tert-Butoxide-Mediated Protodeformylative Decarbonylation of α-Quaternary Homobenzaldehydes

Abstract

tert-Butoxide mediates the Haller–Bauer-type (protodeformylative) decarbonylation of readily accessed α-quaternary homobenzaldehydes and related compounds at room temperature, generating cumene products. Both geminal dialkyl and geminal diaryl substituents are tolerated. gem-Dimethyls are sufficient for decarbonylation of polycyclic arenyl substrates whereas monocyclic aromatic homobenzaldehydes require cyclic gem-dialkyls or gem-diaryls for significant decarbonylation.

 

MissingLinkText

Key words

decarbonylation - C–C bond cleavage - protodeformylation - Haller–Bauer reaction - tert-butoxide - benzylic anion - cumenes

Scheme 1 Comparison of Haller–Bauer-type aldehyde decarbonyl­ation methods

The decarbonylation of aldehydes is an important C–C bond-cleaving reaction in synthesis and in nature.[1] [2] Chemosynthetic decarbonylations mediated by stoichiometric rhodium complexes were first developed by Tsuji and Wilkinson[3] and are notable for their application in natural products total synthesis;[4] flow-type and catalytic variants have been developed to lower the cost.[5] Haller and Bauer popularized the base-mediated debenzoylation of aromatic ketones in the early 1900s;[6] a room-temperature Haller–Bauer-type tert-butoxide-mediated protodebenzoylation was used as the third step to achieve formal protodeformylation of non-enolizable aldehydes (Scheme [1]A).[7] Recently, Madsen and co-workers studied the mechanism of Haller–Bauer-type decarbonylations of enolizable aldehydes (Scheme [1]B) as well as non-enolizable aldehyde substrates like 2,6-dichlorobenzaldehyde (not shown).[8] Similar conditions are known to be capable of deformylating certain non-enolizable aldehydes like triphenylacetaldehyde[9] despite benzaldehydes being especially sensitive to hydroxide-mediated Cannizzaro-type disproportionation into the alcohol and carboxylic acid.[10] Other methods for formal protodeformylation of aldehydes have also been described.[11] [12] [13] Of the single-pot approaches (specifically Wilkinson and Haller–Bauer-type), a mild and general decarbonylation of α-quaternary aldehydes has not been described. Herein, we show that a wide variety of readily accessed α-quaternary homobenzaldehydes are deformylated at ambient temperature using tert-butoxide in THF to afford isopropyl arene (cumene) derivatives (Scheme [1]C).[14] Mechanistically, this presumably occurs via stabilized anion B generated from tert-butoxide adduct A.[15]

The impetus for developing this method stemmed from our interest in alkene functionalization reactions of α-quaternary homobenzylstyrenes and related compounds,[16] whereby we occasionally observed competing decarbonylation of α-quaternary homobenzaldehydes during Wittig olefination if excess tert-butoxide was present. We sought to optimize this reaction using the homonaphthaldehyde substrate shown in Table [1].[17] Excitingly, the use of 1.6 equivalents of KOt-Bu afforded complete substrate conversion and good yield at ambient temperature upon aqueous workup (entry 1). Evaluation of solvent effects showed that DMF was also well tolerated (entry 2) whereas HOt-Bu did not allow appreciable reaction (not shown).[18] The reaction must be performed air-free (entry 3), and the yield decreased somewhat when molecular sieves were employed (entry 4). Adding TEMPO inhibited substrate conversion somewhat (entry 5). NaOt-Bu was similarly effective as KOt-Bu (entry 6), whereas the use of lithium diisopropyl amide (LDA) resulted in complex decomposition (entry 7). Potassium hydroxide afforded no reaction in THF, with or without HOt-Bu present as additive (entries 8 and 9, respectively). Taken together, none of these data refute the canonical mechanism shown in Scheme [1]C.[19] It should be noted that product formation can take place prior to workup via quench by adventitious water, but excess water in the reaction will lead to competing detrimental Cannizzaro disproportionation.

Table 1 Optimization of Aldehyde Decarbonylation^a

Entry	Baseb	Additive	Conv. (%)	Yield (%)
1	KOt-Bu	none	>95	89
2c	KOt-Bu	none	>95	74
3d	KOt-Bu	air	>95	17
4e	KOt-Bu	4 Å MS	>95	70
5	KOt-Bu	TEMPO	78	62
6	NaOt-Bu	none	>95	87
7	LDA	none	>95	<5
8f	KOH	HOt-Bu	<5	n.d.
9	KOH	none	<5	n.d.

^a Reactions were conducted on 0.1 mmol scale in solvent (1.1 mL) under an atmosphere of N₂ unless otherwise noted. Conversions and yields were determined by ¹H NMR analysis using 1,3,5-trimethoxybenzene as an internal standard (n.d. = not detected).

^b Formulations of bases unless otherwise noted: KOt-Bu = 1.6 M solution in THF; KOH = solid; LDA = 2.0 M solution in THF/n-heptane/ethylbenzene; NaOt-Bu = 2.0 M in THF.

^c Solid KOt-Bu and DMF as solvent.

^d Reaction was conducted open to air.

^e 100% w/w of molecular sieves.

^f Base and HOt-Bu (1.6 equiv) sonicated for 5 minutes.

In terms of breadth of scope, phenyl analogues (1a–c) afford lower yield than the optimized naphthyl substrate (Scheme [2]A). In particular, cumene (2a) was only produced in 11% NMR yield; the yield improved significantly by substitution with a para-phenyl group, thereby accessing 2d in 67% yield. In revision, the para-trifluoromethyl analogue was prepared and protodeformylated to afford a modest 20% yield of the corresponding cumene by ¹H NMR analysis.[20] Strained cyclic gem-dialkyl-containing substrates like α-cyclopropyl (1e) and α-cyclobutyl (1f) afford just 9% and 24% yield of their respective methine products, whereas cyclopentyl (1g) and cyclohexyl (1h) substrates were decarbonylated in useful yield (44% and 76%, respectively). Other monoarenyl substrates evaluated include tetralin 1i and triphenylacetaldehyde 1j, both of which afforded decarbonylation products in good yield (61% and 79%, respectively). tert-Butanol was a common byproduct after workup, potentially arising from hydrolysis of the implied tert-butylformate byproduct of C–C bond cleavage of intermediate A in Scheme [1]C.

Scheme 2 Evaluation of the generality of the protodeformylation of α-quaternary homobenzaldehydes. ^a Reactions were conducted with 0.2 mmol of aldehyde unless otherwise noted, and yields refer to isolated yields unless otherwise noted. ^b Yield was determined by ¹H NMR analysis using 1,3,5-trimethoxybenzene as an internal standard. ^c Product is volatile under high vacuum. ^d Reaction was executed on 1.0 mmol scale of 3b.

Fused bicyclic and tricyclic substrates afforded generally excellent decarbonylation yields (Scheme [2]B and C), presumably because the extended conjugation in these compounds affords a relatively stabilized benzylic anion. Among bicyclic arenes (Scheme [2]B), cyclopentane-containing product 4a was accessed with double the yield of the analogous monocyclic arene 2g. A 1.0 mmol scale reaction of 1-naphthyl substrate 3b afforded the highest decarbonylation yield that we observed in the study (93% yield of 4b). 2-Naphthyl and 4-benzofuranyl analogues (4c and 4d) were also accessed in good yield. In contrast, 3-benzofuranyl analogue 4e was not prepared efficiently and a significant amount of dearomatized product 7 was formed (Scheme [3]). A number of benzyl-protected 4-substituted indole analogues (3f–j) were also decarbonylated efficiently, as were a number of benzothiophenyl substrates (3k–n), with the exception of the 3-substituted analogue 3o, which may be prone to dearomatization as observed for 3e.

Scheme 3Dearomative protodeformylation predominates in the case of benzofuran 3e.

Finally, we evaluated four fused tricyclic arenes as shown in Scheme [2]C, including carbazoles (5a and 5b), a dibenzothiophene (5c), and a dibenzofuran (5d), all of which afforded the corresponding decarbonylated products (6a–d) in good yield.

In conclusion, we have developed a tert-butoxide-mediated protodeformylative decarbonylation of α-quaternary homobenzaldehydes.[21] [22] The method enables efficient access to a variety of cumenes. Efforts to expand the scope and better understand the mechanism are ongoing in our lab.

 

MissingLinkText

Conflict of Interest

The authors declare no conflict of interest.

Acknowledgment

We thank a reviewer of a prior version of this manuscript for valuable insight and feedback. A version of this manuscript was deposited on ChemRxiv prior to review.[23]

• References and Notes


For biochemical studies, see:
• 1a Sen K, Hackett JC. J. Phys. Chem. B 2009; 113: 8170
• 1b Sen K, Hackett JC. J. Am. Chem. Soc. 2010; 132: 10293
• 1c Patra T, Manna S, Maiti D. Angew. Chem. Int. Ed. 2011; 50: 12140

For decarbonylations towards biofuel conversion, see:
• 2a Monrad RN, Madsen R. J. Org. Chem. 2007; 72: 9782
• 2b Geilen FM. A, vom Stein T, Engendahl B, Winterle S, Liauw MA, Klankermayer J, Leitner W. Angew. Chem. Int. Ed. 2011; 50: 6831
• 2c Huang Y.-B, Yang Z, Chen M.-Y, Dai J.-J, Guo Q.-X, Fu Y. ChemSusChem 2013; 6: 1348
• 2d Jastrzebski R, Constant S, Lancefield CS, Westwood NJ, Weckhuysen BM, Bruijnincx PC. A. ChemSusChem 2016; 9: 2074

For the original Tsuji–Wilkinson reports, see:
• 3a Tsuji J, Ohno K. Tetrahedron Lett. 1965; 3969
• 3b Osborn JA, Jardine FH, Wilkinson G. J. Chem. Soc. A 1966; 1711
• 3c Ohno K, Tsuji J. J. Am. Chem. Soc. 1968; 90: 99

For reviews, see:
• 3d Tsuji J, Ohno K. Synthesis 1969; 157
• 3e Jardine FH. Prog. Inorg. Chem. 1981; 28: 63

Selected examples:
• 4a Hu P, Snyder SA. J. Am. Chem. Soc. 2017; 139: 5007
• 4b Ziegler FE, Belema M. J. Org. Chem. 1997; 62: 1083
• 4c Kato T, Hoshikawa M, Yaguchi Y, Izumi K, Uotsu Y, Sakai K. Tetrahedron 2002; 58: 9213
• 4d Tanaka M, Ohshima T, Mitsuhashi H, Maruno M, Wakamatsu T. Tetrahedron 1995; 51: 11693
• 4e Hansson T, Wickberg B. J. Org. Chem. 1992; 57: 5370

For a detailed overview, see:
• 5a Richter SC, Oestreich M. Chem. Eur. J. 2019; 25: 8508

Selected examples:
• 5b Min T.-S, Mei Y.-K, Chen B.-Z, He L.-B, Song T.-T, Ji D.-W, Hu Y.-C, Wan B, Chen Q.-A. J. Am. Chem. Soc. 2022; 144: 11081
• 5c Gutmann B, Elsner P, Glasnov T, Roberge DM, Kappe CO. Angew. Chem. Int. Ed. 2014; 53: 11557
• 5d Kreis M, Palmelund A, Bunch L, Madsen R. Adv. Synth. Catal. 2006; 348: 2148

For the earliest reports of this debenzoylation, see:
• 6a Semmler FW. Ber. Dtsch. Chem. Ges. 1906; 39: 2577
• 6b Haller A, Bauer E. C. R. Hebd. Seances Acad. Sci. 1908; 147: 824

For reviews of the Haller–Bauer reaction, see:
• 6c Mehta G, Venkateswaran RV. Tetrahedron 2000; 56: 1399
• 6d Gilday JP, Paquette LA. Org. Prep. Proced. Int. 1990; 22: 167

For works by Paquette and co-workers, see:
• 7a Paquette LA, Gilday JP, Ra CS. J. Am. Chem. Soc. 1987; 109: 6858
• 7b Paquette LA, Gilday JP. J. Org. Chem. 1988; 53: 4972
• 7c Paquette LA, Ra CS. J. Org. Chem. 1988; 53: 4978
• 7d Gilday JP, Gallucci JC, Paquette LA. J. Org. Chem. 1989; 54: 1399
• 7e Paquette LA, Maynard GD, Ra CS, Hoppe M. J. Org. Chem. 1989; 54: 1408
• 7f Paquette LA, Gilday JP, Maynard GD. J. Org. Chem. 1989; 54: 5044

For other examples and applications, see:
• 7g Hamlin KE, Weston AW. Org. React. 1957; 9: 1
• 7h Walborsky HM, Allen LE, Traenckner HJ, Powers EJ. J. Org. Chem. 1971; 36: 2937
• 7i Kaiser EM, Warner CD. Synthesis 1975; 395
• 7j Calas M, Calas B, Giral L. Bull. Soc. Chim. Fr. 1976; 857
• 7k Mehta G, Praveen M. J. Org. Chem. 1995; 60: 279
• 7l Mehta G, Reddy KS, Kunwar AC. Tetrahedron Lett. 1996; 37: 2289
• 7m Mittra A, Bhowmik DR, Venkateswaran RV. J. Org. Chem. 1998; 63: 9555
• 8 Mazziotta A, Makarov IS, Fristrup P, Madsen R. J. Org. Chem. 2017; 82: 5890

For an early report of triphenylacetaldehyde deformylation using hydroxide, see:
• 9a Daniloff S, Venus-Danilova E. Ber. Dtsch. Chem. Ges. 1926; 59: 377
• 9b For a review, see: Artamkina GA, Beletskaya IP. Russ. Chem. Rev. 1987; 56: 983

For the original Cannizzaro disproportionation reaction, see:
• 10a Cannizzaro S. Justus Liebigs Ann. Chem. 1853; 88: 129
• 10b For a review, see: Geissman TA. Org. React. 1944; 2: 94

For a relevant example, see:
• 10c DiBiase SA, Gokel GW. J. Org. Chem. 1978; 43: 447
• 11 For a report of CO-releasing decarbonylation of tertiary aldehydes in water, see: Rodrigues CA. B, Norton de Matos M, Guerreiro BM. H, Goncalves AM. L, Romao CC, Afonso CA. M. Tetrahedron Lett. 2011; 52: 2803

For examples of peroxide-mediated radical decarbonylations of aldehydes, see:
• 12a Doering W. vE, Farber M, Sprecher M, Wiberg KB. J. Am. Chem. Soc. 1952; 74: 3000
• 12b Winstein S, Seubold FH. J. Am. Chem. Soc. 1947; 69: 2916

For a metal-free formal (two-pot) decarbonylation of tertiary aldehydes, see:
• 13a Ref. 5a.
• 13b For a one-pot Pd-catalyzed tandem arylation/cyclization/migration between tertiary benzaldehydes and aryliodides, see: Gou B.-B, Yang H, Sun H.-R, Chen J, Wu J, Zhou L. Org. Lett. 2019; 21: 80
• 13c For an example of a method involving the synthesis of tertiary benzaldehydes as synthetic intermediates, see: Debien L, Zard SZ. J. Am. Chem. Soc. 2013; 135: 3808
• 14 Similar conditions were employed by Giral and co-workers for the debenzoylation of (-quaternary benzophenones. See ref. 7j. For a leading report on cumene synthesis via iron-catalyzed isopropylation of aryl chlorides, see: Sanderson JN, Dominey AP, Percy JM. Adv. Synth. Catal. 2017; 359: 1007
• 15 Intermediate A is analogous to a ketone-derived intermediate invoked by Gilday and Paquette (ref. 7b). For a relevant study on benzylic anion formation via C–C bond cleavage analogous to A→B, see: Cram DJ, Langemann A, Lwowski W, Kopecky KR. J. Am. Chem. Soc. 1959; 81: 5760
• 16a Cai X, Keshavarz A, Omaque JD, Stokes BJ. Org. Lett. 2017; 19: 2626
• 16b Cai X, Tohti A, Ramirez C, Harb H, Fettinger JC, Hratchian HP, Stokes BJ. Org. Lett. 2019; 21: 1574
• 16c Tohti A, Lerda V, Stokes BJ. Synlett 2022; in press; DOI 10.1055/a-1894-8726
• 17 This substrate and many others herein were prepared in one step from the corresponding aryl bromide using a variant of the Pd-catalyzed zinc-enolate cross-coupling developed by Hartwig and co-workers, see: Hama T, Liu X, Culkin DA, Hartwig JF. J. Am. Chem. Soc. 2003; 125: 11176

A similar disparity between aprotic (ethereal) and protic (HOt-Bu) solvents has been observed in tert-butoxide-mediated fragmentations of ketones, see:
• 18a Gassman PG, Lumb JT, Zalar FV. J. Am. Chem. Soc. 1967; 89: 946
• 18b Cristol SJ, Freeman PK. J. Am. Chem. Soc. 1961; 83: 4427
• 19 As further mechanistic support, two deuterium labeling experiments (one employing deuterated aldehyde as substrate, the other employing THF-d ₈ as solvent) both afforded no detectable deuterium incorporation in the product.
• 20 See the Supporting Information for details.
• 21 Protodeformylation; General Procedure: An oven-dried 25-mL round-bottom flask was charged with a PTFE-coated magnetic stir bar, fitted with a rubber septum, and purged with nitrogen for 2 min. Then, under ambient pressure of N₂, KOt-Bu solution (1.6 M in THF, 0.3 mmol, 1.6 equiv, 0.2 mL) was added to the flask, and further diluted with anhydrous THF (1.0 mL). To the flask, an anhydrous THF solution of aldehyde (0.2 M, 1.0 equiv, 1.0 mL) was added dropwise at room temperature. The mixture was then allowed to stir for 5 h under ambient pressure of N₂. The reaction was diluted with EtOAc (2 mL), saturated aqueous NH₄Cl (5 mL) was added, and the mixture was allowed to stir until the solution became decolored. The aqueous layer was then extracted with EtOAc (3 × 5 mL) and the combined organic layers were washed with brine, dried over sodium sulfate, and concentrated in vacuo to afford the crude decarbonylated product, which was then purified by silica gel chromatography.
• 22 Characterization data of representative product 4b: Yield (1.0 mmol scale): 158 mg (93%); colorless oil. ¹H NMR (500 MHz, CDCl₃): δ = 8.16 (dd, J = 8.5, 1.2 Hz, 1 H), 7.90–7.84 (m, 1 H), 7.73 (dt, J = 7.8, 1.1 Hz, 1 H), 7.62–7.38 (m, 4 H), 3.79 (sept, J = 6.9 Hz, 1 H), 1.44 (d, J = 6.9 Hz, 6 H). ¹³C NMR (125 MHz, CDCl₃): δ = 144.6 (C), 133.9 (C), 131.3 (C), 128.9 (CH), 126.3 (CH), 125.7 (CH), 125.6 (CH), 125.2 (CH), 123.3 (CH), 121.7 (CH), 28.5 (C), 23.6 (CH₃)..
• 23 Cai X.; Stokes B. J. ChemRxiv; 2021, preprint; DOI: 10.26434/chemrxiv-2021-q22x8

Publication History

Received: 05 September 2023

Accepted after revision: 04 December 2023

Accepted Manuscript online:
18 December 2023

Article published online:
19 January 2024