A microwave-assisted domino rearrangement of propargyl vinyl ethers to multifunctionalized aromatic platforms

Article abstract of DOI:10.1002/chem.201003532

H makes a difference! A novel reactivity profile of propargyl vinyl ethers has been developed, which is controlled by the presence of a hydrogen atom at the homopropargylic position (see scheme; EWG=electron-withdrawing group). This strategy was conveniently used to construct multifunctionalized phenolic platforms, including salicylaldehydes and the corresponding ketone derivatives. Copyright

Full text of DOI:10.1002/chem.201003532

DOI: 10.1002/chem.201003532
A Microwave-Assisted Domino Rearrangement of Propargyl Vinyl Ethers to
Multifunctionalized Aromatic Platforms
David Tejedor,*[a, b] Gabriela Mꢀndez-Abt,[a, b] Leandro Cotos,[a, b]
Miguel A. Ramirez,[c] and Fernando Garcꢁa-Tellado*[a, b]
In memory of Professor Rafael Suau
Propargyl vinyl ethers (PVEs) 1 constitute a privileged
group of small size, structurally simple, readily available,
and densely functionalized scaffolds.[1–4] Efforts from our
group,[2] and others,[3] have revealed the synthetic potential
of these platforms in accessing important heterocyclic cores.
The key to the chemical reactivity encoded in these struc-
tures is the [3,3] propargylic sigmatropic rearrangement[5]
shown in Scheme 1. The allenyl compounds 2, thus obtained,
and primary amines, via the thermally-assisted formation of
a homoallenyl ester intermediate 2. During the course of
these studies, we discovered a new chemical reactivity of
these platforms when a solution of PVE 3a in toluene was
submitted to microwave (MW) irradiation in a sealed vial
(Scheme 2). The reaction cleanly afforded the unexpected
Scheme 1. ACHTUNGTRENNUNG[3,3] Propargylic sigmatropic rearrangement of PVEs.
are reactive units and well suited to participate in a wide
array of chemical transformations. Thus, in the presence of
metallic catalysts, they have been selectively transformed
into furans,[3a–d] 2H-pyrans,[3e] dihydropyrans,[3f] 1,2-dihydro-
pyridines,[3g] or pyrroles.[3h] Recently, we have described a
metal-free, microwave-assisted domino synthesis of substi-
tuted 1,2-dihydropyridines[2c] and pyridines,[2d] from PVEs 1
Scheme 2. Unexpected new chemical reactivity of 3a, after microwave
(MW) irradiation.
mixture of compounds 4a and 5a in 91% overall yield.
These structures featured an unprecedented chemical out-
come for this domino process, which is enabled by the pres-
ence of a hydrogen atom at the homopropargylic position.
Fascinated by these unexpected results, we undertook the
study and scope of this novel domino reaction. Overall, this
reaction should provide an expedient route to useful multi-
functionalized phenolic platforms,[6] such as 4, which consti-
tute key structural motifs for the preparation of numerous
pharmacologically important natural products (e.g., coumar-
ins,[7a] flavones,[7b] and several mycotoxins[7c]) and catalysts.[8]
In addition, PVEs 3 are easily accessible starting materials,
spanning a wide substitution pattern. They are conveniently
assembled from commercial sources (aldehydes, alkynes,
and alkyl propiolates) in one or two straightforward synthet-
ic steps.[2]
[a] Dr. D. Tejedor, G. Mꢀndez-Abt, L. Cotos, Dr. F. Garcꢁa-Tellado
Quꢁmica Biolꢂgica y Biotecnologꢁa
Instituto de Productos Naturales y Agrobiologꢁa
Consejo Superior de Investigaciones Cientꢁficas
Avda. Astrofꢁsico Francisco Sꢃnchez 3
38206 La Laguna, Tenerife (Spain)
Fax : (+34)922-2260135
E-mail: fgarcia@ipna.csic.es
dtejedor@ipna.csic.es
[b] Dr. D. Tejedor, G. Mꢀndez-Abt, L. Cotos, Dr. F. Garcꢁa-Tellado
Instituto Canario de Investigaciꢂn del Cꢃncer (Spain)
[c] Dr. M. A. Ramirez
Instituto Universitario de Bioorgꢃnica Antonio Gonzꢃlez
Universidad de La Laguna
Avda. Astrofꢁsico Francisco Sꢃnchez 2
38206 La Laguna, Tenerife (Spain)
We hypothesized that the formation of products 4a and
5a should result from a domino process triggered by the ex-
pected microwave-assisted rearrangement of PVE 3a to the
corresponding dienic ester 7a, via the formation of a transi-
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201003532.
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Chem. Eur. J. 2011, 17, 3318 – 3321

COMMUNICATION
ent homoallenyl ester 6a.[9] A subsequent tandem cycliza-
tion–aromatization reaction should afford the corresponding
phenolic derivatives 4a with the concomitant elimination of
one equivalent of methanol. Addition of this liberated meth-
anol to the intermediate 7a should trigger a second reaction
path affording the product 5a via the formation of hemiace-
tal 8a. In this scenario, it was expected that the removal of
the generated methanol should funnel the whole transfor-
mation towards the exclusive formation of 4a. With this
idea, we designed an experimental protocol that included
molecular sieves (4 ꢅ) in the reaction mixture, to act as a
methanol scavenger. Under these new conditions, the forma-
tion of the malonate derivative 5a was totally suppressed.
After several experiments, the reaction was standardized,
and scaffold 3a was conveniently converted into the salicy-
laldehyde 4a in 76% yield (Table 1, entry 1). Salicyladehyde
With the standardized protocol in place, we next studied
the scope of this domino reaction (Table 1). In general, the
reaction was tolerant to substitution of the starting PVE;
the reaction accommodated different aromatic substituents
at the terminal position of the alkyne, regardless of their
electronic nature (Table 1, entries 1–10). However, substitu-
tion of the aromatic substituent with an aliphatic substituent
at this position, resulted in a lower yield of the correspond-
ing salicylaldehyde derivative (Table 1, entry 14). Derivative
3e, with a benzyl substituent at the propargylic position and
a phenyl group at the terminal alkyne position, generated
the p-terphenyl derivative 4e in an excellent yield of 89%
(Table 1, entry 5). Fully substituted propargylic platforms
3k–3m afforded the corresponding phenolic ketones 4k–4m
in good yields (Table 1, entries 11–13). In these cases, the
use of a methanol scavenger is unnecessary because the cor-
responding intermediate ketals 8k–8m (Scheme 2) cannot
rearrange and they remain in equilibrium with their dienic
precursors 7k–7m. Conjugated alkynes 3o–3q were also
convenient substrates for this reaction, affording the corre-
sponding methyl 2-formyl-3-hydroxybenzoate derivatives
4o–4q (Table 1, entries 15–17). Interestingly, the substitution
at the homopropargylic position increased the chemical effi-
ciency of the reaction from 29% (4q) to 70% (4o) and
56% (4p). A silicon substituent at the alkyne position was
also tolerated (Table 1, entry 18), although with diminished
efficiency (30%). Finally, the reaction delivered valuable o-
fluorophenol derivatives in an easy and efficient manner
(Table 1, entry 7).
Table 1. Substitution of R groups on 3 to test the scope of the domino re-
action.
Entry
R1
R2
R3
4
Yield [%][a]
1
2
3
4
5
6
7
8
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Et
H
H
H
H
H
H
H
H
H
H
Me
nPen
Ph
H
H
H
H
H
4a
4b
4c
4d
4e
4 f
4g
4h
4i
4j
4k
4l
4m
4n
4o
4p
4q
4r
76
72
67
27
89
61
63
72
iPr
tBu
H
Ph
PhCH2
F
Et
Et
Et
Et
Et
Et
Et
nPr
Ph
H
With regard to the mechanism of this domino reaction, a
working proposal is outlined in Scheme 3. The reaction
manifold is launched by the microwave-assisted propargyl
Claisen rearrangement of the starting PVE 3 to generate the
p-MeOC6H4
3,4-Cl2C6H3
p-MeC6H4
Ph
Ph
Ph
9
77
81
10
11
12
13
14
15
16
17
18
65[b]
72[b]
75[b]
43[c]
70
nBu
CO2Me
CO2Me
CO2Me
Me3Si
56
29
30
Et
[a] Yield of isolated product. [b] Generally, the reaction gave the same
yields in the absence of molecular sieves 4 ꢅ. [c] Diester 5n was also ob-
tained (see the Supporting Information for details).
4a, incorporating a phenyl substituent at the C6 position of
the ring, can be regarded as a functionalized biphenyl deriv-
ative, and therefore, a pharmacologically privileged structur-
al motif.[10] The common synthetic approach to salicylalde-
hydes relies mainly on the direct electrophilic substitution of
a suitable phenol derivative. From a preparative point of
view, this transformation suffers from regioselective draw-
backs when the positions ortho and para with respect to the
hydroxyl functionality are not conveniently blocked.[11]
From this perspective, the direct generation of a 3,6-disubsti-
tuted salicylaldehyde derivative is notable.
Scheme 3. A mechanistic proposal for the domino process. Microwave-as-
sisted reactions: a) propargyl Claisen rearrangement; b) pseudo-pericyclic
[1,3] hydride shift; c) 4E–4Z isomerization; d) [1,5] hydride shift; e) eno-
lization; f) electrocyclization; g) aromatization.
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F. Garcꢁa-Tellado, D. Tejedor et al.
allenic intermediate 6, which rearranges to the correspond-
ing dienyl intermediate 7 by a thermally allowed pseudo-
pericyclic [1,3] hydride shift.[12] A tandem 4E/4Z isomeriza-
tion–[1,5] hydride shift–enolization reaction affords the key
dienyl enol intermediate 11. Finally, electrocyclization and
aromatization deliver the phenolic derivative 4. Three ex-
perimental observations reinforced this mechanistic picture
(see the Supporting Information for further details): 1) MW
irradiation of the 2H-pyran derivative 13[3b] afforded phenol
15 by the well-established reversible electrocyclic ring open-
ing to 1-oxatriene derivative 14 (Scheme 4)[13]; 2) MW irra-
In summary, we have shown how readily available PVEs
3, can be efficiently converted into convenient multifunc-
tionalized aromatic products by using a microwave-assisted,
novel domino process involving a key electrocyclization re-
action. Efforts directed towards the application of this meth-
odology in natural product synthesis are ongoing in our lab-
oratory and will be reported in due course.
Experimental Section
Representative procedure: Propargyl vinyl ether 3a (0.700 mmol), acti-
vated molecular sieves 4 ꢅ (250 mg) and dry xylene (1 mL) were placed
in a sealed microwave vial and the mixture was irradiated for 1 h in a
single-mode microwave oven (300 W, 2008C). The reaction mixture was
filtered through a pad of celite using dichloromethane as a solvent. After
removing the solvent at reduced pressure, the products were purified by
flash column chromatography (silica gel, n-hexane/EtOAc, 95:5) to yield
1
4a (76%). M.p. 38.8–39.48C; H NMR (400 MHz, CDCl3, 258C): d=1.28
(t, 3J(H,H)=7.2 Hz, 3H), 2.74 (q, 3J(H,H)=7.2 Hz, 2H), 6.83 (d, 3J-
ACTHNUTRGENNUG CAHTUNGTRENNUGN
AHCTUNGERTG(NNUN H,H)=7.6 Hz, 1H), 7.34–7.36 (m, 2H), 7.43–7.46 (m, 4H), 9.84 (s, 1H),
12.22 ppm (s, 1H); 13C NMR (100 MHz, CDCl3, 258C): d=13.6, 22.3,
117.4, 121.0, 128.0, 128.3, 130.1, 132.0, 135.7, 137.7, 145.0, 160.8,
197.4 ppm; IR (CHCl3): n¯ =3021.7, 2974.3, 2933.3, 2880.2, 1641.7, 1426.1,
1316.5, 1222.2 cmÀ1; MS (70 eV): m/z (%): 226 (100) [M+H]+, 225 (27),
211 (62), 208 (22), 197 (20), 165 (14), 152 (14).; elemental analysis calcd
(%) for C15H14O2: C 79.62, H 6.24; found: C 79.68, H 6.22.
Scheme 4. Reversible electrocyclic ring opening of 2H-pyran derivative
13 to 1-oxatriene derivative 14, to give phenol 15.
diation of tetradeuterated PVE derivative 3q delivered ex-
clusively dideuterated salicylate 4q (Scheme 5), excluding
any hydrogen/deuterium (H/D) scrambling during the pro-
cess; 3) (E)-dimethyl 2-(pent-2-en-1-ylidene)malonate did
Acknowledgements
This research was supported by the Spanish MICINN and the European
RDF (CTQ2008-06806-C02-01 and CTQ2008-06806-C02-02), the Spanish
MSC ISCIII (RETICS RD06/0020/1046), FUNCIS (REDESFAC PI01/
06). G.M.A. and L.C. thank the Spanish MEC for FPU and FPI grants,
respectively. The authors thank Dr. T. Martꢁn and Professor V. S. Martꢁn
for insightful discussions, Professor F. Cossꢁo for mechanistic advice, and
Anna Jurado for technical assistance.
Scheme 5. MW irradiation of tetradeuterated PVE derivative 3q to give
exclusive formation of dideuterated salicylate 4q.
Keywords: allenes
·
domino reactions
·
electrocyclic
reactions · heterocycles · propargyl vinyl ethers
not react under the standardized conditions.[14] This finding
highlights the importance of the acyl group, which modu-
lates the acidity of the allylic hydrogen involved in the
double-bond isomerization, to provide the required enol 11.
Preliminary calculations support this mechanistic picture
(see the Supporting Information for details).
Finally, functionalization of the phenolic products can be
easily carried out as exemplified by bromination of 4a by
treatment with N-bromosuccinimide (Scheme 6).
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succinimide.
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Microwave-Assisted Domino Rearrangement of Propargyl Vinyl Ethers
COMMUNICATION
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Received: December 7, 2010
Published online: February 15, 2011
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