PPh3/NaI driven photocatalytic decarboxylative radical cascade alkylarylation reaction of 2-isocyanobiaryls

The first triphenylphosphine/sodium iodide driven photocatalytic decarboxylative cascade cyclization of 2-isocyano-biaryls with alkyl N-hydroxyphthalimide (NHP) esters was developed. This operationally simple protocol results in multiple carbon–carbon bond formation under transition metal free conditions, affording a novel and environmentally benign entry to producing 6-alkyl phenanthridines with moderate to good yields.


Introduction
Visible-light photocatalysis has been widely recognized as a powerful tool in organic synthesis to construct carbon-carbon or carbon-heteroatom bonds. 1 Through reactive intermediates such as radicals and radical ions, unique reactions that are previously inaccessible under thermal conditions can be accessed. Signicant advances have been realized in this eld by employing metal based catalysts 2 or organic dyes 3a-d as photoredox catalysts. However, employing these metal based photoredox catalysts has certain disadvantages: such as; they are expensive, potentially toxic and limited availability. 3e Recently, visible light driven photoredox catalysis employing inexpensive chemicals such as combination of triphenylphosphine/sodium iodide and CeCl 3 emerged as a robust alternative to generate radical entities under mild reaction conditions. 4 This approach replaces metal based photocatalysts by inexpensive catalysts, thus overcoming some of the aforementioned problems.
Phenanthridine, a privileged structural core motif found in natural products. 5 Many synthetic phenanthridine derivatives show bioactive and pharmaceutical properties, including antitumoral, antibacterial, antiviral, cytotoxic, and DNA inhibitory properties. 6,7 In addition, phenanthridine derivatives reveal signicant optoelectronic properties. 8 Therefore, the development of new and efficient methods for the preparation of phenanthridine derivatives has gained signicant importance in academic research. Recently, a cascade radical pathway involving radical addition to 2-isocyanobiaryls and subsequently intramolecular homolytic aromatic substitution has been developed, 9 which allows the rapid assembly of a phenanthridine framework with high efficiency. In 2012, Chatani's group disclosed Mn(III)-mediated radical cascade reaction of 2isocyanobiaryls with boronic acid under thermal conditions. 10 Subsequently, several groups put their efforts for the construction of 6-substituted phenanthridines through the reaction of 2isocyanobiaryls with corresponding carbon radical precursors, such as simple alkanes, 11 alcohols, 11a ethers, 12 aldehydes, 13 2bromide ethyl esters, 14 aryl sulfonyl chlorides 15 and 1,3-dicarbonyl compounds. 16 Although these reported methods have their own specic applications, but remains associated with certain disadvantages such as employing metal catalysts, harsh reaction condition and use of stoichiometric amounts of oxidants. Very recently, few groups reported a metal-free approach that utilizes aryl amines, 17 carboxylic acids, 18 hydrazines 19 acyl peroxides, 20 as a carbon radical precursor, which appears to be an environmentally benign method for accessing 6-substituted phenanthridines. However, most of acyl peroxides, alkyl amines and hydrazenes are commercially unavailable. Thus, further new methodologies are quite desired for the synthesis of 6-substituted phenanthridines.
Recently decarboxylative functionalization of alkyl Nhydroxyphthalimide (NHP) esters in carbon-carbon bond formation reactions have gained a signicant importance, as they convert widely available and inexpensive chemicals into valuable chemicals and reactive intermediates for synthesis. 21 Photo decarboxylation of alkyl N-hydroxyphthalimide (NHP) esters has been widely used for organic synthesis, 22 as the liberation of phthalimide and volatile CO 2 as a by-products indicates a strong driving force for the reaction, forming versatile radical intermediates to build more valuable products. Herein, we report the rst PPh 3 /NaI driven photocatalyzed decarboxylative cascade alkylarylation reaction of 2 isocyanobiaryls in the presence of visible light irradiation at room temperature.

Results and discussions
Inspired by the recent work of Shang and Fu ( Fig. 1) who developed photocatalytic decarboxylative alkylations mediated by triphenylphosphine/sodium iodide, 4d we wondered how these activated carboxylic acids (1) would behave under similar reaction conditions (Fig. 1) in presence of 2-isocyanobiaryls (2). At rst, we chose 1a and 2a as model reactants to optimize the reaction conditions for the desired decarboxylative radical cascade alkylarylation using inexpensive PPh 3 /NaI as a photocatalyst. To our delight, when a solution of 1.5 equiv. of 1a with 1.0 equiv. of 2a in the presence of PPh 3 (20 mol%) and NaI (100 mol%) in acetonitrile was illuminated with a blue LED (455 nm) at 25 C for 24 h, product 3a was formed in 84% yield (Fig. 2, entry 1). Replacement of NaI by KI also proceeded smoothly to give product 3a in 80% yield (Fig. 2, entry 2). The product formation 3a was slightly decreased upon employing other iodide salts (Fig. 2, entries 3 and 4). Solvents such as dimethylsulfoxide (DMSO) and dimethylformamide (DMF) in place of MeCN afforded 3a in 65% and 60% yield respectively (Fig. 2, entries 5 and 6). While solvents such as acetone, chloroform (CHCl 3 ) and EtOAc had a deleterious effect on the reaction outcome (Fig. 2, entries 7-9). When triphenyl phosphine was replaced by other phosphines such as PCy 3 and P(otol) 3 , caused a drastic reduction in the yield of the reaction (Fig. 2, entries 10 and 11). Substitution of PPh 3 by other nitrogen donors such as DMAP, Et 3 N observed trace amount of product (Fig. 2, entries 12 and 13). Additionally, control experiments conrmed that a catalytic amount of PPh 3 and continuous blue light irradiation were necessary for the reaction to occur. Not even traces amount of 3a were observed in the absence of light or the PPh 3 (Fig. 2, entries 15 and 17).
The efficiency of our photocatalytic decarboxylative radical cascade cyclization leads us to conduct some preliminary mechanistic studies (Fig. 4). As anticipated ON/OFF experiment indicated that our reaction required continuous blue light irradiation to proceed (see ESI †). We currently believe that this decarboxylative cascade cyclization reaction could proceed via the generation of alkyl radicals. In a radical clock experiment using alkyl NHP-ester (1s) derived from 2-cyclopropylacetic acid under our reaction conditions, the ring-opened product 3p was isolated (Fig. 4, upper). Moreover, secondary chiral alkyl NHPester (1t) derived from enantiopure (S)-2-methylbutanoic acid provided the racemic 6-alkyl substituted phenanthridines product 3e (Fig. 4, center).
Based on these experimental observations and the report of Rui Shang and Yao Fu et al. 4d we propose that the decarboxylative cascade cyclization reaction proceeds via formation of charge transfer complex (CTC) 23 (see ESI † for UV-visible absorption spectra) between PPh 3 , NaI and NHP-ester (1a) (Fig. 4). 4d Aer photo fragmentation of this CTC complex generates key alkyl radical I and PPh 3 -Ic. Subsequently, the generated alkyl radical is added to 2-isocyanobiaryl 2, which produce imine radical II that can form intermediate III through an intramolecular radical cyclization. Further oxidation of III by PPh 3 -Ic (E red ¼ 0.69 vs. SCE) 4d produces the corresponding carbocation IV and NaI, PPh 3 . The carbocation IV loses a proton under reaction conditions to provide the desired product 3.

Conclusions
In summary, we have developed a general strategy for the catalytic, radical decarboxylative cascade alkyl arylation of alkyl  NHP-esters using an inexpensive PPh 3 /NaI system as a photocatalyst. This operationally simple protocol allows an efficient synthesis of 6-substituted phenanthridines in moderate to good yields under metal free conditions. Furthermore we showed that in our photocatalytic conditions, different carbon radical precursors can be activated to deliver 6-substituted phenanthridines.

Conflicts of interest
There are no conicts to declare.