LETTER
▌85
lAettePr hosphine-Free Approach to Primary Amides by Palladium-Catalyzed
Aminocarbonylation of Aryl and Heteroaryl Iodides Using Methoxylamine
Hydrochloride as an Ammonia Equivalent
Carbonylative Cross-Coupling Reactions
Sandip T. Gadge, Bhalchandra M. Bhanage*
Department of Chemistry, Institute of Chemical Technology, N. Parekh Marg, Matunga, Mumbai 400 019, India
Fax +91(22)33611020; E-mail: bm.bhanage@gmail.com; E-mail: bm.bhanage@ictmumbai.edu.in
Received: 29.08.2013; Accepted after revision: 30.09.2013
system.10a In 2006, Larhed and co-workers used hydrox-
ylamine hydrochloride as an ammonia equivalent along
Abstract: The palladium-catalyzed synthesis of primary amides by
aminocarbonylation of aryl and heteroaryl iodides under phosphine-
free conditions is reported for the first time. Methoxylamine hydro-
with Herrmann’s palladacycle and [(t-Bu) PH]BF as an
3
4
chloride, acting as an ammonia equivalent, undergoes sequential additional ligand, and 1,8-diazabicyclo[5.4.0]undec-7-
carbonylation and demethoxylation under mild reaction conditions. ene (DBU) and N,N-diisopropylethylamine (DIPEA)
1
0b
The procedure does not require a phosphine ligand and takes place
in short reaction times at low temperatures to provide the products
in excellent yields.
as bases.
Furthermore, Xu and Alper used
®
Pd(OAc) /CYTOP 292 along with aqueous ammonia for
the aminocarbonylation of aryl iodides. However, the
2
10c
Key words: amides, carbonylation, palladium, catalysis, phos-
phine-free, cross-coupling
principal drawbacks of all these reported methods are the
low stabilities, poor availability, and cost of the palladium
complexes and phosphine ligands. Phosphine-free cross-
coupling reactions have been investigated because of their
reduced toxicity and cost burden, and the easier isolation
Primary aromatic and heteroaromatic amides constitute
important classes of compounds due to their inherent bio-
activity and the occurrence of this functional group in a
1
1
of the product from the reaction mixture.
Based on our research interest in phosphine-free carbon-
1
plethora of biologically important compounds. Primary
1
2
ylation reactions, we herein report an efficient palladi-
um-catalyzed, phosphine-free protocol for the synthesis
of aromatic primary amides using methoxylamine hydro-
chloride as an ammonia equivalent (Scheme 1). Key to
this success was the use of a palladium(II) chloride–sodi-
um iodide (PdCl –NaI) catalytic system in the presence of
,4-diazabicyclo[2.2.2]octane (DABCO) as the base. This
protocol tolerates a wide range of functional groups and is
applicable to aromatic and heteroaromatic substrates, pro-
viding excellent yields of products under mild reaction
conditions.
amides act as synthetic platforms for further functional-
2
ization into primary amines by reduction, or into nitriles
3
by dehydration. Traditionally, primary amides are syn-
thesized by the reaction of activated carboxylic acid deriv-
atives such as acid chlorides, anhydrides and esters with
4
2
amines, hydration of the corresponding benzonitriles, or
1
by oxidation of benzylamines, benzyl alcohols, or benzal-
5
dehydes. In addition, carbonylation chemistry can also
provide an alternative route for the synthesis of aromatic
primary amides. Compared to secondary and tertiary am-
ide synthesis, the preparation of aromatic primary amides
using carbonylation chemistry has not received similar at-
O
tention.1
PdCl , KI
DABCO, 90 °C, 8 h
2
I
O
X
NH2
+
CO + HCl⋅NH2
Me
X
Various catalysts and phosphine ligands have been em-
ployed for carbonylation, along with different ammonia
equivalents as nucleophilic partners. Such protocols have
used palladium catalysts–ammonia equivalent combina-
tions, such as [PdCl (PPh ) ] and hexamethyldisilazane
R
R
X = C, N, S
R = Me, OMe, NO2,
F, Cl, Br
2
3 4
6
(
HMDS), and [PdCl (PPh ) ] or [Pd(OAc) (dppf)] and Scheme 1 Synthesis of primary amides by aminocarbonylation
2 3 2 2
7
formamide. Beller and co-workers used gaseous ammo-
nia and Pd(OAc) /dppf or Pd(OAc) /nBuP(1-adamantyl)
2
2
2
Initially, we screened various palladium precursors using
iodobenzene as the model substrate for the optimization of
the reaction conditions (Table 1). Palladium(II) chloride
was found to be an effective catalyst in the presence of an
iodide such as sodium iodide, potassium iodide or tetrabu-
tylammonium iodide. In the absence of phosphine li-
gands, rapid deactivation of the catalyst takes place, but
the iodide ligand was found to be effective for maintain-
ing catalytic activity. The iodide can participate in several
different steps in reactions catalyzed by transition metals,
as the catalytic system for the synthesis of primary aro-
8
matic amides. Mori et al. employed Pd (dba) /dppf as a
2
3
catalytic system with titanium–nitrogen complexes as the
9
amine source. Skrydstrup reported the synthesis of pri-
mary aromatic amides using ammonium carbamate as an
ammonia source and Pd(dba) /JosiPhos as the catalytic
2
SYNLETT 2014, 25, 0085–0088
Advanced online publication: 05.11.2013
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1
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0
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DOI: 10.1055/s-0033-1340162; Art ID: ST-2013-D0832-L
Georg Thieme Verlag Stuttgart · New York
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