Copper-catalyzed ligand free ring-opening amination of gem-fluorohalocyclopropanes – An efficient route toward 2-fluoroallylamines

Article abstract of DOI:10.1016/j.jfluchem.2017.01.001

Ring-opening amination of gem-chlorofluoro- and gem-bromofluorocyclopropanes with secondary alkyl, aryl amines or hydroxylamines catalyzed by copper(I) or copper(II) compounds with no additional ligands affords tertiary 2-fluoroallylamines or hydroxylamines in moderate to excellent yields. The reaction pathway involves isomerization of gem-fluorohalocyclopropanes to 2-fluoroallyl halides followed by in situ nucleophilic substitution of a halide by an N-nucleophile. The p-methoxyphenyl (PMP) protective group is efficient in the preparation of secondary 2-fluoroallylamines by this method. Primary 2-fluoroallylamines can only be obtained by a stepwise protocol including CuX-catalyzed isomerization of gem-fluorohalocyclopropanes to 2-fluoroallylic halides followed by amination.

Full text of DOI:10.1016/j.jfluchem.2017.01.001

Accepted Manuscript
Title: Copper-catalyzed ligand free ring-opening amination of
gem-fluorohalocyclopropanes—an efficient route toward
2-fluoroallylamines
Author: <ce:author id="aut0005"
author-id="S002211391630464X-
afd51322210762699895400ed2963015"> Maxim A.
Novikov<ce:author id="aut0010"
author-id="S002211391630464X-
07d675efaef33ba3bcf6c2aff75710cc"> Yaroslav A.
Ibatov<ce:author id="aut0015"
author-id="S002211391630464X-
b8b19b2140a88fb38fe4fb9cc281905e"> Nikolai V.
Volchkov<ce:author id="aut0020"
author-id="S002211391630464X-
1c374568db1d94cb75a5dcf0913bf8e4"> Maria B.
Lipkind<ce:author id="aut0025"
author-id="S002211391630464X-
791b2b0d9e5d9d2cbc1ad25d8146d141"> Sergei E.
Semenov<ce:author id="aut0030"
author-id="S002211391630464X-
edc7dc7dee7650e0b50bc37f917a415d"> Oleg M.
Nefedov
PII:
S0022-1139(16)30464-X
DOI:
Reference:
http://dx.doi.org/doi:10.1016/j.jfluchem.2017.01.001
FLUOR 8926
To appear in:
FLUOR
Received date:
Revised date:
Accepted date:
19-11-2016
31-12-2016
1-1-2017
Please cite this article as: Maxim A.Novikov, Yaroslav A.Ibatov, Nikolai
V.Volchkov, Maria B.Lipkind, Sergei E.Semenov, Oleg M.Nefedov, Copper-
catalyzed ligand free ring-opening amination of gem-fluorohalocyclopropanes—an
efficient route toward 2-fluoroallylamines, Journal of Fluorine Chemistry
http://dx.doi.org/10.1016/j.jfluchem.2017.01.001

This is a PDF file of an unedited manuscript that has been accepted for publication.
As a service to our customers we are providing this early version of the manuscript.
The manuscript will undergo copyediting, typesetting, and review of the resulting proof
before it is published in its final form. Please note that during the production process
errors may be discovered which could affect the content, and all legal disclaimers that
apply to the journal pertain.

Copper-catalyzed ligand free ring-opening amination of gem-
fluorohalocyclopropanes — an efficient route toward 2-fluoroallylamines
Maxim A. Novikova,b*, Yaroslav A. Ibatovb, Nikolai V. Volchkova, Maria B. Lipkinda, and
Sergei E. Semenovb, and Oleg M. Nefedova*
a
N.D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, 47 Leninsky
prosp., 119991 Moscow, Russian Federation
b
Moscow Chemical Liceum 1303, Moscow South-Eastern Lyceum and Grammar School
Complex, 4 Tamozhennyy pr-d, 111033 Moscow, Russian Federation
Fax: +7499 135 63 90; e-mail: manovikov@ioc.ac.ru, nefedov@ioc.ac.ru
Graphical Abstract
(For the Web only)
(For the Print)

Copper-catalyzed
ring-opening
amination
of
gem-chlorofluoro-
and
gem-
bromofluorocyclopropanes easily prepared by carbenic cyclopropanation of olefins affords
tertiary 2-fluoroallyl amines in moderate to excellent yields.
Highlights
 Copper-catalyzed cyclopropyl-allylic rearrangements of gem-
fluorohalocyclopropanes.
 An effective approach to aryl-, alkyl substituted tertiary 2-fluoroallyl amines.
 Preparation of secondary 2-fluoroallyl amines using PMP-protective group.
 Synthesis of primary 2-fluoroallyl amines by Gabriel or Delepin amination of
halides.
Abstract
Ring-opening amination of gem-chlorofluoro- and gem-bromofluorocyclopropanes with
secondary alkyl, aryl amines or hydroxylamines catalyzed by copper(I) or copper(II)
compounds with no additional ligands affords tertiary 2-fluoroallylamines or hydroxylamines
in moderate to excellent yields. The reaction pathway involves isomerization of gem-
fluorohalocyclopropanes to 2-fluoroallyl halides followed by in situ nucleophilic substitution
of a halide by an N-nucleophile. The p-methoxyphenyl (PMP) protective group is efficient in
the preparation of secondary 2-fluoroallylamines by this method. Primary 2-fluoroallylamines
can only be obtained by a stepwise protocol including CuX-catalyzed isomerization of gem-
fluorohalocyclopropanes to 2-fluoroallylic halides followed by amination.

Keywords: gem-fluorohalocyclopropanes, fluorohalocarbenes, copper catalysis, 2-fluoroallyl
amines, ring-opening amination, cyclopropyl-allylic transformation
1. Introduction
The monofluoroalkenyl moiety is of continuously growing interest in modern medicinal
chemistry [1]. It can be found in a wide range of biologically active compounds developed in
the past few decades (figure 1). It manifests anticancer [2], antimicrobial [3], anti-HIV [4],
anti-diabetic [5] and other types of pharmacological activities. Moreover, monofluoroalkenes
can serve as promising bioisosters of amide bonds [6].
Rearrangements of gem-fluorohalocyclopropanes (halogen = fluorine, chlorine,
bromine) were found to be efficient for the construction of the monofluoroalkenyl moiety [7].
gem-Fluorohalocyclopropanes are readily available by carbene cyclopropanation of olefins
using a variety of inexpensive fluorohalocarbene sources [7] that makes these processes an
attractive alternative to other synthetic routes toward monofluoroalkenes [8],[9].
However, the gem-fluorohalocyclopropyl moiety itself is rather stable at elevated
temperatures and under ordinary acidic or basic conditions. The propensity of gem-
fluorohalocyclopropanes to undergo ring-opening rearrangements can be dramatically
increased by electron-donating substituents (e.g. alkoxy [10], amino [11] groups), by a
negative charge at an -position to the three-membered ring [12], or by incorporation into a
strained polycyclic system [13].
Ring-opening of non-activated gem-fluorohalocyclopropanes under mild conditions still
remains a challenge (scheme 1). In fact, thermolytic activation usually requires 350–650°C in
a gas phase or 150–200°C in a liquid phase and leads to the formation of 2-fluoro-1,3-dienes
[14] or fluoroarenes [15]. Silver(I) mediated conditions extensively studied by M. Schlosser,
P. Weyerstahl, R. Kostikov and some other groups are applicable to a variety of gem-
chlorofluoro- and gem-bromofluorocyclopropanes and give 2-fluoroallyl ethers, esters and
alcohols [16]. However, these processes require stoichiometric amounts of relatively
expensive silver(I) salts and this fact partially overrides the benefits generated by the
availability of the starting fluorohalocarbene sources (i.e. CHCl2F, CHBr2F).

Recently we reported the first catalytic ring-opening of gem-chlorofluoro- and gem-
bromofluorocyclopropanes in the presence of CuX (X = Cl, Br) [17]. These conditions made
it possible to synthesize not only 2-fluoroallylic O-derivatives but also 2-fluoroallyl chlorides
and bromides [18,19]. The recently reported [Pd0]/tBu-XPhos-catalyzed ring-opening of gem-
difluorocyclopropanes in the presence of various O,N,C-nucleophiles leading to the
corresponding 2-fluoroallylic compounds should also be mentioned [20]. However, in
addition to the fact that this protocol requires as much as 10 mol.% of Pd(OTFA)2 and
expensive tBu-XPhos ligand, it is also limited only to monosubstituted gem-
difluorocyclopropanes.
In this paper we report the development of ring-opening amination of gem-
chlorofluoro- and gem-bromofluorocyclopropanes that can be effectively catalyzed by
copper(I) or copper(II) compounds in aprotic solvents and requires no additional ligands [21].
2. Results
Optimization of the reaction conditions was performed using 7-chloro-7-fluoro- and 7-
bromo-7-fluorobicyclo[4.1.0]heptanes (1a and 2a) and morpholine as model substrates. The
copper source, additional base/ligand or solvent were varied (see table 1). It is noteworthy
that under all the conditions studied, only endo-Cl/Br-isomers (endo-Cl-1a, endo-Br-2a)
reacted, while exo-Cl/Br-isomers remained unchanged.
We initially heated endo-Cl-1a in the presence of 3.0 equiv. of morpholine in dioxane
at 100°C using 0.20 equiv. of CuCl as the catalyst. The reaction was completed in 24 hours
and gave the target N-(2-fluorocyclohept-2-enyl)morpholine (3aa) in moderate yield (74%,
entry 1). The major side product was identified as 2,2’-difluoro-3,3’-bicycloheptene (4a, 24%
yield). It was formed as a mixture of two diastereomers in ca. 1/1 ratio. The formation of
small amounts of 2-fluorocyclohepta-1,3-diene (5a) was also detected (2% yield).
When the reaction was carried out for only 5 hours (entry 2), the presence of 2-
fluorocyclohept-2-enyl chloride 6a in appreciable amounts (12% yield) and almost complete
conversion of endo-Cl-1a were observed. A further decrease in the morpholine amount to 2.0
and 1.0 equiv. (entries 3,4) showed almost no influence on endo-Cl-1a conversion but
resulted in a dramatic increase in chloride 6a yields. Meanwhile, decreasing the CuCl amount
lowered the conversion of endo-Cl-1a and increased the yield of 6a (entry 5).

Changing the reaction solvent to DMSO resulted in almost complete conversion of
chloride 6a after 5 hours (entry 6). However, a slight decrease in the ring-opening rate of
endo-Cl-1a was also observed. An important advantage of this solvent is a significant
decrease in the yield of dimer 4a from 24% in dioxane to only 10% in DMSO (entry 7).
These initial results are in very good agreement with the previously proposed
mechanism for CuX catalyzed ring-opening isomerization of gem-fluorohalocyclopropanes
and their rearrangements in the presence of O-nucleophiles [17b,c]. As applied to ring-
opening amination, this mechanism involves a cyclopropyl-allylic transformation of
halocyclopropane endo-Cl-1a by the well-known electrocyclic mechanism [22] to give 2-
fluoroallyl chloride 6a as a preliminary product of ion-pair return in intermediate I (schemes
2,3). The latter undergoes nucleophilic substitution with an amine to give 2-fluoroallyl amine
3aa.
The formation of side product 4a is likely a result of single-electron reduction of halide 6a by
copper-amine complexes followed by dimerization of 2-fluoroallyl radicals. Considering this,
it is not surprising that replacement of dioxane with DMSO allowed us to reduce the amounts
of halide 6a and dimer 4a formed, as DMSO is well known to promote SN2 processes (entries
1,2 vs. 6,7).
Therefore, we decided to use gem-bromofluorocyclopropane endo-Br-2a for further
optimizations assuming that much faster nucleophilic substitution in intermediate allyl
bromide 7a vs. allyl chloride 6a would facilitate the formation of amine 3aa [23]. Indeed,
when endo-Br-2a was heated in the presence of 0.20 equiv. of CuBr and 3.0 equiv. of
morpholine at 100°C for 5 hours in various solvents, complete conversions of cyclopropane
endo-Br-2a and allyl bromide 7a were achieved and amine 3aa was obtained in good to
excellent yields (entries 8–14). In most cases, the yield of side product 4a did not exceed 5%
(except in toluene, see entry 14). The best results were obtained in dioxane, DMSO and
MeCN (entries 8–10), while in DMF, MeOH and HFIP (1,1,1,3,3,3-hexafluoro-iso-propanol)
other side processes were detected. For example, in DMF (2-fluorocyclohept-2-
enyl)dimethylamine 3ab was formed in 10% yield (entry 11) due to the presence of free
dimethylamine in the reaction mixture — the product of either thermal decomposition of
DMF or its transamidation with morpholine. In MeOH, (2-fluorocyclohept-2-enyl)methyl
ether 8a was formed in 6% yield (entry 12), while in HFIP, diene 5a was formed in 10%
yield (entry 13).
Attempts were made to reduce the required excess of morpholine using additional bases
or ligands. In fact, the reaction of endo-Br-2a with 1.2 equiv. of morpholine and additional

2.0 equiv. of NEt3 in dioxane or DMSO gave amine 3aa in good yields (entries 15,21). Under
the same conditions, DIPEA (di-iso-propylethylamine) showed a slightly lower yield of 3aa
due to incomplete (95%) conversion of endo-Br-2a (entry 17). In both cases, no allyl bromide
7a was detected. Conversely, inorganic bases (K2CO3, Cs2CO3, NaOH) lead to lower yields
of amine 3aa significantly (entries 18–20). Moreover, additional diamine ligands (Phen,
TMEDA) dramatically increase the yields of side dimers 4a (entries 22,23), while
diphosphine ligand such as dppe and NHC-ligand IPr (1,3-bis(2,6-di-iso-
propylphenyl)imidazol-2-ylidene) inhibit the ring-opening of endo-Br-2a (entries 24,25).
It is interesting that the amination can be catalyzed not only by cuprous halides but also
by other CuI or CuII compounds [24]. In fact, endo-Br-2a could be effectively rearranged in
the presence of 0.20 equiv. of Cu2O, CuO, Cu(OAc)2 or Cu(acac)2 to give amine 3aa in 74–
84% yields (entries 26–29).
Next, solvent effect on the regioselectivity of ring-opening amination was studied. For
this purpose, 2-chloro-2-fluoro- and 2-bromo-2-fluoro-1-phenylcyclopropanes (1b and 2b)
were chosen as model substrates (table 2). N-((Z,E)-3-Phenyl-2-fluoroallyl)morpholine Z,E-
3ba and its regioisomer 9ba are the major products in all the cases. The product of side
reductive dimerization 4b was formed as a mixture of 6 isomers (see table 2).
The best regioselectivity (3ba/9ba ratio) was achieved using gem-
bromofluorocyclopropane 2b in dioxane or DMSO (entries 6,7). In these cases, only traces of
9ba and 4b were formed. It should be noted that in polar aprotic solvents (MeCN and
DMSO) known to facilitate SN2 processes, more E-isomeric 3ba was formed in comparison
to the reactions in dioxane (see entries 2,3 vs. 1 and entries 7,8 vs. 6), whereas in polar protic
solvents (MeOH and HFIP) known to facilitate SN1 processes, more regioisomeric 9ba was
obtained (see entries 4,5 and 9,10).
With optimized conditions in hand, we studied the scope of copper-catalyzed ring-
opening amination of gem-bromofluorocyclopropanes (see tables 3,4). In addition to the one-
step amination protocol (scheme 4, method A), a two-step approach was explored that
involved CuBr-catalyzed isomerization of gem-bromofluorocyclopropane to give 2-
fluoroallylbromide followed by one pot nucleophilic substitution of bromine (scheme 4,
method B).
In addition to cycloheptenyl- and 3-phenylallylamines 3aa and 3ba, N-(3,3-difluoro-2-
fluoroallyl)morpholine 3ca was obtained in 90% yield after heating of 1,1-
diphenylcyclopropane 2c in the presence of 0.20 equiv. of CuBr and 3.0 equiv. of morpholine
at 100°C for 72 hours. The much longer reaction time is probably a result of larger steric

hindrance in the allyl cationic intermediate in the case of 2c in comparison with monophenyl
substituted cyclopropane 2b.
The amination of trans-1-phenyl-2-methylcyclopropane 2d involved significant side
dehydrobromination of the intermediate allyl bromide. Therefore, N-((Z)-3-phenyl-1-methyl-
2-fluoroallyl)morpholine Z-3da was obtained in only 44% yield (Z/E > 99). The
corresponding E-isomeric amine E-3da was not detected, probably due to a higher propensity
of the corresponding (E)-allyl bromide to dehydrobromination.
It is of interest that 2-fluoroallyl amines 3ea, 3fa, 3ga can be obtained by amination of
bicyclopropanes 2e,f and spiroheptane 2g only by one-step method A (table 3, entries 5–7) in
moderate yields. The reactions of these cyclopropanes under CuBr-catalyzed isomerization
conditions (method B) give only oligomeric products.
To make conclusions from these results, the two-step method B gave slightly better
yields of allyl amines in the case of aryl substituted cyclopropanes 2b,c as compared with the
one-step method A, namely, >98% vs. 90–95% (table 3, entries 2,3). This difference is the
result of the side reductive dimerization that occurs under the conditions of copper-catalyzed
ring-opening of gem-bromofluorocyclopropanes in the presence of amines. On the contrary,
the one-step method A is much more preferable for alkyl substituted cyclopropanes 2a,d–g
than method B (table 3, entries 1,4–7) due to the capture of labile intermediate allyl bromides
[25] that form more stable allyl amines under reaction conditions A.
Ring-opening amination of phenylcyclopropane 2b and spiroheptane 2g with 1.2 equiv.
of various secondary alkyl-, arylamines or hydroxylamines in the presence of 2.0 equiv. of
DIPEA in dioxane or DMSO at 100°C gave the corresponding 2-fluoroallyl amines in
moderate to good yields (see table 4). It should be noted that for 2b, it is necessary to use the
more sterically hindered base DIPEA instead of NEt3 to obtain good yields of the allyl amine.
In fact, when amination of 2b was carried out with NEt3 as the base, the formation of
ammonium salt Z-10b in 40–50% yield was detected. In the case of 2g, no significant
benefits of DIPEA compared with NEt3 were found.
Attempts to use N-acetylbenzylamine and N-Boc-glycine methyl ester as nucleophiles
failed. In fact, no amidation products were obtained when reactions of cyclopropanes 2b and
2g were carried out using DIPEA as the base due to the low nucleophilicity of the amide

nitrogen. Instead, the corresponding allyl bromides Z,E-7b and dimers 4b were obtained from
phenylcyclopropane 2b, while complete polymerization of the reaction mixtures was
observed for spirohexane 2g. The use of inorganic bases (K2CO3 or NaH) resulted in
complete deactivation of the copper catalyst probably due to the formation of unreactive
copper amidate complexes. Nevertheless, phenyl substituted allyl amide 3bi and carbamate
3bj were obtained by the two-step procedure (table 4, entries 7,8, method B).
Attempts were made to obtain secondary 2-fluoroallyl amines by our ring-opening
amination method. However, it was found that the reaction of phenylcyclopropane 2b with
0.5–1.2 equiv. of cyclohexylamine resulted in a mixture of mono- and diallylation products
11b and 12b in 1.2–7:1 ratio (scheme 5).
The p-methoxyphenyl (PMP) protective group was shown to be efficient for the
selective preparation of secondary allyl amines. Using this group, the corresponding
cyclohexylamino derivatives 11b and 11g were prepared from phenylcyclopropane 2b or
spirohexane 2g in moderate to good overall yields (scheme 6).
Other protective groups were found to be inefficient. As shown above, various acyl,
carbamate, and sulfonamide groups cannot be used under conditions of copper-catalyzed
ring-opening amination, while the benzyl groups cannot be removed selectively. Thus, in the
cases of N-benzyl- or N-(p-methoxybenzyl)-N-(2-fluoroallyl)amines, hydrogenation
conditions using H2 or HCO2H as the reductants over Pd/C resulted in complex product
mixtures with complete loss of fluorine. Under single-electron oxidative conditions using
(NH4)2[Ce(NO3)6], concurrent cleavage of 2-fluoroallyl and benzyl or p-methoxybenzyl
groups was observed (scheme 7).
Attempts to obtain primary 2-fluoroallyl amines by CuBr catalyzed ring-opening
amination of gem-fluorohalocyclopropanes (1b,1h,2b) either with phthalimide in the
presence of bases (K2CO3, Cs2CO3), or with potassium phthalimide or urotropine, failed.
Under all the conditions, CuBr was totally deactivated and no ring-opening products were
detected.
Therefore, a stepwise procedure was used for the preparation of primary 2-fluoroallyl
amines from gem-fluorohalocylopropanes. This included: (a) CuX catalyzed isomerization of
cyclopropanes to 2-fluoroallyl halides; (b) introduction of an NH2 group by Gabriel or
Delepin methods (scheme 8) [26].
It should be noted that 2-fluoro-3-methylbut-2-enyl amine 13h that we have
synthesized is used for the preparation of new agrochemicals, potential drugs for the

treatment of ophthalmic diseases, potential anti-inflammatory drugs, as well as compounds
exhibiting antiviral activity [27].
3. Conclusions
In summary, we have developed an efficient method for the preparation of various
alkyl, aryl substituted tertiary 2-fluoroallyl amines and hydroxylamines in moderate to
excellent yields by copper-catalyzed ring-opening amination of readily available gem-
chlorofluoro- and gem-bromofluorocyclopropanes. The reaction pathway involves
isomerization of gem-fluorohalocyclopropanes to 2-fluoroallylic halides — products of gem-
fluorohalocyclopropane isomerization, followed by in situ nucleophilic substitution of a
halide by an N-nucleophile. Using these conditions, it became possible to capture labile alkyl
substituted 2-fluoroallyl halides that easily undergo dehydrohalogenation or various
rearrangements and are therefore difficult to be obtained. The p-methoxyphenyl (PMP)
protective group was found to be efficient for the preparation of secondary 2-
fluoroallylamines by copper-catalyzed gem-fluorohalocyclopropane ring-opening. Primary 2-
fluoroallylamines were only obtained by a stepwise protocol involving CuX-catalyzed
isomerization of gem-fluorohalocyclopropanes to 2-fluoroallylic halides followed by Gabriel
or Delepin amination.
4. Experimental
4.1. General information
All reagents were purchased from Acros, Aldrich or Alfa Aesar and used without
further purification. Dioxane was distilled over Na-benzophenone ketyl anion-radical and
stored over 4A Linde type molecular sieves. Anhydrous DMSO stored over 4A Linde type
molecular sieves obtained from Acros was used without additional purification.
gem-Fluorohalocyclopropanes were synthesized by cyclopropanation of corresponding
olefins with CHCl2F or CHBr2F under PTC conditions as previously published [17] or
analogously (see ESI for experimental procedures and characterization data for unpublished
cyclopropanes).
4.2. General procedure for synthesis of (2-fluoroallyl)morpholines
Method A. A 4-ml screw neck vial was charged with gem-fluorobromocyclopropane
(0.50 mmol) and CuBr (0.10 mmol). In a stream of argon dioxane (0.50 mL) was added

followed by morpholine (1.5 mmol). The vial was quickly sealed and the reaction mixture
was stirred at 100°C for 5 hours. GC analysis of a reaction aliquot showed the completion of
the reaction. CH2Cl2 and satd. NH3 were added; the organic layer was washed with water,
then with brine and dried over K2CO3. The solvents were removed in vacuo, affording a
residue which was purified by flash column chromatography providing the desired product.
Method B. A 4-ml screw neck vial was charged with gem-fluorobromocyclopropane
(0.50 mmol) and CuBr (0.10 mmol). In a stream of argon MeCN (0.50 mL) was added. The
vial was quickly sealed and the reaction mixture was stirred at 100°C for 5 hours. GC
analysis of a reaction aliquot showed the completion of the cyclopropane isomerization. Next,
morpholine (1.5 mmol) was added and the reaction mixture was stirred at room temperature
for additional 2 hours. The desired product was isolated as written above.
N-(2-Fluorocyclohept-2-enyl)morpholine (3aa)
A colorless oil (method A: 86.5 mg, 87%; method B: 20.2 mg, 20%) was obtained after
flash column chromatography (n-hexane/EtOAc, gradient from 100/1 to 4/1).
1H NMR (200.1 MHz, CDCl3)  1.38–2.03 (m, 7H), 2.23 (m, 1H, CHH’-CH=), 2.54 (m,
4H, 2CH2N), 2.90 (m, 1H, CH-morpholine), 3.71 (m, 4H, 2CH2O), 5.46 (dddd., 1H,
-CH=, 3JHF = 21.6 Hz, JHH = 8.0, 5.4, 1.3 Hz). 19F NMR (188.3 MHz, CDCl3)  –92.4 (br.
3
13
t, JHF = 20 Hz) C NMR (50.3 MHz, CDCl3)  21.7 (d, CH2, JCF = 11.1 Hz), 23.5 (s,
CH2), 26.3 (d, CH2, JCF = 9.1 Hz), 26.6 (d, CH2, JCF = 0.9 Hz), 51.1 (s, 2CH2N
2
(morpholine)), 65.7 (d, CH-morpholine, JCF = 27.4 Hz), 67.3 (s, 2CH2O (morpholine)),
2
1
108.8 (d, -CH=, JCF = 21.1 Hz), 162.3 (d, -CF=, JCF = 251 Hz). MS (EI) m/z 200
([M+H]+, 10), 199 ([M]+, 78), 198 ([M-H]+, 9), 170 (100), 140 (19), 126 (12), 112 (20), 97
(20), 87 (71), 56 (21), 41 (12). HRMS (ESI), calcd. for C11H18FNO: m/z 200.1445
[M+H+]. Found: m/z 200.1441 [M+H+].
N-(2-Fluoro-3-phenylallyl)morpholine (3ba)
A colorless oil (method A: 105.1 mg, 95% (Z/E = 85/15); method B: 108.7 mg, 98% (Z/E
= 93/7)) was obtained after flash column chromatography (n-hexane/EtOAc, gradient from
50/1 to 5/1). 1H, 19F and 13C NMR were fully consistent with previously published [9e].

N-(2-Fluoro-3,3-diphenylallyl)morpholine (3ca)
A colorless solids (mp 103–104°C; method A: 133.4 mg, 90%; method B: 148.0 mg, 99%)
were obtained after flash column chromatography (n-hexane/EtOAc, gradient from 50/1 to
3/1).
1H NMR (200.1 MHz, CDCl3)  2.38–2.60 (m, 4H, 2CH2N-morpholine), 3.21 (d, 2H,
3
CH2N, JHF = 21.7 Hz), 3.62–3.78 (m, 4H, 2CH2O-morpholine), 7.09–7.44 (m, 10H,
arom.). 19F NMR (188.3 MHz, CDCl3)  –105.6 (t, 3JHF = 21.7 Hz). 13C NMR (50.3 MHz,
CDCl3)  53.2 (s, 2CH2N-morpholine), 57.0 (d, CH2N, 2JCF = 25.3 Hz), 67.0 (s, 2CH2O-
morpholine), 124.6 (d, =CPh2, 2JCF = 13.6 Hz), 127.3 (s, CH-arom.), 127.6 (s, CH-arom.),
128.0 (s, 2CH-arom.), 128.4 (s, 2CH-arom.), 129.6 (d, 2CH-arom., JCF = 5.1 Hz), 130.4
(d, 2CH-arom., JCF = 3.0 Hz), 137.0 (s, C-arom.), 138.2 (d, C-arom., 3JCF = 7.5 Hz), 153.8
(d, –CF=, 1JCF = 264 Hz). MS (EI) m/z 297 ([M+], 22), 276 (2), 266 (2), 239 (9), 220 (15),
211 (58), 209 (37), 196 (23), 191 (84), 178 (54), 165 (29), 133 (100), 100 (20), 86 (51), 56
(31). HRMS (ESI), calcd. for C19H20FNO: m/z 298.1602 [M+H+]. Found: m/z 298.1613
[M+H+].
N-(2-Fluoro-3-phenyl-1-methylallyl)morpholine (3da)
A colorless oil (method A: 52.1 mg, 44% (Z/E > 99); method B: 35.5 mg, 30% (Z/E > 99))
was obtained after flash column chromatography (n-hexane/EtOAc, gradient from 50/1 to
3/1).
3
1H NMR (200.1 MHz, CDCl3) : 1.35 (d, 3H, CH3, JHH = 6.9 Hz), 2.44–2.77 (m, 4H,
3
3
2CH2-morpholine), 3.13 (dq, CH(Me)N<, JHF = 22.7 Hz, JHH = 6.9 Hz), 3.64–3.83 (m,
3
4H, 2CH2-morpholine), 5.62 (d, –CH=, JHF(trans) = 39.6 Hz), 7.15–7.40 (m, 3H, arom.),
19
3
7.44–7.57 (m, 2H, arom.). F NMR (188.3 MHz, CDCl3) : –108.7 (dd, JHF(trans) = 39.6
Hz, 3JHF = 22.7 Hz). 13C NMR (50.3 MHz, CDCl3): 15.0 (d, CH3, JCF = 2.5 Hz), 50.5 (s,
2
2CH2-morpholine), 62.3 (d, CH(Me)N<, JCF = 24.2 Hz), 67.3 (s, 2CH2-morpholine),
108.1 (d, –CH=, 2JCF = 7.4 Hz), 127.3 (d, CH-arom., 6JCF = 2.3 Hz), 128.5 (s, 2CH-arom.),
4
3
128.6 (d, 2CH-arom., JCF = 7.7 Hz), 133.1 (d, C-arom., JCF = 2.2 Hz), 159.8 (d, –CF=,
1JCF = 274 Hz). HRMS (ESI), calcd. for C14H18FNO: m/z 236.1445 [M+H+]. Found: m/z
236.1448 [M+H+].

N-(2-Fluoro-3-cyclopropylallyl)morpholine (3ea)
3ea was obtained only by method A. After flash column chromatography of the crude
product (n-hexane/EtOAc, 3/1), the fractions contained 3ea were evaporated with an
excess of 4.0 M HCl in dioxane. A colorless solids of 3ea·HCl (method A: 89.6 mg, 81%
(Z/E = 72/28)) were obtained. When carried out by method B, starting cyclopropane 2e
reacted completely to give oligomeric products.
1H NMR (200.1 MHz, DMSO-d6) : (a mixture of Z,E-isomers) 0.36–0.53 (m, 2H,
cyclopropyl), 0.68–0.92 (m, 2H, cyclopropyl), 1.51–1.80 (m, 1H, CH, cyclopropyl), 2.90–
3.46 (m, 4H, 2CH2-morpholine), 3.81–4.01 (m, 4H, 2CH2-morpholine), 3.96 (d, 2H,
3
3
CH2N, Z-3ea, JHF = 21.2 Hz), 4.19 (d, 2H, CH2N, E-3ea, JHF = 23.0 Hz), 4.90 (dd, –
3
3
3
CH=, Z-3ea, JHF(trans) = 36.2 Hz, JHH = 10.0 Hz), 5.22 (dd, –CH=, E-3ea, JHF(cis) = 19.7
3
19
3
Hz, JHH = 10.3 Hz). F NMR (188.3 MHz, DMSO-d6) : –107.2 (td, JHF = 23.0 Hz,
3JHF(cis)
19.7 Hz),
=
–115.1 (dt, 3JHF(trans) = 36.2 Hz, 3JHF = 21.2 Hz). 13C NMR (50.3 MHz, DMSO-d6): 6.4–
6.9 (m, CH-cyclopropyl (Z-3ea) + CH2-cyclopropyl (both isomers), 7.4 (d, CH-
3
cyclopropyl (E-3ea), JCF = 9.9 Hz), 50.4 (s, CH2-morpholine, Z-3ea), 50.6 (s, CH2-
2
2
morpholine, E-3ea), 51.9 (d, CH2N, JCF = 28.7 Hz), 55.2 (d, CH2N, E-3ea, JCF = 27.9
2
Hz), 62.9 (s, CH2-morpholine, both isomers), 121.5 (d, –CH=, Z-3ea, JCF = 10.5 Hz),
122.0 (d, –CH=, E-3ea, 2JCF = 21.1 Hz), 148.0 (d, –CF=, E-3ea, 1JCF = 241 Hz), 148.7 (d,
–CF=, Z-3ea, 1JCF = 249 Hz). HRMS (ESI), calcd. for C10H16FNO: m/z 186.1289 [M+H+].
Found: m/z 186.1291 [M+H+].
N-[2-Fluoro-3-(2,2-difluorocyclopropyl)allyl]morpholine (3fa)
A colorless oil (method A: 81.1 mg, 73% (Z/E = 57/43))) was obtained after flash column
chromatography (n-hexane/EtOAc, 1/1). When carried out by method B, starting
cyclopropane 2f reacted completely to give oligomeric products.
1H NMR (300.1 MHz, CDCl3)  1.12–1.28 (m, 1H, СH2-cyclopropyl, Z,E-3fa), 1.61–1.75
(m, 1H, СH2-cyclopropyl, Z,E-3fa), 2.27 (m, 1H, СH-cyclopropyl, E-3fa), 2.52 (m, 1H,
СH-cyclopropyl, Z-3fa, from {1H-19F}-HMBC), 2.46–2.57 (m, 4H, 2CH2N-morpholine,
3
3
Z,E-3fa), 3.07 (d, 2H, CH2N, Z-3fa, JHF = 17.5 Hz), 3.22 (d, 2H, CH2N, E-3fa, JHF
20.6 Hz), 3.69–3.78 (m, 4H, 2CH2O-morpholine, Z,E-3fa), 4.57 (dd, 1H, –CH=, Z-3fa,
3JHF(trans) = 34.5 Hz, 3JHH = 9.1 Hz), 5.05 (ddt, 1H, –CH=, E-3fa, 3JHF(cis) = 18.5 Hz, 3JHH
9.1 Hz, 4JHH = 2.0 Hz). 19F{1H} NMR (282.4 MHz, CDCl3)  (for Z-3fa) –109.6 (d, 1F, –
=
=

5
2
5
CF=, JFF = 2.1 Hz), –129.1 (dd, 1F, CF2, JFF = 155.4 Hz, JFF = 2.1 Hz), –140.5 (d, 1F,
CF2, 2JFF = 155.4 Hz); (for E-3fa) –99.6 (d, 1F, –CF=, 5JFF = 1.6 Hz), –128.7 (dd, 1F, CF2,
2JFF
=
155.6
Hz,
5JFF
=
1.6
Hz),
2
13
–140.5 (dd, 1F, CF2, JFF = 155.6 Hz). C NMR (100.6 MHz, CDCl3)  17.9–18.2 (m,
CH2-cyclopropyl, both isomers), 18.7 (ddd, CH-cyclopropyl, Z-3fa, JCF = 13.3, 10.9, 6.6
Hz), 19.5 (dt, CH-cyclopropyl, E-3fa, JCF = 13.2, 11.2 Hz), 53.3 (s, 2CH2N-morpholine,
2
2
both isomers), 55.9 (d, CH2N, Z-3fa, JCF = 27.2 Hz), 59.2 (d, CH2N, E-3fa, JCF = 26.5
Hz), 66.9 (s, 2CH2O-morpholine, both isomers), 103.4 (ddd, –CH=, Z-3fa, JCF = 12.6, 5.6,
1
1.9 Hz), 105.0 (ddd, –CH=, E-3fa, JCF = 28.5, 5.5, 1.9 Hz), 112.8 (ddd, CF2, JCF = 289,
4
1
4
285 Hz, JCF = 2.2 Hz), 113.2 (ddd, CF2, JCF = 289, 283 Hz, JCF = 1.7 Hz), 158.2 (d, –
1
1
CF=, JCF = 261 Hz), 158.4 (d, –CF=, JCF = 255 Hz). MS (EI) m/z 221 ([M+], 40), 190
(3), 176 (5), 164 (8), 157 (15), 156 (16), 142 (12), 126 (39), 115 (49), 113 (25), 100 (100),
98 (48), 95 (28), 86 (49), 72 (12), 65 (14), 56 (27). HRMS (ESI), calcd. for C10H14F3NO:
m/z 222.1100 [M+H+]. Found: m/z 222.1106 [M+H+].
N-(2-Cyclopentylidene-2-fluoroethyl)morpholine (3ga)
A colorless oil (method A: 76.5 mg, 77%) was obtained after flash column
chromatography (n-hexane/EtOAc, gradient from 20/1 to 1/1). When carried out by
method B, starting cyclopropane 2g reacted completely to give oligomeric products.
1H NMR (300.1 MHz, CDCl3)  1.57–1.75 (m, 4H, 2CH2), 2.19–2.29 (m, 2H, CH2),
2.32–2.42 (m, 2H, CH2), 2.45–2.54 (m, 4H, CH2N-morpholine), 3.12 (d, 2H, CH2N, 3JHF
=
22.1 Hz), 2.69–2.78 (m, 4H, CH2O-morpholine). 19F NMR (188.3 MHz, CDCl3)  –108.5
(t, 3JHF = 22.1 Hz). 13C NMR (75.4 MHz, CDCl3)  26.3 (s, CH2), 27.0 (s, CH2), 27.6 (d,
CH2, JCF = 2.9 Hz), 28.7 (d, CH2, JCF = 4.6 Hz), 53.4 (s, 2CH2N-morpholine), 57.5 (d,
2
2
CH2N, JCF = 27.4 Hz), 66.9 (s, 2CH2O-morpholine), 123.9 (d, =CR2, JCF = 17.1 Hz),
147.7 (d, –CF=, 1JCF = 245 Hz). MS (EI) m/z 199 ([M+], 12), 168 (6), 154 (4), 140 (7), 126
(9), 112 (10), 100 (7), 97 (10), 93 (8), 87 (100), 86 (58), 79 (8), 57 (30), 56 (14). HRMS
(ESI), calcd. for C11H18FNO: m/z 200.1445 [M+H+]. Found: m/z 200.1444 [M+H+].
4.3. General procedure for synthesis of various 2-fluoroallyl amines
Method A. A 4-ml screw neck vial was charged with gem-fluorohalocyclopropane
(0.50 mmol), CuX (0.10 mmol) and HNR2 or HNR2·HCl (0.60 mmol). In a stream of argon
dioxane (0.50 mL) was added followed by DIPEA (1.0 mmol). The vial was quickly sealed
and the reaction mixture was stirred at 100°C for 5 hours. GC analysis of a reaction aliquot

showed the completion of the reaction. CH2Cl2 and satd. NH3 were added, the organic layer
was washed with water, then with brine and dried over K2CO3. The solvents were removed in
vacuo, affording a residue which was purified by flash column chromatography providing the
desired product.
Method B. A 4-ml screw neck vial was charged with gem-fluorohalocyclopropane (0.50
mmol) and CuX (0.10 mmol). In a stream of argon MeCN (0.50 mL) was added. The vial
was quickly sealed and the reaction mixture was stirred at 100°C for 5 hours. GC analysis of
a reaction aliquot showed the completion of the cyclopropane isomerization. Next, HNR2 or
HNR2·HCl (0.60 mmol) and K2CO3 (1.5 mmol) were added and the reaction mixture was
stirred at room temperature for additional 2 hours. The desired product was isolated as
written above.
N-Benzyl-N-(2-fluoro-3-phenylallyl)cyclohexylamine (3bc)
A colorless oil (method A: 129.9 mg, 80% (Z/E = 82/18); method B: 153.1 mg, 95% (Z/E
= 93/7)) was obtained after flash column chromatography (n-hexane/benzene 5/1 to n-
hexane/EtOAc 25/1).
1
(A mixture of Z,E-isomers) H NMR (300.1 MHz, CDCl3)  0.95–2.00 (m, 10H, 5CH2-
Chx), 2.51–2.70 (m, 1H, CHN-Chx), 3.30 (d, 2H, CH2N, Z-3bc, 3JHF = 13.0 Hz), 3.43 (d,
3
2H, CH2N, E-3bc, JHF = 22.0 Hz), 3.64 (s, 2H, CH2Ph, E-3bc), 3.74 (s, 2H, CH2Ph, Z-
3bc), 5.70 (d, 1H, –CH=, Z-3bc, 3JHF(trans) = 39.3 Hz), 6.30 (d, 1H, –CH=, E-3bc, 3JHF(cis)
=
19
21.3 Hz), 7.13–7.49 (m, 10H, arom.). F NMR (188.3 MHz, CDCl3)  –97.4 (td, E-3bc,
3JHF = 22.0 Hz, 3JHF(cis) = 21.3 Hz), –104.4 (dt, Z-3bc, 3JHF(trans) = 39.3 Hz, 3JHF = 13.0 Hz).
13C NMR (75.4 MHz, CDCl3)  26.2 (с., CH2, both isomers), 26.4 (s, CH2, both isomers),
29.1 (s, CH2, E-3bc), 29.2 (s, CH2, Z-3bc), 47.8 (d, CH2N, E-3bc, 2JCF = 25.8 Hz), 51.4 (d,
2
CH2N, Z-3bc, JCF = 29.5 Hz), 54.0 (s, CH2Ph, E-3bc), 54.1 (s, CH2Ph, Z-3bc), 59.3 (s,
2
CH-Chx, Z-3bc), 59.4 (s, CH-Chx, E-3bc), 107.2 (d, –CH=, Z-3bc, JCF = 6.9 Hz), 111.6
(d, –CH=, E-3bc, 2JCF = 27.9 Hz), 126.7–127.0 (m, CH-arom., both isomers), 128.0–129.0
(m, CH-arom., both isomers), 133.8 (d, С-arom., Z-3bc, 3JCF = 2.3 Hz), 133.8 (d, С-arom.,
E-3bc, 3JCF = 12.9 Hz), 140.7 (s, C-arom., Bn, both isomers), 159.4 (d, –CF=, Z-3bc, 1JCF
1
= 269 Hz), 160.4 (d, –CF=, E-3bc, JCF = 256 Hz). MS (EI) m/z 323 ([M+], 2), 280 (3),
267 (1), 232 (12), 176 (16), 135 (24), 133 (11), 115 (38), 109 (5), 91 (100), 83 (3), 65 (11),
55 (7). HRMS (ESI), calcd. for C22H26FN: m/z 324.2122 [M+H+]. Found: m/z 324.2125
[M+H+].

N-(4-Methoxybenzyl)-N-(2-fluoro-3-phenylallyl)cyclohexylamine (3bd)
A yellow oil (method A: 133.9 mg, 76% (Z/E = 79/21); method B: 169.2 mg, 96% (Z/E =
93/7)) was obtained after flash column chromatography (n-hexane/benzene 5/1 to n-
hexane/EtOAc 25/1).
1
(A mixture of Z,E-isomers) H NMR (200.1 MHz, CDCl3)  0.91–1.44 (m, 5H, Chx),
1.47–2.01 (m, 5H, Chx), 2.46–2.75 (m, 1H, >N-CH in Chx, both isomers), 3.29 (d, 2H,
3
3
CH2N, Z-3bd, JHF = 12.7 Hz), 3.41 (d, 2H, CH2N, E-3bd, JHF = 22.1 Hz), 3.57 (s, 2H,
CH2Ph, E-3bd), 3.68 (s, 2H, CH2Ph, Z-3bd), 3.78 (s, 3H, OCH3, both isomers), 5.71 (d,
3
3
1H, =CH–, Z-3bd, JHF(trans) = 39.4 Hz), 6.31 (d, 1H, =CH–, E-3bd, JHF(cis) = 21.5 Hz),
6.75–6.91 (m, 2H, PMB), 7.12–7.38 (m, 5H, Ph + PMB), 7.40–7.52 (m, 2H, Ph). 19F NMR
3
3
(188.3 MHz, CDCl3)  –97.1 (td, E-3bd, JHF = 22.1 Hz, JHF(cis) = 21.5 Hz), –104.4 (dt,
Z-3bd, 3JHF(trans) = 39.4 Hz, 3JHF = 12.7 Hz). 13C NMR (50.3 MHz, CDCl3)  26.2 (s, CH2,
both isomers), 26.4 (s, CH2, both isomers), 28.9 (s, CH2, E-3bd), 29.1 (s, CH2, Z-3bd),
2
2
47.6 (d, CH2N, E-3bd, JCF = 25.8 Hz), 51.1 (d, CH2N, Z-3bd, JCF = 29.5 Hz), 53.2 (s,
CH2Ph, E-3bd), 53.4 (s, CH2Ph, Z-3bd), 55.2 (s, OCH3, both isomers), 59.0 (s, CH in
Chx, Z-3bd), 59.1 (s, CH in Chx, E-3bd), 107.0 (d, =CH–, Z-3bd, 2JCF = 6.8 Hz), 11.5 (d,
2
=CH–, E-3bd, JCF = 27.8 Hz), 113.5 (s, CH in PMB, E-3bd), 113.6 (s, CH in PMB, Z-
3bd), 126.8 (s, CH-arom.), 128.0–129.9 (m, CH-arom., both isomers), 132.5 (s, C-arom.),
3
133.7 (d, C-arom., JCF = 2.2 Hz), 158.5 (s, C(OMe) in PMB, both isomers), 159.5 (d,
1
1
=CF–, Z-3bd, JCF = 269 Hz), 160.4 (d, =CF–, E-3bd, JCF = 255 Hz). MS (EI) m/z 354
([M+H]+, 3), 353 ([M+], 12), 310 (1), 297 (1), 262 (8), 232 (2), 218 (1), 206 (13), 135 (5),
+
122 (9), 121 ([MeOC6H4CH2 ], 100), 115 (5), 91 (2). HRMS (ESI), calcd. for C23H28FNO:
m/z 354.2228 [M+H+]. Found: m/z 354.2224 [M+H+].
N-(4-Methoxyphenyl)-N-(2-fluoro-3-phenylallyl)cyclohexylamine (3be)
A yellow oil (method A: 144.5 mg, 85% (Z/E = 73/27); method B: 161.4 mg, 95% (Z/E =
93/7)) was obtained after flash column chromatography (n-hexane/benzene 5/1 to n-
hexane/EtOAc 25/1).
1
(A mixture of Z,E-isomers) H NMR (200.1 MHz, CDCl3)  0.79–2.10 (m, 10H, CH2 in
Chx, both isomers), 3.25 (m, 1H, CH in Chx, E-3be), 3.53 (m, 1H, CH in Chx, Z-3be),
3.73 (s, 3H, OCH3, E-3be), 3.75 (s, 3H, OCH3, Z-3be), 3.93 (m, 2H, CH2N, Z-3be), 4.07
3
3
(d, 2H, CH2N, E-3be, JHF = 17.0 Hz), 5.71 (d, 1H, =CH–, Z-3be, JHF(trans) = 40.5 Hz),
3
6.30 (d, 1H, =CH–, E-3be, JHF(cis) = 21.0 Hz), 6.63–6.92 (m, 4H, PMP, both isomers),

7.11–7.54 (m, 5H, Ph, both isomers). 19F NMR (188.3 MHz, CDCl3)  –102.7 (dt, E-3be,
3
3
13
3JHF(cis) = 21.0 Hz, JHF = 17.0 Hz), –107.7 (br. d, Z-3be, JHF(trans) = 40.5 Hz). C NMR
(50.3 MHz, CDCl3)  26.8 – 25.4 (m, CH2 in Chx, both isomers), 30.3 (s, CH2 in Chx),
30.7 (s, CH2 in Chx), 45.0 (d, CH2N, E-3be, 2JCF = 25.3 Hz), 48.0 (d, CH2N, Z-3be, 2JCF
=
37.6 Hz), 55.5 (s, OCH3, E-3be), 55.7 (s, OCH3, Z-3be), 58.2 (s, CH in Chx, Z-3be), 59.9
2
(s, CH in Chx, E-3be), 105.8 (d, =CH–, Z-3be, JCF = 5.6 Hz), 110.8 (d, =CH–, E-3be,
2JCF = 27.3 Hz), 114.1 (s, CH in PMP, E-3be), 114.7 (s, CH in PMP, Z-3be), 116.0 (s, CH
in PMP, Z-3be), 120.0 (s, CH in PMP, E-3be), 126.5–129.2 (m, CH in Ph, both isomers),
133.5 (d, C in Ph, Z-3be, 3JCF = 1.9 Hz), 133.7 (d, C in Ph, E-3be, 3JCF = 9.4 Hz), 142.6 (s,
>N–C in PMP, E-3be), 143.1 (s, >N–C in PMP, Z-3be), 152.2 (s, C(OMe) in PMP, Z-
3be), 153.4 (s, C(OMe) in PMP, E-3be), 158.9 (d, =CF–, Z-3be, J = 269 Hz), 159.7 (d,
=CF–, E-3be, J = 257 Hz). MS (EI) m/z 340 ([M+H+], 23), 339 ([M+], 100), 296 (17), 283
(9), 282 (8), 248 (27), 204 (53), 192 (34), 148 (11), 135 (53), 122 (14), 115 (17), 109 (6),
92 (4), 77 (5), 55 (6), 41 (4). HRMS (ESI), calcd. for C22H26FNO: m/z 340.2071 [M+H+].
Found: m/z 340.2073 [M+H+].
N-Benzyl-N-(2-fluoro-3-phenylallyl)-4-methoxyaniline (3bf)
A yellow oil (method A: 149.7 mg, 86% (Z/E = 68/32); method B: 167.1 mg, 96% (Z/E =
90/10)) was obtained after flash column chromatography (n-hexane/benzene 5/1 to n-
hexane/EtOAc from 25/1 to 5/1).
1
(For Z-3bf): H NMR (300.1 MHz, CDCl3)  3.70 (s, 3H, OCH3), 4.09 (d, CH2N, 3JHF
=
3
8.6 Hz), 4.56 (s, 2H, CH2Ph), 5.62 (d, –CH=, JHF(trans) = 39.7 Hz), 6.76–6.80 (m, 4H,
PMP), 7.15–7.34 (m, 8H, arom.), 7.42–7.48 (m, 2H, arom.). 19F NMR (188.3 MHz,
CDCl3)

3
3
–108.0 (dt, JHF(trans) = 39.7 Hz, JHF = 8.6 Hz). 13C NMR (75.4 MHz, CDCl3)  52.7 (d,
2
CH2N, 2JCF = 33.1 Hz), 54.9 (s, CH2Ph), 55.7 (s, OCH3), 107.1 (d, –CH=, JCF = 6.1 Hz),
114.8 (s, 2CH, PMP), 115.1 (s, 2CH, PMP), 126.8–127.4 (m, CH, arom.), 128.3–129.0 (m,
3
CH, arom.), 133.1 (d, C-arom., JCF = 2.3 Hz), 138.6 (s, C-arom.), 143.2 (s, C-arom.),
1
152.4 (s, C-arom.), 156.9 (d, –CF=, JCF = 271 Hz). (For E-3bf): 1H NMR (300.1 MHz,
CDCl3)  3.67 (s, 3H, OCH3), 4.20 (d, CH2N, 3JHF = 18.4 Hz), 4.45 (s, 2H, CH2Ph), 6.38
3
(d, –CH=, JHF(cis) = 21.1 Hz), 6.55–6.72 (m, 4H, PMP), 7.07–7.34 (m, 10H, 2Ph). 19F
3
3
NMR (188.3 MHz, CDCl3)  –104.4 (dt, JHF(cis) = 21.1 Hz, JHF = 18.4 Hz). (For both
isomers): MS (EI) m/z 216 (4), 214 (3), 135 (74), 133 (34), 115 (100), 109 (11), 102 (6),

89 (9), 81 (14), 74 (7), 63 (15), 57 (13), 51 (13). HRMS (ESI), calcd. for C23H22FNO: m/z
348.1758 [M+H+]. Found: m/z 348.1750 [M+H+].
N,O-Dimethyl-N-(2-fluoro-3-phenylallyl)hydroxylamine (3bg)
A colorless oil (method A: 63.6 mg, 65% (Z/E = 71/29); method B: 82.6 mg, 85% (Z/E =
98/2)) was obtained after flash column chromatography (n-hexane/EtOAc, 20/1).
1
(For Z-3bg): H NMR (200.1 MHz, CDCl3)  2.67 (s, 3H, CH3N), 3.44 (d, 2H, CH2N,
3
3JHF = 18.0 Hz), 3.55 (s, 3H, OCH3), 5.71 (d, 2H, –CH=, JHF(trans) = 38.5 Hz), 7.17–7.40
(m, 3H, arom.), 7.47–7.58 (m, 2H, arom.). 19F NMR (188.3 MHz, CDCl3)  –104.7 (dt,
3JHF(trans) = 38.5 Hz, 3JHF = 18.0 Hz). 13C NMR (50.3 MHz, CDCl3)  45.2 (s, CH3N), 60.4
(s, CH3O), 61.9 (d, CH2N, 2JCF = 26.9 Hz), 109.8 (d, –CH=, 2JCF = 7.3 Hz), 127.4 (d, CH-
6
4
arom., JCF = 2.3 Hz), 128.5 (s, 2CH-arom.), 128.7 (d, 2CH-arom., JCF = 7.5 Hz), 133.2
(d, C-arom., 3JCF = 2.8 Hz), 156.1 (d, –CF=, 1JCF = 268 Hz). (For E-3bg): 19F NMR (188.3
3
3
MHz, CDCl3)  –99.5 (dt, JHF(cis) = 21.8 Hz, JHF = 21.8 Hz). (For both isomers): MS
(EI) m/z 195 ([M+], 7), 162 (2), 135 (56), 133 (15), 115 (100), 109 (7). HRMS (ESI),
calcd. for C11H14FNO: m/z 196.1132 [M+H+]. Found: m/z 196.1134 [M+H+].
Methyl N-(2-fluoro-3-phenylallyl)prolinate (3bh)
A colorless oil (method A: 114.6 mg, 87% (Z/E = 86/14); method B: 125.0 mg, 95% (Z/E
= 96/4)) was obtained after flash column chromatography (n-hexane/EtOAc, 3/1).
1
(For Z-3bh): H NMR (200.1 MHz, CDCl3) : 1.70–2.32 (m, 4H, 2CH2), 2.63 (m, 1H,
CHCO2Me), 3.10–3.84 (m, 4H, CH2, CH2N), 3.68 (s, 3H, OCH3), 5.67 (d, 1H, –CH=,
3JHF(trans) = 38.5 Hz), 7.16–7.40 (m, 3H, arom.), 7.44–7.54 (m, 2H, arom.). 19F NMR
3
3
13
(188.3 MHz, CDCl3) : –103.2 (dt, JHF(trans) = 38.5 Hz, JHF = 18.8 Hz). C NMR (50.3
MHz, CDCl3) : 23.3 (s, CH2), 29.6 (s, CH2), 52.0 (s, NCH), 53.4 (s, NCH2), 55.1 (d,
2
2
CH2N, JCF = 27.0 Hz), 64.7 (s, OCH3), 109.1 (d, –CH=, JCF = 7.2 Hz), 127.3 (d, CH-
6
4
arom., JCF = 2.2 Hz), 128.5 (s, 2CH-arom.), 128.7 (d, 2CH-arom., JCF = 7.4 Hz), 133.2
(d, C-arom., 3JCF = 2.8 Hz), 157.3 (d, –CF=, 1JCF = 270 Hz), 174.4 (s, C=O). (For E-3bh):
3
3
19F NMR (188.3 MHz, CDCl3)  –98.5 (д.т., JHF(цис) = 22.7 Hz, JHF = 22.7 Hz). (For
both isomers): MS (EI) m/z 263 ([M+], 3), 204 (33), 135 (100), 133 (24), 115 (93), 109 (9),
83 (4), 68 (11), 59 (5). HRMS (ESI), calcd. for C15H18FNO2: 264.1394 [M+H+], 286.1214
[M+Na+]. Found: 264.1394 [M+H+], 286.1205 [M+Na+].

N-Acetyl-N-(2-fluoro-3-phenylallyl)benzylamine (3bi)
Obtained by method B using NaH (0.60 mmol, dispersion in mineral oil, 55 w/w %) as the
base. A colorless oil (method B: 121.6 mg, 86% (Z/E = 96/4)) was obtained after flash
column chromatography (n-hexane/EtOAc, gradient from 50/1 to 3/1).
1
(For Z-3bi,Z-3bi’, rotamers, a ratio of 1/1): H NMR (200.1 MHz, CDCl3) : 2.19 (s, 3H,
3
CH3), 2.26 (s, 3H, CH3), 4.00 (d, 2H, AllCH2N, JHF = 11.8 Hz), 4.26 (d, 2H, AllCH2N,
3JHF = 16.7 Hz), 4.64 (s, 2H, CH2Ph), 4.69 (s, 2H, CH2Ph), 5.57 (d, 1H, –CH=, 3JHF(trans)
=
3
19
38.5 Hz), 5.62 (d, 1H, –CH=, JHF(trans) = 38.5 Hz), 7.08–7.55 (m, 5H, arom.). F NMR
3
3
(188.3 MHz, CDCl3) : –107.6 (dt, JHF(trans) = 38.5 Hz, JHF = 16.7 Hz), –109.5 (dt,
3JHF(trans) = 38.5 Hz, 3JHF = 11.8 Hz). 13C NMR (50.3 MHz, CDCl3) : 21.6 (s, CH3), 21.7
2
2
(s, CH3), 45.9 (d, AllCH2N, JCF = 29.7 Hz), 47.8 (s, CH2Ph), 48.5 (d, AllCH2N, JCF
=
2
2
32.1 Hz), 51.3 (s, CH2Ph), 108.5 (d, –CH=, JCF = 6.7 Hz), 109.3 (d, –CH=, JCF = 6.9
Hz), 126.4 (s, CH-arom.), 127.4–129.2 (m, CH-arom., 2Ph), 132.2 (d, C-arom., 3JCF = 2.8
3
Hz), 132.7 (d, C-arom., JCF = 2.7 Hz), 136.2 (s, C-arom., Bn), 137.0 (s, C-arom., Bn),
1
1
154.3 (d, –CF=, JCF = 269 Hz), 155.3 (d, –CF=, JCF = 269 Hz), 171.0 (s, C(O)CH3),
171.2 (s, C(O)CH3). (For E-3bi,E-3bi’, rotamers,a ratio of 1/1): 19F NMR (188.3 MHz,
3
3
3
CDCl3) : –106.1 (dt, JHF(cis) = 21.6 Hz, JHF = 18.7 Hz), –107.9 (dt, JHF(cis) = 21.1 Hz,
3JHF = 18.5 Hz). (For both isomers): HRMS (ESI), calcd. for C18H18FNO: 284.1445
[M+H+], 306.1265 [M+Na+]. Found: 284.1445 [M+H+], 306.2163 [M+Na+].
Methyl N-(tert-butyloxycarbonyl)-N-(2-fluoro-3-phenylallyl)glycinate (3bj)
Obtained by method B using NaH (0.60 mmol, dispersion in mineral oil, 55 w/w %) as the
base. A brown oil crystalized upon storage to yellowish solids (method B: 143.0 mg, 83%
(Z/E = 96/4)) was obtained after flash column chromatography (n-hexane/EtOAc, gradient
from 20/1 to 1/1)
(For Z-3bj,Z-3bj’, rotamers, a ratio of 1/1): 1H NMR (300.1 MHz, CDCl3)  1.45 (s, 9H,
3CH3, Boc), 1.49 (s, 9H, 3CH3, Boc), 3.72 (s, 6H, OCH3, both rotamers), 3.99 (s, 2H,
3
CH2CO2Me), 4.09 (s, 2H, CH2CO2Me), 4.13 (d, 2H, CH2N, JHF = 14.8 Hz), 4.19 (d, 2H,
3
3
CH2N, JHF = 16.2 Hz), 5.63 (s, 1H, –CH=, JHF(trans) = 38.3 Hz), 5.70 (d, 1H, –CH=,
19
3JHF(trans) = 38.3 Hz), 7.18–7.56 (m, 5H, arom.). F NMR (282.4 MHz, CDCl3)  –108.8
(dt, 3JHF(trans) = 38.3 Hz, 3JHF = 16.2 Hz), –109.5 (dt, 3JHF(trans) = 38.3 Hz, 3JHF = 14.8 Hz).
13C NMR (75.4 MHz, CDCl3)  28.2 (s, CH3, Boc). 28.3 (s, CH3, Boc), 47.8 (s,

CH2CO2Me), 48.4 (s, CH2CO2Me), 48.9 (d, CH2N, 2JCF = 30.4 Hz), 49.4 (d, CH2N, 2JCF
31.1 Hz), 52.0 (s, CO2CH3), 52.0 (s, CO2CH3), 81.0 (s, CMe3, Boc), 81.1 (s, CMe3, Boc),
=
2
2
108.3 (d, –CH=, JCF = 6.7 Hz), 109.0 (d, –CH=, JCF = 6.8 Hz), 127.3–128.9 (m, CH-
arom., both isomers), 132.7 (m, C-arom., both rotamers), 155.0 (s, C=O, Boc), 155.3 (s,
1
C=O, Boc), 155.5 (d, –CF=, JCF = 268 Hz, both rotamers), 170.2 (s, CO2Me, both
1
rotamers). (For E-3bj,E-3bj’, rotamers, a ratio of 1/1): H NMR (300.1 MHz, CDCl3)
(from {1H,19F}-HMBC)  4.32 (d, 2H, CH2N, 3JHF = 19.5 Hz), 4.38 (d, 2H, CH2N, 3JHF
18.9 Hz), 6.39 (d, –CH=, 3JHF(cis) = 20.6 Hz), 6.43 (d, –CH=, 3JHF(cis) = 21.0 Hz). 19F NMR
=
3
3
(282.4 MHz, CDCl3)  –105.2 (dt, JHF = 20.5, 19.4 Hz), –106.3 (dt, JHF = 20.5, 19.2
Hz). (For both isomers): HRMS (ESI), calcd. for C17H22FNO4: 346.1425 [M+Na+],
362.1164 [M+K+]. Found: 346.1423 [M+Na+], 362.1162 [M+K+].
N-Benzyl-N-(2-fluoro-2-cyclopentylidenethyl)cyclohexylamine (3gc)
Obtained only by method A using DMSO as the solvent. A colorless oil (method A: 88.7
mg, 59%) was obtained after flash column chromatography (n-hexane/EtOAc, 50/1).
When carried out by method B, starting cyclopropane 2g reacted completely to give
oligomeric products.
1H NMR (200.1 MHz, CDCl3)  0.96–1.41 (m, 5H), 1.46–1.68 (m, 5H), 1.69–1.99 (m,
3
4H), 2.00–2.36 (m, 4H), 2.55 (m, 1H, CH in Chx), 3.22 (d, 2H, CH2N, JHF = 21.5 Hz),
19
3.66 (s, 2H, CH2Ph), 7.08–7.48 (m, 5H, Bn). F NMR (188.3 MHz, CDCl3)  –108.9 (t,
13
3JHF = 21.5 Hz). C NMR (50.3 MHz, CDCl3)  26.3 (s, CH2), 26.3 (s, CH2), 26.5 (s,
CH2), 27.0 (s, CH2), 27.6 (d, CH2, JCF = 3.3 Hz), 28.4 (d, CH2, JCF = 5.0 Hz), 29.1 (s,
2
CH2), 49.3 (d, CH2N, JCF = 27.5 Hz), 53.9 (s, CH2Ph), 59.6 (s, CH in Chx), 121.9 (d,
=C<, 2JCF = 17.6 Hz), 126.5 (s, CH in Bn), 128.1 (s, CH in Bn), 128.4 (s, CH in Bn), 141.3
1
(s, C in Bn), 150.0 (d, =CF–, JCF = 246 Hz). MS (EI) m/z 302 ([M+H]+, 5), 301 ([M]+,
24), 300 ([M–H]+, 5), 272 (6), 259 (13), 258 (73), 245 (35), 244 (69), 238 (3), 232 (19),
224 (5), 214 (9), 210 (8), 190 (12), 189 (50), 188 (12), 176 (34), 158 (25), 146 (34), 133
(6), 113 (6), 106 (4), 91 (100). HRMS (ESI), calcd. for C20H28FN: 302.2279 [M+H+].
Found: 302.2283 [M+H+].
N-(4-Methoxybenzyl)-N-(2-fluoro-2-cyclopentylidenethyl)cyclohexylamine (3gd)
Obtained only by method A using DMSO as the solvent. A colorless oil (method A: 92.7
mg, 56%) was obtained after flash column chromatography (n-hexane/EtOAc, 25/1).

When carried out by method B, starting cyclopropane 2g reacted completely to give
oligomeric products.
1H NMR (200.1 MHz, CDCl3)  0.94–1.38 (m, 5H), 1.47–1.69 (m, 5H), 1.69–1.97 (m,
3
4H), 2.03–2.38 (m, 4H), 2.53 (m, 1H, CH in Chx), 3.20 (d, 2H, CH2N, JHF = 21.4 Hz),
3.59 (s, 2H, PMB), 3.79 (s, 3H, OMe), 6.77–6.90 (m, 2H, PMB), 7.21–7.32 (m, 2H,
PMB). 19F NMR (188.3 MHz, CDCl3)  –108.9 (t, 3JHF = 21.4 Hz). 13C NMR (50.3 MHz,
CDCl3)  26.3 (s, CH2), 26.3 (s, CH2), 26.5 (s, CH2), 27.0 (s, CH2), 27.6 (d, CH2, JCF
=
3.3 Hz), 28.4 (d, CH2, JCF = 5.1 Hz), 29.0 (s, CH2), 49.0 (d, CH2N, 2JCF = 27.4 Hz), 53.1
(s, CH2 in PMB), 55.3 (s, OCH3), 59.2 (s, CH in Chx), 113.5 (s, 2CH in PMB), 121.8 (d,
=C<, 2JCF = 17.8 Hz), 129.4 (s, 2CH in PMB), 133.2 (s, C in PMB), 150.1 (d, =CF–, 1JCF
=
246 Hz), 158.4 (s, C(OMe) in PMB). MS (EI) m/z 331 ([M]+, 8), 288 (5), 275 (6), 274 (7),
219 (14), 206 (3), 176 (2), 121 (100). HRMS (ESI), calcd. for C21H30FNO: 332.2384
[M+H+]. Found: 332.2378 [M+H+].
N-(4-Methoxyphenyl)-N-(2-fluoro-2-cyclopentylidenethyl)cyclohexylamine (3ge)
Obtained only by method A using DMSO as the solvent. A colorless oil (method A: 98.1
mg, 62%) was obtained after flash column chromatography (n-hexane/EtOAc, 25/1).
When carried out by method B, starting cyclopropane 2g reacted completely to give
oligomeric products.
1H NMR (200.1 MHz, CDCl3)  0.96–1.45 (m, 5H), 1.49–1.72 (m, 5H), 1.72–1.99 (m,
4H), 2.06–2.41 (m, 4H), 3.28 (m, 1H, CH in Chx), 3.75 (s, 3H, OMe), 3.83 (d, 2H, CH2N,
19
3JHF = 15.6 Hz), 6.70–6.92 (m, 4H, PMP). F NMR (188.3 MHz, CDCl3)  –111.3 (t,
13
3JHF = 15.6 Hz). C NMR (50.3 MHz, CDCl3)  26.0 (s, CH2), 26.1 (s, CH2), 27.2 (s,
CH2), 27.8 (d, CH2, JCF = 3.5 Hz), 28.1 (d, CH2, JCF = 5.0 Hz), 30.7 (s, CH2), 46.9 (d,
2
CH2N, JCF = 30.0 Hz), 55.6 (s, OCH3), 59.5 (s, CH in Chx), 114.2 (s, 2CH in PMP),
2
119.5 (s, 2CH in PMP), 120.5 (d, =C<, JCF = 17.6 Hz), 143.5 (s, C in PMP), 149.3 (d,
1
=CF–, JCF = 246 Hz), 153.1 (s, C(OMe) in PMP). MS (EI) m/z 318 ([M+H]+, 20), 317
([M]+, 100), 302 (2), 288 (4), 275 (8), 274 (40), 261 (28), 260 (33), 248 (8), 205 (27), 204
(37), 192 (7), 174 (15), 162 (42), 149 (13), 134 (15), 122 (7), 108 (5). HRMS (ESI), calcd.
for C20H28FNO: 318.2228 [M+H+]. Found: 318.2234 [M+H+].

N-Benzyl-N-(2-fluoro-2-cyclopentylidenethyl)-4-methoxyaniline (3gf)
Obtained only by method A using DMSO as the solvent. A colorless oil (method A: 104.4
mg, 64%) was obtained after flash column chromatography (n-hexane/EtOAc, 25/1).
When carried out by method B, starting cyclopropane 2g reacted completely to give
oligomeric products.
1H NMR (200.1 MHz, CDCl3)  1.52–1.66 (m, 4H, 2CH2), 2.03–2.15 (m, 2H, CH2),
2.24–2.39 (m, 2H, CH2), 3.71 (s, 3H, OCH3), 3.99 (d, 2H, CH2N, 3JHF = 18.4 Hz), 4.46 (s,
2H, CH2Ph), 6.75–6.80 (m, 4H, PMP), 7.13–7.35 (m, 5H, Ph). 19F NMR (188.3 MHz,
CDCl3)

3
13
–111.7 (t, JHF = 18.4 Hz). C NMR (75.4 MHz, CDCl3)  26.1 (s, CH2), 27.2 (s, CH2),
27.7 (d, CH2, JCF = 3.1 Hz), 28.2 (d, CH2, JCF = 4.7 Hz), 50.6 (d, CH2N, 2JCF = 28.6 Hz),
55.1 (s, CH2Ph), 55.7 (s, OCH3), 114.7 (s, 2CH-arom., PMP), 115.9 (s, 2CH-arom., PMP),
2
122.3 (d, =CR2, JCF = 16.8 Hz), 126.8 (s, CH-arom.), 127.2 (s, 2CH-arom.), 128.5 (s,
2CH-arom.), 139.2 (s, C-arom.), 144.0 (s, C-arom.), 148.8 (d, –CF=, 1JCF = 247 Hz), 152.3
(s, C-arom.). MS (EI) m/z 325 ([M+], 20), 213 (38), 168 (9), 134 (17), 122 (9), 113 (8),
104 (7), 91 (100), 77 (16), 65 (23), 59 (4), 51 (4). HRMS (ESI), calcd. for C21H24FNO:
326.1915 [M+H+]. Found: 326.1907 [M+H+].
Methyl N-(2-fluoro-2-cyclopentylidenethyl)prolinate (3gh)
Obtained only by method A using DMSO as the solvent. A colorless oil (method A: 64.0
mg, 53%) was obtained after flash column chromatography (n-hexane/EtOAc, gradient
from 10/1 to 3/1). When carried out by method B, starting cyclopropane 2g reacted
completely to give oligomeric products.
1H NMR (200.1 MHz, CDCl3)  1.58–1.71 (m, 4H), 1.75–2.01 (m, 3H), 2.07–2.40 (m,
5H), 2.56 (m, 1H, CH2 in proline), 3.18 (m, 1H, CH2 in proline), 3.28 (m, 1H, CH in
proline), 3.33 (dd, 1H, CH2N, 3JHF = 21.0 Hz, 2JHH = 14.1 Hz), 3.43 (dd, 1H, CH2N, 3JHF
=
2
19
24.6 Hz, JHH = 14.1 Hz), 3.72 (s, 3H, –CO2CH3). F NMR (188.3 MHz, CDCl3)  –
13
107.9 (t, 22.8 Hz). C NMR (75.4 MHz, CDCl3)  23.1 (s, CH2), 26.2 (s, CH2), 26.9 (s,
CH2), 27.5 (d, CH2, JCF = 3.3 Hz), 28.5 (d, CH2, JCF = 4.7 Hz), 29.5 (s, CH2), 51.8 (s,
2
OCH3), 51.8 (d, CH2N, JCF = 27.2 Hz), 53.5 (s, CH2 in proline), 64.7 (s, CH in proline),
2
1
123.2 (d, =C<, JCF = 16.8 Hz), 148.8 (d, =CF–, JCF = 246 Hz), 174.4 (s, –CO2Me). MS
(EI) m/z 241 ([M]+, 2), 183 (5), 182 (35), 140 (1), 128 (1), 113 (4), 93 (4), 91 (4), 70 (100),

59 (4). HRMS (ESI), calcd. for C13H20FNO2: 242.1551 [M+H+]. Found: 242.1554
[M+H+].
4.4. Synthesis of secondary 2-fluoroallyl amines
Amination of 2b with cyclohexylamine
According to reaction conditions A described in paragraph 4.3 from 1b (0.5 mmol) and
cyclohexylamine (0.6 mmol) after flash column chromatography following fractions were
collected: (1) — eluted with n-hexane/EtOAc 50/1 — 25.2 mg of yellowish oil that contained
on the basis of NMR and GC 30 w/w % of 12b (Z,Z/Z,E/E,E = 80/20/<1, yield 8%) and 70
w/w % of dimers 4b (yield 26%); (2) — eluted with n-hexane/EtOAc 1/1 — 66.0 mg of 11b
as a yellowish liquid (Z/E = 91/9, yield 56%).
In the same manner, from 1b (1.0 mmol) and cyclohexylamine (0.5 mmol) after flash
column chromatography following fractions were collected: (1) — eluted with n-
hexane/benzene, gradient from 5/1 to 2/1 — 77.9 mg of 12b as a colorless oil (Z,Z/Z,E/E,E =
61/35/4, yield 43% based on CyNH2); (2) — eluted with n-hexane/EtOAc 1/1 — 57.2 mg of
11b as a yellowish liquid (Z/E = 76/24, yield 49% based on CyNH2).
N-(2-Fluoro-3-phenylallyl)cyclohexylamine (11b)
(A mixture of Z,E-isomers) 1H NMR (200.1 MHz, CDCl3)  0.78–2.04 (m, 11H, 5 CH2 in
Chx + NH), 2.36–2.65 (m, 1H, CH in Chx, both isomers), 3.47 (d, 2H, CH2N, Z-11b, 3JHF
3
= 15.8 Hz), 3.57 (d, 2H, CH2N, E-11b, JHF = 22.5 Hz), 5.65 (d, 1H, =CH–, Z-11b,
3JHF(trans) = 39.4 Hz), 6.33 (d, 1H, =CH–, E-11b, 3JHF(cis) = J = 20.9 Hz), 7.13–7.40 (m, 3H,
arom.), 7.43–7.58 (m, 2H, arom.). 19F NMR (188.3 MHz, CDCl3)  –104.7 (td, E-11b,
3JHF = 22.5 Hz, 3JHF(cis) = J = 20.9 Hz), –107.7 (dt, Z-11b, 3JHF(trans) = 39.4 Hz, 3JHF = 15.8
Hz). 13C NMR (75.4 MHz, CDCl3)  24.9 (s, CH2 in Chx, E-11b), 24.9 (s, CH2 in Chx, Z-
11b), 26.1 (s, CH2 in Chx, E-11b), 26.1 (s, CH2 in Chx, Z-11b), 33.3 (s, CH2 in Chx, E-
11b), 33.4 (s, CH2 in Chx, Z-11b), 43.8 (d, CH2N, E-11b, 2JCF = 26.9 Hz), 47.8 (d, CH2N,
Z-11b, 2JCF = 29.1 Hz), 55.4 (s, CH in Chx, Z-11b), 55.7 (s, CH in Chx, E-11b), 107.0 (d,
2
2
=CH–, Z-11b, JCF = 7.6 Hz), 110.2 (d, =CH–, E-11b, JCF = 27.5 Hz), 127.0 (d, CH-
arom., JCF = 2.0 Hz), 128.4 (s, CH-arom.), 128.5 (d, CH-arom., JCF = 7.4 Hz), 133.3 (d, C-
arom., 3JCF = 2.5 Hz), 158.9 (d, =CF–, 1JCF = 267 Hz). MS (EI) m/z 233 ([M+], 8), 213 (3),
190 (14), 142 (10), 135 (100), 133 (21), 115 (84), 109 (9), 98 (15), 86 (10), 77 (4), 55 (16).
HRMS (ESI), calcd. for C15H20FN: 234.1653 [M+H+]. Found: 234.1649 [M+H+].

N,N-Bis(2-fluoro-3-phenylallyl)cyclohexylamine (12b)
(A mixture of Z,Z-12b, Z,E-12b, E,E-12b in a ratio of 61/35/4):
1H NMR (300.1 MHz, CDCl3)  0.93–1.37 (m, 5H, CH2 in Chx), 1.46–1.97 (m, 5H, CH2
in Chx), 3.32 (d, 2H, Z-AllCH2N, Z,E-12b, 3JHF = 12.7 Hz), 3.43 (d, 4H, Z-AllCH2N, Z,Z-
3
12b, 3JHF = 12.9 Hz), 3.48 (d, 4H, E-AllCH2N, E,E-12b, JHF = 22.5 Hz), 3.57 (d, 2H, E-
3
3
AllCH2N, Z,E-12b, JHF = 21.5 Hz), 5.64 (d, 1H, (Z)-CF=CH-, Z,E-12b, JHF(trans) = 39.5
3
Hz), 5.78 (d, 2H, (Z)-CF=CH-, Z,Z-12b, JHF(trans) = 39.4 Hz), 6.34 (d, 2H, (E)-CF=CH-,
E,E-12b, 3JHF(cis) = 21.1 Hz), 6.37 (d, 1H, (E)-CF=CH-, Z,E-12b, 3JHF(cis) = 21.1 Hz), 7.12–
19
7.53 (m, 10H, 2Ph). F NMR (188.3 MHz, CDCl3)  –96.7 (td, 2F, (E)-CF=CH-, E,E-
12b, 3JHF = 22.5 Hz, 3JHF(cis) = 21.1 Hz), –99.0 (td, 1F, (E)-CF=CH-, Z,E-12b, 3JHF = 21.5
Hz,
3JHF(cis)
=
21.1
Hz),
–105.1 (dt, 1F, (Z)-CF=CH-, Z,E-12b, 3JHF(trans) = 39.5 Hz, 3JHF = 12.7 Hz), –105.3 (dt, 2F,
(Z)-CF=CH-, Z,Z-12b, 3JHF(trans) = 39.4 Hz, 3JHF = 12.9 Hz). 13C NMR (75.4 MHz, CDCl3)
 25.8–26.5 (m, CH2 in Chx, all isomers), 28.7–29.9 (m, CH2 in Chx, all isomers), 47.8
2
(d, E-AllCH2N, Z,E-12b, 2JCF = 25.6 Hz), 47.9 (d, E-AllCH2N, E,E-12b, JCF = 26.8 Hz),
2
2
51.2 (d, Z-AllCH2N, Z,E-12b, JCF = 28.9 Hz), 51.6 (d, Z-AllCH2N, Z,Z-12b, JCF = 29.8
2
Hz), 60.1–60.5 (m, CH in Chx, all isomers), 107.4 (d, (Z)-CF=CH-, Z,E-12b, JCF = 8.8
Hz), 107.5 (d, (Z)-CF=CH-, Z,Z-12b, 2JCF = 6.8 Hz), 111.8 (d, (E)-CF=CH-, Z,E-12b, 2JCF
= 27.3 Hz), 112.0 (d, (E)-CF=CH-, E,E-12b, 2JCF = 27.9 Hz), 126.8–127.2 (m, CH arom.,
all isomers), 128.3–129.1 (m, CH arom., all isomers), 133.5–133.8 (m, C arom., all
1
isomers), 158.7 (d, (Z)-CF=CH-, Z,E-12b, JCF = 268 Hz), 158.9 (d, (Z)-CF=CH-, Z,Z-
1
1
12b, JCF = 269 Hz), 159.9 (d, (E)-CF=CH-, E,E-12b, JCF = 254 Hz), 160.0 (d, (E)-
CF=CH-, Z,E-12b, 1JCF = 256 Hz). MS (EI) m/z 367 ([M]+, 4), 324 (2), 276 (7), 220 (20),
136 (10), 135 (100), 133 (27), 116 (10), 115 (97), 109 (15), 91 (8), 83 (5). HRMS (ESI),
calcd. for C24H27F2N: 368.2184 [M+H+]. Found: 368.2190 [M+H+].
Typical procedure for cleavage of PMP-group in 3be with (NH4)2[Ce(NO3)6]. Synthesis
of N-(2-Fluoro-3-phenylallyl)cyclohexylamine (11b).
To a solution of 34.5 mg (0.099 mmol) of 3be (Z/E =73/27) in 1.0 mL of MeCN 0.20
mL of water were added followed by 155.7 mg (0.28 mmol) of (NH4)2[Ce(NO3)6]. The
reaction mixture was stirred at room temperature for 1 hour, diluted with satd. NaHCO3 and
satd. Na2SO3 and stirred for additional 10 min. Resulted mixture was extracted with CH2Cl2,
combined extracts were dried over K2CO3 and concentrated. The residue was purified by

flash column chromatography (n-hexane/EtOAc = 1/1) affording 22.4 mg of 11b as a
yellowish liquid (Z/E = 72/28, yield 97%).
Synthesis of N-(2-Fluoro-2-cyclopentylidenethyl)cyclohexylamine (11g) by cleavage of
PMP-group in 3ge with (NH4)2[Ce(NO3)6]
Using the procedure described above, from 30.4 mg of 3ge after flash column
chromatography (EtOAc) 20.8 mg of 11g as a brown oil were obtained (yield 98%).
1H NMR (300.1 MHz, CDCl3)  0.99–1.35 (m, 5H, CH2), 1.41 (br. s, 1H, NH), 1.56–1.80
(m, 7H, CH2), 1.80–1.92 (m, 2H, CH2), 2.17–2.28 (m, 2H, CH2), 2.29–2.39 (m, 2H, CH2),
3
2.45 (m, 1H, CH in Chx), 3.37 (d, 2H, CH2N, JHF = 20.9 Hz). 19F NMR (282.4 MHz,
CDCl3)  –115.6 (t, 3JHF = 20.9 Hz). 13C NMR (75.4 MHz, CDCl3)  25.1 (s, CH2), 26.3
(d, CH2, JCF = 14.2 Hz), 27.0 (s, CH2), 27.5 (d, CH2, JCF = 3.2 Hz), 28.4 (d, CH2, JCF = 5.1
2
Hz), 33.5 (s, CH2), 45.2 (d, CH2N, JCF = 28.7 Hz), 55.6 (s, CH in Chx), 120.8 (d, =C<,
1
2JCF = 17.5 Hz), 150.1 (d, =CF–, JCF = 243 Hz). MS (EI) m/z 211 ([M]+, 12), 168 (42),
154 (7), 148 (16), 142 (2), 134 (2), 126 (4), 113 (22), 109 (10), 100 (24), 98 (27), 93 (30),
91 (25), 85 (12), 79(18), 77 (23), 70 (16), 67 (22), 59 (13), 56 (100). HRMS (ESI), calcd.
for C13H22FN: 212.1809 [M+H+]. Found: 212.1812 [M+H+].
Cleavage of Bn and PMB-groups in 3bc,3bd,3gc,3gd with (NH4)2[Ce(NO3)6]
According to the procedure described for 3be. Crude product mixtures after work-up
were analyzed by 1H, 19F NMR, GC and GC/MS. Results are presented on Scheme 7.
(Z)-2-Fluoro-3-phenylprop-2-enal (13b)
1
3
(For Z-13b): H NMR (200.1 MHz, CDCl3)  6.61 (d, 1H, –CH=CF–, JHF(trans) = 34.1
3
Hz), 7.11–8.00 (m, 5H, arom.), 9.35 (d, 1H, –CH=O, JHF = 17.0 Hz). 19F NMR (188.3
MHz, CDCl3)  –127.9 (dd, 3JHF(trans) = 34.1 Hz, 3JHF = 17.0 Hz). MS (EI) m/z 150 ([M+],
64), 149 (100), 129 (4), 121 (30), 101 (62), 96 (39), 78 (36), 75 (43), 63 (20), 51 (37). (For
E-13b): 19F NMR (188.3 MHz, CDCl3)  –125.1 (dd, 3JHF(cis) = 19.5 Hz, 3JHF = 17.1 Hz).
MS (EI) m/z 150 ([M+], 42), 149 (100), 121 (14), 101 (33), 96 (32), 78 (15), 75 (29), 63
(9), 50 (20).
4.5. Synthesis of primary 2-fluoroallyl amines
For synthesis and isolation of 2-fluoroallyl chlorides Z-6b and 6h, see refs. [17a,b].

2-Fluoro-3-phenylallyl amine (Z-14b)
Method A. To a solution of 340 mg (2.0 mmol) of Z-6b (Z/E > 99.9) in 2.0 mL of DMF
370 mg (2.0 mmol) of potassium phthalimide were added. The reaction mixture was stirred at
100°C for 3 hours, then diluted with Et2O, washed with water and brine, dried over K2CO3.
After evaporation of volatiles and drying of a residue under high vacuum 560 mg of pure N-
((Z)-2-fluoro-3-phenylallyl)phthalimide Z-15b as colorless solids (yield >99%).
1H NMR (400.1 MHz, CDCl3)  4.53 (d, 2H, CH2N, 3JHF = 15.4 Hz), 5.85 (d, 1H, –CH=,
3JHF(trans) = 37.9 Hz), 7.18–7.32 (m, 3H, Ph), 7.44–7.49 (m, 2H, Ph), 7.68–7.75 (m, 2H,
phthalimide), 7.85–7.90 (m, 2H, phthalimide).19F NMR (282.4 MHz, CDCl3)  –109.7
(dt, 3JHF(trans) = 37.9 Hz, 3JHF = 15.4 Hz). 13C NMR (100.6 MHz, CDCl3)  39.2 (d, CH2N,
2
2JCF = 32.2 Hz), 109.5 (d, –CH=, JCF = 6.4 Hz), 123.6 (s, 2CH, phthalimide), 127.7 (d,
6
4
CH, JCF = 1.8 Hz), 128.5 (s, 2CH), 128.8 (d, 2CH, JCF = 7.3 Hz), 132.1 (s, 2C,
3
phthalimide), 132.5 (d, C, JCF = 2.7 Hz), 134.3 (d, 2CH, phthalimide), 153.6 (d, –CF=,
1JCF = 268 Hz), 167.5 (s, 2C=O). MS (EI) m/z 281 ([M+], 41), 261 (100), 232 (69), 204
(26), 178 (9), 165 (5), 148 (4), 133 (35), 115 (10), 104 (24), 91 (4), 77 (14). HRMS (ESI),
calcd. for C17H12FNO2: m/z 304.0744 [M+Na+]. Found: m/z 304.0742 [M+Na+].
To a solution of 560 mg (2.0 mmol) of Z-15b in 6.0 mL of MeOH 102 L (2.2 mmol)
of N2H4·H2O were added. The reaction mixture was stirred at room temperature for 24 hours,
then was filtered. Under cooling on an ice bath 1 mL (ca. 10 mmol) of conc. HCl was added
and the resulted mixture was concentrated on a rotary evaporator. The residue was dissolved
in 50 mL of water, filtered and washed with CH2Cl2. After that under cooling on an ice bath
ca. 6M solution of NaOH was added to pH = 14. Resulted solution was saturated with NaCl
and extracted with CH2Cl2. Extracts were combined, dried over K2CO3 and concentrated
under reduced pressure. The residue was purified by ‘bulb-to-bulb’ distillation (8 mmHg, 120
to 150°C) to give 270 mg of Z-14b as a colorless liquid (Z/E >99.9, yield 95%).
3
1H NMR (200.1 MHz, CDCl3)  1.48 (br. s, 2H, NH2), 3.44 (d, 2H, CH2N, JHF = 14.3
3
Hz), 5.63 (d, 1H, –CH=, JHF(trans) = 39.3 Hz), 7.13–7.58 (m, 5H, arom.). 19F NMR (188.3
3
3
13
MHz, CDCl3)  –109.8 (dt, JHF(trans) = 39.3 Hz, JHF = 14.3 Hz). C NMR (50.3 MHz,
CDCl3)  43.7 (d, CH2N, 2JCF = 30.8 Hz), 105.4 (d, –CH=, 2JCF = 7.6 Hz), 127.1 (d, CH-
6
4
arom., JCF = 2.2 Hz), 128.4 (s, 2CH-arom.), 128.4 (d, 2CH-arom., JCF = 7.1 Hz), 133.2
3
1
(d, C-arom., JCF = 2.5 Hz), 160.8 (d, –CF=, JCF = 267 Hz). HRMS (ESI), calcd. for
C9H10FN: m/z 152.0870 [M+H+]. Found: m/z 152.0873 [M+H+].

Method B. To a solution of 862 mg (5.1 mmol) of Z-6b (Z/E > 99.9) in 10 mL of
CH2Cl2 1.05 g (5.1 mmol) of urotropine were added. The reaction mixture was stirred under
reflux for 24 hours. Precipitate formed was filtered off, washed with CH2Cl2 and dried under
high vacuum to give 1.55 g of N-(2-fluoro-3-phenylallyl)urotropinium chloride Z-16b as
colorless solids (yield 99%).
3
1H NMR (200.1 MHz, DMSO-d6)  4.14 (d, 2H, CH2N+, JHF = 22.9 Hz), 4.46–4.73 (m,
3
6H, urotropine), 5.27–5.49 (m, 6H, urotropine), 6.41 (d, 1H, –CH=, JHF(trans) = 39.0 Hz),
7.28–7.66 (m, 5H, arom.). 19F NMR (188.3 MHz, DMSO-d6)  –94.1 (dt, 3JHF(trans) = 39.0
Hz, 3JHF = 22.9 Hz). 13C NMR (50.3 MHz, DMSO-d6)  56.4 (d, CH2N+, 2JCF = 28.0 Hz),
2
69.6 (s, 3CH2, urotropine), 78.0 (s, 3CH2, urotropine), 117.2 (d, –CH=, JCF = 4.8 Hz),
128.7 (s, 2CH-arom.), 128.7 (d, CH-arom., 6JCF = 2.0 Hz), 129.3 (d, 2CH-arom., 4JCF = 7.2
3
1
Hz), 131.4 (d, C-arom., JCF = 3.1 Hz), 147.6 (d, –CF=, JCF = 264 Hz). HRMS (ESI),
+
calcd. for C15H20FN4 : m/z 275.1667 [M+]. Found: m/z 275.1672 [M+].
To a well stirred suspension of 1.50 g (4.8 mmol) of Z-16b in 10 mL of EtOH 2 mL
(ca. 20 mmol) of conc. HCl were added. The reaction mixture was stirred under reflux for 24
hours, and then concentrated on a rotary evaporator. Work-up as above followed by ‘bulb-to-
bulb’ distillation afforded 486 mg of Z-14b as a colorless liquid (Z/E >99.9, yield 67%).
2-Fluoro-3-methylbut-2-enyl amine (14h)
Method A. A mixture of 12.3 g (100 mmol) of 2-fluoro-3-methylbut-2-enyl chloride
6h, 18.5 g (100 mmole) of potassium phthalimide and 100 mL of DMF was stirred at 100°C
for 3 hours, then diluted with Et2O, washed with water, brine, and dried over K2CO3. After
evaporation of volatiles and drying of a residue under high vacuum 22.4 g of pure N-((Z)-2-
fluoro-3-phenylallyl)phthalimide 15h as colorless solids (yield 96%).
1H NMR (200.1 MHz, CDCl3)  1.66 (d, 3H, CH3, J = 3.4 Hz), 1.86 (d, 3H, CH3, J = 3.0
Hz), 4.47 (d, 1H, =CH–, J = 20.4 Hz), 7.65–7.78 (m, 2H, arom.), 7.80–7.91 (m, 2H,
19
13
arom.). F NMR (188.3 MHz, CDCl3)  –119.7 (tqq, J = 20.4, 3.4, 3.0 Hz). C NMR
(50.3 MHz, CDCl3)  15.9 (d, CH3, J = 8.5 Hz), 17.6 (d, CH3, J = 4.8 Hz), 35.2 (d, CH2, J
= 31.3 Hz), 113.3 (d, =CMe2, J = 15.4 Hz), 123.4 (s, 2CH-arom.), 132.1 (s, 2C-arom.),
134.0 (s, 2CH-arom.), 148.0 (d, =CF–, J = 243 Hz), 167.8 (s, 2 C=O). MS (EI) m/z 233
([M]+, 20), 218 ([M–CH3]+, 4), 213 ([M–HF]+, 100), 198 (12), 185 (31), 170 (33), 160
(38), 148 (7), 133 (12), 130 (27), 105 (19), 104 (15), 86 (14), 85 (13), 76 (15). HRMS

(ESI), calcd. for C13H12FNO2: 234.0925 [M+H+], 256.0744 [M+Na+]. Found: 234.0920
[M+H+], 274.0738 [M+Na+].
To a solution of 22.4 g (96 mmol) of 15h in 300 mL of MeOH 5.1 mL (106 mmol) of
N2H4·H2O were added dropwise. The reaction mixture was stirred at room temperature for 24
hours, and then was filtered. Under cooling on an ice bath 20 mL (ca. 200 mmol) of conc.
HCl was added and the resulted mixture was concentrated on a rotary evaporator. The residue
was dissolved in 300 mL of water, filtered and washed with CH2Cl2. After that under cooling
on an ice bath ca. 6M solution of NaOH was added to pH = 14. Resulted solution was
saturated with NaCl and extracted with CH2Cl2. Extracts were combined, dried over K2CO3
and concentrated under reduced pressure (25°C, 100 mbar). The residue was distilled under
reduced pressure to give 8.90 g of 2-fluoro-3-methylbut-2-enyl amine 14h as a colorless
liquid (bp 65–66°C/100 mmHg, yield 90%).
1H NMR (200.1 MHz, CDCl3)  1.25 (br. s., 2H, NH2), 1.62–1.67 (m, 6H, 2CH3), 3.40 (d,
19
2H, CH2, J = 21.9 Hz). F NMR (188.3 MHz, CDCl3)  –120.0 (tqq, J = 21.9, 3.0, 3.0
Hz). 13C NMR (50.3 MHz, CDCl3)  15.3 (d, CH3, J = 8.9 Hz), 17.1 (d, CH3, J = 5.5 Hz),
39.1 (d, CH2, J = 31.0 Hz), 108.1 (d, =CMe2, J = 17.2 Hz), 154.3 (d, =CF–, J = 241 Hz).
MS (EI) m/z 103 ([M+], 30), 102 (16), 88 (100), 86 (90), 85 (49), 68 (25), 59 (25), 41 (26).
HRMS (ESI), calcd. for C5H10FN: 104.0870 [M+H+]. Found: 104.0867 [M+H+].
Method B. To a solution of 16.8 g (120 mmol) of urotropine in 150 mL of CH2Cl2 12.3
g (100 mmol) of 2-fluoro-3-methylbut-2-enyl chloride 6h were added dropwise. The reaction
mixture was stirred under reflux for 24 hours. Precipitate formed was filtered off, washed
thoroughly with CH2Cl2 and dried under high vacuum to give 23.4 g of N-(2-fluoro-3-
methylbut-2-enyl)urotropinium chloride 16h as colorless solids (yield 89%).
1H NMR (200.1 MHz, DMSO-d6)  1.74 (d, 3H, CH3, J = 3.2 Hz), 1.79 (d, 3H, CH3, J =
2.5 Hz), 3.92 (d, 2H, CH2, J = 24.8 Hz), 4.43–4.71 (m, 6H, 3CH2-urotropine), 5.26 (s, 6H,
3CH2-urotropine). 19F NMR (188.3 MHz, DMSO-d6)  –106.0 (t, J = 24.8 Hz). 13C NMR
(50.3 MHz, DMSO-d6)  16.3 (d, CH3, J = 8.3 Hz), 18.1 (d, CH3, J = 3.8 Hz), 52.4 (d,
CH2, J = 30.9 Hz), 69.6 (s, 3CH2-urotropine), 77.5 (s, 3CH2-urotropine), 123.2 (d, =CMe2,
+
J = 15.2 Hz), 142.2 (d, =CF–, J = 237 Hz). HRMS (ESI), calcd. for C11H20FN4 : 227.1667
[M+]. Found: 227.1670 [M+].

To a solution of 70 mL (ca. 700 mmol) of conc. HCl in 300 mL of EtOH and 60 mL of
water 23.4 g (89 mmol) of 16h were added. The reaction mixture was stirred under reflux for
24 hours, and then concentrated on a rotary evaporator. Work-up as above followed by
distillation gave 5.41 g of 14h as a colorless liquid (yield 59%).
Acknowledgements
The reported study was funded by RFBR according to the research project № 16-03-01098_а.
References
[1] (a) I. Ojima, Fluorine in Medicinal Chemistry and Chemical Biology, John Wiley &
Sons, Ltd, Chichester, UK, 2009;
(b) A. Tressaud, G. Haufe, Fluorine and Health, Elsevier, Amsterdam, 2008;
(c) P. Kirsch, Modern Fluoroorganic Chemistry: Synthesis, Reactivity, Applications,
Wiley-VCH Verlag GmbH & Co. KGaA, 2004;
(d) W.K. Hagmann, J. Med. Chem. 51 (2008) 4359–4369;
(e) D. O’Hagan, J. Fluorine Chem. 131 (2010) 1071–1081.
[2] (a) S. Osada, S. Sano, M. Ueyama, Y. Chuman, H. Kodama and K. Sakaguchi, Bioorg.
Med. Chem. 18 (2010) 605–611;
(b) J. Kanazawa, T. Takahashi, S. Akinaga, T. Tamaoki and M. Okabe, Anti-Cancer
Drugs 9 (1998) 653-657.
[3] (a) R. J. Sciotti, M. Pliushchev, P. E. Wiedeman, D. Balli, R. Flamm, A. M. Nilius, K.
Marsh, D. Stolarik, R. Jolly, R. Ulrich and S. W. Djuric, Bioorg. Med. Chem. Lett. 12
(2002) 2121–2123;
(b) Y. Asahina, K. Iwase, F. Iinuma, M. Hosaka and T. Ishizaki, J. Med. Chem. 48 (2005)
3194–3202.
[4] S. Oishi, H. Kamitani, Y. Kodera, K. Watanabe, K. Kobayashi, T. Narumi, K. Tomita, H.
Ohno, T. Naito, E. Kodama, M. Matsuoka and N. Fujii, Org. Biomol. Chem. 7 (2009)
2872–2877.