Photomediated Tandem Sulfonyl Addition-Chemoselective N-Cyclization of o-Alkenyl Aryl Ureas: Direct Assembly of Functionalized Dihydroquinazolinones
Photoredox mediated tandem addition-chemoselective cyclization of o-alkenyl aryl ureas are reported for the synthesis of sulfonyl and other electrophilic radical decorated dihydroquinazolinones. By a careful choice of o-alkenyl aryl urea starting materials, we have achieved chemoselective N-cyclization in the presence of a more reactive amidic oxygen. We have demonstrated the scope of the methodology with a variety of o-alkenyl aryl ureas and sulfonyl chlorides including simple aliphatic sulfonyl chlorides, which are less commonly explored. Finally, we also demonstrated the application of our methodology with other electrophilic radicals, which afforded the resultant products in good yields under slightly modified conditions. Quenching studies with TEMPO, revealed a radical mechanism and finally, large-scale synthesis of sulfonyl substituted dihydroquinazolinone showcases the synthetic utility of the methodology.
Introduction:<!>Table 1: Screening table<!>Scheme 2: Scope of o-alkenyl aryl ureas<!>Scheme 3: Scope of aromatic sulfonyl chlorides<!>Scheme 4: Scope of aliphatic sulfonyl chlorides
<p>Photoredox catalysis, an environmentally friendly, mild, and powerful tool for the generation of various radical intermediates, facilitates radical mediated addition reactions in the presence of a suitable radical acceptor. Recently, photomediated tandem radical addition-cyclization reactions have attracted wide attention for their ability to afford functionalized molecular scaffolds in a direct fashion under mild conditions. 1 Although radical cascade addition followed by O-cyclization reactions are common and reported, 2 there are not many reports or studies on radical cascade addition & N-cyclizations 3 of amide/urea type functional groups due to the interference of oxygen. 2a In this direction our group recently reported photoredox catalysed cascade CF3 addition/annulation of o-alkenyl aryl ureas for the construction of 2-amino-1,3-benzoxazines and dihydroquinazolinones in a chemodivergent fashion by controlling the ambident nucleophilicity of aryl ureas via selective N-versus Ocyclization. 4 However, apart from trifluromethyl radicals, other electrophilic radicals were not viable substrates under the reaction conditions due to varied redox potentials and reactivity of different electrophilic radical precursors (Scheme 1).</p><p>Sulfone moieties are well known functional groups in organic synthesis as they play a vital role in forging carbon-carbon double bonds via Julia olefination. 5 They are commonly found in many natural products, drugs 6 and synthetic intermediates for the construction of interesting molecular scaffolds. 7 Although, the generation of sulfonyl radicals via conventional methods are known, 8 they have limitations such as the requirement of high reaction temperatures, strong external oxidants, metal additives etc. 9 Sulfonyl chlorides are commercially available inexpensive reagents, which recently are used for the generation of reactive sulfonyl radicals under mild and environmentally friendly conditions using photoredox catalysis via a single electron transfer process. 10 Dihydroquinazolin-2(1H)-ones on the other hand are an important class of organic molecules found in many bioactive molecules and drugs. For example; DPC-083 is a potent reverse transcriptase inhibitor used for the treatment of HIV infection. 11 Similarly, afacifenacin is used for the treatment of nocturia, which is in phase II clinical trials and Letermovir shows great potential for next generation treatment of HCMV (human cytomegalovirus) infection and has already been approved for phase III clinical trials (Figure 1). 12 Given the importance of both dihydroquinazolin-2(1H)ones and sulfone moieties, it is desirable to develop a mild protocol to access sulfonyl decorated dihydroquinazolin-2(1H)-ones in a single step. In this direction, we designed a tandem addition/chemoselective N-cyclization strategy for the synthesis of sulfonyl functionalized dihydroquinazolinones from o-alkenyl aryl ureas mediated by sulfonyl radicals (and other electrophilic radicals) via photoredox catalysis. We started our investigation using N1-benzyl substituted o-propenyl phenylurea (1a, 1.0 equiv.) as a model substrate and commercially available, inexpensive tosyl chloride (2a, 1.5 equiv.) as a sulfonylating agent in the presence of 2.0 mol% Ru(bpy)3Cl2 photocatalyst and dipotassium hydrogen phosphate (1.5 equiv.) under blue light irradiation in ACN (0.1 M) as solvent. Unfortunately, no expected product was observed under these conditions. Further screening of photocatalysts, revealed fac-Ir(ppy)3 as the optimal catalyst, yielding 42% of dihydroquinazolinone product, 3aa. Further attempts to increase the yield of 3aa by changing the solvents resulted in lower yields with complex reaction mixtures (Table 1, entries 5 & 6). Finally, reducing the temperature to 14°C improved the yield to 60% (Table 1, entry 8).</p><p>Further reduction of reaction temperature to 5°C didn't help and rendered relatively poor yields (Table 1, entry 9). On the other hand, when the reaction was carried out at 8°C with K3PO4 (1.5 equiv.) as base, 74% yield of the desired product was obtained ( With the optimised condition in hand, we further explored the scope of this tandem addition-chemoselective cyclization protocol with a variety of N1,N2-disubstituted oalkenyl phenylureas 1 and tosylchloride, 2a (Scheme 2). Delightfully, N1-benzyl-N2alkyl substituted o-alkenyl aryl ureas (1b-1d) underwent smooth transformation and furnished the corresponding sulfonyl functionalized dihydroquinazolin-2(1H)-ones (3ba, 3ca, 3da) in good yields (74%-81%). Apart from the benzyl substitution at N1, other alkyl substituents such as PMB & ethyl (1e-1g) also afforded the resultant products in good yields (3ea-3ga). Similarly, N2-aryl substituted-o-alkenyl aryl ureas, containing both electron-donating and electron-withdrawing substituents on the phenyl ring afforded the desired products (3ia-3la) in moderate to good yields (58%-77%). Notably, an electron-withdrawing substituent on the phenyl ring at the para position (1l) rendered relatively lower yields (58%) in comparison to substituents at other positions.</p><p>Next we investigated the feasibility of this reaction with regard to a diverse spectrum of aryl sulfonyl chlorides (2a-2l) and as expected a wide range of sulfonyl chlorides were well endured under the reaction conditions (Scheme 3). For example; aryl sulfonyl chlorides with electron donating groups including simple aryl sulfonyl chloride worked well and offered the desired products (3aa-3af) in good yields (71%-82%). Moreover, electron poor aryl sulfonyl chlorides were also well tolerated irrespective of the substituents position (o/m/p) and gave the corresponding products (3ag-3aj) in moderate yields to good yields (60%-69%). Interestingly naphthyl sulfonyl chloride and pyridyl aryl sulfonyl chloride also worked well and afforded 67% & 70% yield of the desired products (3ak, 3al) respectively.</p><!><p>a Reaction conditions: 1a (0.1 mmol, 1.0 equiv), 2a (1.5 equiv), base (1.5 equiv), Solvent (0.1 M), 12 h, 1 H NMR yields with 1,1,2,2-tetrachloroethane as internal standard. b Reaction performed in presence of DABCO(0.1 equiv). c Isolated yield of 3aa. d 3aa' yield is in the parenthesis. e 0.05 M ACN. f 1.0 equiv of base was used.</p><p>g Absence of light.</p><!><p>Reaction conditions: 1 (0.1 mmol, 1.0 equiv), 2a (1.5 equiv), K3PO4 (1.0 equiv), fac-Ir(ppy)3 (2 mol%), ACN (0.05 M), blue LEDs at 8°C for 12 h under an argon atmosphere, isolated yields.</p><!><p>Reaction conditions: 1a (0.1 mmol, 1.0 equiv), 2 (1.5 equiv), K3PO4 (1.0 equiv), fac-Ir(ppy)3 (2 mol%), ACN (0.05 M), blue LEDs at 8°C for 12 h under an argon atmosphere, isolated yields.</p><p>We later studied aliphatic sulfonyl chlorides (ethyl, butyl, 2-chloroethyl, isopropyl and cyclopropyl chlorides) for the desired transformation (Scheme 4) and found them to be suitable reacting partners under the standard reaction conditions to afford the products (3am-3aq, 3gq &3lq) in moderate to good yields (59%-76%).</p><!><p>Reaction conditions: 1 (0.1 mmol, 1.0 equiv), 2 (1.5 equiv), K3PO4 (1.0 equiv), fac-Ir(ppy)3 (2 mol%), ACN (0.05 M), blue LEDs at 8°C for 12 h under an argon atmosphere, isolated yields.</p><p>Next, to demonstrate the synthetic utility of this methodology, we focussed our efforts towards the synthesis of functionalized alkyl radicals decorated dihydroquinazolinones via the same chemoselective tandem addition-cyclization strategy (Scheme 5). By employing 2-bromoacetonitrile (3a) as an alkylating partner under the standard conditions (with some minor modifications) using 1a as the alkene partner, we obtained the desired cyanomethyl functionalized dihydroquinazolinone product (4aa) in a very good yield (81%). Further, we extended the scope of this method with other o-alkenyl aryl ureas (1a, 1b, 1g, 1j, 1l) and pleasingly obtained the corresponding cyanomethyl functionalized dihydroquinazolinone products in good yields (70%-86%).</p><p>Scheme 5: Scope of cyanomethyl functionalized dihydroquinazolin-2(1H)-ones.</p><p>Reaction conditions: 1 (0.1 mmol, 1.0 equiv), 3a (1.5 equiv), K3PO4 (1.0 equiv), fac-Ir(ppy)3 (2 mol%), ACN (0.1 M), blue LEDs at room temperature for 4-6 h under an argon atmosphere, isolated yields.</p><p>With this interesting results, we next extended this methodology to a variety of other activated alkyl halides (3b, 3c and 3d) and got the desired dihydroquinazolinones (5, 6 and 7) in moderate yields (Scheme 6). Later, we performed a scale up experiment and obtained the desired product, 3aa in almost similar yield (73%) in comparison to the standard (0.1 mmol) scale (scheme 7). In order to study the mechanism, we carried out the reaction in the presence of TEMPO, a radical trapping agent, which resulted in no desired transformation with the starting material remaining unreacted, which suggests a radical pathway. To demonstrate the importance of PC and light, we performed control experiments in the absence of PC and light irradiation, and found no desired product in both the cases. Stern-Volmer studies showed the excited Ir(ppy)3 photocatalyst was effectively quenched by sulfonyl chloride, suggesting an oxidative quenching cycle.</p><p>Scheme 6: Scope of other alkyl radicals.</p><p>Reaction conditions: 1 mmol, 1.0 equiv), 3b/3c/3d (1.5 equiv), K3PO4 (1.0 equiv), fac-Ir(ppy)3 (2 mol%), ACN (0.05 M), blue LEDs at room temperature for 16-36 h under an argon atmosphere, isolated yields. a Yield based on the starting material recovery.  aryl ureas and sulfonyl chlorides. In order to demonstrate the synthetic utility of the method a variety of other radical precursors such as cyanobromomethane, α-bromo functionalised carbonyls/phosphates etc. were used to obtain the corresponding functionalized dihydroquinazolinones. Finally, we also demonstrated the method on a large scale using substrate 1a and the resultant product, 3aa was obtained in almost similar yields, showing its potential application.</p>