Synthesis 2020; 52(02): 208-218
DOI: 10.1055/s-0039-1690749
feature
© Georg Thieme Verlag Stuttgart · New York

Direct Transformation of Propargylic Alcohols and O,O-Diethyl Phosphorothioic Acid into S-(2H-Chromen-4-yl) Phosphorothioates

Xian-Rong Song
,
Tao Yang
,
Haixin Ding
,
Qiang Xiao
Institute of Organic Chemistry, Jiangxi Science & Technology Normal University, Jiangxi Province, Nanchang 330013, P. R. of China   Email: xiaoqiang@tsinghua.org.cn
› Author Affiliations

National Science Foundation of China (No. 21676131 and No. 21462019), the Science Foundation of Jiangxi Province (20181BAB203005 and 20143ACB20012), the Education Department of Jiangxi Province (GJJ180616), Jiangxi Science & Technology Normal University (2017QNBJRC004).
Further Information

Publication History

Received: 23 September 2019

Accepted after revision: 31 October 2019

Publication Date:
14 November 2019 (online)

 


Abstract

An environmentally benign and efficient method has been successfully developed to generate S-(2H-chromen-4-yl) phosphorothioates from easily available 2-(3-hydroxyprop-1-ynyl)phenols and O,O-diethyl phosphorothioic acid [(EtO)2P(O)SH] with water as the only byproduct. The reaction proceeds smoothly in moderate to excellent yields. It is noted that (EtO)2P(O)SH acts not only as an acid promoter, but also as the nucleophile to attack the allenic carbocation intermediate.


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Biographical Sketches

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Xian-Rong Song obtained his Ph.D. from Lanzhou University in 2015 under the supervision of Prof. Yong-Min Liang and then joined the research group of Professor Qiang Xiao at Jiangxi Science & Technology Normal University as a lecturer. His research focused on cascade reactions of propargylic alcohols for the synthesis of functionalized carbocycles or heterocycles. He was promoted to associate professor in 2018. From September 2019, he became a postdoctoral researcher in the research group of Prof. Ohyun Kwon at University of California-Los Angeles.

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Tao Yang completed his B.Sc. in pharmacy from Henan university of Science & Technology in 2016. He is currently pursuing his M.Sc. in organic chemistry under the supervision of Prof. Qiang Xiao and Dr. Xian-Rong Song. His research focuses on cascade reactions of propargylic alcohol.

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Haixin Ding received her BA and M.S. in agricultural chemistry from Northwest A&F University in 2004 and 2007, respectively. After that, she joined Prof. Xiao’s group in Jiangxi Science & Technology Normal University as a research assistant. She received her Ph.D. (with Prof. S. Hong and N. Zhang) from Nanchang University in 2018. Now she is an associate professor in organic chemistry. Her current research focuses on the synthesis of bioactive nucleosides and development of novel fluorogenic enzyme substrates for micro­biology application.

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Qiang Xiao is a professor of organic chemistry in Jiangxi Science & Technology University. He obtained his Ph.D. degree from Tsinghua University with Prof. Yufen Zhao in 2003. In 2004–2005, he worked as a research fellow with Prof. Tom Brown at University of Southampton, UK. At present, he serves as the director of both the Key Laboratory of Organic Chemistry in Jiangxi Province and the Institute of Organic Chemistry in Jiangxi Science & Technology University. His research mainly focuses on nucleoside chemistry, new synthetic methodologies for heterocycles, and developing novel fluorogenic and chromogenic enzyme substrates for detecting of pathogenic organisms.

Sulfur-containing organophosphorus compounds display significant biological properties, and provide important utilities in a variety of fields, including medicinal chemistry, agrochemistry, and organic synthesis.[1] Examples of such compounds are found in pesticides, fungicides, and anticholinesterases.[1d] [2] Figure [1] lists some representative examples of biologically active organothiophosphates. Moreover, such compounds are widely used in nucleoside chemistry due to their enhanced stability against nuclease enzymes[3] and their ability to act as labelling agents in metabolism studies.[4] Therefore, much effort has been devoted to the development of new approaches to construct organothiophosphates. Up to now, some methods have been developed through the formation of the P–S bond.[5] [6] [7] [8] [9] [10] These examples can be mainly classified as the following categories: (a) the Michaelis–Arbuzov reaction of P(OR)3 with RSO2Cl;[6] (b) the nucleophilic substitution of (RO)2P(O)Cl with RSH;[7] (c) the coupling-reductive reaction of (RO)2P(O)H and RSO2Cl;[8] (d) the dehydrogenative coupling reaction of (RO)2P(O)H and RSH;[9] and (e) the multicomponent reactions of alkyl halides, arylboronic acids, diazonium, or iodonium salts using elemental sulfur and (RO)2P(O)H compounds.[10] Despite these pioneering works in the synthesis of organothiophosphates, these reactions have some disadvantages, such as highly toxic reagents, harsh reaction conditions, limited substrate scope, or using strong oxidants. Therefore, the development of an ecofriendly and efficient strategy is still attractive and in high demand.

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Figure 1 Representative examples of biologically active organothiophosphates

Phosphorothioic acids [(RO)2P(O)SH], as a powerful P–S source, have played an increasingly important role in the formation of organothiophosphates.[5] Recently, the use of phosphorothioic acids as nucleophiles for the direct transformation with various electrophiles into a series of organothiophosphates has been investigated.[11] For example, in 2010, the Wu group developed a Ga(OTf)3-[11a] or UV-mediated[11b] reaction of allylic alcohols or their methyl ether with diethyl phosphorothioic acid [(EtO)2P(O)SH] to afford phosphorothioates (Scheme [1a]). It is well known that phosphorothioic acids (RO)2P(O)SH can easily tautomerize toward the thione form (RO)2P(S)OH, and it has been proved that the thione–thiol equilibrium of phosphorus thioacids depends to a great extent both on the nature of the solvent and the structure of the tautomeric form.[12] However, in these pioneering works, there is no direct evidence to verify that the structure of the desired products are phosphorothioates [(R1O)2P(O)SR2; 31P NMR: δ = ~25] or thiophosphonates [(R1O)2P(S)OR2; 31P NMR: δ = ~60] when using phosphorothioic acids as the nucleophile. Inspired by Wu’s pioneering work and by our long-standing interest in the field of propargylic alcohols,[13] we herein wish to report an unprecedented chemo- and regioselective cascade cyclization of propargylic alcohols and phosphorothioic acids [(RO)2P(O)SH]. A general and efficient method to access S-(2H-chromen-4-yl) phosphorothioates has thus been developed under mild conditions (Scheme [1]). The alkyne unit that is close to the hydroxyl group plays a critical role in the dehydration process. Notably, the product structure of our cascade reaction was confirmed by X-ray crystallography.

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Scheme 1 Previous works and our strategy for the construction of organothiophosphates

Propargylic alcohols are readily available bifunctional building blocks. Because of the vicinity of the C≡C bond to the hydroxyl group, the potential of propargylic alcohols to undergo reactions are different from those of the isolated alcohols.[14] Herein, our initial investigation began by using 2-(3-hydroxyprop-1-ynyl)phenol 1a as the model substrate with O,O-diethyl phosphorothioic acid [2; (EtO)2P(O)SH] and TFA (1.5 equiv) in CH3NO2 at 60 °C under an air atmosphere for 4.0 h. To our delight, the product S-(2H-chromen-4-yl) phosphorothioate 3a was obtained in 85% yield (Table [1], entry 1). Subsequently, the use of a variety of solvents showed their important influence on the cascade transformation. For example, in CH3CN, the desired product 3a was obtained in 51% yield (entry 2). DCE, CH2Cl2, and THF were ineffective for this reaction (entries 3–5). Taking into consideration the sufficient acidity of (EtO)2P(O)SH, an additional control experiment indicated that TFA was not necessary to initiate the reaction, and 3a was also obtained in 76% yield (entry 6). Notably, in contrast to Wu’s work, the dehydration of the hydroxyl group in the presence of (EtO)2P(O)SH no longer requires additional catalyst or UV-assistance. This clearly demonstrates the unique ability of the alkyne unit to assist the dehydration of hydroxyl group. The yield of 3a could be further increased to 82% at a higher reaction temperature of 80 °C (entry 7). No better result was obtained when the reaction was performed at 100 °C (entry 8). However, lower temperatures are unfavorable for the process and no desired product 3a could be detected when the reaction was performed at room temperature (entry 9). Further investigation on the effect of the amount of (EtO)2P(O)SH showed that 2.5 equiv was optimal for this reaction (entries 10 and 11). Ultimately, optimized reaction was established as following: 0.2 mmol of 2-(3-hydroxyprop-1-ynyl)phenol, 2.5 equiv of (EtO)2P(O)SH in CH3NO2 were stirred at 80 °C for 4.0 h.

Table 1 Optimization of the Reaction for the Synthesis of 3a a

Entry

Acid (equiv)

Solvent

Temp (°C)

Yield (%)

 1

TFA (1.5)

CH3NO2

 60

85

 2

TFA (1.5)

CH3CN

 60

51

 3

TFA (1.5)

CH2Cl2

 60

trace

 4

TFA (1.5)

DCE

 60

15

 5

TFA (1.5)

THF

 60

trace

 6

CH3NO2

 60

76

 7

CH3NO2

 80

82

 8

CH3NO2

100

82

 9

CH3NO2

 rt

trace

10b

CH3NO2

 80

69

11c

CH3NO2

 80

83

a Unless otherwise noted, all reactions were performed using 1a (0.2 mmol), (EtO)2P(O)SH (2; 2.0 equiv), solvent (2.0 mL), 80 °C.

b (EtO)2P(O)SH (1.5 equiv) was added.

c (EtO)2P(O)SH (2.5 equiv) was added.

Table 2 Transformation of Tertiary Propargylic Alcohols 1 into S-(2H-Chromen-4-yl) Phosphorothioates 3 a

a Reaction conditions: 1 (0.2 mmol), 2 (0.5 mmol), CH3NO2 (2.0 mL), 80 °C, 4 h. Isolated yields.

With the optimized reaction conditions in hand, we investigated the generality of this transformation with a series of substituted tertiary propargylic alcohols 1 and O,O-diethyl phosphorothioic acid [2; (EtO)2P(O)SH], the results are presented in Table [2]. Various products S-(2H-chromen-4-yl) phosphorothioates 3as were generated in moderate to excellent yields (up to 90% yield). Firstly, the cascade cyclization of tertiary propargylic alcohols 1 with different R1 and R2 group on either of two aromatic rings was examined. The electronic effect of substituent groups exerts a small influence on this transformation; in general, both electron-rich substituents (Me, OMe) and electron-poor substituents (F, Cl, CF3) could be well tolerated, successfully furnishing target products 3bl in 59–85% yields. The structure of 3f was unequivocally confirmed by X-ray crystallographic analysis (Figure [2]).[15] The ortho-position substituents showed obvious steric effect on this reaction, giving lower yields for the corresponding products 3jk. Halogen functionalities, such as fluorine, chlorine, and bromine, were compatible with this transformation; these halogenated products permit further transformation via metal-catalyzed cross-coupling reactions. Importantly, the reaction was performed successfully for substrates with a multiple ring group (naphthyl group, 1l and 1n) and a heterocyclic group (3-thienyl, 1m), and the corresponding products 3lm were obtained in high yields. In addition, some representative substrates bearing distinct substituents (Me, Cl, Br) were synthesized to investigate the reaction scope for R3, providing the corresponding products 3oq in good yields. Gratifying, the target product 3r was obtained when alkyl-substituted propargylic alcohols 1r was performed. However, substrate 1s, bearing two alkyl groups, failed to give the corresponding product 3s, which is due to the fact that it is difficult to form the allenic carbocation intermediate. Moreover, no desired product 3t was detected in case of 2-(3-hydroxyprop-1-ynyl)aniline 1t. This is may be due the low nucleophilicity or compatibility of the amino group.

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Figure 2 X-ray crystal structure of 3f

Encouraged by the above results, a variety of secondary propargylic alcohols were prepared to further investigate the cascade reaction. The corresponding mono-phenyl-substituted S-(2H-chromen-4-yl) phosphorothioates 3uz were obtained in moderate to good yields as described in Table [3]. We speculated that these transformations might proceed by the intermediate C (Scheme [4]) with poor stability compared to tertiary propargylic alcohols. In general, secondary and tertiary propargylic alcohols showed similar electronic and steric effects.

Table 3 Transformation of Secondary Propargylic Alcohols 1 into S-(2H-Chromen-4-yl) Phosphorothioates 3 a

a Reaction conditions: 1 (0.2 mmol), 2 (0.5 mmol), CH3NO2 (2.0 mL), 80 °C, 4 h. Isolated yields.

Furthermore, in order to evaluate the magnification effect of our approach, a gram-scale reaction was performed under the standard conditions. The target product 3a was obtained in 78% yield (Scheme [2]), which might offer potential application in medicinal chemistry and industry.

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Scheme 2 Scale-up experiment of 3a
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Scheme 3 Synthetic applications. Reagents and conditions: 3a (0.2 mmol), Tf2O (0.3 mmol), pyridine (0.4 mmol), DCM (1.0 mL), 15 min, then ROH (0.6 mmol), 1 h.

Another important merit of this newly developed approach was that the product S-(2H-chromen-4-yl) phosphorothioates offer a potential synthetic application in the construction of a series of mixed alkyl/aryl phosphorothioates, which are difficult to access by other methods. Mixed thiophosphates are important structural scaffolds with a wide range of bioactivities such as antibacterial and insecticide activities.[16] As representative examples, the Tf2O/pyridine-mediated reaction of S-(2H-chromen-4-yl) phosphorothioate 3a with several representative alcohols are presented in Scheme [3];[17] some mixed phosphorothioates 4ac were constructed in good yields.

On the basis of the above results and previous reports,[12] [18] a plausible mechanism is proposed in Scheme [4]. Initially, the dehydration of 2-(3-hydroxyprop-1-ynyl)phenol 1a in the presence of O,O-diethyl phosphorothioic acid [2; (EtO)2P(O)SH] forms propargylic cation intermediate A. The intermediate A can easily produce allenic cation intermediate­ B through tautomerization. Subsequently, nucleophilic attack of the counteranion (EtO)2P(O)S onto intermediate­ B generates intermediate C, which then can undergo the 6-endo-trig cyclization in the presence of proton to afford intermediate D. Finally, the desired product 3a is formed through the release of a proton.

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Scheme 4 Proposed reaction mechanism

In conclusion, we have developed a simple and practical approach for the synthesis of S-(2H-chromen-4-yl) phosphorothioates with high atom-economy from easily prepared 2-(3-hydroxyprop-1-ynyl)phenols and phosphorothioic acids [(EtO)2P(O)SH]. The reaction proceeds without external catalyst or stoichiometric additive in an environmentally benign manner with water as the only byproduct. A series of S-(2H-chromen-4-yl) phosphorothioates could be readily constructed in moderate to excellent yields. Moreover, our approach can be enlarged to a gram scale without any evident erosion in efficiency and the obtained S-(2H-chromen-4-yl) phosphorothioates can be convert smoothly into mixed phosphorothioates. Importantly, (EtO)2P(O)SH acts not only as an acid promoter to initiate the reaction, but also as the nucleophile to attack the allenic carbocation intermediate.

Column chromatography was carried out on silica gel. 1H NMR spectra were recorded on 400 MHz in CDCl3 or acetone-d 6 and 13C NMR spectra were recorded on 100 MHz in CDCl3 or acetone-d 6. Chemical shifts were recorded with TMS as the internal reference standard. HRMS was obtained using a Q-TOF instrument equipped with ESI source. Copies of 1H NMR and 13C NMR spectra are provided in the Supporting Information. Commercially available reagents were used without further purification. All solvents were dried under standard method. Petroleum ether = PE.


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S-(2H-Chromen-4-yl) Phosphorothioates 3; General Procedure

A mixture of 2-(3-hydroxyprop-1-ynyl)phenol 1 (0.2 mmol) and (EtO)2P(O)SH (2; 0.4 mmol) was stirred in CH3NO2 (2.0 mL) at 80 °C under air. After 4.0 h, the reaction was complete (TLC monitoring). Then, the solvent was evaporated and the residue was purified by flash chromatography (silica gel) to afford product 3.


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S-(2,2-Diphenyl-2H-chromen-4-yl) O,O-Diethyl Phosphorothioate (3a)

Purified by column chromatography (silica gel, PE/EtOAc 25:1 to 10:1) to give a yellow liquid; yield: 75.0 mg (0.166 mmol, 83%); Rf = 0.46 (PE/EtOAc 75:25).

1H NMR (400 MHz, CDCl3): δ = 1.20 (t, J = 7.2 Hz, 6 H), 4.04–4.23 (m, 4 H), 6.74 (d, J = 4.4 Hz, 1 H), 6.89–6.95 (m, 2 H), 7.15–7.19 (m, 1 H), 7.24–7.30 (m, 2 H), 7.31–7.34 (m, 4 H), 7.43–7.45 (m, 4 H), 7.59 (d, J = 7.6 Hz, 1 H).

13C NMR (100 MHz, CDCl3): δ = 15.8 (d, J CP = 8.0 Hz), 64.3 (d, J CP = 6.0 Hz), 83.6, 116.8, 121.4 (d, J CP = 14.0 Hz), 121.5 (d, J CP = 11.0 Hz), 125.5, 127.0, 127.8, 128.2, 130.6, 137.7 (d, J CP = 8.0 Hz), 143.8 (d, J CP = 1.0 Hz), 152.6.

31P NMR (162 MHz, CDCl3): δ = 22.32.

HRMS (ESI): m/z [M + H]+ calcd for C25H26O4PS: 453.1284; found: 453.1286.


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S-(2,2-Di-p-tolyl-2H-chromen-4-yl) O,O-Diethyl Phosphorothioate (3b)

Purified by column chromatography (silica gel, PE/EtOAc 25:1 to 10:1) to give a yellow liquid; yield: 64.3 mg (0.134 mmol, 67%); Rf = 0.46 (PE/EtOAc 75:25).

1H NMR (400 MHz, CDCl3): δ = 1.20 (t, J = 7.2 Hz, 6 H), 2.31 (s, 6 H), 4.06–4.14 (m, 2 H), 4.15–4.22 (m, 2 H), 6.70 (d, J = 4.4 Hz, 1 H), 6.88–6.93 (m, 2 H), 7.10–7.18 (m, 5 H), 7.30–7.32 (m, 4 H), 7.57 (d, J = 7.6 Hz, 1 H).

13C NMR (100 MHz, CDCl3): δ = 15.9 (d, J CP = 7.3 Hz), 21.1, 64.4 (d, J CP = 6.3 Hz), 83.5, 116.9, 121.1 (d, J CP = 10.4 Hz), 121.5 (d, J CP = 3.6 Hz), 125.6, 127.0, 128.9, 130.5, 137.5, 138.3 (d, J CP = 8.2 Hz), 141.0, 152.8.

31P NMR (162 MHz, CDCl3): δ = 22.53.

HRMS (ESI): m/z [M + H]+ calcd for C27H30O4PS: 481.1597; found: 481.1603.


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S-[2,2-Bis(4-methoxyphenyl)-2H-chromen-4-yl] O,O-Diethyl Phosphorothioate (3c)

Purified by column chromatography (silica gel, PE/EtOAc 25:1 to 10:1) to give a yellow solid; yield: 77.8 mg (0.152 mmol, 76%); mp 73–75 °C; Rf = 0.41 (PE/EtOAc 75:25).

1H NMR (400 MHz, CDCl3): δ = 1.21 (t, J = 7.2 Hz, 6 H), 3.77 (s, 6 H), 4.07–4.14 (m, 2 H), 4.17–4.23 (m, 2 H), 6.67 (d, J = 4.4 Hz, 1 H), 6.83–6.88 (m, 4 H), 6.90–6.92 (m, 2 H), 7.14–7.18 (m, 1 H), 7.34 (d, J = 8.8 Hz, 4 H), 7.57–7.59 (m, 1 H).

13C NMR (100 MHz, CDCl3): δ = 15.9 (d, J CP = 7.3 Hz), 55.3, 64.3 (d, J CP = 6.3 Hz), 83.3 (d, J CP = 2.1 Hz), 113.5, 116.9, 121.1 (d, J CP = 17.0 Hz), 121.5 (d, J CP = 3.2 Hz), 125.5, 128.5, 130.5, 136.2, 138.4 (d, J CP = 8.1 Hz), 152.7, 159.1.

31P NMR (162 MHz, CDCl3): δ = 22.54.

HRMS (ESI): m/z [M + H]+ calcd for C27H30O6PS: 513.1495; found: 513.1491.


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S-[2,2-Bis(4-fluorophenyl)-2H-chromen-4-yl] O,O-Diethyl Phosphorothioate (3d)

Purified by column chromatography (silica gel, PE/EtOAc 25:1 to 10:1) to give a yellow solid; yield: 73.2 mg (0.150 mmol, 75%); mp 99–101 °C; Rf = 0.51 (PE/EtOAc 75:25).

1H NMR (400 MHz, CDCl3): δ = 1.22 (t, J = 7.2 Hz, 6 H), 4.08–4.16 (m, 2 H), 4.16–4.24 (m, 2 H), 6.66 (d, J = 4.4 Hz, 1 H), 6.91–6.96 (m, 2 H), 6.98–7.03 (m, 4 H), 7.17–7.27 (m, 1 H), 7.40–7.43 (m, 4 H), 7.59 (dd, J = 0.8, 7.6 Hz, 1 H).

13C NMR (100 MHz, CDCl3): δ = 15.9 (d, J CP = 7.3 Hz), 64.4 (d, J CP = 6.4 Hz), 82.8, 115.1, 115.3, 116.9, 121.5 (d, J CP = 3.6 Hz), 121.7, 122.1 (d, J CP = 8.4 Hz), 125.6, 128.9 (d, J CP = 8.3 Hz), 130.8, 137.2 (d, J CP = 7.8 Hz), 139.5, 152.3, 161.1, 163.5.

31P NMR (162 MHz, CDCl3): δ = 22.35.

HRMS (ESI): m/z [M + H]+ calcd for C25H24F2O4PS: 489.1095; found: 489.1098.


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S-[2,2-Bis(4-chlorophenyl)-2H-chromen-4-yl] O,O-Diethyl Phosphorothioate (3e)

Purified by column chromatography (silica gel, PE/EtOAc 25:1 to 15:1) to give a yellow solid; yield: 70.7 mg (0.136 mmol, 68%); mp 129–130 °C; Rf = 0.52 (PE/EtOAc 75:25).

1H NMR (400 MHz, CDCl3): δ = 1.23 (t, J = 7.2 Hz, 6 H), 4.09–4.16 (m, 2 H), 4.17–4.24 (m, 2 H), 6.64 (d, J = 4.4 Hz, 1 H), 6.91–6.96 (m, 2 H), 7.19 (t, J = 8.0 Hz, 1 H), 7.28–7.30 (m, 4 H), 7.37–7.39 (m, 4 H), 7.59 (d, J = 7.6 Hz, 1 H).

13C NMR (100 MHz, CDCl3): δ = 16.0 (d, J CP = 7.2 Hz), 64.5 (d, J CP = 6.4 Hz), 82.7, 116.9, 121.5 (d, J CP = 3.6 Hz), 121.8, 122.5 (d, J CP = 8.3 Hz), 125.7, 128.5 (d, J CP = 4.6 Hz), 130.9, 134.0, 136.5 (d, J CP = 7.8 Hz), 142.0 (d, J CP = 1.4 Hz), 152.2.

31P NMR (162 MHz, CDCl3): δ = 22.26.

HRMS (ESI): m/z [M + H]+ calcd for C25H24Cl2O4PS: 521.0504; found: 521.0512.


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O,O-Diethyl S-[2-(4-Fluorophenyl)-2-(4-methoxyphenyl)-2H-chromen-4-yl] Phosphorothioate (3f)

Purified by column chromatography (silica gel, PE/EtOAc 25:1 to 10:1) to give a brown solid; yield: 83.0 mg (0.166 mmol, 83%); mp 91–93 °C; Rf = 0.48 (PE/EtOAc 75:25).

1H NMR (400 MHz, CDCl3): δ = 1.22 (t, J = 7.2 Hz, 6 H), 3.77 (s, 3 H), 4.07–4.14 (m, 2 H), 4.16–4.23 (m, 2 H), 6.67 (d, J = 4.4 Hz, 1 H), 6.84 (d, J = 8.8 Hz, 2 H), 6.90–6.94 (m, 2 H), 7.00 (t, J = 8.4 Hz, 2 H), 7.15–7.18 (m, 1 H), 7.33 (d, J = 8.8 Hz, 2 H), 7.40–7.44 (m, 2 H), 7.58–7.60 (m, 1 H).

13C NMR (100 MHz, CDCl3): δ = 15.9 (d, J CP = 7.3 Hz), 55.3, 64.4 (d, J CP = 6.3 Hz), 83.0 (d, J CP = 2.0 Hz), 113.6, 114.9, 115.2, 116.9, 121.5, 121.5 (d, J CP = 3.5 Hz), 121.6 (d, J CP = 8.5 Hz), 125.6, 128.4, 128.9 (d, J CP = 8.1 Hz), 130.7, 135.8, 137.8 (d, J CP = 7.9 Hz), 139.9, 152.5, 159.2, 161.0, 163.4.

31P NMR (162 MHz, CDCl3): δ = 22.48.

HRMS (ESI): m/z [M + H]+ calcd for C26H27FO5PS: 501.1295; found: 501.1298.


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O,O-Diethyl S-(2-Phenyl-2-(p-tolyl)-2H-chromen-4-yl) Phosphorothioate (3g)

Purified by column chromatography (silica gel, PE/EtOAc 25:1 to 10:1) to give a white solid; yield: 79.2 mg (0.170 mmol, 85%); mp 72–74 °C; Rf = 0.45 (PE/EtOAc 75:25).

1H NMR (400 MHz, CDCl3): δ = 1.20 (t, J = 7.2 Hz, 6 H), 2.31 (s, 3 H), 4.04–4.24 (m, 4 H), 6.72 (d, J = 4.4 Hz, 1 H), 6.88–6.94 (m, 2 H), 7.11–7.19 (m, 3 H), 7.23–7.27 (m, 1 H), 7.29–7.33 (m, 4 H), 7.43–7.45 (m, 2 H), 7.58 (dd, J = 1.2, 7.6 Hz, 1 H).

13C NMR (100 MHz, CDCl3): δ = 15.9 (d, J CP = 7.3 Hz), 21.1, 64.3 (d, J CP = 6.2 Hz), 83.5 (d, J CP = 2.1 Hz), 116.9, 121.3, 125.6, 127.0 (d, J CP = 5.6 Hz), 127.7, 128.2, 128.9, 130.6, 137.6, 138.0 (d, J CP = 8.0 Hz), 140.9, 144.0, 152.7.

31P NMR (162 MHz, CDCl3): δ = 22.38.

HRMS (ESI): m/z [M + H]+ calcd for C26H28O4PS: 467.1440; found: 467.1444.


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S-[2-(4-Chlorophenyl)-2-phenyl-2H-chromen-4-yl] O,O-Diethyl Phosphorothioate (3h)

Purified by column chromatography (silica gel, PE/EtOAc 25:1 to 10:1) to give a yellow liquid; yield: 81.6 mg (0.168 mmol, 84%); Rf = 0.47 (PE/EtOAc 75:25).

1H NMR (400 MHz, CDCl3): δ = 1.21 (t, J = 7.2 Hz, 6 H), 4.09–4.14 (m, 2 H), 4.17–4.23 (m, 2 H), 6.69 (d, J = 4.4 Hz, 1 H), 6.91–6.95 (m, 2 H), 7.17–7.21 (m, 1 H), 7.26–7.30 (m, 3 H), 7.31–7.35 (m, 2 H), 7.39–7.43 (m, 4 H), 7.58 (d, J = 7.2 Hz, 1 H).

13C NMR (100 MHz, CDCl3): δ = 15.9 (d, J CP = 7.3 Hz), 64.4 (d, J CP = 6.2 Hz), 83.1 (d, J CP = 2.1 Hz), 116.9, 121.5 (d, J CP = 3.7 Hz), 121.6, 122.1 (d, J CP = 8.3 Hz), 125.6, 128.0, 130.8, 133.8, 137.2 (d, J CP = 7.9 Hz), 142.4, 143.5, 152.4.

31P NMR (162 MHz, CDCl3): δ = 22.34.

HRMS (ESI): m/z [M + H]+ calcd for C25H25ClO4PS: 487.0894; found: 487.0896.


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O,O-Diethyl S-{2-Phenyl-2-[4-(trifluoromethyl)phenyl]-2H-chromen-4-yl} Phosphorothioate (3i)

Purified by column chromatography (silica gel, PE/EtOAc 25:1 to 10:1) to give a yellow liquid; yield: 84.2 mg (0.162 mmol, 81%); Rf = 0.48 (PE/EtOAc 75:25).

1H NMR (400 MHz, CDCl3): δ = 1.19–1.23 (m, 6 H), 4.08–4.24 (m, 4 H), 6.74 (d, J = 4.4 Hz, 1 H), 6.92–6.97 (m, 2 H), 7.18–7.22 (m, 1 H), 7.26–7.30 (m, 1 H), 7.32–7.36 (m, 2 H), 7.42–7.44 (m, 2 H), 7.57–7.62 (m, 5 H).

13C NMR (100 MHz, CDCl3): δ = 15.9 (d, J CP = 7.2 Hz), 64.4 (d, J CP = 6.4 Hz), 83.1, 116.9, 121.7, 125.2 (d, J CP = 3.7 Hz), 125.7, 127.0, 127.5, 128.2, 128.4, 130.9, 136.7 (d, J CP = 7.8 Hz), 143.2, 147.8, 152.3.

31P NMR (162 MHz, CDCl3): δ = 22.24.

HRMS (ESI): m/z [M + H]+ calcd for C26H25F3O4PS: 521.1158; found: 521.1163.


#

S-[2-(2-Chlorophenyl)-2-phenyl-2H-chromen-4-yl] O,O-Diethyl Phosphorothioate (3j)

Purified by column chromatography (silica gel, PE/EtOAc 25:1 to 10:1) to give a yellow liquid; yield: 57.3 mg (0.118 mmol, 59%); Rf = 0.49 (PE/EtOAc 75:25).

1H NMR (400 MHz, CDCl3): δ = 1.21 (t, J = 7.2 Hz, 6 H), 4.10–4.16 (m, 2 H), 4.17–4.23 (m, 2 H), 6.91–6.96 (m, 3 H), 7.16–7.20 (m, 1 H), 7.24–7.34 (m, 6 H), 7.37–7.39 (m, 2 H), 7.61 (d, J = 7.6 Hz, 1 H), 7.80 (dd, J = 2.0, 7.6 Hz, 1 H).

13C NMR (100 MHz, CDCl3): δ = 15.9 (q, J CP = 3.1 Hz), 64.4 (d, J CP = 6.3 Hz), 83.5, 116.7, 121.3 (d, J CP = 3.2 Hz), 121.6, 122.2 (d, J CP = 8.6 Hz), 125.7, 126.5, 128.0, 129.4, 129.5, 130.7, 131.7, 132.2, 135.5 (d, J CP = 8.2 Hz), 139.6, 142.2, 152.3.

31P NMR (162 MHz, CDCl3): δ = 22.37.

HRMS (ESI): m/z [M + H]+ calcd for C25H25ClO4PS: 487.0894; found: 487.0893.


#

O,O-Diethyl S-[2-(2-Methoxyphenyl)-2-phenyl-2H-chromen-4-yl] Phosphorothioate (3k)

Purified by column chromatography (silica gel, PE/EtOAc 25:1 to 10:1) to give a yellow liquid; yield: 68.4 mg (0.142 mmol, 71%); Rf = 0.43 (PE/EtOAc 75:25).

1H NMR (400 MHz, CDCl3): δ = 1.14–1.22 (m, 6 H), 3.53 (s, 3 H), 4.03–4.13 (m, 2 H), 4.15–4.21 (m, 2 H), 6.85 (d, J = 8.0 Hz, 1 H), 6.90–6.93 (m, 2 H), 6.98 (t, J = 7.6 Hz, 1 H), 7.02 (d, J = 4.8 Hz, 1 H), 7.16 (t, J = 8.0 Hz, 1 H), 7.22–7.30 (m, 4 H), 7.39–7.40 (m, 2 H), 7.58 (d, J = 7.6 Hz, 1 H), 7.70 (dd, J = 1.2, 8.0 Hz, 1 H).

13C NMR (100 MHz, CDCl3): δ = 15.8 (dd, J CP = 3.6, 7.3 Hz), 55.5, 64.2 (d, J CP = 6.2 Hz), 64.3, 83.0 (d, J CP = 2.1 Hz), 112.3, 116.6, 120.6, 120.7, 121.2, 121.4, 121.4, 125.6, 127.1, 127.4, 127.7, 127.9, 129.3, 130.4, 131.2, 137.3 (d, J CP = 8.4 Hz), 143.5, 152.6, 155.7.

31P NMR (162 MHz, CDCl3): δ = 22.57.

HRMS (ESI): m/z [M + H]+ calcd for C26H28O5PS: 483.1390; found: 483.1394.


#

O,O-Diethyl S-[2-(Naphthalen-2-yl)-2-phenyl-2H-chromen-4-yl] Phosphorothioate (3l)

Purified by column chromatography (silica gel, PE/EtOAc 25:1 to 10:1) to give a white solid; yield: 82.3 mg (0.164 mmol, 82%); mp 144–146 °C; Rf = 0.46 (PE/EtOAc 75:25).

1H NMR (400 MHz, CDCl3): δ = 1.19 (t, J = 7.2 Hz, 6 H), 4.09–4.16 (m, 2 H), 4.17–4.25 (m, 2 H), 6.81 (d, J = 4.8 Hz, 1 H), 6.90 (t, J = 7.6 Hz, 1 H), 6.97 (d, J = 8.0 Hz, 1 H), 7.16 (t, J = 7.6 Hz, 1 H), 7.24–7.31 (m, 1 H), 7.32–7.35 (m, 2 H), 7.44–7.51 (m, 5 H), 7.60 (d, J = 7.6 Hz, 1 H), 7.76–7.81 (m, 2 H), 7.82–7.83 (m, 1 H), 8.02 (s, 1 H).

13C NMR (100 MHz, CDCl3): δ = 15.9 (d, J CP = 7.3 Hz), 64.4 (dd, J CP = 3.0, 6.2 Hz), 83.8 (d, J CP = 2.0 Hz), 117.0, 121.5, 121.7 (d, J CP = 3.5 Hz), 121.8 (d, J CP = 8.6 Hz), 125.1, 125.7, 126.3, 126.4, 126.5, 127.1, 127.6, 127.9, 128.2, 128.3, 128.5, 130.7, 132.8 (d, J CP = 1.8 Hz), 138.0 (d, J CP = 7.9 Hz), 140.8, 143.8, 152.7.

31P NMR (162 MHz, CDCl3): δ = 22.58.

HRMS (ESI): m/z [M + H]+ calcd for C29H28O4PS: 503.1440; found: 503.1442.


#

O,O-Diethyl S-[2-(4-Fluorophenyl)-2-(thiophen-3-yl)-2H-chromen-4-yl] Phosphorothioate (3m)

Purified by column chromatography (silica gel, PE/EtOAc 25:1 to 10:1) to give a white solid; yield: 79.0 mg (0.166 mmol, 83%); mp 83–85 °C; Rf = 0.4 (PE/EtOAc 75:25).

1H NMR (400 MHz, CDCl3): δ = 1.21–1.25 (m, 6 H), 4.10–4.25 (m, 4 H), 6.70 (d, J = 4.4 Hz, 1 H), 6.91–7.05 (m, 6 H), 7.20 (t, J = 8.0 Hz, 1 H), 7.30 (d, J = 5.2 Hz, 1 H), 7.50–7.53 (m, 2 H), 7.60 (d, J = 7.6 Hz, 1 H).

13C NMR (100 MHz, CDCl3): δ = 15.9 (d, J CP = 7.2 Hz), 64.4 (d, J CP = 6.2 Hz), 81.0 (d, J CP = 2.0 Hz), 115.0, 115.2, 117.0, 121.3 (d, J CP = 3.7 Hz), 121.8, 122.4 (d, J CP = 8.2 Hz), 125.7, 126.5, 126.8, 126.9, 128.5, 128.6, 130.8, 136.4 (d, J CP = 7.9 Hz), 139.3, 147.8, 152.1, 161.2, 163.7.

31P NMR (162 MHz, CDCl3): δ = 22.07.

HRMS (ESI): m/z [M + H]+ calcd for C23H23FO4PS2: 477.0754; found: 477.0760.


#

S-(3,3-Diphenyl-3H-benzo[f]chromen-1-yl) O,O-Diethyl Phosphorothioate (3n)

Purified by column chromatography (silica gel, PE/EtOAc 25:1 to 15:1) to give a yellow solid; yield: 90.4 mg (0.180 mmol, 90%); mp 103–105 °C; Rf = 0.50 (PE/EtOAc 75:25).

1H NMR (400 MHz, CDCl3): δ = 0.92 (t, J = 7.2 Hz, 6 H), 3.65–3.71 (m, 2 H), 3.93–3.99 (m, 2 H), 6.77 (d, J = 4.8 Hz, 1 H), 7.19–7.32 (m, 8 H), 7.42–7.47 (m, 5 H), 7.68 (d, J = 8.8 Hz, 2 H), 8.60 (d, J = 8.4 Hz, 1 H).

13C NMR (100 MHz, CDCl3): δ = 15.5 (d, J CP = 7.9 Hz), 64.0 (d, J CP = 5.8 Hz), 83.5 (d, J CP = 2.3 Hz), 116.5 (d, J CP = 2.4 Hz), 118.4, 121.9 (d, J CP = 9.6 Hz), 123.9, 125.8, 125.9, 127.9, 128.6, 129.5, 130.1, 131.6, 141.0 (d, J CP = 8.8 Hz), 143.2 (d, J CP = 1.2 Hz), 152.2.

31P NMR (162 MHz, CDCl3): δ = 22.23.

HRMS (ESI): m/z [M + H]+ calcd for C29H28O4PS: 503.1440; found: 503.1443.


#

O,O-Diethyl S-(6-Methyl-2,2-diphenyl-2H-chromen-4-yl) Phosphorothioate (3o)

Purified by column chromatography (silica gel, PE/EtOAc 25:1 to 10:1) to give a yellow liquid; yield: 74.5 mg (0.160 mmol, 80%); Rf = 0.48 (PE/EtOAc 75:25).

1H NMR (400 MHz, CDCl3): δ = 1.20 (t, J = 7.2 Hz, 6 H), 2.25 (s, 3 H), 4.07–4.16 (m, 2 H), 4.18–4.22 (m, 2 H), 6.72 (d, J = 4.4 Hz, 1 H), 6.84 (d, J = 8.0 Hz, 1 H), 6.97 (d, J = 8.0 Hz, 1 H), 7.25–7.27 (m, 2 H), 7.30–7.33 (m, 4 H), 7.38 (s, 1 H), 7.43 (d, J = 7.2 Hz, 4 H).

13C NMR (100 MHz, CDCl3): δ = 15.9 (d, J CP = 7.2 Hz), 20.8, 64.3 (d, J CP = 6.4 Hz), 83.4, 116.7, 121.2 (d, J CP = 3.6 Hz), 121.7 (d, J CP = 8.5 Hz), 125.9, 127.1, 127.8, 128.2, 130.6, 131.1, 137.8 (d, J CP = 8.1 Hz), 143.9, 150.5.

31P NMR (162 MHz, CDCl3): δ = 22.44.

HRMS (ESI): m/z [M + H]+ calcd for C26H28O4PS: 467.1440; found: 467.1446.


#

S-(6-Bromo-2,2-diphenyl-2H-chromen-4-yl) O,O-Diethyl Phosphorothioate (3p)

Purified by column chromatography (silica gel, PE/EtOAc 25:1 to 15:1) to give a yellow liquid; yield: 87.9 mg (0.166 mmol, 83%); Rf = 0.49 (PE/EtOAc 75:25).

1H NMR (400 MHz, CDCl3): δ = 1.23 (t, J = 7.2 Hz, 6 H), 4.09–4.15 (m, 2 H), 4.18–4.24 (m, 2 H), 6.78 (d, J = 4.8 Hz, 1 H), 6.82 (d, J = 8.8 Hz, 1 H), 7.24–7.27 (m, 3 H), 7.28–7.34 (m, 4 H), 7.40–7.42 (m, 4 H), 7.70 (d, J = 2.4 Hz, 1 H).

13C NMR (100 MHz, CDCl3): δ = 15.9 (d, J CP = 7.3 Hz), 64.6 (d, J CP = 6.4 Hz), 84.0, 113.6, 118.8, 120.7 (d, J CP = 8.7 Hz), 123.5, 127.1, 128.3, 133.2, 139.5 (d, J CP = 8.2 Hz), 143.3, 151.7.

31P NMR (162 MHz, CDCl3): δ = 22.02.

HRMS (ESI): m/z [M + H]+ calcd for C25H25BrO4PS: 531.0389; found: 531.0392.


#

S-(6-Chloro-2,2-diphenyl-2H-chromen-4-yl) O,O-Diethyl Phosphorothioate (3q)

Purified by column chromatography (silica gel, PE/EtOAc 25:1 to 15:1) to give a yellow liquid; yield: 79.7 mg (0.164 mmol, 82%); Rf = 0.49 (PE/EtOAc 75:25).

1H NMR (400 MHz, CDCl3): δ = 1.22 (t, J = 7.2 Hz, 6 H), 4.09–4.16 (m, 2 H), 4.18–4.25 (m, 2 H), 6.79 (d, J = 4.4 Hz, 1 H), 6.88 (d, J = 8.4 Hz, 1 H), 7.11–7.13 (m, 1 H), 7.26–7.35 (m, 6 H), 7.40–7.42 (m, 4 H), 7.56 (d, J = 2.4 Hz, 1 H).

13C NMR (100 MHz, CDCl3): δ = 15.9 (d, J CP = 7.3 Hz), 64.7 (d, J CP = 6.4 Hz), 84.0, 118.3, 120.7 (d, J CP = 8.6 Hz), 123.0 (d, J CP = 3.2 Hz), 125.5, 126.4, 127.0, 128.1, 128.3, 130.3, 139.7 (d, J CP = 8.3 Hz), 143.3, 151.2.

31P NMR (162 MHz, CDCl3): δ = 22.20.

HRMS (ESI): m/z [M + H]+ calcd for C25H25ClO4PS: 487.0894; found: 487.0896.


#

O,O-Diethyl S-(2-Methyl-2-phenyl-2H-chromen-4-yl) Phosphorothioate (3r)

Purified by column chromatography (silica gel, PE/EtOAc 25:1 to 15:1) to give a yellow liquid; yield: 66.3 mg (0.170 mmol, 85%); Rf = 0.53 (PE/EtOAc 75:25).

1H NMR (400 MHz, CDCl3): δ = 1.18–1.25 (m, 6 H), 1.80 (s, 3 H), 4.05–4.14 (m, 2 H), 4.15–4.22 (m, 2 H), 6.55 (d, J = 4.4 Hz, 1 H), 6.88–6.92 (m, 2 H), 7.15–7.19 (m, 1 H), 7.22–7.26 (m, 1 H), 7.29–7.33 (m, 2 H), 7.49–7.54 (m, 2 H), 7.55 (d, J = 6.8 Hz, 1 H).

13C NMR (100 MHz, CDCl3): δ = 15.9 (dd, J CP = 4.7, 7.2 Hz), 29.1, 64.4 (d, J CP = 6.5 Hz), 79.6 (d, J CP = 2.0 Hz), 116.7, 121.2, 121.2 (d, J CP = 8.6 Hz), 121.5 (d, J CP = 3.5 Hz), 125.3, 125.6, 127.6, 128.3, 130.4, 138.3 (d, J CP = 8.0 Hz), 144.6, 153.1.

31P NMR (162 MHz, CDCl3): δ = 22.37.

HRMS (ESI): m/z [M + H]+ calcd for C20H24O4PS: 391.1127; found: 391.1129.


#

O,O-Diethyl S-[2-(4-Methoxyphenyl)-2H-chromen-4-yl] Phosphorothioate (3u)

Purified by column chromatography (silica gel, PE/EtOAc 25:1 to 10:1) to give a yellow liquid; yield: 31.7 mg (0.078 mmol, 39%); Rf = 0.45 (PE/EtOAc 75:25).

1H NMR (400 MHz, CDCl3): δ = 1.24–1.28 (m, 6 H), 3.80 (s, 3 H), 4.09–4.27 (m, 4 H), 5.88 (t, J = 4.4 Hz, 1 H), 6.39 (t, J = 8.0 Hz, 1 H), 6.78 (d, J = 7.6 Hz, 1 H), 6.89 (d, J = 7.6 Hz, 2 H), 6.92–6.96 (m, 1 H), 7.14–7.18 (m, 1 H), 7.38 (d, J = 8.8 Hz, 2 H), 7.61–7.63 (m, 1 H).

13C NMR (100 MHz, CDCl3): δ = 16.0 (d, J CP = 7.3 Hz), 55.3, 64.3, 64.4 (d, J CP = 5.5 Hz), 114.1, 116.4, 121.3, 121.7, 122.2, 125.6, 128.9, 130.5, 131.5, 134.1 (d, J CP = 8.1 Hz), 153.2, 160.0.

31P NMR (162 MHz, CDCl3): δ = 22.30.

HRMS (ESI): m/z [M + H]+ calcd for C20H24O5PS: 407.1077; found: 407.1079.


#

O,O-Diethyl S-[2-(p-Tolyl)-2H-chromen-4-yl] Phosphorothioate (3v)

Purified by column chromatography (silica gel, PE/EtOAc 25:1 to 15:1) to give a yellow liquid; yield: 41.3 mg (0.106 mmol, 53%); Rf = 0.51 (PE/EtOAc 75:25).

1H NMR (400 MHz, CDCl3): δ = 1.24–1.28 (m, 6 H), 2.34 (s, 3 H), 4.10–4.17 (m, 2 H), 4.19–4.25 (m, 2 H), 5.90 (t, J = 4.4 Hz, 1 H), 6.39 (t, J = 4.0 Hz, 1 H), 6.80 (d, J = 8 Hz, 1 H), 6.94 (t, J = 7.2 Hz, 1 H), 7.14–7.18 (m, 3 H), 7.34 (d, J = 7.6 Hz, 2 H), 7.61 (d, J = 8.0 Hz, 1 H).

13C NMR (100 MHz, CDCl3): δ = 15.9 (d, J CP = 7.3 Hz), 21.2, 64.3, 64.4 (d, J CP = 5.8 Hz), 116.4, 121.3, 121.7 (d, J CP = 3.1 Hz), 122.1 (d, J CP = 8.6 Hz), 125.6, 127.3, 129.4, 130.5, 134.1 (d, J CP = 8.2 Hz), 136.4, 138.6, 153.3.

31P NMR (162 MHz, CDCl3): δ = 22.25.

HRMS (ESI): m/z [M + H]+ calcd for C20H24O4PS: 391.1127; found: 391.1132.


#

O,O-Diethyl S-[2-(4-Fluorophenyl)-2H-chromen-4-yl] Phosphorothioate (3w)

Purified by column chromatography (silica gel, PE/EtOAc 25:1 to 10:1) to give a yellow liquid; yield: 48.8 mg (0.124 mmol, 62%); Rf = 0.49 (PE/EtOAc 75:25).

1H NMR (400 MHz, CDCl3): δ = 1.26 (t, J = 7.2 Hz, 6 H), 4.10–4.26 (m, 4 H), 5.91 (t, J = 4.4 Hz, 1 H), 6.39 (t, J = 4.4 Hz, 1 H), 6.80 (d, J = 8.0 Hz, 1 H), 6.96 (t, J = 7.6 Hz, 1 H), 7.05 (t, J = 8.4 Hz, 2 H), 7.18 (t, J = 7.2 Hz, 1 H), 7.43–7.47 (m, 2 H), 7.62 (d, J = 7.6 Hz, 1 H).

13C NMR (100 MHz, CDCl3): δ = 16.0 (d, J CP = 7.3 Hz), 64.4, 64.4 (d, J CP = 5.8 Hz), 115.5, 115.8, 116.4, 121.5, 121.6 (d, J CP = 3.5 Hz), 122.6 (d, J CP = 8.6 Hz), 125.7, 129.2, 129.3, 130.7, 133.4 (d, J CP = 8.2 Hz), 135.2, 153.0, 161.7, 164.1.

31P NMR (162 MHz, CDCl3): δ = 22.16.

HRMS (ESI): m/z [M + H]+ calcd for C19H21FO4PS: 395.0877; found: 395.0873.


#

S-[2-(4-Chlorophenyl)-2H-chromen-4-yl] O,O-Diethyl Phosphorothioate (3x)

Purified by column chromatography (silica gel, PE/EtOAc 25:1 to 10:1) to give a yellow liquid; yield: 42.7 mg (0.104 mmol, 52%); Rf = 0.49 (PE/EtOAc 75:25).

1H NMR (400 MHz, CDCl3): δ = 1.26 (t, J = 7.2 Hz, 6 H), 4.10–4.19 (m, 2 H), 4.20–4.25 (m, 2 H), 5.90 (t, J = 4.4 Hz, 1 H), 6.39 (t, J = 4.4 Hz, 1 H), 6.81 (d, J = 8.0 Hz, 1 H), 6.96 (t, J = 7.6 Hz, 1 H), 7.18 (t, J = 8.0 Hz, 1 H), 7.32–7.35 (m, 2 H), 7.40–7.42 (m, 2 H), 7.61 (d, J = 7.6 Hz, 1 H).

13C NMR (100 MHz, CDCl3): δ = 16.0 (d, J CP = 7.1 Hz), 64.4, 64.5 (d, J CP = 5.6 Hz), 116.4, 121.6 (d, J CP = 4.5 Hz), 122.8 (d, J CP = 8.4 Hz), 125.7, 128.7, 128.9, 130.7, 133.1 (d, J CP = 8.1 Hz), 134.6, 137.9, 153.0.

31P NMR (162 MHz, CDCl3): δ = 22.15.

HRMS (ESI): m/z [M + H]+ calcd for C19H21ClO4PS: 411.0581; found: 411.0590.


#

O,O-Diethyl S-[6-Methyl-2-(p-tolyl)-2H-chromen-4-yl] Phosphorothioate (3y)

Purified by column chromatography (silica gel, PE/EtOAc 25:1 to 10:1) to give a yellow liquid; yield: 37.1 mg (0.92 mmol, 46%); Rf = 0.47 (PE/EtOAc 75:25).

1H NMR (400 MHz, CDCl3): δ = 1.24–1.28 (m, 6 H), 2.28 (s, 3 H), 2.33 (s, 3 H), 4.10–4.19 (m, 2 H), 4.21–4.27 (m, 2 H), 5.85 (t, J = 4.4 Hz, 1 H), 6.38 (t, J = 4.4 Hz, 1 H), 6.70 (d, J = 8.8 Hz, 1 H), 6.96 (d, J = 8.0 Hz, 1 H), 7.16 (d, J = 8.0 Hz, 2 H), 7.33 (d, J = 8.0 Hz, 2 H), 7.41 (d, J = 1.2 Hz, 1 H).

13C NMR (100 MHz, CDCl3): δ = 15.9 (d, J CP = 7.3 Hz), 20.8, 21.2, 64.3 (d, J CP = 5.7 Hz), 64.4, 116.2, 121.4 (d, J CP = 3.4 Hz), 122.2 (d, J CP = 8.7 Hz), 126.0, 127.3, 129.4, 130.5, 131.0, 134.1 (d, J CP = 8.3 Hz), 136.5, 138.6, 151.1.

31P NMR (162 MHz, CDCl3): δ = 22.36.

HRMS (ESI): m/z [M + H]+ calcd for C21H26O4PS: 405.1284; found: 405.1290.


#

S-[6-Chloro-2-(p-tolyl)-2H-chromen-4-yl] O,O-Diethyl Phosphorothioate (3z)

Purified by column chromatography (silica gel, PE/EtOAc 25:1 to 10:1) to give a yellow liquid; yield: 53.4 mg (0.126 mmol, 63%); Rf = 0.50 (PE/EtOAc 75:25).

1H NMR (400 MHz, CDCl3): δ = 1.25–1.29 (m, 6 H), 2.34 (s, 3 H), 4.10–4.19 (m, 2 H), 4.20–4.27 (m, 2 H), 5.90 (t, J = 4.8 Hz, 1 H), 6.45 (t, J = 4.4 Hz, 1 H), 6.72 (d, J = 8.8 Hz, 1 H), 7.10 (dd, J = 2.4, 8.8 Hz, 1 H), 7.18 (d, J = 8.0 Hz, 2 H), 7.31 (d, J = 8.0 Hz, 2 H), 7.59 (d, J = 2.8 Hz, 1 H).

13C NMR (100 MHz, CDCl3): δ = 16.0 (d, J CP = 7.3 Hz), 21.2, 64.6 (d, J CP = 6.1 Hz), 64.7, 117.8, 121.3 (d, J CP = 8.8 Hz), 123.0 (d, J CP = 3.0 Hz), 125.5, 126.2, 130.1, 135.7 (d, J CP = 8.7 Hz), 138.9, 151.7.

31P NMR (162 MHz, CDCl3): δ = 21.99.

HRMS (ESI): m/z [M + H]+ calcd for C20H23ClO4PS: 425.0738; found: 425.0742.


#

S-(2,2-Diphenyl-2H-chromen-4-yl) O-Ethyl O-Propyl Phosphorothioate (4a)

Purified by column chromatography (silica gel, PE/EtOAc 25:1 to 10:1) to give a yellow liquid; yield: 73.6 mg (0.158 mmol, 79%); Rf = 0.46 (PE/EtOAc 75:25).

1H NMR (400 MHz, CDCl3): δ = 0.75 (t, J = 7.2 Hz, 3 H), 1.12 (t, J = 7.2 Hz, 3 H), 1.44–1.53 (m, 2 H), 3.86–4.02 (m, 2 H), 4.03–4.16 (m, 2 H), 6.66 (d, J = 4.4 Hz, 1 H), 6.81–6.87 (m, 2 H), 7.10 (t, J = 7.6 Hz, 1 H), 7.16–7.26 (m, 6 H), 7.36 (d, J = 8.0 Hz, 4 H), 7.51 (d, J = 8.0 Hz, 1 H).

13C NMR (100 MHz, CDCl3): δ = 9.8, 15.8 (d, J CP = 7.0 Hz), 23.4 (d, J CP = 8.0 Hz), 64.3 (d, J CP = 6.0 Hz), 69.7 (d, J CP = 7.0 Hz), 83.6 (d, J CP = 2.0 Hz), 116.8, 121.3 (d, J CP = 19.0 Hz), 121.6 (d, J CP = 7.0 Hz), 125.5, 127.0, 127.7, 128.1, 130.5, 137.7 (d, J CP = 8.0 Hz), 143.8, 152.6.

31P NMR (162 MHz, CDCl3): δ = 22.44.

HRMS (ESI): m/z [M + H]+ calcd for C26H28O4PS: 467.1440; found: 467.1442.


#

S-(2,2-Diphenyl-2H-chromen-4-yl) O-Ethyl O-Isopropyl Phosphorothioate (4b)

Purified by column chromatography (silica gel, PE/EtOAc 25:1 to 10:1) to give a yellow liquid; yield: 60.6 mg (0.130 mmol, 65%); Rf = 0.46 (PE/EtOAc 75:25).

1H NMR (400 MHz, CDCl3): δ = 1.22–1.24 (m, 6 H), 1.31–1.33 (m, 3 H), 4.05–4.24 (m, 2 H), 4.77–4.86 (m, 1 H), 6.81 (d, J = 4.4 Hz, 1 H), 6.91–6.98 (m, 2 H), 7.20 (t, J = 7.6 Hz, 1 H), 7.26–7.36 (m, 6 H), 7.48 (dd, J = 2.4, 7.2 Hz, 4 H), 7.62 (d, J = 7.6 Hz, 1 H).

13C NMR (100 MHz, CDCl3): δ = 15.8 (d, J CP = 7.1 Hz), 23.4 (d, J CP = 5.5 Hz), 23.8, 64.1 (d, J CP = 6.2 Hz), 73.8 (d, J CP = 7.1 Hz), 83.5, 116.7, 121.3, 121.5, 121.6 (d, J CP = 8.4 Hz), 125.6, 127.0 (d, J CP = 4.1 Hz), 127.7, 128.1, 130.5, 137.2 (d, J CP = 7.8 Hz), 143.9, 152.6.

31P NMR (162 MHz, CDCl3): δ = 22.60.

HRMS (ESI): m/z [M + H]+ calcd for C26H28O4PS: 467.1440; found: 467.1439.


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S-(2,2-Diphenyl-2H-chromen-4-yl) O-Ethyl O-(4-Methoxyphenyl) Phosphorothioate (4c)

Purified by column chromatography (silica gel, PE/EtOAc 25:1 to 10:1) to give a yellow liquid; yield: 75.2 mg (0.142 mmol, 71%); Rf = 0.46 (PE/EtOAc 75:25).

1H NMR (400 MHz, CDCl3): δ = 1.15 (t, J = 7.2 Hz, 3 H), 3.65 (s, 3 H), 4.08–4.22 (m, 2 H), 6.60–6.64 (m, 3 H), 6.74–7.78 (m, 1 H), 6.84–6.91 (m, 3 H), 7.05–7.10 (m, 1 H), 7.14–7.26 (m, 6 H), 7.34–7.37 (m, 5 H).

13C NMR (100 MHz, CDCl3): δ = 15.8 (d, J CP = 7.0 Hz), 55.5, 65.0 (d, J CP = 7.0 Hz), 83.6, 114.5, 116.7, 121.1, 121.2 (d, J CP = 6.0 Hz), 121.3 (d, J CP = 3.0 Hz), 125.7, 126.9, 127.0, 127.1, 127.7, 127.8, 128.2, 128.2, 130.5, 138.6 (d, J CP = 9.0 Hz), 143.6, 143.7 (d, J CP = 8.0 Hz), 152.6, 156.8.

31P NMR (162 MHz, CDCl3): δ = 18.99.

HRMS (ESI): m/z [M + H]+ calcd for C30H28O5PS: 531.1390; found: 531.1388.


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Supporting Information



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Figure 1 Representative examples of biologically active organothiophosphates
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Scheme 1 Previous works and our strategy for the construction of organothiophosphates
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Figure 2 X-ray crystal structure of 3f
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Scheme 2 Scale-up experiment of 3a
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Scheme 3 Synthetic applications. Reagents and conditions: 3a (0.2 mmol), Tf2O (0.3 mmol), pyridine (0.4 mmol), DCM (1.0 mL), 15 min, then ROH (0.6 mmol), 1 h.
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Scheme 4 Proposed reaction mechanism