microwave-assisted solution- and solid-phase synthesis … · sulfide oxidation n n r o r1 ar nu...
TRANSCRIPT
Mitra Matloobi and C. Oliver Kappe*
Christian Doppler Laboratory for Microwave Chemistry (CDLMC) and Institute of ChemistryKarl-Franzens-University Graz, Heinrichstrasse 28, A-8010 Graz, Austria
Advances in Microwave-Assisted Organic Synthesis, August 26-27 2006, Budapest, Hungary
email: [email protected] website: http://www.maos.net
Retrosynthetic Analysis
Introduction Displacement of the Sulfonyl Group with Nucleophiles
High Diversity Analogues (40 examples)
The 2-aminopyrimidine structural subunit is contained in a growing number of both
natural products and synthetic compounds with interesting biological properties [1].
Of particular interest are derivatives possessing an aryl ring at the C4 position and
an electron-withdrawing substituent such as an ester or amide group at C5 [2].
Herein we describe the rapid and efficient synthesis of 2-amino-4-arylpyrimidines by
taking advantage of the high diversity initially generated on the pyrimidine core
through a Biginelli multicomponent (MCR) approach using thiourea as starting
material
N
N
N
OHOHOOC
F
Me
SO2Me
Rosuvastatin (Ca-salt)
N
N
NH
N
Me
HN
O
N
NMeGleevec
_
1] Review: Lagoja, I. M. Chem. Biodiversity 2005, 2, 1.
[2] (a) Sehon, C. A.; Lee, D.; Goodman, K. B.; Wang, G. Z.; Viet, A. Q. PCT Int. Appl. WO 2006009889,
2006; Chem. Abstr. 2006, 144, 150383. (b) Drewry, D. H.; Evans, B.; Goodman, K. B.; Green, D. V. S.;
Jung, D. K.; Lee, D.; Stavenger, R. A.; Wad, S. N. PCT Int. Appl. WO 2004112719, 2004; Chem. Abstr.
2004, 142, 93847.
The rapid and efficient synthesis of 2-amino-4-arylpyrimidines of type A is
accomplished by taking advantage of the high diversity initially generated on the
pyrimidine core using a Biginelli MCR. Our method allows for considerable diversity in
all building blocks.
Ar
O H
OR2
O
R1 NH2
H2N S+
NH
NH
R2
O
R1
Ar
S
Biginelli MCR
N
N
R2
O
R1
Ar
SMe
O O
1. S-Methylation2. Aromatization3. Sulfide Oxidation
N
N
R2
O
R1
Ar
Nu
NuH
A[3] For related approaches, see (a) Watanabe, M.; Koike, H.; Ishiba, T.; Okada, T.; Seo, S.; Hirai, K.
Bioorg. Med. Chem. 1997, 5, 437. (b) Vanden Eynde, J. J.; Labuche, N.; Van Haverbeke, Y. ; Tietze, L.
ARKIVOC 2003, (xv), 22.
Synthesis of 2-Sulfonylpyrimidine Precursors
The pyrimidine sulfone precursors of type B were synthesized via a rapid four step,
all microwave synthetic sequence from readily available building blocks and
inexpensive alkylation and oxidation reagents.
OMe
O
EtO
Ph
O HNH2
H2N SNH
NH
Me
O
EtO
Ph
S
(87%)
NH
N
Me
O
EtO
Ph
SMe
(92%)
N
N
Me
O
EtO
Ph
SMe
(82%)
N
N
Me
O
EtO
Ph
SMe
OOB (92%)
+
TMSClMeCN, DMF
MW, 120 °C, 10 min
1. MeI, MeCN MW, 100 °C, 5 min
2. NaOH (1M)
MnO2, DCM
MW, 100 °C, 10 min
Oxone, H2O, MeOH
MW, 100 °C, 20 min
The 2-methylsulfone group on pyrimidine B can be displaced with a variety of
different nitrogen, oxygen, sulfur and carbon nucleophiles, by applying microwave
irradiation in sealed vessels and, in most cases provides excellent yields of the
anticipated 2-functionalized pyrimidines 1-14 in very short reaction times.
N
N
Me
O
EtO
Ph
SMe
OOB
N
N
Me
O
EtO
Ph
Nu
1-14
nucleophile, solvent/base
MW, 70-230 °C, 10-50 min
851070MeCN/Cs2CO3malonodintrile14
8230140THF/K2CO3p-thiocresol13
831570MeCN/Cs2CO3phenol12
4510140THF/ K2CO3N-methyl-methanesulfonamide11
7350230dioxanep-anisidine10
6750230dioxaneaniline9
8120200DMFdimethylaminec8
8215100DMSOammoniab7
8010140THF2-methoxyphenethylamine6
4510140THF4-fluorophenethylamine5
7310140THFbenzylamine4
7410140THFethanolamine3
6810140THFpiperidine2
7210140THFpyrrolidine1
yield (%)atime (min)temp (°C)solvent/basenucleophileComp.
Solid-Phase Synthesis of 2-Aminopyrimidines
In addition to the solution phase protocol outlined above, we also considered a
microwave-assisted solid-phase method in order to be able to prepare large
compound libraries using combinatorial principles in a high-speed format.
Reaction conditions: Single-mode sealed vessel microwave irradiation. a Isolated yields of pure products after chromatography. b Ammonium acetate as substitute for NH3. c Dimethylamine was generated in situ by dec. of DMF.
NH
NH
Me
O
EtO
Ph
SCl
N
N
Me
O
EtO
Ph
S N
N
Me
O
EtO
Ph
SO O
NH
N
Me
O
EtO
Ph
S
N
N
Me
O
EtO
Ph
N
CAN, H2O, DCM
MW, 130 °C, 30 min(or 25 °C, 10 h)
+
DMF, K2CO3
MW, 160 °C, 30 min(or 60 °C, 20 h)
Oxone, H2O, DMF
MW, 150 °C, 45 min(or 25 °C, 16 h)
piperidine , EtOH
MW, 100 °C, 10 min
Conclusion
• Readily available 2-methylsulfonyl-pyrimidines derived via Biginelli multicomponent strategies are excellent precursors for the generation of a variety 2-substituted pyrimidines.
• A variety of 2-substituted pyrimidines were synthesized via displacement of the reactive sulfonyl group with different nitrogen, oxygen, sulfur and carbon nucleophiles.
• The use of high temperature sealed vessel microwave irradiation allows the preparation of the desired target structures in high yields and comparatively short reaction times.
• All synthetic steps required for the synthesis of the target structures were carried out under microwave irradiation, both in solution phase and on solid phase.
Acknowledgement. This work was supported by the Austrian Science Fund. M. M. thanks the University of Graz for a Gandolph Doelter Scholarship. We thank also Biotage AB (Uppsala, Sweden) for the use of the Emrys Synthesizer and Initiator Eight.
Microwave-Assisted Solution- and Solid-Phase Synthesis of 2-Amino-4-arylpyrimidine Derivatives
N
N
O
O
N
Cl
N
N
O
O
NH
O
N
N
O
O
NH
N
N
O
O
S
N
N
O
O
ON
N
O
OCN
CN
N
N
O
O
N
Me
N
N
O
N
N
F
Selected examples: