One-pot consecutive reactions based on the synthesis of conjugated enones by the re-catalysed meyer-schuster rearrangement

Article abstract of DOI:10.1002/chem.201201639

Re catalysis in one-pot reactions: An atom-economical, one-pot strategy that involves alkyne deprotonation and a subsequent rhenium(V)-catalysed Meyer-Schuster rearrangement of the alkynol to provide α,β- unsaturated enones in high yield has been developed (see scheme). Subsequent in situ hydride reduction or Diels-Alder reaction of the enones provided products in good-to-high overall yields. Copyright

Full text of DOI:10.1002/chem.201201639

COMMUNICATION
DOI: 10.1002/chem.201201639
One-Pot Consecutive Reactions Based on the Synthesis of Conjugated
Enones by the Re-Catalysed Meyer–Schuster Rearrangement
Elio Mattia, Alessio Porta, Valentina Merlini, Giuseppe Zanoni, and Giovanni Vidari*[a]
Conjugated enones are one of the most used building
blocks in synthetic organic chemistry[1] and are an important
moiety in natural products and biologically active com-
pounds. Given its high synthetic versatility, the enone
system is involved in several carbon–carbon bond-forming
reactions, such as cyclopropanation, Michael addition,
Diels–Alder and 1,3-dipolar cycloaddition reactions, and in
the conversion to other functional groups, such as allylic al-
cohols, epoxides and amines.[2]
Traditional preparations by well-known protocols, such as
aldol-like condensations and Wittig, Horner–Wadsworth–
Emmons, Julia and Peterson olefinations, usually require
basic conditions, which may be incompatible with different
functional groups and/or the preservation of the original
stereochemistry.[3] Moreover, these procedures are multi-
stage sequences and exhibit an overall low atom economy.[4]
They may also generate noxious byproducts and are usually
highly sensitive to steric congestion around the carbonyl
group.
In contrast to the aforementioned addition/elimination
protocols, the addition of an alkyne to a carbonyl derivative
followed by a rearrangement process offers the prospect of
an efficient and completely atom-economical strategy. In
this regard, several inter- and intramolecular alkyne–carbon-
yl metatheses, involving either a highly electron-rich alkyne,
or an alkyne and a Lewis or Brçnsted acid catalyst, have
been extensively investigated (Scheme 1a).[5] Alternatively,
propargylic alcohols 3, produced by the smooth nucleophilic
1,2 addition of terminal alkynes 2 to carbonyl compounds 1,
may be subjected to isomerisation to the enones 4 by protic
or, more frequently, Lewis acid catalysed Meyer–Schuster
(M–S) rearrangements (Scheme 1b).[6]
In all procedures based on the M–S rearrangement that
have been developed so far, homologation of aldehydes and
ketones has been executed in two distinct stages: by first
preparing the alkynol, and then subjecting it to the M–S re-
action in a separate flask.[6] We deemed it highly desirable
to develop a new, one-pot procedure for the olefination of
carbonyl compounds; the consecutive preparation and iso-
merization of the alkynol in the same flask would effectively
improve the efficiency and atom economy of the entire
pathway. In this way, the entire addition/M–S rearrangement
sequence would correspond more closely to the Wittig and
other traditional olefination protocols, which involve reac-
tion intermediates that collapse directly into the enone
moiety. However, by avoiding most of the drawbacks that
plague the classical procedures, the new protocol would rep-
resent a significant advancement in synthetic organic chem-
istry.
To increase the appeal of the method, we also explored
the possibility of using the resulting enone in additional re-
actions that could take place immediately after the M–S re-
arrangement, without it first being isolated. The reduction
of the carbonyl group to the corresponding allylic alcohol
and the use of the enone moiety in a carbon–carbon bond-
forming reaction, such as a Diels–Alder cycloaddition, ap-
peared feasible. Herein, we describe the achievement of
these goals.
We have recently developed a new general catalytic pro-
cedure for the rapid and efficient M–S rearrangement of
free secondary and tertiary propargylic alcohols to the cor-
responding a,b-unsaturated carbonyl compounds[6b] by using
the readily available rhenium complex [ReOCl
AHCTUNGTRENNUNG
3ACHTUNGTRENUNG(OPPh3)-
Scheme 1. Addition/rearrangement olefination strategies: a) alkyne–car-
bonyl metathesis; and b) nucleophilic 1,2 addition/Meyer–Schuster rear-
rangement.
(SMe2)] (5).[7] The reaction proceeded under neutral condi-
tions, showing virtually complete E stereoselectivity and
preserving the configurational integrity of potentially enolis-
able stereocenters.[6b] Moreover, in striking contrast to the
majority of M–S reactions, which occur in protic solvents,[6]
the Re-promoted rearrangement proceeded smoothly in
either THF or dimethoxyethane (DME). Thus the Re catal-
ysis in an ethereal medium was, in principle, compatible
with the classical conditions for preparing propargylic alco-
hols by a lithium or magnesium acetylide addition to a car-
[a] E. Mattia, Dr. A. Porta, Dr. V. Merlini, Dr. G. Zanoni,
Prof. G. Vidari
Dipartimento di Chimica, Universitꢀ di Pavia
Via Taramelli 12, 27100 Pavia (Italy)
E-mail: vidari@unipv.it
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201201639.
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bonyl compound. However, we anticipated the need to de-
velop an efficient means of quenching the intermediate salt
that would arise from the acetylide addition. In fact, in ac-
cordance with our proposed mechanism for the M–S rear-
rangement, the catalytic cycle is initiated by the addition of
the propargylic free hydroxyl group across the Re=O bond
of the catalyst 5.[6b] Therefore, at the onset of our efforts, we
aimed to develop an effective in situ method for quenching
the lithium or magnesium alkoxide that would not be harm-
ful to the rhenium catalyst.
of salt 9, and its catalytic effect on the M–S rearrangement
was assumed to be very modest. In fact, in the presence of
excess p-TsOH·H2O alone, excluding the catalytically active
complex 5, the M–S rearrangement of 1-(meta-tolyl)hept-2-
yn-1-ol to enone 4a proceeded very slowly with the forma-
tion of several byproducts.[8]
To explore the general applicability of this protocol, dif-
ferent carbonyl compounds 1 were subjected to the one-pot
olefination process with alkyl- and aryl-substituted terminal
alkynes 2 (Table 1). Aromatic substrates gave the corre-
sponding isolated enones 4 with reasonable to excellent
overall yields and, for most reactions, with almost complete
E stereoselectivity. Furthermore, it was notable that the Re
catalyst loading could be reduced to only 1 mol%. In sharp
contrast, the aliphatic aldehyde 1 f gave a modest yield of
enone 4 f (Table 1, entry 6), even in the presence of 5 mol%
of catalyst 5.[9]
In an exploratory experiment, the addition/rearrangement
of propynyl magnesium bromide (6) to meta-tolualdehyde
(1a) was investigated (Scheme 2). As expected, the addition
In later experiments (Table 2), the overall yields of the
(E)-enones 4 were significantly improved by substituting p-
TsOH·H2O with the sulfonic resin Amberlite IR120 H
(compare Table 1, entries 2–4 and 10 with Table 2, entries 1–
4). This improvement in yield was attributed to the absence
of H2O in the reaction medium, the presence of which con-
siderably reduces the catalytic activity of the Re complex
5.[6b]
In conclusion, we have developed a new atom-economical
procedure for the olefination of carbonyl compounds that
demonstrates, for the first time, the feasibility of a one-pot
procedure based on an alkynyl lithium addition followed by
a Meyer–Schuster rearrangement of the intermediate alky-
nol.
Scheme 2. Attempted one-pot olefination of aldehyde 1a with the
Grignard acetylide 6.
of the commercially available Grignard reagent 6 (1.1 equiv)
to aldehyde 1a proceeded readily in DME/THF to produce
the presumed alkoxide 7 (indicated by TLC analysis). Sub-
sequently, the salt was protonated by the addition of solid p-
TsOH·H2O. Freshly prepared complex 5[7] was then added
to the mixture, which was heated at 808C for several hours.
However, rather unexpectedly, no M–S rearrangement prod-
uct was observed, and a workup returned the unaltered 1-
(meta-tolyl)but-2-yn-1-ol intermediate product.
To increase the attractiveness of our protocol, we envis-
aged that an enone 4, obtained from compounds 1 and 2,
could be submitted directly, without isolation, to a variety of
additional reactions that are typically carried out in an ethe-
real solvent, such as DME. In the first set of experiments,
enones 4, obtained from aldehydes 1, were reduced in situ
to the allylic alcohols 10 by exposure to LiAlH4. Parallel ex-
periments showed that product yields were significantly im-
proved by using p-TsOH, instead of the sulfonic resin Am-
berlite, in the aldehyde olefination sequence and by quench-
ing excess LiAlH4 with a base (see the Supporting Informa-
tion for details). Under optimised reaction conditions, the
entire one-pot sequence from 1 to 10 was executed in grati-
fying yields (Table 3). Given the ability of rhenium com-
plexes to catalyse the 1,2 hydrosilylation of enones,[10] we
also examined the possibility of substituting LiAlH4 with
Me2PhSiH as the reducing agent in the reaction sequence
shown in Table 3. However, we observed no reduction of
the intermediate enones 4.
Assuming that bromide or magnesium ions might inhibit
the catalytic activity of complex 5, lithium acetylide 8, gen-
erated by deprotonation of alkyne 2a with BuLi, was added
to aldehyde 1a. After protonation of the intermediate al-
koxyde 9 with p-TsOH·H2O, the corresponding alkynol was
subjected to the in situ Re-catalysed M–S rearrangement
(Scheme 3). Under these conditions the reaction proceeded
uneventfully, producing the expected enone 4a as only the
(E)-isomer (determined by NMR spectroscopy) in 66%
overall yield.
We noticed that the reaction required slightly acidic con-
ditions to proceed; the M–S rearrangement occurred only
when the pH of the medium was about 5–6. On the other
hand, p-TsOH·H2O was required mainly for the protonation
To further increase the molecular complexity of the prod-
ucts by a consecutive carbon–carbon bond-forming reaction,
enones 4 were submitted to an in situ Diels–Alder cycload-
dition. To this end, enones 4 were formed by the M–S rear-
rangement of alkynols 3 and immediately exposed to cyclo-
pentadiene (2 equiv), based on the assumption that the rhe-
nium–oxo catalyst 5 could also be a reasonable Lewis acid
Scheme 3. One-pot olefination of aldehyde 1a with the lithium acetylide
8.
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Synthesis of Enones by the Re-Catalysed Meyer–Schuster Rearrangement
COMMUNICATION
Table 1. One-pot olefination of carbonyl compounds.[a]
Table 2. Amberlite variant of the one-pot olefination of carbonyl com-
pounds.[a]
1
2
4
Yield
[%][b]
1
2
3
4
1b
1c
1d
1d
2a
2a
2a
2b
4b
4c
4d
4j
88
95
82
97
1
2
4
Yield
[%][b]
1
2
3
66
5
2b
93
2a
2a
77[c]
75
[a] See the Supporting Information for details. [b] Yield of the isolated E
isomer.
Table 3. One-pot olefination of aldehydes 1, followed by the in situ re-
duction of intermediate enones 4.[a]
4
5
2a
55[d]
2a
2a
72
1
2
10
Yield
[%][b]
6
7
30
77
1
2
3
4
1a
2a
60
76
60
80
1a
1b
1c
1a
1c
2b
2b
8
9
2b
2b
74
96
[a] See the Supporting Information for details. [b] Yield of the isolated E
isomer.
10
11
1d
1e
2b
2b
69
96
by a Diels–Alder reaction, ranged from reasonable to good.
More interestingly, the combined yields of the two reactions
performed separately were comparable to that of the corre-
sponding one-pot process, demonstrating that the cycloaddi-
tion reaction was not inhibited by the presence of the cata-
lyst 5.
[a] See the Supporting Information for details. [b] Yield of the isolated E
isomer. [c] Mixture of E and Z isomers (75:25). [d] Mixture of Z and E
isomers (61:39).
In summary, we have developed an unprecedented, atom-
economical, one-pot procedure for the olefination of car-
bonyl compounds to form conjugated enones that is based
on the rhenium(V)-catalysed Meyer–Schuster rearrange-
ment of intermediate alkynols. This procedure compares fa-
vourably with other traditional protocols in terms of effi-
ciency, stereoselectivity, simplicity of execution and ready
accessibility of starting materials. Moreover, we have shown
that the rhenium(V) complex 5 is a robust catalyst that is
compatible with a variety of other reagents and can thus be
used in different one-pot operations to quickly assemble a
number of products while generating a minimal amount of
waste. We believe that these new procedures add to other
and thus be capable of catalysing the Diels–Alder reaction.
However, no cycloadduct was formed upon heating the mix-
tures containing an enone 4 and cyclopentadiene, in the
presence of only the rhenium catalyst 5, in DME at reflux
for several hours. Instead, the reactions proceeded smoothly
at RT after the addition of BF3·Et2O (1.1 equiv) to the mix-
ture, providing the expected endo cycloadducts 11
(Table 4).[11] The overall yields of the two consecutive reac-
tions, that is, the M–S rearrangement of alkynol 3 followed
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G. Vidari et al.
Table 4. One-pot Meyer–Schuster rearrangement of alkynols 3, followed
by the in situ Diels–Alder reaction of intermediate enones 4.[a]
times for the coupling reactions of 1 and 2 and the subsequent in situ
Meyer–Schuster rearrangement are reported in Table 1. Enones 4b and
4d were inseparable mixtures of E and Z isomers: 75:25 and 31:69, re-
1
spectively (determined by H NMR spectroscopy data).
General procedure for the one-pot Meyer–Schuster rearrangement of al-
kynols 3, followed by the in situ Diels–Alder reaction of intermediate
enones 4: Complex 5 ([ReOCl3ACTHNUTRGENN(UG OPPh3)ACHTUNGTREN(NUNG SMe2)]; 5 mol%) was added to a
solution of alkynol 3 in DME and the mixture was heated to 808C and
stirred for 1–3 h (Table 4) until the disappearance of starting material 3.
Subsequently, the reaction mixture was cooled to room temperature and
freshly distilled cyclopentadiene (4.0 equiv) was added. The mixture was
then further cooled to À788C and BF3·Et2O (46.5% solution in Et2O,
1.16 equiv) was added. The reaction was stirred for 4 h at À788C, then at
RT for an additional 8 h. The reaction mixture was quenched with a sa-
turated solution of aqueous NaHCO3 and extracted with Et2O. The aque-
ous phase was washed with Et2O (3ꢂ30 mL) and the combined organic
layers were dried over Na2SO4 and concentrated at reduced pressure.
The residue was separated by column chromatography; elution with
hexane/EtOAc (95:5) gave the chromatographically pure endo-norbor-
nene cycloadduct 11. The overall yields of cycloadducts 11 based on alky-
nols 3 are reported in Table 4, and the individual times for the Meyer–
Schuster rearrangement and the Diels–Alder reaction are provided in the
Supporting Information. The endo stereochemistry of each cycloadduct
11 was established by using NOESY and COSY experiments.
Entry
1
3
11
Yield
[%]
55
30
73
75
2
3
4
Acknowledgements
Financial support from the Italian MIUR (funds PRIN 2008 and 2009) is
acknowledged.
[a] See the Supporting Information for details. The endo stereochemis-
tries of adducts 11 were established on the basis of NOESY and 1H–1H-
COSY NMR spectroscopy experiments. Am=C5H11.
Keywords: carbonyl compounds · isomerization · Meyer–
Schuster reactions
methods
· olefination · rhenium · synthetic
protocols of modern organic chemistry by illustrating the
brevity and the efficiency of one-pot, consecutive reaction
processes.[12] Our current work includes efforts to couple the
Re-catalysed M–S rearrangement with different carbon–
carbon bond-forming reactions, and to apply this olefination
strategy in total synthesis.
[1] a) S. Patai, Z. Rappoport, The Chemistry of Enones, Wiley, New
York, 1989; b) C. E. Foster, P. R. Mackie in Comprehensive Organic
Functional Group Transformations II, Vol. 3 (Eds.: A. R. Katritzky,
R. J. K. Taylor), Elsevier, Oxford, 2005, pp. 215–266; c) J. Otera,
Modern Carbonyl Chemistry, Wiley–VCH, Weinheim, 2000.
[2] For reviews, see: a) M. E. Jung in Comprehensive Organic Synthesis,
Vol. 4 (Eds.: B. M. Trost, I. Fleming, M. F. Semmelhack), Pergamon,
Oxford, 1991, pp. 1–67; b) V. J. Lee in Comprehensive Organic Syn-
thesis, Vol. 4 (Eds.: B. M. Trost, I. Fleming, M. F. Semmelhack), Per-
gamon, Oxford, 1991, pp. 69–137, 139–168; c) J. A. Kozlowski in
Comprehensive Organic Synthesis, Vol. 4 (Eds.: B. M. Trost, I. Flem-
ing, M. F. Semmelhack), Pergamon, Oxford, 1991, pp. 169–198.
[3] J. Clayden, N. Greeves, S. Warren, P. Wothers, Organic Chemistry,
Oxford University Press, Oxford, 2001.
Experimental Section
General procedure for the one-pot olefination of carbonyl compounds:
BuLi (1.6m in hexane, 1.1 equiv) was added dropwise to a solution of
alkyne 2 (1.2 equiv) in DME that was cooled at À788C. After stirring for
1 h at À788C, carbonyl compound 1 (1 equiv) was added in a single por-
tion and the reaction mixture was stirred for 1.5–3 h, depending on the
substrate (Table 1), until the complete disappearance of starting material
1 was indicated by TLC. Only in the case of the reaction between ketone
1e and alkyne 2b was the reaction mixture allowed to warm to RT. After
completion of the reaction, the mixture was warmed to RT and a solution
of p-TsOH (1.43 equiv) in DME was added. After checking the acidity of
[4] B. M. Trost, Science 1991, 254, 1471–1477.
[5] a) L. Liu, B. Xu, G. B. Hammond, Beilstein J. Org. Chem. 2011, 7,
606–614; b) D. A. Engel, G. B. Dudley, Org. Biomol. Chem. 2009, 7,
4149–4158, and references therein.
[6] For examples, see: a) R. S. Ramꢃn, N. Marion, S. P. Nolan, Tetrahe-
dron 2009, 65, 1767–1773; b) M. Stefanoni, M. Luparia, A. Porta, G.
Zanoni, G. Vidari, Chem. Eur. J. 2009, 15, 3940–3944; c) see
Ref. [5b]; d) H. Zheng, M. Lejkowski, D. G. Hall, Chem. Sci. 2011,
2, 1305–1310.
[7] a) B. D. Sherry, R. N. Loy, F. D. Toste, J. Am. Chem. Soc. 2004, 126,
4510–4511; b) M. M. Abu-Omar, S. I. Khan, Inorg. Chem. 1998, 37,
4979–4985.
[8] D. A. Engel, G. B. Dudley, Org. Lett. 2006, 8, 4027–4029.
[9] For comparison, the M–S rearrangement of isolated 1-phenylnon-4-
yn-3-ol, catalysed by 5 (1 mol%) in DME, gave the enone 4 f in
41% yield.
the medium, the complex [ReOCl3ACHTNUTRGENNUG(OPPh3)ACHTUGNTERN(NUGN SMe2)] (5; 1 mol%) was
added and the solution was warmed to 808C for a time that varied be-
tween 4 h and 7 days, depending on the substrate (Table 1), until com-
plete disappearance of the intermediate alkynol was indicated by TLC.
The reaction mixture was quenched by the addition of a saturated solu-
tion of aqueous NH4Cl, and the aqueous layer was extracted with Et2O
(3ꢂ20 mL). The combined organic layers were dried over Na2SO4 and
concentrated at reduced pressure. The crude product was purified by
column chromatography (hexane/EtOAc gradient, from 98:2 to 95:5) to
give enone 4. The overall yields (from NMR data) of chromatographical-
ly pure (E)-enones 4 based on carbonyl compounds 1, and the individual
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Synthesis of Enones by the Re-Catalysed Meyer–Schuster Rearrangement
COMMUNICATION
[10] During the course of this work, the one-pot Re-catalysed Meyer–
Schuster rearrangement of propargyl alcohols followed by 1,2 hydro-
group of the enone 4 and/or by coordination to the complex 5,
which is likely to enhance its catalytic activity.
silylation of the enone with Me2PhSiH was reported: K. A. Nolin,
R. W. Ahn, Y. Kobayashi, J. J. Kennedy-Smith, F. D. Toste, Chem.
Eur. J. 2010, 16, 9555–9562.
[12] T. Hudlicky, J. W. Reed, The Way of Synthesis, Wiley–VCH, Wein-
heim, 2007.
Received: May 9, 2012
Revised: June 17, 2012
Published online: && &&, 0000
[11] At this stage, it is premature to speculate whether BF3·Et2O pro-
motes the Diels–Alder reaction by coordination to the carbonyl
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G. Vidari et al.
Domino Reactions
E. Mattia, A. Porta, V. Merlini,
G. Zanoni, G. Vidari* ....... &&&& — &&&&
One-Pot Consecutive Reactions Based
on the Synthesis of Conjugated
Enones by the Re-Catalysed Meyer–
Schuster Rearrangement
Re catalysis in one-pot reactions: An
atom-economical, one-pot strategy that
involves alkyne deprotonation and a
subsequent rhenium(V)-catalysed
Meyer–Schuster rearrangement of the
alkynol to provide a,ß-unsaturated
enones in high yield has been devel-
oped (see scheme). Subsequent in situ
a hydride reduction or Diels–Alder
reaction of the enones provided prod-
ucts in good-to-high overall yields.
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ꢁ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 0000, 00, 0 – 0
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These are not the final page numbers!