Are carboxylic esters really refractory to DAST? On the fluorination of α-hydroxyesters with DAST

Article abstract of DOI:10.1016/j.jfluchem.2014.09.007

Diethyl 2-alkyl-2-hydroxymalonates react with DAST almost exclusively at the ester carbonyl giving a mixture of ethyl 2-(ethoxydifluoromethyl)-2-hydroxyalkanoates, 1,1-bis(ethoxydifluoromethyl)alkan-1-ols when administered at room temperature in dichloromethane. The reaction was exploited in the synthesis of nucleus- and side-chain polyfluorinated indoles. The fluorination of substituted diethyl 2-[(1-tert-butoxycarbonylindol-3-yl)methyl]-2-hydroxymalonates with DAST gave a mixture of ethyl 2-(ethoxydifluoromethyl)-2-hydroxy-3-(1-tert-butoxycarbonylindol-3-yl)propionate, diastereomeric 1′-tert-butoxycarbonyl-2′-hydroxy-2,2-diethoxycarbonylspiro(cyclopropane-1,3′-indoline) and only traces of 1,1-bis(ethoxydifluoromethyl)-2-(1-tert-butoxycarbonylindol-3-yl)ethanol. The composition of these mixtures changes depending on the reaction conditions. Regioselectively substituted ethyl 2-hydroxy-2-[(1-tert-butoxycarbonylindol-3-yl)methyl]-3,3,3-trifluoropropionate reacts with DAST at 0 °C in dichloromethane giving satisfactory yields of the corresponding 1-ethoxy-2-[(1-tert-butoxycarbonylindol-3-yl)methyl]-1,1,3,3,3-pentafluoropropan-2-ols as the exclusive reaction products. In the same reaction conditions, ethyl 3-(1-tert-butoxycarbonylindol-3-yl)-2-hydroxypropionate mainly provides 1′-tert-butoxycarbonyl-2′-hydroxy-2,2-diethoxycarbonylspiro(cyclopropane-1,3′-indoline) together with the “normal” fluorination product ethyl 3-(1-tert-butoxycarbonylindol-3-yl)-2-fluoropropionate. A plausible mechanism of this process is proposed in the following.

Full text of DOI:10.1016/j.jfluchem.2014.09.007

Journal of Fluorine Chemistry 171 (2015) 82–91
Contents lists available at ScienceDirect
Journal of Fluorine Chemistry
journal homepage: www.elsevier.com/locate/fluor
Are carboxylic esters really refractory to DAST? On the fluorination of
a
-hydroxyesters with DAST
*
Susan Lepri, Federica Buonerba, Paola Maccaroni, Laura Goracci, Renzo Ruzziconi
`
Dipartimento di Chimica, Biologia e Biotecnologie, Universita di Perugia, via Elce di Sotto 8, 06123 Perugia, Italy
A R T I C L E I N F O
A B S T R A C T
Article history:
Diethyl 2-alkyl-2-hydroxymalonates react with DAST almost exclusively at the ester carbonyl giving a
mixture of ethyl 2-(ethoxydifluoromethyl)-2-hydroxyalkanoates, 1,1-bis(ethoxydifluoromethyl)alkan-1-
ols when administered at room temperature in dichloromethane. The reaction was exploited in the
synthesis of nucleus- and side-chain polyfluorinated indoles. The fluorination of substituted diethyl
2-[(1-tert-butoxycarbonylindol-3-yl)methyl]-2-hydroxymalonates with DAST gave a mixture of ethyl
Received 2 July 2014
Received in revised form 4 September 2014
Accepted 7 September 2014
Available online 16 September 2014
2-(ethoxydifluoromethyl)-2-hydroxy-3-(1-tert-butoxycarbonylindol-3-yl)propionate,
diastereomeric
and only
Keywords:
10-tert-butoxycarbonyl-20-hydroxy-2,2-diethoxycarbonylspiro(cyclopropane-1,30-indoline)
Hydroxymalonates
DAST
traces of 1,1-bis(ethoxydifluoromethyl)-2-(1-tert-butoxycarbonylindol-3-yl)ethanol. The composition of
these mixtures changes depending on the reaction conditions. Regioselectively substituted ethyl 2-
hydroxy-2-[(1-tert-butoxycarbonylindol-3-yl)methyl]-3,3,3-trifluoropropionate reacts with DAST at 0 8C
in dichloromethane giving satisfactory yields of the corresponding 1-ethoxy-2-[(1-tert-butoxycarbony-
lindol-3-yl)methyl]-1,1,3,3,3-pentafluoropropan-2-ols as the exclusive reaction products. In the same
reaction conditions, ethyl 3-(1-tert-butoxycarbonylindol-3-yl)-2-hydroxypropionate mainly provides 10-
tert-butoxycarbonyl-20-hydroxy-2,2-diethoxycarbonylspiro(cyclopropane-1,30-indoline) together with the
‘‘normal’’ fluorination product ethyl 3-(1-tert-butoxycarbonylindol-3-yl)-2-fluoropropionate. A plausible
mechanism of this process is proposed in the following.
Difluoroethers
Fluoromalonates
Trifluoropyruvates
Fluoroindoles
ß 2014 Elsevier B.V. All rights reserved.
the only example of direct fluorination of carboxylic esters giving
Introduction
a
,
a-difluoroethers reported in the literature [9].
While intriguing, the result was completely disregarded and the
Right from its devising [1], diethylaminosulfur trifluoride
(DAST) is recognized as the best reagent to replace oxygen with
fluorine in organic molecules in very mild reaction conditions. It is
capable of transforming alcohols into the corresponding alkyl
fluorides [2]: carbonyl into gem-difluoroalkanes, and carboxylic
acids into acyl fluorides [3–6]. Furthermore, the latter can be
turned into the corresponding trifluoroalkyl derivatives in more
drastic conditions [7,8]. Esters, however, appear quite refractory to
DAST.
subject has never been revisited since. Nevertheless, we think this
topic should have been more closely examined as a possible access to
a,a-difluoroethers, a very important class of organic compounds
which finds application in several fields including fluorous chemistry
[10,11]. Medicinal chemistry employs many fluorinated ethers in the
treatment of almost all the human pathologies [12]. They are used in
antihypertensive drugs, atherosclerosis agents, antiasthmatics,
anxiolytics, antiulcer drugs, anti-inflammatories, antibiotics, antivi-
ral and antifungal medications and many other clinical applications.
In agrochemistry, their effectiveness has been proven as insecticides,
fungicides, plant growth regulators and herbicides [13,14].
While difluoromethyl alkyl/aryl ethers are easily obtained by
reaction of alkoxides or phenoxides with chlorodifluoromethane in
the presence of sodium hydroxide [15–17], or, alternatively, by SF4-
promoted fluorideoxygenation of alkyl/aryl formats [18], these
Thirty years ago Albert and co-workers found that when the
lactone 1 was exposed to a slight excess of DAST, difluorohex-
ahydrodifurodioxol 2 was obtained as the main reaction product
together with the expected a-fluorolactone 3 (Scheme 1). This was
strategies prove to be unsuitable to the synthesis of superior
difluoroalkylethers due to the competing base promoted-
elimination leading to haloalkenes. Nevertheless,
a
,
b
a
-
-
*
Corresponding author. Tel.: +39 075 5855543; fax: +39 075 5855262.
a,a
-difluoroalkyl
E-mail address: renzo.ruzziconi@unipg.it (R. Ruzziconi).
http://dx.doi.org/10.1016/j.jfluchem.2014.09.007
0022-1139/ß 2014 Elsevier B.V. All rights reserved.

S. Lepri et al. / Journal of Fluorine Chemistry 171 (2015) 82–91
83
products were identified in the crude mixture on the basis of their
GC–MS spectra as well as by the typical 19F NMR signals, the AB
system centered at ꢀ87.61 and the AA’BB’ system centered at
ꢀ85.68 ppm, respectively. The unexpected formation of the
difluoroether 8 and the tetrafluorodiether 9 peaked our curiosity
leading us to extend our investigation to other diethyl 2-alkyl-2-
hydroxymalonates (6, R = Me, nPr, Ph). They were easily affordable
in 83–96% yield from the reaction of the corresponding diethyl 2-
alkylmalonates with air, in DMF at room temperature and in the
presence of cesium fluoride. The reaction of the hydroxymalonates
(6) with DAST in dichloromethane ran slowly at room temperature,
substantially resulting in a mixture of the expected diethyl 2-alkyl-
2-fluoromalonate (7), ethyl 2-(ethoxydifluoromethyl)-2-hydro-
xyalkanoate (8) and 1,1-bis(ethoxydifluoromethyl)alkanol (9)
(Scheme 3, Table 1). Depending on the reaction condition, other
minor products were also detected. The latter were not isolated but
they were identified in the crude mixture as elimination products
10a–c from the substrate 6, the difluorinated ethoxyester 8 and the
tetrafluoroether 9, respectively, on the basis of their GC–MS
spectra as well as of the olefinic proton NMR signals.
Scheme 1. Fluorination products of
a-hydroxylactones with DAST.
Scheme 2. Fluorination of thioesters with DAST giving
a,a-difluoroethers.
alkyl ethers 5 have been obtained by DAST- [19], bis(2-methox-
yethyl)aminosulfur trifluoride (Deoxo-Fluor1)- [20] or BrF3-pro-
moted [21] fluorodesulfuration of the corresponding thioesters 4
(Scheme 2). Therefore, since esters are refractory to this kind of
The data reported in Table 1 show that the molar ratio of the
main reaction products 7–9 depends on the structure of the
starting material as well as on the reaction conditions. A typical
evolution of the reaction of 2-alkyl-2-hydroxymalonates with
DAST is roughly represented by the plot reported in Fig. 1 where
the mixture composition of the reaction of 6 (R = nPr) with DAST
was determined at regular intervals.
The DAST-promoted replacement of the OH group by fluorine,
the ‘‘normal’’ fluorination mode, turned out to be a very slow
process. Moreover, contrarily to what happened in the reaction
of 2-aryl-2-hydroxymalonates, difluorination of the ethoxycar-
bonyl group by DAST competes significantly with the fluorina-
fluorinating reagents, their conversion into
ethers is made possible only after being transformed into the
corresponding thioesters.
a,a-difluoroalkyl/aryl
In a previous research aimed at synthesizing some regioselec-
tively fluorinated profens, we found that 2-aryl-2-fluoropropionic
acid can be easily obtained from the corresponding 2-hydro-
xyesters by DAST-promoted OH/F permutation followed by
alkaline hydrolysis of the resulting 2-fluoroester [22]. At the same
time, we noticed that dialkyl 2-alkyl-2-fluoromalonates were
prepared by exhaustive alcoholysis of hexafluoropropene followed
by base-promoted alkylation of the resulting 2-fluoromalonates
with alkyl halogenides [23] or, alternatively, by fluorination of
dialkyl 2-alkylsodiomalonates with either Xenon difluoride [24] or
electrophilic NF fluorinating reagents [25–27]. However, direct
DAST-promoted fluorination of dialkyl 2-alkyl-2-hydroxymalo-
nates was never reported. Intrigued by this singularity and aiming
to fill this gap, we explored the possibility of accessing dialkyl
2-alkyl-2-fluoromalonates by DAST-promoted fluorination of the
corresponding 2-hydroxyesters.
tion of the hydroxylic
a-carbon. The fluorination mode is also
influenced to a great extent by steric effects. Accordingly, the
OH/F permutation is the most important process in the reaction
of 6 (R = H), whilst the 7/(8 + 9) molar ratio drops significantly
when methyl- in the malonate 6 is replaced by the bulkier ethyl-,
butyl and benzyl groups [compare entry 1 (R = H) with entries 5,
8
and 15 in Table 1]. Furthermore, the amount of the
hydroxytetrafluoroether 9 increases to the detriment of the
difluorohydroxyester 8 to such an extent that, with 4 equiv. of
DAST, at higher temperature and longer reaction times, difluoro
ether 8 is completely converted into tetrafluoro ether 9 (entry 4).
As expected for highly energetic transition states, elimination
products begin to appear when a large excess of DAST is
employed at very long reaction times (entries 7 and 10) or higher
temperatures (entries 11–14). Accordingly, the reaction of the
diethyl 2-benzyl-2-hydroxymalonate 6 (R = Ph) with 7 equiv. of
DAST in refluxing 1,2-dichloroethane rapidly gives 9 which is
slowly transformed into the 1,1-bis(ethoxydifluoromethyl)-1-
pentenes 10.
Results and discussion
Firstly, we exposed diethyl 2-hydroxy-2-methylmalonate (6,
R = H) to DAST (1.5 equiv.) in dichloromethane at room tempera-
ture with the firm belief of obtaining diethyl 2-fluoro-2-
methylmalonate
(7).
Diethyl
2-fluoro-2-methylmalonate
(7, R = H) was obtained as the main reaction product (36%)
together with ethyl 3-ethoxy-3,3-difluoro-2-hydroxy-2-methyl-
propanoate (8, R = H, 4%), and, 1,3-diethoxy-1,1,3,3-tetrafluoro-2-
methylpropan-2-ol (9, R = H, 5%) (Scheme 3). The latter two
Ph
Scheme 3. Fluorination products from of 2-alkyl-2-hydroxymalonates with DAST.

84
S. Lepri et al. / Journal of Fluorine Chemistry 171 (2015) 82–91
Table
1
Composition of the reaction products of diethyl 2-RCH2-2-hydroxymalonate with DAST in CH2Cl2 at different reaction conditions.
Entry
R
Conditions
Eq. of DAST
Composition of the crude product, (%)
Temp. 8C
Time, h
6
7
8
9
10b
1
2
H
1
4
4
4a
1
2
5
1
1
5
1
1
2
7
3
5
7
25
25
25
80
25
25
25
25
25
25
40
40
40
70
25
25
70
3
3
55
50
8
36
42
72
51
5
4
4
4
–
5
4
–
–
3
144
16
16
16
144
5
16
20
18
21
25
1
–
4
29
64
52
49
83
82
42
44
23
30
15
3
–
5
Me
nPr
13
13
9
0
6
7
5
7
6
11
0
8
3
13
12
22
8
9
48
144
5
2
4
0
10
11
12
13
14
15
16
17
6
24
23
31
23
26
11
28
12
6
10
13
9
9
48
5
22
12
9
6
21
36
3
36
24
48
48
14
16
6
Ph
36
23
–
1
11
43
1
6
a
Solvent, C2H4Cl2.
b
Mixture of alkenes stereoisomers formed by elimination from 6 to 9 detected by GC and GC-MS.
On the basis of the data reported in Table 1, as well as the plot in
through the probable formation of the fluoroepoxide intermediate
11. Though stable three-term cyclic acetals are known [28,29], we
were not able to isolate the intermediate 11 in our reaction
conditions. Thus, the quick opening of the epoxide by hydrofluoric
acid developed during the previous steps provides the 2-(ethox-
ydifluoromethyl)-2-hydroxyester 8. On the other hand, that the
Fig. 1, the unusual behavior of 2-alkyl-2-hydroxymalonates
toward DAST could by rationalized by the following mechanistic
hypothesis (Scheme 4):
Clearly, approach of DAST to the OH group of a tertiary alcohol is
made difficult for evident steric reasons. In addition, the presence
of a further electron-withdrawing group on the
a
carbon, such as
presence of the a-hydroxyl group is essential to the fluorination of
the ethoxycarbonyl, strengthens the C–OH bond to the extent that
the sulfonamido group, usually a good leaving group, is hardly
replaced by fluorine. In the case of 6 (R = H), attack of DAST at the
hydroxyl group leading to the ‘‘normal’’ fluorination product 7
(R = H) is still preponderant. As soon as the steric hindrance
increases, the attack of DAST to the carbonyl oxygen prevails to a
the carbonyl ester is proved by the fact that the corresponding
2-methoxymalonate, obtained by methylation of the alcohol with
NaH/CH3I, turned out to be completely inert toward DAST in any
reaction conditions. A similar behavior of the hydroxyl group in
assisting the fluorination of a carbonyl group was also observed in
the DAST-mediated cyclization of
fluorooxazolines [30].
a-acylaminoketones to give
greater extent. Due to the stabilizing effect of the
and mostly to the anchimeric assistance of the adjacent
the fluorosulfonamido group is rapidly replaced by fluoride
a
-ethoxy group,
b
-hydroxy,
Likewise, the fluorinated hydroxyester 8 reacts with DAST to
give 1,1-bis(ethoxydifluoromethyl)alkyl carbinol 9. Significantly,
Fig. 1. Composition of the reaction mixture of the fluorination of diethyl 2-butyl-2-hydroxymalonate with DAST in the time.

S. Lepri et al. / Journal of Fluorine Chemistry 171 (2015) 82–91
85
Scheme 4. The proposed mechanism for the fluorination of 2-alkyl-2-hydroxyesters with DAST.
neither trifluoroester from 8 nor pentafluoro diethers from 9 were
formed by OH/F permutation, even in the presence of a large excess
of DAST or at longer reaction times. This means that, although the
ethoxydifluoromethyl group is less electron-withdrawing than the
ethoxycarbonyl group, it is bulky enough [31,32] to divert the
attack exclusively at the second carbonyl group.
as enophiles, diethyl 2-hydroxy-2-(indol-3-ylmethyl)malonates
(15), ethyl 2-hydroxy-2-(indol-3-ylmethyl)-3,3,3-trifluoropropio-
nate (16) and ethyl 2-hydroxy-2-(indol-3-yl)propionate (17),
respectively, were obtained in satisfactory yields (Scheme 5) [33].
The reaction of diethyl 2-hydroxy-2-(indol-3-ylmethyl)malo-
nate 15 with a slight excess of DAST, in dichloromethane at 0 8C,
In order to develop a synthetic approach to either fluorinated
a-
afforded the expected a,a-difluoroether 18 together with a spiro-
hydroxyester or polyfluorinated ethers, the above process was
applied to the synthesis of nucleus- and side-chain substituted
indole derivatives. To that end, regioselectively substituted 3-
methyleneindolines 14 were prepared by tributyltin hydride-
promoted radical cyclization of the tert-butyl N-bromoaryl-N-
propargylcarbamates 13. When neat 14 were heated 1 h at 100 8C
with 2-oxomalonate, ethyl 3,3,3-trifluorpyruvate or ethyl glioxalate
3-indolinecyclopropyl ester 21 (Scheme 6). Only traces of the
tetrafluoroether 19 were detected in the crude mixture.
The product ratio turned out to be very sensitive to electronic
effects, as it changes significantly withthenature of thesubstituentat
C-5 of the indole nucleus (Table 2). Electron-releasing substituents
favor the formation of an appreciable amount of the spirocompound
21 (compare entries 3 and 8 in Table 2). It becomes the main reaction
Scheme 5. Synthesis of ethyl 2-hydroxy-2-[(indol-3-yl)methyl]esters 15–17 by ene reactions.

86
S. Lepri et al. / Journal of Fluorine Chemistry 171 (2015) 82–91
Scheme 6. Fluorination products of 2-hydroxy-2-[(indol-3-yl)methyl]malonates with DAST.
Table
2
Reaction of diethyl 2-hydroxy-2-[(indol-3-yl)methyl]malonates 15 (1.0 mmol) with DAST in CH2Cl2 at 0 8C.
Entry
R
DAST, eq.
Recovered 15, %
Yield on converted 15, %a
18
50
19
20
21
1
2
3
4
5
6
7
8
5-H
5-F
1.1
6.0
1.1
5.0
1.0
2.0
1.2
1.2
77
9
<1b
<1b
–
31d
<1b
<1b
–
–
–
–
7
–
–
–
–
50
36
17c
62d
71
63
83c
ND
29
41
71
ND
66
35
49
18
13
30
5-Cl
59
5-CH3
6-CF3
29
100
–
a
Yield of isolated product.
b
c
Identified by the typical triplet ( J = 25 Hz) at 161.0 ppm in the 19F NMR spectrum.
In the presence of 4.0 eq. of Pyꢁ(HF)x.
d
Determined by 19F NMR signal integration of the product in the crude mixture relatively to the internal standard 3-bromo-5-fluorobenzotrifluoride.
product by adding of Pyꢁ(HF)x to the reaction mixture (Compare
entries 3 and 4 in Table 2). Both the absence of fluorine
and the presence of two ethoxycarbonyl groups in the spiro
derivative 21 clearly denote the transfer of OH group from the
quite improbable that 21 endures the attack of DAST and HF, both
being present in the reaction medium.
The unexpected formation of the spirocyclopropaneindoline 21
indeed deserves a thorough mechanistic investigation, but this lies
beyond the aim of the present work.
malonate
a carbon to the indole nucleus. Two mechanistic
hypotheses could be formulated: the first considers the
possibility of an intramolecular HF-catalysed transfer of the
OH through a five-membered cyclic transition state (path b);
the second hypothesis (path a) envisages the formation of a
polycyclic intermediate 23 from the previously formed fluor-
ooxiran 22 (Scheme 7). Subsequently, 23 undergoes hydrolyses
to the final spirocyclopropaneindoline 21 during the aqueous
work-up. The latter hypothesis appears more convincing, as it is
Much better results are obtained when ethyl 2-[(indole-3-
yl)methyl]-3,3,3-trifluoropropionates (16a–f) are made to react
with 3 equiv. of DAST in CH2Cl2 at 0 8C. In this case, the pentafluoro-
b-hydroxyethers (24a–f) were exclusively formed in fairly good
yields (Scheme 8). Here, both steric and electronic effects play a
synergic role in promoting the carbonyl fluorination. Though CF3
group exerts an inductive electron-withdrawing effect comparable,
if not slightly lower, to that of –CO2Et group, its steric requirements
Scheme 7. Mechanistic hypothesis for the formation of the spirocompound 21.

S. Lepri et al. / Journal of Fluorine Chemistry 171 (2015) 82–91
87
on a 30 m ꢂ 0.32 mm capillary column loaded with HP-5 MS (5%
phenyl-methylpolysiloxane). Mass spectra were obtained at 70 eV
with an Agilent Technologies GC 7820A/MS 5975 Series apparatus.
HRMS spectra were registered on Agilent Technologies 6540 UHD
Accurate Mass Q-TOF LC/MS. The purity of all final products was
attested to by either elemental analysis performed on Carlo Erba
Elemental Analyzer Mod. 1106 or LC/MS determinations.
Reagents and solvents
Diethyl 2-methy-, 2-ethyl-, 2-butyl-, 2-benzylmalonates,
diethyl ketomalonate, 3,3,3-trifluoropyruvate and ethyl glyoxalate
(technical solution in toluene), cesium fluoride, DAST and the
Olah’s reagent are commercial products and were used without
further purification. Tetrahydrofuran and diethyl ether were
distilled from potassium hydroxide in the presence of cuprous
chloride and redistilled from sodium wire in the presence of
benzophenone. Dichloromethane was distilled from phosphorous
pentoxide after being refluxed for 2 h.
Scheme 8. Fluorination products of ethyl 2-hydroxy-2-(indolylmethyl)pyruvates
16 with DAST.
Diethyl 2-methy- (6R = H)), 2-ethyl- (6R = CH3), 2-butyl-
(6R = nPr) and 2-benzyl-2-hydroxymalonates (6R = Ph) were
prepared in 78–89% of yield by I2-catalyzed air-promoted
photooxygenation of the corresponding 2-alkylmalonates [34],
their spectroscopic characteristics were identical to those reported
in the literature [33,35].
Scheme 9. Fluorination products of ethyl 2-hydroxy-2-(5-fluoroindol-3-
yl)propionate 17 with DAST.
Diethyl 2-[(1-tert-butoxycarbonylindol-3-yl)methyl]-2-hydro-
xymalonates 15a,b,e, ethyl 2-[(1-tert-butoxycarbonylindol-3-
yl)methyl]-2-hydroxy-3,3,3-trifluoropropionates 16b,e and ethyl
3-(1-tert-butoxycarbonylindol-3-yl)-2-hydroxypropionate 17a,b
were available from a previous investigation [28]. Diethyl 2-[(1-
tert-butoxycarbonylindol-3-yl)methyl]-2-hydroxymalonates
15c,d, ethyl 2-[(1-tert-butoxycarbonylindol-3-yl)methyl]-2-hy-
droxy-3,3,3-trifluoropropionates 16a,c,d were prepared by the
same procedure reported in ref. [32] starting from commercial 2-
bromo-4-chloroaniline (for 15c and 16c) and 2-bromo-4-methy-
laniline (for 15d and 16d). The new products exhibited the
following spectroscopic characteristics:
are substantially larger [32] and the attack of DAST to OH group
becomes all the more difficult.
That the steric effect is the main factor accounting for the
outcome of this process is confirmed by the reaction of DAST with
ethyl 2-hydroxy-3-(indol-3-yl)propionate (17), which, in the same
conditions (CH2Cl2, 0 8C), provides a mixture of 2-fluoro-3-(indol-
3-yl)propionate (25) and a mixture of diastereomeric spiroesters
(26), the latter being the main reaction product (Scheme 9). No
a,a-difluoroether was detected, however, evidently because the
secondary OH group is much more accessible to DAST. Moreover, the
absence of a second electron-drawing group, like CF3 or ethoxycarbo-
nyl, greatly facilitates the replacement of the hydroxyl by fluorine.
Diethyl 2-[(1-tert-butoxycarbonyl-5-chloroindol-3-yl)methyl]-
2-hydroxymalonates (15c, 65% from the corresponding 3-
methyleneindoline and diethyl ketomalonate). Colorless oil; 1H
NMR
7.23 (dd, J = 8.8 and 2.0 Hz, 1H), 4.22 (sym.m, 4H), 3.90 (s, 1H),
3.41 (s, 2H), 1.65 (s, 9H), 1.28 (t, J = 7.1 Hz, 6H). 13C NMR
169.8
(2C), 149.1, 133.4, 132.0, 128.1, 126.6, 124.3, 119.2, 116.1, 112.9,
83.9, 78.8, 62.7 (2C), 29.9, 28.1 (3C) 13.9 (2C).
Diethyl 2-[(1-tert-butoxycarbonyl-5-methylindol-3-yl)methyl]-
2-hydroxymalonates (15d, 71% from the corresponding 3-methyle-
neindoline and diethyl ketomalonate). Colorless oil; 1H NMR
d7.96 (bd,
J = 7.0 Hz, 1H), 7.46 (s, 1H), 7.39 (d, J = 1.0 Hz, 1H), 7.09 (dd, J = 8.5 and
1.0 Hz, 1H), 4.21 (sym.m, 4H), 3.95 (bs, 1H), 3.44 (s, 2H), 2.43 (s, 3H),
1.64 (s, 9H), 1.26 (t, J = 7.1 Hz, 6H); 13C NMR
d 169.9 (2C), 149.5, 133.3,
131.6, 131.1, 125.5, 125.1, 119.4, 114.6, 113.3, 83.2, 79.1, 62.3 (2C), 30.0,
28.1 (3C), 21.3, 13.9 (2C).
Ethyl 2-[(1-tert-butoxycarbonylindol-3-yl)methyl]-2-hydroxy-
3,3,3-trifluoropropionate (16a, 76% from the corresponding 3-
methyleneindoline and ethyl 3,3,3-trifluoropyruvate). Colorless oil;
1H NMR
d 8.13 (bd, J = 7.6 Hz, 1H), 7.62 (d, J = 7.8 Hz, 1H), 7.53 (s, 1H),
d 8.01 (bd, J = 8.1 Hz, 1H), 7.57 (d, J = 1.8 Hz, 1H), 7.51 (s, 1H),
Conclusions
d
Our investigation leads to the conclusion that, in particular
conditions,
give -difluoroethers. The reaction is very sensitive to steric and
electroniceffects, thebestresultsbeingobtained whenthe -carbon
a-hydroxyesters may be directly fluorinated by DAST to
a,a
a
isbound tostrongelectron-withdrawinggroups, moresoifthe latter
possess striking steric requirements. The presence of the hydroxy
group
a to the alkoxycarbonyl group is essential to the carbonyl
fluorination. Accordingly, though being inert to DAST, it exerts an
important anchimericassistancemakingthemoreexposedcarbonyl
oxygen easily replaced by two fluorine atoms through the probable
formation of a fluoroepoxide intermediate. These particular condi-
tions have been applied to the synthesis of indole-based
b-hydroxy-
a,a-difluoroethers, a new class of compounds which could find
applications in pharmacology and agrochemistry.
7.32 (td, J = 8.3 and 1.0 Hz, 1H), 7.25 (td, J = 7.8 and 1.0 Hz, 1H), 4.18
(sym.m, 2H), 3.97 (bs, 1H), 3.49 (d, J = 14 Hz, 1H), 3.26 (d, J = 14 Hz,
1H), 1.68 (s, 9H), 1.25 (t, J = 7.3 Hz, 3H); 13C NMR
d168.9, 149.4, 135.1,
Experimental
Unless otherwise specified, 1H NMR and 13C NMR spectra were
recorded at 400 and 100 MHz, respectively, in CDCl3 solution using
tetramethylsilane as an internal standard. 19F NMR spectra were
recorded at 376 MHz in CDCl3 solution using CFCl3 as a reference
standard. IR spectra were registered in CHCl3 solution in the 4000–
625 cmꢀ1 range. Gas-chromatographic analyses were performed
130.5, 127.6, 125.4, 124.4, 123.4 (q, J = 286 Hz), 122.4, 119.4, 115.1,
112.0, 83.7, 78.0 (q, J = 29 Hz), 63.8, 28.1 (3C), 27.2, 13.7.
Ethyl 2-[(1-tert-butoxycarbonyl-5-chloroindol-3-yl)methyl]-
2-hydroxy-3,3,3-trifluoropropionate (16c, 71% from the corre-
sponding 3-methyleneindoline and ethyl 3,3,3-trifluoropyruvate).
Colorless oil; 1H NMR
d 8.03 (bd, J = 9.2 Hz, 1H), 7.57 (d, J = 1.8 Hz,

88
S. Lepri et al. / Journal of Fluorine Chemistry 171 (2015) 82–91
1H), 7.53 (s, 1H), 7.25 (dd, J = 7.4 and 2.1 Hz, 1H), 4.19 (sym.m, 2H),
3.97 (bs, 1H), 3.43 (d, J = 14 Hz, 1H), 3.20 (d, J = 14 Hz, 1H), 1.66 (s,
Ethyl 2-(ethoxydifluoromethyl)-2-hydroxyhexanoate (8R = nPr).
Colorless oil; 1H NMR
4.30 (m, 2H), 3.25 (q, J = 7.1 Hz, 2H),
3.65 (s, 1H), 2.0 (m, 1H), 1.8 (m, 1H), 1.5 (m, 1H), 1.32, (t,
J = 7.1 Hz, 5H), 1.26 (t, J = 7.1 Hz, 3H), 1.02 (m, 1H),
J = 7.3 Hz, 3H). 13C NMR
171.3, 122.6 (t, J = 270 Hz),
J = 30 Hz), 62.7, 59.8 (t, J = 6.6 Hz),
19F NMR
ꢀ85.14 (d, J = 141 Hz, 1F), ꢀ87.41 (d, J = 141 Hz, 1F).
1,1-Bis(ethoxydifluoromethyl)-1-pentanol (9R = nPr). Color-
less oil; 1H NMR
3.99 (q, J = 7.4 Hz, 4H), 2.75 (s, 1H), 1.86 (m, 2H),
1.45 (m, 4H), 1.29 (t, J = 7.4 Hz, 6H), 0.92 (t, J = 7.2 Hz, 3H); 13C NMR
123.0 (t, J = 270 Hz), 62.8, 59.7, 31.0, 24.6, 23.3, 14.9, 13.9; 19F
NMR
ꢀ83.9, (sym.m, AA’BB’ system).
From dimethyl 2-hydroxy-2-benzylmalonate (6R = Ph). Di-
methyl 2-benzyl-2-fluoromalonate (7R = Ph) [36]. 1H NMR
7.4 (m, 2H), 7.2 (m, 3H), 3.79 (s, 6H), 3.48 (d, J = 25 Hz, 2H); 19F
NMR
ꢀ165.53 (t, J = 25 Hz, 1F).
Methyl 2-hydroxy-2-(methoxydifluoromethyl)-3-phenyl-
propionate (8). Colorless oil; 1H NMR
7.3 (m, 5H), 3.77 (s,
3H), 3.64 (s, 3H), 3.60 (s, 1H), 3.33–3.15 (four peaks, AB system,
d
d
d
9H), 1.29 (t, J = 7.0 Hz, 3H); 13C NMR
d
169.0, 149.0, 133.5, 131.6,
128.2, 126.9, 124.5, 123.3 (q, J = 288 Hz), 119.1, 116.2, 111.3, 84.2,
77.7(q, J = 29 Hz)64.0,28.1(3C),27.2, 13.8;19FNMR
d
d
d
d
d
d
d
0.89 (t,
d 78.9 (t,
d
ꢀ78.66(s, 3F).
d
Ethyl 2-[(1-tert-butoxycarbonyl-5-methylindol-3-yl)methyl]-2-
hydroxy-3,3,3-trifluoropropionate (16d, 75% from the correspond-
ing 3-methyleneindoline and ethyl 3,3,3-trifluoropyruvate). Colorless
d
d 31.3, 24.6, 22.3, 14.8, 13.8;
d
oil; 1HNMR
d
7.99 (bd, J = 8.2 Hz, 1H), 7.49 (s, 1H), 7.40 (s, 1H), 7.14 (dd,
d
J = 8.6 and 1.5 Hz, 1H), 4.19 (sym.m, 2H), 4.00 (s, 1H), 3.47 (d, J = 15 Hz,
1H), 3.24 (d, J = 15 Hz, 1H), 2.47 (s, 3H), 1.68 (s, 9H), 1.27 (t, J = 7.1 Hz,
d
3H); 13CNMR
d
169.0, 149.4, 133.3, 131.8, 130.7, 125.8, 125.5, 123.5 (q,
J = 286 Hz), 119.2, 114.7, 111.7, 83.5, 78.0 (q, J = 29 Hz), 63.8, 28.2 (3C),
27.3, 21.3, 13.8; 19F NMR
ꢀ78.59 (s, 3F).
d
d
d
General procedure for the fluorination of diethyl 2-alkyl-2-
d
hydroxymalonates (6) with DAST
d
A suitable amount of DAST (see Table 1) was added to a solution
of diethyl 2-alkyl-2-hydroxymalonates (1.0 mmol) in dichloro-
methane (10 mL) (the same volume of dichloroethane was used for
the reactions carried out at temperatures above 40 8C) and the
mixture was made to react for the suitable time (see Table 1). The
reaction progress was monitored by following the disappearance
of the starting material by gas-chromatographic analysis of
samples collected at regular time. Finally, after cooling to 0 8C,
5%, saturated aqueous sodium bicarbonate was added (20 mL) and
the mixture stirred for 15 min. The organic phase was separated,
the aqueous phase was extracted with dichloromethane
(2 ꢂ 30 mL) and the collected organic phases were dried with
sodium sulfate.
JAB = 14 Hz, 2H). 13C NMR
d 170.6, 134.1, 130.4, 128.1, 127.2, 122.5
(t, J = 271 Hz), 79.4 (t, J = 31 Hz), 53.4, 50.9, 37.8; 19F NMR
(d, J = 139 Hz, 2F), ꢀ89.77 (d, J = 139 Hz, 2F).
d
ꢀ87.40
2-Benzyl-1,3-dimethoxy-1,1,3,3-tetrafluoropropan-2-ol
(9R = Ph). 1H NMR
2H); 19F NMR
ꢀ84.59 ꢀ86.23 (sym.m, AA’BB’ system 4F).
d 7.3 (m, 5H), 3.63 (s, 1H), 3.59 (s, 6H), 3.19 (s,
d
Reaction of diethyl 2-[(1-tert-butoxycarbonylindol-3-yl)]-2-
hydroxymalonates 15a–e with DAST in CH2Cl2 at 0 8C
A suitable amount of DAST (Table 2) was added to a solution of
diethyl 2-hydroxy-2-(indol-3-yl)methylmalonates (1.0 mmol) in
dichloromethane under argon atmosphere (10 mL) and the
mixture was made to react for 5 h at 0 8C. The reaction progress
was monitored by following the disappearance of the starting
material by tlc (2:8 diethyl ether-petroleum ether). A saturated
aqueous solution of sodium bicarbonate was added (10 mL) and
the mixture stirred for 15 min. The organic phase was separated
and the aqueous phase was extracted with dichloromethane (2ꢂ
30 mL). The collected organic phases were then dried with sodium
sulfate and the solvent was evaporated at reduced pressure.
The isolated products were identified as follows:
After solvent evaporation at reduced pressure, a mixture of
hardly separable fluorinated products was obtained. Each compo-
nent in the mixture was identified on the basis of its typical 19F
NMR absorptions, and by comparison with the available literature
data.
From diethyl 2-hydroxy-2-methylmalonate (6R = H). Diethyl
2-fluoro-2-methylmalonate (7R = H) [22]. 1H NMR
d
4.30 (q,
1.31 (t, J = 7.1 Hz, 6H); 13
d 62.5, 20.6 (d, J = 23 Hz), 13.9;
J = 7.1 Hz, 4H),
NMR 166.6, 92.3 (d, J = 193 Hz),
19F NMR
ꢀ157.9 (q, J = 22 Hz).
Ethyl 3-ethoxy-3,3-difluoro-2-hydroxy-2-methylpropionate
(8R = H). colorless oil; 1H NMR
4.28 (q, J = 7.1 Hz, 2H), 3.97 (q,
J = 7.1 Hz, 2H), 2.75 (s, 1H), 1.44 (t, J = 1.1 Hz, 3H), 1.27 (m, 6H); 19
NMR
ꢀ86.25 (d, J = 140 Hz, 1F), ꢀ88.97 (d, J = 140 Hz, 1F).
1,3-Diethoxy-1,1,3,3-tetrafluoro-2-methylpropan-2-ol
d
1.79 (d, J = 22 Hz, 3H),
d
C
d
d
Ethyl
2-[(1-tert-butoxycarbonylindol-3-yl)methyl]-3,3-
d
difluoro-3-ethoxy-2-hydroxypropionate (18a). Chromatography
of the crude product from the reaction of 15a with 6.0 equiv. of
DAST, enabled a colorless oil (0.14 g, 32%) to be collected exhibiting
F
d
the following spectroscopic and analytic characteristics: 1H NMR
d
(9R = H) colorless oil; 1H NMR
d
3.3 (m, 4H), 3.01 (s, 1H), 1.40
8.10 (bd, J = 6.4 Hz, 1H), 7.64 (d, J = 7.2 Hz, 1H), 7.51 (s, 1H), 7.29 (t,
J = 7.2 Hz, 1H), 7.23 (t, J = 7.2 Hz, 1H), 4.2 (m, 1H), 4.0 (m, 3H), 3.83
(s, 1H), 3.50 (d, J = 15 Hz, 1H), 3.22 (d, J = 15 Hz, 1H) 1.66 (s, 9H),
1.32 (t, J = 7.2 Hz, 3H), 1.22 (t, J = 7.2 Hz, 3H); 13C NMR
d 170.4 (2 C),
149.6, 135.1 (d, J = 4.0 Hz), 130.9, 125.3, 122.5 (t, J = 271 Hz), 124.2,
122.2, 119.6, 115.0, 113.2, 83.5, 79.1 (t, J = 29 Hz), 62.9, 60.2 (t,
(quint, J = 1.1 Hz, 3H), 1.21 (t, J = 7.1 Hz, 6H); 19F NMR
d
ꢀ85.59–
85.78 sym.m, AA’BB’ system, 4F).
From diethyl 2-hydroxy-2-methylmalonate (6R = CH3). Diethyl
2-ethyl-2-fluoromalonate (7R = CH3) [22] 1H NMR
4.29 (q,
J = 7.1 Hz, 4H), 2.13 (dq, J = 22 and 6.8 Hz, 2H), 1.27 (t, J = 7.1 Hz,
6H), 0.98 (m, 3H); 19F NMR
ꢀ169.61 (t, J = 24 Hz, 1F).
Ethyl 2-(ethoxydifluoromethyl)-2-hydroxybutanoate (8R = CH3).
1HNMR
4.29 (q, J = 7.1 Hz, 2H), 3.94 (q, J = 7.1 Hz,2H),3.63(s,1H), 2.05
(sym.m, 2H), 1.30 (t, J = 7.1 Hz, 3H), 1.24 (t, J = 7.1 Hz, 3H), 1.00 (t,
J = 7.2, 3H). 13CNMR
171.2, 122.6(t, J = 270 Hz), 79.3(t, J = 31 Hz), 62.7,
d
d
J = 6.4 Hz), 28.2 (3C), 27.1, 14.9, 13.8; 19F NMR
d
ꢀ84.35 (d,
J = 140 Hz, 1F), ꢀ86.74 (d, J = 140 Hz, 1F). Anal. Calcd. for
C21H27F2NO6 C, 59.01; H, 6.37; N, 3.28. Found: C, 59.24; H, 56.37;
d
d
d
N, 3.28. Unreacted malonate (0.036 g, 9%) was collected as the
second eluted product. Finally, an amorphous white solid (0.24 g,
59%) was recovered as a third product and identified as follows:
Diethyl 10-tert-butoxycarbonyl-20-hydroxyspiro[cyclopro-
d
59.8 (t, J = 6.6 Hz), 24.6, 14.8, 14.0, 7.0. 19F NMR
1F), ꢀ87.30 (d, J = 141 Hz, 1F).
d
ꢀ85.06 (d, J = 141 Hz,
1,1-Bis(ethoxydifluoromethyl)-1-propanol (9R = CH3) Color-
pane-1,30-indoline]-2,2-dicarboxylate (21a). 1H NMR
d 7.66
less oil; 1H NMR
(t, J = 7.2 Hz, 6H); 19F NMR
From diethyl 2-butyl-2-hydroxymalonate (6R = nPr). Diethyl 2-
butyl-2-fluoromalonate (7R = nPr) [22]. 1H NMR
4.38 (q,
J = 7.0 Hz, 4H), 2.0 (m, 2H), 1.38–1.26 (m, 12H), 0.93 (t, 7.1 Hz,
3H); 19F NMR
ꢀ167.68 (t, J = 24 Hz, 1F)
d
3.71 (q, J = 6.8 Hz, 4H), 2.34 (q, J = 7.2 Hz, 2H), 0.90
ꢀ83.00 (sym.m, AA’BB’ system, 4F).
(bs, 1H), 7.23 (td, J = 8.1 and 1.2 Hz, 1H), 6.75 (dt, J = 7.7 and
0.7 Hz, 1H), 5.97 (s, 1H), 4.3 (m, 2H), 4.1 (m, 1H), 4.0 (m, 1H), 2.38
(d, J = 6.1 Hz, 1H), 2.12 (d, J = 6.1 Hz, 1H), 1.64 (s, 9H), 1.32 (t,
d
d
J = 7.1 Hz, 3H), 1.07 (t, J = 7.1 Hz, 3H); 13C NMR
d
167.6, 165.9,
152.7, 128.8, 127.6, 122.0, 120.8, 114.5, 83.2, 62.0, 61.6, 42.5, 28.4,
20.8, 13.9, 13.7; IR,
max, 3686, 3586, 1722 cmꢀ1
d
n
.

S. Lepri et al. / Journal of Fluorine Chemistry 171 (2015) 82–91
89
Chromatography on silica gel of the crude product from the
reaction of malonate 15b (0.63 g, 1.5 mmol) with DAST (1.1 equiv.)
allowed us to collect ethyl 2-[(1-tert-butoxycarbonyl-5-fluoroin-
dol-3-yl)methyl]-3,3-difluoro-3-ethoxy-2-hydroxypropionate
(18b) (0.027 g, 6%) as the first eluted product. It was identified on
the basis of the following spectroscopic and analytic characteristics:
112.6, 84.0, 78.9 (t, J = 31 Hz), 63.1, 60.3 (t, J = 6.4 Hz), 28.2 (3C),
27.1, 15.0, 13.8; 19F NMR
J = 141 Hz, 1F). HRMS, calcd. for C21H26ClF2NO6, 461.14167. Found,
461.14161.
After having collected the unreacted 15c (0.080 g, 18%), a third
eluted product was separated and identified as diethyl 10-tert-
butoxycarbonyl-50-chloro-20-hydroxyspiro[cyclopropane-1,30-
indoline]-2,2-dicarboxylate (21c) on the basis of the following
characteristics: white amorphous solid (0.15 g, 34%); 1H NMR
d 7.8
(bs, 0.5H), 7.3 (bs, 0.5H), 7.21 (bd, J = 7.6 Hz, 1H), 6.70 (s, 1H), 5.97
(bs, 1H), 4.3 (m, 2H), 4.1 (m, 2H), 2.40 (bs, 1H), 2.11 (d, J = 6.6 Hz,
1H), 1.63 (s, 9H), 1.32 (t, J = 7.0 Hz, 3H), 1.11 (t, J = 6.8 Hz, 3H); 13
C
d
ꢀ83.86 (d, J = 141 Hz, 1F), ꢀ86.20 (d,
1H NMR
d 8.03 (bs, 1H), 7.53 (s, 1H), 7.29 (dd, J = 9.1 and 2.6 Hz, 1H),
7.00 (td, J = 9.1 and 2.6 Hz, 1H), 4.3 (m, 2H), 4.0 (m, 2H), 3.80 (d,
J = 1.2 Hz, 1H), 3.42 (bd, J = 15 Hz, 1H), 3.17 (dd, J = 15 and 0.9 Hz,
1H), 1.65 (s, 9H), 1.31 (t, J = 7.1 Hz, 3H), 1.23 (t, J = 7.1 Hz, 3H);
13C NMR
d 170.4 (d, J = 2.0 Hz), 159.2 (d, J = 237 Hz), 149.3, 131.9
(d, J = 9.8 Hz), 131.5, 127.0, 122.5 (t, J = 272 Hz), 116.0 (d, J = 9.1 Hz),
113.0 (d, J = 4.0 Hz), 112.0 (d, J = 25 Hz), 111.8, 105.3 (d, J = 24 Hz),
83.8, 79.1 (t, J = 30 Hz), 63.1, 60.3 (t, J = 6.6 Hz), 28.2 (3 C), 27.2, 14.9,
NMR
d 167.3, 165.7, 140.9, 140.1, 128.7, 127.6, 121.2, 115.4, 83.6,
62.4, 62.0, 42.5, 28.4, 21.0, 14.1, 13.9; IR,
n
max, 3680, 3587,
13.8; 19F NMR
d
ꢀ83.91 (d, J = 141 Hz, 1F), ꢀ86.27 (d, J = 141 Hz, 1F),
1720 cmꢀ1. Anal. Calcd. for C21H26ClNO7 C, 57.34; H, 5.96; N,
3.18. Found: C, 57.11; H, 5.96; N, 3.18.
ꢀ121.25 (s, 1F). Anal. Calcd. for C21H26F3NO6 C, 56.63; H, 5.88;
N, 3.14. Found: C, 55.80; H, 5.88; N, 3.14.
From the hydroxylmalonate 15d a crude oily mixture was
obtained from which the following products were separated by
chromatography on silica gel:
Unreacted hydroxymalonate 15b (0.28 g, 66%) was recovered as
the second eluted product and, finally, a third eluted product
consisted of a 1:1.2 diastereomeric mixture of diethyl 10-tert-
butoxycarbonyl-50-fluoro-20-hydroxyspiro[cyclopropane-1,30-
indoline]-2,2-dicarboxylate (21b) according to the following
spectroscopic and analytical characteristics: white solid (0.24 g,
Ethyl 2-[(1-tert-butoxycarbonyl-5-methylindol-3-yl)methyl]-
3,3-difluoro-3-ethoxy-2-hydroxypropionate (18d). Colorless oil
(0.12 g, 27%); 1H NMR
d 7.88 (bs, 1H), 7.38 (s, 1H), 7.33 (s, 1H),
7.02 (d, J = 8.6 Hz, 1H), 4.2 (m, 2H), 4.0 (m, 2H), 3.73 (s, 1H), 3.38 (d,
J = 15 Hz, 1H), 3.12 (d, J = 15 Hz, 1H), 2.37 (s, 3H), 1.57 (s, 9H), 1.24 (t,
57%), 1H NMR
d 7.81, 7.27 (bs, 1H), 6.89 (bt, J = 6.8 Hz, 1H), 6.44 (dd,
J = 8.4 and 5.2 Hz, 1H), 5.95 (bs, 1H), 4.24 (q, J = 6.7 Hz, 2H), 4.1 (m,
1H), 4.0 (m, 1H), 2.35 (bs, 1H), 2.05 (d, J = 5.6 Hz, 1H), 1.60 (s, 9H),
J = 6.9 Hz, 3H), 1.16 (t, J = 7.2 Hz, 3H); 13C NMR
d
170.5, 131.7, 131.1,
125.6, 125.4, 122.6 (t, J = 270 Hz), 119.5, 114.6, 113.0, 83.3, 79.2 (t,
J = 30 Hz), 63.0, 60.3 (t, J = 6.6 Hz), 27.2, 21.5, 15.0, 13.9; 19F NMR
ꢀ83.84 (d, J = 141 Hz, 1F),–86.26 (d, J = 141 Hz, 1F). Anal. Calcd. for
22H29F2NO6 C, 59.85; H, 6.62; N, 3.17. Found: C, 60.08; H, 6.53;
N, 3.23.
Starting hydroxymalonate (0.54 g, 13%) was recovered as the
1.28 (t, J = 7.1 Hz, 3H), 1.07 (t, J = 6.9 Hz, 3H); 13C NMR
d
170.4,
d
165.6, 158.6 (d, J = 239 Hz), 152.5, 137.6, 115.2 (br, 2C), 138.2,
108.3 (b), 85.983.6, 83.3, 62.1, 61.6, 42.5, 28.3, 21.0, 14.0, 13.8;
C
19F NMR
d
ꢀ121.1 (1F), ꢀ121.4 (1F). Anal. Calcd. for C21H26FNO7 C,
59.57; H, 6.19; N, 3.31. Found: C, 59.40; H, 5.97; N, 3.50.
In the same reaction conditions, but using 5 equiv. of DAST, 15b
afforded a 10: 4:1 inseparable mixture (0.28 g) of 18b, 19b and
20b, respectively, after chromatography of the crude product on
silica gel (eluent, 1:1 diethyl ether/petroleum ether). Unreacted
hydroxymalonate (0.15 g, 35%) was also given back. The qualitative
and quantitative composition of the product mixture was drawn
by integrating the characteristic 19F NMR signals centered at ꢀ85.0
(AB system, JAB = 140 Hz, 2F), ꢀ83.0 (AA’BB’ system, 4F) and
ꢀ163.4 (t, J = 25 Hz, 1F), assigned to the fluorine nucleus of 18b,
19b and 20b, respectively, relative to the fluorine signals [ꢀ63.00
(s, 3F), ꢀ108.0 (s, 1F)] of the internal standard 3-bromo-5-
fluorobenzotrifluoride.
second eluted product before a white amorphous solid was
collected. The latter was identified as a diastereomeric mixture of
diethyl 10-tert-butoxycarbonyl-20-hydroxy-50-methylspiro[cy-
clopropane-1,30-indoline]-2,2-dicarboxylate (21d) (0.26 g, 62%)
on the basis of the following characteristics: 1H NMR
d 7.66 (bs,
0.5H), 7.25 (bs, 0.5H), 6.94 (bs, 1H), 6.38 (s, 1H), 5.86 (bs, 1H), 4.2
(m, 2H), 3.97 (m, 2H), 2.28 (bm, 1H), 2.16 (s, 3H), 2.02 (bm, 1H),
1.54 (s, 9H), 1.22 (t, J = 7.1 Hz, 3H), 0.96 (bt, J = 7.1 Hz, 1H); 13C
NMR d 166.1, 131.8, 129.4, 121.4, 114.3, 83.6, 62.2, 61.7, 42.5, 30.3,
29.7, 28.5, 20.9, 14.0, 13.8. Anal. Calcd. for C22H29NO7 C, 62.99; H,
6.97; N, 3.34. Found: C, 62.73; H, 6.97; N, 3.34.
Similarly, from the reaction of trifluoromethylate (indolyl-
methylhy)droxymalonate (15e) with 1.2 equiv. of DAST, the
following products were separated and characterized as follows:
Ethyl 2-[(1-tert-butoxycarbonyl-6-trifluoromethylindol-3-
yl)methyl]-3,3-difluoro-3-ethoxy-2-hydroxypropionate (18e)
(0.35 g, 70%): 1H NMR
d 7.36 (bs, 1H), 7.66 (d, J = 8.2 Hz, 1H),
7.56 (s, 1H), 7.39 (d, J = 8.2 Hz, 1H), 4.01 (m, 4H), 3.74 (s, 1H), 3.42
(d, J = 15 Hz, 1H), 3.16 (d, J = 15 Hz,. 1H), 1.60 (s, 9H), 1.17 (m, 6H);
13C NMR
d 171.2, 170.2, 149.1, 134.2, 133.4, 128.9, 127.8, 126.3 (q,
J = 3.2 Hz), 125.1, 124.8 (q, J = 270 Hz), 122.45 (t, J = 270 Hz), 120.2,
119.0 (q, J = 3.5 Hz), 113.2, 112.7 (q, J = 4.5 Hz), 84.5, 79.1 (t,
J = 31 Hz), 65.9, 63.1, 60.4, 60.3 (t, J = 6.5 Hz), 28.1, 27.0, 22.6, 15.0,
A sample of 1,3-diethoxy-2-[(1-tert-butoxycarbonyl-5-fluor-
oindol-3-yl)methyl]-1,1,3,3-tetrafluoropropan-2ol (19b) sepa-
rated by HPLC on a Waters C18, 7.9 ꢂ 300 mm, 5
(eluent 95:5, v/v acetonitrile/water, flux, 2.9 mL/min) exhibited
the following characteristics: 1H NMR
8.10 (s, 1H), 7.56 (s, 1H),
7.29 (d, J = 9.1 Hz, 1H), 7.02 (t, J = 7.9 Hz, 1H), 4.1 (m, 4H), 3.28 (s,
2H), 2.88(s, 1H), 1.67 (s, 9H) 1.27 (t, J = 7.0 Hz, 6H); 13C NMR
mm column
d
d
170.4, 170.3, 159.2 (d, J = 231 Hz), 149.3, 131.4 (d, J = 10 Hz),
127.3,, 122.7 (t, J = 270 Hz), 116.0 (d, J = 9.1 Hz), 113.2 (d,
J = 4.0 Hz), 111.9 (d, J = 25 Hz), 105.5 (d, J = 25 Hz), 83.8, 61.9
(quint, J = 6 Hz), 60.0 (m, 2C), 28.6 (3C), 26.2, 14.7 (2C); 19F NMR
d
ꢀ83.0 (AA’BB’ system, 4F), ꢀ120.8 (s, 1F). HRMS, calcd. for
14.2, 13.9; 19F NMR
d
ꢀ61.02 (s, 3F), ꢀ83.94 (d, J = 140 Hz, 1F),
C21H26F5NO5 467.17311. Found: 467.17306.
ꢀ86.30 (d, J = 140 Hz, 1F). Anal. Calcd. for C22H26F5NO6 C, 53.33;
From the chromatography of the crude mixture from the
H, 5.29; N, 2.83. Found: C, 53.54; H, 5.29; N, 2.83.
reaction of the hydroxymalonate 15c with 2.0 equiv. of DAST pure
ethyl 2-[(1-tert-butoxycarbonyl-5-chloroindol-3-yl)methyl]-
3,3-difluoro-3-ethoxy-2-hydroxypropionate (18c) was collected
as the first eluted product. Colorless oil (0.22 g, 48%); 1H NMR
General procedure for the reaction of substituted ethyl 2-[(1-tert-
butoxycarbonylindol-3-yl)methyl]-2-hydroxy-3,3,3-
trifluropropionates (16a–e) with DAST
d
7.55 (bd, J = 7.5 Hz, 1H), 7.52 (d, J = 1.2 Hz, 1H), 7.45 (s, 1H), 7.16
(dd, J = 8.8 and 1.3 Hz, 1H), 4.1 (m, 4H), 3.9 (m, 2H), 3.75 (s, 1H),
3.36 (d, J = 15 Hz, 1H), 3.10 (d, J = 15 Hz, 1H), 157 (s, 9H) 1.23 (t,
Diethylaminosulphur trifluoride (2.0 mmol) was added to the
2-indolylmethyl-3,3,3-trifluoropropionate 16 (1.0 mmol) in
dichloromethane (10 mL), under argon atmosphere. The mixture
was stirred until the substrate disappeared (tlc, SiO2, eluent
J = 7.1 Hz, 3H), 1.17 (t, J = 7.2 Hz, 3H); 13C NMR
d
170.4, 166.4,
149.2, 132.1, 128.1, 126.8, 124.4, 122.5 (t, J = 270 Hz), 119.7, 116.1,

90
S. Lepri et al. / Journal of Fluorine Chemistry 171 (2015) 82–91
petroleum ether/diethyl ether 9: 1) (4–7 h). After cooling to 0 8C,
saturated aqueous sodium bicarbonate (10 mL) was cautiously
added, the organic layer was separated and the aqueous phase was
extracted with CH2Cl2 (2 ꢂ 10 mL). The combined organic extracts
were dried with Na2SO4 and the solvent was evaporated at reduced
pressure. Flash chromatography of the crude product on silica gel
(eluent, petroleum ether/diethyl ether 99/1) allowed pure
fluorinated ethers 24 to be obtained. Their structure was assigned
on the basis of the following spectroscopic and analytical
characteristics.
(t, J = 270 Hz), 119.1, 114.8, 111.1, 83.7, 76.5 (quint, J = 28 Hz),
60.4 (t, J = 6.5 Hz), 28.1(3C), 25.7, 21.3, 14.6; 19F NMR
J = 10 Hz, 3F), ꢀ83.00 (dq, J = 144 and 11 Hz, 1F), ꢀ84.20 (dq,
J = 144 and 11 Hz, 1F). Anal. Calcd. for C20H24F5NO4 C, 54.9; H,
5.5; N, 3.2. Found: C, 55.11; H, 5.5; N, 3.2
d
ꢀ76.25 (t,
2-[(1-tert-Butoxycarbonyl-5-trifluoromethoxyindol-3-
yl)methyl]-3-ethoxy-1,1,1,3,3-pentafluoropropan-2-ol
(24f).
Pale yellow oil (0.33 g, 65%); 1H NMR
d
8.14 (bd, J = 8.7 Hz, 1H),
7.60 (s, 1H) 7.46 (d, J = 0.7 Hz, 1H), 7.19 (dd, J = 8.9 and 1.5 Hz 1H),
3.99 (q, J = 7.1 Hz, 2H), 3.37–3.25 (four peaks AB system, JAB = 15 Hz,
2H), 2.96 (bs, 1H), 1.68 (s, 9H), 1.23 (t, J = 7.1 Hz, 3H); 13C NMR
d
149.2, 144.9, 133.4, 131.8, 127.7, 123.6 (q, J = 285 Hz), 122.0 (t,
J = 270 Hz), 120.7 (q, J = 253 Hz), 117.9, 116.0, 112.3, 111.9, 84.4,
76.5 (quint, J = 28 Hz), 60.6 (t, J = 6.4 Hz), 28.1 (3C), 25.7, 14.5; 19F
1-[(1-tert-Butoxycarbonylindol-3-yl)methyl]-1-(ethoxydi-
fluoromethyl)-2,2,2-trifluoroethanol (24a). Colorless oil (0.34 g,
80%); 1H NMR
d 8.16 (bd, J = 7.9, 1H), 7.63 (d, J = 7.7, 1H), 7.57 (s,
1H), 7.35 (td, J = 7.7 and 1.2 Hz, 1H), 7.28 (td, J = 7.7 and 1.2 Hz, 1H),
4.01 (q, J = 7.1, 2H), 3.44–3.31 (four peaks AB system, JAB = 15 Hz,
NMR
d
ꢀ58.6 (s, 3F), ꢀ76.3 (t, J = 10 Hz, 3F), ꢀ83.00 (dq, J = 144 and
2H), 2.98 (s, 1H), 1.69 (s, 9H), 1.25 (t, J = 7.1, 3H); 13C NMR
d
149.5,
9.8 Hz, 1F), ꢀ83.99 (dq, J = 144 and 9.8 Hz, 1F).
135.2, 130.9, 127.9, 126.1, 124.5, 123.6 (q, J = 285 Hz), 122.0 (t,
J = 270 Hz), 122.6, 119.4, 115.1, 111.5, 83.9, 76.6 (quint, J = 28 Hz),
Reaction of ethyl 2-hydroxy-3-(1-tert-butoxycarbonyl-5-fluoroindol-
60.4 (t, J = 6.6), 28.1, 25.7, 14.5; 19F NMR
ꢀ83.15 (dq, J = 144 and 10 Hz, 1F), ꢀ84.25 (dq, JAB = 144,
4JFF = 10 Hz, 1F). Anal. Calcd. for C19H22F5NO4 C, 53.9; H, 5.2; N,
3.3. Found: C, 54.11; H, 5.2; N, 3.3.
d
ꢀ76.24 (t, J = 10 Hz, 3F),
3-yl)propionate (17) with DAST.
2-Hydroxy-3-(1-tert-butoxycarbonyl-5-fluoroindol-3-yl)pro-
pionate (0.35 g, 1.0 mmol) was made to react with DAST
(2.0 mmol) in dichloromethane (10 mL) at 0 8C under argon
atmosphere. The mixture was stirred until the substrate dis-
appeared (tlc, SiO2, eluent petroleum ether/diethyl ether 9:1) (2–
3 h). After usual work-up, flash chromatography of the crude
product on silica gel (eluent, petroleum ether/diethyl ether 99/1)
1-[(1-tert-Butoxycarbonyl-5-fluoroindol-3-yl)methyl]-1-
(ethoxydifluoromethyl)-2,2,2-trifluoroethanol (24b). Colorless
oil (0.26 g, 59%); 1H NMR
d 8.10 (bs, 1H), 7.57 (s, 1H) 7.27 (dd,
J = 9.0 and 2.6, 1H), 7.02 (td, J = 9.0 and 2.6, 1H), 4.01(q, J = 7.1, 2H),
3.36–3.23 (four peaks AB system, JAB = 15 Hz, 2H), 2.98 (s, 1H), 1.67
(s, 9H), 1.26 (t, J = 7.1, 3H); 13C NMR,
d
159.2 (d, J = 228 Hz), 149.2,
allowed pure a-fluoroester 25 (0.95 g, 27%) to be separated from a
132.0 (d, J = 9.7 Hz), 131.5, 127.6, 123.5 (q, J = 285 Hz), 121.9 (t,
J = 270 Hz), 116.1 (d, J = 9.1 Hz), 112.2 (d, J = 25 Hz), 111.6 (d,
J = 3.8 Hz), 105.2 (d, J = 24), 84.1, 76.5 (quint, J = 28 Hz), 60.6 (t,
mixture of diastereomeric spirocyclopropaneindolines 26 (0.21 g,
61%). Their structures were assigned on the basis of the following
spectroscopic and analytical characteristics.
3-(1-tert-Butoxycarbonyl-5-fluoroindol-3-yl)-2-fluoropro-
pionate (25). Colorless oil; 1H NMR
d 8.08 (bs, 1H), 7.54 (s, 1H),
J = 6.5), 28.1, 25.7, 14.5; 19F NMR
d
ꢀ76.25 (t, J = 10 Hz, 3F), ꢀ83.1
(dq, J = 144 and 11 Hz, 1F), ꢀ84.0 (dq, J = 144 and 11 Hz, 1F), 121.1
(s, 1F). Anal. Calcd. for C19H21F6NO4: C, 51.7; H, 4.8; N, 3.2. Found:
C, 51.9; H, 4.8; N, 3.2.
7.19 (dd, J = 9.0 and 2.5 Hz, 1H), 7.03 (td, J = 9.0 and 2.5 Hz, 1H),
6.10 (bs, 1H), 5.15 (ddd, J = 49, 6.8 and 4.3 Hz, 1H), 4.22 (m, 2H),
1-[(1-tert-Butoxycarbonyl-7-fluoroindol-3-yl)methyl]-1-
(ethoxydifluoromethyl)-2,2,2-trifluoroethanol (24c). Colorless
3.25 (sym.m 2H), 1.66 (s, 9H), 1.26 (t, J = 7.1 Hz); 19F NMR
d
ꢀ121.1
(s, 1F), ꢀ188.8 (dt, J = 49 and 26 Hz, 1F). HRMS, calcd. for
oil (0.32 g, 72%); 1H NMR
d
7.60 (s, 1H), 7.39 (d, J = 7.6 Hz, 1H), 7.2
C
18H21F2NO4, 353.14386. Found, 353.14379.
(m, 1H), 7.04 (dd, J = 12 and 8.0 Hz, 1H), 4.00 (q, J = 7.2 Hz, 2H),
3.40–3.27 (four peaks, AB system, JAB = 15 Hz, 2H), 2.92 (bs, 1H),
Ethyl 10-tert-butoxycarbonyl-50-fluoro-20-hydroxyspiro[cy-
clopropane-1,30-indoline]-2-carboxylate (26). Colorles viscous
oil; 1H NMR (Major diastereomer),
d 7.75 (bs, 0.5H), 7.33 (bs, 0.5H),
1.66 (s, 9H), 1.25 (t, J = 7.2 hz, 3H); 13C NMR
d
168.9, 150.0 (d,
J = 251 Hz), 135.3 (d, J = 3.5 Hz), 131.8, 128.5, 123.5 (q, J = 285 Hz),
122.0 (t, J = 270 Hz), 121.9, 115.2 (d, J = 3.6 Hz), 111.8 (d, J = 22 Hz),
111.6, 84.4, 76.4 (sex, J = 28 Hz), 60.6 (t, J = 6.5 Hz), 27.9, 25.7, 14.6;
6.94 (dd, J = 9.0 and 2.1 Hz, 1H), 6.39 (dd, J = 8.0 and 2.6 Hz, 1H),
5.50 (bs, 1H), 4.1 (m, 2H), 2.24 (dd, J = 8.5 and 7.2 Hz, 1H), 2.0 (m,
1H), 1.81 (t, J = 6.5 Hz, 1H), 1.59 (s, 9H), 1.18 (t, J = 7.1 H, 3H). Elem.
Anal. Calcd. for C18H22FNO5 (351.37): C, 61.53; H, 6.31; N,
3.99. Found: C, 61.32; H, 6.28; N, 4.05.
19F NMR
d
ꢀ76.28 (t, J = 10 Hz, 3F), ꢀ83.51 (dq, J = 144 and 10 Hz,
1F), ꢀ84.69 (dq, J = 144 and 10 Hz, 1F), ꢀ116.55 (dd, J = 12 and
3.8 Hz, 1F).
2-[(1-tert-Butoxycarbonyl-5-chloroindol-3-yl)methyl]-3-
ethoxy-1,1,1,3,3-pentafluoropropan-2-ol (24d). Colorless oil
Acknowledgements
(0.32 g, 69%); 1H NMR
d 8.05 (bd, J = 8.4 Hz, 1H), 7.59 (d,
Financial support from the Italian MIUR within the ‘‘FIRB-
Futuro in Ricerca 2010’’ Program – Project RBFR10X5OO and
Molecular Discovery Ltd., UK are gratefully acknowledged.
J = 2.0 Hz, 1H) 7.57 (s, 1H), 7.25 (dd, J = 8.8 and 2.1 Hz, 1H), 4.01
(q, J = 7.1 Hz, 2H), 3.36–3.23 (four peaks AB system, JAB = 15 Hz,
2H), 3.23 (s, 1H), 1.68 (s, 9H), 1.27 (t, J = 7.1 Hz, 3H); 13C NMR
d
149.1, 133.5, 132.2, 128.4, 127.2, 124.5, 123.5 (q, J = 285 Hz), 121.9
(t, J = 270 Hz), 119.3, 115.9, 111.3, 84.2, 76.5 (quint, J = 28 Hz), 60.6
Appendix A. Supplementary data
(t, J = 6.4 Hz), 28.1, 25.7, 14.5. 19F NMR
d
ꢀ76.27 (t, J = 10 Hz, 3F),
ꢀ82.90 (dq, J = 144 and 11 Hz, 1F), ꢀ84.02 (dq, J = 144 and 11 Hz,
1F). Anal. Calcd. for C19H21ClF5NO4: C, 49.9; H, 4.6; N, 3.0. Found: C,
49.71; H, 4.6; N, 3.0
Supplementary material related to this article can be found, in the
online version, at http://dx.doi.org/10.1016/j.jfluchem.2014.09.007.
2-[(1-tert-Butoxycarbonyl-5-methylindol-3-yl)methyl]-3-
ethoxy-1,1,1,3,3-pentafluoropropan-2-ol (24e). Colorless oil
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