2,4-DICHLOROPYRIMIDINE
2,4-Dichloropyrimidine
NHAc
Cl
2,4-DCP
NH2
N
Cl
N
Physical Data: mp 57–61 ◦ C, bp 101 ◦ C @ 23 mm Hg.
Solubility: most organic solvents.
Form Supplied in: off-white crystalline solid.
Handling, Storage, and Precautions: store in a cool dry place
away from light, oxidizing and acidic materials; use fume hood
and standard precautionary measures for handling chemicals;
hazard classification: irritant; avoid inhalation, contact with
skin or eyes.
Nucleophilic Substitutions. The chlorine atoms on 2,4dichloropyrimidine (2,4-DCP) are activated towards substitution
by a variety of common nucleophiles. The displacement can be
accomplished in a regioselective and stepwise fashion with any
number and combination of nucleophiles including amines (alkyl
or aromatic), hydrazine, alkoxides, thiols, and resonance stabilized carbon anions. Nucleophilic substitution reactions (SN Ar)
are generally regioselective, occurring initially at the C-4 position of the pyrimidine ring although the nature of the nucleophile
and reaction conditions plays a role in the level of selectivity
obtained. For example, treatment of 2,4-DCP with the primary
alkyl amine R-2-(tetrahydrofuran-2-yl)-methylamine gave a 3:1
mixture of adducts resulting from substitution of both chlorines
at C-4 and C-2 positions of the pyrimidine ring (eq 1),1 while
the less basic N-(acetyl)-phenylenediamine provided exclusively
the product from reaction at C-4 (eq 2).2 More recently, microwave irradiation has been used to dramatically shorten the reaction times of the SN Ar. The addition of N-phenylpiperazine was
accomplished in only 10 min with the regioselectivity controlled
through the choice of solvent (eq 3).3 Nonheteroatom nucleophiles add regioselectively at the C-4 position as demonstrated by
the sodium anion of benzothiazol-2-yl-acetonitrile, which gave a
mixture of olefin tautomers as products (eq 4).4
N
NH2
O
N
N
2,4-DCP
Et3N, THF
2 h, rt; 85%
Cl
Cl
N
(1)
+
NH
O
NH
3:1
O
Cl
N
+
N
N
(3)
N
Ph
i-PrOH - 5.5:1
toluene - 1.5:1
N
(useful building block for the synthesis of biologically active heterocycles, undergoes regioselective: nucleophilic substitutions,
lithiation, Suzuki, Negishi, Sonogashira, and FeIII couplings)
(2)
Cl
N
2,4-DCP
130 °C, 10 min
NHAc
N
N
H
N
H
N
(MW 148.98)
[3934-20-1]
C4 H2 Cl2 N2
InChI = 1/C4H2Cl2N2/c5-3-1-2-7-4(6)8-3/h1-2H
InChIKey = BTTNYQZNBZNDOR-UHFFFAOYAU
N
THF/EtOH 1:3
NaHCO3, 75 °C
95%
Cl
N
1
N
Ph
Ph
Cl
N
N
NaH, THF, 0 °C
S
N
H
N
CN 2,4-DCP, rt; 84%
(4)
S
CN
Organolithium reagents add to 2,4-DCP at the formal azomethine (C = N) moiety at C-6 of the pyrimidine. For example, PhLi
adds to 2,4-DCP to provide 2,4-dichloro-6-phenyl-pyrimidine
after oxidative work-up (eq 5).5 The activated positions bearing
chlorine atoms are reactive to organolithiums with more complex chloropyrimidines substituted at the C-6 position of the ring
(i.e., other than hydrogen).
Cl
N
Cl
N
N
PhLi
Et2O, –30 to 0 °C, 1 h
DDQ, 92%
Cl
N
Ph
(5)
Cl
Following substitution at C-4 of the pyrimidine, the chlorine
atom at the C-2 position of the pyrimidine can also be displaced by
nucleophiles. In general, substitution at the C-2 position requires
higher temperatures and extended reaction times. This is in part
due to electron-donating substitutents at C-4 on the pyrimidine,
rendering the ring less electrophilic. Additionally, hydrolysis at
C-2 can be carried out with conc. HCl to give a quantitative yield
of the 2-pyrimidinone (eq 6).6
Cl
N
O
N
HCl (aq)
100 °C, 1 h
100%
N
NH
(6)
Lithiation. The ortho directing ability of the chlorine atom
at C-4 allows for the regioselective lithiation of C-5 with strong
hindered amine bases.7 The resulting C-5 lithium species can be
trapped with electrophiles to give the corresponding C-5 substituted pyrimidines in good yields (eq 7).8 After oxidation of the
benzylic alcohol, treatment with hydrazine then provides the fused
pyrazolopyrimidine resulting from substitution at C-4 and condensation onto the carbonyl residing at C-5 (eq 8).8
Avoid Skin Contact with All Reagents
2
2,4-DICHLOROPYRIMIDINE
Cl
Cl
Cl
Cl
N
N
LDA, THF, –78 °C
N
N
N
ArCHO; 80%
Ar
OH
Cl
Cl
N
Ar
N
NH2NH2
N
(8)
EtOH/n-BuOH
reflux; 70%
Cl
NH
N
O
N
O
Cl
N
2,4-DCP
N
SO2Ph
N
(9)
Pd(PPh3)4, DME
K2CO3, 85 °C
85%
N
N
SO2Ph
Cl
O
O
N
N
(11)
TMS
Due to the addition of nucleophiles with good regioselectively
in an iterative manner, 2,4-DCP is heavily utilized in medicinal
chemistry programs as a core scaffold in the exploration of structure activity relationships (SAR) of various drug targets.
1.
B
0.5% Pd(PPh3)2, CuI
THF, Et3N, 65 °C, 4.5 h
87%
Ar
Transition Metal Mediated Coupling. 2,4-DCP undergoes a
host of useful and selective organometalic coupling reactions. The
chlorine atom at C-4 of 2,4-DCP participates in standard transition
metal cross-coupling reactions with the reactivity comparable to
that of an aryl bromide. The palladium-catalyzed cross-coupling
reaction of 2,4-DCP and aryl and heteroaryl boronic acids, the
Suzuki–Miyaura reaction, can occur with a high degree of regioselectivity (eq 9)9 although the transformation may be substrate
and catalyst specific.10 Cross-coupling of 2,4-DCP with aryl and
heteroaryl tin10 and zinc11 reagents proceeds equally well with
high regioselectivity. Both the Suzuki and the Negishi couplings
of 2,4-DCP have recently been examined, exploring the regioselectivity obtained with conventional heating versus microwave
irradiation, palladium source, and reagent stoichiometry.12 Alkyl
substituents can be introduced by FeIII catalyzed cross coupling
of alkyl Grignards.13 The iron-catalyzed reaction with 2,4-DCP
is regioselective and utilizes inexpensive, less toxic reagents and
occurs at much lower temperatures than the corresponding palladium mediated reactions (eq 10). The Sonogashira reaction of
2,4-DCP and TMS-acetylene proceeds in high regioselectivity and
excellent yield (eq 11).14
O
TMS
Cl
Cl
Cl
N
N
(7)
2,4-DCP
MgBr
N
N
Fe(acac)3 –78 °C
THF/NMP 10:1
70%
A list of General Abbreviations appears on the front Endpapers
O
O
(10)
2.
3.
4.
5.
6.
7.
8.
9.
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2002, 12, 3635.
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J. A.; Kumar, R., Bioorg. Med. Chem. Lett. 2005, 15, 3519.
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Bioorg. Med. Chem. Lett. 2006, 16, 490.
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(b) Ple, N.; Turck, A.; Martin, P.; Barbey, S.; Queguiner, G., Tetrahedron
Lett. 1993, 34, 1605.
Revesz, L.; Blum, E.; Di Padova, F. E.; Buhl, T.; Feifel, R.; Gram, H.;
Hiestand, P.; Manning, U.; Neumann, U.; Rucklin, G., Bioorg. Med.
Chem. Lett. 2006, 16, 262.
Huang, S.; Li, R.; Connolly, P. J.; Emanuel, S.; Middleton, S. A., Bioorg.
Med. Chem. Lett. 2006, 16, 4818.
10. Blackaby, W. P.; Atack, J. R.; Bromidge, F.; Castro, J. L.; Goodacre,
S. C.; Hallett, D. J.; Lewis, R. T.; Marshall, G. R.; Pike, A.; Smith, A.
J.; Street, L. J.; Tattersall, D.F.D.; Wafford, K. A., Bioorg. Med. Chem.
Lett. 2006, 16, 1175.
11. (a) Simkovsky, N. M.; Ermann, M.; Roberts, S. M.; Parry, D. M.; Baxter,
A. D., J. Chem. Soc., Perkin Trans. 1. 2002, 16, 1847, (b) Stanetty, P.;
Hattinger, G.; Schnuerch, M.; Mihovilovic, M. D., J. Org. Chem. 2005,
70, 5215.
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Stanetty, P.; Schnuerch, M.; Mihovilovic, M. D., Synlett 2003, 1862.
13. Scheiper, B.; Bonnekessel, M.; Krause, H.; Fuerstner, A., J. Org. Chem.
2004, 69, 3943.
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Curt A. Dvorak
Johnson & Johnson Pharmaceutical Research
& Development, LLC, San Diego, CA, USA