Synthesis of Highly Congested Tertiary Alcohols via the [3,3] Radical Deconstruction of Breslow Intermediates

Abstract

Pericyclic processes such as [3,3]-sigmatropic rearrangements leading to the rapid generation of molecular complexity constitute highly valuable tools in organic synthesis. Herein, we report the formation of particularly hindered tertiary alcohols via rearrangement of Breslow intermediates formed in situ from readily available N-allyl thiazolium salts and benzaldehyde derivatives. Experimental mechanistic studies performed suggest that the reaction proceeds via a close radical pair which recombine in a regio- and diastereoselective manner, formally leading to [3,3]-rearranged products.

Graphical Abstract

Since the seminal reports by Breslow and co-workers on the formation of stabilized carbenes by deprotonation of thiazolium salts,¹ N-heterocyclic carbenes (NHC) have become invaluable tools for the construction of carbon–carbon bonds in organic synthesis.^2,3 In a typical mechanism, the NHC reacts with an aldehyde derivative to form a nucleophilic enaminol species denoted “Breslow intermediate”⁴ capable of reaction with a wide range of electrophiles, eventually leading to a functionalized ketone after NHC regeneration. While two-electron pathways are often operative and have been widely studied,² radical processes have recently emerged,⁵ opening a new realm of reactivities to explore with these versatile enaminol intermediates. More specifically, Ohmiya^5b,6 and others⁷ have shown that persistent α-hydroxy radicals can readily be formed from triazolidene- and thiazolidene-derived Breslow intermediates and react via radical–radical coupling to introduce sterically bulky substituents. Such radical coupling strategies are highly valuable to the synthetic community, since the extreme reactivity of the intermediates involved enables the possibility for C–C bond formation events difficult to achieve by two-electron pathways. In this regard, the elaboration of all-carbon quaternary centers remains a formidable challenge and is of great value to synthetic chemists,⁸ as these constitute ubiquitous units in natural products⁹ and are increasingly relevant to medicinal chemistry research.¹⁰ With this in mind, we reasoned that Breslow intermediates derived from N-allylated thiazolium salts would constitute ideal retrons for highly congested thiazole-containing tertiary alcohols via a [3,3] transform, where aromatization of the thiazole ring could exert an effective driving force. Notably, thiazole derivatives constitute important scaffolds found in synthetic drugs,¹¹ natural products,¹² or organic dyes for solar cells applications.¹³ While McIntosh and co-workers reported that benzothiazolium salts react to form the formal [1,3] (linear) products via radical pairs (Scheme 1a),^14,15 initial experiments performed in our lab with thiazolium analogues instead led us to believe that a fully selective [3,3] disconnection, leading to branched products instead, might be possible.¹⁶

Scheme 1.

Divergent Reactivity of Breslow Intermediates Derived from (Benzo)thiazolium Salts

Herein, we report an expedient synthesis of highly congested tertiary homoallylic alcohols via the rearrangement of Breslow intermediates formed in situ from simple thiazolium salts and benzaldehyde derivatives (Scheme 1b). Mechanistic studies performed via radical trapping and EPR experiments revealed that the reaction likely proceeds via fragmentation of the Breslow intermediate into a close radical pair which can recombine in a regio- and diastereoselective manner, formally affording [3,3]-rearranged products. Divergent fragmentation of the congested tertiary alcohols obtained by this method via various C–C bond cleavage strategies is also documented.

Several N-allylated thiazolium salts 1a–1j with different substitution patterns were readily prepared by simple treatment of thiazole with substituted allyl bromide derivatives at high temperature, followed by recrystallization or purification by flash chromatography (eq 1).¹⁶

(1)

N-Prenylated thiazole 1a was elected as a model substrate for further optimization studies by reaction with benzaldehyde, leading to tertiary homoallylic alcohol 2a (Table 1). DBU was rapidly identified as an ideal base for this transformation, whereas trialkylamines such as DIPEA typically afforded substantial amounts of benzoin side-product 2ab (entries 1–2).^1b,17 Ketone 2ac, presumably formed by radical decomposition of the Breslow intermediate, was also observed as a minor side-product in most cases. When the reaction was run in DMSO, complete conversion was observed in only 4 h at room temperature (entries 3–7), and decreasing the concentration to 0.02 M provided a substantially higher yield of 2a (entries 8–9). Notably, the corresponding linear product was not observed in any case with this substrate, in contrast to analogous reactions reported by McIntosh and co-workers involving benzothiazolium salts instead.¹⁴ In order to allow for isolation of the product by chromatography, the crude reaction mixture was treated with NaBH₄ in methanol to reduce the excess benzaldehyde still present, which was found to coelute with 2a (entries 10–11). Under the optimized conditions, congested alcohol 2a was isolated in 73% yield, and the reaction could be performed on a 1 mmol scale of substrate with similar efficiency (Scheme 2). A range of functionalized benzaldehyde derivatives were found to be compatible in the reaction with thiazolium salt 1a (see 2a–2m), with electron-poor aldehydes often affording the highest yield of desired tertiary alcohol.¹⁸ Aliphatic aldehydes were found to be unsuitable in this transformation likely due to a decreased stabilization of the α-hydroxy radical intermediate (vide infra), with mostly the benzoin product being observed in those cases. Various other substituted thiazolium salts were evaluated as substrates with 4-chlorobenzaldehyde, leading to a range of different branched tertiary alcohols in good yields and moderate diastereoselectivity (3a–3i). X-ray crystal structures obtained for tertiary alcohol 3f and the corresponding minor isomer (3f’)¹⁶ revealed the identity of the major diastereomer formed in each case.¹⁹ Interestingly, while trans- and cis-propyl-substituted thiazolium salts 1d and 1e both reacted to afford similar yields, the major diastereomers observed for 3c and 3d were different, which might be indicative of a nonconcerted rearrangement proceeding via a close radical pair.

Table 1.

Optimization of the Formal [3,3] Deconstruction of Breslow Intermediates to Tertiary Homoallylic Alcohols

entry	solvent	temp (°C)	concn (M)	yield (%)a
				2a	2ab	2ac
1b	Dioxane	80	0.15	36	0	0
2b,c	Dioxane	80	0.15	38	21	5
3	Dioxane	80	0.15	40	0	4
4	DMSO	80	0.15	53	5	11
5	DMSO	70	0.15	56	8	8
6	DMSO	60	0.15	64	4	5
7	DMSO	rt	0.15	65	3	4
8	DMSO	rt	0.075	76	7	2
9	DMSO	rt	0.020	80	3	5
10d	DMSO	rt	0.020	86	1	14
11d	DMSO	rt	0.020	74 (73)e	–	–

^aYield on a 0.1 mmol scale 1a determined by ¹H NMR using triphenylmethane as standard.

^bReaction was stirred for 18 h.

^cN,N-Diisopropylethylamine (2.0 equiv) was used as base.

^d3.0 equiv of benzaldehyde were used.

^eNMR yield of 2a after treatment of the crude mixture with NaBH₄ (isolated yield in parentheses).

Scheme 2.

Scope of Accessible Tertiary Homoallylic Alcohols^a

^aIsolated yields from 1a–1i on a 1 mmol scale after treatment of the crude mixture with NaBH₄ in methanol.

To gain further insight into the mechanism, the reaction with 1a was performed in the presence of various radical trapping reagents (Table 2). While the use of TEMPO²⁰ as an additive did not significantly affect the yield of alcohol observed (entries 1–4), more reactive radical inhibitors such as molecular oxygen (O₂)²¹ or 2-methyl-2-nitrosopropane dimer (MNP) led to an important reduction in the reaction efficiency (entries 5–6). The reactions performed in the presence of TEMPO also produced some 2,2,6,6-tetramethyl-piperidin-1-yl 4-chlorobenzoate (4) via oxidation of the Breslow intermediate,²² although the amounts isolated do not account for the inefficiency of TEMPO to inhibit the reaction. The fact that the reaction is only affected by highly reactive radical traps could be indicative of a mechanism where recombination of the radical pair is faster than diffusion from the solvent cage.²³ Moreover, the diastereomeric mixtures observed when starting from a single thiazolium isomer (see 3b–3i) further point to the presence of radical intermediates, since concerted [3,3]-sigmatropic rearrangements are known to be stereospecific.²⁴ Electron paramagnetic resonance (EPR) experiments were also performed and provided evidence of radical intermediates under the optimal conditions when MNP was employed as a radical trapping reagent.¹⁶ Based on these data and previous work involving thiazolidene-derived intermediates,^5b we propose that the reaction proceeds via fragmentation and rearomatization of the corresponding Breslow intermediate B (or its deprotonated form), generating a close radical pair C in resonance with the more stable (substituted) D (Scheme 3). Rapid radical recombination of D leads to the formation of the congested branched product 2a–2m or 3a–3i. Notably, an oxidized radical form of the enaminol B as an intermediate is also plausible.^17,25

Table 2.

Mechanistic Insights via Radical Inhibition Experiments

entry	Ar	inhibitor (equiv)	product	yield (%)a
1	Ph	–	2a	72
2	4-Cl-C6H4	–	2c	75
3	4-Cl-C6H4	TEMPO (2.0)	2c	71b
4	4-Cl-C6H4	TEMPO (4.0)	2c	65c
5	4-Cl-C6H4	O2 (excess)	2c	13
6	Ph	MNPd (1.0)	2a	17

^aIsolated yield from 1a after treatment of the crude mixture with NaBH₄.

^bProduct 4 (44%) was also isolated.

^cProduct 4 (35%) was also isolated.

^dMNP: 2-methyl-2-nitrosopropane dimer.

Scheme 3.

Proposed Mechanism of the Formal [3,3] Deconstruction of Breslow Intermediates to Tertiary Homoallylic Alcohols

When particularly hindered R²/R³ substituents are present on the thiazolium substrate, the selectivity can be reversed toward a formal [1,3] rearrangement,^14,15 leading to the linear product 3j instead via recombination of radical pair C (Scheme 4a). Moreover, the tertiary alcohols obtained by this method can diverge into ketones via various C–C bond cleaving strategies, as demonstrated here starting from 2a (Scheme 4b). In the presence of methyl triflate, the thiazole ring is effectively eliminated as an NHC under basic conditions to afford α-quaternary ketone 5 (left). Alternatively, the (reverse) prenyl group can be selectively cleaved under acidic conditions via alkene protonation, producing diaryl ketone 6 in good yield (right).

Scheme 4.

Alternative [1,3] Deconstruction with Hindered Substrates (a) and Divergent Product Fragmentation to Ketones (b)

In summary, we report a simple and efficient synthesis of highly congested tertiary homoallylic alcohols via the rearrangement of Breslow intermediates formed in situ from simple N-allyl thiazolium salts and benzaldehyde derivatives.²⁶ Experimental mechanistic studies suggest that the reaction likely proceeds via homolytic fragmentation of the Breslow intermediate into a close radical pair which can recombine in a regio- and diastereoselective manner, formally leading to [3,3]-rearranged products. Deconstruction of the congested tertiary alcohols obtained to various ketones is also shown to be possible via divergent C–C bond cleavage strategies. Considering the difficulty of constructing such congested alcohol motifs and their general prevalence in natural products and other relevant molecules, this method should find significant utility for the elaboration of complex and biologically active compounds.