Synthesis of β-enamino acid and heteroaryl acetic acid derivatives by Pd-catalyzed carbonylation of α-chloroimines and 2-chloromethyl aza-heterocycles

Article abstract of DOI:10.1016/j.tetlet.2016.02.035

β-Enamino esters or amides can be synthesized in a single step by a carbonylative coupling of α-chloroimines with alcohols or amines under Pd-catalysis. The methodology has been also applied to the preparation of heteroaryl acetic acid derivatives starting from chloromethyl heteroaromatic rings containing a C-N double bond. The in situ generation of a β-imino acylpalladium species has been proposed as a key step for the process.

Full text of DOI:10.1016/j.tetlet.2016.02.035

Tetrahedron Letters 57 (2016) 1421–1424
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Tetrahedron Letters
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Synthesis of b-enamino acid and heteroaryl acetic acid derivatives by
Pd-catalyzed carbonylation of
aza-heterocycles
a-chloroimines and 2-chloromethyl
a,
Serena Perrone a, Martina Capua a, Giuseppe Cannazza b, Antonio Salomone a, , Luigino Troisi
⇑
⇑
a Dipartimento di Scienze e Tecnologie Biologiche ed Ambientali, Università del Salento, Prov.le Lecce-Monteroni, Lecce 73100, Italy
b Dipartimento di Scienze della Vita, Università degli Studi di Modena e Reggio Emilia, via Università 4, Modena 41121, Italy
a r t i c l e i n f o
a b s t r a c t
Article history:
b-Enamino esters or amides can be synthesized in a single step by a carbonylative coupling of
-chloroimines with alcohols or amines under Pd-catalysis. The methodology has been also applied to
the preparation of heteroaryl acetic acid derivatives starting from chloromethyl heteroaromatic rings
containing a CAN double bond. The in situ generation of a b-imino acylpalladium species has been
proposed as a key step for the process.
Received 26 December 2015
Revised 5 February 2016
Accepted 9 February 2016
Available online 10 February 2016
a
Ó 2016 Published by Elsevier Ltd.
Keywords:
a-Chloroimines
b-Enamino esters
b-Enamino amides
Arylacetic acids
Pd-catalyzed carbonylation
Introduction
Such a strategy has been previously applied to the synthesis of
a
,b-unsaturated amides by performing the carbonylation reaction
Palladium catalyzed carbonylation is a powerful tool for syn-
thetic organic chemists because it allows the construction of valu-
of allylic halides in the presence of amines.4
On the basis of these results, we reasoned that the employment
able carbonyl compounds in
a
single step with efficiency,
of a-chloroimines as a,b-unsaturated substrates for a Pd-catalyzed
selectivity, and atom economy. As well as the most palladium
mediated CAC bond forming reactions, Pd-catalyzed carbonylation
is compatible with a range of functional groups and gives consider-
able advantages over standard organolithium and Grignard chem-
istry for the synthesis of aldehydes, acids, esters, and amides.1
carbonylation could represent a short way for the formation of
b-enamino esters or amides (Scheme 2).
b-Enamino acid derivatives are a class of valuable synthetic
intermediates. Therefore, the development of new methodologies
for their preparation is desirable for accessing biologically relevant
molecules containing or deriving from this structural motif.5
Moreover, b-enamino acid derivatives have been shown to be
useful building blocks in asymmetric organic synthesis;6 among
them, the noteworthy catalytic enantioselective reduction was
pioneered by Noyori to obtain optically active b-aminoacids.6c
In addition to the classical condensation between b-keto
acid derivatives and amines, the synthesis of b-enamino acid
As part of our previous studies on the carbonylation of
a,b-
unsaturated halides,2 we found that treatment of allyl chloride
with a series of aliphatic and aromatic alcohols, under CO pressure
(27 atm) at 100 °C, in the presence of Pd(OAc)2, NEt3, and PPh3, led
to a number of b,c-unsaturated esters after 10 h (Scheme 1).
Conversely, when the reaction time was increased to 20 h, we
isolated the conjugated a,b-unsaturated ester as the main product
of the reaction (Scheme 1).3 The observed CAC double bond shift in
the product is likely due to thermodynamic reasons. Indeed,
O
O
ROH, Pd(OAc)2, PPh3
a,b-unsaturated esters can benefit of a stabilizing delocalization
Cl
+
OR
OR
CO (27 atm), Et3N
THF, 100 °C
phenomenon with respect to their b,c-unsaturated isomers.
main product
after 10 hours
main product
after 20 hours
⇑
Corresponding authors. Fax: +39 0832 298732.
E-mail addresses: antonio.salomone@unisalento.it (A. Salomone), luigino.troisi@
unisalento.it (L. Troisi).
Scheme 1. Synthesis of unsaturated esters by Pd-catalyzed carbonylative coupling
between the allyl chloride and alcohols.
http://dx.doi.org/10.1016/j.tetlet.2016.02.035
0040-4039/Ó 2016 Published by Elsevier Ltd.

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S. Perrone et al. / Tetrahedron Letters 57 (2016) 1421–1424
Table 1
R1
R
R1
NH O
N
Optimization of reaction conditions for the model carbonylative coupling between
Cl
+ CO +
R3XH
imine 2a and methanola
XR3
R
Ph
Ph
Ph
Ph
O
N
X = O, NH
NH O
PhNH2
MeOH
Cl
Cl
Ph
OMe
Pd-catalyst
Et3N, CO (27 atm)
Temp., Time
dry Et2O
MS (5Å)
Scheme 2. Retrosynthetic analysis for the preparation of
b-aminoacid derivatives from -chloroimines.
a,b-unsaturated
a
-3a
(Z)
1a
2a
derivatives have been recently obtained by different routes involv-
ing the addition of amines to acrylates,7a propiolates,7b–d by the
reaction of imines to activated carbonic acid derivatives,7e or by
lithiation of 5-phenylthioisoxazolines.7f
In this Letter we report a novel one-pot synthetic procedure for
the preparation of b-enamino esters or amides by a Pd-catalyzed
Entry
Catalyst
Temp (°C)
Time (h)
Solvent
(Z)-3a
Yieldb (%)
1
2
3
4
5
6
7
8
Pd(OAc)2
Pd2(dba)3
Pd/C
110
110
110
110
90
20
20
20
20
20
48
48
20
20
20
10
10
THF
THF
THF
THF
THF
THF
THF
THF
Et2O
45
34
20
70
45
20
<5
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
carbonylation of
a-chloroimines in the presence of alcohols or
60
25
amines, respectively.
c
110
110
110
110
110
—
Results and discussion
9
<5
10
11
12
Toluene
THF
THF
18
63
72d
The reaction of the imine 2a with carbon monoxide and metha-
nol, under palladium-catalysis, was chosen as a model experiment
(Table 1).
a
Reagents and conditions on 1 mmol scale:
methanol (3.0 mmol), NEt3 (2.0 mmol), Pd-catalyst (2 mol %), CO (27 atm), dry THF
(15 mL), 110 °C. All reactions were run in duplicate.
a-chloroimine 2a (1.0 mmol),
The
a-chloroimines 2 were prepared by a direct condensation of
the corresponding
a-chloroketone 1a–d (Fig. 1) with an appropri-
b
Isolated yield after column chromatography on silica-gel.
Reaction performed without NEt3.
Reaction performed with 5 equiv of MeOH.
ate primary amine in dry Et2O, according to Taguchi’s protocol
c
(Tables 1 and 2).8
d
Unfortunately, any attempt of isolation of a-chloroimines 2a–f,
by column chromatography on silica gel, resulted ineffective since
O
O
O
O
the product was rapidly hydrolyzed back to the corresponding
Cl
Cl
Cl
Cl
starting
a-chloroketone 1 and amine. For this reason, the crude
imine 2, obtained after filtration of the molecular sieves and
removal of the solvent under vacuum, was used for the carbonyla-
tion reaction without any further purification.9
1a
1b
1c
1d
We began our investigation by trialing the carbonylative cou-
pling under the following experimental conditions: freshly pre-
Figure 1.
a-Chloroketones used in this study.
pared
a-chloroimine 2a (1.0 mmol), methanol (3.0 mmol), NEt3
We next looked at applying our conditions to C-alkyl, N-arylim-
ines, such as the derivatives 2d-f (Table 2, entries 3–5). Pleasingly,
products 3d–f were formed in fairly good to high yields (65–93%),
(2.0 mmol), and Pd(OAc)2 (2 mol %) were dissolved in dry THF
(15 mL). The resulting solution was placed in an autoclave, under
CO pressure (27 atm), and heated at 110 °C for 20 h. Initial results
were encouraging: the use of Pd(OAc)2 as catalyst gave the desired
b-enamino ester (Z)-3a10 in 45% yield (Table 1, entry 1).
Based on our previous experience in the field of carbonylations,
we decided to screen different Pd-catalysts and found that Pd
(PPh3)4 was optimal, increasing the yield up to 70% (Table 1, entries
2–4). Control experiments established that a high temperature
(110 °C), NEt3, and THF were all required for a successful reaction
(Table 1, entries 5–10).
A brief screening of the reaction time and methanol equivalents
demonstrated that after only 10 h the product 3a was already
formed; particularly, it was isolated in 63% and 72% yield when 3
and 5 equiv of methanol were used, respectively (Table 1, entries
11 and 12).
demonstrating that the reaction can be performed also with
a-
chloroimines containing an exocyclic CAN double bond (Table 2,
entry 4) or a bulky group such as a tert-butyl as a C-substituent
(Table 2, entry 5).
The formation of the methyl esters 3a–f, as the main products of
our carbonylation reactions, can be explained if a b-imino acylpal-
ladium species A (Scheme 3) is postulated as an acylating interme-
diate reacting with methanol. On the basis of this assumption we
envisioned that the scope of this reaction could be expanded to
the synthesis of b-enamino amides by replacing the alcohol with
a suitable amine.
With no further optimization of the reaction conditions, we
were pleased to find that when the
a-chloroimines 2a or 2f were
carbonylated in the presence of an excess of isopropylamine or
diethylamine, b-enaminoamides 3g and 3h were isolated in 85%
and 55% yield, respectively (Table 2, entries 6 and 7).
In terms of method limitations, we observed that no carbonyla-
tive coupling occurred when either phenol or aniline was
employed as a nucleophile (Table 2, entries 8 and 9). In these cases,
the dehalogenated imine was the only product detectable by 1H
NMR and GC–MS analyses of the crude mixture.
It is noteworthy that all the synthesized products 3a–h showed
a Z-configuration.12 Such high stereoselectivity of the process can
be rationalized by considering that the formation of a stabilizing
intramolecular hydrogen bond between the enaminic NH and the
carbonyl group with the related formation of a six-membered ring
is allowed only in the Z isomers.13
As a drawback, it is necessary to point out that the
a-chloroi-
mine 2a, used in the model reaction (Table 1), was found to lose
the chlorine atom during the reaction. In fact, beside the target
product 3a we observed the corresponding dehalogenated imine
(detected by 1H NMR and GC–MS on the crude reaction mixture).11
With the best conditions in hand (Table 1, entry 12) we exam-
ined the scope of the reaction by extending the methodology to a
variety of
(Table 2).
a-chloroimines 2b–f and aliphatic alcohols or amines
It was found that, in addition to the C,N-diaryl substituted imine
2a, also the N-alkyl derivatives 2b and 2c were successfully car-
bonylated in the presence of an excess of methanol to afford (Z)-
b-enamino esters 3b and 3c in moderate to good yields (66–85%,
Table 2, entries 1 and 2).

S. Perrone et al. / Tetrahedron Letters 57 (2016) 1421–1424
1423
Table 2
Once 4a was subjected to the carbonylative coupling with
methanol or isopropanol, under the reaction conditions optimized
for 2a, it successfully afforded the expected heteroaryl acetate 5a
and 5b in 87% and 80% yield, respectively (Table 3, entries 1 and 2).
Similarly, we found that the efficiency of the methodology
remained unchanged when benzimidazole derivative 4b was car-
bonylated in the presence of an excess of methanol, to produce
the ester 5c in 85% yield (Table 3, entry 3).
Scope of the carbonylative coupling between
a
-chloroimines 2a–f and alcohols or
aminesa,b
R2
R2
R2NH2
R3XH
O
N
NH O
Cl
Cl
R1
R1
XR3
R1
Pd(PPh3)4
Et3N, CO (27 atm)
110 °C, 10 hours
dry Et2O
MS (5Å)
1a-e
2a-f
(Z)-3b-h
In contrast, when 2-chloromethyl pyridine 4c was subjected to
the coupling with isopropanol, we isolated the 2-pyridylacetate
5d in only 30% yield (Table 3, entry 4). To explain such a dramatic
decrease in the yield, we hypothesize that the pyridine ring can
act as a nucleophile reacting with the acylpalladium intermediate A.
The reaction could be also applied to the synthesis of heteroaryl
acetamides when the chlorides 4a–c were subjected to our car-
bonylation procedure in the presence of primary and secondary
amines (Table 3, entries 5–8). Indeed, benzothiazole and benzimi-
dazole systems well tolerated the methodology leading to the for-
mation of the amides 5e–g in very good yields (90–96%, Table 3,
entries 5–7); unfortunately, the carbonylative coupling between
Entry
1
Imine 2
R1
R2
R3
X
O
Product 3
(Yield %)c
NH O
OMe
2b
2c
2d
Ph
n-Bu
Bn
Me
3b (85%)
NH O
OMe
2
3
Ph
Me
Me
O
O
3c (66%)
NH O
Me
Ph
OMe
3d (75%)
Table 3
Synthesis of heteroaryl-substituted acetic acid derivatives 5a–ha
O
Cl
NH O
O
Pd(PPh3)4
4
2e
Ph
Me
O
Ar Cl
Ar
RXH
+
OMe
XR
Et3N, CO (27 atm)
110 °C, 10 hours
4a-c
5a-h
3e (93%)
Entry
ArCH2Cl
R
X
Product 5
NH O
(Yield %)b
5
6
7
2f
2a
2f
t-Bu
Ph
Ph
Ph
Ph
Me
i-Pr
Et2
O
OMe
N
O
Cl
N
S
OMe
3f (65%)
S
4a
1
2
Me
O
5a (87%)
NH O
i-Pr
NH
N
O
N
N
S
Oi-Pr
H
4a
i-Pr
O
O
3g (85%)
5b (80%)
NH O
N
O
Cl
t-Bu
N
OMe
NEt2
N
H
3
Me
N
H
3h (55%)
4b
8
9
2b
2b
Ph
Ph
n-Bu
n-Bu
Ph
Ph
NH
O
—
—
5c (85%)
O
a
Cl
Reagents and conditions on 1 mmol scale: freshly prepared
a
-chloroimine 2
N
N
4
5
i-Pr
O
N
Oi-Pr
(1.0 mmol), alcohol or amine (5.0 mmol), NEt3 (2.0 mmol), Pd(PPh3)4 (2 mol %), CO
5d (30%)
4c
(27 atm), dry THF (15 mL), 110 °C, 10 h.
b
In the case of entry 4, the structure showed in the column R1 is intended to be as
O
N
NEt2
the whole chloroketone and not a substituent.
c
4a
Et2
Isolated yield after column chromatography on silica-gel.
S
5e (95%)
O
N
NHn-Bu
R2
R1
R2
R2
NH O
6
4a
n-Bu
NH
N
Pd(PPh3)4
MeOH
N
O
S
Cl
R1
OMe
Et3N, CO (27 atm) R1
110 °C, 10 hours
PdCl
5f (96%)
O
2a-f
A
3a-f
N
NHn-Bu
7
8
4b
4c
n-Bu
n-Bu
NH
NH
N
Scheme 3. b-Imino acylpalladium A: supposed key intermediate in the carbonyla-
tive coupling of -chloroimines with O-nucleophiles.
H
a
5g (90%)
O
N
NHn-Bu
5h (15%)
We then moved on to establish whether the present protocol
could be further extended toward the use of unsaturated halides
in which the CAN double bond belongs to an aromatic system.
To this end chloromethyl-substituted benzothiazole, pyridine,
and benzimidazole 4a–c were employed (Table 3).
a
Reagents and conditions on 1 mmol scale: chloromethyl arene 4 (1.0 mmol),
alcohol or amine (5.0 mmol), NEt3 (2.0 mmol), Pd(PPh3)4 (2 mol %), CO (27 atm), dry
THF (15 mL), 110 °C, 10 h.
b
Isolated yield after column chromatography on silica-gel.

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S. Perrone et al. / Tetrahedron Letters 57 (2016) 1421–1424
Organomet. 2008, 27, 5402–5422; (g) Gabriele, B.; Salerno, G.; Costa, M. Top.
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5h in only 15% yield (Table 3, entry 8). GC–MS and 1H NMR analy-
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2. (a) Troisi, L.; De Vitis, L.; Granito, C.; Pilati, T.; Pindinelli, E. Tetrahedron 2004,
60, 6895–6900; (b) Troisi, L.; Ronzini, L.; Granito, C.; Pindinelli, E.; Troisi, A.;
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a competitive nucleophilic attack of
butylamine to 2-chlromethylpyridine occurred.14
To conclude, we developed a mild and high yielding methodol-
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a-chloroimines or chloromethyl heteroaromatic rings containing a
CAN double bond. The reaction provides access to b-enamino acid
derivatives and heteroaryl acetic esters or amides, in a single step
starting from cheap and readily available starting materials. Fur-
ther applications of this chemistry are currently being explored
in our laboratory.
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Acknowledgments
The authors thank the University of Salento and the Consorzio
Interuniversitario Nazionale ‘Metodologie e Processi Innovativi di
Sintesi’ (C.I.N.M.P.I.S).
Supplementary data
8. Westheimer, F. H.; Taguchi, K. J. Org. Chem. 1971, 36, 1570–1572.
9. The purity grade of crude imines 2a–f has been ascertained by 1H NMR with
the internal standard technique, and measured to be in 80–85% range.
10. (Z)-Methyl 3-phenyl-3-(phenylamino)propenoate 3a is known, and its
characterization data resulted in agreement with those reported in the
literature (see Supplementary material).
Supplementary data (synthesis of 2a–f, 3a–h, 5a–h and charac-
terization data for all new compounds) associated with this article
can be found, in the online version, at http://dx.doi.org/10.1016/j.
tetlet.2016.02.035.
11. A similar reactivity has been found in our laboratory when the carbonylation
References and notes
reaction of a-chloroketones has been examined: see Ref. 2e.
12. The relative configuration of products 3a–h has been determined by 2D 1H–1H
NOESY analyses.
1. For selected reviews on Pd-catalyzed carbonylation see: (a) Wu, X.-F.;
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Mutton, S. P. Tetrahedron 2010, 66, 5515–5548; (c) Brennführer, A.; Neumann,
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13. The intramolecular hydrogen bond formation (NAHÁ Á ÁO@C) for derivatives 3a–
h has been postulated by 13C NMR analysis in analogy to a previously reported
work: Fustero, S.; de la Torre, M. G.; Jofre, V.; Carlon, R. P.; Navarro, A.; Fuentes,
A. S.; Carrio, J. S. J. Org. Chem. 1998, 63, 8825–8836.
14. Two by products were found in the crude reaction mixture namely N-(pyridin-
2-ylmethyl)butan-1-amine and N,N-bis(pyridin-2-ylmethyl)butan-1-amine.