Synthesis of o-(Dimethylamino)aryl Ketones, Acridones, Acridinium Salts, and 1H-Indazoles by the Reaction of Hydrazones and Arynes

Abstract

A novel, efficient route to biologically and pharmaceutically important o-(dimethylamino)aryl ketones, acridones, acridinium salts, and 1H-indazoles has been developed starting from readily available hydrazones of aldehydes and o-(trimethylsilyl)aryl triflates. The reaction proceeds through arynes under mild conditions, tolerates a wide range of functional groups, and provides the final products in good to excellent yields.

Introduction

A number of nitrogen-based nucleophiles have been shown to react with arynes: aryl and alkyl amines,^{1, 2} enamines, ³ sulfonamides,¹ amides, ⁴ enamides, ⁵ nitrogen-containing heterocycles,^6,7 and imines.⁸ Two recent approaches to 1H-indazoles involve a [3 + 2] cycloaddition between arynes and 1,3-dipoles generated in situ from N-tosylhydrazones⁹ and hydrazonoyl chlorides.¹⁰ (Scheme 1).

Scheme 1.

Known Couplings of Hydrazone-derived Dipoles and Benzyne

While there has been considerable recent interest in aryne-based methodologies, no reaction of arynes and readily available 1,1-dialkylhydrazones had been reported until our communication in 2011.¹¹ In the present account, we wish to provide a more comprehensive report on the scope and limitations of the reaction of 1,1-dialkylhydrazones and arynes, which leads to various biologically and pharmaceutically important products.

Results and Discussion

Ketimine Generation and Subsequent Transformations

In a preliminary study, it was observed that the reaction of the N,N-dimethylhydrazone derived from benzyl phenyl ketone and o-(trimethylsilyl)phenyl triflate¹² plus CsF at 65 °C in MeCN provided 2,3-diphenyl-2H-azirine in a 47% yield plus diphenylmethylamine, along with unreacted starting material. It appears that these products are formed by initial reaction of the hydrazone nitrogen with the very electrophilic aryne to generate a highly basic aryl anion, which deprotonates one of the methylene protons next to the hydrazone functionality (Scheme 2). An intramolecular S_N2 reaction follows, which leads to formation of the azirine and phenyldimethylamine, which is further converted into diphenylmethylamine by reaction with the benzyne. Although this route to an azirine is not described in the literature, better ways of synthesizing azirines have been previously reported.¹³

Scheme 2.

Azirine Formation from a Ketone-derived Hydrazone.

We felt that if the possibility for proton abstraction in the hydrazone substrate could be eliminated, attack of the aryl anion on the activated imine might afford a five-membered ring dinitrogen heterocycle. To our surprise, the reaction between benzaldehyde N,N-dimethylhydrazone (1) and the benzyne precursor 2 under reaction conditions identical to those used in the reaction of the ketone hydrazone did not yield the expected 1,2-dihydroindazole. Instead, the o-(dimethylamino)phenyl imine 3 was obtained in a 76% yield (Scheme 3).

Scheme 3.

Imine Formation from an Aldehyde-derived Hydrazone.

Formation of the acyclic product 3 can be rationalized as follows (Scheme 3). After formation of the dinitrogen-containing five-membered ring heterocycle 1b, a proton shift occurs from the benzylic position to the highly basic amide anion. The resulting dipole 1c can undergo ring opening to afford the final product 3. It is possible that the proton shift from 1b to 1c occurs without any participation of the solvent, since the reaction also proceeds in less acidic THF,¹⁴ although the yield of the final product drops to 43%.

The imine 3 can be acetylated without isolation by adding ethyl chloroformate to the reaction to yield the corresponding ethyl carbamate 4 in an 82% yield (Scheme 4). An analogous reaction of the imine 3 with Ac₂O provides the N acetylimine derivative 5 in a 68% yield. Reduction of the latter with NaBH₃CN in THF leads to formation of the reduced N-acetylamine 6 in a 55% yield. The same compound 6 can be obtained after NaBH₄ reduction of the imine 3 to the amine 7 (70%), followed by acetylation of the amino group with Ac₂O (92% yield).

Scheme 4.

One-pot Transformations of the Generated Imine 3.

Synthesis of Aminoaryl Ketones

As expected, the imine formed can also be easily hydrolyzed to the corresponding ketone under aqueous HCl conditions. Running the aryne coupling and hydrolysis reaction in the same vessel, o-(dimethylamino)phenyl ketone 8 was isolated in a 93% yield (Table 1, entry 1). Running the reaction at room temperature slightly lowers the yield from 93% to 84%. The high efficiency and mild reaction conditions for this overall transformation are of great importance, since o-(dimethylamino)aryl ketones are generally prepared through pathways involving harsh and regio-random Friedel-Crafts reaction conditions ¹⁵ or nucleophilic aromatic substitutions of o-fluoroaryl ketones, which are not very readily available, by amino or proamino nucleophiles.^16,17

Table 1.

Reaction of 1,1-Dimethylhydrazones with Arynes:^a Substrate Scope.

entry	starting hydrazone	product	yieldb (%)
1			93
2			91
3			33
4			78
5			88
6			0c
7			92
8			94
9			91
10			74
11			67
12			0d
13			45
14			61
15			85
16			100
17			0c
18			77
19			91
20			63
21			82
22			85
23			81
24			90
25			85
26			21
27			84
28			55
29			78
30			82
31			84
32			32
33			66
34			89
35			0c
36			85
37			84e

^aReaction conditions: 0.25 mmol of substrate, 1.1 equiv of 2-(trimethylsilyl)phenyl trifluoromethanesulfonate and 3.0 equiv of CsF in 5 mL of MeCN were heated in a closed vial at 65 °C for 10 h. Then 3 mL of 1M HCl was added and the mixture was heated at 65 oC for 2 h.

^bIsolated yield.

^cA mixture of unidentified products was produced.

^dOne of the major products was very polar, presumably a cyclic intermediate analogous to intermediate 1b.

^e2.2 Equiv of benzyne precursor and 5.0 equiv of CsF were used.

o-(dimethylamino)aryl ketones are quite important from a biological standpoint. Compound D-205 (9) has shown significant anti-inflammatory activity^15b (Figure 1). The quinolinyl and isoquinolinyl ketones 10 and 11 have been found to be very efficient agonists of the cannabinoid CB2 receptor.¹⁸ Some aminoaryl ketones are found in nature,¹⁹ and some are employed as starting materials in the preparation of chiral 1,3-diamine based reagents and ligands,¹⁶ and in recently reported ruthenium catalyzed derivatization processes.²⁰

Figure 1.

Pharmaceutically Important o-(Dimethylamino)aryl Ketones.

The importance of o-(dimethylamino)aryl ketones encouraged us to evaluate the scope of this novel aryne coupling reaction. Various hydrazones have been prepared by reacting the corresponding aldehydes with 1,1-disubstituted hydrazines in CH₂Cl₂ in the presence of MgSO₄ (Scheme 5).²¹ The yields of the hydrazones have ranged from 62% to 98%.

Scheme 5.

Preparation of 1,1-Disubstituted Hydrazones.

We first examined other 1,1-dimethylhydrazones. The 2-naphthyl-substituted substrate 12 provided the corresponding ketone 13 in a 91% yield (Table 1, entry 2). Surprisingly, the mesityl hydrazone 14 did not provide the expected product (entry 3). Presumably due to steric hindrance, the presumed cyclic intermediate did not undergo a proton shift, but retained its cyclic structure. The oxidized and demethylated product 15 has been obtained in a 33% yield. In contrast, a less hindered hydrazone 16 with only one methyl group in the position ortho to the reacting functionality cleanly furnished the expected aminoaryl ketone 17 in a 78% yield (entry 4). The p-nitrobenzaldehyde hydrazone 18 provided the corresponding ketone 19 in an 88% yield (entry 5). In a similar manner, the p-methoxybenzaldehyde hydrazone 26 provided the product 27 in a 91% yield (entry 9). These results suggest that there is very little electronic effect of the substituents on the efficiency of this transformation. A messy mixture was observed when the o-nitrobenzaldehyde substrate 20 (entry 6) was employed, presumably due to the instability of the anticipated cyclic intermediate analogous to intermediate 1b. Other electron-withdrawing substituents, such as cyano and ester groups, resulted in clean formation of the corresponding aminoaryl ketones 23 and 25 in 92% and 94% yields respectively (entries 7 and 8). An electron-donating methoxy group in the ortho position leads to aminoaryl ketone 29 in a 74% yield (entry 10, compare with the o-nitro-substituted substrate 20). Interestingly, the 2,4,5-trimethoxy-substituted substrate 30 provides the corresponding product 31 in a 67% yield (entry 11), while the 2,4,6-trimethoxy-substituted substrate 32 (entry 12) results in formation of a very polar compound, presumably analogous to intermediate 1b. All of our attempts to open the proposed cyclic structure or to dequaternarize the presumed ammonium fragment of the cyclic intermediate failed to provide any recognizable product. One should note a similarity between entries 3 and 12, where both starting materials have substituents at the 2 and 6 positions of the aromatic ring, which evidently causes some disruption in the corresponding rearrangement of 1b to 1c. The p-dimethylamino-substituted substrate 34 led to formation of the corresponding ketone 35 in a low 45% yield, likely due to a competing reaction of the nitrogen of the aniline moiety (entry 13). Halides in the ortho position of the aryl ring are well tolerated in this methodology, providing the corresponding fluoro- and bromo-containing aminoaryl ketones 37 and 39 in 61% and 85% yields respectively (entries 14 and 15). Alkynyl functionality in the para position of the phenyl ring afforded the corresponding product 41 in a quantitative yield (entry 16). It is noteworthy that aminoaryl ketone 41 can potentially be quite useful for further elaboration via Sonogashira coupling reactions.²² In contrast, alkynyl functionality in the ortho position is not tolerated in this transformation (entry 17, compare with the o-nitro substrate 20), providing a mixture of mostly unidentified products.

Unfortunately, 2-alkynal hydrazones did not provide the desired aminoketones, but an inseparable mixture of mostly unidentified products.²³ However, alkenyl functionality is well tolerated in this transformation. Products 45 (entry 18) and 9 (entry 19) have been obtained in 77% and 91% yields respectively from such hydrazones. It is noteworthy that the aminoketone 9 has been previously reported to exhibit significant biological activity.^15b The chiral (−)-myrtenal derived hydrazone 47, the remote alkene containing hydrazone 49, and the furan-containing alkenal hydrazone 51 all provided the expected aminoaryl ketones in good yields (63-85%, entries 20-22).

To our delight, despite benzyne’s dienophilic nature,²⁴ electron-rich pyrrole-, furan-, and thiophene-containing hydrazones have undergone the transformation with good efficiency, providing the 2-pyrrolyl (entry 23), 2-furyl (entry 24), and 2-thienyl (entry 25) ketones 54, 56, and 58 in 81%, 90%, and 85% yields respectively. Unfortunately, the indole-derived hydrazone 59 with the substitution at the C-3 position provided the desired aminoaryl ketone 60 in only a 21% yield (entry 26), along with a number of unidentified side products. However, the isomeric hydrazone 61 with the substitution at the C-4 position of the indole system efficiently provided the corresponding product 62 in an 84% yield (entry 27).

Despite the well-documented reactivity of pyridines with arynes,^7,25 a number of substituted pyridines provided the expected aminoaryl ketones in high yields. Thus, hydrazones derived from nicotinaldehyde (63), 2-methoxynicotinaldehyde (65), and picolinaldehyde (67) provided the corresponding products in 55%, 78%, and 82% yields respectively (entries 28-30). The high efficiency of the transformations for the pyridine-derived hydrazones suggests a significant difference in the nucleophilicities of the NMe₂ groups in the hydrazones and the nitrogen atoms in the pyridine rings towards the benzyne. The 2-quinolinyl-derived hydrazone 69 provided the expected product 70 in an 84% yield (entry 31). It is noteworthy that the aminoketone 70 has been previously reported to exhibit significant biological activity.¹⁸

Ester- and ketone-containing hydrazones 71 and 73 provided the corresponding aminoaryl 1,2-dicarbonyl compounds in 32% and 66% yields respectively (entries 32 and 33). Unfortunately, our attempts to cyclize the compound 72 into an isatin heterocycle were not successful.

The nature of the hydrazone moiety can be modified as well. The 1-aminomorpholine-derived-substrate 75 afforded the corresponding ketone 76 in an 89% yield (entry 34). The apparent high reactivity of the remote NMe unit in the piperazine-derived hydrazone 77 resulted in the formation of unidentified products with none of the expected aminoaryl ketone isolated. However, the piperidine-derived hydrazone 79 cleanly furnished the desired product 80 in an 85% yield (entry 36).

As an interesting application of our method, we were able to obtain a double aryne insertion product 82 from a substrate derived from terephthalaldehyde in an 84% yield (entry 37).

Next, we examined the reactivity of various aryne precursors toward our model substrate 1 (Table 2). The symmetrical naphthalyne precursor 83 afforded the corresponding aminoaryl ketone 84 in a 77% yield (entry 1). The electron-rich symmetrical dimethoxybenzyne afforded the expected product in a 83% yield (entry 2), while the electron-deficient 4,5-difluorobenzyne afforded the ketone 88 in a lower 62% yield, which is generally the case for this highly reactive difluorobenzyne.²⁶ The unsymmetrical 4-methoxy- and 4-methylsilylaryl triflates provided ~1/1 mixtures of regioisomers in 81% and 85% yields respectively (entries 4 and 5). The lack of regiocontrol in these two reactions is good evidence that the transformation being studied indeed occurs via benzyne intermediates.

Table 2.

Reaction of 1,1-Dimethylhydrazones with Arynes: Aryne Scope.^a

entry	aryne precursor	product	yieldb (%)
1			77
2			83
3			62
4			81c
5			85d
6			83e
7			82e

^aReaction conditions: 0.25 mmol of benzaldehyde dimethylhydrazone, 1.1 equiv of aryne precursor and 3.0 equiv of CsF in 5 mL of MeCN were heated in a closed vial at 65 °C for 10 h. Then 3 mL of 1M HCl was added and the mixture was heated at 65 °C for 2 h.

^bIsolated yield.

^cA separable ~1/1 mixture of regioisomers was produced.

^dAn inseparable ~1/1 mixture of regioisomers was produced.

^eSee the experimental section for the structure determination of this product.

The reaction of the 1,1-dimethylhydrazone derived from benzaldehyde with the unsymmetrical aryne precursor 3-methoxy-2-(trimethylsilyl)phenyl triflate resulted in the formation of a single regioisomer 94 in an 83% yield (entry 6). The regiochemistry of the product affirms that it is the NMe₂ group that initially attacks the benzyne, not the nucleophilic carbon through the substrate’s alternative resonance structure as is the case with enamines³ (Scheme 6). ²⁷ Similar regiocontrol is observed with the unsymmetrical naphthalyne precursor 95. A single regioisomer 96, resulting from attack of the dimethylamino group of the hydrazone at the more electrophilic C-2 position of the naphthalyne,²⁸ was produced in an 82% yield (entry 7).

Scheme 6.

Reaction with Unsymmetrical 3-Methoxybenzyne.

Synthesis of N-Methylacridones

We envisioned that the NMe₂ group of the aminoketones generated by our process could further undergo an intramolecular S_NAr reaction if there were a favorably positioned leaving group ortho to the ketone. This would lead to the formation of a cationic N,N-dimethylacridinium salt, which should undergo in situ demethylation to the more stable N-methylacridone in the presence of the nucleophilic fluoride media or the addition of a base, such as NaOMe (Scheme 7).²⁹ This latter heterocycle is a prominent naturally-occurring scaffold³⁰ with many of its members exhibiting a wide range of biological activity, including antitumor,³¹ antimalarial,³² and antiplasmodial³³ activities.

Scheme 7.

Plausible Pathway of the Formation of N-Methylacridones.

To our delight, a closer examination of the reaction of the o-bromobenzaldehyde hydrazone (Table 1, entry 15) indicated that along with the 85% yield of the aminoketone 39, N-methylacridone was generated in a 7% yield. Upon heating the o-aminoketone 39 in MeCN at 100 °C, the ketone quantitatively cyclized to the desired acridone. After optimizing the reaction conditions, we found that N-methylacridone (97) could be obtained in one-pot in a 95% yield (Table 3, entry 1) by reacting the o-bromobenzaldehyde hydrazone 38 with the benzyne precursor 2 in the presence of CsF and subsequently hydrolyzing the imine and at the same time inducing the cyclization in the presence of aqueous HCl at 100 °C. Further addition of a solution of NaOMe and heating the mixture at 100 °C presumably assists in dequaternarizing the initially formed N,N-dimethylacridinium salt.

Table 3.

Synthesis of N-Methylacridones^a

entry	starting hydrazone	product	yieldb (%)
1			95
2		97	91
3		97	94
4			45
5			0
6			84
7			79
8			59
9			87
10			77
11			38
12			0
13			48

^aReaction conditions: 0.25 mmol of substrate, 1.1 equiv of benzyne precursor and 3.0 equiv of CsF in 5 mL of MeCN were heated in a closed vial at 65 °C for 10 h. Then 3 mL of 1 M HCl was added and the mixture was heated at 100 °C for 2 h. Then 5 mL of 1 M NaOMe was added and the mixture was heated at 100 °C for 2 h.

^bIsolated yield.

Excellent yields (91% and 94%) have also been observed using the corresponding o-chloro- and o-fluorobenzaldehyde hydrazones 98 (entry 2) and 36 (entry 3). The 1-bromo-2-naphthaldehyde-derived hydrazone provided the polycyclic acridone 100 in a 45% yield (entry 4). Unfortunately, the reaction of 2-fluoro-6-iodobenzaldehyde dimethylhydrazone with benzyne resulted in the formation of a mixture of unidentified products, likely due to a competitive S_NAr reaction with the iodo- and fluoro-substituents (entry 5). The dihalogenated substrates 103 and 105 provided the corresponding acridones 104 and 106 in 84% and 79% yields respectively (entries 6 and 7). It is noteworthy that the presence of the halide moiety at the C-2 position of the acridone 106 allows further elaboration of this heterocyclic structure by various, well known Pd-catalyzed processes. As a representative example of such methodologies, we have successfully obtained the Suzuki Miyaura coupling product 119 in a 75% yield (Scheme 8).³⁴

Scheme 8.

Suzuki-Miyaura Coupling of an Acridone.

The nitro-substituted acridone 108 was obtained using our aryne methodology, but the limited solubility of the product produced only a modest 59% yield of this acridone (entry 8). The mono- and dimethoxy-substituted o-halobenzaldehyde hydrazones 109 and 111 successfully provided the corresponding N-methylacridones in 87% and 77% yields respectively (entries 9 and 10). Despite similarities between the oxygenated substrates 111 and 113, the final S_NAr step in the latter case was rather sluggish and the desired product 114 was obtained in only a 38% yield (entry 11).

Unfortunately, applying our methodology to an indole system was not successful; none of the desired product was formed under our optimized conditions when hydrazone 115 was employed (entry 12). However, the pyridine-derived hydrazone 117 led to formation of the desired aza-acridone derivative 118 in a 48% yield (entry 13). The latter compound is a type of benzonaphthyridinone, some of which have shown antimicrobial,³⁵ trypanocidal,³⁶ and anticancer³⁷ activities. They have also been shown to reverse the multidrug resistance of tumor cells.³⁸

A number of naturally-occurring acridones have been synthesized utilizing our methodology. The use of the unsymmetrical 3-methoxy-2-(trimethylsilyl)phenyl triflate 93 in the above transformation resulted in the formation of a single regioisomer 120 in an 87% yield with regioselectivity analogous to that described above (Table 2, entry 6). It is noteworthy that compound 120 is a naturally-occurring acridone³⁹ and its demethylated derivative 121 has been shown to exhibit anti-HIV activity. ⁴⁰ We obtained the latter pharmaceutically important product in a 94% yield after HI-induced demethylation of the acridone 120 (i.e. in a 75% overall yield via 3 steps starting from o-fluorobenzaldehyde) (Scheme 9).

Scheme 9.

Synthesis of a Naturally-occurring Acridone.

The use of the unsymmetrical 3,5-dimethoxy-2-(trimethylsilyl)phenyl triflate 122⁴¹ in a reaction with o-fluorobenzaldehyde dimethylhydrazone resulted in the formation of compound 123 in a 78% yield as a single regioisomer (Scheme 10). Compound 123 is found in nature,⁴² as well as its 1-demethylated³³ and 1,3-bisdemethylated⁴³ derivatives. The latter has also been shown to have significant antipsoriatic activity⁴⁴ and has been previously made from compound 123 using an HBr mediated ether cleavage.⁴⁵ It is also noteworthy that the compound 123 has been previously used as a precursor to acronycine (124),⁴⁶ an alkaloid long known for its antitumor properties.⁴⁷

Scheme 10.

Synthesis of a Naturally-occurring Acridone.

The analogous reaction of the unsymmetrical 3,5-dimethoxy-2-(trimethylsilyl)phenyl triflate with the methoxy-analog of 36 resulted in the formation of acridone 125 after additional exposure of the unreacted, uncyclized aminoaryl ketone to elevated temperatures, because of incomplete cyclization under our standard S_NAr reaction conditions. The acridone 125 was isolated in a 60% yield as a single isomer from the aminobenzophenone. The compound 125 is found in nature.⁴⁸ Synthesis of its 1,3,6-trisdemethylated derivative by HBr-mediated demethylation is described in the literature.⁴⁹ The latter is an immediate precursor to the natural product acrimarine-G.^49,50

Synthesis of Acridinium Salts

To further extend the scope of our methodology, we reacted the N-methyl-N-phenyl hydrazone of benzaldehyde (126) with benzyne under our optimized reaction conditions for the synthesis of aminoaryl ketones (Scheme 12). To our surprise, instead of the expected ketone, a very polar compound 127 was obtained with its spectrum identical to that reported in the literature.⁵¹ The formation of the N-methylacridinium salt 127 can be rationalized in the following way (Scheme 12). After ketimine formation, the acid added to the reaction mixture apparently catalyzes an intramolecular Friedel-Crafts reaction of the imine (or of the previously hydrolyzed ketone) with the neighboring phenyl group leading to the formation of a 6-membered ring heterocycle. ⁵² Subsequent deamination (or dehydration) of the intermediate leads to formation of the acridinium salt 127.

Scheme 12.

Plausible Pathway for Acridinium Salt Formation.

A related finding has been recently reported by Greaney’s group, where the cyclization of a secondary amine derivative with simultaneous dehydration leads to formation of an acridine.⁴ It has been found that reacting the hydrazone with 1.8 equiv of the aryne precursor in the presence of 4 equiv of CsF in acetonitrile at room temperature affords, after HCl-catalyzed cyclization and aromatization, the desired product 127 in an 88% yield (Scheme 13).

Scheme 13.

Various Routes to Acridinium Salt Formation.

The same product 127 can be formed in a 41% yield starting from the N-methyl hydrazone 128. Presumably, the first equivalent of benzyne arylates the hydrazone nitrogen,⁵³ essentially forming the starting substrate for the subsequent benzyne insertion/Friedel-Crafts cyclization/aromatization sequence. Also, it has been found that the reaction of (dimethylamino)aryl ketone 8 (obtained from benzaldehyde dimethylhydrazone and benzyne as reported in Table 1, entry 1) with benzyne leads to formation of the same acridinium salt 127. This result can be rationalized in the following way (Scheme 14). After nucleophilic attack of the dimethylamino group onto the benzyne, the expected annulation reaction occurs,⁵⁴ and dequaternarization of the diaryldimethylammonium fragment follows (presumably assisted by the fluoride). Following the addition of hydrochloric acid to the reaction mixture, loss of the hydroxyl group (as water) from the molecule results in formation of the stable aromatic acridinium salt 127, which was formed in a 78% yield using this approach.

Scheme 14.

Plausible Pathway for Acridinium Salt Formation.

Acridinium salts are an intriguing class of compounds used for DNA intercalation studies⁵¹ and as NAD⁺ analogues.⁵⁵ Recently, their analogues, quinolinium salts, have been shown to be effective photocatalysts for the direct oxygenation of benzene to phenol.⁵⁶ Our methodology provides a convenient approach to the synthesis of derivatized acridinium salts. Using the 2-thienaldehyde-derived substrate 129 in place of the model hydrazone 126 in our chemistry afforded the thiophene-containing acridinium chloride 130 in an 88% yield (Scheme 15). The N,N-diphenylhydrazone 131 afforded the N-phenyl acridinium salt 132 in a 31% yield. The lower yield is presumably due to difficulties in removing the phenyl group during the dequaternization step.

Scheme 15.

Synthesis of Substituted Acridinium Salts.

Synthesis of 1H-Indazoles by the Chlorination and Subsequent Cyclization of ortho-Aminoaryl Ketimines

Recently, a convenient method for the preparation of isomeric benzoxazoles was described by Chen and co-workers (Scheme 16).⁵⁷ In that process, o-hydroxyaryl ketimines 133 are intramolecularly cyclized to benzisoxazoles 134 or benzoxazoles 135 upon exposure to chlorinating conditions involving respectively a) NCS in the presence of K₂CO₃ or b) 10% NaOCl.

Scheme 16.

Synthesis of Isomeric Benzoxazoles by the Chen group.

Due to the similar nature of o-hydroxyaryl ketimines and our o-aminoaryl ketimines 3, we attempted to induce a similar cyclization to 1H-indazoles through a one-pot synthesis of aminoaryl ketimines by the reaction of hydrazones with arynes, followed by chlorination with NCS (Scheme 17).⁵⁸ When the reaction mixture containing ketimine 3 was subjected to NCS/K₂CO₃ at 65 °C, only 14% of the desired indazole was isolated. The major product of the reaction, N-chloroketimine 136, was isolated in an 80% yield. The latter cyclized to the desired indazole 137 in a 90% yield upon exposure to elevated temperatures (100 °C) in THF. We noticed that the key cyclization is more facile in THF (as compared to MeCN). However, running the first step (the reaction with the benzyne) in acetonitrile, followed by evaporation and immediate addition of THF, unavoidably causes some hydrolysis of the labile ketimine 3 to the corresponding ketone. We could obtain the indazole 137 in only a 50% yield using the procedure with the two different solvents.

Scheme 17.

Attempts to Develop a One-Pot Synthesis of 1H-Indazoles.

Subjecting the original reaction mixture of the ketimine 3 to the NCS-chlorinating conditions and, after a complete imine-to-chloroimine conversion (as detected by TLC), heating at 130 °C resulted in only a 34% isolated yield of the desired product 137. This result suggests interference of the constituents of the reaction mixture with the intramolecular cyclization step. If one extracts the reaction mixture after the NCS-chlorination step (performed at 65 °C with no K₂CO₃) from water (thus, separating the desired products from all possible water-soluble constituents) and subsequently exposes the reaction mixture to 130 °C in acetonitrile, the desired indazole 137 is formed in a 66% yield in a pseudo one-pot fashion (Scheme 18).

Scheme 18.

Optimization of the Synthesis of Indazoles from Ketimines.

An alternative route to indazoles from o-aminoaryl aldehydes 138 has been recently described by Rebek Jr. (Scheme 19). ⁵⁹ When reacting the latter compounds with hydroxylamine hydrochloride at elevated temperatures, the hydroxyl group of the o aminoaryl aldoximes 139 formed in situ is intramolecularly replaced by the neighboring amino group (after activation by the HCl present in the reaction media), thus leading to the desired indazole moiety 140.

Scheme 19.

Synthesis of Indazoles by Rebek.

Although no attempts to run this transformation on analogous ketones have been reported, we decided to use this approach for the synthesis of an analogue of the natural alkaloid nigellidine (145). Nigellidine and its sulfated analogue have been isolated⁶⁰ from the seeds of the common spice Nigella sativa. After the reaction of the pyrrolidine-derived hydrazone 141 with the silylaryl triflate 2 in the presence of CsF in MeCN at 65 °C, hydroxylamine hydrochloride was added to the imine formed in situ and the reaction was kept at 150 °C for an additional 24 h. As a result, we could successfully isolate the tricyclic compound 143, albeit in a low 37% yield (Scheme 20). Subsequent BBr₃-mediated demethylation⁶¹ furnished the desired nigellidine analogue 144 in a 67% yield.

Scheme 20.

Synthesis of a Nigellidine Analogue.

Conclusions

In summary, we have developed a novel, efficient route to o-(dimethylamino)aryl ketones, acridones, acridinium salts, and 1H-indazoles starting from readily available aldehydes, 1,1-dimethylhydrazine and o-(trimethylsilyl)aryl triflates. In the formation of o-(dimethylamino)aryl ketones, the reaction proceeds through a cyclization-ring opening pathway with intermediate formation of a dihydroindazole. In the case of acridones, the initial transformation is followed by an additional intramolecular S_NAr reaction and demethylation. In the case of acridinium salts, the initial transformation is followed by an intramolecular acid-catalyzed Friedel-Crafts cyclization. In the case of indazoles, after the benzyne-induced cyclization and subsequent ring-opening, the resulting o-aminoaryl ketimine can be cyclized to an 1H-indazole by chlorination of the imine by NCS, followed by intramolecular displacement of the chloride. Additionally, an analogue of nigellidine 144 has been synthesized in only two steps from the starting hydrazone 141 and the commercially available benzyne precursor 2. This array of methods should prove useful for the preparation of a variety of biologically and pharmaceutically important structures. A representative number of naturally-occurring and medicinally-relevant compounds have been obtained using our methodology. A variety of functional groups are compatible with the reaction conditions.

Experimental

General Information

The ¹H and ¹³C NMR spectra were recorded at 300 and 75.5 MHz or 400 and 100 MHz, respectively. Chemical shifts are reported in δ units (ppm) by assigning the TMS resonance in the ¹H NMR spectrum as 0.00 ppm and the CDCl₃ resonance in the ¹³C NMR spectrum as 77.23 ppm. All coupling constants (J) are reported in Hertz (Hz). All commercial reagents were used directly as obtained. Thin layer chromatography was performed using commercially prepared 60-mesh silica gel plates, and visualization was effected with short wavelength UV light (254 nm). All melting points were obtained using an automated melting point apparatus and are uncorrected. High resolution mass spectra (HRMS) were obtained using a Q-TOF mass spectrometer (APCI at a voltage of 70 eV).

The characterization of compounds 1, 8, 9, 12-14, 18-20, 22, 24, 26, 27, 32, 36, 38-40, 44-46, 55-57, 63, 64, 71, 75, 76, 79, 94, 97, 98, 120, 121, 153, and 163 can be found in our earlier reports.¹¹

Synthesis of the Hydrazones

The starting hydrazones were prepared according to the procedure described in our recent communication.^11a

o-Tolylaldehyde dimethylhydrazone (16)

Yellow liquid: ¹H NMR (400 MHz, CDCl₃) δ 2.44 (s, 3H), 3.00 (s, 6H), 7.10-7.23 (m, 3H), 7.44 (s, 1H), 7.81 (d, J = 7.6 Hz, 1H); ¹³C NMR (100 MHz, CDCl₃) δ 19.9, 43.2, 125.2, 126.3, 127.4, 130.7, 131.5, 134.9; HRMS (APCI) calcd for [M+H]⁺ C₁₀H₁₅N₂ 163.1230, found 163.1228.

2-Methoxybenzaldehyde dimethylhydrazone (28)

Light yellow liquid: ¹H NMR (400 MHz, CDCl₃) δ 2.97 (s, 6H), 3.85 (s, 3H), 6.86 (d, J = 8.2 Hz, 1H), 6.93 (t, J = 7.5 Hz, 1H), 7.20 (td, J = 8.3, 1.7 Hz, 1H), 7.61 (s, 1H), 7.85 (dd, J = 7.7, 1.8 Hz, 1H); ¹³C NMR (100 MHz, CDCl₃) δ 43.3, 55.7, 111.0, 121.1, 125.2, 125.6, 128.5, 129.1, 156.7; HRMS (APCI) calcd for [M+H]⁺ C₁₀H₁₅N₂O 179.1179, found 179.1176.

2,4,5-Trimethoxybenzaldehyde dimethylhydrazone (30)

Pale brown solid: mp 60-63 °C; ¹H NMR (400 MHz, CDCl₃) δ 2.87 (s, 6H), 3.76 (s, 3H), 3.82 (s, 3H), 3.83 (s, 3H), 6.42 (s, 1H), 7.36 (s, 1H), 7.53 (s, 1H); ¹³C NMR (100 MHz, CDCl₃) δ 43.4, 56.2, 56.4, 56.8, 97.6, 107.8, 117.6, 129.7, 143.8, 149.6, 151.5; HRMS (APCI) calcd for [M+H]⁺ C₁₂H₁₉N₂O₃ 239.1390, found 239.1388.

4-(N,N-Dimethylamino)benzaldehyde dimethylhydrazone (34)

Red solid: mp 67-68 °C (lit.⁶² mp 65-67 °C); ¹H NMR (400 MHz, CDCl₃) δ 2.90 (s, 6H), 2.97 (s, 6H), 6.70 (d, J = 8.8 Hz, 2H), 7.32 (s, 1H), 7.48 (d, J = 8.8 Hz, 2H); ¹³C NMR (100 MHz, CDCl₃) δ 40.8, 43.6, 112.6, 125.5, 127.2, 135.9, 150.5; HRMS (APCI) calcd for [M+H]⁺ C₁₁H₁₈N₃ 192.1495, found 192.1493.

(−)-Myrtenal dimethylhydrazone (47)

Pale yellow liquid: ¹H NMR (400 MHz, CDCl₃) δ 0.81 (s, 3H), 1.14 (d, J = 8.8 Hz, 1H), 1.32 (s, 3H), 2.07-2.16 (m, 1H), 2.34-2.47 (m, 3H), 2.81 (s, 6H), 2.97 (t, J = 5.4 Hz, 1H), 5.61 (s, 1H), 7.01 (s, 1H); ¹³C NMR (100 MHz, CDCl₃) δ 21.2, 26.4, 31.6, 32.3, 37.9, 40.4, 41.3, 43.3, 124.6, 136.8, 146.8; HRMS (APCI) calcd for [M+H]⁺ C₁₂H₂₁N₂ 193.1699, found 193.1698.

(2E,6Z)-Nonadienal dimethylhydrazone (49)

Red-brown liquid: ¹H NMR (400 MHz, CDCl₃) δ 0.94 (t, J = 7.5 Hz, 3H), 2.02 (quintet, J = 7.3, 2H), 2.13-2.19 (m, 4H), 2.81 (s, 6H), 5.27-5.42 (m, 2H), 5.77-5.84 (m, 1H), 6.17-6.23 (m, 1H), 6.99 (d, J = 8.9 Hz, 1H); ¹³C NMR (100 MHz, CDCl₃) δ 14.5, 20.8, 27.0, 33.0, 43.2, 128.3, 129.5, 132.5, 135.2, 137.0; HRMS (APCI) calcd for [M+H]⁺ C₁₁H₂₁N₂ 181.1699, found 181.1697.

(E)-3-(2-Furyl)-2-propenal dimethylhydrazone (51)

Black solid: mp 37-39 °C; ¹H NMR (300 MHz, CDCl₃) δ 2.90 (s, 6H), 6.26 (d, J = 3.3 Hz, 1H), 6.35-6.43 (m, 2H), 6.82 (dd, J = 15.8, 9.1 Hz, 1H), 7.04 (d, J = 9.2 Hz, 1H), 7.35 (d, J = 1.9 Hz, 1H); ¹³C NMR (75 MHz, CDCl₃) δ 43.0, 108.0, 111.8, 119.3, 126.5, 134.7, 142.3, 153.6; HRMS (APCI) calcd for [M+H]⁺ C₉H₁₃N₂O 165.1022, found 165.1024.

2-Pyrrolecarbaldehyde dimethylhydrazone (53)

Black solid: mp 43-46 °C; ¹H NMR (400 MHz, CDCl₃) δ 2.86 (s, 6H), 6.22 (d, J = 12.5 Hz, 2H), 6.76 (s, 1H), 7.28 (s, 1H), 9.03 (br s, 1H); ¹³C NMR (100 MHz, CDCl₃) δ 43.6, 109.1, 109.4, 119.1, 127.8, 130.3; HRMS (APCI) calcd for [M+H]⁺ C₇H₁₂N₃ 138.1026, found 138.1026.

Indole-3-carbaldehyde dimethylhydrazone (59)

This compound was obtained as a brown solid using 2 mL of MeOH as a co-solvent: mp 90-93 °C; ¹H NMR (400 MHz, CDCl₃) δ 2.97 (s, 6H), 7.18 (d, J = 2.7 Hz, 1H), 7.23-7.29 (m, 3H), 7.74 (s, 1H), 8.35-8.40 (m, 1H), 8.57 (s, 1H); ¹³C NMR (100 MHz, CDCl₃) δ 43.9, 111.5, 114.6, 120.8, 122.1, 123.0, 125.0, 125.2, 133.1, 137.0; HRMS (APCI) calcd for [M+H]⁺ C₁₁H₁₄N₃ 188.1182, found 188.1181.

Indole-4-carbaldehyde dimethylhydrazone (61)

Black oil: ¹H NMR (400 MHz, CDCl₃) δ 3.02 (s, 6H), 7.09-7.30 (m, 5H), 7.62 (s, 1H), 8.31 (br s, 1H); ¹³C NMR (100 MHz, CDCl₃) δ 43.0, 103.1, 110.5, 119.1, 121.8, 124.2, 124.5, 128.6, 134.6, 136.4; HRMS (APCI) calcd for [M+H]⁺ C₁₁H₁₄N₃ 188.1182, found 188.1180.

2-Methoxy-3-pyridinecarboxaldehyde dimethylhydrazone (65)

Colorless liquid: ¹H NMR (400 MHz, CDCl₃) δ 2.98 (s, 6H), 3.97 (s, 3H), 6.85 (dd, J = 7.4, 4.9 Hz, 1H), 7.38 (s, 1H), 7.98 8.09 (m, 2H); ¹³C NMR (100 MHz, CDCl₃) δ 43.1, 53.5, 117.4, 120.2, 126.6, 132.8, 145.3, 160.7; HRMS (APCI) calcd for [M+H]⁺ C₉H₁₄N₃O 180.1131, found 180.1130.

2-Pyridinecarboxaldehyde dimethylhydrazone (67)

Pale brown liquid: ¹H NMR (400 MHz, CDCl₃) δ 3.01 (s, 6H), 7.03 (ddd, J = 7.2, 4.8, 1.3 Hz, 1H), 7.24 (s, 1H), 7.56 (t, J = 7.7, 1H), 7.73 (d, J = 8.1 Hz, 1H), 8.45 (d, J = 4.1 Hz, 1H); ¹³C NMR (100 MHz, CDCl₃) δ 42.8, 118.9, 121.6, 131.8, 136.3, 149.2, 156.1; HRMS (APCI) calcd for [M+H]⁺ C₈H₁₂N₃ 150.1026, found 150.1027.

2-Quinolinecarboxaldehyde dimethylhydrazone (69)

Brown red semisolid: mp 67-68 °C; ¹H NMR (400 MHz, CDCl₃) δ 2.92 (s, 6H), 7.26 (t, J = 7.5 Hz, 1H), 7.31 (s, 1H), 7.51 (ddd, J = 8.5, 7.0, 1.5 Hz, 1H), 7.55 (d, J = 8.0 Hz, 1H), 7.80-7.95 (m, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 42.7, 117.6, 125.7, 127.5, 127.7, 128.7, 129.5, 131.3, 135.8, 148.1, 156.5; HRMS (APCI) calcd for [M+H]⁺ C₁₂H₁₄N₃ 200.1182, found 200.1180.

2-Oxo-2-phenylacetaldehyde aldehyde(dimethylhydrazone) (73)

This compound was obtained as a pale yellow solid from phenylglyoxal monohydrate using 3 equiv (instead of 2) of MgSO₄: mp 41-42 °C; ¹H NMR (400 MHz, CDCl₃) δ 3.19 (s, 6H), 7.05 (s, 1H), 7.40 (t, J = 7.4 Hz, 2H), 7.48 (t, J = 7.3 Hz, 1H), 7.96 (dd, J = 8.3, 1.4 Hz, 2H); ¹³C NMR (75 MHz, CDCl₃) δ 42.8, 126.3, 128.1, 129.8, 131.7, 138.5, 189.7; HRMS (APCI) calcd for [M+H]⁺ C₁₀H₁₃N₂O 177.1022, found 177.1021.

1,4-Benzenedicarboxaldehyde bis(dimethylhydrazone) (81)

Pale yellow solid: mp 164-165 °C; ¹H NMR (400 MHz, CDCl₃) δ 2.96 (s, 12H), 7.22 (s, 2H), 7.53 (s, 4H); ¹³C NMR (100 MHz, CDCl₃) δ 43.1, 127.0, 133.0, 136.1; HRMS (APCI) calcd for [M+H]⁺ C₁₂H₁₉N₄ 219.1604, found 219.1602.

1-Bromo-2-naphthaldehyde dimethylhydrazone (99)

White solid: mp 80-82 °C; ¹H NMR (400 MHz, CDCl₃) δ 3.11 (s, 6H), 7.48 (t, J = 7.4 Hz, 1H), 7.58 (t, J = 7.6 Hz, 1H), 7.74 (d, J = 8.7 Hz, 1H), 7.78-7.80 (m, 2H), 8.13 (d, J = 8.6 Hz, 1H), 8.36 (d, J = 8.5 Hz, 1H); ¹³C NMR (100 MHz, CDCl₃) δ 43.1, 122.2, 124.2, 126.4, 127.3, 127.6, 127.7, 128.4, 131.6, 132.9, 133.9, 134.1; HRMS (APCI) calcd for [M+H]⁺ C₁₃H₁₄BrN₂ 277.0335, found 277.0331.

2-Bromo-5-fluorobenzaldehyde dimethylhydrazone (103)

Colorless liquid: ¹H NMR (300 MHz, CDCl₃) δ 3.05 (s, 6H), 6.77 (ddd, J = 8.7, 7.7, 3.2 Hz, 1H), 7.33 (s, 1H), 7.43 (dd, J = 8.8, 5.3 Hz, 1H), 7.61 (dd, J = 10.3, 3.2 Hz, 1H); ¹³C NMR (75 MHz, CDCl₃) δ 42.9, 112.5 (²J_CF = 24.4 Hz), 115.4 (²J_CF = 23.6 Hz), 116.3 (⁴J_CF = 2.9 Hz), 128.8 (⁴J_CF = 2.7 Hz), 134.1 (³J_CF = 8.2 Hz), 137.8 (³J_CF = 8.1 Hz), 162.3 (¹J_CF = 244.9 Hz); HRMS (APCI) calcd for [M+H]⁺ C₉H₁₁BrFN₂ 245.0084, found 245.0082.

5-Bromo-2-fluorobenzaldehyde dimethylhydrazone (105)

Colorless liquid: ¹H NMR (400 MHz, CDCl₃) δ 3.02 (s, 6H), 6.88 (dd, J = 10.3, 8.7 Hz, 1H), 7.19-7.25 (m, 2H), 7.98 (dd, J = 6.6, 2.6 Hz, 1H); ¹³C NMR (100 MHz, CDCl₃) δ 42.9, 117.3 (J_CF = 3.0 Hz), 117.3 (J_CF = 22.9 Hz), 122.3, 127.0 (J_CF = 11.7 Hz), 128.0 (J_CF = 3.8 Hz), 130.6 (J_CF = 8.4 Hz), 159.1 (¹J_CF = 247.8 Hz); HRMS (APCI) calcd for [M+H]⁺ C₉H₁₁BrFN₂ 245.0084, found 245.0082.

2-Chloro-5-nitrobenzaldehyde dimethylhydrazone (107)

Orange solid: mp 87-91 °C; ¹H NMR (400 MHz, CDCl₃) δ 3.09 (s, 6H), 7.25 (s, 1H), 7.39 (d, J = 8.8 Hz, 1H), 7.86 (dd, J = 8.8, 2.7 Hz, 1H), 8.69 (d, J = 2.7 Hz, 1H); ¹³C NMR (100 MHz, CDCl₃) δ 42.8, 120.5, 121.2, 123.6, 130.6, 136.3, 137.2, 147.1; HRMS (APCI) calcd for [M+H]⁺ C₉H₁₁ClN₃O₂ 228.0534, found 228.0532.

2-Fluoro-3-methoxybenzaldehyde dimethylhydrazone (109)

Colorless liquid: ¹H NMR (300 MHz, CDCl₃) δ 3.00 (s, 6H), 3.86 (s, 3H), 6.79 (td, J = 8.2, 1.6 Hz, 1H), 7.00 (td, J = 8.1, 1.5 Hz, 1H), 7.38 (s, 1H), 7.44 (ddd, J = 8.0, 6.3, 1.6 Hz, 1H); ¹³C NMR (75 MHz, CDCl₃) δ 42.9, 56.4, 111.5, 116.9, 123.9 (J_CF = 4.7 Hz), 124.5 (J_CF = 6.4 Hz), 125.8 (J_CF = 7.6 Hz), 148.0 (J_CF = 10.6 Hz), 150.3 (¹J_CF = 247.9 Hz) (extra signals due to C-F coupling); HRMS (APCI) calcd for [M+H]⁺ C₁₀H₁₄FN₂O 197.1085, found 197.1083.

2-Bromo-4,5-dimethoxybenzaldehyde dimethylhydrazone (111)

White solid: mp 90-91 °C; ¹H NMR (400 MHz, CDCl₃) δ 2.91 (s, 6H), 3.78 (s, 3H), 3.84 (s, 3H), 6.88 (s, 1H), 7.33 (s, 1H), 7.37 (s, 1H); ¹³C NMR (100 MHz, CDCl₃) δ 43.1, 56.1, 56.3, 108.1, 113.3, 115.1, 128.2, 131.6, 148.7, 149.2; HRMS (APCI) calcd for [M+H]⁺ C₁₁H₁₆BrN₂O₂ 287.0390, found 287.0389.

6-Bromopiperonal dimethylhydrazone (113)

White solid: mp 55-57 °C; ¹H NMR (300 MHz, CDCl₃) δ 2.97 (s, 6H), 5.92 (s, 2H), 6.93 (s, 1H), 7.38 (s, 1H), 7.39 (s, 1H); ¹³C NMR (75 MHz, CDCl₃) δ 43.1, 101.9, 105.7, 112.5, 113.7, 129.7, 131.4, 147.9; HRMS (APCI) calcd for [M+H]⁺ C₁₀H₁₂BrN₂O₂ 271.0077, found 271.0077.

2-Chloro-3-pyridinecarboxaldehyde dimethylhydrazone (117)

Pale yellow liquid: ¹H NMR (400 MHz, CDCl₃) δ 3.05 (s, 6H), 7.14 7.19 (m, 1H), 7.29 (s, 1H), 8.15-8.21 (m, 2H); ¹³C NMR (100 MHz, CDCl₃) δ 42.9, 122.9, 125.3, 131.5, 133.9, 147.4, 148.5; HRMS (APCI) calcd for [M+H]⁺ C₈H₁₁ClN₃ 184.0636, found 184.0634.

N-Methyl-N-phenylbenzaldehyde hydrazone (126)

White solid: mp 105-106 °C (lit.⁶³ mp 107-109 °C); ¹H NMR (300 MHz, CDCl₃) δ 3.44 (s, 3H), 6.95 (tt, J = 7.0, 1.3 Hz, 1H), 7.23-7.44 (m, 7H), 7.51 (s, 1H), 7.72 (d, J = 7.0 Hz, 2H); ¹³C NMR (75 MHz, CDCl₃) δ 33.3, 115.5, 120.8, 126.3, 127.9, 128.8, 129.3, 132.1, 137.0, 148.1; HRMS (APCI) calcd for [M+H]⁺ C₁₄H₁₅N₂ 211.1230, found 211.1228. The ¹H and ¹³C NMR spectral data are in good agreement with the literature data.⁶⁴

Benzaldehyde methylhydrazone (128)

Colorless liquid: ¹H NMR (400 MHz, CDCl₃) δ 2.98 (s, 3H), 7.23-7.29 (m, 1H), 7.34 (t, J = 8.0 Hz, 2H), 7.53 (s, 1H), 7.56 (d, J = 8.0 Hz, 2H); ¹³C NMR (100 MHz, CDCl₃) δ 34.7, 125.7, 127.8, 128.5, 135.4, 136.2; HRMS (APCI) calcd for [M+H]⁺ C₈H₁₁N₂ 135.0917, found 135.0917.

N-Methyl-N-phenyl-2-thienaldehyde hydrazone (129)

Pale yellow solid: mp 82-83 °C; ¹H NMR (400 MHz, CDCl₃) δ 3.40 (s, 3H), 6.94 (t, J = 6.3 Hz, 1H), 7.02 (t, J = 4.1 Hz, 1H), 7.11 (d, J = 3.5 Hz, 1H), 7.21 (d, J = 5.1 Hz, 1H), 7.31-7.36 (m, 4H), 7.68 (s, 1H); ¹³C NMR (100 MHz, CDCl₃) δ 33.5, 115.4, 120.9, 125.1, 125.6, 127.1, 127.4, 129.3, 142.9, 147.7; HRMS (APCI) calcd for [M+H]⁺ C₁₂H₁₃N₂S 217.0794, found 217.0790.

Benzaldehyde diphenylhydrazone (131)

Colorless solid: mp 124-125 °C (lit.⁶⁵ mp 125-126 °C); ¹H NMR (400 MHz, CDCl₃) δ 7.18-7.33 (m, 8H), 7.38 (t, J = 7.4 Hz, 2H), 7.47 (d, J = 7.0 Hz, 4H), 7.66 (d, J = 7.5 Hz, 2H); ¹³C NMR (100 MHz, CDCl₃) δ 122.8, 124.8, 126.6, 128.4, 128.8, 130.1, 135.7, 136.4, 143.9; HRMS (APCI) calcd for [M+H]⁺ C₁₉H₁₇N₂ 273.1386, found 273.1396.

Synthesis of Aminoaryl Ketimines and Derivatives

N,N-Dimethyl-2-[imino(phenyl)methyl]aniline (3)

To a mixture of benzaldehyde dimethylhydrazone (0.25 mmol), CsF (0.75 mmol, 3 equiv) and 5 mL of acetonitrile in a 10 mL vial, o-(trimethylsilyl)phenyl triflate (0.28 mmol, 1.1 equiv) was added. The vial was capped and the reaction mixture was allowed to stir for 10 h at 65 °C. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel using hexanes/EtOAc as the eluent to afford the desired ketamine 3. Yellow oil (42.8 mg, 76%): ¹H NMR (400 MHz, CDCl₃) δ 2.67 (s, 6H), 6.94 (t, J = 7.4 Hz, 1H), 7.01 (d, J = 8.2 Hz, 1H), 7.17 (d, J = 7.3 Hz, 1H), 7.30-7.46 (m, 4H), 7.72 (d, J = 7.4 Hz, 2H); ¹³C NMR (100 MHz, CDCl₃) δ 43.6, 117.7, 120.6, 128.3, 128.4, 130.3, 130.4, 130.6, 131.5, 139.1, 151.5, 178.4; HRMS (APCI) calcd for [M+H]⁺ C₁₅H₁₇N₂ 225.1386, found 225.1385.

Ethyl [(2-(dimethylamino)phenyl)(phenyl)methylene]carbamate (4)

To a mixture of benzaldehyde dimethylhydrazone (0.25 mmol), CsF (0.75 mmol, 3 equiv) and 5 mL of acetonitrile in a 10 mL vial, o-(trimethylsilyl)phenyl triflate (0.28 mmol, 1.1 equiv) was added. The vial was capped and the reaction mixture was allowed to stir for 10 h at 65 °C. After cooling to room temperature, ethyl chloroformate (0.3 mmol, 1.2 equiv) was added and the mixture was heated at 65 °C for an additional 2 h. After cooling to room temperature, 25 ml of dichloromethane was added to the residue, and the reaction mixture was poured into 25 ml of water in a separatory funnel. After shaking the layers, the organic fraction was separated and the aqueous layer was extracted with dichloromethane (2 × 10 ml). All organic fractions were combined and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel using hexanes/EtOAc as the eluent to afford the desired product 4. Yellow oil (60.5 mg, 82%): ¹H NMR (400 MHz, CDCl₃) δ 1.17 (t, J = 7.1 Hz, 3H), 2.66 (s, 6H), 4.14 (q, J = 7.1 Hz, 2H), 6.92 (t, J = 7.5 Hz, 1H), 6.97 (d, J = 8.3 Hz, 1H), 7.23 (d, J = 7.5 Hz, 1H), 7.33-7.38 (m, 3H), 7.46 (t, J = 7.4 Hz, 1H), 7.69 (d, J = 8.0 Hz, 2H); ¹³C NMR (100 MHz, CDCl₃) δ 14.5, 43.2, 62.3, 117.6, 120.0, 127.4, 128.3, 129.4, 130.4, 131.1, 131.8, 137.2, 151.5, 163.1, 173.3; HRMS (APCI) calcd for [M+H]⁺ C₁₈H₂₁N₂O₂ 297.1598, found 297.1595.

N-[(2-(Dimethylamino)phenyl)(phenyl)methylene]acetamide (5)

To a mixture of benzaldehyde dimethylhydrazone (0.25 mmol), CsF (0.75 mmol, 3 equiv) and 5 mL of acetonitrile in a 10 mL vial, o-(trimethylsilyl)phenyl triflate (0.28 mmol, 1.1 equiv) was added. The vial was capped and the reaction mixture was allowed to stir for 10 h at 65 °C. After cooling to room temperature, acetic anhydride (0.5 mmol, 2 equiv) was added and the mixture was heated at 65 °C for an additional 2 h. After cooling to room temperature, 25 ml of dichloromethane was added to the residue, and the reaction mixture was poured into 25 ml of water in a separatory funnel. After shaking the layers, the organic fraction was separated and the aqueous layer was extracted with dichloromethane (2 × 10 ml). All organic fractions were combined and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel using hexanes/EtOAc as the eluent to afford the desired product 5. Yellow oil (45.0 mg, 68%): ¹H NMR (300 MHz, CDCl₃) δ 2.15 (s, 3H), 2.68 (s, 6H), 6.92 (t, J = 7.4 Hz, 1H), 6.98 (d, J = 8.3 Hz, 1H), 7.12 (dd, J = 7.6, 1.6 Hz, 1H), 7.31 7.42 (m, 3H), 7.43-7.50 (m, 1H), 7.70-7.76 (m, 2H); ¹³C NMR (75 MHz, CDCl₃) δ 25.2, 43.2, 117.8, 120.1, 127.1, 128.4, 129.5, 130.4, 131.0, 131.6, 137.5, 151.3, 165.7, 185.2; HRMS (APCI) calcd for [M+H]⁺ C₁₇H₁₉N₂O 267.1492, found 267.1489.

N,N-Dimethyl-2-[amino(phenyl)methyl]aniline (7)

To a solution of imine 3 (0.20 mmol) in MeOH (4 mL) in a 10 mL vial, NaBH₄ (0.50 mmol, 2.5 equiv) was added portionwise. The reaction mixture was allowed to stir for 10 h at room temperature. The solvent was removed under reduced pressure and the residue was purified by flash chromatography on silica gel using hexanes/EtOAc as the eluent to afford the desired product. Yellow oil (31.5 mg, 70%): ¹H NMR (400 MHz, CDCl₃) δ 2.01 (br s, 2H, NH₂), 2.63 (s, 6H), 5.75 (s, 1H), 7.09 (t, J = 7.1 Hz, 1H), 7.19-7.24 (m, 3H), 7.28-7.33 (m, 3H), 7.41 (d, J = 7.7 Hz, 2H); ¹³C NMR (100 MHz, CDCl₃) δ 46.1, 54.3, 121.4, 124.8, 126.8, 127.2, 128.1, 128.2, 128.5, 141.0, 144.7, 152.7; HRMS (APCI) calcd for [M+H]⁺ C₁₅H₁₉N₂ 227.1543, found 227.1545.

N-[(2-(Dimethylamino)phenyl)(phenyl)methyl]acetamide (6)

Method A

To a solution of N-acetylimine 5 (0.20 mmol) in THF (4 mL) in a 10 mL vial, NaBH₃CN (0.50 mmol, 2.5 equiv) was added portionwise. The reaction mixture was allowed to stir for 10 h at room temperature. The solvent was removed under reduced pressure and the residue was purified by flash chromatography on silica gel using hexanes/EtOAc as the eluent to afford the desired product in a 55% yield (29.4 mg).

Method B

To a solution of amine 7 (0.20 mmol) in CH₃CN (4 mL) in a 10 mL vial, Ac₂O (0.40 mmol, 2.0 equiv) and Et₃N (0.40 mmol, 2.0 equiv) were added. The reaction mixture was allowed to stir for 2 h at 65 °C. The solvent was removed under reduced pressure and the residue was purified by flash chromatography on silica gel using hexanes/EtOAc as the eluent to afford the desired product. Pale brown solid (49.4 mg, 92%): mp 97-99 °C; ¹H NMR (300 MHz, CDCl₃) δ 2.08 (s, 3H), 2.50 (s, 6H), 6.56 (d, J = 8.6 Hz, 1H), 7.11-7.19 (m, 4H), 7.22-7.35 (m, 5H), 7.58 (d, J = 8.7 Hz, 1H); ¹³C NMR (75 MHz, CDCl₃) δ 23.8, 45.9, 54.6, 122.8, 125.3, 126.7, 126.9, 128.4, 128.8, 129.9, 137.5, 142.7, 152.9, 169.3; HRMS (APCI) calcd for [M+H]⁺ C₁₇H₂₁N₂O 269.1648, found 269.1653.

Synthesis of the Aminoaryl Ketones

To a mixture of the appropriate dialkylhydrazone (0.25 mmol), CsF (0.75 mmol, 3 equiv) and 5 mL of acetonitrile in a 10 mL vial, the silylaryl triflate (0.28 mmol, 1.1 equiv) was added. The vial was capped and the reaction mixture was allowed to stir for 10 h at 65 °C. Then 3 mL of 1M HCl was added and the mixture was heated at 65 °C for an additional 2 h. After cooling to room temperature, 25 ml of dichloromethane was added to the residue, and the reaction mixture was poured into 25 ml of water in a separatory funnel. After shaking the layers, the organic fraction was separated and the aqueous layer was extracted with dichloromethane (2 × 10 ml). All organic fractions were combined and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel using hexanes/EtOAc as the eluent to afford the desired o-(dimethylamino)aryl ketone.

2-(Dimethylamino)-2′-methylbenzophenone (17)

Pale yellow oil (46.4 mg, 78%): ¹H NMR (400 MHz, CDCl₃) δ 2.53 (s, 3H), 2.77 (s, 6H), 6.83 (t, J = 7.4 Hz, 1H), 6.97 (d, J = 8.3 Hz, 1H), 7.16 (t, J = 7.5 Hz, 1H), 7.27 (d, J = 7.7 Hz, 1H), 7.31-7.41 (m, 4H); ¹³C NMR (100 MHz, CDCl₃) δ 21.1, 43.8, 116.6, 118.5, 125.3, 129.3, 130.8, 131.1, 131.7, 132.4, 132.5, 138.8, 139.0, 152.3, 199.2; HRMS (APCI) calcd for [M+H]⁺ C₁₆H₁₈NO 240.1383, found 240.1386.

4-[2-(Dimethylamino)benzoyl]benzonitrile (23)

Light orange crystals (57.8 mg, 92%): mp 99-102 °C, ¹H NMR (400 MHz, CDCl₃) δ 2.62 (s, 6H), 6.95 (t, J = 7.4 Hz, 1H), 7.01 (d, J = 8.3 Hz, 1H), 7.36 (d, J = 7.6 Hz, 1H), 7.44 (ddd, J = 8.6, 7.3, 1.7 Hz, 1H), 7.69 (d, J = 8.4 Hz, 2H), 7.85 (d, J = 8.5 Hz, 2H); ¹³C NMR (100 MHz, CDCl₃) δ 43.8, 115.8, 117.2, 118.5, 120.0, 128.6, 130.2, 131.1, 132.1, 132.7, 141.5, 152.2, 196.7; HRMS (APCI) calcd for [M+H]⁺ C₁₆H₁₅N₂O 251.1179, found 251.1186.

Methyl 4-[2-(dimethylamino)benzoyl]benzoate (25)

Light orange oil (66.7 mg, 94%): ¹H NMR (400 MHz, CDCl₃) δ 2.64 (s, 6H), 3.92 (s, 3H), 6.92 (t, J = 7.4 Hz, 1H), 6.99 (d, J = 8.3 Hz, 1H), 7.35 (d, J = 7.6 Hz, 1H), 7.41 (t, J = 8.3 Hz, 1H), 7.83 (d, J = 8.3 Hz, 2H), 8.06 (d, J = 8.2 Hz, 2H); ¹³C NMR (100 MHz, CDCl₃) δ 43.7, 52.6, 116.9, 119.6, 129.0, 129.5, 129.8, 131.1, 132.2, 133.5, 141.6, 152.1, 166.6, 197.7; HRMS (APCI) calcd for [M+H]⁺ C₁₇H₁₈NO₃ 284.1281, found 284.1289.

2-(Dimethylamino)-2′-methoxybenzophenone (29)

Yellow crystals (47.0 mg, 74%): mp 111-113 °C; ¹H NMR (400 MHz, CDCl₃) δ 2.79 (s, 6H), 3.68 (s, 3H), 6.77 (t, J = 7.4 Hz, 1H), 6.93 (d, J = 8.4 Hz, 2H), 6.99 (t, J = 7.5 Hz, 1H), 7.32-7.36 (m, 2H), 7.44 (ddd, J = 9.3, 7.6, 1.9 Hz, 1H), 7.52 (dd, J = 7.6, 1.9 Hz, 1H); ¹³C NMR (100 MHz, CDCl₃) δ 43.9, 55.9, 111.7, 116.1, 118.1, 120.5, 129.7, 129.9, 131.2, 131.9, 132.1, 132.7, 151.9, 158.5, 196.6; HRMS (APCI) calcd for [M+H]⁺ C₁₆H₁₈NO₂ 256.1332, found 256.1335.

2-(Dimethylamino)-2′,4′,5′-trimethoxybenzophenone (31)

Pale brown solid (52.8 mg, 67%): mp 106-110 °C; ¹H NMR (400 MHz, CDCl₃) δ 2.75 (s, 6H), 3.58 (s, 3H), 3.83 (s, 3H), 3.92 (s, 3H), 6.46 (s, 1H), 6.78 (t, J = 7.4 Hz, 1H), 6.90 (d, J = 8.2 Hz, 1H), 7.20-7.32 (m, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 43.9, 56.3, 56.6, 56.7, 97.3, 114.1, 116.0, 118.4, 120.4, 130.5, 131.2, 131.8, 143.2, 151.3, 153.5, 154.9, 195.8; HRMS (APCI) calcd for [M+H]⁺ C₁₈H₂₂NO₄ 316.1543, found 316.1550.

2,4′-Bis(dimethylamino)benzophenone (35)

Pale yellow oil (30.4 mg, 45%): ¹H NMR (400 MHz, CDCl₃) δ 2.73 (s, 6H), 3.06 (s, 6H), 6.63 (d, J = 9.0 Hz, 2H), 6.87 (t, J = 7.4 Hz, 1H), 6.96 (d, J = 8.3 Hz, 1H), 7.25 (d, J = 8.8 Hz, 1H), 7.34 (t, J = 7.8 Hz, 1H), 7.78 (d, J = 9.0 Hz, 1H); ¹³C NMR (100 MHz, CDCl₃) δ 40.3, 43.7, 110.6, 116.5, 119.0, 125.4, 130.3, 130.6, 130.8, 132.7, 151.3, 153.6, 197.0; HRMS (APCI) calcd for [M+H]⁺ C₁₇H₂₁N₂O 269.1648, found 269.1650.

2-(Dimethylamino)-2′-fluorobenzophenone (37)

Yellow oil (37.3 mg, 61%): ¹H NMR (400 MHz, CDCl₃) δ 2.73 (s, 6H), 6.88 (t, J = 7.5 Hz, 1H), 6.98 (d, J = 8.1 Hz, 1H), 7.04-7.10 (m, 1H), 7.20 (td, J = 7.6, 1.1 Hz, 1H), 7.37-7.43 (m, 2H), 7.45-7.51 (m, 1H), 7.68 (td, J = 7.4, 1.8 Hz, 1H); ¹³C NMR (100 MHz, CDCl₃) δ 43.8, 115.9, 116.1, 116.5, 118.9, 120.1, 123.6, 123.9, 124.0, 127.7, 127.8, 127.9, 129.7, 131.2, 131.3, 132.4, 133.3, 133.4, 152.1, 159.7, 162.3, 193.8 (extra peaks due to C F coupling); HRMS (APCI) calcd for [M+H]⁺ C₁₅H₁₅FNO 244.1132, found 244.1129.

2-(Dimethylamino)-4′-ethynylbenzophenone (41)

Light orange oil (62.2 mg, quantitative yield): ¹H NMR (400 MHz, CDCl₃) δ 2.66 (s, 6H), 3.23 (s, 1H), 6.92 (t, J = 7.4 Hz, 1H), 6.99 (d, J = 8.4 Hz, 1H), 7.32 (dd, J = 7.7, 1.7 Hz, 1H), 7.40 (ddd, J = 8.7, 7.3, 1.7 Hz, 1H), 7.52 (d, J = 8.4 Hz, 2H), 7.76 (d, J = 8.3 Hz, 2H); ¹³C NMR (100 MHz, CDCl₃) δ 43.7, 80.3, 83.3, 116.8, 119.5, 126.5, 129.2, 129.9, 130.9, 132.0, 132.1, 137.8, 151.9, 197.5; HRMS (APCI) calcd for [M+H]⁺ C₁₇H₁₆NO 250.1226, found 250.1229.

[2-(Dimethylamino)phenyl][(1R,5S)-6,6-dimethylbicyclo[3.1.1]hept-2-en-2-yl]methanone (48)

Yellow oil (42.5 mg, 63%): ¹H NMR (400 MHz, CDCl₃) δ 0.83 (s, 3H), 1.13 (d, J = 9.1 Hz, 1H), 1.36 (s, 3H), 2.44 (dt, J = 10.7, 3.1 Hz, 1H), 2.51 (dt, J = 9.1, 5.8 Hz, 1H), 2.73 (s, 1H), 3.00-3.05 (m, 6H), 6.44 (s, 1H), 6.86 (t, J = 7.4 Hz, 1H), 6.93 (d, J = 8.2 Hz, 1H), 7.18 (dd, J = 7.5, 1.7 Hz, 1H), 7.30 (t, J = 7.7 Hz, 1H); ¹³C NMR (100 MHz, CDCl₃) δ 21.1, 26.2, 31.7, 32.9, 38.0, 40.4, 40.7, 43.8, 116.8, 119.1, 130.0, 130.5, 130.7, 140.9, 149.6, 151.3, 197.6; HRMS (APCI) calcd for [M+H]⁺ C₁₈H₂₄NO 270.1852, found 270.1857.

(2E,6Z)-1-[2-(Dimethylamino)phenyl]nona-2,6-dien-1-one (50)

Brown oil (52.5 mg, 82%): ¹H NMR (400 MHz, CDCl₃) δ 0.95 (t, J = 7.5 Hz, 3H), 2.03 (p, J = 7.4 Hz, 2H), 2.18-2.34 (m, 4H), 2.78 (s, 6H), 5.28-5.46 (m, 2H), 6.68 (d, J = 15.8 Hz, 1H), 6.86-6.97 (m, 3H), 7.34 (t, J = 7.8 Hz, 1H), 7.41 (d, J = 7.6 Hz, 1H); ¹³C NMR (75 MHz, CDCl₃) δ 14.5, 20.8, 26.1, 32.8, 44.4, 116.8, 119.9, 127.7, 130.1, 130.6, 131.3, 131.8, 133.0, 147.5, 152.1, 195.8; HRMS (APCI) calcd for [M+H]⁺ C₁₇H₂₄NO 258.1852, found 258.1848.

(E)-1-[2-(Dimethylamino)phenyl]-3-(furan-2-yl)prop-2-en-1-one (52)

Dark red solid (51.1 mg, 85%): mp 80-81 °C; ¹H NMR (400 MHz, CDCl₃) δ 2.82 (s, 6H), 6.45-6.49 (m, 1H), 6.64 (d, J = 3.4 Hz, 1H), 6.93 (t, J = 7.4 Hz, 1H), 7.00 (d, J = 8.2 Hz, 1H), 7.24 (d, J = 15.7 Hz, 1H), 7.37 (t, J = 7.8 Hz, 1H), 7.45 7.53 (m, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 44.6, 112.7, 115.4, 117.0, 120.1, 124.0, 129.1, 130.6, 131.6, 132.1, 144.8, 152.1, 152.4, 194.8; HRMS (APCI) calcd for [M+H]⁺ C₁₅H₁₆NO₂ 242.1176, found 242.1180.

[2-(Dimethylamino)phenyl](1H-pyrrol-2-yl)methanone (54)

Gray green solid (43.6 mg, 81%): mp 96-99 °C; ¹H NMR (400 MHz, CDCl₃) δ 2.81 (s, 6H), 6.24-6.31 (m, 1H), 6.75 (s, 1H), 6.87 (t, J = 7.4 Hz, 1H), 6.97 (d, J = 8.3 Hz, 1H), 7.10 (s, 1H), 7.36 (ddd, J = 8.7, 7.3, 1.8 Hz, 1H), 7.45 (dd, J = 7.6, 1.7 Hz, 1H), 10.23 (br s, 1H, NH); ¹³C NMR (100 MHz, CDCl₃) δ 43.7, 111.0, 116.6, 118.4, 119.5, 125.5, 128.9, 130.9, 131.3, 132.6, 151.3, 187.3; HRMS (APCI) calcd for [M+H]⁺ C₁₃H₁₅N₂O 215.1179, found 215.1180.

[2-(Dimethylamino)phenyl](thiophen-2-yl)methanone (58)

Yellow solid (49.4 mg, 85%): mp 49-51°C; ¹H NMR (400 MHz, CDCl₃) δ 2.78 (s, 6H), 6.87 (t, J = 7.4 Hz, 1H), 6.98 (d, J = 8.2 Hz, 1H), 7.09 (t, J = 4.4 Hz, 1H), 7.35-7.39 (t, J = 7.6 Hz, 2H), 7.54 (d, J = 3.8 Hz, 1H), 7.66 (d, J = 4.9 Hz, 1H); ¹³C NMR (100 MHz, CDCl₃) δ 43.7, 116.7, 118.7, 128.1, 129.1, 130.5, 131.7, 134.3, 134.7, 145.0, 151.2, 190.4; HRMS (APCI) calcd for [M+H]⁺ C₁₃H₁₄NOS 232.0791, found 232.0797.

[2-(Dimethylamino)phenyl](1H-indol-3-yl)methanone (60)

Red oil (14.0 mg, 21%): ¹H NMR (400 MHz, CDCl₃) δ 2.77 (s, 6H), 6.87-6.91 (m, 3H), 7.08 (t, J = 7.4 Hz, 1H), 7.14 (d, J = 8.1 Hz, 1H), 7.32 (t, J = 7.7 Hz, 1H), 7.40-7.45 (m, 2H), 7.70 (d, J = 7.4 Hz, 1H), 8.58 (br s, 1H, NH); ¹³C NMR (100 MHz, CDCl₃) δ 44.0, 110.7, 111.9, 118.6, 120.0, 122.0, 123.1, 125.1, 128.5, 129.9, 133.6, 135.7, 136.2, 150.8, 152.8, 187.0; HRMS (APCI) calcd for [M+H]⁺ C₁₇H₁₇N₂O 265.1335, found 265.1339.

[2-(Dimethylamino)phenyl](1H-indol-4-yl)methanone (62)

Yellow solid (55.6 mg, 84%): mp 173-176 °C; ¹H NMR (300 MHz, DMSO-d₆) δ 2.61 (s, 6H), 6.79 (m, 1H), 6.88 (t, J = 7.4 Hz, 1H), 7.02 (d, J = 8.3 Hz, 1H), 7.09-7.17 (m, 2H), 7.27 (d, J = 7.4 Hz, 1H), 7.37 (ddd, J = 8.7, 7.4, 1.6 Hz, 1H), 7.51 (t, J = 2.7 Hz, 2H), 7.66 (d, J = 8.0 Hz, 1H), 11.47 (br s, 1H, NH); ¹³C NMR (75 MHz, DMSO-d₆) δ 43.8, 102.7, 117.2, 117.4, 119.3, 120.7, 125.0, 127.2, 128.8, 129.1, 130.2, 131.3, 131.6, 137.5, 151.4, 198.9; HRMS (APCI) calcd for [M+H]⁺ C₁₇H₁₇N₂O 265.1335, found 265.1337.

[2-(Dimethylamino)phenyl](2-methoxypyridin-3-yl)methanone (66)

Yellow solid (49.8 mg, 78%): mp 69-71 °C; ¹H NMR (400 MHz, CDCl₃) δ 2.68 (s, 6H), 3.80 (s, 3H), 6.86 (t, J = 7.4 Hz, 1H), 6.92-6.95 (m, 2H), 7.35-7.39 (m, 2H), 7.84 (dd, J = 7.3, 2.0 Hz, 1H), 8.25 (dd, J = 5.0, 2.0 Hz, 1H); ¹³C NMR (100 MHz, CDCl₃) δ 44.1, 53.8, 116.6, 116.7, 119.3, 123.5, 130.1, 131.5, 132.5, 140.1, 149.7, 152.5, 161.9, 195.4; HRMS (APCI) calcd for [M+H]⁺ C₁₅H₁₇N₂O₂ 257.1285, found 257.1287.

[2-(Dimethylamino)phenyl](pyridin-2-yl)methanone (68)

Red oil (46.5 mg, 82%): ¹H NMR (400 MHz, CDCl₃) δ 2.69 (s, 6H), 6.89 (t, J = 7.4 Hz, 1H), 7.00 (d, J = 8.6 Hz, 1H), 7.34-7.44 (m, 3H), 7.81 (t, J = 6.9 Hz, 1H), 7.93 (d, J = 7.7 Hz, 1H), 8.66 (d, J = 4.1 Hz, 1H); ¹³C NMR (100 MHz, CDCl₃) δ 43.9, 117.0, 119.1, 124.2, 126.2, 128.6, 131.4, 132.3, 136.8, 149.3, 152.6, 155.8, 197.1; HRMS (APCI) calcd for [M+H]⁺ C₁₄H₁₅N₂O 227.1179, found 227.1179.

[2-(Dimethylamino)phenyl](quinolin-2-yl)methanone (70)

Yellow crystals (58.3 mg, 84%): mp 111-114 °C; ¹H NMR (400 MHz, CDCl₃) δ 2.70 (s, 6H), 6.92 (t, J = 7.4 Hz, 1H), 7.03 (d, J = 8.3 Hz, 1H), 7.43 (t, J = 7.6 Hz, 1H), 7.53 (d, J = 7.7 Hz, 1H), 7.60 (t, J = 7.3 Hz, 1H), 7.72 (t, J = 7.3 Hz, 1H), 7.85 (d, J = 8.1 Hz, 1H), 7.96 (d, J = 8.5 Hz, 1H), 8.17 (d, J = 8.6 Hz, 1H), 8.25 (d, J = 8.5 Hz, 1H); ¹³C NMR (100 MHz, CDCl₃) δ 44.0, 117.0, 119.0, 120.8, 127.7, 128.3, 128.5, 129.2, 130.0, 130.9, 132.2, 132.5, 136.7, 147.5, 153.0, 155.6, 197.0; HRMS (APCI) calcd for [M+H]⁺ C₁₈H₁₇N₂O 277.1335, found 277.1343. The ¹H and ¹³C NMR spectral data are in good agreement with the literature data.¹⁸

Ethyl 2-[2-(dimethylamino)phenyl]-2-oxoacetate (72)

Yellow oil (17.5 mg, 32%): ¹H NMR (400 MHz, CDCl₃) δ 1.35 (t, J = 7.1 Hz, 3H), 2.71 (s, 6H), 4.33 (q, J = 7.1 Hz, 2H), 7.16 (t, J = 7.5 Hz, 1H), 7.22 (d, J = 8.1 Hz, 1H), 7.55 (t, J = 7.7 Hz, 1H), 7.73 (d, J = 7.7 Hz, 1H); ¹³C NMR (75 MHz, CDCl₃) δ 14.5, 45.8, 61.8, 120.1, 123.7, 129.8, 130.9, 134.9, 155.7, 165.3, 189.1; HRMS (APCI) calcd for [M+H]⁺ C₁₂H₁₆NO₃ 222.1125, found 222.1124.

1-[2-(Dimethylamino)phenyl]-2-phenylethane-1,2-dione (74)

Light brown solid (41.9 mg, 66%): mp 92-93 °C; ¹H NMR (400 MHz, CDCl₃) δ 2.25 (s, 6H), 7.27 (d, J = 8.4 Hz, 1H), 7.33 (t, J = 7.5 Hz, 1H), 7.43 (t, J = 7.5 Hz, 2H), 7.53 (t, J = 7.3 Hz, 1H), 7.61 (td, J = 7.7, 1.7 Hz, 1H), 7.83 (d, J = 7.2 Hz, 2H), 7.97 (dd, J = 7.8, 1.6 Hz, 1H); ¹³C NMR (100 MHz, CDCl₃) δ 45.0, 122.9, 126.1, 128.1, 128.7, 130.3, 133.0, 133.2, 134.3, 135.6, 155.8, 189.3, 196.5; HRMS (APCI) calcd for [M+H]⁺ C₁₆H₁₆NO₂ 254.1176, found 254.1176.

2-(Piperidin-1-yl)benzophenone (80)

Light brown solid (53.3 mg, 80%): mp 94-95 °C; ¹H NMR (400 MHz, CDCl₃) δ 1.11-1.17 (m, 4H), 1.24-1.30 (m, 2H), 2.83 (t, J = 5.3 Hz, 4H), 7.01-7.09 (m, 2H), 7.35-7.46 (m, 4H), 7.51 (t, J = 7.4 Hz, 1H), 7.76 (d, J = 8.3 Hz, 2H); ¹³C NMR (100 MHz, CDCl₃) δ 24.1, 25.8, 53.7, 118.9, 122.0, 128.0, 130.1, 130.4, 131.8, 132.7, 133.4, 137.7, 152.7, 199.1; HRMS (APCI) calcd for [M+H]⁺ C₁₈H₂₀NO 266.1539, found 266.1540.

1,4-Bis(2-dimethylaminobenzoyl)benzene (82)

2.2 Equiv of the benzyne precursor and 5.0 equiv of CsF were used in this synthesis. Orange solid (78.4 mg, 84%): mp 130-131 °C; ¹H NMR (400 MHz, CDCl₃) δ 2.67 (s, 12H), 6.93 (t, J = 7.4 Hz, 2H), 7.00 (d, J = 8.3 Hz, 2H), 7.36 (d, J = 7.6 Hz, 2H), 7.41 (t, J = 7.9 Hz, 2H), 7.81 (s, 4H); ¹³C NMR (100 MHz, CDCl₃) δ 43.8, 116.9, 119.5, 129.1, 129.6, 131.1, 132.2, 141.1, 152.1, 197.8; HRMS (APCI) calcd for [M+H]⁺ C₂₄H₂₅N₂O₂ 373.1911, found 373.1914.

[3-(Dimethylamino)naphthalen-2-yl](phenyl)methanone (84)

Light orange oil (52.7 mg, 77%): ¹H NMR (400 MHz, CDCl₃) δ 2.75 (s, 6H), 7.27 (s, 1H), 7.33 (t, J = 7.5 Hz, 1H), 7.43 (t, J = 7.7 Hz, 2H), 7.49 (t, J = 7.5 Hz, 1H), 7.57 (t, J = 7.4 Hz, 1H), 7.75 (dd, J = 8.2, 3.8 Hz, 2H), 7.83 (s, 1H), 7.87 (d, J = 6.9 Hz, 2H); ¹³C NMR (100 MHz, CDCl₃) δ 44.0, 112.7, 124.3, 126.7, 127.9, 128.1, 128.4, 128.6, 130.3, 130.9, 133.0, 133.2, 135.6, 137.7, 149.3, 198.2; HRMS (APCI) calcd for [M+H]⁺ C₁₉H₁₈NO 276.1383, found 276.1386.

4,5-Dimethoxy-2-(dimethylamino)benzophenone (86)

Yellow crystals (59.0 mg, 83%): mp 101-104 °C; ¹H NMR (400 MHz, CDCl₃) δ 2.58 (s, 6H), 3.80 (s, 3H), 3.93 (s, 3H), 6.55 (s, 1H), 6.94 (s, 1H), 7.39 (d, J = 7.6 Hz, 2H), 7.49 (t, J = 7.4 Hz, 1H), 7.76 (d, J = 7.7 Hz, 2H); ¹³C NMR (100 MHz, CDCl₃) δ 44.3, 56.1, 56.6, 101.6, 114.1, 122.2, 128.1, 129.9, 132.5, 138.6, 143.1, 147.8, 152.1, 197.6; HRMS (APCI) calcd for [M+H]⁺ C₁₇H₂₀NO₃ 286.1438, found 286.1441.

4,5-Difluoro-2-(dimethylamino)benzophenone (88)

Pale yellow oil (40.7 mg, 62%): ¹H NMR (400 MHz, CDCl₃) δ 2.65 (s, 6H), 6.77 (dd, J = 12.9, 6.6 Hz, 1H), 7.17 (dd, J = 10.3, 9.1 Hz, 1H), 7.43 (t, J = 7.7 Hz, 2H), 7.56 (t, J = 7.4 Hz, 1H), 7.79 (d, J = 7.4 Hz, 2H); ¹³C NMR (100 MHz, CDCl₃) δ 43.8, 105.7, 105.9, 115.6, 119.4, 119.6, 124.9, 128.5, 130.0, 133.3, 137.3, 142.5, 142.6, 144.9, 145.0, 149.3, 149.4, 150.9, 151.0, 153.4, 153.5, 195.9 (extra signals due to C-F coupling); HRMS (APCI) calcd for [M+H]⁺ C₁₅H₁₄F₂NO 262.1038, found 262.1041.

Mixture of (2-(Dimethylamino)-4-methoxyphenyl)(phenyl)methanone (90a) and (2-(Dimethylamino)-5-methoxyphenyl)(phenyl)methanone (90b) (~1/1 ratio)

The mixture (51.7 mg, 81%) was separated using preparative TLC.

2-(Dimethylamino)-4-methoxybenzophenone (90a)

Yellow oil: ¹H NMR (400 MHz, CDCl₃) δ 2.71 (s, 6H), 3.85 (s, 3H), 6.40 (d, J = 8.5 Hz, 1H), 6.45 (s, 1H), 7.32 (d, J = 8.5 Hz, 1H), 7.41 (t, J = 7.5 Hz, 2H), 7.52 (t, J = 7.4 Hz, 1H), 7.81 (d, J = 7.2 Hz, 2H); ¹³C NMR (100 MHz, CDCl₃) δ 43.5, 55.5, 102.1, 103.5, 121.6, 128.2, 130.1, 132.5, 133.9, 138.8, 154.0, 162.9, 197.1; HRMS (APCI) calcd for [M+H]⁺ C₁₆H₁₈NO₂ 256.1332, found 256.1333.

2-(Dimethylamino)-5-methoxybenzophenone (90b)

Yellow solid: mp 58-59 °C; ¹H NMR (400 MHz, CDCl₃) δ 2.56 (s, 6H), 3.77 (s, 3H), 6.87 (d, J = 2.8 Hz, 1H), 6.99 (dd, J = 8.9, 2.9 Hz, 1H), 7.04 (d, J = 8.9 Hz, 1H), 7.40 (t, J = 7.6 Hz, 2H), 7.53 (t, J = 7.4 Hz, 1H), 7.80 (d, J = 7.3 Hz, 2H); ¹³C NMR (100 MHz, CDCl₃) δ 44.8, 55.9, 114.4, 117.5, 119.7, 128.3, 130.0, 133.0, 133.6, 137.6, 146.1, 154.4, 198.5; HRMS (APCI) calcd for [M+H]⁺ C₁₆H₁₈NO₂ 256.1332, found 256.1334

Mixture of 2-(Dimethylamino)-4-methoxy-benzophenone (92a) and 2-(dimethylamino)-5-methoxybenzophenone (92b) (~1/1 ratio)

Pale yellow oil (51.0 mg, 85%): ¹H NMR of the mixture (400 MHz, CDCl₃) δ 2.29 (s, 3H, minor isomer), 2.38 (s, 3H, major isomer), 2.63 (s, 6H, minor), 2.70 (s, 6H, major), 6.71 (d, J = 7.7 Hz, 1H, major), 6.79 (s, 1H, major), 6.93 (d, J = 8.3 Hz, 1H, minor), 7.13 (s, 1H, minor), 7.18-7.26 (m, 2H), 7.41 (t, J = 7.7 Hz, 4H), 7.48-7.57 (m, 2H), 7.78-7.86 (m, 4H); ¹³C NMR of the mixture (100 MHz, CDCl₃) δ 20.6, 22.2, 43.7, 44.1, 117.1, 117.2 (×2), 119.8 (×2), 126.4, 128.3, 129.3, 130.1, 130.5, 130.8, 131.4, 132.2, 132.7, 132.9, 137.9, 138.3, 142.2, 149.8, 152.0, 198.2, 198.8; HRMS (APCI) calcd for [M+H]⁺ C₁₆H₁₈NO 240.1383, found 240.1384.

[2-(Dimethylamino)naphthalen-1-yl](phenyl)methanone (96)

Light orange oil (56.2 mg, 82%): ¹H NMR (400 MHz, CDCl₃) δ 2.72 (s, 6H), 7.33-7.43 (m, 5H), 7.53 (t, J = 7.3 Hz, 1H), 7.61-7.66 (m, 1H), 7.78-7.84 (m, 3H), 7.91 (d, J = 8.9 Hz, 1H); ¹³C NMR (100 MHz, CDCl₃) δ 44.7, 119.3, 124.3, 124.5, 127.3, 127.6, 128.3, 128.6, 129.6, 129.9, 130.8, 131.9, 133.3, 138.6, 149.6, 199.8; HRMS (APCI) calcd for [M+H]⁺ C₁₉H₁₈NO 276.1383, found 276.1386.

Note: in a 1D-NOE experiment a correlation of 7.42 (1H) – 2.72 (s, 6H) is observed and in a ¹H-¹H COSY experiment a coupling of 7.42 (1H) to 7.91 (d, 1H) is observed. Were the other regioisomer formed, the latter coupling would be a triplet.

Synthesis of the Acridones

To a mixture of the appropriate dimethylhydrazone (0.25 mmol), CsF (0.75 mmol, 3 equiv) and 5 mL of acetonitrile in a 10 mL vial, the silylaryl triflate (0.28 mmol, 1.1 equiv) was added. The vial was capped and the reaction mixture was allowed to stir for 10 h at 65 °C. Then 3 mL of 1M HCl was added and the mixture was heated at 65 °C for 2 h. Then 5 mL of 1M NaOMe was added and the mixture was heated at 100 °C for an additional 2 h. After cooling to room temperature, 25 ml of dichloromethane was added to the residue, and the reaction mixture was poured into 25 ml of water in a separatory funnel. After shaking the layers, the organic fraction was separated and the aqueous layer was extracted with dichloromethane (2 × 10 ml). All organic fractions were combined and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel using hexanes/EtOAc as the eluent to afford the desired acridone.

N-Methylbenz[c]acridin-7(12H)-one (100)

Red brown solid (29.4 mg, 45%): mp 142-145 °C (lit.⁶⁶ mp 143-144 °C); ¹H NMR (400 MHz, CDCl₃) δ 4.17 (s, 3H), 7.36 (t, J = 7.5 Hz, 1H), 7.55 (t, J = 7.7 Hz, 1H), 7.60-7.67 (m, 2H), 7.76 (t, J = 7.8 Hz, 1H), 7.92 (d, J = 8.1 Hz, 1H), 8.30 (d, J = 8.5 Hz, 1H), 8.44 (d, J = 8.7 Hz, 1H), 8.53 (d, J = 8.1 Hz, 1H); ¹³C NMR (100 MHz, CDCl₃) δ 45.1, 117.4, 121.7, 122.6, 122.8, 123.5, 124.3, 124.9, 125.0, 127.2, 127.5, 128.4, 129.1, 133.6, 137.6, 144.3, 145.9, 178.0; HRMS (APCI) calcd for [M+H]⁺ C₁₈H₁₄NO 260.1070, found 260.1070.

N-Methyl-2-fluoro-9-acridone (104)

Orange crystals (47.5 mg, 84%): mp 173 176 °C; ¹H NMR (400 MHz, CDCl₃) δ 3.76 (s, 3H), 7.20 (t, J = 7.5 Hz, 1H), 7.29-7.40 (m, 3H), 7.63 (ddd, J = 8.7, 7.0, 1.8 Hz, 1H), 8.05 (dd, J = 8.8, 2.9 Hz, 1H), 8.41 (dd, J = 8.1, 1.7 Hz, 1H); ¹³C NMR (100 MHz, CDCl₃) δ 34.1, 111.9, 112.1, 114.9, 117.1, 117.1, 121.5, 121.7, 122.1, 122.3, 123.3, 123.4, 127.7, 134.1, 139.1, 142.4, 156.4, 158.8, 177.3 (extra peaks due to C-F coupling); HRMS (APCI) calcd for [M+H]⁺ C₁₄H₁₁FNO 228.0819, found 228.0823.

N-Methyl-2-bromo-9-acridone (106)

Brown crystals (56.8 mg, 79%): mp 196-198 °C; ¹H NMR (400 MHz, CDCl₃) δ 3.74 (s, 3H), 7.17-7.27 (m, 2H), 7.39 (d, J = 8.7 Hz, 1H), 7.58-7.68 (m, 2H), 8.40 (dd, J = 8.0, 1.8 Hz, 1H), 8.50 (d, J = 2.5 Hz, 1H); ¹³C NMR (100 MHz, CDCl₃) δ 33.9, 114.7, 115.1, 117.0, 121.8, 122.4, 123.6, 127.8, 130.0, 134.2, 136.5, 141.2, 142.3, 176.8; HRMS (APCI) calcd for [M+H]⁺ C₁₄H₁₁BrNO 288.0019, found 288.0020. The ¹H and ¹³C NMR spectral data are in good agreement with the literature data.⁵⁴

N-Methyl-2-nitro-9-acridone (108)

Orange solid (37.7 mg, 59%): mp 284-286 °C (decomp.) (lit.⁶⁷ mp 287 °C); ¹H NMR (400 MHz, CDCl₃) δ 3.98 (s, 3H), 7.42 (t, J = 7.6 Hz, 1H), 7.60 (d, J = 8.8 Hz, 2H), 7.82 (t, J = 8.2 Hz, 1H), 8.52 (dd, J = 17.8, 9.2 Hz, 2H), 9.39 (s, 1H); ¹³C NMR (150 MHz, acetone d₆) δ 34.1, 116.4, 117.3, 121.4, 122.8, 123.3, 127.0, 127.4, 134.7, 141.3, 141.4, 142.9, 146.4, 176.4; HRMS (APCI) calcd for [M+H]⁺ C₁₄H₁₁N₂O₃ 255.0764, found 255.0773. The ¹H NMR spectral data are in good agreement with the literature data.⁶⁸

N-Methyl-4-methoxy-9-acridone (110)

Reddish-yellow solid (52.0 mg, 87%): mp 89-91 °C (lit.⁶⁹ mp 90 °C); ¹H NMR (400 MHz, CDCl₃) δ 3.92 (s, 3H), 3.95 (s, 3H), 7.11 7.27 (m, 3H), 7.47 (d, J = 8.7 Hz, 1H), 7.66 (ddd, J = 8.5, 6.8, 1.7 Hz, 1H), 8.09 (dd, J = 7.7, 1.8 Hz, 1H), 8.43 (d, J = 8.0 Hz, 1H); ¹³C NMR (100 MHz, CDCl₃) δ 41.6, 56.6, 115.7, 116.3, 119.3, 121.5, 122.1, 122.9, 125.6, 127.3, 133.8, 135.8, 145.8, 150.1, 178.6; HRMS (APCI) calcd for [M+H]⁺ C₁₅H₁₄NO₂ 240.1019, found 240.1022.

N-Methyl-2,3-dimethoxy-9-acridone (112)

Light brown needles (51.7 mg, 77%): mp 193-196 °C (lit.⁷⁰ mp 192-195 °C); ¹H NMR (400 MHz, CDCl₃) δ 3.75 (s, 3H), 3.99 (s, 3H), 4.01 (s, 3H), 6.72 (s, 1H), 7.22 7.27 (m, 1H), 7.40 (d, J = 8.7 Hz, 1H), 7.63 (t, J = 7.8 Hz, 1H), 8.52 (d, J = 8.0 Hz, 1H); ¹³C NMR (100 MHz, CDCl₃) δ 34.0, 56.4, 56.4, 96.7, 107.0, 114.8, 116.4, 121.2, 122.2, 127.6, 133.1, 138.9, 142.1, 145.4, 154.9, 176.5; HRMS (APCI) calcd for [M+H]⁺ C₁₆H₁₆NO₃ 270.1125, found 270.1132. The ¹H NMR spectral data are in good agreement with the literature data.⁷⁰

N-Methyl-[1,3]dioxolo[4,5-b]acridone (114)

Light brown solid (24.1 mg, 38%): mp 258-260 °C (lit.⁷⁰ mp 260-263 °C); ¹H NMR (400 MHz, CDCl₃) δ 3.77 (s, 3H), 6.01 (s, 2H), 6.88 (s, 1H), 7.22 (t, J = 7.5 Hz, 1H), 7.43 (d, J = 8.8 Hz, 1H), 7.61 (t, J = 8.0 Hz, 1H), 7.74 (s, 1H), 8.40 (d, J = 8.0 Hz, 1H); ¹³C NMR (100 MHz, CDCl₃) δ 34.5, 94.8, 102.3, 104.2, 115.0, 117.5, 121.6, 121.8, 127.4, 133.4, 140.7, 142.0, 144.0, 154.0, 176.8; HRMS (APCI) calcd for [M+H]⁺ C₁₅H₁₂NO₃ 254.0812, found 254.0821. The ¹H NMR spectral data are in good agreement with the literature data.⁷⁰

N-Methylbenzo[b][1,8]naphthyridin-5(10H)-one (118)

Gay brown solid (25.4 mg, 48%): mp 220-221 °C; ¹H NMR (300 MHz, CDCl₃) δ 4.13 (s, 3H), 7.20-7.27 (m, 1H), 7.33 (dd, J = 7.9, 7.0 Hz, 1H), 7.60 (d, J = 8.7 Hz, 1H), 7.77 (ddd, J = 8.7, 6.9, 1.7 Hz, 1H), 8.52 (dd, J = 8.0, 1.8 Hz, 1H), 8.73 8.80 (m, 2H); ¹³C NMR (100 MHz, CDCl₃) δ 31.0, 115.6, 117.4, 117.6, 122.1, 122.8, 127.8, 134.6, 137.0, 142.6, 151.3, 153.5, 178.6; HRMS (APCI) calcd for [M+H]⁺ C₁₃H₁₁N₂O 211.0866, found 211.0867.

N-methyl-1,3-dimethoxy-9-acridone (123)

Pale yellow solid (52.3 mg, 78%): mp 158-160 °C (lit.⁶⁶ mp 162 163 °C); ¹H NMR (400 MHz, CDCl₃) δ 3.48 (s, 3H), 3.77 (s, 3H), 3.86 (s, 3H), 6.08 (s, 1H), 6.11 (s, 1H), 7.09 (t, J = 7.5 Hz, 1H), 7.13 (d, J = 8.6 Hz, 1H), 7.43 (t, J = 8.6 Hz, 1H), 8.34 (d, J = 9.3 Hz, 1H); ¹³C NMR (75 MHz, CDCl₃) δ 34.7, 55.5, 56.1, 90.2, 92.4, 108.2, 114.4, 121.3, 124.3, 127.4, 132.8, 141.7, 146.7, 163.1, 164.1, 176.9; HRMS (APCI) calcd for [M+H]⁺ C₁₆H₁₆NO₃ 270.1125, found 270.1129. The ¹³C NMR spectral data are in good agreement with the literature data.⁷¹

Note: in a 1D-NOE experiment a correlation of 3.48 (s, 3H) – 7.13 (d, 1H) and 6.11 (s, 1H) is observed. If the other regioisomer had been obtained, a correlation of 3.48 (s, 3H) to one of the OMe groups (3.86 or 3.77 ppm) and lack of 3.48 (s, 3H) – 6.11 (s, 1H) would be expected.

N-Methyl-1,3,5-trimethoxy-9-acridone (125)

The standard procedure yielded the desired acridone (6.8 mg, 9%) and the uncyclized aminoaryl ketone (64.1 mg, 77%). The latter compound was exposed to 150 °C in 5 mL of MeCN for 4 h while stirring. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel using hexanes/EtOAc as the eluent to afford an additional 38.0 mg (51%) of the desired product 125. Thus, 44.8 mg (60% combined yield) of the acridone 125 was obtained. Brown red solid: mp 128-132 °C; ¹H NMR (400 MHz, CDCl₃) δ 3.75 (s, 3H), 3.82 (s, 6H), 3.87 (s, 3H), 6.16 (d, J = 2.1 Hz, 1H), 6.28 (d, J = 2.2 Hz, 1H), 7.00 (dd, J = 7.9, 1.5 Hz, 1H), 7.02-7.26 (m, 1H), 7.93 (dd, J = 7.9, 1.6 Hz, 1H); ¹³C NMR (100 MHz, CDCl₃) δ 42.4, 55.4, 56.1, 56.3, 91.0, 92.5, 108.9, 114.6, 119.0, 121.9, 127.8, 134.5, 149.4, 149.8, 162.4, 163.9, 177.1; HRMS (APCI) calcd for [M+H]⁺ C₁₇H₁₈NO₄ 300.1230, found 300.1239.

Suzuki-Miyaura procedure⁷² for the preparation of N-Methyl-2-(4-methoxyphenyl)-9-acridone (119)

To a 2 mL microwave vial was added the bromoacridone 106 (0.28 mmol), p-methoxyphenyl boronic acid (1.2 equiv), 1M Cs₂CO₃ (0.2 mL), and 5 mol % Pd(PPh₃)₄ in 1/1 DMF/EtOH (1 mL). The solution was vigorously stirred for 5 min at room temperature, flushed with argon, and then heated to 120 °C under microwave irradiation for 20 min. Upon cooling to room temperature, the resulting reaction mixture was diluted with a saturated solution of Na₂SO₄ and extracted with EtOAc. The combined organic layers were dried over MgSO₄, concentrated, and purified by column chromatography on silica gel using hexanes/EtOAc as the eluent to afford the desired product. Yellow needles (66.3 mg, 75%): mp 218-220 °C; ¹H NMR (400 MHz, CDCl₃) δ 3.84 (s, 3H), 3.86 (s, 3H), 6.99 (d, J = 8.8 Hz, 2H), 7.26 (ddd, J = 7.9, 5.9, 1.0 Hz, 1H), 7.48 (dd, J = 13.7, 8.8 Hz, 2H), 7.63 (d, J = 8.8 Hz, 2H), 7.68 (ddd, J = 8.8, 7.0, 1.7 Hz, 1H), 7.88 (dd, J = 9.0, 2.4 Hz, 1H), 8.55 (dd, J = 8.0, 1.7 Hz, 1H), 8.72 (d, J = 2.4 Hz, 1H); ¹³C NMR (100 MHz, CDCl₃) δ 33.8, 55.6, 114.6, 115.0, 115.6, 121.4, 122.6, 122.8, 124.8, 128.0, 128.1, 132.3, 132.4, 133.7, 133.9, 141.5, 142.5, 159.4, 178.3; HRMS (APCI) calcd for [M+H]⁺ C₂₁H₁₈NO₂ 316.1332, found 316.1335.

Synthesis of Acridinium Salts

Method A

To a mixture of the appropriate N,N-disubstituted hydrazone (0.25 mmol), CsF (4 equiv) and 5 mL of acetonitrile in a 10 mL vial, the silylaryl triflate (1.8 equiv) was added. The reaction mixture was allowed to stir for 10 h at room temperature. Then 3 mL of 1M HCl was added and the mixture was heated at 65 °C for an additional 2 h. After cooling to room temperature, 25 ml of dichloromethane was added to the residue, and the reaction mixture was poured into 25 ml of brine in a separatory funnel. After shaking the layers, the organic fraction was separated and the aqueous layer was extracted with dichloromethane (2 × 10 ml). All organic fractions were combined and concentrated under reduced pressure. The residue was eluted with hexanes/EtOAc (1/2) using a preparative thin layer chromatography plate with silica gel. The bright yellow spot of high polarity was collected and put on a short plug of silica gel. CH₂Cl₂/MeOH (1/1, 15 mL) was run through the plug and the solvent was evaporated to afford the desired acridinium salt.

Method B

The silylaryl triflate (2.8 equiv) was added to a mixture of benzaldehyde N-methylhydrazone (0.25 mmol), CsF (5 equiv) and 5 mL of acetonitrile in a 10 mL vial. The reaction mixture was allowed to stir for 10 h at room temperature. The rest of the procedure follows Method A.

Method C

The silylaryl triflate (1.5 equiv) was added to a mixture of the aminoaryl ketone 8 (0.25 mmol), CsF (3 equiv) and 5 mL of acetonitrile in a 10 mL vial. The vial was capped and the reaction mixture was allowed to stir for 10 h at 65 °C. The rest of the procedure follows Method A.

10-Methyl-9-phenylacridin-10-ium chloride (127)

This compound was obtained as a dark yellow-green solid in an 88% yield by Method A (67.4 mg), in a 41% yield by Method B (31.2 mg), and in a 78% yield by Method C (59.9 mg): 201-203 °C; ¹H NMR (400 MHz, CDCl₃) δ 5.04 (s, 3H), 7.44 7.51 (m, 2H), 7.66-7.76 (m, 3H), 7.79 (dd, J = 8.7, 6.7 Hz, 2H), 8.00 (dd, J = 8.7, 1.6 Hz, 2H), 8.38 (ddd, J = 9.0, 6.8, 1.6 Hz, 2H), 8.75 (d, J = 9.2 Hz, 2H); ¹³C NMR (75 MHz, CDCl₃) δ 39.6, 119.1, 126.3, 128.1, 129.3, 130.0, 130.4, 130.7, 133.2, 139.4, 141.8, 161.7; HRMS (APCI) calcd for [M]⁺ C₂₀H₁₆N 270.1277, found 270.1278. The ¹H and ¹³C NMR spectral data are in good agreement with the literature data.⁵¹

10-Methyl-9-(thiophen-2-yl)acridin-10-ium chloride (130)

Dark green solid (68.4 mg, 88% by Method A): mp 136-138 °C (decomp.); ¹H NMR (400 MHz, CDCl₃) δ 4.94 (s, 3H), 7.34-7.41 (m, 2H), 7.72-7.80 (m, 2H), 7.82 (d, J = 5.0 Hz, 1H), 8.18 (d, J = 8.7 Hz, 2H), 8.31 (dd, J = 8.9, 7.1 Hz, 2H), 8.66 (d, J = 9.2 Hz, 2H); ¹³C NMR (100 MHz, CDCl₃) δ 39.5, 118.9, 127.0, 128.2, 128.3, 129.9, 130.8, 131.6, 132.9, 139.3, 141.4, 154.7; HRMS (APCI) calcd for [M]⁺ C₁₈H₁₄NS 276.0841, found 276.0849.

9,10-Diphenylacridin-10-ium chloride (132)

Yellow solid (28.6 mg, 31% by Method A): mp 259-263 °C (decomp.); ¹H NMR (400 MHz, CDCl₃) δ 7.55 (d, J = 9.2 Hz, 2H), 7.66-7.70 (m, 2H), 7.71-7.79 (m, 7H), 7.85-7.92 (m, 3H), 8.03-8.12 (m, 4H); ¹³C NMR (100 MHz, CDCl₃) δ 119.6, 126.2, 127.8, 128.0, 128.9, 130.1, 130.2, 130.5, 131.6, 131.8, 133.0, 137.1, 138.4, 142.1, 163.4; HRMS (APCI) calcd for [M]⁺ C₂₅H₁₈N 332.1434, found 332.1443.

Synthesis of 1-Methyl-3-phenyl-1H-indazole (137)

The silylaryl triflate 2 (0.28 mmol, 1.1 equiv) was added to a mixture of the hydrazone 1 (0.25 mmol), CsF (0.75 mmol, 3 equiv) and 5 mL of acetonitrile in a 10 mL vial. The vial was capped and the reaction mixture was allowed to stir for 10 h at 65 °C. Then NCS (1.5 equiv) was added and the mixture was heated at 65 °C for an additional 2 h. After cooling to room temperature, 25 ml of CH₂Cl₂ was added to the residue, and the reaction mixture was poured into 40 ml of water in a separatory funnel. After shaking the layers, the organic fraction was separated and the aqueous layer was extracted with CH₂Cl₂ (2 × 10 ml). All organic fractions were combined and concentrated under reduced pressure. The residue was dissolved in 5 mL of acetonitrile and heated at 130 °C for 10 h. After cooling to room temperature, 25 ml of CH₂Cl₂ was added to the residue, and the reaction mixture was poured into 40 ml of water in a separatory funnel. After shaking the layers, the organic fraction was separated and the aqueous layer was extracted with CH₂Cl₂ (2 × 10 ml). All organic fractions were combined and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel using hexanes/EtOAc as the eluent to afford the desired 1H-indazole 137. Gray solid (34.2 mg, 66%): mp 81-83 °C; ¹H NMR (400 MHz, CDCl₃) δ 4.13 (s, 3H), 7.21 (s, 1H), 7.42 (t, J = 4.3 Hz, 3H), 7.52 (t, J = 7.6 Hz, 2H), 7.99 (d, J = 8.3 Hz, 2H), 8.04 (d, J = 8.2 Hz, 1H); ¹³C NMR (75 MHz, CDCl₃) δ 35.7, 109.4, 121.1, 121.5, 121.8, 126.5, 127.6, 128.0, 129.0, 133.9, 141.6, 143.9; HRMS (APCI) calcd for [M+H]⁺ C₁₄H₁₃N₂ 209.1073, found 209.1075. The ¹H and ¹³C NMR spectral data are in good agreement with the literature data.⁷³

Synthesis of nigellidine analogue 144

The silylaryl triflate 2 (0.28 mmol, 1.1 equiv) was added to a mixture of the hydrazone 141 (0.25 mmol),⁷⁴ CsF (0.75 mmol, 3 equiv) and 5 mL of acetonitrile in a 10 mL vial. The vial was capped and the reaction mixture was allowed to stir for 10 h at 65 °C. Then NH₂OH^.HCl (2 equiv) and EtOH (3 mL) were added and the mixture was heated at 150 °C for 24 h. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The residue was purified by preparative thin layer chromatography on silica gel using hexanes/EtOAc (1/1) as the eluent to afford the tricyclic product 143 as a dark brown oil (29.3 mg, 37%): ¹H NMR (400 MHz, CDCl₃) δ 2.26-2.52 (m, 4H), 3.92 (s, 3H), 4.70 (dt, J = 19.5, 6.1 Hz, 4H), 7.16 (d, J = 8.8 Hz, 2H), 7.47 (t, J = 7.6 Hz, 1H), 7.68 (d, J = 8.8 Hz, 3H), 7.76-7.83 (m, 2H). BBr₃ (1.0 M solution in CH₂Cl₂, 6 equiv)⁷⁵ was added dropwise to a solution of the compound 143 in CH₂Cl₂ (5 mL) at 0 °C and stirred at room temperature for 5 h. The mixture was extracted with 10% methanol in CH₂Cl₂ (5 mL × 4) and the organic solution was concentrated under reduced pressure. The residue was washed with hexanes (5 mL × 2), diethyl ether (5 mL × 2), and ethyl acetate (5 mL × 2) and dried in vacuo to afford the desired nigellidine analogue 144. Black oil (16.4 mg, 67%): ¹H NMR (400 MHz, CDCl₃ + CD₃OD) δ 2.15-2.38 (m, 4H), 4.56 (dt, J = 31.3, 6.1 Hz, 4H), 6.99 (d, J = 8.6 Hz, 2H), 7.35-7.40 (m, 1H), 7.43 (d, J = 8.6 Hz, 2H), 7.59 (d, J = 8.7 Hz, 1H), 7.68-7.76 (m, 2H); ¹³C NMR (100 MHz, CDCl₃ + CD₃OD) δ 19.4, 20.3, 47.0, 49.1, 110.2, 113.9, 116.9, 119.4, 122.7, 125.8, 131.5, 133.7, 140.6, 144.8, 160.8. HRMS (APCI) calcd for [M+H]⁺ C₁₇H₁₇N₂O 265.1335, found 265.1337.

Scheme 11.

Synthesis of a Naturally-occurring Acridone.