A facile approach to β-amino acid derivatives via palladium-catalyzed hydrocarboxylation of enimides with formic acid

Article abstract of DOI:10.1039/c5ob01304f

An effective Pd(0)-catalyzed hydrocarboxylation of enimides with formic acid in the presence of a catalytic amount of HCOOPh is described. A variety of β-amino acid derivatives are obtained in good yields with high regioselectivities without using external toxic CO gas.

Full text of DOI:10.1039/c5ob01304f

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DOI: 10.1039/C5OB01304F
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A Facile Approach to β-Amino Acid Derivatives via Palladium-
Catalyzed Hydrocarboxylation of Enimides with Formic Acid
Jie Dai,a Wenlong Ren,a Haining Wang,a and Yian Shi*,a,b,c
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
www.rsc.org/
Scheme 2. Hydrocarboxylation with HCOOH
Abstract: An effective Pd(0)-catalyzed hydrocarboxylation of
enimides with formic acid in the presence of catalytic amount of
HCOOPh is described. A variety of β-amino acid derivatives are
obtained in good yields with high regioselectivities without using
external toxic CO gas .
O
O
(η3-C3H5)2Pd2Cl2
COOH
DPEphos
N
N
HCOOPh, HCOOH
R
R
O
O
β-Amino acids are important functional moieties present in
various peptides, peptidomimetics, and biologically active
compounds.1 A variety of effective methods have been developed
N-Vinylphthalimide 1b was used as the test substrate for initial
studies. Only trace amount of acid 2b was formed when 1b was
treated with 5 mol % Pd(PPh3)4, 1.2 equiv HCOOPh, and 1 equiv
HCOOH in toluene at 80 oC for 16 h (Table 1, entry 1). The reaction
was subsequently examined with several Pd catalysts in the
for the synthesis of this class of compounds.2
The
hydrocarbonylation of enamines and related compounds would
provide an attractive approach to β-amino acids and their
derivatives (Scheme 1).3 Thus far, a number of such processes have
been reported primarily with N-ethenylphthalimide as substrate.4-7
Developing a reaction process with a broad substrate scope is highly
desirable. During our continuing studies on the hydrocarbonylation
of olefins without using external CO gas,8-11 we have recently found
that carboxylic acids can be obtained from olefins with HCOOH and
HCOOPh in the presence of Pd(0) catalyst.12 Our further studies
show that this system is also highly effective for various substituted
N-vinylphthalimides, giving the corresponding β-amino acid
derivatives in good yields and high regioselectivities (Scheme 2).
Herein, we wish to report our preliminary results on this subject.
presence of PPh3 (Table 1, entries 2-5).
The best yield was
obtained with (η3-C3H5)2Pd2Cl2 (APD). Further studies showed that
the ligand had a profound impact on the reaction (Table 1, entries
6-14). The best results were obtained with P(p-tolyl)3 and DPEphos
(L3) (Table 1, entries 7 and 14). Acid 2b was obtained in 93% yield
with ligand L3 when 2 equiv HCOOH was used (Table 1, entry 15).
In this case, little ester 3b was observed from the crude reaction
mixture by 1H NMR. A high yield (93%) was still obtained with less
amount of the catalyst (0.5 mol %) and catalytic amount of HCOOPh
(Table 1, entry 16).12 The reaction also proceeded efficiently at
lower temperature (60 oC) (Table 1, entry 17). Ester 3b was isolated
in good yield when the reaction was carried out in the absence of
HCOOH (Table 1, entry 18).
Scheme 1. Hydrocarbonylation with CO
O
As shown in Table 2, the hydrocarboxylation reaction can be
extended to various substituted N-vinylphthalimides, giving the
corresponding carboxylic acids in 60-98% yield (the X-ray structure
of acid 2a is shown in Figure 1). The R group can be both alkyl and
aromatic groups. The alkyl groups can be linear (2b-e) or branched
(2f) alkanes. The phenyl groups can have various substituents (2h-
[CO]
R2N
R2N
X
[M]
a. State Key Laboratory of Coordination Chemistry, Collaborative Innovation Center
of Chemistry for Life Sciences, Center for Multimolecular Organic Chemistry,
School of Chemistry and Chemical Engineering, Nanjing University, Nanjing,
210093, China;
l).
In all cases, the hydrocarboxylation proceeded highly
regioselectively. As illustrated in the case of 2c, the phthalimide
was readily hydrolyzed to the corresponding β-amino acid (3c) in
98% yield with hydrazine hydrate in ethanol (Scheme 3).13
b. Beijing National Laboratory for Molecular Sciences, CAS Key Laboratory of
Molecular Recognition and Function, Institute of Chemistry, Chinese Academy of
Sciences, Beijing 100190, China;
c. Department of Chemistry, Colorado State University, Fort Collins, Colorado 80523,
United States. E-mail: Yian.Shi@colostate.edu
† We gratefully acknowledge the National Natural Science Foundation of China
(0205131566) and Nanjing University for the financial support. Electronic
Supplementary Information (ESI) available: [details of any supplementary
information available should be included here]. See DOI: 10.1039/x0xx00000x
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Table 1. Optimization of the reaction conditionsa
Table 2. Hydrocarboxylation of enimidesa,b
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DOI: 10.1039/C5OB01304F
COOH
0.5 mol %
O
COOPh
nC4H9
O
(η3-C3H5)2Pd2Cl2
[Pd], Ligand
COOH
nC4H9
nC4H9
2b
2 mol % L3
PhthN
PhthN
HCOOPh, HCOOH
PhthN
N
N
R
toluene, 80 oC, 16 h
HCOOH (2.0 equiv)
R
1b
3b
HCOOPh (0.2 equiv)
O
O
toluene, 24 h
yield (%)b
ligand
(mol %)
HCOOH
(equiv)
entry
[Pd] (mol %)
Pd(PPh3)4 (5)
2b
trace
28
29
32
68
0
3b
0
O
O
1
-
1
1
1
1
1
1
1
1
1
1
1
1
1
1
2
2
2
0
COOH
COOH
N
N
2
Pd(OAc)2 (5) PPh3 (20)
0
O
O
3
Pd(dba)2 (5)
Pd(acac)2 (5)
APD (2.5)
APD (2.5)
APD (2.5)
APD (2.5)
APD (2.5)
APD (2.5)
APD (2.5)
APD (2.5)
APD (2.5)
APD (2.5)
APD (2.5)
APD (0.5)
APD (0.5)
APD (2.5)
PPh3 (20)
PPh3 (20)
PPh3 (20)
0
2a,c 91%
2b, 93%
4
5c
0
O
0
O
N
O
COOH
COOH
6
P(o-tolyl)3 (20)
P(p-tolyl)3 (20)
L1 (20)
0
N
7
81
trace
0
0
O
8
0
2d, 95%
2c, 86%
9
dppe (10)
dppp (10)
dppb (10)
dppf (10)
L2 (10)
0
O
O
N
10
11
12
13
14
15
16e, f
17e, g
18 h
27
65
51
58
77
93
93
93
0
0
COOH
COOH
12d
15d
17d
14d
0
N
O
O
O
2f, 98%
O
O
2e, 98%
L3 (10)
O
COOH
L3 (10)
COOH
N
O
N
O
L3 (2)
0
L3 (2)
0
L3 (10)
86
CH3
2g, 80%
2h, 78%
O
O
COOH
COOH
P
CF3
N
O
N
O
O
O
3
PPh2
PPh2
PPh2
PPh2
L1
L2
L3
OCH3
Cl
aThe reactions were carried out with 1b (0.50 mmol), [Pd] (0.0050 mmol),
ligand (0.050 mmol or 0.10 mmol, P/Pd = 4/1), HCOOPh (0.60 mmol), and
HCOOH (0.50-1.0 mmol) in toluene (0.50 mL) at 80 oC for 16 h unless
2i, 60%
2j, 86%
O
O
N
COOH
COOH
N
O
otherwise stated. bIsolated yield. APD = (η3-C3H5)2Pd2Cl2. dThe yield was
c
determined from the crude reaction mixture by 1H NMR with BnOCH3 as an
OCH3
O
internal standard. eWith 0.10 mmol of HCOOPh. At 80 oC for 24 h. gAt 60
f
2k,d 90%
2l, 82%
h
oC for 24 h. In toluene (0.2 mL) at 80 oC for 24 h.
aThe reactions were carried out with 1 (0.50 mmol), (η3-C3H5)2Pd2Cl2 (0.0025
mmol), L3 (0.010 mmol), HCOOPh (0.10 mmol), and HCOOH (1.0 mmol) in
toluene (0.50 mL) at 80 oC for 24 h unless otherwise stated. bIsolated yield.
d
cIn 0.2 mL of toluene. At 60 oC for 24 h.
Figure 2. X-ray structure of compound 2a
Scheme 3. Hydrolysis of phthalimide
O
COOH
NH2NH2 H2O
N
COOH
EtOH, reflux
98%
NH2
O
2c
3c
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A precise understanding of the reaction mechanism
awaits further study. A catalytic cycle analogous to the
previously proposed pathway is shown in Scheme 4.12 The
oxidative addition of Pd(0) to HCOOPh gave palladium hydride
COMMUNICATION
Applications, C. Schmuck and H. Wennemers, Ed.; Wiley-VCH
Verlag GmbH & Co. KGaA, Weinheim, 2004, pp.V6ie3w-8A9rti.cle Online
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2
3
complex 5, which rearranged to complex 6.
The
hydropalladation of the enimide (1a) by 6 generated alkyl
palladium complex 7, which gave acylpalladium complex 8
after a migratory insertion. The PhO group of 8 was
subsequently replaced by the formate to give complex 9,
which underwent a reduction elimination to form mixed
anhydride 10 with regeneration of the Pd(0) catalyst.
Anhydride 10 was converted to carboxylic acid 2a by reacting
with PhOH and/or via decomposition under the reaction
conditions. In the absence of HCOOH, acylpalladium complex
8 can undergo a reductive elimination to an ester (3a).
4
Scheme 4. Proposed catalytic cycle for hydrocarboxylation
COOH
+
HCOOPh
PhthN
PhthN
2a
10
4
PhOH
O
O
H
Pd(0)
HCOOPh
O
4
5
6
For a leading reference on hydroesterification of phthalimide
with CO, see: (a) G. Cavinato, L. Toniolo, J. Organomet.
Chem., 1982, 229, 93; (b) B. C. Zhu and X. Z. Jiang, Appl.
Organometal. Chem., 2006, 20, 277.
O
O
O
PhthN
PhOH
Pd
O
H
PhO
Pd
H
9
5
For a leading reference on hydroesterification of phthalimide
with HCOOMe, see: I. Fleischer, R. Jennerjahn, D. Cozzula, R.
Jackstell, R. Franke, and M. Beller, ChemSusChem, 2013, 6,
417.
HCOOH
PhthN
O
OPh
Pd
7
8
For
a
leading reference on aminocarbonylation of
Pd OPh
H
CO
8
6
phthalimide with CO, see: X. Fang, R. Jackstell and M. Beller,
Angew. Chem. Int. Ed., 2013, 52, 14089.
Pd(0) + CO + PhOH
Pd(0)
O
OPh
Pd
For leading reviews on metal-catalyzed hydrocarboxylation
with CO surrogates, see: (a) G. Jenner, App. Catal. A:
General, 1995, 121, 25; (b) T. Morimoto, K. Kakiuchi, Angew.
Chem. Int. Ed., 2004, 43, 5580; (c) L. Wu, Q. Liu, R. Jackstell,
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Konishi, K. Manabe, Synlett, 2014, 25, 1971; (e) B. Liu, F. Hu,
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Lee, K. Shin, S. Chang, Org. Lett., 2014, 16, 2010.
PhthN
PhthN
OPh
PhthN
CO
3a
1a
7
In summary, we have developed an efficient Pd-catalyzed
hydrocarboxylation of enimides with HCOOH and catalytic
amount of HCOOPh. A variety of β-amino acid derivatives
have been obtained in 60-98% yields with high
regioselectivities. The reaction is operationally simple and
requires no handling of toxic CO gas. The current process
provides a potentially useful method for the synthesis of β-
amino acids and their derivatives. Further efforts will be
devoted to better understanding the reaction mechanism,
further expanding the substrate scope, and developing the
asymmetric process for the hydrocarboxylation reaction.
9
Notes and references
1
For a leading review, see: F. von Nussbaum and P. Spiteller,
in Highlights in Bioorganic Chemistry: Methods and
10 For leading references on Pd-catalyzed hydroesterification
with formates in the absence of CO gas, see: (a) J. Grevin, P.
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Kalck, J. Organomet. Chem., 1994, 476, C23; (b) Y. Katafuchi,
T. Fujihara, T. Iwai, J. Terao, Y. Tsuji, Adv. Synth. Catal., 2011,
353, 475; (c) Reference 6.
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11 H. Wang, B. Dong, Y. Wang, J. Li, Y. Shi, Org. Lett., 2014, 16,
186.
12 Y. Wang, W. Ren, J. Li, H. Wang, Y. Shi, Org. Lett., 2014, 16,
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13 B. Weiner, A. Baeza, T. Jerphagnon, B. L. Feringa, J. Am.
Chem. Soc., 2009, 131, 9473.
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Table of Contents
0.5 mol %
(η3-C3H5)2Pd2Cl2
2 mol % L
O
O
COOH
N
N
O
R
HCOOH (2.0 equiv)
HCOOPh (0.2 equiv)
toluene, 80 oC, 24 h
R
PPh2
PPh2
O
O
L
60-98%
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