N-Alkoxymethylation of heterocyclic compounds with diethyl phosphite via cleavage of P-O bond

Article abstract of DOI:10.1016/j.tet.2011.01.061

N-Alkoxymethylation of heterocyclic compounds with diethyl phosphite via cleavage of P-O bond was investigated and a series of N3-ethoxymethylated heterocyclic compounds were synthesized. A mechanism in which diethyl phosphite acts as an efficient surrogate of ethanol was proposed and supported by several evidences.

Full text of DOI:10.1016/j.tet.2011.01.061

Tetrahedron 67 (2011) 2462e2467
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Tetrahedron
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N-Alkoxymethylation of heterocyclic compounds with diethyl phosphite via
cleavage of PeO bond
,
b
,
a
,
,
,
,b
Zheng-Jun Quan a , Rong-Guo Ren b, Xiao-Dong Jia a b, Yu-Xia Da a b, Zhang Zhang a
,
*
,b,
Xi-Cun Wang a
*
a Key Laboratory of Eco-Environment-Related Polymer Materials, Ministry of Education, China
b Gansu Key Laboratory of Polymer Materials, College of Chemistry and Chemical Engineering, Northwest Normal University, Anning East Road 967#, Lanzhou, Gansu 730070, China
a r t i c l e i n f o
a b s t r a c t
Article history:
N-Alkoxymethylation of heterocyclic compounds with diethyl phosphite via cleavage of PeO bond was
investigated and a series of N3-ethoxymethylated heterocyclic compounds were synthesized. A mech-
anism in which diethyl phosphite acts as an efficient surrogate of ethanol was proposed and supported
by several evidences.
Received 6 November 2010
Received in revised form 14 January 2011
Accepted 21 January 2011
Available online 27 January 2011
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Diethyl phosphite
N3-Substituted dihydropyrimidinones
N-Alkylation
PeO cleavage
1. Introduction
protocols toward the using of dialkyl phosphite derivatives, cleav-
age of PeH bond inevitably involved homolytic cleavage6 as the
Dialkyl phosphites, as a kind of useful phosphorus-containing
reagents, are widely applied to the synthesis of organophosphonate
derivatives, which are an important class of biologically active
compounds.1 A large number of useful transformations have been
achieved during the past decades, in which dialkyl phosphites were
used as standard nucleophilic species for the construction of CeP
bonds, in which various compounds can act as the acceptor, such as
source of P-centered radicals under radical-initiated conditions or
heterolytic cleavage7 (Fig. 1, path a). Besides, there are few reports
showing that dialkyl phosphites could also participate in the con-
struction of CeN and CeO bonds, involving the cleavage of CeO
bond (path b).8 However, to the best of our knowledge, few efforts
were devoted to improving PeO bond cleavage and further using
dialkyl phosphites as an O-nucleophiles to achieve some interesting
transformations (path c).
In the past decades, 3,4-dihydropyrimidinones (Biginelli
compounds or DHPMs) and their derivatives have attracted con-
siderable interest due to their heterocyclic scaffold9 and in-
teresting pharmacological properties, such as calcium channel
modulation, anti-hypertension, a1a adrenergic agonistic and mi-
totic kinesin inhibition, and hepatitis B virus replication sup-
pression.10 The N-substituted reaction of dihydropyrimidinones is
one of the approaches to functionalized dihydropyrimidinones in
order to achieve higher bioactive properties.9 For instance, most of
the pharmacologically attractive forms are N3-substituted ana-
logues, which might exhibit anti-inflammatory, antihypertensive,
analgesic, and anticancer activities.11 Most N-alkylated pyr-
imidinones are obtained from SN2 reaction in which pyrimidinone
as a nucleophile reacts with an electrophile, such as an alkyl halide
and alkyl sulfate. However, unexplained poor regioselectivity
between N3 and N1 were obtained and in most cases N1-alkylated
products of pyrimidinones were isolated as major products.9a,b
imines (ketimines),2 carbonyl groups,3
a,b-unsaturated carbonyl
compounds,4 nitroalkenes,5 and so on. Recently, some new catalyst
systems have also been developed to promote the fully using of
dialkyl phosphites in different ways (Fig. 1). Among those efficient
Fig. 1. Reaction of dialkyl phosphites.
* Corresponding authors. Tel./fax: þ86 931 7971971; e-mail addresses:
quanzhengjun@hotmail.com (Z.-J. Quan), wangxicun@nwnu.edu.cn (X.-C. Wang).
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.01.061

Z.-J. Quan et al. / Tetrahedron 67 (2011) 2462e2467
2463
These limitations have hindered the synthesis of N3-substituted
pyrimidinone derivatives.
according to standard procedure before use) and catalysts was
carried out. The reaction between 1a, paraformaldehyde, and
diethyl phosphite did not occur in refluxing CH2Cl2, THF, and eth-
anol (entries 1e3). A low yield of product 2a was formed when
catalytic amount of SnCl2 or NiCl2 was added (entries 4 and 5). It
was found that product 2a was isolated in 65% yield when the re-
action temperature was increased to 80 ꢀC in benzene for 12 h
(entry 6). Interestingly, higher yields of 2a were obtained in tetra-
chloroethylene (PCE) at 110 ꢀC for 7 h without any catalysis (entries
7 and 8); in contrast, toluene and DMF led to a lower yield of 2a
after 24 h at the same temperature (entries 9 and 10). Lower yields
wereobtained when the ratio of the substrates was changed (Table 1,
entries 11e12). Thus, we decided to use 2 equiv of diethyl phosphite
and 2 equiv of paraformaldehyde in PCE at 110 ꢀC without
catalysis as the optimal reaction conditions for the preparation
of N3-ethoxymethyl DHPMs (Table 1, entry 7). We replaced the
paraformaldehyde with formaldehyde and the desired product 2
was obtained in low yield (Table 1, entry 13). To confirm the
necessity using diethyl phosphite as equivalent of ethanol, we
also performed the reaction of 1, ethanol, and paraformaldehyde
under the standard condition, but no any reaction occurred,
which implied that it is necessary to use diethyl phosphite as
surrogates of the corresponding alcohol.
With these results in hand, we then explored the scope and
generality of this three-component reaction (Table 2). Firstly, we
varied the substituent on the aromatic ring of 1 to test the elec-
tronic effect. From Table 2 we can see, in all cases, the reaction
occurred smoothly affording the desired products in good yields.
Electron-donating groups (entries 1, 4, and 5) seem propitious to
the reaction giving higher yields. This is because the formation of
iminium ion 8 would be accelerated when the nucleophilicity of N3
was increased (see mechanism). We next investigated the influence
of the substituent on R. But no obvious effect was found and even
more bulky substituent (i-Pr) was tolerated in this reaction (entries
8 and 9). Sulfur-containing analogues of 1 exhibited a slightly lower
reactivity, the yields of the desired products decreased about 10%. It
is well known that N1-methoxymethylation occurred as main re-
action by treatment of 3,4-dihydropyrimidinone with chloro
(methoxy)methane.15 However, the NMR spectra of 2aem, in
which 2b and 2k were unambiguously confirmed by X-ray crys-
tallography as representative compounds,16 revealed that the
As part of our ongoing research program on the synthesis of
3,4-dihydropyrimidinone (DHPM) derivatives,12 we recently
reported a regioselective synthesis of the N3-functionalized DHPM
by reaction of DHPM with paraformaldehyde and various reagents
in the presence of chlorotrimethylsilane.13 In continuation of our
efforts to synthesize some new N3-functionalized DHPM de-
rivatives, which might exhibit better biological responses and
pharmacological properties, herein we described a novel and effi-
cient synthesis of N-ethyoxymethyl-3,4-dihydropyrimidinone us-
ing a three component reaction between 3,4-dihydropyrimidinone,
paraformaldehyde, and diethyl phosphite via the PeO bond cleav-
age of diethyl phosphite (Fig. 1, path c).
2. Results and discussion
2.1. Reaction with 3,4-dihydropyrimidinone and
paraformaldehyde
It has been reported that N3-hydroxylmethylated 3,4-dihy-
dropyrimidinone could be achieved by treating 3,4-dihydropyr-
imidinone with aqueous formaldehyde and potassium carbonate
at reflux temperature.14 According to our mechanism design,
we expected that the N3-hydroxylmethylated 3,4-dihydropyr-
imidinones, which produced by the reaction between 3,4-dihy-
dropyrimidinones and paraformaldehyde could subsequently react
with diethyl phosphite and generate phosphorus-containing
3,4-dihydropyrimidinone derivatives. However, to our great sur-
prise, PeO bond cleavage occurred and N-ethyoxymethyl-3,4-dihy-
dropyrimidinone was isolated as a major product. So we focused our
attention on this novel transformation.
Initially, we chose the reaction of DHPM 1a, paraformaldehyde,
and diethyl phosphite as a model reaction to optimize the reaction
conditions. The results were summarized in Table 1. An extensive
investigation of a range of solvents (all solvents were dried
Table 1
Optimization of reaction conditions for product 2aa
O
O
O
Table 2
EtO
NH
N
EtO
OEt
HP(OEt)2
tetrachloroethylene
110 oC, 7 h
Three-component reaction between dihydropyrimidinones, paraformaldehyde, and
+
diethyl phosphite in PCEa
Me
N
H
O
Me
N
H
O
(CH2O)n
1a
2a
O
R
Ar
O
R
Ar
O
HP(OEt)2, (CH2O)n
EtO
N
OEt
EtO
NH
Entry
Equiv of
Solvent
Temperature/ꢀC
Time/h
Isolated
yield/%
1a/(CH2O)n/DEP
PCE, 110 oC, 7-9 h
N
H
X
N
H
X
1
2
3
1/2/2
1/2/2
1/2/2
1/2/2
1/2/2
1/2/2
1/2/2
1/2/2
1/2/2
1/2/2
1/2/1
1/1/1
1/1/1
CH2Cl2
THF
Ethanol
CH2Cl2
THF
Benzene
PCE
PCE
Toluene
DMF
PCE
PCE
PCE
40
65
80
40
65
24
24
9
0
0
0
2
1
4b
5c
6
24
12
24
7
35
48
65
84
88
75
60
38
33
35
Entry
Ar
C6H5
4-NO2C6H4
3-NO2C6H4
4-MeC6H4
4-MeOC6H4
4-FC6H4
4-BrC6H4
C6H5
4-MeOC6H4
C6H5
R
X
2
Time/h
Yield/%
1
2
3
4
5
6
7
8
Me
Me
Me
Me
Me
Me
Me
i-Pr
i-Pr
Me
Me
Me
Me
O
O
O
O
O
O
O
O
O
S
2a
2b
2c
2d
2e
2f
2g
2h
2i
7
8
8
7
7
7
7
7
7
9
9
9
9
84
78
81
88
90
87
83
84
87
78
80
79
76
80
7
110
110
110
110
110
110
110
8c
9
7
24
24
7
7
7
10
11
12
13d
9
Bold values represent optimal reaction conditions for the preparation of
N3-ethoxymethyl DHPMs.
Reaction conditions: DHPM 1a (1 mmol), (CH2O)n (1.5 mmol), and diethyl
phosphite (1.5 mmol) in 2 mL solvent.
10
11
12
13
2j
2k
2l
4-MeC6H4
4-ClC6H4
4-NO2C6H4
S
S
S
a
2m
b
SnCl2 (0.2 equiv) was used.
NiCl2 (0.2 equiv) was used.
Formaldehyde was used instead of paraformaldehyde.
a
c
Reaction conditions: DHPMs 1 (1 mmol), (CH2O)n (2 mmol), and diethyl phos-
phite (2 mmol) in 2 mL tetrachloroethylene (PCE) at 110 ꢀC.
d

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Z.-J. Quan et al. / Tetrahedron 67 (2011) 2462e2467
reactions of 3,4-dihydropyrimidinones, paraformaldehyde, and
diethyl phosphite proceeded in a highly regioselective manner and
no any N1-substituted product was detected.
NiCl2 or SnCl2 catalysis; however, only N-hydroxymethyl phthali-
mide (4d) was isolated (entry 4). In an attempt to obtain
N-ethoxymethyl phthalimide, compound 4d was treated with
diethyl phosphite in the presence of NiCl2 or SnCl2 in tetrachloro-
ethylene at 110 ꢀC for 12 h; however, no reaction was observed.
This may be due to the strong electron withdrawing conjugation
effect of the two carbonyl groups on the nitrogen atom, which re-
duces the electronic density of the nitrogen atom. Finally, we car-
ried out the reaction of heterocyclic primary amine benzo[d]
thiazol-2-amine (3e), giving the N,N-bis(ethoxymethyl)benzo[d]
thiazol-2-amine 4e in high yield (82%).
2.2. Reaction with NH-heterocyclic compounds 3 and
paraformaldehyde
These promising results encouraged us to apply this reaction to
other extensive NH-containing heterocycles substrates to further
explore the use in construction of more variable heterocyclic com-
pounds via PeO cleavage pattern of diethyl phosphite. To our delight,
substrates 3aee were also able to react with formaldehyde and
diethyl phosphite, opening the access to a new type of three-com-
ponentreaction(Table 3). Inthiscase, benzo[d][1,2,3]triazole resulted
in N1-ethoxymethyl benzo[d][1,2,3]triazole (4aa) and N2-ethox-
ymethyl benzo[d][1,2,3]triazole (4ab) with the N1-substituted prod-
uct (4aa) as the main product (entry 1). However, reported synthesis
of 4a needed a three-step process, in which benzo[d][1,2,3]triazole
reacts with formaldehyde to give 1-(hydroxymethyl)benzotriazole,
followed by chlorination with thionyl chloride to 1-(chloromethyl)
benzotriazole. Subsequently, substitution of the chlorine atom with
ethanol gave the products 4a.17 Our method based on PeO cleavage of
diethyl phosphite has the potential to be a powerful synthetic tool for
the construction of such compounds due to its high efficiency.
2.3. Mechanism
A mechanism was proposed to rationalize the formation of
product. First, the NH group of 3,4-dihydropyrimidinone attacked
paraformaldehyde, forming an iminium ion 8 (Scheme 1). The hy-
droxide created in situ initiates a series of electron push processes.
The formation of iminium ion 8e was supported by the LCeMS
experimental results (detected at m/z: 303, 302, 301 for 8e). Then
lone pair electrons in oxygen of diethyl phosphite added to 8 to
produce 9. After that, PeO bond broken producing the corre-
sponding products 2 and monoethyl phosphite.
Table 3
Three-component reaction between NH-heterocycles, paraformaldehyde, and diethyl phosphite in PCEa
O
X
Y
X
Y
HP(OEt)2, (CH2O)n
N
N
H
PCE, 110 oC, 8 h
OEt
4
3
Entry
1
Material
Product
Isolated yield/%
CH2OEt
H
N
N
N
N
N
4aa: 78 4ab: 16
N
CH2OEt
N
N
4ab
3a
N
4aa
H
N
2
N
89
CH2OEt
N
4b
N
3b
H
N
88b
84
N CH2OEt
O
3
4
N
N
4c
3c
O
N
CH2OH
NH
O
O
N
3d
4d
N
CH2OEt
5
82
S
N
S
NH2
3e
CH2OEt
4e
a
Reaction conditions: heterocyclic amines (1 mmol), (CH2O)n (2 mmol), and diethyl phosphite (2 mmol) in 2 mL PCE at 110 ꢀC for 8 h.
Detected by NMR and LCeMS.
b
1H-Imidazole (3b) and 1H-pyrazole (3c) were also tolerated in
3. Conclusion
this reaction giving 4b and 4c in 89% and 88% yields, respectively
(entries 2 and 3). When 1H-pyrazole was involved, a mixture of two
products was obtained, which could not be isolated by column
chromatography and show two sets of closely similar signals in
NMR, demonstrating the existence of two compounds (LCeMS also
indicates the presence of this product). Phthalimide did not pro-
duce any of the desired products in PCE at 110 ꢀC with or without
In summary, we have executed a novel approach in which PeO
bond cleavage of diethyl phosphite occurred and diethyl phosphite
served as an equivalent of alcohol to achieve the synthesis of a series
of N-ethoxymethylated heterocyclic compounds in high regiose-
lectivity and yield. We are currently focused on promoting this novel
transformation and further exploring the use in construction of

Z.-J. Quan et al. / Tetrahedron 67 (2011) 2462e2467
2465
Scheme 1. The plausible reaction mechanism.
more variable heterocyclic compounds. Further investigations in the
mechanism of this reaction are also underway in this laboratory.
OCH2CH3), 2.37 (s, 3H, 6-CH3),1.24 (t, J¼6.8 Hz, 3H, OCH2CH3),1.09 (t,
J¼6.8 Hz, 3H, OCH2CH3); 13C NMR (100 MHz, CDCl3):
¼165.0, 153.0,
d
149.1, 147.5, 146.9, 128.2, 123.8, 101.3, 74.6, 63.9, 60.3, 57.7, 18.5, 14.7,
14.1. MS: m/z¼363 (Mþ). Anal. Calcd for C17H21N3O6 (363.14): calcd C
56.19, H 5.83, N 11.56. Found: C 56.31, H 5.79, N 11.64.
4. Experimental section
4.1. General
4.2.3. Ethyl
1-(ethoxymethyl)-4-methyl-6-(3-nitrophenyl)-2-oxo-
All reagents were obtained commercially and used without fur-
ther purification. Melting points were determined on an XT-4 elec-
trothermal micromelting point apparatus and uncorrected. NMR
spectra were recorded at 400 (1H) and 100 (13C) MHz, respectively,
on a Varian Mercury plus-400 instrument using CDCl3 as solvent and
TMS as internal standard. LCeMass-spectra and mass-spectra were
recorded on a TRACE DSQ instrument. All commercially available
substrates were used as received. TLC was performed on 5ꢁ10 cm
aluminum plates coated with silica gel 60F-254 in an appropriate
solvent. All commerciallyavailable substrates were used as received.
1,2,3,6-tetrahydropyrimidine-5-carboxylate (2c). White solid, mp
168e170 ꢀC, yield: 81% (ethyl acetate/petroleum ether¼1/5); 1H
NMR (400 MHz, CDCl3):
d
¼8.62 (br s, 1H, NH), 8.25e7.49 (m, 4H,
HAr), 5.62 (s, 1H, 4-CH), 5.16 (d, J¼10.8 Hz, 1H, NCHH), 4.48 (d,
J¼10.8 Hz, 1H, NCHH), 4.16e4.06 (m, 2H, OCH2CH3), 3.59e3.52 (m,
1H, OCH2CH3), 3.43e3.36 (m, 1H, OCH2CH3), 2.38 (s, 3H, 6-CH3),
1.26e1.21 (m, 3H, OCH2CH3), 1.11e1.07 (m, 3H, OCH2CH3); 13C NMR
(100 MHz, CDCl3):
d
¼165.0, 153.1, 148.2, 147.1, 144.2, 133.4, 129.5,
122.9,122.4,101.3, 74.6, 63.9, 60.3, 57.7,18.4,14.7,14.1. MS: m/z¼363
(Mþ). Anal. Calcd for C17H21N3O6 (363.14): calcd C 56.19, H 5.83, N
11.56. Found: C 56.30, H 5.79, N 11.62.
4.2. General experimental procedure for the reaction of 3,4-
dihydropyrimidinones and paraformaldehyde with diethyl
phosphite
4.2.4. Ethyl 1-(ethoxymethyl)-4-methyl-2-oxo-6-p-tolyl-1,2,3,6-tetra-
hydropyrimidine-5-carboxylate (2d). White solid, mp 173e175 ꢀC,
yield: 88% (ethyl acetate/petroleum ether¼1/6); 1H NMR (400 MHz,
To a solution of 3,4-dihydropyrimidinone (1) (1 mmol) and
paraformaldehyde (2 mmol) in tetrachloroethylene (2 mL), diethyl
phosphite was added (2 mmol). After completion monitored by
TLC, the reaction mixture was concentrated under reduced pres-
sure. The products were separated by silica gel column chroma-
tography eluted with petroleum ethyl acetate/petroleum ether.
CDCl3):
d¼8.39 (br s, 1H, NH), 7.27e7.22 (m, 2H, HAr), 7.11e7.06 (m,
2H, HAr), 5.47 (s, 1H, 4-CH), 5.23 (d, J¼10.4 Hz, 1H, NCHH), 4.34 (d,
J¼10.4 Hz, 1H, NCHH), 4.15e4.06 (m, 2H, OCH2CH3), 3.62e3.57 (m,1H,
OCH2CH3), 3.47e3.39 (m, 1H, OCH2CH3), 2.30 (s, 3H, 6-CH3), 1.26e1.19
(m, 3H, OCH2CH3), 1.17e1.11 (m, 3H, OCH2CH3); 13C NMR (100 MHz,
CDCl3):
d
¼165.5,153.3,145.9,138.9,137.7,129.1,127.3,102.4, 73.9, 63.8,
60.0, 57.6, 21.1, 18.4, 14.8, 14.2. MS： m/z¼332 (Mþ), C18H24N2O4
4.2.1. Ethyl 1-(ethoxymethyl)-4-methyl-2-oxo-6-phenyl-1,2,3,6-tet-
rahydropyrimidine-5-carboxylate (2a). White solid, mp 172e174 ꢀC,
yield: 84% (ethyl acetate/petroleum ether¼1/5); 1H NMR (400 MHz,
(332.17): calcd C 65.04, H 7.28, N 8.43. Found: C 65.19, H 7.40, N 8.32.
4.2.5. Ethyl
1-(ethoxymethyl)-6-(4-methoxyphenyl)-4-methyl-2-
CDCl3):
d
¼8.34 (br s, 1H, NH), 7.39e7.24 (m, 5H, HAr), 5.50 (s, 1H, 4-
oxo-1,2,3,6-tetrahydropyrimidine-5-carboxylate (2e). White solid,
CH), 5.21 (d, J¼10.8 Hz, 1H, NCHH), 4.37 (d, J¼10.8 Hz, 1H, NCHH),
4.15e4.03 (m, 2H, OCH2CH3), 3.60e3.54 (m, 1H, OCH2CH3),
3.46e3.38 (m, 1H, OCH2CH3), 2.35 (s, 3H, 6-CH3), 1.26e1.22 (m, 3H,
OCH2CH3), 1.18e1.12 (m, 3H, OCH2CH3); 13C NMR (100 MHz, CDCl3):
mp 134e136 ꢀC, yield: 90% (ethyl acetate/petroleum ether¼1/6); 1H
NMR (400 MHz, CDCl3):
d
¼8.51 (br s, 1H, NH), 7.30e7.27 (m, 2H,
HAr), 6.83e6.81 (m, 2H, HAr), 5.45 (s, 1H, 4-CH), 5.34 (d, J¼10.4 Hz,
1H, NCHH), 4.35 (d, J¼10.4 Hz, 1H, NCHH), 4.11e4.05 (m, 2H,
OCH2CH3), 3.80 (s, 3H, OCH3), 3.61e3.57 (m, 1H, OCH2CH3),
3.52e3.42 (m, 1H, OCH2CH3), 2.37 (s, 3H, 6-CH3), 1.24e1.16 (m, 6H,
d
¼165.5, 153.3, 145.9, 141.8, 128.4, 127.9, 127.4, 102.3, 74.1, 63.7, 60.0,
57.9, 18.4, 14.9, 14.2. MS: m/z¼318 (Mþ). Anal. Calcd for C17H22N2O4
(318.16): C 64.13, H 6.97, N 8.80. Found: C 63.95, H 6.88, N 8.91.
OCH2CH3); 13C NMR (100 MHz, CDCl3):
d¼165.5, 153.3, 145.9, 138.9,
137.7, 129.1, 127.3, 102.4, 73.9, 63.8, 60.0, 57.6, 21.1, 18.4, 14.9, 14.2.
MS: m/z¼348 (Mþ). Anal. Calcd for C18H24N2O5 (348.17): C 62.05, H
6.94, N 8.04. Found: C 62.21, H 6.88, N 8.25.
4.2.2. Ethyl
1-(ethoxymethyl)-4-methyl-6-(4-nitrophenyl)-2-oxo-
1,2,3,6-tetrahydropyrimidine-5-carboxylate (2b). White solid, mp
160e161 ꢀC, yield: 78% (ethyl acetate/petroleum ether¼1/10); 1H
NMR (400 MHz, CDCl3):
d
¼8.69 (br s, 1H, NH), 8.18 (d, J¼8.8 Hz, 2H,
4.2.6. Ethyl 1-(ethoxymethyl)-6-(4-fluorophenyl)-4-methyl-2-oxo-1,2,
3,6-tetrahydropyrimidine-5-carboxylate (2f). White solid, mp
164e166 ꢀC, yield: 87% (ethyl acetate/petroleum ether¼1/5); 1H
HAr), 7.57 (d, J¼8.4 Hz, 2H, HAr), 5.61 (s, 1H, 4-CH), 5.15 (d, J¼10.8 Hz,
1H, NCHH), 4.46 (d, J¼10.8 Hz, 1H, NCHH), 4.15e4.09 (m, 2H,
OCH2CH3), 3.55 (q, J¼6.8 Hz, 1H, OCH2CH3), 3.38 (q, J¼6.8 Hz, 1H,
NMR (400 MHz, CDCl3):
d¼8.48 (br s, 1H, NH), 7.36e6.96 (m, 4H,

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Z.-J. Quan et al. / Tetrahedron 67 (2011) 2462e2467
HAr), 5.48 (s, 1H, 4-CH), 5.18 (d, J¼10.8 Hz, 1H, NCHH), 4.38 (d,
J¼10.8 Hz, 1H, NCHH), 4.13e4.06 (m, 2H, OCH2CH3), 3.58e3.54 (m,
1H, OCH2CH3), 3.42e3.38 (m, 1H, OCH2CH3), 2.35 (s, 3H, 6-CH3),
1.26e1.21 (m, 3H, OCH2CH3), 1.19e1.11 (m, 3H, OCH2CH3); 13C NMR
(s, 3H, 6-CH3), 1.28 (t, J¼7.2 Hz, 3H, OCH2CH3), 1.21 (t, J¼7.2 Hz, 3H,
OCH2CH3); 13C NMR (100 MHz, CDCl3):
137.5, 129.3, 127.0, 103.8, 79.0, 64.6, 60.3, 56.9, 21.0, 18.0, 14.9, 14.1.
MS: m/z¼348 (Mþ). Anal. Calcd for C18H24N2O3S (348.15): calcd C
62.04, H 6.94, N 8.04. Found: C 62.13, H 6.98, N 8.00.
d¼176.4, 165.2, 142.0, 138.1,
(100 MHz, CDCl3):
d
¼165.3, 163.5, 153.4, 146.0, 137.7, 129.1, 115.4,
102.2, 74.1, 63.8, 60.1, 57.3, 18.3, 14.8, 14.1. MS: m/z¼352 (Mþ). Anal.
Calcd for C17H21FN2O4 (336.15): calcd C 60.70, H 6.29, N 5.65. Found:
C 60.79, H 6.34, N 5.58.
4.2.12. Ethyl 6-(4-chlorophenyl)-1-(ethoxymethyl)-4-methyl-2-thi-
oxo-1,2,3,6-tetrahydropyrimidine-5-carboxylate (2l). White solid,
mp 128e130 ꢀC, yield: 79% (ethyl acetate/petroleum ether¼1/10);
4.2.7. Ethyl 6-(4-bromophenyl)-1-(ethoxymethyl)-4-methyl-2-oxo-
1,2,3,6-tetrahydropyrimidine-5-carboxylate (2g). White solid, mp
170e172 ꢀC, yield: 83% (ethyl acetate/petroleum ether¼1/5); 1H
1H NMR (400 MHz, CDCl3):
d
¼8.19e8.18 (m, 2H, HAr), 8.17 (br s, 1H,
NH), 7.54e7.51 (m, 2H, HAr), 5.83 (d, J¼10.4 Hz, 1H, NCHH), 5.79 (s,
1H, 4-CH), 4.76 (d, J¼10.4 Hz, 1H, NCHH), 4.22e4.16 (m, 2H,
OCH2CH3), 3.66e3.62 (m, 1H, OCH2CH3), 3.52e3.48 (m, 1H,
OCH2CH3), 2.38 (s, 3H, CH3), 1.28 (t, J¼7.2 Hz, 3H, OCH2CH3), 1.13 (t,
NMR (400 MHz, CDCl3):
d
¼8.17 (br s, 1H, NH), 7.43e7.24 (m, 4H,
HAr), 5.46 (s, 1H, 4-CH), 5.18 (d, J¼10.4 Hz, 1H, NCHH), 4.37 (d,
J¼10.4 Hz, 1H, NCHH), 4.12e4.07 (m, 2H, OCH2CH3), 3.56 (q,
J¼6.8 Hz, 1H, OCH2CH3), 3.40 (q, J¼6.8 Hz, 1H, OCH2CH3), 2.35 (s,
3H, 6-CH3), 1.22 (t, J¼6.8 Hz, 3H, OCH2CH3), 1.13 (t, J¼6.8 Hz, 3H,
J¼7.2 Hz, 3H, OCH2CH3); 13C NMR (100 MHz, CDCl3):
¼176.7, 164.8,
d
147.6, 143.1, 127.9, 124.0, 102.8, 79.7, 64.8, 60.7, 56.6, 18.3, 14.8, 14.1.
MS: m/z¼368 (Mþ). Anal. Calcd for C17H21N2O3S (368.10): calcd C
55.35, H 5.74, N 7.59. Found: C 55.42, H 5.69, N 7.67.
OCH2CH3); 13C NMR (100 MHz, CDCl3):
d
¼165.3, 153.2, 146.3, 140.9,
131.6, 129.1, 121.8, 101.8, 74.2, 63.8, 60.1, 57.5, 18.4, 14.8, 14.1. MS: m/
z¼396 (Mþ). Anal. Calcd for C17H21BrN2O4 (396.07): calcd C 51.40, H
5.33, N 7.05. Found: C 51.34, H 5.37, N 7.09.
4.2.13. Ethyl 1-(ethoxymethyl)-4-methyl-6-(4-nitrophenyl)-2-thioxo-
1,2,3,6-tetrahydropyrimidine-5-carboxylate (2m). White solid, mp
149e151 ꢀC, yield: 76% (ethyl acetate/petroleum ether¼1/10); 1H
4.2.8. Methyl 1-(ethoxymethyl)-4-isopropyl-2-oxo-6-phenyl-1,2,3,6-
NMR (400 MHz, CDCl3):
d
¼8.20 (br s, 1H, NH), 7.30e7.25 (m, 4H,
tetrahydropyrimidine-5-carboxylate
(2h). White
solid,
mp
HAr), 5.90 (d, J¼10.8 Hz, 1H, NCHH), 5.65 (s, 1H, 4-CH), 4.66 (d,
J¼10.8 Hz, 1H, NCHH), 4.19e4.13 (m, 2H, OCH2CH3), 3.67e3.61 (m,
1H, OCH2CH3), 3.56e3.50 (m, 1H, OCH2CH3), 2.36 (s, 3H, CH3), 1.25
(t, J¼7.2 Hz, 3H, OCH2CH3), 1.16 (t, J¼7.2 Hz, 3H, OCH2CH3); 13C NMR
154e156 ꢀC, yield: 84% (ethyl acetate/petroleum ether¼1/10); 1H
NMR (400 MHz, CDCl3):
d¼7.35 (br s,1H, NH), 7.34e7.24 (m, 5H, HAr),
5.48 (s, 1H, 4-CH), 5.18 (d, J¼10.8 Hz, 1H, NCHH), 4.41 (d, J¼10.8 Hz,
1H, NCHH), 4.20e4.13 (m, 1H, 6-CH), 3.67e3.53 (s, 3H, OCH3),
3.43e3.28 (m, 2H, OCH2CH3), 2.36 (s, 3H, 6-CH3), 1.21e1.17 (m, 6H,
CH(CH3)2), 1.13e1.09 (m, 3H, OCH2CH3); 13C NMR (100 MHz, CDCl3):
(100 MHz, CDCl3):
d
¼176.4, 165.0, 142.4, 139.0, 134.1, 128.9, 128.5,
103.3, 79.2, 64.7, 60.5, 56.5, 18.1, 14.9, 14.1. MS: m/z¼379 (Mþ). Anal.
Calcd for C17H21N3O5S (379.12): calcd C 53.81, H 5.58, N 11.07.
Found: C 53.90, H 5.62, N 10.99.
d
¼165.7, 154.3, 141.9, 128.5, 127.9, 127.2, 100.7, 74.3, 63.7, 58.0, 51.1,
27.3, 19.6, 19.5, 14.8. MS: m/z¼332 (Mþ). Anal. Calcd for C18H24N2O4
(332.17): calcd C 65.04, H 7.28, N 8.43. Found: C 64.95, H 7.84, N 8.47.
4.2.14. 1-(Ethoxymethyl)-1H-benzo[d][1,2,3]triazo (4aa). Colorless
liquid, yield: 78% (ethyl acetate/petroleum ether¼1/15); 1H NMR
4.2.9. Methyl 1-(ethoxymethyl)-4-isopropyl-6-(4-methoxyphenyl)-2-
oxo-1,2,3,6-tetrahydropyrimidine-5-carboxylate (2i). White solid, mp
134e136 ꢀC, yield: 87% (ethyl acetate/petroleum ether¼1/10); 1H
(400 MHz, CDCl3):
d
¼8.05e7.31 (m, 4H, HAr), 5. 97 (s, 2H, NCH2),
3.52e3.49 (m, 4H, OCH2CH3), 1.12e1.11 (m, 3H, OCH2CH3); 13C NMR
(100 MHz, CDCl3):
d
¼146.2, 132.6, 127.7, 124.1, 119.8, 109.8, 76.8,
NMR (400 MHz, CDCl3):
d
¼7.41 (br s, 1H, NH), 7.27e6.80 (m, 4H, HAr),
64.8, 14.5. MS: m/z¼177 (Mþ). Anal. Calcd for C9H11N3O (177.09):
543 (s, 1H, 4-CH), 4.39 (d, J¼10.8 Hz, 1H, NCHH), 4.18 (d, J¼10.8 Hz, 1H,
NCHH), 4.15e4.11 (m, 1H, 6-CH), 3.81e3.73 (s, 3H, OCH3), 3.64e3.52
(s, 3H, OCH3), 3.44e3.28 (m, 2H, OCH2CH3), 1.34e1.17 (m, 6H, CH
(CH3)2), 1.16e1.12 (m, 3H, OCH2CH3); 13C NMR (100 MHz, CDCl3):
calcd C 61.00, H 6.26, N 23.71. Found: C 61.08, H 6.20, N 23.60.
4.2.15. 1-(Ethoxymethyl)-1H-benzo[d][1,2,3]triazo (4ab). Colorless
liquid, yield: 16% (ethyl acetate/petroleum ether¼1/15); 1H NMR
d
¼165.7, 159.2, 153.9, 134.0, 128.4, 113.8, 100.9, 74.1, 63.7, 57.3, 55.1,
(400 MHz, CDCl3):
d
¼7.92e7.40 (m, 4H, HAr), 5.94 (s, 2H, NCH2),
51.1, 27.3, 19.6, 14.9. MS: m/z¼362 (Mþ). Anal. Calcd for C19H26N2O5
3.69 (q, J¼7.2 Hz, 2H, OCH2CH3), 1.21 (t, J¼7.2 Hz, 3H, OCH2CH3); 13
C
(362.18): calcd C 62.97, H 7.23, N 7.73. Found: C 63.05, H 7.20, N 7.84.
NMR (100 MHz, CDCl3):
d¼144.6, 126.9, 118.4, 84.1, 66.1, 14.6. MS:
m/z¼175 (Mꢂ2þ). Anal. Calcd for C9H11N3O (177.09): calcd C 61.00,
4.2.10. Ethyl 1-(ethoxymethyl)-4-methyl-6-phenyl-2-thioxo-1,2,3,6-
H 6.26, N 23.71. Found: C 61.12, H 6.11, N 23.64.
tetrahydropyrimidine-5-carboxylate
(2j). White
solid,
mp
118e119 ꢀC, yield: 78% (ethyl acetate/petroleum ether¼1/10); 1H
4.2.16. 1-(Ethoxymethyl)-1H-imidazole (4b). Yellow oil, yield 89%
(ethyl acetate/petroleum ether¼1/1); 1H NMR (400 MHz, CDCl3):
NMR (400 MHz, CDCl3):
d
¼8.06 (br s, 1H, NH), 7.34e7.26 (m, 5H,
HAr), 5.93 (d, J¼10.8 Hz, 1H, NCHH), 5.68 (s, 1H, 4-CH), 4.66 (d,
J¼10.8 Hz, 1H, NCHH), 4.18e4.11 (m, 2H, OCH2CH3), 3.68e3.64 (m,
1H, OCH2CH3), 3.55e3.51 (m, 1H, OCH2CH3), 2.36 (s, 3H, 6-CH3),
d
¼8.29 (s, 1H, CH), 7.99 (s, 1H, CH), 5.53 (s, 2H, NCH2), 3.60 (q,
J¼6.8 Hz, 2H, OCH2CH3), 1.20 (t, J¼6.8 Hz, 3H, OCH2CH3); 13C NMR
(100 MHz, CDCl3):
d¼152.0, 143.6, 96.2, 78.0, 65.5, 14.7. MS: m/
1.25 (t, J¼7.2 Hz, 3H, OCH2CH3), 1.16 (t, J¼7.2 Hz, 3H, OCH2CH3); 13
C
z¼125 (Mꢂ1þ). Anal. Calcd for C6H10N2O (126.08): calcd C 57.12, H
NMR (100 MHz, CDCl3):
d
¼176.5, 165.1, 142.2, 140.5, 128.7, 128.3,
7.99, N 22.21. Found: C 56.98, H 8.04, N 22.30.
127.1, 103.7, 79.2, 64.6, 60.4, 57.2, 18.1, 14.9, 14.1. MS: m/z¼334 (Mþ).
Anal. Calcd for C17H22N2O3S (334.14): calcd C 61.05, H 6.63, N 8.38.
Found: C 61.12, H 6.67, N 8.35.
4.2.17. 1-(Ethoxymethyl)-1H-pyrazole (4c). Colorless liquid, yield:
88% (ethyl acetate/petroleum ether¼1/1); 1H NMR (400 MHz,
CDCl3):
d
¼8.27 (s, 1H, CH), 7.99 (s. 1H, CH), 5.60 (s, 1H, NCH2), 5.52
4.2.11. Ethyl 1-(ethoxymethyl)-4-methyl-2-thioxo-6-p-tolyl-1,2,3,6-
(s, 2H, CH), 3.63e3.55 (m, 2H, OCH2CH3), 1.20e1.05 (m, 3H,
tetrahydropyrimidine-5-carboxylate
(2k). White
solid,
mp
OCH2CH3); 13C NMR (100 MHz, CDCl3):
d
¼152.0, 143.6, 95.8, 77.9,
122e124 ꢀC, yield: 80% (ethyl acetate/petroleum ether¼1/10); 1H
65.4,14.7. MS: m/z¼125 (Mꢂ1þ). Anal. Calcd for C6H10N2O (126.08):
NMR (400 MHz, CDCl3):
d¼8.07 (br s, 1H, NH), 7.29e7.13 (m, 4H,
calcd C 57.12, H 7.99, N 22.21. Found: C 57.18, H 7.93, N 22.26.
HAr), 5.97 (d, J¼10.8 Hz, 1H, NCHH), 5.67 (s, 1H, 4-CH), 4.65 (d,
J¼10.8 Hz, 1H, NCHH), 4.20e4.15 (m, 2H, OCH2CH3), 3.71e3.65 (m,
1H, OCH2CH3), 3.59e3.55 (m, 1H, OCH2CH3), 2.38 (s, 3H, CH3), 2.36
4.2.18. 2-(Hydroxymethyl)isoindoline-1,3-dione (4d). White solid,
mp 168e169 ꢀC, yield: 84% (ethyl acetate/petroleum ether¼1/3);

Z.-J. Quan et al. / Tetrahedron 67 (2011) 2462e2467
2467
1H NMR (400 MHz, CDCl3):
d
¼7.93e7.85 (m, 2H, HAr), 7.79e7.74 (m,
Y.; Chang, L.; Zhao, J.; Shang, D.; Liu, X.; Lin, L.; Feng, X. Adv. Synth. Catal. 2009,
351, 2567 And references cited therein.
4. (a) Wang, F.; Liu, X.; Cui, X.; Xiong, Y.; Zhou, X.; Feng, X. Chem.dEur. J. 2009, 15,
2H, HAr), 5.26 (d, 2H, NCH2), 3.14 (br s, 1H, CH2OH); 13C NMR
(100 MHz, CDCl3):
d
¼134.4, 131.9, 123.7, 61.6. MS: m/z¼177 (Mþ).
589; (b) Maerten, E.; Cabrera, S.; Kjarsgaard, A.; J
4rgensen, K. A. J. Org. Chem.
2007, 72, 8893; (c) Zhao, D.; Yuan, Y.; Chan, A. S. C.; Wang, R. Chem.dEur. J.
2009, 15, 2738; (d) Zhao, D.; Wang, Y.; Mao, L.; Wang, R. Chem.dEur. J. 2009, 15,
10983.
Anal. Calcd for C9H7N2O3 (177.04): calcd C 61.02, H 3.98, N 7.91.
Found: C 61.11, H 3.93, N 8.00.
5. (a) Pudovik, A. N.; Konovalova, I. V. Synthesis 1979, 81; (b) Enders, D.; Saint-
Dizier, A.; Lannou, M. I.; Lenzen, A. Eur. J. Org. Chem. 2006, 29; (c) Zhu, Y.;
Malerich, J. P.; Rawal, V. H. Angew. Chem., Int. Ed. 2010, 49, 153 And references
cited therein.
6. (a) Kagayama, T.; Nakano, A.; Sakaguchi, S.; Ishii, Y. Org. Lett. 2006, 8, 407; (b)
Das, B.; Satyalakshmi, G.; Suneel, K.; Damodar, K. J. Org. Chem. 2009, 74, 8400;
(c) Tayama, O.; Nakano, A.; Iwahama, T.; Sakaguchi, S.; Ishii, Y. J. Org. Chem.
2004, 69, 5494.
7. (a) Palacios, F.; Alonso, C.; de los Santos, J. M. Chem. Rev. 2005, 105, 899; (b)
Moonen, K.; Laureyn, I.; Stevens, C. V. Chem. Rev. 2004, 104, 6177; (c) Kalek, M.;
Jezowska, M.; Stawinski, J. Adv. Synth. Catal. 2009, 351, 3207.
8. (a) Kashman, Y. J. Org. Chem. 1972, 37, 912; (b) Hayashi, M.; Yamauchi, K.; Ki-
noshita, M. Bull. Chem. Soc. Jpn. 1977, 50, 1510.
4.2.19. N,N-Bis(ethoxymethyl)benzo[d]thiazol-2-amine
(4e). Colorless liquid, yield: 82% (ethyl acetate/petroleum ether¼1/
15); 1H NMR (400 MHz, CDCl3):
d
¼7.64e7.62 (m, 2H, HAr), 7.32 (t,
J¼7.2 Hz, 1H, HAr), 7.12 (t, J¼7.2 Hz, 1H, HAr), 5.09 (s, 4H, NCH2), 3.62
(q, J¼7.2 Hz, 4H, OCH2CH3), 1.23 (t, J¼7.2 Hz, 6H, OCH2CH3); 13C
NMR (100 MHz, CDCl3):
d
¼151.9, 143.5, 95.8, 77.9, 65.4, 14.6. MS: m/
z¼266 (Mþ). Anal. Calcd for C13H18N2O2S (266.11): calcd C 58.62, H
6.81, N 10.52. Found: C 58.70, H 6.87, N 10.45.
Acknowledgements
9. For reviews on the Biginelli reaction, see: (a) Kappe, C. O. Tetrahedron 1993, 49,
6937; (b) Kappe, C. O. Acc. Chem. Res. 2000, 33, 879; (c) Kappe, C. O.; Stadler, A.
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We are thankful for the financial support from the National
Nature Science Foundation of China (Nos. 20902073 and 21062017),
the Natural Science Foundation of Gansu Province (No.
096RJZA116), and Scientific and Technological Innovation Engi-
neering program of Northwest Normal University (nwnu-kjcxgc-
03-64).
Supplementary data
These data include the copies of the NMR of the compounds
described in this article. Supplementary data associated with this
article can be found in the online version, at doi:10.1016/
j.tet.2011.01.061. These data include MOL files and InChiKeys of the
most important compounds described in this article.
12. (a) Wang, X.-C.; Quan, Z. J.; Zhang, Z. Tetrahedron 2007, 63, 8227; (b) Wang,
X.-C.; Quan, Z. J.; Wang, J. K.; Zhang, Z.; Wang, M.-G. Bioorg. Med. Chem. Lett.
2006, 16, 4592.
References and notes
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of Its Chemistry, Biochemistry and Uses, 5th ed.; Elsevier: Amsterdam, 1995; (c)
Swaminathan, S.; Narayanan, K. V. Chem. Rev. 1971, 71, 429; (d) Bhattacharya, A.
K.; Thyagarajan, G. Chem. Rev. 1981, 81, 415.
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Heterocycles 2010, 81, 1827.
14. (a) Nagai, H.; Shiozawa, T.; Achiwa, K.; Terao, Y. Chem. Pharm. Bull. 1993, 41,
ꢀ
ꢀ
€ €
1933; (b) Csomos, P.; Kanerva, L. T.; Bernath, G.; Fulop, F. Tetrahedron: Asym-
metry 1996, 7, 1789.
2. For elected examples of reaction of imines and ketimines, see: (a) Merino, P.;
15. Cho, H.; Takeuchi, Y.; Ueda, M.; Mizuno, A. Tetrahedron Lett. 1988, 29, 5405.
16. Crystal data for 2b: Formula: C17H21N3O6; unit cell parameters: a¼12.3053(7),
ꢀ
ꢀ
ꢀ~
Marques-Lopez, E.; Herrera, R. P. Adv. Synth. Catal. 2008, 350, 1195; (b) Ordonez,
M.; Rojas-Cabrera, H.; Cativiela, C. Tetrahedron 2009, 65, 17; (c) Nakamura, S.;
Hayashi, M.; Hiramatsu, Y.; Shibata, N.; Funahashi, Y.; Toru, T. J. Am. Chem. Soc.
2009, 131, 18240; (d) Gambecka, J.; Kafarski, P. Mini-Rev. Med. Chem. 2001, 1, 133.
3. For elected examples of addition to carbonyl compounds, see: (a) Wiemer, D. F.
b¼7.5269(4), c¼19.9403(11);
a
¼90,
b
¼93.831(3),
g
¼90; space group P21/c;
CCDC 756296. Crystal data for 2k: Formula: C18H24N2O3S1; Unit cell parame-
ters: a¼9.5792(6), b¼10.3014(6), c¼11.1462(7); ¼74.857(3), ¼81.282(3),
a
b
g
¼64.763(3); space group Pꢂ1; CCDC 761055. These data can be obtained free
€
Tetrahedron 1997, 53, 16609; (b) Groger, H.; Hammer, B. Chem.dEur. J. 2000, 6,
of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.
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Huang, T.; Zhu, C.; Sun, J. J. Chem. Soc., Perkin Trans. 1 1998, 2097; (e) Yamagishi,
T.; Yokomatsu, T.; Suemune, K.; Shibuya, S. Tetrahedron 1999, 55, 12125; (f)
Cermak, D. M.; Du, Y.; Wiemer, D. F. J. Org. Chem. 1999, 64, 388; (g) Zhou, X.; Liu,
17. Katritzky, A. R.; Rachwal, S.; Caster, K. C.; Mahni, F.; Law, K. W.; Rubio, O. J. Chem.
Soc., Perkin Trans. 1 1987, 781.