophenyl)ethylamine],
1,3-diamino-2-hydroxypropane, ethylenediamine, and
4-amidinobenzamide hydrochloride (7) were purchased
from Aldrich. Ammonium sul®de, 20-22% solution in
water was commercially available from Merck. The follow-
ing chemicals: (1-thyminyl)thioacetamide (1),6 1-(4-cyano-
N-[3-(Dimethylamino)propyl](1-thyminyl)thioacetamide
(3b). 79%; mp 199±2028C (dec.); dH 1.69 (quintet, 2H,
Jˆ7.0 Hz, CH2CH2CH2), 1.76 (d, 3H, Jˆ0.8 Hz, CH3),
2.11 (s, 6H, CH3NCH3), 2.25 (t, 2H, Jˆ6.9 Hz,
CH2CH2N), 3.55 (br m, 2H, CSNHCH2), 4.56 (s, 2H,
NCH2CS), 7.43 (d, 1H, Jˆ1.1 Hz, C6H), 10.21 (br s, 1H),
11.29 (br s, 1H, N3H); dC 12.0, 24.8, 44.1, 45.1, 56.0, 56.8,
107.9, 142.5, 151.0, 164.6, 196.5; HRMS (EI): M1, found
284.1319. C12H20N4O2S requires 284.1307.
N-[2-(1-Piperidino)ethyl](1-thyminyl)thioacetamide (3c).
86%; mp 237±2388C (dec.); dH 1.37 (m, 2H, piperidine
C4H), 1.48 (m, 4H, piperidine C3H and C5H), 1.76 (s,
3H, CH3), 2.35 (m, 4H, piperidine C2H and C6H), 2.46 (t,
2H, Jˆ6.9 Hz, CH2CH2N), 3.63 (t, 2H, Jˆ6.7 Hz,
CSNHCH2), 4.56 (s, 2H, NCH2CS), 7.41 (d, 1H, Jˆ
1.1 Hz, C6H), 10.03 (br s, 1H, CSNH), 11.27 (br s, 1H,
N3H); dC 12.0, 24.0, 25.5, 42.8, 53.9, 55.5, 55.8, 107.7,
142.3, 150.7, 164.3, 196.5; HRMS (EI): M1, found
310.1487. C14H22N4O2S requires 310.1464.
butyl)thymine (5),12 (1-uracilyl)acetonitrile
(9a),13
N-[2-(4-Morpholino)ethyl](1-thyminyl)thioacetamide (3d).
74%; mp 2268C; dH 1.76 (d, 3H, Jˆ0.8 Hz, CH3), 2.39 (m,
4H, morpholine C3H and C5H), 2.51 (t, 2H, Jˆ6.6 Hz,
CH2CH2N), 3.57 (m, 4H, morpholine C2H and C6H), 3.66
(dt, 2H, Jˆ6.5, 5.2 Hz, CSNHCH2), 4.57 (s, 2H, NCH2CS),
7.42 (d, 1H, Jˆ1.1 Hz, C6H), 10.08 (br t, 1H, CSNHCH2),
11.27 (br s, 1H, N3H); dC 12.0, 42.4, 53.2, 55.2, 55.8, 66.1,
107.7, 142.3, 150.7, 164.3, 196.7; HRMS (EI): M1, found
312.1271. C13H20N4O3S requires 312.1256.
(1-thyminyl)acetonitrile (9b),6,14 and 2,5-bis(4-cyano-
phenyl)furan (11)15 were prepared by known methods.
All ®nal samples were dried in a vacuum oven.
General procedure for the synthesis of N-substituted
thymine thioacetamides 3
In a typical experiment (1-thyminyl)thioacetamide (1, 1 g,
0.0051 mol) was suspended in a solution of a primary amine
(2, 0.0051 mol) in ethanol (10 mL). The reaction mixture
was then heated under re¯ux with stirring for 18 h under
anhydrous conditions. Evolution of ammonia was noticed
N-[2-(4-Imidazolyl)ethyl](1-thyminyl)thioacetamide (3e).
77%; mp 245±2468C (dec.); dH 1.77 (s, 3H, CH3), 2.81 (t,
2H, Jˆ7.3 Hz, CH2CH2C), 3.74 (dt, 2H, Jˆ7.2, 5.2 Hz,

7984
J. Spychal¤a / Tetrahedron 56 (2000) 7981±7986
CSNHCH2), 4.58 (s, 2H, NCH2CS), 6.85 (s, 1H, imidazole
C5H), 7.42 (d, 1H, Jˆ0.8 Hz, C6H), 7.53 (d, 1H, Jˆ 1.1 Hz,
imidazole C2H), 10.31 (br t, 1H, Jˆ4.8 Hz, CSNHCH2),
11.30 (s, 1H, N3H), 11.87 (br s, 1H, imidazole NH); dC
12.0, 25.0, 45.3, 55.9, 107.9, 116.8, 134.7 (double intensity),
142.5, 151.0, 164.6, 196.7; HRMS (EI): M1, found
293.0954. C12H15N5O2S requires 293.0946.
166.8; HRMS (EI): M1, found 277.1179. C12H15N5O3
requires 277.1175.
Reactions of 1-(cyanobutyl)thymine (5) and
4-amidinobenzamide (7) with ammonium sul®de
1-(4-Amidinobutyl)thymine hydrochloride (6). The start-
ing nitrile 5 (3.42 g, 0.0165 mol) was dissolved in pyridine
(17 mL) and (NH4)2S, 20±22% solution in water (5.6 mL)
was added. This solution was left to stand at ambient
temperature over several months and examined by TLC
with 7:5:2 CHCl3±CH3OH±NH4OH as developing
solvents. Removal of the solvents at room temperature
gave an amidine. Solid free base was washed with cold
water and changed into its white hydrochloride salt 6
(22%, not optimized) with 1N hydrochloric acid±tetra-
hydrofuran, mp 2068C; dH 1.60 (m, 4H, CH2CH2), 1.76 (s,
3H, CH3), 2.42 (m, 2H, CH2CNH2), 3.66 (m, 2H, N1CH2),
7.62 (d, 1H, Jˆ1.1 Hz, C6H), 8.77 (s, 2H, HNC1NH,
restricted rotation16), 9.11 (s, 2H, HNC1NH), 11.26 (s,
1H, N3H); dC 11.9, 23.2, 27.5, 31.2, 46.6, 108.5, 141.5,
150.9, 164.3, 170.8; HRMS (EI): M1, found 224.1261.
C10H16N4O2 requires 224.1273.
N-[2-(3-Indolyl)ethyl](1-thyminyl)thioacetamide
(3f).
70%; mp 220±2218C (dec.); dH 1.77 (s, 3H, CH3), 3.01 (t,
2H, Jˆ7.4 Hz, CH2CH2C), 3.81 (dt, 2H, Jˆ7.4, 5.5 Hz,
CSNHCH2), 4.59 (s, 2H, NCH2CS), 7.00 (dt, 1H, Jˆ7.4,
0.8 Hz, indole H4), 7.08 (dt, 1H, Jˆ7.4, 1.1 Hz, indole
H5), 7.20 (d, 1H, Jˆ2.2 Hz, indole H2), 7.35 (d, 1H,
Jˆ8.0 Hz, indole H3), 7.40 (d, 1H, Jˆ1.1 Hz, C6H), 7.60
(d, 1H, Jˆ7.7 Hz, indole H6), 10.30 (br t, 1H, Jˆ5.2 Hz,
CSNHCH2), 10.88 (br s, 1H, indole NH), 11.29 (s, 1H,
N3H); dC 12.0, 23.0, 46.0, 55.9, 107.9, 111.2, 111.4,
118.3, 118.4, 121.0, 122.9, 127.1, 136.2, 142.6, 151.0,
164.6, 196.8; HRMS (FAB, dithioerythritol, dithiothreitol,
glycerol): MH1, found 343.1223. C17H19N4O2S requires
343.1229.
N-[2-(4-Aminophenyl)ethyl](1-thyminyl)thioacetamide
(3g). 69%; mp 225±2278C; dH 1.77 (d, 3H, Jˆ0.8 Hz, CH3),
2.70 (t, 2H, Jˆ7.4 Hz, CH2CH2C), 3.63 (dt, 2H, Jˆ7.2,
5.9 Hz, CSNHCH2), 4.56 (s, 2H, NCH2CS), 4.91 (s, 2H,
NH2), 6.51 (d, 2H, J 8.2 Hz, benzene CH), 6.90 (d, 2H,
Jˆ8.2 Hz, benzene CH), 7.41 (d, 1H, Jˆ1.1 Hz, C6H),
10.23 (br t, 1H, Jˆ4.9 Hz, CSNHCH2), 11.26 (br s, 1H,
N3H); dC 11.9, 32.1, 47.2, 55.8, 107.9, 114.1, 125.7,
129.1, 142.7, 147.1, 151.1, 164.8, 197.0; HRMS (EI): M1,
found 318.1168. C15H18N4O2S requires 318.1151. The hy-
drochloride salt of 3g was crystallized from water, mp 234±
2358C; dH 1.76 (d, 3H, Jˆ0.9 Hz, CH3), 2.91 (t, 2H,
Jˆ7.3 Hz, CH2CH2C), 3.74 (dt, 2H, Jˆ7.1, 5.6 Hz,
CSNHCH2), 4.57 (s, 2H, NCH2CS), 7.25 (d, 2H,
Jˆ8.5 Hz, benzene CH), 7.35 (d, 2H, Jˆ8.5 Hz, benzene
CH), 7.42 (d, 1H, Jˆ 1.1 Hz, C6H), 9.94 (br s, 3H, NH13 ),
10.35 (br t, 1H, Jˆ5.1 Hz, CSNHCH2), 11.28 (s, 1H, N3H).
4-(Thiocarbamoyl)benzamide (8).17 For the purpose of
experimental veri®cation of the mechanism, the mixture
of amidine 7 (2.1578 g, 0.0108 mol) and ammonium sul®de,
20±22% solution in water (10 mL) was reacted and moni-
tored by TLC (9:1 CHCl3±CH3OH) as above. The crude
product was recrystallized from methanol to afford yellow
crystals (75%); mp 224±2258C (dec.); dH 7.52 (s, 1H,
CONH), 7.83±7.96 (m, 4H, C6H4), 8.10 (s, 1H, CONH),
9.63 (br s, 1H, CSNH), 10.01 (br s, 1H, CSNH); HRMS
(EI): M1, found 180.0371. C8H8N2OS requires 180.0357.
Syntheses directly from acetonitriles 9
N-[2-(3-Indolyl)ethyl](1-thyminyl)thioacetamide (3f) was
obtained here by the second approach directly from
(1-thyminyl)acetonitrile (9b, 2 g, 0.0121 mol) and trypta-
mine (2f, 1.9403 g, 0.0121 mol) in ethanol (30 mL) by
re¯uxing for 18 hours with stirring in the presence of
ammonium sul®de, 20±22% in water (5 mL). The crude
product was washed with 2-propanol and worked up as
described above for 3. It was puri®ed by repeated recrystal-
lization from methanol to provide the desired product after
standing for several days in the refrigerator (72%).
Hydrolysis of N-[2-(4-imidazolyl)ethyl](1-thyminyl)-
thioacetamide (3e)
The thioamide (3e, 100 mg, 0.34 mmol) in water (10 mL)
was re¯uxed vigorously with stirring for 30 hours during
which time hydrogen sul®de evolved. The hydrolysis
mixture was evaporated to dryness. The residue was
dissolved in hot methanol (ca. 60 mL), ®ltered, diluted
with 2-propanol, and concentrated by distillation to a
smaller volume. The crystals separated upon standing in
the refrigerator, were collected by ®ltration and washed
with 2-propanol to afford chromatographically pure amide
4e (75 mg).
N-(2-Aminoethyl)(1-uracilyl)acetamide hydrochloride
(10a). One hour re¯uxing of (1-uracilyl)acetonitrile (9a,
2.1559 g, 0.0143 mol), ethylenediamine (0.8574 g, 0.0143
mol), ammonium sul®de, 20±22% solution in water
(5.8 mL), in ethanol (40 mL) resulted in precipitation of
the title compound. 2-Propanol (10 mL) was added and
the reaction ¯ask was kept in the refrigerator. The free
base was collected by ®ltration and changed into its hydro-
chloride salt with 1N hydrochloric acid solution. After
evaporation to dryness, the product was recrystallized
from methanol to yield pure colourless material (74%),
mp 224±2258C; nmax(KBr) 3297, 3099, 1668, 1562, 1472,
1457, 1428, 1383, 1355, 1241, 1213, 1176 cm21; dH 2.85 (t,
2H, Jˆ6.4 Hz, CH2CH2NH13 ), 3.35 (dt, 2H, J 6.1, 5.9 Hz,
NHCH2CH2), 4.38 (s, 2H, NCH2CO), 5.57 (d, 1H,
N-[2-(4-Imidazolyl)ethyl](1-thyminyl)acetamide
(4e).
79%; mp 249±2518C (dec.); dH 1.76 (d, 3H, Jˆ0.8 Hz,
CH3), 2.65 (t, 2H, Jˆ7.4 Hz, CH2CH2C), 3.30 (dt, 2H,
Jˆ7.4, 5.8 Hz, CONHCH2), 4.27 (s, 2H, NCH2CO), 6.85
(s, 1H, imidazole C5H), 7.44 (d, 1H, Jˆ1.1 Hz, C6H),
7.62 (s, 1H, imidazole C2H), 8.25 (br t, 1H, Jˆ5.4 Hz,
CONHCH3), 11.31 (br s, 1H, N3H); dC 11.9, 26.7, 38.9,
49.4, 108.0, 116.7, 134.2, 134.6, 142.4, 151.1, 164.6,

J. Spychal¤a / Tetrahedron 56 (2000) 7981±7986
7985
T. K.; D'Cruz, O. J.; Uckun, F. M. Antiviral Chem. Chemother.
2000, 11, 31±39; Siddiqui, A.; McGuigan, C.; Ballatore, C.;
Srinivasan, S.; De Clercq, E.; Balzarini, J. Bioorg. Med. Chem.
Lett. 2000, 10, 381±384. Naundorf, A.; Natsch, S.; Klaffke, W.
Tetrahedron Lett. 2000, 41, 189±192; Onishi, T.; Mukai, C.;
Nakagawa, R.; Sekiyama, T.; Aoki, M.; Suzuki, K.; Nakazawa,
H.; Ono, N.; Ohmura, Y.; Iwayama, S.; Okunishi, M.; Tsuji, T.
J. Med. Chem. 2000, 43, 278±282; Bender, D. M.; Hennings, D. D.;
Williams, R. M. Synthesis 2000, 399±402; Inagaki, J.; Sakamoto,
H.; Nakajima, M.; Nakamura, S.; Hashimoto, S. Synlett 1999,
1274±1276.
 Ã
2. Saintome, C.; Clivio, P.; Fourrey, J.-L.; Woisard, A.; Laugaa,
P.; Favre, A. Tetrahedron 2000, 56, 1197±1206; Chamorro, C.;
Â
De Clercq, E.; Balzarini, J.; Camarasa, M.-J.; San-Felix, A. Anti-
viral Chem. Chemother. 2000, 11, 61±69; Wojczewski, C.; Engels,
J. W. Synthesis 2000, 149±153; Luo, J.; Bruice, T. C. J. Biomol.
Jˆ7.8 Hz, C5H), 7.61 (d, 1H, Jˆ7.8 Hz, C6H), 8.17 (br s,
3H, NH13 ), 8.54 (br t, 1H, Jˆ5.6 Hz, CONHCH2), 11.24 (br
s, 1H, N3H); dC 36.5, 38.4, 49.4, 100.6, 146.6, 151.1, 163.9,
167.6; HRMS (FAB, 3-nitrobenzyl alcohol): MH1, found
213.1000. C8H13N4O3 requires 213.0988.
N-(2-Aminoethyl)(1-thyminyl)acetamide hydrochloride
(10b). This product was obtained by analogy to 10a after
overnight heating under re¯ux (78%), mp 238±2398C;
n
max(KBr) 3420, 3246, 3093, 2996, 1671, 1642, 1593,
1570, 1481, 1422, 1361, 1252, 1176 cm21; dH 1.75 (d,
3H, Jˆ1.1 Hz, CH3), 2.86 (t, 2H, Jˆ6.4 Hz, CH2CH2NH13 ),
3.35 (dt, 2H, Jˆ6.1, 5.9 Hz, NHCH2CH2), 4.34 (s, 2H,
NCH2CO), 7.50 (d, 1H, Jˆ1.2 Hz, C6H), 8.21 (br s, 3H,
NH13 ), 8.53 (br t, 1H, Jˆ5.5 Hz, CONHCH2), 11.31 (br s,
1H, N3H); dC 12.0, 36.5, 38.4, 49.3, 108.0, 142.3, 151.1,
164.5, 167.6; HRMS (FAB, 3-nitrobenzyl alcohol): MH1,
found 227.1129. C9H15N4O3 requires 227.1144. The salts 10
were fairly water-soluble solids. The spots were also
detected by spraying the TLC plates with 0.2% ninhydrin
ethanolic solution and heating (44:8:1 CHCl3±CH3OH±
NH4OH).
Â
Â
Structure Dyn. 2000, 17, 629±631; Valazquez, S.; Tunon, V.;
Jimeno, M. L.; Chamorro, C.; De Clercq, E.; Balzarini, J.;
Camarasa, M. J. J. Med. Chem. 1999, 42, 5188±5196; Hopkins,
A. L.; Ren, J.; Tanaka, H.; Baba, M.; Okamato, M.; Stuart, D. I.;
Stammers, D. K. J. Med. Chem. 1999, 42, 4500±4505.
3. Wallach, O. Ann. 1891, 262, 356; Schlatter, M. J. J. Am. Chem.
Soc. 1942, 64, 2722; Hurd, R. N.; DeLaMater, G. Chem. Rev. 1961,
61, 45±86; Chabrier, P.; Renard, S. H. Bull. Soc. Chim. France
1949, D272±296; Duus, F. In Thiocarbonyl Compounds; Jones,
D. N., Ed.; Comprehensive Organic Chemistry, Vol. 3. Pergamon:
Oxford, 1979; pp. 374±487; Owton, W. M. In N-Substituted
Thionoamides and Their Se and Te Analogs; Katritzky, A. R.,
Meth-Cohn, O., Rees, C. W., Eds.; Compr. Org. Funct. Group
Transform. Elsevier: Oxford, 1995; pp. 629±645, 1161±1308;
Westphal, K.; Andersag, H. Ger. Patent 701,901, Chem. Z. 1941,
1, 3005, Chem. Abstr. 1942, 36, 982; I. G. Farbenindustrie
Akt.-Ges. Dan. Patent 57 825, Chem. Z. 1940, 2, 2960; Westphal,
K.; Andersag, H. Can. Patent 392,513, 1940, Chem. Abstr. 1941,
35, 14135; Westphal, K.; Andersag, H. US Patent 2,265,212,
Chem. Abstr. 1942, 36, 19504.
Synthesis of dicationic diaryl furan 12
2,5-Bis(4-cyanophenyl)furan (11, 1.7 g, 6.29 mmol),
1,3-diamino-2-hydroxypropane (5 g, 0.0555 mol), and
ammonium sul®de, 20±22% in water (5 mL), were re¯uxed
for 20 hours. The solid that sublimed during heating in the
condenser was several times moved down using a glass
spatula. After the reaction, water was added to a volume
of 25 mL and the ¯ask was kept overnight in the refrigera-
tor. The precipitate was collected, successfully washed with
cold water, and acidi®ed with 1N HCl. Crystals were
separated after addition of ethanol (91%). The material
gave a positive ninhydrin test for primary amine (11:4:1
CHCl3±CH3OH±NH4OH). On heating, the crystals decom-
posed, becoming brown, but did not melt below 3008C.
4. Walter, W.; Voss, J. In The Chemistry of Thioamides; Zabicky,
J., Ed.; The Chemistry of Amides, Chapter 8. Interscience
Publishers: London, 1970; pp. 383±475. Dell, C. P. In Thiono-
amides and Their Selenium and Tellurium Analogs; Katritzky,
A. R., Meth-Cohn, O., Rees, C. W., Eds.; Compr. Org. Funct.
Group Transform. Elsevier: Oxford, 1995; pp. 565-628, 1161±
1308.
2,5-Bis{4-[N-(3-amino-2-hydroxypropyl)carbamoyl]-
phenyl}furan dihydrochloride (12). nmax (KBr) 3281,
3034, 2921, 1637, 1612, 1593, 1547, 1518, 1496, 1324,
1289, 1242, 1024 cm21; dH [D2O, (CH3)3SiCD2CD2CO2Na]
3.04 (dd, 2H, Jˆ13.2, 9.9 Hz, CHNH13 ), 3.27 (dd, 2H,
Jˆ13.2, 3.3 Hz, CHNH13 ), 3.44 (dd, 2H, Jˆ14.3, 6.9 Hz
CONHCH), 3.51 (dd, 2H, Jˆ14.3, 5.2 Hz, CONHCH),
4.15 (m, 2H, CHOH), 6.74 (s, 2H, furan CH), 7.50 (d, 4H,
Jˆ8.5 Hz, benzene CH), 7.63 (d, 4H, Jˆ8.5 Hz, benzene
CH); dH 2.71 (dd, 2H, Jˆ12.9, 8.8 Hz, CHNH13 ), 2.95
(dd, 2H, Jˆ12.9, 2.7 Hz, CHNH13 ), 3.25±3.50 (m,
CONHCH2, H2O), 3.90 (m, 2H, CHOH), 5.74 (d, 2H,
Jˆ4.9 Hz, H-bonded OH), 7.30 (s, 2H, furan CH), 7.85±
8.10 (m, 14H, C6H4, NH13 ), 8.86 (t, 2H, Jˆ5.6 Hz,
CONHCH2); dC 42.5, 43.2, 66.3, 110.0, 123.1, 127.9,
132.1, 132.6, 152.3, 165.8; HRMS (FAB, 3-nitrobenzyl
alcohol): MH1, found 453.2138. C24H29N4O5 requires
453.2138.
5. Schaefer, F. C. Nitrile Reactivity. The Chemistry of the Cyano
Group; Rappoport, Z., Ed.; Interscience: London, 1970, p 274.
6. Spychala, J. Synth. Commun. 1997, 27, 3431±3440.
7. Spychala, J. Synth. Commun. 2000, 30, 1083±1094.
8. Kindler, K. Ann. 1923, 431, 187±230; Bernthsen, A. Ann. 1877,
184, 290±316; Bernthsen, A. Ber. 1878, 9, 429±435.
9. Gautier, J.-A.; Miocque, M.; Farnoux, C. C. Preparation and
Synthetic Uses of Amidines. The Chemistry of Amidines and
Imidates; Patai, S. Ed.; Wiley, Interscience: London, 1975, p
312; Chapter 7.
10. Hanford, W. E. US Patent 2,201,170, Chem. Abstr. 1940, 34,
63881, Chem. Z. 1940, 2, 2220; Hanford, W. E. US Patent
2,201,171, Chem. Z. 1940, 2, 2243.
11. Spychala, J. Tetrahedron Lett. 1999, 40, 2841±2844.
12. Spychala, J. Synth. Commun. 2000, 30, 2497±2506.
13. Singh, H.; Aggarwal, P.; Kumar, S. Synthesis 1990, 520±522.
14. Grangier, G.; Aitken, D. J.; Guillaume, D.; Husson, H.-P.
Tetrahedron Lett. 1994, 35, 4355±4356.
References
1. Cheng, Q.; Oritani, T.; Horiguchi, T.; Yamada, T.; Mong, Y.
Bioorg. Med. Chem. Lett. 2000, 10, 517±521; Venkatachalam,
15. Dykstra, C. C.; Tidwell, R. R.; Boykin, D.; Wilson, W.;
Spychala, J.; Das, B. P.; Kumar, A. U.S. Patent 1998, 5,723,288,

7986
J. Spychal¤a / Tetrahedron 56 (2000) 7981±7986
PCT Int. Appl. WO 95 30,901, Chem. Abstr. 1996, 124, 140390f;
Das, B. P.; Boykin, D. W. J. Med. Chem. 1977, 20, 531±536;
Dann, O.; Fick, H.; Pietzner, B.; Walkenhorst, E.; Fernbach, R.;
Zeh, D. Liebigs Ann. Chem. 1975, 160±194.
17. Brownlee, R. T. C.; Sadek, M. Aust. J. Chem. 1981, 34, 1593±
1602; Brownlee, R. T. C.; Sadek, M. Magn. Reson. Chem. 1986,
24, 821±826; Bromilow, J.; Brownlee, R. T. C.; Craik, D. J.; Fiske,
P. R.; Rowe, J. E., Sadek, M. J. Chem. Soc., Perkin Trans. 2 1981,
753±759.
16. Neuman, R. C.; Hammond, G. S.; Dougherty J. Am. Chem.
Soc. 1962, 84, 1506±1507.