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

1

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

C

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): δ 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): δ 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

2- dioxaborolan-2-yl)stilbene (1a). 3. 84.32-7.65 (m).6. found 413. E : Z = 42 : 58 2-Hydroxy-3. for C20H21BCl2O3 [M+Na]+ 413.9.18-7.5. 125. The reaction mixture was poured into water (20 mL) and neutralized with 1 M HCl.65 (s). Wittig reaction of 4-(4.9. 7. CDCl3): δ 25.52 (d.5-tetramethyl-1.43 (s).O B O Cl OH Cl 1a.53-7.36 (s).1.85 (d.05 g. 127.26 mmol) was added to a solution of 4(4. 129. 122. 0.0860.78 mmol) was added to the clear solution at room temperature.5. Sodium tert-butanolate (0. 139.0.3.146 g.2-dioxaboratophenyl)-methyl triphenylphosphonium bromide (11) with various aldehydes (Table 1) 3 .0858.26 (m). and the mixture was stirred for 12 h.38 (s). J = 6 Hz). 7. 1. 0.73 (m). 128.2.4.8.2.0.17 (s). 7.5-tetramethyl-1. 7.3. 5.5. 135. 1H NMR (300 MHz. 5. CDCl3): δ 1. 13C NMR (75 MHz. 7. 7.50-7.08 (d.06-7. 7.7.2. 125. 0. 134.083 g (81%). Yield: 0. 148.38 (m).2.4. 126.81 (d. J = 6 Hz).82-7. 6.4.5-Dichloro-2-hydroxy-benzaldehyde (0. 121. dried over anhydrous Na2SO4 and filtered.5-Tetramethyl-1.61-7. washed with H2O and brine.4. Evaporation of the solvent followed by column chromatography on silica gel to obtain the pure product 1a as a mixture of E/Z. 124.3.2-dioxaboratophenyl)-methyl triphenylphosphonium bromide (11) (0. 6. 125.5.57 (d.55-6.7. J = 6 Hz). 7. 125.7. 132.5. J = 18 Hz).75-6.26 mmol) in anhydrous DMF (7 mL) under nitrogen atmosphere.075 g. 126. J = 12 Hz).1. HRMS (ESI): m/z calcd.5-dichloro-4/-(4.0. 135.3.0. 139. 129. 127.8. Then the resulting mixture was extracted by EtOAc (3 X 10 mL). 7. 148.86 (s).5.3.

062 g. Evaporation of the solvent followed by column chromatography on silica gel to obtain the pure 4 . 6.05 g. Evaporation of the solvent followed by column chromatography on silica gel to obtain the pure product 1b as a mixture of E/Z.2.68 (m). The reaction mixture was poured into water (20 mL) and neutralized with 1 M HCl. 84.5.2-dioxaborolan-2-yl)stilbene (1b).59-6. found 329.5.50-7.0. Then the resulting mixture was extracted by EtOAc (3 X 10 mL).4. for C20H23BO2 [M+Na]+ 329. washed with H2O and brine. HRMS (ESI): m/z calcd. 135. washed with H2O and brine. 13C NMR (75 MHz.40 (m).38 (s).2-dioxaboratophenyl)-methyl triphenylphosphonium bromide (11) (0.70 (d. 7.3. Then the resulting mixture was extracted by EtOAc (3 X 10 mL).124 g (86%).3. 0. 131.10-7. Sodium tertbutanolate (0.05 g. 129. 7. 1.6. and the mixture was stirred for 4 h.58 (m).5. dried over anhydrous Na2SO4 and filtered. HO B HO H 1c O B O E:Z = 64 : 36 4-(Boronic acid)-4/-(4.99 mmol) was added to the clear solution at room temperature. 135.33-7.6.3.67-7.6. The reaction mixture was poured into water (20 mL) and neutralized with 1 M HCl.5. and the mixture was stirred for 4 h. 1H NMR (300 MHz.47 mmol) was added to a solution of 4-(4.5.30 (m). 0.3. 7.47 mmol) in anhydrous DMF (7 mL) under nitrogen atmosphere.2- dioxaborolan-2-yl)stilbene (1c). 128.84 (d. 127. 7.5. 129. 126.6.4.3. CDCl3): δ 1.1689.5-Tetramethyl-1. 137. J = 9 Hz).O B O H 1b E:Z = 74: 26 4-(4. CDCl3): δ 25. 4-formylphenylboronic acid (0.135 g.1.6.184 g.33 mmol) in anhydrous DMF (7 mL) under nitrogen atmosphere. 0.4. Sodium tert-butanolate (0. 140. J = 9 Hz). 0.5-Tetramethyl-1.33 mmol) was added to a solution of 4-(4.81-7.41 mmol) was added to the clear solution at room temperature. 0.2.36 (s). 137.5tetramethyl-1. 7. Yield: 0. Benzaldehyde (0.0.4.2-dioxaboratophenyl)-methyl triphenylphosphonium bromide (11) (0. 130.3. 139.3.1684. 1. 127. dried over anhydrous Na2SO4 and filtered.262 g.5-tetramethyl1.1.

for C 20H24B2O4 [M+Na]+ 373.0.1.40 (s). 135.8.5. for C28H39BO3 [M+Na]+ 457. 7.347. 135.21 mmol) was added to a solution of 4-(4.0. Sodium tert-butanolate (0. Yield: 0.6. 131.18-7. 7. 7.36 (s). 1. 84.3.0.33 (s).2955. 8.05-8.2.6. 2. 7.9.5. 13C NMR (75 MHz. J = 9 Hz). J = 12 Hz).2. 1. 7.3.0. 125.80-7.36 (s).20-7. 126. 1. 7. The reaction mixture was poured into water (20 mL) and neutralized with 1 M HCl.1. 129. 6.5-Di-tert-butyl-2-hydroxy-benzaldehyde (0.2. Then the resulting mixture was extracted by EtOAc (3 X 10 mL).9. 150.5. 128. 134.20 (s).18 (m). washed with H2O and brine. 0.5. CDCl3): δ 1.2890. 129. CDCl3): δ 1. 135.21 mmol) in anhydrous DMF (7 mL) under nitrogen atmosphere. 124.606. 84.2-dioxaboratophenyl)-methyl triphenylphosphonium bromide (11) (0.5-Di-tert-butyl-2-hydroxy-4/-(4.2. CDCl3): δ 25. 140. 140.1757. Yield: 0.80 (m).1.58 (d.05 g. 135. J = 9 Hz). 130. 0.8. 13C NMR (75 MHz. J = 21 Hz). HRMS (ESI): m/z calcd. 5. 7.0.6.19 (s).85 9d. 135.34 (m).4.90 (m).061 g.54-7.1758. 135.39 (s). 125. dried over anhydrous Na2SO4 and filtered.82-7.084 g (72%).3.00-7.8. 128.6.0.4.25 (m).1. 1. 132. CDCl3): δ 25. Evaporation of the solvent followed by column chromatography on silica gel to obtain the pure product 1d as a mixture of E/Z.38 (s). 1235.45 (m).28 (s).10 (m).5-tetramethyl-1.2. 126.74 (d. 7.065 g (71%).5-Tetramethyl- 1. 136.4.80 (m). 7.63-7.0.71-7. 32.5. 7.0. 141. 30. 3. 128. found 457. OH H 1d O B O E:Z = 75 : 25 3. 128. 1.97 (d.4. found 373.25-7.3.25 (m). 35. 5.7. 7.2-dioxaborolan-2-yl)stilbene (1d).3.5. 1H NMR (300 MHz.0. 1H NMR (300 MHz.38 (m). HRMS (ESI): m/z calcd.119 g. 130.90-2. 129.3.80 (m). 122.6. 0. 5 . 143.18 (s).61-6.3.47 (s).18-8.35 (s). 7.50-7. 35. 1. and the mixture was stirred for 12 h.63 mmol) was added to the clear solution at room temperature. 6.product 1c as a mixture of E/Z. 7. 163.68 (m). 8.

5. 7.5.04-8.4. Sodium tert-butanolate (0. 138. 0. 133.57-6. 13C NMR (75 MHz.15-7.38-7. 135.2. J = 9 Hz).5. found 390.8. 1. 0. 7.25-7.3. 8. N H 1f O B O E:Z = 100 : 0 4-{2-[4-(4.086 g. 0.3. 142.34 (s).1. dried over anhydrous Na2SO4 and filtered.5. 6.3. for C20H22BNO5 [M+Na]+ 390. 135. 158.90 mmol) was added to the clear solution at room temperature.06 (d.05 g.56-7.86 (d.30 mmol) was added to a solution of 4(4. J = 9 Hz).5.70 (d. J = 15 Hz).1502.135 g.5-Tetramethyl-1.3.6.19 (d.67-7. 5. CDCl3): δ 25. 158.83-7.17 (m).10 (m).4.2-dioxaboratophenyl)-methyl triphenylphosphonium bromide (11) (0. 7. 116.1. 0.5. 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. The reaction mixture was poured into water (20 mL) and 6 .06-8.3. 126.5-tetramethyl-1.2- dioxaborolan-2-yl)stilbene (1e). 7. 124.2.1. 84. 1H NMR (300 MHz. washed with H2O and brine. 7.6.00 (m). 7.4.4.47 mmol) was added to a solution of 4-(4.44 (d. 126. 121.62 (d.1489.30 mmol) in anhydrous DMF (7 mL) under nitrogen atmosphere.5.4.083 g (76%). 8.5-Tetramethyl-[1.0.3. 1.2]dioxaborolan-2-yl)- phenyl]-vinyl}-pyridine (1f). and the mixture was stirred for 12 h.5. and the mixture was stirred for 4 h. 6. 2-hydroxy-5-nitrobenzaldehyde (0.2.5. 142.O2 N OH O B O H 1e E:Z = 55 : 45 2-Hydroxy-5-nitro-4/-(4.9. 135. 139.47-8. Pyridine-4-carbaldehyde (0.10-8. J = 6 Hz). 0.9.8. J = 18 Hz). 116.41 mmol) was added to the clear solution at room temperature. 123.5tetramethyl-1. 126.7. 125. J = 9 Hz). Then the resulting mixture was extracted by EtOAc (3 X 10 mL).59 (d.05 g. Sodium tertbutanolate (0. J = 6 Hz).263 g.38 (s).30 (m). CDCl3): δ 1. 132.49 (d.167 g. J = 12 Hz). 8.2-dioxaboratophenyl)-methyl triphenylphosphonium bromide (11) (0. HRMS (ESI): m/z calcd. The reaction mixture was poured into water (20 mL) and neutralized with 1 M HCl.4. 8.88-7.65 (s). 128.47 mmol) in anhydrous DMF (7 mL) under nitrogen atmosphere.

69-7.84 (d.36 (s). 6. Evaporation of the solvent followed by column chromatography on silica gel to obtain the pure product 1f as a mixture of E/Z. CDCl3): δ 25. J = 9 Hz). Sodium tert-butanolate (0.8. 129. 140.7. 7. 56. 7. 13C NMR (75 MHz. 7.5. 3. 3.45-8. 135.94 (s). 103.112 g (78%). C23H29BO5 [M+Na]+ 419. CDCl3): δ 25. 13C NMR (75 MHz.7. 6.50 mmol) in anhydrous DMF (7 mL) under nitrogen atmosphere. J = 9 Hz).6.98-7.4.3. 127.55 (d.0. 1H NMR (300 MHz.5. 0. 0.3.72 (d.4.147 g.5.2006.2]dioxaborolane (7a).77 (s). 7.173 g (88%). 150. washed with H2O and brine.2. 145. Then the resulting mixture was extracted by EtOAc (3 X 10 mL). 84. 124.48 (s). J = 12 Hz). J = 15 Hz). 127. 3. washed with H2O and brine.85 (s).65 (m). 129.1816. 1.1.50 mmol) was added to a solution of 4(4. 1H NMR (300 MHz. J = 15 Hz).4. Yield: 0.5.1822. dried over anhydrous Na2SO4 and filtered.285 g. 125. 154. 128. dried over anhydrous Na2SO4 and filtered. The reaction mixture was poured into water (20 mL) and neutralized with 1 M HCl. CDCl3): δ 1.100 g.0. 6.18 (m).36 (s). HRMS (ESI): m/z calcd. 129. 106. found 419.5-Tetramethyl-2-{4-[2-(3. and the mixture was stirred for 2 h. Evaporation of the solvent followed by column chromatography on silica gel to obtain the pure product 7a as a mixture of E/Z.3.4. 56.8.80-6. 7 .67 (s).5-trimethoxy benzaldehyde (12a) (0.0. 6. 129.6.3. MeO MeO MeO O B O 7a E:Z = 67: 33 4. for C19H22BNO2 [M+H]+ 308. 130.50-6.0. Yield: 0. 7.5.neutralized with 1 M HCl.3.5. 84.3. 6. J = 15 Hz).52 mmol) was added to the clear solution at room temperature. J = 12 Hz).5.74 (d.4.52-6.38 (s). 7. 1.6. 134. 127.35 (d.5-tetramethyl-1.5-trimethoxy- phenyl)-vinyl]-phenyl}-[1. J = 9 Hz). J = 6 Hz). 3.4. found 308. 7.0.81-7.51-7.25 (d.57 (d.1. 135.3. 133.47 (d.12 (d.10-7.2087. 3.69-7.2. Then the resulting mixture was extracted by EtOAc (3 X 10 mL).30-7.4.85 (d. 139.227. 134. 6.4.89 (s). 8. J = 6 Hz).2-dioxaboratophenyl)-methyl triphenylphosphonium bromide (11) (0. 61. CDCl3): δ 1.

Then the resulting mixture was extracted by EtOAc (3 X 10 mL). CDCl3): δ 1.5. 1. C21H25BO3 [M+Na]+ 337. 7. 1.3. 0.3. 8 .05 g.1.5. 129.46-7.4. 6. 141.53 (m). CDCl3): δ 25.02 (d. J = 15 Hz). 115. 7.18 (d. 130.3. Yield: 0.0.8.4. 159. J = 9 Hz).13-7.82 (d.101 g (82%).2. 1H NMR (300 MHz.97-7.90-6.78-7. 13C NMR (75 MHz. dried over anhydrous Na2SO4 and filtered.1986.11 mmol) was added to the clear solution at room temperature. The reaction mixture was poured into water (20 mL) and neutralized with 1 M HCl. J = 9 Hz).37 (s). 4-methoxy benzaldehyde (12b) (0. Evaporation of the solvent followed by column chromatography on silica gel to obtain the pure product 7b as a mixture of E/Z. 3.5. 7. J = 15 Hz).37 mmol) was added to a solution of 4(4. Sodium tert-butanolate (0.94 (d.8.207 g. 125.8.2]dioxaborolane (7b).36 (s).8.5-tetramethyl-1. found 337.85 (s).5- tetramethyl-[1. 56. 6.5. 135. 84.MeO O B O 7b E:Z = 97: 3 2-{4-[2-(4-Methoxy-phenyl)-vinyl]-phenyl}-4. 126.37 mmol) in anhydrous DMF (7 mL) under nitrogen atmosphere. 0. and the mixture was stirred for 2 h.2.1975.106 g.1. washed with H2O and brine. 128.2-dioxaboratophenyl)-methyl triphenylphosphonium bromide (11) (0.

O B O PPh3.Br 11 9 .

Br 11 O B O Cl OH Cl 1a.O B O PPh 3. 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 H 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 N H 1f 15 .

O B O N 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 .