Bromophosphoalkoxylation of olefins with organic phosphates, cyclic ethers and NBS

Tetrahedron xxx (2015) 1e6

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Bromophosphoalkoxylation of olefins with organic phosphates, cyclic ethers and NBS Muhammad Sohail a, *, Chang Peng a, Siyang Ning a, Yixin Zhang a, Muhammad Khan b, Zongbao K. Zhao a, * a b

Division of Biotechnology, Dalian Institute of Chemical Physics, CAS, Dalian 116023, China College of Basic Medical Sciences, Dalian Medical University, Dalian 116044, China

a r t i c l e i n f o

a b s t r a c t

Article history: Received 8 September 2015 Received in revised form 24 November 2015 Accepted 2 December 2015 Available online xxx

A variety of structurally novel phosphoalkoxy ester derivatives were prepared via highly regio- and diastereoselective four-component reaction involving olefin, cyclic ether, halogen reagent and organic phosphate. All components can be varied flexibly and moderate to excellent yields were obtained at room temperature. Several of these ester derivatives showed strong anticancer activity against human lung adenocarcinoma cells. Ó 2015 Elsevier Ltd. All rights reserved.

Keywords: Phosphorylation Synthetic methods Organic phosphates Alkenes

1. Introduction Phosphate esters are of great importance because of the ubiquity of phosphate-containing molecules in biological processes including signalling pathways, information storage and energy transfer.1 An enormous variety of biomolecules are encountered in the form of phosphate esters such as nucleotides, proteins and some secondary metabolites.2 As a result, these biodegradable and short-lived compounds have been a topic of interest for many years, with applications mainly directed towards the bioorganic and medicinal chemistries.3 In terms of their modes of action, for example, these compounds are involved in the inhibition of acetylcholine esterase (AChE)4 and thus have also found numerous applications in insecticides, fungicides, herbicides and pesticides.5 Therefore, the development of new protocols with green procedure for the introduction of phosphate would be important, especially in the areas of drug discovery, organic synthesis, and material science. Phosphorylation in biological systems is easily carried out by ATP-dependent enzymes including kinases and phosphatases,6 however, synthetic procedures of phosphorylation are limited and generally involve some hectic and tedious operations,

* Corresponding authors. Tel.: þ86 411 84379066; fax: þ86 411 84379211; e-mail addresses: [email protected] (M. Sohail), [email protected] (Z.K. Zhao).

including extraction and purification. This leads to synthetic inefficiency as well as generates large amount of wastes.7 Many of these reactions are generally performed by using hazardous and toxic inorganic salts.8 This leads to limiting their applications in organic synthesis. In order to overcome these problems and find new bioactive phospho-compounds, we decided to investigate onepot processes consisting of concatenations of elementary organic reactions under similar conditions.9 The ring-opening reactions of cyclic ethers are effective approaches to produce difunctional active intermediates.10 Among ethers, tetrahydrofuran (THF) has been extensively studied. It acts as an important 4-carbon building block for organic synthesis, polymer chemistry and medicinal chemistry.11 Lewis and inorganic acids,12 transition metals13 and others14 have been reported for THF ring opening reactions. However, to the best of our knowledge there are only few reports concerning the ring-opening reactions of cyclic ethers with phosphate allowing the formation of useful phosphorylated synthons for the synthesis of compounds of biological interest.15 Based on these preceding developments of the THF ring opening € nsted acid catalyzed nureactions, recently, we described the Bro cleophilic conjugate addition of cyclic ether to the a,b-unsaturated carbonyl compounds, in which the enolate intermediate was detained by halogen reagent and finally the heterolytic ring cleavage of oxonium cation produced a-bromo-b-alkoxylated carbonyl derivatives (Scheme 1A).11c,d

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Scheme 1. Electrophilic four-component paradigm.

Seeking for further extension of these results, herein, we envisioned a straightforward method of phosphorylation, in which an olefinic double bond is triggered by halogen reagent and cyclic ether joined with the double bond in the presence of phosphate leading to the formation of halophosphoalkoxylated products (Scheme 1B). These highly functionalized compounds are otherwise difficult to prepare and find considerable attention for selfassembly spherical complexes and protein affinity tags.16 2. Results and discussions Our study commenced with phosphoalkoxylation of stilbene 1a with N-bromosuccinimide (NBS) as the halogen source in THF at room temperature. To our surprise, a 21% yield of THF dimerized product 4a was obtained along with the formation of phosphoalkoxy product 3a (Table 1, entry 1).17 Reaction conditions were further optimized to get the desired product 3a. Other brominating reagents, including bromine, nBu4NBr3, 1,3-dibromo-5,5-dimethylhydantoin, KBrO3/KBr were found relatively less effective.17a By employing less reactive Nchlorosuccinimide as a halogen reagent, the products were obtained in similar ratio, with lower yields (Table 1, entry 2). No Table 1 Optimization of reaction conditionsa



desired products were observed, and may decompose, in case of Niodosuccinimide (Table 1, entry 3). Disappointingly, both higher and lower temperatures were substandard (Table 1, entries 4e6). In contrast to our previous reports 11c,d, the addition of various Lewis acid catalysts including GeBr2, YbCl3, CeCl3, etc. decreased the yields of both isomers.17a Further, investigation showed that the reaction yield and the ratio of products were highly dependent on the concentration, in which a higher reaction yield (51%) of 3a was obtained under a diluted (33.3 mM) condition (Table 1, entry 7). Longer reaction time and two equivalents of NBS could improve the yield of 3a to 69% and 73%, respectively (Table 1, entries 8, 9). The yield of 3a was further improved by decreasing the equivalents of 2a (Table 1, entry 10). Thus an appropriate acidic strength is important for optimal yield. Moreover, a mixed co-solvent of CH2Cl2 and THF produced almost the same yield (Table 1, entry 11).17a This observation is not in agreement to our previous results in which THF alone gave the best results; 11c,d hence increase the applicability of this reaction to performs in different reaction media for other applications. Compared to our previous reports,11c,d the yields of isomers also did not change by changing the addition sequence of the reaction components.17a Over the years, phosphates have attracted special attention in natural and synthetic applications.18 However, to the best of our knowledge, this is the first example which involves the THF ring opening and traps the corresponding intermediate for joining with alkene. More significantly, the resulting highly functionalized products are possible synthons which can be easily modified for the introduction of phosphate and different substituents at a-position for medicinally and biological privileged structures.3,19 With the optimized reaction conditions in hand, we next tested the reaction scope by varying organic phosphates. Aliphatic phosphates 2b and 2c worked well under these conditions, leading to the formation of phosphoalkoxylated products in good yields (Table 2, entries 1, 2). Besides, mixtures of diastereomers (dr¼0%) were obtained with good to excellent yields in case of chiral 2d and BINOL derived 2e phosphates, respectively.20

Table 2 Phosphoalkoxylation of stilbene using various phosphatesa

Entry

Temp ( C)

Halogen reagent

Yield (%)b 3a

4a

1 2 3 4 5 6 7c 8d 9e 10f 11g

25 25 25 78 0 65 25 25 25 25 25

NBS NCS NIS NBS NBS NBS NBS NBS NBS NBS NBS

41 29 d d 14 12 51 69 73 79 74

21 18 d d 4 Trace 11 15 17 11 12

a 1a (0.1 mmol), 2a (0.15 mmol, 1.5 equiv), NBS (0.15 mmol, 1.15 equiv), were added in THF (1 mL) and stirred for 12 h at room temperature under argon. b Isolated yield. c THF (3 mL) was used. d Reaction mixture was stirred for 24 h. e NBS (2 equiv) was used. f 2a (1.01 equiv) was used. g The reaction was stirred for 48 h in mixed co-solvent CH2Cl2 and THF.

Entry

(R1)2PO4H

Product

Yield (%)b

1 2

(n-Bu)2PO4H (PhCH2) 2PO4H

3b 3c

71 76

3

3d

75

4

3e

83

a 1a (0.1 mmol), acid (0.101 mmol, 1.01 equiv), NBS (0.2 mmol, 2.00 equiv), were added in THF (3 mL) and stirred for 24 h at room temperature under argon. b Isolated yield.

We also investigated the substrate scope by testing different compounds containing the carbon-carbon double bond, including terminal olefins, cyclic olefins and allene (Table 3). Stereochemistry of the substrate, cis-stilbene, had little influence on the product yield (Table 2, entry 1).20 The transformation maintained its

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M. Sohail et al. / Tetrahedron xxx (2015) 1e6 Table 3 Phosphoalkoxylation of olefinsa

3

Table 3 (continued ) Entry

Substrate

Product

10

Entry

Substrate

Yield (%)b

89

Yield (%)b

Product

11 1

d

NR

81 a 1be1r (0.1 mmol), 2d (0.101 mmol, 1.01 equiv), NBS (0.20 mmol, 2.0 equiv), were added in THF (3 mL) and stirred for 24 h at room temperature under argon. b Isolated yield.

75

2

3

77

4

93

5

91

6

96

7

77

81

8

9

O P PhO O OPh

effectiveness with terminal olefins and products were generated exclusively as the Markovnikov-type product (Table 2, entries 2, 3). Inter aliphatic alkene returned excellent yield (Table 2, entry 4). Allene was readily accommodated in excellent yield with excellent regio and chemo selectivity (Table 3, entry 5). Besides, cyclic olefins also proceeded smoothly to furnish the corresponding products in excellent yields. Privileged results were obtained with cyclohexene and cyclooctene (Table 3, entries 6, 9 vs entries 7, 8). Additionally, only the Markovnikov-type product was isolated in case of methyl substituted cyclohexene (Table 3, entry 10). Although this protocol showed wide substrate scope, however, highly electron deficient substrates, cinnamonitrile and nitrostyrene, are still challenging and thus no phosphoalkoxyl products were detected (Table 3, entry 11). The scope of the phosphoalkoxylation discussed herein appears to be quite broad with regard to not only for the olefine and acid components but also for the cyclic ethers (Scheme 2). Slightly lower yields for 6a and 6b were obtained in case of oxetane and pyran, respectively. Remarkably, when tetrahydro-2-methylfuran was used, compound 6c was isolated as the major product, indicating that the ring-opening process of the cyclic ether was highly regio-selective. Note that no conversion was observed with a,b-unsaturated compounds with substituted THF in our preceding report.11d

Scheme 2. Phosphoalkoxylation of 1a and 2c in the presence of different cyclic ethers.

The structures of all these products were characterized by extensive spectroscopic methods.17a To shed light on the possible mechanism of this reaction, controlled experiments were carried out. First, the sodium salt of 2a was prepared in situ and used in the model reaction. Interestingly, on the contrary to our previous reports,11c,d good yield (53%) of the desired product 3a was obtained (Scheme 3). Phosphoric acid salts are known for the

4O

Br

92

Scheme 3. Phosphoalkoxylation of 1a with the sodium salt of 2a.

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activation of similar halogen reagent and it was also observed in our studies.21 Accordingly, it favored the possibility of bromonium cation in this transformation. Subsequently, the effect of chiral environment by chiral 3d and 3e was investigated. Both enantiomers (S and R) produced mixture of two diastereomers and no enantioinduction was observed, suggesting that the reaction proceeded in a stepwise rather than concerted manner. Profoundly, in 1H NMR, the coupling constants between the protons of the two carbons attached with the halogen atom and the alkoxyl functionality revealed a trans addition product. This assured high anti-diastereoselectivity around the C]C bond due to the nucleophilic attack of cyclic ether at the opposite face of halonium cation.22 Thus, we favor a mechanistic pathway shown in Scheme 4.

Scheme 4. Plausible reaction mechanism for the difunctionalization of olefins.

The reaction involves the Brønsted acid activation of NBS, next, the active electrophilic brominating source (A) generates bromonium intermediate (B) across the C]C. Afterwards, the nucleophilic attack of cyclic ether to the halonium cation results in the formation of oxonium cation (C). And finally, the attack on oxonium cation by nucleophilic anion of phosphate anion furnishes the desired product 3, while products like 4a could be accounted by nucleophilic attack of another cyclic ether molecule followed by phosphate anion. Chemotherapy is the mainstay among other cancer therapies, however, the use and availability of phosphorylated chemotherapeutics is limited.23 While, other functional groups containing cytotoxics are associated with undesirable side effects and long term damaged.24 Having the above novel hybrid phosphorylated compounds in hand, we tested the anticancer activity of compounds 3a and 5f against human lung adenocarcinoma cell line A549 by the MTT method (Fig. 1). It was found that these compounds showed strong anticancer activity. A further study of biological profiles against lung and other cancer cell lines are currently on-going and will be published in due course.

3. Conclusion In conclusion, a highly efficient regio- and diastereoselective four-component reaction involving olefin, cyclic ether, halogen reagent and phosphate has been achieved to provide a direct route for a variety of structurally novel phosphoalkoxy ester derivatives. This reaction is free of external catalyst, readily scalable, and highly practical by using inexpensive and commercially available reagents. Moreover, preliminary results indicated that these compounds may be screened for anticancer activities. 4. Experimental section 4.1. General The reactions were conducted under an atmosphere of nitrogen using typical vacuum-line. The analysis by thin layer chromatography (TLC) was performed using F254 pre-coated silica gel plate. Visualization of the spots on TLC was carried out with UV radiation (256 and 365 nm). Column chromatography was performed with silica gel (300e400 mesh). 1H NMR spectra were recorded on Buruker Avance 400 and Varian Mercury 400. Chemical shifts were reported in ppm downfield from tetramethylsilane (CDCl3, d¼7.26). The 13C NMR were recorded on a Varian Mercury 400 (100 MHz) with complete proton decoupling. Samples were run in CDCl3 and are referenced to CDCl3 as an internal standard at 77.0 ppm. The reagents in liquid state were used after direct distillation or distillation under reduced pressure. The reagents in solid state were used as supplied or after crystallization. 4.2. General procedure Phosphate 2ae2e (0.101 mmol, 1.01 equiv) was added to the solution of olefin 1ae1k (0.10 mmol, 1 equiv) and NXS (0.20 mmol, 2 equiv) in respective cyclic ether (3 mL). The reaction mixture was stirred for 24 at room temperature. The solvent was then removed under reduce pressure and residue was purified by flash column chromatography (gradient elution, EtoOAc: n-hexane; 1:100 v/v, 50 mL; 1:20, v/v 400 mL), to yield the corresponding products. 4.2.1. 4-(2-Bromo-1,2-diphenylethoxy)butyl diphenyl phosphate (3a). Clear oil; 1H NMR (400 MHz, CDCl3): dH¼1.44e1.51 (m, 2H), 1.53e1.60 (m, 2H), 3.16e3.21 (m, 1H), 3.27e3.32 (m, 1H), 4.08e4.13 (m, 2H), 4.66 (d, J¼6.9 Hz, 1H), 4.96 (d, J¼6.9 Hz, 1H), 7.14e7.33 (m, 20H); 13C NMR (100 MHz, CDCl3): dC¼25.4, 26.8 (d, J¼7 Hz), 57.0, 68.8, 69.0 (d, J¼6.5 Hz), 85.7, 120.0, 125.3, 127.7, 128.0, 128.1, 128.2, 128.3, 128.8, 129.7, 138.8, 138.9, 150.6. 31P NMR (CDCl3): dP¼12.3. HRMS (ESI-TOF) m/z: [MþH]þ Calcd for C30H31BrO5P 583.1075; Found 583.1071. 4.2.2. 4-(4-(2-Bromo-1,2-diphenylethoxy)butoxy)butyl diphenyl phosphate (4a). Clear oil; 1H NMR (400 MHz, CDCl3): dH¼1.43e1.49 (m, 4H), 1.54e1.60 (m, 4H), 1.62e1.78 (m, 2H), 3.21e3.26 (m, 3H), 3.29e3.30 (m, 3H), 4.23e4.28 (m, 2H), 4.69 (d, J¼6.7, 1H), 4.98 (d, J¼6.7, 1H), 7.17e7.34 (m, 20H); 13C NMR (100 MHz, CDCl3): dC¼25.6, 26.2, 27.1, 57.1, 69.2, 69.5, 69.7, 70.4, 85.6, 120.0, 125.2, 127.7, 127.9, 128.0, 128.1, 128.9, 129.7, 138.8, 139.1, 150.5, 150.6. HRMS (ESI-TOF) m/z: [MþH]þ Calcd for C34H39BrO6P 655.1650; Found 655.1653.

Fig. 1. Activity against the human lung adenocarcinoma cells.

4.2.3. 4-(2-Bromo-1,2-diphenylethoxy)butyl dibutyl phosphate (3b). Clear oil; 1H NMR (400 MHz, CDCl3): dH¼0.90e0.94 (m, 6H), 1.35e1.44 (m, 4H), 1.53e1.67 (m, 8H), 3.23e3.26 (m, 1H), 3.33e3.37 (m, 1H), 3.88e3.90 (m, 2H), 3.91e4.02 (m, 4H), 4.69 (d, J¼6.8 Hz, 1H) 4.98 (d, J¼6.8, 1H), 7.20e7.35 (m, 10H). 13C NMR (100 MHz, CDCl3): dC¼13.5, 18.6, 25.6, 26.8 (d, J¼7.1 Hz) 32.3 (d, J¼6.7 Hz), 57.0,

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67.3 (d, J¼6.1 Hz), 68.9, 85.7, 127.7, 127.9, 128.0, 128.2, 128.9, 138.7, 138.9. 31P NMR (CDCl3): dP¼0.69. HRMS (ESI-TOF) m/z: [MþH]þ Calcd for C26H39BrO5P 543.1701; Found 543.1707. 4.2.4. Dibenzyl 4-(2-bromo-1,2-diphenylethoxy)butyl phosphate (3c). Clear oil; 1H NMR (400 MHz, CDCl3): dH¼1.42e1.48 (m, 4H), 3.14e3.19 (m, 1H), 3.25e3.30 (m, 1H), 3.83e3.88 (m, 2H), 4.65 (d, J¼6.9 Hz, 1H), 4.94e5.01 (m, 5H), 7.18e7.32 (m, 20H), 13C NMR (125 MHz, CDCl3): dC¼25.4, 26.8 (d, J¼7.4 Hz), 57.0, 67.5 (d, J¼5.8 Hz), 68.9, 69.1 (d. J¼5.6 Hz), 85.7, 127.7, 127.9, 128.0, 128.1, 128.2, 128.5, 128.8, 135.9, 136.0, 138.8, 138.9. 31P NMR (CDCl3): dP¼0.81. HRMS (ESI-TOF) m/z: [MþH]þ Calcd for C32H35BrO5P 611.1388; Found 611.1392. 4.2.5. 4-(2-Bromo-1,2-diphenylethoxy)butyl-1,10 -2,2-dimethyl-3phenylpropyl phosphate (3d). Clear oil; 1H NMR (400 MHz, CDCl3): dH¼0.76 (s, 3H), 1.03 (s, 3H), 1.54e1.63 (m, 4H), 3.21e3.32 (m, 1H), 3.32e3.37 (m, 1H), 3.85e4.00 (m, 3H), 4.15 (d, J¼6.8, 1H) 4.68 (d, J¼6.8 Hz, 1H), 4.96e4.98 (m, 1H), 5.08 (s, 1H), 7.20e7.34 (m, 15H); 13C NMR (125 MHz, CDCl3): dC¼17.0, 20.9, 25.6, 26.9, 36.0 (d, J¼3.5 Hz), 57.0, 68.9, 78.5 (d, J¼6.5 Hz), 85.7, 87.9 (d, J¼6.2 Hz), 127.3, 127.7, 127.9, 128.0, 128.1, 128.3, 128.5, 128.8, 135.5, 135.6, 138.7, 138.8. 31P NMR (CDCl3): dP¼7.2. HRMS (ESI-TOF) m/z: [MþH]þ Calcd for C29H35BrO5P 575.1388; Found 575.1393. 4.2.6. 4-(2-Bromo-1,2-diphenylethoxy)butyl-1,10 -binaphthyl-2,20 diyl phosphate (3e). Clear oil; mixture of isomers, 1H NMR (400 MHz, CDCl3): dH¼1.48e1.53 (m, 2H), 1.56e1.62 (m, 2H), 3.17e3.23 (m, 2H), 4.10e4.22 (m, 2H), 4.66 (d, J¼6.9 Hz, 1H), 4.96 (m, 1H), 7.18e7.48 (m, 17H), 7.58 (d, J¼8.8, 1H), 7.91e8.02 (m, 4H). 13 C NMR (125 MHz, CDCl3): dC¼25.4, 27.0, 27.1, 57.0, 68.8, 69.5, 69.6, 85.7, 120.2, 120.6, 120.7, 121.3, 121.4, 125.8, 126.8, 127.0, 127.2, 127.7, 128.0, 128.1, 128.2, 128.3, 128.4, 128.5, 128.8, 131.1, 131.5, 131.6, 131.9, 132.3, 138.8, 138.9, 146.3, 146.4, 147.4, 147.5. HRMS (ESI-TOF) m/z: [MþH]þ Calcd for C38H33BrO5P 681.1231; Found 681.1228. 4.2.7. 4-(4-(2-Bromo-1,2-diphenylethoxy)butoxy) butyl-1,10 -bi0 naphthyl-2,2 -diyl phosphate (4e). Clear oil; mixture of isomers, 1H NMR (400 MHz, CDCl3): dH¼1.40e1.51 (m, 4H), 1.58e1.63 (m, 2H), 1.76e1.80 (m, 2H), 3.23 (t, J¼6.1 Hz, 3H), 3.32 (t, J¼6.3 Hz, 3H), 4.25e7.38 (m, 2H), 4.69 (d, J¼6.7 Hz, 1H), 4.98 (d, J¼6.7 Hz, 1H), 7.19e7.38 (m, 14H), 7.45e7.49 (m, 2H), 7.59 (d, J¼8.8 Hz, 1H), 7.92e8.04 (m, 4H). 13C NMR (125 MHz, CDCl3): dC¼25.6, 26.2, 27.3, 57.2, 69.5, 69.7, 70.4, 85.6, 120.2, 120.6, 125.7, 126.7, 127.0, 127.2, 127.7, 127.9, 128.0, 128.1, 128.4, 128.5, 128.9, 131.0, 131.4, 132.3, 138.8, 139.1, 146.4, 147.5. HRMS (ESI-TOF) m/z: [MþH]þ Calcd for C42H41BrO6P 753.1806; Found 753.1811. 4.2.8. 4-(2-Bromo-1,2-diphenylethoxy)butyl diphenyl phosphate (5b). Clear oil; 1H NMR (400 MHz, CDCl3): dH¼1.63e1.70 (m, 2H), 1.83e1.90 (m, 2H), 3.35e3.40 (m, 2H), 4.27e4.33 (m, 2H), 4.54 (d, J¼8.3 Hz, 1H), 4.98 (d, J¼8.3 Hz, 1H), 7.02e7.04 (m, 2H), 7.14e7.22 (m, 13H), 7.31 (t, J¼7.8 Hz, 5H); 13C NMR (125 MHz, CDCl3): dC¼25.6, 27.1 (d, J¼6.8 Hz), 59.1, 68.5, 69.1 (d, J¼6.5 Hz), 85.9, 120.1, 125.3, 127.5, 128.1, 128.2, 128.5, 138.2, 138.7, 150.5, 150.6. 31P NMR (CDCl3): dP¼11.8. HRMS (ESI-TOF) m/z: [MþH]þ Calcd for C30H31BrO5P 583.1075; Found 583.1071. 4.2.9. 4-(2-Bromo-1-biphenyl)butyl diphenyl phosphate (5c). Clear oil; 1H NMR (400 MHz, CDCl3): dH¼1.62e1.66 (m, 2H), 1.76e1.82 (m, 2H), 3.30e3.52 (m, 2H), 4.05e4.09 (m, 4H), 4.43 (dd, J¼12.3, 4.2, 1H), 7.29e7.36 (m, 12H), 7.41e7.48 (m, 7H). 13C NMR (125 MHz, CDCl3): dC¼21.6, 27.0 (d, J¼6.8 Hz), 38.4, 68.5, 70.4 (d, J¼6.5 Hz), 81.7, 120.1, 125.3, 126.4, 126.8, 127.1, 127.2, 127.4, 127.9, 128.1, 129.8,

5

133.1, 138.4, 139.4, 144.6. HRMS (ESI-TOF) m/z: [MþH]þ Calcd for C30H31BrO5P 583.1075; Found 583.1073. 4.2.10. 4-(5-Bromooctan-4-yloxy)butyl diphenyl phosphate (5e). Clear oil; 1H NMR (400 MHz, CDCl3): dH¼0.92 (m, J¼7.2, 6H), 1.25e1.50 (m, 4H), 1.55e1.82 (m, 8H), 3.31e3.35 (m, 1H), 3.42e3.55 (m, 2H), 4.04e4.08 (m, 1H), 4.25e4.30 (m, 2H), 7.16e7.25 (m, 6H), 7.33 (t, J¼7.8 Hz, 4H). 13C NMR (125 MHz, CDCl3): dC¼13.4, 14.0, 19.2, 21.1, 26.1, 27.1, 27.2, 32.8, 35.5, 57.7, 69.1 (d, J¼6.6 Hz), 69.7, 82.5, 120.0 (d, J¼5.0 Hz), 125.2, 129.7, 150.5, 150.6. 31P NMR (CDCl3): dP¼11.8. HRMS (ESI-TOF) m/z: [MþH]þ Calcd for C24H35BrO5P 515.1388; Found 515.1391. 4.2.11. 4-(2-Bromo-1-cyclohexylallyloxy)butyl diphenyl phosphate (5f). Clear oil; 1H NMR (400 MHz, CDCl3): dH¼0.81e0.97 (m, 2H), 0.91e0.97 (m, 3H), 1.54e1.71 (m, 7H), 1.80e1.85 (m, 2H), 1.99 (d, J¼12.7, 1H), 3.12e3.18 (m, 1H), 3.23 (d, J¼7.9 1H), 3.45e3.51 (m, 1H), 4.26e4.31 (m, 2H), 5.64 (s, 1H), 5.74 (s, 1H), 7.15e7.34 (m, 10H); 13C NMR (100 MHz, CDCl3): dC¼25.5, 25.7, 25.9, 26.4, 27.1, 28.7, 29.2, 39.9, 67.9, 69.1 (d, J¼6.3), 88.5, 119.4, 120.0, 125.2, 129.7, 134.7, 150.5, 150.6. 31P NMR (CDCl3): dP¼11.8. HRMS (ESI-TOF) m/z: [MþH]þ Calcd for C25H33BrO5P 525.1231; Found 525.1227. 4.2.12. 4-(2-Bromocyclohexyloxy)butyl diphenyl phosphate (5g). Clear oil; 1H NMR (400 MHz, CDCl3): dH¼1.26e1.27 (m, 3H), 1.64e1.69 (m, 5H), 1.86e1.89 (m, 2H), 2.08e2.10 (m, 1H), 2.27e2.30 (m, 1H), 3.21e3.28 (m, 1H), 3.47e3.52 (m, 1H), 3.55e3.62 (m, 1H), 3.88e3.95 (m, 1H), 4.28e4.43 (m, 2H), 7.24e7.38 (m, 4H), 7.44e7.50 (m, 3H), 7.60 (d, J¼8.8 Hz, 1H), 7.93 (dd, J¼2.4, 8.0 Hz, 2H), 8.00e8.03 (m, 2H). 13C NMR (125 MHz, CDCl3): dC¼23.3, 25.5, 25.9, 27.3, 30.8, 35.7, 55.8, 68.6, 68.7, 69.8, 81.8, 120.2, 120.3, 120.6, 120.7, 121.2, 121.3, 121.4, 125.7, 126.7, 127.0, 127.2, 128.4, 128.5, 131.1, 131.4, 131.8, 132.2, 132.3, 146.3, 146.4, 147.4, 147.5. HRMS (ESI-TOF) m/z: [MþH]þ Calcd for C30H31BrO5P 583.1075; Found 583.1077. 4.2.13. 4-(2-Bromocyclopentyloxy)butyl diphenyl phosphate (5h). Clear oil; 1H NMR (400 MHz, CDCl3): dH¼1.56e1.63 (m, 3H), 1.73e1.86 (m, 4H), 1.94e2.01 (m, 1H), 2.06e2.15 (m, 1H), 2.20e2.29 (m, 1H), 3.38e3.50 (m, 2H), 3.98e4.01 (m, 1H), 4.16e4.19 (m, 1H), 4.26 (dd, J¼6.5, 13.9 Hz, 2H), 7.16e7.20 (m, 6H), 7.31e7.35 (m, 4H); 13 C NMR (125 MHz, CDCl3): dC¼21.7, 25.8, 27.1 (d, J¼6.7 Hz), 29.9, 34.7, 54.2, 68.7, 69.0 (d, J¼6.6 Hz), 88.0, 120.0, 125.3, 129.7, 150.5, 150.6. 31P NMR (CDCl3): dP¼11.8. HRMS (ESI-TOF) m/z: [MþH]þ Calcd for C21H27BrO5P 471.0762; Found 471.0759. 4.2.14. 4-(2-Bromocycloheptyloxy)butyl diphenyl phosphate (5i). Clear oil; 1H NMR (400 MHz, CDCl3): dH¼1.60e1.65 (m, 6H), 1.67e1.69 (m, 3H), 1.80e1.85 (m, 1H), 1.98e2.20 (m, 3H), 2.36e2.39 (m, 1H), 3.37e3.44 (m, 1H), 3.49e3.55 (m, 2H), 4.12e4.28 (m, 1H), 4.30e4.32 (m, 2H), 7.16e7.23 (m, 6H), 7.31e7.35 (m, 4H); 13C NMR (125 MHz, CDCl3): dC¼23.9, 24.1, 26.0, 29.7, 31.7, 32.4, 34.1, 56.8, 67.3, 69.2 (d, J¼6.6 Hz), 80.5, 120.0, 125.2, 129.7, 150.5, 150.6. 31P NMR (CDCl3): dP¼11.8. HRMS (ESI-TOF) m/z: [MþH]þ Calcd for C23H31BrO5P 499.1075; Found 499.1076. 4.2.15. 4-(2-Bromocyclooctyloxy)butyl diphenyl phosphate (5j). Clear oil; 1H NMR (400 MHz, CDCl3): dH¼1.72e2.33 (m, 16H), 3.29e3.38 (m, 3H), 4.25e4.32 (m, 3H), 7.18e7.38 (m, 10H). 13C NMR (125 MHz, CDCl3): dC¼23.8, 25.0, 26.7, 27.1, 27.2, 27.9, 29.7, 30.3, 60.5, 68.7, 69.1 (d, J¼6.6 Hz), 86.4, 120 (d, J¼4.9), 125.2, 129.7, 150.5, 150.6. 31P NMR (CDCl3): dP¼11.9. HRMS (ESI-TOF) m/z: [MþH]þ Calcd for C24H33BrO5P 513.1231; Found 513.1225. 4.2.16. 4-(2-Bromo-1-methylcyclohexyloxy)butyl diphenyl phosphate (5k). Clear oil; 1H NMR (400 MHz, CDCl3): dH¼1.26 (s, 3H), 1.35e1.42 (m, 2H), 1.50e1.70 (m, 5H), 1.79e1.85 (m, 4H), 2.18e2.25

Please cite this article in press as: Sohail, M.; et al., Tetrahedron (2015), http://dx.doi.org/10.1016/j.tet.2015.12.008

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M. Sohail et al. / Tetrahedron xxx (2015) 1e6

(m, 1H), 3.32e3.37 (m, 2H), 4.15e4.18 (m, 1H), 4.27e4.32 (m, 2H), 7.16e7.26 (m, 6H), 7.31e7.35 (m, 4H). 13C NMR (125 MHz, CDCl3): dC¼21.8, 26.2, 27.3, 33.1, 59.9, 60.0, 69.2 (d, J¼6.5 Hz), 75.8, 120.0, 125.2, 129.7, 150.5, 150.6. 31P NMR (CDCl3): dP¼11.8. HRMS (ESITOF) m/z: [MþH]þ Calcd for C23H31BrO5P 497.1094; Found 497.1088. 4.2.17. 3-(2-Bromo-1,2-diphenylethoxy)propyl diphenyl phosphate (6a). Clear oil; Yield 76%; 1H NMR (400 MHz, CDCl3): dH 1.69e1.74 (m, 2H), 3.54 (t, J¼5.4 Hz, 2H), 3.92 (t, J¼6.4 Hz, 2H), 4.86 (d, J¼7.1 Hz, 1H), 5.06 (d, J¼7.1 Hz, 1H), 7.27 (d, J¼8.0 Hz, 2H), 7.35e7.41 (m, 11H), 7.51 (t, J¼7.5 Hz, 2H), 7.62 (t, J¼7.5 Hz, 1H), 7.68 (d,J¼8.2 Hz, 2H), 7.99 (d, J¼7.5 Hz, 2H). 13C NMR (125 MHz, CDCl3): dC¼21.6, 69.1, 69.8 (d, J¼6.6 Hz), 81.9, 120.1, 125.3, 127.5, 128.1, 128.2, 128.6, 138.1, 138.5, 150.6, 150.7. HRMS (ESI-TOF) m/z: [MþH]þ Calcd for C29H29BrO5P 569.0918; Found 569.0921. 4.2.18. 5-(2-Bromo-1,2-diphenylethoxy)pentan-2-yl diphenyl phosphate (6c). Clear oil; 1H NMR (400 MHz, CDCl3): dH¼1.24 (d, J¼6.2 Hz, 3H), 1.40e1.51 (m, 4H), 3.12e3.19 (m, 1H), 3.23e3.31 (m, 1H), 4.60e6.63 (m, 2H), 4.65 (d, J¼7.0, 1H), 4.96 (d, J¼7.0 Hz, 1H), 7.16e7.34 (m, 20H); 13C NMR (125 MHz, CDCl3): dC¼21.5, 24.9, 33.6 (d, J¼6.4), 57.0, 68.8, 69.2, 85.6, 120.1, 125.2, 127.7, 128.0, 128.1, 128.8, 129.7, 138.9, 150.6, 150.7. 31P NMR (CDCl3): dP¼12.5. HRMS (ESI-TOF) m/z: [MþH]þ Calcd for C31H33BrO5P 597.1231; Found 597.1229. 4.2.19. 4-(2-Chloro-1,2-diphenylethoxy)butyl diphenyl phosphate 3a (X¼Cl). Clear oil; 1H NMR (400 MHz, CDCl3): dH¼1.4e1.56 (m, 4H), 3.12e3.18 (m, 1H), 3.27e3.32 (m, 1H), 4.07e4.12 (m, 2H), 4.53 (d, J¼6.9 Hz, 1H), 4.88 (d, J¼6.9 Hz, 1H), 7.15e7.34 (m, 20H); HRMS (ESITOF) m/z: [MþH]þ Calcd for C30H31ClO5P 537.1600; Found 537.1595. 4.3. Activity against human lung adenocarcinoma cells The effect of drugs on A549 Lung adenocarcinoma cell viability was measured by MTT assay. Briefly, about 5000 cells were seeded into 96 well tissue culture plates. After 24-h incubation at 37  C, cells were treated with different drugs (2 mL of 130 mM) for 24 h. The MTT reagent was then added to each well (500 mg/mL), and the cells were further incubated for 4 h. Subsequently, 150 mL dimethyl sulfoxide (DMSO) was added to dissolve farmazan crystals, and absorbance was measured at 570 nm in a thermo micro plate reader (Thermo Scientific, USA). 3a and 5f were freshly dissolved in DMSO immediately prior to cellular drug exposure(s). The final concentration of DMSO in all experiments did not exceed 0.08% by volume. Experiments were done in triplicate and error bars indicated standard deviation. Acknowledgements We acknowledge the research support by the National Natural Science Foundation of China (Grant 21325627). Supplementary data Supplementary data (comprising 1H and 13C NMR for all new compounds) associated with this article can be found in the online version, at http://dx.doi.org/10.1016/j.tet.2015.12.008. References and notes 1. (a) Jacek, S.; Adam, K. Acc. Chem. Res. 2002, 35, 952; (b) Zeng, Y.; Tan, X.; Zhang, L.; Long, H.; Wang, B.; Li, Z.; Yuan, Z. Mol. Breed. 2015, 35, 1; (c) Ba1czewski, P.; Skalik, J. Organophosphorus Chem. 2012, 41, 251; (d) Mader, M. M.; Bartlett, P. A. Chem. Rev. 1997, 97, 1281.

2. (a) Boger, D. L.; Lewy, D. S.; Gauss, C. M.; Soenen, D. R. Curr. Med. Chem. 2002, 22, 2005; (b) Peck, S. C.; Gao, J.; Van der Donk, W. A. Methods Enzymol. 2012, 516, 101; (c) Lee, J. H.; Bae, B.; Kuemin, M.; Circello, B. T.; Metcalf, W. W.; Nair, S. K.; Van der donk, W. A. PNAS 2010, 107, 17557. 3. For selective examples, (a) Westheimer, F. H. Science 1987, 235, 1173; (b) Zhang, F.; Wang, L.; Zhang, C.; Zhao, Y. Chem. Commun. 2014, 2046; (c) Beaton, S. A.; Jiang, P. M.; Melong, J. C.; Loranger, M. W.; Mohamady, S.; Veinot, T. I.; Jakeman, D. L. Org. Biomol. Chem. 2013, 11, 5473; (d) Engels, R. Chem. Rev. 1977, 77, 349; (e) Black, R. M.; Harrison, J. M. In The Chemistry of Organophosphorus Compounds; Harley, F. R., Ed.; Willey: Chichester, UK, 1996; pp 781e840; (f) Hampel, T.; € ckner, R. Bioorg. Med. Bruns, M.; Bayer, M.; Handgretinger, R.; Bruchelt, G.; Bru Chem. Lett. 2014, 24, 2728. 4. (a) Alon, M.; Alon, F.; Nauen, R.; Morin, S. Insect Biochem. Mol. 2008, 38, 940; (b) Buchet, J. P.; Lauwerys, R. Biochim. Biophys. Acta 1970, 218, 369; (c) Marina, S.; Franziska, K.; Bernhard, S.; Christoph, B.; Annette, S.; Dirk, S.; Horst, T.; James, K. C.; Christine, P. Chem.-Biol. Interact. 2013, 206, 472. 5. (a) Ye, J.; Zhao, M.; Niu, L.; Liu, W. Chem. Res. Toxicol. 2015, http://dx.doi.org/10. 1021/tx500481n; (b) Al-Badry, S; Mahdiy, C. O. Knowles, Arch. Environ. Con. Tox. 1980, 9, 147; (c) Tang, J.; Xu, H.; Liu, J.; Pan, G.; Wu, X.; Li, W. Organophosphorus fungicide containing pyrimidine and application thereof., CN patent 103766393, May 7, 2014; (d) Makhaeva, G. F.; Aksinenko, A. Y.; Sokolov, V. B.; Serebryakova, O. G.; Richardson, R. J. Bioorg. Med. Chem. Lett. 2009, 19, 5528. 6. (a) Anger, M. Cell Cycle 2010, 9, 2708; (b) Besant, P. G.; Attwood, P. V. Biochem. Soc. Trans. 2012, 40, 290; (c) Kutuzov, M. A.; Andreeva, A. V. Mol. Biochem. Parasitol. 2008, 161, 81. 7. (a) Charmantray, F.; Dellis, P.; Samreth, S.; Hecquet, L. Tetrahedron Lett. 2006, 47, 3261; (b) Plante, O. J.; Palmacci, E. R.; Andrade, R. B.; Seeberger, P. H. J. Am. Chem. Soc. 2001, 123, 9545; (c) Hunt, D. K.; Seeberger, H. Org. Lett. 2002, 4, 2751; (d) Adelt, S.; Plettenburg, O.; Stricker, R.; Reiser, G.; Altenbach, H.-J.; Vogel, G. J. Med. Chem. 1999, 42, 1262. 8. (a) Lampson, G. P.; Lardy, H. A. J. Biol. Chem. 1949, 181, 697; (b) Pederson, R. L.; Liu, K. K.-C.; Rutan, J. F.; Chen, L.; Wong, C.-H. J. Org. Chem. 1990, 55, 4897; (c) rard, C.; Alphand, V.; Archelas, A.; Demuynck, C.; Hecquet, L.; Furstoss, R.; Gue Bolte, J. Eur. J. Org. Chem. 1999, 3399. 9. (a) Alford, J. S.; Davies, H. M. L. J. Am. Chem. Soc. 2014, 136, 10266; (b) Ganem, B. Acc. Chem. Res. 2009, 42, 463; (c) Domling, A. Chem. Rev. 2005, 106, 17; (d) Toure, B. B.; Hall, D. G. Chem. Rev. 2009, 109, 4439; (e) Marek, I.; Minko, Y.; Pasco, M.; Mejuch, T.; Gilboa, N.; Chechik, H.; Das, J. P. J. Am. Chem. Soc. 2014, 136, 2682. 10. (a) Solovyev, A.; Lacote, E.; Curran, D. P. Dalton Trans. 2013, 42, 495; (b) Umeda, R.; Nishimura, T.; Kaiba, K.; Tanaka, T.; Takahashi, Y.; Nishiyama, Y. Tetrahedron 2011, 67, 7217; (c) Enthaler, S.; Weidauer, M. Catal. Lett. 2012, 142, 168; (d) Qin, H.-L.; Lowe, J. T.; Panek, J. S. J. Am. Chem. Soc. 2007, 129, 38; (e) Deng, H.; Shen, Z.; Li, L.; Yin, H.; Chen, J. J. Appl. Polym. Sci. 2014, http://dx.doi.org/10.1002/APP. 40503; (f) Snyder, S A.; Treitler, D. S.; Brucks, A. P.; Sattler, W. J. Am. Chem. Soc. 2011, 133, 15898. 11. (a) He, R.; Jin, X.; Chen, H.; Huang, Z.-T.; Zheng, Q.-Y.; Wang, C. J. Am. Chem. Soc. 2014, 136, 6558; (b) Sohail, M.; Khan, M.; Zhang, Y.; Peng, C.; Chen, Q.; Zhao, Z. K. Tetrahedron Lett. 2015, 26, 5743; (c) Sohail, M.; Zhang, Y.; Sun, G.; Guo, X.; Liu, W.; Liu, C.; Zhao, Z. K. Chem. Commun. 2015, 4774; (d) Sohail, M.; Zhang, Y.; Liu, W.; Chen, Q.; Wang, L.; Zhao, Z. K. RSC Adv. 2015, 5, 17014. 12. (a) Poss, M. J.; Nordhaus, M. A.; Stagliano, K. W. Synthesis 1999, 1193; (b) Fantasia, S.; Welch, J. M.; Togni, A. J. Org. Chem. 2010, 75, 1779; (c) Wang, B.; Gu, Y.; Gong, W.; Kang, Y.; Yang, L.; Suo, J. Tetrahedron 2004, 45, 6599; (d) Yasuhiro, T.; Hamada, M.; Kai, N.; Nagai, T. J. Heterocycl. Chem. 2000, 37, 1351. 13. (a) Kwon, D. W.; Kim, Y. H.; Lee, K. J. Org. Chem. 2002, 67, 9488; (b) Travia, N. E.; Monreal, M. J.; Scott, B. L.; Kiplinger, J. L. Dalton Trans. 2012, 41, 14514; (c) Huang, W.; Xiang, J.; He, W. Chem. Lett. 2014, 43, 893. 14. For selective examples, (a) Arrowsmith, M.; Crimmin, M. R.; Hill, M. S.; Kociok€ hn, G. Dalton Trans. 2013, 42, 9720; (b) Krabbe, S. W.; Angeles, V. V.; Mohan, Ko R. S. Tetrahedron Lett. 2010, 51, 5643; (c) N€ arhi, S. M.; Malo, K.; Oilunkaniemi, R.; Laitinen, R. S. Polyhedron 2013, 65, 308. 15. (a) Meyer, O.; Ponaire, S.; Rohmer, M.; Grosdemange-Billiard, C. Org. Lett. 2006, 8, 4347; (b) Miao, Y.; Phuphuak, Y.; Rousseau, C.; Bousquet, T.; Mortreux, A.; Chirachanchai, S.; Zinck, P. J. Polym. Sci., Part A: Polym. Chem. 2013, 51, 2279. 16. (a) Murase, T.; Sato, S.; Fujita, M. Angew. Chem., Int. Ed. 2007, 46, 1083; (b) Mommen, G. P. M.; Hamzink, M. R. J.; Zomer, G.; Jong, A. P. J. M. D.; Meiring, H. D.; Zomer-Elhadari, J. W. Protein Affinity Tag and Uses Thereof, US patent 0017797, Jan. 16, 2014; 17. (a) Full details appear in the Supporting information; (b) Extremely anhydrous condition was important for higher yields; (c) Trace amount of water increased the formation of a,a-dibromo alkene, a side product. 18. (a) Parra, A.; Reboredo, S.; Castro, A. M. M.; Alem an, J. Org. Biomol. Chem. 2012, 10, 5001; (b) Terada, M.; Li, F.; Toda, Y. Angew. Chem., Int. Ed. 2014, 53, 235. 19. (a) Murai, T.; Takenaka, T.; Inaji, S.; Tonomura, Y. Chem. Lett. 2008, 37, 1198; (b) Barr, L.; Easton, C. J.; Lee, K.; Lincoln, S. F.; Simpson, J. S. Tetrahedron Lett. 2002, 43, 7797. 20. THF dimerized product like 4a was also separated in appreciable amount. 21. Hennecke, U.; MVuller, C. H.; FrVohlich, R. Org. Lett. 2011, 13, 860. 22. Detailed reaction mechanism investigations are highlighted in the supporting information. (a) Lo, H. C.; Han, H.; D’Souza, L. J.; Sinha, S. C.; Keinan, E. J. Am. Chem. Soc. 2007, 129, 1246; (b) Oku, A.; Kimura, K.; Ohwaki, S. Acta Chem. Scand. 1993, 47, 391. 23. (a) van Blitterswijk, W. J.; Verheij, M. Biochim. Biophys. Acta 2013, 1831, 663; (b) Chen, W.; Deng, Z.; Chen, K.; Dou, D.; Song, F.; Li, L.; Xi, Z. Eur. J. Med. Chem. 2015, 93, 172. 24. Mertins, S. D.; Myers, T. G.; Holbeck, S. L. Mol. Cancer Ther. 2004, 3, 849.

Please cite this article in press as: Sohail, M.; et al., Tetrahedron (2015), http://dx.doi.org/10.1016/j.tet.2015.12.008