Insertion of benzene rings into the amide bond: one-step synthesis of acridines and acridones from aryl amides

Article abstract of DOI:10.1021/ol902568x

"Chemical Equation Presented" Insertion of benzene rings into the amide bond using the reactive intermediate benzyne is described. Aromatic amides undergo smooth insertion when treated with O-triflatophenyl silane benzyne precursors, producing versatile a

Full text of DOI:10.1021/ol902568x

ORGANIC
LETTERS
2010
Vol. 12, No. 1
168-171
Insertion of Benzene Rings into the Amide
Bond: One-Step Synthesis of Acridines
and Acridones from Aryl Amides
Didier G. Pintori and Michael F. Greaney*
School of Chemistry, UniVersity of Edinburgh, King’s Buildings, West Mains Rd,
Edinburgh EH9 3JJ, U.K.
Michael.Greaney@ed.ac.uk
Received November 5, 2009
ABSTRACT
Insertion of benzene rings into the amide bond using the reactive intermediate benzyne is described. Aromatic amides undergo smooth
insertion when treated with O-triflatophenyl silane benzyne precursors, producing versatile aminobenzophenone products in good to excellent
yield. The process is entirely metal-free and has been exemplified on the synthesis of biologically active acridones and acridines.
The insertion of a benzene ring into amide bonds represents
a powerful synthetic and topological transformation. The
amide bond is split to form one new aryl C-N and one aryl
C-C bond, forming aminobenzophenone products of fun-
damental importance in the synthesis of biologically active
heterocycles such as benzodiazepines, quinolines, and acri-
dones. While a number of multistep processes for the
transformation can be envisaged,1 a one-step, general method
has yet to be developed. A possible solution to the problem
is to employ the reactive intermediate benzyne in a σ-inser-
tion reaction.2,3 The weakly nucleophilic amide nitrogen can
attack the reactive aryne molecule, forming a zwitterion
intermediate 2, which can rearrange through the intermediacy
of a transient azetidinium ion 3 to produce the desired
aminobenzophenone 4 (Scheme 1).
Scheme 1. Aryne Insertion into the Amide Bond
(1) (a) MacNeil, S. L.; Wilson, B. J.; Snieckus, V. Org. Lett. 2006, 8,
1133–1136. (b) Ding, F.; Zhang, Y.; Qu, B.; Li, G.; Farina, V.; Lu, Z. B.;
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(2) Review Pen˜a, D.; Pe´rez, D.; Guitia´n, E. Angew. Chem., Int. Ed. 2006,
45, 3579–3581
.
The amide insertion reaction has been demonstrated by
Larock for one specific substrate class, activated trifluoro-
acetanilides (R2 ) CF3).4 This valuable precedent, taken with
(3) Recent examples of aryne σ-insertion reactions: (a) Krishnan, S.;
Bagdanoff, J. T.; Ebner, D. C.; Ramtohul, Y. K.; Tambar, U. K.; Stoltz,
B. M. J. Am. Chem. Soc. 2008, 130, 13745–13754. (b) Yoshida, H.; Kishida,
T.; Watanabe, M.; Ohshita, J. Chem. Commun. 2008, 45, 5963–5965. (c)
Yoshida, H.; Morishita, T.; Ohshita, J. Org. Lett. 2008, 10, 3845–3847. (d)
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See also: Yoshida, H.; Shirakawa, E.; Honda, Y.; Hiyama, T. Angew. Chem.,
Int. Ed. 2002, 41, 3247–3249.
1308–1310
.
10.1021/ol902568x  2010 American Chemical Society
Published on Web 12/02/2009

our own interest in new aryne-based methods,5 encouraged
us to develop an amide insertion reaction having broad utility.
Table 1. Amide Insertion
Using the versatile O-triflato silane 5a (R3 ) H) as the
aryne precursor,6 a survey of reaction solvents and fluoride
sources established the viability of the reaction for N-
pivaloylaniline 1a (Table 1, entry 1). Stirring in toluene in
the presence of tetrabutylammonium triphenyldifluorosilicate
(TBAT) triggered a clean insertion at 50 °C, affording the
tert-butylketone 4a in 64% yield. Exploration of substrate
scope7 showed the reaction to be general for a variety of
aniline derivatives, enabling the preparation of diverse
electron-poor and electron-rich aminobenzophenones in very
good yield (entries 1-10). In each case the N-pivaloyl and
N-phenyl derivatives were similarly efficient substrates. The
aryne insertion reaction offers a new entry point to tert-
butylarylketones that is operationally simple and does not
require any metal reagents. Literature routes to this com-
pound class are somewhat restricted and invariably use
stoichiometric organometallics.8
Trifluoroacetanilides, previously investigated by Larock,
were excellent substrates for the reaction, with the sterically
hindered trifluoromethyl amide 1k undergoing insertion in
very high yield (entry 11). The reaction was also effective
for N-heteroaroyl substrates, with the furoyl derivative 1l
undergoing tandem furan Diels-Alder reaction and insertion
in high yield when treated with an excess of benzyne (entry
12). The structure of the highly functionalized product 4l
was secured by X-ray crystallography.
We next examined substituted arynes in the reaction with
N-phenylbenzamide (entries 13-15). The electron-rich me-
thylenedioxy aryne 5b underwent smooth insertion to
produce the oxygenated benzophenone 4m (entry 13). The
unsymmetrical aryne precursors 5c and 5d produced insertion
adducts as single regioisomers (entries 14 and 15), assigned
as drawn on the basis of well-known selectivities in nucleo-
philic additions to unsymmetrical arynes.9 Finally, we
examined the two imide derivatives 1m and 1n in the
reaction, an important substrate class as it permits the
preparation of protected amino ketones as versatile building
blocks for heterocycle synthesis (Scheme 2). Insertion was
selective for the amide over the carbamate linkage in both
cases, providing the Boc and CBz-protected amines 4p and
4q in 70% and 75% yield, respectively.
We exemplified the power of the reaction as a rapid entry
point to nitrogenated heteroaromatics by developing a
divergent synthesis of acridones and acridines. These tricyclic
aza-arenes are important targets in medicinal and materials
chemistry having multifaceted biological (e.g., antimalarial,
(5) (a) Cant, A. A.; Bertrand, G. H. V.; Henderson, J. L.; Roberts, L.;
Greaney, M. F. Angew. Chem., Int. Ed. 2009, 48, 5199–5202. (b) Henderson,
J. L.; Edwards, A. S.; Greaney, M. F. Org. Lett. 2007, 9, 5589–5592. (c)
Henderson, J. L.; Edwards, A. S.; Greaney, M. F. J. Am. Chem. Soc. 2006,
128, 7426–7427.
(6) Himeshima, Y.; Sonoda, T.; Kobayashi, H. Chem. Lett. 1983, 1211–
1214.
(7) See Supporting Information.
a Isolated yields. Reaction conditions: amide (0.25 mmol), TBAT (0.50
mmol), and 5 (0.375 mmol) in toluene (3 mL); 50 °C for 16 h. b 2.8 equiv
of 5a added.
(8) (a) D´ıaz-Valenzuela, M. B.; Phillips, S. D.; France, M. B.; Gunn,
M. E.; Clarke, M. L. Chem.sEur. J. 2009, 15, 1227–1232. (b) Koreeda,
T.; Kochi, T.; Kakiuchi, F. J. Am. Chem. Soc. 2009, 131, 7238–7239.
(9) Sanz, R. Org. Prep. Proced. Int. 2008, 40, 215–291.
Org. Lett., Vol. 12, No. 1, 2010
169

Scheme 2. Imide Insertion
Table 2. Acridone and Acridine Synthesis
anticancer), optical, and redox properties.10 Acridones were
accessed from readily available o-halobenzamides through
initial aryne σ-insertion, followed by an in situ SNAr reaction
(Scheme 3).
Scheme 3. Divergent Synthesis of Acridones and Acridines
We developed a single-step method using just 5 min of
microwave irradiation at 120 °C in the presence of TBAT
(Table 2, entries 1-5). The compatibility of precursors 5
with microwave heating has recently been remarked upon
and is testament to their superb versatility in aryne chem-
istry.11 Yields of acridones were generally excellent; in the
case of the 3-methyl aryne precursor 5d, a 1:1 mixture of
regioisomeric acridones was isolated, underlining the inter-
mediacy of the reactive aryne intermediate in the reaction
(entry 4).12
We could divert the insertion product to the acridine
structure 7 through Lewis acid mediated intramolecular
Friedel-Crafts acylation and dehydration. Again, the ver-
satility of the aryne precursors enabled the development of
a one-pot procedure: adding BF3·OEt2 to the reaction mixture
following insertion and increasing the reaction temperature
to 80 °C produced good yields of diverse acridine products
(Table 2, entries 6-10). Each synthesis incorporates the
aryne moiety into the heterocycle framework and can be
directed toward the display of either N-aryl (acridones) or
C-aryl (acridines) groups according to the cyclization condi-
tions.
a Isolated yields. Reaction conditions: for acridones, amide (0.25 mmol),
TBAT (0.75 mmol), and 5 (0.75 mmol) in toluene (3 mL); 120 °C, 5 min;
for acridines, amide (0.25 mmol), TBAT (0.50 mmol), and 5 (0.425 mmol)
in toluene (3 mL); 50 °C, 16 h, then BF3·Et2O (0.50 mmol), 80 °C, 4 h.
b 1:1 mixture of regioisomers.
Insertion substrates containing hydrogens adjacent to the
amide bond generally underwent preferable N-phenylation
under the reaction conditions. Given that the first step of
the σ-insertion reaction is proceeding, the failure to rearrange
may be due to an intramolecular proton abstraction in the
zwitterion 2 quenching the reaction (Scheme 1).13 To gain
(10) Kelly, J. X.; Smilkstein, M. J.; Brun, R.; Wittlin, S.; Cooper, R. A.;
Lane, K. D.; Janowsky, A.; Johnson, R. A.; Dodean, R. A.; Winter, R.;
Hinrichs, D. J.; Riscoe, M. K. Nature 2009, 459, 270–273.
(11) (a) Ankati, H.; Biehl, E. Tetrahedron Lett. 2009, 50, 4677–4682.
(b) Zhang, F.; Moses, J. E. Org. Lett. 2009, 11, 1587–1590.
(12) For an alternative acridone synthesis involving aryne addition to
aminobenzophenones, see: Zhao, J.; Larock, R. C. J. Org. Chem. 2007, 72,
583–588.
170
Org. Lett., Vol. 12, No. 1, 2010

insight into the mechanism, we carried out deuterium labeling
studies using N-phenylpropionamide 1u (Scheme 4). Stirring
The incorporation of deuterium in the aryl ring of 10
implicates 1,5-hydrogen abstraction as a minority quenching
mechanism for alkyl-substituted amide substrates. The major
quenching pathway is likely from transfer of the amide proton
to the phenyl anion, confirmed by reacting the N-D derivative
of 1u with benzyne and observing deuterium incorporation
into the aryl ring of the product.7
Scheme 4. Deuterium Labelling Studies
In conclusion, we have developed an aryne σ-insertion
reaction for the ubiquitous aryl amide and imide functional
groups. The process is high-yielding and operationally simple
and uses no metal reagents. The process has been applied to
the one-pot synthesis of acridones and acridines; further
applications to biologically relevant targets are underway in
our group.
under the standard conditions of TBAT for 16 h, followed
by aqueous workup, produced the N,N-diphenyl compound
9 in high yield. Repeating the reaction with a D2O quench
produced the same result, as did running the reaction in d6-
benzene as reaction solvent. Repeating the reaction using
the doubly deuterated derivative 1v produced an identical
yield of the N,N-diphenyl compound, as a ca. 1: 2 mixture
of 10 and 11.
Acknowledgment. We thank the University of Edinburgh
for the award of a studentship to D.G.P. and the EPSRC
mass spectrometry service at Swansea. Dr. Fraser White is
thanked for X-ray crystallography.
Supporting Information Available: Experimental pro-
cedures and characterization data for all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
(13) A similar intramolecular quenching mechanism has been identified
in the aza-Fries rearrangement of iodoarylamides when treated with butyl
lithium; see ref 1b.
OL902568X
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