Palladium-catalyzed oxidative carbonylation of N-allylamines for the synthesis of β-lactams

Article abstract of DOI:10.1002/anie.201309081

β-Lactam scaffolds are considered to be ideal building blocks for the synthesis of nitrogen-containing compounds. A new palladium-catalyzed oxidative carbonylation of N-allylamines for the synthesis of α-methylene-β- lactams is reported. DFT calculations suggest that the formation of β-lactams via a four-membered-ring transition state is favorable. Four corners: The β-lactam scaffold is considered to be an ideal building block for the synthesis of nitrogen-containing compounds. A new, simple, and convenient palladium-catalyzed oxidative carbonylation of N-allylamines for the synthesis of α-methylene-β-lactams is reported. DFT calculations suggest that the formation of the β-lactam via a four-membered-ring transition state is favorable. Copyright

Full text of DOI:10.1002/anie.201309081

Angewandte
Chemie
DOI: 10.1002/anie.201309081
Heterocycles
Palladium-Catalyzed Oxidative Carbonylation of N-Allylamines for the
Synthesis of b-Lactams**
Wu Li, Chao Liu, Heng Zhang, Keyin Ye, Guanghui Zhang, Wangzheng Zhang, Zhengli Duan,
Shuli You,* and Aiwen Lei*
Abstract: b-Lactam scaffolds are considered to be ideal
building blocks for the synthesis of nitrogen-containing com-
pounds. A new palladium-catalyzed oxidative carbonylation of
N-allylamines for the synthesis of a-methylene-b-lactams is
reported. DFT calculations suggest that the formation of b-
lactams via a four-membered-ring transition state is favorable.
A
s one of the most important heterocyclic compounds, b-
lactams have been considered a privileged structure in
chemical, pharmaceutical, and materials industries.[1] More-
over, the b-lactam scaffold is considered an ideal building
block for the synthesis of nitrogen-containing compounds
which widely exist in vitamins, alkaloids, antibiotics, etc. For
example, the core structures of penicillin antibiotics, thiena-
mycin antibiotics, and ezetimibe,[2] are b-lactams (Scheme 1).
This four-membered ring has also been used as a synthon in
the preparation of various non-b-lactam compounds of
biological significance.[3] For example, nylon 3 polymers are
synthesized from b-lactams through ring-opening polymeri-
zation.[4]
Scheme 1. Examples of important b-lactam-containing pharmaceuticals
and b-lactam units.
methods, as well as control of the stereoselectivity and
regioselectivity, has attracted the attention of synthetic
chemists, but great challenges still remain.
Carbonylation of organic compounds with CO is an
effective approach for introducing a carbonyl group into
organic molecules, and has attracted much attention from
synthetic chemists in the past two decades.[6] Several
approaches for the synthesis of b-lactams by palladium-
catalyzed carbonylation have been reported. However, these
methods generally require multistep procedures, not-readily-
available starting materials, and substrate pre-functionaliza-
tion, such as organobromides or aziridines.[7] Oxidative
Among the synthetic methods to obtain b-lactams, the
Staudinger synthesis, the formal [2+2] cycloaddition of imines
to ketenes, is well known.[5] However, generation of the
ketene requires treatment of activated carboxylic acid
derivatives such as acyl chlorides which sometimes limits its
potential. Considering the large pharmacological importance
of b-lactams, the search for simple, efficient, and economic
À
À
carbonylation of simple nucleophiles such as C H or Y H
(Y= O, N, etc), has been considered as an ideal carbonylation
approach in recent years.[8] However, to the best of our
knowledge, no example has been reported on the oxidative N-
allylamine carbonylation for the direct synthesis of b-lactams.
Herein, we communicate the first report on a practical
synthesis of b-lactams by palladium-catalyzed oxidative
carbonylation of N-allylamines (Scheme 2).
[*] W. Li, Dr. C. Liu, Prof. H. Zhang, G. Zhang, W. Zhang, Z. Duan,
Prof. A. Lei
College of Chemistry and Molecular Sciences, Wuhan University
Wuhan 430072, Hubei, (P. R. China)
E-mail: aiwenlei@whu.edu.cn
Homepage: http://aiwenlei.whu.edu.cn/Main_Website/
Prof. A. Lei
National Research Center for Carbohydrate Synthesis
Jiangxi Normal University
Nanchang 330022, Jiangxi (P. R. China)
K. Ye, Prof. S. You
State Key Laboratory of Organometallic Chemistry, Shanghai
Institute of Organic Chemistry, Chinese Academy of Sciences
345 Lingling Lu, Shanghai, 200032 (China)
E-mail: slyou@mail.sioc.ac.cn
Scheme 2. Oxidative carbonylation for b-lactam synthesis.
[**] This work was supported by the 973 Program (2012CB725302), the
National Natural ScienceFoundation of China (21390400,
21025206, 21272180, and 21302148), the Research Fund for the
Doctoral Program of Higher Education of China (20120141130002),
and the Program for Changjiang Scholars and Innovative Research
Team in University (IRT1030).
For the initial model reaction, we selected N-allyl-4-
methylaniline (1a) as the substrate. After considerable
optimization, 1 atmoshpere of CO in the presence of PdCl2
(10 mol%), PCy3 (20 mol%), Cu(OAc)2 (2.0 equiv), and
PivOH (2.0 equiv) in DMF at 1008C for 1 hour afforded the
desired product 2a in 71% yield (Table 1, entry 1). The
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201309081.
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Table 1: Carbonylation of N-allyl-4-methylaniline.[a]
Entry
Catalyst
Oxidant
Additive
Yield [%][b]
1
2
3
4
5
6
7
8
9
PdCl2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OPiv)2
Cu(OPiv)2
–
PivOH
PivOH
PivOH
PivOH
HOAc
PivOH
–
71
62
[PdCl2(PPh3)2]
[Pd(dba)2]
PdCl2
PdCl2
PdCl2
PdCl2
PdCl2
–
12
54[c]
56
74 (74)[d]
53
0
0
PivOH
PivOH
Cu(OPiv)2
[a] Reaction conditions: 1a (0.2 mmol), catalyst (0.02 mmol), PCy3
(0.04 mmol), oxidant (0.4 mmol), additive (0.4 mmol), and solvent
(2 mL) under 1 atm of CO at 1008C for 1 h. [b] Yields were determined by
gas chromatography (GC) using biphenyl as an internal standard.
[c] 808C. [d] Yield of isolated product. dba=dibenzylideneacetone,
DMF=N,N-dimethylformamide, Piv=pivaloyl.
1
structure of 2c was confirmed by H/13C NMR spectroscopy,
high-resolution mass spectrometry (HRMS), and X-ray
crystal diffraction analysis (see the Supporting Information).
Other palladium catalysts, such as [PdCl2(PPh3)2] and [Pd-
(dba)2], were less effective and afforded 2a in yields of 62%
and 12%, respectively. When the reaction was carried out at
a lower reaction temperature, the yield decreased to 54%
(Table 1, entry 4). The yield of the desired product decreased
when HOAc was used as an additive (Table 1, entry 5).
Actually, under the reaction conditions used in entry 1 of
Table 1, the N-acetylation product was observed as a side
product and the acetyl group was believed to be generated
from Cu(OAc)2. Therefore, Cu(OPiv)2 was used to replace
Cu(OAc)2 as the oxidant (Table 1, entry 6), thus completely
inhibiting the acylation and increasing the yield of the product
to 74%. In the absence of acid, we only obtained a moderate
yield of the desired product (Table 1, entry 7). It was also
notable that no product was observed in the absence of
Cu(OPiv)2 or PdCl2 (Table 1, entries 8 and 9). After a brief
screen of the reaction conditions we found the optimized
reaction required treatment of 1a with PdCl2 (10 mol%),
PCy3 (20 mol%), Cu(OPiv)2 (2.0 equiv), and PivOH
(2.0 equiv) under 1 atmosphere of CO with DMF as the
solvent at 1008C for 1 hour (Table 1, entry 6).
Scheme 3. Carbonylation of various N-allylanilines to give a-methylene-
b-lactams. Reaction conditions: 1008C, N-allylamine (0.2 mmol), PdCl2
(10 mol%), PCy3 (20 mol%), Cu(OPiv)2 (0.4 mmol), PivOH
(0.4 mmol), CO (1 atm), DMF (2 mL), 1–24 h. Yield of isolated 2 is
given. [a] The reactions were carried out in an autoclave.
Encouraged by these initial results, we next evaluated the
substrate scope of this reaction (Scheme 3). Various N-
allylamines such as N-allylanilines, N-allylbenzylamines, N-
allyl-alkylamines, and branched N-allylamines were tested.
We firstly investigated the linear N-allylamines in which on
the phenyl ring had electron-donating substituents, such as
methyl and methoxy groups, and the carbonylation reaction
proceeded in high efficiency (2a, 2c, and 2d). Electron-
deficient N-allylanilines, for example, N-allyl-4-(trifluorome-
thyl)aniline, was not a good substrate for this reaction, thus
giving a decreased yield of 27% after 24 hours (2h).
Interestingly, N-allyl-4-chloroaniline underwent the carbon-
ylation reaction with a yield of 88% (2 f). Various substituents
such as F, Cl, and Br were also found to be compatible (2e–g),
thus suggesting the potential for further functionalization. N-
allyl benzylamines, N-allyl phenethylamine, and N-(3-phenyl-
propyl)prop-2-en-1-amine exhibited higher reactivity,
although in some cases only moderate yields were obtained
(2i–m). To our delight, a cyclopropyl substituent was well
tolerated in this reaction (2n and 2q). A long-chain N-
allylamine successfully provided the corresponding carbony-
lated product 2o in 62% yield, and the branched N-allyl-
amines surveyed under these reaction conditions led to the
corresponding products (2p, 2r, and 2s) in moderate yields.
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To further investigate the reaction of b-lactams generated
by palladium-catalyzed oxidative carbonylation of N-allyl-
amines, the subsequent study was focused on the enantioen-
riched N-allylamines. To our delight, enantioenriched N-
allylamines could be readily transformed into their corre-
sponding b-lactam derivatives without loss of enantioselec-
tivity under the standard reaction conditions (Table 2). Syn-
thesis of optically pure a-methylene-b-lactam scaffolds pro-
vides a useful platform for the synthesis of various biologically
interesting b-lactam derivatives.
Table 2: Carbonylation of various enantioenriched N-allylamines to give
a-methylene-b-lactams.[a]
Scheme 4. A possible mechanism for carbonylation.
In summary, we have developed a highly selective and
practical method for the synthesis of a-methylene-b-lactams.
Notably, this transformation offers a general, simple, efficient,
and environmentally benign process for converting readily
available N-allylamines directly into potentially useful com-
pounds in the presence of CO. Moreover, various functional
groups were well tolerated under the optimized reaction
conditions. Preliminary mechanistic studies suggest that the
formation of b-lactams via a four-membered-ring transition
state is favorable. This approach has the potential to be used
in many different areas of organic and medicinal chemistry,
and could possibly be applied in the chemical and pharma-
ceutical industries.
Entry Substrate
Product
t [h] Yield [%][b]
1
19
21
36
41
2
3
4
5
5
60
54
Experimental Section
General procedure for the palladium-catalyzed carbonylation of N-
allylamines: A balloon filled with CO was connected to an oven-dried
Schlenk tube equipped with a stir bar, PdCl2 (0.02 mmol), Cu(OPiv)2
(0.4 mmol), and PCy3 (0.04 mmol), PivOH (0.4 mmol), and the tube
was purged five times. DMF (2.0 mL) was then added to reaction
mixture by syringe, and the N-allylamine (0.2 mmol) was introduced.
The Schlenk tube was heated at 1008C for 1–24 h (as monitored by
TLC) and then cooled to room temperature. After the gas in the
balloon was released carefully, the reaction was quenched with
a saturated potassium carbonate solution and extracted three times
with CH2Cl2. The combined organic layers were dried over anhydrous
Na2SO4 and evaporated in vacuum. The desired products were
obtained in the corresponding yields after purification by flash
chromatography on silica gel using petroleum ether and ethyl acetate
(5:1).
[a] Reaction conditions: 1008C, N-allylamine (0.2 mmol), PdCl2
(10 mol%), PCy3 (20 mol%), Cu(OPiv)2 (0.4 mmol), PivOH (0.4 mmol),
CO (1 atm), DMF (2 mL). [b] Yield of isolated product. The ee values
were determined by HPLC using a ciral column.
A possible mechanism for this reaction has been outlined
in Scheme 4. The intermediate A is formed by the chelation of
1 to palladium, and subsequent migratory insertion of the
coordinated CO into the nitrogen–palladium bond forms B.[9]
The key results for the pathways leading to b-lactams are
illustrated in Scheme 5. The calculated free energy of forming
species I from 1-TS is 26.6 kcalmolÀ1. It undergoes b-hydride
elimination via transition-state 2-TS with an activation free
energy of 19.9 kcalmolÀ1. This result is in agreement with the
experimental data for 2b. In contrast, the calculated activa-
tion free energy for the formation of the five-membered
product via transition-state 3-TS is 33.5 kcalmolÀ1, and
undergoes b-hydride elimination through transition-state 4-
TS with an activation free energy of 6.2 kcalmolÀ1, thus
suggesting that thermodynamic control resulting in 3b is, in
this case undesirable.
Received: October 17, 2013
Revised: December 8, 2013
Published online: January 28, 2014
Keywords: allylic compounds · heterocycles · lactams ·
.
palladium · synthetic methods
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