Oxidation of allylic and benzylic alcohols to aldehydes and carboxylic acids

Abstract

An oxidation of allylic and benzylic alcohols to the corresponding carboxylic acids is effected by merging a Cu-catalyzed oxidation using O₂ as a terminal oxidant with a subsequent chlorite oxidation (Lindgren oxidation). The protocol was optimized to obtain pure products without chromatography or crystallization. Interception at the aldehyde stage allowed for Z/E-isomerization, thus rendering the oxidation stereoconvergent with respect to the configuration of the starting material.

---

The direct oxidation of primary alcohols to their corresponding carboxylic acids is an important synthetic transformation that consists of two successive steps.¹ While the first step (alcohol to aldehyde) is usually performed with an electrophilic oxidant, the second oxidation (aldehyde to carboxylic acid) often involves a nucleophilic attack of the oxidant. Alternatively, it is possible to intercept the aldehyde–hydrate equilibrium with an electrophilic oxidant (Scheme 1). The latter strategy requires a significant population of the hydrate,² which is not very favorable in the case of aromatic aldehydes.³

Scheme 1 Oxidation pathways of alcohols and aldehydes to carboxylic acids.

Alcohol-to-carboxylic-acid oxidations can be conducted either in a one-pot fashion or as a two-step procedure with isolation of the intermediate aldehyde. Classical one-pot methods involve chromium-,⁴ tungsten-⁵ or ruthenium-based⁶ oxidants as well as hypervalent iodine derivatives such as IBX.⁷ The Zhao-modification⁸ of Anelli's oxidation⁹ (TEMPO, NaClO₂) constitutes another alternative but also has some drawbacks and, like the other above mentioned oxidants, may give rise to unwanted side reactions.

An elegant solution to these problems has been provided by using oxoammonium salts in combination with NaClO₂.¹⁰ For sensitive substrates however, a two-step protocol is often preferred over the one-pot process using a mild oxidant (e.g. Dess–Martin periodinane¹¹) for the initial oxidation to the aldehyde followed by Lindgren oxidation¹² (NaClO₂ as the oxidant) to give the desired carboxylic acid.

We recently investigated¹³ the stereoconvergent conversion of E- and Z-allylic alcohols into E-α,β-unsaturated aldehydes following in the footsteps of Semmelhack,¹⁴ Sheldon,¹⁵ Markó,¹⁶ Koskinen,¹⁷ and Stahl¹⁸ (Scheme 2). Our studies resulted in a protocol using 1 mol% Cu^IOTf/TEMPO/diMeObpy and DMAP (2 mol%) in acetonitrile as the solvent with oxygen as stoichiometric oxidant.

Scheme 2 Development of Cu-catalyzed aerobic oxidation.

DMAP was shown to play an active role in both the oxidation reaction and the isomerization steps.¹⁹ Herein, we report a two-step one-pot conversion of E- and Z-allylic alcohols into E-α,β-unsaturated carboxylic acids by joining a further refined Cu/TEMPO-catalyzed aerobic oxidation protocol^31,32 with Lindgren's oxidation.

The goal in the first oxidation step (alcohol to aldehyde) was to lower the catalyst loading as much as possible in order to minimize interference with the subsequent steps. Our starting point was built upon important findings from Sheldon, Koskinen and Stahl. Sheldon found the accelerating effect of 2,2′-bipyridine (bpy) ligands while Koskinen's careful kinetic studies¹⁷ established optimal ratios within the catalyst system. Recently, Stahl et al. demonstrated the importance of Cu^I salts¹⁸ supported by mechanistic investigations. As a key result in their subsequent mechanistic studies,²⁰ aliphatic primary²¹ and secondary alcohols²² showed a clearly different behavior from allylic and benzylic primary alcohols.³³

With our substrates limited to allylic and benzylic alcohols, we considered it necessary to re-evaluate Cu^I salts together with symmetrically (1) and newly synthesized²³ unsymmetrically substituted bpy ligands (2–3). Using 4a as test substrate, we found that 0.5 mol% CuI or slightly more reactive CuBr and 1 mol% DMAP resulted in a quantitative conversion of the substrate within 3 h, whereas reactions using Cu(OTf) and CuCl were not complete within 5 h.

In order to compare the efficacies of different bpy derivatives, we further lowered the catalyst loading to 0.4 mol% CuBr·ligand·TEMPO and 0.8 mol% DMAP. The reaction using the parent 2,2′-bipyridine stopped at 70% conversion after 6 h. Ligand 1 afforded 90% conversion whereas the unsymmetrically substituted bipyridines 2 and 3 led to a quantitative conversion, with 3 being significantly faster than 2. Despite these encouraging results, we selected 0.75 mol% CuBr·bpy·TEMPO and 1.5 mol% DMAP in MeCN (0.75 M) as our standard protocol for practical reasons, since we consider these reagents to be inexpensive and in stock in most organic laboratories.

As shown in Table 1, the oxidation of alcohols relevant to our synthetic endeavoura proceeded smoothly with TBS (4a), Ac (4b) and Bn (4c) protecting groups. The difference in the rate of oxidation is negligible, while the rate of the Z/E-isomerization is strongly dependent on the substitution of the Michael acceptor aldehyde. For substrates 4d–4f, the catalyst loading was increased to 1 mol% in order to ensure complete oxidation. In order to accelerate the Z/E-isomerization (entries 4, 5 and 7) 9-azajulolidine,²⁴ a more nucleophilic analogue of 4-DMAP was used. The low yield of volatile aldehyde 5e reflects the difficulties associated with its distillative purification. The oxidation of furfuryl alcohol 4h and the benzyl alcohols 4i–j afforded the corresponding aldehydes in moderate to excellent yields. With this protocol in hand, we next turned our attention to the development of a one-pot oxidation of the alcohols 4a–j to the corresponding carboxylic acids. The Lindgren oxidation of aldehydes to the corresponding carboxylic acids with sodium chlorite is a straightforward reaction. However, the formation of the stronger oxidant hypochlorite as the by-product is often a source of side-reactions. As a result, a variety of hypochlorite scavengers²⁵ such as 2-methyl-2-butene^26,27 have been in use. In order to avoid by-products that are soluble in organic solvents and allow for the isolation of the clean carboxylic acids by extraction, we selected H₂O₂ as a scavenger that was previously used by Dalcanale and Montanari.²⁸ Since oxidation of 4a with NaClO₂/H₂O₂ has been carried out in acetonitrile as the solvent by Sorensen et al. in their hirsutellone studies,²⁹ we were confident of combining both subsequent oxidation steps in a one-pot procedure.

Table 1 Oxidation of alcohols to aldehydes

Entry	Alcohol	Aldehyde	t [h]	[%]^a
a Isolated yield. b 1 mol% catalyst loading. c 9-Azajulolidine was used instead of DMAP.
1			2.5	99
2			1.75	92
3			4	98
4^b^,^c			25	89
5^b^,^c			18	63
6^b			17	97
7^c			16.5	98
8			6	55
9			1	84
10			1	96

---

As shown in Table 2, after formation of the E-α,β-unsaturated aldehydes, a Lindgren oxidation was conducted without prior isolation of the aldehydes. The corresponding carboxylic acids were obtained in high purity and good to excellent yields without further chromatographic purification.³⁰ Furfuryl alcohol was the only problematic substrate in both oxidations. Skipping the isolation of the intermediate volatile aldehyde 5e resulted in a clean conversion of 4e into carboxylic acid 6e and a higher yield (compared to 5e).

Table 2 Oxidation of alcohols to carboxylic acids

Entry	Alcohol	Carboxylic acid	t 1 [h]	t 2 [h]	[%]^a
a Isolated yield. b 1 mol% catalyst loading. c 9-Azajulolidine was used instead of DMAP.
1			3	6.25	93
2			3	6.75	86
3			5	6	97
4^b^,^c			15	19	94
5^b^,^c			16	12	82
6^b			15	12	95
7^c			13	9	95
8			5	8.5	53
9			1	1.25	95
10			1	9	96

---

In conclusion, we have developed an inexpensive system for the aerobic oxidation of allylic and benzylic alcohols to the corresponding aldehydes and carboxylic acids. For the first time, submol% quantities of a Cu^I catalyst were sufficient for converting alcohols into the corresponding aldehydes. The subsequent oxidation to the corresponding carboxylic acids was performed in the same reaction vessel, thereby avoiding isolation of the labile aldehydes. The carboxylic acids were isolated by extraction with sufficient purity without the need for further chromatographic purification thus rendering this protocol both cost and time efficient.

References

1. J.-E. Bäckvall, Modern oxidation methods, Wiley-VCH, Weinheim, Germany, 2nd edn, 2010.
2. A.-K. C. Schmidt and C. B. W. Stark, Org. Lett., 2011, 13, 4164.
3. J. C. Qiu, P. P. Pradhan, N. B. Blanck, J. M. Bobbitt and W. F. Bailey, Org. Lett., 2012, 14, 350.
4. K. Bowden, I. M. Heilbron, E. R. H. Jones and B. C. L. Weedon, J. Chem. Soc., 1946, 39.
5. R. Noyori, M. Aoki and K. Sato, Chem. Commun., 2003, 1977.
6. M. Schröder and W. P. Griffith, J. Chem. Soc., Chem. Commun., 1979, 58.
7. A. Schulze and A. Giannis, Synthesis, 2006, 257.
8. M. Zhao, J. Li, E. Mano, Z. Song, D. M. Tschaen, E. J. J. Grabowski and P. J. Reider, J. Org. Chem., 1999, 64, 2564.
9. P. L. Anelli, C. Biffi, F. Montanari and S. Quici, J. Org. Chem., 1987, 52, 2559.
10. M. Shibuya, T. Sato, M. Tomizawa and Y. Iwabuchi, Chem. Commun., 2009, 1739.
11. D. B. Dess and J. C. Martin, J. Org. Chem., 1983, 48, 4155.
12. B. O. Lindgren and T. Nilsson, Acta Chem. Scand., 1973, 27, 888.
13. D. Könning, W. Hiller and M. Christmann, Org. Lett., 2012, 14, 5258.
14. M. F. Semmelhack, C. R. Schmid, D. A. Cortes and C. S. Chou, J. Am. Chem. Soc., 1984, 106, 3374.
15. R. A. Sheldon, I. W. C. E. Arends, G.-J. ten Brink and A. Dijksman, Acc. Chem. Res., 2002, 35, 774.
16. I. E. Markó, A. Gautier, R. Dumeunier, K. Doda, F. Philippart, S. M. Brown and C. J. Urch, Angew. Chem., Int. Ed., 2004, 43, 1588.
17. E. T. T. Kumpulainen and A. M. P. Koskinen, Chem. – Eur. J., 2009, 15, 10901.
18. J. M. Hoover and S. S. Stahl, J. Am. Chem. Soc., 2011, 133, 16901.
19. G. E. Keck, E. P. Boden and S. A. Mabury, J. Org. Chem., 1985, 50, 709.
20. J. M. Hoover, B. L. Ryland and S. S. Stahl, J. Am. Chem. Soc., 2013, 135, 2357.
21. J. E. Steves and S. S. Stahl, J. Am. Chem. Soc., 2013, 135, 15742.
22. M. B. Lauber and S. S. Stahl, ACS Catal., 2013, 2612.
23. S. Duric and C. C. Tzschucke, Org. Lett., 2011, 13, 2310.
24. I. Held, S. Xu and H. Zipse, Synthesis, 2007, 1185.
25. A. Raach and O. Reiser, J. Prakt. Chem., 2000, 342, 605.
26. G. A. Kraus and M. J. Taschner, J. Org. Chem., 1980, 45, 1175.
27. G. A. Kraus and B. Roth, J. Org. Chem., 1980, 45, 4825.
28. E. Dalcanale and F. Montanari, J. Org. Chem., 1986, 51, 567.
29. S. D. Tilley, K. P. Reber and E. J. Sorensen, Org. Lett., 2009, 11, 701.
30. The NMR spectra of the carboxylic acids shown in the ESI† were recorded on the crude material obtained after extractive workup.
31. For a review on aerobic oxidations with stable radicals, see: Q. Cao, L. M. Dornan, L. Rogan, N. L. Hughes and M. J. Muldoon, Chem. Commun., 2014, 50 10.1039/C3CC47081D.
32. For a review on aerobic Cu-catalyzed reactions, see: S. E. Allen, R. R. Walvoord, R. Padilla-Salinas and M. C. Kozlowski, Chem. Rev., 2013, 113, 6234.
33. Recently, the substrate scope was further extended to amino alcohols: Y. Sasano, S. Nagasawa, M. Yamazaki, M. Shibuya, J. Park and Y. Iwabuchi, Angew. Chem., Int. Ed., 2014, 53, 3236.

---

Footnote

† Electronic supplementary information (ESI) available: Experimental details and spectroscopic data for all compounds. See DOI: 10.1039/c4cc01305k

---