Tandem allylic amination/ring-opening/oxa-Michael addition reactions of chromone-derived Morita-Baylis-Hillman acetates with amines

Article abstract of DOI:10.1016/j.tet.2010.11.089

The reaction of chromone-derived Morita-Baylis-Hillman acetates with amines was developed via tandem allylic amination/chromone ring-opening/oxa-Michael addition to provide 2-substituted-3-aminomethy-lene-chromans in convenient and efficient way, and subs

Full text of DOI:10.1016/j.tet.2010.11.089

Tetrahedron 67 (2011) 1231e1237
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Tetrahedron
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Tandem allylic amination/ring-opening/oxa-Michael addition reactions of
chromone-derived MoritaeBayliseHillman acetates with amines
y
y
*
Chen Wu , Hao Zeng , Li Liu , Dong Wang, Yongjun Chen
Beijing National Laboratory (BNLMS), Laboratory for Chemical Biology, Institute of Chemistry, Chinese Academy of Sciences, Beijing 100080, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
The reaction of chromone-derived MoritaeBayliseHillman acetates with amines was developed via
tandem allylic amination/chromone ring-opening/oxa-Michael addition to provide 2-substituted-
3-aminomethy-lene-chromans in convenient and efficient way, and subsequent applied in the synthesis
of benzopyranylpyrimidine compounds. Various amines exhibited different reactivities depending on
their molecular structural characteristics.
Received 20 September 2010
Received in revised form 9 November 2010
Accepted 26 November 2010
Available online 1 December 2010
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
MBH acetates
Tandom reaction
Amines
1. Introduction
also provide a
-selective products under the catalysis of In(OTf)39 or
FeCl3.10 Chromone-derived MBH adducts bearing cyclic structural
unit have been used in the syntheses of many heterocycles, such as
quinoline derivatives and azepinoindoles (Fig. 1).6,11 We envisioned
that the investigations of the allylic amination of cyclic MBH ace-
tates derived from chromone should be very interesting and valu-
able to develop a novel synthetic approach to heterocycles.
MoritaeBayliseHillman adducts are attracting much attentions
in organic synthesis due to their ready availability and multi-
functionalities.1 Similarly, aza-BayliseHillman reaction can provide
b
-aminocarbonyl compounds, which possess both allyl amino and
Michael acceptor units in an identical molecule and is very im-
portant in the synthesis of bioactive molecules and natural prod-
ucts.1,2 Although aza-BayliseHillman reaction has made great
progresses, it still remains some shortcoming, such as long reaction
time and low yields, moreover second amines are seldom used.3
Alternatively, allylic amination of MoritaeBayliseHillman (MBH)
adducts could provide various aza-ByaliseHillman analogues eas-
ily.4 In most cases, acyclic MBH adducts were used.
Cyclic MBH adducts derived from cycloenones exhibited the
reactive properties different from that of the acyclic adducts, which
could be used to generate fused cyclic frameworks.5 Recently, we
reported an AgOTf-catalyzed highly
stitution of cyclic MBH acetate with indoles,6 and tunable regio-
selective control ( or -selection) when MBH alcohols were used
and iodine as catalyst.7 Chan and co-workers8 reported iron(III)
catalyzed nucleophilic -substitution of cyclic MBH alcohols with
O
X
OR
R'
X = CH2 (cyclic MBH adduct)
X = O (chromone-derived
MBH adduct)
α
γ
Fig. 1. Cyclic MBH adducts.
Moreover, 3-aminomethylchromones (A)12 as well as their de-
rivatives, 3-aminomethylenechromans (B)13 have important bi-
ological activities and are also interesting as a scaffold in the
synthesis of versatile benzopyranyl heterocycle libraries in drug
discovery (Fig. 2). It was found that 3-pyrrolidine substitute
a-regioselective allylic sub-
a
g
a
R
R''
several nucleophiles except amine, a N-nucleophile. It was note-
worthy that the allylic amination of cyclic MBH adducts derived
from cyclopentenones and cyclohexenones with aromatic amines
R'
R' R''
N
O
N
O
N
O
N
R2
R2
R1
R3
R3
R1
R2
O
R1
O
* Corresponding author. Tel.: þ86 10 62554614; fax: þ86 10 62554449; e-mail
A
B
C
address: lliu@iccas.ac.cn (L. Liu).
y
These authors made equal contributions to the paper.
Fig. 2. 3-Aminomethylchromone derivatives.
0040-4020/$ e see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.11.089

1232
C. Wu et al. / Tetrahedron 67 (2011) 1231e1237
chromones could be used as a key intermediate for the synthesis of
benzopyranylpyrimidine (C),14 which exhibit great importance of
biological activities. Therefore, to develop an efficient method to
construct the intermediates is still desired.
To continue our interests in the nucleophilic substitution re-
action of cyclic MBH adducts, we describe herein the results of the
tandem reaction between chromone-derived MBH acetates and
amines in a one pot process. In the process, a cascade allylic ami-
nation/ring-opening/oxa-Michael cyclization was involved to pro-
vide 3-aminomethylenechromans in high yields and subsequent
this protocol was used in the synthesis of benzopyranylpyrimidine
compounds.
was only slightly increased to 62%. In EtOH, the reaction gave
moderate yield of 58%. To our great delight, the yield can be im-
proved to 86% when MeCN was employed as a solvent. Further-
more, water was also used as a solvent and the yield of 3a was as
good as MeCN. However, water was not widely suitable to other
substrates of chromone-derived MBH acetates. So MeCN was cho-
sen as the solvent eventually.
With optimal conditions on hands, we examined the substrate-
suitable scope of the tandem reaction (Scheme 2, Table 2). Cyclic
amines including pyrrolidine (2a) and piperidine (2b) as well as
imidazole (2c) were employed in the reactions with MBH acetates
(1aef) without the use of catalyst to give the corresponding prod-
ucts (3aej) in good to excellent yields (Table 2, entries 1e9), but with
different reaction times. Neither a- nor g-products were detected in
2. Results and discussion
the reaction mixtures. Primaryamine, such as benzyl amine (2d) and
alkylamine (2e) exhibited very high reactivities: the shortest re-
action time (1.5 h) and excellent yields (3l, 90% and 3m, 93%) (entries
12 and 13). However, for aromatic amine, such as aniline (2f) under
the similar conditions the reaction with 1a provided the product 3n
in low yield (49%, Table 2, entry 14) even prolonging reaction time to
48 h, which probably was attributed to the weak nucleophilicity of
aromatic amine. Fortunately, if In(OTf)3 was used as a catalyst
(10 mol %) in the reaction, the yield of 3n increased remarkably to
95% (entry 15). When dipropylamine (2g) was employed in the re-
action with 1a in the presence of In(OTf)3 (10 mol %) in refluxing
MeCN, afterlong reaction time (72 h) relativelylowyield (50%) of the
product 3o was obtained and 43% of starting MBH acetate 1a was
recovered (entry 16). The reason leading to the low reactivity
probably is the steric effect of two substituents on the nitrogen atom
of acyclic secondary aliphatic amine.
2.1. The reaction of MBH acetates with amines
In general, for the allylic substitution of MBH adducts, efficient
catalyst was required to promote the reaction. Considering excel-
lent leaving-ability of the OAc group in nucleophilic substitution
reaction, the catalyst-free reaction conditions were employed in
the allylic amination of the chromone-derived MBH acetates with
amines. According to the reference procedure, the chromone-de-
rived MBH acetates were prepared through the BayliseHillman
reaction of chromones with aldehydes. Initially, the reaction of
(4-oxo-4H-chromen-3-yl)(phenyl)methyl acetate (1a) and pyrroli-
dine (2a) was carried out in refluxing THF for 1 h in the absence of
any catalyst and additives. To our surprise, neither
a- nor g-product
was detected in the reaction mixture, and the tandem reaction
product, 2-phenyl-3-aminomethylene-chroman 3a was formed
exclusively in 57% yield (Scheme 1).
O
OAc
R2
O
R1
R1
R3
O
O
OAc
R3
R4
MeCN
reflux
N
+
N
H
R4
N
no catalyst
solvent, 1h
O
R2
+
O
N
H
2a-g R3,R4: H, aryl,
O
R1: H,Me
R2: aryl
O
1a-g
3a-o
alkyl
1a
2a
3a
Scheme 2. Tandem reaction of chromone-derived MBH acetates with amines.
O
O
N
The molecular structure of the tandem reaction product 3aek
and 3o from the reactions of secondary amines was further con-
firmed by X-ray crystallography analysis of 3f (Fig. 3).15 Based on
the results (E)-configuration of the newly formed double bond
could be determined. For the products (3len) yielded from primary
amine, the configuration of the newly formed double bound was
determined as (Z) owing to the formation of hydrogen bond be-
tween NeH and C]O group.16
O
N
O
-product
Scheme 1. Reaction of 1a with 2a.
-product
Subsequently, solvent screening was performed by means of the
reaction of 1a with 2a under the same conditions, and the results
are summarized in Table 1. As shown in Table 1, the tandem reaction
can be achieved successfully in various solvents. In dichloro-
methane (DCM), the yield of 3a was decreased to 33% (entry 2);
while in the high boiling point solvent, such as toluene, the yield
2.2. The proposed mechanism of the reaction
The plausible mechanism of the tandem reaction of MBH ace-
tates with amine was proposed shown in Scheme 3, taking sec-
ondary amine as an example. The MBH acetate was attacked by
N-nucleophile to form intermediate I through allylic amination
accompanied with the elimination of OAc group. Subsequently,
intermediate I underwent chromone ring-opening to yield an
active iminum ion II, which was followed by intramolecular
oxa-Michael addition to provide 2-substituted-3-amino-
methylenechroman 3.
Table 1
Solvent effect on the reaction of 1a with 2aa
Entry
Solvent
Temp (ꢀC)
Yield of 3a (%)b
1
2
3
4
5
6
THF
DCM
EtOH
Toluene
MeCN
Water
Reflux
Reflux
Reflux
Reflux
Reflux
80
57
33
58
62
86
86
2.3. Synthesis of benzopyranylpyrimidines
According the reference procedure,14d 3a can react with ben-
zamidine hydrochloride (4a, R0¼Ph) in refluxing EtOH by using
a
1a (0.2 mmol), 2a (0.3 mmol), solvents (2 mL), 1 h.
Isolated yield.
b

C. Wu et al. / Tetrahedron 67 (2011) 1231e1237
1233
Table 2
Allylic amination of MBH acetates (1) with amines (2)a
Entry
1
MBH acrtate
Amine
2a
Time (h)
3
Product
Yield (%)b
3a
O
H
O
O
OAc
1a
N
86
N
H
O
O
3b
H
O
O
OAc
1b
N
2
3
4
5
6
2a
2a
2a
2a
2a
2a
3
3
3
3
3
86
O
Br
Br
Cl
3c
3d
3e
3f
O
O
H
H
H
H
O
O
OAc
OAc
OAc
OAc
1c
N
N
75
70
66
72
Cl
F
O
O
O
O
1d
F
O
O
O
1e
N
O
Me
Ph
Me
O
O
O
O
1f
N
H
Ph
3g
O
O
O
O
OAc
1g
Me
N
Me
7
8
9
3
3
3
78
87
70
3h
O
H
H
2b
N
N
1a
1b
N
H
O
O
3i
2b
2b
O
Br
3j
O
O
H
N
10
11
1e
1a
4
68
93
Me
N
3k
O
O
H
N
2c
N
72
N
H
3l
H
O
N
2d
NH2
H
12
1a
1.5
90
O
(continued on next page)

1234
C. Wu et al. / Tetrahedron 67 (2011) 1231e1237
Table 2 (continued )
Entry
MBH acrtate
Amine
Time (h)
1.5
Product
Yield (%)b
3m
H
C11H23
O
O
N
H
13
1a
2e C12H25HN2
93
3n
H
O
O
N
2f
NH2
14
15
1a
1a
48
36
49
H
2f
3n
95c
3o
O
O
H
2g
50c
N
16
1a
72
HN
a
1/2¼1:1.5, in refluxing CH3CN.
Isolated yield.
With ln(OTf)3 (10 mol %) as a catalyst.
b
c
NaOH as a base for emission of the free amine, which participated
in the reaction with 3a, to afford benzopyranylpyrimidine 5a in
yield 85% (Table 3, entry 1). Similarly, 3d, 3f and 3a can undergo the
same reaction with 4a and 4b, respectively, giving corresponding
products 5bed in good yields (Table 3).
Table 3
Synthesis of benzopyranylpyrimidine compounds 5a
R'
O
H
N
O
N
NH
NaOH
EtOH, reflux, 5 h
N
HCl
+
R'
NH2
O
4
R
R
5
3
Entry
3 (R)
Diamine (R0)
Yield (%)b
1
2
3
4
3a, H
3d, F
3f, Me
3a
4a, Ph
4a, Ph
4a, Ph
4b, NH2
5a, 85
5b, 75
5c, 65
5d,14b 78
Fig. 3. ORTEP drawing of 3f with thermal cllipsoids at 30% possibility level.
a
3/4¼1:3.
b
Isolated yield.
3. Conclusion
R2
R3
In summary, we developed the reaction of chromone-derived
MoritaeBayliseHillman acetates with amines for the synthesis of
2-substituted-3-aminomethylenechromans. This protocol com-
bined allylic amination, ring-opening, Michael cyclization in a one
pot process. Various amines exhibited the reactivities with big
differences depending on their molecular structural characteristics.
A tentative mechanism for the tandem reactions was proposed.
Investigation of the tandem reactions and their application in the
synthesis of biologically active compounds is ongoing.
O
O
OAc
R1
O
O
H
N
H
R2
N
2
R3
R1
R2
1
HN
3
R3
-OAc
O
O
R2
R3
O
O
N
R1
R2
4. Experimental
4.1. General
R1
R2
N
H
OH
II
N
R3
OH R1
R3
The 1H and 13C NMR spectra were recorded on Bruker-AV 300
spectrometer and chemical shift reported in CDCl3 or DMSO-d6
with tetramethylsilane as an internal standard. IR spectra were
I
Scheme 3. Proposed mechanism of the reaction of chromone-derived MBH acetate
with secondary amine.

C. Wu et al. / Tetrahedron 67 (2011) 1231e1237
1235
recorded on a Bruker tensor 27 infrared spectrometer. HRMS
spectra were recorded on GCT-Mass Micromass spectrometer.
Melting points were measured on Beijing-Tiker X-4 apparatus
without correction. All reactions were carried out in oven dried
flasks. Common reagents were purchased from commercial sources
and were used without further purification. The MBH acetates
(1aeg) were prepared according to literature methods.17
d 7.98 (s, 1H), 7.81e7.78 (m, 1H), 7.25e7.23 (m, 2H), 7.18e7.12 (m,
1H), 6.98e6.96 (m, 2H), 6.81e6.71 (m, 2H), 6.55 (s, 1H), 3.50e3.45
(m, 2H), 3.35e3.32 (m, 2H), 2.16 (s, 3H),1.79e1.70 (m, 4H); 13C NMR
(75 MHz, CDCl3):
d 180.9, 157.9, 145.4, 138.8, 137.6, 133.6, 129.0,
127.8, 126.9, 123.9, 121.0, 117.8, 101.2, 76.3, 51.6, 25.3, 21.0. HRMS
(EI): m/z calcd for C21H21NO2: 319.1572 (Mþ), found 319.1569.
4.2.6. (E)-2-(Biphenyl-4-yl)-3-(pyrrolidin-1-ylmethylene) chroman-
4-one (3f). Yellow solid, mp 191e193 ꢀC. FTIR(film): nmax 3227,
3212, 3178, 3161, 3149, 3133, 3117, 3019, 1628, 1399, 509 cmꢁ1. 1H
4.2. Typical experimental procedures for the reaction of MBH
acetates with amines
NMR (300 MHz, CDCl3):
d 8.13 (s,1H), 7.93e7.89 (m, 1H), 7.58e7.49
To a solution of (4-oxo-4H-chromen-3-yl)(phenyl)-methyl ace-
tate (1a, 58 mg, 0.2 mmol) in MeCN (2 mL) at room temperature
(m, 6H), 7.42e7.38 (m, 2H), 7.33e7.27 (m, 2H),6.95e6.88 (m, 2H),
6.72 (s, 1H), 3.61e3.60 (m, 2H), 3.48e3.45 (m, 2H), 1.91e1.82 (m,
was added pyrrolidine (2a, 17
mL, 0.3 mmol), followed by stirring at
4H); 13C NMR (75 MHz, CDCl3):
d 180.1, 157.9, 145.6, 140.8, 140.7,
the temperature of refluxing MeCN for 3 h upon completion of the
reaction as judged by TLC. Then the mixture was cooled to room
temperature and evaporated under vacuum to give crude product,
which was purified by flash chromatography on silica gel (eluent:
petroleum ether/ethyl acetate¼1:1) to afford a white solid 3a
(52 mg, 86% yield).
140.5, 133.8, 128.7, 127.4, 127.1, 127.0, 123.9, 121.2, 117.8, 101.0, 76.2,
25.4. HRMS (EI): m/z calcd for C26H23NO2: 381.1729 (Mþ), found
381.1726.
4.2.7. (E)-6-Methyl-2-phenyl-3-(pyrrolidin-1-ylmethylene) chroman-
4-one (3g). Yellow solid, mp 101e104 ꢀC. FTIR(film): nmax 3444,
3059, 1646, 1548, 1420, 1382, 1331, 1139, 752 cmꢁ1 1H NMR
.
4.2.1. (E)-2-Phenyl-3-(pyrrolidin-1-ylmethylene) chromone (3a).
Yellow solid, mp 172e174 ꢀC. FTIR(KBr): nmax 3053, 2960, 2919,
2858, 1649, 1601, 1466, 1277, 1218, 1150, 1100, 1022, 801, 753, 695,
(300 MHz, CDCl3): d 8.00 (s, 1H), 7.60e7.59 (m, 1H), 7.37e7.35 (m,
2H), 7.21e7.11 (m, 3H), 7.00e6.97 (m, 1H), 6.67e6.64 (m, 1H), 6.56 (s,
1H), 3.54e3.47 (m, 2H), 3.38e3.35 (m, 2H), 2.14 (s, 3H),1.84e1.70 (m,
499 cmꢁ1. 1H NMR (300 MHz, CDCl3):
d
8.02 (s, 1H), 7.82e7.80 (m,
4H); 13C NMR (75 MHz, CDCl3):
d 181.1, 155.8, 145.4, 141.8, 134.6,
1H), 7.38e7.36 (m, 2H), 7.21e7.12 (m, 4H), 6.83e6.74 (m, 2H), 6.60
130.4, 128.3, 127.8, 127.8, 126.9, 123.4, 117.5, 25.3, 20.5. HRMS (EI): m/
(s, 1H), 3.51 (m, 2H), 3.40 (m, 2H), 1.81e1.80 (m, 4H); 13C NMR
z calcd for C21H21NO2: 319.1572 (Mþ), found 319.1572.
(75 MHz, CDCl3):
d 180.6, 164.0, 160.7, 157.6, 145.6, 137.5, 127.5,
133.8, 129.6, 127.0, 123.8, 121.1, 117.7, 115.3, 115.0, 100.8, 75.7, 25.3.
4.2.8. (E)-2-Phenyl-3-(piperidin-1-ylmethylene) chroman-4-one (3h).
Yellow oil. FTIR(film): nmax 3219, 3205, 3193, 3178, 3164, 3150, 3136,
HRMS(EI): m/z calcd for C20H19NO2: 305.1416 (Mþ), found 305.1417.
3123, 3110, 1638, 1539, 1465, 1399, 1320, 763, 700 cmꢁ1 1H NMR
.
4.2.2. (E)-2-(4-Bromophenyl)-3-(pyrrolidin-1-ylmethylene) chroman-
(300 MHz, CDCl3):
2H), 7.21e7.12 (m, 4H), 6.82e6.78 (m, 1H), 6.73e6.70 (m, 1H), 6.43 (s,
1H), 3.25 (m, 4H), 1.51 (m, 4H); 13C NMR (75 MHz, CDCl3):
181.0,
d 7.98 (s, 1H), 7.81e7.78 (m, 2H), 7.40e7.38 (m,
4-one (3b). Yellow oil. FTIR(film): nmax 3445, 3214, 3169, 3154, 3127,
1644, 1400, 748 cmꢁ1
.
1H NMR (300 MHz, CDCl3):
d
8.00 (s, 1H),
d
7.80e7.77 (m, 1H), 7.31e7.12 (m, 5H), 6.84e6.80 (m, 1H), 6.73e6.71
(m, 1H), 6.51 (s, 1H), 3.50e3.47 (m, 2H), 3.34 (m, 2H), 1.80e1.74 (m,
157.7, 148.4, 140.3, 133.6, 128.3, 128.2, 128.0, 126.9, 123.7, 121.1, 117.6,
100.0, 76.7, 52.9, 26.423.7. HRMS(EI): m/z calcd for C21H21NO2:
319.1572 (Mþ), found 319.1575.
4H); 13C NMR (75 MHz, CDCl3):
d 180.6, 164.0, 160.7, 157.6, 145.6,
137.5, 127.5, 133.8, 129.6, 127.0, 123.8, 121.1, 117.7, 115.3, 115.0, 100.8,
75.7, 25.3. HRMS(EI): m/z calcd for C20H18BrNO2: 383.0521 (Mþ),
found 383.0524.
4.2.9. (E)-2-4-Bromophenyl-3-(piperidin-1-ylmethylene) chroman-
4-one (3i). Yellow solid, mp:121e124 ꢀC. FTIR(film): nmax 3422,
2935, 2856, 1637, 1586, 1536, 1367, 1329, 1257, 1203, 996, 744 cmꢁ1
.
4.2.3. (E)-2-(4-Chlorophenyl)-3-(pyrrolidin-1-ylmethylene)chro-
man-4-one (3c). Yellow solid, mp 134e135 ꢀC. FTIR(film): nmax
3220, 3191, 3179, 3165, 3152, 3132, 3123, 3116, 3109, 3095, 1648,
1H NMR (300 MHz, CDCl3):
d 7.88e7.85 (m, 2H), 7.37 (q, 4H,
J¼0.9 Hz), 7.29e7.23 (m, 1H), 6.90 (t, 1H, J¼0.9 Hz), 6.80 (d, 1H,
J¼0.9 Hz), 6.44 (s, 1H), 3.34 (d, 4H, J¼0.3 Hz), 1.60 (d, 6H, J¼0.3 Hz);
1587, 1549, 1406, 1336, 1307, 1008, 748 cmꢁ1
.
1H NMR (300 MHz,
13C NMR (75 MHz, CDCl3):
d 180.7, 157.4, 148.5, 139.4, 133.7, 131.5,
CDCl3):
d
8.10 (s, 1H), 7.90e7.87 (m, 1H), 7.40e7.38 (m, 2H),
129.8, 126.9, 123.6, 122.4, 121.4, 117.6, 99.4, 77.0, 52.9, 26.3, 23.6.
HRMS (ESI): m/z calcd for C21H20BrNO2: 398.0745 (Mþ), found
398.0746.
7.32e7.23 (m, 3H), 6.95e6.90 (m, 1H), 6.84e6.81 (m, 1H), 6.63 (s,
1H), 3.64e3.57 (m, 2H), 3.46 (m, 2H), 1.96e1.84 (m, 4H); 13C NMR
(75 MHz, CDCl3):
d 180.7, 157.6, 145.7, 140.2, 133.9, 133.8, 129.2,
128.5, 127.0, 123.8, 121.4, 117.7, 100.6, 75.7, 25.3. HRMS (EI): m/z
4.2.10. (E)-3-(Piperidin-1-ylmethylene)-2-p-tolyl-chroman-4-one
calcd for C20H18ClNO2: 339.1026 (Mþ), found 339.1026.
(3j). Yellow oil. FTIR(film): nmax 3452, 2922, 2852, 1725, 1646, 1547,
1461, 1324, 1257, 1202, 1099, 1023, 755 cmꢁ1 1H NMR (300 MHz,
.
4.2.4. (E)-2-(4-Fluorophenyl)-3-(pyrrolidin-1-ylmethylene) chroman-
CDCl3)：
d
7.36e7.27 (m, 2H), 7.25 (d, 2H, J¼4.8 Hz), 7.24e7.21 (m,
4-one (3d). Yellow solid, mp 173e174 ꢀC. FTIR(film): nmax 3227, 3146,
1H), 7.06 (d, 2H, J¼8.1 Hz), 6.90e6.85 (m, 1H), 6.78 (d, 1H, J¼8.4 Hz),
6.47(s, 1H), 3.34 (d, 4H, J¼2.1 Hz), 2.26 (s, 3H), 1.60e1.54 (m, 6H);
1644, 1551, 1503, 1394, 1334, 1304, 1222, 1002, 762, 490 cmꢁ1 1H
.
NMR (300 MHz, CDCl3):
d
8.08 (s, 1H), 7.90e7.87 (m, 1H), 7.44e7.40
13C NMR (75 MHz, CDCl3):
d 181.0.157.7, 148.3, 137.9, 137.3, 133.6,
(m, 2H), 7.30e7.23 (m, 1H), 6.96e6.87 (m, 3H), 6.82e6.80 (m, 1H),
6.64 (s,1H), 3.60e3.53 (m, 2H), 3.43e3.41 (m, 2H),1.90e1.80 (m,4H);
129.0, 128.0, 126.9, 123.7, 121.1, 117.6, 100.2, 77.0, 52.9, 26.3, 23.7,
21.0. HRMS (ESI): m/z calcd for C22H23NO2: 334.1793(Mꢁ), found
334.1797.
13C NMR (75 MHz, CDCl3):
d 180.6, 164.0, 160.7, 157.6, 145.6, 137.5,
127.5, 133.8, 129.6, 127.0, 123.8, 121.1, 117.7, 115.3, 115.0, 100.8, 75.7,
25.3. HRMS (EI): m/z calcd for C20H18FNO2: 323.1322 (Mþ), found
323.1325.
4.2.11. (E)-2-Phenyl-3-(imidazol-1-ylmethylen)chroman-4-one
(3k). White oil. FTIR(film): nmax 3410, 3110, 1644, 1572, 1495, 1465,
1400, 1351, 1319, 1216, 1075, 760, 741, 723 cmꢁ1. 1H NMR (300 MHz,
4.2.5. (E)-3-(Pyrrolidin-1-ylmethylene)-2-p-tolyl-chroman-4-one
(3e). Yellow oil, mp 101e104 ꢀC. FTIR(film): nmax 3117, 1648, 1554,
1457, 1386, 1334, 1304, 1009, 746 cmꢁ1. 1H NMR (300 MHz, CDCl3):
CDCl3)：
7.08e7.01(m, 3H), 6.86(s, 1H), 6.71(s, 1H); 13C NMR (75 MHz,
CDCl3): 175.5, 156.2, 155.3, 137.1, 136.8, 134.2, 129.4, 129.1, 128.6,
d 7.61e7.56(m, 1H), 7.46(s, 1H), 7.36e7.24(m, 6H),
d

1236
C. Wu et al. / Tetrahedron 67 (2011) 1231e1237
127.3, 126.0, 125.7, 124.0, 123.5, 119.1, 118.2, 56.68. HRMS (ESI): m/z
123.2, 122.5, 121.1, 117.6, 77.9. HRMS (EI): m/z calcd for C23H16N2O:
calcd for C19H14N2O2 303.1125(Mꢁ), found: 303.1125.
336.1263 (Mþ), found 336.1266.
4.2.12. (Z)-3-[(Benzylamino)methylene]-2-phenylchroman-4-one
4.3.2. 5-(4-Fluorophenyl)-2-phenyl-5H-chromeno[4,3-d]pyrimidine
(3l). Yellow solid, mp 146e148 ꢀC. FTIR(film): nmax 3242, 3083,
(5b). White solid, mp 135e137 ꢀC. FTIR(film): nmax 1763, 1565, 1541,
3061, 3025, 2928.38, 2854, 1953, 1644, 1605 cmꢁ1
.
1H NMR
1456, 1425, 738, 657 cmꢁ1. 1H NMR (300 MHz, CDCl3):
d 8.57e8.54
(300 MHz, CDCl3):
d
10.40e10.36 (t, 1H, J¼5.1 Hz), 7.91e7.88 (d, 1H,
(m, 2H), 8.47e8.44 (dd, 1H, J¼1.6, 7.8 Hz), 8.18 (s, 1H), 7.52e7.50 (m,
3H), 7.45e7.43 (m, 3H), 7.20e7.08 (m, 3H), 7.02e6.99 (d, 1H,
J¼8.1 Hz), 6.32, (s, 1H), 2.37 (s, 3H); 13C NMR (75 MHz, CDCl3):
J¼7.4 Hz), 7.46e7.43 (m, 2H), 7.39e7.24 (m, 7H), 7.20e7.17 (m, 2H),
7.02e6.97 (t, 1H, J¼7.4 Hz), 6.93e6.90 (d, 1H, J¼8.2 Hz), 6.40e6.35
(d,1H, J¼12.6 Hz), 5.96 (s,1H), 4.32e4.30 (d, 2H, J¼6.0 Hz); 13C NMR
d
164.8, 164.5, 161.5, 156.5, 155.3, 154.1, 137.5, 133.9, 133.7, 130.9,
(75 MHz, CDCl3):
d
182.3, 158.7, 1511.5, 139.5, 137.5, 134.0, 128.9,
129.8, 129.7, 128.6, 128.3, 125.4, 123.0, 122.6 (m), 121,1, 117.6, 116.1,
115.8, 77.2. HRMS (EI): m/z calcd for C23H15FN2O: 354.1168 (Mþ),
found: 354.1165.
28.6, 128.5, 127.9, 127.8, 127.1, 126.4, 123.9, 121.5, 117.6, 102.4, 81.2,
52.9. HRMS (ESI): m/z calcd for C23H19NO2: 342.1486 (Mþ), found
342.1489. C22H17NO2: 327.1259 (Mþ), found 327.1262.
4.3.3. 2-Phenyl-5-p-tolyl-5H-chromeno[4,3-d]pyrimidine (5c). Yellow
solid, mp 129e131 ꢀC. FTIR(film): nmax 1723, 1646, 1604, 1565, 1541,
4.2.13. (Z)-3-[(Dodecylamino)methylene]-2-phenylchro-man-4-one
(3m). Colourless oil. FTIR(film): nmax 3236, 3062, 2922, 2852, 1647,
1253, 1217, 1028, 892, 755 cmꢁ1 1H NMR (300 MHz, CDCl3):
.
1607 cmꢁ1
.
1H NMR (300 MHz, CDCl3):
d
10.20e10.16 (t, 1H,
d
8.57e8.54 (m, 2H), 8.47e8.43 (dd, 1H, J¼1.6, 7.8 Hz), 8.20 (s, 1H),
J¼5.8 Hz), 7.92e7.89 (d, 1H, J¼7.4 Hz), 7.47e7.32 (m, 6H), 7.03e6.98
(t, 1H, J¼7.4 Hz), 6.93e6.90 (d, 1H, J¼8.2 Hz), 6.32e6.28 (d, 1H,
J¼12.8 Hz), 5.96 (s, 1H), 3.12e3.09 (q, 2H, J¼6.5 Hz), 1.51e1.49 (m,
2H), 1.25 (br, 18H), 0.90e0.85 (t, 3H, J¼5.6 Hz); 13C NMR (75 MHz,
7.51e7.49 (m, 3H), 7.45e7.39 (m, 1H), 7.34e7.32 (m, 2H), 7.25e7.23
(m, 1H), 7.20 (m, 2H), 7.18e7.12 (m, 1H), 7.02e6.99 (d, 1H, J¼8.2 Hz),
6.32 (s, 1H), 2.37 (s, 3H); 13C NMR (75 MHz, CDCl3):
d 164.3, 156.8,
155.3, 154.2, 139.1, 137.6, 135.0, 133.6, 130.7, 129.6, 128.5, 128.2, 127.8,
125.4, 123.4, 122.4, 121.7, 117.7, 77.7, 21.2. HRMS (EI): m/z calcd for
C24H18N2O: 350.1419 (Mþ), found: 350.1422.
CDCl3):
d 181.8, 158.5, 151.9, 139.7, 133.7, 128.6, 128.5, 127.9, 12.3,
124.1, 121.4, 117.5, 101.3, 812, 49.4, 31.9, 31.0, 29.6, 29.6, 295, 29.2,
26.5, 22.7, 14.2. HRMS (ESI): m/z calcd for C28H37NO2: 420.2900
(Mþ), found 420.2897.
Acknowledgements
4.2.14. (Z)-2-Phenyl-3-[(phenylamino)methylene]chroman-4-one
(3n). Yellow solid, mp 101e104 ꢀC. FTIR(film): nmax 3053, 2960,
2919, 2858, 1649,1601, 1466, 1277, 1218, 1150, 1100, 1022, 801, 753,
We thank the National Natural Science Foundation of China,
Ministry of Science and Technology (No. 2009ZX09501-006,
2007CB935900) and the Chinese Academy of Sciences for the fi-
nancial support.
695, 499 cmꢁ1. 1H NMR (300 MHz, CDCl3):
d
11.91 (d,1H, J¼12.0 Hz),
7.95 (dd, 1H, J¼1.6, 7.8 Hz), 7.52e7.35 (m,6H), 7.28e7.23 (m, 2H),
7.08e6.84 (m, 6H), 6.06 (s, 1H); 13C NMR (75 MHz, CDCl3):
182.2,
d
References and notes
158.1, 141.2, 139., 138.0, 133.5, 128.7127.7, 126.8, 125.6, 122.7, 122.6,
120.7, 116.8, 115.2, 104.6, 80.3. HRMS (ESI): m/z calcd for C22H17NO2:
327.1259 (Mþ), found 327.1262.
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103, 811e892; (b) Kataoka, T.; Kinoshita, H. Eur. J. Org. Chem. 2005, 45e58; (c)
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3031, 2961, 2928, 2872, 1645, 1583, 1546, 1461, 1329, 1240, 1010,
759, 722 cmꢁ1. 1H NMR (300 MHz, CDCl3):
d 7.95(s, 1H), 7.88(dd, 1H,
J¼1.2, 7.5 Hz), 7.43(d, 2H, J¼7.2 Hz), 7.28e7.19(m, 4H), 6.90e6.85(t,
1H, J¼7.2 Hz), 6.79(d, 1H, J¼7.5 Hz), 6.41(s, 1H), 3.15e3.09(m, 4H),
1.69e1.62(m, 4H), 0.98e0.84 (m, 6H); 13C NMR (75 MHz, CDCl3):
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d
181.0, 157.6, 148.4, 140.9, 133.7, 128.4, 128.1, 127.9, 127.0, 123.7,
121.2, 117.6, 99.7, 76.7, 22.6, 10.8. HRMS (ESI): m/z calcd for
C22H25NO2: 336.1958(Mꢁ), found 336.1954.
4.3. Typical procedure for the synthesis of benzopyran-
ylpyrimidines
To a solution of 3a (60 mg, 0.2 mmol) and benzamidine hy-
drochloride (4a, 93 mg, 0.6 mmol) in ethanol (2 mL) was added
solid NaOH (16 mg, 0.4 mmol), followed by heating to 80 ꢀC and
stirring for 5 h. After cooling to room temperature, the crude
product was purified by flash chromatography on silica gel (eluent:
petroleum ether/ethyl acetate¼10:1) to give a white solid 5a
(57 mg, 85%).
4.3.1. 5-Diphenyl-5H-chromeno[4,3-d]pyrimidine (5a). White solid,
mp 124e125 ꢀC. FTIR(film): nmax 1701, 1695, 1620, 1584, 1212, 850,
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750, 721, 659 cmꢁ1. 1H NMR (300 MHz, CDCl3):
d 8.53e8.50 (m, 2H),
8.42e8.39 (dd, 1H, J¼1.6, 7.8 Hz), 8.12 (s, 1H), 7.48e7.44 (m, 3H),
7.40e7.34 (m, 6H), 7.13e7.08 (m, 1H), 6.98e6.95 (d, 1H, J¼8.1 Hz),
6.25 (s, 1H); 13C NMR (75 MHz, CDCl3):
d 164.3, 156.8, 155.3, 154.2,
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C. Wu et al. / Tetrahedron 67 (2011) 1231e1237
1237
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