Metal Enolates – Enamines – Enol Ethers: How Do Enolate Equivalents Differ in Nucleophilic Reactivity?

A contribution of Physical Organic Chemistry to systematizing Organic Synthesis. Cordial congratulations on the occasion of the Golden Anniversary of Synthesis.

Published as part of the 50 Years SYNTHESIS – Golden Anniversary Issue

Abstract

The kinetics of the reactions of trimethylsilyl enol ethers and enamines (derived from deoxybenzoin, indane-1-one, and α-tetralone) with reference electrophiles (p-quinone methides, benzhydrylium and indolylbenzylium ions) were measured by conventional and stopped-flow photometry in acetonitrile at 20 °C. The resulting second-order rate constants were subjected to a least-squares minimization based on the correlation equation lg k = s _N(N + E) for determining the reactivity descriptors N and s _N of the silyl enol ethers and enamines. The relative reactivities of structurally analogous silyl enol ethers, enamines, and enolate anions towards carbon-centered electrophiles are determined as 1, 10⁷, and 10¹⁴, respectively. A survey of synthetic applications of enolate ions and their synthetic equivalents shows that their behavior can be properly described by their nucleophilicity parameters, which therefore can be used for designing novel synthetic transformations.

Key words

alkylation - enols - kinetics - linear free energy relationship - reactivity scales

• References

• 1 Current affiliation: School of Chemistry, Joseph Black Building, University of Glasgow, University Avenue, Glasgow, G12 8QQ, UK.
• 2 Caine D. Alkylations of Enols and Enolates . In Comprehensive Organic Synthesis, Vol. 3 . Vol. 3. Trost BM, Fleming I, Pattenden G. Chap. 1.1 Pergamon Press; Oxford: 1991: 1-63
• 3 Stolz D, Kazmaier U. Metal Enolates as Synthons in Organic Chemistry . In The Chemistry of Metal Enolates Part 1 . Zabicky J. Wiley; Chichester: 2009. Chap. 7, 355-410
• 4 Bruckner R. Chemistry of the Alkaline Earth Metal Enolates. In Organic Mechanisms – Reactions, Stereochemistry and Synthesis. Harmata M. Springer-Verlag; Berlin: 2010. Chap. 13, 519-593
• 5 Bates RB, Ogle CA. Carbanion Chemistry . Springer; Berlin: 1983
• 6 Brandsma L. Preparative Polar Organometallic Chemistry, Vol. 2 . Springer; Berlin: 1990: 1-13
• 7 Jung ME. Stabilized Nucleophiles with Electron Deficient Alkenes and Alkynes . In Comprehensive Organic Synthesis, Vol. 4 . Vol. 4. Trost BM, Fleming I, Semmelhack MF. Chap. 1.1 Pergamon Press; Oxford: 1991: 1-67
• 8 Snieckus V. Advances in Carbanion Chemistry . Vol. 1. Snieckus V. JAI Press; Greenwich (CT): 1992
• 9 Buncel E, Dust JM. Carbanion Chemistry . Oxford University Press; Oxford: 2003
• 10 Smith MB. In March’s Advanced Organic Chemistry: Reactions, Mechanisms, and Structure . John Wiley & Sons; Hoboken: 2013. 7th Ed., 221-233
• 11 Minko Y, Marek I. Chem. Commun. 2014; 50: 12597
• 12 Mayr H, Bug T, Gotta MF, Hering N, Irrgang B, Janker B, Kempf B, Loos R, Ofial AR, Remennikov G, Schimmel H. J. Am. Chem. Soc. 2001; 123: 9500
• 13 Lucius R, Loos R, Mayr H. Angew. Chem. Int. Ed. 2002; 41: 91 ; Angew. Chem. 2002, 114, 97
• 14 Mayr H. Tetrahedron 2015; 71: 5095
• 15 Mayr H, Ofial AR. SAR QSAR Environ. Res. 2015; 26: 619
• 16 For a freely accessible database of E, N, and s _N parameters, see: http://www.cup.lmu.de/oc/mayr/DBintro.html (accessed Dec 12, 2018).
• 17 Richter D, Hampel N, Singer T, Ofial AR, Mayr H. Eur. J. Org. Chem. 2009; 3203
• 18 Follet E, Berionni G, Mayer P, Mayr H. J. Org. Chem. 2015; 80: 8643
• 19 Kempf B, Hampel N, Ofial AR, Mayr H. Chem. Eur. J. 2003; 9: 2209
• 20 Derived from molecular geometries calculated using the SMD(acetonitrile)/M06-2X/6-31+g(d,p) level of theory.
• 21 Kanzian T, Lakhdar S, Mayr H. Angew. Chem. Int. Ed. 2010; 49: 9526
• 22 Corral Bautista F, Appel R, Frickel JS, Mayr H. Chem. Eur. J. 2015; 21: 875
• 23 Timofeeva DS, Mayer RJ, Mayer P, Ofial AR, Mayr H. Chem. Eur. J. 2018; 24: 5901
• 24 Denmark SE, Stavenger RA. Acc. Chem. Res. 2000; 33: 432
• 25 Palomo C, Oiarbide M, Garcia JM. Chem. Soc. Rev. 2004; 33: 65
• 26 Schetter B, Mahrwald R. Angew. Chem. Int. Ed. 2006; 45: 7506
• 27 Valnot J.-Y, Maddaluno J. In The Chemistry of Organolithium Compounds, Vol 2 . Vol. 2. Rappoport Z, Marek I. Chap. 8 Wiley; Chichester: 2006: 525-646
• 28 Bertrand J, Gorrichon L, Maroni P. Tetrahedron 1984; 40: 4127
• 29 For a discussion of the ambident reactions of enolate ions, see: Mayr H, Breugst M, Ofial AR. Angew. Chem. Int. Ed. 2011; 50: 6470
• 30 Juaristi E, Beck AK, Hansen J, Matt T, Mukhopadhyay T, Simson M, Seebach D. Synthesis 1993; 1271
• 31 Shankar R, Jha AK, Singh US, Hajela K. Tetrahedron Lett. 2006; 47: 3077
• 32 For a review on the use of K₂CO₃ for the generation of enolate ions in synthetic applications, see: Khachatryan DS, Matevosyan KR. Russ. Chem. Bull. 2016; 65: 14
• 33 Lee VJ. Conjugate Additions of Reactive Carbanions to Activated Alkenes and Alkynes . In Comprehensive Organic Synthesis, Vol 4 . Vol. 4. Trost BM, Fleming I, Semmelhack MF. Chap. 1.2 Pergamon Press; Oxford: 1991: 69-137
• 34 Shrout DP, Lightner DA. Synthesis 1990; 1062
• 35 Unsworth WP, Coulthard G, Kitsiou C, Taylor RJ. K. J. Org. Chem. 2014; 79: 1368

For examples of (3 + 2)-cycloadduct synthesis, see:
• 36a Tsuge O, Kanemasa S, Takenaka S. Bull. Chem. Soc. Jpn. 1985; 58: 3137
• 36b Tsuge O, Kanemasa S, Takenaka S. Bull. Chem. Soc. Jpn. 1985; 58: 3320
• 36c Shestopalov AM, Sharanin YA, Nesterov VN, Rodinovskaya LA, Shklover VE, Struchkov YT, Litvinov VP. Chem. Heterocycl. Compd. 1991; 27: 1006
• 37 Allgäuer DS, Jangra H, Asahara H, Li Z, Chen Q, Zipse H, Ofial AR, Mayr H. J. Am. Chem. Soc. 2017; 139: 13318

For examples of cyclopropanations, see:
• 38a Shestopalov AM, Litvinov VP, Rodinovskaya LA, Sharanin YA. Bull. Acad. Sci. USSR, Div. Chem. Sci. (Engl. Transl.) 1991; 40: 129
• 38b Vo NH, Eyermann CJ, Hodge CN. Tetrahedron Lett. 1997; 38: 7951
• 38c Kojima S, Fujitomo K, Shinohara Y, Shimizu M, Ohkata K. Tetrahedron Lett. 2000; 41: 9847
• 38d Yamada S, Yamamoto J, Ohta E. Tetrahedron Lett. 2007; 48: 855
• 38e Wang Q.-F, Song X.-K, Chen J, Yan C.-G. J. Comb. Chem. 2009; 11: 1007
• 39 For a review on related cyclopropanations of ammonium ylides, see: Roiser L, Zielke K, Waser M. Asian J. Org. Chem. 2018; 7: 852
• 40 Allgäuer DS, Mayer P, Mayr H. J. Am. Chem. Soc. 2013; 135: 15216
• 41 Stork G, Brizzolara A, Landesman H, Szmuszkovicz J, Terrell R. J. Am. Chem. Soc. 1963; 85: 207
• 42a Dyke SF. The Chemistry of Enamines . Cambridge University Press; Cambridge: 1973
• 42b Hickmott PW. Tetrahedron 1982; 38: 1975
• 42c Hickmott PW. Tetrahedron 1982; 38: 3363
• 42d Alt GH, Cook AG. Enamines: Synthesis, Structure, and Reactions . Cook AG. Marcel Dekker Inc; New York: 1988. Chap. 4
• 43 Asahara H, Mayr H. Chem. Asian J. 2012; 7: 1401
• 44a Birkofer L, Kim SM, Engels HD. Chem. Ber. 1962; 95: 1495
• 44b Lewis JW, Myers PL, Readhead MJ. J. Chem. Soc. C 1970; 771
• 44c Katsin N, Ikan R. Synth. Commun. 1977; 7: 185
• 45a Risch N, Esser A. Z. Naturforsch., B: Chem. Sci. 1989; 44: 208
• 45b Mölm D, Flörke U, Risch N. Eur. J. Org. Chem. 1998; 2185
• 46 For stereoselective reactions of enamines with iminium ions (at r.t. in MeCN), see: Kossenjans M, Martens J. Tetrahedron: Asymmetry 1999; 10: 3409
• 47 Timofeeva DS, Ofial AR, Mayr H. J. Am. Chem. Soc. 2018; 140: 11474
• 48 Zhang J, Yang J.-D, Zheng H, Xue X.-S, Mayr H, Cheng J.-P. Angew. Chem. Int. Ed. 2018; 57: 12690
• 49 List B. Acc. Chem. Res. 2004; 37: 548
• 50 Mukherjee S, Yang JW, Hoffmann S, List B. Chem. Rev. 2007; 107: 5471
• 51 Pihko PM, Majander I, Erkkilä A. Enamine Catalysis . In Asymmetric Catalysis . List B. Springer; Heidelberg: 2009: 145-200
• 52 Waser M. Asymmetric Organocatalysis in Natural Product Syntheses. Springer; Wien: 2012: 7-44
• 53 Mayr H, Lakhdar S, Maji B, Ofial AR. Beilstein J. Org. Chem. 2012; 8: 1458
• 54 Jiang H, Albrecht Ł, Dickmeiss G, Jensen KL, Jørgensen KA. TMS-Prolinol Catalyst in Organocatalysis . In Comprehensive Enantioselective Organocatalysis, Vol 1 . Vol. 1. Dalko PI. Chap. 2 Wiley-VCH; Weinheim: 2013: 33-50
• 55 Mahrwald R. Chiral Imidazolidinone (MacMillan’s) Catalyst . In Comprehensive Enantioselective Organocatalysis, Vol 1. Vol. 1. Dalko PI. Chap. 4 Wiley-VCH; Weinheim: 2013: 69-96
• 56 Hansen JH, Zeeshan M. Mini-Rev. Org. Chem. 2014; 11: 432
• 57 List B, Lerner RA, Barbas III CF. J. Am. Chem. Soc. 2000; 122: 2395
• 58 List B, Pojarliev P, Castello C. Org. Lett. 2001; 3: 573
• 59a List B. J. Am. Chem. Soc. 2000; 122: 9336
• 59b List B, Pojarliev P, Biller WT, Martin HJ. J. Am. Chem. Soc. 2002; 124: 827
• 60 List B, Pojarliev P, Martin HJ. Org. Lett. 2001; 3: 2423
• 61 Mielgo A, Palomo C. Chem. Asian J. 2008; 3: 922
• 62 Jensen KL, Dickmeiss G, Jiang H, Albrecht Ł, Jørgensen KA. Acc. Chem. Res. 2012; 45: 248
• 63 Lakhdar S, Maji B, Mayr H. Angew. Chem. Int. Ed. 2012; 51: 5739
• 64 Hayashi Y, Gotoh H, Hayashi T, Shoji M. Angew. Chem. Int. Ed. 2005; 44: 4212
• 65 Roux C, Bressy C. Addition to Nitroolefins and Vinyl Sulfones . In Comprehensive Enantioselective Organocatalysis, Vol 3. Vol. 3. Dalko PI. Chap. 34 Wiley-VCH; Weinheim: 2013: 1013-1042
• 66 For the use of further secondary amines as catalysts for this Michael addition, see: Melchiorre P, Jørgensen KA. J. Org. Chem. 2003; 68: 4151
• 67a Cozzi PG, Benfatti F, Zoli L. Angew. Chem. Int. Ed. 2009; 48: 1313
• 67b Gualandi A, Emer E, Guiteras Capdevila M, Cozzi PG. Angew. Chem. Int. Ed. 2011; 50: 7842
• 68 Benfatti F, Benedetto E, Cozzi PG. Chem. Asian J. 2010; 5: 2047
• 69 Gualandi A, Petruzziello D, Emer E, Cozzi PG. Alpha-Alkylation by S_N1-Type Reactions . In Comprehensive Enantioselective Organocatalysis, Vol 3 . Vol. 3. Dalko PI. Chap. 26 Wiley-VCH; Weinheim: 2013: 729-756
• 70a Gualandi A, Mengozzi L, Giacoboni J, Saulnier S, Ciardi M, Cozzi PG. Chirality 2014; 26: 607
• 70b Gualandi A, Mengozzi L, Manoni E, Cozzi PG. Chem. Rec. 2016; 16: 1228
• 71 Beeson TD, MacMillan DW. C. J. Am. Chem. Soc. 2005; 127: 8826
• 72 Brochu MP, Brown SP, MacMillan DW. C. J. Am. Chem. Soc. 2004; 126: 4108
• 73 Duan X.-H, Mayr H. Org. Lett. 2010; 12: 2238
• 74 Mayr H, Kempf B, Ofial AR. Acc. Chem. Res. 2003; 36: 66
• 75 Hall HK. Jr. Angew. Chem., Int. Ed. Engl. 1983; 22: 440
• 76 Huisgen R. Acc. Chem. Res. 1977; 10: 117
• 77 Mayr H. Angew. Chem., Int. Ed. Engl. 1981; 20: 184
• 78 Mayr H, Striepe W. J. Org. Chem. 1983; 48: 1159
• 79 von der Brüggen U, Lammers R, Mayr H. J. Org. Chem. 1988; 53: 2920
• 80 Isler O, Lindlar H, Montavon M, Rüegg R, Zeller P. Helv. Chim. Acta 1956; 39: 249
• 81 The synthetic scope of the reactions of acetals with alkyl enol ethers is demonstrated in the articles quoted in ref 79.
• 82 Burfeindt J, Patz M, Müller M, Mayr H. J. Am. Chem. Soc. 1998; 120: 3629
• 83 Brownbridge P. Synthesis 1983; 1
• 84 Mukaiyama T, Narasaka K, Banno K. Chem. Lett. 1973; 2: 1011
• 85 Narasaka K, Soai K, Mukaiyama T. Chem. Lett. 1974; 3: 1223
• 86 Mukaiyama T. Angew. Chem., Int. Ed. Engl. 1977; 16: 817
• 87 Mukaiyama T. Pure Appl. Chem. 1983; 44: 1749
• 88 Matsuo J.-i, Murakami M. Angew. Chem. Int. Ed. 2013; 52: 9109
• 89 Lewis Base Catalysis in Organic Synthesis . Vedejs E, Denmark SE. Wiley-VCH; Weinheim: 2016
• 90a Takahashi E, Fujisawa H, Mukaiyama T. Chem. Lett. 2004; 33: 1426
• 90b Takahashi E, Fujisawa H, Mukaiyama T. Chem. Lett. 2005; 34: 84
• 91 Fujisawa H, Takahashi E, Mukaiyama T. Chem. Eur. J. 2006; 12: 5082
• 92 Rendler S, Oestreich M. Synthesis 2005; 1727
• 93 Denmark SE, Beutner GL. Angew. Chem. Int. Ed. 2008; 47: 1560
• 94 Nakagawa T, Fujisawa H, Nagata Y, Mukaiyama T. Chem. Lett. 2004; 33: 1016
• 95 Gawronski J, Wascinska N, Gajewy J. Chem. Rev. 2008; 108: 5227
• 96 Frías M, Cieślik W, Fraile A, Rosado-Abón A, Garrido-Castro AF, Yuste F, Alemán J. Chem. Eur. J. 2018; 24: 10906
• 97 Reetz MT, Maier WF. Angew. Chem., Int. Ed. Engl. 1978; 17: 48
• 98 Reetz MT, Hüttenhain S, Hübner F. Synth. Commun. 1981; 11: 217
• 99 Reetz MT. Angew. Chem., Int. Ed. Engl. 1982; 21: 96
• 100 Danishefsky S, Kitahara T, McKee R, Schuda PF. J. Am. Chem. Soc. 1976; 98: 6715
• 101 Tramontini M, Angiolini L. Tetrahedron 1990; 46: 1791
• 102 Arend M, Westermann B, Risch N. Angew. Chem. Int. Ed. 1998; 37: 1044
• 103 Merino P. Mannich-Type Reactions, In Science of Synthesis: C-1 Building Blocks in Organic Synthesis . van Leeuwen PW. N. M. Thieme Verlag; Stuttgart: 2014. Vol 2, 311-331
• 104 Wang W, Li H, Wang J. Org. Lett. 2005; 7: 1637
• 105 Erkkilä A, Majander I, Pihko PM. Chem. Rev. 2007; 107: 5416
• 106 Birch AJ, Kelly LF, Narula AS. Tetrahedron 1982; 38: 1813
• 107 Stahl I. Chem. Ber. 1985; 118: 1798
• 108 Mayr H, Henninger J, Siegmund T. Res. Chem. Intermed. 1996; 22: 821
• 109 Guo R, Gibe R, Green JR. Can. J. Chem. 2004; 82: 366
• 110 Kanzian T, Mayr H. Chem. Eur. J. 2010; 16: 11670
• 111 Gilmore K, Manoharan M, Wu JI.-C, Schleyer P. vR, Alabugin IV. J. Am. Chem. Soc. 2012; 134: 10584
• 112 Moriarty RM, Prakash I. Synth. Commun. 1985; 15: 649
• 113 Umemoto T, Fukami S, Tomizawa G, Harasawa K, Kawada K, Tomita K. J. Am. Chem. Soc. 1990; 112: 8563
• 114 Differding E, Ofner H. Synlett 1991; 187