Spirocyclization by palladium-catalyzed domino heck-direct C-H arylation reactions: Synthesis of spirodihydroquinolin-2-ones

Article abstract of DOI:10.1021/ol301616w

Treatment of a DMA solution of anilide 1 with a catalytic amount of palladium acetate (0.025 equiv) and XPhos (0.05 equiv) in the presence of potassium carbonate (2.0 equiv) at 100 °C afforded dihydroquinolin-2-ones spiro-fused to dihydrofuranyl, indolinyl, and indanyl 2 in good to excellent yields. The reaction went through a domino sequence involving a 5-exo-trig Heck cyclization followed by an intramolecular direct C-H functionalization.

Full text of DOI:10.1021/ol301616w

SUPPORTING INFORMATION
Spirocyclization by Palladium-Catalyzed
Domino Heck—Direct C-H Arylation Reactions:
Synthesis of Spirodihydroquinolin-2-ones
a,b
b
a,b
Tiffany Piou, Luc Neuville, * Jieping Zhu *
a
Institute of Chemical Sciences and Engineering, École Polytechnique Fédérale de Lausanne,
EPFL-SB-ISIC-LSPN, CH-1015 Lausanne, Switzerland
b
Centre de Recherche de Gif, Institut de Chimie des Substances Naturelles, Laboratoire International Associé,
CNRS, 91198 Gif-sur-Yvette Cedex, France
Table of Contents
S2
General information
S3-S7
Experimental procedure and spectroscopic data of compounds 3-4,
c-1l
1
S8-S12
Experimental procedure and spectroscopic data of compounds 1a (X
I, Br, Cl, OTf), 1p-1r and 1t-1y
=
S13-S14
Experimental procedure and spectroscopic data of compounds 1b and
1
s
S15-S24
S25
Experimental procedure and spectroscopic data of compounds 2a-2y
Experimental procedure and spectroscopic data of deuterated
compounds 2a-D and 2a-D5
1
S26-S28
S29-S32
S34
Determination of intramolecular isotope effect
Determination of intermolecular isotope effect
Chiral ligands screening
1
13
S33-S135
H and C spectra of compounds
S1

General information
Reagents and solvents were purchased from commercial sources (Aldrich, Acros, Merck, Fluka
and VWR international). More sensitive compounds were stored in a desiccator or glove-box if
required. Reagents were used without further purification unless otherwise noted.
All reactions were performed under argon (or nitrogen) and stirring unless otherwise noted.
When needed, glassware was dried overnight in an oven (T > 100 °C) or under vacuum with a
heat gun (T > 200 °C).
When solvents are indicated as dry they were either purchased as such, distilled prior to use or
dried by a passage through a column of anhydrous alumina or copper using a Puresolv MD 5
from Innovative Technology Inc., based on the Grubbs’ design [Pangborn, A. B. et al.
Organometallics 1996, 15, 1518–1520].
Flash column chromatography was performed using Silicycle silica gel: 230-400 mesh (40-63
μm) silica. Reactions were monitored using Merck Kieselgel 60 F254 aluminium. TLC’s were
visualized by UV fluorescence (254 nm) then one of the following: KMnO4, ninhydrine,
pancaldi, p-anisaldehyde or vanillin.
NMR spectra were recorded on a Brüker Avance III-400, Brüker Avance-400 or Brüker DPX-
1
13
4
1
00 spectrometer at room temperature, H frequency is at 400.13 MHz, C frequency is at
00.62 MHz.
Chemical shifts (δ) were reported in parts per million (ppm) relative to residual solvent in
1
13
CDCl [ H: 7.26, C: 77.23]. Coupling constants (J) are reported in Hz to the nearest 0.1 Hz.
3
Multiplicity is indicated as follows s (singlet), d (doublet), t (triplet), q (quartet), quint (quintet)
m (multiplet) and br (broad). Attribution of peaks was done using the multiplicities and
integrals of the peaks. When needed, COSY and/or HSQC experiments were used to confirm
the attribution.
IR spectra were recorded in a Jasco FT/IR-4100 spectrometer outfitted with a PIKE technology
MIRacleTM ATR accessory as neat films compressed onto a Zinc Selenide window. The
-1
spectra are reported in cm .
Mass spectra were determined with a Waters ACQUITY H-class UPLC/MS ACQ-SQD by
electron ionisation (EI positive and negative) or a Finnigan TSQ7000 by electrospray ionization
(ESI+). The accurate masses are done by the mass spectrometry service of the EPFL by ESI-
TOF using a QTOF Ultima from Waters.
Melting points were determined using a Stuart SMP30 and were uncorrected.
S2

Experimental procedure and spectroscopic data of compounds 3-4 and 1c-1l
2
-((2-Iodophenoxy)methyl)acrylic acid (4)
1
To a solution of ethyl 2-((2-iodophenoxy)methyl)acrylate 3 (4.2 g, 12.6 mmol, 1.0 equiv) in
THF (12.0 mL), were added water (12.0 mL) and LiOH (900.0 mg, 37.8 mmol, 3.0 equiv). The
mixture was stirred overnight at 40 °C. After completion of the reaction as shown by TLC, the
THF was evaporated in vacuo, After cooling down to room temperature, the resulting mixture
was extracted with ethyl ether. The aqueous layer was then acidified with 3 N aqueous HCl
solutions (pH < 1.0), and extracted with ethyl acetate, dried over Na SO , evaporated under
2
4
vacuum. The crude acrylic acid 4 were used directly for the subsequent reactions without
further purification.
–
1
White solid. M. p. 110 °C. R (DCM/MeOH/AcOH 9:1:0.1) 0.65. IR (neat, cm ) ν 3673, 2900,
f
1
2
7
6
1
871, 1690, 1435, 1056, 748. H NMR (400 MHz, CDCl3) δ 7.76 (dd, J = 1.6, 7.9 Hz, 1H),
.31 (td, J = 1.1, 8.0 Hz, 1H), 6.93 (dd, J = 1.6, 8.0 Hz, 1H), 6.73 (td, J = 1.1, 7.9 Hz, 1H),
.40 (d, J = 1.6 Hz, 1H), 6.20 (d, J = 1.6 Hz, 1H), 4.77 (s, 2H). C NMR (75 MHz, CDCl3) δ
1
3
-
68.6, 158.4, 140.7, 137.8, 130.9, 127.0, 124.1, 113.7, 87.0, 68.3. HRMS m/z (ES ) calcd for
-
[
C H IO ] 302.9524, found 302.9528.
1
0
8
3
General Procedure A for the Synthesis of N-methyl-N-phenylacrylamide 1c-1l
Acrylic acid 4 (250 mg, 0.82 mmol, 1.0 equiv) was dissolved in dry dichloromethane (3.0 mL),
followed by addition of oxalyl chloride (0.11 mL, 1.23 mmol, 1.5 equiv) and a drop of DMF.
After 2 hours, the volatile were evacuated, the acid chloride 5 was obtained and used directly
for the subsequent reactions without further purification.
1
Szlosek-Pinauda, M.; Diazb, P.; Martineza, J.; Lamaty, F. Tetrahedron 2007, 63, 3340.
S3

To a solution of N-substituted aniline (0.90 mmol, 1.0 equiv) and triethylamine (1.35 mmol, 1.5
equiv) in DCM (2.0 mL) was added dropwise at 0 °C a solution of freshly prepared acid
chloride 5 (0.99 mmol, 1.1 equiv) in DCM (2.0 mL). The mixture was allowed to warm up at
room temperature and stirred overnight. After completion of the reaction as shown by TLC,
water was used to quench the reaction. The organic layer was extracted with ethyl acetate,
washed successively with 1 N aqueous HCl solution, water, 1 N aqueous NaOH and brine. The
crude product was purified by silica gel column chromatography to afford the corresponding
product.
N-benzyl-2-((2-iodophenoxy)methyl)-N-phenylacrylamide (1c)
–
1
Yield = 58%. Yellow solid. M. p. 132 °C R (toluene/acetone 9:1) 0.23. IR (neat, cm ) ν 3675,
f
1
2
1
(
987, 1617, 1497, 1397, 1051, 745, 700. H NMR (400 MHz, CDCl3) δ 7.78 (d, J = 7.5 Hz,
H), 7.28-7.20 (m, 11H), 6.78 (d, J = 7.9 Hz, 1H). 6.71 (t, J = 7.5 Hz, 1H), 5.52 (s, 1H), 5.18
s, 1H), 5.02 (s, 2H), 4.71 (s, 2H). C NMR (75 MHz, CDCl3) δ 168.8, 157.1, 143.0, 139.7,
39.4, 137.2, 129.6, 129.3, 128.7, 128.1, 127.5, 127.4, 123.0, 122.3, 112.5, 86.3, 69.8, 53.7.
HRMS m/z (ES+) calcd for C H INO 470.0617, found 470.0615.
1
3
1
2
3
21
2
2
-((2-iodophenoxy)methyl)-N-(4-methoxyphenyl)-N-methylacrylamide (1d)
–
1
Yield = 62%. White solid. M. p. 119 °C. R (petroleum ether/EtOAc 8:2) 0.13. IR (neat, cm )
f
1
ν 2969, 1623, 1512, 1248, 1017, 906, 727. H NMR (400 MHz, CDCl3) δ 7.77 (dd, J = 1.4,
7
.5 Hz, 1H), 7.28-7.21 (m, 3H), 6.85 (d, J = 8.4 Hz, 2H), 6.76-6.26 (m, 2H), 5.51 (s, 1H), 5.16
1
3
(
s, 1H), 4.64 (s, 2H), 3.80 (s, 3H), 3.39 (s, 3H). C NMR (75 MHz, CDCl3) δ 168.9, 158.6,
57.1, 139.7, 139.6, 137.3, 129.6, 128.4, 123.0, 121.7, 114.6, 112.6, 86.4, 69.7, 55.7, 38.3.
HRMS m/z (ES+) calcd for C H INO 424.0410, found 424.0413.
1
1
8
19
3
S4

2
-((2-Iodophenoxy)methyl)-N-methyl-N-(p-tolyl)acrylamide (1e)
–
1
Yield = 53%. White solid. M. p. 119 °C. R (petroleum ether/EtOAc 8:2) 0.25. IR (neat, cm )
f
1
ν 2929, 1654, 1626, 1513, 1380, 1240, 1017, 952, 760. H NMR (400 MHz, CDCl3) δ 7.76
(dd, J = 1.7, 7.7 Hz, 1H), 7.25 (td, J = 1.7, 7.7 Hz, 1H), 7.19 (d, J = 8.4 Hz, 2H), 7.13 (d, J =
8
1
1
.4 Hz, 2H), 6.75 (dd, J = 1.3, 8.2 Hz, 1H), 6.70 (td, J = 1.3, 7.7 Hz, 1H), 5.51 (s, 1H), 5.16 (s,
H), 4.66 (s, 2H), 3.39 (s, 3H), 2.34 (s, 3H). C NMR (75 MHz, CDCl3) δ 168.9, 157.1,
41.7, 139.6, 129.4, 137.41, 130.1, 129.6, 126.9, 122.9, 121.7, 112.5, 86.3, 69.6, 38.2, 21.2.
1
3
HRMS m/z (ES+) calcd for C H INO 408.0460, found 408.0461.
1
8
19
2
N-(4-cyanophenyl)-2-((2-iodophenoxy)methyl)-N-methylacrylamide (1f)
–
1
Yield = 15%. Yellow solid. M. p. 112 °C. R (toluene/acetone 9:1) 0.15. IR (neat, cm ) ν
2
f
1
926, 2358, 2228, 1660, 1601, 1377, 1277, 1018, 751. H NMR (400 MHz, CDCl3) δ 7.79 (dd,
J = 1.5, 8.0 Hz, 1H), 7.65 (d, J = 8.6 Hz, 2H), 7.54 (d, J = 8.6 Hz, 2H), 7.30 (td, J = 1.5, 8.1
Hz, 1H), 6.84 (dd, J = 1.3, 8.1 Hz, 1H), 6.75 (td, J = 1.3, 8.0 Hz, 1H), 5.58 (s, 1H), 5.10 (s,
1
3
1
1
H), 4.75, (s, 2H), 3.47 (s, 3H). C NMR (75 MHz, CDCl3) δ 168.9, 157.0, 148.5, 139.5,
39.8, 139.1, 133.4, 129.8, 127.5, 123.4, 123.2, 118.4, 112.6, 86.3, 70.1, 37.9. HRMS m/z
(
ES+) calcd for C H IN O 419.0256, found 419.0257.
18 16 2 2
N-(4-fluorophenyl)-2-((2-iodophenoxy)methyl)-N-methylacrylamide (1g)
–
1
Yield = 18%. Colorless oil. R (petroleum ether/EtOAc 8:2) 0.15. IR (neat, cm ) ν 3675, 2920,
f
1
1
1
1
661, 1510, 1240, 1017, 839, 751. H NMR (400 MHz, CDCl3) δ 7.78 (dd, J = 1.4, 7.5 Hz,
H), 7.34-7.26 (m, 3H), 7.03 (t, J = 8.8 Hz, 2H), 6.79 (dd, J = 1.1, 8.2 Hz, 1H), 6.73 (td, J =
.1, 7.5 Hz, 1H). 5.54 (s, 1H), 5.13 (s, 1H), 4.68 (s, 2H), 3.41 (s, 3H). C NMR (75 MHz,
1
3
CDCl3) δ 168.9, 161.4 (d, J = 240.5 Hz), 157.1, 140.5, 139.7, 139.4, 129.7, 128.9 (d, J =
.1Hz), 123.1, 122.1, 116.4 (d, J = 22.5 Hz), 112.6, 86.4, 70.0, 38.4. HRMS m/z (ES+) calcd
for C H FINO 412.0210, found 412.0206.
8
1
7
16
2
S5

Methyl 4-(2-((2-iodophenoxy)methyl)-N-methylacrylamido)benzoate (1h)
–
1
Yield = 49%. Yellow solid. M. p. 99 °C. R (petroleum ether/EtOAc 8:2) 0.13. IR (neat, cm )
f
1
ν 2987, 1715, 1598, 1436, 1275, 1111, 1010, 753. H NMR (400 MHz, CDCl3) δ 8.02 (d, J =
8
.5 Hz, 2H), 7.78 (d, J = 8.0 Hz, 1H), 7.45 (d, J = 8.5 Hz, 2H), 7.28 (t, J = 8.0 Hz, 1H). 6.82
(
3
1
d, J = 8.0 Hz, 1H), 6.73 (t, J = 8.0 Hz, 1H), 5.54 (s, 1H), 5.11 (s, 1H), 4.72 (s, 2H), 3.92 (s,
H), 3.46 (s, 3H). C NMR (75 MHz, CDCl3) δ 168.9, 166.5, 157.1, 148.7, 139.8, 139.2,
30.9, 129.7, 128.6, 126.8, 123.2, 122.8, 112.6, 86.4, 69.9, 52.5, 38.0. HRMS m/z (ES+) calcd
1
3
for C H INO 452.0359, found 452.0359.
1
9
19
4
N-(3,5-dimethylphenyl)-2-((2-iodophenoxy)methyl)-N-methylacrylamide (1i)
–
1
Yield = 93%.White solid. M. p. 98 °C. R (petroleum ether/EtOAc 9:1) 0.13. IR (neat, cm ) ν
2
f
1
919, 1625, 1430, 1380, 1016, 930, 760. H NMR (400 MHz, CDCl3) δ 7.77 (dd, J = 1.7, 8.0
Hz, 1H), 7.25 (td, J = 1.7, 8.0 Hz, 1H), 6.89 (s, 1H), 6.88 (s, 2H), 6.73-6.69 (m, 2H), 5.51 (s,
1
3
1
1
3
H), 5.24 (s, 1H), 4.63, (s, 2H), 3.39 (s, 3H), 2.27 (s, 6H). C NMR (75 MHz, CDCl3) δ
68.7, 157.1, 144.3, 139.7, 139.7, 139.3, 129.6, 129.0, 124.7, 122.9, 121.5, 112.5, 86.4, 69.7,
8.4, 21.4. HRMS m/z (ES+) calcd for C H INO 422.0617, found 422.0624
1
9
21
2
2
-((2-Iodophenoxy)methyl)-N-methyl-N-(m-tolyl)acrylamide (1j)
–
1
Yield = 66%. White solid. M. p. 80 °C. R (petroleum ether/EtOAc 8:2) 0.19. IR (neat, cm ) ν
3
f
1
674, 2972, 1619, 1384, 1227, 1020, 766. H NMR (400 MHz, CDCl3) δ 7.76 (dd, J = 1.7, 7.7
Hz, 1H), 7.27-7.20 (m, 2H), 7.10-7.05 (m, 3H), 6.75-6.69 (m, 2H), 5.51 (s, 1H), 5.19 (s, 1H),
1
3
4
1
2
.64 (s, 2H), 3.40 (s, 3H), 2.31 (s, 3H). C NMR (75 MHz, CDCl3) δ 168.8, 157.1, 144.4,
39.7, 139.6, 139.6, 129.6, 129.3, 128.1, 127.6, 124.3, 123.0, 121.7, 112.5, 86.4, 69.7, 38.3,
1.5. HRMS m/z (ES+) calcd for C H INO 408.0460, found 408.0461.
1
8
19
2
S6

1
-(3,4-dihydroquinolin-1(2H)-yl)-2-((2-iodophenoxy)methyl)prop-2-en-1-one (1k)
–
1
Yield = 56%. White solid. M. p. 132 °C R (toluene/acetone 9:1) 0.13. IR (neat, cm ) ν 3673,
2
1
f
1
926, 1624, 1492, 1388, 1244, 1053. H NMR (400 MHz, CDCl3) δ 7.77 (dd, J = 1.5, 7.8 Hz,
H), 7.54 (d, J = 8.1 Hz, 1H), 7.29 (td, J = 2.0, 8.1 Hz, 1H), 7.15-7.12 (m, 2H), 7.08 (t, J = 8.1
Hz, 1H), 6.86 (d, J = 8.5 Hz, 1H). 6.73 (t, J = 7.7 Hz, 1H), 5.65 (s, 1H), 5.26 (s, 1H), 4.79 (s,
1
3
2
H), 3.90 (t, J = 6.7 Hz, 2H), 2.77 (t, J = 6.7 Hz, 2H), 2.03 (quint, J = 6.7 Hz, 2H). C NMR
(75 MHz, CDCl3) δ 168.8, 157.2, 140.0, 139.7, 139.0, 131.8, 129.7, 128.5, 126.2, 125.7, 125.2,
1
4
23.1, 121.6, 112.6, 86.5, 69.7, 44.4, 27.0, 24.3. HRMS m/z (ES+) calcd for C H INO
19 19 2
12.0210, found 412.0461.
1
-(indolin-1-yl)-2-((2-iodophenoxy)methyl)prop-2-en-1-one (1l)
–
1
Yield = 58%. White solid. M. p. 146 °C. R (petroleum ether/EtOAc 9:1) 0.22. IR (neat, cm )
f
1
ν 2924, 1657, 1612, 1459, 1356, 1133, 980, 841, 749. H NMR (400 MHz, CDCl3) δ 8.11 (s,
1
1
4
1
5
H), 7.75 (d, J = 8.1 Hz, 1H), 7.29 (t, J = 8.1 Hz, 1H), 7.23-7.18 (m, 2H), 7.05 (t, J = 7.1 Hz,
H), 6.88 (d, J = 8.0 Hz, 1H), 6.72 (t, J = 8.1 Hz, 1H), 5.83 (s, 1H), 5.57 (s, 1H), 4.86 (s, 2H),
1
3
.28 (t, J = 8.3 Hz, 2H), 3.16 (t, J = 8.3 Hz, 2H). C NMR (75 MHz, CDCl3) δ 167.4, 156.9,
42.5, 141.0, 139.7, 132.7, 129.7, 127.6, 125.0, 124.5, 123.2, 118.8, 117.6, 112.5, 86.5, 69.6,
0.7, 28.4. HRMS m/z (ES+) calcd for C H INO 406.0304, found 406.0298.
1
8
17
2
S7

Experimental procedure and spectroscopic data of compounds 1a (X = I, Br,
Cl, OTf), 1p-1r and 1t-1y
General Procedure B for the Synthesis of N-methyl-N-phenylacrylamide
2
To a solution of aryl halide 5 (1.0 equiv.) in THF (0.5 M) was added sodium hydride (60%,
1
.1 equiv) and the mixture was stirred at room temperature for 30 min. Allyl halide 6 (1.2
equiv) was then added and the mixture was stirred until the reaction was judged to be
completed by TLC analysis. Water was added and the mixture was diluted with ethyl acetate.
The layers were separated and the organic layer was washed with water (x3) and brine, dried
over anhydrous Na SO and concentrated under reduced pressure. The crude product was
2
4
purified by silica gel column chromatography to afford the corresponding product.
2
-((2-Iodophenoxy)methyl)-N-methyl-N-phenylacrylamide (1a)
–
1
Yield = 84%. White solid. M. p. 89 °C. R (Petroleum ether/EtOAc 7:3) 0.39. IR (neat, cm ) ν
2
f
1
928, 1657, 1626, 1473, 1239, 1010, 749. H NMR (400 MHz, CDCl3) δ 7.76 (dd, J = 1.7, 7.7
Hz, 1H), 7.37-7.24 (m, 6H), 6.76 (dd, J = 1.3, 8.4 Hz, 1H), 6.70 (td, J = 1.3, 7.7 Hz, 1H), 5.52
1
3
(
1
s, 1H), 5.15 (s, 1H), 4.67 (s, 2H), 3.43 (s, 3H). C NMR (75 MHz, CDCl3) δ 168.9, 157.1,
44.5, 139.7, 139.4, 129.7, 129.5, 127.2, 127.2, 123.0, 122.0, 112.6, 86.4, 69.7, 38.3. HRMS
m/z (ES+) calcd for C H INO 394.0304, found 394.0298.
1
7
17
2
2
-((2-bromophenoxy)methyl)-N-methyl-N-phenylacrylamide (1a, X = Br)
2
Jaegli, S.; Vors, J.-P.; Neuville, L.; Zhu, J. Tetrahedron 2010, 66, 8911.
S8

–
1
Yield = 74%. White solid. M. p. 98 °C. R (Petroleum ether/EtOAc 8:2) 0.27. IR (neat, cm ) ν
2
f
1
928, 1625, 1594, 1479, 1382, 1243, 1031, 748, 699. H NMR (400 MHz, CDCl3) δ 7.55 (dd,
J = 1.6, 8.3 Hz, 1H), 7.37-7.32 (m, 4H), 7.28-7.25 (m, 2H), 6.87-6.82 (m, 2H), 5.48 (s, 1H),
1
3
5
1
.13 (s, 1H), 4.70 (s, 2H), 3.42 (s, 3H). C NMR (75 MHz, CDCl3) δ 168.8, 154.9, 144.5,
39.4, 133.5, 129.5, 128.6, 127.2, 127.1, 122.3, 121.8, 113.4, 112.1, 69.6, 38.1. HRMS m/z
(
ES+) calcd for C H BrNO 346.0443, found 346.0441.
17 17 2
2
-((2-chlorophenoxy)methyl)-N-methyl-N-phenylacrylamide (1a, X = Cl)
–
1
Yield = 59%. White solid. M. p. 94 °C. R (Petroleum ether/EtOAc 9:1) 0.14. IR (neat, cm ) ν
2
f
1
940, 1656, 1627, 1480, 1382, 1242, 1010, 760, 701. H NMR (400 MHz, CDCl3) δ 7.37-7.32
(
m, 5H), 7.28-7.25 (m, 1H), 7.18 (td, J = 1.2,8.6 Hz, 1H), 6.91-6.90 (m, 2H), 5.45 (s, 1H), 5.12
1
3
(
s, 1H), 4.71 (s, 2H), 3.42 (s, 3H). C NMR (75 MHz, CDCl3) δ 169.0, 154.0, 144.5, 139.4,
30.4, 129.5, 129.3, 127.9, 127.2, 127.1, 122.8, 121.8, 113.5, 69.6, 38.0. HRMS m/z (ES+)
calcd for C H ClNO 302.0948, found 302.0951.
1
1
7
17
2
2
-((2-(methyl(phenyl)carbamoyl)allyl)oxy)phenyl trifluoromethanesulfonate (1a, X = OTf)
–
1
Yield = 69%. White solid. M. p. 215 °C. R (petroleum ether/EtOAc 8:2) 0.28. IR (neat, cm )
f
1
ν 2971, 1627, 1496, 1420, 1205, 1140, 1097, 890, 758. H NMR (400 MHz, CDCl3) δ 7.35 (t,
J = 8.1 Hz, 2H), 7.29-7.21 (m, 5H), 7.02 (d, J = 8.4 Hz, 1H), 6.98 (t, J = 8.4 Hz, 1H), 5.51 (s,
1
3
1
1
1
H), 5.16 (s, 1H), 4.73 (s, 2H), 3.40 (s, 3H). C NMR (75 MHz, CDCl3) δ 168.6, 150.4,
44.4, 138.9, 138.9, 129.6, 129.4, 127.4, 127.0, 122.5, 122.1, 121.5, 118.9 (q, J = 321.2 Hz),
+
14.8, 69.7, 38.2. HRMS m/z (ES+) calcd for [C H F NO S] 416.0774, found 416.0777.
1
8
17
3
5
methyl 3-iodo-4-((2-(methyl(phenyl)carbamoyl)allyl)oxy)benzoate (1p)
–
1
Yield = 71%. Colorless oil. R (petroleum ether/EtOAc 8:2) 0.23. IR (neat, cm ) ν 2949, 1712,
1
f
1
657, 1594, 1493, 1290, 1263, 991, 758, 700. H NMR (400 MHz, CDCl3) δ 8.45 (d, J = 1.8
Hz, 1H), 7.96 (dd, J = 1.8, 8.7 Hz, 1H), 7.37-7.25 (m, 5H), 6.75 (d, J = 8.7 Hz, 1H), 5.51 (s,
S9

1
3
1
1
5
H), 5.18 (s, 1H), 4.72 (s, 2H), 3.88 (s, 3H), 3.42 (s, 3H). C NMR (75 MHz, CDCl3) δ 168.5,
65.6, 160.6, 144.4, 141.2, 138.8, 131.7, 129.5, 127.3, 127.1, 124.8, 122.5, 111.4, 85.6, 69.9,
2.3, 38.3. HRMS m/z (ES+) calcd for C H INO 452.0359, found 452.0347.
1
9
19
4
2
-(((3-iodo-[1,1'-biphenyl]-4-yl)oxy)methyl)-N-methyl-N-phenylacrylamide (1q)
–
1
Yield = 71%. Colorless oil. R (petroleum ether/EtOAc 8:2) 0.34. IR (neat, cm ) ν 3058, 2932,
f
1
1
7
624, 1478, 1382, 1274, 1014, 762. H NMR (400 MHz, CDCl3) δ 8.03 (d, J = 2.2 Hz, 1H),
.53-7.48 (m, 3H), 7.42 (t, J = 7.6 Hz, 2H), 7.39-7.26 (m, 6H), 6.83 (d, J = 8.3 Hz, 1H), 5.54
s, 1H), 5.18 (s, 1H), 4.72 (s, 2H), 3.45 (s, 3H). C NMR (75 MHz, CDCl3) δ 168.8, 156.5,
1
3
(
1
8
44.4, 139.4, 139.4, 138.1, 136.2, 129.5, 129.0, 128.2, 127.3, 127.2, 127.1, 126.9, 122.0, 112.5,
6.8, 69.8, 38.2. HRMS m/z (ES+) calcd for C H INO 470.0617, found 470.0622.
2
3
21
2
2
-((4-(tert-butyl)-2-iodophenoxy)methyl)-N-methyl-N-phenylacrylamide (1r)
–
1
Yield = 85%. Colorless oil. R (petroleum ether/EtOAc 8:2) 0.27. IR (neat, cm ) ν 2954, 1627,
f
1
1
1
(
594, 1494, 1384, 1255, 1042, 933, 697. H NMR (400 MHz, CDCl3) δ 7.76 (d, J = 2.9 Hz,
H), 7.36-7.26 (m, 6H), 6.71 (d, J = 9.0 Hz, 1H), 5.51 (s, 1H), 5.14 (s, 1H), 4.66 (s, 2H), 3.43
s, 3H), 1.20 (s, 9H). C NMR (75 MHz, CDCl3) δ 168.9, 154.9, 146.1, 144.5, 139.6, 136.7,
29.4, 127.1, 126.5, 121.7, 112.0, 86.3, 69.8, 38.2, 34.2, 31.6. HRMS m/z (ES+) calcd for
C H INO 450.0930, found 450.0927.
1
3
1
21
25
2
2
-((N-(2-iodophenyl)acetamido)methyl)-N-methyl-N-phenylacrylamide (1t)
–
1
Yield = 65%. Yellow oil. R (petroleum ether/EtOAc 5:5) 0.26. IR (neat, cm ) ν 2922, 1648,
f
1
1
1
5
632, 1389, 1283, 1016, 933, 769, 697. H NMR (400 MHz, CDCl3) δ 7.90 (d, J = 7.7 Hz,
H), 7.60 (d, J = 7.7 Hz, 1H), 7.40-7.33 (m, 3H), 4.27-7.24 (m, 3H), 7.06 (t, J = 7.7 Hz, 1H),
.20 (s, 1H), 5.00-4.96 (m, 2H), 3.31 (s, 3H), 3.12 (d, J = 13.1 Hz, 1H), 1.75 (s, 3H). C NMR
13
S10

(75 MHz, CDCl3) δ 170.4, 169.9, 144.5, 143.9, 140.7, 140.0, 131.7, 130.1, 129.6, 129.4, 127.4,
1
4
21.4, 100.1, 51.4, 37.8, 22.9. HRMS m/z (ES+) calcd for C H IN O 435.0569, found
19 20 2 2
35.0558.
2
-((N-(2-iodophenyl)-4-methylphenylsulfonamido)methyl)-N-methyl-N-phenylacrylamide (1u)
–
1
Yield = 86%. Orange oil. R (petroleum ether/EtOAc 7:3) 0.22. IR (neat, cm ) ν 3661, 2956,
f
1
1
1
7
1
1
3
712, 1625, 1595, 1494, 1382, 1256, 1042, 770. H NMR (400 MHz, CDCl3) δ 7.85 (dd, J =
.1, 8.0 Hz, 1H), 7.55 (d, J = 8.5 Hz, 2H), 7.29-7.20 (m, 6H), 7.13 (dd, J = 1.2, 8.1 Hz, 1H),
.02-6.98 (m, 3H), 5.43 (s, 1H), 5.28 (s, 1H), 4.39 (d, J = 17.6 Hz, 1H), 4.00 (d, J = 17.6 Hz,
H), 3.25 (s, 3H), 2.41 (s, 3H). C NMR (75 MHz, CDCl3) δ 169.1, 144.0, 143.9, 141.5,
40.7, 139.8, 136.4, 132.6, 130.0, 129.6, 129.5, 128.7, 128.4, 127.2, 126.7, 124.4, 101.4, 53.6,
8.2, 21.8. HRMS m/z (ES+) calcd for C H IN O S 547.0552, found 547.0553.
13
2
4
24
2
3
2
-((N-(2-iodo-5-methoxyphenyl)acetamido)methyl)-N-methyl-N-phenylacrylamide (1v)
–
1
Yield = 83%. Colorless oil. R (petroleum ether/EtOAc 6:4) 0.32. IR (neat, cm ) ν 2966, 2252,
f
1
1
1
3
1
5
668, 1602, 1475, 1361, 1168, 907, 726. H NMR (400 MHz, CDCl3) δ 7.71 (d, J = 8.9 Hz,
H), 7.37-7.24 (m, 6H), 6.67 (dd, J = 1.8, 8.9 Hz, 1H), 5.20 (s, 1H), 5.20-4.96 (m, 2H), 3.80 (s,
H), 3.31 (s, 3H), 3.07 (d, J = 15.2 Hz, 1H), 1.79 (s, 3H). C NMR (75 MHz, CDCl3) δ 170.3,
70.0, 160.8, 145.2, 143.8, 140.0, 139.8, 129.4, 127.5, 127.4, 121.3, 117.2, 116.9, 87.9, 55.9,
1.4, 37.8, 22.8. HRMS m/z (ES+) calcd for [C H IN O ] 465.0670, found 465.0674.
1
3
+
2
0
22
2
3
2
-((N-(4-cyano-2-iodophenyl)acetamido)methyl)-N-methyl-N-phenylacrylamide
(1w)
–
1
Yield = 87%. Colorless oil. R (petroleum ether/EtOAc 7:3) 0.11. IR (neat, cm ) ν 2923, 1650,
f
1
1
1
5
593, 1495, 1376, 1291, 922, 729, 699. H NMR (400 MHz, CDCl3) δ 8.19 (d, J = 1.6 Hz,
H), 7.94 (d, J = 8.4 Hz, 1H), 7.69 (dd, J = 1.6, 8.4 Hz, 1H), 7.39-7.27 (m, 5H), 5.15 (s, 1H),
.05 (d, J = 12.6 Hz, 1H), 4.87 (s, 1H), 3.33 (s, 3H), 3.08 (d, J = 12.6 Hz, 1H), 1.76 (s, 3H).
C NMR (75 MHz, CDCl3) δ 169.5, 169.3, 148.3, 143.0, 140.1, 133.2, 132.4, 129.3, 127.5,
1
3
S11

+
1
4
27.4, 121.4, 116.4, 114.0, 100.5, 51.2, 37.6, 22.8. HRMS m/z (ES+) calcd for [C H IN O ]
20 19 3 2
60.0516, found 460.0522.
2
-((N-(2-iodo-4-methylphenyl)acetamido)methyl)-N-methyl-N-phenylacrylamide (1x)
–
1
Yield = 77%. Yellow oil. R (petroleum ether/EtOAc 5:5) 0.17. IR (neat, cm ) ν 2930, 2359,
1
1
f
1
659, 1586, 1381, 1303, 1232, 1029, 700. H NMR (400 MHz, CDCl3) δ 7.72 (d, J = 1.1 Hz,
H), 7.46 (d, J = 7.9 Hz, 1H), 7.35 (t, J = 7.6 Hz, 2H), 7.28-7.24 (m, 3H), 7.19 (dd, J = 1.1, 7.9
Hz, 1H), 5.19 (s, 1H), 4.99-4.96 (m, 2H), 3.32 (s, 3H), 3.12 (d, J = 13.7 Hz, 1H), 2.33 (s, 3H),
1
3
1
1
.76 (s, 3H). C NMR (75 MHz, CDCl3) δ 170.7, 170.0, 143.9, 141.9, 140.8, 140.4, 140.3,
31.1, 130.4, 129.4, 127.4, 127.3, 121.2, 99.8, 51.5, 37.9, 22.9 20.8. HRMS m/z (ES+) calcd
+
for [C H IN O ] 449.0720, found 449.0727.
20
22
2
2
2
-((N-(2-iodo-4,6-dimethylphenyl)acetamido)methyl)-N-methyl-N-phenylacrylamide (1y)
–
1
Yield = 56%. Colorless oil. R (petroleum ether/EtOAc 7:3) 0.14. IR (neat, cm ) ν 2973, 2233,
1
7
f
1
668, 1627, 1380, 1293, 1076, 731. H NMR (400 MHz, CDCl3) δ 7.55 (s, 1H), 7.31 (t, J =
.7 Hz, 2H), 7.21 (t, J = 7.7 Hz, 1H), 7.15 (d, J = 7.7 Hz, 2H), 7.02 (s, 1H), 5.34 (s, 1H), 5.26
(
3
1
s,1H), 4.63 (d, J = 14.9 Hz, 1H), 3.30 (d, J = 14.9 Hz, 1H), 3.28 (s, 3H), 2.26 (s, 6H), 1.72 (s,
H). C NMR (75 MHz, CDCl3) δ 171.1, 169.9, 144.1, 141.8, 140.9, 140.0, 138.8, 138.5,
1
3
32.5, 129.4, 127.0, 127.0, 124.4, 100.6, 51.8, 38.2, 22.4, 20.6, 20.0. HRMS m/z (ES+) calcd
+
for [C H IN O ] 463.0877, found 463.0884.
21
24
2
2
S12

Experimental procedure and spectroscopic data of compounds 1b and 1s
4
-(2-Iodophenyl)-2-methylenebutanoic acid (9)
3
To a solution of malonate 7 (3.4 g, 8.7 mmol, 1.0 equiv) in a mixture of ethanol/water (3/1,
1
0.0 mL), was added sodium hydroxide (1.4 g, 34.9 mmol, 4.0 equiv). The mixture was stirred
overnight at rt. After cooling down at rt, the ethanol was evaporated under vacuum, the
resulting mixture was extracted with ethyl ether. The aqueous layer was then acidified with 3 N
aqueous HCl solutions (pH < 1.0), extracted with ethyl acetate. the organic layer was dried over
anhydrous Na SO , filtered, and concentrated under reduced pressure. The crude malonic acid
2
4
8
were used directly for the subsequent reactions without further purification.
To a solution of malonic acid 8 (2.2 g, 6.6 mmol, 1.0 equiv) in 22.0 mL of pyridine were added
formaldehyde (37%aq) (0.7 mL, 8.6 mmol, 1.3 equiv) and piperidine (1.3 mL, 13.2 mmol, 2.0
equiv). The mixture was then stirred for 1 h at rt then 4 h at 60 °C. After completion of the
reaction as shown by TLC, water was added and the pyridine was evaporated under vacuum.
The mixture resulting mixture was extracted with ethyl acetate several times. The organic layer
was washed with 1 N aqueous HCl, water and brine. The organic layer was dried over
anhydrous Na SO , filtered, and concentrated under reduced pressure. The acrylic acid 9 was
2
4
obtain as a white solid (1.8 g, 92%) and directly for the subsequent reactions without further
purification.
–
1
M. p. 73 °C. R (DCM/MeOH/AcOH 9:1:0.1) 0.71. IR (neat, cm ) ν 3060, 2926, 2575, 1678,
1
f
1
436, 1263, 951, 756. H NMR (400 MHz, CDCl3) δ 7.85 (d, J = 7.7 Hz, 1H), 7.30 (t, J = 7.2
Hz , 1H), 7.24 (dd, J = 1.5, 7.7 Hz, 1H), 6.92 (td, J = 1.5, 7.7 Hz, 1H), 6.38 (s, 1H), 5.71 (s,
3
Mukai, C.; Kuroda, N.; Ukon, R.; Itoh, I. J. Org. Chem. 2005, 70, 6282.
S13

1
3
1
1
H), 2.96 (t, J = 8.6 Hz, 2H), 2.63 (t, J = 8.6 Hz, 2H). C NMR (75 MHz, CDCl3) δ 172.7,
43.9, 139.7, 139.0, 129.9, 128.6, 128.5, 128.2, 100.7, 39.9, 32.3. HRMS m/z (ES+) calcd for
+
[
C H IO ] 302.9876, found 302.9530.
1
1
12
2
General procedure C for the synthesis of starting materials 1b and 1s
To a solution of acrylic acid 9 (1.0 equiv) and aniline (1.2 equiv) in DMF (c = 0.3 M), N-(3-
dimethylaminopropyl)-N'-ethyl-carbodiimide hydrochloride (1.5 equiv) was added and the
solution was stirred overnight at rt. The mixture was partitioned between water and ethyl
acetate, the organic layer was washed with 1 N aqueuous HCl, water, 0.5 N aqueous NaOH,
brine, dried over Na SO and evaporated under vacuum. The crude material was
2
4
chromatographed on silica using petroleum ether/AcOEt to give the desired compound.
4
-(2-Iodophenyl)-2-methylene-N-phenylbutanamide (1b)
–
1
Yield = 96%. White solid. M. p. 98 °C. R (petroleum ether/EtOAc 8:2) 0.27. IR (neat, cm ) ν
3
0
f
1
321, 2916, 1618, 1591, 1427, 1010, 754, 699. H NMR (400 MHz, CDCl3) δ 7.84 (dd, J =
.8, 8.0 Hz, 1H), 7.59 (d, J = 7.6 Hz, 2H), 7.57 (brs, 1H), 7.37 (t, J = 7.6 Hz , 2H), 7.32-7.26
(
m, 2H), 7.16 (t, J = 7.3 Hz , 1H), 6.91 (td, J = 0.8, 7.9 Hz, 1H), 5.80 (s, 1H), 5.47 (s, 1H), 2.99
1
3
(
m, 2H), 2.73 (m, 2H). C NMR (75 MHz, CDCl3) δ 166.6, 145.1, 143.8, 139.7, 137.9, 130.0,
29.3, 128.7, 128.3, 124.7, 120.3, 119.4, 100.6, 39.9, 33.2. HRMS m/z (ES+) calcd for
C H INO 378.0355, found 378.0349.
1
17
17
4
-(2-Iodophenyl)-N-methyl-2-methylene-N-phenylbutanamide (1s)
–
1
Yield = 65%. White solid. M. p. 72 °C. R (petroleum ether/EtOAc 8:2) 0.18. IR (neat, cm ) ν
f
1
3
1
1
8
1
055, 16445, 1594, 1466, 1374, 1112, 1011, 920. H NMR (400 MHz, CDCl3) δ 7.79 (dd, J =
.3, 7.9 Hz, 1H), 7.35 (t, J = 7.7 Hz, 2H), 7.28-7.23 (m, 2H), 7.18-7.15 (m, 3H), 6.87 (td, J =
.8, 7.5 Hz, 1H), 5.13 (s, 1H), 5.10 (s, 1H), 3.37 (s, 3H), 2.82 (t, J = 8.3 Hz, 2H), 2.36 (t, J =
.3 Hz, 2H). C NMR (75 MHz, CDCl3) δ 171.7, 144.6, 144.2, 143.9, 139.6, 129.6, 129.5,
28.6, 128.1, 127.2, 127.0, 119.0, 100.6, 39.2, 38.0, 34.2. HRMS m/z (ES+) calcd for
13
C H INO 392.0511, found 392.0506.
18
19
S14

General Procedure for the Synthesis of Spirodihydroquinolin-2-ones
Anilide 2 (0.15 mmol, 1.0 equiv), Pd(OAc) (0.0038 mmol, 0.025 equiv), Xphos (0.0075
2
mmol, 0.050 equiv) and K CO (0.30 mmol, 2.0 equiv) were introduced in a screw cap vial
2
3
equipped with a magnetic stir bar. The vial was purged with argon during 10 min. Degazed
DMA (1.0 mL) was then added and the mixture was stirred at 100 °C until complete
disappearance of the starting material as shown by TLC (usually 6-9 h). The reaction was next
quenched with water and extracted with EtOAc. The combined organic layers were washed
with brine, dried and concentrated under reduced pressure to give a residue which was purified
by flash column chromatography.
1
'-Methyl-1'H,2H-spiro[benzofuran-3,3'-quinolin]-2'(4'H)-one (2a)
–
1
Yield = 85%. White solid. M. p. 140 °C. R (petroleum ether/EtOAc 9:1) 0.21. IR (neat, cm )
f
1
ν 2928, 1626, 1581, 1390, 1239, 1010, 749. H NMR (400 MHz, CDCl3) δ 7.37 (td, J = 1.7,
7
6
3
1
3
.4 Hz, 1H), 7.16-7.06 (m, 4H), 6.82 (dd, J = 0.3, 8.2 Hz, 1H), 6.63 (td, J = 1.1, 7.4 Hz, 1H),
.46 (dd, J = 1.1, 7.4 Hz, 1H), 5.20 (d, J = 8.9 Hz, 1H), 4.33 (d, J = 8.9 Hz, 1H), 3.46 (s, 3H),
1
3
.23 (d, J = 15.4 Hz, 1H), 3.14 (d, J = 15.4 Hz, 1H). C NMR (75 MHz, CDCl3) δ 170.8,
59.9, 140.5, 129.8, 129.2, 129.0, 128.4, 124.0, 123.7, 123.6, 120.7, 114.8, 110.4, 79.2, 51.6,
7.8, 30.7. HRMS m/z (ES+) calcd for C H NO 266.1181, found 266.1181.
1
7
16
2
1
'-benzyl-1'H,2H-spiro[benzofuran-3,3'-quinolin]-2'(4'H)-one (2c)
–
1
Yield = 90%. Yellow oil. R (petroleum ether/EtOAc 9:1) 0.38. IR (neat, cm ) ν 2933, 1667,
f
1
1
7
1
4
609, 1462, 1376, 1188, 978, 751, 730. H NMR (400 MHz, CDCl3) δ 7.31-7.15 (m, 8H),
.06-7.00 (m, 2H), 6.87 (dd, J = 1.4, 7.9 Hz, 1H), 6.67 (td, J = 1.2, 7.6 Hz, 1H), 6.55 (dd, J =
.2, 7.7 Hz, 1H), 5.48 (d, J = 16.6 Hz, 1H), 5.35 (d, J = 9.5 Hz, 1H), 5.01 (d, J = 16.6 Hz, 1H),
13
.42 (d, J = 9.5 Hz, 1H), 3.33 (d, J = 14.7 Hz, 1H), 3.22 (d, J = 14.7 Hz, 1H). C NMR (75
MHz, CDCl3) δ 170.9, 160.0, 139.9, 137.1, 129.9, 129.3, 129.0, 128.8, 128.3, 127.4, 126.6,
S15

1
24.1, 123.7, 120.7, 115.6, 110.6, 79.1, 60.6, 51.6, 47.4, 38.0. HRMS m/z (ES+) calcd for
C H NO 342.1494, found 342.1416.
23
20
2
6
'-methoxy-1'-methyl-1'H,2H-spiro[benzofuran-3,3'-quinolin]-2'(4'H)-one (2d)
–
1
Yield = 97%. Yellow solid. M. p. 104 °C. R (petroleum ether/EtOAc 8:2) 0.22. IR (neat, cm )
f
1
ν 3676, 2924, 1711, 1671, 1478, 1334, 1241, 978, 753. H NMR (400 MHz, CDCl3) δ 7.11 (t,
J = 8.1 Hz, 1H), 7.00 (d, J = 9.2 Hz, 1H), 6.88 (dd, J = 2.3, 9.2 Hz, 1H), 6.81 (d, J = 8.1 Hz,
1
8
H), 6.71 (d, J = 2.3 Hz, 1H), 6.64 (t, J = 7.6 Hz, 1H), 6.48 (d, J = 7.6 Hz, 1H), 5.20 (d, J =
.6 Hz, 1H), 4.32 (d, J = 8.6 Hz, 1H), 3.80 (s, 3H), 3.43 (s, 3H), 3.20 (d, J = 15.6 Hz, 1H), 3.08
1
3
(
d, J = 15.6 Hz, 1H). C NMR (75 MHz, CDCl3) δ 170.2, 159.9, 155.8, 134.0, 129.7, 129.1,
25.1, 124.1, 120.7, 115.8, 115.1, 112.9, 110.4, 79.2, 55.7, 51.5, 38.1, 30.8. HRMS m/z (ES+)
calcd for C H NO 296.1287, found 296.1281.
1
1
8
18
2
1
',6'-Dimethyl-1'H,2H-spiro[benzofuran-3,3'-quinolin]-2'(4'H)-one (2e)
–
1
Yield = 92%. White solid. M. p. 174 °C. R (petroleum ether/EtOAc 9:1) 0.32. IR (neat, cm )
f
1
ν 2972, 1656, 1479, 1360, 1074, 977, 747. H NMR (400 MHz, CDCl3) δ 7.16 (d, J = 8.5 Hz,
1
H), 7.12 (td, J = 0.3, 8.2 Hz, 1H), 6.97 (d, J = 8.2 Hz, 1H), 6.96 (s, 1H), 6.82 (dd, J = 0.3, 8.2
Hz, 1H), 6.64 (td, J = 1.1, 7.5 Hz, 1H), 6.48 (dd, J = 1.1, 7.5 Hz, 1H), 5.20 (d, J = 9.7 Hz, 1H),
4
2
1
.33 (d, J = 9.7 Hz, 1H), 3.43 (s, 3H), 3.19 (d, J = 15.3 Hz, 1H), 3.09 (d, J = 15.3 Hz, 1H),
.32 (s, 3H). C NMR (75 MHz, CDCl3) δ 170.6, 159.9, 138.0, 133.2, 129.9, 129.7, 129.2,
28.7, 124.1, 123.4, 120.7, 114.7, 110.4, 79.2, 51.7, 37.8, 30.7, 20.8. HRMS m/z (ES+) calcd
1
3
for C H NO 280.1338, found 280.1335.
1
8
18
2
S16

1
'-methyl-2'-oxo-2',4'-dihydro-1'H,2H-spiro[benzofuran-3,3'-quinoline]-6'-carbonitrile (2f)
–
1
Yield = 76%. White solid. M. p. 103 °C. R (petroleum ether/EtOAc 8:2) 0.25. IR (neat, cm )
f
1
ν 2927, 2224, 1667, 1605, 1473, 1353, 1130, 981, 833, 765. H NMR (400 MHz, CDCl3) δ
7
1
8
.68 (dd, J = 1.7, 8.3 Hz, 1H), 7.44 (d, J = 1.7 Hz, 1H), 7.18-7.13 (m, 2H), 6.84 (d, J = 8.2 Hz,
H), 6.65 (t, J = 7.3 Hz, 1H), 6.40 (d, J = 7.3 Hz, 1H), 5.19 (d, J = 8.8 Hz, 1H), 4.34 (d, J =
.8 Hz, 1H), 3.47 (s, 3H), 3.25 (d, J = 16.2 Hz, 1H), 3.19 (d, J = 16.2 Hz, 1H). C NMR (75
1
3
MHz, CDCl3) δ 170.5, 159.8, 144.1, 132.9, 132.5, 130.3, 128.1, 124.7, 123.5, 121.0, 118.7,
1
15.2, 110.8, 106.9, 78.9, 51.2, 37.3, 30.9. HRMS m/z (ES+) calcd for C H N O 291.1134,
18 15 2 2
found 291.1133.
6
'-fluoro-1'-methyl-1'H,2H-spiro[benzofuran-3,3'-quinolin]-2'(4'H)-one (2g)
–
1
Yield = 44%. Yellow solid. M. p. 161 °C. R (petroleum ether/EtOAc 9:1) 0.21. IR (neat, cm )
f
1
ν 3661, 2920, 1656, 1505, 1479, 1242, 978, 748. H NMR (400 MHz, CDCl3) δ 7.13 (td, J =
1
6
1
.4, 8.1 Hz, 1H), 7.09-7.01 (m, 2H), 6.89 (dd, J = 2.4, 8.1 Hz, 1H), 6.83 (d, J = 8.1 Hz, 1H),
.65 (t, J = 7.6 Hz, 1H), 6.45 (d, J = 7.6 Hz, 1H), 5.20 (d, J = 9.0 Hz, 1H), 4.33 (d, J = 9.0 Hz,
H), 3.44 (s, 3H), 3.22 (d, J = 14.3 Hz, 1H), 3.11 (d, J = 14.3 Hz, 1H). C NMR (75 MHz,
1
3
CDCl3) δ 170.3, 159.8, 158.9 (d, J = 245.2 Hz), 136.7 (d, J = 2.1 Hz), 130.0, 128.7, 125.7,
1
5
23.8, 120.8, 116.3 (d, J = 22.1 Hz), 116.0 (d, J = 8.0 Hz), 114.7 (d, J = 22.1 Hz), 110.6, 79.1,
1.3, 37.7, 31.0. HRMS m/z (ES+) calcd for C H FNO 284.1087, found 283.1009.
1
7
15
2
Methyl 1'-methyl-2'-oxo-2',4'-dihydro-1'H,2H-spiro[benzofuran-3,3'-quinoline]-6'-carboxylate
2h)
(
S17

–
1
Yield = 91%. Yellow solid. M. p. 110 °C. R (petroleum ether/EtOAc 8:2) 0.33. IR (neat, cm )
f
1
ν 3660, 2925, 1711, 1672, 1264, 1110, 754. H NMR (400 MHz, CDCl3) δ 8.05 (dd, J = 1.9,
8
7
.5 Hz, 1H), 7.83 (d, J = 1.9 Hz, 1H), 7.14-7.11 (m, 2H), 6.82 (d, J = 8.5 Hz, 1H), 6.62 (t, J =
.7 Hz, 1H), 6.42 (d, J = 7.7 Hz, 1H), 5.20 (d, J = 9.3 Hz, 1H), 4.34 (d, J = 9.3 Hz, 1H), 3.90
13
(s, 3H), 3.48 (s, 3H), 3.26 (d, J = 15.8 Hz, 1H), 3.20 (d, J = 15.6 Hz, 1H). C NMR (75 MHz,
CDCl3) δ 170.8, 166.6, 159.9, 144.2, 130.4, 130.3, 130.0, 128.5, 125.1, 123.8, 123.5, 120.8,
1
14.5, 110.6, 79.0, 52.3, 51.4, 37.5, 30.9. HRMS m/z (ES+) calcd for C H NO 324.1236,
19 18 4
found 324.1241.
1
',5',7'-trimethyl-1'H,2H-spiro[benzofuran-3,3'-quinolin]-2'(4'H)-one (2i)
–
1
Yield = 93%. White solid. M. p. 126 °C. R (petroleum ether/EtOAc 9:1) 0.20. IR (neat, cm )
f
1
ν 2921, 1630, 1596, 1481, 1399, 1246, 1017, 751. H NMR (400 MHz, CDCl3) δ 7.12 (t, J =
8
.3 Hz, 1H), 6.82 (d, J = 8.3 Hz, 1H), 6.79 (s, 1H), 6.77 (s, 1H), 6.65 (t, J = 7.2 Hz, 1H), 6.53
(
=
d, J = 8.1 Hz, 1H), 5.16 (d, J = 8.1 Hz, 1H), 4.31 (d, J = 8.1 Hz, 1H), 3.41 (s, 3H), 3.16 (d, J
16.6 Hz, 1H), 3.01 (d, J = 16.6 Hz, 1H), 2.38 (s, 3H), 2.18 (s, 3H). C NMR (75 MHz,
1
3
CDCl3) δ 167.4, 156.9, 142.5, 141.0, 139.7, 132.7, 129.8, 127.6, 125.0, 124.5, 123.2, 118.8,
1
2
17.6, 112.5, 86.5, 69.6, 50.7, 28.4. HRMS m/z (ES+) calcd for C H NO 294.1494, found
19 20 2
94.1497.
1
',7'-Dimethyl-1'H,2H-spiro[benzofuran-3,3'-quinolin]-2'(4'H)-one and 1',5'-dimethyl-1'H,2H-
spiro[benzofuran-3,3'-quinolin]-2'(4'H)-one (2j and 2j')
–
1
Yield = 96%. Yellow solid. M. p. 128 °C. R (petroleum ether/EtOAc 9:1) 0.25. IR (neat, cm )
f
1
ν 2972, 1656, 1479, 1360, 1074, 977, 747. H NMR (400 MHz, CDCl3) δ 7.26 (t, J = 7.6 Hz,
1
=
H-min), 7.13 (td, J = 1.0, 8.2 Hz, 1H-maj+ 1H-min), 7.03 (d, J = 7.4 Hz, 1H-maj), 6.98 (d, , J
7.4 Hz, 1H-min), 6.97 (d, J = 8.2 Hz, 1H-min), 6.91 (s, 1H-maj), 6.90 (d, J = 8.2 Hz, 1H-
maj), 6.83 (d, J = 8.1 Hz, 1H-min), 6.82 (d, J = 8.1 Hz, 1H-maj), 6.66 (td, J = 1.0, 7.2 Hz, 1H-
min), 6.65 (td, J = 1.0, 7.2 Hz, 1H-maj), 6.52 (dd, J = 1.0, 7.2 Hz, 1H-min), 6.49 (dd, J = 1.0,
S18

7
.2 Hz, 1H-maj), 5.20 (d, J = 9.2 Hz, 1H-maj), 5.19 (d, J = 9.2 Hz, 1H-min), 4.34 (d, J = 9.2
Hz, 1H-min), 4.33 (d, J = 9.2 Hz, 1H-maj), 3.45 (s, 3H-maj+3H-min), 3.22 (d, J = 15.4 Hz,
1
1
H-maj), 3.19 (d, J = 15.4 Hz, 1H-min), 3.10 (d, J = 15.4 Hz, 1H-maj), 3.07 (d, J = 15.4 Hz,
H-min), 2.44 (s, 3H-maj), 2.24 (s, 3H-min). C NMR (75 MHz, CDCl3) δ 170.7 (maj), 170.4
1
3
(
(
min), 159.7 (maj), 159.6 (min), 140.4 (min), 140.1 (maj), 138.0 (maj), 136.7 (min), 129.5
maj+min), 129.1 (min), 129.0 (maj), 127.6 (min), 125.4 (min), 124.0 (maj), 123.9 (maj+min),
1
1
23.8 (maj), 122.1 (min), 120.9 (min), 120.5 (maj+min), 120.4 (min), 115.5 (maj), 122.8 (min),
10.2 (min), 110.2 (maj), 79.1 (min) , 79.0 (maj), 51.5 (maj), 51.2 (min) , 37.3 (maj), 34.1
(min), 30.8 (min), 30.5 (min), 21.7 (maj), 19.6 (min). HRMS m/z (ES+) calcd for C18H18NO2
2
80.1338, found 280.1338.
6
',7'-dihydro-1'H,2H-spiro[benzofuran-3,2'-pyrido[3,2,1-ij]quinolin]-3'(5'H)-one (2k)
–
1
Yield = 48%. Colorless oil. R (petroleum ether/EtOAc 8:2) 0.50. IR (neat, cm ) ν 2936, 1665,
1
2
f
1
593, 1477, 1375, 1243, 969. H NMR (400 MHz, CDCl3) δ 7.14-7.10 (m, 2H), 6.97-6.96 (m,
H), 6.82 (d, J = 8.2 Hz, 1H), 6.65 (t, J = 7.4 Hz, 1H), 6.53 (dd, J = 1.0, 7.4 Hz, 1H), 5.23 (d, J
=
8.7 Hz, 1H), 4.34 (d, J = 8.7 Hz, 1H), 4.19 (ddd, J = 5.1, 6.3, 13.1 Hz, 1H), 3.70 (ddd, J =
4
2
1
.5, 7.0, 13.1 Hz, 1H), 3.19 (d, J = 15.1, 1H), 3.11 (d, J = 15.1, 1H), 2.87 (t, J = 5.6 Hz, 2H),
.02-1.97 (m, 2H). C NMR (75 MHz, CDCl3) δ 169.9, 159.9, 136.0, 129.7, 129.3, 128.6,
1
3
27.2, 125.3, 123.9, 123.2, 123.0, 120.8, 110.4, 79.3, 51.3, 42.0, 37.8, 27.5, 21.8. HRMS m/z
+
(ES+) calcd for [C H INO ] 292.1332, found 292.1336.
1
9
18
2
1
',2'-dihydro-2H-spiro[benzofuran-3,5'-pyrrolo[3,2,1-ij]quinolin]-4'(6'H)-one (2l)
–
1
Yield = 38%. Colorless oil. R (petroleum ether/EtOAc 8:2) 0.37. IR (neat, cm ) ν 2938, 1666,
1
f
1
596, 1480, 1392, 1247, 981, 751. H NMR (400 MHz, CDCl3) δ 7.18-7.12 (m, 2H), 6.99-6.98
(m, 2H), 6.84 (d, J = 8.0 Hz, 1H), 6.70-6.65 (m, 2H), 5.25 (d, J = 8.7 Hz, 1H), 4.37 (d, J = 8.7
Hz, 1H), 4.19 (ddd, J = 5.6, 10.5, 12.3 Hz, 1H), 4.10 (ddd, J = 7.6, 10.9, 12.3 Hz, 1H), 3.37-
1
3
3
.14 (m, 4H). C NMR (75 MHz, CDCl3) δ 168.1, 159.5, 141.4, 130.4, 129.9, 128.9, 126.3,
S19

1
24.1, 124.1, 123.4, 120.9, 118.5, 110.5, 79.3, 53.2, 46.2, 38.3, 28.3. HRMS m/z (ES+) calcd
for C H NO 278.1181, found 278.1179.
1
8
16
2
methyl 1'-methyl-2'-oxo-2',4'-dihydro-1'H,2H-spiro[benzofuran-3,3'-quinoline]-5-carboxylate
2p)
(
–
1
Yield = 97%. White solid. M. p. 156°C. R (petroleum ether/EtOAc 8:2) 0.31. IR (neat, cm ) ν
2
f
1
960, 1708, 1667, 1603, 1364, 1283, 1114, 986, 755. H NMR (400 MHz, CDCl3) δ 7.88 (dd,
J = 2.0, 8.5, 1H), 7.39 (t, J = 7.7 Hz, 1H), 7.23 (d, J = 2.0 Hz, 1H), 7.17-7.08 (m, 3H), 6.83 (d,
J = 8.5 Hz, 1H), 5.18 (d, J = 9.1 Hz, 1H), 4.41 (d, J = 9.1 Hz, 1H), 3.76 (s, 3H), 3.46 (s, 3H),
1
3
3
1
5
.22 (d, J = 14.9 Hz, 1H), 3.16 (d, J = 14.9 Hz, 1H). C NMR (75 MHz, CDCl3) δ 170.3,
66.6, 163.9, 140.2, 132.5, 129.6, 129.2, 128.6, 126.2, 123.8, 123.1, 123.1, 115.1, 110.1, 80.1,
+
2.0, 51.4, 37.8, 30.8. HRMS m/z (ES+) calcd for [C H NO ] 342.1230, found 342.1234.
19
18
4
1
'-methyl-5-phenyl-1'H,2H-spiro[benzofuran-3,3'-quinolin]-2'(4'H)-one (2q)
–
1
Yield = 83%. White solid. M. p. 167°C. R (petroleum ether/EtOAc 8:2) 0.40. IR (neat, cm ) ν
2
f
1
960, 1671, 1604, 1489, 1363, 1281, 1126, 977, 732. H NMR (400 MHz, CDCl3) δ 7.41-7.36
(m, 2H), 7.33-7.29 (m, 2H), 7.26-7.19 (m, 4H), 7.12 (t, J = 7.7 Hz, 2H), 6.89 (d, J = 8.5 Hz,
1
3
1
1
3
H), 6.68 (d, J = 1.5 Hz, 1H), 5.25 (d, J = 8.7 Hz, 1H), 4.41 (d, J = 8.7 Hz, 1H), 3.47 (s, 3H),
1
3
.28 (d, J = 15.2 Hz, 1H), 3.19 (d, J = 15.2 Hz, 1H). C NMR (75 MHz, CDCl3) δ 170.7,
59.6, 141.1, 140.5, 134.1, 129.7, 129.3, 128.9, 128.8, 128.4, 126.8, 126.7, 123.7, 123.7, 122.8,
14.9, 110.5, 79.5, 51.7, 37.9, 30.8. HRMS m/z (ES+) calcd for C H NO 342.1494, found
2
3
20
2
42.1501.
S20

5
-(tert-butyl)-1'-methyl-1'H,2H-spiro[benzofuran-3,3'-quinolin]-2'(4'H)-one (2r)
–
1
Yield = 76%. White solid. M. p. 167 °C. R (petroleum ether/EtOAc 8:2) 0.43. IR (neat, cm )
f
1
ν 2925, 2364, 1669, 1604, 1476, 1365, 1126, 976, 909, 758. H NMR (400 MHz, CDCl3) δ
7
5
.38 (t, J = 7.5 Hz, 1H), 7.16-7.06 (m, 4H), 6.73 (d, J = 8.4 Hz, 1H), 6.40 (d, J = 1.2 Hz, 1H),
.23 (d, J = 8.2 Hz, 1H), 4.33 (d, J = 8.2 Hz, 1H), 3.47 (s, 3H), 3.24 (d, J = 16.0 Hz, 1H), 3.11
1
3
(
d, J = 16.0 Hz, 1H), 1.04 (s, 9H). C NMR (75 MHz, CDCl3) δ 171.0, 157.6, 143.5, 140.7,
29.2, 128.3, 128.3, 126.6, 124.1, 123.5, 120.9, 114.7, 109.4, 79.2, 51.6, 37.8, 34.3, 31.6, 30.8.
HRMS m/z (ES+) calcd for C H NO 322.1807, found 322.1795.
1
2
1
24
2
1
'-Methyl-2,3-dihydro-1'H-spiro[indene-1,3'-quinolin]-2'(4'H)-one (2s)
Yield = 53%. Light yellow solid. M. p. 130 °C. R (petroleum ether/EtOAc 8:2) 0.32. IR (neat,
f
–
1
1
cm ) ν 2916, 2849, 1622, 1463, 1367, 1115, 752. H NMR (400 MHz, CDCl3) δ 7.33 (t, J =
7
7
6
.5 Hz, 1H), 7.24 (d, J = 7.3 Hz, 1H), 7.19 (t, J = 7.3 Hz, 1H), 7.14 (d, J = 7.5 Hz, 1H) 7.06-
.03 (m, 3H), 6.81 (d, J = 7.6 Hz, 1H), 3.43 (s, 3H), 3.17 (d, J = 15.9 Hz, 1H), 3.10 (ddd, , J =
.1, 8.1, 16.1 Hz, 1H), 3.05 (d, J = 15.9 Hz, 1H), 2.98 (ddd, J = 6.8, 8.6, 16.1 Hz, 1H), 2.59
1
3
(ddd, , J = 6.1, 8.6, 13.1 Hz, 1H), 1.99 (ddd, , J = 6.8, 8.1, 13.1 Hz, 1H). C NMR (75 MHz,
CDCl3) δ 173.5, 145.1, 144.2, 140.7, 128.7, 127.9, 127.9, 126.7, 125.1, 125.0, 123.9, 123.0,
1
2
14.5, 54.0, 38.4, 36.2, 30.9, 30.4. HRMS m/z (ES+) calcd for C H NO 264.1388, found
18 18
64.1386.
1
-Acetyl-1'-methyl-1'H-spiro[indoline-3,3'-quinolin]-2'(4'H)-one (2t)
S21

–
1
Yield = 92%. White solid. M. p. 183 °C. R (DCM/EtOAc 8:2) 0.28. IR (neat, cm ) ν 2987,
f
1
2
1
1
3
359, 1666, 1480, 1403, 1338, 1127, 754. H NMR (400 MHz, CDCl3) δ 8.23 (d, J = 8.0 Hz,
H), 7.38 (t, J = 7.5 Hz, 1H), 7.20 (t, J = 7.5 Hz, 1H), 7.14-7.07 (m, 3H), 6.78 (t, J = 7.6 Hz,
H), 6.50 (d, J = 7.6 Hz, 1H), 4.80 (d, J = 11.0 Hz, 1H), 3.80 (d, J = 11.0 Hz, 1H), 3.47 (s,
1
3
H), 3.25 (d, J = 15.6 Hz, 1H), 3.15 (d, J = 15.6 Hz, 1H), 2.26 (s, 3H). C NMR (75 MHz,
CDCl3) δ 170.6, 168.7, 142.5, 140.4, 132.5, 129.5, 129.2, 128.5, 123.8, 123.5, 123.3, 117.5,
1
3
14.9, 58.5, 49.8, 38.9, 30.8, 24.5. HRMS m/z (ES+) calcd for C H N O 307.1447, found
19 19 2 2
07.1438.
1
'-methyl-1-tosyl-1'H-spiro[indoline-3,3'-quinolin]-2'(4'H)-one (2u)
–
1
Yield = 80%. Orange solid. M. p. 165°C. R (petroleum ether/EtOAc 7:3) 0.54. IR (neat, cm )
f
1
ν 2966, 2252, 1668, 1475, 1361, 1168, 907, 727. H NMR (400 MHz, CDCl3) δ 7.72 (d, J =
8
(
1
.2, 2H), 7.63 (d, J = 8.2 Hz, 1H), 7.34 (td, J = 1.0, 7.5 Hz, 1H), 7.28 (d, J = 8.2 Hz, 2H), 7.20
td, J = 1.3, 8.2, Hz, 1H), 7.06-7.02 (m, 2H), 6.94 (d, J = 7.9 Hz, 1H), 6.79 (td, J = 1.0, 7.4 Hz,
H), 6.53 (dd, J =1.1, 7.5 Hz, 1H), 4.41 (d, J = 10.5 Hz, 1H), 3.85 (d, J = 10.5 Hz, 1H), 3.41
1
3
(
s, 3H), 2.90 (d, J = 16.1 Hz, 1H), 2.82 (d, J = 16.1 Hz, 1H), 2.40 (s, 3H). C NMR (75 MHz,
CDCl3) δ 170.1, 144.6, 141.4, 140.2, 133.9, 132.9, 130.0, 129.4, 129.2, 128.5, 127.7, 124.4,
23.8, 123.7, 123.4, 114.8, 114.8, 58.4, 50.0, 38.6, 30.8, 21.8. HRMS m/z (ES+) calcd for
1
+
[
C H N O S] 419.1424, found 419.1429.
24 23 2 3
1
-Acetyl-6-methoxy-1'-methyl-1'H-spiro[indoline-3,3'-quinolin]-2'(4'H)-one (2v)
–
1
Yield = 95%. White solid. M. p. 171 °C. R (DCM/EtOAc 9:1) 0.21. IR (neat, cm ) ν 2970,
1
f
1
662, 1603, 1489, 1402, 1127, 1034, 759, 732. H NMR (400 MHz, CDCl3) δ 7.90 (d, J = 1.3
Hz, 1H), 7.37 (t, J = 7.4 Hz, 1H), 7.14-7.06 (m, 3H), 6.34-6.29 (m, 2H), 4.84 (d, J = 10.4 Hz,
1
=
H), 3.81 (d, J = 10.4 Hz, 1H), 3.45 (s, 3H), 3.24 (d, J = 15.0 Hz, 1H), 3.74 (s, 3H), 3.11 (d, J
15.0 Hz, 1H), 2.26 (s, 3H). C NMR (75 MHz, CDCl3) δ 170.8, 168.8, 160.8, 143.8, 140.4,
1
3
1
29.2, 128.5, 124.6, 123.7, 123.7, 133.5, 114.8, 110.2, 103.0, 59.2, 55.7, 49.0, 38.9, 30.8, 24.6.
+
HRMS m/z (ES+) calcd for [C H N O ] 337.1547, found 337.1549.
20
21
2
3
S22

1
-Acetyl-1'-methyl-2'-oxo-2',4'-dihydro-1'H-spiro[indoline-3,3'-quinoline]-5-carbonitrile (2w)
–
1
Yield = 60%. White solid. M. p. 216 °C. R (petroleum ether/EtOAc 5:5) 0.18. IR (neat, cm )
f
1
ν 2970, 2224, 1667, 1601, 1482, 1390, 1329, 908, 727. H NMR (400 MHz, CDCl3) δ 8.31 (d,
J = 8.3 Hz, 1H), 7.50 (dd, J = 1.5, 8.3 Hz, 1H), 7.41 (td, J = 2.3, 7.7 Hz, 1H), 7.20-7.15 (m,
3
=
H), 6.75 (s, 1H), 4.81 (d, J = 10.1 Hz, 1H), 3.86 (d, J = 10.1 Hz, 1H), 3.47 (s, 3H), 3.25 (d, J
14.8 Hz, 1H), 3.15 (d, J = 14.8 Hz, 1H), 2.27 (s, 3H). C NMR (75 MHz, CDCl3) δ 169.5,
1
3
1
5
3
69.3, 146.1, 139.9, 134.4, 133.6, 129.2, 129.1, 127.4, 124.3, 122.3, 119.1, 117.6, 115.2, 106.6,
+
8.6, 49.6, 38.6, 31.0, 24.5. HRMS m/z (ES+) calcd for [C H N O ] 332.1394, found
20
18
3
2
32.1393.
1
-Acetyl-1',5-dimethyl-1'H-spiro[indoline-3,3'-quinolin]-2'(4'H)-one (2w)
–
1
Yield = 94%. White solid. M. p. 205 °C. R (petroleum ether/EtOAc 5:5) 0.18. IR (neat, cm )
f
1
ν 2923, 1666, 1603, 1472, 1369, 1127, 733. H NMR (400 MHz, CDCl3) δ 8.09 (d, J = 8.7 Hz,
1
H), 7.40 (t, J = 7.2 Hz, 1H), 7.15-7.00 (m, 4H), 6.34 (s, 1H), 4.69 (d, J = 11.0 Hz, 1H), 3.78
(
3
1
d, J = 11.0 Hz, 1H), 3.47 (s, 3H), 3.20 (d, J = 14.5 Hz, 1H), 3.15 (d, J = 14.5 Hz, 1H), 2.22 (s,
H), 2.10 (s, 3H). C NMR (75 MHz, CDCl3) δ 170.8, 168.4, 140.3, 140.2, 133.4, 132.7,
1
3
30.0, 129.2, 128.5, 124.1, 123.7, 123.4, 117.1, 114.8, 58.6, 49.9, 38.9, 30.8, 24.4, 21.2.
+
HRMS m/z (ES+) calcd for [C H N O ] 321.1598, found 321.1599.
20
21
2
2
1
-Acetyl-1',5,7-trimethyl-1'H-spiro[indoline-3,3'-quinolin]-2'(4'H)-one (2y)
S23

–
1
Yield = 57%. White solid. R (DCM/EtOAc 9:1) 0.33. IR (neat, cm ) ν 2970, 2224, 1667,
1
f
1
482, 1329, 1127, 908, 727. H NMR (400 MHz, CDCl3) δ 7.36 (t, J = 6.6 Hz, 1H), 7.13 (d, J
=
6.6 Hz, 1H), 7.09-7.06 (m, 3H), 6.86 (s, 1H), 4.62 (d, J = 10.4 Hz, 1H), 3.84 (d, J = 10.4 Hz,
1
3
1
H), 3.42 (s, 3H), 3.14 (d, J = 15.0 Hz, 1H), 3.03 (d, J = 15.0 Hz, 1H), 2.29 (s, 3H), 2.27 (s,
H), 2.09 (s, 3H). C NMR (75 MHz, CDCl3) δ 170.7, 140.3, 135.3, 132.1, 130.9, 128.9,
1
3
28.4, 123.7, 123.6, 121.3, 114.9, 60.1, 50.6, 36.3, 30.5, 24.0, 21.2, 20.4. HRMS m/z (ES+)
+
calcd for [C H N O ] 335.1754, found 335.1755.
21
23
2
2
S24

Synthesis of the Deuterated Starting Materials
2
-((2-Iodophenoxy)methyl)-N-methyl-N-phenylacrylamide-d (1a-D )
5 5
N-methyl-N-phenylacrylamide-D 1a-D was prepared following general procedure A.
5
5
–
1
Yield = 90%. White solid. M. p. 91°C. R (petroleum ether/EtOAc 7:3) 0.39. IR (neat, cm ) ν
f
1
2
1
7
922, 2361, 1622, 1563, 1472, 1241, 1017, 1006. H NMR (400 MHz, CDCl3) δ 7.76 (dd, J =
.7, 7.7 Hz, 1H), 7.26 (td, J = 1.1, 7.7 Hz, 1H), 6.76 (dd, J = 1.3, 8.4 Hz, 1H), 6.70 (td, J = 1.3,
.7 Hz, 1H), 5.52 (s, 1H), 5.15 (s, 1H), 4.67 (s, 2H), 3.43 (s, 3H). C NMR (75 MHz, CDCl3)
13
δ 168.9, 157.1, 144.4, 139.7, 139.4, 129.7, 123.0, 122.0, 112.6, 86.4, 69.7, 38.3. HRMS m/z
(
ES+) calcd for C H D INO 399.0618, found 399.0617.
17 12 5 2
2
-((2-Iodophenoxy)methyl)-N-methyl-N-phenylacrylamide-d (1a-D )
1 1
N-methyl-N-phenylacrylamide-D was prepared following general procedure A, starting from
1
1
4
N-methyl-N-aniline-D (90% deuterium incorporation according to H NMR) and acrylic acid
. Yield = 92%. White solid. M. p. 90 °C. R (petroleum ether/EtOAc 7:3) 0.39. IR (neat, cm )
ν 2922, 2361, 1622, 1563, 1472, 1241, 1017, 1006. H NMR (400 MHz, CDCl3) δ 7.76 (dd, J
1
–
1
4
f
1
=
1.7, 7.7 Hz, 1H), 7.26 (m, 5H), 6.76 (dd, J = 1.3, 8.4 Hz, 1H), 6.70 (td, J = 1.3, 7.7 Hz, 1H),
1
3
5
1
1
.52 (s, 1H), 5.15 (s, 1H), 4.67 (s, 2H), 3.43 (s, 1H). C NMR (75 MHz, CDCl3) δ 168.9,
57.1, 144.4, 139.7, 139.4, 129.7, 129.4 (d, J = 10.0 Hz), 127.1 (d, J = 6.9 Hz), 123.0, 122.0,
12.6, 86.4, 69.7, 38.3. HRMS m/z (ES+) calcd for C H DINO 395.0367, found 395.0363.
1
7
16
2
4
Pinto, A.; Neuville, L.; Retailleau, P.; Zhu, J. Org. Lett. 2006, 8, 4927.
S25

Determination of Intramolecular Isotope Effect
Anilide 1a-D (30 mg, 0.076 mmol, 1.0 equiv), Pd(OAc) (0.43 mg, 0.0019 mmol, 0.025
1
2
equiv), Xphos (2.4 mg, 0.0038 mmol, 0.050 equiv) and K CO (21 mg, 0.15 mmol, 2.0 equiv)
2
3
were introduced in a screw cap vial equipped with a magnetic stir bar. The vial was purged
with argon during 10 min. Degazed DMA (0.5 mL) was then added and the mixture was stirred
at 100 °C during 6 h until complete disappearance of the starting material as shown by TLC.
The reaction was next quenched with water and extracted with EtOAc. The combined organic
layers were washed with brine, dried and concentrated under reduced pressure. The residue was
purified by flash column chromatography (petroleum ether/EtOAc 8/2) to give the expected
spirodihydroquinolinone 2a/2a-D (18 mg, 90%) as a white solid.
1
1
Inspection of the aromatic region of the H NMR spectrum (7.16-7.06 for proton H2, H4, H5,
H13 and 6.82 for proton H14) indicated that the position 2 was 30.5% protonated (after
correction), indicating an intramolecular isotope effect of k /k = 2.53 (by taking account of
H
D
the 90% incorporation of the starting material 1a-D (Figure 1 and 2).
1
S26

Figure 1. Aromatic region of spirodihydroquinolinone 2a
S27

Figure 2. Aromatic region of isolated material from cyclization of monodeuterioanilide 2a-D1
S28

Determination of Intermolecular Isotope Effect
Anilide 1a (30 mg, 0.051 mmol, 0.5 equiv), anilide 1a-D (30 mg, 0.076 mmol, 0.5 equiv),
5
Pd(OAc) (0.85 mg, 0.0038 mmol, 0.025 equiv), Xphos (3.6 mg, 0.0076 mmol, 0.050 equiv)
2
and K CO (42 mg, 0.30 mmol, 2.0 equiv) were introduced in a screw cap vial equipped with a
2
3
magnetic stir bar. The vial was purged with argon during 10 min. Degazed DMA (0.7 mL) was
then added and the mixture was stirred at 100 °C during 3 h. After cooling the reaction mixture,
water was added. the mixture was extracted with EtOAc. The combined organic layers were
washed with brine, dried and concentrated under reduced pressure.
A conversion of 30% was obtained by comparison of proton H6 of 1a+1a-D (5.52 ppm) and
5
H7 of 2a+2a-D (4.33 ppm) (Figure 3). The residue was purified by flash column
5
chromatography (petroleum ether/EtOAc 8/2) to give a mixture of 2a and 2a-D . The ratio
5
between 2a and 2a-D was determinate by integration of the proton H3 (7.37 ppm) and H12
5
(
6.63 ppm) (Figure 4 and 5), indicating an intramolecular isotope effect of k /k = 1.4.
H D
S29

Figure 3. Reaction mixture of the intermolecular competition
S30