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.


O

O

CO2Me

3g

OMe

Methyl (3R,4S)-3-(3-methoxyphenyl)-4-(2-oxo-2-phenylethyl)-3,4-dihydro-1H-

isochromene-3-carboxylate (3g):




(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):



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 =



(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.


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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,


(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


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):



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),


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.


O

O

CO2Et

3m

Ethyl (3R,4S)-4-(2-oxo-2-phenylethyl)-3-phenyl-3,4-dihydro-1H-isochromene-3-

carboxylate (3m):




(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,


(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.


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


S18


(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),


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.


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.


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.


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.


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


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


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


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


O

O

Ph5

O

O

Ph5

intramolecular michael-type trapping of oxonium ylides of ... · alavala gopi krishna reddy,a...

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