enantioselective c-h carbene insertions with homogeneous ... · enantioselective c-h carbene...

1

SUPPORTING INFORMATION

Enantioselective C-H carbene insertions with homogeneous and immobilized copper complexes.

José M. Fraile,* Pilar López-Ram-de-Viu, José A. Mayoral, Marta Roldán, and Jorge Santafé-Valero.

Departamento de Química Orgánica, Instituto de Ciencia de Materiales de Aragón and Instituto Universitario de

Catálisis Homogénea, Facultad de Ciencias, Universidad de Zaragoza-C.S.I.C., E-50009 Zaragoza, Spain

Content Page

General ....................................................................................................................... 2

Catalytic tests ............................................................................................................. 3

Analysis of the insertion reactions

THF ................................................................................................................ 4

THP ................................................................................................................ 10

1,4-Dioxane ................................................................................................... 15

1,3-Dioxolane ................................................................................................. 20

Diisopropylether ............................................................................................. 22

Semi-preparative HPLC .............................................................................................. 24

Electronic Supplementary Material (ESI) for Organic and Biomolecular ChemistryThis journal is © The Royal Society of Chemistry 2011

2

General

Laponite was obtained from Laporte Adsorbents. Bis(oxazoline) ligand 1a was prepared

by condensation of (S)-phenylglycinol with dimethylmalononitrile.1,2 Azabis(oxazoline) ligand 2a

was prepared from (S)-2-amino-4-phenyl-4,5-dihydro-1,3-oxazole and (S)-2-ethoxy-4-phenyl-

4,5-dihydro-1,3-oxazole.3 Azabis(oxazoline) ligands 2b and 2c were prepared from (S)-2-amino-

4-tert-butyl-4,5-dihydro-1,3-oxazole and (S)-2-amino-4-isopropyl-4,5-dihydro-1,3-oxazole

respectively.2,4 Methyl phenyldiazoacetate was prepared by reaction of methyl phenylacetate

with p-acetamidobenzenesulfonylazide.5

Products were identified by NMR spectroscopy (Bruker Avance 400), mass

spectrometry (ESI, Bruker MicroToF-Q), and polarimetry (Jasco J-810 polarimeter). Analysis

were carried out by GC (Hewlett-Packard 5890 Series II, FID) or HPLC (Waters Allience 2690

with PDA 2996 detector).

Preparation of laponite-immobilized catalysts:6 Laponite (1 g) was dried under vacuum

for 24 h prior to use. The chiral ligand (0.37 mmol) and Cu(OTf)2 (115.7 mg, 0.32 mmol) were

dissolved in the minimum required amount of anhydrous dichloromethane under argon

atmosphere, the solution was stirred for 15 min and filtered through a PTFE microfilter. The

solvent was eliminated under vacuum, the complex was re-dissolved in methanol (5.5 mL),

laponite was added and the suspension was stirred for 24 h at room temperature. The solid was

filtered off, washed with methanol (14 ml) and dichloromethane (20 ml), and finally dried under

vacuum for 24 h. Catalysts were characterized by copper analysis (plasma emission

spectroscopy on a Perkin-Elmer Plasma 40 emission spectrometer), elemental analysis (Perkin-

Elmer 2400 elemental analyzer), X ray diffraction of oriented (D-max Rigaku system with

rotating anode), and transmission FTIR (self-supported wafers evacuated at < 10–4 Torr and

50°C in a Nicolet Avatar 360 spectrometer).

1 A. Cornejo, J. M. Fraile, J. I. García, M. J. Gil, V. Martínez-Merino, J. A. Mayoral, E. Pires, I. Villalba, Synlett 2005, 2321. 2 J. M. Fraile, J. I. García, J. A. Mayoral, M. Roldán, Org. Lett. 2007, 9, 731 (supplementary material). 3 J. M. Fraile, J. I. García, C. I. Herrerías, J. A. Mayoral, O. Reiser, A. Socuéllamos, H. Werner, Chem. Eur. J. 2004, 10, 2997. 4 M. Glos, O. Reiser, Org. Lett. 2000, 2, 2045. 5 W. A. J.; Starmans, L. Thijs, B. Zwanenburg, Tetrahedron, 1998, 54, 629. 6 Modification of the method described in ref. 3.


3

Catalytic tests

Homogeneous insertion reaction

The catalyst was prepared with the corresponding ligand (0.025 mmol) and Cu(OTf)2

(0.02 mmol) in anhydrous CH2Cl2 (0.5 mL) under an inert atmosphere. The mixture was stirred

for 30 min, the solution was microfiltered and the solvent removed under an inert gas stream.

This complex was dissolved in anhydrous substrate (THF, THP, 1,4-dioxane, 1,3-dioxolane, or

diisopropylether, 10 mL), n-decane (100 mg) was added as an internal standard and the

solution heated under reflux. A solution of methyl phenyldiazoacetate (1 mmol) in anhydrous

substrate (10 mL) was slowly added during 2 h with a syringe pump. Once the addition had

finished, the reaction mixture was stirred and heated under reflux for 30 min. The yield and

diastereoselectivity were determined by GC.

Heterogeneous insertion reactions

A suspension of dried heterogeneous catalyst (100 mg) in anhydrous substrate (10 mL)

with n-decane (100 mg) as internal standard was heated under reflux under an inert

atmosphere. A solution of methyl phenyldiazoacetate (1 mmol) in anhydrous substrate (10 mL)

was slowly added during 2 h with a syringe pump.

Once the addition had finished, the reaction mixture was stirred and heated under reflux

for 30 min. The catalyst was filtered off and washed with substrate (5 mL). The yield and

diastereoselectivity were determined by GC. The catalyst was dried under vacuum and reused

under the same conditions.

Alternatively, the catalyst was suspended in a mixture of THF (2 mmol) and n-decane

(10 mg) in anhydrous hexane (10 mL). The suspension was heated under reflux under an inert

atmosphere and a solution of methyl phenyldiazoacetate (1 mmol) in anhydrous hexane (10

mL) was slowly added during 2 h with a syringe pump. The reaction was then treated and

analyzed as described above.

Isotopic effect

The catalyst was added to a solution of THF (2 mmol) and d8-THF (2 mmol) in

anhydrous hexane (10 mL). The mixture was heated under reflux under an inert atmosphere

and a solution of methyl phenyldiazoacetate (1 mmol) in anhydrous hexane (10 mL) was slowly

added during 2 h with a syringe pump. The deuterated/non-deuterated products ratio was

determined by GC: HP-Innowax 30 m column; pressure 20 psi (He as carrier gas); oven

temperature program: 60 ºC (3 min) – 1 ºC/min – 200 ºC (20 min); retention times: unlike d8-

products 110.7 min, unlike products 111.2 min, like d8-products 111.5 min, like products 111.9

min. The final non-deuterated/deuterated products ratio was confirmed by NMR.


4

Analysis of the insertion reactions

THF

GC: 30 m phenylsilicone column; pressure 20 psi (He as carrier gas); oven temperature

program: 120 ºC (3 min) – 3 ºC/min – 200 ºC (5 min); retention times: n-decane 2.4 min, methyl

phenyldiazoacetate 7.7 min, unlike products (3) 16.9 min, like products (4) 17.1 min.

Enantioselectivities were determined by HPLC. Column: Chiralcel OD-H; 0.46 cm × 25 cm.

Eluent: hexane/isopropanol (99.4/0.6), 0.8 mL/min. Retention times: 3S (2R,S) 16.7 min, 3R

(2S,R) 20.0 min, like product (enantiomer 1) 24.6 min, like product (enantiomer 2) 26.9 min.

Methyl (2R*,S*)--(oxolan-2-yl)phenylacetate (unlike isomers, 3): 1H NMR (400 MHz, CDCl3):

7.29-7.39 (m, 5H), 4.46 (dt, 1H, J = 7.1, J = 8.3 Hz, H2), 3.81 (dt, 1H, J = 6.8, J = 8.2 Hz, H5),

3.71 (dt, 1H, J = 6.9, J = 8.1 Hz, H5’), 3.67 (s, 3H), 3.63 (d, 1H, J = 8.6 Hz, H), 2.12 (m, 1H,

H3), 1.87 (m, 2H, H4), 1.67 (m, 1H, H3’); 13C NMR (100 MHz, CDCl3): 172.6, 136.6, 128.6,

128.5, 127.5, 80.0 (C2), 68.4 (C5), 56.9 (C), 52.0 (OCH3), 30.2 (C3), 25.7 (C4). HRMS (ESI),

found: 243.0980 (MNa+); calcd for C13H16O3Na: 243.0992; Anal. calc. for C13H16O3: C,70.91; H,

7.27. Found: C, 70.88; H, 7.30. 5S (2R,S) −88.1° (c 0.159, CHCl3).7 3R (2S,R)

+78.1º (c 0.167, CHCl3).

7 Value reported in the literature: −74º (c 0.2, CHCl3). Davies, H. M. L.; Hansen, T.; Churchill, M. R. J. Am. Chem. Soc. 2000, 122, 3063–3070.


5

OCOOMe

Ph2

3

34

5


6

OCOOMe

Ph2

3

34

5


7

Methyl (2R*,R*)--(oxolan-2-yl)phenylacetate (like isomers, 4): 1H NMR (400 MHz, CDCl3):

7.34-7.26 (m, 5H), 4.52 (dt, 1H, J = 7.0, J = 10.0 Hz, H2), 3.92 (dt, 1H, J = 7.0, J = 8.3 Hz, H5),

3.85 (dt, 1H, J = 6.2, J = 8.2 Hz, H5’), 3.70 (s, 3H), 3.53 (d, 1H, J = 10.0 Hz, H), 1.86 (m, 2H,

H4), 1.69 (m, 1H, H3), 1.44 (m, 1H, H3’); 13C NMR (100 MHz, CDCl3): 173.1, 136.0, 128.8,

128.5, 127.8, 80.7 (C2), 68.6 (C5), 57.7 (C), 52.2 (OCH3), 29.7 (C3), 25.6 (C4). HRMS (ESI),

found: 243.0974 (MNa+); calcd for C13H16O3Na: 243.0992. Enantiomer 1 −19.3° (c 0.7,

CHCl3). Enantiomer 2 +18.6º (c 0.7, CHCl3).


8

OCOOMe

Ph2

4

34

5

OCOOMe

Ph2

4

34

5


9

OCOOMe

Ph2

4

34

5


10

THP



phenyldiazoacetate 7.7 min, unlike products (5) 18.9 min, like products (6) 19.1 min.

Enantioselectivities were determined by GC. Column: Cyclodex-, 30 m. pressure 20 psi (He as

carrier gas); oven temperature program: 125 ºC (180 min). Retention times: 5S (2R,S) 162.7

min, 5R (2S,R) 165.2 min, 6 (enantiomer 1) 169.0 min, 6 (enantiomer 2) 172.9 min.

Methyl (2R*,S*)--(oxan-2-yl)phenylacetate (unlike isomers, 5): 1H NMR (400 MHz, CDCl3):

7.25-7.39 (m, 5H), 3.87-3.92 (m, 2H, H2+H6), 3.65 (s, 3H), 3.64 (d, 1H, J = 9.1 Hz, H), 3.34

(dt, 1H, J = 2.7, J = 11.4 Hz, H6’), 1.84 (m, 1H), 1.71 (m, 1H), 1.43-1.58 (m, 3H), 1.30-1.42 (m,

1H); 13C NMR (100 MHz, CDCl3): 172.6, 135.2, 128.9, 128.5, 127.5, 78.6 (C2), 69.0 (C6), 57.7

(C), 52.0 (OCH3), 29.8, 25.8, 23.3. HRMS (ESI), found: 257.1125 (MNa+); calcd for

C14H18O3Na: 257.1154. 7S (2R,S) −76.4° (c 0.55, CCl4). 5R (2S,R) +78.2º (c 0.75,

CCl4).

2

5COOMe

Ph

O

34

5

6


11

2

5COOMe

Ph

O

34

5

6


12

Methyl (2S*,S*)--(oxan-2-yl)phenylacetate (like isomers, 6, not fully purified): 1H NMR (400

MHz, CDCl3): 7.25-7.38 (m, 5H), 4.01 (m, 1H, H6), 3.91 (dt, 1H, J = 2.1, J = 10.7 Hz, H2), 3.68

(s, 3H), 3.54 (d, 1H, J = 10.1 Hz, H), 3.49 (dt, 1H, J = 2.7, J = 11.7 Hz, H6’), 1.8-2.0 (m, 6H); 13C NMR (100 MHz, CDCl3): 172.5, 135.4, 128.8, 128.5, 127.9, 79.5 (C2), 68.9 (C6), 58.4 (C),

52.2 (OCH3), 29.2, 25.9, 23.3.


13

COOMe

Ph2

6

O

34

5

6


14

COOMe

Ph2

6

O

34

5

6


15

1,4-Dioxane



phenyldiazoacetate 7.7 min, like products (7) 19.7 min, unlike products (8) 19.8 min.


carrier gas); oven temperature program: 110 ºC (240 min). Retention times: 7 (enantiomer 1)

213.1 min, 7 (enantiomer 2) 219.1 min, 8 (enantiomer 1) 224.1 min, 8 (enantiomer 2) 228.0 min.

Methyl (2S*,S*)--(1,4-dioxan-2-yl)phenylacetate (like isomers, 7): 1H NMR (400 MHz, CDCl3):

7.28-7.35 (m, 5H), 4.18 (dt, 1H, J = 7.1, J = 9.2 Hz, H2), 3.87 (dd, 1H, J = 2.4, J = 11.4 Hz, H3),

3.69-3.75 (m, 2H), 3.68 (d, 1H, J = 9.0 Hz, H), 3.66 (s, 3H), 3.57-3.65 (m, 2H), 3.44 (dd, 1H, J

= 9.4, J = 11.3 Hz, H3’); 13C NMR (100 MHz, CDCl3): 171.7, 135.3, 128.9, 128.7, 127.8, 75.8

(C2), 69.7 (C3), 67.0, 66.5, 53.7 (C), 52.4 (OCH3). HRMS (ESI), found: 259.0916 (MNa+);

calcd for C13H16O4Na: 259.0946.


16

4550556065707580859095100105110115120125130135140145150155160165170175f1 (ppm)

0

5

10

15

20

25

30

35

40

45

50

55

60

65

70

75

80

85

52.3

753

.73

66.5

267

.05

69.6

975

.83

76.8

477

.16

77.4

8

127.

8512

8.73

128.

87

135.

30

171.

73

Methyl (2R*,S*)--(1,4-dioxan-2-yl)phenylacetate (unlike isomers, 8): 1H NMR (400 MHz,

CDCl3): 7.27-7.34 (m, 5H), 4.23 (dt, 1H, J = 2.6, J = 10.0 Hz, H2), 3.75-3.85 (m, 2H), 3.70 (s,

3H), 3.60 (d, 1H, J = 10.4 Hz, H), 3.55-3.67 (m, 2H), 3.34 (dd, 1H, J = 2.6, J = 11.6 Hz, H3),

3.19 (dd, 1H, J = 9.8, J = 11.6 Hz, H3’); 13C NMR (100 MHz, CDCl3): 172.5, 133.9, 129.1, 128.5,


17

128.3, 76.4 (C2), 69.3 (C3), 67.0, 66.5, 54.6 (C), 52.4 (OCH3). HRMS (ESI), found: 259.0930

(MNa+); calcd for C13H16O4Na: 259.0946.

2

8

COOMe

PhO

O

35

6

2

8

COOMe

PhO

O

35

6


18

2

8

COOMe

PhO

O

35

6


19

1,3-Dioxolane

O

O

+

Ph COOMe

N2

O

OCOOMe

PhO

OCOOMe

PhRS

9S 9R



phenyldiazoacetate 7.7 min, products 9 16.7 min.


carrier gas); oven temperature program: 150 ºC (30 min). Retention times: 9 (enantiomer 1)

21.0 min, 9 (enantiomer 2) 21.9 min.

Methyl -(1,3-dioxolan-2-yl)phenylacetate (9): 1H NMR (400 MHz, CDCl3): 7.29-7.39 (m, 5H),

5.48 (d, 1H, J = 7.1 Hz, H2), 3.90-3.97 (m, 3H), 3.82-3.88 (m, 1H), 3.75 (d, 1H, J = 7.1 Hz, H),

3.72 (s, 3H); 13C NMR (100 MHz, CDCl3): 171.3, 134.2, 128.9, 128.8, 128.1, 104.6 (C2), 65.4

(C3+C4), 56.6 (C), 52.4 (OCH3). HRMS (ESI), found: 245.0782 (MNa+); calcd for C12H14O4Na:

245.0790.


20

O

OCOOMe

Ph

9

2

4

5

O

OCOOMe

Ph

9

2

4

5


21

1.95

0.57

1.00

0.27

3.71

3.86

4.74

4.89

OO O

n

+

O

O4.89 ppm

3.86 ppm

4.74 ppm

3.71 ppm


22

Diisopropylether



phenyldiazoacetate 7.7 min, products 10 8.8 min.

Enantioselectivities were determined by HPLC. Column: Chiralcel IA; 0.46 cm × 25 cm. Eluent:

hexane/chloroform (95/5), 0.5 mL/min. Retention times: 10 (enantiomer 1) 17.4 min, 10

(enantiomer 2) 19.6 min.

Methyl -(isopropoxy)phenylacetate (10): 1H NMR (400 MHz, CDCl3): 7.45 (m, 2H), 7.34 (m,

3H), 5.00 (s, 1H, H), 3.71 (s, 3H), 3.67 (m, 1H, OCHMe2), 1.25 (d, 3H, J = 6.1 Hz), 1.20 (d, 3H,

J = 6.1 Hz); 13C NMR (100 MHz, CDCl3): 172.1, 137.4, 128.7, 128.6, 127.3, 78.6 (C), 71.1

(OCHMe2), 52.4 (OCH3), 22.3, 22.1.

7.22

3.99

1.00

2.91

1.95

1.19

1.21

1.24

1.26

3.66

3.67

3.69

3.71

5.00

7.33

7.34

7.36

7.45

7.45

7.47


23

22.0

922

.30

52.3

6

71.0

676

.84

77.1

677

.48

78.6

1

127.

2612

8.61

128.

69

137.

36

172.

10

Ph COOMe

O 10


24

Semi-preparative HPLC

Resolution of steroisomers by semi-preparative HPLC was carried out from racemic

mixtures obtained by reaction of methyl phenyldiazoacetate with THF or THP catalyzed by

Rh2(OAc)4.8

THF

The crude was purified by column chromatography on silica gel using n-hexane/diethyl

ether (7/3) as an eluent, allowing isolation of 3 and a mixture 3+4. Two semi-preparative HPLC

resolutions were carried out using a a 250 × 20 mm ID Chiralpak® IB column and a mixture n-

hexane/2-propanol (99.5/0.5) as mobile phase at a flow rate of 16 mL/min. 130 mg of racemic 3

were dissolved in 1.4 mL of n-hexane/2-propanol (99.5/0.5) and introduced into the column by

successive injections of 0.1 mL (every 30 minutes). Three separate fractions were collected. 3S

(38 mg) and 3R (36 mg) were obtained in enantiopure form in fractions 1 and 3 respectively.

The mixture of stereoisomers 3+4 (400 mg) was dissolved in 2 mL of the same mixture of

solvents and introduced into the column by successive injections of 0.1 mL (every 30 min).

Seven fractions were collected, and both enantiomers of 4 were obtained from the fifth (20 mg)

and seventh (10 mg) fractions.

(2R,S)-3S: −88.1 (c 0.159, CHCl3).

(2S,R)-3R: +78.1 (c 0.167, CHCl3).

First eluted like enantiomer 4: −19.3 (c 0.7, CHCl3).

Second eluted like enantiomer 4: +18.6 (c 0.7, CHCl3).

THP

The crude was purified by column chromatography on silica gel using n-hexane/ethyl

acetate (9/1) as an eluent, allowing isolation of 5 and a mixture 5+6. Two semi-preparative

HPLC resolutions were carried out using a 250 × 20 mm ID Chiralpak® IA column and a mixture

n-hexane/ethanol (99.8/0.2) as mobile phase at a flow rate of 16 mL/min. 90 mg of racemic 5

were dissolved in 0.9 mL of n-hexane/ethanol (1/1) and introduced into the column by

successive injections of 0.1 mL (every 12 minutes). Three separate fractions were collected. 5S

(20 mg) and 5R (30 mg) (tentatively assigned) were obtained in enantiopure form in fractions 1

and 3 respectively. The mixture of stereoisomers 5+6 (70 mg) was dissolved in 1.5 mL of n-

hexane/ethanol (1/1) and introduced into the column by successive injections of 0.1 mL (every

32 minutes). Seven fractions were collected but it was not possible to separate both

enantiomers of 6. Only in the seventh fraction 5 mg of a 5/95 mixture of both enantiomers were

obtained.

(2R,S)-5S: −76.4 (c 0.55, CCl4).

(2S,R)-5R: +78.2 (c 0.75, CCl4).

8 Reaction conditions: 0.086 mmol Rh2(OAc)4, 40 mL THF (or THP) under reflux, slow addition of a solution of methyl phenyldiazoacetate (4 mmol) in 20 mL THF (or THP).


enantioselective c-h carbene insertions with homogeneous ... · enantioselective c-h carbene...

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