Microwave-Assisted Organocatalyzed Rearrangement of Propargyl Vinyl Ethers to Salicylaldehyde Derivatives: An Experimental and Theoretical Study

Article abstract of DOI:10.1002/chem.201503171

The microwave-assisted imidazole-catalyzed transformation of propargyl vinyl ethers (PVEs) into multisubstituted salicylaldehydes is described. The reaction is instrumentally simple, scalable, and tolerates a diverse degree of substitution at the propargylic position of the starting PVE. The generated salicylaldehyde motifs incorporate a broad range of topologies, spanning from simple aromatic monocycles to complex fused polycyclic systems. The reaction is highly regioselective and takes place under symmetry-breaking conditions. The preparative power of this reaction was demonstrated in the first total synthesis of morintrifolin B, a benzophenone metabolite isolated from the small tree Morinda citrifolia L. A DFT study of the reaction was performed with full agreement between calculated values and experimental results. The theoretically calculated values support a domino mechanism comprising a propargyl Claisen rearrangement, a [1,3]-H shift, a [1,7]-H shift (enolization), a 6π electrocyclization, and an aromatization reaction.

Full text of DOI:10.1002/chem.201503171

DOI: 10.1002/chem.201503171
Full Paper
&
Domino Reactions
Microwave-Assisted Organocatalyzed Rearrangement of Propargyl
Vinyl Ethers to Salicylaldehyde Derivatives: An Experimental and
Theoretical Study
David Tejedor,*[a] Leandro Cotos,[a] Daniel Mµrquez-Arce,[a] Mikel Odriozola-Gimeno,[b]
Miquel Torrent-Sucarrat,[b, c] Fernando P. Cossío,[b] and Fernando García-Tellado*[a]
Abstract: The microwave-assisted imidazole-catalyzed trans-
formation of propargyl vinyl ethers (PVEs) into multisubsti-
tuted salicylaldehydes is described. The reaction is instru-
mentally simple, scalable, and tolerates a diverse degree of
substitution at the propargylic position of the starting PVE.
The generated salicylaldehyde motifs incorporate a broad
range of topologies, spanning from simple aromatic mono-
cycles to complex fused polycyclic systems. The reaction is
highly regioselective and takes place under symmetry-break-
ing conditions. The preparative power of this reaction was
demonstrated in the first total synthesis of morintrifolin B,
a benzophenone metabolite isolated from the small tree
Morinda citrifolia L. A DFT study of the reaction was per-
formed with full agreement between calculated values and
experimental results. The theoretically calculated values sup-
port a domino mechanism comprising a propargyl Claisen
rearrangement, a [1,3]-H shift, a [1,7]-H shift (enolization),
a 6p electrocyclization, and an aromatization reaction.
Introduction
Propargyl vinyl ethers (PVEs) 1 are a privileged group of small-
size, densely functionalized, and readily accessible linear scaf-
folds. The main key to the chemical reactivity encoded in
these structures is the [3,3]-sigmatropic rearrangement (prop-
argyl Claisen rearrangement) shown in Scheme 1A,[1] which
takes place irreversibly and under thermodynamic control to
generate the allene 2.[2] Since the first, seminal thermally
driven rearrangement achieved by Black and Landor in 1965,[3]
which served to determine that propargylic systems could be
accommodated into the Claisen rearrangement, a vast number
of propargyl Claisen rearrangements have been successfully
performed.[1] The main drawback of these rearrangements is
the requirement for high temperatures, which forced the use
[a] Dr. D. Tejedor, Dr. L. Cotos, D. Mµrquez-Arce, Dr. F. García-Tellado
Departamento de Química Biológica y Biotecnología
Instituto de Productos Naturales y Agrobiología
Consejo Superior de Investigaciones Científicas
Avenida Astrofísico Francisco Sµnchez 3
38206 La Laguna, Tenerife (Spain)
E-mail: fgarcia@ipna.csic.es
dtejedor@ipna.csic.es
[b] M. Odriozola-Gimeno, Dr. M. Torrent-Sucarrat, Prof. F. P. Cossío
Facultad de Química
Universidad del País Vasco-Euskal Herriko Unibertsitatea (UPV/EHU)
and Donostia International Physics Center (DIPC)
P. K. 1072, San Sebastian-Donostia (Spain)
[c] Dr. M. Torrent-Sucarrat
Ikerbasque, Basque Foundation for Science
María Díaz de Haro 3, 68, 48013 Bilbao (Spain)
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201503171.
Scheme 1. The MW-assisted propargyl Claisen rearrangement of propargyl
vinyl ethers 1. EWG=electron-withdrawing group.
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of high-boiling solvents and harsh conditions. These experi-
mental difficulties prevented their use in preparative organic
synthesis, in sharp contrast to the counterpart involving allyl
vinyl ethers.[4] However, this scenario dramatically changed in
the last decade with the emergence of milder metal-catalyzed
protocols[5] and the replacement of conventional heating with
laboratory microwave (MW) equipment.[1] Under MW heating,
allenes 2 rearrange to the more stable diene derivatives 3
through a pseudo-pericyclic [1,3]-H shift (Scheme 1A). Overall,
this tandem rearrangement transforms a C3-O-C2 linear struc-
ture, easily assembled through CÀO bond-forming chemistry,
into an all-sp2-linear C5 carbogenic block[6] armed with a reac-
tive carbonyl group (aldehyde or ketone), an ester group, and
a doubly conjugated diene. An exception to this outcome is
represented by the activated allenes 5 (EWG=ester or secon-
dary amide),[7] which directly rearrange to the furan derivatives
6 through a tandem enolization/O cyclization/H transfer pro-
cess (Scheme 1B).[8]
dehydes are commonly prepared by direct formylation of the
corresponding phenol derivatives[15] under the classical
Reimer–Tiemann conditions (CHCl3/KOH)[15a] or the Duff proce-
dure (hexamethylenetriamine/acetic acid /sulfuric acid).[15b,c] In-
terestingly, the 3,6-disubstitution pattern present in salicylalde-
hydes 9 cannot be easily accessed by using these standard
protocols. Among other drawbacks, these reactions have regio-
selectivity problems when the ortho and para positions to the
hydroxyl functionality are not conveniently blocked.[16]
The efficiency and instrumental simplicity of this reaction to-
gether with the importance of the salicylaldehyde motif
prompted us to undertake a systematic study of this reaction
with the aim of transforming it into a general, robust, and
preparative protocol for accessing salicylaldehyde-based struc-
tural motifs. The transformation of this reaction into a standard
synthetic protocol with preparative value (academic and indus-
trial) required implementation of a catalytic version incorporat-
ing the following: 1) the use of a cheap and easy handled cata-
lyst (additive); 2) high tolerance to broad and diverse substitu-
tion patterns on the PVE; and 3) bench-friendly reaction pro-
cessing. We report herein how these conditions could be met
by using imidazole (10 mol%) as a basic catalyst and how this
catalytic manifold could be used for the construction of salicy-
laldehyde motifs supported on a broad range of topologies,
which spanned from simple aromatic monocycles to complex
fused polycyclic systems. We also performed a theoretical
study on this reaction that is in full agreement with the ob-
served experimental results. Finally, the preparative power of
this reaction has been demonstrated in the first total synthesis
of morintrifolin B,[17] a benzophenone metabolite isolated from
the small tree Morinda citrifolia L.
A particularly striking reactivity profile arises from monosub-
stituted PVEs 7 (R3 =H, hereinafter referred to as secondary
PVEs) bearing a linear chain at the propargylic position
(Scheme 1C). In these cases, the rearrangement affords
a roughly equimolar mixture of salicylaldehyde 9 and trisubsti-
tuted olefin 10.[9] The formation of salicylaldehyde 9 can be
formally rationalized through a tandem enolization/6p electro-
cyclization/aromatization process with the net generation of
a methanol molecule per molecule of salicylaldehyde. On the
other hand, the stereoselective formation of the trisubstituted
olefin 10 should be mediated by the formation of the hemi-
acetal 13 to launch an internal redox process involving a [1,5]-
H shift. Overall, this manifold is a divergent chemical process
that can produce two well-differentiated products from the
same reactive intermediate and through two interconnected
pathways (the product of one pathway launches the other). Results and Discussion
Remarkably, the manifold could be selectively funneled toward
Catalytic synthesis of 3,6-disubstituted salicylaldehydes
each of these two products by careful design of the experi-
mental conditions. Thus, salicylaldehydes 9 could be cleanly
obtained in 60–80% yield by MW irradiation of a xylene solu-
tion of PVEs 7 in the presence of 4 Š molecular sieves (MS)
(300 mg per mole substrate).[9] Although initially we used 4 Š
MS as additive, we later discovered that pyridine (200 mol%)
could replace the MS, rendering the process homogenous and
easier to perform.[10] It was assumed that the beneficial action
of the two additives was related to a reduction of the activa-
tion barrier for the enolization process, otherwise the limiting
step of the process. Although this is an uncommon reactivity
for MS, there are some precedents for their use in enolization
processes.[11] On the other hand, the MW irradiation of a metha-
nolic solution of PVEs 7 exclusively afforded the olefin deriva-
tives 10 in good to excellent yields (75–95%) and with com-
plete stereoselectivity (the two alkyl chains are located in trans
positions).[12]
from secondary PVEs
Although pyridine had proved to be a convenient additive for
this transformation,[10] the large excess required (200 mol%)
precluded its use in large-scale preparative reactions. Guided
by the current principles of sustainable chemistry,[18] we
searched for new additives to be used as true catalysts. For
this study, we chose the transformation of PVE 7a into salicyl-
aldehyde 9a (Table 1). We had observed in earlier studies[9,10]
that the substitution pattern of this PVE was one of the worst
tolerated by this reaction with both 4 Š MS (43%)[9] and pyri-
dine (53%).[10] Because the use of pyridine improved the effi-
ciency of the reaction by 10%, we envisioned that this reaction
could be a convenient benchmark for the assay of other basic
additives better suited than pyridine to catalyze the required
enolization of dienal 8 to intermediate 11 (Scheme 1C). With
this idea in mind, we assayed the bases shown in Table 1 (en-
tries 1–15). Additionally, we assayed a set of common acids of
moderate strength to see if they could also be suitable addi-
tives for this reaction (Table 1, entries 16–18). The reactions
were performed under our previously established conditions
[xylene (1 mL), MW (300 watt, 2008C, and closed vessel), 1 h]
The salicylaldehyde motif is an important building block for
the preparation of numerous pharmacologically relevant cou-
marins,[13a] flavonoids,[13b] chromenes,[13c,d] catechols,[13e] and
several mycotoxins,[13f] as well as chiral catalysts based on tran-
sition metal Schiff base complexes (salen catalysts).[14] Salicylal-
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Table 1. Optimization of the additive for the MW-assisted synthesis of
salicylaldehyde 9a.
Entry
Additive[a]
pKa[b]
9a+10a [%]
Ratio 9a/10a[c]
1
2
3
4
5
6
7
8
DABCO
aniline
DMBA
pyridine[d]
imidazole
collidine
DMAP
DIPEA
quinuclidine
DBU
tBuOK
indole
pyrrole
urea
TMP
C6H6CO2H
C5H10NH2+AcOÀ
phenol
4 Š MS[f]
2.97
4.63
4.68
5.2
6.9
7.4
9.2
10.8
11
12
17
21[e]
23[e]
26.9[e]
37[e]
4.2
64
35
36
87
84
68
78
64
44
62
37
34
34
42
74
58
56
55
90
1.5
0.17
0.16
1.6
1.7
1.4
2.1
1.4
0.8
1.5
0.3
0.1
0.1
0.7
1.8
0.8
0.6
0.1
1
9
10
11
12
13
14
15
16
17
18
19
Scheme 2. Imidazole-catalyzed synthesis of salicylaldehydes 9 from secon-
dary propargyl vinyl ethers 7.
ondary PVEs containing the ethoxyacetylene motif (ethoxyacet-
ylene is commercial available) allows for fast access to a broad
range of 3-substituted 6-ethoxysalicylaldehyde platforms.
8.7
9.95
[a] Abbreviations: DMBA: 1,3-dimethylbarbituric acid; DMPA: 4-dimethyla-
minopyridine; DIPEA: N,N-diisopropylethylamine; DBU: 1,8-diazabicy-
clo[5.4.0]undec-7-ene; TMP: 2,2,6,6-tetramethylpiperidine. [b] In H2O.
[c] Determined by NMR spectroscopy. [d] 200 mol%. [e] In DMSO.
Catalytic synthesis of 3,4,6-trisubstituted salicylaldehydes
from tertiary PVEs
[f] 300 mgmmolÀ1
.
Once the catalytic version of the reaction had been standar-
dized, we studied its extension to PVEs 1 bearing two substitu-
ents at the propargylic position (R2 and R3 ¼ H, hereinafter re-
ferred to as tertiary PVEs). The main advantages associated
with the incorporation of tertiary PVEs into the reaction mani-
fold are related to: 1) skeletal complexity: the use of cyclic ke-
tones (mono- or polycycles, simple or fused) should increase
the power of the manifold to generate structural complexity
and topological diversity; 2) reactivity: the presence of two
substituents on the propargylic position of the tertiary PVE
should favor both the propargyl Claisen rearrangement[1] and
the enolization process (see Scheme 1C), which should trans-
late into a net increase in the reaction efficiency. With these
ideas in mind, we prepared an extensive set of tertiary PVEs
1[23] incorporating a wide array of substituents and molecular
topologies (Scheme 3). These PVEs were conveniently prepared
from the corresponding tertiary propargyl alcohols and methyl
propiolate according to our recently reported protocol.[24]
In general, tertiary PVEs proved to be excellent substrates
for this catalytic reaction affording the corresponding aromatic
derivatives in good average yield. The PVEs 1a–d[23] derived
from acyclic ketones delivered the corresponding aromatic de-
rivatives 14a–d in good average yield and incorporated varied
substitution patterns at the aromatic ring, including alkyl, aryl,
and oxygen-containing substituents. Remarkably, the last-
named functional groups are introduced with high efficiency
(14a, 73%) and in a chemo-differentiated manner (one as
a free OH, the another as a protected OH group). This property
enables orthogonal manipulation of each hydroxyl group at
with a catalytic amount (10 mol%) of additive. Imidazole and
4-(N,N-dimethylamino)pyridine proved to be the best additives
(Table 1, entries 5 and 7), with the highest yields (84 and 78%
combined yield) and 9a/10a ratios of 1.7 and 2.1, respectively.
The yields and ratios were in both cases similar to those ob-
tained with an excess of pyridine (Table 1, entry 4) and sub-
stantially better than those obtained with 4 Š MS (90% com-
bined yield, 1:1 ratio, Table 1, entry 19). Practical reasons (price
and availability) made imidazole the preferred catalyst for this
reaction. The use of acid additives had the reverse effect, gen-
erating the olefin 10a as the main product, albeit with moder-
ate efficiency (Table 1, entries 16–18).
The scope and efficiency of the catalytic manifold was first
studied with the transformation of the secondary PVEs 7a–g
into the corresponding salicylaldehydes 9a–g (Scheme 2).[19] In
general, the reaction delivered the corresponding salicylalde-
hydes 9a–f in moderate to good yields (54–72%) depending
on the substitution pattern of the PVE. Esters, isolated double
bonds, and protected hydroxyl groups were well tolerated. In-
terestingly, the PVE 7g bearing an electron-rich alkyne in its
structure could be also transformed into the corresponding hy-
droxylated salicylaldehyde 9g (38%). In spite of this moderate-
to-low yield, the importance of hydroxylated aromatic plat-
forms[20] and the potential use of hydroxylated salicylaldehydes
as convenient building blocks for accessing biologically rele-
vant compounds[13,21,22] ensures a preparative value for this
transformation. In addition, the easy and direct access to sec-
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the aromatic ring without taking special precautions or using
special reagents. An interesting aspect of this reaction is the
breakage of the symmetry observed when symmetrically di-
substituted PVEs (ketones) are used (CH2R2 =R3). In these
cases, the reaction places the R3 substituent at the C5 position
of the ring, delivering the R2 substituent (the sec-alkyl chain) at
the corresponding C6 position. This is a very important proper-
ty and it allows the final differentiation of the otherwise identi-
cal propargylic substituents of the PVE, which increases the di-
versity-generating power of the reaction manifold. The deriva-
tive 14d is a good example of this symmetry-breaking chemi-
cal differentiation (R3 =Et, R2 =Me).
The tertiary PVEs 1e–u,[23] derived from symmetrical mono-
cyclic ketones, were also convenient substrates for the reaction
and provided a broad set of fused bicyclic salicylaldehyde de-
rivatives featuring varied aromatic functionalization. Thus, the
PVEs 1e–o, armed with a cyclohexane motif, delivered the cor-
responding 1-hydroxy-5,6,7,8-tetrahydronaphthalene-2-carbal-
dehydes 14e–o adorned with a wide array of substituents at
the C3 position. The substituents ranged from simple hydro-
gen, the worst case (14k, 17%), to heteroatoms including sili-
con (14j, 85%), bromine (14l, 47%), oxygen (14m, 77%), and
nitrogen (14o, 93%). The low yield of 14k is in accordance
with our previous results using 4 Š MS[9] or pyridine[10] and con-
firms that substitution at the terminal alkyne position (R1 ¼ H)
is necessary to favor the formation of the enol intermediate 11
(see Scheme 1C). Thus, the high efficiency of this reaction
when a bulky tert-butyl group is located at the terminal posi-
tion of the triple bond in the parent PVE (14h, quantitative) is
remarkable. The substitution of this group by less sterically de-
manding groups (n-Bu, Me) lowered the yield (54 and 55%, re-
spectively). On the other hand, generation of the salicylalde-
hyde 14p (31%) incorporating a fused cyclobutene ring is out-
standing and reflects the potential of this catalytic reaction to
generate molecular topologies not easily accessible by other
methods.[25]
Other topologies based on the bicyclo[n.4.0] motive (n=3,
5, and 10) were explored. The reaction proved to be general
with regard to the size of the non-aromatic ring (14p–s). An
interesting case was offered by the derivative 14s incorporat-
ing a C12 ring in its structure. These topologies incorporating
sp3-rich macrocycles are highly appreciated and underexploit-
ed structural motifs for drug discovery.[26] The reaction also al-
lowed efficient access to C6-substituted 8-hydroxy-1,2,3,4-tetra-
Scheme 3. Imidazole-catalyzed synthesis of salicylaldehydes 14 from tertiary propargyl vinyl ethers 1. [a] The reaction was performed on a gram scale (1.1 g,
4.4 mmol). [b] The corresponding PVEs were not isolated. Yields refer to the two-step process: formation of the PVE from the corresponding propargyl alcohol
and MW-assisted rearrangement. See the Experimental Section and the Supporting Information for details. [c] The yield was assigned by quantitative NMR in-
tegration of the crude reaction residue.
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hydroisoquinoline-7-carbaldehydes (14t, 78%) and 1-hydroxy-
5,6,7,8-tetrahydronaphthalene-2-carbaldehydes bearing a pro-
tected ketone at C7 as a convenient handle for further ring
functionalization (14u, 86%). Both structures are interesting
scaffolds for medicinal chemistry.[27] Salicylaldehydes 14v–z are
examples of fused tricyclic structures with natural-product-like
topologies.[28] Interestingly, in these cases, the formation of sali-
cylaldehydes 14 is accompanied by formation of the corre-
sponding benzoate derivatives 15, which could stem from the
6p electrocyclization/aromatization processes of another diene
2 conformation arising from ketone–ester group interchange
(see below). The subtle influence of the ketone skeleton on
the selectivity of the reaction was apparent from the somehow
surprising formation of the benzoate derivative 15n, the only
benzoate detected in the mono- and bicyclic series. An subtle
electronic effect was also observed in the reactions involving
fused bicyclic ketones. Whereas the formation of the 9H-fluo-
rene derivatives 14x–z showed a clear deterioration of the re-
action efficiency with increasing electron richness of the aro-
matic ring (compare 14x with 14y and 14z), the presence of
an oxygen atom at the 9-position of the 9,10-dihydrophenan-
trene core was irrelevant in terms of efficiency, but not in
terms of selectivity (compare 14v/15v and 14w/15w).
Scheme 4, inset), which in turn relies on the relative stability of
the terminal double bonds.
Application to the first total synthesis of morintrifolin B
The easy access to these multisubstituted salicylaldehydes scaf-
folds gave us the opportunity to use them as convenient start-
ing materials for the synthesis of more complex structures em-
bodying the parent aromatic ring. Among the possible struc-
tures, we chose benzophenones because of their chemical and
biological relevance.[29] The family of natural benzophenones
has more than 300 members with great structural diversity
and bioactive properties including antifungal, anti-HIV, antimi-
crobial, antioxidant, and antiviral activity.[30] Morintrifolin B
(19)[17] is a naturally occurring benzophenone isolated from the
small tree Morinda citrifolia L. (Rubiaceae), commonly known
as noni and widely distributed in southern Asia and the Pacific
islands. The plant has found popular medicinal use for the
treatment of asthma, bone fractures, cancer, cholecystitis, dys-
entery, lumbago, menstrual cramps, urinary difficulties, and
many other ailments.[31] In spite of the pharmacological poten-
tial offered by the constituents of the plant, there are no re-
ports to date on synthetic or biological studies on morintrifo-
lin B. Because of our interest in this kind of compounds, we
undertook a short synthesis of this benzophenone metabolite
from the salicylic acid derivative 16 (Scheme 5), readily avail-
The reaction proved to be highly regioselective when asym-
metrically substituted tertiary PVEs (ketones) were used
(Scheme 4). Thus, PVE 1aa bearing two different alkyl substitu-
Scheme 5. Short synthesis of morintrifolin B.
able from salicylaldehyde 9c by simple phenol protection
(BrBn, K2CO3, acetone, 93%) and aldehyde oxidation (NaClO2,
sulfamic acid, THF/H2O, 87%). The trifluoroacetic anhydride-
mediated reductive coupling with the 2-methoxy resorcinol
derivative 17 assembled the benzophenone core of 19, which
was subjected to selective deprotection (H2, Pd/C) to give the
intermediate 18 (49% for two steps) featuring the same hy-
droxylation pattern as the target natural product. Finally, the
acid-controlled transesterification of this intermediate with eth-
ylene glycol afforded morintrifolin B (19) in 80% yield. The
five-step synthesis delivered morintrifolin B in an overall yield
of 32% from the corresponding propargyl vinyl ether 7c. The
Scheme 4. Regioselectivity in the imidazole-catalyzed reaction.
ents at the propargylic position (R2 =Et, R3 =Me) delivered the
salicylaldehyde 14aa in 63% yield (19:1 isomeric ratio). The re-
action manifold selectively incorporated the more substituted
homopropargylic carbon atom into the final aromatic ring. Ex-
quisite regioselectivity was also observed in the synthesis of
the derivative 14ab (86%, 50:1 isomeric ratio), showing a clear
preference for the benzylic position over the alternative one.
The observed regioselectivity could be explained by the rela-
tive stabilities of the isomeric trienol intermediates (see below;
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synthetic extension to other structurally related benzophe-
nones and studies on their biological activity are in progress.
3.1 kcalmolÀ1. The raw data obtained with the B3LYP and M06-
2X results are reported in the Supporting Information (see
Tables S1–S5 in the Supporting Information) along with the
Cartesian coordinates of each stationary point (see Table S6 in
the Supporting Information). The values discussed in the text
and the values reported in Schemes 6 and 7 are relative free
energies evaluated at the M06-2X/6-311+G(d,p)//B3LYP/6-
311+G(d,p) level of theory. All quantum chemistry calculations
in this work were carried out with the Gaussian 09 program
package.[37] The complete list of energies is reported in Ta-
bles S1–S5 of the Supporting Information. Exhaustive poten-
tial-energy surface scans with all the reaction mechanisms
studied and selected geometrical parameters are shown in Fig-
ures S1–S15 of the Supporting Information. The transition
states and intermediates of the studied domino rearrangement
show several conformers with very similar energies (e.g., rota-
tion about sp3 carbon atoms and isomerization of double
bonds).
Computational studies on the reaction mechanism
To provide new insight into the reaction mechanism for the re-
arrangement of the propargyl vinyl ethers, we performed
a computational DFT study using a simplified model denoted R
in Scheme 6, where R1 =R2 =R4 =H and R3 =CH3. Some hydro-
Scheme 7. Reaction mechanism for the domino process leading to the for-
mation of methyl benzoate P2. Transition states including the Imz descriptor
refer to saddle points assisted by a molecule of imidazole (see text). Relative
Scheme 6. Reaction pathway for the domino process leading to the forma-
tion of salicylaldehyde derivative P1. Transition-state descriptors denoted
TS-Imz refer to saddle points assisted by a molecule of imidazole (see text).
free energies are given in kcalmolÀ1
.
Relative free energies are given in kcalmolÀ1
.
gen-transfer processes (enolization and [1,3]-H shifts) show un-
realistically[32] high free-energy barriers (ca. 55 kcalmolÀ1). In
these cases one imidazole molecule can act as a catalyst by
taking advantage of its amphoteric character. The names of
these stationary points end with “-Imz” to indicate the use of
a molecule of imidazole as a suitable additive. All stationary
points on the potential surface were fully optimized with the
hybrid density functional B3LYP[33] and the 6-311+G(d,p) basis
set.[34] Harmonic analyses were performed at this level of
theory to verify the nature of the corresponding stationary
points (minima or transition states), as well as to provide the
zero-point vibrational energy and the thermodynamic contri-
butions to the enthalpy and free energy for T=298 K. More-
over, intrinsic reaction coordinate[35] calculations were per-
formed to ensure that the transition states connect the reac-
tants and products belonging to the reaction coordinate under
study. The final energies were obtained by performing single-
point M06-2X[36] calculations with the 6-311+G(d,p) basis set
at the optimized B3LYP geometries. The average difference be-
tween the B3LYP and M06-2X increments of energy was
The domino reaction starts with a thermally allowed [3,3]sig-
matropic process of R to yield Int1 (Scheme 6). This propargyl
Claisen rearrangement shows an activation free energy barrier
(TS1) of 32.9 kcalmolÀ1, which is the highest activation energy
along the alternative reaction paths (see below). As expected,
TS1 involves the cleavage and formation of a CÀO and a CÀC
bond, respectively, as well as the conversion of a propargyl
and an enol group into an allene and a carbonyl group, re-
spectively (Figure 1 and Figure S1 of the Supporting Informa-
tion). Allenyl intermediate Int1 lies about 14 kcalmolÀ1 below
R. Several conformations of Int1 can be considered, and in this
work we calculated six of them (Int1a to Int1f) with very simi-
lar relative energies (differences smaller than 2 kcalmolÀ1, see
the Supporting Information).
The next step of the domino process consists of conversion
of allene Int1 to unsaturated ester Int3 (Scheme 6). This pro-
cess formally corresponds to a thermal antarafacial [1,3] sigma-
tropic shift involving hydrogen atom H1 and allyl scaffold C1–
C3. The direct process is not geometrically favored, since the
activation energy for this direct process is about 63 kcalmolÀ1
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Figure 2. Fully optimized structures of saddle points TS6,12, associated with
[1,7] sigmatropic shifts, and TS7,13, corresponding to [p6d] electrocycliza-
tions (see Scheme 6 and Scheme 7). Bond lengths are given in ångstrom.
Stars indicate the position of R2 groups in more substituted transition struc-
tures (see Scheme 4).
Figure 1. Fully optimized structures of saddle points TS1 associated with
[3,3] propargyl Claisen rearrangement, TS2-Imz and TS3-Imz corresponding
to [1,3] hydrogen shift, and TS8-Imz associated with the aromatization pro-
cess (see Scheme 6). Bond lengths are given in ångstrom.
ty of dielectric heating to complete these reactions. However,
the effect of R2 substituents in more complex substrates (see
Scheme 4) is not critical, since these groups will always occupy
the outward position in the corresponding [p6d] transition
structures (see the stars in Figure 2).[40]
(see the Supporting Information). However, our calculations in-
dicate that this 1,3-prototropy is feasible under imidazole assis-
tance. Thus, imidazole can remove proton H1 from Int1 via
TS2-Imz and transfer it to C3 via TS3-Imz (see Figure 1 and the
Supporting Information for additional details) with overall acti-
vation energy of about 20 kcalmolÀ1, since the intermediate
ion pair is almost isoenergetic with TS3-Imz. An alternative
route involving the corresponding enol-allene intermediates
Int2 via tautomeric equilibria involving one molecule of imida-
zole can be also considered (see TS4, TS5, and TS4-Imz in Fig-
ures S3 and S6 of the Supporting Information).
Finally, Int5 can be subjected to an aromatization process to
produce salicylaldehyde, P1 with concomitant release of
a methanol molecule (see Scheme 6, Figure 1 and Figures S4
and S7 of the Supporting Information). In this reaction step,
the assistance of one molecule of imidazole is required to ach-
ieve a feasible activation energy (DG° =24.1 kcalmolÀ1, TS8-
Imz). This final step is strongly exergonic and irreversible, as
would be expected from the high resonance energy of the
phenyl group generated in the course of the elimination/aro-
matization reaction.
Oxatriene Int3 can be transformed into triene Int4 via a ther-
mally allowed antarafacial [1,7] sigmatropic shift. It is notewor-
thy that the geometry of saddle point TS6 associated with this
process permits an alternative pseudopericyclic process[38] in-
volving one of the lone pairs of the sp2-hybridized oxygen
atom of Int3 (Figure 2) to be excluded. The activation energy
of this sigmatropic shift is lower than the activation energy as-
sociated with the first suprafacial [3,3] pericyclic reaction via
TS1 (see above).
From Int4 the reaction proceeds through a thermal disrota-
tory electrocyclization to yield 1,3-cyclohexadiene intermediate
Int5 (Scheme 6). The features of saddle point TS7 associated
with this pericyclic step are those expected for a [p6d] process,
in which the hydroxyl group OH2 formed in the previous step
is necessarily inward (pseudoaxial) with respect to the CÀC
bond being formed (Figure 2). It results in destabilizing four-
electron torquoelectronic interactions and steric congestion for
this transition structure.[39] As a consequence, this step shows
a relatively high activation energy, the second highest found in
our calculations along the whole reaction coordinate. It is likely
that this step and the first one associated with the [3,3] sigma-
tropic shift via TS1 (see above) are responsible for the necessi-
An intriguing aspect of these reactions is the formation of
methyl benzoates 15 in several polycyclic systems (see above,
Scheme 3). Our computational model indicates that methyl
benzoate (P2 in Scheme 7) can be formed via oxatriene Int7,
which differs with respect to Int3 in the E configuration of the
C1ÀC2 double bond. Despite this difference, Int7 is almost iso-
energetic with Int3, but its imidazole-assisted formation via
TS9-Imz or (Z)-Int6 (which in turn involves saddle points TS10-
Imz and TS11, see Figures S9 and S12 of the Supporting Infor-
mation) is less favored than in the previous case, which is in
line with the minor formation of benzoates 15 in most cases
(Scheme 3). Beyond Int7, the previously described antarafacial
[1,7] sigmatropic shift leads to triene Int8, disrotatory electro-
cyclization of which leads in turn to cyclohexadienyl alcohol
Int9. The relatively high energy of this pericyclic reaction is as
expected for a transition structure involving an inward OH2
group (see the optimized structure of TS13 in Figure 2). How-
ever, once again, R2 groups in more substituted systems
should occupy outward positions, which in general should not
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synthesis of 1-hydroxy-3-phenyl-5,6,7,8-tetrahydronaphthalene-
2-carbaldehyde (14e): Propargyl vinyl ether 1e (1.0 mmol) and
imidazole (0.10 mmol) in dry xylene (1 mL) were placed in a MW
closed vial and the solution was irradiated for 1 h in a single-mode
MW oven (300 W, 1908C). After removing the solvent at reduced
pressure the products were purified by flash column chromatogra-
phy (silica gel, n-hexane/EtOAc 95/5) to yield 14e as an amorphous
solid (229.6 mg, 91%). 1H NMR (400 MHz, CDCl3, 258C): d=1.71–
1.75 (m, 4H), 2.62–2.65 (m, 2H), 2.68–2.71 (m, 2H), 6.52 (s, 1H),
7.24–7.26 (m, 2H), 7.30–7.35 (m, 3H), 9.67 (s, 1H), 12.27 ppm (s,
1H); 13C NMR (100 MHz, CDCl3, 258C): d=22.13, 22.25, 22.39, 30.5,
115.3, 122.1, 125.3, 127.9, 128.2 (2C), 130.0 (2C), 137.8, 143.6, 147.3,
jeopardize this reaction path. Finally, the imidazole-assisted
elimination/aromatization step from Int9 leads to methyl ben-
zoate P2 with an energy barrier significantly higher than those
found for P1 (see Schemes 6 and 7). This result is in nice agree-
ment with the experimentally found formation of benzoates
15 as minor products, especially in the case of polycyclic sys-
tems.
Conclusion
We have developed a catalytic version of the MW-assisted for-
mation of polysubstituted salicylaldehydes from propargyl
vinyl ethers. The reaction manifold uses imidazole as the cata-
lyst (10 mol%) to deliver an array of topologically diverse sali-
cylaldehyde scaffolds spanning from simple aromatic monocy-
cles to complex fused polycyclic systems. The reaction is scala-
ble and instrumentally simple to perform, highly regioselective,
and symmetry-disrupting: symmetrically substituted PVEs af-
forded asymmetrically (nonredundant) substituted salicylalde-
hydes. The preparative value of this transformation has been
demonstrated in the five-step synthesis of the benzophenone-
derived natural product morintrifolin B. A DFT study on a simpli-
fied model was performed. Calculations underpin a domino
mechanism comprising a [3,3] propargyl Claisen rearrange-
ment/[1,3]-hydrogen shift/[1,7]-hydrogen shift/6p electrocycli-
zation/aromatization process. The use of imidazole lowers the
energy of the two more difficult steps, that is, the 1,3-proto-
tropic rearrangement and the final aromatization step, other-
wise energetically very disfavored.
~
161.2, 196.6 ppm; IR (CHCl3): n=2939.6, 1635.7, 1617.2, 1559.6,
1405.3, 1366.7, 1299.4 cmÀ1; LRMS (70 eV) m/z (%): 252 (100) [M+],
251 (42), 234 (30), 233 (18), 223 (12), 165 (17); HRMS (EI-TOF): m/z
calcd for C17H16O2: 252.1150 [M]+; found: 252.1144.
Representative telescoped procedure for the synthesis of salicy-
laldehydes 14v, 14w, 14x, 14y, and 14z from the corresponding
tertiary propargylic alcohols: synthesis of 1-hydroxy-3-phenyl-
9,10-dihydrophenanthrene-2-carbaldehyde (14v): The corre-
sponding propargyl alcohol (1.0 mmol) and DABCO (0.10 mmol)
were dissolved in hexane (1 mL); a small amount of CH2Cl2 was
used if the alcohol did not dissolved well in hexane. Methyl propio-
late was slowly added dropwise (1.5 mmol) and the reaction mix-
ture was stirred for 5 min. The reaction mixture was filtered
through a short column filled with silica gel with n-hexane/EtOAc
(60/40). The solvent was evaporated off and the mixture was dis-
solved in xylenes (1 mL) and transferred to a MW closed vial. Imida-
zole (0.10 mmol) was added and the reaction mixture was irradiat-
ed for 1 h in a single-mode MW oven (300 W, 1908C). After remov-
ing the solvent at reduced pressure the products were purified by
flash column chromatography (silica gel, n-hexane/EtOAc 95/5) to
give 14v as an amorphous solid (153.2 mg; 51%). 1H NMR
(400 MHz, CDCl3, 258C): d=2.89–2.93 (m, 2H), 2.97–3.01 (m, 2H),
7.28–7.34 (m, 4H), 7.42–7.51 (m, 5H), 7.76–7.79 (m, 1H), 9.83 (s,
1H), 12.36 (s, 1H) ppm; 13C NMR (100 MHz, CDCl3, 258C): d 19.8,
28.1, 116.7, 117.0, 124.4, 124.9, 127.0, 128.1, 128.39 (2C), 128.41,
129.2, 130.1 (2C), 133.1, 138.0, 138.6, 142.1, 145.4, 160.1,
Experimental Section
General remarks
1H NMR and 13C NMR spectra of CDCl3 solutions were recorded at
400 and 100 MHz or at 500 and 125 MHz (Bruker AC 200 and
AMX2–500), respectively. MW reactions were conducted in sealed
glass vessels (capacity 10 mL) with a CEM Discover MW reactor.
FTIR spectra were measured on chloroform solutions with a Perki-
nElmer Spectrum BX FTIR spectrophotometer. Mass spectra (low-
resolution EI/CI) were obtained with a Hewlett-Packard 5995 gas
chromatograph/mass spectrometer. High-resolution mass spectra
were recorded with a Micromass Autospec mass spectrometer. Mi-
croanalyses were performed with a Fisons Instruments EA 1108
carbon, hydrogen, and nitrogen analyzer. Analytical TLC was per-
formed with E. Merck Brinkman UV-active silica gel (Kieselgel 60
F254) on aluminum plates. Flash column chromatography was car-
ried out with E. Merck silica gel 60 (particle size less than
0.020 mm) and appropriate mixtures of ethyl acetate and hexanes,
or ethyl acetate and dichloromethane as eluents. All reactions
were performed in oven-dried glassware. All starting materials
were obtained from commercial suppliers and used as received.
PVEs 1v, 1w, 1x, 1y, and 1z partially rearranged during the isola-
tion and characterization process, so an alternative procedure was
used to prepare 14v, 14w, 14x, 14y, and 14z (see below).
~
196.6 ppm; IR (CHCl3): n=2945.1, 2896.7, 2844.7, 1633.7, 1617.8,
1545.8, 1479.8, 1400.2, 1363.5, 1331.6, 1307.2, 1288.7, 1239.0 cmÀ1
;
LRMS (70 eV): m/z (%): 300 (100) [M+], 299 (41), 282 (27), 281 (32),
253 (16), 252 (21), 239 (12), 165 (15). HRMS (EI-TOF): m/z calcd for
C21H16O2: 300.1150 [M]+; found: 300.1142. Further elution delivered
pure methyl 3-phenyl-9,10-dihydrophenanthrene-2-carboxylate
(15v) as an amorphous solid (31.4 mg; 10%). 1H NMR (400 MHz,
CDCl3, 258C): d=2.93 (brs, 4H), 3.64 (s, 3H), 7.24–7.32 (m, 3H),
7.35–7.44 (m, 5H), 7.33 (d, 3J(H,H)=7.1 Hz, 2H), 7.77 ppm (t,
3J(H,H)=7.1 Hz, 1H); 13C NMR (100 MHz, CDCl3, 258C): d=28.5,
28.8, 51.8, 124.2, 126.1, 127.10, 127.12, 127.8 (2C), 128.3, 128.41
(3C), 129.1, 129.7, 133.4, 136.2, 137.4, 137.9, 141.6, 141.7,
~
168.8 ppm; IR (CHCl3): n=3028.8, 2951.1, 2841.6, 1716.4, 1603.0,
1436.2, 1305.8, 1252.4 cmÀ1; LRMS (70 eV): m/z (%): 314 (57) [M+],
283 (24), 252 (10), 239 (10), 170 (13), 169 (100), 141 (16), 115 (17),
91(20). HRMS (EI-TOF): m/z calcd for C22H18O2: 314.1307 [M]+;
found: 314.1305.
Acknowledgements
This research was supported by the Spanish Ministerio de
Economía y Competitividad (MINECO) and the European Re-
gional Development Fund (CTQ2011-28417-C02-02 and
CTQ2013-45415-P), the UPV/EHU (UFI11/22 QOSYC), and the
Synthesis
Representative procedure for the MW-assisted synthesis of sali-
cylaldehydes from the corresponding propargyl vinyl ethers:
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grant. M.T.-S., M.O.-G., and F.P.C. thank the SGI/IZO- SGIker
UPV/EHU and the DIPC for generous allocation of computa-
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Keywords: domino reactions
·
microwave chemistry
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[40] Another conceivable reaction mechanism involves the formation of
a furan intermediate (see Scheme S1 and Figure S14 in the Supporting
Information). This mechanism was discarded on the basis of its global
free-energy barrier of 57.5 kcalmolÀ1 with respect to R.
Received: August 11, 2015
Published online on October 30, 2015
Chem. Eur. J. 2015, 21, 18280 – 18289
www.chemeurj.org
18289
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