Erratum: A new multicomponent reaction catalyzed by a Lewis acid catalyst: Convenient synthesis of polyfunctional tetrahydropyrimidines (European Journal of Organic Chemistry (2008) (3519-3523))

Full text of DOI:10.1002/ejoc.200900318

RETRACTION
DOI: 10.1002/ejoc.200900318
A New Multicomponent Reaction Catalyzed by a Lewis Acid Catalyst:
Convenient Synthesis of Polyfunctional Tetrahydropyrimidines
Min Zhang[a] and Huan-Feng Jiang*[a]
Keywords: Lewis acids catalysis / Multicomponent reactions / One-pot synthesis / Tetrahydropyrimidine / Heterocycles
After publication of this Full Paper,[1] the authors learned, through
X-ray crystal structure analysis, that the structures of the products
were incorrectly deduced. As such, the names of the given products
were also incorrect. The authors therefore retract this Full Paper and
apologize for any inconvenience this may have caused.
The Autors
[1] M. Zhang, H.-F. Jiang, Eur. J. Org. Chem. 2008, 3519–3523.
Received: March 25, 2009
Published Online: April 28, 2009
[a] School of Chemistry and Chemical Engineering, South China
University of Technology,
Guangzhou 510640, P. R. China
Fax: +86-020-87112906
E-mail: jianghf@scut.edu.cn
Eur. J. Org. Chem. 2009, 2883
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
2883

FULL PAPER
DOI: 10.1002/ejoc.200800289
A New Multicomponent Reaction Catalyzed by a Lewis Acid Catalyst:
Convenient Synthesis of Polyfunctional Tetrahydropyrimidines
Min Zhang[a] and Huan-Feng Jiang*[a]
Keywords: Lewis acids catalysis / Multicomponent reactions / One-pot synthesis / Tetrahydropyrimidine / Heterocycles
A novel and convenient one-pot synthesis of polyfunctional
tetrahydropyrimidine analogues through a Lewis acid cata-
lyzed multicomponent reaction is disclosed. This domino reac-
tion proceeds smoothly in moderate-to-good yields with forma-
tion of four C–N bonds in one step. The products are interesting
nitrogen heterocycles that contain α- and β-amino acid blocks.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2008)
Introduction
Recently, one-pot multicomponent reactions (MCRs)
have emerged as a powerful tool in organic synthesis be-
cause of the significant advantages they offer, such as the
construction of complex molecules from readily available
building blocks, higher yields than almost any sequential
synthesis of the same target, a single purification step, and
easy adaptation to combinatorial synthesis.[1] In the past
several years, the new methodologies developed for MCRs
to create C–N bonds have become extremely popular as
they represent a very efficient entry into different classes of
important nitrogenated heterocycles.[2] In this context, we
have very recently developed MCR processes for the synthe-
sis of N- or N,O-heterocyclic compounds,[3] which are
found in various biologically active natural compounds and
in designed medicinal agents.[4,5] Encouraged by these re-
sults, we further investigated MCRs in order to construct a
new architecture of nitrogen heterocycles by using different
reaction conditions, and we present herein an unexpected
MCR involving the use of a Lewis acid catalyst that leads
to polyfunctional tetrahydropyrimidine analogues.
Scheme 1. A novel self-mediated bulkiness phenomenon.[3a]
Table 1. Optimization of the reaction conditions for the MCRs.[a]
Results and Discussion
Entry
Solvent
Catalyst [mol-%]
t [h]
% Yield[b]
1
DMF
–
24
24
24
24
24
24
8
12
We initially subjected diethyl but-2-ynedioate (1), aniline
(2a), and benzaldehyde (3a) to our previously reported reac-
tion conditions (DMF, 100 °C, reflux) (Scheme 1).[3a] Unex-
pectedly no desired product 4aaЈ was detected. However, to
our surprise, a new nitrogenated cyclic framework of type
2
solvent-free
toluene
MeCN
DMSO
dioxane
NEt3
–
3
3
–
15
4
–
9
6
5
–
6
–
10
7
–
complex
complex
complex
complex
73
8
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
NaOAc (10)
K2CO3 (10)
KOH (10)
ZnCl2 (10)
ZnSO4 (10)
CuBr2 (10)
ZnCl2 (10)
ZnCl2 (10)
8
9
8
8
12
12
12
12
24
10
11
12
13
14
15
[a] School of Chemistry and Chemical Engineering, South China
University of Technology,
56
Guangzhou 510640, P. R. China
37
Fax: +86-020-87112906
78
E-mail: jianghf@scut.edu.cn
76
Supporting information for this article is available on the
WWW under http://www.eurjoc.org or from the author.
[a] All reactions were carried out in sealed tubes. [b] Isolated yields.
Eur. J. Org. Chem. 2008, 3519–3523
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim 3519

M. Zhang, H.-F. Jiang
FULL PAPER
Table 2. One-pot synthesis of polyfunctional tetrahydropyrimidines by the MCR.[a]
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Eur. J. Org. Chem. 2008, 3519–3523

Synthesis of Polyfunctional Tetrahydropyrimidines
Table 2. (Continued)
[a] All the reaction were carried out in sealed tubes. [b] Isolated yields. [c] Although we tried to change the order of addition of the two
amines under the same conditions, only the first drops of aniline resulted in the desired product 4afe, and a very complicated reaction
system was obtained if n-C4H9NH2 was added first.
Scheme 2. Plausible mechanism for this MCR.
Eur. J. Org. Chem. 2008, 3519–3523
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M. Zhang, H.-F. Jiang
FULL PAPER
4aa was furnished in low yield (12%), which was confirmed product 4aa in the presence of 3a by dehydration/cycliza-
1
by H and 13C NMR measurements after purification by tion.
preparative TLC on silica gel. By comparing the structure
of 4aa with those of 4aaЈ and 4aЈ, it was noted that al-
Conclusions
though they were all six-membered tetrahydropyrimidine
rings, the obtained product was dependent on steric hin-
drance to some extent. The reaction of the aldehyde with a
bulky group might favor the formation of less substituted
cyclic compounds. On the other hand, this result also re-
vealed that the switch in product selectivity is perhaps con-
trolled by a crucial factor, which has led to a new synthetic
MCR strategy for the convenient one-pot synthesis of new
polyfunctional 1,2,3,6-tetrahydropyrimidines through a dif-
ferent intramolecular cyclization pathway.
As shown in Table 1, the reaction was performed with
various solvents and under solvent-free conditions and re-
sulted in low yields (Table 1, entries 1–7), although toluene
proved to be the best (entry 3). A very complicated reaction
system was found when bases were added (entries 8–10). To
solve the problem, we turned to Lewis acids. The reaction
yields could be dramatically increased by using different
kinds of Lewis acids, such as ZnCl2, ZnSO4, and CuBr2,
and clearly zinc chloride was the most suitable one for the
cyclization reaction (entries 11–15).
A series of amines 2a–f and aldehydes 3a–e were sub-
jected to the above optimized reaction conditions to
broaden the scope of the MCR (Table 2). We were pleased
to find that all the reactions proceeded smoothly and the
desired products were afforded in moderate-to-good yields.
The steric hindrance effects of the substituents on the aro-
matic rings have a certain influence on the yields: o-substi-
tuted aromatic amine (Table 2, entry 6) provided a relatively
low yield compared with those of others. However, the elec-
tronic effects of the substituents on the aromatic amines or
aldehydes (entries 1 and 3–5) did not significantly influence
the yields. The reaction time for the aliphatic primary
amines (entries 8–12) was shorter than those of the aro-
matic primary amines, which indicated that the activity of
the aliphatic amines is higher.
Scheme 2 shows a plausible mechanism for this MCR.
We inferred that the present methodology comprises the re-
lay process of the following domino sequences: (1) A two-
component hydroamination to form intermediate 5a; (2) a
Lewis acid promoted two-component ester amidation to
give intermediate 6aЈ or 6aЈЈ by route A or B; (3) a two-
component amine/aldehyde dehydration/cyclization process
to produce new compound 4aa.
An efficient Lewis acid catalyst for a novel type of multi-
component reaction that leads to polyfunctional 1,2,3,6-
tetrahydropyrimidine analogues was found. This Lewis acid
catalyzed cascade process proceeds smoothly in moderate-
to-good yields with the formation of four C–N bonds in
one operation. The products obtained in our experiments
are interesting nitrogen heterocyclic molecules that contain
α- and β-amino acid blocks. Our strategy allows the intro-
duction of different substituents into the 1,2,3-positions of
the pyrimidine ring. Thus, the present cascade process al-
lows the assembly of a wide range of polysubstituted tetra-
hydropyrimidines from readily available starting materials.
Further studies and applications of this cascade reaction
are ongoing in our laboratory and will be published in due
course.
Experimental Section
General: All reactions were performed at 100 °C in sealed tubes
containing a magnetic stirring bar. H and 13C NMR spectra were
1
recorded using a Bruker Avance 400 MHz NMR spectrometer. The
chemical shifts are referenced to signals at 7.24 and 77.0 ppm,
respectively, of the chloroform solvent with TMS as the internal
standard. IR spectra were obtained either as potassium bromide
pellets or as liquid films between two potassium bromide pellets
with a Bruker Vector 22 spectrometer. Mass spectra were recorded
on a Shimadzu GCMS-QP5050A spectrometer at an ionization
voltage of 70 eV equipped with a DB-WAX capillary column (in-
ternal diameter: 0.25 mm, length: 30 m). Elemental analyses were
performed with a Vario EL elemental analyzer. TLC was per-
formed by using commercially prepared 100–400 mesh silica gel
plates (GF254) and visualization was effected at 254 nm. All the
other chemicals were purchased from Aldrich Chemicals.
Typical Procedure for the One-Pot Synthesis of 1,2,3,6-Tetra-
hydropyrimidine Analogues by Three-Component Reactions: Benzal-
dehyde (127 mg, 1.2 mmol), toluene (3 mL), and zinc chloride
(14 mg, 0.1 mmol) were added successively to a stirring mixture of
diethyl but-2-ynedioate (1, 170 mg, 1 mmol) and aniline (186 mg,
1 mmol). The mixture was stirred at 100 °C for 12 h, and TLC of
the mixture showed only traces of intermediate 5. The reaction
mixture was diluted with diethyl ether (15 mL) and dried with an-
hydrous MgSO4. Then the mixture was filtered and washed with
diethyl ether (5 mLϫ5). The combined organic solvents were evap-
We examined this MCR step by step and found that in- orated in vacuo and the crude product was purified by preparative
termediate 5 could be obtained even at room temperature.[6]
TLC with hexane/ethyl acetate (10:1) as the eluent to afford the
desired product 4ab (252 mg, 78%) as a yellowish solid, which was
The isolated 5 could react smoothly with formaldehyde and
aniline at 100 °C to form 4aЈ.[3a] When formaldehyde was
further recrystallized from hexane/dichloromethane for elemental
analysis; m.p. 166–169 °C. IR (KBr): ν
= 3062, 2982, 1709,
˜
max
replaced by benzaldehyde, the reaction was accomplished
only in the presence of the Lewis acid.[7] This result clearly
shows that the Lewis acid is crucial for the MCR of diethyl
but-2-ynedioate (1), aniline (2a), and benzaldehyde (3a). We
guessed that the Lewis acid plays a dual role as an efficient
promoter for the isomerization of 5a and the amidation of
1694, 1596, 1534, 1498, 1454, 1370, 1243, 1077, 1035, 901,
831 cm–1. 1H NMR (400 MHz, CDCl3): δ = 8.17 (br. s, 1 H), 7.46–
7.26 (m, 7 H), 7.22–7.06 (m, 8 H), 5.80 (s, 1 H), 3.99 (q, J = 7.2 Hz,
2 H), 0.98 (t, J = 7.2 Hz, 3 H) ppm. 13C NMR (100 MHz, CDCl3):
δ = 164.3, 164.1, 141.9, 138.7, 136.7, 136.5, 128.8, 128.4, 128.3,
128.1, 127.6, 125.6, 124.6, 122.7, 109.8, 63.2, 60.2, 13.7 ppm. MS
5aЈ or 5aЈЈ. Intermediate 7aЈ or 7aЈЈ was converted into (EI): m/z (%) = 398 (48) [M]+, 325 (100), 297 (26). C25H22N2O3
3522
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Synthesis of Polyfunctional Tetrahydropyrimidines
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(398.45): calcd. C 75.36, H 5.57, N 7.03; found C 74.92, H 5.54, N
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Supporting Information (see also the footnote on the first page of
this article): Analytical and spectroscopic data for compounds 4aa–
4afe for this article is available.
Acknowledgments
We thank the National Natural Foundation of China (Nos.
20332030, 20572027, 20625205, and 20772034) and Guangdong
Natural Science Foundation (No. 07118070) for financial support.
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[5]
[6]
A mixture of diethyl but-2-ynedioate (1) (170 mg, 1 mmol), ani-
line (2a) (93 mg, 1 mmol), and DMF (2 mL) was stirred at
room temperature for 30 min. After completion of the reaction
and purification by preparative TLC, intermediate 5 was ob-
tained as a pure compound.
[7] Intermediate 5 can react with benzaldehyde and aniline in the
presence of ZnCl2 in toluene at 100 °C to form product 4aa.
Received: March 19, 2008
[4] a) W. S. Messer Jr, Y. F. Abuh, Y. Liu, S. Periyasamy, D. O.
Ngur, M. A. N. Edgar, A. A. Eissadi, S. Sbeih, P. G. Dunbar,
Published Online: May 27, 2008
Eur. J. Org. Chem. 2008, 3519–3523
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
3523