Facile synthesis of primary amides and ketoamides via a palladium-catalysed carbonylation-deprotection reaction sequence

Article abstract of DOI:10.1016/j.tetlet.2007.02.043

Various primary amides and ketoamides have been obtained in good yields in a two-step reaction sequence. The first step involves the synthesis of aryl/alkenyl N-tert-butyl amides and aryl N-tert-butyl ketoamides from the corresponding iodides via palladium-catalysed carbonylation in the presence of t-BuNH₂ as the nucleophile. Carbonylation was followed by selective cleavage of the t-Bu group using TBDMSOTf as the reagent.

Full text of DOI:10.1016/j.tetlet.2007.02.043

Tetrahedron Letters 48 (2007) 2453–2456
Facile synthesis of primary amides and ketoamides via a
palladium-catalysed carbonylation–deprotection reaction sequence
a
a
a,
b
*
´
´
´
´
Eszter Takacs, Csilla Varga, Rita Skoda-Fo¨ldes and Laszlo Kollar
aUniversity of Pannonia, Institute of Chemistry, Department of Organic Chemistry, Egyetem u. 10,
PO Box 158, H-8200 Veszpre´m, Hungary
bUniversity of Pe´cs, Department of Inorganic Chemistry and Research Group for Chemical Sensors of the Hungarian Academy
of Sciences, Ifju´sa´g u. 6, PO Box 266, H-7624 Pe´cs, Hungary
Received 4 January 2007; revised 29 January 2007; accepted 9 February 2007
Available online 15 February 2007
Abstract—Various primary amides and ketoamides have been obtained in good yields in a two-step reaction sequence. The first
step involves the synthesis of aryl/alkenyl N-tert-butyl amides and aryl N-tert-butyl ketoamides from the corresponding iodides
via palladium-catalysed carbonylation in the presence of t-BuNH2 as the nucleophile. Carbonylation was followed by selective
cleavage of the t-Bu group using TBDMSOTf as the reagent.
Ó 2007 Elsevier Ltd. All rights reserved.
Palladium-catalysed aminocarbonylation of aryl halides
or triflates is a powerful tool for the synthesis of
aromatic secondary and tertiary amides.1 However, the
application of this method to produce primary amides
is restricted to a few examples. Due to the low nucleo-
philicity of ammonia and the difficulties in handling this
toxic reactant, various ammonia-synthons have been
used in most reactions. Morera and Ortar2 reacted
aryl/alkenyl halides with hexamethyldisilazane and CO
in the presence of a palladium catalyst. The primary
amides were formed from the products after acidic
workup. Indolese3 reported on the aminocarbonylation
of aryl halides with formamide under 5 bar CO pressure
using imidazole as a base. Primary amides were also
synthesised using a titanium–nitrogen compound4 or
hydroxylamine5 as the ammonia source.
amides can be synthesised from N-t-Bu amides, obtained
by aminocarbonylation of aryl/alkenyl iodides, via
deprotection of the t-Bu group using tert-butyldimethyl-
silyl triflate (TBDMSOTf) as the reagent (Scheme 1).
Removal of the t-Bu group from amides usually requires
harsh reaction conditions, so it is rarely used for the pro-
tection of primary amides. Recently, Alterman reported
a new method using scandium triflate in combination
with both conventional and microwave heating for this
purpose.7
Although TBDMSOTf was used effectively for the
removal of N-Boc protecting groups of amino acids
during peptide synthesis8 and was shown to cleave the
OCH3 group of Weinreb amides9 in the presence of
2,6-lutidine and Et3N, respectively, to the best of our
knowledge there is no precedent for its application for
the deprotection of N-t-Bu amides.
In the course of our ongoing interest in palladium-cataly-
sed carbonylation reactions6 we have found that primary
NHtBu
I
O
NH2
O
Pd(OAc)2 + 2 PPh3
Et3N, toluene
TBDMSOTf
toluene
+ CO + H2NtBu
Scheme 1. Synthesis of primary amides via a palladium-catalysed aminocarbonylation–deprotection sequence.
Keywords: Primary amide; Ketoamide; TBDMSOTf; Aminocarbonylation.
*
Corresponding author. Tel.: +36 88 624719; fax: +36 88 624469; e-mail addresses: skodane@almos.uni-pannon.hu; skodane@almos.vein.hu
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.02.043

2454
E. Taka´cs et al. / Tetrahedron Letters 48 (2007) 2453–2456
Various alkenyl (Fig. 1, 1 and 2) and aryl iodides (3–6)
were reacted with tert-butylamine in the presence of the
Pd(OAc)2 + 2 PPh3 in situ catalyst and Et3N as the base
under atmospheric CO pressure (Scheme 2). After sepa-
ration of the resulting amides (1a–6a) and ketoamides
(3b–6b) by column chromatography, the pure products
were heated with 1 equiv of TBDMSOTf in toluene at
60 °C (1a, 2a) or 100 °C (3a–6a and 3b–6b).
Under carbonylation conditions, alkenyl iodides 1 and 2
could selectively be converted to the corresponding
amides 1a10 and 2a at 60 °C and the products were
obtained in 95% and 92% isolated yields, respectively.
Similar reactions of aryl iodides led to a mixture of
amides (3a–6a) and ketoamides (3b–6b) even at atmo-
spheric pressure.11 As we had found before during the
aminocarbonylation of iodoferrocene,12 a change in
the temperature had a marked effect on the selectivity
of the reaction, except for substrate 6. At 60 °C the
ketoamides were the main products, while at 100 °C
the formation of the amides was favoured (Table 1).
I
I
Accordingly, aromatic amides 3a–6a were isolated in
52–85% yields and ketoamides 3b–6b in 37–62% yields
from the aminocarbonylation reactions carried out at
100 °C and 60 °C, respectively. All of the products were
MeO
I
2
H
1
I
I
I
1
characterised by H NMR and MS.
Amides 1a–6a and ketoamides 3b–6b were reacted with
TBDMSOTf in toluene under an inert atmosphere.
Amides 1a and 2a could selectively be converted to the
primary amides 713 and 8 at 60 °C, but a higher temper-
ature (100 °C) had to be used for the removal of the t-Bu
group from the aromatic derivatives.
NO2
OMe
3
6
4
5
Figure 1. Alkenyl/aryl iodides used as substrates in the palladium-
catalysed aminocarbonylation.
TLC indicated complete conversion of amides 1a–6a
and ketoamides 3b–6b into the primary derivatives
7–16 under the conditions mentioned above and most
of the products could be isolated in good yields (Table
2). However, ketoamide 13 was obtained only in moder-
ate yield due to the difficulties in the separation of the
product and silicon containing by-products. It should
be mentioned that the presence of a base (Et3N or 2,6-
lutidine) had no effect on the cleavage.
I
Pd(OAc)2 + 2 PPh3
+ CO + H2NtBu
Et3N, toluene
1-6
NHtBu
t
O
NH Bu
O
O
In a typical experiment 1 mmol of alkenyl/aryl iodide
was reacted with 5 mmol of t-BuNH2, 0.05 mmol of
Pd(OAc)2, 0.1 mmol of PPh3 and 3.5 mmol of Et3N in
10 ml of toluene under a CO atmosphere at 60 or
100 °C for 8 h. The reaction progress was followed by
GC. After completion of the reaction, the solvent was
+
1a-6a
3b-6b
Scheme 2. Aminocarbonylation of alkenyl/aryl iodides 1–6.
Table 1. Aminocarbonylation of aromatic iodides 3–6a
Entry
Substrate
Temperature (°C)
Product
distributionb,d (%)
Isolated yield (%)
a
b
a
b
1
2
3c
4c
5
3
3
4
4
5
5
6
6
60
100
60
100
60
100
60
100
24
92
22
74
28
83
52
64
76
8
62
59
51
37
85
58
72
52
78
26
72
17
48
36
6
7c
8c
a Reaction conditions: 1 mmol aryl iodide (3–6), 5 mmol t-BuNH2, 0.05 mmol Pd(OAc)2, 0.1 mmol PPh3, 3.5 mmol Et3N, 10 ml toluene, 1 bar CO,
8 h.
b Determined by GC.
c Reaction time 10 h.
d Practically complete reactions (conversion >99%) were obtained in all cases.

E. Taka´cs et al. / Tetrahedron Letters 48 (2007) 2453–2456
2455
Table 2. Primary amides and ketoamides produced by cleavage of N-t-
Bu-derivativesa
Table 2 (continued)
Entry
Product
Yield (%)
84
Entry Product
Yield (%)
NH
2
O
O
O
NH
2
10
16
1b
7
98
a Reaction conditions: 0.5 mmol amide (1a–6a) or ketoamide (3b–6b),
0.5 mmol TBDMSOTf in 5 ml toluene, 100 °C, 8 h.
b The reaction was carried out at 60 °C.
H
O
NH2
2b
8
75
91
74
removed in vacuo. The residue was dissolved in chloro-
form (20 ml) and washed twice with 5% HCl (20 ml),
saturated NaHCO3 (20 ml), brine (20 ml), dried over
Na2SO4 and the solvent was removed by distillation.
MeO
Chromatography
(silica,
toluene/ethanol = 15/1)
yielded amides 1a–6a and ketoamides 3b–6b. Then
0.5 mmol of amide or ketoamide was heated with
0.5 mmol of TBDMSOTf in 5 ml of toluene at 60 or
100 °C for 8 h. After completion of the reaction, the sol-
vent was removed in vacuo. Chromatography (silica,
toluene/ethanol = 15/1) yielded the desired primary
amides (7–12) or ketoamides (13–16).
O
NH
2
3
9
O
NH2
In conclusion, TBDMSOTf can be used for cleavage of
the N-t-Bu groups of N-t-Bu-amides and ketoamides.
The palladium-catalysed carbonylation–deprotection
reaction sequence proved to be an effective method for
the synthesis of aromatic/alkenyl primary amides and
aromatic primary ketoamides.
4
10
OMe
O
NH2
5
6
7
11
12
13
83
90
52
NO2
Acknowledgements
The authors thank the Hungarian National Science
Foundation for financial support (OTKA T048391,
NI61591). R.S.-F. thanks the Hungarian Academy of
Sciences for the J. Bolyai fellowship.
O
NH
2
NH2
References and notes
O
O
O
´
1. Skoda-Fo¨ldes, R.; Kollar, L. Curr. Org. Chem. 2002, 6,
1097–1119.
2. Morera, E.; Ortar, G. Tetrahedron Lett. 1998, 39, 2835–
2838.
3. Schnyder, A.; Beller, M.; Mehltretter, G.; Nsenda, T.;
Studer, M.; Indolese, A. F. J. Org. Chem. 2001, 66, 4311–
4315.
NH
2
O
4. Ueda, K.; Sato, Y.; Mori, M. J. Am. Chem. Soc. 2000,
122, 10722–10723.
8
14
86
5. Wu, X.; Wannberg, J.; Larhed, M. Tetrahedron 2006, 62,
4665–4670.
OMe
´
6. (a) Skoda-Fo¨ldes, R.; Szarka, Z.; Kollar, L.; Dinya, Z.;
´
Horvath, J.; Tuba, Z. J. Org. Chem. 1999, 64, 2134–2136;
NH
´
´
(b) Skoda-Fo¨ldes, R.; Szekvo¨lgyi, Z.; Kollar, L.; Berente,
2
O
´
Z.; Horvath, J.; Tuba, Z. Tetrahedron 2000, 56, 3415–
O
´
3418; (c) Skoda-Fo¨ldes, R.; Szarka, Z.; Kollar, L. Tetra-
hedron Lett. 2001, 42, 739–741; (d) Skoda-Fo¨ldes, R.;
9
15
86
´
´
´
Takacs, E.; Horvath, J.; Tuba, Z.; Kollar, L. Green Chem.
NO
2
2003, 5, 643–645.

2456
E. Taka´cs et al. / Tetrahedron Letters 48 (2007) 2453–2456
7. Mahalingam, A. K.; Wu, X.; Alterman, M. Tetrahedron
11. (a) Satoh, T.; Kokubo, K.; Miura, M.; Nomura, M.
Organometallics 1994, 13, 4431–4436; (b) Uoumi, Y.; Arii,
T.; Watanabe, T. J. Org. Chem. 2001, 66, 5272–5274.
12. Szarka, Z.; Skoda-Fo¨ldes, R.; Kuik, A.; Berente, Z.;
Lett. 2006, 47, 3051–3053.
8. Sakaitani, M.; Ohfune, Y. J. Org. Chem. 1990, 55, 870–
876.
´
9. Keck, G. E.; McHardy, S. F.; Murry, J. A. Tetrahedron
Lett. 1993, 34, 6215–6218.
Kollar, L. Synthesis 2003, 545–550.
1
13. Selected spectroscopic data for 7: H NMR (d): 6.43 (br s,
10. Selected spectroscopic data for 1a: 1H NMR (d): 6.31 (br s,
1H); 5.45 (br s, 1H); 2.2–0.7 (m, 22H, ring protons); 1.35
(s, 9H); 0.95 (s, 3H); 0.8 (s, 3H). MS (m/z/rel. int.): 357
(M+)/20; 342/30; 285/49; 257/100; 191/53; 161/75; 147/85;
133/71; 119/45; 105/40; 95/44.
1H); 5.60 (br s, 2H); 2.23–0.78 (m, 22H, ring protons); 0.98
(s, 3H); 0.80 (s, 3H). 13C NMR (d): 168.2 (CO); 138.5;
132.3; 57.0; 55.4; 47.5; 46.7; 38.7; 36.7; 35.2; 34.1; 32.2;
31.9; 29.2; 29.1; 27.0; 22.3; 20.9; 16.6; 12.4. MS (m/z/rel.
int.): 301 (M+)/18; 286/39; 257/100.