Ol9b02887 Si 001 PDF

Supporting Information
A Unified Strategy for the Synthesis of Difluoromethyl- and

Vinylfluoride-containing Scaffolds
Nicolas Duchemin,[a] Roberto Buccafusca,[a] Marc Daumas,[b] Vincent Ferey[c] and

Stellios Arseniyadis[a],*
aQueen Mary University of London, School of Biological and Chemical Sciences. Mile End Road, E1 4NS, London (United Kingdom)
bSanofi Chimie, Route d’Avignon, 30390, Aramon (France)
cSanofi R&D, 371 rue du Professeur Blayac, 34080 Montpellier (France)
S1
Table of content
Material and methods S3
List of compounds S4
Experimental and Spectral data S7
I. Synthesis of S-(difluoromethyl)-S-phenyl-N-tosylsulfoximine (I) S7
II. Optimization S10
III. Synthesis of the precursors

General procedure 1 & 2 S18
IV. Synthesis of difluoromethylated compounds

General procedure 3, 4 & 5 S95
Krapcho decarboxylation dehydrofluorination S139
IV. Post-functionalizations S289
V. NMR Experiments S295
S2
Materials and Methods
The reactions were run under argon atmosphere in oven-dried glassware unless otherwise
specified. All commercially available compounds were purchased from Sigma Aldrich, Acros
Organics, Fluorochem, TCI Chemicals or Alfa Aesar, and used as received. Reactions ran at
temperatures were conducted in sealed microwave tubes in an acetone bath which
temperature was controlled by a cryostat. Analytical thin layer chromatography (TLC) was
performed on silica gel plates (Merck 60F254) visualized either with a UV lamp (254 nm) or
by using solutions or KMnO4/K2CO3/AcOH in water followed by heating. Flash
chromatographies were performed on silica gel (60-230 mesh). Organic extracts were dried
over anhydrous Na2SO4 or MgSO4. 1H NMR spectra were recorded on a Bruker AVANCE 400
at 400 MHz in CDCl3 and the observed signals are reported as follows: chemical shift in parts
per million from tetramethylsilane with the solvent as an internal indicator (CDCl 3
δ 7.26 ppm), multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, p = pentet,
m = multiplet or overlap of nonequivalent resonances, br = broad), integration. 13C NMR
spectra were recorded at 100 MHz in CDCl3 and the observed signals were reported as
follows: chemical shift in parts per million from tetramethylsilane with the solvent as an
internal indicator (CDCl3  77.0 ppm). Coupling constants, J, are reported in Hertz (Hz).
19F NMR spectra were recorded on a Bruker AVANCE 400 at 376.5 MHz in CDCl 3 and the
observed signals are reported as follows: chemical shift in parts per million (calibrated from
the 1H NMR spectra), multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, p = pentet,
m = multiplet or overlap of nonequivalent resonances, br = broad), integration. All NMR
spectra were obtained at rt. Mass spectra (MS) were recorded using a Waters HDMS Synapt
G2Si Mass spectrometer.
S3
List of compounds
S4
S5
S6
Experimental and Spectral data
I. Synthesis of S-(difluoromethyl)-S-phenyl-N-tosylsulfoximine (I)
Difluoromethylphenyl sulfide (i)
C7H6F2S (MW = 160.18 g.mol-1)
Synthesized following a procedure reported by Carbonnel and co-workers.1 An oven-dried

500 mL round-bottom flask was charged with sodium chlorodifluoroacetate (15.2 g,
100 mmol, 2 equiv.) and potassium carbonate (10.4 g, 75 mmol, 1.5 equiv.) and dried under
high vacuum for 1 h. DMF (160 mL) was then added followed by thiophenol (5.13 mL,
50 mmol, 1 equiv.). The resulting suspension was stirred at 95 °C for 15 min and allowed to
cool down to rt. H2O (160 mL) and pentane (160 mL) were then added and the resulting
biphasic solution was vigorously stirred for 5 min. The resulting organic layer was washed
with H2O (4 x 100 mL), dried over anhydrous MgSO4 and concentrated under reduced
pressure. The desired product was obtained as a colorless oil (5.5 g, 69%) and used in the
next step without further purification. The data were in accordance with the ones reported
in the literature.1
1H NMR (CDCl3, 400 MHz):  7.51-7.49 (dd, J = 7.9, 1.7 Hz, 2H), 7.34-7.29 (m, 3H), 6.74
(t, J = 57.0 Hz).
13C NMR (CDCl3, 100 MHz):  135.3, 129.8, 129.3, 126.1 (t, J = 3.0 Hz), 121.0 (t, J = 275.0 Hz).
19F NMR (CDCl3, 376.5 MHz):  –91.36 (d, J = 56.9 Hz, 2F).
1
Carbonnel, E.; Besset, T.; Poisson, T.; Labar, D.; Pannecoucke, X.; Jubault, P. Chem. Commun. 2017, 53, 5706-
5709.
S7
(Difluoromethyl)(imino)(phenyl)-6-sulfanone (ii)
C7H7F2NOS (MW = 191.20 g.mol-1)
Synthesized following a procedure reported by Chaabouni and co-workers.2 An oven-dried

round-bottom flask was successively charged with difluoromethylphenyl sulfide (i) (1g,
6.24 mmol), methanol (16 mL), ammonium carbamate (730 mg, 9.36 mmol, 1.5 equiv.) and
(diacetoxyiodo)benzene (4.2 g, 13.1 mmol, 2.1 equiv.). The resulting mixture was stirred at rt
overnight after which 1 equiv. of ammonium carbamate and 1 equiv. of
(diacetoxyiodo)benzene were added. The reaction was stirred for three more hours and the
resulting mixture was concentrated under reduced pressure and purified by flash column
chromatography over silica gel eluting with PE/EA (8:2) to afford the desired product as a
yellow oil (888 mg, 74%). The data were in accordance with the ones reported in the
literature.2
1H NMR (CDCl3, 400 MHz):  8.08 (dd, J = 7.9, 1.5 Hz, 2H), 7.74 (m, 1H), 7.62 (dd, J = 8.4,
7.3 Hz, 2H), 6.14 (t, J = 54.8 Hz, 1H), 3.36 (brs, 1H).
13C NMR (CDCl3, 100 MHz):  134.9, 133.2, 130.5, 129.4, 115.3 (t, J = 287.2 Hz).
19F NMR (CDCl3, 376.5 MHz):  –118.86 (dd, J = 258.5, 54.8 Hz, 1F), –121.9 (dd, J = 258.6,
54.8 Hz, 1F).
2
Chaabouni, S.; Lohier, J.-F.; Barthelemy, A.-L.; Glachet, T.; Anselmi, E.; Dagousset, G.; Diter, P.; Pegot, B.;
Magnier, E.; Reboul, V. Chem. Eur. J. 2018, 64, 17006-17010.
S8
S-(Difluoromethyl)-S-phenyl-N-tosylsulfoximine (iii or I)
C14H13F2NO3 (MW = 345.38 g.mol-1)
Synthesized following a modified procedure reported by Pegot and co-workers.3 In an

oven-dried 100 mL round-bottom flask was dissolved (difluoromethyl)(imino)
(phenyl)-6-sulfanone (ii) (888 mg, 4.64 mmol) in pyridine (1.13 mL, 13.9 mmol, 3.0 equiv.)
and dry DCM (10 mL) at rt under argon. Tosyl chloride (1.33 g, 6.97 mmol, 1.5 equiv.) was
added to the resulting solution which was then heated under reflux overnight. The reaction
mixture was then cooled to 0 °C and quenched with a 1M aqueous solution of HCl (30 mL).
The aqueous phase was extracted with DCM (3 x 10 mL) and the combined organic phases
were dried over anhydrous MgSO4 and concentrated under reduced pressure. The resulting
crude residue was purified by flash column chromatography over silica gel eluting with
PE/DCM (1:1) to afford the desired product as an off-white solid (856 mg, 54%). The data
were in accordance with the ones reported in the literature.3
1H NMR (CDCl3, 400 MHz):  8.06-8.03 (m, 2H), 7.93-7.90 (m, 2H), 7.81 (m, 1H), 7.65 (m,
2H), 7.31 (d, J = 7 Hz, 2H), 7.16 (dd, J = 53.7, 53.5 Hz, 1H), 2.42 (s, 3H).
13C NMR (CDCl3, 100 MHz):  143.7, 139.5, 136.2, 130.8, 129.7, 129.5, 128.0, 126.9, 115.4
(dd, J = 293.1, 291.6), 21.6.
55.3 Hz, 1F).
3
Pegot, B.; Urban, C.; Bourne, A.; Le, T. N.; Bouvet, S.; Marrot, J.; Diter, P.; Magnier, E. Eur. J. Org. Chem. 2015,
3069-3075.
S9
II. Optimization
tert-Butyl 2-oxopiperidine-1-carboxylate (iv)
C10H17NO3 (MW = 199.25 g.mol-1)
Synthesized following a procedure reported by Garnier and co-workers.4 An oven-dried

500 mL round-bottom flask was successively charged with piperidin-2-one (1.5 g, 15.1 mmol)
and dissolved in 150 mL dry THF. The reaction mixture was cooled down to
–78 °C and n-BuLi (2.5 M in hexanes, 5.9 mL, 14.65 mmol, 0.97 equiv.) was added over 5 min.
The resulting mixture was stirred at this temperature for 10 min and a solution of di-tert-
butyl decarbonate (4.96 g, 22.65 mmol, 1.5 equiv.) in dry THF (10 mL) was added. After
45 min, TLC showed complete conversion of the starting material and the reaction mixture
was allowed to warm up to 0 °C and quenched with a saturated aqueous solution of NH4Cl
(50 mL). The aqueous phase was extracted with ethyl acetate (3 x 50 mL). The combined
organic phases were washed with a saturated aqueous solution of brine, dried over
anhydrous MgSO4 and concentrated under reduced pressure. The resulting crude was
purified by flash column chromatography over silica gel eluting with a PE/EA gradient (8:2 to
1:1) to afford the desired product as a colorless oil (2.92 g, 97%). The data were in
accordance with the ones reported in the literature.4
1H NMR (CDCl3, 400 MHz):  3.62 (ddd, J = 6.2, 4.4, 1.4 Hz, 2H), 2.49-2.46 (m, 2H), 1.81-1.78
(m, 4H), 1.50 (s, 9H).
13C NMR (CDCl3, 100 MHz)  171.3, 152.7, 82.8, 46.3, 34.9, 28.0, 22.3, 20.5.
4
Garnier, E.; Liebeskind, L. S. J. Am. Chem. Soc. 2008, 130, 7449-7458.
S10
1-(tert-Butyl) 3-methyl 2-oxopiperidine-1,3-dicarboxylate (v or 1)
C12H19NO5 (MW = 257.29 g.mol-1)
Synthesized following a slightly modified procedure reported by Cossy and co-workers.5 An

oven-dried 50 mL round-bottom flask was charged with tert-butyl
2-oxopiperidine-1-carboxylate (iv) (1.0 g, 5.02 mmol) and 4.5 mL dry THF. The reaction
mixture was cooled down to –78 °C and LiHMDS (1.0 M in THF, 10.5 mL, 10.5 mmol,
2.1 equiv.) was added. The resulting mixture was stirred at this temperature for 10 min and
a methyl chloroformate (386 L, 5.02 mmol, 1.0 equiv.) was slowly added. After 1 h, TLC
showed complete conversion of the starting material and the reaction mixture was allowed
to warm to 0 °C and quenched with a saturated aqueous solution of NH4Cl solution (10 mL).
The aqueous phase was extracted with ethyl acetate (3 x 20 mL) and DCM (1 x 20 mL). The
combined organic phases were dried over anhydrous MgSO4 and concentrated under
reduced pressure. The resulting crude was purified by flash column chromatography over
silica gel eluting with a PE/EA gradient (85:15 to 7:3) to afford the desired product as an off-
white wax (1.23 g, 95%). The data were in accordance with the ones reported in the
literature.5
1H NMR (CDCl3, 400 MHz):  3.76 (s, 3H), 3.70-3.66 (m, 2H), 3.52 (dd, J = 8.9, 6.8 Hz, 1H),
2.22-2.04 (m, 2H), 1.96 (m, 1H), 1.8 (m, 1H), 1.51 (s, 9H).
13C NMR (CDCl3, 100 MHz)  170.3, 167.3, 152.6, 83.4, 52.6, 51.3, 45.8, 28.0, 24.2, 21.0.
5
Cossy, J.; Mirguet, O.; Gomez Pardo, D.; Desmurs, J.-R. New. J. Chem. 2003, 475-482.
S11
1-(tert-Butyl) 3-methyl 3-(difluoromethyl)-2-oxopiperidine-1,3-dicarboxylate (vi or 2)
C13H19F2NO5 (MW = 307.29 g.mol-1)
Synthesized following various C-difluoromethylation procedures (cf optimization study).

Purification by flash column chromatography over silica gel eluting with a PE/EA gradient
(9:1 to 8:2) afforded the desired product as a pale yellow oil (1.23 g, 78%).
RF = 0.4 (PE/EA 8:2)
1H NMR (CDCl3, 400 MHz):  6.51 (t, J = 55.6 Hz), 3.81 (s, 3H), 3.74 (dddd, J = 13.0, 5.9, 4.4,
1.3 Hz, 1H), 3.65 (ddd, J = 13.0, 9.1, 4.2 Hz, 1H), 2.29 (dddd, J = 14.1, 6.0, 4.5, 1.3 Hz, 1H),
2.18 (ddd, J = 14.1, 10.1, 4.6 Hz, 1H), 2.11 (m, 1H), 1.96 (m, 1H), 1.52 (s, 9H).
13C NMR (CDCl3, 100 MHz):  167.9 (d, J = 11.0 Hz), 164.8 (d, J = 8.3 Hz), 152.0, 115.7
(t, J = 246.2 Hz), 84.0, 60.0 (t, J = 22.9 Hz), 53.4, 46.0, 27.9, 22.8, 20.1.
55.6 Hz, 1F).
HRMS: m/z calcd for C13H19F2NO5, [M+Na]: 330.1124, found: 330.1123.
S12
1-(tert-Butyl) 3-methyl 3-(difluoromethyl)-2-oxopiperidine-1,3-dicarboxylate (vi or 2)
S13
S14
Complete conditions screening
An oven-dried microwave tube was charged with lactam (v or 1) (0.1 mmol, 1.0 equiv.) and
solvent. The resulting solution was cooled down to the chosen temperature and the base
was added. The resulting colored solution was stirred at this temperature for 30 min and I
was then added. The reaction was stopped after 12 h with the addition of H2O (5 mL). The
aqueous layer was extracted with ethyl acetate and the combined organic phases were dried
over anhydrous MgSO4. The resulting crude was dissolved in CDCl3 (2 mL) and dibromethane
(3.5 µL, 0.05 mmol) was added as an internal standard. The yield, conversion and
consumption of reagent I were deduced from 1H NMR analysis as exemplified below.
CH 2Br 2
O
CHF 2
Boc
N CO 2Me
S15
Base screening
Concentration and stoichiometry screening
S16
Solvent and temperature screening
S17
III. Synthesis of the precursors (vii to li)
General Procedure 1: C-acylation of lactams / lactones
An oven-dried round-bottom flask was charged with the lactam / lactone (1.0 equiv.) and dry
THF (0.1 M to 1M). The resulting solution was allowed to cool down to –78 °C and base
(LiHMDS/NaHMDS) (2.1 equiv.) was added. The resulting colored solution was stirred at this
temperature for 15 min and the desired chloroformate (1.0 equiv.) was slowly added and
the reaction mixture was stirred at –78 °C. Upon completion, the reaction was stopped by
the addition of a saturated aqueous solution of NH4Cl. The aqueous layer was extracted with
ethyl acetate and the combined organic phases were dried over anhydrous MgSO4 and
purified by flash column chromatography over silica gel.
General Procedure 2: Alkylation of allyl 3-(methoxy(methyl)amino)-3-oxopropanoate
To a stirred solution of allyl 3-[methoxy(methyl)amino]-3-oxopropanoate (187 mg,

1.0 mmol) in dry THF (12 mL) was added potassium tert-butoxide (125 mg, 1.11 mmol,
1.11 equiv.) in one portion at rt. Upon complete dissolution of potassium tert-butoxide, the
chosen alkyl halide (1.11 mmol, 1.11 equiv.) was added dropwise. Once completion was
achieved (accompanied by the formation of a white precipitate), the reaction mixture was
quenched with a saturated aqueous solution of NH4Cl. The resulting aqueous mixture was
extracted with ethyl acetate (3 x 10 mL) and the combined organic phases were dried over
anhydrous MgSO4 and concentrated under reduced pressure. The resulting crude residue
was purified by flash column chromatography over silica gel.
S18
1-Benzylpiperidin-2-one (vii)
C12H15NO (MW = 189.26 g.mol-1)
Synthesized following a procedure reported by Cossy and co-workers.6 In a 500 mL oven-

dried round bottom flask, to a stirred solution of n-BuLi (2.5 M in hexanes) (18.7 mL,
46.7 mmol, 1.13 equiv.) in dry THF (140 mL) at –78 °C was cannulated a solution of piperidin-
2-one (4.1 g, 41.4 mmol, 1 equiv.) in dry THF (40 mL). After 20 min, benzyl bromide (4.93 mL,
41.3 mmol, 1 equiv.) was slowly added to the reaction mixture. The resulting solution was
allowed to warm up to room temperature overnight and consequently quenched with a
saturated aqueous solution of NH4Cl. The aqueous phase was extracted with diethyl ether
(3 x 50 mL). The combined organic phases were washed with a saturated aqueous solution
of brine, dried over anhydrous MgSO4 and concentrated under reduced pressure. The
resulting crude was purified by flash column chromatography over silica gel eluting with a
toluene/acetone gradient (95:5 to 80:20) to afford the desired product as a colorless oil
(2.24 g, 30%). The data were in accordance with the ones reported in the literature.6
1H NMR (CDCl3, 400 MHz):  7.34-7.23 (m, 5H), 4.60 (s, 2H), 3.21-3.18 (m, 2H), 2.47
(t, J = 6.3 Hz, 2H), 1.82-1.73 (m, 4H).
13C NMR (CDCl3, 100 MHz):  169.9, 137.3, 128.6, 128.1, 127.3, 50.1, 47.3, 32.4, 23.2, 21.4.
6
Cossy, J.; de Filippis, A.; Gomez-Pardo, D. Org. Lett. 2003, 5, 3037-3039.
S19
1-Benzylpiperidine-2,6-dione (viii)
C12H13NO2 (MW = 203.29 g.mol-1)
Synthesized following a procedure reported by Song and co-workers. 7 An oven-dried round

bottom flask was charged with glutaramide (2.26 g, 20 mmol) and K2CO3 (3.32 g, 24 mmol,
1.2 mmol) and dried under high vacuum for one hour after which the solids were dissolved
with dry acetone (40 mL). Benzyl bromide (2.6 mL, 22 mmol, 1.1 equiv.) was then added and
the reaction mixture was refluxed for 3 h. The resulting solution was then allowed to cool
down to rt, filtered and concentrated under reduced pressure. The desired product was
obtained as a colorless oil and used in the next step without further purification (3.87 g,
95%). The data were in accordance with the ones reported in the literature.7
1H NMR (CDCl3, 400 MHz):  7.35-7.32 (m, 2H), 7.28-7.19 (m, 3H), 4.93 (s, 2H), 2.65
(t, J = 6.5 Hz, 4H), 1.91 (p, J = 6.7 Hz, 2H).
13C NMR (CDCl3, 100 MHz):  172.4, 137.3, 128.8, 128.4, 127.4, 42.7, 32.9, 17.1.
8-Benzyl-8-azaspiro[4.5]decane-7,9-dione (ix)
C16H19NO2 (MW = 257.33 g.mol-1)
Synthesized following a procedure reported by Song and co-workers.7 An oven-dried round

bottom flask was charged with 8-azaspiro[4.5]decane-7,9-dione (1.67 g, 10 mmol) and K2CO3
(1.66 g, 12 mmol, 1.2 mmol) and dried under high vacuum for one hour after which the
solids were dissolved with dry acetone (20 mL). Benzyl bromide (1.3 mL, 11.0 mmol,
1.1 equiv.) was then added and the reaction mixture was refluxed for 2 h. The resulting
7
Song, T.; Arseniyadis, S.; Cossy, J. Chem. Eur. J. 2018, 24, 8076-8080.
S20
solution was then allowed to cool down to rt, filtered and concentrated under reduced
pressure. The crude oil was purified by flash column chromatography over silica gel eluting
with PE/EA (8:2) to afford the desired product as a white crystalline solid (2.45 g, 96%). The
data were in accordance with the ones reported in the literature.8
1H NMR (CDCl3, 400 MHz):  7.35-7.32 (m, 2H), 7.30-7.21 (m, 3H), 4.95 (s, 2H), 2.61 (s, 4H),
1.71-1.67 (m, 4H), 1.49-1.46 (m, 4H).
13C NMR (CDCl3, 100 MHz):  172.1, 137.3, 128.6, 128.4, 127.4, 44.9, 42.7, 39.5, 37.6, 24.2.
1-Methyl-3,4-dihydroquinolin-2(1H)-one (x)
C10H11NO (MW = 161.20 g.mol-1)
In an oven-dried 50 mL round-bottom flask, 3,4-dihydroquinolin-2(1H)-one (2.0 g,

13.6 mmol) and K2CO3 (2.25 g, 16.30 mmol, 1.2 equiv.) were dissolved with DMF (8 mL).
To this suspension was added methyl iodide (1.7 mL, 27.18 mmol, 2 equiv.) and the resulting
solution was heated at 70 °C for 96 h after which it was allowed to cool down to rt and
quenched with H2O (10 mL). The resulting solution was extracted with ethyl acetate
(3 x 20 mL). The combined organic phases were washed with LiCl solution (1M)
(3 x 10 mL), dried over anhydrous MgSO4 and concentrated under reduced pressure. The
resulting crude oil was purified by flash column chromatography over silica gel eluting with
PE/EA (7:3) to afford the desired product as a beige wax (888 mg, 40%). The data were in
1H NMR (CDCl3, 400 MHz):  7.25 (m, 1H), 7.17 (dd, J = 7.3, 1.4 Hz, 1H), 7.03-6.97 (m, 2H),
3.36 (s, 3H), 2.91 (dd, J = 8.6, 6.1 Hz, 2H), 2.67-2.63 (m, 2H).
8
Popovic-Djordjevic, J. B.; Klaus, A. S.; Zizak, Z. S.; Matic, I. Z.; Drakulic, B. J. J. Enzym. Med. Chem. 2016, 31,
915-923.
9
Liu, B.; Fan, Y.; Gao, Y.; Sun, C.; Xu, C.; Zhu, J. J. Am. Chem. Soc. 2013, 135, 468-473.
S21
13C NMR (CDCl3, 100 MHz):  170.5, 140.6, 127.7, 127.4, 126.2, 122.8, 114.7, 31.8, 29.5,
25.4.
1,3-Dibenzyldihydropyrimidine-2,4(1H,3H)-dione (xi)
C18H18N2O (MW = 294.35 g.mol-1)
In a 50 mL oven-dried round bottom flask, to a stirred suspension of dihydropyrimidine-

2,4(1H,3H)-dione (500 mg, 4.38 mmol) in dry DMF (12 mL) at 0 °C was carefully added
NaH (60 % wt in mineral oil, 386 mg, 9.64 mmol, 2.2 equiv.) in portions. After 30 min, benzyl
bromide (1.15 mL, 9.64 mmol, 2.2 equiv.) was slowly added to the reaction mixture. The
resulting solution was allowed to warm up to rt, stirred until TLC showed completion (2 h)
and quenched with HCl (1N, 10 mL). The aqueous phase was extracted with ethyl acetate
(3 x 20 mL). The combined organic phases were concentrated, dissolved in diethyl ether
(50 mL) and washed with a solution of LiCl (1N, 3 x 20 mL). The organic phase was dried over
was purified by flash column chromatography over silica gel eluting with a PE/EA gradient
(8:2 to 7:3) to afford the desired product as a colorless oil (1.04 g, 81%). The data were in
1H NMR (CDCl3, 400 MHz):  7.43-7.40 (m, 2H), 7.36-7.28 (m, 5H), 7.27-7.24 (m, 3H), 5.02
(s, 2H), 4.63 (s, 2H), 3.27 (t, J = 6.8 Hz, 2H), 2.68 (t, J = 6.9 Hz, 2H).
13C NMR (CDCl3, 100 MHz):  169.0, 153.9, 137.9, 136.4 128.8, 128.6, 128.4, 128.0, 127.9,
127.3, 51.7, 44.0, 40.3, 31.8.
10
Paryzek, Z.; Tabaczka, B. Org. Prep. Proced. Int. 2001, 33, 400-405.
S22
1-Benzylpyrrolidine-2,5-dione (xii)
C11H11NO2 (MW = 189.21 g.mol-1)
Synthesized following a procedure reported by Song and co-workers.7 An oven-dried round

bottom flask was charged with succinimide (1.98 g, 20.0 mmol) and K2CO3 (3.32 g,
24.0 mmol, 1.2 mmol) and dried under high vacuum for one hour after which the solids were
dissolved with dry acetone (40 mL). Benzyl bromide (2.6 mL, 22.0 mmol, 1.1 equiv.) was then
added and the reaction mixture was refluxed for 3 h. The resulting solution was then
allowed to cool down to rt, filtered and concentrated under reduced pressure. The desired
product was obtained as a white solid and used in the next step without further purification
(3.59 g, 94%). The data were in accordance with the ones reported in the literature.7
1H NMR (CDCl3, 400 MHz):  7.41-7.27 (m, 5H), 4.66 (s, 2H), 2.71 (s, 4H).
13C NMR (CDCl3, 100 MHz):  176.8, 135.8, 128.9, 128.6, 128.0, 42.4, 28.2.
tert-Butyl 2-oxoazetidine-1-carboxylate (xiii)
C8H13NO3 (MW = 171.20 g.mol-1)
Synthesized according to a procedure reported by Prasad and co-workers.11 In an oven-dried

100 mL round bottom flask, 2-azetidinone (400 mg, 5.63 mmol) and
4-dimethylaminopyridine (69 mg, 0.56 mmol, 0.1 equiv.) were dissolved in acetonitrile
(25 mL) and cooled down to 0 °C. A solution of di-tert-butyl decarbonate (1.4 g, 6.19 mmol,
1.1 equiv.) in acetonitrile (5 mL) was then added dropwise and the resulting solution was
allowed to warm up to rt and stirred for overnight. The reaction mixture was dissolved with
11
Prasad, G.; Amoroso, J. W.; Borketey, L. S.; Schnarr, N. A. Org. Biomol. Chem. 2012, 10, 1992-2002.
S23
ethyl acetate (50 mL) and washed with HCl (1 N, 20 mL) and a saturated aqueous solution of
(20 mL). The aqueous phase was then extracted with ethyl acetate (2 x 20 mL) and the
reduced pressure. The resulting crude residue was purified by flash column chromatography
over silica gel using a short column and eluting with PE/EA (7:3) to afford the desired
product as a colourless oil (900 mg, 93%). The data were in accordance with the ones
reported in the literature.11
1H NMR (CDCl3, 400 MHz):  3.56 (t, J = 5.1 Hz, 2H), 2.98 (t, J = 5.1 Hz, 2H), 1.52 (s, 9H).
13C NMR (CDCl3, 100 MHz):  164.6, 148.0, 83.2, 37.7, 36.1, 28.1.
1-Benzylazepan-2-one (xiv)
C13H17NO (MW = 203.29 g.mol-1)
Synthesized according to a procedure reported by Hu and co-workers.12 In an oven-dried

250 mL round bottom flask, sodium hydride (60% wt, 1.06 g, 26.6 mmol, 1.5 equiv.) was
suspended in dry THF (80 mL) and cooled down at 0 °C. A solution of aza-2-cycloheptanone
(2 g, 17.7 mmol) in dry THF was slowly added and the reaction mixture was stirred for
30 min at this temperature. Benzyl bromide (4.2 mL, 35.5 mmol, 2.0 equiv.) was then added
and the resulting solution was allowed to warm up to room temperature and stirred
overnight. The reaction was quenched by the dropwise addition of HCl (1 N, 10 mL). The
aqueous phase was then extracted with ethyl acetate (2 x 20 mL) and the combined organic
phases were dried over anhydrous MgSO4 and concentrated under reduced pressure. The
resulting crude residue was purified by flash column chromatography over silica gel eluting
with a PE/EA gradient (5:1 to 3:2) to afford the desired product as a colorless oil (3.57 g,
98%). The data were in accordance with the ones reported in the literature.12
12
Hu Jr., H.; Jagdmann, G. E.; Hughes, P. F.; Nichols, J. B. Tetrahedron Lett. 1995, 36, 3659-3662.
S24
1H NMR (CDCl3, 400 MHz):  7.33-7.25 (m, 5H), 4.58 (s, 2H), 3.30-3.26 (m, 2H), 2.62-2.59
(m, 2H), 1.69 (tt, J = 6.6, 2.5, 4H), 1.51-1.47 (m, 2H).
13C NMR (CDCl3, 100 MHz):  176.0, 137.9, 128.5, 128.2, 127.3, 51.1, 48.9, 37.2, 30.0, 28.1,
23.5.
1-(4-Methoxybenzoyl)-2-pyrrolidinone (xv)
C12H13NO3 (MW = 219.24 g.mol-1)
In an oven-dried 100 mL round bottom flask, 2-pyrrolidinone (1 g, 11.75 mmol) was

dissolved in dry DCM (30 mL). The resulting solution was cooled down at 0 °C and Et 3N
(2.46 mL, 17.6 mmol, 1.5 equiv.) and 4-methoxy-benzoyl chloride (1.91 mL, 14.10 mmol,
1.2 equiv.) were successively added. After 1 h stirring at 0 °C, the reaction was allowed to
warm to rt under continuous stirring and was stopped by addition of H2O (20 mL). The
aqueous phase was then extracted with ethyl acetate (2 x 20 mL) and the combined organic
phases were dried over anhydrous MgSO4 and concentrated under reduced pressure. The
with PE/EA (5:5) to afford the desired product as a colorless oil which was further purified by
recrystallization in MeOH (13 mL) to obtain a white solid (2.06 g, 80%). The data were in
1H NMR (CDCl3, 400 MHz):  7.64 (d, J = 8.8 Hz, 2H), 6.90 (d, J = 8.8 Hz, 2H), 3.94
(t, J = 7.1 Hz, 2H), 3.85 (s, 3H), 2.61 (t, J = 8.0 Hz, 2H), 2.17-2.09 (m, 2H).
13C NMR (CDCl3, 100 MHz):  174.6, 162.9, 131.7, 113.1, 55.4, 46.8, 33.5, 17.8.
13
Karimi, F.; Kihlberg, T.; Làngström, B. J. Chem. Soc., Perkin Trans. 1, 2001, 1528-1531.
S25
1-Methyl-3-phenylpyrrolidine-2,5-dione (xvi)
C12H13NO3 (MW = 219.24 g.mol-1)
Synthesized according to a procedure reported by Ji and co-workers.14 An oven-dried

Schlenk tube was charged with N-methyl maleimide (1 g, 9.0 mmol), phenyl boronic acid
(2.19 g, 18.0 mmol, 2 equiv.), palladium diacetate (101 mg, 0.45 mmol, 0.05 equiv.) and
4,4’-dipyridine (281 mg, 1.8 mmol, 0.2 equiv.). The solids were dissolved in a THF
(18 mL)/H2O (5.4 mL)/AcOH (9 mL) mixture and were stirred at 80 °C for 24 h after which
H2O (100 mL) was added and the resulting solution was neutralized with a saturated
aqueous solution of NaHCO3. The resulting solution was then extracted with
DCM (3 x 50 mL) and the combined organic phases were dried over anhydrous MgSO4 and
concentrated under reduced pressure. The resulting crude residue was purified by flash
column chromatography over silica gel eluting with PE/EA (7:3) to afford the desired product
as a white solid (1.39 g, 82%). The data were in accordance with the ones reported in the
literature.14
1H NMR (CDCl3, 400 MHz):  7.39-7.29 (m, 3H), 7.23-7.21 (m, 2H), 4.03 (dd, J = 9.5, 4.8 Hz,
1H), 3.21 (dd, J = 18.5, 9.5 Hz, 1H), 3.08 (s, 3H), 2.84 (dd, J = 18.5, 4.8 Hz, 1H).
13C NMR (CDCl3, 100 MHz):  177.8, 176.2, 137.1, 129.2, 128.0, 127.4, 46.0, 37.1, 25.2.
14
Ji, J.; Yang, Z.; Liu, R.; Ni, Y.; Lin, S.; Pan, Q. Tetrahedron Lett. 2016, 57, 2723-2726.
S26
(S)-5-{[(tert-Butyldiphenylsilyl)oxy]methyl}pyrrolidin-2-one (xvii)
C21H27NO2Si (MW = 353.54 g.mol-1)
In an oven-dried 100 mL round bottom flask, L-pyroglutaminol (2g, 17.37 mmol) and
imidazole (2.36 g, 34.7 mmol, 2 equiv.) were dissolved in dry DMF (20 mL). The resulting
solution was cooled down to 0 °C and TBDPSCl (4.52 mL, 17.37 mmol, 1.0 equiv.) was added.
The temperature was allowed to reach rt overnight. MTBE (100 mL) was then added and the
solution was washed with H2O (2 x 20 mL). The organic layer was dried over anhydrous
MgSO4 and concentrated under reduced pressure. The resulting crude residue was purified
by flash column chromatography over silica gel eluting with a PE/EA gradient (1:1 to 25:75)
to afford the desired product as a colorless oil (5.22 g, 85%). The data were in accordance
with the ones reported in the ones reported in the literature.15
1H NMR (CDCl3, 400 MHz):  7.64 (dq, J = 6.4, 1.4 Hz, 4H), 7.47-7.37 (m, 6H), 5.84 (brs, 1H),
3.80 (tddd, J = 7.8, 5.5, 3.9, 0.8 Hz, 1H), 3.63 (dd, J = 10.3, 4.0 Hz, 1H), 3.51 (dd, J = 10.3,
7.7 Hz, 1H), 2.33 (ddd, J = 8.2, 7.4, 1.7 Hz, 2H), 2.13 (m, 1H), 1.72 (dddd, J = 13.3, 9.2, 7.7,
5.5 Hz, 1H), 1.05 (s, 9H).
13C NMR (CDCl3, 100 MHz)  177.8, 135.5, 135.5, 133.0, 129.9, 129.9, 127.9, 127.9, 67.5,
55.6, 29.7, 26.8, 22.8, 19.2.
15
Szczesniak, P.; Stecko, S.; Maziarz, E.; Staszewaska-Krajewska, O.; Furman, B. J. Org. Chem. 2014, 79, 10487-
10503.
S27
tert-Butyl (S)-2-{[(tert-butyldiphenylsilyl)oxy]methyl}-5-oxopyrrolidine-1-carboxylate (xviii)
C26H35NO4Si (MW = 453.65 g.mol-1)
In an oven-dried 100 mL round bottom flask, to a solution of

(S)-5-{[(tert-butyldiphenylsilyl)oxy]methyl}pyrrolidin-2-one (xvii) (1.11 g, 3.14 mmol) was
sequentially added di-tert-butyl dicarbonate (754 mg, 3.45 mmol, 1.1 equiv.) and
4-(dimethylamino)-pyridine (38 mg, 0.31 mmol, 0.1 equiv.) at 0 °C. The resulting solution
was allowed to warm to 40 °C. Upon complete conversion of the starting material (reaction
monitored by TLC), the reaction mixture was concentrated and purified by flash column
chromatography over silica gel eluting with PE/EA (7:3) to afford the desired product as a
pale yellow oil (1.41 g, 99%). The data were in accordance with the ones reported in the
literature.16
1H NMR (CDCl3, 400 MHz):  7.65-7.59 (m, 4H), 7.46-7.35 (m, 6H), 4.21 (ddt, J = 6.8, 4.3,
2.5 Hz, 1H), 3.89 (dd, J = 10.5, 4.2 Hz, 1H), 3.70 (dd, J = 10.4, 2.5 Hz, 1H), 2.78 (dt, J = 17.7,
10.2 Hz, 1H), 2.43 (m, 1H), 2.17-2.09 (m, 2H), 1.43 (s, 9H), 1.05 (s, 9H).
13C NMR (CDCl3, 100 MHz):  174.9, 149.8, 135.5, 135.5, 133.1, 132.7, 129.9, 129.9, 127.9,
127.8, 82.7, 65.0, 58.8, 32.3, 28.0, 26.8, 21.1, 19.2.
16
Vu, H.-D.; Renault, J.; Roisnel, T.; Gouault, N.; Uriac, P. Eur. J. Org. Chem. 2014, 4506-5414.
S28
Methyl 1-benzyl-2-oxopiperidine-3-carboxylate (xix)
C14H17NO3 (MW = 247.29 g.mol-1)
Synthesized according to general procedure 1: 1-Benzylpiperidin-2-one (vii) (950 g,

5.0 mmol), LiHMDS (1M in THF, 10.5 mL, 10.5 mmol, 2.1 equiv.) and methyl chloroformate
(386 µL, 5.0 mmol, 1 equiv.) in THF (5 mL). Purification by flash column chromatography over
silica gel eluting with a PE/EA gradient (7:3 to 5:5) afforded the desired product as a pale
pink oil (1.174 g, 95%).
RF = 0.35 (PE/EA 6:4).
1H NMR (CDCl3, 400 MHz):  7.34-7.30 (m, 2H), 7.28-7.25 (m, 3H), 4.64 (d, J = 14.6 Hz, 1H),
4.58 (d, J = 14.7 Hz, 1H), 3.78 (s, 3H), 3.51 (t, J = 7.1 Hz, 1H), 3.30-3.17 (m, 2H),
2.18-2.03 (m, 2H), 1.92 (m, 1H), 1.74 (m, 1H).
13C NMR (CDCl3, 100 MHz):  171.6, 165.8, 136.8, 128.6, 128.0, 127.5, 52.5, 50.3, 49.1, 47.0,
25.2, 20.9.
HRMS: m/z calcd for C14H17NO3, [M+H]: 248.1287, found: 248.1293.
S29
Methyl 1-benzyl-2-oxopiperidine-3-carboxylate (xix)
S30
Benzyl 1-benzyl-2-oxopiperidine-3-carboxylate (xx)
C20H21NO3 (MW = 323.39 g.mol-1)

3.2 mmol), LiHMDS (1M in THF, 6.7 mL, 6.7 mmol, 2.1 equiv.) and benzyl chloroformate
(601 µL, 4.0 mmol, 1.25 equiv.) in THF (5 mL). Purification by flash column chromatography
over silica gel eluting with a PE/EA gradient (3:1 to 1:1) afforded the desired product as a
colorless oil (437 mg, 42%). The data were in accordance with the ones reported in the
literature.17
1H NMR (CDCl3, 400 MHz):  7.39-7.32 (m, 5H), 7.28-7.23 (m, 5H), 5.22 (s, 2H), 4.77
(d, J = 14.7 Hz, 1H), 4.47 (d, J = 14.7 Hz, 1H), 3.57 (t, J = 7.0 Hz, 1H), 3.28-3.16 (m, 2H),
2.19-2.04 (m, 2H), 1.89 (m, 1H), 1.74 (m, 1H).
13C NMR (CDCl3, 100 MHz):  171.0, 165.8, 136.8, 135.7, 128.6, 168.2, 128.2, 128.2, 128.0,
127.4, 67.1, 50.3, 49.4, 47.0, 25.3, 20.9.
17
Moody, C. L.; Franckevicius, V.; Drouhin, P.; Klein, J. E. M. N.; Taylor, R. J. K. Tetrahedron Lett. 2012, 53, 1897-
1899.
S31
Allyl 1-benzyl-2-oxopiperidine-3-carboxylate (xxi)
C16H19NO3 (MW = 273.33 g.mol-1)

5.28 mmol), LiHMDS (1M in THF, 11.1 mL, 11.1 mmol, 2.1 equiv.) and allyl chloroformate
(561 µL, 5.28 mmol, 1 equiv.) in THF (5 mL). Purification by flash column chromatography
colorless oil (1.01 g, 69%).
RF = 0.34 (PE/EA 6:4).
5.7 Hz, 1H), 5.37 (dq, J = 17.2, 1.5 Hz, 1H), 5.26 (dq, J = 10.4, 1.3 Hz, 1H), 4.74-4.67 (m, 3H),
4.53 (d, J = 14.7 Hz, 1H), 3.53 (dd, J = 7.6, 6.5 Hz, 1H), 3.31-3.18 (m, 2H), 2.20-2.05 (m, 2H),
1.92 (m, 1H), 1.74 (m, 1H).
13C NMR (CDCl3, 100 MHz):  170.8, 165.8, 136.8, 131.8, 128.6, 128.0, 127.4, 118.6, 65.9,
50.3, 49.3, 47.0, 25.3, 20.9.
S32
Allyl 1-benzyl-2-oxopiperidine-3-carboxylate (xxi)
S33
Methyl 1-benzyl-2,6-dioxopiperidine-3-carboxylate (xxii)
C14H15NO4 (MW = 261.28 g.mol-1)
Synthesized according to general procedure 1: 1-Benzylpiperidine-2,6-dione (viii) (1.016 g,

5.0 mmol), NaHMDS (1M in THF, 10.1 mL, 10.1 mmol, 2.1 equiv.) and methyl chloroformate
over silica gel eluting with a PE/Acetone gradient (9:1) afforded the desired product as a pale
green oil (812 mg, 62%).
RF = 0.4 (PE/Acetone 8:2).
1H NMR (CDCl3, 400 MHz):  7.37-7.33 (m, 2H), 7.31-7.22 (m, 3H), 5.01 (d, J = 13.9 Hz, 1H),
4.94 (d, J = 13.9 Hz, 1H), 5.28-5.20 (m, 2H), 3.78 (s, 3H), 3.67 (dd, J = 7.5, 5.3 Hz, 1H), 2.80
(ddd, J = 17.9, 8.6, 5.2 Hz, 1H), 2.67 (ddd, J = 17.5, 7.6, 5.1 Hz, 1H), 2.31 (m, 1H), 2.16
(ddt, J = 13.8, 9.3, 5.3 Hz, 1H).
13C NMR (CDCl3, 100 MHz):  171.2, 169.0, 168.6, 136.7, 128.7, 128.4, 127.5, 53.0, 49.0,
43.2, 30.5, 20.5.
HRMS: m/z calcd for C14H15NO4, [M+H]: 262.1079, found: 262.1105
S34
Methyl 1-benzyl-2,6-dioxopiperidine-3-carboxylate (xxii)
S35
Allyl 1-benzyl-2,6-dioxopiperidine-3-carboxylate (xxiii)
C16H17NO4 (MW = 287.32 g.mol-1)
Synthesized according to general procedure 1: 1-Benzylpiperidine-2,6-dione (viii) (1.016 g,

5.0 mmol), NaHMDS (1M in THF, 10.1 mL, 10.1 mmol, 2.1 equiv.) and allyl chloroformate
over silica gel eluting with PE/EA/acetone (75:20:5) afforded the desired product as a
colorless oil (807 mg, 56%).
RF = 0.37 (PE/EA/Acetone 75:20:5).
5.8 Hz, 1H), 5.32 (dq, J = 17.2, 1.5 Hz, 1H), 5.26 (dq, J = 10.4, 1.2 Hz, 1H), 5.02 (d, J = 13.9 Hz,
1H), 4.94 (d, J = 13.9 Hz, 1H), 4.67 (dq, J = 5.9, 1.4 Hz, 1H), 3.69 (dd, J = 7.4, 5.3 Hz, 1H),
2.80 (ddd, J = 17.7, 8.7, 5.2 Hz, 1H), 2.67 (ddd, J = 17.7, 7.5, 5.2 Hz, 1H), 2.32 (m, 1H), 2.16
(ddt, J = 14.0, 8.7, 5.3 Hz, 1H).
13C NMR (CDCl3, 100 MHz):  171.2, 168.5, 168.2, 136.7, 131.1, 128.7, 128.4, 127.5, 119.5,
66.5, 49.2, 43.2, 30.4, 20.6.
S36
Allyl 1-benzyl-2,6-dioxopiperidine-3-carboxylate (xxiii)
S37
Allyl 8-benzyl-7,9-dioxo-8-azaspiro[4.5]decane-6-carboxylate (xxiv)
C20H23NO4 (MW = 341.41 g.mol-1)
Synthesized according to general procedure 1: 8-Benzyl-8-azaspiro[4.5]decane-7,9-dione (ix)

(515 mg, 2.0 mmol), LiHMDS (1M in THF, 4.2 mL, 4.2 mmol, 2.1 equiv.) and allyl
chloroformate (213 µL, 2.0 mmol, 1 equiv.) in THF (20 mL). Purification by flash column
chromatography over silica gel eluting with PE/EA (9:1) afforded the desired product as a
colourless oil (496 mg, 73%).
RF = 0.27 (PE/EA 9:1).
1H NMR (CDCl3, 400 MHz):  7.33-7.27 (m, 4H), 7.23 (m, 1H), 5.84 (ddt, J = 17.3, 10.4, 5.9 Hz,
1H), 5.30 (dq, J = 17.2, 1.5 Hz, 1H), 5.25 (dq, J = 10.4, 1.2 Hz, 1H), 5.03-4.94 (m, 2H), 4.62
(dt, J = 6.0, 1.3 Hz, 2H), 4.94 (d, J = 13.9 Hz, 1H), 3.57 (d, J = 1.7 Hz, 1H), 2.96 (d, J = 17.3 Hz,
1H), 2.55 (ddd, J = 17.3, 1.8 Hz, 1H), 1.84-1.64 (m, 5H), 1.55-1.38 (m, 3H).
13C NMR (CDCl3, 100 MHz)  171.4, 168.4, 167.5, 136.8, 131.0, 128.4, 128.3, 127.3, 119.5,
66.4, 58.9, 49.2, 43.2, 42.2, 41.3, 38.1, 35.9, 23.9, 23.8.
S38
Allyl 8-benzyl-7,9-dioxo-8-azaspiro[4.5]decane-6-carboxylate (xxiv)
S39
Methyl 1-methyl-2-oxo-1,2,3,4-tetrahydroquinoline-3-carboxylate (xxv)
C12H13NO3 (MW = 219.24 g.mol-1)
Synthesized according to general procedure 1: 1-Methyl-3,4-dihydroquinolin-2(1H)-one (x)

(484 mg, 3.0 mmol), LiHMDS (1M in THF, 6.3 mL, 6.3 mmol, 2.1 equiv.) and methyl
chromatography over silica gel eluting with a PE/EA gradient (8:2 to 6:4) afforded the
desired product as a yellow oil (626 mg, 95%). The data were in accordance with the ones
1H NMR (CDCl3, 400 MHz):  7.29 (dd, J = 7.5, 1.5 Hz, 1H), 7.19 (dd, J = 7.4, 1.4 Hz, 1H),
7.04 (td, J = 7.5, 1.1 Hz, 1H), 7.00 (dd, J = 8.1, 1.0 Hz, 1H), 3.74 (s, 3H), 3.64 (dd, J = 9.6,
5.9 Hz, 1H), 3.40 (s, 3H), 3.34 (dd, J = 15.6, 9.6 Hz, 1H), 3.07 (dd, J = 15.6, 5.9 Hz, 1H).
13C NMR (CDCl3, 100 MHz):  169.8, 166.4, 166.2, 139.8, 128.1, 127.9, 124.0, 123.3, 114.9,
52.6, 48.0, 30.0, 28.7.
18
S.-L. Lu, X. Li, W.-B. Qin, J.-J. Liu, Y.-Y. Huang, H. N. C. Wong and G.-K. Liu, Org. Lett. 2018, 20, 6925-6929.
S40
Allyl 1-methyl-2-oxo-1,2,3,4-tetrahydroquinoline-3-carboxylate (xxvi)
C14H15NO3 (MW = 245.28 g.mol-1)
Synthesized according to general procedure 1: 1-Methyl-3,4-dihydroquinolin-2(1H)-one (x)

desired product as a yellow oil (339 mg, 69%).
RF = 0.42 (PE/EA 7:3).
1H NMR (CDCl3, 400 MHz):  7.27 (m, 1H), 7.19 (d, J = 7.4 Hz, 1H), 7.06-6.99 (m, 2H), 5.85
(m, 1H), 5.29-5.17 (m, 2H), 4.63 (qdt, J = 13.2, 5.6, 1.4 Hz, 2H), 3.66 (dd, J = 9.5, 5.7 Hz, 1H),
3.34 (m, 1H), 3.40 (s, 3H), 3.09 (dd, J = 15.6, 5.8 Hz, 1H).
13C NMR (CDCl3, 100 MHz):  169.1, 166.4, 139.9, 131.6, 128.1, 127.9, 124.0, 123.3, 118.4,
114.9, 66.0, 48.2, 30.0, 28.8.
S41
Allyl 1-methyl-2-oxo-1,2,3,4-tetrahydroquinoline-3-carboxylate (xxvi)
S42
Methyl 1,3-dibenzyl-2,4-dioxohexahydropyrimidine-5-carboxylate (xxvii)
C20H20N2O4 (MW = 352.39 g.mol-1)
Synthesized according to general procedure 1: 1,3-Dibenzyldihydropyrimidine-2,4(1H,3H)-

dione (xi) (294 mg, 1.0 mmol), LiHMDS (1M in THF, 2.1 mL, 2.1 mmol, 2.1 equiv.) and methyl
chromatography over silica gel eluting with a PE/DCM/EA gradient (7:2:1 to 6:2:2) afforded
the desired product as a white wax (338 mg, 96%).
RF = 0.25 (PE/DCM/EA 7:2:1).
(d, J = 14.2 Hz, 1H), 5.01 (d, J = 14.2 Hz, 1H), 4.64 (d, J = 14.8 Hz, 1H), 4.58 (d, J = 14.8 Hz, 1H),
3.63 (s, 3H), 3.62-3.59 (m, 2H), 3.45 (q, J = 73 Hz, 1H).
13C NMR (CDCl3, 100 MHz):  167.4, 165.3, 153.1, 137.3, 135.9, 128.9, 128.6, 128.4, 128.3,
128.1, 127.4, 53.0, 51.8, 48.0, 44.6, 43.0, 30.9.
HRMS: m/z calcd for C20H20N2O4, [M+H]: 353.1501, found: 353.1490.
S43
Methyl 1,3-dibenzyl-2,4-dioxohexahydropyrimidine-5-carboxylate (xxvii)
S44
Allyl 1,3-dibenzyl-2,4-dioxohexahydropyrimidine-5-carboxylate (xxviii)
C22H22N2O4 (MW = 378.43 g.mol-1)
Synthesized according to general procedure 1: 1,3-dibenzyldihydropyrimidine-2,4(1H,3H)-

dione (xi) (294 mg, 1.0 mmol), LiHMDS (1M in THF, 2.1 mL, 2.1 mmol, 2.1 equiv.) and allyl
RF = 0.35 (PE/EA 7:3).
1H NMR (CDCl3, 400 MHz):  7.43-7.40 (m, 2H), 7.36-7.26 (m, 5H), 7.28-7.22 (m, 3H),
5.76 (ddt, J = 17.2, 10.4, 5.8 Hz, 1H), 5.28-5.20 (m, 2H), 5.08 (d, J = 14.2 Hz, 1H), 5.00
(d, J = 14.2 Hz, 1H), 4.67-4.54 (m, 3H), 4.47 (ddt, J = 13.1, 5.9, 1.3 Hz, 1H), 3.62 (qd, J = 5.8,
3.8 Hz, 2H), 3.47 (m, 1H).
13C NMR (CDCl3, 100 MHz):  166.7, 165.3, 153.1, 137.3, 135.9, 130.9, 128.9, 128.6, 128.4,
128.3, 128.1, 127.4, 119.4, 66.8, 51.8, 48.1, 44.7, 43.0.
S45
Allyl 1,3-dibenzyl-2,4-dioxohexahydropyrimidine-5-carboxylate (xxviii)
S46
Methyl 1-benzyl-2-oxopyrrolidine-3-carboxylate (xxix)
C13H15NO3 (MW = 233.27 g.mol-1)
Synthesized according to general procedure 1: 1-Benzylpyrrolidin-2-one (876 mg, 5 mmol),

LiHMDS (1M in THF, 10.5 mL, 10.5 mmol, 2.1 equiv.) and methyl chloroformate
(390 µL, 5 mmol, 1 equiv.) in THF (5 mL). Purification by flash column chromatography over
silica gel eluting with a toluene/acetone gradient (95:5 to 9:1) afforded the desired product
as a colorless oil (891 g, 76%). The data were in accordance with the ones reported in the
literature.19
3.51 (dd, J = 9.4, 6.6 Hz, 1H), 3.38 (ddd, J = 9.5, 8.6, 5.2 Hz, 1H), 3.23 (ddd, J = 9.5, 8.3, 5.8 Hz,
1H), 2.38 (dddd, J = 13.0, 8.6, 6.6, 5.8 Hz, 1H), 2.23 (dddd, J = 13.7, 12.6, 8.9, 4.8 Hz, 1H).
13C NMR (CDCl3, 100 MHz)  170.7, 169.7, 135.9, 128.8, 128.1, 127.7, 52.7, 48.4, 47.0, 45.5,
22.2.
19
Adediran, S. A.; Cabaret, D.; Lohier, J.-F.; Wakselman, M.; Pratt, R. F. Bioorg. Med. Chem. 2010, 18, 282-291.
S47
Allyl 1-benzyl-2-oxopyrrolidine-3-carboxylate (xxx)
C15H17NO3 (MW = 259.31 g.mol-1)
Synthesized according to general procedure 1: 1-Benzylpyrrolidin-2-one (1 g, 5.71 mmol),

LiHMDS (1M in THF, 12 mL, 12.0 mmol, 2.1 equiv.) and allyl chloroformate (607 µL, 5.71
mmol, 1 equiv.) in THF (6 mL). Purification by flash column chromatography over silica gel
eluting with a PE/acetone gradient (95:5 to 85:15) afforded the desired product as an off-
white solid (992 mg, 67%).
5.7 Hz, 1H), 5.38 (ddt, J = 17.2, 1.5 Hz, 1H), 5.26 (dq, J = 10.4, 1.3 Hz, 1H), 4.74-4.65 (m, 2H),
4.52-4.22 (m, 2H), 3.53 (dd, J = 9.4, 6.5 Hz, 1H), 3.39 (ddd, J = 9.6, 8.6, 5.3 Hz, 1H), 3.23
(ddd, J = 9.5, 8.3, 5.7 Hz, 1H), 2.38 (ddt, J = 12.6, 8.6, 6.1 Hz, 1H), 2.25 (m, 1H).
13C NMR (CDCl3, 100 MHz):  170.0, 170.0, 135.9, 131.7, 128.7, 128.1, 127.7, 118.6, 66.1,
48.5, 47.0, 45.2, 22.3.
S48
Allyl 1-benzyl-2-oxopyrrolidine-3-carboxylate (xxx)
S49
3-Benzoyl-1-benzylpyrrolidin-2-one (xxxi)
C18H17NO2 (MW = 279.34 g.mol-1)
Synthesized according to general procedure 1: 1-Benzylpyrrolidin-2-one (876 mg, 5 mmol),

LiHMDS (1M in THF, 10.5 mL, 10.5 mmol, 2.1 equiv.) and benzyl chloride (580 µL,
5 mmol, 1 equiv.) in THF (10 mL). Purification by flash column chromatography over silica gel
eluting with a PE/acetone gradient (9:1 to 8:2) afforded the desired product as a dark yellow
oil (1.22 g, 87%) in a 87:13 keto/enol ratio. The data were in accordance with the ones
1H NMR (CDCl3, 400 MHz):  8.16-8.15 (m, 2H), 7.59 (m, 1H), 7.51 (t, J = 7.7 Hz, 2H),
7.34 (dd, J = 8.0, 6.7 Hz, 2H), 7.30-7.28 (m, 2H), 7.25 (d, J = 7.2 Hz, 1H), 4.55 (dd, J = 9.3,
4.9 Hz, 1H), 4.51 (d, J = 14.8 Hz, 1H), 4.44 (d, J = 14.7 Hz, 1H), 3.51 (ddd, J = 9.5, 8.5, 6.4 Hz,
1H), 3.30 (td, J = 9.2, 4.4 Hz, 1H), 2.60 (ddt, J = 13.1, 8.9, 4.7 Hz, 1H), 2.23 (dtd, J = 13.0, 9.1,
6.4 Hz, 1H).
13C NMR (CDCl3, 100 MHz):  196.3, 170.2, 136.2, 136.1, 133.5, 129.6, 128.8, 128.6, 128.1,
127.7, 50.7, 47.1, 45.5, 21.9.
20
Bao, D. H.; Gu, S.-S.; Xie, J.-H.; Zhou, Q.-L. Org. Lett. 2017, 19, 118-121.
S50
Methyl 1-benzyl-2,5-dioxopyrrolidine-3-carboxylate (xxxii)
C13H13NO4 (MW = 247.25 g.mol-1)
Synthesized according to general procedure 1: 1-Benzylpyrrolidine-2,5-dione (xii) (946 mg,

5.0 mmol), NaHMDS (1M in THF, 10.1 mL, 10.1 mmol, 2.1 equiv.) and methyl chloroformate
over silica gel eluting with PE/EA (80:20) afforded the desired product as a pale yellow solid
(741 mg, 60%). The data were in accordance with the ones reported in the literature.7
(dd, J = 18.3, 4.8 Hz, 1H), 2.88 (dd, J = 18.3, 9.4 Hz, 1H).
13C NMR (CDCl3, 100 MHz):  174.6, 171.8, 167.9, 135.1, 128.7, 128.7, 128.1, 46.3, 43.0,
32.2.
S51
Allyl 1-benzyl-2,5-dioxopyrrolidine-3-carboxylate (xxxiii)
C15H15NO4 (MW = 273.29 g.mol-1)
Synthesized according to general procedure 1: 1-Benzylpyrrolidine-2,5-dione (xii) (946 mg,

5.0 mmol), NaHMDS (1M in THF, 10.1 mL, 10.1 mmol, 2.1 equiv.) and allyl chloroformate
over silica gel eluting with a PE/EA gradient (85:15 to 80:20) afforded the desired product as
a pale yellow solid (735 mg, 54%).
RF = 0.4 (PE/EA 80:20).
1H NMR (CDCl3, 400 MHz):  7.37-7.28 (m, 5H), 5.90 (ddt, J = 17.1, 10.4, 5.8 Hz, 1H), 5.35
(dq, J = 17.2, 1.5 Hz, 1H), 5.28 (dq, J = 10.4, 1.2 Hz, 1H) 4.73-4.64 (m, 4H), 3.80 (dd, J = 9.4,
4.7 Hz, 1H), 3.12 (dd, J = 18.3, 4.7 Hz, 1H), 2.91 (dd, J = 18.3, 9.4 Hz, 1H), 3.81-3.77 (m, 4H),
3.12 (dd, J = 18.3, 4.8 Hz, 1H), 2.88 (dd, J = 18.3, 9.4 Hz, 1H).
13C NMR (CDCl3, 100 MHz):  174.6, 171.7, 167.1, 135.2, 130.1, 128.7, 128.1, 119.4, 66.9,
46.5, 43.0, 32.3.
S52
Allyl 1-benzyl-2,5-dioxopyrrolidine-3-carboxylate (xxxiii)
S53
Methyl 1-methyl-2-oxoindoline-3-carboxylate (xxxiv)
C11H11NO3 (MW = 205.21 g.mol-1)
In an oven-dried 100 mL round-bottom flask, sodium hydride (60 % wt in mineral oil, 1.1 g,
27.2 mmol, 4 equiv.) was suspended in dry toluene (13 mL) at rt. A solution of
1-methylindolin-2-one (1 g, 6.8 mmol), and dimethyl carbonate (1.1 mL, 13.6 mmol, 2 equiv.)
in dry toluene (11 mL) was added dropwise to the suspension and the resulting reaction
mixture was allowed to stir at rt until TLC showed completion. Upon completion, glacial
acetic acid (2 mL) was slowly added at 0 °C and the resulting solution was allowed to warm
to rt under continuous stirring. After 1 h, ethyl acetate (20 mL) was added and the reaction
was filtered through Celite©. The filtrate was concentrated under reduced pressure and the
with PE/EA (7:3) to afford the desired product as a blue solid (550 mg, 39% yield, 76%
purity). The data were in accordance with the ones reported in the literature.21
1H NMR (CDCl3, 400 MHz):  7.36-7.33 (m, 2H), 7.09 (t, J = 7.5 Hz, 1H), 6.85 (t, J = 8.0 Hz,
1H), 4.45 (s, 1H), 3.79 (s, 3H), 3.24 (s, 3H).
13C NMR (CDCl3, 100 MHz):  170.6, 167.4, 144.6, 129.3, 124.6, 123.3, 122.9, 108.5, 52.2,
26.6.
21
Ghosh, S.; Chaudhuri, S.; Bisai, A. Org. Lett. 2015, 17, 1373-1376.
S54
Allyl 1-methyl-2-oxoindoline-3-carboxylate (xxxv)
C13H13NO (MW = 231.25 g.mol-1)
In an oven-dried 100 mL round-bottom flask, sodium hydride (60 % wt in mineral oil,

712 mg, 17.8 mmol, 4 equiv.) was suspended in dry toluene (15 mL) at rt. A solution of
1-methylindolin-2-one (648 g, 4.4 mmol), and diallyl carbonate (1.26 mL, 8.8 mmol, 2 equiv.)
in dry toluene (15 mL) was added dropwise to the suspension and the resulting reaction
mixture was allowed to stir at rt until TLC showed completion. Upon completion, glacial
acetic acid (1 mL) was slowly added at 0 °C and the resulting solution was allowed to warm
to rt under continuous stirring. After 1 h, ethyl acetate (20 mL) was added and the reaction
was filtered through Celite©. The filtrate was concentrated under reduced pressure. The
with PE/acetone (7:3) to afford the desired product as a brownish oil (630 mg, 62% yield).
1H NMR (CDCl3, 400 MHz):  7.34 (tt, J = 6.4, 1.2 Hz, 2H), 7.08 (td, J = 7.6, 1.1 Hz, 1H), 6.85
(t, J = 7.6 Hz, 1H), 5.91 (ddt, J = 17.2, 10.5, 5.6 Hz, 1H), 5.32 (dq, J = 17.3, 1.6 Hz, 1H), 5.24
(dq, J = 11.1, 1.3 Hz, 1H), 4.69 (dt, J = 5.8, 1.1 Hz, 2H), 4.46 (s, 1H), 3.24 (s, 3H).
13C NMR (CDCl3, 100 MHz):  170.6, 166.6, 144.6, 131.4, 129.3, 124.6, 122.9, 122.3, 118.8,
108.5, 64.5, 52.3, 26.6.
S55
Allyl 1-methyl-2-oxoindoline-3-carboxylate (xxxv)
S56
1-(tert-Butyl) 3-methyl 2-oxoazetidine-1,3-dicarboxylate (xxxvi)
C10H15NO (MW = 229.23 g.mol-1)
Synthesized according to general procedure 1: tert-Butyl 2-oxoazetidine-1-carboxylate (xiii)

(400 mg, 2.34 mmol), LiHMDS (1M in THF, 4.9 mL, 4.9 mmol, 2.1 equiv.) and methyl
chromatography over silica gel eluting with a PE/acetone gradient (9:1 to 8:2) afforded the
desired product as an off-white solid (176 mg, 33%).
RF = 0.45 (PE/acetone 7:3).
1H NMR (CDCl3, 400 MHz):  4.06 (dd, J = 6.4, 3.6 Hz, 1H), 3.88 (dd, J = 7.0, 3.6 Hz, 1H),
3.80 (s, 3H), 3.72 (dd, J = 7.1, 6.3 Hz, 1H), 1.53 (s, 9H).
13C NMR (CDCl3, 100 MHz):  166.3, 158.9, 147.6, 84.0, 52.9, 28.0.
HRMS: m/z calcd for C14H17NO3, [M+Na]: 252.0842, found: 252.0859
S57
1-(tert-Butyl) 3-methyl 2-oxoazetidine-1,3-dicarboxylate (xxxvi)
S58
Methyl 1-benzyl-2-oxoazepane-3-carboxylate (xxxvii)
C15H19NO3 (MW = 261.32 g.mol-1)
An oven-dried 50 mL round bottom flask was charged with 1-benzylazepan-2-one (xiv)

(1 g, 4.92 mmol) dissolved in dry diethyl ether (7 mL). The resulting solution was cooled to
–78 °C and LDA (1M solution, 10.3 mL, 10.3 mmol, 2.1 equiv.) was added dropwise. The
reaction mixture was stirred at this temperature for one hour and dimethyl carbonate
(414 µL, 4.92 mmol, 1 equiv.) was slowly added. The reaction was allowed to warm to rt
overnight under continuous stirring and was eventually quenched by addition of a saturated
aqueous solution of NH4Cl (10 mL). The aqueous phase was extracted with DCM (3 x 20 mL)
and the combined organic phases were dried over anhydrous MgSO4 and concentrated
under reduced pressure. The resulting crude oil was purified by flash column
chromatography over silica gel eluting with a PE/EA gradient (8:2 to 6:4) to afford the
desired product as a pale yellow oil (695 mg, 54%). The data were in accordance with the
ones reported in the literature.22
1H NMR (CDCl3, 400 MHz):  7.39-7.33 (m, 5H), 4.65 (d, J = 14.6 Hz, 1H), 4.54 (d, J = 14.6 Hz,
1H), 3.79 (s, 3H), 3.70 (dd, J = 10.4, 2.1 Hz, 1H), 3.35 (m, 1H), 3.22 (ddt, J = 15.6, 6.3, 3.1 Hz,
1H), 2.07 (m, 1H), 1.94-1.82 (m, 2H), 1.65-1.49 (m, 2H), 1.28 (m, 1H).
13C NMR (CDCl3, 100 MHz):  172.0, 171.1, 137.3, 129.0, 128.8, 128.6, 128.3, 127.5, 52.3,
51.4, 48.4, 27.9, 27.5, 26.0.
22
Kyorin Pharmaceuticals Co., LTD.EP1780210, 2007, A1.
S59
Allyl 1-benzyl-2-oxoazepane-3-carboxylate (xxxviii)
C17H21NO3 (MW = 287.36 g.mol-1)
An oven-dried 50 mL round bottom flask was charged with 1-benzylazepan-2-one (xiv)

(500 mg, 2.46 mmol) dissolved in dry diethyl ether (4 mL). The resulting solution was cooled
down to –78 °C and LDA (1M solution, 5.17 mL, 5.17 mmol, 2.1 equiv.) was added dropwise.
The reaction mixture was stirred at this temperature for one hour and diallyl carbonate
(353 µL, 4.92 mmol, 1 equiv.) was slowly added. The reaction was allowed to warm to room
temperature overnight and was eventually quenched by addition of a saturated aqueous
solution of NH4Cl (10 mL). The aqueous phase was extracted with DCM (3 x 10 mL) and the
reduced pressure. The resulting crude oil was purified by flash column chromatography over
silica gel eluting with PE/EA (8:2) to afford the desired product as a colorless oil (188 mg,
27%) not separable from a co-eluting minor impurity.
1H NMR (CDCl3, 400 MHz):  7.35-7.26 (m, 5H), 5.97 (ddt, J = 17.2, 10.4, 5.9 Hz, 1H), 5.38
(dq, J = 17.2, 1.5 Hz, 1H), 5.26 (dq, J = 10.4, 1.3 Hz, 1H), 4.71-4.65 (m, 3H), 4.52 (d, J = 14.6
Hz, 1H), 3.73 (dd, J = 10.3, 2.2 Hz, 1H), 3.34 (ddd, J = 15.5, 10.2, 1.4 Hz, 1H), 3.23 (ddd,
J = 15.4, 6.7, 2.2 Hz, 1H), 2.07 (m, 1H), 1.90 (m, 1H), 1.56 (m, 1H), 1.30 (m, 1H).
13C NMR (CDCl3, 100 MHz):  171.8, 170.3, 137.3, 132.1, 128.6, 128.3, 127.5, 118.7, 65.9,
52.5, 51.4, 48.3, 27.8, 27.5, 26.0.
S60
Allyl 1-benzyl-2-oxoazepane-3-carboxylate (xxxviii)
S61
Methyl 2-oxotetrahydrofuran-3-carboxylate (xxxix)
C6H8O4 (MW = 144.13 g.mol-1)
Synthesized according to general procedure 1: -Butyrolactone (430 mg, 5 mmol), LiHMDS

(1M in THF, 10.5 mL, 10.5 mmol, 2.1 equiv.) and dimethyl carbonate (442 µL, 5 mmol,
1 equiv.) in THF (5 mL). Purification by flash column chromatography over silica gel eluting
with a PE/acetone gradient (8:2 to 7:3) afforded the desired product as a colorless oil
(510 mg, 71%). The data were in accordance with the ones reported in the literature.23
1H NMR (CDCl3, 400 MHz):  4.47 (ddd, J = 9.0, 8.1, 5.4 Hz, 1H), 4.33 (dt, J = 9.0, 7.5 Hz, 1H),
3.81 (s, 3H), 3.56 (dd, J = 9.4, 7.6 Hz, 1H), 2.68 (dtd, J = 13.1, 7.9, 7.1 Hz, 1H), 2.50 (dddd,
J = 13.1, 9.3, 7.6, 5.4 Hz, 1H).
13C NMR (CDCl3, 100 MHz):  172.2, 168.2, 67.3, 53.1, 45.8, 26.4.
23
Hazelden, I. R.; Carmona, R. C.; Langer, T.; Pringle, P. G.; Bower, J. F. Angew. Chem. Int. Ed. 2018, 130, 5218-
5222.
S62
Allyl 2-oxotetrahydrofuran-3-carboxylate (xl)
C8H10O4 (MW = 170.16 g.mol-1)
Synthesized according to general procedure 1: -Butyrolactone (430 mg, 5 mmol), LiHMDS

(1M in THF, 10.5 mL, 10.5 mmol, 2.1 equiv.) and allyl chloroformate (558 µL, 5.25 mmol,
1.05 equiv.) in THF (5 mL). Purification by flash column chromatography over silica gel
eluting with a PE/acetone gradient (8:2 to 7:3) afforded the desired product as an off-white
solid (805 mg, 95%). The data were in accordance with the ones reported in the literature.24
1H NMR (CDCl3, 400 MHz):  5.93 (ddt, J = 17.2, 10.4, 5.7 Hz, 1H), 5.37 (dq, J = 17.2, 1.5 Hz,
1H), 5.28 (dq, J = 10.5, 1.3 Hz, 1H), 4.70 (dq, J = 5.8, 1.6 Hz, 1H), 4.48 (ddd, J = 9.0, 8.2, 5.5 Hz,
1H), 4.33 (dt, J = 9.0, 7.4 Hz, 1H), 3.58 (dd, J = 9.3, 7.7 Hz, 1H), 2.69 (m, 1H), 2.52 (dddd,
J = 13.0, 9.3, 7.6, 5.4 Hz, 1H).
13C NMR (CDCl3, 100 MHz):  172.1, 167.4, 131.2, 119.1, 67.3, 66.6, 45.9, 26.4.
24
Rao, V. S. Synth. Commun. 1989, 19, 1389-1393.
S63
N,N-Dimethyl-2-oxotetrahydrofuran-3-carboxamide (xli)
C7H11NO3 (MW = 157.07 g.mol-1)
Synthesized according to general procedure 1: -Butyrolactone (258 mg, 3.0 mmol), LiHMDS
(1M in THF, 6.3 mL, 6.3 mmol, 2.1 equiv.) and N,N-dimethylcarbamoyl chloride
(290 µL, 3.15 mmol, 1.05 equiv.) in THF (1.5 mL). Purification by flash column
desired product as a pale yellow oil (270 mg, 57%).
RF = 0.18 (PE/EA 7:3).
1H NMR (CDCl3, 400 MHz):  4.50 (m, 1H), 4.32 (m, 1H), 3.85 (dd, J = 9.1, 6.3 Hz, 1H), 3.21
(brs, 3H), 3.00 (brs, 3H), 2.84 (m, 1H), 2.36 (m, 1H).
13C NMR (CDCl3, 100 MHz):  173.8, 166.3, 68.0, 43.0, 37.8, 36.2, 26.3.
S64
N,N-Dimethyl-2-oxotetrahydrofuran-3-carboxamide (xli)
S65
3-(Allyloxy)-3-oxopropanoic acid (xlii)
C6H8O (MW = 144.13 g.mol-1
Synthesized according to a procedure reported by Franckevicius and co-workers.25 An oven-

dried 500 mL round-bottom flask was successively charged with malonic acid (5.2 g,
50 mmol), allyl alcohol (6.8 mL, 100 mmol, 2.0 equiv.) and acetonitrile (150 mL). To this
solution was added dropwise a solution of DCC (11.35 g, 55 mmol, 1.1 equiv.) in acetonitrile
(50 mL). The resulting was stirred at rt for 30 min after which it was successively filtered and
concentrated under reduced pressure. The crude oil was dissolved in Et2O (250 mL) and
extracted with a saturated aqueous solution of NaHCO3 solution (2 x 100 mL). The combined
organic phases were acidified to pH 1 with a 1N aqueous HCl solution and finally extracted
with ethyl acetate. The desired product was obtained as a colorless liquid (5.47 g, 74%) and
used in the next step without further purification. The data were in accordance with the
ones reported in the literature.25
1H NMR (CDCl3, 400 MHz):  10.29 (br s, 1H), 5.92 (ddt, J = 17.2, 10.4, 5.8 Hz, 1H), 5.39-5.27
(m, 2H), 4.68 (dt, J = 4.7, 1.7 Hz, 1H), 3.47 (s, 2H).
13C NMR (CDCl3, 100 MHz):  171.2, 166.5, 131.2, 119.2, 66.5, 40.6.
25
Franckevicius, V.; Cuthbertson, J. D.; Pickworth, M.; Pugh, D. S.; Taylor, R. J. K. Org. Lett. 2011, 13, 4264-4267.
S66
Allyl 3-(methoxy(methyl)amino)-3-oxopropanoate (xliii)
C8H13NO4 (MW = 187.20 g.mol-1)
Synthesized according to a procedure reported by Leeder and co-workers.26 An oven-dried

100 mL round-bottom flask was successively charged with 3-(allyloxy)-3-oxopropanoic acid
(xlii) (1 g, 7.0 mmol), dichloromethane (30 mL) and 30 µL of DMF. The reaction mixture was
allowed to cool down to 0 °C and oxalyl chloride (750 µL, 8.75 mmol, 1.25 equiv.) was added
dropwise. The reaction was allowed warm to rt overnight and concentrated under reduced
pressure and dissolved in Et2O (12 mL). In a 100 mL round-bottom flask, potassium
carbonate (1.93 g, 14.0 mmol, 2 equiv.) was dissolved in H2O (12 mL) and
N-O-dimethylhydroxylamide (756 mg, 7.75 mmol, 1.10 equiv.) was added in two portions.
The resulting solution was cooled down at 0 °C and the acyl chloride solution was added
dropwise. The resulting biphasic mixture was vigorously stirred for 30 min after which the
two phases were separated. The aqueous layer was additionally extracted with Et 2O
(2 x 20 mL). The combined organic phases were dried over anhydrous MgSO4 and
concentrated under reduced pressure. The desired product was obtained as a colorless oil
(1.28 g, 98%) and used in the next step without further purification. The data were in
1H NMR (CDCl3, 400 MHz):  5.92 (ddt, J = 17.3, 10.5, 5.7 Hz, 1H), 5.37-5.23 (m, 2H), 4.64
(dt, J = 5.7, 1.4 Hz, 1H), 3.70 (s, 3H), 3.52 (s, 2H), 2.97 (s, 3H).
13C NMR (CDCl3, 100 MHz):  190.0, 167.0, 131.7, 118.6, 65.9, 61.4, 41.2, 32.3.
26
Leeder, A. J.; Heap, R. J.; Brown, L. J.; Franck, X.; Brown, R. C. D. Org. Lett. 2016, 18, 5971-5973.
S67
N-Methoxy-N-methyl-2-phenylacetamide (xliv)
C10H13NO2 (MW = 179.22 g.mol-1)
Synthesized according to a procedure reported by Chanthamath and co-workers.27 An oven-

dried 100 mL round-bottom flask was successively charged with phenyl acetyl chloride
(0.66 mL, 5.0 mmol), N,O-dimethylhydroxylamine hydrochloride (585 mg, 6.0 mmol,
1.2 equiv.) and dichloromethane (20 mL). The resulting solution was allowed to cool down to
0 °C before dry pyridine (0.89 mL, 11.0 mmol, 2.2 equiv.) was added dropwise over 5 min.
The reaction mixture was stirred at this temperature for 10 min and allowed warm up to rt
and stirred for an additional hour after which it was stopped by the addition of HCl (0.1 M,
20 mL). The resulting organic phase was washed with a 0.1 M aqueous solution of HCl
(20 mL), H2O (2 x 20 mL) and a saturated aqueous solution of NaHCO3 (2 x 20 mL). The
resulting organic layer was dried over anhydrous MgSO4 and concentrated under reduced
pressure. The desired product was obtained as a colorless oil (885 mg, 99%) and used in the
next step without further purification. The data were in accordance with the ones reported
in the literature.27
3.19 (s, 2H).
13C NMR (CDCl3, 100 MHz):  135.0, 129.3, 128.5, 126.8, 118.6, 61.3, 39.4, 32.3.
27
Chanthamath, S.; Takaki, S.; Shibatomi, K.; Iwasa, S. Angew. Chem. Int. Ed. 2013, 52, 5818-5821.
S68
Allyl 3-[methoxy(methyl)amino]-2-methyl-3-oxopropanoate (xlv)
C9H15NO4 (MW = 201.22 g.mol-1)
Synthesized according to general procedure 2: Allyl 3-[methoxy(methyl)amino]-3-

oxopropanoate (xliii) (187 mg, 1.0 mmol), potassium tert-butoxide (125 mg, 1.11 mmol,
1.11 equiv.) and iodomethane (70 µL, 1.11 mmol, 1.11 equiv.). Purification by flash column
RF = 0.42 (PE/EA 6:4).
1H NMR (CDCl3, 400 MHz):  5.90 (ddt, J = 17.2, 10.4, 5.7 Hz, 1H), 5. 32 (dq, J = 17.2, 1.5 Hz,
1H), 5. 23 (dq, J = 10.4, 1.3 Hz, 1H), 4.62 (dq, J = 5.7, 1.5 Hz, 1H), 3.76 (q, J = 7.2 Hz, 1H),
3.70 (s, 3H), 3.21 (s, 3H), 1.42 (d, J = 7.2 Hz, 3H).
13C NMR (CDCl3, 100 MHz):  190.0, 170.5, 131.9, 118.3, 65.7, 61.3, 43.2, 32.6, 13.5.
S69
Allyl 3-[methoxy(methyl)amino]-2-methyl-3-oxopropanoate (xlv)
S70
Allyl 2-[methoxy(methyl)carbamoyl]butanoate (xlvi)
C10H17NO4 (MW = 215.25 g.mol-1)

1.11 equiv.) and bromoethane (83 µL, 1.11 mmol, 1.11 equiv.). Purification by flash column
chromatography over silica gel eluting with PE/Et2O (1:1) afforded the desired product as a
pale yellow oil (46 mg, 21%).
RF = 0.38 (PE/Et2O 1:1).
1H NMR (CDCl3, 400 MHz):  5.90 (ddt, J = 17.3, 10.5, 5.7 Hz, 1H), 5. 34-5.29 (m, 1H), 5.22
(dq, J = 10.4, 1.3 Hz, 1H), 4.62 (ddt, J = 5.4, 2.6, 1.5 Hz, 2H), 3.70 (s, 3H), 3.62 (t, J = 7.3 Hz,
1H), 3.21 (s, 3H), 1.95 (m, 1H), 0.98 (t, J = 7.5 Hz, 3H).
13C NMR (CDCl3, 100 MHz):  169.6, 131.9, 118.3, 65.6, 61.3, 50.1, 43.2, 32.5, 22.0, 12.0.
S71
Allyl 2-[methoxy(methyl)carbamoyl]butanoate (xlvi)
S72
Allyl 3-[methoxy(methyl)amino]-3-oxo-2-phenylpropanoate (xlvii)
C14H17NO4 (MW = 263.29 g.mol-1)
Synthesized according to general procedure 1: N-Methoxy-N-methyl-2-phenylacetamide

(358 mg, 2.0 mmol) (xliv), LiHMDS (1M in THF, 4.2 mL, 4.2 mmol, 2.1 equiv.) and allyl
chloroformate (213 µL, 2.0 mmol, 1 equiv.). Purification by flash column chromatography
over silica gel eluting with PE/EA (8:2) afforded the desired product as a pale yellow oil
(432 mg, 82%).
RF = 0.45 (PE/EA 7:3).
5.7 Hz, 1H), 5. 29 (dq, J = 17.2, 1.5 Hz, 1H), 5.21 (dq, J = 10.5, 1.3 Hz, 1H), 5.04 (brs, 1H),
4.65 (dt, J = 5.7, 1.4 Hz, 1H), 3.56 (s, SH), 3.21 (s, 3H).
13C NMR (CDCl3, 100 MHz):  168.3, 133.1, 131.7, 129.7, 128.5, 128.0, 118.4, 66.1, 61.3,
55.0, 32.5.
S73
Allyl 3-[methoxy(methyl)amino]-3-oxo-2-phenylpropanoate (xlvii)
S74
Allyl 2-[methoxy(methyl)carbamoyl]-3-oxooctanoate (xlviii)
C14H25NO4 (MW = 271.18 g.mol-1)

1.11 equiv.) and hexyl iodide (164 µL, 1.11 mmol, 1.11 equiv.). Purification by flash column
yellowish oil (177 mg, 66%).
RF = 0.41 (PE/EA 8:2).
1H NMR (CDCl3, 400 MHz):  5.90 (ddt, J = 17.3, 10.6, 5.7 Hz, 1H), 5.31 (m, 1H), 5.22 (dq,
J = 10.4, 1.3 Hz, 1H), 4.66-4.56 (m, 2H), 3.71-3.67 (m, 4H), 3.21 (s, 3H), 1.91 (dq, J = 14.1, 7.6,
7.1 Hz, 2H), 1.33-1.26 (m, 8H), 0.89-0.85 (m, 3H).
13C NMR (CDCl3, 100 MHz):  169.8, 131.9, 129.1, 118.3, 65.6, 61.3, 48.6, 32.6, 31.6, 29.0,
28.6, 27.5, 22.6, 14.0.
S75
Allyl 2-[methoxy(methyl)carbamoyl]-3-oxooctanoate (xlviii)
S76
Allyl 2-benzyl-3-[methoxy(methyl)amino]-3-oxopropanoate (xlix)
C15H19NO4 (MW = 277.32 g.mol-1)

1.11 equiv.) and benzyl bromide (132 µL, 1.11 mmol, 1.11 equiv.). Purificaton by flash
column chromatography over silica gel eluting with PE/EA (7:3) afforded the desired product
as a colorless oil (269 mg, 98%).
RF = 0.45 (PE/EA 7:3).
1H NMR (CDCl3, 400 MHz):  7.29-7.18 (m, 5H), 5.84 (ddt, J = 17.2, 10.5, 5.7 Hz, 1H),
5.27 (dq, J = 17.3, 1.6 Hz, 1H), 5.20 (dq, J = 10.5, 1.3 Hz, 1H), 4.59 (dt, J = 5.6, 1.5 Hz, 2H),
4.07 (t, J = 7.7 Hz, 1H), 3.50 (s, 3H), 3.24 (qd, J = 13.8, 7.6 Hz, 2H), 3.15 (s, 3H).
13C NMR (CDCl3, 100 MHz):  169.0, 138.6, 131.7, 129.1, 128.4, 126.6, 118.4, 65.8, 61.3,
50.3, 34.6, 32.4.
S77
Allyl 2-benzyl-3-[methoxy(methyl)amino]-3-oxopropanoate (xlix)
S78
Allyl 2-[methoxy(methyl)carbamoyl]pent-4-enoate (l)
C11H17NO4 (MW = 227.26 g.mol-1)

1.11 equiv.) and allyl iodide (102 µL, 1.11 mmol, 1.11 equiv.). Purification by flash column
RF = 0.35 (PE/EA 8:2).
1H NMR (CDCl3, 400 MHz):  5.94-5.76 (m, 2H), 5.31 (dq, J = 17.2, 1.6 Hz, 1H), 5.23
(dq, J = 10.5, 1.3 Hz, 1H), 5.13 (dq, J = 17.1, 1.6 Hz, 1H), 5.05 (ddt, J = 10.2, 2.1, 1.1 Hz, 1H),
4.61 (dq, J = 5.8, 1.5 Hz, 2H), 3.80 (t, J = 7.4 Hz, 1H), 3.70 (s, 3H), 3.21 (s, 3H), 2.73-2.60
(m, 2H).
13C NMR (CDCl3, 100 MHz):  169.1, 134.7, 131.8, 118.4, 117.3, 65.7, 61.4, 48.4, 32.8.
S79
Allyl 2-[methoxy(methyl)carbamoyl]pent-4-enoate (l)
S80
1-Allyl 4-ethyl 2-[methoxy(methyl)carbamoyl]succinate (li)
C12H19NO6 (MW = 273.29 g.mol-1)

1.11 equiv.) and ethyl iodoacetate (131 µL, 1.11 mmol, 1.11 equiv.). Purification by flash
RF = 0.5 (PE/EA 6:4).
1H NMR (CDCl3, 400 MHz):  5.88 (ddt, J = 17.4, 10.8, 5.6, 1H), 5.32 (m, 1H), 5.23 (dt,
J = 10.4, 1.3 Hz, 1H), 4.28 (dd, J = 9.0, 5.7 Hz, 1H), 4.14 (dq, J = 7.2, 1.4 Hz, 1H), 3.77 (s, 3H),
3.23 (s, 3H), 3.02 (dd, J = 17.2, 9.0 Hz, 1H), 2.88 (dd, J = 17.2, 5.6 Hz), 1.25 (t, J = 1.25 Hz, 3H).
13C NMR (CDCl3, 100 MHz):  171.3, 168.6, 131.5, 118.5, 66.0, 61.4, 61.0, 44.5, 32.9, 32.5,
14.1.
S81
1-Allyl 4-ethyl 2-[methoxy(methyl)carbamoyl]succinate (li)
S82
Allyl 2-[methoxy(methyl)carbamoyl]pent-4-ynoate (lii)
C11H15NO4 (MW = 225.24 g.mol-1)

1.11 equiv.) and propargyl bromide (120 µL, 1.11 mmol, 1.11 equiv.). Purification by flash
RF = 0.31 (PE/EA 7:3).
1H NMR (CDCl3, 400 MHz):  5.88 (ddt, J = 17.4, 10.8, 5.6, 1H), 5.32 (m, 1H), 5.23 (dt,
J = 10.4, 1.3 Hz, 1H), 4.28 (dd, J = 9.0, 5.7 Hz, 1H), 4.14 (dq, J = 7.2, 1.4 Hz, 1H), 3.77 (s, 3H),
3.23 (s, 3H), 3.02 (dd, J = 17.2, 9.0 Hz, 1H), 2.88 (dd, J = 17.2, 5.6 Hz), 1.25 (t, J = 1.25 Hz, 3H).
13C NMR (CDCl3, 100 MHz):  168.4, 168.1, 131.6, 118.6, 80.7, 70.2, 66.0, 61.5, 47.6, 32.5,
18.3.
S83
Allyl 2-[methoxy(methyl)carbamoyl]pent-4-ynoate (lii)
S84
Allyl 1-(4-methoxybenzoyl)-2-oxopyrrolidine-3-carboxylate (liii)
C16H17NO5 (MW = 303.31 g.mol-1)
Synthesized according to general procedure 1: 1-(4-Methoxybenzoyl)pyrrolidin-2-one (xv)

RF = 0.36 (PE/EA 7:3).
1H NMR (CDCl3, 400 MHz):  7.67-7.63 (m, 2H), 6.91-6.88 (m, 2H), 5.92 (dt, J = 17.2, 10.4,
5.7 Hz, 1H), 5.36 (dq, J = 17.2, 1.5 Hz, 1H), 5.27 (dq, J = 10.4, 1.3 Hz, 1H), 4.69 (dt, J = 5.8,
1.4 Hz, 2H), 4.04 (ddd, J = 11.2, 8.3, 4.9 Hz, 1H), 3.94 (dt, J = 11.2, 7.6 Hz, 1H), 3.85 (s, 3H),
3.67 (dd, J = 9.1, 8.1 Hz, 1H), 2.51 (dq, J = 13.1, 8.0 Hz, 1H), 2.41 (m, 1H).
13C NMR (CDCl3, 100 MHz):  169.6, 169.6, 168.5, 163.2, 131.8, 131.3, 125.6, 119.0, 113.2,
66.4, 55.4, 50.7, 45.1, 30.9, 22.0.
S85
Allyl 1-(4-methoxybenzoyl)-2-oxopyrrolidine-3-carboxylate (liii)
S86
Allyl 10-oxododecahydro-1H,5H,8H-dipyrido[2,1-f:3',2',1'-ij][1,6]naphthyridine
-11-carboxylate (liv)
C19H28N2O3 (MW = 332.44 g.mol-1)
A 25 mL oven-dried round bottom flask was charged with LDA (1M in THF, 2.43 mL,
2.43 mmol, 3 equiv.) and dry THF (6 mL). The resulting solution was cooled down to –78 °C
and a solution of matrine (200 mg, 0.81 mmol) and diallyl carbonate (151 µL, 1.05 mmol,
1.3 equiv.) in dry THF (4 mL) was slowly added. The resulting solution was stirred at this
temperature for 15 min and allowed to warm up to room temperature. After stirring for 5 h,
the reaction mixture was quenched by the addition of a saturated aqueous solution of NH4Cl
(5 mL) and extracted with ethyl acetate (3 x 15 mL). The resulting crude oil was purified by
two successive flash column chromatography over silica gel eluting with toluene/acetone
(8:2) and PE/acetone (7:3 to 5:5) to afford the desired product as an equimolar mixture of
the two diastereomers (104 mg, 39 %).
RF = 0.25 (1st dia) and 0.35 (2nd dia) (PE/acetone 6:4).
1H NMR (CDCl3, 400 MHz):  5.92 (dtt, J = 17.3, 10.4, 5.7 Hz, 1H), 5.34 (ddq, J = 17.4, 13.0,
1.6 Hz, 1H), 5.23 (dq, J = 10.5, 1.4 Hz, 1H), 4.73-4.57 (m, 2H), 4.38 (ddd, J = 17.4, 12.8, 4.4 Hz,
1H), 3.87 (m, 1H), 3.49 (t, J = 5.1 Hz, 0.5H, 1st dia), 3.29 (m, 0.5H, 2nd dia), 3.09 (td, J = 12.7,
4.2 Hz, 1H), 2.85-2.75 (m, 2H), 2.18 (dddd, J = 11.7, 10.1, 5.9, 3.7 Hz, 1H), 2.09-1.82 (m, 6H),
1.79-1.47 (m, 6H), 1.45-1.35 (m, 4H).
13C NMR (CDCl3, 100 MHz):  170.8, 170.6, 165.3, 164.8, 132.0, 131.8, 118.5, 118.2, 65.8,
65.7, 63.7, 63.5, 57.2, 57.2, 57.2, 53.2, 53.1, 49.9, 48.8, 43.5, 42.9, 42.0, 41.7, 35.3, 32.2,
27.7, 27.7, 26.4, 26.3, 25.7, 23.5, 22.8, 22.5, 21.2, 21.1, 20.8, 20.7.
S87
Allyl 10-oxododecahydro-1H,5H,8H-dipyrido[2,1-f:3',2',1'-ij][1,6]naphthyridine-11-
carboxylate (liv)
S88
Allyl (1R,3aR,5aS,9aS,9bR)-3a,7,7,9a-tetramethyl-2-oxododecahydronaphtho[2,1-b]furan-
1-carboxylate (lv)
C20H30O4 (MW = 334.46 g.mol-1)
An oven-dried 50 mL round-bottom flask was charged with (3aR)-(+)-sclareolide (250 mg)

and dry THF (10 mL). The solution was cooled down to –78 °C and LDA
(1M solution in THF, 1 mL, 1.0 mmol, 1 equiv.) was added dropwise. The resulting solution
was stirred at this temperature for 1 h and allyl chloroformate (213 µL, 2.0 mmol, 2 equiv.)
was then added and the reaction mixture was allowed to warm up to room temperature.
When TLC showed completion (90 min) the reaction was stopped by addition of H2O (5 mL)
and the aqueous phase was extracted with ethyl acetate (3 x 30 mL). The combined organic
layers were dried over anhydrous MgSO4 and concentrated under reduced pressure. The
with PE/Et2O (85:15) to afford the desired product as a single diastereomer as a white
crystals (157 mg, 47%).
RF = 0.32 (PE/Et2O 85:15).
1H NMR (CDCl3, 400 MHz):  5.93 (ddt, J = 17.2, 10.4, 5.9 Hz, 1H), 5.39 (dq, J = 17.2, 1.5 Hz,
1H), 5.28 (dq, J = 10.4, 1.1 Hz, 1H), 4.68 (dq, J = 6.0, 1.3 Hz, 2H), 3.55 (d, J = 13.8 Hz, 1H),
2.53 (d, J = 13.8 Hz, 1H), 2.10 (dt, J = 11.9, 3.3 Hz, 1H), 1.91 (dq, J = 14.1, 3.2 Hz, 1H),
1.79 (td, J = 12.3, 4.3 Hz, 1H), 1.60 (m, 1H), 1.44-1.32 (m, 5H), 1.26-1.09 (m, 3H), 0.97 (s, 3H),
0.89 (s, 3H), 0.83 (s, 3H).
13C NMR (CDCl3, 100 MHz):  172.4, 169.1, 131.3, 119.3, 100.0, 85.8, 66.5, 62.2, 56.2, 47.9,
41.9, 38.6, 38.4, 37.1, 33.2, 32.2, 23.0, 20.9, 20.4, 18.1, 15.5.
S89
Allyl (1R,3aR,5aS,9aS,9bR)-3a,7,7,9a-tetramethyl-2-oxododecahydronaphtho[2,1-b]furan-
1-carboxylate (lv)
S90
Allyl 1-methyl-2,5-dioxo-4-phenylpyrrolidine-3-carboxylate (lvi)
C15H15NO4 (MW = 273.29 g.mol-1)
Synthesized according to general procedure 1: 1-Methyl-3-phenylpyrrolidine-2,5-dione (xvi)

chloroformate (407 µL, 4.0 mmol, 1 equiv.) in THF (4 mL). Purification by two consecutive
flash column chromatographies over silica gel eluting with a PE/EA gradient (9:1 to 8:2) and
PE/DCM/EA (75:20:5) afforded the desired product as a yellow oil (311 mg, 19 %) along with
some minor co-eluting impurities.
RF = 0.37 (PE/EA 8:2).
5.7 Hz, 1H), 5.38 (dq, J = 17.1, 1.5 Hz, 1H), 5.29 (dq, J = 10.5, 1.3 Hz, 1H), 4.79-4.67 (m, 2H),
4.45 (d, J = 5.5 Hz, 1H), 3.89 (d, J = 5.5 Hz, 1H), 3.11 (s, 3H).
13C NMR (CDCl3, 100 MHz):  175.8, 171.1, 166.9, 135.4, 131.0, 129.3, 128.4, 127.7, 119.4,
67.1, 55.2, 50.0, 25.8.
S91
Allyl 1-methyl-2,5-dioxo-4-phenylpyrrolidine-3-carboxylate (lvi)
S92
3-Allyl 1-(tert-butyl) (5S)-5-{[(tert-butyldiphenylsilyl)oxy]methyl}-2-oxopyrrolidine-1,3-
dicarboxylate (lvii)
C30H39NO6Si (MW = 537.73 g.mol-1)
Synthesized according to general procedure 1: tert-Butyl (S)-2-{[(tert-

butyldiphenylsilyl)oxy]methyl}-5-oxopyrrolidine-1-carboxylate (xviii) (454 mg, 1.0 mmol),
LiHMDS (1M in THF, 2.1 mL, 2.1 mmol, 2.1 equiv.) and allyl chloroformate
(106 µL, 1.0 mmol, 1 equiv.) in THF (3 mL). Purification by flash column chromatography over
silica gel eluting with PE/EA/DCM (86:7:7) afforded the desired product as a pale yellow wax
(212 mg, 39%, dr = 9:1).
RF = 0.23 (PE/EA/DCM 86:7:7).
5.6 Hz, 1H), 5.41 (dq, J = 17.2, 1.6 Hz, 1H), 5.97 (dq, J = 10.5, 1.3 Hz, 1H), 4.72 (dt, J = 5.8, 4.3,
1.5 Hz, 2H), 4.28 (dt, J = 8.2, 2.6 Hz, 1H), 3.95 (ddd, J = 11.1, 6.7, 3.0 Hz, 1H), 3.71 (dd,
J = 10.7, 2.3 Hz, 1H), 2.62 (ddd, J = 12.9, 11.1, 9.2 Hz, 1H), 2.33 (ddd, J = 12.9, 9.1, 1.2 Hz, 1H),
1.47 (s, 9H), 1.08 (d, J = 2.7 Hz, 9H).
13C NMR (CDCl3, 100 MHz):  169.0, 169.0, 135.5, 135.5, 132.9, 132.5, 131.6, 129.9, 127.9,
127.9, 118.5, 83.3, 66.3, 64.8, 57.0, 49.8, 28.0, 26.8, 25.5, 19.2.
HRMS: m/z calcd for C30H39NO6Si, [M+Na]: 560.2439, found: 560.2444.
S93
3-Allyl 1-(tert-butyl) (5S)-5-{[(tert-butyldiphenylsilyl)oxy]methyl}-2-oxopyrrolidine-1,3-
dicarboxylate (lvii)
S94
IV. Synthesis of difluoromethylated compounds
General Procedure 3: C-difluoromethylation
An oven-dried microwave tube was charged with the desired substrate (xix to lvi) (0.3 mmol,
1.0 equiv.) and dry DCM (2 mL). The resulting solution was stirred 10 min at 0 °C and
potassium tert-butoxide (71 mg, 0.63 mmol, 2.1 equiv.) was added. The resulting colored
solution was stirred at this temperature for 30 min and cooled down to –40 °C. I (207 mg,
0.6 mmol, 2.0 equiv.) was then added and the resulting solution was stirred for 12h. The
reaction was stopped by the addition of H2O (5 mL). The aqueous layer was extracted with
ethyl acetate and the combined organic phases were dried over anhydrous MgSO4 and
purified by flash column chromatography over silica gel.
General Procedure 4: Krapcho decarboxylation
An oven-dried microwave tube was charged with the difluoromethylated product (1 equiv.)
and lithium chloride (2-3 equiv.). Deuterated DMSO (0.75 mL) and H2O (1-5 equiv.). The
resulting solution was stirred for 15 to 90 minutes min at 100-180 °C. When TLC and 19F NMR
showed completion, the resulting solution was cooled down to room temperature, adsorbed
on Celite® and purified by flash column chromatography over silica gel.
S95
General Procedure 5: Pd-catalyzed decarboxylative protonation
An oven-dried microwave tube was charged with palladium diacetate (1.3 mg, 0.006 mmol,
0.1 equiv.) and 1,2-bis(diphenylphosphino)ethane (3 mg, 0.0075 mmol, 0.125 equiv.) and dry
dioxane (0.6 mL). The resulting solution was stirred 60 min at 40 °C. To this solution was
added formic acid (13.6 µL, 0.36 equiv.) and immediately after a solution of the
difluoromethylated precursor (0.06 mmol, 1.0 equiv.) in dry dioxane (1.2 mL). The resulting
reaction mixture was stirred for 12h, filtered over Celite®, concentrated and purified by flash
column chromatography over silica gel.
S96
Methyl 1-benzyl-3-(difluoromethyl)-2-oxopiperidine-3-carboxylate (3)
C15H17F2NO3 (MW = 297.30 g.mol-1)
Synthesized according to general procedure 3: Methyl 1-benzyl-2-oxopiperidine-3-

carboxylate (xix) (74 mg, 0.3 mmol), potassium tert-butoxide (71 mg, 0.63 mmol,
2.1 equiv.) and I (207 mg, 0.6 mmol, 2 equiv.). Purification by flash column chromatography
over silica gel eluting with a PE/acetone gradient (9:1 to 8:2) afforded the desired product as
a colorless oil (75 mg, 84%).
1H NMR (CDCl3, 400 MHz):  7.38-7.28 (m, 3H), 7.28-7.26 (m, 2H), 6.63 (t, J = 55.8 Hz, 1H),
4.71 (d, J = 14.7 Hz, 1H), 4.62 (d, J = 14.8 Hz, 1H), 3.85 (s, 3H), 3.31-3.27 (m, 2H), 2.27-2.24
(m, 2H), 2.18-2.07 (m, 1H), 1.96-1.88 (m, 1H).
13C NMR (CDCl3, 100 MHz):  168.9 (d, J = 12.1 Hz), 163.6 (d, J = 7.7 Hz), 136.2, 128.7, 127.8,
127.6, 116.2 (dd, J = 248.2, 243.0 Hz), 57.5 (dd, J = 23.7, 22.0 Hz), 65.5, 53.1 (d, J = 1.9 Hz),
50.9, 47.0, 23.2 (d, J = 4.8 Hz), 19.7.
55.9 Hz, 1F).
HRMS: m/z calcd for C15H17F2NO3, [M+H]: 298.1255, found: 298.1250.
S97
Methyl 1-benzyl-3-(difluoromethyl)-2-oxopiperidine-3-carboxylate (3)
S98
S99
Benzyl 1-benzyl-3-(difluoromethyl)-2-oxopiperidine-3-carboxylate (4)
C21H21F2NO3 (MW = 373.40 g.mol-1)
Synthesized according to general procedure 3: Benzyl 1-benzyl-2-oxopiperidine-3-

carboxylate (xx) (97 mg, 0.3 mmol), potassium tert-butoxide (71 mg, 0.63 mmol, 2.1 equiv.)
and I (207 mg, 0.6 mmol, 2 equiv.). Purification by flash column chromatography over silica
gel eluting with a PE/EA gradient (95:5 to 7:3) afforded the desired product as a colorless oil
(99 mg, 88%).
RF = 0.51 (PE/EA 8:2).
(t, J = 55.8 Hz, 1H), 5.26 (s, 3H), 4.76 (d, J = 14.8 Hz, 1H), 4.51 (d, J = 14.8 Hz, 1H), 3.25 (dd,
J = 7.3, 4.6 Hz, 2H), 2.26-2.20 (m, 2H), 2.06 (m, 1H), 1.88 (m, 1H).
13C NMR (CDCl3, 100 MHz):  168.4 (d, J = 12.5 Hz), 163.5 (d, J = 10.1 Hz), 136.2, 135.1,
128.7, 128.7, 128.5, 128.0, 127.8, 127.6, 116.2 (dd, J = 248.3, 242.7 Hz), 67.8, 57.6 (dd,
J = 23.9, 21.9 Hz), 50.8, 46.9, 23.3 (dd, J = 5.2, 1.9 Hz), 19.7.
55.9 Hz, 1F).
S100
Benzyl 1-benzyl-3-(difluoromethyl)-2-oxopiperidine-3-carboxylate (4)
S101
S102
Allyl 1-benzyl-3-(difluoromethyl)-2-oxopiperidine-3-carboxylate (5)
C17H19F2NO3 (MW = 323.13 g.mol-1)
Synthesized according to general procedure 3: Allyl 1-benzyl-2-oxopiperidine-3-carboxylate

(xxi) (1 g, 3.66 mmol), potassium tert-butoxide (863 mg, 7.69 mmol, 2.1 equiv.) and I (2.51 g,
7.32 mmol, 2 equiv.). Purification by flash column chromatography over silica gel eluting
with a PE/EA gradient (9:1 to 75:25) afforded the desired product as a white solid (805 mg,
74%).
RF = 0.37 (PE/EA 85:15).
5.92 (ddt, J = 17.2, 10.5, 5.7 Hz, 1H), 5.36 (dq, J = 17.2, 1.5 Hz, 1H), 5.28 (dq, J = 10.5, 1.2 Hz,
1H), 4.73-4.70 (m, 3H), 4.56 (d, J = 14.8 Hz, 1H), 3.29-3.25 (m, 2H), 2.24 (dd, J = 9.1, 4.8 Hz,
2H), 2.15-2.05 (m, 1H), 1.94-1.86 (m, 1H).
127.8, 127.6, 119.0, 116.2 (dd, J = 246.1, 241.5 Hz), 66.6, 57.6 (dd, J = 23.8, 22.0 Hz), 50.8,
47.0, 23.3 (dd, J = 5.3, 2.1 Hz), 19.7.
55.9 Hz, 1F).
S103
Allyl 1-benzyl-3-(difluoromethyl)-2-oxopiperidine-3-carboxylate (5)
S104
S105
Methyl 1-benzyl-3-(difluoromethyl)-2,6-dioxopiperidine-3-carboxylate (6)
C15H15F2NO4 (MW = 311.28 g.mol-1)
Synthesized according to general procedure 3: Methyl 1-benzyl-2,6-dioxopiperidine-3-

carboxylate (xxii) (78 mg, 0.3 mmol), potassium tert-butoxide (71 mg, 0.63 mmol,
over silica gel eluting with a PE/EA gradient (9:1 to 85:15) afforded the desired product as an
off-white solid (78 mg, 84%).
RF = 0.45 (PE/EA 8:2).
1H NMR (CDCl3, 400 MHz):  7.30-7.24 (m, 5H), 6.55 (t, J = 55.1 Hz, 1H), 5.01 (d, J = 14.0 Hz,
1H), 4.96 (d, J = 14.0 Hz, 1H), 3.78 (s, 3H), 3.00-2.83 (m, 2H), 2.41 (ddd, J = 14.2, 6.0, 4.1 Hz,
1H), 2.30 (ddd, J = 14.2, 11.8, 5.9 Hz, 1H).
13C NMR (CDCl3, 100 MHz):  170.4, 166.3 (d, J = 7.6 Hz), 165.9 (d, J = 9.2 Hz), 136.3, 128.5,
128.4, 127.6, 114.9 (t, J = 247.8 Hz), 57.9 (t, J = 22.6 Hz), 53.8, 43.6, 28.8, 17.9 (t, J = 4.0 Hz).
19F NMR (CDCl3, 376.5 MHz):  −126.68 (dd, J = 284.4, 55.1 Hz, 1F), –131.18 (dd, J = 284.2,
55.1 Hz, 1F).
S106
Methyl 1-benzyl-3-(difluoromethyl)-2,6-dioxopiperidine-3-carboxylate (6)
S107
S108
Methyl 3-(difluoromethyl)-1-methyl-2-oxo-1,2,3,4-tetrahydroquinoline-3-carboxylate (7)
C13H13F2NO3 (MW = 269.25 g.mol-1)
Synthesized according to general procedure 3: Methyl 1-methyl-2-oxo-1,2,3,4-

tetrahydroquinoline-3-carboxylate (xxv) (66 mg, 0.3 mmol), potassium tert-butoxide (71 mg,
0.63 mmol, 2.1 equiv.) and I (207 mg, 0.6 mmol, 2 equiv.). Purification by flash column
chromatography over silica gel eluting with PE/EA/acetone (85:10:5) afforded the desired
product as a colorless oil (78 mg, 96%).
RF = 0.32 (PE/EA/Acetone 85:10:5).
1H NMR (CDCl3, 400 MHz):  7.30-7.26 (m, 2H), 7.09 (td, J = 7.5, 1.1 Hz, 1H), 6.97
(d, J = 7.9 Hz, 1H), 6.64 (t, J = 55.3 Hz, 1H), 3.65 (s, 3H), 3.41-3.30 (m, 1H), 3.41 (s, 3H).
13C NMR (CDCl3, 100 MHz):  166.0 (d, J = 7.8 Hz), 163.5, 138.2, 128.7, 127.9, 124.0, 122.7,
118.7, 114.9 (t, J = 244.5), 114.8, 66.7, 57.2, 53.4, 30.4, 26.3.
55.6 Hz, 1F).
S109
Methyl 3-(difluoromethyl)-1-methyl-2-oxo-1,2,3,4-tetrahydroquinoline-3-carboxylate (7)
S110
S111
Methyl 1,3-dibenzyl-5-(difluoromethyl)-2,4-dioxohexahydropyrimidine-5-carboxylate (8)
C21H20F2N2O4 (MW = 402.40 g.mol-1)
Synthesized according to general procedure 3: Methyl 1,3-dibenzyl-2,4-

dioxohexahydropyrimidine-5-carboxylate (xxvii) (106 mg, 0.3 mmol), potassium
tert-butoxide (71 mg, 0.63 mmol, 2.1 equiv.) and I (207 mg, 0.6 mmol, 2 equiv.). Purification
by flash column chromatography over silica gel eluting with PE/EA (85:15) afforded the
desired product as a yellowish oil (70 mg, 58%).
RF = 0.28 (PE/EA 85:15).
2H), 4.91 (d, J = 14.8 Hz, 1H), 4.42 (d, J = 14.9 Hz, 1H), 3.70 (d, J = 13.2 Hz, 1H), 3.66 (s, 3H),
3.60 (d, J = 13.2 Hz, 1H).
128.9, 128.5, 128.5, 128.4, 128.2, 127.6, 113.8 (dd, J = 250.5, 246.7 Hz), 57.4 (dd, J = 23.2,
20.6 Hz), 53.9, 52.4, 44.9, 41.6 (t, J = 5.0 Hz).
55.7 Hz, 1F).
HRMS: m/z calcd for C21H20F2N2O4, [M+H]: 403.1469, found: 403.1470.
S112
Methyl 1,3-dibenzyl-5-(difluoromethyl)-2,4-dioxohexahydropyrimidine-5-carboxylate (8)
S113
S114
Methyl 1-benzyl-3-(difluoromethyl)-2-oxopyrrolidine-3-carboxylate (9)
C14H15F2NO3 (MW = 283.27 g.mol-1)
Synthesized according to general procedure 3. Methyl 1-benzyl-2-oxopyrrolidine-3-

carboxylate (xxix) (70 mg, 0.3 mmol), potassium tert-butoxide (71 mg, 0.63 mmol, 2.1 equiv.)
gel eluting with a PE/EA gradient (9:1 to 7:3) afforded the desired product as a colorless oil
(66 mg, 78%).
RF = 0.35 (PE/EA 9:1).
4.55 (d, J = 14.8 Hz, 1H), 4.41 (d, J = 14.8 Hz, 1H), 3.83 (s, 3H), 3.41 (td, J = 9.0, 6.6 Hz, 1H),
3.28 (td, J = 9.3, 4.1 Hz, 1H), 2.56-2.40 (m, 2H).
13C NMR (CDCl3, 100 MHz):  167.7 (dd, J = 6.5, 4.6 Hz), 166.7-166.6 (m), 135.3, 128.8,
127.9, 115.0 (t, J = 242.2 Hz), 60.4 (t, J = 23.5 Hz), 53.3 (d, J = 2.4 Hz), 47.1, 44.3, 20.6.
19F NMR (CDCl3, 376.5 MHz):  –129.3 (dd, J = 55.4, 3.6 Hz, 2F).
S115
Methyl 1-benzyl-3-(difluoromethyl)-2-oxopyrrolidine-3-carboxylate (9)
S116
S117
3-Benzoyl-1-benzyl-3-(difluoromethyl)pyrrolidin-2-one (10)
C19H17F2NO2 (MW = 329.25 g.mol-1)
Synthesized according to general procedure 3. 3-Benzoyl-1-benzylpyrrolidin-2-one (xxxi)

(84 mg, 0.3 mmol), potassium tert-butoxide (71 mg, 0.63 mmol, 2.1 equiv.) and I
(207 mg, 0.6 mmol, 2 equiv.). Purification by flash column chromatography over silica gel
eluting with a PE/EA gradient (9:1 to 7:3) afforded the desired product as an off-white solid
(73 mg, 74%).
RF = 0.63 (PE/EA 7:3).
(dd, J = 7.7, 1.8 Hz, 1H), 6.75 (dd, J = 55.6, 54.8 Hz, 1H), 4.69 (d, J = 14.5 Hz, 1H), 4.44
(d, J = 14.5 Hz, 1H), 3.53-3.46 (m, 2H), 2.60 (t, J = 7.2 Hz, 2H).
128.9, 128.7, 128.5, 128.4, 128.1, 115.8 (dd, J = 247.1, 241.6 Hz), 65.5 (t, J = 21.2 Hz), 47.5,
44.4, 21.4 (t, J = 3.2 Hz).
55.7 Hz, 1F).
S118
3-Benzoyl-1-benzyl-3-(difluoromethyl)pyrrolidin-2-one (10)
S119
S120
Methyl 1-benzyl-3-(difluoromethyl)-2,5-dioxopyrrolidine-3-carboxylate (11)
C14H13F2NO4 (MW = 297.26 g.mol-1)
Synthesized according to general procedure 3. Methyl 1-benzyl-2,5-dioxopyrrolidine-3-

carboxylate (xxxii) (74 mg, 0.3 mmol), potassium tert-butoxide (71 mg, 0.63 mmol,
RF = 0.4 (PE/EA 8:2).
2H), 3.84 (s, 3H), 3.25 (d, J = 18.4 Hz, 1H), 3.09 (d, J = 18.4 Hz, 1H).
13C NMR (CDCl3, 100 MHz):  173.3, 165.0 (d, J = 10.3 Hz), 134.5, 128.8, 128.2, 128.1, 113.5
(dd, J = 248.5, 243.0 Hz), 59.5 (t, J = 24.1 Hz), 54.1, 43.3, 31.5 (t, J = 2.6 Hz).
55.4 Hz, 1F).
S121
Methyl 1-benzyl-3-(difluoromethyl)-2,5-dioxopyrrolidine-3-carboxylate (11)
S122
S123
Methyl 3-(difluoromethyl)-1-methyl-2-oxoindoline-3-carboxylate (12)
C12H11F2NO3 (MW = 255.22 g.mol-1)
Synthesized according to general procedure 3. Methyl 1-methyl-2-oxoindoline-3-carboxylate

(xxxiv) [81 mg (76 % purity), 0.3 mmol], potassium tert-butoxide (71 mg, 0.63 mmol,
over silica gel eluting with a PE/acetone gradient (85:15 to 75:25) afforded the desired
product as a brown oil (71 mg, 92%).
RF = 0.3 (PE/Acetone 85:15).
1H NMR (CDCl3, 400 MHz):  7.45-7.41 (m, 2H), 7.15 (td, J = 7.6, 1.0 Hz, 1H), 6.91 (dt, J = 7.4,
1.0 Hz, 1H), 6.54 (t, J = 54.8 Hz, 1H), 3.77 (s, 3H), 3.26 (s, 3H).
13C NMR (CDCl3, 100 MHz):  144.9, 130.4, 125.8, 123.4, 121.5, 114.5 (t, J = 245.2 Hz), 108.8,
62.6 (d, J = 23.2 Hz), 53.6, 26.8.
S124
Methyl 3-(difluoromethyl)-1-methyl-2-oxoindoline-3-carboxylate (12)
S125
S126
1-(tert-Butyl) 3-methyl 3-(difluoromethyl)-2-oxoazetidine-1,3-dicarboxylate (13)
C11H15F2NO5 (MW = 279.24 g.mol-1)
Synthesized according to general procedure 3. 1-(tert-Butyl) 3-methyl 2-oxoazetidine-1,3-

dicarboxylate (xxxvi) (114 mg, 0.6 mmol), potassium tert-butoxide (142 mg,
desired product as an off-white solid (24 mg, 17%).
RF = 0.6 (PE/EA 8:2).
1H NMR (CDCl3, 400 MHz):  6.43 (t, J = 54.5 Hz, 1H), 4.04 (dd, J = 7.4, 1.2 Hz, 1H), 3.90
(d, J = 7.3 Hz, 1H), 3.90 (s, 3H), 1.53 (s, 9H).
13C NMR (CDCl3, 100 MHz):  163.6 (d, J = 10.5 Hz), 155.9 (d, J = 13.0 Hz), 147.1, 112.0
(t, J = 239.7 Hz), 84.8, 66.2 (d, J = 24.5, 23.2 Hz), 53.8, 41.4, 27.9.
54.8 Hz, 1F).
S127
1-(tert-Butyl) 3-methyl 3-(difluoromethyl)-2-oxoazetidine-1,3-dicarboxylate (13)
S128
S129
Methyl 1-benzyl-3-(difluoromethyl)-2-oxoazepane-3-carboxylate (14)
C16H19F2NO3 (MW = 311.33 g.mol-1)
Synthesized according to general procedure 3. Methyl 1-benzyl-2-oxoazepane-3-carboxylate

(xxxvii) (78 mg, 0.3 mmol), potassium tert-butoxide (71 mg, 0.63 mmol, 2.1 equiv.) and
I (207 mg, 0.6 mmol, 2 equiv.). Purification by flash column chromatography over silica gel
eluting with a PE/EA gradient (9:1 to 8:2) afforded the desired product as a colorless oil
(60 mg, 64%).
RF = 0.71 (PE/EA 8:2).
1H NMR (CDCl3, 400 MHz):  7.36-7.24 (m, 5H), 6.61 (t, J = 56.3 Hz, 1H), 4.95 (d, J = 14.7,
1H), 4.31 (d, J = 14.7, 1H), 3.83 (s, 3H), 3.23 (ddd, J = 14.2, 11.2, 2.7 Hz, 1H), 3.14 (dt, J = 15.7,
4.1 Hz, 1H), 2.34-2.29 (m, 1H), 2.08-1.94 (m, 2H), 1.77-1.68 (m, 1H), 1.66-1.56 (m, 1H),
1.49-1.37 (m, 1H).
13C NMR (CDCl3, 100 MHz)  167.9 (d, J = 7.3 Hz), 167.5 (d, J = 7.5 Hz), 137.1, 128.6, 127.9,
127.6, 116.2 (dd, J = 251.7, 243.9 Hz), 61.4 (t, J = 20.7 Hz), 53.2, 51.6, 45.9, 26.1, 22.9 (t,
J = 4.1 Hz), 22.6.
19F NMR (CDCl3, 376.5 MHz)  –127.89 (dd, J = 276.2, 55.9 Hz, 1F), –129.93 (dd, J = 276.2,
57.2 Hz, 1F).
S130
Methyl 1-benzyl-3-(difluoromethyl)-2-oxoazepane-3-carboxylate (14)
S131
S132
Methyl 3-(difluoromethyl)-2-oxotetrahydrofuran-3-carboxylate (15)
C7H8F2O4 (MW = 194.13 g.mol-1)
Synthesized according to general procedure 3: Methyl 2-oxotetrahydrofuran-3-carboxylate

(xxxix) (43 mg, 0.3 mmol), potassium tert-butoxide (71 mg, 0.63 mmol, 2.1 equiv.) and
I (207 mg, 0.6 mmol, 2 equiv.) in dry THF (3 mL). After 3 d stirring at rt, the reaction was
stopped. Crude 1H NMR showed a 39% conversion. Purification by flash column
chromatography over silica gel eluting with a PE/acetone gradient (85:15 to 8:2) afforded
the desired product as a yellowish oil (15 mg, 26%, 67% brsm).
1H NMR (CDCl3, 400 MHz):  6.47 (dd, J = 55.5, 54.6 Hz, 1H), 4.50-4.46 (m, 2H), 3.87 (s, 3H),
2.82 (dddd, J = 13.7, 7.5, 4.5, 0.7 Hz, 1H), 2.74 (ddd, J = 13.6, 8.9, 8.1 Hz, 1H).
13C NMR (CDCl3, 100 MHz):  169.0 (d, J = 9.1 Hz), 165.3 (d, J = 9.8 Hz), 114.1 (dd, J = 246.4,
244.1 Hz), 67.2, 58.7 (t, J = 23.6 Hz), 53.9, 24.7.
54.7, 1F).
HRMS: m/z calcd for C7H8O4, [M+H]: 195.0469, found: 195.0483.
S133
Methyl 3-(difluoromethyl)-2-oxotetrahydrofuran-3-carboxylate (15)
S134
S135
3-(Difluoromethyl)-N,N-dimethyl-2-oxotetrahydrofuran-3-carboxamide (16)
C8H11F2NO3 (MW = 207.07 g.mol-1)
Synthesized according to general procedure 3: N,N-Dimethyl-2-oxotetrahydrofuran-3-

carboxamide (xli) (47 mg, 0.3 mmol), potassium tert-butoxide (71 mg, 0.63 mmol,
2.1 equiv.) and I (207 mg, 0.6 mmol, 2 equiv.). After stirring overnight at –40 °C, the reaction
was allowed to warm up and stirring was continued at rt for an additional 36 h. Purification
by flash column chromatography over silica gel eluting with PE/EA (75:25) afforded the
desired product as a pale yellow solid (41 mg, 65%).
RF = 0.4 (PE/EA 7:3).
1H NMR (CDCl3, 400 MHz):  6.48 (t, J = 55.0 Hz, 1H), 4.55-4.43 (m, 2H), 3.03 (s, 6H), 2.85
(ddd, J = 14.1, 8.4, 5.0 Hz, 1H), 2.79-2.71 (m, 1H).
13C NMR (CDCl3, 100 MHz)  170.9 (dd, J = 5.2, 2.2 Hz), 164.2 (dd, J = 3.7 Hz), 114.7 (dd,
J = 248.6, 245.1 Hz), 66.9, 57.9 (t, J = 21.7 Hz), 37.4, 26.7 (t, J = 3.2 Hz).
19F NMR (CDCl3, 376.5 MHz)  –125.1 (dd, J = 282.5, 55.1 Hz, 1F), –126.1 (dd, J = 285.3,
55.0 Hz, 1F).
S136
3-(Difluoromethyl)-N,N-dimethyl-2-oxotetrahydrofuran-3-carboxamide (16)
S137
S138
(E)-1-Benzyl-3-(fluoromethylene)piperidin-2-one (17) – Krapcho decarboxylation
C13H14FNO (MW = 219.26 g.mol-1)
Synthesized according to general procedure 4: methyl 1-benzyl-3-(difluoromethyl)-2-

oxopiperidine-3-carboxylate (3) (20 mg, 0.06 mmol), deuterated DMS0 (0.75 mL), added LiCl
(8 mg, 0.18 mmol, 3 equiv.) and H2O (5 µL). The resulting solution was allowed to warm up
to the desired temperature and the conversion was determined with 19F NMR analysis. The
with PE/Et2O (6:4) to afford the desired product as a pale yellow solid (12 mg, 92%).
RF = 0.4 (PE/Et2O 6:4).
1H NMR (CDCl3, 400 MHz):  7.61 (dt, J = 82.8, 2.1 Hz, 1H), 7.34-7.27 (m, 3H), 7.26-7.23 (m,
2H), 4.64 (s, 2H), 3.26 (t, J = 5.8 Hz, 2H), 2.54 (ddt, J = 6.8, 5.1, 2.5 Hz, 2H), 1.82-1.76 (m, 2H).
128.0, 127.5, 115.5 (d, J = 13.7 Hz), 50.4, 47.0, 21.9, 21.2 (d, J = 4.7 Hz).
19F NMR (CDCl3, 376.5 MHz):  –123.44 (dt, J = 82.9, 2.9 Hz, 1F).
HRMS: m/z calcd for C13H14FNO, [M+H]: 220.1138, found: 220.1166.
Conversion
Entry R time Temperature Comments
SM (%) V-CHF (%) T-CHF2 (%)
1 Boc 3d 40 °C 100 0 0 -
2 Boc 24 h 100 °C 71 29 0 Lactam opening
3 Boc 48 h 100 °C 17 83 0 Lactam opening
3 Boc 3h 180 °C nd nd nd degradation
4 Bn 3d 40 °C 100 0 0 -
5 Bn 24 h 100 °C 33 67 0 -
6 Bn 48 h 100 °C 17 83 0 -
7 Bn 15 min 180 °C 0 99 0 92% isolated
S139
Mechanistical considerations
The C−F bond is both stabilized by its ionic component and strongly polarized, which
promotes a E1CB elimination process.28 The anion formed after the chloride-induced
decarboxylation is stabilized by the inductive withdrawing effect of the fluorine atomes on
the CHF2 moiety. As the E1CB mechanism proceeds through an anti-elimination, two
transition states are possible (TS-E and TS-Z). TS-E shows two main stabilizing interactions
related to the polarizations of both C-F and the carbonyl bonds: an opposition of two
permanent dipoles and a potential H-bonding. TS-Z, on the contrary, shows a strong
destabilizing dipole interaction. In addition, the conformational preference of the C −F bond
to lie anti-periplanar to the carbonyl of the amide strongly favors TS-E.29
28
O’Hagan, D. Chem. Soc. Rev. 2008, 37, 308-319.
29
Banks, J. W.; Batsanov, A. S.; Howard, J. A. K.; O’Hagan, D.; Rzepa, H. S.; Martin-Santamaria, S. J. Chem. Soc.,
Perkin Trans. 2., 1999, 2409-2411.
S140
(E)-1-Benzyl-3-(fluoromethylene)piperidin-2-one (17)
S141
S142
NOESY
NOESY
S143
HOESY
S144
(E)-1-Benzyl-3-(fluoromethylene)pyrrolidin-2-one (18):
C12H12FNO (MW = 205.23 g.mol-1)
Synthesized according to general procedure 4: Methyl 1-benzyl-3-(difluoromethyl)-2-

oxopyrrolidine-3-carboxylate (9) (17 mg, 0.06 mmol), DMS0 (0.75 mL), LiCl (8 mg, 0.18 mmol,
3 equiv.) and H2O (5.4 µL, 0.3 mmol, 5 equiv.). The reaction mixture was stirred at 180 °C and
monitored by 19F NMR. Complete conversion of the starting material was observed after
15 minutes. Purification by flash column chromatography over silica gel eluting with PE/Et 2O
(7:3) afforded the desired product as a white solid (12 mg, 96%).
RF = 0.35 (PE/Et2O 7:3).
2H), 4.52 (s, 2H), 3.31 (dd, J = 7.4, 6.3 Hz, 2H), 2.79-2.74 (m, 2H).
128.3, 127.8, 116.6 (d, J = 12.4 Hz), 46.9, 44.0, 19.3 (d, J = 1.0 Hz).
S145
(E)-1-Benzyl-3-(fluoromethylene)pyrrolidin-2-one (18):
S146
S147
(E)-1-Benzyl-3-(fluoromethylene)azepan-2-one (19):
C14H16FNO (MW = 233.27 g.mol-1)
Synthesized according to general procedure 4: Methyl 1-benzyl-3-(difluoromethyl)-2-

oxoazepane-3-carboxylate (14) (19 mg, 0.06 mmol), DMS0 (0.75 mL), LiCl (8 mg, 0.18 mmol,
3 equiv.) and H2O (5.4 µL, 0.3 mmol, 5 equiv.). The reaction mixture was stirred at 180 °C and
monitored by 19F NMR. Complete conversion of the starting material was observed after
20 minutes. Purification by flash column chromatography over silica gel eluting with PE/Et 2O
(6:4) afforded the desired product as a white solid (12 mg, 86%).
RF = 0.5 (PE/Et2O 6:4).
1H NMR (CDCl3, 400 MHz):  7.35-7.26 (m, 4H), 7.26 (m, 1H), 7.12 (dt, J = 82.6, 1.6 Hz, 1H),
4.60 (s, 2H), 3.29-3.26 (m, 2H), 2.42-2.38 (m, 2H), 1.71-1.65 (m, 2H), 1.52 (dq, J = 9.4, 5.9 Hz,
2H).
128.2, 127.5, 122.6 (d, J = 9.5 Hz), 51.0, 47.2, 30.3, 26.5, 24.5, 22.3 (d, J = 4.9 Hz).
S148
(E)-1-Benzyl-3-(fluoromethylene)azepan-2-one (19):
S149
S150
(E)-3-(Fluoromethylene)-1-methyl-3,4-dihydroquinolin-2(1H)-one (20):
C11H10FNO (MW = 191.21 g.mol-1)
Synthesized according to general procedure 4: Methyl 3-(difluoromethyl)-1-methyl-2-oxo-

1,2,3,4-tetrahydroquinoline-3-carboxylate (7) (32 mg, 0.12 mmol), DMS0 (1.5 mL), LiCl
(16 mg, 0.26 mmol, 3 equiv.) and H2O (10.8 µL, 0.6 mmol, 5 equiv.). The reaction mixture
was stirred at 180 °C and monitored by 19F NMR. Complete conversion of the starting
material was observed after 10 minutes. Purification by flash column chromatography over
silica gel eluting with PE/Et2O (6:4) afforded the desired product as a white solid (14 mg,
61%).
RF = 0.45 (PE/Et2O 6:4).
1H NMR (CDCl3, 400 MHz):  7.56 (dt, J = 81.4, 2.4 Hz, 1H), 7.27 (m, 1H), 7.20 (m, 1H), 7.05
(td, J = 7.5, 1.1 Hz, 1H), 7.00 (dd, J = 8.2, 1.1 Hz, 1H), 3.77 (t, J = 3.0 Hz, 2H), 3.40 (s, 3H).
127.6, 123.1, 122.1, 114.7, 113.8 (d, J = 14.0 Hz), 30.3, 29.6, 25.1 (d, J = 5.1 Hz).
S151
(E)-3-(Fluoromethylene)-1-methyl-3,4-dihydroquinolin-2(1H)-one (20):
S152
S153
(E)-1,3-Dibenzyl-5-(fluoromethylene)dihydropyrimidine-2,4(1H,3H)-dione (21):
C19H17FN2O2 (MW = 324.36 g.mol-1)
To a solution of methyl 1,3-dibenzyl-5-(difluoromethyl)-2,4-dioxohexahydropyrimidine-5-

carboxylate (8) (36 mg, 0.1 mmol) in deuterated DMS0 (1.5 mL) was added LiCl (9 mg,
0.2 mmol, 2 equiv.) and H2O (1.8 µL, 0.1 mmol, 1 equiv.). The reaction mixture was stirred at
100 °C and monitored by 19F NMR. Complete conversion of the starting material was
observed after 90 minutes. Purification by flash column chromatography over silica gel
eluting with PE/Et2O (7:3) afforded the desired product as a white solid (12 mg, 37%).
RF = 0.4 (PE/Et2O 7:3).
8H), 5.08 (s, 2H), 4.66 (s, 2H), 3.99 (dd, J = 3.6, 2.4 Hz, 2H).
13C NMR (CDCl3, 100 MHz):  160.5, 157.9, 153.8 (d, J = 270.5 Hz), 137.5, 135.7, 128.9,
128.8, 128.4, 128.2, 128.1, 127.5, 125.5, 110.4 (d, J = 12.6 Hz), 51.7, 44.2, 39.8 (d, J = 6.2 Hz),
30.3.
HRMS: m/z calcd for C19H17FN2O2, [M+H]: 325.1352, found: 325.1365.
S154
(E)-1,3-Dibenzyl-5-(fluoromethylene)dihydropyrimidine-2,4(1H,3H)-dione (21):
S155
S156
(E)-1-Benzyl-3-(fluoromethylene)pyrrolidine-2,5-dione (22):
C12H10FNO2 (MW = 219.22 g.mol-1)
Synthesized according to general procedure 4: Methyl 1-benzyl-3-(difluoromethyl)-2,5-

dioxopyrrolidine-3-carboxylate (11) (30 mg, 0.1 mmol), DMS0 (0.75 mL), LiCl (9 mg,
eluting with PE/Et2O (7:3) afforded the desired product as a white solid (16 mg, 73%).
RF = 0.35 (PE/Et2O 7:3).
3H), 4.71 (s, 2H), 2.11 (t, J = 2.6 Hz, 2H).
13C NMR (CDCl3, 100 MHz):  172.3, 168.8 (d, J = 20.5 Hz), 153.8 (d, J = 279.3 Hz), 135.5,
128.9, 128.7, 128.1, 125.5, 111.8 (d, J = 13.3 Hz), 42.5, 30.3, 30.1.
HRMS: m/z calcd for C12H10FNO2, [M+H]: 220.0773, found: 220.0788.
S157
(E)-1-Benzyl-3-(fluoromethylene)pyrrolidine-2,5-dione (22):
S158
S159
(E)-1-Benzyl-3-(fluoromethylene)piperidine-2,6-dione (23):
C13H12FNO2 (MW = 233.24 g.mol-1)
Synthesized according to general procedure 4: methyl 1-benzyl-3-(difluoromethyl)-2,6-

dioxopiperidine-3-carboxylate (6) (31 mg, 0.1 mmol), deuterated DMS0 (0.75 mL), LiCl (9 mg,
eluting with PE/Et2O (7:3) afforded the desired product as a white solid (18 mg, 77%). E
configuration was determined by NOESY and HOESY experiments.
RF = 0.37 (PE/Et2O 7:3).
3H), 4.99 (s, 2H), 2.70 (m, 4H).
128.8, 128.5, 127.6, 114.0 (d, J = 14.4 Hz), 43.1, 31.3, 30.3, 16.6 (d, J = 4.3 Hz).
S160
(E)-1-Benzyl-3-(fluoromethylene)piperidine-2,6-dione (23):
S161
NOESY
S162
NOESY
HOESY
S163
Allyl 1-benzyl-3-(difluoromethyl)-2,6-dioxopiperidine-3-carboxylate (24)
C17H17F2NO4 (MW = 337.32 g.mol-1)
Synthesized according to general procedure 3: Allyl 1-benzyl-2,6-dioxopiperidine-3-

carboxylate (xxiii) (86 mg, 0.3 mmol), potassium tert-butoxide (71 mg, 0.63 mmol,
over silica gel eluting with a gradient PE/EA (9:1 to 7:3) afforded the desired product as an
off-white solid (88 mg, 89%).
RF = 0.55 (PE/EA 8:2).
1H NMR (CDCl3, 400 MHz):  7.31-7.23 (m, 5H), 6.56 (t, J = 55.1 Hz, 1H), 5.77 (ddt, J = 17.3,
10.4, 5.8 Hz, 1H), 5.30-5.24 (m, 2H), 5.00 (d, J = 14.1 Hz, 1H), 4.97 (d, J = 14.0 Hz, 1H), 4.65
(dt, J = 5.7, 1.3 Hz, 2H), 2.96 (dddd, J = 18.0, 11.9, 6.0, 1.0 Hz, 1H), 2.87 (ddd, J = 18.0, 5.7,
4.1 Hz, 1H), 2.42 (ddd, J = 14.2, 6.1, 4.0 Hz, 1H), 2.32 (ddd, J = 14.3, 12.0, 5.7 Hz, 1H).
128.5, 128.4, 127.6, 120.0, 114.9 (t, J = 248.1 Hz), 67.4, 57.9 (dd, J = 23.7, 22.2 Hz), 43.5,
28.8, 18.0 (m).
55.1 Hz, 1F).
S164
Allyl 1-benzyl-3-(difluoromethyl)-2,6-dioxopiperidine-3-carboxylate (24)
S165
S166
Allyl 8-benzyl-6-(difluoromethyl)-7,9-dioxo-8-azaspiro[4.5]decane-6-carboxylate (25)
C21H23F2NO4 (MW = 391.41 g.mol-1)
Synthesized according to general procedure 3: Allyl 8-benzyl-7,9-dioxo-8-

azaspiro[4.5]decane-6-carboxylate (xxiv) (95 mg, 0.28 mmol), potassium tert-butoxide
(71 mg, 0.63 mmol, 2.1 equiv.) and I (207 mg, 0.6 mmol, 2 equiv.). Allowed to warm up to
room temperature after 24h stirring at –40 °C and stirred for 24 h. Purification by flash
column chromatography over silica gel eluting with a PE/EA/DCM gradient (92:4:4 to 8:1:1)
afforded the desired product as a colorless oil (31 mg, 28%).
RF = 0.49 (PE/EA/DCM 86:7:7).
10.4, 6.0 Hz, 1H), 5.31-5.24 (m, 2H), 5.00 (s, 2H), 4.63 (dt, J = 6.0, 1.3 Hz, 2H), 4.65 (dt, J = 5.7,
1.3 Hz, 2H), 2.78-2.68 (m, 2H), 2.29-2.21 (m, 1H), 2.05-1.98 (m, 1H), 1.82-1.56 (m, 6H),
1.51-1.34 (m, 2H).
13C NMR (CDCl3, 100 MHz):  170.2, 167.1 (d, J = 2.9 Hz), 165.9 (dd, J = 6.2, 3.5 Hz), 136.4,
130.3, 128.5, 128.4, 127.5, 120.3, 116.0 (t, J = 252.7 Hz), 67.2, 64.0 (t, J = 19.0 Hz), 44.3, 43.7,
43.0, 35.3 (t, J = 2.3 Hz), 33.8 (t, J = 3.1 Hz), 24.4, 23.8.
53.5 Hz, 1F).
S167
Allyl 8-benzyl-6-(difluoromethyl)-7,9-dioxo-8-azaspiro[4.5]decane-6-carboxylate (25)
S168
S169
Allyl 3-(difluoromethyl)-1-methyl-2-oxo-1,2,3,4-tetrahydroquinoline-3-carboxylate (26)
C15H15F2NO3 (MW = 295.29 g.mol-1)
Synthesized according to general procedure 3: Allyl 1-methyl-2-oxo-1,2,3,4-

tetrahydroquinoline-3-carboxylate (xxvi) (74 mg, 0.3 mmol), potassium tert-butoxide (71 mg,
RF = 0.4 (PE/Et2O 7:3).
1H NMR (CDCl3, 400 MHz):  7.30-7.26 (m, 2H), 7.08 (td, J = 7.5, 1.1 Hz, 1H), 6.98 (d,
J = 8.0 Hz, 1H), 6.65 (t, J = 55.3 Hz, 1H), 5.72-5.62 (m, 1H), 5.15-5.08 (m, 2H), 4.52 (dq, J = 5.6,
1.5 Hz, 2H), 3.41-3.31 (m, 1H), 3.40 (s, 3H).
127.9, 123.9, 122.7, 118.7, 114.9 (dd, J = 249.6, 244.5 Hz), 114.8, 66.7, 57.2 (dd, J = 23.6,
21.5), 30.3, 26.4 (dd, J = 4.9, 3.6 Hz).
55.6 Hz, 1F).
S170
Allyl 3-(difluoromethyl)-1-methyl-2-oxo-1,2,3,4-tetrahydroquinoline-3-carboxylate (26)
S171
S172
Allyl 1,3-dibenzyl-5-(difluoromethyl)-2,4-dioxohexahydropyrimidine-5-carboxylate (27)
C23H22F2N2O4 (MW = 428.44 g.mol-1)
Synthesized according to general procedure 3: Allyl 1,3-dibenzyl-2,4-

dioxohexahydropyrimidine-5-carboxylate (xxviii) (114 mg, 0.3 mmol), potassium tert-
butoxide (71 mg, 0.63 mmol, 2.1 equiv.) and I (207 mg, 0.6 mmol, 2 equiv.). Purification by
flash column chromatography over silica gel eluting with PE/EA (9:1) afforded the desired
product as a yellowish oil (101 mg, 78%).
RF = 0.45 (PE/EA 8:2).
10.3, 5.9 Hz, 1H), 5.25 (m, 1H), 5.21 (m, 1H), 5.03-4.96 (m, 3H), 4.56 (dq, J = 5.9, 1.1 Hz, 2H),
4.35 (d, J = 14.7 Hz, 1H), 3.70 (d, J = 13.1 Hz, 1H), 3.61 (d, J = 13.2 Hz, 1H), 3.70 (d, J = 13.2 Hz,
1H), 3.66 (s, 3H), 3.60 (d, J = 13.2 Hz, 1H).
130.2, 128.9, 128.5, 128.5, 128.2, 127.6, 120.0, 113.9 (t, J = 250.6, 246.7 Hz), 67.9, 57.4
(dd, J = 23.3, 20.4 Hz), 52.2, 45.0, 41.6 (t, J = 5.1 Hz).
54.7 Hz, 1F).
S173
Allyl 1,3-dibenzyl-5-(difluoromethyl)-2,4-dioxohexahydropyrimidine-5-carboxylate (27)
S174
S175
Allyl 1-benzyl-3-(difluoromethyl)-2-oxopyrrolidine-3-carboxylate (28)
C16H17F2NO3 (MW = 309.31 g.mol-1)
Synthesized according to general procedure 3: Allyl 1-benzyl-2-oxopyrrolidine-3-carboxylate

(xxix) (78 mg, 0.3 mmol), potassium tert-butoxide (71 mg, 0.63 mmol, 2.1 equiv.) and
eluting with a PE/acetone gradient (9:1 to 8:2) afforded the desired product as a colourless
oil (70 mg, 75%).
5.89 (ddt, J = 17.3, 10.5, 5.7 Hz, 1H), 5.35 (dq, J = 17.2, 1H), 5.28 (dq, J = 10.4, 1.3 Hz, 1H),
4.78-4.68 (m, 2H), 4.52 (d, J = 15.0 Hz, 1H), 4.47 (d, J = 15.2 Hz, 1H), 3.42 (td, J = 9.0, 6.8 Hz,
1H), 3.29 (td, J = 9.2, 4.1 Hz, 1H), 2.57-2.43 (m, 2H).
13C NMR (CDCl3, 100 MHz) :  166.9, 166.6, 135.3, 130.9, 128.8, 127.9, 127.9, 119.1, 115.0
(t, J = 245.3 Hz), 66.8, 60.4 (t, J = 23.4 Hz), 47.2, 44.4, 20.7.
19F NMR (CDCl3, 376.5 MHz):  −129.4 (dd, J = 55.4, 13.9 Hz, 2F).
S176
Allyl 1-benzyl-3-(difluoromethyl)-2-oxopyrrolidine-3-carboxylate (28)
S177
S178
Allyl 1-benzyl-3-(difluoromethyl)-2,5-dioxopyrrolidine-3-carboxylate (29)
C16H15F2NO4 (MW = 323.30 g.mol-1)
Synthesized according to general procedure 3: Allyl 1-benzyl-2,5-dioxopyrrolidine-3-

carboxylate (xxxiii) (82 mg, 0.3 mmol), potassium tert-butoxide (71 mg, 0.63 mmol,
yellowish oil (88 mg, 91%).
RF = 0.6 (PE/EA 8:2).
10.4, 5.8 Hz, 1H), 5.32-5.25 (m, 2H), 4.79 (dd, J = 6.5, 1.7 Hz, 2H), 3.25 (dd, J = 18.5, 1.1 Hz,
1H), 3.10 (d, J = 18.5 Hz, 1H).
128.8, 128.1, 120.0, 113.5 (dd, J = 248.2, 242.8 Hz), 67.7, 59.5 (t, J = 24.0 Hz), 43.3, 31.5
(t, J = 2.6 Hz).
55.4 Hz, 1F).
S179
Allyl 1-benzyl-3-(difluoromethyl)-2,5-dioxopyrrolidine-3-carboxylate (29)
S180
S181
Allyl 1-benzyl-3-(difluoromethyl)-2-oxoazepane-3-carboxylate (30)
C18H21F2NO3 (MW = 337.37 g.mol-1)
Synthesized according to general procedure 3: Allyl 1-benzyl-2-oxoazepane-3-carboxylate

(xxxviii) (86 mg, 0.3 mmol), potassium tert-butoxide (71 mg, 0.63 mmol, 2.1 equiv.) and
eluting with a PE/EA gradient (92:8 to 8:2) afforded the desired product as a colourless oil
(72 mg, 71%).
RF = 0.8 (PE/EA 8:2).
1H NMR (CDCl3, 400 MHz):  7.33-7.22 (m, 5H), 6.60 (dd, J = 56.6, 54.9 Hz, 1H), 5.88
(ddt, J = 17.2, 10.4, 6.0 Hz, 1H), 5.35 (dq, J = 17.2, 1.4 Hz, 1H), 5.27 (dq, J = 10.4, 1.2 Hz, 1H),
5.02 (d, J = 14.7, 1H), 4.75-4.65 (m, 2H), 4.19 (d, J = 14.7, 1H), 3.26-3.18 (m, 1H), 3.14-3.08
(m, 1H), 2.34-2.28 (m, 1H), 2.08-1.93 (m, 2H), 1.77-1.68 (m, 1H), 1.63-1.56 (m, 1H), 1.51-1.39
(m, 1H).
13C NMR (CDCl3, 100 MHz):  167.9 (d, J = 7.3 Hz), 167.6 (d, J = 7.8 Hz, 166.6, 137.1, 130.9,
128.6, 128.0, 127.6, 119.7, 116.2 (dd, J = 251.9, 243.4 Hz), 66.9, 61.3 (t, J = 20.7 Hz), 51.5,
45.8, 26.0, 22.8, 22.6.
57.4 Hz, 1F).
S182
Allyl 1-benzyl-3-(difluoromethyl)-2-oxoazepane-3-carboxylate (24)
S183
S184
Allyl 3-(difluoromethyl)-2-oxotetrahydrofuran-3-carboxylate (31)
C9H10F2O4 (MW = 220.17 g.mol-1)
Synthesized according to general procedure 3: Allyl 2-oxotetrahydrofuran-3-carboxylate (xl)

(51 mg, 0.3 mmol), potassium tert-butoxide (71 mg, 0.63 mmol, 2.1 equiv.) and I (207 mg,
0.6 mmol, 2 equiv.) in dry THF (3 mL). After 3d stirring at the reaction was stopped. Crude
1H NMR showed a 47% conversion. Purification by flash column chromatography over silica
gel eluting with a PE/EA gradient (85:15 to 7:3) afforded the desired product as a yellow oil
(25 mg, 37%, 70% brsm).
RF = 0.42 (PE/EA 8:2).
1H NMR (CDCl3, 400 MHz):  6.49 (dd, J = 55.5, 54.6 Hz, 1H), 5.91 (ddt, J = 17.2, 10.5, 5.8 Hz,
1H), 5.37 (dq, J = 17.1, 1.4 Hz, 1H), 5.31 (dq, J = 10.5, 1.2 Hz, 1H), 4.75 (dq, J = 5.8, 1.3 Hz,
1H), 4.50-4.45 (m, 2H), 2.84-2.80 (m, 1H), 2.78-2.73 (m, 1H).
114.1 (dd, J = 246.4, 244.1 Hz), 67.5, 67.2, 58.7 (t, J = 24.0 Hz), 24.7.
55.4 Hz, 1F).
HRMS: m/z calcd for C9H10F2O4, [M+H]: 221.0625, found: 221.0627.
S185
Allyl 3-(difluoromethyl)-2-oxotetrahydrofuran-3-carboxylate (25)
S186
S187
Allyl 2-(difluoromethyl)-3-(methoxy(methyl)amino)-2-methyl-3-oxopropanoate (32)
C10H15F2NO4 (MW = 251.23 g.mol-1)
Synthesized according to general procedure 3: Allyl 3-(methoxy(methyl)amino)-2-methyl-3-

oxopropanoate (xlv) (60 mg, 0.3 mmol), potassium tert-butoxide (71 mg, 0.63 mmol,
over silica gel eluting with PE/EA/Acetone (84:8:8) afforded the desired product as a
RF = 0.40 (PE/EA/Acetone 8:1:1).
1H NMR (CDCl3, 400 MHz):  6.30 (t, J = 55.5 Hz, 1H), 5.89 (ddt, J = 17.3, 10.5, 5.8 Hz, 1H),
5.37-5.24 (m, 2H), 4.66-4.67-4.65 (m, 2H), 3.63 (s, 3H), 3.20 (s, 3H), 1.56 (t, J = 1.3 Hz, 3H).
13C NMR (CDCl3, 100 MHz):  169.0 (d, J = 3.9 Hz), 167.2 (d, J = 4.4 Hz), 131.3, 118.9, 114.5
(t, J = 245 Hz), 66.2, 60.7, 57.3 (t, J = 21.5 Hz), 33.1, 13.2 (t, J = 4.7 Hz).
S188
Allyl 2-(difluoromethyl)-3-(methoxy(methyl)amino)-2-methyl-3-oxopropanoate (32)
S189
S190
Allyl 2-(difluoromethyl)-2-[methoxy(methyl)carbamoyl]butanoate (33)
C11H17F2NO4 (MW = 265.26 g.mol-1)
Synthesized according to general procedure 3: Allyl 2-[methoxy(methyl)carbamoyl]

butanoate (xlvi) (52 mg, 0.23 mmol), potassium tert-butoxide (54 mg, 0.48 mmol, 2.1 equiv.)
gel eluting with PE/EA/acetone (86:7:7) afforded the desired product as a yellowish oil
(42 mg, 69%).
RF = 0.45 (PE/EA/acetone 8:1:1).
5.33 (dq, J = 17.2, 1.5 Hz, 1H), 5.25 (dq, J = 10.3, 1.2 Hz, 1H), 4.70-4.60 (m, 2H), 3.60 (s, 3H),
3.20 (s, 3H), 2.17 (q, J = 7.6 Hz, 2H), 1.00 (t, J = 7.6 Hz, 3H).
13C NMR (CDCl3, 100 MHz):  168.0 (m), 166.8 (dd, J = 5.6, 2.2 Hz), 131.4, 118.9, 115.1
(t, J = 247.5 Hz), 66.1, 60.6, 60.6 (dd, J = 25.5, 20.2 Hz), 33.0, 22.1 (t, J = 3.4 Hz), 9.2.
19F NMR (CDCl3, 376.5 MHz):  –126.2 (dd, J = 281.2, 54.8, 1F), –127.7 (dd, J = 281.2, 54.9,
1F).
S191
Allyl 2-(difluoromethyl)-2-(methoxy(methyl)carbamoyl)butanoate (33)
S192
S193
Allyl 2-(difluoromethyl)-3-(methoxy(methyl)amino)-3-oxo-2-phenylpropanoate (34)
C15H17F2NO4 (MW = 313.30 g.mol-1)
Synthesized according to general procedure 3: Allyl 3-(methoxy(methyl)amino)-3-oxo-2-

phenylpropanoate (xlvii) (79 mg, 0.3 mmol), potassium tert-butoxide (71 mg, 0.63 mmol,
RF = 0.27 (PE/EA/Acetone 85:15:5).
1H), 4.74 (dt, J = 5.9, 1.4 Hz, 2H), 3.19 (s, 3H), 2.94 (s, 3H).
13C NMR (CDCl3, 100 MHz):  181.0 164.4 (d, J = 3.2 Hz), 135.6, 131.3, 130.6, 129.6, 129.2,
128.5, 128.1, 119.0, 114.8 (t, J = 249.5 Hz), 66.6, 64.7 (t, J = 21.0 Hz), 60.2, 33.3.
S194
Allyl 2-(difluoromethyl)-3-(methoxy(methyl)amino)-3-oxo-2-phenylpropanoate (34)
S195
S196
Allyl 2-(difluoromethyl)-2-(methoxy(methyl)carbamoyl)-3-oxooctanoate (35)
C15H23F2NO2 (MW = 321.36 g.mol-1)
Synthesized according to general procedure 3: Allyl 2-(methoxy(methyl)carbamoyl)-3-

oxooctanoate (xlviii) (81 mg, 0.3 mmol), potassium tert-butoxide (71 mg, 0.63 mmol,
over silica gel eluting with PE/EA (9:1) afforded the desired product as a colorless oil (84 mg,
87%).
RF = 0.6 (PE/EA 8:2).
3.20 (s, 3H), 2.08 (dd, J = 9.4, 7.0 Hz, 2H), 1.42-1.24 (m, 8H), 0.89-0.86 (m, 3H).
13C NMR (CDCl3, 100 MHz):  168.2 (m), 166.8 (dd, J = 5.4, 2.1 Hz), 131.4, 118.9, 115.1
(t, J = 247.6 Hz), 66.2, 60.6, 60.4 (dd, J = 20.8, 19.4 Hz) 33.1, 31.4, 29.8, 29.0 (t, J = 3.1 Hz),
24.4, 22.6, 14.0.
55.1 Hz, 1F).
S197
Allyl 2-(difluoromethyl)-2-(methoxy(methyl)carbamoyl)-3-oxooctanoate (35)
S198
S199
Allyl 2-benzyl-2-(difluoromethyl)-3-(methoxy(methyl)amino)-3-oxopropanoate (36)
C16H19F2NO4 (MW = 327.33 g.mol-1)
Synthesized according to general procedure 3: Allyl 2-benzyl-3-(methoxy(methyl)amino)-3-

oxopropanoate (xlix) (83 mg, 0.3 mmol), potassium tert-butoxide (71 mg, 0.63 mmol,
colorless oil (96 mg, 97%) along with traces of I (3%).
RF = 0.27 (PE/EA/Acetone 85:5:10).
1H NMR (CDCl3, 400 MHz):  7.30-7.24 (m, 3H), 7.17 (dd, J = 7.7, 1.8 Hz, 2H), 6.08
(t, J = 54.0 Hz, 1H), 5.88 (ddt, J = 17.2, 10.4, 5.8 Hz, 1H), 5.34 (dq, J = 17.2, 1.5 Hz, 1H), 5.25
(dq, J = 10.4, 1.3 Hz, 1H), 4.69 (ddt, J = 13.2, 5.8, 1.4 Hz, 1H), 4.61 (ddt, J = 13.3, 5.9, 1.4 Hz,
1H), 3.63 (s, 3H), 3.54-3.40 (m, 2H), 3.22 (s, 3H).
13C NMR (CDCl3, 100 MHz):  166.9, 166.2, 134.4, 131.3, 130.3, 128.5, 127.4, 119.0, 114.8
(d, J = 250.4, 245.1 Hz), 66.3, 60.4, 60.3, 35.7, 33.1.
19F NMR (CDCl3, 376.5 MHz):  –126.6 (ddd, J = 277.3, 54.0, 3.3 Hz, 1F), –129.6 (dd,
J = 277.9, 54.5 Hz, 1F).
S200
Allyl 2-benzyl-2-(difluoromethyl)-3-(methoxy(methyl)amino)-3-oxopropanoate (36)
S201
S202
Allyl 2-(difluoromethyl)-2-(methoxy(methyl)carbamoyl)pent-4-enoate (37)
C12H17F2NO4 (MW = 277.27 g.mol-1)
Synthesized according to general procedure 3: Allyl 2-(methoxy(methyl)carbamoyl)pent-4-

enoate (l) (68 mg, 0.3 mmol), potassium tert-butoxide (71 mg, 0.63 mmol, 2.1 equiv.) and
eluting with PE/EA/Acetone (85:10:5) afforded the desired product as a colorless oil (75 mg,
90%).
RF = 0.35 (PE/EA/Acetone 85:10:5).
1H), 5.18 (dq, J = 16.9, 1.5 Hz, 1H), 5.13 (ddt, J = 10.1, 2.0, 1.3 Hz, 1H), 4.72-4.61 (m, 2H),
3.62 (s, 3H), 3.20 (s, 3H), 2.94-2.83 (m, 2H).
119.0, 114.9 (dd, J = 247.3, 246.6 Hz), 66.3, 60.5, 60.3 (dd, J = 21.1, 20.2 Hz), 33.5, 33.1
(t, J = 3.2 Hz).
54.9 Hz, 1F).
S203
Allyl 2-(difluoromethyl)-2-(methoxy(methyl)carbamoyl)pent-4-enoate (37)
S204
S205
1-Allyl 4-ethyl 2-(difluoromethyl)-2-(methoxy(methyl)carbamoyl)succinate (38)
C13H19F2NO6 (MW = 323.29 g.mol-1)
Synthesized according to general procedure 3: 1-Allyl 4-ethyl 2-[methoxy(methyl)carbamoyl]

succinate (li) (82 mg, 0.3 mmol), potassium tert-butoxide (71 mg, 0.63 mmol, 2.1 equiv.) and
eluting with PE/DCM/EA (7:2:1) afforded the desired product as a yellowish oil (89 mg, 92%).
RF = 0.33 (PE/DCM/EA 7:2:1).
5.35 (dq, J = 17.2, 1.5 Hz, 1H), 5.27 (dq, J = 10.4, 1.2 Hz, 1H), 4.74-4.65 (m, 2H), 4.14
(qd, J = 7.1, 1.7 Hz), 3.60 (s, 3H), 3.28 (dt, J = 16.8, 1.0 Hz, 1H), 3.22 (s, 3H), 3.11 (d, J = 16.8
Hz, 1H), 1.24 (t, J = 7.1 Hz, 3H).
13C NMR (CDCl3, 100 MHz):  169.7, 166.6 (m), 165.7 (dd, J = 6.1, 2.4 Hz), 131.1, 119.2,
117.0, 114.5 (t, J = 247.3 Hz), 66.7, 61.0, 60.6, 59.1 (t, J = 21.3 Hz), 33.6 (t, J = 3.6 Hz), 33.5,
14.0.
55.2 Hz, 1F).
S206
1-Allyl 4-ethyl 2-(difluoromethyl)-2-(methoxy(methyl)carbamoyl)succinate (38)
S207
S208
Allyl 2-(difluoromethyl)-2-(methoxy(methyl)carbamoyl)pent-4-ynoate (39)
C12H15F2NO4 (MW = 275.25 g.mol-1)
Synthesized according to general procedure 3: Allyl 2-(methoxy(methyl)carbamoyl)pent-4-

ynoate (lii) (68 mg, 0.3 mmol), potassium tert-butoxide (71 mg, 0.63 mmol, 2.1 equiv.) and
eluting with toluene/acetone (97:3) afforded the desired product as a colorless oil (74 mg,
87% pure, 78%) along with an unknown difluoromethylated impurity.
RF = 0.35 (toluene/acetone 95:5).
3.23 (s, 3H), 3.10 (m, 1H), 2.99 (ddd, J = 17.7, 2.8, 0.8 Hz), 2.08 (t, J = 2.8 Hz, 1H).
13C NMR (CDCl3, 100 MHz):  165.4 (m), 166.0 (m), 131.1, 119.1, 114.5 (t, J = 248.1 Hz), 72.0,
66.6, 60.7, 59.4 (t, J = 20.7 Hz), 33.1, 19.4 (t, J = 4.5 Hz).
J = 280.7, 54.6, 1F).
S209
Allyl 2-(difluoromethyl)-2-(methoxy(methyl)carbamoyl)pent-4-ynoate (39)
S210
S211
1-Benzyl-3-(difluoromethyl)piperidin-2-one (40)
C13H15F2NO (MW = 239.27 g.mol-1)
Synthesized according to general procedure 5: 1-Benzyl-3-(difluoromethyl)piperidin-2-one

(5) (1.04 g, 3.12 mmol), palladium diacetate (70 mg, 0.31 mmol, 0.1 equiv.),
1,2-bis(diphenylphosphino)ethane (156 mg, 0.39 mmol, 0.125 equiv.) and formic acid
(728 µL, 18.7 mmol, 6 equiv.). Purification by a fast flash column chromatography over silica
gel eluting with PE/EA (7:3) + 0.1% formic acid afforded the desired product as a colorless oil
(611 mg, 82%).
RF = 0.45 (PE/EA 7:3).
1H NMR (CDCl3, 400 MHz):  7.35-7.27 (m, 3H), 7.24-7.21 (m, 2H), 6.52 (td, J = 56.4, 1.9 Hz,
1H), 4.63 (d, J = 14.7 Hz, 1H), 4.58 (d, J = 14.7 Hz, 1H), 3.25-3.21 (m, 2H), 2.88 (m, 1H),
2.06-1.92 (m, 3H), 1.73 (m, 1H).
13C NMR (CDCl3, 100 MHz):  172.8 (d, J = 3.4 Hz), 136.6, 128.7, 127.9, 127.5, 116.4 (dd,
J = 242.2, 239.9 Hz), 50.3, 47.1, 45.7 (t, J = 23.4 Hz), 21.5, 18.8 (t, J = 3.8 Hz).
19F NMR (CDCl3, 376.5 MHz):  –126.38 (ddd, J = 280.3, 56.3, 8.8 Hz, 1F), –127.39 (ddd,
J = 280.5, 56.5, 26.2 Hz, 1F).
HRMS: m/z calcd for C13H15F2NO, [M+H]: 240.1200, found: 240.1208.
S212
1-Benzyl-3-(difluoromethyl)piperidin-2-one (40)
S213
S214
1-Benzyl-3-(difluoromethyl)piperidine-2,6-dione (41)
C13H13F2NO2 (MW = 253.25 g.mol-1)
Synthesized according to general procedure 5: Allyl 1-benzyl-3-(difluoromethyl)-2,6-

dioxopiperidine-3-carboxylate (24) (20 mg, 0.06 mmol), palladium diacetate (1.3 mg,
0.006 mmol, 0.1 equiv.), 1,2-bis(diphenylphosphino)ethane (3 mg, 0.0075 mmol,
0.125 equiv.) and formic acid (13.6 µL, 0.36 mmol, 6 equiv.). Purification by flash column
chromatography over silica gel eluting with PE/Et2O (65:35) afforded the desired compound
RF = 0.4 (PE/Et2O 65:35).
J = 13.8 Hz, 1H), 4.92 (d, J = 13.9 Hz, 1H), 3.07-2.97 (m, 1H), 2.93 (dt, 17.5, 4.2 Hz, 1H),
2.61 (ddd, J = 17.8, 12.7, 5.7 Hz, 1H), 2.22-2.04 (m, 2H).
13C NMR (CDCl3, 100 MHz):  171.0, 169.2 (dd, J = 9.2, 3.4 Hz), 136.6, 128.7, 128.5, 127.7,
114.7 (dd, J = 242.9, 241.2 Hz), 46.2 (t, J = 24.3 Hz), 43.1, 31.4, 30.3, 14.9 (t, J = 4.2 Hz).
19F NMR (CDCl3, 376.5 MHz):  –126.89 (m, 2F).
S215
1-Benzyl-3-(difluoromethyl)piperidine-2,6-dione (41)
S216
S217
8-Benzyl-6-(difluoromethyl)-8-azaspiro[4.5]decane-7,9-dione (42)
C17H19F2NO2 (MW = 307.34 g.mol-1)
Synthesized according to general procedure 5: Allyl 8-benzyl-6-(difluoromethyl)-7,9-dioxo-8-

azaspiro[4.5]decane-6-carboxylate (25) (23 mg, 0.06 mmol), palladium diacetate (1.3 mg,
chromatography over silica gel eluting with PE/Et2O (7:3) afforded the desired compound as
a colorless oil (11 mg, 62%).
RF = 0.28 (PE/Et2O 7:3).
J = 14.0 Hz, 1H), 4.96 (d, J = 14.0 Hz, 1H), 2.98 (tt, 18.0, 1.9 Hz, 1H), 2.80 (d, 17.7 Hz, 1H),
2.59 (dq, J = 17.8, 1.5 Hz, 1H), 1.81-1.66 (m, 4H), 1.64-1.48 (m, 4H).
13C NMR (CDCl3, 100 MHz):  171.1, 168.7 (dd, J = 7.1, 2.5 Hz), 136.7, 128.4, 128.4, 127.5,
115.9 (t, J = 247.4 Hz), 56.0 (t, J = 24.3 Hz), 43.3, 41.7 (t, J = 1.8 Hz), 40.7 (d, J = 2.2 Hz), 38.8,
35.4, 23.8, 23.0.
J = 287.7, 54.3, 18.4 Hz, 1F).
S218
8-Benzyl-6-(difluoromethyl)-8-azaspiro[4.5]decane-7,9-dione (42)
S219
S220
3-(Difluoromethyl)-1-methyl-3,4-dihydroquinolin-2(1H)-one (43)
C11H11F2NO (MW = 211.21 g.mol-1)
Synthesized according to general procedure 5: Allyl 3-(difluoromethyl)-1-methyl-2-oxo-

1,2,3,4-tetrahydroquinoline-3-carboxylate (26) (18 mg, 0.06 mmol), palladium diacetate
(1.3 mg, 0.006 mmol, 0.1 equiv.), 1,2-bis(diphenylphosphino)ethane (3 mg, 0.0075 mmol,
chromatography over silica gel eluting with PE/Et2O (7:3) afforded the desired product
(11 mg, 87%) in a mixture with 18% of its dehydrofluorinated analogue.
RF = 0.35 (PE/Et2O 8:2).
(d, J = 8.1 Hz, 1H), 6.48 (td, J = 55.5, 2.3 Hz, 1H), 3.38 (s, 3H), 3.16-2.95 (m, 3H).
13C NMR (CDCl3, 100 MHz):  139.5, 128.2, 127.9, 124.0, 123.5, 115.0 (dd, J = 243.3,
238.3 Hz), 114.9, 44.4 (d, J = 23.4, 22.9 Hz), 29.8, 23.2 (dd, J = 5.8, 3.7 Hz).
19F NMR (CDCl3, 376.5 MHz):  –125.92 (ddd, J = 286.8, 55.8, 7.7 Hz, 1F), –128.22
(ddd, J = 284.0, 55.9, 21.6 Hz, 1F).
S221
3-(Difluoromethyl)-1-methyl-3,4-dihydroquinolin-2(1H)-one (43)
S222
S223
1,3-Dibenzyl-5-(difluoromethyl)dihydropyrimidine-2,4(1H,3H)-dione (44)
C19H18F2N2O2 (MW = 344.36 g.mol-1)
Synthesized according to general procedure 5: allyl 1,3-dibenzyl-5-(difluoromethyl)-2,4-

dioxohexahydropyrimidine-5-carboxylate (27) (26 mg, 0.06 mmol), palladium diacetate
RF = 0.25 (PE/Et2O 8:2).
(d, J = 14.2 Hz, 1H), 4.99 (d, J = 14.1 Hz, 1H), 4.66 (s, 2H), 3.49 (dd, J = 12.7, 11.3 Hz, 1H), 3.39
(dd, J = 12.7, 6.3 Hz, 1H), 3.22-3.10 (m, 1H).
13C NMR (CDCl3, 100 MHz):  152.9, 137.2, 135.7, 129.0, 128.7, 128.5, 128.2, 127.6, 113.8
(dd, J = 244.5, 241.1 Hz), 52.0, 45.0, 44.7 (dd, J = 24.5, 21.9 Hz), 44.5, 38.6 (m).
J = 286.8, 54.7, 21.08 Hz, 1F).
S224
1,3-Dibenzyl-5-(difluoromethyl)dihydropyrimidine-2,4(1H,3H)-dione (44)
S225
S226
1-Benzyl-3-(difluoromethyl)pyrrolidin-2-one (45)
C12H13F2NO (MW = 225.24 g.mol-1)
Synthesized according to general procedure 5: Allyl 1-benzyl-3-(difluoromethyl)-2-

oxopyrrolidine-3-carboxylate (28) (18 mg, 0.06 mmol), palladium diacetate (1.3 mg,
chromatography over silica gel eluting with PE/Acetone (6:4) afforded the desired product as
a pale yellow oil (10 mg, 59% yield).
1H), 4.52 (d, J = 14.8 Hz, 1H), 4.43 (d, J = 14.7 Hz, 1H), 3.33-3.22 (m, 2H), 3.11-2.94 (m, 1H),
2.27 (ddt, J = 13.8, 9.0, 6.9 Hz, 1H), 2.18-2.09 (m, 1H).
13C NMR (CDCl3, 100 MHz):  170.0 (d, J = 14.6 Hz), 135.8, 128.8, 128.0, 127.8, 115.4
(t, J = 241.2 Hz), 46.8, 46.3 (t, J = 22.8 Hz), 45.0, 29.7, 16.4.
19F NMR (CDCl3, 376.5 MHz):  –122.98 (ddd, J = 283.6, 55.5, 6.1 Hz, 1F), –127.83
(ddd, J = 283.7, 56.3, 28.9 Hz, 1F).
S227
1-Benzyl-3-(difluoromethyl)pyrrolidin-2-one (45)
S228
S229
1-Benzyl-3-(difluoromethyl)pyrrolidine-2,5-dione (46)
C12H11F2NO2 (MW = 239.22 g.mol-1)
Synthesized according to general procedure 5: Allyl 1-benzyl-3-(difluoromethyl)-2,5-

dioxopyrrolidine-3-carboxylate (29) (19 mg, 0.06 mmol), palladium diacetate (1.3 mg,
pale yellow oil (10 mg, 73%) along with 6% of its dehydrofluorinated analogue.
RF = 0.35 (PE/Et2O 6:4).
1H NMR (CDCl3, 400 MHz):  7.35-7.27 (m, 5H), 6.28 (td, J = 55.0, 2.7 Hz, 1H), 4.72-4.64
(m, 2H), 3.40-3.28 (m, 1H), 2.96 (dd, J = 18.5, 4.8 Hz, 1H), 2.80 (dd, J = 18.5, 9.5 Hz, 1H).
13C NMR (CDCl3, 100 MHz):  174.5, 172.7 (d, J = 13.2 Hz), 135.1, 128.8, 128.6, 128.2, 113.4
(dd, J = 243.7, 242.5 Hz), 44.6 (t, J = 24.9 Hz), 42.8, 27.3 (dd, J = 5.1, 1.8 Hz).
19F NMR (CDCl3, 376.5 MHz):  –116.26 (dd, J = 77.7, 2.7 Hz, 0.06F, dehydrofluorinated
product), –122.27 (ddd, J = 287.6, 54.7, 5.6 Hz, 1F), –127.39 (ddd, J = 287.7, 55.8, 28.0 Hz,
1F).
S230
1-Benzyl-3-(difluoromethyl)pyrrolidine-2,5-dione (46)
S231
S232
1-Benzyl-3-(difluoromethyl)azepan-2-one (47)
C14H17F2NO (MW = 253.29 g.mol-1)

oxoazepane-3-carboxylate (30) (20 mg, 0.06 mmol), palladium diacetate (1.3 mg,
RF = 0.8 (PE/EA 1:1).
1H NMR (CDCl3, 400 MHz):  7.33-7.24 (m, 5H), 6.22 (ddd, J = 56.6, 55.2, 4.8 Hz, 1H), 4.68
(d, J = 14.6 Hz, 1H), 4.48 (d, J = 14.6 Hz, 1H), 3.40 (dd, J = 15.5, 11.5 Hz, 1H), 3.22 (ddd,
J = 15.4, 5.8, 2.1 Hz, 1H), 3.02-2.91 (m, 1H), 2.07-1.97 (m, 2H), 1.72-1.66 (m, 1H), 1.60-1.46
(m, 2H).
13C NMR (CDCl3, 100 MHz):  172.3, 137.3, 128.7, 128.4, 127.6, 116.3 (t, J = 239.6 Hz), 50.8,
48.6 (t, J = 21.9 Hz), 28.5, 27.4, 23.0 (t, J = 5.0 Hz).
J = 280.5, 56.5, 26.2 Hz, 1F).
S233
1-Benzyl-3-(difluoromethyl)azepan-2-one (47)
S234
S235
3,3-Difluoro-N-methoxy-N-methyl-2-phenylpropanamide (48)
C11H13F2NO (MW = 229.23 g.mol-1)
Synthesized according to general procedure 5: Allyl 2-(difluoromethyl)-3-

[methoxy(methyl)amino]-3-oxo-2-phenylpropanoate (34) (19 mg, 0.06 mmol), palladium
diacetate (1.3 mg, 0.006 mmol, 0.1 equiv.), 1,2-bis(diphenylphosphino)ethane (3 mg,
0.0075 mmol, 0.125 equiv.) and formic acid (13.6 µL, 0.36 mmol, 6 equiv.). Purification by
flash column chromatography over silica gel eluting with PE/EA (7:3) afforded the desired
product as a colorless oil (69 % NMR yield, product highly volatile).
RF = 0.55 (PE/EA 7:3).
1H NMR (CDCl3, 400 MHz):  7.44-7.33 (m, 5H), 6.31 (ddd, J = 56.6, 55.4, 7.3 Hz, 1H), 4.48
(m, 1H), 3.49 (s, 3H), 3.20 (s, 3H).
13C NMR (CDCl3, 100 MHz):  169.4, 135.6, 130.6, 129.6, 129.0, 129.0, 128.4, 116.5 (d,
J = 243.8, 241 Hz), 61.4, 55.3 (dd, J = 23.1, 22.0 Hz), 33.3.
J = 279.9, 56.6, 10.3 Hz, 1F).
S236
3,3-Difluoro-N-methoxy-N-methyl-2-phenylpropanamide (48)
S237
S238
2-(Difluoromethyl)-N-methoxy-N-methyl-3-oxooctanamide (49)
C11H21F2NO2 (MW = 237.29 g.mol-1)
Synthesized according to general procedure 5: Allyl 2-(difluoromethyl)-2-

[methoxy(methyl)carbamoyl]-3-oxooctanoate (35) (20 mg, 0.06 mmol), palladium diacetate
RF = 0.40 (PE/EA 9:1).
1H NMR (CDCl3, 400 MHz):  5.89 (ddd, J = 57.2, 56.3, 7.2 Hz, 1H), 3.72 (s, 3H), 3.37 (m, 1H),
3.22 (s, 3H), 1.88-1.62 (m, 2H), 1.29-1.24 (m, 8H), 0.90-0.86 (m, 3H).
13C NMR (CDCl3, 100 MHz):  172.3, 61.6, 45.9, 31.9, 31.5, 29.7, 29.2, 26.6, 22.6, 14.0.
J = 282.3, 57.3, 10.5 Hz, 1F).
S239
2-(Difluoromethyl)-N-methoxy-N-methyl-3-oxooctanamide (49)
S240
S241
2-Benzyl-3,3-difluoro-N-methoxy-N-methylpropanamide (50)
C12H15F2NO2 (MW = 243.25 g.mol-1)

[methoxy(methyl)amino]-3-oxopropanoate (36) (20 mg, 0.06 mmol), palladium diacetate
colorless oil (9 mg, 63 %).
RF = 0.4 (PE/EA 8:2).
1H), 3.69 (m, 1H), 3.31 (s, 3H), 3.11-3.05 (m, 4H), 2.99 (dd, J = 13.2, 4.1 Hz, 1H).
13C NMR (CDCl3, 100 MHz):  137.5, 129.1, 128.5, 128.8, 116.8 (t, J = 243.7 Hz), 61.2, 47.9
(dd, J = 20.0, 17.6 Hz), 33.1 (dd, J = 5.5, 1.7 Hz), 31.8.
J = 283.2, 57.0, 10.4 Hz, 1F).
S242
2-Benzyl-3,3-difluoro-N-methoxy-N-methylpropanamide (50)
S243
S244
Ethyl 3-(difluoromethyl)-4-(methoxy(methyl)amino)-4-oxobutanoate (51)
C9H15F2NO4 (MW = 239.22 g.mol-1)
Synthesized according to general procedure 4: 1-Allyl 4-ethyl 2-(difluoromethyl)-2-

[methoxy(methyl)carbamoyl]succinate (38) (19 mg, 0.06 mmol), palladium diacetate
chromatography over silica gel eluting with PE/EA (8:2) + 0.1 % formic acid afforded the
desired product as a clear oil (12 mg, 75% (NMR yield), 79% final purity) along with two co-
eluting minor impurities (respectively 14% of unreacted starting material and 8% of the
dehydrofluorinated analogue).
RF = 0.35 (PE/EA 8:2).
1H NMR (CDCl3, 400 MHz):  5.94 (td, J = 56.3, 6.2 Hz, 1H), 4.14 (qd, J = 7.1, 2.8 Hz, 2H),
3.86 (brs, 1H), 3.81 (s, 3H), 3.24 (s, 3H), 2.99 (dd, J = 17.1, 10.5 Hz, 1H), 2.65 (ddd, J = 17.1,
3.9, 1.0 Hz, 1H), 1.25 (t, J = 7.1 Hz, 3H).
13C NMR (CDCl3, 100 MHz):  171.1, 157.2, 115.3 (t, J = 244.4 Hz), 61.4, 61.1, 42.4 (t,
J = 21.7 Hz), 33.4, 32.2, 14.1.
J = 283.8, 56.8, 16.6 Hz, 1F).
S245
Ethyl 3-(difluoromethyl)-4-(methoxy(methyl)amino)-4-oxobutanoate (52)
S246
S247
Allyl 3-(difluoromethyl)-1-(4-methoxybenzoyl)-2-oxopyrrolidine-3-carboxylate (52)
C17H17F2NO5 (MW = 353.52 g.mol-1)
Synthesized according to general procedure 3: Allyl 1-(4-methoxybenzoyl)-2-oxopyrrolidine-

3-carboxylate (liii) (91 mg, 0.3 mmol), potassium tert-butoxide (71 mg, 0.63 mmol,
over silica gel eluting with a PE/Et2O gradient (7:3 to 6:4) afforded the desired product as a
white solid (48 mg, 45%).
RF = 0.45 (PE/Et2O 6:4).
1H NMR (CDCl3, 400 MHz):  7.63-7.60 (m, 2H), 6.92-6.89 (m, 2H), 6.47 (t, J = 55.1, 1H),
1H), 4.72 (dt, J = 5.7, 1.4 Hz, 1H), 4.10 (dt, J = 10.9, 8.1 Hz, 1H), 4.01 (ddd, J = 10.9, 8.4,
4.3 Hz, 1H), 3.86 (s, 3H), 2.68-2.56 (m, 2H).
13C NMR (CDCl3, 100 MHz):  179.0, 169.2, 163.5, 131.8, 130.6, 125.0, 119.7, 113.4, 67.2,
64.0, 62.2, 55.5, 44.6, 20.2.
19F NMR (CDCl3, 376.5 MHz):  –128.90 (d, J = 54.7 Hz, 1F), –128.74 (d, J = 55.5 Hz, 1F).
S248
Allyl 3-(difluoromethyl)-1-(4-methoxybenzoyl)-2-oxopyrrolidine-3-carboxylate (52)
S249
S250
Allyl 11-(difluoromethyl)-10-oxododecahydro-1H,5H,8H-dipyrido[2,1-f:3',2',1'-
ij][1,6]naphthyridine-11-carboxylate (53)
C20H28F2N2O3 (MW = 382.45 g.mol-1)
Synthesized according a slightly modified version of the general procedure 3: Matrine-

CO2Allyl (liv) (100 mg, 0.3 mmol), potassium tert-butoxide (104 mg, 0.93 mmol,
3.1 equiv.) and I (310 mg, 0.9 mmol, 3 equiv.). Reaction mixture was stirred for 12h at –40 °C
and 72 h at 40 °C. NMR analysis of the crude residue showed a 33% NMR yield. Purification
by flash column chromatography over silica gel eluting with PE/EA (6:4) followed by
PE/acetone (8:2) afforded the desired product as a yellow oil (31 mg, 27%) as an inseparable
mixture of two diastereomers (dr = 55:45). The product was used in the next step without
further purification.
1H NMR (CDCl3, 400 MHz):  6.56 (t, J = 55.9 Hz, 0.55 H, 1st dia), 6.55 (t, J = 55.9 Hz, 0.45 H,
2nd dia), 5.88 (m, 1H), 5.33 (dd, J = 17.2, 1.7 Hz, 1H), 5.25 (dt, J = 10.5, 1.4 Hz, 1H), 4.72-4.62
(m, 2H), 4.34 (dd, J = 13.9, 4.4 Hz, 0.55H), 4.28 (dd, J = 12.5, 4.4 Hz, 0.45H), 4.04 (dt, J = 10.3,
4.7 Hz, 0.45H), 3.85 (td, J = 10.2, 5.6 Hz, 0.55H), 3.15 (q, J = 12.6 Hz, 1H), 2.86-2.76 (m, 2H)
2.28-1.84 (m, 7H), 1.78-1.55 (m, 5H), 1.54-1.36 (m, 5H).
13C NMR (CDCl3, 100 MHz):  168.1 (d, J = 11.7 Hz), 167.5 (d, J = 10.2 Hz), 162.8 (d, J = 7.9
Hz), 162.2 (d, J = 9.0 Hz), 131.2, 131.1, 118.9, 118.7, 116.5 (dd, J = 244.0, 225.8 Hz), 116.1 (t,
J = 246.2 Hz), 66.5, 66.4, 63.7, 63.2, 57.3, 57.2, 57.2, 57.2, 57.2, 57.1, 53.1, 53.0, 43.6, 43.1,
42.1, 40.9, 36.0, 35.1, 27.7, 26.5, 26.2, 26.3, 22.8, 21.2, 21.1, 20.7, 20.7.
19F NMR (CDCl3, 376.5 MHz):  –126.70 (dd, J = 280.2, 56.0 Hz, 0.22F, 1st dia), –127.62 (dd,
J = 279.4, 55.5 Hz, 0.27F, 2nd dia), –130.79 (dd, J = 280.2, 55.8 Hz, 0.23F, 1st dia), –131.11 (dd,
J = 279.4, 56.3 Hz, 0.28F, 2nd dia).
S251
Allyl 11-(difluoromethyl)-10-oxododecahydro-1H,5H,8H-dipyrido[2,1-f:3',2',1'-
ij][1,6]naphthyridine-11-carboxylate (53)
S252
S253
Allyl (1R,3aR,5aS,9aS,9bS)-1-(difluoromethyl)-3a,7,7,9a-tetramethyl-2-
oxododecahydronaphtho[2,1-b]furan-1-carboxylate (54)
C21H30F2O4 (MW = 384.46 g.mol-1)
Synthesized according to general procedure 3: Allyl (1R,3aR,5aS,9aS,9bR)-3a,7,7,9a-

tetramethyl-2-oxododecahydronaphtho[2,1-b]furan-1-carboxylate (lv) (100 mg, 0.3 mmol,
1 equiv.), potassium tert-butoxide (71 mg, 0.63 mmol, 2.1 equiv.) and I (207 mg, 0.6 mmol,
2 equiv.). Purification by flash column chromatography over silica gel eluting with a PE/Et2O
gradient (9:1 to 8:2) afforded the desired product as an colorless oil (75 mg, 65%, dr = 99:1).
RF = 0.47 (PE/Et2O 8:2).
1H NMR (CDCl3, 400 MHz):  6.42 (dd, J = 55.7, 53.3 Hz, 1H), 5.92 (ddt, J = 17.2, 10.3, 6.1 Hz,
1H), 5.41 (dq, J = 17.2, 1.4 Hz, 1H), 5.33 (dq, J = 10.4, 1.1 Hz, 1H), 4.77 (ddt, J = 12.8, 6.1,
1.3 Hz, 1H), 4.71 (ddt, J = 12.9, 6.1, 1.3 Hz, 1H), 2.35 (d, J = 1.9 Hz, 1H), 2.12-2.05 (m, 2H),
1.92 (dq, J = 14.3, 3.3 Hz, 1H), 1.74-1.62 (m, 2H), 1.67-1.56 (m, 1H), 1.55 (d, J = 1.1 Hz, 3H),
1.47-1.36 (m, 2H), 1.26-1.10 (m, 2H), 1.07 (d, J = 12.6, 2.8 Hz, 1H) 0.96 (s, 3H), 0.89 (s, 3H),
0.83 (s, 3H).
13C NMR (CDCl3, 100 MHz):  167.7, 166.5 (dd, J = 6.6, 1.2 Hz), 130.1, 120.6, 114.7 (dd,
J = 251.7, 248.5 Hz), 85.2, 67.3, 61.8, 61.4 (dd, J =20.7, 17.7 Hz), 57.9, 41.8, 40.3, 38.8, 38.7,
33.4, 33.4, 23.8, 20.9, 20.4, 18.0, 16.2.
J = 282.7, 56.6, 1F).
S254
Allyl (1R,3aR,5aS,9aS,9bS)-1-(difluoromethyl)-3a,7,7,9a-tetramethyl-2-
oxododecahydronaphtho[2,1-b]furan-1-carboxylate (54)
S255
S256
Allyl 3-(difluoromethyl)-1-methyl-2,5-dioxo-4-phenylpyrrolidine-3-carboxylate (55)
C16H15F2NO4 (MW = 323.30 g.mol-1)
Synthesized according to general procedure 3: Allyl 1-methyl-2,5-dioxo-4-phenylpyrrolidine-

3-carboxylate (lvi) (68 mg, 0.25 mmol), potassium tert-butoxide (58 mg, 0.52 mmol,
over silica gel eluting with a toluene/acetone gradient (99:1 to 95:5) afforded the desired
product as an off-white solid (58 mg, 60%) as a single diastereomer.
RF = 0.52 (toluene/acetone 95:5).
1H NMR (CDCl3, 400 MHz):  7.34-7.30 (m, 3H), 7.22 (dd, J = 6.7 Hz, 2.9 Hz), 6.52
(t, J = 54.4 Hz, 1H), 5.47 (ddt, J = 16.6, 10.5, 5.9 Hz, 1H), 5.15-5.08 (m, 2H), 4.63 (s, 1H), 4.28
(ddt, J = 12.9, 5.8, 1.4 Hz, 1H), 4.07 (ddt, J = 13.0, 6.0, 1.3 Hz, 1H), 3.21 (s, 3H).
13C NMR (CDCl3, 100 MHz):  164.7, 163.5 (d, J = 9.5 Hz), 131.3, 130.1, 130.0, 129.9, 128.6,
128.6, 119.7, 113.4 (dd, J = 250.2, 242.8 Hz), 67.0, 64.6, 49.1, 26.0.
54.6 Hz, 1F).
S257
Allyl 3-(difluoromethyl)-1-methyl-2,5-dioxo-4-phenylpyrrolidine-3-carboxylate (55)
S258
S259
Allyl 3-(difluoromethyl)-1-methyl-2-oxoindoline-3-carboxylate (56)
C14H13F2NO3 (MW = 281.26 g.mol-1)
Synthesized according to general procedure 3: Allyl 1-methyl-2-oxoindoline-3-carboxylate

(xxxv) (69 mg (63% pure), 0.3 mmol), potassium tert-butoxide (71 mg, 0.63 mmol, 2.1 equiv.)
gel eluting with a PE/EA gradient (85:15 to 7:3) afforded the desired product as a yellow oil
(44 mg, 83%).
RF = 0.38 (PE/EA 8:2).
1H NMR (CDCl3, 400 MHz):  7.43 (ddd, J = 8.0, 6.4, 1.6 Hz, 2H), 7.15 (td, J = 7.6, 1.0 Hz, 1H),
6.91 (dd, J = 8.1, 1.0 Hz, 1H), 6.55 (t, J = 54.8 Hz, 1H), 5.82 (ddt, J = 17.2, 10.7, 5.5 Hz, 1H),
5.23 (dq, J = 8.9, 1.4 Hz, 1H), 5.21-5.19 (m, 1H), 4.67 (ddt, J = 5.3, 3.8, 1.5 Hz, 1H), 3.26 (s,
3H).
13C NMR (CDCl3, 100 MHz):  144.9, 130.7, 130.4, 125.8, 123.4, 121.5, 118.9, 114.5
(t, J = 246.6 Hz), 108.8, 66.8, 62.8, 26.8.
S260
Allyl 3-(difluoromethyl)-1-methyl-2-oxoindoline-3-carboxylate (56)
S261
S262
3-Allyl 1-(tert-butyl) (5S)-5-{[(tert-butyldiphenylsilyl)oxy]methyl}-3-(difluoromethyl)-2-
oxopyrrolidine-1,3-dicarboxylate (57)
C31H39F2NO6Si (MW = 587.74 g.mol-1)
Synthesized according to general procedure 3: 3-Allyl 1-(tert-butyl) (5S)-5-{[(tert-

butyldiphenylsilyl)oxy]methyl}-2-oxopyrrolidine-1,3-dicarboxylate (lvi) (161 mg, 0.3 mmol),
potassium tert-butoxide (71 mg, 0.63 mmol, 2.1 equiv.) and I (207 mg, 0.6 mmol,
2 equiv.). Purification by flash column chromatography over silica gel eluting with a PE/Et2O
gradient (8:2 to 7:3) afforded the desired product as an off-white wax (79 mg, 44%).
NMR analysis of the crude reaction mixture allowed to determine the diastereoselectivity
(dr = 2:1).
RF = 0.25 (PE/Et2O 8:2).
5.84 (ddt, J = 16.5, 10.4, 5.7 Hz, 1H), 5.33 (ddt, J = 16.5, 10.4, 5.7 Hz, 1H), 5.24 (dq, J = 10.5,
1.3 Hz, 1H), 4.65 (dq, J = 5.9, 1.5 Hz, 2H), 4.25 (ddt, J = 8.7, 6.3, 4.3 Hz, 1H), 3.89-3.83 (m,
2H), 2.92 (dd, J = 14.3, 4.3 Hz, 1H), 2.59 (dd, J = 14.3, 9.1 Hz, 1H), 1.40 (s, 9H), 1.07 (s, 9H).
13C NMR (CDCl3, 100 MHz):  166.2 (dd, J = 6.5, 4.4 Hz), 165.5 (dd, J = 6.3, 3.8 Hz), 149.0,
135.6, 135.5, 133.2, 133.0, 130.8, 129.8, 127.8, 127.8, 119.4, 115.1 (t, J = 245.9 Hz), 84.2,
67.2, 63.7, 61.3 (t, J = 23.3 Hz), 56.5, 27.8, 26.8, 21.9 (t, J = 2.5 Hz), 19.3.
19F NMR (CDCl3, 376.5 MHz):  –128.09 (dd, J = 55.5, 7.7 Hz, 2F) and traces of the minor
diastereoisomer.
HRMS: m/z calcd for C31H39F2NO6Si, [M+Na]: 610.2413, found: 610.2444.
S263
3-Allyl 1-(tert-butyl) (5S)-5-{[(tert-butyldiphenylsilyl)oxy]methyl}-3-(difluoromethyl)-2-
oxopyrrolidine-1,3-dicarboxylate (57)
S264
S265
3-(difluoromethyl)-1-(4-methoxybenzoyl)pyrrolidin-2-one (58)
C13H13F2NO3 (MW = 269.25 g.mol-1)
Synthesized according to general procedure 5: Allyl 3-(difluoromethyl)-1-(4-

methoxybenzoyl)-2-oxopyrrolidine-3-carboxylate (52) (21 mg, 0.06 mmol), palladium
diacetate (1.3 mg, 0.006 mmol, 0.1 equiv.), 1,2-bis(diphenylphosphino)ethane (3 mg,
0.0075 mmol, 0.125 equiv.) and formic acid (13.6 µL, 0.36 mmol, 6 equiv.). Purification by
flash column chromatography over silica gel eluting with PE/Acetone (85:15) afforded the
desired product as a colorless oil (13 mg, 79%) in a mixture with the co-eluting fluorovinyl
analog (2%).
RF = 0.5 (PE/Acetone 85:15).
1H NMR (CDCl3, 400 MHz):  7.65-7.62 (m, 2H), 6.92-6.90 (m, 2H), 6.20 (ddd, J = 56.3, 55.0,
2.1 Hz, 1H), 4.03-3.88 (m, 2H), 3.86 (s, 3H), 3.25-3.13 (m, 1H), 3.25-3.13 (m, 1H), 2.41
(dt, J = 13.3, 8.9 Hz, 1H), 2.35-2.26 (m, 1H).
13C NMR (CDCl3, 100 MHz):  169.5, 163.3, 131.8, 131.6, 125.5, 119.7, 114.6 (t, J = 241.8 Hz),
113.3, 113.2, 55.4, 48.3 (t, J =23.6 Hz), 44.9, 16.2 (dd, J = 4.7, 1.6 Hz).
J = 286.4, 56.3, 27.5 Hz, 1F).
S266
3-(difluoromethyl)-1-(4-methoxybenzoyl)pyrrolidin-2-one (58)
S267
S268
11-(Difluoromethyl)dodecahydro-1H,5H,10H-dipyrido[2,1-f:3',2',1'-ij][1,6]naphthyridin-10-
one (59)
C16H24F2N2O (MW = 298.38 g.mol-1)
Synthesized according to general procedure 5: Matrine-Q-CHF2 (53) (25 mg, 0.065 mmol),
palladium diacetate (1.4 mg, 0.0065 mmol, 0.1 equiv.), 1,2-bis(diphenylphosphino)ethane
(3.1 mg, 0.0078 mmol, 0.125 equiv.) and formic acid (15 µL, 0.39 mmol, 6 equiv.).
NMR Analysis of the crude residue showed a 59% NMR yield. Purification by flash column
chromatography over silica gel eluting with DCM/MeOH (97:3) afforded the desired product
as a bright yellow oil (11.5 mg, 58%) as an inseparable mixture of the two diastereomers
(dr = 65:35).
RF = 0.23 (DCM/MeOH 97:3).
1H NMR (CDCl3, 400 MHz):  6.48 (td, J = 56.3, 1.1 Hz, 0.35H, 1st dia), 6.40 (td, J = 56.4,
2.1 Hz, 0.65 H, 2nd dia), 4.39 (dd, J = 13.2, 4.2 Hz, 0.35H, 1st dia), 4.33 (dd, J = 12.6, 4.4 Hz,
0.65H, 2nd dia), 3.97 (m, 0.65H, 2nd dia), 3.81 (m, 0.35H, 1st dia), 3.11 (q, J = 12.8 Hz, 1H),
2.86-2.78 (m, 2H), 2.65 (m, 0.35H, 1st dia), 2.29 (m, 0.65H, 2nd dia), 2.14 (m, 1H), 2.06-1.80
(m, 6H), 1.78-1.55 (m, 5H), 1.47-1.30 (m, 5H).
13C NMR (CDCl3, 100 MHz):  165.0 (d, J = 12.9 Hz), 165.0 (d, J = 12.6 Hz), 116.6
(t, J = 241.8 Hz), 116.5 (t, J = 241.5 Hz), 64.0, 63.7, 63.4, 57.3, 57.2, 57.1, 53.1, 53.0, 52.9,
45.9 (t, J = 22.0 Hz), 45.4 (t, J = 22.9 Hz), 43.9, 42.9, 41.2, 41.0, 36.1, 35.1, 31.9, 27.7, 27.7,
26.6, 26.3, 26.2, 22.7, 22.2, 21.2, 21.1, 20.7, 20.7.
19F NMR (CDCl3, 376.5 MHz):  –126.17 (m, 0.32F, 2nd dia), –126.32 (m, 0.32F, 2nd dia),
–126.86 (ddd, J = 279.9, 56.4, 8.9 Hz 0.18F, 1st dia), –127.93 (ddd, J = 279.9, 56.1, 24.3 Hz,
0.18F, 1st dia).
HRMS: m/z calcd for C16H24F2N2O, [M+H]: 299.1935, found: 299.1964.
S269
11-(Difluoromethyl)dodecahydro-1H,5H,10H-dipyrido[2,1-f:3',2',1'-ij][1,6]naphthyridin-10-
one (59)
S270
S271
(1S,3aR,5aS,9aS,9bR)-1-(Difluoromethyl)-3a,7,7,9a-tetramethyldecahydronaphtho[2,1-
b]furan-2(1H)-one (60)
C17H26F2O2 (MW = 300.39 g.mol-1)
Synthesized according to general procedure 5: Sclareolide-Q-CHF2 (54) (23 mg, 0.06 mmol),
palladium diacetate (1.3 mg, 0.006 mmol, 0.1 equiv.), 1,2-bis(diphenylphosphino)ethane
(3 mg, 0.0075 mmol, 0.125 equiv.) and formic acid (13.6 µL, 0.36 mmol, 6 equiv.).
Purification by flash column chromatography over silica gel eluting with PE/EA (92:8)
afforded the desired product as a single enantiomer as a white solid (14 mg, 74%).
RF = 0.37 (PE/EA 85:15).
1H NMR (CDCl3, 400 MHz):  6.33 (dd, J = 56.4, 54.9 Hz, 1H), 3.02 (ddd, J = 19.9, 13.5, 11.5
Hz, 1H), 2.21 (d, J = 13.5 Hz, 1H), 2.11 (dt, J = 11.9, 3.3 Hz, 1H), 1.94 (dq, J = 14.2, 3.3 Hz, 1H),
1.75-1.60 (m, 3H), 1.56-1.30 (m, 3H), 1.38 (d, J = 1.0 Hz, 3H), 1.33-1.16 (m, 2H), 1.12 (dd,
J = 12.6, 2.8 Hz, 1H), 0.98 (s, 3H), 0.90 (s, 3H), 0.85 (s, 3H).
13C NMR (CDCl3, 100 MHz):  172.9 (d, J = 15.7 Hz), 115.0 (dd, J = 245.0, 241.1 Hz), 85.0,
57.6, 56.3, 45.4 (dd, J =25.2, 22.6 Hz), 41.9, 39.4, 38.4, 37.1, 33.4, 29.7, 23.0, 21.0, 20.5, 18.1,
15.8.
19F NMR (CDCl3, 376.5 MHz):  -117.45 (dddd, J = 281.9, 56.4, 11.5, 1.8 Hz, 1F), -124.65
(dddd, J = 281.9, 54.9, 19.9, 2.2 Hz, 1F).
S272
(1S,3aR,5aS,9aS,9bR)-1-(Difluoromethyl)-3a,7,7,9a-tetramethyldecahydronaphtho[2,1-
b]furan-2(1H)-one (60)
S273
S274
(E)-3-(Fluoromethylene)-1-methyl-4-phenylpyrrolidine-2,5-dione (61)
C12H10FNO2 (MW = 219.22 g.mol-1)
Synthesized according to general procedure 5: Allyl 3-(difluoromethyl)-1-methyl-2,5-dioxo-

4-phenylpyrrolidine-3-carboxylate (55) (18 mg, 0.06 mmol), palladium diacetate (1.3 mg,
0.125 equiv.) and formic acid (13.6 µL, 0.36 mmol, 6 equiv.). The crude reaction mixture was
concentrated in the presence of silica and Et3N and purified by flash column chromatography
over silica gel eluting with PE/Et2O (6:4) to afford the desired product as a yellow solid (8 mg,
61%).
RF = 0.5 (PE/Et2O 6:4).
1H NMR (CDCl3, 400 MHz):  7.68 (dd, J = 76.6, 2.3 Hz, 1H), 7.40-7.30 (m, 3H), 7.29-7.26
(m, 2H), 7.00 (d, J = 8.1 Hz, 1H), 4.61 (t, J = 2.4 Hz, 1H), 3.10 (s, 3H).
129.1, 128.3, 127.6, 115.9 (d, J = 11.2 Hz), 47.4, 25.2.
S275
(E)-3-(Fluoromethylene)-1-methyl-4-phenylpyrrolidine-2,5-dione (61)
S276
S277
(E)-3-(Fluoromethylene)-1-methylindolin-2-one (62)
C10H8FNO (MW = 177.18 g.mol-1)
Synthesized according to general procedure 5: Allyl 3-(difluoromethyl)-1-methyl-2-

oxoindoline-3-carboxylate (56) (17 mg, 0.06 mmol), palladium diacetate (1.3 mg,
chromatography over silica gel eluting with PE/Acetone (85:15) afforded the desired product
as a single diastereomer as yellow crystals (8 mg, 79%).
RF = 0.45 (PE/Acetone 85:15).
1H NMR (CDCl3, 400 MHz):  7.72 (d, J = 77.7 Hz, 1H), 7.63-7.61 (m, 1H), 7.32 (td, J = 7.8 Hz,
1.2 Hz, 1H), 7.09-7.05 (m, 1H), 6.83 (dt, J = 7.9, 0.8 Hz, 1H), 3.23 (s, 3H).
13C NMR (CDCl3, 100 MHz):  167.5, 155.6 (d, J = 287.1 Hz), 142.4, 129.7, 124.5, 124.4,
122.6, 108.1, 26.0.
HRMS: m/z calcd for C10H8NO, [M+H]: 178.0668, found: 178.0678.
S278
(E)-3-(Fluoromethylene)-1-methylindolin-2-one (62)
S279
NOESY
S280
HOESY
S281
tert-Butyl (S,E)-5-{[(tert-butyldiphenylsilyl)oxy]methyl}-3-(fluoromethylene)-2-
oxopyrrolidine-1-carboxylate (63)
C27H34FNO4Si (MW = 483.66 g.mol-1)
Synthesized according to general procedure 5: 3-Allyl 1-(tert-butyl) (5S)-5-{[(tert-

butyldiphenylsilyl)oxy]methyl}-3-(difluoromethyl)-2-oxopyrrolidine-1,3-dicarboxylate (57)
(32 mg, 0.06 mmol), palladium diacetate (1.3 mg, 0.006 mmol, 0.1 equiv.),
1,2-bis(diphenylphosphino)ethane (3 mg, 0.0075 mmol, 0.125 equiv.) and formic acid
(13.6 µL, 0.36 mmol, 6 equiv.). The crude reaction mixture was concentrated in the presence
of silica and Et3N and purified by flash column chromatography over silica gel eluting with
PE/Et2O (6:4) to afford the desired product as a single diastereomer (E only) as a yellow oil
(16 mg, 55%).
RF = 0.42 (PE/Et2O 7:4).
1H NMR (CDCl3, 400 MHz):  7.63-7.56 (m, 4.5 H), 7.44-7.34 (m, 6.5 H), 4.26 (ddd, J = 9.1,
4.1, 2.1 Hz, 1H), 3.89 (dd, J = 10.4, 3.8 Hz, 1H), 3.65 (dd, J = 10.4, 2.3 Hz, 1H), 2.91-2.86 (m,
1H), 2.77 (ddt, J = 17.0, 8.6, 4.0 Hz, 1H), 1.46 (s, 9H), 1.01 (s, 9H).
13C NMR (CDCl3, 100 MHz):  155.5, 151.3 (d, J = 292.2 Hz), 149.9, 135.5, 135.5, 133.0,
132.7, 129.9, 127.8, 127.8, 117.3, 83.1, 64.6, 56.3, 28.0, 26.6, 22.9, 19.2.
19F NMR (CDCl3, 376.5 MHz):  –123.46 (m, 1F).
HRMS: m/z calcd for C27H34FNO4Si, [M+Na]: 506.2191, found: 506.2194.
S282
tert-Butyl (S,E)-5-{[(tert-butyldiphenylsilyl)oxy]methyl}-3-(fluoromethylene)-2-
oxopyrrolidine-1-carboxylate (63)
S283
S284
C13H14FNO
(MW = 219.26 g.mol-1)
To a solution of 1-benzyl-3-(difluoromethyl)piperidin-2-one (34) (24 mg, 0.1 mmol) in dry

THF (0.5 mL) was slowly added LDA (1M in THF, 150 µL, 0.15 mmol, 1.5 equiv.) at
–78 °C. The resulting solution was stirred at this temperature until TLC showed completion
(90 min) upon which it was quenched with a saturated aqueous solution of NH4Cl (5 mL). The
aqueous phase was extracted with Et2O (3 x 10 mL). The combined organic phases was dried
over anhydrous MgSO4 and concentrated under reduced pressure. The resulting crude
residue was purified by flash column chromatography over silica gel eluting with PE/Et2O
(6:4) to afford the desired product as a pale yellow solid (13 mg, 59%). NOESY and HOESY
experiments confirmed the (E) configuration.
RF = 0.4 (PE/Et2O 6:4).
2H), 4.64 (s, 2H), 3.26 (t, J = 5.8 Hz, 2H), 2.54 (ddt, J = 6.8, 5.1, 2.5 Hz, 2H), 1.82-1.76 (m, 2H).
128.0, 127.5, 115.5 (d, J = 13.7 Hz), 50.4, 47.0, 21.9, 21.2 (d, J = 4.7 Hz).
S285
S286
NOESY
S287
NOESY
HOESY
S288
V. Post-functionalizations
1-Benzyl-3-(difluoromethyl)-2-oxopiperidine-3-carboxamide (64)
C14H16F2N2O2
(MW = 282.29 g.mol-1)
Methyl 1-benzyl-3-(difluoromethyl)-2-oxopiperidine-3-carboxylate (3) (75 mg, 0.25 mmol)

was dissolved in an ammonia solution in MeOH (7M, 5 mL) and was stirred at 65 °C for 7 d.
Upon completion, the resulting solution was cooled down to room temperature and
concentrated under reduced pressure. The resulting crude residue was purified by flash
column chromatography over silica gel eluting with PE/acetone (75:25) to afford the desired
product as a pale yellow solid (55 mg, 78%).
RF = 0.4 (PE/acetone 75:25).
1H NMR (CDCl3, 400 MHz):  7.66 (brs, 1H), 7.36-7.26 (m, 3H), 7.20-7.18 (m, 2H), 6.45
(t, J = 56.1 Hz, 1H), 5.55 (brs, 1H), 4.66 (d, J = 14.8 Hz, 1H), 4.80 (d, J = 14.9 Hz, 1H), 3.31-3.19
(m, 2H), 2.71 (m, 1H), 1.95-1.87 (m, 2H), 1.83-1.71 (m, 2H).
127.6, 116.6 (dd, J = 251.0, 248.1 Hz), 58.4 (dd, J = 23.3, 20.4 Hz), 51.0, 47.6, 20.2 (t,
J = 3.1 Hz), 19.6.
J = 277.8, 56.3 Hz, 1F).
S289
1-Benzyl-3-(difluoromethyl)-2-oxopiperidine-3-carboxamide (64)
S290
S291
(1-Benzyl-3-(difluoromethyl)piperidin-3-yl)methanol (65)
C14H19F2NO
(MW = 255.31 g.mol-1)
To a solution of allyl 1-benzyl-3-(difluoromethyl)-2-oxopiperidine-3-carboxylate (5) (70 mg,

0.22 mmol) in dry THF (8 mL) was added LiAlH4 (41 mg, 1.1 mmol, 5 equiv.) in two portions
at 0 °C. The resulting solution was allowed to warm up to room temperature and then
refluxed. Upon completion, the resulting solution was cool down to 0 °C and slowly
quenched with a saturated aqueous solution of and stirred for 1 hour. The resulting aqueous
phase was extracted with EA (3 x 20 mL). The combined organic phases was dried over
was purified by flash column chromatography over silica gel eluting with PE/EA (7:3) to
afford the desired product as an off-white solid (25 mg, 52%).
RF = 0.31 (PE/EA 8:2).
3.85 (d, J = 11.1 Hz, 1H), 3.76 (d, J = 11.1 Hz, 1H), 3.49 (d, J = 13.2 Hz, 1H), 3.44 (d, J = 13.1 Hz,
1H), 3.21 (brs, 1H), 2.68 (t, J = 10.3 Hz, 2H), 2.23 (d, J = 11.4 Hz, 1H), 2.13 (td, J = 11.4 Hz, 1H),
1.88 (m, 1H), 1.68-1.59 (m, 2H), 1.50 (ddd, J = 14.7, 11.1, 5.5 Hz, 1H).
13C NMR (CDCl3, 100 MHz):  138.2, 129.2, 129.0, 128.7, 128.3, 128.2, 127.5, 118.0 (t,
J = 241.2 Hz), 63.4, 53.7, 52.9 (t, J = 5.8 Hz), 40.4 (t, J = 19.7 Hz), 24.0, 23.5 (t, J = 4.4 Hz).
19F NMR (CDCl3, 376.5 MHz):  –130.64 (dt, J = 281.6, 56.3 Hz, 1F), –131.70 (dt, J = 281.3,
56.8 Hz, 1F).
S292
(1-Benzyl-3-(difluoromethyl)piperidin-3-yl)methanol (65)
S293
S294
VI. NMR Experiments
In an oven-dried MW tube, methyl 1-benzyl-2-oxopiperidine-3-carboxylate (xix) (25 mg,

0.1 mmol) was dissolved in dry DCM (2 mL). The resulting solution was cooled down to 0 °C
and potassium tert-butoxide (24 mg, 0.21 mmol, 2.1 equiv.) was added. The resulting
solution was stirred at this temperature for 30 min and cooled down to –40 °C.
I (69 mg, 0.2 mmol, 2 equiv.) was then added. The resulting solution was stirred at this
temperature and 0.3 mL aliquots were collected at chosen times, injected in a NMR tube,
dissolved with 0.3 mL CD2Cl2 and directly submitted to 19F NMR spectroscopy. The ratio
between the O- and C-difluoromethylated products was determined by comparing the
following signals: 19F NMR (CD2Cl2, 376.5 MHz):  –78.45 (d, J = 79.3 Hz, 2F,
O-difluoromethylated), –128.51 (dd, J = 281.2, 55.7 Hz, 1F, C-difluoromethylated), –131.10
(dd, J = 281.2, 56.0 Hz, 1F, C-difluoromethylated).
Mechanistical considerations
S295
O-difluoromethylated C-difluoromethylated
 -78.45 (d, J = 79.3 Hz, 2F)  -128.51 (dd, J = 281.2, 55.7 Hz, 1F)
-131.10 (dd, J = 281.2, 56.0 Hz, 1F)
Spectrum Time Ratio O/C

1 10 min 5.3:94.7
2 1h 2.1:97.6
3 2h 1.5:98.5
4 3h 0.7:99.3
5 4h 0.1:99.9
6 16 h (after work-up) 100 % C-difluoro
S296
Several attempts to conduct a direct -difluoromethylation on substrates lacking the ester
moiety were made, first on the Boc-protected -valerolactam itself and then on the
Boc-protected -valerolactam bearing a phenyl substituent at the -position (Scheme 1). In
both cases, no conversion was observed even when using a stronger base such as LiHMDS
although one equivalent of the difluoromethylating agent was consumed.
Scheme 1: Direct difluoromethylation attempts
In addition, the presence of the -keto ester moiety to achieve the difluoromethylation is
important but not sufficient to guaranty the feasibility of this transformation. Indeed, this
difluoromethylation proved unproductive on unsubstituted -keto esters such as malonates
and Weinreb amides, although, once again, one equivalent of the difluoromethylating agent
was consumed (Scheme 2).
Scheme 2: Difluoromethylation of secondary substrates attempts
It is important to emphasize the fact that the tertiary -keto ester doesn’t only play the role
of the nucleophile, it is also responsible for the generation of the difluorocarbene species.
S297

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Supporting Information

A Unified Strategy for the Synthesis of Difluoromethyl- and

Nicolas Duchemin,[a] Roberto Buccafusca,[a] Marc Daumas,[b] Vincent Ferey[c] and

Material and methods S3

Experimental and Spectral data S7

I. Synthesis of S-(difluoromethyl)-S-phenyl-N-tosylsulfoximine (I) S7

II. Optimization S10

III. Synthesis of the precursors

IV. Synthesis of difluoromethylated compounds

IV. Post-functionalizations S289

V. NMR Experiments S295

I. Synthesis of S-(difluoromethyl)-S-phenyl-N-tosylsulfoximine (I)

Difluoromethylphenyl sulfide (i)

C7H6F2S (MW = 160.18 g.mol-1)

Synthesized following a procedure reported by Carbonnel and co-workers.1 An oven-dried

C7H7F2NOS (MW = 191.20 g.mol-1)

Synthesized following a procedure reported by Chaabouni and co-workers.2 An oven-dried

C14H13F2NO3 (MW = 345.38 g.mol-1)

Synthesized following a modified procedure reported by Pegot and co-workers.3 In an

tert-Butyl 2-oxopiperidine-1-carboxylate (iv)

C10H17NO3 (MW = 199.25 g.mol-1)

Synthesized following a procedure reported by Garnier and co-workers.4 An oven-dried

C12H19NO5 (MW = 257.29 g.mol-1)

Synthesized following a slightly modified procedure reported by Cossy and co-workers.5 An

C13H19F2NO5 (MW = 307.29 g.mol-1)

Synthesized following various C-difluoromethylation procedures (cf optimization study).

RF = 0.4 (PE/EA 8:2)

HRMS: m/z calcd for C13H19F2NO5, [M+Na]: 330.1124, found: 330.1123.

Concentration and stoichiometry screening

General Procedure 1: C-acylation of lactams / lactones

General Procedure 2: Alkylation of allyl 3-(methoxy(methyl)amino)-3-oxopropanoate

To a stirred solution of allyl 3-[methoxy(methyl)amino]-3-oxopropanoate (187 mg,

C12H15NO (MW = 189.26 g.mol-1)

Synthesized following a procedure reported by Cossy and co-workers.6 In a 500 mL oven-

C12H13NO2 (MW = 203.29 g.mol-1)

Synthesized following a procedure reported by Song and co-workers. 7 An oven-dried round

C16H19NO2 (MW = 257.33 g.mol-1)

Synthesized following a procedure reported by Song and co-workers.7 An oven-dried round

C10H11NO (MW = 161.20 g.mol-1)

In an oven-dried 50 mL round-bottom flask, 3,4-dihydroquinolin-2(1H)-one (2.0 g,

C18H18N2O (MW = 294.35 g.mol-1)

In a 50 mL oven-dried round bottom flask, to a stirred suspension of dihydropyrimidine-

C11H11NO2 (MW = 189.21 g.mol-1)

Synthesized following a procedure reported by Song and co-workers.7 An oven-dried round

tert-Butyl 2-oxoazetidine-1-carboxylate (xiii)

C8H13NO3 (MW = 171.20 g.mol-1)

Synthesized according to a procedure reported by Prasad and co-workers.11 In an oven-dried

C13H17NO (MW = 203.29 g.mol-1)

Synthesized according to a procedure reported by Hu and co-workers.12 In an oven-dried

C12H13NO3 (MW = 219.24 g.mol-1)

In an oven-dried 100 mL round bottom flask, 2-pyrrolidinone (1 g, 11.75 mmol) was

C12H13NO3 (MW = 219.24 g.mol-1)

Synthesized according to a procedure reported by Ji and co-workers.14 An oven-dried

C21H27NO2Si (MW = 353.54 g.mol-1)

C26H35NO4Si (MW = 453.65 g.mol-1)

In an oven-dried 100 mL round bottom flask, to a solution of

C14H17NO3 (MW = 247.29 g.mol-1)

Synthesized according to general procedure 1: 1-Benzylpiperidin-2-one (vii) (950 g,

RF = 0.35 (PE/EA 6:4).

HRMS: m/z calcd for C14H17NO3, [M+H]: 248.1287, found: 248.1293.

C20H21NO3 (MW = 323.39 g.mol-1)

Synthesized according to general procedure 1: 1-Benzylpiperidin-2-one (vii) (600 g,

C16H19NO3 (MW = 273.33 g.mol-1)