Alternate and step-economic synthesis of the β-Methylstyrene chelating pre-ligand of the Hoveyda-Grubbs II catalyst

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Alternate and Step-Economic Synthesis
of the β-Methylstyrene Chelating Pre-
ligand of the Hoveyda-Grubbs’ II Catalyst
Sebastian O. Simonettia, Enrique L. Larghia & Teodoro S. Kaufmana
a Instituto de Química Rosario (IQUIR, CONICET-UNR) and Facultad
de Ciencias Bioquímicas y Farmacéuticas-Universidad Nacional de
Rosario, Suipacha 531, S2002LRK Rosario, Argentina
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Published online: 13 May 2015.
To cite this article: Sebastian O. Simonetti, Enrique L. Larghi & Teodoro S. Kaufman (2015) Alternate
and Step-Economic Synthesis of the β-Methylstyrene Chelating Pre-ligand of the Hoveyda-Grubbs’ II
Catalyst, Organic Preparations and Procedures International: The New Journal for Organic Synthesis,
47:3, 227-231, DOI: 10.1080/00304948.2015.1025021
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Organic Preparations and Procedures International, 47:227–231, 2015
Copyright Ó Taylor & Francis Group, LLC
ISSN: 0030-4948 print / 1945-5453 online
DOI: 10.1080/00304948.2015.1025021
OPPI BRIEF
Alternate and Step-Economic Synthesis of the
b-Methylstyrene Chelating Pre-ligand of the
Hoveyda-Grubbs’ II Catalyst
Sebastian O. Simonetti, Enrique L. Larghi,
and Teodoro S. Kaufman
ꢀ
Instituto de Quımica Rosario (IQUIR, CONICET-UNR) and Facultad de
ꢀ
Ciencias Bioquımicas y Farmaceuticas-Universidad Nacional de Rosario,
Suipacha 531, S2002LRK Rosario, Argentina
ꢀ
The Hoveyda-Grubbs (HG)1 series of olefin metathesis catalysts are more selective, recy-
clable, and heat, air and moisture stable than their predecessors.2 b-Methylstyrenes, such
as E-1-isopropoxy-2-propenylbenzene (3, Scheme 1), are cur-
rently preferred as pre-ligands for the synthesis of the second gen-
eration of the HG catalysts (HG-II),3 because they are less costly,
easier to prepare, more stable and less prone to undergo spontane-
ous polymerization or homo-dimerization than the styrenes
unsubstituted at the b-position, originally used for that purpose.4,5
Previous syntheses of compound 3 (Scheme 1), the chelating pre-ligand of HG-II and
related olefin metathesis catalysts,6 involved several steps, some of which were slow or
tedious, requiring long reaction times,3 or proceeded only in moderate yields,3 employed
high excess of alkylating agents, stoichiometric amounts of organometallic reagents,7 or
afforded undesirable E/Z mixtures of olefins.8 In addition, an approach to related b-meth-
ylstyrenes via the Wittig reaction has been found to proceed in relatively low yields, and
required the removal and disposal of large amounts of triphenylphosphine oxide; there-
fore, it was discarded as a viable route toward 3.3,7
We have recently reported an efficient one-pot sequential homo-bimetallic catalytic
propenylation of haloarenes with allyltri(n-butyl)tin under palladium catalysis and opti-
mized the reaction conditions.9,10 As a further application of this novel strategy, with
impact in fine chemistry, herein we report an alternate and convenient, step-economic
synthesis of 3, from commercial 2-halophenols 8a,b (Scheme 2).
Submitted by June 28, 2014
Address correspondence to Teodoro S. Kaufman, Instituto de Quımica Rosario (IQUIR, CONI-
ꢀ
ꢀ
ꢀ
CET-UNR) and Facultad de Ciencias Bioquımicas y Farmaceuticas Universidad Nacional de
Rosario, Suipacha 531, S2002LRK Rosario, Argentina. E-mail: kaufman@iquir-conicet.gov.ar
227

228
Kaufman et al.
Scheme 1
a) K2CO3, Cs2CO3 (cat.), i-PrI, DMF, 40ꢀC, 24–48 h (93%); b) RhCl3.3H2O (cat.), p-TsOH.H2O
(cat.), 90% aq. EtOH, reflux, 5 h (71%, E/Z D 14.3:1) or CH2=CHOTMS, Grubbs II (cat.), CH2Cl2,
35ꢀC, 24 h (66%); c) 1. (PPh3)2Cl2Ru, 70ꢀC, 17.5 h; 2. P(CH2OH)3 [> 99% (GC), E/Z D 45:55];
d) K2CO3 (2 equiv.), i-PrBr (2 equiv.), DMF, 60ꢀC, 48 h (93%); e) K2CO3, i-PrBr, DMF, 60ꢀC,
9 h; f) EtMgCl, THF, ¡15ꢀC; g) TsOH, PhMe, 90ꢀC, 1.5 h (58% overall, E/Z D 96:4).
The Williamson etherification of 8a or 8b was performed with 2-bromopropane and
K2CO3 in EtOH1 (Scheme 2), to afford 9a and 9b in 84% and 86% yield respectively,
after 5 h of heating under reflux. This contrasted with previous preparations of 9a,b
involving comparatively poor eco-friendly solvents, strong bases,12 or the relatively more
expensive isopropyl iodide.
Next, the key homo-bimetallic catalytic reaction of allyltri(n-butyl)tin with the bro-
moethers 9a,b was carried out in the presence of Pd(PPh3)2Cl2 in diglyme at 130ꢀC for
14 h. This process cleanly executed the Stille cross-coupling to the allyl intermediate3
which further underwent an in situ palladium-catalyzed conjugative double bond migra-
tion to give compound 3.
Removal of triphenylphosphine by oxidation to triphenylphosphine oxide with H2O2,13
followed by treatment of the crude extract of the reaction with an activated fluorous silica
gel phase (10% w/w),14 led to the complete elimination of all tin residues (GC-MS analysis),
affording the expected product 3 in yields of 73% and 60% from 9a and 9b, respectively.
The present two-step alternative approach to 3 complements previously reported syn-
theses of this important and valuable b-methylstyrene derivative. It can be easily carried
out in a short time transforming the sequence into a cost-competitive process, counter-
balancing the expense of the chemicals involved. The wider scope of the present route
and its adaptability to access similar compounds with various functional groups10 make it
Scheme 2
a) Me2CHBr, K2CO3, EtOH, reflux, 5h (9a, 84%; 9b, 86%); b) n-Bu3SnCH2CH=CH2, Pd
(PPh3)2Cl2, LiCl, PPh3, Diglyme, 130ꢀC, 6 h; c) 130ꢀC, 8 h (73% from 9a; 60% from 9b).

b-Methylstyrene Chelating Pre-ligand of the Hoveyda-Grubbs’ II Catalyst
229
useful for the preparation of related otherwise less accessible, pre-ligand members of this
family.15 The availability of redundant pathways for the synthesis of small molecules
with relevance in fine chemistry is always desirable, because of the potential economic
value of such compounds. This is especially critical when intellectual property protection
conditions restrict the use of the patent-protected processes.6,7
‘
Experimental Section
The reactions were carried out under dry argon atmospheres, employing oven-dried glass-
ware. Ethanol was dried by treatment with Mg turnings and a catalytic amount of I2, and
distilled from the resulting magnesium ethoxide. Diglyme was distilled from sodium ben-
zophenone ketyl.16 Anhydrous solvents were stored in dry Schlenk tubes. The remaining
reagents were used as received. The IR spectra were acquired on a Shimadzu Prestige
1
21 spectrophotometer, as thin films. The H and 13C NMR spectra were recorded at
300.13 and 75.48 MHz respectively, on a Bruker Avance 300 spectrometer, employing
CDCl3 [dH 7.26 (residual CHCl3) and dC 76.9 ppm] as internal standard. Chemical shifts
are reported in d scale and the coupling constants (J) are given in Hertz. The GC-MS data
were obtained on a Shimadzu QP2010 plus instrument (EI D 70 eV). The high resolution
MS were obtained on a Bruker MicroTOF-Q II instrument. Detection of the ions was per-
formed with electrospray ionization in positive ion mode. The compounds gave single
spots when run on Kieselgel 60 GF254 TLC plates, employing hexane-EtOAc as the sol-
vent system. The chromatographic spots were detected by exposing the plates to UV light
(254 nm), followed by spraying with p-anisaldehyde/sulfuric acid reagent in EtOH and
careful heating up to 120ꢀC.
General Procedure for the Synthesis of 1-halo-2-isopropoxybenzenes (9a and 9b)
A mixture of the 2-halophenol (8a,b 1.156 mmol), 192 mg (1.2 equiv. anhydrous K2CO3
(1.20 equiv.) and sodium iodide (4 mg) in absolute EtOH (3 mL) was magnetically
stirred at ambient temperature under argon. The 2-bromopropane (1.20 equiv.), was
added slowly and the mixture was then refluxed for 5 h, cooled to ambient temperature
prior to the removal of the solvent under reduced pressure. Addition of EtOAc (50 mL)
gave a solution which was washed successively with 1M NaOH and brine (15 mL each).
The organic phase was dried over Na2SO4, and evaporated under reduced pressure to
give a residue that was purified by flash column chromatography.
1-Bromo-2-isopropoxybenzene (9a)17
Oil; yield: 84%. IR (film): 602, 748, 953, 1030, 1107, 1275, 1385, 1472, 1587,
2978 cm¡1. 1H NMR (300 MHz, CDCl3): d 1.38 (d, J D 5.9, 6H, CHMe2), 4.55 (septet, J
D 5.9, 1H, OCHMe2), 6.81 (dt, J D 1.2 and 7.6, 1H, 3-H), 6.91 (dd, J D 0.6 and 7.9, 1H,
5-H), 7.22 (dt, J D 1.5 and 8.0, 1H, 4-H), 7.53 (dd, J D 1.6 and 7.9, 1H, 6-H). 13C NMR
(75 MHz, CDCl3): d 22.1 (Me2-CH), 72.1 (Me2¡CH), 113.8 (1-C), 115.9 (5-C), 121.9 (3-
C), 128.2 (4-C), 133.5 (6-C), 154.6 (2-C). MS (EI, 70 eV): m/z (%) 172 (100), 174 (95),
214 [M]C (25), 216 [MC2]C (25).
1-Iodo-2-isopropoxybenzene (9b)18
Oil; yield: 86%. IR (film): 648, 748, 953, 1045, 1126, 1273, 1381, 1470, 1577, 2931,
2978 cm¡1. 1H NMR (300 MHz, CDCl3): d 1.39 (d, J D 5.9, 6H, CHMe2), 4.56 (septet, J

230
Kaufman et al.
D 5.9, 1H, OCHMe2), 6.69 (dt, J D 1.6 and 8.0, 1H, 3-H), 6.85 (dd, J D 1.6 and 8.0, 1H,
5-H), 7.25 (dt, J D 1.6 and 8.0, 1H, 4-H), 7.78 (dd, J D 1.6 and 8.0, 1H, 6-H). 13C NMR
(75 MHz, CDCl3): d 22.1 (Me2-CH), 72.1 (Me2-CH), 88.6 (1-C), 114.4 (3-C), 122.5 (5-
C), 129.3 (4-C), 139.6 (6C), 156.8 (2-C). MS (EI, 70 eV): m/z (%) 65 (37), 93 (34), 220
[M-C3H6]C (100), 262 [M]C (25).
E-1-Isopropoxy-2-propenylbenzene (3)
A degassed solution containing the aryl bromide (9a, 183 mg, 0.852 mmol), anhydrous
LiCl (286 mg, 6.82 mmol), Ph3P (112 mg, 0.426 mmol) and Pd(Ph3P)2Cl2 (71.7 mg,
0.102 mmol) in anhydrous diglyme (2 mL, final concentration of 9a ca. 0.15 M) was
treated dropwise with allyltri(n-butyl)tin (0.32 mL, 1.02 mmol). The reaction mixture
was heated at 130ꢀC under an argon atmosphere. A sample taken at 6 h and worked up
allowed the isolation of 1-allyl-2-isopropoxybenzene.3
IR (film): 605, 734, 864, 995, 1046, 1174, 1287, 1372, 1383, 1489, 1587, 1638, 2931,
2978, 3077 cm¡1. 1H NMR (300 MHz, CDCl3): d 1.33 (d, J D 6.0 Hz, 6H), 3.37 (d, J D
6.7 Hz, 2H), 4.54 (septet, J D 6.0 Hz, 1H), 5.00–5.09 (m, 2H), 5.93–6.03 (m, 1H), 6.83–
6.89 (m, 2H), 7.12–7.18 (m, 2H). 13C NMR (75 MHz, CDCl3): d 22.2, 34.6, 69.9, 113.0,
115.2, 120.2, 127.1, 129.7, 129.9, 137.2, 155.5. MS (EI, 70 eV): m/z (%) 91 (13), 115
(12), 119 (46), 133 (46), 134 (100), 135 (10), 176 [M]C (66), 177 [MC1]C (9). MS found:
176.1207; C12H16O requires m/z: 176.1201.
When the reaction was heated during 14 h, complete consumption of the starting
material took place, as determined by GC analysis. Then, the reaction mixture was
allowed to attain ambient temperature and was diluted with 25 mL of hexanes and filtered
through a short pad of Florisil and Celite (1:1). The filtrate was washed successively with
saturated NaF (4 £ 10 mL), H2O (3 £ 10 mL), brine (15 mL) and H2O2 (10 mL of a
0.12% P/V solution), dried over Na2SO4 and evaporated in vacuo. The oily residue was
re-dissolved in CH2Cl2 and stirred an additional period of 12 h with 200 mg activated flu-
orous silica. Filtration and evaporation of volatiles afforded 90 mg (73%) of the expected
b-methylstyrene (3), as a colorless oil.
IR (film): 606, 782, 862, 959, 1049, 1176, 1289, 1383, 1484, 1596, 1655, 2876, 2933,
3070 cm-1. 1H NMR (300 MHz, CDCl3): d 1.35 (d, J D 5.9, 6H, Me2-CH), 1.90 (dd, J D
1.5 and 6.6, 3H, Me-CH=CH-Ar), 4.57 (septet, J D 5.9, 1H, Me2-CH), 6.22 (dq, J D 6.0,
13.9 and 15.2, 1H, Me-CH=CH-Ar), 6.72 (dq, J D 1.5 and 15.9, 1H, CH3-CH=CH-Ar),
6.85–6.90 (m, 2H, ArH), 7.14 (dt, J D 1.5 and 7.7, 1H, 4-H), 7.41 (dd, J D 1.4 and 7.5,
1H, 6-H). 13C NMR (75 MHz, CDCl3): d 18.9 (Me-CH=CH-Ar), 22.2 (Me2-CH-O), 70.8
(Me2-CH), 114.3 (6-C), 120.7 (5-C), 125.8 (2-C), 125.9 (CH3-CH=CH-Ar), 126.4 (CH3-
CH=CH-Ar), 127.5 (3-C), 128.2 (5-C), 154.6 (1-C). MS (EI, 70 eV): m/z (%) 77 (10), 91
(24), 105 (13), 107 (9), 115 (17), 117 (12), 119 (69), 133 (54), 134 (100), 147 (12), 176
[M]C (52), 177 [MC1]C (7). MS found m/z D 176.1198; C12H16O (MC) requires m/z D
176.1201. The spectral data were in full agreement with those described.2,3,5,8
Acknowledgements
ꢀ
ꢀ
The authors thank Consejo Nacional de Investigaciones Cientıficas y Tecnicas (CONI-
ꢀ
ꢀ
ꢀ
CET) and Agencia Nacional de Promocion Cientıfica y Tecnologica (ANPCyT) for finan-
cial support. S.O.S. thanks CONICET for his fellowship.

b-Methylstyrene Chelating Pre-ligand of the Hoveyda-Grubbs’ II Catalyst
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