A Library of Fluorinated Electrophiles for Chemical Tagging and Materials Synthesis

Article abstract of DOI:10.1021/acs.joc.6b01572

Various applications could benefit from new fluorinated molecules that offer chemical handles for quickly functionalizing reactive surfaces and molecules. Herein, we report the synthesis of a library of fluorinated molecules that contain nonafluoro-tert-butyl groups and electrophilic handles, mostly acrylates and acrylamides. Featuring a variety of hydrophobic and hydrophilic linkers, these molecules could find use in polymer chemistry, biomaterials, biomedical imaging, and protein tagging.

Full text of DOI:10.1021/acs.joc.6b01572

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Note
A Library of Fluorinated Electrophiles for
Chemical Tagging and Materials Synthesis
Jonathan J. Kasper, Jamie E. Hitro, Sabrina R. Fitzgerald, Joseph M.
Schnitter, James Jude Rutowski, John A. Heck, and Jeremy L. Steinbacher
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.6b01572 • Publication Date (Web): 28 Jul 2016
Downloaded from http://pubs.acs.org on August 1, 2016
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A Library of Fluorinated Electrophiles for Chemical Tagging and Materials Synthesis
Jonathan J. Kasper, Jamie E. Hitro, Sabrina R. Fitzgerald, Joseph M. Schnitter, James J.
Rutowski, John A. Heck, and Jeremy L. Steinbacher*
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Department of Chemistry and Biochemistry, Canisius College, 2001 Main Street, Buffalo
NY, 14208-1098
*Corresponding author: steinbaj@canisius.edu, 716ꢀ888ꢀ2343 (T), 716ꢀ888ꢀ3112 (F)
Abstract
Various applications could benefit from new fluorinated molecules that offer chemical handles
for quickly functionalizing reactive surfaces and molecules. Herein, we report the synthesis of a
library of fluorinated molecules that contain nonafluoroꢀtertꢀbutyl groups and electrophilic
handles, mostly acrylates and acrylamides. Featuring a variety of hydrophobic and hydrophilic
linkers, these molecules could find use in polymer chemistry, biomaterials, biomedical imaging,
and protein tagging.
Fluorinated molecules and materials offer many unique properties in a wideꢀrange of
applications. The strong, nonꢀpolarizable CꢀF bond leads to very low reactivity and weak Van
der Waals forces, respectively, and thus, highly fluorinated – “fluorous” – molecules have low
solubility in both aqueous and organic solvents.1,2 These useful properties have lead to an entire
segment of green chemistry that uses fluorous molecules in catalysis, reaction separations, and
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chemical synthesis.3,4 Briefly, the phase separation of fluorinated solvents1 and reagents5ꢀ8 is
used to greatly simplify purification of reaction mixtures. In related applications, fluorinated
porous materials have been used to effect separations in the liquid and gas phases.9ꢀ12 Also, the
low reactivity of CꢀF bonds lends fluorinated materials an important place in materials chemistry,
especially in highꢀperformance engineering polymers like poly(tetrafluoroethylene) and
perfluoroalkoxy alkanes, with remarkable chemical resistance, high thermal stability, and good
mechanical properties.
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Beside the interesting physical and chemical properties of fluorinated molecules, the 19F
nucleus possesses a large gyromagnetic ratio, making it nearly as sensitive as the 1H nucleus in
NMR spectroscopy. A large chemical shift dispersion and large paramagnetic term results in a
great sensitivity to chemical and solvation environment.13,14 These characteristics make fluorine
nuclei useful NMR probes for solvation, conformation, and dynamics15 in biological
macromolecules like proteins and peptides16,17 and cellular structures like lipids.18,19 These NMR
characteristics also allow fluorineꢀcontaining molecules to be used as magnetic resonance
imaging (MRI) contrast agents to complement the usual agents that enhance protonꢀbased
MRI.20ꢀ22
From the heavily fluorous “tags” of organic substrates envisioned by Horváth and Rábai3
to more lightly fluorinated molecules needed for labeling biomolecules16 many of these varied
applications could benefit from new fluorinated molecules that offer chemical handles for
quickly functionalizing reactive surfaces and molecules. Acrylates and acrylamides exhibit good
reactivity with a variety of nucleophiles in Michaelꢀtype conjugate additions, making them
attractive functional groups for such applications. Moreover, these electrophiles are also
advantageous due to their myriad potential uses in polymer chemistry. Unfortunately, few highly
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fluorinated acrylates are currently commercially available, and many of those available contain
long (>6 carbon) perfluoroalkyl chains that have known issues with biopersistence in the
environment.23 Those with smaller, compact perfluorinated groups, which are expected to be less
persistent,24 are rare. Herein we report the synthesis of a small library of new fluorinated
electrophiles (“Fꢀelectrophiles”) that all contain the compact nonafluoroꢀtertꢀbutyl group with
potential uses in diverse applications like protein tagging, 19F NMR contrast agents, modification
of materials, and polymer synthesis. We have avoided “heavy fluorous” molecules to permit
their use in applications where separate fluorous phases are not needed, such as polymer science
and biomedical materials.
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For the reasons listed above, acrylate and acrylamide functional groups are the
electrophilic chemical handles for most of the members of this library. Fꢀelectrophiles 3, 7, and
10 are relatively hydrophobic and could find use as monomers in acrylate polymerizations. Fꢀ
electrophiles 4, 12, 13, and 14 contain hydrophilic linkers (tetraethylene glycol, quaternary
aminium, imidazolium, and phosphorylcholine, respectively) for applications that require
hydrophilicity. Fꢀelectrophiles 17 and 20 contain 3° and 2° amines, respectively, that could
exhibit sensitivity to pH changes in biological applications. Lastly, allyl ether FꢀElectrophile 21
contains 18ꢀchemically equivalent fluorine atoms and is reactive in the radical thiolꢀene
conjugation.
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The syntheses of these compounds generally followed known synthetic organic
transformations. The preparation of acrylates 3 and 4 (Scheme 1) began with the alkylation of
nonafluoroꢀtertꢀbutoxide, generated in situ from the corresponding alcohol with KOH, by
reaction with monotosylated 1,3ꢀpropanediol and tetraethylene glycol, respectively. Despite the
steric bulk of this alkoxide, it is a reasonably good nucleophile under these conditions,25,26
yielding the fluorinated alcohols 1 and 2, of which the former is a known fluorinated compound.5
Esterification with acryloyl chloride then gave 3 and 4 in 24% and 18% overall yields,
respectively.
Scheme 1. Synthesis of 3 and 4.
The preparation of acrylamides 7 and 10 followed the same synthetic procedures except
for the choice of amino alcohol starting materials (Scheme 2). Boc protection of the amines
allowed the subsequent use of the Mitsunobu reaction to install the nonafluoroꢀtertꢀbutyl ether
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groups in 5 and 8. Unlike most alcohols, nonafluoroꢀtertꢀbutanol is sufficiently acidic to use as a
nucleophile in the Mitsunobu (pKa ~ 5),26 as demonstrated previously by others.27,26 Deprotection
of the Boc groups with HCl in diethyl ether lead to the fluorinated amines 6 and 9 as their
hydrochloride salts, both crystalline solids. Conveniently, the isolation of both salts was
facilitated by fluorousꢀpromoted phase separations when diethyl ether was added to concentrated
methanolic solutions of both. The ethylene derivative 6 was previously reported as its free base.28
Lastly, 6 and 9 were acylated using acryloyl chloride to give Fꢀelectrophiles 7 and 10 in 13% and
16% overall yields from the initial aminoalcohols, respectively.
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Scheme 2. Syntheses of 7 and 10
The aminium, imidazolium, and phosphorylcholine Fꢀelectrophiles 12, 13, and 14 were
prepared in only a handful of steps from the fluorinated alcohol 1 (Scheme 3). For 12 and 13,
conversion to the mesylate proceeded quantitatively and in high yield, with only a trace of
unreacted mesyl chloride, which was not purified further. Mesylate 11 was then used to alkylate
N,Nꢀdimethylaminoethyl acrylate or 1ꢀvinylimidazole in DMF at 80 °C. Both nucleophiles
managed conversions of 50 % or less when reacted with only the mesylate, as determined by
NMR analysis of reaction crudes after evaporation of the DMF by shortꢀpath distillation.
Thankfully, we found that catalytic sodium iodide (5 mol %) increased conversion by generating
the iodide in situ. After removal of DMF, Fꢀelectrophiles 12 and 13 were isolated as their
chloride salts through anion exchange on sulfonic acid Dowex resin in 82% and 75% yields,
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respectively, from fluorinated alcohol 1. For aminium 12 there was an intense interference on
one of the methylene groups by H2O in the 1H NMR spectrum (DMSOꢀ6). 1Hꢀ1H TOCSY NMR
spectroscopy alleviated the interference by H2O and clarified the methylene assignments (See the
Supporting Information). Phosphorylcholine Fꢀelectrophile 14 was synthesized following the
recent protocol reported by Hu and Emrick.29 Fluorinated alcohol 1 was phosphorylated with 2ꢀ
chloroꢀ2ꢀoxoꢀ1,3,2ꢀdioxaphospholane to give the phospholane intermediate shown in Scheme 3.
This phospholane was prone to hydrolysis over the span of a few days, so we found it best to
immediately subject it to nucleophilic ringꢀopening by N,Nꢀdimethylaminoethyl acrylate to give
the zwitterionic Fꢀelectrophile 14 in 34% yield from 1.
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Scheme 3. Synthesis of 12 – 14
Amineꢀcontaining Fꢀelectrophiles 17 and 20 followed a synthetic pathway similar to
those of acrylamides 7 and 10 (Scheme 4). Protection of Nꢀmethyldiethanolamine with tertꢀ
butyldiphenylsilyl chloride using an excess of the diol cleanly afforded the monoprotected
species, which was subsequently submitted to Mitsunobu conditions using nonafluoroꢀtertꢀ
butanol as the nucleophile to give 15. A similar sequence, including a Bocꢀprotection of the
secondary amine, resulted in 18. Deprotection with TBAF afforded the fluorinated alcohols 16
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and 19, and subsequent esterification with acryloyl chloride gave acrylates 17 and 20 in 25% and
17% yields overall from the diol starting materials. Perhaps unsurprisingly, attempts to deprotect
the Boc group from 20 resulted in the formation of interꢀ and intramolecular conjugate addition
products. In practice, the secondary amine could be deprotected after polymerization or reaction
onto a substrate.
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Scheme 4. Synthesis of 17 and 20
Highlyꢀfluorinated allylic ether 21 was readily synthesized in one step from the
commercially available diol derived from pentaerythritol shown in Scheme 5. Once again, the
Mitsunobu reaction proved quite capable of installing the nonafluoroꢀtertꢀbutyl ethers, even in
the sterically congested 21. On standard silica gel, the highlyꢀfluorinated 21 exhibited a very
large Rf even in a nonꢀpolar eluent (0.82 in 90:10 petroleum ether/ethyl acetate), eluting even before
unreacted triphenylphosphine from the Mitsunobu coupling. We isolated 21 in 49% yield. Spectroscopic
characterization of 21 was interesting in that the methylenes adjacent to the nonafluoroꢀtertꢀbutyl ether
groups appeared as a heavily skewed doublet of doublets, owing to the diastereotopic nature of the
methylene protons. However, 13Cꢀ1H HMBC NMR spectroscopy proved particularly useful at confirming
the connectivity, as the methylene protons (the doublet of doublets) displayed weak coupling to the
quaternary carbons of the nonafluoroꢀtertꢀbutyl groups across the ether bonds (see the Supporting
Information). The pentaerythritol methylene adjacent to the allyloxy group appeared as a singlet, as
expected.
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Scheme 5. Synthesis of 21
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In conclusion, we have synthesized a library of fluorinated electrophiles that could find
use in biomaterials, omniphobic materials, polymer chemistry, and fluorous tagging of biological
molecules. The fluorous group in each is a nonafluoroꢀtertꢀbutyl ether, which is distinct from the
few highlyꢀfluorinated acrylates and methacrylates now commercially available. Our current
priority is to use some of these molecules to synthesize new fluorous/hydrophilic diblock
copolymers and to rapidly and selectively modify nucleophiles (amines and thiols) immobilized
to inorganic nanoparticles. To demonstrate feasibility, preliminary kinetic experiments on an
NMR scale confirmed that Fꢀelectrophiles 4, 12, and 17 reacted quickly and quantitatively with
thiol and amine nucleophiles using DBU as a basic catalyst (see reactions and spectra in the
Supporting Information). Also, toward preparing superhydrophobic materials,30 we have
synthesized thiolꢀmodified silica nanoparticles via the wellꢀknown Stöber31 method. Conjugation
of Fꢀelectrophiles 3 and 21 to the nanoparticles using DBU as a catalyst or a photoinitiator and
UV254, respectively, resulted in useful degrees of functionalization for silica materials (~2.0
nonafluoroꢀtertꢀbutoxy groups per nm2, see thermogravimetric data in the Supporting
Information). These experiments are proofsꢀofꢀprinciple that just begin to demonstrate the full
suite of applications for the Fꢀelectrophiles presented here.
Experimental Section
General Information. All reagents were purchased from commercial sources in the United States and
were used without further purification unless otherwise noted. The petroleum ether (PE) used in our
experiments was the 35ꢀ60 °C fraction. Dichloromethane, tetrahydrofuran, and diethyl ether were dried in
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a houseꢀbuilt solvent purification system using activated alumina. N,Nꢀdimethylformamide and
acetonitrile were dried by vacuum distillation from calcium hydride and stored under an inert atmosphere.
All column chromatography and TLC were performed using silica with 40ꢀ63 µm particle size. TLC was
visualized with UV254 and/or basic permanganate stain. NMR spectra were acquired on a 400 MHz
instrument and are reported in ppm, referenced to tetramethylsilane (1H in CDCl3), solvent (all 13C and 1H
in DMSOꢀd6), and fluorotrichloromethane (all 19F). High resolution mass spectrometry was performed
with a doubleꢀfocusing magnetic sector instrument; three exceptions (3, 14, and 21, indicated below) used
a timeꢀofꢀflight (TOF) instrument.
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3-(nonafluoro-tert-butoxy)propan-1-ol (1)
First, 3ꢀhydroxypropyl tosylate was synthesized: 1,3ꢀpropanediol (3.63 mL, 50.0 mmol) was
added to a RBF along with CH2Cl2 (20 mL) and TEA (1.53 mL, 11 mmol). A dripping funnel equipped
with a rubber septum was placed on the RBF, which was then flushed with nitrogen and placed in an ice
bath. Separately, tosyl chloride (1.91 g, 10.0 mmol) was dissolved in CH2Cl2 (15 mL) and added to the
dripping funnel. The tosyl chloride solution was then dripped into the RBF over the span of thirty minutes,
and the reaction was stirred overnight for 18 hours, warming to room temperature. Then, the solvent was
removed by rotary evaporation, yielding a viscous, slightlyꢀyellow slurry with solid TEA·HCl. This slurry
was taken up in minimal Et2O (~5 mL) and vacuum filtered through a fritted funnel. Removal of the
solvent by rotary evaporation left a viscous oil, and column chromatography with 60:40 EtOAc:PE
1
yielded 1.96 g (81%) of product tosylate (Rf ~0.38 in 60:40 EtOAc:PE) as a viscous, colorless oil. H
NMR (400 MHz, CDCl3): δ 7.80 (d, J = 8.0 Hz, 2H), 7.35 (d, J = 8.0 Hz, 2H), 4.19 (t, J = 6.2 Hz, 2H),
3.72 (q, J = 5.6 Hz, 2H), 2.45 (s, 3H), 1.89 (quint, J = 6.0 Hz, 2H), 1.48 (broad t, 1H). 13C NMR (100
MHz, CDCl3): δ 145.0, 133.1, 130.0, 128.0, 67.6, 58.5, 31.8, 21.8. These spectroscopic data match the
literature values.32
Next, powdered potassium hydroxide (0.34 g, 6.0 mmol) was added to a RBF along with 2ꢀ
butanone (5 mL), forming a slurry. The flask was sealed with a rubber septum and placed in an ice bath.
Nonafluoroꢀtertꢀbutanol (0.84 mL, 6.0 mmol) was added dropwise via syringe over twenty minutes, at
which point the mixture was heterogeneous. Then, the tosyl alcohol (1.52 g, 6.60 mmol) dissolved in 2ꢀ
butanone (2 mL) was added to the RBF via syringe. The RBF was then placed in a hot sand bath (80 °C)
and refluxed for 20 hours overnight. The solvent was removed by rotary evaporation to yield a viscous
slurry, to which was added water (10 mL), saturated bicarbonate (10 mL), and CH2Cl2 (10 mL). Upon
separation, the aqueous phase was washed with another aliquot of CH2Cl2 (10 mL), then the combined
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organic layers were washed sequentially with saturated bicarbonate (8 mL) and brine (8 mL), dried with
anhydrous sodium sulfate, and vacuum filtered. The solvent was removed by rotary evaporation to yield a
paleꢀyellow oil. Column chromatography with 15:85 EtOAc:PE yielded 0.90 g (51%) of product 1 (Rf
1
~0.16 in 15:85 EtOAc:PE) as a colorless oil. H NMR (CDCl3): δ 4.18 (q, J = 6.0 Hz, 2H), 3.79 (q, J =
5.5 Hz, 2H), 1.94 (quint, J = 5.9 Hz, 2H), 1.38 (t, J = 5.0 Hz, 1H). 13C NMR (100 MHz, CDCl3): δ 120.5
(q, J = 293 Hz), 80.0 (m), 67.1, 59.0, 32.6. 19F NMR (376 MHz, CDCl3): δ ꢀ70.95 (s). These spectroscopic
data match the literature values.5
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3-(nonafluoro-tert-butoxy)propyl acrylate (3)
Fluoroalcohol 1 (0.588 g, 2.00 mmol) and dry CH2Cl2 (10 mL) were added to a RBF. The flask
was stoppered with a rubber septum, placed in an ice bath, flushed with nitrogen, and TEA (0.56 mL, 4.0
mmol) was added via syringe. Acryloyl chloride (0.49 mL, 6.0 mmol) was then added dropwise via
syringe over a span of twenty minutes, and the reaction was allowed to stir overnight, warming to room
temperature. After 18 hours, the solvent was removed by rotary evaporation to yield a sticky, yellow
semiꢀsolid. Column chromatography with 1:99 EtOAc:PE yielded 0.41 g (58%) of product 3 (Rf ~0.18 in
1
1:99 EtOAc:PE) as a colorless oil. H NMR (400 MHz, CDCl3): δ 6.41 (dd, J = 17.4, 1.4 Hz, 1H), 6.12
(dd, J = 17.6, 10.0 Hz, 1H), 5.85 (dd, J = 10.2, 1.4 Hz, 1H), 4.28 (t, J = 6.2 Hz, 2H), 4.14 (t, J = 6.0 Hz,
2H), 2.07 (quint, J = 6.0 Hz, 2H). 13C NMR (100 MHz, CDCl3): δ 166.1, 131.1, 128.3, 120.5 (q, J = 293
Hz), 80 (m, J = 29.7 Hz), 66.4, 60.4, 29.2. 19F NMR (376 MHz, CDCl3): δ ꢀ70.88 (s). HRMS (+ESI TOF)
m/z: [M+H]+ Calcd for C10H10F9O3 349.0481; Found 349.0478.
11-(perfluoro-tert-butoxy)-3,6,9-trioxaundecan-1-ol (2)
First, 2ꢀ(2ꢀ(2ꢀ(2ꢀhydroxyethoxy)ethoxy)ethoxy)ethyl tosylate, TsOꢀTEG, was synthesized.
Tetraethylene glycol (3.45 mL, 20.0 mmol) was added to a RBF along with CH2Cl2 (30 mL) and TEA
(1.67 mL, 12.0 mmol). A dripping funnel equipped with a rubber septum was placed on the RBF, which
was then flushed with nitrogen and placed in an ice bath. Separately, tosyl chloride (1.91 g, 10.0 mmol)
was dissolved in CH2Cl2 (6 mL) in an Erlenmeyer flask and added to the dripping funnel via syringe; the
flask was rinsed with a second aliquot of CH2Cl2 (4 mL) into the dripping funnel. The tosyl chloride
solution was then dripped into the RBF over the span of thirty minutes, and the reaction was stirred
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overnight for 18 hours, warming to room temperature. Then, the solvent was removed by rotary
evaporation, yielding a viscous, slightlyꢀyellow slurry with solid TEA·HCl. This slurry was taken up in
minimal cold CH2Cl2 (~5 mL) and vacuum filtered through a fritted funnel. Removal of the solvent by
rotary evaporation left a viscous oil, and column chromatography with 98:2 changing to 96:4
CH2Cl2:MeOH yielded 1.78 g (51%) of product TsOꢀTEG (Rf ~0.32 in 95:5 CH2Cl2:MeOH) as a viscous,
colorless oil. 1H NMR (CDCl3): δ 7.80 (d, J = 8.0 Hz, 2H), 7.34 (d, J = 8.0 Hz, 2H), 4.17 (t, J = 4.8 Hz,
2H), 3.56 – 3.73 (m, 14H), 2.45 (s, 3H), 2.4 (bs, 1H). 13C NMR (100 MHz, CDCl3): δ 145.0, 133.1, 130.0,
128.1, 72.6, 70.90, 70.81, 70.70, 70.63, 70.49, 69.4, 68.9, 61.9, 21.8. These spectroscopic data match the
literature values.33
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Next, powdered potassium hydroxide (0.42 g, 7.5 mmol) was added to a RBF along with 2ꢀ
butanone (10 mL), forming a slurry. The flask was sealed with a rubber septum and placed in an ice bath.
Nonafluoroꢀtertꢀbutanol (1.05 mL, 7.5 mmol) was added dropwise via syringe over twenty minutes, at
which point the mixture was heterogeneous. Then, TsOꢀTEG (2.86 g, 8.23 mmol) dissolved in 2ꢀbutanone
(5 mL) was added to the RBF via syringe. The RBF was then placed in a hot sand bath (80 °C) and
refluxed for 20 hours overnight. The solvent was removed by rotary evaporation to yield a viscous slurry,
which was vacuum filtered and washed with CH2Cl2 (3 x 5 mL) to remove precipitated potassium tosylate.
The solvent was removed by rotary evaporation to yield a viscous, paleꢀyellow oil. Column
chromatography with 75:25 EtOAc:PE yielded 2.27 g (73%) of product 2 (Rf ~0.18 in 75:25 EtOAc:PE)
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as a colorless oil. 1H NMR (CDCl3): δ 4.16 (t, J = 4.8 Hz, 2H), 3.60 – 3.75 (m, 14H), 2.42 (bs, 1H). C
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NMR (100 MHz, CDCl3): δ. F NMR (376 MHz, CDCl3): δ ꢀ70.83 (s). HRMS (+ESI) m/z: [M + Na]+
Calcd for C12H17F9O5Na 435.0835; Found 435.0839.
11-(nonafluoro-tert-butoxy)-3,6,9-trioxaundecyl acrylate (4)
FluoroꢀTEG (1.5 g, 3.6 mmol) and dry CH2Cl2 (15 mL) were added to a RBF. The flask was
stoppered with a rubber septum, placed in an ice bath, and flushed with nitrogen, then TEA (1.0 mL, 7.2
mmol) was added via syringe. Acryloyl chloride (0.86 mL, 11 mmol) was then added dropwise via
syringe over a span of twenty minutes, and the reaction was allowed to stir overnight, warming to room
temperature. After 18 hours, the solvent was removed by rotary evaporation to yield a viscous slurry with
solid TEA·HCl. This slurry was taken up in minimal CH2Cl2 (~5 mL) and vacuum filtered through filter
paper with rinsing, and the solvent was removed by rotary evaporation. Column chromatography with
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20:80 EtOAc:PE yielded 0.78 g (47%) of product 4 (Rf ~0.21 in 20:80 EtOAc:PE) as a colorless oil. H
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NMR (CDCl3): δ 6.43 (dd, J = 17.4, 1.4 Hz, 1H), 6.15 (dd, J = 17.4, 10.2 Hz, 1H), 5.83 (dd, J = 10.2, 1.4
Hz, 1H), 4.32 (t, J = 4.8 Hz, 2H), 4.15 (t, J = 5 Hz, 2H), 3.74 (q, J = 4.8 Hz, 4H), 3.64 – 3.69 (m, 8H). 13C
NMR (100 MHz, CDCl3): δ 166.3, 131.1, 128.4, 120.5 (q, J = 293 Hz), 79.7 (m), 71.2, 70.8, 69.6, 69.4,
69.2, 63.8. 19F NMR (376 MHz, CDCl3): δ ꢀ70.90 (s). HRMS (+ESI) m/z: [M + Na]+ Calcd for
C15H19F9O6Na 489.0941; Found 489.0932.
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N-(tert-butyloxycarbonyl)-2-amino-1-(nonafluoro-tert-butyoxy)ethane (5)
First, Nꢀ(tertꢀbutyloxycarbonyl)ꢀ2ꢀaminoethanol was synthesized. TEA (13.9 mL, 100 mmol), diꢀ
tertꢀbutyl dicarbonate, Boc2O (5.24 g, 24.0 mmol), and THF (25 mL) were added to a RBF, which was
stoppered with a rubber septum and placed in an ice bath. 2ꢀaminoethanol (1.21 mL, 20.0 mmol) was
added to the RBF via syringe over the span of five minutes, and the reaction was stirred for three hours,
warming to room temperature. The solvent was then removed under reduced pressure to yield a colorless
oil that was transferred to a separatory funnel with deionized water (50 mL) and ethyl acetate (30 mL).
The aqueous layer was washed with two additional aliquots of ethyl acetate, and the combined organic
layers were washed with saturated sodium bicarbonate (30 mL) and brine (30 mL), dried with anhydrous
sodium sulfate, and vacuum filtered. The solvent was removed by rotary evaporation to give 4.31 g of
extracted crude, which consisted of 63 mol % (69 w/w %) Bocꢀprotected aminoalcohol (92% yield), 15
mol % (14 w/w %) of unreacted Boc2O, and 21 mol % (7 w/w%) ethyl acetate. This crude was used in
further steps without additional purification. 1H NMR (CDCl3): δ 4.95 (bs, 1H), 3.71 (distorted t, 2H),
3.30 (distorted q, J = 4.8 Hz, 2H), 2.2 (bs, 1H), 1.45 (s, 9H). 13C NMR (100 MHz, CDCl3): δ 157.0, 79.8,
62.7, 43.4, 28.5. These spectroscopic data match the literature values.34
Then, triphenylphosphine (1.97 g, 7.50 mmol) was added to a flameꢀdried RBF containing a stir
bar along with the NꢀBocꢀprotected aminoalcohol (0.80 g, 5.0 mmol). The flask was stoppered with a
rubber septum and was purged with nitrogen for 15 minutes. Dry THF (13 mL) was added via syringe and
the flask was placed in an iceꢀbath. DEAD (1.18 mL, 7.50 mmol) was added via syringe over five minutes,
at which point the flask was raised from the iceꢀwater bath and allowed to warm to room temperature over
20 minutes. Then, nonafluoroꢀtertꢀbutanol (1.05 mL, 7.50 mmol) was added quickly by syringe, the
septum was replaced with a Teflonꢀtaped glass stopper secured with a Keck clip, and the flask was placed
in a sand bath at 50 °C. The reaction continued overnight for 22 hours, at which point the solvent was
removed by rotary evaporation, yielding a yellow, viscous slurry of precipitated triphenylphosphine oxide.
Column chromatography with 95:5 PE:EtOAc yielded 0.89 g (47%) of 5 as a white, crystalline solid after
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drying under vacuum (Rf ~0.26 in 95:5 PE:EtOAc, mp = 33.7ꢀ34.5 °C). H NMR (400 MHz, CDCl3): δ
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CDCl3): δ 155.9, 120.4 (q, J = 291 Hz), 79.98, 79.87 (m, J = 29.7 Hz), 69.2, 40.5, 28.4. F NMR (376
MHz, CDCl3): δ ꢀ70.90 (s). HRMS (+ESI) m/z: [M – C4H7]+ Calcd for C7H7F9NO3 324.0288, found
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324.02771.
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2-amino-1-(nonafluoro-tert-butyoxy)ethane hydrochloride (6)
To a RBF was added 5 (0.485 g, 1.23 mmol) along with Et2O (2 mL). Concentrated HCl (205 µL,
2.46 mmol) was dripped into the flask over 10 minutes. The flask was stoppered and allowed to stir for a
day, yielding an offꢀwhite, precipitated slurry. The solvent was removed by rotary evaporation to give a
thick, pale yellow slurry, which was taken up in a minimal amount of methanol (~1 mL). The addition of
10 mL of Et2O caused a phase separation, and a small pipette was used to transfer the lower layer to a
clean RBF. The methanol in the dense layer was then removed by rotary evaporation, yielding 0.116 g
(30%) of product 6, a white, powdery solid (mp = 241ꢀ244 °C). 1H NMR (400 MHz, DMSOꢀd6): δ 8.2 (bs,
3H), 4.30 (t, J = 5.0 Hz, 2H), 3.15 (t, J = 5.2 Hz, 2H). 13C NMR (100 MHz, DMSOꢀd6): δ 119.8 (q, J =
292 Hz), 79.2 (m, J = 29.6 Hz), 66.8, 38.3. 19F NMR (376 MHz, DMSOꢀd6): δ ꢀ69.22 (s). MS (+ESI) m/z:
[M – Cl]+ Found 294.20. These spectroscopic data are consistent with the literature values for the free
base.28
N-(2-(nonafluoro-tert-butoxy)ethyl)-acrylamide (7)
Fluorinated amine 6 (0.157 g, 0.50 mmol) and dry CH2Cl2 (2.5 mL) were added to a RBF. The
flask was stoppered with a rubber septum, placed in an ice bath, flushed with nitrogen, and TEA (0.127
mL, 1.5 mmol) was added via syringe. Acryloyl chloride (0.082 mL, 1.0 mmol) was then added dropwise
via syringe over a span of twenty minutes, and the reaction was allowed to stir overnight, warming to
room temperature. After 20 hours, the reaction was quenched by the addition of saturated aqueous
NaHCO3 (10 mL) and poured into a separatory funnel. The aqueous layer was washed with CH2Cl2 (3 x 7
mL), and the combined organic layers were washed with brine (5 mL), dried with NaSO4, and vacuum
filtered. The solvent was removed by rotary evaporation to yield a clear oil. Column chromatography with
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20:80 EtOAc:PE yielded 0.118 g (71%) of product 7 (Rf ~0.34 in 30:70 EtOAc:PE) as a colorless oil. H
NMR (400 MHz, CDCl3): δ 6.30 (dd, J = 17.8, 1.2 Hz, 1H), 6.12 (dd, J = 17.8, 10.4 Hz, 1H), 6.0 (bs, 1H),
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5.69 (dd, J = 10.4, 1.2 Hz, 1H), 4.15 (t, J = 5.0 Hz, 2H), 3.62 (q, J = 5.0 Hz, 2H). C NMR (100 MHz,
CDCl3): δ 165.9, 130.4, 127.3, 120.4 (q, J = 292 Hz), 80.0 (m, J = 29.6 Hz), 68.9, 39.3. 19F NMR (376
MHz, CDCl3): δ ꢀ70.89 (s). HRMS (+ESI) m/z: [M + H]+ Calcd for C9H9F9NO2 334.0495; Found
334.0497.
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N-(tert-butyloxycarbonyl)-3-amino-1-(nonafluoro-tert-butyoxy)propane (8)
First, Nꢀ(tertꢀbutyloxycarbonyl)ꢀ3ꢀaminopropanꢀ1ꢀol was synthesized. TEA (13.9, 100 mmol), diꢀ
tertꢀbutyl dicarbonate, Boc2O (5.24 g, 24.0 mmol), and THF (25 mL) were added to a RBF, which was
stoppered with a rubber septum and placed in an ice bath. Then, 3ꢀaminoethanol (1.58 mL, 20.0 mmol)
was added to the RBF via syringe over the span of five minutes, and the reaction was stirred overnight for
20 hours, warming to room temperature. The solvent was then removed under reduced pressure to yield a
yellow oil that was transferred to a separatory funnel with deionized water (50 mL) and ethyl acetate (30
mL). The aqueous layer was washed with two additional aliquots of ethyl acetate, and the combined
organic layers were washed with saturated sodium bicarbonate (20 mL) and brine (20 mL), dried with
anhydrous sodium sulfate, and vacuum filtered. The solvent was removed by rotary evaporation to give
3.65 g of extracted crude, which consisted of 93 mol % (94 w/w %) product (98% yield) and 7 mol % (6
w/w%) of unreacted Boc2O. This crude was used in further steps without additional purification. 1H NMR
(400 MHz, CDCl3): δ 4.9 (bs, 1H), 3.66 (q, J = 5.7 Hz, 2H), 3.29 (q, J = 6.0 Hz, 2H), 3.1 (broad t, J ~ 6
Hz 1H), 1.67 (quint, J = 6.2 Hz, 2H), 1.45 (s, 9H). 13C NMR (100 MHz, CDCl3): δ 157.3, 79.7, 59.4, 37.0,
33.0, 27.9. These spectroscopic data match the literature values.35
Next, triphenylphosphine (1.97 g, 7.50 mmol) was added to a flameꢀdried RBF containing a stir
bar along with the NꢀBocꢀprotected aminoalcohol (0.88 g, 5.0 mmol). The flask was stoppered with a
rubber septum and was purged with nitrogen for 15 minutes. Dry THF (20 mL) was added via syringe and
the flask was placed in an iceꢀbath. DEAD (1.18 mL, 7.50 mmol) was added via syringe over five minutes,
at which point the flask was raised from the iceꢀwater bath and allowed to warm to room temperature over
20 minutes. Then, nonafluoroꢀtertꢀbutanol (1.05 mL, 7.50 mmol) was added quickly by syringe, the
septum was replaced with a Teflonꢀtaped glass stopper secured with a Keck clip, and the flask was placed
in a sand bath at 55 °C. The reaction continued overnight for 22 hours, at which point the solvent was
removed by rotary evaporation, yielding a light yellow, viscous oil. Column chromatography with 90:10
changing to 80:20 PE:EtOAc yielded 1.10 g (56%) of product 8 (Rf ~0.37 in 90:10 PE:EtOAc) as a
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colorless oil. H NMR (400 MHz, CDCl3): δ 4.6 (bs, 1H), 4.09 (t, J = 5.8 Hz, 2H), 3.25 (q, J = 6.4 Hz,
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2H), 1.89 (quint, J = 6.2 Hz, 2H), 1.44 (s, 9H). C NMR (100 MHz, CDCl3): δ 156.2, 120.6 (q, J = 293
Hz), 79.95 (m, J = 29.7 Hz), 79.46, 68.0, 37.3, 30.3, 28.3. 19F NMR (376 MHz, CDCl3): δ ꢀ70.82 (s).
HRMS (+ESI) m/z: [M – C4H7]+ Calcd for C8H9F9NO3 338.0444, found 338.04395.
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3-amino-1-(nonafluoro-tert-butyoxy)propane hydrochloride (9)
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To a RBF was added 8 (0.635 g, 1.62 mmol) along with Et2O (3 mL). Concentrated HCl (270 µL,
3.2 mmol) was dripped into the flask over 10 minutes. The flask was stoppered and allowed to stir for 20
hr, yielding an offꢀwhite, precipitated slurry. The solvent was removed by rotary evaporation to give a
thick, pale yellow slurry, which was taken up in a minimal amount of methanol (~1 mL). The addition of
10 mL of Et2O caused a phase separation, and a small pipette was used to transfer the lower layer to a
clean RBF. The methanol in the dense layer was then removed by rotary evaporation, yielding 0.251 g
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(47 %) of product 9, a white solid with small, clumpy crystals (mp = 229ꢀ231 °C). H NMR (400 MHz,
DMSOꢀd6): δ 8.0 (bs, 3H), 4.19 (t, J = 6.2 Hz, 2H), 2.86 (distorted q, 2H), 1.96 (quint, J = 7 Hz, 2H). 13C
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NMR (100 MHz, DMSOꢀd6): δ 120.4 (q, J = 291 Hz), 79.6 (m, J = 29.6 Hz), 68.3, 35.7, 27.9 F NMR
(376 MHz, DMSOꢀd6): δ ꢀ69.56 (s). HRMS (+ESI) m/z: [M]+ Calcd for C7H9F9NO 294.0546; Found
294.0555.
N-(3-(nonafluoro-tert-butoxy)propyl)acrylamide (10)
Fluorinated amine 9 (0.230 g, 0.697 mmol) and dry CH2Cl2 (2.0 mL) were added to a RBF. The
flask was stoppered with a rubber septum, placed in an ice bath, flushed with nitrogen, and TEA (0.293
mL, 2.1 mmol) was added via syringe. Acryloyl chloride (0.112 mL, 1.4 mmol) was then added dropwise
via syringe over a span of twenty minutes, and the reaction was allowed to stir overnight, warming to
room temperature. After 20 hours, the reaction was quenched by the addition of saturated aqueous
NaHCO3 (10 mL) and poured into a separatory funnel. The aqueous layer was washed with CH2Cl2 (3 x 7
mL), and the combined organic layers were washed with brine (5 mL), dried with NaSO4, and vacuum
filtered. The solvent was removed by rotary evaporation to yield a clear oil. Column chromatography with
20:80 EtOAc:PE, increasing to 50:50 EtOAc:PE, yielded 0.151 g (62%) of product 10 (Rf ~0.50 in 50:50
EtOAc:PE) as a colorless oil. 1H NMR (400 MHz, CDCl3): δ 6.26 (dd, J = 17.2, 1.2 Hz, 1H), 6.07 (dd, J =
17.2, 10.4 Hz, 1H), 5.9 (bs, 1H), 5.65 (dd, J = 10.4, 1.2 Hz, 1H), 4.13 (t, J = 5.8 Hz, 2H), 3.47 (q, J = 6.3
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Hz, 2H), 1.98 (quint, J = 6.2 Hz, 2H). 13C NMR (100 MHz, CDCl3): δ 165.9, 130.7, 126.7, 120.5 (q, J =
292 Hz), 79.8 (m, J = 29.6 Hz), 68.5, 36.9, 29.5. 19F NMR (376 MHz, CDCl3): δ ꢀ70.86 (s). HRMS
(+ESI) m/z: [M+ H]+ Calcd for C10H11F9NO2 348.0652; Found 348.0649.
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3-(nonafluoro-tert-butoxy)propyl mesylate (11)
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Fluorinated alcohol 1 (1.44 g, 4.89 mmol) was added to a flameꢀdried RBF along with TEA (1.14
mL, 8.00 mmol) and CH2Cl2 (12 mL). The flask was sealed with a rubber stopper and placed in an ice
bath. After five minutes, mesyl chloride (0.62 mL, 8.0 mmol) was added via syringe over the span of five
minutes. The reaction was stirred for an hour and allowed to warm to room temperature, at which time the
reaction was transferred to a separatory funnel with water (20 mL) and CH2Cl2 (10 mL). Upon separation,
the aqueous phase was washed with another aliquot of CH2Cl2 (10 mL), then the combined organic layers
were washed sequentially with saturated bicarbonate (15 mL) and brine (15 mL), dried with anhydrous
sodium sulfate, and vacuum filtered. The solvent was removed by rotary evaporation to yield 1.75 g of a
colorless, thin oil, which consisted of 88 mol % (96 w/w %) product 11 (92% yield) and 12 mol % (4
w/w %) of unreacted mesyl chloride. This crude was used in further steps without additional purification.
1H NMR (CDCl3): δ 4.35 (t, J = 6.0Hz, 2H), 4.18 (t, 5.8 Hz, 2H), 3.02 (s, 3H), 2.15, (quint, J = 5.8 Hz,
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2H). C NMR (100 MHz, CDCl3): δ 120.4 (q, J = 293 Hz), 79.8 (m, J = 29.7 Hz), 65.5, 37.2, 29.6. 19F
NMR (376 MHz, CDCl3): δ ꢀ70.88 (s). HRMS (+ESI) m/z: [M + Na]+ Calcd for C8H9F9O4SNa 394.9981;
Found 394.9974.
N-(2-(acryloyloxy)ethyl)-N,N-dimethyl-3-(nonafluoro-tert-butoxy)propan-1-aminium chloride (12)
Fluorinated mesylate 11 (0.744 g, 2.00 mmol) was added to a RBF along with 2ꢀ
(dimethylamino)ethyl acrylate (0.258 g, 1.80 mmol), sodium iodide (0.015 g, 0.10 mmol), and DMF (4
mL). The flask was stoppered tightly and placed into a sand bath at 78 °C for 44 hours after which time
the DMF was removed via shortꢀpath distillation under reduced pressure. The resulting viscous, orange,
oily slurry was purified via anion exchange chromatography on Dowex 8Xꢀ100 (ꢀSO3H form) by first
eluting nonꢀcharged constituents with Et2O. Then, aminium 12 was eluted with a solution of HCl (2.5 M)
in MeOH, and the solvent was removed by rotary evaporation and high vacuum to give 0.734 g (89%) of
12 as a viscous, slightlyꢀorange oil. 1H NMR (DMSOꢀd6): δ 6.38 (dd, J = 17.2, ~1 Hz, 1H), 6.19 (dd, J =
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17.2 Hz, J = 10.6 Hz, 1H), 6.02 (dd, J = 10.6, ~1 Hz, 1H), 4.54 (s, 2H), 4.17 (t, 5.8 Hz, 2H), 3.78 (t, 4.6
Hz, 2H), 3.48 (m, 2H), 3.15 (s, 6H), 2.16 (m, 2H). 13C NMR (100 MHz, DMSOꢀd6): δ 164.8, 132.5, 127.7,
119.9 (q, J = 292 Hz), 79.2 (m, J = 29.9 Hz), 67.8, 61.9, 60.3, 57.9, 50.8, 23.0. 19F NMR (376 MHz,
DMSOꢀd6): δ ꢀ69.92 (s). HRMS (+ESI) m/z: [M]+ Calcd for C14H19F9NO3 420.1227; Found 420.1219.
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3-(3-(nonafluoro-tert-butoxy)propyl)-1-vinyl-1H-imidazol-3-ium chloride (13)
Fluorinated mesylate 11 (0.744 g, 2.00 mmol) was added to a RBF along with vinyl imidazole
(0.169 g, 1.80 mmol), sodium iodide (0.015 g, 0.10 mmol), and DMF (7 mL). The flask was stoppered
tightly and placed into a sand bath at 80 °C for 24 hours after which time the DMF was removed via
shortꢀpath distillation under reduced pressure. The resulting viscous, orange, oily slurry was purified via
anion exchange chromatography on Dowex 8Xꢀ100 (ꢀSO3H form) by first eluting nonꢀcharged
constituents with Et2O. Then, imidazolium 13 was eluted with a solution of HCl (2.5 M) in MeOH, and
the solvent was removed by rotary evaporation and high vacuum to give 0.591 g (81%) of 13 as a very
viscous, colorless oil. 1H NMR (DMSOꢀd6): δ 9.55 (s, 1H), 8.20 (s, 1H), 7.95 (s, 1H), 7.30 (dd, J = 15.6,
8.4 Hz, 1H), 5.95 (dd, J = 15.6 Hz, J = 2.4 Hz, 1H), 5.43 (dd, J = 8.4, 2.4 Hz, 1H), 4.33 (t, J = 7.2 Hz,
2H), 4.22 (t, 5.4 Hz, 2H), 2.30 (quint, J = 6.4 Hz, 2H). 13C NMR (100 MHz, DMSOꢀd6): δ 135.5, 128.9,
123.3, 119.9 (q, J = 292 Hz), 119.2, , 108.8, 79.2 (m, J = 28.9 Hz), 68.4, 46.6, 29.3. 19F NMR (376 MHz,
DMSOꢀd6): δ ꢀ69.83 (s). HRMS (+ESI) m/z: [M]+ Calcd for C12H12F9N2O 371.0811; Found 371.0814.
2-((2-(acryloyloxy)ethyl)dimethylammonio)ethyl (3-(nonafluoro-tert-butoxy)propyl) phosphate (14)
First, 2ꢀ(3ꢀ(nonafluoroꢀtertꢀbutoxy)propoxy)ꢀ1,3,2ꢀdioxaphospholane 2ꢀoxide was synthesized.
Fluorinated alcohol 1 (1.47 g, 5.00 mmol) was added to a flameꢀdried RBF. The flask was then subjected
to vacuum for several minutes and recharged with nitrogen; this was repeated a second time. Next, dry
THF (8 mL) and TEA (0.695 mL, 5.25 mmol) were added via syringe, and the flask was cooled to ꢀ20 ° C
in an acetone/N2(l) slurry. 2ꢀChloroꢀ2ꢀoxoꢀ1,3,2ꢀdioxaphospholane (0.46 mL, 5.0 mmol) was added via
syringe over 25 min, then the reaction was allowed to warm to room temperature while stirring under
nitrogen. After 3 hours, the copious white precipitate was filtered off with repeated washing with Et2O (6
x 2 mL), and the solvent was removed by rotary evaporation to yield a light yellow oil. Column
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chromatography with 60:40 EtOAc:PE, increasing to 70:30 EtOAc:PE, yielded 1.02 g (51%) of the
fluorinated phospholane product (Rf ~0.24 in 60:40 EtOAc:PE) as a colorless oil. 1H NMR (400 MHz,
CDCl3): δ 4.41ꢀ4.50 (m, 2H), 4.32ꢀ4.41 (m, 2H), 4.27 (dt, J = 8.6, 6.2, 2H), 4.16 (t, J = 5.8 Hz, 2H), 2.10
(quint, J = 5.9 Hz, 2H). 13C NMR (100 MHz, CDCl3): δ 120.4 (q, J = 292 Hz), 79.8 (m, J = 29.6 Hz), 66.2
(d, J = 3.1 Hz), 65.6 (d, J = 2.8 Hz), 64.6 (d, J = 6.1 Hz), 30.8 (d, J = 6.9 Hz), 19F NMR (376 MHz,
CDCl3): δ ꢀ70.98 (s), 31P NMR (162 MHz, CDCl3): δ 17.4 (s).
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Next, 2ꢀ(dimethylamino)ethyl acrylate (0.426 mL, 2.79 mmol) and anhydrous sodium sulfate
(~0.3 g, ~4 mmol) were added directly to the RBF used to isolate the fluorinated phospholane (1.02 g,
2.54 mmol) from the above reaction. The flask was then subjected to vacuum for several minutes and
recharged with nitrogen; this was repeated a second time. Acetonitrile (2 mL, dried by distillation over
CaH2) was then added via syringe, and the slurry was stirred under nitrogen for 30 min. Afterward, the
solution was transferred via cannula to a flameꢀdried RBF; the sodium sulfate was rinsed with 3 x 1.5 mL
of dry acetonitrile, which was also transferred via cannula into the new RBF. The septum was quickly
replaced with a Teflonꢀtaped glass stopper secured with a Keck clip, and the flask was placed in a sand
bath at 70 °C and allowed to stir for 5 days. After cooling to room temperature, Et2O (15 mL) was added,
causing a white precipitate to form, and the flask was placed in the freezer overnight. The offꢀyellow
supernatant was removed via pipette, and the resulting gummy white solid was washed three times with
Et2O through a settling/pipette sequence. A second crop of product was collected from the first
supernatant by removing the solvent by rotary evaporation to yield a gummy solid. This solid was
dissolved in ~1 mL of acetonitrile, then precipitated by the addition of Et2O (10 mL). The resulting
gummy white solid was washed similarly to the first crop. Together, 0.91 g (66%) of product 14 was
collected as a sticky, slightly offꢀwhite gum. 1H NMR (400 MHz, DMSOꢀd6): δ 6.39 (d, J = 17.5, 1H),
6.21 (dd, J = 17.3, 10.3 Hz, 1H), 6.02 (d, J = 10.2, 1H), 4.55 (bs, 1H), 4.14 (t, J = 6.0 Hz, 2H), 4.02 (bs,
1H), 3.80 (m, J = 3.9 Hz, 2H), 3.70 (q, J = 6.5 Hz, 2H), 3.60 (m, J = 4.7 Hz, 2H), 3.17 (s, 6H), 1.88 (quint,
J = 6.2 Hz, 2H). 13C NMR (100 MHz, DMSOꢀd6): δ 164.8, 132.2, 127.9, 120.1 (q, J = 292 Hz), 79.3 (m, J
= 28.9 Hz), 67.7, 64.1, 62.6, 60.0 (d, J = 5.3 Hz), 58.13 (d, J = 4.5 Hz), 58.00, 51.4, 30.9 (d, J = 6.8 Hz).
19F NMR (376 MHz, DMSOꢀd6): δ ꢀ69.77 (s). 31P NMR (162 MHz, DMSOꢀd6): δ ꢀ0.86 (s). HRMS (+ESI
TOF) m/z: [M + H]+ Calcd for C16H24F9NO7P 544.1141; Found 544.1138.
2-((tert-butyldiphenylsilyl)oxy)-N-methyl-N-(2-((nonafluoro-tert-butoxy)ethyl)-ethan-1-amine (15)
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First, 2ꢀ((2ꢀ((tertꢀbutyldiphenylsilyl)oxy)ethyl)(methyl)amino)ethanꢀ1ꢀol was synthesized: Nꢀ
methyldiethanolamine (2.28 g, 20.0 mmol), imidazole (0.68 g, 10.0 mmol), and DMF (15 mL) were
added to a flameꢀdried RBF equipped with a rubber septum and flushed with nitrogen. Tertꢀ
butyldiphenylsilyl chloride (1.28 mL, 5.0 mmol) was added via syringe over a span of 25 minutes.
Stirring was continued overnight at room temperature until the reaction was quenched by the addition of
Et2O (40 mL), deionized H2O (20 mL), and saturated sodium bicarbonate (20 mL). The aqueous layer was
washed with a second aliquot of Et2O (30 mL), then the combined organic layers were washed
sequentially with saturated bicarbonate (20 mL) and brine (20 mL), dried with anhydrous sodium sulfate,
and vacuum filtered. The solvent was removed by rotary evaporation to give 1.666 g of extracted crude,
which consisted of 96 mol % monoprotected product (79% yield) and 4 mol % of the disubstituted
product. This crude, a colorless oil, was used in further steps without additional purification. 1H NMR
(400 MHz, CDCl3): δ 7.67ꢀ7.69 (m, 4H), 7.37ꢀ7.43 (m, 6H), 3.73 (t, J = 5.8 Hz, 2H), 3.54 (t, J = 5.2 Hz,
2H), 2.61 (t, J = 6.0 Hz, 2H), 2.57 (t, J = 5.4 Hz, 2H), 2.27 (s, 3H), 1.05 (s, 9H). 13C NMR (100 MHz,
CDCl3): δ 135.6, 133.7, 129.7, 127.8, 62.1, 59.16, 59.13, 58.5, 42.4, 26.9, 19.2.
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Next, triphenylphosphine (1.57g, 6.0 mmol) was added to a flameꢀdried RBF along with the
TBDPSꢀprotected alcohol from above (1.42 g, 4.0 mmol). The flask was stoppered with a rubber septum
and was purged with nitrogen for 15 minutes. Dry THF (15 mL) was added via syringe and the flask was
placed in an iceꢀbath. DEAD (0.94 mL, 6.0 mmol) was added via syringe over five minutes, at which
point the flask was raised from the iceꢀwater bath and allowed to warm to room temperature over 20
minutes. At this point, nonafluoroꢀtertꢀbutanol (0.84 mL, 6.0 mmol) was added quickly by syringe, the
septum was replaced with a Teflonꢀtaped glass stopper secured with a Keck clip, and the flask was placed
in a sand bath at 50 °C. The reaction continued overnight for 16 hours, at which point the solvent was
removed by rotary evaporation, yielding a light yellow, viscous oil. Column chromatography with 90:10
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PE:EtOAc yielded 1.72 g (75%) of product 15 (Rf ~0.25 in 90:10 PE:EtOAc) as a colorless oil. H NMR
(400 MHz, CDCl3): δ 7.65ꢀ7.67 (m, 4H), 7.36ꢀ7.43 (m, 6H), 4.12 (t, J = 6.0 Hz, 2H), 3.78 (t, J = 6.0 Hz,
2H), 2.86 (t, J = 5.8 Hz, 2H), 2.68 (t, J = 6.0 Hz, 2H), 2.33 (s, 3H), 1.04 (s, 9H). 13C NMR (100 MHz,
CDCl3): δ 135.5, 133.7, 129.9, 128.1, 120.6 (q, J = 292 Hz), 79.7 (m, J = 29.7 Hz), 68.2, 62.3, 59.5, 56.7,
43.4, 26.9, 19.3. 19F NMR (376 MHz, CDCl3): δ ꢀ70.90 (s). HRMS (+ESI) m/z: [M + H]+ Calcd for
C25H31F9NO2Si 576.1986; Found 576.1996.
2-(2-((nonafluoro-tert-butoxy)ethyl)(methyl)amino)ethan-1-ol (16)
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TBDPSꢀprotected fluoroꢀalcohol 15 (1.72 g, 2.98 mmol) was added to a RBF along with
TBAF·H2O (1.89 g, 6.0 mmol) and stirred at room temperature for six hours. The solvent was then
removed under reduced pressure to yield an oil that was transferred to a separatory funnel with a saturated
solution of sodium bicarbonate (20 mL) and ethyl acetate (20 mL). The aqueous layer was washed with
two additional aliquots of ethyl acetate, and the combined organic layers were washed with brine (20 mL),
dried with anhydrous sodium sulfate, and vacuum filtered. The solvent was removed by rotary
evaporation to yield an oil. Column chromatography using 80:20 EtOAc:PE, then 90:10 EtOAc:PE ether
yielded 0.75 g (74%) of product 16 (Rf ~0.15 in 80:20 EtOAc:PE) as a colorless oil. 1H NMR (400 MHz,
CDCl3): δ 4.10 (t, J = 5.4 Hz, 2H), 3.58 (t, J = 5.2 Hz, 2H), 2.79 (t, J = 5.6 Hz, 2H), 2.62 (t, J = 5.4 Hz,
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3H), 2.34 (s, 3H), 2.3 (bs, 1H). C NMR (100 MHz, CDCl3): δ 120.4 (q, J = 292 Hz), 79.9 (m, J = 29.7
Hz), 67.8, 59.1, 58.5, 56.6, 41.9. 19F NMR (376 MHz, CDCl3): δ ꢀ70.86 (s). HRMS (+ESI) m/z: [M + H]+
Calcd for C9H13F9NO2 338.0808; Found 338.0799.
2-((2-((nonafluoro-tert-butoxy)ethyl)(methyl)amino)ethyl acrylate (17)
Fluorinated aminoalcohol 16 (0.67 g, 2.0 mmol) was added to a flameꢀdried RBF along with TEA
(0.56 mL, 4.0 mmol) and dry dichloromethane (10 mL) and the flask was stoppered with a rubber septum.
The flask was placed in an ice bath, cooled for five minutes, and acryloyl chloride (0.32 mL, 4.0 mmol)
was added over 15 minutes. The reaction was stirred overnight, warming to room temperature, for 14
hours, then was quenched by the addition of saturated sodium bicarbonate (10 mL) and additional
dichloromethane (5 mL). After removing the organic layer, the aqueous layer was washed an additional
time with dichloromethane (10 mL), and the organic layers were combined, dried with anhydrous sodium
sulfate, and filtered. The solvent was removed by rotary evaporation to yield a light yellow oil. Column
chromatography using 15:85 EtOAc:PE yielded 0.432 g (56%) of acrylate product 17 (Rf ~0.32 in 20:80
EtOAc:PE) as a very light yellow oil. 1H NMR (400 MHz, CDCl3): δ 6.41 (dd, J = 17.4, 1.4 Hz, 1H), 6.13
(dd, J = 17.2, 10.4 Hz, 1H), 5.83 (dd, J = 10.2, 1.4 Hz, 1H), 4.24 (t, J = 5.6 Hz, 2H), 4.10 (t, J = 6.2 Hz,
2H), 2.75ꢀ2.81 (m, J ~ 6 Hz, 4H), 2.37 (s, 3H). 13C NMR (100 MHz, CDCl3): δ 166.2, 130.9, 128.3, 120.4
(q, J = 291 Hz), 79.9 (m, J = 29.7 Hz), 68.2, 62.3, 56.5, 56.0, 43.0. 19F NMR (376 MHz, CDCl3): δ ꢀ70.85
(s). HRMS (+ESI) m/z: [M + H]+ Calcd for C12H15F9NO3 392.0914; Found 392.0903.
tert-butyl (2-((tert-butyldiphenylsilyl)oxy)ethyl)(2-(nonafluoro-tert-butoxy)ethyl)carbamate (18)
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First, 2ꢀ((2ꢀ((tertꢀbutyldiphenylsilyl)oxy)ethyl)amino)ethanꢀ1ꢀol was synthesized: diethanolamine
(2.47 g, 23.5 mmol), imidazole (1.06 g, 15.6 mmol), and DMF (20 mL) were added to a flameꢀdried RBF
equipped with a rubber septum and flushed with nitrogen. Tertꢀbutyldiphenylsilyl chloride (2.00 mL, 7.79
mmol) was added via syringe over a span of 25 minutes. Stirring was continued overnight at room
temperature until the reaction was quenched by the addition of Et2O (40 mL), deionized H2O (20 mL),
and saturated sodium bicarbonate (20 mL). The aqueous layer was washed with a second aliquot of Et2O
(30 mL), then the combined organic layers were washed sequentially with saturated bicarbonate (20 mL)
and brine (20 mL), dried with anhydrous sodium sulfate, and vacuum filtered. The solvent was removed
by rotary evaporation to give 2.69 g of extracted crude, which consisted of 89 mol % monoprotected
product (5.8 mmol, 74% yield) and 11 mol % of the disubstituted product. This crude, a colorless oil,
was used in further steps without additional purification. 1H NMR (400 MHz, CDCl3): δ 7.65ꢀ7.68 (m,
4H), 7.37ꢀ7.43 (m, 6H), 3.76 (distorted t, J = 5.2 Hz, 2H), 3.60 (distorted t, J = 4.6 Hz, 2H), 2.74ꢀ2.77 (m,
4H), 1.7 (bs, 1H), 1.05 (s, 9H). 13C NMR (100 MHz, CDCl3): δ 135.7, 133.7, 129.9, 127.8, 63.3, 61.0,
51.1, 50.7, 27.0, 19.4.
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Next,
tertꢀbutyl
(2ꢀ((tertꢀbutyldiphenylsilyl)oxy)ethyl)(2ꢀhydroxyethyl)carbamate
was
synthesized. To the RBF containing the TBDPSꢀprotected amino alcohol from above (2.0 g, 5.8 mmol)
was added TEA (2.8 mL, 20 mmol), diꢀtertꢀbutyl dicarbonate, Boc2O (1.32 g, 6.0 mmol), and THF (40
mL). The flask was stoppered with a rubber septum and placed in an ice bath, and the reaction was stirred
overnight for 20 hours, warming to room temperature. The solvent was then removed under reduced
pressure to yield a yellow oil that was transferred to a separatory funnel with deionized water (30 mL) and
ethyl acetate (30 mL). The aqueous layer was washed with two additional aliquots of ethyl acetate, and
the combined organic layers were washed with saturated sodium bicarbonate (20 mL) and brine (20 mL),
dried with anhydrous sodium sulfate, and vacuum filtered. The solvent was removed by rotary
evaporation to give a light yellow oil, which was submitted to column chromatography with 70:30
PE:EtOAc to yield 2.43 g (94%) of the Bocꢀprotected product (Rf ~0.29 in 70:30 PE:EtOAc) as a
1
colorless, viscous oil. H NMR (400 MHz, CDCl3): δ 7.64ꢀ7.67 (m, 4H), 7.37ꢀ7.43 (m, 6H), 3.82/3.75
(bs/t, J = 5.2 Hz, 2H, rotomers), 3.74 (t, J = 5.6 Hz, 2H), 3.47 (distorted q, J ~ 4 Hz, 2 H), 3.4/2.7 (bs, 1H,
rotomers), 3.39 (broad t, J ~ 5 Hz 1H), 1.48/1.38 (s, 9H, rotomers), 1.05 (s, 9H). 13C NMR (100 MHz,
CDCl3): δ 157.4, 135.7, 133.2, 129.9, 127.9, 80.4/80.0 (rotomers), 62.97/62.2 (rotomers), 62.85, 52.0,
51.1/50.8 (rotomers), 28.5 (broad, rotomers), 26.9, 19.2.
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Lastly, triphenylphosphine (1.49 g, 5.68 mmol) was added to a flameꢀdried RBF along with the
TBDPSꢀprotected, Bocꢀprotected alcohol from above (1.62 g, 3.65 mmol). The flask was stoppered with a
rubber septum and was purged with nitrogen for 15 minutes. Dry THF (15 mL) was added via syringe and
the flask was placed in an iceꢀbath. DEAD (0.94 mL, 6.0 mmol) was added via syringe over ten minutes,
at which point the flask was raised from the iceꢀwater bath and allowed to warm to room temperature over
20 minutes. Then, nonafluoroꢀtertꢀbutanol (0.84 mL, 6.0 mmol) was added quickly by syringe, the
septum was replaced with a Teflonꢀtaped glass stopper secured with a Keck clip, and the flask was placed
in a sand bath at 50 °C. The reaction continued overnight for 48 hours, at which point the solvent was
removed by rotary evaporation, yielding a thick, oily slurry. Column chromatography with 95:5
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PE:EtOAc yielded 0.75 g (31%) of product 18 (Rf ~0.58 in 95:5 PE:EtOAc) as a colorless oil. H NMR
(400 MHz, CDCl3): δ 7.63ꢀ7.65 (m, 4H), 7.37ꢀ7.41 (m, 6H), 4.18/4.11 (t, J = 4.6/5.6 Hz, 2H, rotomers),
3.77/3.70 (t, J = 5.2/5.8 Hz, 2H, rotomers), 3.53ꢀ3.57 (m, 2H), 3.39ꢀ3.45 (m, 2H), 1.45/1.37 (s, 9H,
rotomers), 1.04 (s, 9H). 13C NMR (100 MHz, CDCl3): δ 155.4/155.1 (rotomers), 135.6, 133.5, 129.9,
127.9, 120.5 (q, J = 292 Hz), 80.16/80.03 (rotomers), 79.7 (m, J = 30 Hz), 69.07/68.56 (rotomers), 62.9,
51.2/50.5 (rotomers), 48.6/48.3 (rotomers), 28.48/28.42 (rotomers), 26.9, 19.2. 19F NMR (376 MHz,
CDCl3): δ ꢀ70.98 (s). HRMS (+ESI) m/z: [M + Na]+ Calcd for C29H36F9NO4SiNa 684.2162; Found
684.2166.
tert-butyl (2-(nonafluoro-tert-butoxy)ethyl)(2-hydroxyethyl)carbamate (19)
TBDPSꢀprotected fluoroꢀaminoalcohol 18 (0.731 g, 1.11 mmol) was added to a RBF along with
TBAF·H2O (1.11 g, 3.52 mmol) and stirred at room temperature for five hours. The solvent was then
removed under reduced pressure to yield an oil that was transferred to a separatory funnel with a saturated
solution of ammonium chloride (20 mL) and ethyl acetate (20 mL). The aqueous layer was washed with
two additional aliquots of ethyl acetate, and the combined organic layers were washed with brine (20 mL),
dried with anhydrous sodium sulfate, and vacuum filtered. The solvent was removed by rotary
evaporation to yield an oil. Column chromatography using 60:40 PE:EtOAc yielded 0.432 g (92%) of
product 19 (Rf ~0.37 in 60:40 PE:EtOAc) as a colorless oil. 1H NMR (400 MHz, CDCl3): δ 4.22/4.15 (bs,
2H, rotomers), 3.75 (bs, 2H), 3.52 (distorted q, J ~ 5.2 Hz, 2H), 3.45 (distorted q, J ~ 4.4 Hz, 2H), 2.8 (bs,
1H), 1.46 (s, 9H). 13C NMR (100 MHz, CDCl3): δ 156.8/155.5 (rotomers), 120.4 (q, J = 292 Hz),
81.05/80.63 (rotomers), 79.7 (m, J = 29.8 Hz), 68.9/68.5 (rotomers), 62.6/61.8 (rotomers), 51.8, 48.6,
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28.4. 19F NMR (376 MHz, CDCl3): δ ꢀ70.93/ꢀ70.96 (s, rotomers). HRMS (+ESI) m/z: [M + Na]+ Calcd
for C13H18F9NO4Na 446.0984; Found 446.0996.
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Fluorinated aminoalcohol 19 (0.43 g, 1.0 mmol) was added to a flameꢀdried RBF along with TEA
(0.28 mL, 2.0 mmol) and dry dichloromethane (10 mL) and the flask was stoppered with a rubber septum.
The flask was placed in an ice bath, cooled for five minutes, and acryloyl chloride (0.16 mL, 2.0 mmol)
was added over 15 minutes. The reaction was stirred overnight, warming to room temperature, for 14
hours, then was quenched by the addition of saturated sodium bicarbonate (10 mL) and additional
dichloromethane (5 mL). After removing the organic layer, the aqueous layer was washed an additional
time with dichloromethane (10 mL), and the organic layers were combined, dried with anhydrous sodium
sulfate, and filtered. The solvent was removed by rotary evaporation to yield a light yellow oil. Column
chromatography using 90:10 PE:EtOAc yielded 0.42 g (88%) of acrylate product 20 (Rf ~0.31 in 90:10
PE:EtOAc) as a colorless oil. 1H NMR (400 MHz, CDCl3): δ 6.42 (d, J = 16.8 Hz, 1H), 6.12 (dd, J = 17.4,
10.2 Hz, 1H), 5.86 (ddd, J = 10.4, 7.2, 1.2 Hz, 1H), 4.29/4.24 (t, J = 5.5 Hz, 2H, rotomers), 4.21/4.14 (t, J
= 5.2 Hz, 2H, rotomers), 3.49ꢀ3.58 (m, 4H), 1.456/1.450 (s, 9H, rotomers). 13C NMR (100 MHz, CDCl3):
δ 166.1, 155.25/154.99 (rotomers), 131.3, 128.3, 120.4 (q, J = 292 Hz), 80.7, 79.9 (m, J = 29.6 Hz),
68.96/68.48 (rotomers), 62.98/62.91 (rotomers), 48.3/48.1 (rotomers), 47.5, 28.4. 19F NMR (376 MHz,
CDCl3): δ ꢀ70.94/70.98 (s, rotomers). HRMS (+ESI) m/z: [M + Na]+ Calcd for C16H20F9NO5Na 500.1090;
Found 500.1097.
1-(allyloxy)-2,2-bis((nonafluoro-tert-butoxy)methyl)butane (21)
Triphenylphosphine (1.97 g, 7.50 mmol) was added to a flameꢀdried RBF containing a stir bar
along with 2ꢀ((allyloxy)methyl)ꢀ2ꢀethylpropaneꢀ1,3ꢀdiol (0.435 g, 2.5 mmol). The flask was stoppered
with a rubber septum and was purged with nitrogen for 15 minutes. Dry THF (36 mL) was added via
syringe and the flask was placed in an iceꢀbath. DEAD (1.18 mL, 7.50 mmol) was added via syringe over
five minutes, at which point the flask was raised from the iceꢀwater bath and allowed to warm to room
temperature over 20 minutes. Then, nonafluoroꢀtertꢀbutanol (1.05 mL, 7.50 mmol) was added quickly by
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syringe, the septum was replaced with a Teflonꢀtaped glass stopper secured with a Keck clip, and the
flask was placed in a sand bath at 55 °C. The reaction continued overnight for 22 hours, at which point
the solvent was removed by rotary evaporation, yielding a light yellow, viscous oil. Column
chromatography with 90:10 PE:EtOAc yielded 0.74 g (49%) of product 21 (Rf ~0.82 in 90:10 PE:EtOAc)
as a colorless liquid. 1H NMR (400 MHz, CDCl3): δ 5.85 (ddt, J = 17.4, 10.2, 5.5 Hz, 1H), 5.23 (ddt, J =
17.4, 1.6, 1.4 Hz, 1H), 5.17 (ddt, J = 10.2, 1.6, 1.4 Hz, 1H), 3.95 (dd, J = 14.8, 8.4 Hz, 4H), 3.92 (dt, J =
5.5, 1.4 Hz, 2H), 3.28 (s, 2H), 1.50 (q, J = 7.6 Hz, 2H), 0.89 (t, J = 7.6 Hz, 3H). 13C NMR (100 MHz,
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60
19
CDCl3): δ 134.6, 120.7 (q, J = 291 Hz), 117.0, 80.0 (m, J = 29.6 Hz), 72.6, 68.4, 67.9, 44.2, 21.7, 6.8. F
NMR (376 MHz, CDCl3): δ ꢀ70.82 (s). HRMS (+ESI TOF) m/z: [M+H]+ Calcd for C17H17F18O3
611.0885; Found 611.0881.
Acknowledgments
We thank Professors M. O’Sullivan and T. Gregg for helpful discussions and advice, and T.
Stabler and A. Steltermann for general assistance. We are grateful to Canisius College for startꢀ
up funds and summer salary support for students, as well as G. Zon ‘66, for student summer
salary support. This material is based upon work supported by the National Science Foundation
under grant numbers CHEꢀ1229021 and DMRꢀ1410387.
Supporting Information. NMR spectra of all numbered compounds and synthetic intermediates.
This material is available free of charge via the Internet at http://pubs.acs.org.
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