Synthesis of o -(dimethylamino)aryl ketones and acridones by the reaction of 1,1-dialkylhydrazones and arynes

Article abstract of DOI:10.1021/ol2016803

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

Full text of DOI:10.1021/ol2016803

ORGANIC
LETTERS
2011
Vol. 13, No. 15
4136–4139
Synthesis of o-(Dimethylamino)aryl
Ketones and Acridones by the Reaction of
1,1-Dialkylhydrazones and Arynes
Anton V. Dubrovskiy and Richard C. Larock*
Department of Chemistry, Iowa State University, Ames, Iowa 50011, United States
larock@iastate.edu
Received June 22, 2011
ABSTRACT
A novel, efficient route to biologically and pharmaceutically important o-(dimethylamino)aryl ketones and acridones has been developed starting
from readily available 1,1-dimethylhydrazones of aldehydes and o-(trimethylsilyl)aryl triflates. The reaction proceeds under mild conditions,
tolerates a wide range of functional groups, and provides the final products in good to excellent yields.
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 and imines.7 Two recent ap-
proaches to 1H-indazoles involve a [3 þ 2] cycloaddition
between arynes and 1,3-dipoles generated in situ from
N-tosylhydrazones8 and hydrozonyl chlorides.9 While
there has been considerable recent interest in aryne-based
methodologies, no reaction of arynes and readily available
1,1-dialkylhydrazones has ever been reported. We wish to
report that the reaction of 1,1-dialkylhydrazones and arynes
provides easy and efficient access to o-(dimethylamino)-
aryl ketones and acridones.
In a preliminary study, it was observed that the reaction
of the N,N-dimethylhydrazone derived from benzyl phenyl
ketone and o-(trimethylsilyl)phenyl triflate10 plus CsF at
65 °C in CH3CN yielded 2,3-diphenyl-2H-azirine in a 47%
yield and diphenylmethylamine, along with the 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. An intramolecular SN2
reaction follows, which leads to formation of the azirine
and phenyldimethylamine, which is further converted
into diphenylmethylamine by reaction with the benzyne
(Scheme 1). Although this route to azirine is not described
in the literature, more facile ways of synthesizing azirines
have been previously reported.11
(1) Liu, Z.; Larock, R. C. J. Org. Chem. 2006, 71, 3198.
(2) Cant, A. A.; Bertand, G. H. V.; Henderson, J. L.; Roberts, L.;
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(b) Jeganmohan, M.; Bhuvaneswari, S.; Cheng, C.-H. Chem.;Asian
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Soc. 2006, 128, 11040.
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r
10.1021/ol2016803
Published on Web 07/11/2011
2011 American Chemical Society

o-(dimethylamino)aryl ketones are generally prepared
through pathways involving harsh and nonregiospecific
FriedelꢀCrafts reaction conditions.13
Scheme 1. Azirine Formation from a Ketone-Derived Hydra-
zone
o-(Dimethylamino)aryl ketones are quite important
from a biological standpoint. Compound D-205 (5) has
shown significant anti-inflammatory activity13b (Figure 1).
Thequinolinyland isoquinolinylketones6 and7 havebeen
found to be very efficient agonists of the cannabinoid CB2
receptor.14 Some aminoaryl ketones are found in nature,15
and some are employed as starting materials in recently
reported ruthenium-catalyzed derivatization processes.16
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-dimethyl-hydra-
zone (1) and the benzyne precursor 2 under the reaction
conditions identical to those used on the ketone hydrazone
did not yield the expected 1,2-dihydroindazole. Instead,
o-(dimethylamino)phenyl imine 3 was obtained in a 76%
yield (Scheme 2).
Figure 1. Pharmaceutically important o-(dimethylamino)aryl
ketones.
The importance of o-(dimethylamino)aryl ketones en-
couraged us to evaluate the scope of this novel aryne
coupling reaction. Various hydrazones have been pre-
pared by reacting the corresponding aldehydes with 1,1-
dimethylhydrazine or 1-aminomorpholine in CH2Cl2 in
the presence of MgSO4 (Scheme 3).17 The yields of the
hydrazones have ranged from 60 to 98%.
Scheme 2. Imine Formation from an Aldehyde-Derived
Hydrazone
Scheme 3. Preparation of 1,1-Dialkylhydrazones
Formation of the acyclic product 3 can be rationalized as
follows (Scheme 2). 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 or its conjugate base, since the reaction also
proceeds in less acidic THF,12 although the yield of the
final product drops to 43%.
As expected, the imine formed can be easily hydrolyzed
to the corresponding ketone under aqueous HCl condi-
tions. Running the aryne coupling and hydrolysis reac-
tion in the same vessel, o-(dimethylamino)phenyl ketone-
4 was isolated in a 93% yield (Table 1, entry 1). The
high efficiency and mild reaction conditions for this
overall transformation are of great importance, since
We first examined other 1,1-dimethylhydrazones. The
2-naphthyl-substituted substrate 9 provided the correspond-
ing ketone 10 in a 91% yield (Table 1, entry 2). Surprisingly,
the mesityl hydrazone 11 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 dem-
ethylated product 12 has been obtained in a 33% yield.18
The p-nitrobenzaldehyde hydrazone 13 provided the
corresponding ketone 14 in an 88% yield (entry 4). In a
(13) (a) Olah, G. A. FriedelꢀCrafts and Related Reactions; Wiley-
Interscience: New York, 1963. (b) Batt, D. G.; Goodman, J.; Jones, D. G.;
Kerr, J. S.; Mantegna, L. R.; McAllister, C.; Newton, R. C.; Nurnberg, S.;
Welch, P. K.; Covington, M. B. J. Med. Chem. 1993, 36, 1434.
(14) Reux, B.; Nevalainen, T.; Raitio, K. H.; Koskinen, A. M. P.
Bioorg. Med. Chem. 2009, 17, 4441.
(15) Casey, A. C.; Malhotra, A. Tetrahedron Lett. 1975, 401.
(16) Ueno, S.; Chatani, N.; Kakiuchi, F. J. Am. Chem. Soc. 2007, 129,
6098.
(11) Jana, S.; Clements, M. D.; Sharp, B. K.; Zheng, N. Org. Lett.
2010, 12, 3736.
(17) Petroski, R. J. Synth. Commun. 2006, 36, 1727.
(18) The synthesis of N-methylindazoles based on this transforma-
tion will be reported in the near future.
(12) Switching the solvent to THF had a major impact in our
previously reported work: Dubrovskiy, A. V.; Larock, R. C. Org. Lett.
2010, 12, 3117.
Org. Lett., Vol. 13, No. 15, 2011
4137

substituents on the efficiency of this transformation. A
messy mixture has been observed when the o-nitrobenzal-
dehyde substrate 15 (entry 5) was employed, but the
o-bromobenzaldehyde hydrazone 17 afforded the corre-
sponding aminoketone 18 in an 85% yield (entry 6).
Unfortunately, 2-alkynyl hydrazones did not provide
the desired aminoketones, but an inseparable mixture of
mostly unidentified products.19 However, alkenyl func-
tionality is tolerated in this transformation. Products 5
(entry 8) and 23 (entry 9) have been obtained in 91 and
77% yields respectively. It is noteworthy that the amino-
ketone 5 has been previously reported to exhibit significant
biological activity.13b
Table 1. Reaction of 1,1-Dimethylhydrazones with Arynesa
To our delight, despite benzyne’s electrophilic and die-
nophilic nature, the heterocyclic hydrazones 11 and 12
have undergone the transformation with good efficiency,
providing the 3-pyridyl (entry 10) and 2-furyl (entry 11)
ketones 25 and 27 in 55 and 90% yields respectively.
The nature of the hydrazone can be modified as well.
The 1-aminomorpholine-derived substrate 28 afforded the
corresponding ketone 29 in an 89% yield (entry 12).
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 8 in an 83% yield
(Table 1, entry 13). The regiochemistry of the product
affirms that it is the NMe2 group that initially attacks the
benzyne, not the nucleophilic carbon through the sub-
strate’s alternative resonance structure as is the case with
enamines3 (Scheme 4).20
Scheme 4. Reaction with an Unsymmetrical Aryne Precursor
We envisioned that the NMe2 group of the aminoke-
tones generated could further undergo an intramolecular
SNAr reaction if there was a favorably positioned leaving
group ortho tothe ketone. This leads to the formation ofN,
N-dimethylacridones, which undergo insitudemethylation
tothe more stable N-methylacridones inthe presence ofthe
nucleophilic fluoride media. The latter is a prominent
naturally occurring scaffold21 with many of its members
exhibiting a wide range of biological activity, including
antitumor,22 antimalarial,23 and antiplasmodial24 activities.
a Reaction conditions: 0.25 mmol of substrate, 1.1 equiv of benzyne
precursor, and 3.0 equiv of CsF in 5 mL of CH3CN were heated in a
closed vial at 65 °C for 10 h. Then 3 mL of 1 M HCl were added, and the
mixture was heated at 65 °C for 2 h. b Isolated yield. c 3-Methoxy-
2-(trimethylsilyl)phenyl triflate was used as the aryne precursor. d See the
Supporting Information for the structure determination of this product.
(19) One of the identified products appeared to be diphenyl-
methylamine.
(20) For an explanation of the reactivity of the unsymmetrical
monomethoxy benzyne, see ref 1.
(21) Prager, R. H.; Williams, C. M. Sci. Synth. 2005, 15, 1029.
(22) David-Cordnonnier, M.-H.; Laine, W.; Gaslonde, T.; Michel,
similar manner, the p-methoxybenzaldehyde hydrazone 19
provided the product 20 in a 91% yield (entry 7). These
results suggest that there is very little electronic effect of the
ꢀ
ꢀ
S.; Tillequin, F.; Koch, M.; Leonce, S.; Pierre, A.; Bailly, C. Curr. Med.
Chem.: Anti-cancer Agents 2004, 4, 83.
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Org. Lett., Vol. 13, No. 15, 2011

a solution of NaOMe and heating the mixture at 100 °C
presumably assists in dequaternarizing the initially formed
N,N-dimethylacridone. Excellent yields (91 and 94%) have
also been observed using the corresponding o-chloro-
and o-fluorobenzaldehyde hydrazones 31 (entry 2) and
32 (entry 3).
Table 2. Synthesis of N-Methylacridonesa
The use of the unsymmetrical 3-methoxy-2-(trimethylsilyl)-
phenyl triflate in the above transformation resulted in the
formation of a single regioisomer 33 in an 87% yield (entry
4) with a regioselectivity analogous to that described above
(Table 1, entry 13). It is noteworthy that compound 33 is a
naturally occurring acridone25 and its demethylated deri-
vative has been shown to exhibit anti-HIV activity.26 We
obtained the latter pharmaceutically important product in
a 94% yield after HI-induced demethylation of the acri-
done 33(i.e., ina 75% overall yield via 3 steps starting from
o-fluorobenzaldehyde).
In summary, we have developed a novel, efficient
route to o-(dimethylamino)aryl ketones and acridones
starting from readily available aryl-, heteroaryl-, and
alkenyl-substituted aldehydes,27 1,1-dimethylhydrazine,
and o-(trimethylsilyl)aryl triflates. In the formation of
o-(dimethylamino)aryl ketones, the reaction proceeds
through a cyclizationꢀring opening pathway with forma-
tion of a dihydroindazole intermediate. In the case of
acridones, the initial transformation is followed by an
additional intramolecular SNAr reaction and demethyla-
tion. The method should prove useful for the preparation
of these biologically and pharmaceutically important
structures. A variety of functional groups are compatible
with the reaction conditions. Further studies on the scope
of the method and its applications are in progress.
a Reaction conditions: 0.25 mmol of substrate, 1.1 equiv of benzyne
precursor, and 3.0 equiv of CsF in 5 mL of CH3CN were heated in a
closed vial at 65 °C for 10 h. Then 3 mL of 1 M HCl were added, and the
mixture was heated at 100 °C for 2 h. Then 5 mL of 1 M NaOMe were
added, and the mixture was heated at 100 °C for 2 h. b Isolated yield.
c 3-Methoxy-2-(trimethylsilyl)phenyl triflate was used as the aryne
precursor.
To our delight, a closer examination of the reaction
of the o-bromobenzaldehyde hydrazone (Table 1, entry 6)
indicated that, along with the 85% yield of the aminoketone
18, N-methylacridone was generated in a 7% yield. Upon
heating the o-aminoketone 18 in CH3CN at 100 °C, the
ketone quantitatively cyclized to the desired acridone.
After optimizing the reaction conditions, we found that
N-methylacridone 30 could be obtained in one pot in a
95% yield (Table 2, entry 1) by reacting the o-bromoben-
zaldehyde hydrazone 17 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
Acknowledgment. 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
noncommercially available aryne precursors.
(23) Basco, L. K.; Mitaku, S.; Skaltsounis, A. L.; Ravelomanantsoa,
N.; Tillequin, F.; Koch, M.; Le Bras, J. Antimicrob. Agents Chemother.
1994, 38, 1169.
(24) KamdemWaffo, A. F.;Coombes, P. H.;Crouch, N. L.;Mulholland,
D. A.; El Amin, S. M. M.; Smith, P. J. Phytochem. 2007, 68, 663.
(25) Rosza, Z.; Szendrei, K.; Kovacs, Z.; Novak, I.; Minker, E.
Phytochem. 1978, 17, 169.
Supporting Information Available. Detailed experimen-
tal procedure and characterization data for all products.
This material is available free of charge via the Internet at
http://pubs.acs.org.
(26) Fujiware, M.; Okamoto, M.; Okamoto, M.; Watanabe, M.;
Machida, H.; Shigeta, S.; Konno, K.; Yokota, T.; Baba, M. Antiviral
Res. 1999, 43, 189.
(27) The unusual reaction of the hydrazones derived from alkyl
aldehydes will be reported in due course.
Org. Lett., Vol. 13, No. 15, 2011
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