Practical synthesis and mechanistic study of polysubstituted tetrahydropyrimidines with use of domino multicomponent reactions

Article abstract of DOI:10.1016/j.tet.2009.03.071

The practical synthesis of polysubstituted tetrahydropyrimidines 4 from but-2-ynedioates 1, amines 2, and formaldehyde 3 through a domino process of one-pot multicomponent reactions (MCRs) and the detailed mechanistic studies are described. The MCRs were

Full text of DOI:10.1016/j.tet.2009.03.071

Tetrahedron 65 (2009) 4604–4613
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Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Practical synthesis and mechanistic study of polysubstituted
tetrahydropyrimidines with use of domino multicomponent reactions
*
Qiuhua Zhu, Huanfeng Jiang , Jinghao Li, Min Zhang, Xiujun Wang, Chaorong Qi
School of Chemistry and Chemical Engineering, South China University of Technology, 381 Wushan Road, Guangzhou 510640, China
a r t i c l e i n f o
a b s t r a c t
Article history:
The practical synthesis of polysubstituted tetrahydropyrimidines 4 from but-2-ynedioates 1, amines 2,
and formaldehyde 3 through a domino process of one-pot multicomponent reactions (MCRs) and the
detailed mechanistic studies are described. The MCRs were performed under extremely mild reaction
conditions and offered the desired products in excellent yields. The detailed studies on the mechanism of
the MCRs proved that: (1) the proton-promoted domino sequence is composed of hydroamination, aza–
ene-type reaction, nucleophilic addition, and dehydration–cyclization; (2) solvents could control
the hydroamination stereoselectivity of 1 and 2: Z-isomers in proton solvents with Z/E up to 95:5 and
E-isomers in non-proton solvents with E/Z up to 98:2, and Z-isomers are more stable than E-isomers; (3)
Z- and E-enamine intermediates led to the same desired products via aza–ene-type reaction model.
Calculations verified the aza–ene-type process in the MCRs.
Received 8 February 2009
Received in revised form 20 March 2009
Accepted 24 March 2009
Available online 1 April 2009
Ó 2009 Elsevier Ltd. All rights reserved.
1. Introduction
heterocyclic rings with a- and b
-amino acid blocks.12a Quite re-
cently this protocol has been broadened to the MCRs of asymmetric
electron-deficient alkyne, amines, and formaldehyde.12b The MCRs
involve the following domino reactions: hydroamination, Mannich-
type reaction, nucleophilic addition, and dehydration–cyclization
process. This methodology has provided great advantages, such as
atom economy, simplified procedure, excellent yields, and molec-
ular diversity. In addition, the obtained products have been at-
tractive targets in the primary evaluation against human hepatoma
cell line HepG2 in vitro, thereby showing potential as clinical
pharmaceuticals or synthetic intermediates.
In spite of the numerous advantages, the methodology of the
MCRs is likely to be improved based on results obtained in mech-
anistic studies. A more practical and atom-economic multicompo-
nent synthesis of 4 from readily obtained starting materials would
be a more versatile and convenient route to the synthesis of high
structural diversity of pharmaceutical compounds. Therefore,
considerable effort has been dedicated to the development of the
synthesis and mechanism of the MCRs. Herein, we describe a more
efficient and practical synthesis method and a more reasonable
reaction mechanism of the MCRs.
For the recent two decades, tetrahydropyrimidines have received
significant attention for their diverse biological activity,1 and have
served as M1 muscarinic receptor agonists for treatment of Alz-
heimer’s diseases,2 human immunodeficiency virus (HIV) protease
inhibitors,3 and other inhibitors against mycobacterium tuberculo-
sis,4 etc. Structure–activity relationship studies of their poly-
substituted derivatives showed that the substituent groups on
tetrahydropyrimidine ring are all critical for the activity.4,5 Besides
their interesting bioactivities, these compounds are also versatile
building blocks in synthetic organic chemistry.6 However, very few
exampleshavebeenpresentlyreported onthesynthetic methods for
polysubstituted 1,2,3,4-tetrahydropyrimidines (Fig. 1),2b,7–10 and in
the cases, whatsoever, theyhave not been entirelysatisfactory due to
drawbacks such as poor yields, complex procedure, or the difficulties
in obtaining starting materials. Thus, establishment of practical
synthetic methods for the rapid construction of tetrahydropyr-
imidine rings from readily available starting materials remains to be
one of the major challenges in modern organic synthesis.
One-pot multicomponent reactions (MCRs) have emerged as
a powerful tool in synthetic organic chemistry because of their
significant advantages.11 Recently our research group has de-
veloped a new kind of MCRs leading to the formation of 1,2,3,6-
tetrahydropyrimidine-4,5-dicarboxylates 4, a class of important
2. Results and discussion
2.1. Development and optimization of the protocol
Our approach to the development of a more practical, atom-eco-
nomicprotocolfor theMCRswastargetedtoward thereaction ofethyl
* Corresponding author. Tel.: þ86 20 22236518; fax: þ86 20 87112906.
E-mail address: jianghf@scut.edu.cn (H. Jiang).
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.03.071

Q. Zhu et al. / Tetrahedron 65 (2009) 4604–4613
4605
Table 1
Optimization of reaction conditions for the MCRa
R1
HOH2C
ArOC
R2
R1OOC
R3
R2
N
N
CO2Et
CO2Et
EtO2C
EtO2C
N
RON
N
N
AcOH
N
2
2 HCHO
+
+
N
H
R1
solvent, rt
N
H
N
NH2
III
I
II
(1equiv)
(2equiv)
R2
XF2OC
R
CH3OC
R2
1a
2a
3
4aaa
N
N
N
Entry
Solvent
CH2O/AcOH (equiv)
t (h)
Yieldb (%)
N
Ar
R1
N
R1
1
2
3
4
5
6
7
MeOH
DMF
4:2
4:2
4:1
4:0.2
4:0
3:2
2:2
0.5
24
3
98
71
91
89
64
98
80
V
IV
VI
MeOH
MeOH
MeOH
MeOH
MeOH
6
Figure 1. The reported 1,2,3,4-tetrahydropyrimidines.
24
0.5
8
but-2-ynedioate 1a, aniline 2a, and formaldehyde 3 in the presence of
Brønsted acids. Brønsted acids have increasingly been used as cata-
lysts in many types of reactions,13 for example, Mannich reactions,14
Michael-typeadditions,15 becauseoftheircapabilityinaccomplishing
reactionsundermildconditions. Onthebasisof thisconsideration, we
assumed that the MCRs would proceed smoothly in the presence of
a Brønsted acid as well. We first allowed 1a to react with 2.0 equiv of
aniline 2a, 4.0 equiv of 3, and 2.0 equiv of acetic acid (AcOH) in MeOH
at room temperature. The MCR completed almost instantly (de-
termined by TLC) and afforded diethyl 1,2,3,6-tetrahydro-1,3-diphe-
nylpyrimidine-4,5-dicarboxylate 4aaa with 98% isolated yield.
We then turned our attention to screening of the reaction con-
ditions. During this process, MeOH was found to be more appro-
priate solvent (Table 1, entries 1 and 2), and the least amount of 3
for the MCR is 3.0 equiv (Table 1, entries 1, 6, and 7). By decreasing
the amount of AcOH, a significant decrease in the reaction rate and
product yield was observed for the MCR (Table 1, entries 1 and 3–5).
Therefore, the optimal reaction conditions were determined as
follows: mole ratio of 1/2a/3/2a/AcOH¼1:1:3:1:2 in MeOH at room
temperature. Under optimal reaction conditions, product 4aaa
could be afforded as pure lemon crystal from reaction solution after
one day, which was suitable for X-ray measurements (Fig. 2).
a
Reaction was carried out with 1a (1 mmol), 2a (2 mmol), 38% 3 (2–4 mmol), and
AcOH (0–2 mmol) in 6 mL solvents at room temperature for desired time.
b
Isolated yields.
entries 4, 14, and 16). The results indicate that AcOH dramatically
accelerates the MCRs rate.
The reaction time and reactivity of the MCRs were mainly de-
pendent on the structures of NH2R2: 15 min for aliphatic amines,
30 min for aromatic amines, 3 h for 2-aminoethanol, and almost no
reaction for aromatic amines with strong electron-withdrawing
substituents on the phenyl rings, which is in line with the nucle-
ophilic activity of NH2R2. Besides, we also found that ethanol was
the more suitable solvent for the MCRs when aromatic amines were
replaced with aliphatic amines.
2.3. Influence of solvents on the hydroamination
stereoselectivity
It was an interesting and useful finding that the hydro-
amination of 1a and 2a in MeOH and in DMF led to the forma-
tion of Z- and E-isomers with the reverse ratios of Z/E (Eq. 1). The
two isomers were quite different in maximum absorption wave
2.2. Synthesis of 4 under optimized reaction conditions
But-2-ynedioates 1, formaldehyde 3, and different kinds of
amines 2 were subjected to the MCRs under the optimal reaction
conditions, and the most representative results obtained are col-
lected in Table 2. In an effort to obtain further evidence regarding
the mechanism, we compared the results of proton-promoted
MCRs with the heat-promoted MCRs reported in our previous
work.12a We found that all of proton-promoted MCRs with different
kinds of 2 worked well and gave the corresponding 4 in excellent
yields. Although the activity of aromatic amines was obviously
lower than that of aliphatic ones in the heat-promoted MCRs,12a
interestingly the proton-promoted MCRs still proceeded smoothly
(Table 2, entries 1, 12, 14, and 16). Structures of aromatic amines,
with any one of them: electron-donating substituent (Table 2, entry
4), weak electron-withdrawing substituent (Table 2, entries 5, 13,
and 19), or o-substituent (Table 2, entry 6) presented no significant
influence on the product yields. With a strong electron-with-
drawing substituent at the phenyl ring R1, the MCRs also worked
well to give the desired products with high yield (Table 2, entry 20),
although complex products were afforded with such substituents
at the phenyl ring R2.
The replacement of substrate 1 exerted no significant influence
on the one-pot synthesis (Table 2, entries 17–19). Compared with
the previous work,12a the reaction temperature and time were
much lower and shorter, respectively, but the yields of all products
generally were higher especially for aromatic amines (Table 2,
Figure 2. The single crystal X-ray structure of 4aaa.16

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Q. Zhu et al. / Tetrahedron 65 (2009) 4604–4613
Table 2
Scope of one-pot synthesis of tetrahydropyrimidines 4a
CO2R1
R1O2C
R1O2C
R3
AcOH (2 equiv), rt
R3NH2
2HCHO
+
N
+
R2NH2
+
MeOH for aromatic amines
/EtOH for aliphatic amines
CO2R1
(1 equiv)
N
R2
(1 equiv)
(3 equiv)
(1 equiv)
1a (R1=Et)
2a-2j
4aaa-4aka
3
2a-2k
1b (R1=Me)
Entry
R1
R2
R3
t (min)
Product
Yieldb (%)
1
2
3
4
5
6
7
8
Et a
Et a
Et a
Et a
Et a
Et a
Et a
Et a
Et a
Et a
Et a
Et a
Et a
Et a
Et a
Et a
Me b
Me b
Me b
Et a
C6H5 2a
C6H5CH2 2b
n-C4H9 2c
4-CH3C6H4 2d
4-FC6H4 2e
2-CH3C6H4 2f
CH2]CHCH2 2g
C6H11 2h
C6H5 2a
C6H5CH2 2b
C6H5 2a
C6H5 2a
C6H5 2a
C6H5 2a
C6H5 2a
C6H5 2a
C6H5 2a
C6H5CH2 2b
4-FC6H4 2e
4-NO2 C6H4 2k
30 (180)c
15 (60)c
15 (60)c
30 (180)c
30 (180)c
30
4aaa
4abb
4acc
4add
4aee
4aff
4agg
4ahh
4aab
4aba
4aac
4aad
4aae
4aaf
4aai
98 (89)c
90 (92)c
97 (96)c
95 (86)c
94 (88)c
92
30
15
90
95
9
C6H5CH2 2b
C6H5 2a
n-C4H9 2c
4-CH3C6H4 2d
4-FC6H4 2e
2-CH3C6H4 2f
HOCH2CH2 2i
3-CH3C6H4 2j
15 (60)c
30 (60)c
15 (60)c
30 (180)c
30 (180)c
30 (360)c
180
90 (93)c
89 (86)c
92 (90)c
94 (83)c
86 (80)c
93 (62)c
90
10
11
12
13
14
15
16
17
18
19
20d
30 (180)c
30
15
30
4aaj
93 (82)c
98
90
94
4baa
4bbb
4bee
4aka
C6H5 2a
6h
92
a
Reactions were run with 1 (1 mmol), 2 with R2 (1 mmol), 38% 3 (3 mmol), 2 with R3 (1 mmol), and AcOH (2 mmol) in 6 mL MeOH or EtOH at room temperature for
desired time.
b
Isolated yields.
c
The data in parentheses refer to that in our previous report.12a
The reaction was run at 50 ꢀC.
d
(
lmax), color, and the Rf value on TLC. The lmax, color, and the Rf
resulting reaction product mixture in non-proton deuterio solvents
by HPLC and 1H NMR.
value for one isomer were 320 nm, deep yellow, and 0.5 (n-
hexane/ethyl acetate¼10:1), respectively; and those for the other
were 298 nm, almost colorless, and 0.2, respectively. According
to Refs. 17–19 and the properties of the two products, it is not
difficult to conclude that the former is diethyl 2-(phenylamino)
fumarate Z-5a,18 and the latter is diethyl 2-(phenylamino) mal-
eate E-5a.19
OEt
OEt
O
O
O
EtO
EtO2C
EtO
H
rt
rt
NH
N
EtO2C
N
O
(2)
5'a
E-5a
Z-5a
OEt
3%a
97%a
a Ratio determined by 1H NMR
EtO2C
O
H
CO2Et
CO2Et
1a
rt
EtO2C
NH
+
+
EtO2C
N
NH2
Then we investigated the solvent influence on the hydro-
amination stereoselectivity of 1a and aromatic amine 2a. The re-
sults in Table 3 showed that Z-5a was formed as major product
when the hydroamination of 1a and 2a was carried out in proton
solvents (Table 3, entries 1–4) or in the mixtures of proton and non-
proton solvents (Table 3, entries 6 and 7). E-5a was, however,
formed as main product in non-proton solvents (Table 3, entries 5,
9, and 14). The experimental results also showed that the amount of
water in DMSO or in DMF could remarkably influence the hydro-
amination stereoselectivity (Table 3, entries 8 and 10–13), which is
expected because water also is a proton solvent.
Solvent effect on the hydroamination stereoselectivity of 1a and
aliphatic amine 2c was also investigated (Table 3, entries 15–21). In
this case, although the stereoselectivity of the reactions in non-
proton solvents was high with the ratios of E/Z more than 92:8
(Table 3, entries 18 and 21), poor stereoselectivity in proton sol-
vents was observed with the ratios of Z/E less than 63:27 (Table 3,
(1)
2a
Z-5a
E-5a
Solvent Yield(%) Ratio of Z/E
MeOH
DMF
> 99
> 99
77:23 (HPLC and 1H NMR)
2:98 (HPLC)
Although the Rf values of two isomers are quite different, it is
difficult to obtain pure Z- and E-5a because an equilibrium (Eq. 2)
was reached between them through active imine 50a20 during
isolated processes. The equilibrium indicates that Z-5a has much
lower molecular inner energy than E-5a does. However, in non-
proton solvents E-5a was relatively stable. Therefore, the yield and
spectra of E-5a could be obtained only from the analysis of the

Q. Zhu et al. / Tetrahedron 65 (2009) 4604–4613
4607
Table 3
Table 4
Influence of solvents on the ratios of Z- and E-5a and 5ca
Influence of reactant concentrations on the ratio of Z/Ea
HN R2
CO2Et
solvent, rt, 10min
solvents
rt, 10 min
EtO2C
CO2Et
1a
+
1a + 2a
Z-5a
E-5a
+
EtO2C
Entry
Solvents
1a (mol Lꢁ1
)
Z/Eb
R2NH2
2a, 2c
Z- and E-5a, 5c
1
2
3
4
5
6
7
8
9
Solvent-free
DMF
0.1
1
0.4
0.2
0.1
1
0.4
0.2
0.1
30:70
13:87
7:93
5:95
2:98
77:23
77:23
78:22
77:23
Entry
R2
Solvents
Z/Eb
DMF
DMF
DMF
MeOH
MeOH
MeOH
MeOH
1
C6H5 2a
C6H5 2a
C6H5 2a
C6H5 2a
C6H5 2a
C6H5 2a
C6H5 2a
C6H5 2a
C6H5 2a
C6H5 2a
C6H5 2a
C6H5 2a
C6H5 2a
C6H5 2a
n-C4H9 2c
n-C4H9 2c
n-C4H9 2c
n-C4H9 2c
n-C4H9 2c
n-C4H9 2c
n-C4H9 2c
EtOH
MeOH
AcOH
72:28
2c
3
77:23 (77:23)d
95:5
83:17
2:98
74:26
89:11
44:56
4
5
6
7
MeOHþAcOH (1:1)
DMF
DMFþMeOH (1:1)
DMFþAcOH (1:1)
DMFþ H2O (3:1)
DMSO-d6
DMSOþH2O (7:1)
DMSO-d6þ D2O (4:1)
DMSOþH2O (3:1)
DMSOþH2O (1:1)
EtOAc
a
Reactions were run with 1a (0.1–1 mmol) and equiv of 2a in solvents (1 mL) at
room temperature for 10 min in greater than 98% yields.
8
9c
10
11c
12
13
14
15
16
17
18
19
20
21c
5:95 (4:96)d
19:81
b
Ratios determined by HPLC (
l
¼298 nm for E-isomer, 320 nm for Z-isomer,
MeOH/H2O¼80:20, 1 mL minꢁ1, C18/C8, 2
ml sample).
d
33:67 (25:75)
37:63
Reactants not dissolving
12:88
53:47
63:37
Trace products
3:93
42:58
Trace products
4:96 (3:97)d
Table 5
EtOH
MeOH
AcOH
DMF
Influence of substrate structures on the ratios of Z/Ea
HN R2
CO2Et
solvents
rt, 10 min
EtO2C
CO2Et
1a
DMFþ H2O (3:1)
DMFþAcOH (1:1)
DMSO-d6
+
EtO2C
Z- and E-5a-d
R2NH2
2a-d
a
Reactions were run with 1a (0.1 mmol) and 2a or 2c (0.1 mmol) in solvents
Entry
R2
Solvent
Z/Eb
(1 mL) at room temperature for 10 min in greater than 98% yields except entry 16
1
2
3
4
5
6
7
8
C6H5 2a
C6H5 2a
C6H5CH2 2b
C6H5CH2 2b
n-C4H9 2c
n-C4H9 2c
4-CH3C6H4 2d
4-CH3C6H4 2d
DMSO-d6
EtOH
DMSO-d6
EtOH
DMSO-d6
EtOH
DMSO-d6
EtOH
5:95 (4:96)c
65:35
(80% yield).
b
Ratios determined by HPLC (
l
¼275/298 nm for aliphatic/aromatic E-isomer,
7:93 (7:93)c
44:56
300/320 nm for aliphatic/aromatic Z-isomer, MeOH/H2O¼80:20, 1 mL$minꢁ1, C18
/
C8, 2 ml sample).
4:96 (7:93)c
53:47
c
The concentration of substrates in this reaction was 0.2 mol Lꢁ1
.
d
Ratios determined by 1H NMR.
8:92 (3:97)c
58:42
entries 15 and 16). Compared with the hydroamination of 1a and
aromatic amine 2a, the water in non-proton solvents could also
affect the stereoselectivity to a large extent (Table 3, entry 19).
However, AcOH, which could highly increase the yield of Z-5a with
the ratio of Z/E up to 95:5 in the hydroamination of 1a and aromatic
2a, hindered the reaction of 1a and aliphatic amine 2c because 2c
rapidly reacted with AcOH to form a salt. Therefore, it is expected
that the Z/E hydroamination stereoselectivities of 1a and aliphatic
amines in proton solvents are lower than that of 1a and aromatic
amines.
a
Reactions were run with 1a (0.2 mmol) and 2a–d (0.2 mmol) in solvents (1 mL)
at room temperature for 10 min in greater than 98% yields.
b
Ratios determined by HPLC (
l
¼275/298 nm for aliphatic/aromatic E-isomer,
300/320 nm for aliphatic/aromatic Z-isomer, MeOH/H2O¼80:20, 1 mL minꢁ1, C18/C8,
2
m
l sample).
Ratios determined by 1H NMR.
c
key roles on the hydroamination stereoselectivity of 1a and 2 al-
though reactant concentrations and substrate structures could in-
fluence the stereoselectivity to some extent.
When the hydroamination of 1a and 2a was carried out in non-
proton solvents, the nitrogen atom of 2a attacked the alkyne carbon
of 1a and formed a carbanion, and then in intermediate 6 (Scheme
1) occurred an intramolecular proton transfer, which led to E-5a as
a major product at a ratio of E/Z up to 98:2, while in proton solvents
appeared an intermolecular proton transfer from proton solvents to
intermediate 7 (Scheme 2), which gave Z-5a at a ratio of Z/E up to
95:5.
2.4. Influence of reactant concentrations and substrate
structures on the hydroamination stereoselectivity
Subsequently, the influence of reactant concentrations and
substrate structures on the hydroamination of 1a and 2 was in-
vestigated. In this study, reactant concentrations were proved to
have an influence on the stereoselectivity of hydroamination of 1a
and 2a in DMF to some extent (Table 4, entries 2–5), but almost no
influence on that in MeOH (Table 4, entries 6–9). In the meantime,
aromatic amines presented more influence on the stereoselectivity
of the hydroamination in proton solvents than aliphatic amines did
(Table 5).
It is worth mentioning that similar equilibriums to Eq. 2 were
observed between Z- and E-5b–c, which may explain why the
synthesis of only Z-isomers of those compounds has been repor-
ted.18b–c
2.6. Aza–ene-type reaction of enamines 5a with aniline and
formaldehyde
There are two models for the reactions of N-monosubstituted
enamines and imines. The first one is Mannich-type reaction, which
was proved by Mo¨hrle and Reinhardt7 (reaction A in Scheme 3). The
second is aza–ene-type reaction, which was reported by Terada and
co-workers21 (reaction B in Scheme 3).
Experimental facts and theoretical calculation proved that the
reactions of 5a with 8 or 2a and 3 proceeded via aza–ene-type
pathway. As shown in Scheme 4, aza–ene type led to intermediate
90, but Mannich-type reaction led to intermediates Z- and E-9. The
results calculated using density functional theory, B3LYP/6–31G,
proved that the order of molecular energy for the minimum-energy
2.5. The possible routes of the hydroamination in proton or
non-proton solvents
Looking comparatively into these aforementioned in-
vestigations, we found that proton and non-proton solvents played

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Q. Zhu et al. / Tetrahedron 65 (2009) 4604–4613
O O
O O
EtO
O
OEt
O
EtO
OEt
EtO
OEt
non-proton solvents, rt
intramolecular
proton transfer
1a
NH
NH
>99%, E/Z up to 98:2
H
NH2
E-5a
6
2a
Scheme 1. Possible route of hydroamination of 1a and 2a in non-proton solvents.
O
O
EtO
EtO
OEt
H
OMe
OEt
EtO
NH
OEt
proton solvents, rt
O
O
intermolecular
proton transfer
NH
O
>99%, Z/E up to 95:5
1a
O
NH2
H
Z- and E-5a
7
2a
Scheme 2. Possible route of hydroamination of 1a and 2a in proton solvents.
0
0
conformations of the three isomers is E9 >EE-9>EZ-9, that is, E9 ꢁEZ-9
¼
In route I, the MCRs started with the hydroamination of 2a to 1a
in DMF, a non-proton solvent, to afford E-5a with high stereo-
selectivity, subsequently under heat-promoted conditions followed
by a domino process including Mannich-type reaction, nucleophilic
addition, and dehydration–cyclization.12a
38.0 kJ molꢁ1 and EE-9ꢁEZ-9¼13.8 kJ molꢁ1. If the reaction pro-
ceeded via Mannich-type-reaction model, 10 and 4aaa (Scheme 4)
would be obtained with the ratio of 10 larger than that of 4aaa
because the value of EZ-9 is lower than EE-9. The MCR of 1a, 2a, and
3, however, in MeOH using AcOH as catalyst produced 4aaa in 98%
yield (Table 2, entry 1) although the ratio of the intermediates, Z-
and E-5a, was 77:23 (Table 3, entry 2), which proved that both of Z-
and E-5a could lead to the formation of the same product 4aaa. In
contrast, aza–ene-type reaction could best elucidate the experi-
mental facts because more active 90 could instantly and completely
convert into 4aaa in the presence of formaldehyde. On the other
H
EtO2C
EtO2C
EtO2C
NH
aza-ene-type
reaction
H
N
N
EtO2C
hand, the high activity of N–H in Z- and E-5a (the
d
values in 1H
2a
3
NMR spectra for Z- and E-5a are 9.59 and 9.31 ppm, respectively)
interprets the feasibility of the formation of C]N bond.
or
N
9'
H2C
Z- and E-5a
2a +3(or 8)
Mannich-type reaction
8
2.7. Overall mechanism for the MCRs pathway
According to the results mentioned above, we tried to propose
a suitable reaction mechanism (route II in Scheme 5) for the proton-
promoted MCRs in MeOH/EtOH that was different from the one of
the heat-promoted MCRs in DMF reported in Ref. 12a (route I in
Scheme 5).
EtO2C
EtO2C
CO2Et
NH
N
H
N
H
NH
EtO2C
HCHO
Reaction A
H
R2
R3
R2
N
+ HCHO
R2
N
O
N
R3
O
O
R3
HCHO
Z- 9
E- 9
+
HN
R1
H
H
NH
R1
CH2
or
HCHO
NH
R1
N
+
≤
E-Form
Z-Form
R3
R2
EtO2C
EtO2C
Mannich-type
reaction
EtO2C
N
HN
HO
N
N
CO2Et
O
Reaction B
Ph
N
O
10
Ar
H
Ph
NH NCOR
Ph
Ph
NH
4aaa
Ar
The upper dashed arrow represents aza-ene-type
R
O
proton transfer and the lower dashed arrow represents
Mannich-type proton migration.
aza-ene-type
reaction
Scheme 4. The reaction of 5a and 8 (or 2a and 3) in MeOH.
Scheme 3. Some reactions of N-monosubstituted enamines and imines.

Q. Zhu et al. / Tetrahedron 65 (2009) 4604–4613
4609
H2C=N
EtO2C
N
EtO2C
EtO2C
H
8
H
EtO2C
EtO2C
N
EtO2C
NH
CH2=O
NH
Mannich-type
reaction
nucleophilic
addition
OH
NH
E-9
E-5a
Route I: Promoted by heat
EtO2C
EtO2C
N
CO2Et
N
Route I: DMF, 100 °C, 3h, 89%
2 HCHO
+
2
+
Route II: MeOH, AcOH, rt, 0.5h, 98%
NH2
CO2Et
4aaa
3
1a
2a
Route II: Promoted by proton
H
8
H2C=N
EtO2C
EtO2C
EtO2C
N
N
EtO2C
EtO2C
H
H
H
O
EtO2C
N
N
OH2
N
aza-ene -type
reaction
1.nucleophilic
addition
H2C OH
O
2.protonation
11
9'
Z- and E-5a
Scheme 5. Possible mechanisms for the domino MCRs.
The MCRs in route II, however, underwent the following domino
process: hydroamination, aza–ene-type reaction, nucleophilic ad-
dition, and dehydration–cyclization. The aza–ene-type reaction
afforded intermediate 90, followed by intermediate 11 via nucleo-
philic addition of 90 to formaldehyde and protonation. Then the
dehydration of 11 gave the only product 4aaa, which best interprets
why the one-pot synthesis of 4 could produce good to excellent
yields although the formation of intermediate Z- and E-enamines
was influenced by solvents, reactant concentrations, and substrate
structures. In addition, two fundamental mechanisms of acid ca-
talysis, the mechanisms of specific acid catalysis and general acid
catalysis reported by Mark and Eric22 were used to make clear why
AcOH could dramatically accelerate the rate of the MCRs and de-
crease its reaction temperature. It was obvious that AcOH efficiently
promoted the MCRs via the two mechanisms: the mechanism of
reversible protonation of the electrophile (herein such as 3 and 11)
in a pre-equilibrium step prior to nucleophilic attack (the mecha-
nism of specific acid catalysis) and the mechanism of proton transfer
to the transition state (such as the transition states derived from 5a
and 8) in the rate-determining step (the mechanism of general acid
catalysis).
3. Conclusion
In this study, we have developed an efficient and practical one-
pot synthesis of polysubstituted tetrahydropyrimidines via the
proton-promoted MCRs. Compared to our previous work, the pro-
ton-promoted MCRs proceed at lower temperature, in shorter re-
action times, and have simpler experimental workup procedures
providing improved yields of products especially when amines are
aromatic ones.
Furthermore, via the studies of intermediates, Z- and E-5a, we
came to the following findings: (a) the hydroamination stereo-
selectivity of 1 and 2 is influenced by solvents, reactant concen-
trations, and substrate structures, and mainly controlled by
solvents: Z-isomers in proton solvents and E-isomers in non-proton
solvents; (b) an equilibrium exists between Z- and E-isomers.
Although E-isomers are comparatively stable in non-proton sol-
vents, mostly or even almost completely converted to Z-isomers
during isolating process; (c) both Z- and E-enamine intermediates
led to the same desired products.
According to the experimental facts and the theoretic calcula-
tion results, we proposed mechanisms for the proton-promoted

4610
Q. Zhu et al. / Tetrahedron 65 (2009) 4604–4613
MCRs, which proceeded through a domino hydroamination, aza–
ene-type reaction, nucleophilic addition, and dehydration–cycli-
zation sequence, and well explained why AcOH could dramatically
accelerate the MCRs, respectively. The probe into the activity
against human hepatoma cell line HepG2 and structure–activity
relationship of polysubstituted tetrahedropyrimidines is ongoing in
our laboratory.
4.2.4. Diethyl 1,2,3,6-tetrahydro-1,3-di-p-tolylpyrimidine-4,5-
dicarboxylate (4add)12a
Yellow oil; 1H NMR (400 MHz, CDCl3):
d¼7.05–6.81 (m, 8H,
CHar), 4.82 (s, 2H, 2-H), 4.20 (s, 2H, 6-H), 4.16 (q, J¼7.2 Hz, 2H, CH2),
4.00 (q, J¼7.2 Hz, 2H, CH2), 2.28 (s, 3H, PhCH3), 2.24 (s, 3H, PhCH3),
1.24 (t, J¼7.2 Hz, 3H, CH3), 0.99 (t, J¼7.2 Hz, 3H, CH3) ppm.
4.2.5. Diethyl 1,3-bis(4-fluorophenyl)-1,2,3,6-tetrahydro-
pyrimidine-4,5-dicarboxylate (4aee)12a
4. Experimental
4.1. General
Yellow oil; 1H NMR (400 MHz, CDCl3):
d
¼6.92–6.90 (m, 8H,
CHar), 4.78 (s, 2H, 2-H), 4.18 (s, 2H, 6-H), 4.17 (q, J¼7.2 Hz, 2H, CH2),
3.99 (q, J¼7.2 Hz, 2H, CH2), 1.25 (t, J¼7.2 Hz, 3H, CH3), 0.99 (t,
J¼7.2 Hz, 3H, CH3) ppm.
All reactions were performed at room temperature under air
atmosphere in a round bottom flask equipped with magnetic stir
bar. All melting points were taken on an XT-4 micro melting point
apparatus and were uncorrected. 1H NMR (400 MHz) and 13C NMR
(100.6 MHz) spectra were recorded using a Bruker Avance 400 MHz
NMR spectrometer and, respectively, referenced to 7.27 and
77.0 ppm for chloroform-d or 2.50 and 39.9 ppm for dimethyl
sulfoxide-d6 with TMS as internal standard. Mass spectra were
recorded on an API 4000QTRAP. IR spectra were obtained as po-
tassium bromide film with a Brucker Vector 22 spectrometer. An-
alytical HPLC was performed using a Dinex INC Summit 680 with
a reversed-phase Kromasil BT011943 column (250 mmꢂ4.6 mm)
and a UV detector (275, 285, 298/300, and 320 nm) at 30 ꢀC. TLC
was performed using commercially prepared 100–400 mesh silica
gel plates (GF254), and visualization was effected at 254 and
365 nm.
4.2.6. Diethyl 1,2,3,6-tetrahydro-1,3-di-o-tolylpyrimidine-4,5-
dicarboxylate (4aff)
Orange oil; 1H NMR (400 MHz, CDCl3):
d
¼7.26–6.88 (m, 8H,
CHar), 4.53 (d, J¼11.6 Hz,1H, 2-Ha), 4.37 (d, J¼11.6 Hz,1H, 2-Hb), 4.18
(q, J¼7.2 Hz, 2H, CH2), 4.10–4.05 (m, 2H, 6-H), 3.95 (q, J¼7.2 Hz, 2H,
CH2), 2.23 (s, 3H, PhCH3), 2.16 (s, 3H, PhCH3), 1.25 (t, J¼7.2 Hz, 3H,
CH3), 0.90 (t, J¼7.2 Hz, 3H, CH3) ppm; 13C NMR (100 MHz, CDCl3):
d
¼165.9 (CO),164.0 (CO), 148.3 (C-10), 147.9 (C-4), 141.5 (C-100), 136.7
(C-30), 132.7 (C-300), 131.2 (C-50), 130.9 (C-500), 129.2 (C-20), 128.0 (C-
200), 126.7 (C-40), 126.3 (C-400), 124.3 (C-60), 121.4 (C-600), 97.8 (C-5),
69.4 (C-2), 61.4 (CH2), 60.0 (CH2), 48.8 (C-6), 18.1 (PhCH3), 18.0
(PhCH3), 14.3 (CH3), 13.5 (CH3) ppm; IR (cmꢁ1): nmax¼3058, 2980,
1740, 1692, 1597, 1493, 1457, 1372, 1258, 1227,1191, 1107, 761, 722;
MS (ESI): m/z 840 (2MþNaþ, 92), 818 (2MþHþ, 85), 409 (MþHþ,
92), 290 (100). Anal. Calcd for C24H28N2O4: C, 70.57; H, 6.91; N, 6.86.
Found: C, 70.38; H, 6.81; N, 6.73.
All other reagents were purchased commercially and used
without further purification.
4.2.7. Diethyl 1,3-diallyl-1,2,3,6-tetrahydropyrimidine-4,5-
4.2. General procedure for the synthesis of 4
dicarboxylate (4agg)
Yellow oil; 1H NMR (400 MHz, CDCl3):
d
¼5.86–5.69 (m, 2H, CH),
The mixture of MeOH or EtOH (3 mL), 1 (1 mmol), and 2
(1 mmol), which was kept at room temperature for 5–10 min, was
dropwise added into the mixture of MeOH or EtOH (3 mL), 38%
formaldehyde 3 (240 mg, 3 mmol), 2 (1 mmol), and acetic acid
(120 mg, 2 mmol), followed with stirring at room temperature for
desired time (monitored by TLC). After completion of the reactions,
the product mixture was purified by preparative TLC with n-hex-
ane/ethyl acetate (10:1 to 2:1) as eluent to afford the desired
products 4 in 86–98% yields.
5.21–5.12 (m, 4H, ]CH2), 4.31 (q, J¼7.2 Hz, 2H, CH2), 4.06 (q,
J¼7.2 Hz, 2H, CH2), 3.89 (s, 2H, 2-H), 3.58 (d, J¼6 Hz, 2H, CH2), 3.48
(s, 2H, 6-H), 3.14 (d, J¼6.4 Hz, 2H, CH2), 1.32 (t, J¼7.2 Hz, 3H, CH3),
1.18 (t, J¼7.2 Hz, 3H, CH3) ppm; 13C NMR (100 MHz, CDCl3):
¼166.2
d
(CO), 164.8 (CO), 147.7 (C-4), 134.9 (C-20), 133.2 (C-200), 118.4 (C-30),
118.2 (C-300), 92.2 (C-5), 66.1 (C-2), 61.8 (CH2), 59.5 (CH2), 55.8 (C-
10), 53.1 (C-100), 48.2 (C-6), 14.3 (CH3), 13.9 (CH3) ppm; IR (cmꢁ1):
nmax¼3078, 2980, 1739, 1689, 1585, 1470, 1371, 1287, 1242, 1218,
1175, 1109, 1042, 996, 761, 743; MS (ESI): m/z 309 (MþHþ, 100), 240
(96). Anal. Calcd for C16H24N2O4: C, 62.32; H, 7.84; N, 9.08. Found: C,
62.43; H, 7.91; N, 9.13.
The following compounds given in Table 2 were prepared
according to the general procedure.
4.2.1. Diethyl 1,2,3,6-tetrahydro-1,3-diphenylpyrimidine-4,5-
4.2.8. Diethyl 1,3-dicyclohexyl-1,2,3,6-tetrahydropyrimidine-4,5-
dicarboxylate (4ahh)
dicarboxylate (4aaa)12a
Yellow solid, mp 85–86 ꢀC; 1H NMR (400 MHz, CDCl3):
d
¼7.24–
Yellow oil; 1H NMR (400 MHz, CDCl3):
d
¼4.32 (q, J¼7.2 Hz, 2H,
6.89 (m, 10H, CHar), 4.90 (s, 2H, 2-H), 4.25 (s, 2H, 6-H), 4.20 (q,
J¼7.2 Hz, 2H, CH2), 4.00 (q, J¼7.2 Hz, 2H, CH2), 1.26 (t, J¼7.2 Hz, 3H,
CH3), 0.97 (t, J¼7.2 Hz, 3H, CH3) ppm.
CH2), 4.06 (q, J¼7.2 Hz, 2H, CH2), 3.93 (s, 2H, 2-H), 3.48 (s, 2H, 6-
H), 3.01–2.96 (m, 1H, CH), 2.45–2.44 (br s, 1H, CH), 1.90–1.88 (br s,
2H, 200-H), 1.80–1.75 (m, 6H, 20-H, 200-H), 1.60–1.57 (m, 2H, 300-H),
1.37–1.12 (m, 16H, CH3, 30-H, 40-H, 300-H, 400-H) ppm; 13C NMR
4.2.2. Diethyl 1,3-dibenzyl-1,2,3,6-tetrahydropyrimidine-4,5-
(100 MHz, CDCl3):
d
¼166.0 (CO), 165.3 (CO), 148.6 (C-4), 92.7 (C-
dicarboxylate (4abb)12a
5), 61.5 (C-2), 59.7 (CH2), 59.6 (CH2), 59.2 (C-10), 58.8 (C-100), 45.5
(C-6), 31.1 (C-20/60), 30.2 (C-200/600), 25.9 (C-40), 25.7 (C-400), 25.4 (C-
30/50), 25.1 (C-300/500), 14.3 (CH3), 13.9 (CH3) ppm; IR (KBr):
nmax¼3462, 2931, 2855, 1740, 1688, 1585, 1447, 1371, 1287, 1250,
1168, 1107,759 cmꢁ1; MS (ESI): m/z 393 (MþHþ, 93), 282 (100).
Anal. Calcd for C22H36N2O4: C, 67.32; H, 9.24; N, 7.14. Found: C,
67.45; H, 9.40; N, 7.01.
Yellow oil; 1H NMR (400 MHz, CDCl3):
d
¼7.30–7.15 (m, 10H,
CHar), 4.35 (q, J¼7.2 Hz, 2H, CH2), 4.16 (s, 2H, 2-H), 4.11 (q, J¼7.2 Hz,
2H, CH2), 3.82 (s, 2H, PhCH2), 3.60 (s, 2H, PhCH2), 3.56 (s, 2H, 6-H),
1.30 (t, J¼7.2 Hz, 3H, CH3), 1.21 (t, J¼7.2 Hz, 3H, CH3) ppm.
4.2.3. Diethyl 1,3-dibutyl-1,2,3,6-tetrahydropyrimidine-4,5-
dicarboxylate (4acc)12a
Yellow oil; 1H NMR (400 MHz, CDCl3):
CH2), 4.06 (q, J¼7.2 Hz, 2H, CH2), 3.92 (s, 2H, 2-H), 3.45 (s, 2H, 6-H),
2.98 (t, J¼7.6 Hz, 2H, 10-H), 2.48 (t, J¼7.6 Hz, 2H, 100-H), 1.49–1.16 (m,
14H, 20/30/200/300-H, CH3), 0.91–0.84 (m, 6H, CH3) ppm.
d
¼4.32 (q, J¼7.2 Hz, 2H,
4.2.9. Diethyl 1-benzyl-1,2,3,6-tetrahydro-3-phenylpyrimidine-4,5-
dicarboxylate (4aab)12a
Yellow oil; 1H NMR (400 MHz, CDCl3):
d¼7.30–7.13 (m, 10H,
CHar), 4.34 (s, 2H, 2-H), 4.14 (q, J¼7.2 Hz, 2H, CH2), 4.06 (q, J¼7.2 Hz,

Q. Zhu et al. / Tetrahedron 65 (2009) 4604–4613
4611
2H, CH2), 3.81 (s, 2H, PhCH2), 3.72 (s 2H, 6-H), 1.22 (t, J¼7.2 Hz, 3H,
CH3), 1.02 (t, J¼7.2 Hz, 3H, CH3) ppm.
2H, 2-H), 4.25 (s, 2H, 6-H), 3.72 (s, 3H, CH3), 3.56 (s, 3H,
CH3) ppm; 13C NMR (100 MHz, CDCl3):
d
¼166.1 (CO), 164.5 (CO),
148.1 (C-10), 146.5 (C-100), 143.5 (C-4), 129.3 (C-30/50/300/500), 126.5
(C-40), 124.5 (400), 121.2 (C-20/60), 117.8 (200/600), 100.5 (C-5), 68.8 (C-
2), 52.5 (CH3), 51.5 (CH3), 47.5 (C-6) ppm; IR (KBr): nmax¼3463,
2949, 1742, 1700, 1579, 1497, 1436, 1368, 1260, 1235, 1115, 1041,
997, 949, 761, 696 cmꢁ1; MS (ESI) m/z 391 (MþKþ, 73), 375
(MþNaþ, 48), 353 (MþHþ, 58), 248 (100). Anal. Calcd for
C20H20N2O4: C, 68.17; H, 5.72; N, 7.95. Found: C, 68.01; H, 5.80;
N, 7.78.
4.2.10. Diethyl 3-benzyl-1,2,3,6-tetrahydro-1-phenylpyrimidine-
4,5-dicarboxylate (4aba)12a
Yellow oil; 1H NMR (400 MHz, CDCl3):
6.89–6.80 (3H, CHar), 4.41 (s, 2H, 2-H), 4.31 (q, J¼7.2 Hz, 2H, CH2),
4.22 (s, 2H, PhCH2), 4.19 (q, J¼7.2 Hz, 2H, CH2), 4.10(s, 2H, 6-H),
1.30–1.26 (m, 6H, CH3) ppm.
d
¼7.29–7.17 (m, 7H, CHar),
4.2.11. Diethyl 1-butyl-1,2,3,6-tetrahydro-3-phenylpyrimidine-4,5-
dicarboxylate (4aac)12a
4.2.18. Dimethyl 1,3-dibenzyl-1,2,3,6-tetrahydropyrimidine-4,5-
dicarboxylate (4bbb)
Yellow oil; 1H NMR (400 MHz, CDCl3):
d
¼7.30–7.10 (m, 5H,
CHar), 4.36 (s, 2H, 2-H), 4.13 (q, J¼7.2 Hz, 2H, CH2), 4.01 (q, J¼7.2 Hz,
2H, CH2), 3.64 (s, 2H, 6-H), 2.61 (t, J¼7.2 Hz, 2H, 10-H), 1.43–1.39 (m,
2H, 20-H),1.32–1.26 (m, 2H, 30-H),1.22 (t, J¼7.2 Hz, 3H, 40-H), 0.98 (t,
J¼7.2 Hz, 3H, CH3), 0.85 (t, J¼7.2 Hz, 3H, CH3) ppm.
Yellowoil; 1HNMR (400 MHz, CDCl3):
d
¼7.31–7.15 (m,10H, CHar),
4.15 (s, 2H, 2-H), 3.90 (s, 3H, CH3), 3.83 (s, 2H, 2-H), 3.64 (s, 3H, CH3),
3.59 (s, 2H, CH2), 3.54 (s, 2H, 6-H) ppm; 13C NMR (100 MHz, CDCl3):
d
¼166.9 (CO),165.6 (CO),148.1 (C-4), 137.9 (C-100), 136.1 (C-10), 128.7
(C-20/60), 128.3 (C-200/600), 128.0 (C-30/50/300/500), 127.2 (C-40/400), 92.1
(C-5), 65.9 (C-2), 56.9 (PhC0H2), 54.2 (PhC00H2), 52.9 (CH3), 51.1 (CH3),
48.2 (C-6) ppm; IR (KBr): nmax¼3062, 2982, 2936, 2903, 1739, 1695,
1583, 1461, 1371, 1260, 1229, 1209, 1108, 1042, 760, 696 cmꢁ1; MS
(ESI): m/z 419 (MþKþ, 50), 403 (MþNaþ, 27), 381 (MþHþ, 73), 262
(100). Anal. Calcd for C22H24N2O4: C, 69.46; H, 6.36; N, 7.36. Found: C,
69.25; H, 6.43; N, 7.15.
4.2.12. Diethyl 1,2,3,6-tetrahydro-3-phenyl-1-p-tolylpyrimidine-
4,5-dicarboxylate (4aad)12a
Yellow solid, mp 83–84 ꢀC; 1H NMR (400 MHz, CDCl3):
d¼7.26–
6.80 (m, 9H, CHar), 4.85 (s, 2H, 2-H), 4.21(s, 2H, 6-H), 4.19 (q,
J¼7.2 Hz, 2H, CH2), 4.00 (q, J¼7.2 Hz, 2H, CH2), 2.23 (s, 3H, PhCH3),
1.25 (t, J¼7.2 Hz, 3H, CH3), 0.97 (t, J¼7.2 Hz, 3H, CH3) ppm.
4.2.13. Diethyl 1-(4-fluorophenyl)-1,2,3,6-tetrahydro-3-
4.2.19. Dimethyl 1,3-bis(4-fluorophenyl)-1,2,3,6-
tetrahydropyrimidine-4,5-dicarboxylate (4bee)
phenylpyrimidine-4,5-dicarboxylate (4aae)12a
White solid, mp 86–87 ꢀC; 1H NMR (400 MHz, CDCl3):
d
¼7.27–
Yellow oil; 1H NMR (400 MHz, CDCl3):
d
¼6.92–6.88 (m, 8H,
CHar), 4.78 (s, 2H, 2-H), 4.18 (s, 2H, 6-H), 3.72 (s, 3H, CH3), 3.55 (s,
3H, CH3) ppm; 13C NMR (100 MHz, CDCl3):
¼166.0 (CO), 164.3
6.89 (m, 9H, CHar), 4.85 (s, 2H, 2-H), 4.21 (s, 2H, 6-H), 4.19 (q,
J¼7.2 Hz, 2H, CH2), 4.01 (q, J¼7.2 Hz, 2H, CH2), 1.27 (t, J¼7.2 Hz, 3H,
CH3), 0.98 (t, J¼7.2 Hz, 3H, CH3) ppm.
d
(CO), 161.0 (d, J¼960 Hz, 1C, CF), 158.0 (d, J¼960 Hz, 1C, CF), 146.7
(C-10), 144.6 (C-4), 139.4 (C-100), 127.3 (C-30), 127.2 (C-50), 120.1 (C-
300/500), 116.2 (C-20), 116.0 (C-60), 115.9 (C-200), 115.7 (C-600), 99.6 (C-5),
70.4 (C-2), 52.5 (CH3), 51.6 (CH3), 47.7 (C-6) ppm; IR (KBr):
nmax¼3420, 1735, 1650, 1558, 1541, 1509, 1457, 1085, 987 cmꢁ1; MS
(ESI): m/z 411 (MþNaþ, 23), 389 (MþHþ, 100). Anal. Calcd for
C20H18F2N2O4: C, 61.85; H, 4.67; F, 9.78; N, 7.21. Found: C, 61.67; H,
4.71; F, 9.69; N, 7.28.
4.2.14. Diethyl 1,2,3,6-tetrahydro-3-phenyl-1-o-tolylpyrimidine-
4,5-dicarboxylate (4aaf)12a
White solid, 91–92 ꢀC; 1H NMR (400 MHz, CDCl3):
d
¼7.22–6.96
(m, 9H, CHar), 4.61 (s, 2H, 2-H), 4.17 (q, J¼7.2 Hz, 2H, CH2), 4.06 (s,
2H, 6-H), 4.04 (q, J¼7.2 Hz, 2H, CH2), 2.20 (s, 3H, PhCH3), 1.24 (t,
J¼7.2 Hz, 3H, CH3), 0.99 (t, J¼7.2 Hz, 3H, CH3) ppm.
4.2.15. Diethyl 1,2,3,6-tetrahydro-1-(2-hydroxyethyl)-3-
4.2.20. Diethyl 1,2,3,6-tetrahydro-3-(4-nitrophenyl)-1-
phenylpyrimidine-4,5-dicarboxylate (4aai)12a
phenylpyrimidine-4,5-dicarboxylate (4aka)
Yellow oil; 1H NMR (400 MHz, CDCl3):
d
¼7.27–7.07 (m, 5H,
Yellow crystal; 138–139 ꢀC; 1H NMR (400 MHz, CDCl3):
d¼8.12–
CHar), 4.36 (s, 2H, 2-H), 4.09 (q, J¼7.2 Hz, 2H, CH2), 3.98 (q, J¼7.2 Hz,
2H, CH2), 3.63 (s, 2H, 6-H), 3.58 (t, J¼4.2 Hz, 2H, 10-H), 3.04 (br s, 1H,
OH), 2.77 (t, J¼4.2 Hz, 2H, 20-H), 1.19 (t, J¼7.2 Hz, 3H, CH3), 0.95 (t,
8.09 (m, 2H, CHar), 7.19–6.81 (m, 7H, CHar), 4.98 (s, 2H, 2-H), 4.28 (s,
2H, 6-H), 4.24 (q, J¼8 Hz, 2H, CH2), 4.12 (q, J¼8 Hz, 2H, CH2), 1.31 (t,
J¼8 Hz, 3H, CH3), 1.12 (t, J¼8 Hz, 3H, CH3) ppm; 13C NMR (100 MHz,
J¼7.2 Hz, 3H, CH3) ppm; 13C NMR (100 MHz, CDCl3):
d
¼165.9 (CO),
CDCl3):
d
¼165.1 (CO), 163.5 (CO), 150.0 (C-100), 147.5 (C-10), 144.1
163.8 (CO), 145.7 (C-100), 143.5 (C-4), 129.2 (C-300/500), 126.4 (C-400),
125.2 (C-200/600), 97.7 (C-5), 71.0 (C-2), 61.5 (CH2), 60.0 (CH2), 58.8
(C-20), 54.2 (C-10), 48.4 (C-6), 14.2 (CH3), 13.4 (CH3) ppm; IR (KBr):
nmax¼3702, 3432, 2981, 2936, 1740, 1692, 1580, 1496, 1373, 1251,
1209, 1124, 1028, 763, 699 cmꢁ1; MS (ESI): m/z 719 (2MþNaþ, 12),
371 (MþNaþ, 50), 349 (MþHþ, 35), 276 (100). Anal. Calcd for
C18H24N2O5: C, 62.05; H, 6.94; N, 8.04. Found: C, 62.37; H, 6.71;
N, 8.01.
(CNO2), 143.2 (C-3), 129.3 (C-30/50), 124.9 (C-300/500), 122.5 (C-20/60),
121.6 (C-200/600), 117.7 (C-40), 109.3 (C-5), 68.9 (C-2), 62.1 (CH2), 60.9
(CH2), 48.0 (C-6), 14.2 (CH3), 13.6 (CH3) ppm; IR (KBr): nmax¼3444,
1736, 1695, 1587, 1498, 1340, 1257, 1228, 1109, 944, 856, 737, 695,
528 cmꢁ1; MS (ESI): m/z 448 (MþNaþ, 80), 426 (MþHþ, 85), 321
(100). Anal. Calcd for C22H23N3O6: C, 62.11; H, 5.45; N, 9.88. Found:
C, 62.67; H, 5.51; N, 9.79.
4.3. Preparation and spectroscopic data of diethyl 2-
4.2.16. Diethyl 1,2,3,6-tetrahydro-3-phenyl-1-m-tolylpyrimidine-
(phenylamino) fumarate (Z-5a)
4,5-dicarboxylate (4aaj)12a
Yellow oil; 1H NMR (400 MHz, CDCl3):
d
¼7.32–6.72 (m, 9H,
Diethyl but-2-ynedioate 1a (170 mg, 1 mmol) and aniline 2a
(93 mg, 1 mmol) were added into MeOH (5 mL) at room tempera-
ture for 10 min, followed by purification by preparative TLC with
n-hexane and ethyl acetate (10:1) as eluent to afford Z-5a as yellow
CHar), 4.90 (s, 2H, 2-H), 4.27 (s, 2H, 6-H), 4.22 (q, J¼7.2 Hz, 2H, CH2),
4.04 (q, J¼7.2 Hz, 2H, CH2), 2.26 (s, 3H, PhCH3), 1.30 (t, J¼7.2 Hz, 3H,
CH3), 1.03 (t, J¼7.2 Hz, 3H, CH3) ppm.
oil, 210 mg, 80% yield; 1H NMR (400 MHz, DMSO-d6):
d
¼9.59 (s, 1H,
4.2.17. Dimethyl 1,2,3,6-tetrahydro-1,3-diphenylpyrimidine-4,5-
NH), 7.28 (t, J¼7.6 Hz, 2H, CHar), 7.06 (t, J¼7.6 Hz, 1H, CHar), 6.29 (d,
J¼8.0 Hz, 2H, CHar), 5.22 (s, 1H, 3-H), 4.14–4.06 (m, 4H, CH2), 1.21 (t,
J¼7.2 Hz, 3H, CH3), 1.01 (t, J¼7.2 Hz, 3H, CH3); 1H NMR (400 MHz,
dicarboxylate (4baa)
Yellow oil; 1H NMR (400 MHz, CDCl3):
CHar), 6.99–6.96 (m, 2H, CHar), 6.91–6.86 (m, 3H, CHar), 4.90 (s,
d
¼7.27–7.16 (m, 5H,
CDCl3):
d
9.68 (s, 1H, NH), 7.30–7.25 (m, 2H, CHar), 7.09 (t, J¼7.6 Hz,

4612
Q. Zhu et al. / Tetrahedron 65 (2009) 4604–4613
1H, CHar), 6.93 (d, J¼7.6 Hz, 2H, CHar), 5.39 (s, 1H, 3-H), 4.24ꢁ4.13
(m, 4H, CH2), 1.31 (t, J¼7.2 Hz, 3H, CH3), 1.10 (t, J¼7.2 Hz, 3H, CH3);
MS (ESI): m/z 286(MþNaþ, 20), 264(MþHþ, 42), 94 (100). Anal.
Calcd for C28H34N2O8: C, 63.87; H, 6.51; N, 5.32. Found: C, 63.76; H,
6.43; N, 5.28.
4.4.4. The ratio of diethyl 2-(benzylamino)but-2-enedioate
(Z- and E-5b) in DMSO-d6
Diethyl but-2-ynedioate 1a (34 mg, 0.2 mmol) and phenyl-
methanamine 2b (21.4 mg, 0.2 mmol) were added to DMSO-d6
(1 mL) and gave a 7:93 mixture of Z- and E-isomers (indicated by 1H
NMR). HPLC (
major isomer (E-5b), tR¼4.2 min; minor isomer (Z-5b), tR¼8.6 min;
1H NMR (400 MHz, DMSO-d6): Z-isomer:
¼4.90 ppm (s, 1H, 3-H),
other values of Z-isomer could not be read as the signals were too
weak; E-isomer:
CHar), 4.46 (s, 1H, 3-H), 4.28–4.16 (m, 4H, CH2), 3.92 (q, J¼7.2 Hz, 2H,
PhCH2), 1.25 (t, J¼7.2 Hz, 3H, CH3), 1.10 (t, J¼7.2 Hz, 3H, CH3) ppm.
l
¼275 for E-isomer and 300 nm for Z-isomer, C8),
4.4. General procedure for the ratio analysis of intermediates
Z- and E-5a–d
d
d
Diethyl but-2-ynedioate 1a (0.1–1 mmol) and equiv of 2a–2d
were added to solvents (1 mL) and then kept at room temperature
for 10 min to give the hydroamination products: Z- and E-5a–d.
Then the ratios of Z- and E-isomers were determined by HPLC
analysis (using MeOH/H2O¼80:20 as eluent, a C18 or C8 column as
stationary phase, 275, 285, 298/300, and 320 nm as detecting
wavelength, 1.0 mL minꢁ1 as flow rate, 30 ꢀC as column tempera-
d¼7.90 (t, J¼5.6 Hz, 1H, NH), 7.38ꢁ7.25 (m, 5H,
4.4.5. The ratio of diethyl 2-(butylamino)but-2-enedioate
(Z- and E-5c) in DMSO-d6
Diethyl but-2-ynedioate 1a (34 mg, 0.2 mmol) and butan-1-
amine 2c (14.6 mg, 0.2 mmol) were added to DMSO-d6 (1 mL) and
gave a 7:93 mixture of Z- and E-isomers (indicated by 1H NMR). HPLC
ture, and 2 mL as the mount of each sample). And the concentration
of each sample was diluted with MeOH to 0.001 mol Lꢁ1 before
HPLC analysis. If using DMSO-d6 or deuteriomethanol as solvent,
the isomer ratios were determined by HPLC and 1H NMR.
The ratios of Z- and E-enamine isomers in Tables 3–5 were de-
termined according to the general procedure. The following are the
ratios of Z- and E-5a–d in deuteriosolvents in Table 3 and 5 de-
termined by HPLC and 1H NMR.
(
l
¼275 nm for E-isomer and 300 nm for Z-isomer, C8); major isomer
(E-5c): tR¼4.6 min; minor isomer (Z-5c), tR¼9.6 min; 1H NMR
(400 MHz, DMSO-d6); Z-isomer:
d
d¼4.77 ppm (s, 1H, 3-H), other
values of Z-isomer could not be read for the signals were too weak;
E-isomer:
d
¼7.31 (t, J¼4.8 Hz, 1H, NH), 4.42 (s, 1H, 3-H), 4.19 (q,
J¼7.2 Hz, 2H, CH2), 3.92(q, J¼7.2 Hz, 2H, CH2), 2.89(q, J¼7.2 Hz, 2H, 10-
H), 1.46–1.09 (m, 10H, 20/30-H, CH3), 0.86 (t, J¼7.2 Hz, 3H, CH3) ppm.
4.4.1. The ratio of diethyl 2-(phenylamino)but-2-enedioate
(Z- and E-5a) in CD3OD
Diethyl but-2-ynedioate 1a (34 mg, 0.2 mmol) and aniline 2a
(18.6 mg, 0.2 mmol) were added to CD3OD (1 mL) and gave a 77:23
mixture of Z- and E-isomers (determined by 1H NMR). HPLC
4.4.6. The ratio of diethyl 2-(p-tolylamino)but-2-enedioate
(Z- and E-5d) in DMSO-d6
Diethyl but-2-ynedioate 1a (34 mg, 0.2 mmol) and p-toluidine
2d (21.4 mg, 0.2 mmol) were added to DMSO-d6 (1 mL) and gave
a 3:97 mixture of Z- and E-isomers (indicated by 1H NMR). HPLC
(
l
¼298/300 for E-isomer and 320 nm for Z-isomer, C18): major
isomer (Z-5a), tR¼12.8 min; minor isomer (E-5a), tR¼7.0 min; 1H
(
l
¼300 nm for E-isomer and 320 nm for Z-isomer, C8): major iso-
NMR (400 MHz, CD3OD), Z-isomer:
7.15 (m, 1H, CHar), 6.93–6.90 (m, 2H, CHar), 4.20–4.09 (m, 4H, CH2),
d
¼7.28–7.26 (m, 2H, CHar), 7.18–
mer (E-5d), tR¼5.2 min; minor isomer (Z-5d), tR¼10.2 min; 1H NMR
(400 MHz, DMSO-d6), Z-isomer:
3-H), other
d¼9.57 (s, 1H, NH), 5.17 ppm (s, 1H,
1.22 (t, J¼7.2 Hz, 3H, CH3), 1.07 (t, J¼7.2 Hz, 3H, CH3) ppm; E-iso-
d values of Z-isomer could not be read for the signals
mer:
d
¼7.35–7.30 (m, 2H, CHar), 7.15–7.09 (m, 3H, CHar), 4.30 (q,
were too weak; E-isomer:
d
¼9.18 (s, 1H, NH), 7.17–7.10 (m, 2H,
7.2 Hz, 2H, CH2), 4.07 (q, 7.2 Hz, 2H, CH2), 1.34 (t, J¼7.2 Hz, 3H, CH3),
CHar), 7.08–7.02 (m, 2H, CHar), 5.00 (s, 1H, 3-H), 4.22 (q, J¼7.2 Hz,
2H, CH2), 3.96 (q, J¼7.2 Hz, 2H, CH2), 2.24 (s, 3H, PhCH3), 1.26 (t,
J¼7.2 Hz, 3H, CH3), 1.12 (t, J¼7.2 Hz, 3H, CH3) ppm.
1.21 (t, J¼7.2 Hz, 3H, CH3) ppm.
4.4.2. The ratio of diethyl 2-(phenylamino)but-2-enedioate
(Z- and E-5a) in DMSO-d6
Acknowledgements
Diethyl but-2-ynedioate 1a (34 mg, 0.2 mmol) and aniline 2a
(18.6 mg, 0.2 mmol) were added into DMSO-d6 (1 mL) and gave
a 4:96 mixture of Z- and E-isomers (determined by 1H NMR). HPLC
The authors thank the National Natural Science Foundation of
China (nos. 20772034, 20625205, 20572027, and 20332030) and
Guangdong Natural Science Foundation (no. 07118070) for financial
support of this work.
(
l
¼298/300 for E-isomer and 320 nm for Z-isomer, C8): major isomer
(E-5a), tR¼4.5 min; minor isomer (Z-5a), tR¼8.0 min; 1H NMR
(400 MHz, DMSO-d6), E-isomer:
d¼9.27 (s,1H, NH), 7.35–7.31 (m, 2H,
CHar), 7.13–7.07 (m, 3H, CHar), 5.08 (s, 1H, 3-H), 4.19 (q, J¼7.2 Hz, 2H,
CH2), 3.95 (q, J¼7.2 Hz, 2H, CH2), 1.22 (t, J¼7.2 Hz, 3H, CH3), 1.09 (t,
References and notes
J¼7.2 Hz, 3H, CH3) ppm; 13C NMR (100 MHz, DMSO-d6):
d¼167.0
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(CO), 165.3 (CO), 150.4 (C-2), 139.5 (C-10),129.9 (C-30/50), 124.9 (C-40),
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(Z- and E-5a) in DMSO-d6 and D2O (4:1)
Diethyl but-2-ynedioate 1a (34 mg, 0.2 mmol) and aniline 2a
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l
¼298/300 for E-isomer and 320 nm
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(Z-5a), tR¼7.9 min; 1H NMR (400 MHz, DMSO-d6 and D2O), Z-5a:
d
¼7.32–7.12 (m, 2H, CHar), 7.12–7.00 (m, 3H, CHar), 4.07–4.05 (m,
4H, CH2), 1.38 (t, J¼7.2 Hz, 3H, CH3), 0.98 (t, J¼7.2 Hz, 3H, CH3) ppm;
E-5a:
d
¼7.34–7.30 (m, 2H, CHar), 7.12–7.05 (m, 3H, CHar), 4.16 (q,
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CH3), 1.07 (t, J¼7.2 Hz, 3H, CH3) ppm.

Q. Zhu et al. / Tetrahedron 65 (2009) 4604–4613
4613
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