One-pot organocatalytic tandem aldol/polycyclization reactions between 1,3-dicarbonyl compounds and α,β,γ,δ-unsaturated aldehydes for the straightforward assembly of cyclopenta[b]furan-type derivatives: New insight into the Knoevenagel reaction

Article abstract of DOI:10.1002/chem.201103080

A new cascade pathway viable for Knoevenagel chemistry that involves the coupling between 1,3-dicarbonyl systems and α,β,γ,δ- unsaturated aldehydes has been developed. The process comprises the combination of a classic aldol-type condensation and a rare spontaneous metal-free cycloisomerization, representing a convergent and innovative approach for the stereoselective synthesis of cyclopenta[b]furan-type derivatives. The scope and limitations with respect to both reaction partners and mechanistic features were investigated. Meaningfully, our study provides valuable guidance concerning the structural and electronic effects controlling the reactivity of conjugated polyene carbonyl systems. Copyright

Full text of DOI:10.1002/chem.201103080

DOI: 10.1002/chem.201103080
One-Pot Organocatalytic Tandem Aldol/Polycyclization Reactions between
1,3-Dicarbonyl Compounds and a,b,g,d-Unsaturated Aldehydes for the
Straightforward Assembly of Cyclopenta[b]furan-Type Derivatives: New
Insight into the Knoevenagel Reaction
Martꢀn J. Riveira and Mirta P. Mischne*[a]
Abstract:
A
new cascade pathway
and innovative approach for the stereo-
selective synthesis of cyclopenta[b]fur-
an-type derivatives. The scope and lim-
itations with respect to both reaction
partners and mechanistic features were
investigated. Meaningfully, our study
provides valuable guidance concerning
the structural and electronic effects
controlling the reactivity of conjugated
polyene carbonyl systems.
viable for Knoevenagel chemistry that
involves the coupling between 1,3-di-
carbonyl systems and a,b,g,d-unsaturat-
ed aldehydes has been developed. The
process comprises the combination of a
classic aldol-type condensation and a
rare spontaneous metal-free cycloiso-
merization, representing a convergent
Keywords: aldol reaction · cycloiso-
merization · cyclopenta[b]furans ·
domino reactions · electrocyclic re-
actions
Introduction
noid-like structures,[2] eventually giving rise to specific do-
mains, such as bioorganic chemistry[3] and biomimetic syn-
thesis.[4] As a particular class, conjugated polyenes continue
to generate great interest not merely because of their impor-
tant biological functions in nature, but also because they
have been recognized as relevant substrates for a wide vari-
ety of chemical applications. From a synthetic point of view
they are important intermediates, well suited for intramolec-
ular cascade transformations involving pericyclic reactions,
providing efficient and complementary strategies toward
polycycle construction.[5]
In this regard, electrocyclic reactions have witnessed ex-
traordinary progress in recent years, demonstrating their
ability to participate in sequential processes.[6] Since the
spectacular synthesis of endiandric acids establishing the via-
bility and biomimetic characteristics of the 8p–6p electro-
The construction of carbo- and heteropolycyclic molecular
scaffolds has been the focus of extensive research in organic
chemistry. Owing to their diverse structural features and in-
teresting properties, promising as scaffolds for drug discov-
ery, and to their potential applications as precursors for the
chemical synthesis of natural and natural-like products, the
development of innovative and efficient methods for the as-
sembly of multiring frameworks remains an important goal
and represents a constant synthetic challenge. In this area,
cascade polycyclizations of polyunsaturated precursors have
proven to be an extremely useful approach for the rapid and
convergent construction of complex systems.[1] Since these
processes involve multiple transformations taking place in a
minimum number of steps, generally in one-pot, they are in-
trinsically atom economic with substantial minimization of
waste and time.
cyclization cascade to give bicycloACHTUNTRGNEUNG[4.2.0]octadiene struc-
tures,[7] the recent discovery of a series of natural products
containing this bicyclic-octane moiety has fuelled studies on
the pericyclic reactivity of tri- and tetraene-type polyenes
ending up in elegant syntheses of several members of this
unsaturated polyketide family,[8] providing a deeper under-
standing of their complex reactivity modes and facilitating,
at the same time, the development of novel methodology.[9]
Another valuable biomimetic sequence involves the combi-
nation of Knoevenagel-type condensation and hetero-6p-
electrocyclization between enals and 1,3-dicarbonyl sub-
strates. This process, referred to as formal [3+3] cycloaddi-
tion, has become a very useful strategy for the synthesis of
natural 2H-pyran-containing compounds and derivatives in-
cluding aza-heterocycles.[10]
The conceptual key point in this field is the stereoselec-
tive cation–p cyclization of polyolefins containing a repeti-
tive 1,5-diene sequence that has been especially advanta-
geous for the preparation of multicyclic steroid- and terpe-
[a] M. J. Riveira, Dr. M. P. Mischne
Instituto de Quꢀmica Rosario-CONICET
Facultad de Ciencias Bioquꢀmicas y Farmacꢁuticas
Universidad Nacional de Rosario
Suipacha 531, 2000 Rosario (Argentina)
Fax : (+54)341-4370477
E-mail: mischne@iquir-conicet.gov.ar
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201103080. It contains detailed
preparative procedures and spectroscopic data for all new com-
pounds.
A common feature of the mentioned processes is that
they proceed easily under mild conditions, frequently with-
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FULL PAPER
out the isolation of polyene intermediates and in which the
formation of a six-membered ring is generally involved. Due
to the high architectural control and selectivity displayed,
some of these processes are being considered, by analogy to
biology, as covalent “self-assembly”[11] events in which poly-
cyclic molecules exhibit an intrinsic capacity to self-con-
struct correlated to an inherent “chemical predisposition”[12]
established in the precursors. On the contrary, similar peri-
cyclic cascade reactions for cyclopentanoid-ring-system con-
struction from conjugated polyolefinic skeletons are less
common. In this field, the electrocyclization reaction of pen-
tadienyl to cyclopentenyl cations involving 4p-electrons is a
central approach, broadly studied in the case of “oxygen sta-
bilized” cross-conjugated cationic species, the Nazarov reac-
tion, for the synthesis of cyclopentenone derivatives.[13] This
rearrangement requires the use of either strong Brønsted or
Lewis acids, generally in suprastoichiometric amounts. In-
vestigations on rapid and facile cyclizations are of current
interest and cascade processes involving the trapping of 2-
oxidocyclopentenyl cationic intermediates by nucleophilic
species have recently been developed and termed “inter-
rupted Nazarov reactions”.[14] The related chemistry con-
cerning unstabilized divinyl cationic systems is far less devel-
oped and mainly applied to the synthesis of indenes by elec-
trocyclization/elimination of arylallyl cations, generally re-
quiring harsh reaction conditions.[15] Progress in this regard
has been achieved by using alternative arylallenyl precursors
allowing the synthesis of benzofulvenes under catalytic con-
ditions.[16] A related catalytic process comprises the acid-
promoted cycloisomerization of trienoate moieties to
Scheme 1. Aldol/cationic polycyclization cascade for the synthesis of cy-
clopenta[b]furan derivatives.
at understanding the factors governing the particular chemi-
cal reactivity displayed and at validating the intermediacy of
previously proposed cationic intermediates.
Results and Discussion
We initiated our studies by evaluating the aldehyde part-
nerꢃs reactivity profile. A variety of a,b,g,d-unsaturated alde-
hydes (2a–l), either commercially available or readily syn-
thesized by classical methods, were tested by using dime-
done as a model 1,3-dicarbonyl component. Dichlorome-
thane at reflux and ethylenediammonium diacetate
(EDDA) as the organocatalyst[20] were chosen as the opti-
mized reaction conditions and the results are summarized in
Table 1.
bicycloACHTUNGTRENNUNG
[3.1.0]hex-2-enes,[17] for which one possible mechanis-
tic explanation involves a 4p-electrocyclic rearrangement
followed by the intramolecular capture of the formed cyclo-
pentenyl cation by an olefinic function,[8d,18] and would for-
mally represent an example of an “interrupted” type process
on unstabilized cationic species. Since these cationic pentan-
nulations constitute a useful route to cyclopentene deriva-
tives, improvements in this area, paralleling the Nazarov re-
action, would have a significant impact on the design and
development of new approaches to the synthesis of polycyc-
lic frameworks containing five-membered rings.
In a preliminary report, we communicated that the Knoe-
venagel-type condensation between dimedone (1a) or 4-hy-
droxycoumarin (1b) and unsaturated aldehyde (E,E)-2-
methyl-5-phenyl-2,4-pentadienal (2a) resulted in the forma-
tion of unexpected cyclopenta[b]furan-type derivatives 3a
and 3b, respectively, which required consistent structural
elucidation and reliable assignment of their relative stereo-
chemistry.[19] Due to the stereoselective nature of this se-
quence, we have postulated a pentadienyl–cyclopentenyl
cationic rearrangement as a key step, uncovering a new type
of organocatalytic cascade (Scheme 1). Thus, with the lack
of additional information and due to the practical and con-
ceptually important features that emerge from this unex-
plored domino sequence leading to the covalent “self-assem-
bly” of polycycles 3, an extensive investigation toward un-
raveling the substrate requirements was undertaken, aiming
With these data in hand, it became clear that substitution
on the aldehyde carbon chain plays a critical role in the con-
densation pathway. Whereas the reaction of dimedone with
unbranched dienals, such as (E,E)-2,4-hexadienal (2k) and
(E,E)-5-phenyl-2,4-pentadienal (2l),[21] afforded the triene-
dione products 4a and 4b, respectively, substituted ana-
logues reacted by following a specific divergent pathway
leading to the heterocyclic products 3a and 3c–k in moder-
ate to good yields. Under these conditions, all successful ex-
amples gave a single stereoisomer and a marked influence
of substitution pattern was observed; the new domino pro-
cess becomes more efficient for electrophilic partners bear-
ing a-alkyl groups and terminal phenyl substituents (e.g., 3a
or 3c vs. 3k). It has been proposed that the lack of planarity
promoted by strain is the origin of the high reactivity of
polyene systems prone to undergo rapid and facile transfor-
mations.[22] In a similar manner, our results also suggest that
steric effects of substituents would destabilize the triene-
dione open form expected from Knoevenagel condensation
for which no stable planar conformations would be avail-
able, facilitating in this case the novel tandem process in-
volving a striking “interrupted” pentadienyl–cyclopentenyl
cation rearrangement.
Selected substituents that affect the electronic nature of
the aromatic nucleus were also examined. For d-phenyl sub-
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M. P. Mischne and M. J. Riveira
Table 1. Impact of aldehyde component substitution on reactivity.[a]
Aldehyde
t
Product
Yield Aldehyde
[%][b]
t
Product
Yield
[%][b]
[h]
[h]
2a
2b
5
5
3a 82
2g
2h
3
4
3h 65
3c 70
3d 75
3e 63
3i 65
3j 30[c]
3k 40
2c
2d
5
4
2i
2j
4
5
2e
2 f
5
4
3 f 40
2k
2l
4
4
4a 50
3g 60
4b 90
[a] All reactions were run under the following conditions: aldehyde (1 equiv), EDDA (0.2 equiv), dichloromethane (0.2m), reflux. [b] Isolated yield.
[c] 60% of the starting materials were recovered.
stituted dienals, although both electron-withdrawing and
-donating groups were tolerated on the ring, as the electron-
withdrawing strength of the substituent increases the yield
decreases, an effect that is consistent with the cationic
nature of the proposed intermediate (e.g., 3d vs. 3e vs. 3 f).
On the other hand, aldehyde substrates with even more ex-
tended conjugation did not stabilize the conjugated polyene
carbonyl system open form, as expected from enhancement
of mesomeric effects, nor did they give alternative reaction
routes, affording in all cases the same heterocyclic frame-
work with an extra double bond (e.g., 3a vs. 3g or 3h vs.
3k).
To define the scope of the reaction as regards the nucleo-
philic component and to gain a reasonable overview of the
extent of the process, diverse functionalized variants of 1,3-
dicarbonyl structures were screened. As shown in Table 2,
among the numerous reaction pathways available, again
only characteristic Knoevenagel-type condensation and elec-
trocyclization reactions, enriched by the newly discovered
cycloisomerization process, were observed. Nonetheless, the
1,3-dicarbonyl partner showed a stronger impact on reactivi-
ty.
Nucleophilic components different from dimedone but
keeping the cyclohexane-1,3-dione skeleton displayed low
reactivity toward a-substituted aldehydes. The heterocyclic
compounds of interest (3) were indeed the only products
isolated albeit in poor yields due to modest conversion (e.g.,
3l–p). Unfortunately, this problem could not be circumvent-
ed by either using an excess of reagents or catalyst, nor by
prolonging the reaction time. However, for cyclic b-keto
esters 4-hydroxycoumarin (1b) and 4-hydroxy-6-methyl-2-
pyrone (1 f), we found good reactivity and moderate yields
of the cyclized products were obtained. Nevertheless, al-
though yields were low, the process still remains useful for
practical purposes due to the degree of molecular complexi-
ty that is furnished in a single step with remarkable stereo-
selectivity from readily available precursors. To our surprise,
whereas reactions using 4-hydroxycoumarin afforded the de-
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Organocatalytic Tandem Aldol/Polycyclization Reactions
Table 2. Impact of 1,3-dicarbonyl component on reactivity.[a]
FULL PAPER
Dicarbonyl
substrate
Aldehyde
t
Product
Yield Dicarbonyl
[%][b] substrate
Aldehyde
t
Product
Yield
[%][b]
[h]
[h]
1c 2a
6
3l
30[c]
1c 2k
4
4
4c 65
3m
1g 2k
4d 60
1d 2a
9
34[c,d]
3n
1g 2m[f]
4
4
4e 70
1e 2a
1c 2c
1b 2a
7
5
6
3o 25[c,e]
3p 30[c]
3b 48
1h 2a
1h 2c
1h 2b
1h 2g
5a 85
5b 65
5c 60
5d 60
3
5
3
1b 2c
4
9
3q 52
1 f 2a
3r
40
[a] All reactions were run under the following conditions: aldehyde (1 equiv), EDDA (0.2 equiv), dichloromethane (0.2m), reflux. [b] Isolated yields. [c] 60% of
the starting materials were recovered. [d] 3m and 3n were obtained as an 1:1 mixture of separable regioisomers when 4,4-dimethyl-1,3-cyclohexanedione (1d)
was used as the dicarbonyl component. [e] Mixture of diasteroisomers (see the Supporting Information for details). [f] See Scheme 3 for the chemical structure
of aldehyde 2m.
sired cyclopenta[b]dihydrofuran derivatives 3b and 3q, the
use of the nitrogen counterpart 4-hydroxy-1-methyl-2-
ACHTUNGTRENNUNG(1H)quinolone (1h) gave 2H-pyran derivatives 5a–d exclu-
sively, arising from a formal [3+3] cycloaddition. The chemi-
cal behavior of acyclic partners was also studied finding no
evidence for the newly described cationic chemistry. In spite
of all efforts made, we could not find conditions to promote
the condensation between acyclic dicarbonyl substrates, such
as acetylacetone (1g) or ethyl acetoacetate and a-substitut-
ed dienals recovering in all cases only starting materials.
Once again, for a-unsubstituted aldehydes, trienedione
products were obtained (e.g., 4c–e). As illustrated, the iso-
lated products depend on the nature of the system, which
demonstrates a diverse and mechanistically complex behav-
ior and exemplifies the manifold of the Knoevenagel
chemistry.
The selective formation of each individual class of prod-
ucts can be rationalized by considering a common synthetic
intermediate (Scheme 2). Aldol A, resulting from initial 1,2-
addition, may dehydrate to a,b,g,d,e,z-unsaturated com-
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M. P. Mischne and M. J. Riveira
Scheme 2. Mechanism and evolution of possible intermediates.
pounds 4, which if stable, can be isolated. When 4-hydroxy-
1-methyl-2ACHTUNGTRENNUNG(1H)quinolone is used as the dicarbonyl compo-
be considered to be a new type of polyene system capable
of a previously unknown mode of reactivity.
nent, these intermediates were not stable probably due to
steric destabilization and an oxa-6p-electrocyclization would
then follow to afford 2H-pyrans 5. On the other hand, if the
formation of aldol A results in the generation of a cationic
dienyl structure B through protonation and loss of water,
then isomerization and conformational changes to the “U-
form” would set the stage for a 4p-electrocyclization to
occur. The latter ring closure would proceed in a conrotato-
ry manner to form brand new cyclopentenyl cation C, which
would then be consistently trapped by the enolic oxygen to
provide cyclopenta[b]furan derivatives 3 after deprotona-
tion. Although both cascade processes (the aldol/oxa-6p-
electrocyclization and the aldol/pentadienyl–cyclopentenyl
rearrangement/intramolecular cation trapping) are based on
the destabilization of the initially generated p-bond system
we have not observed the formation of both product types
from any reaction.
As is evident from our results, a balance of steric and
electronic factors is needed for the tandem Knoevenagel/
cationic cyclization process to take place, avoiding the char-
acteristic well known chemistry of the dienone moiety. Due
to a steric destabilization of the trienedione open form con-
comitant with a stabilization of the developing positive
charge (presumably reached in the case of the b-keto ester
but not for b-keto amide nucleophiles), a match combina-
tion of dienal and dicarbonyl partners evolves into a direct
precursor of the proposed pentadienyl cation, which is gen-
erated in situ and unusually easily formed without the need
for harsh acidic conditions. These specific structures could
Further experimental evidence supported our current
mechanistic understanding of this scenario. Of particular in-
terest was the condensation between dimedone and (E,E)-4-
methyl-5-phenyl-2,4-pentadienal (2m, Scheme 3). The out-
Scheme 3. Synthesis of trienedione 4 f and further isomerization to cyclo-
penta[b]dihydrofuran 3s.
come of the reaction was the formation of trienedione 4 f in
good yield as a stable product characterized by NMR spec-
troscopy. Unexpectedly, upon standing in deuterated chloro-
form, the conjugated system is not stable enough and rear-
ranges to cyclopenta[b]furan heterocycle 3s (see the Sup-
1
porting Information for H NMR spectroscopic monitoring).
This phenomenon undoubtedly validates trienediones 4 as
possible intermediates toward heterocycles 3 and is probably
induced by acid traces contained in the deuterated solvent.
Unfortunately, this has not been observed for the other tri-
enone products obtained.
To obtain additional support for the cationic nature of the
proposed intermediate involved, the reactivity of (E,E)-2,5-
diphenyl-2,4-pentadienal (2n) was examined by using dime-
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Organocatalytic Tandem Aldol/Polycyclization Reactions
FULL PAPER
Experimental Section
Example procedure for the preparation of aldehydes 2a–d and 2n
through aldol condensation and aldehydes 2e–i through vinylogous aldol
condensation:
AHCTUNGTRENNUNG
a
(0.38 mL, 3.00 mmol) and trans-2-methyl-2-butenal (0.29 mL, 3.00 mmol)
in absolute ethanol (3.0 mL) at 08C. The resulting mixture was warmed
to room temperature and stirred for 72 h. HCl (0.6 n, 0.25 mL) was then
added. Ethanol was evaporated under reduced pressure and the resulting
crude mixture was extracted twice with ethyl acetate (10 mL). The com-
bined organic layers were washed with brine (20 mL), dried (Na2SO4),
and concentrated under reduced pressure. Flash column chromatography
on silica gel (hexanes/ethyl acetate) afforded aldehyde 2 f as an orange
solid (0.355 g, 60% yield). M.p.: 89.5–90.58C; 1H NMR (300 MHz,
CDCl3, 258C, TMS): d=9.46 (s, 1H), 7.47–7.43 (m, 2H), 7.37–7.25 (m,
3H), 6.99–6.70 (m, 5H), 1.89 ppm (d, J=1.0 Hz, 3H); 13C NMR
(75 MHz, CDCl3, 258C): d=194.4, 148.2, 141.3, 137.3, 136.3, 128.6,
128.55, 128.48, 128.0, 127.4, 126.8, 9.4 ppm; IR (KBr): n˜ =3080, 3025,
3014, 2921, 2840, 2728, 1679, 1602, 1229, 1186, 1003 cmÀ1; HRMS: m/z
calcd for C14H14O+H+: 199.1117 [M+H+]; found: 199.1115.
Scheme 4. Evidence for the cationic nature of the intermediate involved.
done as the dicarbonyl component (Scheme 4). We original-
ly hypothesized that the yield of the expected tricyclic prod-
uct would benefit from cationic intermediate stabilization
provided by a phenyl substituent at the a-position where the
charge would be partially located. To our surprise, heterocy-
cle 3t was indeed obtained in fair yield but contaminated
with cyclopentadiene 6. The formation of compound 6 can
be explained to arise from the same cationic intermediate
that gives products 3. Although 3t is produced, as stated
before, through intramolecular trapping of the cyclopentenyl
cation moiety (intermediate C, Scheme 2), 6 could result
from b-elimitation of the same intermediate and therefore
be considered as the “normal” not interrupted product of a
4p-cationic electrocyclization.
General procedure for the condensation of 1,3-dicarbonyl substrates and
unsaturated aldehydes: A mixture of 1,3-dicarbonyl substrate (1 mmol),
unsaturated aldehyde (1 mmol), and EDDA (36.0 mg, 0.2 mmol) in di-
chloromethane (5.0 mL) was heated at reflux for the time indicated in
Tables 1 or 2. The solvent was then evaporated under reduced pressure
and the residue was purified by flash column chromatography on silica
gel (hexanes/ethyl acetate) to afford the corresponding products.
Compound rac-3c: Colorless oil; 1H NMR (300 MHz, CDCl3, 258C,
TMS): d=7.38–7.27 (m, 4H), 7.22–7.16 (m, 1H), 6.07 (dd, J=5.6, 2.4 Hz,
1H), 5.96 (dd, J=5.7, 2.2 Hz, 1H), 4.02 (q, J=2.0 Hz, 1H), 3.20 (q, J=
1.6 Hz, 1H), 2.27 (brs, 2H), 2.24 (d, J=1.3 Hz, 2H), 1.89 (dq, J=14.9,
7.5 Hz, 1H), 1.76 (dq, J=14.5, 7.3 Hz, 1H), 1.11 (s, 3H), 1.08 (s, 3H),
0.87 ppm (t, J=7.4 Hz, 3H); 13C NMR (75 MHz, CDCl3, 258C): d=
194.3, 173.8, 143.5, 137.7, 132.4, 128.2, 127.2, 126.2, 115.6, 107.9, 56.8,
54.1, 50.9, 37.8, 33.8, 30.8, 28.7, 28.1, 7.9 ppm; IR (film): n˜ =3059, 3028,
Conclusion
2963, 2927, 1630, 1401 cmÀ1 HRMS: m/z calcd for C21H24O2 +H+:
;
A new reaction pathway has been investigated in which, as
a result of a Knoevenagel reaction type between 1,3-dicar-
bonyl substrates and a,b,g,d-unsaturated aldehydes, cyclo-
penta[b]furan derivatives are obtained. The development of
this chemistry is based on the specific ability of appropriate
substrates that react under classic condensation conditions
leading to the formation of conjugated polyene carbonyl sys-
tems as reactive intermediates for which electronic and
structural features permit an unusual reaction pathway. Our
study also provides new fundamental insights into factors
that control the reactivity of polyenic systems, identifying
key elements concerning product distribution and structure–
selectivity trends, offering opportunities for the development
of new strategies based on easily formed cationic intermedi-
ates.
The developed protocol represents a useful approach to
cyclopenta[b]dihydrofuran heterocycles[23] that combines
atom, step, and pot economy,[24] validating a new type of
spontaneous cascade reaction that expands the scope and
versatility of one of the most traditional reactions, the aldol
condensation. Further investigations will focus on related
transformations and the development of an enantioselective
version of this tandem process.
309.1849 [M+H+]; found: 309.1848.
Compound 4b: Orange/red crystals; m.p.: 118.0–119.08C; 1H NMR
(300 MHz, CDCl3, 258C, TMS): d=7.89 (dd, J=13.5, 12.4 Hz, 1H), 7.70
(d, J=12.4 Hz, 1H), 7.50–7.45 (m, 2H), 7.39–7.28 (m, 3H), 7.20–7.01 (m,
2H), 6.92 (d, J=14.8 Hz, 1H), 2.52 (brs, 2H), 2.51 (brs, 2H), 1.07 ppm
(s, 6H); 13C NMR (75 MHz, CDCl3, 258C): d=198.6, 197.6, 153.4, 150.4,
141.7, 135.8, 129.7, 129.3, 128.7, 128.2, 128.0, 127.3, 53.7, 52.1, 29.8,
28.3 ppm; IR (KBr): n˜ =3055, 3026, 2947, 2922, 1645, 1533, 1379, 1234,
1175, 1005 cmÀ1; HRMS: m/z calcd for C19H20O2 +H+: 281.1536 [M+H+
]; found: 281.1530.
Compound rac-5a: Colorless crystals; m.p.: 149.0–150.08C; 1H NMR
(300 MHz, CDCl3, 258C, TMS): d=7.92 (brd, J=7.3 Hz, 1H), 7.46 (t,
J=7.4 Hz, 1H), 7.35–7.30 (m, 2H), 7.27–7.13 (m, 5H), 6.69 (brs, 1H),
6.66 (d, J=16.0 Hz, 1H), 6.29 (dd, J=15.8, 7.4 Hz, 1H), 5.40 (d, J=
7.5 Hz, 1H), 3.65 (s, 3H), 1.89 ppm (s, 3H); 13C NMR (75 MHz, CDCl3,
258C): d=160.5, 152.8, 138.6, 135.5, 133.1, 130.2, 128.3, 128.2, 128.0,
126.6, 124.2, 122.6, 121.5, 115.5, 114.9, 113.7, 106.8, 80.1, 29.0, 19.3 ppm;
IR (KBr): n˜ =3060, 3022, 2976, 2910, 1667, 1626, 1590, 1498, 1411, 1183,
1120 cmÀ1; HRMS: m/z calcd for C22H19NO2 +Na+: 352.1308 [M+Na+];
found: 352.1302.
Acknowledgements
We thank the Universidad Nacional de Rosario and Fundaciꢄn Josefina
Prats for financial support. M.J.R. thanks CONICET for fellowships. We
also wish to thank Dr. G.R. Labadie and Dr. C.M.J. Delpiccolo for
HRMS measurements.
Chem. Eur. J. 2012, 18, 2382 – 2388
ꢂ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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2387

M. P. Mischne and M. J. Riveira
[12] a) P. Sharma, N. Griffiths, J. E. Moses, Org. Lett. 2008, 10, 4025–
4027; b) L. L. Etchells, M. Helliwell, N. M. Kershaw, A. Sardarian,
R. C. Whitehead, Tetrahedron 2006, 62, 10914–10927; c) J. D. Su-
therland, J. N. Whitfield, Tetrahedron 1997, 53, 11493–11527.
[13] a) N. Shimada, C. Stewart, M. A. Tius, Tetrahedron 2011, 67, 5851–
5870; b) W. He, I. R. Herrick, T. A. Atesin, P. A. Caruana, C. A.
Kellenberger, A. J. Frontier, J. Am. Chem. Soc. 2008, 130, 1003–
1011; c) A. J. Frontier, Tetrahedron 2005, 61, 7577–7606; d) H. Pel-
lissier, Tetrahedron 2005, 61, 6479–6517; e) M. A. Tius, Acc. Chem.
Res. 2003, 36, 284–290; f) K. L. Habermas, S. E. Denmark, T. K.
Jones in Organic Reactions, Vol. 45 (Ed.: L. A. Paquette), Wiley,
New York, 1994, pp. 1–158.
[14] For a review on “interrupted Nazarov reactions”, see: T. N. Grant,
C. J. Rieder, F. G. West, Chem. Commun. 2009, 5676–5688; for se-
lected recent developments, see: a) C. J. Rieder, K. J. Winberg, F. G.
West, J. Org. Chem. 2011, 76, 50–56; b) Y.-K. Wu, R. McDonald,
F. G. West, Org. Lett. 2011, 13, 3584–3587; c) J. L. Brooks, P. A. Car-
uana, A. J. Frontier, J. Am. Chem. Soc. 2011, 133, 12454–12457;
d) O. Scadeng, M. J. Ferguson, F. G. West, Org. Lett. 2011, 13, 114–
117; e) V. M. Marx, D. J. Burnell, J. Am. Chem. Soc. 2010, 132,
1685–1689.
[1] For selected reviews on metal-promoted cycloisomerizations, see:
a) C. Aubert, L. Fensterbank, P. Garcia, M. Malacria, A. Simonneau,
Chem. Rev. 2011, 111, 1954–1993; b) A. de Meijere, P. von Zezsch-
witz, S. Brꢅse, Acc. Chem. Res. 2005, 38, 413–422; c) S. T. Diver,
A. J. Giessert, Chem. Rev. 2004, 104, 1317–1382; d) E. Negishi, C.
Copꢁret, S. Ma, S.-Y. Liou, F. Liu, Chem. Rev. 1996, 96, 365–394;
e) M. Malacria, Chem. Rev. 1996, 96, 289–306; f) B. M. Trost, Acc.
Chem. Res. 1990, 23, 34–42.
[2] a) R. A. Yoder, J. N. Johnston, Chem. Rev. 2005, 105, 4730–4756;
b) A. Eschenmoser, D. Arigoni, Helv. Chim. Acta 2005, 88, 3011–
3050; c) K. U. Wendt, G. E. Schulz, E. J. Corey, D. R. Liu, Angew.
Chem. 2000, 112, 2930–2952; Angew. Chem. Int. Ed. 2000, 39, 2812–
2833.
[3] E. E. Van Tamelen, Acc. Chem. Res. 1975, 8, 152–158.
[4] W. S. Johnson, Acc. Chem. Res. 1968, 1, 1–8.
[5] a) S. Arns, S. Barriault, Chem. Commun. 2007, 2211–2221; b) A.
Padwa, S. K. Bur, Tetrahedron 2007, 63, 5341–5378; c) K. C. Nico-
laou, D. J. Edmonds, P. G. Bulger, Angew. Chem. 2006, 118, 7292–
7344; Angew. Chem. Int. Ed. 2006, 45, 7134–7186; d) L. F. Tietze,
Chem. Rev. 1996, 96, 115–136.
[6] a) S. Thompson, A. G. Coyne, P. C. Knipe, M. D. Smith, Chem. Soc.
Rev. 2011, 40, 4217–4231; b) C. M. Beaudry, J. P. Malerich, D. Trau-
ner, Chem. Rev. 2005, 105, 4757–4778.
[15] a) C. D. Smith, G. Rosocha, L. Mui, R. A. Batey, J. Org. Chem.
2010, 75, 4716–4727; b) T. S. Sorensen, J. Am. Chem. Soc. 1967, 89,
3794–3803.
[7] a) K. C. Nicolaou, N. A. Petasis, R. E. Zipkin, J. Uenishi, J. Am.
Chem. Soc. 1982, 104, 5555–5557; b) K. C. Nicolaou, N. A. Petasis, J.
Uenishi, R. E. Zipkin, J. Am. Chem. Soc. 1982, 104, 5557–5558;
c) K. C. Nicolaou, R. E. Zipkin, N. A. Petasis, J. Am. Chem. Soc.
1982, 104, 5558–5560; d) K. C. Nicolaou, N. A. Petasis, R. E. Zipkin,
J. Am. Chem. Soc. 1982, 104, 5560–5562.
[8] a) S. J. Eade, M. W. Walter, C. Byrne, B. Odell, R. Rodriguez, J. E.
Baldwin, R. M. Adlington, J. E. Moses, J. Org. Chem. 2008, 73,
4830–4839; b) V. Sofiyev, G. Navarro, D. Trauner, Org. Lett. 2008,
10, 149–152; c) M. F. Jacobsen, J. E. Moses, R. M. Adlington, J. E.
Baldwin, Tetrahedron 2006, 62, 1675–1689; d) A. K. Miller, D. Trau-
ner, Synlett 2006, 2295–2316; e) J. E. Moses, J. E. Baldwin, S. Brꢆck-
ner, S. J. Eade, R. M. Adlington, Org. Biomol. Chem. 2003, 1, 3670–
3684, and references therein.
[16] P. Cordier, C. Aubert, M. Malacria, E. Lacꢇte, V. Gandon, Angew.
Chem. 2009, 121, 8913–8916; Angew. Chem. Int. Ed. 2009, 48, 8757–
8760.
[17] a) D. R. Zuidema, A. K. Miller, D. Trauner, P. B. Jones, Org. Lett.
2005, 7, 4959–4962; b) A. K. Miller, D. H. Byun, C. M. Beaudry, D.
Trauner, Proc. Natl. Acad. Sci. USA 2004, 101, 12019–12023.
[18] C. S. Lꢄpez, O. N. Faza, R. ꢈlvarez, ꢈ. R. de Lera, J. Org. Chem.
2006, 71, 4497–4501.
[19] M. J. Riveira, C. Gayathri, A. Navarro-Vꢉzquez, N. V. Tsarevsky,
R. R. Gil, M. P. Mischne, Org. Biomol. Chem. 2011, 9, 3170–3175.
[20] For examples of the use of EDDA as an organocatalyst for Knoeve-
nagel-type condensations, see: a) C.-N. Huang, P.-Y. Kuo, C.-H. Lin,
D.-Y. Yang, Tetrahedron 2007, 63, 10025–10033; b) Y. R. Lee, J. H.
Choi, S. H. Yoon, Tetrahedron Lett. 2005, 46, 7539–7543; c) J. P.
Malerich, T. J. Maimone, G. I. Elliott, D. Trauner, J. Am. Chem. Soc.
2005, 127, 6276–6283; d) Y. R. Lee, J. H. Choi, D. T. L. Trinh, N. W.
Kim, Synthesis 2005, 3026–3034; e) M. Baidossi, A. V. Joshi, S. Mu-
khopadhyay, Y. Sasson, Tetrahedron Lett. 2005, 46, 1885–1887; f) Y.
Rok Lee, X. Wang, Org. Biomol. Chem. 2005, 3, 3955–3957;
g) M. H. Howard, T. Cenizal, S. Gutteridge, W. S. Hanna, Y. Tao, M.
Totrov, V. A. Wittenbach, Y. Zheng, J. Med. Chem. 2004, 47, 6669–
6672; h) Y. Hu, Z.-C. Chen, Z.-G. Le, Q.-G. Zheng, Synth. Commun.
2004, 34, 3801–3806; i) L. F. Tietze, N. Rackelmann, G. Sekar,
Angew. Chem. 2003, 115, 4386–4389; Angew. Chem. Int. Ed. 2003,
42, 4254–4257; j) L. F. Tietze, Y. Zhou, Angew. Chem. 1999, 111,
2076–2078; Angew. Chem. Int. Ed. 1999, 38, 2045–2047; k) L. F.
Tietze, G. v. Kiedrowski, B. Berger, Synthesis 1982, 683–684.
[21] P. Valenta, N. A. Drucker, J. W. Bode, P. J. Walsh, Org. Lett. 2009,
11, 2117–2119.
[22] a) R. Rodriguez, R. M. Adlington, S. J. Eade, M. W. Walter, J. E.
Baldwin, J. E. Moses, Tetrahedron 2007, 63, 4500–4509; b) J. E.
Moses, J. E. Baldwin, R. M. Adlington, A. R. Cowley, R. Marquez,
Tetrahedron Lett. 2003, 44, 6625–6627; c) C. P. Lillya, A. F. Kluge, J.
Org. Chem. 1971, 36, 1977–1988.
[23] B. A. Bhanu Prasad, A. E. Buechele, S. R. Gilbertson, Org. Lett.
2010, 12, 5422–5425, and references therein.
[24] P. A. Clarke, S. Santos, W. H. C. Martin, Green Chem. 2007, 9, 438–
440.
[9] a) A. L. Lawrence, H. A. Wegner, M. F. Jacobsen, R. M. Adlington,
J. E. Baldwin, Tetrahedron Lett. 2006, 47, 8717–8720; b) K. A.
Parker, Z. Wang, Org. Lett. 2006, 8, 3553–3556; c) A. K. Miller,
M. R. Banghart, C. M. Beaudry, J. M. Suh, D. Trauner, Tetrahedron
2003, 59, 8919–8930.
[10] a) A. R. Hardin Narayan, E. M. Simmons, R. Sarpong, Eur. J. Org.
Chem. 2010, 3553–3567; b) E. J. Jung, B. H. Park, Y. R. Lee, Green
Chem. 2010, 12, 2003–2011; c) H. J. Lee, S. H. Kim, Y. R. Lee, X.
Wang, W. S. Lyoo, Bull. Korean Chem. Soc. 2010, 31, 3027–3030;
d) J. Moreau, C. Hubert, J. Batany, L. Toupet, T. Roisnel, J.-P. Hur-
vois, J.-L. Renaud, J. Org. Chem. 2009, 74, 8963–8973; e) U. K.
Tambar, T. Kano, J. F. Zepernick, B. M. Stoltz, J. Org. Chem. 2006,
71, 8357–8364; f) Y. Tang, J. Oppenheimer, Z. Song, L. You, X.
Zhang, R. P. Hsung, Tetrahedron 2006, 62, 10785–10813; g) R. P.
Hsung, A. V. Kurdyumov, N. Sydorenko, Eur. J. Org. Chem. 2005,
23–44; h) U. K. Tambar, T. Kano, B. M. Stoltz, Org. Lett. 2005, 7,
2413–2416; i) H. Hu, T. J. Harrison, P. D. Wilson, J. Org. Chem.
2004, 69, 3782–3786; j) Y. Kang, Y. Mei, Y. Du, Z. Jin, Org. Lett.
2003, 5, 4481–4484; k) H. C. Shen, J. Wang, K. P. Cole, M. J.
McLaughlin, C. D. Morgan, C. J. Douglas, R. P. Hsung, H. A. Cover-
dale, A. I. Gerasyuto, J. M. Hahn, J. Liu, H. M. Sklenicka, L.-L. Wei,
L. E. Zehnder, C. A. Zificsak, J. Org. Chem. 2003, 68, 1729–1735.
[11] a) E. Gravel, E. Poupon, Eur. J. Org. Chem. 2008, 27–42; b) C. D.
Vanderwal, D. A. Vosburg, S. Weiler, E. J. Sorensen, J. Am. Chem.
Soc. 2003, 125, 5393–5407; c) E. J. Sorensen, Bioorg. Med. Chem.
2003, 11, 3225–3228; d) J. S. Lindsay, New. J. Chem. 1991, 15, 153–
180.
Received: October 1, 2011
Published online: January 16, 2012
2388
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ꢂ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2012, 18, 2382 – 2388