2-Quinolone 2 + 2 cycloaddition

Strong effects of the catalyst on the regioselectivity have been observed in the cycloadditions of a variety of heterocyclic dienophiles. Some results of the BF3-catalyzed reactions of quinoline-5,8-dione (21) and isoquinoline-5,8-dione (22) with isoprene (2) and (E)-piperylene (3) [25], and of the cycloadditions of 4-quinolones (23a, 23b) as well as 4-benzothiopyranone (23c) with 2-piperidino-butadienes, are reported [26] in Scheme 3.8 and Equation 3.2. The most marked... 

Intermolecular cycloaddition reactions include that of (158) and RCH = CHOEt to give quinoline (159). The 2-quinolone (161) is obtained from (160) and HC = COEt. 

Quinolines have also been prepared on insoluble supports by cyclocondensation reactions and by intramolecular aromatic nucleophilic substitution (Table 15.26). Entry 10 in Table 15.26 is an example of a remarkable palladium-mediated cycloaddition of support-bound 2-iodoanilines to 1,4-dienes. Reduction of the nitro group of polystyrene-bound 2-nitro-l-(3-oxoalkyl)benzenes with SnCl2 (Entry 11, Table 15.26) leads to the formation of quinoline /Y-oxides. These intermediates can be reduced to the quinolines on solid phase by treatment with TiCl3. 4-Quinolones have been prepared by thermolysis of resin-bound 2-(arylamino)methylenemalonic esters [311]. 

A 1,3-dipolar cycloaddition using oxime derivatives yielded the tetrahydroquinoline derivative 25 (Equation 58) <2005S3423>. It was advantageous that the product precipitated out of the aqueous reaction medium in excellent yield. Carbenoid-insertion reactions have been demonstrated to produce the ring-extended quinolone structure 26 from simple substituted anilines (Equation 59) <2003TL7433>. The C-H insertion onto the aromatic ring can vary. 

Bach T, Bergmann H (2000) Enantioselective intermolecular [2+21-photo-cycloaddition reactions of alkenes and a 2-quinolone in solution. J Am ChemSoc 122 11525-11526... 

Cycloaddition of but-l-yne to the quinolone (58a) gave the head-to-tail [2 + 2] adduct (59). This approach was coupled with a ring-opening reaction to provide a synthesis of quinolones bearing a substituent at C-3. For example, the cycloadduct (60), obtained from the quinolone (58b) and 2-methylbut-3-yn-2-ol, was transformed into edulinine (61). The photocycloaddition of allene to the quinolone (58b) affords the two [2 + 2] adducts (62, 59.6%) and (63, 9.7%). Diketene has also been used in cycloadditions to quinolones (58c) and (58d). The addition process is selective in that cycloaddition to (58c) yields the adduct (64) whereas (58d) affords (65). In the latter case, the cycloadduct is accompanied by the rearranged product (66). These adducts were used in further chemical transformations. 

Benzodithioles 197 (dienophiles) were employed in aza-Diels-Alder reactions with A -arylimines 198 as a versatile approach to tetrahydroquinolines 199. Subsequent transformations of the latter under reductive and oxidative conditions provided an access to 2,3-disubstituted tetrahydroquinolines 200, inaccessible through the conventional [4+2] cycloaddition strategy, and also to 2,3-dihydro-4-quinolones 201 and 4-quinolones 202 (Scheme 23) <20020L4411>. 

Photocycloaddition of 1,1-dichloroethene to the quinolone (110) affords the adduct (111). The triplet excited state of the enones (112) are photoreactive and undergo addition to alkenes to afford reasonable yields of the azetidines (113). - Both electron rich and electron deficient alkenes photochemically add to the enone (114) to afford the cyclobutane adducts (115). Normally the C=N Is unreactive to (2+2)-cycloadditions but the authors believe that in this case the C=N system is activated by the trifluoromethyl group. The azetidine-2-ones (116) can be readily prepared by irradiation of the enones (114) in the presence of ketene. ... 

The regioselectivity of analogous cycloadditions in 4-(alkenyloxy)-quinolin-2-(1H)-ones is determined by the chain length irradiation of quinolone (92 n=1), for example, gave the adduct (93), whereas the related quinolone (92 n=3) was converted photochemically into the adduct (94). Intramolecular [ 2 + 2] photocycloaddition has also been employed in the preparation of photoresponsive cyclobutane-1,2-dicarbonyl-capped[2.n]diazacrown ethers. 

Two reports have dealt with the result of the photoaddition of ethyne to the hexenulose 70. This reaction occurs stereo-specifically to afford the adduct 71. The adduct can be readily reduced to the corresponding cyclobutane derivative or can be elaborated into optically active tricothecene derivatives. Acetone-sensitized irradiation of the pyrone 72 in the presence of ethyne affords the adduct 73 and the rearrangement product 14 . The formation of this latter adduct presumably involves cyclobutene ring-opening followed by crossed addition of the diene. Cycloaddition of but-l-yne to the quinolone 75 affords the head-to-tail (2 + 2)-cycloadduct 76 while addition to hex-3-yne yields 77 h The route using the adducts 76 has been developed as a synthetic path to 3-substituted quinolones. 

Cycloaddition reactions are not only used to construct quinoline derivatives, but also used to elaborate them. Phenanthridone derivatives were prepared by Diels-Alder reactions with 2(l )-quinolones and butadiene derivatives <01CPB407>. The synthesis of pyranoquinolines via a formal [3 + 3] cycloaddition was also reported. For example, aldehyde 66 was treated with piperidine and acetic anhydride to afford the corresponding iminum ion which undergoes a [3 + 3] cycloaddition with 4-hydroxyquinolone (67) to give pyranoquinoline 68. Intermediates such as pyranoquinoline 68 were used in the total syntheses of simulenoline and huajiaosimuline <01JOC1049>. 

Abstract Phosphacumulene ylides of the general formula Ph3P=C=C=X [X=0, S, NR, (0R)2] are versatile C2-building blocks. They can act either as C-nudeophiles-only in a manner typical of phosphorus ylides, or as cumulenes undergoing [2 + n -cycloadditions with other cumulenes such as CO2, COS, RNCO etc. Most prominent is their tandem addition-Wittig alkenation of hydroxy- or amino-substituted carbonyl compounds. With aptly chosen reaction partners all these pathways may lead to heterocyclic products. Some recent applications of these methods to the syntheses of azetidines, five-membered lactams, lactones, tetramates, tetronates and pyrroles as well as to six-membered quinolones and to macrolides are delineated. 

C-CN activation via oxidative addition can be followed by the activation of another C-C bond to develop cycloaddition reactions. The reaction of o-arylcarboxyben-zonitrile with alkynes proceeds in this manner to give coumarins, aryl cyanides, and an alkyne-arylcyanation product in the presence of catalytic amounts of nickel and aluminum-based Lewis acid (Scheme 18) [61]. Likewise, o-cyanophenyl-benzamides undergo the transformation to give quinolones (Scheme 18 [62]. A catalytic cycle involving a five-membered nickelacycle intermediate, generated possibly by the oxidative addition of Ar-CN bonds, and the subsequent C-C bond activation [63] is proposed (Scheme 19). 

Ynamines react with phenyl isocyanate to give a mixture of the 2- (493) and the 4-quinolone (494). The formation of the 2-quinolone can be explained as a result of a [4+2] cycloaddition reaction in which the phenyl isocyanate reacts as the diene component. ... 

In contrast, the imidoylketene 50 undergoes an intramolecular [4+2] cycloaddition reaction to give the quinolone derivative 51". The mechanism of this reaction was verified as a 1,3-shift by labelling experiments". ... 

Reaction under these conditions led to the enantioselective 2+2 cycloaddition of some 2-quinolones, both 4-alkenylo3qr (2) and (less satisfactory) 3-alkenyloxy (3), as illustrated in Scheme 3 by using either stereoisomer of the photocatalyst (see Scheme 3). ... 

He also found the enantioselective intermolecular [2 + 2] photocycloaddition of isoquinolone (37) with vinyl phosphinates (38)" and intramolecular [2 + 2] cycloaddition of quinolones (41) using chiral additives (40) and (43), assisted by strong hydrogen-bonding (Scheme 15). 

The cycloaddition reaction of azomethine 43 with alkenes proceeds in regio- and stereoselective manner and represents a convenient way to obtain a variety of stereoisomeric 7-isoxazolidinyl quinolones 44-48 [166,167] (Scheme 21). 

Synthesis of new hydroxybisphosphonate derivatives of ciprofloxacin 49 has been performed by using Cu-catalyzed 1,3-dipolar cycloaddition reaction between the corresponding azide and N-alkynyl substituted quinolone [169] (Scheme 22). Derivatives of gati- and moxifloxacin have been obtained similarly. All of these modified compounds maintained antibacterial activity of the starting quinolones and, in addition to that, exhibit osteotropic properties. 

As mentioned in Chapter 7, soon afterwards, Hong reported another unexpected formation of cyclopenta[c]pyran derivative 317 by a [6-h3] cycloaddition of dimethylaminofulvene 109 and />-benzoquinone 174 [108]. He developed a solid-phase synthesis of 317 and cyclopenta[c]quinolone derivatives 318 using a resin-bonded fulvene derivative and a hetero [6+3] cycloaddition sequence (Scheme 6.78) [101]. 

In 2011, Nakai et al. found that acyclic compounds also participated in cycloaddition through carbon-carbon bond activation (Scheme 12.22). Reaction of o-arylcarboxybenzonitrile 56 and 4-octyne in the presence of a nickel catalyst, prepared in situ from Ni(cod)2 and PMes, and MAD in toluene at 120 °C for 12 h resulted in the formation of coumarin 58 in 80% yield. Sequential inter- and intramolecular carbon-carbon cleavage in the presence of a nickel catalyst has been used to construct flve-membered oxanickelacycle 57, which reacts with alkynes to furnish cycloadducts [27]. Detailed observations revealed that the catalytic reaction proceeded with the elimination of aryl cyanide. A similar sequence has been utilized for the synthesis of quinolone derivative 59 (Scheme 12.23). These reaction outcomes suggest an unusual mechanistic aspect cleavage of two independent C—CN and C—CO bonds via the formation of a heteronickelacycle intermediate. 

R1NH2) were subjected to a formal [3 + 2] cycloaddition reaction with anhydrides in the presence of 4A molecular sieves, producing a series of resin-bound carboxy-y-lactams and carboxy-2-quinolones. The carboxylic acid group was converted into an amide by coupling with various primary amines (R2NH2) to increase molecular diversity. As the last step, the resin was treated with HF/pyridine-releasing carboxy-y-lactams 161 and 162 and carboxy-2-quinolones... 

---