Structure, Mechanism and Reactivity of Hantzsch Esters
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1 Structure, chanism and eactivity of antzsch Esters Jamie Tuttle MacMillan Lab Group eting 08/25/04 Lead eferences: Lavilla,. J. Chem. Soc., Perkin Trans., 2002, 1, Stout, D. M. and yers, A. I. Chem. ev., 1982, 82, 223. Kuthan, J. and Kurfürst, A. Ind. Eng. Chem. Prod. es. Dev.,1982, 21, 191. Eisner, U. and Kuthan, J. Chem. ev., 1972, 1, 1.
2 A little background on the antzsch ester Et Et E! First discovered in 1882 by Arthur antzsch! Derivatives exhibit important pharmacological properties such as antihypertensive, antibiotic, antiinflammatory, and antifungal activity nefipidine 2 - Calcium antagonist vasodilator. Treats high blood pressure and angina. - Adalat (Bayer 1999) $1 bill. Procardia (Pfizer 1998) $822 mill.! ther dihydropyridine derivatives are used as rocket fuel additives, antioxidants, and photographic materials! Closely related to AD, a ubiquitous biological reductant found in the biosphere
3 Bioreductants and their inspired organoreductants! educed nicotinamide adenine dihydropyridine (AD) 2 P P AD 2 10-methylacridan! educed flavin adenine mononucleotide (FAD) is the other major reductant found in biology nicotinamide 2 isoalloxazine! A non-biomimetic organoreductant = AMP and D-ibitol.. Garrett and C. M. Grisham, in Biochemistry, Saunders College Publishing 1995, p S benzothiazoline - usually used in conjuction with AlCl 3 to reduce enones. Chikashita,. et al. J. Chem. Soc. Perkin Trans , 699
4 Some interesting enzymatic transformations! Enzymes catalyze the following reactions to produce chiral products! Most AD biochemical transformations are reversible redox reactions -UDP AD UDP galactose-4-epimerase -UDP - Biosynthesis of UDP-galactose occurs via oxidation/reduction of UDP-glucose. AD Malate dehydrogenase lactate dehyd. alcohol dehyd. ' '' AD+ ' '' ' '' AD glutamate dehyd. AD+ ' 2 ''.. Garrett and C. M. Grisham, in Biochemistry, Saunders College Publishing 1995, p
5 Pertinent enzymatic transformations con't. ' '' + C 2 AD isocitrate dehydrogenase 6-phosphogluconate dehyd. AD+ ' '' ' AD aldehyhde dehyd. AD+ ' AD dihydrosteroid dehyd. AD+ AD dihydrofolate reductase AD+.. Garrett and C. M. Grisham, in Biochemistry, Saunders College Publishing 1995, p
6 ! Theoretically, 5 isomeric DP forms can exist General structure considerations Increasing susceptibility towards oxidation ~ = >>> 3 ~ 3 ~ = = Structures 1 and 2 are the most common. Presumably, the lone pair delocalization into the pi system stabilizes the structure. bserve, 5 sp 2 hybridized centers in 1 and 2 versus 4 in 3-5.! Substituent effects - EWG's capable of resonance interaction (C, C 2, C, 2 ) in the 3,5 positions stabilize 1,4 DP's by extending conjugation. - Conversely, electron donating groups (S, ) in the 3,5 position destabilize the molecule. - itrogen alkyl substitution, though possible to prepare, destabilizes 1,4 DP's. - 2,6 alkyl substitution remains largely unexplored yers, A. I. and Stout, D. M. Chem. ev. 1982, 82, 223. Kuthan, J. and Kurfurst, A. Ind. Eng. Chem. Prod. es. Dev. 1982, 21, 191.
7 antzsch esters adopt two potential conformations! X-ray studies - 4-unsubstituted antzsch esters adopt a planar conformation. - aryl and pyridyl substituents at the 4-position induce a puckered ("flat boat") configuration. Puckered conformation Planar Conformation Et Et Et Et Goldmann, S. et al. J. d. Chem. 1990, 33, Fossheim,. et al. J. d. Chem. 1982, 25, 126. Leustra, A. et al. Bull. Soc. Chi. Belg. 1979, 133.
8 Three postulates aim to explain the reduction mechanism of 1,4 dihydropyridines! The following mechanisms have been proposed: I. Single step hydride transfer II. Two step electron transfer-hydrogen atom abstraction III. Three step electron transfer-proton transfer-electron transfer! Data supporting each process were derived from nicotinamide analogues and antzsch ester derivatives! o unified mechanism has been established
9 Single-step hydride transfer! ccurs in most antzsch ester reductions that proceed under thermal conditions! General scheme! +! -! + E + A + [E A] E + + A! Experimental results that support this mechanism C Br = C, C 2 Et Et Et C 3 C, dry, deaerated T, 7h, dark C 90%, only isomer - Free energy calculations indicate the single electron transfer mechanism is less likely than hydride transfer by two-fold (for C kj/mol vs kj/mol). - Deuterated C-4 and antzsch analogues were used to determine hydride source via M. C 2 Et Et Et vs. Et Et + + Zhu, X. et al. J. rg. Chem. 1999, 64, 8980.
10 Various studies support single-step hydride transfer! Deuterated product detected by 1 and 19 F M. Authors support hydride transfer mechanism Et D D Et + or CF 3 C 2 pyridinium perchlorate, reflux 24h, reflux 39h 20% D CF 3 D C 2 orcross, B. E., Klinedinst, Jr., P. E., Westheimer, F.. J. Amer. Chem. Sci. 1962, 84, 797.! Kinetic isotope effect and thermodynamics support single step hydride transfer. 38% Et Et = D or D Et Et 0.1M ClC 2 C 0.1M a K (30% aq) C 3 C, p 3.0 BF 4 - Deuterium KIE value of 4.16 indicates direct hydride dissociation from C-4 is rate limiting step. - Presence of the bulky phenyl group decreases reaction rate ~10 4 fold. - Electrochemical experiments support direct hydride transfer for both cases. Cheng, J.-P. et al. Tet Lett. 2000, 41, 257.
11 Further evidence for a single-step hydride mechanism! Thermodynamic and kinetic studies provide an arguement for this process.! Deuterium regiochemistry determined by 1 M and MS. C C C benzylidinemalononitriles or 4,4,-d 2 -E C 3 C, deaerated, dark 24 h D C C 94% C C 2 Et alphacyanocinnamates D 94% - A KIE comparison of -d and C-d,d antzsch derivatives gave values <1.4 and >5.2, respectively. Values above 2.0 indicate the C- bond is being broken in the rate determining step. - Free energy changes of electron transfer were kj/mol vs hydride kj/mol. Zhu, X. Q. et al. J. Chem. Soc., Perkin Trans , 1857.! Molecular electrostatic potential and M/LUM comparisons support a hydride attack C C C C 2 Et C E Et C C C C Garden, S. J. et al. J. rg. Chem. 2003, 68, 8815.
12 Two step transfer: 1 electron- 1 hydrogen! General scheme E + A + 1e - [E... 1 A ] E + + A! ccurs predominantly under photoexcited conditions or with strong oxidants! Evidence is found in specific cases Et Et + C C 2 Et Br single isomer C 3 C, dry, deaerated hv, 420 nm Et Et + Br C C 2 Et Br Et Et Et 2 C C C C 2 Et Et 2 C C C C 2 Et Z 30% E 70% C 2 C 2 - nly the Z isomer is reacted. - Deuterium studies indicate a proton is abstracted from C-4. Zhu, X.- Q. et al. J. rg. Chem. 1999, 64, 8980.
13 1 Electron, 1-ydrogen evidence continues...! Three AD analogues are analyzed kinetically and thermodynamically Et Et E or 30% C 3 C 70% 2 (v/v) KCl Acr 2 2 BA E + Xn + [E... Xn + ] A Xn ] fast slow e - T T fast E + + Xn - A slight endothermic electron transfer was followed by a large exothermic proton transfer. - E, despite being a poorer electron donor than BA (0.446V, 0.182V, respectively), reacts faster. - Failure of CF 3 CD to deuterate the intermediate radical anion suggests electron and proton steps may overlap. Cheng, J. - P. and Lu, Y. J. ys. rg. Chem. 1997, 10, 577.
![.. Xn + ] A Xn ] fast slow e - T T fast E + + Xn - A slight endothermic electron transfer was followed by a large exothermic proton transfer.](/docs-images/46/21249581/images/page_13.jpg "- E, despite being a poorer electron donor than BA (0.446V, 0.182V, respectively), reacts faster.")
14 Multi-step transfer: electron-proton-electron (e e - )! General scheme E + A 1e - [E... A] 1 + [E... A] 1e - E + + A! Cheng returns with the same reductants and a different mechanistic postulate. 2 Et Et Et Et (omitted 6 nicotinamide derivatives) 2 Et C 3 C Et Et Et Cl 4 - Uses titration calorimetry and electrochemistry to develop hypotheses. - In this experiment, E can deliver a hydride or undergo the e e - mechanism with equal probability. - -substituents on nicotinamide derivatives have a large effect. EWG's favor heterolytic bond cleavage, EDG's favor homolytic bond cleavage. Cheng, J. - P. et al. Chem. Eur. J. 2003, 9, 871.
15 An interesting effect of e e - on 4-substituted antzsch DP's! Creates a potential source of alkyl cations Et Et PI()Ts C 2 Cl 2, T 1-3 mins. >90% yield Et + -I- + - Ts Et Et Et - - Ts or - Et PI()Ts or -I- SET Et C C ClC C 6 4 C 6 5 C=C C=C C 3 C 2 5 C 6 5 C 2 (C 3 ) 2 C Et Et Et SET Et - - TS or - Et Lee, K. -. and Ko, K. - Y. Bull. Korean Chem. Soc. 2002, 23, 1505.
16 antzsch DP ester groups may play a role sterically and electronically! icotinamide amides can exist in either a cis or trans geometry 2 7 kcal/mol 2 Cis Trans Cis = ground state Trans = reduction transition state! The carbonyl is slightly tilted towards the incoming electropositive substrate a b 2! Electrostatic interaction of both carbonyl groups with electrophile ' '' Et Et ouk, K.. et al. J. Am. Chem. Soc. 1995, 117, Cheng, J. - P. and Lu, Y. J. ys. rg. Chem. 1997, 10, 577.
17 rbital overlap may provide a key for understanding antzsch DP orientation during hydride delivery! Two interesting concepts arise when analyzing FM's = 2 Et!! Et = " - ouk's nicotinamide models indicate a favorable LUM donor/lum receiver overlap that lowers the activation energy. - Garden's M coefficient calculations show! = and " = ! Based on these data, it may be possible to determine antzsch ester/substrate overlap by analyzing LUM/LUM coefficients. = Et Et = ouk, K.. et al. J. Am. Chem. Soc. 1995, 117, Garden, S. J. et al. J. rg. Chem. 2003, 68, 8815.
18 antzsch ester preparation! Many methods provide reasonable routes leading to antzsch derivatives! Cyclocondensation routes are the most efficient and predictable! eduction of pyridine derivatives has been used with mixed success vs.! Main methods of preparation (reactants will be discussed) 1) Warming the reagents in alcohol (usually Et). 2) Using hexamethlyenetetramine in place of formaldehyde and ammonia. 3) Utilization of 4 Ac and primary amine salts with acetic acid or pyridine as solvents! General trends for varying certain substituents on the antzsch DP If 1 = varied, while 2 =,, 2, 3 = and 4 =, then use method If 1 = varied, while 2 =, 2, Et,, -i-pr, -n-bu, 3 = and 4 = alkyl, aryl, then use method 1. - If 2 = varied, while 1 = 4 = and 3 =, then use method 2. - If 3 = varied and 1 = varied, while 2 = Et and 4 =, then use method 3. Kuthan, J. and Kurfurst, A. Ind. Eng. Chem. Prod. es. Dev. 1982, 21, 191.
19 amesake Preparation is most efficient! Best way to introduce diversity in and 1 positions. + 1 C 2 Et 3 Et 2 C 1 C 2 Et 1 3 C 2 Et 1 enolate C 2 Et 1 aldol C 2 Et C 2 Et E1cb C 2 Et C 2 Et enamine formation C 2 Et Et 2 C C 2 Et conj. add'n. tautomerization Et 2 C C 2 Et Et 2 C 3 3 C 2 Et Et 2 C C 2 Et 1 ur ero 1 antzsch, A. Ann. 1882, 215, 1. Li, J. J. ame eactions, Ed. 2, Springer - Verlag, Berlin, 2003,
20 Cyclization/condensation methods lead to a variety of antzsch derivatives! Use of enamino ketones, esters and nitriles (X groups) X 4 - Great way to introduce nitrile groups to the 3 and 5 positions.! Use of 1,5 diketones X X X 3 Et Et 2 C 2 Et C 2 Et 4 Ac/Ac Et 2 C C 2 Et - The diester intermediate is not isolated.! Use of!-" unsaturated ketones 2 3 Et 2 C C C 2 Et - Can react with enamines or ketones to provide unsymmetrical products. Kuthan, J. and Kurfurst, A. Ind. Eng. Chem. Prod. es. Dev. 1982, 21, 191. Eisner, U. and Kuthan J. Chem. ev. 1072, 72, 1.
21 The advent of microwave technology has streamlined the synthesis! Useful modifications of antzcsh's synthesis - examethylenetetramine provides a cheap and easily handled source of ammonia and formaldehyde The advent of microwave technology has reduced reaction time to minutes. Many functional groups can tolerate these conditions or Ac no solvent ipr ipr 2 C 2 Et C 2 C 2 tbu CC 3 C C 2 Et C C 2 Et C C 2 Et C Barbry, D. et al. Molecules 2002, 7, 528.
22 antzsch esters reduce imine derivatives! Imine, both preformed and under reductive amination conditions E +! Ketimine 1 C 3 C, T, o/n 1 1 % yield p- p aphthyl 89 p- o- 79 p E + C 2 Cl 2, 0.2 M TFA, o/n 60% yield! Bisarylidene-ethylenediamines E + C 3 C, T, o/n 1 % yield p-cl 50 45! Enamines % yield E + C 2 Cl 2, 0.2 M TFA, o/n - (C 2 ) (C 2 ) C 2 C 2-50 Singh, S. et al. J. Chem. Soc. Perkin Trans. 1, 1985, 437.
23 ther imine derivative examples! Steroid unsaturated iminium gives a single isomer Cl 4 E (1.2 eq) C, 24 h, reflux ~ 70% Pandit, U. K. et al. J. Chem. Soc. Chem. Comm. 1974, 327.! Steroid iminium gives a single isomer Cl 4 E (1.2 eq) C, 24 h, reflux ~ 90% Pandit, U. K. et al. J. Chem. Soc. Chem. Comm. 1975, 211.
24 Effect of substitution on hydride regioselection with!-" unsaturated iminium salts! eductions proceed with 2 eq.e and are run in C 3 C at T. Yields are all > 90%. x X Cl 4 Cl 4 Cl 4 Cl 4 X X substrate 1 1 X C 2 E1/2 (V) pka amine ratio C=C:C= attack 100:0 100: C 3 C 3 F Br C 2 Et C :23 29:71 28:72 21:79 10:90 0:100 0:100 0:100 - E1/2 is a measure of the relative LUM energy. Data shows that E1/2 values below lead to C=C attack. E1/2 values above lead to iminium attack. - Aromatic substituents have a significant effect on regioselectivity. - Sterics are more important than FM interactions as shown in 3(Br) and Br :0 100: :0 ie-sarink, M. J. and Pandit, U. K. Tet. Lett. 1979, 26, 2449.
25 antzsch esters effectively reduce electrophilic olefins! These substrates were shown earlier in a deuterium labeling experiment C 2 E (1:1), reflux C % CF 3 CF % orcross, B. E., Klinedinst, Jr., P. E., Westheimer, F.. J. Amer. Chem. Soc. 1962, 84, 797.! The second step in these reactions proceeds using the crude reduced product Cl 1)E (1:1) dioxane, 85 C, 2 2) Bn 1:1 Bn >70% Cl " 2) 1:1 >70% Cl " 2) Bn 1:1 10% Bn Pandit, U. K. et al. Bioorg. Chem. 1973, 2, 293.
26 itro- and carbonyl alkene reductions!!-nitroalkene derivatives E (1.3 eq) Ac (0.18 eq) benzene, 2, 80 C, 15h Benzoic (pka = 4.21), formic (pka = 3.75), and chloroacetic (pka = 2.87) acids also worked. - Dichloroacetic (pka = 1.26) and trifluoroacetic (pka = 0.3) did not. 2 1 p-c 3 m-c 3 p-c 3 p-cl p- 2 m-c 3 2 C 3 C 3 yield 100 (glc) (glc) ! "-! unsaturated aldehydes and ketones yield 76 (ere used TFA) E (1.3 eq) Ac (0.18 eq) toluene, 2, 80 C, 15h A = 13 B = trace A B Inoue, Y. et al. Bull. Chem. Soc. Jpn. 1988, 61, 3020
27 Various substrates! Maleic anydride is reduced non-regioselectively 1) d 2 -E dioxane, reflux 2) /Cl(g) D 1) d 2 -E dioxane, reflux 2) /Cl(g) D (1:1) D! Stabilized sulfonium salts are reduced by -methylated antzsch esters S Cl 4 - Best case shown. -E acetone, 60 C Pandit, U. K. et al. Bioorg. Chem. 1973, 2, % Et Et + Et Et Et Et Van Bergen, T. J. and Kellogg,. M. J. Am. Chem. Soc. 1964, 98, 1962.
28 ther interesting reductions! Preparation of cyclic compounds E (2.0 eq) C 3 C, deaerated, dark Ar C time (h) % yield 7-11 >90 Br 2 C C = C, C 2 Et C C 2 Et >91 E " >92 Br 2 C C 2 Et C C E C 2 Et C Br = C, C 2 Et, S 2 " C C C 2 ET S Br " Zhu, X. -Q. et al. J. rg. Chem. 2001, 66, 344.
29 A brief look at Lewis acid catalyzed antzsch reactions! lefin reduction with Si 2 E (1.5 eq) Si g benzene, 80 C, dark 17 h 88% 67% hno, A. et al. Tet. Lett. 1984, 25, 36.! eductive amination using Sc(Tf) 3 and LiCl E (1 eq) Sc(Tf) 3 (2 mol %) TF, Ar, T, 24 h 99% 2 + E (1.5 eq) LiCl 4 (2 eq) C 3 C, T, 4d, dark 35% hsawa, A. et al. Tet. Lett. 2002, 43, hno, A. et al. Tet. Lett. 1977, 52, 4593.
30 A look at asymmetric antzsch variants! Asymmetric versions Mg Et Pr Mg(Cl 4 ) 2 (1.0 eq) C 3 C, 20 days 83% yield 72% ee Et Pr Tanner, D. and Li, X. Tet. Lett. 1996, 37, eq Et Mg(Cl 4 ) 2 (1.2 eq) C 3 C, 1-2 days 80% yield 86% ee Mg2 + Kellogg,. M. et al. J. Am. Chem. Soc. 1981, 103, 2091.
31 AD regeneration! Most of the current approaches require the use of enzymes or whole cell lysates Kroutil, W. et al. Curr. p. Chem. Bio. 2004, 8, 120. van der Donk, W. A. and Zhao,. Curr. p. Chem. Bio. 2003, 14, 421.! A reasonable possibility [Cp * h(bpy)()] + C 2 + h 2 + Bn >93% ee, 90% yield h h 2 2+ Bn 2 LAD Enzyme ac 2 = Lo,. C. and Fish,.. Angew. Chem. Int. Ed. 2002, 41, 478
32 Future Directions! Preparation of fused ring systems Et Et Bn Br =,! Extending 3,5 ester alkyl chains may increase enantioselectivity ' ''! Develop a catalytic cycle
33 Conclusions! eduction mechanisms are highly dependent on substrates! Effectively lowering the LUM of electrophiles facilitates reduction with antzsch esters! Based on mechanistic postulates, enantioselectivity may be increased with different antzsch derivatives! A catalytic cycle may be created with careful selection of the second reductant and hydride source
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