Transition-Metal-Free Activation of Amide Bond by Arynes - MDPI

molecules Review Review

Transition-Metal-Free Activation Activation of of Amide AmideBond Bond by Transition-Metal-Free Arynes by Arynes Hideto Miyabe Miyabe Hideto Pharmacy, Hyogo Hyogo University University of of Health Health Sciences, Sciences, Minatojima Minatojima1-3-6, 1-3-6,Chuo-ku, Chuo-ku,Kobe Kobe650-8530, 650-8530,Japan; Japan; School of Pharmacy, [email protected]; Tel.: +81-78-304-3094

Received: 33 August Accepted: 24 Received: August 2018; 2018; Accepted: 24 August August 2018; 2018; Published: Published: 27 27 August August 2018 2018

Abstract: Highly reactive arynes activate the N–C and C=O bonds of amide groups under transition metal-free conditions. This review highlights the insertion of arynes into the N–C and and C=O C=O bonds of the amide group. The insertion of arynes into the N–C bond gives the unstable four-membered ring intermediates, which are easily converted into ortho-disubstituted arenes. On On the the other other hand, hand, ortho-disubstituted arenes. the selective insertion of arynes into the C=O bond is observed when the sterically sterically less-hindered formamides are employed to give a reactive reactive transient transient intermediate. intermediate. Therefore, the trapping reactions of oftransient transientintermediates intermediateswith with a variety of reactants the formation of oxygen a variety of reactants leadlead to thetoformation of oxygen atomatom-containing heterocycles. As relative functional groups are activated, the reactions of arynes containing heterocycles. As relative functional groups are activated, the reactions of arynes with with sulfinamides, phosphoryl amides, cyanamides, sulfonamides, thioureas, vinylogous amides sulfinamides, phosphoryl amides, cyanamides, sulfonamides, thioureas, andand vinylogous amides are are summarized. alsoalso summarized. Keywords: amide; arynes; insertion; activation; heterocycles; organic synthesis; synthesis; multi-component multi-component coupling reaction

1. Introduction 1. Introduction In In recent recent years, years, the the use use of of arynes arynes as as highly highly reactive reactive and and strained strained intermediates intermediates in in organic organic synthesis has attracted substantial attention [1–15]. Arynes have been extensively utilized synthesis has attracted substantial attention [1–15]. Arynes have been extensively utilized in in transition-metal-catalyzed reactions[16,17]. [16,17].The Thedevelopment developmentofof ortho-trimethylsilyl aryltriflates transition-metal-catalyzed reactions ortho-trimethylsilyl aryltriflates 1 as1 as mild aryne precursors to growing activity this field (Scheme 1) [18].AArynes A can be mild aryne precursors led toled growing activity in this in field (Scheme 1) [18]. Arynes can be generated generated in situ from triflate 1 and fluoride ion under mild reaction conditions. Therefore, the aryne in situ from triflate 1 and fluoride ion under mild reaction conditions. Therefore, the aryne chemistry chemistry using aryltriflates 1 hassome achieved some remarkable success, particularly in the metal-free transition using aryltriflates 1 has achieved remarkable success, particularly in the transition metal-free reactions. reactions. R

F

TMS

R

R

OTf

Nu

Diels-Alder reaction

[2+2] cycloaddition

2 dipolar cycloaddition R

x

+

+ A

Nu

B

R

R

E

Nu

A

1

R

E

y

+ z

A

A

Transition metal-free reaction of arynes. Scheme 1. Transition Molecules 2018, 23, x; doi: Molecules 2018, 23, 2145; doi:10.3390/molecules23092145

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Most of of transition transition metal-free metal-free reactions reactions proceed proceed through through the the addition addition of of nucleophiles nucleophiles to to arynes arynes Most Most of transition metal-free reactions proceed through the addition of nucleophiles to arynes A A and the subsequent trapping of intermediates B with electrophiles to give multi-substituted arenes A and the subsequent trapping of intermediates B with electrophiles to give multi-substituted arenes and the subsequent trapping of intermediates B with electrophiles to give multi-substituted arenes with structural diversity and complexity. The transition metal-free concerted reactions, such as the with structural diversity and complexity. The transition metal-free concerted reactions, such as the with structural diversity Thereaction, transition metal-free concerted reactions, such as also the Diels-Alder reaction, [2 and 2]complexity. cycloaddition reaction, and dipolar cycloaddition cycloaddition reaction, are also Diels-Alder reaction, [2 ++ 2] cycloaddition and dipolar reaction, are Diels-Alder reaction, [2 + 2] cycloaddition reaction, and dipolar cycloaddition reaction, are also synthetically useful [6,7,11,12]. synthetically useful [6,7,11,12]. synthetically useful [6,7,11,12]. When the the nitrogen atom of of amides amides acts acts as as nucleophiles nucleophiles toward toward arynes, arynes, the the insertion insertion of of arynes arynes When nitrogen atom When the nitrogen atom of amides acts as nucleophiles toward arynes, the insertion of arynes into into the N–C bond is induced to give the N–C insertion products 3, via the formation of fourinto the N–C bond is induced to give the N–C insertion products 3, via the formation of fourthe N–C bond is induced to give the N–C insertion products 3, via the formation of four-membered membered ring intermediates, C (Scheme 2). In contrast, insertion into the C=O bond is promoted by membered ring intermediates, C (Scheme 2). In contrast, insertion into the C=O bond is promoted by ring intermediates, C (Scheme In contrast, the (Scheme C=O bond is by the the nucleophilic nucleophilic addition of the the2). oxygen atom of ofinsertion amides to tointo arynes (Scheme 3). In In promoted the C=O C=O insertion insertion the addition of oxygen atom amides arynes 3). the nucleophilic addition of the oxygen atom of amides to arynes (Scheme 3). In the C=O insertion reaction, reaction, the four-membered ring intermediates D and ortho-quinone methides E are highly reactive reaction, the four-membered ring intermediates D and ortho-quinone methides E are highly reactive the four-membered ring of intermediates D and ortho-quinone E are highly reactive [19,20]; thus, aa variety variety of further transformations transformations using D Dmethides or EE have have been developed as[19,20]; multi[19,20]; thus, further using or been developed as multithus, a variety of further transformations using D or E33have developed as multi-component component coupling reactions [9]. As As shown shown in Section Section withbeen the C=O C=O bond activation, activation, the suitable suitable component coupling reactions [9]. in with the bond the coupling reactions [9]. As shown in Section 3 with the C=O bond activation, the suitable amides for amides for C=O insertion are the sterically less-hindered formamides, such as N,Namides for C=O insertion are the sterically less-hindered formamides, such as N,NC=O insertion are the sterically less-hindered formamides, such as N,N-dimethylformamide (DMF). dimethylformamide (DMF). (DMF). dimethylformamide

Scheme2. 2.Activation Activationof ofamide amideN–C N–Cbond bondby byarynes. arynes. Scheme Scheme 2. Activation of amide N–C bond by arynes.

Scheme3. 3.Activation Activationof ofamide amideC=O C=Obond bondby byarynes. arynes. Scheme Scheme 3. Activation of amide C=O bond by arynes.

2.N–C N–CBond BondActivation Activation 2. 2. N–C Bond Activation Atfirst, first,the the insertion of arynes arynes into the N–C N–C bond of the amide amide group was reported reported in the the At insertion of of arynes intointo the N–C bondbond of theof amide group was reported in the reaction At first, the insertion the the group was in reaction of ureas with arynes [21]. In the presence of CsF, treatment of 3-methoxy-2-(trimethylsilyl) of ureas with arynes In the presence of CsF, treatment of 3-methoxy-2-(trimethylsilyl) phenyl reaction of ureas with[21]. arynes [21]. In the presence of CsF, treatment of 3-methoxy-2-(trimethylsilyl) phenyl triflate 4 as an aryne precursor with 1,3-dimethyl-2-imidazolidinone (DMI) 5 gave 1,4triflate as an aryne 1,3-dimethyl-2-imidazolidinone (DMI) 5 gave 1,4-benzodiazepine phenyl4 triflate 4 asprecursor an arynewith precursor with 1,3-dimethyl-2-imidazolidinone (DMI) 5 gave 1,40 benzodiazepine derivative 6 in 77% yield (Scheme 4). Under similar reaction conditions, N,N′derivative 6 in 77% yield (Scheme 4). Under reaction conditions, N,N -dimethylpropyleneurea benzodiazepine derivative 6 in 77% yieldsimilar (Scheme 4). Under similar reaction conditions, N,N′dimethylpropyleneurea (DMPU) 7 worked well to give 1,5-benzodiazocine derivative 8.N–C The (DMPU) 7 worked well to give 1,5-benzodiazocine derivative 8. The insertion of aryne into the dimethylpropyleneurea (DMPU) 7 worked well to give 1,5-benzodiazocine derivative 8. The 0 0 insertion of aryne into the N–C bond of acyclic N,N,N′,N′-tetramethylurea 9 also proceeded. In these bond of acyclic N,N,N 9 also proceeded. In these reactions, aryne is generated by insertion of aryne into ,N the-tetramethylurea N–C bond of acyclic N,N,N′,N′-tetramethylurea 9 also proceeded. In these reactions, aryne isgenerated generated bythe thereaction reaction ofof triflate 4with with thefluoride fluoride anionof ofCsF. CsF. Thesequential sequential the reactionaryne of triflate 4 with the fluoride anion CsF. 4The sequential transformation is The achieved via a reactions, is by of triflate the anion transformation is achieved via route involving the addition of the the followed urea nitrogen nitrogen atom to an an aryne, aryne, route involving is the additionvia ofaathe urea nitrogenthe atom to an aryne, by the intramolecular transformation achieved route involving addition of urea atom to followed by the intramolecular nucleophilic attack on the carbonyl carbon atom. The resulting fournucleophilic attack on the carbonyl carbon atom. resulting four-membered ringresulting intermediate followed by the intramolecular nucleophilic attack The on the carbonyl carbon atom. The fourmembered ring intermediate readily undergoes ring opening to afford the N–C insertion products 6, readily undergoes ring opening to afford the N–C insertion products 6, the 8, and 10.insertion products 6, membered ring intermediate readily undergoes ring opening to afford N–C 8, and and 10. 10. 8,

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Scheme 4. 4.Reaction Scheme Reactionofofureas ureaswith witharyne. aryne. Scheme 4. Reaction of ureas with aryne.

The reaction of pyridynes with ureas was studied [22]. In the presence of CsF, the reaction of 4The reaction of pyridynes with ureas was studied [22]. In the presence of CsF, the reaction of triethylsilyl-3-trifluoromethanesulfonyloxypyridine 11 as a 3,4-pyridyne precursor with DMI 5 gave The reaction of pyridynes with ureas was studied the presenceprecursor of CsF, the reaction 44-triethylsilyl-3-trifluoromethanesulfonyloxypyridine 11[22]. as aIn 3,4-pyridyne with DMI of 5 gave pyridodiazepine derivatives 12 and 13 in 86% yield and a ratio of 65:35 (Scheme 5). High triethylsilyl-3-trifluoromethanesulfonyloxypyridine a 3,4-pyridyne precursor withregioselectivity DMI 5 gave pyridodiazepine derivatives 12 and 13 in 86% yield and11aas ratio of 65:35 (Scheme 5). High regioselectivity was obtained by using the 3,4-pyridyne precursor 14 having a methoxy group at the pyridodiazepine derivatives 12 and 13precursor in 86% yield and aa methoxy ratio of 65:35 5). High to was obtained by using the 3,4-pyridyne 14 having group(Scheme at the 2-position 2-position to give the product 15, selectively. The use of DMPU 7 instead of DMI 5 led to the formation regioselectivity was obtained by using the 3,4-pyridyne precursor 14 having a methoxy group at thethe giveofthe 15, selectively. The use of instead of DMI 5 led 17 to the theproduct corresponding pyridodiazocine, 16.DMPU When 71-methyl-2-oxazolidone wasformation employed,ofthe 2-position to give the product 15, selectively. The use of DMPU 7 instead of DMI 5 led to the formation corresponding pyridodiazocine, When 17 was employed, the selective selective insertion into the N–C16. bond of 171-methyl-2-oxazolidone proceeded to give pyridooxazepine 18. of the into corresponding pyridodiazocine, 16. to When insertion the N–C bond of 17 proceeded give 1-methyl-2-oxazolidone pyridooxazepine 18. 17 was employed, the selective insertion into the N–C bond of 17 proceeded to give pyridooxazepine 18. O Me O N TES O NMe Me CsF O MeN NMe + N N TES + NMe N N NMe CsF OTf N 86% NMe + N + MeN Me N N O NMe 11 OTf 5 12:13=65:35 N 86% 12 13 Me O 11 5 12:13=65:35 12 13 Me MeN N TES Me CsF MeN CsF N N 5 + N 14 + 7 TES N N NMe CsF CsF OTf NMeO O Me + 5 N 14 7 + MeO O NMe NMeO N OTf 16 (52%) Me MeO 15 O (91%) MeO O MeO 14 16 (52%) 15 (91%) 14 Me N O Me CsF N N O O O 14 + MeN CsF N MeO O O O 14 + MeN 17 (52%) MeO18 O 17

18 (52%)

Scheme 5. Insertion of pyridynes into N–C bond.

Scheme intoN–C N–Cbond. bond. Scheme5.5.Insertion Insertion of of pyridynes pyridynes into

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The reaction of DMI 5 with 4,5-benzofuranyne precursor 19 was also studied (Scheme 6) [23]. The reaction of DMI 5 with 4,5-benzofuranyne precursor 19 was also studied (Scheme 6) [23]. The N–C product was4,5-benzofuranyne regioselectively obtained in 90% yield as a studied result of (Scheme the initial attack The insertion reaction DMI 520with precursor 1990% wasyield also [23]. The N–C insertionofproduct 20 was regioselectively obtained in as a result of the6)initial of DMI 5 at C5 of 4,5-benzofuranyne. The N–C insertion product 20 was regioselectively obtained in 90% yield as a result of the initial attack of DMI 5 at C5 of 4,5-benzofuranyne. attack of DMI 5 at C5 of 4,5-benzofuranyne.

Scheme Insertion of Scheme 6. 6. Insertion of 4,5-benzofuranyne 4,5-benzofuranyne into into N–C N–C bond. bond. Scheme 6. Insertion of 4,5-benzofuranyne into N–C bond.

It is reported that silylaryl bromides and iodides can be used as aryne aryne precursors precursors under the It is reported that silylaryl bromides and iodides can be used as aryne precursors the triflates, such as precursors 4, 11, 19under [24]. The conditions similar similar to tothose thoseemployed employedfor forsilylaryl silylaryl triflates, such as precursors 4, and 11, and 19 [24]. conditions similar to those employed for silylaryl triflates, such as precursors 4, 11, and 19 [24]. The utility of silylaryl bromides 21a–c was demonstrated inin the The utility of silylaryl bromides 21a–c was demonstrated theN–C N–Cbond bondreaction reaction(Scheme (Scheme 7). 7). In the utility of silylaryl bromides 21a–c was demonstrated in the N–C bond reaction (Scheme 7). In the presence of of tetramethylammonium tetramethylammonium fluoride fluoride (TMAF), (TMAF), 1-bromo-3-methoxy-2-(dimethylsilyl) 1-bromo-3-methoxy-2-(dimethylsilyl) benzene benzene presence presence of tetramethylammonium fluoride (TMAF), 1-bromo-3-methoxy-2-(dimethylsilyl) benzene 21a reacted reacted with with DMPU DMPU 77 to to give give 22a 22a in in 64% 64% yield. yield. Silylaryl Silylaryl bromides bromides 21b 21b and and 21c 21c also also worked worked well. well. 21a 21a reacted with DMPU 7 to give 22a in 64% yield. Silylaryl bromides 21b and 21c also worked well.

Scheme 7. Reaction of silylaryl bromides 21a–c with DMPU 7. Scheme Reaction of Scheme 7. 7. Reaction of silylaryl silylaryl bromides bromides 21a–c 21a–c with with DMPU DMPU 7. 7.

The insertion of arynes into the N–C bond of N-phenyltrifluoroacetamides proceeded effectively insertion ofof arynes the N–C ofbond N-phenyltrifluoroacetamides proceeded effectively insertion the bond N–C of N-phenyltrifluoroacetamides proceeded [25]. The In the presence of arynes CsF,into theinto reaction of N-phenyltrifluoroacetamide 24a with triflate 23 as an [25]. In the presence of CsF, the reaction of N-phenyltrifluoroacetamide 24a with triflate 23 as Nan effectively [25]. Ingave the presence CsF, the product reaction 25a of N-phenyltrifluoroacetamide 24a with triflate 23 aryne precursor the N–Cof insertion in 77% yield (Scheme 8). The substituted aryne precursor gave the N–C insertion product 25a in 77% yield (Scheme 8). The substituted Nas an aryne precursor gave the N–C insertion product 25a in 77% yield (Scheme 8). The substituted aryltrifluoroacetamides 24b–d also afforded the corresponding products 25b–d in good yields. Since aryltrifluoroacetamides alsoalso afforded the corresponding products 25b–d in good yields. Since N-aryltrifluoroacetamides afforded the corresponding products in good yields. the CF3 group on amides24b–d is 24b–d critical to the success of these transformations, they25b–d propose the reaction the CFthe 3 group on amides is critical to of thethe success of these transformations, propose theasreaction Since CFinvolving on is critical tohydrogen the success thesenitrogen transformations, they propose the 3 group mechanism theamides abstraction on of amide bythey fluoride anion a base. mechanism involving the abstraction of the hydrogen on amide nitrogen by fluoride anion as a base. reaction mechanism involving the abstraction of the hydrogen on amide nitrogen by fluoride anion as a The products 25a–d are obtained via the attack of amide nitrogen anion to aryne, the intramolecular The products 25a–d are obtained via the attack of amide nitrogen anion to aryne, the intramolecular base. The products 25a–d obtainedcarbon via theatom, attackand of amide nitrogen anion to aryne, the intramolecular trapping process with theare carbonyl the four-membered ring opening. process with with the thecarbonyl carbonylcarbon carbonatom, atom,and andthe thefour-membered four-memberedring ringopening. opening. trapping process

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Scheme Scheme 8. 8. Reaction Reaction of of N-phenyltrifluoroacetamides N-phenyltrifluoroacetamides with with aryne. aryne.

To develop the amide insertion reaction having broad utility, the reaction of N-pivaloylaniline To develop develop the the amide amide insertion insertion reaction reaction having having broad broad utility, utility, the the reaction reaction of of N-pivaloylaniline N-pivaloylaniline To 26a with triflate 23 was investigated by changing solvents and fluoride sources [26]. Employing 26a with with triflate triflate 23 23 was was investigated investigated by by changing changing solvents solvents and and fluoride fluoride sources sources [26]. [26]. Employing Employing 26a tetrabutylammonium triphenyldifluorosilicate (TBTA) as a fluoride source, amide 26a underwent the tetrabutylammonium triphenyldifluorosilicate (TBTA) as a fluoride source, amide 26a underwent tetrabutylammonium triphenyldifluorosilicate (TBTA) as a fluoride source, amide 26a underwent the the N–C insertion insertion in toluene toluene at at◦ 50 50 °C to to afford the the tert-butylketone tert-butylketone 27a 27a in in 64% 64% yield yield (Scheme 9). 9). N–C N–C insertion inin toluene at 50 C to°C affordafford the tert-butylketone 27a in 64% yield (Scheme 9). (Scheme Exploration Exploration of substrate scope showed that N-phenyl derivatives 26b and 26c were similarly efficient Exploration of substrate scope that N-phenyl 26b derivatives and 26c were similarly efficient of substrate scope showed thatshowed N-phenyl derivatives and 26c 26b were similarly efficient substrates. substrates. substrates.

Scheme 9. Reaction of N-phenyltrifluoroacetamides N-phenyltrifluoroacetamides with aryne. Scheme 9. Scheme 9. Reaction Reaction of of N-phenyltrifluoroacetamides with with aryne. aryne.

Additionally, this reaction was applied to the synthesis of acridines (Scheme (Scheme 10). 10). of acridones acridones and and acridines acridines (Scheme 10). The one-step synthesis of acridone 29 was achieved by the reaction of ortho-halobenzamide 28, with one-step synthesis synthesisofofacridone acridone was achieved by the reaction of ortho-halobenzamide 28, The one-step 2929 was achieved by the reaction of ortho-halobenzamide 28, with triflate 23 microwave irradiation at °C presence of with triflate 23 under microwave irradiation at 120 C the in the presence TBAT.Acridone Acridone29 29 was was formed triflate 23 under under microwave irradiation at 120 120 °C ◦in in the presence ofofTBAT. TBAT. Acridone 29 was formed via route involving the N–C insertion, followed by the intramolecular In contrast, contrast, via a a route route involving involving the the N–C N–C insertion, insertion, followed followed by by the the intramolecular intramolecular SS SNNNAr Ar reaction. reaction. In In contrast, a one-pot one-pot procedure procedure using using BF BF333··OEt ·OEt via a route route involving the N–C acridine 31 was synthesized by aa OEt222 via via a one-pot procedure using BF insertion amide 30 followed aa BF Friedel-Crafts acylation and insertion 30 into aryne,aryne, followed by a BF3by -mediated Friedel-Crafts acylation and dehydration. insertion ofof ofamide amide 30 into into aryne, followed by BF33-mediated -mediated Friedel-Crafts acylation and dehydration. dehydration.

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Scheme 10. acridoneand andacridine. acridine. Scheme 10.Synthesis Synthesis of acridone Scheme 10. Synthesis of acridone and acridine. The reaction of β-lactam 32 with aryne gave acridone 29 in 50% yield by employing 3.5

The reaction of β-lactam 32 with aryne gave acridone 29 in 50% yield by employing 3.5 equivalents of the aryne precursor 23 in the presence of CsF (Scheme 11) [27]. In this transformation, equivalents the aryne in the presence CsF (Scheme 11) [27]. Ininsertion this transformation, Theofreaction of precursor β-lactam 3223with gave of acridone 29 in of50% employing 3.5 2,3-dihydroquinolin-4-one 33 is formed asaryne an intermediate as a result N–Cyield bondby of aryne 2,3-dihydroquinolin-4-one formed asthe anthe intermediate a result insertion of aryne equivalents of 32. theIn aryne precursor 23under in presence of CsFas (Scheme 11)of[27]. Inbond this transformation, into β-lactam fact,33 33isreacted same reaction conditions toN–C give acridone 29 in 77% 2,3-dihydroquinolin-4-one 33 is 29 formed as an a result of N–C bond of aryne into β-lactam In fact,of3333reacted under theintermediate same reaction conditions giveinsertion acridone 29the in 77% yield. The 32. conversion into will proceed through theasN-arylation of 33to with second aryne, β-lactam 32. In fact, 33 reacted under the same reaction conditions to give acridone 29 in 77% yield.into The conversion of 33 into 29 will proceed through the N-arylation of 33 with second aryne, subsequent cyclization, the extrusion of ethylene, and the final N-arylation with third aryne. yield. The conversion of 33 into 29 will proceed through the N-arylation of 33 with second aryne, the the subsequent cyclization, the extrusion of ethylene, and the final N-arylation with third aryne. subsequent cyclization, the extrusion of ethylene, and the final N-arylation with third aryne.

Scheme 11. Reaction of β-lactam with aryne leading to acridone. Reaction β-lactam aryne leading to to acridone. 11.11. Reaction ofofβ-lactam with aryne leading acridone. The insertionScheme ofScheme arynes into the N–C bond ofwith imides was investigated [28]. The formation of simple N-arylated products could be suppressed when the reactions of imides 34a–d with triflate 23 The insertion of arynesatinto the N–C bond of imides investigated The formation of wereinsertion carried outofinarynes toluene °C in the presence TBATwas (Scheme 12). The [28]. desired The into60the N–C bond of of imides was investigated [28]. N–C The insertion formation of simple N-arylated products could be suppressed when the reactions of imides 34a–d with triflate 23 products 35a–d were selectively obtained. Additionally, this reaction was applied to the one-pot simple N-arylated products could suppressed when the reactions of The imides 34a–d with triflate 23 were carried out in toluene at 60 be °CCamps in the presence ofusing TBAT (Scheme desired N–C insertion synthesis of quinolone 36 through cyclization KOH and 12). 18-crown-6. ◦ C in were products carried out in toluene at 60 the presence of TBAT (Scheme 12). The desired N–C insertion 35a–d were selectively obtained. Additionally, this reaction was applied to the one-pot products 35a–d were selectively obtained. Additionally, was applied to the one-pot synthesis of quinolone 36 through Camps cyclization using this KOHreaction and 18-crown-6.

synthesis of quinolone 36 through Camps cyclization using KOH and 18-crown-6.

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Scheme 12. 12. Reaction Reaction of of imides imides with with aryne. aryne. Scheme Scheme 12. Reaction of imides with aryne.

C=O Bond Bond Activation Activation 3. C=O 3. C=O Bond Activation C=O bond bond of of the the amide amide group group was was reported reported [29]. [29]. Aryne, Aryne, At first, the insertion of arynes into the C=O At first, the insertion of arynes into the C=O bond of the amide group was reported [29]. Aryne, (DMF) to to give salicylaldehyde 38 generated from from precursor precursor37, 37,reacted reactedwith withN,N-dimethylformamide N,N-dimethylformamide (DMF) give salicylaldehyde generated from precursor 37, reacted with N,N-dimethylformamide (DMF) to give salicylaldehyde in 32% yield (Scheme 13).13). 38 in 32% yield (Scheme 38 in 32% yield (Scheme 13).

Scheme 13. Reaction of N,N-dimethylformamide with aryne. Scheme Scheme 13. 13. Reaction of of N,N-dimethylformamide N,N-dimethylformamide with with aryne. aryne.

When the bulky N,N-dimethylacetamide (DMA) was used, competitive insertion into the C=O When the the bulky N,N-dimethylacetamide N,N-dimethylacetamide (DMA) was was used, competitive competitive insertion insertion into into the the C=O C=O When and N–C bondsbulky of DMA was observed [30]. In (DMA) the presenceused, of TBAF, treatment of 4 with DMA gave and N–C N–C bonds bonds of of DMA DMA was was observed observed [30]. [30]. In In the presence presence of of TBAF, TBAF, treatment treatment of 44 with with DMA DMA gave gave and the C=O insertion product 39 in 34% yield, andthe the N–C insertion product 40 inof10% yield (Scheme the C=O insertion product 39 in 34% yield, and the N–C insertion product 40 in 10% yield (Scheme the C=O productthat 39 inthe 34% yield, and the N–C insertion product 40the in 10% yieldnucleophiles (Scheme 14). 14). This insertion result indicates sterically less-hindered formamides are suitable 14). This result indicates that the sterically less-hindered formamides are the suitable nucleophiles This result indicates that the sterically less-hindered formamides are the suitable nucleophiles for C=O for C=O insertion. The insertion into the C=O bond will proceed via the stepwise mechanism for C=O insertion. The into insertion intobond the will C=Oproceed bond will proceed via mechanism the stepwise mechanism insertion. The insertion the C=O via the stepwise involving the involving the addition of the oxygen atom of amide to an aryne, followed by the intramolecular involving the addition of the oxygen atom of amide to an aryne, followed by the intramolecular addition of the oxygen atom of amide to an aryne, followed by the intramolecular nucleophilic attack nucleophilic attack on the iminium. nucleophilic attack on the iminium. on the iminium.

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Scheme witharyne. aryne. Scheme14. 14.Reaction Reactionof of N,N-dimethylacetamide N,N-dimethylacetamide with with aryne. Scheme 14. Reaction N,N-dimethylacetamide

Thesequential sequentialreaction reaction involving involving the the trapping trapping process process of transient intermediates with The sequential reaction involving the The trapping process of of transient transientintermediates intermediateswith with organometallic reagents was studied [30,31]. After a solution of triflate 4 in DMF was stirred in thethe organometallic reagents was studied [30,31]. After a solution of triflate 4 in DMF was stirred in the organometallic reagents was studied [30,31]. After a solution of triflate 4 in DMF was stirred in presence of of CsF, CsF, aa solution solution of Et Et22Zn Zn in in hexane hexane was was added added to to the the reaction reaction mixture mixture (Scheme (Scheme 15). 15). The The presence presence of CsF, a solution of Etof2 Zn in hexane was added to the reaction mixture (Scheme 15). The desired desired aminophenol aminophenol 41 41 was was obtained obtained in in 71% 71% yield. yield. Diethyllzinc Diethyllzinc also also trapped trapped the the transient transient desired aminophenol 41 was obtained in 71% yield. Diethyllzinc also trapped the transient intermediate intermediate generated generated from from triflate triflate 44 and and formamide formamide 42, 42, to to give give the the aminophenol aminophenol 43 43 by by aa one-pot one-pot intermediate generated from triflate 4 and formamide 42, to give the aminophenol 43 by a one-pot procedure. procedure. procedure.

Scheme15. 15.Reaction Reactionfor for trapping trapping the the transient transient intermediates. Scheme 15. Reaction Scheme trapping transientintermediates. intermediates.


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Three-component sequential coupling of arynes, DMF, and diaryliodonium salts was studied Three-component sequential coupling of arynes, DMF, and diaryliodonium salts was studied [32]. [32]. In the presence of KF, a three-component coupling reaction was found using triflate 23 and Three-component coupling ofcoupling arynes, DMF, and diaryliodonium salts was studied In the presence of KF, asequential three-component reaction was found using triflate 23 and diphenyliodonium triflate 44 in DMF-facilitated 2-phenoxybenzaldehyde 45 in 87% yield (Scheme [32]. In the presence three-component2-phenoxybenzaldehyde coupling reaction was found 23 and 16). diphenyliodonium triflateof44KF, in aDMF-facilitated 45 inusing 87% triflate yield (Scheme diphenyliodonium triflatediphenyliodonium 44 in DMF-facilitated 2-phenoxybenzaldehyde 45 in 87% yield (Scheme the 16). In this transformation, triflate 44 acted as an electrophile by trapping In this transformation, diphenyliodonium triflate 44 acted as an electrophile by trapping the oxygen 16).atom In this diphenyliodonium triflate 44 acted as an electrophile by trapping the oxygen of atransformation, transient intermediate. atom of a transient intermediate. oxygen atom of a transient intermediate.

.

.

Scheme 16.16. Trapping diphenyliodonium salt. Scheme Trappingreaction reaction using using diphenyliodonium salt. Scheme 16. Trapping reaction using diphenyliodonium salt.

Thecoupling 2:1 coupling reaction twomolar molaramounts amounts of molar amount of DMF was was The 2:1 reaction of of two of aryne aryneand andone one molar amount of DMF The 2:1 coupling reaction of two the molar amounts of aryne one molar amount of DMF reported (Scheme 17) [33]. Initially, reaction of precursor 23 and and DMF gives salicylaldehyde 38 was reported (Scheme 17) [33]. Initially, the reaction of precursor 23 and DMF gives salicylaldehyde 38 reported (Scheme 17) [33]. Initially,intermediate. the reaction9-Hydroxyxanthene of precursor 23 and gives via the hydrolysis of a transient 46 DMF is formed bysalicylaldehyde the reaction of 38 via the hydrolysis of a transient intermediate. 9-Hydroxyxanthene 46 is formed by the reaction of salicylaldehyde 38awith aryne. intermediate. 9-Hydroxyxanthene 46 is formed by the reaction of via the hydrolysis of transient salicylaldehyde 38 with aryne. salicylaldehyde 38 with aryne.

Scheme 17. 2:1-Coupling reaction.

The trapping reactions of transient intermediates generated from arynes precursors and DMF Scheme 17. 2:1-Coupling 2:1-Coupling reaction. Scheme 17. reaction. with a variety of reactants have been widely studied as being synthetic approaches to oxygen atomcontaining heterocycles [34–43]. The synthesis of 2H-coumarin derivatives was also studied [34–36]. The trapping ofof transient intermediates generated fromfrom arynes and Three-component coupling reactions leading to chromene 48 was achieved by arynes theprecursors use of acetate 47,DMF trappingreactions reactions transient intermediates generated precursors and having an aryl group as a nucleophile for trapping the unstable intermediate (Scheme 18). In the with a variety of reactants have been widely studied as being synthetic approaches to oxygen atomDMF with a variety of reactants have been widely studied as being synthetic approaches to presence of KF, the reaction ofThe triflate 23 and acetate 47 was carried out in DMF 80 °C to givewas the also containing heterocycles [34–43]. synthesis of 2H-coumarin wasatderivatives also studied [34–36]. oxygen atom-containing heterocycles [34–43]. The synthesis ofderivatives 2H-coumarin coumarin 48 in 95% yield [35]. The synthesis of 2-aryliminochromene skeleton of biologically active Three-component coupling reactions leading to chromene 48towas achieved use of acetate 47, studied [34–36]. Three-component coupling reactions leading chromene 48 by wasthe achieved by the use compounds was studied by using a three-component coupling reaction [36]. A transient intermediate, having an47, aryl group a nucleophile for trapping unstable intermediate (Scheme(Scheme 18). In the of acetate having anas aryl group as a nucleophile for the trapping the unstable intermediate 18). generated from triflate 23 and DMF, could be trapped by N,S-keteneacetal 49 to give the biologically ◦ Cgive presence of KF,of the reaction of triflate 23 and acetate 47 was carried out in DMF at 80at°C to the In theimportant presence KF, the reaction of triflate 23 and acetate 47 was carried out in DMF 80 to give arylimino-2H-chromene-3-carboxamide 50 in 81% yield. The synthesis of 4H-chromene coumarin 48 in yield [35]. The synthesis ofof 2-aryliminochromene skeleton of active the coumarin 4895% in 95% yield [35]. The synthesis 2-aryliminochromene skeleton ofbiologically biologically derivatives was also achieved by using a three-component coupling reaction involving the hetero compounds wasreaction studiedbetween by usingtransient aa three-component reaction [36]. A three-component coupling reaction Atransient transientintermediate, intermediate, Diels-Alder intermediatescoupling and dienophiles [37].

generated from triflate 23 23 and DMF, could be trapped by N,S-keteneacetal 49 49 to give the biologically important arylimino-2H-chromene-3-carboxamide 50 in 81% yield. The synthesis of 4H-chromene arylimino-2H-chromene-3-carboxamide 50 in The derivatives derivatives was also achieved by using a three-component coupling reaction involving the hetero Diels-Alder reaction between transient intermediates and dienophiles dienophiles [37]. [37].


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Scheme derivatives. Scheme18. 18.Synthesis Synthesis of of coumarin coumarin derivatives. Scheme 18. Synthesis of coumarin derivatives. The synthesisofofbenzofurans benzofurans was also studied studied [38–40]. The The synthesis was also [38–40]. The use useofofα-halogenated α-halogenatedenolate, enolate, generated from α-chloromalonate 51 and Et 2Zn, led to the formation of benzofuran 52 (Scheme 19) generated from α-chloromalonate 51 and Et2 Zn, led to the formation of benzofuran 52 (Scheme 19) [38]. synthesis of of CsF, benzofurans was also studied [38–40]. use of α-halogenated enolate, [38].presence InThe the presence treatment of aryne precursor 4 andThe α-chloromalonate 51 Zn with 2Zn in In the of CsF, treatment of aryne precursor 4 and α-chloromalonate 51 with Et in Et DMF gave generated from α-chloromalonate 51 and Et 2Zn, led to the formation of benzofuran 522(Scheme 19) DMF gave 52 in 59% yield. In this transformation, α-chloromalonate acts as a nucleophilic and 52 in [38]. 59% In yield. In this transformation, α-chloromalonate acts as a nucleophilic and electrophilic one theone presence of CsF,for treatment of aaryne precursor 4 and α-chloromalonate with Et2Zn invia electrophilic carbon-unit trapping transient intermediate. Benzofuran 52 51 will be formed carbon-unit for trapping transient intermediate. Benzofuran 52 will beacts formed a route involving DMF gave 52 in 59%a yield. In this transformation, α-chloromalonate as a via nucleophilic and a route involving the retro-aldol type reaction. The simple one-pot synthesis of benzofurans was also the retro-aldol reaction. The simple one-pot synthesis of benzofurans was reported electrophilictype one carbon-unit for trapping a transient intermediate. Benzofuran 52 willalso be formed via [40]. reported [40]. When 2-bromoacetophenone 53 was used as a nucleophilic and electrophilic reactant, route involving the retro-aldol type reaction. The simple one-pot synthesis of benzofurans was also 54 Whena 2-bromoacetophenone 53 was used as a nucleophilic and electrophilic reactant, benzofuran benzofuran 54 was obtained in 79% yield. reported [40]. When 2-bromoacetophenone 53 was used as a nucleophilic and electrophilic reactant, was obtained in 79% yield. benzofuran MeO MeO 54 was obtained in 79% yield. O O CsF O MeO MeO TMS NMe2 Et2Zn O O Me CsF Me + + TMS O O Me O NMe2 Cl Me Et2Zn OTf Me

+

4

OTf 4

MeO

NMe2

51

MeO

O

O

O

ZnEt

O

NMe2 Cl Cl

O

O

Me

COMe COMe Et Et O OO Me Me

Me MeO

retro-aldol

OTf OTf 2323

COMe Et Me Et O O Me O

NMe2

NMe2

COMe

COMe

retro-aldol

O

52

52

O

O

++

NMeCOMe 2

O

MeO

NMe2

NMe2

MeO

Me

Me

52 (59%)

MeO

ZnEt

NMe2

TMS TMS

O Me 52 (59%)

51 Cl

DMF

MeO

MeO

+

O DMF

NMe NMe2

2

OO DMF DMF

Br Br ++

Ph Ph

O O

KF, 18-crown-6 18-crown-6 KF, CO3 KK22CO 3

53 53

Scheme ofbenzofurans. benzofurans. Scheme 19. Synthesis of benzofurans. Scheme19. 19.Synthesis Synthesis of

OO OO

(79%) 5454(79%)

PhPh

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Additionally, the trapping reaction of transient intermediates was successfully applied to a Additionally, the trapping reaction of transient intermediates was successfully applied to a fourfour-component coupling reaction for the convenient synthesis of xanthene derivatives [34,41,42]. component coupling reaction for the convenient synthesis of xanthene derivatives [34,41,42]. Molecules 2018, 23, x

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4. Activation of Relative Bonds 4. Activation of Relative Bonds Additionally, the trapping transient intermediates was was successfully applied a four- of The insertion of arynes into reaction the N–Sofbond of sulfinamides studied [25]. In thetopresence The insertion of arynes intoforthe bond of sulfinamides was derivatives studied [25]. In the presence of component coupling reaction theN–S convenient synthesis of xanthene [34,41,42]. n-Bu4 NF, the reaction of N-phenyltrifluoromethanesulfinamides 55a–c with triflate 23 as an aryne n-Bu4NF, the reaction of N-phenyltrifluoromethanesulfinamides 55a–c with triflate 23 as an aryne precursor gave the insertion products 56a–c in good yields (Scheme 20). 4. Activation ofcorresponding Relative Bonds N–S precursor gave the corresponding N–S insertion products 56a–c in good yields (Scheme 20). The insertion of arynes into the N–S bond of sulfinamides was studied [25]. In the presence of n-Bu4NF, the reaction of N-phenyltrifluoromethanesulfinamides 55a–c with triflate 23 as an aryne precursor gave the corresponding N–S insertion products 56a–c in good yields (Scheme 20).

Scheme 20. 20. Reaction Reaction of of N-phenyltrifluoromethanesulfinamides N-phenyltrifluoromethanesulfinamides with Scheme with aryne. aryne. Scheme 20. Reaction of N-phenyltrifluoromethanesulfinamides with aryne.

arylphosphoryl amides was studied [44]. In the The insertion of arynes into the P–N bonds of arylphosphoryl presence of KF and 18-crown-6, the reaction of diphenylphosphinic amideswas 57a–c with[44]. triflate 23 was The insertion of arynes into the P–N bonds of arylphosphoryl amides studied In the ◦ °C in a18-crown-6, sealed tube The ortho-aniline-substituted arylphosphine oxides carried out atof 80KF Cand 21). presence the(Scheme reaction of diphenylphosphinic amides 57a–c with triflate 23 was This 21). proceeded through the addition out at 80 °C a sealed tube (Scheme The ortho-aniline-substituted arylphosphine oxidesof the 58a–ccarried were obtained ininmoderate yields. transformation 58a–c wereofobtained yields. transformation proceeded through addition of opening. the ring nitrogen atom of57a–c 57a–c tomoderate an aryne, theThis intramolecular trapping, the the four-membered nitrogen atom toinan aryne, the intramolecular trapping, and theand four-membered ring nitrogen atom of 57a–c to an aryne, the intramolecular trapping, and the four-membered ring opening. Additionally, the P–N insertion 58a was converted to ortho-amine-substituted Additionally, the P–N insertion product 58a product was converted to ortho-amine-substituted arylphosphine opening. Additionally, the P–N insertion product 58a was converted to ortho-amine-substituted arylphosphine 59 in 96% yield by the reduction using HSiCl 3 . 59 in 96% yield by the reduction using HSiCl3 . arylphosphine 59 in 96% yield by the reduction using HSiCl3.

Scheme 21.21. Reaction amides with aryne. Scheme Reactionofofdiphenylphosphinic diphenylphosphinic amides with aryne.

Scheme 21. Reaction of diphenylphosphinic amides with aryne.

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The insertion presence Molecules 23, of x arynes into the N–C bonds of aryl cyanamides was reported [45]. In the 12 of 16 The2018, insertion of arynes into the N–C bonds of aryl cyanamides was reported [45]. In the presence of CsF, triflate 23 reacted with aryl cyanamides 60a–e to give the 1,2-bifunctional aminobenzonitriles of CsF, triflate 23 reacted with aryl cyanamides 60a–e to give the 1,2-bifunctional aminobenzonitriles The insertion of arynes into the N–C bonds of aryl cyanamides was reported [45]. Information the presence 61a–e61a–e in good yields (Scheme 22). insertion alsoproceeds proceeds in good yields (Scheme 22).This ThisN–C N–C bond bond insertion also viavia thethe formation of theof the of CsF, triflate 23 reacted with aryl cyanamides 60a–e to give the 1,2-bifunctional aminobenzonitriles four-membered ringring intermediates. four-membered intermediates. 61a–e in good yields (Scheme 22). This N–C bond insertion also proceeds via the formation of the four-membered ring intermediates.

Scheme 22. Reaction of aryl cyanamides with aryne.

Scheme 22. Reaction of aryl cyanamides with aryne. 22. Reaction of aryl cyanamides with aryne. The synthesis of biarylScheme compounds was achieved by using the reaction of aryl sulfonamides with The synthesis of biaryl compounds achieved using the reaction of aryl arynes [46]. In the presence of KF and was 18-crown-6, arylbysulfonamides 62a–c having ansulfonamides electronThe synthesis of biaryl compounds was achieved by using the reaction of aryl sulfonamides with with withdrawing arynes [46].group In the presence of KF and 18-crown-6, aryl sulfonamides having an reacted with aryne to afford 2-amino-biaryls 63a–c (Scheme 23). 62a–c This reaction arynes [46]. In the presence of KF and 18-crown-6, aryl sulfonamides 62a–c having an electroninvolves the additiongroup of sulfonamides to aryne, and the subsequent Smiles-type ipso-substitution with 23). electron-withdrawing reacted with aryne to afford 2-amino-biaryls 63a–c (Scheme withdrawing group reacted with aryne to afford 2-amino-biaryls 63a–c (Scheme 23). This reaction sulfur dioxide SO 2 extrusion. This involves reactionthe involves addition ofto sulfonamides to aryne,Smiles-type and the subsequent Smiles-type addition the of sulfonamides aryne, and the subsequent ipso-substitution with ipso-substitution with sulfur dioxide SO extrusion. 2 sulfur dioxide SO2 extrusion.

Scheme 23. Reaction of aryl sulfonamides with aryne. Scheme 23. Reaction of aryl sulfonamides with aryne. Formal π-insertionScheme into the23. C=S bond was observed in the reaction of thioureas with aryne [47]. Reaction of aryl sulfonamides with aryne. When a solution of triflate 23 and thiourea 64 in toluene/MeCN was heated in the presence of CsF, Formal π-insertion into the C=S bond was observed in the reaction of thioureas with aryne [47]. amidine 65 was formed in 70% yield, accompanied with the simple S-arylated product 66 in 20% Formal into the C=Sthiourea bond was observed in the reaction of in thioureas withofaryne When a π-insertion solution of triflate 23 and 64 in toluene/MeCN was heated the presence CsF, [47]. 65 was formed 23 in and 70% thiourea yield, accompanied with the simple S-arylated product 66 in 20% Whenamidine a solution of triflate 64 in toluene/MeCN was heated in the presence of CsF,

amidine 65 was formed in 70% yield, accompanied with the simple S-arylated product 66 in 20% yield (Scheme 24). The sequential transformation leading to 65 was started by the reaction of the sulfur

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yield (Scheme24). 24).The The sequential transformation transformation leading started the of of thethe yield leading to to 65 65was was startedby thereaction atom of (Scheme 64 with an aryne,sequential which was followed by intramolecular trapping toby give areaction four-membered sulfur atomofof6464with withan anaryne, aryne, which which was was followed followed by give a foursulfur atom by intramolecular intramoleculartrapping trappingtoto give a fourring intermediate. The amidine 66 was obtained via the four-membered ring opening and subsequent membered ring intermediate.The Theamidine amidine 66 66 was was obtained ring opening and membered ring intermediate. obtainedvia viathe thefour-membered four-membered ring opening and S-arylation by an aryne. by an aryne. subsequent S-arylation subsequent S-arylation by an aryne.

Scheme24. 24.Reaction Reaction of Scheme of thiourea thioureawith witharyne. aryne. Scheme 24. Reaction of thiourea with aryne. The C=C double bond of vinylogous amide derivatives reacted with aryne [48,49]. In the The C=C double bond of vinylogous amide derivatives reacted with [48,49]. Incarbonyl the presence presence of CsF, the reaction vinylogous amide witharyne arynearyne gave the The C=C double bond ofofvinylogous amide derivatives derivatives67a–b reacted with [48,49]. In the of presence CsF, the reaction of vinylogous amide derivatives 67a–b with aryne gave the carbonyl compounds compounds 68a–b in good yields (Scheme 25). This transformation proceeded via the [2 + 2] of CsF, the reaction of vinylogous amide derivatives 67a–b with aryne gave the carbonyl cycloaddition between aryne and 67a–b and the four-membered ring opening. The bulky vinylogous 68a–b in good yields (Scheme 25). This transformation proceeded via the [2 + 2] cycloaddition between compounds 68a–b in good yields (Scheme 25). This transformation proceeded via the [2 + 2] amides 69a–c and having ester, ketone, or cyano group as anThe electron-withdrawing group reacted well aryne and 67a–b thearyne four-membered ring bulky amides having cycloaddition between and 67a–b and theopening. four-membered ringvinylogous opening. The bulky 69a–c vinylogous with aryne to give the corresponding products 70a–c in good yields. ester, ketone, or cyano group as an electron-withdrawing group reacted well with aryne to give the

amides 69a–c having ester, ketone, or cyano group as an electron-withdrawing group reacted well corresponding 70a–c in good products yields. 70a–c in good yields. with aryne toproducts give the corresponding

Scheme 25. Reaction of vinylogous amides with aryne.

Scheme25. 25.Reaction Reaction of of vinylogous vinylogous amides Scheme amideswith witharyne. aryne.

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5. Concluding Remarks Arynes are highly reactive intermediates that can activate the N–C and C=O bonds of an amide group under transition-metal-free conditions. As described above, the insertion of arynes into the N–C bond has been studied as a powerful method for preparing ortho-disubstituted arenes. In contrast, the selective insertion of arynes into the C=O bond proceeds when sterically less-hindered formamides are employed. Moreover, the trapping reactions of transient intermediates with a variety of reactants, leading to the multi-component coupling reaction, disclosed a broader aspect of the utility of N–C bond insertion for the synthesis of oxygen atom-containing heterocycles. I hope that this review will inspire new creative contributions to organic chemists. Funding: This research received no external funding. Conflicts of Interest: The author declares no conflict of interest.

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