Hypervalent iodine mediated direct one pot transformation of aldehydes to ketones

Abstract

An environmentally benign, step economical synthesis of ketones directly from aldehydes has been developed using hypervalent iodine as an oxidant. The key features of this protocol are its mild conditions without the use of any heavy and toxic metals for the synthesis of a wide range of ketones.

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The high abundance of ketone motifs present in many biologically active natural products/heterocycles (Fig. 1) and the strategic usefulness of ketones¹ for further functional group manipulation in organic synthesis is reflected in the myriad strategies for its construction. The majority of strategies involve either the alkylation of aldehyde followed by subsequent oxidation^1e–i or by alkylation of dithianes² followed by unmasking the carbonyl functionality (umpolung method). But both these strategies are less direct and require two or more steps. As conversion of aldehydes to ketones is a very common chemical transformation in synthetic labs and chemical industries, use of conventional toxic transition metal (Cr, Mn & V) based oxidants causes environmental damage. Keeping in view of the environment³ a direct conversion of aldehydes to ketones in single step using less expensive, non-toxic reagent is more attractive compared to the conventional metal-based two-step procedures. Transition metal catalysed aldehydic carbon–hydrogen (C–H) bond activation/functionalization have received much attention in recent years.⁴

Fig. 1 Therapeutic and biologically active ketone motifs.

The limited synthetic protocols available for direct conversion of aldehydes to ketones include the use of organovanadium reagents,^5a magnesium-mediated addition/Oppenauer oxidation,^5b,c boron-Wittig process,^5d N-tert-butylphenylsulfinimidoyl chloride,^5e and the transition metal-catalyzed coupling of aldehydes with the coupling partners such as aryl halides,^6a aryl boronic acid^6b and esters.⁷ Even though existing protocols provide a wider choice for direct conversion of aldehydes to ketones, limitations such as use of expensive and toxic metal catalyst/reagent, elaborate reaction procedures, longer reaction times and limited substrate scope still needs to be addressed. Therefore, there is a need to develop a practical, economical and environmentally benign procedure for the direct oxidative alkylation of aldehydes with wide substrate scope.

In the recent decade, hypervalent iodine reagents have emerged as a useful alternative for wide array of organic transformations⁸ due to its easy handling, high stability, low toxicity, and easy availability. It is widely considered as a valuable oxidant for conducting environmentally benign reactions. Recent reports on hypervalent iodine mediated amidation^9a and organocatalytic arylation^9b of aldehydic C–H bond prompted us to explore its use along with Grignard reagents. We presumed that aromatic aldehydes upon sequential treatment with Grignard reagent and hypervalent iodine reagents might directly lead to ketones due to oxidative and electrophilic nature of hypervalent iodine. To test our hypothesis, a model reaction was performed with 3,4-dimethoxybenzaldehyde 1a, as expected addition of methyl magnesium iodide followed by diacetoxyiodobenzene (DIB) to 3,4-dimethoxybenzaldehyde gave us ketone 3a in excellent yield (Table 1, entry 1).

Table 1 Screening of various hypervalent iodine reagents for oxidative alkylation of 1^a

Entry	Oxidant	Time (h)	Yield^b (%)
a Reaction conditions: benzaldehyde (0.5 mmol), Grignard reagent (1.5 equiv.) in THF (1 mL) at 0 °C, then oxidant (2 equiv.) at 0 °C to rt.b Isolated yield of purified products.
1	PhI(OAc)2	1	93
2	PhI(OCOCF3)2	1	90
3	PhI(OH)(OTs)	1	89
4	Dess Martin periodinane	1	87
5	IBX	12	57

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In order to test the influence of hypervalent iodine oxidant, various electron rich and electron deficient hypervalent iodine reagents such as PhI(OCOCF₃)₂, PhI(OH)(OTs), Dess Martin periodinane and 2-iodoxybenzoic acid (IBX) were screened. Comparable results were observed with almost all hypervalent iodine oxidants (Table 1, entries 1–4) except with IBX (Table 1, entry 5). The best result was found with DIB, affording the 1-(3,4-dimethoxyphenyl)ethanone 3a in 93% yield, at rt for 1 h (Table 1, entry 1). We therefore decided to continue our further studies with DIB as oxidant.

To ascertain the wide application of this procedure, diverse electron rich and electron deficient aromatic, hetero-aromatic and organometallic aldehydes (Table 2) were examined with methyl magnesium iodide and DIB under the optimized reaction condition. To our delight, the desired ketones (Table 2, entries 3a–k) were obtained in good to excellent yields (Table 2). Apparently, electron donating/withdrawing (Table 2, entries 3a–n) nature and the position of substitution on the aromatic ring did not make much difference to reactivity, even the reaction with sensitive aldehydes i.e. piperonal & O-tetrahydropyran (THP) protected m-hydroxybenzaldehyde and ferrocene carboxaldehyde, proceeded smoothly and produced good yields (Table 2, entries 3c, 3d & 3g). Reaction of benzaldehyde 1a with Grignard reagents such as butyl, isopropyl, cyclopropyl magnesium bromides also produced corresponding ketones (Table 2, entries 3l–n) in good yields. For the synthesis of biaryl ketones DIB as internal oxidant produced low yields along with some side products. After screening several hypervalent iodine reagents, the best result was observed with IBX under refluxing THF condition. The optimized condition was screened with various aldehydes (Table 2, entries 3o–r) and obtained good results. The generality of this reaction is further confirmed, by treatment of acetaldehyde with phenylmagnesium bromide and DIB produced the acetophenone 3e in 94% yield, which is comparable to the 92% yield (Table 1) obtained using benzaldehyde as starting material.

Table 2 One pot oxidative alkylation/arylation of aldehyde^a,b

a Isolated yield of purified products.b Reaction conditions for entries 3a–n: aldehyde (0.5 mmol), Grignard reagent (1.5 equiv.) in THF (1 mL) at 0 °C, then DIB (2 equiv.) at 0 °C to rt. For entries 3o–r: IBX (3 equiv.) is used as oxidant instead of DIB under refluxing conditions.

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A plausible reaction mechanism for the hypervalent iodine mediated direct oxidative alkylation/arylation of aldehydes to ketones is depicted in Scheme 1. Both the reactions follows similar pattern in functionalizing the aldehydes. The two key steps are trans alkoxylation of Grignard adduct A with the hypervalent iodine (i.e. DIB or IBX) to produce the corresponding intermediates B or C and reductive elimination of the intermediates B or C to produce the desired ketones along with the corresponding reduced hypervalent iodine i.e. iodobenzene in case of DIB or iodoso benzoic acid in case of IBX.

Scheme 1 Plausible mechanism for the direct one pot synthesis of the ketone.

In order to ascertain the mechanism of this reaction a test reaction was performed by concomitant addition of Grignard reagent and DIB to 3,4-dimethoxybenzaldehyde, this apparently did not produce the desired ketone in good yield, suggesting a possible side reaction between Grignard reagent and DIB, it also justifies the involvement of stepwise mechanism (Scheme 1) and the need for deferred addition of the hypervalent iodine reagent. During purification of crude reaction mixtures, we have often isolated a less polar spot, which was found to be iodobenzene, this evidence again reinforces our proposed mechanism.

Conclusions

In conclusion, an operationally simple and environmentally benign one pot synthesis of variety of ketones directly from aldehydes using Grignard and hypervalent iodine reagents were described. Reduction of one step, generation of non-toxic by-products, step economy, and shorter reaction time periods,³ attributes this strategy as a environmentally benign protocol for the synthesis of ketones from aldehydes. Further studies with various other Grignard and organometallic reagents are in progress.

Acknowledgements

Financial assistance by Department of Science and Technology, New Delhi under Fast Track Scheme and SEED grant by IIT Mandi is gratefully acknowledged. RC is thankful to IIT Mandi for a postdoctoral fellowship.

Notes and references

1. (a) F. Epifano and S. Genovese, Chemistry and Pharmacology of Naturally Occurring Bioactive Compounds, CRC Press Publishing, USA, 2013; (b) C. Cheng, L. Pan, Y. Chen, H. Song, Y. Qin and R. Li, J. Comb. Chem., 2010, 12, 541; (c) J. M. Frost, M. J. Dart, K. R. Tietje, T. R. Garrison, G. K. Grayson, A. V. Daza, O. F. El-Kouhen, B. B. Yao, G. C. Hsieh, M. Pai, C. Z. Zhu, P. Chandran and M. D. Meyer, J. Med. Chem., 2010, 53, 295; (d) D. B. Ramachary, M. Kishor and Y. V. Reddy, Eur. J. Org. Chem., 2008, 975; (e) J. Otera, Modern Carbonyl Chemistry, John Wiley & Sons Publishing, 2001; (f) K. Lafleur, D. Huang, T. Zhou, A. Caflisch and C. Nevado, J. Med. Chem., 2009, 52, 6433; (g) J. I. Kawakami, K. Kimura and M. Yamaoka, Org. Process Res. Dev., 2007, 11, 206; (h) S. Roy, A. Sharma, B. Dhotare, P. Vichare, A. Chattopadhyay and S. Chattopadhyay, Synthesis, 2007, 1082; (i) Z. Li and V. Gevorgyan, Angew. Chem., Int. Ed., 2011, 50, 2808.
2. (a) V. Bertini, F. Lucchesini, M. Pocci and A. D. Munno, Tetrahedron Lett., 1998, 39, 9263; (b) D. J. Callis, N. F. Thomas, D. P. J. Pearson and B. V. L. Potter, J. Org. Chem., 1996, 61, 4634; (c) V. Bertini, F. Lucchesini, M. Pocci and A. D. Munno, J. Org. Chem., 2000, 65, 4839; (d) G. Biswas, S. G. Ghorai and A. Bhattacharjya, Org. Lett., 2006, 8, 313; (e) S. Perreault and C. Spino, Org. Lett., 2006, 8, 4385.
3. (a) P. T. Anastas and J. C. Warner, Green Chemistry Theory and Practice, Oxford University Press, Oxford, 1998; (b) P. A. Clarke, S. Santos and W. H. C. Martin, Green Chem., 2007, 9, 438; (c) M. Poliakoff, J. M. Fitzpatrick, T. R. Farren and P. T. Anastas, Science, 2002, 297, 807; (d) S. L. Y. Tang, R. L. Smith and M. Poliakoff, Green Chem., 2005, 7, 761.
4. (a) M. C. Willis, Chem. Rev., 2010, 110, 725; (b) K. Ekoue-Kovi and C. Wolf, Chem. – Eur. J., 2008, 14, 6302.
5. (a) T. Hirao, D. Misu and T. Agawa, J. Am. Chem. Soc., 1985, 107, 7179; (b) R. J. Kloetzing, A. Krasovskiy and P. Knochel, Chem. – Eur. J., 2007, 13, 215; (c) B. Byrne and M. Karras, Tetrahedron Lett., 1987, 28, 769; (d) A. Pelter, K. Smith, S. Elgendy and M. Rowlands, Tetrahedron Lett., 1989, 30, 5643; (e) J. J. Crawford, K. W. Henderson and W. J. Kerr, Org. Lett., 2006, 8, 5073.
6. (a) Y. C. Huang, K. K. Majumdar and C. H. Cheng, J. Org. Chem., 2002, 67, 1682; (b) M. Pucheault, S. Darses and J. P. Genet, J. Am. Chem. Soc., 2004, 126, 15356.
7. (a) J. Karthikeyan, K. Parthasarathy and C. H. Cheng, Chem. Commun., 2011, 47, 10461; (b) L. Yang, T. Zeng, Q. Shuai, X. Guo and C.-J. Li, Chem. Commun., 2011, 47, 2161; (c) G. Mora, S. Darses and J. P. Genet, Adv. Synth. Catal., 2007, 349, 1180; (d) O. Chuzel, A. Roesch, J. P. Genet and S. Darses, J. Org. Chem., 2008, 73, 7800.
8. (a) V. V. Zhdankin and P. J. Stang, Chem. Rev., 2008, 108, 5299; (b) E. A. Merritt and B. Olofsson, Angew. Chem., Int. Ed., 2009, 48, 9052; (c) V. V. Zhdankin, J. Org. Chem., 2011, 76, 1185; (d) A. Duschek and S. F. Kirsch, Angew. Chem., Int. Ed., 2011, 50, 1524; (e) E. A. Merritt and B. Olofsson, Synthesis, 2011, 517.
9. (a) V. Prasad, R. R. Kale, B. B. Mishra, D. Kumar and V. K. Tiwari, Org. Lett., 2012, 14, 2936; (b) Q. Y. Toh, A. McNally, S. Vera, N. Erdmann and M. J. Gaunt, J. Am. Chem. Soc., 2013, 135, 3772.

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Footnotes

† Dedicated to the memory of Prof. A. Srikrishna.

‡ Electronic supplementary information (ESI) available. See DOI: 10.1039/c4ra01748j

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