The Biginelli and Related (Passerini and Ugi) Reactions

Mike DeMartino Group Meeting: August 27, 2003 Overview • How these reactions are related • The Biginelli Reaction – Mechanism – Modifications and chemical manipulation – Biology – Synthetic examples • The – Mechanism – Synthetic examples • The – Mechanism – Synthetic Reactions • Concluding Remarks Similarities

• All are multicomponent Reactions (MCRs) • In MCRs, “three or more reactants come together in a single reaction vessel to form products that contain portions of all the components.” » Kappe, C. O. Acc. Chem. Res. 2000, 33, 879. • Has advantages over traditional linear syntheses.

• Manifestations in a variety of chemical sects. The Biginelli Reaction The Biginelli Reaction

• Synthesis of 3,4-dihydropyrimidin-2(1H)-ones was discovered in 1893 by Pietro Biginelli » Biginelli, P. Gazz. Chim. Ital. 1893, 23, 360.

EtO2C O + + O H2N NH2 O H

+ EtOH, H heat

Ph => Biginelli-type EtO C 2 NH compounds

Me N O H The Mechanism: a Century of Uncertainty • First proposal in 1933 » Folkers, K., Johnson, T.B. J. Am. Chem. Soc. 1933, 55, 3784.

EtO C O 2

O O HN NH2 O 2 X + R H2N NH2 R H HN NH2 O O HO Me Ph CO Et HN N 2 EtO C 2 NH R H HN NH H O 2 2 Me N O H O The Mechanism: a Century of Uncertainty • Second proposal in 1973 » Sweet, F., Fissekis, J.D.. J. Am. Chem. Soc. 1973, 95, 8741.

O EtO2C H + + H H O O O O HO O O OEt OEt OEt

O

H2N NH2 Ph CO Et HN 2 H O HN OEt O N Me O H H2O O NH2 The Mechanism: a Century of Uncertainty • Latest proposal in 1997 » Kappe, C.O. J. Org. Chem. 1997, 62(21), 7203. O Ph OH Ph H O H+ H + HN NH H N NH 2 N NH2 2 2 -H2O H O O O

HN NH2 R HN NH2 Ph O Ph Ph EtO C EtO2C 2 NH NH EtO C 2 NH O O H2N Me N O H O 2 Me O O Hu, E.H., et.al. H H N J. Org. Chem. 1998. 63, 3454. 2 The Atwal* modification

• Brought about by the need for better yields: • Ortho-substituted aryl • Aliphatic aldehydes

R 1 R1 H R1 H NH RO2C 2 RO2C Deprotect RO2C H + NaHCO3 N NH HN X DMF R Mostly 60-91% Me O Me N X 2 yield Me N X R2 H H X = O, S (With an appropriate protecting group)

• Since R1 can be significantly varied w/little affect on yield, the “finicky” problem can be circumvented.

*Atwal, K. S., et. al. J. Org. Chem. 1989, 54, 5898. Synthetic Manipulation • So, with the dihydropyrimidine in hand, what can be done? • Partial of full oxidation (not trivial) • Reduction of the ring to the hexahydropyrimidine • Alkylation and acylation of the heteroatoms • Manipulation of the ester at C(5) • Manipulation of the methyl group at C(6) (halogenation, nitration, etc.) • Ring condensing reactions to make bi,tri-cycles Ph 4 EtO2C 5 3NH 6 2 Me N1 O H Biology • The biological activity is what make these pyrimdines such attractive targets • (A 1930 patent for use of a Biginelli cmpd for protection of wool from moths!?!) • Antiviral activity • Antibacterial activity Ar H RO C • Antitumor 2 NH • Antiinflammatiry Me N X • Analgesic H • Blood palette aggregation inhibitor • Cardiovascular activity • Potent calcium channel blockers • Etc. Synthetic Examples • Solid phase synthesis for combinatorial scaffolds of Biginelli compounds – First example: Wipf, P., Cunningham, A. Tet. Lett. 1995, 36, 7819. Ar O Ar O H O R NH2 1. THF, HCl, 55°C O NH R + O 2. TFA, CH Cl R N O HN O 2 2 1 OH R1 O O P O O • Fluorous-Phase modifications – Studer, A., et. al. J. Org. Chem., 1997, 62, 2917. Ar

O H O Ar O 1. HCl, THF/BTF, 50°C R R + NH2 O NH O TAG 2. Extract w/FC-72 HN O R N O R O 3. TBAF, THF/BTF 1 1 O O

O O Tag = Si(CH2CH2C10F21)3 Synthetic Examples

• Synthesis of rac-Monastrol • Mitosis blocker by kinase Eg5 inhibition • Utilization and extension (to thioureas) of the

Yb(OTf)3 work » Dondoni, A., et. al. Tet. Lett. 2001, 43, 5913

OH HO O O H EtO Yb(OTf) EtO2C + H 3 NH Me O S THF, reflux, 12 h Me N S H H2N NH2 (+/-) Monastrol Synthetic Examples • Inorganic catalysis – Indium(III) Chloride mediated Biginelli reactions » Brindaban, C. R., et. al. J. Org. Chem. 2000, 65, 6270

R 2

O H O R2 X InCl3, THF O O + R1 NH H2N NH2 81-95 % R R 1 R N X X = O, S H • Heavy-Metal catalysis » Ma, Y., et. al. J. Org. Chem. 2000, 65, 3864 R 2

O H O R2 O Yb(OTf)3 (5 mol %) O O + R1 NH H2N NH2 100°C R R 1 81-99% R N O H Synthetic Examples • Natural Product Synthesis – The use of tethered Biginelli condensations for syntheses of structurally diverse guanidine alkaloids O O • (–)-Ptilomycalin A: H H N O N NH 14 2 NH N N 2 OH H O

Overman, L., et. al. J. Am. Chem. Soc. 1995, 117, 2657

H R3O C H 2 N R1 3 R A: Morpholinium Acetate R O2C 1 R N X CF3CH2OH, 60°C, 48 hr 2 H syn + HO N H + R O B: Polyphosphonate ester 2 CH Cl , 23°C, 48 hr H2N X 2 2 H R3O C H 2 N R1 R N X anti MacDonald, A. , Overman, L. J. Org. Chem. 1999, 64, 1520 2 H Synthetic Examples • Total synthesis of the HIGHLY POTENT NEUROTOXIN: Saxitoxin – Tanini, H. et. al., J. Am. Chem. Soc. 1977, 99, 2818

O

O NH2 H H N NH H2N N N NH H 2 HO OH Key Step: H O MeO2C Me MeO2C Me ether NH2 MeO C 2 NH NH RT + N O NH C N O O The Passerini Reaction Details of the Passerini Reaction • Discovered in 1921 by Passerini » Passerini, M. Gazz. Chim. Ital. 1921, 51, 126. • A three component reaction involving: – Aldehyde (or ) – – • Generally,

2 O R O O H + 3 NC 1 2 + R 1 N 3 R OH R H R O R O More on • Only stable organic functionality with divalent carbon • Found in many natural products

• Preparation: Dehydration of N-monosubstituted formamides with phosgene or derivatives thereof • Like carbenes, isocyanides can react with both neucleophiles and electrophiles at the same carbon center • Used heavily in the synthesis of various heterocycles Mechanism • Mechanism is still a subject of uncertainty – Kinetic studies were conducted – Termolecular reaction (3rd order rate law), first order in each of the reactants » Baker, R.H., Stanonis, D. J. Am. Chem. Soc. 1951, 73, 699. – Ugi discovered that the reaction is accelerated in aprotic (indicating a non-ionic mechanism) – Based on this work (Ugi, I., Meyr, R., Chem. Ber. 1961, 94, 2229) and on the work of Baker et. al., Ugi postulated the following mechanism: H O O O O 1 + 2 R OH R H 1 R O R 2 1 H R O O 3 NC + R 3 O O 1 R R O R 2 N H O 2 1 H R R 2 O R 3 O O H R 1 N 3 N H R O R O O H R 2 Mechanism continued • Most of the many suggested mechanisms suggest some sort of electrophilic activation of the carbonyl, followed by neucleophilic attack of the isocyanide. • One exception: » Saegusa, N., et. al. Tet. 1968, 24, 3795 2 O 1 H+ R R AcOH + 3 3 1 2 NC C C N R R R R O

2 2 1 1 R R R R 3 H 3 C C N R C C N R OH OCMe Rearrangement OCMe O O O Details of the Reaction

• Done at high reactant concentration

• Done at low temperature

• Little limitations on the aldehyde/ketone used (extremely sterically bulky ) Synthetic Examples • Total synthesis of Eurystatin A (a prolyl endopeptidase inhibitor) -- Owens, T.D. et. al. Tet, Lett. 2001, 6271 O H HO O O Diphosgene

HCl·H N CO2Bn H N CO Bn 2 Et3N, 0°C ->RT 2 Dehydration H CN CO2Bn

O NHCbz CH Cl FmocHN N CO2Bn H 2 2 H + + FmocHN 0°C ->RT, O O CN CO2Bn O 3-5 days BocHN CO2H BocHN

O O CbzHN

HN HN O O NH ps! ste NH ~ 9 O Eurystatin A Synthetic Examples • Total synthesis of hydrastine, a phthalideisoquinoline alkaloid, using a an intramolecular Passerini reaction » Zeigler, T., et. al. Tet. Lett. 1981, 22, 619 O

O NC + H O CH2Cl2 OH O O O NH O O O

O O O O O N O Me

Hydrastine O O O O The Ugi Reaction Details of the Ugi Reaction • Discovered in 1959 » Ugi, I., et. al. Angew. Chem. 1959, 71, 386 • Four component condensation involving: – (secondary or primary) – Aldehyde (or ketone) – Carboxylic Acid – Isocyanide • Generally: 1 4 O R R O O 3 + 2 NH + + 4 NH 1 2 3 NC R N R H R R OH R R2 O • Mechanism involves linear and parallel sequences first and second order reactions (no third or above!) Mechanism

1 1 2 R N 2 R CHO + R NH2 R

O H O 1 + 1 R N 2 3 R N 2 + 3 R HO R R O R

4 H R 1 N 1 R N 2 R R + R4NC O 3 R O 3 HN 2 R O R O 4 R 1 4 N O R R 1 Rearrangement R 3 NH O R N 3 HN 2 R2 O R O R Generally Observed Properties of the Ugi Reaction

• Rxn is exothermic and usually complete in seconds- minutes at room temperature • Aprotic, polar solvents are best, though the low- molecular weight alcohols have been used • Can be performed in biphasic media • High (0.5-2M) reactant concentrations are best • By virtue of the mechanism, Lewis acids can accelerate the reaction • Precondensation of the amine and the carbonyl (preformation of the Schiff base) can increase yields. Synthetic Examples of the Ugi Reaction • The Ugi reaction can be utilized to make peptides and peptoids – Tripeptides in one pot – Couple two peptide fragments » Waki, M., Meienhofer, J. J. Am. Chem. Soc. 1977., 99, 6075

R2CHCONH Z-Gly-Ala-OH O + + Condensation CN Z-Gly-Ala-NCHCO-Gly-OtBu H-Leu-Gly-Ot Bu R H

CH2CH(CH3)2

Cleavage Z-Gly-Ala-Leu-Gly-OR by hn Synthetic Examples of the Ugi Reaction • Synthesis of non-natural amino acids – Yamada, T. et. al. Synthesis. 1998, 991

BocHN COOH CN O + H COOCH3 CH2Cl2, RT N BocHN N COOCH3 H 14 days O

NH Synthetic Examples • Concise synthesis of benzodiazepines » Hulme, C., et. al. J. Org. Chem. 1998, 63, 8021

H 1 O 1 O R R H O N 4 OH 2 MeOH 4 N R + R 2 R NH2 R O NBoc 3N 3 R Boc R NC

O 2 R N AcCl/MeOH 4 1 R R Heat N O R3 Synthetic Examples • Synthesis of the carbacephems containing a b- moiety commonly found in antibiotics » Neyer, G., Achtaz, J., Danzer, B. Ugi, I. Heterocycles, 1990, 30, 863 O DPO H H DPO O Ethylene Glycol/ + O Glycerol N NH3 O O NC N H

Ph N DPO = * Ph O

N O X CO2H Carbacephems (X = OR, SR, Cl) Synthetic Examples of the Ugi Reaction • Total synthesis of the cyclopeptidic alkyloid natural product: Nummularine - F » Bowers, M.M., et. al. J. Chem. Soc. Perkin Trans. 1, 1989, 857

CN

O CN COOCH3 O O O + + COOCH3 OH N HN N O

O O O NH N N H N O Nummularine-F Synthetic Examples of the Ugi Reaction

OAc OAc H AcO AcO EtO CO Pr + Pr + 2 + CN O H2N O O CO2H H O 2 Pr N N Pr H

CO2Et HO HO Pr O N O N HN O Pr O NH O R O HO H HO H R = or HO CH2OH CO2Et Bicyclomycin

-T. Fukuyama, et. al. Tet. Lett. 1981, 22, 4155 Concluding Remarks

• The Biginelli, Passerini, and Ugi reactions are all multicomponent reactions that are manifested in many facets of chemistry

• The Biginelli and Passerini reactions were discovered very early on and were underappreciated and underutilized until the late 1950s

• All three reactions have interesting mechanistic and synthetic problems associated with them, some having been solved, some yet to be Synthetic Examples • Titanium Tetrachloride assisted Passerini reaction – Carofiglio, T., et. al. Organomett., 1993, 12, 2726

1 1 R R 2 2 O R R TiCl + (RNC, R1R2CO) Ti O 4 Cl Ti L N L Cl N R R

1 R 2 O O R R OH Ti N L N H R1 R2 R