Supporting Information

Design and Synthesis of Pinacolylboronate-Containing

Combretastatin( antimitotic agent) Analogues
Bhaskar C. Das a, b, * , Sakkarapalayam M . Mahalingam b, Todd Evans ,c
Departments of aNuclear Medicine, bDevelopmental & Molecular Biology ,Albert Einstein
College of Medicine, NY-10461. cDepartment of Surgery, Weill Cornell Medical College,
Cornell University, New York, NY-10021.

bdas@aecom.yu.edu
General considerations.S2
Preparation of the 4-(4,4,5,5-tetramethyl-1,3,2-dioxaboratophenyl)-methyl
triphenylphosphonium bromide (11).S2
Wittig Reaction of Aldehydes with ylide 11 (1a-f, 7a and 7b).S3-S7
NMR spectra of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaboratophenyl)-methyl
triphenylphosphonium bromide (11).....S8-S9
NMR spectra of compounds 1a-f....S9-S15
NMR spectra of compounds 7a (via approach B)....S15-S16
NMR spectra of compounds 7b....S17-S18
NMR spectra of compounds 7a (via approach A)....S18-S19

General
All reagents were purchased from commercial sources and used
without treatment, unless otherwise indicated. The products were
purified by column chromatography over silica gel. 1H NMR and

13

NMR spectra were recorded at 25 C at 300 MHz and 75 MHz,

respectively, with TMS as internal standard. Abbreviations for signal
coupling are as follows: s, singlet; d, doublet; t, triplet; q, quartet; m,
multiplet; br, broad. Column chromatography was performed using
SiO2 (0.040 0.063 mm, 230 400 mesh ASTM) from Merck. All
reagents were obtained from commercial sources. Mass spectra were
recorded on Varian MS mass spectrometer.
Preparation of the 4-(4,4,5,5-tetramethyl-1,3,2-dioxaboratophenyl)-methyl
triphenylphosphonium bromide (11)

O
BO
PPh3.Br
11

A mixture of 2-[4/-(bromomethyl)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (11)

(4 g, 1.0 mmol) and triphenylphosphine (3.568 g, 1.01 mmol) in acetonitrile (40 mL) was
heated in an oil bath at 90 oC. After 12 h, the reaction mixture was cooled to rt and then
the solvent was evaporated and dried under high vacuum to obtain the crude compound 8,
then triturated with diethyl ether (3 X 5 mL) to obtain the desired pure compound 8 as a
white solid (6.92 g, 92% yield). 1H NMR (300 MHz, CDCl3): 1.32 (s, 12H), 5.36-5.42
(d, J = 18 Hz, 2H), 7.03-7.10 (m, 2H), 7.53-7.57 (d, J = 2 Hz), 7.57-7.66 (m, 6H), 7.667.82 (m, 9H). 13C NMR (75 MHz, CDCl3): 25.3, 84.4, 117.5, 118.8, 130.5, 130.6,
131.2, 131.3, 134.7, 134.8, 135.4. HRMS (ESI): m/z calcd. for C31H33BO2P [M]+
479.2311, found 479.2323.
2

O
B

Cl
OH
Cl

1a; E : Z = 42 : 58

2-Hydroxy-3,5-dichloro-4/-(4,4,5,5-Tetramethyl-1,3,2-

dioxaborolan-2-yl)stilbene (1a).
3,5-Dichloro-2-hydroxy-benzaldehyde (0.05 g, 0.26 mmol) was added to a solution of 4(4,4,5,5-tetramethyl-1,3,2-dioxaboratophenyl)-methyl

triphenylphosphonium

bromide

(11) (0.146 g, 0.26 mmol) in anhydrous DMF (7 mL) under nitrogen atmosphere. Sodium
tert-butanolate (0.075 g, 0.78 mmol) was added to the clear solution at room temperature,
and the mixture was stirred for 12 h. The reaction mixture was poured into water (20 mL)
and neutralized with 1 M HCl. Then the resulting mixture was extracted by EtOAc (3 X
10 mL), washed with H2O and brine, dried over anhydrous Na2SO4 and filtered.
Evaporation of the solvent followed by column chromatography on silica gel to obtain
the pure product 1a as a mixture of E/Z. Yield: 0.083 g (81%). 1H NMR (300 MHz,
CDCl3): 1.36 (s), 1.38 (s), 5.65 (s), 5.86 (s), 6.55-6.65 (m), 6.75-6.81 (d, J = 18 Hz),
7.06-7.08 (d, J = 6 Hz), 7.17 (s), 7.18-7.26 (m), 7.32-7.38 (m), 7.43 (s), 7.50-7.52 (d, J =
6 Hz), 7.53-7.57 (d, J = 12 Hz), 7.61-7.73 (m), 7.82-7.85 (d, J = 6 Hz). 13C NMR (75
MHz, CDCl3):

25.3, 84.3, 121.0, 122.7, 124.1, 125.2, 125.5, 125.7, 125.9, 126.2,

126.5, 127.5, 127.7, 128.4, 129.0, 129.2, 132.0, 134.1, 135.2, 135.6, 139.0, 139.8, 148.8,
148.9. HRMS (ESI): m/z calcd. for C20H21BCl2O3 [M+Na]+ 413.0858, found 413.0860.
Wittig reaction of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaboratophenyl)-methyl
triphenylphosphonium bromide (11) with various aldehydes (Table 1)

O
B
O

H
1b

E:Z = 74: 26

4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)stilbene

(1b).
Benzaldehyde (0.05 g, 0.47 mmol) was added to a solution of 4-(4,4,5,5-tetramethyl1,3,2-dioxaboratophenyl)-methyl triphenylphosphonium bromide (11) (0.262 g, 0.47
mmol) in anhydrous DMF (7 mL) under nitrogen atmosphere. Sodium tert-butanolate
(0.135 g, 1.41 mmol) was added to the clear solution at room temperature, and the
mixture was stirred for 4 h. The reaction mixture was poured into water (20 mL) and
neutralized with 1 M HCl. Then the resulting mixture was extracted by EtOAc (3 X 10
mL), washed with H2O and brine, dried over anhydrous Na2SO4 and filtered. Evaporation
of the solvent followed by column chromatography on silica gel to obtain the pure
product 1b as a mixture of E/Z. Yield: 0.124 g (86%). 1H NMR (300 MHz, CDCl3):
1.36 (s), 1.38 (s), 6.59-6.68 (m), 7.10-7.30 (m), 7.33-7.40 (m), 7.50-7.58 (m), 7.67-7.70
(d, J = 9 Hz), 7.81-7.84 (d, J = 9 Hz). 13C NMR (75 MHz, CDCl3): 25.3, 84.2, 126.2,
127.0, 127.6, 128.6, 129.1, 129.3, 130.6, 131.3, 135.1, 135.6, 137.5, 137.6, 139.5, 140.0.
HRMS (ESI): m/z calcd. for C20H23BO2 [M+Na]+ 329.1689, found 329.1684.

HO
B
HO

H
1c

O
B
O

E:Z = 64 : 36

4-(Boronic

acid)-4/-(4,4,5,5-Tetramethyl-1,3,2-

dioxaborolan-2-yl)stilbene (1c).
4-formylphenylboronic acid (0.05 g, 0.33 mmol) was added to a solution of 4-(4,4,5,5tetramethyl-1,3,2-dioxaboratophenyl)-methyl triphenylphosphonium bromide (11) (0.184
g, 0.33 mmol) in anhydrous DMF (7 mL) under nitrogen atmosphere. Sodium tertbutanolate (0.062 g, 0.99 mmol) was added to the clear solution at room temperature, and
the mixture was stirred for 4 h. The reaction mixture was poured into water (20 mL) and
neutralized with 1 M HCl. Then the resulting mixture was extracted by EtOAc (3 X 10
mL), washed with H2O and brine, dried over anhydrous Na2SO4 and filtered. Evaporation
of the solvent followed by column chromatography on silica gel to obtain the pure
4

product 1c as a mixture of E/Z. Yield: 0.084 g (72%). 1H NMR (300 MHz, CDCl3):
1.36 (s), 1.39 (s), 7.20 (s), 2.90-2.97 (d, J = 21 Hz), 6.61-6.80 (m), 7.18-7.34 (m), 7.347.45 (m), 7.50-7.80 (m), 7.80-7.90 (m), 8.05-8.18 (m), 8.18-8.25 (m). 13C NMR (75 MHz,
CDCl3):

25.3, 84.2, 126.4, 125.5, 128.6, 128.9, 129.1, 129.2, 130.5, 130.6, 131.0,

135.0, 135.1, 1235.6, 135.9, 140.0, 141.8, 163.2. HRMS (ESI): m/z calcd. for C 20H24B2O4
[M+Na]+ 373.1758, found 373.1757.

OH

H
1d

O
B
O
E:Z = 75 : 25

3,5-Di-tert-butyl-2-hydroxy-4/-(4,4,5,5-Tetramethyl-

1,3,2-dioxaborolan-2-yl)stilbene (1d).
3,5-Di-tert-butyl-2-hydroxy-benzaldehyde (0.05 g, 0.21 mmol) was added to a solution of
4-(4,4,5,5-tetramethyl-1,3,2-dioxaboratophenyl)-methyl triphenylphosphonium bromide
(11) (0.119 g, 0.21 mmol) in anhydrous DMF (7 mL) under nitrogen atmosphere. Sodium
tert-butanolate (0.061 g, 0.63 mmol) was added to the clear solution at room temperature,
and the mixture was stirred for 12 h. The reaction mixture was poured into water (20 mL)
and neutralized with 1 M HCl. Then the resulting mixture was extracted by EtOAc (3 X
10 mL), washed with H2O and brine, dried over anhydrous Na2SO4 and filtered.
Evaporation of the solvent followed by column chromatography on silica gel to obtain
the pure product 1d as a mixture of E/Z. Yield: 0.065 g (71%). 1H NMR (300 MHz,
CDCl3): 1.28 (s), 1.33 (s), 1.35 (s), 1.36 (s), 1.38 (s), 1.47 (s), 5.18 (s), 5.19 (s), 6.606.80 (m), 7.00-7.10 (m), 7.20-7.25 (m), 7.25-7.38 (m), 7.40 (s), 7.54-7.58 (d, J = 12 Hz),
7.63-7.68 (m), 7.71-7.74 (d, J = 9 Hz), 7.82-7.85 9d, J = 9 Hz). 13C NMR (75 MHz,
CDCl3): 25.3, 30.3, 32.0, 35.0, 35.3, 84.3, 122.8, 124.1, 125.5, 126.1, 128.6, 128.8,
129.0, 132.4, 134.0, 135.0, 135.2, 135.6, 136.0, 140.5, 143.7, 150.2. HRMS (ESI): m/z
calcd. for C28H39BO3 [M+Na]+ 457.2890, found 457.2955.

O2 N

OH

O
B
O

H
1e

E:Z = 55 : 45

2-Hydroxy-5-nitro-4/-(4,4,5,5-Tetramethyl-1,3,2-

dioxaborolan-2-yl)stilbene (1e).
2-hydroxy-5-nitrobenzaldehyde (0.05 g, 0.30 mmol) was added to a solution of 4(4,4,5,5-tetramethyl-1,3,2-dioxaboratophenyl)-methyl

triphenylphosphonium

bromide

(11) (0.167 g, 0.30 mmol) in anhydrous DMF (7 mL) under nitrogen atmosphere. Sodium
tert-butanolate (0.086 g, 0.90 mmol) was added to the clear solution at room temperature,
and the mixture was stirred for 12 h. The reaction mixture was poured into water (20 mL)
and neutralized with 1 M HCl. Then the resulting mixture was extracted by EtOAc (3 X
10 mL), washed with H2O and brine, dried over anhydrous Na2SO4 and filtered.
Evaporation of the solvent followed by column chromatography on silica gel to obtain
the pure product 1e as a mixture of E/Z. Yield: 0.083 g (76%). 1H NMR (300 MHz,
CDCl3): 1.34 (s), 1.38 (s), 5.65 (s), 6.57-6.62 (d, J = 15 Hz), 6.88-7.00 (m), 7.15-7.19
(d, J = 12 Hz), 7.25-7.30 (m), 7.38-7.44 (d, J = 18 Hz), 7.56-7.59 (d, J = 9 Hz), 7.67-7.70
(d, J = 9 Hz), 7.83-7.86 (d, J = 9 Hz), 8.04-8.06 (d, J = 6 Hz), 8.06-8.10 (m), 8.10-8.17
(m), 8.47-8.49 (d, J = 6 Hz). 13C NMR (75 MHz, CDCl3): 25.3, 84.4, 116.1, 116.3,
121.8, 132.1, 123.5, 124.6, 125.5, 126.0, 126.7, 126.9, 128.1, 133.2, 135.4, 135.5, 135.9,
138.2, 139.5, 142.2, 142.5, 158.6, 158.8. HRMS (ESI): m/z calcd. for C20H22BNO5
[M+Na]+ 390.1489, found 390.1502.

H
1f

O
B
O
E:Z = 100 : 0

4-{2-[4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-

phenyl]-vinyl}-pyridine (1f).
Pyridine-4-carbaldehyde (0.05 g, 0.47 mmol) was added to a solution of 4-(4,4,5,5tetramethyl-1,3,2-dioxaboratophenyl)-methyl triphenylphosphonium bromide (11) (0.263
g, 0.47 mmol) in anhydrous DMF (7 mL) under nitrogen atmosphere. Sodium tertbutanolate (0.135 g, 1.41 mmol) was added to the clear solution at room temperature, and
the mixture was stirred for 4 h. The reaction mixture was poured into water (20 mL) and

neutralized with 1 M HCl. Then the resulting mixture was extracted by EtOAc (3 X 10
mL), washed with H2O and brine, dried over anhydrous Na2SO4 and filtered. Evaporation
of the solvent followed by column chromatography on silica gel to obtain the pure
product 1f as a mixture of E/Z. Yield: 0.112 g (78%). 1H NMR (300 MHz, CDCl3):
1.36 (s), 6.52-6.57 (d, J = 15 Hz), 6.80-6.85 (d, J = 15 Hz), 7.10-7.12 (d, J = 6 Hz), 7.227.25 (d, J = 9 Hz), 7.69-7.72 (d, J = 9 Hz), 8.45-8.47 (d, J = 6 Hz). 13C NMR (75 MHz,
CDCl3): 25.3, 84.3, 124.0, 128.8, 129.0, 134.5, 135.3, 139.7, 145.6, 150.4. HRMS
(ESI): m/z calcd. for C19H22BNO2 [M+H]+ 308.1822, found 308.1816.

MeO
MeO
MeO

O
B
O
7a E:Z = 67: 33

4,4,5,5-Tetramethyl-2-{4-[2-(3,4,5-trimethoxy-

phenyl)-vinyl]-phenyl}-[1,3,2]dioxaborolane (7a).
3,4,5-trimethoxy benzaldehyde (12a) (0.100 g, 0.50 mmol) was added to a solution of 4(4,4,5,5-tetramethyl-1,3,2-dioxaboratophenyl)-methyl

triphenylphosphonium

bromide

(11) (0.285 g, 0.50 mmol) in anhydrous DMF (7 mL) under nitrogen atmosphere. Sodium
tert-butanolate (0.147 g, 1.52 mmol) was added to the clear solution at room temperature,
and the mixture was stirred for 2 h. The reaction mixture was poured into water (20 mL)
and neutralized with 1 M HCl. Then the resulting mixture was extracted by EtOAc (3 X
10 mL), washed with H2O and brine, dried over anhydrous Na2SO4 and filtered.
Evaporation of the solvent followed by column chromatography on silica gel to obtain
the pure product 7a as a mixture of E/Z. Yield: 0.173 g (88%). 1H NMR (300 MHz,
CDCl3): 1.36 (s), 1.38 (s), 3.67 (s), 3.85 (s), 3.89 (s), 3.94 (s), 6.48 (s), 6.50-6.65 (m),
6.77 (s), 6.98-7.18 (m), 7.30-7.35 (d, J = 12 Hz), 7.51-7.55 (d, J = 12 Hz), 7.69-7.74 (d, J
= 15 Hz), 7.81-7.84 (d, J = 9 Hz). 13C NMR (75 MHz, CDCl3): 25.3, 56.1, 56.8, 61.5,
84.4, 103.7, 106.6, 125.5, 127.0, 127.2, 127.4, 129.0, 129.3, 129.5, 130.1, 133.2, 134.5,
135.0, 140.4, 154.6. C23H29BO5 [M+Na]+ 419.2006, found 419.2087.

MeO

O
B
O
7b E:Z = 97: 3

2-{4-[2-(4-Methoxy-phenyl)-vinyl]-phenyl}-4,4,5,5-

tetramethyl-[1,3,2]dioxaborolane (7b).
4-methoxy benzaldehyde (12b) (0.05 g, 0.37 mmol) was added to a solution of 4(4,4,5,5-tetramethyl-1,3,2-dioxaboratophenyl)-methyl

triphenylphosphonium

bromide

(11) (0.207 g, 0.37 mmol) in anhydrous DMF (7 mL) under nitrogen atmosphere. Sodium
tert-butanolate (0.106 g, 1.11 mmol) was added to the clear solution at room temperature,
and the mixture was stirred for 2 h. The reaction mixture was poured into water (20 mL)
and neutralized with 1 M HCl. Then the resulting mixture was extracted by EtOAc (3 X
10 mL), washed with H2O and brine, dried over anhydrous Na2SO4 and filtered.
Evaporation of the solvent followed by column chromatography on silica gel to obtain
the pure product 7b as a mixture of E/Z. Yield: 0.101 g (82%). 1H NMR (300 MHz,
CDCl3): 1.36 (s), 1.37 (s), 3.85 (s), 6.90-6.94 (d, J = 9 Hz), 6.97-7.02 (d, J = 15 Hz),
7.13-7.18 (d, J = 15 Hz), 7.46-7.53 (m), 7.78-7.82 (d, J = 9 Hz). 13C NMR (75 MHz,
CDCl3):

25.3, 56.1, 84.5, 115.2, 125.8, 126.8, 128.5, 129.8, 130.0, 135.1, 141.2,

159.8. C21H25BO3 [M+Na]+ 337.1975, found 337.1986.

O
B

PPh3.Br

11

O
B

PPh 3.Br

11

O
B

Cl
OH
Cl

1a; E : Z = 42 : 58

10

O
B
O

Cl

H
Cl

OH

1a

O
B
O
H
1b

11

O
B
O
H
1b

O
B
O

HO
B
HO

H
1c

12

HO
B
HO

O
B
O

1c

OH

13

O
B
O

H
1d

OH

O
B
O

H
1d

O
B
O

O2N

H
OH

14

1e

O
B
O

O2N

H
OH

1e

O
B
O

H
1f

15

O
B
O

H
1f

MeO

O
B
O

MeO
MeO

7a

16

MeO

O
B
O

MeO
MeO

7a

MeO

O
B
O

MeO
MeO

7a

17

O
B
O

MeO
7b

O
B
O

MeO
7b

18

O
B
O

MeO
7b

via approach A

MeO

O
B
O

MeO
MeO

7a

E : Z = 50 : 50

19

via approach A

MeO

O
B
O

MeO
MeO

7a

E : Z = 50 : 50

20