Synthesis of dibenzylamino-1-methylcyclohexanol and dibenzylamino-1-trifluoromethylcyclohexanol isomers

Article abstract of DOI:10.1039/c5ob01924a

The isomers of dibenzylamino-1-methylcyclohexan-1-ol and dibenzylamino-1-trifluoromethylcyclohexan-1-ol have been prepared. The stereochemistry of these compounds was unequivocally assigned through a combination of NMR spectroscopy and single crystal X-ra

Full text of DOI:10.1039/c5ob01924a

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Synthesis of dibenzylamino-1-methylcyclohexanol
and dibenzylamino-1-trifluoromethylcyclohexanol
isomers†
Cite this: DOI: 10.1039/c5ob01924a
D. Heulyn Jones,a Stefano Bresciani,a James P. Tellam,a Justyna Wojno,a
Anthony W. J. Cooper,b Alan R. Kennedya and Nicholas C. O. Tomkinson*a
The isomers of dibenzylamino-1-methylcyclohexan-1-ol and dibenzylamino-1-trifluoromethyl-
cyclohexan-1-ol have been prepared. The stereochemistry of these compounds was unequivocally
assigned through a combination of NMR spectroscopy and single crystal X-ray analysis. The cis-isomer of
3-N,N-dibenzylamino-1-trifluoromethylcyclohexanol and its derivatives display an unusual conformation-
al behaviour in both solution-phase and the solid-state, where the amino group usually adopts an axial
conformation.
Received 16th September 2015,
Accepted 8th October 2015
DOI: 10.1039/c5ob01924a
www.rsc.org/obc
heteroatom bonds on aromatic and heteroaromatic rings
allowing for the rapid introduction of diversity and complexity
Introduction
The introduction of three-dimensional shape through an on these frameworks to establish and probe structure activity
increase in the proportion of sp3 hybridised centres (Fsp3) has knowledge.11
been correlated to compound progress in a drug-discovery
A common motif found in many drug molecules is the
setting.1–5 The reduction of aromatic ring count has also been aminophenol functionality. This can easily be introduced
shown to have beneficial effects on the development properties through a variety of bond construction procedures and both
of oral drug candidates, including aqueous solubility, lipo- the amine and hydroxyl groups provide excellent synthetic
philicity, serum albumin binding, CyP450 inhibition and handles through which to selectively introduce a variety of
hERG inhibition.6 Based upon these important factors there additional groups. Introduction of this functionality on a rigid
has been significant interest in robust synthetic routes to aromatic scaffold can provide both hydrogen bond donor and
building blocks and fragments which confer both shape and hydrogen bond acceptor properties along with the provision of
fixed conformation on a molecule through the introduction of mildly basic and acidic functional groups. Therefore, this
saturation.7–9
pharmacophore is prevalent in many bioactive molecules.
Whilst there are advantages to the reduction in the number A selection of marketed drugs which contain a 1,4-, 1,3- or 1,2-
of aromatic rings within a compound,6 the conformational aminophenol functionality are collected in Fig. 1. Dofetilide 1
constraints of a ring provide clear benefits in a medicinal is a class III antiarrhythmic used for the maintenance of
chemistry setting, where functional groups can be held in posi- sinus rhythm.12 Terconazole 2 is a broad spectrum antifungal
tions to maximise ligand–receptor interaction.10 For this agent which ultimately inhibits the ergosterol biosynthesis
reason the introduction of functional groups on an aromatic pathway.13 Neostigmine 3 is a reversible acetylcholinesterase
scaffold has provided significant benefits within drug-discov- inhibitor which stimulates both nicotinic and muscarinic recep-
ery. In addition, there are many simple and effective pro- tors.14 Ivacaftor 4 is effective in the treatment of cystic fibrosis.15
cedures for the formation of carbon–carbon and carbon– Suvorexant 5 is a orexin receptor antagonist,16 approved for the
treatment of insomnia and Eltombopag 6, interacts with the
thrombopoietin receptor and leads to an increased platelet
count in patients.17 These selected examples show the diversity
aWestCHEM, Department of Pure and Applied Chemistry, Thomas Graham Building,
in protein targets for this class of compound and highlight the
importance and prevalence of the aminophenol functionality in
compounds with profound biological activities.
From the examples outlined in Fig. 1 there are clear
benefits to the use of aromatic rings to fix the aminophenol
functionality in space. However, the correlation between
University of Strathclyde, 295 Cathedral Street, Glasgow, G1 1XL, UK.
E-mail: Nicholas.Tomkinson@strath.ac.uk
bMolecular Discovery Research, GlaxoSmithKline, Medicines Research Centre,
Hertfordshire, SG1 2NY, UK
†Electronic supplementary information (ESI) available: 1H, 13C and 19F spectra
for compounds reported. CCDC 1064075–1064082. For ESI and crystallographic
data in CIF or other electronic format see DOI: 10.1039/c5ob01924a
This journal is © The Royal Society of Chemistry 2015
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Fig. 1 Drug molecules containing the 1,4-, 1,3- and 1,2-aminophenol functionalitY.
developing an oral drug candidate and the number of aromatic
rings in a compound provides a strong impetus to develop
saturated analogues of common aromatic motifs found in
drug molecules.6 As part of an ongoing investigation we
hypothesised that saturation of the aminophenol framework
would provide a particularly useful series of aminocyclo-
hexanol fragments for discovery research. Examination of the
patent literature reveals a number of compounds which
contain the aminocyclohexanol functionality suggesting that
this grouping also has potential in the drug-discovery setting.
Recent examples include the benzoxazole 7 which has been
shown to be an mPGES-1 inhibitor and the 2-amidopyridine
derivative 8, synthesised as a potential 11β-HSD1 inhibitor
(Fig. 2).18,19
Fig. 3 Possible 1-methyl- and 1-trifluoromethyl dibenzylaminocyclo-
A convenient synthetic precursor to the amino cyclohexanol
framework would be a suitably N-protected derivative. A typical
example that can readily be unmasked to reveal the desired
functionality is dibenzylamino-1-methylcyclohexan-1-ol and
dibenzylamino-1-trifluoromethylcyclohexan-1-ol, which each
have six structural isomers 9–20 (Fig. 3).
Despite the prevalence of this framework in the patent lit-
erature relatively few syntheses of this scaffold have been
reported in the primary literature. In an isolated report, Yama-
moto described the ytterbium triflate-mediated ring opening
hexanol isomers.
of epoxide 21 with dibenzylamine to give the amino alcohol 22
together with 23 as
a 9 : 1 mixture of regioisomers
(Scheme 1).20 Although the stereochemistry of this product
was not unequivocally assigned it is expected that this would
be the trans-isomer 13.
In the trifluoromethyl series (15–20) only the 4-amino-1-
trifluoromethylcyclohexanol 15 has been reported, as
a
mixture along with minor isomer 16.19 This mixture was pre-
pared through reaction of the dibenzylamino ketone 24 with
Ruppert’s reagent (CF3SiMe3) in the presence of tetra-n-butyl-
ammonium fluoride (TBAF) followed by acidic cleavage of the
siloxy intermediate to give the products 15 and 16 as a
Fig. 2 Examples from recent patent literature containing the 4-amino-
cyclohexanol functionality.
Scheme 1 Epoxide ring opening route to the 1,2-isomer.
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Scheme 2 Preparation of the trifluoromethyl substituted 1,4-isomer 15.
Scheme 4 Synthesis of cis- and trans-4-dibenzylamino-1-methyl-
cyclohexanol 10 and 9.
6 : 1 mixture of diastereoisomers (Scheme 2), the trans-isomer
15 predominating.
Whilst these isolated reports are of use to those wishing to
exploit this functionality in their efforts, the synthesis and
stereochemical assignment of all twelve isomers of this cyclo-
hexyl motif would be of direct use in adding stereochemical
complexity and 3-dimensional shape to discovery projects.
Within this paper we describe the synthesis, isolation and
purification of all 1-methyl- and 1-trifluoromethyl dibenzyl-
aminocyclohexan-1-ol isomers 9–20 in three steps or fewer
from readily available precursors, and unequivocally assign
their stereochemistry based upon NMR spectroscopy and X-ray
crystallographic experiments.
Fig. 4 X-Ray crystal structures of 10 and 9.
Introduction of the trifluoromethyl group was achieved
under standard conditions using Ruppert’s reagent in the
presence of TBAF, delivering the two diastereomeric products
15 and 16 in a 9 : 1 ratio as determined by 1H NMR and 19F
NMR spectroscopy (Scheme 5). Although a small amount of
the major diastereomer was purified by column chromato-
graphy, efficient separation of 15 and 16 could not be achieved
due to their similar affinities to silica, and the mixture of dia-
stereomers was isolated in 81% yield. X-Ray crystallography
showed the major diastereoisomer from this transformation to
be the trans-isomer 15 where the trifluoromethyl group had
been introduced in an axial position.
The complete reversal of cis/trans selectivity when compared
to methyl analogues 9 and 10 is likely due to pre-complexation
of the approaching nucleophile in the addition of the Grignard
reagent, whereas the axial addition of the trifluoromethyl
group relieves gauche interactions within the transition state.22–24
Although the cis-diastereoisomer 16 was present within the
crude reaction mixture, its isolation proved challenging. We
therefore examined alternative synthetic strategies to access
this isomer. Initial attempts at using stoichiometric amounts
Results and discussion
Our investigations began with the preparation of the 4-dibenz-
ylamino derivatives 9, 10, 15 and 16 which were accessed from
the common intermediate 24. Dibenzylation of 4-aminocyclo-
hexanol hydrochloride 25 followed by Swern oxidation pro-
vided the known ketone 24 in 84% yield (Scheme 3).21
Treatment of a THF solution of 24 with methylmagnesium
chloride at −78 °C and allowing the reaction mixture to warm
slowly to room temperature followed by an acidic workup pro-
vided access to the two diastereoisomers 10 and 9 in a 70 : 30
ratio, which were separated by column chromatography provid-
ing the products in 56% (10) and 18% (9) isolated yields
(Scheme 4).
The stereochemistry of each isomer was confirmed by X-ray
crystallographic analysis (Fig. 4). The cis-isomer 10 showed two
crystallographically independent molecules within the unit
cell characterised by slightly different conformations of the
cyclohexane ring which formed a hydrogen-bonded closed
tetramer of molecules.
Scheme 5 Synthesis
of
4-dibenzylamino-1-trifluoromethyl-
Scheme 3 Preparation of 4-dibenzylaminocyclohexanone 24.
cyclohexanols 15 and 16.
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of the bulky Lewis acid methylaluminium bis(2,6-di-tert-butyl-
Conveniently, the four possible 1,2-isomers 13, 14, 19 and
4-methyl)phenoxide to encourage the equatorial approach of 20 could be prepared and isolated from a common intermedi-
the nucleophile were unsuccessful.25 In addition, the more ate, greatly simplifying the synthesis of these compounds
sterically demanding trifluoromethylating agent hexafluoro- (Scheme 7). Intermediate 28 was prepared through a two-step
acetone hydrate-1,8-diaza-bicyclo[5.4.0]undec-7-ene salt only literature procedure involving the ring opening of cyclohexene
returned starting materials.26 However, 16 was successfully oxide 27 followed by Swern oxidation of the resulting amino-
prepared through the sequence outlined in Scheme 6. alcohol to give 28 in 39% isolated yield (Scheme 7).20 Addition
Trifluoromethylation of the mono-protected cyclohexanedione of methylmagnesium chloride to 28 at 0 °C gave the cis-amino-
26 followed by deprotection and subsequent reductive amin- alcohol 14 in 89% isolated yield as a single isomer. Single
ation27 gave the diastereomeric cis- and trans-isomers 16 and crystal X-ray analysis of the hydrochloride salt of 14 confirmed
15 in an 80 : 20 ratio, from which the required cis-isomer 16 the relative stereochemistry of this compound (Fig. 6) with the
could be isolated through purification by column chromato- methyl group adopting an equatorial position. Chelation of
graphy in a poor but acceptable yield for the three steps (17%). the Grignard reagent to the carbonyl oxygen and the secondary
The relative configuration of both the trans- and cis-diastereo- amine would be expected to deliver the methyl group from an
isomers 15 and 16 was confirmed through X-ray crystallo- equatorial position, as was observed.
graphy (Fig. 5).
Changing the nucleophile to methyllithium resulted in the
formation of both the cis- and trans-products 14 and 13 in a
80 : 20 ratio (1H NMR analysis of the crude reaction mixture).
The isomers were separated by column chromatography, and
the 1H NMR spectrum of the minor trans-isomer 13 agreed
with the values reported for the product from ring-opening of
1-methylcyclohexene oxide by dibenzylamine.20 Therefore, the
diastereomers 13 and 14 can be accessed as single isomers in
good yield via two complimentary routes.
Treatment of 28 with Ruppert’s reagent and TBAF resulted
in a 80 : 20 mixture of the expected products 19 and 20, which
were purified by column chromatography and isolated in 58%
and 13% yields respectively (Scheme 7). The major diastereo-
mer was shown to be the trans-isomer 19 by single crystal X-ray
analysis (Fig. 7), and was supported by the observation of long
range splitting of the axial NC-H proton by the trans-CF3 group
Scheme 6 Alternative synthesis of cis-4-dibenzylamino-1-trifluoro-
methylcyclohexanol (16).
1
in the H NMR spectrum. This coupling was not observed for
the cis-isomer 20.
Having successfully prepared each of the 1,4- and 1,2-
isomers our attention moved to the synthesis of the 1,3-substi-
tuted amino alcohols 11, 12, 17 and 18. Once again, these
could be prepared from a common intermediate (30), which
itself was prepared using a bismuth nitrate catalysed conjugate
addition of dibenzylamine to cyclohexenone 29 (Scheme 8).28
Isolation of the key intermediate 30 by chromatography proved
Fig. 5 X-Ray crystal structure of 15 and 16.
Scheme 7 Synthesis of 2-dibenzylamino-1-substituted cyclohexan-1-ols 13, 14, 19 and 20.
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Fig. 8 X-Ray crystal structure of major trans-1,3-isomer 11.
Fig. 6 X-Ray crystal structure of 14·HCl.
CDCl3, 18 adopted a conformation (A) where the large
dibenzylamino group resided in an axial position due to an
intramolecular hydrogen bond, whereas in the H-bonding
deuterated solvent CD3OD the amino group adopted the
more common equatorial conformation (B) (Fig. 9).
This solvent-dependant conformational change has been
observed previously for cis-1,5,5-trimethylcyclohexane-1,3-diol
and cis-1,5,5-trimethyl-3-aminocyclohexanol in CDCl3/D2O,29
but it is impressive that such a bulky dibenzylamino group dis-
plays this strong conformational fluxionality. The effect can in
part be attributed to the size of the trifluoromethyl group,
although the fact that the effect is reversed in CD3OD suggests
there is a hydrogen-bonding interaction involved (Fig. 9). Inter-
estingly, this is not seen in the methyl analogue 12 which
suggests that the trifluoromethyl group plays a pivotal role in
the conformation adopted by 18 in solution, presumably by
tuning the acidity of the alcohol.30 1H NMR analysis of 18·HCl
(in CDCl3) showed the dibenzylamino group in an equatorial
position, supporting the proposal that an intramolecular
hydrogen bond alters the conformational preference of 18 in
non-polar solvents.
Fig. 7 X-Ray crystal structure of trans-isomer 19.
problematic due to decomposition of the adduct on silica,
however, direct crystallisation from the crude reaction mixture
using petroleum ether gave the amino ketone in 32% yield on
scale without the need for chromatography.
Addition of methylmagnesium chloride to 30 gave a 80 : 20
diastereomeric mixture of the expected trans-11 and cis-12 pro-
ducts, which were separated by column chromatography and
isolated in 80% and 9% yields respectively. The identity of the
major trans-isomer 11 was confirmed by single crystal X-ray
analysis where the dibenzylamino group adopted an equatorial
position (Fig. 8).
Treatment of 30 with Ruppert’s reagent in the presence of
TBAF gave a 50 : 50 mixture of the diastereomeric products 17
and 18, which were separated by column chromatography and
isolated in 37% and 41% yields respectively (Scheme 8). The
stereochemistry of cis-isomer 18 was deduced by 1H NMR
spectroscopy due to its intriguing behaviour in solution. In
This behaviour was further investigated through the prepa-
ration of a series of analogues of 18 (Scheme 9). Deprotection
of the amine through hydrogenolysis gave the amine 31 (94%)
which was acylated under standard conditions to give the
amide 32 (69%). Reduction of the amide with borane gave the
secondary amine 33 (76%).
The relative stereochemistry of amine 31 was confirmed by
single crystal X-ray where the amine substituent adopts an
Scheme 8 Synthesis of 3-dibenzylamino-1-substituted cyclohexanol derivatives.
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Conclusion
The twelve isomers of amino-1-methylcyclohexan-1-ol and
amino-1-trifluoromethylcyclohexan-1-ol were successfully pre-
pared in three-steps or fewer from commercially available start-
ing materials. The stereochemistry of each isomer was
assigned via a combination of 1H NMR spectroscopy and
single crystal X-ray analysis. An interesting conformational
behaviour was observed and investigated for cis-3-amino-1-
trifluoromethylcyclohexan-1-ol derivatives, which could have
structural implications for molecules containing this motif.
This work provides robust routes to the isomers of amino-1-
methylcyclohexan-1-ol and amino-1-trifluoromethylcyclohexan-
1-ol, which will be of use for introducing 3D shape to drug-like
molecules.
Fig. 9 Solvent-dependant conformational change of 18 in solution.
Experimental
Materials and methods
All commercial materials were used as received without further
purification. THF was dried using a solvent purification
system. Flash chromatography was carried out using Merck
Kieselgel 60 H silica. Analytical thin layer chromatography was
carried out using aluminum-backed plates coated with Merck
Kieselgel 60 GF254 that were visualized under UV light (at
254 nm) or stained using KMnO4. Nuclear magnetic resonance
(NMR) spectra were recorded on a Bruker Avance III or a
Bruker Avance spectrometer, operating at 400 MHz (1H),
376 MHz (19F) and 101 MHz (13C). Chemical shifts were
reported in parts per million (ppm) in the scale relative to
residual solvent signals. Multiplicities are abbreviated as:
s, singlet; d, doublet; t, triplet; q, quartet; dd, doublet of
doublets; tt, triplet of triplets; pent; pentet; hept, heptet;
m, multiplet; br, broad. Coupling constants are measured
in Hertz (Hz). High-resolution mass spectra (HRMS) were
obtained courtesy of the EPSRC National Mass Spectrometry
Facility at Swansea University, U.K.
Scheme 9 Derivatisation of the amine 18.
axial conformation (Fig. 10). 1H NMR analysis of 31 showed
the NH2 group adopts an axial conformation in solution in
both CDCl3 and CD3OD showing the subtle interplay of sterics
and electronics in the benzylated analogue 18. Amide 32
and secondary amine 33 displayed the same conformational
behaviour, suggesting that all cis-3-amino-1-trifluoromethyl-
cyclohexanols possessing groups bonded to nitrogen that are
less bulky than two benzyl groups are likely to always adopt a
conformation with the amino functionality axial. This has
interesting implications for adopting these monomers in a
drug-discovery setting, where functional group disposition is
critical to ligand–receptor interaction. It is entirely feasible
that for compounds containing the cis-3-amino-cyclohexan-1-
ol motif as exemplified by 12 and 18, axial/equatorial confor-
mation could be controlled through incorporation of either a
methyl or a trifluoromethyl group.
trans-4-(Dibenzylamino)cyclohexan-1-ol
Cesium carbonate (51.4 g, 158 mmol) was added to a solution
of trans-4-aminocyclohexanol (7.9 g, 52.3 mmol) in acetonitrile
(150 mL). Benzyl bromide (12.7 mL, 106 mmol) was added and
the mixture left to stir at room temperature for 2 days. The
crude reaction mixture was filtered, and the solid washed with
additional acetonitrile (100 mL). The filtrate was concentrated
under reduced pressure, dissolved in dichloromethane
(100 mL) and washed with water (3 × 50 mL). The organic
extract was dried over MgSO4, filtered and concentrated under
reduced pressure to give trans-4-(dibenzylamino)cyclohexan-
1-ol as a colourless solid (15.1 g, 98%); 1H NMR (400 MHz,
CDCl3) δ 7.37 (4H, d, J = 7.2 Hz), 7.29 (4H, ddd, J = 7.1, 6.1 Hz),
7.19–7.24 (2H, m), 3.62 (4H, s), 3.54 (1H, tt, J = 10.9, 4.3 Hz),
2.53 (1H, tt, J = 11.8, 3.5 Hz), 1.95–2.04 (2H, m), 1.87–1.94 (2H,
m), 1.36–1.61 (1H, br s), 1.36–1.49 (2H, m), 1.12–1.30 (2H, m);
13C NMR (100 MHz, CDCl3) δ 141.0 (quat C), 128.5 (CH),
Fig. 10 X-Ray crystal structure of 31.
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128.3 (CH), 126.8 (CH), 71.0 (CH), 56.9 (CH), 54.1 (CH2), colourless solid (0.85 g, 18%); 1H NMR (400 MHz, CDCl3)
35.0 (CH2), 26.0 (CH2); HRMS calc. for C20H26ON 296.2009 δ 7.36 (4H, d, J = 7.1 Hz), 7.26–7.31 (4H, m), 7.21 (2H, dt, J =
(M+ + 1), found 296.2011.
7.2, 1.3 Hz), 3.63 (4H, s), 2.56 (1H, tt, J = 11.6, 3.7 Hz),
1.78–1.88 (2H, m), 1.67–1.77 (2H, m), 1.32–1.55 (4H, m), 1.25
(3H, s); 13C NMR (100 MHz, CDCl3) δ 141.0 (quat C), 128.5
General Procedure 1. Swern oxidation
A solution of DMSO (11.6 mL, 163 mmol) in anhydrous (CH), 128.3 (CH), 126.8 (CH), 71.0 (quat C), 57.5 (CH), 54.3
dichloromethane (20 mL) was added drop-wise via a dropping (CH2), 39.8 (CH2), 25.6 (CH2), 25.5 (CH3); HRMS calc. for
funnel to a cooled solution of oxalyl chloride (6.8 mL, C21H28ON 310.2165 (M+ + 1), found 310.2168. Crystals were
80.8 mmol) in anhydrous dichloromethane (100 mL) at grown by slow evaporation of a solution in cyclohexane.
−78 °C. The reaction mixture was left to stir for an additional
General Procedure 3. Reaction with Ruppert’s reagent
15 minutes following completion of addition, and a solution
of trans-4-(dibenzylamino)cyclohexan-1-ol (14.0 g, 47.5 mmol) To a solution of 24 (2.0 g, 6.83 mmol) in anhydrous THF
in anhydrous dichloromethane (50 mL) was added drop-wise (15 mL) cooled to 0 °C, was added trifluoromethyltrimethyl-
via a dropping funnel. Following completion of addition, the silane (1.2 mL, 8.20 mmol) under a N2 atmosphere. The
reaction mixture was stirred for 30 minutes before triethyl- mixture was stirred rapidly, and a solution of TBAF (5 mg, cat)
amine (46 mL, 328 mmol) was added slowly drop-wise via in anhydrous THF (1 mL) was added slowly drop-wise. Follow-
syringe, and the cooling bath removed to allow the reaction ing completion of addition, the cooling bath was removed and
mixture to warm to room temperature. The rubber septa were the reaction mixture left to warm to room temperature and
removed to allow the evaporation of SMe2, and the mixture left stirred until consumption of starting material was apparent by
to stir overnight at room temperature. The crude reaction TLC (1.5 h). The reaction mixture was exposed to air, 4 M HCl
mixture was concentrated under reduced pressure, dissolved (aq) solution (10 mL) was added and the reaction mixture left
in ethyl acetate (150 mL) and washed with water (3 × 100 mL). to stir at room temperature until consumption of the siloxy
The organic extract was dried over MgSO4, filtered and concen- intermediate was apparent by TLC (2 h). The pH was adjusted
trated under reduced pressure to give the crude product, to 7 by the drop-wise addition of a saturated solution of
which was purified by column chromatography on silica (8 : 1 K2CO3, and dichloromethane (30 mL) was added. The mixture
petroleum ether : ethyl acetate) to give 24 as peach coloured was washed with water (3 × 15 mL), dried over MgSO4, filtered
1
solid (13.9 g, 86%); H NMR (400 MHz, CDCl3) δ 7.38 (4H, d, and concentrated under reduced pressure to give the crude
J = 7.2 Hz), 7.29–7.34 (4H, m), 7.21–7.26 (2H, m), 3.66 (4H, s), product, which was purified by column chromatography on
3.02 (1H, tt, J = 11.5, 3.4 Hz), 2.37–2.45 (2H, m), 2.12–2.33 (4H, silica (10 : 1 petroleum ether : ethyl acetate) to give 15 and 16
m), 1.76–1.89 (2H, m); 13C NMR (100 MHz, CDCl3) δ 211.1 as a colourless solid as a 9 : 1 trans : cis mixture of diastereo-
(quat C), 140.4 (quat C), 128.5 (CH), 128.4 (CH), 127.0 (CH), mers (2.0 g, 81%). A small amount of pure trans-15 was
55.9 (CH), 54.2 (CH2), 40.3 (CH2), 27.5 (CH2); HRMS calc. for obtained and used for characterisation purposes; 1H NMR
C20H24ON 294.1852 (M+ + 1), found 294.1854.
(400 MHz, CDCl3) δ 7.27–7.36 (8H, m), 7.19–7.24 (2H, m), 3.65
(4H, s), 2.73 (1H, pent, J = 6.3 Hz), 2.18 (2H, app dt, J = 10.7,
4.5 Hz), 1.83 (4H, app q, J = 6.7 Hz), 1.52–1.57 (1H, br s), 1.47
General Procedure 2. Addition of methylmagnesium chloride
To a solution of 24 (4.41 g, 15.05 mmol) in anhydrous THF (2H, app dt, J = 14.0, 7.0 Hz); 13C NMR (100 MHz, CDCl3)
(45 mL) cooled to −78 °C under a N2 atmosphere, was added δ 140.3 (quat C), 128.6 (CH), 128.3 (CH), 126.9 (CH), 126.8
3.0 M MeMgCl in THF (8.02 mL, 24.06 mmol) drop-wise. Fol- (quat C, q, J = 283 Hz), 72.4 (quat C, q, J = 30.3 Hz), 55.3 (CH),
lowing completion of addition, the cooling bath was removed 53.9 (CH2), 29.9 (CH2), 23.5 (CH2); 19F{1H} NMR (376 MHz,
and the reaction mixture left to warm to room temperature CDCl3) δ −80.1; HRMS calc. for C21H25ONF3 364.1883 (M+ + 1),
and stirred overnight. Water (10 mL) was added drop-wise, and found 364.1882; Crystals obtained from cold toluene.
the aqueous layer extracted with diethyl ether (3 × 20 mL). The
4-Oxo-1-(trifluoromethyl)cyclohexan-1-ol
combined organic extracts were washed with water (20 mL)
and brine (20 mL), dried over MgSO4, filtered and concen- 4-Oxo-1-(trifluoromethyl)cyclohexan-1-ol was prepared using
trated under reduced pressure to give the crude products, General Procedure 3 (reaction mixture was stirred overnight at
which were purified by column chromatography on silica (5 : 1 rt following addition of 4 M HCl (aq) solution) from 1,4-dioxa-
petroleum ether : ethyl acetate followed by 4 : 1 and finally spiro[4.5]decan-8-one (2.00 g, 12.8 mmol), trifluoromethyltri-
3 : 1) to give 10 as a colourless solid (2.62 g, 56%); 1H NMR methylsilane (2.08 mL, 14.1 mmol), anhydrous THF (30 mL)
(400 MHz, CDCl3) δ 7.38 (4H, d, J = 7.2 Hz), 7.29 (4H, app t, J = and a solution of TBAF (5 mg) in THF (1.0 mL) to give the
7.6 Hz), 7.21 (2H, t, J = 7.3 Hz), 3.67 (4H, s), 2.43–2.53 (1H, m), crude product, which was purified by column chromatography
1.62–1.83 (6H, m), 1.25–1.38 (2H, m), 1.17 (3H, s); 13C NMR on silica (3 : 1 petroleum ether : ethyl acetate) to give 4-oxo-
(100 MHz, CDCl3) δ 141.2 (quat C), 128.5 (CH), 128.2 (CH), 1-trifluoromethylcyclohexan-1-ol as a colourless solid (1.28 g,
126.7 (CH), 69.2 (quat C), 57.2 (CH), 54.1 (CH2), 38.5 (CH2), 55%); 1H NMR (400 MHz, d6-Acetone) δ 5.30 (1H, s), 2.69
31.4 (CH3), 23.5 (CH2); HRMS calc. for C21H28ON 310.2165 (2H, ddd, J = 14.4, 6.4, 6.4 Hz), 2.06–2.27 (6H, m); 13C NMR
(M+ + 1), found 310.2157. A sample was crystallised by slow (100 MHz, d6-Acetone) δ 208.3 (quat C), 127.7 (quat C, q, J =
evaporation of a solution in cyclohexane. Followed by 9 as a 308 Hz), 71.8 (quat C, q, J = 22 Hz), 35.8 (CH2), 30.4 (CH2);
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19F{1H} NMR (376 MHz, d6-Acetone) δ −93.4; HRMS calc. for 14.1 mmol), triethylamine (3.92 mL, 28.1 mmol) and anhydrous
C7H8O2F3 181.0482 (M+ − 1), found 181.0485.
dichloromethane (30 mL in total) to give the crude product,
which was purified by column chromatography on silica (8 : 1
petroleum ether : ethyl acetate) to give 28 as a light yellow solid
cis-4-(Dibenzylamino)-1-(trifluoromethyl)cyclohexan-1-ol 16
Following the procedure reported by Abdel-Magid,27 4-oxo- (0.93 g, 78%); 1H NMR (400 MHz, CDCl3) δ 7.39 (4H, d, J =
1-trifluoromethylcyclohexan-1-ol (0.20 g, 1.1 mmol), dibenzyl- 7.2 Hz), 7.26–7.32 (4H, m), 7.18–7.24 (2H, m), 4.00 (2H, d, J =
amine (0.21 mL, 1.1 mmol), NaBH(OAc)3 (0.33 g, 1.5 mmol) 14.3 Hz), 3.76 (2H, d, J = 14.3 Hz), 3.31 (1H, dd, J = 12.4, 5.7),
and acetic acid (0.13 mL, 2.2 mmol) were mixed in anhydrous 2.34–2.44 (1H, m), 2.10–2.25 (2H, m), 1.76–2.02 (3H, m),
THF (5 mL). The resulting mixture was stirred under an Ar 1.44–1.66 (2H, m); 13C NMR (100 MHz, CDCl3) δ 212.2 (quat C),
atmosphere for 16 h, before further portions of NaBH(OAc)3 140.8 (quat C), 128.5 (CH), 128.3 (CH), 126.9 (CH), 66.6 (CH),
(0.33 g, 1.5 mmol) and acetic acid (0.13 mL, 2.2 mmol) were 54.9 (CH2), 42.6 (CH2), 31.7 (CH2), 27.2 (CH2), 25.1 (CH2);
added and the mixture stirred for a further 6 h. The reaction HRMS calc. for C20H24ON 294.1852 (M+ + 1), found 294.1852.
mixture was quenched with 1 M NaOH (aq) solution (20 mL),
cis-2-(Dibenzylamino)-1-methylcyclohexan-1-ol 14
poured into a separating funnel and extracted with dichloro-
Compound 14 was prepared following General Procedure 2 at a
reduced temperature of 0 °C, from 28 (0.25 g, 0.85 mmol),
anhydrous THF (10 mL) and 3.0 M MeMgCl in THF (0.45 mL,
1.35 mmol), and was isolated as a yellow oil (0.23 g, 89%);
1H NMR (400 MHz, CDCl3) δ 7.39 (4H, d, J = 7.3 Hz), 7.30 (4H,
app t, J = 7.3 Hz), 7.22 (2H, t, J = 7.3 Hz), 4.14 (2H, d, J =
13.8 Hz), 3.39 (2H, d, J = 13.8 Hz), 2.29 (1H, dd, J = 12.2,
3.4 Hz), 1.80–1.90 (2H, m), 1.65–1.79 (1H, m), 1.48–1.57 (2H,
m), 1.38–1.48 (1H, m), 1.08–1.27 (5H, m); 13C NMR (100 MHz,
CDCl3) δ 141.2 (quat C), 129.0 (CH), 128.2 (CH), 126.7 (CH),
74.3 (quat C), 63.1 (CH), 55.9 (CH2), 41.4 (CH2), 29.2 (CH3),
26.4 (CH2), 21.8 (CH2), 20.1 (CH2); HRMS calc. for C21H28ON
310.2165 (M+ + 1), found 310.2166. The HCl salt of 14 was pre-
pared by forming a saturated HCl solution in diethyl ether.
Crystals were grown by the slow evaporation of a concentrated
solution of the salt 14·HCl in methanol.
methane (3 × 15 mL). The combined organic extract was
washed with water (20 mL), dried over MgSO4, filtered and
concentrated under reduced pressure to give the crude
product, which was purified by column chromatography on
silica (6 : 1 petroleum ether : ethyl acetate) to give cis 16 (0.12 g,
31%); 1H NMR (400 MHz, CDCl3) δ 7.38 (4H, d, J = 7.2 Hz),
7.31 (4H, app t, J = 7.2 Hz), 7.23 (2H, t, J = 7.2 Hz), 3.68 (4H, s),
2.46–2.62 (1H, m), 1.72–1.90 (6H, m), 1.67 (1H, br s), 1.55 (1H,
app td, J = 12.5, 5.1 Hz); 13C NMR (100 MHz, CDCl3) δ 140.8
(quat C), 128.5 (CH), 128.4 (CH), 126.9 (CH), 126.4 (quat C, q,
J = 280 Hz), 72.5 (quat C, q, J = 30 Hz), 56.6 (CH), 54.0 (CH2),
29.7 (CH2), 22.0 (CH2); 19F{1H} NMR (376 MHz, CDCl3)
δ −84.5; HRMS calc. for C21H25ONF3 364.1883 (M+ + 1), found
364.1880. Crystals were grown by slow evaporation of a satu-
rated solution in CHCl3.
trans-2-(Dibenzylamino)cyclohexan-1-ol
trans-2-(Dibenzylamino)-1-methylcyclohexan-1-ol 13 and
cis-2-(dibenzylamino)-1-methylcyclohexan-1-ol 14
Following the procedure reported by Yamamoto,20 dibenzyl-
amine (3.9 mL, 20.0 mmol) was added to a mixture of cyclo-
hexene oxide (1.0 mL, 10.0 mmol), ytterbium triflate (0.62 g,
1.0 mmol) and anhydrous THF (10 mL). The mixture was
refluxed under an Ar atmosphere for 14 h. Ethyl acetate
(30 mL) was added, and the solution was washed with a satu-
rated solution of K2CO3 (20 mL), dried over MgSO4, filtered
and concentrated under reduced pressure to give the crude
product, which was purified by column chromatography on
silica (9 : 1 petroleum ether : ethyl acetate) to give trans-
2-(dibenzylamino)cyclohexan-1-ol as a colourless solid (1.5 g,
50%); 1H NMR (500 MHz, CDCl3) δ 7.22–7.36 (10H, m), 3.87
(2H, d, J = 13.3 Hz), 3.73–3.77 (1H, br s), 3.52 (1H, app td, J =
10.1, 4.5 Hz), 3.40 (2H, d, J = 13.3 Hz), 2.37 (1H, ddd, J = 10.9,
10.6, 3.5 Hz), 2.04–2.12 (1H, m), 1.96–2.02 (1H, m), 1.75–1.85
(1H, m), 1.61–1.72 (1H, m), 1.05–1.33 (4H, m); 13C NMR
(100 MHz, CDCl3) δ 139.6 (quat C), 129.1 (CH), 128.6 (CH),
Compounds 13 and 14 were prepared following General Pro-
cedure 2 at a reduced temperature of 0 °C, using 28 (0.050 g,
0.17 mmol), dry THF (10 mL) and a 1.6 M solution of MeLi in
diethyl ether (0.16 mL, 0.26 mmol) to give the crude products,
which were purified by column chromatography on silica
(10 : 1 petroleum ether : ethyl acetate) to give 14 (0.023 g, 44%)
which was identical to an authentic sample, followed by 13 as
a colourless residue (0.007 g, 13%); 1H NMR (400 MHz, CDCl3)
δ 7.17–7.46 (10H, m), 3.85 (2H, d, J = 13.7 Hz), 3.42 (2H, d, J =
13.7 Hz), 2.61 (1H, app d, J = 10.6 Hz, CH), 1.84, (2H, app d, J =
8.8 Hz), 1.50–1.72 (4H, m), 1.36–1.47 (2H, m), 1.27 (3H, s);
HRMS calc. for C21H28ON 310.2165 (M+ + 1), found 310.2166.
trans-2-(Dibenzylamino)-1-(trifluoromethyl)cyclohexan-1-ol 19
and cis-2-(dibenzylamino)-1-(trifluoromethyl)cyclohexan-1-ol 20
127.3 (CH), 69.2 (CH), 64.3 (CH), 53.7 (CH2), 33.3 (CH2), 25.6 Compounds 19 and 20 were prepared using General Procedure
(CH2), 24.2 (CH2), 22.2 (CH2); HRMS calc. for C20H26ON 2 in which 4 M HCl was added after 3 h, using 28 (0.234 g,
296.2009 (M+ + 1), found 296.2010.
0.80 mmol), trifluoromethyltrimethylsilane (0.14 mL,
0.95 mmol), anhydrous THF (10 mL) and a solution of TBAF
(5 mg) in THF (1.0 mL) to give the crude products, which were
2-(Dibenzylamino)cyclohexan-1-one 28
Compound 28 was prepared using General Procedure 1 from purified by column chromatography on silica (5 : 1, followed by
trans-2-(dibenzylamino)cyclohexan-1-ol (1.20 g, 4.1 mmol), 5 : 2 petroleum ether : ethyl acetate) to give 19 as a colourless
oxalyl chloride (0.48 mL, 5.6 mmol), DMSO (1.00 mL, solid (0.167 g, 58%); 1H NMR (400 MHz, CDCl3) δ 7.26–7.44
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(10H, m), 3.69–4.15 (2H, br s), 3.63 (1H, s), 3.36 (2H, d, J = J = 12.2, 3.4 Hz), 1.80–1.95 (2H, m), 1.36–1.67 (4H, m),
13.3 Hz), 2.78–2.89 (1H, m), 2.21–2.31 (1H, m), 1.91–2.01 (2H, 1.15–1.30 (5H, m), 0.98 (1H, br s); 13C NMR (100 MHz, CDCl3)
m), 1.75–1.91 (1H, m), 1.28–1.69 (3H, m), 1.19 (1H, dddd, J = δ 141.1 (quat C), 128.6 (CH), 128.3 (CH), 126.7 (CH), 71.0
16.4, 9.4, 4.6, 2.3 Hz); 13C NMR (100 MHz, CDCl3) δ 139.4 (quat (quat C), 54.0 (CH2), 53.7 (CH), 41.1 (CH2), 38.7 (CH2), 32.1
C), 129.2 (CH), 128.7 (CH), 127.6 (CH), 127.2 (quat C, q, J = (CH3), 27.7 (CH2), 20.7 (CH2); HRMS calc. for C21H28ON
293.0 Hz), 72.3 (quat C, q, J = 20.1 Hz), 66.3 (CH), 55.9 310.2165 (M+ + 1), found 310.2164; crystallised from cold
(CH2, br), 34.1 (CH2), 26.0 (CH2), 21.5 (CH2), 21.4 (CH2); MeOH. Followed by 12 as a colourless oil that solidified on
1
19F{1H} NMR (376 MHz, CDCl3) δ −69.4; HRMS calc. for standing (0.04 g, 9%); H NMR (400 MHz, CDCl3) δ 7.27–7.39
C21H25ONF3 364.1883 (M+ + 1), found 364.1878; crystallised (8H, m), 7.22 (2H, t, J = 7.0 Hz), 3.71 (2H, d, J = 14.0 Hz), 3.65
from cold MeOH. Followed by 20 as a colourless solid (0.037 g, (2H, d, J = 14.0 Hz), 2.74 (1H, app tt, J = 9.4, 3.4 Hz), 1.64–1.85
13%); 1H NMR (400 MHz, CDCl3) δ 7.38–7.46 (4H, m), 7.35 (4H, m), 1.39–1.62 (3H, m), 1.17–1.30 (1H, m), 1.12 (3H, s,
(4H, app t, J = 7.2 Hz), 7.28 (2H, t, J = 7.2 Hz), 3.66–4.38 (2H, br CH3); 13C NMR (100 MHz, CDCl3) δ 140.0 (quat C), 128.9 (CH),
s), 3.52 (2H, d, J = 13.8 Hz), 3.00 (1H, dd, J = 10.1, 4.4 Hz), 128.3 (CH), 126.9 (CH), 71.6 (quat C), 55.3 (CH), 53.6 (CH2),
2.31–2.58 (1H, m), 1.72–1.94 (4H, m), 1.47–1.64 (3H, m), 41.1 (CH2), 40.4 (CH2), 28.6 (CH2), 27.4 (CH3), 21.0 (CH2);
1.16–1.40 (1H, m); 13C NMR (100 MHz, CDCl3) δ 139.7 HRMS calc. for C21H28ON 310.2165 (M+ + 1), found 310.2160.
(quat C), 129.2 (CH), 128.4 (CH), 127.1 (CH), 126.4 (quat C, q,
trans-3-(Dibenzylamino)-1-(trifluoromethyl)cyclohexan-1-ol 17
J = 293.0 Hz), 76.3 (quat C, q, J = 20.2 Hz), 58.6 (CH), 55.5
and cis-3-(dibenzylamino)-1-(trifluoromethyl)cyclohexan-1-ol 18
(CH2, br), 32.8 (CH2), 25.2 (CH2), 20.8 (CH2), 20.5 (CH2);
19F{1H} NMR (376 MHz, CDCl3) δ −78.2; HRMS calc. for
Compounds 17 and 18 were prepared following General
C21H25ONF3 364.1883 (M+ + 1), found 364.1883.
Procedure 3 quenching with 4 M HCl after 2.5 h, from 30
(1.40 g, 4.75 mmol), trifluoromethyltrimethylsilane (0.77 mL,
5.21 mmol), anhydrous THF (20 mL) and a solution of TBAF
(5 mg) in THF (1.0 mL) to give the crude products, which were
3-(Dibenzylamino)cyclohexan-1-one 30
Following the procedure reported by Banik and Srivastava,28
purified by column chromatography on silica (3 : 1 petroleum
ether : ethyl acetate) to give 17 as a colourless solid (0.64 g,
37%); 1H NMR (400 MHz, CDCl3) δ 7.36 (4H, d, J = 7.3 Hz),
7.30 (4H, app t, J = 7.4 Hz), 7.22 (2H, t, J = 7.4 Hz), 3.62 (4H, br
s), 1.89–2.03 (1H, m), 1.89–2.02 (2H, m), 1.42–1.79 (6H, m),
1.27–1.41 (1H, m); 13C NMR (100 MHz, CDCl3) δ 140.5
(quat C), 128.6 (CH), 128.4 (CH), 126.9 (CH), 126.1 (quat C, q,
J = 283 Hz), 74.5 (quat C, q, J = 30.3 Hz), 53.9 (CH2), 52.3 (CH),
32.1 (CH2), 29.7 (CH2), 27.4 (CH2), 19.7 (CH2); 19F{1H} NMR
(376 MHz, CDCl3) δ −84.8; HRMS calc. for C21H25ONF3
364.1883 (M+ + 1), found 364.1885. Followed by 18 as a colour-
less solid (0.70 g, 41%); 1H NMR (400 MHz, CDCl3) δ 7.39–7.48
(1H, br s), 7.29–7.36 (4H, m), 7.22–7.29 (6H, m), 3.81 (2H, d,
J = 14.3 Hz), 3.76 (2H, d, J = 14.3 Hz), 3.19 (1H, app pent, J =
3.2 Hz), 2.48 (1H, app d, J = 14.1 Hz), 2.03–2.17 (1H, app d, J =
14.3 Hz), 1.83–1.95 (1H, app d, J = 11.6 Hz), 1.44–1.82 (5H, m);
1H NMR (400 MHz, CD3OD) δ 7.25–7.34 (8H, m), 7.17–7.23
(2H, m), 3.68 (2H, d, J = 13.8 Hz), 3.61 (2H, d, J = 13.8 Hz), 2.91
(1H, app tt, J = 10.8, 3.6 Hz), 2.18–2.28 (1H, m), 1.95–2.05 (1H,
m), 1.75–1.84 (1H, m), 1.62–1.74 (2H, m), 1.26–1.60 (3H, m);
13C NMR (100 MHz, CDCl3) δ 137.3 (quat C), 129.5 (CH), 128.7
(CH), 127.6 (CH), 126.0 (quat C, q, J = 284 Hz), 73.8 (quat C, q,
J = 28.7 Hz), 54.9 (CH), 53.2 (CH2), 31.2 (CH2), 30.2 (CH2), 28.3
(CH2), 16.4 (CH2); 19F{1H} NMR (376 MHz, CDCl3) δ −84.4;
HRMS calc. for C21H25ONF3 364.1883 (M+ + 1), found 364.1885.
bismuth(III) nitrate pentahydrate (10.0 g, 21 mmol) was added
to a solution of cyclohexen-1-one (10 mL, 103 mmol) and
dibenzylamine (20 mL, 104 mmol) in dichloromethane (80 mL).
Most of the dichloromethane was removed under reduced
pressure, and the resulting slurry stirred at room temperature
overnight. Dichloromethane (100 mL) was added and the result-
ing suspension filtered by gravity filtration through filter paper.
The filtrate was washed with sat. NaHCO3 (2 × 30 mL) and brine
(2 × 30 mL), dried over MgSO4, filtered once again and the
dichloromethane removed under reduced pressure (taking care
not to heat above 40 °C) to give the crude product. Purification
was achieved by twice recrystallising from warm petroleum
ether to give 30 as colourless crystals (9.7 g, 32%); 1H NMR
(400 MHz, CDCl3) δ 7.36 (4H, d, J = 7.0 Hz), 7.27–7.33 (4H, m),
7.20–7.25 (2H, m), 3.72 (2H, d, J = 14.0 Hz), 3.62 (2H, d, J =
14.0 Hz), 2.95 (1H, app tt, J = 12.2, 3.7 Hz), 2.61–2.69 (1H, m),
2.39–2.49 (1H, m), 2.27–2.36 (1H, m), 2.15–2.27 (1H, m),
1.95–2.13 (2H, m), 1.65–1.78 (1H, m), 1.61–1.69 (1H, br s),
1.33–1.48 (1H, m); 13C NMR (100 MHz, CDCl3) δ 210.8 (quat C),
140.0 (quat C), 128.5 (CH), 128.4 (CH), 127.1 (CH), 58.2 (CH),
53.8 (CH2), 44.3 (CH2), 41.3 (CH2), 27.9 (CH2), 22.6 (CH2);
HRMS calc. for C20H24ON 294.1852 (M+ + 1), found 294.1855.
trans-3-(Dibenzylamino)-1-methylcyclohexan-1-ol 11 and
cis-3-(dibenzylamino)-1-methylcyclohexan-1-ol 12
Compounds 11 and 12 were prepared following General Proce-
dure 2 at a reduced temperature of 0 °C, using 30 (0.40 g,
cis-3-Amino-1-(trifluoromethyl)cyclohexan-1-ol 31
1.36 mmol), anhydrous THF (15 mL) and 3.0 M MeMgCl in Pearlman’s catalyst (10% palladium hydroxide on carbon,
THF (0.73 mL, 2.18 mmol), and the products purified by 0.49 g, 5.38 mmol) and 18 (1.96 g, 0.538 mmol) were added to
column chromatography on silica (6 : 1 petroleum ether : ethyl a Schlenk flask which was evacuated and back-filled with N2.
1
acetate) to give 11 as a colourless solid (0.34 g, 80%); H NMR Ethanol (20 mL) was added and the flask evacuated using a
(400 MHz, CDCl3) δ 7.36 (4H, d, J = 7.4 Hz), 7.28 (4H, app t, J = diaphragm pump and back-filled with H2 from a balloon three
7.4 Hz), 7.19 (2H, t, J = 7.4 Hz), 3.63 (3H, s), 2.92 (1H, app tt, times. The reaction mixture was left to stir vigorously until
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consumption of starting material was apparent by TLC analysis the mixture was stirred for an additional 30 minutes at room
(2 days at room temperature). Ethyl acetate (20 mL) was added, temperature, after which the volatiles were removed under
and the mixture passed through a short Celite plug using reduced pressure to give the aqueous residue. The aqueous
additional ethyl acetate. The filtrate was concentrated under residue was adjusted to pH 10 using 2 M NaOH (aq), and
reduced pressure to give 31 as a light yellow oil, which crystal- extracted with ethyl acetate (3 × 20 mL). The combined organic
1
lised upon standing (0.93 g, 93%); H NMR (400 MHz, CDCl3) extracts were washed with brine (20 mL), dried over MgSO4, fil-
δ 3.35–3.30 (1H, m), 1.86–1.96 (2H, m), 1.79–1.82 (2H, m,), tered and concentrated under reduced pressure to give the
1.74–1.78 (1H, m), 1.64–1.74 (2H, m), 1.54–1.63 (1H, m); crude product, which was purified by column chromatography
13C NMR (100 MHz, CDCl3) δ 127.5 (quat C, q, J = 283.0 Hz), on silica (3 : 1 dichloromethane : methanol) to give 33 as a
74.0 (quat C, q, J = 30.3 Hz), 46.8 (CH), 35.3 (CH2), 32.9 (CH2), light yellow oil (0.68 g, 76%); 1H NMR (400 MHz, CDCl3) δ 7.10
31.2 (CH2), 16.5 (CH2); 19F{1H} NMR (376 MHz, CDCl3) (2H, d, J = 8.8 Hz), 6.83 (2H, d, J = 8.8 Hz), 3.78 (3H, s), 3.65
δ −85.2; HRMS calc. for C7H13ONF3 184.0944 (M+ + 1), found (1H, app t, J = 6.4 Hz), 3.14 (1H, app pent, J = 3.0 Hz), 2.46–2.77
184.0941.
(4H, m), 1.67–2.03 (7H, m), 1.43–1.65 (4H, m); 13C NMR
(100 MHz, CDCl3) δ 158.0 (quat C), 133.7 (quat C), 129.4 (CH),
125.8 (quat C, q, J = 281 Hz), 114.0 (CH), 73.4 (quat C, q, J =
30 Hz), 55.4 (CH3), 53.0 (CH), 47.0 (CH2), 34.5 (CH2),
N-cis-3-Hydroxy-3-(trifluoromethyl)cyclohexyl)-3-(4-methoxy-
phenyl)propanamide 32
3-(4-Methoxyphenyl)propionic acid (0.79 g, 4.38 mmol) was 32.6 (CH2), 31.8 (CH2), 31.3 (CH2), 30.6 (CH2), 15.3 (CH2);
refluxed in thionyl chloride (0.58 mL, 8.0 mmol) under an 19F{1H} NMR (376 MHz, CDCl3) δ −85.2; HRMS calc. for
atmosphere of N2 for 2 h. Excess thionyl chloride was removed C17H25O2NF3 332.1832 (M+ + 1), found 332.1836.
under reduced pressure to give the crude acid chloride, which
was used without further purification. In a separate flask, a
solution of 31 (0.73 g, 3.99 mmol) and triethylamine (0.61 mL,
4.38 mmol) in anhydrous diethyl ether (20 mL) under a N2
Acknowledgements
atmosphere was cooled to 0 °C. A solution of the freshly pre-
We thank the EPSRC for financial support and the Mass
pared acid chloride in anhydrous ether (2 mL) was added
Spectrometry Service, Swansea, for high-resolution spectra.
drop-wise with vigorous stirring of the reaction mixture. Upon
completion of addition, the cooling bath was removed and the
mixture left to stir overnight at room temperature. The reaction
mixture was poured into a separating funnel containing water
(20 mL), and was extracted with ethyl acetate (3 × 15 mL).
Notes and references
The combined organic extract was washed with 1 M HCl
(2 × 20 mL), water (20 mL), dried over MgSO4, filtered and con-
centrated under reduced pressure to give the crude product,
which was purified by column chromatography on silica
(1 : 9 methanol : ethyl acetate) to give 32 as a yellow oil (0.96 g,
69%); 1H NMR (400 MHz, CDCl3) δ 7.10 (2H, d, J = 8.6 Hz),
6.81 (2H, d, J = 8.6 Hz), 6.77 (1H, br d, J = 8.2 Hz), 4.28–4.36
(1H, m), 3.76 (3H, s), 2.88 (2H, t, J = 7.4 Hz), 2.40 (2H, t, J =
7.4 Hz), 1.67–1.83 (4H, m), 1.48–1.64 (3H, m), 1.32–1.42 (1H,
m); 13C NMR (100 MHz, CDCl3) δ 171.3 (quat C), 158.3
(quat C), 132.9 (quat C), 129.5 (CH), 125.8 (quat C, q, J =
289 Hz), 114.1 (CH), 73.6 (quat C, q, J = 28 Hz), 55.4 (CH3),
42.9 (CH), 39.3 (CH2), 32.3 (CH2), 31.2 (CH2), 29.8 (CH2),
29.3 (CH2), 15.1 (CH2); 19F{1H} NMR (376 MHz, CDCl3)
δ −85.1; HRMS calc. for C17H23O3NF3 346.1625 (M+ + 1), found
346.1626.
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