tert-butyl amine,4 benzyl amine,4e,5 allyl amine,6 and
others,7 which upon workup or simple deprotection would
release the primary amide functionality. Alternatively, the
nongaseous precursors for both CO and ammonia. CO
was successfully applied in near-stoichiometric and sub-
stoichiometric quantities making this approach suitable
for 13C-isotope labeling using a 13C-labeled acid chloride
as the CO-source.
€
groups of Bernard and Skoda-Foldes utilized the in situ
release of ammonia from solid precursors such as NH4Cl
and ammonium carbamate.1,8 Especially, the method
developed by Larhed et al. deserves attention, whereby
Mo(CO)6 acts as the source of CO while simultaneously
performing the in situ reduction of hydroxylamine to
ammonia during the palladium-catalyzed formation of
primary amides under microwave irradiation.9 Other
methods utilize the decomposition of formamides into
CO and ammonia/amines; however, this decomposition
only occurs at high temperatures in the presence of strong
bases.10
Table 1. Optimization of the Aminocarbonylationa
[NH3]/
equiv
CO/
base/
equiv
conv [%]b/
(yield) [%]
entry
mmol
L
1 c,d
2 c,d
3 c,d
4 c,d
5d
1
0.5
3
3
3
4
4
4
4
4
4
4
4
4
4
NaOAc (1.3)
81 (62)
71
Scheme 1. Ex situ Generation of CO for the Synthesis of Primary
Amides in a Two-Chamber System
1.1
1.1
1
0.5
NaOAc (1.4)
0.75
0.33
0.33
0.33
0.33
0.33
0.33
0.33
0.65
0.65
0.65
NaHCO3 (1.4)
NaHCO3 (1.4)
NaHCO3 (1.3)
NaHCO3 (1.3)
NaHCO3 (1.3)
NaHCO3 (2.2)
Na2CO3 (2.2)
NaHCO3 (1.4)
NaHCO3 (1.3)
NaHCO3 (1.3)
NaHCO3 (1.3)
100 (62)e
29e
1
51e
6
7d
2
88e
2
68e
8
2
74e
9
2
61e
10
1.1
1.3
1.3
1.3
86e
11
95 (93)
93
12f
13g
38
a Chamber A: 1 (0. Y mmol), Pd(dba)2 (5 mol %), HBF4P(tBu)3
(5 mol %), DIPEA (1.5 equiv) in dioxane (3 mL). Chamber B: Iodo-
anisole or bromoanisole (0.5 mmol), Pd(dba)2 (5 mol %), L (5 mol %) in
dioxane (3 mL). b Determined by 1H NMR analysis. c Iodoanisole used
as the electrophile. d Reaction performed at 80 °C. e Based on limiting
CO. f Pd(dba)2 (3 mol %), 4 (3 mol %) g Pd(dba)2 (1 mol %), 4 (1 mol %).
Recently we reported on a novel approach to the safe
release, handling, and incorporation of CO from a solid
acid chloride precursor such as 1 in a sealed two-chamber
system.11 CO is produced ex situ, which avoids the com-
plication of having the CO-precursor or CO-synthon
mixed in with the reagents and thereby retaining a high
chemical scope in CO-chemistry (Scheme 1). Already
having established the method in carbonylative MizorokiÀ
Heck couplings12 as well as alkoxy- and aminocarbo-
nylations and inspired by the above-mentioned ammonia
synthons, we set forth to investigate its application for the
synthesis of primary amides.
The conditions required for the palladium-catalyzed
CO-production in chamber A by decarbonylation of 1
were taken directly from our previous reports (Scheme 1
and Table 1).11,12 Initial screenings were performed using
iodoanisole as the electrophile applying NH4Cl and am-
monium carbonate13 as the ammonia precursors. Testing
PPh3 and DPPF as ligands in combination with bases such
as triethylamine, diisopropylethylamine (DIPEA), or po-
tassium carbonate at 80 °C did lead to the desired amide
albeit in low yields (results not shown). Changing the
ammonia precursor to ammonium carbamate as reported
In this paper, we wish to report a protocol for the for-
mation of primary amides based on palladium-catalyzed
aminocarbonylation of aromatic bromides using solid
(6) Appukkuttan, P.; Axelsson, L.; Eycken, E.; Van der.; Larhed, M.
Tetrahedron Lett. 2008, 49, 5625.
(7) Ueda, K.; Sato, Y.; Mori, M. J. Am. Chem. Soc. 2000, 122, 10722.
ꢀ
ꢀ
ꢀ
€
(8) Balogh, J.; Maho, S.; Hada, V.; Kollar, L.; Skoda-Foldes, R.
Synthesis 2008, 19, 3040.
(9) Wu, X.; Wannberg, J.; Larhed, M. Tetrahedron 2006, 62, 4665.
(10) (a) Wan, Y.; Alterman, M.; Larhed, M.; Hallberg, A. J. Comb.
Chem. 2003, 5, 82. (b) Wan, Y.; Alterman, M.; Larhed, M.; Hallberg, A.
J. Org. Chem. 2002, 67, 6232. (c) Schnyder, A.; Beller, M.; Mehltretter,
G.; Nsenda, T.; Studer, M.; Indolese, A. F. J. Org. Chem. 2001, 66, 4311.
(11) Hermange, P.; Lindhardt, A. T.; Taaning, R. H.; Bjerglund, K.;
Lupp, D.; Skrydstrup, T. J. Am. Chem. Soc. 2011, 133, 6061.
(12) Hermange, P.; Gøgsig, T. M.; Lindhardt, A. T.; Taaning, R. H.;
Skrydstrup, T. Org. Lett. 2011, 13, 2444.
(13) Ammonium carbonate can either liberate 1 equiv of ammonia by
reaction with base or two from the thermal decomposition of this salt.8
In any case, all reactions were performed behind a blast shield (see
Supporting Information). It should be noted though that no amide
formation from the reaction of acid chloride 1 with ammonia was
observed in the CO producing chamber in any of the reactions studied,
suggesting that the release of CO is significantly faster than the nucleo-
philic acyl substitution reaction.
Org. Lett., Vol. 13, No. 16, 2011
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