Lewis Basic Salt-Promoted Organosilane Coupling Reactions with Aromatic Electrophiles

Abstract

Lewis basic salts promote benzyltrimethylsilane coupling with (hetero)aryl nitriles, sulfones and chlorides as a new route to 1,1-diarylalkanes. This method combines the substrate modularity and selectivity characteristic of cross-coupling with the practicality of a base-promoted protocol. In addition, a Lewis base strategy enables a complementary scope to existing methods, employs stable and easily prepared organosilanes and achieves selective arylation in the presence of acidic functional groups. The utility of this method is demonstrated by the synthesis of pharmaceutical analogues and its use in multicomponent reactions.

Graphical abstract

1,1-Diarylalkanes are valuable compounds often prepared by coupling functionalized benzylic reagents with aromatic electrophiles.¹ In practice, the benzylic coupling partner and mechanism for achieving C–C bond formation define the scope and suitability of a given method. A widely used strategy is transition metal-catalyzed coupling of aryl (pseudo)halides with benzyl magnesium, zinc and boron compounds.^2,3 This approach enables robust and predictable reactivity often at the expense of using reactive benzylic reagents prepared in situ. Significant recent effort has been focused on alternative coupling partners and strategies to increase the efficiency and scope of 1,1-diarylalkane synthesis.^1,4-6

Benzylic deprotonation represents one such attractive strategy that generates carbanion intermediates for metal-catalyzed⁷ and catalyst-free⁸ reactions with aryl electrophiles (Figure 1, left). Direct deprotonative arylation is perhaps ideal as no catalyst is needed and only inexpensive reagents are used. However, this approach often leads to multiarylation side products and typically requires acidic pronucleophiles such as diarylmethanes.⁸ Deprotonative activation also limits the coupling scope to relatively simple substrates in which the most acidic proton is at the desired benzylic position.

Figure 1.

Background and motivation for Lewis base-promoted arylation reactions of organotrimethylsilanes.

We sought a new benzylic arylation method that blends the modularity and selectivity of cross-coupling with the practicality of a base-promoted protocol. This drew our attention toward Lewis base activation of Lewis acidic benzyl compounds, an underdeveloped approach for aryl Csp²-Csp³ coupling.⁹ In this regard, benzyltrimethylsilanes could be ideal coupling partners as they are air stable, non-hygroscopic and easily accessed in great diversity.¹⁰ Furthermore, distinct synthetic routes are available to complex benzyltrimethylsilanes that cannot be used to access analogous organometallic reagents.¹¹ To date, the high stability of benzyltrimethylsilanes has rendered them unreactive in metal-catalyzed cross-coupling¹² and thus their use in arylation reactions is limited.¹³ More specialized silanes are required to overcome this challenge in conjunction with Pd- and metallaphotoredox-catalyzed methodology (Figure 1, right).¹⁴

We herein report that Lewis basic salts promote the direct coupling of benzyltrimethylsilanes to a range of aromatic electrophiles (Figure 1, bottom). Benzylic arylation outcompetes potential anionic side reactions to enable monoselective coupling in the presence of acidic and electrophilic functional groups. This strategy can be extended to other organosilanes and reaction sequences, including the tandem arylation/isomerization of allylsilanes as a new route to alkenyl arenes. Thus, Lewis base-promoted arylation provides a practical coupling protocol with a reaction scope that complements established methods.

We recently reported the monoselective defluoroallylation of trifluoromethylarenes enabled by fluoride activation of allyltrimethylsilanes (Scheme 1a).¹⁵ This reaction is proposed to operate through an anionic allyl intermediate that undergoes single electron transfer (SET) to the trifluoromethylarene, leading to C–F bond cleavage and allylation of the resulting difluorobenzylic radical. This sequence has similarities to photoinduced electron transfer (PET) allylation of 1,4-dicyanoarenes using allyltrimethylsilane, namely SET prior to C–C bond formation.¹⁶ Benzyltrimethylsilane has also been examined in PET studies, although these reactions suffer from low regioselectivity and side product formation while requiring use of ultraviolet light (Scheme 1b).^16a,17 Based on these precedents, we hypothesized Lewis base activation of organotrimethylsilanes could promote their direct coupling with aromatic electrophiles beyond trifluoromethylarenes.

Scheme 1. Reported organosilane reactions with aryl electrophiles and development of base-promoted arylation.

^aYields determined by ¹H NMR spectroscopy; 18-crown-6 added as a 1M solution in THF. 18 h time for salts other than CsF. ^bYields improve to 57% and 84% at 100 °C without 18-crown-6 for Cs₂CO₃ and KF, respectively.

To test this hypothesis, we examined the reaction of 4-cyanopyridine (1) with benzyltrimethylsilane (2) and found 18-crown-6-ligated cesium fluoride promotes monoselective coupling in 3 h at room temperature (rt) in DMSO (95% yield, Scheme 1c). Less basic anions, including carbonate, bifluoride and phosphate salts, promote arylation in moderate yields. Conditions in the boxes of Scheme 1c show the ability to adjust reaction parameters depending on priority, ranging from the use of fluoride-free salts without 18-crown-6 to short reaction times or large reaction scale.

Table 1 contains a product scope for benzyltrimethylsilane coupling with cyanoarenes using CsF and 18-crown-6 in DMSO. Primary, secondary and tertiary benzylsilanes react with 2- and 4-cyanopyridines and electron-deficient cyanobenzenes (Table 1a and b). The products feature redox-active and electrophilic aryl substituents such as alkynes (6), styrenes (9), nitriles (7, 10, 12, 16), sulfones (8), trifluoromethyl groups (11) and activated halides (17, 18, 20, 22, 25). Acidic and electrophilic functional groups, including alkyl benzoates (17), phthalimides (18), alkenes (19), alkyl pyridines (19-21) and esters (22-24) are also tolerated. Table 1c shows products of α-heteroatom benzylsilanes (25-27) and with paroxetine (28) and bepotastine (29) drug substructures. Product 27, derived from an α,α-difluorobenzyltrimethyl-silane prepared via trifluoromethylarene defluorosilylation, illustrates a benzylic coupling partner unique to this method.^11a,18 In sum, the scope features substitution patterns and functionalities that are difficult to access or not tolerated in alternative arylation strategies.

Table 1.

Product scope using cyanoarene electrophiles.^a

^aIsolated yields from reactions using 1.0 mmol of cyanoarene; 18-crown-6 added as a 1M solution in THF.

^b1.5 equiv of silane.

^c2.0 equiv of silane.

We next examined aryl electrophiles that do not generate cyanide byproducts (Scheme 2a). 2-Chloro-1,3-azoles are effective coupling partners (30-32), as are chlorides with extended π-systems, such as 1,3-dichloroisoquinoline (33), 9-chloroacridine (34) and the 2-chloroquinoline derivative of the anti-tumor drug imiquimod (35). Although 4-halopyridines do not react under these conditions, 4-sulfonylpyridines provide good yields (Scheme 2b).¹⁹ To show the benefits of this finding, 4-chloropyridine 37, for which the 4-cyano congener is not commercially available, was converted to sulfone 38 on multigram scale without chromatography (Scheme 2c).²⁰ Benzylsilane coupling to 38 under the standard conditions without crown ether yielded 5.9 g of diarylalkane 39. Thus, base-promoted benzylation is applicable to heteroaryl halides either directly or after sulfonyl group installation.

Scheme 2. Expansion of aryl electrophile scope.

^aIsolated product yields. ^bYields determined by ¹H NMR spectroscopy of crude reaction mixtures. 18-Crown-6 added as a 1M solution in THF.

This method can facilitate access to 1,1-diarylalkane compound libraries from abundantly available cyano and chloroarenes. We selected the antihistamine chlorpheniramine to demonstrate this concept, for which the corresponding benzylsilane precursor 40 can be readily prepared on 75 mmol scale (Figure 2).²¹ Coupling of 40 with eight arene electrophiles generates diverse chlorpheniramine analogues, including trifluoromethyl- (41), methyl- (42), halo- (43, 44) and aryl-substituted (46) variants. A 2-chloro-1,3-benzothiazole (45), a 4-cyanoquinazoline (47) and 4-chloroquinoline (48) also react to access greater structural variety.

Figure 2.

Synthesis of chlorpheniramine analogues. Yields shown are of purified products. 18-Crown-6 added as a 1M solution in THF. ^a Chloroarene substrate used.

We next performed studies on the reaction selectivity for arylation over other anionic processes. When the aryl electrophile is removed from the standard conditions, toluene forms in 80% yield after 2 h (Scheme 3a).²² This suggests benzylic protonation is a competing pathway with arylation; however, it is interesting to note that benzylation of 4-cyanopyridine occurs in solvents significantly more acidic than toluene (Scheme 3b).^23,24 Furthermore, separate reactions of two benzylsilane isomers (50 and 52) led to regioselective arylation for the original position of the −SiMe₃ group (Scheme 3c). These results demonstrate arylation occurs preferentially over potential proton transfer events.²⁵ An important implication is that deprotonation of acidic diarylalkane products is minimized, thus preventing multiarylation side reactions. These findings also illustrate critical advantages of a Lewis base-promoted arylation method, as a Brønsted base approach would not generate benzylic carbanions in the presence of more acidic protons, and would likely lead to multiarylation and poor selectivities in substrates with multiple benzylic positions.²⁶

Scheme 3. Investigation of benzylic arylation selectivity.

^aYields determined by ¹H NMR spectroscopy of crude reaction mixture. ^bIsolated product yields. 18-Crown-6 added as 1M solution in THF.

To explain the high arylation selectivity, we propose an anionic benzylic intermediate²⁵ undergoes rapid aromatic substitution via a polar or SET-based mechanism (Figure 3).²⁷ The SET mechanism is the base-promoted analogous pathway to PET reactions of organosilanes with 1,4-dicyanoarenes.^17,28,29 A polar process is also plausible as cyano- and sulfonylarenes can participate in typical addition-elimination substitution reactions.³⁰ Distinguishing between these processes is known to be challenging for addition of anionic reagents to similar electrophiles^31,32 and we have made observations explainable by both pathways.³³ The coupling mode may also be substrate dependent, although arylation uniformly outcompetes other anionic reactions as monoselectivity occurs for all reported substrates.³⁴

Figure 3.

Potential pathways and rationale for selective arylation.

From these studies, we realized organosilane arylation could be incorporated into tandem base-promoted reaction sequences. First, we found allyltrimethylsilanes react to form allyl arene intermediates that undergo stereoselective isomerization to aryl alkenes 54, 55 and 56 (Scheme 4a).^35,36

Scheme 4. Expanded scope using new coupling partners.^a.

^aYields are of purified product; diastereoselectivities determined by ¹H NMR spectroscopy; 18-crown-6 added as 1M solution in THF. ^b>10:1 alkene E:Z ratios observed. ^cReaction performed at 60 °C. ^dCorresponding 4-phenylsulfonyl pyridine used as substrate. ^eArCN (1 equiv), organosilane (1.2 equiv) and acrylamide (1-2 equiv) used.

Next, we proposed a three-component coupling process between organosilanes, aryl electrophiles and Michael acceptors. We hypothesized selective benzylic arylation would occur and the remaining catalytic organosilane/fluoride combination could initiate a Michael addition reaction (Scheme 4b).³⁷ Thus, γ,γ-diaryl amides 57 and 58 can be prepared via this strategy. Using methallyltrimethylsilane, tetrasubstituted alkene 59 forms through three selective base-promoted processes (arylation, addition and alkene isomerization).

In conclusion, Lewis basic salts provide a practical means of engaging benzyl- and allyltrimethylsilanes in arylation reactions. This approach enables regio- and monoselective access to 1,1-diarylalkane and aryl alkene products with complementary scope to existing methods. The strategic application of multiple base-promoted processes also facilitates advanced coupling sequences, a prospect we continue to explore.