One-pot amide synthesis from allyl or benzyl halides and amines by Pd-catalysed carbonylation

Article abstract of DOI:10.1016/j.tetlet.2009.11.023

Amides can be prepared from allyl or benzyl halides and primary or secondary amines, using Pd(0) catalyst under CO pressure, in a one-pot synthesis. The reaction proceeds through the acyl palladium halide formation which undergoes an acylic nucleophilic substitution from the amine.

Full text of DOI:10.1016/j.tetlet.2009.11.023

Tetrahedron Letters 51 (2010) 371–373
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
One-pot amide synthesis from allyl or benzyl halides and amines
by Pd-catalysed carbonylation
*
Luigino Troisi , Catia Granito, Francesca Rosato, Valeria Videtta
Dipartimento di Scienze e Tecnologie Biologiche ed Ambientali, University of Salento, via Prov.le Lecce-Monteroni, 73100 Lecce, Italy
a r t i c l e i n f o
a b s t r a c t
Article history:
Amides can be prepared from allyl or benzyl halides and primary or secondary amines, using Pd(0) cat-
alyst under CO pressure, in a one-pot synthesis. The reaction proceeds through the acyl palladium halide
formation which undergoes an acylic nucleophilic substitution from the amine.
Ó 2009 Elsevier Ltd. All rights reserved.
Received 29 September 2009
Revised 30 October 2009
Accepted 9 November 2009
Available online 12 November 2009
Keywords:
Amides
Halides
Amines
Palladium-catalysed carbonylation
The amide bond is one of the most important linkages in organ-
ic chemistry and constitutes the key functional group in peptides,
for b-lactam5a (Scheme 2). The reaction times were shorter than
those of b-lactams formation and the N-Ph-acetamide was isolated
as a main product with 82% of yield (Table 1, entry 1). However, as
it might be expected, nucleophilic mono- and di-substitution prod-
ucts, 1b and 1c, respectively, were also formed.
polymers and many natural products and pharmaceuticals.1
A
number of syntheses by which amides could be constructed are
known and new methods have been developed recently.2 Some
of these methodologies were based on metal-free3 or transition
metal catalyst4 carbonylation. Our approach was inspired by the
study of palladium catalyst [2+2] cycloaddition reaction between
allyl halides5 or phosphate6 and imines, with Et3N under CO pres-
sure, for the one-pot synthesis of b-lactam rings. The reaction pro-
ceeds initially with the formation of the allyl-palladium complex A
and then with the insertion of CO generating the 3-butenyl-palla-
dium halide (or phosphate) B (Scheme 1). The compound B is sub-
sequently deprotonated and the carbanion C reacts with the imine
carrying out the 2-azetidinone ring D.
O
CO
Pd(0)
X
PdX
B
A
PdX
Et3N
Ar
O
N
Ar'
O
N
PdX
Ar
Ar'
D
C
Scheme 1. Synthesis of b-lactams.
The same pathway was noticed in the reaction between benzyl
halides and imines,7 but the [2+2] cycloaddition is slower than that
observed with allyl palladium halides as a consequence of the
harder formation of benzyl-Pd-complex A. In the second case, also
the yield was lower because of the formation of N-Ar0-phenylaceta-
mides. In fact, Ar0NH2, produced by the imines degradation during
longer reaction times, gave a nucleophilic substitution on the acyl
Pd-halides generating amides. Encouraged by these results, we
have treated, in the same experimental conditions used for the
synthesis of 2-azetidinone ring, but without Et3N, the benzyl chlo-
ride with the aniline instead of the imine.8 It was noticed that the
reaction proceeded with a catalytic cycle similar to that illustrated
X
O
Pd(0)
NHR
PdX
A
CO
RNH2
O
PdX
B
* Corresponding author. Fax: +39 (0832) 298732.
E-mail address: luigino.troisi@unisalento.it (L. Troisi).
Scheme 2. Catalytic cycle for amide synthesis.
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.11.023

372
L. Troisi et al. / Tetrahedron Letters 51 (2010) 371–373
Table 1
Synthesis of amides from benzyl or pyridinyl halides and primary amines
CO (300 psi),
Pd(OAc)2
O
R
Ar
R
Ar
N
H
Ar
N
R
1c, 2c
Ar
H2NR
N
H
Ar
X
Ph3P, THF,
110 °C
1a-5a
1b-5b
Entry
Ar
X
R
Time (h)
Yielda (%)
Product distributionb (%)
1
2
3
4
5
6
7
8
Ph
Ph
Ph
Ph
Ph
Ph
Cl
Br
Cl
Br
Br
Cl
Br
Cl
Ph
Ph
nBu
nBu
15
10
15
10
15
20
10
15
82
75
75
73
80
60
87
91
1a (81)c
1b (15)c
1b (23)
2b (27)c
2b (18)
3b (37)c
4b (15)
4b (54)
5b (3)c
1c (4)c
1a (70)
2a (43)c
2a (23)
3a (63)c
4a (85)c
4a (46)
5a (97)
1c (7)
2c (30)c
2c (59)
tBu
/
/
/
/
PhCHCH3
PhCHCH3
tBu
Ph
4Pyd
a
b
c
Overall yield (%) after chromatographic purification on silica gel.
Product distribution determined by GC analysis.
Commercially available product.
d
Py = pyridinyl.
The reaction afforded similar results either when the benzyl
ophilic substitution and afforded a greater amount of amide.
Moreover, branched allylchlorides afforded exclusively the amides
with quantitative yields (Table 2, entries 12–14).
It was also verified that the methodology could be successfully
used with secondary amines, whose results are reported in Table 3.
The reaction trend was similar to that observed between primary
amines and halides.
Furthermore, the isomerisation of 3-butenamides in 2-butena-
mides was observed. In detail, the electron-withdrawing groups
(pyridinyl, thiazolyl and benzothiazolyl groups) on the amides
9a–11a favoured the double-bond shift in conjugate position with
the carbonyl unit giving the isomeric distribution shown in Scheme
3. Isomerisation was not noticed either using aliphatic amines and
aniline (Table 2, products 6a–8a) or using branched allylchloride,
such as 3-methyl-1-chloro-2-butene (Table 2, products 12a–14a).
The isomerisation was also noticed for the compounds 16a and 17a.
In summary, we have achieved an efficient one-pot Pd-catalysed
synthesis of amides, through the formation of acyl palladium spe-
cies, starting from allyl or benzyl halides and different primary
chloride reacted with aliphatic amines, such as the n-butylamine
and the 1-Ph-etanamine (Table 1, entries 3 and 6, respectively),
or when 4-picolyl chloride reacted with t-butylamine (Table 1, en-
try 8). Instead, the benzyl bromide, even though reacting in a
shorter reaction time, gave a smaller amount of amides and a lar-
ger amount of substitution products (Table 1, entries 2, 4, 5 and 7).
According to the same general procedure, reactions between allyl
chlorides and/or bromides and aliphatic and aromatic amines were
conducted (Table 2).
In detail, the reactions of allyl halides with aliphatic amines
were faster (2–3 h) and proceeded with 73–80% of yield, but the
bromide afforded only the amine, while the chlorides generated
preferably the amides (Table 2, entries 1–3). A similar trend was
observed also using aniline (Table 2, entries 4 and 5).
On the contrary, the lower nucleophilicity of heteroaromatic
amines, such as the 2-pyridinylamine (Table 2, entries 6 and 7),
the 2-thiazolylamine (Table 2, entries 8 and 9) and the 2-benzo-
thiazolylamine (Table 2, entries 10 and 11), unfavoured the nucle-
Table 2
Synthesis of amides from allyl halides and primary amines
CO (300 psi),
Pd(OAc)2
O
R
R
R
R'
N
R'
R'
N
H
RX
H2NR'
R
N
H
Ph3P, T H F,
110 °C
6c, 8c
6a-14a
6b, 8b-11b
a
Entry
R
X
R0
Time (h)
Yieldb (%)
Product distributionc (%)
1
2
3
4
5
6
7
8
CH2CHCH2ꢀ
CH2CHCH2ꢀ
CH2CHCH2ꢀ
CH2CHCH2ꢀ
CH2CHCH2ꢀ
CH2CHCH2ꢀ
CH2CHCH2ꢀ
CH2CHCH2ꢀ
CH2CHCH2ꢀ
CH2CHCH2ꢀ
CH2CHCH2ꢀ
Me2CCHCH2ꢀ
Me2CCHCH2ꢀ
Me2CCHCH2ꢀ
Cl
Br
Cl
Cl
Br
Cl
Br
Cl
Br
Cl
Br
Cl
Cl
Cl
PhCHMe
PhCHMe
tBu
Ph
Ph
2Py
2Py
2Tz
2Tz
2BTz
2BTz
Ph
2Py
2BTz
3
3
2
75
80
73
51
90
63
60
82
60
75
55
90
89
85
6a(35)
6b(32)d
6b(56)
6c(33)9
6c(44)
/
7a(100)10
8a(63)11
/
/
/
/
15
10
15
12
12
12
12
12
12
12
12
8b(37)d
8b(60)
8c(40)d
9a(100)
9a(93)e
10a(100)e
10a(92)
11a(100)e
11a(82)
12a(100)13
13a(100)
14a(100)
/
/
/
/
/
/
/
/
/
/
9b(7)d
/
9
10b(8)12
10
11
12
13
14
/
11b(18)
/
/
/
a
b
c
Py = pyridinyl, Tz = thiazolyl, BTz = benzothiazolyl.
Overall yield (%) after chromatographic purification on silica gel.
Product distribution determined by GC analysis.
Commercially available product.
d
e
3-Butenamide isomerises as described in Scheme 3.

L. Troisi et al. / Tetrahedron Letters 51 (2010) 371–373
373
Table 3
Synthesis of amides with secondary amines
CO (300 psi),
O
Pd(OAc)2
R'
R
R'
RCl
HNR'R''
R
N
N
Ph3P, THF,
110 °C
R''
R''
15a-17a
15b, 16b
Entry
R
R’
R’’
Time (h)
Yielda (%)
Product distributionb (%)
1
2
3
PhCH2
CH2CHCH2
CH2CHCH2
Et
Me
Ph
Et
Ph
Ph
15
15
15
41
55
12
15a (54)c
15b (46)c
16a (42)d14
16b (58)c
17a (100)d15
/
a
b
c
Overall yield (%) determined by GC analysis on the base of formed amides or benzyl chloride transformed.
Product distribution determined by GC analysis.
Commercially available product.
d
3-Butenamide isomerises as described in Scheme 3.
R''
N
R''
N
R''
N
2. Bailey, P. D.; Mills, T. J.; Pettecrew, R.; Price, R. A. In Comprehensive Organic
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1362; (b) Troisi, L.; Pindinelli, E.; De Vitis, L.; Granito, C.; Ronzini, L. Tetrahedron
2006, 62, 1564–1574; (c) Troisi, L.; Ronzini, L.; Granito, C.; Pindinelli, E.; Troisi,
A.; Pilati, T. Tetrahedron 2006, 62, 12064–12070; (d) De Vitis, L.; Troisi, L.;
Granito, C.; Pindinelli, E.; Ronzini, L. Eur. J. Org. Chem. 2007, 356–362.
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R'
R'
R'
O
a''O
a''' O
a'
9a' (46%)
10a' (92%)
11a' (65%)
9a'' (42%)
10a'' (6%)
11a'' (32%)
9a''' (12%)
10a''' (2%)
11a''' (3%)
16a' (65%)
17a' (76%)
16a'' (31%)
17a'' (24%)
16a''' (4%)
Scheme 3. Isomerisation of 3-butenamides (isomeric distribution determined by
GC analysis).
and secondary amines. In the literature only one similar methodol-
ogy was reported for the amide bond preparation, which uses allylic
carbonate in DMF in the presence of Pd(II), CO and L-alanine to gen-
erate a precursor of antillatoxin.16 Our methodology could be a no-
vel and general access to the functionalisation of amine groups in
biologically active molecules through the amide bond formation.
These are on-going studies and more results will be reported in
the future.
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20, 368–374.
8. General procedure for the amides synthesis: A solution of amine (1 equiv), allyl or
benzyl halide (1 equiv), PPh3 (0.08 equiv) and Pd(OAc)2 (0.02 equiv) in THF
(10 mL) was placed under CO pressure (300 psi) and heated to 110 °C for 2–
15 h. The solvent was removed under reduced pressure and the resulting
residue was directly purified by chromatography on silica gel.
9. Rahman, O.; Kihlberg, T.; Långström, B. Org. Biomol. Chem. 2004, 2, 1612–1616.
10. Ojima, I.; Korda, A.; Shay, W. R. J. Org. Chem. 1991, 56, 2024–2030.
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Acknowledgements
Thanks are due to the MIUR, the University of Salento and the
C.I.N.M.P.I.S. (Consorzio Interuniversitario Nazionale Metodologie
e Processi Innovativi di Sintesi) for financial support.
References and notes
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