Synthesis and studies on gem-fluorinated 2-azabicyclo[n.1.0]alkanes

Article abstract of DOI:10.1016/j.jfluchem.2015.03.008

Three novel amines all possessing gem-difluorocyclopropane, secondary amino group and a fused aliphatic cycle were synthesized by difluorocyclopropanation of N-Boc protected enamides. The compounds were stable when amino group was blocked by protonation o

Full text of DOI:10.1016/j.jfluchem.2015.03.008

Accepted Manuscript
Title: Synthesis and studies on gem-fluorinated
2-azabicyclo[n.1.0]alkanes
Author: Vladimir Kubyshkin Yurii Kheylik Pavel K.
Mykhailiuk
PII:
S0022-1139(15)00090-1
DOI:
Reference:
http://dx.doi.org/doi:10.1016/j.jfluchem.2015.03.008
FLUOR 8533
To appear in:
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Received date:
Revised date:
Accepted date:
23-2-2015
16-3-2015
22-3-2015
Please cite this article as: V. Kubyshkin, Y. Kheylik, P.K. Mykhailiuk, Synthesis and
studies on gem-fluorinated 2-azabicyclo[n.1.0]alkanes, Journal of Fluorine Chemistry
(2015), http://dx.doi.org/10.1016/j.jfluchem.2015.03.008
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*Graphical Abstract - Pictogram
Page 1 of 42

*Graphical Abstract - Synopsis
The paper describes three novel amines – analogues of pyrrolidine, piperidine and
azepane – in terms of their stability, integral properties and structure. The amines have
their pKa around neutral values, and the transition to the basic form triggers their quick
fragmentation. In addition, we discuss the lipophilicity impact of the
difluorocyclopropane moiety and structural features.
Page 2 of 42

*Highlights (for review)
- the substances obtained via direct difluorocyclopropanation of corresponding ene-carbamates;
- deprotected substances possess different stability;
- fragmentation occurs by either intramolecular or intermolecular cyclopropane opening;
- the free amines undergo acid-base transition at neutral pH values;
- CF -fusion gives only minute impact on lipophilicity (slight increase).
2
Page 3 of 42

*Manuscript
Synthesis and studies on gem-fluorinated 2-azabicyclo[n.1.0]alkanes
Vladimir Kubyshkin1,2*, Yurii Kheylik1, Pavel K. Mykhailiuk1,3*
1 Enamine Ltd., Chervonotkatska str., 78, 02660, Kyiv, Ukraine
2 Institute of Organic Chemistry, Karlsruhe Institute of Technology (KIT), Fritz-Haber-Weg, 6, 76131,
Karlsruhe, Germany
Present address: Institute of Chemistry, Technical University of Berlin, Müller-Breslau-Str., 10, 10623,
Berlin, Germany
3 Chemistry Department, Kyiv National Taras Shevchenko University, Volodymyrska str., 64, 01601, Kyiv,
Ukraine
*corresponding authors:
Vladimir Kubyshkin (V.K.) kubyshkin@win.tu-berlin.de
Tel: +493031423661; Fax.: +493031428279
Pavel K. Mykhailiuk (P.K.M.) pavel.mykhailiuk@gmail.com; pavel.mykhailiuk@mail.enamine.net
Abstract
1
Page 4 of 42

Three novel amines all possessing gem-difluorocyclopropane, secondary amino group and a fused
aliphatic cycle were synthesized by difluorocyclopropanation of N-Boc protected enamides. The
compounds were stable when amino group was blocked by protonation or acylation, but otherwise
underwent fragmentation already at the room temperature. Chemical structure, physico-chemical
properties and fragmentation mechanisms of the fluorinated amines are studied in details.
Keywords
cyclic amine; cyclopropane; difluorocyclopropane; 19F MNR; fragmentation
2
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1. Introduction
Cyclic aliphatic amines 1 are important structural fragments in medicinal and combinatorial
chemistry (Fig. 1) [1]. Through variations of the skeletons and ring substituents in such cyclic structures it
is possible to modulate several important features of the parent moieties, such as electronic and
conformational properties. Through these structural variations it is possible to realize a modulation in the
pKa values, or to fix certain conformational angles important for the molecular recognition and
biomolecular affinity. Also, changes to corresponding amide bond properties are also important;
particularly nitrogen pyramidalization and the conjugation energies and rotational barriers [2]. Considering
biomedical applications, modifications to cyclic amine moieties should not lead to a significant increase in
the molecular size and lipophilicity, i.e. the final compounds should fulfill Lipinski‟s rule of 5.
The high importance of the development of new small molecular fragments in drug design has
been emphasized [3]. One of the more recent examples of this is design of 4-aryl-piperidines 2 with the
cyclic fusion at the β,γ-site, with respect to the nitrogen, that enabled controlled modification of the
molecular conformation [4].
Fig.1. Cyclic aliphatic amines: 1 – general structure which allows variability in the ring size and substituents; 2 – recently reported 4-
aryl-piperidines with systematic variations of the β,γ-fused ring for different conformational restriction; 3, 4 – 4,5-methanoprolines;
5 – gem-difluoro-4,5-trans-methanoproline unstable as free amino acid (5), but stable in peptides (5a).
It is not only medicinal chemistry that requires availability of the cyclic amine scaffolds. Through
the simple introduction of the carboxyl group, this transforms cyclic amines into amino acids, α-[5], β-[6],
3
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γ- and so on. The former will make corresponding amine an analogue of proline (Pro), and depending on
the ring size, an analogue of azetidin-2-carboxylic acid (Aze) or pipecolic acid (Pip). These analogues are
powerful tools for modifications of the peptides and proteins towards site-specific polarity changes [7].
Furthermore, since the initial cyclic scaffolds bear a certain degree of conformational restriction,
incorporation of further substituents into the ring system may enhance conformational populations, for
example the proline puckers and amide bond rotamers in fluoroprolines [8]. Drawing analogies with
proline, these chiral cyclic secondary amines are potential candidates for catalytical activity in asymmetric
cascade reaction [9]. For example, 4,5-methanoprolines (3,4) have demonstrated good organocatalytic
performance due to the strong conformational impact of the cyclopropane moiety [10].
The cyclopropane moiety has one of the strongest influences on the conformational properties of
various substrates [11,12]. When fused to a cyclic amine [13] a cyclopropane ring may also significantly
change electronic properties of the amino functions, especially when the fusion site is α,β-. The
conventional methods for formation of a cyclopropane ring on a donor scaffold, such as Simmons-Smith
reaction, cyclopropanation with diazomethane or organometalic reagents [14] often suffer from poor
yields and often present significant safety issues. Interestingly, one of the easiest ways to construct a
cyclopropane ring on a desired scaffold molecule is through difluorocyclopropanation (for instance, this
was the case for 2a). This requires generation of highly electrophilic difluorocarbene species, which then
readily reacts with donor alkenes [15]. New methods for difluorocyclopropanation are being regularly
developed, and new relatively mild methods with safe reagents become more and more available [16].
Fig. 2. Known amino-gem-difluorocyclopropanes 6-8. 9 – electronic effects in amino-gem-difluorocyclopropanes.
Construction of difluorocyclopropanes with an amino functionality in close proximity may cause
certain instabilities of the formed structures. For instance, from a number of published amino-
difluorocyclopropanes 5-8 (Fig. 2) [17,18,19,20] conditions for a ring push-pull opening 9 are reported for
4
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most of them. In particular, we recently reported the preparation of a novel amino acid –
difluoromethanoproline (F2MePro, 5), analogue of the trans-4,5-methanoproline 4 [21]. The substance
was stable when the amine functionality was protected (for instance, in peptides, 5a), but as a free amino
acid it rapidly decomposed at room temperature. One particularly interesting property of the F2MePro
residue is the dispersion of the 19F NMR chemical shift: two inequivalent geminal fluorine atoms appeared
extremely distant from one another in terms of the isotropic chemical shift (about 25 ppm difference).
Thus, three anisotropic parameters can be extracted from corresponding solid state 19F NMR spectra: two
chemical shift anisotropy values for individual fluorine atoms and one strong (dipolar) coupling for
orientation of the CF2-fragment as whole. Therefore, F2MePro was not only found to be an analogue of
proline for conformational changes, but a very promising 19F NMR probe as well [22].
Instability of the difluorocyclopropane with the oxygen substituents has not been a big concern
since several studies reported them to be stable [23]. Only very recently, a difluorocyclopropane ring-
opening has been recognized as a synthetic method towards fluoroenones, or difluorohomologation
(Scheme 1) [24,25].
Scheme 1. Synthetic methods based upon fragmentation of siloxydifluorocyclopropanes: A. reported by Kageshima et al. on cyclic
scaffolds [24]; B. reported by Kosobokov et al. investigation towards difluorohomologation of ketons [25].
In this work, we designed, synthesized and studied novel 2-azabicyclo[n.1.0]alkanes 10-12 (Fig.
3). Due to the close positioning of the amino group to the difluorocyclopropane in a constrained bicyclic
system we expected a significant mutual electronic and conformational influences. These properties will
make 10-12 useful for various applications, both as amine moieties and as molecular skeletons for the
5
Page 8 of 42

construction of functionalized molecules (e.g. amino acids). However, the first question to be answered
was: how stable are these substrates and what are the factors affecting their stability? Can they be
handled and which conditions are they able to tolerate?
Fig. 3. Amines 10-12 reported in this study.
6
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2. Results and discussion
2.1. Synthesis
Scheme 2. Synthesis of the amines 10*TFA, 11*TFA, 12*TFA.a
a TFA = trifluoroacetic acid, TFDA = trimethylsilyl difluoro(fluorosylfonyl)acetate.
Highly energetic gem-difluorocyclopropanes are active towards chemical transformations [26,27].
Therefore, their synthesis requires a source of more reactive difluorocarbene species. We performed the
preparation of the desired amines by difluorocyclopropanation of the corresponding N-Boc enamides,
obtained in turn from the N-Boc lactams [28] (Scheme 2).
First we tried the oldest, and certainly one of the cheapest reagents - sodium chlorodifluoroacetate
[29,30]. Despite the drastic reaction conditions (refluxing diglyme, large excess of the carbene precusor)
we managed to obtain the N-Boc amines 14 and 15 in 73 and 36% yields, respectively (Scheme 2). Ten
equivalents of the salt were enough to achieve the full conversion of the starting compounds [31]. The
same synthesis on the 5-membered ene-carbamate 13 (N-Boc pyrroline) failed, yielding a complex
mixture.
7
Page 10 of 42

Subsequently we attempted the reaction with the Dolbier reagent - FSO2CF2CO2TMS (TFDA) [32]. In
fact, the desired N-Boc amine 13 was obtained in 52% yield with TFDA. Also, with TFDA we improved the
yield of product 15 to 64%.
As a short summary, we obtained the stable N-Boc amines 13-15 in gram scale. However, we
noticed that (only) carbamate 13 changed its color to more intense upon storage during several months at
the room temperature, and precipitated visible amounts of solid byproducts. We were also able to detect
impurities by NMR, with the substrate showing complete decomposition after about a year and a half.
8
Page 11 of 42

2.2. Stability
The N-Boc protection group in 13-15 was removed with trifluoroacetic acid (TFA) in dichloromethane
in a conventional manner (Scheme 2). The resulting salts contained approximately 2 equivalents of TFA
1
per amine 10-12. Stability studies were conducted then by H and 19F NMR spectroscopy; this data is
summarized in Table 1.
Table 1. Properties of substances 5 and 10-12.
δ(1H) of
Half-life
Compound
pKa
CH-1,
ppma
TFA salts
D2O
Free amines
CDCl3
pH = 7.6b
CDCl3
pH = 4.4b
n.d.c
instant
n.d.c 110±10
39±5
min
n.d.c
3.93
3.78
n.d.c
min[d]
decompositione
3±1
> 6.4
3±1 days
stablef
58±11 min
38±2 days
instant decomposition
days
2±1
7.1±0.1
6.7±0.1
3.34
3.48
stablef
stablef
80±5 min
days
6±2
stablef
72±6 days
120±10 min
days
a
b
c
d
Measured in D2O solution of the trifluoroacetates. In sodium phosphate buffer. Not determined. The number found for
the corresponding methyl ester (the free amino acid salt was found to be insoluble in chloroform). e The measurement was made in
deuterium oxide and extrapolated on other conditions here. f Measurements were conducted for 5 (CDCl3) and 15 (D2O) months.
9
Page 12 of 42

Several conclusions can be made from data in Table 1: 1) none of the amines was stable under
all the conditions investigated; 2) the basic forms are less stable than the protonated ones; 3) their
stability increases with the enlargement of the ring size. The drastic difference in stability occurred
between 10 and 11, when just one additional methylene in the ring led to a much more stable amine.
Thus we proved that the intrinsic instability of the amino acid 5 was mainly caused by the instability of its
bicyclic core. In general the stability row can be summarized as following: 5 < 10 << 11 < 12.
We noticed that in aqueous phosphate buffers the salt and base forms of 11 and 12 exhibited
somewhat different 19F NMR chemical shifts and 2JF-F couplings displaying characteristic sigmoidal curves
(Fig. 3). Thus direct pKa determination was possible, and the corresponding values were found to be 7.1
and 6.7, for 11 and 12 respectively. In contrast, 10 only underwent a massive decomposition starting
2
already from pH 6.2-6.4 without any deviation for values of chemical shift or J. This was an indication
that decomposition of 10 underwent instantaneously when transformed to the free base. If we consider
the latter event to occur on the beginning of the sigmoidal transition, then the pKa of 10 should not be
lower than its homologs 11 and 12. If we compare the observed pKa values to common cyclic secondary
amines such as piperidine (pKa = 11.2) we find general reduction of the basicity by four orders of
magnitude. Such a decrease is quite close to the predicted values [33]. Also, we demonstrated recently,
that three β-fluorine atoms can reduce the basicity by up to six orders of magnitude [34], therefore two β-
fluorines in 10-12 can be estimated to four orders difference within a linear approximation.
10
Page 13 of 42

Figure 3. pH dependence of the exo-19F resonance positions of 10-12.a
a with respect to the TFA signal (-75 ppm); measured in aqueous phosphate buffers at 25°C.
1
Comparison of the H NMR spectra for 10*TFA and 11*TFA revealed an interesting tendency,
that all the resonances in the former case were shifted by 0.31-0.55 ppm downfield. The most critical
position is CH-1, which is a prominent electrophilic center of the molecule, was shifted downfield by
0.44 ppm. Nevertheless, systematic comparison of the CH-1 chemical shift for the entire row (Table 1) did
not correlate with the stabilities in a straightforward manner.
For the amines 10-12 we found several J-coupling constants which correlated with the stability -
those were 2JF-F, 1JC-H within the cyclopropane ring and N-CH2 (Table 2). Curiously, couplings of this type
have a strong Fermi contact term contribution [35,36,37]. The interpretation of the J-coupling tendencies
2
1
is not a straightforward task. However, neither geminal JF-F nor cyclopropane JC-H exhibit sensitivity to
hybridization state of the cyclopropane carbons [35,37]. Therefore we could assume those differences do
not arise from the changes in cyclopropane hybridization state and geometry associated with it (see also
chapter „structure‟ below). We presume, such a systematic change of the J-values reveals a different
electrophilic influence of the CH2-chained (large) ring to the cyclopropane similar to what we emphasized
for the chemical shifts above. Indeed, increasing numbers of the CH2 may lead to a better electron
donating compensation (acc to +I effect) to the electronically poor amino-difluorocyclopropane system 9,
11
Page 14 of 42

increasing its stability. This is why, we suspect, amino acid 5 (with an additional electron-withdrawing
carboxyl-group) turned out to be less stable than its parent amine 10.
Table 2. J-coupling values deviated along with the ring size variations in 10-12*TFA salts.a
amine*TFA 2JF-F, Hz
1JC-H-1, Hz 1JC-H-3, Hz 1JC-H-(4+n), Hz
10, n = 1
11, n = 2
12, n = 3
177
173
171
195
189
187
150
147
145
177
167
167
a Measured in deuterium oxide solutions of the trifluoroacetates at 298 K.
However, such simple treatment does not explain the fact that the amines 10-12 are significantly
unstable in the first place. For instance, other cyclic structures 7 reported by Nowak et al. [18] required
2
high temperatures to undergo fragmentation. Among them the ones with the highest JF-F 152 Hz
delivered lowest yields in the synthesis and also required lower temperature for their full decomposition
2
(e.g. 1 h at 100 °C).Nevertheless, from the practical perspective we can propose to use the value JF-F as
a simple criterion for predicting the instability of homologous difluorocyclopropanes: a higher J value
would imply lower stability expectations.
12
Page 15 of 42

2.3 Mechanism
Figure 4. 19F NMR spectra of the fragmentation of products 16 and 17.a
a
1
The two fluorine resonances correspond to the two diastereomers and the J-couplings originate from the neighboring H nuclei
(removed when 1H decoupled). The spectra also contained the TFA singlet (at -75 ppm) and inorganic fluoride (at -120 ppm).
We were able to assign the major product of the decomposition of amines 11, 12. Overnight
fragmentation of 11 and 12 under basic conditions (pH 7.6) led to formation of the substances 16 and 17
respectively. The assignment was based on the extensive NMR studies of the reaction mixtures (see SI).
One particularly characteristic observation was the presence of two 19F resonances at -207 – -211 ppm
1
(Fig. 4). They corresponded to two diastereomeric forms of the cyclic azomethine products (different H
multiplicity). Mechanistically, their formation should include cyclopropane ring-opening followed by
addition of a water molecule to the formed α-fluoro-α,β-unsaturated azomethines (Scheme 3). Though,
substances 16 and 17 turned out to be the sole fluorine-containing products along with the inorganic
fluoride (resonance at -120 ppm). Also both processes: the degradation of 11 and 12 and formation of 16
and 17 were found to be of the same 1st order kinetics and with the same τ of the reactions meaning that
½
the cyclopropane ring-opening was the rate-limiting step of the fragmentation. We also found very similar
19F NMR resonances in the final mixtures after three months fragmentation of 11 and 12 under acidic pH
= 4.4.
13
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Scheme 3. Fragmentation of the amines 11 and 12 in aqueous phosphate buffer.a
a
as found by detection of 16 and 17 respectively; pH 7.6, 25 °C.
We reported already that decomposition of the amino acid 5*TFA proceeds via formation of the
aldehyde 18, which thereafter undergoes further degradation [21]. However, upon monitoring the
decomposition of its parent amine 10*TFA (pH 4.4) we did not find any prominent dominant signals such
as the azomethine or aldehyde type, but solely the formation of a complex mixture. We suspect that the
kinetics of the reaction are unfavorable for the observation of the characteristic intermediates previously
described. For instance, if similar aldehyde to 18 (with R = H) were to form, it would not be formed in a
detectable amount in the mixture because its formation will be much slower (τ days vs minutes for 10
½
and 5 respectively). However, the fact that 10 decomposed already from the protonated form was
evidence that it decomposed according to a mechanism different from amines 11 and 12. For the rest of
the decomposition processes, referred in the Table 1, the mixture was found to be complex, and without
major distinguishable products. In particular, the degradation in chloroform was particularly complicated
because the formation of a defined product according to the above mentioned mechanisms would require
the presence of a water molecule (solvolysis).
14
Page 17 of 42

Scheme 4. Fragnemtation of F2MePro*TFA (5*TFA) in deuterium oxide solution as reported in [21].a
a
The starting substance degraded within the first 3 hours, whereas intermediate product was collecting in the mixture, reached
maximal concentration after 3 hours of observation and then degraded completely within the next 20 hours of monitoring.
Scheme 5. Fragmentation mechanisms for amino- and oxy-difluorocyclopropanes.
According to our findings and the literature data [18,19,20,24,25] of amino- and oxy-
difluorocyclopropanes, we can summarize their fragmentation mechanisms as depicted on Scheme 5.
Noteworthy, all of them involve the cleavage of the same C-C bond in cyclopropane on the initial step.
Mechanism A is an intermolecular nucleophilic attack (solvolysis) which occurs with the most electron
deficient species (like 5 or 10) and can proceed easily when amino-group is protonated. Mechanism B is
an intramolecular nucleophilic attack. This is the only mechanism possible for the amines 11 and 12 and
15
Page 18 of 42

also the mechanism for the pyrolysis of 7. In addition, this occurs when RX is a silyloxyl-substituent, in
particular when removing a silyl-protecting group (TBAF / THF, -78 °C) releases a highly nucleophilic
negatively charged O- which thereafter attacks the cyclopropane ring [24]. Mechanism C has only been
described for X = O, and it produces useful α,α-difluoroketones. therefore, this mechanism was the target
for the development of corresponding synthetic routes [24,25]. In particular in [25] it was the sole
fragmentation pathway when the initial cyclopropanated compound was treated with a strong acid in a
poorly nucleophilic medium (HCl / dioxane; HBr / acetic acid). It should be also noted, that only in the
case when X = N, the two mechanisms A and B can be discriminated based upon the observation of the
degradation products. Whereas when X = O, the two mechanisms produce the same α,β-unsaturated
ketone species.
16
Page 19 of 42

2.4. Derivatives
Scheme 6. Synthesis of amides 19, 20.
In order to demonstrate the practical potential of the synthesized amines 10-12, we performed their
acylation by 4-fluorobenzoylchloride in pyridine (Scheme 6). The derivatives 19 and 20 were prepared in
45% and 79% yields respectively, whereas amine 10 decomposed upon N-deprotection (0% yield). The
reaction yields correlated well with the previously observed stability order: 10 << 11 ≤ 12.
The solid acylated compounds 19, 20 (similar to N-Boc derivatives 14, 15) were stored at room
temperature without any detectable decomposition. Apparently the nitrogen lone pair was sufficiently
locked within either the amide or carbamate conjugated system, so that the intramolecular opening was
effectively impossible.
17
Page 20 of 42

2.5. Integral properties
For the stable substances 19 and 20, we measured the parameters important for medicinal
chemistry – water solubility, lipophilicity, metabolic stability – and compared the data to those of the
parent N-substituted piperidine (19) and azepane (20) (Table 3). In fact, the difluorocyclopropane slightly
increased the lipophilicity of both of the substances, but unexpectedly decreased the metabolic stability
(usually F-atom increases it), while keeping the water solubility almost constant. However, slide increase
in the lipophilicity may indeed reduce their metabolical stability [38].
It is also worth mentioning, that the difluorocyclopropane ring increased the melting point of the
compounds, probably by reducing (“freezing”) their conformational plasticity.
Table 3. Integral properties of the N-4-fluorobenzoyl secondary amines.
Solubility,
168±6
2.6±0.6
50
181±14
2.2±0.3
169±4
179±6
μMa
b
logD7.2
3.0±0.3
2.7±0.3
CLint ,
μl•mg-
42
82
76
1•min-1c
Melting
point, °C
62-63
108-109 oil
68-69
a In 10 mM potassium K-phosphate buffer (pH = 7.4) with 140 mM inorganic chloride. b Distribution between n-octanol and the
same buffer. c In mouse hepatic microsomes
An impact of a cyclopropane fusion on the net lipophilicity was expected to be small. Incorporation of
fluorine at a certain position in place of hydrogens has a dual influence. On the one hand, fluorine
substitution would increase the polarity, hence hydrophilicity, and on the other hand, increasing the
18
Page 21 of 42

molecular volume would increase lipophilicity [39,40]. The data we reported here on solubility and
distribution coefficient of amides 19-22 allow us to conclude, that the net influence of a
difluorocyclopropane fusion was rather modest. Previously, we reported on the gramicidin S analog with
the difluoromethanoproline 5 in place of one proline in the structure [22]. We found that the RP-HPLC
retention time (which is a very characteristic parameter for amphipathic peptides such as gramicidin S
[41]) was only slightly higher for the analog if compared to the wild type structure. Resultingly, the
microbiological activity values obtained for the analog were close to that of the gramicidin S wild type.
This observation supports our conclusion, that fusion with a difluorocyclopropane would generally
increase lipophilicity, albeit only slightly.
19
Page 22 of 42

2.6. Structure
Figure 5. X-ray crystal structures of the compounds 15, 19 and 20.a
a The sums of the nitrogen valency angles and the ring conformations are denoted.
Several compounds (15, 19 and 20) produced high quality crystals that could be analyzed by
X-ray diffraction [42]. The corresponding structures are shown on Fig. 5. In general, the structures were
consistent with what has been already known for difluorocyclopropanes [26]. Namely, the incorporation of
two geminal fluorine atoms in the cyclopropane unit led to shortening of the F2C-CH bonds (1.46-1.47 Å)
and stretching of the remaining CH-CH bond (1.54-1.55 Å). The latter C-C bond is the weakest one and it
is exactly the one that breaks in the fragmentation of corresponding amines. The F-C-F valency angle
20
Page 23 of 42

was also significantly shortened to about 108.3°, whereas in the parent cyclopropane H-C-H angle is
expected to be 115° [43].
Interestingly, the conformation of the large rings was found to be the same as if it was one carbon
atom shorter i.e. an envelope for the 6-membered ring in 19 and chair for the 7-membered ring in 15 and
20. Significant repulsion between the cyclopropane and the substituents at the carbonyl species led to
observable degree of nitrogen pyramidalization. Finally, the phenyl ring in 19 and 20 was found to be
pushed out of carbonyl plane significantly (by ~ 40°) regardless on the rotational state of the carbonyl (s-
cis in 19 or s-trans in 20).
The corresponding rotational properties of the carbamates (13-15) and amides (19-20) were
determined in the chloroform solution by EXSY NMR (Table 4). The rotational constants and
corresponding activation energies displayed several interesting properties. First, the amides were rotating
more freely than the carbamates, whereas for non-cyclopropanated species exactly the opposite would
normally be expected. This fact can be explained by considering the structure; we observed significant
repulsion of the phenyl-ring from the aliphatic ring, which might destabilize the ground structure of the
amide. For the carbamate species such a repulsion would not play a large role. Second, amide 20 and
carbamate 15 with a 7-membered large rings were rotating more freely than corresponding species with
the 6-membered large ring, 19 and 14 (7-8 kJ/mol difference in the activation energies). This was
surprising due to the fact that the amides of piperidine or morpholine are normally more freely rotating
than corresponding azepane or pyrrolidine derivatives [44]. Here again the heterocyclic rings exhibit
properties as if they were one carbon atom shorter, in a similar fashion as was seen in the structural
overview previously.
21
Page 24 of 42

Table 4. Amide rotamers rotational parameters for the N-Boc and N-4-fluorobenzoyl derivatives.a
Compo Kb
und
k1, s-1 c
Ea (k1),
kJ/mold
64
k-1, s-1 c
13
14
15
19
1.60±0.15 36.7±0.5
4.70±0.11 5.5±0.3
7.65±0.15 190
22.2±1.3
1.2±0.05
24
69
60
2.89±0.06 33.0±1.6
64
11.1±0.4
20
3.0±0.3
350
58
120
a
b
the major rotamer was not determined due to the fast transition; determined by integration of the 1H and 19F NMR spectra
c
d
(chloroform, 25 °C); measured by either EXSY or coalescence; derived from the large rotation rate k1 according to the Eyring
equation.
22
Page 25 of 42

3. Conclusions
We have reported the synthesis and characterization of a series of novel bicyclic fluorinated amines 10-
12. The critical parameter of the substances was their stability, which increased with the enlargement of
the heterocyclic ring from 5- to 7-membered as 10 < 11 < 12. The most unstable substance 10
decomposed as protonated salt, whereas this was only possible if 11 and 12 were present as the free
bases, and thus followed different degradation mechanism. Though, the substances were stable as
amides or carbamates. Given their appropriate ADMET profile (lipophilicity, water solubility, metabolic
stability), we believe these compounds will become useful, in particular, in drug discovery as promising
building blocks.
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4. Experimental
4.1. General information
All chemicals were obtained from common sources. Diglyme was distilled under
sodium/benzophenone/argon, toluene was distilled under phosphorus pentoxide/air. The initial N-Boc 2-
pyrroline, 2,3-dehydropyrrolidine and 2,3-dehydroazepane were obtained by the convenient literature
protocol starting from pyrrolidone, valerolactame and caprolactame respectively [28]. For bulk
chromatographic separation silica gel 230-400 mesh of CC grade (Sudambe chemicals) was used.
1H and 13C{1H} spectra were recorded on Bruker Avance 400, Bruker Avance DRX 500 and Bruker
Avance III 500 devices and referenced to TMS using deuterium lock signal as the internal standard. 19F
NMR spectra were recorded on Varian UNITY Plus 400 and Bruker Avance III 500 spectrometers and
referenced to Freon-11. Mass spectra were recorded on Finnigan MAT90 device using EI ionization (70
eV). IR spectra were taken at Bruker Alpha spectrometer with a diamond ATR module. CHN-analysis was
done on varioMICRO cube analyzer. Thin layer chromatography was done on ALUGRAM® Xtra SIL
G/UV.
The NMR chemical shifts are given in ppm in the δ scale. The IR bands are in cm-1.
4.2. Difluorocyclopropanation
4.2.1. Tert-butyl 6,6-difluoro-2-azabicyclo[3.1.0]hexane-2-carboxylate (13)
Anhydrous toluene (150 ml), N-Boc 2-pyrroline (1.5 g; 8.9 mmol) and anhydrous lithium fluoride
(23 mg; 0.88 mmol) were mixed under argon, and the mixture was heated to reflux. After 30 min TFDA
(3.88 g; 15.5 mmol) in toluene solution (10 ml mixture volume) was added by 1 ml portions to the reaction
mixture over 140 min, while reflux was continued. The reaction mixture was refluxed for additional 5 h.
The solvent was removed under reduced pressure and resulting crude material was purified on a silica
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gel column using hexane – ethyl acetate 2:1 mixture as an eluent (Rf = 0.4). 1.01 g of the product was
obtained as orange oil (yield 52 %).
1H NMR (CDCl3, 500 MHz), Boc-rotamers (ratio 3:2): 3.86 and 3.71 (br m, 1H, N-CH) 3.68 (br m,
1H, N-CHH), 3.28 and 3.15 (two br m, 1H, N-CHH), 2.19 (m, 3H, CH-CH2), 1.45 (s, 9H, CH3). 13C NMR
(CDCl3, 126 MHz), Boc-rotamers: 154.3 (s, C=O), 111.9 (dd, J = 293 and 302 Hz, CF2), 80.0 (s, CMe3),
46.6 (br s, major) and 46.0 (br s, minor, N-CH2), 41.4 (dd, J = 11 and 15 Hz, N-CH), 27.9 (s, CH3), 26.7
(m, major) and 25.3 (m, minor, CH), 22.9 (s, minor) and 22.2 (s, major, CH2). 19F NMR (CDCl3, 376 MHz),
Boc-rotamers: -128.9 (dd, JF-F = 161, JF-H = 11 Hz, major) and -129.3 (dm, JF-F = 160 Hz, minor, exo-F), -
153.9 (d, JF-F = 160 Hz, minor) and -154.4 (d, JF-F = 161 Hz, major, endo-F). IR: 3076, 2974, 1683. Mass-
spectrum (m/z): 200, 164 [M-tBu+1]. CHN (found/calc.): 54.40/54.79 C, 6.86/6.90 H, 6.42/6.39 N.
4.2.2. Tert-butyl 7,7-difluoro-2-azabicyclo[4.1.0]heptane-2-carboxylate (14)
Solution of N-Boc 2,3-dehydropyrrolidine (1.5 g, 8.1 mmol) in anhydrous diglyme (100 ml) under
argon was heated to reflux in an oil bath (175-180°C in bath). Suspension of ClF2CCO2Na (12.5g, 82
mmol) in anhydrous diglyme (40 ml) was added to the reaction mixture over 25 min upon stirring. After 10
min the bath was removed and the mixture was allowed to cool down to ambient temperature. The
solvent was removed under reduced pressure and resulting crude material was purified on a silica gel
column using hexane – diethyl ether 2:1 mixture as an eluent (Rf = 0.5). 1.39 g of the product was
obtained as a pale yellow oil (yield 73 %).
1H NMR (CDCl3, 400 MHz), Boc-rotamers (ratio 4:1): 3.78 (dt, J = 13 and 4 Hz, major) and 3.54
(dt, J = 13 and 5 Hz, minor, 1H, N-CHH), 3.22 (dd, J = 8 and 11 Hz) and 3.12 (ddd, J = 2, 8 and 10 Hz,
major, 1H, N-CH), 2.67 (tm, J = 11 Hz, minor) and 2.48 (ddt, J = 11, 13 and 2 Hz, major, 1H, N-CHH),
1.81-1.62 (m, 3H, CH-CH2-CH2-CH2-N), 1.54-1.37 (m, 2H, CH-CH2), 1.41 (s, 9H). 13C NMR (CDCl3, 101
MHz), Boc-rotamers: 156.0 (s, C=O), 111.2 (dd, J = 286 and 290 Hz, CF2), 80.3 (s, minor) and 80.2 (s,
major, CMe3), 41.2 (s, minor) and 39.6 (d, J = 2 Hz, major, N-CH2), 33.1 (dd, J = 10 and 16 Hz, N-CH),
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28.3 (s, minor) and 28.2 (s, major, CH3), 22.0 (m, minor) and 21.8 (t, J = 2 Hz, major, CH2-CH2-N), 19.9 (t,
J = 11 Hz, major) and 19.6 (m, minor, CH), 14.8 (s, major) and 14.7 (s, minor, CH-CH2). 19F NMR (CDCl3,
376 MHz), Boc-rotamers: -131.5 (ddd, JF-F = 163, JF-H = 12 and 8 Hz, minor) and -132.0 (ddd, JF-F = 163,
JF-H = 13 and 8 Hz, major, exo-F), -153.7 (d, JF-F = 163 Hz, major) and -154.4 (d, JF-F = 163 Hz, minor,
endo-F). IR: 2976, 2940, 2870, 1699. Mass-spectrum (m/z): 134 [M]+, 114. CHN (found/calc.):
56.40/56.64 C, 7.12/7.35 H, 5.91/6.00 N.
4.2.3. Tert-butyl 8,8-difluoro-2-azabicyclo[5.1.0]octane-2-carboxylate (15)
Anhydrous toluene (150 ml), N-Boc 2,3-dehydroazepane (2.56 g, 13.0 mmol) and lithium fluoride
(17 mg, 0.65 mmol) were mixed under argon, and the mixture was heated to reflux. After 30 min TFDA
(5.18 g, 20.7 mmol) in toluene solution (10 ml mixture volume) was added to the stirred refluxed mixture
by 1 ml portions over 100 min. The mixture was refluxed for additional 4 h. The solvent was removed
under reduced pressure and the residue was purified on a silica gel column using hexane – ethyl acetate
4:1 mixture as an eluent (Rf = 0.35). 2.07 g of the product was obtained as colorless oil, which then
crystallized as white crystals (yield 64 %).
2,3-dehydroazepane (1.5 g; 7.6 mmol) was dissolved in anhydrous diglyme (75 ml) under argon
atmosphere, and the mixture was heated to reflux by an oil bath (175-180°C in bath). Suspension of
ClF2CCO2Na (11.6 g, 76 mmol) in anhydrous diglyme (40 ml) was added to the reaction mixture over 1 h
upon stirring. After 15 min the bath was removed and the mixture was allowed to cool down to ambient
temperature. The solvent was removed under reduced pressure and the residue was purified on a silica
gel column using hexane – diethyl ether 9:1 mixture as an eluent (Rf = 0.3). 0.68 g of the product was
obtained as a yellow oil (yield 36 %).
1H NMR (CDCl3, 500 MHz): 3.95 (d, J = 13 Hz, 1H, N-CHH), 2.93 (dd, J = 10 and 13 Hz, 1H, N-
CH), 2.79 (t, J = 12 Hz, 1H, N-CHH), 1.99 (m, 1H, CHH), 1.80-1.64 (m, 3H, CHH, CHH and CH), 1.54-
1.36 (m, 3H, CHH, CHH and CHH), 1.42 (s, 9H). 13C NMR (CDCl3, 126 MHz): 155.9 (s, C=O), 111.4 (t, J
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