Development, scope and mechanisms of multicomponent reactions of asymmetric electron-deficient alkynes with amines and formaldehyde

Article abstract of DOI:10.1002/chem.200801471

Based on the reactive behaviour of the substrates, two synthetic routes to polysubstituted pyrimidine derivatives are presented herein: 1) A catalyst-free multicomponent reaction of electron-deficient alkynes, aliphatic amines and formaldehyde and 2) Ag1catalyzed synthesis of pyrimidines from electron-deficient alkynes, anilines and formaldehyde by a domino reaction. Under optimized conditions, the multicomponent reactions were accomplished with high regioselectivity and excellent yields. A computational study was carried out by using the B3LYP density functional theory to elucidate the mechanisms of the catalyst-free hydroamination reaction. Calculations showed the activation free energies of aliphatic amines were lower than those of anilines, which is consistent with the experimental results.

Full text of DOI:10.1002/chem.200801471

FULL PAPER
DOI: 10.1002/chem.200801471
Development, Scope and Mechanisms of Multicomponent Reactions of
Asymmetric Electron-Deficient Alkynes with Amines and Formaldehyde
Hua Cao, Xiujun Wang, Huanfeng Jiang,* Qiuhua Zhu, Min Zhang, and Haiyang Liu[a]
Dedicated to Professor Xiyan Lu on the occasion of his 80th birthday
Abstract: Based on the reactive behav-
iour of the substrates, two synthetic
routes to polysubstituted pyrimidine
derivatives are presented herein: 1) A
catalyst-free multicomponent reaction
of electron-deficient alkynes, aliphatic
amines and formaldehyde and 2) AgI-
catalyzed synthesis of pyrimidines from
electron-deficient alkynes, anilines and
formaldehyde by a domino reaction.
Under optimized conditions, the multi-
component reactions were accom-
plished with high regioselectivity and
excellent yields. A computational study
was carried out by using the B3LYP
density functional theory to elucidate
the mechanisms of the catalyst-free hy-
droamination reaction. Calculations
showed the activation free energies of
aliphatic amines were lower than those
of anilines, which is consistent with the
experimental results.
Keywords: catalyst-free reactions ·
density functional calculations
·
multicomponent reactions · pyrimi-
dines · silver catalyst
Introduction
cated organic molecules and drugs can be easily prepared
from simple compounds in one reaction sequence.[6] Al-
though a range of strategies involving the sequential genera-
tion of radical and anionic species have been used for such
transformations,[7] relatively few transition-metal-catalyzed
MCRs have been reported for the synthesis of complex
cyclic compounds.[8] Thus, the development of new MCRs
that allow assembly of polysubstituted heterocycles in a re-
gioselective manner is in high demand.
Pyrimidines are important chemicals that exhibit a wide
range of biological activities.[9] Many naturally occurring
compounds contain a pyrimidine skeleton as a key structural
motif.[10] Because of the wide range of applications of pyri-
midines in pharmaceutical research, such as muscarinic ago-
nist activity,[11] protein–nucleic acid interactions,[12] antiviral
activity[13] and inflammatory activity,[14] the development of
efficient methods for their synthesis has continuously at-
tracted the attention of many chemists. In modern organic
synthesis, the hexahydropyrimidine nucleus has been em-
ployed as a protecting group in selective acylations and ad-
ditions of 1,3-diamines owing to its easy cleavage in mildly
acidic media.[15] Hexahydropyrimidines are classically pre-
pared by condensation of substituted propane-1,3-diamines
with aldehydes and ketones.[16–18] The convergent synthesis
of these polysubstituted pyrimidine derivatives from readily
available starting materials along this line also remains to be
developed.[19,20]
Multicomponent reactions (MCRs) are very attractive pro-
cesses that push the limits of synthetic efficiency by using
more than two reactants to create novel products with an
optimal number of new bonds and functionalities.[1] The
strategy of MCRs has been developed to enable the rapid
construction of complex and diverse structures from readily
accessible starting materials in a single operation under mild
conditions.[2,3] Although the sequence of MCRs has been el-
egantly developed at the current stage of investigation in
this field,[4] the multicomponent synthesis of heterocycles
that are susceptible to further scaffold diversification and
amplification is rare.[5] Some MCRs are catalyst-free, but
most of these procedures usually need to be activated by a
transition metal. Transition-metal-catalyzed MCRs have at-
tracted considerable attention due to the fact that compli-
[a] H. Cao, Prof. X. Wang, Prof. H. Jiang, Q. Zhu, M. Zhang,
Prof. H. Liu
School of Chemistry and Chemical Engineering
South China University of Technology
Guangzhou 510640 (P.R. of China)
Fax : (+86)20-87112906
E-mail: jianghf@scut.edu.cn
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.200801471.
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Table 1. One-pot synthesis of polyfunctional tetrahydropyrimidines by a
catalyst-free MCR.[a]
Recently, we reported a convenient one-pot synthesis of
polysubstituted tetrahydropyrimidines by catalyst-free
MCRs (Scheme 1).[21] This process not only represents a
Scheme 1. One-pot synthesis of polysubstituted tetrahydropyrimidines by
a catalyst-free MCR. DMF=dimethylformamide.
convenient procedure for the clean synthesis of polysubsti-
tuted pyrimidines, but also opens up a potential route for
the preparation of other polysubstituted heterocycles.[22] In
our further exploration of the scope of this novel domino re-
action, we employed ethyl phenylpropiolate as the substrate
and surprisingly found that aliphatic amines can finish the
MCRs smoothly but that anilines cannot under the same
conditions, which is quite different from the result obtained
by using the electron-withdrawing alkyne diethyl acetylene-
dicarboxylate.[21] In the process of this research, we explored
the reactive behaviour of different kinds of starting materi-
als, the addition selectivity of amines to the carbon–carbon
triple bond and the order of the domino sequences. With
the goal of broadening the utility of MCR methodology in
organic synthesis, we are interested in studying the reactive
behaviour of the substrates, exploring the key step in
domino sequences and understanding the mechanisms of the
processes in detail.
Alkynoate R2NH2 R3NH2
t
Product
Yield[b]
[%]
[h]
1
1a
2a
6
89
2
3
1a
1a
2b
2c
8
6
90
90
In recent computational studies, the mechanism of hydro-
amination reactions in a catalytic system has been investi-
gated,[22] which will be helpful in understanding a multitude
of steps in our MCRs. Herein, we report the development of
effective procedures for the MCRs of asymmetric electron-
deficient alkynes, amines and formaldehyde, and the mecha-
nistic investigation of all steps in the both the catalyst-free
and catalytic cycle MCRs by using a combination of the
B3LYP density functional theory (DFT) and experimental
methods.
4
1a
1a
1a
2d
8
6
6
89
81
80
5[c]
2a
2a
2 f
2g
Results and Discussion
6[c]
MCRs and their regioselectivity under catalyst-free condi-
tions: At the beginning of this study, we found that asym-
metric ethyl phenylpropiolate (1a) could react smoothly
with benzylamine (2a) and formaldehyde under catalyst-
free conditions at room temperature for 6 h. The isolated
product (4a) was obtained in 89% yield (Table 1, entry 1).
7
8
1a
1a
2 f
2g
2a
2a
14
14
n.d.[d]
n.d.
–
–
1
Besides the analytical results of H and 13C NMR spectra,
9
1b
2a
5
88
the intermediate product (Scheme 2), which has been identi-
fied by X-ray crystallography (Figure 1), showed that the re-
action was carried out with high regioselectivity and only
gave the Markovnikov addition product. In addition, similar
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Multicomponent Reactions
FULL PAPER
Table 1. (Continued)
Table 1. (Continued)
Alkynoate R2NH2 R3NH2
Alkynoate R2NH2 R3NH2
t
Product
Yield[b]
[%]
t
Product
Yield[b]
[%]
[h]
[h]
10
11
1b
1b
2b
2c
5
5
89
88
20
1e
1a
5
86
21
22
1e
1 f
1b
1a
5
5
86
90
12
1b
2d
5
87
13
14
15
1c
1c
1c
2a
2b
2c
2.5
2.5
2.5
93
93
92
23
24
1g
1h
1a
1a
5
5
85
85
[a] Reaction conditions unless stated otherwise: alkynoate (1.0 mmol), ali-
phatic amine (2.2 mmol), formaldehyde (4.0 mmol), RT. [b] Isolated yields.
[c] Reaction conditions: ethyl phenylpropiolate (1.1 mmol), phenylmethan-
amine (1 mmol), anilines (1.2 mmol), formaldehyde (4.0 mmol), RT.
[d] n.d.=not detected.
16
17
1c
1c
2d
2e
2.5
92
90
3
Scheme 2. Hydroamination of benzylamine with ethyl phenylpropiolate.
18
19
1d
2a
5
5
87
91
desired products 4b–d could be formed in good yields if 2b–
d were substituted for benzylamine (Table 1, entries 2–4).
When two different amines were employed in this reac-
tion, an interesting phenomenon was observed (Table 1, en-
tries 5, 6). The reaction proceeded smoothly and resulted in
good yields if 2a was added first. In contrast, no desired
products were detected if aromatic amine 2 f or 2g was
added first (Table 1, entries 7, 8); however, the fact that 4e
and 4 f are obtained from the former reaction indicates that
hydroamination between 1a and 2a cannot take place.
When 1a was replaced by methyl oct-2-ynoate (1b) or ethyl
propiolate (1c) in this MCR, we found that a range of sub-
1d
2b
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H. Jiang et al.
Table 2. Catalyst and temperature screening results.[a]
Catalyst
Additive
T [8C]
t [h]
Yield[b] [%]
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
AuCl3
PdCl2
–
–
–
–
–
–
–
100
100
100
100
50
RT
RT
RT
RT
RT
RT
RT
RT
RT
RT
100
14
14
14
14
14
14
14
6
6
6
6
6
8
–
–
Pd
N
AgOAc
AgOAc
AgOAc
AgBF4
AgBF4
AgBF4
AgBF4
AgBF4
AgOAc
Ag2CO3
AgNO3
Ru3(CO)12
AuCl3
30
31
35
40
80
30
10
27
13
20
37
35
8
Figure 1. X-ray structures of 3a. Ellipses are drawn at the 40% probabili-
ty level.
l-proline
PPh3
Et3N
tBuNH2
DABCO[c]
l-proline
l-proline
l-proline
–
stitutions on the aliphatic amines were well tolerated under
our conditions, and the isolated yields obtained for 4g–o
varied from 87 to 93% (Table 1, entries 9–17). Interestingly,
the reaction of 1c with aliphatic amines and formaldehyde
is more effective and the reaction time was dramatically re-
duced to 2.5–3 h (Table 1, entries 13–17). In addition, steri-
cally hindered substituted amines, such as tert-butylamine
(2e), also gave high yields (4o; Table 1, entry 17). It is
worth mentioning that all the desired products were formed
with high regioselectivity in our experiments.
10
10
10
14
[a] Reaction conditions: alkynoate (1.0 mmol), anlines (2.2 mmol), form-
aldehyde (3.5 mmol), RT. [b] Isolated yields. [c] DABCO=1,4-
diazabicycloACTHNUTRGENUGN[2.2.2]octane.
MCRs and their regioselectivity under catalytic condi-
tions: When aromatic substituted amines were employed as
the substrates in the MCRs of 1a under catalyst-free condi-
tions, we found that the desired products were not observed
even after 14 h at room temperature (Table 2, entries 7, 8).
Further examination showed that domino sequences were
impeded at the hydroamination step (Table 1, entries 5, 6).
Considering that hydroamination is the triggering sequence,
we then focused our effort on the search for a catalyst to
promote the hydroamination step and complete the transfor-
mation. The transition-metal catalysts emerged as the pre-
ferred choice because they have been proven to be the most
powerful and useful tools for hydroamination reactions.[23]
More good processes that use early- and late-transition-
metal catalysts have recently been developed. In general,
the advantage of late-transition-metal catalysts is their
greater tolerance of polar functional groups. The first suc-
such as PdCl2 (Table 2, entry 2) and PdACHTGNUTERNUN(G NO3)2 (Table 2,
entry 3), were employed, no conversion was observed, as in-
dicated by the complete recovery of ethyl phenylpropiolate
and aniline. These results clearly indicate that an appropri-
ate transition-metal catalyst for this domino reaction should
not only serve as a good catalyst to complete the hydroami-
nation step in high yield and regioselectivity, but should also
promote sequences such as Mannich-type reactions and de-
hydration–cyclization. After much effort, we were delighted
to find that MCRs gave the desired product in 30% yield at
1008C for 14 h with AgOAc as the catalyst (Table 2,
entry 4), and to our pleasure AgOAc could catalyze MCRs
even at room temperature (Table 2, entry 6). The experi-
mental results showed that Ag catalysts are a good choice
for these domino sequences. After a series of further optimi-
zations, AgBF4/l-proline was chosen as the most effective
catalyst (Table 2, entries 7–12). In the presence of 5 mol%
AgBF4 and 5 mol% l-proline, the desired product can be
obtained in 80% yield at room temperature and the reac-
tion time was dramatically reduced to 6 h (Table 2, entry 8).
Other catalysts, such as Ag2CO3, AgNO3 and Ru3(CO)12,
were employed in the reaction but only led to moderate
yields of product (Table 2, entries 13–15). Different solvents
were also examined and excellent results were obtained by
using DMF.
cessful demonstration of this process was with RhIII[24] and
[26,27]
IrIII[25] complexes. More recently, Ru3(CO)12
(cod)2]BF4
and [Rh-
[28]
(cod=cyclooctadiene) have been applied to
the catalytic intermolecular hydroamination of aniline deriv-
atives and terminal alkynes. Therefore, we still chose ethyl
phenylpropiolate, 4-fluoroaniline and formaldehyde as the
standard substrates to search for potential catalysts and suit-
able reaction conditions. We first examined the reaction in
the presence of 3 mol% AuCl3. Although the hydroamina-
tion step proceeded, the desired product, 4af, was obtained
in only 8% yield after stirring at 1008C in DMF for 14 h
(Table 2, entry 1). If other late-transition-metal catalysts,
With AgBF4/l-proline as a suitable catalytic system, we
then attempted to improve the yield by adjusting the ratio
of the reactants (Table 3). The reaction proceeded in DMF
with AgBF4/l-proline as the catalyst. The amount of 1a was
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Multicomponent Reactions
FULL PAPER
Table 3. Screening results for the best ratio of the three reactants.
Table 4. AgBF4/l-proline-catalyzed MCRs of asymmetric electron-defi-
cient alkynes, anilines and formaldehyde.[a]
Alkynonate
[mmol]
4-Fluoroaniline
[mmol]
Formaldehyde
ACHTUNGTRNE[NUNG mmol]
Yield[a]
[%]
H
A
1
2
3
4
5
6
7
8
9
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
2.0
2.0
2.0
2.0
2.0
2.0
2.1
2.2
2.3
2.4
2.5
3.0
2.5
3.0
3.5
4.0
4.5
5.0
4.0
4.0
4.0
4.0
4.0
4.0
68
71
73
76
75
70
75
77
80
82
81
76
Electron-de-
ficient
Aromatic
amine
t
Product
Yield[b]
[%]
[h]
alkyne
10
11
12
1
2
1a
6
6
83
80
[a] Isolated yields.
fixed to 1 mmol. When the amounts of 4-fluoroaniline and
formaldehyde were increased, the yield of the desired prod-
uct increased until the ratio of 1a, 4-fluoroaniline and form-
aldehyde reached 1:2.4:4 (Table 3, entry 10).
1a
On the basis of the above experiments, we chose the fol-
lowing optimized reaction conditions: 5 mol% AgBF4 and
5 mol% l-proline as the catalyst and electron-deficient
alkyne, anilines and formaldehyde in a ratio of 1:2.4:4 in
DMF stirred at room temperature for an appropriate time.
The results are summarized in Table 4.
3
1a
6
82
From Table 4, we found that the reaction conditions
proved to be useful for alkenes 1a–c, inert anilines (2 f–k)
and formaldehyde, and the MCRs usually went to comple-
tion in 2.5–6 h. For the reaction of ethyl phenylpropiolate
(1a), 2 f–m and formaldehyde, both electron-rich and elec-
tron-poor anilines, which are suitable partners in this pro-
cess, gave good yields (4af–al; Table 4, entries 1–8). Of the
various substituted amines, 4-fluoroaniline (2 f), 4-chloroa-
miline (2h) and 4-bromoamiline (2i; Table 4, entries 1, 3, 4)
reacted more smoothly with 1a in the presence of the
AgBF4/l-proline catalytic system. This indicates that nearly
all the anilines that have different substituent groups on the
aromatic ring could react smoothly, and the resulting corre-
sponding products were obtained in good yields. Interesting-
ly, sterically hindered substituted amines, such as 2-methyl-
aniline (2m), also gave high yields, which infers that groups
around the -NH2 group do not affect the reactivity of the
amine (Table 4, entry 8). When 1a was replaced by 1b or 1c
in this reaction, we found that a range of substitutions on
the anilines was well tolerated under optimum conditions
(4bm–ck; Table 4, entries 9–15). The molecular structure of
representative product 4af was determined by X-ray crystal-
lography (Figure 2). It was proven that regioselective prod-
ucts have been obtained in our study.
4
5
6
1a
1a
1a
6
5
5
81
80
81
7
1a
6
78
The stereoselectivity of the hydroamination step: In this
domino sequence, the hydroamination of 1a with amines is
the key step. To gain further insight into the stereoselectivity
of the catalyst-free and AgI-catalyzed hydroamination pro-
cesses and the nature of the observed high cis selectivity, we
carried out a series of reactions with electron-deficient al-
kynes. The configuration of the enamino double bond in
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H. Jiang et al.
Table 4. (Continued)
Table 4. (Continued)
Electron-de-
ficient
Aromatic
amine
t
Product
Yield[b]
[%]
Electron-de-
ficient
Aromatic
amine
t
Product
Yield[b]
[%]
[h]
[h]
alkyne
alkyne
16
17
1d
2j
5
5
82
79
8
9
1a
1b
5
6
80
72
2m
1d
10
11
12
1c
1c
1c
2 f
2.5
2.5
2.5
85
85
86
18
1e
2n
5
84
[a] Reaction conditions: electron-deficient alkyne (1.0 mmol), anilines
(2.4 mmol), formaldehyde (4.0 mmol), RT. [b] Isolated yields.
2g
2h
13
14
15
1c
1c
1c
2i
2.5
2.5
2.5
83
84
81
2j
Figure 2. X-ray structure of 4af. Ellipses are drawn at the 32% probabili-
ty level.
products 3a and 3c–n (Table 5) was identified by 1H and
13C NMR spectroscopy. The molecular structures of repre-
sentative product 3a (Figure 1) and 3d (Figure 3) were de-
termined by X-ray crystallography. The downfield chemical
2k
À
shift of the N H proton (d>8 ppm) is a typical feature of a
hydrogen bond with oxygen in a carbonyl group, which indi-
cates a chelated Z configuration. We believe that this reac-
tion proceeds via intermediate 3b, which contains both a
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Multicomponent Reactions
FULL PAPER
Table 5. AgBF4/l-proline-catalyzed hydroamination of electron-deficient
alkynes with anilines.[a]
Electron-defi-
cient alkyne
Aromatic
amine
t
Product
Yield[b]
[%]
[h]
1
2
3
1a
1a
1a
2j
2h
2 f
5
5
5
85
82
82
Figure 3. X-ray structure of 3d. Ellipses are drawn at the 62% probabili-
ty level.
six- and a four-membered ring (Scheme 3). This explains the
high cis selectivity of the hydroamination process well.[29]
High stereoselectivity was obtained due to the formation of
a hydrogen bond[30] that stabilizes 3b. From 3b, there are
two possible routes a and a’ to form 3d and 3d’, respective-
ly. It is obvious that route a is the favourable one due to the
lower steric hindrance and the formation of a hydrogen
bond that stabilizes 3b.
4
5
1a
1a
2g
2i
5
5
81
84
Mechanism: In an effort to understand why and how
these MCRs could be carried out under catalyst-free and
catalytic conditions, a mechanistic study of the MCRs was
undertaken by using a combination of experimental and the-
oretical methods. Experimental work on the hydroamination
reaction of asymmetric electron-deficient alkynes proved
the regioselectivity by verifying two possible structures of
the products (Scheme 2). A computational study was carried
out by using ab initio calculations to elucidate the activation
free energy of the substrates.
6
7
1a
1a
2k
2l
5
5
81
83
In the regiochemistry of asymmetric electron-deficient al-
kynes, the addition reaction of amine to a carbon–carbon
triple bond is highly regioselective due to the nucleophilic
attack by the nitrogen atom of the amine. Our study demon-
strates that both the catalyst-free and the Ag-catalyzed pro-
cesses stereoselectively promote the cis-selective hydroami-
nation of ethyl phenylpropiolate with amines. Therefore, the
Ag-catalyzed process is an example to describe the detailed
mechanism of this domino sequence. To study the order of
the domino sequences, three experiments were performed
as shown in Scheme 4. First, we prepared intermediate prod-
uct 3c, which was determined by GCMS under AgBF4/l-
proline catalytic conditions. The reactions of 3c with formal-
dehyde and with aniline were retarded under both catalyst
and catalyst-free conditions after stirring at room tempera-
ture in DMF. However, the desired product (4aj) was ob-
tained after 3c, formaldehyde and N-methyleneaniline (5)
were stirred at room temperature in DMF. This result sug-
gests that the order of this domino reaction is hydroamina-
tion, a Mannich-type reaction and then dehydration–cycliza-
tion.
8
9
1a
1a
2m
5
5
84
80
10
11
1c
1 f
2i
5
5
86
85
2n
[a] Reaction conditions: electron-deficient alkyne (1.0 mmol), anlines
(2.4 mmol), RT. [b] Isolated yields.
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H. Jiang et al.
formed by a Mannich-type re-
action of 3c and 5. Finally, with
the addition of formaldehyde,
4aj was obtained via dehydra-
tion–cyclisation.
DFT calculations: From the
mechanistic study, it can be
seen that the hydroamination
reaction is the rate-determining
step in the MCRs. A computa-
tional study was carried out by
using ab initio calculations to
Scheme 3. Two possible routes for the formation of enamino intermediates.
elucidate the activation free
energy of the substrates. DFT
was used to elucidate the mechanism of the catalyst-free hy-
droamination reaction of 1a, 1b, 1c and diethyl acetylenedi-
carboxylate (1i) with 2j or 2a. All calculations were carried
out by using the Gaussian 03 programs.[31] The geometrical
optimizations of all intermediates and transition states were
performed by using Beckeꢁs three-parameter exchange func-
tional and the non-local correlation functional of Lee, Yang
and Parr[32] (B3LYP) with the 6–31G(d) basis set for all
atoms. Frequency calculations at the same level were per-
formed to confirm each stationary point as either a mini-
mum or a transition structure (TS). In the following discus-
sion, the energies are relative Gibbs free energies (DG298).
The DFT-computed energy surface in the gas phase for
the hydroamination reaction between 1i with 2a or 2j is
given in Figure 4. The activation free energy DG for 2j is
given in brackets. The first step of hydroamination reaction
starts with a nucleophilic addition of 2j or 2a to the triple
bond of 1i (Figure 4). Complex S1 has a carbine atom in its
structure. The calculations indicate that the singlet state of
S1 is much more stable than the triplet state. DG0 are the
activation free energy of the nucleophilic addition reactions.
The conversion from S1 to intermediate S2 via a four-mem-
bered-ring transition structure is a [1,3]-hydrogen shift pro-
cess with an activation free energy of DG1. The four-mem-
bered ring is composed of ethynyl, nitrogen and hydrogen
atoms. DGs, the sum of DG0 and DG1, is the activation free
energy of the catalyst-free hydroamination reaction. DG2 is
the activation free energy of
Scheme 4. Examination of the MCR mechanism by studying the reactions
of 3c under different conditions.
On the basis of these results, we depict a possible mecha-
nism in Scheme 5. 1a is activated by [Ag/proline]+ to gener-
ate the cationic AgI–alkyne complex A, followed by coordi-
nation of aniline to the Ag centre (B). The coordination of
AgBF4 to alkynoates lowers the electron density of the
carbon–carbon triple bond, which makes the nucleophilic
attack of anilines toward alkynoates easier and smoother.
À
Intermediate B further undergoes C N bond formation to
give polarized intermediate C prior to the formation of hy-
droaminating adduct 3c. Subsequently, compound D was
the reverse reaction for this
step. During the second step,
intermediate S2 transforms via
transition structure TS2 into
product S3, which is much
more
thermodynamically
stable. The activation free
energy of the second step is
DG3. Because the absolute
value of DG3 is smaller than
that of DG2, the second reac-
tion proceeds smoothly. Conse-
quently, the whole reaction is a
kinetically controlled process.
The values of DG0, DG1 and
Scheme 5. Proposed mechanism for AgBF4/l-proline-catalyzed MCRs. L=l-proline.
11630
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Chem. Eur. J. 2008, 14, 11623 – 11633

Multicomponent Reactions
FULL PAPER
for aliphatic amines were lower than those for anilines,
which is consistent with the experimental results. Further-
more, the good product yields, mild reaction conditions and
use of simple starting materials are the main advantages of
this method.
Experimental Section
General methods: All reactions were performed at RT under air in a
round bottom flask equipped with a magnetic stir bar. 1H and 13H NMR
spectra were recorded by using a Bruker Avance 400 MHz NMR spec-
trometer and referenced to d=7.24 and 77.0 ppm for chloroform with
TMS as the internal standard. IR spectra were obtained as potassium
bromide pellets or as liquid films between two potassium bromide pellets
by using a Brucker Vector 22 spectrometer. Mass spectra were recorded
by using a Shimadzu GCMS-QP5050 A instrument set at an ionization
voltage of 70 eV and equipped with a DB-WAX capillary column (inter-
nal diameter=0.25 mm, length=30 m). Elemental analysis was per-
formed by using a Vario EL elemental analyzer. TLC was performed by
using commercially prepared 100–400 mesh silica gel plates (GF254), and
visualization was performed at 254 nm and 365 nm. All chemicals were
purchased from Aldrich Chemicals.
Figure 4. DFT-computed energy surfaces for the catalyst-free hydroami-
nation reactions between 1i with 2a or 2j.
DG2 for different reactions are listed in Table 6. From
Table 6, all DG values for benzylamine (2a) were lower
than those for aniline (2j). Therefore, the hydroamination
CCDC-706544 (3a), -706546 (4af) and -706545 (3d) contain the supple-
mentary crystallographic data for this paper. These data can be obtained
free of charge from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
Table 6. The computed Gibbs free energies [kcalmolÀ1] for the hydro-
ACHTUNGTRENNUNG
General procedure for the synthesis of ethyl 1,3-dibenzyl-6-phenyl-
1,2,3,4-tetrahydropyrimidine-5-carboxylate four-component reactions:
Benzylamine (2.2 mmol) and DMF (3 mL) were successively added with
stirring to ethyl phenylpropiolate (1 mmol). The mixture was stirred at
RT for 6 h, then formaldehyde (4 mmol) was added. After completion of
the reaction (as monitored by TLC), the solution was evaporated to dry-
ness under reduced pressure and then water (8 mL) was added. The
aqueous solution was extracted with diethyl ether (3ꢂ15 mL) and the
combined extract was dried with anhydrous MgSO4. The solvent was re-
moved and the crude product was separated by column chromatography
to give a pure sample of ethyl 1,3-dibenzyl-6-phenyl-1,2,3,4-tetrahydro-
pyrimidine-5-carboxylate (4a).
DG0
DG1
DGs
DG2
44.9
35.3
43.2
35.5
37.0
28.4
32.7
18.4
3.0
5.5
4.1
4.9
4.7
6.8
5.3
11.3
47.9
40.8
47.3
40.4
41.7
35.2
38.0
29.7
À66.7
À62.9
À70.9
-63.5
À78.7
À72.6
À64.4
À58.4
1a
2j
2a
2j
2a
2j
2a
2j
1b
1c
1i
General procedure for the synthesis of ethyl 1,3,6-triphenyl-1,2,3,4-tetra-
hydropyrimidine-5-carboxylate by three-component reactions: Aniline
(2.4 mmol), AgBF4 (5 mol%), l-proline (5 mol%) and DMF (3 mL)
were successively added with stirring to ethyl phenylpropiolate (1 mmol).
The mixture was stirred at RT for 5 h, then formaldehyde (4 mmol) was
added. After completion of the reaction (as monitored by TLC), the so-
lution was evaporated to dryness under reduced pressure and then water
(8 mL) was added. The aqueous solution was extracted with diethyl ether
(3ꢂ15 mL) and the combined extract was dried with anhydrous MgSO4.
The solvent was removed and the crude product was separated by
column chromatography to give a pure sample of ethyl 1,3,6-triphenyl-
1,2,3,4-tetrahydropyrimidine-5-carboxylate (4af).
reaction of benzylamine (2a) should be faster than that of
aniline (2j), which is consistent with our experimental re-
sults. In our experiments, all the hydroamination reactions
of 2a and the reaction between 1i with 2j can easily pro-
ceed even under catalyst-free conditions. As a result, we be-
lieve that DG=41 kcalmolÀ1 may be the threshold activa-
tion free energy. If the activation free energy is lower than
this threshold energy, the hydroamination reactions can pro-
ceed under catalyst-free conditions, whereas if the activation
energy is higher than 41 kcalmolÀ1, the hydroamination re-
action can only be performed with the aid of a suitable cata-
lyst.
Acknowledgements
We thank the National Natural Foundation of China (Nos. 20332030,
20572027, 20625205 and 20772034) and Guangdong Natural Science
Foundation (No. 07118070) for financial support.
Conclusion
In summary, we have reported two novel multicomponent
reactions that lead to polysubstituted pyrimidine starting
from simple and readily available inputs. The reactions are
highly regioselective in that only the Markovnikov addition
product is observed and no anti-Markovnikov product was
formed. DFT calculations show the activation free energies
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Multicomponent Reactions
FULL PAPER
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Received: July 21, 2008
Revised: August 22, 2008
Published online: November 14, 2008
Chem. Eur. J. 2008, 14, 11623 – 11633
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
11633