α-nitrogen activating effect in the room temperature copper-promoted N-arylation of heteroarylcarboxamides with phenyl siloxane or p-toluylboronic acid

Article abstract of DOI:10.1016/S0040-4039(01)00203-9

Heteroarylcarboxamides containing α-nitrogens undergo copper-promoted N-phenylation with hypervalent phenyl trimethylsiloxane at room temperature, in the absence of base and in air. Arylboronic acid can substitute for phenyl trimethylsiloxane as the organ

Full text of DOI:10.1016/S0040-4039(01)00203-9

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 2427–2429
a-Nitrogen activating effect in the room temperature
copper-promoted N-arylation of heteroarylcarboxamides with
phenyl siloxane or p-toluylboronic acid
Patrick Y. S. Lam,a,* Sophie Deudon,a Elisabeth Hauptmanb and Charles G. Clarka
aDuPont Pharmaceuticals Co., Experimental Station, PO Box 80500, Wilmington, DE 19880-0500, USA
bThe DuPont Company, Central Research and Development Department, PO Box 80328, Experimental Station, Wilmington,
DE 19880-0328, USA
Received 5 October 2000; revised 29 January 2001; accepted 30 January 2001
Abstract—Heteroarylcarboxamides containing a-nitrogens undergo copper-promoted N-phenylation with hypervalent phenyl
trimethylsiloxane at room temperature, in the absence of base and in air. Arylboronic acid can substitute for phenyl trimethylsilox-
ane as the organometalloid. The a-heteroatom chelating effect is in the decreasing order of N>O, S. This discovery opens up the
possibility of using other a-nitrogen functional groups to direct the N-arylation of peptides and simple amides under conditions
as mild as that of amide bond formation. © 2001 Dupont Pharmaceutical Company. Published by Elsevier Science Ltd. All rights
reserved.
There is a lack of mild (room temperature, no base and
air) methodologies for the N-arylation of amides using
readily available commercial starting materials. Recent
elegant work by Buchwald1 and Shakespeare2 has
demonstrated the palladium catalyzed N-arylation of
amides with aryl halides. The former occurs at 45–
100°C in the presence of cesium carbonate. The latter
occurs at 120°C with sodium tert-butoxide. Hartwig3
has also reported an analogous N-arylation of carba-
mates. In the search for a mild N-arylation methodol-
ogy for benzamides, we discovered that hypervalent aryl
trimethylsiloxane is an efficient arylating agent for 2-
picolinamide 1 in the presence of copper(II) acetate at
room temperature4 (Scheme 1). This is an extension of
the copper-promoted CꢀN/CꢀO bond cross-coupling
with arylboronic acids first reported by Chan, Evans
and Lam.5 Many applications of this new methodology
have been reported recently.6,7 However, in contrast to
the initial report,5d simple and common amides such as
alkylamides6a and benzamides (vida infra) do not
undergo N-arylation. We decided to investigate the
reason for the ease of N-arylation of 2-picolinamide 1.
The reaction involves the addition of a stoichiometric
amount of tetrabutylammonium fluoride (TBAF) to
phenyl trimethylsiloxane in the presence of 2-picoli-
namide 1 and copper(II) acetate in methylene chloride
and is allowed to react at room temperature for 2 days.8
N-Phenyl-2-picolinamide 2 was obtained in 61% yield.
Benzamide 3, in contrast to compound 1, gave only 9%
yield of 4 upon heating at 70°C (Table 1). 3-Picoli-
namide 5 and 4-picolinamide 7 are very poor sub-
strates. There appears to be a beneficial chelating effect
of the nitrogen alpha to the amide group of 2-picoli-
namide in the formation of a copper intermediate
according to our proposed mechanism of N-arylation4
(Scheme 2).
H
N
PhSi(OMe)3 / Cu(OAc)2 / TBAF
DMF / RT
NH2
N
N
61%
O
O
1
2
Scheme 1. N-Phenylation of 2-picolinamide with hypervalent phenyl trimethylsiloxane.
* Corresponding author. E-mail: patrick.y.lam@dupontpharma.com
0040-4039/01/$ - see front matter © 2001 Dupont Pharmaceutical Company. Published by Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)00203-9

2428
P. Y. S. Lam et al. / Tetrahedron Letters 42 (2001) 2427–2429
Table 1. Cross-coupling reactions of a-heteroarylcarbox-
amide 11 gave only 36 and 22% N-arylation, respec-
tively. After determining that nitrogen is the best
a-heteroatom, we investigated other a-nitrogen-con-
taining heteroarylcarboxamides. 2-Pyrazinecarboxam-
ide 13 yielded 52% of 14. 2-Imidazoylcarboxamide 15
gave 50% yield of a mixture of 16 and 17 (2:1). 4-Oxa-
zolylcarboxamide 18, on the other hand, gave only 27%
yield of 19, probably because of the electron-withdraw-
ing oxygen reducing the nitrogen chelating effect. In
contrast, 4-thiazolylcarboxamide 20 and 3-isothiazolyl-
carboxamide 22 gave 64 and 73% yields, respectively.
amides with phenyl siloxane
% Isolated
Yields
Substrates
Products
Entry
H
N
NH2
N
61%
1
N
O
O
1
2
4
6
8
H
N
NH2
9%a
2
3
4
5
6
7
O
3
5
O
O
O
O
We have previously demonstrated that both aryl-
boronic acids and hypervalent aryl siloxanes are
efficient organometalloids for copper-promoted CꢀN
cross-coupling reactions.4,5 As expected, p-toluyl-
boronic acid can replace phenyl trimethylsiloxane to
give 44% yield of 24 (Scheme 3).
H
N
N
N
N
N
<14%a
<12%a
36%
NH2
NH2
NH2
O
O
H
N
7
9
Instead of stoichiometric Cu(OAc)2, Collman7c
H
N
has
recently
demonstrated
that
catalytic
[Cu(OH)·TMEDA]2Cl2 can replace Cu(OAc)2 to pro-
mote our CꢀN bond cross coupling of arylboronic acids
and imidazoles under an oxygen atmosphere. By using
10 mol% of [Cu(OH)·TMEDA]2Cl2 instead of 100
mol% Cu(OAc)2, we found that the cross coupling
between phenyl trimethylsiloxane and 2-picolonamide
gave 45% yield of 2 in air. An oxygen atmosphere did
not appear to increase the yield.
O
O
S
O
10
12
14
H
N
NH2
22%
52%
S
O
O
11
13
H
N
N
N
N
NH2
N
N
O
O
In summary, we have discovered that heteroarylcarbox-
amides containing a-nitrogen can undergo copper-pro-
moted N-phenylation with hypervalent phenyl
trimethylsiloxane at room temperature, in the absence of
base and in air. Arylboronic acid can substitute for
phenyl trimethylsiloxane as the organometalloid.9 The
a-heteroatom chelating effect is in the decreasing order
of N>O, S. This discovery opens up the possibility of
using other a-nitrogen functional groups to direct the
N-arylation of peptides and simple amides under condi-
tions as mild as that of amide bond formation with no
risk of racemization as shown in Scheme 4.10 The key
feature is for one to find the optimal activating group A
for the a-amino group of peptides. Peptoids thus
derived should have interesting biological activities.
O
N
H
2
:
1
O
N
16
17
+
N
8
NH2
50%
O
N
15
N
N
N
O
O
O
N
N
H
N
NH2
NH2
27%
64%
73%
9
O
O
19
18
20
22
O
N
N
NH
10
11
S
S
21
23
O
O
Acknowledgements
NH2
N
H
N
N
S
S
aReaction heated at 70˚C
We thank Dr. Paul S. Anderson and Dr. Ruth R.
Wexler for their support of this research and Professor
Philip DeShong and Professor David A. Evans for
helpful discussions.
Other heteroatoms were investigated and it was found
that 2-furanylcarboxamide 9 and 2-thiophenylcarbox-
H
O
N
O2
H
II
Cu
N
N
Reductive Elimination
N
OAc
O
2
Scheme 2. a-Nitrogen chelating effect.

P. Y. S. Lam et al. / Tetrahedron Letters 42 (2001) 2427–2429
2429
B(OH)2
H
NH2
N
N
N
Cu(OAc)2 / pyridine / CH2Cl2
44%
O
O
4Å molecular sieves / RT
1
24
Scheme 3. N-Arylation of 2-picolinamide with p-toluylboronic acid.
Activation
O
R
Ar
A2N
R'
H2N
Ar
N
H
N
Iterative amidation,
H2N
N
1. N-arylation
N
peptide
n
peptide
R'
peptide
R' Ar'
O
N-arylation and
removal of A
2. Removal
of A
O
O
Peptoids with selective
N-aryl groups
A = activating and
protecting group
Scheme 4. Proposed N-arylation of peptides.
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