Last of the gem-Difluorocycloalkanes 2: Synthesis of Fluorinated Cycloheptane Building Blocks

Article abstract of DOI:10.1002/ejoc.202001530

The gem-difluorocycloalkane family was extended to all possible regioisomers of the gem-difluorocycloheptane, monofunctionalized by carboxilic-, amino- or keto- group, that were synthesized on a multigram scale. The preparation of the corresponding building blocks was achieved from readily accessible starting materials either via six-membered ring homologation or deoxofluorination of the appropriate seven-membered cyclic ketones.

Full text of DOI:10.1002/ejoc.202001530

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Last of the gem-Difluorocycloalkanes 2: Synthesis of
Fluorinated Cycloheptane Building Blocks
Maksym Herasymchuk,[a, b] Kostiantyn P. Melnykov,[a, b] Dmytro V. Yarmoliuk,[a]
Dmytro Serhiichuk,[a] Valeriia Rotar,[a, c] Timur Pukhovoi,[a, c] Yuliya O. Kuchkovska,[a, b]
Sergey Holovach,[a, d] Dmitriy M. Volochnyuk,[a, b, d] Sergey V. Ryabukhin,*[a, b] and
Oleksandr O. Grygorenko[a, b]
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The gem-difluorocycloalkane family was extended to all possible
regioisomers of the gem-difluorocycloheptane, monofunctional-
ized by carboxilic-, amino- or keto- group, that were synthesized
on a multigram scale. The preparation of the corresponding
building blocks was achieved from readily accessible starting
materials either via six-membered ring homologation or
deoxofluorination of the appropriate seven-membered cyclic
ketones.
Introduction
conformational flexibility of cycloalkane scaffolds can be used
to fix the spatial orientation of the dipole moments of both
fluorinated fragments and additional functional groups. For
example, O’Hagan and colleagues implemented this approach
into the design of facially-polarized ‘Janus face’ all-cis trifluor-
Fluorinated substituents have found a broad application in
medicinal chemistry[1–5] and chemical biology,[6,7] and have
become outstanding isosteric replacements for diverse func-
tional groups.[8,9] Introduction of fluorine atoms is commonly
used for the modulation of physicochemical and pharmacoki-
netic properties, potency, and selectivity. A prominent feature
of such optimization is the possibility to control the degree of
various properties alteration by rational selection of the
fluorinated fragment along with position the most suitable to
introduce it.[10–13] Therefore, the design and synthesis of new
fine-tuned fluorinated motifs have become a promising topic
with a great potential for application in other research fields.[14]
Mono-, di- and polyfluoro-substituted cycloalkanes are
among the most attractive types of fluorinated compounds
which have gained increased attention recently. The decreased
ocyclopropanes 1,[15] tetrafluorocyclohexanes
2 (and their
penta- and hexa-fluorinated analogs),[16–19] as well as tetrafluor-
ocyclohexane derivatives 3[20] containing two gem-
difluoromethylene moieties (Figure 1A).
Gem-difluorocyclohexane and gem-difluorocyclobutane mo-
tifs present in marketed drugs maraviroc[21] and ivosidenib[22]
(approved in 2007 and 2018, respectively, Figure 1B) are the
representative compounds with the fluorinated cycloalkane
substituents that have already found successful application in
medicinal chemistry.
[a] M. Herasymchuk, Dr. K. P. Melnykov, D. V. Yarmoliuk, D. Serhiichuk,
V. Rotar, T. Pukhovoi, Y. O. Kuchkovska, S. Holovach,
Prof. Dr. D. M. Volochnyuk, Prof. Dr. S. V. Ryabukhin, Dr. O. O. Grygorenko
Enamine Ltd.
Chervonotkatska Street 78
Kyiv 020941, Ukraine
E-mail: s.v.ryabukhin@gmail.com
www.enamine.net
[b] M. Herasymchuk, Dr. K. P. Melnykov, Y. O. Kuchkovska,
Prof. Dr. D. M. Volochnyuk, Prof. Dr. S. V. Ryabukhin, Dr. O. O. Grygorenko
Taras Shevchenko National University of Kyiv
Volodymyrska Street 60
Kyiv 01601, Ukraine
[c] V. Rotar, T. Pukhovoi
National Technical University of Ukraine ‘Igor Sikorsky Kyiv Polytechnic
Institute’
Prospect Peremogy 37
Kyiv 03056, Ukraine
[d] S. Holovach, Prof. Dr. D. M. Volochnyuk
Institute of Organic Chemistry,
National Academy of Sciences of Ukraine
Chervonotkatska Street 78
Kyiv 02094, Ukraine
Figure 1. Face-polarized trifluorocyclopropanes and tetrafluorocyclohexanes
reported by O’Hagan et al. (A); marketed drugs containing gem-difluorocy-
clohexane and gem-difluorocyclobutane motifs (B)
Supporting information for this article is available on the WWW under
https://doi.org/10.1002/ejoc.202001530
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All the aforementioned works motivated us to develop
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convenient synthetic routes to all isomeric gem-difluorocyclo-
alkanes which can be used to access multigram quantities of
the corresponding building blocks. To date, we have reported
the preparation of three-to-six-membered fluorinated alicyclic
compounds.[23–28] Yet, a Reaxys database search[29] has revealed
that the synthesis and application of higher homologs – gem-
difluorinated cycloheptane derivatives – remain to be scarcely
explored both in papers[30–32] and patents (Figure 2A). Mean-
while, it should be stressed that the aforementioned cyclo-
heptane building blocks are not just other representatives of
the gem-difluorocycloalkane homologous series. Recently, we
have shown that seven-membered rings provide a unique
three-dimensional disposition of the functional groups attached
that cannot easily be achieved by lower homologs.[33] Therefore,
gem-difluorinated cycloheptanes can be considered as promis-
ing building blocks for drug discovery that substantially extend
possible relative orientations of the corresponding functional
moieties present in their molecules.
In this work, we describe the straightforward and efficient
synthesis of gem-difluorocycloheptanes monofunctionalized by
carboxilic-, amino- or keto- group in α-, β- or γ- position on a
multigram scale (Figure 2B). In particular, we have focused on
the preparation of the corresponding carboxylic acids 4, 7, 10,
amine derivatives 5, 8, 11, and ketones 6, 9, 12 due to the
versatile utility of these functional groups in medicinal
chemistry. Noteworthy (and somewhat unexpectedly), the
previous methodologies for the synthesis of the corresponding
five- and six-membered counterparts appeared not to be
applicable for the preparation of building blocks 4–12; there-
fore, the development of different synthetic pathways was
required for these compounds.
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Figure 2. (A) Reaxys® database search of papers/patents referencing mono-
substituted gem-difluorocycloalkanes; (B) structures of gem-difluorocyclo-
heptane building blocks obtained in this work.
Prof. Dr. Sergey V. Ryabukhin is a Professor at
the Institute of High Technologies, Kyiv Na-
tional Taras Shevchenko University. He was
awarded his Ph.D. by Kyiv National University
in 2008 and obtained Dr. Sci. in 2018. He has
10+ years’ experience in managing combina-
torial chemistry departments as well as chem-
ical outsourcing projects having previously
worked in contract research organizations
(2005–2010: Director of Combinatorial
Chemistry department at Enamine Ltd., 2010–
2014: Vice-President at CurplyxÀ Macrochem,
2014–2017: CRO Curpys Chemicals). Now he is
also working at Enamine Ltd. as a senior
scientific advisor. Dr. Ryabukhin is an expert in
combinatorial and medicinal chemistry, orga-
nometallics, heterocyclic chemistry, new
methodologies in organic synthesis. He has a
strong collaboration with numerous synthetic
scientific groups at both Enamine Ltd and
Kyiv National Taras Shevchenko University.
This paper is a result of such collaboration
with his perennial friend, colleague, and co-
author Prof. Dr. Dmitriy M. Volochnyuk, the
scientific group of Dr. Kostiantyn P. Melnykov,
who was obtained his Ph.D. degree in 2019
under his supervision, and the team of young
perspective postgraduate Dmytro V. Yarmo-
liuk. All these researchers focus their interests
in particular on fluorine chemistry and fluorine
contained building blocks.
On the photo (from left to right): Prof. Dr.
Dmitriy M. Volochnyuk, Maksym Herasymchuk,
Dmytro V. Yarmoliuk, Dr. Kostiantyn P. Melny-
kov, and Prof. Dr. Sergey V. Ryabukhin.
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Results and Discussion
boration–oxidation of 18 gave alcohol 19 (64% yield from 6)
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that was further oxidized to carboxylic acid 4 with high (97%)
yield using RuCl3À NaIO4 system.
Our initial attempts to access 2,2-difluorocycloheptanecarbox-
ylic acid 4 were based on deoxofluorination of the cyclo-
heptanone moiety of ketoester 13 (Scheme 1A). However, no
reaction took place when 13 was treated with Et2NSF3 (DAST).
In our previous report on the deoxofluorination of β-keto
esters, it was also shown that 13 reacted unselectively upon
treatment with SF4 and gave target derivative 14 with low
conversion.[34] These results motivated us to examine an
alternative approach – homologation of the corresponding
six-membered ring derivatives.
Synthesis of 3,3-difluorocycloheptanecarboxylic acid
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commenced from testing the possibility of scaling up the
procedure that was previously reported by Dowd and Choi
(Scheme 2A).[39,40] According to their work, a milligram amount
of ester 20 was obtained by alkylation of β-keto ester 21
followed by AIBN-promoted radical rearrangement of 22. It
was shown that this transformation proceeded with the
formation of 20 (73% yield) in a mixture with a trace amount
of 23 under high dilution conditions (1 mM solution of n-
Bu3SnH) or upon prolonged addition of n-Bu3SnH using a
syringe pump (10 mM solution). However, all our attempts to
decrease the dilution level and adjust the reported procedure
for the synthesis of 20 on the multigram scale were
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A facile transformation of cyclohexanone (15) into 2,2-
difluoro-substituted cycloheptanone 6 (Scheme 1B) was pre-
viously described by Amii and colleagues.[35] In their work,
BrCF2CO2Na was used as the difluorocarbene source that was
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added to silyl enol ether 16 at 150 C to give siloxydifluor-
ocyclopropane intermediate 17. In contrast to Amii’s report,
herein we suggested the application of the TMSCF3À NaI
system for the formation of difluorocarbene under milder
conditions.[26,27,36–38] With this system, up to 150 g of 6 could be
obtained in one load (60% yield from 15). Next reductive
amination of 6 followed by treatment with 4 M HCl in dioxane
allowed access to the target amine derivative 5 in 45% yield.
Furthermore, 2,2-difluorocycloheptanone (6) was also used as
a synthetic intermediate for the preparation of carboxylic acid
4. In this case, Wittig olefination of 6 followed by hydro-
Scheme 2. (A) Unsuccessful attempts of preparation of 20 by AIBN-promoted
radical rearrangement of 22; (B) synthesis of gem-difluorocycloheptane
derivatives 7, 8, (C), and 9.
Scheme 1. (A) Unsuccessful attempts of deoxofluorination of β-keto ester 13;
(B) synthesis of gem-difluorocycloheptane derivatives 4–6.
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unsuccessful and led to the predominant formation of 23.
(31) with ethyl diazoacetate followed by acidic hydrolysis and
decarboxylation of 33 was used for the preparation of 4,4-
difluorocycloheptanone (12) (67% over two steps). The next
reductive amination of 12 along with protonation in 4 M HCl
solution in 1,4-dioxane provided target product 11 in 57%
yield.
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Therefore, the six-membered ring homologation strategy was
abandoned in the case of fluorinated cycloheptane derivative
7.
Meanwhile, the application of cyclohept-2-enone (24) as a
starting material for the synthesis of fluorinated cycloheptanes
7–9 appeared to be a convenient alternative and allowed us
to obtain carboxylic acid 7 in just three steps (Scheme 2B).
Hydrocyanation of 24 followed by deoxofluorination of 25
with DAST was used to form gem-difluorocycloheptane-
derived nitrile 26 (55% yield over two steps). Next alkaline
hydrolysis of 26 gave the target compound 7 in 86% yield.
Derivative 7 was further converted into amine hydrochloride 8
by Curtius rearrangement – Boc-deprotection of 27 in 75%
overall yield.
Analogously, 3,3-difluorocycloheptanone (9) was prepared
in just four synthetic steps starting from 24 (Scheme 2C).
Sequential addition of HOAc to 24 (54% yield) and deoxo- Conclusions
fluorination of 28 with DAST (62% yield) provided fluorinated
intermediate 29. After alkaline hydrolysis of 29, the resulting
alcohol 30 was subjected to an oxidation reaction using PCC
to give target ketone 9 in 89% yield over two steps.
Finally, the remaining gem-difluorocycloheptane deriva-
tives 10–12 were obtained from either cyclohexanone sub-
strate 31 or 32 by ring homologation using diazoalkane
reagent (Scheme 3A). Treatment of 4,4-difluorocyclohexanone
Alternatively,
ring
homologation
of
ethyl
4-
oxocyclohexanecarboxylate (32) followed by diester hydrolysis
and decarboxylation under basic conditions was carried out
for the preparation of seven-membered δ-keto carboxylic acid
34 (Scheme 3B). Compound 34 was further converted into
ester 35 (41% yield from 32) and next subjected to deoxo-
fluorination step using DAST (63% yield). Alkaline hydrolysis of
the obtained intermediate 36 allowed to obtain carboxylic
acid 10 in 69% yield.
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A previously synthesized library of three-to-six membered
cycloalkanes bearing a gem-difluoromethylene moiety was
complemented with nine functionalized gem-difluorocyclo-
heptane derivatives. The target building blocks were obtained
in two to six synthetic steps from commercially available
starting materials. Three strategies were used to access the
target compounds with the additional group in a variable
position: cyclohexanone homologation with difluorocarbene
for the preparation of 1-functionalized 2,2-difluoro-substituted
cycloheptanes (27–60% overall yield), cyclohept-2-enone
functionalization/deoxofluorination – for 3,3-difluoro-substi-
tuted cycloheptanes (30–48% yield), and homologation of
either fluorinated or non-fluorinated cyclohexanones using
diazoalkane reagent – for 4,4-difluoro-substituted cyclohep-
tanes (18–67% yield). The described synthetic approaches
allowed us to obtain target products on multigram scale (up
to 133 g). The accessed fluorinated motifs present a great
interest in medicinal chemistry and can be potentially used in
drug optimization programs.
Experimental Section
General methods
The solvents were purified according to the standard procedures.[41]
Melting points were measured on MPA100 OptiMelt automated
melting point system. Analytical TLC was performed using Poly-
chrom SI F254 plates. Column chromatography was performed
using Kieselgel Merck 60 (230–400 mesh) as the stationary phase.
1H, 19F, and 13C NMR spectra were recorded at 500 MHz or 400 MHz,
470 or 376 MHz, and 126 MHz or 101 MHz, respectively. Elemental
analyses were performed at the Laboratory of Organic Analysis,
Department of Chemistry, Taras Shevchenko National University of
Kyiv. Mass spectra were recorded on an Agilent 1100 LCMSD SL
instrument (chemical ionization (APCI), electrospray ionization (ESI))
and Agilent 5890 Series II 5972 GCMS instrument (electron impact
ionization (EI)).
Scheme 3. (A) Synthesis of gem-difluorocycloheptane derivatives 12, 11, (B)
and 10.
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2,2-Difluorocycloheptanone (6)
(2,2-Difluorocycloheptyl)methanol (19)
To suspension of triphenylphosphonium iodide (15.0 g,
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Compound 15 (161 g, 1.64 mol) and triethylamine (180 mL,
2.46 mol) were dissolved in DMF (2.5 L), and Me3SiCl (184 mL,
1.97 mol) was added in one portion. The mixture was stirred at
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37.1 mmol) in THF (100 mL), t-BuOK (4.00 g, 35.6 mmol) was added
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at 0–5 C, and the mixture was stirred for 30 min. A solution of
ketone 6 (5.00 g, 33.8 mmol) in THF (50 mL) was added dropwise at
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80 C for 12 h. The mixture was cooled to rt, poured into ice-cold
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water (2.5 L), and then washed with hexane (5×800 mL). The
combined organic phases were washed with ice-cold water (3×
500 mL) and brine (2×400 mL), dried over Na2SO4, filtered, and
concentrated to obtain compound 16 (250 g) as an orange liquid.
the same temperature. The reaction mixture was stirred at 0–5 C
for 15 min and at rt for 4 h (monitored by 19F NMR spectra). After
the starting material disappeared, the reaction mixture was filtered,
and the filtrate containing 18 was used in the next step. A solution
of I2 (10.3 g, 40.5 mmol) in THF (100 mL) was added to a suspension
of powdered NaBH4 (3.20 g, 84.4 mmol) in THF (70 mL) dropwise at
rt. The reaction mixture was stirred for 30 min, which was
accompanied by discoloring. Then, the solution of alkene 18 in THF
was added dropwise over 10 min, and the resulting mixture was
stirred for 90 min (monitored by 19F NMR spectra). 3 M aq NaOH
(45 mL) was added dropwise over 30 min (CAUTION! Exothermic
reaction). Then, 30% aq H2O2 (16 mL) was added dropwise over the
next 30 min. The resulting mixture was stirred at rt for 1 h, diluted
with brine (200 mL), and extracted with EtOAc (3×100 mL). The
combined organic layers were evaporated in vacuo, and the residue
was redissolved in CH2Cl2 (150 mL). The traces of water were
separated; the organic layer was dried over Na2SO4, filtered, and
evaporated in vacuo. The residue was purified by column
chromatography to give 19. Yield 3.55 g (64%). Yellowish oil. 1H
NMR (500 MHz, CDCl3) δ 3.87 (dd, J=11.3, 5.3 Hz, 1H), 3.63 (t, J=
11.3, 6.2 Hz, 1H), 2.18–1.96 (m, 3H), 1.95–1.83 (m, 2H), 1.78–1.71 (m,
2H), 1.70–1.63 (m, 1H), 1.54–1.48 (m, 1H), 1.47–1.39 (m, 3H) ppm.
13C NMR (101 MHz, CDCl3) δ 128.2 (dd, J=243.3, 241.7 Hz), 62.4 (dd,
J=8.7, 3.2 Hz), 49.6 (t, J=22.2 Hz), 37.8 (t, J=26.0 Hz), 28.7, 27.6,
25.1 (d, J=8.9 Hz), 20.9 (dd, J=8.3, 4.9 Hz) ppm. 19F NMR (376 MHz,
CDCl3) δ À 86.5 (d, J=242.6 Hz), À 102.1 (d, J=242.6 Hz) ppm. MS
(EI): m/z=144 [MÀ HF]+, 114 [MÀ HFÀ CH2O]+. Anal. Calcd. for
C8H14F2O: C 58.52; H 8.59. Found: C 58.36; H 8.36.
Crude product 16 (250 g) and NaI (44.0 g, 0.294 mol) were dissolved
in THF (3 L) in a conical flat-bottomed flask, and CF3SiMe3 (402 mL,
2.94 mol) was added (CAUTION! The reaction may proceed too
vigorously at the higher scale, so that further scale-up should be
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°
avoided). The reaction mixture was heated carefully to 61 C in an
oil bath upon stirring. When the reaction started, the stirring was
stopped; shortly after, a vigorous reaction occurred that caused
boiling of the solution. After that, the external heating was
continued for additional 18 h. Then the mixture was cooled to rt
and evaporated. The residue was dissolved in t-BuOMe (1400 mL)
and stirred for 15 min. The precipitate was filtered off, and the
solution was concentrated to give 17 (283 g) that was used further
without purification.
Crude product 17 (283 g) was dissolved in MeOH (4 L), and Na2CO3
(136 g, 1.28 mol) was added. The mixture was stirred at rt for
30 min, the inorganic sludge was filtered off, and the filtrate was
concentrated under reduced pressure. The residue was dissolved in
t-BuOMe (1.5 L) and washed with water (3×400 mL). The organic
phase was dried over Na2SO4, filtered, and evaporated in vacuo. The
crude product was subjected to column chromatography (gradient
hexane to hexane – t-BuOMe (85:15) as eluent) to produce
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compound 6. Yield 133 g (55% over 3 steps). Colorless liquid. H
NMR (400 MHz, CDCl3) δ 2.66 (t, J=6.7 Hz, 2H), 2.07 (tt, J=15.2,
6.1 Hz, 2H), 1.87–1.78 (m, 2H), 1.75–1.67 (m, 2H), 1.65–1.58 (m, 2H)
ppm. 13C NMR (126 MHz CDCl3) δ 201.4 (t, J=27.3 Hz), 118.7 (t, J=
250.9 Hz), 39.0, 33.9 (t, J=23.9 Hz), 27.7, 23.7, 23.0 (t, J=5.8 Hz)
ppm. 19F NMR (376 MHz, CDCl3) δ À 105.5 ppm. MS (EI): m/z=148
[M]+. Anal. Calcd. for C7H10F2O: C 56.75; H 6.80. Found: C 56.35; H
6.78.
2,2-Difluorocycloheptanecarboxylic Acid (4)
To a mixture of alcohol 19 (3.80 g, 23.1 mmol) and NaIO4 (19.8 g,
92.6 mmol) in CCl4 (40 mL), CH3CN (40 mL), H2O (60 mL), and
RuCl3·xH2O (0.260 g, 1.16 mmol) were added, the mixture was
stirred at rt for 2 h and neutralized with saturated aq. NaHCO3
(30 mL). The precipitate was filtered and washed with H2O (20 mL).
The combined filtrates were extracted with CHCl3 (2×25 mL), the
aqueous phase was separated, acidified with 10% aq NaHSO4 to
pH=3, and extracted with EtOAc (3×40 mL). The combined
organic phases were dried over Na2SO4, filtered, and concentrated
2,2-Difluorocycloheptanaminium chloride (5)
Compound 6 (94.7 g, 0.640 mol) was dissolved in MeOH (3.5 L), and
ammonium acetate (493 g, 6.40 mol) was added. The reaction
mixture was stirred at rt for 1 h, then NaBH3CN (121 g, 1.93 mol)
was added in five nearly equal portions, and the mixture was stirred
for 18 h. The mixture was concentrated, diluted with water (1.2 L),
and 10% aq NaOH was added to pH=12. The aqueous phase was
extracted with CH2Cl2 (3×500 mL), the combined organic phases
were dried over Na2SO4 and filtered. 4 M HCl in dioxane (750 mL)
under reduced pressure to give 4. Yield 4.00 g (97%). Colorless
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°
solid, mp 51–53 C. H NMR (400 MHz, CDCl3) δ 11.60 (s, 1H), 3.09
(dtd, J=17.2, 9.6, 3.6 Hz, 1H), 2.36–2.07 (m, 2H), 2.04–1.78 (m, 3H),
1.77–1.64 (m, 2H), 1.61–1.45 (m, 3H) ppm. 13C NMR (126 MHz, CDCl3)
δ 177.0 (d, J=6.8 Hz), 124.5 (dd, J=246.6, 243.0 Hz), 52.8 (dd, J=
26.8, 23.9 Hz), 36.8 (t, J=25.1 Hz), 27.4, 25.8, 25.2 (t, J=4.5 Hz), 20.7
(dd, J=8.2, 4.8 Hz) ppm. 19F NMR (376 MHz, CDCl3) δ À 85.8 (d, J=
249.0 Hz), À 93.1 (d, J=249.0 Hz) ppm. MS (APCI): m/z=177 [MÀ H]À .
Anal. Calcd. for C8H12F2O2: C 53.93; H 6.79. Found: C 53.76; H 6.85.
was added to the CH2Cl2 solution, and the precipitate formed was
filtered to give 5. Yield 53.6 g (45%). White solid, mp 144–146 C. H
1
°
NMR (400 MHz, DMSO-d6) δ 8.64 (s, 3H), 3.66 (dt, J=19.5, 8.6 Hz,
1H), 2.26–2.04 (m, 2H), 1.99–1.87 (m, 1H), 1.82–1.72 (m, 1H), 1.71–
1.36 (m, 6H) ppm. 13C NMR (151 MHz, DMSO-d6) δ 124.0 (dd, J=
247.1, 242.8 Hz), 55.3 (dd, J=25.8, 21.9 Hz), 33.9 (t, J=23.7 Hz),
26.1, 26.0, 23.0, 18.9 (t, J=6.4 Hz) ppm. 19F NMR (376 MHz, DMSO-
d6) δ À 88.8 (d, J=240.6 Hz), À 106.2 (d, J=240.6 Hz) ppm. MS
(APCI): m/z=150 [MÀ Cl]+. Anal. Calcd. for C7H14ClF2N: C 45.29; H
7.60; N 7.55; Cl 19.10. Found: C 45.34; H 7.93; N 7.37; Cl 19.44.
3-Oxocycloheptanecarbonitrile (25)[42]
A mixture of cyclohept-2-enone (100 g, 91% purity, 0.908 mol) and
AcOH (55 mL, 0.960 mol) in THF (1.8 L) was added to a solution of
KCN (117 g, 1.80 mol) in H2O (300 mL). The reaction mixture was
°
stirred at 80 C overnight, cooled to rt, and diluted with H2O (1.8 L).
The resulting solution was extracted with CH2Cl2 (3×1 L). The
combined organic layers were dried over anhydrous Na2SO4 and
then concentrated under vacuo. The obtained residue was
dissolved in t-BuOMe (1 L) and filtered through a plug of silica gel
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1
°
(800 g) that was washed with additional t-BuOMe (1 L). The
resulting solution was concentrated in vacuo to give the crude
product with 90% purity (110 g). Purification of the title compound
0.39). Beige solid, mp 77–79 C. H NMR (400 MHz, CDCl3) δ 4.59 (s,
1H), 3.81 (s, 1H), 2.40 (q, J=13.1 Hz, 1H), 2.21–1.92 (m, 4H), 1.80–
1.65 (m, 2H), 1.63–1.49 (m, 3H), 1.44 (s, 9H) ppm. 13C NMR (126 MHz,
CDCl3) δ 154.9, 125.1 (dd, J=241.6, 238.3 Hz), 79.6, 46.0, 44.2 (t, J=
25.2 Hz), 37.6 (t, J=25.9 Hz), 35.7, 28.5, 25.1, 21.5 ppm. 19F{1H} NMR
(376 MHz, CDCl3) δ À 86.1 (d, J=247.0 Hz), À 87.6 (d, J=247.0 Hz)
ppm. MS (EI): m/z=249 [M+), 193 [MÀ C(CH3)2CH2]+, 149 [MÀ CO2À C-
(CH3)2CH2]+. Anal. Calcd. for C12H21F2NO2: C 57.81; H 8.49; N 5.62.
Found: C 57.92; H 8.56; N 5.49.
1
2
3
4
5
6
7
8
°
was performed by vacuo distillation (120 C/0.5 mbar). Yield 90.8 g
1
°
(72%). Yellow oil, bp=120 C/0.5 mbar. H NMR (400 MHz, CDCl3) δ
3.05–2.93 (m, 1H), 2.86–2.71 (m, 2H), 2.68–2.57 (m, 1H), 2.55–2.46
(m, 1H), 2.03–1.89 (m, 3H), 1.81–1.67 (m, 3H) ppm. 13C NMR
(126 MHz, CDCl3) δ 209.1, 120.8, 45.5, 43.7, 33.4, 27.4, 26.7,
23.5 ppm. MS (EI): m/z=137 [M]+. Anal. Calcd. for C8H11NO: C 70.04;
H 8.08; N 10.21. Found: C 69.78; H 7.74; N 10.07.
9
3,3-Difluorocycloheptanaminium chloride (8)
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
3,3-Difluorocycloheptanecarbonitrile (26)
Crude compound 27 (12.1 g) was dissolved in 4 M HCl in dioxane
(100 mL) and stirred at rt for 18 h. The resulting solution was
concentrated under reduced pressure, and the residue was
triturated with t-BuOMe. The solid product was filtered and dried
To a solution of ketone 25 (25.0 g, 182 mmol) in CH2Cl2 (1 L),
Et2NSF3 (DAST, 146.8 g, 911 mmol) was added dropwise at rt. The
°
reaction mixture was stirred at 40 C for 48 h and then poured into
sat aq NaHCO3 (1 L). After stirring for 30 min, the layers were
separated and aqueous phase was extracted with CH2Cl2 (2×
400 mL). The combined organic layers were dried over anhydrous
Na2SO4 and then concentrated under vacuo to give 27.5 g of the
crude product. Purification of the title compound was performed
by column chromatography (hexanes – EtOAc (40:1) as eluent, Rf =
0.30).Yield 22.3 g (77%). Yellow oil. 1H NMR (400 MHz, CDCl3) δ 2.89
(t, J=9.2 Hz, 1H), 2.57–2.27 (m, 2H), 2.19–2.03 (m, 3H), 1.98–1.78 (m,
2H), 1.72–1.58 (m, 3H) ppm. 13C NMR (101 MHz, CDCl3) δ 124.4 (t,
J=241.0 Hz), 121.4, 40.2 (t, J=29.3 Hz), 37.3 (t, J=26.0 Hz), 32.3,
26.1, 24.7 (dd, J=10.2, 5.4 Hz), 20.7 (dd, J=7.8, 4.8 Hz) ppm. 19F
NMR (470 MHz, CDCl3) δ À 85.0 (ddq, J=249.5, 22.1, 11.0 Hz), À 90.3
(dtt, J=249.5, 23.5, 13.0 Hz) ppm. MS (EI): m/z=159 [M]+. Anal.
Calcd. for C8H11F2N: C 60.36; H 6.97; N 8.80. Found: C 60.52; H 7.34;
N 8.88.
under vacuo. Yield 7.50 g (75%) over 2 steps from 7 (9.50 g,
1
°
53.3 mmol). White solid, mp 187–189 C. H NMR (400 MHz, DMSO-
d6) δ 8.31 (s, 3H), 3.36–3.31 (m, 1H), 2.48–2.42 (m, 1H), 2.39–2.23 (m,
1H), 2.20–2.08 (m, 1H), 2.07–1.93 (m, 2H), 1.83–1.69 (m, 1H), 1.69–
1.55 (m, 2H), 1.55–1.39 (m, 2H) ppm. 13C NMR (126 MHz, DMSO-d6) δ
124.8 (dd, J=239.4, 239.0 Hz), 45.6 (dd, J=12.7, 2.4 Hz), 41.2 (t, J=
28.0 Hz), 36.6 (t, J=25.4 Hz), 32.7, 24.2, 20.2 (t, J=6.4 Hz) ppm. 19F
{1H} NMR (376 MHz, DMSO-d6) δ À 82.0 (d, J=243.8 Hz), À 87.0 (d,
J=243.8 Hz) ppm. MS (APCI): m/z=150 [MÀ Cl]+. Anal. Calcd. for
C7H14ClF2N: C 45.29; H 7.60; N 7.55; Cl 19.10. Found: C 45.58; H 7.24;
N 7.88; Cl 19.30.
3-Oxocycloheptyl acetate (28)
To a solution of cyclohept-2-enone (30.0 g, 91% purity, 273 mmol)
in glacial AcOH (75 mL), KOAc (30.0 g, 306 mol) was added. After
the maximum conversion of 60% was achieved (7 days), the
reaction mixture was neutralized carefully with saturated aq
NaHCO3 and extracted with CH2Cl2 (3×300 mL). The combined
organic layers were dried over anhydrous Na2SO4 and then
concentrated under vacuo. The product was purified by column
chromatography (hexanes – EtOAc (4:1) as eluent, Rf =0.48).
Cyclohept-2-enone (12.2 g) was also recovered from the reaction
mixture (Rf =0.81). Yield 25.3 g (54%). Colorless oil. 1H NMR
(400 MHz, CDCl3) δ 5.14–5.07 (m, 1H), 2.80–2.74 (m, 2H), 2.51–2.45
(m, 2H), 2.01 (s, 3H), 1.95 (q, J=7.1 Hz, 1H), 1.88–1.76 (m, 2H),
1.7xt5–1.66 (m, 3H) ppm. 13C NMR (126 MHz, CDCl3) δ 210.4, 170.0,
69.3, 48.3, 44.4, 35.2, 24.9, 23.9, 21.2 ppm. MS (EI): m/z=170 [M]+,
110 [MÀ CH3CO2H]+. Anal. Calcd. for C9H14O3: C 63.51; H 8.29. Found:
C 63.23; H 8.06.
3,3-Difluorocycloheptanecarboxylic acid (7)
A solution of KOH (35.2 g, 628 mmol) in H2O (200 mL) was added to
a solution of nitrile 26 (20.0 g, 126 mmol) in EtOH (200 mL), and the
°
solution was heated at 70 C for 72 h. The resulting solution was
allowed to cool to rt and concentrated under reduced pressure. The
residue was diluted with H2O (200 mL) and washed with CH2Cl2
(150 mL). The aqueous layer was then separated, acidified with
NaHSO4 and extracted with CH2Cl2 (3×200 mL). The combined
organic layers were dried over anhydrous Na2SO4 and then
concentrated under vacuo to give pure product. Yield 19.2 g (86%).
Yellowish oil. 1H NMR (400 MHz, CDCl3) δ 11.54 (br s, 1H), 2.65 (t, J=
10.8 Hz, 1H), 2.49 (q, J=12.9 Hz, 1H), 2.25–1.99 (m, 4H), 1.85–1.74
(m, 1H), 1.73–1.51 (m, 4H) ppm. 13C NMR (126 MHz, CDCl3) δ 181.7,
125.4 (dd, J=239.3, 239.2 Hz), 39.1 (dd, J=29.3, 27.5 Hz), 38.7 (d,
J=10.9 Hz), 37.8 (t, J=26.2 Hz), 31.6, 26.8, 21.1 (t, J=6.3 Hz) ppm.
19F{1H} NMR (376 MHz, CDCl3) δ À 84.3 (d, J=244.7 Hz), À 91.8 (d, J=
244.7 Hz) ppm. MS (APCI): m/z=177 [MÀ H]-. Anal. Calcd. for
C8H12F2O2: C 53.93; H 6.79. Found: C 54.22; H 6.92.
3,3-Difluorocycloheptyl acetate (29)
Compound 28 (5.00 g, 29.4 mmol) was dissolved in CH2Cl2 (500 mL),
and DAST (23.8 g, 148 mmol) was added dropwise at rt. The
°
reaction mixture was stirred at 40 C for 48 h, then DAST (4.75 g,
29.5 mmol) was added, and the mixture was stirred at the same
temperature for additional 18 h. The reaction mixture was poured
into saturated aq NaHCO3 (1500 mL). After stirring for 30 min, the
organic layer was separated, and the aqueous layer was extracted
with CH2Cl2 (2×200 mL). The organic layers were combined, dried
over Na2SO4, filtered, and the solvents were removed in vacuo. The
compound was purified by column chromatography (hexanes –
tert-Butyl (3,3-difluorocycloheptyl)carbamate (27)
To a solution of carboxylic acid 7 (9.50 g, 53.3 mmol) in t-BuOH
(100 mL), Et3N (6.40 g, 63.9 mmol) was added and was followed by
the addition of (PhO)2P(O)N3 (DPPA, 17.6 g, 63.9 mmol). After
°
heating the reaction mixture at 80 C for 18 h, it was allowed to
cool to rt and was concentrated under reduced pressure. The
residue was dissolved in t-BuOMe (200 mL), washed with sat aq
Na2CO3 (2×100 mL) and with aq NaHSO4 (100 mL), dried over
anhydrous Na2SO4 and then concentrated under vacuo. The crude
product (12.1 g) was used in the next step without additional
purification. An analytical sample was obtained after purification by
column chromatography (hexanes – EtOAc (4:1) as eluent, Rf =
EtOAc (20:1) as eluent, Rf =0.45). Yield 3.51 g (62%). Yellowish oil,
1
°
bp 33 C/0.5 mbar. H NMR (500 MHz, CDCl3) δ 5.06–4.93 (m, 1H),
2.47–2.27 (m, 2H), 2.23–2.05 (m, 2H), 2.04 (s, 3H), 1.98–1.90 (m, 1H),
1.80–1.69 (m, 2H), 1.68–1.56 (m, 3H) ppm. 13C NMR (101 MHz, CDCl3)
δ 170.1, 124.5 (t, J=239.9 Hz), 68.9 (dd, J=10.1, 5.4 Hz), 43.1 (t, J=
27.8 Hz), 37.8 (t, J=26.0 Hz), 34.2, 24.3, 21.5 (t, J=6.4 Hz), 21.3 ppm.
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19F{1H} NMR (376 MHz, CDCl3) δ À 84.4 (d, J=245.2 Hz), À 87.7 (d, J=
4,4-Difluorocycloheptanone (12)
1
2
3
4
5
6
7
8
9
245.2 Hz) ppm. MS (EI): m/z=112 [MÀ CH3CO2HÀ HF]+. Anal. Calcd.
A mixture of 33 (250 g, 1.13 mol) and 3 M aq HCl (600 mL) was
heated at reflux overnight, then cooled to rt and evaporated
under reduced pressure. The residue was purified by flash
for C9H14F2O2: C 56.24; H 7.34. Found: C 56.41; H 7.21.
chromatography (gradient hexanes to hexanes
– t-BuOMe
3,3-Difluorocycloheptanol (30)
(85:15) as eluent). Yield 150 g (90%). Yellowish liquid. 1H NMR
(400 MHz, CDCl3) δ 2.62–2.51 (m, 4H), 2.23–2.03 (m, 4H), 1.92–
1.81 (m, 2H) ppm. 13C NMR (126 MHz, CDCl3) δ 211.7, 124.0 (t, J=
240.3 Hz), 43.3, 38.1 (t, J= 26.2 Hz), 35.8 (t, J= 6.6 Hz), 32.3 (t, J=
27.8 Hz), 17.7 (t, J=6.4 Hz) ppm. 19F NMR (376 MHz, CDCl3) δ
À 93.6 ppm. MS (EI): m/z=148 [M]+, 128 [MÀ HF]+. Anal. Calcd. for
C7H10F2O: C 56.75; H 6.80. Found: C 56.80; H 6.84.
Compound 29 (0.300 g, 1.56 mmol) was dissolved in MeOH (5 mL),
and a solution of KOH (0.360 g, 6.42 mmol) in water (2 mL) was
added. The reaction mixture was stirred at rt for 1 h (monitored by
TLC). MeOH was removed in vacuo, the residue was diluted with
water (5 mL) and extracted with CH2Cl2 (3×30 mL). The combined
organic layers were dried over Na2SO4, filtered, and evaporated in
vacuo. Yield 0.231 g (99%). Yellowish oil. 1H NMR (500 MHz, CDCl3)
δ 3.98 (s, 1H), 2.43 (q, J=13.9 Hz, 1H), 2.31–2.08 (m, 2H), 2.04–1.89
(m, 2H), 1.83–1.73 (m, 1H), 1.72–1.61 (m, 2H), 1.60–1.46 (m, 3H)
ppm. 13C NMR (126 MHz, CDCl3) δ 124.8 (t, J=239.5 Hz), 66.9 (dd,
J=10.8, 4.1 Hz), 46.4 (t, J=26.0 Hz), 38.2, 37.9 (t, J=26.1 Hz), 24.3,
21.5 (t, J=6.3 Hz) ppm. 19F{1H} NMR (376 MHz, CDCl3) δ À 84.1 (d,
J=246.6 Hz), À 87.5 (d, J=246.6 Hz) ppm. MS (EI): m/z=130
[MÀ HF]+, 112 [MÀ HFÀ H2O]+. Anal. Calcd. for C7H12F2O: C 55.99; H
8.05. Found: C 56.38; H 7.98.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
4,4-Difluorocycloheptanaminium chloride (11)
Compound 12 (12.0 g, 81.0 mmol) was dissolved in MeOH
(350 mL). Ammonium acetate (62.4 g, 0.810 mol) was added, and
the reaction mixture was stirred at rt for 30 min. Then NaBH3CN
(15.3 g, 244 mmol) was added, and the resulting mixture was
stirred at rt overnight, and then diluted with water (180 mL). 10%
aq Na2CO3 was added to pH=12, and the mixture was extracted
with CH2Cl2 (3×100 mL). The organic phase was washed with
brine (90 mL), dried over Na2SO4, filtered, and concentrated under
reduced pressure. 4 M HCl in dioxane (100 mL) was added to the
residue, and the resulting mixture was stirred at rt for 3 h. The
3,3-Difluorocycloheptanone (9)
Compound 30 (100 mg, 0.667 mmol) was dissolved in CH2Cl2
(5 mL), and pyridinium chlorochromate (0.334 g, 1.55 mmol) was
added in one portion. The reaction mixture was stirred at rt for
5 h (monitored by TLC), then filtered through a silica gel pad
(1 g) that was then washed with CH2Cl2 (50 mL). The solvent was
removed in vacuo to obtain 9. Yield 89.8 mg (91%). Yellowish oil.
1H NMR (400 MHz, CDCl3) δ 3.10 (t, J=14.5 Hz, 2H), 2.58–2.53 (m,
2H), 2.19 (t, J=13.4 Hz, 2H), 1.86–1.78 (m, 4H) ppm. 13C NMR
(101 MHz, CDCl3) δ 205.5 (t, J= 7.4 Hz), 121.6 (t, J=241.5 Hz),
52.2 (t, J= 28.0 Hz), 44.0, 38.5 (t, J= 25.5 Hz), 23.4, 23.2 (t, J=
6.4 Hz) ppm. 19F{1H} NMR (376 MHz, CDCl3) δ À 91.7 ppm. MS (EI):
m/z=148 [M]+, 128 [MÀ HF]+. Anal. Calcd. for C7H10F2O: C 56.75; H
6.80. Found: C 56.48; H 6.69.
precipitate was filtered, washed with diethyl ether (100 mL), and
dried in vacuo. Yield 8.27 g (55%). Beige solid, mp 186–188 C. H
1
°
NMR (400 MHz, DMSO-d6) δ 8.26 (s, 3H), 3.31–3.17 (m, 1H), 2.31–
1.87 (m, 6H), 1.82–1.36 (m, 4H) ppm. 13C NMR (101 MHz, DMSO-d6)
δ 126.6 (t, J=238.7 Hz), 50.4, 37.3 (t, J=26.2 Hz), 32.1, 32.0 (t, J=
27.2 Hz), 24.5 (dd, J=9.1, 4.0 Hz), 17.2 (dd, J=6.9, 4.9 Hz) ppm. 19F
NMR (376 MHz, DMSO-d6) δ À 83.8 (d, J=238.4 Hz), À 85.3 (d, J=
238.4 Hz) ppm. Anal. Calcd. for C7H14ClF2N: C 45.29; H 7.60; N 7.55;
Cl 19.10. Found: C 44.91; H 7.45; N 7.79; Cl 19.04.
Ethyl 4-Oxocycloheptanecarboxylate (35)[43]
Ethyl 4-oxocyclohexanecarboxylate (32) (50.0 g, 294 mmol) was
dissolved in Et2O (750 mL) and cooled to 0 C. A solution of
BF3 À Et2O (55 mL) in Et2O (150 mL) was added dropwise and
then a solution of ethyldiazoacetate (55 mL, 90% solution in
CH2Cl2) in Et2O (150 mL) was added slowly to the reaction
mixture. The resulting solution was stirred at 0 C for 2 h and
then at rt for additional 2 h (monitored by H NMR). After the full
°
Ethyl 5,5-Difluoro-2-oxocycloheptanecarboxylate (33)
A three-necked flask was charged with 31 (70.0 g, 522 mmol) and
dry CH2Cl2 (1.4 L) under nitrogen atmosphere. The mixture was
°
cooled to À 10 C and stirred for 15 min. Then a solution of
°
1
Et2O·BF3 (85.2 mL, 678 mmol) in CH2Cl2 (350 mL) was added
°
dropwise at À 10 C. The resulting mixture was stirred at the same
conversion of starting material was achieved, aq NaHCO3 (1 L)
was added and the mixture was stirred for 10 min. After the
complete neutralization of the solution, the organic layer was
separated and concentrated in vacuo. The residue was dissolved
in MeOH (500 mL), a solution of NaOH (50.0 g, 1.25 mol) in H2O
(450 mL) was added and the reaction mixture was stirred for
24 h. MeOH was evaporated under vacuum. The remaining
aqueous phase was washed with CH2Cl2 (2 ×200 mL), acidified
with aq NaHSO4 to pH=3, and then extracted with t-BuOMe (3 ×
300 mL). The combined organic extracts were dried over
anhydrous Na2SO4 and concentrated in vacuo to give crude 4-
oxocycloheptanecarboxylic acid (34) (35.2 g, ca. 80% purity
temperature for 10 min, and a solution of ethyl diazoacetate
(72.2 mL, 678 mmol) in CH2Cl2 (350 mL) was added dropwise. The
mixture was stirred for an additional 1 h at the same temperature,
then allowed to warm to rt and quenched with 30% aq K2CO3
(700 mL). The organic phase was separated and washed with brine
(2×500 mL), then dried over Na2SO4, filtered, and evaporated in
vacuo. Yield 88.6 g (73%). Orangeish amorphous solid. The
compound existed as ca. 1:2 mixture of ketone and enol
1
tautomers. H NMR (500 MHz, CDCl3) δ 12.68 (s, 0.7H), 4.22 (q, J=
6.0 Hz, 2H), 3.58–3.49 (m, 0.3H), 2.81–2.71 (m, 0.3H), 2.64–2.54 (m,
0.3H), 2.51–2.41 (m, 2.7H), 2.38–2.25 (m, 0.7H), 2.23–2.12 (m, 1H),
2.09–1.99 (m, 1.7H), 1.98–1.85 (m, 1.3H), 1.37–1.24 (m, 3H) ppm.
13C NMR (126 MHz, CDCl3) δ 206.1 (ketone CO), 177.0 (enol COH),
172.4 and 169.6 (CO2Et), 124.4 (m, CF2), 100.8 (enol C(COH)CO2Et),
61.7 (C(CO)CO2Et), 61.0 and 58.6 (OCH2), 36.1 (t, J=24.2 Hz) and
35.4 (t, J=26.9 Hz, CH2CF2), 35.4 (CH2CO), 33.2 (t, J=26.3 Hz) and
32.5 (t, J=28.0 Hz, CH2CF2), 28.0 (t, J=6.8 Hz) and 17.8 (t, J=
6.6 Hz, CH2CH2CF2), 14.4 and 14.2 (CH3) ppm. 19F NMR (376 MHz,
CDCl3) δ À 91.7 (d, J=246.0 Hz), À 96.1 (d, J=246.0 Hz) ppm. Anal.
Calcd. for C10H14F2O3: C 54.54; H 6.41. Found: C 54.31; H 6.81.
1
according to H NMR) which was used in the next step without
1
additional purification. H NMR (400 MHz, CDCl3) δ 10.33 (s, 1H),
2.81–2.30 (m, 5H), 2.23–2.07 (m, 2H), 2.05–1.83 (m, 2H), 1.82–1.61
(m, 2H) ppm. 13C NMR (126 MHz, CDCl3) δ 214.1, 180.9, 46.2, 43.5,
41.5, 32.4, 26.1, 22.3 ppm.
i-Pr2NEt (38.0 g, 294 mmol) was added to a solution of crude
compound 34 (35.2 g, ca. 80% purity) in CH2Cl2 (500 mL). Ethyl
iodide (68.8 g, 441 mmol) was added dropwise and the solution
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was stirred at rt for 48 h. The resulting mixture was washed with aq
Conflict of Interest
1
2
3
4
5
6
7
8
9
NaHSO4 (500 mL). The organic phase was dried over anhydrous
Na2SO4 and solvent was removed in vacuo. The residue was purified
by column chromatography using hexane:t-BuOMe (2:1) as eluent
(Rf =0.4) to give pure compound 35. Yield 22.1 g (41% from
The authors declare no conflict of interest.
1
compound 32). Yellow oil. H NMR (400 MHz, CDCl3) δ 4.13 (q, J=
Keywords: Fluorine
·
Cycloalkane
·
Cycloheptane
·
7.1 Hz, 2H), 2.60 (ddd, J=15.9, 7.3, 2.9 Hz, 1H), 2.56–2.43 (m, 4H),
2.16–2.04 (m, 2H), 2.00–1.81 (m, 2H), 1.78–1.69 (m, 1H), 1.69–1.61
(m, 1H), 1.25 (t, J=7.1 Hz, 3H) ppm. 13C NMR (126 MHz, CDCl3) δ
213.7, 175.1, 60.6, 46.6, 43.6, 41.7, 32.7, 26.4, 22.5, 14.3 ppm. MS (EI):
m/z=184 [M]+, 139 [MÀ OC2H5]+. Anal. Calcd. for C10H16O3: C 65.19;
H 8.75. Found: C 65.33; H 8.63.
Deoxofluorination · Building blocks
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Ethyl 4,4-Difluorocycloheptanecarboxylate (36)
Compound 35 (22.0 g, 119 mmol) was dissolved in CH2Cl2
(440 mL) and DAST (95.9 g, 595 mmol) was added dropwise at rt.
The reaction mixture was stirred for at rt for 72 h and the 85%
conversion of the starting material (according to GCMS) was
achieved (the further addition of DAST (19.2 g, 119 mmol) did not
influence the conversion). The resulting mixture was neutralized
with aq NaHCO3 (1000 mL). The organic layer was separated,
filtered through a thin layer of silica and concentrated in vacuo.
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°
The residue was purified by vacuum distillation (bp 49 C/1 mbar)
to give compound 4. Yield 15.5 g (63%). Yellow oil. 1H NMR
(500 MHz, CDCl3) δ 4.17–4.09 (m, 2H), 2.58–2.50 (m, 1H), 2.27–2.08
(m, 2H), 2.06–1.89 (m, 4H), 1.85–1.70 (m, 3H), 1.60–1.51 (m, 1H),
1.30–1.22 (m, 3H) ppm. 13C NMR (126 MHz, CDCl3) δ 175.7, 126.4 (t,
J=239.5 Hz), 44.6, 38.0 (t, J=26.6 Hz), 35.3 (t, J=27.2 Hz), 30.8,
23.1 (t, J=6.8 Hz), 19.7 (t, J=6.2 Hz), 14.3 ppm. 19F NMR (470 MHz,
CDCl3) δ À 86.0 (dq, J=20.1, 13.9 Hz, 1F),À 86.5 (dq, J=20.1,
13.9 Hz, 1F) ppm. MS (EI): m/z=206 [M]+, 186 [MÀ HF]+, 161
[MÀ OC2H5]+. Anal. Calcd. for C10H16F2O2: C 58.24; H 7.82. Found: C
58.60; H 7.84.
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60–66.
4,4-Difluorocycloheptanecarboxylic Acid (10)
A solution of NaOH (2.33 g, 58.2 mmol) in H2O (4 mL) was added
to the solution of ester 4 (10.0 g, 48.5 mmol) in MeOH (200 mL).
The reaction mixture was stirred at rt overnight. The solution was
concentrated in vacuo, the residue was diluted with water
(100 mL) and then acidified with 20% aq HCl to pH=2. The
product was extracted with CH2Cl2 (3x75 mL). The combined
organic layers were dried over anhydrous Na2SO4 and concen-
trated under vacuum to give pure product 5. Yield 5.96 g (69%).
1
°
Beige solid, mp 74–76 C. H NMR (400 MHz, CDCl3) δ 11.78 (br s,
1H), 2.61 (tt, J=9.4, 4.9 Hz, 1H), 2.33–2.17 (m, 1H), 2.16–1.90 (m,
5H), 1.90–1.72 (m, 3H), 1.66–1.48 (m, 1H) ppm. 13C NMR (126 MHz,
CDCl3) δ 182.2, 126.2 (t, J= 239.7 Hz), 44.2, 38.1 (t, J=26.6 Hz),
35.1 (t, J=27.2 Hz), 30.5, 22.8 (t, J= 6.8 Hz), 19.6 (t, J=6.3 Hz)
ppm. 19F NMR (376 MHz, CDCl3) δ À 86.9, À 87.0 ppm. MS (EI): m/
z=158 [MÀ HF]+. Anal. Calcd. for C8H12F2O2: C 53.93; H 6.79.
Found: C 53.83; H 6.62.
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Acknowledgments
The work was funded by Enamine Ltd. O.O.G. was also funded by
Ministry of Education and Science of Ukraine (Grant No. 19BF037-
03). The authors thank Prof. Andrey A. Tolmachev for his
encouragement and support, and Ms. Mariana Perebiynis for her
help with manuscript preparation.
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Manuscript received: November 23, 2020
Revised manuscript received: December 27, 2020
Accepted manuscript online: January 7, 2021
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M. Herasymchuk, Dr. K. P. Melnykov,
D. V. Yarmoliuk, D. Serhiichuk, V.
Rotar, T. Pukhovoi, Y. O. Kuchkovska,
S. Holovach, Prof. Dr. D. M. Voloch-
nyuk, Prof. Dr. S. V. Ryabukhin*,
Dr. O. O. Grygorenko
A series of isomeric gem-difluorocyclo-
heptane derivatives were obtained in
two to six synthetic steps from readily
available starting materials. The
shown to be efficient for a multigram-
scale synthesis of target compounds
and involved six-membered ring ho-
mologation and/or deoxofluorination
reactions as the key steps.
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1 – 10
Last of the gem-Difluorocycloal-
kanes 2: Synthesis of Fluorinated
Cycloheptane Building Blocks
developed synthetic approaches were