An iodide-accelerated, palladium-catalyzed C-P bond-forming reaction of aryl nonaflates is described. The protocol was optimized for the synthesis of aryl phosphine oxides and was found to be tolerant of a wide range of aryl nonaflates. The general nature of this transformation was established with coupling to other P(O)H compounds for the synthesis of aryl phosphonates and an aryl phosphinate. The straightforward synthesis of stable, isolable aryl nonaflates, in combination with the rapid C-P bond-forming reaction allows facile preparation of aryl phosphorus target compounds from readily available phenol starting materials. The synthetic utility of this general strategy was demonstrated with the efficient preparation of an organic light-emitting diode (OLED) material and a phosphonophenylalanine mimic.
An iodide-accelerated, palladium-catalyzed C-P bond-forming reaction of aryl nonaflates is described. The protocol was optimized for the synthesis of aryl phosphine oxides and was found to be tolerant of a wide range of aryl nonaflates. The general nature of this transformation was established with coupling to other P(O)H compounds for the synthesis of aryl phosphonates and an aryl phosphinate. The straightforward synthesis of stable, isolable aryl nonaflates, in combination with the rapid C-P bond-forming reaction allows facile preparation of aryl phosphorus target compounds from readily available phenol starting materials. The synthetic utility of this general strategy was demonstrated with the efficient preparation of an organic light-emitting diode (OLED) material and a phosphonophenylalanine mimic.
Aryl phosphorus compounds
are important due to their widespread
application in organic, medicinal, and materials chemistry.[1,2] As a consequence, carbon–phosphorus bond formation is a highly
active area of research in organophosphorus chemistry. Traditionally,
aryl C–P bonds were formed via the reaction of Grignard or
organolithium reagents with electrophilic phosphorus compounds.[3] In 1981, pioneering work by Hirao and co-workers
demonstrated that aryl C–P bonds could be generated by palladium-catalyzed
cross-coupling reactions of aryl bromides with P(O)–H compounds
(Scheme a).[4] Since the discovery of the Hirao reaction, efforts
have focused on extending the range of electrophilic aryl substrates,
elucidation of the reaction mechanism and optimization of the reaction
conditions.[5,6]
Scheme 1
Selected Palladium-Catalyzed Reactions for
the Synthesis of Aryl
C–P Bonds
Despite the availability
of aryl halides as coupling reagents,
many complex arenes, particularly natural product-based (e.g., steroids
and amino acids), exist only in phenolic form. For this reason, Hirao-type
reactions using activated sulfonates have been reported. Aryl triflates
have been explored as substrates,[5,6e,7] but the high cost and reactive nature of reagents
limits applications. This has led to the development of metal-catalyzed
aryl C–P bond-forming reactions using mesylates and tosylates.[5,8] For example, the Kwong group has demonstrated the effective phosphorylation
of aryl mesylates and tosylates using low catalyst loadings of Pd(OAc)2 in combination with the CM-Phos ligand (Scheme b).[9] Transformations at 110 °C and a reaction time of 18 h gave
a wide range of phosphonate esters in high yields. Recently, the Ding
and Xu groups independently reported Pd-catalyzed C–P bond-forming
reactions of aryl fluorosulfonates.[10] Following
synthesis of these from phenols and sulfuryl fluoride gas, these compounds
were readily coupled with a range of P(O)–H compounds using
Pd(OAc)2 and either dppf or DPEPhos ligands.Although
advances in palladium-catalyzed C–P bond-forming
reactions with aryl sulfonates have been achieved, we were interested
in developing a method with a short reaction time, which avoided the
need for additional ligands or gaseous reagents, and that could also
be applied for the preparation of a range of aryl phosphorus compounds.
Aryl nonafluorobutylsulfonates [nonaflates, ArOSO2(CF2)3CF3] are easily prepared from phenols
and the inexpensive, industrial product nonaflyl fluoride. In addition,
these are stable and can be readily purified by flash column chromatography.
For these reasons, aryl nonaflates have been used for a wide range
of palladium-catalyzed cross-coupling reactions.[11,12] However, utilization of these for analogous C–P bond-forming
reactions are relatively rare. Apart from a few specific examples,[13] the only methodology study was reported by the
Lipshutz group, who demonstrated the efficient synthesis of triarylphosphine
boranes via the reaction of aryl nonaflates with diphenylphosphine-borane.[14] Herein, we disclose a palladium-catalyzed C–P
bond-forming reaction with aryl nonaflates that can be accelerated
by iodide, resulting in short reaction times (Scheme c). The method does not require additional
ligands or substrates prepared by gaseous reagents. Furthermore, we
demonstrate that the method can be used as part of an effective strategy
for the synthesis of important organophosphorus compounds from phenol
starting materials.
Results and Discussion
Initial studies
focused on the reaction of diphenylphosphine oxide
with the nonactivated starting material, p-tolyl
nonaflate (1a) (Table ). As previous work has shown palladium acetate as
an effective catalyst for C–P bond formation,[6] this was used in combination with triethylamine, originally
utilized as a base by the Hirao group.[4] In addition, dimethylformamide (DMF) was chosen as an effective
solvent for working with aryl nonaflates. Using 1 equiv of diphenylphosphine
oxide, at a reaction temperature of 90 °C, showed only 70% conversion
by 1H nuclear magnetic resonance (NMR) spectroscopy, resulting
in a 41% isolated yield (entry 1). Mechanistic work of palladium-catalyzed
C–P bond-forming reactions by the Stawinski,[6a,6c] Montchamp,[6f,6g] and Keglevich groups[6h,6i] have shown that excess amounts of the P(O)H coupling partner are
required to reduce the palladium(II) catalyst and act as a ligand
(see Scheme ). Therefore,
using 1.5 equiv of diphenylphosphine oxide and an increased reaction
temperature of 110 °C, allowed full conversion after 24 h and
a 58% isolated yield (entry 2). A further increase of reaction temperature
to 120 °C resulted in further improvement in isolated yield (79%);
however, the reaction still required 24 h to reach completion (entry
3). As ionic additives such as chloride and acetate ions are well
known to promote Pd-mediated cross-coupling reactions,[15,16] and facilitate the Hirao reaction,[6a,6c,6e] these were investigated to improve the reaction time.
Interestingly, the addition of stoichiometric quantities of NaOAc
or NaCl (entries 4 and 5) led to no improvement in the reaction time
and gave phosphine oxide 2a in lower isolated yields.
In contrast, the addition of NaI (1 equiv) resulted in a significantly
faster reaction time of 4 h, which gave 2a in 78% yield
(entry 6). This effect was observed to a lesser extent using 0.1 equiv
of NaI (entry 7). In this case, the reaction was complete after 8
h.
Table 1
Optimization Studies for Palladium-Catalyzed
Synthesis of (p-Tolyl)diphenylphosphine Oxide (2a)
entry
additive
(equiv)
time
(h)
temperature (°C)
isolated yield (%)
1a
24
90
41
2
24
110
58
3
24
120
79
4
NaOAc (1)
22
120
55
5
NaCl (1)
32
120
64
6
NaI (1)
4
120
78
7
NaI (0.1)
8
120
76
Using 1 equiv of Ph2P(O)H.
Scheme 6
Proposed Mechanism
for the Iodide-Accelerated, Palladium-Catalyzed
C–P Bond-Forming Reaction
Using 1 equiv of Ph2P(O)H.Having identified rapid and
efficient conditions for the synthesis
of 2a, the scope of the iodide-accelerated reaction was
investigated for the coupling of diphenylphosphine oxide with various
aryl nonaflates (Scheme ). Using NaI (1 equiv) throughout, the process was found to be compatible
with a wide range of substituents and functional groups, forming the
majority of diphenylphosphine oxides after 4 h reaction times. Some
variations to the standard conditions were observed. For example,
the reaction of naphthyl analogue 1f was found to proceed
at 90 °C and was complete after 3 h, while aryl nonaflates with ortho-substituents (1c) or with strong electron-donating
groups (1h) required slightly longer reaction times.
Although the reaction conditions tolerated chloride substituents (1p), attempted coupling of 3-bromophenyl nonaflate (1q) with diphenylphosphine oxide (1.5 equiv) gave a mixture
of compounds. Analysis of the reaction mixture by 1H NMR
spectroscopy showed the presence of bis-phosphine oxide 2q as the major product, along with mono-phosphine oxide by-products.
As a selective reaction was not possible, 1q was allowed
to react with 3 equiv of diphenylphosphine oxide, which gave bis-phosphine
oxide 2q in 57% yield. Pyridin-2-yl nonaflate (1r) was also a substrate for this transformation, giving clean
conversion to 2r in 60% yield. From the series of nonaflates
investigated, only a p-nitrophenyl analogue failed
to generate the desired product. In this case, the reaction conditions
led to decomposition of the nonaflate.
Scheme 2
Reaction Scope of
Aryl Nonaflates,
Isolated
yields.
Reactions performed
at 0.2 or 0.4 mmol
scale.
Reaction performed
at 90 °C.
From 3-bromophenyl
nonaflate using Ph2P(O)H (3 equiv).
Reaction Scope of
Aryl Nonaflates,
Isolated
yields.Reactions performed
at 0.2 or 0.4 mmol
scale.Reaction performed
at 90 °C.From 3-bromophenyl
nonaflate using Ph2P(O)H (3 equiv).Using p-tolyl nonaflate (1a) as a
standard substrate, the study then investigated the use of the reaction
for the preparation of other aryl C–P bonds (Scheme ). In a similar manner to the
synthesis of diphenylphosphine oxide 2a, the iodide-accelerated
reaction with Pd(OAc)2 permitted the synthesis of phosphine
oxide 3a. While Pd(OAc)2 did allow the preparation
of other aryl C–P-containing compounds, the reactions were
less efficient, leading to the products in moderate yields (40–50%).
For this reason, a brief screen for alternative catalysts was performed
that identified Pd(PPh3)4 as an effective substitute.[17] Reaction of 1a with di-n-butylphosphine oxide in the presence of Pd(PPh3)4 and NaI gave dialkylphosphine oxide 3b in 58% yield, after a reaction time of 5 h. Reaction of 1a with the more reactive coupling partners, ethyl phenylphosphinate
and diethyl phosphite was found to proceed at 80 °C and after
reaction times of 4 and 6 h, respectively, gave phosphinate 3c and phosphonate 3d in good yields.
Scheme 3
Reaction
Scope for the Synthesis of Various Aryl Phosphorus Compounds,
Isolated yields.
Reactions performed at 0.2 or 0.4
mmol
scale.
Reaction performed
using Pd(OAc)2 (10 mol %).
Reaction performed using Pd(PPh3)4 (10 mol %).
Reaction
Scope for the Synthesis of Various Aryl Phosphorus Compounds,
Isolated yields.Reactions performed at 0.2 or 0.4
mmol
scale.Reaction performed
using Pd(OAc)2 (10 mol %).Reaction performed using Pd(PPh3)4 (10 mol %).The study next investigated
the combination of the mild conditions
for nonaflate synthesis with the accelerated aryl C–P bond-forming
reaction for the simple conversion of phenols to aryl phosphorus-containing
targets (Scheme ).
Pyrene nonaflate 5 was prepared in 87% yield by the treatment
of 1-hydroxypyrene (4) with nonaflyl fluoride, under
basic conditions. Reaction of 5 with diphenylphosphine
oxide, using Pd(OAc)2 and NaI gave phosphine oxide 6, a blue light-emitting diode material in 73% yield.[18] In a similar manner, commercially available l-tyrosine derivative 7 was converted to the corresponding
aryl nonaflate 8 under mild conditions, in 94% yield.
Iodide-accelerated phosphorylation of 8, performed at
a 1 mmol scale, was found to proceed at 80 °C, and after a reaction
time of 6 h, gave phosphonate ester 9 in 72% yield. With
this transformation, a lower loading of the palladium catalyst was
investigated. Using 5 mol % Pd(PPh3)4 showed
no significant difference in reaction efficiency. Again, at a 1 mmol
scale, the transformation was complete in 7 h and produced phosphonate
ester in 65% yield. Acid-mediated deprotection allowed the isolation
of phosphonophenylalanine 10, a compound used for various
medicinal chemistry applications, such as a component of peptides
that act as thrombin inhibitors and as competitive N-methyl-d-aspartic acid antagonists.[7a,19]
Scheme 4
Synthesis of Various Aryl Phosphorus Target Compounds
Having demonstrated the utility of this method, the possible
role
of iodide in accelerating the C–P bond-forming process was
considered. Initially, the different rates observed during the reaction
of p-tolyl nonaflate (1a) with diphenylphosphine
oxide in the presence of NaI (0, 0.1, and 1 equiv) were further investigated.
A conversion graph generated by 1H NMR spectroscopy confirmed
that while the reaction with NaI (1 equiv) was complete after 4 h
(∼95% conversion), only 12% conversion was observed at the
same time during the reaction without NaI (Figure ).
Figure 1
Conversion graph for the synthesis of 2a (measured
using 1H NMR spectroscopy and dimethyl terephthalate as
an internal standard).
Conversion graph for the synthesis of 2a (measured
using 1H NMR spectroscopy and dimethyl terephthalate as
an internal standard).Halide and acetate additives
have been shown to promote Pd-catalyzed
cross-coupling reactions by the formation of more nucleophilic anionic
palladium complexes.[15,16] However, no accelerating effects
were observed when acetate or chloride ions were employed during this
transformation (Table ). It has also been proposed that iodide accelerating effects during
Pd-catalyzed cross-coupling reactions are due to the faster oxidative
addition of aryl iodide intermediates formed in situ via a Finkelstein
reaction.[20] Using the optimized conditions
for the coupling of p-tolyl nonaflate (1a) with diphenylphosphine oxide, control experiments were conducted
to determine whether p-tolyl iodide (11) was an intermediate (Scheme ). Repeating the reaction under the same conditions, but in
the absence of either diphenylphosphine oxide or Pd(OAc)2, no iodide could be detected (by 1H NMR spectroscopy),
even after 24 h. A final experiment to probe the mechanism investigated
the use of p-tolyl iodide (11) as the
starting material. Previous work using aryl iodides as substrates
for palladium-catalyzed C–P cross-coupling reactions reported
lower yields compared to other halide leaving groups.[21] It was proposed that this was due to competing reduction
of the ArPdI intermediate. Reaction of p-tolyl iodide
(11) using our non-catalyzed, standard conditions was
found to be fast, with completion observed after 1.5 h. However, this
gave phosphine oxide 2a in only 34% isolated yield. This
is in contrast to p-tolyl nonaflate (1a), which under the same conditions required a reaction time of 24
h but gave 2a in 79% yield (Table , entry 3). This difference in reaction times
and isolated yields of 2a suggest that an aryl iodide
and the subsequent oxidative addition product, ArPdI are not intermediates
during the reaction with aryl nonaflates and that the reaction of
these proceeds via an alternative mechanism in the presence of iodide.
Scheme 5
Experiments to Investigate the Role of p-Tolyl Iodide
as an Intermediate
Based on these results
and previous mechanistic studies by the
Stawinski,[6a,6c] Montchamp,[6f,6g] and Keglevich groups,[6h,6i] that implicated the
role of the tautomer form of diphenylphosphine oxide as a reducing
agent to form Pd(0), as a ligand and as the nucleophilic coupling
partner, we propose the following catalytic cycle (Scheme ). Initially, the active palladium species I is
formed by reduction and coordination with the tautomeric form of the
excess P(O)H coupling reagent (30 mol % required for 10 mol % Pd catalyst).
Following oxidative addition of the aryl nonaflate by Pd(0) species I, the presence of NaI may result in the formation of sodium
nonaflate and a coordinatively unsaturated Pd(0) complex II. With the iodide anion weakly bound, this may accelerate coordination
and subsequent reaction with the phosphorus nucleophile,[22] and following reductive elimination, allow overall
faster access to the coupled product. There are other possible roles
of iodide that could result in accelerated reactions. For example,
the larger trans effect of the iodide when complexed
to a Pd intermediate, in comparison to the other ionic additives,
could also lead to an accelerated transformation through faster substitution
reactions.[16]
Conclusions
In summary, aryl nonaflates, which are isolable intermediates,
readily prepared from abundant phenols, were found to be effective
substrates for palladium-catalyzed C–P bond-forming reactions.
Optimization studies revealed that the addition of NaI resulted in
accelerated reactions, allowing the rapid synthesis of a wide range
of aryl phosphine oxides. Extension of the process with other P(O)H
coupling reagents resulted in the synthesis of further aryl phosphorus
compounds, such as an aryl phosphinate and aryl phosphonates. This
included the three-step synthesis of pharmaceutically relevant, phosphonophenylalanine 10 from a commercially available tyrosine derivative in 60%
overall yield. Preliminary mechanistic studies suggested that the
addition of iodide may accelerate the reaction via a coordinatively
unsaturated Pd(0) complex or through the trans effect
of a Pd–I intermediate. Investigation of further applications
of this transformation is currently underway.
Experimental
Section
All reagents and starting materials, including methyl
(2S)-2-[(benzyloxycarbonyl)amino]-3-(4-hydroxyphenyl)propanoate
(7), were obtained from commercial sources and used as
received, unless otherwise stated. Anhydrous dichloromethane was purified
using a PureSolv 500 MD solvent purification system. All reactions
were performed under an atmosphere of air unless otherwise stated.
All reactions performed at elevated temperatures were heated using
an oil bath. Dry glassware was oven-dried at 140 °C for a minimum
of 16 h, cooled to room temperature in vacuo, and
then purged with argon. Brine is defined as a saturated aqueous solution
of sodium chloride. Merck aluminum-backed plates precoated with silica
gel 60 (UV254) were used for thin-layer chromatography
and were visualized under UV light (254/365 nm) and then stained with
iodine, potassium permanganate, vanillin, or ninhydrin solution. Flash
column chromatography was carried out using Merck Geduran Si 60 (40–63
μm). 1H and 13C NMR spectra were recorded
on Bruker DPX 400, Bruker AVI 400, and Bruker AVIII 400 (1H 400 MHz; 13C 101 MHz) spectrometers or a Bruker AVIII
500 (1H 500 MHz; 13C 126 MHz) spectrometer with
chemical shift values reported in ppm relative to tetramethylsilane
(δH 0.00 and δC 0.0), CDCl3 (δH 7.26 and δC 77.2) or 3-(trimethylsilyl)propionic-2,2,3,3-d4 acid sodium salt in D2O (δH 0.00 and δC 0.0). Assignments of 1H and 13C NMR signals are based on COSY, DEPT, HSQC, and
HMBC experiments. Mass spectra were obtained using a JEOL JMS-700
spectrometer or a Bruker microTOFq high-resolution mass spectrometer.
Melting points were determined on a Gallenkamp melting point apparatus
and are uncorrected. Infrared spectra were recorded neat on a Shimadzu
FTIR-84005 spectrometer. Optical rotations were determined as solutions
irradiating with the sodium D line (λ = 598 nm) using an Autopol
V polarimeter. [α]D values are reported in units
10–1 deg cm2 g–1. Di-(n-butyl)phosphine oxide was prepared as previously described
via the reaction of n-butylmagnesium chloride with
diethyl phosphite.[23]
4-Methylphenyl nonafluorobutanesulfonate
(1a)[24]
In an oven-dried
flask under argon, p-cresol (1.08 g, 10.0 mmol) was
dissolved in anhydrous
dichloromethane (33 mL) and cooled to 0 °C. Triethylamine (3.48
mL, 25.0 mmol) was then added followed by perfluoro-1-butanesulfonyl
fluoride (2.70 mL, 15.0 mmol). The reaction mixture was warmed to
room temperature and stirred for 2 h. The crude mixture was then diluted
with dichloromethane (50 mL) and washed with water (3 × 50 mL).
The organic layer was dried (MgSO4), filtered, and concentrated in vacuo. The crude material was purified by flash column
chromatography eluting with 5% diethyl ether in petroleum ether (40–60)
to give 4-methylphenyl nonafluorobutanesulfonate (1a)
as a colorless oil (3.40 g, 87%). Spectroscopic data were consistent
with the literature.[24]1H NMR
(400 MHz, CDCl3) δ 2.38 (s, 3H), 7.16 (d, J = 8.6 Hz, 2H), 7.24 (d, J = 8.6 Hz, 2H); 13C{1H} NMR (101 MHz, CDCl3) δ
21.0 (CH3), 121.2 (2 × CH), 130.8 (2 × CH), 138.6
(C), 148.0 (C); MS (ESI) m/z 413
(M + Na+, 100).
3-Methylphenyl nonafluorobutanesulfonate
(1b)
The reaction was carried out according
to the previously described
procedure for 4-methylphenyl nonafluorobutanesulfonate (1a) using m-cresol (0.209 mL, 2.00 mmol), anhydrous
dichloromethane (5 mL), triethylamine (0.700 mL, 5.02 mmol), and perfluoro-1-butanesulfonyl
fluoride (0.540 mL, 3.00 mmol). The reaction mixture was stirred at
room temperature for 3 h. The crude material was purified by flash
column chromatography eluting with 100% petroleum ether (40–60)
to give 3-methylphenyl nonafluorobutanesulfonate (1b)
as a colorless oil (0.588 g, 76%). IR (neat) 2970, 1740, 1425, 1354,
1231, 1198, 1142, 1117, 930 cm–1; 1H
NMR (400 MHz, CDCl3) δ 2.41 (s, 3H), 7.06–7.12
(m, 2H), 7.17–7.22 (m, 1H), 7.29–7.36 (m, 1H); 13C{1H} NMR (101 MHz, CDCl3) δ 21.5 (CH3), 118.4 (CH), 122.0 (CH), 129.3
(CH), 130.0 (CH), 141.0 (C), 149.9 (C); MS (EI) m/z 390 (M+, 59), 326 (24), 151 (38), 107 (100), 91 (38),
77 (49); HRMS (EI) m/z: [M]+ calcd for C11H7F9O3S 389.9972; found 389.9953.
2-Methylphenyl nonafluorobutanesulfonate
(1c)[24]
The reaction
was carried out according
to the previously described procedure for 4-methylphenyl nonafluorobutanesulfonate
(1a) using o-cresol (0.270 g, 2.50 mmol),
anhydrous dichloromethane (8 mL), triethylamine (0.870 mL, 6.25 mmol),
and perfluoro-1-butanesulfonyl fluoride (0.680 mL, 3.77 mmol). The
reaction mixture was stirred at room temperature for 2 h. The crude
material was purified by flash column chromatography eluting with
5% diethyl ether in hexane to give 2-methylphenyl nonafluorobutanesulfonate
(1c) as a colorless oil (0.708 g, 72%). Spectroscopic
data were consistent with the literature.[24]1H NMR (400 MHz, CDCl3) δ 2.40 (s, 3H),
7.23–7.34 (m, 4H); 13C{1H} NMR (101 MHz,
CDCl3) δ 16.6 (CH3), 121.4 (CH), 127.8
(CH), 128.4 (CH), 131.1 (C), 132.3 (CH), 148.8 (C); MS (ESI) m/z 413 (M + Na+, 100).
The reaction
was carried out according to the previously described procedure for
4-methylphenyl nonafluorobutanesulfonate (1a) using 4-tert-butylphenol (0.300 g, 2.00 mmol), anhydrous dichloromethane
(6 mL), triethylamine (0.700 mL, 5.02 mmol), and perfluoro-1-butanesulfonyl
fluoride (0.540 mL, 3.01 mmol). The reaction mixture was stirred at
room temperature for 5 h. The crude material was purified by flash
column chromatography eluting with 100% hexane to give 4-tert-butylphenyl nonafluorobutanesulfonate (1d) as a colorless
oil (0.802 g, 93%). Spectroscopic data were consistent with the literature.[25]1H NMR (400 MHz, CDCl3) δ 1.33 (s, 9H), 7.20 (d, J = 9.0 Hz, 2H),
7.45 (d, J = 9.0 Hz, 2H); 13C{1H} NMR (101 MHz, CDCl3) δ 31.4
(3 × CH3), 34.9 (C), 120.9 (2 × CH), 127.3 (2
× CH), 147.8 (C), 151.8 (C); MS (ESI) m/z 455 (M + Na+, 100).
Phenyl nonafluorobutanesulfonate
(1e)[26]
The reaction
was carried out according
to the previously described procedure for 4-methylphenyl nonafluorobutanesulfonate
(1a) using phenol (0.200 g, 2.12 mmol), anhydrous dichloromethane
(7 mL), triethylamine (0.740 mL, 5.31 mmol), and perfluoro-1-butanesulfonyl
fluoride (0.570 mL, 3.17 mmol). The reaction mixture was stirred at
room temperature for 3 h. The crude material was purified by flash
column chromatography eluting with 10% diethyl ether in petroleum
ether (40–60) to give phenyl nonafluorobutanesulfonate (1e) as a colorless oil (0.720 g, 90%). Spectroscopic data
were consistent with the literature.[26]1H NMR (400 MHz, CDCl3) δ 7.27–7.33
(m, 2H), 7.37–7.42 (m, 1H), 7.43–7.50 (m, 2H); 13C{1H} NMR (101 MHz, CDCl3) δ
121.5 (2 × CH), 128.5 (CH), 130.4 (2 × CH), 150.0 (C); MS
(EI) m/z 376 (M+, 42),
312 (13), 219 (4), 143 (10), 93 (73), 84 (35), 77 (94), 69 (35), 65
(100).
2-Naphthyl nonafluorobutanesulfonate (1f)[27]
The reaction was carried out according
to the previously described procedure for 4-methylphenyl nonafluorobutanesulfonate
(1a) using 2-naphthol (1.00 g, 6.94 mmol), anhydrous
dichloromethane (15 mL), triethylamine (2.42 mL, 17.4 mmol), and perfluoro-1-butanesulfonyl
fluoride (1.87 mL, 10.4 mmol). The reaction mixture was stirred at
room temperature for 1 h. The crude material was purified by flash
column chromatography eluting with 5% ethyl acetate in petroleum ether
(40–60) to give 2-naphthyl nonafluorobutanesulfonate (1f) as a colorless oil (1.97 g, 67%). Spectroscopic data were
consistent with the literature.[27]1H NMR (400 MHz, CDCl3) δ 7.39 (dd, J = 9.0, 2.5 Hz, 1H), 7.54–7.63 (m, 2H), 7.77 (d, J = 2.5 Hz, 1H), 7.84–7.92 (m, 2H), 7.93 (d, J = 9.0 Hz, 1H); 13C{1H} NMR (101
MHz, CDCl3) δ 119.4 (CH), 119.7 (CH), 127.3 (CH),
127.7 (CH), 128.1 (CH), 128.2 (CH), 130.7 (CH), 132.5 (C), 133.5 (C),
147.5 (C); MS (ESI) m/z 425 [(M
– H)−, 100].
The reaction
was carried out according
to the previously described procedure for 4-methylphenyl nonafluorobutanesulfonate
(1a) using 4-methoxyphenol (0.372 g, 3.00 mmol), anhydrous
dichloromethane (10 mL), triethylamine (1.05 mL, 7.50 mmol), and perfluoro-1-butanesulfonyl
fluoride (0.810 mL, 4.50 mmol). The reaction mixture was stirred at
room temperature for 2 h. The crude material was purified by flash
column chromatography eluting with 10% diethyl ether in petroleum
ether (40–60) to give 4-methoxyphenyl nonafluorobutanesulfonate
(1h) as a colorless oil (1.13 g, 93%). Spectroscopic
data were consistent with the literature.[25]1H NMR (500 MHz, CDCl3) δ 3.82 (s, 3H), 6.92 (d, J = 9.2 Hz, 2H), 7.21 (d, J = 9.2 Hz, 2H); 13C{1H} NMR (126
MHz, CDCl3) δ 55.8 (CH3), 115.2 (2 × CH), 122.5 (2 × CH), 143.4 (C), 159.2 (C);
MS (EI) m/z 406 (M+,
12), 219 (5), 123 (100), 95 (14), 69 (11).
The reaction
was carried
out according to the previously described procedure for 4-methylphenyl
nonafluorobutanesulfonate (1a) using 4-acetamidophenol
(0.302 g, 2.00 mmol), anhydrous dichloromethane (6 mL), triethylamine
(0.700 mL, 5.02 mmol), and perfluoro-1-butanesulfonyl fluoride (0.540
mL, 3.01 mmol). The reaction mixture was stirred at room temperature
for 3 h. The crude material was purified by flash column chromatography
eluting with 100% diethyl ether to give 4-acetamidophenyl nonafluorobutanesulfonate
(1i) as a white solid (0.781 g, 90%). Mp 102–103
°C. Spectroscopic data were consistent with the literature.[29]1H NMR (400 MHz, CDCl3) δ 2.19 (s, 3H), 7.23 (d, J = 9.0 Hz, 2H),
7.41 (br s, 1H), 7.60 (d, J = 9.0 Hz, 2H); 13C{1H} NMR (101 MHz, CDCl3) δ 24.7 (CH3), 121.1 (2 × CH), 122.1 (2 × CH), 138.0 (C), 145.7
(C), 168.6 (C); MS (ESI) m/z 456
(M + Na+, 100).
4-Acetylphenyl nonafluorobutanesulfonate
(1j)[25]
The reaction
was carried out according
to the previously described procedure for 4-methylphenyl nonafluorobutanesulfonate
(1a) using 4-hydroxyacetophenone (0.272 g, 2.00 mmol),
anhydrous dichloromethane (6 mL), triethylamine (0.700 mL, 5.02 mmol),
and perfluoro-1-butanesulfonyl fluoride (0.540 mL, 3.01 mmol). The
reaction mixture was stirred at room temperature for 2 h. The crude
material was purified by flash column chromatography eluting with
50% diethyl ether in hexane to give 4-acetylphenyl nonafluorobutanesulfonate
(1j) as a white solid (0.786 g, 94%). Mp 38–40
°C (lit.[25] 38–40 °C); 1H NMR (500 MHz, CDCl3) δ 2.63 (s, 3H), 7.39
(d, J = 8.9 Hz, 2H), 8.06 (d, J =
8.9 Hz, 2H); 13C{1H} NMR (126 MHz, CDCl3) δ 26.8 (CH3), 121.8 (2 × CH), 130.7
(2 × CH), 137.0 (C), 152.9 (C), 196.3 (C); MS (EI) m/z 418 (M+, 30), 403 (100), 339 (38),
219 (8), 131 (11), 120 (37), 107 (38).
4-Nonafluorobutanesulfonyloxybenzophenone
(1k)
The reaction was carried out according
to the previously described
procedure for 4-methylphenyl nonafluorobutanesulfonate (1a) using 4-hydroxybenzophenone (0.200 g, 1.01 mmol), anhydrous dichloromethane
(5 mL), triethylamine (0.350 mL, 2.51 mmol), and perfluoro-1-butanesulfonyl
fluoride (0.270 mL, 1.50 mmol). The reaction mixture was stirred at
room temperature for 16 h. The crude material was purified by flash
column chromatography eluting with 20% ethyl acetate in petroleum
ether (40–60) to give 4-nonafluorobutanesulfonyloxybenzophenone
(1k) as a beige solid (0.341 g, 70%). Mp 42–43
°C; IR (neat) 2980, 1740, 1651, 1424, 1227, 1202, 1138, 889,
797, 731 cm–1; 1H NMR (400 MHz, CDCl3) δ 7.42 (d, J = 8.6 Hz, 2H), 7.52
(t, J = 7.6 Hz, 2H), 7.63 (t, J =
7.6 Hz, 1H), 7.80 (d, J = 7.6 Hz, 2H), 7.91 (d, J = 8.6 Hz, 2H); 13C{1H} NMR (101
MHz, CDCl3) δ 121.5 (2 × CH), 128.7 (2 ×
CH), 130.1 (2 × CH), 132.3 (2 × CH), 133.2 (CH), 136.9 (C),
137.7 (C), 152.3 (C), 194.9 (C); MS (EI) m/z 480 (M+, 100), 169 (89), 105 (84), 84 (93),
63 (81); HRMS (EI) m/z: [M]+ calcd for C17H9F9O4S 480.0078; found 480.0083.
The reaction
was carried
out according to the previously described procedure for 4-methylphenyl
nonafluorobutanesulfonate (1a) using methyl 4-hydroxybenzoate
(0.200 g, 1.32 mmol), anhydrous dichloromethane (5 mL), triethylamine
(0.460 mL, 3.30 mmol), and perfluoro-1-butanesulfonyl fluoride (0.360
mL, 2.00 mmol). The reaction mixture was stirred at room temperature
for 16 h. The crude material was purified by flash column chromatography
eluting with 15% ethyl acetate in petroleum ether (40–60) to
give methyl 4-nonafluorobutanesulfonyloxybenzoate (1l) as a colorless oil (0.526 g, 92%). Spectroscopic data were consistent
with the literature.[25]1H NMR
(400 MHz, CDCl3) δ 3.94 (s, 3H), 7.36 (d, J = 8.9 Hz, 2H), 8.14 (d, J = 8.9 Hz, 2H); 13C{1H} NMR (101 MHz, CDCl3) δ
52.7 (CH3), 121.6 (2 × CH), 130.5 (C), 132.0 (2 ×
CH), 152.9 (C), 165.6 (C); MS (EI) m/z 434 (M+, 70), 403 (40), 339 (100), 151 (38), 123 (42).
4-Cyanophenyl nonafluorobutanesulfonate (1m)[25]
The reaction was carried out according
to the previously described procedure for 4-methylphenyl nonafluorobutanesulfonate
(1a) using 4-cyanophenol (0.200 g, 1.68 mmol), anhydrous
dichloromethane (5 mL), triethylamine (0.590 mL, 4.23 mmol), and perfluoro-1-butanesulfonyl
fluoride (0.460 mL, 2.56 mmol). The reaction mixture was stirred at
room temperature for 2 h. The crude material was purified by flash
column chromatography eluting with 20% ethyl acetate in petroleum
ether (40–60) to give 4-cyanophenyl nonafluorobutanesulfonate
(1m) as a white solid (0.609 g, 90%). Mp 109–110
°C (lit.[25] 111–112 °C); 1H NMR (500 MHz, CDCl3) δ 7.44 (d, J = 9.0 Hz, 2H), 7.79 (d, J = 9.0 Hz, 2H); 13C{1H} NMR (101 MHz, CDCl3) δ
113.0 (C), 117.2 (C), 122.8 (2 × CH), 134.6 (2 × CH), 152.4
(C); MS (EI) m/z 401 (M+, 38), 337 (33), 219 (12), 118 (47), 102 (100), 90 (71), 77 (41),
69 (99).
The reaction was carried
out according to the previously described procedure for 4-methylphenyl
nonafluorobutanesulfonate (1a) using 4-hydroxybenzotrifluoride
(0.200 g, 1.23 mmol), anhydrous dichloromethane (5 mL), triethylamine
(0.430 mL, 3.09 mmol), and perfluoro-1-butanesulfonyl fluoride (0.330
mL, 1.84 mmol). The reaction mixture was stirred at room temperature
for 16 h. The crude material was purified by flash column chromatography
eluting with 20% ethyl acetate in petroleum ether (40–60) to
give 4-(trifluoromethyl)phenyl nonafluorobutanesulfonate (1n) as a colorless oil (0.454 g, 83%). Spectroscopic data were consistent
with the literature.[30]1H NMR
(400 MHz, CDCl3) δ 7.43 (d, J =
8.8 Hz, 2H), 7.75 (d, J = 8.8 Hz, 2H); 13C{1H} NMR (101 MHz, CDCl3) δ 122.2 (2
× CH), 123.4 (q, 1JCF 273.4
Hz, CF3), 127.9 (q, 3JCF 3.6 Hz, 2 × CH), 131.0 (q, 2JCF 33.4 Hz, C), 152.0 (C); MS (EI) m/z 444 (M+, 44), 145 (100), 133 (36), 78 (32),
69 (41).
2-Fluorophenyl nonafluorobutanesulfonate (1o)
The reaction was carried out according to the previously described
procedure for 4-methylphenyl nonafluorobutanesulfonate (1a) using 2-fluorophenol (0.178 mL, 2.00 mmol), anhydrous dichloromethane
(6 mL), triethylamine (0.700 mL, 5.02 mmol), and perfluoro-1-butanesulfonyl
fluoride (0.540 mL, 3.01 mmol). The reaction mixture was stirred at
room temperature for 3 h. The crude material was purified by flash
column chromatography eluting with 10% diethyl ether in hexane to
give 2-fluorophenyl nonafluorobutanesulfonate (1o) as
a colorless oil (0.661 g, 84%). IR (neat) 1612, 1501, 1431, 1227,
1200, 1142, 1096, 895, 760 cm–1; 1H NMR
(400 MHz, CDCl3) δ 7.19–7.24 (m, 1H), 7.27
(ddd, J = 9.8, 8.4, 1.4 Hz, 1H), 7.33–7.41
(m, 2H); 13C{1H} NMR (101 MHz, CDCl3) δ 117.8 (d, 2JCF 18.2
Hz, CH), 123.6 (CH), 125.2 (d, 3JCF 4.1 Hz, CH), 129.8 (d, 3JCF 7.1 Hz, CH), 137.3 (d, 2JCF 13.4 Hz, C), 153.9 (d, 1JCF 254.6 Hz, C); MS (ESI) m/z 417 (M + Na+, 100); HRMS (ESI) m/z: [M + Na]+ calcd for C10H4F10NaO3S 416.9614; found 416.9614.
3-Chlorophenyl
nonafluorobutanesulfonate (1p)[31]
The reaction was carried out according
to the previously described procedure for 4-methylphenyl nonafluorobutanesulfonate
(1a) using 3-chlorophenol (0.257 g, 2.00 mmol), anhydrous
dichloromethane (6 mL), triethylamine (0.700 mL, 5.02 mmol), and perfluoro-1-butanesulfonyl
fluoride (0.540 mL, 3.01 mmol). The reaction mixture was stirred at
room temperature for 2 h. The crude material was purified by flash
column chromatography eluting with 100% hexane to give 3-chlorophenyl
nonafluorobutanesulfonate (1p) as a colorless oil (0.672
g, 82%). Spectroscopic data were consistent with the literature.[31]1H NMR (400 MHz, CDCl3) δ 7.18–7.24 (m, 1H), 7.30–7.33 (m, 1H), 7.37–7.43
(m, 2H); 13C{1H} NMR (101 MHz, CDCl3) δ 119.9 (CH), 122.2 (CH), 129.0 (CH), 131.1 (CH), 135.8 (C),
149.9 (C); MS (EI) m/z 410 (M+, 33), 348 (9), 346 (27), 127 (28), 111 (44), 99 (34), 84
(100).
3-Bromophenyl nonafluorobutanesulfonate (1q)
The reaction was carried out according to the previously described
procedure for 4-methylphenyl nonafluorobutanesulfonate (1a) using 3-bromophenol (0.356 g, 2.06 mmol), anhydrous dichloromethane
(5 mL), triethylamine (0.720 mL, 5.17 mmol), and perfluoro-1-butanesulfonyl
fluoride (0.560 mL, 3.11 mmol). The reaction mixture was stirred at
room temperature for 1 h. The crude material was purified by flash
column chromatography eluting with 100% petroleum ether (40–60)
to give 3-bromophenyl nonafluorobutanesulfonate (1q)
as a colorless oil (0.830 g, 88%). IR (neat) 1582, 1468, 1425, 1354,
1227, 1200, 1142, 1034, 897, 785 cm–1; 1H NMR (400 MHz, CDCl3) δ 7.26 (ddd, J = 8.2, 2.0, 0.8 Hz, 1H), 7.34 (t, J = 8.2 Hz, 1H),
7.47 (t, J = 2.0 Hz, 1H), 7.55 (ddd, J = 8.2, 2.0, 0.8 Hz, 1H); 13C{1H} NMR (101
MHz, CDCl3) δ 120.3 (CH), 123.2 (C), 125.0 (CH),
131.4 (CH), 131.9 (CH), 149.9 (C); MS (EI) m/z 454 (M+, 42), 392 (21), 390 (22), 173 (20),
171 (20), 157 (27), 155 (28), 83 (100), 78 (50), 63 (59); HRMS (EI) m/z: [M]+ calcd for C10H479BrF9O3S 453.8921;
found 453.8920.
Pyridin-2-yl nonafluorobutanesulfonate (1r)[12h]
The reaction was
carried out according
to the previously described procedure for 4-methylphenyl nonafluorobutanesulfonate
(1a) using pyridin-2-ol (0.190 g, 2.00 mmol), anhydrous
dichloromethane (6 mL), triethylamine (0.700 mL, 5.02 mmol), and perfluoro-1-butanesulfonyl
fluoride (0.540 mL, 3.01 mmol). The reaction mixture was stirred at
room temperature for 166 h. The crude material was purified by flash
column chromatography eluting with 30% diethyl ether in hexane to
give pyridin-2-yl nonafluorobutanesulfonate (1r) as a
colorless oil (0.495 g, 66%). Spectroscopic data were consistent with
the literature.[12h]1H NMR (400
MHz, CDCl3) δ 7.19 (br d, J = 8.2
Hz, 1H), 7.40 (ddd, J = 7.4, 4.8, 0.4 Hz, 1H), 7.90
(ddd, J = 8.2, 7.4, 2.0 Hz, 1H), 8.42 (dd, J = 4.8, 2.0 Hz, 1H); 13C{1H} NMR
(101 MHz, CDCl3) δ 115.4 (CH), 124.4 (CH), 141.1
(CH), 148.9 (CH), 156.1 (C); MS (ESI) m/z 400 (M + Na+, 100).
(4-Methylphenyl)diphenylphosphine
Oxide (2a)[32]
General
Procedure Using 1 equiv of Sodium Iodide
A
stirrer bar and sodium iodide (0.0600 g, 0.400 mmol) were added to
a microwave tube and dried in an oven at 140 °C overnight. 4-Methylphenyl
nonafluorobutanesulfonate (1a) (0.156 g, 0.400 mmol)
was dried under high vacuum for 1 h, purged with argon, and dissolved
in anhydrous N,N′-dimethylformamide
(2.4 mL). Diphenylphosphine oxide (0.121 g, 0.600 mmol) was dried in vacuo for 1 h. The oven-dried microwave tube was cooled
to room temperature in vacuo and then purged with
argon. To the tube was added diphenylphosphine oxide and palladium(II)
acetate (0.00900 g, 0.0400 mmol), followed by the 4-methylphenyl nonafluorobutanesulfonate
(1a) solution and triethylamine (0.220 mL, 1.58 mmol).
The tube was sealed, heated to 120 °C, and stirred for 4 h. The
reaction mixture was cooled to room temperature, diluted with ethyl
acetate (15 mL), and washed with 2 M aqueous lithium chloride solution
(3 × 15 mL). The organic layer was dried (MgSO4),
filtered, and concentrated in vacuo. The crude material
was purified by flash column chromatography eluting with 30% ethyl
acetate in dichloromethane to give (4-methylphenyl)diphenylphosphine
oxide (2a) as a white solid (0.0905 g, 78%). Mp 118–120
°C. Spectroscopic data were consistent with previously published
data.[32]1H NMR (400 MHz, CDCl3) δ 2.40 (s, 3H), 7.27 (dd, J = 8.0,
2.8 Hz, 2H), 7.41–7.49 (m, 4H), 7.50–7.59 (m, 4H), 7.62–7.71
(m, 4H); 13C{1H} NMR (101 MHz, CDCl3) δ 21.8 (d, 5JCP =
1.3 Hz, CH3), 128.6 (d, 3JCP = 12.1 Hz, 4 × CH), 129.3 (d, 1JCP = 107.0 Hz, C), 129.4 (d, 3JCP = 12.5 Hz, 2 × CH), 131.9 (d, 4JCP = 2.7 Hz, 2 × CH), 132.2 (d, 2JCP = 9.8 Hz, 4 × CH), 132.3 (d, 2JCP = 10.3 Hz, 2 × CH), 133.0
(d, 1JCP = 104.3 Hz, 2 ×
C), 142.6 (d, 4JCP = 2.7 Hz,
C); MS (ESI) m/z 315 (M + Na+, 100).
Using 0.1 equiv of Sodium Iodide
The reaction was carried
out according to the previously described procedure for (4-methylphenyl)diphenylphosphine
oxide (2a) using sodium iodide (0.00300 g, 0.0200 mmol),
4-methylphenyl nonafluorobutanesulfonate (1a) (0.0780
g, 0.200 mmol), anhydrous N,N′-dimethylformamide
(1.2 mL), diphenylphosphine oxide (0.0610 g, 0.302 mmol), palladium(II)
acetate (0.00450 g, 0.0200 mmol), and triethylamine (0.110 mL, 0.790
mmol). The reaction mixture was stirred at 120 °C for 8 h. The
crude material was purified by flash column chromatography eluting
with 2% methanol in diethyl ether to give (4-methylphenyl)diphenylphosphine
oxide (2a) as a white solid (0.0441 g, 76%). Spectroscopic
data were consistent as described above.
Without Sodium Iodide
The reaction was carried out
according to the previously described procedure for (4-methylphenyl)diphenylphosphine
oxide (2a) using 4-methylphenyl nonafluorobutanesulfonate
(1a) (0.0780 g, 0.200 mmol), anhydrous N,N′-dimethylformamide (1.2 mL), diphenylphosphine
oxide (0.0610 g, 0.302 mmol), palladium(II) acetate (0.00450 g, 0.0200
mmol), and triethylamine (0.110 mL, 0.790 mmol). The reaction mixture
was heated to 120 °C and stirred for 24 h. The crude material
was purified by flash column chromatography eluting with 2% methanol
in diethyl ether to give (4-methylphenyl)diphenylphosphine oxide (2a) as a white solid (0.0461 g, 79%). Spectroscopic data were
consistent as described above.
Using 1 equiv
of Sodium Acetate
The reaction
was carried out according to the previously described procedure for
(4-methylphenyl)diphenylphosphine oxide (2a) using sodium
acetate (0.0328 g, 0.400 mmol), 4-methylphenyl nonafluorobutanesulfonate
(1a) (0.156 g, 0.400 mmol), anhydrous N,N′-dimethylformamide (2.4 mL), diphenylphosphine
oxide (0.121 g, 0.600 mmol), palladium(II) acetate (0.00900 g, 0.0400
mmol), and triethylamine (0.220 mL, 1.58 mmol). The reaction was heated
to 120 °C and stirred for 22 h. The crude material was purified
by flash column chromatography eluting with 2% methanol in diethyl
ether to give (4-methylphenyl)diphenylphosphine oxide (2a) as a white solid (0.0642 g, 55%). Spectroscopic data were consistent
as described above.
Using 1 equiv of Sodium Chloride
The reaction
was carried out according to the previously described procedure for
(4-methylphenyl)diphenylphosphine oxide (2a) using sodium
chloride (0.0234 g, 0.400 mmol), 4-methylphenyl nonafluorobutanesulfonate
(1a) (0.156 g, 0.400 mmol), anhydrous N,N′-dimethylformamide (2.4 mL), diphenylphosphine
oxide (0.121 g, 0.600 mmol), palladium(II) acetate (0.00900 g, 0.0400
mmol), and triethylamine (0.220 mL, 1.58 mmol). The reaction was heated
to 120 °C and stirred for 32 h. The crude material was purified
by flash column chromatography eluting with 2% methanol in diethyl
ether to give (4-methylphenyl)diphenylphosphine oxide (2a) as a white solid (0.0745 g, 64%). Spectroscopic data were consistent
as described above.
(3-Methylphenyl)diphenylphosphine Oxide (2b)[33]
The reaction was
carried out according
to the previously described general procedure for (4-methylphenyl)diphenylphosphine
oxide (2a) using sodium iodide (0.0600 g, 0.400 mmol),
3-methylphenyl nonafluorobutanesulfonate (1b) (0.156
g, 0.400 mmol), anhydrous N,N′-dimethylformamide
(2.4 mL), diphenylphosphine oxide (0.121 g, 0.600 mmol), palladium(II)
acetate (0.00900 g, 0.0400 mmol), and triethylamine (0.220 mL, 1.58
mmol). The reaction mixture was stirred at 120 °C for 4 h. The
crude material was purified by flash column chromatography eluting
with 2% methanol in diethyl ether to give (3-methylphenyl)diphenylphosphine
oxide (2b) as a pale orange solid (0.111 g, 95%). Mp
112–114 °C. Spectroscopic data were consistent with previously
published data.[33]1H NMR (400
MHz, CDCl3) δ 2.36 (s, 3H), 7.29–7.41 (m,
3H), 7.42–7.49 (m, 4H), 7.54 (ttd, J = 7.3,
1.7, 1.6 Hz, 2H), 7.58 (br d, J = 12.4 Hz, 1H), 7.62–7.71
(m, 4H); 13C{1H} NMR (101 MHz, CDCl3) δ 21.6 (CH3), 128.4 (d, 3JCP = 12.9 Hz, CH), 128.6 (d, 3JCP = 12.1 Hz, 4 × CH), 129.3 (d, 2JCP = 10.3 Hz, CH), 132.0 (d, 4JCP = 2.7 Hz, 2 × CH), 132.2 (d, 2JCP = 9.9 Hz, 4 × CH), 132.5 (d, 1JCP = 104.5 Hz, C), 132.6 (d, 2JCP = 9.5 Hz, CH), 132.8 (d, 4JCP = 2.8 Hz, CH), 132.9 (d, 1JCP = 104.2 Hz, 2 × C), 138.6
(d, 3JCP = 12.1 Hz, C); MS
(ESI) m/z 315 (M + Na+, 100).
(2-Methylphenyl)diphenylphosphine Oxide (2c)[32]
The reaction was
carried out according
to the previously described general procedure for (4-methylphenyl)diphenylphosphine
oxide (2a) using sodium iodide (0.0600 g, 0.400 mmol),
2-methylphenyl nonafluorobutanesulfonate (1c) (0.156
g, 0.400 mmol), anhydrous N,N′-dimethylformamide
(2.4 mL), diphenylphosphine oxide (0.121 g, 0.600 mmol), palladium(II)
acetate (0.00900 g, 0.0400 mmol), and triethylamine (0.220 mL, 1.58
mmol). The reaction mixture was stirred at 120 °C for 7 h. The
crude material was purified by flash column chromatography eluting
with 2% methanol in diethyl ether to give (2-methylphenyl)diphenylphosphine
oxide (2c) as an off-white solid (0.0679 g, 58%). Mp
119–121 °C (lit.[32] 121.5–122.9
°C); 1H NMR (400 MHz, CDCl3) δ 2.45
(s, 3H), 7.03 (ddd, J = 14.0, 7.5, 1.3 Hz, 1H), 7.13
(br td, J = 7.5, 2.0 Hz, 1H), 7.28 (br dd, J = 7.5, 4.0 Hz, 1H), 7.41 (tt, J = 7.5,
1.3 Hz, 1H), 7.44–7.50 (m, 4H), 7.55 (ttd, J = 7.4, 1.8, 1.6 Hz, 2H), 7.61–7.70 (m, 4H); 13C{1H} NMR (101 MHz, CDCl3) δ 21.8 (d, 3JCP = 4.6 Hz, CH3),
125.3 (d, 3JCP = 12.9 Hz, CH),
128.7 (d, 3JCP = 12.1 Hz, 4
× CH), 131.0 (d, 1JCP =
103.5 Hz, C), 131.9 (d, 4JCP = 2.8 Hz, 2 × CH), 132.0 (d, 3JCP = 10.5 Hz, CH), 132.1 (d, 2JCP = 9.9 Hz, 4 × CH), 132.2 (d, 4JCP = 2.6 Hz, CH), 133.0 (d, 1JCP = 103.7 Hz, 2 × C), 133.6 (d, 2JCP = 12.8 Hz, CH), 143.5 (d, 2JCP = 8.1 Hz, C); MS (ESI) m/z 315 (M + Na+, 100).
The reaction was carried out according to
the previously described procedure for 4-methylphenyl nonafluorobutanesulfonate
(1a) using methyl (2S)-2-[(benzyloxycarbonyl)amino]-3-(4-hydroxyphenyl)propanoate
(7) (0.988 g, 3.00 mmol), anhydrous dichloromethane (10
mL), triethylamine (1.05 mL, 7.53 mmol), and perfluoro-1-butanesulfonyl
fluoride (0.810 mL, 4.50 mmol). The reaction mixture was stirred at
room temperature for 2 h. The crude material was purified by flash
column chromatography eluting with 50% diethyl ether in hexane to
give methyl (2S)-2-[(benzyloxycarbonyl)amino]-3-[(phenylnonafluorobutanesulfonate)-4′-yl]propanoate
(8) as a colorless oil which solidified upon standing
(1.72 g, 94%). Mp 46–48 °C; IR (neat) 3341, 2959, 1717,
1501, 1423, 1200, 1142, 1015, 891 cm–1; [α]D17 −14.6 (c 0.5, MeOH); 1H NMR (400 MHz, CDCl3) δ 3.09 (dd, J = 14.0, 6.4 Hz, 1H), 3.19 (dd, J = 14.0,
5.6 Hz, 1H), 3.72 (s, 3H), 4.60–4.72 (m, 1H), 5.07 (d, J = 12.2 Hz, 1H), 5.12 (d, J = 12.2 Hz,
1H), 5.26 (d, J = 8.0 Hz, 1H), 7.18 (br s, 4H), 7.28–7.42
(m, 5H); 13C{1H} NMR (101 MHz, CDCl3) δ 37.8 (CH2), 52.6 (CH3), 54.8 (CH),
67.3 (CH2), 121.6 (2 × CH), 128.3 (2 × CH), 128.5
(CH), 128.7 (2 × CH), 131.2 (2 × CH), 136.2 (C), 136.7 (C),
149.0 (C), 155.6 (C), 171.6 (C); MS (ESI) m/z 634 (M + Na+, 100); HRMS (ESI) m/z: [M + Na]+ calcd for C22H18F9NNaO7S 634.0552; found 634.0549.
Methyl (2S)-2-[(benzyloxycarbonyl)amino]-3-[(diethylphenylphosphonate)-4′-yl]propanoate
(9) Using Pd(PPh3)4 (10 mol %)
The reaction was carried out according to the previously described
general procedure for (4-methylphenyl)diphenylphosphine oxide (2a) using sodium iodide (0.150 g, 1.00 mmol), methyl (2S)-2-[(benzyloxycarbonyl)amino]-3-[(phenylnonafluorobutanesulfonate)-4′-yl]propanoate
(8) (0.611 g, 1.00 mmol), anhydrous N,N′-dimethylformamide (6 mL), diethyl phosphite
(0.193 mL, 1.50 mmol), tetrakis(triphenylphosphine)palladium(0) (0.116
g, 0.100 mmol), and triethylamine (0.557 mL, 4.00 mmol). The reaction
mixture was heated to 80 °C and stirred for 6 h. The reaction
mixture was cooled to room temperature, diluted with ethyl acetate
(50 mL), and washed with water (3 × 50 mL). The organic layer
was dried (MgSO4), filtered, and concentrated in
vacuo. The crude material was purified by flash column chromatography
eluting with 2% methanol and 2% toluene in diethyl ether to give methyl
(2S)-2-[(benzyloxycarbonyl)amino]-3-[(diethylphenylphosphonate)-4′-yl]propanoate
(9) as a colorless oil (0.326 g, 72%). IR (neat) 3248,
2983, 1714, 1533, 1225, 1017, 961, 745 cm–1; [α]D23 +50.1 (c 0.1, CHCl3); 1H NMR (400 MHz, CDCl3) δ 1.31 (t, J = 7.0 Hz, 6H), 3.11 (dd, J = 14.0, 6.0
Hz, 1H), 3.20 (dd, J = 14.0, 5.6 Hz, 1H), 3.71 (s,
3H), 4.00–4.20 (m, 4H), 4.61–4.75 (m, 1H), 5.07 (d, J = 12.4 Hz, 1H), 5.11 (d, J = 12.4 Hz,
1H), 5.28 (d, J = 8.0 Hz, 1H), 7.20 (dd, J = 8.2, 3.6 Hz, 2H), 7.27–7.42 (m, 5H), 7.71 (dd, J = 13.2, 8.2 Hz, 2H); 13C{1H} NMR
(101 MHz, CDCl3) δ 16.5 (d, 3JCP = 6.6 Hz, 2 × CH3), 38.3 (CH2), 52.6 (CH3), 54.7 (CH), 62.2 (d, 2JCP = 5.6 Hz, 2 × CH2), 67.2
(CH2), 127.3 (d, 1JCP = 190.3 Hz, C), 128.2 (2 × CH), 128.4 (CH), 128.7 (2 ×
CH), 129.6 (d, 3JCP = 15.4
Hz, 2 × CH), 132.1 (d, 2JCP = 10.3 Hz, 2 × CH), 136.2 (C), 140.7 (d, 4JCP = 2.8 Hz, C), 155.7 (C), 171.7 (C); MS (ESI) m/z 472 (M + Na+, 100); HRMS
(ESI) m/z: [M + Na]+ calcd
for C22H28NNaO7P 472.1496; found
472.1498.
Methyl (2S)-2-[(benzyloxycarbonyl)amino]-3-[(diethylphenylphosphonate)-4′-yl]propanoate
(9) Using Pd(PPh3)4 (5 mol %)
The reaction was carried out according to the previously described
general procedure for (4-methylphenyl)diphenylphosphine oxide (2a) using sodium iodide (0.150 g, 1.00 mmol), methyl (2S)-2-[(benzyloxycarbonyl)amino]-3-[(phenylnonafluorobutanesulfonate)-4′-yl]propanoate
(8) (0.611 g, 1.00 mmol), anhydrous N,N′-dimethylformamide (6 mL), diethyl phosphite
(0.193 mL, 1.50 mmol), tetrakis(triphenylphosphine)palladium(0) (0.058
g, 0.05 mmol), and triethylamine (0.557 mL, 4.00 mmol). The reaction
mixture was heated to 80 °C and stirred for 7 h. The reaction
mixture was cooled to room temperature, diluted with ethyl acetate
(50 mL), and washed with water (3 × 50 mL). The organic layer
was dried (MgSO4), filtered, and concentrated in
vacuo. The crude material was purified by flash column chromatography
eluting with 2% methanol and 2% toluene in diethyl ether to give methyl
(2S)-2-[(benzyloxycarbonyl)amino]-3-[(diethylphenylphosphonate)-4′-yl]propanoate
(9) as a colorless oil (0.294 g, 65%). Spectroscopic
data were consistent as described above.
Methyl (2S)-2-[(benzyloxycarbonyl)amino]-3-[(diethylphenylphosphonate)-4′-yl]propanoate
(9) (0.209 g, 0.465 mmol) was suspended in 6 M aqueous
hydrochloric acid solution (1.70 mL, 10.2 mmol) and stirred under
reflux for 6 h. The reaction mixture was cooled to room temperature
and concentrated in vacuo. The crude material was
purified by trituration with diethyl ether to give (2S)-2-amino-3-[(phenylphosphonate)-4′-yl]propanoic hydrochloride
(10) as a white solid (0.115 g, 88%). Mp 218–220
°C; IR (neat) 2745, 1729, 1605, 1501, 1407, 1135, 921 cm–1; [α]D25 +3.5 (c 0.1, H2O); 1H NMR (400 MHz, D2O) δ 3.25 (dd, J = 14.6, 7.6 Hz, 1H),
3.41 (dd, J = 14.6, 5.6 Hz, 1H), 4.32 (dd, J = 7.6, 5.6 Hz, 1H), 7.43 (dd, J = 8.0,
3.2 Hz, 2H), 7.71 (dd, J = 12.8, 8.0 Hz, 2H); 13C{1H} NMR (101 MHz, D2O) δ 38.6
(CH2), 57.3 (CH), 132.3 (d, 3JCP = 14.5 Hz, 2 × CH), 134.0 (d, 2JCP = 10.2 Hz, 2 × CH), 136.2 (d, 1JCP = 180.5 Hz, C), 140.3 (d, 4JCP = 3.1 Hz, C), 174.7 (C); MS (ESI) m/z 246 (M + Na+, 100); HRMS
(ESI) m/z: [M + Na]+ calcd
for C9H13NO5P 246.0526; found 246.0527.
(4-Methylphenyl)diphenylphosphine Oxide (2a) Using p-Tolyl Iodide (11)[32]
The reaction was carried out according to the previously
described procedure for (4-methylphenyl)diphenylphosphine oxide (2a) using p-tolyl iodide (11) (0.0436 g, 0.200 mmol), anhydrous N,N′-dimethylformamide (1.2 mL), diphenylphosphine oxide (0.0610
g, 0.302 mmol), palladium(II) acetate (0.00450 g, 0.0200 mmol), and
triethylamine (0.110 mL, 0.790 mmol). The reaction mixture was heated
to 120 °C and stirred for 1.5 h. The crude material was purified
by flash column chromatography eluting with 2% methanol in diethyl
ether to give (4-methylphenyl)diphenylphosphine oxide (2a) as a white solid (0.0199 g, 34%). Spectroscopic data were consistent
as described above.
Authors: Weiqin Jiang; George Allan; James J Fiordeliso; Olivia Linton; Pamela Tannenbaum; Jun Xu; Peifang Zhu; Joseph Gunnet; Keith Demarest; Scott Lundeen; Zhihua Sui Journal: Bioorg Med Chem Date: 2006-06-27 Impact factor: 3.641
Scheme 1
Scheme 6
Scheme 2
Scheme 3
Scheme 4
Figure 1
Scheme 5