Enantioselective electrophilic fluorination of α-aryl-tetralones using a preparation of N-fluoroammonium salts of cinchonine

Article abstract of DOI:10.1016/j.jfluchem.2018.11.007

The enantioselective electrophilic fluorination of α-aryl-tetralones is promoted by cinchonine/selectfluor combinations. This strategy allows a facile synthesis of the corresponding 2-fluoro-2-aryl-1-tetralones with excellent yields (up to >98%) and moder

Full text of DOI:10.1016/j.jfluchem.2018.11.007

Accepted Manuscript
Title: Enantioselective electrophilic fluorination of
␣-aryl-tetralones using a preparation of N-fluoroammonium
salts of cinchonine
Authors: Luana G. Souza, Jorge L. de O. Domingos, Talita de
A. Fernandes, Magdalena N. Renno, Jose M. Sansano,
Carmen Najera, Paulo R.R. Costa
PII:
S0022-1139(18)30399-3
DOI:
Reference:
https://doi.org/10.1016/j.jfluchem.2018.11.007
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Accepted date:
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11 November 2018
Please cite this article as: Souza LG, de O. Domingos JL, de A. Fernandes T, Renno
MN, Sansano JM, Najera C, Costa PRR, Enantioselective electrophilic fluorination of
␣-aryl-tetralones using a preparation of N-fluoroammonium salts of cinchonine, Journal
of Fluorine Chemistry (2018), https://doi.org/10.1016/j.jfluchem.2018.11.007
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Journal of Fluorine Chemistry
journal homepage: www.elsevier.com/locate/fluor
Enantioselective electrophilic fluorination of α-aryl-tetralones using a preparation
of N-fluoroammonium salts of cinchonine
Luana G. Souzaa,b,c, Jorge L. de O. Domingosd, Talita de A. Fernandese, Magdalena N. Rennoc, Jose M.
Sansanoa,f, Carmen Najeraa* and Paulo R. R. Costab,*
aDepartamento de Quimica Orgánica, Facultad de Ciencias and Centro de Innovación en Quimica Avanzada (ORFEO-CINQA), Universidad de Alicante,
Apdo. 99, 03080, Alicante, Spain.
bLaboratório de Química Bioorgânica, Instituto de Pesquisa de Produtos Naturais, Universidade Federal do Rio de Janeiro, Ilha do Fundão, CCS, Bloco H
– Sala H27, 21941-902 Rio de Janeiro, RJ, Brazil.
cLaboratório de Modelagem Molecular e Pesquisa em Ciências Farmacêuticas (LAMCIFAR), Núcleo em Ecologia e Desenvolvimento Sócio-Ambiental de
Macaé (NUPEM), Universidade Federal do Rio de Janeiro-Campus Macaé Professor Aloísio Teixeira, Rua São José do Barreto 764, 27965-045Macaé, RJ,
Brazil.
dDepartamento de Química Orgânica, Centro de Tecnologiae Ciências, Universidade do Estado do Rio de Janeiro, Rua São Francisco Xavier 524, Pav.
Haroldo Lisboada Cunha – s 406 – Maracanã, 20550-900, Rio de Janeiro, RJ, Brazil.
eInstituto de Química, Universidade de Brasília (UnB), Campus Universitário Darcy Ribeiro, 70910-900, Brasília, DF, Brazil.
f Instituto de SíntesisOrgánica, Universidad de Alicante.
*Corresponding authors: CarmenNájera (cnajera@ua.es), Paulo R. R. Costa (prrcosta2011@gmail.com)
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Enantioselective electrophilic fluorination of
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α-aryl-tetralones using a preparation of
N-fluoroammoniumsalts of cinchonine
Luana G. Souza, Jorge L. de O. Domingos, Talita de A. Fernandes, Magdalena N. Renno, José M. Sansano, Carmen Nájera*
and Paulo R. R. Costa*

1
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
The enantioselective electrophilic fluorination of α-aryl-tetralones is promoted by
cinchonine/selectfluor combinations. This strategy allows a facile synthesis of the corresponding
2-fluoro-2-aryl-1-tetralones with excellent yields (up to >98%) and moderate to good
enantioselectivity (up to74%).
Available online
2018 Elsevier Ltd. All rights reserved.
Keywords:
Enantioselective synthesis, Fluorination, Cinchona
alkaloid, α-Tetralone
1. Introduction
Several bioactive chiral compounds bearing stereogenic
centers at the -position of carbonyl groups, with one enolizable
hydrogen, can suffer rapidly epimerization under physiological
conditions [1]. For example, in propionic acid derivatives, known
as profens (1) (Figure 1), the α-CH3 group increases
cyclooxygenase inhibitory activity, the S-(+)-enantiomer being
much more potent. Fortunately, R-(-)-enantiomers are in vivo
stereospecifically transformed to the active S-(+)-enantiomers
[2]. Thalidomide (2) is an important example of how the same
molecule has different effects depending on the enantiomer. (R)-
enantiomer (2a) causes the clinically effective sedative hypnotic
effects and the (S)-enantiomer (2b) is responsible for the
teratogenic side effects [3]. Another interesting example of
epimerization occurs in the biosynthesis of isoflavonoids.
Genistein, the main isoflavanone of soybean, is stereospecifically
reduced to (R)-dihydrogenistein (3) (Figure 1), which is further
isomerized to (S)-dihydrogenistein by enzymatic or biological
keto-enol tautomerization, such as occurs in daidzein metabolism
[4]. Both (R)-dihydrogenistein (3) and its enantiomer are
biotransformed into tetracyclic isoflavonoids, as pterocarpans.
configurationally stable quaternary stereogenic centers, prevented
the epimerization process [7]. For example, in 2-
fluoropodophyllotoxin (4) (Figure 1), an antitumor agent, the
fluorination promotes metabolic stability [8]. In the potassium
ion channel modulator MaxiPost (BMS-204352) (5) (Figure 1)
the absolute configuration is important for the biological activity
and this compound was used as a pure enantiomer [9]. In
consequence, chirality plays a key role in the efficacy of many
compounds and thus enantioselective synthesis is an important
strategy in pharmaceutical industry to access these compounds in
enantiomerically pure form [10].
The electrophilic fluorination of the α-carbonyl center is one
of the most common forms to generate fluorine-containing
compounds [11].Some methods to generate enantioselective α-
fluoro-α-aryl cyclic carbonyl compounds can be divided in two
strategies: one is the enantioselective α-arylation of α-
fluoroketones demonstrated by Hartwig and co-workers[12]
using palladium catalysts and chiral ligands (Scheme 1, eq a).
The other one is the enantioselective α-fluorination of α-aryl-
ketones with selectfluor, via cooperative catalysis of enamine and
chiral anionic phase-transfer described by Toste and co-workers
[13] (Scheme 1, eq b).
Figure 1. Propionic acid derivatives (1), (R)-thalidomide (2a), (S)-
thalidomide (2b), (S)-dihydrogenistein (3), 2-fluoropodophyllotoxin (4) and
potassium ion channel modulator MaxiPost (BMS-204352) (5).
Scheme 1. Synthesis of enantiopure α-fluoro-α-aryl cyclic carbonyl
compounds: (eq a) enantioselective α-arylation of fluoro-ketones and (eq b)
enantioselective α-fluorination of α-aryl-ketones.
In the last decades fluorine-containing compounds have
attracted the attention of medicinal chemists and pharmaceutical
industry [5]. The replacement of a hydrogen atom by a fluorine
atom in bioactive compounds promote changes in the stability,
lipophilicity and reactivity [6]. In the particular case of
fluorination at the -position of carbonyl groups, bearing a
tertiary stereogenic center, the obtained substances containing
The α-aryl cyclic carbonyl moiety is present in the structure of
many biological active compounds and is also found in many
natural products like isoflavonoids, which are secondary

2
Journal of Fluorine Chemistry
metabolites present in Leguminosae family [7]. An example is
cajanol 6 (Figure 2), an isoflavanone which has antiproliferative
activity towards MCF-7 human breast cancer cells, promoting
disruption of the cell cycle in the G2/M phase and induction of
apoptosis through ROS-mediated mitochondrial pathway [14].
Bonfield et al. [15] and Amato et al. [16] synthesized
isoflavanone analogues (7a and 7b) which acted as aromatase
inhibitors. Compound 7 showed antiproliferative properties in
MCF7 cells in culture (Figure 2). Carba-analogues of
isoflavanones, like 8 (Figure 2), were also synthesized and
evaluated as hepatitis C virus inhibitors by Manvar et al. [17].
The biological properties of all these compounds were studied in
the racemic form.
Figure 3. Cinchona derived alkaloids used in this work.
Using these last reaction conditions no conversion was
observed. Indeed, this problem was solved by using 2 equiv of
Cinchona derivatives in an equimolar mixture with selectfluor,
like Cahard et al. [10b]. The conditions were optimized by
changing temperature and the Cinchona alkaloids (Table 1). The
highest ee for product 10a was observed when cinchonine was
used as alkaloid at 0 ºC (Table 1, entry 9) although the yields
were higher decreasing the temperature (Table 1, entries 10-13).
No reaction was observed neither when (DHQN)2PHAL was
used (Table 1, entry 14) nor when quinidine was employed at -20
ºC (not depicted in Table 1). So, we extended these reaction
conditions (cinchonine/0ºC) to other α-aryl tetralones with
changes in the A or in the C rings (Scheme 2). The reaction
performed with O-allylated cinchonine or O-allylated
hydrocinchonine afforded racemic compounds (not shown in
Table 1).
Figure 2. Cajanol (6), aromatase inhibitors (7a,b) and hepatitis C virus
inhibitor (8)
So, according to all these precedents, we combined all them in
this work with the idea of synthesizing enantioenriched 2-aryl-2-
fluoro-1-tetralones by enantioselective α-fluorination of o-
substituted α-aryl-tetralones using ammonium salts from
Cinchona alkaloids.
Table 1.
Fluorination of the enolate of α-(2-methoxyphenyl)tetralone (9).
2. Results and discussion
Previous studies on the fluorination of α-benzyl cyclic
carbonyl compounds, including α-benzyl indanones and α-benzyl
tetralones, using achiral N-fluorosulfonamide agents [18], chiral
Pd-complexes [8b] and N-fluoroammonium salts of Cinchona
alkaloid derivatives [5,10b,[19] have been reported in the
literature.
Entry Alkaloid
T (ºC) Yield (%)a ee (%)b
1
Quinine
rt
57
59
67
64
73
82
11
37
74
86
99
81
22
22
0
Several steps are required for synthesizing chiral N-
fluorosulfonamide agents and most common involves the
formation of the N-F bond using elemental fluorine or FClO3 at
low temperatures (-78 ºC), using strong bases (LDA or LiHMDS)
[16]. In contrast, the reactions using N-fluoroammonium salts of
Cinchona alkaloids and their derivatives are performed under
milder conditions. So we examined initially the reaction
employing catalytic amounts (20 mol%) of Cinchona alkaloids
and α-(2-methoxyphenyl)tetralone (9a) [15]. A sodium enolate
of 9a, generated by using sodium hydride in THF, was treated
with selectfluor and NFSI as fluorinating agents and
substoichiometric amounts of quinine, quinidine, cinchonidine,
cinchonine and (DHQN)2PHAL as chiral sources (Figure 3).
2
Quinine
0
3
Quinine
-20
rt
8
4
Cinchonidine
Cinchonidine
Cinchonidine
Cinchonine
Cinchonine
Cinchonine
Cinchonine
Cinchonine
Cinchonine
Quinidine
6
5
0
20
6
6
-20
rt
7
44
74
57
55
60
59
20
8
0
9
-5
-10
-20
-30
rt
10
11
12
13

3
14
(DHQD)2PHAL rt
NR
--
a Isolated yield after column chromatography.
bDetermined by HPLC using Daicel-Chiralpak AD-H column (Hex:IPA
5%).
Compounds 10a-i were obtained at 0 ºC from low to moderate
ee, achieving the maximum 74% ee when 9a was used as starting
compound (Scheme 2). So, the reaction performed with
cinchonine at -20 ºC was next tested for these starting tetralones
and others (Scheme 2). Under these reaction conditions the ee
was higher or remained unaltered with respect to the others
obtained at 0 ºC. The better ee was obtained for the ortho-methyl
derivatives 10c and 10l, with 69% ee and 70% ee, respectively.
By changing the α-aryl substituents from ortho- to meta- and
para-positions the enantiomeric excesses decreased (products
10c, 10j and 10k). It was noted that changing the A ring
substituents, compounds with substituents at C-7 position,
products 10h and 10i kept almost the same results of the model
substrate at -20 ºC with 58% ee and 57% ee, respectively.
Substituents in other positions induced a small decrement of ee.
Scheme 2. Some different products obtained by enantioselective α-
fluorination using the selected conditions at different temperatures.
The absolute configuration was assigned by measurement of
the optical rotation and using the octant rule that is compared
with reported values [1,[20]. Also, vibrational circular dichroism
(VCD) analysis of compound 10l confirmed the (R)-
configuration. The calculated and experimental VCD spectra of
2-Fluoro-2-(4-methoxy-2-methylphenyl)tetralone is illustrated in
Figure 4. It is found that the predicted spectra have a clear and
crucial similarity with the experimental one in the region of the
carbonyl group vibration (~1700 cm-1). The fingerprint region of
the vibrational optical activity spectra (not shown in Figure 4) did
not completely match due to the presence of a 85:15 ratio of
enantiomers in the sample.
Figure 4. VCD analysis of molecule 10l. Calculated plot for the (R)-
enantiomer in red, and experimental spectra in black.
A known effect in medicinal chemistry is the ortho-effect,
which is the result of a conformational change forced by the
introduction of a bulky group [21]. Much work is in process to

4
Journal of Fluorine Chemistry
build a molecular model for justifying this stereoselective
microwave irradiation (100W of initial power, 100 ºC, 60 min,
infrared probe). Then, the mixture was allowed to cool to rt,
diluted in AcOEt, washed with saturated NH4Cl solution, dried
over anhydrous MgSO4, filtered and concentrated under reduced
pressure. The crude material was purified by silica gel column
with n-hexane:AcOEt (95:5) as solvent.
behavior with the transition states developed by Lam and Houk
(2014) [22], which described a stereoselective model for
Cinchona alkaloid-derived primary amines to control the
fluorinations of cyclic ketones by the cyclic TS in chair and boat
conformations.
Compounds 9a [15], 9b [23], 9c [23], 9d [24], 9e [23], 9f
[15], 9g [15], 9h [15], 9j [23] and 9k [23] are known, new
compounds follow:
2. Conclusions
4.2.1.
7-Fluoro-2-(2-methoxyphenyl)-3,4-dihydronaphthalen-
In this work, we have screened different combination of N-
fluoroammonium salts of Cinchona alkaloid derivatives at
various temperatures for the enantioselective electrophilic
fluorination of α-aryl-α-tetralones using an unusual substrate as
model, α-(2-methoxyphenyl)tetralone, due to the importance of
o-substituent compounds in the pharmaceutical chemistry and
synthesis of natural products. The enantioselectivity in this
reaction showed a strong dependence of the substituent in C ring
for electron-donor o-substituent. Although moderately efficient
from the point of view of enantioselectivity (up to 70% ee).
These reactions are highly sensitive to the structure of Cinchona
derivatives, to the nature of the substrates and to the temperature.
To complete the reaction, the sodium enolate of the
corresponding tetralone was allowed to react with fluorinated
agent formed by the most appropriate chiral base cinchonidine
and selectfluor (both used in stoichiometric amounts) in
acetonitrile at 0 or -20 ºC
º
1
1(2H)-one (9i): yellow solid (24 mg, 90%). Mp = 79-82 C. H
NMR (400 MHz, CDCl3) δ 7.74 (dd, J = 9.2, 2.5 Hz, 1H), 7.29–
7.23 (m, 2H), 7.18 (td, J = 8.3, 2.6 Hz, 1H), 7.09 (d, J = 7.4 Hz,
1H), 6.92 (dd, J = 15.3, 7.8 Hz, 2H), 3.99 (dd, J = 12.4, 4.6 Hz,
1H), 3.73 (s, 3H), 3.11 – 3.03 (m, 1H), 2.98 (dt, J = 16.3, 3.8 Hz,
1H), 2.48 (ddd, J = 24.7, 12.5, 4.4 Hz, 1H), 2.26 (ddd, J = 12.9,
8.4, 4.2 Hz, 1H); 13C NMR (101 MHz, CDCl3) δ 197.05 (d, J =
1.8 Hz), 161.55 (d, J = 245.7 Hz), 156.95, 139.76 (d, J = 3.0 Hz),
134.65 (d, J = 6.1 Hz), 130.43 (d, J = 7.1 Hz), 129.42, 128.89,
128.29, 120.76, 120.33 (d, J = 22.2 Hz), 113.43 (d, J = 21.9 Hz),
111.09, 55.41, 49.87, 29.89, 28.75. HRMS (ESI): m/z calcd. for
C17H15FO2: 270.1058; found: 270.1054.
4.2.2.
2-(4-Methoxy-2-methylphenyl)-3,4-dihydronaphthalen-
1(2H)-one (9l): brown solid (231.7 mg, yield 87%). Mp = 77-79
ºC. 1H NMR (400 MHz, CDCl3) δ 8.09 (dd, J = 7.8, 1.0 Hz, 1H),
7.49 (td, J = 7.5, 1.4 Hz, 1H), 7.33 (t, J= 7.6 Hz, 1H), 7.28 (d, J =
7.6 Hz, 1H), 6.97 (d, J = 8.5 Hz, 1H), 6.77 (d, J = 2.7 Hz, 1H),
6.71 (dd, J = 8.5, 2.7 Hz, 1H), 3.90 (dd, J = 11.9, 4.8 Hz, 1H),
3.77 (s, 3H), 3.19 – 3.10 (m, 1H), 3.05 (dt, J = 16.6, 4.2 Hz, 1H),
2.48 – 2.30 (m, 2H), 2.29 (s, 3H); 13C NMR (101 MHz, CDCl3) δ
198.35, 158.25, 144.10, 137.95, 133.38, 133.06, 130.87, 128.80,
128.52, 127.76, 126.74, 116.14, 111.35, 55.17, 50.89, 30.56,
4. Experimental
4.1. General
Reagents and dry solvents were obtained commercially
(Aldrich and Alfa aesar) and used without further purification.
CEM Discovery and Explorer-Coolmate accessory were
employed in the microwave-assisted reactions for the generation
of α-ayltetralones. NMR spectra were recorded in deuterated
chloroform, with tetramethylsilane (TMS) as internal standard,
unless otherwise stated. The samples were analyzed at 300 and
29.53, 20.18. HRMS (ESI): m/z calcd for C18H18O2 [M]+
266.1307, found 266.1310.
=
4.2.3. 2-(2,5-Dimethylphenyl)-3,4-dihydronaphthalen-1(2H)-one
º
1
(9m): yellow solid (27.4 mg, yield 55%). Mp = 66-68 C. H
NMR (300 MHz, CDCl3) δ 8.10 (dd, J = 7.8, 1.1 Hz, 1H), 7.51
(td, J = 7.5, 1.5 Hz, 1H), 7.33 (dd, J = 16.1, 7.8 Hz, 2H), 7.10 (d,
J = 7.7 Hz, 1H), 6.99 (dd, J = 7.7, 1.8 Hz, 1H), 6.88 (d, J = 1.6
Hz, 1H), 3.94 (dd, J = 12.1, 4.8 Hz, 1H), 3.24 – 3.01 (m, 2H),
2.41 (dddd, J = 13.3, 8.8, 3.5, 2.5 Hz, 2H), 2.27 (s, 6H); 13C
NMR (75 MHz, CDCl3) δ 198.21, 144.10, 138.49, 135.47,
133.38, 133.31, 133.08, 130.44, 128.77, 128.39, 127.79, 127.69,
126.77, 51.62, 30.49, 29.58, 21.11, 19.48. HRMS (ESI): m/z
calcd for C18H18O [M]+= 250,1358, found 250.1348.
1
400 MHz H NMR and 75 and 101 MHz 13C NMR using a
Bruker AV300 and a Bruker AV400, respectively. Chemical
shifts are reported as δ values (ppm). The following abbreviations
are used for the multiplicities: s: singlet, d: doublet, dd: doublet
of doublet, t: triplet, q: quadruplet, m: multiplet. Melting points
were uncorrected. Low-resolution electron impact (GC-EI) mass
spectra were obtained at 70 eV using an Agilent 6890N Network
GC system and Agilent 5973 Network Mass Selective Detector.
High resolution mass spectra (GC-EI) were recorded using a
QTOF Agilent 7200 instrument for the exact mass and Agilent
7890B for the GC. Vibrational Circular Dichroism analysis was
performed in a VCD Jasco FVS-6000 incorporating MCT-V
detector. Optical rotations were measured with a Perkin-Elmer
4.3. General procedure for the synthesis of 2-fluoro-2-aryl-1-
tetralones
1
A mixture of cinchonine (58.88 mg, 0.2 mmol) and
selectfluor (70.85 mg, 0.2 mmol) in dry MeCN (1 mL) was
stirred for 1h at rt. This mixture was added to another mixture
containing α-aryltetralone (0.1mmol) and NaH (4.8 mg, 0.2
mmol) in THF (1 mL) under Ar, which was stirred previously 30
min at -20ºC. The resulting mixture was stirred at -20ºC for 20 h
and then water was added (5 mL) extracted with AcOEt (3x5
mL). The organic phase was washed with saturate NaHCO3
solution, dried over anhydrous MgSO4, filtered and concentrated
under reduced pressure. The crude material was purified by silica
gel column with n-hexane:diethyl ether (90:10) as solvent.
341 polarimeter. The progress of reactions was monitored by H
NMR and column chromatography was carried out on silica gel,
the flash column chromatography silica gel 60 (40-60 mm) was
employed. Analytical thin layer chromatography (TLC) was done
using ALUGRAM® Xtra SIL G/ UV254 silica gel plates, and the
spots were determined under UV light (= 254 nm). The
enantiomeric excesses of products were determined by chiral
HPLC analysis at 254 nm using the indicated chiral phase
column.
4.2. General procedure for the synthesis of α-aryl-tetralones
In a microwave tube were added a suspension of Pd(dba)2
(5mol%), tBu3PHBF4 (10mol%), NaOH (2eq), aryl bromide
(1.2eq) and α-tetralone (1.0eq) in a mixture of degassed
dioxane/water (4:1, v/v, 2-4 mL) and heated under Ar and
4.3.1.
2-Fluoro-2-(2-methoxyphenyl)-3,4-dihydronaphthalen-
1(2H)-one (10a): yellow solid (10 mg, 37%, ee 74%). Mp = 110-
o
25
1
112 C. [α]D = -41.88 (c 0.8, CHCl3). H NMR (400 MHz,
CDCl3) δ 8.11 (d, J= 7.8 Hz, 1H), 7.57 (d, J = 7.6 Hz, 1H), 7.52

5
(t, J = 7.4 Hz, 1H), 7.37 (t, J = 7.6 Hz, 1H), 7.33 (dd, J = 12.3,
4.8 Hz, 1H), 7.28 (d, J = 7.7 Hz, 1H), 7.06 (t, J = 7.5 Hz, 1H),
6.86 (t, J = 8.9 Hz, 1H), 3.56 (s, 3H), 3.34 – 3.23 (m, 1H), 2.97 –
2.79 (m, 2H), 2.45 (ddd, J = 17.8, 9.1, 4.2 Hz, 1H); 13C NMR
(101 MHz, CDCl3) δ 191.31 (d, J = 18.1 Hz), 154.91 (d, J = 6.1
Hz), 143.31, 133.43, 131.80, 129.52 (d, J = 1.0 Hz), 128.99 (d, J
= 22.6 Hz), 128.45, 128.17, 126.93, 126.13 (d, J = 13.3 Hz),
121.10 (d, J = 1.7 Hz), 111.57, 94.76 (d, J = 177.6 Hz), 55.38,
34.85 (d, J = 24.0 Hz), 25.14 (d, J = 4.3 Hz); 19F NMR (470
MHz, CDCl3) δ -162.87 (dd, J = 37.5, 13.4 Hz). HPLC (Chiralcel
OD-H column, hex/iPrOH = 95:5, 1.0 mL/min, 254 nm) tR= 8.69
min (minor), tR = 11.20 min (major). GC-MS (EI): m/z calcd. for
C17H15FO2: 270.1056; found: 270.1052.
8.19 (dd, J = 7.9, 1.3 Hz, 1H), 7.53 (td, J = 7.5, 1.5 Hz, 1H),
7.39 (dd, J = 12.9, 5.1 Hz, 1H), 7.36 – 7.30 (m, 2H), 7.23 (d, J =
7.7 Hz, 1H), 6.92 – 6.85 (m, 2H), 3.80 (d, J = 2.2 Hz, 3H), 3.09
(ddd, J = 11.0, 6.4, 4.0 Hz, 1H), 2.93 – 2.61 (m, 3H). 13C NMR
(75 MHz, CDCl3) δ 194.27 (d, J = 18.3 Hz), 160.23 (d, J = 2.2
Hz), 142.94, 134.14, 132.15, 128.78, 128.01 (d, J = 0.7 Hz),
127.90 (d, J = 4.8 Hz), 127.15, 114.04, 95.86 (d, J = 184.6 Hz),
55.27, 34.97 (d, J = 25.5 Hz), 26.66 (d, J = 9.3 Hz); 19F NMR
(282 MHz, CDCl3) δ -145.71 (t, J = 10.7 Hz). HPLC (Chiralcel
OD-H column, hex/iPrOH = 99:1, 1.0 mL/min, 254 nm) tR
=
25.22 min (major), tR = 29.76 min (minor). GC-MS (m/z, relative
intensity): 270.1 (M+, 9), 250.1 (100), 235.1 (14), 207.1 (18),
178.1 (48), 152.1 (18), 118.1 (66), 90.1 (32).
4.3.2.
2-Fluoro-2-phenyl-3,4-dihydronaphthalen-1(2H)-one
4.3.6.
2-Fluoro-5-methoxy-2-(2-methoxyphenyl)-3,4-
23
(10b) [1,21,22]: yellow oil (20.7 mg, yield 89%, ee 16%). [α]D
= +42.35 (c 1.0, CHCl3). 1H NMR (300 MHz, CDCl3) δ 8.20
(dd, J = 7.9, 1.2 Hz, 1H), 7.56 (td, J = 7.5, 1.4 Hz, 1H), 7.45 –
7.41 (m, 1H), 7.37 (s, 5H), 7.26 (d, J = 7.7 Hz, 1H), 3.18 – 3.06
(m, 1H), 2.92 – 2.66 (m, 3H); 13C NMR (75 MHz, CDCl3) δ
193.87 (d, J = 18.3 Hz), 143.14, 136.75 (d, J = 22.6 Hz), 134.23,
132.18, 129.13 (d, J = 2.3 Hz), 128.84, 128.62, 128.11 (d, J = 1.4
Hz), 127.22, 126.09 (d, J = 5.8 Hz), 96.02 (d, J = 184.4 Hz),
35.52 (d, J = 25.0 Hz), 26.38 (d, J = 9.3 Hz); 19F NMR (470
MHz, CDCl3) δ -144.94 (t, J = 10.5 Hz).HPLC (Chiralpack AS-H
column, hex/i-PrOH= 99/1, 1.0 mL/min, 254 nm) tR = 17.45 min
(major), tR = 23.66 min (minor). GC-MS (m/z, relative intensity):
240.1 (M+, 18), 118.1 (100), 90.1 (51).
dihydronaphthalen-1(2H)-one (10f): yellow solid (28 mg, yield
93%, ee 44%). Mp = 122-126 ºC. [α]D23.8 = -12.50 (c 1.0, CHCl3).
1H NMR (300 MHz, CDCl3) δ 7.76 (dd, J = 7.9, 1.0 Hz, 1H),
7.57 (dd, J = 7.6, 1.7 Hz, 1H), 7.39 – 7.31 (m, 2H), 7.11 – 7.04
(m, 2H), 6.92 – 6.87 (m, 1H), 3.90 (s, 3H), 3.62 (s, 3H), 3.01 (dd,
J = 7.5, 4.7 Hz, 2H), 3.00 – 2.78 (m, 1H), 2.54 – 2.39 (m, 1H).
13C NMR (101 MHz, CDCl3) δ 191.58 (d, J = 18.4 Hz), 156.41,
155.26 (d, J = 5.7 Hz), 132.79, 132.40, 129.62 (d, J = 1.1 Hz),
128.58 (d, J = 22.4 Hz), 127.22, 126.38 (d, J = 12.7 Hz), 121.07
(d, J = 1.4 Hz), 119.78, 114.34, 111.68 (d, J = 1.2 Hz), 94.70 (d,
J = 178.0 Hz), 55.72, 55.47, 34.01 (d, J = 24.0 Hz), 18.56 (d, J =
4.7 Hz); 19F NMR (470 MHz, CDCl3) δ -161.44 (dd, J = 36.2,
12.6 Hz). HPLC (Chiralcel OD-H column, hex/iPrOH = 95:5, 1.0
mL/min, 254 nm) tR = 10.40 min (minor), tR = 14.64 min
(major).GC-MS (EI): m/z calcd for C18H17FO3 (M+Na+):
323.1053, found: 323.1057.
4.3.3.2-Fluoro-2-(o-tolyl)-3,4-dihydronaphthalen-1(2H)-one
(10c) [22]: yellow solid (18 mg, yield 71%, ee 69%). Mp = 69-73
ºC. [α]D25 = -66.59 (c 0.3, CHCl3). 1H NMR (400 MHz, CDCl3) δ
8.18 (d, J = 7.8 Hz, 1H), 7.55 (t, J = 7.3 Hz, 1H), 7.40 (t, J = 7.5
Hz, 1H), 7.27 (d, J = 7.7 Hz, 1H), 7.24 – 7.19 (m, 2H), 7.19 –
7.06 (m, 2H), 3.26 – 3.14 (m, 1H), 2.91 – 2.73 (m, 2H), 2.62 –
2.49 (m, 1H), 2.35 (s, 3H). 13C NMR (101 MHz, CDCl3) δ
192.92 (d, J = 19.0 Hz), 143.50, 136.34 (d, J = 20.9 Hz), 135.59,
134.21, 132.29, 131.98, 128.78, 128.57, 128.38, 127.29, 126.12
(d, J = 11.3 Hz), 125.62, 96.90 (d, J = 180.6 Hz), 34.90 (d, J =
24.5 Hz), 25.83 (d, J = 7.0 Hz), 21.34 (d, J = 4.4 Hz); 19F NMR
(470 MHz, CDCl3) δ -154.22 (dd, J = 23.8, 10.9 Hz).HPLC
(Chiralcel OD-H column, hex/iPrOH = 99:1, 1.0 mL/min, 254
nm) tR= 12.94 min (minor), tR = 16.13 min (major).GC-MS (m/z,
relative intensity): 254.2 (M+, 6), 234.1 (40), 118.1 (100), 90.1
(56).
4.3.7.
2-Fluoro-6-methoxy-2-(2-methoxyphenyl)-3,4-
dihydronaphthalen-1(2H)-one (10g): yellow solid (26.6 mg,
24.5
yield 89%, ee 43%). Mp = 89-90 °C. [α]D
= -11.49 (c 0.8,
CHCl3). 1H NMR (300 MHz, CDCl3) δ 8.11 (dd, J = 8.6, 4.7 Hz,
1H), 7.58 (ddd, J = 11.7, 6.3, 5.6 Hz, 1H), 7.39 – 7.31 (m, 1H),
7.11 – 7.03 (m, 1H), 6.95 – 6.87 (m, 2H), 6.77 (d, J = 2.4 Hz,
1H), 3.90 (d, J = 3.1 Hz, 3H), 3.62 (d, J = 3.2 Hz, 3H), 3.31 (ddd,
J = 15.7, 11.5, 4.5 Hz, 1H), 3.05 – 2.76 (m, 2H), 2.50 – 2.31 (m,
1H). 13C NMR (101 MHz, CDCl3) δ 189.86 (d, J = 18.5 Hz),
163.66, 155.01 (d, J = 6.1 Hz), 145.89, 130.78, 129.38, 126.12
(d, J = 13.7 Hz), 125.18, 121.02 (d, J = 1.8 Hz), 120.54, 113.53,
112.31, 111.58 (d, J = 1.5 Hz), 94.78 (d, J = 177.2 Hz), 55.46 (2
overlapped signals), 34.72 (d, J = 24.0 Hz), 25.50 (d, J = 4.3 Hz);
19F NMR (470 MHz, CDCl3) δ -163.30 (dd, J = 38.1, 13.2 Hz).
HPLC (Chiralcel OD-H column, hex/iPrOH = 95:5, 1.0 mL/min,
254 nm) tR = 10.88 min (minor), tR = 15.35 min (major).GC-MS
(EI): m/z calcd for C18H17FO3 (M+Na+): 323.1053, found:
323.1060.
4.3.4.
2-Fluoro-2-(2-fluorophenyl)-3,4-dihydronaphthalen-
1(2H)-one (10d) [22]: yellow solid (14.5 mg, yield 56%, ee
25
1
32%). Mp = 74-76ºC. [α]D = -31.70 (c 0.5, CHCl3). H NMR
(300 MHz, CDCl3) δ 8.18 (dd, J = 7.9, 1.3 Hz, 1H), 7.60 – 7.50
(m, 2H), 7.45 – 7.34 (m, 2H), 7.31 (d, J = 7.7 Hz, 1H), 7.22 (td, J
= 7.6, 1.1 Hz, 1H), 7.12 – 7.04 (m, 1H), 3.35 (ddd, J = 15.4, 8.7,
4.0 Hz, 1H), 3.03 – 2.80 (m, 2H), 2.68 – 2.54 (m, 1H). 13C NMR
(101 MHz, CDCl3) δ 190.60 (d, J = 19.2 Hz), 159.06 (dd, J =
247.1, 5.4 Hz), 143.46, 134.15, 131.03, 130.42 (d, J = 8.3 Hz),
128.68, 127.36 (d, J = 3.6 Hz), 127.19, 126.28 (dd, J = 23.7, 12.7
Hz), 124.27 (d, J = 2.5 Hz), 115.92 (d, J = 21.8 Hz), 94.27 (dd, J
= 181.5, 2.9 Hz), 34.95 (dd, J = 24.0, 3.0 Hz), 25.25 (d, J = 6.0
Hz); 19F NMR (470 MHz, CDCl3) δ -110.95 – -111.10 (m),
161.51 (dd, J = 33.5, 10.8 Hz). HPLC (Chiralcel OD-H column,
hex/iPrOH = 95:5, 1.0 mL/min, 254 nm) tR= 8.36 min (minor), tR
= 11.78 min (major). GC-MS (m/z, relative intensity): 258.1 (M+,
22), 118.1 (100), 90.1 (44).
4.3.8.
2-Fluoro-7-methoxy-2-(2-methoxyphenyl)-3,4-
dihydronaphthalen-1(2H)-one (10h): yellow solid (30.2 mg,
25
yield 100%, ee 58%). Mp = 130-133 °C. [α]D = -37.61 (c 0.6,
1
CHCl3). H NMR (400 MHz, CDCl3) δ 7.57 (d, J = 2.7 Hz, 1H),
7.55 (d, J = 7.7 Hz, 1H), 7.34 – 7.29 (m, 1H), 7.18 (d, J = 8.4 Hz,
1H), 7.09 (dd, J = 8.4, 2.8 Hz, 1H), 7.04 (t, J = 7.4 Hz, 1H), 6.86
(d, J = 8.2 Hz, 1H), 3.89 – 3.81 (m, 3H), 3.57 (s, 3H), 3.24 – 3.15
(m, 1H), 2.91 – 2.72 (m, 2H), 2.41 (ddd, J = 17.8, 9.1, 4.3 Hz,
1H). 13C NMR (101 MHz, CDCl3) δ 191.17 (d, J = 18.4 Hz),
158.55 (s), 154.96 (d, J = 6.0 Hz), 136.00 (s), 132.52 (s), 129.72
(s), 129.50 (s), 128.98 (d, J = 22.8 Hz), 126.18 (d, J = 13.3 Hz),
121.73 (s), 121.09 (d, J = 1.7 Hz), 111.55 (d, J = 1.0 Hz), 110.17
(s), 94.67 (d, J = 177.7 Hz), 55.56 (s), 55.45 (s), 35.02 (d, J =
24.0 Hz), 24.37 (d, J = 4.5 Hz); 19F NMR (470 MHz, CDCl3) δ -
162.74 (dd, J = 37.2, 13.2 Hz). HPLC (Chiralcel OD-H column,
hex/iPrOH = 95:5, 1.0 mL/min, 254 nm) tR = 14.84 min (minor),
4.3.5.
2-Fluoro-2-(4-methoxyphenyl)-3,4-dihydronaphthalen-
1(2H)-one (10e) [22]: orange oil (24.5 mg, yield 91%, ee 6%).
26
1
[α]D = +15.91 (c 0.3, CHCl3). H NMR (300 MHz, CDCl3) δ

6
Journal of Fluorine Chemistry
tR = 21.55 min (major).GC-MS (EI): m/z calcd for C18H17FO3
4.3.12.
2-Fluoro-2-(4-methoxy-2-methylphenyl)-3,4-
(M+): 300.1162, found: 300.1159.
dihydronaphthalen-1(2H)-one (10l): brown oil (27.1 mg, yield
25
1
95%, ee 70%). [α]D = -104.28 (c 0.7, CHCl3). H NMR (400
MHz, CDCl3) δ 8.20 (dd, J = 7.9, 1.1 Hz, 1H), 7.57 (td, J = 7.5,
1.4 Hz, 1H), 7.43 (dd, J = 9.2, 5.6 Hz, 1H), 7.31 – 7.26 (m, 1H),
7.04 (d, J = 8.6 Hz, 1H), 6.79 (d, J = 2.6 Hz, 1H), 6.62 (dd, J =
8.6, 2.6 Hz, 1H), 3.79 (s, 3H), 3.23 – 3.12 (m, 1H), 2.93 – 2.75
(m, 2H), 2.64 – 2.53 (m, 1H), 2.41 (d, J = 2.1 Hz, 3H). 13C NMR
(101 MHz, CDCl3) δ 193.67 (d, J = 18.9 Hz), 159.44, 143.46,
138.02, 134.13, 132.14, 128.75, 128.25, 128.09 (d, J = 21.9 Hz),
127.80 (d, J = 9.8 Hz), 127.24, 118.19, 110.21, 97.12 (d, J =
181.3 Hz), 55.15, 34.98 (d, J = 24.9 Hz), 26.11 (d, J = 7.6 Hz),
21.42 (d, J = 4.7 Hz); 19F NMR (282 MHz, CDCl3) δ -151.55 (dd,
J = 19.9, 10.1 Hz). HPLC (Chiralpack AS-H column, hex/i-
PrOH= 99/1, 1.0 mL/min, 254 nm) tR = 18.42 min (minor), tR =
20.57 min (major). GC-MS (EI): m/z calcd for C18H17FO2 (M+):
284.1213, found: 284.1218.
4.3.9. 2,7-Difluoro-2-(2-methoxyphenyl)-3,4-dihydronaphthalen-
1(2H)-one (10i): yellow solid (23.1 mg, yield 77%, ee 57%). Mp
25
1
= 104-107 °C. [α]D = -32.02 (c 0.7, CHCl3). H NMR (400
MHz, CDCl3) δ 7.76 (dd, J = 9.0, 2.5 Hz, 1H), 7.56 (d, J = 7.6
Hz, 1H), 7.32 (t, J = 7.8 Hz, 1H), 7.27 – 7.19 (m, 2H), 7.06 (t, J =
7.5 Hz, 1H), 6.86 (d, J = 8.2 Hz, 1H), 3.56 (s, 3H), 3.27 – 3.18
(m, 1H), 2.92 – 2.76 (m, 2H), 2.48 – 2.39 (m, 1H). 13C NMR
(101 MHz, cdcl3) δ 190.40 (dd, J = 18.4, 1.7 Hz), 161.72 (d, J =
246.2 Hz), 154.75 (d, J = 6.1 Hz), 139.07 (d, J = 3.1 Hz), 133.33
(d, J = 6.2 Hz), 130.34 (d, J = 7.2 Hz), 129.65 (s), 128.70 (d, J =
22.8 Hz), 126.07 (d, J = 13.2 Hz), 121.18 (d, J = 1.6 Hz), 120.81
(d, J = 22.2 Hz), 113.91 (d, J = 22.0 Hz), 111.55 (d, J = 1.5 Hz),
94.26 (d, J = 177.8 Hz), 55.38 (s), 34.91 (d, J = 24.1 Hz), 24.46
(d, J = 4.3 Hz); 19F NMR (470 MHz, CDCl3) δ -114.52 (dd, J =
13.8, 8.1 Hz), -163.11 (dd, J = 38.0, 13.3 Hz). HPLC (Chiralcel
OD-H column, hex/iPrOH = 95:5, 1.0 mL/min, 254 nm) tR = 7.77
min (minor), tR = 10.64 min (major). GC-MS (EI): m/z calcd for
C17H14F2O2 (M+): 288.0962, found: 288.0958.
4.3.13. 2-(2,5-Dimethylphenyl)-2-fluoro-3,4-dihydronaphthalen-
1(2H)-one (10m): yellow solid (25.4 mg, yield 95%, ee 60%).
25
1
Mp = 96-99 ºC. [α]D = -87.75 (c 0.8, CHCl3). H NMR (400
MHz, CDCl3) δ 8.21 (dd, J = 7.9, 1.1 Hz, 1H), 7.59 (td, J = 7.5,
1.4 Hz, 1H), 7.43 (dd, J = 11.3, 3.9 Hz, 1H), 7.32 (d, J = 7.7 Hz,
1H), 7.11 (dd, J = 9.0, 4.9 Hz, 1H), 7.09 (d, J = 2.5 Hz, 2H), 3.33
– 3.21 (m, 1H), 2.93 – 2.77 (m, 2H), 2.63 – 2.52 (m, 1H), 2.30 (d,
J = 1.3 Hz, 3H), 2.28 (s, 3H). 13C NMR (101 MHz, CDCl3) δ
192.76 (d, J = 19.1 Hz), 143.56, 136.38 (d, J = 20.7 Hz), 135.10,
134.19, 132.14, 132.02 (d, J = 2.6 Hz), 131.89, 129.21, 128.77,
128.45, 127.28, 126.68 (d, J = 11.8 Hz), 96.72 (d, J = 179.4 Hz),
34.98 (d, J = 24.6 Hz), 25.72 (d, J = 6.6 Hz), 21.09, 20.94 (d, J =
3.7 Hz); 19F NMR (470 MHz, CDCl3) δ -154.96 (dd, J = 27.1,
11.3 Hz). HPLC (Chiralpack AS-H column, hex/i-PrOH= 99/1,
1.0 mL/min, 254 nm) tR = 7.94 min (minor), tR = 10.53 min
(major). GC-MS (EI): m/z calcd for C18H17FO (M+): 268.1263,
found: 268.1271.
4.3.10. 2-Fluoro-2-(m-tolyl)-3,4-dihydronaphthalen-1(2H)-one
(10j): brown solid (18.6 mg, yield 73%, ee 11%). Mp = 56-59 ºC.
24
1
[α]D = +28.67 (c 0.1, CHCl3). H NMR (300 MHz, CDCl3) δ
8.21 (dd, J = 7.9, 1.2 Hz, 1H), 7.56 (td, J = 7.5, 1.4 Hz, 1H), 7.41
(t, J = 7.6 Hz, 1H), 7.28 – 7.12 (m, 5H), 3.18 – 3.05 (m, 1H),
2.94 – 2.66 (m, 3H), 2.35 (s, 3H). 13C NMR (75 MHz, CDCl3) δ
194.03 (d, J = 18.1 Hz), 143.17, 138.43, 136.51 (d, J = 22.4 Hz),
134.19, 132.17, 129.97 (d, J = 2.2 Hz), 128.83 (d, J = 28.0 Hz),
128.45, 128.12, 127.19, 126.78 (d, J = 5.7 Hz), 123.19 (d, J = 5.5
Hz), 96.07 (d, J = 184.2 Hz), 35.42 (d, J = 25.1 Hz), 26.45 (d, J =
9.3 Hz), 21.56; 19F NMR (470 MHz, CDCl3) δ -144.19 (t, J =
10.5 Hz). HPLC (Chiralpack AD-H column, hex/i-PrOH= 99/1,
1.0 mL/min, 254 nm) tR = 11.06 min (major), tR = 14.94 min
(minor). GC-MS (EI): m/z calcd for C17H15FO (M+): 254.1107,
found: 254.1110.
Acknowledgment
4.3.11.
2-Fluoro-2-(p-tolyl)-3,4-dihydronaphthalen-1(2H)-one
Financial support from Brazilian agencies CAPES, CNPq,
FAPERJ and UFRJ is acknowledged. L. G. S. thanks Capes for
the fellowship (Process CSF-PVE-S-88887.137162/2017-00).
We gratefully acknowledge financial support from the Spanish
Ministerio de Economía y Competitividad (MINECO) (projects
CTQ2013-43446-P and CTQ2014-51912-REDC) the Spanish
Ministerio de Economía, Industria y Competitividad, Agencia
Estatal de Investigación (AEI) and Fondo Europeo de Desarrollo
Regional (FEDER, EU) (projects CTQ2016-76782-P and
25
(10k) [22]: brown oil (25.4 mg, yield 100%, ee 4%). [α]D
=
+8.79 (c 0.3, CHCl3). 1H NMR (300 MHz, CDCl3) δ 8.20 (dd, J =
7.9, 1.3 Hz, 1H), 7.54 (td, J = 7.5, 1.5 Hz, 1H), 7.41 (dd, J =
11.3, 3.9 Hz, 1H), 7.27 (ddd, J = 13.2, 6.9, 4.6 Hz, 3H), 7.20 –
7.15 (m, 2H), 3.17 – 3.04 (m, 1H), 2.93 – 2.65 (m, 3H), 2.35 (d, J
= 1.6 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 194.17 (d, J = 18.1
Hz), 143.06, 139.20 (d, J = 2.4 Hz), 134.16, 133.36 (d, J = 22.7
Hz), 132.19, 129.34, 128.82, 128.05, 127.17, 126.20 (d, J = 5.2
Hz), 96.01 (d, J = 184.4 Hz), 35.22 (d, J = 25.2 Hz), 26.54 (d, J =
9.4Hz), 21.19; 19F NMR (470 MHz, CDCl3) δ -142.84 (t, J = 9.5
Hz). HPLC (Chiralpack AD-H column, hex/i-PrOH = 99/1, 1.0
mL/min, 254 nm) tR = 12.44 min (major), tR = 17.61 min (minor).
GC-MS (m/z, relative intensity): 254.1 (M+, 16), 234.1 (47),
118.1 (100), 90.1 (37).
CTQ2016-81797-REDC),
the
GeneralitatValenciana
(PROMETEOII/2014/017) and the University of Alicante.
Notes and references
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7
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