Regio- And chemoselective metalation of chloropyrimidine derivatives with TMPMgCl·LiCl and TMP2Zn·2MgCl2·2 LiCl

Article abstract of DOI:10.1002/chem.200801831

Efficient zincation and magnesiation of chlorinated pyrimidines can be performed at convenient temperatures (e.g., 25 and 55°C) by using TMPMgCl·LiCl and TMP₂Zn·2 MgCl₂·2LiCl (TMP = 2,2,6,6-tetramethylpiperidyl) as effective bases. Q

Full text of DOI:10.1002/chem.200801831

DOI: 10.1002/chem.200801831
Regio- and Chemoselective Metalation of Chloropyrimidine Derivatives with
TMPMgCl·LiCl and TMP2Zn·2MgCl2·2LiCl**
Marc Mosrin and Paul Knochel*[a]
Abstract: Efficient zincation and magnesiation of chlorinated pyrimidines can be
performed at convenient temperatures (e.g., 25 and 558C) by using
TMPMgCl·LiCl and TMP2Zn·2MgCl2·2LiCl (TMP=2,2,6,6-tetramethylpiperidyl)
Keywords: chemoselectivity · mag-
as effective bases. Quenching of the resulting zincated or magnesiated pyrimidines
nesium · metalation · pyrimidines ·
with various electrophiles furnishes highly functionalized pyrimidines in 51–93%
regioselectivity · zinc
yield. Oxidative aminations were carried out, thus leading to aminated pyrimi-
dines. By using this methodology, we have also prepared pharmaceutically relevant
pyrazolopyrimidines and the fungicide Mepanipyrim.
Introduction
and TMP2Zn·2MgCl2·2LiCl[8] (2) and enable selective func-
tionalization at all of the positions of the pyrimidine ring
under mild conditions starting from inexpensive commercial
compounds. Applications of this method to the synthesis of
biologically relevant molecules will also be presented.
Pyrimidines are important heterocyclic scaffolds and their
derivatives occupy a privileged position among substances
with pharmaceutical or agrochemical applications.[1] The
direct functionalization of these heterocycles by lithiation is
difficult due to the high reactivity of the ring toward the ad-
dition of organometallic reagents,[2] which implies that low
temperatures are quite often required for the metalation of
pyrimidines.[3] Quꢀguiner and Radinov[4] reported the regio-
selective lithiation of polychloropyrimidines by using classi-
cal lithium amide bases. The sole example of a pyrimidine
deprotonation at the C2 position was reported by Kanamoto
Results and Discussion
We first investigated the metalation of 4,6-dichloro-2-(meth-
ylthio)pyrimidine (3). Thus, the treatment of 3 with reagent
1 (1.1 equiv, 258C, 30 min) leads to a 5-magnesiated pyrimi-
dine 4 (Scheme 1). Trapping with various electrophiles, such
as PhCHO, NCCO2Et, CH3I, (BrCCl2)2, Me3SiCN, or iodo-
methyl pivalate, leads to 5-substituted pyrimidines 5a–f in
76–92% yield (Table 1, entries 1–6). Acylations can also be
readily performed after transmetalation with CuCN·2LiCl.[9]
Quenching of the metalated species with 4-fluorobenzoyl
chloride, 3,3-dimethylbutanoyl chloride, PhCOCl, and furan-
2-carbonyl chloride furnishes 5-ketopyrimidine derivatives
5g–j in 84–93% yield (Table 1, entries 7–10). The metalation
of 2-chloro-4-(methylthio)pyrimidine (6) can also be selec-
tively achieved at position 6 with 1 (1.1 equiv, 258C, 5 min),
thus providing the magnesium reagent 7 (Scheme 1). Iodina-
tion by reaction with I2 leads to the iodopyrimidine deriva-
tive 8a in 71% yield (Table 1, entry 11). Reaction with
(BrCCl2)2 furnishes the bromopyrimidine 8b in 79% yield
(Table 1, entry 12). Chlorination using F2ClCCCl2F leads to
the chloropyrimidine 8c in 72% yield (Table 1, entry 13).
We extended this approach to the functionalization of
other polychloropyrimidines and treated 2,4,6-trichloropyri-
and
ACHTUNGTRENNUNG
co-workers:[5]
4-(tert-butoxycarbonyl)amino-2-(tri-
protonation with lithium 2,2,6,6-tetramethylpiperidine and
trapping with trimethylsilyl chloride (TMSCl). Recently, we
have shown that TMPMgCl·LiCl[6] (1; TMP=2,2,6,6-tetra-
methylpiperidyl) allows direct functionalization of the pyri-
midine rings, including uracil and thiouracil derivatives.[7]
Herein, we report the extension of this method with chloro-
pyrimidines as the starting materials. These complementary
procedures for the metalation of pyrimidine use reagent 1
[a] M. Sc. M. Mosrin, Prof. Dr. P. Knochel
Ludwig—Maximilians Universitꢁt Mꢂnchen
Department Chemie & Biochemie
Butenandtstrasse 5–13, Haus F, 81377 Mꢂnchen (Germany)
Fax : (+49)89-2180-77680
E-mail: paul.knochel@cup.uni-Muenchen.de
[**] TMP=2,2,6,6-tetramethylpiperidyl.
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FULL PAPER
tonation of 10 can also be car-
ried out under mild conditions
with reagent 2 (0.55 equiv) and
affords the zinc species 12 at
258C
within
45 minutes.
Quenching with I2, PhCOCl
(after transmetalation with
CuCN·2LiCl),[9] 3-bromocyclo-
hexene (after the addition of a
catalytic amount of CuCN·2
LiCl), and chloranil[10] affords
the 5-functionalized pyrimi-
dines 14a–d in 72–91% yield
(Table 2, entries 4–7). A further
metalation is also achieved at
C2 by the addition of reagent 2
(0.55 equiv) to 5-substituted
pyrimidines (Scheme 3). Thus,
4,6-dichloro-5-iodopyrimidine
(14a) was converted into the 2-
zincated species at 558C within
1 h and was iodinated by reac-
tion with I2, thus leading to the
2-iodopyrimidine (15a) in 61%
yield (Table 2, entry 8). Reac-
tion with allyl bromide (after
Scheme 1. Chemoselective magnesiation of 4,6-dichloro-2-(methylthio)pyrimidine (3) at C5 and 2-chloro-4-
(methylthio)pyrimidine (6) at C6 by using reagent 1 (1.1 equiv) and trapping with electrophiles (E).
Scheme 2. Regio- and chemoselective metalation of 2,4,6-trichloropyrimidine (9) and 4,6-dichloropyrimidine
(10) at C5 by using reagent 2 (0.55 equiv) and trapping with electrophiles.
the addition of
a
catalytic
amount of CuCN·2LiCl) fur-
nishes the allyl derivative 15b in 51% yield (Table 2,
entry 9). The metalation of 2,5-dichloropyrimidine (16) can
also be performed under mild conditions (Scheme 4). Thus,
the treatment of 16 with reagent 2 (0.55 equiv) provides the
corresponding zinc reagent 17 after 45 min at 258C. Trap-
ping with I2 provides the iodopyrimidine 18a in 72% yield
À
(Table 2, entry 10). The formation of a new C C bond can
also be readily achieved by a Negishi cross-coupling,[11] thus
Scheme 3. Chemoselective metalation and trapping of 5-iodo-4,6-dichlor-
opyrimidine (14a) at C2 by using reagent 2 (0.55 equiv).
giving the 4-substituted pyrimidines 18b and 18c in 78 and
73%
yield,
respectively
(Table 2, entries 11 and 12).
This method is of great utility
for the preparation of pharma-
ceutically active heterocycles
such as pyrazolopyrimidines.[12]
The treatment of 5-ketopyrimi-
dine derivatives 5g–i with
NH2NH2·H2O at 258C allows
the formation of the pyrazolo-
pyrimidines 19a–c in 73–83%
yield (Scheme 5).
Scheme 4. Regio- and chemoselective metalation of 2,5-dichloropyrimidine (16) at C4 by using reagent 2
(0.55 equiv) and trapping with electrophiles.
midine (9) and 4,6-dichloropyrimidine (10) with reagent 2
(0.55 equiv, 258C; Scheme 2). The treatment of 9 with 2
(0.55 equiv) provides the corresponding zinc reagent 11
after 60 min at 258C. Trapping with typical electrophiles (I2,
allyl bromide (after the addition of a catalytic amount of
CuCN·2LiCl), and propionyl chloride (after transmetalation
with CuCN·2LiCl)[9]) furnishes 5-substituted pyrimidines
13a–c in 83–90% yield (Table 2, entries 1–3). Smooth depro-
Aminopyrimidines are also well known for displaying a
large spectrum of biological activity.[13] Recently, we devel-
oped an amination method that tolerates a broad range of
functionalized groups and is not sensitive to the steric hin-
drance in the substrates.[14] By using this method, amination
reactions can also be carried out starting from compound 3.
The deprotonation of 3 with reagent 1 (1.1 equiv, 258C,
30 min) after transmetalation with CuCl·2LiCl leads to the
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1469

P. Knochel, M. Mosrin
dine 22 in 91% yield. Subsequent magnesiation of 22 at po-
sition 6 can be readily achieved with reagent 1 (1.1 equiv,
À608C, 1 h) and provides 2-chloro-4-bromo-6-iodopyrimi-
dine (23) in 96% yield after trapping with (BrCCl2)2. The
Negishi cross-coupling[11] furnishes the 4-methylpyrimidine
derivative 24 in 58% yield. The Sonogashira reaction[16] of
24 then affords the 6-alkynylpyrimidine 25 in 97% yield. Fi-
nally, a Buchwald–Hartwig Pd-catalyzed amination[17] allows
the substitution of the chlorine atom at position 2 to give
Mepanipyrim 26 in 81% yield.
Conclusion
Scheme 5. Synthesis of the pyrazolopyrimidines 19a–c.
In summary, we have reported the efficient metalation of
chlorinated pyrimidines that
proceeds at convenient temper-
atures with 1 and 2 as effective
bases. Quenching of the result-
ing magnesiated or zincated
pyrimidines with various elec-
trophiles has been performed in
satisfactory yields. This method
displays a large scope of applic-
ability and allows functionaliza-
tion of all the positions of a
pyrimidine unit. It may find
broad application in the synthe-
sis of pharmaceutically and
agrochemically relevant mole-
cules. Extension of this method-
Scheme 6. Amination reactions starting from 4,6-dichloro-2-(methylthio)pyrimidine (3), thus furnishing amino-
pyrimidine derivatives 20a–c.
ology to the preparation of new
materials is currently under in-
vestigation in our laboratories.
addition of the lithium amide species and chloranil to the 5-
aminated pyrimidines 20a–c in 68–71% yield (Scheme 6).
To demonstrate the robustness of our metalation method,
Experimental Section
we performed the synthesis of the fungicide Mepanipyrim[15]
(26; Scheme 7). The treatment of 2-chloropyrimidine (21)
with reagent 1 (1.1 equiv, À608C, 2 h) after transmetalation
with ZnCl2 and quenching with I2 leads to the 4-iodopyrimi-
General: All the reactions were carried out in an argon atmosphere in
flame-dried glassware. Syringes that were used to transfer anhydrous sol-
vents or reagents were purged with argon prior to use. THF was continu-
ously heated to reflux and freshly distilled from sodium benzophenone
Scheme 7. Synthesis of the fungicide Mepanipyrim 26.
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Zincation and Magnesiation of Chlorinated Pyrimidines
FULL PAPER
Table 1. Products obtained by the magnesiation of 3 and 6 with reagent 1 and reactions with electrophiles.
Typical procedure 2 (TP2): prepara-
tion of TMP2Zn·2MgCl2·2LiCl (2):
Freshly titrated 1 (100 mmol, 1.00m,
100 mL) in THF was added dropwise
to ZnCl2 (53.0 mmol, 7.22 g), which
had been dried in an argon-flushed
Schlenk flask in vacuo at 1408C for
4 h and then cooled to 258C. The re-
sulting mixture was stirred for 15 h at
258C. The freshly prepared solution of
2 in THF was titrated prior to use at
08C with benzoic acid and 4-(phenyl-
Entry
Substrate
T [8C] t [min] E+
Product
Yield [%][a]
1
3
3
3
3
3
3
3
3
3
3
6
6
6
25
25
25
25
25
25
25
25
25
25
25
25
25
30
30
30
30
30
30
30
30
30
30
5
PhCHO
NCCO2Et
CH3I
5a 90
2
3
5b 86
5c 92
5d 89
5e 79
5 f 76
5g 93[b]
5h 84[b]
5i 90[b]
5j 86[b]
8a 71
8b 79
8c 72
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
4
ACHTUNGTERN(NUNG BrCCl2)2
3
(TP3): general
procedure for the metalation: A dry,
argon-flushed 10-mL Schlenk tube
equipped with a magnetic stirrer and a
5
Me3SiCN
septum was charged with
0.92 mL, 1.1 mmol, 1.1 equiv) in THF
or (0.79m, 1.39 mL, 0.55 mmol,
1 (1.2m,
2
6
iodomethyl pivalate
0.55 equiv) in THF. The pyrimidine
substrate (1.0 mmol) in THF (2 mL)
was added dropwise at temperature
T1. The completion of the metalation
was checked by GC analysis of ali-
quots of the reaction mixture
quenched with a solution of I2 in THF.
The electrophile or its solution in THF
was added at temperature T2. After
completion of the reaction (checked
by GC analysis of aliquots of the reac-
tion mixture quenched with saturated
aqueous NH4Cl), the reaction mixture
was quenched with saturated aqueous
NH4Cl (10 mL). The aqueous layer
was extracted with diethyl ether (5ꢄ
30 mL). The combined organic ex-
tracts were dried with Na2SO4 and
concentrated in vacuo. The crude resi-
due was purified by filter column chro-
matography (CH2Cl2/pentane).
4-fluorobenzoyl chlo-
ride
7
3,3-dimethylbutyryl
chloride
8
9
benzoyl chloride
furan-2-carbonyl chlo-
ride
10
11
12
13
I2
4,6-Dichloro-2-(methylthio)pyrimidin-
5-yl)-phenylmethanol (5a): 4,6-Di-
5
ACHTUNGTERN(NUNG BrCCl2)2
chloro-2-(methylthio)pyrimidine
(3;
292 mg, 1.5 mmol) dissolved in dry
THF (3 mL) was added dropwise at
5
FCl2CCClF2
258C to
a solution of 1 (1.14m,
1.45 mL, 1.65 mmol) in THF and
stirred at the same temperature for
30 min according to TP3. Benzalde-
hyde (239 mg, 2.25 mmol) in dry THF
(3 mL) was slowly added at 258C and
the resulting mixture was stirred for
[a] Yield of the isolated analytically pure product. [b] Transmetalation with CuCN·2LiCl (1.1 equiv) was per-
formed.
ketyl under nitrogen. The yields refer to the yields of isolated compounds
estimated to be >95% pure as determined by 1H NMR spectroscopic
(258C) and capillary GC analysis. Column chromatographic purification
was performed on SiO2 (0.040–0.063 mm, 230–400 mesh ASTM) from
Merck if not specially indicated.
30 min. The reaction mixture was quenched with saturated aqueous
NH4Cl (30 mL), extracted with diethyl ether (5ꢄ30 mL), and dried over
anhydrous Na2SO4. After filtration, the solvent was evaporated in vacuo.
Purification by flash column chromatography (CH2Cl2/pentane 1:3) fur-
1
nished 5a as a colorless solid (405 mg, 90%). M.p. 83.9–84.68C; H NMR
Typical procedure 1 (TP2): preparation of TMPMgCl·LiCl (1): A dry,
argon-flushed 250-mL flask equipped with a magnetic stirrer and a
septum was charged with freshly titrated i-PrMgCl·LiCl (100 mL, 1.2m,
120 mmol) in THF to which 2,2,6,6-tetramethylpiperidine (TMPH; 18.7 g,
132 mmol, 1.1 equiv) was added dropwise at 258C. The reaction mixture
was stirred at 258C until gas evolution was completed (ca. 48 h). The
fresh solution of 1 in THF was titrated at 258C with benzoic acid and 4-
(phenylazo)diphenylamine as the indicator.
(300 MHz, CDCl3): d=7.30–7.36 (m, 5H), 6.52 (s, 1H), 3.48 (bs, 1H),
2.57 ppm (s, 3H); 13C NMR (75 MHz, CDCl3): d=172.0, 160.8, 139.5,
128.2, 127.5, 126.7, 125.0, 70.2, 14.2 ppm; MS (70 eV, EI): m/z (%): 300
[35ClÀM+] (100), 223 (29); IR (attenuated total reflection (ATR)): n˜ =
3561, 3447, 2925, 1538, 1478, 1339, 1308, 1259, 1171, 1111, 1021, 876, 814,
727, 711, 639 cmÀ1
299.9891; found: 299.9878.
;
HRMS (EI): m/z: calcd for C12H1035Cl2N2O32S:
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1471

P. Knochel, M. Mosrin
Table 2. Products obtained by the zincation of 6, 7, and 16 with reagent 2 and reactions with electrophiles.
2982, 2932, 1735, 1550, 1479, 1374,
1346, 1320, 1293, 1217, 1067, 1008, 860,
825, 780 cmÀ1; HRMS (EI): m/z: calcd
for C8H835Cl2N2O232S: 265.9684; found:
265.9689.
Entry
Substrate
T [8C] t [min] E+
Product
Yield [%][a]
1
9
9
9
25
25
25
60
60
60
45
45
45
I2
13a
13b
83
4,6-Dichloro-5-methyl-2-(methylthio)-
pyrimidine
(5c):
Compound
3
(292 mg, 1.5 mmol) in dry THF (3 mL)
was added dropwise at 258C to a solu-
tion of 1 (1.14m, 1.45 mL, 1.65 mmol)
in THF and stirred at the same tem-
perature for 30 min according to TP3.
Iodomethane (426 mg, 3 mmol) was
then slowly added at 258C and the re-
sulting mixture was stirred for 20 min.
The reaction mixture was quenched
2
3
4
5
6
allyl bromide
propionyl chloride
I2
90[c]
13c 86[b]
10 25
10 25
10 25
14a
14b
14c
91
with
saturated
aqueous
NH4Cl
(30 mL), extracted with diethyl ether
(5ꢄ30 mL), and dried over anhydrous
Na2SO4. After filtration, the solvent
was evaporated in vacuo. Purification
by flash column chromatography
(CH2Cl2/pentane 1:1) furnished 5c as a
colorless solid (287 mg, 92%). M.p.
60.2–62.18C; 1H NMR (300 MHz,
CDCl3): d=2.48 (s, 3H), 2.32 ppm (s,
3H); 13C NMR (75 MHz, CDCl3): d=
169.8, 161.1, 122.7, 15.4, 14.2 ppm; MS
(70 eV, EI): m/z (%): 208 [35ClÀM+]
(100), 162 (31), 127 (20); IR (ATR):
n˜ =2930, 2480, 1545, 1480, 1383, 1343,
1316, 1292, 1222, 1190, 1116, 1010, 973,
862, 792, 756, 694 cmÀ1; HRMS (EI):
m/z: calcd for C6H635Cl2N2O232S:
207.9629; found: 207.9620.
benzoyl chloride
86[b]
72[c]
3-bromo-1-cyclohex-
ene
7
8
10 25
14a 55
45
60
chloranil
I2
14d
15a
82
61
9
14a 55
16 25
0
allyl bromide
I2
15b
18a
51[c]
72
4,6-Dichloro-5-bromo-2-(methylthio)-
pyrimidine
(5d):
Compound
3
10
45
(292 mg, 1.5 mmol) dissolved in dry
THF (3 mL) was added dropwise at
258C to
a solution of 1 (1.14m,
1.45 mL, 1.65 mmol) in THF and
stirred at the same temperature for
30 min according to TP3. 1,2-Dibro-
11
12
16 25
16 25
45
45
ethyl 4-iodobenzoate
18b
18c
78[d]
motetrachloroethane
(489 mg,
3-iodobenzo trifluor-
ide
73[d]
2.25 mmol) dissolved in dry THF
(3 mL) was then slowly added at 258C
and the resulting mixture was stirred
for 30 min. The reaction mixture was
quenched with saturated aqueous
NH4Cl (30 mL), extracted with diethyl
ether (5ꢄ30 mL), and dried over an-
hydrous Na2SO4. After filtration, the
solvent was evaporated in vacuo. Pu-
rification by flash column chromatog-
[a] Yield of isolated analytically pure product. [b] Transmetalation with CuCN·2LiCl (1.1 equiv) was per-
formed. [c] Transmetalation with CuCN·2LiCl (5 mol%) was performed. [d] Obtained by Pd-catalyzed cross-
coupling.
4,6-Dichloro-2-(methylthio)pyrimidine-5-carboxylic acid ethyl ester (5b):
Compound 3 (292 mg, 1.5 mmol) dissolved in dry THF (3 mL) was added
dropwise at 258C to a solution of 1 (1.14m, 1.45 mL, 1.65 mmol) in THF
and stirred at the same temperature for 30 min according to TP3. Ethyl
cyanoformate (298 mg, 3 mmol) was slowly added at 258C and the result-
ing mixture was stirred for 20 min. The reaction mixture was quenched
with saturated aqueous NH4Cl (30 mL), extracted with diethyl ether (5ꢄ
30 mL), and dried over anhydrous Na2SO4. After filtration, the solvent
was evaporated in vacuo. Purification by fast flash column chromatogra-
phy (CH2Cl2/pentane 1:5) furnished 5b as a colorless solid (345 mg,
86%). M.p. 63.6–65.58C; 1H NMR (300 MHz, CDCl3): d=4.42 (q, 2H,
J=6 Hz), 2.56 (s, 3H), 1.38 ppm (t, J=6 Hz, 3H); 13C NMR (75 MHz,
CDCl3): d=174.3, 162.5, 157.9, 121.9, 62.9, 14.5, 13.9 ppm; MS (70 eV,
EI): m/z (%): 266 [35ClÀM+] (100), 238 (55), 221 (53); IR (ATR): n˜ =
raphy (CH2Cl2/pentane 1:7) furnished 5d as a colorless solid (365 mg,
89%). M.p. 83.9–84.68C; 1H NMR (300 MHz, CDCl3): d=2.51 ppm (s,
3H); 13C NMR (75 MHz, CDCl3): d=171.2, 161.1, 113.4, 14.7 ppm; MS
(70 eV, EI): m/z (%): 272 [79Br35ClÀM+] (60); IR (ATR): n˜ =2925, 1517,
1470, 1424, 1377, 1326, 1272, 1179, 852, 809, 747 cmÀ1; HRMS (EI): m/z:
calcd for C579Br35Cl2N232S: 271.8577; found: 271.8562.
4,6-Dichloro-2-(methylthio)-5-trimethylsilanyl-pyrimidine (5e): Com-
pound 3 (292 mg, 1.5 mmol) in dry THF (3 mL) was added dropwise at
258C to a solution of 1 (1.14m, 1.45 mL, 1.65 mmol) in THF and stirred
at the same temperature for 30 min according to TP3. Trimethylsilylcya-
nide (179 mg, 1.8 mmol) was then slowly added at 258C and the resulting
mixture was stirred for 20 min. The reaction mixture was quenched with
saturated aqueous NH4Cl (30 mL), extracted with diethyl ether (5ꢄ
30 mL), and dried over anhydrous Na2SO4. After filtration, the solvent
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Zincation and Magnesiation of Chlorinated Pyrimidines
FULL PAPER
was evaporated in vacuo. Purification by flash column chromatography
(CH2Cl2/pentane 1:3) furnished 5e as a colorless solid (317 mg, 79%).
M.p. 82.5–84.08C; 1H NMR (300 MHz, CDCl3): d=2.52 (s, 3H),
0.46 ppm (s, 9H); 13C NMR (75 MHz, CDCl3): d=173.4, 166.9, 124.0,
14.0, 1.8 ppm; MS (70 eV, EI): m/z (%): 266 [35ClÀM+] (56), 251 (100),
178 (18), 166 (23), 95 (24); IR (ATR): n˜ =2956, 2930, 2894, 1509, 1455,
1323, 1284, 1246, 1163, 1034, 845, 799, 778, 701, 636 cmÀ1; HRMS (EI):
m/z: calcd for C8H1235Cl2N228S32Si: 265.9867; found: 265.9825.
4,6-Dichloro-2-methyl(thiopyrimidin-5-yl)-phenylmethanone (5i): Com-
pound 3 (292 mg, 1.5 mmol) in dry THF (3 mL) was added dropwise at
258C to a solution of 1 (1.14m, 1.45 mL, 1.65 mmol) in THF and stirred
at the same temperature for 30 min according to TP3. CuCN·2LiCl
(1.0m, 1.6 mL, 1.6 mmol) in THF was slowly added at À208C and the re-
action mixture was stirred at the same temperature for 30 min. Benzoyl
chloride (421 mg, 3 mmol) was added dropwise at À208C and the result-
ing mixture was stirred at 258C for 60 min. The reaction mixture was
quenched with saturated aqueous NH4Cl (30 mL), extracted with diethyl
ether (5ꢄ30 mL), and dried over anhydrous Na2SO4. After filtration, the
solvent was evaporated in vacuo. Purification by flash column chroma-
tography (CH2Cl2/pentane 1:6) furnished 5i as a colorless solid (402 mg,
90%). M.p. 135.1–136.28C; 1H NMR (300 MHz, CDCl3): d=7.81–7.83
(m, 2H), 7.62–7.66 (m, 1H), 7.46–7.52 (m, 2H), 2.59 ppm (s, 3H);
13C NMR (75 MHz, CDCl3): d=189.2, 174.2, 157.8, 134.8, 129.5, 129.1,
125.7, 14.4 ppm; MS (70 eV, EI): m/z (%): 298 [35ClÀM+] (100), 221 (26),
105 (78), 77 (33); IR (ATR): n˜ =3318, 3060, 2925, 1667, 1594, 1535, 1473,
[4,6-Dichloro-2-(methylthio)pyrimidin-5-yl]methyl pivalate (5 f): Com-
pound 3 (195 mg, 1.0 mmol) in dry THF (2 mL) was added dropwise at
258C to a solution of 1 (1.1m, 1.0 mL, 1.7 mmol) in THF and stirred at
the same temperature for 30 min according to TP3. Iodomethyl pivalate
(339 mg, 1.4 mmol) was then slowly added at À158C and the resulting
mixture was allowed to warm slowly to 258C over 3 h. The reaction mix-
ture was quenched with saturated aqueous NH4Cl (30 mL), extracted
with diethyl ether (5ꢄ30 mL), and dried over anhydrous Na2SO4. After
filtration, the solvent was evaporated in vacuo. Purification by flash
column chromatography (CH2Cl2/pentane 1:3) furnished 5 f as a colorless
1450, 1344, 1308, 1284, 1230, 1173, 1096, 915, 848, 822, 771, 706, 680 cmÀ1
;
HRMS (EI): m/z: calcd for C12H835Cl2N2O32S: 297.9734; found: 297.9739.
1
solid (235 mg, 76%). M.p. 58.3–60.78C; H NMR (300 MHz, CDCl3): d=
5.20 (s, 2H), 2.56 (s, 3H), 1.19 ppm (s, 9H); 13C NMR (75 MHz, CDCl3):
d=177.9, 173.6, 162.5, 120.8, 60.1, 39.0, 27.1, 14.5 ppm; MS (70 eV, EI):
m/z (%): 308 [35ClÀM+] (100), 210 (62), 208 (53), 57 (76); IR (ATR): n˜ =
2976, 2928, 2873, 1723, 1552, 1481, 1458, 1426, 1397, 1382, 1369, 1339,
1317, 1302, 1280, 1227, 1189, 1142, 1122, 1032, 993, 974, 916, 868, 793,
[4,6-Dichloro-2-(methylthio)pyrimidin-5-yl](furan-2-yl)methanone (5j):
Compound 3 (390 mg, 2.0 mmol) in dry THF (3 mL) was added dropwise
at 258C to a solution of 1 (1.1m, 2.0 mL, 2.2 mmol) in THF and stirred at
the same temperature for 30 min according to TP3. CuCN·2LiCl (1.0m,
2.2 mL, 2.2 mmol) in THF was slowly added at À208C and the reaction
mixture was stirred at the same temperature for 30 min. Furan-2-carbonyl
chloride (522 mg, 4 mmol) was added dropwise at À208C and the result-
ing mixture was allowed to warm slowly to 258C overnight. The reaction
mixture was quenched with saturated aqueous NH4Cl (30 mL), extracted
with diethyl ether (5ꢄ30 mL), and dried over anhydrous Na2SO4. After
filtration, the solvent was evaporated in vacuo. Purification by flash
column chromatography (CH2Cl2/pentane 1:4) furnished 5j as a colorless
solid (498 mg, 86%). M.p. 122.8–124.48C; 1H NMR (300 MHz, CDCl3):
d=7.71 (m, 1H), 7.28 (m, 1H), 7.65–7.67 (m, 1H), 2.63 ppm (s, 3H);
13C NMR (75 MHz, CDCl3): d=176.2, 174.6, 158.1, 151.3, 148.7, 124.9,
121.2, 113.3, 14.5 ppm; MS (70 eV, EI): m/z (%): 290 (62), 288 [35ClÀM+]
(100), 221 (12), 95 (55); IR (ATR): n˜ =3140, 3119, 2929, 2464, 1649, 1562,
1536, 1475, 1454, 1446, 1394, 1344, 1320, 1265, 1264, 1222, 1183, 1154,
1122, 1109, 1075, 1030, 1014, 945, 887, 874, 832, 819, 790, 766, 740, 661,
619, 584 cmÀ1; HRMS (EI): m/z: calcd for C10H635 Cl2N2O232S: 287.9527;
found: 287.9530.
770 cmÀ1 HRMS (EI): m/z: calcd for C11H1435Cl2N2O228S: 308.0153;
;
found: 308.0135.
[4,6-Dichloro-2-(methylthio)pyrimidin-5-yl](4-fluorophenyl)methanone
(5g): Compound 3 (292 mg, 1.5 mmol) in dry THF (3 mL) was added
dropwise at 258C to a solution of 1 (1.14m, 1.45 mL, 1.65 mmol) in THF
and stirred at the same temperature for 30 min according to TP3.
CuCN·2LiCl (1.0m, 1.7 mL, 1.7 mmol) in THF was slowly added at
À208C and the reaction mixture was stirred at the same temperature for
30 min. 4-Fluorobenzoyl chloride (476 mg, 3 mmol) was added dropwise
at À208C and the resulting mixture was allowed to warm slowly to 258C
overnight. The reaction mixture was quenched with saturated aqueous
NH4Cl (30 mL), extracted with diethyl ether (5ꢄ30 mL), and dried over
anhydrous Na2SO4. After filtration, the solvent was evaporated in vacuo.
Purification by flash column chromatography (CH2Cl2/pentane 1:5) fur-
nished 5g as
a colorless solid (441 mg, 93%). M.p. 133.5–135.08C;
1H NMR (600 MHz, CDCl3): d=7.85–7.88 (m, 2H), 7.18–7.20 (m, 2H),
2.61 ppm (s, 3H); 13C NMR (150 MHz, CDCl3): d=187.7, 174.6, 167.7,
2-Chloro-4-iodo-6-(methylthio)pyrimidine (8a): 2-Chloro-4-(methylthio)-
pyrimidine (6; 161 mg, 1.0 mmol) dissolved in dry THF (2 mL) was
added dropwise at 258C to a solution of 1 (1.1m, 1.0 mL, 1.1 mmol) in
THF and stirred at the same temperature for 5 min according to TP3.
Iodine (381 mg, 1.5 mmol) in dry THF (2 mL) was then added dropwise
at 258C and the resulting mixture was stirred for 45 min. The reaction
mixture was quenched with saturated aqueous NH4Cl (30 mL) and satu-
rated aqueous Na2S2O3 (10 mL), extracted with diethyl ether (5ꢄ30 mL),
and dried over anhydrous Na2SO4. After filtration, the solvent was
evaporated in vacuo. Purification by flash column chromatography
(CH2Cl2/pentane 1:5) furnished 8a as a colorless solid (203 mg, 71%).
M.p. 97.9–99.68C; 1H NMR (300 MHz, CDCl3): d=7.53 (s, 1H),
2.53 ppm (s, 3H); 13C NMR (75 MHz, CDCl3): d=173.8, 158.7, 127.1,
126.4, 12.8 ppm; MS (70 eV, EI): m/z (%): 286 [35ClÀM+] (100), 123 (13),
98 (53), 83 (16); IR (ATR): n˜ =3080, 3008, 2930, 1517, 1496, 1468, 1414,
1359, 1336, 1320, 1287, 1241, 1194, 1117, 1098, 1031, 964, 946, 838, 822,
809, 750, 708, 659, 602 cmÀ1; HRMS (EI): m/z: calcd for C5H435ClIN2S:
285.8828; found: 285.8812.
165.9, 157.9, 132.4 (d, J
ACHTUNGTRENNUNG(C,F)=9.7 Hz), 131.4 (d, JACHTUNTGREN(NGUN C,F)=3.0 Hz), 125.4,
116.7 (d, J(C,F)=22.2 Hz), 14.4 ppm; MS (70 eV, EI): m/z (%): 316
ACHTUNGTRENNUNG
[35ClÀM+] (68), 221 (10), 123 (100), 95 (36), 75 (10); IR (ATR): n˜ =3071,
2929, 2469, 2359, 1668, 1591, 1547, 1502, 1475, 1409, 1351, 1320, 1291,
1233, 1220, 1185, 1154, 1104, 1093, 969, 919, 848, 814, 774, 750, 684, 663,
637, 624 cmÀ1; HRMS (EI): m/z: calcd for C12H735Cl2FN2O32S: 315.9640;
found: 315.9632.
1-[4,6-Dichloro-2-(methylthio)pyrimidin-5-yl]-3,3-dimethylbutan-1-one
(5h): Compound 3 (975 mg, 5 mmol) in dry THF (5 mL) was added drop-
wise at 258C to a solution of 1 (1.1m, 5.0 mL, 5.5 mmol) in THF and
stirred at the same temperature for 30 min according to TP3. CuCN·2
LiCl (1.0m, 5.5 mL, 5.5 mmol) in THF was slowly added at À208C and
the reaction mixture was stirred at the same temperature for 30 min. 3,3-
Dimethylbutanoyl chloride (1.35 g, 10 mmol) was added dropwise at
À208C and the resulting mixture was stirred at 258C for 60 min. The re-
action mixture was quenched with saturated aqueous NH4Cl (50 mL), ex-
tracted with diethyl ether (5ꢄ50 mL), and dried over anhydrous Na2SO4.
After filtration, the solvent was evaporated in vacuo. Purification by
flash column chromatography (CH2Cl2/pentane 1:7) furnished 5h as a
colorless solid (1.23 g, 84%). M.p. 95.0–96.08C; 1H NMR (300 MHz,
CDCl3): d=2.75 (s, 2H), 2.57 (s, 3H), 1.12 ppm (s, 9H); 13C NMR
(75 MHz, CDCl3): d=197.6, 173.7, 156.6, 128.0, 55.9, 31.0, 29.3, 14.4 ppm;
MS (70 eV, EI): m/z (%): 292 [35ClÀM+] (7), 238 (23), 236 (35), 223 (66),
221 (100), 57 (10); IR (ATR): n˜ =2955, 2929, 2897, 2871, 1715, 1541,
1475, 1425, 1380, 1359, 1327, 1304, 1275, 1249, 1217, 1180, 1154, 1127,
4-Bromo-2-chloro-6-(methylthio)pyrimidine (8b): Compound 6 (161 mg,
1.0 mmol) in dry THF (2 mL) was added dropwise at 258C to a solution
of 1 (1.1m, 1.0 mL, 1.1 mmol) in THF and stirred at the same tempera-
ture for 5 min according to TP3. (BrCl2C)2 (429 mg, 1.5 mmol) dissolved
in dry THF (2 mL) was added dropwise at 258C and the resulting mix-
ture was stirred for 45 min. The reaction mixture was quenched with sa-
turated aqueous NH4Cl (30 mL), extracted with diethyl ether (5ꢄ30 mL),
and dried over anhydrous Na2SO4. After filtration, the solvent was
evaporated in vacuo. Purification by flash column chromatography
(CH2Cl2/pentane 1:4) furnished 8b as a colorless solid (189 mg, 79%).
996, 906, 853, 806, 777 cmÀ1
C11H1435Cl2N2O32S: 292.0204; found: 292.0201.
;
HRMS (EI): m/z: calcd for
Chem. Eur. J. 2009, 15, 1468 – 1477
ꢃ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
1473

P. Knochel, M. Mosrin
M.p. 86.8–88.38C; 1H NMR (300 MHz, CDCl3): d=7.28 (s, 1H),
2.56 ppm (s, 3H); 13C NMR (75 MHz, CDCl3): d=174.9, 159.5, 150.7,
120.0, 13.0 ppm; MS (70 eV, EI): m/z (%): 238 [35ClÀM+] (28), 194 (11),
58 (69), 44 (12), 43 (100); IR (ATR): n˜ =3090, 2997, 2925, 1529, 1481,
1416, 1367, 1321, 1261, 1207, 1189, 1101, 967, 905, 848, 832, 778, 747, 708,
605 cmÀ1; HRMS (EI): m/z: calcd for C5H479Br35ClN2S: 237.8967; found:
237.8958.
M.p. 74.3–75.08C; 1H NMR (300 MHz, CDCl3): d=2.83 (q, J=7.2 Hz,
2H), 1.19 ppm (t, J=7.2 Hz, 3H); 13C NMR (75 MHz, CDCl3): d=198.2,
159.2, 158.3, 131.7, 36.8, 7.2 ppm; MS (70 eV, EI): m/z (%): 238
A
1538, 1501, 1403, 1305, 1210, 1155, 1065, 946, 835, 657 cmÀ1; HRMS (EI):
m/z: calcd for C7H535Cl3N2O: 237.9467; found: 237.9482.
4,6-Dichloro-5-iodo-pyrimidine (14a): 4,6-Dichloropyrimidine (10;
745 mg, 5.0 mmol) dissolved in dry THF (10 mL) was added dropwise at
258C to a solution of 2 (0.79m; 6.96 mL, 2.75 mmol) in THF and stirred
at the same temperature for 45 min according to TP3. Iodine (1.78 g,
7.0 mmol) dissolved in dry THF (5 mL) was slowly added at 258C and
the resulting mixture was stirred for 1 h. The reaction mixture was
quenched with saturated aqueous NH4Cl (50 mL) and saturated aqueous
Na2S2O3 (20 mL), extracted with diethyl ether (5ꢄ50 mL), and dried over
anhydrous Na2SO4. After filtration, the solvent was evaporated in vacuo.
Purification by flash column chromatography (CH2Cl2/pentane 1:4) fur-
2,4-Dichloro-6-(methylthio)pyrimidine (8c): Compound
6
(161 mg,
1.0 mmol) in dry THF (2 mL) was added dropwise at 258C to a solution
of 1 (1.1m; 1.0 mL, 1.1 mmol) in THF and stirred at the same tempera-
ture for 5 min according to TP3. F2ClCCCl2F (281 mg, 1.5 mmol) in dry
THF (2 mL) was added dropwise at 258C and the resulting mixture was
stirred for 45 min. The reaction mixture was quenched with saturated
aqueous NH4Cl (30 mL), extracted with diethyl ether (5ꢄ30 mL), and
dried over anhydrous Na2SO4. After filtration, the solvent was evaporat-
ed in vacuo. Purification by flash column chromatography (CH2Cl2/pen-
tane 1:4) furnished 8c as a colorless solid (140 mg, 72%). M.p. 80.1–
81.88C; 1H NMR (300 MHz, CDCl3): d=7.11 (s, 1H), 2.57 ppm (s, 3H);
13C NMR (75 MHz, CDCl3): d=175.3, 160.0, 159.8, 116.1, 13.0 ppm; MS
(70 eV, EI): m/z (%): 194 [35ClÀM+] (100), 148 (36), 113 (26), 87 (32);
IR (ATR): n˜ =3090, 3002, 2930, 1532, 1483, 1414, 1372, 1321, 1261, 1215,
1197, 1099, 969, 889, 851, 820, 809, 750, 716, 683, 603 cmÀ1; HRMS (EI):
m/z: calcd for C5H435Cl2N2S: 193.9472; found: 193.9467.
nished 14a as
a colorless solid (1.25 g, 91%). M.p. 134.9–136.58C;
1H NMR (300 MHz, CDCl3): d=8.65 ppm (s, 1H); 13C NMR (75 MHz,
CDCl3): d=166.6, 156.8, 98.9 ppm; MS (70 eV, EI): m/z (%): 274
[35ClÀM+] (100), 239 (27), 97 (12), 83 (12), 57 (21); IR (ATR): n˜ =2923,
2855, 1900, 1499, 1386, 11341, 1296, 1214, 1080, 1014, 790, 763, 745 cmÀ1
;
HRMS (EI): m/z: calcd for C4H35Cl2IN2: 273.8561; found: 273.8565.
(4,6-Dichloropyrimidin-5-yl)ACTHNUTRGNE(NUG phenyl)methanone (14b): Compound 10
2,4,6-Trichloro-5-iodo-pyrimidine (13a): 2,4,6-Trichloropyrimidine (9;
186 mg, 1.0 mmol) dissolved in dry THF (2 mL) was added dropwise at
258C to a solution of 2 (0.79m; 1.39 mL, 0.55 mmol) in THF and stirred
at the same temperature for 1 h according to TP3. Iodine (381 mg,
1.5 mmol) dissolved in dry THF (2 mL) was then added dropwise at
258C and the resulting mixture was stirred for 1 h. The reaction mixture
was quenched with saturated aqueous NH4Cl (30 mL) and saturated
aqueous Na2S2O3 (10 mL), extracted with diethyl ether (5ꢄ30 mL), and
dried over anhydrous Na2SO4. After filtration, the solvent was evaporat-
ed in vacuo. Purification by flash column chromatography (CH2Cl2/pen-
tane 1:7) furnished 13a as a colorless solid (256 mg, 83%). M.p. 97.0–
98.08C; 13C NMR (75 MHz, CDCl3): d=167.6, 159.3, 96.5 ppm; MS
(70 eV, EI): m/z (%): 308 [35ClÀM+] (100), 273 (25), 127 (18), 85 (11);
IR (ATR): n˜ =1477, 1270, 1208, 1182, 1009, 851, 806, 752 cmÀ1; HRMS
(EI): m/z: calcd for C435Cl3IN2: 307.8172; found: 307.8162.
(149 mg, 1.0 mmol) in dry THF (2 mL) was added dropwise at 258C to a
solution of 2 (0.79m; 1.39 mL, 0.55 mmol) in THF and stirred at the same
temperature for 45 min according to TP3. CuCN·2LiCl (1.0m; 1.1 mL,
1.1 mmol) in THF was slowly added at À208C and the reaction mixture
was stirred at the same temperature for 30 min. Benzoyl chloride was
slowly added at À208C and the resulting mixture was stirred at 258C for
1 h. The reaction mixture was quenched with saturated aqueous NH4Cl
(30 mL), extracted with diethyl ether (5ꢄ30 mL), and dried over anhy-
drous Na2SO4. After filtration, the solvent was evaporated in vacuo. Pu-
rification by flash column chromatography (CH2Cl2/pentane 1:4) fur-
nished 14b as a colorless solid (215 mg, 86%). M.p. 106.0–108.98C;
1H NMR (300 MHz, CDCl3): d=8.90 (s, 1H), 7.51–7.82 ppm (m, 5H);
13C NMR (75 MHz, CDCl3): d=188.7, 158.6, 158.3, 135.2, 134.3, 132.0,
129.5, 129.4 ppm; MS (70 eV, EI): m/z (%): 252 [35ClÀM+] (21), 167 (11),
149 (100), 105 (40), 77 (39); IR (ATR): n˜ =3329, 3061, 2957, 1726, 1668,
1593, 1581, 1531, 1511, 1453, 1404, 1386, 1348, 1317, 1256, 1242, 1236,
1184, 1162, 1071, 999, 924, 826, 794, 766, 698, 681, 674, 605 cmÀ1; HRMS
(EI): m/z: calcd for C11H635Cl2N2O: 251.9857; found: 251.9850.
5-Allyl-2,4,6-trichloro-pyrimidine (13b): Compound 9 (186 mg, 1.0 mmol)
in dry THF (2 mL) was added dropwise at 258C to a solution of 2
(0.79m; 1.39 mL, 0.55 mmol) in THF and stirred at the same temperature
for 1 h according to TP3. CuCN·2LiCl (1.0m, 5 drops) in THF was added
at À208C, followed by the slow addition of allyl bromide (242 mg,
2.0 mmol) at À608C, and the resulting mixture was allowed to slowly
warm to À208C. The reaction mixture was quenched with saturated
aqueous NH4Cl (30 mL), extracted with diethyl ether (5ꢄ30 mL), and
dried over anhydrous Na2SO4. After filtration, the solvent was evaporat-
ed in vacuo. Purification by flash column chromatography (CH2Cl2/pen-
tane 1:6) furnished 13b as a colorless solid (201 mg, 90%). M.p. 39.2–
40.38C; 1H NMR (300 MHz, CDCl3): d=5.75–5.88 (m, 1H), 5.08–5.18
(m, 2H), 3.61 ppm (dt, 3J=6.4, 4J=1.4 Hz, 2H); 13C NMR (75 MHz,
CDCl3): d=163.0, 157.1, 130.2, 129.3, 118.5, 33.5 ppm; MS (70 eV, EI):
m/z (%): 222 [35ClÀM+] (100), 187 (33), 151 (62), 125 (35), 90 (43); IR
(ATR): n˜ =3087, 2934, 1635, 1533, 1501, 1435, 1330, 1287, 1215, 1185,
1123, 1095, 993, 930, 907, 875, 790 cmÀ1; HRMS (EI): m/z: calcd for
C7H535Cl3N2: 221.9518; found: 221.9494.
4,6-Dichloro-5-(cyclohex-2-enyl)pyrimidine
(14c):
Compound
10
(149 mg, 1.0 mmol) in dry THF (2 mL) was added dropwise at 258C to a
solution of 2 (0.79m; 1.39 mL, 0.55 mmol) in THF and stirred at the same
temperature for 45 min according to TP3. CuCN·2LiCl (1m; 0.05 mL,
5 mol%) in THF was slowly added at À208C. 3-Bromocyclohexene
(322 mg, 2.0 mmol) was slowly added at À308C. The resulting mixture
was allowed to warm slowly to 08C for 4 h. The reaction mixture was
quenched with saturated aqueous NH4Cl (20 mL), extracted with diethyl
ether (5ꢄ30 mL), and dried over anhydrous Na2SO4. After filtration, the
solvent was evaporated in vacuo. Purification by flash column chroma-
tography (CH2Cl2/pentane 1:4) furnished 14c as a colorless oil (165 mg,
72%). 1H NMR (600 MHz, CDCl3): d=8.59 (s, 1H), 5.85–5.87 (m, 1H),
5.50–5.52 (m, 1H), 5.15–5.19 (m, 1H), 4.14–4.20 (m, 2H), 2.13–2.09 (m,
3H), 1.85–1.97 ppm (m, 1H); 13C NMR (150 MHz, CDCl3): d=155.3,
135.4, 128.6, 126.2, 38.4, 25.7, 24.2, 22.5 ppm; MS (70 eV, EI): m/z (%):
230 (55), 228 [35ClÀM+] (81), 215 (26), 213 (44), 202 (19), 200 (29), 193
(20), 139 (31), 112 (21), 54 (100); IR (ATR): n˜ =3025, 2933, 2861, 2836,
2363, 2340, 1531, 1509, 1447, 1408, 1377, 1351, 1329, 1307, 1214, 1162,
1127, 1046, 980, 882, 848, 809, 779, 721, 617, 560 cmÀ1; HRMS (EI): m/z:
calcd for C10H1035Cl2N2: 228.0221; found: 228.0226.
1-(2,4,6-Trichloro-pyrimidin-5-yl)-propan-1-one (13c): Compound
9
(186 mg, 1.0 mmol) in dry THF (2 mL) was added dropwise at 258C to a
solution of 2 (0.79m; 1.39 mL, 0.55 mmol) in THF and stirred at the same
temperature for 1 h according to TP3. CuCN·2LiCl (1.0m; 1.2 mL,
1.2 mmol) in THF was added at À208C and the reaction mixture was
stirred for 30 min at the same temperature. Propionyl chloride (0.231 g,
2.5 mmol) was added dropwise at À208C and the resulting mixture was
stirred at 258C for 1 h. The reaction mixture was then quenched with sa-
turated aqueous NH4Cl (30 mL), extracted with diethyl ether (5ꢄ30 mL),
and dried over anhydrous Na2SO4. After filtration, the solvent was
evaporated in vacuo. Purification by flash column chromatography
(CH2Cl2/pentane 1:5) furnished 13c as a colorless solid (205 mg, 86%).
4,4’,6,6’-Tetrachloro-5,5’-bipyrimidine (14d): Compound 10 (149 mg,
1.0 mmol) in dry THF (2 mL) was added dropwise at 258C to a solution
of 2 (0.79m; 1.39 mL, 0.55 mmol) in THF and stirred at the same temper-
ature for 45 min according to TP3. Chloranil (295 mg, 1.2 mmol) dis-
solved in dry THF (7 mL) was slowly added at À408C for 1 h. The result-
ing mixture was allowed to warm slowly to 258C. The reaction mixture
was quenched with saturated aqueous NH4Cl (20 mL), extracted with di-
1474
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ꢃ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2009, 15, 1468 – 1477

Zincation and Magnesiation of Chlorinated Pyrimidines
FULL PAPER
ethyl ether (5ꢄ30 mL), and dried over anhydrous Na2SO4. After filtra-
tion, the solvent was evaporated in vacuo. Purification by flash column
chromatography (CH2Cl2) furnished 14d as a colorless solid (121 mg,
82%). M.p. 149.0–150.78C; 1H NMR (300 MHz, CDCl3): d=8.93 ppm (s,
2H); 13C NMR (75 MHz, CDCl3): d=161.4, 158.9, 126.6 ppm; MS (70 eV,
EI): m/z (%): 296 (100), 294 [35ClÀM+] (86), 207 (19), 205 (18), 149 (35),
57 (14); IR (ATR): n˜ =3382, 3303, 2928, 1692, 1531, 1507, 1402, 1370,
1288, 1228, 1164, 988, 811, 771, 727, 571 cmÀ1; HRMS (EI): m/z: calcd for
C8H235Cl4N4: 293.9034; found: 293.9045.
dried over anhydrous Na2SO4. After filtration, the solvent was evaporat-
ed in vacuo. Purification by flash column chromatography (CH2Cl2/pen-
tane 1:1) furnished 18b as a yellowish solid (232 mg, 78%). M.p. 86.4–
87.98C; 1H NMR (300 MHz, CDCl3): d=8.67 (s, 1H), 8.16 (d, J=8.2 Hz,
2H), 7.94 (d, J=8.2 Hz, 2H), 4.41 (q, J=7.2 Hz, 2H), 1.41 ppm (t, J=
7.1 Hz, 3H); 13C NMR (75 MHz, CDCl3): d=165.7, 164.1, 160.0, 159.0,
138.1, 132.6, 129.5 (2), 127.9, 61.4, 14.3 ppm; MS (70 eV, EI): m/z (%):
296 [35ClÀM+] (29), 268 (64), 253 (100), 223 (34), 126 (13); IR (ATR):
n˜ =3033, 2992, 2935, 2915, 1718, 1610, 1574, 1545, 1520, 1499, 1486, 1463,
1442, 1401, 1362, 1336, 1315, 1272, 1194, 1170, 1130, 1106, 1095, 1037,
1016, 944, 861, 840, 786, 763, 724, 701, 652 cmÀ1; HRMS (EI): m/z: calcd
for C13H1035Cl2N2O2: 296.0119; found: 296.0117.
4,6-Dichloro-2,5-diiodo-pyrimidine (15a): 4,6-Dichloro-5-iodo-pyrimidine
(14a) 275 mg, 1.0 mmol) in dry THF (3 mL) was added dropwise at 258C
to a solution of 2 (0.79m; 1.39 mL, 0.55 mmol) and stirred at 558C for 1 h
according to TP3. Iodine (508 mg, 2.0 mmol) in dry THF (4 mL) was
slowly added at 258C and the resulting mixture was stirred for 1 h. The
reaction mixture was quenched with saturated aqueous NH4Cl (30 mL),
extracted with diethyl ether (5ꢄ50 mL), and dried over anhydrous
Na2SO4. After filtration, the solvent was evaporated in vacuo. Purifica-
tion by flash column chromatography (CH2Cl2/pentane 1:4) furnished
15a as a colorless solid (241 mg, 61%). M.p. 148.4–150.08C; 13C NMR
(75 MHz, CDCl3): d=165.7, 123.6, 98.7 ppm; MS (70 eV, EI): m/z (%):
400 [35ClÀM+] (100), 273 (71), 127 (14); IR (ATR): n˜ =2950, 2913, 2850,
2,5-Dichloro-4-(3-(trifluoromethyl)phenyl)pyrimidine (18c): Compound
16 (149 mg, 1.0 mmol) in dry THF (2 mL) was added dropwise at 258C
to a solution of 2 (0.79m; 1.39 mL, 0.55 mmol) in THF and stirred at the
same temperature for 45 min according to TP3. 3-Iodobenzotrifluoride
(354 mg, 1.3 mmol, 1.3 equiv) was added to [Pd
ACHTUNGRTEN(NNUG dba)2] (17 mg, 3 mol%)
and P(o-furyl)3 (14 mg, 6 mol%) dissolved in THF (2 mL). This mixture
AHCTUNGTRENNUNG
was transferred by cannula to the reaction mixture. The resulting mixture
was stirred at 658C for 45 min and then quenched with saturated aqueous
NH4Cl (30 mL), extracted with diethyl ether (5ꢄ30 mL), and dried over
anhydrous Na2SO4. After filtration, the solvent was evaporated in vacuo.
Purification by flash column chromatography (CH2Cl2/pentane 1:4) fur-
2628, 2417, 1739, 1460, 1344, 1264, 1249, 1196, 1172, 1001, 806, 745 cmÀ1
;
HRMS (EI): m/z: calcd for C435Cl2I2N2: 399.7528; found: 399.7529.
nished 18c as
a colorless solid (232 mg, 73%). M.p. 45.2–46.68C;
5-Allyl-4,6-dichloro-2-iodopyrimidine (15b): Compound 14a (275 mg,
1.0 mmol) in dry THF (3 mL) was added dropwise at 258C to a solution
of 2 (0.79m; 1.39 mL, 0.55 mmol) in THF and stirred at 558C for 1 h ac-
cording to TP3. CuCN·2LiCl (1.0m, 5 drops) in THF was added at
À208C, followed by the slow addition of allyl bromide (242 mg,
2.0 mmol) at À788C. The resulting mixture was allowed to slowly warm
to À108C and stirred for 4 h. The reaction mixture was quenched with sa-
turated aqueous NH4Cl (30 mL), extracted with diethyl ether (5ꢄ30 mL),
and dried over anhydrous Na2SO4. After filtration, the solvent was
evaporated in vacuo. Purification by flash column chromatography
(CH2Cl2/pentane 1:3) furnished 15b as a colorless solid (160 mg, 51%).
M.p. 74.3–75.68C; 1H NMR (300 MHz, CDCl3): d=5.75–5.88 (m, 1H),
5.08–5.18 (m, 2H), 3.56 ppm (dt, 3J=6.4, 4J=1.4 Hz, 2H); 13C NMR
(75 MHz, CDCl3): d=161.2, 130.1, 130.0, 121.8, 118.5, 33.7 ppm; MS
(70 eV, EI): m/z (%): 314 [35ClÀM+] (100), 187 (59), 151 (13), 99 (12), 58
(30), 43 (69); IR (ATR): n˜ =3087, 3018, 2971, 2923, 2855, 1739, 1726,
1636, 1528, 1478, 1433, 1370, 1341, 1325, 1283, 1228, 1206, 1185, 1156,
1114, 1093, 985, 922, 904, 853, 808, 785, 777, 558 cmÀ1; HRMS (EI): m/z:
calcd for C7H535Cl2IN2: 313.8874; found: 313.8869.
1H NMR (300 MHz, CDCl3): d=8.69 (d, J=5.1 Hz, 1H), 7.62–8.16 ppm
(m, 4H); 13C NMR (75 MHz, CDCl3): d=163.4, 160.1, 159.1, 135.0, 132.7
(2), 131.1 (q, J
A
ACHTUNGERTN(NUNG C,F)=3.7 Hz), 126.4 (q,
J
A
(%): 292 [35ClÀM+] (84), 257 (100), 231 (24), 204 (15), 149 (15), 44 (24);
IR (ATR): n˜ =3090, 3048, 1616, 1547, 1524, 1486, 1449, 1401, 1336, 1324,
1310, 1252, 1198, 1166, 1103, 1071, 1036, 1000, 946, 909, 882, 810, 791,
776, 699, 656, 630 cmÀ1; HRMS (EI): m/z: calcd for C11H535Cl2F3N2:
291.9782; found: 291.9786.
4-Chloro-3-(4-fluorophenyl)-6-(methylthio)-1H-pyrazolo [3,4-d]pyrimi-
dine (19a): Hydrazine (64% in water; 0.12 mL, 2.4 mmol) was added to
a solution of 5g (0.317 g, 1.0 mmol) in THF (2 mL) at 258C. The resulting
mixture was stirred at the same temperature for 10 min and quenched
with saturated aqueous Na2CO3 (10 mL), extracted with diethyl ether
(5ꢄ20 mL), and dried over anhydrous Na2SO4. After filtration, the sol-
vent was evaporated in vacuo. Purification by flash column chromatogra-
phy (CH2Cl2) furnished 19a as a colorless solid (224 mg, 76%). M.p.
225.7–227.28C; 1H NMR (400 MHz, [D6]DMSO): d=7.77 (m, 2H), 7.32–
7.36 (m, 2H), 2.58 ppm (s, 3H); 13C NMR (100 MHz, [D6]DMSO): d=
2,5-Dichloro-4-iodopyrimidine (18a): 2,5-Dichloropyrimidine (16;
149 mg, 1.0 mmol) dissolved in dry THF (2 mL) was added dropwise at
258C to a solution of 2 (0.79m; 1.39 mL, 0.55 mmol) in THF and stirred
at the same temperature for 45 min according to TP3. Iodine (381 mg,
1.5 mmol) in dry THF (2 mL) was added dropwise at 258C and the re-
sulting mixture was stirred for 30 min. The reaction mixture was
quenched with saturated aqueous NH4Cl (30 mL) and saturated aqueous
Na2S2O3 (10 mL), extracted with diethyl ether (5ꢄ30 mL), and dried over
anhydrous Na2SO4. After filtration, the solvent was evaporated in vacuo.
Purification by flash column chromatography (CH2Cl2/pentane 1:5) fur-
nished 18a as a colorless solid (203 mg, 72%). M.p. 118.8–120.28C;
1H NMR (300 MHz, CDCl3): d=8.39 ppm (s, 1H); 13C NMR (75 MHz,
CDCl3): d=156.8, 155.4, 137.5, 134.0 ppm; MS (70 eV, EI): m/z (%): 274
[35ClÀM+] (100), 149 (61), 147 (90), 120 (31), 43 (30); IR (ATR): n˜ =
3075, 3018, 2992, 1883, 1721, 1537, 1514, 1494, 1470, 1362, 1336, 1284,
1192, 1171, 1135, 1034, 944, 812, 752, 659 cmÀ1; HRMS (EI): m/z: calcd
for C4H35Cl2IN2: 273.8561; found: 273.8554.
168.6, 163.8, 161.4, 156.3, 153.0, 144.0, 131.9 (d, J
ACHTUNGTREN(NUNG C,F)=8.6 Hz), 127.8,
115.2 (d, JACTHNUGRTNE(NUG C,F)=31.7 Hz), 106.9, 13.8 ppm; MS (70 eV, EI): m/z (%):
294 [35ClÀM+] (100), 213 (35); IR (ATR): n˜ =3187, 3156, 3076, 3029,
2982, 2918, 1739, 1597, 1531, 1520, 1467, 1420, 1399, 1367, 1322, 1304,
1267, 1217, 1156, 1151, 1098, 1069, 1022, 982, 972, 956, 869, 832, 816, 806,
785, 740, 692, 645, 602, 561 cmÀ1
; HRMS (EI): m/z: calcd for
C12H835ClFN432S: 294.0142; found: 294.0130.
4-Chloro-6-(methylthio)-3-neopentyl-1H-pyrazolo
[3,4-d]pyrimidine
(19b): Hydrazine (64% in water; 0.17 mL, 3.4 mmol) was added to 5h
(0.294 g, 1.0 mmol) in THF at 258C. The resulting mixture was stirred at
the same temperature for 10 min and quenched with saturated aqueous
Na2CO3 (10 mL), extracted with diethyl ether (5ꢄ20 mL), and dried over
anhydrous Na2SO4. After filtration, the solvent was evaporated in vacuo.
Purification by flash column chromatography (CH2Cl2) furnished 19b as
a
colorless solid (199 mg, 73%). M.p. 130.9–132.48C; 1H NMR
(400 MHz, [D6]DMSO): d=2.88 (s, 2H), 2.55 (s, 3H), 0.94 ppm (s, 9H);
13C NMR (100 MHz, [D6]DMSO): d=168.1, 155.6, 152.9, 143.5, 108.5,
31.9, 29.3, 13.8 ppm; MS (70 eV, EI): m/z (%): 270 [35ClÀM+] (12), 214
(100), 57 (24); IR (ATR): n˜ =3203, 3156, 3119, 2960, 2929, 2902, 2860,
2359, 2332, 1739, 1594, 1533, 1483, 1462, 1449, 1412, 1362, 1330, 1291,
1267, 1238, 1209, 1199, 1143, 1101, 1069, 1006, 969, 890, 856, 811, 774,
750, 632, 616, 553 cmÀ1; HRMS (EI): m/z: calcd for C11H1535ClN432S:
270.0706; found: 270.0703.
Ethyl 4-(2,5-dichloropyrimidin-4-yl)benzoate (18b): Compound 16
(149 mg, 1.0 mmol) in dry THF (2 mL) was added dropwise at 258C to a
solution of 2 (0.79m; 1.39 mL, 0.55 mmol) in THF and stirred at the same
temperature for 45 min according to TP3. Ethyl 4-iodobenzoate (359 mg,
1.3 mmol, 1.3 equiv) was added to [Pd
ACHTUNGRTEN(NUNG dba)2] (17 mg, 3 mol%; dba=di-
benzylideneacetone) and P(o-furyl)3 (14 mg, 6 mol%) in THF (2 mL).
AHCTUNGTRENNUNG
This mixture was transferred by cannula to the reaction mixture. The re-
sulting mixture was stirred at 658C for 45 min and quenched with saturat-
ed aqueous NH4Cl (30 mL), extracted with diethyl ether (5ꢄ30 mL), and
4-Chloro-6-(methylthio)-3-phenyl-1H-pyrazolo
N
(19c):
Hydrazine (64% in water; 0.17 mL, 3.4 mmol) was added to 5i (0.298 g,
Chem. Eur. J. 2009, 15, 1468 – 1477
ꢃ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
1475

P. Knochel, M. Mosrin
1.0 mmol) in THF (2 mL) at 258C. The resulting mixture was stirred at
the same temperature for 10 min and was quenched with saturated aque-
ous Na2CO3 (10 mL), extracted with diethyl ether (5ꢄ20 mL), and dried
over anhydrous Na2SO4. After filtration, the solvent was evaporated in
vacuo. Purification by flash column chromatography (CH2Cl2) furnished
19c as a colorless solid (229 mg, 83%). M.p. 201.0–202.38C; 1H NMR
(400 MHz, [D6]DMSO): d=7.70–7.72 (m, 2H), 7.46–7.50 (m, 3H),
2.57 ppm (s, 3H); 13C NMR (100 MHz, [D6]DMSO): d=168.5, 156.4,
153.1, 144.9, 131.3, 129.8, 129.0, 128.1, 106.9, 13.9 ppm; MS (70 eV, EI):
m/z (%): 276 [35ClÀM+] (100), 195 (40), 77 (11); IR (ATR): n˜ =3101,
3023, 2977, 2853, 1612, 1532, 1509, 1463, 1408, 1367, 1321, 1253, 1228,
1155, 1083, 1018, 977, 876, 863, 786, 765, 701, 636 cmÀ1; HRMS (EI): m/z:
calcd for C12H935ClN432S: 276.0236; found: 276.0215.
LiCl (1.0m, 1.1 mL, 1.1 mmol) in THF was slowly added at À508C and
the reaction mixture was stirred at the same temperature for 45 min. N-
Lithium piperidide (2 mmol; prepared by adding nBuLi (2 mmol) to pi-
peridine (0.5m, 171 mg, 2 mmol) in THF at 08C and stirring for 30 min)
was added dropwise and the mixture was further stirred for 90 min at
À508C. The reaction mixture was cooled to À788C, and chloranil
(295 mg, 1.2 mmol) in dry THF (7 mL) was added slowly over 45 min.
The resulting mixture was stirred at À788C for 12 h. Diethyl ether
(10 mL) was added to the crude reaction mixture, which was filtered
through Celite, thoroughly washed with diethyl ether, and the filtrate was
washed with aqueous NH4OH (2.0m, 2ꢄ10 mL). The organic extract was
dried over MgSO4, filtered, and concentrated under reduced pressure.
Purification by flash column chromatography (CH2Cl2) furnished 20c as
a colorless solid (195 mg, 70%). M.p. 91.9–93.68C; 1H NMR (300 MHz,
CDCl3): d=3.01–3.05 (m, 4H), 2.53 (s, 3H), 1.53–1.70 ppm (m, 6H);
13C NMR (75 MHz, CDCl3): d=167.0, 160.5, 136.6, 51.0, 26.7, 24.2,
14.9 ppm; MS (70 eV, EI): m/z (%): 277 [35ClÀM+] (50), 276 [MÀ1]+
(100), 221 (12), 188 (12), 55 (11), 41 (17); IR (ATR): n˜ =2931, 2849,
1537, 1462, 1388, 1344, 1323, 1286, 1255, 1176, 1113, 1064, 1032, 1019,
964, 915, 852, 824, 801, 765, 680, 573 cmÀ1; HRMS (EI): m/z: calcd for
C10H1335Cl2N332S: 277.0207; found: 277.0181.
4,6-Dichloro-5-(morpholin-1-yl)-2-(methylthio)pyrimidine (20a): Com-
pound 3 (195 mg, 1.0 mmol) in dry THF (3 mL) was added dropwise at
258C to a solution of 1 (1.14m; 1.45 mL, 1.65 mmol) in THF and stirred
at the same temperature for 30 min according TP3. CuCl·2LiCl (1.0m,
1.1 mL, 1.1 mmol) in THF was slowly added at À508C and the reaction
mixture was stirred at the same temperature for 45 min. N-Lithium mor-
pholide (2 mmol; prepared by adding nBuLi (2 mmol) to morpholine
(0.5m, 174 mg, 2 mmol) in THF at 08C and stirring for 30 min) was added
dropwise and the reaction mixture was further stirred for 90 min at
À508C. The reaction mixture was cooled to À788C, and chloranil
(295 mg, 1.2 mmol) in dry THF (7 mL) was added slowly over 45 min.
The resulting mixture was stirred at À788C for 12 h. Diethyl ether
(10 mL) was added to the crude reaction mixture, which was filtered
through celite, thoroughly washed with diethyl ether, and the filtrate was
washed with aqueous NH4OH (2.0m, 2ꢄ10 mL). The organic extract was
dried over MgSO4, filtered, and concentrated under reduced pressure.
Purification by flash column chromatography (CH2Cl2) furnished 20a as
2-Chloro-4-iodopyrimidine (22): 2-Chloropyrimidine (21; 684 mg,
6.0 mmol) dissolved in THF (6 mL) was treated with a solution of 1
(1.1m, 6.0 mL, 6.6 mmol) in THF at À608C for 2 h. Transmetalation with
ZnCl2 (1.0m, 6.6 mL, 6.6 mmol) in THF was performed and the resulting
mixture was allowed to warm slowly to room temperature. Iodine
(2.284 g, 9.0 mmol) in dry THF (9 mL) was added dropwise and the re-
sulting mixture was stirred for 1 h at 258C. The reaction mixture was
quenched with saturated aqueous NH4Cl (50 mL) and saturated aqueous
Na2S2O3 (30 mL), extracted with diethyl ether (5ꢄ50 mL), and dried over
anhydrous Na2SO4. After filtration, the solvent was evaporated in vacuo.
Purification by flash chromatography on silica gel (CH2Cl2/pentane 1:4)
furnished 22 as a colorless solid (1.31 g, 91%). M.p. 111.3–112.48C;
1H NMR (300 MHz, CDCl3): d=8.13 (d, J=5.1 Hz, 1H), 7.72 ppm (d,
J=5.1 Hz, 1H); 13C NMR (75 MHz, CDCl3): d=160.1, 158.0, 131.2,
130.2 ppm; MS (70 eV, EI): m/z (%): 240 (47) [35ClÀM+], 127 (17), 115
(22), 113 (64), 86 (16), 58 (39), 52 (15), 43 (100); IR (ATR): n˜ =3094,
1511, 1395, 1342, 1318, 1227, 1192, 1165, 1133, 979, 834, 776, 758, 666,
578 cmÀ1; HRMS (EI): m/z: calcd for C4H235Cl127IN2: 239.8951; found:
239.8950.
a
colorless solid (191 mg, 68%). M.p. 127.5–130.38C; 1H NMR
(300 MHz, CDCl3): d=3.77–3.80 (m, 4H), 3.09–3.12 (m, 4H), 2.52 ppm
(s, 3H, SCH3); 13C NMR (75 MHz, CDCl3): d=168.3, 160.7 (2), 134.9,
67.7 (2), 49.7 (2), 14.9 ppm; MS (70 eV, EI): m/z (%): 279 [35ClÀM+]
(70), 244 (14), 223 (64), 221 (100), 188 (23); IR (ATR): n˜ =2966, 2886,
2855, 1536, 1463, 1381, 1323, 1302, 1273, 1176, 1105, 1068, 1036, 968, 923,
852, 805, 768, 689, 591, 568 cmÀ1
; HRMS (EI): m/z: calcd for
C9H1135Cl2N3O32S: 279.0000; found: 278.9981.
4,6-Dichloro-5-(4-methylpiperazin-1-yl)-2-(methylthio)pyrimidine (20b):
Compound 3 (195 mg, 1.0 mmol) in dry THF (3 mL) was added dropwise
at 258C to a solution of 1 (1.14m; 1.45 mL, 1.65 mmol) in THF and
stirred at the same temperature for 30 min according to TP3. CuCl·2LiCl
(1.0m, 1.1 mL, 1.1 mmol) in THF was slowly added at À508C and the re-
action mixture was stirred at the same temperature for 45 min. N-Lithi-
um 4-methylpiperazide (2 mmol; prepared by adding nBuLi (2 mmol) to
4-methylpiperazine (0.5m, 200 mg, 2 mmol) in THF at 08C and stirring
for 30 min) was added dropwise and the mixture was further stirred for
90 min at À508C. The reaction mixture was cooled to À788C, and chlora-
nil (295 mg, 1.2 mmol) in dry THF (7 mL) was added slowly over 45 min.
The resulting mixture was stirred at À788C for 12 h. Diethyl ether
(10 mL) was added to the crude reaction mixture, which was filtered
through celite, thoroughly washed with diethyl ether, and the filtrate was
washed with aqueous NH4OH (2.0m, 2ꢄ10 mL). The organic extract was
dried over MgSO4, filtered, and concentrated under reduced pressure.
Purification by flash column chromatography (CH2Cl2) furnished 20b as
a colorless solid (208 mg, 71%). M.p. 82.7–83.98C; 1H NMR (300 MHz,
CDCl3): d=3.11 (m, 4H), 2.49 (m, 4H), 2.49 (s, 3H), 2.31 ppm (s, 3H);
13C NMR (75 MHz, CDCl3): d=167.7, 160.3, 135.1, 55.4, 49.1, 46.4,
14.6 ppm; MS (70 eV, EI): m/z (%): 294 (27), 292 [35ClÀM+] (53), 245
(46), 244 (13), 243 (100), 229 (17), 193 (11), 170 (15), 147 (6), 120 (5), 42
(5); IR (ATR): n˜ =2928, 2843, 2836, 2784, 2759, 1539, 1463, 1401, 1379,
1299, 1271, 1154, 1136, 1071, 1006, 964, 927, 845, 801, 779, 767, 729, 613,
571 cmÀ1; HRMS (EI): m/z: calcd for C10H14N435Cl32S: 292.0316; found:
292.0302.
4-Bromo-2-chloro-4-iodopyrimidine (23): Compound 22 (1.21 g, 5 mmol)
dissolved in THF (10 mL) was slowly added at À608C to a solution of 1
(1.1m; 5.5 mL, 5 mmol) in THF and the mixture was stirred at the same
temperature for 1 h. BrCl2CCCl2Br (2.442 g, 7.5 mmol) was added drop-
wise at À788C and the resulting mixture was allowed to warm slowly to
À658C for 3 h. Purification by flash chromatography (pentane/CH2Cl2;
3:1) afforded pyrimidine 23 (1.53 g, 96%) as a colorless solid. M.p.
145.9–147.88C; 1H NMR (300 MHz, CDCl3): d=7.94 ppm (s, 1H);
13C NMR (75 MHz, CDCl3): d=159.0, 152.6, 134.5, 129.6 ppm; MS (EI,
70 eV) m/z (%): 320 (44), 318 (33) [79BrÀM+], 193 (67), 191 (51), 130
(20), 127 (20), 86 (10), 14 (62), 62 (13), 58 (77), 43 (100); IR (ATR): n˜ =
3108, 1486, 1357, 1338, 1267, 1241, 1098, 977, 845, 806, 745, 587 cmÀ1
;
HRMS (EI): m/z: calcd for C4H79Br35Cl127IN2: 317.8056; found: 317.8058.
4-Bromo-2-chloro-6-methylpyrimidine (24): ZnCl2 (1.0m, 6 mL, 6 mmol)
in THF was added dropwise to a stirred solution of CH3MgCl (2.93m,
1.95 mL, 5.65 mmol) in THF at À208C. After the reaction mixture was
stirred for 15 min at this temperature, it was warmed slowly to 258C. A
solution of 23 (1.28 g, 4.0 mmol) and [PdACHTNUTRGNE(UNG PPh3)4] (200 mg, 4 mol%) in
THF (8 mL) was added, and the resulting mixture was stirred at 508C
overnight. The mixture was cooled to 258C and quenched with saturated
aqueous NH4Cl (50 mL), extracted with diethyl ether (5ꢄ50 mL), and
dried over anhydrous Na2SO4. After filtration, the solvent was evaporat-
ed in vacuo. Purification by flash chromatography (pentane/CH2Cl2 4:1)
afforded pyrimidine 24 (483 mg, 58%) as a colorless solid. M.p. 80.6–
82.08C; 1H NMR (300 MHz, CDCl3): d=7.34 (s, 1H), 2.50 ppm (s, 3H);
13C NMR (75 MHz, CDCl3): d=171.1, 160.0, 153.5, 123.5, 23.6 ppm; MS
(EI, 70 eV): m/z (%): 208 (29), 206 (24) [79BrÀM+], 129 (29), 127 (81),
86 (28), 66 (100), 64 (15), 62 (28), 55 (16), 51 (21), 43 (15); IR (ATR):
4,6-Dichloro-5-(piperidin-1-yl)-2-(methylthio)pyrimidine (20c): Com-
pound 3 (195 mg, 1.0 mmol) dissolved in dry THF (3 mL) was added
dropwise at 258C to a solution of 1 (1.14m; 1.45 mL, 1.65 mmol) in THF
and stirred at the same temperature for 30 min according to TP3. CuCl·2
1476
www.chemeurj.org
ꢃ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2009, 15, 1468 – 1477

Zincation and Magnesiation of Chlorinated Pyrimidines
FULL PAPER
n˜ =3124, 3082, 2955, 2918, 2850, 1721, 1552, 1515, 1462, 1430, 1404, 1370,
1354, 1296, 1251, 1228, 1188, 1130, 1040, 1011, 974, 911, 893, 861, 795,
750, 692, 600 cmÀ1; HRMS (EI): m/z: calcd for C5H479Br35ClN2: 205.9246;
found: 205.9240.
ickx, G. Quꢀguiner, Tetrahedron 1998, 54, 9701; d) N. Plꢀ, A. Turck,
A. Heynderickx, G. Quꢀguiner, J. Heterocycl. Chem. 1997, 34, 551.
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2-Chloro-4-methyl-6-(prop-1-ynyl)pyrimidine (25): A mixture of NEt3
[4] a) A. Turck, N. Plꢀ, G. Quꢀguiner, Heterocycles 1994, 37, 2149; b) R.
Radinov, C. Chanev, M. Haimova, J. Org. Chem. 1991, 56, 4793.
[5] A. Wada, J. Yamamoto, Y. Hamaoka, K. Ohki, S. Nagai, S. Kanato-
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(7 mL), CuI (12 mg, 4 mol%), [PdACTHUNRGTENNUG(dba)2] (25 mg, 2 mol%), PAHCUTNGTRENN(UGN o-furyl)3
(21 mg, 4 mol%), and 24 (312 mg, 1.5 mmol) in THF (2 mL) was added
to recondensed propyne (81 mg, 2.0 mol). The reaction mixture was
stirred at 258C for 1.5 h and quenched with saturated aqueous NH4Cl
(30 mL), extracted with diethyl ether (3ꢄ50 mL), and dried over anhy-
drous Na2SO4. After filtration, the solvent was evaporated in vacuo. Pu-
rification by flash chromatography (pentane/CH2Cl2 3:1) afforded pyrimi-
1
dine 25 (241 mg, 97%) as a colorless solid. M.p. 127.4–128.88C; H NMR
(300 MHz, CDCl3): d=7.07 (s, 1H), 2.47 (s, 3H), 2.08 ppm (s, 3H);
13C NMR (75 MHz, CDCl3): d=170.5, 160.9, 153.0, 121.0, 93.8, 77.3, 23.8,
4.5 ppm; MS (EI, 70 eV): m/z (%): 168 (17), 166 (50) [35ClÀM+], 58 (37),
44 (17), 43 (100); IR (ATR): n˜ =3066, 2971, 2923, 2248, 2227, 1562, 1502,
1417, 1386, 1351, 1246, 1193, 1185, 1051, 982, 916, 893, 811, 764, 568 cmÀ1
HRMS (EI): calcd for C8H735ClN2: 166.0298; found: 166.0297.
;
4-Methyl-N-phenyl-6-(prop-1-ynyl)pyrimidin-2-amine (26):
A Schlenk
flask was flushed with nitrogen and charged with xantphos (11 mg, 20
mol%) and dry dioxane (3 mL). After purging the flask with dry argon,
PdACHTUNGTRENNUNG(OAc)2 (58 mg, 10 mol%) was added to the reaction mixture, which
was stirred under nitrogen for 10 min. In another Schlenk flask, 25
(84 mg, 0.5 mmol), aniline (70 mg, 0.75 mmol), and K2CO3 (1.38 g,
10 mmol) were added to dry dioxane (4 mL). The solution of PdACTHNUTRGNEUNG(OAc)2/
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xantphos[16] was transferred by cannula and the resulting mixture was
subsequently heated to 1008C under argon with vigorous stirring for
1.5 h. After cooling, the solid material was filtered off and washed with
CH2Cl2. The solvent was evaporated, and the crude product was purified
by flash chromatography (CH2Cl2), thus affording pyrimidine 26 (91 mg,
81%) as a colorless solid. M.p. 125.5–127.08C; 1H NMR (300 MHz,
CDCl3): d=7.61–7.64 (m, 2H), 7.30–7.33 (m, 2H), 7.21 (bs, 1H), 6.98–
7.03 (m, 1H), 6.63 (s, 1H), 2.38 (s, 3H), 2.07 pm (s, 3H); 13C NMR
(75 MHz, CDCl3): d=168.1, 159.7, 151.3, 139.5, 128.8, 122.3, 119.0, 114.1,
89.9, 78.5, 24.0, 4.4 ppm; MS (EI, 70 eV): m/z (%): 223 (53) [35ClÀM+],
222 (100), 77 (8), 43 (11); IR (ATR): n˜ =3266, 3193, 3124, 3066, 2960,
2908, 2850, 2237, 1602, 1576, 1539, 1494, 1457, 1136, 1380, 1365, 1338,
1246, 1199, 1183, 1069, 1030, 996, 969, 890, 864, 824, 787, 750, 692, 621,
608, 590 cmÀ1
223.1109.
;
HRMS (EI): calcd for C14H13N3: 223.1109; found:
Acknowledgements
We thank the Fonds der Chemischen Industrie, the Deutsche Forschungs-
gemeinschaft (DFG) for financial support; Chemetall GmbH (Frankfurt),
Evonik Degussa GmbH (Hanau), and BASF AG (Ludwigshafen) for the
generous gift of chemicals; and Dr. Andrey Gavryushin for helpful dis-
cussions.
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Received: September 4, 2008
Revised: October 24, 2008
Published online: December 29, 2008
Chem. Eur. J. 2009, 15, 1468 – 1477
ꢃ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
1477