Enantioenriched Quaternary α-Pentafluoroethyl Derivatives of Alkyl 1-Indanone-2-Carboxylates

Article abstract of DOI:10.1021/acs.joc.0c00210

An electrophilic enantioselective catalytic method for the α-pentafluoroethylation of 3-oxoesters is described. Under the use of La(OTf)3 in combination with a (S,R)-indanyl-pybox ligand, good results in terms of yield and enantioselectivities were achieved (up to 89% ee). The reaction proceeds under mild conditions, leading to the formation of enantioenriched quaternary centers. This methodology uses an hypervalent iodine(III)-CF2CF3 reagent, and mechanistic investigations are consistent with the involvement of a radical pathway.

Full text of DOI:10.1021/acs.joc.0c00210

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Article
Enantioenriched quaternary #-pentafluoroethyl
derivatives of alkyl 1-indanone-2-carboxylates
Albert Granados, Anna Ballesteros, and Adelina Vallribera
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.0c00210 • Publication Date (Web): 24 Jul 2020
Downloaded from pubs.acs.org on July 28, 2020
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Enantioenriched quaternary α-pentafluoroethyl derivatives of alkyl
1-indanone-2-carboxylates
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Albert Granados,* Anna Ballesteros and Adelina Vallribera*
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Department of Chemistry and Centro de Innovación en Química Avanzada (ORFEO-CINQA),
Universitat Autònoma de Barcelona, Cerdanyola del Vallès, 08193 Barcelona (Spain)
ABSTRACT: An electrophilic enantioselective catalytic method for the -pentafluoroethylation
of 3-oxoesters is described. Under the use of La(OTf)3 in combination with (S,R)-indanyl-pybox
ligand good results in terms of yield and enantioselectivities were achieved (up to 89% ee). The
reaction proceeds under mild conditions leading to the formation of enantioenriched
quaternary centers. This methodology uses an hypervalent iodine(III)-CF2CF3 reagent and
mechanistic investigations are consistent with the involvement of a radical pathway.
INTRODUCTION
Over the last years, the incorporation of fluorine and fluorine containing groups into organic
molecules in order to change its physical, biological and chemical properties has become a
powerful tool in drug design due to its favourable effects on pharmacological profiles.1 Among
fluoroalkyl groups,2 the pentafluoroethyl (CF2CF3), the bulkier analogue of CF3 group, is
nowadays one of the most attractive groups3 in drug design. Due to its strong electron-
withdrawing nature, a pentafluoroethylated drug would be less likely to be oxidized by P450
enzymes, leading to an increase of its metabolic stability.4 Additionally, the lipophilicity of the
pentafluoroethyl group is comparable to the one of the recognized lipophilic pentafluorosulfanyl
(-SF5) group. On the whole, the presence of a pentafluoroethyl group in drugs can improve their
biological activity due to the combination of a unique steric factor with an increased
electronegativity, lipophilicity and metabolic stability. In this context, Fulvestrant (estradiol
containing a side chain in with CF2CF3 group at the end) was approved by the FDA in 2002 as a
second-line theraphy for advanced breast cancer in postmenopausal women with disease
progression following antiestrogen therapy (Figure 1).5 Moreover, peptidyl pentafluoroethyl
ketones have been reported to inhibit various enzymes, as for example, elastase and the
hepatitis C virus N53 protease.6 In addition, some pentafluoroethyl ketones are powerful
inhibitors of Group VIA Calcium-Independent Phospholipase A2 proteases.7 Recently,
functionalisation of bicalutamide and enobosarm scaffold with pentafluorosulfanyl and
pentafluoroethyl functionality lead to potent agents against prostate cancer (Figure 1).8
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OH
Me
H
HO
H
F3C
X
N
CF2CF3
H
O
O
H
S
CF2CF3
CF3
HO
X = O or S
Fulvestrant
Functionalized Bicalutamides
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Figure 1. Pentafluoroethylated anticancer drugs
Despite the tremendous progress made in trifluoromethylation,9 synthetic methods for
the introduction of longer perfluoroalkyl chains remain underdeveloped. In contrast to
trifluoromethyl, the pentafluoroethyl moiety is still poorly present in drugs in part because the
methods for the incorporation of CF2CF3 are scarcely documented. For example, for the
pentafluoroethylation of a nucleophilic carbon center alfa to carbonyl, only a few electrophilic
pentafluoroethylating reagents have been described,10 such as (pentafluoroethyl)iodonium salts
developed by Yaguposkii11 and Umemoto,12 and the hypervalent 3-iodane reagents 113 and 214
(Scheme 1). Shen’s group15 explored the direct pentafluoroethylation of β-keto esters using
reagent 1 as electrophilic CF2CF3 source, DBU as base in CH3CN affording moderate to good yields
(36-82%). They showed that the bulkiness of the ester group lowered the yield. Togni´s group
performed the -perfluoroethylenation of a lactam-derived ketene silyl amide using 1, obtaining
an excellent yield under TMSNTf2 catalyst (only one example).13b
Moreover, while important catalytic enantioselective trifluoromethylation methods of
the alfa carbon in carbonyl compounds have been developped,16 to date only one isolated
asymmetric pentafluoroethylation of an oxindole has been reported (using MgBr2.Et2O/pybox
and Togni’s reagent 1) in a remarkable Katayev’s work dedicated to the asymmetric
trifluoromethylation of substituted oxindoles.17 As far as we know, there are no examples
regarding the enantioselective -pentafluoroethylation of alkyl 1-indanone-2-carboxylates. In
the past, our group have previously reported the asymmetric introduction of different
electrophiles in β-dicarbonyl systems though lanthanide-pybox catalysis, from α-amination18 to
the most recent fluorination19 and trifluoromethylation20 reactions. Herein, we present our
recent studies on the construction, for the first time, of enantioenriched pentafluoroethylated
quaternary centers on alkyl 1-indanone-2-carboxylates using a combination of La(OTf)3 with
pybox type ligands.
RESULTS AND DISCUSSION
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The first part of this work was dedicated to the synthesis of the reagents 1 and 2 (Figure 2). The
pentafluoroethylated benziodoxole, 1, was fully synthesized as previously described15 in a 95%
yield. On the other hand, the 1-pentafluoroethyl-1,2-benziodoxol-3-(1H)-one reagent, 2, was
prepared in three steps from 2-iodobenzoic acid in 54% overall yield.21 We soon realized that 1
and 2 were not stable and must be kept in a vacuum desiccators’ (see S76 in SI).
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CF3CF2
O
I
CF3CF2
O
I
O
1
2
Figure 2. Pentafluoroethylating hypervalent iodine reagents
Secondly, we proceeded with the synthesis of β-keto esters 3 following the reported
procedures.18d, 20, 22 Additionally, 1,3-diketone 3n was prepared from 1-indanone and acetic acid
using a (CF3CO)2O/CF3SO3H mixture (66% yield).23 These substrates were chosen as a model for
the catalytic system.
Then, we studied the pentafluoroethylation reaction of 3a as a model (Table 1). As said before,
in 2016 Shen’s group15 reported the direct pentafluoroethylation of some β-keto esters using
hypervalent iodine(III)-CF2CF3, 1, and the organic base DBU (2 equiv.). We wanted to study the
reaction using an inorganic base that could be separated by simple filtration. Potassium
carbonate in THF yielded the product 4a in a 23% yield. Other polar solvent as CH2Cl2 and CH3CN
enhanced the yield (51 and 59%, Table 1, entries 2 and 3). When using Cs2CO3 in CH3CN the yield
was raised until 69%. Disturbing is that neither higher nor lower temperatures improve the yield
of 4a. Changing the reagent 1 by 2 did not increase the reaction yield (Table 1, entry 5). Another
way of activation of β-dicarbonyl compounds is the use of Lewis acids. Thus, following the idea
of Katayev and Togni,13b magnesium bromide ethyl etherate (10%) was used obtaining 4a in a
68% yield. With La(OTf)3 (10%) the pentafluoroethylated compound was obtained in a lower
59% yield (entry 9). On the other hand, inspired by the racemic trifluoromethylations reactions
developed by Cahard9a using the trifluoromethylcalconium salts, we added nBu4NI but without
great success. Finally, although Shen’s group reported15 that using DBU 4a was afforded in 60%
yield, another organic base as DIPEA was not a good selection for this reaction.
Table 1. Optimization of the -pentafluoroethylation reaction of 3a.
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O
O
O
1 2
Base, or
O
O
O
Solvent, T
CF2CF3
3a
4a
Ar atmosphere
9
Entry
1
Reagent
Solvent
THF
Base
T (oC)
rt
Additives[a]
Yield (%)[b]
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1
1
1
1
2
1
1
1
1
1
1
K2CO3
K2CO3
K2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
-
-
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51
59
69
60
64
57
68
59
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11
2
CH2Cl2
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
rt
-
3
rt
-
4
rt
-
5
rt
-
6
0
-
7
50
rt[c]
rt
-
MgBr2·Et2O
La(OTf)3
nBu4NI
-
8
9
-
10
11
K2CO3
DIPEA
rt
rt
Reaction conditions: 3a (1 mmol), pentafluoroethylating reagent (1.5 mmol), base (1.5 mmol), and dry
solvent. [a] Added in a 10 mol%. [b] Isolated yield. [c] From -35 oC to rt.
With the optimized reaction conditions in hand, we explored the scope of the reaction
for 3-oxoesters (Scheme 1). The methodology worked with a broad range of 1-indanone-2-
carboxylates including primary (3a-h), secondary (3i-j) and tertiary alcohol (3k,l) derivatives.
Moreover, β-keto esters with either electron donating (4b-d and 4j) or electron-withdrawing
groups (4e-h) at the aromatic ring provided the pentafluoroethylated quaternary carbon center
compounds with good chemical yields (68-78%). To our delight, the methodology could be
extended to additional six membered cyclic β-dicarbonyl compounds, such as methyl 1-
tetralone-2-carboxylate (3m) and 2-acetyl-1-indanone (3n). In both cases the
pentafluoroethylated compounds (4m and 4n) were afforded in high 70 and 71% yields
respectively. Unfortunately, this methodology could not be successfully applied to the acyclic β-
keto ester 3o.
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O
CF3F2C
I
O
O
O
Cs2CO3
O
R
+
O
ACN, rt, Aratm
overnight
CF2CF3
O R
n
n
R2
R2
1
4a-l
7
3a-l
8
9
O
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O
O
O
O
O
MeO
O
O
O
CF2CF3
CF2CF3
CF2CF3
4b
4c
4a
72%
74%
69%
O
O
O
O
O
O
CF3
F
MeO
MeO
O
O
O
CF2CF3
71%
CF2CF3
4f
CF2CF3
4e
4d
69%
77%
O
O
F
O
Br
O
O
O
O
O
O
CF2CF3
4i
CF2CF3
F
CF2CF3
78%
4g
68%
4h
68%
O
O
O
O
O
O
O
MeO
MeO
O
CF2CF3
O
4l
CF2CF3
4k
CF2CF3
71%
4j
67%
76%
O
O
O
O
O
O
O
O
Pr CF2CF3
CF2CF3
CF2CF3
MeO
4o
4m
OMe
4n
70%
0%
71%
Scheme 1. Scope of α-pentafluoroethylating reaction of β-dicarbonyl compounds
O
O
N
O
O
O
O
N
N
N
N
Ph
Ph
N
N
N
N
Ph
Ph
L2
L1
Ph
Ph
L3
Figure 3. Pybox ligands used in the optimization of the electrophilic enantioselective
pentafluoroethylation reaction.
Next, we studied the enantioselective version of this electrophilic pentafluoroethylation
reaction. In the first attempt, we selected 3d and reagent 1 under the combination of
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o
europium(III) triflate and (S,R)-indanyl-pybox (L1, Figure 3) as catalyst at -30 C (Table 2, entry
1). The enantiopure pybox ligand will act as a chiral ligand and base. Compound 4d was obtained
in low yield and enantioselectivity. Next, we moved to yterbium, achieving the fluorinated
product in good yield (76%) and moderate enantioselectivity (45%). Then, we performed the
reaction changing the metal source to lanthanum(III) triflate and we afforded 4d in a 80% ee and
good 72% yield (entry 3). In order to improve these results, we moved to (R,R)-Ph-pybox (L2)
and (S,R)-diPh-pybox (L3), but the reaction was worst in both terms of yield and ee (entries 4
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o
o
and 5). We checked CH2Cl2 as solvent at -78 C, but acetonitrile at -30 C gave better results
(entry 3 vs 6). Performing the reaction at room temperature did not enhance the ee (entry 3 vs
entry 7). Then, we used an automatic injector to make a slow addition of the
pentafluorofluoroethylating agent 1 to the reaction mixture, affording the product with the
same enantioselectivity but slightly lower yield (entry 3 vs 8). Next, we decided to assay
MgBr2·Et2O, a completely different Lewis acid that has been recently used by Katayev’s group in
combination with pybox-type ligands in the trifluoromethylation of oxindoles.17 In our case,
using L1 as chiral ligand, we reached compound 4d in a 74% ee and a 76% yield (Table 2 entry
11). Next, we studied MgBr2·Et2O with L2 and L3 pybox ligands (Figure 3) affording 4d in low ee’s
in both cases (Table 2, entries 12 and 13). In order to test the role of the magnesium counter
anion, we carried out the reaction using the Mg(OTf)2/L1 combination and formation of 4d was
not observed (Table 2, entry 14). In fact, Katayev’s group has previously reported the
dependence of the catalytic behavior, on the different magnesium salts, in the
trifluoromethylation of 3-substituted oxoindoles.13b Finally, we assayed Ga(OTf)3, a Lewis acid
which has showed high efficacy for a great number of electrophilic reactions.24 In our case,
Ga(OTf)3 combined with L1 gave the pentafluoroethylated compound 4d in a 76% yield, but
poorly enantioenriched (20% ee).
Table 2. Optimization of the enantioselective pentafluoroethylation reaction.
O
L
M(OTf)3/pybox ( )
C2F5 Source Reagent
O
O
MeO
MeO
O
O
MeO
MeO
O
Solvent, -30ºC, 4Å MS
3d
4d
CF2CF3
Entry
Metal
Pybox
Solvent
Reagent
Yield[a]
ee[b]
(major R)
50%
1
2
Eu(OTf)3
Yb(OTf)3
L1
L1
MeCN
MeCN
1
1
11%
76%
45%
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La(OTf)3
La(OTf)3
L1
L2
L3
L1
L1
L1
L1
L1
L1
L2
L3
L1
L1
MeCN
MeCN
MeCN
CH2Cl2
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
1
1
1
1
1
1
2
2
1
1
1
1
1
72%
36%
56%
20%
55%
35%
60%
55%
76%
67%
76%
<10%
73%
80%
10%
36%
25%
63%
75%
72%
70%
74%
15%
40%
nd
5
La(OTf)3
6[c]
7[d]
8[e]
9
La(OTf)3
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La(OTf)3
La(OTf)3
La(OTf)3
10
11
12
13
14
15
Eu(OTf)3
MgBr2·Et2O
MgBr2·Et2O
MgBr2·Et2O
Mg(OTf)2
Ga(OTf)3
20%
Reactions conditions: 1 equiv. of 3d, 1.3 equiv. 1 or 2, 0.13 equiv. pybox and 0.10 equiv. metal. [a]
Yields of isolated pure compound 4d. [b] Enantiomeric excesses determined by HPLC. [c] Reaction
done at -78 oC. [d] Reaction done at room temperature. [e] The reagent 1 was added dropwise by
an automatic injector.
Next, we wanted to explore the scope of the reaction (Scheme 2). So, a range of cyclic
3-oxoesters were tested using the optimized pre-catalyst combination, La(OTf)3, L1 and
o
hypervalent iodine(III)-CF2CF3 1 in acetonitrile at -30 C, under argon atmosphere and in
presence of 4Å molecular sieves. The reaction was performed with a series of compounds
derived from primary esters (3a-h). In general, the presence of electron-withdrawing groups at
sixth position of the aromatic ring injures the ee’s (4e and 4f, 50-60% ee). In contrary, those
primary β-keto esters with no substituents or with electron-donating groups (4a,c-e) in the same
t
aromatic position gave around or over 80% ee. The presence of sterically bulky Bu and CF3
groups at sixth position (4b and 4f) diminishes the ee, being lower for the electron-withdrawing
CF3. Once again, the effect of a bulkier ester is harmful for the enantiodifferentiation (4a vs 4k
and 4d vs 4j), as we have previously seen in our related previous work of trifluoromethylation.20
The reaction of the more flexible cyclic six-membered ring 3m gave the pentafluoroethylated
product with a significant decrease of enantioselectivity (34% ee) compared with 3a under the
same conditions (87% ee). We also tested the 1,3-diketone 3n, affording 4n in a high yield (79%)
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but unfortunately as a racemic mixture. Finally, due to the moderate 74% ee obtained for 4d
(Table 2, entry 11) using the MgBr2·Et2O and L1 combination, we decided to assay this pre-
catalyst with two other substrates. Compounds 3k and 3j were selected in order to improve their
enantioselectivites, but 4k and 4j were obtained in 24% and 20% ee’s respectively.
The assignment of the absolute configuration of compounds 4a-h,j-m was based on the
comparison of the signal of their Cotton Effect (all compounds present a negative Cotton effect,
see SI), as well as their negative specific rotation values. Both properties were consistent with
the ones of the previously prepared trifluoromethylated analogues.9a,16c,20 Thus, we assigned the
absolute configuration R to all compounds 4.
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O
La(OTf)3 10%
L1
O
O
CF2CF2
+
I
O
13%
R
O
O
CF2CF3
ACN -30ºC, 4Å MS
R
O R
1
R
3a-k, m-n
4a-k, m-n
O
O
O
O
O
MeO
O
O
O
O
CF2CF3
CF2CF3
CF2CF3
(R)-4a
58% yield, 87% ee
(R)-4c
(R)-4b
63% yield, 89% ee
78% yield, 63% ee
O
O
O
O
O
O
F
MeO
MeO
CF3
O
O
O
CF2CF3
CF2CF3
CF2CF3
(R)-4d
(R)-4e
(R)-4f
72% yield, 60% ee
72% yield, 80% ee
63% yield, 50% ee
O
O
F
Br
O
O
O
O
MeO
MeO
O
O
O
CF2CF3
CF2CF3
CF2CF3
F
(R)-4j
(R)-4g
(R)-4h
47% yield, 30% ee
68% yield, 75% ee
71% yield, 80% ee
O
O
O
O
O
O
O
O
CF2CF3
CF2CF3
CF2CF3
4n
79% yield, 0% ee
(R)-4k
32% yield, 28% ee
(R)-4m
65% yield, 34% ee
Scheme 2. Scope of the enantioselective -pentafluoroethylation of cyclic β-dicarbonyl
compounds.
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The activation of Togni type reagents have been previously studied by 19F NMR in
different research groups.16g,17,20,25 In this work, we mixed 1 with La(OTf)3 (1:1) in deuterated
acetonitrile. After 5 minutes, 1 was converted to a new species with a chemical shift of the CF3
from δ = -81.7 to δ = -79.5 ppm and a chemical shift of the CF2 from δ = -99.7 to δ = -82.6 ppm.
Thus, a very significant change was observed which indicates the coordination of 1 to lanthanide.
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Further F NMR-based titration furnished a Job plot indicating a 1:1 complexation of 1 with
La(OTf)3 (Figure 4), in agreement with some examples in the literature.13b,20 Thus, we propose
the formation of the cationic iodonium species 5 shown in Figure 4.
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La(OTf)2
15
CF3CF2
I
O
10
5
OTf
5
0
0,0
0,2
0,4
0,6
0,8
1,0
1
Figure 4. Job plot (1+La(OTf)3) by 19F NMR (CD3CN, 25 oC, 400 MHz) of the CF2 signal and the
proposed cationic iodonium species, 5, formation.
Next, the enantioselective catalytic reaction was tested in the presence of Galvinoxyl
free radical, which is a classical radical scavenger. After 36 hours, the only products detected in
the reaction of 3d and 1 were the starting material and the pentafluoroethylated Galvinoxyl 6
(Scheme 3). Thus, the presence of Galvinoxyl inhibits the pentafluoroethylation reaction. This
new compound 6 was isolated in a 65% yield and it was completely characterized by
spectroscopic techniques, including HR-ESI-MS. The radical reaction pathway indicated by this
result is in line with the known propensity of hypervalent iodine(III)-CF3 to generate CF3
radicals.13b, 17, 20, 26
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La(OTf)3 (10 mol%)
O
L1
(13 mol%)
CF3CF2
+
I
O
MeO
MeO
O
O
Galvinoxyl
O
O
6
CF3CF2
ACN -30ºC, 4Å MS
3d
1
65%
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Scheme 3. Pentafluoroethylation conducted in the presence of Galvinoxyl.
L1
La(OTf)3 +
TfO
L1
N
I
OH
3a
L1
+
N
N
L1
4a
+
+
La
TfO
OTf
INT1
L1
L1
N
N
N
N
N
OTf
N
L1
·HOTf
La
La
O
O
OTf
O
I
O
O
OMe
OMe
CF2
CF3
INT4
INT2
L1
N
N
OTf
N
TS
SET-induced SN2
1
La
O
I
O
O
F2C
OMe
CF3
INT3
Scheme 4. Proposed catalytic cycle for the formation of (R)-4a from 3a with La(OTf)3, reagent 1
and the pybox ligand L1.
At the present stage we assume that the pentafluoroethylation step proceeds via a
similar mechanistic scenario (Scheme 4) as we suggested in our recent work on the
enantioselective -trifluoromethylation of cyclic -keto esters.20 First, INT1 is formed by
coordination of the pybox ligand to the metal by displacement of a OTf. Pybox ligand is the
responsible for the abstraction of the -H in -keto ester. Next, coordination of enolate-3a and
reagent 1 to metal center is produced to form INT2. The subsequent coordination of reagent 1
to INT2 is based on complex 5, which formation has been demonstrated in this work by 19F NMR
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experiments (Figure 4). Then, the coordination pattern of the enolate-3a in INT3 reveals an
efficient blockage of the prochiral Si face of the La(III) enolate. The hindrance of the Si face of
this intermediate INT3 results in an efficient SN2-like saddle point TS, which consists of a Re
attack of the Cα atom of the enolate moiety on the carbon atom of the CF2CF3 group in 1, with
concomitant departure of the iodine-aryl group. With the CF2CF3 transfer appearing to
proceeded through a nucleophilic substitution and the experimentally demonstrated presence
of CF2CF3 radicals we propose a single–electron transfer(SET) induced SN2-type pathway, that
can explain the control of selectivity. This mechanism has been also proposed by other authors
in the asymmetric catalyzed trifluoromethylation of oxindoles.17 In fact, hypervalent iodine(III)-
CF3 reagent has been described as a precursor of electrophilic CF3 radical species.26 To date
however, there exist only very few examples on its use in asymmetric
trifluoromethylation.13b,17,20 This report is thereby the first example on the construction of
enantioenriched pentafluoroethylated carbon centers using hypervalent iodine-based reagents
proceeding through a SET pathway.
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CONCLUSIONS
In summary, an efficient method for the enantioselective -pentafluoroethylation of
alkyl 1-indanone-2-carboxylates is described. Racemic conditions were optimized using Cs2CO3
as base in acetonitrile (15 examples). The enantioenriched pentafluoroethylated -oxo esters
were prepared using an hypervalent iodine(III)-CF2CF3 reagent and a lanthanide-pybox pre-
catalyst to achieve good chemical yields and ee’s (up to 89%, 11 examples). The
enantioselectivity of the reaction stems from the efficient blockage of one of the prochiral faces
of the La(III) enolate by one unit of the C2-symmetric ligand. We propose that the mechanism
proceeds through a SET pathway involving CF2CF3 radicals.
EXPERIMENTAL SECTION
General information: The chemicals and solvents were purchased from Sigma-Aldrich or
Fluorochem. A silicone bath has been used for reactions that require heating. Solvents were
distilled and stored under argon in molecular sieves. IR spectra were determined either by
transmission or by attenuated total reflectance mode (ATR). Enantiomeric excesses were
determined, unless otherwise stated, by HPLC using a chiral column Daicel-AD-H. Optical
rotation were measured with a Rudolph Autopol I polarimeter and they are reported as follows:
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[α]D rt (c in g per 100 mL, solvent). 1H NMR spectra were recorded operating at 250, 360, and 400
MHz. 13C NMR spectra were registered at 63, 91, and 101 MHz. 19F NMR spectra were recorded
decoupled to protons. Circular Dicroism were recorded in a spectropolarimeter J-715, JASCO,
equipped with Peltier thermostat module. HRMS were recorded by a Bruker micrOTOF-QII mass
spectrometer (fly time analyzer) through positive electrospray ionization. Compounds 3 (3a,20
3b,20 3c,20 3d,15 3e,20 3f,20 3g,20 3h20, 3m20) were prepared as previously reported in our group.
Compounds 3i,19 3k,19 and 3l19 were synthesized by a transesterification reaction from the
corresponding methyl ester following a methodology adapted from a previously reported
method of our group.22 Compound 3n23 was prepared following a reported procedure.
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Pentan-3-yl 5,6-dimethoxy-1-oxo-2,3-dihydro-1H-indene-2-carboxylate (3j): The methodology of
preparation was adapted from a reported procedure:22 In a round-bottomed flask 0.50 g of 3d
(1 eq.), ZnO (0.2 eq.) and pentan-3-ol (10 equivalents) were dissolved in toluene. The reaction
mixture was heated up to 140 oC, under a distillation setup, until total conversion was observed
by TLC. Then, the reaction mixture was filtered through Celite® and the solvent was removed
under reduced pressure. The product obtained was purified by column chromatography on
1
silica-gel (hexane:ethyl acetate (10:1)) obtaining 0.51 g (1.67 mmol) of 3j (84% yield). H NMR
(400 MHz, [D]CDCl3, 25 oC, TMS): δ = 0.84 (m, 6H), 1.53 (m, 4H), 3.23 (dd, 3J(H,H) = 7.2 Hz, 2J(H,H)
=
3
2
3
3
18.0 Hz, 1H), 3.39 (dd, J(H,H) = 3.6, J(H,H) =18.0 Hz, 1H), 3.65 (dd, J(H,H) = 3.6 Hz, J(H,H) = 7.2 Hz,
3
1H), 3.84 (s, 3H), 3.92 (s, 3H), 4.85 (quint, J(H,H) = 7.2 Hz, 1H), 6.87 (s, 1H), 7.11 ppm (s, 1H).
13C[1H] NMR (101 MHz, [D]CDCl3, 25 oC, TMS): δ = 9.5, 9.6, 26.5, 26.5, 30.1, 53.8, 56.0, 56.3, 78.2,
104.7, 107.2, 127.9, 149.2, 149.6, 155.9, 169.3, 198.2 ppm. IR (ATR): 2967, 1731, 1591, 1313,
1194, 1021 cm-1. HR-MS (ESI) m/z: [M+Na]+ Calcd for C17H22O5Na 349.0270; found 349.0264.
Methyl 2-(3,4-dimethoxybenzoyl)pentanoate (3o): In a 250 mL round-bottom flask 2 equiv of
sodium hydride and 2 equiv of dimethyl carbonate were added in 25 mL of THF. Then a solution
of 3,4-dimethoxyacetophenone (1g, 5.55 mmol, 1 equiv) in THF (15 mL) is added dropwise.
When the reaction was finished, it was neutralized with 1 M HCl; and then extractions with
dichloromethane were carried out. The organics were dried, and solvent was removed under
high vacuum. The crude reaction mixture was purified by column chromatography on silica-gel
using hexane:AcOEt (8:2) as eluent, obtaining methyl 3-(3,4-dimethoxyphenyl)-3-
oxopropanoate in a 95% yield (1.25 g). In a 10 mL round-bottom flask provided with a reflux
condenser 1.25 mmol of β-keto ester were dissolved in 3 mL of dry acetone. Then, 1.38 mmol
of K2CO3 and 1.82 mmol of propyl iodide were added. The system was maintained at 40 °C with
stirring up to 24 h. Then, the solution was filtered, the crude was extracted with CH2Cl2 and
washed with 1 M HCl. The organic phase was dried and evaporated. The crude was purified by
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column chromatography on silica-gel using mixtures of hexane:AcOEt (7:3) as eluent yielding 3o
3
in 90% yield (0.31 g). 1H NMR (250 MHz, [D]CDCl3, 25 oC, TMS): δ = 0.95 (t, J(H,H) = 7.5 Hz, 3H),
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9
1.36 (m, 2H), 1.97 (m, 2H), 3.69 (s, 3H), 3.94 (s, 3H), 3.96 (s, 3H), 4.32 (t, 3J(H,H) = 7.5 Hz, 1H), 6.92
(d, 3J(H,H) = 7.5 Hz, 1H), 7.57 (bs, 3J(H,H) = 7.5 Hz, 1H), 7.66 ppm (d, 4J(H,H) = 1.1 Hz, 1H). 13C[1H] NMR
(101 MHz, [D]CDCl3, 25 oC, TMS): δ = 14.3, 21.3, 31.7, 52.8, 53.8, 56.3, 56.5, 110.5, 111.0, 123.7,
129.8, 149.6, 154.1, 171.2, 194.1 ppm. IR (ATR): 2968, 1710, 1607, 1207, 1091, 988 cm-1. HR-MS
(ESI) m/z: [M+Na]+ Calcd for C15H20O5Na 303.1208; found 303.1209.
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General procedure for the enantioselective electrophilic α-pentafluoroethylation of 3-
oxoesters: In a 10 ml dried Schlenk flask in presence of 4Å molecular sieves, La(OTf)3 (0.10
equiv.) and (S,R)-indanyl-pybox (0.13 equiv.) were dissolved in dry acetonitrile (3 mL). The
colourless reaction mixture was left stirring at room temperature under inert atmosphere
overnight. Next, the corresponding β-keto ester (80 mg; 1 equiv.) was added to the reaction
mixture and it was left stirring at room temperature for 30 minutes. Then, the reaction mixture
o
was cooled down until -35 C and, once at this temperature, the pentafluoroethylating agent
(1.3 equiv.) was added to the mixture in one portion. The reaction mixture was left at this
temperature under argon atmosphere until complete conversion observed by TLC. Afterwards,
the solvent was removed under reduced pressure and the product was purified by column
chromatography on silica gel.
Methyl (R)-1-oxo-2-(perfluoroethyl)-2,3-dihydro-1H-indene-2-carboxylate (4a):15 According to
the general procedure, 375 mg (1.22 mmol) of 4a were prepared from 400 mg of starting
material 3a (58% yield) as a colourless oil, after purification by column chromatography on silica-
1
o
2
gel (hexane:ethyl acetate (2:1)). H NMR (400 MHz, [D]CDCl3, 25 C, TMS): δ = 3.62 (d, J(H,H)
=
17.7 Hz, 1H), 3.82 (s, 3H), 3.93 (d, 2J(H,H) = 17.7 Hz, 1H), 7.47 (t, 3J(H,H) = 7.5 Hz, 1H), 7.55 (d, 3J(H,H)
3
4
3
19
= 7.5 Hz, 1H), 7.71 (td, J(H,H) = 7.5 Hz, J(H,H) = 1.2 Hz, 1H), 7.85 ppm (d, J(H,H) = 7.5 Hz, 1H); F
NMR (376 MHz, CDCl3, 25 oC, TMS): δ = -79.6 (s, 3F), -115.0 (d, 2J(F,F) = 278.0 Hz, 1F), -116.8 ppm
(d, 2J(F,F) = 278.0 Hz, 1F); [α]D20 = -21.9 (c = 0.0032 in MeCN), 87% ee (absolute configuration R).
HPLC: tr(R) = 11.14 min and tr(S) = 18.34 min, Daicel Chiralpack AD-H column (0.46 cm φ x 25 cm)
with hexane:iPrOH (99.5:0.5) as non-stationary phase and 1.0 mL·min-1.
Methyl (R)-6-(tert-butyl)-1-oxo-2-(perfluoroethyl)-2,3-dihydro-1H-indene-2-carboxylate (4b):
According to the general procedure, 86 mg (0.24 mmol) of 4b were synthesized from 75 mg of
starting material 3b (78% yield) as colourless oil, after purification by column chromatography
on silica gel (hexane:dichloromethane (2:1)). 1H NMR (360 MHz, [D]CDCl3, 25 oC, TMS): δ = 1.36
(s, 9H), 3.57 (d, 2J(H,H) = 17.5 Hz, 1H), 3.83 (s, 3H), 3.87 (d, 2J(H,H) = 17.5 Hz, 1H), 7.47 (d, 3J(H,H) = 7.8
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Hz, 1H), 7.57 (d, 3J(H,H) = 7.8 Hz, 1H), 7.82 ppm (bs, 1H); 19F NMR (235 MHz, CDCl3, 25 oC, TMS): δ
=-79.5 (s, 3F), -114.9 (d, 2J(F,F) = 278.1 Hz, 1F), -116.6 ppm (d, 2J(F,F) = 278.1 Hz, 1F). 13C[1H] NMR
(101 MHz, [D]CDCl3, 25 oC, TMS): δ = 31.2, 33.0 (bs), 53.8, 62.7 (dd, 2J(C,F) = 22.2 Hz, 2J(C,F) = 18.2
Hz), 77.2, 115.5 (m), 120.0 (m), 121.7, 125.7, 133.9, 134.4, 149.0, 152.2, 165.0 (d, 3J(C,F) = 6.8 Hz),
192.4 ppm. IR (ATR): 2961, 1785, 1730, 1435, 1191, 1072 cm-1. HR-MS (ESI) m/z: [M+Na]+ Calcd
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for C17H17F5O3Na 387.0990; found 387.0986. [α]D = -12.6 (c = 0.0039 in MeCN), 63% ee
(absolute configuration R). HPLC: tr(R) = 6.37 min and tr(S) = 6.93 min, Daicel Chiralpack AD-H
column (0.46 cm φ x 25 cm) with hexane:iPrOH (99.5:0.5) as non-stationary phase and 1.0
mL·min-1.
Methyl (R)-6-methoxy-1-oxo-2-(perfluoroethyl)-2,3-dihydro-1H-indene-2-carboxylate (4c):
According to the general procedure, 96 mg (0.28 mmol) of 4c were synthesized from 100 mg of
starting material 3c (63% yield) as colourless oil, after purification by column chromatography
on silica gel (hexane:ethyl acetate (2:1)). 1H NMR (250 MHz, [D]CDCl3, 25 oC, TMS): δ = 3.53 (d,
2J(H,H) = 18.0 Hz, 1H), 3.81 (m, 7H), 7.23 (d, 4J(H,H) = 2.3 Hz, 1H), 7.27 (dd, 3J(H,H) = 8.4 Hz, 4J(H,H) = 2.3
Hz, 1H), 7.41 ppm (d, 3J(H,H) = 8.4 Hz, 1H). 19F NMR (235 MHz, CDCl3, 25 oC, TMS): δ =-79.5 (s, 3F),
-114.9 (d, J(F,F) = 278.8 Hz, 1F), -116.5 ppm (d, J(F,F) = 278.8 Hz, 1F). C[1H] NMR (101 MHz,
[D]CDCl3, 25 oC, TMS): δ = 32.8 (bs), 53.9, 55.7, 62.9 (dd, 2J(C,F) = 22.3 Hz, 2J(C,F) = 18.2 Hz), 106.2,
112.8 (m), 127.7 (m), 126.1, 126.9, 135.2, 144.5, 160.1, 165.0 (d, 3J(C,F) = 6.7 Hz), 192.2 ppm. IR
(ATR): 2924, 1725, 1495, 1434, 1194, 1026 cm-1. HR-MS (ESI) m/z: [M+Na]+ Calcd for
C14H11F5O4Na 361.0470; found 361.0467; [α]D20 = -10.0 (c = 0.0027 in MeCN), 89% ee (absolute
configuration R). HPLC: tr(R) = 8.59 min and tr(S) = 10.58 min, Daicel Chiralpack AD-H column
(0.46 cm φ x 25 cm) with hexane:iPrOH (99.5:0.5) as non-stationary phase and 1.0 mL·min-1.
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Methyl (R)-5,6-dimethoxy-1-oxo-2-(perfluoroethyl)-2,3-dihydro-1H-indene-2-carboxylate (4d):15
According to the general procedure, 84 mg (0.23 mmol) of 4d were synthesized from 80 mg of
starting material (72% yield) as colourless solid after purification by column chromatography on
silica gel (hexane:ethyl acetate (2:1)). M.p.: 51-53 oC. 1H NMR (250 MHz, [D]CDCl3, 25 oC, TMS):
δ = 3.51 (d, 2J(H,H) = 17.6 Hz, 1H), 3.82 (m, 4H), 3.94 (s, 3H), 4.02 (s, 3H), 6.93 (s, 1H), 7.21 ppm (s,
1H), 19F NMR (235 MHz, CDCl3) δ (ppm): -79.5 (s, 3F), -114.9 (d, 2J(F,F) = 279.7 Hz, 1F), -117.5 ppm
(d, 2J(F,F) = 279.7 Hz, 1F); [α]D20 = -14.0 (c = 0.0032 in MeCN), 80% ee (absolute configuration R).
HPLC: tr(R) = 44.36 min and tr(S) = 54.47 min, Daicel Chiralpack AD-H column (0.46 cm φ x 25 cm)
with hexane:iPrOH (99:1) as non-stationary phase and 1.0 mL·min-1.
Methyl
(R)-6-fluoro-1-oxo-2-(perfluoroethyl)-2,3-dihydro-1H-indene-2-carboxylate
(4e):
According to the general procedure, 90 mg (0.28 mmol) of 4e were synthesized from 80 mg of
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starting material 3e (72% yield) as colourless oil, after purification by column chromatography
on silica gel (hexane:dichloromethane (7:3)). 1H NMR (400 MHz, [D]CDCl3, 25 oC, TMS): δ = 3.59
6
7
8
9
2
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(d, J(H,H) = 17.5 Hz, 1H), 3.82 (s, 3H), 3.89 (d, J(H,H) = 17.5 Hz, 1H), 7.45 (m, 2H), 7.53 ppm (dd,
3J(H,F) = 8.3 Hz, 4J(H,H) = 2.1 Hz, 1H). 19F NMR (235 MHz, CDCl3, 25 oC, TMS): δ =-78.6 (s, 3F), -112.9
(s, 1F), -114.8 (d, 2J(F,F) = 278.5 Hz, 1F), -116.6 ppm (d, 2J(F,F) = 278.5 Hz, 1F). 13C[1H] NMR (91 MHz,
[D]CDCl3, 25 oC, TMS): δ = 32.9 (d, 3J(C,F) = 3.2 Hz), 54.0, 63.1 (dd, 2J(C,F) = 22.2 Hz, 2J(C,F) = 18.2 Hz),
111.2 (d, 2J(C,F) = 22.5 Hz), 112.2 (m), 117.6 (m), 124.2 (d, 2J(C,F) = 24.0 Hz), 127.7 (d, 3J(C,F) = 8.1 Hz),
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135.7 (d, J(C,F) = 8.1 Hz), 146.9 (d, J(C,F) = 2.2 Hz), 161.5, 164.0, 164.5 (d, J(C,F) = 7.1 Hz), 191.2
ppm. IR (ATR): 2921, 1751, 1721, 1614, 1296, 1149 cm-1. HR-MS (ESI) m/z: [M+Na]+ Calcd for
20
C13H8F6O3Na 349.0270; found 349.0264. [α]D = -19.7 (c = 0.0036 in MeCN), 60% ee (absolute
configuration R). HPLC: tr(R) = 7.34 min and tr(S) = 8.01 min, Daicel Chiralpack AD-H column (0.46
cm φ x 25 cm) with hexane:iPrOH (99:1) as non-stationary phase and 1.0 mL·min-1.
Methyl (R)-6-(trifluoromethyl)-1-oxo-2-(perfluoroethyl)-2,3-dihydro-1H-indene-2-carboxylate
(4f): According to the general procedure, 71 mg (0.16 mmol) of 4f were synthesized from 80 mg
of starting material 3f (63% yield) as colourless oil after purification by column chromatography
on silica gel (hexane: dichloromethane (9:1)). 1H NMR (250 MHz, [D]CDCl3, 25 oC, TMS): δ = 3.68
(d, 2J(H,H) = 17.5 Hz, 1H), 3.83 (s, 3H), 4.01 (d, 2J(H,H) = 17.5 Hz, 1H), 7.70 (d, 3J(H,H) = 8.1 Hz, 1H), 7.95
(dd, 3J(H,H) = 8.1 Hz, 4J(H,H) = 1.7 Hz, 1H), 8.11 ppm (d, 4J(H,H) = 1.7 Hz, 1H). 19F NMR (235 MHz, CDCl3,
25 oC, TMS): δ =-63.2 (s, 3F), -79.6 (s, 3F), -114.7 (d, 2J(F,F) = 278.7 Hz, 1F), -116.7 ppm (d, 2J(F,F)
278.7 Hz, 1F). 13C[1H] NMR (91 MHz, [D]CDCl3, 25 oC, TMS): δ = 33.5 (m), 54.2, 62.6 (dd, 2J(C,F)
=
=
2
3
1
22.2 Hz, J(C,F) = 18.8 Hz), 112.2 (m), 117.6 (m), 122.7 (q, J(C,F) = 3.9 Hz), 123.3 (q, J(C,F) = 273.1
Hz), 127.1, 131.5 (q, 2J(C,F) = 32.7 Hz), 132.7 (d, 3J(C,F) = 3.9 Hz), 134.3, 154.5, 164.2 (d, 3J(C,F) = 7.1
Hz), 191.0 ppm. IR (ATR): 2922, 1751, 1722, 1614, 1257, 1150. cm-1. HR-MS (ESI) m/z: [M+Na]+
20
Calcd for C14H8F8O3Na 399.0238; found 399.0229. [α]D = -8.6 (c = 0.0022 in MeCN), 50% ee
(absolute configuration R). HPLC: tr(R) = 6.04 min and tr(S) = 6.82 min, Daicel Chiralpack AD-H
column (0.46 cm φ x 25 cm) with hexane:iPrOH (99.5:0.5) as non-stationary phase and 1.0
mL·min-1.
Methyl (R)-5,7-difluoro-1-oxo-2-(perfluoroethyl)-2,3-dihydro-1H-indene-2-carboxylate (4g):
According to the general procedure, 73 mg (0.21 mmol) of 4g were synthesized from 70 mg of
starting material 3g (68% yield) as a colourless oil, after purification by column chromatography
on silica gel (hexane: dichloromethane (1:1)). 1H NMR (400 MHz, [D]CDCl3, 25 oC, TMS): δ = 3.59
(d, 2J(H,H) = 18.1 Hz, 1H), 3.85 (s, 3H), 3.94 (dd, 2J(H,H) = 18.1 Hz, 1H), 6.85 (td, 3J(H,F) = 9.0 Hz, 4J(H,H)
= 1.2 Hz, 1H), 7.04 ppm (d, 3J(H,F) = 7.6 Hz, 4J(H,H) = 1.2 Hz, 1H). 19F NMR (235 MHz, CDCl3, 25 oC,
TMS): δ = -79.6 (s, 3F), -95.1 (d, 4J(F,F) = 14.8 Hz, 1F), -107.1 (d, 4J(F,F) = 14.8 Hz, 1F), -114.9 (d, 2J(F,F)
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= 279.5 Hz, 1F), -117.0 ppm (d, 2J(F,F) = 279.5 Hz, 1F). 13C[1H] NMR (91 MHz, [D]CDCl3, 25 oC, TMS):
δ = 33.3, 54.2, 62.9 (dd, 2J(C,F) = 22.0 Hz, 2J(C,F) = 18.5 Hz), 104.9 (dd, 3J(C,F) = 27.0 Hz, 3J(C,F) = 23.1
Hz), 109.5 (dd, 3J(C,F) = 23.1 Hz, 3J(C,F) = 4.3 Hz), 113.4 (m), 116.8 (m), 125.3 (m), 143.3, 155.1 (dd,
3J(C,F) = 12.3 Hz, 4J(C,F) = 3.1 Hz), 160.5 (dd, 1J(C,F) = 270.4 Hz, 3J(C,F) = 14.2 Hz), 164.2 (d, 3J(C,F) = 11.1
1
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Hz), 168.8 (dd, J(C,F) = 270.4 Hz, J(C,F) = 14.2 Hz), 186.5 ppm. IR (ATR): 2968, 1751, 1721, 1622,
1495, 1258 cm-1. HR-MS (ESI) m/z: [M+Na]+ Calcd for C13H7F7O3Na 367.0176; found 367.0176.
[α]D20 = -16.3 (c = 0.0032 in MeCN), 75% ee (absolute configuration R). HPLC: tr(R) = 9.96 min and
tr(S) = 13.48 min, Daicel Chiralpack AD-H column (0.46 cm φ x 25 cm) with hexane:iPrOH
(99.5:0.5) as non-stationary phase and 1.0 mL·min-1.
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Methyl
(R)-7-bromo-1-oxo-2-(perfluoroethyl)-2,3-dihydro-1H-indene-2-carboxylate
(4h):
According to the general procedure, 81 mg (0.21 mmol) of 4h were synthesized from 80 mg of
starting material 3h (71% yield) as a colourless oil, after purification by column chromatography
on silica gel (hexane:dichloromethane (6:4)). 1H NMR (400 MHz, [D]CDCl3, 25 oC, TMS): δ = 3.56
2
2
(d, J(H,H) = 17.6 Hz, 1H), 3.83 (s, 3H), 3.89 (d, J(H,H) = 17.6 Hz, 1H), 7.50 (m, 2H), 7.84 ppm (dd,
3J(H,F) = 7.1 Hz, 4J(H,H) = 1.3 Hz, 1H). 19F NMR (376 MHz, CDCl3, 25 oC, TMS): δ = -79.1 (s, 3F), -1145
(d, 2J(F,F) = 279.1 Hz, 1F), -116.4 ppm (d, 2J(F,F) = 279.1 Hz, 1F). 13C[1H] NMR (101 MHz, [D]CDCl3, 25
2
2
oC, TMS): δ = 32.4 (bs), 54.1, 63.9 (dd, J(C,F) = 22.0 Hz, J(C,F) = 18.5 Hz), 112.5 (m), 117.5 (m),
125.1, 131.5, 133.7, 136.5, 154.1, 164.5 (d, 3J(C,F) = 7.3 Hz), 189.2 ppm. IR (ATR): 2961, 1758, 1722,
1618, 1284 cm-1. HR-MS (ESI) m/z: [M+Na]+ Calcd for C13H8BrF5O3Na 408.9469; found 408.9463.
[α]D20 = -14.3 (c = 0.0031 in MeCN), 80% ee (absolute configuration R). HPLC: tr(R) = 13.58 min
and tr(S) = 19.80 min, Daicel Chiralpack AD-H column (0.46 cm φ x 25 cm) with hexane:iPrOH
(99.5:0.5) as non-stationary phase and 1.0 mL·min-1.
Pentan-3-yl 1-oxo-2-(perfluoroethyl)-2,3-dihydro-1H-indene-2-carboxylate (4i): According to the
general procedure, 99 mg (0.28 mmol) of 4i were synthesized from 100 mg of starting material
3i (68% yield) as a colourless oil, after purification by column chromatography on silica gel
(hexane:dichloromethane (9:1)). 1H NMR (360 MHz, [D]CDCl3, 25 oC, TMS): δ = 0.83 (m, 6H), 1.58
(m, 4H), 3.61 (d, 2J(H,H) = 17.5 Hz, 1H), 3.88 (d, 2J(H,H) = 17.5 Hz, 1H), 4.83 (quint, 3J(H,H) = 7.2 Hz, 1H),
7.46 (t, 3J(H,H) = 7.5 Hz, 1H), 7.54 (d, 3J(H,H) = 7.5 Hz, 1H), 7.69 (td, 3J(H,H) = 7.5 Hz, 4J(H,H) = 1.2 Hz, 1H),
7.83 ppm (d, 3J(H,H) = 7.5 Hz, 1H). 19F NMR (235 MHz, CDCl3, 25 oC, TMS): δ =-78.8 (s, 3F), -114.0
(d, 2J(F,F) = 279.4 Hz, 1F), -115.0 ppm (d, 2J(F,F) = 279.4 Hz, 1F). 13C[1H] NMR (400 MHz, [D]CDCl3, 25
3
2
2
oC, TMS): δ = 9.1, 26.0, 33.6 (d, J(C,F) = 2.6 Hz), 62.7 (dd, J(C,F) = 22.5 Hz, J(C,F) = 18.6 Hz), 80.5,
113.0 (m), 118.1 (m), 125.3, 126.1, 128.4, 134.2, 136.1, 151.4, 164.2 (d, 3J(C,F) = 11.1 Hz), 192.5
ppm. IR (ATR): 2924 1721, 1607, 1464, 1274, 1185. HR-MS (ESI) m/z: [M+Na]+ Calcd for
C17H17F5O3Na 387.0990; found 387.0994.
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Pentan-3-yl (R)-5,6-dimethoxy-1-oxo-2-(perfluoroethyl)-2,3-dihydro-1H-indene-2-carboxylate
(4j): According to the general procedure, 45 mg (0.11 mmol) of 4j were synthesized from 70 mg
of starting material 3j (47% yield) as colourless oil, after purification by column chromatography
on silica gel (hexane:dichloromethane (9:1)). 1H NMR (250 MHz, [D]CDCl3, 25 oC, TMS): δ = 0.87
(m, 6H), 1.61 (m, 4H), 3.50 (d, 2J(H,H) = 17.3 Hz, 1H), 3.78 (d, 2J(H,H) = 17.3 Hz, 1H), 3.94 (s, 3H), 4.02
(s, 3H), 4.85 (quint, 3J(H,H) = 6.9 Hz, 1H), 6.93 (s, 1H), 7.21 ppm (s, 1H). 19F NMR (235 MHz, CDCl3,
25 oC, TMS): δ =-78.6 (s, 3F), -114.2 (d, 2J(F,F) = 278.9 Hz, 1F), -115.4 ppm (d, 2J(F,F) = 278.9 Hz, 1F).
13C[1H] NMR (101 MHz, [D]CDCl3, 25 oC, TMS): δ = 9.3, 26.0, 33.2 (m), 56.2, 56.4, 62.9 (dd, 2J(C,F)
= 22.0 Hz, 2J(C,F) = 18.5 Hz), 80.3, 105.3, 106.9, 112.0 (m), 117.5 (m), 127.0, 143.3, 147.3, 150.2,
164.6 (d, 3J(C,F) = 7.0 Hz), 190.9 ppm. IR (ATR): 2971, 1762, 1714, 1592, 1504, 1201 cm-1. HR-MS
(ESI) m/z: [M+Na]+ Calcd for C19H21F5O5Na 447.1201; found 447.1198. [α]D20 = -6.1 (c = 0.0040 in
MeCN), 30% ee (absolute configuration R). HPLC: tr(S) = 7.19 min and tr(R) = 7.81 min, Daicel
Chiralpack AD-H column (0.46 cm φ x 25 cm) with hexane:iPrOH (99.5:0.5) as non-stationary
phase and 1.0 mL·min-1.
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Tert-butyl (R)-1-oxo-2-(perfluoroethyl)-2,3-dihydro-1H-indene-2-carboxylate (4k):15 According to
the general procedure, 28 mg (0.12 mmol) of 4k were synthesized from 60 mg of starting
material 3k (32% yield) as colourless oil, after purification by column chromatography on silica
gel (hexane:ethyl acetate (9:1)). 1H NMR (250 MHz, [D]CDCl3, 25 oC, TMS): δ = 1.45 (s, 9H), 3.56
(d, 2J(H,H) = 17.7 Hz, 1H), 3.85 (d, 2J(H,H) = 17.7 Hz, 1H), 7.45 (t, 3J(H,H) = 7.5 Hz, 1H), 7.53 (d, 3J(H,H)
=
7.5 Hz, 1H), 7.68 (td, 3J(H,H) = 7.5 Hz, 4J(H,H) = 1.2 Hz, 1H), 7.83 ppm (d, 3J(H,H) = 7.5 Hz, 1H). 19F NMR
(235 MHz, CDCl3, 25 oC, TMS): δ =-78.6 (s, 3F), -113.6 (d, 2J(F,F) = 278.3 Hz, 1F), -115.6 ppm (d, 2J(F,F)
= 278.3 Hz, 1F). [α]D20 = -6.8 (c = 0.0033 in MeCN), 28% ee (absolute configuration R).
Adamantyl 1-oxo-2-(perfluoroethyl)-2,3-dihydro-1H-indene-2-carboxylate (4l): According to the
general procedure, 107 mg (0.25 mmol) of 4l were synthesized from 110 mg of starting material
3l (71% yield) as a colourless oil, after purification by column chromatography on silica gel
(hexane:ethyl acetate (9:1)). 1H NMR (250 MHz, [D]CDCl3, 25 oC, TMS): δ = 1.64 (bs, 6H), 2.08 (bs,
6H), 2.16 (bs, 3H), 3.55 (d, 2J(H,H) = 17.6 Hz, 1H), 3.84 (d, 2J(H,H) = 17.6 Hz, 1H), 7.48 (m, 2H), 7.68
(t, 3J(H,H) = 7.5 Hz, 1H), 7.83 ppm (t, 3J(H,H) = 7.5 Hz, 1H). 19F NMR (235 MHz, CDCl3, 25 oC, TMS): δ
= -78.5 (s, 3F), -113.6 (d, 2J(F,F) = 279.9 Hz, 1F), -115.6 ppm (d, 2J(F,F) = 279.9 Hz, 1F). 13C[1H] NMR
(101 MHz, [D]CDCl3, 25 oC, TMS): δ = 30.9, 33.6 (bs), 35.9, 40.8, 63.2 (dd, 2J(C,F) = 22.2 Hz, 2J(C,F)
=
=
3
18.3 Hz), 84.7, 112.7 (m), 118.6 (m), 125.3, 126.1, 128.3, 134.2, 136.0, 151.6, 162.6 (d, J(C,F)
10.9 Hz), 192.8 ppm. IR (ATR): 2914, 2853, 1752, 1725, 1607, 1457, 1204 cm-1. HR-MS (ESI) m/z:
[M+Na]+ Calcd for C22H21F5O3Na 451.1303; found 451.1296.
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Methyl
1-oxo-2-(perfluoroethyl)-1,2,3,4-tetrahydronaphthalene-2-carboxylate
(4m):15
According to the general procedure, 154 mg (0.47 mmol) of 4l were prepared from 150 mg of
starting material 3l (65% yield) as a colourless oil, after purification by column chromatography
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on silica gel (hexane:Et2O (2:1)). 1H NMR (250 MHz, [D]CDCl3, 25 oC, TMS): δ = 2.52 (ddd, 2J(H,H)
=
8
9
13.6 Hz, 3J(H,H) = 9.9 Hz, 3J(H,H) = 7.3 Hz, 1H), 2.89 (dt, 2J(H,H) = 13.6 Hz, 3J(H,H) = 3.7 Hz, 1H), 3.05 (m,
2H), 3.77 (s, 3H), 7.25 (d, 3J(H,H) = 7.5 Hz, 1H), 7.38 (t, 3J(H,H) = 7.5 Hz, 1H), 7.55 (td, 3J(H,H) = 7.5 Hz,
4J(H,H) = 1.3 Hz, 1H), 8.12 ppm (d, 3J(H,H) = 7.5 Hz, 1H). 19F NMR (235 MHz, CDCl3, 25 oC, TMS): δ = -
76.9 (s, 3F), -111.5 (d, 2J(F,F) = 279.9 Hz, 1F), -113.2 ppm (d, 2J(F,F) = 279.9 Hz, 1F). [α]D20 = -2.1 (c =
0.0038 in MeCN), 34% ee (absolute configuration R). HPLC: tr(R) = 14.51 min and tr(S) = 16.21
min, Daicel Chiralpack AD-H column (0.46 cm φ x 25 cm) with hexane:iPrOH (99.5:0.5) as non-
stationary phase and 1.0 mL·min-1.
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2-Acetyl-2-(perfluoroethyl)-2,3-dihydro-1H-inden-1-one (4n): According to the general
procedure, 118 mg (0.47 mmol) of 4n were synthesized from 120 mg of starting material 3n
(79% yield) as a yellow liquid after purification by column chromatography on silica gel
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o
2
(hexane:Et2O (2:1)). H NMR (250 MHz, [D]CDCl3, 25 C, TMS): δ = 3.53 (s, 3H), 3.39 (d, J(H,H)
=
17.6 Hz, 1H), 4.12 (d, 2J(H,H) = 17.6 Hz, 1H), 7.43 (td, 3J(H,H) = 7.6 Hz, 4J(H,H) = 1.1 Hz, 1H), 7.54 (dd,
3J(H,H) = 7.6 Hz, 4J(H,H) = 1.1 Hz, 1H), 7.69 (td, 3J(H,H) = 7.5 Hz, 4J(H,H) = 1.1 Hz, 1H), 7.79 ppm (d, 3J(H,H)
= 7.6 Hz, 1H). 19F NMR (235 MHz, CDCl3, 25 oC, TMS): δ = -82.5 (s, 3F), -114.0 (d, 2J(F,F) = 281.2 Hz,
1F), -116.3 ppm (d, 2J(F,F) = 281.2 Hz, 1F). 13C[1H] NMR (63 MHz, [D]CDCl3, 25 oC, TMS): δ = 27.9,
31.0 (bs), 70.4 (m), 125.6, 126.0 (m), 126.7, 127.9 (m), 128.6, 136.8, 143.8, 152.8, 193.9 (bs),
195.3 ppm (bs). IR (ATR): 2928, 1718, 1204, 1096 cm-1. HR-MS (ESI) m/z: [M+Na]+ Calcd for
C13H9F5O2Na 315.0415; found 315.0415. HPLC: tr(1) = 14.14 min and tr(2) = 16.84 min, Daicel
Chiralpack AD-H column (0.46 cm φ x 25 cm) with hexane:iPrOH (99.8:0.2) as non-stationary
phase and 0.5 mL·min-1.
2,6-Di-tert-butyl-4-(3,5-di-tert-butyl-4-(pentafluoroethoxy)benzylidene)cyclohexa-2,5-dien-1-
one (6): Yellowish oil, 1H NMR (250 MHz, [D]CDCl3, 25 oC, TMS): δ = 1.30 (bs, 36H), 6.59 (bs, 3H),
6.84 ppm (bs, 2H). 19F NMR (235 MHz, CDCl3, 25 oC, TMS): δ = -77.8 (s, 3F), -117.1 ppm (s, 2F).
o
13C[1H] NMR (63 MHz, [D]CDCl3, 25 C, TMS): δ = 29.3, 29.6, 35.0, 35.6, 115.2 (m), 121.2 (m),
124.3, 133.5, 134.8, 135.5, 150.5, 186.3 ppm. HR-MS (ESI) m/z: [M+H]+ Calcd for C31H41F5O2
563.2919; found 563.2911.
ASSOCIATED CONTENT
The Supporting Information includes the preparation of 1 and 2, as well as 1H NMR, 13C NMR, 19F
NMR spectra and ESI and HPLC chromatograms.
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AUTHOR INFORMATION
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* E-mail: albert.granados@uab.es
* Email: adelina.vallribera@uab.es
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ORCID
Albert Granados: 0000-0002-5362-5966
Adelina Vallribera: 0000-0002-6452-4589
ACKNOWLEDGMENTS
A previous version of this manuscript has been deposited on the preprint server ChemRxiv.27 We
are thankful for financial support from Spain’s MICINN (RTI2018-097853-B-I00) and MEC
(CTQ2016-81797-REDC, RED2018-102387-T). Funding from DURSI-Generalitat de Catalunya
(2017-SGR465). UAB is also acknowledged by A.G. for his postdoctoral contract.
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TOC
O
O
10 mol% La(OTf)3
13 mol% (S,R)-indanyl-pybox
F3C
F2C
O
I
O
OR'
CF2
O
+
ACN, 4Å MS, -30ºC, Ar
R
OR'
CF3
R
Proposed intermediate
N
N
OTf
N
La
O
O
R
O
I
F2C
OR'
CF3
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