Difluoro-Substituted Bicyclo[1.1.1]pentanes for Medicinal Chemistry: Design, Synthesis, and Characterization

Article abstract of DOI:10.1021/acs.joc.9b01947

A practical synthetic approach to the difluoro-substituted bicyclo[1.1.1]pentanes was developed. The key step was an addition of difluorocarbene (:CF₂) to electron-rich bicyclo[1.1.0]butanes by the CF₃TMS/NaI system. The obtained dif

Full text of DOI:10.1021/acs.joc.9b01947

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Article
Difluoro-substituted bicyclo[1.1.1]pentanes for medicinal
chemistry: design, synthesis and characterization.
Roman M. Bychek, Valeriia Hutskalova, Julia P. Bas, Olga A.
Zaporozhets, Sergey Zozulia, Vadym V. Levterov, and Pavel K. Mykhailiuk
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b01947 • Publication Date (Web): 25 Sep 2019
Downloaded from pubs.acs.org on September 25, 2019
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Page 1 of 14
The Journal of Organic Chemistry
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Difluoro-substituted bicyclo[1.1.1]pentanes for medicinal
chemistry: design, synthesis and characterization
Roman M. Bychek,† Valeriia Hutskalova,†, Julia P. Bas, Olga A. Zaporozhets, Sergey Zozulia,
†,
§
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†
†,
#
Vadym V. Levterov, and Pavel K. Mykhailiuk *
†Enamine Ltd., Chervonotkatska 78, 02094, Kyiv (Ukraine), www.enamine.net
#Taras Shevchenko National University of Kyiv, Chemistry Department, Volodymyrska 64, 01601, Kyiv (Ukraine),
www.mykhailiukchem.org
§Bienta, Chervonotkatska 78, Kyiv 02094 (Ukraine), www.bienta.net
CF3TMS
F
F
NaI
CO2Me
CO2Me
THF, t
41-68%
Ar, vinyl
[1.1.0]
Saturated bioisosters
of the phenyl ring
via [:CF2]
F
F
F
F
F
F
Ar
CO2H Ph
NH2 HO2C
CO2Me
Acids
Amines
Bifunctional linkers
ABSTRACT: A practical synthetic approach to the difluoro-substituted bicyclo[1.1.1]pentanes was developed. The key step was
an addition of difluorocarbene (:CF2) to electron-rich bicyclo[1.1.0]butanes by CF3TMS/NaI system. The obtained difluoro-
bicyclo[1.1.1]pentanes are suggested as saturated bioisosteres of the benzene ring for drug discovery projects.
patents of academic groups and commercial companies
(Figure 1).
INTRODUCTION
Benzene ring is a popular structural element in many
bioactive compounds.1 Its fragment is included in over five
hundred drugs.2 In the context of a concept named Escape
from Flatland,3 replacing benzene rings with saturated
bioisosteres is an important strategy to obtain novel patent-free
molecules with improved biological activity and physico-
chemical profile.4 In particular, in 2012 Stepan and colleagues
substituted the phenyl fragment in a ɣ-secretase inhibitor with
the bicyclo[1.1.1]pentyl skeleton. The obtained analogue
showed higher activity, solubility and metabolic stability.5
Moreover, the bicyclo[1.1.1]pentyl-containing compound was
patent-free, representing an example of evading patents of
pharmaceutical companies on benzene-containing bioactive
molecules. Since then, bicyclo[1.1.1]pentyl-containing
derivatives have been often used in medicinal chemistry. They
have already been mentioned in more than one hundred
An increasing demand from pharmaceutical institutions,
initiated many academic research projects aimed at elaboration
of novel synthetic approaches to bicyclo[1.1.1]pentyl-
substituted building blocks. Most of the work in this area is
devoted to the synthesis of mono- and 1,3-disubstituted
derivatives.7-9 At the same time, however, aspirations about
the new generation of bicyclo[1.1.1]pentanes with
a
2-substitution at the side chain are frequently discussed at
scientific conferences on medicinal chemistry. Such structures,
in turn, would give access into novel 3D-shaped chemical
space, and will additionally provide with an opportunity to
mimic the ortho-substituted benzenes. Although several
bridge-substituted propellanes are known,10 they are obtained
through multistep synthetic procedures often employing
gaseous reagents and photochemical transformations. It is
important to mention that 2,2-dichloro[1.1.1]propellane was
1
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Page 2 of 14
reported, but was unstable.11 This suggests that other
either reported or modified conditions failed. The remaining
1
2
3
4
5
6
7
8
propellanes with the bridge substituents which can act as
leaving groups - oxygen, sulphur and presumably fluorine, –
might be also unstable. As a result, the bicyclo[1.1.1]pentanes
with the substitution at the bridge positions are very rare.12 Not
surprising that over the years, many pharma-companies
initiated internal research projects trying to access these
structures. Only recently, the first report on the synthesis of
difluorinated bicyclo[1.1.1]pentanes by Merck chemists
appeared.13
starting material was only observed in the reaction mixture.
Increasing the reaction temperature and time only led to
decomposition of the starting compound. Presumably,
compound 2 was too rigid to adopt the proper conformation
for the CH-activation. Previously, we observed similar effect,
as several conformationally restricted analogues of proline did
not react under the standard directed CH-arylation
conditions.14b
9
In 2016, Hrdina and colleagues showed that for the
conformationally rigid 1-adamantane-carboxylic acid,
8-aminoquinoline was ineffective directing group in
Pd-catalyzed CH-arylation reactions. The authors also found
that the more flexible 2-aminomethyl pyridine worked well in
this role.15 We wanted to take advantage of this discovery and
to provide our model substrate even with more flexibility: we
took a homologue of acid 1 – acid 4 having one additional
methylene group (Scheme 1). Reaction of acid 4 with
2-aminomethyl pyridine in the presence of EDC as a
condensing reagent in dichloromethane afforded the target
model amide 5 in 80% yield. Similar to amide 2, however, all
our efforts to perform Pd-catalyzed CH-fluorination of
compound 5 were unsuccessful, only the starting material was
observed. We did not observe the formation of the required
product under all conditions we tried. Again, prolongation of
the reaction time and increasing temperature only led to a
decomposition of the starting material.
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Herein, we present our studies towards the preparation of
difluoro-substituted
at
the
bridge
position
bicyclo[1.1.1]pentanes – a class of compounds unknown
before (Figure 1).
>500 drugs
Escape
from
F
F
+[F]
Flatland
Stepan
(2012)
Ref. 13
and
This work
p-substituted
Bicyclo-
F2-bicyclo-
Benzene
[1.1.1]pentanes
[1.1.1]pentanes
>100 patents since 2012
NH2
Me
N
Me
Me
NH
N
N
O
N
O
O
N
N
O
N
N
Me
N
N
H
NH2
Ph
Cl
EGFR inhibitor
Inhibitor of mutant IDH enzymes
2016
Modulator of the ISR
2017
Selectfluor
2017
Kalyra Pharm.
Merck
Calico Sci.
WO2017/193030
or NFSI
Pd(OAc)2
F
WO2017/205459
WO2016/89833
N
HOBt, EDC
Het-NH2
HN
O
CO2H
HN
O
CH2Cl2
68%
MeO2C
Ag2CO3
Piv-OH
toluene
O
1
3
110 o
C
O
NH
O
2
not observed
O
N
N
O
O
OMe
Ar
N
Selectfluor
or NFSI
HO2C
N
Pd(OAc)2
HN
HOBt, EDC
Het-NH2
F
N
N
CO2H
O
Treatment of CFTR-associated diseases
Inhibitor of the PAR-2 signaling pathway
Ag2CO3
Piv-OH
toluene
CH2Cl2
80%
2016
2015
HN
Abbvie
Vertex Pharm.
WO2016/69757
WO2015/48245
O
110 o
C
4
6
Figure 1. Application of bicyclo[1.1.1]pentanes in medicinal
chemistry. Objectives of this work: side-chain fluorinated
bicyclo[1.1.1]pentanes.
not observed
5
Scheme 1. Attempted Pd-catalyzed directed CH-fluorination
of bicyclo[1.1.1]pentanes 2 and 5.
RESULT AND DISCUSSION
It is worth mentioning, that substrates 2 and 5 also failed to
1) Attempted directed CH-fluorination. In 2015, Xu and
coworkers described palladium-catalyzed CH-fluorination of
aliphatic amides of 8-aminoquinoline.14 Therefore, we first
tried to extend this reaction to bicyclo[1.1.1]pentane core.
give any arylation product with PhI under the previously
16
developed conditions.14b, At this point we decided to stop
working in this direction and concentrated our efforts onto
another approach – electrochemical fluorination.
2) Attempted electrochemical CH-fluorination. There are
several precedents in the literature on the direct
functionalization of bicyclo[1.1.1]dicarboxylate (7) with
chlorine and fluorine gases. For example, in 1989, Robinson
Reaction of acid
1
with 8-aminoquinoline using
carbonyldiimidazole EDC as an amide-coupling reagent in
dichloromethane as a solvent smoothly gave the needed amide
2 in 68% yield (Scheme 1). Unfortunately, all our attempts to
perform directed CH-fluorination of compound 2 following
2
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The Journal of Organic Chemistry
and Michl reported on the direct chlorination of diacid 7 with Ester 13 was obtained by column chromatography in 83%
chlorine gas under irradiation.17 The selectivity of the reaction
was achieved by careful control of the reaction temperature
and time. The reaction with molecular bromine or iodine did
not take place. In 1997, the same group treated diacid 7 with
fluorine gas: the reaction was unselective, however, giving a
complex mixture of polyfluorinated derivatives.18 On the other
hand, recently Baran and coworkers developed a practical
electrochemical CH-fluorination protocol of aliphatic
compounds.19 Being involved in this project, we wanted next
to expend this methodology onto diacid 7. In fact, a dilute
solution of compound 7, Selectfluor and mediator NaNO2 in
acetonitrile was electrolyzed under a constant current of 3 mA
during different periods of time. The consumed charge was
varied between 0.1-3.0 F/mol. Unfortunately, we did not
observe the formation of the desired product – 19F-NMR of the
reaction mixture showed no needed signals (Scheme 2). Over
the time, only slow decomposition of the starting material took
place.
isolated yield over three steps starting from acid 10.
Cyclization of compound 13 with NaHMDS gave the needed
model substrate 9 in 71% yield.
1
2
3
4
5
6
7
8
CO2H
CO2H
CO2H
HO
HCl aq.
Cl
PhMgCl
THF, rt
toluene, rt
O
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
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60
10
11
12
CO2Me
MeI
K2CO3
CO2Me
NaHMDS
Cl
THF, 70 o
71%
C
DMF, rt
83%
(over 3 steps)
13
9
Scheme 3. Synthesis of the starting substrate 9.
Failure in both CH-activation and electrochemical
fluorination prompted us to focus on the third strategy of the
synthesis of fluorinated bicyclo[1.1.1]pentanes.
Finally, we studied an addition of difluorocarbene to
bicyclo[1.1.0]butane 9 (Table 1). First, we tried the oldest, and
certainly one of the cheapest reagents
-
sodium
A
F
RVC(+)
RVC(-)
chlorodifluoroacetate, - that we successfully used for the
difluorocyclopropanation of various alkenes previously.23
Indeed, we observed the formation of product 14, but in low
yields (Table 1, entries 1-3). In our hands, the use of Hg(CF3)2
or Dolbier reagent - FSO2CF2CO2TMS (TFDA) - did provide
the product in up to 50% yield (Table 1, entries 4-7). Finally,
we studied the system CF3TMS/NaI that was used before for
the difluorocyclopropanation of various functionalized
alkenes.24 The reaction already efficiently proceeded with 3
eq. of CF3TMS, but increasing its amount to 10 equiv allowed
the isolation of the difluoro-compound 14 in 68% yield (Table
1, entries 8-11). The use of larger excess of CF3TMS,
modifying amount of NaI or using other solvents did not give
any further boost in yield (Table 1, entries 11-15). For further
studies on small scale we used ten equivalents of CF3TMS, but
for the subsequent multigram synthesis, this amount could be
safely reduced to two-three equivalents.
It is worth mentioning that even under the optimized
conditions, we also isolated a side product 15 in 19% yield
from a reaction mixture (Scheme 4). Compounds of this type
are usually formed as the main products in the reaction
bicyclo[1.1.0]butanes with carbene obtained by photolysis of
diazomethane,25 or with metal-carbenoids under the Simmons-
Smith conditions.26 Formation of bicyclo[1.1.1]pentanes was
never observed in those reactions. With singlet dibromo- and
dichlorocarbenes, bicyclo[1.1.1]pentanes were formed, but
only as minor components, whereby dienes of type 16
prevailed.20a,b The highly electrophilic nature of
difluorocarbene21 changed the reaction profile, as the
HO2C
CO2H
HO2C
CO2H
Selectfluor
NaNO2, CH3CN
3 mA, 3.0 F/mol
8
7
not observed
Scheme 2. Attempted electrochemical fluorination of diacid 7.
3) Addition of difluorocarbene to bicyclo[1.1.0]butanes.
There are several precedents in the literature on the addition of
dibromocarbene (:CBr2) and dichlorocarbene (:CCl2) to
bicyclo[1.1.0]butanes to form the dihalosubstituted
bicyclo[1.1.1]pentanes in 16-48% yields.20,12c Mechanistically,
this reaction represents an analogy to the cyclopropanation of
alkenes, where a p-rich central bond of bicyclo[1.1.0]butane
reacts with electrophilic dibromo- or dichlorocarbenes.
Keeping this in mind, we wondered whether the same
transformation could occur with (:CF2). Due to the even higher
electrophilicity of difluorocarbene compared with :CCl2 and
:CBr2,21 we expected that this reaction would be feasible, and
even expected the higher yields of products. First, we
synthesized a model compound 9 following the experimental
procedure published in a patent literature (Scheme 3).22 The
commercially available and relatively cheap acid 10 (25 g / 60
$) was treated with two equivalents of PhMgCl in
tetrahydrofurane at room temperature to afford alcohol 11 as a
mixture of two stereoisomers. Reaction of the latter with
concentrated aqueous hydrochloric acid in toluene gave the
chloride 12. Carboxylic function in 12 was alkylated with MeI
in dimethylformamide using potassium carbonate as a base.
3
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bicyclo[1.1.1]pentane 14 was formed as a main reaction Hydrolysis of the ester group in compound 14 smoothly
1
2
3
4
5
6
7
8
product, while compound 15 – as a minor side product.
Table 1. Optimization of the reaction conditions.
gave acid 17 which is a valuable building block for medicinal
chemistry projects (Scheme 5). Next, we challenged its gram-
scale synthesis. The only modification to the previously
elaborated procedure was the amount of CF3TMS in the
addition of difluorocarbene. To reduce the costs of the
synthesis, we decreased an excess of CF3TMS from 10 equiv.
to 3 equiv. This affected the reaction yield, but not
dramatically - product 14 was isolated in 63% yield.
Significant formation of the side product 15 was also
observed. Finally, hydrolysis of the ester group in 14 gave acid
17 as a white solid in 7 g scale.
F
F
Conditions
CO2Me
CO2Me
[:CF2]
9
14
9
Entrya
Reagent
Solvent
Addit.
T (°C)b Yield (%)c
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
58
59
60
1
2
CF2ClCO2Na (3 eq.)
CF2ClCO2Na (5 eq.)
toluene
xylene
110
150
12
16
3
4
5
6
CF2ClCO2Na (10 eq.)
TFDA (3 eq.)
glyme
toluene
toluene
toluene
170
110
110
110
23
32
44
51
LiF (5%)
LiF (10%)
LiF (20%)
1) CF3TMS
NaI (cat.)
THF, t
X-Ray
TFDA (5 eq.)
F
F
TFDA (10 eq.)
63%
7
8
(CF3)2Hg (2 eq.)
CF3TMS (1 eq.)
CF3TMS (3 eq.)
CF3TMS (5 eq.)
CF3TMS (10 eq.)
CF3TMS (20 eq.)
THF
THF
THF
THF
THF
THF
NaI (20%)
NaI (20%)
NaI (20%)
NaI (20%)
NaI (20%)
NaI (20%)
70
70
70
70
70
70
21
44
Ph
CO2Me
Ph
CO2H
2) LiOH
THF, H2O
98%
9
61
17
7 g scale
9
10
11
12
66
73(68)d
71
Scheme 5. Gram-scale two-step synthesis of acid 17.
13
14
15
CF3TMS (10 eq.)
CF3TMS (10 eq.)
CF3TMS (10 eq.)
THF
THF
NaI (40%)
NaI (10%)
70
70
70
70
72
62
CH3CN
NaI (20%)
b
The molecular structure acid 17 was confirmed by X-Ray
analysis (Figure 2).
a
Reactions were performed on 0.1 mmol scale. Temperature in the oil bath.
Yield determined by 1H-NMR with CH2Br2 as an internal standard. Yield of
d
isolated product. Abbreviations: nd = not detected.
Mechanistically, it seems reasonable to assume that the
central p-rich bond in compound
9
attacks the
electrophilic :CF2 to form a stable benzylic carbocation A. The
rearrangement of the latter gives a putative alkene 16 (Scheme
4). Although we did not isolate alkene 16 in the individual
1
state, we did observe in H NMR of the reaction mixture the
formation of characteristic alkene protons at 5.5-6.0 ppm that
disappeared over the time in a course of the reaction. Indeed,
styrene 16 rapidly reacted with an excess of difluorocarene to
give the side product 15. Acrylic double bond in 15 is far less
reactive towards difluorocarbene, however, upon prolonged
reaction times we did also observe its slow
difluorocyclopropanation.
17
Figure 2. X-Ray crystal structure of acid 17. Atoms are shown as
ellipsoids at 25% probability level. Atoms of fluorine – green,
oxygen – red.
F
F
F
CF3TMS
NaI (cat.)
F
Having elaborated
a practical procedure to phenyl-
CO2Me
CO2Me
THF, t
19%
substituted bicyclo[1.1.1]pentane 14, we wanted to understand
how sensitive the reaction was to the substituents at the phenyl
ring. Although, a detailed scope of this transformation is
beyond the scope of this communication, we synthesized some
representative key starting compounds bearing either the
electron-withdrawing substituents at the phenyl ring (18-20) or
an electron-donating methyl-group (21), or simple vinyl
substituent (22). All compounds were easily synthesized in
several steps from acid 10 following the previously described
strategy (Scheme 3). Compounds 18 and 19 reacted with
side
product
9
15
:CF2
:CF2
F
F
CF2
CO2Me
CO2Me
16
A
observed in 1H NMR of r.m.
Scheme 4. Proposed mechanism for the formation of the side
product 15.
CF3TMS/NaI
to
form
the
needed
fluorinated
bicyclo[1.1.1]pentanes 23 and 24 in 41% and 65% yield
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respectively (Scheme 6). Compounds 25 and 26 were reaction time led to the formation of complex mixtures. Some
signals corresponding to the alkene fragment in 1H NMR
indicated the formation of alkenes of the type 16 apart from
other side products.
Synthesis of building blocks. Next, we performed several
representative postmodifications of difluoro-substituted
bicyclo[1.1.1]pentanes to obtain the corresponding building
blocks for the direct use in drug discovery projects. For
1
2
3
4
5
6
7
8
synthesized in 47% and 67% yield.
The reactivity of substrate 22 (prepared also from acid 10)
towards the difluorocarbene is noteworthy. The reaction
occurred first selectively at the central bond of
bicyclo[1.1.0]butane (Scheme 6). The present –CH=CH2
double bond started to react only when the reaction of the
central bond was finished. Therefore, monitoring the reaction
by TLC and NMR (reaction time was approximately 10 h)
allowed the isolation of the needed vinyl-substituted product
27 in 60% yield.
example, Curtius rearrangement
of acid 17 with
9
(PhO)2P(O)N3 in tert-butanol, followed by acidic N-Boc
deprotection gave amine 31 in the form of hydrochloride as a
white solid (Scheme 7). Reduction of the ester group in 14
with LiAlH4 in tetrahydrofuran smoothly provided alcohol 32
in 95% yield. Hydrolysis of esters 24, 26 and 27 with LiOH at
room temperature gave acids 33-37 in 100-300 mg scale.
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
58
59
60
CF3TMS
NaI (cat.)
F
F
THF, 65 o
41%
C
CF3
CO2Me
CF3
CO2Me
18
23
*HCl
1) (PhO)2P(O)N3
F
F
CF3TMS
NaI (cat.)
NEt3, t-BuOH
F
F
(R=H)
THF, 65 o
65%
C
NH2
2) 4N HCl
Dioxane, r.t.
F
Br
CO2Me
CO2Me
CO2Me
F
CO2Me
CO2Me
CO2Me
F
F
70%
31
32
19
20
24
CO2R
CF3TMS
NaI (cat.)
F
F
17
14
(R=H)
(R=Me)
F
F
F
LiAlH4
THF, 65 o
47%
C
(R=Me)
Br
THF, r.t.
95%
OH
25
LiOH
THF, H2O, r.t.
F
F
CF3TMS
NaI (cat.)
F
CF3/F
CO2H
THF, 65 o
67%
C
97% (CF3)
96% (F)
Me
Me
100 mg
F
F
33
35
34
(F)
(CF3),
F
R
CO2Me
21
22
26
F
LiOH
20
21
20
21
(R=C6H4CF3)
(R=C6H4F)
(R=C6H4Br)
(R=C6H4Me)
CF3TMS
NaI (cat.)
THF, H2O, r.t.
F
F
Br/Me
CO2H
THF, 65 o
60%
C
95% (Br)
98% (Me)
300 mg
CO2Me
CO2Me
36
(Br),
F
(Me)
27
LiOH
THF, H2O, r.t.
F
F
Limitations:
CO2H
75%
F
F
Me
CO2Me
CO2Me
SO2Tol
30
37
CO2Me
28
29
no formation of bicyclo[1.1.1]pentanes
F
NaIO4
RuCl3
27
HO2C
CO2Me
CH3CN,
CCl4, H2O, r.t.
50%
HO2C
CO2Me
38
Scheme
6.
Synthesis
of
difluoro-substituted
39
bicyclo[1.1.1]pentanes 23-27. Unreactive substrates 28-30.
proposed
approach
literature
approach
Refs. 5, 27
F
F
Despite the advantages outlined herein, the developed
strategy is not without limitation: the aryl/vinyl-substituents at
the bicyclo[1.1.0]butane core were found to be crucial for the
formation of bicyclo[1.1.1]pentanes. Unfortunately, none, of
the tested substrates 28-30 gave the expected products. In
every case, the compounds were unreactive. Increasing the
reaction temperature in the external oil bath, and the prolonged
bifunctional comp-s
bifunctional comp-s
Scheme 7. Synthesis of mono- (31-37) and bifunctional
difluoro-substituted bicyclo[1.1.1]pentane 38.
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Table 2. Selected parameters of bicyclo[1.1.1]pentanes 17, 40,
41 according to X-Ray crystal data: bond lengths (Å), angles
(°), and distances (Å).
1
2
3
4
5
6
7
8
All
previously
described
difluoro-substituted
bicyclo[1.1.1]pentanes contained aryl-substituents. Therefore,
we also oxidized the vinyl group in compound 27 with NaIO4
and the catalytic amount of RuCl3 to obtain mono-acid 38.
Compound 38 opens up a way to synthesize various
bifunctional derivatives: amino acids, amines, diamines etc.
This tactic is being used routinely these days to synthesize
difunctional bicyclo[1.1.1]pentyl derivates from non-
fluorinated acid 39 (Scheme 7).5, 27
d
3
1
2
1
2
4
5
9
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
58
59
60
F
F
3
Chemical stability. Indeed, because the donor-acceptor
cyclobutanes sometimes undergo ring-fragmentation,28 we
Ph
tBu Ar
iPr
Ph
CO2H
4
2
Compound
41a
next checked
bicyclo[1.1.1]pentaines,
a
chemical stability of difluoro-
being strained cyclobutanes.
17
40
Bond (Å)
C(2)-C(3)
C(3)-C(4)
C(1)-C(2)
C(4)-C(5)
Angle (°)
Treatment of acid 17 and amine 31 with aq. 1M hydrochloric
acid, or aq. 1M sodium hydroxide at room temperature for 24
hours did not lead to any decomposition of the starting
materials. These experiments indicate that described herein
products possess sufficient chemical stability and, indeed, can
be used as building blocks in medicinal chemistry.
1.529
1.515
1.491
1.491
1.546-1.556
1.553-1.560
1.493
1.540-1.557
1.542-1.552
1.489
1.517
1.518
C(2)-C(3)-C(4)
C(1)-C(2)-C(4),
78.2
178.0
179.1
75.2-74.9
178.6
74.5-75.3
178.3
Crystallographic analysis. In 2011, O’Hagan and coworkers
showed that gem-difluorination of cycloalkanes altered
significantly their geometry.29 In particular, in gem-difluoro
compounds, the average C-CF2-C angle is 118° and the
average F-C-F angle is 104°, significantly wider and narrower,
respectively, than the standard tetrahedral angle 109°.29 We
next checked whether incorporation of fluorine atoms would
have an effect on the geometry of the bicyclo[1.1.1]pentane
skeleton. Fortunately, there are two related non-fluorinated
compounds 40 and 41 reported in the literature with the known
crystallography data.30 Therefore, we compared geometric
parameters of all three molecules 17, 40 and 41 (Table 2).
Incorporation of gem-difluoro unit slightly shortened C(2)-
C(3) and C(3)-C(4) bonds: 1.515-1.529 Å (17) vs 1.540-1.560
Å (40, 41). Also, it increased the internal C(2)-C(3)-C(4)
angle: 78.2° (17) vs 74.5-75.3° (40, 41), but because of the
conformationally rigid structure of bicyclo[1.1.1]pentane, this
effect was less pronounced than the one described by O’Hagan
(109° vs 118°). The factors describing the collinearity of
substituents - angles γ1 and γ2, - did not deviate significantly
from the ideal value of 180°: 178.0-179.1° (17) vs 178.3-
179.6° (40, 41). The distance between the bridgehead carbon
atom C(2)-C(4) of the bicyclo[1.1.1]pentane was somewhat
elongated: 1.919 Å (17) vs 1.882-1.891 Å (40, 41).

C(2)-C(4)-C(5),
179.2
179.6

Distance (Å)
C(2)-C(4)
1.919
4.901
1.891
4.901
1.882
4.889
C(1)-C(5), d
a Ar = 4-TMS-C6H4.
Acidity/basicity of functional groups. Incorporation of
fluorine atoms into organic molecules changes significantly
acidity/basicity of the neighboring functional groups.31 For this
reason we experimentally measured pKa values of acids 17, 42
and amine hydrochlorides 31, 42 (Figure 3). Thus, gem-
difluorination of acid 42 increased its acidity by one
magnitude of order: pKa (42) = 4.0 vs pKa (17) = 3.0. On the
other hand, gem-difluorination of amine 43 reduced its
basicity by three magnitudes of order: pKa (43*HCl) = 7.9 vs
pKa (31*HCl) = 4.9. The much bigger impact of fluorination
on the basicity than on the acidity can be explained in terms of
-(I)-inductive effect of fluorine atoms. In acid 17, fluorine
atoms and the acidic hydrogen atom are distanced by five
single bonds. At the same time, in amine 31, fluorine atoms
and the basic nitrogen atom are distanced by three single
bonds; hence an effect of fluorination on the basicity is bigger.
Importantly, however, that the key parameter, distance
between the substituents - d, - was not changed at all: 4.901 Å
(17) vs 4.889-4.901 Å (40, 41).
In short summary, although gem-difluorination slightly
changed some bond lengths and internal angles of the
bicyclo[1.1.1]pentane core, it did not affect its key
characteristics that are important for medicinal chemistry:
overall 3D-shape, collinearity of the substituents (178-179°)
and distance between them (4.9 Å).
Water solubility and lipophilicity. Fluorination is known
also to affect the physico-chemical properties of organic
compounds, such as water solubility and lipophilicity.31
Therefore, we first synthesized model amides 44-46 (Scheme
8) and measured their experimental logD and water solubility
values.
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F
F
Table 3. Experimental lipophilicity and solubility data of
model compounds 44-46.
1
Acidity
Acidity
CO2H
CO2H
2
3
4
5
6
7
8
9
Model compound
LogD(7.4)a Sol(7.4)b
pKa = -1.0
42
17
O
N
pKa:
4.0
3.0
44
45
3.6
3.4
104
370
*HCl
F
F
*HCl
O
NH2
Basicity
NH2
pKa = -3.0
N
43
31
10
11
12
pKa:
7.9
4.9
F
F
O
N
Figure 3. Experimental pKa values of acids 17, 42; and
conjugated amines 31*HCl and 43*HCl.
46
3.6
250
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
58
59
60
aExperimental n-octanol/water distribution coefficient (log) at pH 7.4;
As it was expected,5, 6a, 32 replacement of the benzene ring in
compound 44 by bicyclo[1.1.1]pentane increased the water
solubility by almost 4-times: 104 uM (44) vs 370 uM (45)
(Table 3). Gem-fluorination of compound 45 slightly reduced
its water solubility: 370 uM (45) vs 250 uM (46). Nevertheless,
bKinetic aqueous solubility (uM) in 50 mM phosphate buffer (pH 7.4).
Possible application areas. After a practical synthesis of
gem-difluorinated bicyclo[1.1.1]pentanes, and demonstration
that their chemical and physico-chemical properties are
compatible with medicinal chemistry requirements, we also
thought to suggest areas where these building blocks might be
useful. Indeed, they can be considered as advanced mimics for
substituted benzene rings, but there are some particular cases
that in our opinion are worth mentioning (Scheme 9).
For example, in 2012, Stepan and colleagues made an
intriguing discovery: the authors replaced a fluorophenyl
moiety in the ɣ-secretase inhibitor 47 (BMS-708,163) with a
bicyclo[1.1.1]pentyl skeleton to obtain compound 48 (Scheme
9a).5 Synthetically, compound 48 was obtained from acid 39 in
7 steps. Compound 48 showed better activity, and higher
solubility than 47. On the other hand, the original compound
47 possessed a fluoro-substituted phenyl ring, and it is
strategically reasonable also to test the fluorinated analogues
of compound 48, because fluorine atoms are often involved in
the specific ligand-protein interactions.33 In particular, the
synthesis of F2-48 could have been realized from acid 38
(Scheme 7).
Resveratrol is a natural compound exhibiting anticancer
activity (Scheme 9b). In 2017, Adsool and co-workers
replaced the phenyl ring in Resveratrol by bicyclo[1.1.1]pentyl
skeleton (49).27c Compound 49 was synthesized in 11 steps
from acid 43. Compared to Resveratrol, compound 49 had
40-times better water solubility and almost identical activity
against cancer cells. However, replacement of the aromatic
phenol moiety by aliphatic bicyclo[1.1.1]pentan-ol led to
decrease in OH-acidity: pKa = 10 (Resveratrol) vs 15 (49).
From the strategic standpoint it would have been desirable
also to synthesize and test the fluorinated compound F2-49 that
might have a much closer acidity of the OH-group to that of
Resveratrol: pKa (F2-49) = 12. The synthesis could have been
also started from acid 38.
the
water
solubility
of
gem-difluorinated
bicyclo[1.1.1]pentane 46was almost 2.5-times higher than that
of the benzene-containing containing compound 44: 250 uM
(46) vs 104 uM (44).
An effect of benzene substitution and fluorination of
bicyclo[1.1.1]pentane onto lipophilicity was less profound
(Table 3). The replacement of the benzene ring in compound
44 by bicyclo[1.1.1]pentane slightly reduced its lipophilicity,
as measured by logD(7.4) index: 3.6 (44) vs 3.4 (45). Gem-
difluorination of bicyclo[1.1.1]pentane again increased the
lipophilicity, logD(7.4): 3.4 (44) vs 3.6 (45).
CDI
piperidine
O
CO2H
CH2Cl2
N
93%
42
17
45
46
CDI
piperidine
F
F
F
F
O
N
CO2H
CH2Cl2
91%
Scheme 8. Synthesis of model amides 45 and 46.
In short summary, gem-difluorination
of
bicyclo[1.1.1]pentane decreased its water solubility, and
slightly reduced lipophilicity (logD). On the other hand,
replacement of the benzene ring (44) with gem-difluoro
bicyclo[1.1.1]pentane (46) selectively increased significantly
its water solubility and did not affect its lipophilicity, which
might be beneficially used in medicinal chemistry programs.
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CONCLUSIONS
Page 8 of 14
5
C-F benzene
a)
O
(2012, Stepan):
1
2
3
4
5
6
7
8
Cl
Cl
Herein, we developed a practical synthesis of the previously
unknown gem-difluorinated bicyclo[1.1.1]pentanes (F2-BCPs).
The key synthetic step was an addition of :CF2-carbene,
generated in situ from CF3TMS/NaI mixture, to aryl/vinyl-
substituted bicyclo[1.1.0]butanes. The synthesis was
optimized to obtain up to 7 g of the target compounds (acid
17) in one run. Experimental physico-chemical properties, -
acidity, basicity, lipophilicity and water solubility, - were
measured for the obtained compounds. Based on this data,
gem-difluorinated bicyclo[1.1.1]pentanes are suggested as
novel saturated mimics for the benzene ring in medicinal
chemistry projects.
CF3
CF3
O
Act.
Sol.
O
S
S
O
O
N
N
N
N
N
N
O
NH2
NH2
O
O
F
48
47
(BMS-708,163)
9
7 steps
F
F
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
58
59
60
F
F
N
N
O
HO2C
CO2Me
HO2C
CO2Me
39
38
48
F2-
27c
pK modulation
b)
(2017, Adsool):
OH
a
The synthetic approaches described herein give access to
mono- and bifunctional F2-BCPs. Starting from the
corresponding aryl-substituted bicyclo[1.1.0]butane one could
obtain Ar-substituted F2-BCPs, - like acid 17, amine 31,
alcohol 32 (Schemes 6, 7) - suitable for the replacement of
biphenyl cores in bioactive compounds. On the other hand,
acid 38 (Scheme 7) gives an access to a wide range of
bifunctional compounds, - amino acids, diamines, amino
alcohols, etc, - by stepwise standard modifications of the
carboxylic groups. This work is currently in progress in our
laboratory.
Also, the successful addition of :CF2-carbene to compound 9
(Table 1, Scheme 5) suggests that other carbenes of
type :CF(R) might also be used. To prove this hypothesis, we
also want to disclose our first results in this area: addition
of :CFCl-carbene to compound 9 under the basic conditions
allowed to obtain Cl,F-disubstituted acid 53 in 31% none-
optimized yield (Scheme 10).
OH
OH
Act.
HO
HO
Sol.
OH
pKa = 15a
pKa = 10a
49
Resveratrol
11 steps
F
F
F
F
HO2C
CO2Me
HO
HO2C
CO2Et
pKa = 12a
49
F2-
38
Ar-Ar motifs
50
27d
c)
(2017, Measom, Hirst):
F
F
O
O
N
N
Act.
N
N
CF3
N
S
Sol. CF3
S
O
O
N
Et2N
CHCl2F
Et2N
aq. NaOH (40%)
Cl
F
51
Darapladib
NBu4Br, 0 oC -> rt
3 steps
Ph
CO2Me
Ph
CO2H
31%
Ar: CF3C6H4
F
F
F
F
CF3
CO2H
Ar
Ar
CO2H
9
53
51
F2-
33
52
Scheme 10. Synthesis of Cl,F-acid 53 by an addition
of :CFCl-carbene to substrate 9.
Scheme 9. Possible application areas for gem-difluorinated
bicyclo[1.1.1]pentanes. aCalculated pKa values.
We do believe that with the practical synthetic protocol in
hand and appropriate physico-chemical properties, gem-
difluorinated bicyclo[1.1.1]pentanes (F2-BCPs) will find
practical application in drug discovery projects very soon.
Finally, in 2017, Measom, Hirst and colleagues replaced the
central biphenyl moiety of Darapladib – an agent for the
treatment of atherosclerosis, - with Ar-BCP motif (51, Scheme
9c).27d The obtained compound 51 was more water-soluble
than Darapladib, but slightly less active. The synthesis of 51
was undertaken from acid 52 in three steps. Indeed, bioactive
compounds with the biphenyl motif, like Darapladib, seem to
be the most obvious targets for the incorporation of Ar-F2-
BCP fragments described herein. For example, the synthesis of
F2-52 could have been realized from the corresponding acid
33.
EXPERIMENTAL SECTION
General Considerations. All chemicals were provided by
Enamine Ltd. (www.enamine.net). Autoclaves were provided by
UOSLab (en.uoslab.com). All solvents were treated according to
standard methods. All reactions were monitored by thin-layer
chromatography (TLC) and were visualized using UV light.
Product purification was performed using silica gel column
chromatography. TLC-characterization was performed with pre-
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coated silica gel GF254 (0.2 mm), while column chromatography
3-Hydroxy-3-phenylcyclobutane-1-carboxylic acid (11). To a
1
2
3
4
5
6
7
8
characterization was performed with silica gel (100-200
mesh).1H-NMR, 19F-NMR, 13C-NMR spectra were recorded with
tetramethylsilane (TMS, δ = 0.00 ppm) as the internal standard.
1H-NMR spectra were recorded at 400 or 500 MHz (Varian); 19F-
NMR spectra were recorded at 376 MHz (Varian) and 13C NMR
solution of 10 (41.5 g, 0.36 mol, 1 equiv) in dry THF (500 mL)
was added PhMgBr (2.9 M, 276 mL, 0.8 mol, 2.2 equiv) dropwise
over 6 h at RT under argon. A saturated aq. solution of NH4Cl
(500 mL) was added, and the mixture was acidified with con.
HCl. The mixture was filtered. The resulted solution was
extracted with Et2O. The combined organic layers were washed
with brine, dried over Na2SO4, filtered and concentrated under
reduced pressure to give the desired compound as a white solid.
1
spectra were recorded at 100 or 126 MHz (Varian). H-NMR
chemical shifts are reported downfield from CDCl3 (δ = 7.26
ppm), D2O (δ = 4.79 ppm) or DMSO-d6 (δ = 2.50 ppm). 13C-
NMR chemical shifts for 13C-NMR are reported relative to the
central CDCl3 (δ = 77.16 ppm) or DMSO-d6 (δ = 39.52 ppm).
Coupling constants are given in Hz. High-resolution mass spectra
(HRMS) were recorded on an Agilent LC/MSD TOF mass
spectrometer by electrospray ionization time of flight reflectron
experiments.
1
9
Yield 67.7g, 98%. H NMR (500 MHz, DMSO-d6) δ 12.15 (br s,
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
58
59
60
2H), 7.51 (d, J = 7.5 Hz, 2H), 7.35 (t, J = 7.3 Hz, 2H), 7.24 (t, J =
7.0 Hz, 1H), 5.68 (br s, 1H), 2.74 – 2.65 (m, 1H), 2.61 (t, J = 9.4
Hz, 2H), 2.55 – 2.49 (m, 2H). 13C {1H} NMR (126 MHz, DMSO-
d6) δ 176.0, 146.8, 128.1, 126.7, 125.1, 71.0, 41.0, 28.7. HRMS
(ESI-TOF) m/z: [M + Na]+ calcd for C11H12NaO3, 215.0684;
found 215.0685.
N-(quinolin-8-yl)bicyclo[1.1.1]pentane-1-carboxamide
(2).
Carboxylic acid 1 (0.34 g, 3 mmol, 1 equiv), HOBt (3 mmol, 450
mg, 1 equiv) and the quinolin-8-amine (0.65 g, 4.5 mmol, 1.5
equiv) were dissolved in dry CH2Cl2. EDC*HCl (3 mmol, 576
mg, 1 equiv) was added to the solution. The reaction mixture was
stirred for 12 h. After that, the mixture was washed with water
and partitioned. The organic layer was dried over Na2SO4, filtered
and concentrated under reduced pressure. The crude residue was
3-Chloro-3-phenylcyclobutane-1-carboxylic acid (12). To a
solution of 11 (50 g, 0.238 mol) in toluene (500 mL) was added
con. HCl (500 mL). The resulted mixture was stirred at RT for 4
h. The organic phase was separated, washed with water, brine and
concentrated under reduced pressure to give the title compound as
a white solid. Yield 47.5 g, 95%. The crude product was used for
the next step without purification (Spectra in SI). For analytical
1
1
purified by HPLC. Yield 0.48 g, 68%, beige oil. H NMR (500
data the sample was purified. H NMR (500 MHz, DMSO-d6) δ
MHz, CDCl3) δ 9.95 (s, 1H), 8.83 – 8.80 (m, 1H), 8.79 – 8.75 (m,
1H), 8.13 (d, J = 8.2 Hz, 1H), 7.54 – 7.45 (m, 2H), 7.45 – 7.40
(m, 1H), 2.57 (s, 1H), 2.26 (s, 6H). 13C {1H} NMR (126 MHz,
CDCl3) δ 168.6, 148.4, 138.5, 136.3, 134.2, 128.0, 127.4, 121.7,
121.6, 116.4, 51.3, 45.7, 26.9. LCMS (m/z): 239 (M+H+). HRMS
(ESI-TOF) m/z: [M + H]+ calcd for C15H15N2O, 239.1184; found
239.1182.
12.41 (br s, 1H), 7.44 – 7.29 (m, 5H), 3.53 (p, J = 8.7 Hz, 1H),
2.95 (d, J = 8.8 Hz, 4H). 13C {1H} NMR (126 MHz, DMSO-d6) δ
174.8, 144.9, 128.6, 128.0, 125.1, 69.4, 41.3, 32.2. HRMS (ESI-
TOF) m/z: [M + Na]+ calcd for C11H11ClNaO2, 233.0345; found
233.0347.
Methyl 3-chloro-3-phenylcyclobutane-1-carboxylate (13). To a
solution of 12 (40 g, 0.19 mol, 1 equiv) and K2CO3 (52.4 g, 0.38
mol, 2 equiv) in DMF (400 mL) was added CH3I (54 g, 0.38 mol,
2 equiv). The resulted mixture was stirred at RT overnight. The
mixture was filtered, diluted with water and extracted with
EtOAc. The combined organic layers were washed with brine,
dried over Na2SO4, filtered and concentrated under reduced
pressure. The crude product was purified by column
chromatography on silica gel (EtOAc/hexanes) to give the desired
product as a white solid (38.4 g, 90% yield). The crude product
was used for the next step without purification (Spectra in SI). For
analytical data the sample was purified. 1H NMR (400 MHz,
CDCl3) δ 7.43 – 7.27 (m, 5H), 3.73 (p, J = 9.1 Hz, 1H), 3.68 (s,
3H), 3.11 – 2.93 (m, 4H). 13C {1H} NMR (101 MHz, CDCl3) δ
174.6, 145.0, 128.7, 128.1, 125.1, 68.6, 52.1, 41.9, 32.9. HRMS
(ESI-TOF) m/z: [M + H]+ calcd for C12H14ClO2, 225.0682; found
225.0685.
2-(Bicyclo[1.1.1]pentan-1-yl)-N-(pyridin-2-ylmethyl)acetamide
(5). The same procedure as for 2 was used. Yield 0.56 g, 80%,
white solid, m.p. 94-95 oC. 1H NMR (500 MHz, CDCl3) δ 8.54 (s,
1H), 7.67 (t, J = 7.5 Hz, 1H), 7.28 (d, J = 7.9 Hz, 1H), 7.24 – 7.17
(m, 1H), 6.81 – 6.69 (m, 1H), 4.56 (d, J = 4.4 Hz, 2H), 2.48 (s,
1H), 2.45 (s, 2H), 1.80 (s, 6H). 113C {1H} NMR (126 MHz,
CDCl3) δ 171.0, 156.6, 149.0, 137.0, 122.5, 122.4, 51.4, 44.5,
41.8, 41.0, 28.1. LCMS (m/z): 217 (M+H+). HRMS (ESI-TOF)
m/z: [M + H]+ calcd for C13H17N2O, 217.1341; found 217.1340.
Methyl 3-phenylbicyclo[1.1.0]butane-1-carboxylate (9). To a
solution of NaHMDS (2.0 M in THF, 80 mL, 0.161 mol, 1.2
eqiuv) in THF (300 mL) was added compound 13 (30 g, 0.134
mol, 1 equiv). The resulted mixture heated at reflux for 5 h with a
reflux condenser. The mixture was cooled to RT. After that, a
saturated aq. solution of NH4Cl was added, and the mixture was
filtered. The filtrate was extracted with MTBE. The combined
organic layers were washed with brine, dried over Na2SO4,
filtered and concentrated under reduced pressure. The crude
product was purified by column chromatography on silica gel
(EtOAc/hexanes) to give the desired product as a white solid.
Yield 17.9 g, 71%. 1H NMR (500 MHz, CDCl3) δ 7.43 – 7.20 (m,
5H), 3.50 (s, 3H), 2.94 (s, 2H), 1.62 (s, 2H). 13C {1H} NMR (126
MHz, CDCl3) δ 170.2, 133.7, 128.6, 127.1, 126.1, 52.0, 35.9,
33.1, 23.4. HRMS (ESI-TOF) m/z: [M + H]+ calcd for C12H13O2,
189.0916; found 189.0919.
Methyl-2,2-difluoro-3-phenylbicyclo[1.1.1]pentane-1-
carboxylate (14).
General procedure for the addition of difluorocarbene.
A three-necked, 500 mL, round-bottomed flask was equipped
with a glass stopper, a magnetic stirring bar, an internal
thermometer and a reflux condenser. The flask was charged with
compound 9 (16 g, 0.085 mol, 1 equiv), dissolved in THF (250
mL). TMSCF3 (36.2 g, 0.255 mol, 3 equiv) and NaI (6.4 g, 0.043
mol, 0.5 equiv) were added to the mixture. The resulted mixture
was stirred at 65 °C for 4 h. The mixture was concentrated under
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reduced pressure. The residue was dissolved in MTBE, washed
HRMS (ESI-TOF) m/z: [M + H]+ calcd for C13H12F3O2, 257.0789;
found 257.0791.
Methyl 3-(4-fluorophenyl)bicyclo[1.1.0]butane-1-carboxylate
(19). solution of methyl 3-chloro-3-(4-
1
2
3
4
5
6
7
8
with water, brine and concentrated under reduced pressure. The
crude product was purified by column chromatography (gradient,
hexanes/MTBE) to give the desired product as a white solid (12.8
g, 63% yield). 1H NMR (500 MHz, CDCl3) δ 7.41 – 7.26 (m, 5H),
3.81 (s, 3H), 2.65 (s, 2H), 2.13 (t, J = 10.2 Hz, 2H). 13C {1H}
NMR (126 MHz, CDCl3) δ 165.9, 132.2, 128.7, 128.5, 127.2,
123.0 (t, J = 295.7 Hz), 55.0 (t, J = 19.4 Hz), 52.3, 50.2 (d, J =
19.6 Hz), 43.3 (t, J = 7.2 Hz).19F NMR (470 MHz, CDCl3) δ -
120.9 (t, J = 10.2 Hz). HRMS (ESI-TOF) m/z: [M + H]+ calcd for
C13H13F2O2, 239.0884; found 239.0880.
A
fluorophenyl)cyclobutane-1-carboxylate (17.3 g, 0.071 mol, 1
equiv) in THF (100 mL) was added dropwise to a suspension of
NaH (60%) (4.3 g, 0.107 mol, 1.07 equiv) in THF (150 mL) at
room temperature. The mixture was stirred overnight at room
temperature. The mixture was quenched with water and diluted
with MTBE. The mixture was washed with water, brine, dried
over Na2SO4, filtered und concentrated under reduced pressure to
9
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
58
59
60
1
Methyl
2-((2,2-difluoro-1-phenylcyclopropyl)methyl)-3,3-
give the desired product as yellow oil. Yield 10.3 g, 70%. H
1
difluoroacrylate (15): yield 4.7 g, 19%, yellow oil. H NMR
(500 MHz, CDCl3) δ 7.36 – 7.20 (m, 5H), 3.59 (s, 3H), 2.87 (d, J
= 14.7 Hz, 1H), 2.71 (d, J = 14.5 Hz, 1H), 1.78 – 1.69 (m, 1H),
1.69 – 1.61 (m, 1H). 13C {1H} NMR (126 MHz, CDCl3) δ 164.9
(dd, J = 12.8, 7.4 Hz), 160.4 (dd, J = 310.4, 296.8 Hz), 136.0,
129.7 (d, J = 1.4 Hz), 128.5, 127.9, 113.7 (t, J = 288.2 Hz), 90.09
– 83.75 (m), 52.2, 35.0 (t, J = 10.0 Hz), 29.3 (d, J = 6.6 Hz), 22.1
(t, J = 10.1 Hz). 19F NMR (470 MHz, CDCl3) δ -68.2 (d, J = 6.0
Hz), -72.1, -130.76 (dd, J = 151.8, 11.9 Hz), -137.2 (dd, J =
151.8, 12.5 Hz). HRMS (ESI-TOF) m/z: [M + H]+ calcd for
C14H13F4O2, 289.0852; found 289.0860.
NMR (400 MHz, CDCl3) δ 7.23 (dd, J = 8.6, 5.1 Hz, 2H), 6.97 (t,
J = 8.6 Hz, 2H), 3.48 (s, 3H), 2.86 (s, 2H), 1.58 (s, 2H). 13C {1H}
NMR (101 MHz, CDCl3) δ 170.1, 162.3 (d, J = 246.0 Hz), 129.6,
127.6 (d, J = 8.2 Hz), 115.7 (d, J = 21.8 Hz), 52.0, 36.1, 32.5,
23.0. 19F NMR (376 MHz, CDCl3) δ -115.7 (s). HRMS (ESI-
TOF) m/z: [M + H]+ calcd for C12H12FO2, 207.0821; found
207.0830.
Methyl 3-(4-bromophenyl)bicyclo[1.1.0]butane-1-carboxylate
(20): yield 8.2 g, 78%. The same procedure as for 19 was used. 1H
NMR (400 MHz, CDCl3) δ 7.41 (d, J = 8.3 Hz, 2H), 7.15 (d, J =
8.3 Hz, 2H), 3.49 (s, 3H), 2.88 (s, 2H), 1.60 (s, 2H). 13C {1H}
(101 MHz, CDCl3) δ 169.8, 133.1, 131.7, 127.6, 121.0, 52.1, 36.0,
32.2, 23.7. HRMS (ESI-TOF) m/z: [M + H]+ calcd for
C12H12BrO2, 267.0021; found 267.0028.
2,2-Difluoro-3-phenylbicyclo[1.1.1]pentane-1-carboxylic acid
(17). Compound 14 (7.6 g, 0.032 mol, 1 equiv) was dissolved in
THF (100 mL) and LiOH (1.6 g, 0.064 mol, 2 equiv) was added to
the mixture. The mixture was stirred overnight. Then the mixture
was concentrated under reduced pressure, acidified with a solution
of aq. NaHSO4 and extracted with CHCl3. The combined organic
layers were dried over Na2SO4, filtered und concentrated under
reduced pressure to give the desired product as a yellow solid (7.0
g, 98% yield; a two-step procedure from compound 14 gave
Methyl 3-(p-tolyl)bicyclo[1.1.0]butane-1-carboxylate (21):
1
yield 5.2 g, 50%. The same procedure as for 19 was used. H
NMR (500 MHz, CDCl3) δ 7.19 (d, J = 7.8 Hz, 2H), 7.11 (d, J =
7.7 Hz, 2H), 3.49 (s, 3H), 2.90 (s, 2H), 2.32 (s, 3H), 1.58 (s, 2H).
13C {1H} NMR (126 MHz, CDCl3) δ 170.4, 136.9, 130.5, 129.4,
126.0, 51.9, 35.9, 33.3, 23.0, 21.3. HRMS (ESI-TOF) m/z: [M +
H]+ calcd for C13H15O2, 203.1072; found 203.1073.
1
product 17 in 62% yield). m.p. 150-152 °C. H NMR (500 MHz,
CDCl3) δ 11.01 (br s, 1H), 7.44 – 7.27 (m, 5H), 2.71 (s, 2H), 2.18
(t, J = 10.1 Hz, 2H). 13C {1H} NMR (126 MHz, CDCl3) δ 171.3,
131.9, 128.8, 128.6, 127.2, 121.8 (t, J = 299.7 Hz), 55.3 – 55.0
(m), 50.4 – 50.0 (m), 43.4 (t, J = 5.9 Hz). 19F NMR (470 MHz,
CDCl3) δ -120.85 (t, J = 10.0 Hz). HRMS (ESI-TOF) m/z: [M +
H]+ calcd for C12H10F2NaO2, 247.0547; found 247.0549.
Methyl 3-(4-(trifluoromethyl)phenyl)bicyclo[1.1.0]butane-1-
carboxylate (18)
Methyl-2,2-difluoro-3-(4-
(trifluoromethyl)phenyl)bicyclo[1.1.1]pentane-1-carboxylate
(23) ): yield 3.1 g, 41%. The same procedure as for 14 was used.
1H NMR (400 MHz, CDCl3) δ 7.62 (d, J = 8.9 Hz, 2H), 7.40 (d, J
= 9.0 Hz, 2H), 3.80 (s, 3H), 2.66 (s, 2H), 2.16 (t, J = 11.0 Hz,
2H). 13C {1H} (126 MHz, CDCl3) δ 165.5, 136.0, 130.8 (q, J =
32.6 Hz), 127.7, 125.7 (q, J = 3.7 Hz), 127.5 – 120.1 (m), 54.5 (t,
J = 19.5 Hz), 52.4, 50.5 (t, J = 19.6 Hz), 43.4 (t, J = 7.0 Hz). 19F
NMR (376 MHz, CDCl3) δ -63.3 (s), -121.2 (t, J = 11.0 Hz).
HRMS (ESI-TOF) m/z: [M + H]+ calcd for C14H12F5O2, 307.0757;
found 307.0759.
Methyl-2,2-difluoro-3-(4-fluorophenyl)bicyclo[1.1.1]pentane-
1-carboxylate (24): yield 2.1 g, 65%. The same procedure as for
14 was used. 1H NMR (400 MHz, CDCl3) δ 7.27 – 7.18 (m, 2H),
7.02 (m, 2H), 3.77 (s, 3H), 2.59 (s, 2H), 2.08 (t, J = 8.1 Hz, 2H).
13C {1H} NMR (101 MHz, CDCl3) δ 165.7, 162.9 (d, J = 247.3
Hz), 129.0 (d, J = 8.3 Hz), 128.0, 122.9 (t, J = 295.6 Hz), 115.8
(d, J = 21.8 Hz), 54.3 (t, J = 19.2 Hz), 52.4, 50.3 (t, J = 19.5 Hz),
43.3 (t, J = 7.1 Hz). 19F NMR (376 MHz, CDCl3) δ -113.6, -
121.6. HRMS (ESI-TOF) m/z: [M + H]+ calcd for C13H12F3O2,
257.0789; found 257.0789.
A
solution
of
methyl
3-chloro-3-(4-
(trifluoromethyl)phenyl)cyclobutane-1-carboxylate (15 g, 0.051
mol, 1 equiv) in THF (100 mL) was added dropwise to a
suspension of NaH (60%) (2.2 g, 0.055 mol, 1.07 equiv) in THF
(100 mL) at room temperature. The mixture was stirred overnight
at room temperature. The mixture was quenched with water and
diluted with MTBE. The mixture was washed with water, brine,
dried over Na2SO4, filtered und concentrated under reduced
pressure to give the desired product as yellow oil. Yield 9.8 g,
75%. 1H NMR (400 MHz, CDCl3) δ 7.54 (d, J = 8.1 Hz, 2H), 7.38
(d, J = 8.0 Hz, 2H), 3.49 (s, 3H), 2.95 (s, 2H), 1.65 (s, 2H). 13C
{1H} (126 MHz, CDCl3) δ 169.5, 138.4, 129.1 (q, J = 32.6 Hz),
126.2, 125.5 (q, J = 3.8 Hz), 124.3 (dd, J = 543.7, 271.7 Hz),
52.1, 36.1, 31.7, 24.6. 19F NMR (376 MHz, CDCl3) δ -63.0.
Methyl-3-(4-bromophenyl)-2,2-difluorobicyclo[1.1.1]pentane-
1-carboxylate (25): yield 2.15 g, 47%. 1H NMR (400 MHz,
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The Journal of Organic Chemistry
CDCl3) δ 7.49 (d, J = 8.1 Hz, 1H), 7.15 (d, J = 8.0 Hz, 1H), 3.80
5H), 3.92 (s, 2H), 2.36 (s, 2H), 1.79 (t, J = 10.7 Hz, 2H), 1.68 (s,
1H). 13C {1H} NMR (126 MHz, CDCl3) δ 133.3, 128.6, 128.0,
127.2, 123.9 (t, J = 293.2 Hz), 57.8, 55.3 (t, J = 19.2 Hz), 52.6 (t,
J = 18.8 Hz), 41.0 (t, J = 8.0 Hz). 19F NMR (376 MHz, CDCl3) δ -
123.8 (s). HRMS (ESI-TOF) m/z: [M + Na]+ calcd for
C12H12F2NaO, 233.0754; found 233.0754.
1
2
3
4
5
6
7
8
(s, 2H), 2.61 (s, 1H), 2.11 (t, J = 10.0 Hz, 1H). 13C {1H} (151
MHz, CDCl3) δ 165.6, 131.9, 131.1, 128.9, 122.8 (t, J = 295.8
Hz), 122.7, 54.4 (t, J = 19.4 Hz), 52.4, 50.4 (t, J = 19.6 Hz), 43.3
(t, J = 7.1 Hz). HRMS (ESI-TOF) m/z: [M + H]+ calcd for
C13H12BrF2O2, 316.9989; found 316.9990.
Methyl-2,2-difluoro-3-(p-tolyl)bicyclo[1.1.1]pentane-1-
2,2-Difluoro-3-(4-
carboxylate (26): yield 2.4 g, 67%. The same procedure as for 14
1
(trifluoromethyl)phenyl)bicyclo[1.1.1]pentane-1-carboxylic
acid (33): yield 0.12 g, 97%, white solid. The same procedure as
was used. H NMR (400 MHz, CDCl3) δ 7.22 – 7.05 (m, 4H),
3.79 (s, 3H), 2.61 (s, 2H), 2.35 (s, 3H), 2.09 (t, J = 9.6 Hz, 2H).
13C {1H} NMR (101 MHz, CDCl3) δ 166.0, 138.4, 129.4, 129.1,
1
9
for 17 was used. H NMR (400 MHz, CDCl3) δ 7.64 (d, J = 8.0
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
58
59
60
127.1, 122.8 (t, J = 318.4 Hz), 52.3, 43.3 (t, J = 7.1 Hz), 21.4. 19
F
Hz, 2H), 7.41 (d, J = 7.9 Hz, 2H), 2.72 (s, 2H), 2.21 (t, J = 10.1
Hz, 2H). 13C {1H} (126 MHz, CDCl3) δ 169.9, 135.8, 130.9 (q, J
= 32.6 Hz), 127.7, 125.8 (q, J = 3.6 Hz), 124.1 (q, J = 272.2 Hz),
122.8 (t, J = 296.5 Hz), 54.7 (t, J = 19.5 Hz), 50.3 (t, J = 19.6 Hz),
43.5 (t, J = 6.9 Hz). 19F NMR (376 MHz, CDCl3) δ -63.3, -121.2
(t, J = 11.0 Hz). HRMS (ESI-TOF) m/z: [M + Na]+ calcd for
C13H9F5NaO2, 315.0420; found 315.0425.
2,2-Difluoro-3-(4-fluorophenyl)bicyclo[1.1.1]pentane-1-
carboxylic acid (34): yield 0.1 g, 96%, white solid. The same
procedure as for 17 was used.1H NMR (500 MHz, CDCl3) δ 10.25
(br s, 1H), 7.31 – 7.23 (m, 2H), 7.07 (t, J = 8.3 Hz, 2H), 2.67 (s,
2H), 2.15 (t, J = 9.9 Hz, 2H). 13C {1H} NMR (126 MHz, CDCl3) δ
171.0, 163.0 (d, J = 247.6 Hz), 129.0 (d, J = 8.3 Hz), 127.8, 122.8
(t, J = 296.0 Hz), 115.8 (d, J = 21.7 Hz), 54.5 (t, J = 19.4 Hz),
50.2 (t, J = 19.2 Hz), 43.4 (t, J = 6.9 Hz). 19F NMR (470 MHz,
CDCl3) δ -112.82 – -112.91 (m, 1F), -121.05 (t, J = 9.9 Hz, 2F).
HRMS (ESI-TOF) m/z: [M + Na]+ calcd for C12H9F3NaO2,
265.0452; found 265.0453.
NMR (376 MHz, CDCl3) δ -121.5 (s). HRMS (ESI-TOF) m/z: [M
+ H]+ calcd for C14H15F2O2, 253.1040; found 253.1045.
Methyl 3-vinylbicyclo[1.1.0]butane-1-carboxylate (22)
The same procedure as for 18 was used. The organic phase after
work-up was washed with brine, dried over Na2SO4, filtered and
filtered again through SiO2. The resulted solution was evaporated,
and crude product 22 was immediately used for the next step
without additional purification. Upon storage, compound 22
decomposes at room temperature.
Methyl
-2,2-difluoro-3-vinylbicyclo[1.1.1]pentane-1-
1
carboxylate (27). The same procedure as for 14 was used. H
NMR (500 MHz, CDCl3) δ 5.85 (dd, J = 17.2, 10.9 Hz, 1H), 5.35
– 5.22 (m, 2H), 3.78 – 3.70 (m, 3H), 2.37 (s, 2H), 1.89 (t, J = 10.2
Hz, 2H). 19F NMR (376 MHz, CDCl3) δ -121.9 (s). The crude
product was used for the next step and purified on the last step.
2,2-Difluoro-3-phenylbicyclo[1.1.1]pentan-1-amine
hydrochloride (31). Compound 17 (2.4 g, 0.01 mol, 1 equiv) was
dissolved in 40 mL of t-BuOH. DPPA (3 g, 0.011 mol, 1.1 equiv)
and Et3N (1.7 mL, 0.012 mol, 1.2 equiv) were added to the
mixture. The mixture was brought to reflux for 2 d. Then the
mixture was cooled to RT and concentrated under reduced
pressure. The residue was dissolved in EtOAc, washed with an aq.
solution of NaHCO3 (4 times) and brine (1 time). The mixture was
partitioned. The organic phase was dried over Na2SO4, filtered
and concentrated under reduced pressure. The crude N-Boc
product was dissolved in 4 M HCl-Dioxane (30 mL). The mixture
was stirred overnight. Then the mixture was diluted with 30 mL
of Et2O and filtered. Yield 1.7 g, 70%, white solid.1H NMR (500
MHz, DMSO-d6) δ 9.67 (br s, 2H), 7.43 – 7.37 (m, 3H), 7.33 –
7.29 (m, 2H), 2.45 (s, 2H), 2.22 (t, J = 10.1 Hz, 2H). 13C {1H}
NMR (126 MHz, DMSO-d6) δ 130.2, 128.7, 128.5, 127.2, 122.3
(t, J = 294.7 Hz), 52.8 (t, J = 20.0 Hz), 51.1 (t, J = 18.3 Hz), 42.5
(t, J = 6.4 Hz). 19F NMR (470 MHz, DMSO-d6) δ -122.8 (t, J =
10.3 Hz). Anal. calcd for C11H12ClF2N: C, 57.03; Cl, 15.30; N,
6.05. Found: C, 57.18; Cl, 15.11; N, 6.25.
3-(4-Bromophenyl)-2,2-difluorobicyclo[1.1.1]pentane-1-
carboxylic acid (35): yield 0.315 g, 95%, white solid. H NMR
1
(400 MHz, CDCl3) δ 9.03 (br s, 1H), 7.50 (d, J = 8.2 Hz, 2H),
7.15 (d, J = 8.2 Hz, 2H), 2.66 (s, 2H), 2.15 (t, J = 10.1 Hz, 2H).
13C {1H} (101 MHz, CDCl3) δ 170.5, 132.0, 130.8, 128.9, 122.8,
122.7 (t, J = 296.4 Hz), 54.6 (t, J = 19.4 Hz), 50.2 (t, J = 19.6 Hz),
43.3 (t, J = 7.0 Hz). 19F NMR (376 MHz, CDCl3) δ -121.3 (s).
HRMS (ESI-TOF) m/z: [M + H]+ calcd for C12H9BrF2O2,
301.9754; found 301.9757.
2,2-Difluoro-3-(p-tolyl)bicyclo[1.1.1]pentane-1-carboxylic acid
(36): yield 0.3 g, 98%, white solid. The same procedure as for 17
1
was used. H NMR (500 MHz, CDCl3) δ 7.18 (s, 4H), 2.66 (s,
2H), 2.36 (s, 3H), 2.13 (t, J = 10.1 Hz, 2H). 13C {1H} NMR (126
MHz, CDCl3) δ 171.0, 138.5, 129.5, 128.9, 127.1, 122.9 (t, J =
296.0 Hz), 55.0 (t, J = 19.3 Hz), 50.1 (t, J = 19.5 Hz), 43.4 (t, J =
6.9 Hz), 21.4. 19F NMR (470 MHz, CDCl3) δ -121.0 (t, J = 10.1
Hz). HRMS (ESI-TOF) m/z: [M + Na]+ calcd for C13H12F2NaO2,
261.0703; found 261.0710.
2,2-Difluoro-3-vinylbicyclo[1.1.1]pentane-1-carboxylic
acid
2,2-Difluoro-3-phenylbicyclo[1.1.1]pentan-1-yl)methanol (32).
A solution of compound 14 (5 g, 0.020 mol, 1 equiv) in THF (50
mL) was added to a suspension of LiAlH4 (0.53 g, 0.014 mol, 0.7
equiv) in THF 100 mL at 0 °C dropwise. The mixture was stirred
at RT overnight. Then, a saturated aq. solution of NaHSO4 was
added dropwise. THF was removed under reduced pressure and
the aqueous residue was extracted with CHCl3. The combined
organic layers were dried over Na2SO4, filtered and concentrated
under reduced pressure to give the desired product as colorless oil.
(37): yield 0.15 g, 75%, yellow oil. The same procedure as for 17
was used. 1H NMR (400 MHz, CDCl3) δ 9.92 (br s, 1H), 5.85 (dd,
J = 17.3, 10.9 Hz, 1H), 5.37 – 5.26 (m, 2H), 2.41 (s, 2H), 1.91 (t,
J = 10.2 Hz, 2H). 13C {1H} NMR (126 MHz, CDCl3) δ 173.7,
171.0, 127.6, 123.7 (t, J = 295.7 Hz), 121.0, 54.2 (t, J = 19.4 Hz),
50.5 (t, J = 19.8 Hz), 42.9 (t, J = 7.0 Hz). 19F NMR (376 MHz,
CDCl3) δ -121.9 (s). HRMS (ESI-TOF) m/z: [M + Na]+ calcd for
C8H8F2NaO2, 197.0390; found 197.0395.
1
Yield 4 g, 95%. H NMR (400 MHz, CDCl3) δ 7.49 – 7.07 (m,
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2,2-Difluoro-3-(methoxycarbonyl)bicyclo[1.1.1]pentane-1-
carboxylic acid (38). Compound 27 (0.24 g, 1.28 mmol, 1 equiv)
was dissolved in a mixture of solvents (11 mL of CCl4+13 mL of
CH3CN and 22 mL of water), then NaIO4 (2 g, 8.96 mmol, 7
equiv), NaHCO3 (0.35 g, 4.17 mmol, 3.25 equiv) and cat.
RuCl3*H2O (2 mg, 0.01 equiv) were added. The mixture was
stirred overnight at RT. The mixture was filtered and NaHCO3
(0.35 g, 4.17 mmol, 3.25 equiv) was added to the filtrate. The
mixture was filtered again and the solid residue washed with
CH3OH. The mixture was acidified with NaHSO4 and extracted
with CHCl3. The combined organic phases were concentrated
under reduced pressure to give the desired product. Yield 0.13 g,
50%. 1H NMR (500 MHz, CDCl3) δ 9.40 (br s, 1H), 3.77 (s, 3H),
2.61 (s, 2H), 2.19 (t, J = 9.6 Hz, 2H). 13C {1H} NMR (126 MHz,
CDCl3) δ 169.4, 164.9, 121.7 (t, J = 296.7 Hz), 52.6, 50.7 (t, J =
15.5 Hz), 50.5 (t, J = 15.7 Hz), 43.2 (t, J = 6.1 Hz). 19F NMR (470
MHz, CDCl3) δ -119.4 (t, J = 9.8 Hz). HRMS (ESI-TOF) m/z: [M
+ Na]+ calcd for C8H8F2NaO4, 229.0288; found 229.0291.
purified by column chromatography (EtOAc/hexanes). Yield 0.4
g, 31%, white solid. H NMR (400 MHz, CDCl3) δ 11.18 (br s,
1
1
2
3
4
5
6
7
8
1H), 7.44 – 7.29 (m, 5H), 3.11 (d, J = 10.2 Hz, 1H), 2.66 – 2.57
(m, 1H), 2.48 (s, 1H), 2.22 (dd, J = 18.0, 2.7 Hz, 1H). 13C {1H}
NMR (101 MHz, CDCl3) δ 171.4, 132.0, 128.8, 127.2, 114.3 (d, J
= 297.8 Hz), 57.1 (d, J = 18.4 Hz), 51.9 (d, J = 18.6 Hz), 46.8 (d,
J = 11.1 Hz), 45.3 (d, J = 7.3 Hz). 19F NMR (376 MHz, CDCl3) δ
-111.2 HRMS (ESI-TOF) m/z: [M
+
Na]+ calcd for
C12H10ClFNaO2, 263.0251; found 263.0252.
9
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
58
59
60
ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the
website.
Copies of spectra, X-Ray of compound 17 (CCDC 1922933) and
experimental lipophilicity and solubility data.
AUTHOR INFORMATION
[1,1'-Biphenyl]-4-yl(piperidin-1-yl)methanone (44): yield 0.1 g,
72%, white solid. Compound was prepared according to a
previously reported procedure (S.W, Chung et al. Synlett 2011,
Corresponding Author
*pavel.mykhailiuk@gmail.com, www.mykhailiukchem.org
1
14, 2072). H NMR (500 MHz, DMSO-d6) δ 7.71 (dd, J = 11.5,
8.1 Hz, 4H), 7.47 (dd, J = 17.8, 7.8 Hz, 4H), 7.39 (t, J = 7.1 Hz,
1H), 3.68 – 3.30 (m, 4H), 1.66 – 1.38 (m, 6H). 13C {1H} NMR
(126 MHz, DMSO-d6) δ 168.6, 140.9, 139.4, 135.4, 129.0, 127.8,
127.3, 126.7, 126.6, 49.1 – 48.0 (m), 42.4 – 41.5 (m), 26.0 (br s),
25.3 (br s), 24.0. HRMS (ESI-TOF) m/z: [M + H]+ calcd for
C18H20NO, 266.1545; found 266.1550.
(3-Phenylbicyclo[1.1.1]pentan-1-yl)(piperidin-1-yl)methanone
(45): yield 60 mg, 93%, white solid. 1H NMR (400 MHz, DMSO-
d6) δ 7.35 – 7.20 (m, 5H), 3.62 – 3.53 (m, 2H), 3.46 – 3.37 (m,
2H), 2.29 (s, 6H), 1.64 – 1.54 (m, 2H), 1.53 – 1.45 (m, 2H), 1.47
– 1.36 (m, 2H). 13C {1H} NMR (101 MHz, DMSO-d6) δ 166.8,
139.9, 128.2, 126.7, 125.9, 53.8, 46.0, 42.5, 42.0, 26.3, 25.3, 24.0.
HRMS (ESI-TOF) m/z: [M + H]+ calcd for C17H22NO, 256.1701;
found 256.1705.
(2,2-Difluoro-3-phenylbicyclo[1.1.1]pentan-1-yl)(piperidin-1-
yl)methanone (46): yield 70 mg, 91%, white solid. 1H NMR (500
MHz, DMSO-d6) δ 7.66 – 7.06 (m, 5H), 3.53 (br s, 2H), 3.45 (br
s, 2H), 2.57 (s, 2H), 2.30 (s, 2H), 1.67 – 1.39 (m, 6H). 13C {1H}
NMR (126 MHz, DMSO-d6) δ 161.9, 132.0, 128.6, 128.2, 126.9,
123.7 (t, J = 295.1 Hz), 53.8 (t, J = 19.0 Hz), 52.0 (t, J = 18.4 Hz),
45.5, 43.3 (t, J = 7.2 Hz), 42.5, 26.4, 25.2, 23.9. 19F NMR (470
MHz, DMSO-d6) δ -118.4 (t, J = 10.7 Hz). HRMS (ESI-TOF)
m/z: [M + H]+ calcd for C17H20F2NO, 292.1513; found 292.1513.
2-Chloro-2-fluoro-3-phenylbicyclo[1.1.1]pentane-1-carboxylic
acid (53). Compound 9 (1 g, 5.3 mmol) was dissolved in CH2Cl2.
Bu4NBr (0.84 g, 2.6 mmol) and 50% aqueous solution of NaOH
(16 g) were added to the mixture at 0 °C. Then, CHFCl2 was
bubbled through the mixture for 30 min. The mixture was stirred
overnight at RT. After that, it was diluted with 20 mL of water.
The organic phase was separated. The aqueous layer was washed
with CH2Cl2, acidified with a 2 M solution of NaHSO4 and
extracted with CH2Cl2 (2 × 15 mL). The combined layers were
dried over Na2SO4, filtered and concentrated under reduced
pressure to give the title compound. The crude product was
ACKNOWLEDGMENT
We thank Prof. A. Tolmachev (Enamine) for financial support of
this project, Dr. E. Rusanov (IOC) for X-Ray crystallographic
analysis of acid 17, Dr. S. Shishkina for the help with analysis of
CCDC database, Dr. D. Panov for the synthesis of model
compounds 44-46, Mrs. I. Sadkova for the help with the
preparation of the manuscript.
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