Hypoiodous acid-catalyzed regioselective geminal addition of methanol to vinylarenes: synthesis of anti-Markovnikov methyl acetals

Abstract

A novel metal-free, catalytic geminal dimethoxylation of vinylarenes based on in situ generated HOI species from iodide salt and oxone is reported. The preliminary mechanistic investigations suggest that the key factor for achieving the anti-Markovnikov regioselectivity is the semipinacol rearrangement of an iodo functionalized intermediate, which is confirmed by an isotope labeling experiment. In addition, the reaction involves the de-iodination of a co-iodo intermediate via its oxidation to hypervalent iodine species rather than a common iodide abstraction by electrophiles. The HRESI-MS studies support the conversion of monovalent iodine containing intermediates to trivalent iodine intermediates during the catalytic conversion of aromatic alkenes into the corresponding terminal acetals.

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The development of new methods, that involve simple starting materials and mild and/or environmentally friendly reagents, for the construction of carbon–oxygen bonds signifies one of the great aspects of synthetic organic chemistry because of their ubiquitous presence in many medicinally important compounds and natural products. Since many alkenes are directly obtained from chemical feedstock, their functionalization has received considerable attention in organic synthesis to prepare more complex molecules in one pot with the formation of one or more C–O bonds. For example, the difunctionalization of olefins, particularly vicinal functionalization,¹ has been studied extensively and has profound applications in many branches of chemistry. However, the addition of two nucleophiles to the electron rich alkene moiety, particularly in a geminal fashion, has rarely been achieved for the synthesis of terminal acetals^2–8 and is still remains challenging to synthetic chemists.

Acetalization is the most useful synthetic technique in any targeted organic synthesis for protecting aldehydes and ketones against the attack of nucleophiles, organometallic reagents, oxidants and basic reagents during the manipulation of various multifunctional molecules.⁹ Acetals have enormous industrial importance as diesel additives and polymeric materials and as flavoring agents in beverages, cosmetics and foods.¹⁰ Additionally, acetals constitute a versatile class of synthetic intermediates for the construction of C–C bonds, synthesis of ethers and esters.^11–14 Conventionally, these acetals can be prepared from carbonyl compounds using alcohols in presence of Lewis acids or Bronsted acids or other catalysts (Scheme 1).^9a,15 Generally, these methods require prior synthesis of aldehydes (especially in case of terminal acetals preparation) from alcohols, but the selective oxidation of primary alcohols to aldehydes is a challenging procedure.¹⁶ In addition, the above methods also suffers from one or more drawbacks, such as the use of difficult reaction conditions, high catalyst loadings and use of corrosive and costly reagents or additives. Indeed, in a green chemistry point of view, the synthesis of terminal acetals from cheaper alkenes rather than costlier aldehydes represents one direct and cost-effective approach (Scheme 2).

Scheme 1 Conventional route for the synthesis of terminal acetals.

Scheme 2 Different approaches for anti-Markovnikov acetalization of vinylarenes under intermolecular conditions.

One appealing strategy to transform alkenes into terminal acetals is the palladium-catalyzed acetalization with alcohols, in which the outcome of the reaction mainly depends on either electronic nature of substituents on double bond or directing groups present on alkene.^2,3 In particular, the anti-Markovnikov regioselectivity in the palladium-catalyzed acetalization of vinylarenes can be affected by the ligands^2c–e,5 on metal or steric demand of nucleophiles.^6a On the other hand, in 2012, Lahiri et al. synthesized terminal methyl acetals from styrene derivatives using iron as catalyst in presence of 1.5 equiv. of PhI(OAc)₂ under intermolecular conditions (Scheme 2a).⁷ Additionally, few protocols also appeared in the literature to prepare these acetals under metal-free conditions (Scheme 2b).⁸ Nevertheless, these methods suffer from one or more disadvantages such as the use of transition metals, strong acids as additives, limited substrate scope and stoichiometric or over stoichiometric hypervalent iodine reagents which generate equivalent amounts of organic waste and make purification process more complicated. In view of the above-mentioned drawbacks and importance of acetalization process and its products, there is a pressing need to develop mild and efficient protocols for the synthesis of anti-Markovnikov acetals from vinylarenes under benign metal-free catalytic conditions.

In view of green chemistry, the replacement of toxic metals and hazardous/corrosive reagents with eco-friendly reagents and the development of catalytic rather than stoichiometric procedures are the topics of great importance in modern chemical synthesis. In recent years, a novel class of iodide-based oxidation catalysts, first introduced by Ishihara and co-workers,^17i–k have been attracting considerable attention as environmental benign catalysts for the construction of C–C and C–X bonds.¹⁷ However, to the best of our knowledge, there are no reports on the use of in situ generated hypoiodous acid, from the oxidation of iodide ion by oxidant, in the catalytic addition of two mononucelophilic molecules at single sp² carbon atom of an alkene for the synthesis of anti-Markovnikov acetals.

Herein, we describe a novel metal-free and mild approach for the synthesis of anti-Markovnikov methyl acetals through an iodide salt (pre-catalyst)/oxone (terminal oxidant) mediated geminal difunctionalization of vinylarenes (Scheme 2c). Further, we demonstrate the preliminary mechanistic investigations of the reaction which provide the experimental evidence for the in situ generation of key catalytic species and intermediates of the reaction and supporting the proposed mechanism.

From the previous literature reports on the oxidation of iodide salt to generate the active iodine species and its subsequent use as mild metal-free catalysts,¹⁷ we envisioned that the in situ generated electrophilic iodine species could activate the C–C double bond in alcohols for the synthesis of alcohol addition products. To test our working hypothesis, we initiated our investigation by choosing styrene (1a) as model substrate, NH₄I as pre-catalyst and a cheap, stable, non-toxic and non-nucleophilic oxone as terminal oxidant in methanol. Gratifyingly, the desired geminal dimethoxylation product, i.e., anti-Markovnikov methyl acetal (2a), was obtained in 71% yield at room temperature (Table S1, entry 1, ESI†). In order to find the optimal conditions, we have considered various reaction parameters and were evaluated sequentially.¹⁸ After the extensive screening, we have observed that the 20 mol% of NH₄I and 1 equiv. of oxone with respect to 1a at 30 °C were optimum to obtain the maximum yield of the desired product 2a in methanol (Table S1, entry 2, ESI†).

In order to explore the scope and limitations of this method, a variety of aromatic olefins were evaluated under optimized conditions (Table 1). The alkenes with moderately activating substituents on aromatic ring reacted smoothly to give the desired products 2b and 2c in 83% and 82% yields, respectively (Table 1, entries 2–3). The bulky alkyl group substituted styrene renders the reaction to furnish the targeted product 2d in 83% yield (Table 1, entry 4). The olefin with electron donating MeO group at para position delivered the corresponding dimethoxylated product 2e in 78% yield (Table 1, entry 5), whereas the substrate 1f led to 67% yield of 2f after 8.5 h (Table 1, entry 6), probably due to steric effect of ortho substituted methoxy group. When the strong deactivating group containing styrenes 1g and 1h were used as reactants, the corresponding geminal difunctionalized products 2g and 2h, respectively, were obtained in low to moderate yields, along with substantial amounts of vicinal dimethoxylated products 2g′ and 2h′ (Table 1, entry 7–8). A series of halo substituted styrenes 1i–1n also tolerated under present reaction conditions and gave the corresponding products 2i–2n in 77–81% yields (Table 1, entries 9–14). The use of polyaromatic compound 1o as substrate also provided the respective anti-Markovnikov acetalization product in 46% yield (Table 1, entry 15).

Table 1 Iodide salt mediated catalytic regioselective addition of methanol to alkenes: synthesis of anti-Markovnikov methyl acetals^ab

Entry	Olefin 1	Time (h)	Product 2	Yield (%)
a Reaction conditions: substrate 1 (1 mmol), NH4I (20 mol%), oxone (1 mmol), MeOH (5 mL), 30 °C.b Isolated yields.c Values shown in parenthesis refer to yields of the corresponding vicinal dimethoxylated products (2′).d No reaction was observed.e Yield of the corresponding 1,2-dimethoxylated product 2t′.
1	R = Ph, R^1 = H; 1a	4.95	2a	83
2	R = p-MeC6H4, R^1 = H; 1b	4.33	2b	83
3	R = m-MeC6H4, R^1 = H; 1c	4.35	2c	82
4	R = p-t-BuC6H4, R^1 = H; 1d	6.75	2d	83
5	R = p-MeOC6H4, R^1 = H; 1e	3	2e	78
6	R = o-MeOC6H4, R^1 = H; 1f	8.5	2f	67
7	R = m-NO2C6H4, R^1 = H; 1g	24	2g	22 (56)^c
8	R = p-F3CC6H4, R^1 = H; 1h	24	2h	48 (36)^c
9	R = p-FC6H4, R^1 = H; 1i	4.83	2i	81
10	R = m-FC6H4, R^1 = H; 1j	5	2j	79
11	R = p-ClC6H4, R^1 = H; 1k	5.6	2k	81
12	R = m-ClC6H4, R^1 = H; 1l	6	2l	78
13	R = p-BrC6H4, R^1 = H; 1m	5.7	2m	79
14	R = m-BrC6H4, R^1 = H; 1n	6	2n	77
15	R = 2-naphthyl, R^1 = H; 1o	10	2o	46
16	R = Ph, R^1 = Me; 1p	4.85	2p	85
17	R = Ph, R^1 = CH2OH; 1q	11	2q	66
18	R = Ph, R^1 = COPh; 1r	24	2r	—^d
19	R = Ph, R^1 = NO2; 1s	24	2s	—^d
20	R = R^1 = Ph; 1t	14	2t	45 (44)^c^,^e
21	R = R^1 = Ph; (cis-isomer) 1u	24	2t	52 (37)^c^,^e
22	R = C6H5CH2, R^1 = H; 1v	11	2v	00 (61)^c
23	R = n-decyl, R^1 = H; 1w	24	2w	00 (60)^c

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To further extend the scope of this reaction, we investigated the 1,2-disubstituted aromatic alkenes and aliphatic alkenes using the same conditions. Aromatic olefins containing alkyl substituents on double bond gave the corresponding products 2p and 2q in 66–85% yields (Table 1, entries 16–17). Surprisingly, the both trans- and cis-stilbenes (1t and 1u) afforded the same product (geminal dimethoxylated product) 2t in 45 and 52% yields, respectively, along with corresponding 1,2-dimethoxy derivative 2t′ under similar conditions (Table 1, entries 20–21). The presence of strong electron withdrawing groups either on aromatic ring or double bond of substrate had the significant effect on reaction yield. For example, the reaction of 1g or 1h led to low to moderate yield of desired products, while the trans-chalcone (1r) and trans-β-nitrostyrene (1s) did not react under standard conditions to yield the desired geminal difunctionalized products (Table 1, entries 7–8 and 18–19). Unfortunately, the reactions of allylbenzene (1v) and 1-dodecene (1w) afforded the respective vicinal dimethoxylated products, instead of geminal dimethoxylated (i.e., terminal methyl acetals) products, in 60–61% yields (Table 1, entries 22–23).

After evaluating the scope and limitations of this method, we were interested in gaining insight into the reaction mechanism. In this context, initially, we have performed several control experiments and isotope labeling experiments.¹⁸ These investigations clearly indicating that the reaction proceeds through an isolable intermediate 3 and the de-iodination of stable co-iodo intermediate 3 can be realized in presence of oxone rather than a common iodide abstraction by bronsted acids or electrophilic iodine species. Moreover, the isotope labeling study providing the solid evidence for the involvement of vicinal migration of aryl group in the conversion of 1 to 2 through a semipinacol rearrangement.

The above investigations endorsing that the reaction of 1 under standard conditions proceeds via tandem iodo functionalization followed by de-iodination induced semipinacol rearrangement to provide the desired terminal acetal 2. However, the de-iodination, in presence of oxone, may involve the formation of hypervalent iodine containing intermediate 4. Hence, we have carried out mass spectrometric investigations in order to identify the reactive intermediate 4 and other transient species formed in situ during the conversion of 1 to 2 for a thorough understanding of reaction pathway.

With an intention to detect the reactive intermediates in the metal-free catalytic acetalization of vinylarenes, we have performed the High Resolution Electrospray Ionization Mass Spectrometry (HRESI-MS) experiments on the model reaction of acetalization of styrene. To our delight, these HRESI-MS experiments provided the firm evidence for the formation of hypervalent iodine containing compound (co-iodo compound 4a, see Fig. 1) during the conversion of 1a to 2a, which could be formed in situ by the oxidation of isolable intermediate 3a.¹⁸

Fig. 1 High Resolution ESI-MS (positive mode) spectrum of styrene acetalization reaction mixture after 30 min of reaction time (enlarged between m/z = 223 and m/z = 254).

After the HRESI-MS detection of reactive intermediates, we were interested in identifying the active iodine species generated in situ from the oxidation of iodide ion by oxone in methanol. In this context, we have performed the UV-Vis absorption studies and found that the oxidation of iodide ion by oxone generates transient HOI species, which catalyze the nucleophilic addition of methanol to alkenes.¹⁸

Based on the above investigated results and literature reports, a plausible pathway for the iodide salt/oxone mediated catalytic nucleophilic addition of methanol to vinylarenes is proposed and is shown in Scheme 3. The oxidation of iodide ion by oxone in methanol generates transient HOI species (A). The A reacts competitively with the double bond of an aromatic alkene, to form a stable intermediate 3 (via a short-lived cyclic iodonium ion (B) intermediate), and an unreacted I⁻ (to form triiodide ion). The oxone converts I₃⁻ back into A in situ to participate in the catalytic cycle. The oxidation of 3 by oxone leads to the formation of hypervalent iodine(III) species 4. The species 4 may forms adduct C with methanol^17b and then undergoes reductive elimination to generate a transient phenonium ion D and A. At this stage, the nucleophilic attack of methanol can takes place in two distinct pathways (path a and path b). The acidic nature of the reaction medium, due to the presence of oxone, probably makes methanol molecules as strong nucleophiles. The nucleophilic attack of methanol molecule at the carbon atom, containing methoxide group, of species D followed by migration of aryl group led to desired anti-Markovnikov methyl acetal 2 (path a), while the methanol addition to D following path b affords the vicinal dimethoxylation product 2′. The species A regenerated in the first cycle continues the catalytic cycle until the complete conversion of starting material into the product.

Scheme 3 Plausible mechanism for the iodide salt/oxone mediated catalytic addition of methanol to vinylarenes.

The de-iodination, via oxidation of 3 by oxone to 4 followed by reductive elimination, induced semipinacol rearrangement (path a) is the key step for achieving the anti-Markovnikov regioselectivity in the hypoiodous acid-catalyzed addition of methanol to vinylarenes.

Conclusions

In conclusion, we have developed a novel methodology for the catalytic nucleophilic addition of methanol to vinylarenes for the synthesis of anti-Markovnikov acetals using in situ generated hypoiodous acid from NH₄I and oxone. This metal-free procedure featuring the step economic approach, compared to conventional methods which involve the pre-synthesized aldehydes, for the preparation of terminal acetals and the employment of facilely and commercially available reagents under mild conditions. The other advantages of this method are the exclusion of the need for the use of stoichiometric or over stoichiometric hypervalent iodine compounds, harsh reaction conditions and transition metals. In addition, the scope and limitations of this process are demonstrated with various terminal and internal alkenes. Moreover, the mechanistic investigations provided the solid evidence for the in situ generation of transient HOI as active catalytic species from the oxidation of iodide ion by oxone and the de-iodination of co-iodo intermediate via its oxidation to hypervalent iodine species rather than a common iodide abstraction by electrophiles. Furthermore, the isotope labeling experiment unambiguously confirming that the reaction proceeds through a semipinacol rearrangement, which is the key step for achieving the anti-Markovnikov selectivity in the acetalization of vinylarenes under present catalytic conditions.

Acknowledgements

We thank the CSIR Network project CSC-0125 for financial support. P.S. and K.S. acknowledge the UGC, India and M.N., M.M.R. and C.D. acknowledge the CSIR, India for financial support in the form of fellowships.

Notes and references

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18. see the ESI† for more details.

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Footnote

† Electronic supplementary information (ESI) available. See DOI: 10.1039/c5ra16826k

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