Miaoling Liang Zhenghui xie Institute of Atmospheric Physics, Chinese Academy of Sciences
intramolecular Michael-type trapping of oxonium ylides of ... · Alavala Gopi Krishna Reddy,a...
Transcript of intramolecular Michael-type trapping of oxonium ylides of ... · Alavala Gopi Krishna Reddy,a...
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Supporting Information
of
Diastereoselective synthesis of isochromans via Cu(II)-catalysed
intramolecular Michael-type trapping of oxonium ylides
Alavala Gopi Krishna Reddy,a Farrukh Sajjad,a Taoda Shi,a Zhenghui Kang,a Mingliang Ma,a
Dong Xing,*a and Wenhao Hu*b
aShanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, School of Chemistry and
Chemical Engineering, East China Normal University, Shanghai, China, 200062.
bSchool of Pharmaceutical Scicences, Sun Yat-sen University, Guangzhou, China, 510006.
E-mail: [email protected]; [email protected]
Contents
1. General information S2
2. Substrate synthesis and experimental procedures S2
3. Single crystal X-ray analysis of 3a S8
4. Characterization data of products S9
5. References S24
6. NMR spectra of products S25
Electronic Supplementary Material (ESI) for ChemComm.This journal is © The Royal Society of Chemistry 2018
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1. General information All 1H NMR (400 MHz) and 13C NMR (100 MHz) spectra were recorded on Brucker
Avance III spectrometer by using CDCl3 and DMSO-d6 solvents. CDCl3 and DMSO-d6 were
set as an internal standards (δ = 7.25 and 2.49) for 1H NMR and (δ = 77.0 and 39.5) for 13C
NMR spectra. Chemical shifts are reported in parts per million (ppm) are as follows: chemical
shift, multiplicity (s =singlet, d = doublet, t = triplet, q = quartet, m = multiplet, br = broad).
High-resolution mass spectrometry (HRMS) spectra were recorded on IonSpec FT-ICR or
Waters Micromass Q-TOF micro Synapt High Definition Mass Spectrometer. Single crystal
X-ray diffraction data were recorded on Bruker-AXS SMART APEX II single crystal X-ray
diffractometer. Yields for all compounds are combined yields for all isomers unless otherwise
specified.
CH2Cl2 was distilled over calcium hydride (CaH2). 4 Å molecular sieve was dried in a
Muffle furnace at 250℃ over 5 hrs. Alcohol-tethered enone substrates were prepared according
to literature protocols.1-5 All small-scale reactions were carried out under argon atmosphere in
a well-dried glassware. Reactions were monitored by TLC on silica gel using a combination of
hexane and ethyl acetate as eluents. Reactions were generally run under a nitrogen atmosphere.
Solvents were distilled prior to use; petroleum ether with a boiling range of 60 to 80 C was
used. Silica gel (100–200 mesh and 200-300) were used for column chromatography (20–30 g
per one gram of crude material).
2. Substrate synthesis and experimental procedure:All the alcohol tethered ketones 1 were prepared from the diols 14 by following literature
procedures1
OH
OH
R1 R2
DDQ (20 mol%)Mn(OAc)3.2H2O (6 equiv)
dry. DCMrt., 0.5 to 12 h
OH
O
R1 R2
114
R3 R3
General procedure (GP-1) for the synthesis of alcohol ketones (1): To an oven-dried vial
under nitrogen atmosphere at room temperature were added diol (0.5 mmol), DDQ (20 mol%)
and Mn(OAc)3•2H2O (3 mmol) followed by dry DCM (6 mL). The resultant suspension was
stirred for 0.5 to 12 h. After completion of the reaction, the reaction mixture was filtered
through a short pad of celite and concentrated under reduced pressure. Purification of the crude
residue by silica gel column chromatography (petroleum ether and ethyl acetate) resulted the
alcohol ketones as viscous liquids.
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The following diols were prepared from ortho-bromoaldehydes 9 and allyl alcohols 10 by
following the literature procedures.2
OH
OH Cl
OH
OH Br
OH
OH Me
OH
OH ClF
OH
OH ClMeO
CHO
BrR1 +
OH
XR2
-X = Cl, Br, Me
1a. Pd(OAc)2 (5 mol%)Bn(Et)3NCl (1 equiv)
OH
OH
R1 R2
X
NaHCO3 (2 equiv)
CH3OH, 0 C to rt., 2 h1b. NaBH4 (3 equiv)
CH3CN, 80 C, 24 h
9 10 14
To a flame-dried vial under nitrogen atmosphere, were added Pd(OAc)2 (5 mol%), Bn(Et)3NCl
(1.0 mmol), NaHCO3 (2 mmol), 2-bromobenzaldehydes (1.0 mmol) and aryl allylic alcohols
(1.2 mmol) followed by dry acetonitrile (6 mL). The resulting reaction mixture was stirred at
80 °C for 24 h. The reaction mixture was then quenched using saturated aq. NH4Cl solution,
and then compound was extracted in ethyl acetate, filtered through a short pad of silica and
concentrated under reduced pressure. To the crude residue in methanol (10 mL) at 0 °C was
added NaBH4 (3.0 mmol) in portions and allowed the reaction mixture to stir at room
temperature for 2 h. The reaction mixture was quenched with saturated aq. NH4Cl solution,
extracted with ethyl acetate (3 × 20 mL) and concentrated under vacuum. Purification of the
crude residue by silica gel column chromatography (petroleum ether and ethyl acetate) resulted
the diols as viscous liquids.2
The following diol was prepared from ortho-bromoaldehyde 9 and allyl alcohol 10 in stepwise
manner by following literature procedures.2
OH
OH Br
Me
14
To a flame-dried vial under nitrogen atmosphere, were added Pd(OAc)2 (5 mol%), Bn(Et)3NCl
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(1.0 mmol), NaHCO3 (2 mmol), 2-bromobenzaldehydes (1.0 mmol) and aryl allylic alcohols
(1.2 mmol) followed by dry acetonitrile (6 mL). The resulting reaction mixture was stirred at
80 °C for 24 h. The reaction mixture was then quenched using saturated aq. NH4Cl solution,
and then compound was extracted in ethyl acetate (3 × 15 mL), concentrated under mild
vacuum and purified through silica gel chromatography (petroleum ether and ethyl acetate) to
afford the aldehyde alcohol 15.5
To the solution of aldehyde alcohol 15 (1 mmol) in dry THF (5 mL) under nitrogen atmosphere
at 0 °C was added 1 M solution of methylmagnesium bromide in THF (6 mmol) and the
reaction mixture was allowed to room temperature for 6 h and the formation of diol 14 was
monitored by TLC. The reaction mixture was quenched using saturated aq. NH4Cl solution,
and then compound was extracted with ethyl acetate (3 × 15 mL), concentrated under reduced
pressure and purified through silica gel chromatography (petroleum ether and ethyl acetate) to
afford the diol 14.5
CHO
Br+
OH
Br
-
Pd(OAc)2 (5 mol%)Bn(Et)3NCl (1 equiv) O
OH Br
NaHCO3 (2 equiv)CH3CN, 80 C, 24 h
9 10
MeMgBr
dry. THF
OH
OH Br
Me
1415
The following diols 14 were prepared from ortho-bromoaldehydes 9 in stepwise manner by
following literature procedures.1,3-5
OH
OH
OH
OH
OH
OH
OMe
Me
CHO
BrR1
CHOR1
CO2Et
CH2OHR1
CH2OH
CH2OHR1
CHO
CH2OHR1
OH
R2
Pd(OAc)2 (2 mol%)
PPh3 (4 mol%)Et3N (3 equiv)
toluene, 110 C, 24 h
DIBAL-H(4 equiv)0 C to rt, 4 h
MgBr
DDQ (20 mol%)Mn(OAc)3.2H2O (6 equiv)
dry. DCMrt., 0.5 to 12 h
R2 (5 equiv)
dry THF0 C to rt, 4 h
9 11 12
1413
CO2Et(2equiv)
To a flame dried vial under nitrogen atmosphere, were added aldehyde 9 (1 mmol), Pd(OAc)2
(2.5 mol%), PPh3 (2.5 mol%), Et3N (3 mmol) and dry toluene (3 mL) followed ethyl acrylate
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(2 mmol). The resulting reaction mixture was stirred at 110 °C for 24 h. The reaction mixture
was quenched using saturated aq. NH4Cl solution, extracted with ethyl acetate (3 × 15 mL),
concentrated and purified through silica gel chromatography (petroleum ether and ethyl
acetate) to yield ester 11.3
To the solution of ester 11 (1 mmol) in dry THF (5 mL) under nitrogen atmosphere at 0 °C was
added 1 M DIBAL-H in toluene (4 mmol) and the reaction mixture was allowed to room
temperature for 4 h and the formation of diol 12 was monitored by TLC. The reaction mixture
was quenched using saturated aq. NH4Cl solution, and then compound was extracted with ethyl
acetate (3 × 20 mL), concentrated under reduced pressure and purified through silica gel
chromatography (petroleum ether and ethyl acetate) to afford the diol 12.4
To an oven-dried vial under nitrogen atmosphere at room temperature, were added diol 12 (1
mmol), DDQ (20 mol%) and Mn(OAc)3.2H2O (6 mmol) followed by dry DCM (10 mL). The
resultant suspension was stirred for 0.5 to 12 h. The reaction mixture was filtered through a
short pad of celite and concentrated under reduced pressure. Purification of the crude residue
by silica gel column chromatography (petroleum ether and ethyl acetate) resulted the alcohol
aldehyde 13 as viscous liquid.1
To the solution of aldehyde 13 (1 mmol) in dry THF (5 mL) under nitrogen atmosphere at 0 °C
was added 1 M solution of arylmagnesium bromide in THF (5 mmol) and the reaction mixture
was allowed to room temperature for 4 h and the formation of diol 14 was monitored by TLC.
The reaction mixture was quenched using saturated aq. NH4Cl solution, and then compound
was extracted with ethyl acetate (3 × 15 mL), concentrated under reduced pressure and purified
through silica gel chromatography (petroleum ether and ethyl acetate) to afford the diol 14.5
General procedure (GP-2) for the optimizations towards isochroman 3a:
To a flame-dried vial, at room temperature, under an inert atmosphere, were added
[Rh]/[Pd]/[Cu]-catalyst (0.002‒0.02 mmol) and 4 Å molecular sieves (150 mg) followed by
DCM (1.0 mL). To this well-stirred suspension at stated temperature, was added a solution of
alcohol enone 1 (48 mg, 0.2 mmol) and diazo-acetate 2 (0.4‒0.5 mmol, 2.0 eq) in 1.5 mL of
DCM for one hour through a syringe pump. After completion of the addition, stirring was
continued at the same temperature. Progress of the reaction was monitored by TLC until
complete consumption of alcohol ketone 1. The reaction mixture was filtered through celite
and the filtrate was concentrated to give a residue, which was subjected to 1H NMR analysis
for determination of diastereoselective ratio (dr) values. Purification of the crude mixture by
silica gel flash chromatography (eluents: ethyl acetate/petroleum ether).
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General procedure (GP-3) for the copper-catalyzed synthesis of isochromans 3:
To a flame-dried vial, at room temperature, under an inert atmosphere, were added Cu(OTf)2
(7 mg, 0.02 mmol) and 4 Å molecular sieves (150 mg) followed by DCM (1.0 mL). To this
well-stirred suspension at 40 °C, was added a solution of alcohol enone 1 (48‒64 mg, 0.2 mmol)
and diazo-acetate 2 (0.5 mmol, 2.5 eq) in 1.5 mL of DCM for one hour through a syringe pump.
After completion of the addition, stirring was continued at the same temperature for 12 h.
Progress of the isochroman 3 formation was monitored by TLC until the reaction is completed.
The reaction mixture was filtered through Celite and the filtrate was concentrated to give a
residue, which was subjected to 1H NMR analysis for determination of diastereoselective ratio
(dr) values. Purification of the crude mass by silica gel flash chromatography (eluents: ethyl
acetate/petroleum ether; 4:96 to 25:75) afforded pure isochromans 3 as viscous liquid/semi-
solid/solid.
Results on the Screening of other diazo compounds
EtO2C CO2Et
N2
N2
O
Ph
N2
O
PhPh
CO2Et
N2
Bn
OHPh
O
Cu(OTf)2 (10 mol%)CH2Cl2, 4 A MS0 oC or 40 oC
O
+R1 R2
N2O
O
Ph
R2R1
Ph CO2Et
N2
dp: 81%, >20:1 dr dp not observedonly insertion product
diazo did not decomposeonly intramolecular cyclization of 1a
dp not observedonly insertion product
dp not observedmassy
1a
Results on the Screening of other diazo compounds
OH
CN
1l
Cu(OTf)2 (10 mol%)CH2Cl2, 4 A MS0 oC or 40 oC
O
+Ph CO2Me
N2
2a
O
CN
Ph
CO2Me
major product
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Cu(OTf)2 (1 mol%)additive (15 mol%)
CH2Cl20 oC or 40 oC
OHOEt
O
1k
+Ph CO2Me
N2
2a
OOEt
O
Ph
CO2MeO
Ph
O
PhCO2Me
+
11 12
Entry Catalyst Lewis acid (x mol%) Solvent T (oC) conversion yield of 11 yield of 12
1 Rh2(OAc)4 - DCM RT 100 - 73%
2 Rh2(OAc)4 Cu(OTf)2 (15) DCM RT 100 - 60%
3 Rh2(OAc)4 Ag(OCOCF3) (15) DCM RT 100 - 65%
4 Rh2(OAc)4 InCl3 (15) DCM RT 90 - 60%
5a Rh2(OAc)4 - DCM RT 100 Not clear
6b Rh2(OAc)4 - DCM RT 100 Not clear
7 Rh2(OAc)4 - DCM 40 100 Only insertion
8 Rh2(OAc)4 - DCE 40 75 Only insertion
9 Rh2(OAc)4 - toluene 40 100 Only insertion
10 Rh2(OAc)4 - DCM 0 100 Only insertion
11 Rh2(OAc)4 - toluene 0 100 Only insertion
12 Rh2(OAc)4 Zr-MS-BINOL (10) DCM 0 100 Only insertion
13 Rh2(OAc)4 AgSbF6 (5) DCM 0 100 Only insertion
14 Rh2(OAc)4 FeCl3 (20) DCM 0 100 Only insertion
15 Rh2(OAc)4 Sc(OTf)3 (10) DCM 0 100 Only insertion
16 Rh2(OAc)4 Zn(OTf)2 (10) DCM 0 100 Only insertion
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3. Single crystal XRD data of compound 3a (CCDC 1849633):
O
Ph
OPh
CO2Me
3a X-ray of 3a
Table of Crystal data and structure refinement for compound 3a
Empirical formula C25H22O4
Formula weight 386.42
Temperature/K 293(2)
Crystal system monoclinic
Space group P21/n
a/Å 15.6081(6)
b/Å 6.1955(2)
c/Å 21.7106(8)
α/° 90
β/° 107.330(4)
γ/° 90
Volume/Å3 2004.11(13)
Z 4
ρcalcg/cm3 1.281
μ/mm-1 0.694
F(000) 816.0
Crystal size/mm3 0.18 × 0.12 × 0.08
Radiation CuKα (λ = 1.54184)
2Θ range for data collection/° 8.276 to 134.044
Index ranges -18 ≤ h ≤ 18, -7 ≤ k ≤ 5, -25 ≤ l ≤ 25
Reflections collected 16400
Independent reflections 3564 [Rint = 0.0813, Rsigma = 0.0533]
Data/restraints/parameters 3564/0/263
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Goodness-of-fit on F2 1.053
Final R indexes [I>=2σ (I)] R1 = 0.0514, wR2 = 0.1226
Final R indexes [all data] R1 = 0.0803, wR2 = 0.1349
Largest diff. peak/hole / e Å-3 0.14/-0.17
4. Characterization data of products:O
O
CO2Me
3a
Methyl (3R,4S)-4-(2-oxo-2-phenylethyl)-3-phenyl-3,4-dihydro-1H-isochromene-3-
carboxylate (3a):
Pale yellow solid.1H NMR (400 MHz, CDCl3) δ 7.73 (d, J = 7.4 Hz, 2H), 7.66 (d, J = 7.9 Hz, 2H), 7.44 (t, J =
7.4 Hz, 1H), 7.37 – 7.22 (m, 6H), 7.16 (dd, J = 7.5 and 7.1 Hz, 1H), 7.11 (dd, J = 7.1 and 7.0
Hz, 1H), 7.02 (d, J = 7.5 Hz, 1H), 5.34 (d, J = 15.4 Hz, 1H), 5.22 (d, J = 15.4 Hz, 1H), 4.65
(dd, J = 9.0 and 3.1 Hz, 1H), 3.50 (s, 3H), 3.05 (dd, J = 17.3 and 9.0 Hz, 1H), 2.88 (dd, J =
17.3 and 3.1 Hz, 1H) ppm.13C NMR (100 MHz, CDCl3) δ 198.39, 171.97, 138.55, 137.03, 136.48, 132.83, 131.82,
129.55, 128.59, 128.30, 128.16, 127.92, 126.98, 126.67, 125.55, 124.23, 82.64, 65.73, 52.49,
41.27, 39.82 ppm.
HRMS-ESI: calcd. for C25H22NaO4 [M + Na]+ 409.1410, found 409.1403.
O
O
CO2Me
3b
Cl
Methyl (3R,4S)-3-(3-chlorophenyl)-4-(2-oxo-2-phenylethyl)-3,4-dihydro-1H-
isochromene-3-carboxylate (3b):
Colorless viscous liquid.1H NMR (400 MHz, CDCl3) δ 7.78 (s, 1H), 7.68 (d, J = 7.6 Hz, 2H), 7.58 (d, J = 7.4 Hz, 1H),
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7.46 (t, J = 7.3 Hz, 1H), 7.37 – 7.20 (m, 5H), 7.18 (dd, J = 7.3 and 7.3 Hz, 1H), 7.12 (dd, J =
7.3 and 7.1 Hz, 1H), 7.02 (d, J = 7.4 Hz, 1H), 5.32 (d, J = 15.4 Hz, 1H), 5.22 (d, J = 15.4 Hz,
1H), 4.62 (dd, J = 8.8 and 3.0 Hz, 1H), 3.52 (s, 3H), 3.03 (dd, J = 17.2 and 8.8 Hz, 1H), 2.87
(dd, J = 17.2 and 3.0 Hz, 1H) ppm.13C NMR (100 MHz, CDCl3) δ 198.10, 171.48, 140.53, 136.80, 136.07, 134.77, 132.97,
131.60, 129.83, 129.52, 128.42, 128.36, 127.90, 127.11, 126.80, 126.06, 124.23, 123.75, 82.21,
65.76, 52.70, 41.08, 39.96 ppm.
HRMS-ESI: calcd. for C26H24NaO4 [(M + 2) + Na]+ 445.0991, found 445.1133.
O
O
CO2Me
3c
Br
Methyl (3R,4S)-3-(3-bromophenyl)-4-(2-oxo-2-phenylethyl)-3,4-dihydro-1H-
isochromene-3-carboxylate (3c):
White semi-solid.1H NMR (400 MHz, CDCl3) δ 7.93 (s, 1H), 7.67 (d, J = 7.9 Hz, 2H), 7.61 (d, J = 7.9 Hz, 1H),
7.46 (dd, J = 7.5 and 7.1 Hz, 1H), 7.42 – 7.28 (m, 4H), 7.24 – 7.07 (m, 3H), 7.01 (d, J = 7.5
Hz, 1H), 5.32 (d, J = 15.6 Hz, 1H), 5.22 (d, J = 15.6 Hz, 1H), 4.60 (dd, J = 8.8 and 3.1 Hz,
1H), 3.51 (s, 3H), 3.01 (dd, J = 17.2 and 8.8 Hz, 1H), 2.87 (dd, J = 17.2 and 3.1 Hz, 1H) ppm.13C NMR (100 MHz, CDCl3) δ 198.08, 171.45, 140.73, 136.77, 136.03, 132.96, 131.58,
131.35, 130.08, 129.50, 128.89, 128.36, 127.90, 127.11, 126.79, 124.22, 122.97, 82.13, 65.74,
52.69, 41.07, 39.99 ppm.
HRMS-ESI: calcd. for C25H21BrNaO4 [(M +2) + Na]+ 489.0495, found 489.0500.
O
O
CO2Me
3d
F
Methyl (3R,4S)-3-(4-fluorophenyl)-4-(2-oxo-2-phenylethyl)-3,4-dihydro-1H-
isochromene-3-carboxylate (3d):
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Pale yellow semi-solid.1H NMR (400 MHz, CDCl3) δ 7.77 – 7.62 (m, 4H), 7.45 (dd, J = 7.5 and 7.1 Hz, 1H), 7.38 –
7.28 (m, 3H), 7.17 (dd, J = 7.4 and 7.1 Hz, 1H), 7.12 (t, J = 7.1 Hz, 1H), 7.07 – 6.95 (m, 3H),
5.34 (d, J = 15.6 Hz, 1H), 5.23 (d, J = 15.6 Hz, 1H), 4.65 (dd, J = 8.7 and 3.3 Hz, 1H), 3.51 (s,
3H), 3.03 (dd, J = 17.4 and 8.7 Hz, 1H), 2.89 (dd, J = 17.4 and 3.3 Hz, 1H) ppm.13C NMR (100 MHz, CDCl3) δ 198.17, 171.82, 162.48 (d, J = 248.0 Hz), 136.84, 136.27,
134.25 (d, J = 2.9 Hz), 132.94, 131.64, 129.45, 128.32, 127.86, 127.53 (d, J = 8.1 Hz), 127.05,
126.76, 124.23, 115.43 (d, J = 21.3 Hz), 82.21, 65.72, 52.57, 41.15, 39.74 ppm.
HRMS-ESI: calcd. for C25H21FNaO4 [M + Na]+ 427.1316, found 427.1308.
O
O
CO2Me
3e
Cl
Methyl (3R,4S)-3-(4-chlorophenyl)-4-(2-oxo-2-phenylethyl)-3,4-dihydro-1H-
isochromene-3-carboxylate (3e):
Colorless viscous liquid.1H NMR (400 MHz, CDCl3) δ 7.67 (d, J = 7.7 Hz, 4H), 7.46 (t, J = 7.3 Hz, 1H), 7.38 – 7.26
(m, 5H), 7.17 (dd, J = 7.3 and 7.3 Hz, 1H), 7.12 (dd, J = 7.3 and 7.3 Hz, 1H), 7.02 (d, J = 7.4
Hz, 1H), 5.33 (d, J = 15.4 Hz, 1H), 5.22 (d, J = 15.4 Hz, 1H), 4.64 (dd, J = 8.9 and 2.9 Hz,
1H), 3.51 (s, 3H), 3.04 (dd, J = 17.4 and 8.9 Hz, 1H), 2.87 (dd, J = 17.4 and 2.9 Hz, 1H) ppm.
13C NMR (100 MHz, CDCl3) δ 198.13, 171.64, 137.03, 136.82, 136.17, 134.19, 132.97,
131.61, 129.47, 128.72, 128.33, 127.87, 127.15, 127.09, 126.79, 124.23, 82.25, 65.73, 52.64,
41.15, 39.72 ppm.
HRMS-ESI: calcd. for C25H21ClNaO4 [M + Na]+ 443.1021, found 443.1021.
O
O
CO2Me
3f
Me
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Methyl (3R,4S)-3-(4-methylphenyl)-4-(2-oxo-2-phenylethyl)-3,4-dihydro-1H-
isochromene-3-carboxylate (3f):
Colorless viscous liquid.1H NMR (400 MHz, CDCl3) δ 7.67 (d, J = 7.6 Hz, 2H), 7.60 (d, J = 8.1 Hz, 2H), 7.44 (t, J =
7.4 Hz, 1H), 7.37 – 7.26 (m, 3H), 7.20 – 7.06 (m, 4H), 7.01 (d, J = 7.4 Hz, 1H), 5.34 (d, J =
15.6 Hz, 1H), 5.22 (d, J = 15.6 Hz, 1H), 4.63 (dd, J = 9.0 and 2.9 Hz, 1H), 3.49 (s, 3H), 3.04
(dd, J = 17.2 and 9.0 Hz, 1H), 2.90 (dd, J = 17.2 and 2.9 Hz, 1H) ppm. 13C NMR (100 MHz, CDCl3) δ 198.43, 172.07, 137.87, 136.96, 136.51, 135.54, 132.79,
131.80, 129.51, 129.27, 128.23, 127.91, 126.91, 126.60, 125.39, 124.19, 82.51, 65.66, 52.43,
41.27, 39.74, 21.01 ppm.
HRMS-ESI: calcd. for C26H24NaO4 [M + Na]+ 423.1567, found 423.1573.
O
O
CO2Me
3g
OMe
Methyl (3R,4S)-3-(3-methoxyphenyl)-4-(2-oxo-2-phenylethyl)-3,4-dihydro-1H-
isochromene-3-carboxylate (3g):
Colorless viscous liquid.1H NMR (400 MHz, CDCl3) δ 7.68 (d, J = 7.6 Hz, 2H), 7.45 (t, J = 7.4 Hz, 1H), 7.37 – 7.22
(m, 6H), 7.16 (dd, J = 7.1 and 7.1 Hz, 1H), 7.11 (dd, J = 7.3 and 7.1 Hz, 1H), 7.02 (d, J = 7.4
Hz, 1H), 6.79 (d, J = 7.4 Hz, 1H), 5.32 (d, J = 15.4 Hz, 1H), 5.22 (d, J = 15.4 Hz, 1H), 4.62
(dd, J = 8.9 and 3.3 Hz, 1H), 3.80 (s, 3H), 3.51 (s, 3H), 3.03 (dd, J = 17.2 and 8.9 Hz, 1H),
2.92 (dd, J = 17.2 and 3.3 Hz, 1H) ppm. 13C NMR (100 MHz, CDCl3) δ 198.34, 171.83, 159.77, 140.12, 136.97, 136.45, 132.82,
131.73, 129.59, 129.51, 128.29, 127.92, 126.95, 126.67, 124.18, 117.74, 113.97, 111.06, 82.53,
65.70, 55.24, 52.53, 41.29, 39.94 ppm.
HRMS-ESI: calcd. for C26H25O5 [M + H]+ 417.1697, found 417.1683.
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O
O
CO2Me
12h
OMe
Methyl (3R,4S)-3-(4-methoxyphenyl)-4-(2-oxo-2-phenylethyl)-3,4-dihydro-1H-
isochromene-3-carboxylate (3h):
Colorless viscous liquid.1H NMR (400 MHz, CDCl3) δ 7.67 (d, J = 7.8 Hz, 2H), 7.62 (d, J = 8.7 Hz, 2H), 7.44 (t, J =
7.4 Hz, 1H), 7.37 – 7.27 (m, 3H), 7.15 (dd, J = 7.5 and 7.1 Hz, 1H), 7.10 (dd, J = 7.4 and 7.3
Hz, 1H), 7.00 (d, J = 7.5 Hz, 1H), 6.85 (d, J = 8.7 Hz, 2H), 5.32 (d, J = 15.6 Hz, 1H), 5.20 (d,
J = 15.6 Hz, 1H), 4.61 (dd, J = 8.7 and 3.3 Hz, 1H), 3.75 (s, 3H), 3.49 (s, 3H), 3.02 (dd, J =
17.4 and 8.7 Hz, 1H), 2.92 (dd, J = 17.4 and 3.3 Hz, 1H) ppm. 13C NMR (100 MHz, CDCl3) δ 198.50, 171.19, 159.34, 136.97, 136.51, 132.85, 131.81,
130.56, 129.51, 128.29, 127.94, 126.95, 126.84, 126.66, 124.23, 113.91, 82.31, 65.69, 55.20,
52.47, 41.30, 39.73 ppm.
HRMS-ESI: calcd. for C26H25O5Na [M + Na]+ 439.1516, found 439.1548.
O
O
CO2Me
3i
MeMeMe
Methyl (3R,4S)-3-(4-tert-butylphenyl)-4-(2-oxo-2-phenylethyl)-3,4-dihydro-1H-
isochromene-3-carboxylate (3i):
Pale yellow semi-solid.1H NMR (400 MHz, CDCl3) δ 7.65 (d, J = 7.8 Hz, 2H), 7.61 (d, J = 8.3 Hz, 2H), 7.42 (t, J =
7.4 Hz, 1H), 7.37 – 7.26 (m, 5H), 7.15 (dd, J = 7.2 and 7.1 Hz, 1H), 7.10 (dd, J = 7.3 and 7.1
Hz, 1H), 7.01 (d, J = 7.4 Hz, 1H), 5.34 (d, J = 15.6 Hz, 1H), 5.22 (d, J = 15.6 Hz, 1H), 4.65
(dd, J = 7.5 and 4.3 Hz, 1H), 3.07 – 2.90 (m, 2H), 1.25 (s, 9H) ppm. 13C NMR (100 MHz, CDCl3) δ 198.50, 172.08, 150.95, 137.01, 136.60, 135.32, 132.76,
131.90, 129.48, 128.24, 127.92, 126.89, 126.62, 125.46, 125.19, 124.18, 82.49, 65.66, 52.41,
41.26, 39.80, 34.42, 31.19 ppm.
HRMS-ESI: calcd. for C29H30NaO4 [M + Na]+ 465.2036, found 465.2067.
S14
O
O
CO2Me
3j
Cl
Cl
Methyl (3R,4S)-3-(3,4-dichlorophenyl)-4-(2-oxo-2-phenylethyl)-3,4-dihydro-1H-
isochromene-3-carboxylate (3j):
Colorless viscous liquid.1H NMR (400 MHz, CDCl3) δ 7.85 (s, 1H), 7.67 (d, J = 7.8 Hz, 2H), 7.51 (d, J = 8.5 Hz, 1H),
7.46 (t, J = 7.2 Hz, 1H), 7.42 – 7.27 (m, 4H), 7.18 (dd, J = 7.4 and 7.3 Hz, 1H), 7.13 (dd, J =
7.3 and 7.3 Hz, 1H), 7.02 (d, J = 7.4 Hz, 1H), 5.32 (d, J = 15.4 Hz, 1H), 5.22 (d, J = 15.4 Hz,
1H), 4.60 (dd, J = 8.1 and 3.5 Hz, 1H), 3.52 (s, 3H), 3.00 (dd, J = 17.2 and 8.1 Hz, 1H), 2.89
(dd, J = 17.2 and 3.5 Hz, 1H) ppm. 13C NMR (100 MHz, CDCl3) δ 197.95, 171.23, 138.68, 136.67, 135.88, 133.08, 132.95,
132.47, 131.48, 130.47, 129.46, 128.38, 128.08, 127.86, 127.20, 126.92, 125.11, 124.24, 81.86,
65.78, 52.80, 41.02, 39.99 ppm.
HRMS-ESI: calcd. for C25H20Cl2NaO4 [M + Na]+ 477.0631, found 477.0619.
O
O
CO2Me
3k
Me
Me
Methyl (3R,4S)-3-(3,4-dimethylphenyl)-4-(2-oxo-2-phenylethyl)-3,4-dihydro-1H-
isochromene-3-carboxylate (3k):
Colorless viscous liquid.1H NMR (400 MHz, CDCl3) δ 7.67 (d, J = 7.5 Hz, 2H), 7.50 – 7.26 (m, 6H), 7.20 – 7.05 (m,
3H), 7.01 (d, J = 7.4 Hz, 1H), 5.32 (d, J = 15.6 Hz, 1H), 5.22 (d, J = 15.6 Hz, 1H), 4.61 (dd, J
= 8.2 and 3.9 Hz, 1H), 3.49 (s, 3H), 3.20 – 2.80 (m, 2H), 2.22 (s, 3H), 2.18 (s, 3H) ppm. 13C NMR (100 MHz, CDCl3) δ 198.50, 172.14, 136.96, 136.82, 136.59, 136.52, 135.86,
132.74, 131.80, 129.81, 129.54, 128.20, 127.92, 126.88, 126.62, 126.50, 124.18, 122.86, 82.48,
65.65, 52.46, 41.31, 39.94, 19.91, 19.35 ppm.
S15
HRMS-ESI: calcd. for C27H26NaO4 [M + Na]+ 437.1723, found 437.1725.
O
O
CO2Me
3l
MeO OMe
OMe
Methyl (3R,4S)-4-(2-oxo-2-phenylethyl)-3-(3,4,5-trimethoxyphenyl)-3,4-dihydro-1H-
isochromene-3-carboxylate (3l):
Colorless viscous liquid.1H NMR (400 MHz, CDCl3) δ 7.67 (d, J = 7.6 Hz, 2H), 7.45 (t, J = 7.4 Hz, 1H), 7.37 – 7.27
(m, 3H), 7.17 (dd, J = 7.3 and 7.0 Hz, 1H), 7.13 (dd, J = 7.8 and 7.0 Hz, 1H), 7.02 (d, J = 7.3
Hz, 1H), 6.91 (s, 2H), 5.29 (d, J = 15.6 Hz, 1H), 5.20 (d, J = 15.6 Hz, 1H), 4.65 (dd, J = 7.8
and 3.9 Hz, 1H), 3.85 (s, 6H), 3.74 (s, 3H), 3.53 (s, 3H), 3.07 (dd, J = 17.2 and 3.9 Hz, 1H),
2.89 (dd, J = 17.2 and 7.8 Hz, 1H) ppm. 13C NMR (100 MHz, CDCl3) δ 198.37, 171.84, 153.11, 137.48, 136.86, 136.57, 133.96,
132.93, 131.64, 129.27, 128.32, 127.87, 126.98, 126.85, 124.18, 102.75, 82.38, 65.69, 60.70,
56.10, 52.60, 41.46, 40.00 ppm.
HRMS-ESI: calcd. for C28H28NaO7 [M + Na]+ 499.1727, found 499.1756.
O
O
CO2Et
3m
Ethyl (3R,4S)-4-(2-oxo-2-phenylethyl)-3-phenyl-3,4-dihydro-1H-isochromene-3-
carboxylate (3m):
Colorless viscous liquid.1H NMR (400 MHz, CDCl3) δ 7.75 (d, J = 7.9 Hz, 2H), 7.67 (d, J = 8.0 Hz, 2H), 7.43 (t, J =
7.0 Hz, 1H), 7.39 – 7.21 (m, 6H), 7.16 (dd, J = 7.4 and 7.3 Hz, 1H), 7.10 (dd, J = 7.3 and 7.3
Hz, 1H), 7.02 (d, J = 7.4 Hz, 1H), 5.38 (d, J = 15.4 Hz, 1H), 5.23 (d, J = 15.4 Hz, 1H), 4.64
(dd, J = 9.3 and 1.2 Hz, 1H), 3.96 (q, J = 7.0 Hz, 2H), 3.08 (dd, J = 17.3 and 9.3 Hz, 1H), 2.88
(dd, J = 17.3 and 1.2 Hz, 1H), 0.93 (t, J = 7.0 Hz, 3H) ppm.
S16
13C NMR (100 MHz, CDCl3) δ 198.43, 171.20, 138.54, 137.02, 136.56, 132.82, 132.02,
129.65, 128.50, 128.29, 128.08, 127.90, 126.96, 126.52, 125.58, 124.20, 82.52, 65.71, 61.29,
41.11, 39.97, 13.75 ppm.
HRMS-ESI: calcd. for C26H25NaO4 [M + Na + H]+ 424.1645, found 424.1622.
O
O
CO2Me
3n
Cl
Methyl (3R,4S)-4-[2-(2-chlorophenyl)-2-oxoethyl]-3-phenyl-3,4-dihydro-1H-
isochromene-3-carboxylate (3n):
Colorless viscous liquid.1H NMR (400 MHz, CDCl3) δ 7.73 (d, J = 7.6 Hz, 2H), 7.43 – 7.34 (m, 3H), 7.31 (t, J = 7.1
Hz, 1H), 7.26 – 7.09 (m, 5H), 7.01 (d, J = 7.0 Hz, 1H), 6.90 (d, J = 7.6 Hz, 1H), 5.31 (d, J =
15.4 Hz, 1H), 5.17 (d, J = 15.4 Hz, 1H), 4.64 (dd, J = 8.8 and 3.3 Hz, 1H), 3.51 (s, 3H), 3.01
(dd, J = 17.9 and 8.8 Hz, 1H), 2.87 (dd, J = 17.9 and 3.3 Hz, 1H) ppm. 13C NMR (100 MHz, CDCl3) δ 201.28, 171.86, 139.21, 138.46, 136.23, 131.82, 131.44,
130.62, 130.29, 129.44, 128.59, 128.17, 127.04, 126.76, 126.53, 125.51, 124.18, 82.39, 65.60,
52.51, 45.57, 39.75 ppm.
HRMS-ESI: calcd. for C26H24NaO4 [(M + 2) + Na]+ 445.0991, found 445.0978.
O
O
3o
Br
CO2Me
Methyl (3R,4S)-4-[2-(2-bromophenyl)-2-oxoethyl]-3-phenyl-3,4-dihydro-1H-
isochromene-3-carboxylate (3o):
Colourless viscous liquid.1H NMR (400 MHz, CDCl3) δ 7.73 (d, J = 7.1 Hz, 2H), 7.50 – 7.34 (m, 4H), 7.31 (t, J = 7.3
Hz, 1H), 7.24 – 7.10 (m, 4H), 7.01 (d, J = 7.0 Hz, 1H), 6.85 – 6.75 (m, 1H), 5.31 (d, J = 15.6
Hz, 1H), 5.17 (d, J = 15.6 Hz, 1H), 4.64 (d, J = 8.9 and 3.3 Hz, 1H), 3.50 (s, 3H), 2.99 (dd, J
S17
= 18.2 and 8.9 Hz, 1H), 2.84 (dd, J = 18.2 and 3.3 Hz, 1H) ppm. 13C NMR (100 MHz, CDCl3) δ 201.98, 171.86, 141.37, 138.50, 136.21, 133.49, 131.84,
131.34, 129.56, 128.63, 128.21, 127.07, 126.79, 126.67, 125.55, 124.18, 118.43, 82.40, 65.63,
52.53, 45.44, 39.53 ppm.
HRMS-ESI: calcd. for C25H22BrO4 [M + H]+ 465.0696, found 465.0721.
O
O
CO2Me
3p
Me
Methyl (3R,4S)-4-[2-(2-methylphenyl)-2-oxoethyl]-3-phenyl-3,4-dihydro-1H-
isochromene-3-carboxylate (3p):
White semi-solid.1H NMR (400 MHz, CDCl3) δ 7.73 (d, J = 8.0 Hz, 2H), 7.42 – 7.34 (m, 2H), 7.34 – 7.26 (m,
2H), 7.24 – 7.08 (m, 4H), 7.07 – 6.97 (m, 3H), 5.32 (d, J = 15.6 Hz, 1H), 5.19 (d, J = 15.6 Hz,
1H), 4.63 (dd, J = 9.2 and 1.7 Hz, 1H), 3.50 (s, 3H), 2.93 (dd, J = 17.4 and 9.2 Hz, 1H), 2.80
(dd, J = 17.4 and 1.7 Hz, 1H) ppm. 13C NMR (100 MHz, CDCl3) δ 202.47, 171.99, 138.62, 138.11, 137.67, 136.53, 131.82,
131.66, 131.02, 129.31, 128.62, 128.17, 128.14, 127.02, 126.70, 125.50, 125.39, 124.31, 82.55,
65.65, 52.53, 44.36, 39.77, 20.91 ppm.
HRMS-ESI: calcd. for C26H24NaO4 [M + Na]+ 423.1567, found 423.1573.
O
O
CO2Me
OMe3q
Methyl (3R,4S)-4-[2-(4-methoxyphenyl)-2-oxoethyl]-3-phenyl-3,4-dihydro-1H-
isochromene-3-carboxylate (3q):
Colorless viscous liquid.1H NMR (400 MHz, CDCl3) δ 7.72 (d, J = 7.9 Hz, 2H), 7.65 (d, J = 8.7 Hz, 2H), 7.40 – 7.20
(m, 4H), 7.15 (dd, J = 7.4 and 7.3 Hz, 1H), 7.09 (dd, J = 7.4 and 7.1 Hz, 1H), 7.01 (d, J = 7.5
S18
Hz, 1H), 6.77 (d, J = 8.7 Hz, 2H), 5.34 (d, J = 15.4 Hz, 1H), 5.22 (d, J = 15.4 Hz, 1H), 4.63
(dd, J = 9.3 and 2.8 Hz, 1H), 3.78 (s, 3H), 3.49 (s, 3H), 2.99 (dd, J = 17.1 and 9.3 Hz, 1H),
2.80 (dd, J = 17.1 and 2.8 Hz, 1H) ppm. 13C NMR (100 MHz, CDCl3) δ 196.89, 172.02, 163.25, 138.57, 136.54, 131.76, 130.21,
130.13, 129.57, 128.57, 128.12, 126.92, 126.62, 125.54, 124.18, 113.41, 82.66, 65.73, 55.37,
52.49, 40.80, 39.86 ppm.
HRMS-ESI: calcd. for C26H25O5 [M + H]+ 417.1697, found 417.1681.
O
O
CO2Me
3r
F
Cl
Methyl (3R,4S)-4-[2-(2-chlorophenyl)-2-oxoethyl]-6-fluoro-3-phenyl-3,4-dihydro-1H-
isochromene-3-carboxylate (3r):
Colorless viscous solid.1H NMR (400 MHz, CDCl3) δ 7.70 (d, J = 7.4 Hz, 2H), 7.39 (dd, J = 7.6 and 7.1 Hz, 2H), 7.31
(t, J = 7.1 Hz, 1H), 7.25 (d, J = 2.6 Hz, 2H), 7.20 – 7.07 (m, 2H), 7.05 – 6.95 (m, 2H), 6.91
(ddd, J = 8.5, 8.4 and 2.1 Hz, 1H), 5.27 (d, J = 15.2 Hz, 1H), 5.14 (d, J = 15.2 Hz, 1H), 4.61
(dd, J = 9.0 and 3.1 Hz, 1H), 3.54 (s, 3H), 3.01 (dd, J = 18.2 and 9.1 Hz, 1H), 2.86 (dd, J =
18.2 and 3.0 Hz, 1H) ppm.13C NMR (100 MHz, CDCl3) δ 201.06, 171.64, 161.27 (d, J = 245.8 Hz), 139.04, 138.44 (d, J
= 7.3 Hz), 138.10, 131.60, 130.66, 130.35, 128.67, 128.63, 128.30, 127.40 (d, J = 2.9 Hz),
126.63, 125.89 (d, J = 8.1 Hz), 125.44, 116.01(d, J = 22.0 Hz), 114.59 (d, J = 22.0 Hz), 82.13,
65.23, 52.64, 45.37, 39.63 ppm.
HRMS-ESI: calcd. for C25H20ClFNaO4 [M + Na]+ 461.0926, found 461.0953.
O
O
CO2Me
3s
Me
Methyl (3R,4S)-6-methyl-4-(2-oxo-2-phenylethyl)-3-phenyl-3,4-dihydro-1H-
S19
isochromene-3-carboxylate (3s):
White semi-solid.1H NMR (400 MHz, CDCl3) δ 7.72 (d, J = 7.6 Hz, 2H), 7.66 (d, J = 7.8 Hz, 2H), 7.44 (t, J =
7.4 Hz, 1H), 7.37 – 7.20 (m, 5H), 7.13 (s, 1H), 6.97 (d, J = 7.8 Hz, 1H), 6.90 (d, J = 7.8 Hz,
1H), 5.30 (d, J = 15.3 Hz, 1H), 5.20 (d, J = 15.3 Hz, 1H), 4.62 (dd, J = 8.8 and 3.0 Hz, 1H),
3.51 (s, 3H), 3.02 (dd, J = 17.3 and 8.8 Hz, 1H), 2.89 (dd, J = 17.3 and 3.0 Hz, 1H), 2.24 (s,
3H) ppm. 13C NMR (100 MHz, CDCl3) δ 198.39, 172.07, 138.60, 137.00, 136.37, 136.23, 132.77,
129.82, 128.59, 128.54, 128.25, 128.10, 127.89, 125.50, 124.05, 82.58, 65.65, 52.52, 41.36,
39.61, 21.08 ppm.
HRMS-ESI: calcd. for C26H24NaO4 [M + Na]+ 423.1567, found 423.1573.
O
O
CO2Me
3t
MeO
Cl
Methyl (3R,4S)-4-[2-(2-chlorophenyl)-2-oxoethyl]-6-methoxy-3-phenyl-3,4-dihydro-1H-
isochromene-3-carboxylate (3t):
Colorless viscous liquid.1H NMR (400 MHz, CDCl3) δ 7.71 (d, J = 7.7 Hz, 2H), 7.38 (dd, J = 7.5 and 7.5 Hz, 2H), 7.30
(t, J = 7.4 Hz, 1H), 7.27 – 7.20 (m, 1H), 7.17 – 7.07 (m, 1H), 6.97 – 6.87 (m, 3H), 6.77 (d, J =
8.4 Hz, 1H), 5.24 (d, J = 14.8 Hz, 1H), 5.12 (d, J = 14.8 Hz, 1H), 4.60 (dd, J = 8.6 and 2.9 Hz,
1H), 3.79 (s, 3H), 3.53 (s, 3H), 3.01 (dd, J = 18.1 and 8.6 Hz, 1H), 2.87 (dd, J = 18.1 and 2.9
Hz, 1H) ppm.13C NMR (100 MHz, CDCl3) δ 201.25, 171.88, 158.16, 139.10, 138.45, 137.60, 131.47,
130.61, 130.32, 128.59, 128.16, 126.54, 125.49, 125.34, 123.61, 114.41, 113.13, 82.24, 65.35,
55.25, 52.54, 45.51, 39.86 ppm.
HRMS-ESI: calcd. for C26H23ClNaO5 [M + Na]+ 473.1126, found 473.1148.
O
Me
O
CO2Me
3u
S20
Methyl (3R,4S)-4-(2-oxopropyl)-3-phenylisochromane-3-carboxylate (3u):
Colorless viscous liquid.1H NMR (400 MHz, CDCl3) δ 7.67 (d, J = 7.5 Hz, 2H), 7.38 (dd, J = 7.5 and 7.3 Hz, 2H), 7.34
– 7.27 (m, 2H), 7.23 – 7.10 (m, 2H), 7.02 (d, J = 7.0 Hz, 1H), 5.29 (d, J = 15.6 Hz, 1H), 5.16
(d, J = 15.6 Hz, 1H), 4.44 (d, J = 6.0 Hz, 1H), 3.49 (s, 3H), 2.42 (d, J = 6.0 Hz, 1H), 1.77 (s,
3H) ppm.13C NMR (100 MHz, CDCl3) δ 206.94, 171.86, 138.54, 136.48, 131.79, 129.27, 128.55,
128.15, 126.96, 126.78, 125.55, 124.22, 82.32, 65.58, 55.50, 46.11, 39.54, 30.67 ppm.
HRMS-ESI: calcd. for C20H20NaO4 [M + Na]+ 347.1254, found 348.1257.
O
O
CO2Me
3v
Br
MeOMe
Methyl (3R,4S)-4-(2-(2-bromophenyl)-2-oxoethyl)-7-methoxy-1-methyl-3-
phenylisochromane-3-carboxylate (3v):
Colorless viscous liquid.1H NMR (400 MHz, CDCl3; peaks due to the diastereomeric mixture) δ 7.77 (d, J = 7.8 Hz,
2H), 7.74 (d, J = 7.6 Hz, 2H), 7.52 – 7.28 (m, 8H), 7.23 – 7.13 (m, 6H), 7.11 – 7.07 (m, 2H),
6.85 – 6.69 (m, 3H), 6.66 (s, 1H), 6.66 (s, 1H), 5.45 – 5.35 (m, 1H), 5.28 – 5.18 (m, 1H), 4.63
(dd, J = 9.7 and 2.9 Hz, 1H), 4.55 (dd, J = 8.9 and 2.9 Hz, 1H), 3.83 (s, 3H), 3.80 (s, 3H), 3.78
(s, 3H), 3.51 (s, 3H), 3.40 (s, 3H), 3.05 – 2.90 (m, 2H), 2.88 – 2.75 (m, 2H), 1.83 (d, J = 6.4
Hz, 1H), 1.65 (d, J = 6.5 Hz, 1H) ppm.13C NMR (100 MHz, CDCl3; peaks due to the diastereomeric mixture) δ 202.36, 172.10,
158.56, 141.57, 138.81, 138.73, 138.10, 134.33, 133.49, 131.29, 130.75, 129.66, 128.59,
128.51, 128.34, 128.26, 128.14, 127.11, 125.87, 125.55, 118.42, 112.72, 112.12, 110.02, 83.00,
71.38, 55.19, 52.73, 52.47, 46.48, 39.21, 24.20 ppm.
HRMS-ESI: calcd. for C27H25BrNaO5 [M + Na]+ 531.0778, found 531.0801.
S21
O
Ph
CO2H
O
Ph6
(3R,4S)-4-(2-oxo-2-phenylethyl)-3-phenyl-3,4-dihydro-1H-isochromene-3-carboxylic
acid (6):
To a suspension of isochroman 3a (0.2 mmol) and a mixture of water, THF and methanol (3
mL, 1:1:1) in 20 mL flask at room temperature, was added LiOH (1.0 mmol, 5.0 equiv) and
allowed stir at the same temperature for five more minutes. The resultant reaction mixture was
kept in a pre-heated oil bath to reflux for 12 h. Monitored the reaction by TLC until complete
consumption of isochroman 3a. The reaction mixture was cooled down to room temperature
and quenched with 1 N HCl. The aqueous phase was extracted with ethyl acetate (3 × 20 mL).
The combined organic phase was dried over anhydrous Na2SO4 and concentrated under
vacuum, affording the crude residue. Purification of the crude mass via silica-gel flash column
chromatography using the eluent, petroleum ether and ethyl acetate (80:20 to 10:90) afforded
the pure acid 6 as white semi-solid.1H NMR (400 MHz, DMSO-d6) δ 12.89 (br.s, 1H), 7.70 – 7.58 (m, 4H), 7.51 (t, J = 7.3 Hz,
1H), 7.45 – 7.32 (m, 4H), 7.27 (t, J = 7.0 Hz, 1H), 7.22 – 7.02 (m, 4H), 5.26 (d, J = 15.3 Hz,
1H), 5.22 (d, J = 15.3 Hz, 1H), 4.50 – 4.40 (m, 1H), 3.03 (d, J = 17.1 and 8.8 Hz, 1H), 2.72 (d,
J = 17.1 Hz, 1H) ppm.13C NMR (100 MHz, DMSO-d6) δ 198.18, 172.48, 139.01, 136.52, 136.47, 133.13, 132.50,
128.81, 128.56, 128.34, 127.88, 127.69, 126.76, 126.20, 125.34, 124.40, 81.64, 64.93, 41.11,
39.5 ppm.
HRMS-ESI: calcd. for C24H20NaO4 [M + Na]+ 395.1259, found 395.1252.
O CO2Me
HN
Ph
7
Methyl (3R,4R)-3-phenyl-4-(2-phenyl-1H-indol-3-yl)-3,4-dihydro-1H-isochromene-3-
carboxylate (7):
To an oven dried vial (20 mL) at room temperature were added isochroman 3a (0.2 mmol),
PhNHNH2.HCl (0.4 mmol, 2 equiv), DCE (1 mL) and TfOH (1.8 mmol, 9 equiv) followed by
S22
ethanol (1 mL) and this suspension was allowed to stir at the same temperature for 5 more
minutes. The resultant reaction mixture was allowed to stir at 80 oC for 48 h. Monitored the
reaction by TLC until complete conversion. The reaction mixture was cooled down to room
temperature and quenched with aqueous sodium bicarbonate. The aqueous phase was extracted
with ethyl acetate (3 × 20 mL). The combined organic phase was dried over anhydrous Na2SO4
and concentrated under vacuum, affording the crude residue. Purification of the crude mass via
silica-gel flash column chromatography using the eluent, petroleum ether and ethyl acetate
(90:10 to 80:20) afforded the pure indole derivative 7 as pale yellow semi-solid.1H NMR (400 MHz, DMSO-d6) δ 10.88 (br.s, 1H), 7.90 – 6.50 (m, 18H), 5.45 (d, J = 16.3 Hz,
1H), 5.43 (s, 2H), 5.14 (d, J = 16.3 Hz, 1H), 3.53 (s, 3H) ppm.13C NMR (100 MHz, DMSO-d6) δ 172.23, 139.52, 136.64, 135.92, 135.75, 133.09, 132.23,
129.44, 128.46, 127.87, 127.24, 127.13, 126.90, 126.64, 126.14, 124.31, 123.94, 120.90,
120.71, 118.47, 111.42, 110.74, 84.31, 64.85, 52.54, 39.8 ppm.
HRMS-ESI: calcd. for C31H25NNaO3 [M + Na]+ 482.1727, found 482.1724.
O CO2Me
8
Methyl (4bR,10bS,12R)-12-phenyl-6,10b,11,12-tetrahydro-4bH-dibenzo[c,h]chromene-
4b-carboxylate (8):
To a solution of isochroman 3a (0.2 mmol) in methanol (4 mL) at 0 oC, was added NaBH4 (0.6
mmol) in portions for 15 minutes. The resulted reaction mixture was allowed to stir at room
temperature for 3 h. The reaction mixture was quenched with saturated aq. NaHCO3 solution
and extracted with ethyl acetate (3 20 mL). The organic layer was washed with saturated
NaCl solution, dried over anhydrous Na2SO4, filtered through a small pad of silica gel and
concentrated under reduced pressure. Traces of solvents were removed under high vacuum. To
this crude mass in dry DCM (3 mL) at –20 C, was added anhydrous FeCl3 (0.24 mmol), stirred
the reaction for 1.5 h at the same temperature. The reaction mixture was then quenched with
saturated aqueous NaHCO3 solution and the aqueous layer was extracted with DCM (3 20
mL). The organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under
reduced pressure. The crude product was subjected for 1H-NMR to determine the
S23
diastereoselective ratio (dr). Further, purification of the residue on a silica gel column
chromatography (petroleum ether/ethyl acetate, 98:2 to 93:7) furnished the product 8 as white
semi-solid.1H NMR (400 MHz, CDCl3) δ 7.51 (d, J = 7.9 Hz, 1H), 7.31 (dd, J = 7.3 and 7.0 Hz, 2H), 7.27
– 7.12 (m, 8H), 7.07 – 6.98 (m, 1H), 6.85 (d, J = 7.7 Hz, 1H), 5.50 (d, J = 15.4 Hz, 1H), 5.02
(d, J = 15.4 Hz, 1H), 4.34 – 4.20 (m, 1H), 3.73 (d, J = 12.8 Hz, 1H), 3.61 (s, 3H), 2.29 (dq, J
= 12.8 and 1.8 Hz, 1H), 2.22 – 2.10 (m, 1H) ppm.13C NMR (100 MHz, CDCl3) δ 173.14, 145.20, 140.25, 135.26, 135.11, 132.58, 129.56,
128.87, 128.71, 128.57, 127.78, 126.99, 126.84, 126.60, 124.09, 77.92, 65.56, 52.39, 47.29,
40.55, 38.84 ppm.
HRMS-ESI: calcd. for C25H22NaO3 [M + Na]+ 393.1467, found 393.1502.
O
4
O
Ph
CO2Me
Ph
Methyl ({2-[(1E)-3-oxo-3-phenylprop-1-enyl]benzyl}oxy)(phenyl)acetate (4):
To a flame-dried vial, at room temperature, under an inert atmosphere, were added [Rh]-
catalyst (0.002 mmol) and 4 Å molecular sieves (150 mg) followed by DCM (1.0 mL). To this
well-stirred suspension at stated temperature, was added a solution of alcohol ketone 1 (48 mg,
0.2 mmol) and diazo-acetate 2 (0.4 mmol, 2.0 eq) in 1.5 mL of DCM for one hour through a
syringe pump. After completion of the addition, stirring was continued at the same temperature
for two hours. Progress of the reaction was monitored by TLC until complete consumption of
alcohol ketone 1. The reaction mixture was filtered through celite and the filtrate was
concentrated under reduced pressure. Purification of the crude mixture by silica gel flash
chromatography (ethyl acetate/petroleum ether, 98:2 to 94:6) afforded the insertion product 4
as Pale yellow viscous liquid.1H NMR (400 MHz, CDCl3) δ 8.09 (d, J = 15.6 Hz, 1H), 7.99 (d, J = 7.6 Hz, 2H), 7.72 (d, J =
8.1 Hz, 1H), 7.57 (t, J = 7.4 Hz, 1H), 7.52 – 7.27 (m, 11H), 4.99 (s, 1H), 4.78 (d, J = 11.7 Hz,
1H), 4.67 (d, J = 11.7 Hz, 1H), 3.71 (s, 3H) ppm. 13C NMR (100 MHz, CDCl3) δ 190.54, 170.99, 141.70, 138.04, 136.51, 135.99, 134.46,
132.77, 130.11, 129.96, 128.80, 128.67, 128.59, 127.65, 127.35, 127.03, 124.57, 80.40, 69.33,
S24
52.35 ppm.
O
O
Ph5
2-(1,3-Dihydro-2-benzofuran-1-yl)-1-phenylethanone (5):6
To a flame-dried vial, at room temperature, under an inert atmosphere, were added alcohol
ketone 1a (0.2 mmol), Cu(OTf)2 (0.02 mmol) and 4 Å molecular sieves (150 mg) followed by
DCM (2.0 mL). The resultant reaction mixture was stirred at 40 °C for 12 h. Progress of the
reaction was monitored by TLC until complete consumption of alcohol ketone 1. The reaction
mixture was filtered through celite and the filtrate was concentrated under reduced pressure.
Purification of the crude mass by silica gel flash chromatography (ethyl acetate/petroleum
ether, 98:2 to 94:6) gave the isobenzofuran 5 as a white semi-solid.1H NMR (400 MHz, CDCl3) δ 7.97 (d, J = 7.4 Hz, 2H), 7.54 (t, J = 7.3 Hz, 1H), 7.43 (dd, J =
7.4 and 7.3 Hz, 2H), 7.35 – 7.15 (m, 4H), 5.89 (dd, J = 7.3 and 5.0 Hz, 1H), 5.13 (dd, J = 12.2
and 1.6 Hz, 1H), 5.06 (d, J = 12.2 Hz, 1H), 3.52 (dd, J = 16.7 and 7.3 Hz, 1H), 3.32 (dd, J =
16.7 and 5.0 Hz, 1H) ppm. 13C NMR (100 MHz, CDCl3) δ 197.66, 141.29, 139.09, 136.91, 133.09, 128.46, 128.13,
127.62, 127.30, 121.35, 120.89, 79.99, 72.46, 45.45 ppm.
5. References:(1) C. C. Cosner, P. J. Cabrera, K. M. Byrd, A. M. A. Thomas and P. Helquist, Org. Lett.,
2011, 13, 2071.(2) J. Krishna, P. Niharika and G. Satyanarayana, RSC Adv., 2015, 5, 26749.(3) H. Madhurima, J. Krishna and G. Satyanarayana, Synthesis, 2015, 47, 1245.(4) Y. Iwama, K. Okano, K. Sugimoto and H. Tokuyama, Org. Lett., 2012, 14, 2320.(5) R. Shintani, G. C. Fu, Angew. Chem. Int. Ed., 2002, 41, 1057.(6) X. Liu, B. Sun, Z. Xie, X. Qin, L. Liu and H. Lou, J. Org. Chem., 2013, 78, 3104.
S25
6. NMR Spectra
8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5ppm
6.50 3.042.01 1.04 1.031.03 1.01
7.74
7.73
7.67
7.66
7.44
7.37
7.35
7.33
7.32
7.30
7.26
7.25
7.03
5.37
5.33
5.26
5.22
4.67
4.67
4.65
4.64
3.50
3.09
3.06
3.04
3.02
2.91
2.90
2.87
2.86
1H NMR (400 MHz) spectrum of compound 3a in CDCl3
210 200 190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10ppm
Chloroform-d
39.82
41.27
52.49
65.73
77.00
82.64
124.23
125.55
126.67
126.98
127.92
128.16
128.30
128.59
129.55
132.83
136.48
137.03
171.97
198.39
13C NMR (100 MHz) spectrum of compound 3a in CDCl3
OCO2Me
O
3a
OCO2Me
O
3a
S26
9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0ppm
8.87 3.272.16 1.091.07 1.05
7.78
7.69
7.67
7.57
7.46
7.35
7.33
7.31
7.27
7.26
7.24
7.18
7.03
5.35
5.31
5.25
5.21
4.63
4.63
4.61
4.60
3.52
3.07
3.04
3.02
3.00
2.90
2.89
2.86
2.85
1H NMR (400 MHz) spectrum of compound 3b in CDCl3
210 200 190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10ppm
Chloroform-d
198.10
171.48
140.53
136.80
136.07
132.97
129.83
129.52
128.36
127.90
127.11
126.80
126.06
124.23
123.75
82.21
77.00
65.76
52.70
41.08
39.96
13C NMR (100 MHz) spectrum of compound 3b in CDCl3
O
O
CO2Me
3b
Cl
O
O
CO2Me
3b
Cl
S27
9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0ppm
4.07 3.022.03 1.03 1.021.02 1.01
Chloroform-d
2.85
2.89
2.90
2.98
3.00
3.02
3.04
3.51
4.59
4.59
4.61
4.61
5.20
5.24
5.30
5.34
7.02
7.11
7.17
7.20
7.25
7.31
7.33
7.35
7.36
7.46
7.60
7.66
7.68
7.93
1H NMR (400 MHz) spectrum of compound 3c in CDCl3
210 200 190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10ppm
Chloroform-d
198.08
171.45
140.73
136.03
132.96
131.35
130.08
129.50
128.89
128.36
127.90
127.11
126.79
124.22
82.13
77.00
65.74
52.69
41.07
39.99
13C NMR (100 MHz) spectrum of compound 3c in CDCl3
O
O
CO2Me
3c
Br
O
O
CO2Me
3c
Br
S28
9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0ppm
4.17 3.12 3.08 3.011.08 1.011.00
7.72
7.71
7.70
7.68
7.66
7.45
7.35
7.34
7.32
7.30
7.03
7.02
7.00
5.36
5.32
5.25
5.21
4.66
4.64
4.64
3.51
3.06
3.02
3.00
2.92
2.91
2.88
2.87
1H NMR (400 MHz) spectrum of compound 3d in CDCl3
210 200 190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10ppm
Chloroform-d
198.17
171.82
163.71
161.25
136.84
136.27
134.24
132.94
131.64
129.45
128.32
127.86
127.57
127.05
126.76
124.23
115.54
115.32
82.21
77.00
65.72
52.57
41.15
39.74
13C NMR (100 MHz) spectrum of compound 3d in CDCl3
O
O
CO2Me
3d
F
O
O
CO2Me
3d
F
S29
9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0ppm
5.224.22 3.141.15 1.091.08 1.02
7.68
7.66
7.46
7.35
7.34
7.32
7.32
7.29
7.17
7.16
7.12
7.03
5.35
5.32
5.24
5.20
4.65
4.63
4.63
3.51
3.07
3.05
3.03
3.00
2.90
2.89
2.86
2.85
1H NMR (400 MHz) spectrum of compound 3e in CDCl3
210 200 190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10ppm
Chloroform-d
198.13
171.64
137.03
136.17
132.97
131.61
129.47
128.72
128.33
127.87
127.15
126.79
124.23
82.25
77.00
65.73
52.64
41.15
39.72
13C NMR (100 MHz) spectrum of compound 3e in CDCl3
O
O
CO2Me
3e
Cl
O
O
CO2Me
3e
Cl
S30
9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0ppm
4.10 3.033.022.03 1.04 1.021.00
Chloroform-d
7.68
7.66
7.60
7.58
7.44
7.34
7.32
7.30
7.25
7.15
7.13
7.01
5.34
5.30
5.23
5.19
4.63
4.63
4.61
3.49
3.06
3.04
3.02
2.99
2.92
2.88
2.87
2.28
1H NMR (400 MHz) spectrum of compound 3f in CDCl3
210 200 190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10ppm
Chloroform-d
198.43
172.07
137.87
136.51
132.79
131.80
129.51
129.27
128.23
127.91
126.91
126.60
125.39
124.19
82.51
77.00
65.66
52.43
41.27
39.74
21.01
13C NMR (100 MHz) spectrum of compound 3f in CDCl3
O
O
CO2Me
3f
Me
O
O
CO2Me
3f
Me
S31
8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5ppm
6.85 3.46 3.152.04 1.151.12 1.08 1.021.00
7.69
7.67
7.45
7.33
7.33
7.32
7.30
7.28
7.27
7.25
7.16
7.11
7.03
6.80
6.78
5.34
5.30
5.24
5.21
4.63
4.62
4.61
3.80
3.51
3.06
3.04
3.02
3.00
2.95
2.94
2.91
2.90
1H NMR (400 MHz) spectrum of compound 3g in CDCl3
210 200 190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10ppm
Chloroform-d
198.34
171.83
159.77
140.12
136.97
136.45
132.82
131.73
129.59
128.29
127.92
126.95
126.67
124.18
117.74
113.97
111.06
82.53
77.00
65.70
55.24
52.53
41.29
39.94
13C NMR (100 MHz) spectrum of compound 3g in CDCl3
O
O
CO2Me
3g
OMe
O
O
CO2Me
3g
OMe
S32
9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0ppm
3.403.38 3.192.12 2.05 1.10 1.051.05
Chloroform-d
2.90
2.94
2.99
3.49
3.75
4.62
5.18
5.22
6.84
7.01
7.25
7.31
7.42
7.60
7.63
7.66
7.68
1H NMR (400 MHz) spectrum of compound 3h in CDCl3
210 200 190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10ppm
Chloroform-d
39.73
41.30
52.47
55.20
65.69
77.00
82.31
113.91
124.23
126.66
126.84
127.94
128.29
129.51
130.56
131.81
132.85
136.97
159.34
172.19
198.50
13C NMR (100 MHz) spectrum of compound 3h in CDCl3
O
O
CO2Me
3h
OMe
O
O
CO2Me
3h
OMe
S33
9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0ppm
9.635.464.03 3.00 2.021.091.01 1.00
Chloroform-d
7.66
7.64
7.62
7.60
7.42
7.34
7.32
7.29
7.28
7.15
7.10
7.02
5.36
5.32
5.24
5.20
4.67
4.65
4.65
4.64
3.49
2.99
2.97
2.96
1.25
1H NMR (400 MHz) spectrum of compound 3i in CDCl3
210 200 190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10ppm
Chloroform-d
198.50
172.08
150.95
137.01
136.60
132.76
131.90
129.48
128.24
127.92
126.62
125.46
125.19
124.18
82.49
77.00
65.66
52.41
41.26
39.80
34.42
31.19
13C NMR (100 MHz) spectrum of compound 3i in CDCl3
O
O
CO2Me
3i
MeMeMe
O
O
CO2Me
3i
MeMeMe
S34
9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0ppm
4.18 3.022.04 2.001.17 1.08 1.00
Chloroform-d
7.85
7.68
7.66
7.50
7.46
7.38
7.36
7.35
7.33
7.31
7.18
7.13
7.03
5.34
5.30
5.24
5.20
4.62
4.61
4.60
4.59
3.52
3.03
3.01
2.99
2.97
2.92
2.91
2.88
2.87
1H NMR (400 MHz) spectrum of compound 3j in CDCl3
210 200 190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10ppm
Chloroform-d
197.95
171.23
138.68
136.67
133.08
131.48
130.47
129.46
128.38
127.86
127.20
126.92
125.11
124.24
81.86
77.00
65.78
52.80
41.02
39.99
13C NMR (100 MHz) spectrum of compound 3j in CDCl3
O
O
CO2Me
3j
Cl
Cl
O
O
CO2Me
3j
Cl
Cl
S35
9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0ppm
3.19 3.113.10 3.00 2.021.06 1.01
Chloroform-d
7.68
7.66
7.46
7.44
7.41
7.32
7.30
7.29
7.10
7.09
7.07
7.02
7.00
5.34
5.30
5.24
5.20
4.63
4.62
4.61
4.60
3.49
3.03
2.99
2.97
2.96
2.92
2.91
2.22
2.18
1H NMR (400 MHz) spectrum of compound 3k in CDCl3
210 200 190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10ppm
Chloroform-d
198.50
172.14
136.52
132.74
131.80
129.81
129.54
128.20
127.92
126.88
126.62
126.50
124.18
122.86
82.48
77.00
65.65
52.46
41.31
39.94
19.91
19.35
13C NMR (100 MHz) spectrum of compound 3k in CDCl3
O
O
CO2Me
3k
Me
Me
O
O
CO2Me
3k
Me
Me
S36
9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0ppm
6.193.26 3.052.07 2.00 1.15 1.09 1.09
Chloroform-d
7.68
7.66
7.45
7.34
7.32
7.30
7.25
7.17
7.16
7.15
7.13
7.03
6.91
5.31
5.28
5.22
5.19
4.67
4.66
4.65
4.64
3.85
3.74
3.53
3.09
3.09
3.05
3.04
2.93
2.91
2.88
1H NMR (400 MHz) spectrum of compound 3l in CDCl3
210 200 190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10ppm
Chloroform-d
198.37
171.84
153.11
137.48
136.86
136.57
133.96
132.93
131.64
129.27
128.32
127.87
126.85
124.18
102.75
82.38
77.00
65.69
60.70
56.10
52.60
41.46
40.00
13C NMR (100 MHz) spectrum of compound 3l in CDCl3
O
O
CO2Me
3l
MeO OMe
OMe
O
O
CO2Me
3l
MeO OMe
OMe
S37
9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0ppm
7.80 3.092.16 2.041.07 1.031.02 1.00
7.76
7.74
7.68
7.66
7.43
7.36
7.35
7.33
7.32
7.30
7.28
7.16
7.03
5.40
5.36
5.25
5.21
4.65
4.63
3.98
3.96
3.95
3.93
3.11
3.09
3.07
3.05
2.90
2.86
0.94
0.93
0.91
1H NMR (400 MHz) spectrum of compound 12m in CDCl3
210 200 190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10ppm
Chloroform-d
198.43
171.20
137.02
136.56
132.82
129.65
128.50
128.29
128.08
127.90
126.96
126.52
125.58
124.20
82.52
77.00
65.71
61.29
41.11
39.97
13.75
13C NMR (100 MHz) spectrum of compound 3m in CDCl3
O
O
CO2Et
3m
O
O
CO2Et
3m
S38
9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0ppm
5.78 3.102.15 1.121.05 1.031.03
7.74
7.72
7.40
7.38
7.36
7.31
7.24
7.23
7.20
7.18
7.02
6.91
6.89
5.33
5.29
5.19
5.16
4.65
4.63
4.63
3.51
3.04
3.02
3.00
2.98
2.89
2.89
2.85
2.84
1H NMR (400 MHz) spectrum of compound 3n in CDCl3
210 200 190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10ppm
Chloroform-d
201.28
171.86
139.21
138.46
136.23
131.44
130.29
129.44
128.59
128.17
127.04
126.76
126.53
125.51
124.18
82.39
77.00
65.60
52.51
45.57
39.75
13C NMR (100 MHz) spectrum of compound 3n in CDCl3
O
O
CO2Me
3n
Cl
O
O
CO2Me
3n
Cl
S39
9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0ppm
4.34 4.32 3.352.00 1.22 1.18 1.181.13
Chloroform-d
7.74
7.72
7.43
7.42
7.41
7.39
7.18
7.17
7.15
7.14
7.14
7.13
7.00
6.80
5.33
5.29
5.19
5.15
4.66
4.65
4.64
3.50
3.03
3.00
2.98
2.96
2.86
2.86
2.82
2.81
1H NMR (400 MHz) spectrum of compound 3o in CDCl3
210 200 190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10ppm
Chloroform-d
201.98
171.86
141.37
138.50
133.49
131.84
131.34
129.56
128.63
128.21
127.07
126.79
125.55
124.18
118.43
82.40
77.00
65.63
52.53
45.44
39.53
13C NMR (100 MHz) spectrum of compound 3o in CDCl3
O
O
CO2Me
3o
Br
O
O
CO2Me
3o
Br
S40
9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0ppm
3.183.16 3.042.652.00 1.04 1.041.01
2.30
2.78
2.79
2.83
2.83
2.91
2.93
2.98
3.51
4.65
5.18
5.22
5.31
5.35
7.04
7.05
7.07
7.13
7.26
7.30
7.32
7.37
7.39
7.41
7.73
7.75
1H NMR (400 MHz) spectrum of compound 3p in CDCl3
210 200 190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10ppm
Chloroform-d
20.91
39.77
44.36
52.53
65.65
77.00
82.55
124.31
125.50
126.70
127.02
128.14
128.62
129.31
131.02
131.66
131.82
136.53
137.67
171.99
202.47
13C NMR (100 MHz) spectrum of compound 3p in CDCl3
O
O
CO2Me
3p
Me
O
O
CO2Me
3p
Me
S41
9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0ppm
3.42 3.28 3.112.21 2.00 1.08 1.051.051.03
Chloroform-d
7.73
7.71
7.66
7.64
7.36
7.35
7.33
7.31
7.25
7.15
7.09
7.02
6.78
6.76
5.36
5.32
5.24
5.20
4.64
4.62
4.62
3.78
3.49
3.03
3.00
2.98
2.96
2.82
2.78
2.78
1H NMR (400 MHz) spectrum of compound 3q in CDCl3
210 200 190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10ppm
Chloroform-d
196.89
172.02
163.25
138.57
136.54
131.76
130.21
129.57
128.57
128.12
126.92
126.62
125.54
124.18
113.41
82.66
77.00
65.73
55.37
52.49
40.80
39.86
13C NMR (100 MHz) spectrum of compound 3q in CDCl3
O
O
CO2Me
OMe3q
O
O
CO2Me
OMe3q
S42
9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0ppm
3.30 3.17 3.002.05 1.03 1.021.01
7.71
7.69
7.41
7.39
7.37
7.33
7.31
7.25
7.15
7.12
7.01
6.98
6.96
5.29
5.25
5.16
5.12
4.63
4.62
4.60
4.60
3.54
3.05
3.03
3.00
2.98
2.89
2.88
2.84
2.84
1H NMR (400 MHz) spectrum of compound 3r in CDCl3
210 200 190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10ppm
Chloroform-d
201.06
171.64
162.49
160.05
139.04
138.48
138.10
131.60
130.66
130.35
128.67
128.63
128.30
126.63
125.93
125.44
116.12
115.90
114.70
114.48
82.13
77.00
65.23
52.64
45.37
39.63
13C NMR (100 MHz) spectrum of compound 3r in CDCl3
O
O
CO2Me
3r
F
Cl
O
O
CO2Me
3r
F
Cl
S43
9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0ppm
4.07 3.06 3.062.00 1.051.031.021.00
7.73
7.71
7.67
7.65
7.44
7.36
7.34
7.32
7.31
7.24
7.13
6.96
6.91
6.89
5.32
5.28
5.22
5.18
4.63
4.63
4.61
4.60
3.51
3.06
3.03
3.01
2.99
2.91
2.91
2.87
2.86
2.24
1H NMR (400 MHz) spectrum of compound 3s in CDCl3
210 200 190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10ppm
Chloroform-d
198.39
172.07
138.60
137.00
136.37
136.23
132.77
129.82
128.54
128.25
127.89
125.50
124.05
82.58
77.00
65.65
52.52
41.36
39.61
21.08
13C NMR (100 MHz) spectrum of compound 3s in CDCl3
O
O
CO2Me
3s
Me
O
O
CO2Me
3s
Me
S44
9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0ppm
3.17 3.073.023.002.00 1.031.02 1.01
7.72
7.71
7.40
7.38
7.36
7.32
7.30
7.25
7.12
7.11
6.93
6.91
6.78
6.76
5.26
5.22
5.14
5.10
4.62
4.61
4.59
3.79
3.53
3.04
3.02
3.00
2.97
2.90
2.89
2.85
2.84
1H NMR (400 MHz) spectrum of compound 3t in CDCl3
210 200 190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10ppm
Chloroform-d
201.25
171.88
158.16
139.10
138.45
137.60
131.47
130.61
130.32
128.59
128.16
126.54
125.49
125.34
123.61
114.41
113.13
82.24
77.00
65.35
55.25
52.54
45.51
39.86
13C NMR (100 MHz) spectrum of compound 3t in CDCl3
O
O
CO2Me
3t
MeO
Cl
O
O
CO2Me
3t
MeO
Cl
S45
9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0ppm
4.47 3.05 3.002.07 2.031.17 1.04 1.01
7.68
7.66
7.40
7.38
7.37
7.33
7.31
7.29
7.26
7.20
7.18
7.03
5.31
5.27
5.18
5.14
4.44
3.49
2.43
2.42
1.77
1H NMR (400 MHz) spectrum of compound 3u in CDCl3
210 200 190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10
ppm
Chloroform-d
206.94
171.86
138.54
136.48
131.79
129.27
128.55
128.15
126.96
126.78
125.55
124.22
82.32
77.00
65.58
52.50
46.11
39.54
30.67
13C NMR (100 MHz) spectrum of compound 3u in CDCl3
O
Me
O
CO2Me
3u
O
Me
O
CO2Me
3u
S46
9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0ppm
8.18 7.986.16 3.263.102.96 1.48 1.361.14 1.00
7.78
7.75
7.73
7.40
7.38
7.36
7.31
7.31
7.26
7.20
7.17
7.16
7.10
6.79
6.72
6.56
6.56
5.40
5.39
4.56
4.55
4.54
3.83
3.80
3.78
3.51
3.40
3.01
2.99
2.96
2.94
2.85
2.85
2.81
2.80
1.84
1.82
1.66
1.65
1H NMR (400 MHz) spectrum of compound 3t in CDCl3
210 200 190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10
ppm
Chloroform-d
202.36
172.10
158.56
141.57
138.81
138.10
133.49
131.29
130.75
129.66
128.59
128.34
128.14
127.11
125.87
125.55
118.42
112.72
112.12
110.02
83.00
77.00
71.38
55.19
52.73
52.47
46.48
39.21
24.20
13C NMR (100 MHz) spectrum of compound 3v in CDCl3
O
O
CO2Me
3v
Br
MeOMe
O
O
CO2Me
3v
Br
MeOMe
S47
14 13 12 11 10 9 8 7 6 5 4 3 2 1ppm
5.35 2.05 1.031.020.77
DMSO-d6
12.89
7.66
7.64
7.62
7.51
7.37
7.36
7.27
7.15
7.12
7.10
5.24
4.46
4.44
3.06
3.04
3.02
3.00
2.74
2.70
2.49
1H NMR (400 MHz) spectrum of compound 6 in DMSO-d6
210 200 190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10ppm
DMSO-d6
39.50
41.11
64.93
81.64
124.40
125.34
126.20
126.76
127.69
127.88
128.34
128.56
128.81
133.13
136.47
139.01
172.48
198.18
13C NMR (100 MHz) spectrum of compound 6 in DMSO-d6
OCO2H
O
6
OCO2H
O
6
S48
11 10 9 8 7 6 5 4 3 2 1ppm
19.81 3.002.01 1.060.86
DMSO-d6
2.49
3.53
5.17
5.43
5.48
6.78
6.80
6.89
6.90
7.09
7.11
7.17
7.20
7.36
7.38
7.54
7.56
10.88
1H NMR (400 MHz) spectrum of compound 7 in DMSO-d6
210 200 190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10ppm
DMSO-d6
38.87
39.08
39.30
39.50
39.71
39.92
40.13
52.54
64.85
84.31
110.74
111.42
118.47
120.71
123.94
124.31
126.14
126.64
126.90
127.24
127.87
128.46
129.44
135.75
135.92
136.64
139.52
172.23
13C NMR (100 MHz) spectrum of compound 7 in DMSO-d6
O
7
Ph
CO2Me
HNPh
O
7
Ph
CO2Me
HNPh
S49
9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0ppm
8.79 3.20 2.161.101.06 1.02 1.021.00
7.52
7.50
7.32
7.31
7.29
7.25
7.22
7.20
7.18
7.03
6.86
6.84
5.48
5.04
5.00
4.29
4.27
4.26
3.75
3.72
3.61
2.30
2.28
2.27
2.19
2.19
2.16
2.15
1H NMR (400 MHz) spectrum of compound 8 in CDCl3
210 200 190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10ppm
Chloroform-d
173.14
145.20
140.25
135.11
132.58
129.56
128.87
128.71
128.57
127.78
126.84
126.60
124.09
77.92
77.00
65.56
52.39
47.29
40.55
38.84
13C NMR (100 MHz) spectrum of compound 8 in CDCl3
O
8
CO2Me
O
8
CO2Me
S50
11 10 9 8 7 6 5 4 3 2 1 0ppm
6.72 3.112.01 1.331.10
Chloroform-d
3.71
4.66
4.69
4.77
4.80
4.99
7.32
7.34
7.35
7.37
7.44
7.45
7.47
7.49
7.98
8.00
8.07
8.11
1H NMR (400 MHz) spectrum of compound 4 in CDCl3
210 200 190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10ppm
Chloroform-d
52.35
69.33
77.00
80.40
124.57
127.03
127.35
127.65
128.59
128.67
129.96
130.11
132.77
135.99
138.04
141.70
170.99
190.54
13C NMR (100 MHz) spectrum of compound 4 in CDCl3
O CO2Me
Ph
Ph
O
4
O CO2Me
Ph
Ph
O
4
S51
9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0ppm
4.08 2.092.08 1.14 1.111.00
3.30
3.31
3.34
3.35
3.49
3.51
3.52
3.53
3.55
5.05
5.08
5.12
5.12
5.15
5.15
5.89
7.21
7.22
7.25
7.27
7.28
7.42
7.43
7.45
7.52
7.54
7.96
7.98
1H NMR (400 MHz) spectrum of compound 5 in CDCl3
210 200 190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10ppm
Chloroform-d
45.45
72.46
77.00
79.99
120.89
121.35
127.30
127.62
128.13
128.46
133.09
136.91
139.09
141.29
197.66
13C NMR (100 MHz) spectrum of compound 5 in CDCl3
O
O
Ph5
O
O
Ph5