Synthesis of primary amides by aminocarbonylation of aryl/hetero halides using non-gaseous NH3 and CO sources

Article abstract of DOI:10.1016/j.tetlet.2015.06.054

Abstract A practically simple method for the synthesis of primary amides via the palladium-catalysed aminocarbonylation of aromatic halides by using solid sources of gaseous ammonia and carbon monoxide is described. The system tolerated a wide variety of hindered and functionalized aryl/hetero halides and afforded good to excellent yields (69-94%) of the amide. Pharmacologically active Exalamide and Pyrazinecarboxamide were synthesised in high yields to demonstrate the effectiveness of this method.

Full text of DOI:10.1016/j.tetlet.2015.06.054

Tetrahedron Letters xxx (2015) xxx–xxx
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Synthesis of primary amides by aminocarbonylation of aryl/hetero
halides using non-gaseous NH and CO sources
3
A. S. Suresh a,b, Poongavanam Baburajan b, , Mansur Ahmed a
⇑
a
Research Department of Chemistry, Islamiah College, Vaniyambadi 635752, India
Syngene International Limited, Bangalore 560099, India
b
a r t i c l e i n f o
a b s t r a c t
Article history:
A practically simple method for the synthesis of primary amides via the palladium-catalysed aminocar-
bonylation of aromatic halides by using solid sources of gaseous ammonia and carbon monoxide is
described. The system tolerated a wide variety of hindered and functionalized aryl/hetero halides and
afforded good to excellent yields (69–94%) of the amide. Pharmacologically active Exalamide and
Pyrazinecarboxamide were synthesised in high yields to demonstrate the effectiveness of this method.
Ó 2015 Elsevier Ltd. All rights reserved.
Received 4 May 2015
Revised 19 June 2015
Accepted 20 June 2015
Available online xxxx
Keywords:
Primary amides
Aminocarbonylation
Aryl halides
Co
NH
2
(CO)
Cl
8
4
Ever since the first work of Heck and co-workers in 1974 on
and ammonia gases in one reaction vessel. To overcome this, alter-
three component coupling reaction,1 the transformation of
aromatic halides to a wide variety of aromatic carbonyl derivatives
has been frequently undertaken in organic synthesis. As a result, an
impressive amount of approach has been put forward to effect this
nate sources of gaseous ammonia like hexamethyldisilazane,
11
1
2
13
14
tert-butylamine, benzyl amine, allyl amine or ammoniumcar-
1
5
bamate were developed. But, these methods require carbonyla-
tion and de-protection reaction sequence or selective cleavage by
workup to get the desired primary amides. Also these reactions
use an excess amount of CO gas and initial evacuation of the reac-
2
transformation in high yield and short reaction time. Among all
the palladium mediated carbonylations, synthesis of amides by
aminocarbonylation is very useful in organic synthesis and
pharmaceutical chemistry as they form a central part of many
biologically active molecules.3 An in-depth analysis of the
Comprehensive Medicinal Chemistry database revealed that the
tion vessel is required. Recently aqueous NH
3
was also used in the
synthesis of primary amides from aryl iodides in good yields in the
Ò
2
presence of Pd(OAc) /CYTOP 292, 100 psi of CO gas at 130 °C. But,
aryl bromides cannot be used for the synthesis of primary amides
by this method. Lately, Larhed and his group developed a new pro-
tocol to synthesise primary amides by the decomposition of
hydroxylamine to ammonia at higher temperature, strong base
4
amide group appears in more than 25% of known drugs. This
can be expected, since amides are neutral, stable and have both
5
hydrogen-bond accepting and donating properties. Also the pri-
mary amides serve as useful intermediates for the synthesis of
and excess of Mo(CO)
6
under microwave irradiation.16 Nielsen
nitriles by dehydration,6 benzoxazoles by transition metal
et al. used ammonium carbamate as ammonia source and
9-methyl-9H-fluorene-9-carbonyl chloride (COgen) as CO source
7
8
mediated coupling reaction, and benzyl amines by reduction.
A variety of strategies has been developed for the selective
formation of primary amides. Frequently the carboxylic acids (by
coupling reagents) or acid derivatives (e.g., esters, acid chlorides,
to synthesise aromatic primary amides by
system. These methods are attractive as both the NH and CO
a
two-chamber
1
7
3
sources can easily be handled. However, the reactions are per-
formed either at high temperatures and/or pressures for the
decomposition of the corresponding solid sources to release
ammonia/carbon monoxide or special reaction setups are required.
Thus, there was scope for improvement and development over the
existing methods.
9
anhydrides) are used to synthesise this class of compounds.
Among all the methods, the aminocarbonylation of aryl halides
with ammonia is attractive.10 However, the reaction protocols
require high pressure equipments. Also, there may be difficulty
in handling very toxic, flammable or corrosive carbon monoxide
Recently, we reported that the dicobalt octacarbonyl can be
used as a solid alternate CO source for the palladium mediated car-
bonylation reactions under mild condition. Initial search for an
1
8
⇑
Corresponding author.
http://dx.doi.org/10.1016/j.tetlet.2015.06.054
040-4039/Ó 2015 Elsevier Ltd. All rights reserved.
0
Please cite this article in press as: Suresh, A. S.; et al. Tetrahedron Lett. (2015), http://dx.doi.org/10.1016/j.tetlet.2015.06.054

2
A. S. Suresh et al. / Tetrahedron Letters xxx (2015) xxx–xxx
Table 1
Reaction optimisation of aminocarbonylationa
O
Pd(OAc) /Ligand
Br
2
NH2
Co (CO) , NH Cl
additive, base,
dioxane
2
8
4
O
O
1
a
2a
Entry
NH
4
Cl
Base
(2 equiv)
Ligand
(6 mol %)
Additiveb
(2 equiv)
Temp
(°C)
Time
(h)
Yieldc
(%)
(equiv)
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
4
5
3
3
3
3
3
3
3
3
3
2
2
2
2
2
2
DMAP
DMAP
DBU
Xantphos
Xantphos
Xantphos
Xantphos
Xantphos
dppf
—
—
—
—
—
—
—
—
100
140
100
100
100
100
100
100
100
100
90
90
90
90
90
90
90
8
24
24
24
24
8
8
8
8
5
3
3
3
3
3
3
3
N.R.
N.R.
N.R.
N.R.
N.R.
N.R.
N.R.
N.R.
72
DIPEA
K
2
CO
3
DMAP
DMAP
DMAP
DMAP
DMAP
DIPEA
DIPEA
—
DIPEA
DIPEA
DIPEA
DIPEA
PPh
3
BINAP
Xantphos
Xantphos
dppf
dppf
dppf
dppf
dppf
dppf
dppf
Imidazole
Imidazole
Imidazole
Imidazole
Imidazole
Imidazole
Imidazole
Imidazole
Imidazole
1
1
1
1
1
1
1
1
79
84
90
35
90
91
94
d
e
f
g
87
N.R.-Desired product not obtained.
a
All the reactions were performed with 1 mmol of 1a.
b
c
d
e
f
2
equiv of additives were used.
All the yields reported are isolated by column chromatography.
0
0
0
0
.75 equiv of imidazole was used.
.50 equiv of imidazole was used.
.25 equiv of imidazole was used.
.1 equiv of imidazole was used.
g
alternate source of gaseous NH
3
led us to report that solid ammo-
2 8
carbonyl [Co (CO) ], respectively, thus making this approach sim-
nium chloride can successfully be used as solid in situ ammonia
source for the synthesis of primary amides. NH Cl is much cheaper
ple, comparatively safe and inexpensive.
4
In order to attain the optimal reaction conditions,
and more suitable than other ammonia sources reported for the
synthesis of primary amides. Herein, we report a simple protocol
for the synthesis of primary amides based on palladium-catalysed
aminocarbonylation of aromatic halides (Br/I) using commercially
inexpensive, stable and solid non-gaseous precursors for both
4-bromoanisole (1a) was aminocarbonylated using NH
in the presence of Pd(OAc) , Xantphos, DMAP and Co
dioxane following on our early Letter.
4-methoxybenzamide (2a) was not observed (Table 1, entry 1).
Increasing the reaction temperature to 140 °C and reaction time
to 24 h (Table 1, entry 2) did not produce the desired result.
4
Cl (4 equiv)
(CO) in
However, the expected
2
2
8
1
8b
4
ammonia and CO, that is, ammonium chloride (NH Cl) and cobalt
Table 2
a
Experiment on other solid sources of CO and NH
3
O
Pd(OAc) (5 mol%)
2
Br
dppf (6 mol%)
NH2
CO source,
NH source
imidazole, DIPEA
Dioxane, 90 °C
3
2b
1
b
Entry
Carbonyl source
Ammonia sourceb
Temp (°C)
Time (h)
Yieldc (%)
1
2
3
4
5
6
7
8
9
Co
Co
Co
Co
Co
Co
Mo(CO)
Cr(CO)
W(CO)
2
2
2
2
2
2
(CO)
(CO)
(CO)
(CO)
(CO)
(CO)
8
8
8
8
8
8
6
NH
NH
HCO
NH
NH
NH
NH
NH
NH
4
Cl
90
90
90
90
90
90
90
90
90
3
3
3
3
8
8
8
8
8
82
48
4
CO
2
NH
2
2
NH
CONH
HCO
4
Traces
20
Traces
Traces
39
2
4
2
4
4
4
2
3
OHÁHCl
Cl
Cl
Cl
6
Traces
Traces
6
a
b
c
All the reactions were executed with 1 mmol of 1b.
equiv of ammonia source was used.
All the yields reported are isolated by column chromatography.
2
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A. S. Suresh et al. / Tetrahedron Letters xxx (2015) xxx–xxx
3
Table 3
Table 4
a
a
Aminocarbonylation of aryl halides (Br/I)
Aminocarbonylation of hetero arylbromides
Pd(OAc) /dppf
Pd(OAc) /dppf
2
2
NH Cl (2 equiv)
Imidazole (0.25 equiv)
NH Cl (2 equiv)
Imidazole (0.25 equiv)
O
4
O
4
Ar
X= Br/I
(a-o)
X
Hetero-Ar
NH2
Ar
NH2
2(a- o)b
Hetero-Ar Br
DIPEA (1 equiv),
DIPEA (2 equiv),
4(a- j)b
Co (CO) (0.3 equiv)
3(a-j)
Co (CO) (0.3 equiv)
1
2
8
2
8
Dioxane, 90 °C, 3 h.
Dioxane, 90 °C, 3 h.
O
O
O
NH2
O
NH2
O
H N
O
N
O
NH2
2
NH2
NH2
NH2
O
O
S
NH2
N
4b
N
O
2
b
2d
X = Br, 70%
80%
H
2
a
4a
4c
4d
86%
2c O
X = Br, 82%
X= I, 74%
X = Br, 93%
X= I, 84%
89%
82%
X = Br, 86%
O
NH2
O
O
NH2
O
NH2
O
O
O
NH2
O
NH2
NH2
NH2
N
N
N
N
N
O
4h
6%
NH2
7
O
O
4f
7%
4g
81%
O
Cl
4e
9%
O
7
2
e
O
2f
H
2g
2h
X = Br, 86%
6
O
NH2
X = Br, 90%
X = Br, 79%
X = I, 71%
X = Br, 82%
X = I, 77%
NH2
O
NH2
O
O
O
NH
2
NH2
NH2
N
4
j
S
4
i
84%
O
82%
F
2
i
F3C 2j
2k
O
2l
X = Br, 74%
X = Br, 92%
X = I, 79%
X = Br, 85%
X = I, 80%
X = Br, 87%
b
All the yields reported are isolated by column chromatography.
All the reactions were executed with 1 mmol of corresponding aryl halides
(a–j).
O
NH2
NH2
a
O
O
NH2
3
O
F
Ph
2o
2
m
drastically reduced to 35% when the reaction was performed with-
out the addition of DIPEA (Table 1, entry 13). So, we concluded that
the additional base (DIPEA) in the reaction is essential to get the
desired product in high yields.
Based on the above results, and using the best reaction condi-
tions (Table 1, entry 12), the required amount of catalyst and addi-
tives was studied. After several reaction conditions with decreasing
amounts of imidazole, amide 2a was isolated in 94% yield with
complete conversion of aryl halide 1a (Table 1, entry 16) when imi-
dazole was used in a catalytic amount (0.25 equiv).
To test the effectiveness of the optimised carbon monoxide and
ammonia sources used in this carbonylation reaction, a range of
other solid sources of ammonia and carbon monoxide releasing
reagents were investigated using our optimised reaction condi-
tions. The obtained results are shown in Table 2. We have chosen
1-bromo-4-tertbutylbenzene (1b) as model substrate and isolated
the desired primary amide 2b in 82% yield (Table 2, entry 1) under
stabilized reaction conditions. Then, a number of other ammonia
releasing ammonium salts (ammonium carbamate, ammonium
formamide, urea, ammonium acetate and hydroxylamine
hydrochloride) were screened (Table 2, entries 2–6) in place of
ammonium chloride. However, the results showed that ammo-
nium chloride (Table 2, entry 1) was superior. Similarly when CO
2
n
X = Br, 90%
X = Br, 85%
X = Br, 92%
b
All the yields reported are isolated by column chromatography.
All the reactions were executed with 1 mmol of corresponding aryl halides
a
1
(a–o).
Screening a range of bases (Table 1, entries 3–5) and solvents such
as toluene, DMF, THF and DMSO failed to produce the desired
product (results are not shown). The examination of other
3
different mono and bidentate ligands such as dppf, PPh , BINAP
were also hopeless (Table 1, entries 6–8). During the above
experiments, the observation of the de-brominated (4-
methoxybenzene) and ketone bis(4-methoxyphenyl)methanone
product masses in GCMS analysis indicated that the oxidative
addition of the aryl halide to the palladium centre and the
carbonyl insertion steps occur. But, subsequent nucleophilic
addition of ammonia does not take place. This may be due to the
poor nucleophilicity of ammonia making it less reactive with the
active acyl-palladium centre. In general, the palladium catalysed
carbonylation reaction of the less reactive nucleophiles can be
improved by adding additives.1
9,18c
So, we investigated the effect
of additives on the reaction mixture, which initially react with
the acyl palladium center and form the active acyl intermediate.
To our delight, the addition of imidazole straightaway yielded
releasing other known metal carbonyls [Mo(CO) , Cr(CO)6 and
6
W(CO) ] used in carbonylation reactions were screened (Table 2,
6
entries 7–9), the results were apparent that dicobalt octacarbonyl
7
2% of amide 2a (Table 1, entry 9). After fine tuning in the reaction
is much better than others.
parameters, it was evident that the best results for the formation of
Having established conditions for the synthesis of primary
amide from the corresponding aryl bromide, we investigated the
substrate scope with various aryl halides (Br/I). As shown in
Table 3, the method well tolerated various electronic and steric
substituent patterns of aryl bromides and aryl iodides, all ensuing
good to excellent isolated yields of the primary amides. However,
2
a was obtained in the presence of Pd(OAc)
equiv of NH Cl, imidazole, DIPEA and nearly stoichiometric
(CO) in dioxane at 90 °C for 3 h
Table 1, entry 12). Next, we examined the sensitivity of the base
in the reaction and found that the isolated yield of amide 2a
2
, dppf as a ligand,
2
4
amount (0.3 equiv) of Co
2
8
(
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4
A. S. Suresh et al. / Tetrahedron Letters xxx (2015) xxx–xxx
n-Hexyl
Br
Pd(OAc) /dppf
2
Manickam, Syngene International Limited, for providing the neces-
sary facilities to complete this work.
O
n-Hexyl
O
O
NH Cl (2 equiv)
4
Imidazole (0.25 equiv)
DIPEA (1 equiv),
NH2
Supplementary data
Co (CO) (0.3 equiv)
2
8
5
6 (Hexalamide)
mmol scale: 0.2 g, 92%
mmol scale: 1.4g,91%
Dioxane, 90 °C, 3 h.
1
7
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2015.06.
O
0
54.
N
Br
N
(
same as above)
NH2
References and notes
N
N
8
1
(Pyrazinecarboxamide)
7
mmol scale: 0.09 g, 74%
0 mmol scale: 1.12 g, 76%
1. (a) Schoenberg, A.; Bartoletti, I.; Heck, R. F. J. Org. Chem. 1974, 39, 3318; (b)
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1
2
3
.
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Scheme
Pyrazinecarboxamide.
1. The
synthesis
of
biologically
active
Exalamide
and
1
4
13, 1; (d) Brennfuhrer, A.; Neumann, H.; Beller, M. Angew. Chem., Int. Ed. 2009,
8, 4114; (e) Wu, X. F.; Neumann, H.; Beller, M. Chem. Soc. Rev. 2011, 40, 4986;
in the case of aryl iodides the isolated yields were slightly lower
than the corresponding aryl bromides (2a, 2b, 2f, 2g, 2j, 2k) used.
Various other carbonyl functional groups such as ketone (2c),
esters (2f) and aldehyde (2g) are compatible for this reaction
condition.
The successful results obtained for the formation of aryl pri-
mary amides presented above encouraged us to explore the
aminocarbonylation of various hetero aryl halides. A selection of
heterocyclic aryl bromides were explored under the optimised
conditions and the results are shown in Table 4. It is to be noted
that 3-bromopyridine (3a) and 2-bromothiophene (3b) produced
the corresponding amides in excellent yields (89% and 80%, respec-
tively). More interestingly, a direct aminocarbonylation of the
unprotected 5-bromoindole (3c) yielded the corresponding amide
(f) Wei, R.; Motoki, Y. J. Org. Chem. 2010, 75, 3017; (g) Roberts, B.; Liptrot, D.;
Alcaraz, L.; Luker, T.; Stokes, J. M. Org. Lett. 2010, 12, 4280; (h) Ronald, G.;
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7
8
.
.
9
.
(a) Allen, C. L.; Williams, J. M. J. Chem. Soc. Rev. 2011, 40, 3405.
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(
(
4c) in 82% yield. Similarly, other interesting heterocyclic amides
4d–4j) are isolated from corresponding hetero aryl bromides in
1
1
1. Morera, E.; Ortar, G. Tetrahedron Lett. 1998, 39, 2835.
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good yields with complete conversion.
To further exemplify the potential of this protocol, two
2
0
13. (a) Wannberg, J.; Larhed, M. J. Org. Chem. 2003, 68, 5750; (b) Salvadori, J.;
Balducci, E.; Zaza, S.; Petricci, E.; Taddei, M. J. Org. Chem. 2010, 75, 1841.
biologically important pharmaceutical targets, Exalamide
2-Hexyloxybenzamide, 6) (antifungal agent) and Pyrazine-
(
1
1
1
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carboxamide (2-Pyrazinamide, 8) (antitubercular agent) were
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zene and 2-bromopyrazine in isolated yields of 92% and 74%,
respectively (Scheme 1). The reaction was also successfully
repeated in gram scale without affecting the isolated yields. In con-
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used solid Co
2 8 4
(CO) and NH Cl as convenient sources of CO and
1
2
2
9. Martinelli, R.; Clark, P.; Watson, P.; Munday, H.; Buchwald, L. Angew. Chem., Int.
Ed. 2007, 46, 8460.
0. (a) Bavin, E. M.; Seymour, F. J.; Waterhouse, P. D. J. Pharm. Pharmacol. 1952, 4,
NH to the synthesis of primary amides in excellent isolated
3
2
2
yields. The method works well for both aryl and hetero aryl
halides. The new protocol also allows the efficient synthesis of bio-
logically active Exalamide and Pyrazinecarboxamide even at
872; (b) Kusunoki, T.; Harada, S. J. Dermatal. 1984, 11, 227.
1. Loots, D. T.; Wiid, I. J.; Page, B. J.; Mienie, L. J.; Helden, P. D. J. Pineal. Res. 2005,
38, 100.
1
0 mmol scale reaction in good yields which further exemplifies
the importance of this method. Since non-gaseous NH and CO
sources are used (NH Cl and Co (CO) , respectively), this method
is well suited for both laboratory scale and library synthesis of aro-
22. General procedure for the synthesis of primary amides: To a stirred solution of
aryl halide (Br/I) (1 mmol) in dry dioxane in a 25 mL sealed tube, was added
Pd(OAc) (5 mol %), dppf (6 mol %), DIPEA (2 mmol), imidazole (0.25 mmol),
2
3
4
2
8
ammonium chloride (2 mmol) and then Co (CO)8 (0.3 mmol). The seal tube
2
was closed immediately and stirred at 90 °C for 3 h. After the reaction time the
2
3
reaction mixture was cooled to room temperature. The reaction mixture was
filtered through celite pad and washed with dioxane, the filtrate was
concentrated under reduced pressure and the residue obtained was purified
by column chromatography.
matic primary amides.
Acknowledgments
23. Note: Carbon monoxide gas is highly toxic and should be handled by trained
professionals in well ventilated fume hood with appropriate ventilation. In all
One of the authors (A.S.S.) acknowledges Syngene International
Limited to carry out this research work. Also thankful to Dr. G.
2 8
the reactions, Co (CO) was handled carefully in Fume hoods and by using
appropriate personal protective clothing and equipment.
Please cite this article in press as: Suresh, A. S.; et al. Tetrahedron Lett. (2015), http://dx.doi.org/10.1016/j.tetlet.2015.06.054