Atom-economic synthesis of 4-pyrones from diynones and water

Article abstract of DOI:10.3390/molecules22010109

Transition-metal-free synthesis of 4-pyrones via TfOH-promoted nucleophilic addition/cyclization of diynones and water has been developed. This transformation is simple, atom economical and environmentally benign, providing rapid and efficient access to s

Full text of DOI:10.3390/molecules22010109

molecules
Communication
Atom-Economic Synthesis of 4-Pyrones from
Diynones and Water
Yan-Li Xu 1,†, Qing-Hu Teng 2,†, Wei Tong 2, Heng-Shan Wang 2, Ying-Ming Pan 2,* and
Xian-Li Ma 1,
*
1
College of Pharmacy, Guilin Medical University, Guilin 541004, China; yanlixu@163.com
State Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources,
School of Chemistry and Pharmaceutical Sciences of Guangxi Normal University, Guilin 541004, China;
qinghuteng@163.com (Q.-H.T.); m18778391736@163.com (W.T.); whengshan@163.com (H.-S.W.)
Correspondence: panym2013@hotmail.com (Y.-M.P.); mxl78@glmc.edu.cn (X.-L.M.);
Tel.: +86-773-584-6279 (Y.-M.P.); Fax: +86-773-5803930 (Y.-M.P.); +86-773-5893619 (X.-L.M.)
These authors contributed equally to this work.
2
*
†
Academic Editor: Georgiy B. Shul’pin
Received: 21 December 2016; Accepted: 5 January 2017; Published: 10 January 2017
Abstract: Transition-metal-free synthesis of 4-pyrones via TfOH-promoted nucleophilic addition/
cyclization of diynones and water has been developed. This transformation is simple, atom
economical and environmentally benign, providing rapid and efficient access to substituted 4-pyrones.
Keywords: 4-pyrones; diynones; water; transition-metal-free
1. Introduction
Water (H2O) is inexpensive, safe, and environmentally friendly [
eco-friendly solvent available in Nature and therefore highly desirable for chemical reactions [
Generally, water offers several “green chemistry” benefits as a solvent in organic transformations,
including high efficiency, lower cost, ease of process, green and environmental protection [ ].
Recently, there are many reports of clean transformations in water medium [ 19], such as
coupling reactions [20 30], cyclizations [31 34], Michael additions [35 39], and condensations [40 41].
Additionally, H2O also participates in organic reactions as a nucleophile [42 43] to provide various
kinds of functional compounds such as imidazo[1,2-a]pyridines [44], amino acid salts [45], -amino
1
]. It is the most economic and
2].
3,4
5–
–
–
–
,
,
α
ketones [46], and 1,3-oxazinan-2-ones [47]. Thus, the studies of organic reactions in aqueous solvents
or H2O-participating reactions are attractive in synthetic chemistry.
4-Pyrones are heterocycles with multiple biological activities [48
in biologically active natural products and functional chemicals [51
funicones and rapicones possess potent anti-HIV activity (Figure 1) [60
are prepared via the well-known condensation cyclization reaction of carbonyl compounds with
polystep reactions [63 67]. Additionally, a transformation of isoxazoles to substituted pyran-4-ones
–
–
50], which are widely found
59]. Particularly, phenoxans,
62]. In general, 4-pyrones
–
–
in the presence of Mo(CO)6 and HCO2H in a two-step procedure was established [68]. Although
these reported methods have made significant contributions to the applications of 4-pyrones in
pharmacology and food manufacture [69], the development of efficient and practical synthetic methods
for 4-pyrones from easily accessible starting materials is still highly desirable. Continuing our interest
in the conversion of alkynes to heterocycles [70–77], herein, we would like to describe an efficient,
transition-metal-free synthesis of 4-pyrones through TfOH-promoted cyclization of diynones. Water
acts as both the substrate and solvent, obviating the need for an organic co-solvent. Overall, the reaction
is atom-economical and environmentally benign.
Molecules 2017, 22, 109; doi:10.3390/molecules22010109
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Figure 1. 4-Pyrones disclosed as biologically active organic molecules.
2. Results and Discussion
1,5-Diphenylpenta-1,4-diyn-3-one (1a) was chosen as model substrate to identify the optimal
conditions for this reaction (Table 1). Originally, the reaction was carried out in the presence of 1 equiv.
TfOH for 24 h to afford the desired product 2a in 70% yield (Table 1, entry 1). When other acid catalysts
such as CH3COOH, PTSA, HCl, H3PO4 and PhCOOH were screened, the yield of 2a decreased (Table 1,
entries 2–6). Further experiments demonstrated that decreasing the amount of TfOH was detrimental
to the yield of 2a (Table 1, entries 7 and 8), and no obvious improvement of yield was noted by using
2 equiv. of TfOH (Table 1, entry 9). Poor yield of 2a was obtained when the reaction was performed
at 80 ◦C, while not much change was noted between 100 ◦C and 130 ◦C (Table 1, entries 10 and 11).
In addition, an 83% yield was achieved when the reaction time was extended to 36 h (Table 1, entry 12).
Thus, the best conditions for this transformation involved 1 equiv. of TfOH in H2O at 100 ◦C for 36 h.
Table 1. Optimization of reaction conditions a.
Yield (%) b
Entry
Catalyst
Time (h)
1
2
3
4
5
TfOH
CH3COOH
PTSA
24
24
24
24
24
24
24
24
24
24
24
36
70
0
50
0
HCl
H3PO4
PhCOOH
TfOH
TfOH
TfOH
TfOH
TfOH
TfOH
0
6
10
10
50
80
20
75
83
b
7 c
8 d
9 e
10 f
11 g
12
Reaction conditions: 1a (0.5 mmol), catalyst (1 equiv.), H2O (1 mL), at 100 ◦C; Isolated yields; TfOH
a
c
(0.2 equiv.); d TfOH (0.5 equiv.); e TfOH (2 equiv.); f At 80 ◦C; g The reaction was carried out in a sealed tube at
130 ◦C.
Under the optimized reaction conditions, the one-pot reaction worked well using all kinds of
diynones, as shown in Scheme 1. Firstly, various symmetric diynones were identified as suitable
substrates for the reaction and provided the desired products in moderate to good yields (Scheme 1,
2b
and 2f
yields (Scheme 1, 2e). Gratifyingly, aliphatic diynones worked smoothly to generate the corresponding
–2j). Aryl groups with electron-donating groups (EDG) gave satisfactory yields (Scheme 1, 2b
–2d
–
2h), whereas aryl groups with electron-withdrawing groups (EWG) afforded slightly lower

Molecules 2017, 22, 109
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cyclization products 2i and 2j in 50% and 57%, respectively (Scheme 1, 2i and 2j). After exploring the
reaction substrate scope of symmetric diynones, we next examined asymmetric diynones substrates.
To our delight, the corresponding 4-pyrones products were obtained in moderate to good yields
under the standard conditions (Scheme 1, 2k
55%–78% yields when asymmetric diynones substrates 1k
–
2r). The desired products 2k
–2q were obtained in
–
1q (R2 = Ph, R1 = aryl- or alkyl-) were
subjected to this reaction. Obviously, aryl groups with electron-donating groups gave higher yields
than diynones featuring electron-withdrawing groups on the phenyl ring (Scheme 1, 2l and 2m vs.
2n and 2p). Notably, diynone 1p, which possess an electron-withdrawing group at the ortho-position
of the phenyl ring (R1 = 2-Cl-Ph, R2 = Ph) reacted readily to afford 2p in 61% yield (Scheme 1, 2p).
Furthermore, diynone 1q, which bear both a EDG-incorporated aryl ring and a EWG-incorporated
aryl ring (R1 = 4-OMe-Ph, R2 = 4-F-Ph) also participated well in the reaction and offered 2q in 63%
yield (Scheme 1, 2q). Finally, diynone 1r also worked smoothly to give 2r in 50% yield (Scheme 1, 2r).
O
O
TfOH (1 equiv.)
H2O, 100 o
C
R1
R2
R1
O
R2
1
2
O
O
O
O
O
O
R1
O
R1
R1
O
R1
R1
R1
R1
R1
R1 = 4-Me-Ph
R1 = 4-tBu-Ph
R1 = 4-F-Ph
R1 = 4-OMe-Ph
2b 85%
2d 86%
2e 60%
2c 81%
O
O
O
O
R1
O
R1
R1
O
R1
R1
O
R1
R1
O
R1
R1 = n-Pr
2i 50%
R1 = 3-Me-Ph
R1 = 4-nPentyl-Ph
R1 = 4-Et-Ph
2h 73%
2f 84%
2g 82%
O
O
O
O
O
R1
O
R2
R1
O
R2
R1
O
R2
R1 = 4-OMe-Ph
R2 = Ph
R1 = 4-Me-Ph
R2 = Ph
R1 = n-Pr
R2 = Ph
2k 78%
2j 57%
2m 70%
2l 65%
O
O
O
O
O
O
R1
R2
O
R2
R1
R1 = 4-OMe-Ph
R2
4-F-Ph
2q 63%
O
R2
R1
O
R2
O
Ph
R1 = 2-Cl-Ph
R2 = Ph
R2 = Ph
R1 = 4-F-Ph
R2 = Ph
2r 50%
2o 55%
=
2p 61%
2n 58%
a
Scheme 1. Synthesis of 4-pyrone derivatives a,b
.
Reaction conditions:
1
(0.5 mmol), TfOH (1 equiv.),
◦
H2O (1 mL), at 100 C, 36 h; b Isolated yields.
To better understand the reaction mechanism, we carried out control experiments as outlined
in Scheme 2. Deuterium-labeled D2O was used in the reaction with diynone 1a to give the
deuterium-labeled product 2a-d in 80% yield, where over 95% of deuterium was incorporated into the
cyclization product.
This result demonstrated that H2O was introduced into the 4-pyrones. Moreover, an O18-labeled
experiment further showed that H2O reacted with diynones to form 4-pyrones.
On the basis of the above results and existing literature [78], a plausible mechanistic description
of the nucleophilic addition and cyclization reaction is shown in Scheme 3. First, the carbonyl of
the diynone substrate was activated by TfOH, followed by nucleophilic addition of H2O to the
carbon
Then intermediate
promoted by elevated temperature. Subsequently, an intramolecular nucleophilic attack of the oxhydryl
group to the carbon carbon triple bond of lead to a cyclization intermediate . Finally, deprotonation
of C gave the desired 4-pyrone 2.
−
carbon triple bond of diynone and keto–enol tautomerization [79
,80] to form intermediate A.
A
was converted to through protonation and C–C bond rotation, which was
B
−
B
C

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Scheme 2. Control experiments.
Scheme 3. Proposed mechanism.
The treatment of 1,5-diphenylpenta-1,4-diyn-3-one 1a in H2O at 100 ◦C for 36 h in the presence
of TfOH afforded the corresponding cyclization product 2a in 83% yield. The preparation of this
compound 2a on gram-scale afforded 53% of the isolated product (Scheme 4).
Scheme 4. Gram-scale synthesis.
3. Materials and Methods
3.1. General Information
All manipulations were performed under an air atmosphere unless otherwise stated. Column
chromatography was performed on silica gel (300–400 mesh). NMR spectra were obtained using

Molecules 2017, 22, 109
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an Avance 500 spectrometer (1H at 500 MHz and 13C at 125 MHz) or an Avance 400 spectrometer
(1H at 400 MHz and 13C at 100 MHz) (Bruker Corporation, Karlsruhe, Germany). IR spectra were
recorded on a Nicolet ESP 360 FT-IR spectrometer (Nicolet, Madison, WI, USA) and only major peaks
are reported in cm−1. High resolution mass spectra (HRMS) were recorded on an Exactive Mass
Spectrometer (Thermo Fisher Scientific, Waltham, MA, USA) equipped with ESI or APCI ionization
sources. Unless stated otherwise, commercial reagents were used without further purification. All
reagents were weighed and handled at room temperature. Compounds 1a–1r were prepared by the
reported methods [78 81]. The NMR spectra and HRMS spectra of the products can be found in the
,
Supplementary Materials.
3.2. General Procedure for the Synthesis of Compound 2
The reaction mixture of
stirred at 100 ◦C for 36 h, and monitored periodically by TLC. Upon completion, the reaction mixture
was diluted with water (5 mL) and extracted with ethyl acetate (3 5 mL). The combined organic
1 (0.5 mmol), TfOH (1 equiv.) and H2O (1 mL) in a 15 mL test tube was
×
layers were washed with water and brine, dried over MgSO4 and filtered. The solvent was removed
under vacuum. The residue was purified by flash column chromatography (petroleum ether and ethyl
acetate, v/v = 5:1 to 2:1) to afford 4-pyrones 2 (Scheme 5).
Scheme 5. Synthesis of Compounds 2.
2,6-Diphenyl-4H-pyran-4-one (2a) [82]. The general procedure was used with 1,5-diphenylpenta-
1,4-diyn-3-one (115.04 mg, 0.5 mmol, 1 equiv.) and water (1 mL). The crude obtained was purified by
column chromatography (petroleum ether/ethyl acetate = 5:1 to 2:1) to afford the product as a yellow
solid (102.90 mg, 83%); m.p. 135.3–136.2 ◦C (lit: 139–140 ◦C); 1H-NMR (500 MHz, CDCl3)
δ
7.89–7.82
(m, 4H), 7.55–7.50 (m, 6H), 6.81 (s, 2H) ppm; 13C-NMR (125 MHz, CDCl3)
δ 180.2, 163.3, 131.4, 131.4,
129.1, 125.9, 111.4 ppm; IR (KBr): 3060, 2925, 1647, 1614, 1604, 1493, 1450, 1392, 943, 770, 683 cm−1
;
HRMS (m/z) (APCI): calcd. for C17H13O2 249.0917 [M + H+]; found 249.0906.
2,6-Di-p-tolyl-4H-pyran-4-one (2b) [78]. The general procedure was used with 1,5-di-p-tolylpenta-
1,4-diyn-3-one (129.05 mg, 0.5 mmol, 1 equiv.) and water (1 mL). The crude obtained was purified
by column chromatography (petroleum ether/ethyl acetate = 5:1 to 2:1) to afford the product as a
yellow solid (117.35 mg, 85%); m.p. 180.5–183.1 ◦C (lit: 178 ◦C); 1H-NMR (500 MHz, CDCl3)
δ
7.74
(d, J = 8.2 Hz, 42H), 7.32 (d, J = 8.0 Hz, 4H), 6.76 (s, 2H), 2.43 (s, 6H) ppm; 13C-NMR (125 MHz, CDCl3)
δ
180.4, 163.4, 141.9, 129.8, 128.7, 125.8, 110.7, 21.5 ppm; IR (KBr): 3066, 1646, 1605, 1507, 1413, 1383,
942, 819, 478 cm−1; HRMS (m/z) (APCI): calcd. for C19H17O2 277.1230 [M + H+]; found 277.1219.
2,6-Bis(4-methoxyphenyl)-4H-pyran-4-one (2c) [82]. The general procedure was used with 1,5-bis
(4-methoxyphenyl)penta-1,4-diyn-3-one (145.05 mg, 0.5 mmol, 1 equiv.) and water (1 mL). The crude
obtained was purified by column chromatography (petroleum ether/ethyl acetate = 5:1 to 2:1) to afford
◦
◦
the product as a yellow solid (124.78 mg, 81%); m.p. 190–193.8 C (lit: 189–191 C); 1H-NMR (500 MHz,
CDCl3)
(125 MHz, CDCl3)
δ
7.79 (d, J = 8.9 Hz, 4H), 7.02 (d, J = 8.9 Hz, 4H), 6.70 (s, 2H), 3.88 (s, 6H) ppm; 13C-NMR
163.2, 162.1, 134.4, 127.5, 123.9, 114.5, 109.7, 55.5 ppm; IR (KBr): 2983, 2875, 2765,
1651, 1607, 1507, 1387, 1262, 1226, 1177, 1020, 829 cm−1; HRMS (m/z) (APCI): calcd. for C19H17O4
δ
309.1129 [M + H+]; found 309.1115.
2,6-Bis(4-(tert-butyl)phenyl)-4H-pyran-4-one (2d) [82]. The general procedure was used with 1,5-bis(4-
(tert-butyl)phenyl)penta-1,4-diyn-3-one (171.10 mg, 0.5 mmol, 1 equiv.) and water (1 mL). The crude

Molecules 2017, 22, 109
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obtained was purified by column chromatography (petroleum ether/ethyl acetate = 5:1 to 2:1) to
afford the product as a yellow solid (154.89 mg, 86%); m.p. 192.5–193.1 ◦C (lit: 192–194 ◦C); 1H-NMR
(500 MHz, CDCl3)
δ 7.79 (d, J = 7.2 Hz, 4H), 7.54 (d, J = 7.4 Hz, 4H), 6.81 (s, 2H), 1.36 (s, 18H) ppm;
13C-NMR (125 MHz, CDCl3)
δ
180.5, 163.5, 155.0, 128.6, 126.0, 125.7, 34.9, 31.0 ppm; IR (KBr): 3064,
3003, 2998, 2970, 2868, 1715, 1667, 1650, 1450, 1340, 1250, 910 cm−1; HRMS (m/z) (APCI): calcd. for
C25H29O2 361.2169 [M + H+]; found 361.2153.
2,6-Bis(4-fluorophenyl)-4H-pyran-4-one (2e) [82]. The general procedure was used with 1,5-bis
(4-fluorophenyl)penta-1,4-diyn-3-one (133.12 mg, 0.5 mmol, 1 equiv.) and water (1 mL). The crude
obtained was purified by column chromatography (petroleum ether/ethyl acetate = 5:1 to 2:1) to
◦
◦
afford the product as a white solid (85.22 mg, 60%); m.p. 160–161.3 C (lit: 167–170 C); 1H-NMR
(500 MHz, CDCl3)
(125 MHz, CDCl3)
δ
7.84 (dd, J = 8.5, 5.2 Hz, 4H), 7.22 (t, J = 8.4 Hz, 4H), 6.75 (s, 2H) ppm; 13C-NMR
179.9, 164.6 (d, J = 253.4 Hz), 162.5, 128.1 (d, J = 8.8 Hz), 127.6 (d, J = 3.3 Hz),
δ
116.5(d, J = 22.2 Hz), 111.3 ppm; IR (KBr): 3059, 2924, 1662, 1599, 1504, 1417, 1380, 1241, 1223, 1160,
837 cm−1; HRMS (m/z) (APCI): calcd. for C17H11F2O2 285.0729 [M + H+]; found 285.0716.
2,6-Bis(4-pentylphenyl)-4H-pyran-4-one (2f). The general procedure was used with 1,5-bis(4-pentylphenyl)
penta-1,4-diyn-3-one (185.11 mg, 0.5 mmol, 1 equiv.) and water (1 mL). The crude obtained was
purified by column chromatography (petroleum e◦ther/ethyl acetate = 5:1 to 2:1) to afford the product
δ 7.76 (d, J = 8.1 Hz,
as a yellow solid (163.06 mg, 84%); m.p. 66.7–67.9 C; 1H-NMR (500 MHz, CDCl3)
4H), 7.32 (d, J = 8.1 Hz, 4H), 6.77 (s, 2H), 2.70–2.66 (m, 4H), 1.69–1.61 (m, 4H), 1.36–1.33 (m, 8H), 0.90
(t, J = 6.9 Hz, 6H) ppm; 13C-NMR (125 MHz, CDCl3)
δ
180.5, 163.5, 146.9, 129.2, 128.9, 125.9, 110.7, 35.8,
31.4, 30.8, 22.5, 13.9 ppm; IR (KBr): 3032, 2956, 2929, 2857, 1717, 1649, 1609, 1419, 1380, 1186, 944, 849,
649 cm−1; HRMS (m/z) (APCI): calcd. for C27H33O2 389.2482 [M + H+]; found 389.2466.
2,6-Bis(4-ethylphenyl)-4H-pyran-4-one (2g) [78]. The general procedure was used with 1,5-bis(4-ethylphenyl)
penta-1,4-diyn-3-one (143.07 mg, 0.5 mmol, 1 equiv.) and water (1 mL). The crude obtained was
purified by column chromatography (petroleum ether/ethyl acetate = 5:1 to 2:1) to afford the product
◦
as a brown solid (124.70 mg, 82%); m.p. 119.5–121.5 C; 1H-NMR (500 MHz, CDCl3)
δ
7.77 (d, J = 8.1 Hz,
4H), 7.34 (d, J = 8.1 Hz, 4H), 6.77 (s, 2H), 2.72 (q, J = 7.6 Hz, 4H), 1.28 (t, J = 7.6 Hz, 6H) ppm; 13C-NMR
(125 MHz, CDCl3) δ 180.4, 163.5, 148.2, 128.9, 128.6, 125.9, 110.6, 28.8, 15.2 ppm; IR (KBr): 3070, 2965,
2875, 1647, 1610, 1510, 1451, 1420, 1383, 1187, 1014, 945, 837, 643 cm−1; HRMS (m/z) (APCI): calcd. for
C21H21O2 305.1543 [M + H+]; found 305.1532.
2,6-Di-m-tolyl-4H-pyran-4-one (2h) [78]. The general procedure was used with 1,5-di-m-tolylpenta-
1,4-diyn-3-one (129.05 mg, 0.5 mmol, 1 equiv.) and water (1 mL). The crude obtained was purified by
column chromatography (petroleum ether/ethyl acetate = 5:1 to 2:1) to afford the product as a light
◦
yellow solid (100.78 mg, 73%); m.p. 73.5–75.5 C; 1H-NMR (500 MHz, CDCl3)
δ
7.66–7.62 (t, J = 7.6 Hz,
4H), 7.41 (t, J = 7.6 Hz, 2H), 7.34 (d, J = 7.6 Hz, 2H), 6.78 (s, 2H), 2.45 (s, 6H) ppm; 13C-NMR (125 MHz,
CDCl3)
δ 163.6, 138.9, 132.1, 131.4, 129.0, 126.5, 123.1, 111.3, 21.5 ppm; IR (KBr): 3063, 2923, 1646, 1611,
1485, 1384, 1260, 1075, 929, 784, 694, 435 cm−1; HRMS (m/z) (APCI): calcd. for C19H17O2 277.1230
[M + H+]; found 277.1219.
2,6-Dipropyl-4H-pyran-4-one (2i) [78]. The general procedure was used with undeca-4,7-diyn-6-one
(81.05 mg, 0.5 mmol, 1 equiv.) and water (1 mL). The crude obtained was purified by column
chromatography (petroleum ether/ethyl acetate = 5:1 to 2:1) to afford the product as a brown oil
(45.03 mg, 50%); 1H-NMR (500 MHz, CDCl3)
δ 6.05 (s, 1H), 2.44 (t, J = 7.5 Hz, 4H), 1.69–1.61 (m, 4H),
0.95 (td, J = 7.4, 1.1 Hz, 6H) ppm; 13C-NMR (125 MHz, CDCl3)
δ 180.6, 169.1, 113.0, 35.4, 20.1, 13.3 ppm;
IR (KBr): 3437, 2965, 2875, 1663, 1619, 1411, 1398, 1148, 933, 864 cm−1; HRMS (m/z) (APCI): calcd. for
C11H14O2 181.1230 [M + H+]; found 181.1221.
2,6-Dicyclopropyl-4H-pyran-4-one (2j) [78]. The general procedure was used with 1,5-dicyclopropylpenta-
1,4-diyn-3-one (79.04 mg, 0.5 mmol, 1 equiv.) and water (1 mL). The crude obtained was purified by
column chromatography (petroleum ether/ethyl acetate = 5:1 to 2:1) to afford the product as a white

Molecules 2017, 22, 109
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solid (50.19 mg, 57%); m.p. 146.7–150.7 ◦C; 1H-NMR (500 MHz, CDCl3)
δ
6.04 (s, 2H), 1.72 (tt, J = 8.3,
5.0 Hz, 2H), 1.00–0.95 (m, 4H), 0.92–0.88 (m, 4H) ppm; 13C-NMR (125 MHz, CDCl3)
δ 179.5, 168.6,
111.1, 13.7, 7.8 ppm; IR (KBr): 3045, 3010, 2955, 1655, 1602, 1586, 1401, 1095, 1053, 858 cm−1; HRMS
(m/z) (APCI): calcd. for C11H13O2 177.0917 [M + H+]; found 177.0908.
2-Phenyl-6-propyl-4H-pyran-4-one (2k) [78]. The general procedure was used with 1-phenylocta-
1,4-diyn-3-one (98.04 mg, 0.5 mmol, 1 equiv.) and water (1 mL). The crude obtained was purified by
column chromatography (petroleum ether/ethyl acetate = 5:1 to 2:1) to afford the product as a brown
solid (83.50 mg, 78%); m.p. 49.8–51.5 ◦C; 1H-NMR (500 MHz, CDCl3)
δ
7.75 (dd, J = 7.7, 1.8 Hz, 1H),
7.51–7.46 (m, 1H), 6.72 (s, 1H), 6.19 (s, 1H), 2.60 (t, J = 7.5 Hz, 1H), 1.82–1.73 (m, 1H), 1.03 (t, J = 7.4 Hz,
1H) ppm; 13C-NMR (125 MHz, CDCl3)
δ 180.1, 168.8, 163.6, 131.5, 131.3, 129.0, 125.8, 114.0, 111.1, 35.6,
20.3, 13.5 ppm; IR (KBr): 3060, 2926, 1653, 1617, 1493, 1450, 1409, 1061, 937, 866, 772, 691 cm−1; HRMS
(m/z) (APCI): calcd. for C14H15O2 215.1074 [M + H+]; found 215.1065.
2-Phenyl-6-(p-tolyl)-4H-pyran-4-one (2l) [83]. The general procedure was used with 1-phenyl-5-(p-tolyl)
penta-1,4-diyn-3-one (112.04 mg, 0.5 mmol, 1 equiv.) and water (1 mL). The crude obtained was
purified by column chromatography (petroleum ether/ethyl acetate = 5:1 to 2:1) to afford the product
as a yellow solid (85.18 mg, 65%); m.p. 155.1–156.4 ◦C (lit: 150 ◦C); 1H-NMR (500 MHz, CDCl3)
δ
7.88–7.83 (m, 2H), 7.75 (d, J = 8.2 Hz, 2H), 7.54–7.51 (m, 3H), 7.32 (d, J = 8.1 Hz, 2H), 6.83–6.78 (m, 2H),
2.44 (s, 3H) ppm; 13C-NMR (125 MHz, CDCl3)
180.4, 163.6, 163.3, 142.0, 131.5, 131.4, 129.8, 129.1,
δ
128.6, 125.91, 125.86, 111.3, 110.7, 21.5 ppm; IR (KBr): 3064, 2922, 2854, 1646, 1606, 1448, 1413, 1387, 943,
816 cm−1; HRMS (m/z) (APCI): calcd. for C18H15O2 263.1074 [M + H+]; found 263.1061.
2-(4-Methoxyphenyl)-6-phenyl-4H-pyran-4-one (2m) [78]. The general procedure was used with
1-(4-methoxyphenyl)-5-phenylpenta-1,4-diyn-3-one (130.04 mg, 0.5 mmol, 1 equiv.) and water (1 mL).
The crude obtained was purified by column chromatography (petroleum ether/ethyl acetate = 5:1 to
2:1) to afford the product as a brown solid (97.33 mg, 70%); m.p. 161.3–162.2 ◦C (lit: 162 ◦C); 1H-NMR
(500 MHz, CDCl3)
δ 7.82 (dd, J = 6.6, 3.0 Hz, 2H), 7.78 (d, J = 8.9 Hz, 2H), 7.50 (dd, J = 5.0, 1.7 Hz, 3H),
7.00 (d, J = 8.9 Hz, 2H), 6.76 (d, J = 1.7 Hz, 1H), 6.70 (d, J = 1.7 Hz, 1H), 3.86 (s, 3H) ppm; 13C-NMR
(125 MHz, CDCl3)
δ 180.2, 163.3, 163.0, 162.2, 131.5, 131.2, 129.0, 127.5, 125.8, 123.6, 114.5, 111.1, 109.8,
55.4 ppm; IR (KBr): 3443, 3067, 2900, 2843, 1647, 1604, 1509, 1448, 1423, 1383, 1023, 832, 767, 684 cm−1
;
HRMS (m/z) (APCI): calcd. for C18H15O3 279.1014 [M + H+]; found 279.1013.
2-(4-Fluorophenyl)-6-phenyl-4H-pyran-4-one (2n). The general procedure was used with 1-(4-fluorophenyl)-
5-phenylpenta-1,4-diyn-3-one (124.03 mg, 0.5 mmol, 1 equiv.) and water (1 mL). The crude obtained
was purified by column chromatography (petroleum ether/ethyl acetate = 5:1 to 2:1) to afford the
◦
product as a yellow solid (77.16 mg, 58%); m.p. 145.5–150.6 C; 1H-NMR (500 MHz, CDCl3)
δ
7.89–7.82
(m, 4H), 7.56–7.51 (m, 3H), 7.22 (t, J = 8.5 Hz, 2H), 6.82 (d, J = 1.8 Hz, 1H), 6.77 (d, J = 1.8 Hz, 1H) ppm;
13C-NMR (125 MHz, CDCl3)
180.1, 165.6, 163.6, 163.4, 162.5, 131.5, 131.3, 129.2, 128.1 (d, J = 8.9 Hz),
δ
127.6, 125.9, 116.4 (d, J = 22.1 Hz), 111.3 (d, J = 24.2 Hz) ppm; IR (KBr): 3061, 2924, 1659, 1505, 1508,
1417, 1449, 1388, 1232, 1162 cm−1; HRMS (m/z) (APCI): calcd. for C17H12FO2 267.0823 [M + H+];
found 267.0813.
2-Cyclopropyl-6-phenyl-4H-pyran-4-one (2o) [84]. The general procedure was used with 1-cyclopropyl-
5-phenylpenta-1,4-diyn-3-one (97.04 mg, 0.5 mmol, 1 equiv.) and water (1 mL). The crude obtained was
purified by column chromatography (petroleum ether/ethyl acetate = 5:1 to 2:1) to afford the product
as a yellow solid (58.33 mg, 55%); m.p. 106.5–107.8 ◦C (lit: 106 ◦C); 1H-NMR (500 MHz, CDCl3)
δ
7.67
(dd, J = 7.9, 1.7 Hz, 2H), 7.50–7.45 (m, 3H), 6.69 (d, J = 2.1 Hz, 1H), 6.23 (d, J = 2.1 Hz, 1H), 1.90 (tt,
J = 7.9, 5.4 Hz, 1H), 1.12 (tt, J = 4.7, 2.5 Hz, 4H) ppm; 13C-NMR (125 MHz, CDCl3)
179.8, 169.5, 162.7,
δ
131.3, 131.2, 129.0, 125.6, 111.6, 111.0, 14.1, 8.5 ppm; IR (KBr): 3059, 2927, 1651, 1609, 1544, 1496, 1448,
1394, 1253, 1193, 1087, 931, 878, 766, 685 cm−1; HRMS (m/z) (APCI): calcd. for C14H13O2 213.0917
[M + H+]; found 213.0908.

Molecules 2017, 22, 109
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2-(2-Chlorophenyl)-6-phenyl-4H-pyran-4-one (2p) [85]. The general procedure was used with
1-(2-chlorophenyl)-5-phenylpenta-1,4-diyn-3-one (132.02 mg, 0.5 mmol, 1 equiv.) and water (1 mL).
The crude obtained was purified by column chromatography (petroleum ether/ethyl acetate = 5:1
to 2:1) to afford the product as a yellow solid (86.03 mg, 61%); m.p. 123.5–124.6 ◦C (lit: 122–124 ◦C);
1H-NMR (400 MHz, CDCl3)
7.52–7.48 (m, 2H), 7.48–7.46 (m, 1H), 7.44 (dd, J = 6.6, 1.7 Hz, 1H), 7.41 (dd, J = 7.4, 1.4 Hz, 1H), 6.86 (d,
J = 2.2 Hz, 1H), 6.67 (d, J = 2.2 Hz, 1H) ppm; 13C-NMR (100 MHz, CDCl3)
178.0, 164.1, 162.6, 132.8,
δ 7.86–7.81 (m, 2H), 7.60 (dd, J = 7.5, 1.8 Hz, 1H), 7.57–7.54 (m, 1H),
δ
131.9, 131.5, 131.4, 131.2, 130.9, 130.7, 129.1, 127.2, 126.0, 116.8, 111.2 ppm; IR (KBr): 3059, 2931, 1667,
1650, 1600, 1580, 1403, 1250, 1000, 910, 665 cm−1; HRMS (m/z) (ESI): calcd. for C17H12ClO2 283.0528
[M + H+]; found 283.0513.
2-(4-Fluorophenyl)-6-(4-methoxyphenyl)-4H-pyran-4-one (2q) [85]. The general procedure was used with
1-(4-fluorophenyl)-5-(4-methoxyphenyl)penta-1,4-diyn-3-one (139.04 mg, 0.5 mmol, 1 equiv.) and
water (1 mL). The crude obtained was purified by column chromatography (petroleum ether/ethyl
◦
acetate = 5:1 to 2:1) to afford the product as a yellow solid (93.27 mg, 63%); m.p. 138.7–140.5 C
◦
(lit: 144–148 C); 1H-NMR (400 MHz, CDCl3)
δ
7.86–7.82 (m, 2H), 7.80–7.77 (m, 2H), 7.27–7.18 (m, 2H),
7.05–7.00 (m, 2H), 6.72 (dd, J = 3.7, 1.9 Hz, 2H), 3.89 (s, 3H) ppm; 13C-NMR (100 MHz, CDCl3)
δ
180.2,
165.8, 163.4, 163.3, 162.2 (d, J = 8.9 Hz), 128.1 (d, J = 8.8 Hz), 127.8 (d, J = 3.3 Hz), 127.6, 123.6, 116.4
(d, J = 22.1 Hz), 114.6, 111.0, 109.9, 55.5 ppm; IR (KBr): 3673, 3067, 2969, 1657, 1610, 1509, 1422, 1385,
1270, 1227, 1169, 1074, 1021, 841 cm−1; HRMS (m/z) (ESI): calcd. for C18H14FO3 297.0929 [M + H+];
found 297.0913.
2-Phenyl-4H-pyran-4-one (2r) [86]. The general procedure was used with 1-phenylpenta-1,4-diyn-3-one
(77.02 mg, 0.5 mmol, 1 equiv.) and water (1 mL). The crude obtained was purified by column
chromatography (petroleum ether/ethyl acetate = 5:1 to 2:1) to afford the product as a yellow solid
◦
◦
(43.02 mg, 50%); yellow solid; m.p. 102.2–103.5 C (lit: 100–102 C); 1H-NMR (400 MHz, CDCl3)
δ
7.84
(d, J = 5.8 Hz, 1H), 7.74 (dd, J = 7.9, 1.7 Hz, 2H), 7.51–7.44 (m, 3H), 6.78 (d, J = 2.3 Hz, 1H), 6.38 (dd,
J = 5.8, 2.3 Hz, 1H) ppm; 13C-NMR (100 MHz, CDCl3)
179.0, 163.9, 154.8, 131.4, 131.0, 129.0, 125.7,
δ
117.0, 112.3 ppm; IR (KBr): 3090, 1675, 1650, 1590, 1549, 1490, 1450, 1402, 1350, 1050, 931, 875, 795, 730,
650 cm−1; HRMS (m/z) (ESI): calcd. for C11H9O2 173.0604 [M + H+]; found 173.0603.
3.3. Control Experiments
3.3.1. Deuterium Labeling Experiments
The reaction mixture of
stirred at 100 ◦C for 36 h, and monitored periodically by TLC. Upon completion, the reaction mixture
was diluted with water (5 mL) and extracted with ethyl acetate (3 5 mL). The combined organic
1 (0.5 mmol), TfOH (1 equiv.), and D2O (1 mL) in a 15 mL test tube was
×
layers were washed with water and brine, dried over MgSO4 and filtered. The solvent was removed
under vacuum. The residue was purified by flash column chromatography (petroleum ether and ethyl
◦
acetate, v/v = 5:1 to 2:1) to afford 4-pyrone 2a-d (100.04 mg, 80%) as a yellow solid; m.p. 116.1–119.5 C;
1H-NMR (500 MHz, CDCl3) δ 7.90–7.83 (m, 4H), 7.55–7.51 (m, 6H), 6.84 (s, 0.12H) (Scheme 6).
Scheme 6. Deuterium Labeling Experiments.

Molecules 2017, 22, 109
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3.3.2. O18-Labelling Experiment
The reaction mixture of 1a (0.5 mmol), TfOH (1 equiv.), and H2O18 (1 mL) in a 15 mL test tube was
stirred at 100 ◦C for 36 h, and monitored periodically by TLC. Upon completion, the reaction mixture
was diluted with water (5 mL) and extracted with ethyl acetate (3
×
5 mL). The combined organic
layers were washed with water and brine, dried over MgSO4 and filtered. The solvent was removed
under vacuum. The residue was purified by flash column chromatography (petroleum ether and ethyl
acetate, v/v = 5:1 to 2:1) to afford 4-pyrone O18-2a (78%) (Scheme 7).
Scheme 7. O18-Labelling Experiment.
3.3.3. Gram-Scale Synthesis
The reaction mixture of 1a (5 mmol), TfOH (1 equiv.) and H2O (10 mL) in a 50 mL round-bottom
◦
flask was stirred at 100 C for 36 h, and monitored periodically by TLC. Upon completion, the reaction
mixture was diluted with water (30 mL) and extracted with ethyl acetate (3
×
30 mL). The combined
organic layers were washed with water and brine, dried over MgSO4 and filtered. The solvent was
removed under vacuum. The residue was purified by flash column chromatography (petroleum ether
and ethyl acetate, v/v = 5:1 to 2:1) to afford 4-pyrone 2a (53%) (Scheme 8).
Scheme 8. Gram-Scale Synthesis.
4. Conclusions
We have developed a simple and efficient transition-metal-free method for the synthesis of
substituted 4-pyrones from diynones and H2O. Water is a cheap, green and readily available staring
material, which converted to the desired 4-pyrone products via a nucleophilic addition/cyclization/
dehydrogenation process. The operational simplicity, good yields, and environmentally benign nature
of this method make it an attractive route to 4-pyrones. Further studies on the applications of 4-pyrones
in drug design are currently ongoing in our laboratory.
Supplementary Materials: Supplementary materials can be accessed at: http://www.mdpi.com/1420-3049/22/
1/109/s1: copies of NMR spectra and HRMS spectra of products.
Acknowledgments: We would like to thank the National Natural Science Foundation of China (21362002 and
81260472), Guangxi Natural Science Foundation of China (2014GXNSFDA118007 and 2016GXNSFEA380001),
Project of Guangxi Department of Education (KY2014037), State Key Laboratory for Chemistry and Molecular
Engineering of Medicinal Resources (CMEMR2014-A02 and CMEMR2012-A20), the Fund of Guangxi Key
Laboratory of Functional Phytochemicals Research and Utilization (FPRU2015-2), and Guangxi’s Medicine
Talented Persons Small Highland Foundation (1306).

Molecules 2017, 22, 109
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Author Contributions: Yan-Li Xu and Qing-Hu Teng conceived and designed the experiments. The experimental
work was conducted by Qing-Hu Teng under the supervision of Ying-Ming Pan and Xian-Li Ma who are the lead
author; Qing-Hu Teng and Wei Tong analyzed the data; Heng-Shan Wang contributed reagents/materials/analysis
tools; Yan-Li Xu and Qing-Hu Teng wrote the paper.
Conflicts of Interest: The authors declare no conflict of interest.
Abbreviations
TfOH
PTSA
HCl
HIV
HOAc
Ph
trifluoromethanesulfonic acid
4-methylbenzenesulfonic acid
hydrochloric acid
human immunodeficiency virus
acetic acid
phenyl
Me
methyl
OMe
Et
methoxyl
ethyl
tBu
tertiary butyl
n-propyl
nPr
NMR
HRMS
nuclear magnetic resonance
high-resolution mass
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