FeCl₃-Catalyzed Reduction of Ketones and Aldehydes to Alkane Compounds

Abstract

Ketones can efficiently be reduced to the corresponding methylene compound using the convenient and inexpensive combination of PMHS and FeCl₃.

The use of iron-catalyzed reactions have recently emerged as efficient alternatives to promote reactions, traditionally carried out in the presence of noble metals. [¹] [²] These developments have been driven up by the abundance, the low toxicity, and the low price characteristics of the iron salts. The iron-catalyzed hydrosilylation [³] of ketones (aldehydes) 1 for the synthesis of secondary (primary) alcohols, have particularly been described, including asymmetric versions (Scheme  [¹] ). [4] [5]

In the context of the development of iron-catalyzed reactions, [6] we planned to use the Lewis acid character of the iron salts to promote a further reduction of the O-silylated intermediate 2 in order to obtain the methylene derivative 3 (Scheme  [¹] ). The defunctionalization of ketones to methylenes is a key reaction in the organic chemist tool box and many methodologies have been described in the literature. The textbook Clemensen [7] and Wolff-Kischner [8] ­reactions are probably the most famous, but more recently milder reactions have been developed. Among these is the use of catalytic amounts, but expensive, B(C₆F₅)₃ Lewis acid in the presence of polymethylhydrosiloxane ­(PMHS), a byproduct of the silicone industry which is inexpensive, easy to handle, and environmentally friendly reducing agent. [9] The development of catalytic, simple, and inexpensive reaction conditions is thus still highly ­desirable. In this paper, we would like to describe the reduction of ketones (aromatic and aliphatic ones) and aldehydes under simple conditions in the presence of the nonexpensive FeCl₃ catalyst (10%) and PMHS reducing agent, both of them being simple, easy to handle, and inexpensive reagents.

Table 1 Reduction of Acetonaphthone (4) with PMHS

Entry	Conditions	GC yield (isolated yield, %)
1	NaAuCl4˙2H2O (5 mol%), DCE, MW, 1 h, 120 ˚C	92
2	FeCl3 (10 mol%), DCE, MW, 1 h, 120 ˚C	91
3	FeCl3˙6H2O (10 mol%), DCE, MW, 1 h, 120 ˚C	100 (98)
4	FeCl3˙6H2O (10 mol%), toluene, MW, 1 h, 120 ˚C	48
5	FeCl3˙6H2O (10 mol%), MeOH, MW, 1 h, 120 ˚C	NR
6	FeCl3˙6H2O (10 mol%), DCE, reflux, 8 h, 90 ˚C	34

Thus, the reduction of the commercially available aceto­naphthone (4) with PMHS was first set up as a model ­reaction (Table  [¹] ). Gratifyingly, under microwave irradiation in DCE at 120 ˚C, very good conversions to the formation of the reduced product 5 could be observed in the presence of NaAuCl₄˙2H₂O and FeCl₃ (Table  [¹] , entries 1 and 2). Best conditions were, however, found to be in the presence of FeCl₃˙6H₂O (10% mol) where compound 5 was isolated in 98% yield (Table  [¹] , entry 3). Testing methanol and toluene as alternative solvents led to more deceptive results (Table  [¹] , entries 4 and 5). Finally, under traditional thermal conditions, in refluxing DCE at 90 ˚C, a lower yield was observed (Table  [¹] , entry 6).

Table 2 The PMHS Reduction of Aromatic Ketones in the Presence of FeCl₃˙6H₂O under Microwave Irradiation

Entry	Ketone	Product	Yield (%)
1	4	5	98
2	6	7	91
3	8	9	81
4	10	11	94
5	12	13	82

We then examined the PMHS reduction with a set of aromatic ketones in the presence of FeCl₃˙6H₂O (10% mol) under microwave irradiation (Table  [²] ). 1-Tetralone (6), benzophenone (10), substituted acetophenone 8, and propiophenone (12) have been reduced in good yields (81-98%). Extension to nonaromatic ketones was next investigated and results are summarized in Table  [³] . These substrates are efficiently reduced in slightly lower yields.

Table 3 The PMHS Reduction of Nonaromatic Ketones in the Presence of FeCl₃˙6H₂O under Microwave Irradiation

Entry	Ketone	Product	Yield (%)
1	14	7	83
2	15	16	51
3	17	16	64
4	18	13	63
5	19	20	61

Aromatic and aliphatic aldehydes are also suitable substrates in these reactions as illustrated in Table  [4] . Limitations of the methodology have been reached with esters, anhydrides and β-keto esters 28-30 where no reaction or extensive decomposition could be observed (Figure  [¹] ).

Table 4 The PMHS Reduction of Aromatic and Aliphatic Aldehydes in the Presence of FeCl₃˙6H₂O under Microwave Irradiation

Entry	Aldehyde	Product	Yield (%)
1	21	22	73
2	23	13	74
3	24	25	78
4	26	27	62

In conclusion, we have developed a simple and convenient method for the reduction of ketones and aldehydes (aromatic and aliphatic ones) in the presence of PMHS and FeCl₃ (10 mol%) as catalyst.

Experimental Procedure

To a solution of ketone or aldehyde (0.15 mmol) in DCE (4 mL) was added FeCl₃˙6H₂O (0.015 mmol, 97% ACS reagent, finely ground) and PMHS (0.4 mmol, Fluka, viscosity 15-40 mPa˙s). The round-bottom flask equipped with a magnetic stirring bar and sealed with a septum. The flask was then placed in a microwave reactor [CEM microwaves Discover (300W)] at 120 ˚C for 1 h. The gelatinous mixture was next filtered under a plug of Celite and concentrated under gentle vacuum. The crude material was then loaded on to a SiO₂ column and chromatographed with heptane to give the reduced product.

Acknowledgment

We are grateful to the CNRS for financial support (ATIPE jeune équipe) and the Institut de Chimie des Substances Naturelles for a grant (CDZ).

References

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References

• For recent reviews, see:
• 1a Bolm C. Legros J. Le Paih J. Zani L. Chem. Rev.  2004,  104:  6217 
  Search in Google Scholar
• 1b Enthaler S. Junge K. Beller M. Angew. Chem. Int. Ed.  2008,  47:  3317 
  Search in Google Scholar
• 1c Correa A. García Mancheño O. Bolm C. Chem. Soc. Rev.  2008,  37:  1108 
  Search in Google Scholar
• 2 Fürstner A. Majima K. Martin R. Krause H. Kattnig E. Goddard R. Lehmann CW. J. Am. Chem. Soc.  2008,  130:  1992 
  Search in Google Scholar
• 3a Mimoun H. J. Org. Chem.  1999,  64:  2582 
  Search in Google Scholar
• 3b Riant O. Mostefaï N. Courmacel J. Synthesis  2004,  2943 
• 3c Gevorgyan V. Rubin M. Benson S. Liu J.-X. Yamamoto Y. J. Org. Chem.  2000,  65:  6179 
  Search in Google Scholar
• 3d Mimoun H. De Saint Laumer J.-Y. Giannini L. Scopelliti R. Floriani C. J. Am. Chem. Soc.  1999,  121:  6158 
  Search in Google Scholar
• 4a Brunner H. Fisch K. J. Organomet. Chem.  1991,  412:  11 
  Search in Google Scholar
• 4b Furuta A. Nishiyama H. Tetrahedron Lett.  2008,  49:  110 
  Search in Google Scholar
• 4c Furuta A. Nishiyama H. Chem. Commun.  2007,  760 
• 4d Bart SC. Lobkovsky E. Chirik PJ. Org. Lett.  2008,  10:  2789 
  Search in Google Scholar
• 4e Tondreau AM. Lobkovsky E. Chirik PJ. J. Am. Chem. Soc.  2004,  126:  13794 
  Search in Google Scholar
• 4f Shaikh NS. Junge K. Beller M. Org. Lett.  2007,  9:  5429 
  Search in Google Scholar
• 5a Shaikh NS. Enthaler S. Junge K. Beller M. Angew. Chem. Int. Ed.  2008,  47:  2497 
  Search in Google Scholar
• 5b Langlotz BK. Wadepohl H. Gade LH. Angew. Chem. Int. Ed.  2008,  47:  4670 
  Search in Google Scholar
• 6a Michaux J. Terrasson V. Marque S. Wehbe J. Prim D. Campagne JM. Eur. J. Org. Chem.  2007,  2601 
• 6b Terrason V. Michaux J. Gaucher A. Wehbe J. Marque S. Prim D. Campagne JM. Eur. J. Org. Chem.  2007,  5332 
• 6c Dal Zotto C. Wehbe J. Virieux D. Campagne JM. Synlett  2008,  2033 
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• 8 Kürti L. Czako B. Strategic Applications of Named Reactions in Organic Synthesis   Elsevier; Amsterdam: 2005.  p.496 
• 9 Chandrasekhar S. Raji Reddy C. Nagendra Babu B. J. Org. Chem.  2002,  67:  9080 
  CrossrefPubMedSearch in Google Scholar