Synthesis and conformational analysis of α,α-difluoroalkyl heteroaryl ethers

Article abstract of DOI:10.1016/j.tetlet.2009.07.060

We report the efficient synthesis of difluoroalkyl aryl ethers from the rearrangement of heteroaryl ketones and aldehydes, mediated by xenon difluoride and HF/pyridine in methylene chloride at room temperature. Computational analysis of difluoroalkylether

Full text of DOI:10.1016/j.tetlet.2009.07.060

Tetrahedron Letters 50 (2009) 5452–5455
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Tetrahedron Letters
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Synthesis and conformational analysis of a,a-difluoroalkyl heteroaryl ethers
*
*
Daniel B. Horne , Michael D. Bartberger , Matthew R. Kaller, Holger Monenschein,
Wenge Zhong, Stephen A. Hitchcock
Departments of Medicinal Chemistry and Molecular Structure and Design, Amgen, Inc., One Amgen Center Drive, Thousand Oaks, CA 91320-1799, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
We report the efficient synthesis of difluoroalkyl aryl ethers from the rearrangement of heteroaryl
ketones and aldehydes, mediated by xenon difluoride and HF/pyridine in methylene chloride at room
temperature. Computational analysis of difluoroalkylethers shows that there is potential to allow access
to conformational space not accessible to the hydrogenated parent.
Received 8 June 2009
Revised 26 June 2009
Accepted 1 July 2009
Available online 17 July 2009
Ó 2009 Elsevier Ltd. All rights reserved.
The increasing use of fluorine atoms as compact lipophilic and
metabolic stabilizing groups in potential drug candidates1 has
stimulated the interest in the development of new reactions and
reagents to introduce fluorine into molecules.2 During the course
of the synthesis of several aryl ether-containing lead compounds
for a drug discovery project, it was postulated that a heteroaryl
(entries 5 and 6) and in the case of neat 70 wt % HF in pyridine re-
sulted in degradation of the product (entry 7).
Variation of the alkyl group showed the reaction is tolerant to a
variety of simple alkyl groups and that an aldehyde also gives the
rearranged product in good yield (Table 2). However, the reaction
appears to be somewhat limited by sterics as the reaction with
the i-Pr substituent failed to give complete conversion resulting
in moderate yield (entry 4) and in the reaction with a bulky t-butyl
group <5% conversion was observed (entry 5). The more electron-
rich phenyl ring migrated preferentially over the quinoline ring
to give a single regioisomer (entry 6), but a poor yield resulted
due to concomitant formation of a byproduct resulting from aro-
matic ring fluorination at the para position of the electron-rich
phenoxy group.
Next, a range of aryl and heteroaryl ketones were subjected to
the optimized rearrangement conditions and in most cases gave
good yields of the desired products (Table 3). Of the substrates
run in this reaction, four substrates failed to give the desired prod-
ucts (entries 9–12). First, the indole and N-methylindole did not
participate in the reaction and resulted in low conversion to prod-
uct (entries 9 and 10). Also, acetylpyrazine was not tolerated in the
reaction, and only degradation products were observed (entry 11).
Finally, the trifluoromethylketone failed to react and led only to
recovered starting material (entry 12).
core compound containing a
a,a-difluoroalkylether group might
confer additional potency, stability, and improved efficacy com-
pared to its alkyl ether analogs. XeF2,3 a relatively mild electro-
philic fluorinating reagent, has been used in organic synthesis for
fluorodecarboxylation4 as well as electrophilic fluorination of
hydrocarbons,5 aromatic compounds,6 and alkenes.7 The XeF2-
mediated rearrangement of arylketones and aldehydes to a,a-dif-
luoroalkylethers has also been described (Fig. 1).8 However, the
rearrangement with heteroaryl carbonyls, leading to products typ-
ically used in drug discovery, has not been published. In addition,
many acetophenone substrates suffered from poor reactivity and
low yields due to competitive electrophilic aromatic ring fluorina-
tion. We postulated that the lower nucleophilicity of some hetero-
aryl ketones might preclude the undesirable aromatic ring
fluorination and lead to a more efficient and general method to
prepare heterocyclic difluoroethers.
We began our initial efforts centered on the rearrangement of
3-acetylquinoline to 3-(1,1-difluoroethoxy)quinoline and screen-
ing reaction conditions to obtain optimal yields (Table 1).9 Our ini-
tial screening conditions, 1.0 equiv of XeF2 with 5.0 equiv of HF in
pyridine resulted in only 5% conversion to product (entry 1). Addi-
tional HF (30 equiv) facilitated the reaction and increased the con-
version to 90%, resulting in 75% isolated yield (entry 2). Increasing
the quantity of XeF2 to 2.0 equiv with 30 equiv of HF forced the
reaction to completion and resulted in 87% isolated yield (entry
3). A limited solvent screen showed no improvement over CH2Cl2
Since our original interest in the
a,a-difluoroalkylether group
came from a medicinal chemistry project where attempts to gain
potency with alkoxyether groups appended to the inhibitor were
O
O
F
XeF2, HF/pyridine
Aryl
R
Aryl
R
F
* Corresponding authors. Tel.: +1 805 323 5250; fax: +1 850 480 3016 (D.B.H.).
E-mail addresses: dhorne@amgen.com (D.B. Horne), mbartber@amgen.com
(M.D. Bartberger).
1
2
Figure 1. Xenon difluoride arylketone rearrangement.
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.07.060

D. B. Horne et al. / Tetrahedron Letters 50 (2009) 5452–5455
5453
Table 1
Optimization of 3-acetylquinoline rearrangement
O
F
O
XeF2, HF/pyridine
CH2Cl2, rt
F
N
N
unsuccessful. We proposed, based upon literature observa-
tions,10,11 that the lipophilic portion of our substrate molecule,
which was accessible and led to increased potency with alkyl
groups, might also be accessed by the special structural features
quantum mechanical calculations and several experimental stud-
ies8 have demonstrated that while methoxybenzene adopts a pla-
nar conformation (uCortho–Cipso–O–Calkyl = 0°), the –OCF3 group of
trifluoromethoxybenzene adopts an orientation perpendicular to
the plane of the aryl ring.
inherent in the
a,a-difluoroalkylether group. These observations
*
were born out both in the computational analysis described below
and in observed increases in potency between alkylether and fluo-
rinated analogs in in vitro enzyme assays.
Figure 2 depicts the B3LYP/6-31G torsional potential for
a,a-
difluoroaryl system 2 of Table 2, along with its dihydro analog. It
is predicted that for quinoline-derived species 2, although a,a-
Fluorination of aryl ethers on the alkyl chain adjacent to oxygen
imparts significant changes to the accessible and preferred confor-
mations of the tether,7 potentially allowing for access to conforma-
tional space not accessible to the hydrogenated parent. Large basis
difluorination does not fully give rise to a preference for the per-
pendicular conformation, the energy difference between the planar
(u = 0°) global minimum energy structure and the near-perpendic-
ular (u = 75.3°) local minimum12 in 2 is reduced to only 0.5 kcal/
Table 2
Substitution of alkyl group in rearrangement
Entry
ArC@OR
Product
Yield (%)
74
O
H
F
O
1
F
F
N
N
O
O
O
O
F
O
2
87
N
N
F
O
O
O
3
68
F
N
N
N
N
N
N
F
F
4a
39
F
F
5
<5% conversion
O
F
O
F
6
53
N
N
a
Reaction only proceeded to 52% conversion.

5454
D. B. Horne et al. / Tetrahedron Letters 50 (2009) 5452–5455
Table 3
Aryl and heteroaryl ketones
Entry
ArC@OR
Product
Yield (%)
53
O
F
O
1
F
Br
Br
O
F
O
2
3
56
90
F
F
N
N
O
F
O
N
N
N
N
O
4a
73
O
F
F
S
N
O
S
N
O
F
5
6
76
54
F
S
N
O
S
N
O
F
F
O
F
O
S
N
S
N
7
82
F
F
O
O
O
N
N
F
F
N
N
8
70
O
F
9
0
O
N
N
O
F
10
11
Trace
N
H
F
N
H
N
N
N
N
F
0
0
O
O
F
O
O
F
F
F
F
12
F3C
F
Br
Br
a
Reaction was run with 4.0 equiv XeF2 and 60 equiv HF.

D. B. Horne et al. / Tetrahedron Letters 50 (2009) 5452–5455
5455
*
Figure 2. Dihedral angle plot (B3LYP/6-31G ) for difluoro-, dihydroethoxy-, and n-propyl-substituted aryl species.
mol. This is in stark contrast to the perhydro system, the perpen-
References and notes
dicular orientation of which (a transition state for interconversion
between planar minima) lies nearly 3.5 kcal/mol above the global
minimum (u = 0°). In the case of non-aza aryl ethers, such as diflu-
oroethoxybenzene (Fig. 2), the energy difference is even less (ca.
0.2 kcal/mol) and thus the population of the near-perpendicular lo-
cal minimum conformation further increases. Electron withdrawal
resulting from successive fluorination reduces the availability and
conjugation of oxygen lone pairs into the arene pi system. The
0.2 kcal/mol versus 0.5 kcal/mol difference in energy between the
near-perpendicular and planar conformations of phenyl-derived
versus quinoline-derived aryl ethers can be attributed to the com-
peting electron-withdrawing effect of the ring nitrogen in the lat-
ter, facilitating some degree of additional conjugation with the
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9. Warning, xenon difluoride is toxic and has a low vapor pressure. A well-
ventilated fume hood should be used for all procedures using the reagent and
reaction workup. General procedure: To a polyethylene vial are added the
ketone substrate (0.30 mmol) and CH2Cl2 (1.0 mL). Xenon difluoride
(0.60 mmol, 2.0 equiv) is added followed by 70% HF in pyridine (9.0 mmol,
0.25 mL, 30 equiv). The vial is sealed and stirred overnight at room
temperature. The reaction mixture is diluted with CH2Cl2 (10 mL), and the
reaction is quenched by slow addition to saturated aqueous NaHCO3 (10 mL)
containing excess solid NaHCO3 (0.500 g). The organic layer was extracted, the
aqueous layer extracted with CH2Cl2 (2 Â 10 mL), the combined organic layers
were dried (MgSO4), and concentrated. Purification by flash chromatography
gives the product.
ring. Thus, a-fluorination of aryl ethers allows access to conforma-
tional space both coplanar and perpendicular to the plane of the
ring. This is in contrast to the non-fluorinated analogs, where the
alkyl or alkoxy substituent is more restricted to perpendicular or
coplanar conformations, respectively.
In summary, we describe a general method for difluoroether
formation from heteroaryl ketones or aldehydes. The reaction
was shown to be compatible with a wide array of heteroaryl car-
bonyl compounds to allow efficient entry to 1,1-difluoroalkyle-
thers. Given the utility of fluorination in improving metabolic
stability of drug-like molecules, fluorinated aryl ethers may find
utility as replacements for alkyl-substituted aromatic rings with
potentially increased metabolic stability, while retaining confor-
mational characteristics more similar to alkyl-substituted arenes
than those bearing alkoxyl substituents.
10. Böhm, H.-J.; Banner, D.; Bendels, S.; Kansy, M.; Kuhn, B.; Müller, K.; Obst-
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12. From unconstrained B3LYP/6-31G
GAUSSIAN 03; Frisch et al., Gaussian, Inc., Wallingford, CT, 2004).
*
optimization and frequency analysis
(
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2009.07.060.