Trans-tetrahydrofurans by OH-assisted Ru-catalyzed isomerization of 2-butene-1,4-diols

Article abstract of DOI:10.1002/ejoc.201001166

We herein report a general method for the synthesis of 1,2-annulated trans-tetrahydrofurans by the OH-assisted Ru-catalyzed isomerization of (Z)-2-butene-1,4-diols (using Chaudret's catalyst), followed by reduction of the incipient lactol (using Et₃SiH and Amberlyst 15). Alternatively, the lactol can be oxidized to the corresponding lactone (using Ikariya's catalyst). It was shown by labeling experiments that an addition/elimination pathway is (at least to some extent) operative for the isomerization reaction. Only 0.5 mol-% of Chaudret's Ru catalyst is sufficient for the rapid and stereoselective isomerization of enediols of the type shown. This allows ready access to trans-tetrahydrofurans.

Full text of DOI:10.1002/ejoc.201001166

SHORT COMMUNICATION
DOI: 10.1002/ejoc.201001166
trans-Tetrahydrofurans by OH-Assisted Ru-Catalyzed Isomerization of
2-Butene-1,4-diols
Charles Fehr,*[a] Iris Magpantay,[a] Lionel Saudan,[a] and Horst Sommer[a]
Keywords: Isomerization / Lactols / Alcohols / Ruthenium / Oxygen heterocycles
We herein report a general method for the synthesis of 1,2-
annulated trans-tetrahydrofurans by the OH-assisted Ru-cat-
be oxidized to the corresponding lactone (using Ikariya’s cat-
alyst). It was shown by labeling experiments that an ad-
alyzed isomerization of (Z)-2-butene-1,4-diols (using Chaud- dition/elimination pathway is (at least to some extent) opera-
ret’s catalyst), followed by reduction of the incipient lactol
(using Et3SiH and Amberlyst 15). Alternatively, the lactol can
tive for the isomerization reaction.
tivity has been devoted to Ir-,[4] Rh-,[5] and in particular
Ru-catalyzed[6–8] isomerizations of allylic alcohols or ethers,
an internally assisted stereoselective isomerization by com-
plexation to one or two polar groups has never been re-
ported. Many of the known isomerization catalysts require
high reaction temperatures or are only successful with steri-
cally unhindered olefins.
We now report that the OH-assisted Ru-catalyzed isom-
erization of (Z)-2-butene-1,4-diols, using Chaudret’s cata-
lyst,[9] is quite general and highly selective for different diol
systems and substitution patterns.
Introduction
Recently, we described a stereoselective synthesis of rac-
Superambrox (1).[1] The trans configuration of the tetra-
hydrofuran ring was obtained by an unprecedented, highly
selective OH-assisted Ir- or Ru-catalyzed isomerization of
diol 3 and subsequent reduction of lactol 4 by using Et3-
SiH[2] (Scheme 1). Conversely, 1,4-reduction of butenolide
2 selectively afforded cis-lactone 5.
Results and Discussion
We found that the OH-assisted Ru-catalyzed isomeriza-
tion of (Z)-2-butene-1,4-diols, using Chaudret’s catalyst,
also works when the primary OH group is replaced by a
OMe group (Scheme 2). Thus, isomerization of 6 afforded
stereoselectively (E)-enol ether 7 together with acetal 8. Re-
duction of 7/8 (1:1) by using Et3SiH and Amberlyst 15[2b]
afforded pure 1 in 73% yield.
Scheme 1. Synthesis of rac-Superambrox by Ir- or Ru-catalyzed
OH-directed isomerization of 3.[1]
The lack of general methods for the synthesis of trans-
tetrahydrofurans (trans-THFs), in particular 1,2-annulated
trans-THFs that are, in general, more strained than cis-
THFs,[3] prompted us to study a general approach starting
from 2-butene-1,4-diols. Although extensive research ac-
Scheme 2. The OH-directed isomerization of 6. Reagents and con-
ditions: (a) [RuH(η5-C8H11)2][BF4] (2.6 mol-%) (Chaudret’s cata-
lyst), CH2Cl2, room temp., 30 min; (b) Et3SiH (2.0 equiv.), Am-
berlyst 15, room temp., 1 h.
[a] Firmenich SA, Corporate R&D Division,
P. O. Box 239, 1211 Geneva 8, Switzerland
Fax: +41-22-780-3334
Analogously, racemic Ambrox (Cetalox, 11)[10] and furan
14,[10b] two constituents of ambergris tincture, could be pre-
pared with excellent stereocontrol from the corresponding
lactones 9[11] and 12[12] (Scheme 3).
E-mail: charles.fehr@firmenich.com
cgfehr@bluewin.ch
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201001166.
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C. Fehr, I. Magpantay, L. Saudan, H. Sommer
SHORT COMMUNICATION
Ph2P(CH2)2NH2}[16] to isomerize diol 3 as an access route
to 1. However, smooth dehydrogenation led to lactone 2
(Scheme 1) in 90% yield.[17,18] Indeed, [Cp*Ru{Ph2P(CH2)2-
NH2}]Cl under basic conditions (KOtBu) is known to ox-
idize 1,4-diols to γ-butyrolactones in the presence of ace-
tone.[19] Surprisingly, diol 3 was oxidized even in the ab-
sence of a hydride acceptor (acetone), as the reaction was
performed in toluene!
This led us to devise a new protocol for the transforma-
tion of 2-butene-1,4-diols into trans-γ-butyrolactones by a
sequential isomerization–dehydrogenation process. Thus,
isomerization of diol 3 by using Chaudret’s catalyst, fol-
lowed by dehydrogenation catalyzed by Ikariya’s catalyst,
led to elusive trans-lactone 23 in 79% yield (Scheme 5). In
addition, the formation of a trace amount (2%) of doubly
unsaturated lactone 2 (Scheme 1) is interesting from a
mechanistic point of view (see below).
Scheme 3. The OH-directed isomerization of 10 and 13. Reagents
and conditions: (a) LiAlH4 (1.0 equiv.), Et2O, reflux, 30 min;
(b) [RuH(η5-C8H11)2][BF4] (1.0 mol-% for 10; 0.5 mol-% for 13)
(Chaudret’s catalyst), CH2Cl2, room temp., 30 min; (c) Et3SiH
(2.0 equiv.), Amberlyst 15, room temp., 1 h.
It should be mentioned that the syntheses of 11 and 14
by acid-catalyzed polyenol cyclizations are less selective,
due to concomitant isomerization of the polyenol and the
final product.[10]
To investigate whether a diol with a secondary OH group
(instead of a tertiary OH group) was still amenable to the
same isomerization reaction, alcohol 16, readily obtained
from lactone 15[13] by reduction, was submitted to the Ru-
catalyzed isomerization/reduction sequence (Scheme 4).
Scheme 5. trans-γ-Butyrolactone 23 by OH-directed isomerization–
dehydrogenation of 3. Reagents and conditions: (a) [RuH(η5-
C8H11)2][BF4] (0.5 mol-%), CH2Cl2, room temp., 20 min;
(b) [Cp*Ru(OMe)]2 (1 mol-%), Ph3P(CH2)2NH2 (2.1 mol-%),
KOtBu (2.0 mol-%), acetone, room temp., 45 min.
In order to gain further insight into the reaction course,
[D2]-3 (prepared by LiAlD4 reduction of 2) was submitted
to the Ru-catalyzed isomerization reaction. The isomeriza-
tion occurred with clean 1,3-D shift to afford after silane
reduction [D2]-1 (CHDO center 7:1)[20] (Scheme 6).
Scheme 4. The OH-directed isomerization of 16 and 20. Reagents
and conditions: (a) LiAlH4 (1.0 equiv.), Et2O, reflux, 30 min;
(b) [RuH(η5-C8H11)2][BF4] (0.5 mol-%) (Chaudret’s catalyst),
CH2Cl2, room temp., 30 min; (c) Et3SiH (2.0 equiv.), Amberlyst 15,
room temp., 1 h.
The overwhelming part of tetrahydrofuran formed was
trans-THF 17, accompanied by some cis-THF 18, which
may arise from C=C bond isomerization of 16 towards the
secondary alcohol function. The same reaction sequence
starting from menthalactone 19,[14] possessing a tetrasubsti-
tuted C=C bond is an especially sterically hindered case.
To our delight, the isomerization was complete after
15 min at room temperature, and trans-THFs 21 and 22[15]
were formed as the only products, demonstrating that the
C=C bond stereoselectively migrates towards the primary
alcohol function.
Scheme 6. Putative mechanism of the isomerization of 2-butene-
1,4-diols. Reagents and conditions: (a) [RuH(η5-C8H11)2][BF4]
(0.5 mol-%) (Chaudret’s catalyst), CH2Cl2, room temp., 30 min;
(b) Et3SiH (2.0 equiv.), Amberlyst 15, room temp., 1 h (66% from
Finally, as [Cp*Ru(PN)] catalysts are known to isomerize
allylic alcohols to ketones under mild conditions,[7b] we
tested the ability of a [Cp*Ru(PN)] catalyst {PN = [D2]-3).
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trans-Tetrahydrofurans by OH-Assisted Ru-Catalyzed Isomerization
There are three plausible pathways for this OH-directed
transition-metal-catalyzed isomerization:[6] an oxidation/re-
duction by a Ru-complexed α,β-unsaturated aldehyde fol-
lowed by 1,4-reduction,[7] an oxidative addition that gener-
ates a π–allyl ruthenium complex, followed by reductive eli-
mination,[6] or a stereoselective addition of [Ru]-H (or [Ru]-
D) leading to A, followed by elimination to B (Scheme 6).
Experimental Section
21/22: In a first flask, a solution of 20 (1.00 g; 5.88 mmol) in dry
CH2Cl2 (15 mL; dried with 4 Å MS) was degassed (freezing in li-
quid N2, then vacuum, then purging with N2. The process was re-
peated twice). A Schlenk tube was charged (in the glove box) with
Chaudret’s Ru catalyst (12.0 mg, 0.0294 mmol, 0.5 mol-%). The
contents of the first flask were added to the catalyst under N2. The
Whereas the two first processes occur with an intramolecu- reaction mixture was stirred at room temperature. After 15 min, all
starting material 20 was consumed. The formed lactol was treated
with Et3SiH (1.36 g, 1.86 mL, 11.7 mmol) and Amberlyst 15
(2.00 g). The mixture was stirred open to air[2b] for 45 min at room
temperature, filtered, concentrated and bulb-to-bulb distilled (oven
temp. 100–125 °C, 0.6 mbar) to afford 985 mg of 21 (GC: 30%), 22
(GC: 25%), and (Et3Si)2O (GC: 40%). Yield of 21/22: 59%. Flash
chromatography on SiO2 (50 g; cyclohexane/AcOEt, 95:5) afforded
445 mg of 21/22 (100% pure; 49%).[15]
[D2]-1 was prepared in the same manner as 1.[1] Yield from [D2]-3:
66%. Characteristic signals for [D2]-1: 1H NMR (CDCl3): δ = 3.83
(dd, J = 8, 8 Hz, 1 H; major isomer), 3.95 (m, 1 H, minor isomer)
ppm. 13C NMR (CDCl3): δ = 56.7 (t, J = 19.1 Hz, CD), 65.1 (d,
CH, t, J = 22.3 Hz, CD] ppm.
lar 1,3-H (or D) shift, the addition/elimination process con-
sists of an intermolecular H (or D) transfer.[8]
Because the Ru-catalyzed isomerization works with
either ether 6 or diol 3 as substrate, the intermediacy of an
enal is not required for effective isomerization (Scheme 2)
and the oxidation/reduction pathway is improbable. To dis-
tinguish between the other two pathways, a crossover ex-
periment was performed by submitting a 1:1 mixture of the
structurally very similar [D2]-3 and non-deuterated diol 10
to the Ru-catalyzed isomerization reaction. This resulted in
a significant amount of H/D-scrambling (Scheme 7). It can
therefore be assumed that the addition/elimination pathway
(via A and B; Scheme 6) is – at least to some extent – opera-
tive. Probably the catalyst first coordinates with the two OH
groups and with the C=C bond under concomitant re-
ductive displacement of one cyclooctadiene ligand. The re-
quired Ru-H(D) species necessary for entering the catalytic
cycle is then generated by the dehydrogenation reaction,
previously observed as a very minor pathway (see above,
formation of trace amounts of lactone 2).[21,22]
Characteristic signal for [D1]-11: 13C NMR (CDCl3): δ = 59.6 (t, J
= 19.0 Hz, CD).
Supporting Information (see footnote on the first page of this arti-
cle): Spectral data for all new compounds.
Acknowledgments
We thank Dr. C. Mazet (University of Geneva, Switzerland) for
stimulating discussions and the gift of the BArF-modified Crabtree
catalyst.[4b]
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Scheme 7. Crossover experiment with [D2]-3 and 10. Reagents and
conditions: (a) [RuH(η5-C8H11)2][BF4] (1.0 mol-%), CH2Cl2, room
temp., 30 min; then Et3SiH (2.0 equiv.), Amberlyst 15, room temp.,
1 h.
We are confident that this reaction will find broad appli-
cation and initiate new stereoselective Ru-catalyzed isomer-
ization reactions based on polar group assistance.
Conclusion
In conclusion, we have developed a general access route
to trans-THFs (and trans-γ-butyrolactones), which are less
accessible than the corresponding cis-fused heterocycles.
[9] F. Bouachir, B. Chaudret, F. Dahan, F. Agbossou, I. Tkatch-
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SHORT COMMUNICATION
H. Wüest, Helv. Chim. Acta 2005, 88, 3069; D. Jacoby, B Nef-
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[11] Prepared in the same way as lactone 2. For another synthesis
of the individual enantiomers, see: R. C. Cambie, B. D. Palmer,
Aust. J. Chem. 1981, 34, 1265.
[12] Racemic dihydroactinidiolide (or tea lactone) 12 is used at Fir-
menich as a flavor compound. Syntheses: G. M. Rubottom,
H. D. Juve Jr., J. Org. Chem. 1983, 48, 422; K. F. Eidman, B. S.
MacDougall, J. Org. Chem. 2006, 71, 9513 and references cited
therein.
[13] Prepared from ethyl(6,6-dimethyl-1-cyclohexen-1-yl)acetate (C.
Fehr, B. Winter, I. Magpantay, Chem. Eur. J. 2009, 15, 9773):
[14] (–)-Menthalactone (or Mintlactone) 19 is used at Firmenich as
a flavor compound. Review: H. M. C. Ferraz, L. S. Longo Jr.,
M. V. A. Grazini, Synthesis 2002, 2155.
[15] G. Ohloff, K.-H. Schulte-Elte, B. Willhalm, Helv. Chim. Acta
1966, 49, 2135.
[16] For convenience, the catalyst was prepared in situ from
[Cp*Ru(OMe)]2 and Ph2P(CH2)2NH2.
[17] A solution of 3, [Cp*Ru(OMe)]2 (1 mol-%), and Ph2P(CH2)2-
NH2 (2.1 mol-%) in toluene was stirred at room temp. for 3 h.
[18] Use of Mazet’s Ir catalyst (BArF-modified Crabtree catalyst)[4b]
in THF or Chaudret’s Ru catalyst in THF was less efficient in
terms of rate and yield.
[19] M. Ito, A. Osaku, A. Shiibashi, T. Ikariya, Org. Lett. 2007, 9,
1821.
[20] The same result was observed with Crabtree’s catalyst.
[21] An analogous dehydrogenation of 6 would lead via an oxenium
species to “dehydro-8”.
(1) m-CPBA (1.4 equiv.), CH2Cl2, 0 °C to room temp., 1 h [22] The facial selectivity of the Ru species is possibly also governed
(96%); (2) addition of a cooled (–30 °C) solution of formed
epoxide in THF to cooled (–30 °C) LDA (1.0 equiv.), THF,
45 min (35%).
by steric factors.
Received: August 18, 2010
Published Online: October 4, 2010
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Eur. J. Org. Chem. 2010, 6153–6156