An Expedient Procedure for the Oxidative Cleavage of Olefinic Bonds with PhI(OAc)₂, NMO, and Catalytic OsO₄

Abstract

PhI(OAc)₂ in the presence of OsO₄ (cat.) and 2,6-lutidine cleaves olefinic bonds to yield the corresponding carbonyl compounds, albeit, in some cases, with α-hydroxy ketones as by-products. A more practical and clean protocol to effect oxidative cleavage of olefinic bonds involves NMO, OsO₄ (cat.), 2,6-lutidine, and PhI(OAc)₂.

The oxidative cleavage of olefinic bonds, either through their ozonides or diols, is used widely in organic synthesis as a useful method to truncate carbon chains or, more usefully, to prepare carbonyl compounds. The most common methods employed to carry out these operations involve ozonolysis (Scheme 1a) or Johnson–Lemieux oxidation¹ [NaIO₄, OsO₄ (cat.)], and its variants² (Scheme 1b), including the recent improvement (addition of 2,6 lut.) introduced by Jin et al.,³ all of which are onestep procedures. The disadvantages involved with these methods (e.g. safety,⁴ drastic or inconvenient conditions) led to the introduction of the two-step procedure employing sequential Upjohn dihydroxylation⁵ [NMO, OsO₄ (cat.)] and periodate cleavage of the resulting 1,2-diol (Scheme 1c), which became as popular, if not more, than the first two methods. More recent attempts to improve upon these protocols led to the procedures of Borhan et al.⁶ [oxone, OsO₄(cat.)] and Ochiai et al.⁷ [mCPBA, HBF₄, ArI(cat.)] that oxidatively cleave olefinic bonds. The use of strong conditions, and the fact that both of these procedures lead to carboxylic acids, also endows them with certain limitations.

Scheme 1.

Common Methods for Cleaving Olefinic Bonds to Carbonyl Compounds

As part of a total synthesis program we recently developed practical and convenient protocols for cleaving 1,2-diols and olefinic bonds to aldehydes and ketones employing hypervalent iodine reagents [e.g. PhI(OAc)₂]⁸ as the main oxidant. In this letter we highlight the practicality of using PhI(OAc)₂ to achieve a clean oxidative cleavage of 1,2-diols and demonstrate its compatibility and effectiveness in oxidatively cleaving olefinic bonds into the corresponding carbonyl compounds when coupled with dihydroxylation conditions.

PhI(OAc)₂ is an excellent reagent for the cleavage of 1,2-diols,⁹ and it is rather surprising that it is not commonly employed in that capacity, despite a seven decade old publication by Criegee and Beucker⁸ demonstrating its ability to effect this transformation. More recently, Arseniyadis et al. elegantly employed this reagent to initiate cascade sequences that lead to novel heterocyclic systems through transient dialdehydes.^9a A polymer-supported version of this reagent has also been reported, but its use has been limited.¹⁰

The rarity of reports¹¹ using PhI(OAc)₂ to cleave 1,2 diols can be attributed to the absence of a systematic study demonstrating its capabilities in this regard. Thus, in order to illustrate the generality and scope of PhI(OAc)₂ as an efficient 1,2 diol cleaving reagent, and as a prelude to our subsequent investigations, we employed it to that effect on a variety of diol substrates as shown in Table 1 (entries 1–10). In all the examples studied, a clean conversion of the diol into the corresponding aldehydes/ketones was observed. Experimentally, the procedure involves mixing of the substrate and PhI(OAc)₂ in CH₂Cl₂ at room temperature, and upon completion, the product could conveniently be isolated in pure form by removal of the solvent and chromatography.^12,13

Table 1.

Cleavage of 1,2-Diols to Aldehydes by PhI(OAc)₂^a

entry	substrate	product	time [h]	yield [%]b
1	1	1a	1	86
2	2	2a	1	65c
3	3	3a	0.75	99
4	4	4a	0.25	92
5	5	5a	8	99
6	6	6a	8	84
7	7	7a	2.5	97
8	8	8a	0.5	92
9	9	9a	3	95
10	10	10a	1	99

^aReactions were carried out on 100 mg scale at 0.1 M concentration in CH₂Cl₂ with 1.2 equiv PhI(OAc)₂ at ambient temperature.

^bIsolated yield.

^cCompetitive over-oxidation observed.

Importantly, the PhI(OAc)₂-based diol cleavage strategy offers an opportunity for further reactions of the resulting carbonyl compounds in the same pot. Thus, as shown in Scheme 3a, addition of the stabilized phosphorane 11 to the resulting mixture of the cleavage of diol substrate 1 led to the isolation of conjugated ester 12 in high overall yield (81%). Likewise, Grignard addition to the same aldehyde produced propargylic alcohol 13 in 86% overall yield (Scheme 3b). On the other hand, addition of DIBAL-H to the resulting mixture of the cleavage of diol substrate 2 led to isolation of diol 14 in 60% overall yield for the one-pot sequence (Scheme 3c). Finally, reductive amination¹⁴ (Scheme 3d) and dithiane protection (Scheme 3e) were also achieved in high yields (94% and 85%, respectively) by adding the indicated reagents to the aldehyde generated in situ from 1,2-diol 3 according to the conditions of Table 1. Additional such sequential reactions are envisioned, thus making this technology potentially appealing for applications in a variety of situations.

Scheme 3.

One-pot Applications of PhI(OAc)₂ Cleavage of 1,2-Diols

We then proceeded to explore the usefulness of PhI(OAc)₂ in cleaving olefinic bonds in the presence of catalytic amounts of OsO₄ and 2,6-lutidine. As shown in Scheme 4 and Table 2, this reaction works well in most instances (Table 2, entries 1–6) but fails to go to completion or leads to by-products, namely α-hydroxy ketones in certain cases (Table 2, entries 7–10). It should be noted that such by-products are also observed under Johnson Lemieux conditions.³

Scheme 4.

Oxidative Cleavage of Olefins to Aldehydes and/or Ketones with PhI(OAc)₂ and OsO₄ (cat.) in the Presence of 2,6-Lutidine

Table 2.

Oxidative Cleavage of Olefins to Aldehydes and/or Ketones with PhI(OAc)₂ and OsO₄ (cat.) in the Presence of 2,6-Lutidine^a

entry	substrate	product	time [h]	yield [%]b
1	17	17a	9	98
2	18	18a	8	97
3	19	19a	1	98
4	20	20a	6	68
5	21	21a	24	81
6	22	22a	1.5	89
7	23	23a	18	41c
8	24	24a	48	46d
9	25	25a 25b	0.75	7
				68e
10	26	26a 26b	0.25	10
				70

^aReactions were carried out on 100 mg scale at 0.1 M concentration in THF with 0.1 mL H₂O, 2.3 equiv PhI(OAc)₂, 2.5 equiv 2,6-lutidine, and 0.02 equiv OsO₄ at ambient temperature.

^bIsolated yield.

^cor 67% yield based on 60% conversion.

^dor 49% based on 93% conversion.

^eInseparable mixture; ratio by ¹H NMR.

From a more practical perspective, we discovered that a one-pot combination of dihydroxylation using Upjohn conditions followed by diol cleavage with PhI(OAc)₂ was a superior method to cleave olefins (Scheme 5 and Table 3, entries 1–10). Thus, treating olefins with NMO and 2,6-lutidine in the presence of catalytic OsO₄ in acetone:water (ca. 10:1) followed by the addition of PhI(OAc)₂ effected the cleavage of olefinic bonds in one pot to give the corresponding carbonyl compounds. This process obviously proceeds through the corresponding diol and liberates two molar equivalents of AcOH and one molar equivalent of PhI, both of which can be removed easily on work-up and chromatography, respectively.

Scheme 5.

Cleavage of Olefins to Aldehydes and/or Ketones by NMO, OsO₄ (cat.)/PhI(OAc)₂ in the Presence of 2,6-Lutidine

Table 3.

Cleavage of Olefins to Aldehydes and/or Ketones by NMO, OsO₄ (cat.)/PhI(OAc)₂ in the Presence of 2,6-Lutidine^a

entry	substrate	product	time [h]	yield [%]b
1	27	27a	20	87
2	24	24a	2	89
3c	28	28a	6	75
4	23	23a	8	90
5	25	25a	3.5	90
6	26	26a	3.5	83
7	29	29a	20	83
8	30	30a	8	83
9d	31	31a	0.8	79
10d	32	32a	1	76

^aReactions were carried out on 100 mg scale at 0.1 M concentration in 10:1 acetone:H₂O with 2.0 equiv 2,6-lutidine, 1.5 equiv NMO, 0.02 equiv OsO₄ 1.5 equiv PhI(OAc)₂ at ambient temperature.

^bIsolated, yield.

^c2.2 equiv PhI(OAc)₂ were used.

^dCarried out on 1 mmol scale.

The PhI(OAc)₂-NMO-OsO₄ protocol leads to aldehydes and ketones in high yields and admirably avoids the formation of the α-hydroxy ketone side products (compare Table 2, entries 9 and 10 with Table 3, entries 5 and 6). Notably, epoxides (entry 2, Table 3) survive these oxidative cleavage conditions compared with conditions that employ sodium periodate which lead to oxidative cleavage of the epoxide moiety.¹⁵ The reaction accommodates both cyclic and acyclic olefins, as well as mono-, di-, and tri-substituted alkenes.

The described synthetic methods offer a convenient, robust, and economical¹⁶ alternative to the traditional olefin cleavage methods for laboratory operations. In addition to achieving high yields in most cases, all the protocols described here involve essentially homogeneous media, endowing them with certain advantages over the hetrogeneous Johnson–Lemieux-type oxidations.

Scheme 2.

Cleavage of 1,2-Diols to Aldehydes by PhI(OAc)₂