Multicomponent reactions of methyl substituted all-cis tetrafluorocyclohexane aldehydes

Article abstract of DOI:10.1039/c5ob02334c

This paper reports the preparation of methyl substituted all-cis tetrafluorocyclohexanes prepared from a Birch reduction of benzoic acid, worked up with a methyl iodide quench. The resultant methylcyclohexadiene carboxylic acid was reduced to the alcohol,

Full text of DOI:10.1039/c5ob02334c

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DOI: 10.1039/C5OB02334C
Multicomponent reactions of methyl substituted all-cis
tetrafluorocyclohexane aldehydes
Tetiana Bykova, Nawaf AlꢀMaharik, Alexandra M. Z. Slawin, David O’Hagan*
School of Chemistry, University of St Andrews, North Haugh, St Andrews, KY16
9ST, UK.
ABSTRACT
This paper reports the preparation of methyl substituted allꢀcis
tetrafluorocyclohexanes prepared from a Birch reduction of benzoic acid, worked up
with a methyl iodide quench. The resultant methylcyclohexadiene carboxylic acid was
reduced to the alcohol and protected. The cyclohexadienyl ring was then epoxidised
and the CꢀO bonds sequentially converted through deoxyfluorination reactions to two
sets of isomers of allꢀcis tetrafluorocyclohexane isomers. Deprotection of the benzylic
ether and then oxidation gave aldehydes which were then used in Ugi and Passerini
multicomponent reactions, allowing this facially polarised cyclohexane to be
incorporated into peptidic structural motifs.
1. Introduction
We have recently described the synthesis and properties of the allꢀcis 2,3,5,6ꢀ
tetrafluorocyclohexane 1 ring system1. The stereochemistry is such that in the chair
conformation the four fluorine atoms are all on one face of the cyclohexane ring. Also
two of the CꢀF bonds are 1,3ꢀdiaxial and align parallel to each other and this results in
an orientated polarity, which is supplemented by the two equatorial CꢀF bonds which
are also on the upper face of the cyclohexane ring. The outcome is a large molecular
dipole moment of 5.2 Dy for 11. The motif is polar hydrophobic and an interesting
and unusual aspect of the cyclohexane ring system is that it has facial polarity,
therefore it becomes attractive to access building blocks which might be used to
introduce the motif into drug discovery and agrochemical research programmes.
Derivatives of the ring system are relatively challenging to prepare, however recently
we reported the preparation of phenyl derivative 2 and then access to a variety of aryl
derivatives by standard electrophilic aromatic substitution reactions of 22-4.
1

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Figure 1: Allꢀcisꢀtetrafluorocyclohexane 1 is facially polarised (ꢁ = 5.2 D), with a more
negative fluorine face and a more positive hydrogen face.1
In order to build further diversify around this structural motif, cyclohexane carboxylic
acid derivatives of this motif are reported. Reduction to aldehydes and utility of the
aldehydes in multicomponent reactions has allowed a library of peptidic analogues to
be prepared5,6.
2. Results and discussion
At the outset a direct oxidation of phenyl derivative 2 was explored. The
corresponding carboxylic acid 3 was the anticipated product, however it proved
difficult to characterize in our hands as it is very vulnerable to hydrogen fluoride
elimination to products related to 4, due to the relatively acidic hydrogen atom, alpha
to the carboxylic acid derivative.
Scheme 1 Carboxylic acid 3 is unstable to dehydrofluorination
In order to circumvent this problem it became an objective to replace the alpha
hydrogen with a methyl group and generate a more stable motif. Following a
literature procedure, the Birch reduction of benzoic acid 5 followed by in situ
methylation afforded αꢀmethylated carboxylic diene 6, which was then reduced with
LiAlH4 to give alcohol 7 in good yield7. Protection of the primary alcohol 7 with
2

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benzyl bromide furnished ether 8 (80% yield), which was then epoxidised using an
excess of mCPBA8,9. Three diastereoisomers of the diepoxide were generated, cis (9a
and 9b) and trans (9c) in 6:4:1 ratio.
Scheme 1: Synthesis of diepoxides 9a, b, c from benzoic acid 5.
The trans-diepoxide stereoisomer 9c was separated (7%) from the inseparable cis-
diepoxides 9a and 9b (70%). The configuration of the epoxides was determined by 1H
NMR spectroscopy. The cis-diepoxides (9a and 9b) could be differentiated from the
trans through the methylene hydrogen atoms Hꢀ4a and Hꢀ4b. For the transꢀ
diastereoisomer, both hydrogens are in similar environments and appear as unresolved
signals (δ 2.30 ppm), whereas for the cis-diepoxides (9a and 9b), these hydrogens are
nonꢀequivalent and resolve into a pair of multiplets (δ 2.77 ppm and δ 2.24 ppm).
3

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Scheme 3: Ring opening fluorination of diepoxides 9a and 9b and then activation to
ditriflates 11a and 11b.
Treatment of the diepoxide mixture 9a and 9b with Et3N.3HF at 140 °C, resulted in
their full conversion to difluoro diols 10a and 10b as determined by NMR (Scheme
3). This mixture was then reacted with triflic anhydride which resulted in the
diastereoisomeric triflates 11a and 11b. These products could be separated by
chromatography and were recovered in yields of 30% (11a) and 28% (11b)
respectively (Scheme 3).
Diastereoisomer 11a was treated with Et3N.3HF at 110 °C for a prolonged period
which generated tetrafluorocyclohexane 12a. OꢀDebenzylation (10% Pd/C/H2)
generated alcohol 13a as illustrated in Scheme 410.
4

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12a
13a
Scheme 4: Preparation of aldehyde 14a from diꢀtriflate 11a and showing the Xꢀray structures
of 12a and 13a.
The structures and stereochemistry of products 12a and 13a were confirmed by Xꢀray
crystallography and are shown in Scheme 4. An analogous procedure was carried out
on diastereoisomer 11b, to generate aldehyde diastereoisomer 14b. Again the Xꢀray
structures of benzyl ether 12b and deprotected alcohol 13b were obtained to confirm
stereochemistry and they are shown in Scheme 5. Finally oxidation of alcohols 13a
and 13b using IBX in DMSO, gave aldehydes 14a (90%) and 14b (68%)
respectively.11,12
5

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Scheme 5: Preparation of aldehyde 14b from ditriflate 11b and showing the Xꢀray structures
of 12b and 13b.
The application of aldehydes 14a and 14b in Ugi fourꢀcomponent reactions was
explored.13 In the first instance imines 15 were formed from the condensation of
tetrafluoro aldehydes 14a/14b with a candidate amines A1/A2, and then individual
isocyanides B and carboxylic acids C were added as illustrated in Scheme 6.
Scheme 6: General Ugi procedure involving aldehydes 14a and 14b and a range of amines
(A1-2), isocyanides (B1-2) and carboxylic acids (C1-3).
6

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A series of reactions were conducted to generate a small chemical library of
peptidomimetics 16ꢀ32 carrying the tetrafluorocyclohexyl ring motif. These
compounds are all racemic as a new stereogenic centre is generated.
F
F
F
F
F
O
F
F
O
F
O
N
O
N
HN
HN
16
25
F
F
F
F
F
O
F
F
O
F
O
O
N
N
HN
HN
17
26
F
F
F
F
F
F
O
O
F
O
F
N
HN
O
O
HN
32
20
OMe
Figure 2: Xꢀray structures of a selected αꢀaminoacyl amides 16, 17, 25, 26, 32 which derive
from reaction entries 1,2,8,9 and 14 in Table 1, and of the Passerini byꢀproduct 20 from
reaction entry 3 of Table 1.
While some products were obtained by classic four component Ugi reactions, others
derive from the Passerini reaction (Table 1 and 2), through direct reaction of the free
aldehyde 14 rather than the preformed imine 15, with the added isocyanides B and
carboxylic acids C.13ꢀ17 In most cases the four component reactions were found to
produce both, the αꢀaminoacyl amide Ugi derivatives and αꢀhydroxy carboxamide
Passerini type products. The crystal structures of several Ugi products 16-17, 25-26,
32 and a Passerini αꢀacyloxy amide 20 are shown of Figure 2. In each case
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compensating enantiomers of these racemic products are obvious in the unit cell of
each crystal structure. The 19F{1H}ꢀNMR spectra of these compounds merit some
comment. For example the 19F{1H}ꢀNMR spectra of aldehydes 4a and 4b have two
sets of equivalent fluorines, which show clear AA’XX’ second order spectra, however
for the multicomponent products the four fluorines all become chemically nonꢀ
equivalent, and they all resolve to varying extents.
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Entry R1CNH2 R2CN R3COOH Conditions
Ugi
(yield)
Passerini
(yield)
Ratio
(1: 2)
(time, temp,
solvent)
-
1
2
A1
A1
B1
B1
C1
C2
40 h, 30°C, DCM
N/A
16 (58%)
40 h, 25°C, DCM
2:1
17 (25%)
18 (20%)
3
4
A1
A1
B2
B2
C1
C2
40 h, 25°C, DCM
-
N/A
19 (82%)
40 h, 25°C, DCM
-
N/A
20 (79%)
5
6
A1
A2
B1
B1
C3
C1
40 h, 25°C, DCM
40 h, 25°C, DCM
1:2.5
4:5
21 (22%)
23 (25%)
23 (53%)
22 (30%)
24 (37%)
7
A2
B1
C1
40 h, 25°C, MeOH
N/A
Table 1: Compounds produced using aldehyde 10a in Uꢀ4CC reactions
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Entry R1CNH2 R2CN R3COOH Conditions
Product 1
(yield)
By-product
(yield)
Ratio
(1: 2)
(time, temp,
solvent)
40 h, 30 °C, DCM
8
A1
B1
C1
N/A
ꢀ
25 (72%)
9
A1
A1
B1
B2
C2
C1
40 h, 25 °C, DCM
N/A
ꢀ
26 (80%)
10
40 h, 25 °C, DCM
1:2
27 (26%)
28 (41%)
11
A1
B2
C2
40 h, 25 °C, DCM
1:2
29 (18%)
30 (25%)
12
13
A1
A2
B1
B1
C3
C1
40 h, 25 °C, DCM
N/A
ꢀ
31 (46%)
40 h, 25 °C, DCM
1:8
32
33 (43%)
14
A2
B1
C1
40 h, 25 °C, MeOH
N/A
ꢀ
32 (46%)
Table 2: Compounds produced using aldehyde 10b in Uꢀ4CC reactions
10

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3. Conclusion
In summary we report the synthesis of aldehyde diastereoisomers 14a and 14b,
containing the all-syn 1,2,4,5ꢀtetrafluorocyclohexane motif. These aldehydes are
rendered stable to dehydrofluorination by having a blocking alpha methyl group.
Aldehydes 14a and 14b were used as key components for Ugi four component
reactions and in the event both αꢀaminoacyl amide and αꢀhydroxy carboxamide
derivatives were generated. This approach allows the facially polarized allꢀcis
tetrafluorocyclohexane motif to be introduced into peptidomimetic scaffolds for
exploration in bioactivity screening programmes.
Acknowledgements
We thank EPSRC for supporting this work and DO’H is grateful for a Royal Society
Wolfson Research Merit Award. We also thank the EPSRC Mass Spectrometry
Service at Swansea for analyses.
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