Synthesis of o -(dimethylamino)aryl ketones, acridones, acridinium salts, and 1 H -indazoles by the reaction of hydrazones and arynes

Article

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Synthesis of o‑(Dimethylamino)aryl Ketones, Acridones, Acridinium

Salts, and 1H‑Indazoles by the Reaction of Hydrazones and Arynes

Anton V. Dubrovskiy and Richard C. Larock*

Department of Chemistry, Iowa State University, Ames, Iowa 50011, United States

S

* Supporting Information

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

RESULTS AND DISCUSSION

■

A number of nitrogen-based nucleophiles have been shown to

react with arynes: aryl and alkyl amines,^1,2enamines,³

sulfonamides,¹amides,⁴enamides,⁵nitrogen-containing hetero-

cycles,^6,7and imines.⁸Two recent approaches to 1H-indazoles

involve a [3 + 2] cycloaddition between arynes and 1,3-dipoles

generated in situ from N-tosylhydrazones⁹and hydrazonoyl

chlorides.¹⁰(Scheme 1).

Ketimine Generation and Subsequent Transforma-

tions. In a preliminary study, it was observed that the reaction

of the N,N-dimethylhydrazone derived from benzyl phenyl

ketone and o-(trimethylsilyl)phenyl triﬂate¹²plus 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 1. Known Couplings of Hydrazone-Derived Dipoles

and Benzyne

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).

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 communica-

tion in 2011.¹¹In 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.

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

Received: October 27, 2012

Published: December 3, 2012

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Scheme 2. Azirine Formation from a Ketone-Derived Hydrazone

Scheme 3. Imine Formation from an Aldehyde-Derived Hydrazone

Scheme 4. One-Pot Transformations of the Generated Imine 3

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,¹⁴although the yield of the ﬁnal

product drops to 43%.

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 NaBH₄reduction of the imine 3 to the amine

7 (70%), followed by acetylation of the amino group with Ac₂O

(92% yield).

The imine 3 can be acetylated without isolation by adding

ethyl chloroformate to the reaction to yield the corresponding

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a

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

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Table 1. continued

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Table 1. continued

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Table 1. continued

a

Reaction conditions: 0.25 mmol of substrate, 1.1 equiv of 2-(trimethylsilyl)phenyl triﬂuoromethane-sulfonate and 3.0 equiv of CsF in 5 mL of

b

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 65 °C for 2 h. Isolated

yield. A mixture of unidentiﬁed products was produced. One of the major products was very polar, presumably a cyclic intermediate analogous to

intermediate 1b. 2.2 equiv of benzyne precursor and 5.0 equiv of CsF were used.

c

d

e

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

regiorandom Friedel−Crafts reaction conditions¹⁵or nucleophilic

aromatic substitutions of o-ﬂuoroaryl ketones, which are not very

readily available, by amino or proamino nucleophiles.^16,17

o-(Dimethylamino)aryl ketones are quite important from a

biological standpoint. Compound D-205 (9) has shown signiﬁ-

cant anti-inﬂammatory activity^15b(Figure 1). The quinolinyl

Figure 1. Pharmaceutically important o-(dimethylamino)aryl ketones.

and isoquinolinyl ketones 10 and 11 have been found to be

very eﬃcient agonists of the cannabinoid CB2 receptor.¹⁸Some

aminoaryl ketones are found in nature,¹⁹and some are employed

as starting materials in the preparation of chiral 1,3-diamine-

based reagents and ligands¹⁶and in recently reported ruthenium-

catalyzed derivatization processes.²⁰

The importance of o-(dimethylamino)aryl ketones encour-

aged us to evaluate the scope of this novel aryne coupling

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reaction. Various hydrazones have been prepared by reacting

the corresponding aldehydes with 1,1-disubstituted hydrazines

in CH₂Cl₂in the presence of MgSO₄(Scheme 5).²¹The yields

of the hydrazones have ranged from 62 to 98%.

that aminoaryl ketone 41 can potentially be quite useful for further

elaboration via Sonogashira coupling reactions.²²In 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.²³However, alkenyl functionality is well

tolerated in this transformation. Products 45 (entry 18) and 9

(entry 19) have been obtained in 77 and 91% yields, res-

pectively, from such hydrazones. It is noteworthy that the

aminoketone 9 has been previously reported to exhibit signiﬁ-

cant biological activity.^15bThe 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).

Scheme 5. Preparation of 1,1-Disubstituted Hydrazones

To our delight, despite benzyne’s dienophilic nature,²⁴

electron-rich pyrrole-, furan-, and thiophene-containing hydra-

zones 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 hydra-

zone 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 cor-

responding product 62 in an 84% yield (entry 27).

Despite the well-documented reactivity of pyridines with

arynes,^7,25a 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 pro-

ducts 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 NMe₂groups in the hydrazones and the

nitrogen atoms in the pyridine rings toward 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

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 because of 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 inter-

mediate 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 dequater-

narize 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-dimethylami-

no-substituted substrate 34 led to formation of the correspond-

ing 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

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 cor-

responding 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 amino-

aryl ketone 84 in a 77% yield (entry 1). The electron-rich

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a

Table 2. Reaction of 1,1-Dimethylhydrazones with Arynes: Aryne Scope

a

Reaction 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

b

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 65 °C for 2 h. Isolated yield.

c

d

e

A separable ∼1/1 mixture of regioisomers was produced. An inseparable ∼1/1 mixture of regioisomers was produced. See the Experimental

Section for the structure determination of this product.

Scheme 6. Reaction with Unsymmetrical 3-Methoxybenzyne

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symmetrical dimethoxybenzyne aﬀorded the expected pro-

duct 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 diﬂuor-

obenzyne.²⁶The 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.

The reaction of the 1,1-dimethylhydrazone derived from

benzaldehyde with the unsymmetrical aryne precursor

3-methoxy-2-(trimethylsilyl)phenyl triﬂate resulted in the for-

mation 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).²⁷Similar 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,²⁸was produced in an 82%

yield (entry 7).

Synthesis of N-Methylacridones. We envisioned that the

NMe₂group of the aminoketones generated by our process

could further undergo an intramolecular S_NAr reaction if there

was 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).²⁹This latter heterocycle is a prominent naturally

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.

Excellent yields (91 and 94%) have also been observed using

the corresponding o-chloro- and o-ﬂuorobenzaldehyde hydra-

zones 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 correspond-

ing 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

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 correspond-

ing 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,³⁵trypanocidal,³⁶and anticancer³⁷activities. They

have also been shown to reverse the multidrug resistance of

tumor cells.³⁸

Scheme 7. Plausible Pathway of the Formation of N-

Methylacridones

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 acridone,³⁹and its

demethylated derivative 121 has been shown to exhibit anti-HIV

activity.⁴⁰We 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).

The use of the unsymmetrical 3,5-dimethoxy-2-(trimethylsilyl)-

phenyl triﬂate 122⁴¹in 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,⁴²as well as its 1-demethylated³³and

1,3-bisdemethylated⁴³derivatives. The latter has also been shown

to have signiﬁcant antipsoriatic activity⁴⁴and has been previously

made from compound 123 using an HBr-mediated ether

cleavage.⁴⁵It is also noteworthy that the compound 123 has

occurring scaﬀold³⁰with many of its members exhibiting a wide

range of biological activities, including antitumor,³¹antimalarial,³²

and antiplasmodial³³activities.

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

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a

Table 3. Synthesis of N-Methylacridones

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Table 3. continued

a

Reaction 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

b

mixture was heated at 100 °C for 2 h. Isolated yield.

Scheme 8. Suzuki−Miyaura Coupling of an Acridone

Scheme 9. Synthesis of a Naturally Occurring Acridone

been previously used as a precursor to acronycine (124),⁴⁶an

alkaloid long known for its antitumor properties.⁴⁷

of its 1,3,6-trisdemethylated derivative by HBr-mediated deme-

thylation is described in the literature.⁴⁹The 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.⁵¹The

The analogous reaction of the unsymmetrical 3,5-dimethoxy-

2-(trimethylsilyl)phenyl triﬂate with the methoxy-analogue 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 (Scheme 11).⁴⁸Synthesis

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Scheme 10. Synthesis of a Naturally Occurring Acridone

Scheme 11. Synthesis of a Naturally Occurring Acridone

Scheme 12. Plausible Pathway for Acridinium Salt Formation

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.⁵²Subsequent deamination (or dehydration) of the

intermediate leads to formation of the acridinium salt 127.

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.⁴It 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,⁵³essentially

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,⁵⁴and dequaternarization of the

diaryldimethylammonium fragment follows (presumably assisted

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Scheme 14. Plausible Pathway for Acridinium Salt Formation

Scheme 15. Synthesis of Substituted Acridinium Salts

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.

Acridinium salts are an intriguing class of compounds used

for DNA intercalation studies⁵¹and as NAD⁺analogues.⁵⁵

Recently, their analogues, quinolinium salts, have been shown

to be eﬀective photocatalysts for the direct oxygenation of

benzene to phenol.⁵⁶Our 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.

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).⁵⁷In 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 K₂CO₃or (b)

10% NaOCl.

Because of 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).⁵⁸When

the reaction mixture containing ketimine 3 was subjected to

NCS/K₂CO₃at 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 cycliza-

tion 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.

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 pro-

duct 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 16. Synthesis of Isomeric Benzoxazoles by the Chen

Group

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

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Scheme 17. Attempts to Develop a One-Pot Synthesis of 1H-Indazoles

Scheme 18. Optimization of the Synthesis of Indazoles from Ketimines

Scheme 19. Synthesis of Indazoles by Rebek

Scheme 20. Synthesis of a Nigellidine Analogue

the HCl present in the reaction media), thus leading to the

desired indazole moiety 140.

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 demethylation⁶¹furnished the

desired nigellidine analogue 144 in a 67% yield.

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 isolated⁶⁰from 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

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,

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2,4,5-Trimethoxybenzaldehyde dimethylhydrazone (30).

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 a 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 method-

ology. A variety of functional groups are compatible with the

reaction conditions.

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]⁺C₁₂H₁₉N₂O₃239.1390, found 239.1388.

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

Red solid: mp 67−68 °C (lit.⁶²mp 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]⁺C₁₁H₁₈N₃192.1495, found 192.1493.

(−)-Myrtenal dimethylhydrazone (47).

EXPERIMENTAL SECTION

■

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

1

Pale yellow liquid: H NMR (400 MHz, CDCl₃) δ 0.81 (s, 3H), 1.14

1

resonance in the H NMR spectrum as 0.00 ppm and the CDCl₃

(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]⁺

C₁₂H₂₁N₂193.1699, found 193.1698.

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

(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]⁺C₁₁H₂₁N₂181.1699, found 181.1697.

o-Tolylaldehyde dimethylhydrazone (16).

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

1

Black solid: mp 37−39 °C; H NMR (300 MHz, CDCl₃) δ 2.90 (s,

Yellow liquid: H 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]⁺C₁₀H₁₅N₂163.1230,

found 163.1228.

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-Methoxybenzaldehyde dimethylhydrazone (28).

2-Pyrrolecarbaldehyde dimethylhydrazone (53).

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.

1

Black solid: mp 43−46 °C; H 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]⁺C₇H₁₂N₃138.1026, found

138.1026.

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Indole-3-carbaldehyde dimethylhydrazone (59).

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).

This compound was obtained as a brown solid using 2 mL of MeOH

as a cosolvent: 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]⁺C₁₁H₁₄N₃188.1182,

found 188.1181.

1

Pale yellow solid: mp 164−165 °C; H 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]⁺

C₁₂H₁₉N₄219.1604, found 219.1602.

Indole-4-carbaldehyde dimethylhydrazone (61).

1-Bromo-2-naphthaldehyde dimethylhydrazone (99).

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]⁺C₁₁H₁₄N₃188.1182, found

188.1180.

1

White solid: mp 80−82 °C; H 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]⁺C₁₃H₁₄BrN₂277.0335, found

277.0331.

2-Methoxy-3-pyridinecarboxaldehyde dimethylhydrazone (65).

2-Bromo-5-ﬂuorobenzaldehyde dimethylhydrazone (103).

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.

1

Colorless liquid: H NMR (300 MHz, CDCl₃) δ 3.05 (s, 6H), 6.77

2-Pyridinecarboxaldehyde dimethylhydrazone (67).

(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]⁺

C₉H₁₁BrFN₂245.0084, found 245.0082.

1

Pale brown liquid: H 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]⁺C₈H₁₂N₃150.1026, found 150.1027.

2-Quinolinecarboxaldehyde dimethylhydrazone (69).

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]⁺C₉H₁₁BrFN₂245.0084, found

245.0082.

1

Brown-red semisolid: mp 67−68 °C; H 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]⁺

C₁₂H₁₄N₃200.1182, found 200.1180.

2-Chloro-5-nitrobenzaldehyde dimethylhydrazone (107).

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

1

Orange solid: mp 87−91 °C; H 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]⁺C₉H₁₁ClN₃O₂228.0534, found

228.0532.

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);

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2-Fluoro-3-methoxybenzaldehyde dimethylhydrazone (109).

135.4, 136.2; HRMS (APCI) calcd for [M + H]⁺C₈H₁₁N₂135.0917,

found 135.0917.

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

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,

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.

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).

Benzaldehyde diphenylhydrazone (131).

1

White solid: mp 90−91 °C; H NMR (400 MHz, CDCl₃) δ 2.91

Colorless solid: mp 124−125 °C (lit.⁶⁵mp 125−126 °C); H NMR

1

(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]⁺

C₁₁H₁₆BrN₂O₂287.0390, found 287.0389.

(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]⁺C₁₉H₁₇N₂273.1386, found

273.1396.

6-Bromopiperonal dimethylhydrazone (113).

Synthesis of Aminoaryl Ketimines and Derivatives. N,N-

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

1

White solid: mp 55−57 °C; H 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]⁺C₁₀H₁₂BrN₂O₂271.0077,

found 271.0077.

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]⁺C₁₅H₁₇N₂225.1386, found 225.1385.

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

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]⁺C₈H₁₁ClN₃184.0636, found 184.0634.

N-Methyl-N-phenylbenzaldehyde hydrazone (126).

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

White solid: mp 105−106 °C (lit.⁶³mp 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]⁺C₁₄H₁₅N₂211.1230, found

1

211.1228. The H and ¹³C NMR spectral data are in good agreement

with the literature data.⁶⁴

Benzaldehyde methylhydrazone (128).

1

Colorless liquid: H NMR (400 MHz, CDCl₃) δ 2.98 (s, 3H), 7.23−

(60.5 mg, 82%): H 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),

7.29 (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,

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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]⁺C₁₈H₂₁N₂O₂297.1598, found 297.1595.

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 1 M 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 chromato-

graphy on silica gel using hexanes/EtOAc as the eluent to aﬀord the

desired o-(dimethylamino)aryl ketone.

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.

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

1

Pale yellow oil (46.4 mg, 78%): H 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).

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

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.

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]⁺C₁₅H₁₉N₂227.1543, found

227.1545.

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

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

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.

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).

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

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; H 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);

1

Yellow crystals (47.0 mg, 74%): mp 111−113 °C; H 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]⁺C₁₆H₁₈NO₂256.1332, found

256.1335.

1

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

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

1

Pale brown solid (52.8 mg, 67%): mp 106−110 °C; H 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]⁺C₁₈H₂₂NO₄316.1543,

found 316.1550.

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).

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

1

Pale yellow oil (30.4 mg, 45%): H 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.

1

Dark red solid (51.1 mg, 85%): mp 80−81 °C; H 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]⁺C₁₅H₁₆NO₂242.1176, found 242.1180.

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

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

1

Yellow oil (37.3 mg, 61%): H NMR (400 MHz, CDCl₃) δ 2.73 (s,

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.

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)phenyl](thiophen-2-yl)methanone (58).

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

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).

1

Light orange oil (62.2 mg, quantitative yield): H 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).

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.

1

Yellow oil (42.5 mg, 63%): H 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.

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

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1

Yellow solid (55.6 mg, 84%): mp 173−176 °C; H 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.

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]⁺C₁₆H₁₆NO₂254.1176, found 254.1176.

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

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

1

Light brown solid (53.3 mg, 80%): mp 94−95 °C; H NMR (400

(66).

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

Yellow solid (49.8 mg, 78%): mp 69−71 °C; H 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]⁺C₁₅H₁₇N₂O₂257.1285, found

257.1287.

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; H

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

1

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]⁺C₂₄H₂₅N₂O₂373.1911, found 373.1914.

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.

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

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

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.

1

Yellow crystals (58.3 mg, 84%): mp 111−114 °C; H 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,

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

1

Yellow crystals (59.0 mg, 83%): mp 101−104 °C; H NMR (400

1

found 277.1343. The H and ¹³C NMR spectral data are in good

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]⁺C₁₇H₂₀NO₃286.1438, found 286.1441.

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

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]⁺C₁₂H₁₆NO₃222.1125, found 222.1124.

1

Pale yellow oil (40.7 mg, 62%): H 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.

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

1

Light brown solid (41.9 mg, 66%): mp 92−93 °C; H 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,

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

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 chromato-

graphy on silica gel using hexanes/EtOAc as the eluent to aﬀord the

desired acridone.

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]⁺C₁₆H₁₈NO₂256.1332, found 256.1333.

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

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

Red brown solid (29.4 mg, 45%): mp 142−145 °C (lit.⁶⁶mp 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.

1

Yellow solid: mp 58−59 °C; H 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.

N-Methyl-2-ﬂuoro-9-acridone (104).

Mixture of 2-(Dimethylamino)-4-methoxy-benzophenone (92a)

and 2-(dimethylamino)-5-methoxybenzophenone (92b) (∼1/1

ratio).

1

Orange crystals (47.5 mg, 84%): mp 173−176 °C; H 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.

1

Pale yellow oil (51.0 mg, 85%): H 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.

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

1

Brown crystals (56.8 mg, 79%): mp 196−198 °C; H NMR (400

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

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

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.

1

288.0020. The H and ¹³C NMR spectral data are in good agreement

with the literature data.⁵⁴

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

Note: In a 1D-NOE experiment, a correlation of 7.42 (1H) to 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. If the other regioisomer was

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 1 M HCl was added, and

the mixture was heated at 65 °C for 2 h. Then 5 mL of 1 M 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

Orange solid (37.7 mg, 59%): mp 284−286 °C (decomp.) (lit.⁶⁷mp

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]⁺

1

C₁₄H₁₁N₂O₃255.0764, found 255.0773. The H NMR spectral data

are in good agreement with the literature data.⁶⁸

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

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) to

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) to 6.11 (s, 1H) would be

expected.

Reddish-yellow solid (52.0 mg, 87%): mp 89−91 °C (lit.⁶⁹mp 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]⁺C₁₅H₁₄NO₂240.1019, found 240.1022.

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

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]⁺

C₁₇H₁₈NO₄300.1230, found 300.1239.

Light brown needles (51.7 mg, 77%): mp 193−196 °C (lit.⁷⁰mp 192−

1

195 °C); H 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)

1

calcd for [M + H]⁺C₁₆H₁₆NO₃270.1125, found 270.1132. The H

NMR spectral data are in good agreement with the literature data.⁷⁰

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

Suzuki−Miyaura Procedure⁷²for the Preparation of N-Methyl-2-

(4-methoxyphenyl)-9-acridone (119).

Light brown solid (24.1 mg, 38%): mp 258−260 °C (lit.⁷⁰mp 260−

1

263 °C); H NMR (400 MHz, CDCl₃) δ 3.77 (s, 3H), 6.01 (s, 2H),

To a 2 mL microwave vial was added the bromoacridone 106

(0.28 mmol), p-methoxyphenyl boronic acid (1.2 equiv), 1 M Cs₂CO₃

(0.2 mL), and 5 mol % Pd(PPh₃)₄in 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 Na₂SO₄and 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.

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

1

for [M + H]⁺C₁₅H₁₂NO₃254.0812, found 254.0821. The H NMR

spectral data are in good agreement with the literature data.⁷⁰

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

1

Yellow needles (66.3 mg, 75%): mp 218−220 °C; H 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.

1

Gray brown solid (25.4 mg, 48%): mp 220−221 °C; H 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.

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 1 M 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

N-Methyl-1,3-dimethoxy-9-acridone (123).

Pale yellow solid (52.3 mg, 78%): mp 158−160 °C (lit.⁶⁶mp 162−163

1

°C); H 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]⁺C₁₆H₁₆NO₃270.1125, found 270.1129.

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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.

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

1

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

1H-indazole 137. Gray solid (34.2 mg, 66%): mp 81−83 °C; H 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

1

[M + H]⁺C₁₄H₁₃N₂209.1073, found 209.1075. The H and ¹³C NMR

spectral data are in good agreement with the literature data.⁷³

Synthesis of Nigellidine Analogue 144.

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; H NMR

1

(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 H and ¹³C NMR spectral data are in

1

good agreement with the literature data.⁵¹

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

The silylaryl triﬂate 2 (0.28 mmol, 1.1 equiv) was added to a mixture

of the hydrazone 141 (0.25 mmol),⁷⁴CsF (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)⁷⁵was 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.

Dark green solid (68.4 mg, 88% by Method A): mp 136−138 °C

1

(decomp.); H 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).

1

Black oil (16.4 mg, 67%): H 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.

Yellow solid (28.6 mg, 31% by Method A): mp 259−263 °C

1

(decomp.); H 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.

ASSOCIATED CONTENT

■

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

S

* Supporting Information

¹H and ¹³C NMR data for compounds. This material is

available free of charge via the Internet at http://pubs.acs.org.

AUTHOR INFORMATION

■

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 CH₂Cl₂was added to the

Corresponding Author

*E-mail: larock@iastate.edu.

Notes

The authors declare no competing ﬁnancial interest.

11254

dx.doi.org/10.1021/jo302378w | J. Org. Chem. 2012, 77, 11232−11256

The Journal of Organic Chemistry

Article

(29) A similar approach has been recently reported by Greaney,

where an N-aryl aniline underwent an intramolecular S_NAr reaction

under microwave conditions with the formation of N-arylacridones;

see ref 4.

(30) Prager, R. H.; Williams, C. M. Sci. Synth. 2005, 15, 1029.

(31) David-Cordnonnier, M.-H.; Laine, W.; Gaslonde, T.; Michel, S.;

ACKNOWLEDGMENTS

■

We thank the National Science Foundation and the National

Institutes of Health Kansas University Center of Excellence in

Chemical Methodology and Library Development (P50

GM069663) for their generous ﬁnancial support. We also

thank Dr. Feng Shi, while at Iowa State University, for the

preparation of some of the noncommercially available aryne

precursors.

Tillequin, F.; Koch, M.; Leo

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11256

dx.doi.org/10.1021/jo302378w | J. Org. Chem. 2012, 77, 11232−11256

Article Doi

Synthesis of o -(dimethylamino)aryl ketones, acridones, acridinium salts, and 1 H -indazoles by the reaction of hydrazones and arynes

DOI: 10.1021/jo302378w

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