Diastereoselective synthesis of 2,3,4,5,6-pentafluoroheptanes

Article abstract of DOI:10.1021/jo901360e

(Chemical Equation Presented) A stereocontrolled synthesis of alkanes containing five contiguous fluorine atoms is presented. The compounds were prepared by sequential fluorination of diastereoisomeric alcohol-diepoxides. The chemistry involved epoxide ri

Full text of DOI:10.1021/jo901360e

pubs.acs.org/joc
The incorporation of fluorine has therefore emerged as an
Diastereoselective Synthesis of 2,3,4,5,6-
Pentafluoroheptanes
important tool in the design for example of performance
materials such as liquid crystals.7 Current challenges exist in
placing fluorine at a stereogenic center, rather than the
incorporation of fluoroaryl and CF3 groups, and rapid
progress is being made.8,9 Our focus has been to investigate
strategies for the synthesis of molecules containing fluorine
atoms at adjacent stereogenic centers and this has led to the
study of a new class of multivicinal fluoroalkanes, which
consist of sequential fluoromethylene (CHF) groups.10 This
structural motif is intermediate in structure between alkanes
and perfluoroalkanes. Stereocontrolled syntheses of such
motifs require the controlled introduction of the C-F bonds
and we have recently reported the preparation of different
diastereoisomers of tetra- and hexafluoro compounds such
as 1 and 2 (Figure 1).11-14
Daniel Farran,† Alexandra M. Z. Slawin,† Peer Kirsch,‡ and
David O’Hagan*,†
†School of Chemistry and Centre for Biomolecular Sciences,
University of St. Andrews, North Haugh, St. Andrews KY16
9ST, United Kingdom, and ‡Merck Ltd. Japan, New
Technology Office, 4084 Nakatsu, Aikawa-machi, Aiko-gun,
243-0303 Kanagawa, Japan
do1@st-andrews.ac.uk
Received July 3, 2009
FIGURE 1. Tetra- and hexavicinal fluorine motifs. The all-syn
isomers only are illustrated.
It emerged from these studies that individual stereo-
isomers display very different conformational behavior. In
this Note we report the stereoselective synthesis of three
unique diastereoisomers 3a-c of 2,3,4,5,6-pentafluorohep-
tane-1,7-diol (Figure 2). These diols represent novel building
blocks and have the potential to allow the incorporation of
this pentafluoro motif in larger molecular architectures.
A stereocontrolled synthesis of alkanes containing five
contiguous fluorine atoms is presented. The compounds
were prepared by sequential fluorination of diastereoiso-
meric alcohol-diepoxides. The chemistry involved epox-
ide ring-opening with HF NEt3 and deshydroxyfluori-
3
nation reactions of free alcohols with Deoxo-Fluor. The
fluorination reactions were all highly stereospecific, with
all five fluorines being incorporated in three sequential
steps. Three different diastereoisomers of the 2,3,4,5,6-
pentafluoroheptyl motif were prepared as heptane-1,7-
diol derivatives, a structural format amenable for incor-
poration of the vicinal pentafluoro scaffold into larger
molecular architectures.
FIGURE 2. Pentafluoroalkane diastereoisomers.
To access diastereoisomers 3a-c a synthesis was devel-
oped that incorporated stereochemical flexibility. Starting
from propargyl alcohol 4, the key allylic epoxide 7 was
prepared in an enantioselective manner by using a protocol
of Schreiber and Trost (Scheme 1).15-17 A subsequent epox-
idation was carried out with mCPBA to provide a mixture of
The introduction of fluorine atoms can have a significant
influence on the physical and chemical behavior of organic
molecules and as a consequence the strategy is widely used in
optimizing structure activity relationships in medicinal1-3
and agrochemicals4 development as well as in organic mate-
rials.5 Fluorine is often regarded as an isostere of hydrogen;
however, its high electronegativity induces stereoelectronic
and electrostatic consequences when such a change is made.6
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Published on Web 08/20/2009
DOI: 10.1021/jo901360e
r
2009 American Chemical Society

Farran et al.
JOCNote
SCHEME 1. Synthesis of the Five Vicinal Fluorine Motif 3aa
SCHEME 2. Synthesis of Five Vicinal Fluorine Motif 3ba
aReagents and conditions: (a) tBuOOH, Ti(OiPr)4, L(þ)DIPT,
DCM, -20 °C; (b) Deoxo-Fluor, DCM, rt; (c) Et3N 3HF, neat,
3
150 °C, overnight, sealed reactor; (d) Deoxo-Fluor, THF,
reflux; (e) H2, Pd/C, MeOH.
SCHEME 3. Synthesis of Five Vicinal Fluorine Motif 3ca
aReagents and conditions: (a) NaH, BnBr, DMF; (b) nBuLi,
THF, -78 °C, EtOCHO; (c) Red-Al, THF, -40 °C; (d) tBuO-
OH, Ti(OiPr)4, D(-)DIPT, DCM, -20 °C; (e) mCPBA, DCM,
aReagents and conditions: (a) DIPAD, PPh3, p-(NO2)C6H4CO2H,
toluene, -25 °C; (b) K2CO3, MeOH; (c) Deoxo-Fluor, DCM, rt;
(d) Et3N 3HF, neat, 150 °C, overnight, sealed reactor; (e) H2, Pd/
3
0 °C; (f) Deoxo-Fluor, DCM, rt; (g) Et3N 3HF, neat, 150 °C,
C, MeOH.
3
overnight, sealed reactor; (h) H2, Pd/C, MeOH.
SCHEME 4. Synthesis of Ditosylates 16 and Pentafluorohepta-
nes 17
the two diastereoisomers 8 and 9. This mixture was treated
with Deoxo-Fluor ((MeOCH2CH2)2NSF3). converting the
free alcohol to fluorine, in the presence of the epoxides, and
generating 10 and 11 in a 68:32 diastereoisomeric ratio.
Treatment then with Et3N 3HF, under forcing conditions,
3
allowed two additional fluorines to be introduced in one
step, despite a modest yield. Nucleophilic ring-opening of the
epoxides occurs exclusively away from the central fluorine.
Diastereoisomers 12 and 13 could be easily separated by
chromatography. Fluorine substitutions of the two remain-
ing hydroxyl groups of 12 generated 14a in a moderate yield,
although advantageously two fluorines were installed in this
step. Finally hydrogenolysis of the peripheral benzyl ethers
furnished diol 3a. Although this synthesis suffers from some
modest yields, it is emphasized that the five fluorine atoms
were incorporated in a stereospecific manner in three succes-
sive steps, to give a stereochemically pure product 14a.
The synthesis of diastereoisomer 3b was achieved as illu-
strated in Scheme 2. A Sharpless epoxidation enabled con-
versionof 7tothemesodiepoxide9, asa singlestereoisomer.18
Then, the previous reaction sequence [(i) dehydroxyfluorina-
tion; (ii) epoxide opening; (iii) didehydroxyfluorination;
(iv) hydrogenation] allowed completion of the synthesis of
3b. However, intermediate 13 was more resistant than 12 in
the difluorination reaction and mild heating was required for
successful substitution to generate 14b. This gave rise to some
elimination side products, although these could be removed
by chromatography.
Execution of the synthesis of the all-syn diastereoisomer 3c
required a configurational inversion of the central hydroxyl
group of diepoxide alcohol 9 (Scheme 3). A Mitsunobu
reaction was successfully employed to achieve this generat-
ing isomer 15 in good yield.19 The all-syn pentafluoro isomer
3c was then prepared following the synthesis protocols
described for 3a and 3b.
With the diastereoisomers of the pentadiols 3a-c in hand,
each was converted to its corresponding ditosylate 16a-c, to
generate activated intermediates for further functionaliza-
tion. It was also attractive to use these ditosylates to prepare
the parent pentafluoroheptane alkanes. Thus the individual
ditosylates 16a-c were then treated with LiAlH4 to achieve a
smooth conversion to the individual 2,3,4,5,6-pentafluoro-
heptanes 17a-c (Scheme 4). These heptanes are volatile and
were prepared at an anylatical level in deuterated solvents,
such that they could be analyzed directly by NMR.
(18) Ibuka, T.; Tanaka, M.; Yamamoto, Y. J. Chem. Soc., Chem. Com-
mun. 1989, 967–969.
(19) Masaki, H.; Maeyama, J.; Kamada, K.; Esumi, T.; Iwabuchi, Y.;
Hatakeyama, S. J. Am. Chem. Soc. 2000, 122, 5216–5217.
J. Org. Chem. Vol. 74, No. 18, 2009 7169

Farran et al.
JOCNote
FIGURE 3. Crystal structures of 16a, 16b, and 3b.
FIGURE 4. DFT calculated (B3LYP/6-31G(d)) minimum zero en-
ergy conformation (left) for heptanes 17 and the extended linear
conformation (right), similar to that observed in the X-ray structures.
Ditosyls 16a and 16b and the diol 3b were crystallized and
a suitable crystal of each was used for X-ray structure
analysis as shown in Figure 3. The structures confirm the
relative configuration of each stereoisomer, consistent with
configurational inversions during each C-F bond forma-
tion. The structure of the ditosylate 16a indicates that the
molecule adopts an extended zigzag chain conformation
resulting in two sets of gauche C-F relationships at C2/C3
and C5/C6. The central C(4)-F bond adopts one gauche and
one anti relationship relative to each of its vicinal C-F bonds.
This conformation is close (1.56 kcal mol-1 above) to the energy
minimum of the parent heptane as determined by DFT calcula-
tions at the B3LYP/6-31G(d) level of theory.20 The calculated
structures are illustrated in Figure 4, where the extended
structure is presumably more compatible with unit cell packing.
A comparison of the structures of 3b and 16b, the diol and
ditosylate of the same diastereoisomeric series, shows that
they also adopt extended zigzag main chain conformations in
the solid state with two pairs of gauche C-F bonds at C2/C3
and C5/C6. The central fluorine on C4 orients anti to each of
its vicinal fluorines and there is perhaps unexpectedly a 1,3
to each other in a helical arrangement, similar to previous
observations for the all-syn tetra and hexa series.11-14 How-
ever, this low energy conformer does not crystallize presum-
ably because it lacks sufficient symmetry for unit cell
packing. NMR indicates (see below) too that the molecule
is dynamic in solution indicating competing low-energy
conformers.
Some insight into the conformations in solution of these
1
diastereoisomers can be gleaned from H and 19F NMR
coupling constants (3JHH and 3JHF). In a similar manner to
H/H (3JHH) coupling constants, vicinal H/F (3JHF) coupling
constants obey Karplus-type angular relationships.21 Com-
pounds 14a and 3a have almost identical coupling constants
and therefore very similar solution conformations, despite
different peripheral functionalities. For each molecule of
3
the a series, JHF values for HC(2)-C(3)F were measured
at ∼28 Hz, a large value consistent with a trans relationship.
3
On the other hand JHF for FC(3)-C(4)H had a value of
4.6 Hz, a small value consistent with a tight gauche relation-
ship between C-F and C-H bonds. These values suggest
a rather stable conformation in solution, similar to that
revealed in the X-ray stucture of 16a.
F
F interaction between the C-F bond on C3 and C5.
3 3 3
This is anticipated to be a repulsive interaction due to dipole
alignment. Computational analyses of the corresponding
pentafluoroheptane 17b revealed a more twisted structure
as the global minimum in the gas phase (Figure 4); however,
the observed extended conformation revealed in the X-ray
structures of 3b and 16b (Figure 3) is calculated to be only
1.4 kcal mol-1 higher in energy and again this latter con-
formation is presumably adopted in the solid state, due to its
symmetry, and its relatively low energy.
The all-syn diol 3c is the only diol of the three that is a
liquid at room temperature and despite considerable effort
we were unable to obtain a suitable crystal of the correspond-
ing ditosyl derivative 16c, which in our hands remained an
amorphous solid. The extended zigzag conformer of the
parent heptane c is now calculated to be 8.43 kcal mol-1
higher in energy than the minimum (Figure 4), and is clearly
a strained structure with fluorine-fluorine repulsion, so the
extended ditosyl structure 16c is unlikely to be amenable to
crystallization unlike 16a and 16b. The calculated minimum
energy conformer of 17c has all of the fluorine atoms gauche
Diastereoisomers b and c have molecular symmetry and
they generate second order 1H and 19F NMR spectra, which
require simulation to extract the coupling constants (see the
Supporting Information). Diastereoisomers 14b and 3b have
3
vicinal JHF couplings for HC(2)-C(3)F measured at 23.7
and 26.6 Hz, respectively, whereas values for FC(3)-C(4)H
were recorded at 12.1 and 10.2 Hz, respectively. These are
consistent with the observed solid state structure as a major
contributor, but the lower anti and higher gauche values
suggest a more dynamic molecule in solution with other
conformers contributing, lowering (anti) and raising
(gauche) the values relative to the a series. For stereochemical
series c we could not obtain any X-ray structural informa-
tion. The DFT theory study suggested that the linear ex-
tended structure is energetically unfavorable and that this
diastereoisomer will prefer a helical stucture (Figure 4). 19F
NMR gave three 3JHF coupling constants of between 21 and
(20) Gaussian 03, Revision E.01; Frisch, J. M. et al. ; Gaussian, Inc.,
Wallingford, CT, 2004.
(21) Thibaudeau, C.; Plavec, J.; Chattopadhyaya, J. J. Org. Chem. 1998,
63, 4967–4984.
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Farran et al.
JOCNote
22 Hz indicating a conformationally dynamic structure and
suggesting a number of contributing low-energy conformers
in solution.
In conclusion, the synthesis of three diastereoisomers of a
pentavicinal fluoroalkane was demonstrated as a novel motif in
organic chemistry. The parent 2,3,4,5,6-pentafluoro heptanes
were prepared and the pentafluoro 1,7-diol and 1,7-ditosyl
diastereoisomers a-c were generated armed for incorporation
of these building blocks into larger molecular scaffolds.
NaHCO3 (3 mL) and dried over anhydrous MgSO4. The solvent
was removed in vacuo and the residue was purified by silica gel
chromatography (hexane/CH2Cl2 100/0 f 40/60) to obtain the
pentafluoro product.
Data for 3a: mp 144-147 °C; [R]20D -2.1 (c 0.97, MeOH); IR
(neat) νmax (cm-1) 3353, 3174, 2868, 1055; 1H NMR (CD3OD,
300 MHz) δ 5.21-4.54 (m, 5H), 4.01-3.74 (m, 4H); 1H {19F dec}
NMR (CD3OD, 300 MHz) δ 5.13-4.69 (m, 5H), 3.97-3.78 (m,
4H); 19F NMR (CD3OD, 282 MHz) δ -205.0 (m, 1F), -206.0
(m, 1F), -206.0 (m, 1F), -218.0 (m, 2F); 19F {1H dec} NMR
(CD3OD, 282 MHz) δ -202.7 (dd, J=13.4, 2.7 Hz, 1F), -212.7
(dd, J=8.9, 3.0 Hz, 1F), -216.2 (m, 1F), -217.9 (ddd, J=13.4,
9.3, 3.5 Hz, 1F), -218.2 (ddd, J=14.2, 8.9, 3.5 Hz, 1F); 13C
NMR (CD3OD, 75 MHz) δ 94.4 (m, CH), 92.2 (m, CH), 89.9 (m,
CH), 61.6 (dd, J=22.2, 8.6 Hz, CH2), 60.6 (dd, J=26.0, 6.6 Hz,
CH2); HRMS (ESI, þve) m/z calcd for C7H11O2F5Na [M þ
Naþ] 245.0577, found 245.0581.
Experimental Section
General Procedure for Epoxides Opening with HF. A solution
of monofluorinated diepoxide (1.20 mmol) in Et3N 3HF (3 mL)
3
was heated in a reactor at 150 °C overnight. The mixture was
then carefully quenched with a saturated aqueous solution of
NaHCO3 (20 mL). Dichloromethane (20 mL) was added and the
organic layer was dried over anhydrous MgSO4. The solvent
was removed in vacuo and the crude residue was purified by
silica gel chromatography (CH2Cl2/EtOAc 100/0 f 95/5) to
obtain the desired compound.
Acknowledgment. We gratefully acknowledge the EPSRC
for funding this research.
Supporting Information Available: Experimental proce-
dures and characterization data for all new compounds, X-ray
structural information of 3b, 16a, and 16b, and calculation data
for 17a, 17b, and 17c. This material is available free of charge via
the Internet at http://pubs.acs.org.
General Procedure for the Synthesis of 14. Neat Deoxo-Fluor
(1.79 mmol) was added to a solution of trifluorinated diol
(0.36 mmol) in dry CH2Cl2 (3 mL) at rt. The mixture was stirred
overnight under argon. The mixture was diluted with EtOAc
(6 mL) then washed with a saturated aqueous solution of
J. Org. Chem. Vol. 74, No. 18, 2009 7171