Download PDF
Synthesis 2012; 44(10): 1521-1525
DOI: 10.1055/s-0031-1290806
special topic
© Georg Thieme Verlag Stuttgart · New York

Copper-Catalyzed Aerobic Oxidative Trifluoromethylation of H-Phospho­nates Using Trimethyl(trifluoromethyl)silane

Lingling Chu
a   Key Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345 Lingling Lu, Shanghai 200032, P. R. of China
,
Feng-Ling Qing*
a   Key Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345 Lingling Lu, Shanghai 200032, P. R. of China
b   College of Chemistry, Chemical Engineering and Biotechnology, Donghua University, 2999 North Renmin Lu, Shanghai 201620, P. R. of China, Fax: +86(21)64166128   Email: flq@mail.sioc.ac.cn
› Author Affiliations
Further Information

Publication History

Received: 16 February 2012

Accepted after revision: 05 March 2012

Publication Date:
11 April 2012 (online)

 
 PDF Download Permissions and Reprints All articles of this category


Abstract

Copper-catalyzed aerobic oxidative trifluoromethylation of readily accessible H-phosphonates was demonstrated for the first time. This method not only provides an alternative method for the facile synthesis of a series of biologically important CF3-phosphonates, but also demonstrates the first example of the efficient construction of a P–CF3 bond via transition-metal catalysis.


#

Key words

copper catalysis - phosphonates - trifluoromethylation

The introduction of the trifluoromethyl (CF3) group into organic molecules can bring about remarkable changes in physical, chemical, and biological properties because of the strongly electron-withdrawing nature and large hydrophobic domain of the trifluoromethyl group.[ 1 ] As a consequence, tremendous effort has been devoted to the introduction of the trifluoromethyl group into organic structures. This has led to numerous methods for the efficient incorporation of the trifluoromethyl group into diverse organic molecules using nucleophilic, electrophilic, or radical sources.[2] [3] Recently, the transition-metal-mediated or -catalyzed fluoroalkyl cross-coupling reaction has proven to be an attractive and efficient trifluoromethylation protocol.[ 3 ] In particular, it is now possible to fulfill the direct trifluoromethylation of C–H bonds of aromatics, alkynes, or olefins in the presence of transition-metal catalysts, precluding the need for the prefunctionalization of substrates.[ 4 ] Despite this extensive progress, current trifluoromethylation methods are limited to the construction of C–CF3 linkages. In contrast, the analogous generation of heteroatom–CF3 bonds from heteroatom–H bonds without the need for prefunctionalization remains largely unexplored,[ 5 ] particularly via transition-metal catalysis. In fact, to the best of our knowledge, the sole protocol involving direct trifluoromethylation at a heteroatom is the electrophilic trifluoromethylation of N-, O-, S, or P-centered nucleophiles developed by Umemoto[5a] [b] and Togni.[5c] [d] [e] [f] [g] [h] Herein, we disclose a new methodology for catalytically constructing P–CF3 bonds via aerobic oxidative trifluoromethylation of H-phosphonates with a nucleophilic trifluoromethylating reagent (Scheme [1]).

Zoom Image
Scheme 1 Oxidative trifluoromethylation of H-phosphonates

Phosphonates are an important class of compounds because of their potential as analogues of biologically important phosphates, and a number of new phosphonates have been investigated for their diverse biological activity.[ 6 ] However, there has been relatively little investigation of fluorinated phosphonates,[ 7 ] although fluorinated phosphonates were found to be excellent mimics of phosphate esters[ 6 ] as well as analogues of enzyme inhibitors.[ 8 ] The dearth of fluorinated phosphonates especially trifluoromethylated phosphonates can be attributed to a lack of synthetic methods since common methods used for the preparation of phosphonates cannot be directly applied to trifluoromethylated analogues. For example, chlorotri­fluo­romethane and trifluoroiodomethane were found to be totally unreactive under the traditional conditions of the Michaelis–Arbuzov reaction, and a photochemical modification of the Arbuzov reaction was required for the preparation of CF3-phosphonates.[ 9 ] In recent years, only rare examples of synthetic methodology for these compounds have been reported.[10] [11] [12] In 1997, Burton reported a photochemically induced radical reaction of tetraethyl diphosphite [(EtO)2POP(OEt)2] and trifluoroiodomethane in the presence of di-tert-butyl peroxide providing diethyl trifluoromethylphosphonate in moderate yield.[ 11 ] Later, synthesis of CF3-phosphonates via nucleophilic trifluoromethylation of fluorophosphines followed by oxidation or direct nucleophilic trifluoromethylation of P-fluorophosphonates was reported,[ 12 ] however, the starting materials are not common and are also not commercially available. Alternatively, Yagupolskii has shown that CF3-phosphonates can be prepared from readily available H-phosphonates using diaryltrifluoromethylsulfonium salts as the electrophilic trifluoromethylating reagent.[ 13 ] Obviously, the development of a simpler and general methodology to install the trifluoromethyl group into phosphonates is still desired.

Recent reports from our group regarding a copper-mediated or -catalyzed oxidative trifluoromethylation protocol using the nucleophilic trifluoromethylating reagent trimethyl(trifluoromethyl)silane (Ruppert–Prakash reagent, CF3SiMe3), have allowed direct and efficient introduction of the trifluoromethyl group into various substrates such as terminal alkynes,[ 4b ] aryl boronic acids[ 3h ] and heteroaromatics.[ 4k ] In light of these results, we hypothesized that a similar copper-catalyzed oxidative trifluoromethylation protocol might allow the formation of a P(O)–CF3 bond.

Table 1 Copper-Catalyzed Aerobic Trifluoromethylation of Diethyl Phosphonatea

Entry

Cu catalyst (30 mol%)

Ligand (30 mol%)

Solvent (0.3 M)

Yieldb (%)

 1

Cu(OH)2

phen

DCE

63

 2

Cu(OEt)2

phen

DCE

60

 3

Cu(OAc)2

phen

DCE

29

 4

CuOAc

phen

DCE

54

 5

CuCl2

phen

DCE

20

 6

Cu(OH)2

phen

DCE

56 (78)c

 7

Cu(OH)2

TMEDA

DCE

–

 8

Cu(OH)2

2,2′-bipyridine

DCE

–

 9

Cu(OH)2

2,4,6-trimethylpyridine

DCE

–

10

Cu(OH)2

phen

CH2Cl2

trace

11

Cu(OH)2

phen

toluene

77

12

Cu(OH)2

phen

DMF

–

13

Cu(OH)2

phen

THF

15

a Reaction conditions: 1a (0.3 mmol), copper catalyst (0.09 mmol), ligand (0.09 mmol), CF3SiMe3 (1.2 mmol), K2CO3 (1.2 mmol), solvent (1 mL), 50 °C, 24 h, under air.

b Yield was determined by 19F NMR analysis using (trifluoromethyl)benzene as an internal standard.

c The reaction was conducted for 36 h.

We first examined the ability of various copper salts to catalyze the oxidative trifluoromethylation of diethyl phosphonate (1a) using trimethyl(trifluoromethyl)silane as the trifluoromethylating reagent and potassium carbonate as the base under an air atmosphere (Table [1]). The result showed that copper(II) hydroxide was a good catalyst for the reaction affording the desired product 2a in 63% yield together with the remaining starting material (entry 1). In contrast, 1a was totally consumed in the presence of other Cu(I) or Cu(II) salts while the formation of side product 3a (detected by GC-MS)[ 14 ] diminished the reaction efficiency (entries 2–5). The complete transformation of the starting material 1a was fulfilled by simply prolonging the reaction time from 24 hours to 36 hours and 2a could be obtained in 78% yield (entry 6). The use of 1,10-phenanthroline (phen) as the ligand is essential for this transformation (entry 6). Switching to other ligands such as N,N,N′,N′-tetramethylethylenediamine (TMEDA), 2,2′-bipyridine, and 2,4,6-trimethylpyridine led to no observed formation of 2a (entries 7–9). Further optimization of the solvent suggested that the solvent highly affected this reaction. Although toluene gave a comparable yield of 2a, dichloromethane, N,N-dimethylformamide, and tetrahydrofuran­ dramatically suppressed the reaction (entries 10–13).

Table 2 Copper-Catalyzed Oxidative Trifluoromethylation of H-Phosphonatesa

Entry

Substrate

R

Copper salt (mol%)

Product

Yieldb (%)

1

1a

Et

Cu(OH)2 (30)

2a

56

2

1b

Pr

Cu(OH)2 (60)

2b

73

3

1c

Bu

Cu(OEt)2 (30)

2c

87

4

1d

i-Bu

Cu(OEt)2 (30)

2d

85

5

1e

(CH2)5Me

Cu(OH)2 (60)

2e

90

6

1f

(CH2)4Cl

Cu(OH)2 (30)

2f

70

7

1g

cyclohexyl

Cu(OEt)2 (30)

2g

76

a Reaction conditions: 1 (0.3 mmol), copper catalyst (0.09 mmol or 0.18 mmol), phen (0.09 mmol or 0.18 mmol), CF3SiMe3 (1.2 mmol), K2CO3 (1.2 mmol), DCE (1 mL), 50 °C, 36 h, under air, sealed tube.

b Isolated yield.

With the optimized condition in hand, we next tested the scope of the reaction with other H-phosphonates. The copper-catalyzed aerobic oxidative trifluoromethylation protocol can be applied to other H-phosphonates to produce the corresponding CF3-phosphonates (Table [2]). However, the reaction efficiency was highly dependent on the substrate. In the presence of 30 mol% copper(II) hydroxide, only substrates 1a and 1f readily gave the desired coupling products in moderate yields (entries 1, 6), while other H-phosphonates were almost unreactive (entries 2–5, 7). Increasing the loading of copper(II) hydroxide from 30 mol% to 60 mol% only encouraged the desired oxidative trifluoromethylation of the two substrates (1b, 1e) and led to moderate yields of the corresponding CF3-phosphonates (entries 2, 5). To our delight, switching the catalyst copper(II) hydroxide to the more reactive copper(II) ethoxide dramatically facilitated the transformation of substrates 1c, 1d, and 1g, providing the corresponding products in high to excellent yields (entries 3, 4, 7). The reason for the high substrate-dependence remains obscure.

In summary, a copper-catalyzed oxidative trifluoromethylation of readily accessible H-phosphonates with trimethyl(trifluoromethyl)silane was revealed for the first time. The new methodology not only allows for the facile synthesis of biologically important trifluoromethylphosphonates without the need for prefunctionalization, but also has potential for the formation other new transition-metal-catalyzed heteroatom–CF3 bonds, such as N–CF3, O–CF3, and S–CF3 bonds. Ongoing studies are focused on the clarification of the reaction mechanism and expanding the scope of this transformation.

Unless otherwise noted, all reactions were heated on hot plates with oil baths calibrated to an external thermometer. Prior to starting experiments, the hot plate was turned on, and the oil bath was allowed to equilibrate to the desired temperature over 30 min. 1H and 19F NMR spectra (CFCl3 as outside standard and low field is positive) were recorded on a Bruker AM300 spectrometer. 13C NMR was recorded on a Bruker AM400 spectrometer. Unless otherwise noted, all reagents were obtained commercially and used without further purification. Substrates 1a–d were purchased from commercial sources (Aldrich, Alfa and TCI) and used as received. Substrates 1e–g were prepared according to literature procedures.[ 5g ] Reactions were performed under an atmosphere of air using glassware that was flame-dried under vacuum.


#

Trifluoromethylphosphonates 2a–g; General Procedure

To an oven-dried 40-mL sealed tube containing a magnetic stir bar in air, were added Cu(OH)2 (0.09 mmol or 0.18 mmol) or Cu(OEt)2 (0.09 mmol), 1,10-phenanthroline (0.09 mmol or 0.18 mmol), K2CO3 (1.20 mmol), DCE (1 mL), then substrate 1 (0.03 mmol) and CF3SiMe3 (1.20 mmol) (see also Table [2]). The vessel was sealed with a Teflon-lined septum, and was vigorously stirred at 50 °C for 36 h. The mixture was cooled to r.t. and diluted with CH2Cl2, filtered through a short pad of Celite, washed with CH2Cl2, and concentrated in vacuo. The resulting residue was purified by flash column chromatography (silica gel, hexanes–EtOAc, 100:1 to 10:1, depending on the substrate).


#

Diethyl Trifluoromethylphosphonate (2a)

Yellow oil; yield: 35 mg (56%).

IR (neat): 1233, 1146, 1045, 420 cm–1.

1H NMR (300 MHz, CDCl3): δ = 4.39–4.31 (m, 4 H), 1.42 (t, J = 5.4 Hz, 6 H).

13C NMR (100 MHz, CDCl3): δ = 119.89 (dq, J = 282.5 Hz, J = 307.9 Hz), 65.68 (d, J = 6.2 Hz), 16.12 (d, J = 5.0 Hz).

19F NMR (282 MHz, CDCl3): δ = –73.06 (d, 2 J P,F = 122 Hz, 3 F).

31P{1H} NMR (CDCl3): δ = –2.56 (q, 2 J P,F = 124 Hz).

HRMS (ESI): m/z [M + Na]+ calcd for C5H10F3NaO3P: 229.0212; found: 229.0216.


#

Dipropyl Trifluoromethylphosphonate (2b)

Yellow oil; yield: 51 mg (73%).

IR (neat): 1736, 1217, 1206, 423 cm–1.

1H NMR (300 MHz, CDCl3): δ = 4.26–4.18 (m, 4 H), 1.76 (sextet, J = 5.1 Hz, 4 H), 0.99 (t, J = 5.4 Hz, 6 H).

13C NMR (100 MHz, CDCl3): δ = 119.95 (dq, J = 283.2 Hz, J = 307.9 Hz), 70.03 (d, J = 6.6 Hz), 23.03 (d, J = 5.9 Hz), 9.6.

19F NMR (282 MHz, CDCl3): δ = –72.74 (d, 2 J P,F = 123 Hz, 3 F).

31P{1H} NMR (CDCl3): δ = –2.38 (q, 2 J P,F = 123 Hz).

HRMS (ESI): m/z [M + Na]+ calcd for C7H14F3NaO3P: 257.0526; found: 257.0531.


#

Dibutyl Trifluoromethylphosphonate (2c)

Yellow oil; yield: 68 mg (87%).

IR (neat): 1470, 1226, 419 cm–1.

1H NMR (300 MHz, CDCl3): δ = 4.30–4.22 (m, 4 H), 1.71 (quint, J = 5.7 Hz, 4 H), 1.71 (quint, J = 5.7 Hz, 4 H), 1.42 (sextet, J = 5.4 Hz, 4 H), 0.94 (t, J = 5.4 Hz, 6 H).

13C NMR (100 MHz, CDCl3): δ = 119.95 (dq, J = 282.9 Hz, J = 307.9 Hz), 69.19 (d, J = 6.7 Hz), 32.11 (d, J = 5.4 Hz), 18.29, 13.24.

19F NMR (282 MHz, CDCl3): δ = –72.71 (d, 2 J P,F = 123 Hz, 3 F).

31P{1H} NMR (CDCl3): δ = –2.38 (q, 2 J P,F = 123 Hz).

HRMS (ESI): m/z [M + Na]+ calcd for C9H18F3NaO3P: 285.0838; found: 285.0839.


#

Diisobutyl Trifluoromethylphosphonate (2d)

Yellow oil; yield: 66 mg (85%).

IR (neat): 1738, 1372, 1217, 1032, 421 cm–1.

1H NMR (300 MHz, CDCl3): δ = 4.05–3.97 (m, 4 H), 2.03–1.94 (m, 2 H), 0.95 (d, J = 5.7 Hz, 12 H).

13C NMR (100 MHz, CDCl3): δ = 120.09 (dq, J = 279.6 Hz, J = 307.9 Hz), 75.12 (d, J = 6.9 Hz), 29.73 (d, J = 6.3 Hz), 18.28, 18.26.

19F NMR (282 MHz, CDCl3): δ = –72.51 (d, 2 J P,F = 123 Hz, 3 F).

31P{1H} NMR (CDCl3): –2.44 (q, 2 J P,F = 123 Hz).

HRMS (ESI): m/z [M + Na]+ calcd for C9H18F3NaO3P: 285.0838; found: 285.0845.


#

Dihexyl Trifluoromethylphosphonate (2e)

Yellow oil; yield: 86 mg (90%).

IR (neat): 2933, 1137, 1020, 420 cm–1.

1H NMR (300 MHz, CDCl3): δ = 4.30–4.22 (m, 4 H), 1.72 (quint, J = 6.8 Hz, 4 H), 1.43–1.37 (m, 4 H), 1.33–1.29 (m, 8 H), 0.90 (t, J = 6.8 Hz, 6 H).

13C NMR (100 MHz, CDCl3): δ = 120.03 (dq, J = 284.8 Hz, J = 310.7 Hz), 69.59 (d, J = 6.4 Hz), 31.09, 30.19 (d, J = 5.6 Hz), 24.79, 22.39, 13.82.

19F NMR (282 MHz, CDCl3): δ = –72.24 (d, 2 J P,F = 122 Hz, 3 F).

31P{1H} NMR (CDCl3): δ = –2.34 (q, 2 J P,F = 124 Hz).

HRMS (ESI): m/z [M + Na]+ calcd for C13H26F3NaO3P: 341.1464; found: 341.1469.


#

Bis(4-chlorobutyl) Trifluoromethylphosphonate (2f)

Yellow oil; yield: 69 mg (70%).

IR (neat): 2964, 1282, 1141, 1027, 431 cm–1.

1H NMR (300 MHz, CDCl3): δ = 4.36–4.31 (m, 4 H), 3.59 (t, J = 5.4 Hz, 4 H), 1.93–1.89 (m, 8 H).

13C NMR (100 MHz, CDCl3): δ = 119.89 (dq, J = 284.1 Hz, J = 308.02 Hz), 68.76 (d, J = 5.9 Hz), 44.01, 29.27, 27.59 (d, J = 6.1 Hz).

19F NMR (282 MHz, CDCl3): δ = –72.21 (d, 2 J P,F = 124 Hz, 3 F).

31P{1H} NMR (CDCl3): δ = –2.26 (q, 2 J P,F = 124 Hz).

HRMS (ESI): m/z [M + Na]+ calcd for C9H16Cl2F3NaO3P: 353.0058; found: 353.0062.


#

Dicyclohexyl Trifluoromethylphosphonate (2g)

Yellow oil; yield: 71 mg (76%).

IR (neat): 2942, 1453, 1138, 420 cm–1.

1H NMR (300 MHz, CDCl3): δ = 4.69–4.61 (m, 2 H), 1.97–1.94 (m, 4 H), 1.78–1.74 (m, 4 H), 1.68–1.58 (m, 4 H), 1.55–1.48 (m, 2 H), 1.42–1.23 (m, 6 H).

13C NMR (100 MHz, CDCl3): δ = 119.99 (dq, J = 284.6 Hz, J = 307.9 Hz), 79.77 (d, J = 7.0 Hz), 33.60 (d, J = 3.2 Hz), 33.05 (d, J = 4.9 Hz), 24.81, 23.20 (d, J = 3.5 Hz).

19F NMR (282 MHz, CDCl3): δ = –73.35 (d, 2 J P,F = 122 Hz, 3 F).

31P{1H} NMR (CDCl3): δ = –4.60 (q, 2 J P,F = 123 Hz).

HRMS (ESI): m/z [M + Na]+ calcd for C13H22F3NaO3P: 337.1151; found: 337.1148.


#
#

Acknowledgment

National Natural Science Foundation of China (21072028, 20832008) and National Basic Research Program of China (2012CB21600) are gratefully acknowledged for funding this work.

Supporting Information

    for this article is available online at http://www.thieme-connect.com.accesdistant.sorbonne-universite.fr/ejournals/toc/synthesis.
  • Supporting Information


   Permissions and Reprints All articles of this category
Zoom Image
Scheme 1 Oxidative trifluoromethylation of H-phosphonates