Rolf Huisgen Baran Lab Hafensteiner The Chemical Adventurer

Born: 1920 The Beginning Adventures: Diazo Compounds

"Luckily, the uninspiring high school chemistry instruction was limited to 1 year, not R H enough to squelch my enthusiasm." 0 °C N N N Ar N N N MeOH Ar N N PhD: Student of Heinrich Wieland R N N N -Work focused around vomicine, a strychnine alkaloid form Strychos nux vomica parts Cl N of which were conducted in air raid bunkers during World War II Cl Ar Me 1,3 dipolar N — N2 cycloaddition O N Ar N H

H H R R = H – HCl N H O H Cl Cl H O H N H O N N Ar N Ar CN Ar N R Ar N R N vomicine 80% Investigations into the Reactivity of Lactones: cis vs trans - Dipole moments indicitive of conformation in lactones Faculty Positions:

- University of Tübingen (1949 – 1952) O –

O

- University of Munich (1952 – present) – – – – O – O (CH2)n

cis trans

n Dipole Moment (Debye) 5 4.09 6 4.22 7 4.45 - Open chain aliphatic esters 8 3.7 have a dipole moment ~ 1.79 D 9 2.25 - Rates of hydrolysis decrease 10 2.01 by 104–105 in the transition from 11 1.88 cis to trans 12 1.86 13 1.86 - Analysis extended to cyclic 14 1.86 carbonates, lactams, N- 16 1.86 nitosolactams Butyl caproate 1.79 Baran Lab R o l f H u i s g e n Hafensteiner

The 1,3 Dipolar Cycloaddition Story The Principles - 94 full papers, 109 communications, 28 review articles with ~80 full papers yet to be - Sextet vs Octet written as of 1994 involving 1,3 dipolar cycloadditions, 513 references by SciFinder® - Atom A of sextet structure has incomplete valence with a positive charge (six - General concept solidified under Huisgen's guidance in 1958 but had been recognized electrons), C has a negative charge and nonbonding electron pair by L. I. Smith in 1938 but never exploited - Atom A of octet structure has a complete valence (8 electrons) and atom B is L. I. Smith Chem. Rev. 1938, 23, 193–285 cationic, C retains the negative charge and nonbonding electron pair - Project began modestly, growing in three years to 17 co-workers

B N A C A B C B = N N N N N PhN

Rates unaffected by solvent polarity, evidence for non-zwitterionic intermediates B B A C A C B = N–R, O R2C, RN, O are isoelectronic as well as RC and N leading to the postulation of new 1,3 dipoles in 1960, nitrosoimines and nitrosoxides have yet to be used in 1,3 dipolar cycloaddition to date R R sextet octet N N O O Internal Octet Stabilization R2C CR2 R2C CR2 R2C CR2 R C CR2 2 - Cations of C, O, N in the A position are stabilized by resonance donation from a Azomethine ylides Carbonyl ylides nonbonding electron pair on B R R B A = C, N, O N N O O A C R2C NR R2C NR R2C NR R2C NR Azomethine imines Carbonyl imines R N N R R C CR2 R C N CR2 N CR2 N N CR2 N N O O R2C O R2C O R2C O R2C O Nitrile Ylides Diazoalkanes Nitrones Carbonyl oxides R R R N N C NR R C N NR N NR N N NR N N O O RN O RN O RN NR RN NR Nitrile Imines Azides Azoxy compounds Nitrosoimines R R R N N N N O O C O R C N O N O N N O O O O O RN O RN O Nitro compounds Nitroso oxides Nitrile Oxides Nitrous Oxide

R. Huisgen, Angew. Chem. Int. Ed. 1963, 2, 565–598 Baran Lab R o l f H u i s g e n Hafensteiner

- Investigations into ene reactions: Venturing towards Azomethine Imines: Beginnings of 1,3 dipolar cycloadditions

CO2Et Cl O N CO2Et N EtO N H N OEt N CN O N N N 95% N DEAD N CN Cl - Rate increased by radical initiators and decreased by inhibitors

DEAD

N EtO2C NH N D NAr CO2Et N Ar N Ar N N ArN - No effect on rate due to radical initiators or inhibitors H N - Postulated synchronous process OMe

R. Huisgen, F. Jakob Justus Liebigs Ann. Chem. 1954, 590, 37–47 R. Huisgen, H. Bohl Chem. Ber. 1960, 93, 527–540 R. Huisgen, R. Fleischmann, A. Eckell Tetrahedron Lett., 1960, 12, 1–4

CO Et DEAD, hn 2 CO2Et DEAD N NH N N CO2Et

CO2Et

- light needed for isomerization of NN double bond

R. Askani Chem. Ber. 1965, 98, 2551–2555 G. O. Schenk, H. R. Kopp, B. Kim, E. Z. Koerner von Gustorf Naturforsch, 1965, 20b, 637–639 Baran Lab R o l f H u i s g e n Hafensteiner

Nitrile Ylides Other Dipolarophiles

R N C CR2 R C N CR2 RO2C CO2R Ph CO2R

Cl 49% 37% 49% NEt3, 20 °C N N O

Ph O reactive NO2 NO2 reactive violet color EtO N N CO2Me O 58% CN 86% O NO N 2 N R Ph Ph N H+; CH N Ph N 2 2 Ph O NO2 NO2 NO2 R

CO2Me CN R = Me (37%), Ph (63%)

N Pyrrole Synthesis O NO2 N H NO2 N Ph N CO2Me Ph N Ph O N NO 2 Ph Ph NO2 CO2Me

cylcoreversion, 38% NO2 N Ph O N CN CO Me 2 Ph NO2 R. Huisgen, H. Stangl, H. J. Sturm, H. Wagenhofer Angew. Chem. Int. Ed. Eng. 1962, 1, 50 Baran Lab R o l f H u i s g e n Hafensteiner

Nitrile Imines - nitrile imines must be generated in situ, can dimerize

R N N 150 °C Ph R C N NR Ph C NR N Ph N N N N Nitrile Imines Ph

Synthesis Ph N 150 °C Ph N Ph N N R Ph D N N benzonitrile N N N Ph N N 63% Ph Ph N N R = Ph, Me – N2 N R Ph 150 °C Ph O Ph N N R1 N N benzaldehyde N N R R1 D 75% N R N N Ph Ph – ethylene R. Huisgen, M. Seidel, J. Sauer, J. W. McFarland, G. Wallbillich J. Org. Chem. 1959, 24, 892–893 Ph Ph N Ph NBS•DMS Ph N Ph NEt3 N N Ph N N O Ph3P–CX4 Cl H H H H NCS•DMS N N 61% - 80% Cl Ph N Ph CH3CN Ph N Ph H 40–65% –40 °C, CH2Cl2

NBS•DMS P. Wolkoff Can. J. Chem. 1975, 53, 1333-1335 R N Ph R N Ph N NCS•DMS N N N H H NaN3, LiCl HN N 61% - 80% Cl NC CN –60 °C, CH Cl N NH 2 2 D, 172 hr. N N 91% R Yield J. Sauer, R. Huisgen, H. J. Sturm Tetrahedron, 1960, 11, 241–251 69% R. Huisgen, J. Sauer, M. Seidel Chem. Ber. 1961, 94, 2503–2509 O Ph 41% O Bn Ph Ph 60 hr. 71% N CN BnN3 Ph neat 29% 98% N N N 69% Z. Demko, K. B. Sharpless Angew. Chem. Int. Ed. 2002, 41, 2113–2116 F. Himo, Z. Demko, L. Noodleman, K. B. Sharpless J. Am. Chem. Soc. 2003, 125, 9983–9987 H. V. Patel, K. A. Vyas, S. P. Pandey, P. S. Fernandes Tetrahedron, 1996, 52, 661–668 Baran Lab R o l f H u i s g e n Hafensteiner

Nitrile Imines OnPr Ph CO2Me Ph N OnPr C NR R C N NR 80 °C, 56% 170 °C, 79% 20 °C, 71% 1 R = Ph R = CH, R = H R = CO2Me Nitrile Imines Ph CO Et MeO C CO Me Synthesis 2 2 2 165 °C, 84% 165 °C, 56% R = Ph, R1 = CO Et N 2 Me N Ph NaOH Me N Ph CO2Et Me N N NPh - monosubstituted acetylenes give 5-substituted pyrozoles directly H Na NO NO CH3CN 2 2 85% Dipolarophile: C O , C S CO2Et isolable salt CHO NEt Ph N Ph 3 Ph N Dipolarophile: Alkene, Alkyne N NPh H 80 °C Cl O NEt , 76% Ph N Ph 3 D Ph N chloranil Ph N N NPh NPh Ph H (CH ) 89% oxodiazoline Cl 2 2 81% pyrazoline R1 R R. Huisgen, R. Grashey, M. Seidel, H. Knupfer, R. Schmidt Liebigs Ann. pyrazole Chem. 1962, 658, 169

O Ph • - C S is a great dipolarophile, not a good dienophile C5H11 S NEt Ph Ph N Ph 3 Ph N N NPh 90 °C, 85% 20 °C, 94% 80 °C, 24% 80 °C, 78% H Ph Ph 20 °C 1 1 Cl R = C5H11 R = H R = Ph, Ph 72% S Ph Ph thiodiazoline - other good thiocarbonyl dipolarophiles

S S S 80 °C, 0% 80 °C, 73% 80 °C, 78% 20 °C, 58% 1 1 1 R = CH, R = CH2 R = CH, R = CH2 R2N R RO R RO NR2 - increased conjugation increases reactivity, tri and tetrasubstituted unreactive

R. Huisgen, M. Seidel, G. Wallbillich, H. Knupfer Tetrahedron, 1962, 17, 3–29 - isothiocyanates undergo cyloaddition but with low regioselectivity Baran Lab R o l f H u i s g e n Hafensteiner

Nitrile Imines Nitrile Oxides

Ph N R N C NR R C N NR C O R C N O

Nitrile Imines Nitrile Oxides

Dipolarophile: C–N multiple bonds Synthesis

- imine both aromatic and aliphatic good dipolarophiles (better than carbonyls) N Na CO Ph Ph N 2 3 O Me Ph N OH Ph N O Ph N Ph NEt3 NPh N N Me Cl H N Me 84% N Ph Cl O Me

triazoline A. Warner, H. Buss Ber. Dtsch. Chem. Ges. 1894, 27, 2193 H. Weiland Ber. Dtsch. Chem. Ges. 1907, 40, 1667 Ph N Ph N Ph NEt3 NPh N N R H N KHCO3 N 84% Ar Cl Ar N O R OH dipolarophile triazole R D R Ar = Ph, p-tol, 13 – 100% MeO N PhO N Ph N R R

> 70% > 70% 72% R = OMe R = OPh R = Ph NCS, KHCO3 N Ar Ar N O Cl OH dipolarophile Me N N R EtO2C N D R NO2 PhO 13 – 100% R R 97% 15% 80% R = CO2Et R = Me R = CH2OPh N - isocyanates reactive, carbodiimides give bis-adducts NEt3 Ar MeO Ar N O OH OMe - C N less reactive than C C dipolarophile R R Cl D R R - strongest s-bond formation in products allows prediction of regiochemistry A. R. Katritzy, M. A. C. Button, S. N. Denisenko J. Heterocyclic Chem. 2000, 37, 1505–1510 R. Huisgen, R. Grashey, M. Seidel, G. Wallibillich, H. Knupfer, R. Schmidt Leibigs Ann. Chem. 1962, 653, 105 Baran Lab R o l f H u i s g e n Hafensteiner

Nitrile Oxides - dimerization of nitrile oxides extremely facile

R N R C N O C O Ph N NEt3 dropwise OH dipolarophile Product 80–100% Nitrile Oxides Cl Synthesis 100% 85% 100% CO2Et ONa O N -H2O Ph Ph N O - to avoid dimerization, dipolarophile and dipole precursor are mixed, NEt3 is added OH MeO OMe dropwise to reaction solution Cl MeO2C OMe - mono substituted and 1,1 disubstituted olefins give 5–substituted isoxazolines - tri-and tetrasubstituted olefins are unreactive - allenes react slowly to give bis adducts T. Mukaiyama, T. Hoshino, J. Am. Chem. Soc. 1960, 82, 5339 A. Quilico, G. Stagno d'Alcontres, P. Grünanger Gazz. Chim. Ital. 1950, 80, 479 N. Barbulescu, P. Grünanger, M. R. Langella, A. Quilico Tetrahedron Lett. 1961, 2, 89–91 Dipolarophile: Alkyne

Dipolarophile: Alkene - high yields and isoxazoles formed directly alkene R N O isoxazoline A. Quilico, G. Speroni Gazz. Chim. Ital. 1946, 76, 148 A. Quilico, G. Gaudinau, A. Ricca Tetrahedron 1959, 7, 24 O O 41% 61% 80% Dipolarophile: Carbonyl and Imine N Ph carbonyl / imine O O Ph N O X = N, O Ph X 55% 22% 69% R O O O CHO 45% 41% H 67% Br Br EtO 48%, 40% 56% 91% Ph H 1:1 1:2 O

O O O O H 65% Me 91% Me 81% 100% 100% 85% EtO Me O O O Baran Lab R o l f H u i s g e n Hafensteiner

N Nitrile Oxides O

61% R N EtO CN 71% H N 73% C O R C N O

Nitrile Oxides N O O 62% 68% 68% Dipolarophile: Carbonyl and Imine ClH2C N CN N Ph carbonyl / imine O Ph N O X = N, O G. Leandri, M. Pallotti Ann. Chim. 1957, 47, 376 X R. Huisgen, W. Mack, E. Anneser Tetrahedron Lett. 1961, 2, 587 Cl R O CHO Dipolarophile: Thiocarbonyl N 84% 44% 94% Cl3C H S S S S S

O R R1 R OR1 R SR1 RO OR1 RS SR1 N CHO EtO OEt 75% 75% NH 78% - cycloreversions are possible to give the isothiocyanates O O N Ph 90–150 °C O O S • S R R. Huisgen, W. Mack Tetrahedron Lett. 1961, 2, 583 R R1 PhN R1 Dipolarophile: Nitriles S Ph N 20 °C O - aromatic nitriles reactive Ph N O OPh - aliphatic nitriles containing electron withdrawing group are reactive PhO OPh Ether S 92% OPh 100 °C 100% O Ph N S nitrile O • Ph N O PhO OPh PhN N R R. Huisgen, W. Mack, E. Anneser Angew. Chem. 1961, 73, 656 Baran Lab R o l f H u i s g e n Hafensteiner

Sydnones O O H isoamyl nitrite N NH 1 1 HCl N R R N CN • HCl R N CN Et2O R RN R O R O N N N O N O 71–93% E. N. Beal, K. Turnbull Syn. Comm. 1992, 22, 673–676 - 1,2,3 oxadiazolium-5-olates were discovered by Sydney in 1935 M. Sindler–Kulyk, K. Jakopcic, A. D. Mance J. Het. Chem. 1992, 29, 1013–1015 - much work done by D. Ollis in addition to Huisgen's efforts C. W. Lo, W. L. Chen, Y. S. Szeto, C. W. Yip Heterocycles, 1999, 51, 1433–1436 K. Turnbull, R. N. Beladakere, N. D. McCall J. Het. Chem. 2000, 37, 383–388 D. Ollis, C. A. Ramsden Adv. Het. Chem. 1976, 19, 1–122 W. H. Nyberg, C. C. Cheng J. Med. Chem. 1965, 8, 531–533

- first experiments by the Huisgen group were immediately successful Dipolarophile: Alkynes Ph R1 R1 Ph N R O N H N N 1 D R O R R N 95 °C N Ph Ph CO2Et O N O 1 N O 84 hr R R CO2Et O Me pyrazole Ph H H H C6H13 H Ph N –CO2 N Me 170 °C, 25 hr. 140 °C, 30 hr. 120 °C, 20 hr. 75% 78% 79% unkown regiochemistry R1 = Ph Ph CO2Et 83% O Me Ph H CO Me - regioselectivity follows that of nitrile imines 2 Ph - methyl propriolate is a bidentate dipolarophile giving Me regioisomers 140 °C, 20 hr. 100 °C, 48 hr. 130 °C, 12 hr. - CO2 is released only at higher temperatures 74% 92% 100% unknown regiochemistry 1 1 R = CO2Me (70%) R = Ph Synthesis R = CO2Me (22%)

O O O N O H H isoamyl nitrite TfO2 N MeO2C CO2Me Ph N CN OH N CN R DME RN Ph R 115 °C, 24 hr. 90 °C, 4 hr. 140 °C, 16 hr. 74% 92% 82% 48–90% 1 1 R = CH2OH R = Ph J. Applegate, K. Turnbull Synthesis 1988, 12, 1011–1012 Baran Lab R o l f H u i s g e n Hafensteiner

Sydnones Synthesis R1 R1 Me Me N R O R O Ph N N Ph N Ph Ac2O Ph N O N O O CO2H O O Dipolarophile: Alkenes H Ph N Ph Ph N Ph 50% in DMF - olefins generate pyrazolines 0.3 % in Acetone - disubstituted olefins generate pyrazoles O O 0.01% in CHCl3 O O H Bn Me N R. Huisgen, H. Gotthardt, H. O. Bayer, F. C. Schaefer Angew. Chem. Int. Ed. Eng. 1964, 3, 136– Bn O 140 °C Me –CO2 137 N Ph N H. O. Bayer, R. Huisgen, R. Knorr, F. C. Schaefer Chem. Ber. 1970, 103, 2581–2597 O Ph N O 24 hr 89% O H Dipolarophile: Alkynes H N N Me Ph 72% Me Ph Bn Bn Bn MeO2C CO2Me N N N O H 1,3 H shift H –CH4 H N HN N O MeO2C CO2Me Me Me - Huisgen Pyrrole synthesis Ph Ph Ph - yields range from 55–98% with activated alkynes pyrazoline Dipolarophile: Alkenes

N N R. Huisgen, H. Gotthardt, R. Grashey Angew. Chem. Int. Ed. Eng. 1962, 1, 49 Ph Ph 120 °C Ph Ph MeO2C R. Huisgen, R. Grashey, H. Gotthardt, R. Schmidt Angew. Chem. Int. Ed. Eng. 1962, 1, 48–49 O CO2Me 67% Münchnones O MeO2C CO2Me H N N R. Huisgen, H. Gotthardt, H. O. Bayer Tetrahedron Lett. 1964, 481–485 R R R R R. Huisgen, H. Gotthardt, H. O. Bayer Chem. Ber. 1970, 103, 2368–2387 R. Knorr, R. Huisgen Chem. Ber. 1970, 103, 2598–2610 O O R. Knorr, R. Huisgen Chem. Ber. 1970, 103, 2611–2624 O O - term coined by the Huisgen group stems from the nomenclature established for sydnones Baran Lab R o l f H u i s g e n Hafensteiner

Münchnones Diazoalkanes H R N R R N R base R N R N N N O O Reactivity O O

Dipolarophile: imines, thioketones, aldehydes, nitroso compounds Ph RO2C ROC RO2C N N > N N > N N > N N > N N - addition occurs followed by cylcoreversion for aldehydes, nitroso compounds, and Ph RO2C thioketones - reactions with alkenes yield pyrazolines Me H - pyrazolines when heated evolve N2 and cyclopropanes are formed N - C–terminus is nucleophilic Ph N Ph N Ph Ph O 97% O N O Dipolarophile: Alkynes Ph O N 20 °C N N N MeO2C CO2Me Me Et2O 85% Ph N Ph MeO2C CO2Me E. Buchner Ber. Dtsch. Chem. Ges. 1889, 22, 842 Ph N O N Ph Ph Ph N Me N N R R1 Me Ph Ph Ph N Ph R R1 Ph N Ph mechanism N Ph O Me N O H Ph H CO Me EtO C CO Et Me O 2 2 2 O krel 1 900 8200

CO2Et N2 40 °C EtO2C N2 N –N2, –CO2 N E. Funke, R. Huisgen, F. C. Schaefer Chem. Ber. 1970, 103, 2611–2624 CO2H Review: K. T. Potts in 1,3 Dipolarcycloaddition Chemistry; A. Padwa, Ed.; Wiley: NY, 1984, 12, 1–84 W. D. Ollis, S. P. Stanforth, C. A. Ramsden Tetrahedron 1985, 41, 2239–2329 R. Huisgen, H. Stengl, H. J. Sturm, H. Wagenhofer Angew. Chem. 1961, 73, 170 R. Huisgen, R. Knorr Naturwissenschafen 1961, 48, 716 Baran Lab R o l f H u i s g e n Hafensteiner

Diazoalkanes Mechanistic Inquiries

base R N R N - diazoalkanes, azides, nitrile ylides react with each end of the 1,3 dipole acting as N N electrophile and nucleophile Dipolarophile: Carbonyls, Thiocarbonyls, Imines - regioselectivity changes as the interaction of molecular orbitals change - with an electron deficient dipolarophile, LUMO of dipolarophile interacts with HOMO of - Arndt –Eistert homologation 1,3 dipole O -with increasing electron density, LUMO of dipolarophile is elevated and less favorable O O N overlap occurs N N N R1 1 R R R R R1 LUMO N LUMO N R O E HOMO R1 R. Eistert Angew. Chem. 1941, 54, 99 HOMO

- reaction with ketenes

O Ph Ph Ph N Stereospecificity N • N N - H. Dorn proposed an acyclic zwitterionic intermediate due to 15–20% inversion Ph O Ph Ph Ph Ph N O N NO2 N Ph Ph Ph N * NO2 - reaction with imines O Ph 15–20% inversion N 10 – 75% N H. Dorn, R. Ozegowski, E. Gründemann J. Prakt. Chem. 1979, 321, 555–564 R NH N N NH R P. K. Kabada, J. O. Edwards J. Org. Chem. 1961, 26, 2331 - inversion range is questionable because krot / kcyc should be consistent if consistent reaction conditions are used - sec–nitro alkanes are stronger acids than phenol Baran Lab R o l f H u i s g e n Hafensteiner

Stereospecificity - under "highly sterile" conditions, full retention of alkene geometry mantained O

Ph O N N NO2 N S Ph Ph N * NO2 NC CN O MeO2C CN Ph MeO C CO Me 99.992% stereospecificity NC CO2Me 2 2 by GC analysis

N O O 100% MeO2C N rotation N N CO Me S S Et2O, 20 °C 2

99.997% stereospecificity CN CN MeO2C NC by GC analysis CO2Me CO2Me NC MeO2C R. Huisgen, J. Rapp J. Am. Chem. Soc. 1987, 109, 902–903

Forcing a Two Step Mechanism - high energy ylides combined with low MO dipolarophiles would encourage a two step CDCl3, 10 min. mechanism 85 °C

O O O S O S

S CN CN S MeO2C NC N CN CO2Me CO2Me N MeO2C

dimethyldicayanofumarate 61:39 dimethyldicayanomaleate 25:75

MeO2C CN

NC CO2Me G. Molston, E. Langhals, R. Huisgen Tetrahedron Lett. 1989, 30, 5373–5376 Baran Lab R o l f H u i s g e n Hafensteiner

Aziridines and Oxiranes - aziridines and oxiranes can undergo ring opening to give azomethine ylides - ylides are ~8 kcal/ mol higher in energy than the rings but have ~21 kcal/ mol barrier to and carbonyl ylides reconstitution

Ph Ph 100 °C O Ph O Ph N N O Ph Ph D Ph O Ph Ph CN CN MeO C CO Me MeO C CO Me 2 2 2 2 Ph CN CN MeO2C CO2Me MeO2C CO2Me Ph CO2Me 54 46 N CO2Me MeO2C

CO2Me O CN O CN O Ph Ph R. Huisgen, W. Scheer, H. J. Huber J. Am. Chem. Soc. 1967, 89, 1753–1755 D Ph O Ph R. Huisgen, H. Mäder Angew. Chem. Int. Ed. Eng. 1969, 8, 604–606 CN Ph Ph Ph Ph CN MeO2C CO2Me MeO2C CO2Me MeO2C Ar CO2Me MeO2C Ar H N N 150x slower opening 63 37

H H H CO2Me h A. Dahmen, H. Hamberger, R. Huisgen, J. J. Markowski J. Chem. Soc. Chem. n Comm. 1971, 1192–1194

Ar Ar 1,4 Dipolar Cycloaddition H N CO2Me rotation MeO2C N CO2Me - nucleophilic and electrophilic termini without conjugation between termini

CO2Me H - reactions proceed in two step fashion - dipoles can easily dimerize or form 4–membered rings

O Ar Ar MeO2C CO2Me N CO2Me N N MeO2C MeO2C N CO2Me CO2Me N PhN Ph 46% CO2Me

MeO2C CO2Me MeO2C CO2Me O

"...our results...offer the first verification of [the Woodward–Hoffman] principle R. Huisgen, M. Morikawa, K. Herbig, E. Brunn Chem. Ber. 1967, 100, 1094–1106 Baran Lab R o l f H u i s g e n Hafensteiner

1,4 Dipolar Cycloaddition 2+2 of Ketenes Ph O O 99% Ph Ph O MeO2C CO2Me N CO2Me BuO 20 °C, 3 hr. N Ph BuO EtO2C CO2Et 70% O CO2Me Ph O EtO2C CO2Et O 97% Ph Ph C H 4 9 100 °C, 8 hr. R. Huisgen, M. Morikawa, K. Herbig, E. Brunn Chem. Ber. 1967, 100, 1094–1106 Ph C4H9

Ph O DMAD O 97% Ph Ph N N CO2Me 20 °C 8 months Ph Me R. Huisgen, L. A. Feiler, P. Otto Chem. Ber. 1969, 102, 3045–3427 MeO2C CO2Me

CO2Me - increased electron density of olefin increases rate significantly of 2+2 O DMAD Ph 40 °C OEt N N N 20 °C N benzonitrile Ph O 89% Ph Ph Ph O

Ph 1 580 800,000 O

R. Huisgen, L. A. Feiler, P. Otto Chem. Ber. 1969, 102, 3444–3459 - heteroaromatic bases forfeit their aromaticity to engage in these reactions

R. Huisgen, K. Herbig, M. Morikawa Chem. Ber. 1967, 100, 1107–1115 - examined rates of cis vs. trans alkenes O Review: W. D. Ollis, S. P. Sanforth, C. A. Ramsden Tetrahedron, 1985, 41, 2239–2329 3 days O 90 °C Ph 96% Ph O Ph Ph 3 months 90 °C incomplete Ph Ph R. Huisgen, H. Mayr Tetrahedron Lett, 1975, 2965–2968 Baran Lab R o l f H u i s g e n Hafensteiner

Quotes

"Wolfgang Scheer had magic hands in experimenting. I did not then "I have profited immensely from these assets of Munich, all the more object to the beer bottles on his bench." because I regard theater, music, and art as a world complimentary to that of science, with exposure to one acting as a stimulus for the other."

"Playfulness is an incentive for the scientist and a driving force of "Both art and science moreover are founded on creativity and the progress" power of imagination."

"Stubborn pursuit of a goal is often praised as a virtue, and "The effective techniques for motivating young associates are limited, sometimes leads to success. However, accidental observations can I believe. The professor's own level of enthusiasm is, of course, disclose new horizons, far off the original target and sometimes essential. In the end, however, most of the motivation and more valuable. The luck chance might lurk just outside the enthusiasm must come from the student." experimenter’s door, but the door is not always open. Opening it "Thorough thinking is valued over quickness." brings serendipity – acceptance of Fortuna's gift." "Fashions come and go in both ladies' apparel and scientific "The solution of one problem usually generates a bevy of new ones. research." The inexperienced young scientist often lacks the willpower to resist the temptation of dealing with a new problem while working on the "When I asked Bob Woodward in 1961 why he had wanted to first one." synthesize chlorophyll, the roguish answer was 'because nobody else could do it'."

"I am far from holding adverse conditions – maybe a crowded air raid "The elegant and innovative synthesis will remain a domain of the shelter does not provide optimal conditions for creative thinking – masters. In my opinion, the mere stringing of known reaction steps responsible for my lackluster findings on the strychnine problem. At for building complex natural products is not the most rational use of the age of 22 I was not experienced and mature enough to crack one time and funds, and I hope the fashion will soon swing to more of the hardest nuts of alkaloid chemistry. Children sometimes retain rewarding areas of research." an aversion to books that are beyond their intellectual capacity when they first tackle them. I wonder whether similar reasons prevented "The Adventure Playground of Mechanisms and Novel Reactions" by Rolf Huisgen, my return to natural products after forays into other fields" Profiles, Pathways, and Dreams; J. I. Seeman Ed.; American Chemical Society, Washington D.C., 1994 "What makes us praise novel achievements as imaginative or highly original?...Scientific imagination is not so much wild fantasy that is completely detached from the existing body of experience as it is absence of prejudice about what can be done and what cannot."