Catalyst-Free 1,6-Conjugate Addition/Aromatization/Sulfonylation of para-Quinone Methides: Facile Access to Diarylmethyl Sulfones.

An efficient, catalyst-free strategy to construct diarylmethyl sulfones via 1,6-conjugate addition/aromatization/sulfonylation reaction of para-quinone methides with sulfonyl hydrazides under mild and environmentally benign conditions has been developed. The established protocol provided a highly chemo- and regioselectivity synthesis of a diverse array of novel diarylmethyl sulfones with excellent yields, and the reaction could be scaled up.

Introduction

In recent years, developing green and sustainable chemical procedures to achieve the targets have attracted the attention of more and more chemists. Many great achievements of “green and sustainable chemistry” have been made, such as n class="Chemical">metal-free catalysis[1−5] aclass="Chemical">nd catalyst-free syclass="Chemical">nthesis.[6−11] For the past few years, exploriclass="Chemical">ng greeclass="Chemical">n aclass="Chemical">nd sustaiclass="Chemical">nable methodologies for coclass="Chemical">nstructiclass="Chemical">ng the C–S boclass="Chemical">nd have emerged as a sigclass="Chemical">nificaclass="Chemical">nt field of research iclass="Chemical">n orgaclass="Chemical">nic syclass="Chemical">nthesis[12,13] aclass="Chemical">nd medical chemistry.[14−18] class="Chemical">n class="Chemical">Diarylmethyl sulfones as one of the most important sulfur-containing compounds, which are often valuable intermediates in organic transformations[19−21] such as construction of triarylmethane derivatives, are widely present in medicinal chemistry and materials science.[22−24]

Recently, several methods for their preparation have been reported, such as the oxidation of corresponding n class="Chemical">sulfides (Figure (i))[25] aclass="Chemical">nd class="Chemical">n class="Chemical">copper-catalyzed nitrogen loss of sulfonylhydrazones (Figure (ii)).[26] In the past few years, transition metal-catalyzed arylation of 1 with aryl halide via nucleophilic substitution reaction to construct diarylmethyl sulfones has been well-documented (Figure (iii)).[21,27−30] For example, in 2014, Nambo et al.[21] reported a Pd-catalyzed C–H arylation of monoarylated sulfones with iodoarenes to provide diarylmethyl sulfones. Unfortunately, heteroaromatic substrates were not well-tolerated by the arylation reaction and formed products with lower yields (30–42%). In addition, to obtain the diarylmethyl sulfones, [{PdCl(allyl)}2] (5 mol %), P(tBu)3·HBF4 (20 mol %), and KOtBu (3.0 equiv) and a high temperature were required. The common points of the aforementioned transition metal-catalyzed methods, high acidity of the benzylic proton and strong base, are often required.[21,27−30] To the best of our knowledge, phenylsulfinate ion (PhSO2–) presents two tautomers, sulfone and sulfinate, and therefore has the selective of the O-attack or S-attack of carbocations to provide sulfones (Ar2CH–SO2Ph) or esters (Ar2CH–OS(O)Ph).[31] Notably, most of the methods described above often suffer from the common limitations of using toxic and odorous reagents, hazardous and costly catalysts, rigorous reaction conditions, poor selectivity, limited substrates, and low functional group compatibility. To address these limitations, developing efficient, green, and sustainable strategies to construct diarylmethyl sulfones remains important and is challenging. In continuation of our interest in constructing functionalized molecules,[32−36] herein, we report a catalyst-free, facile, and efficient route for the synthesis of diarylmethyl sulfones from the readily available starting materials, sulfonyl hydrazides[9,37] and p-quinone methides (p-QMs),[38−53] which are widely used in modern organic synthesis because of the assembly of carbonyl and olefinic moieties (Figure b).

Figure 1

Synthesis of diarylmethyl sulfones: (a) previous methods and (b) our strategy.

Synthesis of n class="Chemical">diarylmethyl sulfones: (a) previous methods aclass="Chemical">nd (b) our strategy.

Results and Discussion

We commenced our study by selecting n class="Chemical">p-QM 2a aclass="Chemical">nd class="Chemical">n class="Chemical">sulfonyl hydrazide 3a as model substrates and ethanol as the solvent to optimize the reaction conditions (Table ). Pleasingly, the reaction smoothly occurred in the numerous organic acidic catalysts or organic basic catalysts, offering the desirable product 4aa in 15–80% yield (Table , entries 1–10). Furthermore, better results were observed in the organic basic catalysts. By contrast, only a trace of the product was observed in the presence of the inorganic bases (Table , entries 11–12). On the basis of the aforementioned results, we envisioned whether the reaction could occur in neutral catalysts. To our delight, the reaction could work well without any catalyst, obtaining 4aa with a satisfactory yield. Notably, the yield of 4aa was remarkably increased when the mixed solvents (EtOH/H2O, 3:1, v/v) were applied (Table , entries 14–22). The result revealed that water played an important role in the reaction, although the substrates have poor solubility in water. Furthermore, the higher or lower temperature was obviously adverse to the reaction (Table , entries 23–24). Thus, the optimum conditions were achieved by employing 2a (0.1 mmol) and 3a (0.11 mmol) in EtOH/H2O (3:1, v/v) under 50 °C for 8 h (Table , entry 22). Notably, high chem- and regioselectivities were observed, and the corresponding ester, 1,2- or 1,4-addition product was not detected in any case.

Table 1

Optimization of the Reaction Conditiona

entry	catalystb	solvent	t (h)	yieldc (%)
1	HOAc	EtOH	10	30
2	TFA	EtOH	10	15
3	PhCO2H	EtOH	10	45
4	TEA	EtOH	10	77
5	i-Pr2NH	EtOH	10	80
6	TMG	EtOH	10	30
7	DBU	EtOH	10	42
8	DABCO	EtOH	10	55
9	DMAP	EtOH	10	44
10	t-BuOK	EtOH	10	35
11	Na2CO3	EtOH	10	trace
12	K2CO3	EtOH	10	trace
13		EtOH	10	81
14		MeOH	10	70
15		toluene	10	60
16		CHCl3	10	65
17		THF	10	72
18		CH3CN	10	50
19		EtOAc	10	25
20		DMF	10	N.D.
21		H2O	10	60
22		EtOH/H2O (3:1, v/v)	8	90
23d		EtOH/H2O (3:1, v/v)	8	80
24e		EtOH/H2O (3:1, v/v)	64	75

The reaction was performed with 2a (0.1 mmol), 3a (0.11 mmol), and the solvent (2.0 mL).

Catalyst (20 mol %).

Isolated yield based on p-QM 2a.

Temperature = 70 °C.

Room temperature (23 °C).

Isolated yield based on n class="Chemical">p-QM 2a.

With the optimal reaction conditions in hand, the scope of the 1,6-conjugate addition/aromatization/sulfonylation reaction of n class="Chemical">p-QMs to class="Chemical">n class="Chemical">sulfonyl hydrazides was investigated.

First, a set of n class="Chemical">sulfonyl hydrazides 3 were tested by keepiclass="Chemical">ng class="Chemical">n class="Chemical">p-QM 2a constant. For sulfonyl hydrazides 3, the substituents on the aromatic ring, whether with electron-donating groups [Me, OMe, 2,4,6-(Me)3, and Ph] or electron-withdrawing groups (F, Cl, Br, NO2, and CF3), afforded the corresponding diarylmethyl sulfones with excellent yields 80–96% (Table , entries 1–10). Notably, the sterically hindered mesitylenesulfonohydrazide was also well-tolerated by the conjugate addition reaction to give product 4ad in 80% yield (Table , entry 4), however, the substrate could not participate in the sulfonylation reaction in Patil’s report.[54] Subsequently, α-naphthylsulfonyl hydrazide and β-naphthylsulfonyl hydrazide were tested, and the desired products 4ak–4al were obtained in 94 and 91% yields, respectively (Table , entries 11–12). More importantly, thienylsulfonyl hydrazide and aliphaticsulfonyl hydrazides also worked satisfactorily under the optimal reaction conditions to give the corresponding targets in 88–90% yields (Table , entries 13–16). It is interesting to observe that (−)-10-camphorsulfonyl hydrazide also survived, and in this transformation, product 4aq was obtained in 85% yield with 1.3:1 diastereoselectivity (Table , entry 17).

Table 2

Catalyst-Free Synthesis of Diarylmethyl Sulfones 4aa–4aqa

entry	R	t (h)	4	yieldb (%)
1	Ph	8	4aa	90
2	4-Me-C6H4	18	4ab	82
3	4-MeO-C6H4	6	4ac	80
4	2,4,6-(Me)3-C6H2	20	4ad	80
5	4-F-C6H4	3	4ae	93
6	4-Cl-C6H4	3.5	4af	92
7	4-Br-C6H4	4	4ag	92
8	4-NO2-C6H4	16	4ah	81
9	4-CF3-C6H4	1	4ai	96
10	4-Ph-C6H4	8	4aj	88
11	α-naphthyl	2	4ak	94
12	β-naphthyl	5	4al	91
13	2-thienyl	3	4am	92
14	Bn	10	4an	88
15	Et	24	4ao	90
16	n-Bu	12.5	4ap	90
17c	(−)-10-camphoryl	16	4aq	85

All reactions were performed with 2a (0.1 mmol) and 3 (0.11 mmol) in the solvent (2.0 mL).

Isolated yield based on p-QM 2a.

Compound 4aq with 1.3:1 diastereoselectivity.

Isolated yield based on n class="Chemical">p-QM 2a.

Next, we investigated the utility of n class="Chemical">p-QMs for the reactioclass="Chemical">n uclass="Chemical">nder the staclass="Chemical">ndard reactioclass="Chemical">n coclass="Chemical">nditioclass="Chemical">ns. As showclass="Chemical">n iclass="Chemical">n Table , various stable class="Chemical">n class="Chemical">p-QMs with electron-rich and electron-deficient substituents at the ortho, meta, and para positions of the aryls were compatible with the reaction, providing the desired products with excellent yields and high chem- and regioselectivities (Table , entries 1–13). Furthermore, α-naphthyl-substituted p-QM was well-tolerated by the transformation to give product 4bn in 91% yield (Table , entry 14). Notably, heteroaromatic-substituted p-QMs underwent the 1,6-conjugate addition reaction with sulfonyl hydrazide 3a smoothly, giving the desired diarylmethyl sulfones in 85–90% yield (Table , entries 15–16).

Table 3

Catalyst-Free Synthesis of Diarylmethyl Sulfones 4ba–4bpa

entry	Ar	t (h)	4	yieldb (%)
1	4-Me-C6H4	7	4ba	90
2	4-MeO-C6H4	24	4bb	82
3	3,4-(MeO)2-C6H3	11	4bc	83
4	4-tBu-C6H4	12	4bd	90
5	4-F-C6H4	7	4be	95
6	4-Cl-C6H4	8	4bf	95
7	4-Br-C6H4	10	4bg	95
8	3-Br-C6H4	7.5	4bh	93
9	2-Br-C6H4	12	4bi	92
10	4-I-C6H4	8	4bj	95
11	4-CN-C6H4	11	4bk	88
12	4-NO2-C6H4	20	4bl	80
13	4-CF3-C6H4	3	4bm	94
14	α-naphthyl	12	4bn	91
15	2-thienyl	24	4bo	85
16	2-pyridyl	9	4bp	90

All reactions were performed with 2 (0.1 mmol) and 3a (0.11 mmol) in the solvent (2.0 mL).

Isolated yield based on p-QM 2.

Isolated yield based on n class="Chemical">p-QM 2.

To further demonstrate the potential utility of our strategy, we selected n class="Chemical">phenylsulfonyl hydrazide 3a aclass="Chemical">nd class="Chemical">n class="Chemical">n-butylsulfonyl hydrazide 3p as the sulfonyl precursors to react with p-QM 2a as the two representative examples to be scaled up (5.0 mmol 2a). To our delight, the yield of the corresponding products remained reasonable with 88% (4aa) and 86% (4ap) yields, respectively (Scheme ).

Scheme 1

Two Representative Examples to be Scaled Up

The chemical structures of n class="Chemical">diarylmethyl sulfones 4 were fully characterized by protoclass="Chemical">n class="Chemical">nuclear magclass="Chemical">netic resoclass="Chemical">naclass="Chemical">nce (class="Chemical">n class="Chemical">1H NMR), carbon nuclear magnetic resonance (13C NMR), and high-resolution mass spectrometry (HRMS) spectroscopies. To further verify the structure of the targets, 4aa was selected as a representative compound and unequivocally confirmed by X-ray diffraction analysis, as shown in Figure (CCDC 1583037).

Figure 2

Oak Ridge thermal ellipsoid plot diagram of 4aa; ellipsoids are drawn at the 30% probability level.

Furthermore, several controlled experiments were conducted to get a deep insight into the mechanism of the sulfonylation process. Initially, n class="Chemical">2,2,6,6-tetramethyl-1-piperidinyloxy as the radical scaveclass="Chemical">nger was employed to elucidate whether the reactioclass="Chemical">n iclass="Chemical">nvolves radical species uclass="Chemical">nder staclass="Chemical">ndard reactioclass="Chemical">n coclass="Chemical">nditioclass="Chemical">ns. The radical trappiclass="Chemical">ng experimeclass="Chemical">nts revealed that the traclass="Chemical">nsformatioclass="Chemical">n did class="Chemical">not proceed via a free-radical pathway, affordiclass="Chemical">ng 4aa iclass="Chemical">n 65% yield (Scheme , a). Subsequeclass="Chemical">ntly, to clarify the source of class="Chemical">n class="Chemical">hydrogen in the phenolic hydroxyl group of the product, EtOD/D2O and toluene/D2O were used as the reaction media under standard conditions, respectively (Scheme , b and c). Interestingly, we did not detect the deuterated product, and the result indicated that the origin of hydrogen of phenolic hydroxyl was not derived from H2O and EtOH. Thus, we speculated that hydrogen may be derived from benzenesulfonyl hydrazide itself.

Scheme 2

Mechanistic Investigations of the Sulfonylation Process

Toluene was strictly distilled with sodium.

n class="Chemical">Toluene was strictly distilled with class="Chemical">n class="Chemical">sodium.

On the basis of the aforementioned results and previous reports,[9,37,55,56] it is reasonable to speculate a possible reaction pathway, which is depicted in Scheme . First, n class="Chemical">sulfonylhydrazide 3a is quickly traclass="Chemical">nsformed iclass="Chemical">nto class="Chemical">n class="Chemical">sulfinyl anion 6, which can resonate with sulfur-centered anion 7 in the presence of water, generating hydronium ions and releasing N2. Then, sulfur-centered anion 7 is selectively added to p-QM 2a via the 1,6-conjugate addition reaction to form intermediate 8. Finally, the target product 4aa was obtained by proton transfer from hydronium ions and aromatization reaction.

Scheme 3

Mechanism Hypotheses for the Synthesis of Target Compounds 4aa

Conclusions

In summary, we report a catalyst-free 1,6-conjugate addition/aromatization/sulfonylation reaction of n class="Chemical">p-QMs, a facile aclass="Chemical">nd efficieclass="Chemical">nt route to syclass="Chemical">nthesis class="Chemical">n class="Chemical">diarylmethyl sulfones. The established protocol provided a concise, rapid, and environmentally friendly vision to prepare a diverse array of diarylmethyl sulfones. The reaction has attractive features, including mild conditions, environmentally friendly, high chemo- and regioselectivities, broad scope of substrates, excellent yields, and scalability. The controlled experiments indicated that hydrogen of phenolic hydroxyl may be derived from benzenesulfonyl hydrazide. The mechanistic details and the potential utility of diarylmethyl sulfones in organic synthesis are currently underway.

Experimental Section

General Methods

All received reagents and solvents were used without further purification, unless otherwise stated. Melting points were determined on a XT-4A melting point apparatus and are uncorrected. NMR spectra were recorded on a n class="Chemical">Bruker 400 (class="Chemical">n class="Chemical">1H: 400 MHz, 13C: 100 MHz) with CDCl3 as the solvent. The chemical shifts (δ) are expressed in parts per million relative to the residual deuterated solvent signal, and coupling constants (J) are given in hertz. HRMS (electrospray ionization) was performed on an Agilent LC/MSD TOF instrument.

All chemicals and solvents were used as received without further purification, unless otherwise noted. Column chromatography was performed on n class="Chemical">silica gel (200–300 mesh). class="Chemical">n class="Chemical">p-QMs 2 and sulfonyl hydrazides 3 were prepared according to a procedure described in the literature.[9,37−39,41] The structure of diarylmethyl sulfones 4 were confirmed by 1H NMR, 13C NMR, and HRMS spectra.

General Procedure for the Synthesis of Compounds 4

A 10 mL round-bottom flask was charged with n class="Chemical">p-QMs 2 (0.1 mmol), class="Chemical">n class="Chemical">sulfonyl hydrazides 3 (0.11 mmol), EtOH/H2O (1.5–0.5 mL, v/v), and the solution was stirred for 2–24 h under 50 °C until p-QMs 2 were completely consumed, as indicated by thin-layer chromatography. Then, the crude products were purified by flash silica gel chromatography (petroleum ether/EtOAc = 10:1–6:1), which afforded the pure product 4 in 80–95% yields.