Pd-catalyzed tandem cyclization of ethyl glyoxalate and amines: Rapid assembly of highly substituted cyclic dehydro-α-amino acid derivatives

Article abstract of DOI:10.1021/ol302483f

A novel cascade cyclization of ethyl glyoxalate and amines proceeds in the presence of Pd(TFA)₂ (5 mol %) to give the cyclic dehydro-α-amino acid derivatives. This method provides a fast and simple access to highly substituted dihydro-pyrrol-2-ones in good yields.

Full text of DOI:10.1021/ol302483f

ORGANIC
LETTERS
2012
Vol. 14, No. 22
5640–5643
Pd-Catalyzed Tandem Cyclization of Ethyl
Glyoxalate and Amines: Rapid Assembly
of Highly Substituted Cyclic
Dehydro-r-Amino Acid Derivatives
Yueting Luo,† Xiaoxia Lu,‡ Yong Ye,*,† Ya Guo,† Huanfeng Jiang,† and Wei Zeng*,†
School of Chemistry and Chemical Engineering, South China University of Technology,
No. 381, Wushan Road, Tianhe District, Guangzhou 510641, China, and Chengdu
Institute of Biology, Academy of Sciences, Chengdu 610041, China
yeyong@scut.edu.cn; zengwei@scut.edu.cn
Received September 9, 2012
ABSTRACT
A novel cascade cyclization of ethyl glyoxalate and amines proceeds in the presence of Pd(TFA)2 (5 mol %) to give the cyclic dehydro-R-amino acid
derivatives. This method provides a fast and simple access to highly substituted dihydro-pyrrol-2-ones in good yields.
Dihydro-pyrrol-2-one (DPO) derivatives are widely uti-
lized as key building blocks for the construction of various
biologically active natural products and pharmaceutical
molecules,1 and their importance has already triggered
many efficient synthetic strategies to access such a lactam
family.2 Among these versatile synthetic methods, transi-
tion-metal catalyzed multicomponent reactions (MCRs)
involved in aldehydes and amines have attracted particular
attention, as they can provide expedient synthesis of multi-
substituted pyrrol-2-one compounds.2gÀi In all of these
transformations, imines derived from aldehydes and amines
were proposed as intermediates which then further reacted
with the third reactive partner such as an alkene, alkyne,
etc. to furnish the target DPO analogs (Scheme 1a).2gÀi
However, despite much progress in this field, studies on
transition-metal catalyzed rapid assembly of DPO mole-
cules only from an aldehyde and an amine were unprece-
dented. Nevertheless, given that ethyl glyoxalate (1a) and
(3) (a) Olmos, A.; Louis, B.; Pale, P. Chem.;Eur. J. 2012, 18, 4894.
(b) Li, X.; Mao, Z.; Dai, X.; Lu, P.; Wang, Y. Chem. Commun. 2011, 47,
6620. (c) Olmos, A.; Sommer, J.; Pale, P. Chem.;Eur. J. 2011, 17, 1907.
(d) Saupe, J.; Roske, Y.; Schillinger, C.; Kamdem, N.; Radetzki, S.;
Diehl, A.; Oschkinat, H.; Krause, G.; Heinemann, U.; Rademann, J.
ChemMedChem 2011, 6, 1411. (e) Borrione, E.; Prato, M.; Scorrano, G.;
Stivanello, M.; Lucchini, V. J. Heterocycl. Chem. 1988, 25, 1831.
(4) For selected examples about insertion of Co(I), Rh(I), and Ru(0)
into aldehyde Csp2ÀH bond, see: (a) Garralda, M. A. Dalton Trans.
2009, 3635. (b) Krug, C.; Hartwig, J. F. J. Am. Chem. Soc. 2002, 124,
1674. (c) Lenges, C. P.; White, P. S.; Brookhart, M. J. Am. Chem. Soc.
1998, 120, 6965. (d) Ko, S.; Han, H.; Chang, S. Org. Lett. 2003, 5, 2687.
(e) Kwong, F. Y.; Li, Y. M.; Lam, W. H.; Qiu, L. Q.; Lee, H. W.; Yeung,
C. H.; Chang, K. S.; Chan, A. S. C. Chem.;Eur. J. 2005, 11, 3872. For
examples about insertion of Pd(II) into aldehyde Csp2ÀH bond, see: (f)
Wu, Y.; Li, B.; Mao, F.; Li, X.; Kwong, F. Y. Org. Lett. 2011, 13, 3258.
† South China University of Technology.
‡ Chengdu Institute of Biology, Academy of Sciences.
(1) For selected examples, see: (a) Lewis, J. R. Nat. Prod. Rep. 1994,
11, 329. (b) Rigby, J. H.; Hughes, R. C.; Heeg, M. J. J. Am. Chem. Soc.
1995, 117, 7834. (c) Celmer, W. D.; Salomons, J. A. J. Am. Chem. Soc.
1955, 77, 2861. (d) Mandal, A. K.; Hines, J.; Kuramochi, K.; Crews.,
C. M. Bioorg. Med. Chem. Lett. 2005, 15, 4043.
(2) For selected examples, see: (a) Montforts, V. F. P.; Schwartz,
U. M. Angew. Chem. 1985, 97, 767. (b) Albrecht, D.; Basler, B.; Bach, T.
J. Org. Chem. 2008, 73, 2345. (c) Hughes, G.; Kimura, M.; Buchwald,
S. L. J. Am. Chem. Soc. 2003, 125, 11253. (d) Li, W. R.; Lin, S. T.; Hsu,
N. M.; Chern, M. S. J. Org. Chem. 2002, 67, 4702. (e) Tekkam, S.; Alam,
M. A.; Jonnalagadda, S. C.; Mereddy, V. R. Chem. Commun. 2011, 47,
ꢀ
(g) Alvarez-Bercedo, P.; Flores-Gaspar, A.; Correa, A.; Martin, R.
J. Am. Chem. Soc. 2010, 132, 466. (h) Waldo, J. P.; Zhang, X.; Shi, F.;
Larock, R. C. J. Org. Chem. 2008, 73, 6679. (i) Wei, L.; Wei, L.; Pan, W.;
Wu, M. Synlett 2004, 1497. (j) Sakakibara, K.; Yamashita, M.; Nozaki,
K. Tetrahedron Lett. 2005, 46, 959. (k) Flores-Gaspar, A.; Marin, R.
Adv. Synth. Catal. 2011, 353, 1223. (l) Shibahara, F.; Kinoshita, S.;
Nozaki, K. Org. Lett. 2004, 6, 2437. (m) Pan, C.; Jia, X.; Cheng, J.
Synthesis 2012, 5, 677.
€
3219. (f) Anders, J. T.; Gorls, H.; Langer, P. Eur. J. Org. Chem. 2004,
1897. (g) Zhu, Q.; Jiang, H.; Li, J.; Liu, S.; Xia, C.; Zhang, M. J. Comb.
Chem. 2009, 11, 685. (h) Sun, J.; Wu, Q.; Xia, E. Y.; Yan, C. G. Eur. J.
Org. Chem. 2011, 2981. (i) Roy, S.; Reiser, O. Angew. Chem., Int. Ed.
2012, 51, 4722.
r
10.1021/ol302483f
Published on Web 10/26/2012
2012 American Chemical Society

amines (2) were often employed in most MCRs to con-
struct multifunctionalized heterocycles,3 we envisioned
that the oxidative addition of aldehyde Csp2ÀH to transi-
tionmetal salts (M) could provide the MÀH species A4 and
the subsequent imine (B) insertion to A,5 reductive elim-
ination, carbonyl reduction and dehydration would possi-
bly lead to the formation of enamine E, which could be
further cross-coupled or cyclized with R-imino ester B to
furnish DPO derivatives 3 (Scheme 1b). To test this
hypothesis, herein we describe a convenient synthesis of
highly substituted 1,5-dihydro-2H-pyrrol-2-ones through
Pd(II)-catalyzed cascade cyclization of ethyl glyoxalate
and amine.
Table 1. Optimization Results for the Palladium-Catalyzed
Cascade Cyclization of Ethyl Glyoxalate with p-Anisidinea
1a/2a
temp
yield
(%)b
entry
catalyst
Pd(OAc)2
(equiv)
(°C)
solvent
1
1/1
1/1
1/1
1/1
1/1
1/1
1/1
1/1
1/2
2/1
2/1
2/1
2/1
2/1
2/1
2/1
25
25
25
25
25
25
25
25
25
25
70
90
70
70
70
70
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
CH2Cl2
EtOAc
10
18
15
8
2
PdCl2(CH3CN)2
PdCl2
3
Scheme 1. Synthetic Strategies of the Pyrrol-2-ones Derivatives
4
PdCl2(Ph2PCH2)2
PdCl2(PhCN)2
PdCl2(PPh3)2
Pd(TFA)2
À
5
trace
10
37
0
6
7
8
9
Pd(TFA)2
Pd(TFA)2
Pd(TFA)2
Pd(TFA)2
Pd(TFA)2
Pd(TFA)2
Pd(TFA)2
Pd(TFA)2
trace
61
63
42
42
43
11
10
11
12
13
14
15
16
CH3CN
toluene
68c
a Reactions were run with 1a (0.15À0.60 mmol), 2a (0.30 mmol),
Pd(II) salt (5 mol %), and solvent (2.0 mL) under Ar in a sealed pressure
tube at the given temperature for 24 h unless otherwise noted. b Isolated
yield. c Reaction time: 48 h.
At the outset of our study, we conducted the Pd(II)-
catalyzed tandem assembly of 1, 5-dihydro-2H-pyrrol-2-
one using ethyl glyoxalate (1a) and p-anisidine (2a) as
model substrates to screen the reaction conditions for the
optimization of the catalyst, solvent, and temperature under
an Ar atmosphere. First, ethyl glyoxalate 1a (0.30 mmol)
was treated with Pd(OAc)2 (5 mol %) and p-anisidine 2a
(0.30 mmol) in toluene (2.0 mL) at 25 °C for 24 h. As
expected, we obtained a 10% yield of pyrrol-2-one 3a
(Table 1, entry 1), and this positive result encouraged us
to further screen various palladium salts such as PdCl2,
PdCl2(PhCN)2, etc. to achieve satisfying yields (entries
1À7). To our delight, Pd(TFA)2 gave a 37% yield of
target compound 3a (entry 7). It is noteworthy that no 3a
formation was observed in the absence of palladium salts
(entry 8). We then switched to using 2.0 equiv of 2a to
increase the yield of this trasnformation. Again, no reac-
tion was noted (entry 9). Subsequently, the increased yield
(68%) was obtained by using 2.0 equiv of 1a at 70 °C for
48 h (compare entries 10À11 with 16). A further increase
in reaction temperature (90 °C) or use of other polar
solvents such as ethyl acetate, acetonitrile, etc. resulted in
poorer yields (entries 12À15) (see Supporting Informa-
tion (SI) for more details).
Having established an efficient reaction protocol that
enables the rapid assembly of DPO, we next applied this
method to the synthesis of a focused DPO library. As
shown in Table 2, common functional groups on the
benzene rings attached to the amine nitrogen, including
alkoxyl (entries 1 and 5), alkyl (entries 2À4 and 8), amide
(entry 7), halogen (entries 9À13), ester (entries 15 and 16),
and ketone (entry 17), were all compatible with this
cascade cyclization and gave moderate-to-good yields of
DPO derivatives. Meso-substituted arylamines led to a
substantialdecreasein product yield presumably due tothe
increased steric hindrance around the amine nitrogen
(compare entries 2, 3, and 8; 9 and 10; 12 and 13).
Unfortunately, no reaction occurred for the 4-nitrobenze-
namine, possibly due to the strong electron-withdrawing
inductive effect from the nitro group (entry 18). Alkyl
amines such as benzylamine, cyclopropylamine, and cy-
clobutylamine underwent slightly worse conversion and
provided a lower yield of target products (34À56%, entries
14, 19À20). The structure of 3a was unambiguously as-
signed by its single crystal X-ray analysis (see Figure 1 and
SI for more details).
(5) For selected examples about insertion of Pd species into imine
CdN bond, see: (a) Roesch, K. R.; Larock, R. C. J. Org. Chem. 2001, 66,
412. (b) Roesch, K. R.; Larock, R. C. Org. Lett. 1999, 1, 1551. (c) Qian,
B.; Guo, S.; Shao, J.; Zhu, Q.; Yang, L.; Xia, C.; Huang, H. J. Am. Chem.
Soc. 2010, 132, 3650. (d) Ma, G. N.; Zhang, T.; Shi, M. Org. Lett. 2009,
11, 875.
Finally, we also ran the Pd(II)-catalyzed cascade cross-
cyclization of 1a (3.0 equiv) with 2a (1.0 equiv) and
4-chloroaniline (2i) (1.0 equiv) under standard conditions.
As expected, we obtained the corresponding cross-cyclization
Org. Lett., Vol. 14, No. 22, 2012
5641

Table 2. Pd(II)-Catalyzed Cascade Cyclization of Ethyl Glyoxalate with Amines to 2,5-Dihydropyrro-2-one Derivativesa
a Reactions were run with ethyl glyoxalate 1a (0.60 mmol), aimines 2 (0.30 mmol), Pd(TFA)2 (5 mol %), and toluene (2.0 mL) under Ar in a sealed
pressure tube at 70 °C for the given time unless otherwise noted. b Isolated yield. c Using ethyl acetate as solvent.
products 3u (22% yield) and 3v (18% yield) besides 3a
(9% yield) and 3i (16% yield) (see Scheme 2).6
To further probe the reaction mechanism, we conducted
the Pd(II)-catalyzed cascade cyclization of ethyl glyoxalate
(1a) and p-anisidine (2a) and monitored the reaction
progress using GC-MS spectra to detect some possible
byproducts and intermediates.7 After the reaction was
carried out for 24 h, we could observe the formation of
2-(4-methoxy-phenylamino)-3-oxo-succinic acid diethyl
ester (D-a)8 (<5% isolated yield) and N-(4-methoxy-
phenyl)-oxalamic acid ethyl ester (I-a)8 (<10% isolated
(7) See SI for the detailed GC-MS spectra.
(8) We have already separated and characterized the byproduct D-a
and I-a by 1H NMR, 13C NMR, and HR-MS spectra (see SI for more
detail).
(9) Palacious, F.; Vicario, J.; Aparicio, D. Eur. J. Org. Chem. 2006,
2843.
(6) We also ran the cascade cross-cyclization of p-anisidine (0.6
mmol, 2.0 equiv) with ethyl glyoxalate (0.3 mmol, 1.0 equiv) and
benzaldehyde (0.3 mmol, 1.0 equiv) under standard conditions; unfor-
tunately, only a 25% yield of 3a was obtained, and no other cross-
cyclization produts were observed.
5642
Org. Lett., Vol. 14, No. 22, 2012

in Figure 2. For the first step, Pd(TFA)2 activated the
aldehyde carbonyl group of 1a and facilitated the addition
of amines. After β-hydride elimination, I was formed with
the formation of the Pd(0) species, the subsequent oxida-
tive addition of Pd(0) to the aldehyde Csp2ÀH bond of 1a
afforded the hydrogenÀpalladium species HÀPd(II)-
ÀCOCO2Et (A),4 and then the following iminoester B
insertion into A5 and reductive elimination provided inter-
mediate D8 which could be reduced to alcohol E by HÀPd
species A. On the other hand, species A also could lead to
the formation of byproduct I8 via ligand exchange with
amines 2 and reductive elimination. Further dehydration
of E gave enamine F, and the subsequent cross-coupling
and cyclization of F with iminoester B produced the cyclic
dehydro-R-amino acid derivatives 3.2g,9
Figure 1. Single crystal structure of pyrrol 2-one 3a.
Scheme 2. Pd(II)-Catalyzed Cascade Cross-Cyclization of Ethyl
Glyoxalate (1a) with p-Anisidine (2a) and 4-Chloroaniline (2i)
Figure 2. Proposed the possible reaction mechanism.
yield) which have already been identified by 1H NMR, 13
C
NMR, and MS spectra. The byproduct I-a was possibly
derived from a cross-coupling reaction of ethyl glyoxalate
and p-anisidine via a nucleophilic reaction and subsequent
β-hydride elimination (Scheme 3).
In summary, we have developed a novel method of
synthesizing highly substituted 1,5-dihydro-2H-pyrrol-2-
one derivatives from the palladium-catalyzed cascade
cyclization of ethyl glyoxalate and amines. Further inves-
tigations of their possible biological activities will make
these compounds even more valuable and are also cur-
rently underway in our laboratory.
Scheme 3. Byproducts from the Pd(II)-Catalyzed Cascade Re-
action of Ethyl Glyoxalate (1a) and p-Anisidine (2a)
Acknowledgment. The authors thank the NCET (No.
10-0371), NSFC (No. 21072063), SRF for ROCS (No.
2010-1174), RFDP (No. 20100172120020), and GNSF
(No. 10351064101000000) for financial support.
Supporting Information Available. Detailed experimen-
tal procedures and characterization of products. This
material is available free of charge via the Internet at
http://pubs.acs.org.
On the basis of the above-mentioned experimental
results, a possible mechanism for this reaction is outlined
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 22, 2012
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