Letter Cite This: Org. Lett. 2018, 20, 4938−4941
pubs.acs.org/OrgLett
Tf2O‑Promoted Activating Strategy of Phosphate Analogues: Synthesis of Mixed Phosphates and Phosphinate Hai Huang,†,‡ Jeffrey Ash,† and Jun Yong Kang*,† †
Org. Lett. 2018.20:4938-4941. Downloaded from pubs.acs.org by UNIV OF SOUTH DAKOTA on 08/17/18. For personal use only.
Department of Chemistry and Biochemistry, University of Nevada Las Vegas, 4505 South Maryland Parkway, Las Vegas, Nevada 89154-4003, United States ‡ Department of Applied Chemistry, College of Chemistry and Molecular Engineering, Nanjing Tech University, No. 30 Puzhu Road (S), Nanjing 211816, People’s Republic of China S Supporting Information *
ABSTRACT: A metal-, toxic chloride reagent-free activating strategy of various phosphates has been developed. This method enables the facile synthesis of functional phosphates such as alkyl phosphates, aza phosphates, thiophosphate, and mixed diaryl phosphates. A transient phosphorylpyridin-1-ium species in situ generated from phosphates with Tf2O/pyridine readily undergoes a substitution reaction with diverse nucleophiles to form versatile phosphate compounds.
reagents due to their chemical inertness. In 2014, Feringa and co-workers reported an elegant activation strategy of phosphonate substrates for the synthesis of mixed alkyl aryl phosphonates via a copper-catalyzed direct arylation of dialkylphosphonates with diaryliodonium salts.8 However, the current activating strategies of chemically inert pentavalent phosphorus species mainly rely on stepwise processes, which involve a substitution reaction of a pregenerated alkyl phosphorus electrophile with nucleophiles.2a,9 Thus, a direct functionalization strategy of inertial phosphates is of great necessity, yet it remains a challenge.10 The Tf2O-triggered activation of carbonyl compounds,11 sulfoxides,12 and phosphine oxides13 has become an important synthetic tool in organic synthesis. Recently, we reported a direct nucleophilic substitution reaction of dialkyl phosphonates with hydroxyl compounds for the synthesis of mixed phosphonates in which a highly reactive phosphorylpyridin-1ium intermediate A could be in situ generated (Scheme 2, a).14 With an enduring interest in organophosphorus compounds and as part of our continued effort to contribute to diverse
Organophosphate analogues are ubiquitous structural motifs widely present in pharmaceuticals and bioactive small molecules.1 The development of an efficient method for the synthesis of these analogues is highly desirable but challenging in organophosphorus chemistry. Over the past decades, a number of synthetic methods for phosphate derivatives employing different phosphorus reagents have been developed. Prefunctionalized P(O)−X substrates have been commonly used for the construction of organophosphate compounds (Scheme 1, a).2 Nevertheless, this procedure suffered from Scheme 1. Methods for the Synthesis of Phosphates
shortcomings such as stepwise synthesis, limited functional group tolerance, and moisture-sensitive reagents. Atherton and Todd introduced dialkyl phosphites (P(O)−H) as a phosphorylation reagent in 1947 (Scheme 1, b).3 A highly reactive in situ formed halogen phosphonate intermediate is responsible for phosphorylation of alcohol and amine nucleophiles via a substitution reaction.3,4 In addition, dialkyl phosphates (P(O)−OH) with a chemically differentiated −OH group on the phosphorus atom are efficiently activated under basic conditions, and they have been subjected to esterification,5 alkylation,6 and coupling reactions7 to give phosphate compounds (Scheme 1, c). On the other hand, pentavalent phosphorus species such as phosphate/phosphonate/phosphinate moieties are underused as phosphorylation © 2018 American Chemical Society
Scheme 2. Activation Strategies of Phosphonates/ Phosphates as P-reagents
Received: July 2, 2018 Published: August 8, 2018 4938
DOI: 10.1021/acs.orglett.8b02073 Org. Lett. 2018, 20, 4938−4941
Letter
Organic Letters Scheme 3. Scope of Nucleophilesa
organophosphate synthesis employing the chemically stable phosphate moieties, we hypothesized that trialkyl phosphates could be also activated by Tf2O/pyridine to afford the phosphorylpyridin-1-ium intermediate,15 which is then converted to functional phosphates via a nucleophilic substitution reaction (Scheme 2, b). Herein, we report a general activating strategy of phosphate analogues for the synthesis of phosphate derivatives and mixed phosphates. To test our hypothesis, we used triethyl phosphate 1a and phenol 2a as model substrates to optimize the reaction conditions (Table 1). When our previous optimized reaction Table 1. Optimization of the Reaction Conditionsa
entry
base
X/Y/Z
yieldb (%)
1 2 3 4 5 6 7 8 9 10
pyridine pyridine pyridine pyridine pyridine pyridine lutidine DMAP DABCO DBU
1.5/2.0/2.5 1.5/2.0/2.0 1.5/2.0/1.5 2.0/2.0/2.0 1.5/1.1/2.0 1.5/1.5/2.0 1.5/2.0/2.0 1.5/2.0/2.0 1.5/2.0/2.0 1.5/2.0/2.0
96 99 (92)c 43 92 80 70 d d d d
a
Reaction conditions: 1a (0.2 mmol), Tf2O (X equiv), base (Y equiv) in DCM (1.0 mL) for 10 min, then 2a (Z equiv) for 30 min. bYield was determined by 1H NMR on the crude reaction mixture using 1,3,5-trimethylbenzene as an internal standard. cIsolated yield. dMajor product was PhOTf.
a
Reaction conditions: 1 (0.2 mmol), Tf2O (0.3 mmol), pyridine (0.4 mmol) in DCM (1.0 mL) for 10 min, then 2 (0.4 mmol) for 30 min; isolated yields are given. bA gram-scale experiment with 6.0 mmol of 1a.
sesamol, and ferulate demonstrated good functional group tolerance (e.g., carbonate, ester, ether, and acrylate), yielding the corresponding products in high yields (Scheme 3, 3o−r). Importantly, the reaction of 1a with a cholesterol-derived phenol provided a phosphorylated cholesteryl ester 3s with a biologically important phosphate moiety in 76% yield (Scheme 3, 3s). Furthermore, we evaluated the reactivity of other nucleophiles under the standard reaction conditions (Scheme 3, 3t−aa). Both primary and secondary aliphatic alcohols were also efficiently coupled with phosphate 1a to yield alkyl phosphates 3t−v in 49−87% yields. Finally, we demonstrated that amine and thiol nucleophiles can be employed in this transformation to provide the aza phosphates 3w−z and thiophosphate 3aa in acceptable to moderate yields. However, amine and thiol nucleophiles could also undergo a substitution reaction directly with Tf2O to form amine triflates and thiol triflate, respectively, due to their strong nucleophilicity. The synthesis of mixed diaryl phosphates from aryl dialkylphosphates is a challenging synthetic transformation in organophosphate chemistry since it requires exquisite control of reactivity and chemoselectivity to prevent dual substitution reaction of the two alkoxy groups.16 Hence, we explored a selective synthesis of mixed diaryl phosphates from the aryl dialkylphosphates shown in Scheme 4. Phenyl phosphate 3a was used as a starting material, and it was efficiently coupled with arenols bearing different substituents such as methyl, halo, CN, CF3, and aryl groups to afford the corresponding mixed diarylphosphates 4a−g in 74−88% yields. 1-Naphthol and 2-
conditions for mixed phosphonate were employed, the desired phenyl phosphate 3a was generated in 96% yield by NMR (Table 1, entry 1). Further control experiments revealed that the optimized reaction conditions need 2 equiv of phenol 2a, providing the target compound with 92% isolated yield (Table 1, entries 2−6). Evaluation of other bases such as lutidine, DMAP, DABCO, and DBU provided no target products (Table 1, entries 7−10). With the optimized reaction conditions in hand, the scope of this reaction was explored with phosphates 1 and diverse arenol nucleophiles 2 to synthesize phosphate derivatives 3 (Scheme 3). To demonstrate scalability of this reaction, we first performed a gram-scale reaction of 1a (1.09 g, 6.0 mmol) with 2a, which afforded the target phosphonate product 3a (1.24 g) in 90% yield (Scheme 3, 3a). Generally, the electronic effects of substituents on the phenyl ring have a negligible effect on this transformation. The reaction tolerates various phenols with diverse substituents (Me, MeO, Br, I, NO2, Ph) and polycyclic aromatic alcohols such as 1-naphthol and 2naphthol, providing the desired aryl phosphates in 71−91% yields (Scheme 3, 3b−k). However, a bulky nucleophile such as 2,6-diisopropyl phenol reduced the reactivity and provided the target product 3m in 53% yield due to steric hindrance. On the other hand, a sterically bulky phosphate electrophile, triisopropyl phosphate 1b, afforded the corresponding diisopropyl phosphate 3n in 73% yield (Scheme 3, 3n). Next, we investigated the late-stage phosphorylation of various natural products. The phosphorylation of quinol, coumarin, 4939
DOI: 10.1021/acs.orglett.8b02073 Org. Lett. 2018, 20, 4938−4941
Letter
Organic Letters Scheme 4. Synthesis of Mixed Phosphatesa
Scheme 6. Continuous-Flow System for Phosphate Synthesis
a
Reaction conditions: 3a (0.2 mmol), Tf2O (0.3 mmol), pyridine (0.4 mmol) in DCM (1.0 mL) for 10 min, then 2 (0.4 mmol) for 30 min; isolated yields are given.
Scheme 7. Proposed Mechanistic Pathway
naphthol were also proven to be suitable substrates under the standard reaction conditions, providing the mixed diarylphosphates 4h and 4i in 73% and 85% yields, respectively. In addition, a natural compound sesamol also furnished the corresponding mixed diaryl phosphate 4j in 81% yield. Furthermore, this reaction tolerates an azo functional group on a phenyl ring, which generated the desired product 4k in high yield (87%). Finally, this synthetic protocol has been successfully applied for the conversion of an alkylphosphinate to an arylphosphinate,17 demonstrating a general activating procedure of all three different oxygen-containing pentavalent phosphorus compounds (phosphate, phosphonate,14a and phosphinate). When diphenyl ethylphosphinate 1c was treated with p-cresol, the target arylphosphinate 5a was obtained in 74% yield (Scheme 5).
transformed to the phosphates 3 via a substitution reaction with different nucleophiles. In summary, we have developed a new synthetic strategy for the activation of pentavalent organophosphorus compounds (phosphate, phosphinate) in which a phosphorylpyridin-1-ium intermediate is generated in situ from a phosphate with Tf2O/ pyridine. This electrophilic P-species efficiently undergoes a nucleophilic substitution reaction with various nucleophiles (aliphatic alcohols, arenols, amines, and thiol) to provide functional phosphate compounds under metal-free reaction conditions. The synthetic utility of this phosphorylation has been demonstrated by late-stage phosphorylation of natural compounds. In addition, a continuous-flow system for the synthesis of phosphates has been demonstrated. Further studies on the development of an efficient synthesis of functional phosphorus compounds based on the in situ generated P-species, especially for improving the product yields of aza phosphates and thio phosphates, are underway.
Scheme 5. Direct Arylation of Alkyl Phosphinate
With the potential application of this versatile synthetic transformation (short reaction time, high tolerance of functional groups, and mild reaction conditions) to the chemical enterprise, we explored the development of a continuous-flow synthesis system to further demonstrate the synthetic utility of this method.5a,18 While enzymatic synthesis of phosphorylated compounds via continuous-flow reactor has been reported,19 chemical synthesis of phosphorus compounds using flow chemistry is underdeveloped. Hence, an aryloxylation reaction was conducted to test amenability in a continuous-flow reactor as described in Scheme 6. This continuous-flow procedure efficiently furnished the desired aryl phosphate 3a in 78% yield (see the Supporting Information for the details). In addition, a natural compound sesamol can also afford the corresponding phosphate 3q in moderate yield (42% yield) under this continuous-flow system. Based on our previous work,14 we propose a plausible mechanism for the formation of phosphates 3 (Scheme 7). Phosphate 1a reacts with Tf2O to give a phosphonium intermediate I. Next, TfO-substituted phosphonate II and ethyl triflate byproduct are generated from the intermediate I via an SN1-type mechanism.8 Then pyridine attacks the intermediate II to form a highly reactive electrophilic phosphorylpyridin-1-ium III. Finally, this intermediate III is
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ASSOCIATED CONTENT
S Supporting Information *
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.8b02073. Experimental details (PDF) Spectral data of all new compounds (PDF)
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AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. ORCID
Jun Yong Kang: 0000-0002-7178-2981 4940
DOI: 10.1021/acs.orglett.8b02073 Org. Lett. 2018, 20, 4938−4941
Letter
Organic Letters Notes
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The authors declare no competing financial interest.
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ACKNOWLEDGMENTS This work was supported by the University of Nevada Las Vegas. Maciej Kukula at SCAAC is acknowledged for mass spectral data.
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DOI: 10.1021/acs.orglett.8b02073 Org. Lett. 2018, 20, 4938−4941
