Efficient one-pot synthesis of the GABAB positive allosteric modulator (R,S)-5,7-Di-tert-butyl-3-hydroxy-3-trifluoromethyl-3H-benzofuran-2- one

Article abstract of DOI:10.1080/00397910801979403

The GABA_B positive allosteric modulator (R,S)-5,7-di-tert-butyl- 3-hydroxy-3-trifluoromethyl-3H-benzofuran-2-one (1) was synthesized in one pot from the anhydrous lithium salt of 2,4-di-tert-butylphenol and methyl trifluoropyruvate mediated by a stoichiometric amount of anhydrous gallium(III) chloride in 64% overall yield. The enantiomers of 1 were separated by chiral-phase HPLC (Chiralpak AD), and the absolute configuration was determined by X-ray crystallography. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/00397910801979403

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Efficient One-Pot Synthesis
of the GABAB Positive
Allosteric Modulator
(R,S)-5,7-Di-tert-butyl-3-
hydroxy-3-trifluoromethyl-3H-
benzofuran-2-one
Andre M. Alker a , François Grillet a , Pari Malherbe
a , Roger D. Norcross a , Andrew W. Thomas a &
Raffaello Masciadri a
a Hoffmann-La Roche AG , Basel, Switzerland
Published online: 30 Sep 2008.
To cite this article: Andre M. Alker , François Grillet , Pari Malherbe , Roger D.
Norcross , Andrew W. Thomas & Raffaello Masciadri (2008) Efficient One-Pot Synthesis
of the GABAB Positive Allosteric Modulator (R,S)-5,7-Di-tert-butyl-3-hydroxy-3-
trifluoromethyl-3H-benzofuran-2-one, Synthetic Communications: An International
Journal for Rapid Communication of Synthetic Organic Chemistry, 38:20, 3398-3405,
DOI: 10.1080/00397910801979403
To link to this article: http://dx.doi.org/10.1080/00397910801979403
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Synthetic Communications1, 38: 3398–3405, 2008
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910801979403
Efficient One-Pot Synthesis of the GABAB
Positive Allosteric Modulator (R,S)-5,7-Di-tert-
butyl-3-hydroxy-3-trifluoromethyl-3H-
benzofuran-2-one
Andre M. Alker, Franc¸ois Grillet, Pari Malherbe, Roger D. Norcross,
Andrew W. Thomas, and Raffaello Masciadri
Hoffmann-La Roche AG, Basel, Switzerland
Abstract: The GABAB positive allosteric modulator (R,S)-5,7-di-tert-butyl-3-
hydroxy-3-trifluoromethyl-3H-benzofuran-2-one (1) was synthesized in one pot
from the anhydrous lithium salt of 2,4-di-tert-butylphenol and methyl trifluoro-
pyruvate mediated by a stoichiometric amount of anhydrous gallium(III) chloride
in 64% overall yield. The enantiomers of 1 were separated by chiral-phase HPLC
(Chiralpak AD1), and the absolute configuration was determined by X-ray
crystallography.
Keywords: (R,S)-5,7-Di-tert-butyl-3-hydroxy-3-trifluoromethyl-3H-benzofuran-2-
one, GABAB positive allosteric modulator, gallium(III) chloride, one-pot
synthesis
INTRODUCTION
In the course of our investigations directed at the discovery of novel
GABAB positive allosteric modulators,[1] We identified (R,S)-5,7-di-tert-
butyl-3-hydroxy-3-trifluoromethyl-3H-benzofuran-2-one (1) (Scheme 1)
as a screening hit from our corporate compound collection. We set out
to resynthesize lactone 1 in a larger quantity needed for enantiomer separ-
ation and derivatization. This lactone 1 was first reported in the Russian
literature.[2] We have evaluated a range of methods for the synthesis of
lactone 1 encompassing Lewis acid and transition-metal-catalyzed
Received January 15, 2008.
Address correspondence to Raffaello Masciadri, Klybeckstrasse 228, CH-4057
Basel, Switzerland. E-mail: raffaello.masciadri@bluewin.ch
3398

Efficient One-Pot Synthesis of a New GABAB Modulator
3399
Scheme 1. (a) n-Bu Li (1 eq), THF, ꢀ70 to 20 ꢁC, distill off THF; (b) GaCl3
(1 eq), DCE, ꢀ10 to 80 ꢁC, 15 min; (c) CF3COCO2Me (1 eq), DCE, 0–20ꢁC;
(d) DCE, 28–80ꢁC.
protocols: AlCl3,[3] TiCl4,[4] (S)-t-Bu-BOX-Cu(OTf)2,[5] Ga(OTf)3,[6]
In(OTf)3,[7] (S)-2,20-Bis(diphenylphosphino)-1,10-binaphthyl (BINAP)-
PdCl2, and (S)-5,50-Bis(diphenylphosphino)-4,40-bi-1,3-benzodioxide
(SEGPHOS)-PdCl2.[8] Our choice fell on the Casiraghi[3] protocol, wherein
we replaced AlCl3 by GaCl3 in analogy to the modified protocol for the
Sugasawa reaction.[9,10]
RESULTS AND DISCUSSIONS
Lithium phenolate 3 (Scheme 1) was prepared in tetrahydrofuran (THF)
at low temperature by treatment of 2,4-di-tert-butylphenol (2) with n-
butyl lithium. THF was replaced with 1,2-dichloroethane (DCE) before
addition of a stoichiometric amount of anhydrous gallium(III) chloride
at ꢀ10ꢁC. Brief heating under reflux led to the precipitation of LiCl with
concomitant formation of the gallium phenolate 4. Addition of the
highly electrophilic methyl trifluoropyruvate (5) led to gallium-directed
regiospecific ortho-alkylation of the phenolate 4 to afford the aldol-type
intermediate 6, which cyclized in situ upon heating to afford lactone 1
in 74% isolated yield. The use of DCE as solvent was essential because
the reaction failed in toluene, the solvent originally used by Casiraghi,
due to transfer of the tert-butyl groups from the substrate 2 to toluene,
a well-known process.[11] GaCl3 was superior to AlCl3 in promoting this
one-pot process. We have attempted to eliminate the need to switch sol-
vent after generation of the lithium phenolate 3 by using sodium

3400
A. M. Alker et al.
ꢁ
Scheme 2. (a) 1 N NaOH (2 eq), dioxane, 0–20 C, 16 h; (b) 1 N HCl, AcOEt,
0ꢁ C, upon extraction.
trimethylsilanolate (NaOTMS), which had been previously used for mild
ester hydrolysis in DCE under non aqueous conditions.[12] However, the
yield was less then 30%.
Hydrolysis of lactone 1 (Scheme 2) occurred readily with 2 equiva-
lents of 1 N NaOH in dioxane at 20 ꢁC, and a highly lipophilic sodium
salt 7 could be extracted with hot toluene. Interestingly, acidification of
the sodium salt 7 with 1 equivalent of 1 N HCl gave lactone 1 again
and only trace amounts of the expected hydroxyl acid 8. Thus the ring
closure of the hydroxy acid 8 to lactone 1 occurred rapidly under acidic
conditions, probably as a consequence of the Thorpe–Ingold effect.[13]
Separation of the enantiomers of racemic lactone 1 was carried out
(Scheme 3) by chiral-phase medium-pressure chromatography on a
Chirapak AD1 column with heptane=2-propanol 97:3 as the eluent.
To determine the absolute configuration, we prepared a derivative of
the ( þ )-enantiomer of 1 with (R)-( ꢀ)-1-(naphthyl)ethyl isocyanate.
Unexpectedly, we obtained the oxazolidine-2,4-dione 9, which became
evident only after X-ray crystal analysis (Fig. 1). From these data, the
(R)-configuration could be assigned to the ( þ )-enantiomer of 1. (CCDC
643853 contains the supplementary crystallographic data for this article.
These data can be obtained free of charge via www.ccdc.cam.ac.uk/data_
request/cif, by e-mailing data_request@ccdc.cam.ac.uk or by contacting
Scheme 3. (a)Chromatography on Chiralpack AD, heptane=2-propanol 97:3; (b)
(R)-( ꢀ )-1-(1-naphthyl)ethyl isocyanate (1 eq), cat. DMAP, toluene, reflux, 1 h.

Efficient One-Pot Synthesis of a New GABAB Modulator
3401
Figure 1. ORTEP plot of the X-ray structure of 9.
the Cambridge Crystallographic Data Centre, 12 Union Road, Cam-
bridge CB2 1EZ, UK; fax: þ 44 1223 336033.
CONCLUSIONS
In summary we have developed an efficient one-pot synthesis of racemic
5,7-di-tert-butyl-3-hydroxy-3-trifluoromethyl-3H-benzofuran-2-one, sep-
arated the enantiomers by chromatography on a chiral stationary phase,
and determined the absolute configuration via X-ray crystal analysis of a
suitable derivative.
EXPERIMENTAL
(R,S)-5,7-Di-tert-butyl-3-hydroxy-3-trifluoromethyl-3H-benzofuran-
2-one (1)
2,4-Di-tert-butylphenol (2) (28 g, 28.5 mmol) was dissolved in THF (250 mL)
ꢁ
under argon and cooled to ꢀ70 C. A 1.6 M solution of n-butyllithium in
hexane (85 mL, 135.7 mmol) was added, and the solution was allowed to
reach 20ꢁC. THF was distilled off and replaced by DCE (250 mL), which
was distilled off again and replaced with DCE (250 mL). After cooling in
ice=MeOH, a fresh ampoule of gallium(III) chloride (25 g, 142.5 mmol)
was added (exothermic, 5ꢁC). The resulting solution was heated under reflux
for 15 min, affording a white precipitate of LiCl. The suspension was cooled

3402
A. M. Alker et al.
in ice, then methyl trifluoropyruvate (14.5 mL, 142.5 mmol) dissolved in
DCE (20 mL) was added, and stirring continued for 13 h at 20ꢁC. The reac-
tion was driven to completion by heating under reflux for 3.5 h. After cool-
ing, the suspension was extracted with DCM (2 ꢂ), cold 1 M HCl (2 ꢂ ), and
NaCl (1 ꢂ). The crude product was purified by chromatography on silica gel
in heptane=DCM 2:1. The purified product (37 g) was recrystallized from
cold heptane (150 mL), and dried at 50ꢁC=1 mbar for 5 h to afford 28.9 g
(64%) of white crystals. From mixed fractions and the mother liquor,
ꢁ
1
another 4.4 g (10%) of white crystals were isolated. Mp 83 C. HNMR
(400MHz, DMSO-d6) d ¼ 1.31 (s, 9 H, t-Bu), 1.37 (s, 9 H, t-Bu), 7.40 (s, 1
H, ArH), 7.47 (s, 1 H, ArH), 8.26 (s, 1 H, OH). IR (nujol) 3401 (s, OH),
3350 (s, OH), 2956 (s), 2854 (s), 1812 (s, CO), 1621 (w), 1608 (w), 1483 (s),
1463 (s), 1111 (s, CF3), 1086 (s, OH). MS (EI): m=z ¼ 330 (20, M), 315
(95, M-CH3), 287 (100, M-CH3CO); HRMS (FT-ICR): calcd. for
C19H24F3O5 (M ꢀH þ CH3COOH) ꢀ 389.158143; found 389.15797.
(R,S)-2-(3,5-Di-tert-butyl-2-hydroxy-phenyl)-3,3,3-trifluoro-2-hydroxy-
propionic Acid, Disodium Salt (7)
(R,S)-5,7-Di-tert-butyl-3-hydroxy-3-trifluoromethyl-3H-benzofuran-2-one
(1) (7.69 g, 23.3 mmol) was dissolved in dioxane (50 mL), cooled in ice,
treated with 1 N NaOH (51.2 mL, 51.2 mmol), and stirred for 16 h at
20ꢁC. The yellow solution was evaporated to dryness. The residue was
heated to 100 ꢁC in toluene (100 mL), and the hot solution was filtered to
remove residual solids. The filtrate was evaporated to dryness, and the
resulting white solid was heated to 80ꢁC in heptane (100 mL). The slurry
was allowed to cool to 20ꢁC and then stirred in ice for 15 min. The white
solid was filtered off and washed with heptane to afford 8.87g (97%) of
1
white solid. HNMR (400 MHz, DMSO-d6) d ¼ 1.14 (s, 9 H, t-Bu), 1.31
(s, 9 H, t-Bu), 6.78 (s, 1 H, ArH), 7.50 (s, 1 H, ArH), 17.4 (s, 1 H, OH).
MS (EI): m=z ¼ 347 (M ꢀH)); HRMS (FT-ICR): calcd. for C17H22F3O4
(M þ H ꢀ 2 Na)ꢀ 347.14757; found 347.14752.
(R,S)-5,7-Di-tert-butyl-3-hydroxy-3-trifluoromethyl-3H-benzofuran-2-one
(1) and (R,S)-2-(3,5-Di-tert-butyl-2-hydroxy-phenyl)-3,3,3-trifluoro-2-
hydroxy-propionic Acid (8) via Acidification of Disodium Salt 7
Lactone 1 (10 g, 30.2 mmol) was dissolved in dioxane (60 mL) and treated
with 1 N NaOH (66.6 mL, 66.6 mmol) for 2 h (slightly exothermic upon
mixing, 30ꢁC). The reaction was followed by high pressure liquid chroma-
tography (HPLC) and thin layer chromatography (TLC) in heptane=
ethyl acetate 1:1, which indicated at least 95% conversion. The mixture

Efficient One-Pot Synthesis of a New GABAB Modulator
3403
was evaporated to dryness at 50 ꢁC=1 mbar, yielding the sodium salt 7 as a
white solid. This solid was extracted with ethyl acetate (2 ꢂ), cold 1 N HCl
(1 ꢂ), and sat. NaCl (1 ꢂ). During this process, the sodium salt reverted
almost quantitatively to the corresponding lactone. The crude product
was purified by chromatography on silica gel with a gradient of ethyl acet-
ate in heptane from 0 to 100%. The lactone was eluted first (UV active),
followed by a small amount of hydroxy acid (not UV active). The lactone
fraction was crystallized from cold heptane (50 mL) by seeding with auth-
entic material to afford 7.09 g (71%) of the lactone 1 as white crystals,
1.4 g of the mother liquor, which was discarded, and 722 mg (7%) of
1
hydroxy acid 8 as a gum. Compound 1: HNMR (400 MHz, DMSO-d6)
d ¼ 1.31 (s, 9 H, t-Bu), 1.37 (s, 9 H, t-Bu), 7.40 (s, 1 H, ArH), 7.47 (s,
1 H, ArH), 8.26 (s, 1 H, OH). MS (EI): m=z ¼ 330 (20, M), 315 (95,
1
M-CH3), 287 (100, M-CH3CO). compound 8: HNMR (400 MHz, d6-
DMSO) d ¼ 1.22 (s, 9 H, tBu), 1.35 (s, 9 H, t-Bu), 6.0–6.3 (s, br, 1 H,
OH), 7.12 (s, 1 H, ArH), 7.60 (s, 1 H, ArH), 8.25 (s, 1 H, OH), 13.4 (s,
br, 1 H, COOH). MS (ISP): m=z ¼ 347 (M ꢀH); HRMS (FT-ICR): calcd.
for C17 H22F3O4 (M ꢀH) ꢀ 347.14757; found: 347.14748.
Separation of the Enantiomers (R)-(+)-5,7-Di-tert-butyl-3-hydroxy-3-
trifluoromethyl-3H-benzofuran-2-one and (S)-(–)-5,7-Di-tert-butyl-3-
hydroxy-3-trifluoromethyl-3H-benzofuran-2-one
(R,S)-5,7-Di-tert-butyl-3-hydroxy-3-trifluoromethyl-3H-benzofuran-2-one
(1) (1.5 g, 4.5 mmol) was separated on Chiralpak AD1 with heptane=2-
propanol 97:3. The ( þ )-enantiomer (534 mg, 35%) was eluted first and
20
gave white crystals, MS (EI): m=z ¼ 330 (M). [a]D ¼ þ 33.47 (CHCl3,
c ¼ 0.765)); HRMS (FT-ICR): calcd. for C19H24F3O5 (M ꢀH þ
CH3COOH) ꢀ 389.158143; found: 389.15797. The (ꢀ)-enantiomer
(580 mg, 39%) was eluted last and gave white crystals, MS (EI): m=z ¼ 330
330 (M). [a]D ¼ ꢀ33.27 (CHCl3, c ¼ 0.679). 1HNMR (400MHz,
20
DMSO-d6) d ¼ 1.31 (s, 9 H, t-Bu), 1.37 (s, 9 H, t-Bu), 7.40 (s, 1 H,
PhH), 7.47 (s, 1 H, PhH), 8.27 (s, 1 H, OH); HRMS (FT-ICR): calcd.
for C19H24F3O5 (M ꢀH þ CH3COOH) ꢀ 389.158143; found: 389.15799.
Determination of the Absolute Configuration of (R)-(+)-5,7-Di-tert-
butyl-3-hydroxy-3-trifluoromethyl-3H-benzofuran-2-one via X-ray
Analysis of (R)-5-(3,5-Di-tert-butyl-2-hydroxy-phenyl)-3-((R)-1-
naphthalen-1-yl-ethyl)-5-trifluoromethyl-oxazolidine-2,4-dione (9)
(R)-( þ )-5,7-Di-tert-butyl-3-hydroxy-3-trifluoromethyl-3H-benzofuran-2-
one (100 mg, 0.3 mmol), (R)-( ꢀ)-1-(1-naphthyl)ethyl isocyanate (0.058

3404
A. M. Alker et al.
mL, 0.33 mmol), and 4-dimethylaminopyridine (3.7 mg, 0.03 mmol) were
heated under reflux in toluene (1 mL) for 1 h under nitrogen. The resulting
solution was evaporated to dryness, and the residue was purified by chro-
matography on silica gel with a gradient of ethyl acetate in heptane from 0
to 100% in 20 min and then with heptane=DCM 3:1 to afford 60 mg (37%)
of white crystals. Crystals suitable for X-ray analysis were obtained by
slow evaporation of a standing DCM solution at ambient temperature.
1HNMR (400 MHz, CDCl3) d ¼ 1.27 (s, 9 H, t-Bu), 1.38 (s, 9 H, t-Bu),
1.97 (d, 3 H, J ¼ 8 Hz, Me), 6.16 (q, 1 H, J ¼ 8 Hz, CHMe), 7.27 (m, 1
H, ArH), 7.52 (s, 1 H, ArH), 7.57 (m, 3 H, ArH), 7.83 (dd, 1 H, ArH),
8.0 (m, 3 H, ArH), 8.6 (s, 1 H, OH); MS (ISP): m=z ¼ 545 (M þ NH4)þ ;
HRMS (FT-ICR): calcd. for C30H36F3N2O4 (M þ NH4)þ 545.26217;
found: 545.26227.
ACKNOWLEDGMENTS
We thank Daniel Zimmerli for separation of the enantiomers of 1 and the
1
analytical department PRBD-E for measuring and interpreting HNMR
and MS spectra.
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