A facile N-arylation of acetanilides with arynes

Article abstract of DOI:10.1016/j.tetlet.2011.08.146

An efficient, mild and transition-metal-free method for the N-arylation of acetanilides, leading to a range of unsymmetrical diarylamine products is reported. Reactions of ortho-silylaryl triflates with acetanilides in the presence of tetrabutylammonium triphenyldifluorosilicate (TBAT) in toluene afforded the desired products in good to excellent yields. Regioselectivity was also observed when unsymmetrical aryne precursors were used.

Full text of DOI:10.1016/j.tetlet.2011.08.146

Tetrahedron Letters 52 (2011) 5847–5850
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A facile N-arylation of acetanilides with arynes
⇑
James C. Haber, Michael A. Lynch , Stacey L. Spring, Anthony D. Pechulis, Joseph Raker, Yi Wang
Medicinal Chemistry Department, Albany Molecular Research, Inc. (AMRI), PO Box 15098, 26 Corporate Circle, Albany, NY 12212, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient, mild and transition-metal-free method for the N-arylation of acetanilides, leading to a range
of unsymmetrical diarylamine products is reported. Reactions of ortho-silylaryl triflates with acetanilides
in the presence of tetrabutylammonium triphenyldifluorosilicate (TBAT) in toluene afforded the desired
products in good to excellent yields. Regioselectivity was also observed when unsymmetrical aryne pre-
cursors were used.
Received 20 July 2011
Revised 22 August 2011
Accepted 24 August 2011
Available online 31 August 2011
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Arynes
N-Arylation
Acetanilides
ortho-Silylaryl triflates
Tetrabutylammonium
triphenyldifluorosilicate
The development of efficient methods for the synthesis of N-
aryl amides has been an active area in organic chemistry due to
the abundance of amide moieties in biologically active molecules.1
The Goldberg reaction (copper-mediated N-arylation of amides
with aryl halides in the presence of CuI and K2CO3) was the first
method utilized to synthesize this class of compounds.2 However,
high temperatures (>200 °C) and often greater than stoichiometric
amounts of copper salts or copper metal were necessary to achieve
moderate yields of the cross-coupled products. More recently, sig-
nificant advances have been made in this area utilizing copper cat-
alysts with 1,2-diamine, diamine, b-ketoester, amino acid, and
hydrazone ligands.3 However, relatively high temperatures
(>100 °C) are still required and undesired reactivity with some li-
gands still pose limitations to the definition of generalized condi-
tions. To overcome these difficulties, palladium-catalyzed
methods were developed, which use sterically hindered phosphine
ligands to couple aryl halides with amides under relatively mild
conditions.4 However, the need to optimize the matching of cata-
lyst, ligand, solvent, and base to the appropriate substrate pair is
often required, and the sensitivity of some reagents to air and
moisture limits the scope of this process.
simple amides remains problematic under these conditions proba-
bly due to the fact that simple primary amides are often not nucle-
ophilic enough to directly attack benzyne.7 In
a recent
communication, Greaney6a described an N-arylation of N-phenyl-
propionamide in the context of a deuterium labeling study, which
is the only literature example of an acetanilide substrate undergo-
ing an intermolecular benzyne mediated N-arylation reaction re-
ported to date.8 Therefore, we felt that a simple and general
procedure to generate N-arylation products from simple acetani-
lides under mild conditions would be desirable. Herein, we de-
scribe the development of an efficient N-arylation of acetanilides
from arynes generated in situ along with the scope and limitations
of this transformation.
Our initial study focused on finding optimal conditions for the
N-arylation of phenyl acetamide (1a, Table 1). To our initial disap-
pointment, the reaction of 1a with benzyne precursor 2a in the
presence of cesium fluoride in toluene at 50 °C did not afford any
desired product 3a (Entry 1). In addition, under Larock’s conditions
(cesium fluoride in acetonitrile), only a trace amount of product
was observed (Entry 2). After several unsuccessful attempts utiliz-
ing various solvents (Entries 3–5), the combination of the alterna-
tive fluoride source tetrabutylammonium triphenyldifluorosilicate
(TBAT) in toluene, was the key to reproducibly achieve this reac-
tion in good yields (Entries 6–8). When 1.5 equiv of 2a and 2 equiv
of TBAT were used, the desired product was isolated in 68% yield
(Entry 6). Increasing the amount of TBAT to 3 equiv did not lead
to any improvement (Entry 7); however, higher amounts of both
TBAT and 2a afforded an 85% isolated yield of 3a (Entry 8).
With the optimized conditions in hand, the scope of this method
was studied by reacting a variety of acetanilides with ortho-silylaryl
Since Kobayashi reported a mild method for the in situ prepara-
tion of benzyne,5 much attention has been paid to applying ortho-
silylaryl triflates as benzyne precursors to a variety of synthetically
useful transformations.6 In particular, arylation of amines, sulfona-
mides, and carboxylic acids under very mild conditions were inten-
sively investigated by the Larock group.7 However, N-arylation of
⇑
Corresponding author.
E-mail address: michael.lynch@amriglobal.com (M.A. Lynch).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.08.146

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J. C. Haber et al. / Tetrahedron Letters 52 (2011) 5847–5850
Table 1
Optimization of reaction conditions
H
OTf
fluoride source
N
CH3
N
CH3
+
solvent
temperature
time
TMS
O
O
1a
2a
3a
Entry
2a (equiv)
Fluoride source (equiv)
Solvent
Temperature (°C)
Time (h)
Yield (%)
1
2
3
4
5
6
7
8
1.5
1.2
1.5
1.5
1.5
1.5
1.5
2
CsF (3)
CsF (2)
Toluene
MeCN
MeCN
DME
50
rt
12
12
20
24
24
24
24
18
0
Trace
Trace
Trace
Trace
68a
TBAT (2)
TBAT (2)
TBAT (2)
TBAT (2)
TBAT (3)
TBAT (4)
50
50
50
50
50
50
THF
Toluene
Toluene
Toluene
68a
85a
a
Isolated yield.
Table 2
Facile N-arylation of carboxamidesa
R1
OTf
R1
H
N
TMS
R2
N
R2
Ar
Ar
TBAT
O
O
toluene
50 ºC
1
3
OTf
OTf
OTf
H3C
TMS
TMS
TMS
OCH3
2a
2b
2c
Entry
Amide
Silylaryl triflate
Product
Time (h)
Isolated yield
H
N
CH3
O
N
O
CH3
1
2a
18
85%
1a
3a
H
N
CH3
O
Br
N
CH3
2
2a
18
81%
1b
O
N
Br
3b
H
N
CH3
O
H3CO
CH3
3
2a
24
72%
1c
O
H3CO
3c

J. C. Haber et al. / Tetrahedron Letters 52 (2011) 5847–5850
5849
Table 2 (continued)
Entry Amide
Silylaryl triflate
Product
Time (h)
Isolated yield
H
N
CH3
O
NC
N
CH3
4
2a
5
85%
1d
O
NC
3d
CF3
H
N
CH3
CF3
O
N
CH3
CH3
N
5
6
7
2a
2a
2a
12
57%
66%
78%
1e
O
3e
CH3
H
N
CH3
CH3
O
N
7
1f
O
3f
H
N
H3C
CH3
O
H3C
CH3
20
1g
O
3g
OCH3
CH3
8
1a
2b
N
28
70%
O
3h
CH3
83%
N
CH3
9
1d
2c
24
meta:para
1.2:1
O
NC
3i
a
Reaction conditions: 0.25 mmol of amide 1, 0.50 mmol of aryne precursor 2, 1.00 mmol of TBAT in 3 mL of toluene at 50 °C, also see Ref. 9.
triflates 2a–2c, the results of which are summarized in Table 2.9
Acetanilides of varying electronic characteristics, both electron
donating or withdrawing reacted very well with silylaryl triflate
2a to afford the desired products in good yields, with electron poor
acetanilides undergoing conversion much faster (Entries 4 and 5). It
is noteworthy that a bromo substituent (Entry 2), which is unlikely
to be tolerated under palladium-catalyzed coupling conditions, was
readily tolerated under our much milder protocol. The reaction ap-
pears to be sensitive to steric hindrance with Entries 5 and 6 show-
ing only moderate yields for ortho-substituted acetanilide
substrates. The regiochemistry of the arylation with unsymmetrical
arynes was also investigated. The reaction of methoxy substituted
silylaryl triflate 2b clearly generated a single regioisomer 3h as
the only product (Entry 8), which can be readily explained by steric
and electronic effects.7a,10 However, when the electronically neutral
N
CH3
NH
KOH
O
EtOH, H2O
70 ºC, 5 h
96%
Br
Br
4
3b
Scheme 1.
aryl triflate 2c was used, a mixture of 1.2:1 meta- and para-substi-
tuted regioisomers (determined by 1H NMR) was isolated (Entry 9).
This is not unexpected considering the distance of the methyl sub-

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J. C. Haber et al. / Tetrahedron Letters 52 (2011) 5847–5850
3. (a) Klapars, A.; Huang, X.; Buchwald, S. L. J. Am. Chem. Soc. 2002, 124, 7421; (b)
Klapars, A.; Antilla, J. C.; Huang, X.; Buchwald, S. L. J. Am. Chem. Soc. 2001, 123,
7727; (c) Mino, T.; Harada, Y.; Shindo, H.; Sakamoto, M.; Fujita, T. Synlett 2008,
614; (d) Ley, S. V.; Thomas, A. W. Angew. Chem., Int. Ed. 2003, 42, 5400; (e) Lv,
X.; Bao, W. J. Org. Chem. 2007, 72, 3863; (f) Hosseinzadeh, R.; Tajbakhsh, M.;
Mohadjerani, M.; Ghorbani, E. Chin. J. Chem. 2008, 26, 2120; (g) Monnier, F.;
Tailefer, M. Angew. Chem., Int. Ed. 2009, 48, 6954; (h) Surry, D. S.; Buchwald, S. L.
Chem. Sci. 2010, 1, 13.
4. (a) Hicks, J. D.; Hyde, A. M.; Cuezva, A. M.; Buchwald, S. L. J. Am. Chem. Soc. 2009,
131, 16720; (b) Fors, B. P.; Dooleweerdt, K.; Zeng, Q.; Buchwald, S. L.
Tetrahedron 2009, 65, 6576; (c) Shen, Q.; Hartwig, J. F. J. Am. Chem. Soc. 2007,
129, 7734; (d) Yin, J.; Buchwald, S. L. Org. Lett. 2000, 2, 1101; (e) Dooleweerdt,
K.; Fors, B. P.; Buchwald, S. L. Org. Lett. 2010, 12, 2350; (f) Surry, D. S.; Buchwald,
S. L. Angew. Chem., Int. Ed. 2008, 47, 6338.
5. Himeshima, Y.; Sonoda, T.; Kobayashi, H. Chem. Lett. 1983, 1211.
6. (a) Pintori, D. G.; Greaney, M. F. Org. Lett. 2010, 12, 168; (b) Liu, Z.; Larock, R. C. J.
Am. Chem. Soc. 2005, 127, 13112; (c) Jin, T.; Yamamoto, Y. Angew. Chem., Int. Ed.
2007, 46, 3323; (d) Liu, Z.; Larock, R. C. Angew. Chem., Int. Ed. 2007, 46, 2535; (e)
Liu, Z.; Larock, R. C. J. Org. Chem. 2007, 72, 223; (f) Zhao, J.; Larock, R. C. J. Org.
Chem. 2007, 72, 583; (g) Yoshida, H.; Kishida, T.; Watanabe, M.; Oshita, J. Chem.
Commun. 2008, 5963; (h) Tambar, U. K.; Stolz, B. M. J. Am. Chem. Soc. 2005, 127,
5340.
stituent from the in situ generated benzyne reacting center. It
should be pointed out that our attempts to extend this method to
additional substrates such as indolin-2-one were unsuccessful,
which we attributed to the complications of steric hindrance. We
also found that acetamide and benzamide failed to provide the cor-
responding N-aryl products using this method, which further sug-
gests that primary carboxamides are not sufficiently nucleophilic
enough to react with benzyne generated under these conditions.
The removal of the acetyl group from the nitrogen of N-aryl
acetanilide product 3b was also performed as proof of principle
for the utility of the protocol (Scheme 1). As expected, a diaryl-
amine product 4 was isolated in high yield, providing this unsym-
metrical diarylamine in a manner that should find its applicability
as a general method.
In summary, we developed an efficient, mild and transition-me-
tal-free method for the N-arylation of acetanilides that is tolerant
of a range of functional groups. This chemistry offers a convenient
and mild alternative method to metal-catalyzed protocols to afford
N-arylation products. Due to relative ease of removal of acetyl
group on nitrogen,11 this method should serve as a useful approach
to the preparation of many unsymmetrical diarylamines.12
7. (a) Liu, Z.; Larock, R. C. J. Org. Chem. 2006, 71, 3198; (b) Liu, Z.; Larock, R. C. Org.
Lett. 2003, 5, 4673.
8. For an intramolecular reaction between N-alkyl benzamides and substituted
benzynes to produce N-benzoylindolines, see: Gonzalez, C.; Perez, D.; Guitian,
E.; Catedo, L. J. Org. Chem. 1995, 60, 6318.
9. Typical procedure for the preparation of N,N-diphenylacetamide (3a):
A
mixture of 1a (34 mg, 0.250 mmol), 2a (149 mg, 0.500 mmol) and TBAT
(540 mg, 1.00 mmol) in toluene (3 mL) was stirred at 50 °C for 18 h. After this
time, the reaction mixture was cooled to ambient temperature and
concentrated under reduced pressure. The residue obtained was purified by
flash chromatography (silica, heptane to 2:3 ethyl acetate/heptane) to afford 3a
(45 mg, 85%) as an off-white solid: mp 73–75 °C; 1H NMR (300 MHz, DMSO-d6)
d 7.41–7.39 (m, 10H), 1.93 (s, 3H); 13C NMR (75 MHz, DMSO-d6) d 169.2, 143.2,
134.5, 129.2, 127.7, 23.3; ESI MS m/z 212 [M+H]+; HRMS ESI m/z [M+H]+ calcd
for C14H14NO: 212.1075; found: 202.1084.
Acknowledgments
Drs. R. Jason Herr and Keith D. Barnes are gratefully acknowl-
edged for helpful discussions and suggestions during the course
of this study.
References and notes
10. Kessar, S. V. In Comprehensive Organic Synthesis; Trost, B. M., Fleming, I., Eds.;
Pergamon Press: Oxford, England, 1991; Vol. 4, p 483.
11. Greene, T. W.; Wuts, P. G. M. Protecting Groups in Organic Synthesis, 3rd ed.;
John Wiley & Sons: New York, 1999. p 494.
12. (a) He, C.; Chen, C.; Cheng, J.; Liu, C.; Liu, W.; Lei, A. Angew. Chem., Int. Ed. 2008,
47, 6414; (b) Correa, A.; Carril, M.; Bolm, C. Chem. Eur. J. 2008, 14, 10919.
1. Negwer, M. Organic-Chemical, Drugs and their Synonyms: An International
Survey, 7th ed.; Akademie: Berlin, 1994.
2. (a) Goldberg, I. Chem. Ber. 1906, 39, 1691; (b) Kunz, K.; Scholz, U.; Ganzer, D.
Synlett 2003, 2428.