Synthesis of Substituted Imidazoles viaOrganocatalysis
Doug E. Frantz, Louis Morency, Arash Soheili, Jerry A. Murry,Edward J. J. Grabowski, and Richard D. Tillyer
Department of Process Research,Merck Research Laboratories,
Merck & Co.
Michael Rishel @ Wipf Group 1 3/27/04
Imidazoles as Targets in Medicinal Chemistry
N
N
N
N
HN
N
N
N
NNH
NN
OH
Cl
Losartan
N
NNH
O
SO3H
O
N
CO2H
O PO3H2
Orally available Angiotensin IIinhibitor -- Lilly
R1
R2
RR2
R1
X
N
N
N
X
Y
Imidazole CSAID Ligands -- SKB
N
N
HOOC
COOH
S
Eprosartan
p38 MAP kinase inhibitors
Michael Rishel @ Wipf Group 2 3/27/04
Debus Reaction
Debus imidazole synthesis
RR
O
O
O
R' H+
NH3
H2O NH
NR'
R
R
Debus, H. Liebigs Ann. Chem. 1858, 107, 199.
reaction provides 2- monosbstituted, and 2,(3,4 homo)trisubstitutedimidazoles
Michael Rishel @ Wipf Group 3 3/27/04
Proposed Mechanism of the Debus Reaction
RR
NH
NH
NH
R' H+
HNR
R
N
R'
H2N
H
NN
R
R
HR'
NH3
HN
NR'
R
R
Michael Rishel @ Wipf Group 4 3/27/04
Wallach Reaction
NH
HN R
O
O
RPCl5, POCl3
heat
Wallach chloroimidazole synthesis
Wallach, O. Ber. Dtsch. Chim. Ges. 1881, 14, 420.
N
N
Cl
R
R
II
Provides 1,2 disubstituted chloroimidazoles
Michael Rishel @ Wipf Group 5 3/27/04
Proposed Mechanism of the Wallach Reaction
N
N
Cl
R
R
NH
HN R
O
O
R
PCl5N
N RR
Cl
Cl
-Cl-
+Cl-
N
N
R
Cl
R
-H+
+H+
N
N
R
Cl
R
+H+
-H+
N
N
R
R
ClH
H
-H+
+H+Cl
N
N
H
RH
R
+H+
-H+Cl
N
N
R
R
+Cl- -Cl-
+Cl--Cl-
NN R
R
Cl
H
NN R
R
Cl
H H Cl
HCl
-Cl-
-Cl- II
II
I
I
Benincori, T.; Brenna, E.; Sannicolo, F. J. Chem Soc. Perk. Trans. I 1993, 675-679.
Michael Rishel @ Wipf Group 6 3/27/04
TosMIC Based Imidazole Synthesis
Synthesis from TosMIC
R'' NC
SO
O
TosMIC = tosylmethyl isocyanide
N
R
R'+
van Leusen, A. M.; Wildeman, J.; Oldenziel, O. H. J. Org. Chem. 1977, 42, 1153-9
1. NaH, DME2. H2O3. K2CO3, MeOH N
N
R'R
R'' Process regioselectively provides 1,5-di and a limited number of 1,4,5-trisubstituted imidazoles
Michael Rishel @ Wipf Group 7 3/27/04
Mechanism of TosMIC based Imidazole Synthesis
R''
NS
OO
C
N
R
R'+ [3+2]
NS
OO
R''R
NR N
N
R'R
R''
SO
O
+
Michael Rishel @ Wipf Group 8 3/27/04
Extension of the TosMIC Chemistry
Horne, D. A.; Yakushijin, K.; Buchi, G. Heterocycles, 1994, 139
NC
SO
O O
R+
H
O
N
R
SO
OR''NH2
N
N
R''
R
An Extension of the TosMIC chemistry
R'
R' = H or AlkR'' = H or AlkR and R' cannot both = Alk
R'
R'
Process regioselectively provides 4, 1,4, and 4,5mono- and disubstituted imidazoles
1,4,5 trisubstituted imidazoles are not easily madewith this methodology as a regioisomeric mixture of products results.
Michael Rishel @ Wipf Group 9 3/27/04
Modified TosMIC Imidazole Mechanism
O
N
R
SO
O R''NH2
R'
O
N
R
R'
NHR''R''NH2
O
NH
R
NHR''R''HNH
heat
HNNHR''OHR
NR''
+when R' = H
when R' = alk
O
NH
R
AlkNR''
N
N RHO
N HN
R''NH
R''
H2O
N
NHR''
N+
R
R''H
H
R''NH2
N
N+
R
R''H
H
HN
N
R
R''
HH
R''R
Alk
?
Michael Rishel @ Wipf Group 10 3/27/04
Synthesis of Imidazoles from Amidines
Selective synthesis of 1,2,5 substituted imidazoles
NH
R NHR' X
OR''
Br
X = CHO, CN
+K2CO3
CHCl3, H2ON
NR'
R
X
major
N
NR'
R
minor
+
modest yields, good selectivityammenable to the synthesis ofmultikilogram quantities of pharmaceutical intermediates
X
Shilcrat, S. C.; Mokhallalati, M. K.; Fortunak, J. M. D.; Pridgen, L. N. J. Org. Chem. 1997, 62, 8449.
Michael Rishel @ Wipf Group 11 3/27/04
Imidazoles from Amidines -- Mechanism
NH
R NHR' X
OR''
Br
+ N
R NHR'
XR''O
BrH
N N
R
R'
XHR''O
N N
R
R'
X
major
minor R'N
R NH
XR''O
BrH
N N
R
R'
X
Michael Rishel @ Wipf Group 12 3/27/04
Imidazole carboxylates from BICAs
1,5 imidazole carboxylates from amines and 3-bromo-2-isocyanoacrylates (BICAs)
R
Br
NC
COOMe
R'NH2
DMF, Et3NN
N
R'
COOMe
R
Nunami, K.-I.; Yamada, M.; Fukui, T.; Matsumoto, K. J. Org. Chem. 1994, 59, 7635.
Complementary to the amidine methodology
Michael Rishel @ Wipf Group 13 3/27/04
BICA Mechanism
R
Br
NC
COOMeR'NH2 +
NC
COOMe
A
B
R
NC
COOMeR'HN
R'HN
H
R
NC
COOMeR'N H
R
NC
COOMeR'HNR
NHR'
R
N
COOMeR'HN
N
HN
C
COOMe
R'R
N
N COOMe
R'R
Michael Rishel @ Wipf Group 14 3/27/04
Hetero Cope Rearrangement -- A Strategy to HighlySubstituted Imidazoles
Hetero-Cope Rearrangements to regioselectively provide highly Substituted imidazoles
Lantos, I.; Zhang, W.-Y.; Shui, X,; Eggleston, D. S. J. Org Chem. , 1993, 58, 7092.
R
NR'OH
NR''
Cl Ph+
R
NR'O
Ph NHR''
R''N Ph
N
NR1
R2
R3
Ph
highly regioselective synthsis of tetrasubstituted imidazoles. Limited by R-group requirements.
Michael Rishel @ Wipf Group 15 3/27/04
Mechanism of the Hetero Cope RearrangementApproach
R
NR'O
Ph NR''
N Ph R
NR'O
Ph NR''
R''N Ph
R''R
NR'O
Ph NHR''
R''N Ph
R
NR'O
Ph N+
R''N Ph
H
R''
H
R
NR'
R''N Ph
O
Ph NHR''N
NR1
R2
R3
Ph
PhCONHR''
Michael Rishel @ Wipf Group 16 3/27/04
Highly Substituted Imidazoles From b-Ketoamides
Regioselective synthesis of tetrasubstuted imidazoles from b-ketoamides under neutral reaction conditions
N
O
R2
O
R1
N
X
ammonium trifluoroacetateN
N
R2
R1
N
X
Methodology tolerates variance at positions 1,2 and 5 quite well.
Position 4 usually, but not always, aromatic.
Claiborne, C. F.; Liverton, N. J.; Nguyen, K. Tetrahedron Lett. 1998, 39, 8939.
Michael Rishel @ Wipf Group 17 3/27/04
Synthesis of b-Ketoamides… Nontrivial??
Michael Rishel @ Wipf Group 18 3/27/04
A Traceless Synthesis of b-Ketoamides
OO
H1. RNH22. LiBH4 O
HN R1
R3R2
O
X
ON R1
R2
R3
O
R4 Cl
O
OCl
R4 NR3
O
O
R1
R2
+
N
N
R1
R2
R3
R4
Lee, H. B.; Balasubramanian, S. Org. Lett. 2000, 2, 323.
A traceless entry into b-ketoamides -- and tetrasubstituted imidazoles
Michael Rishel @ Wipf Group 19 3/27/04
Thiazolium Catalyzed Synthesis of b-Ketoamides
O
HR1 R2 NH
R3
SO2Tol
+
SN OHR4
X
Et3N, CH2Cl2 35 oC
R2HN R3
OOR1
Murry, J. A.; Frantz, D. E.; Soheili, A.; Tillyer, R.; Grabowski, E. J. J.; Reider, P. J. Am.Chem. Soc. 2001, 9696.
Michael Rishel @ Wipf Group 20 3/27/04
Mechanism of b-Ketoamide Synthesis byOrganocatalysis
Murry, J. A.; Frantz, D. E.; Soheili, A.; Tillyer, R.; Grabowski, E. J. J.; Reider, P. J. J. Am. Chem. Soc. 2001, 123, 9696.
Michael Rishel @ Wipf Group 21 3/27/04
Regioselective, “One Pot” Synthesis of SubstitutedImidazole
Michael Rishel @ Wipf Group 22 3/27/04
One-Pot Synthesis of Di- andTrisubstituted Imidazoles
Michael Rishel @ Wipf Group 23 3/27/04
Synthesis of Tetrasubstituted Imidazoles
Michael Rishel @ Wipf Group 24 3/27/04
Application to the Synthesis of Substituted Oxazolesand Thiazoles
Michael Rishel @ Wipf Group 25 3/27/04
Conclusions
• A rapid, one-pot, regioselective, organocatalyzed synthesis of highlyfunctionalized imidazoles from b-ketoamides has been described
• The methodology has been extended to the synthesis of substitutedoxazoles and thiazoles
Michael Rishel @ Wipf Group 26 3/27/04