Photoinduced Nonstabilized Azomethine Ylide Formation for the Preparation of Fluorine Containing Pyrrolidines

Article abstract of DOI:10.1021/acs.joc.9b00244

A mild and reproducible method for the formation of a nonstabilized azomethine ylide was developed by photoinduced reaction catalyzed with eosin Y under green light irradiation. Resulting 1,3-dipole was trapped with fluoroalkenes, fluoroalkylated alkenes,

Full text of DOI:10.1021/acs.joc.9b00244

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Note
Photoinduced Non–stabilized Azomethine Ylide Formation
for the Preparation of Fluorine Containing Pyrrolidines
Thibault Thierry, Cyril Lebargy, Emmanuel Pfund, and Thierry Lequeux
J. Org. Chem., Just Accepted Manuscript • Publication Date (Web): 05 Apr 2019
Downloaded from http://pubs.acs.org on April 5, 2019
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The Journal of Organic Chemistry
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Photoinduced Non–stabilized Azomethine Ylide Formation for the
Preparation of Fluorine Containing Pyrrolidines
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Thibault Thierry, Cyril Lebargy, Emmanuel Pfund, Thierry Lequeux*
Normandie Université, Laboratoire de Chimie Moléculaire et Thioorganique UMR 6507, ENSICAEN, UNICAEN, CNRS, 6
Bd. du Maréchal Juin, 14050 Caen, France.
Supporting Information Placeholder
F
RF
EWG
EWG
MeO
BnN
EY green LED
N
Bn
R1
BnN
EY*
EY
F
R2
Me3Si
EY
N
Bn
ABSTRACT: A mild and reproducible method for the formation of a non–stabilized azomethine ylide
was developed by photoinduced reaction catalyzed with eosin Y under green light irradiation. Resulting
1,3-dipole was trapped with fluoroalkenes, fluoroalkylated alkenes and representative dipolarophiles to
access pyrrolidine scaffolds, including spirocyclic compounds. The mechanism involved in this
transformation was investigated, showing clearly a catalytic redox cycle with eosin Y.
Pyrrolidines and in particular 3-fluoro- and 3-fluoroalkylpyrrolidines play an important role in drug
discovery,1 as illustrated by the development of new important classes of antibiotics, modified amino-
acids or nucleoside phosphorylase inhibitors.2 The preparation of these derivatives was achieved by 1,3-
dipolar cycloaddition reaction from alkenes and non-stabilized azomethine ylide precursor 1 (Scheme
1). While the cycloaddition reaction with non-stabilized azomethine ylides 2 was widely explored from
trifluoromethylalkenes,3 studies from mono- and di-fluoroalkenes were scarcely described. Recent
works have been realized in this field,4 and in some reports this reaction appeared capricious when the
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formation of the dipole 2 was performed from amine 1 in the presence of a catalytic amount of
trifluoroacetic acid (TFA) at 0 °C.5 Some modifications were introduced to improve the yield or to reach
completion, including the reaction temperature (55°C up to 160 °C), the solvent nature (CH3CN or
neat), and the use of LiF instead of TFA. For trisubstituted alkenes,4c such as ethyl 2-fluoro-3-phenyl
acrylate 3, a longer reaction time and highest reaction temperature were necessary (55 °C instead of 0
°C) to form and trap the azomethine ylide 2 (Scheme 1). The corresponding pyrrolidine 4 was obtained
in a modest 19% yield (Scheme 1), illustrating the limitations of these reaction conditions.
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Scheme 1. Typical limits of 1,3-dipolar cycloaddition with non-stabilized ylides4c
The recent growing interest for photoredox reactions has stimulated mainly groups to develop
photocatalytic cycloaddition reactions involving azomethine ylides. These works were exclusively
focused on stabilized azomethine ylide formation in the presence of ruthenium complexes, Rose Bengal,
or eosin Y (EY) under visible irradiation using LED light.6
Inspired by these previous works, we developed a mild photoinitiated 1,3-dipolar cycloaddition
reaction from the commercially available Achiwa's reagent 1. Our initial investigations focused on
examining the feasibility of the reaction with the poorly reactive dipolarophile 3 in the presence of eosin
Y disodium salt, as photoactivator (Scheme 2). The reaction occurred in the presence of EY (4 mol%)
and 1 under irradiation with a house green LED (5W) over 18 h at 20 °C. In this case, the corresponding
pyrrolidine 4 was obtained in 56% yield, although the reaction reached up to 70–85% completion
(determined by 19F NMR analysis of the crude).
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The Journal of Organic Chemistry
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Scheme 2. Photoinduced 1,3-dipolar cycloaddition
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While excess of dipole precursor 1 had a modest effect on the yield, slow addition of a solution of 1 (2
equiv) over 2 h followed by additional 1 h of stirring allowed to reach completion and afforded 4 in
77% yield (Scheme 2). Indeed, a short reaction time is preferred given the low stability of 2 in the
medium. This result contrasts sharply with the reaction carried out with catalytic TFA (Scheme 1), the
yield rising from 19% to 77%. The reaction was then applied to access representative fluorinated
pyrrolidine derivatives from readily available fluoroalkenes (Table 1).7 For these experiments, the
corresponding pyrrolidines 10-14 were obtained in 50-95% yield depending on the alkene nature. In
some cases, when applied, the product cis/trans ratio reflected the Z/E ratio of the alkene involved in the
reaction, confirming the concerted mechanism expected for such cycloaddition reaction. From
conjugated ester 5 substituted by an alkyl chain the pyrrolidine 10 was obtained in 50% yield (Table 1,
Entry 1). In contrast, with terminal alkene 6 or trisubtituted vinylsulfones 7, corresponding adducts 11,
12 were isolated in 75% and 78% yield respectively (Table 1, Entry 2). The oxetanyl and N-Boc
azetidinyl fluoroalkenes 8 and 9 gave the corresponding spirocyclic oxetanyl and azetidinyl pyrrolidine
derivatives 13a and 14 in 70-95% yield. These spirocyclic compounds are of interest for new drugs
discovery.8 Fluoropyrrolidines 13a and 14 were recently synthesized through a 1,3-dipolar cycloaddition
reaction from 1.4a In this case, authors relied on the original method (TFA or LiF) to form and trap the
dipole 2 but longer reaction time up to 18 h at 20 °C or high temperature up to 60 °C were required. The
reaction carried on with alkene 8 and dipole precursor bearing a N–phenylethylamine group instead of a
benzyl group afforded a mixture of adducts 13b in 1:1 ratio.
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Table 1. Photoinduced 1,3-dipolar cycloaddition with fluoroalkenes
1
2
3
4
5
Productb
Yield (%)c
Entry
Alkenea
6
7
8
9
F
C8H17
CO2Et
CO2Et
C8H17
F
N
1
Bn
(Z:E = 7:3)
(cis:trans = 7:3)
10
11
12
13
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15
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17
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5
10 (50)
2
3
4
5
6: R = H
7: R = C6H13
(Z:E = 3:7)
11: R = H (75)
12: R = C6H13 (78)
(cis:trans = 3:7)
CO2Et
O
F
8
13a (95)
O
F
CO2Et
CO2Et
N
O
F
8
1:1
13b (65)
F
BocN
CO2Et
CO2Et
BocN
F
N
Bn
9
14 (70)
a Z:E ratio determined by 19F NMR. b cis:trans geometry
determined by HOESY experiments.c Isolated yield in parenthesis.
Other photosensitizers were tested, and experiments were realized in the presence of Rose Bengal
(RB, green LED) in THF and acridinium derivative (Mes-Acr-Me+, blue LED) in CH3CN (4 mol%).
After 3 h of reaction performed with 8 and 1, spirocyclic adduct 13a was isolated in non–optimized
yields of 66% and 74% respectively.
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Table 2. Photoinduced 1,3-dipolar cycloaddition with tri- and di-fluoromethyl–alkenes
1
2
3
4
5
6
Productb
Entry
Alkenea
Yield (%)c
CO2Bn
F3C
CO2Bn
7
8
9
F3C
N
1
Bn
15
19 (81)
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CO2Bn
(iPrO)2(O)PF2C
CO2Bn
(OiPr)2(O)PCF2
2
3
N
Bn
16
20 (87)
NO2
(iPrO)2(O)PF2C
NO2
(OiPr)2(O)PCF2
N
Bn
17
21 (85)
F
(OiPr)2(O)PCF2
CO2Et
4
(E:Z = 9:1)
18
22 (70)
a Z:E ratio determined by 19F NMR. b cis:trans ratio determined
by NOESY experiments. c Isolated yield in parenthesis.
The reaction was extended to trifluoromethylalkene 15 and gem–difluoromethylalkenes 16–18 (Table
2). The reaction carried out with disubstituted alkenes such as benzyl trifluorocrotonate 15, and
difluoromethylphosphonates 16, 17 afforded the corresponding pyrrolidines 19–21 in 81–87% yield
(Table 2, Entries 1–3). From
a
trisubstituted fluoroalkene such as 18 bearing
a
phosphonodifluoromethyl group, the corresponding adduct 22 was isolated in good yield (Table 2, Entry
4). This last reaction tested following the original Achiwa's experimental conditions in the presence of
catalytic amount of TFA (10 mol%) in dichloromethane was unsuccessful, and no adduct 22 was
detected even after 18 h at 20 °C, showing again the photoinduced reaction is most efficient.
This method was not limited to fluorinated alkenes since good results were observed with other
representative dipolarophiles (Table 3). The photoinduced reaction performed with 1 and ethylacrylate,
or maleimide afforded the corresponding pyrrolidines 28 and 29 in 62% and 70% yield, respectively
(Entries 1, 2).9a,5 The dearomatization reaction of nitroindole was then tested, and was successful
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leading to the corresponding dihydro–pyrroloindole 30 in 92% yield (Entry 3).9b Finally, the reaction
was realized with two heterodipolarophiles, such as benzaldehyde and corresponding imines (Entries 4,
5). In these cases, adducts were obtained in moderate to good yields. These additional examples
illustrated the scope of the photoinduced reaction.
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Table 3. Photoinduced 1,3-dipolar cycloaddition with representative dipolarophiles
Producta
Entry
dipolarophile
Yield (%)b
EtO2C
EtO2C
1
N
Bn
23
289a (62)
Ph
N
O
O
Ph
N
O
O
2
N
Bn
24
295 (70)
NO2
3
4
N
Ts
309b (92)
25
Ph
O
Ph
O
N
Bn
26
319c (78)
Ph
NR
Ph
NR
N
Bn
5
27a (R = Ts)
27b (R = S(O)tBu
32a9d (60)
32b9e (65)
a Reaction performed with 1 (2 equiv), eosin Y (4 mol%), 3 h, 20 °C, CH3CN.
b Isolated yield in parenthesis.
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The Journal of Organic Chemistry
The mechanism of formation of the 1,3-dipole 2 under visible light irradiation was examined. Early
1
2
studies reported the formation of -amino radicals by irradiation of silylalkylamines.10 It has been
clearly established that the first step of the reaction is a photoinduced electron transfer (PET) occurring
from the nitrogen centre to the excited photosensitizer to afford the corresponding -silyl amino radical
cation. The latter undergoes a selective desilylation reaction induced by a protic solvent (methanol) to
give the -amino radical. This method was applied to the formation of azomethine ylide but from the
bis-silylated amine (Me3SiCH2)2NBn only.11 To our knowledge no precedent work has been reported
with Achiwa's reagent 1.
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Scheme 3. Formation of 1,3-dipole 2 from amine 1
The formation of the 1,3-dipole 2 from the silylated alkoxymethylamine 1 will follow a similar
mechanism where EY* is reduced by a PET from amine 1 to lead to the radical cation 1A (Scheme 3).
This radical cation then gives the unstable and highly reactive intermediate iminium radial 1B,12 and
next the dipole 2 after its reduction. The formation of intermediate radical in our experiment was
evaluated by performing the reaction in the presence of radical scavengers (MeHQ) 4-methoxyphenol,
and (BHT) dibutylhydroxytoluene (15 and 30 mol%). For these latter, the formation of the 1,3-dipole 2
was partially (15 mol%) or totally (30 mol%) inhibited (Scheme 4), suggesting a probable formation of
intermediate radicals. The reaction was performed in the presence of tetramethylpiperidine N–oxide
(TEMPO, 2 equiv), however no trapping product was detected, TEMPO seems to react with eosin Y.13
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Contrasting with the previous works performed with silylalkylamines,10, 11 the absence of methanol as
co-solvent is essential for the TMS transfer to occur. Indeed, the formation of 1,3-dipole 2 from amine 1
was inhibited when realized in methanol/acetonitrile (1:1). In addition, the absence of oxygen in the
medium is important and was confirmed by experiments realized in nitrogen saturated CH3CN and air
saturated CH3CN. While the reaction reached completion for the former, a completion of 40% was
reached for the latter.
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Scheme 4. Effect of additives and experiment control
This mechanism is supported considering the redox potential of EY, RB, and Mes-Acr-Me+ under
their excited state (EredT1) of +0.83, +0.81 and +1.45 V vs SCE, respectively.14 These photosensitizers
are able to oxidize tertiary amines (E1/2ox = +0.78 V vs SCE)15 to initiate the formation of radical cation
1A and corresponding reduced form of the photosensitizer (PS•–). With eosin Y, the radical 1B obtained
after TMSOMe ejection, can be easily reduced into dipole 2, EY•– acting as strong reductant in its
ground state (E1/2red = -1.08 V vs SCE).
The reaction was monitored by UV-Vis analysis. The UV-Vis absorption spectrum of eosin Y (4
mol%) were recorded over time in the presence of alkene 8 (1 equiv) and amine 1 (1 equiv) in CH3CN
solution (Figure 1A). While unchanged UV-Vis spectra profile of eosin Y was observed after addition
of alkene 8, the intensity absorption was affected upon addition of amine 1 to the mixture eosin
Y/alkene 8. Again, the inhibitory effect of methanol was confirmed as the absorption profile of eosin Y
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The Journal of Organic Chemistry
was found unaffected when the spectra of the mixture (eosin Y; alkene 8; amine 1) were recorded over
1
2
3
time in CH3CN/CH3OH solution (Figure 1B).
4
5
6
1,6
7
1,4
8
9
Reaction mixture
1,2
After 15 min irradiation
After 30 min irradiation
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After 45 min irradiation
0,8
0,6
0,4
0,2
0
400
450
500
550
Wavelenght (nm)
600
650
(A)
(B)
Figure 1. (A) UV-Vis absorption spectra of EY after addition of reagents 1 and 8. (B) Spectra
after addition of methanol
The quenching rate for alkene 8 and amine 1 was directly evaluated using standard Stern–Volmer
analyses. Fluorescence quenching was realized by following the emission intensity of eosin Y disodium
salt with the gradual increase of the amount of each reagent (alkene 8 and amine 1). Addition of alkene
8 has no influence of the emission intensity (see Figure S8), while amine 1 induced a gradual decrease
(see Figure S7), confirming an interaction between the excited EY* and amine 1. A possible electron
transfer would be definitively confirmed by transient spectroscopy.
An alternative mechanism, involving the formation of amino radical cation 1A by oxidation of amine
1 with iminium radical 1B is not excluded (Scheme 4, blue).16 Our model reaction performed from 1 (1
equiv), and 8 realized in an NMR tube (CD3CN) was followed by 19F NMR (see Figure S11). The
reaction run in the absence of light was slower and needed 24 h at 20 °C to reach completion to afford
the expected adduct 13a. In this experiment, no trace of intermediate fluorinated compounds was
observed. This reaction carried on larger scale in the dark afforded 13a in 74% yield after 24 h at 20 °C.
In this case, it is presumed that EY initiated the formation of amino radical cation 1A during the sample
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preparation, and the subsequent generation of amino radical cation 1A results from oxidation of amine 1
by iminium radical 1B. Both mechanisms could work in parallel.
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2
3
4
5
6
7
8
To conclude, the formation of a non–stabilized azomethine ylide 2 under mild experimental conditions
was achieved based on a photoinduced electron transfer catalyzed with organic photosensitizers using
LED light. This method was exemplified by the synthesis of useful fluorinated pyrrolidine scaffolds,
and representative pyrrolidines, including spirocyclic compounds, in reproducible high yields. The
mechanistic information collected will be of interest to investigate other cycloaddition reactions
involving silylated azomethine ylide precursors.
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EXPERIMENTAL SECTION
General Information.
All commercially available reagents were bought and used as received. For anhydrous conditions, the
glassware was flame dried under a continuous nitrogen flow and cooled to 20 °C before running the
experiment. Anhydrous solvents (THF, CH3CN) were dried in a solvent generator, which uses an
activated alumina column to remove water. Et3N was distilled under CaH2 or molecular sieves (4 Å).
Products were detected by thin layer chromatography, on which the spots were visualized by a 254 nm
UV lamp and/or KMnO4 solution. NMR spectra were recorded with a 500 MHz or 600 MHz apparatus
in deuterated solvent at 25 °C. All 13C NMR spectra are decoupled from the 1H (13C{1H}). The chemical
shifts (δ) and coupling constants (J) are expressed in ppm and Hz respectively. The following
abbreviations are used: s: singlet; d: doublet; t triplet; q: quadruplet; quint: quintet; sext: sextet; sept:
septet; m: multiplet; br: broad signal. High-resolution mass spectroscopic data were recorded with a
Micromass Q-TOF instrument with an electrospray source in the EI or ESI mode.
Preparation of alkene compounds 5 to 9 and 15 to 18. Ethyl 2-fluoro-undec-2-enoate (5). Compound
5 was synthesized according to literature procedure.15 Dibromoethane (0.128 mL, 1.48 mmol, 1.5
equiv)was added dropwise to a suspension of Mg0(34 mg, 1.38 mmol, 1.4 equiv) in THF (5 mL) at 20°C
under N2. After disappearance of all magnesium (1 h of stirring), a solution containing nonaldehyde
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The Journal of Organic Chemistry
(305 mg, 1.18 mmol, 1.2 equiv) and 2-(1-Ethylfluoroacetate)sulfonyl-1,3-benzothiazole (300 mg, 0.989
mmol, 1 equiv) in THF (1 mL) was added. After 10 min, DBU (0.21 mL, 1.38 mmol, 1.4 equiv) was
added dropwise, and the solution was stirred for 2h at 20°C. The reaction was quenched with a saturated
solution of NH4Cl (1 mL) and brine (2 mL), then extracted with CH2Cl2/Et2O (1:1, 20 mL). The
organiclayer was washed with brine, dried over MgSO4, filtered, and evaporated under reduced
pressure. The crude product was purified by chromatography (silica, pentane/AcOEt 92:8) to afford 5 (
198 mg, 0.860 mmol, 87%) (Z:E = 7:3) (E)-isomer 1H NMR (500 MHz, CDCl3): δ 5.93 (dt, 3JHF = 21.8
Hz, 3JHH = 7.9 Hz, 1H), 4.25–4.33 (m, 2H), 2.20–2.55 (m, 2H), 1.22–1.48 (m, 15H), 0.88 (t, 3JHH = 7.1
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19
3
1
Hz, 3H). F NMR (470 MHz, CDCl3): δ –122.8 (d, JFH = 21.8 Hz). (Z)-isomer H NMR (500 MHz,
3
3
CDCl3): δ 6.00 (dt, JHF = 33.5 Hz, JHH = 7.9 Hz, 1H); 4.25–4.33 (m, 2H), 2.20–2.55 (m, 2H), 1.22–
1.48 (m, 15H), 0.88 (t, 3JHH = 7.1 Hz, 3H). 19F NMR (470 MHz, CDCl3): δ –131.2 (d, 3JFH = 33.5 Hz).
NMR data are in agreement with literature data.15
2-[(1-Fluorovinyl)sulfonyl]-1,3-benzothiazole (6). Compound 6 was synthesized according to literature
procedure.16 To a solution of 2-benzothiazolylsulfonyl-2-fluoroethanol (300 mg, 1.14 mmol, 1 equiv)
and MsCl (110 µL, 1.38 mmol, 1.2 equiv) in CH2Cl2 (4 mL) cooled to 0 °C was added dropwise NEt3
(400 µL, 2.85 mmol, 2.5 equiv). The mixture was stirred for 30 min at 0 °C and then quenched with a
saturated solution of NH4Cl (1 mL). The aqueous layer was extracted with CH2Cl2 (20 mL). Combined
organic layers were washed with a saturated solution of NaHCO3 (2 mL), dried over MgSO4, filtered,
1
and evaporated under reduced pressure to furnish 6 (259 mg, 92%) as a white solid. H NMR (500
2
MHz, CDCl3): δ 8.19–8.22 (m, 1H), 7.96–7.99 (m, 1H), 7.54–7.64 (m, 2H), 6.06 (dd, JHH = 5.0 Hz,
2
3
3JHF = 40.7 Hz, 1H), 5.65 (dd, JHH = 5.0 Hz, JHF = 11.7 Hz, 1H). NMR data are in agreement with
literature data.16
2-(1-Fluorooct-1-ene-1-sulfonyl)-1,3-benzothiazole (7). In a 50 mL oven dried flask was added LiCl (69
mg, 1.63 mmol, 1.2 eq.), the flask was flame dried under argon flush and cooled to room temperature.
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THF (30 mL) and diethyl ((benzothiazol-2-ylsulfonyl)fluoromethyl)phosphonate (500 mg, 1.36 mmol,
1.0 eq.) were added. After cooling at 0 °C, Et3N (0.21 mL, 1.50 mmol, 1.1 eq.) was added dropwise,
followed after 10 min of stirring by the addition of heptanal (155 mg, 1.36 mmol). After 18 h of stirring,
the reaction mixture was quenched with 2 mL of 3N hydrochloric aqueous solution. After extraction
with Et2O, the organic layer was washed with brine, dried over magnesium sulfate, filtrated and
evaporated under reduced pressure. The crude residue was purified by flash chromatography using
Pentane/AcOEt (95:5) as eluent. A 3:7 ratio (Z:E) of compound 7 was obtained as a colorless oil (416
mg, 89%). (Z)-isomer 1H NMR (500 MHz, CDCl3): δ 8.28–8.26 (m, 1H), 8.04–8.03 (m, 1H), 7.67–7.61
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
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48
49
50
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52
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55
56
57
58
59
60
3
3
(m, 2H), 6.15 (dt, JHF = 21.2 Hz, JHH = 8.6 Hz, 1H), 2.70 (m, 2H), 1.54–1.47 (m, 2H), 1.40–1.25 (m,
13
6H), 0.88 (m, 3H). C{1H} NMR (126 MHz, CDCl3): δ 164.3, 152.8, 150.3 (1JCF = 286.9 Hz), 137.4,
128.4 (2C), 127.8 (2C), 125.9, 125.0 (d, 2JCF = 10.8 Hz), 122.3, 31.5, 29.1 (dd, 4JCF = 2.2 Hz), 28.7, 24.9
(d, 3JCF = 3.0 Hz), 22.6, 14.1. 19F NMR (470 MHz, CDCl3): δ –116.4 (d, 3JFH = 21.2 Hz). (E)-isomer 1H
3
NMR (500 MHz CDCl3): δ 8.26–8.24 (m, 1H), 8.03–8.01 (m, 1H), 7.67–7.59 (m, 2H), 6.51 (dt, JHF
=
3
32.0 Hz, JHH = 8.1 Hz, 1H), 2.30 (m, 2H), 1.51–1.47 (m, 2H), 1.40–1.25 (m, 6H), 0.87 (m, 3H).
13C{1H} NMR (126 MHz, CDCl3): δ 163.8, 152.8, 152.0 (1JCF = 293.7 Hz), 137.5, 128.4 (2C), 127.8
(2C), 125.9, 123.4 (d, 2JCF = 7.4 Hz), 122.3, 31.4, 28.7, 27.9 (dd, 4JCF = 1.8 Hz), 24.8 (d, 3JCF = 1.8 Hz),
22.5, 14.0. 19F NMR (470 MHz, CDCl3): δ –128.3 (dt, 3JFH = 32.0 Hz, 4JFH = 2.5 Hz). HRMS-ESI (m/z)
+
[M+H] +: calculated for C15H19NO2FS2 328.0841 found 328.0848.
Ethyl 2-fluoro-2-(oxetan-3-ylidene)acetate (8). DBU (5.55 mL, 37.2 mmol, 1.5 equiv.) was added
dropwise to a THF (50 mL) solution of triethyl 2-fluoro-2-phosphonoacetate (6.0 g, 24.78 mmol) and 3-
oxetanone (1.97 g, 27.25 mmol, 1.2 equiv.). The resulting mixture was stirred 2 h at 20 °C. The reaction
was monitored by TLC and quenched with a saturated NH4Cl solution. The aqueous layer was extracted
twice with CH2Cl2. The organic layers were combined, washed with brine, dried with MgSO4, filtered
and evaporated under reduced pressure. The crude product was purified by flash SiO2 column
chromatography with DCM as eluent to give compound 8 (3.97 g, 84 %).1H NMR (500 MHz, CDCl3): δ
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5.44–5.31 (m, 4H), 4.28 (q, 3JHH = 7.2 Hz, 2H), 1.32 (t, 3JHH = 7.2 Hz, 3H). 19F NMR (472 Hz, CDCl3):
δ –136.4, (quint, 4JHF = 3.8 Hz). NMR data are in good agreement with literature data.17
1
2
3
4
5
6
7
8
9
Tert-butyl 3-(2-ethoxy-1-fluoro-2-oxoethylidene)azetidine-1-carboxylate (9). DBU (0.46 mL, 3.1 mmol,
1.5 equiv.) was added dropwise to a THF (5 mL) solution of triethyl 2-fluoro-2-phosphonoacetate (0.5
g, 2.07 mmol) and tert-butyl 3-oxoazetidine-1-carboxylate (0.389 g, 2.27 mmol, 1.2 equiv.). The
resulting mixture was stirred 4 h 30 at 20 °C. The reaction was monitored by TLC and quenched with a
saturated NH4Cl solution. The aqueous layer was extracted twice with CH2Cl2. The organic layers were
combined, washed with brine, dried with MgSO4, filtered and evaporated under reduced pressure. The
crude product was purified by flash SiO2 column chromatography with pentane/AcOEt (80/20) as eluent
10
11
12
13
14
15
16
17
18
19
20
21
22
23
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25
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45
46
47
48
49
50
51
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54
55
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59
60
1
to give compound 8 (0.44 g, 82 %). H NMR (500 MHz, CDCl3): δ 4.74–4.73 (m, 2H), 4.31–4.27 (m,
2H), 4.31 (q, 3JHH = 7.2 Hz, 2H), 1.47 (s, 9H), 1.33 (t, 3JHH = 7.2 Hz, 3H). 19F NMR (471 MHz, CDCl3):
δ –133.9 (quint, 4JHF = 3.8 Hz). NMR data are in good agreement with literature data.17
(E)-Benzyl 4,4,4-trifluoro-3-(trifluoromethyl)but-2-enoate (15). In a 50 mL oven dried flask was added
LiCl (88 mg, 2.07 mmol, 1.2 eq.), the flask was flame dried under Argon flush and cooled to room
temperature. THF (4 mL) and benzyl 2-(diethoxyphosphoryl)acetate (494 mg, 1.72 mmol) was added.
After cooling at 0 °C, Et3N (0.3 mL, 1.9 mmol, 1.1 eq.) was added dropwise followed after 10 min of
stirring by the addition of 1-methoxy-2,2,2-trifluoroethanol (225 mg, 1.72 mmol). After 18 h of stirring,
the reaction mixture was quenched with 2 mL of 3N hydrochloric aqueous solution. After extraction
with Et2O, the organic layer was washed with brine, dried over magnesium sulfate, filtrated and
evaporated under reduced pressure. The crude residue was purified by flash chromatography using
1
Pentane/EtOAc (90 :10) as eluent to obtain compound 15 as a colorless oil (320 mg, 62%). H NMR
(500 MHz, CDCl3): δ 7.42–7.37 (m, 5H), 6.82 (dq, 3JHH = 15.8 Hz, 3JHF = 6.5 Hz, 1H), 6.55 (dq, 3JHH
=
4
13
15.8 Hz, JHF = 2.0 Hz, 1H), 5.26 (s, 2H). C{1H} NMR (126 MHz, CDCl3): δ 163.9, 135.1, 131.9 (q,
2JCF = 35.6 Hz), 128.9 (2C), 128.8, 128.8 (q, 3JCF = 6.2 Hz), 128.6 (2C), 122.0 (q, 1JCF = 269.7 Hz), 67.6
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19F NMR (470 MHz, CDCl3): δ –65.60 (d.br, 3JFH = 6.5 Hz, 4JFH not resolved). HRMS-ESI (m/z) [M+H]
1
2
3
+
+: calculated for C11H10F3O2 [M + H]+ 231.0634, found 231.0632.
4
5
6
7
8
9
(E)-Benzyl (2)-4-(diisopropoxyphosphoryl)-4,4 difluorobut-2-enoate (16). In a 50 mL oven dried flask
was added LiCl (39 mg, 0.91 mmol, 1.2 eq.), the flask was flame dried under argon flush and cooled to
room temperature. THF (4 mL) and benzyl 2-(diethoxyphosphoryl)acetate (218 mg, 0.76 mmol, 1.0 eq.)
was added. After cooling at 0 °C, Et3N (0.12 mL, 0.84 mmol, 1.1 eq.) was added dropwise, followed
after 10 min of stirring by the addition of diisopropyl 1,1-difluoro-2,2-dihydroxyethylphosphonate (200
mg, 0.76 mmol) in THF solution (1 mL). After 18 h of stirring, the reaction mixture was quenched with
2 mL of 3N hydrochloric aqueous solution. After extraction with Et2O, the organic layer was washed
with brine, dried over magnesium sulfate, filtrated and evaporated under reduced pressure. The crude
residue was purified by flash chromatography using Pentane/EtOAc (80 :20) as eluent. Compound 16
was obtained as a colorless oil (251 mg, 87%). 1H NMR (500 MHz CDCl3): δ 7.39–7.36 (m, 5H), 6.98–
6.89 (m, 1H), 6.47–6.43 (m, 1H), 5.23 (s, 2H), 4.86 (dsept, 3JHP = 3JHH = 6.2 Hz, 2H), 1.39 (d, 3JHH = 6.2
Hz, 2H), 1.36 (d, 3JHH = 6.2 Hz, 2H). 13C{1H} NMR (126 MHz, CDCl3): δ 164.3, 136.2 (dt, 2JCF = 22.1
Hz, 2JCP = 13.1 Hz), 135.3, 128.7 (2C), 128.5, 128.4 (2C), 127.4 (dt, 3JCF = 9.5 Hz, 3JCP = 5.5 Hz), 115.8
(dt, 1JCF = 260.1 Hz, 1JCP = 218.6 Hz), 74.3 (d, 2JCP = 7.0 Hz, 2C), 67.1, 24.1 (d, 3JCP = 3.6 Hz, 2C), 23.7
10
11
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16
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45
46
47
48
49
50
51
52
53
54
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58
59
60
(d, 3JCP = 4.9 Hz, 2C). 19F NMR (470 MHz, CDCl3): δ–112.51 (ddd, 2JFP = 107.8 Hz, 3JFH = 12.7, 4JFH
=
31
2
1.5 Hz). P NMR (202 MHz, CDCl3): δ 3.12 (tt, JPF = 107.8 Hz, 3JPH = 6.2 Hz). HRMS-ESI (m/z)
[M+Na] + : calculated for C17H23F2O5PNa+ 399.1149 found 399.1150.
(E)-diisopropyl-1,1-difluoro-3-nitroprop-2-en-1-ylphosphonate (17). In a 50 mL oven dried flask was
added KF (44 mg, 0.76 mmol, 1.0 eq), the flask was flame dried under argon flush and cooled to room
temperature. Isopropanol (4 mL) and diisopropyl 1,1-difluoro-2,2-dihydroxyethylphosphonate (200 mg,
0.76 mmol, 1.0 eq.) was added. After 10 min of stirring at room temperature, nitromethane (0.12 mL,
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The Journal of Organic Chemistry
2.29 mmol, 3.0 eq.) was added. After 18 h of stirring at room temperature, the reaction mixture was
diluted with Et2O, the organic layer was washed twice with brine, dried over magnesium sulfate,
filtrated and evaporated under reduced pressure. The crude residue was diluted in CH2Cl2 then cooled to
0 °C. Mesyl chloride (0.16 mL, 2.11 mmol, 3.0 eq.) was added and the reaction mixture was stirred 30
min at 0 °C under argon. Et3N (0.28 mL, 2.11 mmol, 3.0 eq.) was added dropwise. After 1 h 30 min at
room temperature the reaction mixture was quenched with water and extracted with Et2O. Organic layer
was washed with brine, dried over magnesium sulfate, filtrated and evaporated under reduced pressure.
The crude yellow residue was purified by flash chromatography using Pentane/EtOAc 80/20 as eluent.
Compound 17 was obtained as a slight yellow oil (124 mg, 61%). 1H NMR (500 MHz, CDCl3): δ 7.37–
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
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24
25
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27
28
29
30
31
32
33
34
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59
60
3
3
7.34 (m, 1H), 7.22–7.14 (m, 1H), 4.90 (dsept, 3JHP = JHH = 6.3 Hz, 2H), 1.41 (d, JHH = 6.3 Hz, 6H),
1.39 (d, 3JHH = 6.3 Hz, 6H). 13C{1H} NMR (126 MHz, CDCl3): δ 144.1 (m), 130.6 (td, 2JCF = 23.0 Hz,
2JCP = 13.6 Hz), 115.0 (td, 1JCF = 263.0 Hz, 1JCP = 218.5 Hz), 75.1 (d, 2JCP = 7.1 Hz, 2C), 24.1 (d, 3JCP
=
3.7 Hz, 2C), 23.7 (d, 3JCP = 4.9 Hz, 2C). 19F NMR (470 MHz, CDCl3): δ –112.43 (dd, 3JFP = 102.9 Hz,
31
3
3JFH = 11.9 Hz). P NMR (202 MHz, CDCl3): δ 1.86 (tt, JPF = 102.9 Hz, 3JHP = 6.3 Hz). HRMS-ESI
(m/z) [M+Na] +: calculated for C9H16F2NO5PNa+ 310.0632 found 310.0640.
4-(diisopropoxyphosphoryl)-2,4,4-trifluorobut-2-enoate (18). In a 50 mL oven dried flask was added
LiCl (57 mg, 1.34 mmol, 1.2 eq.), the flask was flame dried under argon flush and cooled to room
temperature. THF (10 mL) and ethyl 2-(diethoxyphosphoryl)-2-fluoroacetate (270 mg, 1.12 mmol, 1.0
eq.) was added. After cooling at 0 °C, Et3N (0.2 mL, 1.23 mmol, 1.1 eq.) was added dropwise, followed
after 10 min of stirring by the addition of diisopropyl 1,1-difluoro-2,2-dihydroxyethylphosphonate (291
mg, 0.37 mmol) in THF solution (1 mL). After 18 h of stirring, the reaction mixture was quenched with
2 mL of 3N hydrochloric aqueous solution. After extraction with Et2O, the organic layer was washed
with brine, dried over magnesium sulfate, filtrated and evaporated under reduced pressure. The crude
residue was purified by chromatography using DCM/MeOH (95:5) as eluent. A (90:10) mixture of (E:Z)
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compound 18 was obtained as a colorless oil (90 mg, 24%). (E) isomer: 1H NMR (500 MHz CDCl3): δ
1
2
3
3
3
3
5.93 (dtd, 3JHF = 18.5 Hz, JHF = 15.0 Hz, JHP = 3.5 Hz, 1H), 4.92–4.85 (dsept, 3JHP = JHH = 6.3 Hz,
4
5
6
2H), 4.38–4.34 (q, 3JHH = 7.1 Hz 2H), 1.40–1.36 (m, 15H). 13C{1H} NMR (126 MHz, CDCl3) : δ 158.8
2
4
1
3
1
1
7
8
(dd, JCF = 34.0, JCF = 1.4 Hz), 153.7 (d, JCF = 271.7, JCF = 9.9 Hz), 114.5 (ddt, JCF = 260.9, JCP =
9
224.8, 3JCF = 15.1 Hz), 108.4 (dtd, 2JCF = 26.1, 2JCF = 23.4, 2JCP = 15.4 Hz), 74.4 (d, 2JCP = 6.7 Hz, 2C),
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
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29
30
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46
47
48
49
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56
57
58
59
60
3
3
19
62.7, 24.1 (d, JCP = 3.5 Hz, 2C), 23.7 (d, JCP = 5.2 Hz, 2C), 13.8. F NMR (376 MHz, CDCl3): δ –
103.59 (ddt, 3JFH = 18.5 Hz, 4JFP = 9.5 Hz, 4JFF = 4.4 Hz, 1F), –105.96 (ddd, 2JFP = 106.8 Hz, 3JFH = 15.0
Hz, 4JFF = 4.4 Hz, 2F). 31P NMR (CDCl3, 202 MHz): δ 3.64 (td, 2JPF = 106.8 Hz, 3JPH = 9.5 Hz). HRMS-
ESI (m/z) [M + Na]+: calculated for C12H8F6O2Na+ 355.0895 found 355.0890. (Z) isomer visible on 1H,
19F and 31P spectra: 1H NMR (500 MHz CDCl3): δ 6.24 (dtd, 3JHF = 29.5 Hz, 3JHF = 14.3 Hz, 3JHP = 3.5
Hz, 1H), 19F NMR (376 MHz, CDCl3): δ –109.4 (ddd, 2JFP = 107.6 Hz, 4JFF = 23.1 Hz, 3JFH = 14.3 Hz,
2F), –113.5 (dtd, 3JFH = 29.5 Hz, 4JFF = 23.1 Hz, 4JFP = 7.2 Hz, 1F). 31P NMR (CDCl3, 202 MHz): δ 2.8
(td, 2JPF = 107.6 Hz, 3JPH = 7.2 Hz).
General procedure for the 1,3-dipolar cycloadditions. A CH3CN (1.0 mL) solution of N-
methoxymethyl-N-(trimethylsilylmethyl)benzylamine 1 (2.2 eq.) was added during 2 h (with syringe
pump) to an irradiated CH3CN (2.0 mL) solution of dipolarophile (1.0 eq.) and eosin Y disodium salt (4
mol%) with a 5W green LED. After 3 h of irriadiation, the solvent was removed under reduced pressure.
Residue was purified via SiO2 column chromatography to give corresponding cycloadducts.
(cis)-Ethyl-1-Benzyl-3-fluoro-4-phenylpyrrolidine-3-carboxylate (4). Compound 4 was obtained, in
accordance with general procedure, from (Z)-2-fluoro-3-phenyl acrylate 3 (0.10 g, 0.52 mmol), 1 (0.3
mL, 1.03 mmol) and Eosin Y (0.01 g, 0.02 mmol). The crude product was purified by chromatography:
1
eluent (80:20) pentane/AcOEt to give a colorless oil (0.13 g, 77%). H NMR (500 MHz, CDCl3): δ
3
2
7.22−7.40 (m, 10H), 4.26 (q, J = 7.1 Hz, 2H), 3.78−3.92 (m, 3H), 3.49−3.58 (dd, JHF = 29.0, JHH
=
11.9, 1H), 3.25−3.29 (m, 1H), 3.14 (m, 1H), 3.08 (dd, 3JHF = 30.5, 2JHH = 11.9, 1H), 1.28 (t, J = 7.1 Hz,
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19
3
3
3
3H). F NMR (471 MHz, CDCl3): δ –161.5 (ddd, JHF = JHF = 30.5, JHF = 29.0). NMR data are in
1
2
3
agreement with those reported in the literature.4c
4
5
6
7
8
Ethyl-1-benzyl-3-fluoro-4octylpyrrolidine-3-carboxylate (10). A 3:7 (trans/cis) diastereoisomeric
mixture of compound 10 was obtained, in accordance with general procedure, from a 3:7 (E/Z) mixture
of ethyl-2-fluoroundec-2-enoate 5 (0.10 g, 0.43 mmol), 1 (0.2 mL, 0.87 mmol) and Eosin Y (0.01 g,
0.02 mmol). The crude residue was purified by chromatography: eluent (80:20) pentane/Et2O to give a
9
10
11
12
13
14
15
16
17
18
19
20
21
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1
not separable mixture of isomers as colorless oil (0.08 g, 50%). (cis) isomer : H NMR (500 MHz,
CDCl3): δ 7.36–7.25 (m, 5H), 4.32–4.24 (m, 2H), 3.70 (d, 2JHH = 13.0 Hz, 1H), 3.62 (d, 2JHH = 13.0 Hz,
3
2
1H), 3.28–3.21 (m, 2H), 2.93 (dd, JHF = 26.0 Hz, JHH = 11.8 Hz, 1H), 2.70–2.50 (m, 1H), 2.14–2.11
(m, 1H), 1.49–1.39 (m, 1H), 1.34–1.17 (m, 16H), 0.88 (t, 3JHH = 7.1 Hz, 3H). 13C{1H} NMR (126 MHz,
2
1
CDCl3) : δ 169.8 (d, JCF = 28,0 Hz), 138.1, 128.4 (2C), 128.0 (2C), 126.6, 102.0 (d, JCF = 196.3 Hz),
2
2
62.8 (d, JCF = 24.8 Hz), 61.3, 59.2, 49.7 (d, JCF = 24.1 Hz), 31.5, 29.3, 29.0, 28.9, 28.5, 28.1, 22.7,
14.3, 14.1. 19F NMR (470 MHz, CDCl3): δ –166.72 (ddd, 3JFH = 3JFH = 30.0 Hz, 3JFH = 26.0 Hz). (trans)
isomer : 1H NMR (500 MHz, CDCl3) : δ 7.36–7.25 (m, 5H), 4.32–4.24 (m, 2H), 3.76 (d, 2JHH = 13.0 Hz,
1H), 3.69 (d, 2JHH = 13.0 Hz, 1H), 3.41 (dd, 3JHF = 27.1 Hz, 2JHH = 11.8 Hz, 1H), 3.10–3.06 (dd, 2JHH
=
9.1 Hz, 3JHH = 7.2 Hz, 1H), 2.85 (dd, 3JHF = 19.8 Hz, 2JHH = 11.0 Hz, 1H), 2.70–2.50 (m, 1H), 2.48–2.45
3
(m, 1H), 1.59–1.51 (m, 1H), 1.49–1.39 (m, 1H), 1.34–1.17 (m, 15H) 0.88 (t, JHH = 7.1 Hz, 3H).
2
13C{1H} NMR (126 MHz, CDCl3) 170.9 (d, JCF = 28.0 Hz) , 138.4, 128.7 (2C), 128.4 (2C), 127.1,
100.1 (d, 1JCF = 197.1 Hz), 64.0 (d, 2JCF = 24.8 Hz), 61.9, 60.3, 58.3, 47.5 (d, 2JCF = 20.2 Hz), 31.9, 29.7,
19
3
29.4, 29.2, 28.0, 26.3, 22.7, 14.2, 14.1. F NMR (470 MHz, CDCl3): δ –144.35 (ddd, JFH = 30.0 Hz,
3JFH = 27.1 Hz 3JFH = 19.8 Hz). HRMS-ESI (m/z) [M+H] + calculated for C22H35NO2F+ 364.2652, found
364.2654.
2-((1-Benzyl-3-fluoropyrrolidin-3-yl)sulfonyl)benzothiazole (11). Compound 11 was obtained, in
accordance with general procedure, from 6 (0.10 g, 0.41 mmol), 1 (0.2 mL, 0.82 mmol) and Eosin Y
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(0.01 g, 0.02 mmol). The crude residue was purified by chromatography: eluent (90:10) pentane/Et2O to
give a colorless oil (0.12 g, 77%).1H NMR (500 MHz, CDCl3) : δ 8.25–8.22 (m, 1H), 8.00–7.95 (m,
1H), 7.61–7.58 (m, 2H), 7.29–7.25 (m, 5H), 3.70 (d, 2JHH = 13.1 Hz, 1H), 3.68 (d, 2JHH = 13.1 Hz, 1H),
3.50 (dd, 3JHF = 24.5 Hz, 2JHH = 12.5 Hz, 1H), 3.18–2.92 (m, 3H), 2.70 (m, 1H), 2.28 (ddd, 3JHF = 28.8,
2JHH = 13.0, 3JHH = 7.1 Hz, 1H). 13C{1H} NMR (126 MHz, CDCl3): δ 161.9, 152.9, 137.7, 137.7, 128.6
(2C), 128.5 (2C), 128.4, 127.8, 127.4, 126.0, 122.2, 114.2 (d, 1JCF = 230.3 Hz), 59.5 (d, 2JCF = 23.2 Hz),
1
2
3
4
5
6
7
8
9
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59.4, 52.8, 33.7 (d, 2JCF = 21.2 Hz). 19F NMR (471 MHz, CDCl3): δ –139.0 (dddd, 3JFH = 28.8 Hz, 3JFH
=
3
3JFH = 24.5 Hz, JFH = 19.1 Hz). HRMS-ESI (m/z) [M+H] + calculated for C18H18N2O2S2F+ 377.0794,
found 377.0799.
((1-Benzyl-3-fluoro-4-hexylpyrrolidin-3-yl)sulfonyl)benzothiazole
(12).
A
7:3
(trans/cis)
diastereoisomeric mixture of compound 12 was obtained, in accordance with general procedure, from a
7:3 (E/Z) mixture of 7 (0.10 g, 0.31 mmol), 1 (0.2 mL, 0.61 mmol) and Eosin Y (0.01 g, 0.02 mmol).
The crude residue was purified by chromatography: eluent 90:10 pentane/Et2O to give a not separable
mixture of isomers as colorless oil (0.11 g, 78%). (trans) isomer 1H NMR (500 MHz, CDCl3) : δ 8.29–
8.25 (m, 1H), 8.05–7.98 (m, 1H), 7.71–7.56 (m, 2H), 7.35–7.22 (m, 5H), 3.90 (dd, 3JHF = 17.7 Hz, 2JHH
= 12.5 Hz, 1H), 3.70 (d, 2JHH = 13.1 Hz, 1H), 3.67 (d, 2JHH = 13.1 Hz, 1H), 3.20–3.06 (m, 2H), 2.83 (dd,
2
3
3JHF = 27.5 Hz, JHH = 12.5 Hz, 1H), 2.47–2.44 (m, 1H), 1.50–1.10 (m, 10H), 0.83 (t, JHH = 7.0 Hz,
13
3H). C{1H} NMR (126 MHz, CDCl3) : δ 162.1, 152.9, 137.8, 137.7, 128.6 (2C), 128.5 (2C), 128.4,
127.8, 127.3, 126.0, 122.2, 114.0 (d, 1JCF = 233.6 Hz), 60.5 (d, 2JCF = 24.3 Hz), 59.1, 58.6, 43.2 (d, 2JCF
= 18.6 Hz), 31.5, 29.2, 27.9, 27.4 (d, 3JCF = 10.8 Hz), 22.5, 14.1. 19F NMR (470 MHz, CDCl3): δ –155.6
3
(ddd, 3JFH = 27.5 Hz, 3JFH = JFH = 17.7 Hz). (cis) isomer 1H NMR (500 MHz, CDCl3) : δ 8.29–8.25 (m,
3
1H), 8.05–7.98 (m, 1H), 7.71–7.56 (m, 2H), 7.35–7.22 (m, 5H), 3.71–3.70 (m, 2H), 3.58 (dd, JHF
=
2
2
3
28.5 Hz, JHH = 12.80 Hz, 1H), 3.24 (dd, JHH = 9.1 Hz, JHH = 7.0 Hz, 1H), 3.20–3.06 (m, 1H), 2.88–
2.76 (m, 1H), 2.47–2.44 (m, 1H), 1.50–1.10 (m, 10H), 0.83 (t, 3JHH = 7.0 Hz, 3H). 13C{1H} NMR (126
MHz, CDCl3) : δ 163.4, 152.7, 137.8, 137.7, 128.6 (2C), 128.5 (2C), 128.4, 127.7, 127.4, 126.0, 122.2,
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114.9 (d, 1JCF = 231.4 Hz), 61.0 (d, 2JCF = 24.3 Hz), 59.8, 59.1, 50.0 (d, 2JCF = 21.1 Hz), 31.7, 29.1, 28.7,
1
2
3
3
19
26.8 (d, JCF = 4.0 Hz), 22.6, 14.1. F NMR (470 MHz, CDCl3): δ –132.19––132.24 (m). HRMS-ESI
4
5
6
+
(m/z) [M+H] + calculated for C24H29N2O2FS2 461.1729, found 461.1735.
7
8
9
Ethyl-6-benzyl-8-fluoro-2-oxa-6-azaspiro[3.4]octane-8-carboxylate (13a). Compound 13a was
obtained, in accordance with general procedure, from 8 (0.10 g, 0.63 mmol), 1 (0.32 mL, 1.2 mmol) and
Eosin Y (0.03 g, 0.05 mmol). The crude residue was purified by chromatography: eluent (70:30)
pentane/EtOAc to give a colorless oil (0.35 g, 95%). 1H NMR (500 MHz, CDCl3): δ 7.39–7.28 (m, 5H),
5.00 (d, 2JHH = 6.5 Hz, 1H), 4.57 (d, 2JHH = 6.5 Hz, 1H), 4.39–4.28 (m, 4H), 3.68–3.66 (m, 2H), 3.28 (d,
2JHH = 9.3 Hz, 1H), 3.15 (dd, 3JHF = 26.0, 2JHH = 11.6 Hz, 1H), 3.04 (dd, 3JHF = 26.0 Hz, 2JHH = 11.6 Hz,
1H), 2.98 (d, 2JHH = 9.3 Hz, 1H), 1.36 (t, 3JHH = 7.1 Hz, 3H). 19F NMR (471 MHz, CDCl3): δ –158.95 (t,
3JFH = 26.0 Hz). NMR data are in good agreement with those reported in the literature.4a
Rose bengale reaction: compound 13a was obtained, in accordance with general procedure, from 8 (0.10
g, 0.63 mmol), 1 (0.32 mL, 1.2 mmol) and rose bengale (0.008 g, 0.008 mmol) in THF (2 mL). The
crude residue was purified by chromatography: eluent (90:10) pentane/acetone to give a colorless oil
(0.12 g, 66%).
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9-mesityl-10-methylacridinium perchlorate reaction: compound 13a was obtained, in accordance with
general procedure, from 8 (0.10 g, 0.63 mmol), 1 (0.32 mL, 1.2 mmol) and 9-mesityl-10-
methylacridinium perchlorate (0.01 g, 0.024 mmol) under blue light LED irradiation (230V/5W). The
crude residue was purified by chromatography: eluent (7:3) pentane/AcOEt to give a colorless oil (0.135
g, 74%).
Ethyl 5-fluoro-7-[(1S)-1-phenylethyl]-2-oxa-7-azaspiro[3.4]octane-5-carboxylate (13b). Compound
13b was obtained, in accordance with general procedure, from 8 (0.3 g, 1.9 mmol), (1S)-N-
(methoxymethyl)-1-phenyl-N-(trimethylsilylmethyl)ethanamine (0.94 g, 3.75 mmol) and Eosin Y (0.052
g, 0.08 mmol). The crude residue was purified by chromatography: eluent (95:5) pentane/AcOEt to give
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a yellow oil (0.38 g, 65%). 1H NMR (500 MHz, CDCl3, both diastereomers): δ 7.40–7.15 (m, 5H), 4.98
(t, J = 6.5 Hz, 1H), 4.55 (dd, J = 11.3, 7.0 Hz, 1H), 4.42–4.20 (m, 4H), 3.41–2.72 (m, 5H), 1.42–1.30
(m, 6H). 13C{1H} NMR (126 MHz, CDCl3, , both diastereomers): δ 169.4 (d, 2JCF = 28.0 Hz), 169.3 (d,
1
2
3
4
5
6
1
2JCF = 28.2 Hz), 144.5, 144.4, 128.67 (2C), 128.65 (2C), 127.4 (2C), 127.1 (4C), 99.5 (d, JCF = 198.8
7
8
9
Hz), 99.4 (d, 1JCF = 198.2 Hz), 77.1 (d, 3JCF = 7.0 Hz), 76.6 (d, 3JCF = 6.5 Hz), 76.1 (d, 2JCF = 17.5 Hz),
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11
12
13
14
15
16
17
18
19
20
21
22
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30
31
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47
48
49
50
51
52
53
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56
57
58
59
60
2
2
2
75.7 (d, JCF = 17.5 Hz), 64.7, 64.6, 62.5, 62.36, 62.34, 62.2, 62.0 (d, JCF = 25.1 Hz), 61.9 (d, JCF
=
25.3 Hz), 52.0 (d, 2JCF = 22.6 Hz), 51.9 (d, 2JCF = 22.6 Hz), 23.0, 22.9, 14.4 (2C). 19F NMR (471 MHz,
CDCl3): δ –158.54 (t, 3JFH = 26.9 Hz), –158.84 (t, 3JFH = 26.5 Hz). HRMS-ESI (m/z) [M+H] + calculated
for C17H23NO3F+ 308.1662, found 308.1664.
2-(Tert-butyl) 8-ethyl-6-benzyl-8-fluoro-2,6-diazaspiro[3.4]octane-2,8-dicarboxylate (14). Compound
14 was obtained, in accordance with general procedure, from 9 (0.10 g, 0.39 mmol), 1 (0.2 mL, 0.77
mmol) and Eosin Y (0.01 g, 0.02 mmol). The crude residue was purified by chromatography: eluent 9:1
pentane/EtOAc to give a colorless oil (0.13 g, 70%). 1H NMR (500 MHz, CDCl3): δ 7.35–7.30 (m, 5H),
2
4.32–4.25 (m, 3H), 3.80 (d, JHH = 9.5 Hz, 1H), 3.67–3.65 (m, 4H), 3.28–3.25 (m, 1H), 3.05–2.99 (m,
2H), 2.88 (d, 2JHH = 9.5 Hz, 1H), 1.41 (s, 9H), 1.33 (t, 3JHH = 7.2 Hz, 3H). 19F NMR (471 MHz, CDCl3):
δ –157.3 (m). NMR data are in good agreement with those reported in the literature.4a
(trans)-Benzyl-1-benzyl-4-(trifluoromethyl)pyrrolidine-3-carboxylate (19). Compound 19 was obtained,
in accordance with general procedure, from 15 (0.10 g, 0.44 mmol), 1 (0.22 mL, 0.87 mmol) and Eosin
Y (0.01 g, 0.02 mmol). The crude residue was purified by chromatography: eluent 85:15 pentane/Et2O
to give a colorless oil (0.13 g, 81%). 1H NMR (500 MHz, CDCl3): δ 7.44–7.16 (m, 10H), 5.17 (d, 2JHH
=
12.3 Hz, 1H), 5.13 (d, 2JHH = 12.3 Hz, 1H), 3.62 (d, 2JHH = 13.1 Hz, 1H), 3.56 (d, 2JHH = 13.1 Hz, 1H),
3.42–3.36 (m, 1H), 3.15 (dd, JHH = 12.9, JHH = 6.3 Hz, 1H), 2.88–2.85 (m, 3H), 2.66 (dd, 2JHH = 9.7,
2
3
3JHH = 6.3 Hz, 1H). C{1H} NMR (126 MHz, CDCl3): δ 172.8, 138.0, 135.6, 128.6 (2C), 128.5 (2C),
13
1
3
128.4 (2C), 128.3, 128.1 (2C), 127.3, 127.2 (q, JCF = 277.3 Hz), 67.2, 59.1, 56.8, 53.2 (q, JCF = 2.5
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Hz), 44.35 (q, 2JCF = 28.2 Hz), 43.8 (q, 3JCF = 2.1 Hz). 19F NMR (471 MHz, CDCl3): δ –70.56 (d, 3JHH
=
1
2
3
+
9.5 Hz). HRMS-ESI (m/z) [M+H] + calculated for C20H21NO2F3 364.1524, found 364.1528.
4
5
6
7
8
9
(trans)-Benzyl 1-benzyl-4-((diisopropoxyphosphoryl)difluoromethyl)pyrrolidine-3-carboxylate (20).
Compound 20 was obtained, in accordance with procedure, from 16 (0.10 g, 0.27 mmol), 1 (0.1 mL,
0.53 mmol) and Eosin Y (0.01 g, 0.02 mmol). The crude residue was purified by chromatography:
eluent 85:15 pentane/acetone to give a colorless oil (0.12 g, 87%). 1H NMR (500 MHz, CDCl3): δ 7.36–
7.24 (m, 10H), 5.20 (d, 2JHH = 12.4 Hz, 1H), 5.11 (d, 2JHH = 12.4 Hz, 1H), 4.83–4.81 (m, 2H), 3.65 (d,
2JHH = 13.0 Hz, 1H), 3.55 (d, 2JHH = 13.0 Hz, 1H), 3.52–3.43 (m, 1H) 3.38–3.35 (m, 1H), 2.99 (dd, 2JHH
= 9.5 Hz, 3JHH = 9.1 Hz, 1H), 2.92 (dd, 2JHH = 9.5 Hz, 3JHH = 4.6 Hz 1H), 2.73–2.67 (m, 2H), 1.39–1.28
(m, 12H). 13C{1H} NMR (126 MHz, CDCl3) : δ 173.2, 138.4, 135.9, 128.6 (2C), 128.6 (2C), 128.3
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11
12
13
14
15
16
17
18
19
20
21
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23
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31
32
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34
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59
60
2
(2C), 128.2, 128.0 (2C), 127.1, 119.9 (dt, 1JCF = 267.5 Hz, 1JCP = 215.5 Hz), 73.8 (d, JCP = 5.6 Hz) ,
2
3
73.8 (d, JCP = 5.6 Hz), 66.8, 59.3, 57.1, 53.5–53.7 (m), 44.1–44.3 (m), 43.1–43.2 (m), 24.2 (d, JCP
=
3
3
3
19
3.5 Hz), 24.1 (d, JCP = 3.5 Hz), 23.7 (d, JCP = 5.0 Hz), 23.6 (d, JCP = 5.0 Hz). F NMR (471 MHz,
CDCl3): δ –113.82 (ddd, 2JFF = 299.5, 2JFP = 108.8 Hz, 3JFH = 15.3 Hz), –117.50 (ddd, 2JFF = 299.5 Hz,
2JFP = 106.9 Hz, 3JFH = 20.5 Hz). 31P NMR (202 MHz, CDCl3): δ 4.54 (t, 2JFP = 108.0 Hz). HRMS-ESI
(m/z) [M+H] + calculated for C26H34NO5F2P+ 510.2221, found 510.2215.
(trans)-Diisopropyl ((-1-benzyl-4-nitropyrrolidin-3-yl)difluoromethyl)phosphonate (21). Compound 21
was obtained, in accordance with general procedure, 17 (0.10 g, 0.35 mmol), 1 (0.18 mL, 0.70 mmol)
and Eosin Y (0.01 g, 0.02 mmol). The crude residue was purified by chromatography: eluent (70:30)
pentane/acetone to give a colorless oil (0.13 g, 87%). 1H NMR (500 MHz, CDCl3): δ 7.34–7.26 (m, 5H),
5.17–5.14 (m, 1H), 4.85 (dsept, 3JHP = 3JHH = 6.2 Hz, 2H), 3.93–3.86 (m, 1H), 3.67 (d, 2JHH = 13.1 Hz,
2
2
2
3
1H), 3.60 (d, JHH = 13.1 Hz, 1H), 3.42 (d, JHH = 11.1 Hz, 1H), 3.23 (dd, JHH = JHH = 8.9 Hz, 1H),
2.79 (dd, 2JHH = 11.1 Hz, 3JHH = 7.0 Hz, 1H), 2.59 (dd, 2JHH = 3JHH = 8.9 Hz, 1H), 1.58–1.33 (m, 12H).
13C{1H} NMR (126 MHz, CDCl3): δ 137.5, 128.5 (2C), 128.5 (2C), 127.5, 118.4 (dt, 1JCF = 264.3 Hz,
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2
2
1JCP = 220.5 Hz) 84.0, 74.5 (d, JCP = 7.1 Hz), 74.4 (d, JCP = 7.1 Hz), 58.9, 58.8, 52.7 (m), 46.2 (m),
1
2
3
24.1 (d, 3JCP = 3.5 Hz), 24.0 (d, 3JCP = 3.5 Hz), 23.7 (d, 3JCP = 3.5 Hz), 23.7 (d, 3JCP = 3.5 Hz). 19F NMR
4
5
6
2
2
3
(471 MHz, CDCl3): δ –115.11 (ddd, JFF = 303.1 Hz, JFP = 106.2 Hz, JFH = 17.5 Hz), –115.73 (ddd,
2
3
31
2
2JFF = 303.1 Hz, JFP = 103.2 Hz, JFH = 17.5 Hz). P{1H} NMR (202 MHz, CDCl3): δ 3.63 (t, JPF
=
7
8
9
104.8 Hz). HRMS-ESI (m/z) [M+H] + calculated for C18H28N2O5F2P+ 421.1704, found 421.1704.
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17
18
19
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Ethyl -1-benzyl-4-((diisopropoxyphosphoryl)difluoromethyl)-3-fluoropyrrolidine-3-carboxylate (22). A
9:1 ratio of (trans/cis) compound 22 was obtained, in accordance with general procedure, from 18 (0.13
g, 0.39 mmol), 1 (0.2 mL, 0.78 mmol) and Eosin Y (0.01 g, 0.02 mmol). The crude residue was purified
by chromatography: eluent 80:20 pentane/acetone to give a trans 22 contaminated with cis isomer as
1
colorless oil (0.13 g, 70%). (trans) isomer: H NMR (500 MHz, CDCl3): δ 7.36–7.25 (m, 5H), 4.82
(dsept, 3JHP = 3JHH = 6.2 Hz, 2H), 4.35–4.22 (m, 2H), 3.76 (d, 2JHH = 12.8 Hz, 1H), 3.64 (d, 2JHH = 12.8
3
2
Hz, 1H), 3.45–3.25 (m, 3H), 3.00 (dd, JHF = 26.8 Hz, JHH = 11.6 Hz, 1H), 2.64–2.61 (m, 1H), 1.37–
1.30 (m, 15H). 13C{1H} NMR (126 MHz, CDCl3): δ 168.6 (d, 2JCF = 28.5 Hz), 137.8, 128.7 (2C), 128.4
1
2
(2C), 127.3, 115.8 (dt, 1JCF = 228.1 Hz, 1JCP = 189.0 Hz), 98.5 (d, JCF = 197.1 Hz) 74.3 (d, JCP = 7.1
Hz) , 74.3 (d, 2JCP = 7.1 Hz), 63.4 (d, 2JCF = 23.8 Hz), 62.3, 59.7, 54.1, 29.7, 24.1 (d, 3JCP = 3.5 Hz), 24.1
(d, 3JCP = 3.5 Hz), 23.7 (d, 3JCP = 5.0 Hz), 23.6 (d, 3JCP = 5.0 Hz), 13.9. 19F NMR (471 MHz, CDCl3): δ
2
2
2
2
3
–109.40 (dd, JFF = 303.7, JFP = 103.4 Hz), –118.87 (ddd, JFF = 303.7, JFP = 108.6 Hz, JFH = 31.0
3
3
3
31
Hz), –140.96 (ddd appears q, JFH = JFH = JFH = 25.8 Hz). P{1H} NMR (202 MHz, CDCl3): δ 3.53
2
+
(t, JPF = 106.4 Hz). HRMS-ESI (m/z) [M+H] calculated for C21H32NO5F3P+ 466.1970, found
466.1964. (cis) isomer visible on 19F spectra: 19F NMR (376 MHz, CDCl3): δ –112.07 (ddd, 2JFF = 309.8
Hz, 2JFP =102.8, 4JFF =11.6 Hz), –116.77 (dddd appears ddt, 2JFF = 309.8 Hz, 2JFP = 106.8, 3JFH = 4JFF =
3
3
4
3
4
28.4 Hz), –166.27 (ddddd appears quintd, JFH = JFH = JFF = 28.4 Hz, JFH = 25,4 Hz, JFF =11.6 Hz
Hz).
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ethyl 1-benzylpyrrolidine-3-carboxylate (28). Compound 28 was obtained, in accordance with general
procedure, from ethyl acrylate 23 (0.10 g, 1.0 mmol), 1 (0.51 mL, 2.0 mmol) and Eosin Y (0.028 g, 0.04
mmol). The crude residue was purified by chromatography: eluent (80:20) pentane/AcOEt to give a
colorless oil (0.145 g, 62%). 1H NMR (500 MHz, CDCl3): δ 7.34–7.12 (m, 5H), 4.15 (q, 3JHH = 7.1 Hz,
2H), 3.65 (d, 2JHH = 12.9 Hz, 1H), 3.63 (d, 2JHH = 12.9 Hz, 1H), 3.07–2.99 (m, 1H), 2.92 (dd, 2JHH = 9.3
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
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28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
3
2
3
Hz, JHH = 8.6 Hz, 1H), 2.75–2.71 (m, 1H), 2.62 (dd, JHH = 9.3 Hz, JHH = 7.5 Hz, 1H), 2.52 (ddd
3
appears q, 2JHH = JHH = 3JHH = 7.7 Hz, 1H), 2.15–2.05 (m, 2H), 1.27 (t, 3JHH = 7.1 Hz, 3H).
NMR data are in agreement with those reported in the literature.9a
2-benzyl-5-phenyl-1,3,3a,6a-tetrahydropyrrolo[3,4-c]pyrrole-4,6-dione (29). Compound 29 was
obtained, in accordance with general procedure, from N-phenylmaleimide 24 (0.1 g, 0.58 mmol), 1
(0.30 mL, 1.16 mmol) and Eosin Y (0.016 g, 0.02 mmol). The crude residue was purified by
chromatography: eluent (60:40) pentane/AcOEt then recrystallized in (90:10) pentane/EtOH to give
1
white powder (0.18 g, 70%). H NMR (500 MHz, CDCl3): δ 7.45–7.15 (m, 10H), 3.57 (s, 1H), 3.39–
3.22 (m, 4H), 2.45–2.37 (m, 2H). NMR data are in agreement with those reported in the literature.5
(3aS,8bS)-2-benzyl-8b-nitro-4-(p-tolylsulfonyl)-3,3a-dihydro-1H-pyrrolo[3,4-b]indole (30). Compound
30 was obtained, in accordance with general procedure, from 3-nitro-1-(p-tolylsulfonyl)indole 25 (0.05
g, 0.16 mmol), 1 (0.08 mL, 0.32 mmol) and Eosin Y (0.004 g, 0.006 mmol). The crude residue was
1
purified by chromatography: eluent (80:20) pentane/AcOEt to give a white solid (0.065 g, 92%). H
3
NMR (500 MHz, CDCl3): δ 7.82–6.80 (m, 13H), 5.23 (dd, JHH = 6.5 Hz, 3JHH = 4.4, Hz, 1H), 3.53 (s,
2
2H), 3.45–3.35 (m, 1H), 3.32–3.21 (m, 1H), 2.97 (d, JHH = 10.4 Hz, 1H), 2.94–2.85 (m, 2H), 2.28 (s,
3H). NMR data are in agreement with those reported in the literature.9b
3-benzyl-5-phenyl-oxazolidine (31). Compound 31 was obtained, in accordance with general procedure,
from benzaldehyde 26 (0.05 g, 0.47 mmol), 1 (0.24 mL, 0.94 mmol) and Eosin Y (0.013 g, 0.02 mmol).
The crude residue was purified by chromatography: eluent (80:20) pentane/AcOEt to give a colorless oil
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1
3
(0.09 g, 78%). H NMR (500 MHz, CDCl3): δ 7.40–7.27 (m, 10H), 5.08 (dd appears t, JHH = 7.3 Hz,
1
2
3
2
3
2
1H), 4.64–4.61 (m, 2H), 3.85 (s, 2H), 3.45 (dd, JHH = 11.4 Hz, JHH = 6.7 Hz, 1H), 2.85 (dd, JHH
=
4
5
6
11.4 Hz, 3JHH = 7.9 Hz, 1H). NMR data are in agreement with those reported in the literature.9c
7
8
9
1-Benzyl-4-phenyl-3-tosylimidazolidine (32a). Compound 32a was obtained, in accordance with general
procedure, from N-benzylidene-4-methyl-benzenesulfonamide 27a (0.3 g, 1.16 mmol), 1 (0.591 mL,
2.31 mmol) and Eosin Y (0.032 g, 0.05 mmol). The crude residue was purified by chromatography:
eluent (90:10) pentane/AcOEt to give a yellow oil (0.27 g, 60%). 1H NMR (500 MHz, CDCl3): δ 7.62–
7.61 (m, 2 H), 7.36–7.22 (m, 10H), 7.15–7.13 (m, 2H), 4.75 (dd appears t, 3JHH = 7.5 Hz, 1H), 4.43 (d,
2JHH = 8.3 Hz, 1H), 4.09 (d, 2JHH = 8.3 Hz, 1H), 3.58 (d, 2JHH = 13.2 Hz, 1H), 3.41 (d, 2JHH = 13.2 Hz, 1
H), 3.27 (dd, 2JHH = 10.4 Hz, , 3JHH = 7.1 Hz, 1H), 2.67 (dd, 2JHH = 10.4 Hz, 3JHH = 7.8 Hz, 1H), 2.44 (s,
3 H). NMR data are in agreement with those reported in the literature.9d
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1-Benzyl-3-tert-butylsulfinyl-4-phenyl-imidazolidine (32b). Compound 32b was obtained, in accordance
with general procedure, from N-benzylidene-2-methyl-propane-2-sulfonamide 27b (0.09 g, 0.43 mmol),
1 (0.22 mL, 0.86 mmol) and Eosin Y (0.012 g, 0.017 mmol). The crude residue was purified by
1
chromatography: eluent (90:10) pentane/AcOEt to give a colorless oil (0.95 g, 65%). H NMR (500
MHz, CDCl3): δ 7.69–6.72 (m, 10H), 5.02 (t, 3JHH = 7.4 Hz, 1H), 4.27 and 4.19 (AB system, 2JHH = 9.1
2
2
Hz, 2H), 3.73 and 3.63 (AB system, JHH = 13.0 Hz, 2H), 3.38–3.33 (m, 1H), 2.65 (dd, JHH = 10.7,
3JHH =7.4 Hz, 1H), 0.94 (s, 9H). NMR data are in agreement with those reported in the literature.9e
ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the ACS Publications website.
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NMR spectra (1H, C, and F, or P) for all new compounds. NMR HOESY spectra for compounds
10-12-18. UV-Vis and fluorescence spectra (PDF).
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The Journal of Organic Chemistry
AUTHOR INFORMATION
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Corresponding Author
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* Thierry.Lequeux@ensicaen.fr
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ACKNOWLEDGMENTS
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This work was supported by the excellence laboratory LabEx SYNORG (ANR-11-LABX-0029), the
Conseil Régional de Normandie and the European FEDER funding. Dr S. Lakhdar is acknowledged for
the helpful discussion to establish the proposed redox mechanisms.
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