Modern Synthesis and Chemistry of Stabilized Ketene N,O-Acetals

Ketene N,O-acetals are robust and versatile synthons. Herein, we outline the synthesis of stable ketene N,O-acetals in the twenty-first century. In addition, we review recent developments in the chemistry of ketene N,O-acetals, as it applies to the vinylogous Mukaiyama aldol reaction, electrolysis, and pericyclic transformations. While dated reports rely on in situ use, modern methods of ketene N,O-acetal synthesis are heavily oriented towards producing products with high ‘bench’ stability; moreover, in the present century, chemists typically enhance the stability of ketene N,O-acetals by positioning an electron-withdrawing group at the β-terminus or at the N-position. As propitious substrates in the vinylogous Mukaiyama aldol reaction, ketene N,O-acetals readily provide polyketide adducts with high regioselectivity. When exposed to electrolysis conditions, the title functional group forms a reactive radical cation and cleanly couples with a variety of activated olefins. Given their electron-rich nature, ketene N,O-acetals act as facile substrates in several rearrangement reactions; further, ketene N,O-acetals reserve the ability to act as either dienophiles or dienes in Diels–Alder reactions. Lastly, ketene N,O-acetals are seemingly more stable than their O,O-counterparts and more reactive than analogous N,N- or S,S-acetals; these factors, in combination, make ketene N,O-acetals advantageous substitutes for other ketene acetal homologues.

1 Introduction

2 Select Methods of Stabilization-Oriented Ketene N,O-Acetal Synthesis

3 Ketene N,O-Acetals in the Vinylogous Mukaiyama Aldol Reaction

4 Ketene N,O-Acetals in Anodic Coupling and Electrochemical Oxidation Reactions

5 Rearrangement and Diels–Alder Reactions of Ketene N,O-Acetals

6 Conclusions, Perspectives, and Directions

Key words

ketene acetals - push-pull alkenes - imide enolates - vinylogous Mukaiyama aldol reaction - Kobayashi reaction - electrolysis - rearrangement - Diels–Alder reactions

Full Text

References

References
1 McElvain SM. Chem. Rev. 1949; 45: 453
2 Zhang L, Dong J, Xu X, Liu Q. Chem. Rev. 2016; 116: 287

For general information, see the following, as well as the references cited therein:

3a Hasek RH, Meen RH, Martin JC. J. Org. Chem. 1965; 30: 1495
3b Hasek RH, Gott G, Martin JC. J. Org. Chem. 1964; 29: 2513

4 Quast H, Ach M, Balthasar J, Hergenrother T, Regnat D, Lehmann J, Banert K. Helv. Chim. Acta 2005; 88: 1589
5 Fukuda H, Oda M, Endo T. J. Polym. Sci. Part A: Polym. Chem. 1999; 37: 699
6 Beyerstedt F, McElvain SM. J. Am. Chem. Soc. 1936; 58: 529
7 For details regarding the versatility of ketene N,O-acetals, or ‘push-pull,’ ketene N,O-acetals, see: Huang F, Wu P, Wang L, Chen J, Sun C, Yu Z. J. Org. Chem. 2014; 79: 10553
8 Basu S, Gupta V, Nickel J, Schneider C. Org. Lett. 2014; 16: 274
9 For the contemporary use, and growing importance, of ketene N,O-acetals, see: Cornia A, Felluga F, Frenna V, Ghelfi F, Parsons AF, Pattarozzi M, Roncaglia F, Spinelli D. Tetrahedron 2012; 68: 5863
10 Barnes HM, Kundiger D, McElvain SM. J. Am. Chem. Soc. 1940; 62: 1281
11 Padwa A, Price AT, Zhi L. J. Org. Chem. 1996; 61: 2283
12 For sensitivity of ketene N,O-acetals to moisture and the importance of in situ use, see: Meyers AI, Nazarenko N. J. Am. Chem. Soc. 1972; 94: 3243

For details regarding the mechanism of ketene N,O-acetal hydrolysis:

13a Franz A, Eschler P.-Y, Tharin M, Stoeckli-Evans H, Neier R. Synthesis 1996; 1239
13b Kresge AJ, Leibovitch M. J. Am. Chem. Soc. 1992; 114: 3099
13c Hershfield R, Yeager MJ, Schmir GL. J. Org. Chem. 1975; 40: 2940

14 McElvain SM, Tate BE. J. Am. Chem. Soc. 1945; 67: 202
15 Fukuda H, Oda M. Macromolecules 1996; 29: 3043
16 Beccalli EM, Marchesini A. Tetrahedron 1997; 53: 10433

17a Huang Z.-T, Zhang P.-C. Synth. Commun. 1990; 20: 1399
17b Huang Z.-T, Zhang P.-C. Synth. Commun. 1989; 19: 2999

18 For information regarding the increased stability of ketene N,O-acetals, due to intramolecular hydrogen bonding, see: Huang Z.-T, Wang M.-X. Synth. Commun. 1991; 21: 1177

For fundamental, structural information regarding ‘push-pull’ alkenes, see:

19a Kleinpeter E. J. Serb. Chem. Soc. 2006; 71: 1
19b Kleinpeter E, Schulenburg A. Tetrahedron Lett. 2005; 46: 5995
19c Kleinpeter E, Klod S, Rudorf W.-D. J. Org. Chem. 2004; 69: 4317
19d Fabian WM. F, Dworczak R, Junek H, Pawar BN. J. Chem. Soc., Perkin Trans. 2 1995; 903
19e Sandstrom J. Top. Stereochem. 1983; 14: 83

20 Padwa A, Austin DJ, Precedo L, Zhi L. J. Org. Chem. 1993; 58: 1144
21 Brannock KC, Burpitt RD, Thweatt JG. J. Org. Chem. 1964; 29: 940
22 Hosomi A, Miyashiro Y, Yoshida R, Tominaga Y, Yanagi T, Hojo M. J. Org. Chem. 1990; 55: 5310
23 Cao L, Pittman CU. Jr. J. Polym. Sci. Part A: Polym. Chem. 1999; 37: 2823
24 For examples of ketene N,O-acetals reacting with carbonyl compounds in an aldol-fashion: Huang Z.-T, Zhang P.-C. Chem. Ber. 1989; 122: 2011
25 For general and mechanistic information, see: Myers AG, Widdowson KL, Kukkola PJ. J. Am. Chem. Soc. 1992; 114: 2765
26 Okada M, Kitagawa O, Hanano T, Taguchi T. Tetrahedron 1997; 53: 6825
27 For examples of the ketene N,O-acetal moiety being incorporated into heterocyclic structure, see: Huang Z.-N, Li Z.-M. Synth. Commun. 1995; 25: 3603
28 Franz A, Eschler P.-Y, Tharin M, Neier R. Tetrahedron 1996; 52: 11643
29 See the following, with an emphasis on the references cited therein: Boger DL, Kochanny MJ. J. Org. Chem. 1994; 59: 4950
30 Metz P, Mues C. Synlett 1990; 97
31 Brannock KC, Burpitt RD, Thweatt JG. J. Org. Chem. 1963; 28: 1697

Since 2000, ketene N,O-acetals have been utilized in several synthetic applications. These include: ring-opening reactions, radical cyclizations, coupling with isocyanates, aminomethylations, the synthesis of heterocycles, and nucleophilic arylation. For brevity, we have cited these here, but do not discuss the chemistry in detail. For further information, see:

32a Zhou A, Pittman CU. Jr. J. Comb. Chem. 2006; 8: 262
32b Zhou A, Njogu MN, Pittman CU. Jr. Tetrahedron 2006; 62: 4093
32c Zhou A, Cao L, Li H, Liu Z, Cho H, Henry WP, Pittman CU. Jr. Tetrahedron 2006; 62: 4188
32d Moumne R, Denise B, Guitot K, Rudler H, Lavielle S, Karoyan P. Eur. J. Org. Chem. 2007; 1912
32e Avula S, Koppireddi S, Komsani JR, Nanubolu JB, Yadla R. RSC Adv. 2013; 3: 20990
32f Nayak S, Prabagar B, Sahoo AK. Org. Biomol. Chem. 2016; 14: 803
32g Takeda N, Futaki E, Kobori Y, Ueda M, Miyata O. Angew. Chem. Int. Ed. 2017; 56: 16342
32h Huang F, Wu P, Yu Z. J. Org. Chem. 2020; 85: 4373

33 An in-depth investigation, regarding silyl ketene O,O-acetals and their reactivity, has been performed: Feist H, Langer P. Synthesis 2007; 327
34 Wang K.-M, Yan S.-J, Lin J. Eur. J. Org. Chem. 2014; 6: 1129
35 Huang Z.-T, Wang M.-X. Heterocycles 1994; 37: 1233
36 Rajappa S. Tetrahedron 1981; 37: 1453
37 Wang L, He W, Yu Z. Chem. Soc. Rev. 2013; 42: 599
38 Pan L, Bi X, Liu Q. Chem. Soc. Rev. 2013; 42: 1251
39 Pan L, Liu Q. Synlett 2011; 1073
40 Junjappa H, Ila H, Asokan CV. Tetrahedron 1990; 46: 5423
41 Kolb M. Synthesis 1990; 171
42 Dieter RK. Tetrahedron 1986; 42: 3029

For an essential discussion of heterocyclic aromaticity, and the inherent stability thereof, see:

43a Randic M, Trinajstic N, Knop JV, Jericevic Z. J. Am. Chem. Soc. 1985; 107: 849
43b Krygowski TM, Cyranski MK. Chem. Rev. 2001; 101: 1385 ; and references cited therein

44 Kim BT, Min YK, Park NK, Cho KY, Jeong IH. Heterocycles 1995; 41: 641 ; and references cited therein
45 Metwally MA, Abdel-Latif E. J. Sulfur Chem. 2004; 25: 359
46 Elgemeie GH, Elghandour AH, Abd Elaziz GW. Synth. Commun. 2003; 33: 1659
47 Chanu LG, Singh OM, Jang SH, Lee S.-G. Bull. Korean Chem. Soc. 2010; 31: 859
48 Narayanan K, Shanmugam M, Vasuki G, Kabilan S. J. Mol. Struct. 2014; 1056: 70

For examples of the application of cyclic ketene N,O-acetals to the synthesis of pharmaceutically-important heterocycles, see:

49a Yan SJ, Niu YF, Huang R, Lin J. Synlett 2009; 2821
49b Yan S, Huang C, Su C, Ni Y, Lin J. J. Comb. Chem. 2010; 12: 91

For potential routes of ketene N,O-acetal application in material science, see:

50a Williams DJ. Angew. Chem., Int. Ed. Engl. 1984; 23: 690
50b Kanis DR, Ratner MA, Marks TJ. Chem. Rev. 1994; 94: 195

51 Song Y, De Silva HI, Henry WP, Ye G, Chatterjee S, Pittman CU. Jr. Tetrahedron Lett. 2011; 52: 4507
52 Song Y, Henry WP, De Silva HI, Ye G, Pittman CU. Jr. Tetrahedron Lett. 2011; 52: 853
53 De Silva HI, Song Y, Henry WP, Pittman CU. Jr. Tetrahedron Lett. 2012; 53: 2965
54 Woodbury RP, Rathke MW. J. Org. Chem. 1978; 43: 881
55 For a seminal report, regarding silylation of enolates as a route to ketene acetals, see: Corey EJ, Gross AW. Tetrahedron Lett. 1984; 25: 495
56 Kim S, Lim CJ, Song C, Chung W.-J. J. Am. Chem. Soc. 2002; 124: 14306

For earlier reports that corroborate the stabilizing effects of the designated N-substituted groups, see:

57a Boivin J, Schiano A.-M, Zard SZ. Tetrahedron Lett. 1994; 35: 249
57b Boivin J, Fouquet E, Zard SZ. Tetrahedron Lett. 1991; 32: 4299

Support for this method can be found in more dated reports:

58a Jiang J, DeVita RJ, Doss GA, Goulet MT, Wyvratt MJ. J. Am. Chem. Soc. 1999; 121: 593
58b Nicolaou KC, Shi G.-C, Gunzner P, Gartner P, Yange Z. J. Am. Chem. Soc. 1997; 119: 5467

For information regarding Evans’ chiral auxiliary in asymmetric reactions, see:

59a Heravi MM, Zadsirjan V, Farajpour B. RSC Adv. 2016; 6: 30498
59b Nazari A, Heravi MM, Zadsirjan V. J. Organomet. Chem. 2021; 932: 121629

60 For a pilot study, with regards to this field of synthesis, see: Moeller KD, Tinao LV. J. Am. Chem. Soc. 1992; 114: 1033
61 Shirokawa S.-I, Kamiyama M, Nakamura T, Okada M, Nakazaki A, Hosokawa S, Kobayashi S. J. Am. Chem. Soc. 2004; 126: 13604
62 Denmark SE, Heemstra JR. Jr. J. Am. Chem. Soc. 2006; 128: 1038
63 Shinoyama M, Shirokawa S.-I, Nakazaki A, Kobayashi S. Org. Lett. 2009; 11: 1277
64 Nakamura T, Harachi M, Kano T, Mukaeda Y, Hosokawa S. Org. Lett. 2013; 15: 3170
65 Huang Y.-T, Moeller KD. Tetrahedron 2006; 62: 6536
66 Symkenberg G, Kalesse M. Org. Lett. 2012; 14: 1608
67 Cook AM, Wolf C. Angew. Chem. Int. Ed. 2016; 55: 2929
68 Smith DL, Goundry WF, Lam HW. Chem. Commun. 2012; 48: 1505
69 Naito H, Hata T, Urabe H. Tetrahedron Lett. 2008; 49: 2298

70a Heterocycles in Natural Product Synthesis . Majumdar KC, Chattopadhyay SK. Wiley-VCH; Weinheim: 2011
70b Jampilek J. Molecules 2019; 24: 3839
70c Cabrele C, Reiser O. J. Org. Chem. 2016; 81: 10109

71 Shapiro JD, Sonberg JC, Schafer BC, Williams CC, Ferris HR, Reinheimer EW, Van Wynsberghe AW, Kriley CE, Majireck MM. Molecules 2018; 23: 413
72 Paris TJ, Schwartz C, Willand-Charnley R. J. Org. Chem. 2021; 86: 2369
73 For a seminal review, regarding use of the vinylogous Mukaiyama aldol reaction (VMAR) prior to 2000, see: Casiraghi G, Zanardi F, Appendino G, Rassu G. Chem. Rev. 2000; 100: 1929

For additional reviews, regarding the VMAR, see (as well as the references cited therein):

74a Cordes MH. C, Kalesse M. Org. React. 2019; 98: 173-773
74b Soriente A, De RM, Villano R, Scettri A. Curr. Org. Chem. 2004; 8: 993
74c Denmark SE, Heemstra JR. Jr, Beutner GL. Angew. Chem. Int. Ed. 2005; 44: 4682

75 Mukaiyama T, Narasaka K, Banno K. Chem. Lett. 1973; 1011

For early, related works detailing the use of vinyloxyboranes, see:

76a Mukaiyama T, Inomata K, Masayoshi M. J. Am. Chem. Soc. 1973; 95: 967
76b Inomata K, Muraki M, Mukaiyama T. Bull. Chem. Soc. Jpn. 1973; 46: 1807

77 Matsuo J, Murakami M. Angew. Chem. Int. Ed. 2013; 52: 9109
78 Hosokawa S. Tetrahedron Lett. 2018; 59: 77
79 Bisai V. Synthesis 2012; 44: 1453

For select examples:

80a Sengupta A, Hosokawa S. Synlett 2019; 30: 709
80b Suzuki T, Fujimura M, Fujita K, Kobayashi S. Tetrahedron 2017; 73: 3652
80c Zhang Y.-H, Liu R, Liu B. Chem. Commun. 2017; 53: 5549
80d Kanoh N, Kawamata A, Itagaki T, Miyazaki Y, Yahata K, Kwon E, Iwabuchi Y. Org. Lett. 2014; 16: 5216
80e Ramesh P, Meshram HM. Tetrahedron 2012; 68: 9289
80f Wang L, Gong J, Deng L, Xiang Z, Chen Z, Wang Y, Chen J, Yang Z. Org. Lett. 2009; 11: 1809

For applications of the Kobayashi reaction to the synthesis of natural products, see the following reviews:

81a Cordes M, Kalesse M. Molecules 2019; 24: 3040
81b Kalesse M, Cordes M, Symkenberg G, Lu H.-H. Nat. Prod. Rep. 2014; 31: 563

82 For a review, written by the named author, regarding the use of TiCl₄, see: Mukaiyama T. Angew. Chem., Int. Ed. Engl. 1977; 16: 817

83a Tsukada H, Mukaeda Y, Hosokawa S. Org. Lett. 2013; 15: 678
83b Mukaeda Y, Kato T, Hosokawa S. Org. Lett. 2012; 14: 5298

For additional information, regarding application of Kobayashi technology to the synthesis of natural products, see:

84a Hosokawa S. Acc. Chem. Res. 2018; 51: 1301
84b Kalesse M. Top. Curr. Chem. 2005; 244: 43

For natural product synthesis, via electrolysis, see:

85a Mihelcic J, Moeller KD. J. Am. Chem. Soc. 2004; 126: 9106
85b Liu B, Duan S, Sutterer AC, Moeller KD. J. Am. Chem. Soc. 2002; 124: 10101

86 For heterocycle synthesis, via anodic coupling reactions, see: Sperry JB, Whitehead CR, Ghiviriga I, Walczak RM, Wright DL. J. Org. Chem. 2004; 69: 3726
87 For a review focused on anodic coupling reactions, in general, see: Moeller KD. Tetrahedron 2000; 56: 9527

For select examples of anodic coupling with enol ethers:

88a Chiba K, Miura T, Kim S, Kitano Y, Tada M. J. Am. Chem. Soc. 2001; 123: 11314
88b Schmittel M, Burghart A, Werner H, Laubender M, Sollner R. J. Org. Chem. 1999; 64: 3077
88c Ryter K, Livinghouse T. J. Am. Chem. Soc. 1998; 120: 2658
88d Hudson CM, Marzabadi MR, Moeller KD, New DG. J. Am. Chem. Soc. 1991; 113: 7372

For select examples of anodic coupling with dithioketene acetals:

89a Sun Y, Moeller KD. Tetrahedron Lett. 2002; 43: 7159
89b Sun Y, Liu B, Kao J, d’Avignon DA, Moeller KD. Org. Lett. 2001; 3: 1729
89c Reddy SH. K, Chiba K, Sun Y, Moeller KD. Tetrahedron 2001; 57: 5183

90 Huang Y.-T, Moeller KD. Org. Lett. 2004; 6: 4199
91 Wu H, Moeller KD. Org. Lett. 2007; 9: 4599
92 Zeng C.-C, Liu F.-J, Ping D.-W, Hu L.-M, Cai Y.-L, Zhong R.-G. J. Org. Chem. 2009; 74: 6386
93 Bai Y.-X, Ping D.-W, Little RD, Tian H.-Y, Hu L.-M, Zeng C.-C. Tetrahedron 2011; 67: 9334
94 Neuschütz K, Simone J.-M, Thyrann T, Neier R. Helv. Chim. Acta 2000; 83: 2712
95 Suzuki T, Inui M, Hosokawa S, Kobayashi S. Tetrahedron Lett. 2003; 44: 3713
96 Qu H, Gu X, Min BJ, Liu Z, Hruby VJ. Org. Lett. 2006; 8: 4215
97 Breuning M, Hauser T. Tetrahedron 2007; 63: 934
98 Tang F, Yao Y, Xu Y.-J, Lu C.-D. Angew. Chem. Int. Ed. 2018; 57: 15583
99 Konopelski JP, Boehler MA. J. Am. Chem. Soc. 1989; 111: 4515
100 Müller J, Troschütz R. Synthesis 2006; 1513