The intriguing role of hypervalent iodine reagents in synthetic transformations has
amazed organic chemists over the years.[1]
[2]
[3]
[4]
[5] Beside their highly selective oxidizing properties, hypervalent iodine reagents
are also associated with inherent low toxicity, an environmentally benign character,
high stability, and mild reaction conditions, which make them good or superior alternatives
to toxic transition-metal-based oxidants.[6,7] Hypervalent iodine moieties, as hypernucleofuges, exhibit an electrophilic character
and generate cationic intermediates.[8,9] This permits their use as versatile reagents for many organic transformations, including
oxidative functionalization, cyclization, dearomatization, fragmentation, atom-transfer,
and coupling reactions, as well as rearrangements through ring contractions, ring
expansions, or aryl migrations, etc.[10]
[11]
[12]
[13]
[14]
[15]
[16]
[17]
[18]
[19]
[20]
[21]
[22]
Oxidative 1,2-aryl migration reactions form a unique class of organic transformations
that are used extensively in synthetic chemistry. Many elegant studies mediated by
1,2-aryl migration reactions or by combinations of these with other transformations
have been established as alternative methods for accessing compounds whose synthesis
would otherwise be quite complex and which are not otherwise easily accessible. Examples
of such transformations include stereocontrolled total syntheses of numerous natural
products,[23]
[24]
[25] various heterocycles,[26–29] intricate carbocycles,[30–31] and drugs.[32]
[33]
[34]
[35] The attractive and exceptional features of 1,2-aryl migration reactions continually
inspire synthetic chemists to utilize the synthetic potential of these reaction in
generating structurally complex entities from such precursors as unsaturated carbonyl
compounds. Unsaturated carbonyl compounds are readily accessible through aldol condensations
between aryl methyl ketones and aryl aldehydes. Numerous elegant studies on carbonyl
compounds make these entities the most exploited building blocks in synthetic chemistry.
Scheme 1 Synthetic protocol for β,β-ditosyloxy ketones 2
The synthetic utility of hypervalent iodine moieties in the oxidation of α,β-unsaturated
carbonyl compounds has been well investigated and remains a promising area of research.[36] Hypervalent iodine reagents, when treated with α,β-unsaturated carbonyl compounds,
serve as electrophiles Ph(L)I+ and generate phenyliodinated intermediates that are available for further nucleophilic
attack and give rearranged product through 1,2-aryl migration.[37]
[38] Here, we describe a stereoselective oxidative 1,2-aryl migration following the reaction
of an α,β-unsaturated carbonyl compound with the hypervalent iodine reagent hydroxy(tosyloxy)iodobenzene
(HTIB) in an aprotic polar solvent (dichloromethane) to give novel gem-β,β-ditosyloxy ketones.
Initially, we synthesized the gem-β,β-ditosyloxy ketone 2a by treatment of (2E)-3-(4-methoxyphenyl)-1-(4-methylphenyl)prop-2-en-1-one (1a) with two equivalents of HTIB by following the synthetic protocol shown in Scheme
[1].[39]
The structure of product 2a was confirmed by studying its spectral data (IR, 1H, 13C, HMBC 2D NMR). The IR spectrum of compound 2a exhibited a characteristic absorption band at about 1666 cm–1 assigned to CO stretching. The 1H NMR spectrum of compound 2a showed characteristic doublets assigned to vicinal protons in the ranges δ = 4.95–4.97
and 6.95–6.98 ppm. Four singlets also appeared in the spectrum. The one corresponding
to the three protons of the methoxy group in the para-position of the aryl group appeared at δ = 3.72 ppm, and the others, assigned to
the three methyl groups (one substituent of the aryl group and two substituents of
the tosyl group), appeared at δ = 2.31, 2.39, and 2.40 ppm. All aromatic protons resonated
in the expected region δ = 6.62–7.78 ppm with similar values and patterns. The structure
of compound 2a was also analyzed by 13C NMR spectroscopy, which showed a characteristic signal for the carbonyl carbon at
δ = 193.96 ppm. Two more characteristic signals, one for the carbon in the position
α to the carbonyl group and the other in the β-position appeared at δ = 56.86 and
99.69 ppm, respectively. The structure of compound 2a was confirmed by HMBC 2D NMR spectroscopy, the results of which were in good agreement
with the expected values (Figure [1]).
Figure 1 Overview of spectral data (1H NMR, 13C NMR, and IR) for 2-(4-methoxyphenyl)-3-(4-methylphenyl)-1,1-di(tosyloxy)propan-3-one
(2a)
Single-crystal x-ray diffraction analysis of product 2a was also carried out and further explicitly confirmed the formation of the β,β-ditosyloxy
ketone in this reaction. The β,β-ditosyloxy ketone 2a crystallized in the monoclinic P1 21/c1 space group.[40] An ORTEP diagram of 2a is shown in Figure [2].
Figure 2 Single-crystal ORTEP diagram for the β,β-ditosyloxy ketone 2a
When the same synthetic protocol was attempted with various substituted chalcones,
the reaction proceeded in a similar manner to give the corresponding β,β-ditosyloxy
ketones 2b–n (Scheme [1]). However, it pertinent to mention here that Koser et al.[41] have reported an example of vicinal ditosyloxylation of the C=C double bond of α,β-unsaturated
carbonyl compounds through treatment with HTIB and syn-addition to the double bond (Scheme [2]).
Scheme 2 Synthesis of an α,β-ditosyloxy ketone 3
As a result, in many previous investigations, our research group assumed that the
structure of the ditosyloxy ketones corresponded to that of the vicinal α,β-ditosyloxy
ketone 3 (Scheme [3]).[42]
[43]
[44]
Scheme 3 Reported syntheses of pyrazoles 4, isoxazoles 5, α-aryl β-keto dialkylacetals 6, and desoxybenzoins 7, assuming that the structure of the ditosyloxy ketone was that of the vicinal α,β-ditosyloxy
ketone 3
Reports in the literature and the results obtained from various reactions of ditosyloxy
ketones performed by our research group encouraged us to study the actual mechanism
of the ditosyloxylation of α,β-unsaturated ketones mediated by HTIB. As a result,
we compared the physical and spectral data of the ditosyloxy ketones in powdered and
single-crystal forms. This investigation was performed to reveal the actual structure
of the product formed during the reaction. The similar physical (color and melting
point) and spectral data (IR, 1H, 13C, HMBC 2D NMR) for the powdered and crystalline forms led us to a new finding that
the structure of these compounds is actually that of geminal β,β-ditosyloxy ketones
rather than that of vicinal α,β-ditosyloxy ketones.
To support our experimental findings, we performed density functional theory (DFT)
calculations with the Gaussian 09 quantum-chemical package[45] to analyze the relative thermodynamic stability of both the geminal and vicinal
forms of the ditosyloxy ketones, along with two conformations (syn and anti) of the vicinal ditosyloxy ketone. The various structures were optimized by using
the 6-31+G(d,p) polarized split-valence basis set with diffuse functions for heavy
atoms. A hybrid functional B3LYP[46] consisting of Becke’s three-parameter exchange functional[47] and the Lee–Yang–Parr correlation functional[48] was used to treat the electron-exchange and correlation (x–c) interactions. The quantum-chemical calculations showed that the geminal structure
for the ditosyloxy ketone is the most stable form, followed by the vicinal syn structure (Figure [3]); the vicinal anti-configuration of the ditosyloxy ketone was found to be the thermodynamically least
favored. The geminal structure was predicted to be lower in energy than the vicinal
syn-configuration of the ditosyloxy ketone by 16.11 kJ/mol, and was therefore found to
be thermodynamically favored over the previously reported syn-configuration. This extra stability of the geminal structure might originate from
π–π stacking interactions between the two aryl rings, one bearing the tosylate group
and the other bearing the methoxy substituent, whereas the vicinal configurations
lack these π–π stacking interactions.
Figure 3 Structures and relative energies of various configurations of the ditosyloxy ketone
2a
The oxidative rearrangements of aryl-substituted unsaturated carbonyl compounds mediated
by hypervalent iodine reagents in polar protic solvent system had previously been
established to give geminal β,β-substituted carbonyl compounds through 1,2-migration.[37]
[38] Moreover, Ollis et al.[49–51] reported an oxidative rearrangement of chalcone promoted by thallium(III) acetate
in methanol in which the methoxy ion (CH3O–) served as the nucleophile, and which resulted in the formation of β,β-geminal disubstituted
carbonyl compounds, i.e. acetals, through a 1,2-aryl shift. Furthermore, Moriarty
et al.[38] also reported that acetals formed as oxidative products through a 1,2-aryl migration
when chalcone was treated with HTIB in methanol. In this case, the methoxy ion (MeO–), being more nucleophilic than the tosylate ion (TsO–), which was also present in the reaction mixture, acted as nucleophile, resulting
in the rearranged geminally substituted product.
The solvent composition plays a crucial role in oxidative rearrangements mediated
by hypervalent iodine reagents.[52] In polar protic solvent system, the solvent can serve as a competent nucleophile
and can significantly influence the transformation,[38] whereas polar aprotic solvents do not possess such a nucleophilic nature. We can
therefore state that ditosyloxylation of the C=C double bond of α,β-unsaturated carbonyl
compounds in dichloromethane with HTIB entails an oxidative 1,2-aryl migration and,
feasibly, results in a geminal β,β-ditosyloxy ketone.
A plausible mechanism for this transformation is suggested in Scheme [4]. Initial electrophilic addition of Ph(OH)I+ (generated by simple dissociation of HTIB)[53] to the double bond of the chalcone results in the cyclic organoiodine intermediate
8. This intermediate undergoes nucleophilic attack by the tosylate ion (OTs–), present in the reaction mixture. As the possibility of competitive nucleophilic
attack by the tosylate ion at the carbon α to carbonyl group in structure 8 appears to be low due to the presence of the electron-withdrawing COAr group that
restrict the development of a positive charge on the α-carbon, attack on the carbon
β to the carbonyl group occurs instead to give the hydroxyiodinane 9. Thereafter, release of a hydroxide ion (OH–) and iodobenzene, and 1,2 migration of the aryl group, which might be facilitated
by the lone pair of electrons on the oxygen atom, results in the formation of intermediate
10. Nucleophilic attack by a second tosylate ion, generated by simple dissociation of
HTIB, on the carbon β to the carbonyl group finally results in the formation of the
geminal ditosyloxy ketone.
Scheme 4 Plausible mechanism for the ditosyloxylation of α,β-unsaturated ketones
Some features of the proposed mechanism need to be considered. First, the existence
of the organoiodine intermediate 8 has already been established in an earlier investigation by Rebrovic and Koser[41] and confirmed by Moriarty et al.[38] The formation of intermediates 9 and 10 is supported by the rearrangement resulting from HTIB-mediated reaction of chalcones
in methanol reported by Moriarty et al.[38] in which the more nucleophilic methoxy ion (MeO–), instead of the tosylate ion (TsO–), attacks the chalcone. However, in the absence of methanol, the tosylate ion (TsO–) should act as nucleophile.
At this stage it is important to mention that our previous investigations[42]
[43]
[44] that reported a vicinal structure for the ditosyloxy ketone 3 can also be justified in terms of the geminal β,β-ditosyloxy ketone structure 2, as shown in Scheme [5].
Scheme 5 Plausible mechanisms for the formation of pyrazoles, isoxazoles, α-aryl β-keto dialkyl
acetals and desoxybenzoins from a β,β-ditosyloxy ketone as precursor
As stated, the synthesis of 1,4,5-trisubstituted pyrazoles 4 and 4,5-disubstituted isoxazole 5 can be demonstrated to involve the geminal ditosyloxy ketone 2. Although the mechanism for the conversion of 2 into 4 or 5 is a matter of investigation, the geminal ditosyloxy ketone 2 might either behave in an identical manner to the β-keto aldehyde 11 or act as a synthon for the latter. The proposed mechanism for the regioselective
formation of 1,4,5-trisubstituted pyrazoles and 4,5-disubstituted isoxazoles is outlined
in Scheme [5]. The first step of the reaction might be nucleophilic substitution of one of the
tosyloxy groups by an NH2 group of the nucleophile (phenylhydrazine, semicarbazide, thiosemicarbazide, or hydroxylamine).
This substitution might be followed by further elimination of another tosyloxy group
with participation of the lone pair of electrons on the nitrogen or oxygen atom, resulting
in the formation of intermediate 2-II or 2-V, which subsequently undergoes cyclization in the usual manner to afford the required
product.
Moreover, the formation of α-aryl β-keto dialkyl acetals and desoxybenzoins can also
be explained by assuming that the geminal ditosyloxy ketone 2 is a precursor (Scheme [5]). It is possible that an alkoxy ion (RO–), being more nucleophilic than a tosylate ion, has a crucial role in the transformation.
In summary, we efficiently synthesized β,β-ditosyloxy ketone derivatives by the ditosyloxylation
of α,β-unsaturated carbonyl compounds mediated by a hypervalent iodine reagent in
a polar aprotic solvent. We also proposed a mechanistic pathway for the synthesis
of geminal β,β-ditosyloxy ketones. These outcomes are noteworthy as they contradict
earlier reported syntheses of α,β-ditosyloxy ketones through HTIB-mediated ditosyloxylation
of unsaturated carbonyl compound. We also explained our earlier investigations that
wrongly implicated an α,β-ditosyloxy ketone by invoking a β,β-ditosyloxy ketone as
a precursor.
The chemical versatility and relative stability of β,β-ditosyloxy ketones, along with
the ease of their preparation, make them unique synthons in synthetic chemistry. The
products reported here can act as precursors of β-keto aldehydes, and therefore have
widespread synthetic applications in organic chemistry. Investigations on the intriguing
chemistry of ditosyloxy ketones, especially their use in syntheses of medicinally
important heterocyclic and other compounds, are currently in progress.
