Copper(I)-catalyzed solvolysis of gem-chlorofluoro- and gem-bromofluorocyclopropanes. Preparation of 2-fluoroallylic ethers, esters and alcohols

Article abstract of DOI:10.1016/j.jfluchem.2015.09.001

Copper(I)-catalyzed solvolysis of gem-chlorofluoro- and gem-bromofluorocyclopropanes in MeOH, NaOAc/AcOH, NaOAc/DMF, HCO₂Na/HCO₂H or water/dioxane affords 2-fluoroallylic ethers, esters or alcohols in moderate to excellent yields. Th

Full text of DOI:10.1016/j.jfluchem.2015.09.001

Accepted Manuscript
Title: Copper(I)-catalyzed solvolysis of gem-chlorofluoro- and
gem-bromofluorocyclopropanes. Preparation of 2-fluoroallylic
ethers, esters and alcohols
Author: Maxim A. Novikov Nikolai V. Volchkov Maria B.
Lipkind Oleg M. Nefedov
PII:
S0022-1139(15)00266-3
DOI:
Reference:
http://dx.doi.org/doi:10.1016/j.jfluchem.2015.09.001
FLUOR 8653
To appear in:
FLUOR
Received date:
Revised date:
Accepted date:
26-6-2015
1-9-2015
3-9-2015
Please cite this article as: M.A. Novikov, N.V. Volchkov, M.B. Lipkind,
O.M.
and
Nefedov,
gem-bromofluorocyclopropanes.
Copper(I)-catalyzed
solvolysis
Preparation
of
gem-chlorofluoro-
of
2-fluoroallylic
ethers, esters and alcohols, Journal of Fluorine Chemistry (2015),
http://dx.doi.org/10.1016/j.jfluchem.2015.09.001
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1
Copper(I)-catalyzed solvolysis of gem-
chlorofluoro- and gem-bromofluorocyclopropanes easily prepared by carbenic cyclopropanation
of olefins affords 2-fluoroallylic ethers, esters or alcohols in moderate to excellent yields.
Highlights
Solvolysis of gem-fluorohalocyclopropanes in protic solvents catalyzed by CuX.
Cyclopropyl-allylic ring opening forming 2-fluoroallylic ether, esters and alcohols.
Two-stage reaction pathway through intermediate formation of fluoroallylic halides.
Multigram scale synthesis.
Copper(I)-catalyzed solvolysis of gem-chlorofluoro- and gem-bromofluorocyclopropanes.
Preparation of 2-fluoroallylic ethers, esters and alcohols†
Maxim A. Novikov*, Nikolai V. Volchkov*, Maria B. Lipkind and Oleg M. Nefedov*
N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, 47 Leninsky prosp.,
119991 Moscow, Russian Federation
Fax: +7499 135 63 90; e-mail: manovikov@ioc.ac.ru, volchkov@ioc.ac.ru, nefedov@ioc.ac.ru
Abstract
† For the previous part, see [1].
Page 1 of 35

2
Copper(I)-catalyzed solvolysis of gem-chlorofluoro- and gem-bromofluorocyclopropanes in
MeOH, NaOAc/AcOH, NaOAc/DMF, HCO2Na/HCO2H or water/dioxane affords 2-fluoroallylic
ethers, esters or alcohols in moderate to excellent yields. The reaction pathway involves
isomerization of gem-fluorohalocyclopropanes to 2-fluoroallylic halides followed by
nucleophilic substitution of a halide onto an O-nucleophile. The applicability of the procedure
that we developed in preparative synthesis was demonstrated within the 100–200 mmol scale.
Keywords
gem-fluorohalocyclopropanes, fluorohalocarbenes, fluoroallylic compounds, copper catalysis,
solvolysis, cyclopropyl-allylic transformation
1. Introduction
Cyclopropyl-allylic transformations of cyclopropyl halides are among the most important
reactions in cyclopropane chemistry [2]. The majority of these rearrangements occur as
elimination of a halide anion and synchronous electrocyclic orbital-symmetry controlled
cyclopropane ring opening. The chemoselectivity of halide elimination and stereoselectivity of
ring opening in these processes are governed by Woodward–Hoffmann–DePuy rules [3].
Cyclopropyl-allylic transformations were shown to be powerful tools in syntheses of a wide
range of organic compounds including complex or highly strained carbo- and heterocyclic
structures [2a]. These rearrangements in the case of fluorinated cyclopropanes are of special
interest as they result in fluorinated organic molecules [4]. In particular, 2-fluoroallylic
compounds can be prepared from gem-chlorofluoro- and gem-bromofluorocyclopropanes
[2c,d,5]. This approach involves the cyclopropanation of the C=C double bond of an alkene with
chlorofluoro- or bromofluorocarbene followed by ring opening in the resulting three-membered
ring via cleavage of the C-C bond opposite to the dihalomethylene group and 1,2-migration or
nucleophilic substitution of the chlorine or bromine atom (scheme 1). As a result, formal
“insertion” of a C-F moiety into the alkene C=C double bond occurs.
F
F
R1
X
R1
R2
R3
R4
Y-
R3
:CFX
R1
Y
R3 R4
R2
R2 R4
R1 - R4 = H, Alk, Ar, etc.;
X = Cl, Br;
Y = Cl, Br, OH, OR, OCOR;
Scheme 1. Preparation of 2-fluoroallylic compounds via gem-fluorohalocyclopropanes.
Page 2 of 35

3
Since this synthetic route uses inexpensive and widely available precursors for the synthesis
of gem-fluorohalocyclopropanes, namely, CHX2F or CX2FCO2H as fluorohalocarbene sources
[2c,d,6] and olefins, it is an attractive alternative to the other synthetic approaches to 2-
fluoroallylic structures [7], e.g. fluoroolefination [8] or fluoroalkenylation [9a-c] of carbonyl
compounds or carbon monoxide [9d], allylic substitution of fluorine in α,α-difluoroalkenes [10],
α-oxidation of fluoroalkenes [11] and electrophilic fluorination of allenes [12].
Despite all its benefits, the approach toward 2-fluoroallylic compounds based on ring-
opening rearrangements of gem-fluorohalocyclopropanes found only limited synthetic
application, likely because selective and mild methods to induce these transformations are not
available. Thermolytic induction requires relatively high temperatures for isomerization of alkyl-
, alkenyl-, and chloro-substituted gem-chlorofluorocyclopropanes to 2-fluoroallylic chlorides. So
ring-opening isomerization under these conditions is complicated by side reactions such as
dehydrohalogenation [13], aromatization [14] and radical rearrangements [15]. While the
easiness of these side reactions resulted in development of highly efficient methods for 2-fluoro-
1,3-diene [13d,e] and fluoroarene [14a] synthesis, it makes selective preparation of 2-
fluoroallylic halides through gem-fluorohalocyclopropanes a challenging task. Only a few 2-
fluoroallylic chlorides were isolated by preparative GC from mixtures of gem-
chlorofluorocyclopropane rearrangement products [13b,15,16]. Alkoxy-substituted gem-
fluorohalocyclopropanes generally undergo ring-opening transformations under much milder
conditions compared to the corresponding unsubstituted cyclopropanes [2a–c,17]. Nevertheless,
side reactions of dehydrohalogenation [17a] or formation of carbonyl compounds [17b–g] are
predominant in these cases.
Solvolytic ring opening to give allylic ethers and esters provides good results in case of non-
fluorinated cyclopropyl chlorides and bromides [2a], while gem-fluorohalocyclopropanes react
slowly or not at all under typical solvolytic conditions [18a]. Their solvolysis can be induced by
silver(I)-assistance [18], which requires stoichiometric amounts of AgI salts (AgNO3, AgOAc,
AgClO4, etc.). However, application of catalytic Lewis acids (e.g. BF3) or silver salts with a non-
solvating counter-ion (e.g. AgClO4, AgBF4) or high reaction temperatures (140–180°C) are
required for gem-chlorofluorocyclopropanes. 2-Fluoroallylic methyl ethers, 2-fluoroallylic
acetates and 2-fluoroallylic alcohols were prepared using silver-mediated methanolysis,
acetolysis and hydrolysis of alkyl-, aryl-substituted gem-fluorohalocyclopropanes [18].
Page 3 of 35

4
Recently [1] we have published the first example of catalytic induction of ring-opening
isomerization of aryl-, alkyl-, chloro-, vinyl-, cyclopropyl-substituted and bicyclic gem-
chlorofluorocyclopropanes by CuCl in aprotic solvents (MeCN, dioxane, diglyme). This method
can be used for facile preparation of aryl-, alkyl-substituted or cyclic 2-fluoroallyl chlorides or
bromides in good to excellent yields from gem-chlorofluoro- and gem-
bromofluorocyclopropanes (scheme 2).
F
X
CuX
X
MeCN
F
80-150°C
1 (X = Cl);
2 (X = Br);
Z,E-3 (X = Cl), see ref. [1];
Z,E-4 (X = Br), see ESI;
> 95%
Scheme 2. Representative examples of preparation of 2-fluoroallylic halides by CuX catalyzed
isomerization of gem-fluorohalocyclopropanes
Herein we report results of our investigation on copper(I)-catalyzed solvolysis of gem-
fluorohalocyclopropanes in protic solvents to give 2-fluoroallylic methyl ethers, 2-fluoroallylic
acetates, formates and 2-fluoroallylic alcohols [19].
2. Results
2.1. Reactions of 2-chloro-2-fluoro-1-phenylcyclopropane (1) and 2-bromo-2-fluoro-1-
phenylcyclopropane (2) in MeOH
Solvolysis of 2 in MeOH in the presence of 0.20 equiv. CuBr at 60°C gave mixtures of 2-
fluoroallyl methyl ethers 5,6 and 2-fluoroallyl bromides 4 (table 1, entry 4). The ratio between
ethers and bromides depended on reaction time. At early stages of the reaction, bromides 4 were
predominant, and even at full conversion of 2 (after 8 hours) the amount of 4 was comparable to
that of ethers 5,6. Further heating (24 hours) resulted in almost complete solvolysis of 4 to 5,6
that was formed in 88% yield in a Z-5/E-5/6 = 48/2/50 ratio, with only 5% yield of residual 4
(Z/E = 79/21). The yield of (E)-isomeric ether E-5 in the reaction did not exceed ca. 3%.
The same results were obtained for solvolytic ring opening of 1 (table 1, entry 1). After 24
hours at 60°C in the presence of 0.50 equiv. of CuCl in MeOH, compound 1 was converted to
ethers 5,6 in 70% yield (Z-5/E-5/6 = 32/1/67) and chlorides Z,E-3 in 30% yield (Z/E = 51/49).
Increasing the reaction temperature to 120°C gave ethers Z,E-5,6 as the only products in 89%
Page 4 of 35

5
yield and in a 86/3/11 ratio (table 1, entry 3). Microwave irradiation (8-10W, 150°C) of 1 in
MeOH in the presence of 1.0 equiv. CuCl afforded exclusively ethers Z,E-5,6 formed in 11 min
in 99% yield and in a 84/4/12 ratio (table 1, entry 5).
Table 1. Rearrangements of 2-chloro-2-fluoro-1-phenylcyclopropane 1 (syn/anti = 56/44) and 2-bromo-2-fluoro-1-
phenylcyclopropane 2 (syn/anti = 47/53)) in the presence of CuX (X = Cl, Br) in MeOH
OMe
X
F
X
F
CuX
+
+
+
Ph
OMe
Ph
Ph
X
MeOH
60-120°C
or
Ph
F
F
F
Ph
syn-1 (X = Cl);
syn-2 (X = Br);
anti-1 (X = Cl);
anti-2 (X = Br);
Z,E-5
6
Z,E-3 (X = Cl);
Z,E-4 (X = Br);
150°C (MW)
Conversion of 1 or 2
Yield of
5,6,
(%)b
13
Yield of 3 or
CuX,a
(equiv.)
ratio
Z-5/E-5/6
ratio
Z/E
Entry cyclopropane
T,°C
60°
time
(%)
4,
(%)b
20
30
(5)
0
13
24
44
59
syn
13
anti
61
1
0.50
1 h
24 h
10 h
10 h
0.5 h
1 h
2 h
5 h
8 h
24 h
1 min
23/0/77
32/1/67
48/11/41
86/3/11
30/0/70
33/0/67
35/1/64
43/3/54
46/3/51
48/2/50
22/0/78
70/30
51/49
55/45
—
75/25
74/26
72/28
69/31
76/24
79/21
45/55
1
100
100
100
11
100
100
100
21
70
2
3
4
0.20
0.20
0.20
100°
120°
60°
(91)
(89)
3
6
12
36
57
95 (88)
36
1
1
2
22
37
45
67
90
98
99
100
28
100
100
76
43
5 (5)
11
5
1.0
150°
(Microwa
ve
1
1.5 min
66
98
64
50/2/48
15
33/67
heating, 2 min
8–10 W) 3 min
5 min
78
93
98
100
100
100
100
72
83
97
99
53/3/44
64/2/36
74/3/23
84/4/12
16
11
2
38/62
45/55
0/100
—
11 min
100
0
a CuCl was used for 1, CuBr — for 2; b 19F NMR yields, isolated yields are in parentheses.
2.2. Reactions of 1,2 in AcOH
When glacial AcOH was used as a reaction medium, compound 1 in the presence of 0.20
equiv. CuCl at 100°C reacted slowly. After 35 hours (at 64% conversion of syn-1 and full
conversion of anti-1), 2-fluoroallyl chlorides 3 formed predominantly (32% yield, Z/E = 78/22),
along with 2-fluoroallylic acetate Z-7 (17% yield) (table 2, entry 1). Addition of 2.0 equiv.
NaOAc to the reaction mixture made it possible to accelerate ring opening in 1 and replace
chlorine in 3 by an acetoxy group. In this way, full conversion of syn- and anti-1 was achieved in
40 hours, to give acetates 7,8 in 56% yield (Z-7/E-7/8 = 56/8/36) along with residual 3 in 10%
yield (Z/E = 9/91) (table 2, entry 2). Increasing the NaOAc excess to 3.0 equiv. did not reduce
the allyl chloride amount significantly, and E-3 was isolated in 9% yield (E/Z > 99/1) after 40
hours at 100°C (table 2, entry 3). The yield of the mixture of acetates 7,8 was 65% in this case
Page 5 of 35

6
(Z-7/E-7/8 = 44/28/28). Isomeric 1,6-, 1,4- or 3,4-diphenyl-2,5-difluorohexa-1,5-dienes 9 also
formed in 13–20% yields in the presence of NaOAc.
Table 2. Rearrangements of 2-chloro-2-fluoro-1-phenylcyclopropane 1 (syn/anti = 56/44) and 2-bromo-2-fluoro-1-
phenylcyclopropane 2 (syn/anti = 47/53)) in the presence of CuX (X = Cl, Br) in AcOH, NaOAc/AcOH, NaOAc/DMF;
OAc
X
F
X
F
CuX
+
+
Ph
OAc
Ph
X
+
+
9
Ph
NaOAc
AcOH or DMF
100°C
Ph
F
F
Ph
F
Z,E-7
-1 (X = Cl);
-2 (X = Br);
-1 (X = Cl);
-2 (X = Br);
3 (X = Cl);
4 (X = Br);
syn
syn
anti
anti
Z,E-
Z,E-
8
cyclopropa CuX,a
NaOAc
(equiv.) (equiv.)
time, Yield of 7,8,
hours
ratio
Z-7/E-7/8
Yield of 3 or ratio Yield of 9,
Entry
Solvent
ne
(%) b
4, (%) b
Z/E
(%) b
1
2
3
4
5
6
7
8
9
0.20
0.20
0.20
—
—
2.0
3.0
—
2.0
—
2.0
2.0
2.0
2.0
2.0
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
DMF
35
40
40
24
24
24
10
40
24
24
24
17c
56d
65e
2c
only Z-7
56/8/36
44/28/28
only Z-7
82/6/12
—
75/6/19
54/46/0
77/23/0
40/42/18
38/35/27
32c
10
9
78/22
9/91
only E-3
92/8
73/27
96/4
—
0
13
20
0
1
1
1
2
2
2
2
1
2
1
1
30c
2c
23g
0
—
36c
n.d.f
93
0
0.20
0.20
0.20
0.20
0.20h
0.20i
n.d.f
0
71
0
0
0
0
—
—
—
—
19
6
DMF
DMF
DMF
89
10
11
12c
5c
3c
1c
b
a CuCl was used for 1, CuBr — for 2; Isolated yields; c 19F NMR yield; d Pure Z-7 was isolated in 32% yield after column
f
chromatography; e Pure Z-7 was isolated in 29% yield after column chromatography; not determined; g GC purity ca. 90%;
h (SIPr)CuCl was used as the catalyst; i (IPr)CuCl was used as the catalyst;
Isomers of 9 formed (Z,Z-9/α,Z-9/α,E-9/Z,E-9/α,α-9/α,α-9’ = 28/44/4/6/8/10)
F
F
Ph
F
F
Ph
F
Ph
Ph
Ph
Ph
F
F
Ph
F
Ph
F
Ph
F
Ph
Z,Z-9
Z,E-9
α ,Z-9
α,E-9
α,α-9,9'
In contrast to 1, rearrangements of 2 in AcOH occurred even in the absence of copper salts.
In this way, compound 2 in AcOH at 100°C was converted to bromides 4 (Z/E = 92/8) in 30%
yield and Z-7 in only 2% yield after 24 hours (table 2, entry 4). In the presence of additional 2.0
equiv. of NaOAc, the reaction of 2 in 24 hours gave predominantly acetates 7,8 (Z-7/E-7/8 =
82/6/12) in 36% yield, whereas the yield of 4 was as small as 2% (Z/E = 73/27) (table 2, entry 5).
In both cases, ca. 10% conversion of syn-2 and 50—60% conversion of anti-2 were achieved.
Rearrangements of 2 in AcOH catalyzed by 0.20 equiv. CuBr at 100°C completed in 24
hours but large quantities of polymeric materials were formed. Only bromides 4 (Z/E = 96/4)
could be isolated under these conditions in 23% yield with ca. 90% GC purity (table 2, entry 6).
Rearrangement of 2 catalyzed by 0.20 equiv. CuBr with addition of 2.0 equiv. NaOAc smoothly
gave acetates 7,8 (75/6/19) in 93% isolated yield in 10 hours at 100°C (table 2, entry 7).
Moreover, in contrast to 1, only traces of side product 9 (less than 1%) were detected by GC in
this case.
Page 6 of 35

7
The regioselectivity of acetate formation can be changed by replacement of AcOH with
DMF (table 2, entries 8 vs. 2,3 for 1 and 9 vs. 7 for 2). In this way, 1 in the presence of 0.20
equiv. CuCl and 2.0 equiv. of NaOAc in DMF underwent complete rearrangement in 40 hours at
100°C to give acetates 7 (Z/E = 54/46) in 71% yield along with isomeric 9 in 19% yield. Under
the same conditions, the reaction starting from 2 (with CuBr instead of CuCl) carried out for 24
hours gave acetates 7 (Z/E = 77/23) in 89% yield and 9 in only 6% yield. In both cases, less than
1% of regioisomeric acetate 8 could be detected by GC.
2.3. Reactions of 1 in formic acid
A significant increase in 1 ring opening rate was achieved by using HCO2H as the reaction
medium. In this way, 1 in the presence of 0.20 equiv. CuCl and 2.0 equiv. HCO2Na in HCO2H
underwent complete rearrangement in 5 hours at 80°C and gave allylic formate Z-10 as the
predominant product which was isolated in pure form in 79% yield (scheme 3).
F
O
Cl
0.20 eq. CuCl
2.0 eq. HCO2Na
O
HCO2H
80°C
5 h
F
10
1
Z-
79%
Scheme 3. Solvolysis of 1 catalyzed by CuCl in HCO2H in the presence of HCO2Na
O
F
O
F
11
Scheme 4. Structure of 11
Such a dramatic effect of HCO2H on the reaction is likely due to its high ionization ability,
which is in good agreement with the formation of side phenyl-ring allylated product 11 in 2–3%
yield in this reaction (scheme 4). It should also be noted that performing this reaction at higher
temperatures, e.g. 100°C, resulted in partial decomposition of HCO2H to CO and H2O with
formation of up to 30% of (Z)-2-fluoro-3-phenylallyl alcohol Z-12.
2.4. Reactions of 1 in aqueous medium
Hydrolysis of 1 in the presence of CuCl in water was also studied (tables 3,4). In the
presence of 0.20 equiv. CuCl in water, compound 1 underwent complete rearrangement in 24
Page 7 of 35

8
hours at 100°C and gave allylic alcohols 12,13 and diallylic ethers 14,15 as the major products
(table 3, entry 1). However, Z-12 was obtained in only 38% yield under these conditions, along
with 15% of diallylic ethers 14,15. Hydrolysis of 1 in the presence of a phase transfer catalyst,
TEBAC (triethylbenzylammonium chloride, used ratio CuCl/TEBAC = 1/1), allowed us to
increase the yield of Z-12 significantly, to 60% (19F NMR) and 53% (isolated) (table 3, entry 2).
In this case, the yield of 14,15 remained approximately the same, viz. 12%.
The use of a mixed solvent (water/dioxane in 1/1 ratio) further improved the yield of Z-12 to
77% (19F NMR) and 68% (isolated) (table 3, entry 3), while diallylic ethers 14,15 were formed in
a slightly lower yield, viz. 9%. It is interesting to note that in all cases dimer 16, a side product of
electrophilic allylation of benzene ring in Z-12, was formed in ca. 5% yield.
Table 3. Rearrangements of 2-chloro-2-fluoro-1-phenylcyclopropane 1 (syn/anti = 56/44) in
the presence of CuCl in water
OH
F
Cl
F
Cl
CuCl
+
+
+
Ph
OH
Ph
Cl
+
14,15,16
Ph
water
F
F
Ph
Ph
100°C
F
syn-1
anti-1
Z,E-12
13
Z,E-3
Additive
(equiv.)
time,
hours
Entry
Solvent
Yield,a (%)
Z-12b
Z-3b
13
14
15
7
5
16
6
4
1
2
water
water
—
24
24
38
2
0.5
0.5
8
7
TEBAC (0.20)
60 (53)c < 0.5
water/dioxane
(1/1)
3
—
24
77 (68)c
4
4
5
4
4
a 19F NMR yields; b Only traces of E-3 and E-12 (< 0.5%) were detected by GC and NMR
after 24 h; c Isolated yield after column chromatography;
Structures of major side products:
Ph
F
OH
O
Ph
F
Ph
O
Ph
F
F
F
F
15
16
14
Similarly to solvolysis in MeOH, allylic chlorides 3 were formed in significant amounts at
early stages of the reaction in water/dioxane (1/1) (see table 4). Further hydrolysis of 3 resulted
in Z-12 and 13 in comparable amounts followed by isomerization of 13 into thermodynamically
Z-12 that is more stable under the reaction conditions. During the reaction, only traces of E-12
(up to 1%) were detected.
Page 8 of 35

9
Table 4. The ratio between chlorides 3 and alcohols 12,13 in CuCl-
catalyzed hydrolysis of 1 depending on reaction time a
time,
hours
0.5
1
2
5
10
20
Conversion, (%)
Yields,b (%)
syn-1
83
anti-1
100
100
100
100
100
100
Z-12
17
26
28
53
E-12
0
0.3
0.4
0.5
0.7
0.8
Z-3
32
24
23
14
10
5
E-3
15
15
13
5
13
26
33
34
26
14
6
97
99
100
100
100
72
82
1
0.4
a A mixture of 1 (2.0 mmol), CuCl (0.40 mmol), water (1.0 mL) and
dioxane (1.0 mL) was stirred at 100°C for the time specified; b 19F NMR
yields relative to 4-fluoroanisole (0.50 mmol, internal standard).
2.5. Usage of Cu-NHC complexes as catalysts
In the past decades, copper complexes with N-heterocyclic carbene (NHC) ligands were
found to have unique reactivity compared to ordinary copper salts [20]. Previously we have
shown that PPh3 as ligand reduces the catalytic system reactivity in CuCl catalyzed ring-opening
isomerization of 1 [1b], whereas diamine ligands induce side reductive dimerization of
fluoroallylic halides to give 9 [21]. Therefore, in order to improve the catalytic system in copper
catalyzed ring-opening rearrangements of gem-fluorohalocyclopropanes, we examined the
reactivity of two (NHC)CuCl compounds (NHC = SIPr, IPr, scheme 5).
Ar
Ar
N
N
Cu Cl
Cu Cl
Ar =
N
N
Ar
(IPr)CuCl
Ar
(SIPr)CuCl
Scheme 5. Structures of (NHC)CuCl compounds studied
Unlike CuCl, the (SIPr)CuCl and (IPr)CuCl complexes showed no reactivity in
rearrangements of 1 in MeOH and MeCN at 60°C and 80°C, respectively, whereas the same
compounds (0.10 equiv.) did catalyze the isomerization of 1 in 1,4-dioxane, o-dichlorobenzene
(o-DCB) or CDCl3 to give 2-fluoroallylic chlorides 3 in >90% to quantitative yields (3–4 days at
100°C, table 5).
It is interesting that in o-DCB, dioxane and CDCl3, regioisomeric allylic chloride 3’ was
formed in significant amounts at early stages of the reactions in the presence of both complexes.
On further heating, almost complete isomerization of 3’ into thermodynamically more stable
Page 9 of 35

10
isomer 3 was observed. It should be noted that only traces of 3’ were detected in CuCl catalyzed
isomerizations of 1 [1].
The same difference in regioselectivity between CuCl and (NHC)CuCl catalysts was found
for rearrangements of 1 in DMF in the presence of NaOAc. Ring-opening in 1 catalyzed by 0.20
equiv. of (SIPr)CuCl or (IPr)CuCl in the presence of 2.0 equiv. of NaOAc (24 hours at 100°C)
gave acetates 7,8 in 12 and 5% yields, respectively, in 40/42/18 and 38/35/27 ratios (table 2,
entries 10,11). It should be noted that (SIPr)CuCl and (IPr)CuCl are less active catalysts than
CuCl in this reaction. Conversions of 1 for these complexes in 24 hours were 14 and 4% (for
syn-1) and 23 and 8% (for anti-1), respectively.
Table 5. Isomerization of 1 (syn/anti = 56/44) catalyzed by (NHC)CuCl (NHC = SIPr or IPr)
in different solventsa
Cl
Cl
Cl
F
F
(NHC)CuCl
+
Ph
Cl
Ph
+
Solv.
F
F
Ph
Ph
80-100°C
-1
syn
-1
3'
anti
3
Z,E-
time, Conversion Conversion Yield of
ratio
Entry NHC Solvent
T,°C
hours of syn-1
of anti-1
3,3’, (%) Z-3/E-3/3’
1
2
SIPr
SIPr dioxane
MeCN
80°
100°
24
2
5
0
4
0
15
42
86
100
100
100
9
66
96
11
66
92
99
100
52
93
100
100
27
0
9
—
56/19/25
73/21/6
76/23/1
70/30/0
72/28/0
74/26/0
26/33/41
68/30/2
70/29/1
28/33/39
55/33/13
66/33/1
67/32/1
80/19/1
70/30/0
71/29/0
72/28/0
84/16/0
32/31/37
41/32/27
46/35/19
62/36/2
14
41
87
97
98
4
46
83
5
48
79
93
100
27
59
80
100
18
48
73
100
27
60
92
98
99
6
53
85
8
55
83
93
95
37
70
85
91
22
56
79
100
10
25
35
40
4
13
22
4
13
22
32
80
12
21
30
79
5
3
4
SIPr
IPr
o-DCB
o-DCB
100°
100°
5
6
SIPr diglyme 100°
IPr
CDCl3
100°
14
24
73
64
86
100
a Reaction procedure: 0.50 mmol 1, 0.050 mmol (NHC)CuCl, 0.15 mmol 4-fluoroanisole
Page 10 of 35

11
(internal standard) in 0.50 mL of the solvent were heated in an NMR tube at the specified
temperature. After cooling to r.t., the yields were determined by 19F NMR.
2.6. Effects of additional acids on CuCl-catalyzed rearrangements of gem-
chlorofluorocyclopropanes
As one can see from the stoichiometry of the reactions, one equivalent of the corresponding
hydrohalic acid (HX) is formed in CuX catalyzed gem-fluorohalocyclopropane solvolysis in
protic solvents (MeOH, AcOH, water) in the absence of other nucleophiles. The effects of HX
on copper(I)-catalyzed ring opening of gem-fluorohalocyclopropanes were studied for
isomerizations of phenyl-substituted gem-chlorofluorocyclopropane 1 and 7-chloro-7-
fluorobicyclo[4.1.0]heptane 17 catalyzed by CuCl in MeCN in the presence of HF (as NEt3·3HF
(TREAT HF), see table 6) or HCl (as 4.0 M solution in dioxane, see scheme 6, table 7).
In fact, addition of HF (0.2–1.0 equiv., as TREAT HF) accelerated ring opening of 1 in
MeCN at 80°C ca. 1.5-fold with only a weak dependence on the HF amount added (table 6). On
the other hand, addition of 1.0 equiv. of 4.0 M HCl solution in dioxane in the isomerization of
endo-Cl-17 mediated by 1.0 equiv. CuCl in MeCN showed only a negligible acceleration effect
at 80°C (table 7, entries 3,4), while this effect was more pronounced at room temperature (table
7, entries 1,2). As expected [1,2a], the exo-Cl-isomer of 17 remained unchanged under these
conditions.
Cl
H
Cl
CuCl
+
F
F
HCl/dioxane
MeCN
F
H
r.t. – 80°C
18
endo-Cl-17
19
H
F
Cl
H
exo-Cl-17
Scheme 6. CuCl-catalyzed isomerization of 17
Page 11 of 35

12
Table 6. Effect of TREAT HF on isomerization of 1 catalyzed
by CuCla
Conversion, (%)
Yields, (%)
Entry HF (eq.)
syn-1
50
anti-1
93
Z-3
E-3
16
21
22
23
25
24
1
2
3
4
5
6
—
53
57
56
56
57
59
0.20
0.40
0.60
0.80
1.0
64
95
64
95
64
95
68
98
71
98
a
A mixture of 1 (0.50 mmol), CuCl (0.10 mmol), TREAT HF
and MeCN (0.50 mL) was heated in an NMR tube at 80°C for 5
hours. The yields were determined by 19F NMR.
Table 7. Effect of HCl on isomerization of 17 catalyzed by CuCla
Conv.,
Yields, (%)
time,
hours
(%)
endo-Cl-
17
Entry
T, °C
18
19
1b
2
r.t.
r.t.
80°С
80°C
24
24
1
11
18
59
62
11
18
58
62
0
0
1
0
3b
4
1
a A mixture of 1 (0.40 mmol), CuCl (0.40 mmol), 4.0 M solution of
HCl in dioxane (0.10 mL) and MeCN (0.40 mL) was used. The
yields were determined by 19F NMR using exo-Cl-17 as the internal
standard; b pure dioxane was used instead of HCl solution.
2.7. Preparative scale synthesis of 2-fluoroallylic methyl ethers, 2-fluoroallylic acetates,
formates and alcohols
The feasibility of preparative synthesis of 2-fluoroallylic compounds by copper-catalyzed
gem-fluorohalocyclopropane rearrangements was studied. Besides phenyl-substituted
cyclopropanes 1,2, 7-chloro-7-fluorobicyclo[4.1.0]heptane 17, 1,1-dimethyl- and trans-1,2-
dimethyl substituted gem-chlorofluorocyclopropanes 20 and 21 were also tested (scheme 7).
These cyclopropanes can be easily obtained by carbene cyclopropanation of the corresponding
olefins, viz. styrene for 1 and 2, cyclohexene for 17, isobutylene for 20, trans-but-2-ene for 21,
under phase transfer conditions using CHCl2F or CHBr2F as carbene sources [2c,22].
Page 12 of 35

13
F
R1
X
CHX2F
R1
KOH(aq.)
R3
CH2Cl2
R2
F
TEBAC
0°C - r.t.
R2
R3
Cl
Br
F
F
Cl
Me
F
Cl
F
Me
Cl
Ph
Me
Me
Ph
1
2
17
20
88%
21
73%
81%
76%
62%
(syn/anti =
56/44)
(syn/anti =
47/53)
(endo-Cl/exo-Cl =
65/35)
Scheme 7. Synthesis of gem-chlorofluorocyclopropanes
In good agreement with the results presented above, methanolysis of 1 (200 mmol) in the
presence of 0.10 equiv. CuCl in MeOH for 5 hours at 150°C afforded a mixture of allyl methyl
ethers Z,E-5 and 6 in a 95/2/3 ratio. Pure Z-5 was isolated in 84% yield by fractional distillation
of this mixture. In the same way, (Z,E)-4-methoxy-3-fluoropent-2-ene Z,E-22 (Z/E = 85/15) was
obtained in 74% yield from trans-1,2-dimethyl substituted cyclopropane 21 in the presence of
0.10 equiv. CuCl in 10 hours at 120°C. The Z- and E-isomers of 22 were not separated because
their boiling points are close. In the case of 7-chloro-7-fluorobicyclo[4.1.0]heptane 17 (endo-
Cl/exo-Cl = 65/35), endo-Cl-17 was completely converted to 3-methoxy-2-fluorocycloheptene
23 in the presence of 1.0 equiv. CuCl in 24 hours at 60°C, while exo-Cl-17 was completely
unreactive. However, because of the close boiling points of 23 and exo-Cl-17, isolation of 23
from the reaction mixture was inconvenient. Nevertheless, pure 23 was easily prepared by a two-
stage procedure that involved CuCl-catalyzed isomerization of endo-Cl-17 in MeCN [1]. The
product of 3-chloro-2-fluorocycloheptene 18 was separated in 79% yield from unreacted exo-Cl-
17 by careful distillation in a Fischer HMS-500 rectification column. Conversion of the isolated
18 in the presence of 0.50 equiv. CuCl in MeOH for 24 hours at 60°C gave pure 23 in 90% yield
(71% yield based on endo-Cl-17).
Cl
F
OMe
F
Me
OMe
OMe
F
F
Me
Z,E-22
74%
(Z/E = 85/15)
18
79%
(on endo-Cl-17)
23
90% (on 18)
Z-5
84%
Scheme 8. Synthesis of 2-fluoroallylic methyl ethers
Acetolysis of 20 (200 mmol) in the presence of 0.20 equiv. CuCl and 2.0 equiv. NaOAc in
glacial AcOH at 100°C for 5 hours gave a mixture of 1-acetoxy-2-fluoro-3-methylbut-2-ene 24
Page 13 of 35

14
and 3-acetoxy-2-fluoro-3-methylbut-1-ene 25 in 24/76 ratio in 88% yield. These acetates were
easily separated by fractional distillation to afford pure 24 in 14% yield and pure 25 in 57%
yield. Under the same conditions, 21 gave (Z,E)-4-acetoxy-3-fluoropent-2-enes Z,E-26 (Z/E =
85/15) in 89% isolated yield. In the case of 17 (endo-Cl/exo-Cl = 65/35), its endo-Cl-isomer
formed 3-acetoxy-2-fluorocycloheptene 27 under these conditions. The latter was easily
separated from unreacted exo-Cl-17 by fractional distillation in 75% yield (based on endo-Cl-
17).
OAc
F
F
F
OAc Me
OAc
Me
OAc
F
Me Me
Me
Me
Z,E-26
24
25
57%
27
14%
(Z/E = 85/15)
75%
(on endo-Cl-17)
89%
Scheme 9. Synthesis of 2-fluoroallylic acetates
As shown above, formate Z-10 and alcohol Z-12 are the major products of 1 ring opening in
HCO2H and water/dioxane solvents, respectively. These isomers were isolated by simple
fractional distillation in 68% and 53% yields when the reactions were carried out on 200 mmol
scale. Formate Z-10, however, was not be separated from alcohol Z-12 admixture, so isolated Z-
10 contained 95 w/w % of the main component along with 5 w/w % of Z-12, as determined by
NMR.
O
O
OH
F
F
Z-10
68%
Z-12
53%
(95% purity)
OH
F
F
F
Me
OH
OH
Me
OH
F
Me
Me
29
95% (on 25)
Me
Z/E-30
(Z/E = 85/15)
97% (on 26)
Me
28
31
93% (on 27)
92% (on 24)
Scheme 10. Synthesis of 2-fluoroallylic formates and alcohols
Attempts to use copper-catalyzed hydrolysis for preparative synthesis of allylic alcohols
from 20 failed, since the process was complicated by formation of significant amounts of methyl
vinyl ketone due to acid-mediated hydrolysis of 2-fluoro-3-methylbuta-1,3-diene [18a]. In view
of this, 2-fluoro-3-methylbut-2-enol 28, 3-fluoro-2-methylbut-3-en-2-ol 29, (Z,E)-3-fluoropent-
Page 14 of 35

15
3-en-2-ol Z,E-30 (Z/E= 85/15) and 2-fluorocyclohept-2-enol 31 were prepared by K2CO3/MeOH
mediated cleavage of the corresponding acetates in more than 90% yields.
3. Discussion
3.1. Mechanistic aspects
Formation of 2-fluoroallyl halides at early stages of solvolysis. Results presented in tables
1–4 for CuX catalyzed solvolysis of 1,2 in MeOH, AcOH and water, namely formation of large
quantities of allyl halides 3,4 at early stages of the process and comparable rates of cyclopropane
ring opening and allyl halide solvolysis, show that allyl ethers, ester and alcohol are
predominantly formed by a two-stage pathway that involves CuX-catalyzed isomerization of 1 or
2 to give 3 or 4, followed by nucleophilic substitution (presumably copper-assisted [23]) where
chlorine or bromine is replaced by methoxy, acetoxy or hydroxy groups (scheme 11).
F
X
F
34
[CuI]
F
X
[CuI]
– X– Nu– (SN2 pathway)
Nu–
or NuH
X
F
32
[CuI]
– X– or HX
Nu
33
(SN1 pathway)
35
X = Cl, Br;
NuH = MeOH, AcOH, HCO2H, H2O;
Scheme 11. A plausible scheme of copper(I)-catalyzed fluorohalocyclopropane solvolysis
(substituents and ligands are omitted for clarity)
[CuI]
I
[Cu]
δ-
δ-
X
H
H
X
H
H
δ+
δ+
Ph
H
F
F
H
Ph
G2
G1
Scheme 12. Proposed transition states for copper catalyzed ring-openings of syn-1,2 (G1) and
anti-1,2 (G2)
Based on non-catalytic and silver-mediated halocyclopropane solvolysis extensively studied
previously, we assumed that the key step in copper-catalyzed ring opening of
fluorohalocyclopropanes consists of electrocyclic cationic cyclopropyl-allylic transformation
[2a,3] (schemes 11,12) that involves elimination of a halide anion from 32 accompanied by
Page 15 of 35

16
disrotatory ring opening of the 3-member cycle to give a contact ion pair 33 consisting of an allyl
cation and halide anion X–. Ion-pair return leads to allyl halide 34 that was detected in significant
amounts not only in our copper-catalyzed reactions (vide supra) but also by many authors before
in solvolysis of cyclopropyl chlorides and bromides [24] and even in silver-mediated processes
[25]. The accelerating effect of cuprous salts is likely a result of Lewis acid activation of halide
elimination as shown in scheme 12. Formation of solvolysis products 35 is a result of
nucleophilic substitution in 34 (SN2 pathway) or in its ionized forms, 33 or others (SN1 pathway).
Under typical solvolytic conditions, i.e. in a protic solvent (MeOH, AcOH, etc.), the SN1
pathway is likely to be predominant [2a].
The significant amounts of allyl halides formed in solvolysis of 1,2 (table 1–4) allow us to
assume that ion-pair return for intermediate 33 is much faster than its reaction with a
nucleophile, probably due to high destabilization of cationic form 33 by a fluorine atom [23a].
The comparable rates of cyclopropane ring opening and allyl halide solvolysis observed in the
cases of 1,2 and 3,4 (see tables 1,4) are also in agreement with the mechanism presented in
scheme 11 as it assumes that these two processes occur through similar (or same) cationic
transition states.
Relative reactivity of syn- and anti-isomeric gem-fluorohalocyclopropanes. The
observed higher reactivities of anti-isomers of 1,2 compared to syn-1,2 (see tables 1,4,5) are in
agreement with the Woodward–Hoffmann–DePuy rules [3] for electrocyclic ring opening of
cyclopropyl halides. This mechanism requires rotation of substituents that are syn to the halogen
being eliminated inward the ring (scheme 12). Steric hindrance in transition state G1 compared
to G2 provides the observed difference in reactivity.
The difference in reactivity is much more dramatic for bicyclic cyclopropane 17 where the
exo-Cl-isomer is completely unreactive under the reaction conditions studied. It is well known
that ring opening with elimination of an exo-halogen in such bicyclic structures should give
cycloalkenes with trans configuration of the double bond that is sterically unfavorable for a 7-
member ring [2a]. Elimination of endo-fluorine in the case of exo-Cl-17 is also unfavorable
because of the high dissociation energy of the C-F bond.
Isomer ratios of allylic structures formed. The relative ratios of allyl ethers, esters and
alcohols formed in CuX catalyzed solvolysis of phenyl substituted gem-fluorohalocyclopropanes
1,2 (tables 1–4) are similar to those observed previously in silver-assisted solvolysis of 2 [17b,c]
and are in agreement with the results obtained for other halocyclopropanes [2a].
Page 16 of 35

17
It was shown that solvolysis of 1,2 in protic solvents (MeOH, AcOH, HCO2H, H2O) gave
predominantly products with (Z)-internal (Z-5, Z-7, Z-10, Z-12) and terminal (6, 8, 13) double
bonds. Besides, isomerization of kinetic products 6, 8, 13 to thermodynamically more stable Z-5,
Z-7, Z-12 occurs in acidic media (MeOH, AcOH in the absence of NaOAc, or H2O acidified with
HX formed during solvolysis) [26]. It seems that these processes require that hydrohalic acids be
formed in the reactions. Thus, no isomerization of 8 to Z-7 was observed if solvolysis of 1,2 was
carried out in the presence of NaOAc. In a polar aprotic solvent (DMF), acetates 7 with a (Z,E)-
isomeric internal double bonds were formed exclusively. These results are in agreement with the
suggestion that formation of 2-fluoroallylic ethers, esters and alcohols occurs predominantly as
two stage processes. Predominant formation of ethers, esters and alcohols with (Z)-internal and
terminal double bonds in MeOH, HCO2H, AcOH and water conforms to the expected [27] SN1-
like nucleophilic substitution in 3,4 in these solvents, while predominant formation of (Z,E)-
isomeric acetates in DMF conforms to the expected [27] SN2-like nucleophilic substitution.
Effect of ionisation ability of the reaction medium. Considering the SN1-like character of
solvolytic ring-opening of halocyclopropanes [2a], the rate of these processes should strongly
depend on the ionization ability of the reaction medium. In accordance with this, a significant
acceleration of both ring-opening of 1 and of ester formation was observed when the solvolysis
was carried out in HCO2H instead of AcOH. The much higher ionization ability of HCO2H
compared to AcOH is well known and can be quantitatively illustrated by Grunwald–Winstein
parameters Y that are 2.05 for HCO2H and –1.64 for AcOH [27].
Effect of additional salts or acids. Accelerating effects of additional salts or acids on the
ring-opening of gem-fluorohalocyclopropanes in the presence of Cu salts were found: (1)
addition of LiCl to CuCl is crucial for isomerization of 1 in dioxane and diglyme [1]; (2) addition
of LiCl, TREAT HF or HCl to CuCl-catalyzed isomerizations of 1 or 17 in MeCN accelerates
the reactions (see [1] and tables 6,7); (3) addition of NaOAc to solvolysis of 1,2 in AcOH in the
presence of CuX increases ring opening rates (see table 2, entries 2,3 vs. 1); (4) however,
addition of NaOAc in solvolysis of 2 in AcOH in the absence of CuBr only affects the product
distribution but not the ring opening rate (see table 2, entries 4,5). These salt and acid effects can
be explained by the following reasons:
(1) An increase in CuX solubility. Cuprous halides have very low solubility in most organic
solvents and in water [28]. Therefore, the complete lack of activity of CuCl in dioxane and
diglyme is not surprising. Its activity in MeOH and AcOH can be attributed either to the low but
Page 17 of 35

18
still sufficient solubility or to formation of traces of soluble and catalytically active CuI
methoxides or acetates. Alkali metal salts and hydrogen halides are well known to increase the
solubility of CuX by formation of complex anions [28]. However, it should be noted here that it
is hard to imagine that complex cuprous anions like [CuX2]– would serve as Lewis acids in
activation of a halocyclopropane ring. Thus, either a different mechanism of copper catalysis
works, or a counter ion (alkali metal ion or proton) provides the required Lewis acidic activation.
(2) An increase in the dielectric constant of the reaction medium by the salts added. This
reason probably does not affect significantly the ring opening rates as it was shown that addition
of NaOAc affected only slightly the rate of ring-opening of 2 in AcOH in the absence of CuBr.
(3) Hydrogen bonding. The ability of HF to promote hydrolysis of alkyl fluorides was
documented [29]. This effect was rationalized as activation of fluorine elimination by hydrogen
bonding with HF. Since the rate limiting step in gem-fluorohalocyclopropane solvolysis also
involves dissociation of a C–X bond, its activation by hydrogen bonding of halogen with
Brønsted acids becomes possible.
3.2. Preparative aspects
As noted above, from retrosynthetic point of view, the method of preparation of 2-
fluoroallylic compounds through fluorohalocarbenes is formal “insertion” of a C-F moiety into
an alkene C=C double bond (scheme 1). In comparison with other methods [6–12], it utilizes
more available and less expensive fluorine sources, viz. CHX2F, CX2FCO2H, for generation of
fluorocarbenes. The main drawback of this carbene approach is the lack of mild and functional
group tolerant methods for generation, from these sources, of fluorocarbenes reactive enough for
cyclopropanation of not only electron-rich, but also electron-neutral and electron-poor olefins
[2c,d]. However, in case of simple alkyl- and aryl substituted aliphatic and cyclic alkenes, the
corresponding gem-fluorohalocyclopropanes can be obtained in good yields. Moreover, our
copper(I) catalyzed ring opening isomerization or solvolysis of gem-fluorohalocyclopropanes to
2-fluoroallylic structures (see also [1]) seems to be the most efficient method for induction of
such processes known to date for fluorinated halocyclopropanes [30] in terms of yields,
selectivity, mildness of reaction conditions, scalability and catalyst cost. Thus, the synthetic
sequence of alkene cyclopropanation with fluorohalocarbenes followed by copper catalyzed
isomerization or solvolysis of gem-fluorohalocyclopropanes formed (scheme 1) is an efficient
and reliable method for preparation of simple alkyl- and aryl-substituted 2-fluoroallylic
Page 18 of 35

19
chlorides, bromides, ethers, esters and alcohols as building blocks for further functionalization
[31].
4. Conclusions
In conclusion, this paper discloses an efficient copper-catalyzed method for conversion of
gem-fluorohalocyclopropanes to the corresponding 2-fluoroallylic methyl ethers, 2-fluoroallylic
acetates, formates and alcohols. Copper-catalyzed processes occur predominantly in two stages
via initial copper-catalyzed cyclopropyl-allylic type ring-opening isomerization of gem-
chlorofluoro- or gem-bromofluorocyclopropanes to give 2-fluoroallylic chlorides or bromides,
followed by nucleophilic substitution of the allylic halogen atom by an appropriate nucleophile
(containing methoxy, acetoxy, formyloxy, hydroxyl groups) present in the reaction medium. The
copper-catalyzed solvolysis of gem-fluorohalocyclopropanes that we developed was used for
preparative syntheses (100–200 mmol) of dimethyl-, phenyl substituted and cyclic 2-fluoroallylic
methyl ethers, 2-fluoroallylic acetates, formates and alcohols from widely available starting
materials.
5. Experimental
General information
CuCl, CuBr, NaOAc (dry), HCO2Na, glacial AcOH, HCO2H (99%), dioxane (anhydrous),
diglyme and other reagents were purchased from Acros, Aldrich, Alfa Aesar or BASF and used
without further purification. MeOH was distilled over Mg(OMe)2 prior to use. DMF was distilled
over CaH2 and stored over 4Å Linde molecular sieves. gem-Chlorofluorocyclopropanes
1,17,20,21 were synthesized according to [1], gem-bromofluorocyclopropane 2 — according to
[32], (SIPr)CuCl and (IPr)CuCl — according to [33].
Typical procedure for solvolysis of 1 in MeOH
A mixture of 341 mg (2.0 mmol) of 1, 99 mg (1.0 mmol) of CuCl and 2.0 mL of MeOH was
stirred at 60°C under argon atmosphere. Aliquots (ca. 0.1 mL) of the reaction mixture were
taken, diluted with Et2O, washed with water, dried over Na2SO4, concentrated and analyzed by
19F NMR. Data are summarized in table 1.
The same reaction mixture was stirred at 60°C for 24 h. After cooling to room temperature,
the internal standard (4-fluoroanisole, 56.6 µL, 0.50 mmol) was added to the reaction mixture.
Page 19 of 35

20
An aliquot the resulting solution (ca. 0.4 mL) was placed in an NMR tube with ca. 0.1 mL of
CD3OD and analyzed by 19F NMR. The following yields were found: 70% of 5,6 (a ratio
Z-5/E-5/6 = 32/1/67) and 30% of 3 (a ratio Z/E = 51/49).
Reaction of 1 in MeOH in the presence of CuCl under MW heating
The reactions were carried out in a CEM Discovery LabMate microwave oven in 10 mL
tubes sealed with a Teflon/silicon septum and a pressure sensor. A mixture of 85 mg (0.50
mmol), 49 mg (0.50 mmol) of CuCl and 1.0 mL of MeOH was irradiated using a MW power of
8—10 W for 60, 90, 120, 180, 300 or 660 sec. During these periods the temperature of the
reaction mixture measured by IR sensor increased to 150°C in the first 60 sec and then remained
at this level to within ±5°C. After that, irradiation was stopped and the mixture was cooled with a
stream of air for 10 min and analyzed by GC. Then it was diluted with 20 mL of CH2Cl2, washed
3x50 mL of water, dried over Na2SO4 and concentrated in a rotary evaporator. The residue was
analyzed by 1H and 19F NMR. The results are summarized in table 1.
Typical procedure for solvolysis of 1 in AcOH in the presence of CuCl and NaOAc
A mixture of 851 mg (5.0 mmol) of 1, 100 mg (1.0 mmol) of CuCl, 826 (10 mmol) of dry
NaOAc and 5.0 mL of glacial AcOH was heated with stirring under argon atmosphere at 100°C
in an oil bath for 40 hours. The reaction progress was monitored by GC. The mixture was diluted
with Et2O, washed successively with diluted (1:1) concentrated NH3, water, sat. NaCl and dried
over Na2SO4. The solvent was evaporated under reduced pressure and the residue was subjected
to column chromatography on silica gel (40–63 µm, 100:1, eluent — n-hexane/EtOAc (10/1)).
Three fractions were collected: (1) a mixture of 88 mg of Z,E-3 (Z/E = 91/9, 0.52 mmol, 10%
yield) and 90 mg of isomeric 9 (0.33 mmol, 13% yield); (2) 241 mg of E-7,8 (a ratio 18/82, 1.2
mmol, 24% yield); (3) 307 mg of Z-7 (isomeric purity > 99%, 1.6 mmol, 32% yield).
(1Z,5Z)-2,5-Difluoro-1,6-diphenylhexa-1,5-diene (Z,Z-9)
1
Colorless needles, mp 101-102°C. H NMR δH (200.1 MHz, CDCl3) 2.57-2.82 (m, 4H,
2CH2), 5.54 (d, 2H, 2 =CH-, J = 38.9 Hz), 7.15-7.60 (m, 10H, arom.). 19F NMR δF (188.3 MHz,
13
CDCl3) -102.8 (m). C NMR δC (50.3 MHz, CDCl3) 30.6 (d, 2CH2, J = 27.1 Hz), 107.0 (d, 2
=CH-, J = 8.5 Hz), 127.1 (d, 4CH-arom., J = 1.9 Hz), 128.5 (d, 4CH-arom., J = 7.4 Hz), 128.6
(s, 2CH-arom.), 133.6 (s, 2C-arom.), 159.2 (d, 2 =CF-, J = 267 Hz). MS (EI) m/z 271 ([M+H]+,
Page 20 of 35

21
3), 270 ([M]+, 16), 136 (10), 135 ([PhCH=CF-CH2]+, 100), 133 (15), 115 (42), 109 (8). Anal.:
calcd. for C18H16F2: C, 79.98%; H, 5.97%. Found: C, 79.79%; H, 6.05%.
19
Z,E-9: F NMR δF (188.3 MHz, CDCl3): -100.6 (dt, 1F, -CF=CH– (E), J = 22, 22 Hz), -102.1
(dt, 1F, –CF=CH– (Z), J = 37, 18 Hz). MS (EI) m/z 271 ([M+H]+, 3), 270 ([M]+, 14), 135
([PhCH=CF-CH2]+, 100), 133 (18), 115 (50), 109 (10).
α,Z-9: 1H NMR δH (200.1 MHz, CDCl3): 2.71 (ddd, 1H, CH2, J = 19.5, 14.7, 7.8 Hz), 2.95 (ddd,
1H, CH2, J = 19.5, 14.7, 7.8 Hz), 3.86 (dt, 1H, CHPh, J = 19.0, 7.8 Hz), 4.41 (dd, 1H, =CH2
(trans- to F), J = 49.6, 3.1 Hz), 4.65 (dd, 1H, =CH2 (cis- to F), J = 17.5, 3.1 Hz), 5.41 (d, 1H,
=CH-, J = 39.2 Hz), 7.2-7.5 (m, 10H, arom.). 19F NMR δF (188.3 MHz, CDCl3): -100.4 (ddd, 1F,
–CF=CH2, J = 49.6, 19.0, 17.5 Hz), -103.35 (dt, 1F, -CF=CH–, J = 39.2, 19.5 Hz). MS (EI) m/z
271 ([M+H]+, 2), 270 ([M]+, 9), 135 ([PhCH=CF-CH2]+, 100), 133 (13), 115 (47), 109 (7).
α,E-9: 19F NMR δF (188.3 MHz, CDCl3): -98.7 (dt, 1F, -CF=CH2, J = 49.7, 17.5 Hz), -101.1 (td,
1F, –CF=CH–, J = 22.1, 18.5 Hz). MS (EI) m/z 271 ([M+H]+, 2), 270 ([M]+, 8), 135
([PhCH=CF-CH2]+, 100), 133 (16), 115 (50), 109 (8).
1
α,α-9: H NMR δH (200.1 MHz, CDCl3): 4.01 (m, 2H, 2CHPh), 4.16 (dd, 2H, =CH2 (trans- to
F), J = 49.5, 3.1 Hz), 4.33 (dd, 2H, =CH2 (cis- to F), J = 17.7, 3.1 Hz), 7.2-7.5 (m, 10H, arom.).
19F NMR δF (188.3 MHz, CDCl3): -103.3 (m). MS (EI) m/z 271 ([M+H]+, 1), 270 ([M]+, 6), 135
([PhCH=CF-CH2]+, 100), 133 (17), 115 (48), 109 (7).
α,α-9’: 19F NMR δF (188.3 MHz, CDCl3): -104.2 (m). MS (EI) m/z 271 ([M+H]+, 1), 270 ([M]+,
6), 135 ([PhCH=CF-CH2]+, 100), 133 (16), 115 (46), 109 (8).
Typical procedure for ring opening of 1 in DMF in the presence of CuCl and NaOAc
A mixture of 85 mg (0.50 mmol) of 1, 10 mg (0.10 mmol) of CuCl, 82 mg (1.0 mmol) of dry
NaOAc and 0.50 mL of dry degassed DMF was heated in an NMR tube at 100°C in an oil bath.
After heating to 100°C, the reaction mixture became a clear solution. On further heating, the
precipitation of the resulting NaCl occurred. The mixture was periodically cooled to r.t. and the
19
reaction progress was checked by F NMR. After complete conversion of syn- and anti-1 (40
hours) the mixture was diluted with Et2O, washed successively with diluted (1:1) concentrated
NH3, water, sat. NaCl and dried over Na2SO4. The solvent was evaporated under reduced
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22
pressure and the residue was purified by column chromatography on silica gel (40–63 µm, 50 : 1,
eluent — n-hexane/EtOAc (10/1)). Two fractions were collected: 69 mg of Z,E-7 (Z/E = 54/46,
71% yield) and 13 mg of isomeric 9 (19% yield).
Solvolysis of 1 in HCO2H in the presence of CuCl and HCO2Na
A mixture of 349 mg (2.0 mmol) of 1, 40 mg (0.40 mmol) of CuCl, 275 mg (4.0 mmol) of
HCO2Na and 2.0 mL of HCO2H was heated at 80°C for 5 hours in an oil bath. The reaction
progress was monitored by GC. After reaction completion, the mixture was diluted with CH2Cl2
and sat. NaHCO3, the organic layer was washed with sat. NaHCO3 and water and dried over
Na2SO4. Evaporation of the solvent gave 362 mg of a yellowish oil. Column chromatography on
silica gel (40–63 µm, 50 : 1, eluent — n-hexane/EtOAc (10/1)) gave the following fractions: (1)
284 mg of Z-10 as a colorless mobile liquid (79% yield); (2) 21 mg of 11 with NMR purity ca.
80%.
Fraction (2) was further re-purified by column chromatography on silica gel (40—63 µm,
19
200:1, eluent — n-hexane/EtOAc (5/1)) affording 10 mg of 11. Purity was estimated by F
NMR to be ca. 95%. The main impurity (ca. 3%) is believed to be an isomer of 11 at the
disubstituted benzene ring.
(Z)-2-Fluoro-3-phenylprop-2-enyl formate (Z-10)
1
Colorless mobile liquid, bp 85-86°C/4 mmHg. H NMR δH (200.1 MHz, CDCl3) 4.82 (dd,
2H, OCH2, J = 17.6, 0.9 Hz), 5.87 (d, 1H, =CH-, J = 37.2 Hz), 7.21-7.42 (m, 3H, arom.), 7.47-
7.57 (m, 2H, arom.), 8.13 (t, 1H, CHO, J = 0.9 Hz). 19F NMR δF (188.3 MHz, CDCl3) -111.4 (dt,
13
J = 37.2, 17.6 Hz). C NMR δC (50.3 MHz, CDCl3) 62.2 (d, OCH2, J = 31.2 Hz), 111.6 (d,
=CH-, J = 6.8 Hz), 128.1 (d, CH-arom., J = 2.3 Hz), 128.6 (s, CH-arom.), 129.0 (d, CH-arom., J
= 7.4 Hz), 132.1 (d, C-arom., J = 3.2 Hz), 153.3 (d, =CF-, J = 266 Hz), 160.2 (d, CHO, J = 2.9
Hz). MS (EI) m/z 181 ([M+1]+, 9), 180 ([M]+, 92), 152 ([M–CO]+, 8), 151 ([M–HCO]+, 12), 135
([M–OCHO]+, 62), 133 ([M–CHO–H2O]+, 100), 115 ([M–HCO2H–F]+, 72), 109 (16), 91 (40),
78 (57). Anal.: calcd. for C10H9FO2: C, 66.66%; H, 5.04%. Found: C, 66.42%; H, 5.11%.
(Z)-2-Fluoro-3-[4-((Z)-2-fluoro-3-phenylprop-2-enyl)phenyl]prop-2-enyl formate (11)
1H NMR δH (200.1 MHz, CDCl3) 3.64 (d, 2H, CH2, J = 17.0 Hz), 4.83 (dd, 2H, CH2O, J =
17.7, 0.9 Hz), 5.52 (d, 1H, -CH=CF-CH2, J = 38.6 Hz), 5.87 (d, 1H, -CH=CF-CH2O, J = 37.2
Page 22 of 35

23
Hz), 7.13-7.59 (m, 9H, arom.), 8.14 (t, 1H, CHO, J = 0.9 Hz). 19F NMR δF (188.3 MHz, CDCl3)
-100.0 (dt, 1F, -CH=CF-CH2, J = 38.6, 17.0 Hz), -111.4 (dt, -CH=CF-CH2O, J = 37.2, 17.7 Hz).
13C NMR δC (100.4 MHz, CDCl3): 39.5 (d, CH2, J = 28.1 Hz), 62.3 (d, CH2O, J = 31.3 Hz),
107.6 (d, -CH=CF-CH2Ar, J = 8.2 Hz), 111.3 (d, -CH=CF-CH2O, J = 6.7 Hz), 127.1 (d, CH-
arom., J = 2.2 Hz), 128.5 (d, 2CH-arom., J = 7.2 Hz), 128.5 (s, 2CH-arom.), 129.3 (s, 2CH-
arom.), 129.3 (d, 2CH-arom., J = 6.7 Hz), 131.0 (d, C-arom., J = 3.3 Hz), 133.5 (d, C-arom., J =
2.5 Hz), 136.3 (s, C-arom.), 153.4 (d, -CH=CF-CH2O, J = 266 Hz), 159.2 (d, -CH=CF-CH2Ar, J
= 267 Hz), 160.3 (s, -CHO). MS (EI) m/z 316 ([M+2]+, 2), 315 ([M+1]+, 19), 314 ([M]+, 100),
268 (11), 248 (6), 233 (7), 209 (6), 191 (11), 171 (7), 146 (5), 135 (49), 115 (41), 109 (11), 91
(23). Anal.: calcd. for C19H16F2O2: C, 72.60%; H, 5.13%. Found: C, 72.50%; H, 5.19%.
Typical procedure for hydrolysis of 1 in water/dioxane
A mixture of 341 mg (2.0 mmol) of 1, 40 mg (0.40 mmol) of CuCl, 1.0 mL of dioxane and
1.0 mL of water was stirred under argon atmosphere at 100°C for 24 h. The reaction mixture was
cooled to room temperature, diluted with sat. NaCl and extracted 3 times with CH2Cl2. Extracts
were combined, dried over MgSO4 and concentrated. Residual dioxane was not removed at this
step. The internal standard (p-fluoroanisole, 56.6 µL, 0.50 mmol) was added and the resulting
mixture was analyzed by 1H, 19F and 19F{1H} NMR. The following yields were found: 77% of Z-
12, 1% of E-12, 4% of 13, 4% of Z-3, < 0.5% of E-3, 5% of 14, 4% of 15 and 4% of 16.
Similarly, a crude product (1.66 g) was obtained by aqueous treatment from the mixture
formed in the reaction of 1.71 g (10.0 mmol) of 1, 98 mg (1.0 mmol) of CuCl, 5.0 mL of dioxane
and 5.0 mL of water in 48 h at 100°C. Column chromatography on silica gel (40–63 µm, 50:1,
eluent — CHCl3/MeOH, gradient from 100/1 to 25/1) afforded 1.03 g of Z-12 (68% yield).
Bis((Z)-2-fluoro-3-phenylprop-2-enyl) ether (14)
1H NMR δH (300.1 MHz, CDCl3) 4.23 (d, 4H, 2CH2, J = 15.7 Hz), 5.80 (d, 2H, 2 =CH, J =
38.2 Hz), 7.18-7.57 (m, 10H, arom.). 19F NMR δF (188.3 MHz, CDCl3) -110.6 (dt, J = 38.2, 15.7
13
Hz). C NMR δC (100.6 MHz, CDCl3) 68.8 (d, 2CH2, J = 31.1 Hz), 109.8 (d, 2 =CH-, J = 6.4
Hz), 127.8 (d, 2CH-arom., J = 2.0 Hz), 128.6 (s, 4CH-arom.), 128.9 (d, 4CH-arom., J = 7.3 Hz),
132.6 (d, 2C-arom., J = 2.6 Hz), 155.7 (d, 2 =CF-, J = 268 Hz). MS (EI) m/z 286 ([M]+, 2), 266
([M-HF]+, 4), 235 (9), 210 (2), 179 (6), 166 (3), 149 (14), 136 (48), 135 (100), 115 (58), 109
(16), 103 (13), 77 (8).
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24
(Z)-2-Fluoro-3-phenylprop-2-enyl 2-fluoro-1-phenylprop-2-enyl ether (15)
1H NMR δH (300.1 MHz, CDCl3) 4.19 (d, 2H, CH2O, J = 15.2 Hz), 4.69 (dd, 1H, =CH2
(trans- to F), J = 48.5, 3.3 Hz), 4.81 (dd, 1H, =CH2 (cis- to F), J = 16.8, 3.3 Hz), 4.97 (br d, 1H, -
CH(OAll)-, J = 11.5 Hz), 5.76 (d, 1H, =CH-, J = 38.2 Hz), 7.22-7.59 (m, 10H, arom.). 19F NMR
δF (188.3 MHz, CDCl3) -110.6 (dt, 1F, -CH=CF-CH2O-, J = 38.2, 15.2 Hz), -107.9 (ddd, 1F, -
OCH(Ph)-CF=CH2, J = 48.5, 16.8, 11.5 Hz). 13C NMR δC (100.6 MHz, CDCl3) 67.5 (d, CH2O, J
= 31.4 Hz), 78.9 (d, CH(OAll), J = 31.6 Hz), 92.7 (d, =CH2, J = 16.7 Hz), 109.7 (d, =CH- J = 6.3
Hz), 127.45 (s, CH-arom., ), 127.7 (d, CH-arom., J = 2.1 Hz), 128.5-129.0 (5 lines, 8 CH-arom.),
132.7 (d, C-arom., J = 2.7 Hz), 137.1 (s, C-arom.), 155.6 (d, -CF=, J = 268 Hz), 163.5 (d, =CF-,
J = 262 Hz). MS (EI) m/z 286 ([M]+, 11), 182 (10), 180 (8), 166 (4), 149 (10), 136 (34), 135
(100), 133 (23), 115 (58), 109 (21), 104 (22), 103 (12), 77 (8).
(Z)-2-Fluoro-3-[4-((Z)-2-fluoro-3-phenylprop-2-enyl)phenyl]prop-2-enol (16)
1H NMR δH (300.1 MHz, CDCl3) 1.97 (br s, 1H, OH), 3.62 (d, 2H, CH2, J = 16.9 Hz), 4.27
(d, 2H, CH2O, J = 14.3 Hz), 5.51 (d, 1H, -CH=CF-CH2, J = 38.7 Hz), 5.77 (d, 1H, -CH=CF-
CH2O, J = 38.7 Hz), 7.12-7.54 (m, 9H, arom.). 19F NMR δF (188.3 MHz, CDCl3) -113.0 (dt, 1F,
-CH=CF-CH2O, J = 38.7, 14.3 Hz), -99.9 (dt, 1F, -CH=CF-CH2, J = 38.7, 16.9 Hz). 13C NMR δC
(100.6 MHz, CDCl3) 39.4 (d, -CH=CF-CH2, J = 28.1 Hz), 62.0 (d, -CH=CF-CH2O, J = 32.7 Hz),
107.3 (d, -CH=CF-CH2O, J = 6.8 Hz), 107.5 (d, -CH=CF-CH2, J = 8.2 Hz), 127.0 (d, CH-arom.,
J = 2.1 Hz), 128.5 (d, 2CH-arom., J = 7.1 Hz), 128.5 (s, 2CH-arom.), 129.1 (d, 2CH-arom., J =
7.2 Hz), 129.2 (s, 2CH-arom.), 131.6 (d, C-arom., J = 2.6 Hz), 133.6 (d, C-arom., J = 2.5 Hz),
135.59 (s, C-arom.), 157.47 (d, -CH=CF-CH2O, J = 266 Hz), 160.12 (d, -CH=CF-CH2, J = 267
Hz). MS (EI) m/z 287 ([M+H]+, 19), 286 ([M]+, 100), 268 (5), 247 (5), 233 (6), 209 (7), 189 (7),
146 (10), 135 (18), 133 (33), 115 (21), 109 (10), 103 (5), 91 (14).
Preparative scale syntheses of 2-fluoroallylic methyl ethers, 2-fluoroallylic acetates,
formates and alcohols.
(Z)-3-Methoxy-2-fluoro-1-phenylpropene (Z-5)
A mixture of 34.1 g (200 mmol) of 1, 1.98 g (20 mmol) of CuCl and 81 mL of MeOH and a
magnetic stirring bar were placed into a glass cylinder, which in turn was inserted into a stainless
steel autoclave. The latter was kept in an oil bath (150°) with stirring for 5 hours. After cooling
to room temperature, the reaction mixture was diluted with 50 mL of CH2Cl2 and 50 mL of
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25
water. The organic layer was washed with 3x50 mL of dilute HCl (ca. 1M) and 3x50 mL of
water and then dried over CaCl2. GC analysis of the organic layer indicated that exclusively Z,E-
5,6 in a 95/2/3 ratio were formed. All volatiles were removed in a rotary evaporator and the
residue was fractionated under reduced pressure in a 200 mm Vigreux column. The fraction with
bp 119-120°C/27 mmHg was collected (pure Z-5, 27.9 g, yield 84%).
(Z)-2-Fluoro-3-phenylprop-2-enyl formate (Z-10)
A mixture of 34.1 g (200 mmol) of 1, 3.96 g (40 mmol) of CuCl, 27.2 g (400 mmol) of
HCO2Na and 200 mL of HCO2H was stirred at 100°C (oil bath) under argon atmosphere for 5
hours. The reaction was controlled by GC. After cooling to room temperature, the mixture was
diluted with 200 mL of CH2Cl2, 500 mL of water, then ca. 200 g of ice was added. After that a
solution of 223 g (5.3 mol with a purity ca. 95%) of NaOH in 500 mL of water was slowly added
with stirring. Slow addition of the alkali is necessary at this point to avoid gas evolution (or
boiling of CH2Cl2). After that a concentrated NH3 solution (ca. 100 mL) was added. However, it
did not dissolve most of the solids present in the mixture, unlike in case of acetolysis (vide
supra). So the solids were removed by filtration through a short celite pad (ca. 10 mm). The
resulting organic layer was separated and the water layer was extracted with 3x100 mL of
CH2Cl2. The combined organic layers were dried over Na2SO4 and the solvent was distilled off
to afford 34.4 g of crude Z-10 (purity ca.80% according to NMR) that was fractionated under
reduced pressure in a 200 mm Vigreux column. The fraction with bp 85-86°C/4 mmHg was
collected (26.1 g, 69% yield, containing 95 w/w % of Z-10 and 5 w/w % of Z-12 according to
NMR).
(Z)-2-Fluoro-3-phenylprop-2-enol (Z-12)
A mixture of 17.1 g (100 mmol) of 1, 2.01 g (20 mmol) of CuCl, 50 mL of diglyme and 50
mL of water was stirred under reflux in an argon atmosphere for 20 hours. After cooling to room
temperature, the mixture was diluted with 200 mL of CH2Cl2 and 500 mL of water, the organic
layer was washed with 1x250 mL of concentrated NH3 solution, 1x250 ml of 1M HCl, 5x250
mL of water, dried over Na2SO4 and concentrated in a rotary evaporator. The residue, 27.5 g of a
yellow oil, was fractionated under reduced pressure in a 200 mm Vigreux column. Residual
allylic chlorides and isomeric alcohols were distilled off until the distillate started to freeze in the
condenser. Then the condenser was removed and distillation was continued; the distillate was
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26
collected directly into the receiving flask. In this way, 8.03 g of Z-12 was obtained as a colorless
solid (bp 87-88°C/1.5 mmHg, mp 37-38°C, yield 53%).
(Z,E)-4-Methoxy-3-fluoropent-2-ene (Z,E-22)
A mixture of 2.45 g (20 mmol) of 20, 198 mg (2.0 mmol) of CuCl and 8.1 mL (200 mmol)
of MeOH and a magnetic stirring bar was placed into a glass cylinder, which in turn was inserted
into a stainless steel autoclave. The latter was kept in an oil bath (120°) with stirring for 10
hours. The reaction mixture was diluted with Et2O, washed with twice diluted NH3, then with
water and dried over Na2SO4. Et2O was distilled off in a 200 mm Vigreux column and the
residue was fractionated under atmospheric pressure. The fraction with bp 100–101°C/atm. was
collected (Z,E-22, 1.75 g, Z/E = 85/15, yield 74%).
1
For Z-22: H NMR δH (200.1 MHz, CDCl3) 1.29 (d, 3H, CH(OMe)CH3, J = 6.5 Hz), 1.61 (dd,
3H, CH3CH=, J = 6.9, 2.4 Hz), 3.28 (s, 3H, OCH3), 3.68 (dq, 1H, CH(OMe), J = 18.0, 6.5 Hz),
19
4.79 (dq, 1H, =CH-, J = 36.9, 6.9 Hz). F NMR δF (188.3 MHz, CDCl3) -127.6 (ddq, J = 36.9,
13
18.0, 2.4 Hz). C NMR δC (50.3 MHz, CDCl3) 8.5 (d, CH(OMe)CH3, J = 6.3 Hz), 18.2 (s,
CH3CH=), 56.2 (s, OCH3), 75.7 (d, CH(OMe), J = 28.8 Hz), 102.4 (d, -CH=, J = 14.4 Hz), 158.2
(d, =CF-, J = 259 Hz. MS (EI) m/z 118 ([M]+, 6), 103 ([M-CH3]+, 100), 87 ([M-OCH3]+, 16), 59
(22), 41 (15).
1
For E-22: H NMR δH (200.1 MHz, CDCl3) 1.31 (d, 3H, CH(OMe)CH3, J = 6.6 Hz), 1.61 (dd,
3H, CH3CH=, J = 7.4, 2.4 Hz), 3.28 (s, 3H, OCH3), 4.14 (dq, 1H, CH(OMe), J = 26.9, 6.6 Hz),
19
5.26 (dq, 1H, =CH-, J = 21.9, 7.4 Hz). F NMR δF (188.3 MHz, CDCl3) -123.8 (ddq, J = 26.9,
21.9, 2.4 Hz). 13C NMR δC (50.3 MHz, CDCl3) 9.8 (d, CH(OMe)CH3, J = 9.3), 17.8 (d,
CH3CH=, J = 1.7 Hz), 56.0 (s, OCH3), 70.8 (d, CH(OMe), J = 28.1 Hz), 104.0 (d, -CH=, J =
22.7 Hz), 157.3 (d, =CF-, J = 251 Hz). MS (EI) m/z 118 ([M]+, 5), 103 ([M-CH3]+, 100), 86 ([M-
CH3OH]+, 44), 59 (23), 41 (12).
Anal.: calcd. for C6H11FO: C, 60.99%; H, 9.38%. Found: C, 60.97%; H, 9.45%.
3-Methoxy-2-fluorocycloheptene (23)
Method A.
A mixture of 308 mg (2.1 mmol) of 17 202 mg (2.0 mmol) of CuCl and 2.0 mL of MeOH
was heated under argon atmosphere at 60°C for 24 hours. The resulting solution was diluted with
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27
CH2Cl2, washed once with dilute HCl, 3 times with water and dried over Na2SO4. The solvent
was evaporated under reduced pressure to afford 290 mg of brown oil (64 w/w % of 23 and 36
w/w % exo-Cl-17 according to 1H, 19F NMR).
Method B.
A mixture of 31.4 g (210 mmol) of 17, 4.19 g (42.4 mmol) of CuCl and 100 mL of MeCN
was heated with stirring under argon atmosphere at 120°C for 2 hours in a stainless steel
autoclave with glass liner. After cooling to room temperature, the mixture was diluted with
CH2Cl2 and water. The organic phase was separated, washed once with concentrated NH3, 3
times with water and dried over Na2SO4. The solvent was distilled off under atmospheric
pressure and the residue was redistilled under reduced pressure. The fraction with bp 70-80°C /
53 mmHg was collected to afford 25.4 g of a mixture containing (GC) 21% of exo-Cl-17, 3%
endo-Cl-17 and 75% of 18. Endo/exo-Cl-17 were distilled off from the distillate in a Fischer
HMS-500 rectification column (ca. 90 theoretical plates at atmospheric pressure) and the residue
was redistilled again to give 16.1 g of the target 18 (yield 79% based on endo-Cl-17).
A mixture of 7.41 g (0.50 mmol) of 18, 2.48 g (25 mmol) of CuCl and 50 mL of MeOH was
stirred at 60°C under argon atmosphere for 24 hours. After cooling to room temperature, it was
diluted with CH2Cl2, washed once with twice diluted NH3(sat.), 3 times with water, once with
NaCl(sat.) and dried over CaCl2. The solvent was removed by distillation under atmospheric
pressure in a 150 mm column filled with glass beads (d = 2.85-3.3 mm). The residue was
distilled under reduced pressure in a 200 mm Vigreux column to collect the fraction with bp
87.0-87.2°C/69 mmHg (6.48 g, 90% yield).
23: 1H NMR δH (200.1 MHz, CDCl3) 1.37-2.28 (m, 8H, 4CH2), 3.40 (d, 3H, OCH3, J = 1.6 Hz),
3.88 (ddt, 1H, -CH-OMe, J = 15.0, 6.1, 1.9 Hz), 5.50 (dddd, 1H, -CH=, J = 22.1, 7.3, 5.4, 1.6
Hz). 19F NMR δF (188.3 MHz, CDCl3) –97.3 (br t, J = 19 Hz). 13C NMR δC (50.3 MHz, CDCl3)
22.5 (d, CH2, J = 10.7 Hz), 23.3 (s, CH2), 27.2 (s, CH2), 29.4 (d, CH2, J = 9.8 Hz), 57.0 (s,
OCH3), 78.83 (d, CH(OMe), J = 30.6 Hz), 109.9 (d, -CH=, J = 21.2 Hz), 162.0 (d, -CF=, J = 252
Hz). MS (EI) m/z 144 ([M]+, 4), 143 ([M-H]+, 4), 129 ([M-CH3]+, 3), 115 (77), 112 ([M-
CH3OH]+, 100), 102 (16), 97 (73), 89 (13), 85 (20), 79 (18), 77 (12), 63 (18), 59 (17), 53 (8), 41
(13), 39 (12). Anal.: calcd. for C8H13FO: C, 66.64%; H, 9.09%. Found: C, 66.50%, H, 9.05%.
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28
Typical procedure for 2-fluoroallylic acetate synthesis
A mixture of 12.3 g (100 mmol) of 21, 1.98 g (20 mmol) of CuCl, 16.5 g (200 mmol) of
NaOAc and 100 mL (1.75 mol) of glacial AcOH was stirred in an argon atmosphere at 100°C for
5 hours. After cooling to room temperature, the solids were filtered off and washed with 4x25mL
of CH2Cl2. 250 mL of water and ca. 200 g of ice were added to the combined filtrates. After that,
a solution of 70 g (1.75 mol) of NaOH in 300 mL of water was slowly added with stirring. The
precipitate that formed was dissolved by adding concentrated NH3 solution (ca. 25 mL). The
resulting organic layer was separated and the water layer was extracted with 3x100 mL of
CH2Cl2. The combined organic layer was dried over MgSO4, the solvent was distilled off in a
150 mm column filled with glass beads (d = 2.85-3.3 mm). The residue was fractionated in a 150
mm Vigreux column under reduced pressure.
(Z,E)-3-Fluoropent-3-en-2-yl acetate (Z,E-26)
Colorless liquid, bp 78-79/74 mmHg, Z/E = 85/15, yield 89%.
1
For Z-26: H NMR δH (200.1 MHz, CDCl3) 1.38 (d, 3H, CH(OAc)CH3, J = 6.7 Hz), 1.62 (dd,
3H, =CHCH3, J = 6.9, 2.5 Hz), 2.07 (s, 3H, C(O)CH3), 4.93 (dq, 1H, -CH=, J = 36.3, 6.9 Hz),
19
5.37 (dq, 1H, CH(OAc), J = 18.1, 6.7 Hz). F NMR δF (188.3 MHz, CDCl3) -126.0 (ddq, J =
36.3, 18.1, 2.5 Hz). 13C NMR δC (50.3 MHz, CDCl3) 8.7 (d, CH3, J = 5.8 Hz), 17.1 (d, CH3, J =
2.7 Hz), 21.2 (s, C(O)CH3), 68.5 (d, CH(OAc), J = 29.8 Hz), 103.3 (d, -CH=, J = 14.5 Hz),
157.3 (d, -CF=, J = 255 Hz), 170.1 (s, C(O)CH3). MS (EI) m/z 146 ([M+·], 3), 104 ([M+· -
CH2=C=O], 72), 89 ([M+· - CH2=C=O - CH3], 13), 87 ([CH3-+CH-CF=CH-CH3], 23), 86
([CH3=CH-CF=CH-CH3 ], 15), 85 ([CH3=CH-CF=CH-CH2 ], 49), 43 ([CH3CO+], 100).
+·
+
1
For E-26: H NMR δH (200.1 MHz, CDCl3) 1.40 (d, 3H, CH(OAc)CH3, J = 6.7 Hz), 1.66 (dd,
3H, =CHCH3, J = 7.4, 2.5 Hz), 2.07 (s, 3H, C(O)CH3), 5.21 (dq, 1H, -CH=, J = 20.6, 7.4 Hz),
19
5.71 (dq, CH(OAc), J = 26.8, 6.7 Hz). F NMR δF (188.3 MHz, CDCl3) -124.1 (ddq, J = 26.8,
13
20.6, 2.5 Hz). C NMR δC (50.3 MHz, CDCl3) 10.0 (d, CH3, J = 8.7 Hz), 16.7 (d, CH3, J = 2.5
Hz), 21.1 (s, C(O)CH3), 64.3 (d, CH(OAc), J = 28.0 Hz), 104.2 (d, -CH=, J = 22.2 Hz), 156.8 (d,
-CF=, J = 248 Hz), 170.1 (s, C(O)CH3). MS (EI) m/z 146 ([M+·], 3), 104 ([M+· - CH2=C=O], 74),
89 ([M+· - CH2=C=O - CH3], 13), 87 ([CH3-+CH-CF=CH-CH3], 24), 86 ([CH3=CH-CF=CH-
+·
+
CH3 ], 15), 85 ([CH3=CH-CF=CH-CH2 ], 49), 43 ([CH3CO+], 100).
Anal.: calcd. for C7H11FO2: C, 57.52%; H, 7.59%. Found: C, 57.28%; H, 7.52%.
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29
2-Fluorocyclohept-2-enyl acetate (27)
1
Colorless liquid, bp 78-79°C/8 mmHg, yield 75% based on endo-17. H NMR δH (200.1 MHz,
CDCl3) 1.51-2.30 (m, 8H, 4CH2), 2.10 (s, 3H, C(O)CH3), 5.48 (m, 1H, CH(OAc), 5.59 (ddddd,
19
1H, -CH=, J = 21.8, 6.4, 5.8, 0.7 Hz). F NMR δF (188.3 MHz, CDCl3) -104.7 (ddtd, J = 21.8,
13
11.7, 3.5, 3.5 Hz). C NMR δC (50.3 MHz, CDCl3) 21.1 (s, C(O)CH3), 22.3 (d, CH2, J = 9.9
Hz), 22.8 (s, CH2), 26.9 (s, CH2), 29.0 (d, CH2, J = 8.3 Hz), 71.6 (d, CH(OAc), J = 31.5 Hz),
111.4 (d, -CH=, J = 21.3 Hz), 158.9 (d, -CF=, J = 249 Hz), 170.3 (s, C(O)CH3). MS (EI) m/z 172
([M+·], 5), 130 ([M+·-CH2=C=O], 2), 124 (6), 112 ([M+· - CH2=C=O - H2O], 55), 97 (100), 84
(13), 82 (28), 67 (19), 43 ([CH3CO+], 97). Anal.: calcd. for C9H13FO2: C, 62.78%; H, 7.61%.
Found: C, 62.71%; H, 7.60%.
Cleavage of the AcO group in 24, 25, Z,E-26, 27.
A mixture of 25 mmol of 2-fluoroallyl acetate, 345 mg (2.5 mmol) of K2CO3 and 12 mL of
MeOH was stirred at room temperature for 5 hours, filtered through a short pad of celite and
fractionated under reduced pressure.
(Z,E)-3-Fluoropent-3-en-2-ol (Z,E-30)
Colorless liquid, bp 59-63°C/73 mmHg, Z/E = 5/1, yield 97%.
1
For Z-30: H NMR δH (200.1 MHz, CDCl3) 1.34 (dd, 3H, CH3CH(OH), J = 6.6, 0.6 Hz), 1.61
(ddd, 3H, CH3CH=, J = 6.9, 2.4, 0.9 Hz), 2.40 (br. s, 1H, OH), 4.26 (dqqd, 1H, CH3CH(OH), J =
19
14.2, 6.6, 0.9, 0.6 Hz), 4.85 (dqd, 1H, =CH-, J = 37.4, 6.9, 0.6 Hz). F NMR δF (188.3 MHz,
13
CDCl3) -126.1 (ddq, J = 37.4, 14.2, 2.4 Hz). C NMR δC (50.3 MHz, CDCl3) 8.5 (d, CH3, J =
6.4 Hz), 20.1 (d, CH3, J = 2.0 Hz), 66.6 (d, CH(OH), J = 31.0 Hz), 100.0 (d, =CH-, J = 14.6 Hz),
161.1 (d, =CF-, J = 255). MS (EI) m/z 104 ([M]+, 9), 89 ([M-CH3]+, 100), 84 (28), 69 (57), 59
(12), 45 (18), 43 (37), 41 (61), 39 (14).
1
For E-30: H NMR δH (200.1 MHz, CDCl3) 1.37 (dd, 3H, CH3CH(OH), J = 6.6, 0.4 Hz), 1.61
(dd, 3H, CH3CH=, J = 7.4, 2.4 Hz), 4.66 (dq, 1H, CH3CH(OH), J = 26.2, 6.6 Hz), 5.11 (dq, 1H,
19
CH3CH=, J = 21.4, 7.4 Hz). F NMR δF (188.3 MHz, CDCl3) -126.6 (ddq, J = 26.2, 21.4, 2.4
13
Hz). C NMR δC (50.3 MHz, CDCl3) 9.8 (d, CH3, J = 9.4 Hz), 20.0 (d, CH3, J = 1.7 Hz), 62.3
(d, CH(OH), J = 28.6 Hz), 101.4 (d, =CH-, J = 22.9 Hz), 159.9 (=CF-, J = 249 Hz). MS (EI) m/z
104 ([M]+, 6), 89 ([M-CH3]+, 100), 84 (21), 69 (57), 59 (13), 45 (19), 43 (36), 41 (69), 39 (18).
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