Preparation of pyrrole and pyrrolidine derivatives of pyrimidine. 1-(2-Pyrimidinyl)pyrrole - An inhibitor of X. Phaseoli and X. Malvacearum

Article abstract of DOI:10.1002/jhet.5570410306

Pyrrole and pyrrolidine derivatives of pyrimidine were prepared in which the nitrogen atom of the pyrrole or pyrrolidine ring is bonded directly to the 2- or 4-carbon atom of the pyrimidine ring. Pyrrole derivatives were prepared by the dry distillation of an intimate mixture of an aminopyrimidine with mucic acid and by the reaction of a chloropyrimidine with potassium pyrrole. Pyrrolidine derivatives were prepared by the reaction of a chloropyrimidine with pyrrolidine and, in a single instance, by the catalytic hydrogenation of a pyrimidinylpyrrole. At a concentration of 200 mcg/mL, 1-(2-pyrimidinyl)pyrrole inhibited two plant pathogenic bacteria -Xanthomanus phaseoli (pathogenic on the bean plant) and Xanthomanus malvacearum (pathogenic on the cotton plant).

Full text of DOI:10.1002/jhet.5570410306

May-Jun 2004
343
Preparation of Pyrrole and Pyrrolidine Derivatives of Pyrimidine. 1-(2-
Pyrimidinyl)pyrrole - an Inhibitor of X. Phaseoli and X. Malvacearum
Irwin Becker
Department of Chemistry, Villanova University, Villanova, PA 19085 [1]
Received July 27, 2003
Pyrrole and pyrrolidine derivatives of pyrimidine were prepared in which the nitrogen atom of the pyrrole
or pyrrolidine ring is bonded directly to the 2- or 4-carbon atom of the pyrimidine ring. Pyrrole derivatives
were prepared by the dry distillation of an intimate mixture of an aminopyrimidine with mucic acid and by
the reaction of a chloropyrimidine with potassium pyrrole. Pyrrolidine derivatives were prepared by the
reaction of a chloropyrimidine with pyrrolidine and, in a single instance, by the catalytic hydrogenation of a
pyrimidinylpyrrole. At a concentration of 200 mcg/mL, 1-(2-pyrimidinyl)pyrrole inhibited two plant patho-
genic bacteria —Xanthomanus phaseoli (pathogenic on the bean plant) and Xanthomanus malvacearum
(pathogenic on the cotton plant).
J. Heterocyclic Chem., 41, 343 (2004).
Just as Pictet and Crepieux [2] prepared l-(3-
pyridinyl)pyrrole by the dry distillation of a mixture of 3-
aminopyridine with mucic acid in an early step in the syn-
thesis of nicotine, we prepared 1-(2-pyrimidinyl)pyrrole
1976 prepared 6 by the reaction of 2,5-diethoxytetrahyro-
furan with 5 [4-6]. These same workers failed to prepare 6
by the reaction of 2-chloro-4,6-dimethylpyrimidine with
potassium pyrrole [5].
(3) and 1-(4-methyl-2-pyrimidinyl)pyrrole (4) by the dis-
tillation of a mixture of 2-aminopyrimidine (1) with mucic
acid and by the distillation of a mixture of 2-amino-4-
methylpyrimidine (2) with mucic acid, respectively.
Subsequent to our work carried out in 1955, Nonoyama in
The second method employed for the preparation of
pyrimidinylpyrroles involved heating a mixture of a
chloropyrimidine with potassium pyrrole in pyrrole as sol-
vent. By this method we prepared 1-(2-pyrimidinyl)pyrrole
(3) and 1-(2-amino-4-methyl-6-pyrimidinyl)pyrrole (7)
from the requisite chloropyrimidine (see Table I).
Replacement of a chlorine atom in the 2-, 4-, or 6-position of
the pyrimidine ring by a nucleophile is well documented [7].
Pyrrolidine derivatives of pyrimidine were prepared by
the reaction of a chloropyrimidine with pyrrolidine (see
Table II). In this way we prepared 1-(2-pyrimidinyl)pyrrol-
idine (8) [8,9], 1-(2-amino-4-methyl-6-pyrimidinyl)-
pyrrolidine (9), and 1-(4,6-dimethyl-2-pyrimidinyl)pyrroli-
dine (10) [10] from the requisite chloropyrimidine.
Reaction of 2-amino-4,6-dichloropyrimidine with a limited
amount of pyrrolidine (2.3 mol pyrrolidine to 1 mol pyrim-
idine) with no heating gave 1-(2-amino-4-chloro-6-pyrim-
idinyl)pyrrolidine (11). At a much higher mol ratio (9:1)
with heating, the disubstituted product, namely, 2-amino-
4,6-di(1-pyrrolidinyl)pyrimidine (1 2), was obtained [11].
In a single instance, a pyrimidinylpyrrolidine was prepared
1987 prepared 3 by refluxing a solution of 2,5-
dimethoxytetrahydrofuran and 2-aminopyrimidine (1) in
acetic acid for 1 h [3]. The 1H nmr spectrum of his product
was identical to that of our product.
We obtained no 1-(4,6-dimethyl-2-pyrimidinyl)pyrrole
(6) from the dry distillation of a mixture of 2-amino-4,6-
dimethylpyrimidine and mucic acid. However, subsequent
to our attempt made in 1955, Katritzky and coworkers in

344
I. Becker
Vol. 41
by the selective catalytic hydrogenation of the pyrrole ring
of a pyrimidinylpyrrole. Specifically, 1-(2-pyrimidinyl)-
pyrrolidine (8) was prepared by the catalytic hydrogenation
of reactions D and E had the same melting point. A mix-
ture melting point of the two products was not depressed.
1
The H nmr spectra of the two products were identical to
each other and indicated that the 2-pyrimidinyl moiety was
bonded to the nitrogen atom of pyrrole. Other physical
properties of the two products were the same. The prod-
ucts of reactions B and C were pale yellow oils and were
characterized as picrates. The two picrates had the same
melting point. A mixture melting point of the two picrates
was not depressed. The 1H nmr spectra of the two picrates
were identical to each other and indicated that the structure
of the two oils is given by 8. In reaction C, the pyrrole ring
was selectively reduced to the pyrrolidine ring.
At a concentration of 200 µg/mL, 1-(2-pyrimidinyl)pyr-
role (3) inhibited two plant pathogenic bacteria –
Xanthomanus phaseoli (pathogenic on the bean plant) and
Xanthomanus malvacearum (pathogenic on the cotton
plant) [12].
EXPERIMENTAL
1-(2-Pyrimidinyl)pyrrole (3) from 2-Aminopyrimidine and
Mucic Acid.
This compound was prepared in a manner similar to that
described by Pictet and Crepieux for the preparation of 1-(3-
pyridinyl)pyrrole from 3-aminopyridine and mucic acid [2]. In a
typical experiment, an intimate mixture of 15.0 g (0.158 mol) of
2-aminopyrimidine and 15.0 g (0.0714 mol) of mucic acid was
placed in a 200-mL round-bottomed flask fitted with a bent glass
tube connected to a short air-cooled condenser (downward). The
flask was heated in a Wood's metal bath (bath temperatures 145-
335°). Most of the liquid distilled over at about 230° to about
270°. White fumes evolved from the condenser during distilla-
tion. The distillate solidified in the receiver (small beaker), form-
ing yellow and white solids. The solids were broken up and
mixed well with water (15 mL). The mixture was collected by
vacuum filtration, using four small portions of water to complete
the transfer. This crude product was dried by suction, by standing
in air (45 min), and by heating in the air-oven at 50-55° (50 min),
white crystals, 1.5 g (14%), mp 77-79°, soluble in cold ethanol,
soluble in cold ether, insoluble in cold and hot water. For elemen-
tal analysis, the once-recrystallized products from four experi-
ments were combined (0.54 g) and the combined lot was recrys-
tallized from the solvent pair of 95% ethanol (10 mL) and water
(22 mL), allowing crystals to form spontaneously over 1 h, white
of 1-(2-pyrimidinyl)pyrrole (3) which, in turn, was pre-
pared by the dry distillation of a mixture of 2-aminopyrim-
idine (1) with mucic acid.
The reactions given in Scheme 1 support the structures
of both 1-(2-pyrimidinyl)pyrrole (3) and 1-(2-pyrim-
idinyl)pyrrolidine (8). The synthesis of 8 from the reaction
of 2-chloropyrimidine with pyrrolidine (reaction B) is con-
sidered to be an unambiguous synthesis of 8. The products
1
needles, mp 78-79°, dried in air-oven at 45-60° (31 h). H nmr
(CDC1 ): δ 6.38 (complex t, 2x β-H, pyrrole),7.82 (complex t,
3
2x α-H, pyrrole), 7.10 (t, 5-H, pyrimidine), 8.66 (d, 4-H & 6-H,
pyrimidine).
Anal. Calcd. for C H N : C, 66.19; H, 4.86. Found: C, 66.34;
H, 5.04.
8
7 3
1-(2-Pyrimidinyl)pyrrole (3) from 2-Chloropyrimidine and
Potassium Pyrrole.
The required 2-chloropyrimidine was prepared from 2-amino-
pyrimidine according to the directions given by Kogon, Minin, and
Overberger [13]. The crude 2-chloropyrimidine had mp 56-65°.

May-Jun 2004
Preparation of Pyrrole and Pyrrolidine Derivatives of Pyrimidine
345
The required potassium pyrrole was prepared by the reaction
of pyrrole with potassium hydroxide. Thus, a mixture of 10.0 g
(0.149 mol) of freshly distilled pyrrole and 6.0 g of 85% potas-
sium hydroxide pellets, equivalent to 5.1 g (0.091 mol) of pure
potassium hydroxide, was refluxed for a few minutes during
which time all of the potassium hydroxide went into solution
(yellow). The hot contents was poured into a copper flask and
heated over a wire gauze for about 5 min while compressed air
was directed into the flask, forming a crust. Then the flask was
allowed to cool in a desiccator to room temperature. The crusty
solid was quickly broken up and pulverized, giving tan potassium
pyrrole. This product was stored in a vial under nitrogen.
1-(2-Pyrimidinyl)pyrrole was prepared by heating a mixture of
2.00 g (0.0174 mol) of crude 2-chloropyrimidine (mp 57-64°),
2.0 g (0.019 mol) of crude potassium pyrrole (tan), and 10.0 mL
of freshly distilled pyrrole on a steam bath for about 3 min, giv-
ing an olive colored mixture. The mixture then was heated over a
wire gauze until the mixture began to boil. At this point, heating
was stopped and the flask was swirled until boiling ceased. This
procedure of heating over a wire gauze and swirling was repeated
eight times more. The dark mixture was filtered while still hot,
using 3x3 mL absolute alcohol to complete the transfer. The solid
in the funnel was washed with 3x5 mL absolute alcohol and then
the solid was discarded. The combined filtrate was evaporated to
a few milliliters. This liquid was cooled in an ice-water bath. The
soft dark brown solid that formed was collected by vacuum filtra-
tion. A smaller portion of dark brown solid was obtained by
evaporating the filtrate to near dryness, cooling, and filtering.
Both portions of solid were combined and recrystallized (char-
coal) from the solvent pair of 95% ethanol (10 mL) and water (20
mL). The hot ethanol-water solution was cooled in an ice-water
bath. The purified product was collected by filtration and sucked
dry (0.5 h), tan powder, 89 mg (3.5%), mp 80-82.5°.
This oil was assumed to be 1-(2-pyrimidinyl)pyrrolidine. The
crude picrate of this oil had mp 150-174°. After five recrystal-
lizations from 95% ethanol, the picrate had mp 164-173°. This
picrate, after drying in the air-oven at 80° for 16 h, was submitted
1
for elemental analysis. H nmr of picrate (CDC1 ): δ 2.15 (com-
3
plex t, 4x β-H, pyrrolidine), 3.77 (complex t, 4x α-H, pyrroli-
dine), 6.80 (t, 5-H, pyrimidine), 8.50 (d, 4-H & 6-H, pyrimidine),
8.91 (s, 3-H & 5-H, picric acid), about 11.50 (very broad s, OH,
picric acid).
Anal. Calcd. for C
44.84; H, 3.69.
H N O : C, 44.45; H, 3.73. Found: C,
14 14 6 7
In another experiment, 3.5 g (0.049 mol) of practical pyrroli-
dine (clear, yellow) were caused to react with 2.0 g (0.017 mol)
of 2-chloropyrimidine (mp 57-64°). After workup, a portion of
the pale yellow oil (product) was converted to a picrate in 95%
ethanol, mp 160-170°. After two recrystallizations from 95%
ethanol, the picrate had mp 165-173°. This picrate was allowed to
dry in the air for 35 days and dried in the air oven at 75° for 1 h.
Anal. Calcd. for C
Found: C, 44.69; H, 3.51; N, 22.21.
H N O : C, 44.45; H, 3.73; N, 22.22.
14 14 6 7
1-(2-Pyrimidinyl)pyrrolidine (8) by Catalytic Hydrogenation of
1-(2-Pyrimidinyl)pyrrole (3) from 2-Aminopyrimidine and
Mucic Acid.
A mixture of 1-(2-pyrimidinyl)pyrrole (3.2 g, 0.022 mol, mp
78-80°, prepared from 2-aminopyrimidine and mucic acid), 0.8 g
of 10% Pd/C, and 100 mL of ethanol was shaken in a Parr hydro-
genation apparatus at 27° for 14.5 h at an initial pressure of
hydrogen of 31 psi. The mixture then was filtered through an
infusorial earth mat. The filtrate was distilled to remove ethanol,
leaving a clear yellow-orange liquid (about 3 mL). Water (25
mL) was added to this liquid. The mixture was cooled in an ice-
water bath. The solid in the mixture was collected by suction fil-
tration and dried at 55° for 70 min, white and crystalline, 0.22 g,
mp 74-81.5°. This solid was assumed to be unreacted 1-(2-pyrim-
idinyl)pyrrole. The clear pale yellow filtrate was evaporated on
the steam bath to give a clear yellow oil above a yellow-brown
scum. This mixture was put in a test tube and centrifuged. The
top layer of clear yellow oil, assumed to be 1-(2-pyrimidinyl)-
pyrrolidine, was converted to a picrate, mp 167-174.5°. This
picrate was recrystallized from 95% ethanol. The picrate was
sucked with the water aspirator for 2 h, mp 165.5-172.5°. This
picrate was used for the elemental analysis, for the mixture melt-
Another experiment was carried out in the same way, except
that 6.0 mL (not 10 mL) of freshly distilled pyrrole was used. The
crude product was recrystallized from 50% ethanol-water, giving
white flattened needles, 55 mg (2.2%), mp 81.5-84°. A mixture
melting point of this product (mp 81.5-84°) and the product (mp
80-83°) from the dry distillation of a mixture of 2-aminopyrimi-
dine and mucic acid was 80.5-82.5°. Since no depression of the
melting points occurred, the identity of the two products was
indicated. Additionally, the two products had the same musty
odor, were both soluble in cold ethanol, were both insoluble in
cold water, both consisted of white needles when precipitated
1
ing point, and for the H nmr spectrum. The mp of a mixture of
1
the picrate (mp 165.5-172.5°) formed in this experiment with the
once-recrystallized picrate (mp 166-174.5°) formed from the
product of the reaction of 2-chloropyrimidine with pyrrolidine
was 166-172.5°. Since no depression of the melting points
from ethanol-water, and both had identical H nmr spectra.
1-(2-Pyrimidinyl)pyrrolidine (8) from 2-Chloropyrimidine and
Pyrrolidine.
1
occurred, the identity of the two picrates was indicated. The H
nmr spectrum of the picrate formed in this experiment was iden-
To 3.5 g (0.049 mol) of pyrrolidine in a 50 mL erlenmeyer
flask, 2.0 g (0.017 mol) of 2-chloropyrimidine (mp 56-65°) was
added in small portions with swirling. The flask became
extremely hot. After the addition was complete, the contents con-
sisted of a clear yellow oil. The flask was fitted with a mini
reflux condenser and the contents was heated on the steam bath
for 1.5 h and then was gently refluxed over a wire gauze for 2.5 h,
giving a dark brown viscous liquid. This liquid, in a 10 mL distil-
lation flask, was distilled at the reduced pressure offered by the
water aspirator while the flask was heated in an oil bath (bath
temperatures 170-220°). A clear pale yellow oil, 1.44 g (54%),
distilled over. This oil was again distilled, this time at 762
mmHg. A clear pale yellow oil was collected at about 230-240°.
1
tical to the H nmr spectrum of the picrate formed from the prod-
uct of the reaction of 2-chloropyrimidine with pyrrolidine.
Anal. Calcd. for C H N O : C, 44.45; H, 3.73; N, 22.22.
14 14 6 7
Found: C, 44.51; H, 3.64; N, 22.21.
1-(4-Methyl-2-pyrimidinyl)pyrrole (4).
The requisite 2-amino-4-methylpyrimidine was prepared in
three steps. Condensation of guanidine carbonate with ethyl ace-
toacetate in refluxing ethanol gave 2-amino-4-methyl-6-hydroxy-
pyrimidine [14]. This 6-OH compound was converted to the 6-Cl
compound by refluxing with an excess of phosphorus oxychlo-

346
I. Becker
Vol. 41
ride [15,16]. In this step, after the main reaction, excess phos-
phorus oxychloride was destroyed by pouring the reaction mix-
ture onto cracked ice. The 6-Cl atom was removed by heating
with zinc dust in aqueous ammonium chloride [17]. The crude 2-
amino-4-methylpyrimidine so prepared consisted of yellow flat-
tened needles, mp 156-158°.
Both solids were combined and extracted by adding absolute
ethanol (10 mL) and charcoal and heating the mixture on the
steam bath for about 5 min. The hot mixture was filtered by grav-
ity. The solid on the filter paper was extracted again (no charcoal)
in the same way, collecting both filtrates in the same container.
The combined filtrate was heated on the steam bath and the hot
brown solution was allowed to stand for 2 h and then cooled in an
ice water bath for 5 min. The needles that separated were collected
by filtration, washed with 3xl mL water, and sucked dry giving tan
flat needles, 0.417 g, mp 153-155.5°. A third extraction (no char-
coal) of the dark brown solid gave light tan short fine glistening
needles, 0.056 g, mp 153-155°. Both portions of crude product
were combined (0.473 g, 32.6%) and recrystallized (charcoal)
from 50% ethanol-water (11 mL), letting the hot filtrate cool spon-
taneously for 12 h, followed by cooling in an ice water bath for
nearly 4 h. The crystals that separated were collected by filtration,
using 5x2 mL water to complete the transfer. The crystals, after
being dried at 100-105° for about 2.5 h, had mp 152-154.5°. The
Beilstein test was negative (no Cl). For elemental analysis, the
product was recrystallized from 50% ethanol-water (8 mL),
allowing the filtrate to cool spontaneously for nearly 2 h. The
purified product was collected by filtration and washed with 2 mL
of water, long flattened white needles, dried at 95-100° for 13 h,
The method and apparatus used for the preparation of the title
compound were the same as those used for the preparation of 1-
(2-pyrimidinyl)pyrrole by the dry distillation of a mixture of 2-
aminopyrimidine with mucic acid. Thus, an intimate mixture of
5.0 g (0.046 mol) of 2-amino-4-methylpyrimidine and 15.0 g
(0.0714 mol) of mucic acid was heated at about 140-360° (bath
temperatures) giving a yellow to dark orange distillate that solid-
ified to white and yellow solids in the receiver cooled in an ice-
water bath. Yellow-brown solid scraped from the condenser was
combined with the solids in the receiver. The combined solid was
recrystallized (charcoal) from the solvent pair of 95% ethanol (10
mL) and water (20 mL). The water-ethanol solution was refriger-
ated for 14.5 h, giving mostly colorless flat needles and some
pale yellow crystals and grey particles. These solids were col-
lected by filtration and sucked dry, 2.63 g, mp 37-130°. Another
recrystallization (charcoal) was carried out using the solvent pair
of 95% ethanol (17 mL) and enough hot water to reach the cloud
point. The hot mixture was let stand at room temperature for 15 h
and cooled in an ice-water bath for 1 h. The light grey long flat
nacreous needles that precipitated were collected by filtration,
0.75 g (13%), mp 43-45°. A second crop was obtained from the
filtrate by adding 2 mL of water and cooling in an ice-water bath
for 2.5 h, 80 mg (1.3%), light tan flattened needles, mp 41-43.5°.
Both crops were combined (0.83 g, 14%) and recrystallized from
the solvent pair of 95% ethanol (10 mL) and enough hot water to
reach the cloud point. The hot pale yellow alcohol-water mixture
was allowed to stand for 14 h and then cooled in an ice-water
bath for 1 h. The crystals that formed were collected by filtration,
washed with 8x5 mL water, sucked dry, and dried in the air for
nearly 4 h to give long flat transparent needles, mp 44-46°. For
elemental analysis, a final recrystallization was carried out in the
same manner as just described. The product was collected,
washed with 3x5 mL water, and sucked dry for 3.25 h resulting in
1
mp 152-154.5°. H nmr (CDC1 ): δ 2.37 (s, 4-CH , pyrimidine),
3
3
5.25 (broad s, 2-NH , pyrimidine), 6.48 (s, 5-H, pyrimidine), 6.33
2
(complex t, 2x β-H, pyrrole), 7.47 (complex t, 2x α- H, pyrrole).
Anal. Calcd. for C H N : C, 62.05; H, 5.79. Found: C, 62.46;
H, 6.03.
9
10 4
1-(2-Amino-4-methyl-6-pyrimidinyl)pyrrolidine (9).
To 1.0 g (0.014 mol) of practical pyrrolidine (pale yellow) in a
50 mL erlenmeyer flask was added 1.0 g (0.0070 mol) of 2-
amino-4-methyl-6-chloropyrimidine in portions with stirring and
heating on the steam bath. Additional pyrrolidine (40 drops) was
added in portions along the way inasmuch as the mixture became
very dry. The white mixture was heated strongly on the steam
bath for 7 min and then allowed to cool to room temperature.
Water (10 mL) was added with vigorous stirring. The chalky
white solid was collected by filtration, using 12 mL of water to
complete the transfer. The solid was washed with 2x5mL of
water, sucked with the vacuum, and allowed to dry in air for 13 h,
0.95 g (79%), mp 170-173°. This crude product was recrystal-
lized from the solvent pair of 95% ethanol (10 mL) and water
(110 mL), allowing the hot ethanol-water solution to cool sponta-
neously for 1 h, adding 53 drops of water, and stirring the solution
with scratching to cause precipitation of fine white crystals. The
product was collected by filtration, using three small portions of
water to complete the transfer. The product was sucked dry for
1.75 h, 0.58 g, mp 171-172°. A second crop was obtained by cool-
ing the filtrate (3.75 h), collecting the product by filtration, and
sucking the product with the vacuum (40 min), fine white crystals,
0.10 g, mp 170-171.5°. Both crops were combined (0.68 g, 57%).
For elemental analysis, the product was recrystallized from the
solvent pair of 95% ethanol (10 mL) and water (about 45 mL),
allowing the solution to cool in an ice-water bath for 1 h, stirring
the solution vigorously to cause precipitation of crystals, cooling
for 25 min more, and letting the mixture stand at room tempera-
ture for 22 h. The product was collected by filtration, using a
small portion of water to complete the transfer, and dried at 100-
1
long transparent needles, mp 44.5-46°. H nmr (CDC1 ): δ 6.38
3
(complex t, 2x β-H, pyrrole), 7.84 (complex t, 2x α-H, pyrrole),
2.54 (s, 4-CH , pyrimidine), 6.96 (d, 5-H, pyrimidine), 8.51 (d, 6-
3
H, pyrimidine).
Anal. Calcd. for C H N : C, 67.90; H, 5.70. Found: C, 68.07;
9 3
9
H, 5.67.
1-(2-Amino-4-methyl-6-pyrimidinyl)pyrrole (7).
In a 50-mL erlenmeyer flask, a mixture of 1.2 g (0.083 mol) of
2-amino-4-methyl-6-chloropyrimidine, 1.0 g (0.095 mol) of crude
potassium pyrrole, and 10.0 mL of freshly distilled pyrrole was
heated on the steam bath for 3 min, giving a dark brown mixture.
The flask then was heated over a wire gauze until boiling started
(foaming occurred). At this point heating was stopped and the
flask was swirled and allowed to stand on the wire gauze until
boiling ceased. This procedure of heating over the wire gauze,
swirling, and standing was repeated twelve times more. The dark
brown mixture was cooled in an ice-water bath for 1 h and
allowed to stand at room temperature for 15 h. The dark brown
partly crystalline solid was collected by filtration. The filtrate was
concentrated to a few milliliters and the concentrate was cooled in
an ice water bath to give about 0.1 g more of dark brown solid.
1
105° for 28 h, fine white crystals, mp 169-170°. H nmr
(CDC1 ): δ 1.96 (broad complex t, 4x β-H, pyrrolidine), 3.41
3

May-Jun 2004
Preparation of Pyrrole and Pyrrolidine Derivatives of Pyrimidine
347
was added in two portions. About half of the pyrrolidine was
added. An immediate exothermic reaction ensued, causing the
contents to boil. When this reaction subsided, the remainder of the
pyrrolidine was added, causing the same exothermic reaction.
After the reaction subsided, the solid was broken up and 5 mL of
water were added with swirling. The tan solid was collected by fil-
tration, using several small portions of water (total of 15 mL) to
complete the transfer. The tan solid was allowed to dry in air for 1
h and dried at 80-85° for 100 min, mp softened at 137-144° and
melted only partially above 144°. The solid was recrystallized
(charcoal) from 95% ethanol (20 mL), allowing the yellow filtrate
to cool in an ice-water bath for 1.5 h. The white solid that formed
was collected and sucked dry, mp 155-170°, positive Beilstein test
(Cl present), dried in air overnight, 0.27 g (23%). The solid was
recrystallized from the solvent pair of 95% ethanol (15 mL) and
water (10 mL), allowing the ethanol-water solution to cool in the
ice-water bath for 3.5 h. The product was collected and sucked
dry, soft fine white crystals, mp 165-172°. To these crystals 10 mL
of 95% ethanol were added and the mixture was heated on the
steam bath until it was slightly turbid. The mixture was filtered.
The turbid filtrate was cooled in an ice-water bath for 15 min.
Flocculent solid formed. The mixture was filtered. To the nearly
clear filtrate 10 mL of water were added, giving a milky suspen-
sion that was heated briefly on the steam bath with stirring. The
flocculent solid that formed was removed by filtration. The
slightly cloudy filtrate was let stand for 1.5 h whereupon more
flocculent solid formed. The mixture was filtered. The clear fil-
trate was cooled in an ice-water bath for nearly 3 h during which
time fine white nacreous needles formed. These needles were col-
lected and dried at 95-100° for 2.5 h, mp 177.5-179.5°. For ele-
mental analysis the sample was dried for an additional 17.5 h at
(broad s, 4x α-H, pyrrolidine), 2.21 (s, 4-CH , pyrimidine), 5.63
3
(s, 5-H, pyrimidine), 4.75 (broad s, 2-NH , pyrimidine).
2
Anal. Calcd. for C H N : C, 60.64; H, 7.92. Found: C, 60.67;
9
14 4
H, 7.95.
1-(4,6-Dimethyl-2-pyrimidinyl)pyrrolidine (10).
The requisite 2-chloro-4,6-dimethylpyrimidine was prepared
in two steps. Condensation of guanidine carbonate with 2,4-pen-
tanedione (acetylacetone) in refluxing 95% ethanol afforded 2-
amino-4,6-dimethylpyrimidine [18]. Diazotization of this
aminopyrimidine with aqueous sodium nitrite in an excess of
hydrochloric acid gave the 2-chloro compound [13].
To 3.0 g (0.021 mol) of 2-chloro-4,6-dimethylpyrimidine, 7.5
g (0.11 mol) of practical pyrrolidine was added in two portions.
About half of the pyrrolidine was added with shaking. The mix-
ture became progressively warmer and spontaneously boiled,
forming an orange-brown viscous liquid. When boiling ceased,
the remainder of the pyrrolidine was added with shaking. The
mixture was concentrated by heating on steam and the concen-
trate was cooled to room temperature. An excess of 10% sodium
hydroxide was added, giving two layers. The lower aqueous layer
was separated from the upper dark orange-brown layer. The
aqueous layer was extracted with two portions of ether and both
extracts were added to the dark orange-brown layer. The ether
was removed by heating the solution on the steam bath. The
remaining dark orange-brown viscous liquid was distilled at 3
mmHg, giving a pale yellow distillate (bp 114-116°/3 mmHg)
and hard white waxy solid that collected in the condenser. The
pale yellow distillate, upon scratching, solidified completely,
forming pale yellow crystals. These crystals were combined with
the hard white waxy solid removed from the condenser, 2.5 g
(67%), mp 49.5-51°, negative Beilstein test (no Cl), soluble in
cold 95% ethanol, insoluble in cold water, insoluble in 5%
sodium hydroxide, soluble in cold 5% hydrochloric acid. This
product was recrystallized (charcoal) from the solvent pair of
95% ethanol (about 7 mL) and water (about 6 mL), allowing the
ethanol-water solution to cool in an ice-water bath. Upon seed-
ing, crystals formed rapidly. The mixture was cooled for 0.5 h
more. The soft white glistening needles (larger portion) were col-
lected, washed with water, and dried at room temperature over
calcium chloride for 22 h, 1.57 g (42%), mp 49.5-50.5°. The pale
yellow needles in the filtrate (smaller portion) were collected,
washed with water, and dried in the same way, 0.14 g (3.8%), mp
49.5-51.2°. The larger portion was recrystallized from the solvent
pair of ethanol and water, allowing the solution to cool in an ice-
water bath for 1.75 h. The crystals (major crop) that formed were
collected and washed with water, long white needles with a faint
yellowish color. The soft long white needles (minor crop) that
formed in the filtrate were collected and washed twice with
water. Both crops were dried at room temperature over phospho-
1
95-100°. No sample was available for a H nmr spectrum.
Anal. Calcd. for C H N Cl: C, 48.37; H, 5.58. Found: C,
48.74; H, 5.48.
8
11 4
2-Amino-4,6-di(1-pyrrolidinyl)pyrimidine (12).
To 1.02 g of 99% pure 2-amino-4,6-dichloropyrimidine, equiv-
alent to 1.00 g (0.00610 mol) of 100% pure compound, cooled in
an ice water bath, were added 1.77 g (2.06 mL) of 99% pure
pyrrolidine. A vigorous exothermic reaction occurred. The ice-
water bath was removed and the mixture was heated on the steam
bath for 32 min. Then 1.1 g (1.3 mL) of 99% pyrrolidine was
added through the top of the condenser and the mixture was
heated for 28 min. Then 1.1 g (2.06 mL) of 99% pyrrolidine was
added and the mixture was heated for 2 h 21 min more. Thus the
reactants were heated on the steam bath for a total of 3 h 21 min.
A total of 3.99 g of 99% pyrrolidine, equivalent to 3.93 g (0.0553
mol) of 100% pure pyrrolidine, was used in the reaction. The
resulting heterogeneous mixture was allowed to stand at room
temperature in the dark for 43.5 h. The solids were broken up and
collected by filtration, using 2x4 mL water to complete the trans-
fer. The cream-colored solid was washed with 2x6 mL water and
dried at 62° for 2.5 h, 1.29 g, mp 204-211° with softening and
sintering occurring over many degrees before 204°. This solid
was recrystallized from the solvent pair of 95% ethanol and
water. About one-third of the solid did not dissolve in the hot
95% ethanol. This insoluble solid was discarded. The ethanol-
water mixture was let stand at room temperature for 111 min. The
soft nacreous off-white crystals that separated were collected by
filtration, using 4x3 mL water to complete the transfer. The crys-
tals were washed with 7 mL water, sucked with the vacuum for
rus pentoxide in vacuo for 67.5 h. The major crop had mp 49.7-
1
51°. The minor crop had mp 49-50°. H nmr (CDC1 ): δ 1.98
3
(broad complex t, 4x β-H, pyrrolidine), 3.62 (broad complex t, 4x
α-H, pyrrolidine), 2.31 (s, 4-CH & 6-CH , pyrimidine), 6.30 (s,
3
3
5-H, pyrimidine).
Anal. Calcd. for C
67.15; H, 8.44.
H
10 15
N : C, 67.76; H, 8.53. Found: C,
3
1-(2-Amino-4-chloro-6-pyrimidinyl)pyrrolidine (11).
To 1.0 g (0.0061 mol) of 2-amino-4,6-dichloropyrimidine (mp
216-217°), 1.0 g (0.014 mol) of practical pyrrolidine (pale yellow)

348
I. Becker
Vol. 41
[8] We prepared 1-(2-pyrimidinyl)pyrrolidine (8) from 2-
chloropyrimidine and pyrrolidine in 1956. N. Chatani, T. Asaumi, S.
Yorimitsu, and S. Murai, J. Am. Chem. Soc., 123, 10,935 (2001) state that
they prepared 8 (no experimental details are given) by the reaction of 2-
chloropyrimidine with pyrrolidine according to A. Hassner, A. L. R.
Krepski, and V. Alexanian, Tetrahedron , 3 4, 2069 (1978). Hassner's
paper, however, does not mention 8.
[9] A paper by J. W. Liebescheutz and coworkers, Pesticide
Science, 50, 250 (1997) states that 1-(2-pyrimidinyl)pyrrolidine (8) was
prepared from 2-chloropyrimidine and pyrrolidine but the usual experi-
11 min, and dried in the air-oven at 60-61° for 128 min, 0.239 g
(16.8%), negative Beilstein test (no Cl), mp 207-213.5° with
most of the melting occurring at 211-213.5°. The product was
again recrystallized from the solvent pair of 95% ethanol and
water, allowing the hot ethanol-water mixture to stand at room
temperature for 160 min. The nacreous off-white crystals that
separated were collected by filtration, using 2x2 mL water to
complete the transfer, washed with 2x4 mL water, sucked with
the vacuum for 10 min, and dried in the air-oven at 75° for 5.75 h,
long flat narrow rectangular transparent needles (x100), 96 mg
1
mental details are lacking. However, H nmr data for the product are
1
(6.8%), negative Beilstein test (no Cl), mp 209-212.5°. H nmr
(CDC1 ): δ 1.91-1.96 (broad complex t, 8x β-H, pyrrolidine),
given: (90 MHz): δ 8.37 (2H, d, J=4.5 Hz), 6.50 (1H, t, J=4.5 Hz), 3.60
(4H, m), 2.0 (4H, m).
3
3.35-3.44 (broad complex t, 8x α-H, pyrrolidine), 4.49 (broad s,
2-NH , pyrimidine), 4.69 (s, 5-H, pyrimidine).
[10] Subsequent to our work carried out in 1965, H. Grube and H.
Suhr, B e r., 1 0 2, 1570 (1969) prepared 1-(4,6-dimethyl-2-pyrimidinyl)-
pyrrolidine (10) by the same method used in this work. The mp of their
product (mp 51-52°) was virtually the same as the mp of our product (mp
49.7-51° uncorrected). Grube and Suhr prepared 10 in 88% yield by heat-
ing the reactants at 50° for 3 h. They determined the rate constant of the
reaction.
2
Anal. Calcd. for C
H N : C, 61.77; H, 8.21; N, 30.02.
12 19 5
Found: C, 61.81; H, 7.87; N, 30.00.
Acknowledgement.
I thank Professor Walter Boyko, Director of NMR Services, and
1
Professor John Buzby for the determination of the H nmr spectra
and for help in the interpretation of the spectra. I thank Professor
Jim Barnes for preparing the computer disk of the manuscript.
[11] We prepared 2-amino-4,6-di(l-pyrrolidinyl)pyrimidine (1 2)
in 2003. Subsequently we discovered that two groups of workers – des-
ignated (a) and (b) – had prepared 12 earlier. (a) W. B. Cowden and N.
W. Jacobsen, Austral. J. Chem., 3 2, 2049 (1979) had prepared 12 by
essentially the same method we used. Our mol ratio of pyrrolidine to
pyrimidine was 9:1 whereas Cowden and Jacobsen's mol ratio was 38:1.
We gently heated the reactants on the steam bath for 3 h 21 min whereas
Cowden and Jacobsen refluxed the reactants for 4 h. The mp of our ana-
lytically pure product was 209-212.5° whereas the mp of Cowden and
REFERENCES AND NOTES
[1] The major portion of this work was carried out in 1954-1956
in the College of Liberal Arts and Sciences of Temple University,
Philadelphia, PA, as part of my requirements for the degree of Master of
Arts, under the direction of Professor William T. Caldwell, now deceased.
A minor portion of this work was subsequently carried out in the School
of Pharmacy, Temple University, and in the Department of Chemistry,
Villanova University. None of this work has heretofore been submitted
for publication. This paper is dedicated to the memory of my parents —
Myer and Tootsie (Yetta) Becker.
°
1
Jacobsen's product was 221-222 . The H nmr spectrum of our product
confirmed its structure. Cowden and Jacobsen give no spectral data. (b)
J. N. Low and coworkers, Acta Crystallographica, C58, 289 (2002)
also had prepared 12 but under conditions of reaction different from
ours. They refluxed a solution of 2-amino-4,6-dichloropyrimidine,
pyrrolidine, triethylamine, and butanol, with stirring, for 56 h. The mol
ratio of pyrrolidine to pyrimidine was 3.5:1. They characterized their
1
13
product by mp (224°), by H nmr and C nmr spectra, and by X-ray
crystallography. Their single crystal X-ray diffraction data indicated
that the molecules of 12 take the form of a chain of fused rings, that the
molecules are associated through hydrogen bonds involving donor
hydrogen atoms of the 2-amino group and acceptor nitrogen atoms in
the pyrimidine ring, that the nitrogen atoms of the pyrrolidine moieties
do not participate in hydrogen bonds, and that aromatic π - π stacking
interactions are absent.
[2] A. Pictet and P. Crepieux, Ber., 28, 1904 (1895).
[3] M. Nonoyama, Transition Metal Chemistry, 12 , 1 (1987).
Nonoyama's method seemingly is patterned after the procedure described
by N. Clauson-Kaas and Z. Tyle, Acta Chem. Scand., 6, 667 (1952) for
the preparation of N-substituted pyrroles by the reaction of a 2,5-
dialkoxytetrahydrofuran with a primary amine.
[4] A. R. Katritzky, J. Lewis, G. Musumarra, and G. Ogretir, La
Chimica e L'Industria, 58, 381 (1976).
[5] A. R. Katritzky, J. Lewis, G. Musumurra, and G. Ogretir,
Chimica Acta Turcica, 4, 71 (1976).
[12] Biological testing was carried out by Eli Lilly and Co.
[13] I. C. Kogon, R. Minin, and C. G. Overberg e r, O rg a n i c
Syntheses, 35, 34 (1955).
[6] Katritzky and coworkers [4,5] state that they used the method
of R. A. Jones, Austral. J. Chem., 19, 289 (1966) for the preparation of N-
substituted pyrroles. Jones's method is the same as that devised by
Clauson-Kaas and Tyle in 1952. See [3].
[14] R. Behrend, Ber., 19, 219 (1886).
[15] S. Gabriel and J. Colman, Ber., 32, 2919 (1899).
[16] E. A. Falco, P. B. Russell, and G. H. Hitchings, J. Am. Chem.
Soc., 73, 3753 (1951).
[17] K. Sugino and coworkers, Chem. Abstr., 47, 4920 (1953).
[18] H. Amazu and J. Inone, Chem. Abstr., 47, 1746 (1953).
[7] See, for example, D. J. Brown, The Pyrimidines, Interscience
Publishers, NY, 1962, pp 181-182 and pp 187-201.