Palladium-catalyzed synthesis of monofluoroalkenes from 3,3-difluoropropenes using dimethylmalonate and derivatives as nucleophiles

Article abstract of DOI:10.1039/c7ob00376e

The synthesis of monofluoroalkenes bearing a malonate or its derivatives at the β position is presented. The reaction can be performed with various 3,3-difluoropropenes. A preliminary result for an enantioselective variant is also reported. Further synthetic transformations of a monofluoroalkene were also accomplished.

Full text of DOI:10.1039/c7ob00376e

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Palladium-catalyzed synthesis of monofluoroalkenes
from 3,3-difluoropropenes using dimethylmalonate
and derivatives as nucleophiles†
Cite this: DOI: 10.1039/c7ob00376e
Myriam Drouin, Sébastien Tremblay and Jean-François Paquin*
Received 15th February 2017,
Accepted 21st February 2017
The synthesis of monofluoroalkenes bearing a malonate or its derivatives at the β position is presented.
The reaction can be performed with various 3,3-difluoropropenes. A preliminary result for an enantio-
selective variant is also reported. Further synthetic transformations of a monofluoroalkene were also
accomplished.
DOI: 10.1039/c7ob00376e
rsc.li/obc
Introduction
Because of the distinctive properties of the fluorine atom,1
fluorine-containing molecules have an important role in med-
icinal chemistry, agrochemistry and material sciences.2–4
Hence, considerable effort has been devoted in recent years to
the discovery and improvement of methods for the preparation
of organofluorine compounds.5 Out of the various fluorinated
motifs, monofluoroalkenes have found applications in medic-
inal chemistry as a useful enol or amide mimic.5h,6,7
As part of our work exploring new methods for the syn-
thesis of monofluoroalkenes,8 we were interested in preparing
ones bearing a malonate substituent (or a derivative) at the β
position. Initial experiments toward this end from 3,3-difluoro-
propenes and using our platinum system were unsuccessful
(Fig. 1, eqn (1)).9 We later succeeded in preparing a single
example of the targeted compound from a gem-chlorofluoro-
propene by exploiting a difference in leaving group ability
(Fig. 1, eqn (2)).10 However, while simple and straightforward,
the starting material required for this strategy was more chal-
lenging to prepare. In addition, this approach offered no
handle for a potential asymmetric variant. Considering those
issues and our previous success in the preparation of
β-aminofluoroalkenes from 3,3-difluoropropenes using palla-
dium catalysis,11–14 we sought to explore the compatibility of
malonates and derivatives as nucleophiles under this system.
Herein, we report the successful development of this trans-
formation (Fig. 1, eqn (3)).
Fig. 1 Previous and current work.
Results and discussion
The reactivity was initially investigated using 3,3-difluoro-
propene 1a, which was easily obtained from α-tetralone in three
steps. Under the conditions used previously for the Pd-cata-
lyzed amination of 3,3-difluoropropenes,11a a moderate yield
of 47% was obtained (Table 1, entry 1). A solvent screening
revealed that THF was the best one (Table 1, entries 2–6). In
the case of toluene, a higher temperature (110 °C) resulted in a
slightly lower yield (Table 1, entry 7). When using THF as the
solvent, conducting the reaction at 50 °C (Table 1, entry 8), or
with 1.5 or 1.0 equivalent of both NaH and dimethylmalonate
CCVC, PROTEO, Département de chimie, 1045 avenue de la Médecine,
Université Laval, Québec, Québec, Canada, G1V 0A6.
E-mail: jean-francois.paquin@chm.ulaval.ca; Tel: +1-418-656-2131 ext. 11430
†Electronic supplementary information (ESI) available: Full experimental details
for the synthesis of the 3,3-difluoropropenes and 1H, 13C, and 19F NMR spectra
for all the new compounds. See DOI: 10.1039/c7ob00376e
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Table 1 Selected optimization results using 3,3-difluoropropene 1a
Table 2 Scope for the addition of dimethylmalonate to various 3,3-
difluoropropenesa
Entry
[Pd cat.]
L (mol%)
Solvent
Yielda (%)
1b
2
3
4
5
Pd(dppf)Cl2·CH2Cl2
Pd(dppf)Cl2·CH2Cl2
Pd(dppf)Cl2·CH2Cl2
Pd(dppf)Cl2·CH2Cl2
Pd(dppf)Cl2·CH2Cl2
Pd(dppf)Cl2·CH2Cl2
Pd(dppf)Cl2·CH2Cl2
Pd(dppf)Cl2·CH2Cl2
Pd(dppf)Cl2·CH2Cl2
Pd(dppf)Cl2·CH2Cl2
Pd(PPh3)4
—
—
—
—
—
—
—
—
CH3CN
THF
DMF
CH2Cl2
Et2O
Toluene
Toluene
THF
THF
THF
THF
THF
47
77 (77)c
27
63
70
67
63
53
62
55
68
6
7d
8e
9f
10g
11
12
13
14
15
16
—
—
—
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
PPh3 (5)
dppe (2.5)
dppp (2.5)
dppf (2.5)
rac-BINAP (5)
62
69
44
THF
THF
THF
THF
64
[Pd(allyl)Cl]2
74 (74)c
a Yield determined by NMR analysis of the crude mixture using
2-fluoro-4-nitrotoluene as an internal standard. b Reaction time was
18 h. c Isolated yield. d Reaction conducted at 110 °C. e Reaction con-
ducted at 50 °C. f Reaction conducted with 1.5 equiv. of (MeO2C)2CH2
and NaH respectively. g Reaction conducted with
(MeO2C)2CH2 and NaH respectively.
1 equiv. of
(Table 1, entries 9–10) resulted in lower yields. At this point,
other palladium sources and ligands were examined. Hence,
Pd(PPh3)4 or Pd2(dba)3 combined with various ligands (PPh3,
dppe, dppb or dppf) all provided lower yields (Table 1, entries
11–15). Finally, using [Pd(allyl)Cl]2 with rac-BINAP provided
almost the same result at the best one obtained thus far
(Table 1, entry 16). Overall and considering the above results,
the conditions in entry 2 were chosen as the optimal ones.
With the optimal conditions in hand, the scope of the reac-
tion was performed with other 3,3-difluoropropenes using di-
methylmalonate (Table 2). Substrates derived from α-tetralone,
4-chromanone, 4-thiochromanone and protected 6-hydroxy-
tetralone performed well and the corresponding monofluoro-
a Isolated yield unless stated otherwise. b Conditions: [Pd(allyl)Cl]2
(5 mol%), rac-BINAP (10 mol%), THF, 70 °C, 18 h. c NMR yield using
2-fluoro-4-nitrotoluene as an internal standard. d 5 mol% of Pd(dppf)
Cl2·CH2Cl2 was used. e Ratio determined by 19F NMR analysis. f E and Z
configurations could not be assigned unambiguously. g Conditions: Pd
(dppf)Cl2·CH2Cl2 (10 mol%), dimethylmalonate (5 equiv.), NaH (5
equiv.), toluene, 100 °C, 18 h.
alkenes 2a–d were obtained in moderate to good yields fluoroalkene in lower yields (e.g., 2f, 2g or 2j), a number of un-
(48–77%).15 Using a trisubstituted 3,3-difluoropropene (i.e., identified side-products (mainly non-fluorinated ones) were
with R3 = Me), the racemic product 2e was isolated in 76% observed in the crude mixture which not only diminished the
yield. In this case, the use of the [Pd(allyl)Cl]2/rac-BINAP yields, but also rendered the purification problematic. We
system (Table 1, entry 16) was necessary in order to obtain a hypothesize that some of these non-fluorinated products arise
good yield. A substrate derived from 1-indanone provided a from the attack of the malonate nucleophile at the carbon
moderate yield (53%) of 2f, whereas the one prepared from 6,7- bearing the fluorine on the π-allyl palladium intermediate. A
dihydro-4-benzo[b]thiophenone only gave 38% yield of 2g. related side-reaction was previously observed when using
Acyclic 3,3-difluoropropenes could also be used, and 2h and 2i amines as nucleophiles.11a Further fine-tuning of the reaction
could be obtained in good yields.16 Notably, the reaction of a conditions should allow a better control over this undesired
phenylalanine-derived 3,3-difluoropropene17 provided the pathway.
corresponding functionalized monofluoroalkene 2j in low iso-
The use of derivatives of dimethylmalonate as nucleophiles
lated yield, although the NMR yield was of 58%. For a number was next investigated using 3,3-difluoropropene 1a and the
of reactions, particularly the ones that provided the mono- results are shown in Table 3. Substituted diethylmalonates
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Table 3 Scope for the reaction of 3,3-difluoropropene 1a with other
nucleophilesa
Scheme 1 Preliminary enantioselective variant.
Finally, to demonstrate the potential utility of the mono-
fluoroalkenes generated in this study, some transformations of
2a were explored (Scheme 2). Hydrogenation under standard
conditions provided the product cis-5 as a single diastereo-
isomer in moderate yield.20,21 Reduction of 2a using LiAlH4
gave the diol 6 (62% yield) contaminated with 10% of the
defluorinated diol. Alkylation alpha to the methyl esters of 2a
using benzyl bromide was also possible and compound 3d was
isolated in 67% yield. Finally, as demonstrated previously,10 2a
can be transformed to 7 in a two-step sequence (decarboalkoxy-
lation22/hydrolysis) in 75% overall yield. Considering that
monofluoroalkenes can be used as amide mimics, compound
7 would resemble an amide bond between an N-substituted-
β-glycine and an amino acid.
a Isolated yield. b Yield determined by NMR analysis of the crude
mixture using 2-fluoro-4-nitrotoluene as an internal standard. c The
product exists as a tautomeric mixture of ketone (29%) and enol
(22%). d 11% of the product resulting from double addition was also
detected in the crude reaction mixture.
bearing a methyl or an ethyl group, or a fluorine atom, all pro-
vided the products (3a–c) in good yields (53–78%). The pres-
ence of a benzyl group was somehow detrimental as shown by
a moderate NMR yield of 45% of 3d. In this case, the desired
product could not be separated from the excess nucleophile.
β-Ketoesters could also be employed, generating 3e–g in mod-
erate to good yields (51–76%). Finally, when methyl cyano-
acetate was used, the desired monofluoroalkene (3h) was
observed along with 11% of the product resulting from a double
addition. Unfortunately, further optimization using a larger
excess of the nucleophile (4 or 10 equiv.) or more diluted con-
ditions (0.06 M) did not provide any improvement in the yield
of 3h. When blocking the double addition process using
methyl 2-cyanopropanoate as the nucleophile, the desired
product was isolated in 44% yield. Other nucleophiles such as
ethyl nitroacetate, ethyl 2-nitropropionate or 2,2-dimethyl-1,3-
dioxane-4,6-dione (Meldrum’s acid) only provided trace
amounts of the desired products (not shown).
We next explored the possibility of an asymmetric variant
using 3,3-difluoropropene 4 (Scheme 1). Considering that the
reaction conditions to prepare the racemic compound used
rac-BINAP as the ligand (cf. Table 2), (R)-BINAP was used for
the preliminary investigation. When using (Z)-4, a good yield
of the product was obtained, but chiral HPLC analysis revealed
a racemic product (<1% ee). Interestingly, when the E-isomer
was tested, a promising 55% ee was obtained. Efforts at deter-
mining the absolute stereochemistry of the product generated
and improving the yield/enantioselectivity are underway.18
Notably, this represents a rare example of enantioselective
reaction involving a C–F bond activation.19
Scheme 2 Synthetic transformations of 2a. Reaction conditions: (a) H2,
10% Pd/C, EtOH, rt, 22 h (50%); (b) LiAlH4, THF, −78 °C to rt, 18 h (62%).
(c) NaH, benzyl bromide, DMF, 0 °C to 100 °C, 2 h (67%).
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Scope for the addition of dimethylmalonate to various 3,3-
difluoropropenes (Table 2)
Conclusions
In conclusion, the palladium-catalyzed reaction of 3,3-difluoro-
propenes with dimethylmalonate and derivatives as nucleo-
Dimethyl 2-((2-fluoro-3,4-dihydronaphthalen-1-yl)methyl)
philes was described. This transformation allows the synthesis malonate (2a). Following the general procedure on a 0.28 mmol
of functionalized monofluoroalkenes. Notably, a preliminary scale of 1a, the desired product (62 mg, 77%) was isolated as a
result for an enantiomeric variant was also reported and will colourless oil by flash chromatography (10% EtOAc/hexanes).
be the subject of further investigation.
Spectroscopic data were in agreement with the literature.10
Dimethyl 2-((3-fluoro-2H-chromen-4-yl)methyl)malonate
(2b). Following the general protocol on a 0.28 mmol scale of
1b, the desired product (50 mg, 62%) was isolated as a
colourless oil by flash chromatography (10% EtOAc/hexanes).
IR (neat) ν = 3458, 2954, 2847, 1787, 1731, 1488, 1435, 1232,
Experimental section
Materials and methods
1
1152, 1040 cm−1; H NMR (500 MHz, CDCl3) δ 7.14–7.09 (2H,
The following includes general experimental procedures,
specific details for representative reactions and isolation, and
spectroscopic information for the new compounds prepared.
All reactions were carried out under an argon atmosphere with
dry solvents. Et2O, THF, CH3CN, CH2Cl2 and toluene were pur-
ified using a Vacuum Atmospheres Inc. Solvent Purification
System. All other commercially available compounds were
used as received. Thin-layer chromatography (TLC) analysis of
reaction mixtures was performed using Silicycle silica gel 60 Å
F254 TLC plates, and visualized under UV (λ = 254 nm) or by
staining with potassium permanganate. Flash column chrom-
atography was carried out on Silicycle silica gel 60 Å,
m), 6.96 (1H, tdd, J = 7.6, 0.8 Hz), 6.85 (1H, ddd, J = 8.0, 1.3,
0.4 Hz), 4.76 (2H, dt, J = 2.1, 1.0 Hz), 3.71 (6H, s), 3.62 (1H, t,
J = 7.7 Hz), 3.14 (2H, ddt, J = 7.6, 2.0, 1.1 Hz); 19F NMR
(470 MHz, CDCl3) δ −116.8 (1F, s); 13C NMR (126 MHz, CDCl3)
δ 169.0, 151.4 (d, JC–F = 271.1 Hz), 151.8, 128.1 (d, JC–F
=
2.2 Hz), 123.1 (d, JC–F = 6.6 Hz), 122.1, 121.1 (d, JC–F = 4.3 Hz),
116.1, 108.3 (d, JC–F = 10.8 Hz), 63.5 (d, JC–F = 37.1 Hz), 52.7,
49.9 (d, JC–F = 2.4 Hz), 22.2 (d, JC–F = 2.7 Hz); HRMS-ESI calcd
for C15H19FNO5 [M + NH4]+ 312.1242, found 312.1222.
Dimethyl 2-((3-fluoro-2H-thiochromen-4-yl)methyl)malonate
(2c). Following the general protocol on a 0.25 mmol scale
of 1c, the desired product (47 mg, 63%) was isolated as a
colourless oil by flash chromatography (10% EtOAc/hexanes).
IR (neat) ν = 3001, 2952, 1731, 1676, 1470, 1433, 1227, 1150,
1027, 753 cm−1; 1H NMR (500 MHz, CDCl3) δ 7.30 (1H, ddd, J =
7.7, 1.4, 0.5 Hz), 7.24 (1H, dd, J = 7.8, 1.4 Hz), 7.17 (1H, tdd, J =
7.9, 1.4, 0.7 Hz), 7.10 (1H, td, J = 7.5, 1.4 Hz), 3.68 (6H, s),
3.59–3.46 (3H, m), 3.22 (1H, dd, J = 7.8, 2.6 Hz); 19F NMR
(470 MHz, CDCl3) δ −95.8 (1F, t, J = 9.2 Hz); 13C NMR
(126 MHz, CDCl3) δ 169.2, 153.8 (d, JC–F = 275.2 Hz), 132.1
(d, JC–F = 4.4 Hz), 129.8, 127.4, 127.0 (d, JC–F = 2.3 Hz), 126.2,
124.6 (d, JC–F = 5.8 Hz), 112.5 (d, JC–F = 15.0 Hz), 52.6, 50.1
(d, JC–F = 2.4 Hz), 25.5 (d, JC–F = 31.2 Hz), 24.1 (d, JC–F = 4.8 Hz);
HRMS-ESI calcd for C15H16FO4S [M + H]+ 311.0748, found
311.0735.
Dimethyl-2-((2-fluoro-6-(pivaloyloxy)-3,4-dihydronaphthalen-
1-yl)methyl)malonate (2d). Following the general protocol on a
0.16 mmol scale of 1d, the desired product (30 mg, 48%) was
isolated as a colourless oil by flash chromatography (15%
EtOAc/hexanes). IR (neat) ν = 2968, 1742, 1712, 1681, 1481,
1385, 1235, 1129, 1112, 901 cm−1; 1H NMR (400 MHz, CDCl3) δ
7.15 (1H, d, J = 8.4 Hz), 6.88 (1H, dd, J = 8.3, 2.5 Hz), 6.83 (1H,
d, J = 2.6 Hz), 3.69 (6H, s) 3.58 (1H, t, J = 7.7 Hz), 3.15 (2H, d, J
1
230–400 mesh. H, 13C and 19F NMR spectra were recorded in
CDCl3 at ambient temperature using Agilent DD2 500 and
1
Varian Inova 400 spectrometers. H, 13C, and 19F NMR chemi-
cal shifts are reported in ppm downfield of tetramethylsilane
(1H NMR) or residual CHCl3 (1H and 13C NMR) as the
internal standard, or CFCl3 (19F NMR) as the external
standard. Coupling constants (J) are measured in hertz (Hz).
Multiplicities are reported using the following abbreviations:
s = singlet, d = doublet, t = triplet, q = quartet, p = pentet,
sext = sextet, m = multiplet, bs = broad signal. High-resolution
mass spectra were obtained on a LC/MS-TOF Agilent 6210
using electrospray ionization (ESI) or atmospheric pressure
photoionization (APPI). Infrared spectra were recorded using a
Thermo Scientific Nicolet 380 FT-IR spectrometer. Melting
points were recorded on a Stanford Research System OptiMelt
capillary melting point apparatus and are uncorrected. Optical
rotation were measured on a Jasco DIP-360 Polarimeter with a
sodium lamp at ambient temperature. Enantiomeric excesses
were determined by HPLC analysis with a Hewlett Packard
1200 Series.
General procedure
To a solution of NaH (2 equiv.) in THF (1 mL) was added drop- = 7.9 Hz), 2.90 (2H, td, J = 8.2, 2.7 Hz), 2.52 (2H, td, J = 8.2, 5.1
wise dimethyl malonate (2 equiv.) at rt and the resulting reac- Hz), 1.34; 19F NMR (376 MHz, CDCl3) δ −101.0 (1F, s); 13C
tion mixture was stirred for 15 min. The 3,3-difluoropropene NMR (75 MHz, CDCl3) δ 177.2, 169.3, 160.0 (d, JC–F = 269.1
(1 equiv.) in THF (1 mL) was added dropwise, followed by Hz), 149.3 (d, JC–F = 2.4 Hz), 134.7, 130.6 (d, JC–F = 6.2 Hz),
Pd(dppf)Cl2·CH2Cl2 (5 mol%) in THF (1 mL). The reaction 123.2 (d, JC–F = 6.9 Hz), 120.9, 119.4, 110.2 (d, JC–F = 13.8 Hz),
mixture was then warmed to 70 °C and stirred for 18 h. The 52.6 (d, JC–F = 2.7 Hz), 50.2 (d, JC–F = 2.3 Hz), 39.1, 28.6 (d, JC–F
reaction mixture was then quenched with H2O and extracted = 7.2 Hz), 27.1, 24.6 (d, JC–F = 24.9 Hz), 23.0 (d, JC–F = 4.7 Hz);
with Et2O (3×). The combined organic layers were washed with HRMS-ESI calcd for C21H26FO6 [M + H]+ 393.1714, found
brine, dried over MgSO4 and concentrated.
393.1700.
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Dimethyl
2-(1-(2-fluoro-3,4-dihydronaphthalen-1-yl)ethyl)
Dimethyl 2-(2-([1,1′-biphenyl]-4-yl)-3-fluoroallyl)malonate
malonate (2e). To a solution of NaH (21 mg, 0.52 mmol, (2h). Following the general protocol on a 0.22 mmol scale of
2 equiv.) in THF (1 mL) was added dropwise dimethyl malonate 1h and using mol% of Pd(dppf)Cl2·CH2Cl2 (7.9 mg,
5
(59 μL, 0.52 mmol, 2 equiv.) at rt and the resulting reaction 0.011 mmol), the desired product, contaminated by dimethyl
mixture was stirred for 15 min. The 3,3-difluoropropene 1e malonate, was obtained by flash chromatography (10% EtOAc/
(50 mg, 0.26 mmol, 1 equiv.) in THF (1 mL) was added drop- hexanes). The yield (59%, 54 : 46) was calculated by NMR ana-
wise, followed by [Pd(allyl)Cl]2 (2.4 mg, 0.0065 mmol, 5 mol%) lysis of the crude mixture using 2-fluoro-4-nitrotoluene as an
and rac-BINAP (8.0 mg, 0.013 mmol, 5 mol%) in THF (1 mL). internal standard. The E and Z configurations could not be
The reaction mixture was then warmed to 70 °C and stirred for assigned unambiguously. IR (neat) ν = 3027, 2951, 1752, 1731,
18 h. The reaction mixture was then quenched with H2O and 1654, 1486, 1433, 1232, 1126, 731 cm−1 1H NMR (500 MHz,
;
extracted with Et2O (3×). The combined organic layers were CDCl3) δ 7.64–7.30 (9H, m), 6.85 (0.36H, d, J = 84.0 Hz,
washed with brine, dried over MgSO4 and concentrated. minor isomer), 6.74 (0.64H, d, J = 83.3 Hz, major isomer), 3.71
Purification by flash chromatography (10% EtOAc/hexanes) (3.32H, s, major isomer), 3.66 (1.99H, s, minor isomer), 3.51
afforded the racemic product (60 mg, 76%) as a colourless oil. (0.42H, t, J = 7.8 Hz, minor isomer), 3.47 (0.62H, t, J = 7.6 Hz,
IR (neat) ν = 2951, 2885, 2257, 1754, 1732, 1670, 1433, 1280, major isomer), 3.23 (0.71H, ddd, J = 7.7, 2.7, 0.9 Hz, minor
1
1145, 728 cm−1; H NMR (500 MHz, CDCl3) δ 7.42 (1H, d, J = isomer), 2.97 (1.23H, ddd, J = 7.6, 3.3, 1.1 Hz, major isomer);
7.8 Hz), 7.21 (1H, m), 7.11–7.09 (2H, m), 4.05 (1H, dd, J = 11.4, 19F NMR (470 MHz, CDCl3) −126.7 (0.46F, d, J = 83.5 Hz,
0.5 Hz), 3.78 (3H, s), 3.62 (1H, m), 3.49 (3H, s), 2.86 (2H, tt, J = minor isomer), −126.8 (0.54F, d, J = 83.1 Hz, major isomer);
8.1, 2.6 Hz), 5.51–2.42 (2H, m), 1.32 (dd, J = 7.0, 0.9 Hz); HRMS-ESI calcd for C20H23FNO4 [M + NH4]+ 360.1606, found
19F NMR (470 MHz, CDCl3) δ −97.7 (1F, s); 13C NMR (126 MHz, 360.1604.
CDCl3) δ 169.2, 168.6, 160.8 (d, JC–F = 269.4 Hz), 134.0 (d, JC–F
=
Triethylsilyl dimethyl 2-(3-fluoro-4-hydroxy-4-phenylbut-2-
8.5 Hz), 133.1, 127.3, 126.8, 126.1 (d, JC–F = 1.9 Hz), 123.0 en-1-yl)malonate (2i). To a solution of NaH (34 mg, 0.86 mmol,
(d, JC–F = 6.5 Hz), 116.2 (d, JC–F = 10.6 Hz), 56.3 (d, JC–F
5.7 Hz), 52.6, 52.2, 32.1, 29.1 (d, JC–F = 6.7 Hz), 25.4 (d, JC–F
=
=
5 equiv.) in toluene (1 mL) was added dropwise dimethyl malo-
nate (98 μL, 0.86 mmol, 5 equiv.) at rt and the resulting
24.9 Hz), 17.6 (d, JC–F = 2.9 Hz); HRMS-ESI calcd for C17H20FO4 reaction mixture was stirred for 15 min. The 3,3-difluoro-
[M + H]+ 307.1340, found 307.1342.
propene 1i (50 mg, 0.17 mmol, 1 equiv.) in toluene (1 mL) was
Dimethyl-2-((2-fluoro-1H-inden-3-yl)methyl)malonate (2f). added dropwise, followed by Pd(dppf)Cl2·CH2Cl2 (12.6 mg,
Following the general protocol on a 0.30 mmol scale of 1f, the 0.017 mmol, 10 mol%) in toluene (1 mL). The reaction mixture
desired product (42 mg, 53%) was isolated as a yellow oil was then warmed to 110 °C and stirred for 18 h. The reaction
by flash chromatography (10% EtOAc/hexanes). IR (neat) ν = mixture was quenched with H2O and extracted with Et2O (3×).
2954, 2850, 1789, 1731, 1666, 1435, 1243, 1149, 1018, The combined organic layers were washed with brine, dried
720 cm−1; 1H NMR (500 MHz, CDCl3) δ 7.31–7.26 (2H, m), 7.23 over MgSO4 and concentrated. Purification by flash chromato-
(1H, m), 7.16 (1H, td, J = 7.4, 1.3 Hz), 3.79 (1H, t, J = 7.7 Hz), graphy (7% EtOAc/hexanes) afforded the monofluoroalkene 2i
3.72 (6H, s), 3.44 (2H, dt, J = 1.5, 0.7 Hz), 3.11 (2H, dd, J = 7.7, (48 mg, 70%) as an isomeric mixture (E/Z = 36 : 64) of a colour-
1.3 Hz); 19F NMR (470 MHz, CDCl3) −124.4 (1F, s); 13C NMR less oil. IR (neat) ν = 2954, 2876, 1752, 1735, 1452, 1435, 1269,
(126 MHz, CDCl3) δ 169.2, 164.0 (d, JC–F = 281.8 Hz), 142.3 1235, 837, 726 cm−1; 1H NMR (500 MHz, CDCl3) δ 7.43 (0.78H,
(d, JC–F = 6.3 Hz), 134.8 (d, JC–F = 8.0 Hz), 126.9, 124.6 (d, JC–F
4.4 Hz), 123.7 (d, JC–F = 1.6 Hz), 118.7 (d, JC–F = 6.7 Hz), 114.4 5.10 (0.8H, d, J = 10.2 Hz, Z-isomer), 5.03 (0.71H, m, Z-isomer),
(d, JC–F = 10.0 Hz), 52.7, 50.0 (d, JC–F = 2.8 Hz), 35.0 (d, JC–F 4.94 (0.4H, m. E-isomer), 3.73 (2.22H, d, J = 13.1 Hz, E-isomer),
20.8 Hz), 22.4 (d, JC–F = 1.1 Hz); HRMS-ESI calcd for C15H16FO4 3.68 (3.84H, d, J = 10.8 Hz, Z-isomer), 3.41 (1.05H, q, J =
[M + H]+ 279.1027, found 279.1011.
7.3 Hz), 2.82 (0.89H, m), 2.67 (1.46H, m), 0.95–0.88 (9H, m),
=
m), 7.39–7.23 (4.5H, m), 5.51 (0.5H, d, J = 22.6 Hz, E-isomer),
=
Dimethyl 2-((5-fluoro-6,7-dihydrobenzo[b]thiophen-4-yl) 0.67–0.51 (6H, m); 19F NMR (470 MHz, CDCl3) −114.1 (0.36F, t,
methyl)malonate (2g). Following the general protocol on a J = 21.8 Hz, E-isomer), −118.1 (0.64F, d, J = 36.2, 10.2 Hz,
0.27 mmol scale of 1g, the desired product (30 mg, 38%) was Z-isomer); 13C NMR (126 MHz, CDCl3) δ 169.14 (Z-isomer),
isolated as a yellow oil by flash chromatography (10% EtOAc/ 169.12 (Z-isomer), 169.0 (E-isomer), 168.9 (E-isomer), 161.6
hexanes). IR (neat) ν = 2946, 2884, 2834, 1731, 1676, 1432, (d, JC–F = 261.5 Hz, Z-isomer), 160.6 (d, JC–F = 256.5 Hz,
1
1355, 1226, 1133, 750 cm−1; H NMR (500 MHz, CDCl3) δ 7.07 E-isomer), 140.5 (Z-isomer), 140.3 (E-isomer), 128.2 (Z and
(1H, d, J = 5.1 Hz), 6.90 (1H, dd, J = 5.2, 0.5 Hz), 3.70 (6H, s), E-isomers), 128.1 (Z and E-isomers), 127.9 (Z-isomer), 127.8
3.61 (1H, t, J = 7.7 Hz), 3.05 (2H, ddt, J = 7.7, 2.1, 1.1 Hz), 2.99 (E-isomer), 126.5 (Z-isomer), 126.2 (E-isomer), 103.2 (d, JC–F
=
(2H, td, J = 9.1, 2.5 Hz), 2.64 (2H, tdd, J = 9.3, 4.3, 0.9 Hz); 23.9 Hz, E-isomer), 100.9 (d, JC–F = 12.0 Hz, Z-isomer), 72.5
19F NMR (470 MHz, CDCl3) δ −110.3 (1F, s); 13C NMR (d, JC–F = 33.0 Hz, Z-isomer), 69.6 (d, JC–F = 29.5 Hz, E-isomer),
(126 MHz, CDCl3) δ 169.3, 158.3, 156.2, 134.5 (d, JC–F = 6.3 Hz), 52.7 (d, JC–F = 2.3 Hz, E-isomer), 52.5 (d, JC–F = 1.7 Hz, Z-isomer),
130.4, 123.4 (d, JC–F = 5.6 Hz), 122.9, 108.5 (d, JC–F = 15.3 Hz), 51.7 (d, JC–F = 2.5 Hz, E-isomer), 51.2 (d, JC–F = 1.9 Hz, Z-isomer),
52.6, 50.7 (d, JC–F = 2.8 Hz), 25.6 (d, JC–F = 25.7 Hz), 24.8 24.5 (d, JC–F = 9.5 Hz, E-isomer), 23.0 (d, JC–F = 5.0 Hz, Z-isomer),
(d, JC–F = 3.7 Hz), 23.3 (d, JC–F = 8.0 Hz); HRMS-ESI calcd for 6.7 (Z and E-isomers), 4.7 (Z and E-isomers); HRMS-ESI calcd
C14H16FO4S [M + H]+ 299.0748, found 299.0766.
for C21H35FNO5Si [M + NH4]+ 428.2263, found 428.2263.
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(S)-Dimethyl-2-(4-((tert-butoxycarbonyl)amino)-3-fluoro-5- Et2O/toluene). IR (neat) ν = 2977, 2941, 2883, 1726, 1673, 1445,
1
phenylpent-2-en-1-yl)malonate (2j). To a solution of NaH 1387, 1179, 1030, 755 cm−1; H NMR (500 MHz, CDCl3) δ 7.24
(8 mg, 0.20 mmol, 2 equiv.) in THF (0.33 mL) was added drop- (1H, m), 7.15–7.02 (3H, m), 4.03–3.83 (4H, m), 3.2 (2H, d, J =
wise dimethyl malonate (23 μL, 0.20 mmol, 2 equiv.) at rt and 2.4 Hz), 2.89 (2H, td, J = 8.0, 2.7 Hz), 2.47 (2H, td, J = 8.0,
the resulting reaction mixture was stirred for 15 min. The 3,3- 5.5 Hz), 1.88 (2H, q, J = 7.5 Hz), 1.16 (6H, t, J = 7.2 Hz), 0.88
difluoropropene 1j (30 mg, 0.10 mmol, 1 equiv.) in THF (3H, t, J = 7.4 Hz); 19F NMR (470 MHz, CDCl3) δ −97.6 (1F, s);
(0.33 mL) was added dropwise, followed by [Pd(allyl)Cl]2 13C NMR (126 MHz, CDCl3) δ 171.4, 161.6 (d, JC–F = 269.3 Hz),
(1.0 mg, 0.0025 mmol, 5 mol%) and rac-BINAP (3.0 mg, 134.1 (d, JC–F = 6.6 Hz), 133.3, 127.3, 126.0, 125.9 (d, JC–F
=
0.010 mmol, 5 mol%) in THF (0.33 mL). The reaction mixture 1.9 Hz), 123.0 (d, JC–F = 6.2 Hz), 109.9 (d, JC–F = 13.4 Hz), 61.0,
was then warmed to 70 °C and stirred for 18 h. The reaction 57.9 (d, JC–F = 2.3 Hz), 28.9 (d, JC–F = 6.7 Hz), 25.1 (d, JC–F
mixture was quenched with H2O and extracted with Et2O (3×). 25.1 Hz), 25.1, 25.0, 24.9 (d, JC–F = 3.4 Hz), 13.9, 8.6 (d, JC–F
=
=
The combined organic layers were washed with brine, dried 3.2 Hz); HRMS-ESI calcd for C20H26FO4 [M + H]+ 349.1810,
over MgSO4 and concentrated. The desired product (11 mg, found 349.1801.
28%, E/Z = 7 : 93) was obtained as a colourless oil by flash
Diethyl 2-fluoro-2-((2-fluoro-3,4-dihydronaphthalen-1-yl)
chromatography (10% EtOAc/hexanes). IR (neat) ν = 3363, methyl)malonate (3c). Following the general protocol on a
2973, 2950, 1732, 1699, 1495, 1435, 1391, 1192, 743 cm−1
;
0.28 mmol scale of 1a and 2 equiv. of diethyl fluoromalonate
1H NMR (Z-isomer, 500 MHz, CDCl3) δ 7.31–726 (2H, m), 7.23 (88 μL, 0.56 mmol), the desired product (67 mg, 71%) was
(1H, d, J = 7.4 Hz), 7.15 (2H, d, J = 7.0 Hz), 4.62 (1H, dt, J = isolated as a yellow oil by flash chromatography (10% CH2Cl2/
36.5, 7.8 Hz), 4.41 (1H, m), 3.70 (6H, d, J = 5.2 Hz), 3.30 (1H, t, hexanes). IR (neat) ν = 2981, 2942, 1748, 1677, 1487, 1440,
J = 7.5 Hz), 2.90 (2H, d, J = 7.0 Hz), 2.61 (2H, t, J = 7.5 Hz), 1368, 1275, 1070, 757 cm−1; H NMR (500 MHz, CDCl3) δ 7.21
1
1.39 (9H, s); 19F NMR (470 MHz, CDCl3) −117.0 (0.04F, m, (1H, m), 7.15 (1H, m), 7.10–7.06 (2H, m), 4.24–4.10 (4H, m),
E-isomer), −119.5 (0.03F, m, E-isomer rotamer), −120.0 (0.14F, 3.47 (2H, d, J = 22.9 Hz), 2.94 (2H, td, J = 8.2, 2.7 Hz), 2.53
m, Z-isomer rotamer), 120.4 (0.79F, dd, J = 37.0, 17.5 Hz, (2H, td, J = 8.1, 5.2 Hz), 1.24 (6H, t, J = 7.2 Hz); 19F NMR
Z-isomer); 13C NMR (Z-isomer, 126 MHz, CDCl3) δ 169.0, 168.9, (470 MHz, CDCl3) δ −97.4 (1F, s), −163.7 (1F, td, J = 23.1,
158.6 (d, JC–F = 263.0 Hz), 154.7, 136.5, 129.3, 128.4, 126.7, 8.0 Hz); 13C NMR (126 MHz, CDCl3) δ 166.0, 165.8, 161.9
102.7 (d, JC–F = 12.8 Hz), 79.9, 65.9, 52.6 (d, JC–F = 6.1 Hz), 51.1 (d, JC–F = 271.2 Hz), 133.5 (d, JC–F = 5.7 Hz), 132.9, 127.3,
(d, JC–F = 1.8 Hz), 38.6, 29.7, 28.3, 22.9 (d, JC–F = 5.6 Hz); 126.4, 126.2 (d, JC–F = 2.0 Hz), 123.3 (2C, d, JC–F = 6.5, 2.9 Hz),
HRMS-ESI calcd for C21H32FN2O6 [M + NH4]+ 427.2239, found 107.3 (d, JC–F = 12.9 Hz), 94.5 (d, JC–F = 2.3 Hz), 92.9 (d, JC–F
=
427.2251.
2.0 Hz), 62.6, 28.7 (d, JC–F = 7.0 Hz), 28.1 (d, JC–F = 4.4 Hz), 27.9
(d, JC–F = 4.4 Hz), 24.9 (d, JC–F = 24.3 Hz), 13.8; HRMS-ESI calcd
for C18H24F2NO4 [M + NH4]+ 356.1668, found 356.1651.
Dimethyl 2-benzyl-2-((2-fluoro-3,4-dihydronaphthalen-1-yl)
Scope for the reaction of 3,3-difluoropropene 1a with other
nucleophiles (Table 3)
Diethyl 2-((2-fluoro-3,4-dihydronaphthalen-1-yl)methyl)-2- methyl)malonate (3d). Following the general protocol on a
methylmalonate (3a). Following the general protocol on a 0.28 mmol scale of 1a and using 2 equiv. of dimethyl benzyl-
0.28 mmol scale of 1a and using 2 equiv. of diethyl methyl- malonate (123 mg, 0.56 mmol), the desired product was
malonate (95 μL, 0.56 mmol), the desired product (72 mg, obtained in a 19F NMR yield of 45% using 2-fluoro-4-nitro-
78%) was isolated as a colourless oil by flash chromatography toluene as internal standard since it was not possible to separ-
(50% toluene/hexanes), followed by a second flash chromato- ate the excess dimethyl benzylmalonate. 1H NMR (400 MHz,
graphy (2% Et2O/toluene). IR (neat) ν = 2979, 2941, 1727, 1673, CDCl3) δ 7.26–7.03 (9H, m), 3.38 (6H, s), 3.30 (2H, d, J =
1486, 1444, 1313, 1272, 1102, 754 cm−1 1H NMR (500 MHz, 2.2 Hz), 3.25 (2H, s), 2.92 (2H, td, J = 8.1, 2.8 Hz), 2.56–2.45
;
CDCl3) δ 7.22 (1H, dd, J = 7.7, 1.2 Hz), 7.16–7.03 (3H, m), (2H, m); 19F NMR (376 MHz, CDCl3) δ −96.4 (1F, s); HRMS-ESI
4.10–3.94 (4H, m), 3.23 (2H, d, J = 2.5 Hz), 2.91 (2H, td, J = 8.1, calcd for C23H24FO4 [M + H]+ 383.1653, found 383.1644.
2.7 Hz), 2.49 (2H, td, J = 8.1, 5.3 Hz), 1.36 (3H, d, J = 1.7 Hz),
1.19, (6H, t, J = 7.1 Hz); 19F NMR (470 MHz, CDCl3) δ −97.6 butanoate (3e). Following the general protocol on a 0.28 mmol
(1F, s); 13C NMR (126 MHz, CDCl3) δ 172.0, 161.3 (d, JC–F
scale of 1a, using 2 equiv. of ethyl acetoacetate (70 μL,
269.0 Hz), 134.1 (d, JC–F = 6.2 Hz), 133.2, 127.4, 126.2, 126.0 (d, 0.56 mmol) and using mol% of Pd(dppf)Cl2·CH2Cl2
Ethyl 2-((2-fluoro-3,4-dihydronaphthalen-1-yl)methyl)-3-oxo-
=
5
JC–F = 1.9 Hz), 123.0 (d, JC–F = 6.3 Hz), 109.9 (d, JC–F = 13.3 Hz), (10.2 mg, 0.014 mmol), a pure fraction of the desired product
61.2, 53.5 (d, JC–F = 1.9 Hz), 28.9 (d, JC–F = 6.8 Hz), 28.0 (d, could be isolated as a colourless oil by flash chromatography
JC–F = 3.7 Hz), 25.0 (d, JC–F = 24.9 Hz), 19.9 (d, JC–F = 1.7 Hz), (20% Et2O/hexanes) followed by a second purification (15%
13.9; HRMS-ESI calcd for C19H24FO4 [M + H]+ 335.1653, found Et2O/hexanes). The yield (76%) was calculated by NMR analysis
335.1651.
of the crude mixture using 2-fluoro-4-nitrotoluene as an
Diethyl 2-ethyl-2-((2-fluoro-3,4-dihydronaphthalen-1-1yl) internal standard. IR (neat) ν = 2980, 2942, 1734, 1712, 1515,
1
methyl)malonate (3b). Following the general protocol on a 1451, 1220, 1147, 1017, 758 cm−1; H NMR (500 MHz, CDCl3)
0.28 mmol scale of 1a and using 2 equiv. of diethyl ethyl- δ 7.20 (1H, m), 7.17–7.04 (3H, m), 4.16 (2H, qq, J = 7.1, 3.6 Hz),
malonate (104 μL, 0.56 mmol), the desired product (50 mg, 3.66 (1H, t, J = 7.4 Hz), 3.18–3.05 (2H, m), 2.92 (2H, td, J = 8.3,
53%) was isolated as a yellow oil by flash chromatography (1% 2.7 Hz), 2.57–2.49 (2H, m), 2.23 (3H, s), 1.23 (3H, t, J = 7.1 Hz);
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19F NMR (470 MHz, CDCl3) δ −100.4 (1F, s); 13C NMR
Methyl 2-cyano-3-(2-fluoro-3,4-dihydronaphthalen-1-yl)
(126 MHz, CDCl3) δ 202.5, 169.5, 160.0 (d, JC–F = 268.4 Hz), propanoate (3h). To a solution of NaH (111 mg, 2.78 mmol,
133.2, 133.1, (d, JC–F = 6.3 Hz), 127.6, 126.8, 126.3 (d, JC–F 10 equiv.) in THF (3 mL) was added dropwise methyl cyano-
=
2.0 Hz), 122.5 (d, JC–F = 6.3 Hz), 110.9 (d, JC–F = 13.3 Hz), 61.5, acetate (0.25 mL, 2.8 mmol, 10 equiv.) at rt and the resulting reac-
58.0 (d, JC–F = 2.3 Hz), 29.0, 28.7 (d, JC–F = 7.1 Hz), 24.8 (d, tion mixture was stirred for 15 min. The 3,3-difluoropropene
JC–F = 24.8 Hz), 22.1 (d, JC–F = 4.7 Hz), 14.0; HRMS-ESI calcd for 1a (50 mg, 0.278 mmol, 1 equiv.) in THF (1 mL) was
C17H20FO3 [M + H]+ 291.1391, found 291.1390.
added dropwise, followed by Pd(dppf)Cl2·CH2Cl2 (5 mg,
Ethyl 2-((2-fluoro-3,4-dihydronaphthalen-1-yl)methyl)-3-oxo- 0.0064 mmol, 2.5 mol%) in THF (1 mL). The reaction mixture
3-phenylpropanoate (3f). Following the general protocol on a was then warmed to 70 °C and stirred for 18 h. The reaction
0.28 mmol scale of 1a and using 2 equiv. of ethyl benzoylace- mixture was quenched with H2O and extracted with Et2O (3×).
tate (96 μL, 0.56 mmol), the desired product (56 mg, 57%) was The combined organic layers were washed with brine,
isolated as a colourless oil by flash chromatography (8% dried over MgSO4 and concentrated.23 Purification by flash
EtOAc/hexanes), followed by a second flash chromatography chromatography (15% EtOAc/hexanes) afforded the desired
(60% CH2Cl2/hexanes). IR (neat) ν = 2979, 2889, 1730, 1679, product (7.4 mg, 11%) as a colourless oil. IR (neat) ν = 3019,
1596, 1464, 1224, 1020, 995, 707 cm−1 1H NMR (500 MHz, 2953, 2838, 2251, 1744, 1680, 1487, 1435, 1262, 759 cm−1
; ;
CDCl3) δ 7.87 (2H, d, J = 7.0 Hz), 7.53 (1H, t, J = 7.4 Hz), 7.39 1H NMR (500 MHz, CDCl3) δ 7.24–7.06 (4H, m), 3.80 (3H, s),
(2H, t, J = 7.6 Hz), 7.21 (2H, d, J = 1.2 Hz), 7.15–6.98 (2H, m), 3.73 (1H, dd, J = 9.6, 6.2 Hz), 3.31–3.23 (1H, m), 3.15 (1H, m),
4.53 (1H, t, J = 7.4 Hz), 4.14–4.00 (2H, m), 3.26 (2H, d, J = 3.09–2.90 (2H, m), 2.66–2.54 (2H, m); 19F NMR (470 MHz,
7.4 Hz), 2.86–2.67 (2H, m), 2.51–2.35 (2H, m), 1.11 (3H, t, J = CDCl3) δ −98.6 (1F, s); 13C NMR (126 MHz, CDCl3) δ 166.2,
7.1 Hz); 19F NMR (470 MHz, CDCl3) δ −100.0 (1F, s); 13C NMR 161.5 (d, JC–F = 271.8 Hz), 133.3, 132.0 (d, JC–F = 5.7 Hz), 128.0,
(126 MHz, CDCl3) δ 195.1, 169.6, 160.1 (d, JC–F = 268.9 Hz), 136.4, 126.9, 126.7 (d, JC–F = 2.3 Hz), 121.8 (d, JC–F = 6.7 Hz), 115.9,
133.4 (2C, m), 133.3 (2C, m), 128.5 (d, JC–F = 10.1 Hz), 127.6, 109.0 (d, JC–F = 12.8 Hz), 53.6, 36.3 (d, JC–F = 2.3 Hz), 38.5 (d,
126.8, 126.2 (d, JC–F = 2.3 Hz), 122.5 (d, JC–F = 6.6 Hz), 110.9 (d, JC–F = 7.1 Hz), 24.7 (d, JC–F = 24.2 Hz), 24.3 (d, JC–F = 5.2 Hz);
JC–F = 13.3 Hz), 61.5, 52.4 (d, JC–F = 2.2 Hz), 28.6 (d, JC–F = 7.1 Hz), HRMS-ESI calcd for C15H18FN2O2 [M + NH4]+ 277.1347, found
24.7 (d, JC–F = 24.6 Hz), 23.0 (d, JC–F = 4.6 Hz), 13.9; HRMS-ESI 277.1341.
calcd for C22H22FO3 [M + H]+ 353.1548, found 353.1571.
Methyl 2-cyano-3-(2-fluoro-3.4-dihydronaphthalen-1-yl)-
Ethyl 4,4,4-trifluoro-2-((2-fluoro-3,4-dihydronaphthalen-1-yl) 2-methylpropanoate (3i). Following the general protocol on a
methyl)-3-oxobutanoate (3g). Following the general protocol 0.28 mmol scale of 1a and using 2 equiv. of methyl 2-cyano-
on a 0.28 mmol scale of 1a, using 2 equiv. of ethyl trifluoroace- propanoate (63 mg, 0.56 mmol), the desired product (39 mg,
tate (81 μL, 0.56 mmol) and using 5 mol% of Pd(dppf) 44%) was isolated as a yellow sticky oil by flash chromato-
Cl2·CH2Cl2 (10 mg, 0.014 mmol), the desired product (24 mg, graphy (10% EtOAc/hexanes). IR (neat) ν = 2948, 2889, 2250,
25%) was isolated as a mixture with the enol tautomer (ketone/ 1734, 1673, 1485, 1437, 1370, 1180, 731 cm−1 1H NMR
;
enol = 57 : 43) as a yellow oil by flash chromatography (15% (500 MHz, CDCl3) δ 7.21–7.08 (4H, m), 3.52 (3H, s), 3.17 (2H,
EtOAc/hexanes). IR (neat) ν = 2943, 2899, 1769, 1739, 1681, qd, J = 14.4, 1.5 Hz), 3.05–2.87 (2H, m), 2.61–2.52 (2H, m), 1.63
1451, 1367, 1147, 994, 758 cm−1 1H NMR (500 MHz, CDCl3) (3H, s); 19F NMR (470 MHz, CDCl3) δ −96.1 (1F, s); 13C NMR
;
δ 7.24–7.11 (4H, m), 4.91 (0.37H, s, enol), 4.66 (0.39H, s, enol), (126 MHz, CDCl3) δ 169.3, 162.3 (d, JC–F = 271.9 Hz), 133.1,
4.16 (1.1H, qd, J = 7.2, 0.8 Hz, ketone), 4.07 (1H, m, ketone), 132.9 (d, JC–F = 5.7 Hz), 127.7, 126.5 (d, JC–F = 2.3 Hz), 126.4,
3.98 (0.45H, m, enol), 3.28–3.03 (2.57H, m), 2.97–2.87 (2.33H, 122.7 (d, JC–F = 6.3 Hz), 119.8, 108.9 (d, JC–F = 12.5 Hz), 53.5,
m), 2.62–2.41 (2.14H, m), 1.22 (1.82H, t, J = 7.1 Hz, ketone), 43.6 (d, JC–F = 2.1 Hz), 31.4 (d, JC–F = 3.9 Hz), 28.7 (d, JC–F
=
1.10 (1H, t, 7.2 Hz, enol); 19F NMR (470 MHz, CDCl3) δ −77.9 6.8 Hz), 24.8 (d, JC–F = 24.5 Hz), 23.1; HRMS-ESI calcd for
(3F, s, ketone), −83.6 (3F, s, enol), −99.6 (1F, s, ketone), −100.9 C16H17FNO2 [M + H]+ 274.1238, found 274.1234.
(1F, s, enol); 13C NMR (126 MHz, CDCl3) δ 186.7 (q, JC–F = 36.7
Preliminary enantioselective variant (Scheme 1)
Hz, ketone), 174.5 (enol), 166.7 (ketone), 160.6 (d, JC–F = 270.3,
ketone), 160.1 (d, JC–F = 268.6 Hz, enol), 133.3 (ketone), 133.0 (d, Using the same conditions as the racemic experiment (see 2e),
JC–F = 6.2 Hz, enol), 132.9 (enol), 132.5 (d, JC–F = 5.9 Hz, ketone), but using (E)-4 with (R)-BINAP (8.0 mg, 0.013 mmol, 5 mol%)
127.8 (ketone), 127.5 (enol), 126.9 (2C, m), 126.5 (d, JC–F
2.0 Hz, ketone), 126.3 (d, JC–F = 2.1 Hz, enol), 122.7 (q, JC–F
=
=
instead of rac-BINAP, the product (44 mg, 56%) was obtained
as a colourless oil by flash chromatography (10% EtOAc/
286.9 Hz, ketone), 122.4 (d, JC–F = 6.6 Hz, enol), 122.1 (d, hexanes), followed by a second flash chromatography (50%
JC–F = 6.6 Hz, ketone), 115.2 (q, JC–F = 292.7 Hz, enol), 110.4 CH2Cl2/hexanes). [α]2D1 = +8.99 (c 0.04, MeOH); 55% ee (deter-
(d, JC–F = 13.3 Hz, enol), 109.7 (d, JC–F = 12.8 Hz, ketone), 93.8 mined using chiral HPLC, OJ-H, hexanes : 2-propanol = 98 : 2,
(q, JC–F = 32.3 Hz, enol), 62.4 (ketone), 61.9 (enol), 51.6 (d, JC–F
2.7 Hz, ketone), 45.9 (d, JC–F = 1.9 Hz, enol), 28.7 (d, JC–F
=
=
flow rate 1.1 mL min−1, tr,minor = 26.6 min, tr,major = 29.9 min,
wavelength = 254 nm).
6.8 Hz, enol), 28.5 (d, JC–F = 6.8 Hz, ketone), 24.8 (d, JC–F = 24.4 Hz,
ketone), 22.0 (d, JC–F = 4.8 Hz, ketone), 21.1–20.8 (1C, m),
15.2 (enol), 13.8 (2C, m); HRMS-ESI calcd for C17H20F4NO3
[M + NH4]+ 362.1374, found 362.1389.
Synthetic transformations of 2a (Scheme 2)
Dimethyl 2-((2-fluoro-1,2,3,4-tetrahydronaphthalen-1-yl)
methyl)malonate (cis-5). The monofluoroalkene 2a (45 mg,
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0.15 mmol, 1 equiv.) was added to EtOH (1.7 mL), followed by found 237.1282; HRMS-ESI calcd for 6′ C14H19O2 [M + H]+
Pd/C (10%, 10 mg). The mixture was stirred under H2 219.1380, found 219.1356.
atmosphere for 22 h. Then it was filtered over a celite pad
Dimethyl 2-benzyl-2-((2-fluoro-3,4-dihydronaphthalen-1-yl)
and concentrated. Flash chromatography (10% EtOAc/hexanes) methyl)malonate (3d). NaH (60% in mineral oil, 11 mg,
afforded the final product (23 mg, 50%) as a colourless oil. 0.26 mmol, 1.1 equiv.) was added to DMF (2.4 mL) at 0 °C,
IR (neat) ν = 2953, 2848, 1749, 1730, 1432, 1276, 1206, 1148, followed by the monofluoroalkene 2a (70 mg, 0.24 mmol,
1015, 761 cm−1 1H NMR (400 MHz, CDCl3) δ 7.26 (1H, m), 1 equiv.) and the mixture was stirred for 15 min. Benzyl bromide
;
7.20–7.13 (2H, m), 7.09 (1H, m), 5.06 (1H, dddd, J = 49.2, 8.5, (34 μL, 0.39 mmol, 1.2 equiv.) was added and the reaction was
4.7, 3.3 Hz), 3.78–3.73 (7H, m), 3.11–2.98 (2H, m), 2.78 (1H, heated at 100 °C for 2 h. EtOAc was added, and the organic
m), 2.46–2.31 (2H, m), 2.24 (1H, m), 2.01 (1H, m); 19F NMR layer was washed with brine (3×) to remove the DMF, and then
(376 MHz, CDCl3) δ −188.1 (1F, dddd, J = 49.3, 24.6, 17.4, dried over MgSO4 and concentrated. Purification by flash
7.8 Hz); 13C NMR (75 MHz, CDCl3) δ 169.9, 169.8, 136.4 (d, chromatography afforded the final product (61 mg, 67%) as a
JC–F = 5.5 Hz), 135.3 (d, JC–F = 1.7 Hz), 128.9, 128.7, 126.7, white solid. Mp = 49–52 °C; IR (neat) ν = 2946, 2889, 2247,
126.3, 91.3 (d, JC–F = 3.5 Hz), 89.5 (d, JC–F = 3.4 Hz), 52.6 (dd, 1726, 1673, 1485, 1434, 1179, 1099, 779 cm−1
;
1H NMR
JC–F = 5.5, 2.9 Hz), 49.9 (d, JC–F = 2.8 Hz), 40.0 (d, JC–F (400 MHz, CDCl3) δ 7.26–7.03 (9H, m), 3.38 (6H, s), 3.30 (2H,
=
19.3 Hz), 30.7 (d, JC–F = 4.8 Hz), 26.0 (d, JC–F = 9.5 Hz), 25.5 d, J = 2.2 Hz), 3.25 (2H, s), 2.92 (2H, td, J = 8.1, 2.8 Hz),
(d, JC–F = 20.1 Hz); HRMS-ESI calcd for C16H20FO4 [M + H]+ 2.56–2.45 (2H, m); 19F NMR (376 MHz, CDCl3) δ −96.4 (1F, s);
295.1340, found 295.1344. Dimethyl 2-((1,2,3,4-tetrahydro- 13C NMR (75 MHz, CDCl3) δ 171.2, 161.6 (d, JC–F = 269.9 Hz),
naphthalen-1-yl)methyl)malonate was also Isolated as a colour- 136.6, 134.0 (d, JC–F = 6.6 Hz), 133.4, 130.1 (d, JC–F = 1.6 Hz),
less oil (12 mg, 29%). IR (neat) ν = 3014, 2932, 2862, 1750, 128.1, 127.3, 126.8, 126.2, 126.0 (d, JC–F = 1.8 Hz), 123.2 (d,
1731, 1433, 1323, 1230, 1143, 759 cm−1
;
1H NMR (400 MHz, JC–F = 6.2 Hz), 109.8 (d, JC–F = 13.1 Hz), 59.2 (d, JC–F = 2.1 Hz),
CDCl3) δ 7.20 (1H, d, J = 6.7 Hz), 7.16–7.04 (3H, m), 3.77 (3H, 51.9 (d, JC–F = 1.9 Hz), 39.8 (d, JC–F = 1.6 Hz), 28.9 (d, JC–F
=
s), 3.74 (3H, s), 3.57 (1H, dd, J = 9.6, 5.6 Hz), 2.82–2.67 (3H, 6.7 Hz), 27.6 (d, JC–F = 2.9 Hz), 25.2 (d, JC–F = 25.1 Hz); HRMS-ESI
m), 2.38 (1H, ddd, J = 14.2, 9.6, 4.8 Hz), 2.09 (1H, ddd, J = 14.1, calcd for C23H24FO4 [M + H]+ 383.1653, found 383.1644.
9.7, 5.7 Hz), 1.91–1.81 (2H, m), 1.79–1.62 (2H, m); 13C NMR
(75 MHz, CDCl3) δ 170.0, 169.8, 139.5, 137.0, 129.2, 128.9,
125.9, 125.7, 52.6, 49.9, 47.5, 35.9, 35.4, 29.4, 27.1, 19.2;
Acknowledgements
HRMS-ESI calcd for C16H21FO4 [M + H]+ 277.1434, found
277.1449.
This work was supported by the Natural Sciences and
2-((2-Fluoro-3,4-dihydromaphthalen-1-yl)methyl)propane- Engineering Research Council of Canada (NSERC), the FRQNT
1.3-diol (6). The monofluoroalkene 2a (42 mg, 0.14 mmol, Centre in Green Chemistry and Catalysis (CCVC), the FRQNT
1 equiv.) was added to THF (4.8 mL) at −78 °C. Then, LiAlH4 Network for Research on Protein Function, Engineering, and
(33 mg, 0.86 mmol, 6 equiv.) was added by small portions. The Applications (PROTEO), and the Université Laval. M. D. thanks
mixture was stirred at −78 °C for 1 h, then allowed to warm to NSERC for a Vanier Canada Graduate Scholarship.
room temperature overnight. The reaction was cooled to 0 °C,
sat. aq. Na2CO3 was added and the reaction was filtered using
Et2O. The organic layer was separated, dried over Na2SO4 and
concentrated. Flash chromatography (5% MeOH/CH2Cl2)
Notes and references
afforded a mixture of the final diol 6 and the reduction
product 6′ as a white solid (27 mg, total yield of 72% with
NMR ratio 6/6′ = 6.1/1, 62% of the diol 6 and 10% of the
reduction product 6′). Mp = 48–56 °C; IR (neat) ν = 3326, 3252,
1 (a) T. Hiyama, in Organofluorine Compounds; Chemistry and
Applications, ed. H. Yamamoto, Springer, New York, 2000
and references cited therein; (b) D. O’Hagan, Chem. Soc.
Rev., 2008, 37, 308.
1
2917, 2895, 1673, 1482, 1355, 1147, 1112, 765 cm−1; H NMR
2 Selected recent reviews: (a) K. Müller, C. Faeh and
F. Diederich, Science, 2007, 317, 1881; (b) S. Purser,
P. R. Moore, S. Swallow and V. Gouverneur, Chem. Soc. Rev.,
2008, 37, 320; (c) W. K. Hagmann, J. Med. Chem., 2008, 51,
4359; (d) K. L. Kirk, Org. Process Res. Dev., 2008, 12, 305;
(e) I. Ojima, Fluorine in Medicinal Chemistry and Chemical
Biology, Wiley-Blackwell, Chichester, 2009; (f) J. Wang,
M. Sánchez-Roselló, J. L. Aceña, C. del Pozo,
A. E. Sorochinsky, S. Fustero, V. A. Soloshonok and H. Liu,
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(400 MHz, CDCl3) δ 7.25–7.07 (4H, m), 5.89 (0.12H, t, J =
4.6 Hz, 6′), 3.86–3.68 (4.07H, m), 2.96 (1.75H, td, J = 8.1,
2.6 Hz, 6), 2.74 (0.25H, t, J = 8.0 Hz, 6′), 2.60–2.33 (6H, m), 2.25
(0.38H, td, J = 7.9, 4.4 Hz, 6′), 1.99 (1.13, tt, J = 7.4, 4.0 Hz, 6);
19F NMR (376 MHz, CDCl3) δ −102.4 (1F, s, 6); 13C NMR
(75 MHz, CDCl3) δ 159.5 (d, JC–F = 264.9 Hz, 6), 136.9 (6′), 134.2
(d, JC–F = 8.1 Hz, 6), 133.8 (d, JC–F = 6.7, 6), 133.2 (6), 127.7 (6′),
127.5 (6), 127.0 (2C, 6′), 126.8 (6′), 126.7 (6), 126.4 (6′), 126.2
(d, JC–F = 2.2 Hz, 6), 122.9 (d, JC–F = 6.6 Hz, 6), 122.8 (6′), 112.0
(d, JC–F = 13.7 Hz, 6), 66.0 (6′), 65.7 (6), 47.5 (6′), 40.6 (d, JC–F
=
2.2 Hz, 6), 40.1 (6′), 31.4 (6′), 29.7 (6′), 28.8 (d, JC–F = 7.4 Hz, 6),
28.4 (6′), 24.7 (d, JC–F = 25.3 Hz, 6), 23.11 (6′), 21.5 (d, JC–F
=
3 Selected reviews: (a) P. Jeschke, ChemBioChem, 2004, 5, 570;
(b) P. Jeschke, Pest Manage. Sci., 2010, 66, 10; (c) P. Jeschke,
4.7 Hz, 6); HRMS-ESI calcd for 6 C14H18FO2 [M + H]+ 237.1285,
Org. Biomol. Chem.
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Organic & Biomolecular Chemistry
Paper
The Unique Role of Halogen Substituents in the Design of 10 J.-D. Hamel, M. Cloutier and J.-F. Paquin, Org. Lett., 2016,
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R. T. Mosley, S. Bansal, M. Keilman, A. M. Lam, 15 NMR analysis of the crude mixture revealed ca. 10% of the
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alkene and the hydrogenolysis of the C–F bond (i.e., rac-5
without the fluorine atom) was also isolated in 29% yield.
7 For reviews on their synthesis, see: (a) G. Landelle, 21 The stereochemical relationship between the two substitu-
M.-O. Turcotte-Savard, M. Bergeron and J.-F. Paquin, Chem. ents was assumed to be cis.
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329.
23 The conditions using 10 equiv. of nucleophile and a con-
centration of 0.06 M allowed the synthesis and the isolation
of the desired product without traces of the double
addition product albeit in only 11% yield.
This journal is © The Royal Society of Chemistry 2017
Org. Biomol. Chem.