Improved synthesis of 2,2′-bipyrimidine

Article abstract of DOI:10.1021/jo0255781

A high-yield synthesis was developed for the preparation of 2,2′-bipyrimidine (1) using the Ullmann coupling of 2-iodopyrimidine. The new procedure was also used for the preparation of 4,4′,6,6′-tetramethyl-2,2′-bipyrimidine (2) and 5,5′-dibromo-2,2′-bipyrimidine (3).

Full text of DOI:10.1021/jo0255781

Im p r oved Syn th esis of 2,2′-Bip yr im id in e
we used the published 1:1 ratio between 2-chloropyrimi-
dine and NiCl ‚6H O (Table 1). It has been reported that
the yield of the in situ formed coupling species Ni(PPh
could be very low in the presence of water. Therefore,
we tried to modify the procedure by removing the water
2
2
3 4
)
G a´ bor Vl a´ d and Istv a´ n T. Horv a´ th*
6
Department of Chemical Technology and Environmental
Chemistry, E o¨ tv o¨ s University, P a´ zm a´ ny P e´ ter s e´ t a´ ny 1/ A,
H-1117 Budapest, Hungary
from the solution of NiCl
distillation with toluene, but the formation of 1 could not
2
2
‚6H O in DMF by azeotropic
be detected. A similar result was obtained when the
istvan.t.horvath@hit-team.net
Received February 2, 2002
water-free nickel precursor Ni(acac)
changed the ratio between 2-chloropyrimidine and NiCl
O from 1:1 to 2:1, which resulted in 21% yield.
Further increase of the ratio between 2-chloropyrimidine
and NiCl ‚6H O up to 4:1 did not give higher yields. It
2
was used. Next, we
2
‚
6
H
2
Abstr a ct: A high-yield synthesis was developed for the
preparation of 2,2′-bipyrimidine (1) using the Ullmann
coupling of 2-iodopyrimidine. The new procedure was also
used for the preparation of 4,4′,6,6′-tetramethyl-2,2′-bipy-
rimidine (2) and 5,5′-dibromo-2,2′-bipyrimidine (3).
2
2
should be noted that a similar yield (16%) was reported
for the Ni-assisted coupling of 4-methyl-2-bromopyrimi-
5
dine. In general, the reactivity of iodoaryl compounds
is much higher in cross-coupling reactions than that of
chloroaryl compounds. Accordingly, the Ni-assisted cou-
7
2
,2′-Bipyrimidine (1) has been used as a ligand in
pling of 2-iodopyrimidine resulted in 33% 2,2′-bipyrimi-
1
inorganic and organometallic chemistry and exhibits a
remarkable stability in acidic medium. Periana has
dine (1).
Since it is also well established that iodoaryl com-
shown that the (2,2′-bipyrimidine)PtX
complexes are extremely stable in oleum during the
2
(X ) Cl,1b OSO
3
H)
pounds could readily undergo Ullmann coupling, we
8
have finally investigated the reactivity of 2-iodopyrimi-
dine. The Ullmann coupling was started by reacting
2-iodopyrimidine with activated copper powder in abso-
lute DMF between 80 and 85 °C. After 7 h, the temper-
ature was increased to 120-130 °C for 2 h. The suspen-
sion was then cooled to 0 °C, and the coordinated copper
was removed with potassium cyanide in a 25% aqueous
solution of ammonia to give 2,2′-bipyrimidine (1) in 90%
yield.
2
catalytic functionalization of methane at 180 °C. Since
the reproducibility of the published procedures3 for the
synthesis of 2,2′-bipyrimidine was rather low, we have
developed a high-yield synthesis using the Ullmann
coupling of 2-iodopyrimidine. In addition, the new pro-
cedure was used for the preparation of 4,4′,6,6′-tetra-
methyl-2,2′-bipyrimidine (2) and 5,5′-dibromo-2,2′-bipy-
rimidine (3) as well.
-5
2
,2′-Bipyrimidine (1) was first synthesized by Bly and
Mellon utilizing the Ullmann coupling of 2-bromopyri-
midine in the presence of metallic copper.3 Since the
reported reproducibility of this procedure was rather low
and the yields varied from 10 to 50%, we have first tested
4
a Ni-assisted coupling of 2-chloropyrimidine. Unfortu-
nately, we were unable to reproduce the reported 60%
yield. In fact, only a trace amount of 1 was formed when
It should be emphasized that the careful activation of
the metallic copper, described in the Experimental Sec-
tion, is very important to achieve a high yield.
(
1) (a) Hunziker, M.; Ludi, A. J . Am. Chem. Soc. 1977, 99, 7370-
The new procedure was also tested for the coupling of
7
1
2
371. (b) Kiernan, P. M.; Ludi, A. J . Chem. Soc., Dalton Trans. 1978,
127-1130. (c) Dose, E. V.; Wilson, L. J . Inorg. Chem. 1978, 17, 2660-
666. (d) Petty, R. H.; Welch, B. R.; Wilson, L. J .; Bottomley, L. A.;
8,9
4
,6-dimethyl-2-iodopyrimidine
and 5-bromo-2-iodo-
1
0-12
pyrimidine
resulting in 4,4′,6,6′-tetramethyl-2,2′-
Kadish, K. M. J . Am. Chem. Soc. 1980, 102, 611-620. (e) Rillema, D.
bipyrimidine (2) and 5,5′-dibromo-2,2′-bipyrimidine (3)
in 50 and 38% isolated yield, respectively.
P.; Callahan, R. W.; Mack, K. B. Inorg. Chem. 1982, 21, 2589-2596.
(
(
1
1
f) Ruminski, R. R.; Petersen, J . D. Inorg. Chem. 1982, 21, 3706-3708.
g) Rillema, D. P.; Allen, G.; Meyer, T. J .; Conrad, D. Inorg. Chem.
Exp er im en ta l Section
983, 22, 1617-1622. (h) Lanza, S. Inorg. Chim. Acta 1983, 75, 131-
33. (i) Moore, K. J .; Petersen, J . D. Polyhedron 1983, 2, 279-284. (j)
2
-Chloropyrimidine (97%), 2-hydroxypyrimidine hydrochlo-
Sutcliffe, V. F.; Young, G. B. Polyhedron 1984, 3, 87-94. (k) Ruminski,
R. R.; Petersen, J . D. Inorg. Chim. Acta 1985, 97, 129-134. (l) De
Munno, G.; Viau, G.; J ulve, M.; Lloret, F.; Faus, J . Inorg. Chim. Acta
ride, and 57% aqueous solution of hydriodic acid were obtained
from commercial sources. DMF was either distilled from calcium
1
997, 257, 121-129. (m) Rugge, A.; Clarck, C. D.; Hoffman, M. Z.;
Rillema, D. P. Inorg. Chim. Acta 1998, 279, 200-205. (n) Baumann,
F.; Stange, A.; Kaim, W. Inorg. Chem. Commun. 1998, 1, 305-308.
(6) Wilke, G.; M u¨ ller, E. W.; Kr o¨ ner, M. Angew. Chem. 1961, 73,
33-34.
(o) J i, Z.; Huang, S. D.; Guadalupe, A. R. Inorg. Chim. Acta 2000, 305,
(7) Prepared in 84% yield by the reaction of 2-chloropyrimidine with
hydroiodic acid at 0 °C using a slightly modified procedure of Brown,
D. J .; Waring, P. Aust. J . Chem. 1973, 26, 443-447.
(8) Caton, M. P. L.; Hurst, D. T.; McOmie, J . F. W.; Hunt, R. R. J .
Chem. Soc. C 1967, 1204-1209.
1
27-134.
2) Periana, R. A.; Taube, D. J .; Gamble, S.; Taube, H.; Satoh, T.;
Fujii, H. Science 1998, 280, 560-564.
3) Bly, D. D.; Mellon, M. G. J . Org. Chem. 1962, 27, 2945-46; Anal.
Chem. 1963, 35, 1386-1392.
4) (a) Nasielski, J .; Standaert, A.; Nasielski-Hinkens, R. Synth.
(
(
(9) Kosolapoff, G. M.; Roy, C. H. J . Org. Chem. 1961, 26, 1895-
1898.
(
Commun. 1991, 21, 901-906. (b) Fort, Y.; Becker, S.; Caub e` re, P.
(10) Crosby, D. G.; Berthold, R. V. J . Org. Chem. 1960, 25, 1916-
1919.
(11) Brown, D. J .; Lyall, J . M. Aust. J . Chem. 1964, 17, 794-802.
(12) Goodby, J . W.; Hird, M.; Lewis, R. A.; Toyne, K. J . J . Chem.
Soc., Chem. Commun. 1996, 2719-2720.
Tetrahedron 1994, 50, 11893-11902.
(5) Mukkala, V.-M.; Sund, C.; Kwiatkowski, M.; Pasanen, P.; H o¨ g-
berg, M.; Kankare, J .; Takalo, H. Helv. Chim. Acta 1992, 75, 1621-
1
632.
1
0.1021/jo0255781 CCC: $22.00 © 2002 American Chemical Society
Published on Web 08/03/2002
6
550
J . Org. Chem. 2002, 67, 6550-6552

TABLE 1.
coupling precursor (mmol)
2-X-pyrimidine (mmol)
PPh3 (mmol)
Zn (mmol)
solvent (mL)
time (h)
yield (%)
NiCl2‚6H2O (8.73)
Ni(acac)2 (6.56)
NiCl2‚6H2O (6.56)
NiCl2‚6H2O (1.45)
copper (338)
X ) Cl; 8.73
X ) Cl; 8.73
X ) Cl; 13.1
X ) I; 1.94
X ) I; 72.8
34.9
26.2
26.2
5.83
0
121.5
9.36
9.35
2.08
0
45
45
60
10
60
5
5
5
5
9
trace
0
21
33
90
hydride at atmospheric pressure under
molecular sieves (3 Å) or degassed by purging with N
fine powder, >230 mesh, 25 g) was activated by washing it on
a glass filter with a 1:1 mixture of acetone and 37% aqueous
solution of hydrochloric acid (100 mL), acetone (100 mL), distilled
water (100 mL), 5% aqueous solution of ammonia (100 mL),
absolute ethanol (until the filtrate’s blue color disappeared),
acetone (100 mL), and diethyl ether (250 mL). Finally, all
residual solvents were removed in a vacuum.
P r ep a r a tion of 2-Iod op yr im id in e. Hydroiodic acid (160.0
mL, 57%), precooled to 0 °C, was added to solid 2-chloropyrimi-
dine (40.0 g, 194 mmol) in a 500 mL round-bottomed flask. The
mixture was kept and vigorously stirred at 0 °C for 50 min. The
light brownish green suspension was quickly neutralized at 0
N
2
and stored on
g, 0.125 mol) and phosphorus oxychloride (110 mL) was refluxed
for 10 h, after which time the residual phosphorus oxychloride
was removed in vacuo. The residual oil was poured into 50 g of
ice and neutralized below 10 °C with a concentrated aqueous
solution of potassium hydroxide. The resulting mixture and 300
mL of diethyl ether was vigorously stirred for 10 h. The organic
extract was evaporated to dryness. The residual crude product
was recrystallized from a minimal amount of petroleum ether
(bp 40-70 °C) giving 13.8 g (77%) of 4,6-dimethyl-2-chloropyri-
2
. Copper
(
9
midine as colorless plates. Mp: 37-38 °C (uncorrected; lit. mp
1
38-39 °C). H NMR (CDCl
3
): δ 6.89 (s), 2.37 (s).
8
P r ep a r a tion of 4,6-Dim eth yl-2-iod op yr im id in e. The het-
erogeneous mixture of 4,6-dimethyl-2-chloropyrimidine (2.0 g,
14.0 mmol) and hydroiodic acid (5.0 mL, 57%) was vigorously
stirred in a capped round-bottomed flask at room temperature
for 5 h. The brownish green suspension was neutralized at 10
°C with saturated aqueous solution of potassium carbonate and
decolorized with potassium disulfite. The white precipitate was
collected and recrystallized from petroleum ether (bp 40-70 °C)
giving 2.05 g (62%) of 4,6-dimethyl-2-iodopyrimidine as snow-
°
C with a saturated aqueous solution of potassium carbonate
and decolorized with potassium disulfite at 0 °C. The aqueous
solution was extracted with diethyl ether (5 × 300 mL), dried
over desiccated magnesium sulfate, filtered, and evaporated
under reduced pressure. The light yellow oil was dissolved in a
minimal amount of boiling petroleum ether (bp 30-50 °C) and
crystallized at 0 °C to give 60.5 g (84%) of colorless 2-iodopyri-
8
white needles. Mp: 128-129 °C (uncorrected; lit. mp 128-129
7
1
midine: mp 30-32 °C (uncorrected; lit. mp 30-32 °C). Anal.
°C). H NMR (CDCl
3
): δ 6.98 (s), 2.40 (s).
Calcd for C
H, 1.60; N, 14.05. H NMR (CDCl
4
H
3
IN
2
: C, 23.32; H, 1.47; N, 13.60. Found: C, 23.60;
P r ep a r a t ion of 4,4′,6,6′-Tet r a m et h yl-2,2′-b ip yr im id in e
(2). 4,6-Dimethyl-2-iodopyrimidine (0.300 g, 1.28 mmol) and
activated copper powder (480 mg, 7,55 mmol) were placed in a
1
3
): δ 8.45 (d, J ) 4.90 Hz),
1
3
1
7
1
3
.32 (t, J ) 4.90 Hz). C{ H} NMR (CDCl ): δ 158.9, 130.0,
21.0.
4 mL flask fitted with a reflux condenser, a N
magnetic stirrer. Absolute DMF (1.5 mL) was added, and the
flask was flushed with N for 10 min. The reaction mixture was
2
inlet, and a
P r ep a r a tion of 2,2′-Bip yr im id in e (1) by Ullm a n n Cou -
p lin g. 2-Iodopyrimidine (15.0 g, 72.8 mmol) and activated copper
2
powder (17.5 g, 275 mmol) were placed in a 250 mL double-
heated to 85 °C with vigorous stirring and the temperature kept
between 85 and 90 °C. After 3.5 h, 120 mg (1.89 mmol) of
necked flask fitted with a reflux condenser, a N
magnetic stirrer. Absolute DMF (60 mL) was added, and the
flask was flushed with N for 10 min. The reaction mixture was
2
inlet, and a
activated copper powder was added to the mixture, and the N
2
2
inlet was replaced with a calcium chloride tube. After another
3.5 h, the temperature was increased to 120-130 °C and the
stirring was continued for 2 h. The suspension was then cooled
to 0 °C, carefully drowned into a solution of 1.0 g potassium
cyanide in 5 mL of 25% aqueous solution of ammonia, and
filtered. The solid residue on the filter was extracted with the
same amount of cyanide solution and filtered again. The
combined filtrates were treated with 50 mg of potassium cyanide
and extracted with chloroform (5 × 20 mL). The organic phases
were dried over desiccated potassium carbonate, filtered, and
evaporated to dryness. Recrystallization of the crude product
from ethyl acetate-petroleum ether (bp 40-70 °C) gave 69 mg
(50%) of pale tan 4,4′,6,6′-tetramethyl-2,2′-bipyrimidine (2).
heated to 80 °C with vigorous stirring and the temperature kept
between 80 and 85 °C. After 3.5 h, 4.0 g (63.0 mmol) of activated
copper powder was added to the mixture, and the N inlet was
2
replaced with a calcium chloride tube. After another 3.5 h, the
temperature was increased to 120-130 °C and the stirring was
continued for 2 h. The suspension was then cooled to 0 °C,
carefully drowned into a solution of 23.0 g potassium cyanide
in 115 mL of 25% aqueous solution of ammonia, and filtered.
The solid residue on the filter was extracted with the same
amount of cyanide solution and filtered again. The combined
filtrates were treated with 1.2 g of potassium cyanide and
extracted with chloroform (5 × 300 mL). The organic phases
were dried over desiccated potassium carbonate, filtered, and
evaporated to dryness. Re-crystallization of the crude product
from ethyl acetate/methanol 19:1 with addition of petroleum
ether (bp 40-70 °C) gave 5.16 g (90%) of pale tan 2,2′-
4
a
1
Mp: 131-132 °C (uncorrected; lit. mp 131-132 °C). H NMR
(CDCl ): δ 7.12 (s), 2.62 (s).
3
P r ep a r a tion of 2-Hyd r oxyp yr im id in e Bisu lfa te. The
solution of 2-hydroxypyrimidine hydrochloride (26.54 g, 0.200
mol) in 50 mL of distilled water was mixed with 95% sulfuric
acid (20.67 g, 0.200 mol) and evaporated to dryness at 100 °C
under reduced pressure. Drying in a vacuum with desiccated
potassium hydroxide gave 39.0 g (∼100%) of crystalline 2-hy-
droxypyrimidine bisulfate.
P r ep a r a tion of 2-Hyd r oxyp yr im id in e. 2-Hydroxypyrimi-
dine bisulfate (39.0 g, 0.200 mol) was dissolved in 300 mL of
distilled water , added to a solution of barium acetate (51.3 g,
0.201 mol) in 400 mL of distilled water, treated with gasous
carbon dioxide, and filtered through Celite500. The resulted
solution was evaporated to dryness at 100 °C under reduced
pressure. Drying in a vacuum with desiccated potassium hy-
3
bipyrimidine (1). Mp: 112-114 °C (uncorrected; lit. mp 113-
1
8 6 4
15 °C). Anal. Calcd for for C H N : C, 60.75; H, 3.82; N, 35.42.
1
Found: C, 60.37; H, 3.88; N, 35.71. H NMR (CDCl
3
): δ 8.95 (d,
): δ
63.3, 158.2, 121.8. IR: 3049 w, 2979 w, 1565 m, sh, 1557 s,
403 vs, 1142 w, 989.9 w, 808.5 w, 773.7 w. EIMS: 158 (M, base
1
3
1
J ) 4.90 Hz), 7.42 (t, J ) 4.90 Hz). C{ H} NMR (CDCl
1
1
3
peak), 159 (M - H).
P r ep a r a tion of 4,6-Dim eth yl-2-h yd r oxyp yr im id in e Hy-
9
d r och lor id e. Urea (12.0 g, 0.20 mol) in 100 mL of boiling
ethanol was treated with acetylacetone (20.0 g, 0.20 mol), and
the hot solution was treated with 27 mL of concentrated
hydrochloric acid with stirring. The mixture was refluxed for
2
4 h, after which time 24.0 g (75%) of 4,6-dimethyl-2-hydroxy-
droxide gave 18.8 g (97.5%) 2-hydroxypyrimidine as a light
1
pyrimidine hydrochloride was isolated by filtration and subse-
quent washing with cold ethanol and diethyl ether.
yellow powder. H NMR (DMSO-d
(t, J ) 5.0 Hz).
6
): δ 8.26 (d, J ) 5.0 Hz), 6.36
P r ep a r a tion of 4,6-Dim eth yl-2-ch lor op yr im id in e.9 The
mixture of 4,6-dimethyl-2-hydroxypyrimidine hydrochloride (20.0
P r ep a r a tion of 5-Br om o-2-h yd r oxyp yr im id in e.10 2-Hy-
droxypyrimidine (18.58 g, 0.193 mol) was added to a stirred
J . Org. Chem, Vol. 67, No. 18, 2002 6551

solution of bromine (33.5 g, 0.210 mol) in 7400 mL of water at
room temperature. After 5 min, the water was removed in vacuo,
and the residual brownish yellow oil was treated with water
leading to the precipitation of crude 5-bromo-2-hydroxypyrimi-
dine. The off-white powder was recrystallized from 90% aqueous
ethanol giving 16.8 g (50%) of 5-bromo-2-hydroxypyrimidine.
2
necked flask fitted with a reflux condenser, a N inlet, and a
magnetic stirrer. Absolute DMF (7 mL) was added, and the flask
was flushed with N for 10 min. The reaction mixture was heated
2
to 90 °C with vigorous stirring and the temperature kept
between 90 and 95 °C. After 3.5 h, 0.35 g (5.5 mmol) of activated
copper powder was added to the mixture, and the N inlet was
2
4 3 2
Anal. Calcd for C H BrN H
O: Br, 45.66. Found: Br, 45.43. 1
replaced with a calcium chloride tube. After another 3.5 h, the
temperature was increased to 120-130 °C, and the stirring was
continued for 2 h. The suspension was then cooled below 10 °C,
carefully drowned in a solution of 2.7 g potassium cyanide in 14
mL of 25% aqueous solution of ammonia, and filtered. The solid
residue on the filter was extracted with the same amount of
cyanide solution and filtered again. The combined filtrates were
treated with 0.1 g of potassium cyanide and extracted with
chloroform (6 × 70 mL). The organic phases were dried over
desiccated potassium carbonate, filtered, and evaporated to
dryness. Recrystallization of the crude product from ethyl
acetate/chloroform 9:1 with addition of petroleum ether (bp 40-
NMR (DMSO-d
6
): δ 8.46 (s), ∼3.4 (s, broad).
P r ep a r a tion of 5-Br om o-2-ch lor op yr im id in e.11 5-Bromo-
2
-hydroxypyrimidine (16.75 g, 95.7 mmol), phosphoroxy chloride
(125 mL), and N,N-dimethylaniline (4.2 mL) were refluxed for
4
h. The cooled reaction mixture was poured onto 500 g of ice
and extracted with diethyl ether (5 × 200 mL). The extract was
neutralized with aqueous solution of sodium bicarbonate, dried
over magnesium sulfate, and evaporated to dryness. The re-
crystallization of the crude product from a minimal amount of
diethyl ether gave 13.5 g (73%) of 5-bromo-2-chloropyrimidine.
Mp: 78-79 °C (uncorrected; lit. mp 79-80 °C). 1H NMR
1
1
(
3
CDCl ): δ 8.70 (s).
1
2
70 °C) and refrigeration gave 0.51 g (38%) of pale tan 5,5′-
P r ep a r a tion of 5-Br om o-2-iod op yr im id in e. Precooled
-10 °C) 57% hydroiodic acid (48 mL) was added drowise to a
1
dibromo-2,2′-bipyrimidine (3). H NMR (CDCl
3
): δ 9.06 (s). IR
(
(in KBr): 3014 m, 1540 w, 1523 vs, 1411 vs, 1361 m, 1236 w,
cooled, stirred solution of 5-bromo-2-chloropyrimidine (13.50 g,
1
137 vs, 1008 s, 932 w, 758 s, 641 s. EIMS: 314-316-318 (M,
6
9.8 mmol) in dichloromethane (42 mL). The mixture was stirred
base peak, triplet by two isotopes of bromine atom).
at 0 °C for 5 h, neutralized carefully with solid potassium
carbonate, and decolorized with a saturated aqueous solution
of sodium disulfite. Water was added until the solution was
formed. The organic layer was separated, and the aqueous layer
was extracted with dichloromethane (5 × 100 mL), dried over
potassium carbonate, filtered, and evaporated to dryness. The
crude product was recrystallized from petroleum ether (bp 40-
Ack n ow led gm en t. This work was partially sup-
ported by the Hungarian National Scientific Research
Fund (OTKA-T032850) and ExxonMobil Research and
Engineering Co., Annandale, NJ . We thank Prof. J o´ zsef
R a´ bai for his suggestions. We are also grateful to Mrs.
J udit Szt a´ ray and Mr. D a´ vid Frigyes for MS measure-
ments.
7
1
0 °C) yielding 14.5 g (73%) of 5-bromo-2-iodopyrimidine. Mp:
01 °C (uncorrected; lit.12 mp 101-102 °C).
P r ep a r a tion of 5,5′-Dibr om o-2,2′-bip yr im id in e (3). 5-Bro-
mo-2-iodopyrimidine (2.40 g, 8.42 mmol) and activated copper
powder (2.00 g, 31.5 mmol) were placed in a 20 mL double-
J O0255781
6
552 J . Org. Chem., Vol. 67, No. 18, 2002