Preparation of (Z)-1-fluoro-1-alkenyl carboxylates, carbonates and carbamates through chromium mediated transformation of dibromofluoromethylcarbinyl esters and the reactivity as double acyl group donors

Article abstract of DOI:10.1016/j.jfluchem.2011.07.022

CrCl₂/Mn-mediated transformation of various dibromofluoromethylcarbinyl esters including carboxylates, carbonates and carbamates provided 1-fluoro-1-alkenyl esters via [2,3]-sigmatropic rearrangement of ester group. Reaction proceeded by using CrCl₂/Mn system under mild conditions (in THF at room temperature) to give 1-fluoro-1-alkenyl esters in good yield with an excellent Z selective manner. 1-Fluoro-1-alkenyl ester thus obtained acts as a double acyl donor in the reaction with necleophiles such as amine, thiol, alcohol as well as bifunctional necleophiles such as ethylene diamine derivative.

Full text of DOI:10.1016/j.jfluchem.2011.07.022

Journal of Fluorine Chemistry 133 (2012) 38–51
Contents lists available at ScienceDirect
Journal of Fluorine Chemistry
journal homepage: www.elsevier.com/locate/fluor
Preparation of (Z)-1-fluoro-1-alkenyl carboxylates, carbonates and carbamates
through chromium mediated transformation of dibromofluoromethylcarbinyl
esters and the reactivity as double acyl group donors
a
a
b
Akio Saito a,1, Manabu Tojo a, Hikaru Yanai a, , Fukiko Wada , Muga Nakagawa , Midori Okada ,
*
Azusa Sato b, Rieko Okatani b, Takeo Taguchi a,
*
a School of Pharmacy, Tokyo University of Pharmacy and Life Sciences, 1432-1 Horinouchi, Hachioji, Tokyo 192-0392, Japan
b Tokyo Women’s Medical University, 8-1 Kawada-cho, Shinjuku-ku, Tokyo 162-8666, Japan
A R T I C L E I N F O
A B S T R A C T
Article history:
CrCl2/Mn-mediated transformation of various dibromofluoromethylcarbinyl esters including carbox-
ylates, carbonates and carbamates provided 1-fluoro-1-alkenyl esters via [2,3]-sigmatropic rearrange-
ment of ester group. Reaction proceeded by using CrCl2/Mn system under mild conditions (in THF at
room temperature) to give 1-fluoro-1-alkenyl esters in good yield with an excellent Z selective manner.
1-Fluoro-1-alkenyl ester thus obtained acts as a double acyl donor in the reaction with necleophiles such
as amine, thiol, alcohol as well as bifunctional necleophiles such as ethylene diamine derivative.
ß 2011 Elsevier B.V. All rights reserved.
Received 11 July 2011
Accepted 19 July 2011
Available online 26 July 2011
This paper is dedicated to Professor
Wei-Yuan Huang on the occasion of
his 90th birthday.
Keywords:
Fluoroalkenyl ester
Chromous chloride
Dibromofluoromethyl
Fluorocarbene
2,3-Sigmatropic rearrangement
Enzyme inhibitor
Acylation
Acyl donor
1. Introduction
1-alkenyl ether derivatives from dibromofluoromethylcarbinyl
alkyl ethers and silyl ethers [5]. Concerning these chromium
Development of new and efficient synthetic methods for
fluorinated olefins has been extensively investigated, since
fluorinated olefins are an important class of compounds in both
synthetic chemistry, as well as in medicinal chemistry and
material sciences [1,2]. Our research group has been also engaging
in this field, in which our recent development of stereoselective
construction of functionalized fluorinated olefins directed to the
fluoroalkene dipeptide isosteres is one of the representative
achievements [3]. We have also developed new methods for
fluoroalkene synthesis utilizing chromium chemistry. This
involves the Cr(II)-mediated stereospecific fluoroalkenylation
reaction of aldehyde using 1-bromo-1-fluoroalkenes (kinetic
separation) [4] and the stereoselective synthesis of (Z)-2-fluoro-
chemistries, similar study to the former one was also reported by
Pannecouk group [6] and the related study to the latter was
reported by Falck and Mioskowski group [7]. Cr(II)-Mediated
Reformatsky type reaction of bromofluoroacetates was also
reported by Falck and Mioskowski group [8].
Cr(II)-mediated chloroalkenylation reaction using trichloro-
methyl substrates were investigated by several groups and a
variety of synthetic reactions have been explored [9–11]. In 2001,
Takai reported the Z-selective chloroalkenylation of aldehydes
with putative chloroalkenyl chromium species in situ generated via
gem-dichromium intermediate by treating trichloromethylcarbi-
nyl acetate 1-Cl with CrCl2 in the presence of DMF to give the allyl
alcohol 2-Cl. In this paper it was pointed out that 1-chloroalkenyl
acetate 3-Cl was also detected as a side product (Scheme 1) [12].
We found that its formation could be realized when the starting
ester 1-Cl was simply react with CrCl2 in THF under reflux
conditions. However, detail on the chemistry of 1-chloroalkenyl
ester such as mechanistic aspects, scope and limitations of the
substrates and the utility of the products had not been examined.
* Corresponding authors. Tel.: +81 426 76 3257; fax: +81 426 76 3257.
E-mail addresses: yanai@toyaku.ac.jp (H. Yanai), taguchi@toyaku.ac.jp
(T. Taguchi).
1
Present address: Showa Pharmaceutical University, 3-3165 Higashi Tamaga-
wagakuen, Machida, Tokyo 194-8543, Japan.
0022-1139/$ – see front matter ß 2011 Elsevier B.V. All rights reserved.
doi:10.1016/j.jfluchem.2011.07.022

A. Saito et al. / Journal of Fluorine Chemistry 133 (2012) 38–51
39
Me
O
Me
OH
n-C8H17
CrCl2 (8 equiv)
DMF (8 equiv)
O
O
O
Ph
n-C8H17CHO
Ph
THF, 0 °C, 24 h
Cl
Ph
CCl3
Cl
1-Cl
2-Cl 62%
3-Cl 29%
O
Me
CrCl2 (4 equiv)
THF, reflux, 3 h
O
1-Cl
Ph
Cl
3-Cl 80%
Scheme 1.
R2
enzyme
O
R2
O
X
R2
CrCl2 (3 equiv)
THF, reflux
O
O
X
enzymatic
hydrolysis
NH
R'
O
O
O
O
F
O
R1
N
R1
R'
H
R1
CX3
R
O
O
F
O
R
CrCl2X
3 (X = Cl, F)
76~98%
1
4
3
O
H2O
(CX3 = CCl3 ,CBr2F)
R = recognition site for enzymes
R' = labeling site
Nu
Scheme 2.
Scheme 3.
Later, in 2005 Falck and Mioskowski reported this ester group
rearrangement reaction of trihalomethylcarbinol esters 1 leading
to highly Z-selective and high yield synthesis of 1-chloro or 1-
fluoro-1-alkenyl esters 3 (Scheme 2) [7]. Generally, for these
reactions, 3.0 equiv. of CrCl2 in THF under reflux conditions was
employed. Mechanistic discussion indicating the intramolecular
nucleophilic attack of the nonbonded electrons of carbonyl oxygen
atom to the Fischer chromium halocarbene intermediate 4 to
induce [2,3]-sigmatropic rearrangement was also provided. For the
synthesis of fluorinated derivatives 3 (X = F), dibromofluoromethyl
substrates were subjected to the Cr(II)-mediated reaction as we
had also reported [13]. In 2009, as an extension of this chromium
chemistry, the same group reported a highly stereoselective
synthesis of (1Z,3E)-1-halo-1,3-dienol esters [14].
halofluorination of alkenyl esters and the subsequent selective
dehydrohalogenation reaction. There have been no reports dealing
with such reactions and these remain as the future subjects. Ram
reported the preparation of 1-chloro-1-alkenyl esters via radical
acyloxy group rearragement (Surzur–Tanner reaction) of trichlor-
omethylcarbinyl esters promoted by CuCl/bipyridine complex
[17]. We applied this reaction to dibromofluoromethyl derivatives
for the synthesis of fluoroalkeny ester, but the reaction proceeded
very slowly and the yield of the fluoroalkeny ester was very low
[18].
It is expected that reaction of 1-fluoro-1-alkenyl ester 3 with a
nucleophile (Nu–H) including enzymatic hydrolysis will deliver
the acylated compound (RCONu) and the acyl fluoride (R0CH2COF)
converted from the liberated fluoroenol, which can act as the
second acyl transfer reagent to the nucleophilic center to give the
acylated compound (R0CH2CONu). Schematic enzymatic hydrolysis
leading to the second acylation step by acyl fluoride is illustrated in
Scheme 3. The idea is similar to those of Windlanski’s bromovinyl
As will be mentioned below, we were interested in 1-fluoro-1-
alkenyl ester structure from the view point of a molecular design of
hydrolytic enzyme inhibitors and the synthetic utility as unique
double acyl group donors to nucleophiles.
As a general consideration, synthetic methods for 1-halo-1-
alkenyl esters are quite limited. Windlanski reported the synthesis
of 1-bromovinyl esters by the addition of bromine to vinyl esters
followed by dehydrobromination of the dibromide with strong
base such as LiHMDS at low temperature [15]. This method was
also demonstrated to be applicable to the synthesis of 1-
bromovinyl phosphate 5 (in Scheme 4), which was shown to act
as an inhibitor of phosphotyrosine phosphatase [15,16]. For the
synthesis of 1-fluoro-1-alkeny ester by adapting the similar
protocol, we have to develop an efficient conditions for both
phosphate 5 as phosphatase inhibitor [15,16] or Halazy’s
a-1,1-
difluoroethyl glycoside 6 as -glucosidase inhibitor [19] (Scheme
a
4). In both cases, enzymatic reactions provided reactive acylating
reagents, which caused the irreversible inhibition by trapping
nucleophic centers in the enzyme.
In this paper, we report a stereoselective synthesis of various
(Z)-1-fluoro-1-alkenyl esters through Cr(II)-mediated [2,3]-rear-
rangement of a variety type of dibromofluoromethylcarbinyl esters
phosphotyrosin
O
P
EtO
Br
O
phosphatase
O
Nu-Enzyme
O
EtO
Br
Nu-Enzyme
H2O
5
OH
O
α-glucosidase
CHFCl
Nu-Enzyme
OH
O
O
HO
HO
F
F
HO
ClFHC
ClFHC
F
ClFHC
Nu-Enzyme
O
Glc-OH
6
F
F
Scheme 4.

40
A. Saito et al. / Journal of Fluorine Chemistry 133 (2012) 38–51
H
CrCl2 (4 equiv)
Ph
O
Mn (8 equiv)
H
R
FBr2C
O
O
F
O
THF, rt, 24 h
H
H
Ph
O
O
8d (R = 3β-cholestery)
Ph
9d 81% (Z only)
O
1) CrCl2 (4 equiv), Mn (8 equiv)
THF, rt, 24 h
F
O
OTMSE
Ph
FBr2C
O
N
O
N
H
CO2H
2) TFA, rt, 15 min
Boc O
15 46% (2 steps)
10k
Scheme 5.
including carbonates
8
and carbamates 10 leading to the
we chose carboxylate of dibromofluoroethanol (primary alcohol) 1a
and those of two dibromofluoromethylcarbinols (secondary alco-
hol) 1b–c, as well as ethyl carbonates 8a–b and N,N-dimethyl
carbamates 10a–b. In the case of dibromofluoroethyl benzoate 1a,
reaction proceeded slowly when treating with 4 equiv. of CrCl2 in
THF at room temperature and after 13 h we obtained 1-fluorovinyl
benzoate 3a in 55% isolated yield (entry 1). Addition of Mn powder
was found to be effective to enhance the reaction rate and to reduce
the amount of expensive CrCl2 [20]. That is, as shown in entry 2, a
combined use of 1.5 equiv. of CrCl2 and 4.0 equiv. of Mn in THF at
room temperature resulted in the consumption of 1a within 5 h to
give 3a in 65% yield. Effect of Mn powder as an additive on the
efficiency of the reaction was much more significant in the reaction
of less reactive esters of secondary alcohols. For example, while the
reaction of 1b and 8a did not proceed at room temperature by the
single use of CrCl2 (4 equiv., entries 4 and 7 vs. entry 1), a combined
use of 2.0 equiv. of CrCl2 and 8.0 equiv. of Mn in THF at room
temperature for 16 h promoted the reaction to give the desired
products 3b and 9a in excellent yields in both cases (entries 5 and 8).
Under the same conditions, not only these benzylic substrates 1b
and 8a, aliphatic substrates 1c and 8b also provided the
corresponding fluoroalkenyl esters 3c and 9b in excellent yields
(entries 6 and 9). It should be noted that the reactions proceeded in
completely stereoselective manner to give Z-configurated products
[7]. Similar transformationwas foundtobeapplicable tocarbamates
10a and 10b to give the products 11a and 11b in 61% and 65%,
respectively under the same conditions. Thus, CrCl2/Mn system
works nicely for the transformation of dibromofluoromethylcarbi-
nol esters into 1-fluoro-1-alkeny esters under mild conditions such
as in THF at room temperature.
compounds of biological interest such as 9d and 15 (Scheme 5).
By employing CrCl2/Mn system reaction proceeded smoothly at
room temperature. Furthermore, we demonstrate that 1-fuoro-1-
alkenyl ester 3 thus obtained can serve as a double acyl group
donor in the reaction with necleophiles such as amine, thiol,
alcohol as well as bifunctional necleophiles such as 1,2-diamine
derivatives (Scheme 6).
2. Results and discussion
2.1. Preparation of 1-fluoro-1-alkenyl esters
During our early stage to explore fluoroalkenylation reaction of
aldehydes with fluoroalkenyl chromium species, we conducted the
Barbier type reaction of 2,2-dibromo-2-fluoroethyl benzoate 1a
with benzaldehyde in the presence of CrCl2 pretreated with DMF
according to Takai’s chloroalkenylation reaction as described in
Scheme 1 [12]. Even under our optimized conditions for the
fluoroalkenylation, the desired fluoroallyl alcohol 7 was obtained
only in 10% yield, but, in stead, 1-fluorovinyl benzoate 3a was a
major product isolated in 48% yield and at the same time 1a was
recovered in 16% (Scheme 7).
Since the product, 1-fluoro-1-alkenyl ester 3a, attracted our
attention as described above, we examined in detail to establish
the optimized reaction conditions together with the scope and
limitations of the substrates, in particular toward molecular design
of inhibitors for some hydrolytic enzymes.
Selected results of the survey of reaction conditions for the ester
group rearrangement are summarized in Table 1. As the substrates
Et3N (2.0 equiv)
O
O
F
O
O
O
+
Ph
O
NH NH2
F
Me
NH HN
THF, rt, 11 h
H2N
NH2
Ph
Ph
Me
(1.0 equiv)
3a
18b 56%
Scheme 6.
CrCl2 (2.0 euiv)
Mn (4.0 equiv)
DMF (1.2 equiv)
OH
O
O
F
+
Ph
F
7 10%
PhCHO
+
Ph
O
CBr2F
Ph
O
THF, rt , 24 h
1a
3a 48%
CrX3
F
Scheme 7.

A. Saito et al. / Journal of Fluorine Chemistry 133 (2012) 38–51
41
Table 1
Survey of reaction conditions for ester rearrangement.
R1
O
O
F
CrCl2/additive
R1
R2
R2
O
CBr2F
O
THF, rt
1, 8 or 10
3, 9 or 11
Entry
Substrate
R1
R2
CrCl2 (equiv.)
Additive (equiv.)
Time (h)
Product
Yielda (%)
1
1a
H
Ph
4.0
1.5
3.0
4.0
2.0
2.0
4.0
2.0
2.0
2.0
2.0
None
13
5
3a
55
65
2
1a
H
Ph
Mn (4.0)
Mn (2.0)/(Ph3P)2NiCl2 (0.1)
None
3a
3
1a
H
Ph
6
3a
55
0b
98c
95c
0b
88c
98c
61d
65c
4
1b
1b
1c
Ph
Me
20
15
16
20
16
16
23
15
3b
3b
3c
5
Ph
Me
Mn (8.0)
Mn (8.0)
None
6
PhCH2CH2
Ph
Me
7
8a
EtO
EtO
EtO
Me2N
Me2N
9a
8
8a
Ph
Mn (8.0)
Mn (8.0)
Mn (8.0)
Mn (8.0)
9a
9
8b
10a
10b
PhCH2CH2
Ph
9b
11a
11b
10
11
PhCH2CH2
a
Isolated yield.
b
c
No reaction.
(Z)-isomer only.
Z/E = 11:1.
d
CrCl2 (1.5 equiv)
Mn (4.0 equiv)
a,b-unsaturated ester, afforded the fluorovinyl ester 3f in
moderate (49%) yield. Silyl ether moiety (TBDPS ether) was not
affected under the present transformation reaction as shown in the
O
O
F
R
O
CBr2F
R
O
THF, rt
2 h
reaction of
66% yield.
g-silyloxybutylate 1g giving rise to the product 3g in
82%
85%
49%
1d (R = 4-MeOC6H4)
1e (R = 2,4,6-Me3C6H2)
1f (R = PhCH=CH)
3d
3e
3f
5 h
2 h
Since carbonate derivatives can be used as the substrate (Table
1, entries 7–9), we designed 3 -cholesteryl fluoroalkenyl carbon-
b
ate 9 as a model structure of inhibitor for cholesterol esterase
(CEase) [21]. Cholesterol esterase (CEase) catalyzes hydrolysis of
sterol esters into cholesterol and fatty acid resulting in the
elevation of cholestrol level [22,23]. Inhibitor of cholesterol
esterase (CEase) is expected to lower cholesterol level by the
different mechanism from that of the inhibitor of HMG-CoA
reductase, which is responsible for the rate determining step of
CrCl2 (1.5 equiv)
Mn (4.0 equiv)
O
TBDPSO
O
CBr2F
Bn
THF, rt, 5 h
1g
O
F
TBDPSO
O
cholesterol biosynthesis [21]. Several O-3b-cholesteryl N-aryl
Bn
carbamates were reported as a inhibitor of CEase [24]. The starting
substrates 8c–e were prepared in good yields by esterification of
dibromofluoromethylcarbinols with commercially available cho-
lesteryl chloroformate. Transformation into fluoroalkenyl carbo-
nates 9c–e proceeded rather slowly with these substrates 8c–e and
thus, reactions were completed by using 4.0 equiv. of CrCl2 and
8.0 equiv. of Mn powder in THF at room temperature for 24 h to
give 9c in 29%, 9d in 81% and 9e in 97% yield, respectively. Similarly
to other examples, reaction proceeded in Z-selective manner for 9d
and 9e (Scheme 9).
3g 66%
Scheme 8.
Followings are additional examples of the transformation of
dibromofluoroethyl carboxylates using CrCl2/Mn system (Scheme
8). Reaction of 2,4,6-trimethylbenzoate 1e, a sterically bulky
substrate, also proceeded smoothly to give the expected product
3e in high (85%) yield. Under the same conditions, cinnamate 1f,
R1
O
R
Cl
O
FBr2C
OH
Et3N
H
CrCl2 (4.0 equiv)
Mn (8.0 equiv)
R1
O
H
R
F
O
FBr2C
O
O
H
H
THF, rt, 24 h
R1
(R = 3β-cholesteryl)
O
O
8c (R1 = H)
82%
89%
9c 29%
8d (R1 = Ph)
9d
81% (Z only)
97% (Z only)
8e (R1 = PhCH2CH2) quant.
9e
Scheme 9.

42
A. Saito et al. / Journal of Fluorine Chemistry 133 (2012) 38–51
Scheme 10.
O
F
O
F
We found that thiocarbonate is also used in this transformation.
TFA
n-Bu
Ph
n-Bu
Ph
Thus, when the thiocarbonate 8f was reacted under the similar
conditions appliedtothecarbonate8a–b(Table1), therearranged1-
fluorothiovinyl derivative 9f was obtained in 50% yield. This result
indicated that the reaction possibly proceeded via five membered
sulfonium yield intermediate 13 formed by the attack of sulfur atom
on the fluorocarbenoid species 12 (Scheme 10) [7,14].
N
O
N
H
O
CH2Cl2, rt, 10 min
Teoc
11f
11g 95%
Scheme 11.
Next, attempts were made toward chemical modification of
amino acids by introducing N-fluoroalkenyloxycarbonyl group. As
shown before (Table 1) N,N-dimethyl carbamates 10a or 10b,
which does not have a hydrogen atom on the nitrogen atom
performed as a nice substrate providing the desired fluoroalkenyl
carbamates 11a or 11b in moderate yields. However, as shown in
Table 2, it was found that CrCl2/Mn-mediated transformation of N-
H substrates such as 10c or 10d gave a somewhat sluggish mixture
and the expected fluoroalkenyl products 11c and 11d were isolated
only in 12% and 39% yield, respectively (Table 2, entries 2, 3). To
overcome such low yield with N–H substrates, we examined N-
protection. N-Boc group should be the first choice for this purpose
due to the accumulated data as the most common N-protective
group concerning its introduction, reactivity and deprotection. As
expected, reaction of N-Boc N-isopropyl derivative 10e under the
standard conditions proceeded much more cleanly to give the
rearranged product 11e in 51% yield (entry 4). Likewise, the use of
N-2-(trimethylsilyl)ethyloxycarbonyl (Teoc) was also effective.
That is, N-Teoc N-butyl derivative 10f was converted to the
fluoroalkenyl carbamate 11f in 65% yield (entry 5).
Deprotection of these Boc and Teoc group can be performed by
treating with trifluoroacetic acid (TFA) without a remarkable affect
on fluoroalkenyl ester moiety. For example, treatment of the N-
Teoc derivative 11f with TFA (6 equiv.) in CH2Cl2 at room
temperature for 10 min gave the deprotected N–H compound
11g in 95% yield (Scheme 11) [25]. Deprotection of N-Boc group
was also achieved by the conventional conditions such as TAF
treatment at room temperature as shown in the case of glycine
derivative (see Scheme 13).
As the structurally simplest amino acid, sarcosine (N-methyl-
glycine) methyl ester was selected. Three dibromofluoromethyl-
carbinyl carbamates 10h–j were prepared by esterification
reaction with N-chloroformyl intermediate generated by treating
sarcosine methyl ester with triphosgene (see Section 4). CrCl2/Mn-
mediated transformation proceeded smoothly to give the products
11h–j in good yields with Z selective manner for 11i and 11j
(Scheme 12). Unfortunately, selective conversion of methyl ester to
free acid form was difficult under both basic and acidic conditions.
Above results suggested that for the preparation of N-1-fluoro-
1-alkenyloxycarbonyl a-amino acids as its N-H and free acid form
such as glycine derivative 15, protection of both amino group and
carboxyl group is required at the Cr(II)-mediated transformation
step. On the basis of successful deprotection of 2-(trimethylsily-
l)ethyl ester (TMSE ester) by TFA within a short period (Scheme
11), we examine the use of N-Boc glycine TMSE ester 10k as a
model substrate. Scheme 13 illustrates the whole reaction steps.
Esterification of N-Boc-glycine with 2-(trimethylsilyl)ethanol in
the presence of EDCꢀHCl (96% yield) followed by chloroformylation
with triphosgene and pyridine gave the crude carbamoyl chloride
14, which in turn was reacted with dibromofluoromethylphenyl-
carbinol to give 10k in 82% yield. Reaction of 10k with CrCl2/Mn
system proceeded smoothly to give the rearranged product 11k in
65% yield. Deprotection of both N-Boc group and TMSE ester was
effected by TFA treatment for 15 min without the use of solvent
and the desired final product 15 was isolated in 70% yield (Scheme
13). When the TFA treatment was carried out in CH2Cl2, N-Boc
group was deprotected prior to TMSE ester moiety.
Table 2
Preparation of 1-fluoro-1-alkenyl carbamates.
CrCl2 (4.0 equiv)
Mn (8.0 equiv)
O
F
O
R
R1
R
R1
N
O
N
O
CBr2F
R2
R2
THF, rt
10
11
Entry
10
R
R1
R2
Time (h)
11
Yielda (%)
1b
2
10a
10c
10d
10e
10f
Ph
H
Me
Me
H
23
16
18
24
20
11a
11c
11d
11e
11f
61c
12
n-Pr
n-Pr
i-Pr
3
Ph
H
H
39d
51
4
Boce
Teocf
5
Ph
n-Bu
65d
a
Isolated yield.
Table 1, entry 10.
Z/E = 11:1.
b
c
d
e
f
(Z)-isomer only.
tert-Butyloxycarbonyl.
2-(Trimethylsilyl)ethyloxycarbonyl.

A. Saito et al. / Journal of Fluorine Chemistry 133 (2012) 38–51
43
O
R
F
O
CrCl2 (4.0 equiv)
Mn (8.0 equiv)
OMe
R
OMe
Br2FC
O
N
O
N
THF, rt
Me
O
Me
O
10h (R = H)
10i (R = Ph)
10j (R = PhCH2CH2)
11h 69%
11i 82% (Z only)
11j 75% (Z only)
Scheme 12.
O
O
Ph
a), b)
c)
O
OTMSE
Boc-Gly-OH
Cl
N
SiMe3
Ph
Br2FC
O
N
Boc O
14
Boc O
10k
F
O
F
O
d)
e)
Ph
OTMSE
OH
O
N
H
O
N
O
Boc O
11k (Z only)
15
Scheme 13. Reagents and conditions: a) 2-(trimethylsilyl)ethanol, EDCꢀHCl, CH2Cl2, rt, 3 h, 96%); b) triphosgene, pyridine, CH2Cl2, ꢁ30 8C to rt, 24 h; c) CBr2FCH(Ph)OH, Et3N,
DMAP, THF, rt, 24 h, 81% (2 steps); d) CrCl2 (2.0 equiv.), Mn (8.0 equiv.), THF, rt, 24 h, 65%; e) TFA, rt, 15 min, 70%.
As described above, we have developed a facile synthetic
procedure for a variety type of 1-fluoro-1-alkenyl esters through
the Cr(II)-mediated ester rearrangement of dibromofluoromethyl-
carbinyl esters. In particular, a successful synthesis of cholesterol
and amino acid derivatives would attract much interests in the
field of bioorganic and medicinal chemistry.
(dodecane-1-thiol) and a primary alcohol (benzyl alcohol). In
the presence of triethylamine (2 equiv.), reaction of the fluorovinyl
benzoate 3a with dodecane-1-thiol (2 equiv.) in THF at room
temperature for 14 h provided the benzoly 16b and acetyl thiol
ester 17b in 87% and 83% yield, respectively. In the case of benzyl
alcohol (2 equiv. in the presence of 1.2 equiv. of Et3N), while the
reaction did not proceed at room temperature, at 40 8C for 21 h in
THF the reaction completed giving rise to the benzoate 16c in 82%
and the acetate 17c in 60% yield, respectively. These examples
clearly indicated that 1-fluoro-1-alkenyl ester 3a shows a similar
reactivity to that of methyl or ethyl benzoate. Furthermore, nearly
equal production of benzoyl and acetyl derivatives (16 and 17) in
the reaction with these nucleophiles (2 equiv.) indicated that the
fluoroalkenyl moiety also acts as a highly reactive acetyl donor
(Table 3).
The results mentioned above clearly indicated that 1-fluoro-1-
alkenyl ester 3 can act as a double acylating reagent via stepwise
reactions. Thereby, if the acyl transfer reaction of 1-fluoro-1-
alkenyl ester with a bifunctional nucleophile proceeds selectively
at one of the two nucleophilic centers for the first step, subsequent
acylation of the other nucleophilic center by the acyl fluoride
generated in situ would result in the unsymmetrical diacylation of
the bifunctional substrate. Path a in Scheme 14 shows an example
using ethylene diamine as a model nucleophile. In Scheme 14, path
2.2. Reaction of 1-fluoro-1-alkenyl ester with nucleophiles
As mentioned before (Scheme 3), it is expected that nucleo-
philic cleavage of 1-fluoro-1-alkenyl ester such as by aminolysis or
alcoholysis would provide the corresponding acyl fluoride, which
further acts as a reactive acylating reagent. If such a reaction can be
performed by a certain hydrolytic enzymes (esterase and peptidase
e.g.), irreversible inhibition of the enzyme by the acylation of the
nucleophilic center in the enzyme can be possibly realized. To
confirm chemically that 1-fluoro-1-alkenyl ester can serve as a
double acylating reagent, we conducted the reaction of 1-
fluorovinyl benzoate 3a with a primary amine, thiol and alcohol
under neutral or slightly basic conditions.Reaction of 1-fluorovinyl
benzoate 3a with benzylamine (2 equiv.) in the presence of
triethylamine as HF scavenger proceeded at room temperature to
give the benzamide 16a and acetoamide 17a in 92% and 91% yield,
respectively. Similar results were obtained on using a thiol
Table 3
Reaction of 1-fluorovinyl benzoate 3a with nucleophiles.
Et3N
THF
O
F
O
O
Nu
H
Ph
O
Ph
Nu
Me
Nu
(2.0 equiv)
3a
16
17
(Nu = BnNH, n-C12H25S, BnO)
.
Entry
Nu–H
Et3N (equiv.)
Temp. (8C)
Time (h)
Yielda (%)
16
17
1
2
3
BnNH2
1.0
2.0
1.2
rt
19
14
21
16a
16b
16c
92
87
82
17a
17b
17c
91
83
60
n-C12H25SH
BnOH
rt
40
a
Isolated yield.

44
A. Saito et al. / Journal of Fluorine Chemistry 133 (2012) 38–51
O
O
H
N
O
O
path a
Me
Ph
Ph
N
H
a
NH
Me
F
2
O
F
H N
2
O
O
18a (major)
Ph
O
NH2
b
F
Ph
N
H
3a
H
path b
path c
N
Ph
Ph
O
N
H
O
19a (minor)
NH
2
O
F
O
F
H N
2
Ph
O
Ph
O
3a
3a
Nu1
Nu2
NH2
=
H2N
bifunctional
nucleophiles
H2N
NH2
Scheme 14.
b and path c would be possible competitive reactions leading to the
symmetrically diacylated product 19a, where path b shows a
stepwise reaction and path c shows that both nucleophilic centers
react almost at the same time. For the ease of analysis of the
products, we chose symmetrical bifunctional nucleophiles such as
ethylene diamine and trans-cyclohexane 1,2-diamine as the model
substrates.
Reaction of 3a with ethylene diamine (1.0 equiv.) in the
presence of triethylamine (1.2 equiv.) in THF (0.125 M of 3a) at
room temperature for 21 h led to the isolation of unsymmetrically
diacylated amide 18a in 46% yield accompanying the dibenzoy-
lated amide 19a in 15% yield, thus the ratio of 18a and 19a was
3.1:1 (entry 1, Table 4). Similar results were obtained by changing
the concentration of the substrate (0.5 M of 3a, rt, 21 h; 18a (46%):
19a (18%) = 2.6:1, entry 2) or by lowering the reaction temperature
(Et3N 2.0 equiv., 0 8C, 21 h; 18a (40%): 19a (15%) = 2.6:1, entry 4). It
is obvious that low selectivity of unsymmetrical diacylation is due
to the competitive benzoylation of both amino groups at the same
time rather than the ideal stepwise reaction, since ethylene
diamine is
a sterically unhindered bifunctional nucleophile
resulting in the facile approach of both amino groups to the ester
carbonyl group of 3a (path c in Scheme 14).
To achieve a higher selectivity, we examined trans-cyclohexane
1,2-diamine as a conformationally more rigid and sterically more
crowded nucleophile. As expected, reaction of 3a with trans-
cyclohexane 1,2-diamine (1.0 equiv.) in the presence of Et3N
(2.0 equiv.) in THF (0.125 M of 3a) at room temperature for 11 h
gave the unsymmetrically diacylated amide 18b (56% yield) and
dibenzoylated amide 19b (5% yield) in a ratio 11: 1 (Scheme
15).Although more data are required to see the insight of the
present double acylation reaction of bifunctional nucleophiles,
structure design of nucleophile is one of the important factors to
realize a stepwise acyl transfer reaction. As an alternative design of
the 1-fluoro-1-alkenyl ester compound, we examined O-protected
Table 4
Survey of reaction conditions for desymmetrization of ethylene diamine with 3a.
O
O
H
N
H
Et3N
O
F
NH2
Me
N
Ph
H2N
(1.0 equiv)
Ph
N
H
Ph
N
H
THF, 21 h
Ph
O
O
O
3a
18a
19a
Entry
Concentration of 3a (mol Lꢁ1
)
Et3N (equiv.)
Temp. (8C)
Yielda (%)
18a/19ab
18a
19a
1
2
3
4
0.125
0.5
1.2
1.2
1.2
2.0
rt
rt
rt
0
46
46
42
40
15
18
19
15
3.1:1
2.6:1
2.2:1
2.6:1
0.25
0.25
a
Isolated yield.
b
Based on isolated yield.
Et3N (2.0 eq)
O
F
O
O
O
O
Ph
O
NH HN
NH HN
19b 5%
THF (0.125 M)
rt, 11 h
H2N
NH2
Ph
Me
Ph
Ph
(1.0 equiv)
3a
18b 56%
Scheme 15.

A. Saito et al. / Journal of Fluorine Chemistry 133 (2012) 38–51
45
F
O
O
F
F
Nu
Nu-H
F
R
R
F
O
O
R
R
O
O
O
O
O
21
Si
23
20
O
22
Scheme 16.
MeO
OMe
F
O
O
p-anisidine (1.0 equiv)
O
O
N
THF (0.125 M)
0 °C, 2 h, then rt, 2 h
N
H
H
Bn OTBDPS
Bn OR
3g
24-Si (R = TBDPS) 22 %
24-H (R = H) 7 %
23a 29%
p-anisidine (1.0 equiv)
TBAF (2.0 equiv)
OMe
O
O
Bn
TBDPS-F
3g
TBDPS-OH
O
N
H
THF (0.125 M)
0°C, 2 h, then rt, 2 h
23a 57%
22a 30%
25 40%
26 46%
Scheme 17.
4-hydroxybutanoyl derivative 20 (Scheme 16). With such a
substrate selective O-deprotection to generate an alkoxide form
acetyl fluoride, which finally reacted with the co-existing
nucleophile p-anisidine (Scheme 17).
21 would initiate the intramolecular lactonization to give
g-
butyrolactone 22 accompanying the in situ generation of acyl
fluoride, which in turn reacts with a co-existing nucleophile giving
rise to the product 23. Reaction of silyl ether with fluoride
(tetrabutylammonium fluoride: TBAF) would be expected to
realize a selective cleavage of O-protection to generate the
alkoxide form as shown in Scheme 16.
3. Conclusion
We have developed an efficient procedure for the stereo-
selective synthesis of (Z)-1-fluoro-1-alkenyl esters through the
CrCl2/Mn-mediated reaction of dibromofluoromethylcarbinyl
esters including carboxylates, carbonates and carbamates. Fur-
thermore, we demonstrated that nucleophilic acyl substitution of
1-fluoro-1-alkenyl ester with amines and alcohols delivers acyl
fluoride which act as the second acylating reagent in the same
reaction system. These results and a successful synthesis of
cholesterol and amino acid derivatives would provide important
informations toward to the molecular design of inhibitors for
hydrolytic enzymes.
For the ease of handling of the products benzyl group was
introduced at
a position of the model ester substrate 3g (Scheme
17). As a control experiment we checked a suitable nucleophile for
this substrate. We found that reaction of 1-fluorovinyl ester 3g
having tert-butyldiphenylsilyl (TBDPS) ether moiety with p-
anisidine proceeded fairly slowly as compared to that with
primary alkylamine such as benzylamine. That is, treatment of
3g with p-anisidine (1 equiv.) in THF at 0 8C for 2 h, then at room
temperature for 2 h gave the three amides 24-Si, 24-H and 23a in
22%, 7% and 29% yield, respectively accompanying the recovery of
3 g (ca 60%). The isolated amides 24-Si and 24-H were derived by
nucleophilic attack of p-anisidine on ester carbonyl group of 3g and
the acetyl derivative 23a was formed by the reaction of p-anisidine
with in situ generated acetyl fluoride. The ratio of 24-Si/24-H and
23a was 1:1 indicating that an almost single reaction course
(aminolysis of 3g and the subsequent acetylation by acetyl
fluoride) was involved in this case. Next, fluoride-promoted O-
desilylation reaction in the presence of p-anisidine was conducted.
Thus, on using TBAF (2 equiv., 1 M THF solution) complete
consumption of 3g was observed and the expected lactone
compound 22a and the acetoanilide derivative 23a were isolated
in 30% and 57% yield, respectively. TBDPS-F 25 and TBDPS-OH 26
were also isolated in 40% and 46% yield, indicating the complete
cleavage of silyl ether bond. In this case, direct aminolysis of 3g by
p-anisidine was possibly excluded due the absence of the anilide
24-Si and/or 24-H in the reaction mixture. As a consequence, the
main reaction course involved the stepwise O-desilylation by TBAF
followed by the intramolecular lactonization and the liberation of
4. Experimental
4.1. General
All reactions were carried out under argon atmosphere. 1H and
13C NMR spectra were taken on a Bruker dpx400 spectrometer or
Varian Mercury 300 spectrometer, and chemical shifts were
reported in parts per million (ppm) using CHCl3 (7.26 ppm) in
CDCl3 for 1H NMR, and CDCl3 (77.01 ppm) for 13C NMR as an
internal standard, respectively. 19F NMR spectra were taken on a
Bruker dpx400 spectrometer, and chemical shifts were reported in
parts per million using benzotrifluoride as a standard. Infrared (IR)
spectra were recorded on a JASCO FT/IR-620 infrared spectropho-
tometer. Mass spectra (MS) were obtained on a VG Auto Spec (EI)
and a Micromass LCT (ESI-TOF). Medium pressure liquid chroma-
tography (MPLC) was performed using prepacked column (silica
gel, 50
mm) with UV or RI detector. Anhydrous CrCl2 was
purchased from Aldrich. 2,2-Dibromo-2-fluoroethanol was pre-
pared by LiBH4 reduction of ethyl dibromofluoroacetate in the
presence of (MeO)3B [5]. 2,2-Dibromo-2-fluoro-1-phenylethanol

46
A. Saito et al. / Journal of Fluorine Chemistry 133 (2012) 38–51
and 1,1-dibromo-1-fluoro-4-phenylbutan-2-ol were prepared
according to the reported procedure [26,27].
4.2.6. 2,2-Dibromo-2-fluoroethyl-2-benzyl-4-(tert-
butyldiphenylsilyloxy)butanoate (1g)
60% yield; colorless oil; IR (neat)
n
2931, 2854, 1752, 1146,
1.04 (9H, s),
4.2. General procedure for the preparation of
1109, 741, 702 cmꢁ1 1H NMR (400 MHz, CDCl3)
;
d
dibromofluoromethylcarbinyl esters (1, 8 and 10)
1.78–1.82 (1H, m), 1.98–2.05 (1H, m), 2.83 (1H, dd, J = 13.5, 6.9 Hz),
3.03 (1H, dd, J = 13.5, 7.9 Hz), 3.06–3.17 (1H, m), 3.71 (2H, t,
J = 6.1 Hz), 4.53–4.68 (2H, m), 7.16–7.24 (3H, m), 7.26–7.31 (2H,
m), 7.36–7.41 (6H, m), 7.60–7.64 (4H, m); 13C NMR (100 MHz,
A
mixture of the dibromofluoroalcohol (1.0 equiv.), acid
chloride (1.1–1.5 equiv.) and triethylamine (2.2–3.0 equiv.) in
THF was stirred for 1 h at 0 8C, then for additional appropriate
period (usually 2–3 h) at room temperature. As in the cases of 1e,
1f, 8c–e catalytic amount of 4-dimethylaminopyridine was also
added. Usual workup (addition of water, extraction with diethyl
ether or ethyl acetate, dried over MgSO4) followed by purification
by silica gel column chromatography (mixture of hexane and
EtOAc as eluent) gave the corresponding ester.
CDCl3)
d 19.2, 26.8, 34.2, 38.1, 43.8, 61.5, 72.1 (d, JC–F = 22.4 Hz),
91.0 (d, JC–F = 321.1 Hz), 126.5, 127.7, 128.5, 129.0, 129.64 and
129.66, 133.56 and 133.64, 135.53 and 135.57, 138.6, 173.5; 19F
NMR (376.5 MHz, CDCl3)
d 3.3 (1F, t, JF–H = 15.7 Hz); HRMS (ESI-
TOF) calcd for C29H34Br2FO3Si [M+H]+, 635.0628; found, 635.0619;
Anal. calcd for C29H33Br2FO3Si: C, 54.73; H, 25.23. Found: C, 54.90;
H, 5.36.
4.2.1. 2,2-Dibromo-2-fluoroethyl benzoate (1a) [7]
4.2.7. 2,2-Dibromo-2-fluoro-1-phenylethyl ethyl carbonate (8a)
96% yield; colorless semi-solid; Mp. 27.0–28.0 8C; IR (neat)
1735 cmꢁ1; 1H NMR (400 MHz, CDCl3)
4.98 (2H, d, JH–F = 15.4 Hz),
7.46–7.51 (2H, m), 7.60–7.64 (1H, m), 8.11–8.13 (2H, m). 13C NMR
(100 MHz, CDCl3) 72.7 (d, JC–F = 22.6 Hz), 91.2 (d, JC–F = 320.9 Hz),
128.6, 128.7, 130.1, 133.8, 164.7. 19F NMR (376.5 MHz, CDCl3)
3.2
(1F, t, JF–H = 15.4 Hz). HRMS (EI) calcd for C9H7Br2FO2 [M]+,
323.8797; found, 323.8799; Anal. calcd for C9H7Br2FO2: C,
33.16; H, 2.16. Found: C, 33.20; H, 2.30.
n
92% yield; colorless oil; IR (neat)
1092, 1006, 786, 699 cmꢁ1; 1H NMR (400 MHz, CDCl3)
J = 7.1 Hz), 4.21–4.31 (2H, m), 6.12 (1H, d, JH–F = 11.9 Hz), 7.38–
7.58 (5H, m); 13C NMR (100 MHz, CDCl3)
14.2, 65.3, 84.6 (d, JC–
F = 2.9 Hz), 96.1 (d, JC–F = 322.5 Hz), 128.3, 129.1, 129.9, 132.4,
n
2984, 1757, 1456, 1253,
d
d
1.34 (3H, t,
d
d
d
153.4; 19F NMR (376.5 MHz, CDCl3)
d-0.7 (1F, d, JF–H = 11.9 Hz); MS
(EI) m/z 368 [M]+, 370 [M+2]+, 372 [M+4]+; Anal. calcd for
C11H11Br2FO3: C, 35.71; H, 3.00. Found: C, 36.09; H, 3.21.
4.2.2. 2,2-Dibromo-2-fluoro-1-phenylethyl acetate (1b)
4.2.8. 1-[Dibromo(fluoro)methyl]-3-phenylpropyl ethyl carbonate
82% yield; colorless oil; IR (neat)
1217, 1201, 1061, 781, 696 cmꢁ1; 1H NMR (400 MHz, CDCl3)
(3H, s), 6.31 (1H, d, JH–F = 12.8 Hz), 7.37–7.55 (5H, m); 13C NMR
(100 MHz, CDCl3) 20.8, 81.3 (d, JC–F = 22.5 Hz), 96.6 (d, JC–
F = 322.9 Hz), 128.2, 129.2, 129.7, 132.9, 168.5; 19F NMR
n
3037, 2937, 2849, 1761,
(8b)
d
2.22
71% yield; colorless oil; IR (neat)
1756, 1496, 1456, 1247, 1123, 1028, 783, 698 cmꢁ1
(400 MHz, CDCl3) 1.37 (3H, t, J = 7.1 Hz), 2.16–2.24 (1H, m), 2.33–
2.39 (1H, m), 2.69–2.86 (2H, m), 4.29 (2H, q, J = 7.1 Hz), 5.22 (1H,
ddd, JH–H = 9.2, 1.5 Hz, JH–F = 8.3 Hz), 7.21–7.33 (5H, m); 13C NMR
n
3028, 2983, 2937, 2865,
.
1H NMR
d
d
(376.5 MHz, CDCl3) d–0.3 (1F, d, JF–H = 12.8 Hz); MS (EI) m/z 338
[M]+, 340 [M+2]+, 342 [M+4]+; Anal. calcd for C10H9Br2FO2: C,
35.33; H, 2.67. Found: C, 35.54; H, 2.88.
(100 MHz, CDCl3)
97.1 (d, JC–F = 321.5 Hz), 126.4, 128.4, 128.6, 140.0, 154.1; 19F NMR
(376.5 MHz, CDCl3) 2.2 (1F, d, JF–H = 8.3 Hz); HRMS (EI) calcd for
13H15Br2FO3 [M]+, 395.9372; found, 395.9366.
d 14.2, 31.3, 32.5, 65.2, 82.6 (d, JC–F = 21.9 Hz),
d
4.2.3. 2,2-Dibromo-2-fluoroethyl 4-methoxybenzoate (1d)
C
70% yield; colorless solid; Mp. 50.0–51.2 8C; IR (neat)
1721, 1606, 1262, 1064, 1023, 768 cmꢁ1 1H NMR (400 MHz,
CDCl3) 3.88 (3H, s), 4.96 (2H, d, JH–F = 15.5 Hz), 6.96 (2H, d,
J = 9.0 Hz), 8.08 (2H, d, J = 9.0 Hz); 13C NMR (100 MHz, CDCl3)
55.5, 72.6 (d, JC–F = 22.8 Hz), 91.5 (d, JC–F = 320.8 Hz), 113.9, 121.1,
n 2972,
;
4.2.9. 2,2-Dibromo-2-fluoroethyl (3S,10R,13R,17R)-17-[(1R)-1,5-
dimethylhexyl]-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15,16,17-
tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl carbonate (8c)
d
d
82% yield; colorless amorphous solid; [
CHCl3); Mp. 110–111 8C; IR (KBr)
1749 cmꢁ1; 1H NMR (400 MHz,
CDCl3) 0.68 (3H, s), 0.86 (3H, d, J = 6.6 Hz), 0.87 (3H, d. J = 6.6 Hz),
a]
25–23.1 (c = 1.0,
D
132.2, 164.1, 164.4; 19F NMR (376.5 MHz, CDCl3)
d
3.3 (1F, t, JF–
n
H = 15.5 Hz); MS (EI) m/z 354 [M]+, 356 [M+2]+, 358 [M+4]+; Anal.
d
calcd for C10H9Br2FO3: C, 33.74; H, 2.55. Found: C, 33.77; H, 2.65.
0.91 (3H, d, J = 6.5 Hz), 0.94–2.04 (29H, m), 2.42 (2H, brd,
J = 7.8 Hz), 4.49–4.58 (1H, m), 4.77 (2H, d, JH–F = 15.5 Hz), 5.41
(1H, brd, J = 4.2 Hz); 13C NMR (100 MHz, CDCl3)
d 11.9, 18.7, 19.3,
4.2.4. 2,2-Dibromo-2-fluoroethyl 2,4,6-trimethylbenzoate (1e)
79% yield; colorless oil; IR (neat)
1165, 1053 cmꢁ1 1H NMR (400 MHz, CDCl3)
(6H, s), 4.99 (2H, d, JH–F = 15.6 Hz), 6.89 (2H, s); 13C NMR (100 MHz,
CDCl3) 20.2, 21.1, 72.8 (d, JC–F = 22.5 Hz), 90.7 (d, JC–F = 321.1 Hz),
128.7, 129.1, 136.0, 140.2, 168.0; 19F NMR (376.5 MHz, CDCl3)
3.1
(1F, t, JF–H = 15.6 Hz); MS (EI) m/z 366 [M]+, 368 [M+2]+, 370
[M+4]+; Anal. calcd for C12H13Br2FO2: C, 39.16; H, 3.56. Found: C,
39.28; H, 3.69.
n
2956, 2924, 1740, 1246,
21.0, 22.6, 22.8, 23.8, 24.3, 27.5, 28.0, 28.2, 31.8, 31.9, 35.8, 36.2,
36.5, 36.8, 37.8, 39.5, 39.7, 42.3, 50.0, 56.1, 56.7, 74.9 (d, JC–
F = 22.4 Hz),79.4, 90.6 (d, JC–F = 321.2 Hz), 123.3, 139.0, 153.1; 19F
;
d
2.30 (3H, s), 2.36
d
NMR (376.5 MHz, CDCl3) d 2.2 (1F, t, JF–H = 15.5 Hz); MS (EI) m/z
d
396 [M–C3H2Br2FO3]+; Anal. calcd for C30H47Br2FO3: C, 56.79; H,
7.47. Found: C, 56.79; H, 7.26.
4.2.10. 2,2-Dibromo-2-fluoro-1-phenylethyl (3S,10R,13R,17R)-17-
[(1R)-1,5-dimethylhexyl]-10,13-dimethyl-
4.2.5. 2,2-Dibromo-2-fluoroethyl cinnamate (1f)
2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-
cyclopenta[a]phenanthren-3-yl carbonate (8d)
78% yield; colorless oil; IR (neat)
766 cmꢁ1; 1H NMR (400 MHz, CDCl3)
6.52 (1H, d, J = 16.0 Hz), 7.40–7.43 (3H, m), 7.56–7.58 (2H, m), 7.82
(1H, d, J = 16.0 Hz); 13C NMR (100 MHz, CDCl3)
72.3 (d, JC–
F = 22.3 Hz), 91.3 (d, JC–F = 320.9 Hz), 116.2, 128.4, 129.0, 130.8,
133.9, 147.1, 165.0; 19F NMR (376.5 MHz, CDCl3)
3.3 (1F, t, JF–
H = 15.7 Hz); HRMS (ESI-TOF) calcd for C11H10Br2FO2 [M+H]+
n
1725, 1635, 1148, 921,
d
4.89 (2H, d, JH–F = 15.7 Hz),
89% yield (a mixture of diastereomers in a ratio of 1:1); colorless
amorphous solid; Mp. 126–127 8C; IR (KBr)
(400 MHz, CDCl3) 0.68 (3H, s), 0.86 (3H, d, J = 6.6 Hz), 0.87 (3H, d.
n
1690 cmꢁ1; 1H NMR
d
d
J = 6.6 Hz), 0.92 (3H, d, J = 6.5 Hz), 0.95–2.05 (29H, m), 2.34–2.49
(2H, m), 4.47–4.55 (1H, m), 5.38 (1H, dd, J = 24.0, 0.5 Hz), 6.13 (1H,
d, JH–F = 12.0 Hz), 7.39–7.58 (5H, m); 13C NMR (100 MHz, CDCl3)
d
d
,
350.9032; found, 350.9060; Anal. calcd for C11H9Br2FO2: C, 37.53;
H, 2.58. Found: C, 37.83; H, 2.76.
11.9, 18.7, 19.3, 21.0, 22.6, 22.8, 23.8, 24.3, 27.5, 27.6, 28.0, 28.2,
31.8, 31.9, 35.8, 36.2, 36.5, 36.8, 37.8, 39.5, 39.7, 42.3, 50.0, 56.1,

A. Saito et al. / Journal of Fluorine Chemistry 133 (2012) 38–51
47
56.7, 79.4, 84.4 (d, JC–F = 23.3 Hz), 84.5 (d, JC–F = 22.6 Hz), 96.2 (d,
JC–F = 323.0 Hz), 96.2 (d, JC–F = 322.5 Hz), 123.2, 123.2, 128.3, 129.1,
4.2.16. 2,2-Dibromo-2-fluoro-1-phenylethyl propylcarbamate (10d)
Similar to 10c, this compound was prepared from 2,2-dibromo-
2-fluoro-1-phenylethanol, n-propylisocyanate and triethylamine.
129.9, 132.4, 139.1, 152.8; 19F NMR (376.5 MHz, CDCl3)
d-0.6 (0.5F,
d, J = 12.0 Hz),–0.7 (0.5F, d, J = 12.0 Hz).
Colorless oil; IR (neat)
CDCl3) 0.92 (3H, t, J = 7.4 Hz), 1.49–1.58 (2H, m), 3.12–3.23 (2H,
m), 5.07 (1H, br.s), 6.23 (1H, d, JH–F = 12.2 Hz), 7.37–7.54 (5H, m);
13C NMR (100 MHz, CDCl3)
11.1, 23.0, 43.0, 81.8 (d, JC–
F = 22.7 Hz), 97.5 (d, JC–F = 322.7 Hz), 128.1, 129.0, 129.5, 133.3,
n ;
3422, 1718 cmꢁ1 1H NMR (400 MHz,
d
4.2.11. 1-[Dibromo(fluoro)methyl]-3-phenylpropyl
(3S,10R,13R,17R)-17-[(1R)-1,5-dimethylhexyl]-10,13-dimethyl-
2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-
cyclopenta[a]phenanthren-3-yl carbonate (8e)
d
153.9; 19F NMR (376.5 MHz, CDCl3)
d 0.4 (1F, d, JF–H = 12.2 Hz);
98% yield (a mixture of diastereomers in a ratio of 1:1); colorless
HRMS (ESI-TOF) calcd for C12H15Br2FNO2 [M+H]+, 381.9454; found,
381.9475.
solid; Mp. 88–90 8C; IR (KBr)
CDCl3) 0.69 (3H, s), 0.87 (3H, d, J = 6.6 Hz), 0.88 (3H, d. J = 6.6 Hz),
n ;
1753 cmꢁ1 1H NMR (400 MHz,
d
0.93 (3H, d, J = 6.5 Hz), 0.95–2.04 (29H, m), 2.12–2.41 (4H, m),
2.66–2.86 (2H, m), 4.52–4.59 (1H, m), 5.22 (1H, ddd, JH–
F = 9.2 Hz, JH–H = 9.2, 2.0 Hz), 5.43 (1H, brs), 7.21–7.33 (5H, m);
4.2.17. tert-Butyl 2,2-dibromo-2-fluoroethyl
isopropyldicarbonimidoate (10e)
A
mixture of 10d (2.0 mmol), di-tert-butyldicarbonate
13C NMR (100 MHz, CDCl3)
d
11.9, 18.7, 19.3, 21.1, 22.6, 22.8, 23.8,
(5.0 mmol) and DMAP (5 mg) in THF was stirred for 24 h at room
temperature and the following purification by silica gel column
chromatography (hexane/EtOAc = 50:1) gave 10e (1.75 mmol, 87%
24.3, 27.5, 28.0, 28.2, 31.3, 31.8, 31.9, 32.5, 35.8, 36,2, 36.5, 36.8,
36.8, 37.8, 39.5, 39.7, 42.3, 50.0, 56.2, 56.7, 79.2, 82.5 (d, JC–
F = 22.3 Hz), 97.2 (d, JC–F = 321.8 Hz), 123.2, 126.4, 128.4, 128.6,
yield). Colorless oil; IR (neat)
(400 MHz, CDCl3) 1.35 (6H, d, J = 6.8 Hz), 1.52 (9H, s), 4.48
(1H, septet, J = 6.8 Hz), 4.82 (1H, d, JH–F = 15.8 Hz); 13C NMR
(100 MHz, CDCl3) 20.4, 27.9, 49.9, 73.8 (d, JC–F = 22.0 Hz), 83.5,
90.7 (d, JC–F = 321.2 Hz), 152.1, 152.2; 19F NMR (376.5 MHz, CDCl3)
3.1 (1F, t, JF–H = 15.8 Hz); HRMS (ESI-TOF) calcd for
n .
1750, 1712 cmꢁ1 1H NMR
139.0, 139.1, 140.0, 153.5; 19F NMR (376.5 MHz, CDCl3)
d
2.1 (0.5F,
d, JH–F = 9.2 Hz), 2.1 (0.5F, d, JH–F = 9.2 Hz); Anal. calcd for
38H55Br2FO3: C, 61.79; H, 7.51. Found: C, 61.94; H, 7.32.
d
C
d
4.2.12. O-(2,2-Dibromo-2-fluoroethyl) O-phenyl carbonothioate (8f)
98% yield; pale yellow oil; IR (neat)
1289 cmꢁ1 1H NMR
(400 MHz, CDCl3) 5.18 (1H, d, JH–F = 15.0 Hz), 7.15–7.47 (5H, m);
13C NMR (100 MHz, CDCl3)
79.8 (d, JC–F = 22.5 Hz), 89.0 (d, JC–
F = 321.4 Hz), 121.6, 126.9, 129.7, 153.4, 193.3; 19F NMR
d
n
;
C11H18Br2FNNaO2 [M+Na]+, 427.9498; found, 427.9521; Anal.
calcd for C11H18Br2FNO4: C, 32.46; H, 4.46; N, 3.44. Found: C,
32.66; H, 4.57; N, 3.35.
d
d
(376.5 MHz, CDCl3)
[M–C2H2Br2F]+.
d
2.7 (1F, t, JF–H = 15.0 Hz); MS (EI) m/z 203
4.2.18. 2,2-Dibromo-2-fluoro-1-phenylethyl 2-(trimethylsilyl)ethyl
butyldicarbonimidoate (10f)
Under argon atmosphere at ꢁ30 8C, to triphosgene (1.0 M
solution in CH2Cl2, 1.0 mL, 1.0 mmol) was added a mixture of 2-
(trimethylsilanyl)ethyl butylcarbamate (217 mg, 1.0 mmol) and
pyridine (0.25 mL, 3.0 mmol) in CH2Cl2 (2 mL) and then, the
reaction mixture was stirred for 21 h, during these period
temperature raised slowly to room temperature. Extractive work
up (addition of iced water, Et2O for extraction, dried over MgSO4)
followed by concentration under reduced pressure gave the crude
carbamoyl chloride. A mixture of the crude carbamoyl chloride,
4.2.13. 2,2-Dibromo-2-fluoro-1-phenylethyl dimethylcarbamate
(10a)
84% yield; colorless oil; IR (neat)
(400 MHz, CDCl3) 2.95 (3H, s), 3.10 (3H, s), 6.23 (1H, d, JH–
F = 11.3 Hz), 7.35–7.56 (5H, m); 13C NMR (100 MHz, CDCl3)
36.0,
36.8, 82.4 (d, JC–F = 23.0 Hz), 97.7 (d, JC–F = 322.5 Hz), 128.1, 129.0,
n ;
1723 cmꢁ1 1H NMR
d
d
129.5, 133.4, 153.9; 19F NMR (376.5 MHz, CDCl3)
d 0.8 (1F, d, JF–
H = 11.3 Hz); HRMS (ESI-TOF) calcd for C11H13Br2FNO2 [M+H]+,
367.9297; found, 367.9288.
2,2-dibromo-2-fluoro-1-phenylethanol
(300 mg,
1.0 mmol),
triethylamine (0.28 mL, 2.0 mmol) and DMAP (5 mg) in THF
(2 mL) and CH2Cl2 (1 mL) was stirred for 24 h at room temperature.
Extractive work up (addition of iced water, Et2O for extraction,
dried over MgSO4) followed by purification by silica gel column
chromatography (hexane/EtOAc = 50: 1) gave 10f (387 mg, 72%
4.2.14. 1-[Dibromo(fluoro)methyl]-3-phenylpropyl
dimethylcarbamate (10b)
67% yield; colorless oil; IR (neat)
(400 MHz, CDCl3) 2.06–2.42 (2H, m), 2.77 (2H, t, J = 7.9 Hz), 2.95
(3H, s), 2.98 (3H, s), 5.35 (1H, ddd, JH–H = 10.1, 2.4 Hz, JH–F = 7.7 Hz),
7.18–7.34 (5H, m); 13C NMR (100 MHz, CDCl3)
31.4, 32.8, 35.9,
36.8, 80.4 (d, JC–F = 21.9 Hz), 98.8 (d, JC–F = 322.0 Hz), 126.2, 128.4,
n ;
1720 cmꢁ1 1H NMR
d
yield). Colorless oil; IR (neat)
(400 MHz, CDCl3) -0.09 (9H, s), 0.81 (3H, t, J = 7.4 Hz), 0.96–
n ;
1758, 1729 cmꢁ1 1H NMR
d
d
1.01 (2H, m), 1.20–1.26 (2H, m), 1.48–1.56 (2H, m), 3.63–3.67 (2H,
m), 4.19–4.23 (2H, m), 6.18 (1H, d, J = 11.2 Hz), 7.22–7.43 (5H, m);
128.5, 140.7, 154.8; 19F NMR (376.5 MHz, CDCl3)
d
3.3 (1F, d, JF–
H = 7.7 Hz); HRMS (ESI-TOF) calcd for C13H17Br2FNO2 [M + H]+,
395.9610; found, 395.9632.
13C NMR (100 MHz, CDCl3)
d
-1.7, 13.7, 17.5, 19.8, 30.9, 46.7, 65.8,
83.3 (d, JC–F = 23.2 Hz), 96.2 (d, JC–F = 322.2 Hz), 128.1, 129.0, 129.7,
132.4, 151.1, 153.3; 19F NMR (376.5 MHz, CDCl3)
0.1 (1F, d, JF–
d
4.2.15. 2,2-Dibromo-2-fluoro-1-phenylethyl propylcarbamate (10c)
A mixture of 2,2-dibromo-2-fluoroethanol (220 mg, 1.0 mmol),
triethylamine (0.42 mL, 3.0 mmol) and n-propylisocyanate
(0.25 mL, 2.50 mmol) was stirred for 10 h at room temperature.
Usual work up (addition of water, extraction with ether, dried over
MgSO4) followed by purification by silica gel column chromatog-
raphy (hexane/EtOAc = 10:1) gave 10c (293 mg, 96% yield).
H = 11.2 Hz); Anal. calcd for C19H28Br2FNO4Si: C, 42.16; H, 5.21; N,
2.59. Found: C, 42.16; H, 5.16; N, 2.45.
4.2.19. Methyl 2-
[{[dibromo(fluoro)methoxy]carbonyl}(methyl)amino]acetate (10h)
Similar to 10f, this compound was prepared in 70% yield via N-
chloroformylation of sarcosine methyl ester hydrochloride by
Colorless oil; IR (neat)
CDCl3) 0.93 (3H, t, J = 7.4 Hz), 1.50–1.60 (2H, m), 3.19 (2H, dt,
J = 6.8 Hz, 6.8 Hz), 4.72 (2H, d, JH–F = 15.8 Hz), 4.98 (1H, brs); 13C
NMR (100 MHz, CDCl3) 11.1, 23.0, 43.0, 72.7 (d, JC–F = 22.1 Hz),
3.0 (1F, t, JF–
n
3342, 1720 cmꢁ1
.
1H NMR (400 MHz,
triphosgene treatment. Colorless oil; IR (neat)
1H NMR (400 MHz, CDCl3)
3.01 (1.5H, s) and 3.04 (1.5H, s), 3.73
(3H, s), 4.03 (1H, s), 4.04 (1H, s), 4.71 (1H, d, JH–F = 15.4 Hz), 4.75
(1H, d, J = 15.4 Hz); 13C NMR (100 MHz, CDCl3)
35.4, 36.3, 50.3,
n ;
1747, 1713 cmꢁ1
d
d
d
d
92.2 (d, JC–F = 321.2 Hz); 19F NMR (376.5 MHz, CDCl3)
d
50.7, 52.1, 52.2, 73.4 (d, JC–F = 22.4 Hz), 73.5 (d, J = 22.4 Hz), 91.6 (d,
JC–F = 321.0 Hz), 91.8 (d, JC–F = 321.0 Hz), 153.9, 154.7, 169.3, 169.4;
H = 15.8 Hz). HRMS (ESI-TOF) calcd for C6H11Br2FNO2 [M + H]+,
305.9141; found, 305.9164.
19F NMR (376 MHz, CDCl3)
d 2.6 (0.5F, d, JF–H = 15.4 Hz) and 2.9

48
A. Saito et al. / Journal of Fluorine Chemistry 133 (2012) 38–51
(0.5F, d, JF–H = 15.4 Hz); HRMS (ESI-TOF) calcd for C7H11Br2FNO4;
4.3.2. (Z)-1-Fluoro-2-phenylethenyl acetate (3b)
98% yield; colorless oil; IR (neat) 3033, 2926, 1742, 1374,
1231, 1177, 1052, 721, 697 cmꢁ1; 1H NMR (400 MHz, CDCl3)
2.28
(3H, s), 5.48 (1H, d, JH–F = 28.3 Hz), 7.35–7.45 (5H, m); 13C NMR
(100 MHz, CDCl3) 20.3, 95.3 (d, JC–F = 15.8 Hz), 127.3, 128.1 (d, JC–
F = 3.1 Hz), 128.5, 131.2 (d, JC–F = 6.0 Hz), 150.3 (d, JC–F = 291.1 Hz),
349.9039 [M+H]+, found: 349.9063.
n
d
4.2.20. Methyl 2-[[(2,2-dibromo-2-fluoro-1-
phenylethoxy)carbonyl](methyl)amino]acetate (10i)
d
64% yield; colorless oil; IR (neat)
(400 MHz, CDCl3) 3.03 (1.5H, s) and 3.17 (1.5H, s), 3.72 (1.5H, s)
n ;
1754, 1725 cmꢁ1 1H NMR
d
167.2; 19F NMR (376.5 MHz, CDCl3)
d
ꢁ17.6 (1F, d, JF–H = 28.3 Hz);
and 3.76 (1.5H, s), 4.05 (1H, s), 4.10 (0.5H, d, J = 17.9 Hz) and 4.18
(0.5H, d, J = 17.9 Hz), 6.20 (0.5H, d, JH–F = 10.5 Hz) and 6.23 (0.5H, d,
HRMS (EI) calcd for C10H9FO2 [M]+, 180.0587; found, 180.0599.
JH–F = 10.5 Hz), 7.35–7.55 (5H, m). 13C NMR (100 MHz, CDCl3)
d
4.3.3. (Z)-1-Fluoro-4-phenyl-1-butenyl acetate (3c) [7]
35.9, 36.9, 50.6, 50.8, 52.2, 52.3, 82.7 (d, JC–F = 23.5 Hz), 82.8 (d, JC–
F = 23.1 Hz), 97.1 (d, JC–F = 322.0 Hz), 97.3 (d, JC–F = 322.5 Hz),
128.1, 128.2, 128.9, 129.6, 133.0, 153.5, 154.4, 169.4, 169.5; 19F
95% yield; colorless oil; 1H NMR (400 MHz, CDCl3)
d 1.54 (3H, s),
2.42 (2H, dtd, J = 7.6, 7.6, 2.0 Hz), 2.73 (2H, t, J = 7.6 Hz), 4.44 (1H,
dt, JH–F = 27.3 Hz, JH–H = 7.6 Hz), 7.19–7.32 (5H, m); 13C NMR
NMR (376.5 MHz, CDCl3)
d, JF–H = 10.5 Hz); HRMS (ESI-TOF) calcd for C13H14Br2FNO4Na
[M+Na]+, 447.9171; found: 447.9198.
d
0.4 (0.5F, d, JF–H = 10.5 Hz) and 0.7 (0.5F,
(100 MHz, CDCl3)
128.4, 128.4, 141.1, 150.2 (d, JC–F = 280.4 Hz), 167.3; 19F NMR
(376.5 MHz, CDCl3)
d 20.2, 24.9, 35.4, 92.3 (d, JC–F = 22.7 Hz), 126.0,
d
ꢁ26.4 (1F, d, JF–H = 27.3 Hz); Anal. calcd for
C12H13FO2: C, 69.22; H, 6.29. Found: C, 69.26; H, 6.43.
4.2.21. Methyl 2-[({1-[dibromo(fluoro)methyl]-3-
phenylpropoxy}carbonyl)(methyl)amino] acetate (10j)
4.3.4. 1-Fluorovinyl 4-methoxybenzoate (3d)
55% yield; colorless oil; IR (neat)
n
1752, 1721 cmꢁ1
;
1H NMR
82% yield; colorless oil; IR (neat) 1755, 1606, 1214,
n
(400 MHz, CDCl3) 2.05–2.22 (1H, m), 2.35–2.43 (1H, m), 2.74–
d
1167 cmꢁ1 1H NMR (400 MHz, CDCl3)
;
d 3.82 (3H, s), 4.21 (1H,
2.85 (2H, m), 3.09 (1.5H, s) and 3.09 (1.5H, s), 3.79 (1.5H, s) and 3.80
(1.5H, s), 3.94 (0.5H, d, J = 18.0 Hz) and 4.05 (0.5H, d, J = 17.7 Hz),
4.15 (0.5H, d, J = 18.0 Hz) and 4.18 (0.5H, d, J = 17.7 Hz),5.38 (1H,
dt, JH–F = 8.2 Hz, JH–H = 2.2 Hz), 7.22–7.35 (5H, m); 13C NMR
dd, JH–F = 37.5 Hz, JH–H = 3.9 Hz), 4.40 (1H, t, JH–F = 3.9 Hz, JH–
H = 3.9 Hz), 6.90 (2H, d, J = 8.9 Hz), 7.98 (2H, d, J = 8.9 Hz); 13C
NMR (100 MHz, CDCl3)
132.7, 155.5 (d, JC–F = 281.1 Hz), 162.2 (d, JC–F = 2.6 Hz), 164.6; 19
NMR (376.5 MHz, CDCl3) -14.7 (1F, dd, JF–H = 37.5, 3.9 Hz); MS (EI)
m/z 135 [M–C2H2FO]+, 107 [M–C3H2FO2]+; Anal. calcd for
10H9FO3: C, 61.22; H, 4.62. Found: C, 61.34; H, 4.74.
d 55.5, 77.4 (d, JC–F = 27.7 Hz), 114.1, 119.7,
F
(100 MHz, CDCl3)
d
31.0, 31.1, 32.7, 32.8, 35.8, 36.9, 50.3, 50.8,
d
52.1, 52.2, 80.4 (d, JC–F = 21.9 Hz), 80.7 (d, JC–F = 22.2 Hz), 98.1 (d,
JC–F = 321.8 Hz), 98.2 (d, JC–F = 321.8 Hz), 126.7, 128.8, 128.8, 128.9,
140.4, 140.5, 154.2, 155.5, 169.3, 169.4; 19F NMR (376.5 MHz,
C
CDCl3)
d
2.7 (0.5F, d, JF–H = 8.2 Hz) and 3.4 (0.5F, d, JF–H = 8.2 Hz);
4.3.5. 1-Fluorovinyl 2,4,6-trimethylbenzoate (3e)
HRMS (ESI-TOF) calcd for C15H19Br2FNO4 [M+H]+, 453.9665; found,
453.9641; Anal. calcd for C15H18Br2FNO4: C, 39.59; H, 3.99; N, 3.08.
Found: C, 39.43; H, 4.04; N, 2.81.
85% yield; colorless oil; IR (neat)
n
2927, 1767, 1709, 1211,
1157 cmꢁ1 1H NMR (400 MHz, CDCl3)
;
d 2.31 (3H, s), 2.38 (6H, s),
4.28 (1H, dd, JH–F = 37.2 Hz, JH–H = 3.8 Hz), 4.48 (1H, t, JH–
F = 3.8 Hz, JH–H = 3.8 Hz), 6.90 (2H, s); 13C NMR (100 MHz, CDCl3)
4.2.22. 2-(Trimethylsilyl)ethyl 2-{(tert-butoxycarbonyl)[(2,2-
d
20.0, 21.2, 77.5 (d, JC–F = 26.8 Hz), 127.7, 128.8, 136.4, 140.9,
dibromo-2-fluoro-1-phenyl-ethoxy)carbonyl]amino}acetate (10k)
155.2 (d, JC–F = 282.4 Hz), 165.5; 19F NMR (376.5 MHz, CDCl3)
d-
81% yield; colorless oil; IR (neat)
NMR (400 MHz, CDCl3) 0.03 (9H, s), 0.93–0.98 (2H, m), 1.55 (9H,
s), 4.20–4.24 (2H, m), 4.46 (2H, s), 6.29 (1H, d, JH–F = 12.6 Hz), 7.38–
7.54 (5H, m); 13C NMR (100 MHz, CDCl3)
n
1773, 1742, 1705 cmꢁ1
.
1H
15.2 (1F, dd, JF–H = 37.2, 3.8 Hz); MS (EI) m/z 147 [M–C2H2FO]+, 119
[M–C3H2FO2]+; Anal. calcd for C12H13FO2: C, 69.22; H, 6.29. Found:
C, 69.19; H, 6.42.
d
d
ꢁ1.5, 15.3, 28.0, 47.7,
63.9, 83.8 (d, JC–F = 22.5 Hz), 84.5, 95.9 (d, JC–F = 322.8 Hz), 128.2,
129.2, 129.9, 132.2, 150.9, 151.1, 168.5; 19F NMR (376.5 MHz,
4.3.6. 1-Fluorovinyl cinnamate (3f)
49% yield; colorless oil. IR (neat)
n
1758, 1633, 1177, 1109, 983,
4.25 (1H, dd, JH–
CDCl3)
d
ꢁ0.6 (1F, d, JF–H = 12.6 Hz); HRMS (ESI-TOF) calcd for
765 cmꢁ1 1H NMR (400 MHz, CDCl3)
;
d
C21H31Br2FNO6Si [M+H]+, 598.0271; found, 598.0253.
F = 37.6 Hz, JH–H = 4.0 Hz), 4.43 (1H, t, J = 4.0 Hz), 6.31 (1H, d,
J = 16.0 Hz), 7.40–7.45 (3H, m), 7.55–7.57 (2H, m), 7.86 (1H, d,
4.3. General procedure for CrCl2/Mn mediated transformation of
dibromofluoromethylcarbinyl esters
J = 16.0 Hz); 13C NMR (100 MHz, CDCl3)
d
77.3 (d, JC–F = 27.3 Hz),
115.1, 128.5, 129.1, 131.3, 133.6, 148.7, 155.3 (d, JC–F = 280.5 Hz),
162.5; 19F NMR (376.5 MHz, CDCl3)
d
ꢁ15.1 (1F, dd, J = 37.6,
Under argon atmosphere, after a mixture of CrCl2 (740 mg,
6.0 mmol) and Mn powder (880 mg, 16 mmol) suspended in THF
(8.0 mL) was sonicated by ultrasound for 10 min, was added
dibromofluoro ester 1e (1.50 g, 4.0 mmol) and the reaction mixture
was stirred for 5 h at room temperature. Extractive work up
(addition of water, Et2O for extraction, dried over MgSO4) followed
by purification by silica gel column chromatography (hexane/
EtOAc = 20:1) gave 3e (708 mg, 82% yield).
3.1 Hz); MS (EI) m/z 131 [M–C2H2FO]+, 103 [M–C3H2FO2]+, 77
[C6H5]+; Anal. calcd for C11H9FO2: C, 68.74; H, 4.72. Found: C,
68.93; H, 4.97.
4.3.7. 1-Fluorovinyl-2-benzyl-4-(tert-
butyldiphenylsilyloxy)butanoate (3g)
66% yield; colorless solid; Mp. 37.1–39.5 8C; IR (neat)
2932, 2857, 2361, 1783, 1709, 1110, 1082, 702 cmꢁ1 1H NMR
(400 MHz, CDCl3) 1.06 (9H, s), 1.79–1.88 (1H, m), 1.95–2.07 (1H,
n 3069,
;
d
4.3.1. 1-Fluoroethenyl benzoate (3a) [7]
m), 2.88 (1H, dd, J = 13.7, 6.9 Hz), 3.02 (1H, dd, J = 13.7, 8.0 Hz),
3.10–3.20 (1H, m), 3.72 (2H, t, J = 5.6 Hz), 3.92 (1H, dd, JH–
F = 37.7 Hz, JH–H = 3.7 Hz), 4.28 (1H, dd, JH–H = 3.7 Hz, JH–F = 3.0 Hz),
7.18 (2H, brd, J = 7.0 Hz), 7.21–7.33 (3H, m), 7.34–7.46 (6H, m),
65% yield; colorless oil; 1H NMR (400 MHz, CDCl3)
d 4.31 (1H,
dd, JH–F = 37.4 Hz, JH–H = 4.0 Hz), 4.49 (1H, dd, JH–H = 4.0 Hz, JH–
F = 3.7 Hz), 7.48–7.52 (2H, m), 7.63–7.68 (1H, m), 8.09–8.12 (2H,
m); 13C NMR (100 MHz, CDCl3)
d
77.6 (d, JC–F = 27.0 Hz), 127.6,
128.8, 130.5, 134.4, 155.4 (d, JC–F = 281.5 Hz), 162.6; 19F
NMR (376.5 MHz, CDCl3)
7.61–7.67 (4H, m); 13C NMR (100 MHz, CDCl3)
d 19.2, 26.9, 34.1,
38.0, 43.6, 61.3, 77.0 (d, JC–F = 26.7 Hz), 126.7, 127.7, 128.6, 129.0,
129.7, 133.5 and 133.6, 135.54 and 135.56, 138.2, 155.2 (d, JC–
F = 281.7 Hz), 171.3 (d, JC–F = 3.0 Hz); 19F NMR (376.5 MHz, CDCl3)
d
ꢁ15.3 (1F, dd, JF–H = 37.4, 3.7 Hz);
Anal. calcd for C9H7FO2: C, 65.05; H, 4.25. Found: C, 64.94;
H, 4.65.
d
-15.3 (1F, dd, JF–H = 37.7, 3.0 Hz); MS (ESI-TOF) m/z 477 [M + H]+;

A. Saito et al. / Journal of Fluorine Chemistry 133 (2012) 38–51
49
Anal. calcd for C29H33FO3Si: C, 73.07; H, 6.98. Found: C, 73.09; H,
7.19.
JH–F = 26.5 Hz, JH–H = 7.6 Hz), 5.47 (1H, d, J = 2.6 Hz), 7.24–7.37
(5H, m); 13C NMR (100 MHz, CDCl3)
11.9, 18.7, 19.2, 21.1, 22.6,
d
22.8, 23.8, 24.3, 25.0, 27.4, 28.0, 28.2, 31.8, 31.9, 35.3, 35.8, 36,2,
36.5, 36.7, 37.7, 39.5, 39.7, 42.3, 50.0, 56.2, 56.7, 79.9, 92.0 (d, JC–
F = 23.0 Hz), 123.4, 126.1, 128.4, 128.4, 138.8, 141.0, 150.6 (d, JC–
F = 281.8 Hz), 151.0 (d, JC–F = 3.6 Hz); 19F NMR (376.5 MHz,
4.3.8. Ethyl (Z)-1-fluoro-2-phenylethenyl carbonate (9a)
88% yield; colorless oil; IR (neat)
n 3030, 2987, 2916, 1783,
1715, 1262, 1218, 1153, 694 cmꢁ1 1H NMR (400 MHz, CDCl3)
;
d
1.40 (3H, t, J = 7.1 Hz), 4.36 (2H, q, J = 7.1 Hz), 5.55 (1H, d, JH–
CDCl3)
C
C, 78.84; H, 9.26.
d-27.7 (1F, brd, JF–H = 26.5 Hz); MS (EI) m/z 369 [M–
F = 27.5 Hz), 7.24–7.28 (1H, m), 7.33–7.37 (2H, m), 7.42–7.44 (2H,
11H11FO3]+; Anal. calcd for C38H55FO3: C, 78.85; H, 9.58. Found:
m); 13C NMR (100 MHz, CDCl3)
d
14.0, 66.1, 95.0 (d, JC–F = 16.0 Hz),
127.5 (d, JC–F = 1.6 Hz), 128.2 (d, JC–F = 6.9 Hz), 128.6, 131.0 (d, JC–
F = 6.3 Hz), 150.4 (d, JC–F = 292.7 Hz), 151.4 (d, JC–F = 3.8 Hz); 19F
4.3.13. S-(1-Fluorovinyl) O-phenyl carbonothioate (9f)
NMR (376.5 MHz, CDCl3)
d
–19.7 (1F, d, JF–H = 27.5 Hz); Anal. calcd
98% yield; colorless oil; IR (neat)
(400 MHz, CDCl3) 5.22 (1H, dd, JH–F = 40.5 Hz, JH–H = 3.3 Hz), 5.44
(1H, dd, JH–F = 9.4 Hz, JH–H = 3.3 Hz), 7.19–7.43 (5H, m); 13C NMR
(100 MHz, CDCl3) 107.2 (d, JC–F = 21.2 Hz), 121.0, 126.6, 129.6,
151.1, 153.3 (d, JC–F = 302.0 Hz), 164.8 (d, JC–F = 4.6 Hz); 19F NMR
n ;
1752 cmꢁ1 1H NMR
for C11H11FO3: C, 62.85; H, 5.27. Found: C, 62.99; H, 5.29.
d
4.3.9. Ethyl (Z)-1-fluoro-4-phenyl-1-butenyl carbonate (9b)
d
98% yield; colorless oil; IR (neat)
n 3028, 2917, 2849, 1782,
1731, 1267, 1191, 1162, 700 cmꢁ1 1H NMR (400 MHz, CDCl3)
;
d
(376.5 MHz, CDCl3)
198 [M]+.
d–15.1 (1F, dd, JF–H = 40.5, 9.4 Hz); MS (EI) m/z
1.34 (3H, t, J = 7.1 Hz), 2.41 (2H, dt, J = 7.7, 7.7 Hz), 2.73 (2H, t,
J = 7.7 Hz), 4.30 (2H, q, J = 7.1 Hz), 4.53 (dt, 1H, JH–F = 26.5 Hz, JH–
H = 7.7 Hz), 7.17–7.23 (3H, m), 7.26–7.32 (2H, m); 13C NMR
4.3.14. (Z)- and (E)-1-Fluoro-2-phenylethenyl dimethylcarbamate
(Z-11a and E-11a)
(100 MHz, CDCl3)
126.1, 128.4, 128.4, 149.1, 150.5 (d, JC–F = 281.2 Hz), 151.6; 19F
NMR (376.5 MHz, CDCl3) -28.0 (1F, d, JF–H = 26.5 Hz); Anal. calcd
d 14.0, 24.9, 35.3, 65.7, 92.0 (d, JC–F = 22.8 Hz),
Z-11a 57% yield; colorless solid; Mp. 44.0–45.1 8C; IR (KBr)
n
d
1713 cmꢁ1
;
1H NMR (400 MHz, CDCl3)
d
3.00 (3H, s), 3.07 (3H, s),
5.45 (1H, d, JH–F = 27.7 Hz), 7.20–7.44 (5H, m); 13C NMR (100 MHz,
CDCl3) 36.5, 36.9, 95.1 (d, JC–F = 17.9 Hz), 127.0, 128.0 (d, JC–
F = 6.9 Hz), 128.4, 131.7 (d, JC–F = 6.3 Hz), 150.9 (d, JC–F = 290.9 Hz),
152.2 (d, JC–F = 3.7 Hz); 19F NMR (376.5 MHz, CDCl3)
-15.8 (1F, d,
for C13H15FO3: C, 65.53; H, 6.35. Found: C, 65.88; H, 6.22.
d
4.3.10. (2S,4aR,6aR,7R)-7-[(1R)-1,5-Dimethylhexyl]-4a,6a-dimethyl-
1,2,3,4,4a,4b,5,6,6a,7,8,9, 10,10a,10b,11-hexadecahydro-2-chrysenyl
d
1-fluorovinyl carbonate (9c)
JF–H = 27.7 Hz); HRMS (ESI-TOF) calcd for C11H13FNO2 [M+H]+,
210.0930; found, 210.0910; Anal. calcd for C11H12FNO2: C, 63.15;
H, 5.78; N, 6.69. Found: C, 63.21; H, 5.71; N, 6.65.
25
29% yield; colorless solid; Mp. 69.0–70.5 8C; [
a
]
D
ꢁ 30.0
(c = 1.0, CHCl3); IR (KBr)
n
1782 cmꢁ1; 1H NMR (400 MHz, CDCl3)
d
0.68 (3H, s), 0.88 (3H, d, J = 6.6 Hz), 0.88 (3H, d. J = 6.6 Hz), 0.92 (3H,
d, J = 6.5 Hz), 0.95–2.65 (29H, m), 2.26–2.42 (2H, m), 4.23 (1H, dd,
JH–F = 36.5 Hz, JH–H = 4.0 Hz), 4.35 (1H, dd, J = 4.0, 2.9 Hz), 4.53–
E-11a 5% yield; colorless oil; IR (neat)
(400 MHz, CDCl3) 3.05 (3H, s), 3.10 (3H, s), 5.79 (1H, d, JH–
F = 5.9 Hz), 7.20–7.40 (5H, m); 13C NMR (100 MHz, CDCl3)
36.7,
n ;
1712 cmꢁ1 1H NMR
d
d
4.60 (1H, m) 5.42 (1H, d, J = 5.0 Hz); 13C NMR (100 MHz, CDCl3)
d
37.0, 94.9 (d, JC–F = 35.5 Hz), 127.0, 127.6 (d, JC–F = 3.2 Hz), 128.5,
131.8 (d, JC–F = 7.9 Hz), 151.2 (d, JC–F = 6.0 Hz), 151.2 (d, JC–
11.9, 18.7, 19.3, 21.1, 22.6, 22.8, 23.8, 24.3, 27.4, 28.0, 28.2, 31.8,
31.9, 35.8, 36,2, 36.5, 36.8, 37.7, 39.5, 39.7, 42.3, 50.0, 56.2, 56.7,
76.9 (d, JC–F = 30.2 Hz), 80.2, 123.5, 138.8, 150.2 (d, JC–F = 2.3 Hz),
F = 281.1 Hz); 19F NMR (376.5 MHz, CDCl3)
d
ꢁ15.5 (1F, d, JF–
H = 5.9 Hz); HRMS (ESI-TOF) calcd for C11H13FNO2 [M+H]+,
210.0930; found, 210.0919; Anal. calcd for C11H12FNO2: C,
63.15; H, 5.78; N, 6.69. Found: C, 63.09; H, 5.90; N, 6.37.
155.3 (d, JC–F = 282.4 Hz); 19F NMR (376.5 MHz, CDCl3)
d
-17.1 (1F,
brd, JF–H = 36.5 Hz); MS (EI) m/z 369 [M–C3H3FO3]+; Anal. calcd for
30H47FO3: C, 75.91; H, 9.98. Found: C, 75.74; H, 9.85.
C
4.3.15. (Z)-1-Fluoro-4-phenyl-1-butenyl dimethylcarbamate (11b)
4.3.11. (2S,4aR,6aR,7R)-7-[(1R)-1,5-Dimethylhexyl]-4a,6a-dimethyl-
1,2,3,4,4a,4b,5,6,6a,7,8,9, 10,10a,10b,11-hexadecahydro-2-chrysenyl
65% yield; colorless oil; IR (neat)
(400 MHz, CDCl3) 2.42 (2H, dt, J = 7.7, 7.7 Hz), 2.72 (2H, t,
J = 7.7 Hz), 2.97 (3H, s), 2.97 (3H, s), 4.43 (1H, dt, JH–F = 26.7 Hz, JH–
H = 7.7 Hz), 7.19–7.32 (5H, m); 13C NMR (100 MHz, CDCl3)
25.1,
35.5, 36.4, 36.8, 92.0 (d, JC–F = 25.0 Hz), 126.0, 128.4, 128.4, 141.3,
150.9 (d, JC–F = 280.1 Hz), 152.5 (d, JC–F = 4.0 Hz); 19F NMR
n ;
1751 cmꢁ1 1H NMR
d
(Z)-1-fluoro-2-phenylethenyl carbonate (9d)
25
81% yield; colorless solid; Mp. 107–108 8C; [
(c = 1.0, CHCl3); IR (KBr)
1691 cmꢁ1
0.69 (3H, s), 0.87 (3H, d, J = 6.6 Hz), 0.87 (3H, d. J = 6.6 Hz), 0.91
a
]
D
ꢁ 27.7
d
n
;
1H NMR (400 MHz, CDCl3)
d
(3H, d, J = 6.5 Hz), 0.91–2.05 (29H, m), 2.42–2.53 (2H, m), 4.55–
4.65 (1H, m), 5.43 (1H, brd), 5.45 (1H, d, JH–F = 27.5 Hz), 7.23–7.43
(376.5 MHz, CDCl3)
d
ꢁ24.4 (1F, d, JF–H = 26.7 Hz); HRMS (ESI-
TOF) calcd for C13H17FNO2 [M+H]+, 238.1243; found, 238.1250.
(5H, m); 13C NMR (100 MHz, CDCl3)
d 11.9, 18.7, 19.3, 21.1, 22.6,
22.8, 23.8, 24.3, 27.5, 28.0, 28.2, 31.9, 35.8, 36,2, 36.5, 36.8, 37.7,
39.5, 39.7, 42.3, 50.0, 56.2, 56.7, 80.4, 95.0 (d, JC–F = 16.1 Hz), 123.6,
127.4, 128.2 (d, JC–F = 6.0 Hz), 128.6, 131.1 (d, JC–F = 6.4 Hz), 138.8,
150.5 (d, JC–F = 292.6 Hz), 150.7 (d, JC–F = 3.2 Hz); 19F NMR
4.3.16. 1-Fluorovinyl propylcarbamate (11c)
12% yield; colorless oil; IR (neat)
(400 MHz, CDCl3) 0.94 (3H, t, J = 7.4 Hz), 1.52–1.62 (2H, m), 3.19
n ;
1713 cmꢁ1 1H NMR
d
(2H, dt, J = 6.8, 6.7 Hz),.13 (1H, dd, JH–F = 37.1 Hz, JH–H = 3.6 Hz),
4.31 (1H, dd, JH–H = 3.6 Hz, JH–F = 2.9 Hz), 5.04 (1H, brs); 13C NMR
(376.5 MHz, CDCl3)
d
ꢁ19.6 (1F, d, JF–H = 27.5 Hz); MS (EI) m/z
369 [M–C9H7FO3]+; Anal. calcd for C36H51FO3: C, 78.50; H, 9.33.
Found: C, 78.35; H, 9.20.
(100 MHz, CDCl3)
155.4 (d, JC–F = 280.4 Hz); 19F NMR (376.5 MHz, CDCl3)
brd, JF–H = 37.1 Hz); MS (ESI-TOF) m/z 171 [M+H+Na]+.
d
11.1, 22.8, 43.1, 76.8 (d, JC–F = 29.4 Hz), 151.4,
d
ꢁ14.5 (1F,
4.3.12. (2S,4aR,6aR,7R)-7-[(1R)-1,5-Dimethylhexyl]-4a,6a-dimethyl-
1,2,3,4,4a,4b,5,6,6a,7,8,9, 10,10a,10b,11-hexadecahydro-2-chrysenyl
4.3.17. (Z)-1-Fluoro-2-phenylethenyl propylcarbamate (11d)
39% yield; colorless oil; IR (neat)
1713 cmꢁ1 1H NMR
(400 MHz, CDCl3) 0.97 (3H, t, J = 7.4 Hz), 1.56–1.65 (2H, m), 3.21–
3.26 (2H, m), 5.03 (1H, brs), 5.45 (1H, d, JH–F = 27.8 Hz), 7.20–7.43
(5H, m); 13C NMR (100 MHz, CDCl3)
11.1, 22.9, 43.2, 95.0 (d, JC–
(Z)-1-fluoro-4-phenyl-1-butenyl carbonate (9e)
n
;
25
97% yield; colorless solid; Mp. 94–95 8C;
(c = 1.0, CHCl3); IR (KBr)
1768 cmꢁ1
CDCl3) 0.74 (3H, s), 0.93 (3H, d, J = 6.6 Hz), 0.93 (3H, d.
[
a
]
ꢁ 26.9
d
D
n
;
1H NMR (400 MHz,
d
d
J = 6.6 Hz), 0.98 (3H, d, J = 6.5 Hz), 1.05–2.06 (29H, m), 2.45–2.50
(4H, m), 2.78 (2H, t, J = 7.6 Hz), 4.52–4.64 (1H, m) 4.58 (1H, dt,
F = 17.9 Hz), 127.1, 128.1 (d, JC–F = 6.8 Hz), 128.5, 131.6 (d, JC–
F = 6.3 Hz), 150.7 (d, JC–F = 290.9 Hz), 151.8 (d, JC–F = 3.6 Hz); 19F

50
A. Saito et al. / Journal of Fluorine Chemistry 133 (2012) 38–51
NMR (376.5 MHz, CDCl3)
d
ꢁ16.4 (1F, d, JF–H = 27.8 Hz); HRMS (ESI-
4.3.23. Methyl 2-[({[(Z)-1-fluoro-4-phenyl-1-
TOF) calcd for C12H15FNO2 [M+H]+, 224.1087; found, 224.1077.
butenyl]oxy}carbonyl)(methyl)amino]acetate (11j)
75% yield; colorless oil; IR (neat)
(400 MHz, CDCl3) 2.43–2.50 (2H, m), 2.74–2.79 (2H, m), 3.07
(1.5H, s) and 3.08 (1.5H, s), 3.81 (1.5H, s) and 3.81 (1.5H, s), 4.07
n ;
1746 cmꢁ1 1H NMR
4.3.18. tert-Butyl 1-fluorovinyl isopropyldicarbonimidoate (11e)
d
51% yield; colorless oil; IR (neat)
n
1773, 1729 cmꢁ1
;
1H NMR
(400 MHz, CDCl3) 1.36 (6H, d, J = 6.8 Hz), 1.52 (9H, s), 4.21 (1H,
dd, JH–F = 36.8 Hz, JH–H = 4.0 Hz), 4.37 (1H, dd, JH–H = 4.0 Hz, JH–
F = 2.9 Hz), 4.46 (1H, septet, J = 6.8 Hz); 13C NMR (100 MHz, CDCl3)
d
(1H, s), 4.10 (1H, s), 4.48 (0.5H, dt, JH–F = 26.5 Hz, JH–H = 7.6 Hz) and
4.54 (0.5H, dt, JH–F = 26.5 Hz, JH–H = 7.6 Hz), 7.23–7.36 (5H, m); 13
C
NMR (100 MHz, CDCl3) d 25.0, 35.4, 35.8, 36.2, 50.6, 52.2, 52.3, 92.2
d
20.2, 27.8, 50.3, 77.2 (d, JC–F = 28.0 Hz), 83.9, 149.7 (d, JC–
(d, JC–F = 24.2 Hz), 92.3 (d, JC–F = 24.1 Hz), 125.9, 128.3, 128.4,
141.2, 150.4 (d, JC–F = 281.0 Hz), 150.5 (d, JC–F = 280.2 Hz), 152.1 (d,
JC–F = 3.7 Hz), 152.9 (d, JC–F = 4.0 Hz), 169.0, 169.0. 19F NMR
F = 3.2 Hz), 151.6, 155.1 (d, JC–F = 282.0 Hz); 19F NMR (376.5 MHz,
CDCl3)
d
ꢁ16.0 (1F, dd, JF–H = 36.8, 2.9 Hz); HRMS (ESI-TOF) calcd
for C11H18FNO4Na [M+Na]+; 270.1118, found: 270.1118.
(376.5 MHz, CDCl3) d-25.4 (1F, d, JF–H = 26.5 Hz); HRMS (ESI-
TOF) calcd for C15H18FNNaO4 [M+Na]+, 318.1118; found, 318.1120;
Anal. calcd for C15H18FNO4: C, 61.01; H, 6.14; N, 4.74. Found: C,
60.93; H, 6.24; N, 4.47.
4.3.19. (Z)-1-Fluoro-2-phenylethenyl 2-(trimethylsilyl)ethyl
butyldicarbonimidoate (11f)
65% yield; colorless oil; IR (neat)
(400 MHz, CDCl3) 0.07 (9H, s), 0.96 (3H, t, J = 7.3 Hz), 1.10–1.14
n ;
1729, 1713 cmꢁ1 1H NMR
d
4.3.24. 2-(Trimethylsilyl)ethyl 2-[(tert-butoxycarbonyl)({[(Z)-1-
(2H, m), 1.32–1.43 (2H, m), 1.60–1.68 (2H, m), 3.76 (2H, t,
J = 7.5 Hz), 4.33–4.38 (2H, m), 5.54 (1H, d, JH–F = 27.6 Hz), 7.22–
fluoro-2-phenylethenyl]oxy}-carbonyl)amino]acetate (11k)
65% yield; colorless oil; IR (neat)
NMR (400 MHz, CDCl3) 0.05(9H, s), 1.03(2H, t, J = 8.6 Hz), 1.54(9H,
s), 4.29 (2H, t, J = 8.6 Hz), 4.44 (2H, s), 5.55 (1H, d, JH–F = 27.5 Hz),
7.24–7.43 (5H, m); 13C NMR (100 MHz, CDCl3)
-1.6, 17.4, 27.8, 47.7,
n ;
1746, 1729, 1713 cmꢁ1 1H
7.44 (5H, m); 13C NMR (100 MHz, CDCl3)
30.8, 47.1, 66.4, 95.8 (d, JC–F = 15.8 Hz), 127.4 (d, JC–F = 1.5 Hz),
128.1 (d, JC–F = 6.9 Hz), 128.5, 131.1 (d, JC–F = 6.2 Hz), 150.0 (d, JC–
F = 292.7 Hz), 150.1 (d, JC–F = 3.8 Hz), 153.0; 19F NMR (376.5 MHz,
d
ꢁ1.6, 13.7, 17.5, 19.8,
d
d
64.1, 84.9, 95.8(d, JC–F = 15.4 Hz), 127.4 (d, JC–F = 1.3 Hz), 128.2 (d, JC–
F = 6.9 Hz), 128.5, 130.9 (d, JC–F = 6.3 Hz), 149.8 (d, JC–F = 292.9 Hz),
149.9 (d, JC–F = 3.8 Hz), 150.5, 168.2; 19F NMR (376.5 MHz, CDCl3)
d
CDCl3)
d
ꢁ18.4 (1F, d, JF–H = 27.6 Hz); HRMS (ESI-TOF) calcd for
C19H28FNNaO4Si [M+Na]+; 404.1669, found: 404.1650; Anal. calcd
for C19H28FNO4Si: C, 59.82; H, 7.40; N, 3.67. Found: C, 59.98; H,
7.49; N, 3.41.
ꢁ18.8 (1F, d, JF–H = 27.5 Hz); HRMS (ESI-TOF) calcd for
C
21H30FNNaO6Si [M+Na]+, 462.1724; found, 462.1692.
4.3.20. (Z)-1-Fluoro-2-phenylethenyl butylcarbamate (11g)
4.3.25. 2-[[({(Z)-1-Fluoro-2-
95% yield; colorless oil; IR (neat)
(400 MHz, CDCl3) 0.95 (3H, t, J = 7.3 Hz), 1.34–1.43 (2H, m), 1.52–
1.59 (2H, m), 3.26 (2H, dt, J = 6.7, 6.7 Hz), 5.02 (1H, brs), 5.45 (1H, d,
JH–F = 27.8 Hz), 7.21–7.43 (5H, m); 13C NMR (100 MHz, CDCl3)
n
1713 cmꢁ1
;
1H NMR
phenylethenyl}oxy)carbonyl]amino]acetic acid (15)
70% yield; colorless solid; Mp. 198–200 8C (dec.); IR (KBr)
d
n
3294, 1733, 1717 cmꢁ1; 1H NMR (400 MHz, CD3COOD)
d
4.08 (2H,
s), 5.56 (1H, d, JH–F = 28.0 Hz), 7.27–7.43 (5H, m); 13C NMR
(100 MHz, CD3COOD) 43.2, 96.3 (d, JC–F = 17.4 Hz), 128.2, 129.0
d
13.6, 19.8, 31.6, 41.2, 95.1 (d, JC–F = 18.0 Hz), 127.1 (d, JC–F = 1.5 Hz),
128.1 (d, JC–F = 7.0 Hz), 128.5, 131.7 (d, JC–F = 6.1 Hz), 150.7 (d, JC–
d
(d, JC–F = 7.1 Hz), 129.5, 132.6 (d, JC–F = 7.2 Hz), 151.6 (d, JC–
F = 289.2 Hz), 174.7, 178.1; 19F NMR (376.5 MHz, CD3COOD)
d
ꢁ17.4 (1F, d, JF–H = 28.0 Hz).
F = 290.4 Hz), 151.8; 19F NMR (376.5 MHz, CDCl3)
d
ꢁ16.2 (1F, d, JF–
H = 27.8 Hz); HRMS (ESI-TOF) calcd for C13H17FNO2 [M+H]+,
238.1243; found, 238.1242.
4.4. Reaction of 1-fluorovinyl benzoate 3a with trans-cyclohexane
4.3.21. Methyl 2-[{[(1-
1,2-diamine
fluorovinyl)oxy]carbonyl}(methyl)amino]acetate (11h)
69% yield; colorless oil; IR (neat)
n
1748, 1713 cmꢁ1
;
1H NMR
A mixture of 1-fluorovinyl benzoate 3a (83.0 mg, 0.5 mmol),
trans-cyclohexane 1,2-diamine (60 L, 0.5 mmol) and triethyla-
mine (140 L, 1.0 mmol) in THF (4.0 mL) was stirred for 11 h at
room temperature. Addition of water (10 mL), extraction with
EtOAc (15 mL ꢂ 3) and the subsequent purification by silica gel
column chromatography (eluted by ethyl acetate) gave N-(2-
acetylaminocyclohexyl)benzamide 18b (72.6 mg, 56% yield) and
N,N0-1,2-cyclohexanediylbisbenzamide 19b (8.2 mg, 5.0% yield).
Structures of products were determined by comparing NMR data
with those of authentic samples [28].
(400 MHz, CDCl3) 3.03 (1.5H, s) and 3.05 (1.5H, s), 3.76 (1H, s),
d
m
3.77 (1H, s), 4.02 (1H, s), 4.05 (1H, s), 4.12 (0.5H, dd, JH–F = 34.3 Hz,
JH–H = 3.3 Hz), 4.17 (0.5H, dd, JH–F = 34.3 Hz, JH–H = 3.3 Hz), 4.30–
m
4.34 (1H, m); 13C NMR (100 MHz, CDCl3)
d 35.8, 36.3, 50.7, 52.2,
52.3, 77.0 (d, JC–F = 28.2 Hz), 77.1 (d, JC–F = 29.2 Hz), 155.4 (d, JC–
F = 293.7 Hz), 168.9 (d, JC–F = 5.9 Hz), 171.0; 19F NMR (376.5 MHz,
CDCl3)
d
ꢁ14.8 (0.5F, dd, JF–H = 34.3, 3.3 Hz) and ꢁ14.9 (0.5F, dd, JF–
H = 34.3, 3.3 Hz); HRMS (ESI-TOF) calcd for C7H11FNO4 [M+H]+,
192.0672; found, 192.0678; Anal. calcd for C7H10FNO4: C, 43.98; H,
5.27; N, 7.33. Found: C,44.01; H, 5.51; N, 6.93.
4.5. Reaction of 1-fluorovinyl 4-silyloxybutanoate 3g with TBAF in the
4.3.22. Methyl 2-[({[(Z)-1-fluoro-2-
presence of p-anisidine
phenylethenyl]oxy}carbonyl)(methyl)amino]acetate (11i)
82% yield; colorless oil; IR (neat)
n
1747, 1713 cmꢁ1
;
1H NMR
A mixture of fluorovinyl ester 3g (143 mg, 0.30 mmol), p-
anisidine (37 mg, 0.30 mmol) and TBAF (0.6 mL, 0.6 mmol) in THF
(2.4 mL) was stirred for 2 h at 0 8C, then for additional 2 h at room
temperature. Addition of water (10 mL), extraction with ethyl
acetate (15 mL ꢂ 3) and the subsequent purification by silica gel
column chromatography (hexane/EtOAc = 100:1 ꢃ 5:1) gave, in
the order of elution, TBDPS-F 25 (30 mg, 40% yield), TBDPS-OH 26
(32 mg, 46% yield), butyrolactone 22a (16 mg, 30% yield) and 4-
methoxyacetoanilide 23a (28 mg, 57% yield), respectively. These
products were unambiguously determined by comparison of
spectra data with those of authentic samples [29].
(400 MHz, CDCl3) 3.05 (1.5H, s) and 3.09 (1.5H, s), 3.77 (1.5H, s)
d
and 3.79 (1.5H, s), 4.06 (1H, s), 4.07 (1H, s), 5.44 (0.5H, d, JH–
F = 25.8 Hz) and 5.50 (0.5H, d, JH–F = 25.8 Hz), 7.20–7.43 (5H, m);
13C NMR (100 MHz, CDCl3)
d 35.8, 36.3, 50.8, 52.1, 52.2, 95.1 (d, JC–
F = 17.4 Hz), 95.2 (d, JC–F = 17.4 Hz), 127.5, 128.1 (d, JC–F = 6.9 Hz),
128.8, 131.6 (d, JC–F = 5.6 Hz), 150.6 (d, JC–F = 291.3 Hz) 150.7 (d, JC–
F = 290.4 Hz), 151.8 (d, JC–F = 3.1 Hz), 152.6 (d, JC–F = 3.4 Hz), 168.9.
19F NMR (376.5 MHz, CDCl3)
d
ꢁ16.9 (0.5F, d, JF–H = 25.8 Hz) and
ꢁ17.0 (0.5F, d, JF–H = 25.8 Hz); HRMS (ESI-TOF) calcd for
C13H15FNO4 [M+H]+, 268.0985; found, 268.0995.

A. Saito et al. / Journal of Fluorine Chemistry 133 (2012) 38–51
51
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