N‐Heterocyclic Carbene Catalyzed Photoenolization/Diels–Alder Reaction of Acid Fluorides

Abstract The combination of light activation and N‐heterocyclic carbene (NHC) organocatalysis has enabled the use of acid fluorides as substrates in a UVA‐light‐mediated photochemical transformation previously observed only with aromatic aldehydes and ketones. Stoichiometric studies and TD‐DFT calculations support a mechanism involving the photoactivation of an ortho‐toluoyl azolium intermediate, which exhibits “ketone‐like” photochemical reactivity under UVA irradiation. Using this photo‐NHC catalysis approach, a novel photoenolization/Diels–Alder (PEDA) process was developed that leads to diverse isochroman‐1‐one derivatives.

Recent years have seen ar esurgence of interest in photochemical activation as am eans of accessing new reactivity modes in organic synthesis.Incontrast to thermally activated processes,p hotochemical reactions proceed via excited-state species and duly exhibit dramatically different reactivity and selectivity.R eactions involving the activation of aromatic aldehydes and ketones with UVAl ight are among the most widely studied photochemical transformations.U pon excitation, the biradical-like (n,p*) states of these compounds undergo arange of synthetically important processes,such as Norrish fragmentations,Y ang cyclizations,a nd Paternò-Büchi cycloadditions. [1] While such reactions are well established for aldehydes and ketones,a nalogous transformations with substrates at the carboxylic acid oxidation level are scarce.T hese compounds typically absorb light at shorter wavelengths than the corresponding ketones while many populate lowest-energy (p,p*) excited states with inherently different photochemical reactivity. [2,3] Inspired by the recent successes achieved by combining light activation with other catalysis modes, [4,5] we wondered whether the scope of carbonyl photochemistry could be expanded by merging light activation with N-heterocyclic carbene (NHC) organocatalysis. [6] An overview of our proposed photo-NHC catalysis concept is shown in Scheme 1. As demonstrated in several elegant processes, NHCs can react with activated aryl carboxylic acid derivatives to afford benzoyl azolium intermediates.T hese species are formally ketones and could be expected to populate excited states comparable to those of structurally related benzophenone derivatives upon light irradiation. Furthermore,i n providing as econd aromatic system for p-conjugation, the NHC can influence the absorption characteristics of the carbonyl function, enabling excitation at longer wavelengths compared with the parent carboxylic acid derivative.F ollowing al ight-mediated process of the type typically observed with aromatic ketones and elimination of the NHC organocatalyst, new classes of product for carbonyl photochemistry would be provided.
Thephoto-NHC concept represents anew catalysis mode for NHCs.T hese compounds most often facilitate umpolung reactions of aldehydes while transformations involving acyl azolium salts or enolates have also been developed. [7] Most processes are considered to proceed through polar mechanisms;h owever, recent studies have revealed new radical activation modes,w hich exploit the ability of NHCs to stabilize unpaired electron density. [8][9][10] In photo-NHC catalysis,t he role of the NHC is again different. In temporarily changing the absorption profile and photochemical reactivity of acarbonyl group during the catalytic cycle,the NHC can be considered as a" transient aryl group" that enables hitherto unsuitable substrates to engage in photochemical transformations.M oreover,a st he catalyst remains bound to the substrate throughout the cycle,e nantioselective variants could be potentially realized by using chiral NHCs.
We initially sought to validate the photo-NHC catalysis concept by investigating an independently synthesized stoichiometric acyl azolium salt. As ap roof-of-concept transformation, ap hotoenolization process was selected starting from ortho-toluoyl imidazolium salt 1. [11] Upon irradiation with UVAlight, excitation of the carbonyl group followed by intramolecular 1,5-hydrogen atom transfer (HAT) would lead to ah ydroxy-o-quinodimethane (o-QDM) species.C ompound 1 was thus prepared (see the Supporting Information) and subjected to irradiation from UVALEDs (l max = 365 nm) in am ixture of degassed CD 3 CN and CD 3 CO 2 D( 9:1). After 16 h, we were delighted to observe extensive incorporation of deuterium (68 %) at the o-methyl group consistent with deuteration of an o-QDM intermediate while no reaction was observed without light (Scheme 2a). This result demonstrates that acyl azolium species are capable of both absorbing light at wavelengths similar to other aromatic ketones and of exhibiting analogous photochemical reactivity.I nafurther experiment, aphotoenolization/Diels-Alder (PEDA) process leading to isochroman-1-ones was investigated by reacting 1 with ketone 2a.A nalogous non-NHC-catalyzed reactions affording the corresponding hemiacetals have been described for aromatic aldehydes and ketones. [12,13] After 16 ho f irradiation in degassed MeCN,c lean conversion into the desired product 3aa was observed in 62 %NMR yield while, as for the deuteration experiment, no reaction occurred without light (Scheme 2b).
Annulation reactions are among the most important classes of NHC-catalyzed transformation. [14] As such, novel reactivity modes for NHCs that open up new strategies for annulation reactions are especially desirable.T he proposed PEDAreaction has some attractive features in comparison to alternative NHC-catalyzed routes to isochroman-1-ones 3. Previously published processes have employed either o-CH 2 Br-substituted benzaldehydes [15] or o-CH 2 SiMe 3 -substituted esters, [16] which can be laborious to prepare.T he only example of directly using simple o-toluic acid derivatives was reported recently by Li, Yao, and co-workers. [17,18] This nonphotochemical process,h owever, was successful only for highly electron-deficient substrates whose o-benzylic positions are sufficiently acidic to be deprotonated by an amine base.
Am echanistic proposal consistent with PEDAr eactions of ketones is shown in Scheme 4. [11][12][13] Upon deprotonation of the NHC precursor with Cs 2 CO 3 ,t he imidazolylidene IMe reacts with acid fluoride 4,r eleasing F À and generating the o-toluoyl azolium intermediate A. [19] This benzophenone-like species is excited under UVAi rradiation affording,a fter intersystem crossing (isc), atriplet excited state T 1 (A). [21] Fast 1,5-HATf rom the o-benzylic position to the radical-like carbonyl oxygen atom gives rise to the triplet dienol biradical T 1 (B).Rotation of this species before relaxation leads to the ground-state o-QDM (E)-B,w hich can react with the dienophile 2 in ac ycloaddition process.T his reaction could feasibly occur in aconcerted Diels-Alder fashion or, as shown in Scheme 4, through at wo-step sequence involving intermediate C.Finally,elimination of the NHC from cycloadduct D in the presence of the base releases the product 3 and completes the catalytic cycle.
Time-dependent DFT calculations ((TD-)CAM-B3LYP/ 6-311G**) [22] on o-toluoyl azolium intermediate A provide support for the above mechanism. Irradiation of this species in the UVAr egion results in at riplet excited state (T 1 (A)) with significant unpaired electron density at the oxygen atom ( Figure 1). 1,5-HATp roceeds readily from this species, resulting in T 1 (B).C onversely,e xcitation of acid fluoride 4a occurs only at shorter wavelengths,w ith the analogous HAT from the triplet state T 1 (4 a) being highly endergonic (see the Supporting Information). Thel ack of photoenolization was experimentally corroborated by subjecting 4a to the deuteration conditions with CD 3 CN/CD 3 CO 2 D(see Scheme 2a). No incorporation of deuterium was observed after 16 h, highlighting the key role of the NHC in modifying the photochemistry of the carbonyl function.
In conclusion, the merger of NHC organocatalysis with light activation has enabled the annulation of o-toluoyl fluorides with trifluoroacetophenones.Stoichiometric studies and TD-DFT calculations support am echanistic scenario where addition of the NHC to the acid fluoride results in at emporary change in the absorption characteristics and photochemical reactivity of the carbonyl function during the catalytic cycle.T his allows these hitherto unsuitable substrates at the carboxylic acid oxidation level to engage in aU VA -light-mediated photochemical reaction previously observed only with aromatic aldehydes and ketones.W e believe that photo-NHC catalysis could prove useful for expanding the scope of carbonyl photochemistry,and further investigations are underway in our laboratory.