Synthesis and crystallographic analysis of meso-2,3-difluoro-1,4-butanediol and meso-1,4-dibenzyloxy-2,3-difluorobutane

Article abstract of DOI:10.3762/bjoc.6.62

A large-scale synthesis of meso-2,3-difluoro-1,4-butanediol in 5 steps from (Z)-but-2-enediol is described. Crystallographic analysis of the diol and the corresponding benzyl ether reveals an anti conformation of the vicinal difluoride moiety. Monosilylation of the diol is high-yielding but all attempts to achieve chain extension through addition of alkyl Grignard and acetylide nucleophiles failed.

Full text of DOI:10.3762/bjoc.6.62

Synthesis and crystallographic analysis of meso-2,3-
difluoro-1,4-butanediol and meso-1,4-dibenzyloxy-
2,3-difluorobutane
Bruno Linclau*, Leo Leung, Jean Nonnenmacher and Graham Tizzard
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2010, 6, No. 62. doi:10.3762/bjoc.6.62
School of Chemistry, University of Southampton, Highfield,
Southampton SO17 1BJ, UK
Received: 19 February 2010
Accepted: 17 May 2010
Published: 08 June 2010
Email:
Bruno Linclau* - bruno.linclau@soton.ac.uk
Guest Editor: D. O’Hagan
* Corresponding author
© 2010 Linclau et al; licensee Beilstein-Institut.
License and terms: see end of document.
Keywords:
building block; epoxide opening; gauche effect; organofluorine; vicinal
difluoride
Abstract
A large-scale synthesis of meso-2,3-difluoro-1,4-butanediol in 5 steps from (Z)-but-2-enediol is described. Crystallographic
analysis of the diol and the corresponding benzyl ether reveals an anti conformation of the vicinal difluoride moiety. Monosilyla-
tion of the diol is high-yielding but all attempts to achieve chain extension through addition of alkyl Grignard and acetylide nucleo-
philes failed.
Introduction
Selective fluorination of bioactive compounds is a widely corresponding anti conformation [7-9]. O’Hagan has demon-
employed strategy for the modification of their properties [1]. strated that vicinal difluoride substitution along a hydrocarbon
Fluorine atoms can be introduced to modulate the pKa of adja- chain of a fatty acid leads to conformational rigidity or disorder
cent acidic and basic functional groups as well as the lipophili- depending on the relative stereochemistry of the fluorine atoms,
city, chemical and metabolic stability of the compound. Recent which originates from the enforcing or opposing fluorine
exciting reports describe weak but stabilising interactions gauche and hydrocarbon anti low-energy conformations [10].
between a C–F moiety and protein residues, which is certain to As an extension, multi-vicinal tri- to hexafluorinated chains
have implications in drug design [2,3]. Further important have been synthesised [11-16], which revealed yet another
applications include molecular imaging using 18F [4], and effect on the conformational behaviour, i.e. that conformations
modification of high-performance materials [5].
containing parallel 1,3-C–F bonds are destabilised. As an
application, liquid crystals have been prepared containing a
In recent years, the vicinal difluoride motif has received vicinal difluoride motif [14,17,18].
increasing attention due to the conformational properties
instilled by the ‘gauche effect’ [6], which results in the vicinal Efficient stereodefined synthesis of vicinal difluoride moieties
difluoro gauche conformation being more stable than the is not straightforward. Direct methods include fluorination of
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Beilstein J. Org. Chem. 2010, 6, No. 62.
Results and Discussion
alkenes with F2 [19], XeF2 [20], or hypervalent iodine species
[21]. Such approaches often display poor stereoselectivity or Synthesis
result in rearrangement products. Treatment of 1,2-diols with The synthesis of 3 was achieved from meso-epoxide 4, which
SF4 [22,23], DAST [24], or deoxofluor [25] also leads to vicinal was obtained from (Z)-2-butene-1,4-diol in excellent yield
difluorides. Reaction with vicinal triflates has also been according to the published two-step sequence [35]. The optim-
successful in some cases [7,26]. A common two-step method isation of the reaction of 4 with fluoride sources is shown in
involves opening of an epoxide to give the corresponding Table 1.
fluorohydrin [27], followed by the conversion of the alcohol
moiety to the fluoride [28]. Another two-step method is halo- Reaction with Olah’s reagent [29] proceeded in excellent yield
fluorination of alkenes and subsequent halide substitution with (Table 1, entry 1), however, the product was isolated as a mix-
silver fluoride [9,29,30].
ture of isomers, which were not further characterised. Reaction
with potassium hydrogen difluoride in ethylene glycol [36,37]
The introduction of multiple fluorine atoms is often a cumber- gave the fluorohydrin in only modest yield (entry 2). Interest-
some process, and in many cases a fluorinated building block ingly, the product arising from epoxide ring opening by
approach [31,32] is more efficient. Known vicinal difluoride ethylene glycol, 6, was isolated in 50% yield. The addition of
containing building blocks include (racemic) C2-symmetric and molecular sieves (entry 3) led to complete conversion to 6 (TLC
meso-2,3-difluorosuccinic acids (or esters) 1,2 (Figure 1) analysis). No reaction took place when DMSO (entry 4) or
[9,22,23,33,34].
DMF/18-crown-6 were used as solvents [38,39] (entry 5). With
Bu4NH2F3 as the fluoride source [40,41], 11% of the desired
product (together with some elimination byproducts) was
obtained when xylene was used as solvent (entry 6). However,
reaction with a mixture of Bu4NH2F3 and KHF2 in the absence
of solvent [42-44] led to an excellent 91% yield of the desired
product 5 albeit after a relatively long reaction time (entry 8).
Figure 1: Vicinal difluoride containing building blocks.
The subsequent conversion to 3 is shown in Scheme 1. Treat-
ment of 5 with DAST in DCM at reflux temperature only gave
Herein we describe the first synthesis of meso-2,3-difluoro-1,4- 7 in 29% yield (not shown). A slight improvement (40% yield)
butanediol 3 as a further simple vicinal difluoride building was obtained when the reaction was conducted in hexane or
block as well as its successful monosilylation, and our attempts toluene, but a procedure in which DAST was added to a solu-
to employ 3 for the synthesis of fluorinated hydrocarbons.
tion of 5 in toluene at room temperature, followed by the add-
Table 1: Conversion of epoxide 4 to the fluorohydrin.
Entry
Reaction conditions
5a
6a
4a
1
2
3
4
5
6
7
8
HF•py (70% HF), r.t., 3 h
80b
34
–
–
50
c
–
–
–
d
KHF2, ethylene glycol, 150 °C, 3 h
KHF2, ethylene glycol, mol. Sieves, 150 °C, 3 h
KHF2, DMSO, 150 °C, 16 h
–
–
–
–
–
–
d
KHF2, DMF, 18-crown-6, reflux, 16 h
Bu4NH2F3 (1 equiv), xylene, reflux, 3 d
Bu4NH2F3 (1 equiv), KHF2 (1 equiv), 130 °C, 16 h
Bu4NH2F3 (1 equiv), KHF2 (1 equiv), 115 °C, 2.5 d
–
11
71
91
57
–
–
a Isolated yield.
b Mixture of isomers.
c Complete conversion to 6 (TLC analysis).
d No reaction observed.
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Beilstein J. Org. Chem. 2010, 6, No. 62.
was activated as the corresponding tosylate 9, triflate 10,
mesylate 11, and bromide 12 as precursors for chain extension.
Nucleophilic substitution of similar tosylates with phenolate
nucleophiles has been previously described [18]. Reaction of
9–12 with a number of carbon nucleophiles was investigated.
Unfortunately, reaction of 9–12 with alkyl Grignard and acet-
ylide reagents did not lead to the desired chain extension. Reac-
tion of 9 or 10 with a sodium or lithium acetylide led to decom-
position, while 12 did not react under these conditions. Treat-
ment of 11 with C9H19MgBr/CuBr was unsuccessful, whilst
surprisingly, when 12 was subjected to this reagent combina-
Scheme 1: Synthesis of meso-2,3-difluoro-1,4-butanediol.
ition of pyridine [28] and heating the reaction mixture for a tion (Scheme 3), the defluorinated reaction products 13 and 14
prolonged period gave the desired vicinal difluoride in good were obtained. We have not yet deduced an acceptable explan-
yield. Nevertheless, while this procedure was deemed suffi- ation for this unexpected result.
ciently safe to conduct at about the 50 mmol scale, further
upscaling with a more thermally stable fluorinating reagent such
as deoxofluor [45], Fluolead [46], or aminodifluorosulfinium
tetrafluoroborate [47] would be recommended. Subsequent
alcohol deprotection gave the target compound in almost quant-
itative yield in multigram quantities.
The potential of 3 as a building block, in particular for the
construction of longer aliphatic chains of varying length, was
investigated next. Thus (Scheme 2), the diol moiety in 3 was
Scheme 3: Reaction of 12 leading to defluorinated products.
monoprotected as a silyl ether, and the remaining alcohol group
Crystallographic analysis
Compounds 7 and 3 yielded colourless crystals suitable for
study by single crystal X-ray diffraction [48]. The dibenzyl
ether 7 crystallises in the monoclinic P21/c space group with
half a molecule of 7 in the asymmetric unit. The molecule pos-
sesses crystallographic inversion symmetry. Two conformers
are present in the crystal (55:45) which differ only in the sign of
the torsion angle of the rings (Figure 2). The disparity in the
amounts of each conformer present gives rise to the disorder
observed in the crystal structure.
Scheme 2: Monoprotection of 3, and activation of the remaining
Figure 2: Molecular overlay of both conformers of 7.
alcohol.
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Beilstein J. Org. Chem. 2010, 6, No. 62.
The vicinal difluoro group adopts an anti conformation with the molecules are arranged helically about the crystallographic 41
F–C–C–F dihedral angle exactly 180°, which manifests itself in screw axes. Thus the crystal structure comprises of alternating
the crystallographic inversion centre. Nevertheless, each left and right handed hydrogen bonded helical constructs with
benzyloxy group does adopt a gauche conformation with its each molecule part of two adjacent helices (Figure 5).
adjacent fluoro substituent where the F–C–C–O dihedral angle
is 71.5°. Although strong H-bonding interactions are absent
within the crystal, each molecule displays eight short contacts
less than the sum of the van der Waals radii to its four nearest
neighbours; three C–F···H–C contacts (2.554 Å, 2.581 Å and
2.637 Å) for each fluorine, and a pair of C–H···π contacts (2.662
Å to centroid of ring). The hydrogen atoms involved in the C–F
contacts are an aromatic proton, the CHF and a CHHOBn
proton (Figure 3).
Figure 5: Crystal packing of 3 viewed along the c axis. H-bonds are
shown in light blue.
Examination of the Cambridge Structural Database [49] (V5.31,
November 2009) revealed three more meso-vic-difluoro com-
pounds: 1,2-difluoro-1,2-diphenylethane, 2,3-difluorosuccinic
Figure 3: Crystal packing of 7 viewed along the b axis. Short contacts
(see text) are shown in light blue.
acid and 2,3-difluorosuccinate benzylamide, all reported by
O’Hagan [9]. Of these, only difluorosuccinic acid crystallises
with the vicinal difluoro group in the expected gauche conform-
The diol 3 crystallises in the tetragonal space group I41/a with ation, whilst both other structures, in common with the struc-
half a molecule of 3 in the asymmetric unit. This molecule also tures described in this work, contain the vicinal difluoro group
displays crystallographic inversion symmetry. In common with in an anti conformation. The conformation of vicinal difluor-
7, the vicinal difluoro group of 3 adopts an anti conformation ides in solution can also be deduced from NMR studies.
with a symmetry-constrained dihedral angle of 180°, and the Schlosser has reported that the 3JH-F is around 22 Hz when the
hydroxyl groups adopt gauche conformations with the adjacent fluorines are in the syn configuration, because of a preferred
fluoro atoms with F–C–C–O dihedral angles of 66.8° gauche conformation, and around 14 Hz when in the anti con-
(Figure 4).
figuration, because there is no overall preferred conformation
[28]. Unfortunately, we were unable to extract 3JH-F values
from the second order signals in both the 1H and 19F NMR
spectra of 3 and 7, however, analysis of the coupling constants
in 11 revealed two 3JH-F values of 10.1 and 9.6 Hz (3JF-F
13.5 Hz). Walba et al. have reported the 3JH-F values of a very
similar syn-1-hydroxy-4-aryloxy-2,3-difluorobutane system to
be around 22.0 Hz [17]. Hence, this value is indeed much
higher than the 3JH-F values for 11, from which it can be
concluded that the gauche effect in 11 (anti) is operating in
solution.
Figure 4: Crystal structure of 3.
Conclusion
There is strong hydrogen bonding between the hydroxyl groups The synthesis of meso-2,3-difluoro-1,4-butanediol 3 was
of the molecule with each hydroxyl group acting both as donor achieved in 5 steps from (Z)-1,4-butenediol in 40% overall yield
and acceptor (O–H···O: 2.685 Å, 170.1°). The hydrogen bonded on a multigram scale. A high-yielding (94%) monosilylation
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Beilstein J. Org. Chem. 2010, 6, No. 62.
was also achieved, but all attempts for chain extension met with to afford fluorohydrin 5 as a colourless oil (17.0 g, 91%). IR
failure. Crystallographic analysis revealed that the vicinal νmax (cm−1) 3062 w, 3030 w, 2993 w, 2858 w, 1496 w, 1453 m,
fluorine atoms in 3 and its dibenzyl ether 7 are in the anti 1369 w, 1088 s; 1H NMR (400 MHz, CDCl3) 7.42–7.20 (10H,
conformation.
m, ArH), 4.74 (1H, ddt, J = 47.5, 5.5, 3.5 Hz, CHF), 4.60 (1H,
d, J = 12.0 Hz, CHaHbPh), 4.58 (1H, d, J = 12.0 Hz, CHcHdPh),
4.56 (1H, d, J = 12.0 Hz, CHaHbPh), 4.54 (1H, d, J = 12.0 Hz,
Experimental
1H and 13C NMR spectra were recorded at room temperature on CHcHdPh), 4.04 (1H, dm, J = 22.0 Hz, CHOH), 3.80 (1H, ddd,
a Bruker DPX400 or AV300 spectrometer as indicated. Low J = 23.0, 11.0, 4.0 Hz, CHaHbOBn), 3.76 (1H, ddd, J = 24.0,
resolution ES mass and EIMS were recorded on a Waters ZMD 11.0, 5.0 Hz, CHaHbOBn), 3.63 (1H, ddd, J = 10.0, 5.0, 1.0 Hz,
and Thermoquest TraceMS quadrupole spectrometers, respect- CHcHdOBn), 3.59 (1H, ddd, J = 10.0, 6.5, 1.0 Hz, CHcHdOBn),
ively. Infrared spectra were recorded as neat films on a Nicolet 2.61 (1H, bd, J = 4.0 Hz, OH) ppm; 13C NMR (100 MHz,
Impact 380 ATR spectrometer. Melting points were recorded on CDCl3) 137.9 (CAr), 137.7 (CAr), 128.6 (CHAr), 128.0 (CHAr),
a Gallencamp Melting Point Apparatus and are uncorrected.
127.9 (CHAr), 91.8 (d, J = 175.0 Hz, CHF), 73.9 (CH2Ph), 73.7
(CH2Ph), 70.37 (d, J = 5.5 Hz, CH2OBn), 70.34 (d, J = 20.0
Column chromatography was performed on 230–400 mesh Hz, CHOH), 69.8 (d, J = 23.0 Hz, CH2OBn) ppm; 19F NMR
Matrex silica gel. Preparative HPLC was carried out using a (282 MHz, CDCl3) −204.3 (1F, dq, J = 46.7, 23.4) ppm; ES+ m/
Biorad Biosil D 90-10, 250 × 22 mm column eluting at 20 mL z (%) 327 ((M+Na)+, 100); HRMS (ES+) for C18H21FO3Na
min−1, connected to a Kontron 475 refractive index detector. (M+Na)+: Calcd 327.1367; Measured 327.1364.
Reactions were monitored by TLC (Merck) with detection by
Data for syn-3-(2-hydroxyethyl)-1,4-
bis(benzyloxy)butan-2-ol (6)
KMnO4 or anisaldehyde stains.
Reaction solvents were dried before use as follows: THF and
Et2O were distilled from sodium/benzophenone; CH2Cl2 and
Et3N were distilled from CaH2; toluene was distilled from
sodium.
X-ray data crystal structure analyses: Suitable crystals were Colourless oil. IR νmax (cm−1) 3399 br, 3062 w, 3030 w, 2863
selected and data collected on a Bruker Nonius Kappa CCD w, 1496 w, 1483 m, 1091 s; 1H NMR (400 MHz, CDCl3)
Area Detector equipped with a Bruker Nonius FR591 rotating 7.40–7.27 (10H, m), 4.54 (4H, s), 3.87 (1H, q, J = 5.5 Hz),
anode (λ(MoKα) = 0.71073 Å) at 120 K driven by COLLECT 3.78–3.60 (7H, m), 3.58 (1H, dd, J = 10.0, 5.0 Hz), 3.51 (1H,
[50] and processed by DENZO [51] software and corrected for dd, J = 9.5, 6.0 Hz), 3.25–2.30 (2H, br, OH) ppm; 13C NMR
absorption by using SADABS [52]. The structures were deter- (100 MHz, CDCl3) 137.9 (CAr), 137.7 (CAr), 128.61 (CHAr),
mined in SHELXS-97 and refined using SHELXL-97 [53]. All 128.59 (CHAr), 128.01 (CHAr), 127.99 (CHAr), 127.92 (CHAr),
non-hydrogen atoms were refined anisotropically with hydrogen 79.4 (CHO), 73.7 (CH2Ph), 73.6 (CH2Ph), 73.2 (CH2O), 71.0
atoms included in idealised positions with thermal parameters (CH2O), 70.9 (CHOH), 70.6 (CH2O), 62.3 (CH2O) ppm; ES+
riding on those of the parent atom.
m/z (%) 715 ((2M+Na)+, 20); HRMS (ES+) for C20H26O5Na
(M+Na)+: Calcd 369.1672; Measured 369.1667.
syn-1,4-Bis(benzyloxy)-3-fluorobutan-2-ol (5)
meso-1,4-Bis(benzyloxy)-2,3-difluorobutane
(7)
KHF2 (9.57g, 123 mmol) was added to a mixture of epoxide 4
(17.4 g, 61.3 mmol) and Bu4NH2F3 (10.6 g, 35.2 mmol) and the
mixture stirred at 115 °C for 2.5 days. Et2O (300 mL) was DAST (9.6 mL, 72.7 mmol) was added to a solution of fluoro-
added and the solution poured into sat. NaHCO3 (200 mL). The hydrin 5 (17.0 g, 55.9 mmol) in toluene (75 mL) and the mix-
organic layer was washed successively with sat. NaHCO3 ture stirred at r.t. for 5 min. Pyridine (11.9 mL, 145 mmol) was
(100 mL) and brine (200 mL), dried over MgSO4, filtered and then added and the solution stirred at 70 °C for a further 16 h.
concentrated in vacuo. The crude product was purified by The reaction mixture was cooled, poured into sat. NaHCO3
column chromatography (EtOAc/petroleum ether 10% to 20%) (100 mL) and Et2O (100 mL). The organic layer was washed
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Beilstein J. Org. Chem. 2010, 6, No. 62.
successively with sat. NaHCO3 (100 mL) and brine (100 mL), and the mixture stirred at r.t. for 30 min. TBDMSCl (5.26 g,
dried over MgSO4, filtered and concentrated in vacuo. The 34.9 mmol) was then added and the solution stirred at r.t. for a
crude product was quickly purified by column chromatography further 2 h. The reaction mixture was quenched with H2O
(EtOAc/petroleum ether 0% to 5%) to afford a mixture which (150 mL) and extracted with Et2O (200 mL × 3). The combined
was recrystallised from hot petroleum ether. The filtrate was organic layers were dried over MgSO4, filtered and concen-
concentrated and recrystallised again from hot petroleum ether. trated in vacuo. The crude product was purified by column
The recrystallisation process was carried out for a third time to chromatography (neat petroleum ether, then acetone/petroleum
afford difluoride 7 as a white crystalline solid (overall yield ether 10%) to afford silyl ether 8 as a colourless oil (7.14 g,
10.1 g, 59%). mp 56–57 °C; IR νmax (cm−1) 3058 w, 3030 w, 94%). IR νmax (cm−1) 3354 br, 2954 m, 2930 m, 2858 m, 1254
2916 w, 2878 w, 1607 w, 1496 w, 1449 m, 1137 s, 1048 s; s, 1055 s; 1H NMR (400 MHz, CDCl3) 4.84–4.58 (2H, m, CHF
1H NMR (400 MHz, CDCl3) 7.40–7.27 (10H, m, ArH), × 2), 4.03–3.76 (4H, m, CH2O × 2), 2.47 (1H, br, OH), 0.91
4.96–4.78 (2H, m, CHF × 2), 4.61 (4H, s, CH2Ph × 2), (9H, s, SiC(CH3)3), 0.09 (6H, s, SiCH3 × 2) ppm; 1H{19F}
3.88−3.71 (4H, m, CH2OBn) ppm; 13C NMR (100 MHz, NMR (400 MHz, CDCl3) 4.77 (1H, ddd, J = 6.0, 5.0, 3.0 Hz,
CDCl3) 137.8 (CAr × 2), 128.6 (CHAr × 4), 128.0 (CHAr × 2), CHF), 4.69 (1H, dt, J = 6.1, 3.5 Hz, CHF) ppm; 13C NMR
127.8 (CHAr × 4), 90.0 (dd, J = 175.5, 27.5 Hz, ABX, 13CHF- (100 MHz, CDCl3) 90.8 (dd, J = 170.5, 21.0 Hz, CHF), 90.5
12CHF × 2), 73.8 (CH2Ph × 2), 68.4 (m, ABX, 13CH2CHFCHF (dd, J = 178.5, 30.5 Hz, CHF), 61.7 (dd, J = 21.5, 5.0 Hz,
× 2) ppm; 19F NMR (282 MHz, CDCl3) −198.7 ppm; ES+ m/z CH2O), 61.3 (dd, J = 21.5, 5.0 Hz, CH2O), 25.9 (SiC(CH3)3),
(%) 329 ((M+Na)+, 100); HRMS (ES+) for C18H20F2O2Na 18.4 (SiC), −5.38 (CH3), −5.43 (CH3) ppm; 19F NMR (376.5
(M+Na)+: Calcd 329.1324; Measured 329.1319.
MHz, CDCl3) −201.6 (d, J = 13.0 Hz), −201.9 (d, J = 13.0 Hz)
ppm; ES+ m/z (%) 263 ((M+Na)+, 100); HRMS (ES+) for
C10H22F2O2SiNa (M+Na)+: Calcd 263.1249; Measured
263.1256.
meso-2,3-Difluorobutane-1,4-diol (3)
anti-4-tert-Butyldimethylsilanyloxy-2,3-
difluorobutyl methanesulfonate (11)
Pd/C (5%; 13.9 g, 6.5 mmol) was added to a solution of diflu-
oride 7 (10.0 g, 32.7 mmol) in THF (108 mL) and the mixture
stirred at r.t. for 16 h under a H2 atmosphere (balloon). The
suspension was filtered through celite, washed with MeOH and
concentrated in vacuo. The crude product was purified by MsCl (3.39 mL, 43.8 mmol) was added to a mixture of alcohol
column chromatography (acetone/petroleum ether 30% to 50%) 8 (7.0 g, 29.2 mmol) and Et3N (6.6 mL, 46.7 mmol) in DCM
to afford diol 3 as a white crystalline solid (4.0 g, 97%). (64 mL) and the mixture stirred at r.t. for 2 h. The reaction mix-
mp 99–101 °C; IR νmax (cm−1) 3329 br, 2936 br, 1647 br, 1042 ture was cooled to 0 °C, filtered, washed with cold Et2O/petro-
s; 1H NMR (400 MHz, CDCl3) 4.85–4.70 (2H, m, CHF × 2), leum ether 1:1 and concentrated in vacuo. The crude product
4.08–3.83 (4H, m, CH2OH × 2), 1.92 (2H, t, J = 6.5 Hz, OH × was purified by column chromatography (EtOAc/petroleum
2) ppm; 13C NMR (100 MHz, acetone-d6) 92.6 (dd, J = 173.0, ether 15:85) to afford mesylate 11 as a colourless oil (9.29 g,
26.0 Hz, ABX, 13CHF-12CHF × 2), 61.2 (m, ABX, 99%). [TLC monitoring should be performed using DCM/petro-
13CH2CHFCHF × 2) ppm; 19F{1H} NMR (282 MHz, acetone- leum ether 6:4 until the complete consumption of the starting
d6) −200.5 ppm; HRMS (ES+) for C4H8F2O2Na (M+Na)+: material, which has the same Rf value as the product when
Calcd 149.0385; Measured 149.0384.
eluted with EtOAc/petroleum ether.] IR νmax (cm−1) 2955 m,
2931 m, 2858 m, 1473 w, 1360 s, 1256 m, 1178 s, 836 vs;
1H NMR (400 MHz, CDCl3) 4.98 (1H, ddtd, J = 46.9, 10.1, 6.6,
2.0 Hz, CHCH2OS), 4.68 (1H, dddt, J = 46.0, 9.6, 6.6, 3.3 Hz,
CHCH2OSi), 4.62 (1H, ddt, J = 26.8, 12.1, 2.0 Hz, CHaHbOS),
4.49 (1H, dddd, J = 25.3, 12.1, 6.1, 2.0 Hz, CHaHbOS), 3.98
(1H, dddd, J = 18.5, 12.5, 3.5, 2.5 Hz, CHaHbOSi), 3.87 (1H,
dddd, J = 30.5, 12.5, 3.5, 2.5 Hz, CHaHbOSi), 3.06 (3H, s,
SCH3), 0.91 (9H, s, SiC(CH3)3), 0.09 (6H, s, SiCH3 × 2) ppm;
anti-4-tert-Butyldimethylsilanyloxy-2,3-
difluorobutan-1-ol (8)
NaH (60% dispersion in mineral oil; 1.40 g, 34.9 mmol) was 1H{19F} NMR (400 MHz, CDCl3) 4.98 (1H, td, J = 6.1, 2.0 Hz,
added to a solution of diol 3 (4.0 g, 31.7 mmol) in THF (64 mL) CHCH2OS), 4.68 (1H, dt, J = 6.6, 3.0 Hz, CHCH2OSi) ppm;
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Beilstein J. Org. Chem. 2010, 6, No. 62.
13C NMR (100 MHz, CDCl3) 90.2 (dd, J = 176.5, 27.0 Hz, (1.2 mL). The mixture was then transferred to a solution of bro-
CHCH2OSi), 87.5 (dd, J = 177.0, 27.5 Hz, CHCH2OS), 67.8 mide 12 (140 mg, 0.462 mmol) in THF (1.2 mL) at 0 °C,
(dd, J = 21.0, 6.0 Hz, CH2OS), 61.3 (dd, J = 21.5, 4.5 Hz, warmed to r.t. and stirred for 3 h. The reaction mixture was
CH2OSi), 37.7 (SCH3), 25.9 (SiC(CH3)3), 18.4 (SiC), −5.4 quenched with H2O (10 mL) and extracted with Et2O (10 mL ×
(CH3), −5.5 (CH3) ppm; 19F{1H} NMR (282 MHz, CDCl3) 3). The combined organic layers were dried over MgSO4,
−198.6 (d, 3JF-F = 13.5 Hz), −202.0 (d, 3JF-F = 13.5 Hz) ppm; filtered and concentrated in vacuo. The crude product was puri-
ES+ m/z (%) 341 ((M+Na)+, 10); HRMS (ES+) for fied by column chromatography (DCM/petroleum ether 0% to
C11H24F2O4SSiNa (M+Na)+: Calcd 341.1025; Measured 20%) to afford alkene 13 [54] as a mixture of isomers (1:11) as
341.1030.
a yellow oil (24.1 mg, ~15%) and alkene 14 as a yellow oil
(26.2 mg, ~20%) along with 72.0 mg (51%) of the starting bro-
mide 12.
anti-4-Bromo-2,3-difluoro-1-tert-butyl-
dimethylsilanyloxybutane (12)
Alkene 13: IR νmax (cm−1) 2955 w, 2924 s, 2854 m, 1463 w,
1378 w, 834 s, 774 s; 1H NMR ((E)-isomer only, 400 MHz,
CDCl3) 5.64 (1H, dtt, J = 15.5, 6.5, 1.5 Hz, CH=CH), 5.53 (1H,
dtt, J = 15.0, 5.0, 1.0 Hz, CH=CH), 4.13 (2H, dq, J = 5.5, 1.5
Hz, CH2O), 2.06–2.00 (2H, m, CH2), 1.40–1.21 (16H, m, CH2
TBAB (9.94 g, 30.8 mmol) was added to a solution of mesylate × 8), 0.92 (9H, s, SiC(CH3)3), 0.93–0.86 (3H, m, CH3), 0.08
11 (8.91 g, 28.0 mmol) in THF (28 mL) and the mixture stirred (6H, s, SiCH3 × 2) ppm; 13C NMR (100 MHz, CDCl3) 131.8
at reflux for 3 h. The reaction mixture was concentrated in (CH=CH), 129.3 (CH=CH), 64.3 (CH2O), 32.4 (CH2), 32.0
vacuo and the crude product purified by column chromatog- (CH2), 29.8 (CH2), 29.7 (CH2), 29.5 (CH2), 29.4 (CH2), 26.2
raphy (EtOAc/petroleum ether 0% to 25%) to afford bromide (SiC(CH3)3), 22.9 (CH2), 18.6 (SiC), 14.3 (CH3), −4.9 (SiCH3
12 as a yellow oil (6.95 g, 82%). IR νmax (cm−1) 2954 w, × 2) ppm; EI m/z (%) 255.3 ((M-tBu)+, 57); HRMS (ES+) for
2930 w, 2886 w, 2858 w, 1472 w, 1464 w, 1256 m, 836 vs, C19H40OSiNa (M+Na)+: Calcd 335.2746; Measured 335.2741.
778 s; 1H NMR (400 MHz, CDCl3) 4.90 (1H, ddtd, J = 46.0,
12.0, 6.5, 3.0 Hz, CHF), 4.66 (1H, dddt, J = 46.0, 9.0, 6.5, 3.5 Alkene 14: Our spectra were in accord with literature copies of
Hz, CHF), 3.99 (1H, dddd, J = 19.5, 12.0, 3.0, 2.5 Hz, CHaHb), the spectra [55]: 1H NMR (400 MHz, CDCl3) 5.99−5.79 (2H,
3.89 (1H, dddd, J = 30.5, 12.5, 4.0, 3.0 Hz, CHaHb), 3.75 (1H, m, CH=CH), 4.21 (2H, ddd, J = 4.0, 2.5, 1.5 Hz, CH2), 3.98
dddd, J = 23.5, 12.0, 3.0, 1.5 Hz, CHcHd), 3.63 (1H, dddd, J = (2H, ddd, J = 7.5, 2.0, 1.0 Hz, CH2), 0.92 (9H, s, SiC(CH3)3),
24.0, 12.0, 6.0, 2.0 Hz, CHcHd), 0.92 (9H, s, SiC(CH3)3), 0.10 0.08 (6H, s, SiCH3 × 2) ppm; 13C NMR (100 MHz, CDCl3)
(6H, s, SiCH3 × 2) ppm; 13C NMR (100 MHz, CDCl3) 91.0 134.7 (CH=CH), 125.8 (CH=CH), 62.6 (CH2O), 32.4 (CH2Br),
(dd, J = 176.5, 27.0 Hz, CHF), 88.1 (dd, J = 177.0, 28.0 Hz, 25.9 (SiC(CH3)3), 18.4 (SiC), −5.3 (SiCH3 × 2); EI m/z (%) 207
CHF), 61.3 (dd, J = 21.5, 4.0 Hz, CH2OSi), 30.4 (dd, J = 22.0, and 209 ((M-tBu)+, 31, 1:1); HRMS (EI+) for C6H12O79BrSi
4.5 Hz, CH2Br), 25.8 (SiC(CH3)3), 18.3 (SiC), −5.5 (CH3), (M-tBu)+: Calcd 206.9835; Measured 206.9841.
−5.6 (CH3) ppm; 19F NMR (282 MHz, CDCl3) −192.6 (d, J =
15.0 Hz), −201.3 (d, J = 13.0 Hz) ppm; EI m/z (%) 245 ((M- Acknowledgements
tBu)+, 5), 303 and 305 (1:1, M+, 10).
LL and JN thank CRUK for funding.
(E)-1-tert-Butyldimethylsilanyloxytridec-2-ene
(13) and (E)-1-bromo-4-tert-butyldimethyl-
silanyloxybut-2-ene (14)
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