Base-promoted formal [4?+?1+1] annulation of aldehyde, N-benzyl amidine and DMSO toward 2,4,6-triaryl pyrimidines

Article abstract of DOI:10.1016/j.tetlet.2017.11.020

A base-promoted formal [4 + 1+1] annulation of aldehyde, N-benzyl amidine and DMSO was developed, leading to a series of 2,4,6-triaryl pyrimidines in moderate to good yields. Notably, DMSO served as a methine source, which was activated by base rather than either Lewis acid or electrophile. Molecular O₂ was the sole eco-friendly oxidant during this procedure.

Full text of DOI:10.1016/j.tetlet.2017.11.020

Accepted Manuscript
Base-Promoted Formal [4+1+1] Annulation of Aldehyde, N-Benzyl Amidine
and DMSO toward 2,4,6-Triaryl Pyrimidines
Jin Yuan, Jingbo Li, Bingbing Wang, Song Sun, Jiang Cheng
PII:
S0040-4039(17)31423-5
https://doi.org/10.1016/j.tetlet.2017.11.020
TETL 49463
DOI:
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
10 October 2017
8 November 2017
10 November 2017
Please cite this article as: Yuan, J., Li, J., Wang, B., Sun, S., Cheng, J., Base-Promoted Formal [4+1+1] Annulation
of Aldehyde, N-Benzyl Amidine and DMSO toward 2,4,6-Triaryl Pyrimidines, Tetrahedron Letters (2017), doi:
https://doi.org/10.1016/j.tetlet.2017.11.020
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Base-Promoted Formal [4+1+1] Annulation
of Aldehyde, N-Benzyl Amidine and DMSO
toward 2,4,6-Triaryl Pyrimidines
Jin Yuan, Jingbo Li, Bingbing Wang, Song Sun, and Jiang Cheng*

1
Tetrahedron Letters
journal homepage: www.els evier.com
Base-Promoted Formal [4+1+1] Annulation of Aldehyde, N-Benzyl Amidine and
DMSO toward 2,4,6-Triaryl Pyrimidines
Jin Yuan, Jingbo Li, Bingbing Wang, Song Sun, and Jiang Cheng*1
School of Petrochemical Engineering, Jiangsu Key Laboratory of Advanced Catalytic Materials & Technology, Jiangsu Province Key Laboratory of Fine
Petrochemical Engineering, Changzhou University, Changzhou 213164, P. R. China.
ARTICLE INFO
ABSTRACT
Article history:
Received
A base-promoted formal [4+1+1] annulation of aldehyde, N-benzyl amidine and DMSO was
developed, leading to a series of 2,4,6-triaryl pyrimidines in moderate to good yields. Notably,
DMSO served as a methine source, which was activated by base rather than either Lewis acid or
electrophile. Molecular O2 was the sole eco-friendly oxidant during this procedure.
Received in revised form
Accepted
Available online
Keywords:
Base-Promoted
Annulation
N-Benzyl Amidine
2,4,6-Triaryl Pyrimidines
Pyrimidines are ubiquitous in natural products,1
agrochemicals,2 and functional materials.3 Moreover, they also
serve as anti-inflammatory,4 antimicrobial,5 and antimalarial
agents,6 as well as cytotoxic inhibitors.7 Among the abundant
reported synthetic methodologies,8 the [3+3]9 and [4+2]
annulations10 provide a rapid and facile avenue to access
polysubstituted pyrimidines. Notably, a sustainable [3+2+1]
reaction between two alcohols and amidine was developed by
Kempe.11 Nevertheless, the development of new annulation type
starting from readily available reaction partners remains an
attractive research area.
electrophilic C1 synthon and an amphiphilic four-atom
component under base condition (Scheme 1). With this regard,
herein, we wish to report a formal [4+1+1] annulation of
aldehyde, N-benzyl amidine and DMSO toward a series of 2,4,6-
triaryl pyrimidines. Notably, in sharply contrast with the reported
annulations involving DMSO, the activation of DMSO is
promoted by base rather than either Lewis acid or electrophile.
Table 1. The optimization of reaction conditions.a
Scheme 1. Design Plan.
Formal [4+1+1] annulation involving DMSO
Entry
Base
Oxidant
O2
O2
Yieldb (%)
15
1
2
KOtBu
K3PO4
Na2CO3
CsOAc
CsF
Ar
Y
O
S
CH- -
39
<1
X
H
This Work
base
X
C
CH3
3
O2
O2
Ar'
Y
Ar"
4
<1
23
CH- -
ArC+
+
Ar'
Ar"
+
5
6
O2
O2
four-atom component
one-atom components
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
73, 61c, 70d
7
air
41
9e
<1e
36e
Recently, dimethyl sulfoxide (DMSO), activated by either
Lewis acid or electrophile, was reported as a series of building
blocks in organic synthesis.12,13 Besides, DMSO also served as a
source of methine (=CH-) fragment14 to construct hetero-
8
9
10
TBHP
BPO
DCP
a
aromatic
compounds
whereby
sequential
Reaction conditions: 1a (0.1 mmol), 2a (0.15 mmol), base (2 equiv), in
b
DMSO (2 mL), under O2, 120 oC, 12 h, in sealed tube. Isolated yield. c 100
oC. d 140 oC. e oxidant (2 equiv).
annulation/aromatization reaction. Although, to date, there is
only one example on base-promoted activation of DMSO as a
methine fragment,15 we reasoned the inherent character of
sulfoxide group would enable DMSO to be a binucleophilic C1
synthon in the annulation reaction. Thus, a formal [4+1+1]
Initially, we test the reaction of benzaldehyde 1a, N-benzyl
o
phenylamidine 2a and DMSO (2 mL, as a solvent) at 120 C in
the presence of KOtBu under atmospheric pressure of O2 (Table
annulation is highly expected in combination with an
———
1* Corresponding author. E-mail:jiangcheng@cczu.edu.cn

2
Tetrahedron
1). To our delight, this three-component reaction took place,
phenyl sulfoxide resulted in no reaction under the standard
procedure.
and 2,4,6-triphenyl pyrimidine 4a was isolated in 15% yield
(Table 1, entry 1). Replacing KOtBu with K3PO4 and CsF
increased the yields to 39% and 23%, respectively (Table 1,
entries 2 and 5); while Na2CO3 and CsOAc inhibited the reaction
(< 1%, Table 1, entries 3 and 4). The reaction efficiency was
further increased by using Cs2CO3 (73%, Table 1, entry 6).
Elevating or reducing the reaction temperature resulted in low
Figure 2. Scope of aldehydea
o
o
yields (61% under 100 C and 70% under 140 C). In addition,
we explored the influence of oxidants on the yield (Table 1,
entries 7-10). Unfortunately, air (41%), TBHP (9%), BPO (< 1%),
and DCP (36%) all can’t couple well in this procedure and O2
(73%) was the best.
With the optimized reaction conditions in hand, the scope of
N-benzyl arylamidine was investigated, as shown in Figure 1. For
aryl attached in the imino group, halo substituents, including
fluoro, chloro and bromo all could be well tolerated, providing
the corresponding annulation products 4b, 4c and 4d in 63%,
69% and 64% yields, respectively. Notably, this procedure
allowed to construct 2-cyclopropyl 4,6-diphenylpyrimidine (4i)
in 59% yield. Particularly, N-benzyl 2-pyridinecarboximidamide
also ran smoothly to afford 4h in 67% yield. Importantly,
substitutions were tolerated on the benzylic arene, as 4j, 4l, 4p
were isolated in 55%, 44%, 49% yields.
Figure 1. Scope of N-benzyl phenylamidinea
Ph
NH
H
O
S
Cs2CO3 (2 equiv)
O2, 120 oC, 12 h
N
C
+
+
Ar"
PhCHO
Ar'
N
H
CH3
Ar'
N
Ar"
(sol.)
4
1a
2
3
Ph
Ph
Ph
N
H
H
C
H
N
C
N
N
C
N
Ph
N
Ph
Ph
a
Reaction conditions: aldehyde 1 (0.1 mmol), N-benzyl arylamidine 2a (0.15
mmol), Cs2CO3 (2 equiv), in DMSO (2 mL), under O2, 120 oC, 12 h.
Br
Cl
F
4b
4c
, 69%
4d
, 63%
, 64%
Ph
Ph
To our delight, this procedure was also applicable to a 2 mmol
scale, and 4a was isolated in an acceptable 65% yield.
Ph
H
H
H
N
C
N
C
N
C
Some control experiments were conducted to get insights into
this transformation. First, replacing DMSO with DMSO-d6, 5-d-
2,4,6-triphenyl pyrimidine d-4a was isolated in 67% yield (98%
d, Scheme 2, eq. 1), which not only confirmed the participation
of DMSO in the annulation reaction, but also provided a facile
route to access 5-d-2,4,6-triphenyl pyrimidine. Secondly, (E)-
methyl styryl sulfoxide was subjected to the reaction with N-
benzyl amide, and 4a was isolated in a comparable 58% yield
(Scheme 2, eq. 2). Thus, (E)-methyl styryl sulfoxide may serve as
a key intermediate in this procedure.
N
Ph
N
Ph
N
Ph
4e
4f
4g
, 58%
, 49%
, 57%
H
Ph
Ph
Ph
H
H
N
C
N
C
N
C
N
Ph
N
N
Ph
Ph
N
tBu
4h
, 67%
4i
, 59%
4j
, 55%
a
Scheme 2. Mechanism Studies
Reaction conditions: phenyl aldehyde 1a (0.1 mmol), N-benzyl
arylamidine 2 (0.15 mmol), Cs2CO3 (2 equiv), in DMSO (2 mL), under
O2, 120 oC, 12 h.
Next, the scope of aryl aldehyde was investigated, as shown in
Figure 2. Generally, the reaction ran smoothly to afford
corresponding 2,4,6- triaryl pyrimidine 4 in moderate yields (4k-
4q, 44%-53%). Notably, bromide survived well and 4l was
isolated in 44% yield. In particular, this procedure was applicable
for the ortho- substituted aryl aldehyde, as 4p was isolated in
49% yield and 2-thenaldehyde took part in this transformation
and 4q was isolated in 46% yield. However, propionaldehyde
failed to work in this reaction and we got 4r in 0% yield. Besides,
any attempts to access 5-substituted-2,4,6-triaryl pyrimidine
failed since replacing DMSO with diethyl sulfoxide, and methyl
Based on these experimental results, a proposed mechanism
was outlined in Scheme 3. In the presence of base, the reaction of
DMSO with aldehyde provides (E)-methyl styryl sulfoxide.16

3
After that, the addition of N-benzyl amide to electron-deficient
alkene produces intermediate A (path I). Besides, another way to
form intermediate A cannot be excluded. Dimsyl anion was
formed by DMSO in the presence of base,17 and condensation of
amidine with benzaldehyde would provide intermediate 1,18
which followed by michael type addition with dimsyl anion to
produce intermediate A (path II). After the tautomerization of
intermediate A to intermediate B, the deprotonation affords
intermediate C. Then, intramolecular cycloaddition takes place to
produce cyclized intermediate D, which is oxidized by O2 leading
to intermediate E. Finally, the elimination of methanesulfinic
acid provides the final product 2,4,6-triphenyl pyrimidine.
Supplementary data associated with this article can be found,
in the online version, at
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Scheme 3 Proposed Mechanism
In conclusion, we have developed a base-promoted formal
[4+1+1] annulation of aryl aldehyde, N-benzyl arylamidines and
DMSO to access to a series of 2,4,6-triaryl pyrimidines in
moderate to good yields. Notably, DMSO served as a methine
source, which was promoted by base rather than either Lewis
acid or electrophile. The molecular O2 was the sole eco-friendly
oxidant in this procedure.
6
7
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We thank the National Natural Science Foundation of China (no.
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&
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Supplementary data

4
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5
1. In this procedure, the starting materials are easy to be
prepared.
2. This strategy leads to a series of unsymmetric 2,4,6-
triaryl pyrimidines.
3. DMSO was activated by base rather than either Lewis
acid or electrophile.