One-Pot Cascade Heterocyclization of γ- And β-Ketomalononitriles to 2,4-Dichloro-Substituted Pyrano[2,3- d]pyrimidines and Furo[2,3- d]pyrimidines Mediated by Triphosgene and Triphenylphosphine Oxide

Article abstract of DOI:10.1021/acs.joc.8b00669

A one-pot cascade heterocyclization strategy has been developed for the synthesis of 2,4-dichloro-substituted pyrano[2,3-d]pyrimidines and furo[2,3-d]pyrimidines from linear γ- and β-ketomalononitriles using triphosgene and triphenylphosphine oxide. The reaction afforded synthetic useful products with moderate to good yields, bypassing the conventional harsh conditions of chlorination. The mechanistic study revealed that the reaction proceeded with a non-isocyanate route, and the second step may conduct in a triphenylphosphine oxide-catalyzed manner.

Full text of DOI:10.1021/acs.joc.8b00669

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Article
A One-Pot Cascade Heterocyclization of #- and #-Ketomalononitriles
to 2,4-diChloro Substituted Pyrano[2,3-d]Pyrimidines and Furo[2,3-
d]Pyrimidines Mediated by Triphosgene and Triphenylphosphine Oxide
Zhen-Hua Li, Zhi-Jiang Jiang, Qiao-Ling Shao, Jin-Jing Qin, Qiang-Feng Shu, Wen-Hao Lu, and Wei-Ke Su
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b00669 • Publication Date (Web): 21 May 2018
Downloaded from http://pubs.acs.org on May 21, 2018
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A One-Pot Cascade Heterocyclization of γ- and β-Ketomalononitriles to 2,4-
diChloro Substituted Pyrano[2,3-d]Pyrimidines and Furo[2,3-
d]Pyrimidines Mediated by Triphosgene and Triphenylphosphine Oxide
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Zhen-Hua Li1,*, Zhi-Jiang Jiang2, Qiao-Ling Shao2, Jin-Jing Qin,1 Qiang-Feng Shu,1 Wen-Hao Lu1, and Wei-Ke Su2,*
1. Key Laboratory for Green Pharmaceutical Technologies and Related Equipment of Ministry of Education, College of
Pharmaceutical Sciences, Zhejiang University of Technology, Hangzhou 310014, P. R. China;
2. National Engineering Research Center for Process Development of Active Pharmaceutical Ingredients, Collaborative
Innovation Center of Yangtze River Delta Region Green Pharmaceuticals, Zhejiang University of Technology,
Hangzhou 310014, P. R. China.
Abstract
A one-pot cascade heterocyclization strategy had been developed for the synthesis of 2,4-dichloro substituted
pyrano[2,3-d]pyrimidines and furo[2,3-d]pyrimidines from linear γ- and β-ketomalononitriles using
triphosgene and triphenylphosphine oxide. The reaction afforded synthetic useful products with moderate to
good yields bypassing the conventional harsh conditions of chlorination. The mechanistic study revealed the
reaction underwent a non-isocyanate route, and the second step may conduct in a triphenylphosphine oxide-
catalyzed manner.
Ar2
O
CN
CN
O
Cl
O
Cl
Cl
Cl
Cl
Cl
CN
CN
Ar1
Ar1
O
O
R
Ph3P
O
Cl
Cl
N
N
N
N
O
Ph3P Cl
Cl
O
Cl
Cl
Ar1
R
Ar1
Ar2
- one-pot, two-heterocyclization from linear malononitrile
- two-chlorinated site for further functionalization
Introduction
2,4-disubstituted pyrimidines are important pharmacophore and synthetic motif, and have already been
embedded in several antihypertensives (doxazosin, prazosin, et al.) and tyrosine kinase inhibitors (imatinib,
dasatinib, et al.).1 Among them, the 2,4-disubstituted pyrano[2,3-d]pyrimidines and furo[2,3-d]pyrimidines
have shown their biological activities such as antimicrobial, antioxidant, and anticancer (Scheme 1a).2 Despite
the wide interest in these compounds, the synthetic methods remain limited. One of the most popular routes
employs the nucleophilic attack from barbituric acid to 2-methylenemalononitriles or α-chloroketones
(Scheme 1b, Route A),2b,2g,3 providing pyrimidiones for rapid reductive amination. Meanwhile, another
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prevailing route starts from the 2-amino-pyran(or furan)-3-carbonitriles affording 2,4-disubstituted products
for biological assessment directly (Scheme 1b, Route B).2a,2j,4 Pd-catalyzed 5-endo-dig cyclization also provides
a way to access the furo[2,3-d]pyrimidines.5 Hitherto, abundant compounds have been synthesized using
these strategies, however, the relative narrow structural diversity at 2,4-position constrained their further
investigation. Chloride substituted at 2,4-positions have been proved as a useful method, however, the harsh
conditions are usually required to obtain those synthetic useful substrates.6 Thus, it’s highly desired for a novel
protocol affording pyrano[2,3-d]pyrimidines and furo[2,3-d]pyrimidines with 2,4-dichloro substituted,
which may benefit the following functionalization.
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a. Biological active 2,4-disubstituted pyrimidines
N
N
O
O
HN
O
O
N
O
O
N
N
N
N
N
N
H
N
NH2
Doxazosin
Imatinib
OH
Ph
H
N
NH2
N
HN
O
N
O
N
Ph
EGFR Kinase Inhibitor
O
N
Antimicrobial Agent
b. conventional synthetic strategies
X
O
CN
NH2
( )n
O
R
R
N
N
NC
Cl
B
A
CN
R'
N
H
+
O
HN
NH
+
or
O
Y
R
O
O
( )n
R
R'
O
n = 0 or 1
Route A: X = O, Y = O
Route B: X = alkyl or aryl, Y = N-Akyl
CHO
Scheme 1. Biological active 2,4-disubstituted pyrimidines and conventional synthetic route of 2,4-
disubstituted pyrano[2,4-d]pyrimidines.
Triphosgene, also known as bis(trichloromethyl)carbonate (BTC) or solid phosgene, has been considered as
a safe and easy-handled alternative of highly toxic phosgene. The reagent has been used in various situations
including chlorination, acylation, and cyclization.7 During our continuous effort expanding the chemistry of
BTC,7c,8 an eco-friendly method has been developed transforming notorious triphenylphosphine oxide
(TPPO) to a versatile chlorination reagent triphenylphosphine dichloride (TPPDC).9 Previously, the system
had been applied in the construction of 2,4-dichloro benzopyrimidines and benzochromeno[2,3-
d]pyrimidines (Scheme 2a),10 and a similar diphosgene/acetonitrile strategy had also been employed in the
synthesis of heterocycle-fused 2,4-dichloro-pyrimidines.11 Despite the success, the stepwise synthesis of 2-
amino-3-cyano heterocycles still intrigued us about the possibility to furnish 2,4-dichloropyrimidines from
their precursor ketomalonitriles directly.12 Fortunately, during the efficacy evaluation of different BTC
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systems, this envisioned transformation was achieved by an accidental misoperation, where (E)-2-(3-oxo-1-
phenyl-3-(p-tolyl)prop-1-en-1-yl)malononitrile was added into the BTC/TPPO mixture before heating. The
structure of the product was carefully identified and supported by the subsequent single-crystal X-ray
diffraction (Scheme 2b). Herein, we wish to uncover our latest work about the direct construction from γ-
ketomalononitriles to 2,4-dichloro pyrano[2,3-d]pyrimidines, and its further expansion to 2,4-dichloro
furo[2,3-d]pyrimidines. The mechanistic investigation implicated the reaction was highly sensitive to the
substrate addition temperature, and the classical isocyanate-mechanism may be absent in this transformation.
Thus, a tentative non-isocyanate mechanism was proposed based on the temperature-sensitive base-free
pathway of BTC/TPPO to TPPDC.
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Previous Works
Cl
CN
N
NH2
N
Cl
BTC/TPPO
PhCl
(a)
Ar
Ar Cl
CN
N
O
NH2
O
N
Cl
This Work
Cl
Ar2
N
O
N
BTC/TPPO
PhCl
O
(b)
Cl
CN
CN
( )n
Ar1
( )n
One-pot
Two-Ring
Synthesis
Ar1
Ar2
n = 0 or 1
Scheme 2. The one-pot strategies for the 2,4-dichloro pyrimidines. ORTEP diagram with 50% ellipsoid
probability for non-H atoms of the compound of to 2j (CCDC number 1562782).
Result and Discussion
Synthetic study of 2,4-dichloro pyrano[2,3-d]pyrimidines. The transformation of 2-(1-(4-chlorophenyl)-3-
oxo-3-phenylpropyl)malononitrile (1a) to 2,4-dichloro-5-(4-chlorophenyl)-7-phenyl-5H-pyrano[2,3-
d]pyrimidine (2a) was chosen as model reaction for optimization, where the selected results was summarized
in Table 1. At the commencement, the usage of BTC/TPPO system and its combination ratio were examined.
According to our previous works,10b optimal ratio of BTC/TPPO was 1/3, which showed a similar result in
this reaction (Table 1, entries 1-4). Increasing the usage of BTC/TPPO gave better results (Table 1, entries
5-7), and the optimal ratio of was found to be 1/1/3. Attempts failed to use a catalytic amount of TPPO as
previous reported (Table 1, entries 8, 9),9b,10a which indicated the necessity of the large amount TPPO.
Fortunately, the product could be separated conveniently by n-hexane extraction, and the TPPO could be
recovered by recrystallization from ethanol efficiently.13 Subsequent screening of solvents didn't offer better
yields (Table 1, entries 10-14). Although toluene also gave an acceptable result, the reaction time was
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prolonged dramatically to over 12 hours. Besides, the yield increased with higher temperature (Table 1, entries
15-17), but the refluxing didn't give any superior result. Further tracking of reaction process found the
transformation ended at 1.5 hours (Table 1, entry 18).
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Table 1. Optimization of Reaction Condition. a
Cl
Cl
N
N
BTC/TPPO
O
O
Cl
CN
CN
Solvent (0.1 M)
2a
Cl
1a
Ratio
entry
Solvent
T/°C time/hr % yield b
1a : BTC : TPPO
1 : 0.34 : 1.00
1 : 0.34 : 0.34
1 : 0.34 : 0.67
1 : 0.34 : 1.34
1 : 0.67 : 2.00
1 : 1.00 : 3.00
1 : 1.34 : 4.00
1 : 1.00 : 0.20
1 : 1.00 : 0.30
1 : 1.00 : 3.00
1 : 1.00 : 3.00
1 : 1.00 : 3.00
1 : 1.00 : 3.00
1 : 1.00 : 3.00
1 : 1.00 : 3.00
1 : 1.00 : 3.00
1 : 1.00 : 3.00
1 : 1.00 : 3.00
1
2
PhCl
PhCl
110
110
110
110
110
110
110
110
110
40
5
5
45
n.d.
10
3
PhCl
5
4
PhCl
5
44
5
PhCl
5
71
6
PhCl
5
85
7
PhCl
5
85
8
PhCl
24
24
24
24
24
12
16
5
trace
trace
n.d.
65
9
PhCl
10
11
12
13
14
15
16
17
18
CH2Cl2
C2H4Cl2
2-MeTHF
Toluene
Dioxane
PhCl
80
80
50
110
110
80
80
75
72
PhCl
100
131
110
5
80
PhCl
5
84
PhCl
1.5
85
a Reaction conditions unless specified otherwise: BTC and TPPO in solvent (0.1 M) was premixed under ice-bath, and
stirred at room temperature for 30 min. Then, 1a was added and the mixture was heated to the specified temperature. b
isolated yield based on 1a.
With optimal condition established, a series of 2-(3-oxo-propyl)malononitriles was exposed to the standard
condition, and the results were presented in Table 2. Firstly, the substitution effect was tested at 7 and 5
positions of pyrano-ring. For phenyl substituted at 7 position, the electron-donating substitutions (2c-e) gave
better results than their electron-withdrawing counterpart (2f-h), where the lower electron density retarded
the enolate's nucleophilic attack to nitrile group. Interestingly, nucleophilic phenolic group (1e) was also
tolerated with a slight drop in yield, which prone to dimerize under BTC systems.7a Unfortunately, 2-
phenylethyl at 7 position (2i) didn't react under this condition indicating the alkyl group may not suitable for
this position. On the other side, the substitution effect at 5-phenyl group was not prominent, and similar yields
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were obtained comparing with unsubstituted ones (2a, j-n). However, the steric hindrance at this site may
cause significant decline on the outcomes, where a dramatically drop in yield was found using the 2,6-
dimethylphenyl substrate (2o). 5-Ethyl and methyl derivatives both afforded desired products (2p-q) with
moderate yields, however, much-hindered n-heptyl and benzyl failed in the tests. Besides, 5-unsubstituted
substrate also gave acceptable result of 67%. Subsequent tests of furyl and thienyl substrate (1s, t) showed
both heterocycles at 5-position survived under the standard condition, affording the corresponding product
with a moderate yield of 76% and 73%, respectively. However indolyl or pyridyl substrates (1u, v) didn’t
provide corresponding products.14 Cinnamyl derived substrate (1w) with internal double bond proceed
smoothly, while cyclohexanone derived one (1x) also survived. Additional attempts failed to install other
groups at 6-position including 2y. The scalability of this protocol was also examined at 20 mmol using the
model reaction (1a to 2a), which afforded a good yield of 91% within 3 hours with 95% recovery of TPPO.
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Table 2 Substrate scope of 2,4-dichloro pyrano[2,3-d]pyrimidines. a
Cl
Cl
2b
R
1 = H
82% (91%)b
91%
85%
75%
79%
N
N
2c R1 = 4-Me
2d R1 = 4-OMe
2e R1 = 4-OH
2f R1 = 4-F
N
N
O
Cl
O
Cl
7
2g R1 = 3-Br
81%
R1
2h
R
1 = 4-Cl
77%
Ph
Me
2i, n.r.
Cl
Cl
2a R2 = 4-Cl
85%
N
N
N
N
2j
R2 = 4-Me
87%
83%
74%
R2 = 2,4-diCl
R2 = 4-NO2
O
Cl
2k
2l
O
Cl
Cl
5
R2
Me
N
OMe
2m, 94%
Cl
Cl
N
N
N
N
N
Cl
Me
Cl
O
O
O
Cl
R3
Ph
Me
F
Cl
Me
Cl
N
42%
51%
67%
2p
2q
R
3 = Et
2n, 76%
Cl
2o, 45%
R3 = Me
2r R3 = H
Cl
N
N
N
N
N
O
Cl
O
Cl
O
Cl
X
N
76%
73%
2u, n.r.
2v, n.r.
2s X = O
2t X = S
NH
Me
Cl
Me
Cl
N
Cl
N
O
N
N
N
O
N
Cl
O
Cl
Cl
Ph
Me
Me
Me
2y, n.r.
Me
2w, 79%
2x, 57%
a
Reaction conditions unless specified otherwise: BTC (1.0 mmol) and TPPO (3.0 mmol) in chlorobenzene (0.1 M) was
premixed under ice-bath, and stirred at room temperature for 30 min. Then, 1 (1.0 mmol) was added and the mixture was
heated to the 110 °C. Isolated yield based on 1. b 20 mmol scale reaction. n.r. = no reaction.
Synthetic study of 2,4-dichloro furo[2,3-d]pyrimidines. After the investigation of one-pot synthesis of 2,4-
dichloro pyrano[2,3-d]pyrimidines, we wondered if the method could be further introduced into the
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preparation of 2,4-dichloro furo[2,3-d]pyrimidine derivatives. Fortunately, the model substrate 2-(2-oxo-2-
phenylethyl)malononitrile 3a transformed to 2,4-dichloro-6-phenylfuro[2,3-d]pyrimidine 4a with a yield of
62% under the same condition. After a simple optimization, the yield was improved to 81% with the ratio of
3a/BTC/TPPO of 1/1.34/4. Then, a preliminary substrate scope test was performed (Table 3). Both
electron-donating and withdrawing substitutes on the 6-aryl group (4b and c) gave acceptable yields (4b-e).
5,6-diaryl substituted products could also be synthesized using the protocol(4f-i) where a slight drop in yields
was found from the electron-withdrawing group on 5-position. Noteworthy, the 2,4-dichloro-6-
phenylthieno[2,3-d]pyrimidine (5a) could also be obtained with a moderate yield, which has also been
investigated in a series anticancer biological assessment.15
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
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32
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Table 3 Substrate scope of 2,4-dichloro furo[2,3-d]pyrimidines. a
Cl
N
O
CN
CN
BTC (1.34 equiv.)
TPPO (4.0 equiv.)
PhCl (0.1 M)
110 °C, 1.5 hr
N
O
Ar1
R
Cl
Ar1
R
3
4
Cl
N
Cl
Cl
N
N
N
N
N
O
6
O
S
6
5
Cl
Cl
Cl
R1
R1
4a
R2
5a, 58%
R
1 = H
81%
78%
1 = 4-OMe 85%
4b R1 = 4-Me
4f R1 = H, R2 = H
84%
86%
4g R1 = 4-OMe, R2 = H
4c
4d
R
1 = 4-Cl
70%
87%
4h R1 = 4-OMe, R2 = 2-Cl 77%
R
4e R1 = 4-F
4i
R
1 = 4-OMe, R2 = 2-F
81%
a Reaction conditions unless specified otherwise: BTC (1.34 mmol) and TPPO (4.0 mmol) in chlorobenzene (0.1 M) was
premixed under ice-bath, and stirred at room temperature for 30 min. Then, 1 (1.0 mmol) was added and the mixture was
heated to the 110 °C. Isolated yield based on 1.
Mechanistic Study. Although the substrate examination gave satisfying results, the usage of 3.0 equivalent of
TPPO still intrigued us to investigate the reason for its necessity. Previously, an isocyanate-based mechanism
has been proposed by us and others.10-11 However, when rescrutinizing the work of benzochromeno[2,3-
d]pyrimidines,10a the failure of TPPO catalysis could hardly be explained by this mechanism as well as the
protocol presented here. Thus, several control experiments were conducted for insight (Scheme 3). Firstly,
the substrate 1a was treated by BTC from low to an elevated temperature, where the substrate remained intact
without any trace of chlorination (Scheme 3a). Then, 1a was added to the activated BTC/TPPO mixture at
room temperature and stirred for 24 hours without heating. Although the substance consumed rapidly in 30
minutes, no product or theoretical intermediate 2-amino-4H-pyran-3-carbonitrile was detected (Scheme 3b).
The only information obtained from the TLC plate was a series inseparable high polarity spots. To avoid the
possible consumption of intermediate generated, the ratio of 1a/BTC/TPPO was reduced to 1/0.34/1, which
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still gave an inseparable mixture with a little unconsumed substrate. Next, attempts failed to capture the
isocyanate intermediate using alcohols, where no corresponding carbamates were detected (Scheme 3c).16
Treating 2-amino-4-(4-chlorophenyl)-6-phenyl-4H-pyran-3-carbonitrile with the standard condition only
gave a much lower yield (33%) than its linear precursor (Scheme 3d, Condition A). And an extremely low
yield (12%) was obtained under our previous TPPO-catalytic system, which indicated the reaction should be
conducted from linear substrate directly.
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Scheme 3 Control Experiments
Subsequently, the temperature of substrate addition was carefully examined (Figure 1). Interestingly, a
dramatic decrease in yield was observed during temperature progressing. Noticeably, addition at 20 minutes
(after 10 minutes stabilizing at 110 °C) gave nearly no product after 24 hours’ heating, and 75% of the substrate
was recovered from the reaction.
Figure 1 Experiment of adding substrate at different temperature (Black Column: Isolated yields based on 1a; Red curve:
average temperature at the time). Detailed data: 0 min, ca. 15 °C (before heating), 85% yield; 2 min, ca. 23°C, 84% yield; 4
min, ca. 40 °C, 73% yield; 6 min, ca. 75 °C, 42% yield; 8 min, ca. 85°C, 24% yield; 10 min, ca. 110 °C, 21% yield; 15 min, 110 °C,
5% yield; 20 min, 110°C, 3% yield (75% recovery of 1a).
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These experiments and optimization data above implied that: 1) BTC and TPPDC cannot trigger the first
heterocyclization, and 2) the activated BTC/TPPO mixture may form a low-temperature species
before the TPPDC formation by CO2 extrusion under high temperature. 3) This low-temperature
species is responsible for the consumption of substrate giving a highly active or high polarity
intermediate, 4) and TPPDC only participates the final step to afford products. The signal of the low-
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temperature species and corresponding intermediate were detected by the P-NMR study (See Supporting
Information for more details). Besides, 5) a base-free BTC/TPPO system could generate TPPDC under
high temperature,10b thus the formation of 2,4-dichloropyrimidine motif may undergo catalytic manner.
However, due to the failure of catalysis, 6) the first step of heterocyclization may afford an intermediated
embedded a triphenylphosphine oxide molecule, rather than previously proposed 2-amino-4H-pyran-
3-carbonitrile based on the isocyanate intermediates.
Thus, based on the well-established mechanism of BTC activation9-10 and the inference above, a plausible
mechanism was proposed in scheme 4. After the mixture of BTC and TPPO, the nucleophilic attack from
TPPO to BTC generates the ((chlorocarbonyl)oxy)triphenylphosphonium chloride (A) as low-temperature
species during the activation step (30 min string at room temperature). After the substrate addition, the
deprotonation occurs at more acidic malononitrile’s methenyl position rather than α-hydrogen of the carbonyl
group, which is then captured by A affording intermediate (B). Subsequently, the nucleophilic attack from
enolate to C=N bond forms the first pyrano-ring (C). Then, with the temperature progressing, TPPDC is
generated from excessive A by CO2 extrusion. The closure of pyrimidine ring is then triggered by chloride’s
nucleophilic attack on the cyano group, and the cascade electron transfer is captured by TPPDC. Finally, the
product is afforded by SNAr mechanism replacing oxygen atom by chloride anion.
Scheme 4. Proposed non-isocyanate mechanism.
BTC/TPPO activation
O
O
slow at low temp.
fast at high temp.
Cl3CO
OCCl3
Cl-
Ph3P Cl Cl-
TPPDC
Ph3P
O
Ph3P
O
Cl
A
Cyclizatioin and Chlorination
O
Ph3P
O
O
O
O
Cl
Ph3P
H+
PPh3
N
N
CN
H
HN
O
N
C
H
CN
O
O
Cl-
O
Cl-
Ar1
Ar2
Ar1
Ar2
Ar1
Ar2
C
HCl
H
B
Ph3P Cl
Cl
Cl-
N
PPh3
Cl
O
O
Cl-
N
N
H
O
N
N
N
O
Cl
Ar2
O
Cl
Ar2
Cl
Ar2
TPPO
Ar1
TPPO
Ar1
HCl
Ar1
D
E
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Based on this mechanism, the second step should be a TPPO-catalyzed procedure. However, during the
reaction, TPPO detached from the intermediate was then participated in the transformation to TPPDC,
which makes the overall reaction worked in a non-catalytic manner. To ensure this hypothesis, the ratio of
1/1/1.2 was tested for 6 substrates. Generally, the desired products were obtained within 5 hours, while an
average drop of 10% for 2 and 25% for 4 was observed, respectively (Scheme 5). This higher sensitivity of 2-
(2-oxo-ethyl)malononitrile substrates to mixture concentration matched well with higher concentration
requirement of A. Thus, the over usage of TPPO in this reaction was supposed to facilitate the first
heterocyclization. Besides, it’s believed that previous synthesis of benzochromeno[2,3-d]pyrimidine may
share the similar mechanism, where substoichiometric data also consisted with this hypothesis (55% yield for
substrate/BTC/TPPO=1/1/1, and 68% yield for 1/1/2).10b
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Cl
N
N
R
N
BTC (1 equiv.)
TPPO (1.2 equiv.)
O
R
O
Cl
Cl
PhCl (0.1 M)
110 °C, 5 hr
n = 0 or 1
CN
CN
( )n
Ar
( )n
Ar
Cl
Cl
N
N
N
N
N
O
Cl
O
Cl
O
Cl
Cl
Me Me
Cl
OMe
2a, 74%
2j, 76%
2m, 85%
Cl
N
Cl
N
N
O
N
N
N
O
O
Cl
Cl
Cl
Ph
4f, 61%
Cl
4a, 54%
4d, 45%
Scheme 5. Reaction tests using a reduced ratio of 1/1/1.2. Reaction conditions unless specified otherwise:
BTC (1.0 mmol) and TPPO (1.2 mmol) in chlorobenzene (0.1 M) was premixed under ice-bath, and stirred
at room temperature for 30 min. Then, 1 (1.0 mmol) was added and the mixture was heated to the 110 °C.
Isolated yield based on 1.
Conclusion
In the work presented, a one-pot direct construction of 2,4-dichloro pyrano[2,3-d]pyrimidines and furo[2,3-
d]pyrimidines from γ- and β-ketomalononitriles had been achieved by a BTC/TPPO mediated cascade
heterocyclization, which afforded desired products with moderate to high yields. The mechanistic study
revealed the reaction underwent a non-isocyanate mechanism, where the component of BTC/TPPO system
under different temperature played crucial rules in both steps of cyclization. Besides, the proposed mechanism
implicated the TPPDC worked in a catalytic manner in the second heterocyclization, which was shaded by the
high concentration requirement of the first heterocyclization. The protocol provided a convenient way to
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access the 2,4-dichloro pyrano[2,3-d]pyrimidines and furo[2,3-d]pyrimidines, where the chlorinated sites
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could be functionalized easily for further biological investigation.
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Experiment Section
General Information Synthetic reagent were purchased from Aladdin, and used without further purification,
unless otherwise indicated. DANGEROUS: BTC WILL RELEASE PHOSGENE IN MOISTURE
ENVIRONMENT, ESPECIALLY AT ELEVATED TEMPERATURE. IT'S HIGHLY NOT
RECOMMEND TO ADD BTC OVER 80 °C. Analytical TLC (thin-layer chromatography) was performed
with 0.25 mm Silica gel G with a 254 nm fluorescent indicator. Melting points (m.p.) were obtained on a digital
melting point apparatus and uncorrected. NMR spectra were recorded with 400 and 600 MHz spectrometer
for 1H NMR, 151 and 101 MHz for 13C NMR, and 243 MHz for 31P NMR. TMS was used as internal standard
1
13
31
for H and C NMR, while D2O and phosphoric acid was used as internal standard for P NMR. High
resolution mass spectra were measured with HRMS-EI-Q-TOF and HRMS-ESI-Q-TOF. Single-crystal
diffraction data for compound 2i were collected with an Xcalibur, Eos, Gemini Ultra diffractometer. CCDC
1562782 (for 2i) contain the supplementary crystallographic data for this paper. Purification of products was
accomplished by column chromatography (n-hexane/ethyl acetate = 10/1) on Silica gel. The substrate 2-(3-
oxo-1,3-diarylpropyl)malononitrile and 2-(2-oxo-2-phenylethyl)malononitrile were synthesized according to
well established methods.17
General Procedure for the synthesis of 2,4-dichloro pyrano[2,3-d]pyrimidine. BTC (297 mg, 1 mmol in
5 mL PhCl) was added to a stirred solution of TPPO (834 mg, 3 mmol in 5 mL PhCl) dropwise under ice
bath. After complete addition, the mixture was stirred for 30 minutes at room temperature. Then 2-(1-(4-
chlorophenyl)-3-oxo-3-phenylpropyl)malononitrile 1a (309 mg, 1 mmol) was added, and the mixture was
heated to 110 °C until completion of reaction (followed by TLC, n-hexane/ethyl acetate = 10/1). After
cooling down, the mixture was then pour in to the ice water, and extracted with dichloromethane, the organic
layer was dried over anhydrous Na2SO4, concentrated. After the concentration of organic layer extracted
during the work-ups, the residue was stirred vigorously in n-hexane (20 mL x 3) for 30 mins. Then, the
remaining paste was recrystallized using ethanol, which afford TPPO (676 mg, 81% recovery) as a white solid.
The n-hexane portion was then concentrated and purified over column chromatography (n-hexane/ethyl
acetate = 10/1) to afford the pure product: 2,4-dichloro-5-(4-chlorophenyl)-7-phenyl-5H-pyrano[2,3-
d]pyrimidine (2a). White solid (330 mg, 85% yield), m.p. 137.7-138.4 ˚C; 1H NMR (400 MHz, Chloroform-
d) δ 7.70-7.64 (m, 2H), 7.43-7.36 (m, 3H), 7.32 (dt, J = 2.8, 9.2 Hz, 2H), 7.18 (dt, J = 2.4, 8.8 Hz, 2H), 5.78(d,
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J = 5.2 Hz, 1H), 4.83 (d, J = 5.2 Hz, 1H); C{1H} NMR (101 MHz, Chloroform-d) δ 165.3, 162.4, 158.0,
147.3, 140.3, 133.5, 131.0, 129.6, 129.4, 129.1, 128.5, 124.7, 112.9, 102.3, 38.6; HRMS (EI-Q-TOF) m/z:
[M]+ Calcd for C19H11Cl3N2O 387.9937; Found 387.9939.
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2,4-dichloro-5,7-diphenyl-5H-pyrano[2,3-d]pyrimidine (2b). White solid (292 mg, 82% yield), m.p. 88.4-
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90.0 ˚C; H NMR (400 MHz, Chloroform-d) δ 7.74-7.63 (m, 2H), 7.44-7.31 (m, 5H), 7.31-7.15 (m, 3H),
5.83 (d, J = 5.2 Hz, 1H), 4.85 (d, J = 5.2 Hz, 1H); C{1H} NMR (101 MHz, Chloroform-d) δ 165.4, 162.4,
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157.8, 147.0, 141.8, 131.2, 129.4, 128.9, 128.4, 128.1, 127.6, 124.6, 113.4, 102.8, 39.2; HRMS (EI-Q-TOF)
m/z: [M]+ Calcd for C19H12Cl2N2O 354.0327; Found 354.0327.
2,4-dichloro-5-phenyl-7-p-tolyl-5H-pyrano[2,3-d]pyrimidine (2c). White solid (334 mg, 91% yield), m.p.
121.6-123.5 ˚C; 1H NMR (400 MHz, Chloroform-d) δ 7.57 (d, J = 8.4 Hz, 2H), 7.38-7.16 (m, 7H), 5.77 (d, J
= 5.2 Hz, 1H), 4.82 (d, J = 5.2 Hz, 1H), 2.39 (s, 3H); 13C{1H} NMR (101 MHz, Chloroform-d) δ 165.7, 162.7,
158.0, 147.4, 142.3, 139.8, 129.4, 129.1, 128.7, 128.4, 127.8, 124.8, 113.8, 102.2, 39.5, 21.7; HRMS (EI-Q-
TOF) m/z: [M]+ Calcd for C20H14Cl2N2O 368.0483; Found 368.0486.
2,4-dichloro-7-(4-methoxyphenyl)-5-phenyl-5H-pyrano[2,3-d]pyrimidine (2d). Yellow solid (326 mg, 85%
yield), m.p. 153.5-155.1 ˚C; 1H NMR (400 MHz, Chloroform-d) δ 7.61 (d, J = 8.8 Hz, 2H), 7.37-7.19 (m, 5H),
6.90 (d, J = 8.8 Hz, 2H), 5.68 (d, J = 4.8 Hz, 2H), 4.82 (d, J = 4.8 Hz, 2H), 3.84 (s, 3H); 13C{1H} NMR (101
MHz, Chloroform-d) δ165.5, 162.4, 160.5, 147.0, 146.8, 142.2, 128.8, 128.1, 127.5, 126.2, 123.9, 113.9, 113.6,
101.1, 55.4, 39.2; HRMS (ESI-Q-TOF) m/z: [M + H]+ Calcd for C20H15Cl2N2O2 385.0505; Found 385.0491.
4-(2,4-dichloro-5-phenyl-5H-pyrano[2,3-d]pyrimidin-7-yl)phenol (2e). White solid (294 mg, 75% yield),
m.p. 193.3-195.2 ˚C; 1H NMR (400 MHz, Chloroform-d) δ 7.55 (dt, J = 3.2, 9.6 Hz, 2H), 7.37-7.20 (m, 5H),
6.86 (dt, J = 3.2, 9.6 Hz, 2H), 5.67 (d, J = 4.8 Hz, 1H), 5.56 (br s, 1H), 4.81 (d, J = 4.8 Hz, 1H); 13C{1H} NMR
(101 MHz, Chloroform-d) δ 165.5, 162.5, 156.9, 147.1, 142.1, 128.9, 128.1, 127.6, 126.5, 123.9, 116.0, 115.5,
113.6, 101.1, 39.2; HRMS (ESI-Q-TOF) m/z: [M + Na]+ Calcd for C19H12Cl2N2O2Na 393.0168; Found
393.0161.
2,4-dichloro-7-(4-fluorophenyl)-5-phenyl-5H-pyrano[2,3-d]pyrimidine (2f). White solid (293 mg, 79%
1
yield), m.p. 149.8-151.3 ˚C; H NMR (400 MHz, Chloroform-d) δ 7.70-7.62 (m, 2H), 7.38-7.32 (m, 2H),
7.31-7.20 (m, 3H), 7.13-7.03 (m, 2H), 5.76 (d, J = 5.2 Hz, 1H), 4.83 (d, J = 4.8 Hz, 1H); 13C{1H} NMR (101
MHz, Chloroform-d) δ 165.2, 163.5 (d, 1JC-F= 190 Hz), 161.9, 157.8, ,146.2, 141.8, 128.9, 128.0, 127.6, 127.5,
126.7 (d, 3JC-F = 8.3 Hz),115.5 (d, 2JC-F = 22 Hz), 113.3, 102.7, 39.2; HRMS (EI-Q-TOF) m/z: [M]+ Calcd for
C19H11Cl2FN2O 372.0232; Found 372.0225.
7-(3-bromophenyl)-2,4-dichloro-5-phenyl-5H-pyrano[2,3-d]pyrimidine (2g). White solid (259 mg, 81%
yield), m.p. 149.8-151.3 ˚C; 1H NMR (400 MHz, Chloroform-d) δ 7.84 (s, 1H), 7.60 (d, J = 7.6 Hz, 1H), 7.50
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(d, J = 8.0 Hz, 1H), 7.39-7.17 (m, 6H), 5.84 (d, J = 5.2 Hz, 1H), 4.84 (d, J = 4.8 Hz, 1H); 13C{1H} NMR (101
MHz, Chloroform-d) δ165.1, 162.6, 157.9, 145.7, 141.5, 133.3, 132.4, 129.9, 129.0, 128.1, 127.7, 123.2, 122.7,
113.2, 104.1, 39.2; HRMS (ESI-Q-TOF) m/z: [M + H]+ Calcd for C19H12Cl2BrN2O 432.9505; Found
432.9499.
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2,4-dichloro-7-(4-chlorophenyl)-5-phenyl-5H-pyrano[2,3-d]pyrimidine (2h). White solid (298 mg, 77%
1
yield), m.p. 169.4-173.4 ˚C; H NMR (400 MHz, Chloroform-d) δ 7.61 (dt, J = 2.8, 9.2 Hz, 2H), 7.40-7.31
13
(m, 4H), 7.31-7.21 (m, 3H), 5.81 (d, J = 5.2 Hz, 1H), 4.84 (d, J = 5.2 Hz, 1H); C{1H} NMR (101 MHz,
Chloroform-d) δ 165.2, 162.5, 157.9, 146.1, 141.6, 135.4, 129.8, 128.9, 128.7, 128.0, 127.7, 126.0, 113.3, 103.3,
39.2; HRMS (EI-Q-TOF) m/z: [M]+ Calcd for C19H11Cl3N2O 387.9937; Found 387.9939.
2,4-dichloro-7-phenyl-5-p-tolyl-5H-pyrano[2,3-d]pyrimidine (2j). White solid (320 mg, 87% yield), m.p.
121.6-123.5 ˚C; 1H NMR (400 MHz, Chloroform-d) δ 7.74-7.62 (m, 2H), 7.43-7.36 (m, 3H), 7.19-7.10 (m,
4H), 5.81 (d, J = 4.8 Hz, 1H), 4.80 (d, J = 5.2 Hz, 1H), 2.34 (s, 3H); 13C{1H} NMR (101 MHz, Chloroform-
d) δ 165.3, 162.4, 157.6, 146.8, 138.9, 137.3, 131.2, 129.5, 129.3, 128.4, 128.0, 124.6, 113.6, 103.0, 38.7, 21.2;
HRMS (EI-Q-TOF) m/z: [M]+ Calcd for C20H14Cl2N2O 368.0483; Found 368.0486. The X-ray analysis data
of 2j is shown in the Supporting Information, Table S1.
2,4-dichloro-5-(2,4-dichlorophenyl)-7-phenyl-5H-pyrano[2,3-d]pyrimidine (2k). White solid (350 mg, 83%
1
yield), m.p. 182.4-185.6 ˚C; H NMR (400 MHz, Chloroform-d) δ 7.70-7.62 (m, 2H), 7.48-7.35 (m, 4H),
7.22 (dd, J = 4.0, 8.0 Hz, 1H), 6.92 (d, J = 8.0 Hz, 1H), 5.75 (d, J = 4.8 Hz, 1H), 5.35(d, J = 4.8 Hz, 1H);
13C{1H} NMR (101 MHz, Chloroform-d) δ 165.9, 162.5, 158.5, 147.7, 137.8, 134.0, 133.2, 131.0, 130.6, 129.6,
128.4, 128.1, 124.6, 111.9, 100.2, 35.9; HRMS (EI-Q-TOF) m/z: [M]+ Calcd for C19H10Cl4N2O 421.9547;
Found 421.9546.
2,4-dichloro-5-(4-nitrophenyl)-7-phenyl-5H-pyrano[2,3-d]pyrimidine (2l). White solid (295 mg, 74%
1
yield). m.p. 153.4-155.2 ˚C; H NMR (400 MHz, Chloroform-d) δ 8.22 (d, J = 8.8 Hz, 2H), 7.73-7.65 (m,
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2H), 7.46-7.39 (m, 5H), 5.78 (d, J = 4.8 Hz, 1H), 5.01 (d, J = 5.2 Hz, 1H); C{1H} NMR (101 MHz,
Chloroform-d) δ 165.3, 162.4, 158.6, 148.6, 148.0, 147.1, 130.7, 129.9, 129.2, 129.0, 124.7, 124.2, 112.1, 101.2,
39.1; HRMS (EI-Q-TOF) m/z: [M]+ Calcd for C19H11Cl2N3O3 399.0177; Found 399.0171.
2,4-dichloro-5-(4-methoxyphenyl)-7-p-tolyl-5H-pyrano[2,3-d]pyrimidine (2m). White solid (374 mg, 94%
yield), m.p. 139.8-141.5 ˚C; 1H NMR (400 MHz, Chloroform-d) δ 7.57 (d, J = 8.0 Hz, 2H), 7.20 (d, J = 8.0
Hz, 2H), 7.16 (dt, J = 2.8, 9.6 Hz, 2H), 6.86 (d, J = 3.2, 10.0 Hz, 2H), 5.75 (d, J = 5.2 Hz, 1H), 4.77 (d, J = 5.2
13
Hz, 1H), 3.80 (s, 3H), 2.39 (s, 3H); C{1H} NMR (101 MHz, Chloroform-d) δ 165.3, 162.4, 158.8, 157.6,
147.0, 139.5, 134.3, 129.2, 129.1, 128.6, 124.6, 114.2, 113.8, 102.2, 55.3, 38.3, 21.4; HRMS (EI-Q-TOF) m/z:
[M]+ Calcd for C21H16Cl2N2O2 398.0589; Found 398.0594.
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2,4-dichloro-5-(4-chlorophenyl)-7-(4-fluorophenyl)-5H-pyrano[2,3-d]pyrimidine (2n). White solid (308
mg, 76% yield), m.p. 146.6-148.2 ˚C; 1H NMR (400 MHz, Chloroform-d) δ 7.73-7.57 (m, 2H), 7.32 (d, J =
8.4 Hz, 2H), 7.17 (d, J = 8.4 Hz, 2H), 7.13-7.03 (m, 2H), 5.71 (d, J = 5.2 Hz, 1H), 4.82 (d, J = 4.8 Hz, 1H);
1
13C{1H} NMR (101 MHz, Chloroform-d) δ 165.1, 163.5 (d, JC-F = 199.4 Hz), 162.0, 158.0, 146.5, 140.2,
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133.5, 129.4, 129.1, 127.3, 126.7 (d, 3JC-F = 8.3 Hz), 115.6 (d, 2JC-F = 22 Hz), 112.8, 102.1, 38.6; HRMS (EI-Q-
TOF) m/z: [M]+ Calcd for C19H10Cl3FN2O 405.9843; Found 405.9850.
2,4-dichloro-5-(2,6-dimethylphenyl)-7-(p-tolyl)-7H-pyrano[2,3-d]pyrimidine (2o). White solid (179.1
mg, 45%), m.p. 178.3-179.0 °C; 1H NMR (600 MHz, Chloroform-d) δ 7.56 (d, J = 8.4 Hz, 2H), 7.19 (d, J =
8.4 Hz, 2H), 7.13 – 7.07 (m, 2H), 6.95 (m, 1H), 5.51 (d, J = 4.8 Hz, 1H), 5.33 (d, J = 4.8 Hz, 1H), 2.57 (s,
3H), 2.37 (s, 3H), 2.00 (s, 3H); 13C{1H} NMR (151 MHz, CDCl3) δ 166.5, 161.9, 158.2, 147.7, 139.8, 137.3,
137.2, 136.3, 131.1, 129.4, 128.9, 128.6, 127.8, 124.7, 114.0, 99.2, 34.7, 21.4, 21.4, 20.1; HRMS (ESI-Q-TOF)
m/z: [M + H]+ Calcd for C22H19Cl2N2O 397.0869; Found 397.0857.
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2,4-dichloro-5-ethyl-7-phenyl-5H-pyrano[2,3-d]pyrimidine. (2p). Yellow oil (128.8 mg, 42%); H NMR
(600 MHz, Chloroform-d) δ 7.73 – 7.69 (m, 2H), 7.46 – 7.39 (m, 3H), 5.76 (d, J = 5.4 Hz, 1H), 3.80-3.74 (m,
1H), 1.93 – 1.79 (m, 2H), 0.97 (t, J = 7.5 Hz, 3H); 13C{1H} NMR (151 MHz, CDCl3) δ 166.8, 161.6, 157.7,
149.3, 131.8, 129.6, 128.8, 124.9, 114.3, 102.0, 33.7, 28.9, 9.7; HRMS (ESI-Q-TOF) m/z: [M + H]+ Calcd for
C15H13Cl2N2O 307.0399; Found 307.0388.
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2,4-dichloro-5-methyl-7-phenyl-5H-pyrano[2,3-d]pyrimidine (2q). Colorless oil (148 mg, 51% yield); H
NMR (600 MHz, Chloroform-d) δ 7.73 – 7.62 (m, 2H), 7.44 – 7.35 (m, 3H), 5.73 (d, J = 4.8 Hz, 1H)3.77 (qd, J
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= 6.6, 4.8 Hz, 1H), 1.45 (d, J = 6.6 Hz, 3H); C NMR (151 MHz, Chloroform-d) δ 166.1, 161.7, 157.8, 148.2,
131.8, 129.6, 128.7, 124.8, 115.5, 104.0, 27.8, 22.7; HRMS (ESI-Q-TOF) m/z: [M + Na]+ Calcd for
C14H10Cl2N2NaO 315.0062; Found 315.0071.
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2,4-dichloro-7-phenyl-5H-pyrano[2,3-d]pyrimidine (2r). White solid (186 mg 67% yield), 170.5-171.2 °C; H
NMR (600 MHz, Chloroform-d) δ 7.67 – 7.59 (m, 2H), 7.42 – 7.33 (m, 3H), 5.64 (t, J = 2.4 Hz, 1H), 3.52 (d, J =
4.2 Hz, 2H); 13C NMR (151 MHz, Chloroform-d) δ 166.3, 161.8, 157.9, 149.0, 131.6, 129.5, 128.6, 124.5, 110.4,
97.2, 22.5; HRMS (ESI-Q-TOF) m/z: [M + Na]+ Calcdfor C13H8Cl2N2NaO 300.9906; Found 300.9897.
2,4-dichloro-5-(furan-2-yl)-7-phenyl-5H-pyrano[2,3-d]pyrimidine (2s). White solid (262 mg, 76% yield),
m.p. 85.6-87.6 ˚C; 1H NMR (400 MHz, Chloroform-d) δ 7.76-7.66 (m, 2H), 7.43-7.37 (m, 3H), 7.33 (dd, J
= 0.8, 2.0 Hz, 1H), 6.34 (dd, J = 1.6, 3.2 Hz, 1H), 6.18 (d, J = 3.2 Hz, 1H), 5.83 (d, J = 4.8 Hz, 1H), 5.02 (d, J
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=5.2 Hz, 1H); C{1H} NMR (101 MHz, Chloroform-d) δ 165.4, 162.3, 157.9, 152.7, 148.5, 142.4, 131.1,
129.5, 128.4, 124.7, 111.0, 110.5, 107.2, 99.4, 32.6; HRMS (EI-Q-TOF) m/z: [M]+ Calcd for C17H10Cl2N2O2
344.0119; Found 344.0123.
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2,4-dichloro-7-phenyl-5-(thien-2-yl)-5H-pyrano[2,3-d]pyrimidine (2t). White solid (264 mg, 73% yield),
m.p. 85.6-87.6 ˚C; 1H NMR (400 MHz, Chloroform-d) δ 7.75-7.64 (m, 2H), 7.44-7.38 (m, 3H), 7.24 (dd, J
= 1.6, 5.2 Hz, 1H), 7.00-6.94 (m, 2H), 5.92 (d, J = 5.2 Hz, 1H), 5.19 (d, J = 5.2 Hz, 1H); 13C{1H} NMR (101
MHz, Chloroform-d) δ164.9, 162.3, 157.8, 147.8, 145.2, 131.2, 129.6, 128.5, 126.9, 125.7, 125.4, 124.8, 113.2,
102.2, 33.8; HRMS (EI-Q-TOF) m/z: [M]+ Calcd for C17H10Cl2N2OS 359.9891; Found 359.9885.
(E)-2,4-dichloro-7-styryl-5-(p-tolyl)-5H-pyrano[2,3-d]pyrimidine (2w). White solid (311.7 mg, 79%),
m.p. 158.0-158.4 °C; 1H NMR (600 MHz, Chloroform-d) δ 7.63 – 7.60 (dt, J = 8.4, 1.8 Hz, 2H), 7.38 – 7.34
(m, 2H), 7.31 – 7.25 (m, 4H), 7.23 (d, J = 7.8 Hz, 2H), 6.56 (d, J = 15.6 Hz, 1H), 6.20 (dd, J = 16.2, 7.8 Hz,
1H), 5.70 (d, J = 5.4 Hz, 1H), 4.46 (dd, J = 7.8, 5.4 Hz, 1H), 2.39 (s, 3H); 13C{1H} NMR (151 MHz, CDCl3)
δ 165.8, 162.5, 158.1, 148.8, 140.0, 136.2, 132.8, 129.5, 128.8, 128.8, 128.3, 127.8, 126.6, 124.8, 113.0, 99.9,
36.1, 21.5; HRMS (ESI-Q-TOF) m/z: [M + H]+ Calcd for C22H17Cl2N2O 395.0712; Found 395.0720.
(E)-2,4-dichloro-9-(4-methylbenzylidene)-5-(p-tolyl)-6,7,8,9-tetrahydro-5H-chromeno[2,3-
d]pyrimidine (2x). White solid (254.9 mg, 57%), m.p. 168.9-169.3 °C; 1H NMR (600 MHz, Chloroform-d)
δ 7.23 (d, J = 8.4 Hz, 2H), 7.19 (s, 1H), 7.16 (d, J = 8.4 Hz, 2H), 7.12 (s, 4H), 4.45 (s, 1H), 2.79 – 2.73 (m,
1H), 2.63 – 2.56 (m, 1H), 2.36 (s, 3H), 2.32 (s, 3H), 1.73 – 1.58 (m, 4H); 13C{1H} NMR (151 MHz, CDCl3)
δ 165.3, 162.1, 157.7, 142.5, 138.3, 137.7, 136.9, 134.1, 129.7, 129.5, 129.1, 128.6, 128.0, 124.4, 116.1, 114.3,
43.8, 27.5, 27.1, 22.3, 21.4, 21.2; HRMS (ESI-Q-TOF) m/z: [M + H]+ Calcd for C26H23Cl2N2O 449.1182;
Found 449.1174.
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General Procedure for the synthesis of 2,4-dichloro furo[2,3-d]pyrimidine. BTC (385 mg, 1.3 mmol in 5 mL
PhCl) was added to a stirred solution of TPPO (1112 mg, 4 mmol in 5 mL PhCl) dropwise under ice bath.
After complete addition, the mixture was stirred for 30 minutes at room temperature. Then 2-(2-oxo-2-
phenylethyl)malononitrile 3a (184 mg, 1 mmol) was added, and the mixture was heated to 110 °C until
completion of reaction (followed by TLC, n-hexane/ethyl acetate = 10/1). After cooling down, the mixture
was then pour in to the ice water, and extracted with dichloromethane, the organic layer was dried over
anhydrous Na2SO4, concentrated. After the concentration of organic layer extracted during the work-ups, the
residue was stirred vigorously in n-hexane (20 mL x 3) for 30 mins. Then, the remaining paste was
recrystallized using ethanol, which afford TPPO (676 mg, 81% recovery) as a white solid. The n-hexane
portion was then concentrated and purified over column chromatography (n-hexane/ethyl acetate = 10/1) to
afford the pure product: After cooling down, the mixture was then pour in to the ice water, and extracted with
dichloromethane, the organic layer was dried over anhydrous Na2SO4, concentrated and purified over column
chromatography (n-hexane/ethyl acetate = 10/1) to afford the pure product: 2,4-dichloro-6-phenylfuro[2,3-
d]pyrimidine (4a). White solid (213 mg, 81% yield), m.p. 173.2-174.7 ˚C; 1H NMR (400 MHz, Chloroform-
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d) δ 7.86 (dd, J = 1.7, 7.8 Hz, 2H), 7.65-7.42 (m, 3H), 7.05 (s, 1H); 13C{1H} NMR (101 MHz, Chloroform-
d) δ 166.8, 157.3, 153.6, 152.5, 130.6, 129.1, 127.5, 125.4, 118.4, 97.4; HRMS (ESI-Q-TOF) m/z: [M + Na]+
Calcd for C12H6Cl2N2NaO 286.9749; Found 286.9743.
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2,4-dichloro-6-(p-tolyl)furo[2,3-d]pyrimidine (4b). White solid (216 mg, 78%), m.p. 169.5-170.6 ˚C; H
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NMR (400 MHz, Chloroform-d) δ 7.74 (d, J = 8.2 Hz, 2H), 7.29 (d, J = 8.2), 6.97 (s, 1H), 2.43 (s, 3H);
13C{1H} NMR (101 MHz, Chloroform-d) δ 166.8, 157.6, 153.2, 152.2, 141.1, 129.8, 125.4, 124.7, 118.5, 96.5,
21.6; HRMS (ESI-Q-TOF) m/z: [M + H]+ Calcd for C13H9Cl2N2O 279.0086; Found 279.0099.
2,4-dichloro-6-(4-methoxyphenyl)furo[2,3-d]pyrimidine (4c). White solid (250 mg, 85% yield), m.p.
183.6-184.7 ˚C; 1H NMR (400 MHz, Chloroform-d) δ 7.80 (d, J = 8.9 Hz, 2H), 7.02 (d, J = 8.9 Hz, 2H), 6.89
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(s, 1H), 3.89 (s, 3H); C{1H} NMR (101 MHz, Chloroform-d) δ 166.3, 161.0, 157.0, 126.8, 119.9, 118.5,
114.4, 95.3, 55.6; HRMS (ESI-Q-TOF) m/z: [M + H]+ Calcd for C13H9Cl2N2O2 295.0036; Found 295.0025.
2,4-dichloro-6-(4-chlorophenyl)furo[2,3-d]pyrimidine (4d). Yellow solid (208 mg, 70% yield), m.p. 209.1-
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210.6 ˚C; H NMR (400 MHz, Chloroform-d) δ 7.80 (d, J = 8.5 Hz, 2H), 7.49 (d, J = 7.1 Hz, 2H), 7.05 (s,
1H); 13C{1H} NMR (101 MHz, Chloroform-d) δ 166.3, 155.6, 153.4, 152.3, 136.4, 129.1, 126.4, 125.8, 118.0,
97.7; HRMS (ESI-Q-TOF) m/z: [M + H]+ Calcd for C12H6Cl3N2O 298.9540; Found 298.9532.
2,4-dichloro-6-(4-fluorophenyl)furo[2,3-d]pyrimidine (4e). Orange solid (351 mg, 87%); m.p. 196.9-198.2
˚C; 1H NMR (400 MHz, Chloroform-d) δ 7.86 (dd, J = 5.2, 8.7 Hz, 2H), 7.20 (t, J = 8.5 Hz, 2H), 7.00 (s, 1H);
13C{1H} NMR (101 MHz, Chloroform-d) δ 166.2, 163.3 (d, 1JC-F = 250.5 Hz), 155.8, 153.2, 152.1, 127.3 (d,
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JC-F = 8.6 Hz), 123.6, 118.1, 116.2 (d, 2JC-F = 22.0 Hz) , 97.0; HRMS (ESI-Q-TOF) m/z: [M + H]+ Calcd for
C12H6Cl2FN2O 282.9836; Found 282.9822.
2,4-dichloro-5,6-diphenylfuro[2,3-d]pyrimidine (4f). White solid (285 mg, 84% yield), m.p. 121.7-123.9 ˚C;
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1H NMR (400 MHz, Chloroform-d) δ 7.58-7.40 (m, 7H), 7.39-7.27 (m, 3H); C{1H} NMR (101 MHz,
Chloroform-d) δ 165.5, 153.2, 152.6, 151.7, 131.8, 130.1, 129.6, 129.2, 128.5, 128.5, 128.3, 127.5, 126.8, 117.4,
114.7; HRMS (ESI-Q-TOF) m/z: [M + Na]+ Calcd for C18H10Cl2N2NaO 363.0062; Found 363.0086.
2,4-dichloro-6-(4-methoxyphenyl)-5-phenylfuro[2,3-d]pyrimidine (4g). White solid (318 mg, 86% yield),
m.p. 147.2-148.1 ˚C; 1H NMR (400 MHz, Chloroform-d) δ 7.54-7.38 (m, 7H), 6.83 (d, J = 8.6 Hz, 2H), 3.84
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(s, 3H); C{1H} NMR (101 MHz, Chloroform-d) δ 166.0, 160.8, 153.1, 152.4, 152.4, 130.6, 129.8, 128.8,
120.4, 118.0, 114.2, 113.1, 55.4; HRMS (ESI-Q-TOF) m/z: [M + Na]+ Calcd for C19H12Cl2N2NaO2 393.0168;
Found 393.0163.
2,4-dichloro-5-(2-chlorophenyl)-6-(4-methoxyphenyl)furo[2,3-d]pyrimidine (4h). White solid (311 mg,
77% yield), m.p. 148.2-149.7 ˚C; 1H NMR (400 MHz, Chloroform-d) δ 7.60 (d, J = 8.0 Hz, 1H) 7.52-7.43 (m,
3H), 7.39 (d, J = 4.8 Hz, 2H), 6.85 (d, J = 8.6 Hz, 2H), 3.82 (s, 3H); 13C{1H} NMR (101 MHz, Chloroform-
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d) δ 166.1, 161.0, 153.3, 152.8, 152.4, 135.4, 132.2, 130.5, 129.9, 129.3, 128.4, 127.2, 120.3, 117.9, 114.4, 110.1,
55.4; HRMS (ESI-Q-TOF) m/z: [M + Na]+ Calcd for C19H11Cl3N2NaO2 426.9778; Found 426.9783.
2,4-dichloro-5-(2-fluorophenyl)-6-(4-methoxyphenyl)furo[2,3-d]pyrimidine (4i). White solid (314 mg,
81% yield), m.p. 161.1-162.2 ˚C; 1H NMR (400 MHz, Chloroform-d) δ 7.53 - 7.47 (m, 3H), 7.39 (td, J = 7.5,
1.9 Hz, 1H), 7.30-7.21 (m, 2H), 6.85 (dt, J = 8.0, 2.2 Hz, 2H), 3.82 (s, 3H); 13C{1H} NMR 165.6, 161.3, 160.5,
158.8, 152.7, 151.9, 132.0, 130.9, 130.8, 128.2, 124.2, 120.0, 117.7, 117.5, 116.0, 115.7, 114.1, 106.3, 55.6;
HRMS(ESI-Q-TOF) m/z: [M + H]+ Calcd for C19H12Cl2FN2O2 389.0254; Found 389.0266.
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2,4-dichloro-6-phenylthieno[2,3-d]pyrimidine (5a). Brown oil (163 mg, 58% yield); H NMR (400 MHz,
Chloroform-d) δ 7.73-7.65 (m, 2H), 7.53 (s, 1H), 7.51-7.41 (m, 3H); 13C{H} NMR (101 MHz, Chloroform-
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d) δ C{1H} NMR (101 MHz, Chloroform-d) δ 169.0, 154.2, 153.3, 146.3, 131.8, 129.8, 129.5, 129.1, 126.5,
113.7; HRMS (ESI-Q-TOF) m/z: [M + H]+ Calcd for C12H7Cl2N2S 280.9702; Found 280.9688.
General Procedure for the In-situ 31P NMR test. The reaction was conducted in a standard 5 mm NMR
tube with D2O and phosphonic acid in an internal standard capillary. The signal was collected at 25 °C. The
reaction was performed under 0.05 mmol scale and heated outside the apparatus, which was sent to test at the
time designated on the spectrums. After the NMR test, the yield of 2a was about 40%.
Associate Content
The Supporting Information is available free of charge on the ACS Publications website at DOI: .
31P NMR study of low-temperature species, single crystal X-ray diffraction data for compound 2j, 1H and 13C
NMR spectrum for all compounds (PDF)
X-ray crystallographic data for compound 2j (CIF)
Author Information
Corresponding Authors
E-mail: lizhenhua@zjut.edu.cn.
E-mail: pharmlab@zjut.edu.cn.
Notes
The authors declare no competing financial interest.
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Acknowledgement
This work was supported by the National Natural Science Foundation of China (21376221, 21506190). J. Z.-
J. also thank the financial support from The Prominent Ph.D Thesis Supporting Project of Zhejiang University
of Technology. Dr. Jin-Ping Gu, Dr. Feng Su, and Mr. Ji-Peng Chen are thanked for X-ray crystallography and
31P NMR analysis. Prof. Wei-Hui Zhong, and Prof. Yi-Yi Weng of Zhejiang University of Technology are
thanked for helpful discussion. We thank anonymous reviewers for helpful suggestion on the earlier drafts of
the manuscript.
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References and Notes
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