Multiple regio- and chemoselective functionalizations of pyrimidine derivatives using TMPMgCl·LiCl and TMP2Mg·2 LiCl

Article abstract of DOI:10.1055/s-0028-1083208

The multiple successive regio- and chemoselective magnesiation of commercially available 2-bromopyrimidine at the C4, C6, and C5 positions allows the regioselective functionalization of all positions of the pyrimidine ring. Georg Thieme Verlag Stuttgart ·

Full text of DOI:10.1055/s-0028-1083208

PRACTICAL SYNTHETIC PROCEDURES
3697
Multiple Regio- and Chemoselective Functionalizations of Pyrimidine
Derivatives Using TMPMgCl·LiCl and TMP2Mg·2 LiCl
Multiple Regio- and Ch
a
e
moselecti
r
ve Func
c
tionalizations of
P
M
yrimidine osrin, Marilena Petrera, Paul Knochel*
Department Chemie und Biochemie, Ludwig-Maximilians-Universität München,
Butenandtstrasse 5-13, Haus F, 81377 München, Germany
Fax +49(89)218077680; E-mail: paul.knochel@cup.uni-muenchen.de
Received 21 July 2008
PSP
No137
Abstract: The multiple successive regio- and chemoselective magnesiation of commercially available 2-bromopyrimidine at the C4, C6,
and C5 positions allows the regioselective functionalization of all positions of the pyrimidine ring.
Key words: Grignard reagents, pyrimidines, regioselective magnesiation, magnesium bases
Procedure 1:
1. TMP2Mg⋅2LiCl (3)
(1.1 equiv), THF,
–10 °C, 40 min
1. TMPMgCl⋅LiCl (1)
(1.1 equiv), THF,
–60 °C, 1.5 h
1. TMPMgCl⋅LiCl (1)
(1.1 equiv), THF,
–60 °C, 45 min
SPh
SPh
Cl
O
SPh
N
N
N
N
2. CuCN⋅2LiCl
(1.1 equiv), THF,
–20 °C, 30 min
2. PhSO2SPh
2. ClF2CCCl2F
N
Br
N
Br
Cl
N
Br
Cl
N
Br
2
5a: 77%
6a: 90%
7a: 77% (1 g scale)
3. 2-chlorobenzoyl
chloride
Scheme 1
Introduction
Scope and Limitations
Pyrimidines are privileged structures in drug discovery A variety of pyrimidine derivatives can be easily prepared
and display a broad spectrum of biological activity.1 Their starting
from commercially available 2-
direct functionalization by lithiation is difficult due to the bromopyrimidine7 (2). The treatment of 2 with TMP-
electrophilic character of the ring, which readily under- MgCl·LiCl (1, 1.1 equiv, –60 °C, 1.5 h) leads to the 4-
goes the addition of various organometallics in positions magnesiated pyrimidine 4, which can be trapped by elec-
4 and 6.2 This implies that low temperatures are required trophiles such as S-phenyl benzenethiosulfonate, iodine,
for the metalation of pyrimidines.3 Recently, we have or 1,1,2-trichloro-1,2,2-trifluoroethane furnishing the
shown that 2,2,6,6-tetramethylpiperidin-1-ylmagnesium functionalized pyrimidines 5a–c in 71–80%. The forma-
chloride–lithium chloride complex (TMPMgCl·LiCl, 1)4 tion of a new C–C bond can be easily performed by a
allows full functionalization of the pyrimidine scaffold Negishi8 or Sonogashira9 cross-coupling reaction of in
under mild conditions.5 Herein, we wish to report a com- situ generated 2-bromo-4-iodopyrimidine (5b) giving 4-
plementary metalation procedure of 2-bromopyrimidine substituted pyrimidines 5d–f in 56–67% (Scheme 3).
(2) using 2,2,6,6-tetramethylpiperidin-1-ylmagnesium
Further magnesiation is readily carried out at position 6 by
chloride–lithium chloride complex (TMPMgCl·LiCl, 1)
the addition of TMPMgCl·LiCl (1) to selected 4-substitut-
or
bis(2,2,6,6-tetramethylpiperidin-1-yl)magnesium–
ed-2-bromopyrimidines. Thus, the 2-bromo-4-(phenylsul-
fanyl)pyrimidine (5a) is magnesiated quantitatively with
TMPMgCl·LiCl (1, 1.1 equiv, –60 °C, 45 min) and react-
ed with tosyl cyanide, 1,1,2-trichloro-1,2,2-trifluoroeth-
ane, or 1,2-dibromo-1,1,2,2-tetrachloroethane affording
the expected 4,6-disubstituted 2-bromopyrimidines 6a–c
in 67–90% yield (Table 1, entries 1–3). Similarly, 2-bro-
mo-4-iodopyrimidine (5b) is converted within one hour at
–60 °C into the magnesiated species, which is trapped
bis(lithium chloride) complex6 (TMP2Mg·2LiCl, 3)
(Schemes 1 and 2) by successive magnesiations.
SYNTHESIS 2008, No. 22, pp 3697–3702
x
x.
x
x
.
2
0
0
8
Advanced online publication: 23.10.2008
DOI: 10.1055/s-0028-1083208; Art ID: T12008SS
© Georg Thieme Verlag Stuttgart · New York

3698
M. Mosrin et al.
PRACTICAL SYNTHETIC PROCEDURES
N
Br
E1
N
Br
E1
N
Br
E1
E3
N
Br
2
4
5
1) 1
1) 1
1) 3
2) E2
2) E3
2) E1
N
N
N
N
6
E2
E2
2
5a–f
6a–f
7a–c
Cl
Cl
N
Mg⋅2LiCl
N Mg
Li
N
1 : TMPMgCl⋅LiCl
(1.1 equiv)
3 : TMP2Mg⋅2LiCl
(1.1 equiv)
Scheme 2 Magnesiation of 2-bromopyrimidine (2) at positions 4, 6, and 5 using TMPMgCl·LiCl (1, 1.1 equiv) or TMP2Mg·2LiCl (3, 1.1
equiv)
TMPMgCl·LiCl (1)
(1.1 equiv)
E1
N
Br
LiCl·ClMg
N
Br
N
Br
E1
N
N
N
THF, –60 °C, 1.5 h
5a–f: 56–80%
4
2
Cl
Bu
X
N
Br
N
Br
N
Br
N
Br
S
N
N
N
N
5a: X = SPh; 77%
5b: X = I; 80%
5c: X = Cl; 71%
5d: 67%
5f: 56%
5e: 62%
Scheme 3 Magnesiation of 2-bromopyrimidine (2) at position 4 using TMPMgCl·LiCl (1, 1.1 equiv)
with iodine leading to 2-bromo-4,6-diiodopyrimidine All reactions were carried out under argon atmosphere in dried
glassware. All starting materials were purchased from commercial
suppliers and used without further purification unless otherwise
stated. THF was continuously refluxed and freshly distilled from Na
(6d) in 82% yield (Table 1, entry 4).
Reaction with 1,2-dibromo-1,1,2,2-tetrachloroethane fur-
nishes the bromopyrimidine 6e in 67% yield (Table 1, en-
try 5). Trapping with trimethylsilyl cyanide provides the
pyrimidine derivative 6f in 89% (Table 1, entry 6). The
last position (position 5) can also be magnesiated at –10
°C within 40 minutes using TMP2Mg·2LiCl (3, 1.1 equiv).
Trapping with 2-chlorobenzoyl chloride (after transmeta-
lation with CuCN·2LiCl),10 allyl bromide (after succes-
sive transmetalations with ZnCl2 and in the presence of a
benzophenone ketyl under N2. Yields refer to isolated compounds
estimated to be >95% pure as determined by 1H NMR and capillary
GC analysis.
Isopropylmagnesium Chloride–Lithium Chloride
Mg turnings (110 mmol) and anhyd LiCl (100 mmol) were placed
in an argon-flushed flask dried and THF (50 mL) was added. A soln
of i-PrCl (100 mmol) in THF (50 mL) was slowly added at 25 °C.
The reaction started within a few minutes. When the addition was
catalytic amount of CuCN·2LiCl) or S-methyl methane- finished, the mixture was stirred at 25 °C for 12 h. The grey soln of
i-PrMgCl·LiCl was cannulated from the excess Mg to a different
thiosulfonate leads to the fully substituted pyrimidines
flask under argon. A yield of ca. 95–98% of i-PrMgCl·LiCl was ob-
7a–c in 77–89% yield (Table 1, entries 7–9).
tained. The reagent was titrated prior to use by the method of
Paquette,11a or the method developed in our laboratory.12
An efficient and convergent multiple regio- and chemose-
lective magnesiation of commercially available 2-bro-
mopyrimidine using TMPMgCl·LiCl and TMP2Mg·2LiCl
was demonstrated. In summary, we have extended our
previous work to the scaled-up and optimized preparation
of highly functionalized pyrimidines. This reaction could
be performed with standard laboratory glassware and did
not require the use of expensive chemicals or catalysts.
2,2,6,6-Tetramethylpiperidin-1-ylmagnesium Chloride–Lithi-
um Chloride Complex (1)
A dry, N2-flushed 250-mL Schlenk flask, equipped with a magnetic
stirring bar and a septum, was charged with freshly titrated 1.2 M
i-PrMgCl·LiCl in THF (100 mL, 120 mmol). 2,2,6,6-Tetramethyl-
piperidine (18.7 g, 132 mmol, 1.1 equiv) was added dropwise at 25
°C. The mixture was stirred at 25 °C until gas evolution was com-
pleted (ca. 24 h). The reagent was titrated prior to use [benzoic acid
with 4-(phenylazo)diphenylamine as the indicator].11b
Synthesis 2008, No. 22, 3697–3702 © Thieme Stuttgart · New York

PRACTICAL SYNTHETIC PROCEDURES
Multiple Selective Functionalizations of Pyrimidine
3699
1 M Copper(I) Cyanide–Bis(lithium chloride) in Tetrahydro-
furan Solution
Table 1 Products Obtained by Magnesiations of Pyrimidines of
Type 5 and 6 and Quenching with Electrophiles
A dry, argon-flushed 50-mL Schlenk flask, equipped with a mag-
netic stirrer and a glass stopper, was charged with LiCl (848 mg, 20
mmol) and heated to 130 °C under high vacuum for 1 h. After cool-
ing to 25 °C under argon, CuCN (869 mg, 10 mmol) was added un-
der an inert atmosphere inside a glove box. The Schlenk flask was
further heated to 140 °C for 5 h under high vacuum and cooled to
25 °C. It was then charged with freshly distilled THF (20 mL) under
an argon flush and wrapped with aluminum foil to protect it from
light. The mixture was stirred vigorously until all the solid had gone
into solution to furnish 1.0 M CuCN·2LiCl in THF.
Entry Substrate
of type 5 and 6
Electrophile
Products
Yielda
(%)
PhS
N
Br
PhS
N
Br
N
N
E
1
2
3
5a
5a
5a
ClCF2CCl2F
TsCN
6a E = Cl
90
67
85
6b E = CN
2-Bromo-4-(phenylsulfanyl)pyrimidine (5a); Typical Proce-
dure Using TMPMgCl·LiCl (1) or TMP2Mg·2 LiCl (3)
BrCCl2CCl2Br 6c E = Br
A dry and argon-flushed Schlenk flask, equipped with a magnetic
stirrer and a septum, was charged with 1.1 M TMPMgCl·LiCl (1) in
THF (10 mL, 11 mmol) and cooled to –60 °C. 2-Bromopyrimidine
(2, 1.60 g, 10 mmol) dissolved in THF (10 mL) was added and the
mixture was stirred at –60 °C for 1.5 h. PhSO2SPh (3.0 g, 12 mmol)
in THF (12 mL) was added dropwise at –60 °C, the resulting mix-
ture was allowed to warm up rapidly to –30 °C and then slowly to
25 °C and stirred at this temperature for 15 min. Purification by
flash chromatography (pentane–Et2O, 4:1) afforded 5a (2.07 g,
77%) as a white solid; mp 83.7–85.0 °C.
I
N
Br
I
N
Br
N
N
E
4
5
6
5b
5b
5b
I2
BrCCl2CCl2Br 6e E = Br
Me3SiCN 6f E = SiMe3
6d E = I
82
67
89
IR (ATR): 3060, 3021, 1542, 1509, 1473, 1443, 1396, 1314, 1158,
1144, 1092, 1067, 1020, 1001, 974, 828, 790, 757, 691, 675 cm–1.
1H NMR (300 MHz, CDCl3): d = 8.09 (d, J = 5.4 Hz, 1 H), 7.45–
7.60 (m, 5 H), 6.64 (d, J = 5.4 Hz, 1 H).
13C NMR (75 MHz, CDCl3): d = 172.6, 157.3, 151.9, 135.4, 130.5,
130.1, 126.7, 115.5.
MS (EI, 70 eV): m/z (%) = 267 (100), 265 (96) [(79Br)M+], 187 (79),
109 (17).
HRMS (EI): m/z [M]+ calcd for C10H7BrN2S: 265.9513; found:
265.9505.
PhS
N
Br
PhS
E
N
Br
N
N
Cl
Cl
7
8
9
6a
6a
6a
2-ClC6H4COClb 7a E = 2-ClC6H4CO 77
allyl bromidec,d 7b E = allyl
89
80
MeSO2SMe 7c E = SMe
a Yield of analytically pure product.
b Transmetalation with CuCN·2LiCl (1.1 equiv) was performed.
c Transmetalation with ZnCl2 (1.1 equiv) was performed.
d Transmetalation with CuCN·2LiCl (5 mol%) was performed.
2-Bromo-4-chloro-6-(phenylsulfanyl)pyrimidine (6a)
Following the typical procedure using 1.1 M TMPMgCl·LiCl (1) in
THF (10 mL, 11 mmol) and 2-bromo-4-(phenylsulfanyl)pyrimidine
(5a, 2.67 g, 10 mmol) in THF (10 mL) with stirring at –60 °C for 45
min. ClCF2CCl2F (2.81 g, 15 mmol) was added dropwise at –60 °C;
the mixture was allowed to warm up rapidly to –30 °C and slowly
to –15 °C for 1 h. Purification by flash chromatography (pentane–
CH2Cl2, 2:1) afforded 6a (2.65 g, 90%) as a white solid; mp 66.8–
67.9 °C.
Bis(2,2,6,6-tetramethylpiperidin-1-yl)magnesium–Bis(lithium
chloride) Complex (3)
A dry, argon flushed 250-mL Schlenk flask, equipped with a mag-
netic stirrer and a septum, was charged with freshly distilled
2,2,6,6-tetramethylpiperidine (5.07 mL, 30 mmol) dissolved in
THF (30 mL). This soln was cooled to –40 °C and 2.4 M BuLi in
hexane (12.5 mL, 30 mmol) was added dropwise. When the addi-
tion was complete, the mixture was warmed to 0 °C and stirred at
this temperature for 30 min. Freshly titrated 1.0 M TMPMgCl·LiCl
(1) in THF (30 mL, 30 mmol) was then added dropwise to the mix-
ture and it was stirred at 0 °C for 30 min, warmed to 25 °C, and
stirred for 1 h. The solvents were then removed under vacuum to af-
ford a yellowish solid. Freshly distilled THF was then slowly added
with vigorous stirring until the salts were completely dissolved. The
resulting soln of TMP2Mg·2LiCl (3) was titrated prior to use at 0 °C
[benzoic acid with 4-(phenylazo)diphenylamine as the indicator].11b
A concentration of 0.6 M in THF was obtained.
IR (ATR): 3107, 1516, 1489, 1442, 1360, 1339, 1256, 1188, 1102,
1093, 970, 844, 801, 757, 692 cm–1.
1H NMR (600 MHz, CDCl3): d = 7.51–7.59 (m, 5 H), 6.58 (s, 1 H).
13C NMR (150 MHz, CDCl3): d = 177.5, 161.0, 151.5, 135.6, 131.1,
130.5, 126.1, 114.9.
MS (EI, 70 eV): m/z (%) = 302 (69), 301 (100), 300 (50) [(79Br)M+],
265 (36), 221 (26).
HRMS (EI): m/z [M]+ calcd for C10H6BrClN2S: 299.9124; found:
299.9120.
[2-Bromo-4-chloro-6-(phenylsulfanyl)pyrimidin-5-yl](2-chlo-
rophenyl)methanone (7a)
1 M Zinc Chloride in Tetrahydrofuran Solution
Following the typical procedure using 0.55 M TMP2Mg·2LiCl (3)
in THF (6 mL, 3.3 mmol) and cooled to –10 °C. 2-Bromo-4-chloro-
6-(phenylsulfanyl)pyrimidine (6a, 0.91 g, 3.0 mmol) dissolved in
THF (6 mL) was slowly added and the mixture was stirred at –10
°C for 40 min. The mixture was cooled to –20 °C, 1.0 M
CuCN·2LiCl in THF (3.3 mL, 3.3 mmol) was added and the mixture
A dry, argon-flushed 500-mL Schlenk flask, equipped with a mag-
netic stirrer and a glass stopper, was charged with ZnCl2 (20.45 g,
150 mmol) and heated to 150 °C under high vacuum for 5 h. After
cooling to 25 °C under argon, anhyd THF (150 mmol) was added
and the mixture was stirred continuously until the salts had dis-
solved. The reagent ZnCl2 (1 M in THF) appears as a colorless soln.
Synthesis 2008, No. 22, 3697–3702 © Thieme Stuttgart · New York

3700
M. Mosrin et al.
PRACTICAL SYNTHETIC PROCEDURES
was stirred for 30 min. Then, 2-chlorobenzoyl chloride (1.05 g, 6.0
mmol) was added dropwise at –20 °C and the resulting mixture was
stirred at 35 °C for 30 min. Purification by flash chromatography
(pentane–CH2Cl2, 3:1) afforded the pyrimidine 7a (1.02 g, 77%) as
a white solid; mp 132.4–134.0 °C.
THF (10 mL) and mixed with 1-chloro-4-iodobenzene (2.86 g, 12
mmol) were then transferred via cannula to the mixture. The result-
ing mixture was stirred at 50 °C for 1 h. Purification by flash chro-
matography (pentane–CH2Cl2; 2:1) afforded 5d (1.81 g, 67%) as a
yellowish solid; mp 130.5–132.7 °C.
IR (ATR): 3065, 1678, 1584, 1520, 1476, 1438, 1318, 1282, 1218,
1197, 1140, 1106, 1055, 918, 819, 773, 750, 736, 717, 704, 688, 656
cm–1.
1H NMR (600 MHz, CDCl3): d = 7.41–7.84 (m, 9 H).
IR (ATR): 3094, 1594, 1561, 1523, 1488, 1423, 1397, 1337, 1167,
1088, 1060, 1010, 982, 817, 802, 763, 723, 660, 628 cm–1.
1H NMR (300 MHz, CDCl3): d = 8.56 (d, J = 5.3 Hz, 2 H), 8.02 (d,
J = 8.6 Hz, 1 H), 7.63 (d, J = 5.3 Hz, 1 H), 7.47 (d, J = 8.6 Hz, 2 H).
13C NMR (150 MHz, CDCl3): d = 189.6, 172.3, 156.3, 150.7, 135.4,
134.8, 134.6, 133.7, 132.1, 131.4, 130.3, 129.4, 128.3, 127.5, 126.2.
13C NMR (75 MHz, CDCl3): d = 165.6, 159.7, 153.6, 138.3, 133.4,
129.6, 128.7, 115.2.
MS (70 eV, EI): m/z (%) = 438 (1) [(79Br)M+], 405 (100), 403 (69),
MS (70 eV, EI): m/z (%) = 270 (100), 268 (73) [(79Br)M+], 191 (50),
139 (18), 111 (14).
137 (17).
HRMS (EI): m/z [M]+ calcd for C17H9BrCl2N2OS: 437.8996; found:
HRMS (EI): m/z [M]+ calcd for C10H6BrClN2: 267.9403; found:
437.9003.
267.9412
2-Bromo-4-iodopyrimidine (5b)
2-Bromo-4-(thiophen-2-yl)pyrimidine (5e)
Following the typical procedure using 1.1 M TMPMgCl·LiCl (1) in
THF (10 mL, 11 mmol) and 2-bromopyrimidine (2, 1.60 g, 10
mmol) in THF (10 mL) with stirring at –60 °C for 1.5 h. 1.0 M
ZnCl2 in THF (12 mL, 12 mmol) was added dropwise at –60 °C; the
mixture was allowed to warm up slowly to 25 °C. I2 (3.04 g, 12
mmol) dissolved in anhyd THF (12 mL) added dropwise and the
mixture was stirred at 25 °C for 45 min. Purification by flash chro-
matography (pentane–CH2Cl2, 3:1) afforded 5b (2.29 g, 80%) as a
white solid; mp 103.5–104.7 °C.
Following the typical procedure using 1.1 M TMPMgCl·LiCl (1) in
THF (10 mL, 11 mmol) and 2-bromopyrimidine (2, 1.60 g, 10
mmol) in THF (10 mL) with stirring at –60 °C for 1.5 h. 1.0 M
ZnCl2 in THF (12 mL, 12 mmol) was added dropwise at –60 °C; the
mixture was allowed to warm up slowly to 25 °C for 3 h. Pd(dba)2
(115 mg, 2 mol%) and (2-furyl)3P (93 mg, 4 mol%) dissolved in
THF (10 mL), and mixed with 2-iodothiophene (2.73 g, 13 mmol)
were then transferred via cannula to the mixture. The resulting mix-
ture was stirred at 20 °C for 30 min. Purification by flash chroma-
tography (pentane–EtOAc, 4:1) afforded 5e (1.49 g, 62%) as a
yellowish solid; mp 127.4–129.1 °C.
IR (ATR): 3090, 3006, 1513, 1388, 1312, 1180, 1150, 976, 832,
750, 662 cm–1.
IR (ATR): 3080, 3047, 1564, 1515, 1434, 1413, 1358, 1331, 1240,
1166, 1113, 999, 980, 852, 842, 762, 721, 674, 622 cm–1.
1H NMR (300 MHz, CDCl3): d = 8.44 (d, J = 5.3 Hz, 1 H), 7.79–
7.81 (dd, J = 1.1 Hz, J = 2.7 Hz, 1 H), 7.56–7.58 (dd, J = 1.1 Hz,
J = 2.7 Hz, 1 H), 7.14–7.17 (dd, J = 4.8 Hz, J = 1.2 Hz, 1 H), 7.48
(d, J = 5.3 Hz, 1 H).
1H NMR (300 MHz, CDCl3): d = 8.05 (d, J = 5.1 Hz, 1 H), 7.74 (d,
J = 5.1 Hz, 1 H).
13C NMR (75 MHz, CDCl3): d = 157.7, 151.2, 131.5, 129.9.
MS (70 eV, EI): m/z (%) = 286 (73), 284 (73) [(79Br)M+], 157 (100),
127 (26).
HRMS (EI): m/z [M]+ calcd for C4H2BrIN2: 283.8446; found:
283.8438.
13C NMR (75 MHz, CDCl3): d = 172.6, 157.3, 151.9, 135.4, 130.5,
130.1, 126.7, 115.5.
MS (EI, 70 eV): m/z (%) = 242 (51), 240 (49) [(79Br)M+], 161 (100).
HRMS (EI): m/z [M]+ calcd for C8H5BrN2S: 239.9357; found:
2-Bromo-4-chloropyrimidine (5c)
Following the typical procedure using 1.1 M TMPMgCl·LiCl (1) in
THF (10 mL, 11 mmol) and 2-bromopyrimidine (2, 1.60 g, 10
mmol) in THF (10 mL) with stirring at –60 °C for 1.5 h.
ClCF2CCl2F (2.81 g, 15 mmol) was added dropwise at –60 °C; the
mixture was allowed to warm up slowly to –45 °C and then stirred
overnight at –45 °C. Purification by flash chromatography (pen-
tane–CH2Cl2, 1:1) afforded 5c (1.38 g, 71%) as a yellowish solid;
mp 46.5–47.7 °C.
239.9353.
2-Bromo-4-(hex-1-ynyl)pyrimidine (5f)
Prepared from in situ generated 2-bromo-4-iodopyrimidine 5b
[starting from 2-bromopyrimidine (2, 1.6 g, 10 mmol)]. Pd(dba)2
(114 mg, 2 mol%) and (2-furyl)3P (93 mg, 4 mol%) dissolved in
THF (10 mL) and mixed with CuI (40 mg, 0.2 mmol, 2 mol%) and
Et3N (70 mL) were transferred via cannula to the mixture. Hex-1-
yne (0.98 g, 12 mmol) was then slowly added at 20 °C and the re-
sulting mixture was stirred at the same temperature for 1 h. Purifi-
cation by flash chromatography (pentane–CH2Cl2, 1:1) afforded 5f
(1.34 g, 56%) as a yellow oil.
IR (ATR): 3090, 3048, 1720, 1526, 1404, 1318, 1189, 1161, 1092,
979, 859, 815, 789, 755, 680 cm–1.
1H NMR (300 MHz, CDCl3): d = 8.44 (d, J = 5.3 Hz, 1 H), 7.35 (d,
J = 5.3 Hz, 1 H).
13C NMR (75 MHz, CDCl3): d = 162.1, 159.7, 152.2, 120.7.
MS (EI, 70 eV): m/z (%) = 194 (62), 192 (49) [(79Br)M+], 157 (10),
IR (ATR): 2958, 2933, 2226, 1556, 1516, 1466, 1416, 1325, 1166,
1088, 980, 954, 843, 794, 779, 768, 739, 680 cm–1.
1H NMR (300 MHz, CDCl3): d = 8.47 (d, J = 5.0 Hz, 1 H), 7.27 (d,
J = 5.0 Hz, 1 H), 2.47 (t, J = 7.3 Hz, 2 H), 1.61 (p, J = 7.1 Hz, 2 H),
1.46 (s, J = 7.3 Hz, 2 H), 2.47 (t, J = 7.3 Hz, 3 H).
115 (37).
HRMS (EI): m/z [M]+ calcd for C4H2BrClN2: 191.9090; found:
191.9075.
13C NMR (75 MHz, CDCl3): d = 158.8, 153.5, 152.9, 122.0, 99.6,
78.0, 29.8, 22.0, 19.2, 13.5.
2-Bromo-4-(4-chlorophenyl)pyrimidine (5d)
Following the typical procedure using 1.1 M TMPMgCl·LiCl (1) in
THF (10 mL, 11 mmol) and 2-bromopyrimidine (2, 1.60 g, 10
mmol) in THF (10 mL) with stirring at –60 °C for 1.5 h. 1.0 M
ZnCl2 in THF (12 mL, 12 mmol) was added dropwise at –60 °C; the
mixture was allowed to warm up slowly to 25 °C for 3 h. Pd(dba)2
(115 mg, 2 mol%) and (2-furyl)3P (93 mg, 4 mol%) dissolved in
MS (EI, 70 eV): m/z (%) = 240 (28), 238 (27) [(79Br)M+], 211 (88),
209 (85), 198 (99), 196 (100), 116 (42).
HRMS (EI): m/z [M]+ calcd for C10H11BrN2: 238.0106; found:
238.0101.
Synthesis 2008, No. 22, 3697–3702 © Thieme Stuttgart · New York

PRACTICAL SYNTHETIC PROCEDURES
Multiple Selective Functionalizations of Pyrimidine
3701
2-Bromo-6-(phenylsulfanyl)pyrimidine-4-carbonitrile (6b)
Following the typical procedure using 1.1 M TMPMgCl·LiCl (1) in
THF (10 mL, 11 mmol) and 2-bromo-4-(phenylsulfanyl)pyrimidine
(5a, 2.67 g, 10 mmol) in THF (10 mL) with stirring at –60 °C for 45
min. TsCN (2.72 g, 15 mmol) in THF (20 mL) was then added drop-
wise at –60 °C; the mixture was stirred at –30 °C for 2 h. Purifica-
tion by flash chromatography (pentane–CH2Cl2, 1:1) afforded 6b
(1.96 g, 67%) as a white solid; mp 104.3–106.4 °C.
the mixture was allowed to warm up slowly to –60 °C for 1 h. Puri-
fication by flash chromatography (pentane–CH2Cl2, 3:1) afforded
6e (1.22 g, 67%) as a white solid; mp 145.6–147.2 °C.
IR (ATR): 3101, 2925, 1476, 1352, 1323, 1235, 1096, 972, 858,
776, 737 cm–1.
1H NMR (400 MHz, THF-d8): d = 8.29 (s, 1 H).
13C NMR (100 MHz, THF-d8): d = 152.7, 150.4, 136.1, 131.0.
MS (EI, 70 eV): m/z (%) = 364 (95), 362 (49) [(79Br)M+], 239 (46),
237 (100), 235 (50), 132 (35), 127 (39).
IR (ATR): 3107, 3057, 1593, 1542, 1494, 1476, 1444, 1379, 1285,
1219, 1174, 1133, 971, 875, 809, 753, 690 cm–1.
1H NMR (600 MHz, CDCl3): d = 7.54–7.61 (m, 5 H), 6.88 (s, 1 H).
HRMS (EI): m/z [M]+ calcd for C4HBr2IN2: 361.7551; found:
13C NMR (150 MHz, CDCl3): d = 179.0, 152.5, 141.0, 135.5, 131.5,
130.8, 125.3, 118.6, 114.2.
361.7562
2-Bromo-4-iodo-6-(trimethylsilyl)pyrimidine (6f)
MS (70 eV, EI): m/z (%) = 292 (100), 291 (69) [(79Br)M+], 212 (99),
185 (29), 109 (40), 77 (10), 65 (30).
HRMS (EI): m/z [M]+ calcd for C11H6BrN3S: 290.9466; found:
290.9442.
Following the typical procedure using 1.1 M TMPMgCl·LiCl (1)
THF (5.5 mL, 5 mmol) and 2-bromo-4-iodopyrimidine (5b, 1.42 g,
5 mmol) in THF (10 mL) with stirring at –60 °C for 1 h. Me3SiCN
(0.74 g, 6.0 mmol) was then added dropwise; the mixture was al-
lowed to warm up slowly to –35 °C for 2 h. Purification by flash
chromatography (pentane–CH2Cl2, 3:1) afforded 6f (1.59 g, 89%)
as a white solid; mp 64.3–66.6 °C.
2,4-Dibromo-6-(phenylsulfanyl)pyrimidine (6c)
Following the typical procedure using 1.1 M TMPMgCl·LiCl (1) in
THF (5.5 mL, 5 mmol) and 2-bromo-4-(phenylsulfanyl)pyrimidine
(5a, 1.51 g, 5 mmol) in THF (10 mL) with stirring at –60 °C for 45
min. BrCCl2CCl2Br (2.44 g, 7.50 mmol) was slowly added; the mix-
ture was allowed to warm up rapidly to –30 °C and then to warm up
slowly to –15 °C for 1 h. Purification by flash chromatography
(pentane–CH2Cl2, 3:1) afforded 6c (1.47 g, 85%) as a white solid;
mp 62.0–64.0 °C.
IR (ATR): 2957, 2898, 1518, 1449, 1250, 1218, 1168, 1134, 1120,
1078, 970, 837, 776, 744, 728, 625 cm–1.
1H NMR (400 MHz, THF-d8): d = 8.03 (s, 1 H), 0.31 (s, 9 H).
13C NMR (100 MHz, THF-d8): d = 182.8, 151.9, 137.1, 131.0, –2.7.
MS (70 eV, EI): m/z (%) = 358 (13), 356 (11) [(79Br)M+], 340 (22),
338 (15), 276 (62), 231 (100), 229 (98), 139 (41), 137 (39).
IR (ATR): 3093, 3055, 1512, 1476, 1440, 1352, 1245, 1177, 1092,
1026, 965, 921, 842, 806, 765, 743, 683 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.47–7.57 (m, 5 H), 6.75 (s, 1 H).
HRMS (EI): m/z [M]+ calcd for C7H10BrIN2Si: 355.8841; found:
355.8829
13C NMR (75 MHz, CDCl3): d = 176.8, 152.0, 150.5, 135.5, 131.0,
5-Allyl-2-bromo-4-chloro-6-(phenylsulfanyl)pyrimidine (7b)
Following the typical procedure using 0.55 M TMP2Mg·2LiCl (3)
in THF (6 mL, 3.3 mmol) cooled to –10 °C. 2-Bromo-4-chloro-6-
(phenylsulfanyl)pyrimidine (6a, 0.91 g, 3 mmol) in THF (6 mL)
was slowly added and the mixture was stirred at –10 °C for 40 min.
1.0 M ZnCl2 in THF (9 mL, 9 mmol) was then added dropwise at
–10 °C and the mixture was stirred at this temperature for 30 min.
Then, 1.0 M CuCN·2LiCl in THF (0.15 mL, 5 mol%) was added at
–20 °C and the mixture was cooled down to –60 °C. Allyl bromide
(0.72 g, 6 mmol) was added to the reaction and the resulting mixture
was allowed to warm up slowly to –30 °C. Purification by flash
chromatography (pentane–CH2Cl2, 3:1) afforded 7b (0.91 g, 89%)
as a white solid; mp 49.5–51.1 °C.
130.4, 126.0, 118.8.
MS (EI, 70 eV): m/z (%) = 345 (100), 344 (42) [(79Br)M+], 265 (75),
109 (37).
HRMS (EI): m/z [M]+ calcd for C10H6Br2N2S: 343.8618; found:
343.8595.
2-Bromo-4,6-diiodopyrimidine (6d)
Following the typical procedure using 1.1 M TMPMgCl·LiCl (1) in
THF (10 mL, 11 mmol) and 2-bromo-4-iodopyrimidine (5b, 2.84 g,
10 mmol) in THF (20 mL) with stirring at –60 °C for 1 h. 1.0 M
ZnCl2 in THF (12 mL, 12 mmol) was added dropwise at –60 °C; the
mixture was allowed to warm up slowly to –20 °C for 1 h. I2 (3.04
g, 12 mmol) in THF (12 mL) was slowly added at –20 °C and the
resulting mixture was stirred for 60 min at –20 °C. The mixture was
then quenched with sat. aq Na2S2O3 (50 mL). Purification by flash
chromatography (pentane–CH2Cl2, 4:1) afforded 6d (3.35 g, 82%)
as a white solid; mp 186.4–188.0 °C.
IR (ATR): 3052, 3011, 1638, 1522, 1480, 1442, 1435, 1418, 1309,
1280, 1211, 1190, 1009, 1084, 1022, 992, 978, 939, 900, 853, 790,
776, 748, 707, 688 cm–1.
1H NMR (600 MHz, CDCl3): d = 7.43–7.52 (m, 5 H), 5.84–5.91 (m,
1 H), 5.18–5.21 (m, 2 H), 3.55 (dt, 3J = 6.3 Hz, 4J = 1.5 Hz, 2 H).
13C NMR (150 MHz, CDCl3): d = 173.0, 159.4, 148.1, 135.4, 130.3,
130.0, 129.3, 126.8, 125.9, 118.2, 32.8.
MS (EI, 70 eV): m/z (%) = 340 (5) [(79Br)M+], 327 (100), 325 (72),
109 (10).
HRMS (EI): m/z [M]+ calcd for C13H10BrClN2S: 339.9437; found:
339.9435.
IR (ATR): 3101, 2925, 1465, 1344, 1305, 1228, 1109, 1091, 972,
840, 768, 721 cm–1.
1H NMR (400 MHz, THF-d8): d = 8.05 (s, 1 H).
13C NMR (100 MHz, THF-d8): d = 149.8, 142.7, 130.2.
MS (70 eV, EI): m/z (%) = 412 (100), 410 (98) [(79Br)M+], 283 (65),
178 (48), 127 (55), 77 (25).
HRMS (EI): m/z [M]+ calcd for C4HBrI2N2: 409.7412; found:
409.7400.
2-Bromo-4-chloro-5-(methylsulfanyl)-6-(phenylsulfanyl)pyri-
midine (7c)
Following the typical procedure using 0.55 M TMP2Mg·2 LiCl (3)
in THF (6 mL, 3.3 mmol) and cooling to –10 °C. 2-Bromo-4-chlo-
ro-6-(phenylsulfanyl)pyrimidine (6a, 0.91 g, 3 mmol) dissolved in
THF (6 mL) was slowly added and the mixture was stirred at –10
°C for 40 min. MeSO2SMe (1.14 g, 9.0 mmol) was then added drop-
wise and the resulting mixture was stirred at 25 °C for 30 min. Pu-
2,4-Dibromo-6-iodopyrimidine (6e)
Following the typical procedure using 1.1 M TMPMgCl·LiCl (1) in
THF (5.5 mL, 5 mmol) and 2-bromo-4-iodopyrimidine (5b, 1.42 g,
5 mmol) in THF (10 mL) with stirring at –60 °C for 1 h.
BrCCl2CCl2Br (2.442 g, 7.5 mmol) was added dropwise at –78 °C;
Synthesis 2008, No. 22, 3697–3702 © Thieme Stuttgart · New York

3702
M. Mosrin et al.
PRACTICAL SYNTHETIC PROCEDURES
rification by flash chromatography (pentane–CH2Cl2, 3:1) afforded
7c (0.83 g, 80%) as a white solid; mp 64.5–66.3 °C.
N.; Turck, A.; Heynderickx, A.; Quéguiner, G. Tetrahedron
1998, 54, 9701. (d) Plé, N.; Turck, A.; Heynderickx, A.;
Quéguiner, G. J. Heterocycl. Chem. 1997, 34, 551.
(3) (a) Turck, A.; Plé, N.; Mongin, F.; Quéguiner, G.
Tetrahedron Lett. 2001, 42, 4489. (b) Schlosser, M.;
Lefebvre, O.; Ondi, L. Eur. J. Org. Chem. 2006, 6, 1593.
(4) (a) Krasovskiy, A.; Krasovskaya, V.; Knochel, P. Angew.
Chem. Int. Ed. 2006, 45, 2958. (b) Lin, W.; Baron, O.;
Knochel, P. Org. Lett. 2006, 8, 5673.
IR (ATR): 3060, 2922, 1487, 1463, 1440, 1274, 1255, 1195, 1087,
1068, 1042, 1023, 1000, 972, 914, 828, 794, 744, 703, 686 cm–1.
1H NMR (600 MHz, CDCl3): d = 7.45–7.51 (m, 5 H), 2.47 (s, 3 H).
13C NMR (150 MHz, CDCl3): d = 179.2, 164.0, 149.8, 135.2, 130.0,
129.3, 127.9, 124.7, 17.1.
MS (EI, 70 eV): m/z (%) = 348 (100), 346 (65) [(79Br)M+], 315 (31),
313 (27), 269 (14), 267 (27), 109 (25), 77 (19).
HRMS (EI): m/z [M]+ calcd for C11H8BrClN2S2: 345.9001; found:
345.9014.
(5) Mosrin, M.; Knochel, P. Org. Lett. 2008, 10, 2497.
(6) Clososki, G. C.; Rohbogner, C. J.; Knochel, P. Angew.
Chem. Int. Ed. 2007, 46, 7681.
(7) 2-Bromopyrimidine is commercially available from Acros,
Aldrich, Fluka (ca $15 for 1 g).
(8) (a) Negishi, E.; Valente, L. F.; Kobayashi, M. J. Am. Chem.
Soc. 1980, 102, 3298. (b) Negishi, E.; Kobayashi, M. J. Org.
Chem. 1980, 45, 5223. (c) Negishi, E. Acc. Chem. Res.
1982, 15, 340. (d) Milne, J. E.; Buchwald, S. L. J. Am.
Chem. Soc. 2004, 126, 13028.
(9) (a) Benderitter, P.; de Araujo, J. X. Jr.; Schmitt, M.;
Bourguignon, J. J. Tetrahedron 2007, 63, 12465. (b) Kim,
J. T.; Gevorgyan, V. Org. Lett. 2002, 4, 4697.
Acknowledgment
We thank the Fonds der Chemischen Industrie and the DFG for
financial support. We also thank Chemetall GmbH (Frankfurt) and
BASF AG (Ludwigshafen) for the generous gift of chemicals.
References
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Synthesis 2008, No. 22, 3697–3702 © Thieme Stuttgart · New York