Synthesis and Wagner-Meerwein Rearrangement of 9-(α-Hydroxyalkyl)xanthenes to 10-Substituted Dibenz[b,f]oxepins: Scope, Limitations and ab initio Calculations
04 August 2005 (eFirst)
A series of 9-(hydroxy)alkyl xanthenes 5 was prepared in good yields via: (a) addition of 9-lithioxanthene to functionalized acetaldehydes, or, via a new method, (b) addition of carbanions to xanthene-9-carbaldehyde. A practical and efficient synthesis was found for the latter. Under acidic catalysis, the majority of the addition products underwent Wagner-Meerwein rearrangement to give either the corresponding, 10-substituted dibenz[b,f]oxepin 6 or the xanthenylid-9-ene β-elimination product 7. The first Wagner-Meerwein rearrangement of a homobenzylic cyanohydrin is reported. The dibenz[b,f]oxepins are potential precursors of neuroactive substances. To rationalize product distribution, and probe the scope of the new rearrangement, ab initio quantum mechanical calculations have been carried out on products and transition states in selected cases.
Wagner-Meerwein rearrangement - dibenz[b,f]oxepin - 9-hydroxyalkyl-xanthene - dehydration - β-elimination - transition state stability
BurkeER. KholodilovNG. Ann. Neurol. 1998, 44: 126
ZimmermannK. WaldmeierPC. TattonWG. Pure Appl. Chem. 1999, 71: 2039
Mück-elerD. PivacN. IDrugs 2000, 3: 530
CloosPAC, JensenFR, BoissyP, and StahlhutM. inventors; WO 2004039773, A20513. 2004
WaldmeierPC. BoultonAA. CoolsAR. KatoAC. TattonWG. Adv. Res. Neurodegen. 2000, 8: 197
SagotY. ToniN. PerreletD. LurotS. KingB. RixnerH. MattenbergerL. WaldmeierPC. KatoAC. Br. J. Pharmacol. 2000, 131: 721
LeWittPA. Neurology 2004, 63: S23
OliveraR. SanMartinR. ChurrucaF. DominguezE. J. Org. Chem. 2002, 67: 7215
SanMartinR. OliveraR. ChurrucaF. TellituI. DominguezE. Trends Heterocycl. Chem. 2003, 9: 259
BischoffS. In Novel Antipsychotic Drugs Meltzer; New York: 1992. p.117-134
MercepM, MesicM, and PesicD. inventors; PCT Int. Appl., WO 2003099822, 20031204. 2003
KiyamaR. HonmaT. HayashiK. OgawaM. HaraM. FujimotoM. FujishitaT. J. Med. Chem. 1995, 38: 2728
LambrouGN, LatourE, and WaldmeierP. inventors; WO 2004066993, A10812. 2004
ZimmermannK. RoggoS. KragtenE. FürstP. WaldmeierP. Bioorg. Med. Chem. Lett. 1998, 8: 1195
KannoS, and OkitaT. inventors; JP 2000044568, A20215. 2000
ArnoldLA. WenchenL. GuyRK. Org. Lett. 2004, 6: 3005
- 9 Tosylate 8:
AnetFAL. BavinPMG. Can. J. Chem. 1957, 35: 1081 . In this work, sulfonate esters of the parent alcohols 5a-m were not investigated as starting materials for the Wagner-Meerwein rearrangement
- 10 Other authors reproduced this reaction in boiling benzene and found 85% yield of dibenz[b,f]oxepin:
HessBA. BaileyAS. BartusekB. BoekelheideV. J. Am. Chem. Soc. 1969, 91: 1665
Smith Kline & French patent; US 3100207, 1963; claims a more lengthy approach to 10-aminomethyldibenz[b,f]oxe-pins via 9-hydroxymethyl-9-aminoalkylxanthenes.
- 11b Bergmann and Rabinovitz claimed the rearrangement of 9-(α-hydroxybenzyl)xanthene (5d) to 10-phenyldibenz-[b,f]oxepin but proof of structure was tentative (only IR, mp given):
BergmannD. RabinovitzM. Isr. J. Chem. 1963, 1: 125
- In our hands, the substrate 5d did not rearrange, but rather gave the β-elimination product (7d, Table 1), in accordance with the theoretical calculations (vide supra, Table 3).
- 11c Xanthene pKHA[THF] = 31.4:
FraserRR. MansourTS. SavardS. J. Org. Chem. 1985, 50: 3232
- 11d The 9-lithiation of xanthene was originally reported by Nakai et al.:
NakaiR. SugiiM. TomonoH. Bull. Inst. Chem. Res., Kyoto Univ. 1955, 33: 211
- It was also reported by Mahesh et al.:
MaheshVB. SeshadriTR. J. Sci. Ind. Res., Sect. B 1955, 14: 608
- 12 Only one other, more cumbersome method of preparation for this aldehyde (careful DIBAL-reduction of xanthene-9-carbonyl chloride) has been reported:
RochlinE. RappoportZ. J. Am. Chem. Soc. 1992, 114: 230. In our hands, this procedure gave mostly xanthone after aqueous workup and silica gel chromatography of the crude product
ReichardtC. Solvents and Solvent Effects in Organic Chemistry VCH-Wiley; Weinheim, N.Y.: 1988. p.140ff
- 16 Jaguar 5.5 Schrödinger, LLC; Portland, OR: 1991-2003.
SzaboA. OstlundNS. Modern Quantum Chemistry, Introduction to Advanced Electronic Structure Theory MacMillan; New York: 1982.
KochW. HolthausenMC. A Chemist’s Guide to Density Functional Theory John Wiley and Sons; New York: 2001.
PachuauZ. LyngdohD. J. Chem. Sci. 2004, 116: 83
- The putative spirocyclopropyl cyclohexadienyl transition state dates back to the pioneering work of Winstein et al., where this transition state had been invoked to rationalize rates of solvolysis and alkyl group migration in substituted, primary phenethyl tosylates and related systems; compare:
WinsteinS. LindegrenCR. MarshallH. IngrahamLL. J. Am. Chem. Soc. 1953, 75: 147
DenneyDB. GoldsteinB. J. Am. Chem. Soc. 1957, 79: 4948
WinsteinS. FainbergAH. J. Am. Chem. Soc. 1958, 80: 459
RaberDJ. HarrisJM. SchleyerPVR. J. Am. Chem. Soc. 1971, 93: 4829
LoupyA. Seyden-PenneJ. Tetrahedron 1973, 29: 1015
Current address: Amgen Inc., One Amgen Center Drive, P. O. Box, Thousand Oaks, CA 91320-1799, USA.13
Typical procedure (5k): To a solution of xanthene 3 (3.64 g, 20 mmol) in anhyd THF (60 mL) under Ar at -65 °C was added n-BuLi (1.1 equiv, 8.1 mL, 2.7 M solution in n-heptane). After stirring at -65 °C for 30 min, a fine red suspension formed. Ethyl formate (1.77 g, 24 mmol) in THF (12 mL) was added dropwise at -65 °C. Stirring at -60 °C to -70 °C for 3 h resulted in a clear, orange solution. After HPLC had indicated complete conversion of 3, glacial AcOH (1.32 g, 22 mmol) was added slowly, such that the temperature did not exceed -60 °C. To the resulting yellowish solution of 4 Huenig’s base (3.1 g, 24 mmol), followed by nitromethane (1.46 g, 24 mmol) were added. The turbid mixture was warmed to r.t. overnight. After quenching with aq AcOH and adjusting the pH to neutral, extraction with CH2Cl2 and purification of the crude product by silica gel chromatography afforded 5k (4.63 g, 85%) as a slightly yellowish solid. Similarly were prepared: 5i [KCN (1.0 equiv), -40 °C to r.t., no base, 91% yield), and 5j [ HPO(OEt)2 (1.1 equiv), -40 °C to r.t., Huenig’s base (1.2 equiv), 91% yield].14
For substrates obtained using method B, it is best to avoid workup and isolation (see ref. 12), and instead use the in situ-prepared aldehyde(4) solution (see ref. 13) directly in the next step.